WO2019011217A1 - Pyrrolo[1,2-b]pyridazine compounds or pharmacologically acceptable salts thereof and use thereof - Google Patents

Abstract

Provided are pyrrolo[1,2-b]pyridazine compounds or pharmacologically acceptable salts thereof and use thereof. The pyrrolo[1,2-b]pyridazine compounds or pharmacologically acceptable salts thereof have inhibitory effects on poly(ADP-ribose) polymerase (PARP), and in particular, have selective inhibitory effects on PARP-1 and PARP-2 in a PARP family, and show good bioactivity both in vitro and in vivo, and therefore can be used as PARP inhibitors in pharmaceutical compositions for preventing and/or treating of PARP-related diseases, such as tumors, ischemic diseases, and neurodegenerative diseases.

Description

Pyrrole [1,2-b]pyridazines or pharmaceutically acceptable salts thereof and uses thereof Technical field

The present invention relates to the field of medicinal chemistry, and in particular to pyrrole [1,2-b]pyridazine compounds or pharmaceutically acceptable salts thereof and uses thereof.

Background technique

Poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) is a type of ribozyme that is found in most eukaryotic cells. Its main function is to cleave Nicotinamide adenine dinucleotide (NAD ⁺ ) into nicotinamide and ADP-ribose, and form long-chain or branched ADP-ribose polymer on the target protein. In order to regulate the function of proteins, these proteins include histones, topoisomerases 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). The ADP-ribosyltransferases (ARTs) currently have a total of 18 subtypes found and identified, of which only 6 subtypes have the ability to form poly ADP-ribosylation, which are PARP-1, PARP, respectively. - 2, PARP-3, PARP-4 (vPARP), PARP-5a (TNKS1) and PARP-5b (TNKS2); while other ARTs 7-17 subtypes (also commonly referred to as PARPs 6-16) only have formation The function of a single ADP-ribose modification. PARP-1 is the most abundant and widely studied member, playing more than 90% of the functions in the PARP family. Human PARP-1 is a polypeptide chain with a molecular weight of 113 kDa and consists of three major functional domains: a DNA binding domain (DBD) containing two zinc finger fingers at the amino (N)-terminus. ), an Automodification domain, and a Catalytic domain at the carboxyl (C)-terminus. Human PARP-2 is a polypeptide chain with a molecular weight of 62 kDa, which is structurally most similar to PARP-1. Its catalytic domain shares 69% homology with the catalytic domain of PARP-1 and the DNA binding domain does not contain zinc finger structure. (Amé, Jean-Christophe; Splenehauer, Catherine; de Murcia, Gilbert. The PARP superfamily. BioEssays 2004, 26, 882-893). PARP-1 and PARP-2 play an important role in DNA damage repair, genomic stability, and apoptosis regulation through base excision repair, making it one of the most important anti-tumor drug research targets in recent years (Yelamos, J.; Farres, Jordi.; Llacuna, Laura.; Ampurdanes, Coral; Martin-Caballero, Juan.; PARP-1 and PARP-2: New players in tumour development. Am. J. Cancer Res. 2011 1(3), 328-346; Weaver, AN; Yang, ESBeyond DNA repair: additional functions of PARP-1 in cancer. Front. Oncol. 2013, 3, 290).

Human DNA is caused by exogenous factors (such as ultraviolet radiation, particle radiation, alkylating agents, topoisomerase and platinum drugs) or endogenous factors (such as the spontaneous metabolism of human body and the chemical nature of DNA itself) Under the action of sexual reaction, DNA gaps are easily generated, and most of these gaps will be converted into DNA single-strand breaks, causing DNA damage. DNA damage can affect a wide range of cellular processes and is an important cause of tumorigenesis and other diseases. Studies have shown that the catalytic activity of PARP-1/2 is rapidly activated by DNA strand breaks. When DNA is damaged, activated PARP-1 binds to the single-stranded gap of the damaged DNA, while catalyzing the formation of a linear or branched poly ADP-ribose polymer on the target protein (such as histone or PARP-1 itself). . This will cause the interaction between the histones and DNA forming the poly ADP-ribose to become loose, facilitating the DNA repair enzyme to approach the damaged DNA, and finally completing the repair of the DNA. For cancer treatment, since radiation therapy and many chemotherapeutic methods work to target DNA damage, PARP inhibitors can be used as chemical and radiosensitizers for cancer treatment (Miwa, Masanao; Masutani, Mitsuko. PolyADP- Ribosylation and cancer. Cancer science 2007, 98, 1528-1535).

PARP inhibitors have been shown to be useful for the specific killing of breast cancer-associated genes BRCA-1 and BRCA-2 deficient tumors. BRCA-1/2 is a key repair factor for the Homologous recombination (HR) repair pathway. In BRCA-1 and BRCA-2 deficient tumor cells, inhibition of PARP will result in increased accumulation of DNA single-strand breaks, and due to the collapse of the replication fork in progress, DNA single-strand breaks will be converted into double-strand breaks, and these tumor cells will The double-strand break can be repaired because of the inability to initiate the HR pathway, which ultimately leads to cell death due to genomic instability. The inhibition of PARP and the phenomenon of BRCA-1/2 deficiency in killing cells are also known as synthetic lethality. The use of synergistic lethal theory provides new strategies and new ideas for the treatment of malignant tumors, and opens up a new era of PARP inhibitors as a new anti-tumor drug. (References: Farmer, H.; McCabe, N.; Lord, CJ; Tutt, ANJ; Johnson, DA; Richardson, TB; Santarosa, M.; Dillon, KJ; Hickson, I.; Knights, C.; Martin , NMB; Jackson, SP; Smith, GCM; Ashworth, A.. Targeting the DNA repair defect in BRCA mutant cell as a therapeutic strategy. Nature 2005, 434, 917-921; Kaelin, WG 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 repair and maintenance of genomic stability, PARP is involved in multiple biological processes, including gene transcription, cell cycle progression, cell death, and chromatin function. At the same time, PARP inhibitors have been proven to be useful in a number of therapeutic medicinal chemistries (in addition to malignant tumors), including stroke, myocardial ischemia, inflammation, antiviral and diabetes (Reference: Virág, L Szabó, C., The Therapeutic Potential of Poly (ADP-Ribose) Polymerase Inhibitors. Pharmacol Rev 2002, 54(3), 375-429).

The vast majority of PARP inhibitors to date are competitive inhibitors that compete with NAD ⁺ for binding to the catalytic site of the enzyme. At present, inhibitors still fail to meet the clinical needs. These compounds generally have shortcomings such as poor solubility and lack of selectivity for PARP subtypes. Therefore, it is urgent to provide effective inhibitors of novel PARP.

The pyrrole [1,2-b]pyridazine structure is an advantageous structure in medicinal chemistry. Compounds containing such structures exhibit a wide variety of biological activities in the pharmaceutical field, such as hypolipidemic/cholesterol (patent CN 1056690 discloses a class of compounds containing this predominant structure and their use in the treatment of hypercholesterolemia and high Application in lipemia), anti-tumor (patent WO 2011/014817 discloses JANUS kinase inhibitors containing such structures), anti-inflammatory, antibacterial (Butnariu, RM; Mangalagiu, II, New pyridazine derivatives: Synthesis, chemistry and Biological activity. Bioorg Med Chem 2009, 17(7), 2823-2829; Tucaliuc, R.-A.; Cotea, VV; Niculaua, M.; Tuchilus, C.; Mantu, D.; Mangalagiu, II, New pyridazine -fluorine derivatives: Synthesis, chemistry and biological activity. Part II. Eur J Med Chem 2013, 67 (0), 367-372; Butnariu, RM; Caprosu, MD; Bejan, V.; Mangalagiu, II; Ungureanu, M. ; Poiata, A.; Tuchilus, C.; Florescu, M., Pyridazine and phthalazine derivatives with potential antimicrobial activity. J Heterocyclic Chem 2007, 44(5), 1149-1152), antiviral (patent CN103288832 discloses a class to Pyrrole [1,2-b]pyridazine derivatives for the treatment or prevention of HIV infection or other viral infections; WO 2004/087708 A1 and WO 2007/069671 respectively disclose corticotropin releasing factor (CRF) inhibition with this predominant structure The use of the agent in pharmacy and the patent WO2010022240A1 disclose a class of derivatives containing such structures, which are capable of modulating the activity and/or activity of hypoxia-inducible factor (HIF) by effectively inhibiting the activity of HIF hydroxylase.

None of the reported pyrrole [1,2-b]pyridazine derivatives described above covers and relates to the compounds of the invention and their content as PARP inhibitors.

Summary of the invention

Based on this, it is an object of the present invention to provide a pyrrole [1,2-b]pyridazine compound represented by the general formula I or a pharmaceutically acceptable salt thereof:

among them,

R ¹ is hydrogen, C _1-4 alkyl or halogen;

R ² is

R ³ is hydrogen, -C(=O)R ⁶ , -SO ₂ R ⁷ , substituted or unsubstituted C _1-4 alkyl or substituted or unsubstituted C _3-6 cycloalkyl, wherein said R ⁶ and R ^{7 are} independently a substituted or unsubstituted C _1-4 alkyl group, a substituted or unsubstituted C _3-6 cycloalkyl group or a substituted or unsubstituted C _6-10 aryl group, the substitution being selected Substituting at least one substituent from a halogen, a C _1-4 alkyl group, an amino group, a nitrile group, a hydroxyl group, and a nitro group;

R ⁴ is hydrogen, halogen, C _1-4 alkyl or C _1-4 alkoxy;

R ⁵ is -CH ₂ - or -C=O;

X ₁ is S, O or NH;

X ₂ is CH or N;

Y ₁ , Y ₂ , Y ₅ and Y _{6 are} independently a substituted or unsubstituted methylene group, a substituted or unsubstituted ethylene group, a substituted or unsubstituted propylene group or a substituted or unsubstituted butylene group. The substitution is substituted with at least one substituent selected from the group consisting of halogen, C _1-6 alkyl, C _3-6 cycloalkyl and C _1-4 alkoxy;

Y ₃ and Y _{4 are} independently hydrogen, substituted or unsubstituted C _1-4 alkyl or substituted or unsubstituted C _3-6 cycloalkyl, the substituent being selected from halogen, C _1-6 alkyl Substituting at least one substituent of C _3-6 cycloalkyl and C _1-4 alkoxy;

Y ₇ is NR ⁸ or CHR ⁹ ,

Wherein R ⁸ is hydrogen, -C(=O)R ¹⁰ , -SO ₂ R ¹¹ , substituted or unsubstituted C _1-4 alkyl, substituted or unsubstituted C _3-6 cycloalkyl or substituted Or an unsubstituted C _6-10 aryl group, wherein said R ¹⁰ and R ^{11 are} independently a substituted or unsubstituted C _1-4 alkyl group, a substituted or unsubstituted C _3-6 cycloalkyl group, substituted or not a substituted five- to six-membered saturated heterocyclic group or a substituted or unsubstituted C _6-10 aryl group selected from the group consisting of halogen, C _1-4 alkyl, C _1-4 haloalkyl, amino, and Substituting at least one substituent of at least one C _1-4 alkyl substituted amino group, nitrile group, hydroxyl group, and nitro group,

The R ⁹ is hydrogen, -OR ¹² , an amino group substituted with at least one C _1-4 alkyl group, or a substituted or unsubstituted five- to six-membered saturated heterocyclic group, wherein the R ¹² is hydrogen, substituted or An unsubstituted C _1-4 alkyl group or a substituted or unsubstituted C _3-6 cycloalkyl group, which is selected from the group consisting of halogen, C _1-4 alkyl, C _1-4 haloalkyl, amino, at least At least one substituent of a C _1-4 alkyl-substituted amino group, a nitrile group, a hydroxyl group, and a nitro group is substituted.

Preferably, in the general formula I,

R ¹ is hydrogen, methyl, ethyl, propyl, fluorine, chlorine or bromine;

R ² is

R ³ is hydrogen, methyl, ethyl or propyl;

R ⁴ is hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy or propoxy;

R ⁵ is -CH ₂ - or -C=O;

X ₁ is S, O or NH;

X ₂ is CH or N;

Y ₁ , Y ₂ , Y ₅ and Y _{6 are} independently a substituted or unsubstituted methylene group, a substituted or unsubstituted ethylene group, a substituted or unsubstituted propylene group or a substituted or unsubstituted butylene group. The substitution is selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, and ring. Substituting at least one substituent of pentyl, cyclohexyl, methoxy, ethoxy or propoxy;

Y ₃ and Y _{4 are} independently hydrogen, methyl, ethyl, propyl, isopropyl or butyl;

Y ₇ is NR ⁸ or CHR ⁹ ,

Wherein R ⁸ is hydrogen, -C(=O)R ¹⁰ , -SO ₂ R ¹¹ , methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, ring A hexyl group, or a substituted or unsubstituted phenyl group, wherein said R ¹⁰ and R ^{11 are} independently a substituted or unsubstituted group: methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl Base, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, dioxolane or a phenyl group, the substitution being selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, trifluoromethyl, amino, N-methylamino, N-ethylamino, N, Substituting at least one substituent of N-dimethylamino, N,N-diethylamino, nitrile, hydroxy and nitro,

The R ⁹ is hydrogen, -OR ¹² , N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino, pyrrolidinyl, tetrahydrofuranyl, piperidine Or a piperazinyl group, a morpholinyl group or a dioxane group, wherein the R ¹² is hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl or a ring Hexyl, the substitution is selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, trifluoromethyl, amino, N-methylamino, N-ethylamino, N, N Substituting at least one substituent of dimethylamino, N,N-diethylamino, nitrile, hydroxy and nitro.

In one embodiment, the Formula I has the structure represented by Formula II:

Preferably, said R ¹ is a halogen, more preferably chlorine.

Preferably, said X ₁ is S or O, more preferably S.

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

In one embodiment, the Formula I has a structure represented by Formula III:

Preferably, said R ¹ is a halogen, more preferably chlorine.

Preferably, said R ⁴ is a halogen, more preferably fluorine.

Preferably, said R ⁵ is -CH ₂ -.

Preferably, said Y ₃ and Y _{4 are} independently hydrogen, methyl, ethyl, propyl, isopropyl or butyl, more preferably methyl. Preferably, the general formula III has the structure represented by the general formula III-a:

In one embodiment, the Formula I has a structure represented by Formula IV:

Preferably, said R ¹ is a halogen, more preferably chlorine.

Preferably, said R ⁴ is a halogen, more preferably fluorine.

Preferably, said R ⁵ is -CH ₂ - or -C=O.

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

In one embodiment, the Formula I has a structure represented by Formula V:

Preferably, said R ¹ is a halogen, more preferably chlorine.

Preferably, said R ⁴ is hydrogen or halogen, and said halogen is preferably fluorine.

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

Preferably, the pyrrole [1,2-b]pyridazine compound represented by the general formula I is one of the following compounds:

The invention further provides the use of a pyrrole [1,2-b]pyridazine compound of the formula I or a pharmaceutically acceptable salt thereof for the preparation of a PARP inhibitor.

In one embodiment, the PARP inhibitor has a selective inhibitory effect on PARP-1 and/or PARP-2.

The invention also provides a pharmaceutical composition comprising one or more therapeutically effective amounts of a pyrrole [1,2-b]pyridazine compound of the formula I or a pharmaceutically acceptable salt thereof, or a Or a plurality of therapeutically effective amounts of an ester, prodrug, hydrate or crystal of the pyrrole [1,2-b]pyridazine compound.

In one of the embodiments, the pharmaceutical composition has an inhibitory effect on PARP, particularly a selective inhibitory effect on PARP-1 and/or PARP-2.

In one embodiment, the pharmaceutical composition is for use in preventing and/or treating a PARP-related disease, including a tumor (breast cancer, ovarian cancer, liver cancer, melanoma, prostate cancer, colon cancer) , solid tumors such as gastric cancer), ischemic diseases (brain, heart, etc.) and neurodegenerative diseases (Parkinson's disease, Alzheimer's disease, etc.).

The invention further provides a preparation method of the pyrrole [1,2-b]pyridazine compound represented by the general formula I, comprising the following steps:

After the esterification reaction of the pyrrole-2-carboxylic acid methyl ester derivative, the iodo and amination reactions are carried out successively or the amination and the iodo reaction are successively carried out to obtain N-amino-5-iodopyrrole-2 in the following reaction formula. - methyl formate derivative Ia;

Aromatic aldehyde is reacted with a solution of ethynylmagnesium bromide in tetrahydrofuran (THF) to obtain an aromatic alkynyl alcohol I-b in the following reaction formula;

The N-amino-5-iodopyrrole-2-carboxylic acid methyl ester derivative Ia and the aromatic acetylenic alcohol Ib are subjected to a coupling cyclization reaction in a solvent under microwave conditions in the presence of palladium acetate, cuprous iodide and DBU. Compound I-0;

Compound I-0 is used as a solvent in a saturated methanol solution of ammonia gas, and sealed at 90 ° C for 20 hours to 24 hours, or directly with concentrated ammonia water, the solvent is methanol, and the reaction tube is reacted at 90 ° C for 20 hours to 24 hours to obtain the above. a pyrrole [1,2-b]pyridazine-7-carboxamide compound represented by the formula I;

The present invention further provides a method for preparing a pyrrole [1,2-b]pyridazine compound represented by the general formula II or the general formula II-a, and the synthesis route thereof is as follows:

Specifically, the following steps are included:

Compound E is condensed with an acid chloride or a carboxylic acid to give the corresponding amide F;

The amide F is fused to a ring to obtain a compound under the action of phosphorus oxychloride, and then the compound is reduced under the condition of sodium borohydride to further reduce the imine and further protect the free amino group with Boc anhydride to obtain the compound I;

Compound I is reacted with n-butyllithium in solvent THF, and further added to DMF to obtain 2-formyl substituted thiophene derivative J;

Compound J is reacted with a solution of ethynylmagnesium bromide in THF to give compound I-c;

Compound I-c is coupled with the above compound I-a for cyclization, and the protecting group is removed with trifluoroacetic acid and further aminolysis to give the compound of the formula II.

