WO2007082470A1

WO2007082470A1 - Pyrrolo-pyridazine derivatives,their preparation methods and uses

Info

Publication number: WO2007082470A1
Application number: PCT/CN2007/000176
Authority: WO
Inventors: Peng Cho Tang; Jun Feng; Lei Zhang
Original assignee: Shanghai Hengrui Pharmaceutical Co.Ltd.
Priority date: 2006-01-17
Filing date: 2007-01-17
Publication date: 2007-07-26
Also published as: CN101003537A

Abstract

The present application discloses pyrrolo-pyridazine derivatives of formula (I), (II), (III), their preparation methods, pharmaceutical compositions containing the same and their uses of acting as therapeutic agents especially tyrosine kinase inhibitors. The definitions of substituents of formula (I)-(III) are the same as description.

Description

Pyrrolopyridazine derivatives and preparation method and use thereof

The present invention relates to a novel pyrrolopyridazine derivative, a process for the preparation thereof, and a pharmaceutical composition containing the same and its use as a therapeutic agent, particularly as a tyrosine acid inhibitor. Background technique

Cellular signaling is a fundamental mechanism of action in which extracellular stimuli are transmitted to the interior of the cell, which in turn regulates the progression of different cells. These signals regulate a variety of physiological responses, including cell proliferation, differentiation, apoptosis, and exercise, in the form of different types of lytic factors, including growth factors that are dominated by paracrine, autocrine, and endocrine factors. By binding to specific transmembrane receptors, growth factor ligands transmit extracellular signals to intracellular signaling pathways, causing individual cells to respond to extracellular signals. Many signaling processes are reversible processes that utilize protein phosphorylation involving specific protein kinases and phosphorylating enzymes.

Protein kinases (PKs) are enzymes that catalyze the phosphorylation of hydroxyl groups on tyrosine, serine, and threonine residues of proteins. The reverse mechanism of protein kinases and phosphorylases balances and regulates signal flow during signaling. A protein phosphorylation state can affect its conformation, enzyme activity, cell localization, and the corresponding roles of protein kinases and phosphatases are modified. Phosphorylation is an important regulatory mechanism in signal transduction, and abnormalities during signal transduction. Lead to abnormal differentiation, transformation and growth of cells. For example, cells can become cancer cells by converting part of their DNA into oncogenes, which are the growth factor receptor proteins encoded by such carcinogenic S; tyrosine kinases can also be mutated into activated forms leading to more A variation of human cells, it can be said that over-expressed normal tyrosine kinase can cause abnormal cell proliferation. '

Tyrosine kinases (PKs) can be conveniently divided into two classes: protein tyrosine kinases (PTKs) and serine-threonine kinases (STKs). PTKs phosphorylate tyrosine residues on proteins, and STKs phosphorylate serine and threonine residues on proteins. Tyrosine kinases can be not only receptor type (including extracellular domain, intracellular domain and transmembrane cell domain) but also non-receptor type (including all intracellular domains). A major aspect of PTK activity is that they are involved as cell surface protein growth factor receptors. Growth factor receptors with PTK activity are called receptor tyrosine kinases ("RTKs"), and 90 tyrosine kinases in human genes are distinguished by i, of which about 60 are receptor types, about 30 species. Non-receptor type, these growth factor receptor families can be further divided into 20 receptor tyrosine kinase subfamilies and 10 non-receptor tyrosine kinase subfamilies (Robinson et al, Oncogene, 2000, 19, 5548-5557 ).

The RTKs subfamily includes the following: (1) EGF families, such as EGF, TGFa, Neu and erbB; (2) Insulin family, including insulin receptor, insulin-like growth factor I receptor (IGF1) and insulin receptor-related Sexual receptor (IRF); (3) Chuan-type family, such as platelet-derived growth factor receptor (PDGF, Including PDGFa and PDGFp receptors, stem cell factor RTKs (SCF RTK, commonly referred to as c-Kit), fms-associated tyrosine kinase 3 (Flt3) receptor tyrosine kinase, and colony stimulating factor 1 receptor (CSF) -1 R) Tyrosine kinase and the like. They play a key role in controlling cell growth and differentiation and are key players in cell signaling leading to the production of growth factors and cytokines (see Schlessinger and Ullrich, Neuron 1992, 9, 383). A portion of the non-limiting kinases include Abl, ARaf, ATK, ATM, bcr-abi, Blk, BRaf, Brk, Btk, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CHK, AuroraA, AuroraB, AuroraC, cfms, c-fms, c-Kit, c-Met, cRafl, CSF1 R, CSK, c-Src, EGFR, ErbB2, ErbB3, ErbB4, ERK, ERK1, ERK2, Fak, fes, FGFR1, FGFR2, FGFR3 , FGFR4, FGFR5, Fgr, FLK-4, Fps, Frk, Fyn, GSK, gsk3a, gsk3b, Hck, Chk, Axl, Pim-1, Plh-1, IGF-IR, IKK, IKK1, IKK2, IKK3, INS -R, Integrin-linked kinase, Jak, JAK1, JAK2, JAK3, JNK, JNK, Lck, Lyn, MEK, MEK1, MEK2, p38, PDGFR, PIK, PKB1, PKB2, PKB3, PKC, P Ca, PKCb, PKCd , PKCe, PKCg, PKC1, PKCm, PKCz, PLK1, Polo-like kinase, PYK2, tiei, tie ₂ , TrkA, TrkB, TrkC, UL13, UL97, VEGF-R1, VEGF-R2, Yes and Zap70. PKs are thought to be associated with central nervous system diseases such as Alzheimer's disease (see Mandelkow, EM et al. FEBS Lett. 1992, 314, 315; Sengupta, A. et al. Mol. Cell. Biochem. 1997, 167, 99), pain (see Yashpal, KJ Neurosci. 1995, 15, 3263-72), inflammation such as arthritis (see Badger, J. Pharmn Exp. Then 1996, 279, 1453), psoriasis (see Dvir, et al, J. Cell Biol. 1991, 1 13, 857), bone diseases such as osteoporosis (see Tanaka et al, Nature, 1996, 383, 528), cancer (see Hunter and Pines, Cell 1994, 79, 573), atherosclerosis (see Hajjar and Pomerantz, FASEB) J. 1992, 6, 2933), thrombosis (see Salari, FEBS 1990, 263, 104), metabolic disorders such as diabetes (see Borthwick, AC et al. Biochem. Biophys. Res. Commun. 1995, 210, 738), vascular proliferative Diseases such as angiogenesis (see Strawn et al. C8ticer Res. 1996, 56, 3540; Jackson et al. Pharm. Exp. Ther. 1998, 284, 687), autoimmune diseases and transplant rejection (see Bolen and Brugge, \ 7/?. Rev. Immunol. 1997, 15, 371), infectious diseases such as viruses (see Littler, E. Nature 1992, 358, 160) is closely related to the targets of diseases such as fungal infections (see Lum, RT PCT Int Appl., WO 9805335 A1 980212).

During PTKs signaling, specific growth factors (ligands) interact extracellularly, followed by receptor dimerization, which activates the intrinsic activity of protein kinases in an instant and undergoes phosphorylation. The binding site of the internal signaling molecule is generated to form a complex with the cytoplasmic signaling molecule, promoting various cellular responses such as cell division (proliferation), expression of extracellular microenvironment metabolism, and the like.

The binding site for phosphorylation of the receptor tyrosine kinase is also a binding site with a high affinity for the SH2 (synchronous to src) domain of the signaling molecule. Many intracellular substrate proteins associated with receptor tyrosine kinases have been identified and can be divided into two categories: (1) substrate with catalytic domain (2) substrate without catalytic region, but can be used as a combination, And related to certain catalytically active molecules. The specificity of the interaction of a receptor or protein with the substrate SH2 domain is determined by the amino acid sequence near the phosphorylated tyrosine residue, the amino acid sequence surrounding the SH2-domain and the phosphorylated tyrosine sequence, and the specific The difference in bulk binding is consistent with the difference in substrate phosphorylation. Protein tyrosine kinase function can be determined by expression pattern and ligand availability, as well as by downstream region signaling pathways activated by specific receptors. Thus, phosphorylation provides an important, regulatable step that determines the selectivity of signaling and the differentiation factor receptor that is activated by a particular receptor. Abnormal expression or mutation of a receptor tyrosine kinase may result in uncontrolled cell proliferation (such as malignant tumor growth) or loss of key developmental processes.

Tyrosine kinases, in most human tumors, such as leukemia, breast cancer, prostate cancer, non-small cell lung cancer (including adenocarcinoma, lung squamous cell carcinoma), gastrointestinal cancer (including colon cancer, rectal cancer, and gastric cancer) In cancers such as bladder cancer, esophageal cancer, ovarian cancer, and pancreatic cancer, mutations or overexpression may occur. The ubiquity and association of tyrosine kinases have been further confirmed by detection of human tumor cells. For example - EGFR tyrosine kinases are mutated and overexpressed in human cancers including lung, brain, neck, gastrointestinal, breast, esophageal, ovarian, uterine, bladder and thyroid cancers.

The "HER" or "Erb" receptor tyrosine kinase subfamily includes EGFR, HER2, HER3 and HER4. These subfamilies consist of an extracellular glycosylation ligand binding domain, a transmembrane domain, and an intracellular cytoplasmic catalytic domain that phosphorylates the tyrosine sequence on the protein. The receptor tyrosine kinase catalytic activity can be activated by receptor overexpression or ligand-mediated dimerization. The HER2 family of polymers has both homodimers and heterodimers. An example of homodimerization is the polymerization of HER1 (EGFR) with EGF family ligands (including EGF, transforming growth factor a, betacellulin, heparin-binding EGF, epiregulin), between four HER tyrosine kinases. The heterodimerization can be accelerated by binding to the heregulin (also known as neuregulin) family of ligands. Although _HER:? No one receptor activity but HER2 and HER3, or a HER3 and HER4 profiled dimerization also significantly stimulated tyrosine kinase receptor dimerization. In various cell types, receptor overexpression activates the activity of HER2 kinase. Activation of receptor homodimers and heterodimers phosphorylates receptors and other intracellular protein tyrosine sequences, followed by intracellular signaling pathways such as microtubule-associated protein kinases (MAP kinases) and phosphatidylinosides Alcohol (-3) kinase (PI3 kinase) is also activated, and activation of these signaling pathways promotes cell proliferation and inhibits cell apoptosis.

Another subfamily of RTK includes the insulin receptor (IR), the insulin-like growth factor-1 receptor (IGF-1R), and the insulin receptor-related receptor (IRR). IR, IGF-1 R interacts with insulin, IGF-I and IGF-II to form two completely extracellular glycosylated alpha subunits and two tyrosine kinase domain beta subunits Heterotetramer.

The third subgroup of RTK refers to the platelet-derived growth factor receptor (PDGFR) family, including PDGFRa, PDGFRp, CSFIR, c-Kit and c-fms. These receptors are composed of a variety of immunoglobulin-like cyclic glycosylated extracellular domains and an extracellular domain in which the tyrosine kinase domain in the intracellular domain is blocked by an unrelated amino acid sequence. Platelet-derived growth factor receptors such as PDGFRa and PDGFRP are also transmembrane tyrosine kinase receptors. When they are combined with a ligand, either form a homodimer (PDGF-AA, PDGF-BB), or a heterodimer (PDGF-AB). Subsequent receptor dimerization, tyrosine kinase is activated, signaling downstream regions to promote tumor growth. Mutations in genes are responsible for the receptor's inability to bind to ligands and are a driving force for tumorigenesis. It is found to activate PDGFR growth factor-PDGF expression in a variety of different tumor cell lines, particularly breast cancer, colon cancer, ovarian cancer, prodramide, sarcoma and glioma cells, of which brain tumors, The research data of malignant gliosis in prostate cancer (including adenocarcinoma and bone metastases) has research value.

c-Kit is a member of the PDGF receptor family and is activated when it binds to the ligand SCF (stem cell factor). The c-Kit expression pattern was studied in various solid tumors, and c-Kit was overexpressed in sarcoma, gastrointestinal glioma (GIST), seminoma and carcinoid tumors. [See Weber et al., 丄 Clin. Oncol. 22(14S), 9642 (2004)]. GIST is a non-epithelial cell tumor, most of which is present in the stomach, a few in the small intestine, rarely in the esophagus, but also in the liver, peritoneal cavity and other parts.

GIST is derived from Cajal interstitial cells (ICC), which can form part of the intestinal autonomic nervous system and participate in the control of gastric motility. Most (50~80%) GIST production is due to mutation of c-Kit gene. In the digestive tract, c-Kit/CD117 staining is generally GIST, and c-Kit mutation can make it independent of SCF activation. c-Kit function, resulting in increased cell division rate, leading to instability of the genome. In the cases of distorted mast cell tumor, mast cell proliferative disease, myeloproliferative syndrome, urticaria and other diseases, c-Kit expression can also be detected, and c-Kit expression is also found in acute AML and malignant lymphoma, in small cells. Bronchial carcinoma, seminoma, dysgerminoma, testis, intraepithelial neoplasia, melanoma, breast cancer, neuroblastoma, Ewing sarcoma have c-Kit expression (see Schdtte et al., innovartis) 3/2001). As we all know, RET (rearranged during transfection). Proto-oncogene genetic mutations are tumorigenic, and patients with multiple endocrine neoplasia 2 (MEN 2) may cause pheochromocytoma, medullary thyroid carcinoma, and parathyroid adenoma and hyperplasia ( See Huang et al., Cancer Res. 60, 6223-6 (2000)).

Because the fetal liver kinase (Flk) receptor subfamily is very similar to the PDGFR subfamily, it is sometimes attributed to this family. This subfamily consists of a kinase-containing insertion domain-receptor fetal liver kinase-1 (KDR/FLK-1, VEGFR2), Flk-1 R, Flk-4 and fms-like tyrosine kinase 1 (Flt-1).

Another member of the tyrosine kinase growth factor receptor family is the fibroblast growth factor (FGF) receptor subfamily. This subfamily consists of four receptors, FGFR1-4, seven ligands and FGF1-7. Although not yet determined, these receptors are composed of an extracellular domain comprising various immunoglobulin-like circular glycosylation and an intracellular domain in which the tyrosine kinase sequence is blocked by an unrelated amino acid sequence.

Another member of the tyrosine kinase growth factor receptor family is the vascular endothelial growth factor (VEGF) receptor subfamily. Similar to PDGF, VEGF is a dimeric glycoprotein, but its biological function is different from that of in vivo target cells. In particular, VEGFR is involved in angiogenesis, inhibits angiogenesis by inhibiting VEGFRs, and is being used in clinical treatment of tumors, and has achieved good therapeutic effects. VEGF in various malignant Solid tumors, such as lung cancer, breast cancer, non-Hodgkin's lymphoma, ovarian cancer, pancreatic cancer, malignant pleural mesothelioma, and melanoma are strongly expressed and associated with the progression of cancer, in leukemia and lymphoid There are also expressions in the tumor. In addition to its angiogenic activity, VEGFR. VEGF ligands also promote tumor growth by directly pro-survival properties in tumor cells, and PDGF also has an angiogenic effect. The process of neovascularization plays a key role in the continued growth of the tumor. Under normal circumstances, the formation of new blood vessels is very important in the various processes of human physiological processes such as embryo growth, wound healing and female reproduction. However, unanticipated or pathological angiogenesis is associated with a range of conditions, such as diabetic retinopathy, psoriasis, cancer, rheumatoid arthritis, atheroma, Kaposi's sarcoma, and hemangioma. Wait. The production of vascular endothelial cells activates angiogenesis and stimulates the production of vascular endothelial cells in vivo - some peptides have been identified, including acidic, basic fibroblast growth factors (aFGF and bFGF) and vascular endothelial growth factor. Due to the restricted expression of the VEGF receptor, its growth factor activity is relatively specific to endothelial cells compared to aFGF and bFGF activity. Recent evidence suggests that VEGF is a frequently important stimulant during angiogenesis and vascular infiltration in both normal and pathological conditions. VEGF induces a vascular sprouting phenotype that induces endothelial cell proliferation, protease expression and migration to promote capillary formation, thereby forming a super-osmotic, immature vascular network, which is typical of typical pathological angiogenesis. It is expected that antagonizing VEGF activity can be of value in the treatment of diseases associated with angiogenesis or vascular permeability, such as tumors, particularly tumor growth inhibition.

