CN109232575A - Pyrroles's [1,2-b] pyridazine compound or its officinal salt and their purposes - Google Patents

Abstract

The present invention relates to pyrroles's [1,2-b] pyridazine compound or its officinal salt and their purposes.Pyrroles [1 in the present invention, 2-b] pyridazine compound or its officinal salt have inhibitory effect to Poly adenosine diphosphate-ribose polymerase-1 (PARP), especially there is selective depression effect to the PARP-1 and PARP-2 of PARP family, and good bioactivity is all shown in vivo and in vitro, therefore it may be used as PARP inhibitor, for in pharmaceutical composition, to prevent and/or treat disease relevant to PARP, such as tumour, ischemic disease and neurodegenerative disease.

Description

Pyrroles's [1,2-b] pyridazine compound or its officinal salt and their purposes

Technical field

The present invention relates to field of medicinal chemistry, more particularly to pyrroles's [1,2-b] pyridazine compound or its officinal salt And their purposes.

Background technique

Poly adenosine diphosphate-ribose polymerase-1 (Poly (adenosine diphosphate [ADP]-ribose) Polymerase, PARP) it is a kind of cell ribozyme being present in most eukaryocytes.Its major function is by Buddhist nun gram acyl Amine adenine-dinucleotide (Nicotinamide adenine dinucleotide, NAD⁺) it is cracked into niacinamide and ADP- Ribose, and the ADP- ribose polymers of formation long-chain or branch on targeting proteins, with the function of this modulin, these eggs White includes histone, topoisomerase and PARP itself (Schreiber, V.；Dantzer,F；Ame,J.-C.and De Murcia G..Poly(ADP-ribose):novel functions for an old molecule.Nat.Rev.Mol.Cell Bio,2006,7,517-528).ADP- phosphoribosynltransferase family (ADP- Ribosyltransferases, ARTs) it finds and the subtype protein determined contains 18 in total at present, wherein only 6 Hypotype have forms the ribosylating ability of poly- ADP-, they be respectively PARP-1, PARP-2, PARP-3, PARP-4 (vPARP), PARP-5a (TNKS1) and PARP-5b (TNKS2)；And others ARTs 7-17 hypotype (also commonly referred to as PARPs 6-16) is only Has the function to form single ADP- ribose modifier.PARP-1 is as most abundant and studies widest member, 90% or more function is played in PARP family.Mankind PARP-1 is the polypeptide chain that a molecular weight is 113kDa, by three masters It wants Functional domains to form: being located at the DNA binding domain of zinc fingers (Zinc finger) containing there are two at the end amino (N)- (DNA binding domain, DBD), it itself modifies domain (Automodification domain) and is located at carboxyl (C)-and hold Catalytic domain (Catalytic domain).Mankind PARP-2 is the polypeptide chain that a molecular weight is 62kDa, it is in structure Most like with PARP-1, the catalytic domain of catalytic domain and PARP-1 reach 69% homology and DNA binding domain does not contain zinc finger Structure (Am é, Jean-Christophe；Spenlehauer,Catherine；de Murcia,Gilbert.The PARP superfamily. BioEssays 2004,26,882-893).PARP-1 and PARP-2 is damaged by base excision repair in DNA Wound reparation, Genome stability, Apoptosis adjust aspect and play a significant role, and become of greatest concern in recent years resist Tumour medicine studies one of target spot (Yelamos, J.；Farres,Jordi.；Llacuna,Laura.； Ampurdanes, Coral；Martin-Caballero,Juan.；PARP-1and PARP-2:New players in tumour development.Am.J.Cancer Res.2011 1(3),328-346；Weaver,A.N.；Yang,E. S.Beyond DNA repair:additional functions of PARP-1in cancer.Front.Oncol.2013, 3,290)。

Human DNA is in extrinsic factor (such as ultraviolet radioactive, particle radiation, alkylating reagent, topoisomerase and platinum class Drug etc.) or endogenous factor (as human homergy's active material and DNA itself chemical nature it is intrinsic spontaneous anti- Answer) under the action of be easy to produce DNA notch, these notch overwhelming majority can be changed into DNA single-strand break, cause DNA damage. DNA damage can influence various kinds of cell process extensively, be a major reason for causing tumour to occur with Other diseases.Study table The catalytic activity of bright PARP-1/2 can be broken acute activation by DNA chain.When DNA is damaged, the PARP-1 and damaged dna of activation Single stranded gaps combine, while catalysis forms the poly- of linear chain or branched chain on target protein (such as histone or PARP-1 itself) ADP- ribose polymers.This effect that will lead between the histone and DNA to form poly- ADP- ribose becomes loose, is conducive to DNA repair enzyme finally completes the reparation of DNA close to damaged dna.For treatment of cancer, due to radiotherapy and many Chemo-Therapy Treatment method is worked with targeting DNA damage, so PARP inhibitor can be used as the chemistry and radiosensitization for the treatment of of cancer Agent (Miwa, Masanao；Masutani, Mitsuko.PolyADP-ribosylation and cancer.Cancer science 2007,98,1528-1535)。

PARP inhibitor has been found the specificity that can be used for breast cancer related gene BRCA-1 and BRCA-2 defect tumour Killing.BRCA-1/2 is the crucial reparative factor that homologous recombination (Homologous recombination, HR) repairs approach. In the tumour cell of BRCA-1 and BRCA-2 defect, inhibits the effect of PARP to will lead to the accumulation of DNA single-strand break and increase, by Replication fork in traveling collapses, and DNA single-strand break translates into double-strand break, these tumour cells will be because of can not open Dynamic HR approach repairs double-strand break, finally leads to cell death due to the unstability of genome.The inhibition of PARP The phenomenon that effect and BRCA-1/2 defect kill cell jointly also referred to as cooperates with lethal (synthetic lethality).Benefit New strategy and new approaches are provided for the treatment of malignant tumour with the lethal theory of collaboration, and opens PARP inhibitor conduct New era of new type antineoplastic medicine research and development.(bibliography: Farmer, H.；McCabe,N.； Lord,C.J.；Tutt, A.N.J.；Johnson,D.A.；Richardson,T.B.；Santarosa,M.；Dillon,K. J.；Hickson,I.； Knights,C.；Martin,N.M.B.；Jackson,S.P.；Smith,G.C.M.；Ashworth,A..Targeting the DNA repair defect in BRCA mutant cell as a therapeutic strategy.Nature 2005, 434,917-921；Kaelin,W.G.The Concept of Synthetic Lethality in the Context of Anticancer Therapy.Nat Rev cancer 2005,5(9),689-698；He JX, Yang CH,Miao ZH.PARP inhibitors as promising cancer therapeutics.Acta Pharmacol.Sin.2010, 31,1172-1180.)

In addition to DNA is repaired and maintains the stability of genome, PARP also takes part in multiple bioprocess, including gene turns Record, cell cycle progression, cell death, chromatin function.PARP inhibitor has been found can be used for multinomial with treatment simultaneously The field of medicinal chemistry (disease in addition to malignant tumour) of meaning, including apoplexy, myocardial ischemia, inflammation, antiviral and glycosuria (the bibliography: Vir á g, L. such as disease；Szabó,C.,The Therapeutic Potential of Poly(ADP-Ribose) Polymerase Inhibitors.Pharmacol Rev 2002,54(3),375-429)。

Up to now most PARP inhibitor belong to competitive inhibitor, they and NAD⁺Emulative knot Together in the catalytic site of enzyme.Existing inhibitor is still unable to satisfy clinical demand, the generally existing dissolution of these compounds at present The disadvantages of poor, to PARP hypotype shortage selectivity is spent, therefore there is an urgent need to provide effective inhibitor of the PARP of structure novel.

Pyrroles [1,2-b] pyridazine structure is a dominance structure in pharmaceutical chemistry.Compound containing this class formation exists Drug field shows various bioactivity, for example (patent CN1056690 discloses one kind to reducing blood lipid/norcholesterol Compound containing this dominance structure and its application in terms for the treatment of hypercholesterolemia and hyperlipidemia), antitumor (patent WO 2011/014817 discloses the JANUS kinase inhibitor containing this class formation), anti-inflammatory, antibacterial (Butnariu, R.M.； Mangalagiu,I.I.,New pyridazine derivatives:Synthesis, chemistry and biological activity.Bioorg Med Chem 2009,17(7),2823-2829； Tucaliuc,R.-A.； Cotea,V.V.；Niculaua,M.；Tuchilus,C.；Mantu,D.；Mangalagiu,I. I.,New pyridazine- fluorine derivatives:Synthesis,chemistry and biological activity. Part II.Eur J Med Chem 2013,67(0),367-372；Butnariu,R.M.；Caprosu,M.D.； Bejan,V.； Mangalagiu,I.I.；Ungureanu,M.；Poiata,A.；Tuchilus,C.；Florescu,M., Pyridazine and phthalazine derivatives with potential antimicrobial activity.J Heterocyclic Chem 2007,44 (5), 1149-1152), it is antiviral that (patent CN103288832 discloses one kind and is used for Treat or prevent pyrroles [1,2-b] pyridyl derivatives of HIV infection or other virus infections)；WO 2004/087708A1 and WO 2007/069671 individually discloses cortex hormone of aadrenaline releasing factor (CRF) inhibitor containing this dominance structure in pharmacy Application and patent WO2010022240A1 disclose a kind of derivative containing this class formation, by effectively inhibiting HIF hydroxyl The activity for changing enzyme can adjust hypoxia inducible factor (HIF) stability and/or active isoreactivity.

Above-described reported pyrroles [1,2-b] pyridyl derivatives do not cover and are related to of the present inventionization Close object and its content as PARP inhibitor.

Summary of the invention

Based on this, the object of the present invention is to provide a kind of pyrroles's [1,2-b] pyridazine compound indicated by general formula I or Its officinal salt:

Wherein,

R¹For hydrogen, C_1-4Alkyl or halogen；

R²For

R³For hydrogen ,-C (=O) R⁶、-SO₂R⁷, substituted or unsubstituted C_1-4Alkyl or substituted or unsubstituted C_3-6Cycloalkanes Base, wherein the R⁶And R⁷It independently is substituted or unsubstituted C_1-4Alkyl, substituted or unsubstituted C_3-6Naphthenic base or substitution Or unsubstituted C_6-10Aryl, the substitution are by selected from halogen, C_1-4In alkyl, amino, itrile group, hydroxyl and nitro at least One substituent group replaces；

R⁴For hydrogen, halogen, C_1-4Alkyl or C_1-4Alkoxy；

R⁵For-CH₂Or-C=O；

X₁For S, O or NH；

X₂For CH or N；

Y₁、Y₂、Y₅And Y₆Independently be substituted or unsubstituted methylene, substituted or unsubstituted ethylidene, substitution or Unsubstituted propylidene or substituted or unsubstituted butylidene, the substitution are by selected from halogen, C_1-6Alkyl, C_3-6Naphthenic base and C_1-4At least one substituent group in alkoxy replaces；

Y₃And Y₄It independently is hydrogen, substituted or unsubstituted C_1-4Alkyl or substituted or unsubstituted C_3-6Naphthenic base, it is described Substitution is by selected from halogen, C_1-6Alkyl, C_3-6Naphthenic base and C_1-4At least one substituent group in alkoxy replaces；

Y₇For NR⁸Or CHR⁹,

Wherein, the R⁸For hydrogen ,-C (=O) R¹⁰、-SO₂R¹¹, substituted or unsubstituted C_1-4It is alkyl, substituted or unsubstituted C_3-6Naphthenic base or substituted or unsubstituted C_6-10Aryl, wherein the R¹⁰And R¹¹It independently is substituted or unsubstituted C_1-4 Alkyl, substituted or unsubstituted C_3-6Naphthenic base, substituted or unsubstituted five yuan do not take to hexa-atomic saturated heterocyclyl or substitution or The C in generation_6-10Aryl, the substitution are by selected from halogen, C_1-4Alkyl, C_1-4Halogenated alkyl, amino, by least one C_1-4Alkyl At least one substituent group in substituted amino, itrile group, hydroxyl and nitro replaces,

The R⁹For hydrogen ,-OR¹², by least one C_1-4Alkyl-substituted amino is five yuan to six substituted or unsubstituted First saturated heterocyclyl, wherein the R¹²For hydrogen, substituted or unsubstituted C_1-4Alkyl or substituted or unsubstituted C_3-6Naphthenic base, The substitution is by selected from halogen, C_1-4Alkyl, C_1-4Halogenated alkyl, amino, by least one C_1-4Alkyl-substituted amino, nitrile At least one substituent group in base, hydroxyl and nitro replaces.

More preferably, in the general formula I,

R¹For hydrogen, methyl, ethyl, propyl, fluorine, chlorine or bromine；

R²For

R³For hydrogen, methyl, ethyl or propyl；

R⁴For hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxyl group, ethyoxyl or propoxyl group；

R⁵For-CH₂Or-C=O；

X₁For S, O or NH；

X₂For CH or N；

Y₁、Y₂、Y₅And Y₆Independently be substituted or unsubstituted methylene, substituted or unsubstituted ethylidene, substitution or Unsubstituted propylidene or substituted or unsubstituted butylidene, the substitution are by selected from fluorine, chlorine, bromine, methyl, ethyl, third Base, isopropyl, normal-butyl, sec-butyl, isobutyl group, tert-butyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, methoxyl group, second At least one substituent group in oxygroup or propoxyl group replaces；

Y₃And Y₄It independently is hydrogen, methyl, ethyl, propyl, isopropyl or butyl；

Y₇For NR⁸Or CHR⁹,

Wherein, the R⁸For hydrogen ,-C (=O) R¹⁰、-SO₂R¹¹, methyl, ethyl, propyl, isopropyl, cyclopropyl, ring fourth Base, cyclopenta, cyclohexyl or substituted or unsubstituted phenyl, wherein the R¹⁰And R¹¹Independently be it is substituted or unsubstituted such as Lower group: methyl, ethyl, propyl, isopropyl, normal-butyl, sec-butyl, isobutyl group, tert-butyl, cyclopropyl, cyclobutyl, ring penta Base, cyclohexyl, pyrrolidinyl, tetrahydrofuran base, piperidyl, piperazinyl, morpholinyl, dioxane or phenyl, the substitution Be by selected from fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, trifluoromethyl, amino, N- methylamino, N- ethylamino, N, N- dimethylamino, N, at least one substituent group in N- diethylamino, itrile group, hydroxyl and nitro replace,

The R⁹For hydrogen ,-OR¹², N- methylamino, N- ethylamino, N, N- dimethylamino, N, N- diethylamino, Pyrrolidinyl, tetrahydrofuran base, piperidyl, piperazinyl, morpholinyl or dioxane, wherein the R¹²For hydrogen, methyl, second Base, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopenta or cyclohexyl, the substitution are by selected from fluorine, chlorine, bromine, methyl, second Base, propyl, isopropyl, trifluoromethyl, amino, N- methylamino, N- ethylamino, N, N- dimethylamino, N, N- diethyl At least one substituent group in amino, itrile group, hydroxyl and nitro replaces.

The general formula I has the structure indicated by general formula II in one of the embodiments:

Preferably, the R¹For halogen, more preferably chlorine.

Preferably, the X₁For S or O, more preferably S.

Preferably, the general formula II has the structure indicated by general formula II-a:

The general formula I has the structure indicated by general formula III in one of the embodiments:

Preferably, the R¹For halogen, more preferably chlorine.

Preferably, the R⁴For halogen, more preferably fluorine.

Preferably, the R⁵For-CH₂-。

Preferably, the Y₃And Y₄It independently is hydrogen, methyl, ethyl, propyl, isopropyl or butyl, more preferably methyl.

Preferably, the general formula III has the structure indicated by general formula III-a:

The general formula I has the structure indicated by general formula IV in one of the embodiments:

Preferably, the R¹For halogen, more preferably chlorine.

Preferably, the R⁴For halogen, more preferably fluorine.

Preferably, the R⁵For-CH₂Or-C=O.

Preferably, the general formula IV has the structure indicated by general formula IV-a:

The general formula I has the structure indicated by general formula V in one of the embodiments:

Preferably, the R¹For halogen, more preferably chlorine.

Preferably, the R⁴For hydrogen or halogen, the halogen is preferably fluorine.

Preferably, the general formula V has the structure indicated by general formula V-a:

Preferably, pyrroles's [1,2-b] pyridazine compound that the general formula I is indicated is one of following compounds:

Invention further provides general formula I pyrroles's [1,2-b] pyridazine compounds indicated or its officinal salt to make Purposes in standby PARP inhibitor.

The PARP inhibitor imitates PARP-1 and/or PARP-2 with selective depression in one of the embodiments, Fruit.

The present invention also provides a kind of pharmaceutical compositions, indicate it includes the general formula I of one or more therapeutically effective amounts Pyrroles's [1,2-b] pyridazine compound or its officinal salt, or the pyrroles comprising one or more therapeutically effective amounts The ester, prodrug, hydrate or crystallization of [1,2-b] pyridazine compound.

Described pharmaceutical composition has inhibitory effect to PARP in one of the embodiments, especially to PARP-1 And/or PARP-2 has selective depression effect.

Described pharmaceutical composition is for preventing and/or treating and PARP related disease, institute in one of the embodiments, Stating with PARP related disease includes that (breast cancer, oophoroma, liver cancer, melanoma, prostate cancer, colon cancer, gastric cancer etc. are real for tumour Body tumor), ischemic disease (brain, heart etc.) and neurodegenerative disease (Parkinson's disease, Alzheimer's disease etc.).

The present invention further provides the preparation method of general formula I pyrroles [1,2-b] pyridazine compound indicated, packets Include following steps:

After pyrroles's -2- methyl formate derivative carries out esterification, iodo and ammoxidation or first laggard are successively carried out Row amination and iodide reaction obtain the N- amino -5- iodol -2- methyl formate derivative I-a in following reaction equations；

Tetrahydrofuran (THF) solution reaction of aromatic aldehyde and acetenyl magnesium bromide obtains the aromatic alkyne in following reaction equations Alcohol I-b；

N- amino -5- iodol -2- methyl formate derivative I-a and fragrance alkynol I-b in palladium acetate, cuprous iodide with In the presence of DBU, coupling cyclization is carried out in a solvent, under microwave condition and obtains compound I-0；

Compound I-0 makees solvent with the saturation methanol solution of ammonia, reacts -24 hours 20 hours at 90 DEG C of tube sealing, or Directly and concentrated ammonia liquor, solvent are methanol, react at 90 DEG C of tube sealing and obtain within -24 hours 20 hours the pyrroles that the general formula I is indicated [1,2-b] pyridazine -7- Carbox amide；

The present invention further provides the preparations of general formula II or general formula II-a pyrroles [1,2-b] pyridazine compound indicated Method, synthetic route are as follows:

Specifically includes the following steps:

Compound E is condensed to yield corresponding amide F with acyl chlorides or carboxylic acid；

Amide F condenses cyclization and obtains compound, the subsequent compound is in sodium borohydride under the action of phosphorus oxychloride Under the conditions of reduction imines and further with Boc acid anhydrides protect free amine group obtain compound I；

Compound I is in solvent THF, after reacting with n-BuLi, DMF is further added reacts to obtain 2- formoxyl and take The thiophene derivant J in generation；

Compound J reacts to obtain compound I-c with the THF solution of acetenyl magnesium bromide；And

Compound I-c and above compound I-a carry out coupling cyclisation, with trifluoroacetic acid deprotection base and further ammonia Solution obtains compound shown in general formula II.

For the present invention with pyrroles [1,2-b] pyridazine -7- formamide as mother nucleus structure, design has synthesized a series of PARP suppressions Preparation, compound of the present invention have selective depression effect to the PARP-1 and PARP-2 of PARP family, and in body It is inside and outside all to show good bioactivity, be expected to develop into novel anti-tumor drug and prevention and/or treatment with The drug of PARP related disease.

Specific embodiment

Inhibit PARP living the structure and preparation method of compound involved in the present invention and inside and outside below with reference to embodiment The effect of property is further elaborated, but does not limit the present invention.

" alkyl " described herein refers to linear or branched alkyl group.

" alkoxy " described herein refers to straight or branched alkoxyl.

" substitution " described herein refers to replacing one or more hydrogen atoms.

" tumour " described herein includes benign tumour and malignant tumour.

" pyrroles [1,2-b] pyridazine compound " described herein includes optical isomer.

