CN107652293A - Imidazopyridazines IRAK4 inhibitor and its preparation method and application - Google Patents

Abstract

The invention belongs to drug field, more particularly to a kind of Imidazopyridazines or its pharmaceutically acceptable salt and preparation method thereof and its Pharmaceutical composition are in treatment tumour, inflammation, the application in disease such as are immunized.Imidazopyridazines of the present invention are a kind of novel protein kinase IRAK4 inhibitor, can selective depression IRAK4 and its downstream signaling pathway.Compound of the present invention has structural formula I.

Description

Imidazolopyridazine IRAK4 inhibitor and its preparation method and application

technical field

The invention belongs to the field of medicine, and in particular relates to an imidazopyridazine compound or a pharmaceutically acceptable salt thereof, a preparation method thereof and an application as an IRAK4 inhibitor.

Background technique

Four IRAK family members have been found in mammals: IRAK1, IRAK2, IRAK-M and IRAK4. Interleukin-1 (IL-1) receptor-associated kinase-4 (IRAK4) is an intracellular serine/threonine protein kinase that includes a central kinase domain and a death domain (DD), which is expressed in Toll IL-1 receptors (TIRs) play a crucial role in signal transduction (Janssens S, et al. Mol Cell. 2003, 11(2), 293-302). When the ligand binds to the IL-1 receptor family and Toll-like receptors, the adapter protein myeloid differentiation factor 88 (MyD88) is recruited, and MYD88 recruits IRAK4 through the homotype interaction of its death domain, and activates its kinase activity, and through IRAK1 interaction activates and phosphorylates it, thereby initiating NF-κB-mediated transcriptional activation signals. At the same time, TLR7, 8, 9 signaling can induce and activate the expression of transcription factors IRF5, IRF7 and INF. As the downstream of TLRs and IL-1 receptor family, IRAK4 signaling plays a bridge role in innate immunity and acquired immunity (Liu Y, et al. Clin Rev Allergy Immunol. 2013, 47, 136-147). In the case of overexpression, IRAK proteins are involved in mediating NF-κB and MAPK cascade signaling pathways, however only IRAK1 and IRAK4 exhibit activated kinase activity. At the same time, IL-1-induced NF-κB signal activation does not require the kinase activity of IRAK1 but requires the kinase activity of IRAK4 (Li S, et al. Proc Natl Acad Sci USA99(8), 2002, 5567-5572).

Stimulation of IRAK4-deficient or IRAK4-knockout mouse models with TLR2, TLR4 or TLR9 ligands significantly reduced the expression levels of cytokines in vivo (Lye E, et al. Eur J Immunol, 2008, 38(3), 870-876 ), demonstrated that a series of diseases including atherosclerosis, rheumatoid arthritis, psoriasis, systemic lupus erythematosus and inflammatory bowel disease are all related to MyD88-dependent TLRs. IRAK4 plays an extremely important role in the signal transduction process of TIRs, but patients with IRAK4 deletion are only prone to infection with a relatively narrow antimicrobial spectrum (pyogenic bacteria) in infancy, and with age No longer susceptible to infection (Cheng-Lung Ku, et al. J Exp Med. 204(10), 2007, 2407-2422). The observed phenotypes of IRAK4-deficient patients suggest that specific IRAK4 inhibitors have considerable clinical safety.

Recent studies have shown that sirukumab and siltuximab, two interleukin-6 (IL-6) inhibitors, can effectively improve the depression symptoms of low mood and anhedonia in patients with immune diseases. a new way of thinking. IRAK4 inhibitors can effectively reduce the production of IL-6, so IRAK4 inhibitors can also achieve antidepressant effects.

Enhanced IRAK4 expression and activity is thought to be associated with Alzheimer's disease. Through immunohistochemical analysis, microglia and astrocytes in postmortem Alzheimer's disease brain tissue had increased IRAK4 protein compared with normal conditions. showed increased IRAK4 protein kinase activity in Alzheimer's disease patients. In vitro studies have shown that IRAK1/4 inhibitors can reduce the secretion of monocyte chemoattractant protein-1 (MCP-1) induced by lipopolysaccharide from microglia and the secretion of MCP-1 from astrocytes induced by IL-1β. and IL-6 secretion. Meanwhile, the ability of microglia and astrocytes to uptake amyloid-β in vitro was not affected by IRAK1/4. Thus, selective inhibition of IRAK1/4 suppresses pro-inflammatory responses without affecting glial uptake of amyloid, suggesting that IRAK4 signaling is a potential target for modulating neuroinflammation in Alzheimer's disease. (Hoozemans. J.J.M. et al., Clin. Cell. Immunol 2014, 5:4)

Fibrosis is associated with matrix deposition leading to loss of organ function. Pericytes are the precursors of myofibroblasts and the source of pathological matrix deposition. The researchers found that MyD88 and its downstream effector kinase IRAK4 internally control the migration and transformation of pericytes into myofibroblasts. In vivo studies have found that specific knockout of MyD88 or the use of IRAK4 inhibitors can effectively prevent kidney injury by largely reducing tissue damage, activating and transforming into myofibroblasts. The findings suggest that blocking the IRAK4 signaling pathway in pericytes is a potentially effective therapeutic approach to inhibit fibrosis and promote regeneration. (IrinaA.Leaf, et al.Clin Cancer Res, 2017, 127(1):321-334.) In activated B-cell-like (ABC) diffuse large B-cell lymphoma (DLBCL), 29% of cases The 265-position leucine of MyD88 was mutated to proline (L265P), which was the main activating mutation in ABC DLBCL, and IRAK4 assumed most of the functions of MYD88. Nimbus compounds ND-2110 and ND-2158 have outstanding anti-tumor effects in the xenograft OCI-Ly10 mouse model, and have good combined drug effects with the BTK inhibitor ibrutinib and the BCL-2 inhibitor ABT-199 ( Kelly, P.N. et al. J Exp Med, 2015, 212(13), 2189-2201).

The 5-year overall survival rate of pancreatic ductal carcinoma (PDAC) does not exceed 6%. Studies have shown that compared with p-IRAK4-negative tumor patients, pIRAK4-positive PDAC patients have a higher recurrence rate after surgery and a worse prognosis. Through shRNA and CRISPR/Cas9n technology, the researchers found that gemcitabine and 5-fluorouracil can more effectively kill pancreatic ductal carcinoma cells after inhibiting IRAK4. It was also found that IRAK1/4 can drive the production of inflammatory cytokines and chemokines, leading to the metastasis, invasion and proliferation of cancer-associated fibroblasts (CAFs). (Daoxiang Zhang, et al. Clin Cancer Res, 2017, 7(23), 1748-1759.). Another study showed that knocking out IRAK4 in mice can effectively reduce the number of lung tumors in mice without changing the cell composition of bronchoalveolar infusion fluid (BALF) (Susana Castro, et al.AACR.2017).

Contents of the invention

It is an object of the present invention to provide a novel class of amide-substituted imidazopyridazines which are potent inhibitors of the protein kinase IRAK4.

In one aspect, the present invention provides a compound or a pharmaceutically acceptable salt thereof, the compound has general formula (I):

in:

Ring A is an aromatic ring or an aromatic heterocyclic ring;

n is an integer from 0 to 4;

X is selected from N or O;

R ₀ is selected from (C ₁ ~C ₄ ) alkyl, heterocycle, -OCH ₃ , -CF ₃ , -CHF ₂ , -CN, -CONH ₂ , halogen, -(CH2) _m -R _a , -O- (CH ₂ ) _m -R _a ;

m is an integer from 1 to 4;

R _a is a heterocyclic ring containing a nitrogen atom, wherein the heterocyclic ring containing a nitrogen atom may be optionally substituted by one or more substituents selected from halogen, -OH, -CH ₃ , -OCH ₃ ;

R ₂ and R ₃ are independently selected from a hydrogen atom, a heterocycle, -CH ₂ CH ₂ -N(R _b ) ₂ , R ₂ and R ₃ can be connected through a nitrogen atom to form a heterocycle, wherein the above heterocycle can be further replaced by one or Replaced by multiple R _c ;

R _b is selected from a hydrogen atom, (C ₁ ~C ₄ ) alkyl or acetyl;

R _c is selected from -CF ₃ , -CHF ₂ , -OH, -NH ₂ or formyl.

On the other hand, the present invention preferably relates to a small molecule compound represented by the following general formula (II) or a pharmaceutically acceptable salt thereof:

in:

n is an integer from 1 to 3;

X is selected from N or O;

R ₁ is selected from heterocycles containing nitrogen atoms, -(CH ₂ ) _m -R _a , -O-(CH2) _m -R _a ;

m is an integer of 1 to 3;

R _a is a heterocyclic ring containing a nitrogen atom, wherein the heterocyclic ring containing a nitrogen atom may be optionally substituted by one or more substituents selected from halogen, -OH, -CH ₃ , -OCH ₃ ;

R ₂ and R ₃ are independently selected from a hydrogen atom, a heterocycle, -CH ₂ CH ₂ -N(R _b ) ₂ , R ₂ and R ₃ can be connected through a nitrogen atom to form a heterocycle, wherein the above heterocycle can be further replaced by one or Replaced by multiple R _c ;

R _b is selected from a hydrogen atom, (C ₁ ~C ₄ ) alkyl or acetyl;

R _c is selected from -CF ₃ , -CHF ₂ , -OH, -NH ₂ , formyl;

R ₄ is selected from hydrogen atom, halogen, -OCH ₃ , -CHF ₂ , -CF ₃ .

