CN101312977B

CN101312977B - Fused heterocyclic compounds useful as kinase modulators

Info

Publication number: CN101312977B
Application number: CN2006800436245A
Authority: CN
Inventors: 韦恩·瓦卡罗; 陈中; 达姆帕尔·S·多德; 特兰姆·N·赫因; 詹姆斯·林; 刘春健; 克里斯托弗·P·马萨里; 约翰·S·托卡斯基; 戴维·R·托托拉尼; 斯蒂芬·T·弗罗布莱斯基
Original assignee: Bristol Myers Squibb Co
Current assignee: Bristol Myers Squibb Co
Priority date: 2005-09-22
Filing date: 2006-09-22
Publication date: 2012-06-13
Anticipated expiration: 2026-09-22
Also published as: CN101312977A; ZA200802549B

Abstract

Compounds having the formula (I), and enantiomers, and diastereomers, pharmaceutically-acceptable salts, and hydrates, thereof, (I) are useful as kinase modulators, including MK2 modulation, wherein one of E and F is a nitrogen atom and the other of E and F is a carbon atom, and Z is N or CR3, and R1, R2, R3, X and Y are as defined herein.

Description

Condensed heterocyclic compouds as kinase modulator

Related application

The application requires the right of priority of the U.S. Provisional Application 60/719,519 of submission on September 22nd, 2005 according to Title 35 § 119 (e), at this its content is incorporated herein by reference.

Technical field

The present invention relates to the useful as kinase regulator condensed heterocyclic compouds of (comprising adjusting) to MAPKAP kinases-2 (MK2).The invention still further relates to and be used to treat the pharmaceutical composition that comprises at least a The compounds of this invention and the active method of inhibition Mammals kinases (comprising MK2) that kinases is regulated associated conditions.

Background technology

A variety of cytokines are participated in inflammatory response, and these cytokines comprise IL-1, IL-6, IL-8 and TNF-α.A variety of diseases relate to the for example excessive generation of IL-1 and TNF-α of cytokine, and these diseases comprise inflammatory bowel, rheumatoid arthritis, psoriasis, multiple sclerosis, endotoxin shock, osteoporosis, alzheimer's disease (Alzheimer ' s disease) and congestive heart failure.Referring to for example Henry et al., Drugs Fut., Vol.24 (1999), at pp.1345-1354 and Salituro et al., Curr.Med.Chem., Vol.6 (1999), at pp.807-823.The evidence of human patients shows that the protein antagonist of cytokine can be treated chronic inflammatory disease effectively, and these protein antagonists for example are that the monoclonal antibody (Enbrel) of TNF-α is (referring to Rankin et al.; Br.J.Rheumatol.; Vol.34 (1995), at pp.334-342) and soluble TNF-α acceptor-Fc fusion rotein (Etanercept) (referring to Moreland et al., Ann.Intern.Med.; Vol.130 (1999), at pp.478-486).

In response to external stimulus for example mitogen (mitogen), infectious organism or wound, the biosynthesizing of TNF-α appears in the various kinds of cell type.The important medium that produces TNF-α is mitogen activated protein (MAP) kinases, comprises p38 kinases (p38).The activation of p38 need come Threonine and tyrosine in the Thr-Gly-Tyr motif characteristic of p38 isozyme are carried out dual phosphorylation through upper reaches map kinase (MKK3 and MKK6).The p38 kinases is the upper reaches kinases of mitogen activated protein kinase activated protein kinase-2 (MAPKAP K2 or MK2).Referring to Freshney et al., Cell, Vol.78 (1994), at pp.1039-1049.

The protein of MK2 in cell, as if mainly regulating through p38.In fact, MK2 is first substrate of p38 α to be determined, and external, for the MK2 activation, need come MK2 is carried out phosphorylation through p38 α.Next MK2 makes substrate phosphorylation; These substrates include but not limited to Heat shock protein 27 (HSP27), lymphocyte specific albumen 1 (lymphocyte-specific protein 1; LAP-1), leukocyte specific albumen-1 (leukocyte-specific protein-1; LSP-1), 5-lipoxidase (5-LO), cAMP reply conjugated protein (the cAMP response element-bindingprotein of assembly; CREB), ATF1, serum response factor (serum response factor, SRF), tyrosine hydroxylase and the most important assembly (ARE) conjugated protein (adenosine anduridine-rich element binding protein) that is rich in adenosine and uridine.The mRNA stability of the conjugated protein adjusting inflammatory mediator of ARE (for example TNF α and COX-2).

Target sudden change (targeted mutation) is imported mouse MK2 gene, this causes the generation of MK2 deficient mice.Referring to Kotlyarov et al., Nat.Cell Biol., Vol.1 (1999), at pp.94-97.These MK2 deficient mices are compared with the mouse that maintains the MK2 gene, and the endotoxin shock that LPS is brought out demonstrates the stress tolerance property (stress resistance) of increase, and has higher survival rate.Referring to same document.Have TNF α, IL-1 β, IL-6 and the IFN γ that level reduces from these isolating splenocytes of mouse that excite with LPS.Referring to same document.Recently; People such as Lehner report that the MK2 deficient mice demonstrates the susceptibility that Listeria moocytogenes is infected of increase, and infer that MK2 possibly resist the indispensable effect of performance in the intracellular bacteria the host through adjusting TNF α and IFN γ (in the machine-processed needed cytokine of activation antimicrobial effect thing (antibacterial effector) two kinds).Referring to Lehner et al., J.Immunol., Vol.168 (2002), at pp.4667-4673.And; Because MK2 is located immediately at the downstream of p38 in the p38 signal transduction path; So will be recognized that MK2 can be used as has more the focus of optionally regulating inflammation path (inflammatory pathway), reduce the possibility that spinoff occurs not expecting thus.

In WO 2004076458 (A1), disclosed pyrazolo [1,5-a] pyrimidine derivatives, and had kinase inhibiting activity according to describing it.

In treatment cytokine disease and illness that for example TNF α is mediated, active new compound of kinases (comprising MK2) and novel method are regulated in expectation.Even more expectation be to provide effect to improve and do not expect the MK2 suppressor factor that spinoff reduces.

Summary of the invention

The present invention is provided for treating formula (I) compound or its enantiomer, diastereomer or the pharmacologically acceptable salt of inflammatory diseases or immunological disease:

Wherein

One among E or the F is N, and among E or the F another is C;

X is NR ₄R ₅

Z is N or CR ₃, its restricted condition is: if E is N, then Z is N;

Y is selected from hydrogen, alkyl, substituted alkyl, thiazolinyl, substituted thiazolinyl, alkynyl, substituted alkynyl, halogen, nitro, cyanic acid, SR ₈, S (O) _pR ₈, OR ₈, NR ₆R ₇, CO ₂R ₈, C (=O) R ₈, O-C (=O) R ₈, C (=O) NR ₈R ₉, naphthenic base, cycloalkenyl group, cycloalkynyl radical, heterocyclic radical, aryl and heteroaryl, its restricted condition is: if Y is hydrogen, then R ₄For being substituted with the phenyl of formamido group;

R ₁And R ₂Independently be selected from (i) hydrogen, alkyl, substituted alkyl, thiazolinyl, substituted thiazolinyl, alkynyl, substituted alkynyl, halogen, nitro, cyanic acid, SR ₁₀, OR ₁₀, NR ₁₀R ₁₁, NR ₁₀C (=O) R ₁₁, CO ₂R ₁₀, C (=O) R ₁₀,-O-C (=O) R ₁₀, C (=O) NR ₁₀R ₁₁, naphthenic base, heterocyclic radical, aryl and heteroaryl; Or (ii) R ₁And R ₂And the annular atoms that they connected forms the assorted alkyl of 5,6 or 7 yuan of naphthenic base of condensed, aryl, heteroaryl or ring together;

R ₃Be selected from hydrogen, halogen, alkyl, substituted alkyl, thiazolinyl, substituted thiazolinyl, alkynyl, substituted alkynyl, nitro, cyanic acid, SR ₁₃, OR ₁₃, NR ₁₃R ₁₄, NR ₁₃C (=O) R ₁₄, CO ₂R ₁₃, C (=O) R ₁₃,-O-C (=O) R ₁₃,-C (=O) NR ₁₃R ₁₄, naphthenic base, heterocyclic radical, aryl and heteroaryl;

R ₄, R ₅, R ₆And R ₇Independently be selected from hydrogen, alkyl, substituted alkyl, thiazolinyl, substituted thiazolinyl, alkynyl, substituted alkynyl, OR ₁₅, SR ₁₅, C (=O) R ₁₅, CO ₂R ₁₅, C (=O) NR ₁₅R ₁₆, C (W) OR ₁₆, S (O) _pR ₁₇, SO ₂NR ₁₅R ₁₆, naphthenic base, heterocyclic radical, aryl and heteroaryl; Or (ii) R ₄And R ₅And their nitrogen-atoms of all being attached thereto form heteroaryl or heterocyclic radical together, and/or R ₆And R ₇And the nitrogen-atoms that they all are attached thereto forms heteroaryl or heterocyclic radical together;

R ₈, R ₉, R ₁₀, R ₁₁, R ₁₃, R ₁₄, R ₁₅And R ₁₆When occurring, all independently be selected from (i) hydrogen, alkyl, substituted alkyl, thiazolinyl, substituted thiazolinyl, alkynyl, substituted alkynyl, naphthenic base, aryl, heteroaryl and heterocyclic radical at every turn; Or (ii) R ₈And R ₉Reach the nitrogen-atoms that they connected and form heteroaryl or heterocyclic radical together, and/or R ₁₀And R ₁₁Reach the nitrogen-atoms that they connected and form heteroaryl or heterocyclic radical together, and/or R ₁₃And R ₁₄Reach the nitrogen-atoms that they connected and form heteroaryl or heterocyclic radical together, and/or R ₁₅And R ₁₆And the nitrogen-atoms that they connected forms heteroaryl or heterocyclic radical together;

R ₁₂, R ₁₇And R ₁₈When occurring, all independently be selected from alkyl, substituted alkyl, thiazolinyl, substituted thiazolinyl, alkynyl, substituted alkynyl, naphthenic base, aryl, heteroaryl and heterocyclic radical at every turn;

W is O, S, N, CN or NH when occurring at every turn; And

P is 1 or 2,

It has following restricted condition:

(1) if E is that C, F are that N, Z are CR ₃And X is NH (Me), NH (Me) ₂, NH (unsubstituted phenyl) or NHNH ₂, then Y is not a hydrogen or halogen; And

(2) if E is that N, F are that C, Z are that N and Y are NR ₆R ₇,

(a) then X is not NH (C _1-4Alkyl), N (C _1-4Alkyl) ₂, NH (C _1-4Thiazolinyl), NH (CH ₂-furyl), NHNH ₂, NH (methoxyl group alkylidene group) and NHAc;

(b) and if X be NH (CH ₂-(replace or unsubstituted) pyridyl) or NH (CH ₂-(replacement or unsubstituted) phenyl), then Y does not do

NH (substituted piperidines) or NH (CH ₂-pyridine);

(c) and if X be NH (cyclopentyl), then Y is not NH (cyclopentyl);

(d) and if X be N (CH ₃) (substituted phenyl) or N (CH ₃) (pyridyl), then Y does not do

Or

(e) and if X be NH (substituted phenyl), then Y is not

The present invention also relates to be used for (comprising the adjusting (especially suppressing) to MK2) relevant disease is regulated in treatment with kinases pharmaceutical composition, it comprises formula (I) compound or pharmaceutically acceptable salt thereof and pharmaceutically acceptable carrier or thinner.The invention still further relates to treatment and kinases and regulate the method for (comprising the adjusting to MK2) relevant disease, it comprises that compound with the formula (I) of treating significant quantity needs the patient of this treatment.

Embodiment

It below is definition to used term in this specification sheets and the appended claims.Except as otherwise noted, the original definition to group or term that the application provided is applicable to and spreads all over specification sheets and claims this group or term everywhere no matter its exist singly still is as the part of another group.

Term " alkyl " refers to the straight or branched alkyl that has 1 to 12 carbon atom, be preferably 1 to 8 carbon atom.The low alkyl group i.e. alkyl of 1 to 4 carbon atom is most preferred.When numeral appears at symbol " C " afterwards the time with the form of subscripts, subscript more specifically defines the number of the carbon atom that concrete group can comprise.For example, " C _1-6Alkyl " refer to have a straight chain and a branched-chain alkyl to six carbon atom, such as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, the tertiary butyl, n-pentyl etc.Subscript " 0 " digital.Therefore, term hydroxyl (C _0-2) alkyl or (C _0-2) hydroxyalkyl comprises hydroxyl, methylol and hydroxyethyl.

Term " substituted alkyl " refers to have one, two or three and be selected from following substituent alkyl as preceding text are defined: halogen (for example trifluoromethyl), thiazolinyl, substituted thiazolinyl, alkynyl, nitro, cyanic acid, oxo (=O), OR _a, SR _a, (=S) ,-NR _aR _b,-N (alkyl) ₃ ⁺,-NR _aSO ₂,-NR _aSO ₂R _c,-SO ₂R _c-, SO ₂NR _aR _b,-SO ₂NR _aC (=O) R _b, SO ₃H ,-PO (OH) ₂,-OC (O) R _a,-C (=O) R _a,-CO ₂R _a,-C (=O) NR _aR _b,-C (=O) (C _1-4Alkylidene group) NR _aR _b,-C (=O) NR _a(SO ₂) R _b,-CO ₂(C _1-4Alkylidene group) NR _aR _b,-NR _aC (=O) R _b,-NR _aCO ₂R _b,-NR _a(C _1-4Alkylidene group) CO ₂R _b,=N-OH ,=N-O-alkyl, aryl, naphthenic base, heterocyclic radical and/or heteroaryl, wherein R _aAnd R _bBe selected from hydrogen, alkyl, thiazolinyl, CO ₂H, CO ₂(alkyl), C _3-7Naphthenic base, phenyl, benzyl, styroyl, naphthyl, four to seven membered heterocyclic base or five to six membered heteroaryl, or R _aAnd R _bCan combine to form heterocyclic radical or heteroaryl, R when connecting same nitrogen-atoms _cBe selected from and R _aAnd R _bIdentical group but be not hydrogen.Each R _aAnd R _b(when being not hydrogen) and each R _cAll choose wantonly and have at the most three and be connected in R _a, R _bAnd/or R _cAny available carbon atom or other substituting group of nitrogen-atoms, said substituting group (or a plurality of substituting group) is selected from: (C _1-6) alkyl, (C _2-6) thiazolinyl, hydroxyl, halogen, cyanic acid, nitro ,=O (when valency allows), CF ₃, O (C _1-6Alkyl), OCF ₃, C (=O) H, C (=O) (C _1-6Alkyl), CO ₂H, CO ₂(C _1-6Alkyl), NHCO ₂(C _1-6Alkyl) ,-S (C _1-6Alkyl) ,-NH ₂, NH (C _1-6Alkyl), N (C _1-6Alkyl) ₂, N (CH ₃) ₃ ⁺, SO ₂(C _1-6Alkyl), C (=O) (C _1-4Alkylidene group) NH ₂, C (=O) (C _1-4Alkylidene group) NH (alkyl), C (=O) (C _1-4Alkylidene group) N (C _1-4Alkyl) ₂, C _3-7Naphthenic base, phenyl, benzyl, styroyl, phenoxy, benzyloxy, naphthyl, four to seven membered heterocyclic base or naphthenic base or five to six membered heteroaryl.When substituted alkyl is substituted with aryl (comprising for example phenyl and naphthyl), heterocyclic radical, naphthenic base or heteroaryl, said ring such as hereinafter definition, therefore, also such as hereinafter definition can have zero, one, two or three substituting groups.

It will be understood by those skilled in the art that working as the application uses sign " CO ₂" time, its expectation is shown group

When term " alkyl " uses (such as in " arylalkyl ") with another group, this combination more specifically defined substituted alkyl at least a in the substituting group that should comprise.For example, " arylalkyl " refer in the substituting group wherein at least one for aryl like the defined substituted alkyl of preceding text, such as benzyl.Therefore, term aryl (C _0-4) alkyl comprises the substituted low alkyl group with at least one aryl substituent, also comprises the aryl that directly is connected with another group, i.e. aryl (C ₀) alkyl.

Term " thiazolinyl " refers to have the straight or branched alkyl of 2 to 12 carbon atoms and at least one two key.The thiazolinyl that has 2 to 6 carbon atoms and have two keys is most preferred.

Term " alkynyl " refers to have the straight or branched alkyl of 2 to 12 carbon atoms and at least one three key.The alkynyl that has 2 to 6 carbon atoms and have one three key is most preferred.

Term " alkylidene group " refers to the straight key of divalence or branched-chain hydrocarbon base, the for example { CH that have 1 to 12 carbon atom, be preferably 1 to 8 carbon atom ₂- _n, wherein n is 1 to 12, is preferably 1-8.The low-grade alkylidene i.e. alkylidene group of 1 to 4 carbon atom is most preferred.Such as preceding text definition, term " alkenylene " and " alkynylene " refer to divalence thiazolinyl and divalence alkynyl respectively.

When with regard to substituted thiazolinyl, alkynyl, alkylidene group, alkenylene or alkynylene, these groups be substituted with once to three like the defined substituting group of the substituted alkyl of preceding text.

The application's use a technical term " assorted alkylidene group (heteroalkylene) "; Be used in reference to the saturated and undersaturated divalence straight or branched alkyl that has 2 to 12 carbon atoms, is preferably 2 to 8 carbon atoms, wherein one or two carbon atom in the straight chain be selected from-O-,-S-,-S (=O)-,-SO ₂-,-NH-and-NHSO ₂-heteroatoms (or a plurality of heteroatoms) substitute.Therefore, term " assorted alkylidene group " comprises like the defined divalence alkoxyl group of hereinafter, sulfane base and aminoalkyl group and in alkyl chain, has alkylidene group and the alkenylene that heteroatoms makes up.For example, " the assorted alkylidene group " among the application can comprise following group: such as-S-(CH ₂) _1-5NH-CH ₂-,-O-(CH ₂) _1-5S (=O)-CH ₂-,-NHSO ₂-CH ₂-,-CH ₂-NH-etc.Preferably, assorted alkylidene group does not have two simultaneously and is selected from-the adjacent atom of O-and-S-.When subscript is used (for example at C with the assorted alkylidene group of term _2-3In the assorted alkylidene group) time, subscript refers to the number of the carbon atom except that heteroatoms in the group.Therefore, C for example _1-2Assorted alkylidene group can comprise following group: such as-NH-CH ₂-,-CH ₂-NH-CH ₂-,-CH ₂-CH ₂-NH-,-S-CH ₂-,-CH ₂-S-CH ₂-,-O-CH ₂-NH-CH ₂-, CH ₂-O-CH ₂Deng.

Term " substituted assorted alkylidene group " refers to that like the defined assorted alkylidene group of preceding text at least one in the wherein assorted alkylidene chain in nitrogen-atoms or the carbon atom is connected (or being substituted with non-hydrogen group) with non-hydrogen group.Carbon atom instead in the assorted alkylidene chain has and is selected from preceding text with regard to the cited group of substituted alkyl, or is substituted with other alkyl or substituted alkyl.The nitrogen-atoms instead of assorted alkylidene chain has and is selected from following group: alkyl, thiazolinyl, alkynyl, cyanic acid or A ₁-Q-A ₂-R _h, A wherein ₁Be key, C _1-2Alkylidene group or C _2-3Alkenylene; Q be key ,-C (=O)-,-C (=O) NR _d-,-C (=S) NR _d-,-SO ₂-,-SO ₂NR _d-,-CO ₂-or-NR _dCO ₂-; A ₂Be key, C _1-3Alkylidene group, C _2-3Alkenylene ,-C _1-4Alkylidene group-NR _d-,-C _1-4Alkylidene group-NR _dC (=O)-,-C _1-4Alkylidene group-S-,-C _1-4Alkylidene group-SO ₂-or-C _1-4Alkylidene group-O-, wherein said A ₂Alkylidene group is side chain or straight chain, and such as the application with regard to substituted alkylidene group definition, said A ₂Alkylidene group is optional substituted; R _hBe hydrogen, alkyl, substituted alkyl, thiazolinyl, substituted thiazolinyl, aryl, heteroaryl, heterocyclic radical or naphthenic base; R _dBe selected from hydrogen, like the defined alkyl of the application with like the defined substituted alkyl of the application, yet its restricted condition is: with regard to substituted assorted alkylidene group, work as A ₁, Q and A ₂When each all is key, R _hBe not hydrogen.Work as R _hDuring for aryl, heteroaryl, naphthenic base or heterocyclic radical, these rings are optional again to be substituted with one to three like hereinafter defined group in the definition to these terms.

Term " alkoxyl group " refers to by defined alkyl of the application or the substituted Sauerstoffatom of substituted alkyl.For example, term " alkoxyl group " comprises-O-C _1-6Alkyl.

Term " alkylthio " refers to by defined alkyl of the application or the substituted sulphur atom of substituted alkyl.For example, term " alkylthio " comprises-S-C _1-6Alkyl etc.

Term " alkylamino " refers to by defined alkyl of the application or the substituted amino of substituted alkyl.For example, term " alkylamino " comprises-NR-C _1-12Alkyl (wherein R is preferably hydrogen, but can comprise like defined alkyl of preceding text or substituted alkyl).

When use timestamp down with regard to alkoxyl group, sulfane base or aminoalkyl group, subscript refers to the number of the carbon atom that group can comprise except that heteroatoms.Therefore, monovalence C for example _1-2Aminoalkyl group comprises-CH ₂-N (CH ₃) ₂With-(CH ₂) ₂-NH ₂Amino low alkyl group comprises having an aminoalkyl group to four carbon atom.Term (C _1-4Alkyl) _0-2Amino comprises NH ₂,-NH (C _1-4Alkyl) and-N (C _1-4Alkyl) ₂" amino " refers to NH ₂" substituted amino " refer to such as preceding text just assorted alkylidene chain nitrogen-atoms substituted amino the description, comprise for example term alkylamino and amido (NR _dC (O) R _e).

Alkoxyl group, sulfane base or aminoalkyl group can be monovalence or divalence.The meaning of " monovalence " is, the valency of group (promptly with another group bonded ability) is one, and the meaning of " divalence " is that the group valency is two.Therefore, for example the monovalence alkoxyl group comprises like-O-C _1-12The group that alkyl is such, and the divalence alkoxyl group comprises like-O-C _1-12The group of alkylidene group-that kind.

It should be understood that those skilled in the art can select all groups, comprise for example alkoxyl group, sulfane base and aminoalkyl group, so that stable compound to be provided.Therefore, for example in formula (I) compound, as the nitrogen-atoms (N of G with ring A ^*) connect and G when being selected from alkoxyl group or alkylthio, said alkoxyl group and alkylthio can have at least one directly with encircle A (at N ^*The place) carbon atom that connects, and said Sauerstoffatom or sulphur atom and said nitrogen-atoms are at a distance from least one atom.

Term " carbonyl " refer to divalence carbonyl-C (=O)-.When term " carbonyl " uses (for example in " heterocyclic radical carbonyl ") with another group, this combination more specifically defined substituted carbonyl at least a in the substituting group that should comprise.For example, " heterocyclic radical carbonyl " refers to that wherein at least one in the substituting group is heterocyclic radical, such as morpholinyl like the defined carbonyl of preceding text.

Term " acyl group " refers to the carbonyl that is connected with organic group, more specifically is C (=O) R _eR _cThe defined alkyl of optional the application freely, thiazolinyl, alkynyl, aminoalkyl group, substituted alkyl (being substituted alkylidene group), substituted thiazolinyl, substituted alkynyl, naphthenic base, heterocyclic radical, aryl or heteroaryl.Work as R _eDuring for aryl, heteroaryl, naphthenic base or heterocyclic radical, these rings are optional again to be substituted with one to three like hereinafter defined group in the definition to these terms.

The carboxyl that term " carbalkoxy " refers to be connected with organic group ( Or

) (CO ₂R _e) with the divalence-CO that in formula (I) compound, is connected with organic group ₂-,-CO ₂R _e-, R wherein _eSuch as preceding text with regard to acyl group definition.The organic group that carboxyl connected can be monovalence (for example-CO ₂-alkyl or-OC (=O) alkyl) or divalence (for example-CO ₂-alkylidene group ,-OC (=O) alkylidene group etc.).Therefore, in formula (I) compound, when enumerating G and can be " carbalkoxy ", this is intended to contain being chosen as-CO G ₂-and-CO ₂R _e-or-R _eCO ₂-, wherein in this case, R _eCan be selected from divalent group, for example alkylidene group, alkenylene, alkynylene, divalence aminoalkyl group, substituted alkylidene group, substituted alkenylene or substituted alkynylene.

Term " methane amide " or " formamido group " refer to-NR _dC (=O) R _e, R wherein _dAnd R _eDefine cited in the definition to assorted alkyl, carbalkoxy and acyl group like preceding text.For example,

Be R wherein _eBe the defined substituted heterocyclic formamido group of the application.

Term " acid amides " or " amido " refer to-C (=O) NR _aR _b, R wherein _aAnd R _bDefine cited in the definition to substituted alkyl like preceding text.

Term " urea " refers to-NR _dC (=O) NR _aR _b, radicals R wherein _a, R _bAnd R _dDefine cited in the definition to substituted alkyl like preceding text.In addition, urea groups can be a divalence, in this case, and R _aAnd R _bIn one can be key.Therefore, in formula (I) compound, when description G can be urea, its meaning was that under suitable situation, G is-NR _d(C (=O) NR _a-.

Term " alkylsulfonyl " refers to the sulfoxide group that is connected with organic group in formula (I) compound, more specifically is monovalence-S (O) ₂-R _eIn addition, alkylsulfonyl can be a divalence, in this case, and R _eBe key.Therefore, in formula (I) compound, when enumerating G and can be " alkylsulfonyl ", its meaning is, under suitable situation, G is-and S (O)-.R _eBe selected from preceding text with regard to acyl group and the cited group of carbalkoxy, but R _eBe not hydrogen.

Term " sulphonamide " or " sulfonamido " refer to-S (O) ₂NR _aR _b, R wherein _aAnd R _bSuch as preceding text with regard to substituted alkyl definition.

Term " naphthenic base " refers to 3 to 9 carbon atoms, is preferably the undersaturated hydrocarbon ring of complete saturated and part of 3 to 7 carbon atoms (therefore comprising the hydrocarbon ring that is also referred to as " cyclenes basic ring ").Term " naphthenic base " comprise have zero, one, two or three be selected from following substituent above-mentioned ring: halogen, trifluoromethyl, trifluoromethoxy, alkyl, substituted alkyl, thiazolinyl, substituted thiazolinyl, alkynyl, nitro, cyanic acid, oxo (=O), OR _a, SR _a, (=S) ,-NR _aR _b,-N (alkyl) ₃ ⁺,-NR _aSO ₂,-NR _aSO ₂R _c,-SO ₂R _c,-SO ₂NR _aR _b,-SO ₂NR _aC (=O) R _b, SO ₃H ,-PO (OH) ₂,-C (=O) R _a,-CO ₂R _a,-C (=O) NR _aR _b,-C (=O) (C _1-4Alkylidene group) NR _aR _b,-C (=O) NR _a(SO ₂) R _b,-CO ₂(C _1-4Alkylidene group) NR _aR _b,-NR _aC (=O) R _b,-NR _aCO ₂R _b,-NR _a(C _1-4Alkylidene group) CO ₂R _b,=N-OH ,=N-O-alkyl, aryl, naphthenic base, heterocyclic radical and/or heteroaryl, wherein R _a, R _bAnd R _cSuch as preceding text with regard to substituted alkyl definition, and like preceding text cited in the definition to substituted alkyl, R _a, R _bAnd R _cAlso be optional further substituted.Term " naphthenic base " also comprises having with above-mentioned ring condensed second ring (for example comprising phenyl ring, heterocyclic ring or heteroaryl ring) or have the above-mentioned ring of the carbon-to-carbon bridge of 3 to 4 carbon atoms.When cycloalkyl substituted has other ring (or having and its condensed second ring), optional again one or two the following group that is substituted with of said ring: (C _1-4) alkyl, (C _2-4) thiazolinyl, (C _2-4) alkynyl, halogen, hydroxyl, cyanic acid, nitro, CF ₃, O (C _1-4Alkyl), OCF ₃, C (=O) H, C (=O) (C _1-4Alkyl), CO ₂H, CO ₂(C _1-4Alkyl), NHCO ₂(C _1-4Alkyl) ,-S (C _1-4Alkyl) ,-NH ₂, NH (C _1-4Alkyl), N (C _1-4Alkyl) ₂, N (C _1-4Alkyl) ₃ ⁺, SO ₂(C _1-4Alkyl), C (=O) (C _1-4Alkylidene group) NH ₂, C (=O) (C _1-4Alkylidene group) NH (alkyl), C (=O) (C _1-4Alkylidene group) N (C _1-4Alkyl) ₂And/or the optional phenyl that is substituted with any above-mentioned group.When valency allowed, if said other ring is naphthenic base or heterocyclic radical, then its extra choosing wantonly was substituted with=O (oxo).

Therefore, in formula (I) compound, term " naphthenic base " comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, two ring octyl groups etc. and following ring system:

etc., these groups can choose wantonly at any available atom place of ring (or a plurality of ring) and be substituted.Preferred naphthenic base comprises cyclopropyl, cyclopentyl, cyclohexyl and

Term " halogen " refers to chlorine, bromine, fluorine and iodine.

The meaning of term " haloalkyl " is to have the substituted alkyl of one or more halogenic substituents.For example, " haloalkyl " comprises a methyl fluoride, difluoromethyl and trifluoromethyl.

The meaning of term " halogenated alkoxy " is to have the alkoxyl group of one or more halogenic substituents.For example, " halogenated alkoxy " comprises OCF ₃

Term " aryl " refers to phenyl, xenyl, fluorenyl, 1-naphthyl and 2-naphthyl.Term " aryl " comprise have zero, one, two or three be selected from following substituent above-mentioned ring: halogen, trifluoromethyl, trifluoromethoxy, alkyl, substituted alkyl, thiazolinyl, substituted thiazolinyl, alkynyl, nitro, cyanic acid, OR _a, SR _a, (=S), SO ₃H ,-NR _aR _b,-N (alkyl) ₃ ⁺,-NR _aSO ₂,-NR _aSO ₂R _c,-SO ₂R _c,-SO ₂NR _aR _b,-SO ₂NR _aC (=O) R _b, SO ₃H ,-PO (OH) ₂,-C (=O) R _a,-CO ₂R _a,-C (=O) NR _aR _b,-C (=O) (C _1-4Alkylidene group) NR _aR _b,-C (=O) NR _a(SO ₂) R _b,-CO ₂(C _1-4Alkylidene group) NR _aR _b,-NR _aC (=O) R _b,-NR _aCO ₂R _b,-NR _a(C _1-4Alkylidene group) CO ₂R _b, aryl, naphthenic base, heterocyclic radical and/or heteroaryl, wherein R _a, R _bAnd R _cSuch as preceding text with regard to substituted alkyl definition, and as preceding text are cited, R _a, R _bAnd R _cAlso be optional further substituted.In addition, two substituting groups that are connected with aryl (especially phenyl) can be in conjunction with forming other ring, such as condensed ring or volution, and for example cyclopenta or cyclohexyl or condensed heterocycle base or heteroaryl.When aryl is substituted with other ring (or having and its condensed second ring), optional again one or two the following group that is substituted with of said ring: (C _1-4) alkyl, (C _2-4) thiazolinyl, (C _2-4) alkynyl, halogen, hydroxyl, cyanic acid, nitro, CF ₃, O (C _1-4Alkyl), OCF ₃, C (=O) H, C (=O) (C _1-4Alkyl), CO ₂H, CO ₂(C _1-4Alkyl), NHCO ₂(C _1-4Alkyl) ,-S (C _1-4Alkyl) ,-NH ₂, NH (C _1-4Alkyl), N (C _1-4Alkyl) ₂, N (C _1-4Alkyl) ₃ ⁺, SO ₂(C _1-4Alkyl), C (=O) (C _1-4Alkylidene group) NH ₂, C (=O) (C _1-4Alkylidene group) NH (alkyl), C (=O) (C _1-4Alkylidene group) N (C _1-4Alkyl) ₂And/or the optional phenyl that is substituted with any above-mentioned group.When valency allowed, if said other ring is naphthenic base or heterocyclic radical, then its extra choosing wantonly was substituted with=O (oxo).

Therefore, the instance of aryl comprises:

(fluorenyls) etc., these groups can be chosen wantonly at any available carbon atom or nitrogen-atoms place and be substituted.Preferred aryl groups is optional substituted phenyl.