The preparation method of pyrroles [1,2-b] pyridazine compound that general formula I is indicated, comprising the following steps:

(1) N- amino -5- iodol -2- methyl formate derivative I-a is prepared, following scheme can be passed through:

Scheme 1:

Scheme 2:

Wherein, scheme 1 includes: pyrroles -2- methyl formate derivative A alkali (such as 4-dimethylaminopyridine (DMAP)) Under effect, compound B can be made by being heated to reflux in solvent (such as methanol), work of the compound B in silver trifluoroacetate and elemental iodine It under, is stirred overnight at room temperature in solvent (such as chloroform) and compound C can be obtained, compound C is in alkali (such as potassium tert-butoxide) and O- Under the action of (4- nitro benzoyl) azanol, being stirred overnight at room temperature in solvent (such as N-Methyl pyrrolidone (NMP)) can Compound I-a is made；

Scheme 2 includes: compound B under the action of alkali (such as potassium tert-butoxide) and O- (4- nitro benzoyl) azanol, Compound D can be made by being stirred overnight at room temperature in solvent (such as NMP), compound D under conditions of potassium iodide and hydrogen peroxide, Compound I-a can be made by being stirred at room temperature in solvent (such as acetic acid) 3 hours；

(2) fragrant alkynol I-b is prepared, tetrahydrofuran (THF) solution by corresponding aromatic aldehyde and acetenyl magnesium bromide is anti- It should obtain；

(3) N- amino -5- iodol -2- methyl formate derivative I-a and fragrance alkynol I-b are in palladium acetate, cuprous iodide Under the action of DBU, in solvent such as toluene, tetrahydrofuran in dioxanes, carries out coupling cyclization and obtains under microwave condition Compound I-0；With

(4) compound I-0 makees solvent with the saturation methanol solution of ammonia, reacts -24 hours 20 hours at 90 DEG C of tube sealing, Or can also directly and concentrated ammonia liquor, solvent is to react to obtain within -24 hours 20 hours the general formula I and indicate at 90 DEG C of methanol tube sealing Pyrroles [1,2-b] pyridazine compound；

The reaction equation of above-mentioned preparation method is as follows,

In following all examples, intitation reagents, solvent, material unless otherwise specified is that traditional Chinese medicines reagent group supplies It answers；Microwave reaction uses CEMNULL type microwave reaction instrument；¹H NMR is by BrucherAM-400 type or GeMINI-300 type nuclear-magnetism Resonate instrument record, and chemical shift is indicated with δ (ppm)；Mass spectrum is by Agilent1200-6110 type list quadrupole rod liquid chromatography mass Combined instrument record.Separation is Haiyang Chemical Plant, Qingdao's production 200-300 mesh column chromatography silica gel with silica gel.Wherein english abbreviation institute The chemical reagent of representative is as follows:

NBS:N- bromo-succinimide

DMAP:N, N- lutidines

NaBH₄: sodium borohydride

BH₃THF solution: the tetrahydrofuran solution of borine

EDCI:1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride

HOBt:1- hydroxybenzotriazole

11 carbon -7- alkene of DBU:1,8- diazabicyclo [5.4.0]

THF: tetrahydrofuran

NMP:N- methyl pyrrolidone

Embodiment 1

The preparation and synthesis of compound

The preparation method of the chloro- 2- trichloroacetyl pyrroles (compound 2) of 4-

Into the 500mL round-bottomed flask equipped with stirrer, addition 2- trichloroacetyl pyrroles 1 (40 grams, 190 mmol, on Hai Shuya Pharmaceutical Technology Co., Ltd) and methylene chloride 200mL, be slowly added dropwise at -10 DEG C into sulfonic acid chloride (31 grams, 227mmol), it drips within about 45 minutes, is continually maintained in and stirs 1 hour at this temperature, be then transferred into stirred at room temperature Night.After reaction carries out (thin-layer chromatography tracking) completely, reaction solution is poured into 300mL methylene chloride, ice water is added and quenches It goes out, isolates organic phase, water phase is extracted in two times with methylene chloride 400mL, merges organic phase, then use unsaturated carbonate hydrogen respectively Sodium solution, saturated common salt water washing, anhydrous sodium sulfate is dry, is concentrated to get 32 grams of crude products, yield 69%.

¹H NMR(300MHz,CDCl₃) δ 9.42 (brs, 1H), 7.27 (dd, J=3.2,1.5Hz, 1H), 7.11 (dd, J =3.2,1.5Hz, 1H)；LC-MS(ESI):m/z 246.2[M+H]⁺。

The preparation method of the chloro- pyrroles -2- methyl formate (compound 3) of 4-

Into the 250mL round-bottomed flask equipped with stirrer, compound 2 (8.1 grams, 32.8mmol) and DMAP (800 is added Milligram), the anhydrous methanol of 100mL is poured into, is stirred 1 hour at 70 DEG C, is cooled to room temperature, solvent is removed under reduced pressure.Add acetic acid Ethyl ester 100mL and 3M HCl solution 30mL, extraction and separation go out organic phase, and water layer uses ethyl acetate 50mL extraction primary again.Merge Organic phase, then uses saturated common salt water washing, and anhydrous sodium sulfate is dry.Vacuum concentration obtains 5.1 grams of white solid, and yield is 98%.

¹H NMR(300MHz,CDCl₃) δ 9.31 (brs, 1H), 6.90 (dd, J=3.2,1.5Hz, 1H), 6.81 (dd, J =3.2,1.5Hz, 1H), 3.86 (s, 3H)；LC-MS(ESI):m/z 160.1[M+H]⁺。

The preparation of the iodo- pyrroles -2- methyl formate (compound 4) of the chloro- 5- of 4-

Into the 100mL round-bottomed flask equipped with stirrer, it is added compound 3 (5.3 grams, 33mmol), silver trifluoroacetate (7 Gram, 33mmol) and chloroform 60mL, elemental iodine (4.7 grams, 36 mmol) are added under ice bath, use N₂It displaced air 3 times, is protected from light, It is stirred at room temperature 7 hours.After complete reaction, saturated sodium thiosulfate solution 25mL is added, after stirring 15 minutes, vacuum It filters, filter cake chloroform and water washing isolate the organic phase of filtrate, organic phase saturated common salt water washing, anhydrous sodium sulfate It is dry.Evaporating column chromatography (petroleum ether: ethyl acetate=30:1) obtains 8.3 grams of white solid, yield 76%.

¹H NMR(300MHz,CDCl₃) δ 9.55 (s, 1H), 6.80 (d, J=2.8Hz, 1H), 3.91 (s, 3H)；LC-MS (ESI):m/z 286.1[M+H]⁺。

The preparation method of O- (4- nitrobenzene formyl) hydroxylamine (compound 5)

At 0 DEG C, by methylene chloride (50mL) solution of paranitrobenzoyl chloride (13.2 grams, 70mmol) be slowly added dropwise into Containing N-Boc azanol (9.4 grams, 70.0mmol), 5.4mL triethylamine methylene chloride (45 mL) in, add within about 45 minutes.After It is continuous to stir 10 minutes at such a temperature, it is then transferred into and stirs 1.5 hours at room temperature.After thin-layer chromatography detects fully reacting, add Enter 60mL water quenching reaction, continues stirring 30 minutes.Organic phase is isolated, organic phase is washed with 1% sodium bicarbonate solution 48mL It washs, then separates organic phase.9mL methanesulfonic acid is added into organic phase at room temperature, starts that white solid is precipitated.After standing 6 hours, N-hexane 30mL is added, filters out white solid and obtains 5 mesylate.White solid is put into the beaker of 500mL again, Methylene chloride 200mL is added, is then added dropwise to saturated sodium bicarbonate solution again, until white solid all dissolves.It has isolated Machine phase, and with saturated common salt water washing.Anhydrous magnesium sulfate is dry, is concentrated to get 8.9 grams of white solid, yield 71%.

¹H NMR(300MHz,CDCl₃)δ8.35-8.28(m,2H),8.23-8.18(m,2H),6.74(s, 2H)；LC-MS (ESI): m/z 183.1 [M+H]⁺。

The preparation method of chloro- -2 methyl formate of pyrroles (compound 7) of N- amino -4-

Method 1:

By 6 grams of ammonium chlorides, 10mL ammonium hydroxide, 120mL ether is sequentially added in 500mL round-bottomed flask, will at -10 DEG C The liquor natrii hypochloritis 140mL of 5% (mass percent) is added dropwise in above-mentioned mixed liquor, is added, and is maintained at this within about 30 minutes At a temperature of stir 1 hour, organic phase is then demultiplex out, and washed with ice saturated salt solution 60mL.Anhydrous calcium chloride is dry, and Dry 1 hour is placed at -40 DEG C for use.

Under ice bath, compound 3 (2.5 grams, 15.7mmol) is dissolved in the anhydrous DMF (being purchased from lark waffle) of 30mL, NaH (800 milligrams, 20mmol, 60%, be dispersed in mineral oil, be purchased from lark waffle) are added in two portions.Stirring 30 minutes Afterwards, the above-mentioned chloro amine aqueous solution 100mL made is added, stirs 4 hours at room temperature, thin-layer chromatography detects fully reacting.It is added full Water 100mL is added, isolates organic phase, water layer uses ethyl acetate again after stirring 15 minutes with hypo solution 30mL Extraction.Merge organic phase, then with saturated common salt water washing.Concentration, column chromatography (petroleum ether: ethyl acetate=20:1) elute To 2.3 grams of white solid, yield 85%.

Method 2:

In the round-bottomed flask of the 500mL equipped with stirrer, compound 3 (2 grams, 12.6 mmol), ammonium chloride are sequentially added (4 grams, 75.5mmol), 3- octylmethylammonium chloride (Aliquat-336,0.5mL), ammonium hydroxide 15mL, water 5mL, K₂CO₃(4.6 Gram, 33.3mmol) and methyl tertiary butyl ether(MTBE) 45mL, liquor natrii hypochloritis 160mL is then added dropwise by constant pressure funnel, about It is added dropwise within 30 minutes.It stirs at room temperature 6-7 hours, after complete reaction, saturated sodium thiosulfate solution 50mL is added, stirs It mixes after ten minutes, isolates organic phase, water layer uses ethyl acetate mL to extract again.Merge organic phase, saturated sodium chloride solution is washed It washs, is concentrated, column chromatography (petroleum ether: ethyl acetate=20:1) affords 1.8 grams of yellow solid, yield 82%.

¹H NMR(300MHz,CDCl₃) δ 6.91 (d, J=1.9Hz, 1H), 6.73 (d, J=2.2Hz, 1H), 5.54 (s, 2H),3.82(s,3H)；LC-MS (ESI): m/z 143.2 (100%) [M-CH₃O]⁺。

The preparation method of the iodo- pyrroles -2- methyl formate (compound 6) of 1- amino -4- chloro- 5

Method 1:

Under ice bath, potassium tert-butoxide (526 milligrams, 4.7mmol) is added to the N- first of compound 4 (857 milligrams, 3 mmol) In base pyrrolidones (10mL) solution, after stirring 15 minutes, O- (4- nitro benzoyl)-azanol is added into mixed liquor The 5 solution mL of tetrahydrofuran of (692 milligrams, 3.6mmol), is stirred overnight at room temperature.Saturated salt solution 50mL is added into reaction solution With ethyl acetate 30mL, organic phase is isolated, water layer uses ethyl acetate 50mL to extract one time again.Organic phase after merging is used again Water and brine It.Organic phase is concentrated, column chromatography (petroleum ether: ethyl acetate=100:1) affords white solid 180 Milligram, yield 13%, while 260 milligrams of raw material are recycled, conversion ratio 50.1%.

Method 2:

Compound 7 (625 milligrams, 3.6mmol) is dissolved in 10 milliliters of glacial acetic acid, addition potassium iodide (900 milligrams, 5.4mmol), it is then added dropwise to 30%H again₂O₂Solution 2mL, reaction solution gradually become purple solution, and it is small to be stirred to react 3 at room temperature When, saturated sodium thiosulfate solution 5mL is added, continues stirring after ten minutes, ethyl acetate is added, isolates organic phase, water layer It being extracted with ethyl acetate again, merges organic phase, saturated common salt water washing is concentrated, column chromatography (petroleum ether: ethyl acetate=30: 1) 700 milligrams of white solid are afforded, yield 78%.

¹H NMR(300MHz,CDCl₃)δ6.91(s,1H),5.74(s,2H),3.84(s,3H)；LC-MS (ESI):m/z 269.2 (100%) [M-CH₃O]⁺。

The preparation method of 1- (4- diethoxymethyl phenyl) propilolic alcohol (compound 9)

In the round-bottomed flask of 250mL equipped with stirrer, addition 4- diethoxymethyl benzaldehyde 8 (780 milligrams, 3.8mmol is purchased from TCI chemistry) and anhydrous tetrahydro furan 50mL, acetenyl magnesium bromide is then added by constant pressure funnel THF solution (0.5M, 10mL are purchased from lark waffle), add within about 15 minutes, continue stirring at room temperature 0.5~1 hour, After TLC detects fully reacting, 20 milliliters of saturated ammonium chloride solution are added, stirring after ten minutes, isolates organic phase, water layer is again It is extracted with ethyl acetate, merging organic phase, after saturated common salt water washing, concentration, column chromatographs (petroleum ether: ethyl acetate=5:1) 390 milligrams of grease are afforded, yield 44%.

¹H NMR(300MHz,CDCl₃) δ 7.52 (q, J=8.2Hz, 4H), 5.50 (s, 1H), 5.47 (dd, J=6.2, 2.1Hz,1H),3.67-3.47(m,4H),2.68-2.65(m,1H),2.35-2.29(m,1H),1.28 -1.19(m,6H)。 LC-MS(ESI):m/z 257.2[M+H]⁺。

The system of 2- (4- diethoxymethyl phenyl) the chloro- pyrroles of -5- [1,2-b] pyridazine -7- methyl formate (compound 10) Preparation Method

In a 25mL microwave tube equipped with stirrer, it is added compound 6 (150 milligrams, 0.5mmol), compound 9 (234 milligrams, 1mmol), palladium acetate (2.24 milligrams, 0.01mmol), cuprous iodide (1 milligram, 0.005mmol) and toluene 5 Milliliter replaces N₂After 3 times, DBU (380 milligrams, 2.5mmol) are rapidly added, microwave cap is next, is placed in microwave reaction instrument In, it is reacted 40 minutes under 90 DEG C (λ=180W), after cooling, chloroform 25mL dilution is added, is transferred to 100mL round-bottomed flask In, concentration, column chromatography (petroleum ether: ethyl acetate=30:1) affords 62 milligrams of yellow oil, yield 32%.

¹H NMR(300MHz,CDCl₃) δ 8.06 (d, J=8.3Hz, 2H), 7.94 (d, J=9.4Hz, 1H), 7.62 (d, J =8.4Hz, 2H), 7.47 (s, 1H), 7.35 (d, J=9.5Hz, 1H), 5.58 (s, 1H), 3.96 (s, 3H), 3.60 (dd, J= 13.7,7.0Hz, 4H), 1.26 (t, J=7.1Hz, 6H)；LC-MS(ESI):m/z 389.2[M+H]⁺。

The preparation method of 2- (4- Fonnylphenyl) -5- chloro- pyrroles [1,2-b] pyridazine -7- methyl formate (compound 11)

In the 50mL round-bottomed flask equipped with stirrer, compound 10 (62 milligrams, 0.16mmol) and anhydrous methanol is added 10mL adds 3N HCl solution 5mL, is stirred at room temperature 30 minutes, after complete reaction, adjusts PH with NaOH solution (2.5M) It is worth 7~8.Organic phase is then demultiplex out, aqueous layer with ethyl acetate extraction merges organic phase, and saturated common salt water washing is anhydrous Sodium sulphate is dry, is concentrated to get 40 milligrams of yellow solid, yield 80%.

LC-MS(ESI):m/z 315[M+H]⁺。

The system of 2- (4- dimethylamino methyl phenyl) -5- chloro- pyrroles [1,2-b] pyridazine -7- formamide (compound I-1) Preparation Method

In the 50mL round-bottomed flask equipped with stirrer, it is added compound 11 (50 milligrams, 0.16mmol), dimethylamine salt Hydrochlorate (20 milligrams, 0.24mmol), a few drop acetic acid and methanol 5mL, are stirred at room temperature after five minutes, add sodium cyanoborohydride (50 milligrams, 0.8mmol) continue stirring 1 hour, and after complete reaction, evaporating solvent under reduced pressure adds chloroform 10mL, Water 4mL, extraction and separation go out organic phase, and water layer is used chloroform extraction 2 times again, merge organic phase, concentration, and column chromatographs (dichloromethane Alkane: methanol=20:1) afford 40 milligrams of crude product, LC-MS (ESI): m/z 344.2 [M+H]⁺；It is slightly produced above-mentioned Product are added in 25mL tube sealing, and the methanol solution of ammonia is added, is subsequently placed in tube sealing reaction 18~24 hours at 80~90 DEG C, will be anti- Liquid is answered to be cooled to room temperature, evaporating solvent under reduced pressure, column chromatography (methylene chloride: methanol=10:1) affords 25 milli of yellow solid Gram, two step total recoverys 47%.

¹H NMR(300MHz,CD₃OD) δ 8.08 (d, J=9.5Hz, 1H), 8.01 (d, J=8.3Hz, 2H), 7.61 (d, J =8.3Hz, 2H), 7.50-7.43 (m, 2H), 4.03 (s, 2H), 2.63 (s, 6H)；LC-MS (ESI):m/z 329.2[M+H ]⁺。

The preparation of the chloro- 2- of 5- (4- Methylaminomethyl phenyl) pyrroles's [1,2-b] pyridazine -7- formamide (compound I-2) Method

Compound 11 (50 milligrams, 0.16mmol) and methylamine alcohol solution (2mL) are raw material, the preparation of reference compound I-1 Process obtains 20 milligrams of yellow solid, two step total recoverys 40%:.

¹H NMR(300MHz,CD₃OD) δ 8.00 (ddd, J=8.4,7.2,1.6Hz, 3H), 7.69-7.59 (m, 2H), 7.42 (dt, J=10.7,1.5Hz, 2H), 4.28 (d, J=1.6Hz, 2H), 2.77 (s, 3H), 1.96- 1.89 (m, 1H)；LC- MS(ESI):m/z 315.2[M+H]⁺。

2- (4- diethylamino methyl phenyl) -5- chloro- pyrroles [1,2-b] pyridazine -7- formamide (compound I-3) Preparation method

Compound 11 (50 milligrams, 0.16mmol) and diethylamine alcoholic solution (1mL) are raw material, the system of reference compound I-1 Standby process, obtains 24 milligrams of yellow solid, two step total recoverys 42%.

¹H NMR(300MHz,CD₃OD) δ 8.20 (dd, J=9.5,1.3Hz, 1H), 8.17-8.11 (m, 2H), 7.75- 7.70 (m, 2H), 7.58-7.52 (m, 2H), 4.42 (s, 2H), 3.22 (q, J=7.3Hz, 4H), 1.37 (t, J=7.3Hz, 6H)；LC-MS(ESI):m/z 357.2[M+H]⁺。

2- [4- (pyrrolin -1- base) aminomethyl phenyl] the chloro- pyrroles of -5- [1,2-b] pyridazine -7- formamide (compound I-4) Preparation method

Compound 11 (50 milligrams, 0.16mmol) and tetrahydro pyrrolidine (1mL) are raw material, the preparation of reference compound I-1 Method obtains 15 milligrams of yellow solid, two step total recoverys 26%.

¹H NMR(300MHz,CD₃OD) δ 8.18 (dd, J=9.4,1.4Hz, 1H), 8.12 (dd, J=8.3,1.5Hz, 2H), 7.73 (d, J=8.1Hz, 2H), 7.58-7.49 (m, 2H), 4.46 (s, 2H), 3.35 (d, J=6.0Hz, 4H), 2.15- 2.06(m,4H)；LC-MS(ESI):m/z 355.2[M+Na]⁺。

2- [4- (piperazine -1- base)-aminomethyl phenyl] -5- chloro- pyrroles [1,2-b] pyridazine -7- formamide (compound I-5) Preparation method

In the methanol 5mL of compound 11 (50 milligrams, 0.16mmol) and N-boc piperazine (45 milligrams, 0.24mmol), add Enter the drop of glacial acetic acid 2, is stirred at room temperature after five minutes, is added sodium cyanoborohydride (50 milligrams), after stirring 3 hours at room temperature, directly It is concentrated to get grease, is charged with water 3mL and chloroform 5mL, isolates organic phase, water layer chloroform extraction, Merge organic phase, saturated common salt water washing, anhydrous sodium sulfate is dry, is concentrated to get grease and direct plunges into next step, past above-mentioned 10 milliliters of chloroform are added in grease, trifluoroacetic acid 1.5mL is slowly added dropwise, stirs 1 hour at room temperature, uses 3N under ice bath It is 8~9 that HCl solution, which adjusts pH value, isolates organic phase, and water layer chloroform extraction merges organic phase, saturated salt solution Washing, after not purified direct concentration, is transferred in 25mL tube sealing with methanol 5mL, is added the methanol solution 8mL of saturated ammonia, and 80 Tube sealing reaction 18~24 hours, reaction solution is cooled to room temperature at~90 DEG C, and vacuum decompression removes solvent, and column chromatographs (dichloromethane Alkane: methanol=10:1) 10 milligrams of yellow solid are afforded, three step total recoverys 17%.

¹H NMR(300MHz,CD₃OD) δ 8.12-8.06 (m, 1H), 7.92 (dd, J=8.1,2.0Hz, 2H), 7.52 (dd, J=8.3,2.0Hz, 2H), 7.46 (ddd, J=5.9,3.8,2.3Hz, 2H), 3.67 (d, J=2.0Hz, 2H), 3.34 (d, J=1.6Hz, 1H), 3.19 (t, J=5.5Hz, 4H), 2.69 (t, J=4.8Hz, 4H)；LC-MS(ESI):m/z 370.2 [M+H]⁺。

2- [4- (3- thyl-piperazin -1- base) aminomethyl phenyl] the chloro- pyrroles of -5- [1,2-b] pyridazine -7- formamide (compound I-6 preparation method)

Compound 11 (50 milligrams, 0.16mmol) and (24 milligrams, 0.24mmol) of 2- methyl piperazine are raw material, referenceization The preparation method for closing object I-1, obtains 15 milligrams of yellow solid, yield 25%.

¹H NMR(300MHz,CD₃OD) δ 8.11 (dd, J=9.5,3.4Hz, 1H), 7.94 (dq, J=8.6,2.3, 1.8Hz, 2H), 7.54 (dd, J=8.2,3.3Hz, 2H), 7.51-7.45 (m, 2H), 3.68 (s, 2H), 3.20-3.09 (m, 1H), 3.05-2.93 (m, 2H), 2.44-2.32 (m, 1H), 2.26-2.10 (m, 2H), 2.02 (s, 1H), 1.93 (dd, J= 3.8,2.8Hz, 1H), 1.29 (d, J=3.1Hz, 3H)；LC-MS(ESI): m/z 384.2[M+H]⁺。

2- [4- (4- cyclopropylpiperazin -1- base)-aminomethyl phenyl] the chloro- pyrroles of -5- [1,2-b] pyridazine -7- formamide (chemical combination Object I-7) preparation method

Compound 11 (50 milligrams, 0.16mmol) and (30 milligrams, 0.24mmol) of N- cyclopropylpiperazin are raw material, reference The preparation method of compound I-1 obtains 24 milligrams of yellow solid, two step total recoverys 37%.

¹H NMR(300MHz,CD₃OD) δ 8.10 (dd, J=9.4,1.7Hz, 1H), 7.95-7.88 (m, 2H), 7.52 (dd, J=6.8,1.6Hz, 3H), 7.44 (dd, J=9.5,1.6Hz, 1H), 3.64 (s, 2H), 2.80- 2.65 (m, 4H), 2.64-2.45(m,4H),0.91-0.80(m,1H),0.52-0.47(m,2H),0.45- 0.37(m,2H)；LC-MS(ESI): m/z 410.2[M+H]⁺。

2- [4- (4- isopropyl-piperazine -1- base)-aminomethyl phenyl] the chloro- pyrroles of -5- [1,2-b] pyridazine -7- formamide (is changed Close object I-8) preparation method

Compound 11 (50 milligrams, 0.16mmol) and (31 milligrams, 0.24mmol) of N- isopropyl piperazine are raw material, reference The preparation method of compound I-1 obtains 25 milligrams of yellow solid, two step total recoverys 38%.