FLT3 (Fms-like tyrosine kinase) is a member of the tyrosine kinase (PTK) type III family, and has excessive white blood cells in adult and young children with acute myeloid leukemia (AML), acute myeloid leukemia, and myelodysplastic syndrome. In the case of the disease, the FLT3 gene is abnormally expressed. In 35 % of patients with acute myeloid leukemia, FLT3 mutations are activated and the prognosis is poor. Most of the mutations have intrastructural replication in the proximal membrane domain, and 5-10% of patients have a point mutation in asparagine 835. The tyrosine kinase activity of FLT3 is activated, resulting in the presence of a signal and proliferation in the absence of a ligand. According to the study, patients with mutant forms of receptor expression have a reduced chance of cure. In conclusion, in human leukemia and myelodysplastic syndromes, FLT3 mutations are associated with tumorigenesis.

Hepatocyte growth factor (HGF) receptor (c-MET or HGFR) tyrosine kinases have been shown to be involved in tumorigenesis, cell motility, invasion and metastasis (see Ma, PC et al. (2003b). Cancer Metastasis Rev, 22, 309-25; Maulik, G. et al. (2002b). Cytokine Growth Fsctor Rev, 13, 41-59). Overexpression or mutation in various tumors, including small cell lung cancer (SCLC), activates c-MET (HGFR) (see Ma, P.C. et al. (2003a). Cancer Res, 63, 6272-6281).

The proto-oncogene c-Met encodes a hepatocyte growth factor receptor, which is a cell membrane glycoprotein with tyrosine kinase activity, which has important physiological regulation effects on various cell proliferation and differentiation. The c-met gene has been used in many malignant tumors. Expression is an important factor in the carcinogenesis of thyroid follicular epithelial cells and is closely related to the pathological stage, invasion and metastasis of thyroid cancer.

For the PKT subfamily, Plowman et al. are more detailed in DN&P 7(6): 334-339 (1994). Description, the document is incorporated herein by reference in its entirety.

In addition to PTKs, there are additional families of cellular enzymes called receptor tyrosine kinase inhibitors, and the latter name is used here, abbreviated as "CTK". CTKs themselves lack the extracellular domain and the transmembrane domain. Currently, more than 24 CTKs have been identified in 11 subfamilies (Src, Frk, Btk, Csk, Abl, Zap70, Fes/Fps, Fak, Jak, Ack and LIMK). So far, the number of Src subfamily CTKs seems to be the highest, including Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk, and Src subfamily enzymes are involved in tumorigenesis. For a more detailed description of CTKs, see Old olen, 1993, Oncogen 8: 2025-2031, the entire disclosure of which is incorporated herein by reference in its entirety in its entirety herein.

Similar to CTKs, serine-threonine kinases or STKs are dominant in the cell, although there are only a few STK-type receptor kinases. STKs are the most common cytosolic kinases, that is, they perform their functions in part of the cytoplasm, not in cytoplasmic organelles. The cytosol is a region within the cell where the metabolism and biosynthesis activity occurs in most cells; for example, proteins are synthesized on cytosol ribosomes.

One of the characteristics of diseases such as cancer associated with hyperproliferation is the destruction of the cell conduction pathway, which controls the progression through the cell cycle. In eukaryotic cells, the cell cycle is closely related to the phosphorylation order cascade of proteins. In the signaling mechanism, many families of PKs appear to play a key role in the cell division cycle cascade.

With regard to cancer, two major hypotheses are proposed to explain excessive cell proliferation, which drives tumor development associated with functions known to be regulated by PK. That is, it is thought that the growth of malignant tumors is caused by the destruction of the mechanism that controls cell division or proliferation. Proto-oncogene protein products can interfere with signaling pathways that regulate cell growth and proliferation. The protein products of these proto-oncogenes include the extracellular growth factors discussed above, transmembrane growth factor PTK receptors (RTKs), cytoplasmic PTKs (CTKs), and Cytosolic STKs. It is expected to be able to synthesize inhibitors with anti-tumor cell proliferation activity, and hope to inhibit one or more of PTKs, CTKs or STKs, effectively treat and improve super-mediated by PTKs, CTKs or STKs and angiogenesis. Proliferative physiological disorders. Summary of the invention

In order to overcome the deficiencies of the prior art, it is an object of the present invention to provide novel pyrrolopyridazines of the formulae I, II and III, as well as their tautomers, enantiomers, Diastereomers, racemates and pharmaceutically acceptable salts, as well as metabolites and metabolic precursors or prodrugs.

In the above formula:

X is selected from W(C3⁄4), (CH ₂ )W, or W, wherein W is 0, S, SO, S0 _2; or -N ₈ (wherein R ₈ is a hydrogen atom or an alkyl group);

When X is - ₈ and R ₈ is an alkyl group, it may form a 4 to 8 membered heterocyclic group with R1; wherein the 5 to 8 membered heterocyclic ring may contain one or more N, 0, S atoms, and 4~ The 8-membered heterocyclic ring may be further substituted with one or more fluorenyl groups, halogen, aryl, heteroaryl, halofluorenyl, halodecyloxy, hydroxy, amino, alkylamino, amide, aminyl, Cyano, alkoxy, aryloxy, aminyl, hydroxyalkyl, heterocycloalkyl, carboxylic acid, carboxylic acid ester or substituted with _-5 ;

Selected from hydrogen atom, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, wherein fluorenyl, cycloalkyl, heterocycloalkyl, aryl, hetero The aryl, arylfluorenyl or heteroarylalkyl group may be further substituted by one or more alkyl, halogen, aryl, hydroxy, amino, alkynyl, alkylamino, amide, aminyl, decyloxy, aryloxy, a heterocyclic fluorenyl group, a carboxylic acid, a carboxylic acid ester or a substituent of -NR ₅ ; wherein an aryl group, a heteroaryl group, an arylalkyl group or a heteroaralkyl group may be combined into a bicyclic ring;

R _{2 is} selected from the group consisting of a hydrogen atom, a fluorenyl group, a trifluoromethyl group, a cyclodecyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an aralkyl group or a heteroarylalkyl group, wherein an alkyl group, a cycloalkyl group, a heterocyclic ring An anthracenyl group, an aryl group, a heteroaryl group, an indenyl group or a heteroaryl group may further be one or more fluorenyl groups, a halogen, an aryl group, a hydroxy group, an amino group, a decylamino group, an amide group, an amino group, a decyl group, Substituted with an aryloxy group, a heterocycloalkyl group, a carboxylic acid, a carboxylic acid ester or -NR ₅ R6;

Selected from a hydrogen atom, an alkyl group, an aryl group, a heteroaryl group, a heteroaryloxy group, -C(=0)R ₇ , -C(=S)R ₇ , -NC(=0)R ₇ , -(CH ₂ ) _n O(C=0)R ₇ , -(CH ₂ ) _n O(C=S)R ₇ , -(CH ₂ ) _n R ₇ , -(CH ₂ CH ₂ 0) _n R _{8 ;} , heteroaryl, heteroaryloxy, -(C3⁄4) _n R ₇ may be further protected by one or more thiol groups, -(CH ₂ ) _n R ₇ , =C(0), halogen, trifluoromethyl, Substituted by a carboxylic acid, a carboxylic acid ester;

Selected from hydrogen atom, fluorenyl, cycloalkyl, heterocycloalkyl, -(C3⁄4CH ₂ 0) _n R ₈ , alkenyl or alkynyl, wherein alkyl, cyclodecyl, heterocycloalkyl, alkenyl or alkyne The group may be further substituted by one or more alkyl, hydroxy, decyloxy, cyano, amino, alkylamino, -NR ₅ , carboxylic acid or carboxylic acid esters;

R ₅ and each selected from the group consisting of a hydrogen atom, a fluorenyl group, a cyclodecyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group or a heteroarylalkyl group, respectively, wherein an indenyl group, a cyclodecyl group, a heterocycloalkyl group, or an aromatic group Base, heteroaryl or heteroaralkyl Further one or more alkyl, halogen, aryl, hydroxy, amino, decylamino, amide, aminyl, cyano, alkoxy, aryloxy, aminyl, hydroxyalkyl, heterocycloalkane Substituted by a carboxylic acid or a carboxylic acid ester;

Meanwhile, R ₅ and may form a 4-8 membered heterocyclic group; wherein the 5 to 8 membered heterocyclic ring may contain one or more N, 0, S atoms, and the 4 to 8 membered heterocyclic ring may be further subjected to a Or a plurality of alkyl, halogen, aryl, heteroaryl, alkyl, methoxy, hydroxy, amino, amide, aminyl, cyano, alkoxy, aryloxy, amidino, Substituted with hydroxymethyl, heterocycloalkyl, carboxylic acid, carboxylic acid ester or -NR ₅ R6;

R _{7 is} selected from the group consisting of hydroxy, decyloxy, aryloxy, heterocycloalkoxy, aryloxy, -N(R ₈ )(CH ₂ ) _n R ₉ , -N ₈ [CH ₂ CH ₂ 0] _n R ₈ , -NR ₅ or -N (CH ₂ ) _n [CH(OH)C3⁄4] _r Z (wherein Z is aryl, heteroaryl, heterocycloalkyl, -NR ₅ , -COOR ₈ or CON ₅ R6 );

Selected from a hydrogen atom or an alkyl group;

R _{9 is} selected from - R ₅ R6, hydroxy, aryl, heteroaryl, alkoxy, -S(0) ₂ CH ₃ , -O 〖C3⁄4CH ₂ 0] _r R ₈ , -1^(0-)3⁄43⁄4 , -N(OH)R ₅ , -Li. (0). Or - COR ₁₀ (wherein R _w is a fluorenyl group, a halogenated fluorenyl group or a aryl group);

R ₁₀ is an embankment, haloalkyl or aryl alkyl with

n is 0~6;

r is 1 to 2. Specifically, the present invention includes a compound represented by the following formula (I) or a salt thereof:

X is selected from W(CH ₂ ), (CH ₂ )W, or W, wherein W is 0, S, SO, S0 ₂ ; or -N (wherein R ₈ is a hydrogen atom or an alkyl group);

When X is -N and R _s is a fluorenyl group, R ₈ may form a 4 to 8 membered heterocyclic group with R1; wherein the 5 to 8 membered heterocyclic ring may contain one or more N, 0, S atoms, and The 4 to 8 membered heterocyclic ring may be further substituted with one or more fluorenyl groups, halogen, aryl, heteroaryl, haloalkyl, haloalkoxy, hydroxy, amino, alkylamino > amide, aminyl, cyano, Alkoxy, aryloxy, aminyl, hydroxyalkyl, heterocycloalkyl, carboxylic acid, carboxylic acid ester or -Ν3⁄4 substituted;

Selected from hydrogen atom, alkyl, cycloalkyl, heterocyclic heptyl, aryl, heteroaryl, aralkyl or heteroaryl, wherein alkyl, cyclodecyl, heterocycloalkyl, aryl, hetero Aryl, aralkyl or heteroaralkyl can be further Step by one or more of the formula, aryl, aryl, hydroxy, amino, alkynyl, decylamino, amido, aminyl, alkoxy, aryloxy, heterocycloalkyl, carboxylic acid, carboxylic acid ester or Substituted by -NR ₅ R6; wherein the aryl, heteroaryl, aralkyl or heteroaryl group may be combined into a bicyclic ring;

Selected from hydrogen atom, fluorenyl, trifluoromethyl, cyclodecyl, heterocycloalkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl, wherein fluorenyl, cyclodecyl, heterocycloalkyl , aryl, heteroaryl, arylalkyl or heteroarylalkyl may be further substituted by one or more alkyl, halo, aryl, hydroxy, amino, decylamino, amide, aminyl, decyloxy, aryloxy Substituted by a heterocycloalkyl group, a carboxylic acid, a carboxylic acid ester or -NR ₅ ;

R _{3 is} selected from the group consisting of a hydrogen atom, a fluorenyl group, an aryl group, a heteroaryl group, a heteroaryloxy group, -C(=0)R ₇ , -C(=S)R ₇ , -NC(=0)R ₇ , (CH ₂ ) _n O(C=0)R ₇ , -(CH ₂ ) _n O(C=S)R ₇ , -(CH ₂ )„R ₇ , -(CH ₂ CH ₂ 0) _n R _g ; Wherein aryl, heteroaryl, heteroaryloxy, -(CH ₂ ) _n R ₇ may be further substituted by one or more alkyl groups, -(CH ₂ ) _n R ₇ , =C(0), , trifluoromethyl Substituted by a carboxylic acid, a carboxylic acid ester;

R4 is selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, -(CH ₂ CH ₂ 0) _n R ₈ , an alkenyl group or an alkynyl group, wherein a fluorenyl group, a cyclodecyl group, a heterocycloalkyl group, an alkene group Or alkynyl may be further substituted by one or more mercapto, hydroxy, decyloxy, cyano, amino, decylamino, -NR ₅ 3⁄4, carboxylic acid or carboxylic acid ester;

And each selected from the group consisting of a hydrogen atom, a fluorenyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group or a heteroaryl group, wherein a fluorenyl group, a cycloalkyl group, a heterocyclic group, an aryl group, The heteroaryl or heteroarylalkyl group may be further substituted by one or more of fluorenyl, halogen, aryl, hydroxy, amino, decylamino, amide, aminyl, cyano, decyloxy, aryloxy, amidoxime Substituted with a hydroxy group, a heterocycloalkyl group, a carboxylic acid or a carboxylic acid ester;

Meanwhile, a 4 to 8 membered heterocyclic group may be formed; wherein the 5 to 8 membered heterocyclic ring may contain one or more N, 0, S atoms, and the 4 to 8 membered heterocyclic ring may be further subjected to one or more Sulfhydryl, halogen, aryl, heteroaryl, alkyl, methoxy, hydroxy, amino, amide, amino, cyano, methoxy, aryloxy, alkoxy, hydroxyalkyl Substituted by a heterocyclic fluorenyl group, a carboxylic acid, a carboxylic acid ester or -NR ₅ R6;

R _{7 is} selected from the group consisting of hydroxy, decyloxy, aryloxy, heterocycloalkoxy, aralkyloxy, -N(R ₈ )(CH ₂ ) _n R ₉ , - R ₈ [CH ₂ CH ₂ 0] _n R ₈ , -N ₅ R6 or -NR ₈ (CH ₂ ) _n [CH(OH)C3⁄4] _r Z (wherein Z is aryl, heteroaryl, heterocycloalkyl, -NR ₅ R ₆ , -COOR ₈ Or CONR ₅ R6);

Selected from a hydrogen atom or an alkyl group;

R _{9 is} selected from -NR ₅ R6, hydroxy, aryl, heteroaryl, decyloxy, -S(0) ₂ C3⁄4, -0[CH ₂ CH ₂ 0] _r R ₈ , - (0') , - N(OH)R ₅ , -NHC(0)R _1G or -COR ₁₀ (wherein R ₁₀ is alkyl, haloalkyl or aryl fluorenyl);

R ₁₀ is an alkyl group, a halogenated fluorenyl group or an aralkyl group

n is 0~6;

r is 1 to 2. Further, the present invention includes a compound represented by the following formula (π) or a salt thereof:

among them:

X is selected from W(CH ₂ ), (CH ₂ )W, or W, wherein W is 0, S, SO, S0 ₂ ; or -N (wherein R ₈ is a hydrogen atom or a fluorenyl group);

When X is -N and R ₈ is an alkyl group, a 4 to 8 membered heterocyclic group may be formed with R1; wherein the 5 to 8 membered heterocyclic ring may contain one or more N, 0, S atoms, and 4~ The 8-membered heterocyclic ring may be further substituted with one or more alkyl, halogen, aryl, heteroaryl, halodecyl, halodecyloxy, hydroxy, amino, decylamino, amide, aminyl, cyanide a group, a methoxy group, an aryloxy group, an aminoalkyl group, a hydroxyalkyl group, a heterocyclic fluorenyl group, a carboxylic acid, a carboxylic acid ester or a substituted group of R ₅ ;

Selected from hydrogen atom, alkyl, cyclodecyl, heterocycloalkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl, wherein alkyl, cycloalkyl, heterocycloalkyl, aryl, hetero The aryl, aralkyl or heteroarylalkyl group may be further substituted by one or more fluorenyl, halogen, aryl, hydroxy, amino, alkynyl, alkylamino, amide, aminyl, alkoxy, aryloxy, a heterocyclic fluorenyl group, a carboxylic acid, a carboxylic acid ester or a substituted group; wherein the aryl group, the heteroaryl group, the aryl fluorenyl group or the heteroaryl fluorenyl group may be combined into a bicyclic ring;

Selected from hydrogen atom, fluorenyl, trifluoromethyl, cyclodecyl, heterocycloalkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl, wherein alkyl, cycloalkyl, heterocycloalkyl , aryl, heteroaryl, arylalkyl or aralkyl may be further substituted by one or more fluorenyl, halogen, aryl, hydroxy, amino, hydrazine, amide, aminyl, decyloxy, aryloxy Substituted by a heterocyclic fluorenyl group, a carboxylic acid, a carboxylic acid ester or -NR ₅ ;

R _{3 is} selected from the group consisting of a hydrogen atom, an alkyl group, an aryl group, a heteroaryl group, a heteroaryloxy group, -C(=0)R ₇ , -C(=S)R ₇ , -NC(=0)R ₇ , (CH ₂ ) _n O(C=0)R ₇ , -(CH ₂ ) _n O(C=S)R ₇ , -(CH ₂ ) _n R ₇ , -(CH ₂ CH ₂ 0) _n R ₈ ; Wherein aryl, heteroaryl, heteroaryloxy, -(CH ₂ ) _n R ₇ may be further substituted by one or more alkyl groups, -(CH ₂ ) _{n 7} , =C(0), > trifluoromethyl Substituted by a carboxylic acid or a carboxylic acid ester;

Selected from hydrogen atom, alkyl, cyclodecyl, heterocycloalkyl, -(C3⁄4CH ₂ 0) _n R ₈ , alkenyl or alkynyl, wherein alkyl, cycloalkyl, heterocycloalkyl, alkenyl or alkyne The group may be further substituted by one or more alkyl, hydroxy, alkoxy, cyano, amino, alkylamino, -NR ₅ , carboxylic acid or carboxylic acid esters;

And R ₆ are each independently selected from the group consisting of a hydrogen atom, a fluorenyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group or a heteroarylalkyl group, wherein the alkyl group, the cycloalkyl group, the heterocycloalkyl group, and the aryl group a heteroaryl or heteroarylalkyl group which may be further substituted by one or more of fluorenyl, halogen, aryl, hydroxy, amino, alkylamino, amide, aminyl, cyano, alkoxy, aryloxy, Acridine, hydroxyalkyl, heterocycloalkyl, carboxylic acid or carboxylic acid ester Meanwhile, R ₅ and Re may form a 4 to 8 membered heterocyclic group; wherein the 5 to 8 membered heterocyclic ring may contain one or more N, 0, S atoms, and the 4 to 8 membered heterocyclic ring may be further subjected to a Or a plurality of fluorenyl groups, halogen, aryl, heteroaryl, haloalkyl, halomethoxy, hydroxy, amino, amide, aminyl, cyano, alkoxy, aryloxy, alkoxy Substituted with hydroxyindenyl, heterocycloalkyl, carboxylic acid, carboxylic acid ester or -R ₅ R6;

R _{7 is} selected from the group consisting of hydroxy, alkoxy, aryloxy, heterocycloalkoxy, aralkyloxy, -N(R ₈ ; CH ₂ ) _n R ₉ , - ₈ [CH ₂ CH ₂ 0] _n R ₈ , -NRsRfi or - NR _s (C3⁄4) _n [CH(OH)CH ₂ ] _r Z (wherein Z is aryl, heteroaryl, heterocycloalkyl, -NRsR^, -COOR ₈ or CON 5R6);

Selected from a hydrogen atom or a sulfhydryl group;

R _{9 is} selected from -NR ₅ R6, hydroxy, aryl, heteroaryl, decyloxy, -S(0) ₂ CH ₃ , -O[CH ₂ CH ₂ 0] _r R ₈ , -^(0-) 3⁄43⁄4, -N(OH)R ₅ , -NHC(0)R ₁₍₎ or - COR ₁₀ (wherein R ₁₀ is a fluorenyl group, a haloalkyl group or an aryl fluorenyl group);

R _{1 ()} is a fluorenyl group, a halogenated fluorenyl group or an aryl group

n is 0~6;

r is 1 to 2. Further, the present invention includes a compound represented by the following formula (III) or a salt thereof:

among them:

X is selected from W(CH ₂ ), (CH ₂ )W, or W, wherein W is 0, S, SO, S0 ₂ ; or -NR ₈ (wherein a hydrogen atom or a sulfhydryl group);

When X is -NR ₈ and R ₈ is a fluorenyl group, R ₈ may form a 4 to 8 membered heterocyclic group with R1; wherein the 5 to 8 membered heterocyclic ring may contain one or more 0, S atoms, and 4 The ~8 membered heterocyclic ring may be further substituted with one or more alkyl groups, halogen, aryl, heteroaryl, haloalkyl, haloalkoxy, hydroxy, amino, alkylamino, amide, aminyl, cyano , alkoxy, aryloxy, aminyl, hydroxyalkyl, heterocycloalkyl, carboxylic acid, carboxylic acid ester or substituted with _-5 ;

Selected from hydrogen atom, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, wherein alkyl, cycloalkyl, heterocycloalkyl, aryl, hetero The aryl, aralkyl or heteroarylalkyl group may be further substituted by one or more fluorenyl, halogen, aryl, hydroxy, amino, alkynyl, decylamino, amide, aminyl, alkoxy, aryloxy, a heterocycloalkyl group, a carboxylic acid, a carboxylic acid ester or a substituted group of - R ₅ ; a heteroaryl group, an arylalkyl group or a heteroaralkyl group may be combined into a bicyclic ring;

R _{2 is} selected from the group consisting of a hydrogen atom, a fluorenyl group, a trifluoromethyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an aryl fluorenyl group or a heteroaryl group, wherein a fluorenyl group, a cycloalkyl group, a heterocyclic ring Alkyl, aryl, heteroaryl, aralkyl or heteroaryl can be further protected by one or more fluorenyl, aryl, aryl, hydroxy, amino, alkylamino, amide, aminyl, alkoxy, An aryloxy group, a heterocycloalkyl group, a carboxylic acid, a carboxylic acid ester or a substituted group of -> 3⁄4 ₅ ;

Selected from a hydrogen atom, an alkyl group, an aryl group, a heteroaryl group, a heteroaryloxy group, -C(=0)R ₇ , -C(=S)R ₇ , -NC(=0)R ₇ , -(CH ₂ ) _n O(C=0)R ₇ , -(CH ₂ ) _n O(C=S)R ₇ , -(CH ₂ )„R ₇ , -(CH ₂ CH ₂ 0) _n R ₈ ; , heteroaryl, heteroaryloxy, -(C3⁄4) _n R ₇ may be further protected by one or more thiol groups, -(CH ₂ ) _n R ₇ , =C(0), halogen, trifluoromethyl, Substituted by a carboxylic acid, a carboxylic acid ester;

Selected from hydrogen atom, fluorenyl, cyclodecyl, 'heterocycloalkyl, -(CH ₂ CH ₂ 0) _n R ₈ , alkenyl or alkynyl, wherein alkyl, cyclodecyl, heterocycloalkyl, alkene Or alkynyl may be further substituted by one or more alkyl, hydroxy, decyloxy, cyano, amino, alkylamino, -RjF, carboxylic acid or carboxylic acid esters;

R ₅ and Re are each independently selected from the group consisting of a hydrogen atom, a fluorenyl group, a cyclodecyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group or a heteroarylalkyl group, wherein an alkyl group, a cycloalkyl group, a heterocyclic fluorenyl group, Aryl, heteroaryl or heteroarylalkyl may be further substituted by one or more alkyl, halo, aryl, hydroxy, amino, decylamino, amide, aminyl, cyano, decyloxy, aryloxy Substituted with an amidino group, a hydroxyalkyl group, a heterocyclic fluorenyl group, a carboxylic acid or a carboxylic acid ester;

Meanwhile, R ₅ and may form a 4 to 8 membered heterocyclic group; wherein the 5 to 8 membered heterocyclic ring may contain one or more N, 0, S atoms, and the 4 to 8 membered heterocyclic ring may be further subjected to a Or a plurality of alkyl, halogen, aryl, heteroaryl, alkyl, methoxy, hydroxy, amino, amide, aminyl, cyano, methoxy, aryloxy, amidino, Substituted by a hydroxyalkyl group, a heterocycloalkyl group, a carboxylic acid, a carboxylic acid ester or -NR ₅ ;

R _{7 is} selected from the group consisting of hydroxy, alkoxy, aryloxy, heterocycloalkoxy, aryloxy, -N(R ₈ )(C3⁄4) _n R ₉ , -NR ₈ [CH ₂ C3⁄40] _n R ₈ , -NR ₅ or -NR ₈ (C3⁄4) _n [CH(OH)C3⁄4] _r Z (wherein Z is aryl, heteroaryl, heterocycloalkyl, -NR ₅ R6, -COOR ₈ or CO RsRe);

R _{8 is} selected from a hydrogen atom or an alkyl group;

R _{9 is} selected from the group consisting of - sRi, hydroxy, aryl, heteroaryl, decyloxy, -S(0) ₂ CH ₃ , -0[CH ₂ CH ₂ 0] _r R ₈ , -]^"(0-) 3⁄4]3⁄4, -N(0H)R ₅ , -NHC(0)R ₁₍₎ or - CORw (wherein Rio is an alkyl group, a halogenated fluorenyl group or a aryl group);

R _{1 ()} is an alkyl group, a haloalkyl group or an aryl group

n is 0~6;

r is 1 to 2. In the compound of the formula (I) of the present invention or a salt thereof, it is preferred that X is hydrazine (wherein a hydrogen atom or a ~3⁄4 alkyl group). In the compound of the formula (I) of the present invention or a salt thereof, it is preferred that R2 is a methyl group or a trifluoromethyl group. Specifically, the compound of the formula (I) or a salt thereof includes:

4-(3-chloro-4-fluoro-aniline)-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-(4-(morpholine-4-yl)-piperidinyl Carboxamide

4-(3-chloro-4-fluoro-aniline)-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-(2-diethylaminoethyl)carboxamide 4-( 3-chloro-4-fluoro-aniline)-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-(2-morphinolin-4-yl-ethyl)carboxamide

4-(3-ynyl-aniline)-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-(2-diethylaminoethyl)carboxamide 4-(3-yne -Benzylamine)-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-(4-(morphinolin-4-yl)-piperidinyl)carboxamide

4-(3-ynyl-aniline)-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-(2-pyrrolidinyl)-ethyl)formamide

4-(3-ynyl-aniline)-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-(2-morphinolin-4-yl)-ethyl)formamide

4-[3-Chloro-4-(3-fluorobenzyloxy)-aniline]-3-methyl-1H-pyrrolo[2,3-d]indole-2-(2-pyrrolidin-1-yl) ) - ethyl)carboxamide

4-[3-Chloro-4-(3-fluorobenzyloxy)-aniline]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-(3-morphocolin-4-yl) - propyl) formamide

4-[3-Chloro-4-(3-fluorobenzyloxy)-aniline]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-(2-diethylamino-B Formamide

4-[3-Chloro-4-(3-fluorobenzyloxy)-aniline]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-(2-pyrrolidin-1yl- Methyl-pyrrolidin-1-yl)carboxamide

'4-[3-Chloro-4-(3-fluorobenzyloxy)-aniline]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-(4-(morpholine-4) -yl)-piperidinyl)carboxamide

4-[3-Chloro-4-(3-fluorobenzyloxy)-aniline]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-(2-morphinolin-4-yl) - ethyl)carboxamide

4-[3-Chloro-4-(3-fluorobenzyloxy)-aniline]-3-methyl-1H-pyrrolo[2,3-d]pyridazin-2-yl-diethylaminocarbamate

4-[3-Chloro-4-(3-fluorobenzyloxy)-aniline]-3-methyl-1-methyl-pyrrolo[2,3-d]pyridazine-2-(2-diethylamine) Base-ethyl)formamide

4-[3-Chloro-4-(3-fluorobenzyloxy)-aniline]-3-methyl-1-methyl-pyrrolo[2,3-d]pyridazine-2-(2-pyrrolidine- 1-yl-ethyl)carboxamide

4-[3-chloro-4-(3-fluorobenzyloxy)-aniline]-1,3-dimethyl-P-pyrolo[2,3-d]pyridazine-2 (2-morpholine-4 -yl-ethyl)-carboxamide

4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid [2-( 4- Methyl-piperazin-1-yl)-ethyl-formamide

4-[3-chloro-4-(3-fluoro-oxy)-phenylamino]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid [2-(4 - methyl-piperazine small group)-propyl]-carboxamide

4-[1-(3-fluorobenzyl)-1Η-carbazole-5-amino]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-(2-methoxyethyl) Formamide

4-[1-(3-fluorobenzyl)-1H-indazole-5-amino]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-(2-diethylamine) Base-ethyl) formamide

4-[3-Chloro-4-(pyridine-2-methoxy)-aniline]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-(2-diethylamino) -ethyl)formamide

4-[3-chloro-4-(pyridine-2-methoxy)-aniline]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-[(2-pyrrolidine- 1-yl)-ethyl]carboxamide

4-[3-chloro-4-(P-pyridyl-2-methoxy)-aniline]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-[(2-morphine) Phenyl-4-yl)-ethyl]carboxamide

4-[3-Chloro-4-(pyridine-2-methoxy)-aniline]-3-methyl-1H-pyrrolo[2,3-d]indole-2-[(3-morpholine- 4-yl)-ethyl]carboxamide

4-[3-chloro-4-(pyridine-2-methoxy)-aniline]- 1, 3-dimethyl-1H-pyrrolo[2,3-d]pyridazine-2-[(2- Ethylamino)-ethyl]carboxamide

₄ _[3-chloro-4-(pyridine-2-methoxy)-aniline]-1,3-dimethyl-1H-pyrrolo[2,3-d]pyridazine-2-[(2- Pyrrolidin-1-yl)-ethyl]carboxamide

₄ _[ ₃ _Chloro_4-(pyridine-2-methoxy)-aniline] - 1, 3-dimethyl-1H-pyrrolo[2,3-d]pyridazine-2-[(3- Morpholinolin-4-yl)-ethyl]carboxamide

4-[3-chloro-4-(pyridine-2-methoxy)-aniline]- 1, 3-dimethyl-1H-pyrrolo[2,3-d]pyridazine-2-[(2- Morpholinolin-4-yl)-ethyl]carboxamide