Term " Heterocyclylalkyl ", " heterocyclic radical " or " heterocycle " interchangeable use; And refer to replace and 3 to 7 yuan of monocyclic groups of unsubstituted non-aromatics, 7 to 11 yuan of bicyclic groups and 10 to 15 yuan of three cyclic groups; In the wherein above-mentioned ring at least one has at least one heteroatoms (O, S or N), comprises said heteroatomic ring and preferably has 1,2 or 3 heteroatoms that is selected from O, S and N.Each ring that comprises in the heteroatomic above-mentioned group all can comprise one or two Sauerstoffatom or sulphur atom and/or one to four nitrogen-atoms; Its restricted condition is: heteroatomicly in each ring add up to four or still less, and other restricted condition is: ring comprises at least one atom.It is oxidation that nitrogen-atoms and sulphur atom can be chosen wantonly, and nitrogen-atoms can to choose wantonly be quaternised.The condensed ring that forms two rings and three cyclic groups can only comprise carbon atom, and can be saturated, fractional saturation or undersaturated.Heterocyclic radical can connect at any available nitrogen-atoms or carbon atom place.Heterocyclic ring can comprise zero, one, two or three and be selected from following substituting group: halogen, trifluoromethyl, trifluoromethoxy, alkyl, substituted alkyl, thiazolinyl, substituted thiazolinyl, alkynyl, nitro, cyanic acid, oxygen (oxo), OR _a, SR _a, (=S) ,-NR _aR _b,-N (alkyl) ₃ ⁺,-NR _aSO ₂,-NR _aSO ₂R _c,-SO ₂R _c,-SO ₂NR _aR _b,-SO ₂NR _aC (=O) R _b, SO ₃H ,-PO (OH) ₂,-C (=O) R _a,-CO ₂R _a,-C (=O) NR _aR _b,-C (=O) (C _1-4Alkylidene group) NR _aR _b,-C (=O) NR _a(SO ₂) R _b,-CO ₂(C _1-4Alkylidene group) NR _aR _b,-NR _aC (=O) R _b,-NR _aCO ₂R _b,-NR _a(C _1-4Alkylidene group) CO ₂R _b,=N-OH ,=N-O-alkyl, aryl, naphthenic base, heterocyclic radical and/or heteroaryl, wherein R _a, R _bAnd R _cSuch as preceding text with regard to substituted alkyl definition, and as preceding text are cited, R _a, R _bAnd R _cAlso be optional further substituted.When heterocyclic radical is substituted with other ring, optional again one or two the following group that is substituted with of said ring: (C _1-4) alkyl, (C _2-4) thiazolinyl, (C _2-4) alkynyl, halogen, hydroxyl, cyanic acid, nitro, CF ₃, O (C _1-4Alkyl), OCF ₃, C (=O) H, C (=O) (C _1-4Alkyl), CO ₂H, CO ₂(C _1-4Alkyl), NHCO ₂(C _1-4Alkyl) ,-S (C _1-4Alkyl) ,-NH ₂, NH (C _1-4Alkyl), N (C _1-4Alkyl) ₂, N (C _1-4Alkyl) ₃ ⁺, SO ₂(C _1-4Alkyl), C (=O) (C _1-4Alkylidene group) NH ₂, C (=O) (C _1-4Alkylidene group) NH (alkyl), C (=O) (C _1-4Alkylidene group) N (C _1-4Alkyl) ₂And/or the optional phenyl that is substituted with any above-mentioned group.When valency allowed, if said other ring is naphthenic base or heterocyclic radical, then its extra choosing wantonly was substituted with=O (oxo).

Exemplary monocyclic groups comprises azelidinyl, pyrrolidyl, oxa-cyclobutyl, imidazolinyl, oxazolidinyl, isoxazoline-3-yl, thiazolidyl, isothiazole alkyl, tetrahydrofuran base, piperidyl, piperazinyl, 2-oxo piperazinyl, 2-oxo-piperidine base, 2-oxo-pyrrolidine base, 2-oxo azepine

base, azepine base, 4-piperidone base, THP trtrahydropyranyl, morpholinyl, parathiazan base, parathiazan base sulfoxide, parathiazan base sulfone, 1; 3-dioxo penta ring and tetrahydrochysene-1,1-dioxo thienyl etc.Exemplary bicyclic heterocycles group comprises quinuclidinyl.

Preferred heterocyclic radical comprises in formula (I) compound:

These groups may optionally be substituted generations.

Term " heterocyclic aryl " refers to replace and unsubstituted aromatics 5 or 6 yuan of monocyclic groups, 9 or 10 yuan of bicyclic groups and 11 to 14 yuan of three cyclic groups; These groups have at least one heteroatoms (O, S or N) at least one ring, saidly comprise heteroatomic ring and preferably have 1,2 or 3 heteroatoms that is selected from O, S and N.Each ring that comprises in the heteroatomic heteroaryl all can comprise one or two Sauerstoffatom or sulphur atom and/or one to four nitrogen-atoms, and its restricted condition is: heteroatomicly add up to four or littler in each ring, and each ring all has at least one carbon atom.The condensed ring that forms two rings and three cyclic groups can only comprise carbon atom, and can be saturated, fractional saturation or undersaturated.It is oxidation that nitrogen-atoms and sulphur atom can be chosen wantonly, and nitrogen-atoms can to choose wantonly be quaternised.Two rings or trinucleated heteroaryl must comprise at least one complete aromatic ring, but other condensed ring or a plurality of condensed ring can be aromatics or non-aromatics.Heteroaryl can be in any available nitrogen-atoms or the connection of carbon atom place of ring arbitrarily.The heteroaryl ring system can comprise zero, one, two or three and be selected from following substituting group: halogen, trifluoromethyl, trifluoromethoxy, alkyl, substituted alkyl, thiazolinyl, substituted thiazolinyl, alkynyl, nitro, cyanic acid, OR _a, SR _a, (=S) ,-NR _aR _b,-N (alkyl) ₃ ⁺,-NRaSO ₂,-NR _aSO ₂R _c,-SO ₂R _c,-SO2NR _aR _b,-SO ₂NR _aC (=O) R _b, SO ₃H ,-PO (OH) ₂,-C (=O) R _a,-CO ₂R _a,-C (=O) NR _aR _b,-C (=O) (C _1-4Alkylidene group) NR _aR _b,-C (=O) NR _a(SO ₂) R _b,-CO ₂(C _1-4Alkylidene group) NR _aR _b,-NR _aC (=O) R _b,-NR _aCO ₂R _b,-NR _a(C _1-4Alkylidene group) CO ₂R _b, aryl, naphthenic base, heterocyclic radical and/or heteroaryl, wherein R _a, R _bAnd R _cSuch as preceding text with regard to substituted alkyl definition, and as preceding text are cited, R _a, R _bAnd R _cAlso be optional further substituted.When heteroaryl is substituted with other ring, optional again one or two the following group that is substituted with of said ring: (C _1-4) alkyl, (C _2-4) thiazolinyl, (C _2-4) alkynyl, halogen, hydroxyl, cyanic acid, nitro, CF ₃, O (C _1-4Alkyl), OCF ₃, C (=O) H, C (=O) (C _1-4Alkyl), CO ₂H, CO ₂(C _1-4Alkyl), NHCO ₂(C _1-4Alkyl) ,-S (C _1-4Alkyl) ,-NH ₂, NH (C _1-4Alkyl), N (C _1-4Alkyl) ₂, N (C _1-4Alkyl) ₃ ⁺, SO ₂(C _1-4Alkyl), C (=O) (C _1-4Alkylidene group) NH ₂, C (=O) (C _1-4Alkylidene group) NH (alkyl), C (=O) (C _1-4Alkylidene group) N (C _1-4Alkyl) ₂And/or the optional phenyl that is substituted with any above-mentioned group.When valency allowed, if said other ring is naphthenic base or heterocyclic radical, then its extra choosing wantonly was substituted with=O (oxo).

Exemplary bicyclic heteroaryl comprises pyrryl, pyrazolyl, pyrazolinyl, imidazolyl 、 oxazolyl 、 isoxazolyl, thiazolyl, thiadiazolyl group, isothiazolyl, furyl, thienyl 、 oxadiazole base, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, triazinyl etc.

Exemplary bicyclic heteroaryl comprise indyl, benzothiazolyl, benzo dioxane pentadienyl, benzoxazolyl, benzothienyl, quinolyl, tetrahydro isoquinolyl, isoquinolyl, benzimidazolyl-, benzopyranyl, indolizine base, benzofuryl, chromone base, tonka bean camphor base, benzopyranyl,

Cinnolines base, quinoxalinyl, indazolyl, pyrrolopyridinyl, furo pyridyl, dihydro-iso indolyl, tetrahydric quinoline group etc.

Exemplary tricyclic heteroaryl comprises carbazyl, benzindole base (benzidolyl), phenanthroline base (phenanthrollinyl), acridyl, phenanthridinyl, xanthenyl etc.

Preferred heteroaryl comprises in formula (I) compound:

etc., these groups can be chosen wantonly at any available carbon atom or nitrogen atom place and be substituted.Aromatic ring also can be named through the not breaking ring in the aromatic ring.For example, the core ring of formula (I) is

representes bicyclic heteroaryl.

Except as otherwise noted; When with regard to aryl (for example phenyl), naphthenic base (for example cyclohexyl), heterocyclic radical (for example pyrrolidyl, piperidyl and morpholinyl) or the heteroaryl (for example tetrazyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl and furyl) of concrete name; Only if specify in addition; These groups are intended to comprise to have 0 to 3 under suitable situation, be preferably 0-2 and be selected from preceding text with regard to the cited substituent ring of aryl, naphthenic base, heterocyclic radical and/or heteroaryl.

Usually, for the unstructured substituting group of expression moiety combinations, only if specify in addition, the last group of said combination is the point that connects with the adjacent group that is connected subsequently.Therefore, for example term " aminocyclohexyl methyl " is intended to refer to

and N-(n-propyl) sulfonamido is intended to refer to

Term " heteroatoms " can comprise oxygen, sulphur and nitrogen.

The meaning of term " carbocyclic ring " is saturated or unsaturated monocycle or two rings, and wherein all atoms of all rings all are carbon.Therefore, said term comprises naphthenic base and aromatic ring.Carbocyclic ring can be substituted, and in this case, substituting group is selected from preceding text with regard to naphthenic base and the cited group of aryl.

When the application was used for ring or group with term " unsaturated ", ring or group can be unsaturated fully or part is undersaturated.

When the application was used for ring or group with term " optional replace ", ring or group can be to replace or unsubstituted.

Run through this specification sheets, those skilled in the art can select group and substituting group thereof, stable residue and compound to be provided and to can be used as the compound of pharmaceutically acceptable compound and/or can be used for preparing the midbody compound of pharmaceutically acceptable compound.

According to the definition of preceding text, the present invention is provided at the compound in have formula (Ia), (Ib) or formula (Ic) (I) scope:

R wherein ₁, R ₂, R ₃, X and Y such as the application definition.

Formula (I) compound can form also salt within the scope of the present invention.Except as otherwise noted, it should be understood that compound of the present invention comprises its salt.Acid salt and/or base addition salt that term " salt (or various salts) " expression and inorganic bronsted lowry acids and bases bronsted lowry and/or organic bronsted lowry acids and bases bronsted lowry form.In addition, term " salt (various salts) " can comprise zwitter-ion (inner salt), for example when formula (I) compound comprises alkali residue (such as amine or pyridine or imidazole ring) and sour residue (such as carboxylic acid).Pharmaceutically acceptable (be nontoxic physiologically acceptable) salt is preferred, for example wherein not remarkably influenced of positively charged ion salt toxicity or bioactive acceptable metal and amine salt.Yet, can use other salt in the for example during preparation spendable isolated or purified step, therefore, these salt are also within the scope of the invention.The salt of formula (I) compound can for example prepare through following method: in the sedimentary therein medium of medium such as salt or in aqueous medium, make formula (I) compound and a certain amount of acid or alkali reaction such as monovalent, next carry out freeze-drying.

Exemplary acid salt comprise acetate (such as with acetate or the three halogenated acetic acids salt that forms of trifluoroacetic acid for example); Adipate; Alginates; Ascorbate salt; The asparagus fern amino acid salt; Benzoate; Benzene sulfonate; Hydrosulfate; Borate; Butyrates; Citrate trianion; Camphorate; Camsilate; Cipionate; Digluconate; Dodecyl sulfate; Esilate; Fumarate; Glucose enanthate (glucoheptanoate); Glycerophosphate; Hemisulphate; Enanthate; Hexanoate; Hydrochloride (with the salt of hydrochloric acid formation); Hydrobromate (with the salt of hydrogen bromide formation); Hydriodate; The 2-isethionate; Lactic acid salt; PHENRAMINE MALEATE (with the salt of toxilic acid formation); Mesylate (with the salt of methylsulfonic acid formation); The 2-naphthalenesulfonate; Nicotinate (nicotinate); Nitrate salt; Oxalate; Pectate (pectinate); Persulphate; 3-phenylpropionic acid salt; Phosphoric acid salt; Picrate; Pivalate; Propionic salt; Salicylate; SUMATRIPTAN SUCCINATE; Vitriol (such as the salt that forms with sulfuric acid); Sulphonate (such as mentioned those of the application); Tartrate; Thiocyanate-; Tosylate (toluenesulfonate) (such as tosylate (tosylate)); Undecane hydrochlorate etc.

Exemplary base addition salt comprises ammonium salt; An alkali metal salt is such as sodium salt, lithium salts and sylvite; Alkaline earth salt is such as calcium salt and magnesium salts; Barium salt, zinc salt and aluminium salt; Salt with following organic bases (for example organic amine) formation: such as trialkylamine (such as triethylamine), PROCAINE HCL, PHARMA GRADE, dibenzyl amine, N-benzyl-β-phenylethylamine, 1-ephenamine (1-ephenamine), N, N '-dibenzoyl quadrol, dehydroabietylamine, N-ethylpiperidine, benzene methanamine, dicyclohexyl amine or similar pharmaceutically acceptable amine; With the salt that forms with amino acid (such as l-arginine, Methionin etc.).It is quaternized that the alkalescence nitrogen-containing group can use following reagent: such as elementary alkyl halide (for example methyl, ethyl, propyl group and butyl muriate, bromide and iodide), dialkylsulfates (for example dimethyl-, diethylammonium, dibutyl and diamyl sulfuric ester), long-chain halogenide (for example decyl, lauryl, myristyl and stearyl-muriate, bromide and iodide), aralkyl halide (for example benzyl and styroyl bromination thing) etc.Preferred salt comprises a hydrochloride, hydrosulfate, mesylate, phosphoric acid salt or nitrate salt.

The present invention also comprises the prodrug and the solvolyte of The compounds of this invention.Term " prodrug " is illustrated in when giving study subject through metabolic process or chemical process and compound and/or its salt and/or the solvolyte of a chemical conversion accepted way of doing sth (I) compound.Any compound that can change into biologically active substance (being formula I compound) in vivo all is the prodrug in the scope of the invention and purport.For example, the compound that comprises carboxyl can form hydrolyzable ester on the physiology, and said ester comes self production (I) compound through hydrolysis in vivo as prodrug.Owing to mainly take place under the influence at digestive ferment in hydrolysis under the multiple situation, so these prodrugs preferably come administration with oral way.Have under the active situation or at ester self and to betide under the situation in the blood in hydrolysis, capable of using non-through enteral administration.The embodiment of hydrolyzable ester comprises C on the physiology of formula (I) compound _1-6Alkyl benzyl ester, 4-methoxy benzyl ester, indane ester, phthalyl ester (phthalyl), methoxyl group methyl esters, C _1-6Alkanoyloxy-C _1-6Alkyl ester (for example acetoxyl group methyl esters, new pentane acyloxy methyl esters or propionyloxy methyl esters), C _1-6Alkoxy-carbonyl oxy-C _1-6Hydrolyzable ester on alkyl ester (for example methoxycarbonyl oxygen base methyl esters or ethoxy carbonyl oxygen base methyl esters), glycyl oxygen base methyl esters, phenyl glycyl oxygen base methyl esters, (5-methyl-2-oxo-1,3-Dioxol-4-yl)-methyl esters and other well-known physiology that for example in penicillium mould and cynnematin field, uses.These esters can prepare through the routine techniques that is known in the art.

In the art, various forms of prodrugs are well-known.The instance of these prodrug derivants referring to:

a)Design?of?Prodrugs，edited?by?H.Bundgaard，(Elsevier，1985)andMethods?in?Enzymology，Vol.112，pp.309-396，edited?by?K.Widder，et?al.(Acamedic?Press，1985)；

B) A Textbook of Drug Design and Development; Edited byKrosgaard-Larsen and H.Bundgaard, Chapter 5, " Design and Application ofProdrugs; " By H.Bundgaard, pp.113-191 (1991); With

C) H.Bundgaard, Advanced Drug Delivery Reviews, Vol.8, pp.1-38 (1992) is incorporated herein by reference every piece in the above document at this.

Formula (I) compound and salt thereof can exist by tautomeric form, and wherein Wasserstoffatoms replaces to other part of molecule, so the chemical bond between the atom is reset in the molecule.It it should be understood that various tautomeric forms, as long as can exist promptly and comprise in the present invention.In addition, the compound of Fa Benming can have trans and cis-isomeride, and can comprise one or more chiral centres, therefore exists with enantiomer and diastereo-isomerism form.The present invention includes the mixture of all these isomer and cis and trans-isomer(ide), the mixture of diastereomer and the racemic mixture of enantiomer (optical isomer).When the configuration of specifically not mentioning compound (or asymmetric carbon) (cis, trans or R or S), be intended to comprise in the above-mentioned isomer any one or more than a kind of mixture of isomers.The preparation method can be with racemic modification, enantiomer or diastereomer as starting raw material.When preparation enantiomerism or diastereo-isomerism product, these products can for example chromatogram or fractional crystallization separate through ordinary method.Compound of the present invention can be free form or hydrated form.

The solvolyte (for example hydrate) that should also be understood that formula (I) compound also within the scope of the invention.Usually, the method for solvation is well known in the art.

Preferred compound

Preferred compound is for to have with compound or its enantiomer, diastereomer, pharmacologically acceptable salt or hydrate in following formula (Ia), (Ib) or formula (Ic) (I) (preceding text) scope:

Selectively, various (Ia), (Ib) or compound (Ic) are preferred.

At various (Ia), (Ib) or (Ic) other preferred compound in the scope, comprise its enantiomer, diastereomer, pharmacologically acceptable salt or hydrate, for having the compound of following characteristic:

R ₄For-AM;

R ₅Be hydrogen or C _1-4Alkyl (R ₅More preferably hydrogen or methyl);

Or R ₄And R ₅Reach the nitrogen-atoms that they connected and form 5,6 or 7 yuan of bicyclic heteroaryls or monocyclic heterocycles basic ring together, or form 7 to 11 yuan of bicyclic heteroaryls or bicyclic heterocycles basic ring, each ring is all chosen wantonly and is substituted with one to three group is T ₁, T ₂And/or T ₃

A is key, C _1-3Alkylidene group, C _2-4Alkenylene, C _2-4Alkynylene ,-C (O)-or-SO ₂-;

M is (i) hydrogen, NR ₁₅R ₁₆, alkyl, alkoxyl group or thiazolinyl; Or (ii) naphthenic base, heterocyclic radical, aryl or heteroaryl, each group is all chosen wantonly and is substituted with one to three group is T ₁, T ₂And/or T ₃

T ₁, T ₂And T ₃Independently be selected from (i) halogen, alkyl, substituted alkyl, thiazolinyl, substituted thiazolinyl, alkynyl, substituted alkynyl, nitro, cyanic acid, SO ₃H, SR ₁₉, S (O) _pR ₂₁, S (O) _pNR ₁₉R ₂₀, NR ₁₉S (O) _pR ₂₁, OR ₁₉, NR ₁₉R ₂₀, NR ₁₉C (=O) ₂₀, NR ₁₉C (=O) NR ₁₉R ₂₀, CO ₂R ₁₉, C (=O) R ₁₉,-O-C (=O) R ₁₉,-C (=O) NR ₁₉R ₂₀, naphthenic base, heterocyclic radical, aryl and heteroaryl, wherein p is 1 or 2; And/or two groups that (ii) are positioned on the adjacent ring atom are T ₁And T ₂And the annular atoms that they connected forms condensed naphthenic base, aryl, heteroaryl or heterocyclic radical together;

R ₁₉, R ₂₀And R ₂₁When occurring, all independently be selected from (i) hydrogen, alkyl, substituted alkyl, thiazolinyl, substituted thiazolinyl, naphthenic base, aryl, heteroaryl and heterocyclic radical at every turn; Or (ii) R ₁₉And R ₂₀And the nitrogen-atoms that they all are attached thereto forms heteroaryl or heterocyclic radical together; And

R ₂₁When occurring, all be selected from alkyl, substituted alkyl, thiazolinyl, substituted thiazolinyl, alkynyl, substituted alkynyl, naphthenic base, aryl, heteroaryl and heterocyclic radical at every turn.

More preferably compound in formula (I) scope comprises its enantiomer, diastereomer, pharmacologically acceptable salt or hydrate, for having the compound of following characteristic:

R ₄For-AM;

A be key ,-C (O)-,-S (O) ₂-or C _1-3(A is key more preferably for alkylidene group; Methylene radical or ethylidene especially are key);

M be (i) hydrogen ,-NH (aryl), C _1-6Alkyl, C _2-4Thiazolinyl or-OC _1-4Alkyl; Or (ii) C _3-6Naphthenic base, phenyl, fluorenyl, 1-naphthyl or 2-naphthyl, each group are all chosen wantonly and be substituted with one to three group is T ₁, T ₂And/or T ₃Or (iii) 5,6 or 7 yuan of monocycles or 7 to 11 yuan of bicyclic heteroaryls or bicyclic heterocycles basic ring, each ring is all chosen wantonly and is substituted with one to three group is T ₁, T ₂And/or T ₃(C more preferably _3-6Naphthenic base or 5,6 or 7 yuan of aryl, heteroaryl or heteroaryl rings, each ring is all chosen wantonly and is substituted with 1 to 3 T ₁, T ₂And/or T ₃, especially be 5,6 or 7 yuan of aryl, heteroaryl or heteroaryl rings, each ring is all chosen wantonly by 1 to 2 T ₁And/or T ₂Replace); And

T ₁, T ₂And T ₃Independently be selected from (i) C _1-4Alkyl, substituted C _1-4Alkyl, C _1-4Alkoxyl group, substituted C _1-4Alkoxyl group, C _1-4Alkylthio, phenoxy ,-NR ₁₉R ₂₀, halogen, hydroxyl, cyanic acid, SO ₃H, COOH ,-C (O) (R ₁₉), C (O) NR ₁₉R ₂₀, NR ₁₉C (O) R ₂₀, S (O) ₂R ₂₁, S (O) ₂NR ₁₉R ₂₀And NR ₁₉(C (O) NR ₁₉R ₂₀And/or (ii) phenyl, cyclopropyl, cyclohexyl, tetrazyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, furyl and morpholinyl, it is R that each in the said group allows former choosing to be substituted with one to three group at valency ₂₂, R ₂₃And/or R ₂₄And/or two groups that (iii) are substituted on the adjacent ring atom are T ₁And T ₂And annular atoms that they connected forms condensed 5 to 7 yuan of naphthenic base, condensed phenyl or condensed 5 or 6 yuan of heterocyclic radicals or heteroaryl together, and it is R that each in the said group allows former choosing to be substituted with one to three group at valency ₂₂, R ₂₃And/or R ₂₄And

R ₁₉And R ₂₀When occurring, all independently be selected from every turn (i) hydrogen ,-(CH ₂) _vOH and C _1-4Alkyl; Or (ii)-(CH ₂) _vCyclohexyl ,-(CH ₂) _vPhenyl ,-(CH ₂) _vMorpholinyl ,-(CH ₂) _vPyridyl ,-(CH ₂) _vPyrazolyl ,-(CH ₂) _vCyclopropyl ,-(CH ₂) _vPyrrolidyl ,-(CH ₂) _vPiperidyl ,-(CH ₂) _vFuryl ,-(CH ₂) _vImidazolyl ,-(CH ₂) _vPyrimidyl ,-(CH ₂) _vPiperazinyl and-(CH ₂) _vPyridazinyl, it is R that each in the said group allows former choosing to be substituted with one to three group at valency ₂₂, R ₂₃And/or R ₂₄Or R ₁₉And R ₂₀And their nitrogen-atoms of all being attached thereto form pyrrolidyl, morpholinyl, piperidyl, pyridazinyl or piperazinyl together, and it is R that each in the said group allows former choosing to be substituted with one to three group at valency ₂₂, R ₂₃And/or R ₂₄

R ₂₁When occurring, all be selected from (i)-(CH at every turn ₂) _vOH and C _1-4Alkyl; Or (ii)-(CH ₂) _vCyclohexyl ,-(CH ₂) _vPhenyl ,-(CH ₂) _vMorpholinyl ,-(CH ₂) _vPyridyl ,-(CH ₂) _vPyrazolyl ,-(CH ₂) _vCyclopropyl ,-(CH ₂) _vPyrrolidyl ,-(CH ₂) _vPiperidyl ,-(CH ₂) _vFuryl ,-(CH ₂) _vImidazolyl ,-(CH ₂) _vPyrimidyl ,-(CH ₂) _vPiperazinyl and-(CH ₂) _vPyridazinyl, it is R that each in the said group allows former choosing to be substituted with one to three group at valency ₂₂, R ₂₃And/or R ₂₄R ₂₂, R ₂₃And R ₂₄When occurring, all independently be selected from (C at every turn _1-4) alkyl, (C _2-4) thiazolinyl, halogen, hydroxyl, cyanic acid, nitro, CF ₃,=O, O (C _1-4Alkyl), OCF ₃, C (=O) H, C (=O) (C _1-4Alkyl), CO ₂H, CO ₂(C _1-4Alkyl), NHCO ₂(C _1-4Alkyl) ,-S (C _1-4Alkyl) ,-NH ₂, NH (C _1-4Alkyl), N (C _1-4Alkyl) ₂, N (C _1-4Alkyl) ₃ ⁺, SO ₂(C _1-4Alkyl), C (=O) (C _1-4Alkylidene group) NH ₂, C (=O) (C _1-4Alkylidene group) NH (alkyl), C (=O) (C _1-4Alkylidene group) N (C _1-4Alkyl) ₂With optional substituted phenyl; And v is 0,1,2 or 3.

In formula (I) scope other be compound more preferably, comprises its enantiomer, diastereomer, pharmacologically acceptable salt or hydrate, for having the compound of following characteristic:

A is key, methylene radical or ethylidene;

M is hydrogen, methoxyl group, phenyl, fluorenyl, pyridyl, cyclopropyl, cyclohexyl, sec.-propyl, ethyl, positive propenyl, isopentyl, n-propyl, normal-butyl, pyrazolyl or pyrimidyl, and each group is all chosen wantonly and is substituted with one or two and is selected from T ₁And T ₂Group; And

T ₁And T ₂Independently be selected from oxyethyl group, methoxyl group, methyl, n-butoxy, phenyl, benzyloxy, dimethylamino, chlorine, iodine, trifluoromethyl, fluorine, hydroxyl, cyanic acid, carboxylic acid, N-methyl-N-(pyridyl ethyl) amido, ethyl tetrazyl, phenoxy, chloro-phenyl-, aminomethyl phenyl, benzyl, morpholinyl, sec.-propyl, n-propyl, normal-butyl, ethyl, isopropoxy, positive propoxy, methylthio group, cyclohexyl, the tertiary butyl, trifluoromethoxy, amino, triazolyl, dichloro-imidazole base, dimethyl pyrazole base, methyl-triazole base, methylimidazolyl, methylthiazol base, methyl furan base, N; N-dimethyl-amido, benzenesulfonyl, morpholinyl alkylsulfonyl, pyrrolidyl alkylsulfonyl, N; N-diethylammonium amido, N-methyl amido, N-sulfonyloxy methyl amino, methanesulfonamido, N; N-dimethyl methyl amido, N; N-diethylammonium sulfonamido, N-sulfonyl propyl amino, N-ethyl sulfonamido, N-sulfonyloxy methyl amino, sulfonamido, amino methyl, amido, N-(furyl methyl) amido, N-(imidazolyl methyl) amido, N-(pyridylmethyl) amido, (Phenylpiperidine base) carbonyl, piperidino carbonyl, N-benzyl amido, N-p-methoxy-phenyl amido, N-phenyl amido, N-(hydroxyethyl) amido, 1-morpholinyl carbonyl, N-(pyridyl) amido, N-(pyridylmethyl) amido, N-(pyridyl ethyl) amido, N, N-diethylammonium amido, N-cyclopropyl amido, N-(cyclohexyl methyl) amido, N-(cyclohexyl) amido, N-(methylpyrazole base) amido, N-((oxo-pyrrolidine base) propyl group) amido, 3-phenylurea and 1-(fluorophenyl)-N-methyl-oxo-dihydropyridine-3-formamido group;

Or be substituted in the T on the adjacent atom of M ₁And T ₂Reach the atom that they connected and form condensed ring together, form thus and be selected from following ring system: indyl, methylbenzothiazole base, naphthyl, skatole base, tetrahydric quinoline group, fluorenyl, quinolyl and dihydro-indazol-ketone-Ji.

Other preferred compound in formula (I) scope comprises its enantiomer, diastereomer, pharmacologically acceptable salt or hydrate, for having the compound of following characteristic:

Y is hydrogen, halogen, OR ₈Or NR ₆R ₇(Y is NR more preferably ₆R ₇);

R ₆Be selected from hydrogen or choose wantonly and be substituted with one to three C that is selected from following group _1-4Alkyl: halogen, C _1-4Alkyl, nitro, cyanic acid, amino, C _1-4Alkoxyl group and OH (R ₆More preferably hydrogen or C _1-4Alkyl);

R ₇And R ₈Independently be selected from alkyl, naphthenic base, heterocyclic radical, aryl and heteroaryl, each in the said group all chosen wantonly and be substituted with one to three group is T ₄, T ₅And/or T ₆(R ₇C more preferably _1-4Alkyl, C _3-6Naphthenic base or 5,6 or 7 yuan of heterocyclic radicals, each group are all chosen wantonly and are substituted with one to three group is T ₄, T ₅And/or T ₆R ₈C more preferably _3-6Naphthenic base is especially for being substituted with the cyclohexyl of following group: C _1-4Alkyl, amino, be substituted with C _1-4The amino of alkyl, substituted C _1-4Alkyl, furyl or piperidyl);

Or R ₆And R ₇Reach the nitrogen-atoms that they connected and form heteroaryl or heterocyclic ring (5,6 or 7 yuan of rings more preferably) together, each ring is all chosen wantonly and is substituted with one to three group is T ₄, T ₅And/or T ₆

T ₄, T ₅And T ₆Independently be selected from (i) halogen, alkyl, substituted alkyl, thiazolinyl, substituted thiazolinyl, alkynyl, substituted alkynyl, nitro, cyanic acid, SR ₁₉, OR ₁₉, NR ₁₉R ₂₀, NR ₁₉C (=O) R ₂₀, CO ₂R ₁₉, C (=O) R ₁₉,-O-C (=O) R ₁₉,-C (=O) NR ₁₉R ₂₀, naphthenic base, heterocyclic radical, aryl and heteroaryl; And/or two groups that (ii) are substituted on the adjacent ring atom are T ₄And T ₅And the annular atoms that they connected forms condensed naphthenic base, heterocyclic radical, aryl or heteroaryl (T together ₄, T ₅And T ₆C more preferably _1-4Alkyl and NR ₁₉R ₂₀); And

R ₁₉And R ₂₀When occurring, all independently be selected from (i) hydrogen, alkyl, substituted alkyl, thiazolinyl, substituted thiazolinyl, naphthenic base, aryl, heteroaryl and heterocyclic radical at every turn; Or (ii) R ₁₉And R ₂₀And the nitrogen-atoms that they all are attached thereto forms heteroaryl or heterocyclic radical together.