¹H NMR(300MHz,CD₃OD) δ 8.13 (d, J=9.5Hz, 1H), 7.97 (d, J=8.3Hz, 2H), 7.55 (d, J =8.3Hz, 2H), 7.50 (dd, J=5.2,4.3Hz, 2H), 3.71 (s, 2H), 3.36-3.32 (m, 1H), 3.22-3.10 (m, 4H), 2.85-2.65 (m, 4H), 1.31 (d, J=6.6Hz, 6H)；LC-MS (ESI):m/z 412.2[M+H]⁺。

2- [4- (4- dimethylamino piperidine -1- base)-aminomethyl phenyl] the chloro- pyrroles of -5- [1,2-b] pyridazine -7- formamide (is changed Close object I-9) preparation method

Compound 11 (50 milligrams, 0.16mmol) and (31 milligrams, 0.24mmol) of 4- dimethylamino piperidine are raw material, ginseng According to the preparation method of compound I-1,26 milligrams of yellow solid are obtained, two step total recoverys 39%.

¹H NMR(300MHz,CD₃OD) δ 8.12 (dd, J=9.4,0.6Hz, 1H), 7.95 (dd, J=8.4,2.2Hz, 2H),7.56-7.46(m,4H),3.64(s,2H),3.11-3.02(m,2H),3.01-2.92(m, 1H),2.74(s,6H), 2.23-2.12(m,2H),2.08-1.98(m,2H),1.80-1.64(m,2H)； LC-MS(ESI):m/z 412.2[M+H]⁺。

2- { 4- [4- (pyrrolidin-1-yl)-piperidin-1-yl]-aminomethyl phenyl } the chloro- pyrroles of -5- [1,2-b] pyridazine -7- first The preparation method of amide (compound I-10)

Compound 11 (50 milligrams, 0.16mmol) and (37 milligrams, 0.24mmol) of 4- pyrrolidin-1-yl-piperidines are original Material, the preparation method of reference compound I-1 obtain 15 milligrams of yellow solid, yield 21%.

¹H NMR(300MHz,CD₃OD) δ 8.13 (d, J=9.5Hz, 1H), 7.99-7.93 (m, 2H), 7.58-7.52 (m, 2H), 7.51 (dd, J=5.5,4.0Hz, 2H), 3.67 (s, 2H), 3.42-3.35 (m, 3H), 3.22-3.13 (m, 1H), 3.11-3.02(m,2H),2.25-2.11(m,4H),2.10-2.02(m,4H), 1.85-1.70(m,3H)；LC-MS(ESI): m/z 438.2[M+H]⁺。

2- [4- (4- morpholinyl piperidin-1-yl)-aminomethyl phenyl] the chloro- pyrroles of -5- [1,2-b] pyridazine -7- formamide (chemical combination Object I-11) preparation method

Compound 11 (50 milligrams, 0.16mmol) and (41 milligrams, 0.24mmol) of morpholine of 4- (4- piperidyl) are raw material, The preparation method of reference compound I-1 obtains 10 milligrams of yellow solid, two step total recoverys 14%.

¹H NMR(300MHz,CD₃OD) δ 8.16 (dd, J=9.5,2.0Hz, 1H), 8.05-7.97 (m, 2H), 7.64- 7.56(m,2H),7.55-7.48(m,2H),3.83(s,2H),3.76-3.68(m,4H),3.21- 3.10(m,2H),2.74- 2.64(m,4H),2.52-2.30(m,3H),2.06-1.97(m,2H),1.73- 1.62(m,2H)；LC-MS(ESI):m/z 454.2[M+H]⁺。

2- [4- (4- p-trifluoromethyl phenyl-piperazine -1- base)-aminomethyl phenyl] the chloro- pyrroles of -5- [1,2-b] pyridazine -7- first The preparation method of amide (compound I-12)

Compound 11 (50 milligrams, 0.16mmol) and (55 milligrams, 0.24mmol) of p-trifluoromethyl phenyl piperazine are original Material, the preparation method of reference compound I-1 obtain 20 milligrams of yellow solid, two step total recoverys 24%.

¹H NMR(300MHz,CD₃OD) δ 8.17 (d, J=9.4Hz, 1H), 8.00 (d, J=7.8Hz, 2H), 7.60 (d, J =7.9Hz, 2H), 7.54 (dd, J=6.5,2.8Hz, 2H), 7.47 (d, J=8.3Hz, 2H), 7.04 (d, J=8.7Hz, 2H),3.73(s,2H),3.37-3.32(m,4H),2.79-2.62(m,4H)； LC-MS(ESI):m/z 514.2[M+H]⁺。

4- (4- Fonnylphenyl)-piperazine -1- t-butyl formate (compound 13) preparation method

Take one be equipped with stirrer 50mL round-bottomed flask, sequentially add 4- formylbenzoate 12 (3.1 grams, 20.7mmol), the tertiary fourth oxygen formyl piperazine of N- (3.6 grams, 19.4mmol), EDCI (3.86 grams, 20.2mmol), HOBt (2.68 Gram, 19.8mmol) methylene chloride 25mL, finally add DMAP (20 milligrams), be stirred at room temperature 20~24 hours, wait react It after completely, is added 5 milliliters of NaOH solution (2.5M), stirring after five minutes, isolates organic phase, water layer is extracted with chloroform again It takes, merges organic phase, concentration, column chromatography (petroleum ether: ethyl acetate=2:1) affords 4.5 grams of white solid, yield 73%.

¹H NMR(300MHz,CDCl₃) δ 10.0 (s, 1H), 7.93 (d, J=8.2Hz, 2H), 7.54 (d, J=8.1Hz, 2H),3.82-3.67(m,2H),3.58-3.30(m,6H),1.46(s,9H)；LC-MS(ESI):m/z 319.2[M+H]⁺。

The preparation of 4- { 4- [1- (1- hydroxyl -2-propynyl)] benzoyl } piperazine -1- t-butyl formate (compound 14) Method

The 50mL round-bottomed flask that stirrer is housed is taken, is added compound 13 (650 milligrams, 2.05 mmol), it is anhydrous 20 milliliters of THF, after being completely dissolved, the THF solution (0.5M, 7mL) of acetenyl magnesium bromide, thin layer chromatography detection reaction is added Completely, saturated ammonium chloride solution 10mL is added to be quenched, continues stirring 10 minutes, ethyl acetate 10mL is added, isolates organic Phase, water layer continue to be extracted with ethyl acetate, and merge organic phase, saturated common salt water washing, concentration, column chromatography (petroleum ether: acetic acid Ethyl ester=1:1) 305 milligrams of yellow oil are afforded, yield 50%.

¹H NMR(300MHz,CDCl₃) δ 7.58 (dd, J=10.5,8.0Hz, 2H), 7.39 (ddd, J=10.2,8.2, 1.8Hz, 2H), 5.52-5.44 (m, 1H), 3.55 (d, J=96.8Hz, 8H), 2.67 (ddd, J=8.4,2.2,0.9Hz, 1H), 2.16 (q, J=1.6Hz, 1H), 1.46 (s, 9H)；LC-MS(ESI):m/z 367.2 [M+Na]⁺。

2- [4- (N- tert-butoxy formoxyl) piperazinyl formoxyl] the chloro- pyrroles of phenyl -5- [1,2-b] pyridazine -7- formic acid The preparation method of methyl esters (compound 15)

The 25mL microwave reaction pipe that stirrer is housed is taken, compound 6 (160 milligrams, 0.52 mmol) are sequentially added, Compound 14 (305 milligrams, 0.9mmol), Pd (OAc)₂(7 milligrams, 0.01mmol), CuI (1 milligram, 0.005mmol) and first Benzene 8mL replaces N₂After 3 times, in N₂Protection is lower to be added DBU (380 milligrams, 2.5mmol), after covering microwave tube cap, is placed in micro- Wave reacts in instrument, reacts 40 minutes under 90 DEG C (λ=180W), and after cooling, chloroform 25mL dilution is added, is transferred to 100 millis It rises in round-bottomed flask, concentration, column chromatography (petroleum ether: ethyl acetate=2:1) affords 121 milligrams of yellow oil, receives Rate 47%.

¹H NMR(300MHz,CDCl₃) δ 8.17-8.10 (m, 2H), 7.99 (dd, J=9.5,2.5Hz, 1H), 7.59- 7.52 (m, 2H), 7.50 (d, J=3.0Hz, 1H), 7.35 (dd, J=9.4,3.0Hz, 1H), 3.96 (s, 3H), 3.82-3.70 (m,2H),3.58-3.36(m,6H),1.49(s,9H)；LC-MS (ESI): m/z 521.2 [M+Na]⁺。

The hydrochloride of the chloro- 2- of 5- [4- (piperazinyl -1- formoxyl) phenyl]-pyrroles [1,2-b] pyridazine -7- methyl formate The preparation method of (compound 16)

It takes compound 15 (120 milligrams, 0.24mmol) to be put in the round-bottomed flask of 100mL, anhydrous methylene chloride is added 5mL adds the methyl acetate solution 5mL of HCl, stirs 2 hours at 40 DEG C, white solid is precipitated, after being cooled to room temperature, Filtering, obtains the hydrochloride of the chloro- 2- of 5- [4- (N- piperazinyl formoxyl) phenyl]-pyrroles [1,2-b] pyridazine -7- methyl formate 100 milligrams.

¹H NMR(300MHz,DMSO-d₆)δ9.19-9.07(m,2H),8.29-8.20(m,3H),7.68 -7.62(m, 2H),3.86(s,3H),3.55-3.48(m,4H),3.22-3.10(m,4H)；LC-MS(ESI): m/z 399.2[M+H]⁺。

The chloro- 2- of 5- [4- (piperazinyl -1- formoxyl) phenyl]-pyrroles [1,2-b] pyridazine -7- formamide (compound I-13) Preparation method

It takes the methanol 10mL solution transfer of compound 16 (50 milligrams) into the tube sealing of 25mL, NH is added₃Methanol solution 8mL reacts 20~24 hours at 80~90 DEG C, is cooled to room temperature, is transferred in 100 milliliters of round-bottomed flasks, is concentrated, column chromatography (methylene chloride: methanol=10:1) affords 35 milligrams of yellow solid.

¹H NMR(300MHz,DMSO-d₆) δ 8.26 (dt, J=9.4,1.1Hz, 1H), 8.21 (s, 1H), 8.14-8.05 (m, 2H), 7.98 (s, 1H), 7.65-7.59 (m, 1H), 7.59-7.53 (m, 2H), 7.51 (p, J=1.2Hz, 1H), 3.62- 3.50(m,2H),3.29-3.22(m,2H),2.80-2.60(m,4H)；LC-MS (ESI):m/z 384.2[M+H]⁺。

2- { 4- [4- (cyclopropyl formoxyl)-piperazine -1- base] Fonnylphenyl } -5- chloro- pyrroles [1,2-b] pyridazine -7- The preparation method of formamide (compound I-14)

It takes compound 16 (50 milligrams, 0.13mmol), anhydrous methylene chloride 15mL is added, is added dropwise to 0.5mL respectively NEt₃, Cyclopropyl carbonyl chloride (30 μ l) stirs 15 minutes at room temperature, after thin-layer chromatography detects fully reacting, 2mL methanol is added, It is stirred at room temperature 10 minutes, is concentrated, obtains yellow solid, be the chloro- 2- of crude product 5- { 4- [(4- cyclopropyl formoxyl)-piperazinyl -1- Formoxyl] phenyl }-pyrroles [1,2-b] pyridazine -7- methyl formate, it is transferred in 25mL tube sealing with methanol 10mL, is added 8mL's Methanolic ammonia solution is reacted 20~24 hours at 80~90 DEG C, is cooled to room temperature, and is concentrated, column chromatography (methylene chloride: methanol= 45 milligrams of yellow solid 20:1) are afforded, two step total recoverys 79%.

¹H NMR(300MHz,DMSO-d₆) δ 8.27 (dt, J=9.4,1.4Hz, 1H), 8.21 (s, 1H), 8.11 (dt, J =8.3,1.7Hz, 2H), 7.99 (d, J=3.2Hz, 1H), 7.71-7.57 (m, 3H), 7.52 (d, J=1.0Hz, 1H), 3.85-3.45(m,8H),1.41-1.28(m,1H),0.82-0.65(m,4H)；LC-MS (ESI):m/z 452.2[M+H]⁺。

2- [4- (3- methyl-1-oxo butyl)-piperazine-1- base-formoxyl]-chloro- pyrroles of phenyl-5- [1,2-b] pyridazine- The preparation method of 7- formamide (compound I-15)

It takes compound 16 (50 milligrams, 0.16mmol), anhydrous methylene chloride 5mL is added, is added dropwise to 0.5mL respectively NEt₃, isoveryl chloride (30 milligrams, 0.24mmol) stirs 30 minutes at room temperature, after thin-layer chromatography detects fully reacting, is added 3mL methanol stirs 5 minutes at room temperature, and concentration obtains 65 milligrams of crude product, is 2- [(N- isovaleryl) piperazine -1- base formyl Base]-chloro- the pyrroles of phenyl -5- [1,2-b] pyridazine -7- methyl formate；It is transferred into 25mL tube sealing, is added with methanol 10mL 8mL NH₃Methanol solution, react 20~24 hours at 80~90 DEG C, be cooled to room temperature, be concentrated, column chromatography (methylene chloride: Methanol=20:1) 40 milligrams of yellow solid are afforded, two step total recoverys 53%.

¹H NMR(300MHz,CDCl₃) δ 8.69 (s, 1H), 8.05 (dd, J=9.4,2.1Hz, 1H), 7.99- 7.89 (m, 2H), 7.65 (d, J=2.1Hz, 1H), 7.64-7.54 (m, 2H), 3.85-3.40 (m, 8H), 2.30- 2.22 (m, 2H), 2.20-2.08(m,1H),1.04-0.94(m,6H)；LC-MS(ESI):m/z 468.2 [M+H]⁺。

The preparation method of 4- (the fluoro- 4- Fonnylphenyl of 3-)-Formyl-piperazine -1- t-butyl formate (compound 17)

The fluoro- 4- formylbenzoate of 3- (1 gram, 6mmol, its preparation method reference literature EP2526945A1, original used The material fluoro- 4- methyl benzoic acid of 3- is purchased from the sub- medicine of Shanghai book), N- tert-butoxy formyl piperazine (1.1 grams, 5.66mmol), HOBt (764 milligrams, 5.66mmol), EDCI (1.3 grams, 6.8mmol) and (20 milligrams) of DMAP are raw material, according to compound 13 Preparation method, obtain 1.7 grams of white solid, yield 89%.

¹H NMR(300MHz,CDCl₃) δ 10.38 (d, J=0.7Hz, 1H), 7.93 (d, J=8.3Hz, 1H), 7.33- 7.17(m,2H),3.85-3.23(m,8H),1.43(s,9H)；LC-MS(ESI):m/z 359.2 [M+Na]⁺。

The system of 4- [the fluoro- 4- of 3- (1- hydroxypropyn -2- base) benzoyl]-piperazine -1- t-butyl formate (compound 18) Preparation Method

The THF solution (0.5M, 6.5 mL) of compound 17 (600 milligrams, 1.8mmol) and acetenyl magnesium bromide is raw material, The preparation method of reference compound 14 obtains 420 milligrams of white solid, yield 65%.

¹H NMR(300MHz,CDCl₃) δ 7.72 (t, J=7.6Hz, 1H), 7.23-7.10 (m, 2H), 5.75 (dd, J= 5.8,2.2Hz,1H),3.82-3.28(m,8H),2.68-2.66(m,1H)；LC-MS(ESI):m/z 385.2[M+Na]⁺。

2- [fluoro- (the tertiary fourth oxygen formyl piperazine -1- base formoxyl of the 4-) phenyl of 2-] -5- chloro- pyrroles [1,2-b] pyridazine -7- The preparation method of methyl formate (compound 19)

Compound 6 (218 milligrams, 0.7mmol) and (420 milligrams, 1.2mmol) of compound 18 are raw material, reference compound 15 preparation method obtains 160 milligrams of yellow solid, yield 44%.

¹H NMR(300MHz,CDCl₃) δ 8.14 (t, J=7.8Hz, 1H), 7.96 (d, J=9.5Hz, 1H), 7.51 (s, 1H),7.41-7.19(m,4H),3.94(s,3H),3.80-3.65(m,2H),3.55-3.35(m, 6H),1.47(s,9H)； LC-MS(ESI):m/z 539.2[M+Na]⁺。

2- [the fluoro- 4- of 2- (piperazine -1- base-formoxyl) phenyl] the chloro- pyrroles of -5- [1,2-b] pyridazine -7- methyl formate (is changed Close object 20) preparation method

It takes compound 19 (150 milligrams, 0.3mmol) to be dissolved in methylene chloride, is added dropwise to trifluoroacetic acid (1.5 mL), TLC It is 7~8 that NaOH solution (2.5M) is added after detecting fully reacting, under ice bath and adjusts pH value, isolates organic phase, and water layer is with three Chloromethanes extraction, merges organic phase, concentration, and column chromatographs (methylene chloride: a few drop NH of methanol=10:1+₃Methanol solution) elution 100 milligrams of yellow solid are obtained, yield 80%.

LC-MS(ESI):m/z 417.2[M+H]⁺。

2- [the fluoro- 4- of 2- (4- cyclopropyl formyl piperazine -1- base-formoxyl) phenyl] the chloro- pyrroles of -5- [1,2-b] pyridazine - The preparation method of 7- formamide (compound I-16)

0.5mL NEt is added in the anhydrous methylene chloride 10mL solution of compound 20 (60 milligrams, 0.15mmol)₃And cyclopropyl Base formyl chloride (26 milligrams, 0.25mmol) stirs 30 minutes at room temperature, and after TLC detects fully reacting, 4mL methanol is added, dense Contracting, obtains 65 milligrams of crude product, the chloro- 2- of 5- [the fluoro- 4- of 3- (4- cyclopropyl formyl piperazine -1- formoxyl) phenyl] pyrroles [1,2- B] pyridazine -7- methyl formate；It is transferred into 25mL tube sealing with methanol 10mL, is added the methanol solution 8mL of ammonia, 80~90 It reacts 20~24 hours, is cooled to room temperature at DEG C, be concentrated, it is solid that column chromatography (methylene chloride: methanol=20:1) washes to obtain yellow 30 milligrams of body, two step total recoverys 43%.

¹H NMR(300MHz,DMSO-d₆)δ8.83-8.48(s,1H),8.33-8.24(m,1H),8.18 (s,1H), 8.04-7.92(m,2H),7.58-7.52(m,1H),7.51-7.39(m,2H),3.87-3.36(m, 8H),0.85-0.66(m, 5H)；LC-MS(ESI):m/z 470.2[M+H]⁺。

2- [the fluoro- 4- of 2- [4- [(2S) -2- methylamino -1- oxygen-propyl]-piperazine -1- base formoxyl] phenyl] -5- is chloro- The preparation method of pyrroles's [1,2-b] pyridazine -7- formamide (compound I-17)

Compound 20 (100 milligrams, 0.24mmol), Boc-N- methyl-L-alanine (54 milligrams, 0.27 mmol), EDCI Methylene chloride (15mL) solution of (55 milligrams, 0.29mmol), HOBt (32 milligrams, 0.24mmol) and DMAP (5 milligrams), room It temperature lower stirring 14 hours, is added 3 milliliters of solution of NaOH (2.5M), stirs 5 minutes at room temperature, isolate organic phase, water layer chlorine Imitative extraction merges organic phase, concentration, and column chromatography (methylene chloride: methanol=50:1) obtains 58 milligrams of yellow solid, LC-MS (ESI): m/z 624.2[M+Na]⁺；Into the methylene chloride 20mL of above-mentioned solid, CF is added₃COOH 1.5mL, is stirred at room temperature It mixes 2 hours, and adjusts pH value to 8~9 with NaOH (2.5M) solution, isolate organic phase, water layer is extracted with chloroform, is associated with Machine phase, concentration, column chromatography (methylene chloride: methanol=10:1) afford 40 milligrams of yellow solid, and LC-MS (ESI): m/z 502.2[M+Na]⁺；It is transferred in 25mL tube sealing with methanol 10mL, the methanol solution 8mL of ammonia is added, reacts 20 at 80~90 DEG C It~24 hours, being cooled to room temperature, is concentrated, column chromatography (methylene chloride: methanol=20:1) washes to obtain 30 milligrams of yellow solid, Three step total recoverys 26%.

¹H NMR(300MHz,DMSO-d₆) δ 8.29 (d, J=9.5Hz, 1H), 8.17 (s, 1H), 8.04- 7.95 (m, 2H), 7.59-7.49 (m, 2H), 7.45 (ddd, J=11.4,8.8,1.7Hz, 2H), 4.22-4.02 (m, 1H), 3.78-3.39 (m,8H),2.36(s,3H),1.24-1.16(m,3H)；LC-MS(ESI):m/z 487.2[M+Na]⁺。

2- [4- (4- isopropelsulfonyl piperazine -1- base-formoxyl) phenyl] the chloro- pyrroles of -5- [1,2-b] pyridazine -7- first The preparation method of amide (compound I-18)

Pyridine 1mL and isopropyl sulphonyl chloride are added in the chloroform 5mL of compound I-13 (10 milligrams, 0.024mmol) 250ul is stirred 4 hours at room temperature, and 3N HCl solution 3mL is added, and isolates organic phase, and water layer chloroform extraction merges Organic phase, concentration, column chromatography (methylene chloride: methanol=20:1) afford 8 milligrams of yellow solid, yield 67%.