_{_[3-chloro-4} _ _ ₍₃ - fluoro - benzyloxy) - phenoxy] - {3-methyl-2 - [(2-morpholin-4-yl - ethylamino) - methyl] -1H -pyrrolo[2,3-d]pyridazin-4-ylamine

[ ₃ _Chloro- ₄ _(3-fluoro-benzyloxy)-phenoxy] -1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid (2-pyrrolidin-1-yl- Ethylformamide,

4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy]-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid (2-diethyl)- Ethyl)-amide

4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy]-1-(2-methoxy-ethyl)-3-methyl-1H-pyrrolo[2,3 -d] pyridazine-2-carboxylic acid ethyl ester

₄ _[ ₃ _Chloro_4-(3-fluoro-benzyloxy)-phenoxy small (2-methoxy-ethyl)-3-methyl-1H-pyrrolo[2,3-d] Pyridazine-2-carboxylic acid (2-diethylamino-ethyl)-amide

4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy]-1-(2-methoxy-ethyl)-3-methyl-1H-pyrrolo[2,3 -d] pyridazine-2-carboxylic acid [2-(4-methyl-piperazin-1-yl)-ethyl]-amide 4-[3-chloro-4-(3-fluoro-benzyloxy)-phenoxy]sodium(2-methoxy-ethyl)-3-methyl-1H-pyrrolo[2,3-d Pyridazine-2-carboxylic acid [3-(4-methyl-piperazin-1-yl)-propyl]-amide

4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy]-1-(2-methoxy-ethyl)-3-methyl-1H-pyrrolo[2,3 -d 哒pyridazine-2-carboxylic acid (2-pyrrole-1-yl-ethyl)-amide

4-[3-Chloro-4-(3-fluoro-p-ethoxy)-phenoxy]sodium[(2-methoxy-ethoxy)-ethyl]-3-methyl-1H-pyrrole [2,3-d]pyridazine-2-carboxylic acid ethyl ester

4-[3-Chloro-4-(3-fluoro-p-ethoxy)-phenoxy]-1-[(2-methoxy-ethoxy)-ethyl]-3-methyl-1H- Pyrrolo[2,3-d]pyridazine-2-carboxylic acid (2-diethylamino-ethyl)-amide

4-[3-Chloro-4-(3-fluoro-p-ethoxy)-phenoxy]-1-[(2-methoxy-ethoxy)-ethyl]-3-methyl-1- (2-morpholin-4-yl-ethyl)-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid ethyl ester

4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy]-1-[(2-methoxy-ethoxy)-ethyl]-3-trifluoromethyl- 1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid ethyl ester

4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy]-1-[(2-methoxy-ethoxy)-ethyl]-3-trifluoromethyl- 1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid benzyl ester

4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy]-1-[(2-methoxy-ethoxy)-ethyl]-3-trifluoromethyl- 1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid (2-diethylamino-ethyl)-amide

4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy]-1-[(2-methoxy-ethoxy)-ethyl]-3-trifluoromethyl- 1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide

[3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy]-[2-(5-diethylaminomethyl-furan-2-yl)-3-methyl-1H-pyrrole [2,3-d]oxazin-4-yl]amide

[3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy]-[2-(3-diethylaminomethyl-methyl)-3-methyl-1H-pyrrolo[2, 3-d]pyridazine-4,yl]amide

7-[3-Chloro-4-(3-fluoro-oxy)-phenoxy]-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid (2-diethylamino-ethyl ) - amide

7-[3-Chloro-4-(3-fluoro-oxy)-phenoxy]-1Η-pyrrolo[2,3-d]pyridazine-2-carboxylic acid (2-2-pyrrolidine-1 -yl-ethyl)-amide

7-[3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy]-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid (2-morpholin-4- Base-ethyl)-amide

7-[3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy]-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid (3-morpholin-4- Base-propyl)-amide

7-[3-Chloro-4-(3-fluoro-p-ethoxy)-phenoxy]-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid (2-piperidin-1- Base-ethyl)-amide

7-[3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy]-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid [3-(4-methyl) -piperazine small group)-propyl]-amide

7-[3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy]-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid-2-(4-methyl -piper Pyrazin-1-yl)-ethyl]-amide

4-[3-Chloro-4-(3-fluoro-oxy)-phenyl]-7-methyl-6H-pyrrolo[3,4-d]piperazine-5-carboxylate

[3-Chloro(3-fluoro-benzyloxy)-phenyl]-(5-methyl-6H-pyrrolo[3,4-d]piperazine-1-yl)-ethylamine

4-[1-(3-fluorobenzyl)-1H-indazole-5-amino]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-[(2-pyrrolidine)

-1-yl)-ethyl]carboxamide

4-[1-(3-fluorobenzyl)-1H-indazole-5-amino]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-[(2-morpholine) -4-yl)-ethyl]carboxamide

[3-Chloro-4-(3-fluorobenzyloxy)-phenyl]-(2-{3-[(2-methanesulfonylethylamino)-methyl]-phenyl}-3-methyl- 1H-pyrrolo[2,3-d]pyridazin-4-yl)-amine

[ ₃ _Chloro-4-(3-fluorobenzyloxy)-phenyl]-(2-{5-[(2-methanesulfonylethylamino)-methyl]-furan-2-yl}-3- Methyl-1H-pyrrolo[2,3-d]pyridazin-4-yl)-amine

Or a pharmaceutically acceptable salt thereof.

Wherein the salt is a salt of a compound of the above formula and an acid selected from the group consisting of malic acid, lactic acid, maleic acid, hydrochloric acid, methanesulfonic acid, sulfuric acid, phosphoric acid, citric acid, tartaric acid, acetic acid or trifluoroacetic acid. .

In another aspect of the invention, there is provided a pharmaceutical composition comprising a compound, a salt or a prodrug of the formula (1), (II) or (III) and a pharmaceutically acceptable carrier or excipient.

In another aspect of the invention, a method of modulating the catalytic activity of a protein kinase comprises contacting a protein kinase with a compound or salt of formula (1), (II) or (ΠΙ). This protein kinase is selected from the group consisting of a receptor tyrosine kinase, a non-receptor tyrosine kinase, and a serine-threonine kinase. In another aspect of the invention, a method of treating a mammal having and preventing a protein kinase-associated disease in a mammal, the method comprising administering to the mammalian organism a therapeutically effective dose of the present invention Inventive pharmaceutical composition. Among them, the protein kinase-related diseases are selected from the group consisting of EGFR, HER-2, HER-3, HER-4, PDGFR, VEGFR-2, c-Kit, c-Met, FGFR, Flt3 related diseases. Diseases associated with protein kinases can also be leukemia, diabetes, autoimmune diseases, hyperproliferative diseases, psoriasis, osteoarthritis, rheumatoid arthritis, angiogenesis, cardiovascular disease, Von-Heppel-Lindau's disease, inflammation, Fibrosis disease. Protein kinase-related diseases can also be squamous cell carcinoma, renal cell carcinoma, Kaposi sarcoma, non-small cell lung cancer, small cell lung cancer, lymphoma, thyroid cancer, breast cancer, head and neck cancer, uterine cancer, esophageal cancer, melanin. Cancer, bladder cancer, genitourinary cancer, gastrointestinal cancer, glial cancer, colorectal cancer and ovarian cancer. The mammals treated by these methods can be human.

In another aspect of the invention is a method of treating cancer comprising administering to a patient in need of treatment an anti-cancer drug, such as taxol or carboplatin, simultaneously.

In another aspect of the invention, a process for the preparation of a compound of formula (1), (Π) or (III).

In another aspect, the invention relates to the use of a compound of the invention in the manufacture of a medicament for the treatment of a disease associated with a protein kinase. The protein kinase-associated disease is selected from the group consisting of EGFR, HER-2, HER-3, a disease associated with HER-4, PDGFR, VEGFR-2, c-Kit, c-Met, FGFR or Flt3; wherein the protein kinase-related disease is selected from the group consisting of leukemia, diabetes, autoimmune disease, hyperproliferative disease, psoriasis, Osteoarthritis, rheumatoid arthritis, angiogenesis, cardiovascular disease, Von-Heppel-Lindau's disease, inflammatory or fibrotic disease; wherein the protein kinase-related disease is cancer, selected from squamous cell carcinoma, Renal cell carcinoma, Kaposi sarcoma, non-small cell lung cancer, small cell lung cancer, lymphoma, thyroid cancer, breast cancer, head and neck cancer, uterine cancer, esophageal cancer, melanoma, bladder cancer, genitourinary cancer, gastrointestinal cancer, nerve Glial cancer, colorectal cancer or ovarian cancer.

The present invention relates to a compound which discriminates the catalytic activity of a protein kinase, which contacts a cell expressing the protein kinase with a compound or salt of the present invention, and then detects the effect on the cell.

The present invention also relates to a compound which discriminates the catalytic activity of a protein kinase by contacting an artificially recombinant synthetic kinase protein with a compound or salt of the present invention, and then detecting the effect on the kinase activity by the Elisa method. Detailed description of the invention

Unless otherwise stated, the following terms used in the specification and claims have the following meanings. "Mercapto" refers to a saturated aliphatic hydrocarbon group including straight chain and branched chain groups of 1 to 20 carbon atoms. Preference is given to medium-sized mercapto groups having 1 to 10 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, pentyldenyl. More preferred are lower fluorenyl groups having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl or t-butyl groups and the like. The alkyl group may be substituted or unsubstituted, and when substituted, preferred groups are halogen, hydroxy, lower decyloxy, aryl, aryloxy, heteroaryl, heterocyclic fluorenyl, C(0)R ⁷ , R ⁵ R ⁶ and C(0)N ⁵ R ⁶ .

"Cyclopentyl" means a 3 to 8 membered all-carbon monocyclic, all-carbon 5/6 or 6/6 fused or polycyclic fused ring ("fused" ring system means each in the system The rings share an adjacent pair of carbon atoms) groups with other rings in the system, wherein one or more of the rings may contain one or more double bonds, and none of the rings have a fully conjugated pi-electron system. Examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclopentene, cyclohexanyl, cyclohexadiene, adamantane, cycloheptane, cycloheptatriene and the like. The cycloalkyl group can be substituted or unsubstituted. When substituted, the substituent is preferably one or more substituents independently selected from the group consisting of lower fluorenyl, trihaloalkyl, halogen, hydroxy, lower decyloxy, aryl (optionally selected from one or more groups) a group substituted, the substituents are independently of each other a halogen, a hydroxyl group, a lower alkyl group or a lower alkoxy group), an aryloxy group (which may be selected by one or more groups, and the substituents are independently of each other a halogen, a hydroxyl group, a lower fluorenyl or lower alkoxy group, a 6-membered heteroaryl group having 1 to 3 nitrogen atoms in the ring, the carbon in the ring being optionally substituted by one or more groups, the substituents being independently of each other halogen, a hydroxy, lower alkyl or lower decyloxy), 5-membered heteroaryl (having from 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, the carbon and nitrogen atoms of which are optionally one or more Substituted, the substituents are, independently of each other, halogen, hydroxy, lower alkyl or lower alkoxy), or 5 or 6 membered heterocycloalkyl (having 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, The carbon and nitrogen atoms of the group, if any, optionally taken by one or more groups Substituents are each independently halogen, hydroxy, lower a fluorenyl or lower decyloxy group, a fluorenyl group, a (lower fluorenyl) thio group, an arylthio group (optionally substituted by one or more groups, the substituents being independently of one another halogen, hydroxy, lower alkyl or Low-grade alkoxy), cyano. Acyl, thioacyl, 0-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-acylamino, nitro, N-sulfonate Amido, S-sulfonylamino, R ⁵ S(0)-, R ⁵ S(0) ₂ , -C(0)OR ⁵ .

"Alkenyl" means a fluorenyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond. Representative examples include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, and the like.

"Alkynyl" means a fluorenyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond. Representative examples include, but are not limited to, ethynyl, 1-propynyl, 2-propyn'yl, 1-, 2- or 3-butynyl, and the like.

"Aryl" means a group having at least one aromatic ring structure, that is, an aromatic ring having a conjugated π-electron system, including a carbocyclic aryl group, a heteroaryl group, and a biaryl group. The aryl group may be optionally substituted by one or more substituents selected from the group consisting of halogen, trihalomethyl, hydroxy, SR, nitro, cyano, decyloxy, alkyl and R ⁵ R ⁶ .

"Heteroaryl" means an aryl group having from 1 to 3 heteroatoms as ring atoms, the remaining ring atoms being carbon, and heteroatoms including oxygen, sulfur and nitrogen. The ring may be a 5- or 6-membered ring. Examples of the heterocyclic aryl group include a furyl group, a thienyl group, a pyridyl group, a pyrrole, an N-fluorenylpyrrolyl group, a pyrimidinyl group, a pyrazinyl group, an imidazolyl group and the like.

"Heterocyclic fluorenyl" is a monocyclic or fused ring radical having 5 to 9 ring atoms in the ring, wherein one or two ring atoms are selected from nitrogen, oxygen or S(0)n (where n is An integer of 0 to 2) of a hetero atom whose anthracene ring is carbon. These rings may also have one or more double bonds, however, these rings do not have a fully conjugated pi-electron system. Unsubstituted heterocycloalkyl group includes, but is not limited to, pyrrolidinyl, piperidino, piperazino, morpholinyl, thiomorpholinyl, piperazine, etc., heterocyclic fluorenyl may be substituted or Unsubstituted. When substituted, the substituents are preferably one or more, more preferably one, two or three, and still more preferably one or two, independently selected from lower alkyl, trihalofluorenyl, halogen, hydroxy, lower Alkoxy, fluorenyl, (lower fluorenyl) thio, cyano, acyl, thioacyl, 0-carbamoyl, fluorenyl-carbamoyl, 0-thiocarbamoyl, hydrazine-thiocarbamoyl , C-amido, oxime-amido, nitro, oxime-sulfonylamino, S-sulfonylamino, R ⁵ S(0)-, R ⁵ S(0) ₂ , -C(0)OR ⁵ , A group consisting of R ⁵ C(0)O- and NR ⁵ R ⁶ , and R ⁵ and R ^{6 are} as defined above. Preferably, the heteroaryl group may be selected from one or two substituents, and the substituents are independently selected from halogen, lower fluorenyl, trihaloalkyl, hydroxy, decyl, cyano, N-acylamino, mono or di Alkylamino, carboxy or N-sulfonylamino.

"Hydroxy" means an -OH group.

"Alkoxy" means -0-(fluorenyl) and -0- (unsubstituted fluorenyl). Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like.

"Haloalkoxy" means -0-(haloalkyl). Representative examples include, but are not limited to, trifluoromethoxy, tribromomethoxy, and the like. 07 000176

"Aryloxy" means -o-aryl and -0-heteroaryl, and aryl and heteroaryl are as defined above. Representative examples include, but are not limited to, phenoxy, pyridyloxy, furanoxy, thienyloxy, pyrimidinyloxy, pyrazinyloxy, and the like, and derivatives thereof.

"Mercapto" refers to the -SH group.

"Indolyl" refers to -0-(indenyl) and -0-(unsubstituted cycloalkyl). Representative examples include, but are not limited to, methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, and the like.

"Arylthio" means -S-aryl and -S-heteroaryl, and aryl and heteroaryl are as defined above. Representative examples include, but are not limited to, phenylthio, pyridylthio, furanthio, thiophenothionyl, pyrimidinyl, and the like, and derivatives thereof,

"Acyl" means a -C(0)-R" group, wherein R" is selected from hydrogen, lower alkyl, trihalomethyl, unsubstituted cycloalkyl, aryl (optionally one or more, Preferably one, two or three substituents are selected from the group consisting of lower alkyl, trihalomethyl, lower decyloxy, halogen and -NR ⁵ R ⁶ ), heteroaryl (via ring carbon bonding) (optionally one or more, preferably one, two or three substituents selected from the group consisting of lower alkyl, trihalomethyl, lower alkoxy, halogen and -NR ⁵ R ⁶ And a heteroalicyclic group (bonded by a ring carbon) (optionally substituted by one or more, preferably one, two or three substituents selected from lower alkyl, trihalomethyl, a group consisting of a lower alkoxy group, a halogen and a -KR ⁵ R ⁶ ). Representative acyl groups include, but are not limited to, acetyl, trifluoroacetyl, benzoyl, and the like.