On the other hand, the present invention preferably relates to a small molecule compound represented by the following general formula (III) or a pharmaceutically acceptable salt thereof:

in:

R ₅ is (C ₁ ~C ₃ ) alkyl;

X is selected from N or O;

R ₂ and R ₃ are independently selected from a hydrogen atom, a heterocycle, -CH ₂ CH ₂ -N(R _b ) ₂ , R ₂ and R ₃ can be connected through a nitrogen atom to form a heterocycle, wherein the above heterocycle can be further replaced by one or Replaced by multiple R _c ;

R _b is selected from a hydrogen atom, (C ₁ ~C ₄ ) alkyl or acetyl;

R _c is selected from -CF ₃ , -CHF ₂ , -OH, -NH ₂ , formyl;

R ₆ is selected from -CHF ₂ , -CF ₃ , -CN, -CONHR _d ;

R _d is selected from a hydrogen atom and a (C ₁ -C ₄ ) alkyl group.

Specifically, the imidazopyridazine compound described in general formula I or a pharmaceutically acceptable salt thereof is characterized in that the compound is preferably selected from:

(R)-N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-6-(piperidin-3-ylamino)imidazo[1,2-b]pyridazine -3-formamide;

(R)-N-(3-cyano-1-methyl-1H-pyrazol-4-yl)-6-(piperidin-3-ylamino)imidazo[1,2-b]pyridazine- 3-formamide;

(R)-N-(3-(Difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-6-(piperidin-3-ylamino)imidazo[1,2-b ]pyridazine-3-carboxamide;

6-((2-aminoethyl)amino)-N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazine-3- Formamide;

N-(3-cyano-1-methyl-1H-pyrazol-4-yl)-6-(piperazin-1-yl)imidazo[1,2-b]pyridazine-3-carboxamide;

6-(4-acetylpiperazin-1-yl)-N-(3-cyano-1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazine-3 - Formamide;

6-((2-Acetamidoethyl)amino)-N-(3-cyano-1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazine-3- Formamide;

N-(3-cyano-1-methyl-1H-pyrazol-4-yl)-6-(1H-imidazol-1-yl)imidazo[1,2-b]pyridazine-3-carboxamide ;

(R)-6-(3-aminopiperidin-1-yl)-N-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)imidazo[1,2 -b] pyridazine-3-carboxamide;

(R)-N-(4-morpholino-2-(trifluoromethyl)phenyl)-6-(piperidin-3-ylamino)imidazo[1,2-b]pyridazine-3- Formamide;

(R)-N-(4-(4-acetylpiperazin-1-yl)-2-(trifluoromethyl)phenyl)-6-(piperidin-3-ylamino)imidazo[1,2 -b] pyridazine-3-carboxamide;

(R)-N-(2-methoxy-4-morpholino)-6-(piperidin-3-ylamino)imidazo[1,2-b]pyridazine-3-carboxamide;

(R)-N-(4-(4-acetylpiperazin-1-yl)-2-methoxyphenyl)-6-(piperidin-3-ylamino)imidazo[1,2-b] Pyridazine-3-carboxamide;

(R)-6-(3-aminopiperidin-1-yl)-N-(2-methoxy-4-(4-(methylsulfonyl)piperazin-1-yl)phenyl)imidazo [1,2-b]pyridazine-3-carboxamide;

(R)-6-(3-aminopiperidin-1-yl)-N-(2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)imidazo[1,2 -b] pyridazine-3-carboxamide;

(R)-6-(3-aminopiperidin-1-yl)-N-(2-methoxy-4-(piperazin-1-yl)phenyl)imidazo[1,2-b]pyridine Oxyzine-3-carboxamide;

(R)-6-(3-aminopiperidin-1-yl)-N-(3-methoxy-4-morpholinophenyl)imidazo[1,2-b]pyridazine-3-metha amides;

(R)-6-(3-aminopiperidin-1-yl)-N-(2-methoxy-4-(morpholinomethyl)phenyl)imidazo[1,2-b]pyridazine -3-formamide;

(R)-6-(3-aminopiperidin-1-yl)-N-(2-methoxy-4-(2-morpholinoethoxy)phenyl)imidazo[1,2-b ]pyridazine-3-carboxamide;

N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-6-methoxyimidazo[1,2-b]pyridazine-3-carboxamide.

The compound codes involved in the following pharmacological experiments are equal to the compounds corresponding to the codes here.

Another object of the present invention is to provide the preparation method of the compound shown in general formula I, it is characterized in that:

a) Use 6-chloro-3-aminopyridazine as raw material to react with N,N-dimethylformamide dimethyl acetal to generate N-(6-chloropyridazin-3-yl)-N,N-di Methylformamidine 1,1 and ethyl bromoacetate via intermediate 2 to generate 6-chloroimidazo[1,2-b]pyridazine-3-carboxylate ethyl ester 3,3 and corresponding amine to generate 4a-e, The target compounds A-1~A-4 and A-10~A-19 were finally condensed with corresponding amines to form amides of 5a-e after hydrolysis with lithium hydroxide:

Wherein, R ₀ , R ₂ , R ₃ and n are as defined above;

b) Ethyl 6-chloroimidazo[1,2-b]pyridazine-3-carboxylate is hydrolyzed by lithium hydroxide under the participation of methanol to obtain 6-methoxyimidazo[1,2-b]pyridazine -3-Carboxylic acid 8,8 and the corresponding aminopyrazole are amide-formed to obtain the target compound A-20:

Wherein, R ₅ and R ₆ are as defined above;

c) Hydrolysis of ethyl 6-chloroimidazo[1,2-b]pyridazine-3-carboxylate into 6-chloroimidazo[1,2-b]pyridazine-3-carboxylic acid in lithium hydroxide 6 , 6 undergoes a substitution reaction with the corresponding amine to obtain the target compounds A-5～A-8:

Wherein, R ₂ , R ₃ , R ₅ and R ₆ are as defined above.

The present invention also provides a pharmaceutical composition, which is composed of a therapeutically effective amount of active components and pharmaceutically acceptable excipients; the active components include compounds of general formula I or pharmaceutically acceptable salts thereof one or more. The pharmaceutically acceptable auxiliary materials include pharmaceutically acceptable carriers, diluents and/or excipients.

In the present application, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. "Pharmaceutically acceptable acid addition salt" refers to a salt formed with an inorganic or organic acid that retains the biological effectiveness of the free base without other side effects. The inorganic acids include but not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; the organic acids include but not limited to formic acid, acetic acid, trifluoroacetic acid, propionic acid, caprylic acid, hexanoic acid, capric acid, undecene Acid, glycolic acid, gluconic acid, lactic acid, oxalic acid, adipic acid, glutaric acid, malonic acid, maleic acid, succinic acid, fumaric acid, tartaric acid, citric acid, palmitic acid, stearic acid, oleic acid, Cinnamic acid, lauric acid, malic acid, glutamic acid, pyroglutamic acid, aspartic acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acid, alginic acid, ascorbic acid, salicylic acid, etc. These acids can be prepared by methods known in the art.

Another aspect of the present invention relates to a pharmaceutical composition, which comprises the compound of formula I described in the present invention or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipients. In yet a further embodiment, the pharmaceutical composition of the present invention may also contain one or more active substances selected from the following: immunosuppressants, glucocorticoids, non-steroidal anti-inflammatory drugs, vinblastine compounds, Paclitaxel, DNA damaging agents, Bcl-2 inhibitors, BTK inhibitors, JAK inhibitors, Hsp inhibitors, ALK inhibitors, Flt3 inhibitors, PI3K inhibitors, and SYK inhibitors.

Another aspect of the present invention relates to the use of the compound of general formula I or a pharmaceutically acceptable salt thereof in the preparation of a drug with IRAK4 activity and a drug for preventing or treating diseases mediated by IRAK4.

In this application, IRAK4-mediated diseases include autoimmune diseases, inflammatory diseases, fibrotic diseases, heteroimmune conditions or diseases, thromboembolic diseases and cancer.

Detailed ways

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. Therefore, the examples provided below are only to further illustrate the present invention and are not meant to limit the scope of the present invention in any way.

Starting materials may be obtained from commercial sources or prepared by methods known in the art or as described herein.

The structures of the compounds were determined by nuclear magnetic resonance ( ¹ H-NMR) and/or mass spectroscopy (MS). The NMR measurement is carried out with an ACF-300BRUK nuclear magnetic resonance instrument, the measurement solvent is deuterated chloroform (CDCl ₃ ) or deuterated dimethyl sulfoxide (DMSO-D ₆ ), and TMS is used as the internal standard. The determination of MS uses a HP1100 mass spectrometer. For column chromatography, 200-300 mesh silica gel (produced by Qingdao Haiyang Chemical Factory) was used.

English abbreviations of some reagents used:

HATU: 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate

DIPEA: N,N-Diisopropylethylamine

Example 1

(R)-N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-6-(piperidin-3-ylamino)imidazo[1,2-b]pyridazine - Preparation of 3-formamide trifluoroacetate. The structural formula is as follows:

Step 1) Preparation of (E)-N-(6-chloropyridazin-3-yl)-N,N-dimethylformamidine

Dissolve 6-chloro-3-aminopyridazine (7.46g, 57.1mmol) in N,N-dimethylformamide dimethyl acetal (7.46g, 60.49mmol) for 2 hours under reflux, cool to room temperature, and precipitate A large amount of solid was suction filtered, washed with ethyl acetate, and dried to obtain 9.77 g of off-white solid. Yield: 91.9%. ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.47(s, 1H), 7.57(d, J=9.1Hz, 1H), 7.14(d, J=9.1Hz, 1H), 3.12(s, 3H) , 3.01(s, 3H).