¹H NMR(400MHz,CD₃OD) δ 8.14 (d, J=9.4Hz, 1H), 8.07 (d, J=8.2Hz, 2H), 7.63 (d, J =8.2Hz, 2H), 7.54 (s, 1H), 7.48 (d, J=9.5Hz, 1H), 3.63-3.54 (m, 2H), 3.52-3.46 (m, 1H), 3.43-3.37 (m, 6H), 1.34 (d, J=6.9Hz, 6H)；LC-MS(ESI): m/z 490.2[M+H]⁺。

N- (the fluoro- 5- formyl-benzoyl of 2-)-piperazine -1- base-t-butyl formate (compound 21) preparation method

The fluoro- 5- formylbenzoate of 2- (850 milligrams, 5mmol its preparation method reference literature), N-Boc piperazine (1.1 Gram, 6.1mmol), EDCI (1.2 grams, 6.1mmol), HOBt (688 milligrams, 5.1mmol) and (80 milligrams) of DMAP are raw material, ginseng According to the preparation method of compound 13,1.4 grams of white solid are obtained, yield 83%.

¹H NMR(300MHz,CDCl₃) δ 9.97 (s, 1H), 8.00-7.93 (m, 2H), 7.28 (d, J=8.6 Hz, 1H), 3.81-3.74 (t, J=5.3Hz, 2H), 3.53 (t, J=5.3Hz, 2H), 3.42 (t, J=5.1Hz, 2H), 3.32-3.24 (t, J=5.3Hz, 2H), 1.45 (s, 9H)；LC-MS(ESI):m/z 359.2[M+Na]⁺。

N- [the fluoro- 5- of 2- (1- hydroxyl-propine -2- base) benzoyl]-piperazine -1- base-t-butyl formate (compound 22) Preparation method

The THF solution (0.5M, 5mL) of compound 21 (500 milligrams, 1.5mmol) and acetenyl magnesium bromide is raw material, ginseng According to the preparation method of compound 14,520 milligrams of yellow oil are obtained, yield 94%.

¹H NMR(300MHz,CDCl₃) δ 7.64-7.56 (m, 2H), 7.11 (ddd, J=9.0,8.1,1.0 Hz, 1H), 5.45 (dd, J=5.9,2.2Hz, 1H), 3.82-3.74 (m, 2H), 3.52 (t, J=5.3Hz, 2H), 3.41 (t, J= 5.0Hz, 2H), 3.34-3.27 (m, 2H), 2.73 (d, J=6.2Hz, 1H), 2.68 (d, J=2.2 Hz, 1H), 1.46 (s, 9H)；LC-MS(ESI):m/z 385.2[M+Na]⁺。

2- [3- (N- tert-butoxy-Formyl-piperazine -1- base-formoxyl) -4- fluoro-phenyl] the chloro- pyrroles of -5- [1,2-b] The preparation method of pyridazine -7- methyl formate (compound 23)

Compound 6 (270 milligrams, 0.9mmol), (520 milligrams, 1.5mmol) of compound 22 are raw material, reference compound 15 preparation method obtains 160 milligrams of yellow solid, yield 34%.

¹H NMR(300MHz,CDCl₃) δ 8.25-8.20 (m, 1H), 8.05-8.02 (m, 1H), 7.98 (d, J=8.3Hz, 1H),7.48(s,1H),7.29-7.17(m,2H),3.95(s,3H)3.85-3.75(m,2H), 3.58-3.52(m,2H), 3.48-3.42(m,2H),3.38-3.32(m,2H),1.47(s,9H)；LC-MS (ESI):m/z 539.2[M+Na]⁺。

2- [3- (piperazine -1- base)-formoxyl -4- fluoro-phenyl] the chloro- pyrroles of -5- [1,2-b] pyridazine -7- methyl formate (is changed Close object 24) preparation method

In the methylene chloride 10mL solution of compound 23 (108 milligrams, 0.23mmol), trifluoroacetic acid is added at room temperature (1.5mL) continues stirring 1 hour, after thin-layer chromatography detects fully reacting, adjusts pH value with NaOH (2.5M) solution under ice bath At alkaline (8~9), organic phase is isolated, water layer chloroform extraction merges organic phase, concentration, and column chromatographs (dichloromethane Alkane: methanol=10:1) 80 milligrams of yellow solid are afforded, yield 83%.

LC-MS(ESI):m/z 417.2[M+H]⁺。

2- [3- (N- cyclopropane carbonyl-piperazine -1- base)-formoxyl -4- fluoro-phenyl] the chloro- pyrroles of -5- [1,2-b] pyridazine - The preparation method of 7- formamide (compound I-19)

The dichloromethane solution 10mL of compound 24 (50 milligrams, 0.12mmol), is added a few drop triethylamines, cyclopropyl formyl Chlorine (20 milligrams, 0.18mmol) stirs 1 hour at room temperature, and methanol 5mL is added, and continues stirring 10 minutes, and concentration obtains oily Object is 2- [3- (N- cyclopropane carbonyl-piperazine -1- base)-formoxyl -4- fluoro-phenyl] -5- chloro- pyrroles [1,2-b] pyridazine -7- Methyl formate, LC-MS (ESI): m/z 485.2 [M+H]⁺；It is transferred in 25mL tube sealing with methanol 10mL, the methanol of ammonia is added Solution 8mL reacts 20~24 hours at 80~90 DEG C, is cooled to room temperature, is concentrated, column chromatographs (methylene chloride: methanol=20:1) 21 milligrams of yellow solid are afforded, two step total recoverys 38%.

¹H NMR(300MHz,CDCl₃) δ 7.99 (d, J=9.4Hz, 1H), 7.98-7.83 (m, 2H), 7.56 (s, 1H), 7.27 (t, J=8.8Hz, 1H), 7.19 (d, J=9.4Hz, 1H), 3.90-3.65 (m, 6H), 3.44-3.33 (m, 2H), 1.75-1.65(m,1H),0.96-0.92(m,2H),0.82-0.75(m,2H)； LC-MS(ESI):m/z 470.2[M+H]⁺。

2- [3- [N- [(2S)-pyrrolin -2- base]-Formyl-piperazine -1- base]-formoxyl] -4- fluoro-phenyl] -5- is chloro- The preparation method of pyrroles's [1,2-b] pyridazine -7- formamide (compound I-20)

Compound 24 (50 milligrams, 0.12mmol), Boc-L- proline (28 milligrams, 0.13mmol), EDCI (28 milligrams, It is 0.15mmol) raw material, the preparation side of reference compound I-17 with HOBt (17 milligrams, 0.12mmol) and (5 milligrams) of DMAP Method obtains 15 milligrams of yellow solid, three step total recoverys 25%.

¹H NMR(300MHz,CDCl₃) δ 8.29 (d, J=9.5Hz, 1H), 8.25-8.11 (m, 3H), 8.00 (s, 1H), 7.67-7.61 (m, 1H), 7.59 (d, J=9.3Hz, 1H), 7.53 (s, 1H), 4.47-4.30 (m, 1H), 3.62 (dd, J= 53.7,20.3Hz, 8H), 3.16 (d, J=5.0Hz, 2H), 3.01 (s, 1H), 2.28 (s, 1H), 1.76 (s, 4H)；LC-MS (ESI):m/z 499.2[M+H]⁺。

The preparation method of 3- (4- methoxy piperide -1- base-formoxyl) fluoro- benzaldehyde of -4- (compound 25)

The fluoro- 5- formylbenzoate of 2- (370 milligrams, 2.2mmol), 4- methoxy piperide hydrochloride (300 milligrams, 2mmol, its preparation method reference literature US2011092475A1), EDCI (460 milligrams, 2.4mmol), HOBt (300 millis Gram, 2.2mmol) methylene chloride 40mL in, be added DMAP (20 milligrams), at room temperature stir 20~24 hours, thin-layer chromatography inspection After surveying fully reacting, NaOH (2.5M) solution 5mL is added, stirring after ten minutes, isolates organic phase, water layer chloroform Extraction merges organic phase, concentration, and column chromatography (petroleum ether: ethyl acetate=2:1) affords 370 milligrams of white solid, receives Rate 70%.

1H NMR(300MHz,CDCl₃) δ 9.97 (t, J=0.5Hz, 1H), 7.98-7.89 (m, 2H), 7.30-7.22 (m, 1H), 4.05-3.97 (m, 1H), 3.88-3.80 (tt, J=8.7,4.1Hz, 1H), 3.68- 3.63 (m, 1H), 3.53- 3.42(m,2H),3.36(s,3H),3.20-3.10(m,1H),3.07-2.93(m, 1H),1.98-1.92(m,1H),1.87- 1.73(m,1H)；LC-MS(ESI):m/z 266.2[M+H]⁺。

The fluoro- 5- of 2- (1- hydroxyl-propine -2- base)-phenyl-(4- methoxy piperide -1- base)-methyl ketone (compound 26) Preparation method

In the anhydrous THF40mL of compound 25 (370 milligrams, 1.4mmol), the THF solution of acetenyl magnesium bromide is added (0.5M, 4mL) is stirred 1~1.5 hour at room temperature, saturated ammonium chloride solution 20mL is added, isolates organic phase, water layer second Acetoacetic ester extraction merges organic phase, and saturated common salt water washing is concentrated, and column chromatography (petroleum ether: ethyl acetate=1:1) elutes To 370 milligrams of yellow oil, yield 90%.

1H NMR(300MHz,CDCl₃)δ7.61-7.50(m,2H),7.13-7.05(m,1H),5.43(s, 1H), 4.05-3.98(s,1H),3.86-3.79(m,1H),3.65-3.45(m,3H),3.36(s,3H),3.20- 3.12(m,1H), 3.05-2.92 (m, 1H), 2.66 (d, J=2.2Hz, 1H), 1.99-1.76 (m, 2H)； LC-MS(ESI):m/z 314.2[M+ Na]⁺。

2- [3- (4- methoxy piperide -1- base-formoxyl) -4- fluoro-phenyl] the chloro- pyrroles of -5- [1,2-b] pyridazine -7- first The preparation method of amide (compound I-21)

It takes in the 25-mL microwave tube equipped with stirrer, is added compound 6 (210 milligrams, 0.7mmol), compound 26 (370 milligrams, 1.3mmol), palladium acetate (8 milligrams), cuprous iodide (1 milligram) and toluene 10mL replace N₂After 3 times, N₂It protects DBU (532 milligrams) are rapidly added under shield, microwave cap is next, is placed in microwave reaction instrument, reacts 40 under 90 DEG C (λ=180W) Minute, after cooling, 25 milliliters of chloroform dilutions are added, are transferred in 100 milliliters of round-bottomed flasks, are concentrated, column chromatographs (petroleum Ether: ethyl acetate=3:1) 40 milligrams of yellow solid are afforded, it is 2- [3- (4- methoxy piperide -1- base-formoxyl) -4- Fluoro-phenyl] the chloro- pyrroles of -5- [1,2-b] pyridazine -7- methyl formate crude product, yield 13%, LC-MS (ESI): m/z 446.2 [M+ H]⁺；It is transferred into 25mL tube sealing with methanol 10mL, the methanol solution 8mL of ammonia is added, reacts 20~24 at 80~90 DEG C Hour, it is cooled to room temperature, is concentrated, column chromatography (methylene chloride: methanol=20:1) affords 20 milligrams of yellow solid, yield 51%.

¹H NMR(300MHz,DMSO-d₆) δ 8.24 (d, J=9.5Hz, 1H), 8.15 (ddd, J=8.7,5.1,2.5Hz, 2H), 8.07 (dd, J=6.4,2.4Hz, 1H), 7.95 (s, 1H), 7.62 (d, J=9.5Hz, 1H), 7.55-7.46 (m, 2H), 3.99-3.88(m,1H),3.49-3.34(m,3H),3.25(s,3H),3.18-3.00 (m,2H),1.95-1.85(m,1H), 1.82-1.74(s,1H),1.51-1.41(m,1H)；LC-MS(ESI): m/z 431.2[M+H]⁺。

The preparation method of 4- (4- methoxy piperide -1- base)-formylbenzaldehyde (compound 27)

4- formylbenzoate (330 milligrams, 2.2mmol) and 4- methoxy piperide hydrochloride (302 milligrams, 2mmol) are Raw material obtains 320 milligrams of white solid, yield 65% according to the preparation method of compound 25.

¹H NMR(300MHz,CDCl₃) δ 10.02 (d, J=0.6Hz, 1H), 7.94-7.87 (d, J=8.3Hz, 2H), 7.55-7.49 (d, J=8.3Hz, 2H), 4.04-3.94 (m, 1H), 3.64-3.45 (m, 3H), 3.35 (s, 3H), 3.25- 3.09(m,1H),2.64-2.44(m,1H),2.02-1.90(m,1H),1.83-1.65 (m,2H)；LC-MS(ESI):m/z 248.2[M+H]⁺。

The system of 4- (1- hydroxyl-propine -2- base)-phenyl-(4- Methoxy-piperidin -1- base)-methyl ketone (compound 28) Preparation Method

The THF solution (0.5M, 4mL) of compound 27 (320 milligrams, 1.3mmol) and acetenyl magnesium bromide is raw material, is pressed According to the preparation method method of compound 26,210 milligrams of grease are obtained, yield 59%.

¹H NMR(300MHz,CDCl₃) δ 7.61-7.55 (m, 2H), 7.43-7.38 (m, 2H), 5.49 (dd, J=6.1, 2.3Hz,1H),4.06-4.02(m,1H),3.65-3.45(m,4H),3.36(s,3H),3.25- 3.18(m,1H),2.68(d, J=2.2Hz, 1H), 2.47 (d, J=6.1Hz, 1H), 1.81-1.61 (m, 3H)； LC-MS(ESI):m/z 274.2[M+H]⁺。

2- [4- (4- methoxy piperide -1- base-formoxyl)-phenyl] the chloro- pyrroles of -5- [1,2-b] pyridazine -7- formamide The preparation method of (compound I-22)

Compound 28 (210 milligrams, 0.8mmol), compound 6 (150 milligrams, 0.5mmol), palladium acetate (8 milligrams), CuI (380 milligrams) of (1 milligram) and DBU obtain 40 milligrams of yellow solid, two steps according to the preparation method of compound I-21 for raw material Total recovery 10%.

¹H NMR(300MHz,DMSO-d₆) δ 8.25 (d, J=9.5Hz, 1H), 8.21 (drs, 1H), 8.08 (d, J= 8.0Hz, 2H), 7.96 (drs, 1H), 7.65-7.57 (m, 2H), 7.53 (d, J=15.8Hz, 2H), 3.99-3.84 (m, 1H), 3.50-3.38(m,2H),3.35-3.29(m,2H),3.25(s,3H),1.87(m, 2H),1.47(m,2H)；LC-MS(ESI): m/z 428.2[M+H]⁺。

The preparation method of the fluoro- 4- of 2- (4- methoxy piperide -1- base)-formylbenzaldehyde (compound 29)

The fluoro- 4- formyl-benzoic acid of 2- (370 milligrams, 2.2mmol), 4- methoxy piperide hydrochloride (300 milligrams, 2mmol) 360 milligrams of white solid are obtained, yield 50% according to the preparation method of compound 25 for raw material.

¹H NMR(300MHz,CDCl₃) δ 10.37 (d, J=0.7Hz, 1H), 7.92 (dd, J=7.9,6.9 Hz, 1H), 7.29(m,2H),4.00-3.89(m,1H),3.65-3.45(m,3H),3.37(s,3H),3.25- 3.18(m,2H),1.98- 1.88(m,1H),1.82-1.68(m,2H)；LC-MS(ESI):m/z 266.2 [M+H]⁺。

The fluoro- 4- of 3- (1- hydroxyl-propine -2- base)-phenyl-(4- methoxy piperide -1- base)-methyl ketone (compound 30) Preparation method

The THF solution (0.5M, 2.5 mL) of compound 29 (360 milligrams, 1.4mmol) and acetenyl magnesium bromide is raw material, According to the preparation method of compound 26,330 milligrams of yellow oil are obtained, yield 80%.

¹H NMR(300MHz,CDCl₃) δ 7.69 (t, J=7.6Hz, 1H), 7.19 (dd, J=7.7,1.5Hz, 1H), 7.11 (dd, J=10.1,1.5Hz, 1H), 5.74 (d, J=3.8Hz, 1H), 4.04-3.84 (m, 1H), 3.60-3.42 (m, 3H), 3.36 (s, 3H), 3.28-3.18 (m, 2H), 2.74 (d, J=5.8Hz, 1H), 2.66 (d, J=2.2Hz, 1H), 1.91 (d, J=11.1Hz, 3H)；LC-MS(ESI):m/z 314.2[M+H]⁺。

2- [4- (4- methoxy piperide -1- base)-formoxyl -2- fluoro-phenyl] the chloro- pyrroles of -5- [1,2-b] pyridazine -7- first The preparation method of amide (compound I-23)

Compound 30 (330 milligrams, 1.2mmol), (180 milligrams, 0.6mmol) of compound 6 are raw material, according to compound The preparation method of I-21 obtains 44 milligrams of yellow solid, two step total recoverys 17%.

¹H NMR(300MHz,DMSO-d₆) δ 8.27 (d, J=9.4Hz, 1H), 8.17 (s, 1H), 8.01- 7.92 (m, 2H), 7.54 (d, J=1.1Hz, 1H), 7.49 (dd, J=11.5,1.5Hz, 1H), 7.45-7.37 (m, 2H), 3.96-3.86 (m, 1H), 3.50-3.40 (m, 2H), 3.25 (s, 3H), 3.23-3.12 (m, 2H), 1.95- 1.74 (m, 2H), 1.45 (d, J= 16.3Hz,2H)；LC-MS(ESI):m/z 431.2[M+H]⁺。

The preparation method of the fluoro- 4- of 2- (the fluoro- 4- methoxy piperide -1- base of 3-) formylbenzaldehyde (compound 31)

The fluoro- 4- formyl-benzoic acid of 2- (370 milligrams, 2.2mmol) and the fluoro- 4- methoxy piperide of 3- (340 milligrams, 2mmol) 320 milligrams of white solid are obtained, yield 56% according to the preparation method of compound 25 for starting material.

¹H NMR(300MHz,CDCl₃) δ 10.38 (d, J=0.8Hz, 1H), 7.93 (dd, J=7.9,6.8 Hz, 1H), 7.34-7.20(m,2H),4.78-4.60(m,1H),4.50-4.32(m,1H),3.62-3.50(m, 1H),3.46(s,3H), 3.20-3.05(m,2H),1.98-1.90(m,2H),1.78-1.68(m,1H)； LC-MS(ESI):m/z 284.2[M+H]⁺。

The fluoro- 4- of 3- (1- hydroxyl-propine -2- base)-phenyl-(the fluoro- 4- methoxy piperide -1- base of 3-) methyl ketone (compound 32) preparation method

The THF solution (0.5M, 4.2 mmol) of compound 31 (320 milligrams, 1.1mmol) and acetenyl magnesium bromide is original Material, according to the preparation method of compound 26, obtains 190 milligrams of yellow oil, yield 56%.

¹H NMR(300MHz,CDCl₃) δ 7.72 (t, J=7.5Hz, 1H), 7.16 (d, J=10.1Hz, 2H), 5.76- 5.73 (m, 1H), 4.78-4.62 (m, 1H), 4.45-4.32 (m, 1H), 4.02-3.93 (m, 1H), 3.62-3.54 (m, 1H), 3.45 (s, 3H), 3.19-3.08 (m, 2H), 2.67 (d, J=2.2Hz, 1H), 2.57- 2.53 (m, 1H), 1.96-1.90 (m, 1H)；LC-MS(ESI):m/z 332.2[M+H]⁺。

2- [the fluoro- 4- of 2- (the fluoro- 4- Methoxy-piperidin -1- base of 3-)-Fonnylphenyl] the chloro- pyrroles of -5- [1,2-b] pyridazine - The preparation method of 7- formamide (compound I-24)

Compound 32 (190 milligrams, 0.6mmol), compound 6 (115 milligrams, 0.38mmol), Pd (OAc)₂(5 milligrams), CuI (1 milligram) and (300 milligrams) of DBU obtain 20 milligrams of yellow solid according to the preparation method of compound I-21 for raw material, Two step total recoverys 12%.

¹H NMR(300MHz,DMSO-d₆) δ 8.28 (d, J=9.4Hz, 1H), 8.17 (d, J=3.0Hz, 1H), 8.03- 7.92 (m, 2H), 7.55 (s, 1H), 7.50-7.35 (m, 3H), 5.09-4.74 (m, 2H), 4.41 (d, J=20.0Hz, 1H), 3.83 (d, J=14.4Hz, 1H), 3.55 (s, 3H), 2.98 (dd, J=10.0,5.0 Hz, 1H), 1.90-1.82 (m, 1H), 1.69 (d, J=17.1Hz, 2H)；LC-MS(ESI):m/z 449.2 [M+H]⁺。

The preparation method of the fluoro- 4- of 2- (3- methoxypyrrole quinoline -1- base) formylbenzaldehyde (compound 33)

The fluoro- 4- formylbenzoate of 3- (370 milligrams, 2.2mmol) and 3- methoxypyrrole quinoline (274 milligrams, 2mmol, Its preparation method reference literature US2011092475A1) it is raw material, according to the preparation method of compound 25, it is solid to obtain white 240 milligrams of body, yield 48%.

¹H NMR(300MHz,CDCl₃) δ 10.37 (d, J=0.9Hz, 1H), 7.91 (t, J=7.4Hz, 1H), 7.44- 7.29 (m, 2H), 4.00 (d, J=28.9Hz, 1H), 3.88-3.68 (m, 2H), 3.68-3.39 (m, 2H), 3.32 (d, J= 27.5Hz,3H),2.20-1.82(m,2H)；LC-MS(ESI):m/z 252.2 [M+H]⁺。

The fluoro- 4- of 3- (1- hydroxyl-propine -2- base)-phenyl-(3- methoxymethyl-pyrrolidin -1- base) methyl ketone (compound 34) Preparation method

The THF solution (0.5M, 3mL) of compound 33 (240 milligrams, 1mmol) and acetenyl magnesium bromide is raw material, according to The preparation method of compound 26 obtains 180 milligrams of grease, yield 65%.