Y is NR ₆R ₇

R ₆Be selected from hydrogen or C _1-4Alkyl (R ₆Hydrogen more preferably);

R ₇Be selected from C _1-4Alkyl, cyclopentyl, cyclohexyl, two ring [2.2.2] octyl group, pyrrolidyl and piperidyls, each in the said group all chosen wantonly and be substituted with one to three group is T ₄, T ₅And/or T ₆(R ₇More preferably cyclohexyl and two encircles [2.2.2] octyl groups, and it is T that each group all is substituted with a group ₄);

Or R ₆And R ₇Reach the nitrogen-atoms that they connected and form piperazinyl, piperidyl, pyrrolidyl or diazacyclo heptyl (diazepanyl) together, each in the said group all chosen wantonly and be substituted with one to three group is T ₄, T ₅And/or T ₆(R ₆And R ₇And the nitrogen-atoms that they all are attached thereto more preferably forms unsubstituted piperidines basic ring together); And

T ₄, T ₅And T ₆Independently be selected from (i) C _1-4Alkyl, OH, NH ₂, NH (C _1-4Alkyl), furyl and N (C _1-4Alkyl) ₂And wherein pyrimidyl is substituted with the NH (pyrimidyl) of halogen; Or (ii) be substituted with the C of cyclohexyl or OH _1-4Alkyl, wherein said cyclohexyl is substituted with NH ₂(T ₄, T ₅And T ₆More preferably be selected from NH ₂, NH (C _1-4Alkyl) and (4-NH ₂-cyclohexyl) methyl).

R ₆Be hydrogen;

R ₇Be methyl, ethyl, n-propyl, normal-butyl, cyclopentyl, cyclohexyl, two ring [2.2.2] octane, pyrrolidyl or piperidyls, each in the said group all chosen wantonly to be substituted with and is selected from amino, methyl, aminocyclohexyl methyl, dimethylamino, furyl, ethylamino, methylamino-, piperidyl and (chloropyrimide base) amino T ₄Or

R ₆And R ₇Reach the nitrogen-atoms that they connected and form piperazinyl, piperidyl, pyrrolidyl and diazacyclo heptyl ring together, each ring is all chosen wantonly and is substituted with the T that is selected from amino, hydroxyethyl, amino-pyrroles alkyl and methyl ₄

Other preferred compound; Comprise its enantiomer, diastereomer, pharmacologically acceptable salt or hydrate; Be compound or its enantiomer, diastereomer or the pharmacologically acceptable salt in having formula (Ia), (Ib) or formula (Ic) (I) (preceding text) scope, wherein

Wherein

X is NR ₄R ₅

Y is hydrogen, halogen, OR ₈Or NR ₆R ₇(Y is NR more preferably ₆R ₇);

R ₁And R ₂Independently be selected from hydrogen, halogen, OR ₁₀, cyanic acid, C _1-4Alkyl, CO ₂R ₁₀And C (O) NR ₁₀R ₁₁

R ₃Be selected from (i) hydrogen, halogen, nitro, cyanic acid, OR ₁₀, NR ₁₀R ₁₁, CO ₂R ₁₀And C (=O) R ₁₀Or (ii) C _1-4Alkyl, substituted C _1-4Alkyl, naphthenic base, aryl and heteroaryl;

R ₄For-AM;

R ₅Be hydrogen or C _1-4Alkyl;

M is (i) hydrogen, NR ₁₅R ₁₆, alkyl, alkoxyl group or thiazolinyl; Or (ii) naphthenic base, heterocyclic radical, aryl or heteroaryl, each ring is all chosen wantonly and is substituted with one to three group is T ₁, T ₂And/or T ₃

R ₆Be selected from hydrogen or choose wantonly and be substituted with one to three C that is selected from following group _1-4Alkyl: halogen, C _1-4Alkyl, nitro, cyanic acid, amino, C _1-4Alkoxyl group and OH;

R ₇And R ₈Independently be selected from alkyl, naphthenic base, heterocyclic radical, aryl and heteroaryl, each in the said group all chosen wantonly and be substituted with one to three group is T ₄, T ₅And/or T ₆(R ₈Be preferably C _3-6Naphthenic base, especially be the optional NH that is substituted with ₂, NH (C _1-4Alkyl) and (4-NH ₂-cyclohexyl) cyclohexyl of methyl);

Or R ₆And R ₇Reach the nitrogen-atoms that they connected and form heteroaryl or heterocyclic ring together, each ring is all chosen wantonly and is substituted with one to three group is T ₄, T ₅And/or T ₆

R ₁₀And R ₁₁When occurring, all independently be selected from (i) hydrogen, C at every turn _1-4Alkyl and substituted C _1-4Alkyl; Or (ii) R ₁₀And R ₁₁And the nitrogen-atoms that they all are attached thereto forms optional substituted 5,6 or 7 yuan of heteroaryls or heterocyclic radical together;

R ₁₅And R ₁₆Independently be selected from (i) hydrogen, alkyl, substituted alkyl, thiazolinyl, substituted thiazolinyl, alkynyl, substituted alkynyl, naphthenic base, aryl, heteroaryl and heterocyclic radical; Or (ii) R ₁₅And R ₁₆And the nitrogen-atoms that they connected forms heteroaryl or heterocyclic radical together;

T ₁, T ₂And T ₃Independently be selected from (i) halogen, alkyl, substituted alkyl, thiazolinyl, substituted thiazolinyl, alkynyl, substituted alkynyl, nitro, cyanic acid, SO ₃H, SR ₁₉, S (O) _pR ₂₁, S (O) _pNR ₁₉R ₂₀, NR ₁₉S (O) _pR ₂₁, OR ₁₉, NR ₁₉R ₂₀, NR ₁₉C (=O) ₂₀, NR ₁₉C (=O) NR ₁₉R ₂₀, CO ₂R ₁₉, C (=O) R ₁₉,-O-C (=O) R ₁₉,-C (=O) NR ₁₉R ₂₀, naphthenic base, heterocyclic radical, aryl and heteroaryl, wherein p is 1 or 2; And/or two groups that (ii) are positioned on the adjacent ring atom are T ₁And T ₂And the annular atoms that they connected forms condensed naphthenic base, aryl or heteroaryl or heterocyclic radical together;

T ₄, T ₅And T ₆Independently be selected from (i) halogen, alkyl, substituted alkyl, thiazolinyl, substituted thiazolinyl, alkynyl, substituted alkynyl, nitro, cyanic acid, SR ₁₉, OR ₁₉, NR ₁₉R ₂₀, NR ₁₉C (=O) R ₂₀, CO ₂R ₁₉, C (=O) R ₁₉,-O-C (=O) R ₁₉,-C (=O) NR ₁₉R ₂₀, naphthenic base, heterocyclic radical, aryl and heteroaryl; And/or two groups that (ii) are substituted on the adjacent ring atom are T ₄And T ₅And the annular atoms that they connected forms condensed naphthenic base, heterocyclic radical, aryl or heteroaryl together; And

R ₁₉And R ₂₀When occurring, all independently be selected from (i) hydrogen, alkyl, substituted alkyl, thiazolinyl, substituted thiazolinyl, naphthenic base, aryl, heteroaryl and heterocyclic radical at every turn; Or (ii) R ₁₉And R ₂₀And the nitrogen-atoms that they all are attached thereto forms heteroaryl or heterocyclic ring together; And

R ₂₁When occurring, all be selected from alkyl, substituted alkyl, thiazolinyl, substituted thiazolinyl, alkynyl, substituted alkynyl, naphthenic base, aryl, heteroaryl and heterocyclic radical at every turn;

It has following restricted condition:

(2) if E is that N, F are that C, Z are that N and Y are NR ₆R ₇:

NH (substituted piperidines) or NH (CH ₂-pyridine);

(c) and if X be NH (cyclopentyl), then Y is not NH (cyclopentyl);

Or

(e) and if X be NH (substituted phenyl), then Y is not

Preferred especially compound comprises its enantiomer, diastereomer, pharmacologically acceptable salt or hydrate, is the compound in having formula (Ia), (Ib) or formula (Ic) (I) (preceding text) scope, wherein

R ₁And R ₂Independently be selected from hydrogen, halogen, OR ₁₀, cyanic acid, C _1-4Alkyl, CO ₂R ₁₀With-C (O) NR ₁₀R ₁₁(R ₁More preferably be selected from hydrogen and C _1-4Alkyl especially is hydrogen and methyl; R ₂More preferably be selected from hydrogen, halogen, cyanic acid, nitro, alkoxyl group, hydroxyl, C (O) NH ₂(be substituted with the N of following group, the dibasic amido of N-: (i) hydrogen with substituted amido; And/or (ii) one or two is selected from alkyl, thiazolinyl, C _3-7Naphthenic base, phenyl, benzyl, styroyl, naphthyl, four are to seven membered heterocyclic base and five groups to six membered heteroaryl; Or (iii) two groups can combine to form heterocyclic radical or heteroaryl when connecting same nitrogen-atoms); R ₂Especially be hydrogen, cyanic acid, fluorine or C (O) NH ₂);

R ₃Be selected from (i) hydrogen, halogen, nitro, cyanic acid, OR ₁₀, NR ₁₀R ₁₁, CO ₂R ₁₀And C (=O) R ₁₀Or (ii) C _1-4Alkyl, naphthenic base, aryl and heteroaryl, each in the said group all are optional substituted (R ₃More preferably be hydrogen, halogen, C _1-4Alkyl and aryl especially are hydrogen, chlorine, methyl, ethyl, sec.-propyl and phenyl); And

R ₁₀And R ₁₁Independently be selected from (i) hydrogen, C _1-4Alkyl and substituted C _1-4Alkyl (preferably is substituted by one to three and independently is selected from hydrogen, halogen, nitro, cyanic acid, OH, phenyl and OC _1-4The group of alkyl); Or (ii) R ₁₀And R ₁₁And the nitrogen-atoms that they all are attached thereto forms optional substituted 5,6 or 7 yuan of heteroaryls or heterocyclic radical together.

Even more preferred compound, comprise its enantiomer, diastereomer, pharmacologically acceptable salt or hydrate, be the compound in having formula (Ia), (Ib) or formula (Ic) (I) (preceding text) scope, wherein NR ₄R ₅Be selected from:

Selectable even more preferred compound comprises its enantiomer, diastereomer, pharmacologically acceptable salt or hydrate, is the compound in formula (I) scope, wherein NR ₆R ₇Be selected from: NH-(CH ₂) ₂-NH ₂, NH-(CH ₂) ₄-NH ₂,

Other preferred compound or its enantiomer, diastereomer or pharmacologically acceptable salt in formula (I) scope, wherein

R ₄Be selected from C _3-6Naphthenic base, 5,6 or 7 yuan of aryl, heteroaryls or optionally be substituted with 1 to 3 and be selected from T ₁, T ₂And T ₃The heteroaryl ring of group.(R ₄More preferably be selected from phenyl, pyridyl, pyrimidyl, cyclohexyl and piperidyl, each group is all chosen wantonly and is substituted with 1 to 2 group is T ₁And/or T ₂Preferably, T ₁And/or T ₂Be selected from oxyethyl group, methoxyl group, methyl, ethyl, n-butoxy, phenyl, benzyloxy, dimethylamino, chlorine, iodine, trifluoromethyl, fluorine, hydroxyl, cyanic acid, carboxylic acid, N-methyl-N-(pyridyl ethyl) amido, ethyl tetrazyl, phenoxy, chloro-phenyl-, aminomethyl phenyl, benzyl, morpholinyl, sec.-propyl, n-propyl, normal-butyl, ethyl, isopropoxy, positive propoxy, methylthio group, cyclohexyl, the tertiary butyl, chlorine, trifluoromethoxy, amino, triazolyl, dichloro-imidazole base, dimethyl pyrazole base, methyl-triazole base, methylimidazolyl, methylthiazol base, methyl furan base, N; N-dimethyl-amido, morpholinyl alkylsulfonyl, pyrrolidyl alkylsulfonyl, N; N-diethylammonium amido, N-methyl amido, N-sulfonyloxy methyl amino, N-sulfonyloxy methyl amino, methanesulfonamido, N; N-dimethyl methyl amido, N; N-diethylammonium sulfonamido, N-sulfonyl propyl amino, N-ethyl sulfonamido, N-sulfonyloxy methyl amino, sulfonamido, amino methyl, amido, N-(furyl methyl) amido, N-(imidazolyl methyl) amido, N-(pyridylmethyl) amido, (Phenylpiperidine base) carbonyl, piperidino carbonyl, N-benzyl amido, N-p-methoxy-phenyl amido, N-phenyl amido, N-(hydroxyethyl) amido, 1-morpholinyl carbonyl, N-(pyridyl) amido, N-(pyridylmethyl) amido, N-(pyridyl ethyl) amido, N, N-diethylammonium amido, N-cyclopropyl amido, N-(cyclohexyl methyl) amido, N-(cyclohexyl) amido, N-(methylpyrazole base) amido, N-((oxo-pyrrolidine base) propyl group) amido, phenylurea and 1-(fluorophenyl)-N-methyl-oxo-dihydropyridine-3-formamido group);

Or be positioned at the T on the adjacent atom of M ₁And T ₂Reach the atom that they connected and form condensed ring together, form thus and be selected from the following ring system that condenses: indyl, methylbenzothiazole base, naphthyl, skatole base, tetrahydric quinoline group, fluorenyl, quinolyl and dihydro-indazol-ketone-Ji.

Other preferred compound comprises its enantiomer, diastereomer, pharmacologically acceptable salt or hydrate, is the compound in formula (I) scope, wherein NR ₆R ₇Be selected from:

The all respects of preferred compound comprise variable separately definition, can make up with others, to form other preferred compound.

The preparation method

Compound of the present invention can be through being that exemplary method described in the A to E prepares in following reaction scheme.The exemplary reagent and the method that are used for these reactions are recited in hereinafter.Starting raw material is purchased, or those of ordinary skills can easily prepare said starting raw material.Those skilled in the art can use known method to come the method for scheme is made amendment.With regard to all schemes, except as otherwise noted, R ₁And R ₂Such as the application with regard to formula (I) compound description.Those of ordinary skills can easily select to be often referred to and be decided to be R ', R ", Z, P ' and P " group and suitable solvent, temperature, pressure, starting raw material (having desired substituent starting raw material) and other reaction conditions.What expect is that under possible situation, those of ordinary skills can further process the product of reaction scheme hereinafter described.

Wherein E=C and F=N and Z=CR ₃General formula (I) (being formula (Ia)) compound can described in option A, B and C, prepare like hereinafter.

Option A

In alcohol property solvent (such as ethanol), make the 3-amino-4 of easy preparation, 6-dihalo pyridazine 1With the 2-halogenated aldehyde or the 2-halogenated ketone that are purchased or prepare easily 2Or its Equivalent condensation, obtain 6,8-dihalo imidazo [1,2-b] pyridazine 3In suitable solvent (such as N-Methyl pyrrolidone or alcohol), under the situation that has appropriate base (such as triethylamine or cesium carbonate), make 3With the amine reaction, obtain 6-halo imidazo [1,2-b] pyridazine 4Selectively, in suitable solvent (such as N or THF) and suitable alkali (such as sodium hydride), make 3With non-reacted nucleophilic reagent (non-reactivenucleophile) (such as the aniline of electron deficiency) reaction, can obtain formula 4Compound.Under purified condition, or in solvent (such as N-Methyl pyrrolidone), under the situation that has appropriate base (such as cesium carbonate), make 6-halo imidazo [1,2-b] pyridazine 4 and nucleophilic reagent (such as amine) reaction, obtain imidazo [1,2-b] pyridazine (Ia).

Option b

Formula (Ia) compound also can obtain through following method: in suitable solvent (such as chloroform or acetonitrile); With halogenating agent (such as NBS, NCS, NIS, Selectfluor (electrophilic fluorizating agent)) handle as described in option A, prepare 6,8-dihalo imidazo [1,2-b] pyridazine 3; Obtain corresponding 3; 6,8-three halo imidazos [1,2-b] pyridazine 5In suitable solvent (such as N-Methyl pyrrolidone or alcohol), under the situation that has appropriate base (such as triethylamine or cesium carbonate), make 5With the amine reaction, obtain 3,6-dihalo imidazo [1,2-b] pyridazine 6Selectively, in suitable solvent (such as N or THF) and suitable alkali (such as sodium hydride), make 5With non-reacted nucleophilic reagent (such as the aniline of electron deficiency) reaction, can obtain formula 6Compound.Under purified condition, or in solvent (such as N-Methyl pyrrolidone 、 diox), under the situation that has appropriate base (such as cesium carbonate), have or the situation of catalyst-free (such as acid chloride) under, make 6-halo imidazo [1,2-b] pyridazine such as 6With the amine reaction, obtain imidazo [1,2-b] pyridazine (Ia).Selectively, those skilled in the art can use aryl halide is changed into a kind of in the several different methods of other functional group, come easily to make 3,6-dihalo imidazo [1,2-b] pyridazine 63 transform, obtain 6-halo imidazo [1,2-b] pyridazine such as 7, R wherein ₂It is not halogen.Can come further to be processed in R through known method ₂The new functionality of introducing (functionality) in place obtains other analogue.Under purified condition, or in solvent (such as N-Methyl pyrrolidone 、 diox), exist under the situation of appropriate base (such as cesium carbonate), have or the situation of catalyst-free (such as acid chloride) under, make 6-halo imidazo [1,2-b] pyridazine such as 7With nucleophilic reagent (such as amine or alcohol) reaction, obtain imidazo [1,2-b] pyridazine (Ia).

Scheme C

Formula (Ia) compound also can obtain through following method: in suitable solvent (such as ethanol) and suitable alkali (such as triethylamine), handle imidazo [1,2-b] pyridazine with nucleophilic reagent (such as amine) 8, obtain imidazo [1,2-b] pyridazine 9Referring to for example Synthesis Vol.8 (1971) at pp 424.Make imidazo [1,2-b] pyridazine 9With nucleophilic reagent (such as amine) reaction, obtain imidazo [1,2-b] pyridazine 7Under hydrogen pressure (such as 55psi), in suitable solvent (such as ethanol), handle imidazo [1,2-b] pyridazine with appropriate catalyst (such as platinum oxide) 10, obtain imidazo [1,2-b] pyridazine (Ia), wherein R ₁, R ₂And R ₃Independently be selected from H and Cl.

Wherein the general formula of E=N, F=C and Z=N (I) (being formula (Ib)) compound can be as preparing described in scheme D.

Scheme D

In suitable solvent (such as diox), handle method for preparation of pyrazolotriazine with nucleophilic reagent (such as amine) 11, obtain method for preparation of pyrazolotriazine 12Referring to for example Journal of Heterocyclic Chemistry Vol.11 (2) (1974) at pp.199.In suitable solvent (such as DMF), (such as MCPBA) handles method for preparation of pyrazolotriazine with suitable oxygenant 12, obtain method for preparation of pyrazolotriazine 13Under purified condition, handle method for preparation of pyrazolotriazine with nucleophilic reagent (such as amine) 13, obtain method for preparation of pyrazolotriazine (Ib).

Wherein the general formula of E=C, F=N and Z=N (I) (being formula (Ic)) compound can be as preparing described in scheme E.

Scheme E

Under purified condition, handle imidazo-triazine with nucleophilic reagent (such as amine) 14, obtain imidazo-triazine 15Referring to for example Journal of The Chemical Society, Perkins Transactions I, Vol.20 (1999) at pp.2929.In suitable solvent (such as DMF), (such as MCPBA) handles imidazo-triazine with suitable oxygenant 15, obtain method for preparation of pyrazolotriazine 16Under purified condition, handle imidazo-triazine with nucleophilic reagent (such as amine) 16, obtain imidazo-triazine (Ic).

Purposes

Compound of the present invention is regulated kinase activity, comprises regulating MAPKAP kinases-2 (MK2).The kinase activity of other type can be regulated through compound of the present invention, includes but not limited to AKT1, AKT2, AKT3, DMPK1, MRCKA, GPRK4, GPRK5, GPRK6, NDR2, PKACA, PKACB, PRKX, PKACA, PDK1, PKCA, PKCD, PKCT, PKCH, PKCI, PKCZ, PKG1, PKG2, PKN2, MSK1, MSK2, RSK1, RSK2, RSK4, YANK2, YANK3, ADCK3, ADCK4, CAMK1A, CAMK1d, CAMK1G, CAMK2A, CAMK2B, CAMK2D, CAMK2G, AMPKA1, AMPKA2, BRSK2, LKB1, MARK1, MARK2, MARK4, QIK, STK33, DAPK2, DAPK3, DRAK1, DRAK2, DCAMKL3, MNK2, SKMLCK, PHKG1, PHKG2, PIM1, PIM2, CK1A2, CK1d, CK1E, CK1G1, CK1G2, CDK2, CDK2, CDK5, CDK5, PCTAIRE1, CLK1, CLK2, CLK3, CLK4, GSK3A, GSK3B, GSK3B, ERK1, ERK2, JNK1, JNK2, JNK3, NLK, P38A, P38B, P38G, SRPK1, AURA, AURB, AURC, CAMKK1, CAMKK2, CK2A1, CK2A2, IKKB, AAK1, BIKE, GAK, MPSK1, NEK2, NEK6, NEK7, NEK9, GCN2, PLK1, PLK3, PLK4, TLK1, TLK2, TTK, FUSED, ULK3, MYT1, MAP3K4, MAP3K5, HPK1, KHS1, KHS2, ZC1/HGK, ZC2/TNIK, MST1, MST2, PAK1, PAK2, PAK3, PAK4, PAK5, PAK6, LOK, SLK, MST3, MST4, YSK1, ABL, ARG, ACK, TNK1, ALK, LTK, AXL, MER, TYRO3, CSK, DDR2, EGFR, HER2/ERBB2, HER4/ERBB4, EPHA 1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHB1, EPHB2, EPHB3, EPHB4, FAK, PYK2, FER, FES, FGFR1, FGFR2, FGFR3, FGFR4, IGF1R, INSR, IRR, IGF1R, INSR, JAK1, JAK2, TYK2, JAK2, MET, MUSK, FLT3, FMS, KIT, PDGFRA, PDGFRB, FLT3, RET, ROS, BLK, BRK, FGR, FRK, FYN, HCK, LCK, LYN, SRC, YES, LCK, SYK, ZAP70, BMX, BTK, ITK, TXK, TIE2, TRKA, TRKB, TRKC, TRKA, TRKB, FLT1, FLT4, KDR, LIMK1, LIMK2, TESK1, HH498, MLK3, BRAF, BRAF, RAF1, RIPK2, ALK1, ALK2, ALK4, BMPR1A, TGFBR1, ACTR2, ACTR2B and their two mutants.

Therefore, formula (I) compound has purposes in relevant especially relevant with the selectivity inhibition MK2 activity illness with the adjusting kinase activity of treatment.These illnesss comprise wherein conducts the disease of regulating cytokine levels through the intracellular signal via p38 approach (MK2 is as the downstream kinase substrate), especially with the relevant disease of excessive generation of cytokine IL-1, IL-6, IL-8, IFN γ and TNF-α.Responsiveness (responsive) measure or preventive measures contained in the employed term of the application " treatment "; Or contain responsiveness measure and preventive measures, for example be designed to suppress or postpone disease or illness outbreak, realize reducing wholly or in part and/or being designed to alleviate, improving, alleviate or the measure of cure diseases or illness and/or its symptom of symptom or morbid state.

In view of the activity of formula (I) compound as the MK2 selective depressant; Can formula (I) compound be used to treat the cytokine associated conditions; Include but not limited to inflammatory diseases respectively, such as segmental enteritis (Crohn ' s disease) and ulcerative colitis, asthma, graft versus host disease, chronic obstructive pulmonary disease; Autoimmune disorder is such as Graves disease (Grave ' s disease), rheumatoid arthritis, systemic lupus erythematous, psoriasis; Destructive osteopathia (destructive bone disorder) is such as bone-resorbing disease (bone resorption disease), osteo-arthritis, osteoporosis, multiple myeloma related bone disease; Proliferative disease (proliferative disorder) is such as acute myelogenous leukemia, chronic lymphocytic leukemia; Angiogenic disease (angiogenic disorder) is such as the angiogenic disease that comprises solid tumor, eye neovascularization and children's vascular tumor (infantile haemangioma); Communicable disease is such as sepsis (sepsis), septic shock (septic shock) and shigellosis; Neurodegenerative disease is such as alzheimer's disease, Parkinson's disease (Parkinson ' s disease), the caused cerebral ischemia of traumatic damage or neurodegenerative disease; Tumour and virus disease are such as metastatic melanoma, Kaposi sarcoma (Kaposi ' s sarcoma), multiple myeloma and HIV infects and the CMV retinitis, AIDS.

More specifically, available The compounds of this invention particular condition of treating or disease include but not limited to pancreatitis (acute or chronic), asthma, transformation reactions, adult respiratory distress syndrome, chronic obstructive pulmonary disease, glomerulonephritis, rheumatoid arthritis, systemic lupus erythematous, scleroderma, chronic thyroiditis, Graves disease, autoimmunity gastritis (autoimmune gastritis), mellitus, autoimmune hemolytic anemia, autoimmune neutropenia (autoimmuneneutropenia), thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel, ulcerative colitis, segmental enteritis, psoriasis, graft versus host disease, Inflammatory response that intracellular toxin brought out, white plaque, atherosclerosis, myodegeneration (muscle degeneration), emaciation, arthritic psoriasis, reiter syndrome (Reiter ' ssyndrome), gout, traumatic arthritis, rubella arthritis, acute synovitis, pancreatic beta cell disease (pancreatic β-cell disease); Be characterized as the disease of a large amount of neutrophilic infiltrations; Rheumatoid spondylitis; Urarthritis and other disorder of joint; Cerebral malaria; Chronic pneumonia disease (chronicpulmonary inflammatory disease); Silicosis; Sarcoidosis of lung (pulmonary sarcoisosis); Bone-resorbing disease; Allograft rejection; Infect caused fever and myalgia; Be secondary to the emaciation of infection; Meloid formation; Scar tissue forms; Ulcerative colitis; Pyreticosis (pyresis); Influenza; Osteoporosis; Osteo-arthritis; Acute myeloid leukaemia; Chronic lymphocytic leukemia; Metastatic melanoma; Kaposi sarcoma; Multiple myeloma; Sepsis; Septic shock and shigellosis; Alzheimer's disease, Parkinson's disease, the caused cerebral ischemia of traumatic damage or refreshing degenerative disorders; Angiogenic disease comprises solid tumor, eye neovascularization and children's vascular tumor; Virus disease comprises that acute hepatitis infects (comprising hepatitis A, hepatitis B and hepatitis C), HIV infects and the CMV retinitis, AIDS, ARC or malignant tumour and bleb; Apoplexy; Myocardial ischemia; Ischemic in the apoplexy heart attack (stroke heart attack); Organ anoxic (organ hyposia); Vascular hyperplasia (vascular hyperplasia); Heart and kidney reperfusion injury; Thrombosis; Cardiac hypertrophy; The platelet aggregation that zymoplasm brings out; Inner toxemia and/or toxic shock syndrome; With relevant illness and the pemphigus vulgaris of prostaglandin(PG) endoperoxidase synthase-2 (prostaglandin endoperoxidase syndase-2).Preferred treat-ment is that wherein illness is selected from following treat-ment: segmental enteritis and ulcerative colitis, allograft rejection, rheumatoid arthritis, psoriasis, ankylosing spondylitis, arthritic psoriasis and pemphigus vulgaris person.Selectable preferred therapeutic method is that wherein illness is selected from following treat-ment: ischemical reperfusion injury comprises the caused cerebral ischemia re-pouring injured and caused heart ischemia reperfusion damage of myocardial infarction of apoplexy.Another kind of preferred treat-ment is that wherein illness is the treat-ment of multiple myeloma.

In addition, MK2 suppressor factor of the present invention suppresses derivable proinflammatory protein (such as the expression of prostaglandin endoperoxide synthase-2 (prostaglandin endoperoxide synthase-2 PGHS-2) (is also referred to as cyclooxygenase-2 (COX-2))).Therefore, other MK2 associated conditions comprises oedema, aponia, fever and pain (such as neuromuscular pain, headache, the caused pain of cancer, toothache and arthritis ache).Also can compound of the present invention be used to treat veterinary science virus infection (such as slow virus infection), these veterinary science virus infectiones include but not limited to equine infectious anemia virus (anemia virus) or retroviral infection (comprising feline immunodeficiency virus, bovine immunodeficiency virus and dog immunodeficiency virus).

When the application used a technical term " MK2 associated conditions " or " MK2 relative disease or illness ", each in these terms all was intended to contain preceding text determined repeatedly various illnesss and any other illness of influenced by the MK2 kinase activity in detail.

Therefore, the present invention is provided for treating the method for these illnesss, comprises that at least a formula (I) compound or its salt with the treatment significant quantity needs its patient." treatment significant quantity " is intended to comprise the amount that when individually dosed or administation of combination, effectively suppresses the The compounds of this invention of MK2.

The method of treatment MK2 kinases associated conditions can comprise separately or come giving construction (I) compound with combination with one another and/or with other mode that is used to treat the appropriate therapeutic agent combination of these illnesss.Therefore, " treatment significant quantity " also be intended to comprise the amount of combination of effective inhibition MK2 of the compound of prescription protection.Combination of compounds is preferably synergistic combination.The effect (of the present invention situation under be restraining effect to P2Y1) of compound when administation of combination greater than compound as single medicine and the accumulative action when individually dosed; Synergy appears this moment (for example at Chou and Talalay; Adv.Enzyme Regul.1984 makes description among the 22:27-55).Usually, at the suboptimal concentration of compound, synergy shows the most obviously.With each ratio of component, synergy can have following performance: lower cytotoxicity, the anti-thrombosis function of increase or some other useful compound actions.

The substituted imidazo of 4-[1, the 2-A] quinoxaline that the exemplary embodiment of these other therapeutical agents comprises cortical steroid, rolipram, presses down kinases plain (calphostin), cell factor inhibiting anti-inflammatory agent (CSAID), USP 4,200,750 is disclosed; Interleukin-10, glucocorticosteroid, salicylate (salt), nitrogen oxide and other immunosuppressor; The nuclear translocation suppressor factor, and all deoxidation spergualins (deoxyspergualin, DSG); NSAIDs (NSAID) is such as Ibuprofen BP/EP, celecoxib and rofecoxib; Steroid is such as prednisone or DEXAMETHASONE BP98; Antiviral drug is such as Abacavir; Antiproliferative pharmaceutical is such as methotrexate, leflunomide, FK506 (tacrolimus, Prograf); Cytotoxic drug is such as azathioprine and endoxan; TNF-alpha inhibitor (such as tenidap), anti-TNF antibodies or soluble TNF acceptor and rapamycin (sirolimus or Lei Paming) or derivatives thereof.

When uniting use with compound of the present invention, other therapeutical agent of preceding text can use by following amount: the amount of for example in Physicians ' Desk Reference (PDR), being indicated or determined other amount of those of ordinary skills.In the method for the invention, other therapeutical agent of this type (or multiple other therapeutical agent) can or give after giving The compounds of this invention before giving The compounds of this invention, with the The compounds of this invention while.The present invention also provides and can treat the pharmaceutical composition that MK2 kinases associated conditions as stated comprises the illness that IL-1, IL-6, IL-8, IFN γ and TNF-α are mediated.

Compsn of the present invention can comprise aforesaid other therapeutical agent; And can prepare:, use conventional solid or liquid vehicle or thinner and be suitable for the medicinal additive type (for example vehicle, tackiness agent, sanitas, stablizer, spices etc.) of desired mode of administration for example according to well-known technology in the medicinal prepns field through following method.

Therefore, the present invention also comprises the compsn that contains one or more formulas I compound and pharmaceutically acceptable carrier.

" pharmaceutically acceptable carrier " refers in the art just biologically active substance to be sent to the common medium of accepting with regard to the animal (especially Mammals).Pharmaceutically acceptable carrier is prepared according to controlled a plurality of factors in those of ordinary skills' limit of power.These factors include but not limited to: the type of the active substance of being prepared and character; Wait to contain the study subject of drug composition; The compsn route of administration of wanting; Treatment indication with target.Pharmaceutically acceptable carrier comprises water-based and non-aqueous liquid medium and multiple solid and semisolid dosage form.Except that active substance, these carriers can comprise multiple different components and additive, owing to multiple reason well known to those of ordinary skill in the art, for example in order to make active substance, tackiness agent etc. stable, these extra compositions are included in the preparation.In the multiple resource that is easy to obtain, for example at Remington ' s Pharmaceutical Sciences, 17th ed., in 1985, suitable pharmaceutically acceptable carrier has been described and when selecting them related factor, at this it is incorporated herein by reference in full.