The present invention designs and synthesizes a series of PARP inhibitors by using pyrrole [1,2-b]pyridazine-7-carboxamide as a core structure, and the compounds of the present invention have a selection of PARP-1 and PARP-2 of the PARP family. It has a sexual inhibitory effect and exhibits good biological activity both in vitro and in vivo, and is expected to develop into a novel antitumor drug and a drug for preventing and/or treating a PARP-related disease.

Detailed ways

The structure and preparation method of the compound of the present invention and the effect of inhibiting PARP activity in vitro and in vivo will be further described below with reference to the examples without restricting the present invention.

As used herein, "alkyl" refers to a straight or branched alkyl group.

As used herein, "alkoxy" refers to a straight or branched alkoxy group.

As used herein, "substituted" refers to the replacement of one or more hydrogen atoms.

"Tumors" as referred to herein include benign tumors and malignant tumors.

The "pyrrole [1,2-b]pyridazine compound" described herein includes optical isomers.

A method for preparing a pyrrole [1,2-b]pyridazine compound represented by the formula I, comprising the steps of:

(1) Preparation of N-amino-5-iodopyrrole-2-carboxylic acid methyl ester derivative I-a by the following scheme:

plan 1:

Scenario 2:

Wherein, the scheme 1 comprises: the pyrrole-2-carboxylic acid methyl ester derivative A is obtained by heating under reflux of a base (such as 4-dimethylaminopyridine (DMAP)) in a solvent (such as methanol) to obtain a compound B, a compound B is stirred under the action of silver trifluoroacetate and iodine in a solvent such as chloroform to obtain Compound C in a base such as potassium t-butoxide and O-(4-nitrobenzoyl). Under the action of hydroxylamine, in a solvent (such as N-methylpyrrolidone (NMP)) stirred at room temperature overnight to obtain compound Ia;

Scheme 2 includes: Compound B can be prepared by stirring a base (such as potassium t-butoxide) and O-(4-nitrobenzoyl)hydroxylamine in a solvent (such as NMP) at room temperature overnight to obtain compound D. D can be prepared under conditions of potassium iodide and hydrogen peroxide in a solvent (such as acetic acid) for 3 hours at room temperature;

(2) preparing an aromatic alkynyl alcohol I-b, which is obtained by reacting a corresponding aromatic aldehyde with a solution of ethynylmagnesium bromide in tetrahydrofuran (THF);

(3) N-amino-5-iodopyrrole-2-carboxylic acid methyl ester derivative Ia and aromatic acetylenic alcohol Ib under the action of palladium acetate, cuprous iodide and DBU in a solvent such as toluene, tetrahydrofuran or dioxane Coupling cyclization reaction under microwave conditions to obtain compound I-0;

(4) Compound I-0 is treated with a saturated methanol solution of ammonia as a solvent, and sealed at 90 ° C for 20 hours to 24 hours, or directly with concentrated ammonia, and the solvent is methanol sealed at 90 ° C for 20 hours -24 The pyrrole [1,2-b]pyridazine compound represented by the above formula I is obtained in an hour;

The reaction formula of the above preparation method is as follows.

In all the following examples, the starting reagents, solvents and materials except the special instructions are supplied by Sinopharm Reagent Group; the microwave reaction uses CEMNULL type microwave reactor; ¹ H NMR is performed by Brucher AM-400 or GeMINI-300 NMR spectrometer Recording, chemical shifts are expressed in δ (ppm); mass spectra were recorded by an Agilent Model 1200-6110 Single Quadrupole Liquid Chromatography Mass Spectrometer. Separation silica gel is used to produce 200-300 mesh column chromatography silica gel from Qingdao Ocean Chemical Plant. The chemical reagents represented by the English abbreviation are as follows:

NBS: N-bromosuccinimide

DMAP: N,N-lutidine

NaBH ₄ : sodium borohydride

THF solution of BH ₃ : borane in tetrahydrofuran solution

EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

HOBt: 1-hydroxybenzotriazole

DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene

THF: tetrahydrofuran

NMP: N-methylpyrrolidone

Example 1

Preparation and synthesis of compounds

Preparation method of 4-chloro-2-trichloroacetylpyrrole (Compound 2)

To a 500 mL round bottom flask equipped with a stir bar, add 2-trichloroacetylpyrrole 1 (40 g, 190 mmol, Shanghai Shuiya Pharmaceutical Technology Co., Ltd.) and 200 mL of dichloromethane, and slowly add sulfonate at -10 °C. The acid chloride (31 g, 227 mmol) was added dropwise over about 45 minutes, stirring was continued at this temperature for 1 hour, then transferred to room temperature and stirred overnight. After the reaction was completed (thin layer chromatography), the reaction solution was poured into 300 mL of dichloromethane, and then quenched with ice water, the organic phase was separated, and the aqueous phase was extracted twice with dichloromethane (400 mL). The mixture was washed with a saturated aqueous solution of sodium bicarbonate and brine, dried over anhydrous sodium sulfate and evaporated.

_{^{1 H NMR (300MHz, CDCl 3}} ) δ9.42 (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] ⁺ .

Method for preparing methyl 4-chloro-pyrrole-2-carboxylate (compound 3)

To a 250 mL round bottom flask equipped with a stirrer, compound 2 (8.1 g, 32.8 mmol) and DMAP (800 mg) were added, poured into 100 mL of anhydrous methanol, stirred at 70 ° C for 1 hour, cooled to room temperature, and decompressed. Remove the solvent. Further, 100 mL of ethyl acetate and 30 mL of a 3 M HCl solution were added, and the organic phase was separated by extraction, and the aqueous layer was extracted once again with 50 mL of ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. Concentration in vacuo gave 5.1 g of a white solid.

_{^{1 H NMR (300MHz, CDCl 3}} ) δ9.31 (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] +.

Preparation of methyl 4-chloro-5-iodo-pyrrole-2-carboxylate (Compound 4)

To a 100 mL round bottom flask equipped with a stirrer, compound 3 (5.3 g, 33 mmol), silver trifluoroacetate (7 g, 33 mmol) and chloroform 60 mL were added, and iodine (4.7 g, 36 mmol) was added in an ice bath. The air was replaced with N _{2 for} 3 times, protected from light, and stirred at room temperature for 7 hours. After the reaction was completed, 25 mL of a saturated sodium thiosulfate solution was added, and after stirring for 15 minutes, the mixture was filtered under vacuum, and the filter cake was washed with chloroform and water, and the organic phase of the filtrate was separated, and the organic phase was washed with saturated aqueous sodium sulfate. dry. Concentration column chromatography (petroleum ether: ethyl acetate = 30:1) gave 8.3 g of white solid.

_{^{1 H NMR (300MHz, CDCl 3}} ) δ9.55 (s, 1H), 6.80 (d, J = 2.8Hz, 1H), 3.91 (s, 3H); LC-MS (ESI): m / z 286.1 [M +H] ⁺ .

Method for preparing O-(4-nitrobenzoyl)hydroxylamine (Compound 5)

A solution of p-nitrobenzoyl chloride (13.2 g, 70 mmol) in dichloromethane (50 mL) was slowly added dropwise to dichloromethane containing N-Boc Hydrolamine (9.4 g, 70.0 mmol), 5.4 mL of triethylamine. In 45 ml, the addition was completed in about 45 minutes. Stirring was continued at this temperature for 10 minutes and then transferred to room temperature and stirred for 1.5 hours. After the reaction was completed by thin layer chromatography, the reaction was quenched by the addition of 60 mL of water and stirring was continued for 30 minutes. The organic phase was separated and the organic phase was washed with aq. 9 mL of methanesulfonic acid was added to the organic phase at room temperature to initiate a white solid. After standing for 6 hours, 30 mL of n-hexane was added, and a white solid was filtered to give a methanesulfonic acid salt. The white solid was placed in a 500 mL beaker, and 200 mL of dichloromethane was added thereto, followed by dropwise addition of a saturated sodium hydrogencarbonate solution until all the white solid was dissolved. The organic phase was separated and washed with brine. Dry over anhydrous magnesium sulfate and concentrate to give 8.9 g of white solid.

_{^{1 H NMR (300MHz, CDCl 3}} ) 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] ⁺ .

Method for preparing methyl N-amino-4-chloro-pyrrole-2carboxylate (Compound 7)

method 1:

6 g of ammonium chloride, 10 mL of ammonia water and 120 mL of diethyl ether were successively added to a 500 mL round bottom flask, and 140 mL of a 5% (mass%) sodium hypochlorite solution was added dropwise to the above mixture at -10 ° C, and the addition was completed in about 30 minutes. While stirring at this temperature for 1 hour, the organic phase was separated and washed with ice-saturated brine (60 mL). The anhydrous calcium chloride was dried and dried at -40 ° C for 1 hour for use.

Under ice bath, compound 3 (2.5 g, 15.7 mmol) was dissolved in 30 mL of anhydrous DMF (purchased in Benzing Chemical), and added NaH (800 mg, 20 mmol, 60%, dispersed in mineral oil, purchased separately In Belleville Chemical). After stirring for 30 minutes, 100 mL of the above prepared chloroamine solution was added, and the mixture was stirred at room temperature for 4 hours, and the reaction was confirmed by thin layer chromatography. After adding 30 mL of a saturated sodium thiosulfate solution and stirring for 15 minutes, 100 mL of water was added, the organic phase was separated, and the aqueous layer was extracted with ethyl acetate. The organic phases were combined and washed with brine. Concentration, column chromatography (petroleum ether: ethyl acetate = 20:1) eluted

Method 2:

In a 500 mL round bottom flask equipped with a stir bar, compound 3 (2 g, 12.6 mmol), ammonium chloride (4 g, 75.5 mmol), 3-octylmethylammonium chloride (Aliquat-336, 0.5 mL), 15 mL of ammonia water, 5 mL of water, K ₂ CO ₃ (4.6 g, 33.3 mmol) and 45 mL of methyl tert-butyl ether, and then 160 mL of sodium hypochlorite solution was added dropwise through a constant pressure dropping funnel, and the addition was completed in about 30 minutes. After stirring at room temperature for 6-7 hours, after completion of the reaction, 50 mL of a saturated sodium thiosulfate solution was added, and after stirring for 10 minutes, the organic phase was separated and the aqueous layer was extracted with ethyl acetate. The combined organic phases were washed with EtOAc EtOAc (EtOAc m.

_{^{1 H NMR (300MHz, CDCl 3}} ) δ6.91 (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-CH 3 O] +.

Method for preparing methyl 1-amino-4-chloro-5iodo-pyrrole-2-carboxylate (compound 6)

method 1:

Potassium tert-butoxide (526 mg, 4.7 mmol) was added to a solution of compound 4 (857 mg, 3 mmol) in N-methylpyrrolidone (10 mL), and stirred for 15 min. A solution of (4-nitrobenzoyl)-hydroxylamine (692 mg, 3.6 mmol) in tetrahydrofuran 5 was stirred at room temperature overnight. 50 mL of saturated brine and 30 mL of ethyl acetate were added to the reaction mixture, and the organic phase was separated, and the aqueous layer was extracted with 50 mL of ethyl acetate. The combined organic phases were washed with water and brine. The organic phase was concentrated, and purified by column chromatography (ethyl ether: ethyl acetate = 100:1) to yield white solid (yield: 13%).

Method 2:

Compound 7 (625 mg, 3.6 mmol) was dissolved in 10 ml of glacial acetic acid, potassium iodide (900 mg, 5.4 mmol) was added, then ₂ mL of 30% H ₂ O ₂ solution was added dropwise, and the reaction solution gradually turned into a purple solution at room temperature. The reaction was stirred for 3 hours, and 5 mL of a saturated sodium thiosulfate solution was added thereto. After stirring for 10 minutes, ethyl acetate was added, the organic phase was separated, and the aqueous layer was extracted with ethyl acetate. Column chromatography (petroleum ether: ethyl acetate = 30:1) eluted to afford a white solid (yield: 78).

_{^{1 H NMR (300MHz, CDCl 3}} ) δ6.91 (s, 1H), 5.74 (s, 2H), 3.84 (s, 3H); LC-MS (ESI): m / z 269.2 (100%) [M- CH ₃ O] ⁺ .

Method for preparing 1-(4-diethoxymethylphenyl)propynyl alcohol (Compound 9)

In a 250 mL round bottom flask equipped with a stir bar, 4-diethoxymethylbenzaldehyde 8 (780 mg, 3.8 mmol, purchased from TCI Chemical) and 50 mL of anhydrous tetrahydrofuran were added, and then added through a constant pressure dropping funnel. A solution of ethynylmagnesium bromide in THF (0.5 M, 10 mL, purchased from Celler Chemical,), added over 15 minutes, stirring was continued for 0.5 to 1 hour at room temperature, and after completion of TLC reaction, 20 ml of saturated ammonium chloride solution was added. After stirring for 10 minutes, the organic phase was separated, the aqueous layer was extracted with ethyl acetate, and the organic phase was combined, washed with saturated brine, concentrated, and purified by column chromatography (ethyl ether: ethyl acetate = 5:1) The oil was 390 mg in a yield of 44%.

_{^{1 H NMR (300MHz, CDCl 3}} ) δ7.52 (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] +.

Method for preparing methyl 2-(4-diethoxymethylphenyl)-5-chloro-pyrrole [1,2-b]pyridazine-7-carboxylate (Compound 10)

In a 25 mL microwave tube equipped with a stirrer, compound 6 (150 mg, 0.5 mmol), compound 9 (234 mg, 1 mmol), palladium acetate (2.24 mg, 0.01 mmol), copper iodide (1 mg) , 0.005 mmol), and 5 ml of toluene. After replacing N ₂ 3 times, DBU (380 mg, 2.5 mmol) was quickly added, and the microwave cap was tightly placed, placed in a microwave reactor, and reacted at 90 ° C (λ = 180 W). After 40 minutes, after cooling, it was diluted with 25 mL of chloroform, transferred to a 100 mL round bottom flask, concentrated, and purified by column chromatography ( petroleum ether: ethyl acetate = 30:1). %.

_{^{1 H NMR (300MHz, CDCl 3}} ) δ8.06 (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 = 9.5 Hz, 1H), 5.58 (s, 1H), 3.96 (s, 3H), 3.60 (dd, J = 13.7, 7.0 Hz, 4H), 1.26 (t, J = </RTI>^</RTI>^</RTI>^< RTI ID=0.0>^</RTI>^</RTI>^<RTIgt;

Method for preparing methyl 2-(4-formylphenyl)-5-chloro-pyrrole [1,2-b]pyridazine-7-carboxylate (Compound 11)

In a 50 mL round bottom flask equipped with a stirrer, add compound 10 (62 mg, 0.16 mmol) and 10 mL of anhydrous methanol, then add 5 mL of 3N HCl solution, and stir at room temperature for 30 minutes. After the reaction is complete, use NaOH solution (2.5 M) Adjust the pH to 7-8. The organic phase was separated, and the aqueous layer was evaporated, evaporated, evaporated, evaporated

LC-MS (ESI): m / z 315 [M + H] +.

Preparation method of 2-(4-dimethylaminomethylphenyl)-5-chloro-pyrrole [1,2-b]pyridazine-7-carboxamide (Compound I-1)

In a 50 mL round bottom flask equipped with a stirrer, compound 11 (50 mg, 0.16 mmol), dimethylamine hydrochloride (20 mg, 0.24 mmol), a few drops of acetic acid and methanol 5 mL, and stirred at room temperature for 5 minutes. Further, sodium cyanoborohydride (50 mg, 0.8 mmol) was added, and stirring was continued for 1 hour. After the reaction was completed, the solvent was evaporated under reduced pressure, and then 10 mL of chlorobenzene and 4 mL of water were added, and the organic phase was separated and extracted. The mixture was extracted twice with chloroform. EtOAc (EtOAc m. H] ⁺ ; The crude product obtained above is added to a 25 mL sealed tube, a solution of ammonia in methanol is added, and then the reaction is sealed at 80 to 90 ° C for 18 to 24 hours, the reaction solution is cooled to room temperature, and the solvent is distilled off under reduced pressure. Column chromatography (dichloromethane:methanol = 10:1) eluted to afford 25 mg as a yellow solid.

_{^{1 H NMR (300MHz, CD 3}} OD) δ8.08 (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] ⁺ .

Preparation method of 5-chloro-2-(4-methylaminomethylphenyl)pyrrole [1,2-b]pyridazine-7-carboxamide (Compound I-2)

Compound 11 (50 mg, 0.16 mmol) and a methylamine solution (2 mL) were used as a starting material, and a compound of the compound I-1 was obtained to give 20 mg of a yellow solid.