1H NMR(300MHz,CDCl₃) δ 7.68 (t, J=7.6Hz, 1H), 7.39-7.10 (m, 2H), 5.78-5.58 (m, 1H), 4.06-3.88 (m, 1H), 3.72 (dd, J=8.0,5.2Hz, 2H), 3.68-3.39 (m, 2H), 3.31 (d, J= 29.2Hz, 3H), 3.18 (t, J=5.4Hz, 1H), 2.64 (d, J=2.3Hz, 1H), 2.18-1.82 (m, 2H)；LC-MS (ESI):m/z 300.2[M+Na]⁺。

2- [the fluoro- 4- of 2- (3- methoxypyrrolidin -1- base) Fonnylphenyl] the chloro- pyrroles of -5- [1,2-b] pyridazine -7- first The preparation method of amide (compound I-25)

Compound 34 (180 milligrams, 0.65mmol), compound 6 (120 milligrams, 0.4mmol), Pd (OAc)₂(5 milligrams), CuI (1 milligram) and (300 milligrams) of DBU obtain 23 milligrams of yellow solid according to the preparation method of compound I-21 for raw material, Two step total recoverys 14%.

¹H NMR(500MHz,DMSO-d₆) δ 8.31 (dd, J=9.5,1.4Hz, 1H), 8.20 (d, J=3.7 Hz, 1H), 8.00 (tt, J=7.9,4.6Hz, 2H), 7.62 (dd, J=11.1,1.6Hz, 1H), 7.57 (d, J=9.0Hz, 2H), 7.46 (dt, J=9.6,2.3Hz, 1H), 4.01 (dtt, J=39.6,4.6,2.2Hz, 1H), 3.72- 3.46 (m, 4H), 3.24 (d, J =47.8Hz, 3H), 2.06-1.94 (m, 2H)；LC-MS(ESI):m/z 417.2[M+H]⁺。

The preparation method of 4- (3- methoxypyrrole quinoline -1- base)-formylbenzaldehyde (compound 35)

4- formylbenzoate (330 milligrams, 2.2mmol) and (274 milligrams, 2mmol) of 3- methoxypyrrolidin are original Material, the preparation method of reference compound 25 obtain 320 milligrams of white solid, yield 69%.

LC-MS(ESI):m/z 234.2[M+H]⁺。

The system of 4- (1- hydroxyl-propine -2- base)-phenyl-(3- methoxypyrrole quinoline -1- base) methyl ketone (compound 36) Preparation Method

The THF solution (0.5M, 5mL) of compound 35 (320 milligrams, 1.4mmol) and acetenyl magnesium bromide is raw material, ginseng According to the preparation method of compound 26, yellow oil, yield are obtained.

¹H NMR(300MHz,CDCl₃) δ 7.72-7.32 (m, 4H), 5.48 (d, J=4.7Hz, 1H), 3.97 (d, J= 35.4Hz, 1H), 3.76-3.70 (m, 2H), 3.64-3.40 (m, 2H), 3.31 (d, J=32.4 Hz, 3H), 2.74 (d, J= 6.1Hz, 1H), 2.67 (d, J=2.1Hz, 1H), 2.13-1.97 (m, 2H)； LC-MS(ESI):m/z 282.2[M+Na]⁺。

2- [4- (3- methoxypyrrole quinoline -1- base)-Fonnylphenyl] the chloro- pyrroles of -5- [1,2-b] pyridazine -7- formamide The preparation method of (compound I-26)

Compound 36 (200 milligrams, 0.77mmol), compound 6 (128 milligrams, 0.43mmol), Pd (OAc)₂(6 millis Gram), CuI (1 milligram) and (327 milligrams) of DBU are raw material, and the preparation method of reference compound I-21 obtains 28 milli of yellow solid Gram, two step total recoverys 17%.

¹H NMR(500MHz,DMSO-d₆) δ 8.28 (dd, J=9.4,1.7Hz, 1H), 8.24 (s, 1H), 8.11 (dd, J =8.1,5.9Hz, 2H), 8.02 (s, 1H), 7.72 (dd, J=8.3,2.1Hz, 2H), 7.65 (dd, J=9.5,3.5Hz, 1H), 7.54 (s, 1H), 4.00 (dtt, J=43.0,4.6,2.2Hz, 1H), 3.68-3.45 (m, 4H), 3.23 (d, J= 54.9Hz,3H),2.06-1.91(m,2H)；LC-MS(ESI):m/z 399.2[M+H]⁺。

3- methyl -4- (the fluoro- 4- formoxyl benzene of 3-)-Formyl-piperazine -1- base-t-butyl formate (compound 37) system Preparation Method

The fluoro- 4- formylbenzoate of 3- (370 milligrams, 2.2mmol) and 3- methyl piperazine -1- t-butyl formate (400 millis Gram, 2mmol) it is raw material, the preparation method of reference compound 25 obtains 470 milligrams of white solid, yield 67%.

¹H NMR(300MHz,CDCl₃) δ 10.38 (s, 1H), 7.94 (t, J=7.6Hz, 1H), 7.39-7.03 (m, 2H), 4.15-4.10 (m, 1H), 3.95-3.85 (m, 2H), 3.24-2.85 (m, 4H), 1.47 (s, 9H), 1.27 (d, J=6.7Hz, 3H)；LC-MS(ESI):m/z 373.2[M+Na]⁺。

The fluoro- 4- of 3- (1- hydroxyl-propine -2- base) phenyl-(the tertiary fourth oxygen Formyl-piperazine -1- base of 2- methyl -4-) methyl ketone The preparation method of (compound 38)

The THF solution (0.5M, 5mL) of compound 37 (470 milligrams, 1.4mmol) and acetenyl magnesium bromide is raw material, ginseng According to the preparation method of compound 26,350 milligrams of yellow oil are obtained, yield 66%.

¹H NMR(300MHz,CDCl₃) δ 7.72 (t, J=7.7Hz, 1H), 7.21-7.01 (m, 2H), 5.74 (d, J= 5.5Hz, 1H), 4.05-3.84 (m, 3H), 3.25-2.80 (m, 4H), 2.73-2.69 (m, 1H), 2.67 (d, J=2.3Hz, 1H),1.47(s,9H),1.26-1.21(m,3H)；LC-MS(ESI):m/z 399.2 [M+Na]⁺。

2- [the fluoro- 4- of 2- (2- methyl -4- tert-butoxy Formyl-piperazine -1- base)-Fonnylphenyl] the chloro- pyrroles of -5- The preparation method of [1,2-b] pyridazine -7- methyl formate (compound 39)

Compound 38 (350 milligrams, 0.93mmol), compound 6 (155 milligrams, 0.52mmol), (7 millis of Pd (OAc) 2 Gram), CuI (1 milligram) and (450 milligrams) of DBU are raw material, and the preparation method of reference compound 15 obtains 63 milli of yellow solid Gram, yield 23%.

LC-MS(ESI):m/z 553.2[M+Na]⁺。

The chloro- 2- of 5- [the fluoro- 4- of 2- (2- methyl -4- cyclopropyl Formyl-piperazine -1- base)-Fonnylphenyl] pyrroles [1,2- B] pyridazine 7- formamide (compound I-27) preparation method

In the methylene chloride 10mL of compound 39 (65 milligrams, 0.13mmol), 1.5 mL of trifluoroacetic acid, thin-layer chromatography is added After detecting fully reacting, pH value is adjusted at alkalescent (8~9) with NaOH (2.5M) solution under ice bath, isolates organic phase, water Layer chloroform extraction, merges organic phase, concentration, and column chromatography (methylene chloride: methanol=10:1) affords yellow solid 52 milligrams, be (the chloro- 2- of 5- [the fluoro- 4- of 2- (2- thyl-piperazin -1- base)-Fonnylphenyl] pyrroles [1,2-b] pyridazine -7- first Sour methyl esters)；It is dissolved in anhydrous methylene chloride 10mL, a few drop triethylamines and Cyclopropyl carbonyl chloride (300 milligrams), room is added Temperature lower stirring 1 hour, methanol 5mL is added, stirs 10 minutes at room temperature, is concentrated to get the chloro- 2- of crude product 5- [2- fluoro- 4- (2- first Base -4- cyclopropyl Formyl-piperazine -1- base)-Fonnylphenyl] pyrroles [1,2-b] pyridazine 7- methyl formate；With methanol 10 ML is transferred in 25mL tube sealing, and the methanol solution of 8mL ammonia is added, reacts 20~24 hours, is cooled to room temperature at 80~90 DEG C, Concentration, column chromatography (methylene chloride: methanol=20:1) afford 40 milligrams of yellow solid, three step total recoverys 63%.

¹H NMR(300MHz,DMSO-d₆) δ 8.35-8.23 (m, 1H), 8.18 (d, J=2.9Hz, 1H), 8.03-7.93 (m, 1H), 7.55 (d, J=1.3Hz, 1H), 7.53-7.37 (m, 3H), 6.78-6.68 (m, 1H) 4.78-4.05 (m, 3H), 3.52-2.70 (m, 4H), 1.95 (dd, J=20.7,9.5Hz, 1H), 1.35-1.03 (m, 3H), 0.81-0.67 (m, 2H), 0.64-0.56(m,2H)；LC-MS(ESI):m/z 484.2[M+H]⁺。

The preparation of 2- methyl -4- (the fluoro- 4- formoxyl benzene of 3-)-Formyl-piperazine -1- t-butyl formate (compound 40) Method

The fluoro- 4- formylbenzoate of 3- (370 milligrams, 2.2mmol) and 2- methyl piperazine -1- t-butyl formate (400 millis Gram, 2mmol) it is raw material, the preparation method of reference compound 25 obtains 420 milligrams of white solid, yield 60%.

¹H NMR(300MHz,CDCl₃)δ10.38(s,1H),7.98-7.84(m,1H),7.33-7.05(m, 2H), 4.62-4.21 (m, 1H), 3.98-3.82 (m, 2H), 3.35-2.85 (m, 4H), 1.47 (d, J=1.2Hz, 9H), 1.30- 1.01(m,3H)；；LC-MS(ESI):m/z 373.2[M+Na]⁺。

The fluoro- 4- of 3- (1- hydroxyl-propine -2- base)-phenyl-(the tertiary fourth oxygen Formyl-piperazine -1- base of 3- methyl -4-) methyl The preparation method of ketone (compound 41)

The THF solution (0.5M, 4.3 mL) of compound 40 (420 milligrams, 1.2mmol) and acetenyl magnesium bromide is raw material, The preparation method of reference compound 26 obtains 365 milligrams of yellow oil, yield 81%.

¹H NMR(300MHz,CDCl₃) δ 7.72 (t, J=7.5Hz, 1H), 7.17 (dd, J=22.3,8.9 Hz, 2H), 5.75 (d, J=5.0Hz, 1H), 4.61-4.18 (m, 2H), 3.94-3.80 (m, 1H), 3.50- 2.89 (m, 4H), 2.70- 2.66 (m, 1H), 2.69-2.63 (m, 1H), 1.46 (s, 9H), 1.11 (d, J=6.3Hz, 3H)；LC-MS(ESI):m/z 399.2[M+Na]⁺。

2- [the fluoro- 4- of 2- (3- methyl -4- tert-butoxy Formyl-piperazine -1- base)-Fonnylphenyl] the chloro- pyrroles of -5- The preparation method of [1,2-b] pyridazine -7- methyl formate (compound 42)

Compound 41 (364 milligrams, 0.97mmol), compound 6 (160 milligrams, 0.54mmol), Pd (OAc)₂(11 millis Gram), CuI (1 milligram) and (410 milligrams) of DBU are raw material, and the preparation method of reference compound 15 obtains 146 milli of yellow solid Gram crude product, yield 52%.

¹H NMR(300MHz,CDCl₃) δ 8.14 (t, J=7.7Hz, 1H), 7.97 (d, J=9.5Hz, 1H), 7.52 (s, 1H),7.40-7.27(m,3H),4.59-4.22(m,2H),3.94(s,3H),3.42-3.33(m, 1H),3.18-2.90(m, 4H),1.47(s,9H),1.21-1.08(d,3H)；LC-MS(ESI):m/z 538.2 [M+Na]⁺。

The chloro- 2- of 5- [the fluoro- 4- of 2- (3- methyl -4- cyclopropyl Formyl-piperazine -1- base)-Fonnylphenyl] pyrroles [1,2- B] pyridazine 7- formamide (compound I-28) preparation method

(80 milligrams, 0.16mmol) of compound 42 are raw material, and it is solid to obtain yellow for the preparation method of reference compound I-27 45 milligrams of body, yield 61%.

¹H NMR(300MHz,DMSO-d₆) δ 8.30 (dd, J=9.5,0.8Hz, 1H), 8.19 (s, 1H), 8.01 (dd, J =10.4,5.3Hz, 2H), 7.62-7.39 (m, 4H), 4.85-3.95 (m, 4H), 3.79-2.79 (m, 3H), 1.52-1.43 (tt, J=7.4,5.1Hz, 1H), 1.34-1.07 (m, 3H), 0.84-0.67 (m, 4H)；LC-MS(ESI):m/z 484.2[M+ H]⁺。

The preparation method of 2- (4- bromophenyl) dimethyl malenate (compound 43)

Under ice bath, by sodium silk (4.6 grams, 0.2mol), anhydrous methanol 100mL is put into, the variation of temperature is controlled, prevents Excessive exothermic, after Na all dissolution, vacuum decompression removes solvent and obtains sodium methoxide solid.Add 4- bromo-acid methyl esters (22 grams；0.1mol) anhydrous THF100 milliliters, at room temperature stir 25 minutes after, add dimethyl carbonate (42mL, 0.5mol), it stirs 48 hours at room temperature, the solvent of 2/3 volume is removed under reduced pressure, water and ethyl acetate, ultrasound, which is then added, to be made to mix The solid closed in liquid all dissolves, and isolates organic phase, and water layer is extracted with ethyl acetate again, merges organic phase, saturated sodium-chloride Solution washing, concentration, column chromatography (petroleum ether: ethyl acetate=50:1) afford 20 grams of white solid, yield 70%.

¹H NMR(300MHz,CDCl₃) δ 7.50 (d, J=8.5Hz, 2H), 7.28 (d, J=8.5Hz, 2H), 4.60 (s, 1H),3.76(s,6H)；LC-MS(ESI):m/z 287.2[M+H]⁺,289.2[M+3H]⁺。

1- (4- bromophenyl)-propane -1,1,3- tricarboxylic acid trimethyl (compound 44) preparation method

Under ice bath, Na (370 milligrams, 16mmol) are added into anhydrous methanol 100mL, all after dissolution, 2- is added (4- bromophenyl) dimethyl malenate (10 grams, 35mmol) stirs 30 minutes at room temperature, adds methyl acrylate (8mL), It stirs 24 hours at room temperature, is directly added into silica gel column chromatography (petroleum ether: ethyl acetate=100:1) and affords white solid 9 Gram, yield 70%.

¹H NMR(300MHz,CDCl₃) δ 7.51-7.42 (d, J=8.7Hz, 2H), 7.24 (d, J=8.7 Hz, 2H), 3.75(s,6H),3.64(s,3H),2.67-2.54(m,2H),2.32-2.25(m,2H)；LC-MS (ESI):m/z 373.2[M +H]⁺,375.2[M+3H]⁺。

The preparation method of the amyl- 1,5- diacid (compound 45) of 2- (4- bromophenyl)

It takes compound 44 (5.2 grams, 14mmol) to be added in the round-bottomed flask of 250mL, potassium hydroxide solid (3.8 is added Gram, 67.2mmol) and water 100mL, stirs 3 hours at 110 DEG C, after being cooled to room temperature, is added 10 milliliters of the concentrated sulfuric acid, continues to exist 110 DEG C are stirred 9 hours, are cooled to room temperature, and ethyl acetate extracts 2 times, merge organic phase, concentration, and column chromatographs (chloroform: first Alcohol=50:1) 3.6 grams of grease are afforded, yield 90%.

H-NMR(300MHz,CDCl₃) δ 7.47 (d, J=8.5Hz, 2H), 7.18 (d, J=8.5Hz, 2H), 3.63 (t, J =7.5Hz, 1H), 2.42-2.29 (m, 3H), 2.13-2.03 (m, 1H)；LC-MS(ESI):m/z 286.2[M+H]⁺,288.2 [M+3H]⁺。

The preparation method of 2- (4- bromophenyl) amyl- 1,5- dihydroxy-bis- (4- tosylate) (compounds 46)

In the anhydrous THF80mL of compound 45 (3.6 grams, 12.6mmol), BH is slowly added to by constant pressure funnel₃ THF solution (1M is purchased from Shanghai up to auspicious chemical company) 50mL, add within about 25 minutes, stir 1 hour at room temperature, slowly drip Methanol solution is added, until no longer generating bubble, continues stirring 30 minutes, vacuum decompression removes solvent, and water and acetic acid second is added Each 100 milliliters of ester, organic phase is isolated, water layer is extracted with ethyl acetate again, merges organic phase, and saturated common salt water washing is anhydrous Sodium sulphate is dry, is concentrated to get 3.05 grams of grease, direct plunges into next step, yield 95%；Dichloro is added into above-mentioned crude product Methane 100mL, pyridine 5mL are added in two portions 4- toluene sulfochloride (7.5 grams, 40 mmol), stir at room temperature all after dissolution Overnight, 3N HCl solution 10mL is added, stirring after ten minutes, is added water 50mL, organic phase, water layer dichloro is then demultiplex out Methane extraction, merges organic phase, concentration, and column chromatography (petroleum ether: ethyl acetate=8:1) affords colorless oil 2.8 Gram, two step total recoverys 64%.

H-NMR(300MHz,CDCl₃) δ 7.74 (d, J=8.1Hz, 2H), 7.59 (d, J=8.3Hz, 2H), 7.33 (dd, J=8.4,1.8Hz, 4H), 7.28 (d, J=8.1Hz, 2H), 6.86 (d, J=8.4Hz, 2H), 4.04-3.96 (m, 1H), 3.91 (t, J=5.9Hz, 2H), 2.85-2.73 (m, 1H), 2.45 (s, 6H), 1.83-1.68 (m, 1H), 1.54-1.38 (m, 3H)；LC-MS(ESI):m/z 567.2[M+H]⁺,569.2[M+3H]⁺。

The preparation method of 3- (4- bromophenyl) -1- (4- methoxy-benzyl)-piperidines (compound 47)

In Isosorbide-5-Nitrae-dioxane 100mL of compound 46 (1.85 grams, 3.2mmol), 4- methoxybenzylamine (700 millis are added Gram, 5.1mmol), it stirs 48 hours at 110 DEG C, is cooled to room temperature, be concentrated, column chromatographs (petroleum ether: ethyl acetate=25:1) 1.6 grams of yellow solid are afforded, yield 89%.

¹H NMR(300MHz,CDCl₃) δ 7.42-7.36 (m, 2H), 7.25-7.18 (m, 2H), 7.08 (d, J=8.4Hz, 2H), 6.87-6.80 (m, 2H), 3.79 (s, 3H), 3.47 (s, 2H), 2.96-2.85 (m, 2H), 2.78 (tt, J=11.4, 3.7Hz, 1H), 1.92-1.84 (m, 2H), 1.79-1.63 (m, 3H), 1.39 (qd, J=12.0,4.9Hz, 1H)；LC-MS (ESI):m/z 360.2[M+H]⁺,362.2[M+3H]⁺。

The preparation method of 3- (4- bromophenyl) piperidines (compound 48)

In the acetonitrile 50mL of compound 47 (1.8 grams, 5mmol), the aqueous solution of ammonium ceric nitrate (11 grams, 20mmol) is added (20mL), is stirred overnight at room temperature, and vacuum decompression removes the solvent of half volume, and ethyl acetate extraction is added, isolates organic Phase, saturated sodium chloride solution washing, concentration, column chromatography (methylene chloride: methanol=10:1) afford 1 gram of colourless liquid, receive Rate 89%.

¹H NMR(300MHz,CDCl₃) δ 7.42 (d, J=8.3Hz, 2H), 7.11 (d, J=8.3Hz, 2H), 3.68 (t, J =11.0Hz, 2H), 3.31 (dd, J=1.9,1.3Hz, 1H), 3.16-2.98 (m, 3H), 2.06 (d, J=4.2Hz, 3H)； LC-MS(ESI):m/z 240.2[M+H]⁺,242.2[M+3H]⁺。

The preparation method of 3- (4- bromophenyl) piperidines -1- t-butyl formate (compound 49)

In the methylene chloride 50mL of compound 48 (600 milligrams, 2.5mmol), pyridine 1mL and boc acid anhydrides (820 is added Milligram, 3.8mmol) methylene chloride (10mL) solution, at room temperature stir 3 hours, be added 10 milliliters of 3N HCl solution, continue Stirring 10 minutes, isolates organic phase, and water layer is extracted with dichloromethane, and merges organic phase, and saturated sodium chloride solution washing is dense Contracting, column chromatography (petroleum ether: ethyl acetate=80:1) afford 460 milligrams of white solid, yield 54%.

¹H NMR(400MHz,CDCl₃) δ 7.46-7.39 (d, J=8.3Hz, 2H), 7.13-7.06 (d, J=8.3Hz, 2H), 4.13 (s, 2H), 2.68 (dd, J=28.8,11.4Hz, 3H), 2.04-1.90 (m, 1H), 1.81- 1.68 (m, 1H), 1.60-1.52(m,2H),1.46(s,9H)；LC-MS(ESI):m/z 340.2[M+H]⁺。

3- (4- Fonnylphenyl)-piperidines -1- t-butyl formate (compound 50) preparation method

In the 250mL three-necked bottle for taking a predrying, the anhydrous THF of compound 49 (500 milligrams, 1.5mmol) is added 50 milliliters of solution, Ar₂Under protection, -78 DEG C are cooled to, is slowly added dropwise into n-BuLi (2.5M, 1mL), is continually maintained in the temperature Lower stirring 30 minutes, is then added anhydrous DMF 5mL, continues stirring 2 hours, and saturated ammonium chloride solution 10mL is then added, stirs It mixes to be transferred to after ten minutes and stir 30 minutes at room temperature, isolate organic phase, aqueous layer with ethyl acetate extraction merges organic phase, Saturated common salt water washing, concentration, column chromatography (petroleum ether: ethyl acetate=10:1) afford 250 milligrams of yellow oil, Yield 58%.