Formula (I) compound can be through being suitable for treating that sanatory any means gives, the amount that this can be depending on the needs of loci Idiotype treatment or treats delivering drugs.Topical is normally preferred for skin related disease, and whole body therapeutic is normally preferred for cancer or precancerosis disease, though also comprise other delivery modality.For example, compound of the present invention can be such as coming oral delivery by following form: tablet, capsule, granule, powder agent or liquid preparation (comprising syrup); Such as coming local delivery: solution, suspensoid, gelifying agent or ointment by following form; Send in the hypogloeeis; (bucally) sends in the oral cavity; Non-ly send such as coming: subcutaneous, intravenously, intramuscular or breastbone inner injection or the infusion techn form of aseptic injection aqueous solution non-aqueous solution or suspension-s (for example with) through intestines through following technology; Such as coming nasal delivery there through sucking spraying; Such as coming local delivery with the form of ointment or ointment; Such as coming rectum to send with the form of suppository; Or send with the form of liposome.The dosage unit preparations that can comprise nontoxic pharmaceutically acceptable carrier or thinner.Compound of the present invention can come administration by the form that is suitable for discharging immediately or postpone to discharge.Discharge immediately or postpone to discharge available suitable pharmaceutical compositions and realize, especially under the situation that postpones release, realize with device such as hypodermic implant or osmotic pump.

The exemplary composition that is used for topical comprises topical vehicle, such as

(with the MO (mineral oil) of Vilaterm gelling).

The exemplary composition that is used for oral administration comprises suspensoid; Said suspensoid can comprise and for example be used to obtain volumetrical Microcrystalline Cellulose (microcrystalline cellulose for imparting bulk), as the alginic acid (alginic acid) of suspending agent or sodium alginate (sodium alginate), as methylcellulose gum and the sweetener or the seasonings of thickening material, such as be known in the art those; The exemplary composition that is used for oral administration comprises quick-release tablet; Said quick-release tablet can comprise for example Microcrystalline Cellulose, Lin Suanergai, starch, Magnesium Stearate and/or lactose and/or other vehicle, tackiness agent, swelling agent, disintegrating agent, thinner and lubricant, such as be known in the art those.Also can pass through hypogloeeis or orally administering, for example send compound of the present invention with molded tablet, compressed tablets or lyophilize tablet.Exemplary compsn can comprise rapidly-soluble thinner, such as N.F,USP MANNITOL, lactose, sucrose and/or Schardinger dextrins.In addition; Being included in these preparations can be the HMW vehicle, such as Mierocrystalline cellulose

or polyoxyethylene glycol (PEG); The vehicle that helps mucous membrane to adhere to is such as hydroxypropylcellulose (HPC), Vltra tears (HPMC), Xylo-Mucine (SCMC) and/or copolymer-maleic anhydride (for example

); With the material that is used for sustained release, such as acrylic copolymer (CARBOPOL

).For the ease of preparation and use, also can add lubricant, glidant, spices, tinting material and stablizer.

The exemplary composition that is used for nose aerosol or inhalation comprises solution; Said solution can comprise phenylcarbinol for example or other suitable sanitas, increase and absorb and/or absorption enhancer and/or other solubilizing agent or the dispersion agent of bioavailability, such as be known in the art those.

Be used for non-exemplary composition and comprise Injectable solution or suspension-s through enteral administration; Said Injectable solution or suspension-s can comprise for example suitable nontoxic non-through intestines acceptable diluent or solvent; Such as N.F,USP MANNITOL, 1,3 butylene glycol, water, Ringer's solution (Ringer ' s solution), isotonic sodium chlorrde solution or other suitable dispersion agent or wetting agent and suspending agent (comprising synthetic direactive glyceride or two glyceryl ester and lipid acid (comprising oleic acid)).

The exemplary composition that is used for rectal administration comprises suppository; Said suppository can comprise for example suitable non-irritating vehicle, and such as theobroma oil, synthetic glyceryl ester or polyoxyethylene glycol, these vehicle are solid at normal temperature; But liquefaction and/or dissolving in rectal tract, thereby discharge medicine.

Those of ordinary skills can confirm the treatment significant quantity of The compounds of this invention; Said treatment significant quantity comprises the exemplary dosage of about 0.05-1000mg active compound/kg body weight/day, 1-1000mg active compound/kg body weight/day, 1-50mg active compound/kg body weight/day, 5-250mg active compound/kg body weight/day, 250-1000mg active compound/kg body weight/day with regard to Mammals; Said exemplary dosage can give by single dose, or gives by each broken dose such as 1 to 4 time/day.It should be understood that; Given dose level and administration frequency with regard to arbitrarily concrete study subject can change; This depends on multiple factor, comprises the severity of species, age, body weight, general health, sex and diet, mode of administration and time, discharge rate, drug combination and concrete illness of metabolic stability and effect duration, the study subject of the activity of employed specific compound, said compound.The preferred study subject of receiving treatment comprises animal, most preferably is mammalian species, such as human and performing animal (such as dog, cat, horse etc.).Therefore, when the application used a technical term " patient ", said term was intended to comprise and receives all study subjects that the MK2 enzyme level is regulated to be influenced, most preferably is mammalian species.

in following mensuration or multinomial in tested formula (I) embodiment of explanation in " embodiment " part hereinafter, these embodiment have IC as the suppressor factor of MK2 enzyme ₅₀Less than 30 μ M preferably less than the activity of 10 μ M; And these embodiment with less than 100 μ M preferably less than the IC of 30 μ M ₅₀Suppress TNF-α.

Biological assay

Produce activatory MK2 kinases

Synthesized DNA oligonucleotide PCR primer, and used it for from the MK2 dna sequence dna (NCBIRefseq NM_032960.2) of template DNA amplification coding natural amino acid residue (native amino acid residue) 47-400.Become to make the DNA that is increased also to be coded in zymoplasm cleavable joint N-before terminal (His) said PCR design of primers ₆-affinity purification label.This amplified production is inserted in the pET28N carrier.With MK2 (47-400)-pET28N plasmid transformation escherichia coli BL21 (DE3) bacterial strain, cultivate in defined medium at 37 ℃ then.IPTG (0.5mM) is added to substratum, induced expression of recombinant proteins 18 hours at 20 ℃.Cell mass (cell paste) is collected through depositing, and is freezing at-80 ℃.

The refrigerated cell mass is thawed, use Micro Fluid appearance (microfluidizer) that it is dissolved in the damping fluid at 4 ℃.MK2 albumen comes purifying through the order chromatogram on SP-Sepharose Fast Flow chromatographic column and Ni-NTASuperflow chromatographic column.N-terminal (His) ₆-label is removed from the MK2 albumen of purifying through next being followed successively by benzamidine-agarose and Superdex 200 size exclusion chromatographies with zymoplasm digestion.

With MK2 (47-400) dialysis, then at damping fluid (20mM HEPES (pH is 7.5), 5% glycerine, 2mM DTT, 20mM MgCl ₂, 1mM ATP, 8 μ g/ml activatory (His) ₅-p38 α) in it is diluted to MK2 (47-400) and is the end reaction damping fluid of 0.5mg/ml.To be reflected at 25 ℃ and hatch 1 hour, add the fresh ATP of other 1mM after this.Hatched again 30 minutes at 25 ℃, react afterwards through following method and stop: reaction is placed on ice, add NaCl and EDTA to 200mM and 30mM then respectively.

Protein in the priming reaction is concentrated, filter, then buffer-exchanged is become another kind of damping fluid (25mM HEPES (pH is 7.2), 400mM NaCl, 20mM imidazoles, 5% glycerine, 10mM 2 mercapto ethanol, 0.5mM TCEP).The void volume peak that derives from SP-Sepharose Fast Flow chromatographic column (void volume peak) concentrated, be loaded into then and catch (His) on the Ni-NTA chromatographic column ₅-p38 albumen.Activatory MK2 (47-400) albumen is not retained, and is eluted in the outflow cut (flow-throughfraction).The cut that will comprise activation MK2 (47-400) compiles, and replenishes with 10mM EDTA, concentrates; Be loaded into Superdex 200 chromatographic columns then (with damping fluid (20mM HEPES (pH is 7.5), 100mM NaCl, 10% (v/v) glycerine; 0.1mM EDTA, 2mM DTT) come balance) on.Activatory MK2 (47-400) albumen compiles the cut at the center that derives from said peak with the form wash-out at single big peak, and it such as is divided at separatory, and is freezing at-80 ℃ then.

MK2 measures

The MK2 radioactivity measurement carries out in non-binding XPS at the bottom of 96 hole circles (Corning 3605).Final to measure volume be 30 μ l, and it forms through following method: the mensuration damping fluid (20mM HEPES (pH is 7.5), 25mM β-Phosphoric acid glycerol esters (β-glycerolphosphate), the 15mMMgCl that add 10 μ l enzymes ₂, 1mM DTT), add the mensuration damping fluid of 10 μ l substrates (HSP-27 and ATP) and add the mensuration damping fluid of 10 μ l test compounds.To be reflected at RT and hatch 30min, and add to each sample through 0.5M EDTA then and come termination reaction 20 μ l.Then, the reaction mixture with 40 μ l is transferred on the Millipore Multiscreen phosphorylated cotton filter plate (MAPHNOB50) of pre-wetted (2% phosphoric acid).Said reaction mixture is filtered through Millipore Multiscreen vacuum-resistant manifold (resistvacuum manifold).Filter plate is with 2% phosphoric acid washing 3 times, air-dry then.Filter plate is placed PackardMultiscreen adaptation board (adapter plate).The Microscint 20 of 50 μ l is added to each hole,, on Packard Top Count NXT, count then with the plate seals sealing.In ABASE, use the Excel match to analyze the inhibition data.In the mensuration ultimate density of reagent be 5 μ M ATP, 10 μ Ci/ μ l [γ- ³³P] ATP, 5ng MK2 enzyme, 30 μ M HSP-27 and the 0.3%DMSO that is used to screen.

Molecular Devices IMAP MAPKAP K2 Assay Kit uses in HE black microtest plate (microplate) (Molecular Devices 75-000-005).Final mensuration volume is 10 μ l (being made up of 2.5 μ l compounds, 5 μ l ATP/ peptides and 2.5 μ l MK2 enzymes).In the mensuration ultimate density of reagent be 1 μ M ATP, 200nM peptide and 0.070nM MK2 enzyme (annotate: the MK2 enzyme concn should produce about 70% 380mP=/-the 40mP peak signal).Use zero(ppm) water, (complete reaction buffer CRB), adds DTT to 1mM ultimate density then to prepare 1 * complete reaction damping fluid from 5 * storing solution.CRB is used for the initial reaction preparation.Be reflected at incubated at room 30 minutes with covering in the paper tinsel.Use zero(ppm) water, prepare 1 * buffer A from 5 * buffer A storing solution.Through diluting 400 times, IMAP reagent is added to buffer A.The damping fluid of the IMAP reagent of 30 μ l is added to each hole.Cover in the paper tinsel, incubated at room 30 minutes.On the LJL analyser, utilize 485 to excite 530 emissions to read.

Caliper LabChip 3000 Assay carry out in 384 orifice plates at the bottom of the U-shaped.Final mensuration volume is 30 μ l, and it forms through following method: the mensuration damping fluid (100mM HEPES (pH is 7.4), the 10mM MgCl that add 15 μ l enzymes and substrate (MK2 peptide and ATP) ₂, 0.015% Brij35,4mMDTT) and add the mensuration damping fluid of 15 μ l test compounds.Reaction begins through making up MapKapK2 and substrate and test compounds.To be reflected at incubated at room 60min, and add to each sample through 35mM EDTA then and come termination reaction 30 μ l.On Caliper LabChip 3000, reaction mixture is analyzed through fluorogenic substrate and phosphorylation product are carried out electrophoretic separation.Suppressing data calculates through following method: compare with the no enzyme control reaction of 100% inhibition and the only carrier reaction of 0% inhibition.The ultimate density of reagent is ATP 1 μ M, MK2 peptide 1.5 μ M, MapKapK20.08nM, Brij35 0.015% and DMSO 99.8MIN. 1.6% in the mensuration.Obtain dose response curve, thereby confirm to suppress the needed concentration (IC of 50% kinase activity ₅₀).Compound is dissolved in the DMSO 99.8MIN. (DMSO) with 10mM, and estimates with 11 kinds of concentration, each concentration all repeats to estimate.IC ₅₀Value obtains through nonlinear regression analysis.

The PBMC that stimulates through LPS produces TNF-α

The human whole blood that EDTA handles derives from the healthy volunteer.PMBC (PBMC) comes purifying through Ficoll-Hypaque density gradient centrifugation (Lympho Separation Media Cellgro #-25-072-CV) from human whole blood, then with 2.5 * 10 ⁶The concentration of/ml is suspended in again to be measured in the substratum (the RPMI substratum that comprises 10% foetal calf serum).The cell suspending liquid of 100 μ l was hatched 1 hour in 96 hole tissue culturing plates at 37 ℃ with the test compounds (in comprising the mensuration substratum of 0.3%DMSO, being 4 * concentration) of 50 μ l.Then, the LPS (400ng/ml storing solution) of 50 μ l is added to cell suspending liquid, the ultimate density that makes LPS is 100ng/ml, then plate is hatched 5 hours at 37 ℃.After hatching, collect substratum, measure then.The ELISA external member of use standard (R&D SystemsCat#-DY210) is come the TNF-α concentration in the quantitative culture medium.Use softmax software, utilize 4 parametric line matches to calculate the IC of concentration and the test compounds of TNF-α ₅₀Value (the TNF-α generation to LPS stimulated has 50% inhibiting compound concentration).

Embodiment

Following examples are explained the embodiment of The compounds of this invention and starting raw material, rather than are intended to limit the scope of claims.For ease of reference, the application uses following abbreviation:

Abbreviation

The BOC=tertbutyloxycarbonyl

The bp=boiling point

The Bu=butyl

The DMAP=4-Dimethylamino pyridine

DIPEA or DIEA=N, the N-diisopropylethylamine

DME=1, the 2-glycol dimethyl ether

The DMF=N

EDCI=1-(3-dimethylamino-propyl)-3-ethyl carbodiimide

The Et=ethyl

Et ₂The O=diethyl ether

The HOBT=1-hydroxybenzotriazole

EtOAc=ETHYLE ACETATE

EtOH=ethanol

The g=gram

H=hydrogen

The l=liter

The mCPBA=metachloroperbenzoic acid

The Me=methyl

The MeCN=acetonitrile

MeOH=methyl alcohol

The NMP=1-N-methyl-2-2-pyrrolidone N-

The Ph=phenyl

The Pr=propyl group

The PS=PS

The TEA=triethylamine

The TFA=trifluoroacetic acid

The mg=milligram

Ml or mL=milliliter

μ l=microlitre

The mmol=mmole

μ mol=micromole

The mol=mole

The mp=fusing point

The RT=room temperature

The HPLC=HPLC

The LC/MS=liquid chromatography/mass spectrometry

Example I (1)

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-[4-(oxyethyl group) phenyl] imidazo [1,2-b] pyridazine-6, the 8-diamines

(1a) (9.71g, 3.15mL 60.75mmol) dropwise add to 3-amino-6-chlorine pyridazine (7.87g, (115mL) solution of methyl alcohol 60.75mmol) and sodium hydrogencarbonate (10.22g, mixture 121.67mmol) with bromine.Resulting mixture stirring at room 16 hours, is filtered then.(500mL) adds to filtrating with water, and resulting then solution is with ETHYLE ACETATE (3 * 500mL) extractions.Organic layer is merged, then vacuum concentration.Resulting resistates comes purifying through flash chromatography with 1/1 hexane/ethyl acetate wash-out, obtains 5.40g (43%) 3-amino-4-bromo-6-chlorine pyridazine.

(1b) (16.32g 104.6mmol) adds to 3-amino-4-bromo-6-chlorine pyridazine (4.2g, ethanol 20.2mmol) (28mL) solution that derives from 1a for 50% the aqueous solution, 13.2mL with monochloroacetaldehyde solution.Resulting solution is heated to 50 ℃, kept 16 hours, then vacuum concentration.(22mL) adds to resistates with acetone, and solid is collected through vacuum filtration then, washs with cold acetone.Obtain 8-bromo-6-chlorine imidazo [1, the 2-b] pyridazine of 4.3g (79%) after air-dry, be hydrochloride.

(1c feasible method 1) is with p-phenetidine (131mg; 0.956mmol) and the THF of 1.0M KOt-Bu (2.39mmol) solution adds to the 8-bromo-6-chlorine imidazo [1 that derives from 1b for 2.5 equivalents, 2.4ml; 2-b] pyridazine (257mg, 0.956mmol) mixture in THF (2.0ml).Resulting mixture was heated 1 hour at 50 ℃.Then,, obtain thick 6-chloro-N-(4-ethoxyl phenenyl) imidazo [1,2-b] pyridazine-8-amine, be solid solution for vacuum concentration.Then, said solid uses in following steps with current state.

(1c feasible method 2) with p-phenetidine (1.0 equivalents, 0.149mmol) and triethylamine (33mg 0.327mmol) adds to 8-bromo-6-chlorine imidazo [1,2-b] pyridazine hydrochloride (40mg, 0.149mmol) mixture in EtOH (1.5mL) that derives from 1b.With resulting mixture heating up to 90 ℃ and stirred 24-48 hour.Then, with solution for vacuum concentration, obtain thick 6-chloro-N-(4-ethoxyl phenenyl) imidazo [1,2-b] pyridazine-8-amine.

(1d) will be anti--1, (1000mg 8.77mmol) adds to thick 6-chloro-N-(4-ethoxyl phenenyl) imidazo [1, the 2-b] pyridazine-8-amine (0.149mmol) that derives from 1c to the 4-DACH.With resulting mixture heating up to 160 ℃, make its fusing.Stirred 24-48 hour at 160 ℃, afterwards liquid mixture is cooled to room temperature.Add water, next use dichloromethane extraction.With the organic layer vacuum concentration.Resulting resistates comes purifying through anti-phase preparation property HPLC, obtains the preceding text title compound, is tfa salt, and yield is about 35%. ¹H?NMR(400MHz，MeOH)δppm?7.59(1H，s)，7.29(1H，s)，7.23(2H，d，J＝8.8Hz)，6.95(2H，d，J＝8.8Hz)，5.85(1H，s)，4.04(2H，q，J＝7Hz)，3.51-3.61(1H，m)，2.65-2.73(1H，m)，2.10(2H，d，J＝12.30Hz)，1.92(2H，d，J＝12.30Hz)，1.38(3H，t，J＝7Hz)，1.20-1.33(4H，m)。LC/MS：m/e?367(M+1)。HPLC?Rt：2.11min。YMC ODSC18 chromatographic column (4.6 * 50mm).0％-100％B。Solvent B: (90%MeOH, 10%H ₂O, 0.1%TFA).Solvent orange 2 A: (10%MeOH, 90%H ₂O, 0.1%TFA).Gradient: being initiated with %B=0, finally is %B=100, and the gradient time is 4min, keeps 1min at 100%B, and flow velocity is 4mL/min.

The embodiment of preparation lists in table 1 in a similar manner.

Selectively, example I (1) also can prepare through following method.

(1e) with p-phenetidine (100mg, 0.731mmol) and triethylamine (86mg 0.804mmol) adds to perchloro-imidazo [1; 2-b] pyridazine (perchloroimidazo [1,2-b] pyridazine) (Synthesis1971,8; 424) (213mg, EtOH 0.731mmol) (5mL) solution.Resulting mixture was heated 5 hours at 90 ℃.Then, solution is cooled to 0 ℃.Resulting solid is collected through vacuum filtration, with cold EtOH washing.Be separated to the thick 2,3,6 of 191mg (67%) after air-dry, 7-tetrachloro-N-(4-ethoxyl phenenyl) imidazo [1,2-b] pyridazine-8-amine.

(1f) will be anti--1, the 4-DACH (360mg 3.16mmol) adds to and derives from 2,3,6 of 1e, and 7-tetrachloro-N-(4-ethoxyl phenenyl) imidazo [1,2-b] pyridazine-8-amine (184mg, 0.47mmol).Make resulting mixture 120 ℃ of fusings, kept 1.5 hours.Then, make the melt cooling, dilute with water is used ethyl acetate extraction then.Then, with the organic layer vacuum concentration, obtain the crude product of 200mg (91%).Then, the above-mentioned product of 20mg comes purifying through preparation property HPLC.So obtained the N of 8.0mg ⁶-(4-aminocyclohexyl)-2,3,7-three chloro-N ⁸-(4-ethoxyl phenenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines is tfa salt.

(1g) in 500ml PARR bottle, 10% palladium/carbon (175mg) is added to the thick N of the free alkali form that derives from 1f ⁶-(4-aminocyclohexyl)-2,3,7-three chloro-N ⁸-(4-ethoxyl phenenyl) imidazo [1,2-b] pyridazine-6,8-diamines (140mg, 0.300mmol) mixture in EtOH (10ml).Then, the PARR bottle is with the H of 55psi ₂Fill, room temperature concussion 24 hours.Then, with catalyst filtration, the vacuum concentration of will filtrating obtains the crude mixture of 3 kinds of compounds.Said mixture comes purifying through preparation property HPLC, and the example I (1) that obtains 4.7mg is N ⁶-(4-aminocyclohexyl)-N ⁸-(4-ethoxyl phenenyl) imidazo [1,2-b] pyridazine-6, the N of 8-diamines (being tfa salt, LC/MS:m/e 367 (M+1)), 9.0mg ⁶-(4-aminocyclohexyl)-3-chloro-N ⁸-(4-ethoxyl phenenyl) imidazo [1,2-b] pyridazine-6, the N of 8-diamines (LC/MS:m/e 401 (M+1)) and 18.5mg ⁶-(4-aminocyclohexyl)-2,3-two chloro-N ⁸-(4-ethoxyl phenenyl) imidazo [1,2-b] pyridazine-6,8-diamines (LC/MS:m/e 435 (M+1)).

According to the method that is similar to example I (1), use suitable starting raw material and come preparation formula (Ia) compound, wherein R with illustrated substantially the same method ₁, R ₂, R ₃, X and Y have value listed in table 1.

Table 1

^*With regard to substituent X and Y, the replacement on core texture (formula Ia) occurs in available nitrogen-atoms place

Example II (1)

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(2, the 6-difluorophenyl) imidazos [1,2-b] pyridazine-6, the 8-diamines

(1a) with 2, (24mg 0.186mmol) adds to 60%NaH (22.5mg, DMF 0.563mmol) (400 μ l) solution to the 6-difluoroaniline.Stirred 5 minutes at RT, add THF (1000 μ l) afterwards, and 8-bromo-6-chlorine imidazo [1, the 2-b] pyridazine that next adds as described in example I (1) step (1b), prepare (50mg, 0.186mmol).To be reflected at 50 ℃ of heating 3 hours.Reaction is dripped with number and methyl alcohol stops.Then, with solution for vacuum concentration, obtain thick 6-chloro-N-(2, the 6-difluorophenyl) imidazos [1,2-b] pyridazine-8-amine.

(1b) will be anti--1, (1000mg 8.77mmol) adds to thick 6-chloro-N-(2, the 6-difluorophenyl) imidazo [1, the 2-b] pyridazine-8-amine (0.186mmol) that derives from 1a to the 4-DACH.Make resulting mixture 160 ℃ of fusings, kept 24 hours.Then, make the melt cooling, add water, next use dichloromethane extraction.Then, with the organic layer vacuum concentration, resulting resistates comes purifying through anti-phase preparation property HPLC, obtains the title compound of 50.6mg (46%), is tfa salt.LC/MS：m/e?359(M+1)。HPLC?Rt：1.7min。YMC ODSC18 chromatographic column (4.6 * 50mm).0％-100％B。Solvent B: (90%MeOH, 10%H ₂O, 0.1%TFA).Solvent orange 2 A: (10%MeOH, 90%H ₂O, 0.1%TFA).Gradient: being initiated with %B=0, finally is %B=100, and the gradient time is 4min, keeps 1min at 100%B, and flow velocity is 4mL/min.The embodiment of preparation lists in table 2 in a similar manner.

According to the method that is similar to example II (1), use suitable starting raw material and come preparation formula (Ia) compound, wherein R, R with illustrated substantially the same method ₂, R ₃, X and Y have value listed in table 2.

Table 2

EXAMPLE III (1)

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-[4-(oxyethyl group) phenyl]-7-Methylimidazole is [1,2-b] pyridazine-6 also, the 8-diamines

(1a) in the microwave tube (microwave tube) of sealing, with 3, (4.2g, 26mmol Alfa) are suspended in 28%NH to 6-two chloro-4-methyl pyridazines ₄In the OH aqueous solution (14mL), at 155 ℃ of heating 1.5h.Microwave tube is opened,, in ice bath, stirred 30min then at stirring at room 30min.To the come off solid filtering of (crashout), dry then with the frozen water washing, obtain the mixture (3.4g, 91%) of 6-chloro-5-methyl pyridazine-3-amine and 3-chloro-5-methyl pyridazine-6-amine.

(1b) will derive from the 6-chloro-5-methyl pyridazine-3-amine of 1a and the mixture of 3-chloro-5-methyl pyridazine-6-amine (1.45g, 10mmol) and NaHCO ₃(2.1g 25mmol) is suspended among the MeOH (20mL), uses Br then ₂(0.57mL 11mmol) handles.Resulting mixture at stirring at room 4h, is filtered then.The vacuum concentration of will filtrating.Resulting resistates is resuspended among the EtOAc (100mL), uses saturated NaHCO then successively ₃The aqueous solution (2 * 20mL) with the NaCl aqueous solution (1 * 20mL) washing.Resulting solution is used MgSO ₄Dry.The solvent vacuum is removed, obtain thick 4-bromo-6-chloro-5-methyl pyridazine-3-amine (1g).

(1c) with monochloroacetaldehyde (1.6ml, 10mmol, 50% H ₂O solution) add to thick 4-bromo-6-chloro-5-methyl pyridazine-3-amine (0.5g, EtOH 2mmol) (5mL) solution that derives from 1b.Resulting mixture is heated 2h at 110 ℃ in the bottle of sealing.The solvent vacuum is removed, then resulting solid is suspended in acetone/Et ₂O (1/1,5mL) in, filter, use Et then ₂The O washing obtains also [1,2-b] pyridazine HCl salt (0.5g, purity＞90%) of 8-bromo-6-chloro-7-Methylimidazole.

The 8-bromo-6-chloro-7-Methylimidazole that (1d) will derive from 1c also [1,2-b] pyridazine HCl salt (30mg, 0.1mmol), right-anisidine (20 μ L, 0.15mmol) and K ₂CO ₃Mixture (75mg) is suspended among the NMP (600 μ L), in microwave, heats 15min at 225 ℃.Resulting mixture is cooled to room temperature, uses H then ₂O (5mL) handles.With the solid filtering that is precipitated out, use water washing, dry then, obtain also [1,2-b] pyridazine-8-amine (21mg is through definite purity＞90% of HPLC) of 6-chloro-N-(4-ethoxyl phenenyl)-7-Methylimidazole.

6-chloro-N-(4-the ethoxyl phenenyl)-7-Methylimidazole that (1e) will derive from 1d also [1,2-b] pyridazine-8-amine (20mg, 0.067mmol) with anti--1,4-DACH (150mg) combination is at 165 ℃ of heating 70h.Resulting mixture is cooled to room temperature, and water (10mL) dilution then is with EtOAc extraction (4 * 5mL).Organic layer is merged, then vacuum concentration.Resulting resistates utilization preparation property HPLC comes purifying, obtains the preceding text title compound, is tfa salt (4.5mg, 11%). ¹H?NMR(400MHz，CD ₃OD)δ7.97(d，J＝2.4Hz，1H)，7.67(d，J＝2.4Hz，1H)，6.90(m，4H)，4.05(q，2H，J＝7.2Hz)，4.00(m，1H)，3.20(m，1H)，2.30(m，2H)，2.20(m，2H)，2.15(s，3H)，1.60(m，4H)，1.40(t，J＝7.2H，3H)。LC/MS：m/e?381(M+1)。HPLC?Rt：2.1min。YMC ODSC18 chromatographic column (4.6 * 50mm).0％-100％B。Solvent B: (90%MeOH, 10%H ₂O, 0.1%TFA).Solvent orange 2 A: (10%MeOH, 90%H ₂O, 0.1%TFA).Gradient: being initiated with %B=0, finally is %B=100, and the gradient time is 4min, keeps 1min at 100%B, and flow velocity is 4mL/min.

Use suitable starting raw material and come preparation formula (Ia) compound, wherein R according to the method that is similar to EXAMPLE III (1) with illustrated substantially the same method ₁, R ₂, R ₃, X and Y have value listed in table 3.

Table 3

EXAMPLE IV (1)

N ⁶-(anti--the 4-aminocyclohexyl)-7-chloro-N ⁸-[4-(oxyethyl group) phenyl] imidazo [1,2-b] pyridazine-6, the 8-diamines

(1a) with 3-hydroxyl-4, (5.34g 32.5mmol) adds to the H of being fuming of stirring to the 5-dichloro-pyridazine ₂SO ₄(14.0mL is 273mmol) with dense H ₂SO ₄(7.3mL, solution 137mmol).Next, add KNO lentamente in room temperature ₃(9.0g, 88mmol).Reaction mixture is heated to 90 ℃, then temperature is remained on 90 ℃, last 18 hours.Make resulting solution cooling, incline to frozen water then.Stirred one hour, and afterwards suspended solid was filtered, obtain 3-hydroxyl-4,5-two chloro-6-nitro pyridazines (4.2g, 62%) are white solid.

(1b) with Na ₂S ₂O ₄(0.65g 3.6mmol) adds to the 3-hydroxyl-4 that derives from 1a of stirring, 5-two chloro-6-nitro pyridazines (0.26g, and THF 1.2mmol) (4.0mL, 0.3M) and H ₂O (4.0mL, 0.3M) solution.Resulting reaction mixture is heated to backflow, adds ETHYLE ACETATE after 1 hour.Each layer separated, and organic layer is used H then ₂Next O (10mL) washing uses salt solution (10mL) washing.Organic layer is used Na ₂SO ₄Drying, vacuum concentration then.Resulting resistates is ground with diethyl ether, filter then, obtain 3-hydroxyl-4,5-two chloro-6-MW01-070Cs (0.165g, 67%) are white solid.

(1c) with monochloroacetaldehyde (0.57ml, 4.6mmol, 50% H ₂O solution) add to the 3-hydroxyl-4 that derives from 1b, 5-two chloro-6-MW01-070Cs (0.165g, EtOH 0.92mmol) (1.3mL, 0.7M) solution.In microwave, with heating 15 minutes at 150 ℃ in the bottle that is reflected at sealing.The solvent vacuum is removed, then resulting solid is resuspended in the diethyl ether (10mL), filter, clean with diethyl ether then, obtain 6-hydroxyl-7, the 8-dichloro-imidazole is [1,2-b] pyridazine (0.3g, 60%) also, is HCl salt.

(1d) in 1 dram bottle, with the 6-hydroxyl-7 that derives from 1c, the 8-dichloro-imidazole also [1,2-b] pyridazine (0.1g 0.5mmol) adds to POCl ₃(0.4mL, 1.4M).With resulting mixture heating up to 120 ℃, kept 2 days.CH is added in the cooling back ₂Cl ₂, then resulting mixture is inclined to frozen water.Each layer separated, and water layer is used CH then ₂Cl ₂(15mL) extraction.Organic layer is merged, use H then ₂Next O (5mL) washing uses salt solution (5mL) washing.Resulting solution is used Na ₂SO ₄Drying, vacuum concentration obtains 6,7 then, and 8-trichlorine imidazo [1,2-b] pyridazine (0.04g, 37%) is the brown solid.

(1e) will derive from 6,7 of 1d, 8-trichlorine imidazo [1; 2-b] pyridazine (0.04g, 0.18mmol), p-ethoxyaniline (0.025g, 0.18mmol) and triethylamine (0.055mL; 0.4mmol) mixture be suspended among the EtOH (1.0mL), be heated to 90 ℃, kept 2.5 hours.Then, make reaction mixture be cooled to room temperature, vacuum concentration then, obtain thick 6,7-two chloro-N-(4-ethoxyl phenenyl) imidazos [1,2-b] pyridazine-8-amine (0.05g, 86%).