Step 2) Preparation of ethyl 6-chloroimidazo[1,2-b]pyridazine-3-carboxylate

The product obtained in step 1 (5.48g, 29.68mmol) was dissolved in acetonitrile (50ml), ethyl bromoacetate (9ml) was added to reflux for 3 hours, cooled to room temperature, a large amount of solid precipitated, suction filtered, washed with ether, ethyl acetate /acetonitrile recrystallization to obtain a yellow solid. Dissolve the obtained product in acetonitrile (30ml), add N,N-diisopropylethylamine (6ml), react at room temperature for 3 hours, concentrate under reduced pressure, add water (30ml) to make slurry for 2 hours, filter with suction, and dry to obtain 3.83g of yellow solid. Yield: 57.2%. ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.37(d, J=9.7Hz, 2H), 7.62(d, J=9.5Hz, 1H), 4.36(s, 2H), 1.32(t, J= 7.1Hz, 3H).

Step 3) Preparation of (R)-6-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)imidazo[1,2-b]pyridazine-3-carboxylic acid ethyl ester

The step 2 product (1g, 4.43mmol) was dissolved in 10ml dimethyl sulfoxide, (R)-3-aminopiperidine-1-carboxylic acid tert-butyl ester (1.6g, 7.98mmol) and anhydrous potassium fluoride ( 2.57g, 44.32mmol), react overnight at 100°C, cool to room temperature, add 50ml of water and 50ml of ethyl acetate for extraction, wash the ethyl acetate layer with saturated brine three times, dry over anhydrous sodium sulfate, suction filter, and concentrate under reduced pressure. Flash column chromatography (dichloromethane/methanol = 75:1 elution) gave 1.33 g of light yellow oil. Yield: 77.0%. ¹ H NMR (300MHz, DMSO-d ₆ ) δ7.99(d, J=2.6Hz, 1H), 7.84(d, J=9.5Hz, 1H), 7.08(s, 1H), 6.89(d, J= 9.5Hz, 1H), 4.29(q, J=7.1Hz, 2H), 3.79(d, J=31.9Hz, 2H), 1.88(d, J=55.9Hz, 2H), 1.52-0.89(m, 14H) .MS (ESI, m/z): [M+Na] ⁺ = 412

Step 4) Preparation of (R)-6-((1-(tert-butoxycarbonyl)piperidin-3-yl)amino)imidazo[1,2-b]pyridazine-3-carboxylic acid

The product of step 3 (0.62g, 1.59mmol) was dissolved in a mixed solution of methanol/tetrahydrofuran/water (9ml/9ml/3ml), and lithium hydroxide hydrate (201mg, 4.78mmol) was added, reacted overnight at 30°C, and concentrated under reduced pressure , add water and 1mol/L dilute hydrochloric acid to adjust the pH to 3-4, extract 3 times with ethyl acetate (25ml), combine the ethyl acetate layers, dry over anhydrous sodium sulfate, filter with suction, and concentrate under reduced pressure to obtain 320 mg of an off-white solid. Yield: 55.6%. ¹ H NMR (300MHz, DMSO-d ₆ ) δ12.49(s, 1H), 7.98(s, 1H), 7.86(d, J=9.7Hz, 1H), 7.15(d, J=6.1Hz, 1H) , 6.91(d, J=9.7Hz, 1H), 3.74(s, 2H), 3.39(s, 3H), 1.72(m, 4H), 1.14(m, 9H).

Step 5) Preparation of 4-nitro-1H-pyrazole-3-carboxylic acid methyl ester

Dissolve 4-nitro-1H-pyrazole-3-carboxylic acid in methanol (50ml), add thionyl chloride (2.5ml) dropwise under ice-cooling, transfer to room temperature to react overnight, concentrate under reduced pressure to obtain 4.36g white solid. Yield: 100%

Step 6) Preparation of 4-nitro-1-methyl-pyrazole-3-carboxylic acid methyl ester

The product obtained in step 5 (4.36g) was dissolved in anhydrous tetrahydrofuran (35ml), sodium hydride (1.22g, 60%) was added in batches, ice bathed for 30 minutes, methyl iodide (2.4ml) was added dropwise, and the reaction was carried out overnight at room temperature , quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered with suction, concentrated under reduced pressure, and separated by flash column chromatography (eluted with dichloromethane/methanol=100:1) to obtain 3.55 g of a white solid. Yield: 75.2%. ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.95(d, J=1.5Hz, 1H), 3.94(d, J=1.5Hz, 3H), 3.88(d, J=0.8Hz, 3H).

Step 7) Preparation of 1-methyl-4-nitro-1H-pyrazole-3-carboxamide

The product obtained in Step 6 (1.5 g) was dissolved in ammonia-methanol solution (20 ml), reacted overnight at 50° C., and concentrated under reduced pressure to obtain 1.35 g of a white solid. Yield: 97.9%.

Step 8) Preparation of 4-amino-1-methyl-1H-pyrazole-3-carboxamide

Dissolve 0.3 g of the product obtained in step 7 in methanol (25 ml), add palladium carbon (5%, 45 mg), react with a hydrogen balloon for 1 hour, filter with diatomaceous earth, concentrate the filtrate under reduced pressure, and separate by flash chromatography (dichloromethane /methanol=50:1), to obtain 0.18 g of powdery white solid. Yield: 72.8%, ¹ H NMR (300MHz, DMSO-d ₆ ): δ=3.72(s, 3H), 4.60(s, 2H), 6.88(s, 1H), 7.05(m, 2H).

Step 9) (R)-3-((3-((3-carbamoyl-1-methyl-1H-pyrazol-4-yl)carbamoyl)imidazo[1,2-b]pyridazine Preparation of -6-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

The product of step 4 (100mg, 0.276mmol) and the product of the eighth step (32mg, 0.230mmol) were dissolved in 4ml of acetonitrile, HATU (175mg, 0.461mmol) and DIPEA (74mg, 0.576mmol) were added to react at room temperature for 1 hour, and water (15ml ) and ethyl acetate (15ml), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, flash column chromatography (dichloromethane/methanol=50:1 elution), 100mg of light yellow solid. Yield: 89.7%.

Step 10) (R)-N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-6-(piperidin-3-ylamino)imidazo[1,2-b ] Preparation of pyridazine-3-carboxamide trifluoroacetate

The product of step 9 was dissolved in 4 ml of dichloromethane, 1 ml of trifluoroacetic acid was added, reacted at room temperature for 2 hours, concentrated under reduced pressure, dissolved in dichloromethane, and then added with n-hexane to precipitate a solid, which was filtered by suction and dried to obtain 78 mg of a white solid. ¹ H NMR (300MHz, DMSO-d ₆ ) δ10.70(s, 1H), 8.89(s, 1H), 8.55(s, 1H), 8.37(s, 1H), 8.18(d, J=10.6Hz, 2H), 7.96(d, J=10.2Hz, 2H), 7.58(s, 1H), 6.93(d, J=9.7Hz, 1H), 4.65(s, 1H), 3.48(d, J=11.8Hz, 2H), 2.84(m, 2H), 1.85-2.11(m, 2H), 1.82-1.54(m, 2H). MS(ESI, m/z): [M+H] ⁺ =384.

Example 2

(R)-N-(3-cyano-1-methyl-1H-pyrazol-4-yl)-6-(piperidin-3-ylamino)imidazo[1,2-b]pyridazine- Preparation of 3-formamide trifluoroacetate. The structural formula is as follows:

Step 1) Preparation of 1-methyl-4-nitro-1H-pyrazole-3-carbonitrile

Dissolve 1-methyl-4-nitro-1H-pyrazole-3-carboxamide (1.04g, 6.11mmol) in 30ml of dichloromethane, add DIPEA (4.74g, 36.68mmol) under ice-cooling, and then slowly drop Add phosphorus oxychloride (2.81g, 18.34mmol), after dropping, move to room temperature to react for 4 hours, add 30ml saturated sodium carbonate solution to quench, separate layers, dichloromethane layer is washed three times with saturated sodium carbonate solution, anhydrous sulfuric acid Dry over sodium, filter with suction, and separate by flash column chromatography (elution with ethyl acetate/petroleum ether=1:2) to obtain 0.574 g of a white solid. Yield: 61.7%.

Step 2) Preparation of 4-amino-1-methyl-1H-pyrazole-3-carbonitrile

The preparation process is the same as Step 8 of Example 1. ¹ H NMR (300MHz, DMSO-d ₆ ) δ7.18(s, 1H), 4.76(s, 2H), 3.75(s, 3H).

Step 3) (R)-N-(3-cyano-1-methyl-1H-pyrazol-4-yl)-6-(piperidin-3-ylamino)imidazo[1,2-b] Preparation of pyridazine-3-carboxamide trifluoroacetate

The preparation process is the same as Steps 9 and 10 of Example 1. ¹ H NMR (300MHz, DMSO-d ₆ ) δ10.30(s, 1H), 8.67(s, 2H), 8.42(s, 1H), 8.12(s, 1H), 7.99(d, J=9.8Hz, 1H), 7.65(d, J=6.8Hz, 1H), 6.96(d, J=9.8Hz, 1H), 4.28(s, 1H), 3.98(s, 3H), 3.23(m, 4H), 2.00( d, J=11.8Hz, 2H), 1.74 (d, J=9.2Hz, 2H). MS (ESI, m/z): [M+H] ⁺ =366.

