CN107353286A

CN107353286A - Novel imidazole simultaneously [1,2-b] pyridazine amide-type Bcr-Abl kinase inhibitors and its preparation method and application

Info

Publication number: CN107353286A
Application number: CN201610304561.XA
Authority: CN
Inventors: 张志远; 黄少强; 任艳; 崔博; 曹伟业; 刘春燕; 刘晓
Original assignee: National Institute of Biological Sciences Beijin
Current assignee: National Institute of Biological Sciences Beijin
Priority date: 2016-05-10
Filing date: 2016-05-10
Publication date: 2017-11-17

Abstract

The invention discloses a kind of imidazo [1,2 b] pyridazine amide-type Bcr Abl kinase inhibitors and its preparation method and application, the general structure of the inhibitor is shown in formula I.It is used to prepare the medicine of prevention and/or treatment and protein kinase activity exception relevant disease, the method particularly with the medicine of Bcr Abl protein kinase activity exception relevant diseases present invention also offers the pharmaceutically acceptable salt of the compound comprising Formulas I, composition and using the salt, composition.

Description

Novel imidazole simultaneously [1,2-b] pyridazine amide-type Bcr-Abl kinase inhibitors and its preparation Methods and applications

Technical field

The present invention provides a kind of novel imidazole simultaneously [1,2-b] pyridazine amide compound, or such compound can pharmaceutically connect The salt received, its preparation method, its pharmaceutical composition, and it is used to prepare prevention and/or treatment and protein kinase activity is abnormal The medicine of relevant disease, the method particularly with the medicine of Bcr-Abl protein kinase activity exception relevant diseases.

Background technology

Protein kinase is that the phosphate group on ATP is transferred on protein into specific serine, threonine or tyrosine Enzyme on residue.The phosphorylation of protein causes the activation of signal transduction path, and key has been played to internal complicated bioprocess Effect, including cell growth, metabolism, differentiation and death.It is abnormal as caused by abnormal or unsuitable protein kinase activity It is relevant with many diseases known to signal, including cancer, inflammation, autoimmune disease, metabolic disease, infection, nervous centralis Systemic disease and angiocardiopathy etc..Therefore, protein kinase be drug development in recent years popular target spot (Cohen, Nat.Rev.Drug Discovery 2002,1,309)。

The bcr gene phase reciprocity of c-abl genes and No. 22 chromosome long arm distal end on human body Chromosome 9 Position, generates two fusions：Bcr-Abl genes on 22q- chromosomes and the Abl-Bcr bases on 9q+ chromosomes Cause.Bcr-Abl genes are Philadelphia chromosomes, and it expresses 210kD protein (p210Bcr-Abl).Bcr-Abl protein EGFR-TK of the Abl parts containing Abl, it is tightly adjusted in the c-abl of prototype, but merges egg in Bcr-Abl Continuously activated in white matter, so as to cause the out of control of cell growth.Bcr-Abl is present in 95% CML patient, and In the patient of 10-25% ALLs (ALL).Imatinib (Imatinib) is a kind of Bcr-Abl tyrosine The inhibitor of kinases, and clinic is proved to be a kind of effective preparation (Druker et for treating CML al.N.Engl.J.Med.2006,355,2408).However, although continue treatment with imatinib, some CML patients late or The blast phase of crisis can recur, and reason is to produce the resistance to the action of a drug to medicine.Drug-fast molecular basis is Bcr-Abl kinases knot There is the variant to Imatinib resistance in structure region.At present, second generation Bcr-Abl kinase inhibitors have listed, and mainly have and reach Sand replaces Buddhist nun (dasatinib), AMN107 (nilotinib), bosutinib (bosutinib) and Ponatinib (ponatinib).Although these medicines can show encouraging effect initial stage in listing, some researchers report it Will trigger new mutation after use in Bcr-Abl kinases area.Therefore, the Bcr-Abl kinases for mutant of renewal is developed Inhibitor seems necessary.

The content of the invention

The present invention provides a kind of imidazo [1,2-b] pyridazine amide-type Bcr-Abl kinase inhibitors, and it is with following logical Compound or its pharmaceutically acceptable salt shown in Formulas I：

In above-mentioned formula I：

(a)R₁It is independent hydrogen, or methyl；R₂It is any substituted n membered cyclic alkyls, wherein n=3-11, and on ring Including at most n-1 hetero atom, these hetero atom independences are selected from nitrogen, oxygen, sulphur and phosphorus, or

(b)R₁And R₂Connection forms a m member azepine cyclic hydrocarbon radical arbitrarily substituted, wherein m=3-11, and includes on ring At most m-2 other hetero atoms, these hetero atom independences are selected from nitrogen, oxygen, sulphur and phosphorus.

The present invention provides the compound or its pharmaceutically acceptable salt as described in formula I, and described can pharmaceutically connect The salt received includes but is not limited to hydrochloride, phosphate, sulfate, acetate, trifluoroacetate, maleate, benzene sulfonate, first Base benzene sulfonate, fumarate, tartrate etc..

The present invention provides a kind of Pharmaceutical composition, and it includes the compound as described in formula I of unit dose, a kind of pharmacy Upper acceptable carrier and excipient, and optional other Bcr-Abl kinase activations mediation treatment for diseases agent.

The present invention provides the pro-drug of the compound as described in formula I.

Compound or its pharmaceutically acceptable salt of the present invention offer as described in formula I are preparing prevention and/or treatment Application in the disorder agent mediated by Bcr-Abl kinase activations.The Bcr-Abl kinase activations mediation illness can be propagation Property disease.The proliferative diseases specifically may be selected from：Solid tumor, sarcoma, CML, chronic myelocytic leukemia, gastrointestinal stromal tumor (GIST), acute myeloblastic leukemia (ALL), thyroid cancer, stomach cancer, the carcinoma of the rectum, Huppert's disease, neoplasia and other Hypertrophic or proliferative diseases or its combination.

In specific embodiments：

The present invention provides compound or its pharmaceutically acceptable salt as shown in formula I, wherein (a) R₁

It is independent hydrogen, or methyl；R₂It is any substituted n membered cyclic alkyls, wherein n=3-11, and include at most on ring N-1 hetero atom, these hetero atom independences are selected from nitrogen, oxygen, sulphur and phosphorus.

The present invention provides the compound or its pharmaceutically acceptable salt as shown in formula I, wherein (a) R₁It is independent Hydrogen, or methyl；R₂It is any substituted n member cycloalkyl, wherein n=3-11, and include at most n-1 hetero atom on ring, These hetero atom independences are selected from nitrogen, oxygen, sulphur and phosphorus.

The present invention provides the compound or its pharmaceutically acceptable salt as shown in formula I, wherein (a) R₁It is independent Hydrogen, or methyl；R₂It is any substituted n member cycloalkyl, wherein n=6-11, and include at least one nitrogen-atoms on ring, and At most n-2 hetero atom, these hetero atom independences are selected from nitrogen, oxygen, sulphur and phosphorus.