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

Preparation method of 2-(4-diethylaminomethylphenyl)-5-chloro-pyrrole [1,2-b]pyridazine-7-carboxamide (Compound I-3)

Compound 11 (50 mg, 0.16 mmol) and diethylamine alcohol solution (1 mL) were used as a starting material, and the procedure of the compound I-1 was used to obtain 24 mg of a yellow solid. The total yield of the two steps was 42%.

_{^{1 H NMR (300MHz, CD 3}} OD) δ8.20 (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 = 7.3 Hz, 4H), 1.37 (t, J = 7.3 Hz, 6H); LC-MS (ESI): m/z 357.2 [M+H] ⁺ .

Preparation method of 2-[4-(pyrroline-1-yl)methylphenyl]-5-chloro-pyrrole [1,2-b]pyridazine-7-carboxamide (Compound I-4)

Compound 11 (50 mg, 0.16 mmol) and tetrahydropyrrolidine (1 mL) were used as a starting material to give a yellow solid (15 mg).

¹ H NMR (300 MHz, CD ₃ OD) δ 8.18 (dd, J = 9.4, 1.4 Hz, 1H), 8.12 (dd, J = 8.3, 1.5 Hz, 2H), 7.73 (d, J = 8.1 Hz, 2H ), 7.58-7.49 (m, 2H), 4.46 (s, 2H), 3.35 (d, J = 6.0 Hz, 4H), 2.15-2.06 (m, 4H); LC-MS (ESI): m/z 355.2 [M+Na] ⁺ .

Process for preparing 2-[4-(piperazin-1-yl)-methylphenyl]-5-chloro-pyrrole [1,2-b]pyridazine-7-carboxamide (Compound I-5)

Compound 11 (50 mg, 0.16 mmol) and N-boc piperazine (45 mg, 0.24 mmol) in methanol (5 mL), EtOAc (EtOAc) After stirring at room temperature for 3 hours, it was directly concentrated to give an oily crystals, and then, 3 ml of water and 5 ml of chloroform, and the organic phase was separated, and the aqueous layer was extracted with chloroform. Dry and concentrate to obtain the oil and directly put into the next step. Add 10 ml of chloroform to the above oil, slowly add 1.5 mL of trifluoroacetic acid, stir at room temperature for 1 hour, adjust the pH value with 3N HCl solution in ice bath. ～9, the organic phase was separated, the aqueous layer was extracted with chloroform, the organic phase was combined, washed with saturated brine, concentrated directly without purification, then transferred to a 25 mL sealed tube with 5 mL of methanol, and 8 mL of a saturated ammonia methanol solution was added. The reaction was sealed at 80 to 90 ° C for 18 to 24 hours, and the reaction solution was cooled to room temperature. The solvent was evaporated under reduced pressure in vacuo, and purified by column chromatography (dichloromethane:methanol = 10:1) The total yield was 17%.

¹ H NMR (300 MHz, CD ₃ OD) δ 8.12 - 8.06 (m, 1H), 7.92 (dd, J = 8.1, 2.0 Hz, 2H), 7.52 (dd, J = 8.3, 2.0 Hz, 2H), 7.46 (ddd, J=5.9, 3.8, 2.3 Hz, 2H), 3.67 (d, J = 2.0 Hz, 2H), 3.34 (d, J = 1.6 Hz, 1H), 3.19 (t, J = 5.5 Hz, 4H) , 2.69 (t, J = 4.8Hz , 4H); LC-MS (ESI): m / z 370.2 [m + H] +.

2-[4-(3-Methyl-piperazin-1-yl)methylphenyl]-5-chloro-pyrrole[1,2-b]pyridazine-7-carboxamide (Compound I-6) Preparation

Compound 11 (50 mg, 0.16 mmol) and 2-methylpiperazine (24 mg, 0.24 mmol) were used as a starting material to give a yellow solid 15 mg (yield: 25%).

_{^{1 H NMR (300MHz, CD 3}} OD) δ8.11 (dd, J = 9.5,3.4Hz, 1H), 7.94 (dq, J = 8.6,2.3,1.8Hz, 2H), 7.54 (dd, J = 8.2, 3.3 Hz, 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, 2.8 Hz, 1H), 1.29 (d, J = 3.1 Hz, 3H); LC-MS (ESI): m/ Z384.2[M+H] ⁺ .

2-[4-(4-Cyclopropylpiperazin-1-yl)-methylphenyl]-5-chloro-pyrrole[1,2-b]pyridazine-7-carboxamide (Compound I-7) Preparation method

Compound 11 (50 mg, 0.16 mmol) and N-cyclopropylpiperazine (30 mg, 0.24 mmol) were used as a starting material to give a yellow solid (yield: 24 mg).

¹ H NMR (300 MHz, CD ₃ OD) δ 8.10 (dd, J = 9.4, 1.7 Hz, 1H), 7.95-7.88 (m, 2H), 7.52 (dd, J = 6.8, 1.6 Hz, 3H), 7.44 (dd, J=9.5, 1.6 Hz, 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-piperazin-1-yl)-methylphenyl]-5-chloro-pyrrole[1,2-b]pyridazine-7-carboxamide (Compound I-8 Preparation method

Compound 11 (50 mg, 0.16 mmol) and N-isopropylpiperazine (31 mg, 0.24 mmol) were used as a starting material to give a yellow solid 25 mg.

_{^{1 H NMR (300MHz, CD 3}} OD) δ8.13 (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, 4.3 Hz, 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-Dimethylaminopiperidin-1-yl)-methylphenyl]-5-chloro-pyrrole[1,2-b]pyridazine-7-carboxamide (Compound I-9) Preparation method

Compound 11 (50 mg, 0.16 mmol) and 4-dimethylaminopiperidine (31 mg, 0.24 mmol) were used as a starting material to give a yellow solid (yield: 26 mg).

¹ H NMR (300 MHz, CD ₃ OD) δ 8.12 (dd, J = 9.4, 0.6 Hz, 1H), 7.95 (dd, J = 8.4, 2.2 Hz, 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]-methylphenyl}-5-chloro-pyrrole[1,2-b]pyridazine-7-carboxamide (Preparation method of compound I-10)

Compound 11 (50 mg, 0.16 mmol) and 4-pyrrolidin-1-yl-piperidine (37 mg, 0.24 mmol) were used as a starting material to give a yellow solid 15 mg (yield: 21%). .

_{^{1 H NMR (300MHz, CD 3}} OD) δ8.13 (d, J = 9.5Hz, 1H), 7.99-7.93 (m, 2H), 7.58-7.52 (m, 2H), 7.51 (dd, J = 5.5, 4.0 Hz, 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), </RTI>^< RTI ID=0.0></RTI>^</RTI>^<RTIgt;

2-[4-(4-Morpholinylpiperidin-1-yl)-methylphenyl]-5-chloro-pyrrole[1,2-b]pyridazine-7-carboxamide (Compound I-11) Preparation method

Compound 11 (50 mg, 0.16 mmol) and 4-(4-piperidinyl)morpholine (41 mg, 0.24 mmol) were used as a starting material. The rate is 14%.

_{^{1 H NMR (300MHz, CD 3}} OD) δ8.16 (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-Trifluoromethylphenyl-piperazin-1-yl)-methylphenyl]-5-chloro-pyrrole[1,2-b]pyridazine-7-carboxamide ( Method for preparing compound I-12)

Compound 11 (50 mg, 0.16 mmol) and p-trifluoromethylphenylpiperazine (55 mg, 0.24 mmol) were used as a starting material. %.

_{^{1 H NMR (300MHz, CD 3}} OD) δ8.17 (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, 2.8 Hz, 2H), 7.47 (d, J = 8.3 Hz, 2H), 7.04 (d, J = 8.7 Hz, 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] +.

Method for preparing 4-(4-formylphenyl)-piperazine-1-carboxylic acid tert-butyl ester (Compound 13)

A 50 mL round bottom flask equipped with a stirrer was added, followed by 4-formylbenzoic acid 12 (3.1 g, 20.7 mmol), N-tert-butoxycarbonylpiperazine (3.6 g, 19.4 mmol), EDCI (3.86). Gram, 20.2 mmol), HOBt (2.68 g, 19.8 mmol) in dichloromethane 25 mL, finally add DMAP (20 mg), stir at room temperature for 20 to 24 hours, after the reaction is complete, add NaOH solution (2.5 M) 5 ml After stirring for 5 minutes, the organic phase was separated, the aqueous layer was extracted with chloroform, and the organic phase was combined, concentrated, and purified by column chromatography (ethyl ether: ethyl acetate = 2:1). The rate is 73%.

¹ H NMR (300MHz, CDCl ₃ ) δ 10.0 (s, 1H), 7.93 (d, J = 8.2 Hz, 2H), 7.54 (d, J = 8.1 Hz, 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] +.

Method for preparing 4-{4-[1-(1-hydroxy-2-propynyl)]benzoyl}piperazine-1-carboxylic acid tert-butyl ester (Compound 14)

A 50 mL round bottom flask equipped with a stirrer was added, and compound 13 (650 mg, 2.05 mmol) was added, and 20 ml of anhydrous THF was added. After completely dissolved, ethynylmagnesium bromide in THF (0.5 M, 7 mL) was added. The reaction was completed by thin-layer chromatography. The mixture was quenched with saturated aqueous ammonium chloride solution (10 mL), and the mixture was stirred for 10 minutes, and then 10 mL of ethyl acetate was added to separate the organic phase. The aqueous layer was extracted with ethyl acetate. Water washing, concentration and column chromatography (petrole ether: ethyl acetate = 1:1) eluted to afford 305 mg as a yellow oil.

_{^{1 H NMR (300MHz, CDCl 3}} ) δ7.58 (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 = 96.8 Hz, 8H), 2.67 (ddd, J = 8.4, 2.2, 0.9 Hz, 1H), 2.16 (q, J = 1.6 Hz, 1H), 1.46 (s, 9H); LC-MS (ESI): m/z 367.2 [M+Na] ⁺ .

Preparation of methyl 2-[4-(N-tert-butoxycarbonyl)piperazinylformyl]phenyl-5-chloro-pyrrole [1,2-b]pyridazine-7-carboxylate (Compound 15) method

A 25 mL microwave reaction tube equipped with a stirrer was added, followed by the addition of compound 6 (160 mg, 0.52 mmol), compound 14 (305 mg, 0.9 mmol), Pd(OAc) ₂ (7 mg, 0.01 mmol), CuI ( 1 mg, 0.005 mmol) and 8 mL of toluene. After replacing N ₂ 3 times, DBU (380 mg, 2.5 mmol) was added under N ₂ protection, and the microwave tube cap was placed and placed in a microwave reactor at 90 ° C (λ). The reaction was carried out for 40 minutes, and after cooling, it was diluted with chloroform (25 mL), transferred to a 100 ml round bottom flask, concentrated, and purified by column chromatography ( petroleum ether: ethyl acetate = 2:1) to give a yellow oil. 121 mg, yield 47%.

_{^{1 H NMR (300MHz, CDCl 3}} ) δ8.17-8.10 (m, 2H), 7.99 (dd, J = 9.5,2.5Hz, 1H), 7.59-7.52 (m, 2H), 7.50 (d, J = 3.0 Hz, 1H), 7.35 (dd, J=9.4, 3.0 Hz, 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] +.

Method for preparing hydrochloride of 5-chloro-2-[4-(piperazinyl-1-formyl)phenyl]-pyrrole [1,2-b]pyridazine-7-carboxylic acid methyl ester (Compound 16)

The compound 15 (120 mg, 0.24 mmol) was placed in a 100 mL round bottom flask, 5 mL of anhydrous dichloromethane was added, and 5 mL of HCl methyl acetate solution was added thereto, and the mixture was stirred at 40 ° C for 2 hours to precipitate a white solid to be cooled. After room temperature, it was filtered to give the hydrochloride salt of methyl 5-chloro-2-[4-(N-piperazinyl)phenyl]-pyrrole[1,2-b]pyridazin-7-carboxylate. Mg.

^{1 H NMR (300MHz, DMSO-} d 6) 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] +.

Process for preparing 5-chloro-2-[4-(piperazinyl-1-formyl)phenyl]-pyrrole [1,2-b]pyridazine-7-carboxamide (Compound I-13)

10 mL of methanol of compound 16 (50 mg) was dissolved and transferred to a 25 mL sealed tube, 8 mL of a methanol solution of NH ₃ was added, and the reaction was carried out at 80 to 90 ° C for 20 to 24 hours, cooled to room temperature, and transferred to a 100 ml round bottom flask. Concentration, column chromatography (dichloromethane:methanol = 10:1) elute

^{1 H NMR (300MHz, DMSO-} d 6) δ8.26 (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 = 1.2 Hz, 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-(cyclopropylformyl)-piperazin-1-yl]formylphenyl}-5-chloro-pyrrole[1,2-b]pyridazine-7-carboxamide (compound) Preparation method of I-14)

Compound 16 (50 mg, 0.13 mmol) was added, and 15 mL of anhydrous dichloromethane was added thereto, and 0.5 mL of NEt ₃ and cyclopropylcarbonyl chloride (30 μl) were added dropwise thereto, and the mixture was stirred at room temperature for 15 minutes, and the reaction was completed by thin layer chromatography. Add 2 mL of methanol, stir at room temperature for 10 minutes, and concentrate to give a yellow solid as crude 5-chloro-2-{4-[(4-cyclopropylformyl)-piperazinyl-1-formyl]phenyl} - Pyrrole [1,2-b]pyridazine-7-carboxylic acid methyl ester, transferred to a 25 mL sealed tube with 10 mL of methanol, added 8 mL of ammonia methanol solution, reacted at 80-90 ° C for 20-24 hours, and cooled to room temperature. Concentration, column chromatography (dichloromethane:methanol = 20:1) eluted to afford a brown solid (yield: 45 mg).

^{1 H NMR (300MHz, DMSO-} d 6) δ8.27 (dt, J = 9.4,1.4Hz, 1H), 8.21 (s, 1H), 8.11 (dt, J = 8.3,1.7Hz, 2H), 7.99 ( d, J = 3.2 Hz, 1H), 7.71 - 7.57 (m, 3H), 7.52 (d, J = 1.0 Hz, 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-oxobutyl)-piperazin-1-yl-formyl]-phenyl-5-chloro-pyrrole[1,2-b]pyridazine-7- Method for preparing formamide (compound I-15)

Compound 16 (50 mg, 0.16 mmol) was added, and 5 mL of anhydrous dichloromethane was added thereto, and 0.5 mL of NEt ₃ and isovaleryl chloride (30 mg, 0.24 mmol) were added dropwise thereto, and the mixture was stirred at room temperature for 30 minutes, and the reaction was examined by thin layer chromatography. After completion, 3 mL of methanol was added, and the mixture was stirred at room temperature for 5 minutes, and concentrated to give a crude product (yield: 65 mg, 2-[(N-isovalyl)piperazin-1-ylformyl]-phenyl-5-chloro-pyrrole [ 1,2-b]pyridazine-7-carboxylic acid methyl ester; transferred to a 25 mL sealed tube with 10 mL of methanol, added 8 mL of a methanol solution of NH ₃ , reacted at 80 to 90 ° C for 20 to 24 hours, and cooled to room temperature. Concentration, column chromatography (dichloromethane:methanol = 20:1) eluted to afford 40 mg of yellow solid.

_{^{1 H NMR (300MHz, CDCl 3}} ) δ8.69 (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); MS (ESI): m / z 468.2 [m + H] +.

Method for preparing 4-(3-fluoro-4-formylphenyl)-formyl-piperazine-1-carboxylic acid tert-butyl ester (Compound 17)

3-fluoro-4-formylbenzoic acid (1 g, 6 mmol, its preparation method refers to document EP2526945A1, the raw material used is 3-fluoro-4-methylbenzoic acid purchased from Shanghai Shuya Medicine), N-tert-butoxy Formylpiperazine (1.1 g, 5.66 mmol), HOBt (764 mg, 5.66 mmol), EDCI (1.3 g, 6.8 mmol) and DMAP (20 mg) were used as the starting material. The yield was 89%.

_{^{1 H NMR (300MHz, CDCl 3}} ) δ10.38 (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] +.

Method for preparing 4-[3-fluoro-4-(1-hydroxypropyn-2-yl)benzoyl]-piperazine-1-carboxylic acid tert-butyl ester (Compound 18)

Compound 17 (600 mg, 1.8 mmol) and ethynylmagnesium bromide in THF (0.5 M, 6.5 mL) were used as a starting material.

_{^{1 H NMR (300MHz, CDCl 3}} ) δ7.72 (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-[2-Fluoro-(4-tert-butoxycarbonylpiperazin-1-ylformyl)phenyl]-5-chloro-pyrrole [1,2-b]pyridazine-7-carboxylic acid methyl ester (compound 19) Preparation method

The compound 6 (218 mg, 0.7 mmol) and the compound 18 (420 mg, 1.2 mmol) were used as a starting material.

_{^{1 H NMR (300MHz, CDCl 3}} ) δ8.14 (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] ⁺ .

Preparation of 2-[2-fluoro-4-(piperazin-1-yl-formyl)phenyl]-5-chloro-pyrrole [1,2-b]pyridazine-7-carboxylic acid methyl ester (Compound 20) method

Compound 19 (150 mg, 0.3 mmol) was dissolved in dichloromethane, and trifluoroacetic acid (1.5 mL) was added dropwise. After the reaction was completed by TLC, NaOH solution (2.5 M) was added under ice bath to adjust the pH to 7-8. , organic phase was separated, the aqueous layer was extracted with chloroform and the combined organic phases were concentrated and column chromatography (dichloromethane: methanol = 10: 1 + a few drops of NH ₃ in methanol) to afford 100 mg of a yellow solid, The yield was 80%.