Example 3

(R)-N-(3-(Difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-6-(piperidin-3-ylamino)imidazo[1,2-b ] Preparation of pyridazine-3-carboxamide trifluoroacetate. The structural formula is as follows:

Step 1) Preparation of (1-methyl-4-nitro-1H-pyrazol-3-yl)methanol

4-Nitro-1-methyl-pyrazole-3-carboxylic acid methyl ester (0.54g, 2.92mmol) was dissolved in 12ml of dichloromethane, and diisobutylaluminum hydride (4.5ml, 1M n-hexane solution), react at room temperature for 8 hours, add 1M HCl solution to quench, concentrate under reduced pressure, extract with ethyl acetate (25ml) and water (25ml), dry over anhydrous sodium sulfate, filter with suction, concentrate under reduced pressure, ethyl acetate Ester/petroleum ether was recrystallized to obtain 260 mg of light yellow solid. Yield: 56.7%.

Step 2) Preparation of 1-methyl-4-nitro-1H-pyrazole-3-carbaldehyde

Dissolve (1-methyl-4-nitro-1H-pyrazol-3-yl)methanol (0.514g, 3.27mmol) in 5ml DMSO, add 2-iodylbenzoic acid, react at room temperature for 2 hours, add 16ml of water and Take 30ml of ethyl acetate, filter with suction, extract the filtrate with ethyl acetate (15ml*3), dry over anhydrous sodium sulfate, filter with suction, and concentrate under reduced pressure to obtain 0.35g of a light yellow solid. Yield: 68.9%. ¹ H NMR (300MHz, DMSO-d ₆ ) δ10.22(s, 1H), 8.98(s, 1H), 4.00(s, 4H).

Step 3) Preparation of 3-(difluoromethyl)-1-methyl-4-nitro-1H-pyrazole

Dissolve 1-methyl-4-nitro-1H-pyrazole-3-carbaldehyde (0.25g, 1.61mmol) in 5ml of dichloromethane, cool to -25°C in a cold trap, add diethylamino trifluoride dropwise Sulfur (0.52g, 3.22mmol), reacted at room temperature for 16 hours, extracted with 15ml of dichloromethane and 15ml of water, dried over anhydrous sodium sulfate, filtered with suction, concentrated under reduced pressure, and separated by flash column chromatography (ethyl acetate/petroleum ether=1: 3) to obtain 185 mg of yellow oil. Yield: 64.8%. ¹ H NMR (300MHz, DMSO-d ₆ ) δ9.00(s, 1H), 7.31(tq, J=52.9, 2.4Hz, 1H), 3.95(q, J=2.4Hz, 3H).

Step 4) 3-(Difluoromethyl)-1-methyl-4-amino-1H-pyrazole

The preparation process is the same as Step 8 of Example 1. ¹ H NMR (300MHz, Chloroform-d) δ6.96(s, 1H), 6.92-6.43(m, 1H), 3.80(d, J=6.3Hz, 3H), 3.01(s, 2H).

Step 5) (R)-N-(3-(Difluoromethyl)-1-methyl-1H-pyrazol-4-yl)-6-(piperidin-3-ylamino)imidazo[1, 2-b] Preparation of pyridazine-3-carboxamide trifluoroacetate

The preparation process is the same as Steps 9 and 10 of Example 1. ¹ H NMR (300MHz, DMSO-d ₆ ) δ9.94(s, 1H), 8.67(s, 2H), 8.27(s, 1H), 8.09(s, 1H), 7.97(d, J=9.8Hz, 1H), 7.58(d, J=6.6HZ, 1H), 6.94(d, J=9.2Hz, 2H), 4.16(s, 1H), 4.05-3.78(m, 3H), 3.14(d, J=38.5 Hz, 4H), 1.99(s, 2H), 1.70(s, 2H). MS(ESI, m/z): [M+H] ⁺ =391.

Example 4

6-((2-aminoethyl)amino)-N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazine-3- Preparation of formamide trifluoroacetate. The structural formula is as follows:

Step 1) Preparation of 6-((2-((tert-butoxycarbonyl)amino)ethyl)amino)imidazo[1,2-b]pyridazine-3-carboxylic acid

The preparation process is the same as Steps 3 and 4 of Example 1. MS (ESI, m/z): [M+Na] ⁺ = 344.20.

Step 2) 6-((2-aminoethyl)amino)-N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazine - Preparation of 3-formamide

The preparation process is the same as Steps 9 and 10 of Example 1. ¹ H NMR (300MHz, DMSO-d ₆ ) δ10.99(s, 1H), 8.48(s, 1H), 8.21(s, 1H), 8.05(s, 1H), 7.95(d, J=9.8Hz, 1H), 7.90-7.63(m, 5H), 6.94(d, J=9.8Hz, 1H), 3.87(d, J=6.3Hz, 2H), 3.05(s, 2H).MS(ESI, m/z ): [M+H] ⁺ ＝344.

Example 5

N-(3-cyano-1-methyl-1H-pyrazol-4-yl)-6-(piperazin-1-yl)imidazo[1,2-b]pyridazine-3-carboxamide tri Preparation of fluoroacetate. The structural formula is as follows:

Step 1) Preparation of 6-chloroimidazo[1,2-b]pyridazine-3-carboxylic acid

Dissolve ethyl 6-chloroimidazo[1,2-b]pyridazine-3-carboxylate (0.6g, 2.66mmol) in tetrahydrofuran/water solution (12ml/4ml), add hydrated lithium hydroxide at 30°C for 3 hours , concentrated under reduced pressure, added 4ml of water to dissolve, then added 1 mol/L dilute hydrochloric acid solution to adjust the pH value to 3, a solid precipitated, was suction filtered, and dried to obtain 0.375g of a white solid. Yield: 71.4%. ¹ H NMR (300MHz, DMSO-d ₆ ) δ12.92(s, 1H), 8.13(d, J=10.5Hz, 2H), 7.09(d, J=9.7Hz, 1H).

Step 2) Preparation of 6-chloro-N-(3-cyano-1-methyl-1H-pyrazole 4-yl)imidazo[1,2-b]pyridazine-3-carboxamide

6-Chlorimidazo[1,2-b]pyridazine-3-carboxylic acid (0.35g, 1.77mmol) and 4-amino-1-methyl-1H-pyrazole-3-carbonitrile (0.197g, 1.61mmol) was dissolved in 10ml of acetonitrile, then HATU (1.22g, 3.22mmol) and DIPEA (0.52g, 4.03mmol) were added, reacted at room temperature for 2 hours, and 30ml of water was added to precipitate a solid, which was filtered by suction and dried by infrared to obtain 0.41g of white solid. Yield: 84.4%. ¹ H NMR (300MHz, DMSO-d ₆ ) δ10.47(s, 1H), 8.46(d, J=9.8Hz, 2H), 8.40(s, 1H), 7.67(d, J=9.6Hz, 1H) , 3.93(s, 3H).

Step 3) 4-(3-((3-cyano-1-methyl-1H-pyrazol-4-yl)carbamoyl)imidazo[1,2-b]pyridazin-6-yl)piper Preparation of tert-butyl oxazine-1-carboxylate

Dissolve the product obtained in the previous step (67mg, 0.22mmol) and tert-butyl piperazine-1-carboxylate (62mg, 0.33mmol) in 4ml of dimethyl sulfoxide, add anhydrous potassium fluoride (129mg, 2.22mmol), 100°C After reacting for 5 hours, 15 ml of water was added to precipitate a solid, which was adjusted to acidity with 1M HCl, filtered by suction, dried by infrared, and recrystallized from acetonitrile/water to obtain 60 mg of a white solid. Yield: 59.8%.

Step 4) N-(3-cyano-1-methyl-1H-pyrazol-4-yl)-6-(piperazin-1-yl)imidazo[1,2-b]pyridazine-3- Preparation of formamide trifluoroacetate

The preparation process is the same as Steps 9 and 10 of Example 1. ¹ H NMR (300MHz, DMSO-d ₆ ) δ10.19(s, 1H), 9.07(s, 2H), 8.49(s, 1H), 8.37-8.04(m, 2H), 7.50(d, J=10.2 Hz, 1H), 3.97(s, 3H), 3.86(s, 4H), 3.30(s, 4H). MS(ESI, m/z): [M+H] ⁺ =352.

Example 6

6-(4-acetylpiperazin-1-yl)-N-(3-cyano-1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazine-3 - Preparation of formamide. The structural formula is as follows:

The preparation process is the same as Step 3 of Example 5. ¹ H NMR (300MHz, DMSO-d ₆ ) δ10.30(s, 1H), 8.50(s, 1H), 8.31-8.03(m, 2H), 7.48(d, J=10.1Hz, 1H), 3.98( s, 3H), 3.65(s, 8H), 2.05(s, 3H). MS (ESI, m/z): [M+H] ⁺ =394.

Example 7

6-((2-Acetamidoethyl)amino)-N-(3-cyano-1-methyl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazine-3- Preparation of formamide. The structural formula is as follows:

The preparation process is the same as Step 3 of Example 5. ¹ H NMR (300MHz, DMSO-d ₆ ) δ10.49(s, 1H), 8.45(d, J=1.1Hz, 1H), 8.07(d, J=1.1Hz, 1H), 7.98-7.85(m, 2H), 7.61(d, J=5.6Hz, 1H), 6.90(dd, J=9.7, 1.2Hz, 1H), 3.59-3.44(m, 2H), 1.77(s, 3H).MS(ESI, m /z): [M+H] ⁺ ＝368.