The present invention provides the compound or its pharmaceutically acceptable salt as shown in formula I, wherein (a) R₁It is independent Hydrogen, or methyl；R₂It is any substituted n member azacycloalkyls, wherein n=6-11, and ring substituents are selected from methyl, halogen Plain substituent, hydroxyl and amino.

The present invention provides the compound or its pharmaceutically acceptable salt as shown in formula I, wherein (a) R₁It is independent Hydrogen, or methyl；R₂It is methyl substituted n members azacycloalkyl, wherein n=6-11.

The present invention provides the compound or its pharmaceutically acceptable salt as shown in claim 1, wherein (a) R₁It is independent Hydrogen, or methyl；R₂Selected from following radicals：

The present invention provides the compound or its pharmaceutically acceptable salt as shown in formula I, wherein (b) R₁And R₂Connect shape Into the m arbitrarily substituted a member azepine cyclic hydrocarbon radical, wherein m=3-11, and include at most m-2 other hetero atoms on ring, These hetero atom independences are selected from nitrogen, oxygen, sulphur and phosphorus.

The present invention provides the compound or its pharmaceutically acceptable salt as shown in formula I, wherein (b) R₁And R₂Connect shape Into the m arbitrarily substituted a member azacycloalkyl, wherein m=3-11, and include at most m-2 other hetero atoms on ring, These hetero atom independences are selected from nitrogen, oxygen, sulphur and phosphorus.

The present invention provides the compound or its pharmaceutically acceptable salt as shown in formula I, wherein (b) R₁And R₂Connect shape Into the m arbitrarily substituted a member azacycloalkyl, wherein m=5-7, and include at most m-2 other hetero atoms on ring, this A little hetero atom independences are selected from nitrogen, oxygen, sulphur and phosphorus.

The present invention provides the compound or its pharmaceutically acceptable salt as shown in formula I, wherein (b) R₁And R₂Connect shape Into the m arbitrarily substituted a member azacycloalkyl, wherein m=5-7, and include 0-1 other nitrogen-atoms on ring.

The present invention provides the compound or its pharmaceutically acceptable salt as shown in formula I, wherein (b) R₁And R₂Connect shape Into the m arbitrarily substituted a member azacycloalkyl, wherein m=5-7, include 0-1 other nitrogen-atoms, and substituent on ring Selected from methyl, halogenic substituent, hydroxyl and amino.

The present invention provides the compound as shown in formula I, and its structural formula is selected from following table：

The present invention provides the compound as shown in formula I, its structural formula such as P16：

The present invention provides the compound as shown in formula I, its structural formula such as P17：

Compared with prior art, the invention has the advantages that：

Imidazo [1,2-b] pyridazine amide-type Bcr-Abl kinase inhibitors provided by the invention, it is that new having resists The compound of Bcr-Abl kinase activities, there is good inhibitory activity to Bcr-Abl kinases in vitro.Bcr-Abl kinases is thin Played a significant role in born of the same parents' signal transduction and conversion, it is by phosphorylation and activates a series of stream substrates, promotes CML maturation grains Cell infinite multiplication.Bcr-Abl is not expressed in normal cell, is the ideal targets for treating CML.Bcr-Abl inhibitor passes through Suppress the purpose that Bcr-Abl kinase activities can reach treatment CML.Result of the test shows the imidazo [1,2- prepared by the present invention B] pyridazine amide-type Bcr-Abl kinase inhibitors can effectively suppress Bcr-Abl activity and suppress the growth of tumour cell And propagation.Illustrate that such imidazo [1,2-b] pyridazine amide-type Bcr-Abl kinase inhibitors can be used for preparing Bcr-Abl suppression Agent medicine and antineoplastic.

The preparation method of imidazo [1,2-b] pyridazine amide-type Bcr-Abl kinase inhibitors provided by the invention, there is original The advantages of material is easy to get, and reaction condition is gentle, and course of reaction is simple to operate, and agents useful for same is cheap.

Embodiment

The exemplary of the present invention is described more fully below.However, these embodiments are only for illustration purpose, and It is not intended to limitation the scope of the present invention.

Definition

Following term used herein and expression are with the implication specified.

" pharmaceutically acceptable salt " refers to the form for the basic group in parent compound being converted into salt.Pharmaceutically may be used The salt of receiving is include but not limited to, the inorganic or organic acid salt of basic group such as amine (ammonia) base.The present invention pharmaceutically may be used The salt of receiving can be synthesized by parent compound, i.e., the acid of the basic group in parent compound and 1-4 equivalents is in a solvent Reacted in system.

Present invention additionally comprises the prodrug of the compound.Prodrug is a pharmacological agents (medicine), is derived by parent drug Out.Once entering in vivo, prodrug, which is just metabolized, is transformed into parent drug.Prodrug can pass through the one or more to parent drug Functional group is substituted and prepared, and its substituted radical will be degraded and discharge parent compound in vivo.

Specifically, protein kinase of the present invention also includes the kinases of mutation, and the Abl and Bcr-Abl of such as mutation swash Enzyme.Abl the and Bcr-Abl kinases of mutation includes, and has one or more following mutant：G250E、E255V、T315I、 F317L and M351T etc..

" IC50 " refers to the number that specific test compound produces 50% maximum suppression effect in the experiment for testing the effect Amount, concentration or dosage.

Preparation method

The compound of the present invention can be prepared by known chemical reaction and step.Some have been shown below and has synthesized this hair The representational method of bright compound.It is well known that the property of the substituent needed for desired target compound often determines The method for optimizing of synthesis.

Another aspect of the present invention is related to the preparation method of compound of Formula I.The compound of the present invention can use following The step of and method prepare.

General steps

The compound prepared in the embodiment of the present invention can use scheme 1 or the two schemes of scheme 2.Compared compared with scheme 2, side Case 1 needs to participate in reaction with the intermediate (SM4) with protection group (PG), can be obtained in the final step deprotection base of synthesis To target compound.

Scheme 1

Scheme two

The compound of this patent protection can be synthesized using this synthetic route.The iodo- methyl 4 methylbenzoates of 3- (SM1) with Trimethyl silicane ethyl-acetylene occurs Sonogashira coupling reactions under the catalysis of bi triphenyl phosphorus palladium chloride and obtains intermediate 1.It is right Intermediate 1 implements de- trimethyl silicon-based protecting group and obtains intermediate 2.Imidazo [1,2-b] pyridazine (SM2) and N- iodo succinyl Imines heats in DMF and obtains iodo intermediate 3.Intermediate 2 reacts in DMF with intermediate 3, with palladium catalyst, such as four (three Phenylphosphine) palladium, so as to obtain intermediate 4.Intermediate 4 is in methanol and tetrahydrofuran in the mixed solvent alkali such as lithium hydrate Obtain intermediate 5.2- fluoro-5-nitro trifluor toluenes (SM3) are with SM4 or SM5 in the basic conditions if potassium carbonate is in a kind of solvent Reaction obtains nitro compound intermediate 6 or 8 in system such as acetonitrile.By the nitro on intermediate 6 or 8 in a kind of solvent such as first Reacted in alcohol with hydrogen, make catalyst with palladium carbon, obtain intermediate 7 or 9.Intermediate 5 and intermediate 7 or 9 use one kind in DMF Condensation reaction occurs for condensing agent such as EDCI, obtains target compound or further slough protection group in acid condition obtaining target Compound P1-P19.