(1f) will derive from the thick 6 of 1e, (0.03g, 0.09mmol) with anti--1, (0.07g 0.6mmol) mixes the 4-DACH 7-two chloro-N-(4-ethoxyl phenenyl) imidazos [1,2-b] pyridazine-8-amine.With resulting mixture heating up to 120 ℃, kept 1.5 days.CH is added in the cooling back ₂Cl ₂(10mL) and H ₂O (10mL) separates each layer then.Organic layer is used Na with salt solution (5mL) washing ₂SO ₄Drying, vacuum concentration then.Resulting oily matter comes purifying through preparation property HPLC, obtains preceding text title compound (0.010g, 29%), is tfa salt. ¹H?NMR(MeOH)δ8.00(s，1H)，7.70(s，1H)，7.13(d，J＝8.8Hz，2H)，6.98(d，J＝8.8Hz，2H)，4.09(q，J＝7.0Hz，2H)，4.00-3.90(m，1H)，3.24-3.15(m，1H)，2.30-2.23(m，2H)，2.20-2.10(m，2H)，1.65-1.57(m，4H)，1.50(t，3H)。LC/MS：m/e?402(M+1)。HPLC?Rt：1.95min。YMCODSC18(4.6×100mm)。20％-100％B。Solvent B: (90%MeOH, 10%H ₂O, 0.1%TFA).Solvent orange 2 A: (10%MeOH, 90%H ₂O, 0.1%TFA).Gradient: being initiated with %B=20, finally is %B=100, and the gradient time is 10min, keeps 2min at 100%B, and flow velocity is 4mL/min.

EXAMPLE V (1)

N ⁸-[4-(oxyethyl group) phenyl]-N ⁶-piperidines-3-base imidazo [1,2-b] pyridazine-6, the 8-diamines

In 500ml PARR bottle, 10%Pd/C (20mg) and 3 Glacial acetic acid min. 99.5 are added to N ⁶-(1-benzyl piepridine-3-yl)-N ⁸-(4-ethoxyl phenenyl) imidazo [1; 2-b] pyridazine-6,8-diamines tfa salt (14mg, 0.021mmol) and the mixture of MeOH (5mL); The method of said tfa salt through example I (1) used 1-benzyl piepridine-3-amine replacement instead-1 in step (1d), the 4-DACH prepares.Then, the PARR bottle is with the H of 55psi ₂Fill, room temperature concussion 5 hours.Then, reaction mixture is filtered the vacuum concentration of to filtrate then.Resistates comes purifying through preparation property HPLC, and next spent ion exchange resin neutralizes, and obtains the title compound of 0.5mg (7%). ¹H?NMR(500MHz，MeOH)δppm?7.57(1H，s)，7.31(1H，s)，7.24(2H，d，J＝8.7Hz)，6.97(2H，d，J＝8.7Hz)，5.89(1H，s)，4.05(2H，q，J＝6.9Hz)，3.85(1H，m)，3.45(1H，m)，3.10(1H，m)，2.85(1H，m)，2.75(1H，m)，2.05(1H，m)，1.90(1H，m)，1.70(1H，m)，1.55(1H，m)，1.39(3H，t，J＝6.9Hz)。LC/MS：m/e?353(M+1)。HPLC?Rt：2.04min。YMC ODSC18 chromatographic column (4.6 * 50mm).0％-100％B。Solvent B: (90%MeOH, 10%H ₂O, 0.1%TFA).Solvent orange 2 A: (10%MeOH, 90%H ₂O, 0.1%TFA).Gradient: being initiated with %B=0, finally is %B=100, and the gradient time is 4min, keeps 1min at 100%B, and flow velocity is 4mL/min.

Use suitable starting raw material and come preparation formula (Ia) compound, wherein R according to the method that is similar to EXAMPLE V (1) with illustrated substantially the same method ₁, R ₂, R ₃, X and Y have value listed in table 4.

Table 4

Example VI (1)

6-[(3S)-3-amino-pyrrolidine-1-yl]-N-[4-(oxyethyl group) phenyl] imidazo [1,2-b] pyridazine-8-amine

With (S)-3-amino-1-N-boc-tetramethyleneimine (180mg, 0.96mmol) add to as 6-chloro-N-(4-ethoxyl phenenyl) imidazo [1,2-b] pyridazine-8-amine of described in example I (1) step (1c), preparing (26mg, 0.090mmol).With resulting mixture at 225 ℃ with microwave treatment 1 hour.Then, make the melt cooling, add water, next use dichloromethane extraction.Then,, come purifying through preparation property HPLC then, obtain the title compound of 0.9mg (2%), be tfa salt (annotate: during reaction, cracking takes place Boc, the 1-nitrogen generation addition of tetramethyleneimine) the organic layer vacuum concentration. ¹H?NMR(500MHz，MeOH)δppm?7.99(1H，s)，7.88(1H，s)，7.31(2H，d，J＝7.7Hz)，7.03(2H，d，J＝7.7Hz)，6.18(1H，s)，4.07(2H，q，J＝6.9Hz)，4.0(1H，m)，3.80(1H，m)，3.55(3H，m)，2.50(1H，m)，2.15(1H，m)，1.40(3H，t，J＝6.9Hz)。LC/MS：m/e?339(M+1)。HPLC?Rt：1.83min。YMC ODSC18 chromatographic column (4.6 * 50mm).0％-100％B。Solvent B: (90%MeOH, 10%H ₂O, 0.1%TFA).Solvent orange 2 A: (10%MeOH, 90%H ₂O, 0.1%TFA).Gradient: being initiated with %B=0, finally is %B=100, and the gradient time is 4min, keeps 1min at 100%B, and flow velocity is 4mL/min.

Example VII A (1)

N ²-(anti--the 4-aminocyclohexyl)-N ⁴-[4-(oxyethyl group) phenyl] pyrazolo [1,5-a] [1,3,5] triazine-2, the 4-diamines

(1a) (3.16g 24.07mmol) adds to 3-amino-pyrazol (Aldrich) (2.0g, acetone 24.07mmol) (20mL) solution with ethoxycarbonyl isothiocyanate.With reaction mixture stirring at room 1 hour.Then, cold water (100mL) is added to reaction mixture.Resulting solid precipitation is collected through filtering, and water (50mL) washing is air-dry then, obtains 1H-pyrazoles-5-base carbamyl sulfonyl urethanum (ethyl 1H-pyrazol-5-ylcarbamothioylcarbamate) of 4.64g (90%).

(1b) will derive from that the 1H-pyrazoles of 1a-(4.64g 21.68mmol) adds to 2N NaOH solution (51mL) to 5-base carbamyl sulfonyl urethanum.Reaction mixture stirring at room 2.5 hours, is used 2N H then ₂SO ₄Acidifying.Resulting deposition is collected through vacuum filtration, uses water washing, and is next with the diethyl ether washing, air-dry then, obtains the 2-sulfo--2 of 3.32g (82%), and 3-dihydro-pyrazolo [1,5-a] [1,3,5] triazines-4 (1H)-ketone are light yellow solid.

(1c) (39.52mmol 22.58ml) adds to the 2-sulfo--2 that derives from 1b, 3-dihydro-pyrazolo [1,5-a] [1,3,5] triazines-4 (1H)-ketone (3.32g, anhydrous EtOH (80mL) suspension 19.76mmol) with 1.75N NaOH solution.Then, add methyl-iodide (2.80g, 19.76mmol), with reaction mixture stirring at room 2 hours.Resulting deposition is collected through vacuum filtration, and it is suspended in the water (110mL), uses 2N H then ₂SO ₄Acidifying.Resulting solution was stirred 5 minutes at 0 ℃, and new then deposition is collected through vacuum filtration, uses cold water washing, and is air-dry then, obtains 2-(methylthio group) pyrazolo [1,5-a] [1,3,5] triazines-4 (the 3H)-ketone of 1.88g (52%).

(1d) with N, (601mg 4.96mmol) adds to 2-(methylthio group) pyrazolo [1,5-a] [1,3,5] triazines-4 (3H)-ketone (1.88g, POCl 10.33mmol) that derives from 1c to accelerine ₃(29mL) suspension.Reaction mixture is heated to backflow, kept 7 hours, be cooled to room temperature then, vacuum concentration it, use cold water (110mL) dilution then.Resulting solid is collected through vacuum filtration, and is air-dry then with cold water and hexane wash, obtains 4-chloro-2-(methylthio group) pyrazolo [1,5-a] [1,3, the 5] triazine of 1.68g (81%).

(1e) with p-phenetidine (3.09g, 22.51mmol) add to 4-chloro-2-(methylthio group) pyrazolo [1,5-a] [1,3, the 5] triazine that derives from 1d (300mg, 1.5mmol) 1, the mixture in the 4-diox (6mL).With resulting mixture heating up to 100 ℃, kept 0.5 hour.Then, (15mL) adds to reaction mixture with water, and resulting then deposition is collected through vacuum filtration; With cold water and hexane wash, air-dry then, obtain N-(4-ethoxyl phenenyl)-2-(methylthio group) pyrazolo [1 of 360mg (80%); 5-a] [1,3,5] triazine-4-amine.

(1f) (702mg 4.06mmol) adds to N-(4-ethoxyl phenenyl)-2-(methylthio group) pyrazolo [1,5-a] [1,3,5] triazine-4-amine (360mg, DMF 1.19mmol) (10mL) solution that derives from 1e with mCPBA in room temperature.With the reaction mixture vacuum concentration, next add saturated sodium bicarbonate after 1 hour.Then, the resulting aqueous solution is used ethyl acetate extraction, and organic layer is dry, obtains N-(4-ethoxyl phenenyl)-2-(methyl sulphonyl) pyrazolo [1,5-a] [1,3, the 5] triazine-4-amine of 250mg (63%).

(1g) will be anti--1, the 4-DACH (200mg, 1.75mmol) add to N-(4-ethoxyl phenenyl)-2-(methyl sulphonyl) pyrazolo [1,5-a] [1,3,5] triazine-4-amine of deriving from 1f (50mg, 0.15mmol) in.Make reaction mixture 100 ℃ of fusings, kept 1 hour.Then, melt is cooled to room temperature.Add water, next use ethyl acetate extraction.Then, with the organic layer vacuum concentration, resulting then resistates comes purifying through preparation property HPLC, obtains the preceding text title compound of 35.3mg (20%), is tfa salt. ¹H?NMR(500MHz，DMSO)δppm?7.90(3H，m)，7.63(2H，m)，6.88(2H，m)，3.98(2H，m)，3.60(1H，m)，2.95(1H，m)，1.92(4H，m)，1.30(7H，m)。LC/MS：m/e?368(M+1)。HPLC?Rt：2.05min。YMC ODSC18 chromatographic column (4.6 * 50mm).0％-100％B。Solvent B: (90%MeOH, 10%H ₂O, 0.1%TFA).Solvent orange 2 A: (10%MeOH, 90%H ₂O, 0.1%TFA).Gradient: being initiated with %B=0, finally is %B=100, and the gradient time is 4min, keeps 1min at 100%B, and flow velocity is 4mL/min.

Embodiment XIII

N ²-(anti--the 4-aminocyclohexyl)-N ⁴-(4-ethoxyl phenenyl)-imidazo [2,1-f] [1,2,4] triazine-2, the 4-diamines

(1a) make as at Journal of The Chemical Society, Perkins Transactions I 1999,20; Prepare described in 2929 2, two (methylthio group) imidazos [1,2-f] [1 of 4-; 2,4] triazine (0.077g, 0.36mmol) and p-phenetidine (0.75g; 5.46mmol) together in bottle 90 ℃ of fusings, kept 6 hours.Make resulting mixture cooling, use HCl (1N) dilution then.Resulting brown precipitate is filtered, and vacuum-drying then obtains N-(4-ethoxyl phenenyl)-2-(methylthio group) imidazo [1,2-f] [1,2, the 4] triazine-4-amine of 0.103g (95%).

(1b) bottle is with N-(4-ethoxyl phenenyl)-2-(methylthio group) imidazo [1,2-f] [1,2 that derives from 1a; 4] triazine-4-amine (0.103g; 0.34mmol), metachloroperbenzoic acid (0.286g, 1.16mmol) and N (5mL) fill, stirring at room 2 hours.Resulting mixture is used the saturated sodium bicarbonate aqueous solution cancellation, uses ethyl acetate extraction, concentrates, and vacuum-drying then obtains thick N-(4-ethoxyl phenenyl)-2-(methyl sulphonyl) imidazo [1,2-f] [1,2,4] triazine-4-amine of 0.105g.

(1c) bottle is equipped with N-(4-ethoxyl phenenyl)-2-(methyl sulphonyl) imidazo [1,2-f] [1,2,4] triazine-4-amine of deriving from 1b (0.105g, 0.32mmol) with anti--1, (0.54g 4.7mmol), makes it 100 ℃ of fusings to 4-cyclohexyl diamines, keeps 6 hours.Resulting mixture is cooled to room temperature,, comes purifying through preparation property HPLC then, obtain the title compound of 0.006g (11%), be tfa salt with the methyl alcohol dilution. ¹H?NMR(500MHz，CD ₃OD)δppm?7.75(4H，m)，6.95(2H，m)，4.03(2H，m)，3.68(1H，m)，3.11(1H，m)，2.22(2H，m)，2.10(2H，m)，1.4(7H，m)。LC/MS：m/e?368(M+1)。HPLC?Rt：2.18min。Waters Sunfire C18 chromatographic column (4.6 * 50mm).0％-100％B。Solvent B: (90%MeOH, 10%H ₂O, 0.1%TFA).Solvent orange 2 A: (10%MeOH, 90%H ₂O, 0.1%TFA).Gradient: being initiated with %B=0, finally is %B=100, and the gradient time is 4min, keeps 1min at 100%B, and flow velocity is 4mL/min.

Example I X (1)

N ⁶-(suitable-the 4-aminocyclohexyl)-N ⁸-[4-(oxyethyl group) phenyl]-7-Methylimidazole is [1,2-b] pyridazine-6 also, the 8-diamines

With suitable-1, the 4-DACH (250mg, 2.19mmol) add to derive from EXAMPLE III (1) step 1d 6-chloro-N-(4-ethoxyl phenenyl)-7-Methylimidazole also [1,2-b] pyridazine-8-amine (40mg, 0.14mmol).Resulting mixture was heated 48 hours at 165 ℃.Then, make the reaction mixture cooling,, come purifying through preparation property HPLC then with the methyl alcohol dilution.Then, with the elutriant vacuum concentration, with methyl alcohol (2mL) dilution, through coming purifying and neutralization through 500mg SCX (cation-exchange chromatography post).Elutriant is concentrated, obtain the title compound of 6.0mg (11.3%). ¹H?NMR(500MHz，MeOH)δppm?7.65(1H，s)，7.25(1H，s)，6.85(4H，m)，3.95(2H，d，J＝7.2Hz)，3.95(1H，m)，3.05(1H，m)，1.95(2H，m)，1.85(3H，s)，1.80(4H，m)，1.65(2H，m)，1.35(3H，t，J＝7.2Hz)。LC/MS：m/e?381(M+1)。HPLC?Rt：1.91min。Waters?Sunfire?C18?4.6×50。0％-100％B。B：(90％MeOH，10％H ₂O，0.1％TFA)。A：(10％MeOH，90％H ₂O，0.1％TFA)。The gradient time is 4min, keeps 1min at 100%B, and flow velocity is 4mL/min.

Use suitable starting raw material and come preparation formula (Ia) compound, wherein R according to the method that is similar to example I X (1) with illustrated substantially the same method ₁, R ₂, R ₃, X and Y have value listed in table 5.

Table 5

Embodiment X (1)

(1a) will to the anisole methylamine (1.0 equivalents, 1.49mmol) and triethylamine (330mg 3.27mmol) adds to 8-bromo-6-chlorine imidazo [1,2-b] pyridazine hydrochloride (40mg, 1.49mmol) mixture in EtOH (15mL) that derives from example I (1) step 1b.With resulting mixture heating up to 90 ℃ and stirred 24 hours.Then, with resulting solution for vacuum concentration.Resulting resistates comes purifying through anti-phase preparation property HPLC, obtains 6-chloro-N-(4-methoxy-benzyl) imidazo [1,2-b] pyridazine-8-amine, is tfa salt.LC/MS：m/e?288.97(M+1)。HPLC?Rt：2.84min。Waters SunfireC18 chromatographic column (4.6 * 50mm).0％-100％B。Solvent B: (90%MeOH, 10%H ₂O, 0.1%TFA).Solvent orange 2 A: (10%MeOH, 90%H ₂O, 0.1%TFA).Gradient: being initiated with %B=0, finally is %B=100, and the gradient time is 4min, keeps 1min at 100%B, and flow velocity is 4mL/min.

(1b) will be anti--1, the 4-DACH (1000mg, 8.77mmol) add to 6-chloro-N-(4-methoxy-benzyl) imidazo [1,2-b] pyridazine-8-amine of deriving from 1a (426mg, 1.475mmol).With resulting mixture heating up to 160 ℃, make its fusing.Stirred 7 days at 160 ℃, afterwards liquid mixture is cooled to room temperature.Add water, next use dichloromethane extraction.With the organic layer vacuum concentration.Resulting resistates comes purifying through anti-phase preparation property HPLC, obtains N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(4-methoxy-benzyl) imidazo [1,2-b] pyridazine-6,8-diamines (0.315g) is tfa salt, yield is about 44%.LC/MS：m/e?367.27(M+1)。HPLC?Rt：1.81min。Waters Sunfire C18 chromatographic column (4.6 * 50mm).0％-100％B。Solvent B: (90%MeOH, 10%H ₂O, 0.1%TFA).Solvent orange 2 A: (10%MeOH, 90%H ₂O, 0.1%TFA).Gradient: being initiated with %B=0, finally is %B=100, and the gradient time is 4min, keeps 1min at 100%B, and flow velocity is 4mL/min.

(1c) TFA (2mL) is added to the N that derives from 1b ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(4-methoxy-benzyl) imidazo [1,2-b] pyridazine-6, the methylene dichloride of 8-diamines (5mL) solution.Stirred 2 hours at RT,, obtain thick N afterwards with the reaction soln vacuum concentration ⁶-(anti--the 4-aminocyclohexyl) imidazo [1,2-b] pyridazine-6, the 8-diamines, it uses under situation about not being further purified.LC/MS：m/e?247.16(M+1)。HPLC?Rt：0.73min。Waters Sunfire C18 chromatographic column (4.6 * 50mm).0％-100％B。Solvent B: (90%MeOH, 10%H ₂O, 0.1%TFA).Solvent orange 2 A: (10%MeOH, 90%H ₂O, 0.1%TFA).Gradient: being initiated with %B=0, finally is %B=100, and the gradient time is 4min, keeps 1min at 100%B, and flow velocity is 4mL/min.

(1d) triethylamine (31.6mg, 0.313mmol, 1.1 equivalents) and BOC acid anhydride (68.2mg, 0.313mmol, 1.1 equivalents) are added to the N that derives from 1c ⁶-(anti--the 4-aminocyclohexyl) imidazo [1,2-b] pyridazine-6, THF (3mL) solution of 8-diamines (70mg, 0.284mml, 1.0 equivalents).Reaction soln was stirred 2 hours at RT.Then, with resulting solution for vacuum concentration, obtain thick (instead)-4-(8-aminooimidazole also [1,2-b] pyridazine-6-base is amino) cyclohexyl t-butyl carbamate, it uses with current state in ensuing reaction.LC/MS：m/e?347.23(M+1)。HPLC?Rt：2.50min。Waters Sunfire C18 chromatographic column (4.6 * 50mm).0％-100％B。Solvent B: (90%MeOH, 10%H ₂O, 0.1%TFA).Solvent orange 2 A: (10%MeOH, 90%H ₂O, 0.1%TFA).Gradient: being initiated with %B=0, finally is %B=100, and the gradient time is 4min, keeps 1min at 100%B, and flow velocity is 4mL/min.

(25mg 0.072mmol) adds to 60%NaH (2.9mg, THF 0.072mmol) (2ml) solution to the cyclohexyl t-butyl carbamate (1e) will to derive from (instead)-4-(also [1,2-b] pyridazine-6-base is amino for the 8-aminooimidazole) of 1d.Stirred 1 hour at RT, add Benzoyl chloride 99min. (20.3mg, 0.144mg, 2.0 equivalents) afterwards, reaction soln was heated 3 days at 60 ℃.Reaction is dripped with number and methyl alcohol stops.Then, with resulting solution for vacuum concentration.Resulting resistates comes purifying through anti-phase preparation property HPLC, obtains (instead)-4-(8-benzamido-imidazo [1,2-b] pyridazine-6-base is amino) cyclohexyl t-butyl carbamate (9.1mg), is tfa salt, and yield is about 10%.LC/MS：m/e?451.26(M+1)。HPLC?Rt：2.99min。Waters Sunfire C18 chromatographic column (4.6 * 50mm).0％-100％B。Solvent B: (90%MeOH, 10%H ₂O, 0.1%TFA).Solvent orange 2 A: (10%MeOH, 90%H ₂O, 0.1%TFA).Gradient: being initiated with %B=0, finally is %B=100, and the gradient time is 4min, keeps 1min at 100%B, and flow velocity is 4mL/min.

(1f) TFA (1mL) is added to methylene dichloride (2mL) solution of (instead)-4-of deriving from 1e (8-benzamido-imidazo [1,2-b] pyridazine-6-base is amino) cyclohexyl t-butyl carbamate.Stirred 2 hours at RT, afterwards with the reaction soln vacuum concentration.Resulting resistates comes purifying through SCX chromatographic column (300mg is with the methanol solution wash-out of 2M ammonia), obtains title compound, is tfa salt, and yield is about 50%. ¹H?NMR(500MHz，MeOH)δppm?8.07(2H，d，J＝7.7Hz)，7.69(2H，s)，7.65(1H，t)，7.55(2H，t)，7.36(1H，s)，3.65(1H，m)，2.72(1H，m)，2.17(2H，m)，1.95(2H，m)，1.31(4H，t)。LC/MS：m/e?351.21(M+1)。HPLC?Rt：1.70min。Waters Sunfire C18 chromatographic column (4.6 * 50mm).0％-100％B。Solvent B: (90%MeOH, 10%H ₂O, 0.1%TFA).Solvent orange 2 A: (10%MeOH, 90%H ₂O, 0.1%TFA).Gradient: being initiated with %B=0, finally is %B=100, and the gradient time is 4min, keeps 1min at 100%B, and flow velocity is 4mL/min.

Embodiment XI (1)

1-(6-((anti--the 4-aminocyclohexyl) amino) imidazo [1,2-b] pyridazine-8-yl)-3-phenylurea

(1a) (instead)-4-(8-benzamido-imidazo [1,2-b] pyridazine-6-base is amino) cyclohexyl t-butyl carbamate (25mg, 0.072mmol prepare) is added to 60%NaH (2.9mg, THF 0.072mmol) (2ml) solution in embodiment X step 1d.Stirred 1 hour at RT, add phenylcarbimide (17mg, 0.144mmol, 2.0 equivalents) afterwards, reaction soln was heated 3 days at 60 ℃.Reaction is dripped with number and methyl alcohol stops.Then, with solution for vacuum concentration.Resulting resistates comes purifying through anti-phase preparation property HPLC, obtains (instead)-4-(8-(3-phenyl urea groups) imidazo [1,2-b] pyridazine-6-base is amino) cyclohexyl t-butyl carbamate (6.5mg), is tfa salt, and yield is approximately less than 10%.LC/MS：m/e466.29(M+1)。HPLC?Rt：3.39min。Waters Sunfire C18 chromatographic column (4.6 * 50mm).0％-100％B。Solvent B: (90%MeOH, 10%H ₂O, 0.1%TFA).Solvent orange 2 A: (10%MeOH, 90%H ₂O, 0.1%TFA).Gradient: being initiated with %B=0, finally is %B=100, and the gradient time is 4min, keeps 1min at 100%B, and flow velocity is 4mL/min.

(1b) TFA (1mL) is added to (instead)-4-(8-(3-phenyl urea groups) imidazo [1,2-b] pyridazine-6-base is amino) cyclohexyl t-butyl carbamate (6.3mg, methylene dichloride 0.135mmol) (2mL) solution that derives from 1a.Stirred 2 hours at RT, afterwards with the reaction soln vacuum concentration.Resulting resistates comes purifying through SCX chromatographic column (300mg is with the methanol solution wash-out of 2M ammonia), obtains title compound (3.2mg, 64%), is tfa salt. ¹H?NMR(500MHz，MeOH)δppm?7.64(1H，s)，7.47(2H，m)，7.31(2H，m)，7.06(2H，m)，6.71(2H，m)，3.63(1H，m)，2.71(1H，m)，2.15(2H，m)，1.91(2H，m)，1.28-1.33(4H，t)。LC/MS：m/e?366.27(M+1)。HPLC?Rt：2.18min。Waters Sunfire C18 chromatographic column (4.6 * 50mm).0％-100％B。Solvent B: (90%MeOH, 10%H ₂O, 0.1%TFA).Solvent orange 2 A: (10%MeOH, 90%H ₂O, 0.1%TFA).Gradient: being initiated with %B=0, finally is %B=100, and the gradient time is 4min, keeps 1min at 100%B, and flow velocity is 4mL/min.

Embodiment XII (1)

N, N '-two (4-anti--aminocyclohexyl) imidazo [1,2-b] pyridazine-6,8-diamines

Will be anti--1, the 4-DACH (430mg, 3.8mmol) add to 8-bromo-6-chlorine imidazo [1, the 2-b] pyridazine that derives from example I (1) step 1b (50mg, 0.19mmol).Resulting mixture is heated 48h at 180 ℃.Reaction vessel is cooled to RT, and water (10mL) dilution then is with DCM (3 * 10mL) extractions.Organic extract liquid is merged, and vacuum concentration uses preparation property HPLC to come purifying then, obtains title compound (40mg, 30%), is tfa salt. ¹H?NMR(400MHz，MeOH)δppm7.90(1H，d，J＝2Hz)，7.81(1H，d，J＝2Hz)，6.06(1H，s)，3.75(1H，m)，3.50(1H，m)，3.20(2H，m)，2.28(4H，M)，2.16(4H，m)，1.70-1.48(6H.m)，1.42(2H，m)。LC/MS：m/e?344(M+1)。HPLC?Rt：1.01min。Waters Sunfire C18 chromatographic column (4.6 * 50mm).0％-100％B。Solvent B: (90%MeOH, 10%H ₂O, 0.1%TFA).Solvent orange 2 A: (10%MeOH, 90%H ₂O, 0.1%TFA).Gradient: being initiated with %B=0, finally is %B=100, and the gradient time is 4min, keeps 1min at 100%B, and flow velocity is 4mL/min.

Embodiment XIII (1)

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(4-ethoxyl phenenyl)-7-phenylimidazole is [1,2-b] pyridazine-6 also, the 8-diamines

(1a) with 3,6-two chloro-4-phenyl pyridazine (J.Med.Chem.2005,48,7089; 5.93g 26.3mmol) branch installs in 6 microwave tubes, then with dense NH ₄OH (7mL) adds to each pipe.After the sealing each pipe is all heated 1h at 140 ℃.Microwave tube is opened,, used cold water washing then with sedimentation and filtration.The deposition that derives from each reaction is merged, add Et to it then ₂O (150mL).With remaining solid filtering, use Et after the stirred overnight ₂O cleans, and is dry then, obtains 6-chloro-5-phenyl pyridazine-3-amine (3.06g, 56%).

(1b) under nitrogen with NaHCO ₃(1.09g 13.0mmol) adds to 6-chloro-5-phenyl pyridazine-3-amine (1.01g, methyl alcohol 4.9mmol) (25mL) suspension that derives from 1a.At 0 ℃, last 5min add bromine (methanol solution of 0.55M, 10mL, 5.5mmol).Behind the 1h cryostat is removed, then reaction mixture is stirred to room temperature, last 6h.Behind the vacuum concentration resulting resistates is absorbed in CH ₂Cl ₂With saturated Na ₂S ₂O ₅In the aqueous solution, then each layer separated.Organic layer is used saturated NaHCO ₃The aqueous solution and brine wash are used Na ₂SO ₄Drying is filtered, and vacuum concentration obtains thick 4-bromo-6-chloro-5-phenyl pyridazine-3-amine (1.28g) then.

(1c) (2.0mL 31.5mmol) adds to thick 4-bromo-6-chloro-5-phenyl pyridazine-3-amine (0.193g, EtOH 0.676mmol) (5.0mL) solution that derives from 1b with monochloroacetaldehyde.Resulting mixture is heated 5h at 118 ℃ in the pipe of sealing.Be cooled to after the room temperature the reaction mixture vacuum concentration, be suspended in acetone/Et then ₂O (1: 1,3mL) in, filter, use Et ₂The O washing obtains also [1,2-b] pyridazine HCl salt (0.147g, purity＞94%) of 8-bromo-6-chloro-7-phenylimidazole.

(1d) at 0 ℃ under nitrogen, with KOtBu (the THF solution of 1N, 0.32mL; 0.32mmol) add to the 8-bromo-6-chloro-7-phenylimidazole also [1 that derives from 1c; 2-b] (0.0431g is 0.125mmol) with 4-phenetidine (the THF solution of 0.31M, solution 0.40mL) for pyridazine HCl salt.Behind the 1min cryostat is removed, then reaction mixture is stirred to room temperature, last 1h.Behind the vacuum concentration resulting resistates is absorbed in CH ₂Cl ₂In water, then each layer separated.Water layer is used CH ₂Cl ₂Extraction (2 *).Organic layer is merged, use Na ₂SO ₄Drying is filtered, then vacuum concentration.Grind with hexane, obtain also [1,2-b] pyridazine-8-amine (0.0334g) of 6-chloro-N-(4-ethoxyl phenenyl)-7-phenylimidazole.

6-chloro-N-(4-the ethoxyl phenenyl)-7-phenylimidazole that (1e) will derive from 1d also [1,2-b] pyridazine-8-amine (0.0201g, 0.058mmol) with (instead)-hexanaphthene-1, (0.1702g 1.49mmol) heated 6 days at 165 ℃ the 4-diamines.After being cooled to room temperature resulting mixture is absorbed in CH ₂Cl ₂In water, then each layer separated.Water layer is used CH ₂Cl ₂Extraction (2 *).Organic layer is merged, use Na ₂SO ₄Drying is filtered, then vacuum concentration.Resistates utilization preparation property HPLC comes purifying.Collect suitable cut, add NaHCO to it then ₃(solid).With said cut vacuum concentration, but unlikely drying is used CH then ₂Cl ₂Extraction (2 *).Organic layer is merged, use Na ₂SO ₄Drying is filtered, and vacuum concentration obtains preceding text title compound (1.5mg, yield is 4.0%) then.LC/MS：m/e?443.40(M+1)。HPLC?RT：2.29min。YMC ODSC18 chromatographic column (4.6 * 50mm).0％-100％B。Solvent B: (90%MeOH, 10%H ₂O, 0.1%TFA).Solvent orange 2 A: (10%MeOH, 90%H ₂O, 0.1%TFA).Gradient: being initiated with %B=0, finally is %B=100, and the gradient time is 4min, keeps 1min at 100%B, and flow velocity is 4mL/min.

Use suitable starting raw material and come preparation formula (Ia) compound, wherein R according to the method that is similar to embodiment XIII (1) with illustrated substantially the same method ₁, R ₂, R ₃, X and Y have value listed in table 6.

Table 6

Embodiment XIV (1)

4-((6-((anti--the 4-aminocyclohexyl) amino) imidazo [1,2-b] pyridazine-8-yl) amino)-N-(2-(4-pyridyl) ethyl) BM

(1a) under nitrogen atmosphere, in the 250ml round-bottomed flask, add 8-bromo-6-chlorine imidazo [1, the 2-b] pyridazine derive from example I (1) step 1b (5.0g, 18.6mmol), 4-aminobenzoic tert-butyl acrylate (3.95g, 20.5mmol) and DMF (30ml).Resulting solution is cooled to 0 ℃, dropwise adds THF (46ml) solution of 1.0M potassium tert.-butoxide then through syringe, last 30 minutes.To be reflected at stirring at room 30 minutes, and be warmed to 50 ℃ then, keep 2 hours, vacuum concentration is removed THF then.Resulting solution absorption in ETHYLE ACETATE, is used H then ₂O (3 * 300ml) and salt solution (1 * 50ml) washing.Organic layer is merged, use Na ₂SO ₄Drying is filtered then.Next with solvent evaporation, obtain the crude product of 6.0g.Be further purified through grinding, obtain 4-(6-chlorine imidazo [1,2-b] pyridazine-8-base the is amino) t-butyl perbenzoate of 2.2g after the filtration, be brown solid with 3: 1 diethyl ether/heptane.

(1b) in the 50ml round-bottomed flask, (1.07g is 3.1mmol) with 1 of 4M HCl, 4-diox (8.0ml, 31.0mmol) solution to add 4-(6-chlorine imidazo [1,2-b] pyridazine-8-base the is amino) t-butyl perbenzoate that derives from 1a.To be reflected at stirring at room 18 hours, then vacuum concentration.Resulting 4-(6-chlorine imidazo [1,2-b] pyridazine-8-base is amino) phenylformic acid HCl salt (1.05g) uses with the form of crude product.