Example 8

N-(3-cyano-1-methyl-1H-pyrazol-4-yl)-6-(1H-imidazol-1-yl)imidazo[1,2-b]pyridazine-3-carboxamide preparation. The structural formula is as follows:

The preparation process is the same as Step 3 of Example 5. ¹ H NMR (300MHz, DMSO-d ₆ ) δ10.27(s, 1H), 8.73(s, 1H), 8.61(d, J=9.8Hz, 1H), 8.45(d, J=7.4Hz, 2H) , 8.17(s, 1H), 8.08(d, J=9.8Hz, 1H), 7.20(s, 1H), 3.98(s, 3H). MS(ESI, m/z): [M+H] ⁺ = 334.

Example 9

((R)-6-(3-aminopiperidin-1-yl)-N-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)imidazo[1, 2-b] the preparation of pyridazine-3-carboxamide trifluoroacetate.The structural formula is as follows:

Step 1) Preparation of (R)-6-(3-((tert-butoxycarbonyl)amino)piperidin-1-yl)imidazo[1,2-b]pyridazine-3-carboxylic acid

The preparation process is the same as Steps 3 and 4 of Example 1. ¹ H NMR (300MHz, DMSO-d ₆ ) δ12.65(s, 1H), 8.04(s, 1H), 7.95(d, J=9.9Hz, 1H), 7.31(d, J=10.1Hz, 1H) , 7.00(d, J=7.4Hz, 1H), 4.26-3.85(m, 3H), 3.06(s, 2H), 1.80(d, J=16.1Hz, 2H), 1.39(m, 11H).

Step 2) (R)-6-(3-aminopiperidin-1-yl)-N-(3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)imidazo[ Preparation of 1,2-b]pyridazine-3-carboxamide trifluoroacetate

The preparation process is the same as Steps 9 and 10 of Example 1. ¹ H NMR (300MHz, DMSO-d ₆ ) δ9.99(s, 1H), 8.38(s, 1H), 8.29-7.94(m, 5H), 7.37(d, J=10.1Hz, 1H), 7.32( s, 1H), 3.91(s, 3H), 3.77(s, 1H), 3.52-3.27(m, 3H), 1.95-2.10(m, 1H), 1.78-1.94(m, 1H), 1.68(s, 2H ). MS (ESI, m/z): [M+H] ⁺ = 391.

Example 10

(R)-N-(4-morpholino-2-(trifluoromethyl)phenyl)-6-(piperidin-3-ylamino)imidazo[1,2-b]pyridazine-3- Preparation of formamide hydrochloride. The structural formula is as follows:

Step 1) Preparation of 4-(4-nitro-3-(trifluoromethyl)phenyl)morpholine

4-fluoro-1-nitro-2-(trifluoromethyl)benzene (0.2g, 0.96mmol) was dissolved in 6ml of acetonitrile, and morpholine (0.167g, 1.91mmol) and triethylamine (0.242g, 2.39 mmol) was refluxed for 4 hours, 30ml of water was added to precipitate a solid, filtered by suction, and dried by infrared to obtain 0.247g of a yellow solid. Yield: 93.5%. ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.08 (d, J=9.4Hz, 1H), 7.29 (d, J=2.9Hz, 1H), 7.23 (dd, J=9.2, 2.8Hz, 1H) , 3.45 (ddd, J=6.9, 4.1, 2.0Hz, 4H).

Step 2) Preparation of 4-morpholino-2-(trifluoromethyl)aniline

Dissolve 4-(4-nitro-3-(trifluoromethyl)phenyl)morpholine (0.23g, 0.832mmol) in methanol/tetrahydrofuran (20ml/4ml), add palladium on carbon (5%, 45mg), React with a hydrogen balloon for 1 hour, filter with diatomaceous earth, and concentrate the filtrate under reduced pressure to obtain 0.2 g of a brown solid.

Step 3) (R)-3-((3-((4-morpholino-2-(trifluoromethyl)phenyl)carbamoyl)imidazo[1,2-b]pyridazine-6- The preparation of base) amino) piperidine-1-carboxylic acid tert-butyl ester

The product obtained in Step 4 of Example 1 (90 mg, 0.249 mmol) and the product of the previous step (55 mg, 0.226 mg) were dissolved in 4 ml of acetonitrile, pyridine (54 mg, 0.679 mmol) was added, and phosphorus oxychloride (52 mg, 0.339mmol), react at room temperature for 2 hours. It was quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered with suction, concentrated under reduced pressure, and separated by flash column chromatography (eluted with dichloromethane/methanol=60:1) to obtain 120 mg of a light yellow solid. Yield: 89.9%. MS (ESI, m/z): [MH] ⁺ = 588.15.

Step 4) (R)-N-(4-morpholino-2-(trifluoromethyl)phenyl)-6-(piperidin-3-ylamino)imidazo[1,2-b]pyridazine - Preparation of 3-formamide hydrochloride

The product from the previous step (0.12 g, 0.203 mmol) was dissolved in 5 ml of ethyl acetate, and dry hydrogen chloride gas was passed through for 15 minutes under an ice bath, concentrated under reduced pressure, beaten with ethyl acetate, filtered with suction, and dried by infrared to obtain 80 mg of a light yellow solid. ¹ H NMR (300MHz, DMSO-d ₆ ) δ9.97(s, 1H), 9.36(d, J=42.0Hz, 2H), 8.79(d, J=7.4Hz, 1H), 8.53(s, 1H) , 8.16(d, J=9.9Hz, 1H), 7.49(d, J=8.8Hz, 1H), 7.39(d, J=9.9Hz, 1H), 7.36-7.23(m, 2H), 4.11(s, 1H), 3.77(t, J=4.7Hz, 4H), 3.24(t, J=4.9Hz, 5H), 2.88-3.15(m, 3H), 1.91(s, 3H), 1.76-1.52(m, 2H) ). MS (ESI, m/z): [M+H] ⁺ = 490.

Example 11

(R)-N-(4-(4-acetylpiperazin-1-yl)-2-(trifluoromethyl)phenyl)-6-(piperidin-3-ylamino)imidazo[1,2 -b] Preparation of pyridazine-3-carboxamide hydrochloride. The structural formula is as follows:

Step 1) Preparation of 1-(4-(4-amino-3-(trifluoromethyl)phenyl)piperazin-1-yl)ethan-1-one

The preparation process is the same as Steps 1 and 2 of Example 10.

Step 2) (R)-N-(4-(4-acetylpiperazin-1-yl)-2-(trifluoromethyl)phenyl)-6-(piperidin-3-ylamino)imidazo[ 1,2-b] Preparation of pyridazine-3-carboxamide hydrochloride

The preparation process is the same as Steps 3 and 4 of Example 10. ¹ H NMR (300MHz, DMSO-d ₆ ) δ9.95(s, 1H), 9.35(s, 1H), 9.14(s, 1H), 8.39(d, J=7.2Hz, 1H), 8.25(s, 1H), 8.04(d, J=9.4Hz, 1H), 7.49(d, J=8.6Hz, 1H), 7.28(d, J=17.5Hz, 2H), 7.16(d, J=9.2Hz, 1H) , 3.60(s, 4H), 3.38-2.90(m, 9H), 2.05(s, 3H), 1.91(d, J=10.1Hz, 2H), 1.49-1.75(m, 2H).MS(ESI, m /z): [M+H] ⁺ = 531.20. MS (ESI, m/z): [M+H] ⁺ = 531.

Example 12

(R)-N-(2-methoxy-4-morpholino)-6-(piperidin-3-ylamino)imidazo[1,2-b]pyridazine-3-carboxamide trifluoroethyl Salt preparation. The structural formula is as follows:

Step 1) Preparation of 4-(3-methoxy-4-nitrophenyl)morpholine

Dissolve 4-fluoro-2-methoxy-1-nitrobenzene (0.1g, 0.584mmol) in 3ml of morpholine, add potassium carbonate (161mg, 1.17mmol), react at 80°C for 1 hour, add water to precipitate a solid, pump Filtration and infrared drying gave 133 mg of a yellow solid. Yield: 95.5%.

Step 2) Preparation of 2-methoxy-4-morpholinoaniline

The preparation process is the same as step 2 of Example 10.

Step 3) ((R)-N-(2-methoxy-4-morpholino)-6-(piperidin-3-ylamino)imidazo[1,2-b]pyridazine-3-methanol Preparation of amide trifluoroacetate

The preparation process is the same as Steps 9 and 10 of Example 1. ¹ H NMR (300MHz, DMSO-d ₆ ) δ10.20(s, 1H), 8.64(s, 1H), 8.52(s, 1H), 8.10(s, 1H), 8.00(dd, J=9.1, 3.9 Hz, 2H), 7.69(d, J=5.7Hz, 1H), 6.98(d, J=9.7Hz, 1H), 6.72(s, 1H), 6.56(d, J=8.8Hz, 1H), 4.17( s, 1H), 3.88(s, 3H), 3.77(d, J=6.0Hz, 4H), 3.36-2.97(m, 8H), 2.02(s, 2H), 1.82(s, 1H), 1.67(s , 1H). MS (ESI, m/z): [M+H] ⁺ =452.