Embodiment 1

4- methyl -3- ((trimethyl silicon substrate) acetenyl) methyl benzoate

The iodo- methyl 4 methylbenzoates of 3- (SM1) (30g, 0.471mol) are dissolved in tetrahydrofuran (1200mL).Add Enter trimethyl silicane ethyl-acetylene (92.3g, 0.942mol) and diisopropyl ethyl amine (72.9g, 0.565mol).System vacuumizes, Then inflated with nitrogen.Add cuprous iodide (8.92g, 0.047mol) and bi triphenyl phosphorus palladium chloride (16.5g, 0.024mol). System vacuumizes, then inflated with nitrogen.Stirred 4 hours in 80 DEG C under nitrogen atmosphere, after being cooled to room temperature, the mixture uses diatom Soil filtering, diatomite are thoroughly washed with ethyl acetate.Filtrate uses water and saturated common salt water washing successively, and sodium sulphate is dried, filtering Be concentrated to dryness.Crude by column chromatography purifies (ethyl acetate/petroleum ether=1:50), obtain title compound (95.1g, 82.6%) it is brown solid.LC-MS (m/z)=247.6 [M+H]+.1H NMR(400MHz,CDCl3)δ8.19(s,1H), 7.86 (d, J=8.4Hz, 1H), 7.30 (d, J=8.4Hz, 1H), 3.41 (s, 3H), 2.32 (s, 3H), 0.11 (s, 9H).

3- acetenyl methyl 4 methylbenzoates

By 4- methyl -3- ((trimethyl silicon substrate) acetenyl) methyl benzoates (95g, 0.386mol) and potassium fluoride (67.2g, 1.158mol) stirring is dissolved in 1000mL methanol, is stirred overnight at room temperature.It is concentrated to dryness, crude product purifies (second through column chromatography Acetoacetic ester/petroleum ether=1:50) it is yellow solid, to obtain title compound (51g, 76.1%).LC-MS (m/z)=175.2 [M +H]+.1H NMR (400MHz, CDCl3) δ 8.29 (s, 1H), 7.82 (d, J=8.4Hz, 1H), 7.34 (d, J=8.4Hz, 1H), 4.15(s,1H),3.85(s,3H),2.41(s,3H)。

3- iodine imidazo [1,2-b] pyridazine

By imidazo [1,2-b] pyridazine (40g, 0.336mol), N- N-iodosuccinimides (90g, 0.402mol) are dissolved in DMF (500mL), displacement nitrogen 3 times.By mixture, 80 DEG C are heated 3 hours, add a collection of N- iodos in addition Succimide (45g, 0.201mol), continue to heat 4 hours at 80 DEG C.Cooling, water (250mL) is poured into by reactant mixture In, and extracted with dichloromethane (2 × 150mL).Organic phase is collected, Na2SO4 is dried, filtered, is concentrated to dryness.Crude product is through post layer Analysis purifying (ethyl acetate/petroleum ether=1:10) it is brown solid, to obtain title compound (45g, 54.9%).LC-MS (m/z)= 246.1[M+H]+.1H NMR (400MHz, CDCl3) δ 8.46 (d, J=4.4Hz, 1H), 7.92 (d, J=9.2Hz, 1H), 7.85 (s, 1H), 7.08 (dd, J=4.4,9.2Hz, 1H).

3- (imidazo [1,2-b] pyridazine -3- acetenyls)-methyl 4 methylbenzoate

3- iodine imidazo [1,2-b] pyridazine (10g, 0.041mol), 3- acetenyl 4- methylbenzene first are added into 100mL bottles Sour methyl esters (7.14g, 0.041mol), tetrakis triphenylphosphine palladium (1.42g, 0.0021mol), cuprous iodide (0.778g, 0.0041mol), diisopropyl ethyl amine (6.35g, 0.049mol) and N ' dinethylformamides (50mL).Mixture is put Change nitrogen and heat 80 DEG C afterwards three times and stir 4 hours, then cool down, reactant mixture is poured into water (150mL), and with acetic acid second Ester (3 × 100mL) extracts.Organic phase is collected, Na2SO4 is dried, filtered and be concentrated to dryness.Crude product purifies (acetic acid through column chromatography Ethyl ester/petroleum ether=1:5) it is white solid, to obtain title compound (10g, 84.7%).LC-MS (m/z)=292.6 [M+H]+. 1H NMR (400MHz, CDCl3) δ 8.76 (d, J=3.2Hz, 1H), 8.29 (s, 1H), 7.98 (dd, J=3.2Hz, 9.2Hz, 1H), 7.90 (d, J=8.4Hz, 1H), 7.85 (s, 1H), 7.34 (d, J=8.4Hz, 1H), 7.22 (d, J=9.2Hz, 1H), 3.86(s,3H),2.35(s,3H)。

3- (imidazo [1,2-b] pyridazine -3- acetenyls) -4- methyl benzoic acids

3- (imidazo [1,2-b] pyridazine -3- acetenyls)-methyl 4 methylbenzoate (10g, 0.034mol) is dissolved in four Hydrogen furans/methanol/water (2:2:Lithium hydroxide (3.3g, 0.137mol) 1,200mL) is added afterwards.Reaction system is stirred at room temperature Overnight.After reaction terminates, system removes organic solvent under reduced pressure, and gains are adjusted to pH 5~6 with 6N hydrochloric acid solutions.In system The white precipitate of generation is filtered, and it is faint yellow solid to obtain title compound (9g, 94.6%) after washing, drying.LC-MS(m/ Z)=276.1 [M-H]-.1H NMR (400MHz, CDCl3) δ 11.03 (s, 1H), 8.76-8.75 (d, J=3.2Hz, 1H), 8.45 (s, 1H), 8.07-8.05 (d, J=8.4Hz, 1H), 7.97-7.94 (dd, J1=3.2Hz, J2=9.2Hz, 1H), 7.85 (s, 1H), 7.44-7.42 (d, J=8.4Hz, 1H), 7.23-7.20 (d, J=9.2Hz, 1H), 2.47 (s, 3H).

(R)-(1- (4- nitros -2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) t-butyl carbamate

By fluoro- 4- nitros -2- (trifluoromethyl) benzene (2g, 9.57mmol) of 1-, R) -3- t-butoxycarbonyl amino pyrrolidines (1.9g, 10.5mmol) is dissolved in acetonitrile (30mL) and adds potassium carbonate (2.9g, 21.1mmol) afterwards.Reaction system stirs at 80 DEG C Overnight, then cool down, reactant mixture is poured into water (20mL), and extracted with ethyl acetate (3 × 20mL).Collect organic Phase, Na2SO4 are dried, are filtered and be concentrated to dryness.Crude product purifies (ethyl acetate/petroleum ether=1 through column chromatography:5), obtain titled Compound (2.7g, 74%) is white solid.LC-MS (m/z)=376.4 [M+H]+.