"Thioxo" refers to a -C(S)-R" group, wherein R" is as defined above.

"Acetyl" means -C (0) CH ₃ group.

"Halogen" means fluoro, chloro, bromo or iodo, preferably fluoro or chloro.

"Trihalomethyl" means -C3⁄4, wherein X is a halogen as defined above.

"Trihalomethylsulfonyl" means a 3⁄4CS(=0)2 group. wherein X is as defined above.

"Optional" or "optionally" means that the event or environment described subsequently may, but need not, occur, including where the event or environment occurs or does not occur. For example, "optionally substituted with a fluorenyl group" means that the fluorenyl group may, but need not be, the case where the heterocyclic group is substituted by a thiol group and the case where the heterocyclic group is not substituted by a thiol group.

"Pharmaceutical composition" means a mixture of one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, with other chemical components, such as a physiological/pharmaceutically acceptable carrier. And excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to the organism. Method for synthesizing the compound of the present invention In order to accomplish the object of the present invention, the present invention adopts the following technical scheme - a method for preparing the compound of the present invention (I) or a salt thereof, comprising the following steps:

The method for preparing the compound of the formula (I) or a salt thereof of the present invention comprises the following steps:

A method for preparing a compound of the formula (II) or a salt thereof according to the present invention, comprising the following steps

11-2 A method for producing a compound of the formula (III) or a salt thereof according to the present invention, comprising the following steps -

detailed description

The invention is further described in the following examples, but these examples are not intended to limit the scope of the invention. The structure of the example compounds was determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). The NMR shift (δ) is given in parts per million (ppm). The NMR was measured by a Bruker AVANCE-400 nuclear magnetic apparatus. The solvent was deuterated chloroform (CDC1 ₃ ), deuterated dimethyl sulfoxide (DMSO-D ₆ ), and the internal standard was trimethylsilyl (TMS). shifts are 10- ⁶ (ppm) given as a unit.

The MS was measured using a FINMGAN LCQAd (ESI) mass spectrometer.

Kinase inhibition rate and IC ₅ . The value is determined by NovoStar microplate reader (BMG, Germany). Thin layer of silica gel is used in Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.

Column chromatography generally uses Yantai Huanghai silica gel 200~300 mesh silica gel as the carrier.

DMSO-D ₆ : deuterated dimethyl sulfoxide;

CDC1 ₃ : deuterated chloroform; Example 1

4-(3-Chloro-4-fluoro-aniline 3-methyl-1H-pyrrolo- 2,3-dl哒嗉 -2-(4-(morpholine-4-yl-piperidinyl)formyl

First step

Ethyl 5-formyl-3-methyl-1Η-pyrrole-2,4-dicarboxylate ethyl 3,5-dimethyl-1H-pyrrole-2,4-dicarboxylate la (4.79 g, 20 mmol) was dissolved in tetrahydrofuran (100 mL), and then a mixed solvent of acetic acid (120 mL) and water (100 mL) was added, and ammonium cerium nitrate (44.4 g, 81 mmol) was added in one portion at room temperature for 1.5 hours. Add water (200 mL) to the system, extract the reaction solution with dichloromethane (100 mL×3), combine the organic phases, wash the organic phase with saturated sodium bicarbonate solution until the pH is alkaline, and then use saturated chlorination. The sodium solution was washed (25 mL EtOAc), EtOAcjjjjjjjjjjj Ethyl 1H-pyrrole-2,4-dicarboxylate lb (2.544 g, white solid). Yield: 65.09%.

MS m/z (ESI): 254 [M-1]

'HNMR (400MHZ, CDCI3-): 510.27(s, 1H), 4.39(m, 4H), 2.60(s, 3H), 1.37(q, 6H)

Ethyl 3-methyl-4-carbonyl-3a,4,5,7a-tetrahydro-1H-pyrrolo[2,3-d]pyridazine-2carboxylate 5-formyl-3- at room temperature Ethyl methyl-1H-pyrrole-2,4-dicarboxylate lb (2.544 g, 10 mmol, ) was dissolved in acetic acid (43 mL), and 85% hydrazine hydrate solution (0.65 mL, 11 mmol) was added with stirring. A yellow precipitate formed, stirring was continued, and the mixture was heated to 100 Torr for 2 hours. The reaction solution was cooled to room temperature and allowed to stand overnight. The next day, suction filtration under reduced pressure and solid dried to give the title product 3-methyl-4-carbonyl-3a, 4, 5, 7a-tetrahydro-1H-pyrrolo[2,3-d]pyridazine-2carboxylate Ethyl ester lc (1.74 g, yellow powdery solid). Yield: 78.73%.

MS m/z (ESI): 222 [M+ 1]

1HNMR (400MHz, D SO-^): 58.09(s, 1H), 4.34 (q, 2H, J = 7.2 Hz), 2.63 (s, 3H), 1.35(t, 3H, J=7.2 Hz) Step 3

Ethyl 3-methyl-4-chloro-3a,4,5,7a-tetrahydro-1H-pyrrolo[2,3-d]pyridazine-2carboxylate under nitrogen atmosphere at 100 mL three neck In the flask, ethyl 3-methyl-4-carbonyl-3a,4,5,7a-tetrahydro-1H-pyrrolo[2,3-d]pyridazine-2carboxylate lc (553 mg, 2.5 mmol Dissolve in anhydrous acetonitrile (15 mL), slowly add anhydrous phosphorus oxychloride (0.465 mL, 5 mmol) with stirring at room temperature. After the addition is completed, heat to reflux to a yellow solid lc gradually dissolve to a yellow solution and continue to reflux. 0.5 hours. The reaction solution was transferred to a 100 mL eggplant-shaped flask, and acetonitrile was distilled off under reduced pressure. Then, n-hexane (10 mL) was added to the reaction mixture, and the mixture was evaporated to dryness and dried three times (removing residual phosphorus oxychloride). The title product 3-methyl-4-chloro-3a,4,5,7a-tetrahydro-1H-pyrrolo[2,3-d]pyridazine-2carboxylate Id (yellow solid) was obtained, Do the next step directly.

This step can also be purified. The solid is placed in a 50 mL eggplant-shaped flask, added to tetrahydrofuran (8 mL), stirred at room temperature for 30 minutes, and filtered to give the title product 3-methyl-4-chloro-3a, 4 , 5,7 _a - tetrahydro -1H- pyrrolo [2,3-d] pyridazine -2-carboxylate as a yellow solid Id (569 mg, pale yellow solid), yield: 94.9%. MS m/z (ESI): 240 [M+ 1]

^{! HNMR (400MHz, DMSO-i¾} ): 69.5 l (s, 1H), 4.43 (q, 2H, J = 7.2 Hz), 2.77 (s, 3H), 1.39 (t, 3H, J = 7.2 Hz)

, the fourth step '

4-(3-Chloro-4-fluoro-aniline)-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid ethyl ester hydrochloride in the third step 3- Methyl chloride-3a,4,5,7a-tetrahydro-1H-pyrrolo[2,3-d]pyridazine-2carboxylic acid ethyl ester Yellow solid Id in an eggplant-shaped flask, directly added with isopropanol under stirring ( 15 mL) and 3-chloro-4-fluoro-aniline (546 mg, 3.75 mmol), heated to reflux, and the spot was traced until the starting material disappeared. The reaction solution was cooled to room temperature, then cooled with EtOAc EtOAc EtOAc (EtOAc) Aniline)-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid ethyl ester hydrochloride (440 mg, yellow solid). Yield: 50.4%.

MS m/z (ESI): 349[M+ 1] Step 5

4-(3-chloro-4-fluoro-aniline)-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid in a 100 mL eggplant-shaped flask, 4-(3- Chloro-4-fluoro-aniline) 3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid ethyl ester (440 mg, 1.26 mmol) dissolved in ethanol (30 mL) In addition, add sodium hydroxide solution (5 mL, 1 mol / L), heat to reflux, point plate tracking until the disappearance of the raw materials, the reaction solution was cooled to room temperature overnight, and the ethanol was evaporated under reduced pressure, and 1 N hydrochloric acid was stirred with stirring. The solution was adjusted to pH 2 and a large amount of solid precipitated. Filtration under reduced pressure, the solid was washed with distilled water and dried to give the title product 4-(3-chloro-4-fluoro-aniline)-3-methyl-1H- Pyrrolo[2,3-d]pyridazine-2-carboxylic acid lf (367 mg, yellow solid). Yield: 91%.

MS m/z (ESI): 319 [M-1]

Add 4-(3-chloro-4-fluoro-aniline)-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid If (320 mg) to a 100 mL eggplant-shaped flask , 1 mmol), N-ethyl-N,-(dimethylaminopropyl)-carbodiimide (288 mg, 1.5 mmol), hydroxybenzothiazole (203 mg, 1.5 mmo) and N'N- Dimethylformamide (30 mL), after stirring until dissolved, was added triethylamine (0.35 mL, 2.5 mmol). After stirring for 5 min, 4-(morpholinolin-4-yl)-piperidine (255 mg, 1.5 mmol) After stirring at room temperature overnight, the plate was monitored until the disappearance of the starting material. The reaction solution was poured into ice water (200 mL), and the reaction mixture was extracted with ethyl acetate (80 mL×4), and the organic phase was combined. The sodium solution was washed (25 mL), EtOAcjjjjjjjjjjjjjj Benzene)-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-(4-(morphinolin-1-yl)-piperidinyl)carboxamide 1 (43 mg, yellow solid) . Yield: 9%.

MS m/z (ESI): 473[M+1]

1HNMR (400MHz, DMSO-i3⁄4): δ 8.89 (s, 1H), 7.99 (d, 1H), 7.62 (t, 1H), 7.34 (q, 1H), 3.57 (s, 4H), 3.45 (s, 9H) ), 2.47(s, 3H), 1.84 (m, 2H), 1.36 (m, 2H) Example 2

4-(3-Chloro-4-fluoro-aniline 3-methyl-1H-pyrrolof2,3-dloxazin-2-(2-diethylaminoethyl)carboxamide

The reaction of the first step to the fifth step of Example 1 of the present invention was repeated, using the compound 4-(3-chloro-4-fluoro-aniline)-3-methyl-1H-pyrrole obtained in the above fifth step. 2,3-d]pyridazine-2-carboxylic acid If as a starting material, the reaction of the starting material with diethylethylenediamine is carried out in the same manner as described in the sixth step of the present invention, to obtain the title product 4-(3). -chloro-4-fluoro-aniline)-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-(2-diethylaminoethyl)carboxamide 2 (239 mg, yellow solid ). Yield: 38%.

MS m/z (ESI): 419 [M+ 1]

'HNMR (400MHZ, DMSO-C3⁄4: δ 8.91 (s, 1H), 7.98 (d, 1H), 9.60 (d ₅ 1H), 7.34 (t, 1H), 3.39(t, 2H), 2.71(s, 3H), 2.64(t, 2H), 2.57(m, 4H), 1.00(t, 6H) Example 3

4-(3-Chloro-4-fluoro-aniline)-3-methyl-1H-pyrrolo-2,3-dloxazin-2-(2-morpholine-4-yl-ethyl)carboxamide

3 Repeat the reaction of the first step to the fifth step of the first embodiment of the present invention, using the compound 4-(3-chloro-4-fluoro-aniline)-3-methyl-1H-pyrrole obtained in the above fifth step. [2,3-d]pyridazine-2-carboxylic acid If as a starting material, the reaction of the starting material with morpholine-4-yl-ethylenediamine is carried out in the same manner as described in the sixth step of the present invention, to obtain the title product. 4-(3-chloro-4-fluoro-aniline)-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-(2-morphinolin-4-yl-ethyl)carboxamide 3 (248 mg, yellow solid). Yield: 38.4%.

MS m/z (ESI): 433 [M+ 1]

1H MR (400MHz, DMSO-^): δ 8.92(s, 1H), 7.99(d, 1H), 7.62(d, 1H), 7.34 (t, 1H), 3.59(t, 4H), 3.43(t, 2H), 2.71(s, 3H), 2.50(t, 2H), 2.44(s, 4H) Example 4

4-Π-alkynyl-aniline)-3-methyl-1H-pyrrolof2,3-dlpyridazine-2-ί2-diethylaminoethylformamide

4

first step

4-(3-ynyl-aniline)-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid ethyl ester hydrochloride as described in Example 1, third and fourth steps In the same way, in a 100 mL three-necked flask under a nitrogen atmosphere, 3-methyl-4-carbonyl-3a,4,5,7a-tetrahydro-1H-pyrrolo[2,3-d]pyridazine- 2 Carboxylic acid ethyl ester lc (1.549 g, 7 mmol) was dissolved in anhydrous acetonitrile (50 mL), and anhydrous phosphorus oxychloride (1.3 mL) was slowly added dropwise with stirring at room temperature. After the addition was completed, the mixture was heated to reflux. The solid lc gradually reacted to dissolve into an orange-red solution and continued to reflux for 30 minutes. The reaction solution was transferred to a 150 mL eggplant-shaped flask, and acetonitrile was removed by vacuum distillation under reduced pressure. Then, hexane (10 mL) was added to the reaction mixture, and the mixture was evaporated to dryness and dried three times (removing residual phosphorus oxychloride). Obtaining 3-methyl-4-chloro-3a,4,5,7a-tetrahydro-1H-pyrrolo[2,3-d]pyridazine-2carboxylic acid ethyl ester Id (yellow solid), in the shape of eggplant Isopropanol (35 mL) and m-ethynylaniline (0.9 g, 7.7 mmol) were added directly to the flask, and the mixture was heated under reflux for 3 hours, and the spot was traced until the starting material disappeared. The reaction solution was cooled to room temperature, cooled with ice-cooled water and stirred, and then evaporated, evaporated, evaporated, evaporated, evaporated. Aniline)-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid ethyl ester hydrochloride 4a (1.194 g, yellow solid). Yield: 44.22%.

MS m/z (ESI): 321 [M+ l] Step 2

4-(3-ynyl-aniline)-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid In the same manner as described in the fifth step of Example 1 of the present invention, 4- (3-blockyl-aniline)-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid ethyl ester hydrochloride 4a as a starting material, the title product 4-(3) - alkynyl-aniline)-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid 4b (970 mg, yellow solid).

MS m/z (ESI): 219 [M+ 1] Step 3

4-(3-ynyl-aniline)-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-(2-diethylaminoethyl)carboxamide according to Example 1 of the present invention In the same manner as described in the sixth step, 4-(3-ynyl-aniline)-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid 4b is used as a raw material to carry out the raw material and The reaction of diethylethylenediamine gives the title product 4-(3-ynyl-aniline)-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-(2-diethyl) Aminoethyl)carboxamide 4 (253 mg, white solid). Yield: 43.2%.