Example 13

(R)-N-(4-(4-acetylpiperazin-1-yl)-2-methoxyphenyl)-6-(piperidin-3-ylamino)imidazo[1,2-b] Preparation of pyridazine-3-carboxamide hydrochloride. The structural formula is as follows:

Step 1) Preparation of 1-(4-(3-methoxy-4-nitrophenyl)piperazin-1-yl)ethan-1-one

Dissolve 4-fluoro-2-methoxy-1-nitrobenzene (0.3g, 1.75mmol) and 1-ethoxypiperazine (337mg, 2.63mmol) in 5ml DMF, add potassium carbonate (484mg, 3.51mmol ), reacted at 90°C for 6 hours, added 30ml of water, extracted with ethyl acetate (20ml*3), separated by flash column chromatography (dichloromethane/methanol=200:1 elution), and obtained 0.34g of yellow solid. Yield: 69.4%. ¹ H NMR (300MHz, Chloroform-d) δ8.01 (d, J=9.2Hz, 1H), 6.43 (dd, J=9.3, 2.5Hz, 1H), 6.33 (d, J=2.5Hz, 1H), 3.97(s, 3H), 3.82(t, J=5.4Hz, 2H), 3.69(t, J-5.3Hz, 2H), 3.45(dt, J=14.2, 5.2Hz, 4H), 2.17(s, 3H ).

Step 2) Preparation of 1-(4-(4-amino-3-methoxyphenyl)piperazin-1-yl)ethan-1-one

The preparation process is the same as step 2 of Example 10.

Step 3) (R)-N-(4-(4-acetylpiperazin-1-yl)-2-methoxyphenyl)-6-(piperidin-3-ylamino)imidazo[1,2 -b] Preparation of pyridazine-3-carboxamide hydrochloride

The preparation process is the same as Steps 3 and 4 of Example 10. ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.55(s, 1H), 8.37(s, 1H), 8.13(s, 1H), 8.01(d, J=9.3Hz, 2H), 7.66(s, 1H), 7.00(d, J=9.9Hz, 1H), 6.76(s, 1H), 6.58(d, J=8.7Hz, 1H), 4.16(s, 1H), 3.97-3.80(m, 3H), 3.60(s, 4H), 3.15(d, J=18.5Hz, 8H), 2.06(m, 7H). MS(ESI, m/z): [M+H] ⁺ =493.

Example 14

(R)-6-(3-aminopiperidin-1-yl)-N-(2-methoxy-4-(4-(methylsulfonyl)piperazin-1-yl)phenyl)imidazo Preparation of [1,2-b]pyridazine-3-carboxamide trifluoroacetate. The structural formula is as follows:

Step 1) Preparation of 2-methoxy-4-(4-(methylsulfonyl)piperazin-1-yl)aniline

The preparation process is the same as Steps 1 and 2 of Example 13.

Step 2) (R)-6-(3-aminopiperidin-1-yl)-N-(2-methoxy-4-(4-(methylsulfonyl)piperazin-1-yl)phenyl ) Preparation of imidazo[1,2-b]pyridazine-3-carboxamide trifluoroacetate

The preparation process is the same as Steps 9 and 10 of Example 1. ¹ H NMR (300MHz, DMSO-d ₆ ) δ9.59(s, 1H), 8.86(d, J=7.9Hz, 1H), 8.28(t, J=4.4Hz, 2H), 8.08(s, 3H) , 6.83(d, J=8.0Hz, 1H), 6.73(d, J=2.5Hz, 1H), 6.56(dd, J=9.0, 2.4Hz, 1H), 4.21(d, J=14.6Hz, 2H) , 3.88(s, 3H), 3.66(d, J=12.4Hz, 2H), 3.25(d, J=3.0Hz, 8H), 2.93(s, 3H), 1.62-2.09(m, 6H).MS( ESI, m/z): [M+H] ⁺ =529.

Example 15

(R)-6-(3-aminopiperidin-1-yl)-N-(2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)imidazo[1,2 -b] Preparation of pyridazine-3-carboxamide trifluoroacetate. The structural formula is as follows:

Step 1) Preparation of 2-methoxy-4-(4-methylpiperazin-1-yl)aniline

The preparation process is the same as Steps 1 and 2 of Example 13.

Step 2) (R)-6-(3-aminopiperidin-1-yl)-N-(2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)imidazo[ Preparation of 1,2-b]pyridazine-3-carboxamide trifluoroacetate

The preparation process is the same as Steps 9 and 10 of Example 1. ¹ H NMR (300MHz, DMSO-d ₆ ) δ10.20(s, 2H), 8.26-8.06(m, 5H), 7.36(d, J=10.1Hz, 1H), 6.77(d, J=2.5Hz, 1H), 6.61(dd, J=9.0, 2.4Hz, 1H), 4.00(d, J=13.1Hz, 1H), 3.90(s, 5H), 3.68-3.32(m, 5H), 3.18(s, 2H ), 2.82-3.12 (m, 5H), 2.15-1.57 (m, 5H).MS (EsI, m/z): [M+H] ⁺ =465.20.MS (ESI, m/z): [M+ H] ⁺ ＝465.

Example 16

(R)-6-(3-aminopiperidin-1-yl)-N-(2-methoxy-4-(piperazin-1-yl)phenyl)imidazo[1,2-b]pyridine Preparation of oxazine-3-carboxamide trifluoroacetate. The structural formula is as follows:

The preparation process is the same as Steps 9 and 10 of Example 1. ¹ H NMR (300MHz, DMSO-d ₆ ) δ10.17(s, 1H), 8.93(s, 2H), 8.19-8.05(m, 5H), 7.32(d, J=10.1Hz, 1H), 6.72( d, J=2.5Hz, 1H), 6.56(dd, J=9.0, 2.5Hz, 1H), 3.97(d, J=12.4Hz, 1H), 3.86(s, 4H), 3.52(dd, J=13.3 , 7.6Hz, 3H), 3.40-3.17(m, 8H), 1.82-2.01(m, 2H), 1.68(d, J=7.5Hz, 2H). MS (ESI, m/z): [M+H ] ⁺ = 451.

Example 17

(R)-6-(3-aminopiperidin-1-yl)-N-(3-methoxy-4-morpholinophenyl)imidazo[1,2-b]pyridazine-3-metha Preparation of amide trifluoroacetate. The structural formula is as follows:

Step 1) Preparation of 4-(2-methoxy-4-nitrophenyl)morpholine

Dissolve 1-fluoro-2-methoxy-4-nitrobenzene (0.2g, 1.17mmol) and morpholine (2.03mg, 2.34mmol) in 5ml of DMF, add potassium carbonate (323mg, 2.34mmol), 80°C After reacting for 6 hours, water was added to precipitate a solid, filtered by suction, and dried by infrared to obtain 221 mg of a yellow solid. Yield: 79.4%. ¹ H NMR (300MHz, Chloroform-d) δ7.89(d, J=8.9Hz, 1H), 7.02-6.81(m, 1H), 4.22-3.65(m, 7H), 3.25(q, J=3.9Hz , 4H).

Step 2) Preparation of 3-methoxy-4-morpholinoaniline

The preparation process is the same as step 2 of Example 13.

Step 3) (R)-6-(3-aminopiperidin-1-yl)-N-(3-methoxy-4-morpholinophenyl)imidazo[1,2-b]pyridazine- Preparation of 3-formamide trifluoroacetate

The preparation process is the same as Steps 9 and 10 of Example 1. ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.32-7.95(m, 5H), 7.53-7.33(m, 2H), 6.95(d, J=8.5Hz, 1H), 4.00(d, J=12.8 Hz, 1H), 3.81(s, 3H), 3.74(t, J=4.4Hz, 3H), 2.97(t, J=4.5Hz, 4H), 2.09-1.84(m, 2H), 1.72(d, J = 8.1 Hz, 2H), MS (ESI, m/z): [M+H] ⁺ = 452.

Example 18

(R)-6-(3-aminopiperidin-1-yl)-N-(2-methoxy-4-(morpholinomethyl)phenyl)imidazo[1,2-b]pyridazine - Preparation of 3-formamide trifluoroacetate. The structural formula is as follows:

Step 1) Preparation of 4-(bromomethyl)-2-methoxy-1-nitrobenzene

2-Methoxy-4-methyl-1-nitrobenzene (0.2g, 1.20mmol), N-bromosuccinimide (319mg, 1.79mmol) and dibenzoyl peroxide (43mg, 0.179 mmol) was dissolved in 10ml ethyl acetate, refluxed overnight, removed insoluble solids by suction filtration, extracted with dichloromethane (15ml*2) and water, washed with saturated brine, dried over anhydrous sodium sulfate, suction filtered, concentrated under reduced pressure, and directly Throw in the next step.

Step 2) Preparation of 4-(3-methoxy-4-nitrobenzyl)morpholine

Dissolve the product from the previous step and morpholine (141mg, 1.63mmol) in 4ml of DMSO, add potassium carbonate (225mg, 1.63mmol), react at 80°C for 4 hours, add 25ml of water and ethyl acetate (20ml*3) for extraction, saturated salt Wash with water, dry over anhydrous sodium sulfate, filter with suction, concentrate under reduced pressure, and separate by flash column chromatography (eluted with dichloromethane/methanol=100:1) to obtain 242 mg of a brown solid. ¹ H NMR (300MHz, Chloroform-d) δ7.84(s, 1H), 7.16(s, 1H), 7.01(d, J=8.5Hz, 1H), 4.10-3.93(m, 3H), 3.75(s , 4H), 3.56(s, 2H), 2.71-2.23(m, 4H).

Step 3) Preparation of 2-methoxy-4-(morpholinomethyl)aniline

The preparation process is the same as step 2 of Example 13.