LC-MS (ESI): m / z 417.2 [M + H] +.

2-[2-Fluoro-4-(4-cyclopropylformylpiperazin-1-yl-formyl)phenyl]-5-chloro-pyrrole[1,2-b]pyridazine-7-carboxamide (Preparation method of compound I-16)

Compound 20 (60 mg, 0.15mmol) in 10mL anhydrous dichloromethane was added 0.5mL NEt ₃ and cyclopropanecarbonyl chloride (26 mg, 0.25 mmol), stirred at room temperature for 30 min, TLC the reaction was complete, a solution of 4 mL of methanol, concentrated to give a crude product (yield: 65 mg, 5-chloro-2-[3-fluoro-4-(4-cyclopropylformylpiperazine-1-formyl)phenyl]pyrrole [1,2-b] Methyl oxazine-7-carboxylate; transfer it to a 25 mL sealed tube with 10 mL of methanol, add 8 mL of ammonia in methanol, react at 80-90 ° C for 20-24 hours, cool to room temperature, concentrate, column chromatography (two Methyl chloride:methanol = 20:1) was washed to give 30 mg of a yellow solid.

^{1 H NMR (300MHz, DMSO-} d 6) 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-[2-Fluoro-4-[4-[(2S)-2-methylamino-1-oxo-propyl]-piperazin-1-ylformyl]phenyl]-5-chloro-pyrrole [ Method for preparing 1,2-b]pyridazine-7-carboxamide (compound I-17)

Compound 20 (100 mg, 0.24 mmol), Boc-N-methyl-L-alanine (54 mg, 0.27 mmol), EDCI (55 mg, 0.29 mmol), HOBt (32 mg, 0.24 mmol) and DMAP ( 5 mg) in dichloromethane (15 mL), stirred at room temperature for 14 hours, added 3 ml of NaOH (2.5 M) solution, stirred at room temperature for 5 min, the organic phase was separated, and the aqueous layer was extracted with chloroform. , by column chromatography (dichloromethane: methanol = 50: 1) to give 58 mg of a yellow solid, LC-MS (ESI): m / z 624.2 [m + Na] +; 20mL methylene chloride to the solid was added CF ₃ COOH 1.5mL, stir at room temperature for 2 hours, and adjust the pH to 8-9 with NaOH (2.5M) solution, separate the organic phase, extract the aqueous layer with chloroform, combine the organic phase, concentrate, column chromatography (dichloro Methane:methanol = 10:1) eluted to give 40 mg of a yellow solid, LC-MS (ESI): m/z 502.2 [M+Na] ⁺ ; with 10 mL of methanol, transferred to a 25 mL sealed tube, 8 mL of ammonia in methanol The reaction was carried out at 80 to 90 ° C for 20 to 24 hours, cooled to room temperature, concentrated, and subjected to column chromatography (dichloromethane: methanol = 20:1) to afford 30 mg of a yellow solid.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.29 (d, J = 9.5 Hz, 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, 1.7 Hz, 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-Isopropylsulfonylpiperazin-1-yl-formyl)phenyl]-5-chloro-pyrrole[1,2-b]pyridazine-7-carboxamide (Compound I- 18) Preparation method

Add 1 mL of pyridine and 250 ul of isopropylsulfonyl chloride to 5 mL of chloroform of compound I-13 (10 mg, 0.024 mmol), stir at room temperature for 4 hours, add 3 mL of 3N HCl solution, separate the organic phase, and use trichlorochloride in the aqueous layer. The methane was extracted, and the organic phase was combined, concentrated, and purified by column chromatography (dichloromethane:methanol = 20:1)

¹ H NMR (400 MHz, CD ₃ OD) δ 8.14 (d, J = 9.4 Hz, 1H), 8.07 (d, J = 8.2 Hz, 2H), 7.63 (d, J = 8.2 Hz, 2H), 7.54 ( s, 1H), 7.48 (d, J = 9.5 Hz, 1H), 3.63 - 3.54 (m, 2H), 3.52-3.46 (m, 1H), 3.43 - 3.37 (m, 6H), 1.34 (d, J = </RTI>^</RTI>^</RTI>^< RTI ID=0.0></RTI>^</RTI>^<RTIgt;

Preparation method of N-(2-fluoro-5-formyl-benzoyl)-piperazin-1-yl-carboxylic acid tert-butyl ester (Compound 21)

2-fluoro-5-formylbenzoic acid (850 mg, 5 mmol of which was prepared by reference), N-Boc piperazine (1.1 g, 6.1 mmol), EDCI (1.2 g, 6.1 mmol), HOBt (688 mg, 5.1 mmol) and DMAP (80 mg) were used as a starting material, and a white solid of 1.4 g was obtained with reference to the preparation method of Compound 13.

¹ H NMR (300 MHz, CDCl ₃ ) 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 = 5.3 Hz, 2H), 3.53 (t, J = 5.3 Hz, 2H), 3.42 (t, J = 5.1 Hz, 2H), 3.32-3.24 (t, J = 5.3 Hz, 2H), 1.45 (s, 9H); LC- MS (ESI): m / z 359.2 [m + Na] +.

Preparation method of N-[2-fluoro-5-(1-hydroxy-propyn-2-yl)benzoyl]-piperazin-1-yl-carboxylic acid tert-butyl ester (Compound 22)

Compound 21 (500 mg, 1.5 mmol) and ethynylmagnesium bromide in THF (0.5 M, 5 mL) were used as a starting material.

_{^{1 H NMR (300MHz, CDCl 3}} ) δ7.64-7.56 (m, 2H), 7.11 (ddd, J = 9.0,8.1,1.0Hz, 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-piperazin-1-yl-formyl)-4-fluoro-phenyl]-5-chloro-pyrrole[1,2-b]pyridazine- Method for preparing 7-methyl formate (compound 23)

Compound 6 (270 mg, 0.9 mmol) and Compound 22 (520 mg, 1.5 mmol) were used as a starting material.

_{^{1 H NMR (300MHz, CDCl 3}} ) δ8.25-8.20 (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] +.

Methyl 2-[3-(piperazin-1-yl)-formyl-4-fluoro-phenyl]-5-chloro-pyrrole[1,2-b]pyridazine-7-carboxylate (Compound 24) Preparation

To a solution of compound 23 (108 mg, 0.23 mmol) in dichloromethane (10 mL), trifluoroacetic acid (1.5 mL) was added at room temperature, stirring was continued for 1 hour, and the reaction was completed by thin layer chromatography. The solution is adjusted to be alkaline (8-9), the organic phase is separated, the aqueous layer is extracted with chloroform, the organic phase is combined, concentrated, and purified by column chromatography (dichloromethane:methanol = 10:1) The yellow solid was 80 mg in a yield of 83%.

LC-MS (ESI): m / z 417.2 [M + H] +.

2-[3-(N-Cyclopropionyl-piperazin-1-yl)-formyl-4-fluoro-phenyl]-5-chloro-pyrrole[1,2-b]pyridazine-7-A Method for preparing amide (compound I-19)

10 mL of a solution of compound 24 (50 mg, 0.12 mmol) in dichloromethane, and a few drops of triethylamine, cyclopropanoyl chloride (20 mg, 0.18 mmol), stirred at room temperature for 1 hour, and then added 5 mL of methanol and stirring for 10 minutes. Concentration gave the oil as 2-[3-(N-cyclopropanoyl-piperazin-1-yl)-formyl-4-fluoro-phenyl]-5-chloro-pyrrole [1,2-b] pyridazin-7-carboxylic acid methyl ester, LC-MS (ESI): m / z 485.2 [m + H] +; 8mL methanol solution was transferred with methanol to 10mL 25mL sealed tube, add ammonia, 80 ~ 90 ℃ reaction After 20 to 24 hours, it was cooled to room temperature, concentrated, and purified by column chromatography (dichloromethane:methanol = 20:1) to afford 21 mg of yellow solid.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.99 (d, J = 9.4 Hz, 1H), 7.98-7.83 (m, 2H), 7.56 (s, 1H), 7.27 (t, J = 8.8 Hz, 1H) , 7.19 (d, J=9.4 Hz, 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-yl]-formyl-piperazin-1-yl]-formyl]-4-fluoro-phenyl]-5-chloro-pyrrole [ Method for preparing 1,2-b]pyridazine-7-carboxamide (compound I-20)

Compound 24 (50 mg, 0.12 mmol), Boc-L-valine (28 mg, 0.13 mmol), EDCI (28 mg, 0.15 mmol) and HOBt (17 mg, 0.12 mmol), and DMAP (5 mg) The starting material, referring to the preparation method of the compound I-17, gave a yellow solid 15 mg, and a three-step total yield of 25%.

_{^{1 H NMR (300MHz, CDCl 3}} ) δ8.29 (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 = 9.3 Hz, 1H), 7.53 (s, 1H), 4.47 - 4.30 (m, 1H), 3.62 (dd, J = 53.7, 20.3 Hz, 8H), 3.16 (d, J = 5.0 Hz, 2H) ), 3.01 (s, 1H), 2.28 (s, 1H), 1.76 (s, 4H); LC-MS (ESI): m/z 499.2 [M+H] ⁺ .

Process for preparing 3-(4-methoxypiperidin-1-yl-formyl)-4-fluoro-benzaldehyde (Compound 25)

2-Fluoro-5-formylbenzoic acid (370 mg, 2.2 mmol), 4-methoxypiperidine hydrochloride (300 mg, 2 mmol, which was prepared according to the document US2011092475A1), EDCI (460 mg, 2.4) Methanol (40 mg, 2.2 mmol) in 40 mL of dichloromethane, DMAP (20 mg) was added and stirred at room temperature for 20 to 24 hours. After the reaction was completed by thin layer chromatography, 5 mL of NaOH (2.5 M) solution was added. After stirring for 10 minutes, the organic phase was separated, the aqueous layer was extracted with chloroform, and the organic phase was combined, concentrated, and purified by column chromatography (ethyl ether: ethyl acetate = 2:1) 70%.

_{1H NMR (300MHz, CDCl 3)} δ9.97 (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, 4.1 Hz, 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), </ RTI>^< / RTI>^< / RTI>^< / RTI>^< / RTI>^<RTIgt;

Process for preparing 2-fluoro-5-(1-hydroxy-propyn-2-yl)-phenyl-(4-methoxypiperidin-1-yl)-methyl ketone (Compound 26)

To a solution of compound 25 (370 mg, 1.4 mmol) in anhydrous THF (40 mL), EtOAc (EtOAc, EtOAc, EtOAc The aqueous layer was extracted with EtOAc. EtOAc (EtOAc)EtOAc.

_{1H NMR (300MHz, CDCl 3)} 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 = 2.2 Hz, 1H), 1.99 -1.76 (m, 2H); LC -MS (ESI): m / z 314.2 [m + Na] +.

2-[3-(4-Methoxypiperidin-1-yl-formyl)-4-fluoro-phenyl]-5-chloro-pyrrole[1,2-b]pyridazine-7-carboxamide ( Method for preparing compound I-21)

Take a 25-mL microwave tube equipped with a stir bar and add compound 6 (210 mg, 0.7 mmol), compound 26 (370 mg, 1.3 mmol), palladium acetate (8 mg), cuprous iodide (1 mg) And 10 mL of toluene, after replacing N ₂ 3 times, DBU (532 mg) was quickly added under N ₂ protection, and the microwave cap was tightly placed, placed in a microwave reactor, and reacted at 90 ° C (λ = 180 W) for 40 minutes, and cooled. After that, it was diluted with 25 ml of chloroform, transferred to a 100 ml round bottom flask, concentrated, and purified by column chromatography ( petroleum ether: ethyl acetate = 3:1) to yield 40 mg as a yellow solid as 2-[3- (4-methoxypiperidin-1-yl-formyl)-4-fluoro-phenyl]-5-chloro-pyrrole [1,2-b]pyridazine-7-carboxylic acid methyl ester crude, yield 13 %, LC-MS (ESI): m/z 446.2 [M+H] ⁺ ; </ RTI>^< / RTI>^< / RTI>^< / RTI>^< / RTI>^< / RTI>^< / RTI>^< / RTI>^< / RTI>^< / RTI>^< / RTI>^< / RTI>^< / RTI>^< / RTI>^< / RTI> After cooling to room temperature, concentration and column chromatography (dichloromethane:methanol = 20:1) eluted

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.24 (d, J = 9.5 Hz, 1H), 8.15 (dd, J = 8.7, 5.1, 2.5 Hz, 2H), 8.07 (dd, J = 6.4, 2.4 Hz, 1H), 7.95 (s, 1H), 7.62 (d, J = 9.5 Hz, 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] ⁺ .

Method for preparing 4-(4-methoxypiperidin-1-yl)-formylbenzaldehyde (Compound 27)

4-formylbenzoic acid (330 mg, 2.2 mmol) and 4-methoxypiperidine hydrochloride (302 mg, 2 mmol) were used as a starting material. .

_{^{1 H NMR (300MHz, CDCl 3}} ) δ10.02 (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] +.

Method for preparing 4-(1-hydroxy-propyn-2-yl)-phenyl-(4-methoxy-piperidin-1-yl)-methyl ketone (Compound 28)

Compound 27 (320 mg, 1.3 mmol) and ethynylmagnesium bromide in THF (0.5 M, 4 mL) were used as a starting material.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.61 - 7.55 (m, 2H), 7.43 - 7.38 (m, 2H), 5.49 (dd, J = 6.1, 2.3 Hz, 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 = 2.2 Hz, 1H), 2.47 (d, J = 6.1 Hz, 1H) </ RTI>^< / RTI>^<RTIgt;^< / RTI>^<RTIgt;^< / RTI>^<RTIgt;

2-[4-(4-Methoxypiperidin-1-yl-formyl)-phenyl]-5-chloro-pyrrole[1,2-b]pyridazine-7-carboxamide (Compound I-22 Preparation method

Compound 28 (210 mg, 0.8 mmol), compound 6 (150 mg, 0.5 mmol), palladium acetate (8 mg), CuI (1 mg) and DBU (380 mg) were used as starting materials, according to the preparation of compound I-21, A yellow solid of 40 mg was obtained in a two-step total yield of 10%.

^{1 H NMR (300MHz, DMSO-} d 6) δ8.25 (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 = 15.8 Hz, 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] +.

Method for preparing 2-fluoro-4-(4-methoxypiperidin-1-yl)-formylbenzaldehyde (Compound 29)

2-Fluoro-4-formyl-benzoic acid (370 mg, 2.2 mmol), 4-methoxypiperidine hydrochloride (300 mg, 2 mmol) as a starting material. The yield is 50%.

_{^{1 H NMR (300MHz, CDCl 3}} ) δ10.37 (d, J = 0.7Hz, 1H), 7.92 (dd, J = 7.9,6.9Hz, 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] ⁺ .

Process for preparing 3-fluoro-4-(1-hydroxy-propyn-2-yl)-phenyl-(4-methoxypiperidin-1-yl)-methyl ketone (Compound 30)

Compound 29 (360 mg, 1.4 mmol) and ethynylmagnesium bromide in THF (0.5 M, 2.5 mL) were used as a starting material.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.69 (t, J = 7.6 Hz, 1H), 7.19 (dd, J = 7.7, 1.5 Hz, 1H), 7.11 (dd, J = 10.1, 1.5 Hz, 1H) , 5.74 (d, J = 3.8 Hz, 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 = 5.8 Hz, 1H), 2.66 (d, J = 2.2 Hz, 1H), 1.91 (d, J = 11.1 Hz, 3H); LC-MS (ESI): m/z 314.2 [M+H] ⁺ .

2-[4-(4-Methoxypiperidin-1-yl)-formyl-2-fluoro-phenyl]-5-chloro-pyrrole[1,2-b]pyridazine-7-carboxamide ( Method for preparing compound I-23)

Compound 30 (330 mg, 1.2 mmol), Compound 6 (180 mg, 0.6 mmol) was used as a starting material to give a yellow solid (yield: 44 mg).

^{1 H NMR (300MHz, DMSO-} d 6) δ8.27 (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, 1.5 Hz, 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 = 16.3 Hz, 2H); LC-MS (ESI): m/z 431.2 [M+H] ⁺ .

Preparation method of 2-fluoro-4-(3-fluoro-4-methoxypiperidin-1-yl)formylbenzaldehyde (Compound 31)

2-fluoro-4-formyl-benzoic acid (370 mg, 2.2 mmol) and 3-fluoro-4-methoxypiperidine (340 mg, 2 mmol) were used as starting materials. The solid was 320 mg in a yield of 56%.

_{^{1 H NMR (300MHz, CDCl 3}} ) δ10.38 (d, J = 0.8Hz, 1H), 7.93 (dd, J = 7.9,6.8Hz, 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] +.

Process for preparing 3-fluoro-4-(1-hydroxy-propyn-2-yl)-phenyl-(3-fluoro-4-methoxypiperidin-1-yl)methyl ketone (Compound 32)

Compound 31 (320 mg, 1.1 mmol) and ethynylmagnesium bromide in THF (0.5 M, 4.2 mmol) were used as a starting material.