(R)-(1- (4- amino -2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) t-butyl carbamate

By (R)-(1- (4- nitros -2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) t-butyl carbamate (2.0g, 5.3mmol) it is dissolved in methanol (40mL) and adds Pd/C (10%, 200mg) afterwards.System vacuumizes, and is then flushed with hydrogen gas.In hydrogen balloon atmosphere It is stirred at room temperature under enclosing overnight, mixture is filtered with diatomite, and diatomite is thoroughly washed with methanol.The thick production of gained after filtrate concentration Thing purifies (ethyl acetate/petroleum ether=1 through column chromatography:1) it is white solid, to obtain title compound (1.7g, 91%).LC- MS (m/z)=346.4 [M+H]+.

(R)-N- (4- (3- amino-pyrrolidine -1- bases) -3- (trifluoromethyl) phenyl) -3- (imidazo [1,2-b] pyridazine - 3- acetenyls) -4- methyl benzamides

Into 20mL single port bottles add 3- (imidazo [1,2-b] pyridazine -3- acetenyls) -4- methyl benzoic acids (100mg, 0.36mmol), (R)-(1- (4- amino -2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) t-butyl carbamate (125mg, 0.36mmol), 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (104mg, 0.54mmol), 4- diformazan ammonia Yl pyridines (66mg, 0.54mmol), N ' dinethylformamides (5mL).Mixture displacement nitrogen is heated into 50 DEG C afterwards three times to stir Mix 3 hours, then cool down, reactant mixture is poured into water (10mL), and extracted with dichloromethane (3 × 10mL).Collection has Machine phase, Na2SO4 are dried, are filtered and be concentrated to dryness.Crude product is dissolved in trifluoroacetic acid (0.5mL) dichloromethane (5mL) solution, room Temperature reaction 2 hours.Reactant mixture is concentrated, with ethanol/methylene recrystallize title compound trifluoroacetate (113mg, 43%) is white solid.LC-MS (m/z)=505.6 [M+H]+.1H NMR(400MHz,DMSO-d6)δ10.42 (s, 1H), 8.74 (dd, J=1.6,4.4Hz, 1H), 8.28 (dd, J=1.6,9.2Hz, 1H), 8.24 (s, 1H), 8.21 (d, J =1.6Hz, 1H), 8.13 (d, J=2.4Hz, 1H), 8.00 (dd, J=2.4,9.2Hz, 1H), 7.96 (dd, J=1.6, 7.6Hz, 1H), 7.56 (d, J=8.4Hz, 1H), 7.42 (q, J=4.4Hz, 1H), 7.29 (d, J=8.4Hz, 1H), 3.51- 3.45(m,2H),3.27-3.22(m,2H),3.15-3.11(m,1H),2.55(s,3H),2.51-2.33(m,2H)。

Example 2 below -10 is all prepared according to the method for scheme 1 and embodiment 1.

Embodiment 2

(S)-N- (4- (3- amino-pyrrolidine -1- bases) -3- (trifluoromethyl) phenyl) -3- (imidazo [1,2-b] pyridazine - 3- acetenyls) -4- methyl benzamides

LC-MS (m/z)=505.1 [M+H]+.1H NMR(400MHz,DMSO-d6)δ10.42(s,1H),8.74(dd,J =1.6,4.4Hz, 1H), 8.28 (dd, J=1.6,9.2Hz, 1H), 8.24 (s, 1H), 8.21 (d, J=1.6Hz, 1H), 8.13 (d, J=2.4Hz, 1H), 8.00 (dd, J=2.4,9.2Hz, 1H), 7.96 (dd, J=1.6,7.6Hz, 1H), 7.56 (d, J= 8.4Hz, 1H), 7.42 (q, J=4.4Hz, 1H), 7.29 (d, J=8.4Hz, 1H), 3.70-3.77 (m, 2H), 3.51-3.45 (m, 2H), 3.27-3.22 (m, 2H), 3.15 (q, J=4.8Hz, 1H), 2.61 (s, 3H).

Embodiment 3

(R) -3- (imidazo [1,2-b] pyridazine -3- acetenyls) -4- methyl-N- (4- (3- (methylamino) pyrrolidines -1- Base) -3- (trifluoromethyl) phenyl) benzamide

LC-MS (m/z)=519.4 [M+H]+.1H NMR(400MHz,DMSO-d6)δ10.52(s,1H),9.24-9.16 (m, 1H), 9.82 (dd, J=1.2,4.4Hz, 1H), 8.37 (s, 1H), 8.34 (dd, J=1.2,9.2Hz, 1H), 8.22 (d, J =2.0Hz, 1H), 8.17 (d, J=2.4Hz, 1H), 8.03 (dd, J=2.4,8.8Hz, 1H), 7.98 (dd, J=2.0, 8.8Hz, 1H), 7.56-7.50 (m, 1H), 7.42 (d, J=9.2Hz, 1H), 3.87-3.80 (m, 1H), 3.51-3.46 (m, 1H),3.35-3.29(m,2H),3.23-3.17(m,1H),2.61(s,3H),2.60-2.57(m,3H),2.33-2.28(m, 1H),2.12-2.03(m,1H)。

Embodiment 4

N- (4- ((3S, 4S) -3- amino-4-hydroxies pyrrolidin-1-yl) -3- (trifluoromethyl) phenyl) -3- (imidazos [1,2-b] pyridazine -3- acetenyls) -4- methyl benzamides, and N- (4- ((3R, 4R) -3- amino-4-hydroxy pyrrolidines -1- Base) -3- (trifluoromethyl) phenyl) -3- (imidazo [1,2-b] pyridazine -3- acetenyls) -4- toluyl amine blends

LC-MS (m/z)=521.6 [M+H]+.1H NMR (400MHz, CDCl3) δ 8.61 (dd, J=1.6,4.4Hz, 1H), 8.14 (d, J=2.0Hz, 1H), 8.08 (dd, J=1.6,9.2Hz, 1H), 8.05 (s, 2H), 7.90-7.86 (m, 2H), 7.46 (s, 1H), 7.36-7.30 (m, 2H), 4.25-4.22 (m, 1H), 3.68-3.58 (m, 3H), 3.35-3.33 (m, 1H), 3.25-3.22(m,2H),3.20-3.10(m,1H),2.64(s,3H)。

Embodiment 5

(R) -3- (imidazo [1,2-b] pyridazine -3- acetenyls) -4- methyl-N- (4- (piperidines -3- bases-amino) -3- (three Methyl fluoride) phenyl) benzamide

LC-MS (m/z)=519.4 [M+H]+.1H NMR (400MHz, CDCl3) δ 8.28 (d, J=1.2Hz, 2H), 7.74-7.72 (m, 2H), 7.62-7.60 (m, 2H), 7.32 (d, J=8.0Hz, 2H), 6.78 (d, J=8.8Hz, 2H), 6.58 (br, 1H), 3.53-3.51 (m, 1H), 3.21 (dd, J=2.4,11.6Hz, 1H), 2.91-2.86 (m, 1H), 2.77-2.71 (m,1H),2.64-2.59(m,1H),2.48(s,3H),1.94-1.92(m,1H),1.60-1.51(m,3H)。