Step 4) (R)-6-(3-aminopiperidin-1-yl)N-(2-methoxy-4-(morpholinomethyl)phenyl)imidazo[1,2-b] Preparation of pyridazine-3-carboxamide trifluoroacetate

The preparation process is the same as Steps 9 and 10 of Example 1. ¹ H NMR (300MHz, DMSO-d ₆ ) δ10.41(s, 1H), 9.94(s, 1H), 8.45(d, J=8.2Hz, 1H), 8.22(s, 1H), 8.17(d, J=10.0Hz, 1H), 8.01(s, 3H), 7.39(d, J=10.2Hz, 1H), 7.31(s, 1H), 7.14(d, J=8.3Hz, 1H), 4.35(s, 2H), 3.99(d, J=19.1Hz, 7H), 3.59(dd, J=22.3, 14.7Hz, 5H), 3.36-3.03(m, 4H), 2.12-1.64(m, 4H).MS(ESI , m/z): [M+H] ⁺ = 466.

Example 19

(R)-6-(3-aminopiperidin-1-yl)-N-(2-methoxy-4-(2-morpholinoethoxy)phenyl)imidazo[1,2-b ] Preparation of pyridazine-3-carboxamide trifluoroacetate. The structural formula is as follows:

Step 1) Preparation of 4-(2-(3-methoxy-4-nitrophenoxy) ethyl) morpholine

4-Fluoro-2-methoxy-1-nitrobenzene (0.2g, 1.17mmol) and 2-morpholine ethanol (306mg, 2.34mmol) were dissolved in 6ml of toluene, and benzyltriethylammonium bromide ( 53mg, 0.233mmol), then add 6ml of 25% aqueous potassium hydroxide solution, react at 60°C for 24 hours, extract with ethyl acetate (20ml*3) and 20ml of water, wash with saturated brine, dry over anhydrous sodium sulfate, suction filter, reduce Concentrate under reduced pressure and separate by flash column chromatography (dichloromethane/methanol=50:1 elution) to obtain 140 mg of yellow oil. Yield: 42.4%.

Step 2) Preparation of 2-methoxy-4-(2-morpholinoethoxy)aniline

The preparation process is the same as step 2 of Example 13.

Step 3) (R)-6-(3-aminopiperidin-1-yl)-N-(2-methoxy-4-(2-morpholinoethoxy)phenyl)imidazo[1, 2-b] Preparation of pyridazine-3-carboxamide trifluoroacetate

The preparation process is the same as Steps 9 and 10 of Example 1. ¹ H NMR (300MHz, DMSO-d ₆ ) δ10.45(s, 1H), 8.51-7.89(m, 6H), 7.36(t, J=8.1Hz, 1H), 6.76(s, 1H), 6.64( d, J=8.4Hz, 1H), 4.09-3.67(m, 9H), 3.30(m, 9H), 2.09-1.60(m, 4H). MS (ESI, m/z): [M+H] ⁺ = 496.20. MS (ESI, m/z): [M+H] ⁺ = 496.

Example 20

Preparation of N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-6-methoxyimidazo[1,2-b]pyridazine-3-carboxamide. The structural formula is as follows:

Step 1) Preparation of 6-methoxyimidazo[1,2-b]pyridazine-3-carboxylic acid

Dissolve ethyl 6-chloroimidazo[1,2-b]pyridazine-3-carboxylate in tetrahydrofuran/water/methanol (4ml/4ml/2ml), react at 60°C for 5 hours, concentrate under reduced pressure, add 3ml water, adjusted to pH = 3 with 1 mol/L dilute hydrochloric acid, a solid precipitated, filtered with suction, and dried to obtain 162 mg of a white solid. Yield: 94.6%. ¹ H NMR (300MHz, DMSO-d ₆ ) δ12.96(s, 1H), 8.12(d, J=11.2Hz, 2H), 7.08(d, J=9.6Hz, 1H), 3.96(s, 3H) .

Step 2) Preparation of N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-6-methoxyimidazo[1,2-b]pyridazine-3-carboxamide 4-Amino-1-methyl-1H-pyrazole-3-carboxamide (40 mg, 0.285 mmol) and the previous product (61 mg, 0.314 mmol) were dissolved in 5 ml of acetonitrile, HATU (217 mg, 0.571 mmol) and DIPEA were added (92mg, 0.713mmol), reacted at room temperature for 2 hours, extracted with ethyl acetate (10ml*3) and 15ml of water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered with suction, concentrated under reduced pressure, beaten with ethyl acetate/petroleum ether , to obtain 55 mg of white solid. Yield: 61.1%. ¹ H NMR (300MHz, DMSO-d ₆ ) δ11.03(s, 1H), 8.45(s, 1H), 8.27-8.17(m, 2H), 7.64(s, 1H), 7.45(s, 1H), 7.12(d, J=9.7Hz, 1H), 4.25(s, 3H), 3.94(s, 3H). MS(ESI, m/z): [M+H] ⁺ =316.

Example 21: IRAK4 Kinase Activity Test

Specifically, it has passed the Caliper mobility shift assay test by Shanghai ChemPartner. First set up 8 drug concentration gradients (3 μM to 1 nM, two replicate wells for each concentration), add IRAK4 kinase (3.5 nM, Carna Company) in the kinase base buffer and transfer to the test plate (10% DMSO containing 5 μL of the drug) Solution), then add FAM-labeled peptide and ATP (37 μM), incubate at 28°C for a period of time, add 10 μL of stop buffer to terminate the reaction, Caliper collects data.

Table 1 shows the activity of selected compounds of the present invention in the IRAK4 activity inhibition analysis, wherein the symbol "+++" indicates that the compound IC ₅₀ ≤ 0.1 μM; the symbol "++" indicates that the compound is 0.1 μM ≤ IC ₅₀ ≤ 1 μM; the symbol "+" indicates that the IC ₅₀ of the compound is >1 μM.

Table 1 The inhibitory activity of compounds of the present invention to IRAK4

Embodiment 22: HPAC cell growth inhibition rate experiment

Cells were cultured in high glucose DMEM medium containing 10% fetal bovine serum. Cells in the logarithmic growth phase were inoculated in 96-well plates with HPAC8000 cells/well/100 μL, and 100 μL of DMEM medium was added to the blank control, and put back into the incubator for culture. After the cells adhered to the wall for about 16 hours, diluted with DMEM medium The sample to be tested is made to be 2 times of the final concentration (starting at 50 μM, 3-fold dilution, 6 drug concentrations, and three replicate wells for each concentration). Add the diluted sample to be tested at 100 μL/well to the experimental wells inoculated with cells, and add 100 μL of DMEM medium to the positive control and blank control wells, respectively. Put the 96-well plate back into the incubator for 72 hours, add 20 μL MTT to each well, put the 96-well plate back into the incubator, continue to incubate for 4 hours, suck off the supernatant, add 150 μL DMSO to each well to dissolve, and put in the enzyme label The instrument was oscillated for 5 minutes, and the OD value was measured at a wavelength of 490nm, and the IC ₅₀ was calculated accordingly. The results are shown in Table 2.

Table 2 Compounds of the present invention inhibit HPAC cell growth analysis results

compound _IC50 A-2 5.7μM A-3 5.2μM A-15 1.7μM A-19 8.7μM

Claims (10)

1. Imidazopyridazines or its pharmaceutically acceptable salt shown in logical formula (I)：

Wherein：

A rings are aromatic ring or heteroaromatic；

N is 0~4 integer；

X is selected from N or O；

R₀Selected from (C₁~C₄) alkyl, heterocycle ,-OCH₃、-CF₃、-CHF₂、-CN、-CONH₂, halogen ,-(CH2)_m-R_a、-O- (CH2)_m-R_a；

M is 1~4 integer；

R_aFor nitrogen atom heterocycle, wherein nitrogen atom heterocycle can be optionally by one or more selected from halogen ,-OH ,-CH₃、-OCH₃ Substituent substitution；

R₂And R₃It is independently selected from hydrogen atom, heterocycle ,-CH₂CH₂-N(R_b)₂, R₂And R₃It can connect to form heterocycle by nitrogen-atoms, its In above-mentioned heterocycle can be further by one or more R_cSubstituted；

R_bSelected from hydrogen atom, (C₁~C₄) alkyl or acetyl group；

R_cSelected from-CF₃、-CHF₂、-OH、-NH₂Or formoxyl.

2. according to logical formula (I) compound or its pharmaceutically acceptable salt described in claim 1, it is shown in logical formula (II) Compound or its pharmaceutically acceptable salt：

Wherein：

N is 1~3 integer；

X is selected from N or O；

R₁Selected from nitrogen atom heterocycle ,-(CH2)_m-R_a、-O-(CH2)_m-R_a；

M is 1~3 integer；

R_aFor nitrogen atom heterocycle, wherein nitrogen atom heterocycle can be optionally by one or more selected from halogen ,-OH ,-CH₃、-OCH₃ Substituent substitution；

R₂And R₃It is independently selected from hydrogen atom, heterocycle ,-CH₂CH₂-N(R_b)₂, R₂And R₃It can connect to form heterocycle by nitrogen-atoms, its In above-mentioned heterocycle can be further by one or more R_cSubstituted；

R_bSelected from hydrogen atom, (C₁~C₄) alkyl or acetyl group；

R_cSelected from-CF₃、-CHF₂、-OH、-NH₂, formoxyl；

R₄Selected from hydrogen atom, halogen ,-OCH₃、-CHF₂、-CF₃。

3. according to logical formula (I) compound or its pharmaceutically acceptable salt described in claim 1, it is logical formula (III) institute The compound shown or its pharmaceutically acceptable salt：

Wherein：

R₅For (C₁~C₃) alkyl；

X is selected from N or O；

R₂And R₃It is independently selected from hydrogen atom, heterocycle ,-CH₂CH₂-N(R_b)₂, R₂And R₃It can connect to form heterocycle by nitrogen-atoms, its In above-mentioned heterocycle can be further by one or more R_cSubstituted；

R_bSelected from hydrogen atom, (C₁~C₄) alkyl or acetyl group；

R_cSelected from-CF₃、-CHF₂、-OH、-NH₂, formoxyl；

R₆Selected from-CHF₂、-CF₃、-CN、-CONHR_d；

R_dSelected from hydrogen atom, (C₁~C₄) alkyl.