_{^{1 H NMR (300MHz, CDCl 3}} ) δ7.72 (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 = 2.2 Hz, 1H), 2.57-2.53 (m, 1H), 1.96-1.90 (m, 1H); LC-MS (ESI): m/z 332.2 [M+H] ⁺ .

2-[2-Fluoro-4-(3-fluoro-4-methoxy-piperidin-1-yl)-formylphenyl]-5-chloro-pyrrole[1,2-b]pyridazine-7 Method for preparing formamide (Compound I-24)

Compound 32 (190 mg, 0.6 mmol), compound 6 (115 mg, 0.38 mmol), Pd(OAc) ₂ (5 mg), CuI (1 mg) and DBU (300 mg) The preparation method gave 20 mg of a yellow solid in a two-step total yield of 12%.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.28 (d, J = 9.4 Hz, 1H), 8.17 (d, J = 3.0 Hz, 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 = 20.0 Hz, 1H), 3.83 (d, J = 14.4 Hz, 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 = 17.1 Hz, 2H); LC-MS (ESI): m/z 449.2 [M +H] ⁺ .

Preparation method of 2-fluoro-4-(3-methoxypyrroline-1-yl)formylbenzaldehyde (Compound 33)

3-fluoro-4-formylbenzoic acid (370 mg, 2.2 mmol) and 3-methoxypyrroline (274 mg, 2 mmol, which was prepared by reference to US2011092475A1) were prepared according to the preparation method of compound 25. White solid 240 mg, yield 48%.

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

Process for preparing 3-fluoro-4-(1-hydroxy-propyn-2-yl)-phenyl-(3-methoxy-pyrrolidin-1-yl)methyl ketone (Compound 34)

Compound 33 (240 mg, 1 mmol) and ethynylmagnesium bromide in THF (0.5 M, 3 mL) were used as a starting material.

_{1H NMR (300MHz, CDCl 3)} δ7.68 (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, 5.2 Hz, 2H), 3.68-3.39 (m, 2H), 3.31 (d, J = 29.2 Hz, 3H), 3.18 (t, J = 5.4 Hz, 1H), 2.64 (d, J = 2.3 Hz, 1H), 2.18-1.82 (m, 2H); LC-MS (ESI): m/z 300.2 [M+Na] ⁺ .

2-[2-Fluoro-4-(3-methoxypyrrolidin-1-yl)formylphenyl]-5-chloro-pyrrole[1,2-b]pyridazine-7-carboxamide (Compound I -25) preparation method

Compound 34 (180 mg, 0.65 mmol), compound 6 (120 mg, 0.4 mmol), Pd (OAc) ₂ (5 mg), CuI (1 mg) and DBU (300 mg) The preparation method gave 23 mg of a yellow solid with a total yield of 14% in two steps.

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.31 (dd, J = 9.5, 1.4 Hz, 1H), 8.20 (d, J = 3.7 Hz, 1H), 8.00 (tt, J = 7.9, 4.6 Hz, 2H), 7.62 (dd, J = 11.1, 1.6 Hz, 1H), 7.57 (d, J = 9.0 Hz, 2H), 7.46 (dt, J = 9.6, 2.3 Hz, 1H), 4.01 (dtt, J = 39.6) , 4.6, 2.2 Hz, 1H), 3.72-3.46 (m, 4H), 3.24 (d, J = 47.8 Hz, 3H), 2.06-1.94 (m, 2H); LC-MS (ESI): m/z 417. 2[M+H] ⁺ .

Preparation method of 4-(3-methoxypyrroline-1-yl)-formylbenzaldehyde (Compound 35)

4-formylbenzoic acid (330 mg, 2.2 mmol) and 3-methoxypyrrolidine (274 mg, 2 mmol) were used as a starting material to give a white solid.

LC-MS (ESI): m / z 234.2 [M + H] +.

Method for preparing 4-(1-hydroxy-propyn-2-yl)-phenyl-(3-methoxypyrrolidin-1-yl)methyl ketone (Compound 36)

Compound 35 (320 mg, 1.4 mmol) and ethynylmagnesium bromide in THF (0.5 M, 5 mL) were used as a starting material.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.72 - 7.32 (m, 4H), 5.48 (d, J = 4.7 Hz, 1H), 3.97 (d, J = 35.4 Hz, 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 = 6.1 Hz, 1H), 2.67 (d, J = 2.1 Hz, 1H), 2.13 1.97 (m, 2H); LC -MS (ESI): m / z 282.2 [m + Na] +.

2-[4-(3-Methoxypyrroline-1-yl)-formylphenyl]-5-chloro-pyrrole[1,2-b]pyridazine-7-carboxamide (Compound I-26) Preparation method

Compound 36 (200 mg, 0.77 mmol), compound 6 (128 mg, 0.43 mmol), Pd(OAc) ₂ (6 mg), CuI (1 mg) and DBU (327 mg) The preparation method gave 28 mg of a yellow solid with a total yield of 17% in two steps.

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.28 (dd, J = 9.4, 1.7 Hz, 1H), 8.24 (s, 1H), 8.11 (dd, J = 8.1, 5.9 Hz, 2H), 8.02 ( s, 1H), 7.72 (dd, J = 8.3, 2.1 Hz, 2H), 7.65 (dd, J = 9.5, 3.5 Hz, 1H), 7.54 (s, 1H), 4.00 (dtt, J = 43.0, 4.6, 2.2 Hz, 1H), 3.68-3.45 (m, 4H), 3.23 (d, J = 54.9 Hz, 3H), 2.06-1.91 (m, 2H); LC-MS (ESI): m/z 399.2 [M+ H] ⁺ .

Process for preparing 3-methyl-4-(3-fluoro-4-formylbenzene)-formyl-piperazin-1-yl-carboxylic acid tert-butyl ester (Compound 37)

3-fluoro-4-formylbenzoic acid (370 mg, 2.2 mmol) and 3-methylpiperazine-1-carboxylic acid tert-butyl ester (400 mg, 2 mmol) were used as a starting material. 470 mg, yield 67%.

_{^{1 H NMR (300MHz, CDCl 3}} ) δ10.38 (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 = 6.7 Hz, 3H); LC-MS (ESI): m/z 373.2 [M+Na ] ⁺ .

3-fluoro-4-(1-hydroxy-propyn-2-yl)phenyl-(2-methyl-4-tert-butoxycarbonyl-piperazin-1-yl)methyl ketone (compound 38) Preparation

Compound 37 (470 mg, 1.4 mmol) and ethynylmagnesium bromide in THF (0.5 M, 5 mL) were used as a starting material.

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

2-[2-Fluoro-4-(2-methyl-4-tert-butoxycarbonyl-piperazin-1-yl)-formylphenyl]-5-chloro-pyrrole [1,2-b] Method for preparing oxazine-7-carboxylic acid methyl ester (compound 39)

Compound 38 (350 mg, 0.93 mmol), compound 6 (155 mg, 0.52 mmol), Pd(OAc) 2 (7 mg), CuI (1 mg) and DBU (450 mg) as starting materials, and the preparation of reference compound 15 , a yellow solid of 63 mg was obtained in a yield of 23%.

LC-MS (ESI): m / z 553.2 [M + Na] +.

5-Chloro-2-[2-fluoro-4-(2-methyl-4-cyclopropylformyl-piperazin-1-yl)-formylphenyl]pyrrole[1,2-b]pyridazine Method for preparing 7-carboxamide (compound I-27)

Compound 39 (65 mg, 0.13 mmol) in 10 mL of dichloromethane was added 1.5 mL of trifluoroacetic acid. After the reaction was completed by thin layer chromatography, the pH was adjusted to be weakly basic with NaOH (2.5 M) solution under ice bath ( 8～9), the organic phase is separated, the aqueous layer is extracted with chloroform, the organic phase is combined, concentrated, and purified by column chromatography (dichloromethane:methanol = 10:1) Chloro-2-[2-fluoro-4-(2-methyl-piperazin-1-yl)-formylphenyl]pyrrole [1,2-b]pyridazine-7-carboxylic acid methyl ester); Dissolve in 10 mL of anhydrous dichloromethane, add a few drops of triethylamine and cyclopropylcarbonyl chloride (300 mg), stir at room temperature for 1 hour, add 5 mL of methanol, stir at room temperature for 10 minutes, concentrate to give crude 5-chloro- 2-[2-Fluoro-4-(2-methyl-4-cyclopropylformyl-piperazin-1-yl)-formylphenyl]pyrrole[1,2-b]pyridazine 7-carboxylic acid Ester; transfer 10 mL of methanol to a 25 mL sealed tube, add 8 mL of ammonia in methanol, react at 80-90 ° C for 20-24 hours, cool to room temperature, concentrate, column chromatography (dichloromethane: methanol = 20:1) Elution yielded 40 mg of a yellow solid with a total yield of 63% in three steps.

^{1 H NMR (300MHz, DMSO-} d 6) δ8.35-8.23 (m, 1H), 8.18 (d, J = 2.9Hz, 1H), 8.03-7.93 (m, 1H), 7.55 (d, J = 1.3 Hz, 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, 9.5 Hz , 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] ⁺ .

Method for preparing 2-methyl-4-(3-fluoro-4-formylbenzene)-formyl-piperazine-1-carboxylic acid tert-butyl ester (Compound 40)

3-fluoro-4-formylbenzoic acid (370 mg, 2.2 mmol) and 2-methylpiperazine-1-carboxylic acid tert-butyl ester (400 mg, 2 mmol) were used as a starting material. 420 mg, yield 60%.

_{^{1 H NMR (300MHz, CDCl 3}} ) 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 = 1.2 Hz, 9H), 1.30-1.01 (m, 3H); LC-MS (ESI): m/z 373.2 [M+Na ] ⁺ .

3-fluoro-4-(1-hydroxy-propyn-2-yl)-phenyl-(3-methyl-4-tert-butoxycarbonyl-piperazin-1-yl)methyl ketone (Compound 41) Preparation method

Compound 40 (420 mg, 1.2 mmol) and ethynylmagnesium bromide in THF (0.5 M, 4.3 mL) were used as a starting material.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.72 (t, J = 7.5 Hz, 1H), 7.17 (dd, J = 22.3, 8.9 Hz, 2H), 5.75 (d, J = 5.0 Hz, 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 = 6.3 Hz, 3H); LC-MS (ESI): m/z 399.2 [M+Na] ⁺ .

2-[2-Fluoro-4-(3-methyl-4-tert-butoxycarbonyl-piperazin-1-yl)-formylphenyl]-5-chloro-pyrrole [1,2-b] Method for preparing oxazine-7-carboxylic acid methyl ester (compound 42)

Compound 41 (364 mg, 0.97 mmol), Compound 6 (160 mg, 0.54 mmol), Pd(OAc) ₂ (11 mg), CuI (1 mg) and DBU (410 mg) were used as starting materials. The crude solid was obtained as a yellow solid 146 mg (yield: 52%).

¹ H NMR (300MHz, CDCl ₃ ) δ 8.14 (t, J = 7.7 Hz, 1H), 7.97 (d, J = 9.5 Hz, 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] +.

5-Chloro-2-[2-fluoro-4-(3-methyl-4-cyclopropylformyl-piperazin-1-yl)-formylphenyl]pyrrole[1,2-b]pyridazine Method for preparing 7-carboxamide (compound I-28)

Compound 42 (80 mg, 0.16 mmol) was used as a starting material. m.p.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.30 (dd, J = 9.5, 0.8 Hz, 1H), 8.19 (s, 1H), 8.01 (dd, J = 10.4, 5.3 Hz, 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, 5.1 Hz, 1H), 1.34-1.07 (m, 3H), </RTI>^</RTI>^< RTI ID=0.0>^</RTI>^</RTI>^< RTI ID=0.0>^</RTI>

Method for preparing dimethyl 2-(4-bromophenyl)malonate (compound 43)

Under ice bath, sodium silk (4.6 g, 0.2 mol) was added to 100 mL of anhydrous methanol to control the change in temperature to prevent excessive exotherm. After all Na was dissolved, the solvent was removed under vacuum to obtain a sodium methoxide solid. Further, 100 ml of methyl 4-bromophenylacetate (22 g; 0.1 mol) in anhydrous THF was added, and the mixture was stirred at room temperature for 25 minutes, and then dimethyl carbonate (42 mL, 0.5 mol) was added thereto, and the mixture was stirred at room temperature for 48 hours. 2/3 volume of solvent was removed, then water and ethyl acetate were added, the solid in the mixture was completely sonicated, the organic phase was separated, the aqueous layer was extracted with ethyl acetate, and the organic phase was combined and washed with saturated sodium chloride solution. Concentration, column chromatography (petroleum ether: ethyl acetate = 50:1) eluted to afford 20 g of white solid.

_{^{1 H NMR (300MHz, CDCl 3}} ) δ7.50 (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] +.

Method for preparing trimethyl 1-(4-bromophenyl)-propane-1,1,3-tricarboxylate (compound 44)

Add Na silk (370 mg, 16 mmol) to 100 mL of anhydrous methanol under ice-cooling. After all dissolved, add 2-(4-bromophenyl)malonic acid dimethyl ester (10 g, 35 mmol), stir at room temperature After 30 minutes, methyl acrylate (8 mL) was further added, and the mixture was stirred at room temperature for 24 hours, and directly added to silica gel column chromatography ( petroleum ether: ethyl acetate = 100:1) to afford 9 g of white solid.

¹ H NMR (300MHz, CDCl ₃ ) δ 7.51 - 7.42 (d, J = 8.7 Hz, 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] ⁺ .

Method for preparing 2-(4-bromophenyl)penta-1,5-dioic acid (Compound 45)

Compound 44 (5.2 g, 14 mmol) was added to a 250 mL round bottom flask, potassium hydroxide solid (3.8 g, 67.2 mmol) and water 100 mL were added, and stirred at 110 ° C for 3 hours. After cooling to room temperature, concentrated sulfuric acid was added. The mixture was stirred at 110 ° C for 9 hours, cooled to room temperature, extracted twice with ethyl acetate. The organic phase was combined, concentrated, and purified by column chromatography (trichloromethane:methanol = 50:1) to yield 3.6 g of oil. The rate is 90%.

H-NMR (300 MHz, CDCl ₃ ) δ 7.47 (d, J = 8.5 Hz, 2H), 7.18 (d, J = 8.5 Hz, 2H), 3.63 (t, J = 7.5 Hz, 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] +.

Method for preparing 2-(4-bromophenyl)penta-1,5-dihydroxy-bis(4-toluenesulfonate) (Compound 46)

Compound 45 (3.6 g, 12.6 mmol) in anhydrous THF 80 mL, slowly added to a solution of BH ₃ in THF (1 M, purchased from Shanghai Darui Chemical Co., Ltd.) 50 mL through a constant pressure dropping funnel, and added at room temperature for about 25 minutes. After stirring for 1 hour, the methanol solution was slowly added dropwise until no more bubbles were formed. Stirring was continued for 30 minutes. The solvent was removed under reduced pressure in vacuo. Water and ethyl acetate (100 mL) were evaporated. The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated, evaporated, evaporated, evaporated, evaporated, evaporated 4-toluenesulfonyl chloride (7.5 g, 40 mmol) was added in two portions, stirred at room temperature overnight, 10 mL of 3N HCl solution was added, and after stirring for 10 min, 50 mL of water was added, then the organic phase was separated and the aqueous layer was extracted with dichloromethane. The combined organic phases were concentrated and purified with EtOAc EtOAc EtOAc EtOAc

_{H-NMR (300MHz, CDCl 3} ) δ7.74 (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 = 8.1 Hz, 2H), 6.86 (d, J = 8.4 Hz, 2H), 4.04-3.96 (m, 1H), 3.91 (t, J = 5.9 Hz, 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] ⁺ .

Process for preparing 3-(4-bromophenyl)-1-(4-methoxybenzyl)-piperidine (compound 47)

To a solution of compound 46 (1.85 g, 3.2 mmol) in EtOAc EtOAc (EtOAc (EtOAc) Column chromatography (petroleum ether: ethyl acetate = 25:1) eluted to afford a white solid (yield:

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.42-7.36 (m, 2H), 7.25-7.18 (m, 2H), 7.08 (d, J = 8.4 Hz, 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, 3.7 Hz, 1H), 1.92-1.84 (m, 2H), 1.79-1.63 ( m, 3H), 1.39 (qd, J = 12.0, 4.9 Hz, 1H); LC-MS (ESI): m/z 360.2 [M+H] ⁺ , 362.2 [M+3H] ⁺ .

Method for preparing 3-(4-bromophenyl)piperidine (compound 48)

To a solution of compound 47 (1.8 g, 5 mmol) in EtOAc (EtOAc (EtOAc) The organic phase was washed with a saturated aqueous solution of sodium chloride, and concentrated and purified by column chromatography (dichloromethane:methanol = 10:1) to yield 1 g.

_{^{1 H NMR (300MHz, CDCl 3}} ) δ7.42 (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, 1.3 Hz, 1H), 3.16-2.98 (m, 3H), 2.06 (d, J = 4.2 Hz, 3H); LC-MS (ESI): m/z 240.2 [M+H] ⁺ , 242.2 [M+3H] ⁺ .