(1c) in the 50ml round-bottomed flask, add 4-(6-chlorine imidazo [1,2-b] pyridazine-8-base is amino) the phenylformic acid HCl salt derive from 1b (0.53g, 1.6mmol), methylene dichloride (10ml) and DMF (20 μ l).To this solution dropwise add pure oxalyl chloride (0.71ml, 8.2mmol).With resulting solution stirring 1 hour, vacuum concentration then.So obtain 4-(6-chlorine imidazo [1,2-b] pyridazine-8-base the is amino) Benzoyl chloride 99min. of 0.5g, be faint yellow solid.

(1d) will derive from 4-(the 6-chlorine imidazo [1 of 1c; 2-b] pyridazine-8-base amino) Benzoyl chloride 99min. (0.024g; 0.070mmol), methylene dichloride (0.7ml; 0.1M), 2-(pyridin-4-yl) ethamine (0.017ml, 0.13mmol) and diisopropylethylamine (0.012ml 0.18mmol) adds to a dram concave surface bottle (concavevial).With reaction sealed (cap), then stirring at room 2 hours.The solvent vacuum is removed, add then anti--1,4-cyclohexyl diamines.To react sealing, stir 18 hours at 165 ℃ then.After the cooling with resulting sample dissolution in methyl alcohol (25%)/water (75%) mixture (containing 4 trifluoroacetic acids).Resulting solution comes purifying through HPLC (5-60% methyl alcohol gradient), obtains the tfa salt (0.0.128g, 21%) of title compound, is brown solid. ¹H?NMR(400MHz，MeOH)δppm?8.75(2H，d，6.6Hz)，8.04-8.06(2H，dd，6.5Hz)，8.01(1H，d，2Hz)，7.88-7.90(3H，m)，7.43(2H，d，J＝8.6Hz)，6.74(1H，s)，3.81-3.83(3H，m)，3.30-3.34(2H，m)，3.10-3.20(1H，m)，2.30(2H，m)，2.10(2H，m)，1.55-1.58(2H，m)，1.35-1.45(2H，m)。LC/MS：m/e?471(M+1)。HPLC?Rt：1.39min。YMC ODSC18 chromatographic column (4.6 * 50mm).0％-100％B。Solvent B: (90%MeOH, 10%H ₂O, 0.1%TFA).Solvent orange 2 A: (10%MeOH, 90%H ₂O, 0.1%TFA).Gradient: being initiated with %B=0, finally is %B=100, and the gradient time is 4min, keeps 1min at 100%B, and flow velocity is 4mL/min.

Use suitable starting raw material and come preparation formula (Ia) compound, wherein R according to the method that is similar to embodiment XIV (1) with illustrated substantially the same method ₁, R ₂, R ₃, X and Y have value listed in table 7.

Table 7

Embodiment XV (1)

4-((6-((anti--the 4-aminocyclohexyl) amino) imidazo [1,2-b] pyridazine-8-yl) amino)-N-(1-(4-fluorophenyl)-2-oxo-1,2-dihydro-3-pyridyl) BM

(1a) with 4-(6-chlorine imidazo [1; 2-b] pyridazine-8-base is amino) phenylformic acid (0.050g, 0.17mmol is as preparing), derive from 3-amino-1-(4-fluorophenyl) pyridine-2 (1H)-ketone (0.053g of 1a-1 and 1a-2 hereinafter described described in embodiment XIV step 1b; 0.26mmol), EDCI (0.050g; 0.26mmol), HOBt (0.035g, 0.26mmol), TEA (0.07ml, 0.51mmol), DMF (0.8ml) and CH ₃CN (0.8ml) adds to 2 dram bottles.To be reflected at 50 ℃ stirred 12 hours.After the cooling solvent vacuum is removed, use methyl alcohol (2ml) dilution then.Resulting solution comes purifying through HPLC (20-100% methyl alcohol gradient), obtains 4-(6-chlorine imidazo [1,2-b] pyridazine-8-base is amino)-N-(1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-yl) BM of 0.0.12g.

(1a-1) with 4-fluorophenyl boric acid (Combi-block, 6.0mmol, 840mg), venus crystals (II) (Aldrich; 4.5mmol, 815mg) and pyridine (2mL) add to 2-hydroxy-3-nitropyridine (Aldrich, 3.0mmol; 420mg) 1,4-diox (20mL) solution.To be reflected at 80 ℃ of heating 20h.Be cooled to the cold water that adds 30mL after the room temperature.Formed solid by filtration is collected, and with volatile caustic and water washing, vacuum-drying then obtains 1-(4-fluorophenyl)-3-nitropyridine-2 (1H)-ketone (610mg, yield is 87%), is solid.

(1a-2) with ammonium chloride (695mg; 13.0mmol, EMD) with Zn powder (Zn dust) (850mg, 13.0mmol; Aldrich) add to 1-(4-fluorophenyl)-3-nitropyridine-2 (1H)-ketone (610mg, THF 2.6mmol) (50mL) and MeOH (50mL) solution that derives from 1a-1.With reaction mixture at stirring at room 3h; With the EtOAc dilution of 200mL, filter through

pad then.The vacuum concentration of will filtrating obtains 3-amino-1-(4-fluorophenyl) pyridine-2 (1H)-ketone (530mg, yield is 100%), is brown solid.

(1b) will be anti--1, the 4-DACH (0.5g, 57.0mmol) add to 4-(6-chlorine imidazo [1,2-b] pyridazine-8-base is amino)-N-(1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-yl) BM of deriving from 1a (0.011g, 0.023mmol).Make resulting mixture 160 ℃ of fusings, kept 12 hours.Then, make the melt cooling, dilute with water is used dichloromethane extraction then.Then, with the organic layer vacuum concentration, obtain the crude product of 0.020g.HPLC comes purifying through preparation property, obtains the title compound of 0.006g, is tfa salt. ¹H?NMR(400MHz，MeOD)δppm?8.56(1H，dd，J＝7.38，1.78Hz)，7.92-8.10(3H，m)，7.88(1H，d，J＝2.03Hz)，7.42-7.61(3H，m)，7.39(1H，dd，J＝7.12，1.53Hz)，7.30(2H，t，J＝8.65Hz)，6.77(1H，s)，6.54(1H，t，J＝7.12Hz)，3.97(1H，s)，3.66-3.84(1H，m)，3.03-3.24(1H，m)，2.26(2H，m)，2.00-2.20(2H，m)，1.44-1.68(2H，m)，1.22-1.46(2H，m)。LC/MS：m/e533(M+1)。HPLC?Rt：2.14min。YMC ODSC18 chromatographic column (4.6 * 50mm).0％-100％B。Solvent B: (90%MeOH, 10%H ₂O, 0.1%TFA).Solvent orange 2 A: (10%MeOH, 90%H ₂O, 0.1%TFA).Gradient: being initiated with %B=0, finally is %B=100, and the gradient time is 4min, keeps 1min at 100%B, and flow velocity is 4mL/min.

Use suitable starting raw material and come preparation formula (Ia) compound, wherein R according to the method that is similar to embodiment XV (1) with illustrated substantially the same method ₁, R ₂, R ₃, X and Y have value listed in table 8.

Table 8

Embodiment XVI (1)

1-(4-((6-((anti--the 4-aminocyclohexyl) amino) imidazo [1,2-b] pyridazine-8-yl) amino) phenyl)-3-phenylurea

(1a) with p-aminophenyl amine (0.48g, 4.4mmol) and triethylamine (1.3mg 9.2mmol) adds to 8-bromo-6-chlorine imidazo [1,2-b] pyridazine HCl salt (1.0g, EtOH 4.2mmol) (20mL) solution that derives from example I (1) step 1b.With resulting mixture heating up to 90 ℃ and stirred 1 hour.Then, with resulting solution for vacuum concentration, obtain thick N ¹-(6-chlorine imidazo [1,2-b] pyridazine-8-yl) benzene-1, the 4-diamines.Then, add cold ethanol, thick solid is cleaned 3 times.After filtering, collected the desired material of 0.45g.

(1b) will be anti--1, (1.7g 15.0mmol) adds to the N that derives from 1a to the 4-DACH ¹-(6-chlorine imidazo [1,2-b] pyridazine-8-yl) benzene-1, and the 4-diamines (0.2g, 0.77mmol).Make resulting mixture 160 ℃ of fusings, kept 3 days.Then, make the melt cooling, dilute with water is used dichloromethane extraction then.Then, with the organic layer vacuum concentration, obtain the thick N of 0.4g ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(4-aminophenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines.

(1c) N that derives from 1b is being housed ⁶-(instead)-4-aminocyclohexyl)-N ⁸-(4-aminophenyl) imidazo [1,2-b] pyridazine-6, (0.39g 1.1mmol) and in the 200ml round-bottomed flask of methylene dichloride (10ml), adds tert-Butyl dicarbonate (0.25g, methylene dichloride 1.1mmol) (2ml) solution to the 8-diamines.To be reflected at stirring at room 30min, concentrate then, in silica gel (ethyl acetate/heptane, 20min gradient: 15-100% ETHYLE ACETATE) go up purifying.Obtain (instead)-4-(8-(the 4-aminophenyl is amino) imidazo [1,2-b] pyridazine-the 6-base is amino) cyclohexyl t-butyl carbamate (0.050g), be white solid.

(1d) in 2 dram bottles; Add (instead)-4-(8-(the 4-aminophenyl the is amino) imidazo [1 that derives from 1c; 2-b] pyridazine-6-base is amino) the cyclohexyl t-butyl carbamate (and 0.04g, 0.09mmol), ethylene dichloride (1.0ml) and phenylcarbimide (0.05ml, 0.5mmol).To react and stir 2 hours, be concentrated into dried then.Add diethyl ether, resulting suspension is stirred 30min.Filter the back and collect (instead)-4-(8-(4-(3-phenyl urea groups) phenyl amino) imidazo [1,2-b] pyridazine-6-base is amino) cyclohexyl t-butyl carbamate (0.035g), under situation about not being further purified, use then.

(1e) in 2 dram bottles; Add (instead)-4-(8-(4-(the 3-phenyl urea groups) phenyl amino) imidazo [1 that derives from 1d; 2-b] pyridazine-6-base amino) (0.035g is 0.06mmol) with 1 of 4.0M HCl, 4-diox (2.0ml) solution for the cyclohexyl t-butyl carbamate.To be reflected at 25 ℃ and stir 1 hour, concentrate, grind with diethyl ether then.Title compound is leached, be HCl salt (0.018g). ¹H?NMR(400MHz，DMSO-D6)δppm?9.36(1H，s)，9.00(1H，s)，8.88(1H，s)，8.67(1H，s)，8.60(1H，s)，8.10(1H，s)，7.87(2H，d，J＝5.09Hz)，7.54(1H，d，J＝9.16Hz)，7.44(2H，t，J＝7.63Hz)，7.34(1H，s)，7.20-7.31(2H，m)，6.85-7.04(2H，m)，6.27(1H，s)，3.38(1H，s)，3.02(1H，s)，2.04(2H，m)，1.95(2H，m)，1.31-1.53(2H，m)，1.11-1.29(2H，m)。LC/MS：m/e?457(M+1)。HPLC?Rt：1.93min。YMCODSC18 chromatographic column (4.6 * 50mm).0％-100％B。Solvent B: (90%MeOH, 10%H ₂O, 0.1%TFA).Solvent orange 2 A: (10%MeOH, 90%H ₂O, 0.1%TFA).Gradient: being initiated with %B=0, finally is %B=100, and the gradient time is 4min, keeps 1min at 100%B, and flow velocity is 4mL/min.

Use suitable starting raw material and come preparation formula (Ia) compound, wherein R according to the method that is similar to embodiment XVI (1) with illustrated substantially the same method ₁, R ₂, R ₃, X and Y have value listed in table 9.

Table 9

Embodiment XVII (1)

N-(4-((6-((anti--the 4-aminocyclohexyl) amino) imidazo [1,2-b] pyridazine-8-yl) amino)-phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydro-3-pyridine carboxamide

(1a) in 2 dram reaction bottle; Add 8-bromo-6-chlorine imidazo [1,2-b] the pyridazine hydrochloride derive from example I (1) step 1b (0.5g, 1.9mmol), 4-N-methyl-p-nitroaniline (0.27g; 1.9mmol), the THF solution of 1.0M potassium tert.-butoxide (7.6ml, 7.6mmol) and DMF (1.4ml).To be reflected at N ₂Stirred 16 hours at 50 ℃ down, then vacuum concentration.Resulting material absorbing in ETHYLE ACETATE, is used H ₂(salt solution (1 * 20ml) washing is used in 2 * 50ml) washings to O then.Organic layer is merged, use Na ₂SO ₄Drying is filtered then.With solvent evaporation, obtained thick 6-chloro-N-(4-nitrophenyl) imidazo [1,2-b] pyridazine-8-amine of 0.42g afterwards.

(1b) in 2 dram reactions bottle, add thick 6-chloro-N-(4-nitrophenyl) imidazo [1,2-b] pyridazine-8-amine of deriving from 1a (0.42g, 1.4mmol) with anti--1, the 4-DACH (1.0g, 8.0mmol).Make resulting mixture 160 ℃ of fusings, kept 8 hours.Then, make the melt cooling, dilute with water is used dichloromethane extraction then.Organic layer is concentrated, obtain thick N ⁶-((instead)-4-aminocyclohexyl)-N ⁸-(4-nitrophenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines, it uses under situation about not being further purified.

(1c) N that derives from 1b is being housed ⁶-(instead)-4-aminocyclohexyl)-N ⁸-(4-nitrophenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines (0.31g, 0.85mmol), triethylamine (0.13ml, 0.93mmol) and in the 100ml round-bottomed flask of methylene dichloride (10ml), add tert-Butyl dicarbonate (0.3ml, 1.3mmol).To be reflected at 25 ℃ stirred 0.5 hour; Concentrate then; In silica gel (ethyl acetate/heptane, 20min gradient: 25-100% ETHYLE ACETATE) go up purifying, obtain (instead)-4-(8-(the 4-nitrophenyl is amino) imidazo [1; 2-b] pyridazine-6-base amino) cyclohexyl t-butyl carbamate (0.090g), be white solid.

(1d) in the 50ml round-bottomed flask; Add (instead)-4-(8-(the 4-nitrophenyl the is amino) imidazo [1 that derives from 1c; 2-b] pyridazine-6-base amino) cyclohexyl t-butyl carbamate (0.090g; 0.19mmol), chloroform (2.0ml), methyl alcohol (2.0ml), ammonium chloride (0.12g, 0.19mmol) and zinc powder (0.13g, 0.19mmol).To be reflected at stirring at room 30min.Then, will react and filter, clean with methylene dichloride then, obtain thick (instead)-4-(8-(the 4-aminophenyl is amino) imidazo [1,2-b] pyridazine-the 6-base is amino) cyclohexyl t-butyl carbamate of 0.1g through diatomaceous earth filler.

(1e) will derive from thick (instead)-4-(8-(4-aminophenyl amino) imidazo [1 of 1d; 2-b] pyridazine-6-base is amino) the cyclohexyl t-butyl carbamate (0.064g, 0.15mmol), 1-(4-fluorophenyl)-2-oxo-1 of preparing described in step 1e-1, the 1e-2 like hereinafter, 2-dihydropyridine-3-carboxylic acid (0.051g; 0.22mmol), EDCI (0.043g; 0.22mmol), HOBt (0.030g, 0.22mmol), TEA (0.06ml, 0.45mmol) and CH ₃CN (1ml) adds to 2 dram bottles.To be reflected at about 25 ℃ stirred 16 hours.Then, the solvent vacuum is removed, resulting sample dilutes with MeOH (4ml).Resulting solution comes purifying through HPLC (20-100% methyl alcohol gradient); Obtain (instead)-4-(8-(4-(5-(4-fluorophenyl)-6-oxo hexamethylene-1 of 0.025g; 3-diene formamido group) phenyl amino) imidazo [1,2-b] pyridazine-6-base is amino) the cyclohexyl t-butyl carbamate, be tfa salt.

(1e-1) in the 200ml round-bottomed flask, add 2-oxo-2H-piperazine to mutter-the 3-carboxylate methyl ester (5.45g, 35.0mmol), the 4-fluoroaniline (3.35ml, 35.0mmol) and DMF (63ml).To be reflected at stirring at room 3 hours.Then, add EDCI (9.4g, 50.0mmol) and DMAP (0.3g 2.0mmol), will be reflected at stirred overnight at room temperature.Reaction stops with the 1N HCl of 50ml, adds ETHYLE ACETATE then.Each layer separated ethyl acetate extraction 2 times of resulting then water.The organic phase that merges is used Na then with 10% lithium chloride solution washing 2 times ₂SO ₄Dry.With solid filtering, vacuum concentration obtains product afterwards then, is yellow solid.

(1e-2) in the 200ml round-bottomed flask, add 5-(4-fluorophenyl)-6-oxo hexamethylene-1,3-diene carboxylate methyl ester (1.1g, 4.3mmol), THF (8ml), MeOH (8ml) and 1N NaOH solution (13ml).To be reflected at stirred overnight at room temperature.Volatile matter (volatile) is concentrated the resulting basic soln in back with diethyl ether extraction 2 times.Then, water is acidified to pH 3 with 1N HCl, next uses dichloromethane extraction 2 times.Organic phase is collected, with saturated NaCl washing, each layer separated then.Resulting organic solution is used Na ₂SO ₄Drying is filtered, then vacuum concentration.The product that has so obtained 0.7g is 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid.

(1f) in the 50ml round-bottomed flask; Add (instead)-4-(8-(4-(5-(4-fluorophenyl)-6-oxo hexamethylene-1 that derives from 1e; 3-diene formamido group) imidazo [1 phenyl amino); 2-b] pyridazine-6-base is amino) (0.025g is 0.04mmol) with methylene dichloride (4ml) solution of 20% trifluoroacetic acid for the cyclohexyl t-butyl carbamate.To be reflected at stirring at room 5min.Then, will react vacuum concentration,, come purifying through HPLC (20-100% methyl alcohol gradient) then, obtain title compound (0.007g), be tfa salt with the methyl alcohol dilution. ¹HNMR(400MHz，MeOD)δppm?12.11(1H，s)，8.68(1H，dd，J＝7.38，2.29Hz)，7.87-8.13(2H，m)，7.71-7.88(3H，m)，7.41-7.63(2H，m)，7.33(4H，t，J＝8.65Hz)，6.65-6.82(1H，m)，6.43(1H，s)，3.54-3.88(1H，m)，2.96-3.17(1H，m)，2.23(2H，m)，2.08(2H，m)，1.44-1.68(2H，m)，1.17-1.43(2H，m)。LC/MS：m/e?553(M+1)。HPLC?Rt：2.14min。YMC ODSC18 chromatographic column (4.6 * 50mm).0％-100％B。Solvent B: (90%MeOH, 10%H ₂O, 0.1%TFA).Solvent orange 2 A: (10%MeOH, 90%H ₂O, 0.1%TFA).Gradient: being initiated with %B=0, finally is %B=100, and the gradient time is 4min, keeps 1min at 100%B, and flow velocity is 4mL/min.

Use suitable starting raw material and come preparation formula (Ia) compound, wherein R according to the method that is similar to embodiment XVII (1) with illustrated substantially the same method ₁, R ₂, R ₃, X and Y have value listed in table 10.

Table 10

Embodiment XVIII (1)

N-(4-((6-((anti--the 4-aminocyclohexyl) amino) imidazo [1,2-b] pyridazine-8-yl) amino) phenyl) BM

In 2 dram reaction bottle, add N ¹-(6-chlorine imidazo [1,2-b] pyridazine-8-yl) benzene-1, and 4-diamines (0.050g, 0.19mmol prepare in embodiment XVI step 1a), methylene dichloride (1.0ml) and triethylamine (0.040ml, 0.29mmol).To resulting solution dropwise add Benzoyl chloride 99min. (0.025ml, 0.21mmol).25 ℃ be will be reflected at and 30min, vacuum concentration then stirred.Add to resulting material anti--1, the 4-DACH (0.5g, 23.0mmol).Make resulting mixture 160 ℃ of fusings, kept 24 hours.Then, make the melt cooling, dilute with water is used dichloromethane extraction then.Then, with the organic layer vacuum concentration, obtain the crude product of 0.036g.Then, said thick material comes purifying through preparation property HPLC, obtains the title compound of 0.018g, is tfa salt. ¹H?NMR(400MHz，MeOD)δppm?7.94(3H，m)，7.76-7.88(3H，m)，7.45-7.67(3H，m)，7.36(2H，d，8.8Hz)，6.45(1H，s)，3.59-3.87(1H，m)，3.01-3.21(1H，m)，2.24(2H，m)，2.09(2H，m)，1.46-1.65(2H，m)，1.24-1.42(2H，m)。LC/MS：m/e?442(M+1)。HPLC?Rt：1.80min。YMC ODSC18 chromatographic column (4.6 * 50mm).0％-100％B。Solvent B: (90%MeOH, 10%H ₂O, 0.1%TFA).Solvent orange 2 A: (10%MeOH, 90%H ₂O, 0.1%TFA).Gradient: being initiated with %B=0, finally is %B=100, and the gradient time is 4min, keeps 1min at 100%B, and flow velocity is 4mL/min.

Embodiment XIX (1)

N-(4-((6-((anti--the 4-aminocyclohexyl) amino) imidazo [1,2-b] pyridazine-8-yl) amino) phenyl) ethanamide

In 2 dram reaction bottle, add N ¹-(6-chlorine imidazo [1,2-b] pyridazine-8-yl) benzene-1, and 4-diamines (0.050g, 0.19mmol is as preparing described in embodiment XVI step 1a), methylene dichloride (1.0ml) and triethylamine (0.040ml, 0.29mmol).To resulting solution dropwise add diacetyl oxide (0.022ml, 0.23mmol).25 ℃ be will be reflected at and 30min, vacuum concentration then stirred.Add to resulting material anti--1, the 4-DACH (0.5g, 4.3mmol).Make resulting mixture 160 ℃ of fusings, kept 24 hours.Then, make the melt cooling, dilute with water is used dichloromethane extraction then.Then, with the organic layer vacuum concentration, obtain the crude product of 0.030g.Then, said thick material comes purifying through preparation property HPLC.So obtain the title compound of 0.008g, be tfa salt. ¹H?NMR(400MHz，MeOD)δppm?7.95(1H，d，J＝2.03Hz)，7.86(1H，d，J＝2.03Hz)，7.65(2H，d，J＝8.65Hz)，7.29(2H，d，J＝9.16Hz)，6.40(1H，s)，3.60-3.81(1H，m)，3.02-3.24(1H，m)，2.17-2.30(2H，m)，2.13(3H，s)，2.04-2.12(2H，m)，1.43-1.64(2H，m)，1.24-1.42(2H，m)。LC/MS：m/e?380(M+1)。HPLC?Rt：1.62min。YMC ODSC18 chromatographic column (4.6 * 50mm).0％-100％B。Solvent B: (90%MeOH, 10%H ₂O, 0.1%TFA).Solvent orange 2 A: (10%MeOH, 90%H ₂O, 0.1%TFA).Gradient: being initiated with %B=0, finally is %B=100, and the gradient time is 4min, keeps 1min at 100%B, and flow velocity is 4mL/min.

Embodiment XX (1)

3-((6-((anti--the 4-aminocyclohexyl) amino)-7-Methylimidazole is [1,2-b] pyridazine-8-yl also) amino) phenol

(1a) in microwave bottle (microwave vial), add 8-bromo-6-chloro-7-Methylimidazole also [1,2-b] pyridazine (0.070g, 0.24mmol is as preparing), NMP (1.4ml), K described in EXAMPLE III step 1c ₂CO ₃(0.17g, 1.2mmol) and 3-(benzyloxy) aniline (0.050g, 0.24mmol).Reaction is heated 15min through microwave at 225 ℃.The resulting solution in cooling back comes purifying through preparation property HPLC then with MeOH (2ml) dilution.So obtained 3-(6-chloro-7-Methylimidazole also [1,2-b] pyridazine-8-base the is amino) phenol of 0.011g.m/z＝275。(annotate: cracking during reaction takes place in benzyl oxide)

(1b) in 2 dram reactions bottle, add 3-(6-chloro-7-Methylimidazole also [1,2-b] pyridazine-8-base the is amino) phenol that derives from 1a (0.011g, 0.028mmol) with anti--1, the 4-DACH (1.0g, 8.0mmol).Make resulting mixture 160 ℃ of fusings, kept 24 hours.Then, make the melt cooling, water and MeOH dilution come purifying through preparation property HPLC then, obtain the title compound of 0.005g, are tfa salt. ¹H?NMR(400MHz，MeOD)δppm?8.01(1H，s)，7.73(1H，s)，7.11(1H，t，J＝8.14Hz)，6.48(1H，d，J＝7.63Hz)，6.28(1H，s)，3.88-4.10(1H，m)，3.05-3.27(1H，m)，2.24-2.37(2H，m，J＝8.65Hz)，2.11-2.23(5H，m)，1.45-1.70(4H，m)。LC/MS：m/e?353(M+1)。HPLC?Rt：1.20min。YMCODSC18 chromatographic column (4.6 * 50mm).0％-100％B。Solvent B: (90%MeOH, 10%H ₂O, 0.1%TFA).Solvent orange 2 A: (10%MeOH, 90%H ₂O, 0.1%TFA).Gradient: being initiated with %B=0, finally is %B=100, and the gradient time is 4min, keeps 1min at 100%B, and flow velocity is 4mL/min.

Embodiment XXI (1)

N-(4-((6-chlorine imidazo [1,2-b] pyridazine-8-yl) amino) phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydro-3-pyridine carboxamide

With N ¹-(6-chlorine imidazo [1,2-b] pyridazine-8-yl) benzene-1,4-diamines (0.078g; 0.3mmol, as described in embodiment XVI step 1a, preparing), 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (0.10g; 0.45mmol, as described in embodiment XVII step 1e-2, preparing), EDCI (0.086g, 0.45mmol), HOBt (0.061g; 0.45mmol), TEA (0.12ml, 0.9mmol), DMF (0.8ml) and CH ₃CN (1.5ml) adds to 2 dram bottles.To be reflected at about 50 ℃ stirred 12 hours.After the cooling solvent vacuum is removed, use methyl alcohol (2ml) dilution then.Resulting solution comes purifying through HPLC (20-100% methyl alcohol gradient), obtains the title compound of 0.014g, is tfa salt. ¹H?NMR(400MHz，CHLOROFORM-D)δppm?11.88(1H，s)，8.70(1H，dd，J＝7.12，2.03Hz)，7.71-7.91(3H，m)，7.67(1H，s)，7.50-7.63(1H，m)，7.10-7.43(5H，m)，6.64(1H，s)，6.56(1H，t，J＝7.12Hz)。LC/MS：m/e?475(M+1)。HPLCRt：2.82min。YMC ODSC18 chromatographic column (4.6 * 50mm).0％-100％B。Solvent B: (90%MeOH, 10%H ₂O, 0.1%TFA).Solvent orange 2 A: (10%MeOH, 90%H ₂O, 0.1%TFA).Gradient: being initiated with %B=0, finally is %B=100, and the gradient time is 4min, keeps 1min at 100%B, and flow velocity is 4mL/min.

Embodiment XXII (1)

1-(4-fluorophenyl)-N-(4-(imidazo [1,2-b] pyridazine-8-base is amino) phenyl)-2-oxo-3-piperidyl urea

In 500ml PARR bottle; 10%Pd/C (20mg) and 2 triethylamines are added to N-(4-((the 6-chlorine imidazo [1 that derives from embodiment XXI; 2-b] pyridazine-8-yl) amino) phenyl)-1-(4-fluorophenyl)-2-oxo-1; 2-dihydro-3-pyridine carboxamide tfa salt (0.013g, 0.027mmol) and the suspension of EtOH (4mL).Then, the PARR bottle is with the H of 55psi ₂Fill, room temperature concussion 12 hours.Then, reaction mixture is filtered the vacuum concentration of to filtrate then.Resulting resistates comes purifying through preparation property HPLC, obtains the title compound of 0.008g, is tfa salt.LC/MS：m/e?445(M+1)。HPLC?Rt：1.81min。YMC ODSC18 chromatographic column (4.6 * 50mm).0％-100％B。Solvent B: (90%MeOH, 10%H ₂O, 0.1%TFA).Solvent orange 2 A: (10%MeOH, 90%H ₂O, 0.1%TFA).Gradient: being initiated with %B=0, finally is %B=100, and the gradient time is 4min, keeps 1min at 100%B, and flow velocity is 4mL/min.

Embodiment XXIII (1)

1-(4-fluorophenyl)-N-(4-(imidazo [1,2-b] pyridazine-8-base is amino) phenyl)-2-oxo-1,2-dihydro-3-pyridine carboxamide

(1a) N is being housed ¹-(6-chlorine imidazo [1,2-b] pyridazine-8-yl) benzene-1, in the 100ml round-bottomed flask of 4-diamines (0.5g, 1.9mmol is as preparing described in the embodiment XVI step 1b) and THF (10ml), the interpolation tert-Butyl dicarbonate (0.44g, 1.9mmol).To be reflected at 50 ℃ and stir 5 hours, concentrate then, in silica gel (ethyl acetate/heptane; 20min gradient: 5-50% ETHYLE ACETATE) go up purifying; Obtain 4-(6-chlorine imidazo [1,2-b] pyridazine-8-base is amino) the phenylcarbamic acid tert-butyl ester (0.050g), be white solid.

(1b) in 500ml PARR bottle, with 10%Pd/C (0.02g) and 2 triethylamines add to 4-(6-chlorine imidazo [1,2-b] pyridazine-8-base is amino) the phenylcarbamic acid tert-butyl ester that derives from 1a (0.1g, 0.28mmol) and the mixture of EtOH (4mL).Then, the PARR bottle is with the H of 55psi ₂Fill, room temperature concussion 12 hours.Then, reaction mixture is filtered, the vacuum concentration of will filtrate then obtains thick 4-(imidazo [1,2-b] pyridazine-8-base amino) the phenylcarbamic acid tert-butyl ester of 0.085g.

(1c) in 2 dram bottles, (0.085g is 0.26mmol) with 1 of 4M HCl, 4-diox (5.0ml) solution to add 4-(imidazo [1,2-b] pyridazine-8-base is amino) the phenylcarbamic acid tert-butyl ester that derives from 1b.To be reflected at 25 ℃ and stir 2 hours, concentrate.Obtain N ¹-(imidazo [1,2-b] pyridazine-8-yl) benzene-1, the 4-diamines is two HCl salt (0.085g).Said product uses under situation about not being further purified.

(1d) will derive from the N of 1c ¹-(imidazo [1,2-b] pyridazine-8-yl) benzene-1,4-diamines two HCl salt (0.080g; 0.3mmol), 1-(4-fluorophenyl)-2-oxo-1; 2-dihydropyridine-3-carboxylic acid (0.13g, 0.57mmol), EDCI (0.11g, 0.57mmol), HOBt (0.077g; 0.57mmol), TEA (0.16ml, 1.1mmol) and CH ₃CN (4ml) adds to 2 dram bottles.To be reflected at about 25 ℃ stirred 12 hours.Then, the solvent vacuum is removed, resulting then sample dilutes with MeOH (4ml).Resulting solution comes purifying through HPLC (20-100% methyl alcohol gradient), obtains the title compound of 0.015g, is tfa salt. ¹H?NMR(400MHz，DMSO-D6)δppm?11.96(1H，s)，9.47(1H，s)，8.59(1H，dd，J＝7.38，2.29Hz)，7.99-8.27(3H，m)，7.67-7.85(3H，m)，7.55-7.67(2H，m，J＝9.16，5.09Hz)，7.33-7.49(3H，m)，6.66-6.82(1H，m)，6.55(1H，d，J＝6.10Hz)。LC/MS：m/e?441(M+1)。HPLC?Rt：2.64min。YMC ODSC18 chromatographic column (4.6 * 50mm).0％-100％B。Solvent B: (90%MeOH, 10%H ₂O, 0.1%TFA).Solvent orange 2 A: (10%MeOH, 90%H ₂O, 0.1%TFA).Gradient: being initiated with %B=0, finally is %B=100, and the gradient time is 4min, keeps 1min at 100%B, and flow velocity is 4mL/min.