¹H NMR(300MHz,CDCl₃)δ9.98(s,1H),7.86-7.80(m,2H),7.43-7.37(m, 2H),4.24- 4.08 (m, 2H), 2.75 (d, J=13.3Hz, 3H), 2.09-1.97 (m, 1H), 1.82-1.72 (m, 1H), 1.66-1.58 (s, 2H),1.47(s,9H)；LC-MS(ESI):(m/z)290.2[M+H]⁺。

The preparation method of 3- [4- (1- hydroxyl-propine -2- base) phenyl]-piperidines -1- t-butyl formate (compound 51)

In the anhydrous THF solution 50mL of compound 50 (280 milligrams, 1mmol), the THF solution of acetenyl magnesium bromide is added (0.5M, 4mL) is stirred 1 hour at room temperature, saturated ammonium chloride solution 20mL is added, and is continued stirring after twenty minutes, has been isolated Machine phase, aqueous layer with ethyl acetate extraction merge organic phase, saturated sodium chloride solution washing, concentration, column chromatography (petroleum ether: second Acetoacetic ester=4:1) 200 milligrams of white solid are afforded, yield 63%.

¹H NMR(300MHz,CDCl₃) δ 7.50 (d, J=8.1Hz, 2H), 7.30-7.21 (d, J=8.1 Hz, 2H), 5.45 (dd, J=6.2,2.2Hz, 1H), 4.12 (dd, J=15.3,9.0Hz, 2H), 2.84-2.54 (m, 4H), 2.30 (d, J =6.2Hz, 1H), 2.04-1.94 (m, 1H), 1.75 (dt, J=8.7,2.8Hz, 1H), 1.58 (d, J=3.3Hz, 1H), 1.46(s,9H)；LC-MS(ESI):m/z 338.2[M+Na]⁺。

The chloro- 2- of 5- [4- (1- tert-butoxy formyl piperidine -3- base) phenyl] pyrroles [1,2-b] pyridazine -7- methyl formate The preparation method of (compound 52)

It takes in the 25mL microwave tube with microwave cap, is added compound 51 (200 milligrams, 0.63mmol), compound 6 (120 milligrams, 0.4mmol), palladium acetate (5 milligrams), cuprous iodide (1 milligram) and 10 milliliters of toluene, N₂After displacement 3 times, N₂It protects Shield is lower to be added DBU (300 milligrams), covers tightly microwave cap, and lower 90 DEG C of microwave (λ=180W) are reacted 40 minutes, is cooled to room temperature Afterwards, chloroform dilutes, and is transferred in 100 milliliters of round-bottomed flasks, is concentrated, and column chromatographs (petroleum ether: ethyl acetate=7:1) 146 milligrams of yellow solid are afforded, yield 78%.

¹H NMR(300MHz,CDCl₃) δ 8.01 (d, J=8.0Hz, 2H), 7.93 (dd, J=9.4,0.8Hz, 1H), 7.46 (d, J=0.9Hz, 1H), 7.35 (ddd, J=10.4,8.9,1.1Hz, 3H), 4.15 (d, J=14.0 Hz, 3H), 3.95 (s,3H),2.84-2.70(m,4H),2.08-1.98(m,1H),1.82-1.74(m,1H), 1.47(s,9H)；LC-MS (ESI):m/z 492.2[M+Na]⁺。

The chloro- 2- of 5- [4- (1- tert-butoxy formyl piperidine -3- base) phenyl] pyrroles [1,2-b] pyridazine -7- formamide (is changed Close object 53) preparation method

20 milliliters of methanol of compound 52 (145 milligrams, 0.31mmol) are added in 50 milliliters of tube sealings, and the first of ammonia is added 15 milliliters of alcoholic solution, 90 DEG C tube sealing reaction 20 hours, after being cooled to room temperature, concentration, column chromatography (methylene chloride: methanol= 110 milligrams of yellow solid 50:1) are afforded, yield 78%.

¹H NMR(400MHz,CDCl₃) δ 8.80 (d, J=3.7Hz, 1H), 8.00 (d, J=9.4Hz, 1H), 7.85- 7.74 (m, 2H), 7.63 (d, J=0.5Hz, 1H), 7.41 (d, J=8.3Hz, 2H), 7.23 (d, J=9.4Hz, 1H), 5.97 (s, 1H), 4.17 (s, 2H), 2.91-2.63 (m, 3H), 2.07 (d, J=12.1Hz, 1H), 1.84-1.76 (m, 1H), 1.76- 1.53(m,2H),1.48(s,9H)；LC-MS(ESI):m/z 477.2 [M+H]⁺。

2- (4- [(3S)-tert-butoxy formyl piperidine -3- base]-phenyl) the chloro- pyrroles of -5- [1,2-b] pyridazine -7- formyl The preparation method of amine (compound 53-S)

The chirality SFC method of purification chiral separation of raceme 53, CO₂As supercritical fluid, chiral column: Chiralcel OJ-H, 0.46cm I.D. × 25cm L, flow velocity: 2.5mL/min, Detection wavelength: 254 nm of UV, column temperature: 35 DEG C, mobile phase: CO₂: MeOH:DEA=60:40:0.1.The retention time of first enantiomer is 8.68min, and solvent is removed under reduced pressure and obtains yellow Solid: 2- (4- [(3R)-tert-butoxy formyl piperidine -3- base]-phenyl) the chloro- pyrroles of -5- [1,2-b] pyridazine -7- formamide (compound 53-R, 99.9%ee).The retention time of second enantiomer is 9.07min, and solvent is removed under reduced pressure, and to obtain yellow solid Body: 2- [4- [(3S)-tert-butoxy formyl piperidine -3- base]-phenyl] the chloro- pyrroles of -5- [1,2-b] pyridazine -7- formamide (compound 53-S, 98%ee).

- 90.4,¹H NMR(400MHz,CDCl₃) δ 8.80 (d, J=3.7Hz, 1H), 8.00 (d, J=9.4Hz, 1H), 7.85-7.74 (m, 2H), 7.63 (d, J=0.5Hz, 1H), 7.41 (d, J=8.3Hz, 2H), 7.23 (d, J=9.4Hz, 1H), 5.97 (s, 1H), 4.17 (s, 2H), 2.91-2.63 (m, 3H) 2.07 (d, J=12.1Hz, 1H), 1.84-1.76 (m, 1H),1.76-1.53(m,2H),1.48(s,9H)；LC-MS(ESI): m/z 477.2[M+Na]⁺.Without deleting

2- [4- [(3R)-tert-butoxy formyl piperidine -3- base]-phenyl] the chloro- pyrroles of -5- [1,2-b] pyridazine -7- formyl The preparation method of amine (compound 53-R)

93.4(c 0.004,CH₃OH),H NMR(400MHz,CDCl₃) δ 8.80 (d, J=3.7Hz, 1H), 8.00 (d, J=9.4Hz, 1H), 7.85-7.74 (m, 2H), 7.63 (d, J=0.5Hz, 1H), 7.41 (d, J=8.3Hz, 2H), 7.23 (d, J=9.4Hz, 1H), 5.97 (s, 1H), 4.17 (s, 2H), 2.91-2.63 (m, 3H) 2.07 (d, J=12.1Hz, 1H), 1.84-1.76(m,1H),1.76-1.53(m,2H),1.48(s,9H)； LC-MS(ESI):m/z 477.2[M+Na]⁺。

The preparation of the chloro- 2- of 5- [4- (piperidines -3- base) phenyl] pyrroles's [1,2-b] pyridazine -7- formamide (compound I-29) Method

In the chloroform 10mL of compound 53 (50 milligrams, 0.11mmol), it is added trifluoroacetic acid (1.8 mL), at room temperature Stirring 1 hour adjusts pH value at alkalescent (8~9) with NaOH solution (2.5M) under ice bath, isolates organic phase, and water layer is with three Chloromethanes extraction merges organic phase, saturated common salt water washing, concentration, column chromatography (methylene chloride: methanol=10:1,1L elution Add the methanol solution of 5 milliliters of ammonia in agent) 35 milligrams of yellow solid are afforded, yield 90%.

H-NMR；LC-MS(ESI):m/z 355.2[M+H]⁺。

The chloro- 2- of 5- [4- ((3S)-piperidines -3- base) phenyl] pyrroles's [1,2-b] pyridazine -7- formamide (compound I-30) Preparation method

(50 milligrams, 0.11mmol) of compound 53-S are raw material, and the preparation method of reference compound I-29 obtains yellow 35 milligrams of solid, yield 89%.

¹H NMR(400MHz,CDCl₃) δ 8.79 (d, J=3.8Hz, 1H), 7.98 (d, J=9.4Hz, 1H), 7.80 (d, J =8.2Hz, 2H), 7.61 (s, 1H), 7.39 (d, J=8.3Hz, 2H), 7.21 (d, J=9.5Hz, 1H), 6.16 (d, J= 3.8Hz,1H),3.32-3.17(m,2H),2.93-2.85(m,1H),2.81-2.68(m, 2H),2.12-1.84(m,2H), 1.81-1.63(m,2H)；LC-MS(ESI):m/z 355.2[M+H]⁺。

The chloro- 2- of 5- [4- ((3R)-piperidines -3- base) phenyl] pyrroles's [1,2-b] pyridazine -7- formamide (compound I-31) Preparation method

(50 milligrams, 0.11mmol) of compound 53-R are raw material, and the preparation method of reference compound I-31 obtains yellow 34 milligrams of solid, yield 88%.

¹H NMR(400MHz,CDCl₃) δ 8.79 (d, J=3.8Hz, 1H), 7.98 (d, J=9.4Hz, 1H), 7.80 (d, J =8.2Hz, 2H), 7.61 (s, 1H), 7.39 (d, J=8.3Hz, 2H), 7.21 (d, J=9.5Hz, 1H), 6.16 (d, J= 3.8Hz,1H),3.32-3.17(m,2H),2.93-2.85(m,1H),2.81-2.68(m, 2H),2.12-1.84(m,2H), 1.81-1.63(m,2H)；LC-MS(ESI):m/z 355.2[M+H]⁺。

6,7- dihydro-thiophene [3,2-c] pyridine -5 (4H)-t-butyl formate (compound 54) preparation method

In the methylene chloride 150mL of 4,5,6,7- thiophanes [3,2-c] pyridine hydrochloride (10 grams, 56.9mmol), add Enter triethylamine 9mL, the dichloromethane solution of Boc acid anhydrides (13.7 grams, 62.8mmol) stirs 1 hour at room temperature, and saturation is added 20 milliliters of ammonium chloride solution, stirring after ten minutes, isolates organic phase, and water layer is extracted with dichloromethane, and merges organic phase, satisfies It is washed with sodium chloride solution, anhydrous sodium sulfate is dry, is concentrated to get 12.5 grams of white solid, yield: 92%.

¹H NMR(300MHz,CDCl₃) δ 7.12 (d, J=5.1Hz, 1H), 6.78 (d, J=5.1Hz, 1H), 4.50 (s, 2H), 3.71 (t, J=5.3Hz, 2H), 2.84 (t, J=5.3Hz, 2H), 1.48 (s, 9H)；LC-MS (ESI):m/z 240.2 [M+H]⁺。

The preparation side of 2- formoxyl -6,7- dihydro-thiophene [3,2-c] pyridine -5 (4H)-t-butyl formate (compound 55) Method

In the 250mL three-necked bottle for taking a predrying, the anhydrous THF of compound 54 (5.3 grams, 22.2mmol) is added Solution 50mL, Ar₂Under protection, -78 DEG C are cooled to, is slowly added dropwise into n-BuLi (1.6M, 22mL), is continually maintained in the temperature Lower stirring 30 minutes, is then added 5 milliliters of anhydrous DMF, continues stirring 2 hours, and 10 milli of saturated ammonium chloride solution is then added It rises, stirring is transferred to after ten minutes stirs 30 minutes at room temperature, isolates organic phase, and aqueous layer with ethyl acetate extraction is associated with Machine phase, saturated common salt water washing, concentration, column chromatography (petroleum ether: ethyl acetate=10:1) afford yellow oil 3.8 Gram, yield 64%.

¹H NMR(300MHz,CDCl₃) δ 9.83 (s, 1H), 7.47 (s, 1H), 4.53 (s, 2H), 3.74 (t, J= 5.8Hz, 2H), 2.92 (t, J=5.6Hz, 2H), 1.49 (s, 9H)；LC-MS(ESI):m/z 268.2 [M+H]⁺。

2- (1- hydroxyl-propine -2- base) -6,7- dihydro-thiophene [3,2-c] pyridine -5 (4H)-t-butyl formate (compound 56 preparation method

In 80 milliliters of anhydrous THF of compound 55 (2.3 grams, 8.4mmol), the THF solution of acetenyl magnesium bromide is added (0.5M, 25mL) is stirred 1 hour at room temperature, after TLC detects fully reacting, is added 30 milliliters of saturated ammonium chloride solution, is continued Stirring after ten minutes, isolates organic phase, and aqueous layer with ethyl acetate extraction merges organic phase, and saturated common salt water washing is concentrated, Column chromatography (petroleum ether: ethyl acetate=8:1) affords 1.8 grams of yellow solid, yield 72%.

H-NMR(300MHz,CDCl₃) δ 6.89 (d, J=0.9Hz, 1H), 5.57 (d, J=2.5Hz, 1H), 4.43 (t, J =1.7Hz, 2H), 3.75-3.65 (m, 2H), 2.80 (d, J=6.0Hz, 2H), 2.68 (d, J=2.2 Hz, 1H), 1.48 (s, 9H).

2- [chloro- 7- methoxy methyl acyl pyrroline [1,2-b] pyridazine -2- base of 5-] -6,7- dihydro-thiophene [3,2-c] pyridine - The preparation method of 5 (4H)-t-butyl formates (compound 57)

It takes in the 25mL microwave tube with microwave cap, is added compound 56 (470 milligrams, 1.6mmol), compound 6 (330 milligrams, 1.1mmol), palladium acetate (15 milligrams), cuprous iodide (2 milligrams) and toluene 10mL, N₂After displacement 3 times, N₂Protection Lower addition DBU (840 milligrams) covers tightly microwave cap, and lower 90 DEG C of microwave (λ=180W) are reacted 40 minutes, after being cooled to room temperature, Chloroform dilution, and be transferred in 100 milliliters of round-bottomed flasks, it is concentrated, column chromatographs (petroleum ether: ethyl acetate=7:1) elution 135 milligrams of yellow solid are obtained, yield 28%.

¹H NMR(300MHz,CDCl₃) δ 7.84 (d, J=9.4Hz, 1H), 7.41 (d, J=0.6Hz, 1H), 7.35 (s, 1H), 7.17 (d, J=9.4Hz, 1H), 4.55 (s, 2H), 3.95 (s, 3H), 3.75-3.64 (m, 2H), 2.93 (t, J= 5.6Hz,2H),1.49(s,9H)；LC-MS(ESI):m/z 448.2[M+H]⁺。

The chloro- 2- of 5- (4,5,6,7- thiophane [3,2-c] pyridine -2- base) pyrroles [1,2-b] pyridazine -7- methyl formate The preparation method of (compound 58)

In 25 milliliters of chloroform of compound 57 (440 milligrams, 0.98mmol), trifluoroacetic acid 2.5mL, room temperature is added After lower stirring 1 hour, after TLC detects fully reacting, adjusting pH value with NaOH (2.5M) under ice bath is 8~9, is isolated organic Phase, water layer chloroform extraction merge organic phase, saturated sodium chloride solution washing, concentration, column chromatography (methylene chloride: first Alcohol=50:1) 250 milligrams of yellow solid are afforded, yield 74%.

LC-MS(ESI):m/z 348.2[M+H]⁺。

2- (4,5,6,7- thiophane [3,2-c] pyridine -2- base) the chloro- pyrroles of -5- [1,2-b] pyridazine -7- methyl formate The preparation method of (compound I-32)

10 milliliters of methanol solution of compound 58 (250 milligrams) are added in 25 milliliters of tube sealings, 8 milliliters of ammonia are added Methanol solution reacts 20 hours at 90 DEG C, is cooled to room temperature, the decompression volume of reaction solution is spun off 2/3, by consolidating for precipitation Body filtering, vacuum drying obtain 180 milligrams of yellow solid, yield 75%.

¹H NMR(400MHz,DMSO-d₆) δ 8.10 (dd, J=24.6,13.5Hz, 3H), 7.69 (s, 1H), 7.51 (d, J =9.5Hz, 1H), 7.41 (s, 1H), 3.85 (s, 2H), 3.06 (d, J=6.0Hz, 2H), 2.80 (d, J=6.0Hz, 2H)； LC-MS(ESI):m/z 333.2[M+H]⁺。

The chloro- 2- of 5- (5- methyl -4,5,6,7- thiophane [3,2-c] pyridine -2- base) pyrroles [1,2-b] pyridazine -7- first The preparation method of sour methyl esters (compound I-33)

In the methanol 5mL of compound 58 (75 milligrams, 0.21mmol), a few drop acetic acid and 37% formalin is added 1.5mL stirs after ten minutes at room temperature, NaCNBH is being added₃(50 milligrams), are stirred overnight at room temperature, concentration, column chromatography (two Chloromethanes: methanol=25:1) afford 55 milligrams of crude products, LC-MS (ESI): m/z 361.2 [M+H]⁺.Turned with 10mL methanol It moves on in 25mL tube sealing, the methanol solution of 8mL ammonia is added, is reacted 20 hours at 90 DEG C, room temperature is cooled to, by reaction solution Decompression volume spins off 2/3, filters the solid of precipitation, and vacuum drying obtains 52 milligrams, yield 71%.

¹H NMR(300MHz,CD₃OD) δ 7.86 (d, J=9.5,1H), 7.42 (d, J=1.2Hz, 1H), 7.31 (s, 1H), 7.19 (d, J=9.5,1H), 3.55 (s, 2H), 2.94 (d, J=5.8Hz, 2H), 2.83 (t, J=5.7Hz, 2H), 2.50 (s,3H)；LC-MS(ESI):m/z 347.2[M+H]⁺。

4,5- dihydro-thiophene [2,3-c] pyridine -6 (7H)-t-butyl formate (compound 59) preparation method

Into 50 milliliters of methylene chloride of 4,5,6,7- thiophane [2,3-c] pyridine hydrochlorides (3 grams, 17.1mmol), Triethylamine 2mL is added, methylene chloride (10mL) solution of Boc acid anhydrides (4.1 grams, 18.9mmol) stirs 1 hour at room temperature, adds Enter saturated ammonium chloride solution 20mL, stirring after ten minutes, isolates organic phase, and water layer is extracted with dichloromethane, and merges organic Phase, saturated sodium chloride solution washing, anhydrous sodium sulfate is dry, is concentrated to get 4.0 grams of grease, yield 98%.

¹H NMR(300MHz,CDCl₃) δ 7.13 (d, J=5.0Hz, 1H), 6.79 (d, J=5.1Hz, 1H), 4.62 (s, 2H), 3.67 (t, J=5.4Hz, 2H), 2.70 (t, J=5.4Hz, 2H), 1.8 (s, 9H)；LC-MS (ESI):m/z 240.2[M +H]⁺。

Bromo- 4,5- dihydro-thiophene [2,3-c] pyridine -6 (7H) of 2--t-butyl formate (compound 60) preparation method

Toward NBS (3.3 grams, 18.8mmol) are added in the acetonitrile 80mL of 59 (4.0 grams, 16.7mmol), then at room temperature Stirring 1 hour, concentration, column chromatography (petroleum ether: ethyl acetate=100:1) afford 4.8 grams of yellow oil, yield 89%.

LC-MS(ESI):m/z 318.2[M+H]⁺。

The preparation side of 2- formoxyl -4,5- dihydro-thiophene [2,3-c] pyridine -6 (7H)-t-butyl formate (compound 61) Method

In the 250mL three-necked bottle for taking a predrying, the anhydrous THF of compound 60 (4.8 grams, 15.1mmol) is added Solution 50mL, Ar₂Under protection, -78 DEG C are cooled to, is slowly added dropwise into n-BuLi (1.6M, 17mL), is continually maintained in the temperature Lower stirring 30 minutes, is then added anhydrous DMF 5mL, continues stirring 2 hours, and saturated ammonium chloride solution 10mL is then added, stirs It mixes to be transferred to after ten minutes and stir 30 minutes at room temperature, isolate organic phase, aqueous layer with ethyl acetate extraction merges organic phase, Saturated common salt water washing, concentration, column chromatography (petroleum ether: ethyl acetate=10:1) afford 3.1 grams of yellow oil, receive Rate 77%.

¹H NMR(300MHz,CDCl₃) δ 9.84 (d, J=1.1Hz, 1H), 7.48 (s, 1H), 4.68 (s, 2H), 3.69 (t, J=5.6Hz, 2H), 2.75 (t, J=5.8Hz, 2H), 1.48 (s, 9H)；LC-MS(ESI): m/z 268.2[M+H]⁺。

2- (1- hydroxyl-propine -2- base) -4,5- dihydro-thiophene [2,3-c] pyridine -6 (7H)-t-butyl formate (compound 62) preparation method

The THF solution (0.5M, 42mL) of compound 61 (3.1 grams, 11.6mmol) and acetenyl magnesium bromide is raw material, ginseng According to the preparation method of compound 56,2.8 grams of yellow solid are obtained, yield 82%.

¹H NMR(300MHz,CDCl₃) δ 6.89 (s, 1H), 5.58 (dd, J=6.4,2.3Hz, 1H), 4.58 (s, 2H), 3.65 (t, J=5.7Hz, 2H), 2.70-2.60 (m, 2H), 2.47 (d, J=6.9Hz, 1H), 1.48 (d, J=2.5Hz, 9H)； LC-MS(ESI):m/z 316.2[M+Na]⁺。

The chloro- 2- of 5- (tertiary fourth oxygen formoxyl -4,5- dihydro-thiophene [2,3-c] pyridine -2- base of 5-) pyrroles [1,2-b] pyridazine - The preparation method of 7- methyl formate (compound 63)

Compound 62 (228 milligrams, 0,78mmol), compound 6 (50 milligrams, 0.16mmol), Pd (OAc)₂(8 milligrams), CuI (1 milligram) and (460 milligrams) of DBU are raw material, and the preparation method of reference compound 57 obtains 20 milligrams of yellow solid, are received Rate 28%.