Embodiment 6

(R)-N- (4- (3- amino piperidine -1- bases) -3- (trifluoromethyl) phenyl) -3- (imidazo [1,2-b] pyridazine -3- Acetenyl) -4- methyl benzamides

LC-MS (m/z)=519.4 [M+H]+.1H NMR(400MHz,DMSO-d6)δ10.59(s,1H),8.20-8.09 (m, 5H), 7.96 (d, J=7.6Hz, 1H), 7.57-7.53 (m, 2H), 7.40-7.37 (m, 2H), 3.16-3.13 (m, 2H), 2.85-2.83(m,1H),2.72-2.70(m,2H),2.60(s,3H),2.04-2.01(m,1H),1.84-1.81(m,1H), 1.64-1.56(m,1H),1.50-1.45(m,1H)。

Embodiment 7

(S)-N- (4- (3- amino piperidine -1- bases) -3- (trifluoromethyl) phenyl) -3- (imidazo [1,2-b] pyridazine -3- Acetenyl) -4- methyl benzamides

LC-MS (m/z)=519.5 [M+H]+.1H NMR (400MHz, DMSO-d6) δ 10.57 (s, 1H), 8.74 (d, J= 7.6Hz, 1H), 8.21-8.18 (m, 2H), 8.12 (dd, J=1.6,8.8Hz, 1H), 8.03 (m, 2H), 7.96 (dd, J=1.6, 7.6Hz, 1H), 7.58 (t, J=8.8Hz, 2H), 7.41 (m, 1H), 3.23 (m, 1H), 3.15-3.12 (m, 1H), 2.86-2.83 (m,1H),2.74-2.68(m,2H),2.60(s,3H),2.03-2.00(m,1H),1.85-1.82(m,1H),1.65-1.56 (m,1H),1.48-1.41(m,1H)。

Embodiment 8

(R) -3- (imidazo [1,2-b] pyridazine -3- acetenyls) -4- methyl-N- (4- (3- (methylamino) piperidin-1-yl) - 3- (trifluoromethyl) phenyl) benzamide

LC-MS (m/z)=533.6 [M+H]+.1H NMR(400MHz,DMSO-d6)δ10.58(s,1H),8.75-8.71 (m, 3H), 8.21-8.19 (m, 2H), 8.12 (d, J=8.0Hz, 1H), 7.96 (d, J=8.0Hz, 1H), 7.59-7.54 (m, 2H), 7.41 (m, 1H), 3.24-3.19 (m, 2H), 2.87-2.84 (m, 1H), 2.73 (q, J=10.0Hz, 2H), 2.61 (s, 6H),2.12-2.09(m,1H),1.88-1.84(m,1H),1.65-1.55(m,1H),1.49-1.44(m,1H),1.27-1.16 (m,1H)。

Embodiment 9

N- (4- (4- amino piperidine -1- bases) -3- (trifluoromethyl) phenyl) -3- (imidazo [1,2-b] pyridazine -3- acetylene Base) -4- methyl benzamides

LC-MS (m/z)=519.5 [M+H]+.1H NMR (400MHz, DMSO-d6) δ 10.55 (s, 1H), 8.74 (d, J= 3.6Hz, 1H), 8.20 (s, 1H), 8.17 (d, J=1.6Hz, 1H), 8.09-8.03 (m, 3H), 7.95 (d, J=8.0Hz, 1H), 7.57 (t, J=8.0Hz, 2H), 7.40 (m, 1H), 2.97-2.94 (m, 2H), 2.85-2.76 (m, 3H), 2.60 (s, 3H), 1.99-1.97(m,2H),1.72-1.64(m,2H)。

Embodiment 10

(R) -3- (imidazo [1,2-b] pyridazine -3- acetenyls) -4- methyl-N- (4- (methyl (piperidines -3- bases) amino) - 3- (trifluoromethyl) phenyl) benzamide

LC-MS (m/z)=533.2 [M+H]+.1H NMR(400MHz,DMSO-d6)δ10.53(s,1H),8.74(dd,J =1.6,4.4Hz, 1H), 8.28 (dd, J=1.6,9.2Hz, 1H), 8.21 (d, J=2.0Hz, 1H), 8.17 (d, J=2.4Hz, 1H), 8.09 (dd, J=2.4,8.8Hz, 1H), 7.96 (dd, J=1.6,8.0Hz, 1H), 7.63-7.57 (m, 2H), 7.56 (d, J=8.0Hz, 1H), 7.42 (q, J=4.4Hz, 1H), 3.02 (d, J=11.6Hz, 1H), 2.85-2.82 (m, 2H), 2.61 (s, 3H),2.56(s,3H),2.36-2.31(m,2H),1.85-1.82(m,1H),1.63-1.59(m,1H),1.24(m,2H)。

Embodiment 11

(R)-N, N- dimethyl -1- (4- nitros -2- (trifluoromethyl) phenyl) pyrrolidines -3- amine

By fluoro- 4- nitros -2- (trifluoromethyl) benzene (300mg, 1.4mmol) of 1-, (R)-(+) -3- dimethylamino pyrrolidines Dihydrochloride (261mg, 1.4mmol) is dissolved in acetonitrile (20mL) and adds potassium carbonate (387mg, 2.8mmol) afterwards.Reaction system is 80 It is stirred overnight at DEG C, then cools down, reactant mixture is poured into water (10mL), and is extracted with ethyl acetate (3 × 20mL).Receive Collect organic phase, Na2SO4 is dried, filtered and be concentrated to dryness.Crude title compound (320mg) is obtained to be directly used in for yellow solid React in next step.LC-MS (m/z)=304.4 [M+H]+.

(R) -1- (4- amino -2- (trifluoromethyl) phenyl)-N, N- dimethyl pyrrolidine -3- amine

By (R)-N, N- dimethyl -1- (4- nitros -2- (trifluoromethyl) phenyl) pyrrolidines -3- amine (310mg, 1mmol) It is dissolved in methanol (15mL) and adds Pd/C (10%, 31mg) afterwards.System vacuumizes, and is then flushed with hydrogen gas.In room under hydrogen balloon atmosphere Temperature is stirred overnight, and mixture is filtered with diatomite, and diatomite is thoroughly washed with methanol.Gained crude product is through post layer after filtrate concentration Analysis purifying (ethyl acetate/petroleum ether=1:1) it is yellow solid, to obtain title compound (265mg, 97%).LC-MS(m/z) =274.2 [M+H]+.