Embodiment XXIV (1)

6-((anti--the 4-aminocyclohexyl) amino)-8-((4-(oxyethyl group) phenyl) amino) imidazo [1,2-b] pyridazine-3-formonitrile HCN

(1a) in the 200ml round-bottomed flask, add 8-bromo-6-chlorine imidazo [1,2-b] the pyridazine hydrochloride derive from example I (1) step 1b (3.0g, 11.2mmol), chloroform (55ml) and NBS (3.0g, 16.8mmol).To be reflected at 80 ℃ of heating 1 hour, and be cooled to room temperature, volatile matter is removed in decompression then.Add ETHYLE ACETATE, the mixture of gained is used Na ₂CO ₃(H is used in 2 * 100ml) washings ₂(salt solution (1 * 25ml) washing is used in 2 * 100ml) washings to O then.Organic layer is merged, use Na ₂SO ₄Drying concentrates then.So obtained the thick 3 of 1.8g, 8-two bromo-6-chlorine imidazo [1,2-b] pyridazines.

(1b) with p-phenetidine (0.38ml, 2.9mmol) and triethylamine (0.8ml 5.8mmol) adds to and derives from 3 of 1a, 8-two bromo-6-chlorine imidazo [1,2-b] pyridazine (0.83g, 2.67mmol) mixtures in EtOH (10mL).With resulting mixture heating up to 80 ℃ and stirred 16 hours.Then, with resulting solution for vacuum concentration, obtain thick 3-bromo-6-chloro-N-(4-ethoxyl phenenyl) imidazo [1,2-b] pyridazine-8-amine.

(1c) in 5ml microwave bottle, add 3-bromo-6-chloro-N-(4-ethoxyl phenenyl) imidazo [1, the 2-b] pyridazine-8-amine derive from 1b (0.3g, 0.8mmol), Pd (PPh ₃) ₄(0.18g, 0.16mmol), Zn (CN) ₂(0.47g, 4.0mmol) and DMF (3ml).Reaction is heated 25min through microwave at 200 ℃.Cooling afterreaction mixture dilutes with ETHYLE ACETATE, filters through diatomaceous earth filler then.The solvent vacuum is removed, and resulting material is through silica gel chromatography (ethyl acetate/heptane, 25min gradient: 5-50% ETHYLE ACETATE) come purifying, obtain 6-chloro-8-(the 4-ethoxyl phenenyl is amino) imidazo [1, the 2-b] pyridazine-3-formonitrile HCN of 0.11g.

(1e) in 2 dram reactions bottle, add 6-chloro-8-(the 4-ethoxyl phenenyl is amino) imidazo [1, the 2-b] pyridazine-3-formonitrile HCN that derives from 1c (0.055g, 0.017mmol) with anti--1, the 4-DACH (1.0g, 8.0mmol).Make resulting mixture 160 ℃ of fusings, kept 1.5 hours.Then, make the melt cooling, dilute with water is used dichloromethane extraction then.Organic layer is concentrated,, come purifying through preparation property HPLC then, obtain the title compound of 0.039g, be tfa salt with the MeOH dilution. ¹HNMR (500MHz, solvent) δ ppm 7.91 (1H, s), 7.23 (2H, d, J=8.80Hz), 6.96 (2H, d; J=8.80Hz), 5.96 (1H, s), 4.04 (4H, q, J=6.78Hz), 3.61-3.80 (1H, m); 2.99-3.19 (1H, m), 2.16-2.35 (2H, m, J=11.55Hz), 2.01-2.16 (2H, m, J=12.65Hz); 1.47-1.65 (2H, m), 1.39 (3H, t, J=7.15Hz), 1.24-1.36 (2H, m).LC/MS：m/e?392(M+1)。HPLC?Rt：2.69min。YMC ODSC18 chromatographic column (4.6 * 50mm).0％-100％B。Solvent B: (90%MeOH, 10%H ₂O, 0.1%TFA).Solvent orange 2 A: (10%MeOH, 90%H ₂O, 0.1%TFA).Gradient: being initiated with %B=0, finally is %B=100, and the gradient time is 4min, keeps 1min at 100%B, and flow velocity is 4mL/min.

Use suitable starting raw material and come preparation formula (Ia) compound, wherein R according to the method that is similar to embodiment XXIV (1) with illustrated substantially the same method ₁, R ₂, R ₃, X and Y have value listed in table 11.

Table 11

Embodiment XXV (1)

6-((4-anti--aminocyclohexyl) amino)-7-methyl-8-(phenyl amino) imidazo [1,2-b] pyridazine-3-formonitrile HCN

(1a) in the 200ml round-bottomed flask, add derive from EXAMPLE III step 1c 8-bromo-6-chloro-7-Methylimidazole also [1,2-b] pyridazine hydrochloride (0.52g, 1.8mmol), chloroform (10ml) and NBS (0.5g, 2.7mmol).To be reflected at 80 ℃ of heating 1 hour, and be cooled to room temperature, volatile matter is removed in decompression then.Add ETHYLE ACETATE, resulting mixture is used Na ₂CO ₃(H is used in 2 * 100ml) washings ₂(salt solution (1 * 25ml) washing is used in 2 * 100ml) washings to O then.Organic layer is merged, use Na ₂SO ₄Drying concentrates then.So obtained the crude product of 1.8g, then said crude product has been loaded on the silica gel with dry method, used 30% ETHYLE ACETATE to come purifying as mobile phase through column chromatography.So obtained 0.14g simple 3,8-two bromo-6-chloro-7-Methylimidazoles are also [1,2-b] pyridazine.

(1b) in 2 dram reactions bottle, add deriving from 3 of 1a, 8-two bromo-6-chloro-7-Methylimidazoles also [1,2-b] pyridazine (0.14g, 0.43mmol), THF (1.0ml) solution and the THF (1.4ml) of 1.0M potassium tert.-butoxide.To be reflected at N ₂Down stirring at room 1 hour, vacuum concentration then.Resulting material absorbing in ETHYLE ACETATE, is used H ₂(salt solution (1 * 20ml) washing is used in 2 * 50ml) washings to O then.Organic layer is merged, use Na ₂SO ₄Drying is filtered then.With solvent evaporation, obtained the crude product of 0.14g afterwards.(ethyl acetate/heptane, the 25min gradient: 5-50% ETHYLE ACETATE) be further purified, the 3-bromo-6-chloro-7-methyl-N-phenylimidazole that obtains 0.053g is [1,2-b] pyridazine-8-amine also through silica gel chromatography.

(1c) in 5ml microwave bottle, add derive from 1b 3-bromo-6-chloro-7-methyl-N-phenylimidazole also [1,2-b] pyridazine-8-amine (0.053g, 0.16mmol), Pd (PPh ₃) ₄(0.036g, 0.032mmol), Zn (CN) ₂(0.088g, 0.78mmol) and DMF (3ml).To react through microwave at 180 ℃ of heating 30min.Cooling afterreaction mixture dilutes with ETHYLE ACETATE, filters through diatomaceous earth filler then.The solvent vacuum is removed, and resulting then material comes purifying through preparation property HPLC, and the 3-bromo-6-chloro-7-methyl-N-phenylimidazole that obtains 0.013g is [1,2-b] pyridazine-8-amine also.

(1d) in 2 dram reactions bottle, add derive from 1c 3-bromo-6-chloro-7-methyl-N-phenylimidazole also [1,2-b] pyridazine-8-amine (0.013g, 0.045mmol) with anti--1, the 4-DACH (1.0g, 8.0mmol).Make resulting mixture 160 ℃ of fusings, keep 45min.Then, make the melt cooling, dilute with water is used dichloromethane extraction then.Organic layer is concentrated,, come purifying through preparation property HPLC then, obtain title compound, be tfa salt then with the MeOH dilution. ¹H?NMR(400MHz，MeOD)δppm?7.99(1H，s)，7.19-7.33(2H，m)，6.97(1H，t，J＝7.38Hz)，6.87(2H，d，J＝7.63Hz)，3.88-4.02(1H，m)，3.07-3.25(1H，m)，2.25-2.40(2H，m，J＝12.21Hz)，2.07-2.22(2H，m，J＝12.21Hz)，1.94(3H，s)，1.41-1.72(4H，m)。LC/MS：m/e?362(M+1)。HPLC?Rt：2.58min。YMC ODSC18 chromatographic column (4.6 * 50mm).0％-100％B。Solvent B: (90%MeOH, 10%H ₂O, 0.1%TFA).Solvent orange 2 A: (10%MeOH, 90%H ₂O, 0.1%TFA).Gradient: being initiated with %B=0, finally is %B=100, and the gradient time is 4min, keeps 1min at 100%B, and flow velocity is 4mL/min.

Use suitable starting raw material and come preparation formula (Ia) compound, wherein R according to the method that is similar to embodiment XXV (1) with illustrated substantially the same method ₁, R ₂, R ₃, X and Y have value listed in table 12.

Table 12

Embodiment XXVI (1)

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(4-(oxyethyl group) phenyl)-3-flumizole is [1,2-b] pyridazine-6 also, the 8-diamines

(1a) in 20ml reaction bottle, add 8-bromo-6-chlorine imidazo [1,2-b] the pyridazine hydrochloride that derives from example I (1) step 1b (0.33g, 1.4mmol), CH ₃CN (7.0ml) and Selectflor (0.5g, 1.4mmol).To be reflected at 50 ℃ and stir 6 hours, be concentrated into dried then.(ethyl acetate/heptane, the 25min gradient: 5-50% ETHYLE ACETATE) come purifying, the 8-bromo-6-chloro-3-flumizole that obtains 0.085g is [1,2-b] pyridazine also through silica gel chromatography.

(1b) with p-phenetidine (0.044ml, 0.34mmol) and triethylamine (0.1ml 0.75mmol) adds to 8-bromo-6-chloro-3-flumizole [1,2-b] pyridazine (0.085g, 0.34mmol) mixture in EtOH (1.7mL) also that derives from 1a.With resulting mixture heating up to 80 ℃ and stirred 16 hours.Then, with resulting solution for vacuum concentration, obtain also [1,2-b] pyridazine-8-amine of thick 6-chloro-N-(4-ethoxyl phenenyl)-3-flumizole.

(1c) in 2 dram reactions bottle, add derive from 1b 6-chloro-N-(4-ethoxyl phenenyl)-3-flumizole also [1,2-b] pyridazine-8-amine (0.080g, 0.26mmol) with anti--1, the 4-DACH (1.0g, 8.0mmol).Make resulting mixture 160 ℃ of fusings, kept 5 hours.Then, make the melt cooling, dilute with water is used dichloromethane extraction then.Organic layer is concentrated,, come purifying through preparation property HPLC then, obtain title compound, be tfa salt then with the MeOH dilution. ¹H NMR (500MHz, solvent) δ ppm 7.32 (1H, d, J=6.05Hz), 7.24 (2H, d, J=8.80Hz), 6.98 (2H; D, J=8.80Hz), 5.99 (1H, s), 4.05 (2H, q, J=7.15Hz), 3.66-3.79 (1H; M), and 3.04-3.18 (1H, m), 2.16-2.28 (2H, m, J=11.55Hz), 1.99-2.12 (2H, m; J=12.10Hz), 1.46-1.62 (2H, m), 1.39 (3H, t, J=6.87Hz), 1.25-1.36 (2H, m).LC/MS：m/e?385(M+1)。HPLC?Rt：2.25min。YMC ODSC18 chromatographic column (4.6 * 50mm).0％-100％B。Solvent B: (90%MeOH, 10%H ₂O, 0.1%TFA).Solvent orange 2 A: (10%MeOH, 90%H ₂O, 0.1%TFA).Gradient: being initiated with %B=0, finally is %B=100, and the gradient time is 4min, keeps 1min at 100%B, and flow velocity is 4mL/min.

Embodiment XXVII (1)

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(4-(oxyethyl group) phenyl)-3-Methylimidazole is [1,2-b] pyridazine-6 also, the 8-diamines

(1a) with the acetic acid soln of 4 35%HBr add to thick 4-bromo-6-chloro-pyridazine-3-amine of deriving from example I (1) step 1b (0.5g, 2.3mmol), 2-chloro-1,1-Propanal dimethyl acetal (1.6ml), EtOH (5ml) and H ₂The mixture of O (2ml).To be reflected at 100 ℃ stirred 16 hours.Then, reaction is concentrated into dried, grinds with diethyl ether then.Obtain also [1,2-b] pyridazine and 6 of 8-bromo-6-chloro-3-Methylimidazole after the filtration, 8-two chloro-3-Methylimidazoles are the mixture of [1,2-b] pyridazine also, is HCl salt.

(1b) with p-phenetidine (0.068g, 0.5mmol) and triethylamine (0.15ml 1.1mmol) adds to the 8-bromo-6-chloro-3-Methylimidazole also [1 that derives from 1a; 2-b] pyridazine and 6; 8-two chloro-3-Methylimidazoles are [1,2-b] pyridazine (0.011g, 0.5mmol) mixture in EtOH (10mL) also.With resulting mixture heating up to 90 ℃ and stirred 30 hours.Then, with resulting solution for vacuum concentration, obtain also [1,2-b] pyridazine-8-amine of thick 6-chloro-N-(4-ethoxyl phenenyl)-3-Methylimidazole.

(1c) in 2 dram reactions bottle, add derive from 1b thick 6-chloro-N-(4-ethoxyl phenenyl)-3-Methylimidazole also [1,2-b] pyridazine-8-amine (0.15g, 0.5mmol) with anti--1, the 4-DACH (1.0g, 8.0mmol).Make resulting mixture 160 ℃ of fusings, kept 48 hours.Then, make the melt cooling, dilute with water is used dichloromethane extraction then.Organic layer is concentrated,, come purifying through preparation property HPLC then, obtain title compound, be tfa salt then with the MeOH dilution. ¹H?NMR(400MHz，MeOD)δppm?7.62(1H，s)，7.25(2H，d，J＝9.16Hz)，6.99(2H，d，J＝9.16Hz)，6.21(1H，s)，4.05(2H，q，J＝7.12Hz)，3.64-3.89(1H，m)，3.00-3.22(1H，m)，2.48(3H，s)，2.17-2.38(2H，m，J＝11.19Hz)，1.99-2.18(2H，m，J＝12.21Hz)，1.45-1.71(2H，m)，1.22-1.46(5H，m)。LC/MS：m/e?381(M+1)。HPLC?Rt：1.91min。YMC ODSC18 chromatographic column (4.6 * 50mm).0％-100％B。Solvent B: (90%MeOH, 10%H ₂O, 0.1%TFA).Solvent orange 2 A: (10%MeOH, 90%H ₂O, 0.1%TFA).Gradient: being initiated with %B=0, finally is %B=100, and the gradient time is 4min, keeps 1min at 100%B, and flow velocity is 4mL/min.

Embodiment XXVIII (1)

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(4-(oxyethyl group) phenyl)-2,3-dimethyl-imidazo [1,2-b] pyridazine-6,8-diamines

(1a) will derive from example I (1) step 1a 4-bromo-6-chloro-pyridazine-3-amine (0.1g, 0.48mmol), 3-neoprene-2-ketone (0.42g, 3.3mmol) and the mixture of EtOH (1ml) stirred 48 hours at 90 ℃.Then, reaction is concentrated into dried, grinds with diethyl ether then.Obtain oily mater after the filtration.Comprise said oily solid melt (frit) and use washed with methanol, then resulting material is collected, be 8-bromo-6-chloro-2,3-dimethyl-imidazo [1,2-b] pyridazine and 6,8-two chloro-2, the mixture of 3-dimethyl-imidazo [1,2-b] pyridazine (HCl salt).

(1b) with p-phenetidine (0.04g, 0.29mmol) and salt of wormwood (0.12g 0.87mmol) adds to the 8-bromo-6-chloro-2 that derives from 1a; 3-dimethyl-imidazo [1; 2-b] pyridazine and 6,8-two chloro-2,3-dimethyl-imidazo [1; 2-b] pyridazine (HCl salt) (0.063g, 0.29mmol) mixture in EtOH (1.0mL).With resulting mixture heating up to 90 ℃ and stirred 48 hours.Then, with resulting solution for vacuum concentration, come purifying through preparation property HPLC (20-100% methanol gradient) then.6-chloro-N-(4-the ethoxyl phenenyl)-3-Methylimidazole that has so obtained 0.013g is [1,2-b] pyridazine-8-amine also.

(1c) in 2 dram reactions bottle, add the thick 6-chloro-N-(4-ethoxyl phenenyl)-2 that derives from 1b, 3-dimethyl-imidazo [1,2-b] pyridazine-8-amine (0.013g, 0.04mmol) with anti--1, the 4-DACH (1.0g, 8.0mmol).Make resulting mixture 160 ℃ of fusings, kept 4 days.Then, make the melt cooling, dilute with water is used dichloromethane extraction then.Organic layer is concentrated,, come purifying through preparation property HPLC then then with the MeOH dilution.So obtain the title compound of 0.005g, be tfa salt. ¹H?NMR(500MHz，MeOD)δppm?7.24(2H，d，J＝8.25Hz)，7.00(2H，d，J＝8.80Hz)，6.17(1H，s)，4.05(2H，q，J＝6.96Hz)，3.62-3.83(1H，m)，3.02-3.21(1H，m)，2.47(3H，s)，2.42(3H，s)，2.18-2.29(2H，m，J＝11.55Hz)，2.03-2.14(2H，m，J＝12.65Hz)，1.45-1.62(2H，m)，1.39(3H，t，J＝6.87Hz)，1.26-1.36(2H，m)。LC/MS：m/e?395(M+1)。HPLC?Rt：2.49min。YMC ODSC18 chromatographic column (4.6 * 50mm).0％-100％B。Solvent B: (90%MeOH, 10%H ₂O, 0.1%TFA).Solvent orange 2 A: (10%MeOH, 90%H ₂O, 0.1%TFA).Gradient: being initiated with %B=0, finally is %B=100, and the gradient time is 4min, keeps 1min at 100%B, and flow velocity is 4mL/min.

Embodiment XXIX (1)

N-(6-((anti--the 4-aminocyclohexyl) amino) imidazo [1,2-b] pyridazine-8-yl) benzsulfamide

(1a) with benzsulfamide (58mg, 0.37mmol), three (dibenzalacetones) close two palladiums (0) (2mg, 0.0022mmol), 4; Two (diphenylphosphino)-9 of 5-; 9-dimethyl-xanthene (4mg, 0.0077mmol) and cesium carbonate (240mg 1.25mmol) adds to 16 * 100mm pipe.Said pipe is vacuumized, recharge with nitrogen then.Then, add 8-bromo-6-chlorine imidazo [1, the 2-b] pyridazine derive from example I (1) step 1b (120mg, 0.4466mmol) with 1,4-diox (1.0ml).Resulting mixture was heated 16 hours at 100 ℃.Then, resulting solution dilutes with methylene dichloride, filters, and vacuum concentration obtains thick N-(6-chlorine imidazo [1,2-b] pyridazine-8-yl) benzsulfamide (100mg, 73%) then.

(1b) will be anti--1, the 4-DACH (1000mg, 8.77mmol) add to N-(6-chlorine imidazo [1, the 2-b] pyridazine-8-yl) benzsulfamide that derives from 1a (100mg, 0.325mmol).Resulting mixture is melted at 165C, kept 3 days.Then, make the melt cooling, add water, next use dichloromethane extraction.Then, with the organic layer vacuum concentration, come purifying through preparation property HPLC then.So having obtained the title compound of 4.5mg (2%), is two tfa salts. ¹H?NMR(500MHz，MeOH-D ₃)δppm?7.97(2H，d，J＝5Hz)，7.85(1H，s)，7.71(1H，s)，7.63(1H，m)，7.56(2H，m)，6.63(1H，s)，3.64(1H，m)，3.12(1H，m)，2.23-2.04(4H，m)，1.51(2H，m)，1.34(2H，m)。LC/MS?m/e?387(MH+)。HPLC?Rt：1.600min。Waters?Sunfire?C184.6×50。0％-100％B。B：(90％MeOH，10％H ₂O，0.1％TFA)。A：(10％MeOH，90％H ₂O，0.1％TFA)。

Embodiment XXXI (1)

6-((anti--the 4-aminocyclohexyl) oxygen base)-8-phenylamino imidazo [1,2-b] pyridazine-3-formonitrile HCN

(1a) (215mg 1mmol) is dissolved in the dry DMF (4mL), places under the nitrogen atmosphere, in ice bath, is cooled to 0 ℃ with N-(4-methoxy-benzyl) aniline.Add potassium tert.-butoxide (1mL, 1mmol, the THF solution of 1M), resulting mixture is stirred 10min at 0 ℃, then at stirring at room 30min.Resulting mixture is cooled to 0 ℃.Add the solid 3 that derives from embodiment XXIV step 1a, and 8-two bromo-6-chlorine imidazo [1,2-b] pyridazines (310mg, 1mmol).Resulting mixture is stirred 30min at 0 ℃, then in stirred overnight at room temperature.Said mixture is used 10%LiCl, water and brine wash successively with ETHYLE ACETATE (100mL) dilution, uses anhydrous magnesium sulfate drying then.The solvent vacuum is removed, and (ethyl acetate/heptane, the 25min gradient: 5-50% ETHYLE ACETATE) come purifying, 3-bromo-6-chloro-N-(4-the methoxy-benzyl)-N-phenylimidazole that obtains 0.27g is [1,2-b] pyridazine-8-amine also through silica gel chromatography for resulting then material.

(1b) the microwave bottle is equipped with 3-bromo-6-chloro-N-(4-the methoxy-benzyl)-N-phenylimidazole also [1 that derives from step 1a; 2-b] pyridazine-8-amine (220mg; 0.49mmol), zinc cyanide (34.8mg, 0.3mmol), three (dibenzalacetones) close two palladiums (0) (22.7mg, 0.025mmol), 1; 1 '-two (diphenylphosphino) ferrocene (19.8mg, 0.036mmol) and DMF (2mL).Resulting mixture is heated 15min at 150 ℃ in microwave.Make resulting solution cooling,,, use anhydrous magnesium sulfate drying, then vacuum concentration with saturated LiCl solution washing with the ETHYLE ACETATE dilution.Resulting resistates comes purifying through silica gel chromatography (5% ethyl acetate/heptane), and 6-chloro-3-cyanic acid-N-(4-the methoxy-benzyl)-N-phenylimidazole that obtains 91mg is [1,2-b] pyridazine-8-amine also.

(1c) in the bottle of the usefulness diaphragm seals that is lined with Teflon, with 6-chloro-3-cyanic acid-N-(4-the methoxy-benzyl)-N-phenylimidazole that derives from 1b [1,2-b] pyridazine-8-amine (20mg also; 0.05mmol), (instead)-4-hydroxy-cyclohexyl t-butyl carbamate (22mg; 0.1mmol), acid chloride (II) (1.1mg, 0.005mmol), 1,2; 3; 4,5-pentapheneyl-1 '-(di-t-butyl phosphino-) ferrocene (7.5,0.01mmol) and the mixture of cesium carbonate (100mg) be suspended in no Shui diox (1mL).Said container is used purification for argon, then at 105 ℃ of heating 48h.LCMS shows product (m/z, M+1,569.4) and starting raw material coexistence (transformation efficiency is about 25%).Make reaction cooled, filter through diatomaceous earth filler, Celite pad cleans with the ETHYLE ACETATE of about 5ml then.The solvent vacuum is removed, then resulting oily matter is suspended among the TFA of 1mL, at 50 ℃ of heating 2h.Reaction and display is removed methoxy-benzyl protection base fully.TFA removes under airflow, then resulting mixture is absorbed among the MeOH (2mL), and HPLC comes purifying through preparation property, obtains the title compound of 2.2mg, is tfa salt.MS?m/e?349(M+1)。 ¹H?NMR(MeOH，δ)8.1(1H，s)，7.48(2H，t，J＝8Hz)，7.39(2H，d，J＝8Hz)，7.27(1H，t，J＝8Hz)，6.21(1H，s)，5.00(1H，m)，3.21(1H，m)，2.38(2H，m)，2.15，(2H，m)，1.62(4H，m)。

Embodiment XXXII (1)

6-((anti--the 4-aminocyclohexyl) amino)-8-phenylamino imidazo [1,2-b] pyridazine-3-methane amide

(1a) with 6-chloro-3-cyanic acid-N-(4-the methoxy-benzyl)-N-phenylimidazole that derives from embodiment XXXI (1) step 1b in the bottle also [1; 2-b] pyridazine-8-amine (25mg; 0.0625mmol), 6N NaOH (0.1mL); (0.1mL) is with the mixture heating up to 100 of diox (1mL) ℃ keeps 16h to MeOH.Resulting mixture is cooled to room temperature, then vacuum concentration.Form deposition after adding 1M HCl.Said deposition is collected through filtering, and is dry then, obtains thick 6-chloro-8-((4-methoxy-benzyl) (phenyl) amino) imidazo [1,2-b] pyridazine-3-methane amide of 35mg.

(1b) will be anti--1, (250mg 2.18mmol) adds to the bottle that comprises thick 6-chloro-8-((4-methoxy-benzyl) (phenyl) amino) imidazo [1, the 2-b] pyridazine-3-methane amide (35mg) that derives from 1a to 4-cyclohexyl diamines.With resulting mixture heating up to 160 ℃, keep 4h.Said mixture is cooled to room temperature, and dilute with water forms deposition then.To precipitate collection, use water washing, dry then, obtain thick 6-((instead)-4-aminocyclohexyl is amino)-8-((4-methoxy-benzyl) (phenyl) amino) imidazo [1,2-b] pyridazine-3-methane amide.

Thick 6-((instead)-4-aminocyclohexyl amino)-8-((4-methoxy-benzyl) (phenyl) amino) imidazo [1, the 2-b] pyridazine-3-methane amide that (1c) will derive from 1b is suspended in the trifluoroacetic acid (1mL), is heated to 50 ℃, keeps 2h.Resulting mixture is cooled to room temperature, trifluoroacetic acid is evaporated under nitrogen gas stream.Resulting resistates is suspended in the methyl alcohol, filters, remove solid, come purifying through preparation property HPLC then, obtain the title compound of 2.1mg, be tfa salt.MS?m/e?366(M+1)。 ¹H?NMR(MeOH，δ)8.1(1H，s)，7.46(2H，t，J＝8Hz)，7.39(2H，d，J＝8Hz)，7.23(1H，t，J＝8Hz)，6.31(1H，s)，3.62(1H，m)，3.17(1H，m)，2.30(2H，m)，2.13(2H，m)，1.55(2H，m)，1.42(2H，m)。

Embodiment XXXIII (1)

N ⁶-(anti--the 4-aminocyclohexyl)-7-ethyl-N ⁸-phenylimidazole is [1,2-b] pyridazine-6 also, the 8-diamines

(1a) at 50 ℃, with sulfuric acid (11.54mL, 0.227ml; 3.0 water equivalent) (125mL) solution adds to 3,6-dichloro-pyridazine (11.25g, 0.076mol; 1.0 equivalent), Silver Nitrate (6.41g, 0.038mol, 0.5 equivalent) and propionic acid (8.39g; 0.113mol, 1.5 equivalents) and suspension in water (125ml).Resulting solution is heated to 60 ℃, in 20 minutes, adds ammonium persulfate solution (51.7g, 0.227mol, 3.0 equivalents) then lentamente.Then, resulting solution is heated to 75 ℃, kept 30 minutes.Said reaction soln is inclined in frozen water, be adjusted to pH 7 with 30% solution of ammonium hydroxide then.Product 1 usefulness dichloromethane extraction (3 *), resulting extraction liquid water, brine wash are used dried over sodium sulfate, then vacuum concentration.Resulting resistates utilizes ISCO chromatographic system (120g silica gel tube, the n-heptane solution of 5% ETHYLE ACETATE) to come purifying, obtains compound 3,6-two chloro-4-ethyl pyridazines (7.3g, yield is 54%).LC/MS：m/e?177.15(M+1)。HPLC?Rt：2.03min。Waters Sunfire C18 chromatographic column (4.6 * 50mm).0％-100％B。Solvent B: (90%MeOH, 10%H ₂O, 0.1%TFA).Solvent orange 2 A: (10%MeOH, 90%H ₂O, 0.1%TFA).Gradient: being initiated with %B=0, finally is %B=100, and the gradient time is 4min, keeps 1min at 100%B, and flow velocity is 4mL/min.

(1b) in the microwave tube of sealing, with deriving from 3 of 1a, (3.5g 0.020mol) is suspended in 28%NH to 6-two chloro-4-ethyl pyridazines ₄In the OH aqueous solution (12mL), at 145 ℃ of heating 1h.Make the reaction soln cooling, heat 1h again at 145 ℃ then.Microwave tube is opened,, in ice bath, stirred 30min then at stirring at room 30min.The solid filtering that will come off washs with frozen water, and is dry then, obtains the mixture of the desired regional isomer of 3.5g (regioisomer) 6-chloro-5-ethyl pyridazine-3-amine and 6-chloro-4-ethyl pyridazine-3-amine.LC/MS：m/e?158.19(M+1)。HPLC?Rt：0.78min。Waters Sunfire C18 chromatographic column (4.6 * 50mm).0％-100％B。Solvent B: (90%MeOH, 10%H ₂O, 0.1%TFA).Solvent orange 2 A: (10%MeOH, 90%H ₂O, 0.1%TFA).Gradient: being initiated with %B=0, finally is %B=100, and the gradient time is 4min, keeps 1min at 100%B, and flow velocity is 4mL/min.

(1c) will derive from the 6-chloro-5-ethyl pyridazine-3-amine of 1b and the mixture of 6-chloro-4-ethyl pyridazine-3-amine (3.50g, 0.022mol) and NaHCO ₃(3.73g, 0.044mol, 2 equivalents) are suspended among the MeOH (20mL), use Br then ₂(1.25mL 0.024mol) handles.Resulting mixture at stirring at room 24h, is filtered then.The vacuum concentration of will filtrating.Resulting resistates is resuspended among the EtOAc (100mL), uses saturated NaHCO then successively ₃The aqueous solution (2 * 20mL) with the NaCl aqueous solution (1 * 20mL) washing.Resulting solution is used dried over sodium sulfate.The solvent vacuum is removed, obtain thick 4-bromo-6-chloro-5-ethyl pyridazine-3-amine.LC/MS：m/e?236(M+1)。HPLC?Rt：2.15min。Waters SunfireC18 chromatographic column (4.6 * 50mm).0％-100％B。Solvent B: (90%MeOH, 10%H ₂O, 0.1%TFA).Solvent orange 2 A: (10%MeOH, 90%H ₂O, 0.1%TFA).Gradient: being initiated with %B=0, finally is %B=100, and the gradient time is 4min, keeps 1min at 100%B, and flow velocity is 4mL/min.

(1d) with monochloroacetaldehyde (17.26ml, 0.111mmol, 50% H ₂O solution) add to thick 4-bromo-6-chloro-5-ethyl pyridazine-3-amine (5.23g, EtOH 0.022mol) (30mL) solution that derives from 1c.Resulting mixture is heated 24h at 50 ℃ in the bottle of sealing.The solvent vacuum is removed, then resulting solid is resuspended in acetone/Et ₂O (1/1,5mL) in, filter, use Et then ₂The O washing obtains also [1,2-b] pyridazine (3.02g, purity＞80%) of 8-bromo-6-chloro-7-ethyl imidazol(e), is HCl salt.LC/MS：m/e?260(M+1)。HPLC?Rt：2.68min。Waters Sunfire C18 chromatographic column (4.6 * 50mm).0％-100％B。Solvent B: (90%MeOH, 10%H ₂O, 0.1%TFA).Solvent orange 2 A: (10%MeOH, 90%H ₂O, 0.1%TFA).Gradient: being initiated with %B=0, finally is %B=100, and the gradient time is 4min, keeps 1min at 100%B, and flow velocity is 4mL/min.

The 8-bromo-6-chloro-7-ethyl imidazol(e) that (1e) will derive from 1d is [1,2-b] pyridazine (60mg, 0.2mmol also; 1 equivalent), aniline (20.3 μ L, 0.22mmol, 1.1 equivalents) and potassium tert.-butoxide (0.51mL; 0.51mmol, 2.5 equivalents) mixture be suspended among the DMF (3mL), stir 1h at RT.Resulting mixture is used the ETHYLE ACETATE cancellation, with the washing of lithium chloride saturated solution, uses dried over sodium sulfate, then vacuum concentration then.Resulting resistates utilizes ISCO chromatographic system (4g silicon filter cylinder, the n-heptane solution of 5% ETHYLE ACETATE) to come purifying, obtains also [1,2-b] pyridazine-8-amine (22mg) of 6-chloro-N-phenyl-7-ethyl imidazol(e).LC/MS：m/e?273.14(M+1)。HPLC?Rt：2.24min。Waters Sunfire C18 chromatographic column (4.6 * 50mm).0％-100％B。Solvent B: (90%MeOH, 10%H ₂O, 0.1%TFA).Solvent orange 2 A: (10%MeOH, 90%H ₂O, 0.1%TFA).Gradient: being initiated with %B=0, finally is %B=100, and the gradient time is 4min, keeps 1min at 100%B, and flow velocity is 4mL/min.