¹H NMR(300MHz,CDCl₃) δ 7.84 (d, J=9.4Hz, 1H), 7.41 (d, J=0.6Hz, 1H), 7.35 (s, 1H), 7.17 (d, J=9.4Hz, 1H), 4.65 (s, 2H), 3.95 (s, 3H), 3.75-3.64 (m, 2H), 2.73 (t, J= 5.6Hz,2H),1.49(s,9H)；LC-MS(ESI):m/z 448.2[M+H]⁺。

The chloro- 2- of 5- (4,5- dihydro-thiophene [2,3-c] pyridine -2- base) pyrroles [1,2-b] pyridazine -7- methyl formate (chemical combination Object 64) preparation method

(450 milligrams, 1mmol) of compound 63 are raw material, and the preparation method of reference compound 59 obtains yellow solid 310 Milligram, yield 89%.

LC-MS(ESI):m/z 348.2[M+H]⁺。

The chloro- 2- of 5- (4,5- dihydro-thiophene [2,3-c] pyridine -2- base) pyrroles [1,2-b] pyridazine -7- formamide (compound I-34 preparation method)

(310 milligrams, 0.9mmol) of compound 64 are raw material, and it is solid to obtain yellow for the preparation method of reference compound I-32 210 milligrams of body, yield 70%.

¹H NMR(300MHz,CDCl₃) δ 7.73 (d, J=9.5Hz, 1H), 7.25 (s, 1H), 7.20 (s, 1H), 7.04 (d, J=9.5Hz, 1H), 3.96 (s, 2H), 3.05 (t, J=5.8Hz 2H), 2.64 (t, J=5.8Hz, 2H)；LC-MS (ESI):m/z 333.2[M+H]⁺。

The chloro- 2- of 5- (6- methyl -4,5- dihydro-thiophene [2,3-c] pyridine -2- base) pyrroles [1,2-b] pyridazine -7- formamide The preparation method of (compound I-35)

(75 milligrams, 0.21mmol) of compound I-34 are raw material, and the preparation method of reference compound I-33 obtains yellow 54 milligrams of solid, yield 74%.

¹H NMR(300MHz,DMSO-d₆) δ 8.21 (d, J=9.5Hz, 1H), 7.87 (d, J=2.0Hz, 1H), 7.59 (d, J=9.5Hz, 1H), 7.45 (s, 1H), 4.49 (s, 2H), 3.49 (d, J=5.1Hz, 2H), 3.00 (d, J=6.0Hz, 2H),2.92(s,3H)；LC-MS(ESI):m/z 347.2[M+H]⁺。

The preparation method of 7- tert-butyl -4,5- dihydro-thiophene [2,3-c] pyridine (compound 65)

25 milli of methylene chloride of the hydrochloride (500 milligrams, 3.7mmol, buy in skychemical) of 3- thiophene ethamine In liter, 1.5 milliliters of triethylamine and pivaloyl chloride (665 milligrams, 5.5mmol) are added, stir 1 hour at room temperature, methanol 5 is added Milliliter continues stirring after ten minutes, is concentrated to get grease, is crude product N- (2- (thiene-3-yl) ethyl) pivaloyl amine, LC- MS(ESI):m/z 212(M+H).POCl is added into above-mentioned grease₃3 milliliters, and with 65 DEG C at stir 3 hours, to cold But to after room temperature, solvent is removed under reduced pressure, is then added 10 milliliters of mixture of ice and water, adjusts pH value to 7, most with NaOH (2.5M) It is extracted afterwards with ethyl acetate (20 milliliters × 2), anhydrous sodium sulfate is dry, and solvent is removed under reduced pressure, and obtains 580 milli of colorless oil Gram, two step yields 97%.

LC-MS(ESI):m/z 194[M+H]⁺。

Bromo- 7- tert-butyl -4,5- dihydro-thiophene [2,3-c] pyridine -6 (7H) of 2--t-butyl formate (compound 66) system Preparation Method

Into 5 milliliters of anhydrous methanol of compound 65 (580 milligrams, 3mmol), point 2 addition NaBH₄(240 milligrams, 6.3mmol), it is stirred at room temperature 2 hours, then decompression is spin-dried for solvent, and 10 milliliters of ethyl acetate and saturated sodium chloride solution 10 is added Milliliter isolates organic phase, and aqueous layer with ethyl acetate extraction, anhydrous sodium sulfate is dry, is concentrated to get 510 milligrams of grease, is Crude product 7- tert-butyl -4,5,6,7- thiophanes [2,3-c] pyridine, LC-MS (ESI): m/z 196 (M+H)；Toward above-mentioned oily 10 milliliters of methylene chloride are added in object, methylene chloride (5 millis of 0.5 milliliter of triethylamine and Boc acid anhydrides (654 milligrams, 3mmol) Rise) solution, stirs 1 hour at room temperature, ammonium chloride solution is then added, continue stirring 10 minutes, isolate organic phase, water layer It is extracted with dichloromethane, merges organic phase, be concentrated to get 950 milligrams of grease；30 milliliters of acetonitrile of the addition into grease, then It is added NBS (590 milligrams), stirs 1 hour at room temperature, concentration, column chromatography (petroleum ether: ethyl acetate=50:1) affords 1.0 grams of colorless oil, three step total recoverys 84%.

LC-MS(ESI):m/z 396.2[M+Na]⁺。

2- formoxyl -7- tert-butyl -4,5- dihydro-thiophene [2,3-c] pyridine -6 (7H)-t-butyl formate (compound 67) Preparation method

With (1.0 grams, 2.7mmol) of compound 66 for raw material, the preparation method of reference compound 61 obtains yellow oily 450 milligrams of object, yield 52%.

¹H NMR(300MHz,CDCl₃) δ 9.85 (d, J=4.7Hz, 1H), 7.52-7.44 (m, 1H), 5.10 (d, J= 62.0Hz,1H),4.57-4.19(m,1H),3.33-3.07(m,1H),2.86-2.55(m, 2H),1.47(s,9H),1.09 (s,9H)；LC-MS(ESI):m/z 324[M+H]⁺。

2- (1- hydroxyl-propine -2- base) -7- tert-butyl -4,5- dihydro-thiophene [2,3-c] pyridine -6 (7H)-tertiary fourth of formic acid The preparation method of ester (compound 68)

The THF solution (0.5M, 5 milliliters) of compound 67 (420 milligrams, 1.3mmol) and acetenyl magnesium bromide is raw material, The preparation method of reference compound 56 obtains 330 milligrams of yellow oil, yield 73%.

¹H NMR(300MHz,CDCl₃) δ 6.90 (dd, J=6.8,2.9Hz, 1H), 5.62-5.56 (m, 1H), 5.14- 4.87(m,1H),4.53-4.12(m,1H),3.30-3.10(m,1H),2.78-2.39(m, 3H),1.45(s,9H),1.08 (s,9H)；LC-MS(ESI):m/z 372.2[M+Na]⁺。

The chloro- 2- of 5- (6- tert-butoxy formoxyl -7- tert-butyl -4,5- dihydro-thiophene [2,3-c] pyridine -2- base) pyrroles The preparation method of [1,2-b] pyridazine -7- methyl formate (compound 69)

Compound 68 (320 milligrams, 0.9mmol), compound 6 (170 milligrams, 0.6mmol), Pd (OAc)₂(7 milligrams), CuI (1 milligram) and (900 milligrams) of DBU are raw material, and the preparation method of reference compound 62 obtains 90 milligrams of yellow solid, are received Rate 30%.

¹H NMR(300MHz,CDCl₃) δ 7.89-7.80 (m, 1H), 7.42 (s, 1H), 7.39 (d, J=6.0 Hz, 1H), 7.19 (dd, J=9.4,3.9Hz, 1H), 5.10 (d, J=53.8Hz, 1H), 4.60-4.14 (m, 1H), 3.95 (s, 3H), 3.35-3.15(m,1H),2.80-2.60(m,2H),1.47(s,9H),1.13(s,9H)； LC-MS(ESI):m/z 504.2[M +H]⁺。

2- (7- tert-butyl -4,5,6,7- thiophane [2,3-c] pyridine -2- base) -5- chloro- pyrroles [1,2-b] pyridazine -7- The preparation method of methyl formate (compound 70)

(90 milligrams, 0.18mmol) of compound 69 are raw material, and the preparation method of reference compound 64 obtains yellow solid 65 milligrams, yield 89%.

¹H NMR(300MHz,CDCl₃) δ 7.84 (d, J=9.4Hz, 1H), 7.44-7.37 (m, 2H), 7.20 (d, J= 9.5Hz,1H),3.96(s,3H),3.40-3.26(m,1H),2.97-2.81(m,1H),2.70- 2.61(m,2H),2.52(s, 1H),2.06-1.93(m,1H),1.14(s,9H)；LC-MS(ESI):m/z 404.2[M+H]⁺。

2- (7- tert-butyl -4,5,6,7- thiophane [2,3-c] pyridine -2- base) -5- chloro- pyrroles [1,2-b] pyridazine -7- The preparation method of formamide (compound I-36)

(65 milligrams, 0.17mmol) of compound 70 are raw material, and it is solid to obtain yellow for the preparation method of reference compound I-32 40 milligrams of body, yield 64%.

1H NMR(300MHz,CD₃OD) δ 7.98 (d, J=9.5Hz, 1H), 7.77 (s, 1H), 7.77 (s, 1H), 7.49 (s, 1H), 7.43 (s, 1H), 7.38 (d, J=9.5Hz, 1H), 3.86-3.84 (m, 1H), 3.37- 3.34 (m, 1H), 2.92- 2.82(m,1H),2.75-2.63(m,2H),1.13(s,9H)；LC-MS(ESI): m/z 389.2[M+H]⁺。

The preparation method of 7- isobutyl group -4,5- dihydro-thiophene [2,3-c] pyridine (compound 71)

3- thiophene ethamine hydrochloride (500 milligrams, 3.1mmol) and (445 milligrams, 3.7mmol) of isoveryl chloride are raw material, The preparation method of reference compound 65 obtains 560 milligrams of colorless oil, two step total recoverys 93%.

LC-MS(ESI):m/z 194[M+H]⁺。

Bromo- 7- isobutyl group -4,5- dihydro-thiophene [2,3-c] pyridine -6 (7H) of 2--t-butyl formate (compound 72) system Preparation Method

(560 milligrams, 2.9mmol) of compound 71 are raw material, and the preparation method of reference compound 66 obtains colorless oil 895 milligrams of object, yield 83%.

¹H NMR(300MHz,CDCl₃) δ 6.71 (s, 1H), 5.18 (d, J=57.9Hz, 1H), 4.36- 3.98 (m, 1H), 3.11-2.93(m,1H),2.74-2.55(m,1H),2.52-2.43(m,1H),1.78- 1.67(m,3H),1.47(s,9H), 1.02 (d, J=6.2Hz, 3H), 0.95 (d, J=6.3Hz, 3H)；LC-MS (ESI):m/z 374.2[M+H]⁺。

2- formoxyl -7- isobutyl group -4,5- dihydro-thiophene [2,3-c] pyridine -6 (7H)-t-butyl formate (compound 73) Preparation method

(866 milligrams, 2.3mmol) of compound 72 are raw material, and the preparation method of reference compound 61 obtains colorless oil 375 milligrams of object, yield 50%.

¹H NMR(300MHz,CDCl₃) 9.83 (s, 1H), 7.44 (s, 1H), 5.36 (d, J=61.8Hz, 1H), 4.28 (d, J=59.6Hz, 1H), 3.10-2.95 (m, 1H), 2.85-2.70 (m, 1H), 2.66-2.57 (m, 1H), 1.85-1.69 (m, 3H), 1.52-1.43 (m, 9H), 1.05 (d, J=6.3Hz, 3H), 0.97 (d, J=6.4Hz, 3H)；LC-MS(ESI):m/ z 324.2[M+H]⁺。

2- (1- hydroxyl-propine -2- base) -7- isobutyl group -4,5- dihydro-thiophene [2,3-c] pyridine -6 (7H)-tertiary fourth of formic acid The preparation method of ester (compound 74)

The THF solution (0.5M, 3.5 mL) of compound 73 (370 milligrams, 1.2mmol) and acetenyl magnesium bromide is raw material, The preparation method of reference compound 56 obtains 330 milligrams of yellow oil, yield 79%.

1H NMR(300MHz,CDCl₃) δ 6.86 (s, 1H), 5.57 (d, J=6.6Hz, 1H), 5.47-5.09 (m, 1H), 4.44-4.02(m,1H),3.11-2.95(m,1H),2.76-2.65(m,2H),2.55-2.45(m, 1H),2.40-2.35(m, 1H), 1.84-1.63 (m, 2H), 1.47 (s, 9H), 1.03 (d, J=6.3Hz, 3H), 0.96 (d, J=6.3Hz, 3H)；LC-MS (ESI):m/z 350.2[M+H]⁺。

2- (6- tert-butoxy formoxyl -7- isobutyl group -4,5- dihydro-thiophene [2,3-c] pyridine -2- base) pyrroles [1,2-b] The preparation method of pyridazine -7- methyl formate (compound 75)

Compound 74 (330 milligrams, 0.95mmol), compound 6 (180 milligrams, 0.6mmol), Pd (OAc)₂(7 milligrams), CuI (1 milligram) and (654 milligrams) of DBU are raw material, and the preparation method of reference compound 62 obtains 165 milligrams of yellow solid, are received Rate 55%.LC-MS(ESI):m/z 504.2[M+H]⁺。

2- (7- isobutyl group -4,5,6,7- thiophane [2,3-c] pyridine -2- base) -5- chloro- pyrroles [1,2-b] pyridazine -7- The preparation method of methyl formate (compound 76)

(100 milligrams, 0.2mmol) of compound 75 are raw material, and the preparation method of reference compound 59 obtains yellow solid 65 milligrams, yield 80%.LC-MS(ESI):m/z 404.2[M+H]⁺。

2- (7- isobutyl group -4,5,6,7- thiophane [2,3-c] pyridine -2- base) -5- chloro- pyrroles [1,2-b] pyridazine -7- The preparation method of formamide (compound I-37)

(65 milligrams, 0.17mmol) of compound 76 are raw material, and it is solid to obtain yellow for the preparation method of reference compound I-32 40 milligrams of body, yield 61%.

¹H NMR(300MHz,CD₃OD) δ 7.97 (dd, J=9.5,1.7Hz, 1H), 7.67 (d, J=1.8 Hz, 1H), 7.45 (t, J=2.2Hz, 1H), 7.35 (dd, J=9.5,1.7Hz, 1H), 4.10-4.03 (m, 1H), 3.00-2.90 (m, 1H),2.77-2.62(m,2H),2.06-1.86(m,2H),1.70-1.60(m,2H), 1.03-0.98(m,6H)；LC-MS (ESI):m/z 389.2[M+H]⁺。

The preparation method of 4- cyclopropyl -6,7- dihydro-thiophene [3,2-c] pyridine (compound 77)

2 thiophene ethyl amine (1.3 grams, 10mmol, the splendid remote chemistry of desire to buy) and Cyclopropyl carbonyl chloride (1.3 grams, It 12.4mmol) is raw material, the preparation method of reference compound 65 obtains 1.2 grams of crude products of colorless oil.

LC-MS(ESI):m/z 178.2[M+H]⁺。

The preparation side of 4- cyclopropyl -6,7- dihydro-thiophene [3,2-c] pyridine -5 (4H)-t-butyl formate (compound 78) Method

In the anhydrous methanol 15mL of compound 77 (1.2 grams, 7.0mmol), it is added three times NaBH₄(520 milligrams, 13.7mmol), it stirs 2 hours at room temperature, solvent is removed under reduced pressure, be added 20 milliliters and 10 milliliters of water of ethyl acetate, isolated Machine phase, 40 milliliters of aqueous layer with ethyl acetate extractions merge organic phase, and saturated common salt water washing, anhydrous sodium sulfate is dry, concentration Obtain colorless oil.The addition methylene chloride 50mL into above-mentioned grease, triethylamine 2mL and Boc acid anhydrides (2.6 grams, Dichloromethane solution 11.8mmol) stirs 2 hours at room temperature, is added 10 milliliters of saturated ammonium chloride solution, continues stirring 15 Minute, organic phase is isolated, water layer is extracted with dichloromethane, and merges organic phase, saturated common salt water washing, concentration, column chromatography 1.3 grams of colorless oil are obtained, two step total recoverys 59%.

¹H NMR(300MHz,CDCl₃) δ 7.09 (d, J=5.2Hz, 1H), 6.90 (d, J=5.2Hz, 1H), 4.55- 4.32 (m, 2H), 3.30-3.15 (m, 1H), 2.95-2.81 (m, 1H), 2.77-2.68 (m, 1H), 1.46 (d, J=1.1Hz, 9H),1.18-1.05(m,1H),0.69-0.62(m,2H),0.58-0.39(m, 2H)；LC-MS(ESI):m/z 302.2[M+ Na]⁺。

2- formoxyl -4- cyclopropyl -6,7- dihydro-thiophene [3,2-c] pyridine -5 (4H)-t-butyl formate (compound 79) Preparation method

(665 milligrams, 2.3mmol) of compound 78 are raw material, and the preparation method of reference compound 55 obtains yellow oily 260 milligrams of object, yield 36%.

¹H NMR(300MHz,CDCl₃)δ9.83(s,1H),7.59(s,1H),4.46(s,2H),3.22(s, 1H), 3.04-2.66(m,2H),1.47(s,9H),1.20-1.05(m,1H),0.82-0.21(m,4H)； LC-MS(ESI):m/z 308[M+H]⁺。

2- (1- hydroxyl-propine -2- base) -4- cyclopropyl -6,7- dihydro-thiophene [3,2-c] pyridine -5 (4H)-tertiary fourth of formic acid The preparation method of ester (compound 80)

The THF solution (0.5M, 3 milliliters) of compound 79 (260 milligrams, 0.85mmol) and acetenyl magnesium bromide is raw material, The preparation method of reference compound 57 obtains 200 milligrams of yellow oil, yield 71%.

¹H NMR(300MHz,CDCl₃) δ 6.98 (d, J=5.3Hz, 1H), 5.60 (dd, J=9.1,6.6Hz, 1H), 4.50-4.25 (m, 2H), 3.29-3.10 (m, 1H), 2.94-2.56 (m, 2H), 2.39 (dd, J=6.8,5.3Hz, 1H), 1.46(s,9H),1.20-1.02(m,1H),0.93-0.75(m,2H),0.71-0.41(m, 2H)；LC-MS(ESI):m/z 356.2[M+Na]⁺。

2- (4- cyclopropyl -5- tert-butoxy formoxyl -6,7- dihydro-thiophene [3,2-c] pyridine -2- base) the chloro- pyrroles of -5- The preparation method of [1,2-b] pyridazine -7- methyl formate (compound 81)

Compound 80 (200 milligrams, 0.6mmol), compound 6 (120 milligrams, 0.4mmol), Pd (OAc)₂(6 milligrams), CuI (1 milligram) and (304 milligrams) of DBU are raw material, and the preparation method of reference compound 58 obtains 80 milligrams of yellow oil, Yield 41%.

LC-MS(ESI):m/z 488.2[M+H]⁺。

2- (4- cyclopropyl -4,5,6,7- thiophane [3,2-c] pyridine -2- base) -5- chloro- pyrroles [1,2-b] pyridazine -7- The preparation method of formamide (compound I-38)

In the methylene chloride of compound 81 (80 milligrams, 0.17mmol), 2 milliliters of trifluoroacetic acid are added, stirs 1 at room temperature After hour, adjusting pH value with NaOH (2.5M) under ice bath is 8~9, isolates organic phase, and water layer chloroform extraction merges Organic phase, saturated sodium chloride solution washing, concentration, column chromatography (methylene chloride: methanol=20:1) afford yellow solid. With being transferred in 25mL tube sealing after the dissolution of 10mL methanol, is reacted 24 hours at 90 DEG C, be cooled to room temperature, decompression spins off 2/3 body Product solvent, is obtained by filtration 35 milligrams of yellow solid, yield 56%.

1H NMR (300MHz, DMSO-d6) δ 8.18 (d, J=9.5Hz, 1H), 8.07 (s, 2H), 7.89 (s, 1H), 7.68 (d, J=9.5Hz, 1H), 7.44 (s, 1H), 3.58-3.46 (m, 2H), 3.25-3.15 (m, 1H), 3.09-3.01 (m, 2H),1.21-1.06(m,1H),0.90-0.70(m,2H),0.68-0.58(m,2H)； LC-MS(ESI):m/z 373.2[M+ H]⁺。

The preparation method of 4- isobutyl group -6,7- dihydro-thiophene [3,2-c] pyridine (compound 82)

2 thiophene ethyl amine (500 milligrams, 4mmol) and (576 milligrams, 4.8mmol) of isoveryl chloride are raw material, referring to chemical combination The preparation method of object 65 obtains 700 milligrams of colorless oil, yield 91%.

LC-MS(ESI):m/z 194(M+H)。

Bromo- 4- isobutyl group -6,7- dihydro-thiophene [3,2-c] pyridine -5 (4H) of 2--t-butyl formate (compound 83) system Preparation Method

(500 milligrams, 2.6mmol) of compound 82 are raw material, and the preparation method of reference compound 66 obtains colorless oil 750 milligrams of object, yield 78%.

¹H NMR(300MHz,CDCl₃)δ6.71(s,1H),5.23-4.94(m,1H),4.48-4.07(m, 1H),3.17- 2.95(m,1H),2.88-2.72(m,1H),2.64-2.47(m,1H),1.76-1.62(m, 3H),1.46(s,9H),1.03 (d, J=6.4Hz, 3H), 0.93 (d, J=6.5Hz, 3H)；LC-MS(ESI): m/z 374.2[M+H]⁺。

2- formoxyl -4- isobutyl group -6,7- dihydro-thiophene [3,2-c] pyridine -5 (4H)-t-butyl formate (compound 84) Preparation method

(750 milligrams, 2mmol) of compound 83 are raw material, and the preparation method of reference compound 61 obtains colorless oil 300 milligrams, yield 46%.