(R)-N- (4- (3- (dimethyl amine) pyrrolidin-1-yl) -3- (trifluoromethyl) phenyl) -3- (imidazos [1,2-b] Pyridazine -3- acetenyls) -4- methyl benzamides

Into 20mL single port bottles add 3- (imidazo [1,2-b] pyridazine -3- acetenyls) -4- methyl benzoic acids (100mg, 0.36mmol), (R) -1- (4- amino -2- (trifluoromethyl) phenyl)-N, N- dimethyl pyrrolidine -3- amine (96mg, 0.36mmol), 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (140mg, 0.72mmol), 4- diformazan ammonia Yl pyridines (88mg, 0.72mmol), N ' dinethylformamides (10mL).Mixture displacement nitrogen is heated into 50 DEG C afterwards three times to stir Mix 3 hours, then cool down, reactant mixture is poured into water (15mL), and extracted with dichloromethane (3 × 15mL).Collection has Machine phase, Na2SO4 are dried, are filtered and be concentrated to dryness.Crude product purifies (ethanol/methylene=1 through column chromatography:20) title, is obtained Compound (35mg, 13%) is yellow solid.LC-MS (m/z)=533.6 [M+H]+.1H NMR(400MHz,DMSO-d6)δ 10.41 (s, 1H), 8.72 (dd, J=1.6,4.4Hz, 1H), 8.47 (s, 1H), 8.26 (dd, J=1.2,9.2Hz, 1H), 8.24 (d, J=3.2Hz, 1H), 8.21 (d, J=1.6Hz, 1H), 8.18 (d, J=2.8Hz, 1H), 7.95 (dd, J=1.6,8.0Hz, 1H), 7.53 (d, J=5.6Hz, 1H), 7.51 (d, J=6.4Hz, 1H), 7.39 (dd, J=4.4,9.2Hz, 1H), 4.02 (s, 1H), 3.43-3.34 (m, 2H), 3.28-3.23 (m, 1H), 3.14-3.08 (m, 1H), 2.83-2.81 (d, J=9.2Hz, 3H), 2.60(s,3H),2.56-2.53(m,3H),2.37-2.30(m,1H),2.18-2.13(m,1H)。

Example 1 below 2-19 is all prepared according to the method for scheme 2 and embodiment 11.

Embodiment 12

N- (4- ((3R, 4R) -3- azido -4- hydroxyl pyrrolidine -1- bases) -3- (trifluoromethyl) benzene

Base) -3- (imidazo [1,2-b] pyridazine -3- acetenyls) -4- methyl benzamides, and

N- (4- ((3S, 4S) -3- azido -4- hydroxyl pyrrolidine -1- bases) -3- (trifluoromethyl) phenyl) -3- (imidazo [1, 2-b] pyridazine -3- acetenyls) -4- toluyl amine blends

LC-MS (m/z)=547.8 [M+H]+.1H NMR (400MHz, CDCl3) δ 8.55 (d, J=2.0Hz, 1H), 8.11 (dd, J=1.2,8.8Hz, 1H), 8.07 (s, 1H), 8.06 (d, J=2.0Hz, 1H), 7.99 (s, 1H), 7.89 (dd, J= 2.0,8.8Hz, 1H), 7.82 (dd, J=2.0,8.0Hz, 2H), 7.40 (d, J=8.0Hz, 1H), 7.24-7.18 (m, 2H), 4.35-4.29 (m, 1H), 4.05-4.02 (m, 1H), 3.77 (q, J=4.4Hz, 1H), 3.60 (q, J=4.4Hz, 1H), 3.23- 3.14(m,2H),2.65(s,3H),2.05(s,1H)。

Embodiment 13

N- (4- ((3S, 4R) -3- hydroxy-4-methyls pyrrolidin-1-yl) -3- (trifluoromethyl) phenyl) -3- (imidazos [1,2-b] pyridazine -3- acetenyls) -4- methyl benzamides, and N- (4- ((3R, 4S) -3- hydroxy-4-methyl pyrrolidines -1- Base) -3- (trifluoromethyl) phenyl) -3- (imidazo [1,2-b] pyridazine -3- acetenyls) -4- toluyl amine blends

LC-MS (m/z)=520.4 [M+H]+.1H NMR(400MHz,DMSO-d6)δ10.32(s,1H),8.72(dd,J =1.6,4.4Hz, 1H), 8.26 (dd, J=1.6,9.2Hz, 1H), 8.23 (s, 1H), 8.19 (d, J=2.0Hz, 1H), 8.08 (d, J=2.4Hz, 1H), 7.94 (dd, J=2.0,8.0Hz, 1H), 7.89 (dd, J=2.4,9.2Hz, 1H), 7.53 (d, J= 8.0Hz, 1H), 7.39 (dd, J=4.4,9.2Hz, 1H), 7.11 (d, J=9.2Hz, 1H), 5.07 (d, J=4.4Hz, 1H), 3.86-3.84 (m, 1H), 3.51-3.44 (m, 2H), 3.11 (dd, J=4.8,9.6Hz, 1H), 2.94 (dd, J=6.4, 9.2Hz, 1H), 2.60 (s, 3H), 2.10-2.06 (m, 1H), 1.01 (d, J=6.8Hz, 3H).

Embodiment 14

(R)-N- (4- (3- (dimethylamino) piperidin-1-yl) -3- (trifluoromethyl) phenyl) -3- (rattle away by imidazo [1,2-b] Piperazine -3- acetenyls) -4- methyl benzamides

LC-MS (m/z)=547.6 [M+H]+.1H NMR(400MHz,DMSO-d6)δ10.58(s,1H),10.12(s, 1H), 8.73 (d, J=3.2Hz, 1H), 8.28-8.19 (m, 3H), 8.11 (d, J=8.8Hz, 1H), 7.96 (d, J=8Hz, 1H), 7.57 (d, J=8.8Hz, 1H), 7.55 (d, J=8Hz, 1H), 7.40 (m, 1H), 3.29-3.27 (m, 2H), 2.89- 2.70(m,8H),2.61(s,3H),2.16-2.13(m,1H),1.90-1.87(m,1H),1.63-1.53(m,2H),

1.24-1.21(m,1H)。

Embodiment 15

3- (imidazo [1,2-b] pyridazine -3- acetenyls) -4- methyl-N- (4- ((1- methyl piperidine -4- bases) amino) -3- (trifluoromethyl) phenyl) benzamide

LC-MS (m/z)=533.7 [M+H]+.1H NMR (400MHz, CDCl3) δ 9.02 (d, J=4.0Hz, 1H), 8.54 (s, 1H), 8.46 (d, J=9.2Hz, 2H), 8.15 (d, J=2.0Hz, 1H), 7.91 (dd, J=2.0,8.0Hz, 1H), 7.90- 7.86 (m, 2H), 7.74 (dd, J=2.4,8.0Hz, 1H), 7.46 (d, J=8.0Hz, 1H), 7.01 (d, J=9.2Hz, 1H), 3.60 (d, J=13.2Hz, 2H), 3.26-3.20 (m, 2H), 2.92 (d, J=7.6Hz, 3H), 2.63 (s, 3H), 2.31 (d, J =14.0Hz, 2H), 2.16-2.14 (m, 1H), 1.86-1.76 (m, 2H).