The 6-chloro-N-phenyl-7-ethyl imidazol(e) that (1f) will derive from 1e also [1,2-b] pyridazine-8-amine (22mg, 0.08mmol) with anti--1,4-diamino hexane (230mg) was mixed, 165 ℃ of heating 4 days.Resulting mixture is cooled to room temperature, dilutes with methyl alcohol then.Resulting resistates utilization preparation property HPLC comes purifying, obtains preceding text title compound (18.9mg, 66%), is tfa salt. ¹H?NMR(500MHz，CD ₃OD)δ7.95(d，1H)，7.62(d，1H)，7.27(t，J＝7.4Hz，2H)，7.0(t，J＝7.4Hz，1H)，6.85(d，J＝8.2Hz，2H)，4.0(m，1H)，3.20(m，1H)，2.79(m，2H)，2.25(m，2H)，2.14(m，2H)，1.58(m，4H)，1.13(t，J＝7.2Hz，3H)。LC/MS：m/e?351(M+1)。HPLC?Rt：1.67min。Waters Sunfire C18 chromatographic column (4.6 * 50mm).0％-100％B。Solvent B: (90%MeOH, 10%H ₂O, 0.1%TFA).Solvent orange 2 A: (10%MeOH, 90%H ₂O, 0.1%TFA).Gradient: being initiated with %B=0, finally is %B=100, and the gradient time is 4min, keeps 1min at 100%B, and flow velocity is 4mL/min.

Use suitable starting raw material and come preparation formula (Ia) compound, wherein R according to the method that is similar to embodiment XXXIII (1) with illustrated substantially the same method ₁, R ₂, R ₃, X and Y have value listed in table 13.

Table 13

Claims

1. formula (Ia) compound or its enantiomer, diastereomer or pharmacologically acceptable salt:

Wherein

X is NR ₄R ₅

Y is hydrogen, halogen, OR ₈Or NR ₆R ₇

R ₁Be hydrogen or C _1-4Alkyl;

R ₂Independently be selected from hydrogen, C _1-4Alkyl, halogen, cyanic acid, C (=O) NR ₁₀R ₁₁

R ₃Be selected from hydrogen, halogen, C _1-4Alkyl, phenyl;

NR ₄R ₅Be selected from:

NR ₆R ₇Be selected from:

R ₈Be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or suberyl, said naphthenic base is chosen wantonly and is substituted with one to three group is T ₄, T ₅And/or T ₆

R ₁₀And R ₁₁When occurring, all independently be selected from hydrogen and C at every turn _1-4Alkyl;

T ₄, T ₅And T ₆Independent is NR ₁₉R ₂₀

R ₁₉And R ₂₀When occurring, all independently be selected from hydrogen and C at every turn _1-4Alkyl; And

It has following restricted condition:

(1) if X is NH (a unsubstituted phenyl), then Y is not a hydrogen or halogen; And

(2) get rid of following compound:

2. the compound of claim 1 is wherein as NR ₆R ₇Said group

For

3. the compound of claim 1 is wherein as NR ₆R ₇Said group

4. compound is selected from:

(i) N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-[4-(oxyethyl group) phenyl] imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(2-amino-ethyl)-N ⁸-(4-(oxyethyl group) phenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(the amino butyl of 4-)-N ⁸-(4-(oxyethyl group) phenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

7-chloro-N-(4-(oxyethyl group) phenyl)-6-(1-piperazinyl) imidazo [1,2-b] pyridazine-8-amine;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(4-(methoxyl group) phenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(3-(oxyethyl group) phenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-phenylimidazole is [1,2-b] pyridazine-6 also, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(3-(methoxyl group) phenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(3, the 4-3,5-dimethylphenyl) imidazos [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(4-(phenoxy) phenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(4-(butoxy) phenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-4-xenyl imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(4-aminomethyl phenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(3, two (methoxyl group) phenyl of 4-) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(4-((phenyl methyl) oxygen base) phenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(4-(propoxy-) phenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-pyridin-3-yl imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(2-Methyl-1H-indole-5-yl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-methyl-N ⁸-phenylimidazole is [1,2-b] pyridazine-6 also, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-[2-(methoxyl group) phenyl] imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(2-aminomethyl phenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(2, the 3-3,5-dimethylphenyl) imidazos [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(2, the 4-3,5-dimethylphenyl) imidazos [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(2, the 5-3,5-dimethylphenyl) imidazos [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(3-aminomethyl phenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(3, the 5-3,5-dimethylphenyl) imidazos [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-[3-(dimethylamino) phenyl] imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(2-methyl isophthalic acid, 3-benzothiazole-6-yl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(2-methyl isophthalic acid, 3-benzothiazole-5-yl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-cyclopropyl imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-cyclohexyl imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(cyclohexyl methyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(1-methylethyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(phenyl methyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-[(2-chloro-phenyl-) methyl] imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-((4-chloro-phenyl-) methyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-((4-(methoxyl group) phenyl) methyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-ethyl imidazol(e) is [1,2-b] pyridazine-6 also, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(2-(methoxyl group) ethyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(2-(4-(methoxyl group) phenyl) ethyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-2-propylene-1-base imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(3-methylbutyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-propyl imidazole is [1,2-b] pyridazine-6 also, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(cyclopropyl methyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-((3-chloro-phenyl-) methyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

6-(3-amino-piperidino)-N-(4-(oxyethyl group) phenyl) imidazo [1,2-b] pyridazine-8-amine;

N ⁶-(3-aminopropyl)-N ⁸-(4-(oxyethyl group) phenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(2, the 6-difluorophenyl) imidazos [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(4-((4-aminocyclohexyl) methyl) cyclohexyl)-N ⁸-(4-(oxyethyl group) phenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

2-(1-(8-((4-(oxyethyl group) phenyl) amino) imidazo [1,2-b] pyridazine-6-yl)-4-piperidyl) ethanol;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-1H-indoles-5-base imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(2-(oxyethyl group) phenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

6-(3-amino-1-pyrrolidyl)-N-(4-(oxyethyl group) phenyl) imidazo [1,2-b] pyridazine-8-amine;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(2-phenylethyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N-(4-(oxyethyl group) phenyl)-6-(1-piperazinyl) imidazo [1,2-b] pyridazine-8-amine;

N ⁶-(2-(dimethylamino) ethyl)-N ⁸-(4-(oxyethyl group) phenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁸-(4-(oxyethyl group) phenyl)-N ⁶-(2-furyl methyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N-(4-(oxyethyl group) phenyl)-6-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl) imidazo [1,2-b] pyridazine-8-amine;

2-((6-((anti--the 4-aminocyclohexyl) amino) imidazo [1,2-b] pyridazine-8-yl) amino) phenol;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(3-((phenyl methyl) oxygen base) phenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

3-((6-((anti--the 4-aminocyclohexyl) amino) imidazo [1,2-b] pyridazine-8-yl) amino) phenol;

4-((6-((anti--the 4-aminocyclohexyl) amino) imidazo [1,2-b] pyridazine-8-yl) amino) phenol;

N ⁶-(anti--the 4-aminocyclohexyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

3-((6-((anti--the 4-aminocyclohexyl) amino) imidazo [1,2-b] pyridazine-8-yl) amino) cyanobenzene;

4-((6-((anti--the 4-aminocyclohexyl) amino) imidazo [1,2-b] pyridazine-8-yl) amino) cyanobenzene;

3-((6-((anti--the 4-aminocyclohexyl) amino) imidazo [1,2-b] pyridazine-8-yl) amino) phenylformic acid;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-1H-pyrazole-3-yl imidazo [1,2-b] pyridazine-6, the 8-diamines;

4-((6-((anti--the 4-aminocyclohexyl) amino) imidazo [1,2-b] pyridazine-8-yl) amino) phenylformic acid;

4-((6-((anti--the 4-aminocyclohexyl) amino) imidazo [1,2-b] pyridazine-8-yl) amino)-N, the N-dimethyl benzene sulfonamide;

N ⁶(anti--the 4-aminocyclohexyl)-N ⁸-(4-(1H-tetrazolium-5-yl) phenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--4-(ethylamino) cyclohexyl)-N ⁸-phenylimidazole is [1,2-b] pyridazine-6 also, the 8-diamines;

N ⁶-(anti--4-(methylamino-) cyclohexyl)-N ⁸-phenylimidazole is [1,2-b] pyridazine-6 also, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(2-(phenoxy) phenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(4 '-chloro-4-xenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(2 '-methyl-4-xenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(3 '-chloro-4-xenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(4-(phenyl methyl) phenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(4-(4-morpholinyl) phenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(3 '-chloro-3-xenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(4-(1-methylethyl) phenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(4-butyl phenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(5,6,7,8-tetrahydrochysene-1-naphthyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-1-naphthyl imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(3-(phenyl methyl) phenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(4-propyl group phenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(4 '-methyl-4-xenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(3-(1-methylethyl) phenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(3-((1-methylethyl) oxygen base) phenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(3, two (methoxyl group) phenyl of 5-) imidazo [1,2-b] pyridazine-6, the 8-diamines;

Instead-and N-(8-(6-methyl-3,4-dihydro-1 (2H)-quinolyl) imidazo [1,2-b] pyridazine-6-yl)-1, the 4-cyclohexanediamine;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-2-naphthyl imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(3-(methyl sulfenyl) phenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(3-ethylphenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(4-ethylphenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(4-(methyl sulfenyl) phenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-9H-fluorenes-2-base imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(2-ethylphenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(4-cyclohexyl phenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(4-(1, the 1-dimethyl ethyl) phenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(3-(phenoxy) phenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-3-xenyl imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(4-((1-methylethyl) oxygen base) phenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶(anti--the 4-aminocyclohexyl)-N ⁸-(2-chloro-phenyl-) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(4-chloro-phenyl-) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(3-chloro-phenyl-) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(4-chloro-1-naphthyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-3-quinolyl imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(3, the 5-dichlorophenyl) imidazos [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(3-(trifluoromethyl) phenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(4-chloro-2-fluorophenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(2-fluoro-5-aminomethyl phenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(4-chloro-3-aminomethyl phenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(5-phenyl-2-pyridyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶(anti--the 4-aminocyclohexyl)-N ⁸-(3-fluoro-4-aminomethyl phenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(2-methyl-4-pyridyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(4-fluoro-3-aminomethyl phenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(2-fluoro-4-aminomethyl phenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(3-((trifluoromethyl) oxygen base) phenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(4-methyl-3-(trifluoromethyl) phenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(4-ethyl-2-pyridyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(4-(1H-1,2,4-triazol-1-yl) phenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(4-(1H-pyrroles-1-yl) phenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(4-(4,5-two chloro-1H-imidazoles-1-yls) phenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(4-(1H-pyrazol-1-yl) phenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(4-(3,5-dimethyl--1H-pyrazol-1-yl) phenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(4-(4-methyl-4H-1,2,4-triazole-3-yl) phenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(4-(1H-imidazoles-1-yl) phenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(4-(1-methyl isophthalic acid H-imidazoles-2-yl) phenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(4-(2-methyl isophthalic acid, 3-thiazole-4-yl) phenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(4-(5-methyl-2-furyl) phenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(4-(2-ethyl-2H-tetrazolium-5-yl) phenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

4-((6-((anti--the 4-aminocyclohexyl) amino) imidazo [1,2-b] pyridazine-8-yl) amino)-3-hydroxy-n, the N-dimethyl benzene sulfonamide;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(2,3-dihydro-1H-indenes-5-yl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

3-((6-((anti--the 4-aminocyclohexyl) amino) imidazo [1,2-b] pyridazine-8-yl) amino)-N, the N-dimethyl benzene sulfonamide;

4-((6-((anti--the 4-aminocyclohexyl) amino) imidazo [1,2-b] pyridazine-8-yl) amino)-N, the N-dimethyl benzamide;

N ⁶-(anti--4-((2-chloro-4-pyrimidyl) amino) cyclohexyl)-N ⁸-phenylimidazole is [1,2-b] pyridazine-6 also, the 8-diamines;

N ⁶-(3-amino cyclopentyl)-N ⁸-phenylimidazole is [1,2-b] pyridazine-6 also, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(3-(4-morpholinyl alkylsulfonyl) phenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

3-((6-((anti--the 4-aminocyclohexyl) amino) imidazo [1,2-b] pyridazine-8-yl) amino)-N, N-diethylbenzene methane amide;

3-((6-((anti--the 4-aminocyclohexyl) amino) imidazo [1,2-b] pyridazine-8-yl) amino)-N-methyl-N-phenyl benzenesulfonamides;

4-((6-((anti--the 4-aminocyclohexyl) amino) imidazo [1,2-b] pyridazine-8-yl) amino)-2-hydroxy-n, the N-dimethyl benzene sulfonamide;

N ⁶-(amino dicyclo [2.2.2] suffering of 4--1-yl)-N ⁸-phenylimidazole is [1,2-b] pyridazine-6 also, the 8-diamines;

N-(4-((6-((anti--the 4-aminocyclohexyl) amino) imidazo [1,2-b] pyridazine-8-yl) amino) phenyl) Toluidrin;

N ⁶(anti--the 4-aminocyclohexyl)-N ⁸-(4-(3-(dimethylamino)-1-pyrrolidyl) phenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(4-(1-pyrrolidyl alkylsulfonyl) phenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

4-((6-((anti--the 4-aminocyclohexyl) amino) imidazo [1,2-b] pyridazine-8-yl) amino) Phenylsulfonic acid;

4-((6-((anti--the 4-aminocyclohexyl) amino) imidazo [1,2-b] pyridazine-8-yl) amino)-N, the N-diethyl benzene sulfonamide;

4-((6-((anti--the 4-aminocyclohexyl) amino) imidazo [1,2-b] pyridazine-8-yl) amino)-N-propylbenzene sulphonamide;

4-((6-((anti--the 4-aminocyclohexyl) amino) imidazo [1,2-b] pyridazine-8-yl) amino)-N-ethylbenzene sulphonamide;

4-((6-((anti--the 4-aminocyclohexyl) amino) imidazo [1,2-b] pyridazine-8-yl) amino)-N-methyl benzenesulfonamide;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(4-aminophenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

4-((6-((anti--the 4-aminocyclohexyl) amino) imidazo [1,2-b] pyridazine-8-yl) amino) benzsulfamide;

3-((6-((anti--the 4-aminocyclohexyl) amino) imidazo [1,2-b] pyridazine-8-yl) amino) benzsulfamide;

3-((6-((anti--the 4-aminocyclohexyl) amino) imidazo [1,2-b] pyridazine-8-yl) amino) BM;

4-((6-((anti--the 4-aminocyclohexyl) amino) imidazo [1,2-b] pyridazine-8-yl) amino) BM;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(4-(amino methyl) phenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

6-((6-((anti--the 4-aminocyclohexyl) amino) imidazo [1,2-b] pyridazine-8-yl) amino)-1,2-dihydro-3H-indazole-3-ketone;

N ⁶(anti--the 4-aminocyclohexyl)-N ⁸-(3-(amino methyl) phenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-7-chloro-N ⁸-[4-(oxyethyl group) phenyl] imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(3-aminopropyl)-N ⁸-[4-(oxyethyl group) phenyl] imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(2-fluorophenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(2,4 difluorobenzene base) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(3-fluorophenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(4-fluorophenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(3, the 4-difluorophenyl) imidazos [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(2, the 5-difluorophenyl) imidazos [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(2, the 3-difluorophenyl) imidazos [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(3, the 5-difluorophenyl) imidazos [1,2-b] pyridazine-6, the 8-diamines;

N ⁶(anti--the 4-aminocyclohexyl)-N ⁸-(3-iodophenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-[4-(trifluoromethyl) phenyl] imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶(anti--the 4-aminocyclohexyl)-N ⁸-pyridine-2-base imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(4-picoline-2-yl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(5-picoline-2-yl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶(anti--the 4-aminocyclohexyl)-N ⁸-(4,6-lutidine-2-yl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-pyrimidine-2-base imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-[4-(oxyethyl group) phenyl]-7-Methylimidazole is [1,2-b] pyridazine-6 also, the 8-diamines;

N ⁶(anti--the 4-aminocyclohexyl)-7-ethyl-N ⁸-[4-(oxyethyl group) phenyl] imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-7-methyl-N ⁸-phenylimidazole is [1,2-b] pyridazine-6 also, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(3, the 4-3,5-dimethylphenyl)-7-Methylimidazole is [1,2-b] pyridazine-6 also, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-7-methyl-N ⁸-(4-aminomethyl phenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-7-methyl-N ⁸-[3-(methoxyl group) phenyl] imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-biphenyl-4-base-7-Methylimidazole is [1,2-b] pyridazine-6 also, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-7-methyl-N ⁸-[4-(propoxy-) phenyl] imidazo [1,2-b] pyridazine-6, the 8-diamines;

4-((6-((anti--the 4-aminocyclohexyl) amino)-7-Methylimidazole is [1,2-b] pyridazine-8-yl also) amino) phenylformic acid;

4-((6-((4-aminocyclohexyl) amino)-7-Methylimidazole is [1,2-b] pyridazine-8-yl also) amino)-N, the N-dimethyl benzene sulfonamide;

N-(4-((6-((anti--the 4-aminocyclohexyl) amino)-7-Methylimidazole is [1,2-b] pyridazine-8-yl also) amino) phenyl)-N-methylacetamide;

N ⁶(anti--the 4-aminocyclohexyl)-7-ethyl-N ⁸-phenylimidazole is [1,2-b] pyridazine-6 also, the 8-diamines;

N ⁸-[4-(oxyethyl group) phenyl]-N ⁶-piperidines-3-base imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁸-[4-(oxyethyl group) phenyl]-N ⁶-tetramethyleneimine-3-base imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁸-[4-(oxyethyl group) phenyl]-N ⁶-piperidin-4-yl imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁸-(4-(oxyethyl group) phenyl)-7-methyl-N ⁶-3-piperidyl imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁸-phenyl-N ⁶-3-piperidyl imidazo [1,2-b] pyridazine-6, the 8-diamines;

6-[(3S)-3-amino-pyrrolidine-1-yl]-N-[4-(oxyethyl group) phenyl] imidazo [1,2-b] pyridazine-8-amine;

N ²-(anti--the 4-aminocyclohexyl)-N ⁴-[4-(oxyethyl group) phenyl] pyrazolo [1,5-a] [1,3,5] triazine-2, the 4-diamines;

N ²-(anti--the 4-aminocyclohexyl)-N ⁴-(4-ethoxyl phenenyl)-imidazo [2,1-f] [1,2,4] triazine-2, the 4-diamines;

N ⁶-(suitable-the 4-aminocyclohexyl)-N ⁸-[4-(oxyethyl group) phenyl]-7-Methylimidazole is [1,2-b] pyridazine-6 also, the 8-diamines;

N ⁶(suitable-the 4-aminocyclohexyl)-N ⁸-(5-methyl-2-pyridyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(suitable-the 4-aminocyclohexyl)-N ⁸-phenylimidazole is [1,2-b] pyridazine-6 also, the 8-diamines;

N ⁶-(suitable-the 4-aminocyclohexyl)-7-methyl-N ⁸-phenylimidazole is [1,2-b] pyridazine-6 also, the 8-diamines;

N ⁶-(suitable-the 4-aminocyclohexyl)-N ⁸-(4-(oxyethyl group) phenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(suitable-the 4-aminocyclohexyl)-N ⁸-(3, the 4-3,5-dimethylphenyl) imidazos [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(suitable-the 4-aminocyclohexyl)-N ⁸-(5-phenyl-2-pyridyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

4-((6-((suitable-the 4-aminocyclohexyl) amino) imidazo [1,2-b] pyridazine-8-yl) amino)-N, the N-dimethyl benzene sulfonamide;

N ⁶-(suitable-the 4-aminocyclohexyl)-N ⁸-(4-aminomethyl phenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(suitable-the 4-aminocyclohexyl)-N ⁸-(4,6-dimethyl--2-pyridyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(suitable-the 4-aminocyclohexyl)-N ⁸-(4-(1H-pyrazol-1-yl) phenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(suitable-the 4-aminocyclohexyl)-N ⁸-(4-(4-morpholinyl carbonyl) phenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-7-methyl-N ⁸-(2-aminomethyl phenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(2-fluorophenyl)-7-Methylimidazole is [1,2-b] pyridazine-6 also, the 8-diamines;

N ⁶-(suitable-the 4-aminocyclohexyl)-7-methyl-N ⁸-(2-aminomethyl phenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(suitable-the 4-aminocyclohexyl)-N ⁸-(2-fluorophenyl)-7-Methylimidazole is [1,2-b] pyridazine-6 also, the 8-diamines;

N-(6-((anti--the 4-aminocyclohexyl) amino) imidazo [1,2-b] pyridazine-8-yl) BM;

1-(6-((anti--the 4-aminocyclohexyl) amino) imidazo [1,2-b] pyridazine-8-yl)-3-phenylurea;

N, N '-two (4-anti--aminocyclohexyl) imidazo [1,2-b] pyridazine-6,8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(4-ethoxyl phenenyl)-7-phenylimidazole is [1,2-b] pyridazine-6 also, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(phenyl)-7-phenylimidazole is [1,2-b] pyridazine-6 also, the 8-diamines;

N ⁶-(suitable-the 4-aminocyclohexyl)-N ⁸-(phenyl)-7-phenylimidazole is [1,2-b] pyridazine-6 also, the 8-diamines;

N ⁶-(suitable-the 4-aminocyclohexyl)-N ⁸-(4-ethoxyl phenenyl)-7-phenylimidazole is [1,2-b] pyridazine-6 also, the 8-diamines;

4-((6-((anti--the 4-aminocyclohexyl) amino) imidazo [1,2-b] pyridazine-8-yl) amino)-N-(2-(4-pyridyl) ethyl) BM;

4-((6-((anti--the 4-aminocyclohexyl) amino) imidazo [1,2-b] pyridazine-8-yl) amino)-N-(2-furyl methyl) BM;

4-((6-((anti--the 4-aminocyclohexyl) amino) imidazo [1,2-b] pyridazine-8-yl) amino)-N-(1H-imidazol-4 yl methyl) BM;

4-((6-((anti--the 4-aminocyclohexyl) amino) imidazo [1,2-b] pyridazine-8-yl) amino)-N-(3-pyridylmethyl) BM;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(4-((4-phenyl-piperidino) carbonyl) phenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(4-(1-pyrrolidyl carbonyl) phenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(4-(piperidino carbonyl) phenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

4-((6-((anti--the 4-aminocyclohexyl) amino) imidazo [1,2-b] pyridazine-8-yl) amino)-N-(phenyl methyl) BM;

4-((6-((anti--the 4-aminocyclohexyl) amino) imidazo [1,2-b] pyridazine-8-yl) amino)-N-(3-(methoxyl group) phenyl) BM;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(4-((3-phenyl-1-pyrrolidyl) carbonyl) phenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

3-((6-((anti--the 4-aminocyclohexyl) amino) imidazo [1,2-b] pyridazine-8-yl) amino)-N-phenylbenzamaide;

4-((6-((anti--the 4-aminocyclohexyl) amino) imidazo [1,2-b] pyridazine-8-yl) amino)-N-(2-hydroxyethyl) BM;

4-((6-((anti--the 4-aminocyclohexyl) amino) imidazo [1,2-b] pyridazine-8-yl) amino)-N-(3-(2-OXo-1-pyrrolidine base) propyl group) BM;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(4-(4-morpholinyl carbonyl) phenyl) imidazo [1,2-b] pyridazine-6, the 8-diamines;

4-((6-((anti--the 4-aminocyclohexyl) amino) imidazo [1,2-b] pyridazine-8-yl) amino)-N-methyl-N-(2-(2-pyridyl) ethyl) BM;

4-((6-((anti--the 4-aminocyclohexyl) amino) imidazo [1,2-b] pyridazine-8-yl) amino)-N, N-diethylbenzene methane amide;

4-((6-((anti--the 4-aminocyclohexyl) amino) imidazo [1,2-b] pyridazine-8-yl) amino)-N-cyclopropyl-phenyl methane amide;

4-((6-((anti--the 4-aminocyclohexyl) amino) imidazo [1,2-b] pyridazine-8-yl) amino)-N-(cyclohexyl methyl) BM;

4-((6-((anti--the 4-aminocyclohexyl) amino) imidazo [1,2-b] pyridazine-8-yl) amino)-N-3-pyridyl BM;

4-((6-((anti--the 4-aminocyclohexyl) amino) imidazo [1,2-b] pyridazine-8-yl) amino)-N-(1-methyl isophthalic acid H-pyrazoles-5-yl) BM;

4-((6-((anti--the 4-aminocyclohexyl) amino) imidazo [1,2-b] pyridazine-8-yl) amino)-N-(1-(4-fluorophenyl)-2-oxo-1,2-dihydro-3-pyridyl) BM;

4-((6-((anti--the 4-aminocyclohexyl) amino) imidazo [1,2-b] pyridazine-8-yl) amino)-N-phenylbenzamaide;

4-((6-((anti--the 4-aminocyclohexyl) amino) imidazo [1,2-b] pyridazine-8-yl) amino)-N-phenylcyclohexane methane amide;

4-((6-((anti--the 4-aminocyclohexyl) amino) imidazo [1,2-b] pyridazine-8-yl) amino)-N-(4-pyridylmethyl) BM;

1-(4-((6-((anti--the 4-aminocyclohexyl) amino) imidazo [1,2-b] pyridazine-8-yl) amino) phenyl)-3-phenylurea;

1-(4-((6-((suitable-the 4-aminocyclohexyl) amino)-7-Methylimidazole is [1,2-b] pyridazine-8-yl also) amino) phenyl)-3-phenylurea;

1-(4-((6-((anti--the 4-aminocyclohexyl) amino)-7-Methylimidazole is [1,2-b] pyridazine-8-yl also) amino) phenyl)-3-phenylurea;

N-(4-((6-((anti--the 4-aminocyclohexyl) amino) imidazo [1,2-b] pyridazine-8-yl) amino) phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydro-3-pyridine carboxamide;

N-(4-((6-((anti--the 4-aminocyclohexyl) amino) imidazo [1,2-b] pyridazine-8-yl) amino)-2-ethylphenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydro-3-pyridine carboxamide;

N-(4-((6-((anti--the 4-aminocyclohexyl) amino) imidazo [1,2-b] pyridazine-8-yl) amino) phenyl) BM;

N-(4-((6-((anti--the 4-aminocyclohexyl) amino) imidazo [1,2-b] pyridazine-8-yl) amino) phenyl) ethanamide;

3-((6-((anti--the 4-aminocyclohexyl) amino)-7-Methylimidazole is [1,2-b] pyridazine-8-yl also) amino) phenol;

N-(4-((6-chlorine imidazo [1,2-b] pyridazine-8-yl) amino) phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydro-3-pyridine carboxamide;

1-(4-fluorophenyl)-N-(4-(imidazo [1,2-b] pyridazine-8-base is amino) phenyl)-2-oxo-3-piperidyl urea;

1-(4-fluorophenyl)-N-(4-(imidazo [1,2-b] pyridazine-8-base is amino) phenyl)-2-oxo-1,2-dihydro-3-pyridine carboxamide;

6-((anti--the 4-aminocyclohexyl) amino)-8-((4-(oxyethyl group) phenyl) amino) imidazo [1,2-b] pyridazine-3-formonitrile HCN;

6-((anti--the 4-aminocyclohexyl) amino)-8-(phenyl amino) imidazo [1,2-b] pyridazine-3-formonitrile HCN;

6-((4-anti--aminocyclohexyl) amino)-7-methyl-8-(phenyl amino) imidazo [1,2-b] pyridazine-3-formonitrile HCN;

6-((instead)-4-aminocyclohexyl is amino)-7-ethyl-8-(phenyl amino) imidazo [1,2-b] pyridazine-3-formonitrile HCN;

6-((anti--the 4-aminocyclohexyl) amino)-8-phenylamino-7-isopropylimdazole is [1,2-b] pyridazine-3-formonitrile HCN also;

N ⁶(anti--the 4-aminocyclohexyl)-N ⁸-(4-(oxyethyl group) phenyl)-3-flumizole is [1,2-b] pyridazine-6 also, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(4-(oxyethyl group) phenyl)-3-Methylimidazole is [1,2-b] pyridazine-6 also, the 8-diamines;

N ⁶-(anti--the 4-aminocyclohexyl)-N ⁸-(4-(oxyethyl group) phenyl)-2,3-dimethyl-imidazo [1,2-b] pyridazine-6,8-diamines;

N-(6-((anti--the 4-aminocyclohexyl) amino) imidazo [1,2-b] pyridazine-8-yl) benzsulfamide;

6-((anti--the 4-aminocyclohexyl) oxygen base)-8-phenylamino imidazo [1,2-b] pyridazine-3-formonitrile HCN;

6-((anti--the 4-aminocyclohexyl) amino)-8-phenylamino imidazo [1,2-b] pyridazine-3-methane amide;

N ⁶-(anti--the 4-aminocyclohexyl)-7-ethyl-N ⁸-phenylimidazole is [1,2-b] pyridazine-6 also, the 8-diamines; With

N ⁶-(anti--the 4-aminocyclohexyl)-7-sec.-propyl-N ⁸-phenylimidazole is [1,2-b] pyridazine-6 also, the 8-diamines;

(ii) or enantiomer (i), diastereomer or pharmacologically acceptable salt.

5. pharmaceutical composition comprises in one or more claims 1 to 4 each compound and pharmaceutically acceptable carrier or thinner.

6. each compound is used for treating the purposes of the medicine of following illness in preparation in the claim 1 to 4, Inflammatory response, white plaque, atherosclerosis, myodegeneration, emaciation, reiter syndrome, gout, pancreatic beta cell disease that said illness is acute pancreatitis or chronic pancreatitis, asthma, transformation reactions, adult respiratory distress syndrome, chronic obstructive pulmonary disease, glomerulonephritis, systemic lupus erythematous, scleroderma, chronic thyroiditis, Graves disease, autoimmunity gastritis, mellitus, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel, psoriasis, graft versus host disease, intracellular toxin brought out; Be characterized as the disease of a large amount of neutrophilic infiltrations; Rheumatoid spondylitis, cerebral malaria, chronic pneumonia disease, silicosis, sarcoidosis of lung, bone-resorbing disease, allograft rejection, the caused fever of infection and myalgia, scar tissue formation, pyreticosis, influenza, osteoporosis, osteo-arthritis, acute myelogenous leukemia, chronic lymphocytic leukemia, metastatic melanoma, Kaposi sarcoma, multiple myeloma, sepsis, septic shock and shigellosis; Alzheimer's disease, Parkinson's disease, the caused cerebral ischemia of traumatic damage or neurodegenerative disease; Angiogenic disease; Acute hepatitis infects; HIV infects and the CMV retinitis, AIDS, ARC or malignant tumour and bleb; Platelet aggregation, inner toxemia and/or toxic shock syndrome, oedema, aponia, neuromuscular pain, headache, the caused pain of cancer, toothache, arthritis ache that ischemic, organ anoxic, vascular hyperplasia, heart and kidney reperfusion injury, thrombosis, cardiac hypertrophy, zymoplasm in apoplexy, myocardial ischemia, the apoplexy heart attack brings out; Equine infectious anemia virus, feline immunodeficiency virus, bovine immunodeficiency virus, dog immunodeficiency virus; And pemphigus vulgaris.

7. the purposes of claim 6, wherein said angiogenic disease is solid tumor, eye neovascularization or children's vascular tumor.

8. the purposes of claim 6, wherein said acute hepatitis infect and are hepatitis A, hepatitis B or hepatitis C.

9. the purposes of claim 6, wherein said inflammatory bowel is ulcerative colitis or segmental enteritis.

10. the purposes of claim 6, wherein said arthritis ache is rheumatoid arthritis, arthritic psoriasis, traumatic arthritis, rubella arthritis, acute synovitis, urarthritis or other disorder of joint.

11. the purposes of claim 6, wherein said illness are selected from segmental enteritis and ulcerative colitis, allograft rejection, rheumatoid arthritis, psoriasis, arthritic psoriasis and pemphigus vulgaris.

12. the purposes of claim 6, wherein said illness are multiple myeloma.

13. the purposes of claim 6, wherein said emaciation are the emaciation that is secondary to infection.

14. each compound is used for treating the purposes of the medicine of ankylosing spondylitis in the claim 1 to 4 in preparation.

15. each compound is used for treating the purposes of the medicine of ischemical reperfusion injury in the claim 1 to 4 in preparation.

16. the purposes of claim 15, wherein said ischemical reperfusion injury to be apoplexy caused cerebral ischemia re-pouring injured and the caused heart ischemia reperfusion damage of myocardial infarction.