¹H NMR(300MHz,CDCl₃) δ 9.82 (s, 1H), 7.45 (s, 1H), 5.24 (d, J=57.1Hz, 1H), 4.35 (d, J=62.4Hz, 1H), 3.23-2.72 (m, 3H), 1.80-1.60 (m, 3H), 1.48 (s, 9H), 1.07 (d, J=6.3Hz, 3H), 0.97 (d, J=6.5Hz, 3H)；LC-MS(ESI):m/z 324.2[M+H]⁺。

2- (1- hydroxyl-propine -2- base) -4- isobutyl group -6,7- dihydro-thiophene [3,2-c] pyridine -5 (4H)-tertiary fourth of formic acid The preparation method of ester (compound 85)

The THF solution (0.5M, 3.5 milliliters) of compound 84 (300 milligrams, 0.93mmol) and acetenyl magnesium bromide is original Material, the preparation method of reference compound 57 obtain 280 milligrams of yellow oil, yield 86%.

1H NMR(300MHz,CDCl₃) δ 6.88-6.81 (d, J=2.4Hz, 1H), 5.57 (d, J=6.6 Hz, 1H), 5.12 (d, J=52.5Hz, 1H), 4.47-4.16 (m, 1H), 3.17-2.59 (m, 3H), 2.38- 2.31 (m, 1H), 1.74- 1.59 (m, 3H), 1.46 (s, 9H), 1.05 (d, J=6.3Hz, 3H), 0.94 (d, J=6.5Hz, 3H)；LC-MS(ESI):m/z 372.2[M+Na]⁺。

2- (4- isobutyl group -5- tert-butoxy formoxyl -6,7- dihydro-thiophene [3,2-c] pyridine -2- base) pyrroles [1,2-b] The preparation method of pyridazine -7- methyl formate (compound 86)

Compound 85 (280 milligrams, 0.8mmol), compound 6 (141 milligrams, 0.46mmol), Pd (OAc)₂(16 millis Gram), CuI (1 milligram) and (350 milligrams) of DBU are raw material, and the preparation method of reference compound 58 obtains 81 milli of yellow oil Gram, yield 35%.

1H NMR(300MHz,CDCl₃)δ7.86-7.80(m,1H),7.41(s,1H),7.36-7.27(m, 1H),7.18 (d, J=9.2Hz, 1H), 4.48-4.30 (m, 1H), 3.95 (s, 3H), 3.16-2.88 (m, 3H), 2.78-2.68 (m, 1H), 2.06-1.94 (m, 1H), 1.78-1.66 (m, 2H), 1.48 (s, 9H), 1.09 (d, J=5.8Hz, 3H), 0.97 (d, J= 5.8Hz,3H)；LC-MS(ESI):m/z 504.2[M+H]⁺。

2- (4- isobutyl group -4,5,6,7- thiophane [3,2-c] pyridine -2- base) -5- chloro- pyrroles [1,2-b] pyridazine -7- The preparation method of formamide (compound I-39)

(80 milligrams, 0.16mmol) of compound 86 are raw material, and it is solid to obtain yellow for the preparation method of reference compound I-38 35 milligrams of body, yield 56%.

¹H NMR(300MHz,DMSO-d₆) δ 8.20 (d, J=9.5Hz, 1H), 8.07 (d, J=3.9Hz, 2H), 7.92 (s, 1H), 7.66 (d, J=9.6Hz, 1H), 7.43 (s, 1H), 4.31 (d, J=8.2Hz, 1H), 3.45-3.15 (m, 2H), 3.08-2.99 (m, 2H), 2.02-1.94 (m, 1H), 1.90-1.67 (m, 2H), 1.01 (d, J=6.2Hz, 3H), 0.96 (d, J =6.4Hz, 3H)；LC-MS(ESI):m/z 389.2[M+H]⁺。

The preparation method of 4- tert-butyl -6,7- dihydro-thiophene [3,2-c] pyridine (compound 87)

2 thiophene ethyl amine (1.5 grams, 11.8mmol) and (2.1 grams, 4.8mmol) of isoveryl chloride are raw material, reference compound 65 preparation method obtains 1300 milligrams of colorless oil, yield 57%.LC-MS(ESI): m/z 194.2[M+H]⁺。

The preparation side of 4- tert-butyl -6,7- dihydro-thiophene [3,2-c] pyridine -5 (4H)-t-butyl formate (compound 88) Method

Into the ethyl alcohol (40mL) of compound 87 (1.3 grams, 6.7mmol), NaBH is added in two portions₄(500 milligrams), room Temperature lower stirring 1 hour, concentration was added water 10mL and ethyl acetate 20mL, isolates organic phase, aqueous layer with ethyl acetate 10mL Extraction merges organic phase, and anhydrous sodium sulfate is dry, is concentrated to get grease, is directly used in next step；Into above-mentioned grease Methylene chloride 20mL is added, and is added dropwise to NEt respectively₃0.5mL and Boc₂The methylene chloride of acid anhydrides (1.5 grams, 6.9mmol) 8mL is stirred 1 hour at room temperature, and concentration, column chromatography (petroleum ether: ethyl acetate=100:1) affords 1.5 grams of grease, Two step total recoverys 75%.

¹H NMR(300MHz,CDCl₃) δ 7.08 (dd, J=10.3,5.3Hz, 1H), 6.91 (d, J=5.2 Hz, 1H), 4.96 (d, J=50.4Hz, 1H), 4.41 (ddd, J=70.1,13.8,6.3Hz, 1H), 3.45-3.17 (m, 1H), 2.97- 2.66(m,2H),1.47-1.43(s,9H),1.03(s,9H)；LC-MS(ESI):m/z 318.2[M+Na]⁺。

2- formoxyl -4- tert-butyl -6,7- dihydro-thiophene [3,2-c] pyridine -5 (4H)-t-butyl formate (compound 89) Preparation method

With (700 milligrams, 2.4mmol) of compound 88 for raw material, the preparation method of reference compound 55 obtains yellow oily 250 milligrams of object, yield 32%.

¹H NMR(300MHz,CDCl₃) δ 9.84 (s, 1H), 7.60 (s, 1H), 5.00 (d, J=57.3Hz, 1H), 4.45 (ddd, J=69.2,14.2,6.3Hz, 1H), 3.48-3.22 (m, 1H), 2.99-2.68 (m, 2H), 1.47 (s, 9H), 1.05 (s,9H)；LC-MS(ESI):m/z 324.2[M+H]⁺。

2- (1- hydroxyl-propine -2- base) -4- tert-butyl -6,7- dihydro-thiophene [3,2-c] pyridine -5 (4H)-tertiary fourth of formic acid The preparation method of ester (compound 90)

With (250 milligrams, 0.85mmol) of compound 89 for raw material, the preparation method of reference compound 57 obtains grease 140 milligrams, yield 35%.

¹H NMR(300MHz,CDCl₃) δ 7.00 (s, 1H), 5.59 (d, J=6.0Hz, 1H), 4.90 (d, J=50.2Hz, 1H), 4.39 (ddd, J=69.4,13.7,6.3Hz, 1H), 3.44-3.17 (m, 1H), 2.93-2.75 (m, 1H), 2.74- 2.63(m,2H),2.53-2.39(m,1H),1.45(s,9H),1.03(s,9H)；LC-MS (ESI):m/z 372.2[M+Na ]⁺。

2- (4- tert-butyl -5- tert-butoxy formoxyl -6,7- dihydro-thiophene [3,2-c] pyridine -2- base) pyrroles [1,2-b] The preparation method of pyridazine -7- methyl formate (compound 91)

With compound 90 (140 milligrams, 0.4mmol), compound 6 (75 milligrams, 0.25mmol), Pd (OAc)₂(3 millis Gram), CuI (1 milligram) and (190 milligrams) of DBU are raw material, obtain 73 milligrams of yellow solid, yield 56%.

¹H NMR(300MHz,CDCl₃) δ 7.87-7.81 (m, 1H), 7.48-7.37 (m, 2H), 7.19 (dd, J=9.5, 4.9Hz, 1H), 4.99 (d, J=50.9Hz, 1H), 4.42 (d, J=66.6Hz, 1H), 3.95 (s, 3H), 3.45-3.28 (m, 1H),2.96-2.74(m,2H),1.48(s,9H),1.08(s,9H)；LC-MS(ESI): m/z 504.2[M+H]⁺。

2- (4- tert-butyl -4,5,6,7- thiophane [3,2-c] pyridine -2- base) -5- chloro- pyrroles [1,2-b] pyridazine -7- The preparation method of formamide (compound I-40)

With (70 milligrams, 0.14mmol) of compound 91 for raw material, the preparation method of reference compound I-38 obtains yellow 35 milligrams of solid, yield 64%.

¹H NMR(300MHz,DMSO-d₆)δ8.19-8.10(m,2H),8.05(s,1H),7.78(s,1H), 7.68(d,J =9.5Hz, 1H), 7.42 (s, 1H), 3.65 (s, 1H), 3.20 (d, J=7.8Hz, 1H), 2.72 (d, J=4.9Hz, 3H), 0.99(s,9H)；LC-MS(ESI):m/z 388.2[M+H]⁺。

Active testing part

It is active to PARP-1 and PARP-2 in molecular level that the compound of the present invention is tested by following pharmacological evaluation Inhibiting effect

1, ELISA method tests the compound of the present invention in molecular level to the active inhibiting effect of PARP-1 and PARP-2

Experimental method: enzyme linked immunosorbent assay (Enzyme-Linked Immunosorbent Assay, ELISA) (ginseng The enzyme linked immunosorbent assay of document record is delivered according to Decker P.；Bibliography: Decker P, Miranda EA, de Murcia G, Muller S.An Improved nonisotopic test to screen a large series of new inhibitor molecules of Poly(ADP-ribose)Polymerase activity for therapeutic applications.Clinical Cancer Research, 5:1169-1172,1999).Its principle is Substrate histone is coated on 96 orifice plate of adsorptivity, PARP-1 or 2 recombinases, substrate NAD are added⁺, activation DNA make Enzyme reaction occurs for PARP-1 or 2, so that histone is generated product PAR (poly- adenosine diphosphate ribose), anti-PAR is then added (anti-PAR) antibody, detect on 96 orifice plates product PAR on coated histone intensity, so that it may reflect PARP Enzymatic activity.

The calculating of Drug inhibition rate: inhibiting rate (%)=(OD control wells-OD dosing holes)/OD control wells × 100% (OD For absorbance value)；And drug concentration when reaching 50% inhibition, i.e. IC are calculated by Logit method according to inhibiting rate₅₀Value.(dividing The horizontal IC of son₅₀<1000nM,+；<500nM,++；<100nM,+++；It is > 1000nM or undetermined), the results are shown in Table 1:

2, test result

From table 1, it can be found that the compound in the present invention has significant inhibitory activity to PARP-1 and PARP-2.

1. part of compounds of table is in molecular level to the active inhibiting effect of PARP-1 and PARP-2

Growth inhibition effect of the 3.I-34 to human breast carcinoma MDA-MB-436 nude mouse subcutaneous transplantation tumor

Tested material and positive control drug

Mono-hydrochloric salts are made in compound I-34, are yellow powder, dissolve yellowly troubled liquor with water for injection, stand After have precipitating, mixed well before administration, the above compound is prepared weekly once.Positive control medicine AZD2281 (anticancer drug Olaparib olaparib) it is pale yellow powder (Lot:PAR-105), it is configured to mix with 0.5% sodium carboxymethylcellulose weekly It is used after suspension.

Dosage setting

I-34 hydrochloride is respectively provided with two dosage groups, respectively 100mg/kg and 20mg/kg group.Positive control medicine AZD2281 dosage is 30mg/kg.

Experimental animal and inoculating cell

BALB/cA nude mouse, female, 4-5 week old, 19 ± 2g of weight are mentioned by Shanghai Pharmaceutical Inst., Chinese Academy of Sciences For production licence number: SCXK (Shanghai) 2013-001.It is numbered using the quality certification: SYXK (Shanghai) 2013-0049.Every group of animal Number: negative control group 12, administration group 6.Human breast carcinoma MDA-MB-436 cell strain is saved by my room.It is connect with the cell strain Armpit is subcutaneous on the right side of kind nude mouse, and cell inoculation amount is 5 × 106/, after passing for 2 generations in nude mice again after formation transplantable tumor It uses.

Experimental method

The tumor tissue of growth animated period is taken to cut into 1.5mm³Left and right is aseptically inoculated in armpit on the right side of nude mouse Nest is subcutaneous.Nude mouse subcutaneous transplantation tumor vernier caliper measurement transplantable tumor diameter, grows to 200mm to tumor average volume³It is left Behind the right side, animal is grouped at random.Compound I-34 hydrochloride 100mg/kg and 20mg/kg group, once a day oral administration, even Continuous administration 21 days.Positive control medicine AZD2281 30mg/kg, once a day oral administration, successive administration 21 days.Solvent control Give equivalent water for injection.In whole experiment process, transplantable tumor diameter is measured 2 times a week, while weighing mouse weight.Tumour body The calculation formula of product (tumor volume, TV) are as follows: TV=1/2 × a × b², wherein a, b respectively indicate length and width.According to measurement Result calculate relative tumour volume (relative tumor volume, RTV), calculation formula are as follows: RTV=V_t/V₀.Its Middle V₀(d when for sub-cage administration₀) measurement gained gross tumor volume, V_tGross tumor volume when to measure each time.Anti-tumor activity Evaluation index be (1) Relative tumor proliferation rate T/C (%), calculation formula is as follows: T/C (%)=(T_RTV/C_RTV) × 100%, T_RTV: treatment group RTV；C_RTV: negative control group RTV；(2) gross tumor volume growth inhibition rate GI%, calculation formula are as follows:

GI%=[1- (TVt-TV₀)/(CVt-CV₀)] × 100%, TVt be treatment group measure every time knurl product；TV₀For Gained knurl product when treatment group's sub-cage administration；CVt is the knurl product that control group measures every time；CV₀When for control group sub-cage administration Gained knurl product；(3) tumor-like hyperplasia, calculation formula are as follows: tumor-like hyperplasia %=(Wc-W_T)/Wc × 100%, Wc: right According to a group knurl weight, W_T: treatment group's knurl weight.

To the result of the growth inhibition effect of human breast carcinoma MDA-MB-436 nude mouse subcutaneous transplantation tumor

Experimental result is as shown in table 2.

I-34 hydrochloride 100mg/kg and 20mg/kg group, once a day oral administration, successive administration 21 days, to human milk gland The growth of cancer MDA-MB-436 nude mouse subcutaneous transplantation tumor had highly significant inhibiting effect, in the 21st day gained T/C percentage Respectively 1.47% and 5.70%, and high dose group has a mouse tumor to subside completely.

AZD2281 30mg/kg, once a day oral administration are successive administration 21 days, naked to human breast carcinoma MDA-MB-436 The growth of mouse subcutaneous transplanting tumor has certain inhibiting effect, and gained T/C percentage is 51.41% within the 21st day.I-34 hydrochloride Activity is substantially better than AZD2281.

2. compound of table acts on the experimental therapy of human breast carcinoma MDA-MB-436 nude mouse subcutaneous transplantation tumor

T- examines (vs solvent control group), is tumor regression number of mice in p < 0.05**p < 0.001 * " () "

The embodiments described above only express several embodiments of the present invention, and the description thereof is more specific and detailed, but simultaneously Limitations on the scope of the patent of the present invention therefore cannot be interpreted as.It should be pointed out that for those of ordinary skill in the art For, without departing from the inventive concept of the premise, various modifications and improvements can be made, these belong to of the invention Protection scope.Therefore, the scope of protection of the patent of the invention shall be subject to the appended claims.

Claims (9)

1. a kind of pyrroles's [1,2-b] pyridazine compound or its officinal salt indicated by general formula I:

Wherein,

R¹For hydrogen, C_1-4Alkyl or halogen；

R²For

R³For hydrogen ,-C (=O) R⁶、-SO₂R⁷, substituted or unsubstituted C_1-4Alkyl or substituted or unsubstituted C_3-6Naphthenic base, In, the R⁶And R⁷It independently is substituted or unsubstituted C_1-4Alkyl, substituted or unsubstituted C_3-6Naphthenic base or substitution do not take The C in generation_6-10Aryl, the substitution are by selected from halogen, C_1-4At least one of alkyl, amino, itrile group, hydroxyl and nitro take Replace for base；

R⁴For hydrogen, halogen, C_1-4Alkyl or C_1-4Alkoxy；

R⁵For-CH₂Or-C=O；

X₁For S, O or NH；

X₂For CH or N；

Y₁、Y₂、Y₅And Y₆It independently is substituted or unsubstituted methylene, substituted or unsubstituted ethylidene, substituted or unsubstituted Propylidene or substituted or unsubstituted butylidene, the substitution is by selected from halogen, C_1-6Alkyl, C_3-6Naphthenic base and C_1-4Alkane At least one substituent group in oxygroup replaces；

Y₃And Y₄It independently is hydrogen, substituted or unsubstituted C_1-4Alkyl or substituted or unsubstituted C_3-6Naphthenic base, the substitution are It is selected from halogen, C_1-6Alkyl, C_3-6Naphthenic base and C_1-4At least one substituent group in alkoxy replaces；

Y₇For NR⁸Or CHR⁹,

Wherein, the R⁸For hydrogen ,-C (=O) R¹⁰、-SO₂R¹¹, substituted or unsubstituted C_1-4Alkyl, substituted or unsubstituted C_3-6 Naphthenic base or substituted or unsubstituted C_6-10Aryl, wherein the R¹⁰And R¹¹It independently is substituted or unsubstituted C_1-4Alkyl takes Generation or unsubstituted C_3-6Naphthenic base, it is substituted or unsubstituted five yuan to hexa-atomic saturated heterocyclyl or substituted or unsubstituted C_6-10 Aryl, the substitution are by selected from halogen, C_1-4Alkyl, C_1-4Halogenated alkyl, amino, by least one C_1-4Alkyl-substituted ammonia At least one substituent group in base, itrile group, hydroxyl and nitro replaces,

The R⁹For hydrogen ,-OR¹², by least one C_1-4Alkyl-substituted amino or it is substituted or unsubstituted five yuan to hexa-atomic full And heterocycle, wherein the R¹²For hydrogen, substituted or unsubstituted C_1-4Alkyl or substituted or unsubstituted C_3-6Naphthenic base, it is described to take Generation is by selected from halogen, C_1-4Alkyl, C_1-4Halogenated alkyl, amino, by least one C_1-4Alkyl-substituted amino, itrile group, hydroxyl Replace at least one substituent group in nitro.

2. pyrroles's [1,2-b] pyridazine compound according to claim 1 or its officinal salt, which is characterized in that in institute It states in general formula I,

R¹For hydrogen, methyl, ethyl, propyl, fluorine, chlorine or bromine；

R²For

R³For hydrogen, methyl, ethyl or propyl；

R⁴For hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxyl group, ethyoxyl or propoxyl group；

R⁵For-CH₂Or-C=O；

X₁For S, O or NH；

X₂For CH or N；

Y₁、Y₂、Y₅And Y₆It independently is substituted or unsubstituted methylene, substituted or unsubstituted ethylidene, substituted or unsubstituted Propylidene or substituted or unsubstituted butylidene, the substitution is by selected from fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl Base, normal-butyl, sec-butyl, isobutyl group, tert-butyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, methoxyl group, ethyoxyl or third At least one substituent group in oxygroup replaces；

Y₃And Y₄It independently is hydrogen, methyl, ethyl, propyl, isopropyl or butyl；

Y₇For NR⁸Or CHR⁹,

Wherein, the R⁸For hydrogen ,-C (=O) R¹⁰、-SO₂R¹¹, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, ring penta Base, cyclohexyl or substituted or unsubstituted phenyl, wherein the R¹⁰And R¹¹It independently is substituted or unsubstituted following group: Methyl, ethyl, propyl, isopropyl, normal-butyl, sec-butyl, isobutyl group, tert-butyl, cyclopropyl, cyclobutyl, cyclopenta, hexamethylene Base, pyrrolidinyl, tetrahydrofuran base, piperidyl, piperazinyl, morpholinyl, dioxane or phenyl, the substitution is to be selected from Fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, trifluoromethyl, amino, N- methylamino, N- ethylamino, N, N- dimethyl Amino, N, at least one substituent group in N- diethylamino, itrile group, hydroxyl and nitro replace,

The R⁹For hydrogen ,-OR¹², N- methylamino, N- ethylamino, N, N- dimethylamino, N, N- diethylamino, pyrroles Alkyl, tetrahydrofuran base, piperidyl, piperazinyl, morpholinyl or dioxane, wherein the R¹²For hydrogen, methyl, ethyl, third Base, isopropyl, cyclopropyl, cyclobutyl, cyclopenta or cyclohexyl, the substitution are by selected from fluorine, chlorine, bromine, methyl, ethyl, third Base, isopropyl, trifluoromethyl, amino, N- methylamino, N- ethylamino, N, N- dimethylamino, N, N- diethylamino, At least one substituent group in itrile group, hydroxyl and nitro replaces.

3. pyrroles's [1,2-b] pyridazine compound according to claim 1 or its officinal salt, which is characterized in that described Pyrroles's [1,2-b] pyridazine compound be one of following compounds:

4. [1,2-b] pyridazine compound of pyrroles described in any one of -3 or its officinal salt are being made according to claim 1 Purposes in standby PARP inhibitor.

5. pyrroles's [1,2-b] pyridazine compound according to claim 4 or its officinal salt are in preparation PARP inhibitor In purposes, which is characterized in that the PARP inhibitor to PARP-1 and/or PARP-2 have selective depression effect.

6. a kind of pharmaceutical composition, it includes any one of -3 institutes according to claim 1 of one or more therapeutically effective amounts Pyrroles's [1, the 2-b] pyridazine compound stated or its officinal salt, or comprising one or more therapeutically effective amounts according to power Benefit requires ester, prodrug, hydrate or the crystallization of pyrroles described in any one of 1-3 [1,2-b] pyridazine compound.

7. pharmaceutical composition according to claim 6, which is characterized in that described pharmaceutical composition, which has PARP, inhibits effect Fruit.

8. pharmaceutical composition according to claim 6, which is characterized in that described pharmaceutical composition to PARP-1 and/or PARP-2 has selective depression effect.

9. pharmaceutical composition according to claim 6, which is characterized in that described pharmaceutical composition is for preventing and/or controlling Treatment and PARP related disease, described and PARP related disease includes tumour, ischemic disease and neurodegenerative disease.