Embodiment 16

3- (imidazo [1,2-b] pyridazine -3- acetenyls) -4- methyl-N- (4- (methyl (1- methyl piperidine -4- bases) ammonia Base) -3- (trifluoromethyl) phenyl) benzamide

LC-MS (m/z)=547.2 [M+H]+.1H NMR (400MHz, CD3OD) δ 8.63 (dd, J=1.6,4.4Hz, 1H), 8.17 (d, J=1.6Hz, 1H), 8.10 (dd, J=1.6,4.4Hz, 2H), 8.07 (s, 1H), 7.97 (dd, J=2.8, 8.4Hz, 1H), 7.89 (dd, J=2.0,8.0Hz, 1H), 7.54 (d, J=8.8Hz, 1H), 7.48 (d, J=8.0Hz, 1H), 7.36 (q, J=8.8Hz, 1H), 3.03 (d, J=8.4Hz, 2H), 2.72 (s, 3H), 2.65 (s, 3H), 2.41 (s, 3H), 2.34-2.28(m,3H),1.91-1.87(m,2H),1.66-1.58(m,2H)。

Embodiment 17

3- (imidazo [1,2-b] pyridazine -3- acetenyls) -4- methyl-N- (4- (4- methyl isophthalic acids-homopiperazine

Base) -3- (trifluoromethyl) phenyl) benzamide

LC-MS (m/z)=533.4 [M+H]+.1H NMR(400MHz,DMSO-d6)δ10.84(s,1H),8.73(dd,J =1.6,4.4Hz, 1H), 8.26 (dd, J=1.6,9.2Hz, 1H), 8.24 (s, 1H), 8.21 (d, J=1.6Hz, 1H), 8.18 (d, J=2.4Hz, 1H), 8.11 (dd, J=2.4,8.4Hz, 1H), 7.96 (dd, J=2.0,8.0Hz, 1H), 7.62 (d, J= 8.4Hz, 1H), 7.53 (d, J=8.4Hz, 1H), 7.40 (dd, J=4.4,9.2Hz, 1H), 3.50-3.43 (m, 3H), 3.45- 3.28(m,2H),3.20-3.09(m,3H),3.05-3.03(m,1H),2.84(s,3H),2.60(s,3H),2.14-2.09(m, 1H)。

Embodiment 18

3- (imidazo [1,2-b] pyridazine -3- acetenyls) -4- methyl-N- (4- (((3aR, 5r, 6aS) -2- methyl octahydros Pentamethylene [C] pyrroles -5- bases) amino) -3- (trifluoromethyl) phenyl) benzamide

LC-MS (m/z)=559.3 [M+H]+.1H NMR(400MHz,DMSO-d6)δ10.27(s,1H),10.04(s, 1H), 8.73 (d, J=4.4Hz, 1H), 8.28-8.26 (m, 2H), 8.18 (d, J=1.6Hz, 1H), 7.97-7.96 (m, 1H), 7.93 (dd, J=1.6,8.0Hz, 1H), 7.85 (d, J=9.2Hz, 1H), 7.52 (d, J=8.0Hz, 1H), 7.40 (dd, J= 4.4,9.2Hz,1H),7.01-6.98(m,1H),4.41(s,1H),3.83-3.75(m,2H),3.14-3.07(m,2H),2.86 (s,3H),2.60(s,3H),2.44-2.39(m,2H),2.30-2.27(m,1H),1.60-1.53(m,1H),1.42-1.34 (m,2H)。

Embodiment 19

3- (imidazo [1,2-b] pyridazine -3- acetenyls) -4- methyl-N- (4- (methyl ((3aR, 5r, 6aS) -2- methyl Octahydro pentamethylene [C] pyrroles -5- bases) amino) -3- (trifluoromethyl) phenyl) benzamide

LC-MS (m/z)=573.6 [M+H]+.

The suppression that the compound of the present invention is bred to Bcr-Abl protein kinase activities and cell is to use journey described below What sequence was tested.

Embodiment A：The test of Bcr-Abl protein kinase enzymatic activitys

Kinases Abl is purchased from Carna companies, and substrate A TP is purchased from Sigma companies, substrate TK substrate-biotin and inspection Test agent box HTRF KinEASE-TK kit are purchased from Cisbio companies, from HTRF (Homogeneous Time Resolved Fluorescence, homogeneous phase time discrimination fluorescence) method detection target compound Inhibiting enzyme activity, operating method is according to kit Illustrate to carry out.By ATP (10mM) and (500 μM) of TK substrate-biotin with buffer solution (Hepes 50mM pH7.2, MgCl210mM,EGTA 5mM,EDTA 2mM,MnCl2 2mM,Cisbio SEB 50nM,Na3VO4 0.1mM,BSA 0.1mg/ ML, DTT 1mM) dilute the substrate mixed solution (2.2 for being configured to ATP (13.2 μM)-TK substrate-biotin (2.2 μM) ×)；Abl kinases is configured to the 2.2 of Abl (WT 1.8nM, T315I 1.1nM, E255K 0.66nM) with the dilution of above-mentioned buffer solution × enzyme working solution is standby；

Target compound (P1-P19) and positive control drug (Ponatinib) are configured to 1.0 respectively with above-mentioned buffer solution × 10-4mol/L, 3.3 × 10-5mol/L, 1.1 × 10-5mol/L, 3.7 × 10-6mol/L, 1.2 × 10-6mol/L, 4.1 × 10-7mol/L, 1.4 × 10-7mol/L, 4.6 × 10-8mol/L, 1.5 × 10-8mol/L, 5.1 × 10-9mol/L concentration gradient Sample solution (DMSO concentration be 11%), in sequentially adding 5 μ L enzyme solutions and 1 μ L sample solution per hole on 384 orifice plates；Blank Hole adds 5 μ L buffer solutions and 1 μ L11% DMSO solution；26 DEG C are incubated 15 minutes, add 5 μ L ATP-TK substrate Biotin substrate mixed solution initial actions；It is incubated 60 minutes at 26 DEG C；The μ L of HTRF detection reagents 10 are added, are incubated at 26 DEG C 60 minutes.Using fluorescent value of the TR-FRET modules measure of PerkinElmer multi-function microplate readers per hole, miaow of the present invention is calculated Azoles simultaneously inhibiting rate and IC50 of [1,2-b] pyridazine amide-type Bcr-Abl inhibitor to Abl.

Embodiment B：K562 cytoactives are tested

Imidazo [1,2-b] pyridazine amide-type Bcr-Abl inhibitor pair of the present invention is examined using Cell Titer-Glo methods The growth inhibitory activity of tumour cell：Take the logarithm the human chronic polymorpho nuclear leukemia cells (K562 cells) in growth period, with addition The 10%FBS culture mediums of RPMI 1640 are diluted to 3 × 104/mL cell solution, parallel to be inoculated in 96 well culture plates (3000/hole), per hole, inoculation volume is 100 μ L, 37 DEG C, overnight incubation in 5%CO2 incubators；Various concentrations are added per hole The μ L of testing compound 5, make the final concentration of 1 × 10-7mol/L, 3.3 × 10-8mol/L, 1.1 × 10- of compound in hole 8mol/L, 3.7 × 10-9mol/L, 1.2 × 10-9mol/L, 4.1 × 10-10mol/L, 1.4 × 10-10mol/L, 4.5 × 10- 11mol/L, 1.5 × 10-11mol/L, 5.1 × 10-12mol/L, each concentration set 2 multiple holes, and negative control refinement born of the same parents are not added with Compound, if 10 multiple holes, Ponatinib are positive control, continue to cultivate 72h；Cell Titer-Glo50 μ L are added per hole, Vibration 10 minutes, determined per hole values of chemiluminescence, then using the chemiluminescence module of PerkinElmer multi-function microplate readers Cell inhibitory rate is calculated, and IC50 values are obtained according to inhibiting rate.