MS m/z (ESI): 391 [M+ l]

¹ H NMR (400MHz, DMSO-^): 58.913 (s, 1H), 7.884 (s, 1H), 7.660 (d, 1H), 7.311 (t, 1H), 7.068 (d, 1H), 4.082 (s, 1H) ), 3.373(t, 2H), 2.696(s, 3H), 2.596(t, 2H), 2.579~2.513(m, 4H), 0.987(t, 6H) Example 5 4-(-alkynyl-aniline)-3-methyl-1H-pyrrolo-r2,3-d|pyridazine-2-(4-(morpholine-4-yl)-piperidinyl)

The reaction of the first step to the second step of Example 4 of the present invention was repeated, using the compound 4-(3-ynyl-aniline)-3-methyl-1H-pyrrolo[2,3 obtained in the above second step. -d]pyridazine-2-carboxylic acid 4b as a starting material, the reaction of the starting material with 4-(morpholinolin-4-yl)-piperidine is carried out in the same manner as described in the sixth step of the present invention, to obtain the title product. 4-(3-ynyl-aniline)-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-(4-(morphinolin-4-yl)-piperidinyl)carboxamide 5 (122 mg, orange-yellow solid). Yield: 20%.

MS m/z (ESI) : 445 [M+ 1]

^J HNMR (400MHz, DMSO-^): δ 8.89 (s, 1H), 7.84 (s, 1H), 7.67 (d, 1H), 7.32 (t, 1H, -ArH), 7.07 (d, 1H), 4.10 (s, 1H), 3.58(s, 4H), 3.47(s, 9H), 2.46(s, 3H), 1.87 (m, 2H), 1.36 (m, 2H) Example 6

4-(3-ynyl-aniline > -methyl -1H-pyrrolo "2,3-dloxazin-2-(2-pyrrolidin-1-yl)-ethyl)carboxamide

The reaction of the first step to the second step of Example 4 of the present invention was repeated, using the compound 4-(3-ynyl-aniline)-3-methyl-1H-pyrrolo[2,3 obtained in the above second step. -d]pyridazine-2-carboxylic acid 4b as a starting material, the reaction of the starting material with 2-(pyrrolidin-1-yl)-ethylamine is carried out in the same manner as described in the sixth step of the present invention, to obtain the title product. 4-(3-ynyl-aniline)-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-(2-pyrrolidin-1-yl)-ethyl)carboxamide 6 ( 405 mg, pale yellow solid). Yield: 57.9 %

MS m/z (ESI): 389 [M+ 1]

¹ H NMR (400MHz, OMSO-d ₆ ): δ 8.96(s, 1H), 7.84(s, 1H), 7.66(d, 1H), 7.33(t, 1H), 7.09(d, 1H), 4.12(s , 1H), 3.65(t, 2H), 3.35(t, 2H), 2.73(s, 3H), 2.51 (m, 4H), 2.00(m, 4H) Example

4-(3-ynyl-phenylamine)-3-methyl-1Η-pyrrolo-[2,3-dlpyridazine-2- 2-morpholine-4-yl)-ethyl)carboxamide

The reaction of the first step to the second step of Example 4 of the present invention was repeated, using the compound 4-(3-ynyl-aniline)-3-methyl-1H-pyrrolo[2,3 obtained in the above second step. -d]pyridazine-2-carboxylic acid 4b as a starting material, the reaction of the starting material with (2-morphocolin-4-yl)-ethylamine is carried out in the same manner as described in the sixth step of the present invention, to obtain the title product. 4-(3-ynyl-aniline)-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-(2-morphinolin-4-yl)-ethyl)carboxamide 7 ( 139 mg, yellow solid). Yield: 23%.

MS m/z (ESI): 405 [M+ 1]

¹ H NMR (400 MHz, DMSO-rf ₆ ): 58.92 (s, 1H,), 7.85 (s, 1H), 7.67 (d, 1H), 7.3 l (t, 1H), 7.07 (d, lH), 4.09 ( s, 1H), 359(t, 4H), 3.42(q, 2H), 2.70(s, 3H), 2.51(s, 2H), 2.45(q, 4H) Example 8

_4- "3-Chloro-4-(3-fluorobenzyloxylamine 1-3-methylpyrrolo-f2,3-dloxazin-2-(2-pyrrolidin-1-ylethyl)carboxamide

first step

4-[3-Chloro-4-(3-fluorobenzyloxy)-aniline]-3-methyl-1Η-pyrrolo[2,3-d]pyridazine-2-carboxylic acid ethyl ester hydrochloride according to the implementation In the same manner as described in the third and fourth steps of Example 1, 3-methyl-4-carbonyl-3a,4,5,7a-tetrahydro-1H-pyrrole in a 50 mL three-necked flask under nitrogen atmosphere And [2,3-d]pyridazine-2carboxylic acid ethyl ester lc (443 mg, 2 mmd) was dissolved in anhydrous acetonitrile (15 mL), and anhydrous phosphorus oxychloride (0.372 mL) was slowly added dropwise with stirring at room temperature. , 4 mmol), after the completion of the dropwise addition, the mixture was heated to reflux to a yellow solid lc and gradually dissolved to a yellow solution, and reflux was continued for 30 minutes. The reaction solution was transferred to a 100 mL eggplant-shaped flask, and acetonitrile was distilled off under reduced pressure. Then, hexamethylene hydride (10 mL) was added to the reaction system, and the mixture was evaporated to dryness, and then, three times (removal of residual phosphorus oxychloride) was obtained. 3-Methyl-4-chloro-3a,4,5,7a-tetrahydro-1H-pyrrolo[2,3-d]pyridazine-2carboxylic acid ethyl ester Id (yellow solid). Isopropanol (15 mL) and 3-chloro-4-(3-fluorobenzyloxy)-phenylamine hydrochloride (0.576 g, 2.0 mmo) and triethylamine (0.3 mL, 2.2) were added directly to the eggplant flask. Mmmol), heated to reflux for 3 hours, the spot plate was traced until the starting material disappeared. The reaction solution was cooled to room temperature, cooled with ice-water-bath and stirred, and evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. 3-Methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid ethyl ester hydrochloride 8a (0.445 g, yellow solid). Yield: 45.4%. The solid was placed in a 50 mL eggplant-shaped flask, methanol (10 mL) was added, the pH was adjusted to 9 with concentrated aqueous ammonia, stirred at room temperature for 5 min, and filtered to give 4-[3-chloro-4-(3-fluoro Benzyloxy)-aniline]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid ethyl ester (yellow solid).

MS m/z (ESI): 455 [M+ 1] Step 2

4-[3-chloro-4-(3-fluorobenzyloxy)-aniline]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid according to Example 1 of the present invention In the same manner as described above, 4-(3-blockyl-aniline)-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid ethyl ester hydrochloride 8a was used as a starting material. The title product 4-[3-chloro-4-(3-fluorobenzyloxy)-aniline]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid 8b was obtained.

MS m/z (ESI): 427 [MH-1]

third step

4-[3-Chloro-4-(3-fluorobenzyloxy)-aniline]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-(2-pyrrolidinesyl) - Ethyl) formamide

In the same manner as described in the sixth step of Example 1 of the present invention, 4-[3-chloro-4-(3-fluorobenzyloxy)-aniline]-3-methyl-1H-pyrrolo[2,3-d was used. The pyridazine-2-carboxylic acid 8b is used as a starting material to carry out the reaction of the starting material with 2-(B-pyrrolidin-1-yl)-ethylamine to give the title product 4-[3-chloro-4-(3-fluoro Benzyloxy)-aniline]-3-methyl_1H-pyrrolo[2,3-d]pyridazine-2-(2-pyrrolidinyl)-ethyl)carboxamide 8 (80 mg, yellow solid) . Yield: 17.3%.

MS m/z (ESI): 523 [M+ 1]

LC-MS: 98,3 %.

'HNMR (400MHZ, DMSO-^): 58.87 (S, lH), 7.89 (S, 1H), 7.55 (d, 1H), 7.45 (m, 1H), 7.30(m, 2H), 7.17(m, 2H), 5.22(s, 2H), 3.43(t, 2H), 2.69(s, 3H), 2.63(t, 2H), 2.5 l(m, 4H), 1.71(s, 4H) Example 9

The reaction of the first step to the second step of Example 8 of the present invention was repeated, using the compound 4-[3-chloro-4-(3-fluorobenzyloxy)-aniline]-3-methyl obtained in the above second step. -1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid 8b as a starting material, and the starting material and (3-morphocolin-4-yl) are carried out in the same manner as described in the sixth step of the present invention. The reaction of propylamine gives the title product 4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamine]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-( 3-morpholine-4-yl-propyl)carboxamide 9 (174 mg, yellow solid). Yield: 35%.

MS m/z (ESI): 553 [M+1]

¹ H NMR (400MHz, DMSO-t, ί): 58.86 (s, 1H), 7.89 (s, 1H), 7.54 (d, 1H), 7.46 (m, 1H), 7.30 (m, 2H), 7.18 (m) , 2H), 5.22(s, 2H), 3.36(t, 4H), 3.33(t, 2H), 2.69(s, 3H), 2.34(m, 6H), 1.720(t, 2H)

, Example 10

4-Γ3-Chloro-4-G-fluorobenzyloxyaniline 1-3-methyl-1H-pyrrolo 2,3-dlpyridazine-2-(2-diethylamino-ethyl)

The reaction of the first step to the second step of Example 8 of the present invention was repeated, using the compound 4-[3-chloro-4-(3-fluorobenzyloxy)-aniline]-3-methyl obtained in the above second step. -1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid 8b as a starting material, the reaction of the starting material with diethylethylenediamine is carried out in the same manner as described in the sixth step of Example 1 of the present invention, The title product 4-[3-chloro-4-(3-fluorobenzyloxy)-aniline]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-(2-diethylamino) -ethyl)formamide 10 (234 mg, pale yellow solid). Yield: 34.9%. MS m/z (ESI): 525 [M+ 1]

1HNMR (400MHz, DMSO-): 68.86 (s, 1H), 7.88 (s, 1H), 7.56 (d, 1H), 7.46 (m, 1H), 7.30 (m, 2H), 7.17 (m, 2H), 5.22(s, 2H), 3.38(t, 2H), 2.70(s, 3H), 2.61(t, 2H), 2.54(m, 4H), 0.99(t, 6H) Example 11

4-Γ3-chloro-4-(3-fluorobenzyloxy)-aniline 1-3-methyl-1H-pyrrolo-f2,3-dl-pyridazine-2-(2-pyrrolidin-1yl-methyl- Pyrrolidin-1-ylformamide

The reaction of the first step to the second step of Example 8 of the present invention was repeated, using the compound 4-[3-chloro-4-(3-fluorobenzyloxy)-aniline]-3-methyl obtained in the above second step. -1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid 8b as a starting material, and the starting material and 2-pyrrolidin-1yl-methyl- are carried out in the same manner as described in the sixth step of Example 1 of the present invention. The reaction of pyrrolidine gives the title product 4-[3-chloro-4-(3-fluorobenzyloxy)-aniline]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2- (2-Pyrrolidin-1yl-methyl-pyrrolidin-1-yl)carboxamide 11 (100 mg, orange-yellow solid). Yield: 18%.

MS m/z (ESI): 563[ + 1]

¹ H NMR (400MHz, DMSO-^): 58.84 (s, 1H), 7.90 (s, 1H), 7.55 (d, 1H), 7.46 (m, 1H), 7.30 (m, 2H), 7.16 (m, 2H) ), 5.22(s, 2H), 3.46~1.15(m, 20H) Example 12

4-(3-Chloro-4-(3-fluorobenzyloxy)-aniline]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-(4-(morpholinolin-4-yl) )-piperidinyl)carboxamide

Repeat the reaction of the first step to the second step of the embodiment 8 of the present invention, using the chemical obtained in the second step above. 4-[3-chloro-4-(3-fluorobenzyloxy)-aniline]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid 8b as a starting material, according to the present The reaction of the starting material with 4-(morpholinolin-4-yl)-piperidine was carried out in the same manner as in the sixth step of the invention, to give the title product 4-[3-chloro-4-(3-fluorobenzyloxy). - aniline]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2_(4-(morpholine-4-yl)-piperidinyl)carboxamide 12 (31 mg, orange yellow solid). Yield: Ί%.

MS m/z (ESI): 579 [M+ 1]

!HNMR (400MHz, OMSO-d ₆ ): 58.83(s, 1H), 7.88(s, 1H), 7.54(d, 1H), 7.46 (m, 1H), 7.30(m, 2H), 7.16(m, 2H), 5.21(s, 2H), 3.57(s, 4H), 3.45(s, 9H), 2.45(s, 3H), 1.85(s, 2H), 1.36(m, 2H)

, Example 13 . ' ■

4-[3-Chloro-4-(3-fluorobenzyloxy)-aniline]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-(2-morphinolin-4-yl) -ethyl) formamide

The reaction of the first step to the second step of Example 8 of the present invention was repeated, using the compound 4-[3-chloro-4-(3-fluorobenzyloxy)-aniline]-3-methyl obtained in the above second step. -1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid 8b as a starting material, and the starting material and 2-morphinolin-4-yl-ethylamine are carried out in the same manner as described in the sixth step of Example 1 of the present invention. The title product was obtained as the title product 4-[3-chloro-4-(3-fluorobenzyloxy)-aniline]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-(2 - morphinolin-4-yl-ethyl)carboxamide 13 (176 mg, yellow solid). Yield: 30.2%.

MS m/z (ESI): 539 [M+ 1]

'HNMR (400MHZ, OUSO-d ₆ ): 58.87 (s, 1H), 7.8937 (s, 1H), 7.5547 (d, 1H), 7.4 (m, 1H), 7.30 (m, 2H), 7.17 (m, 2H), 5.22(s, 2H), 3.59(t, 4H -), 3.44(t, 2H), 2.7 l(s, 3H), 2.49 (t, 2H), 2.40 (m, 4H) Example 14

_₄ _ _Γ3 - chloro _4_ _[3 - fluoro-benzyloxy) - phenylamine Methyl 1-3- -1H- pyrrolo r2,3-dl pyridazin-2-yl - diethylamino carboxylic acid

II

first step

4-[3-chloro-4-(3-fluorobenzyloxy)-aniline]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-methanol under nitrogen atmosphere, tetrahydrogen lithium Aluminum (120 mg, 3 mmol) was dissolved in tetrahydrofuran (30 mL), stirred well, and the reaction system released some bubbles for use. Then 4-[3-chloro-4-(3-fluorobenzyloxy)-aniline]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid ethyl ester 8a (700 Mg, 1.5 mmol) was dissolved in tetrahydrofuran (70 mL), and the suspension was slowly added dropwise to the above tetrahydrofuran solution of lithium tetraoxide. The reaction system immediately changed from the original gray sputum suspension to a light green suspension. The liquid was continuously refluxed for 3.5 hours, and it was found that the green sputum suspension slowly turned into a khaki suspension, and the spot was traced until the end of the reaction. The reaction mixture was quenched with EtOAc (EtOAc m.) (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH - Pyrrolo[2,3-d]pyridazine-2-methanol 14a (499 mg), yield 81%.

MS m/z (ESI): 413 [M+ 1]

¹ H NMR (400 MHz, DMSO-c3⁄4: 68.80 (s, 1H), 7.88 (s, 1H), 7.52 (d, 1H), 7.45 (m, 1H), 7.30 (m, 2H), 7, 17 (m, 2H), 5.21(s, 2H), 4.62 ( s, 2H), 2.42(s, 3H)

₄ — [3-Chloro-4-(3-fluorobenzyloxy)-aniline]-3-methyl-1H-pyrrolo[2,3-d]pyridazin-2-yl-diethylaminocarbamate

In a 50 mL eggplant-shaped flask, 4-[3-chloro-4-(3-fluorobenzyloxy)-aniline]-3-methyl-1H-pyrrolo[2,3-d]pyridazine- 2-Methanol 14a (206 mg, 0.5 mmol) dissolved in N'N-dimethylformamide (5 mL) The 55%~65% sodium hydride solid (26 mg, 0.6 mmol) was weighed at room temperature and slowly added to the pre-formed pre-solution and stirred at room temperature for 5 minutes. Then, a solution of diethylformyl chloride (82 mg, 0.6 mmol, ) in N,N-dimethylformamide (5 mL) was added dropwise, and the solution changed from yellow to brownish red. Most disappeared and was continuously stirred at room temperature for 3 hours. The reaction was stopped, and the reaction solution was poured slowly into ice water, and a solid was formed, stirring was continued for 30 minutes, and filtered to give the title product 4-[3-chloro-4-(3-fluorobenzyloxy)-aniline]-3- Methyl-1H pyrrolo[2,3-d]pyridazin-2-yl-diethylammoniumcarboxylate 14 (195 mg, yellow solid). The yield was 76%.