Method for preparing tert-butyl 3-(4-bromophenyl)piperidine-1-carboxylate (Compound 49)

To a solution of compound 48 (600 mg, 2.5 mmol) in dichloromethane (1 mL), EtOAc (1 mL, EtOAc, EtOAc (EtOAc) The mixture was stirred for 10 minutes, the organic phase was separated, the aqueous layer was extracted with methylene chloride, and the organic phase was combined, washed with saturated sodium chloride, concentrated, and purified by column chromatography ( petroleum ether: ethyl acetate = 80:1) A white solid of 460 mg was obtained in a yield of 54%.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ7.46-7.39 (d, J = 8.3Hz, 2H), 7.13-7.06 (d, J = 8.3Hz, 2H), 4.13 (s, 2H), 2.68 (dd, J=28.8, 11.4 Hz, 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] ⁺ .

Method for preparing tert-butyl 3-(4-formylphenyl)-piperidine-1-carboxylate (Compound 50)

Take a pre-dried 250 mL three-necked flask, add 50 ml of compound 49 (500 mg, 1.5 mmol) in anhydrous THF, under Ar ₂ protection, cool to -78 ° C, slowly add n-BuLi (2.5 M, 1 mL), continue to stir at this temperature for 30 minutes, then add 5 mL of anhydrous DMF, continue stirring for 2 hours, then add 10 mL of saturated ammonium chloride solution, stir for 10 minutes, then transfer to room temperature and stir for 30 minutes to separate organic The aqueous layer was extracted with EtOAc. EtOAc (EtOAc)EtOAc.

_{^{1 H NMR (300MHz, CDCl 3}} ) 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 =13.3 Hz, 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] ⁺ .

Method for preparing tert-butyl 3-[4-(1-hydroxy-propyn-2-yl)phenyl]-piperidine-1-carboxylate (Compound 51)

Add 50 mL of a solution of compound 50 (280 mg, 1 mmol) in anhydrous THF, EtOAc (0.5 M, 4 mL), EtOAc. After the organic phase was separated, the aqueous layer was extracted with ethyl acetate. EtOAc (EtOAc)EtOAc. The yield was 63%.

_{^{1 H NMR (300MHz, CDCl 3}} ) δ7.50 (d, J = 8.1Hz, 2H), 7.30-7.21 (d, J = 8.1Hz, 2H), 5.45 (dd, J = 6.2,2.2Hz, 1H) , 4.12 (dd, J = 15.3, 9.0 Hz, 2H), 2.84 - 2.54 (m, 4H), 2.30 (d, J = 6.2 Hz, 1H), 2.04-1.94 (m, 1H), 1.75 (dt, J = 8.7, 2.8 Hz, 1H), 1.58 (d, J = 3.3 Hz, 1H), 1.46 (s, 9H); LC-MS (ESI): m/z 338.2 [M+Na] ⁺ .

Preparation of methyl 5-chloro-2-[4-(1-tert-butoxyformylpiperidin-3-yl)phenyl]pyrrole [1,2-b]pyridazine-7-carboxylate (Compound 52) method

Take a 25 mL microwave tube with a microwave cap and add compound 51 (200 mg, 0.63 mmol), compound 6 (120 mg, 0.4 mmol), palladium acetate (5 mg), cuprous iodide (1 mg) and toluene After 10 ml, N _{2 was} replaced 3 times, DBU (300 mg) was added under N ₂ protection, the microwave cap was capped, and the reaction was carried out at 90 ° C for 40 minutes under microwave (λ = 180 W). After cooling to room temperature, chloroform was diluted. It was transferred to a 100 ml round bottom flask, concentrated, and purified by column chromatography (ethyl ether: ethyl acetate = 7:1).

_{^{1 H NMR (300MHz, CDCl 3}} ) δ8.01 (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, 1.1 Hz, 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] ⁺ .

Preparation method of 5-chloro-2-[4-(1-tert-butoxyformylpiperidin-3-yl)phenyl]pyrrole [1,2-b]pyridazine-7-carboxamide (compound 53)

20 ml of compound 52 (145 mg, 0.31 mmol) in methanol was added to a 50 ml sealed tube, 15 ml of a methanol solution of ammonia was added, and the reaction was sealed at 90 ° C for 20 hours. After cooling to room temperature, concentrated, column chromatography (two Methyl chloride:methanol = 50:1) eluted to give a yellow solid, 110 mg, yield 78%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.80 (d, J = 3.7 Hz, 1H), 8.00 (d, J = 9.4 Hz, 1H), 7.85 - 7.74 (m, 2H), 7.63 (d, J = 0.5 Hz, 1H), 7.41 (d, J = 8.3 Hz, 2H), 7.23 (d, J = 9.4 Hz, 1H), 5.97 (s, 1H), 4.17 (s, 2H), 2.91-2.63 (m, 3H), 2.07 (d, J = 12.1 Hz, 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-butoxyformylpiperidin-3-yl]-phenyl)-5-chloro-pyrrole[1,2-b]pyridazine-7-carboxamide (Compound 53 -S) preparation method

Racemate 53 chiral separation by chiral SFC purification, CO ₂ as supercritical fluid, chiral column: Chiralcel OJ-H, 0.46 cm ID × 25 cm L, flow rate: 2.5 mL/min, detection wavelength: UV 254 nm, Column temperature: 35 ° C, mobile phase: CO ₂ : MeOH: DEA = 60: 40: 0.1. The retention time of the first enantiomer was 8.68 min and the solvent was removed in vacuo to give a yellow solid: 2-(4-[(3R)-tert-butoxyformylpiperidin-3-yl]-phenyl)-5 -Chloro-pyrrole [1,2-b]pyridazine-7-carboxamide (Compound 53-R, 99.9% ee). The retention time of the second enantiomer was 9.07 min. The solvent was removed in vacuo to give a yellow solid: 2-[4-[(3S)-tert-butoxyformylpiperidin-3-yl]-phenyl]-5 -Chloro-pyrrole [1,2-b]pyridazine-7-carboxamide (Compound 53-S, 98% ee).

-90.4, ¹ H NMR (400MHz, CDCl ₃ ) δ 8.80 (d, J = 3.7 Hz, 1H), 8.00 (d, J = 9.4 Hz, 1H), 7.85 - 7.74 (m, 2H), 7.63 (d) , J = 0.5 Hz, 1H), 7.41 (d, J = 8.3 Hz, 2H), 7.23 (d, J = 9.4 Hz, 1H), 5.97 (s, 1H), 4.17 (s, 2H), 2.91-2.63 (m, 3H) 2.07 (d, J = 12.1 Hz, 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] ⁺ . No need to delete

2-[4-[(3R)-tert-butoxyformylpiperidin-3-yl]-phenyl]-5-chloro-pyrrole[1,2-b]pyridazine-7-carboxamide (Compound 53 -R) preparation method

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

Preparation method of 5-chloro-2-[4-(piperidin-3-yl)phenyl]pyrrole [1,2-b]pyridazine-7-carboxamide (Compound I-29)

To a solution of compound 53 (50 mg, 0.11 mmol) in chloroform (10 mL), trifluoroacetic acid (1.8 mL) was added, and the mixture was stirred at room temperature for 1 hour, and the pH was adjusted to be weakly alkaline with an NaOH solution (2.5 M) in an ice bath. ～9), the organic phase is separated, the aqueous layer is extracted with chloroform, the organic phase is combined, washed with saturated brine, concentrated, and purified by column chromatography (dichloromethane: methanol = 10:1, 5 ml of 1 L eluent) The ammonia solution in methanol) eluted to give a yellow solid, 35 mg, yield 90%.

H-NMR; LC-MS ( ESI): m / z 355.2 [M + H] +.

Process for preparing 5-chloro-2-[4-((3S)-piperidin-3-yl)phenyl]pyrrole [1,2-b]pyridazine-7-carboxamide (Compound I-30)

The compound 53-S (50 mg, 0.11 mmol) was used as a material.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.79 (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 = 8.3 Hz, 2H), 7.21 (d, J = 9.5 Hz, 1H), 6.16 (d, J = 3.8 Hz, 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 ] ⁺ .

Process for preparing 5-chloro-2-[4-((3R)-piperidin-3-yl)phenyl]pyrrole [1,2-b]pyridazine-7-carboxamide (Compound I-31)

The compound 53-R (50 mg, 0.11 mmol) was used as a material.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.79 (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 = 8.3 Hz, 2H), 7.21 (d, J = 9.5 Hz, 1H), 6.16 (d, J = 3.8 Hz, 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 ] ⁺ .

Method for preparing 6,7-dihydrothiophene [3,2-c]pyridine-5(4H)-carboxylic acid tert-butyl ester (Compound 54)

4,5,6,7-tetrahydrothiophene [3,2-c]pyridine hydrochloride (10 g, 56.9 mmol) in 150 mL of dichloromethane, EtOAc (EtOAc) The methylene chloride solution was stirred at room temperature for 1 hour, 20 ml of a saturated ammonium chloride solution was added, and after stirring for 10 minutes, the organic phase was separated, the aqueous layer was extracted with dichloromethane, and the organic phase was combined and washed with saturated sodium chloride Dry over anhydrous sodium sulfate and concentrate to give 12.5 g of white solid.

¹ H NMR (300MHz, CDCl ₃ ) δ 7.12 (d, J = 5.1 Hz, 1H), 6.78 (d, J = 5.1 Hz, 1H), 4.50 (s, 2H), 3.71 (t, J = 5.3 Hz) , 2H), 2.84 (t, J = 5.3 Hz, 2H), 1.48 (s, 9H); LC-MS (ESI): m/z 240.2 [M+H] ⁺ .

Method for preparing 2-formyl-6,7-dihydrothiophene [3,2-c]pyridine-5(4H)-carboxylic acid tert-butyl ester (Compound 55)

Take a pre-dried 250mL three-necked flask, add 50mL of compound 54 (5.3g, 22.2mmol) in anhydrous THF, under Ar ₂ protection, cool to -78 ° C, slowly add n-BuLi (1.6M) , 22mL), continue to stir at this temperature for 30 minutes, then add 5 ml of anhydrous DMF, continue to stir for 2 hours, then add 10 ml of saturated ammonium chloride solution, stir for 10 minutes, then transfer to room temperature and stir for 30 minutes, separate The organic phase was separated, and the aqueous layer was evaporated,jjjjjjjjjjjjjjj %.

_{^{1 H NMR (300MHz, CDCl 3}} ) δ9.83 (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-Hydroxy-propyn-2-yl)-6,7-dihydrothiophene[3,2-c]pyridine-5(4H)-carboxylic acid tert-butyl ester (Preparation method of compound 56)

Compound 55 (2.3 g, 8.4 mmol) in anhydrous THF (40 mL), EtOAc (EtOAc, m. 30 ml of the solution, after stirring for 10 minutes, the organic phase was separated, the aqueous layer was extracted with ethyl acetate, and the organic phase was combined, washed with brine, concentrated, and purified by column chromatography ( petroleum ether: ethyl acetate = 8:1) The yellow solid was obtained in an amount of 1.8 g, yield 72%.

H-NMR (300MHz, CDCl ₃ ) δ 6.89 (d, J = 0.9 Hz, 1H), 5.57 (d, J = 2.5 Hz, 1H), 4.43 (t, J = 1.7 Hz, 2H), 3.75-3.65 (m, 2H), 2.80 (d, J = 6.0 Hz, 2H), 2.68 (d, J = 2.2 Hz, 1H), 1.48 (s, 9H).

2-[5-Chloro-7-methoxyformylpyrrole[1,2-b]pyridazin-2-yl]-6,7-dihydrothiophene[3,2-c]pyridine-5(4H) -Preparation method of tert-butyl formate (compound 57)

A 25 mL microwave tube with a microwave cap was added and compound 56 (470 mg, 1.6 mmol), compound 6 (330 mg, 1.1 mmol), palladium acetate (15 mg), cuprous iodide (2 mg) and toluene were added. After 10 mL, N _{2 was} replaced 3 times, DBU (840 mg) was added under N ₂ protection, the microwave cap was capped, and the reaction was carried out at 90 ° C for 40 minutes under microwave (λ = 180 W). After cooling to room temperature, chloroform was diluted, and It was transferred to a 100 ml round bottom flask, concentrated, and purified by column chromatography ( petroleum ether: ethyl acetate = 7:1) to yield 135 mg of a yellow solid.

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

Methyl 5-chloro-2-(4,5,6,7-tetrahydrothiophene[3,2-c]pyridin-2-yl)pyrrole[1,2-b]pyridazine-7-carboxylate (Compound 58 Preparation method

Compound 25 (440 mg, 0.98 mmol) in 25 ml of chloroform, added 2.5 mL of trifluoroacetic acid, and stirred at room temperature for 1 hour. After the reaction was completed by TLC, the pH was adjusted with NaOH (2.5 M) in an ice bath. 8～9, the organic phase is separated, the aqueous layer is extracted with chloroform, the organic phase is combined, washed with saturated sodium chloride solution, concentrated, and purified by column chromatography (dichloromethane:methanol=50:1) to obtain a yellow solid 250 Mg, yield 74%.

LC-MS (ESI): m / z 348.2 [M + H] +.

Methyl 2-(4,5,6,7-tetrahydrothiophene[3,2-c]pyridin-2-yl)-5-chloro-pyrrole[1,2-b]pyridazine-7-carboxylate (compound Preparation method of I-32)

10 ml of a solution of compound 58 (250 mg) in methanol was added to a 25 ml sealed tube, and 8 ml of a methanol solution of ammonia was added thereto, and the reaction was carried out at 90 ° C for 20 hours, and after cooling to room temperature, the volume of the reaction solution was rotated under reduced pressure. /3, the precipitated solid was filtered and dried in vacuo to give a yellow solid (yield: 180 mg).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.10 (dd, J = 24.6, 13.5 Hz, 3H), 7.69 (s, 1H), 7.51 (d, J = 9.5 Hz, 1H), 7.41 (s, 1H), 3.85 (s, 2H), 3.06 (d, J = 6.0 Hz, 2H), 2.80 (d, J = 6.0 Hz, 2H); LC-MS (ESI): m/z 333.2 [M+H] ⁺ .

5-Chloro-2-(5-methyl-4,5,6,7-tetrahydrothiophene[3,2-c]pyridin-2-yl)pyrrole[1,2-b]pyridazine-7-carboxylic acid Method for preparing methyl ester (compound I-33)

To a solution of compound 58 (75 mg, 0.21 mmol) in methanol (5 mL), add a few drops of acetic acid and 1.5% of a solution of 1.5% of formaldehyde, and then stirred at room temperature for 10 minutes, then added NaCNBH ₃ (50 mg), stirred at room temperature overnight, concentrated, column chromatography (dichloromethane: methanol = 25: 1) to afford 55 mg of crude product, LC-MS (ESI): m / z 361.2 [m + H] +. Transfer to a 25 mL sealed tube with 10 mL of methanol, add 8 mL of ammonia in methanol, and react at 90 ° C for 20 hours. After cooling to room temperature, the volume of the reaction solution was reduced by 2/3, and the precipitated solid was filtered and dried in vacuo. 52 mg was obtained with a yield of 71%.

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

Method for preparing 4,5-dihydrothiophene [2,3-c]pyridine-6(7H)-carboxylic acid tert-butyl ester (Compound 59)

To 50 ml of 4,5,6,7-tetrahydrothiophene [2,3-c]pyridine hydrochloride (3 g, 17.1 mmol) in dichloromethane, 2 mL of triethylamine, Boc anhydride (4.1 g, 18.9 mmol) of a solution of dichloromethane (10 mL), stirring at room temperature for 1 hour, adding 20 mL of saturated ammonium chloride solution, stirring for 10 minutes, then separating the organic phase, the aqueous layer was extracted with dichloromethane, and the organic phase, saturated The solution was washed with sodium chloride, dried over anhydrous sodium sulfate and evaporated.

¹ H NMR (300MHz, CDCl ₃ ) δ 7.13 (d, J = 5.0 Hz, 1H), 6.79 (d, J = 5.1 Hz, 1H), 4.62 (s, 2H), 3.67 (t, J = 5.4 Hz) , 2H), 2.70 (t, J = 5.4 Hz, 2H), 1.8 (s, 9H); LC-MS (ESI): m/z 240.2 [M+H] ⁺ .

Preparation method of 2-bromo-4,5-dihydrothiophene [2,3-c]pyridine-6(7H)-carboxylic acid tert-butyl ester (compound 60)

NBS (3.3 g, 18.8 mmol) was added to a solution of EtOAc (EtOAc, EtOAc (EtOAc) A yellow oil 4.8 g was obtained in a yield of 89%.

LC-MS (ESI): m / z 318.2 [M + H] +.

Process for preparing 2-formyl-4,5-dihydrothiophene [2,3-c]pyridine-6(7H)-carboxylic acid tert-butyl ester (Compound 61)

Take a pre-dried 250 mL three-necked flask, add 50 mL of compound 60 (4.8 g, 15.1 mmol) in anhydrous THF, under Ar ₂ protection, cool to -78 ° C, slowly add n-BuLi (1.6 M) , 17mL), continue to stir at this temperature for 30 minutes, then add anhydrous DMF 5mL, continue to stir for 2 hours, then add 10mL of saturated ammonium chloride solution, stir for 10 minutes, then transfer to room temperature and stir for 30 minutes, separate organic The aqueous layer was extracted with EtOAc. EtOAc (EtOAc)EtOAc.

_{^{1 H NMR (300MHz, CDCl 3}} ) δ9.84 (d, J = 1.1Hz, 1H), 7.48 (s, 1H), 4.68 (s, 2H), 3.69 (t, J = 5.6Hz, 2H), 2.75 (t, J = 5.8 Hz, 2H), 1.48 (s, 9H); LC-MS (ESI): m/z 268.2 [M+H] ⁺ .