Imidazo [1,2-b] pyridazine amide-type Bcr-Abl kinase inhibitors provided by the invention to Bcr-Abl kinases and The inhibitory activity result of K562 cells, as shown in table 1：

The inhibitor of table 1 is to Bcr-Abl kinase inhibiting activities result (IC50)

ND：Do not detect

As a result show the present invention compound imidazole simultaneously [1,2-b] pyridazine amide-type Bcr-Abl kinase inhibitors to Bcr- Abl kinases and K562 cell growths have stronger inhibitory activity.Bcr-Abl kinases plays critically important in cell signalling Effect, it is by phosphorylation and activates a series of stream substrates, promotes the unlimited hyperplasia of CML maturation granulocytes.Bcr-Abl is just Do not expressed in normal cell, be the ideal targets for treating CML.Above-mentioned imidazo [1,2-b] pyridazine amide-type Bcr-Abl kinase inhibitions Agent is good to the proliferation inhibiting effect of tumour cell, can be used as antineoplastic.

Claims

1. compound or its pharmaceutically acceptable salt shown in formula I：

Wherein：

(a)R₁It is independent hydrogen, or methyl；R₂It is any substituted n membered cyclic alkyls, wherein n=3-11, and include on ring At most n-1 hetero atom, these hetero atom independences are selected from nitrogen, oxygen, sulphur and phosphorus, or

(b)R₁And R₂Connection forms a m member azepine cyclic hydrocarbon radical arbitrarily substituted, wherein m=3-11, and includes at most on ring M-2 other hetero atoms, these hetero atom independences are selected from nitrogen, oxygen, sulphur and phosphorus.

2. compound as claimed in claim 1 or its pharmaceutically acceptable salt, wherein (a) R₁It is independent hydrogen, Huo Zhejia Base；R₂It is any substituted n membered cyclic alkyls, wherein n=3-11, and include at most n-1 hetero atom, these hetero atoms on ring Independent is selected from nitrogen, oxygen, sulphur and phosphorus.

3. compound as claimed in claim 1 or its pharmaceutically acceptable salt, wherein (a) R₁It is independent hydrogen, Huo Zhejia Base；R₂It is any substituted n member cycloalkyl, wherein n=3-11, and include at most n-1 hetero atom, these hetero atoms on ring Independent is selected from nitrogen, oxygen, sulphur and phosphorus.

4. compound as claimed in claim 1 or its pharmaceutically acceptable salt, wherein (a) R₁It is independent hydrogen, Huo Zhejia Base；R₂It is any substituted n member cycloalkyl, wherein n=6-11, and include at least one nitrogen-atoms on ring, and at most n-2 Hetero atom, these hetero atom independences are selected from nitrogen, oxygen, sulphur and phosphorus.

5. compound as claimed in claim 1 or its pharmaceutically acceptable salt, wherein (a) R₁It is independent hydrogen, Huo Zhejia Base；R₂It is that any substituted n member azacycloalkyls, wherein n=6-11, and ring substituents are selected from methyl, halogenic substituent, Hydroxyl and amino.

6. compound as claimed in claim 1 or its pharmaceutically acceptable salt, wherein (a) R₁It is independent hydrogen, Huo Zhejia Base；R₂It is methyl substituted n members azacycloalkyl, wherein n=6-11.

7. compound as claimed in claim 1 or its pharmaceutically acceptable salt, wherein (a) R₁It is independent hydrogen, Huo Zhejia Base；R₂Selected from following radicals：

8. compound as claimed in claim 1 or its pharmaceutically acceptable salt, wherein (b) R₁And R₂Connection forms one and appointed The m member azepine cyclic hydrocarbon radicals of meaning substitution, wherein m=3-11, and include at most m-2 other hetero atoms, these miscellaneous originals on ring Son is independent to be selected from nitrogen, oxygen, sulphur and phosphorus.

9. compound as claimed in claim 1 or its pharmaceutically acceptable salt, wherein (b) R₁And R₂Connection forms one and appointed The m member azacycloalkyls of meaning substitution, wherein m=3-11, and include at most m-2 other hetero atoms, these miscellaneous originals on ring Son is independent to be selected from nitrogen, oxygen, sulphur and phosphorus.

10. compound as claimed in claim 1 or its pharmaceutically acceptable salt, wherein (b) R₁And R₂Connection forms one and appointed The m member azacycloalkyls of meaning substitution, wherein m=5-7, and include at most m-2 other hetero atoms, these hetero atoms on ring Independent is selected from nitrogen, oxygen, sulphur and phosphorus.

11. compound as claimed in claim 1 or its pharmaceutically acceptable salt, wherein (b) R₁And R₂Connection forms one and appointed The m member azacycloalkyls of meaning substitution, wherein m=5-7, and include 0-1 other nitrogen-atoms on ring.

12. compound as claimed in claim 1 or its pharmaceutically acceptable salt, wherein (b) R₁And R₂Connection forms one and appointed Anticipate the m member azacycloalkyls of substitution, wherein m=5-7,0-1 other nitrogen-atoms are included on ring, and substituent is selected from first Base, halogenic substituent, hydroxyl and amino.

13. compound as claimed in claim 1, described compound is selected from following structural formula：

14. compound as claimed in claim 1, described structural formula of compound such as P16：

15. compound as claimed in claim 1, described structural formula of compound such as P17：

16. compound as claimed in claim 1 or its pharmaceutically acceptable salt, described pharmaceutically acceptable salt include But it is not limited to hydrochloride, phosphate, sulfate, acetate, trifluoroacetate, maleate, benzene sulfonate, toluene sulfonic acide Salt, fumarate, tartrate etc..

17. a kind of Pharmaceutical composition, it includes the compound as claimed in claim 1 of unit dose, one kind can pharmaceutically connect The carrier and excipient received, and optional other Bcr-Abl kinase activations mediation treatment for diseases agent.

18. the pro-drug of compound as claimed in claim 1.

19. compound as claimed in claim 1 or its pharmaceutically acceptable salt are preparing prevention and/or treated by Bcr- Application in the disorder agent of Abl kinase activations mediation.

20. application as claimed in claim 19, the Bcr-Abl kinase activations mediation illness is proliferative diseases.

21. application as claimed in claim 20, the proliferative diseases are selected from：Solid tumor, sarcoma, chronic myeloid/grain Chronic myeloid leukemia (CML, chronic myelogenous leukemia), gastrointestinal stromal tumor (GIST), acute myelogenous are white Blood disease (ALL), thyroid cancer, stomach cancer, the carcinoma of the rectum, Huppert's disease, neoplasia and other Hypertrophic or proliferative diseases, Or its combination.