MS m/z (ESI): 512 [M+1]

'HNMR (400MHZ, DMSO-): 58.79 (s, 1H), 7.88 (s, 1H), 7.521 (d, 1H), 7.45 (m, 1H), 7.30 (m, 2H), 7.17 (m, 2H) , 5.21(s, 2H), 4.62( s, 2H), 2.42(s, 3H) Example 15

₄ _Γ3_Chloro- _4- ₍₃ -fluorobenzyloxy)-anilinemethyl-small methyl-B-pyrrolo-l"2,3-dl-pyridazine-2-(2-diethylamino-ethyl) A Amide

first step

1,3,5-trimethyl-pyrrole-ethyl 2,4-dicarboxylate

Stir 55%~65% sodium hydride (240 mg, 5.5 mmol) in a 50 mL eggplant bottle under nitrogen Dissolved in N'N-dimethylformamide (5 mL) and slowly added the crude ethyl 3,5-dimethyl-1H-pyrrole-2,4-dicarboxylate la (1.196 g, 5 mmol) Stir at room temperature for 10 minutes, then add methyl iodide (2.7 mL, 53 mmol), stir at room temperature overnight, and click to stop the reaction. On the next day, the reaction mixture was poured into water, a white solid was evaporated, filtered, and then evaporated to give the title product 15a (1.086 g, white solid). The yield was 86%.

MS m/z (ESI): 254 [M-1] second step

Ethyl 5-formyl-3-methyl-1-methyl-pyrrole-2,4-dicarboxylate The compound obtained in the above first step was used in the same manner as described in the first step of Example 1 of the present invention. 1,3,5-trimethyl-pyrrole-2,4-dicarboxylic acid ethyl ester 15a is used as a raw material, and the reaction of the starting material with ammonium cerium nitrate is carried out to obtain the title product 5-formyl-3-methyl-1. Methyl-pyrrole-2,4-dicarboxylic acid ethyl ester 15b (5.283 g). The yield is 45 %.

MS m/z (ESI): 268 [M+ 1]

^I HNMR (400MHz, COC\ ₃ -d): δ 10.376(s, 1H), 9,915(s, 1H), 4.37(m, 4H), 4.17(s, 3H) _: 2.49(s, 3H), 1.40( q, 6H)

third step

Ethyl 3-methyl-4-carbonyl-3a,4,5,7a-tetrahydro-1-methyl-pyrrolo[2,3-d]pyridazine-2carboxylate according to Example 1 of the present invention In the same manner as described in the above step, the compound 5-formyl-3-methyl small methyl-pyrrole-2,4-dicarboxylate 15b (3.24 g, 12 mmol) obtained in the above second step was used as a starting material. The reaction of the starting material with hydrazine hydrate (0.72 g, 12 mmol) afforded the title product 3-methyl-4-carbonyl-3a,4,5,7a-tetrahydro-s-methyl-pyrrolo[2,3 -d]pyridazine-2carboxylic acid ethyl 15c (2.227 g). The yield was 79.3 %.

MS m/z (ESI): 236 [M+ 1]

'HNMR (400MHZ, DMSO-): δ 8.400(s, 1H), 4.341 (q, 2H, J=7.2 Hz), 3.979(s, 3H,), 2.620(s, 3H), 1.351(t, 3H, J=7.2 Hz) Step 4

4-[3-chloro-4-(3-fluorobenzyloxy)-aniline]-3-methylsuccinyl-pyrrolo[2,3-d]pyridazine-2-carboxylic acid ethyl ester hydrochloride In the same manner as described in the third and fourth steps of the present invention, the compound obtained in the above third step is 3-methyl-4-carbonyl-3a,4,5,7a-tetrahydro-1-methyl. - pyrrolo[2,3-d]pyridazine-2carboxylic acid ethyl ester 15c as a starting material to give the title product 4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamine]-3-methyl 1-methyl-pyrrolo[2,3-d]pyridazine-2-carboxylic acid ethyl ester hydrochloride 15d (1. 642 g, white solid). The yield was 79.7%.

MS m/z (ESI): 468 [M+ 1] the fifth step

4-[3-chloro-4-(3-fluorobenzyloxy)-aniline]-3-methylsuccinyl-pyrrolo[2,3-d]pyridazine-2-carboxylic acid according to the present invention i In the same manner as described in the fifth step, the compound 4-[3-chloro-4-(3-fluorobenzyloxy)-aniline]-3-methyl-1-methyl-pyrrole obtained in the above fourth step was used. And [2,3-d]pyridazine-2-carboxylic acid ethyl ester hydrochloride as a starting material, the title product 4-[3-chloro-4-(3-fluorobenzyloxy)-aniline]-3-methyl Base-I-methyl-pyrrolo[2,3-d]indole-2-carboxylic acid 15e (1.410 g, yellow solid).

MS m/z (ESI): 441 [M+1] Step 6

4-[ ³ -chloro-4-(3-fluorobenzyloxy)-aniline]-3-methyl-1-methyl-pyrrolo[2,3-d]pyridazine-2-(2-diethylamine) Base-ethyl) formamide

In the same manner as described in the sixth step of Example 1 of the present invention, the compound 4-[3-chloro-4-(3-fluorobenzyloxy)-aniline]-3-methyl- obtained in the above fifth step was used. 1-methyl-pyrrolo[2,3-d]pyridazine-2-carboxylic acid 15e as a starting material to give the title product 4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamine]-3 Methyl-1-methyl-pyrrolo[2,3-d]pyridazine-2-(2-diethylamino-ethyl)carboxamide 15 (41 mg, yellow solid).

MS m/z (ESI): 539 [M+ 1]

'HNMR (400MHZ, DMSO-): 59.06 (s, 1H), 7.899 (d, 1H), 7.56 (dd, 1H), 7.45 (m, 1H), 7.30 (m, 2H), 7.17 (m, 2H) , 5.22(s, 2H), 3.83(s, 3H), 3.39(t, 2H), 2.45(m, 9H), 0.990(t, 6H) Example 16

4-Γ3-chloro-4-(-fluorobenzyloxy)-aniline]-3-methyl-1-methyl-pyrrolof2,3-dl哒 bad-2- 2-pyrrolidine-i-yl-B Carboxamide

The reaction of the first step to the fifth step of Example 15 of the present invention was repeated, and the compound 4-[3-chloro-4-(3-fluorobenzyloxy)-aniline]-3-methyl obtained in the above fifth step was used. 1-methyl-pyrrolo[2,3-d]pyridazine-2-carboxylic acid 15e as a starting material, the starting material and 2-(pyrrolidin-1) were carried out in the same manner as described in the sixth step of Example 15 of the present invention. -yl)-ethylamine reaction to give the title product 4-[3-chloro-4-(3-fluorobenzyloxy)-aniline]-3-methyl-1-methyl-pyrrolo[2,3- d] pyridazine-2-(2-pyrrolidin-1-yl)-ethyl)carboxamide 16 (24 mg, yellow solid).

S m/z (ESJ): 537[M+1] 3⁄4 M (400MHz, DMSO-^): 9.07(s, 1H), 7.89(s, 1H), 7.55(m, 1H), 7.45(m, 1H), 7.30(m, 2H), 7.16(m, 2H) ), 5.22(s, 2H), 3.84(s, 3H), 3.55(ί, 2H), 3.10 (m, 6H), 2.55(s, 3H), U8(s, 4H). Example 17

4-|~3-Chloro-4- 3-fluorobenzyloxy)-aniline 1,3-dimethyl-pyrrolo-2,3-cHpyridazine-2 (2-morpholine-4-yl-ethyl ) -carboxamide

The reaction of the first step to the fifth step of Example 15 of the present invention was repeated, using the compound 4-[3-chloro-4-(3-fluorobenzyloxy)-aniline]-3-methyl obtained in the above fifth step. 1-methyl-pyrrolo[2,3-d]pyridazine-2-carboxylic acid 15e as a starting material, the starting material and 2-morpholine-4- are carried out in the same manner as described in the sixth step of Example 15 of the present invention. The reaction of the base-ethylamine gives the title product 4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamine]-1,3-dimethyl-pyrrolo[2,3-d]pyridazine 2-(2-morpholine-4-yl-ethyl)-carboxamide 17 (223 mg, yellow solid). Yield: 51%. MS m/z (ESI): 554[M+ 1]

^{! HNMR (400MHz, DMSO-c} d): 7.90 (s, 1H), 7.66 (m, 1H), 7.33 (m, 2H), 7.20 (m, 2H), 7.16 (m, 2H), 5.21 (s, 2H), 4.23(m, 4H), 3.84(s, 3H), 3.55(t, 2H), 3.10 (m, 4H), 2.53 (s, 3H), 2.05 (m, 4H) Example 18

443-chloro-4-(3-fluoro-benzyloxyphenylamino 3-methyl-1H-pyrrolo[2,3-dloxazin-2-carboxylic acid f2-i4-methyl-piperazine small group V Ethyl 1-carboxamide

The reaction of the first step to the second step of Example 8 of the present invention was repeated, and the compound 4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamine]-3-methyl obtained in the above second step was used. The base-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid 8b is used as a starting material, and the starting material is 2-(4-methyl-piperazine) in the same manner as described in the sixth step of the present invention. -1-base) - B The reaction of the amine gives the title product 4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino: 1- 3-methyl-1H-pyrrolo[2,3-d]pyridazine 2-carboxylic acid [2-(4-methyl-heptazin-1-yl)-ethyl]-carboxamide 18 (90 mg, pale yellow solid). Yield: 15%.

MS m/z (ESI): 553 [M+1]

^{] HNMR (400MHz, DMSO-ί} / ί): 7.97 (s, 1H), 7.66 (m, 1H), 7.54 (m, 1H), 7.43 (m, 1H), 7.18 (m, 2H), 7.15 (m , 2H), 5.22(s, 2H), 4.23 (m, 4H), 3.43(q, 2H), 2.71(s, 3H), 2.49 (m, 4H), 2.34(m,2H), 2.16(s, 3H) Example 19

4-Γ3-chloro-4-(-fluoro-benzyloxy)-phenylamino-1- 3-methyl-1H-pyrrolo-r2,3-dl-pyridazine-2-carboxylic acid hydrazine 2-(4-methyl- Piperidinyl) -propyl 1-carboxamide

The reaction of the first step to the second step of Example 8 of the present invention was repeated, and the compound 4-[3-chloro-4-(3-fluorobenzyloxy)-aniline]-3-methyl obtained in the above second step was used. -1Η-pyrrolo[2,3-d]pyridazine-2-carboxylic acid 8b as a starting material, the starting material and 2-(4-methyl-piperazine-in the same manner as described in the sixth step of Example 1 of the present invention. The reaction of 1-yl)-propylamine gives the title product 4-[3-Chloro(3-fluoro-hydroxy)-phenylamino]-3-methyl § _: 111-pyrrolo[2,3-d] Pyridazine-2-carboxylic acid [2-(4-methyl-piperazin-1-yl)-propyl]-carboxamide 19 (214 mg, pale yellow solid). Yield: 35%.

MS m/z (ESI): 567[M+ 1]

'HNMR (400MHz, DMSO-i3⁄4: 7.97(s, 1H), 7.56(d, 2H), 7.30(m, 1H), 7.18(m, 2H), 7.15(m, 2H), 5.26(s, 2H) , 2.89(s, 3H), 2.38(m, 8H), 2.21(s, 3H), 1.87(m, 4H), 1.26(m, 2H)

Example 20

-"1-(3-Fluorobenzyl)-1H-indazole-5-amino1-3-methyl-1H-pyrrolopyridazine-(2-methoxyethyl)formyl

First step

4-[1-(3-Fluorobenzyl)-1H-indazole-5-amino]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid ethyl ester hydrochloride Example 1 Method of the third and fourth steps, 3-methyl-4-carbonyl-3a,4,5,7a-tetrahydro-1H-pyrrole in a 50 mL three-necked flask under nitrogen atmosphere And [2,3-d]pyridazine-2carboxylic acid ethyl ester lc (1.264 g, 1.2 mmol) was dissolved in anhydrous acetonitrile (15 mL), and anhydrous phosphorus oxychloride (0.223 mL) was slowly added dropwise with stirring at room temperature. After 2.4 g), the mixture was heated to reflux to a yellow solid lc and gradually dissolved to a yellow solution, followed by reflux for 30 minutes. The reaction solution was transferred to a 100 mL eggplant-shaped flask, and acetonitrile was removed by vacuum distillation under reduced pressure. Then, hexane (10 mL) was added to the reaction system, and the mixture was evaporated to dryness and dried three times (removing residual phosphorus oxychloride). Then, isopropanol (15 mL) and 1-(3-fluorobenzyl)-5-amino-1H-carbazole (258 mg, 1.07 mmd) and triethylamine were added to the eggplant flask, and the mixture was heated under reflux for 3 hours. , the point plate tracks the reaction until the raw material disappears. The reaction solution was cooled to room temperature, cooled with ice-cooled water and stirred, and then evaporated, evaporated, evaporated, evaporated, evaporated. -1 - oxazole-5-amino]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid ethyl ester hydrochloride 20a (0.329 g, pale yellow solid). The yield was 66.5 %. MS m/z (ESI): 445 [M+ 1]

1H NMR (400MHz, DMSO-i3⁄4: S8.83 (s, 1 Η), 8.09 (s, 2H), 7.67 (m, 1H), 7.57 (m, 1H), 7.36 (m, 1H), 7.06 (m, 3H) ), 5.68(s, 2H), 4.39(q, 2H), 2.69(s, 3H), 1.37(t, 3H) Step 2 4-[l-(3-Fluorobenzyl)-1Η-indazol-5-amino]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid is practiced in accordance with the invention In the same manner as described in the fifth step of Example 1, 4-[1-(3-fluorobenzyl)-1Η-indazole-5-amino]-3-methyl-1H-pyrrolo[2,3-d] was used. The title product, 4-[1-(3-fluorobenzyl)-1H-indazole-5-amino]-3-methyl-1H-pyrrole, was obtained as the title compound. And [2,3-d]pyridazine-2-carboxylic acid 20b was subjected to the next reaction.

MS m/z (ESI): 517[M+ 1] Step 3

4-[l-(3-fluorobenzyl)-1H-indazole-5-amino]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-(2-methoxyethyl) Formamide

In the same manner as described in the sixth step of Example 1 of the present invention, 4-[1-(3-fluorobenzyl)-1Η-indazole-5-amino]-3-methyl-1H-pyrrolo[2, 3-d]pyridazine-2-carboxylic acid as a starting material, the reaction of the starting material with 2-methoxyethylamine affords the title product 4-[1-(3-fluorobenzyl)-1H-carbazole- 5-Amino]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-(2-methoxyethyl)carboxamide 20 (45 mg, yellow solid). The yield was 8 %.