Process for preparing 2-(1-hydroxy-propyn-2-yl)-4,5-dihydrothiophene [2,3-c]pyridine-6(7H)-carboxylic acid tert-butyl ester (Compound 62)

Compound 61 (3.1 g, 11.6 mmol) and ethynylmagnesium bromide in THF (0.5 M, 42 mL) were used as a starting material.

_{^{1 H NMR (300MHz, CDCl 3}} ) δ6.89 (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 = 6.9 Hz, 1H), 1.48 (d, J = 2.5 Hz, 9H); LC-MS (ESI): m/z 316.2 [M+Na] ⁺ .

5-Chloro-2-(5-tert-butoxycarbonyl-4,5-dihydrothiophene[2,3-c]pyridin-2-yl)pyrrole[1,2-b]pyridazine-7-carboxylic acid Method for preparing ester (compound 63)

Compound 62 (228 mg, 0,78 mmol), compound 6 (50 mg, 0.16 mmol), Pd(OAc) ₂ (8 mg), CuI (1 mg) and DBU (460 mg) as starting material, Preparation of Reference Compound 57 Method, 20 mg of a yellow solid was obtained in a yield of 28%.

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

Process for preparing methyl 5-chloro-2-(4,5-dihydrothiophene [2,3-c]pyridin-2-yl)pyrrole [1,2-b]pyridazine-7-carboxylate (Compound 64)

Compound 63 (450 mg, 1 mmol) was used as a material.

LC-MS (ESI): m / z 348.2 [M + H] +.

Preparation of 5-Chloro-2-(4,5-dihydrothiophene[2,3-c]pyridin-2-yl)pyrrole[1,2-b]pyridazine-7-carboxamide (Compound I-34) method

Compound 64 (310 mg, 0.9 mmol) was used as a starting material. m.p.

_{^{1 H NMR (300MHz, CDCl 3}} ) δ7.73 (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 = 5.8 Hz 2H), 2.64 (t, J = 5.8 Hz, 2H); LC-MS (ESI): m/z 333.2 [M+H] ⁺ .

5-Chloro-2-(6-methyl-4,5-dihydrothiophene[2,3-c]pyridin-2-yl)pyrrole[1,2-b]pyridazine-7-carboxamide (Compound I -35) preparation method

The compound I-34 (75 mg, 0.21 mmol) was used as a starting material. m.p.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.21 (d, J = 9.5 Hz, 1H), 7.78 (d, J = 2.0 Hz, 1H), 7.59 (d, J = 9.5 Hz, 1H), 7.45 (s, 1H), 4.49 (s, 2H), 3.49 (d, J = 5.1 Hz, 2H), 3.00 (d, J = 6.0 Hz, 2H), 2.92 (s, 3H); LC-MS (ESI) :m/z 347.2 [M+H] ⁺ .

Method for preparing 7-tert-butyl-4,5-dihydrothiophene [2,3-c]pyridine (compound 65)

To a solution of 3-thiophenethylamine hydrochloride (500 mg, 3.7 mmol, purchased from EtOAc) (25 mL), m. After the addition of 5 ml of methanol, stirring was continued for 10 minutes, then concentrated to give the title compound mjjjjjjjjjjjjjjjjjjjj (M+H). 3 ml of POCl ₃ was added to the above oil, and stirred at 65 ° C for 3 hours. After cooling to room temperature, the solvent was removed under reduced pressure, then 10 ml of ice water mixture was added, and pH was adjusted to 7 with NaOH (2.5 M). It was extracted with ethyl acetate (20 ml × 2) and dried over anhydrous sodium sulfate.

LC-MS (ESI): m / z 194 [M + H] +.

Preparation method of 2-bromo-7-tert-butyl-4,5-dihydrothiophene [2,3-c]pyridine-6(7H)-carboxylic acid tert-butyl ester (compound 66)

To compound 65 (580 mg, 3 mmol of) in 5 ml of anhydrous methanol, 2 times added NaBH ₄ (240 mg, 6.3 mmol), stirred at room temperature for 2 hours and then under reduced pressure rotary evaporation, and 10 ml of ethyl acetate was added 10 ml of a saturated sodium chloride solution, the organic phase was separated, and the aqueous layer was evaporated. Tetrahydrothiophene [2,3-c]pyridine, LC-MS (ESI): m/z 196 (M+H); (654 mg, 3 mmol) in dichloromethane (5 ml), stirring at room temperature for 1 hour, then adding ammonium chloride solution, stirring was continued for 10 minutes, the organic phase was separated, and the aqueous layer was extracted with dichloromethane. The oil was concentrated to give 950 mg (yield: EtOAc, EtOAc, EtOAc (EtOAc: EtOAc) 1.0 g of a colorless oil was obtained with a total yield of 84% in three steps.

LC-MS (ESI): m / z 396.2 [M + Na] +.

Process for preparing 2-formyl-7-tert-butyl-4,5-dihydrothiophene [2,3-c]pyridine-6(7H)-carboxylic acid tert-butyl ester (Compound 67)

Using a compound 66 (1.0 g, 2.7 mmol) as a starting material, a compound of the compound 61 was obtained to give a crude oil (yield: 450 mg).

_{^{1 H NMR (300MHz, CDCl 3}} ) δ9.85 (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-Hydroxy-propyn-2-yl)-7-tert-butyl-4,5-dihydrothiophene[2,3-c]pyridine-6(7H)-carboxylic acid tert-butyl ester (Compound 68) Preparation method

Compound 67 (420 mg, 1.3 mmol) and ethynylmagnesium bromide in THF (0.5 M, 5 mL) were used as a starting material.

¹ H NMR (300MHz, CDCl ₃ ) δ 6.90 (dd, J = 6.8, 2.9 Hz, 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] ⁺ .

5-Chloro-2-(6-tert-butoxycarbonyl-7-tert-butyl-4,5-dihydrothiophene[2,3-c]pyridin-2-yl)pyrrole [1,2-b] Method for preparing oxazine-7-carboxylic acid methyl ester (compound 69)

Compound 68 (320 mg, 0.9 mmol), compound 6 (170 mg, 0.6 mmol), Pd(OAc) ₂ (7 mg), CuI (1 mg) and DBU (900 mg) as starting materials, and the preparation of reference compound 62 , a yellow solid of 90 mg was obtained in a yield of 30%.

_{^{1 H NMR (300MHz, CDCl 3}} ) δ7.89-7.80 (m, 1H), 7.42 (s, 1H), 7.39 (d, J = 6.0Hz, 1H), 7.19 (dd, J = 9.4,3.9Hz, 1H), 5.10 (d, J = 53.8 Hz, 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-tetrahydrothiophene[2,3-c]pyridin-2-yl)-5-chloro-pyrrole[1,2-b]pyridazine-7 -Preparation method of methyl formate (compound 70)

Compound 69 (90 mg, 0.18 mmol) was used as a starting material. mp.

¹ H NMR (300MHz, CDCl ₃ ) δ 7.84 (d, J = 9.4 Hz, 1H), 7.44 - 7.37 (m, 2H), 7.20 (d, J = 9.5 Hz, 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-tetrahydrothiophene[2,3-c]pyridin-2-yl)-5-chloro-pyrrole[1,2-b]pyridazine-7 Method for preparing formamide (Compound I-36)

Compound 70 (65 mg, 0.17 mmol) was used as a starting material. m.p.

1H NMR (300MHz, CD ₃ OD) δ 7.98 (d, J = 9.5 Hz, 1H), 7.77 (s, 1H), 7.77 (s, 1H), 7.49 (s, 1H), 7.43 (s, 1H) , 7.38 (d, J = 9.5 Hz, 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] +.

Method for preparing 7-isobutyl-4,5-dihydrothiophene [2,3-c]pyridine (compound 71)

3-Thienylethylamine hydrochloride (500 mg, 3.1 mmol) and isovaleryl chloride (445 mg, 3.7 mmol) were used as a starting material, and the preparation of Compound 65 gave 560 mg of colorless oil. %.

LC-MS (ESI): m / z 194 [M + H] +.

Method for preparing 2-bromo-7-isobutyl-4,5-dihydrothiophene [2,3-c]pyridine-6(7H)-carboxylic acid tert-butyl ester (Compound 72)

Compound 71 (560 mg, 2.9 mmol) was used as a material.

¹ H NMR (300MHz, CDCl ₃ ) δ 6.71 (s, 1H), 5.18 (d, J = 57.9 Hz, 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 = 6.2 Hz, 3H), 0.95 (d, J = </RTI>^</RTI>^</RTI>^</RTI>^< RTI ID=0.0>^</RTI>^</RTI>^<RTIgt;

Process for preparing 2-formyl-7-isobutyl-4,5-dihydrothiophene [2,3-c]pyridine-6(7H)-carboxylic acid tert-butyl ester (Compound 73)

The compound 72 (866 mg, 2.3 mmol) was used as a starting material, and 357 mg of a colorless oil was obtained with reference to the preparation of compound 61, yield 50%.

¹ H NMR (300 MHz, CDCl ₃ ) 9.83 (s, 1H), 7.44 (s, 1H), 5.36 (d, J = 61.8 Hz, 1H), 4.28 (d, J = 59.6 Hz, 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 = 6.3 Hz) , 3H), 0.97 (d, J = 6.4 Hz, 3H); LC-MS (ESI): m/z 324.2 [M+H] ⁺ .

2-(1-Hydroxy-propyn-2-yl)-7-isobutyl-4,5-dihydrothiophene[2,3-c]pyridine-6(7H)-carboxylic acid tert-butyl ester (Compound 74) Preparation method

Compound 73 (370 mg, 1.2 mmol) and ethynylmagnesium bromide in THF (0.5 M, 3.5 mL) were used as a starting material.

_{1H NMR (300MHz, CDCl 3)} δ6.86 (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 = 6.3 Hz, 3H), 0.96 (d, J = 6.3 Hz, 3H); LC-MS (ESI): m/z 350.2 [M+H] ⁺ .

2-(6-tert-butoxycarbonyl-7-isobutyl-4,5-dihydrothiophene[2,3-c]pyridin-2-yl)pyrrole[1,2-b]pyridazine-7 -Preparation method of methyl formate (compound 75)

Compound 74 (330 mg, 0.95 mmol), Compound 6 (180 mg, 0.6 mmol), Pd(OAc) ₂ (7 mg), CuI (1 mg) and DBU (654 mg) as starting materials, Preparation of Reference Compound 62 , 165 mg of a yellow solid was obtained in a yield of 55%. LC-MS (ESI): m / z 504.2 [M + H] +.

2-(7-isobutyl-4,5,6,7-tetrahydrothiophene[2,3-c]pyridin-2-yl)-5-chloro-pyrrole[1,2-b]pyridazine-7 -Preparation method of methyl formate (compound 76)

The compound 75 (100 mg, 0.2 mmol) was used as a material. LC-MS (ESI): m / z 404.2 [M + H] +.

2-(7-isobutyl-4,5,6,7-tetrahydrothiophene[2,3-c]pyridin-2-yl)-5-chloro-pyrrole[1,2-b]pyridazine-7 Method for preparing formamide (Compound I-37)

Compound 76 (65 mg, 0.17 mmol) was used as a starting material. m.p.

_{^{1 H NMR (300MHz, CD 3}} OD) δ7.97 (dd, J = 9.5,1.7Hz, 1H), 7.67 (d, J = 1.8Hz, 1H), 7.45 (t, J = 2.2Hz, 1H), 7.35 (dd, J=9.5, 1.7 Hz, 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] +.

Method for preparing 4-cyclopropyl-6,7-dihydrothiophene [3,2-c]pyridine (compound 77)

2-Thiophenethylamine (1.3 g, 10 mmol, purchased from Tosoh Chemical) and cyclopropylcarbonyl chloride (1.3 g, 12.4 mmol) were used as a starting material.

LC-MS (ESI): m / z 178.2 [M + H] +.

Process for preparing 4-cyclopropyl-6,7-dihydrothiophene [3,2-c]pyridine-5(4H)-carboxylic acid tert-butyl ester (Compound 78)

Compound 77 (1.2 g, 7.0mmol) in 15mL of anhydrous methanol, was added three times NaBH ₄ (520 mg, 13.7 mmol), stirred at room temperature for 2 hours, the solvent was removed under reduced pressure, ethyl acetate was added 20 ml of water and 10 The organic phase was separated, EtOAc (EtOAc)EtOAc. 50 mL of dichloromethane, 2 mL of triethylamine and a solution of Boc anhydride (2.6 g, 11.8 mmol) in methylene chloride were added to the above oil, stirred at room temperature for 2 hr, then 10 ml of saturated ammonium chloride solution was added and stirring was continued for 15 min. The organic phase was separated, the aqueous layer was extracted with methylene chloride, and the organic phase was combined, washed with saturated brine, and concentrated.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.09 (d, J = 5.2 Hz, 1H), 6.90 (d, J = 5.2 Hz, 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 = 1.1 Hz, 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] +.

Method for preparing 2-formyl-4-cyclopropyl-6,7-dihydrothiophene [3,2-c]pyridine-5(4H)-carboxylic acid tert-butyl ester (Compound 79)

Compound 78 (665 mg, 2.3 mmol) was used as a material.

_{^{1 H NMR (300MHz, CDCl 3}} ) 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-Hydroxy-propyn-2-yl)-4-cyclopropyl-6,7-dihydrothiophene[3,2-c]pyridine-5(4H)-carboxylic acid tert-butyl ester (Compound 80) Preparation method

Compound 79 (260 mg, 0.85 mmol) and ethynylmagnesium bromide in THF (0.5 M, 3 mL) were used as a starting material.

_{^{1 H NMR (300MHz, CDCl 3}} ) δ6.98 (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, 5.3 Hz, 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-butoxycarbonyl-6,7-dihydrothiophene[3,2-c]pyridin-2-yl)-5-chloro-pyrrole [1,2-b Method for preparing pyridazine-7-formic acid methyl ester (compound 81)

Compound 80 (200 mg, 0.6 mmol), compound 6 (120 mg, 0.4 mmol), Pd(OAc) ₂ (6 mg), CuI (1 mg) and DBU (304 mg) were used as starting materials. The yellow oil was obtained in 80 mg, yield 41%.

LC-MS (ESI): m / z 488.2 [M + H] +.

2-(4-cyclopropyl-4,5,6,7-tetrahydrothiophene[3,2-c]pyridin-2-yl)-5-chloro-pyrrole[1,2-b]pyridazine-7 Method for preparing formamide (Compound I-38)

Compound 81 (80 mg, 0.17 mmol) in dichloromethane, 2 ml of trifluoroacetic acid was added, and stirred at room temperature for 1 hour, and the pH was adjusted to 8 to 9 with NaOH (2.5 M) in an ice bath to separate the organic phase. The aqueous layer was extracted with chloroform. EtOAc (EtOAc m. After dissolving in 10 mL of methanol, it was transferred to a 25 mL sealed tube, and reacted at 90 ° C for 24 hours. After cooling to room temperature, 2/3 volume of solvent was rotated under reduced pressure, and filtered to give a yellow solid, 35 mg, yield 56%.

1H NMR (300MHz, DMSO-d6) δ 8.18 (d, J = 9.5 Hz, 1H), 8.07 (s, 2H), 7.89 (s, 1H), 7.68 (d, J = 9.5 Hz, 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) , </RTI>^< RTI ID=0.0></RTI>^</RTI>^<RTIgt;

Method for preparing 4-isobutyl-6,7-dihydrothiophene [3,2-c]pyridine (compound 82)

2-Thiophenethylamine (500 mg, 4 mmol) and isovaleryl chloride (576 mg, 4.8 mmol) were used as a starting material.

LC-MS (ESI): m.

Preparation method of 2-bromo-4-isobutyl-6,7-dihydrothiophene [3,2-c]pyridine-5(4H)-carboxylic acid tert-butyl ester (compound 83)

Compound 82 (500 mg, 2.6 mmol) was used as a material.

¹ H NMR (300MHz, CDCl ₃ ) δ 6.71 (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 = 6.4 Hz, 3H), 0.93 (d, J = 6.5 Hz, 3H); LC-MS (ESI ): m / z 374.2 [m + H] +.

Process for preparing 2-formyl-4-isobutyl-6,7-dihydrothiophene [3,2-c]pyridine-5(4H)-carboxylic acid tert-butyl ester (Compound 84)

Compound 83 (750 mg, 2 mmol) was used as a material.

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

2-(1-Hydroxy-propyn-2-yl)-4-isobutyl-6,7-dihydrothiophene[3,2-c]pyridine-5(4H)-carboxylic acid tert-butyl ester (Compound 85) Preparation method

A solution of compound 84 (300 mg, 0.93 mmol) and EtOAc (m.

1H NMR (300MHz, CDCl ₃ ) δ 6.88-6.81 (d, J = 2.4 Hz, 1H), 5.57 (d, J = 6.6 Hz, 1H), 5.12 (d, J = 52.5 Hz, 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 = 6.3 Hz, 3H), 0.94 (d, J = 6.5 Hz, 3H); LC-MS (ESI): m/z 372.2[M+Na] ⁺ .