4. lead to formula (I) compound and its officinal salt according to defined in claim 1, it is characterised in that the compound is preferential It is selected from：

(R)-N- (3- carbamoyl -1- methyl isophthalic acid H- pyrazoles -4- bases) -6- (piperidines -3- bases amino) imidazo [1,2-b] is rattled away Piperazine -3- formamides；

(R)-N- (3- itrile group -1- methyl isophthalic acid H- pyrazoles -4- bases) -6- (piperidines -3- bases amino) imidazo [1,2-b] pyridazine -3- Formamide；

(R)-N- (3- (difluoromethyl) -1- methyl isophthalic acid H- pyrazoles -4- bases) -6- (piperidines -3- bases amino) imidazo [1,2-b] is rattled away Piperazine -3- formamides；

6- ((2- amino-ethyls) amino)-N- (3- carbamoyl -1- methyl isophthalic acid H- pyrazoles -4- bases) imidazo [1,2-b] is rattled away Piperazine -3- formamides；

N- (3- cyano group -1- methyl isophthalic acid H- pyrazoles -4- bases) -6- (piperazine -1- bases) imidazo [1,2-b] pyridazine -3- formamides；

6- (4- Acetylpiperazine -1- bases)-N- (3- cyano group -1- methyl isophthalic acid H- pyrazoles -4- bases) imidazo [1,2-b] pyridazine -3- Formamide；

6- ((2- acetamidoethyls) amino)-N- (3- cyano group -1- methyl isophthalic acid H- pyrazoles -4- bases) imidazo [1,2-b] pyridazine - 3- formamides；

N- (3- cyano group -1- methyl isophthalic acid H- pyrazoles -4- bases) -6- (1H- imidazoles -1- bases) imidazo [1,2-b] pyridazine -3- formyls Amine；

(R) -6- (3- amino piperidine -1- bases)-N- (3- (difluoromethyl) -1- methyl isophthalic acid H- pyrazoles -4- bases) imidazo [1,2-b] Pyridazine -3- formamides；

(R)-N- (4- morpholinoes -2- (trifluoromethyl) phenyl) -6- (piperidines -3- bases amino) imidazo [1,2-b] pyridazine -3- first Acid amides；

(R)-N- (4- (4- acetylpiperazine -1- bases) -2- (trifluoromethyl) phenyl) -6- (piperidines -3- bases amino) imidazo [1,2- B] pyridazine -3- formamides；

(R)-N- (2- methoxyl group -4- morpholinoes) -6- (piperidines -3- bases amino) imidazo [1,2-b] pyridazine -3- formamides；

(R)-N- (4- (4- acetylpiperazine -1- bases) -2- methoxyphenyls) -6- (piperidines -3- bases amino) imidazo [1,2-b] is rattled away Piperazine -3- formamides；

(R) -6- (3- amino piperidine -1- bases)-N- (2- methoxyl groups -4- (4- (methyl sulphonyl) piperazine -1- bases) phenyl) imidazoles And [1,2-b] pyridazine -3- formamides；

(R) -6- (3- amino piperidine -1- bases)-N- (2- methoxyl groups -4- (4- methylpiperazine-1-yls) phenyl) imidazo [1,2-b] Pyridazine -3- formamides；

(R) -6- (3- amino piperidine -1- bases)-N- (2- methoxyl groups -4- (piperazine -1- bases) phenyl) imidazo [1,2-b] pyridazine - 3- formamides；

(R) -6- (3- amino piperidine -1- bases)-N- (3- methoxyl group -4- morphlinophenyls) imidazo [1,2-b] pyridazine -3- formyls Amine；

(R) -6- (3- amino piperidine -1- bases)-N- (2- methoxyl groups -4- (morpholinomethyl) phenyl) imidazo [1,2-b] pyridazine - 3- formamides；

(R) -6- (3- amino piperidine -1- bases)-N- (2- methoxyl groups -4- (2- morpholinoes ethyoxyl) phenyl) imidazo [1,2-b] Pyridazine -3- formamides；

N- (3- carbamoyl -1- methyl isophthalic acid H- pyrazoles -4- bases) -6- methoxyl groups imidazo [1,2-b] pyridazine -3- formamides.

5. the preparation method of the Imidazopyridazines according to claim 1-3, it is characterised in that：

A) using the chloro- 3- amino pyridazines of 6- as raw material and DMF dimethylacetal reaction generation N- (6- chlorine pyridazine- 3- yls)-N, N- dimethyl carbonamidine 1,1 is with bromoacetate via generation 6- chlorine imidazo [1, the 2-b] pyridazine -3- carboxylics of intermediate 2 Acetoacetic ester 3,3 and corresponding amine generation 4a-e, then in lithium hydrate obtain 5a-e, finally with corresponding amine into amide condensed Target compound A-1~A-4 and A-10~A-19：

Wherein, R₀, R₂, R₃It is as claimed in claim 1 with n definition；

B) 6- chlorine imidazo [1,2-b] Pyridazine 3 carboxylic acid ethyl ester obtains 6- methoxyl groups in the presence of methanol by lithium hydrate Imidazo [1,2-b] Pyridazine 3 carboxylic acid 8,8 obtains target compound A-20 with corresponding amino-pyrazol into acid amides：

Wherein, R₅And R₆Definition it is as claimed in claim 3；

C) 6- chlorine imidazo [1,2-b] Pyridazine 3 carboxylic acid ethyl ester is hydrolyzed into 6- chlorine imidazo [1,2-b] in lithium hydroxide and rattled away With corresponding amine substitution reaction occurs for piperazine -3- carboxylic acids 6,6, obtains target compound A-5~A-8：

Wherein, R₂, R₃, R₅And R₆Definition it is as claimed in claim 3.

6. a kind of pharmaceutical composition, it is made up of the active component and pharmaceutically acceptable auxiliary material for treating upper effective dose；It is described Active component include Imidazopyridazines as any one of claim 1-4 or its is pharmaceutically acceptable Salt；Described pharmaceutically acceptable auxiliary material includes pharmaceutically acceptable carrier, diluent and/or excipient.

7. the term " pharmaceutically acceptable salt " according to claim 1-4 includes pharmaceutically acceptable sour addition salts With pharmaceutically acceptable base addition salts." pharmaceutically acceptable acid-addition salts " are the biologically effectives for referring to retain free alkali Property and without other side effects, the salt that is formed with inorganic acid or organic acid；Affiliated inorganic acid includes but is not limited to hydrochloric acid, hydrogen bromine Acid, sulfuric acid, nitric acid, phosphoric acid etc.；The organic acid includes being not limited to formic acid, acetic acid, trifluoroacetic acid, propionic acid, octanoic acid, caproic acid, the last of the ten Heavenly stems Acid, undecenoic acid, glycolic, gluconic acid, lactic acid, oxalic acid, adipic acid, glutaric acid, malonic acid, maleic acid, butanedioic acid, richness Horse acid, tartaric acid, citric acid, palmitic acid, stearic acid, oleic acid, cinnamic acid, laurate, malic acid, glutamic acid, pyroglutamic acid, day Winter propylhomoserin, benzoic acid, methanesulfonic acid, p-methyl benzenesulfonic acid, alginic acid, ascorbic acid, salicylic acid etc.；These acid can be by this area It is prepared by the method known.

8. any one of claim 1-4 and 6 compound or its pharmaceutically acceptable salt are preparing IRAK4 kinase inhibitors Application in medicine, the medicine are used to treat the autoimmune disease of patient, inflammatory disease, fibrotic disease, heteroimmune Property disease, thromboembolic disorders or cancer.

9. application according to claim 8, described autoimmune disease and inflammatory disease include but is not limited to：Class wind Wet arthritis, osteoarthritis, COPD, systemic loupus erythematosus, psoriasis, ulcerative colitis, enteron aisle One or more that stress be in syndrome；Described cancer includes but is not limited to：B cell chronic lymphocytic leukemia, urgency Property lymphocytic leukemia, NHL, Hodgkin lymphoma, acute myeloid leukaemia, diffusivity large B cell leaching One or more in bar knurl, Huppert's disease, Pancreatic neoplasms, non-small cell lung cancer.

10. according to the application described in claim 8-9, it is characterised in that further give the Disease and apply one kind or more Kind drug combination mode, one or more can be included and be selected from following active material：It is immunodepressant, glucocorticoid, non- Steroidal anti-inflammatory medicine, vinca compound, taxol, DNA damage agent, Bcl-2 inhibitor, BTK inhibitor, JAK inhibitor, Hsp inhibitor, ALK inhibitor, Flt3 inhibitor, PI3K inhibitor and SYK inhibitor.