2-(4-Isobutyl-5-tert-butoxycarbonyl-6,7-dihydrothiophene[3,2-c]pyridin-2-yl)pyrrole[1,2-b]pyridazine-7 -Preparation method of methyl formate (compound 86)

Compound 85 (280 mg, 0.8 mmol), compound 6 (141 mg, 0.46 mmol), Pd(OAc) ₂ (16 mg), CuI (1 mg) and DBU (350 mg) as starting materials, and the preparation of reference compound 58 , 81 mg of a yellow oil was obtained in a yield of 35%.

_{1H NMR (300MHz, CDCl 3)} 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 = 5.8 Hz, 3H), 0.97 (d, J = 5.8 Hz, 3H); LC-MS (ESI): m/z 504.2 [M+H] ⁺ .

2-(4-Isobutyl-4,5,6,7-tetrahydrothiophene[3,2-c]pyridin-2-yl)-5-chloro-pyrrole[1,2-b]pyridazine-7 Method for preparing formamide (Compound I-39)

Compound 86 (80 mg, 0.16 mmol) was used as a starting material. m.p.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.20 (d, J = 9.5 Hz, 1H), 8.07 (d, J = 3.9 Hz, 2H), 7.92 (s, 1H), 7.66 (d, J = 9.6 Hz, 1H), 7.43 (s, 1H), 4.31 (d, J = 8.2 Hz, 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 = 6.2 Hz, 3H), 0.96 (d, J = 6.4 Hz, 3H); LC-MS (ESI): m/z 389.2 [M+H ] ⁺ .

Method for preparing 4-tert-butyl-6,7-dihydrothiophene [3,2-c]pyridine (compound 87)

2-Thienylethylamine (1.5 g, 11.8 mmol) and isovaleryl chloride (2.1 g, 4.8 mmol) were used as a starting material, and the title compound 1300 mg was obtained with a yield of 57%. LC-MS (ESI): m / z 194.2 [M + H] +.

Method for preparing 4-tert-butyl-6,7-dihydrothiophene [3,2-c]pyridine-5(4H)-carboxylic acid tert-butyl ester (Compound 88)

To compound 87 (1.3 g, 6.7mmol) in ethanol (40 mL), the two points was added NaBH ₄ (500 mg) and stirred at room temperature for 1 hour, concentrated, added water and ethyl acetate 10mL 20mL, organic phase was separated, 10mL aqueous layer was extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give an oil which was used directly in the next step; added to the above oil in methylene chloride 20mL, and added dropwise separately and NEt ₃ 0.5mL Boc ₂ anhydride (1.5 g, 6.9 mmol) in dichloromethane (8 mL), EtOAc. The yield was 75%.

_{^{1 H NMR (300MHz, CDCl 3}} ) δ7.08 (dd, J = 10.3,5.3Hz, 1H), 6.91 (d, J = 5.2Hz, 1H), 4.96 (d, J = 50.4Hz, 1H), 4.41 (ddd, J=70.1, 13.8, 6.3 Hz, 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] ⁺ .

Process for preparing 2-formyl-4-tert-butyl-6,7-dihydrothiophene [3,2-c]pyridine-5(4H)-carboxylic acid tert-butyl ester (Compound 89)

Using Compound 88 (700 mg, 2.4 mmol) as a starting material, a crude oily product (yield:

_{^{1 H NMR (300MHz, CDCl 3}} ) δ9.84 (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-Hydroxy-propyn-2-yl)-4-tert-butyl-6,7-dihydrothiophene[3,2-c]pyridine-5(4H)-carboxylic acid tert-butyl ester (Compound 90) Preparation method

Using the compound 89 (250 mg, 0.85 mmol) as a starting material, and the preparation of the compound 57, an oily substance was obtained (yield: 35%).

_{^{1 H NMR (300MHz, CDCl 3}} ) δ7.00 (s, 1H), 5.59 (d, J = 6.0Hz, 1H), 4.90 (d, J = 50.2Hz, 1H), 4.39 (ddd, J = 69.4, 13.7, 6.3 Hz, 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-butoxycarbonyl-6,7-dihydrothiophene[3,2-c]pyridin-2-yl)pyrrole[1,2-b]pyridazine-7 -Preparation method of methyl formate (compound 91)

Compound 90 (140 mg, 0.4 mmol), compound 6 (75 mg, 0.25 mmol), Pd (OAc) ₂ (3 mg), CuI (1 mg) and DBU (190 mg) The yield was 56%.

_{^{1 H NMR (300MHz, CDCl 3}} ) δ7.87-7.81 (m, 1H), 7.48-7.37 (m, 2H), 7.19 (dd, J = 9.5,4.9Hz, 1H), 4.99 (d, J = 50.9 Hz, 1H), 4.42 (d, J = 66.6 Hz, 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-tetrahydrothiophene[3,2-c]pyridin-2-yl)-5-chloro-pyrrole[1,2-b]pyridazine-7 Method for preparing formamide (compound I-40)

Using a compound 91 (70 mg, 0.14 mmol) as a starting material, m.p.

^{1 H NMR (300MHz, DMSO-} d 6) 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 = 7.8 Hz, 1H), 2.72 (d, J = 4.9 Hz, 3H), 0.99 (s, 9H); LC-MS (ESI): m/z 388.2 [M+H] ⁺ .

Active test section

Inhibition of PARP-1 and PARP-2 activity at the molecular level by the following pharmacological experiments

1. ELISA assay for the inhibition of PARP-1 and PARP-2 activity at the molecular level by the compounds of the invention

Experimental method: Enzyme-Linked Immunosorbent Assay (ELISA) (refer to the enzyme-linked immunosorbent assay described in the literature published by Decker P.; Reference: 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). The principle is to coat the substrate histone in an adsorption 96-well plate, add PARP-1 or 2 recombinase, substrate NAD ⁺ , and activated DNA to enzymatically react PARP-1 or 2 to produce histone production products. PAR (polyadenosine diphosphate ribose), followed by the addition of anti-PAR (anti-PAR) antibodies, the intensity of the product PAR on the histone coated on the 96-well plate can reflect the enzymatic activity of PARP.

Calculation of drug inhibition rate: inhibition rate (%) = (OD control well-OD administration well) / OD control well × 100% (OD is absorbance value); and according to the inhibition rate, calculated by the Logit method to achieve 50% inhibition Drug concentration, which is the IC ₅₀ value. (At the molecular level IC ₅₀ <1000 nM, +; <500 nM, ++; <100 nM, +++; - > 1000 nM or not determined), the results are shown in Table 1:

2, test results

From Table 1, it can be found that the compounds of the present invention have significant inhibitory activities against PARP-1 and PARP-2.

Table 1. Inhibition of PARP-1 and PARP-2 activity at the molecular level by some compounds

3.Inhibition of I-34 on the growth of human breast cancer MDA-MB-436 subcutaneous xenografts in nude mice

Test substance and positive control drug

The compound I-34 was prepared as a monohydrochloride salt as a yellow powder, which was dissolved in a yellow turbid liquid by using water for injection, and precipitated after standing. The mixture was thoroughly mixed before administration, and the above compound was formulated once a week. The positive control drug AZD2281 (anticancer drug olaparib olaparib) was a pale yellow powder (Lot: PAR-105), which was used as a suspension with 0.5% sodium carboxymethylcellulose per week.

Dose setting

I-34 hydrochloride was set up in two dose groups, 100 mg/kg and 20 mg/kg, respectively. The positive control drug AZD2281 dose was 30 mg/kg.

Experimental animals and inoculated cells

BALB/cA nude mice, female, 4-5 weeks old, weighing 19±2 g, provided by Shanghai Institute of Materia Medica, Chinese Academy of Sciences, production license number: SCXK (Shanghai) 2013-001. Use certificate number: SYXK (Shanghai) 2013-0049. The number of animals in each group: 12 in the negative control group and 6 in the drug-administered group. Human breast cancer MDA-MB-436 cell line was preserved by our laboratory. The cell strain was inoculated subcutaneously into the right axilla of the nude mice, and the inoculation amount was 5×106/piece, and the transplanted tumor was formed and then used in nude mice for 2 generations.

experimental method

The tumor tissue in the vigorous growth period was cut into 1.5 mm ³ and inoculated subcutaneously in the right axilla of nude mice under aseptic conditions. The diameter of the transplanted tumor was measured with a vernier caliper in nude mice. After the average tumor volume grew to about 200 mm ³ , the animals were randomly divided into groups. Compound I-34 hydrochloride 100 mg/kg and 20 mg/kg groups were orally administered once a day for 21 consecutive days. The positive control drug AZD2281 30 mg/kg was orally administered once a day for 21 days. The solvent control was given an equal amount of water for injection. The diameter of the transplanted tumor was measured twice a week during the entire experiment, and the body weight of the mice was weighed. The formula for calculating tumor volume (TV) is: TV = 1/2 × a × b ² , where a and b represent length and width, respectively. Based on the measured results, the relative tumor volume (RTV) was calculated, and the formula was: RTV=V _t /V ₀ . Where V ₀ is the measured tumor volume at the time of sub-cage administration (i.e., d ₀ ), and V _t is the tumor volume at each measurement. The evaluation index of antitumor activity is (1) relative tumor proliferation rate T/C (%), and the formula is as follows: T/C (%) = (T _RTV / C _RTV ) × 100%, T _RTV : treatment group RTV; C _RTV : negative control group RTV; (2) tumor volume growth inhibition rate GI%, calculated as follows: GI% = [1-(TVt-TV ₀ ) / (CVt-CV ₀ )] × 100%, TVt is treatment The tumor volume measured in each group; TV ₀ is the tumor volume obtained when the therapeutic component is administered in cage; CVt is the tumor volume measured in each control group; CV ₀ is the tumor volume obtained when the control group is administered in cage; (3) The tumor weight inhibition rate was calculated as follows: tumor weight inhibition rate % = (Wc - W _T ) / Wc × 100%, Wc: control group tumor weight, W _T : treatment group tumor weight.

Results of growth inhibition on human breast cancer MDA-MB-436 nude mice transplanted subcutaneously

The experimental results are shown in Table 2.

I-34 hydrochloride 100mg/kg and 20mg/kg groups were administered orally once a day for 21 days, which had a significant inhibitory effect on the growth of human breast cancer MDA-MB-436 nude mice. The T/C percentages obtained on day 21 were 1.47% and 5.70%, respectively, and one mouse tumor in the high dose group completely resolved.

AZD2281 30mg/kg, once orally administered once a day for 21 days, inhibited the growth of human breast cancer MDA-MB-436 nude mice subcutaneously transplanted. The percentage of T/C obtained on the 21st day was 51.41. %. I-34 hydrochloride activity was significantly better than AZD2281.

Table 2. Experimental treatment of compound on human breast cancer MDA-MB-436 nude mice subcutaneously transplanted tumor

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

The above-mentioned embodiments are merely illustrative of several embodiments of the present invention, and the description thereof is more specific and detailed, but is not to be construed as limiting the scope of the invention. It should be noted that a number of variations and modifications may be made by those skilled in the art without departing from the spirit and scope of the invention. Therefore, the scope of the invention should be determined by the appended claims.

Claims (9)

1. A pyrrole [1,2-b]pyridazine compound represented by the general formula I or a pharmaceutically acceptable salt thereof:

   

   among them,

   R ¹ is hydrogen, C _1-4 alkyl or halogen;

   R ² is

   

   R ³ is hydrogen, -C(=O)R ⁶ , -SO ₂ R ⁷ , substituted or unsubstituted C _1-4 alkyl or substituted or unsubstituted C _3-6 cycloalkyl, wherein said R ⁶ and R ^{7 are} independently a substituted or unsubstituted C _1-4 alkyl group, a substituted or unsubstituted C _3-6 cycloalkyl group or a substituted or unsubstituted C _6-10 aryl group, the substitution being selected Substituting at least one substituent from a halogen, a C _1-4 alkyl group, an amino group, a nitrile group, a hydroxyl group, and a nitro group;

   R ⁴ is hydrogen, halogen, C _1-4 alkyl or C _1-4 alkoxy;

   R ⁵ is -CH ₂ - or -C=O;

   X ₁ is S, O or NH;

   X ₂ is CH or N;

   Y ₁ , Y ₂ , Y ₅ and Y _{6 are} independently a substituted or unsubstituted methylene group, a substituted or unsubstituted ethylene group, a substituted or unsubstituted propylene group or a substituted or unsubstituted butylene group. The substitution is substituted with at least one substituent selected from the group consisting of halogen, C _1-6 alkyl, C _3-6 cycloalkyl and C _1-4 alkoxy;

   Y ₃ and Y _{4 are} independently hydrogen, substituted or unsubstituted C _1-4 alkyl or substituted or unsubstituted C _3-6 cycloalkyl, the substituent being selected from halogen, C _1-6 alkyl Substituting at least one substituent of C _3-6 cycloalkyl and C _1-4 alkoxy;

   Y ₇ is NR ⁸ or CHR ⁹ ,

   Wherein R ⁸ is hydrogen, -C(=O)R ¹⁰ , -SO ₂ R ¹¹ , substituted or unsubstituted C _1-4 alkyl, substituted or unsubstituted C _3-6 cycloalkyl or substituted Or an unsubstituted C _6-10 aryl group, wherein said R ¹⁰ and R ^{11 are} independently a substituted or unsubstituted C _1-4 alkyl group, a substituted or unsubstituted C _3-6 cycloalkyl group, substituted or not a substituted five- to six-membered saturated heterocyclic group or a substituted or unsubstituted C _6-10 aryl group selected from the group consisting of halogen, C _1-4 alkyl, C _1-4 haloalkyl, amino, and Substituting at least one substituent of at least one C _1-4 alkyl substituted amino group, nitrile group, hydroxyl group, and nitro group,

   The R ⁹ is hydrogen, -OR ¹² , an amino group substituted with at least one C _1-4 alkyl group, or a substituted or unsubstituted five- to six-membered saturated heterocyclic group, wherein the R ¹² is hydrogen, substituted or An unsubstituted C _1-4 alkyl group or a substituted or unsubstituted C _3-6 cycloalkyl group, which is selected from the group consisting of halogen, C _1-4 alkyl, C _1-4 haloalkyl, amino, at least At least one substituent of a C _1-4 alkyl-substituted amino group, a nitrile group, a hydroxyl group, and a nitro group is substituted.
2. The pyrrole [1,2-b]pyridazine compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein, in the formula I,

   R ¹ is hydrogen, methyl, ethyl, propyl, fluorine, chlorine or bromine;

   R ² is

   

   R ³ is hydrogen, methyl, ethyl or propyl;

   R ⁴ is hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, methoxy, ethoxy or propoxy;

   R ⁵ is -CH ₂ - or -C=O;

   X ₁ is S, O or NH;

   X ₂ is CH or N;

   Y ₁ , Y ₂ , Y ₅ and Y _{6 are} independently a substituted or unsubstituted methylene group, a substituted or unsubstituted ethylene group, a substituted or unsubstituted propylene group or a substituted or unsubstituted butylene group. The substitution is selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, and ring. Substituting at least one substituent of pentyl, cyclohexyl, methoxy, ethoxy or propoxy;

   Y ₃ and Y _{4 are} independently hydrogen, methyl, ethyl, propyl, isopropyl or butyl;

   Y ₇ is NR ⁸ or CHR ⁹ ,

   Wherein R ⁸ is hydrogen, -C(=O)R ¹⁰ , -SO ₂ R ¹¹ , methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, ring A hexyl group, or a substituted or unsubstituted phenyl group, wherein said R ¹⁰ and R ^{11 are} independently a substituted or unsubstituted group: methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl Base, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, dioxolane or a phenyl group, the substitution being selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, trifluoromethyl, amino, N-methylamino, N-ethylamino, N, Substituting at least one substituent of N-dimethylamino, N,N-diethylamino, nitrile, hydroxy and nitro,

   The R ⁹ is hydrogen, -OR ¹² , N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino, pyrrolidinyl, tetrahydrofuranyl, piperidine Or a piperazinyl group, a morpholinyl group or a dioxane group, wherein the R ¹² is hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl or a ring Hexyl, the substitution is selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, trifluoromethyl, amino, N-methylamino, N-ethylamino, N, N Substituting at least one substituent of dimethylamino, N,N-diethylamino, nitrile, hydroxy and nitro.
3. The pyrrole [1,2-b]pyridazine compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the pyrrole [1,2-b]pyridazine compound is one of the following compounds :

   

   
4. Use of a pyrrole [1,2-b]pyridazine compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 for the preparation of a PARP inhibitor.
5. Use of a pyrrole [1,2-b]pyridazine compound according to claim 4 or a pharmaceutically acceptable salt thereof for the preparation of a PARP inhibitor, characterized in that the PARP inhibitor is for PARP-1 and/or PARP-2 has a selective inhibitory effect.
6. A pharmaceutical composition comprising one or more therapeutically effective amounts of a pyrrole [1,2-b]pyridazine compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, or An ester, prodrug, hydrate or crystal of one or more therapeutically effective amounts of a pyrrole [1,2-b]pyridazine compound according to any one of claims 1-3.
7. The pharmaceutical composition according to claim 6, wherein the pharmaceutical composition has an inhibitory effect on PARP.
8. The pharmaceutical composition according to claim 6, wherein the pharmaceutical composition has a selective inhibitory effect on PARP-1 and/or PARP-2.
9. The pharmaceutical composition according to claim 6, wherein the pharmaceutical composition is for preventing and/or treating a PARP-related disease including a tumor, an ischemic disease, and a neurodegenerative disease. .