MS m/z (ESI): 474 [M+ 1]

1HNMR (400MHz, DMSO-): S8.84 (s, 1H), 8.080 (s, 2H), 7.66 (m, 1H), 7.57 (m, 1H), 7.35 (m, 1H), 7.06 (m, 3H) ), 5.68(s, 2H ), 3.50(t, 2H), 2.72(s, 3H), 2.52(t, 2H) Example 21

4-Γ1-(3-fluorobenzyl)-1H-indazole-5-amino1-3-methyl-1H-pyrrolo-[2,3-dl-pyridazine-2-(2-diethylamino)- Ethyl)formamide

The reaction of the first step to the second step of Example 20 of the present invention was repeated, using the compound 4-[1 3-fluorobenzyl)-1H-indazole-5-amino]-3-methyl obtained in the above second step. The base-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid 20b is used as a raw material, and the reaction of the raw material with diethylethylenediamine is carried out in the same manner as described in the sixth step of the first embodiment of the present invention. The title product 4-[1-(3-fluorobenzyl)-1Η-indazol-5-amino]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-(2) was obtained. -Diethylamino-ethyl)carboxamide 21 (90 m _g , light brown solid). The yield was 13.5%. MS m/z (ESI): 515 [M+ 1]

1HNMR (400MHZ, OMSO-d ₆ ): S8.84(s, 1H), 8.09(s, 2H), 8.07(s, 1H), 7.644(m, 1H), 7.56(m, 1H), 7.35(m, 1H), 7.08(m, 1H), 7.02(m, 2H), 5.68(s, 2H), 3.37(t, 2H), 2.71(s, 3H), 2.55 (m, 6H), 0.94 (t, 6H) Example 22

4-Γ3-chloro-4-(pyridine-2-methoxy)-aniline 1-3-methyl-1H-pyrrolo-2.3-dl-pyridazine-2- 2-diethylamine-ethylformamide

first step

4-[3-Chloro-4-(pyridine-2-methoxy)-aniline]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid ethyl ester hydrochloride

3-methyl-4-carbonyl-3a,4,5,7a-tetrahydro-1H-pyrrole in a 50 mL three-necked flask under nitrogen atmosphere according to the method described in the third and fourth steps of Example 1. And [2,3-d]pyridazine-2carboxylic acid ethyl ester lc (1.1 g, 5 mmol) was dissolved in anhydrous acetonitrile (35 mL), and anhydrous phosphorus oxychloride (0.92 mL) was slowly added dropwise with stirring at room temperature. After completion of the dropwise addition of 10 mmol, 2 eq), the mixture was heated to reflux to a yellow solid and gradually dissolved to a yellow solution, and reflux was continued for 30 minutes. The reaction solution was transferred to a 100 mL eggplant-shaped flask, and acetonitrile was removed by vacuum distillation under reduced pressure. Then, hexane (10 mL) was added to the reaction mixture, and the mixture was evaporated to dryness and dried three times (removing residual phosphorus oxychloride). Then, isopropanol (30 mL) and 3-chloro-4-(pyridine-2-methoxy)-aniline (1.056 g, 4.5 mmol) and triethylamine were added to the eggplant flask, and the mixture was heated under reflux for 12 hours. The point plate is tracked until the material disappears. The reaction solution was cooled to room temperature, then cooled with ice-cooled water and stirred, and evaporated, evaporated, evaporated, evaporated, evaporated. -2-methoxy)-aniline]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2- Ethyl carboxylate hydrochloride 22a (0.939 g, yellow solid). The yield was 42.9%.

MS m/z (ESI): 438 [M+ 1],

4-[3-Chloro-4-(pyridine-2-methoxy)-aniline]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid according to an embodiment of the invention In the same manner as described in the fifth step, 4-[3-chloro-4-(pyridine-2-methoxy)-aniline]-3-methyl-1H-pyrrolo[2,3-d]pyridazine was used. The title product 4-[3-chloro-4-(pyridine-2-methoxy)-aniline]-3-methyl-1H-pyrrole is obtained by using 2-carboxylic acid ethyl ester hydrochloride 22a as a starting material. [2,3-d]pyridazine-2-carboxylic acid 22b (0.686 g, yellow solid). The yield was 79.8%.

MS m/z (ESI): 410[M+ 1] Step 3

In the same manner as described in the sixth step of Example 1 of the present invention, 4-[3-chloro-4-(pyridine-2-methoxy)-aniline]-3-methyl-1H-pyrrolo[2,3 was used. -d]pyridazine-2-carboxylic acid 22b as a starting material, the reaction of the starting material with diethylethylenediamine gives the title product 4-[3-chloro-4-(pyridine-2-methoxy)- Aniline]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-(2-diethylamino-ethyl)carboxamide 22 (25 mg, yellow solid). The yield was 85.1%. MS m/z (ESI): 508 [M+ 1]

^{1 HNMR (400MHz, DMSO-J} 5): δ 8.89 (s, 1H), 8.59 (d, 1H), 7.87 (m, 2H), 7.58 (d, 1H), 7.52 (d, 1H), 7.37 (m , 1H), 7.2 l(d, 1H), 5.26(s, 2H), 3.64(t, 2H), 2.74(s, 3H), 2.50(m, 6H), 1.20(t, 6H) Example 23

The reaction of the first step to the second step of Example 20 of the present invention was repeated, using the compound 4-[3-chloro-4-(pyridine-2-methoxy)-aniline]-3- obtained in the above second step. Methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid 22b is used as a starting material, and the starting material is 2-(pyrrolidin-1-) in the same manner as described in the sixth step of Example 1 of the present invention. Reaction of ethylamine to give the title product 4-[3-chloro-4-(pyridine-2-methoxy)-aniline]-3-methyl-1H-pyrrole [2,3-d]pyridazine-2-[(2-pyrrolidin-1-yl)-ethyl]carboxamide 23 (46 mg, yellow solid). The yield was 56.5 %.

MS m/z (ESI): 506 [M+ 1]

'HNMR: (400MHz, DMSO-i/ ₅ ) 58.86(s, IH), 8.59(d, IH), 7.87 (m, 2H), 7.58(d, IH), 7.53(d, IH), 7.37(m , IH), 7.19(d, IH), 5.25(s, 2H), 3.42(t, 2H), 2.70(s, 3H), 2.63(t, 2H), 2.51 (m, 4H), 1.70(s, 4H) Example 24

4-[3-chloro-4-(pyridine-2-methoxy)-aniline]-3-methyl-IH-pyrrolo[2,3-d]pyridazine-2-[(2-morpholine- 4-yl)-ethyl]carboxamide

The reaction of the first step to the second step of Example 20 of the present invention was repeated, using the compound 4-[3-chloro-4-(pyridine-2-methoxy)-aniline]-3- obtained in the above second step. Methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid 22b is used as a starting material, and the starting material and 2-(2-morpholine) are carried out in the same manner as described in the sixth step of Example 1 of the present invention. The reaction of 4-yl)-ethylamine gives the title product 4-[3-chloro-4-(pyridine-2-methoxy)-phenylamine]-3-methyl-1H-pyrrolo[2,3- d] pyridazine-2-[(2-morphinolin-4-yl)-ethyl]carboxamide 24 (62 mg, yellow solid). Yield: 10.6 %

MS m/z (ESI): 523 [M+ l]

¹ HNM (400MHz, DMSO- ₆ ) S8.86(s, IH), 8.59(d, IH), 7.90 (m, 2H), 7.58(d, IH), 7.54(d, IH), 7.37(m, (H, 4H)

4-Γ3-chloro-4-(pyridine-2-methoxy)-aniline 1-3-methyl-IH-pyrrolo and 2,3-dloxazin-2-indole (-morpholinolin-4-yl) ) -ethyl 1 carboxamide

Repeating the reaction of the first step to the second step of the embodiment 20 of the present invention, using the method obtained in the second step above The compound 4-[3-chloro-4-(pyridine-2-methoxy)-aniline]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid 22b is used as a raw material. The reaction of the starting material with 2-(3-morphocolin-4-yl)-ethylamine was carried out in the same manner as described in the sixth step of Example 1 to obtain the title product 4-[3-chloro-4-(pyridine. -2-methoxy)-aniline]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-[(3-morphorphyrin-4-yl)-ethyl]carboxamide 25 (66 mg, yellow solid). Yield 11

%.

MS m/z (ESI): 537 [M+ 1]

'HNMR (400MHz, DMSO-i3⁄4) 58.86(s, 1H), 8.59(d, 1H), 7.90 (m, 2H), 7.58(d, 1H), 7.54(d, 1H), 7.37(m, 1H) , 7.19(d, 1H), 5.27(s, 2H), 3.57(t, 4H), 3.37(t, 4H), 2.74(s, 3H), 2.51 (m, 4H), 2.37(m, 2H) Example 26

4-f3-chloro-4-(pyridine-2-methoxyaniline 1-1, 3-dimethyl-1H-pyrrolo- 2,3-dl-pyridazine-2-indole (2-ethylamino)- Ethyl 1 carboxamide

first step

4-[3-Chloro-4-(pyridine-2-methoxy)-phenylamino]-1,3-dimethyl-1Η-pyrrolo[2,3-d]pyridazine-2-carboxylic acid B The ester is reacted in the same manner as described in the third and fourth steps of Example 1 of the present invention, using the compound obtained in the above third step, 3-methyl-4-carbonyl-3a, 4,5,7a-tetrahydro-1- Methyl-pyrrolo[2,3-d]pyridazine-2carboxylic acid ethyl ester 15c (2.34 g, 10 mmol) was used as the starting material to give the title product 4-[3-chloro-4-(3-fluorobenzyloxy). ) - Aniline] -1,3-Dimethyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid ethyl ester 26a (3.39 g, yellow solid). The yield was 75.3%. MS m/z (ESI): 452 [M+ 1]

The second step,

4-[3-chloro-4-(pyridine-2-methoxy)-phenylamino]-1,3-dimethyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid In the fifth step of the first embodiment of the present invention, the reaction of the same manner is used, and the compound 4-[3-chloro-4-(3-fluorobenzyloxy)-aniline]-1,3-di which is obtained by the above-mentioned first step is used. Ethylmethyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylate 26a (451 mg, 1 mmol) was used as the starting material to give the title product 4-[3-chloro-4-(pyridine- 2-Methoxy)-phenylamino]-1,3-dimethyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid 26b (150 mg, yellow solid). Yield: 35.6 %.

MS m/z (ESI): 424 [M+ 1] Step 3

4-[3-chloro-4-(pyridine-2-methoxy)-aniline]-1,3-dimethyl-1H-pyrrolo[2,3-d]pyridazine-2-[(2- Ethylamino)-ethyl]carbamamine

According to the same manner as described in the sixth step of the first embodiment of the present invention, the compound 4-[3-chloro-4-(pyridin-2-methoxy)-phenylamino]-1 obtained in the above second step is used. 3-Dimethyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid 2 as a starting material to give the title product 4-[3-chloro-4-(pyridine-2-methoxy) -aniline]-1,3-dimethyl-1H-pyrrolo[2,3-d]pyridazine-2-[(2-ethylamino)-ethyl]carboxamide 26 (154 mg, yellow solid). Yield 27.3

%.

MS m/z (ESI): 523 [M+ 1]

'HNMR (400MHz, OMSO-d ₆ ) 58.86(s, 1H), 8.59(d, 1H), 7.90 (m, 3H), 7.55(m, 2H), 7.35(m, 1H), 7.19(d, 1H ), 5.26(s, 2H), 3.83(s, 3H), 3.38(m, 2H), 3.29(m, 4H), 2.60(m, 4H), 2.56(s, 3H), 0.98(t, 6H) Example 27

4-f3-chloro-4-(pyridine-2-methoxy)-aniline VI, 3-dimethyl-1H-pyrroloindole 2,3-(indole|pyridazine-24 (2-pyrrolidine small group) -ethyl 1 carboxamide

The reaction of the first step to the second step of Example 26 of the present invention was repeated, using the compound 4-[3-chloro-4-(pyridine-2-methoxy)-aniline]-3- obtained in the above second step. Methyl-1Η-pyrrolo[2,3-d]pyridazine-2-carboxylic acid 26b is used as a starting material, and the starting material and 2-(2-pyrrolidine-) are carried out in the same manner as described in the sixth step of Example 1 of the present invention. Reaction of 1-yl)-ethylamine gives the title product 4-[3-chloro-4-(pyridine- ² -methoxy)-phenylamine]-1,3-dimethyl -1H-pyrrolo[2,3-d]pyridazine-2-[(2-pyrrolidin-1-yl)-ethyl]carboxamide 27 (179 mg, yellow solid). The yield was 29.9%.

MS m/z (ESI): 521 [M+ 1]

¹ H MR (400MHz, DMSO-c3⁄4: 59.07(s, 1H), 8.59(d, 1H), 8.49(s,lH), 7.87 (m, 3H), 7.57(m, 2H), 7.36(s, 1H ), 7.19(d, 1H), 5.26(s, 2H), 3.82(s, 3H), 3.43(m, 2H), 3.29(m, 2H), 2.54(s, 3H), 2.50(m, 4H) , 1.70(m, 4H) Example 28'

4-[3-chloro-4-(pyridine-2-methoxy)-aniline 1, 3-dimethyl-1H-pyrrolo-2,3-dl哒嗉-2-indole-3-morpholine-4- -ethyl 1-carboxamide

The reaction of the first step to the second step of Example 26 of the present invention was repeated, using the compound 4-[3-chloro-4-(pyridine-2-methoxy)-aniline]-3- obtained in the above second step. Methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid 26b was used as a starting material, and the starting material and 2-(3-morpholine) were carried out in the same manner as described in the sixth step of Example 1 of the present invention. 4-yl)-ethylamine reaction gave the title product 4-[3-chloro-4-(pyridine-2-methoxy)-aniline-1,3-dimethyl-1H-pyrrolo[2 , 3-d]indole-2-[(3-morpholine-4-yl)-ethyl]carboxamide 28 (68 mg, yellow solid). The yield was 11.4%.

MS m/z (ESI): 551 [M+ 1]

^{! ΗΝΜΚ (400ΜΗζ, DMSO-c¾} ) 59.07 (s, 1H), 8.59 (d, 1H), 8.60 (m, lH), 7.87 (m, 3H), 7.57 (m, 2H), 7.34 (d, 1H) , 7.19(d, 1H), 5.26(s, 2H), 3.81(s, 3H), 3.57(m, 4H), 3.37(m, 2H), 2.53(s, 3H), 2.37(m, 6H), 1.73 (m, 2H)

Example 29

4-"3-Chloro-4-(pyridine-2-methoxy)-aniline 1-1,3-dimethyl-1H-pyrrolo "2,3-dloxazin-24 (2-morpholine- 4-yl)-ethyl 1 carboxamide

The reaction of the first step to the second step of Example 26 of the present invention was repeated, using the compound 4-[3-chloro-4-(pyridine-2-methoxy)-aniline]-3- obtained in the above second step. Methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid 26b was used as a starting material, and the starting material and 2-(2-morpholine) were carried out in the same manner as described in the sixth step of Example 1 of the present invention. The reaction of 4-yl)-ethylamine gives the title product 4-[3-chloro-4-(pyridin-2-yloxy)-aniline]-1,3-dimethyl-1H-pyrrolo[2 , 3-d]pyridazine-2-[(2-morphinolin-4-yl)-ethyl]carboxamide 29 (58 mg, yellow solid). The yield was 10%.

MS m/z (ESI): 537 [M+ 1]

^I H NMR (400 MHz, OMSO-d ₆ ): 59.07 (s, 1H), 8.59 (d, 1H), 8.60 (m, lH), 7.87 (m, 3H), 7.57 (m, 2H), 7.34 (d, 1H), 7.19(d, 1H), 5.26(s, 2H), 3.84(s, 3H), 3.58(m, 4H), 3.47(t, 2H), 3.28(t, 2H), 2.57(s, 3H ), 2.44 (m, 4H), 1.73 (m, 2H) Example 30

"3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy W3-methyl-2-indole (2-morpholin-4-yl-ethylamino)-methyl 1-lH-pyrrole "2,3-dloxazin-4-ylamine

first step

{4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-3-methyl-1H-pyrrole[2,3-d]pyridazin-2-yl}-methanol at 250 Lithium aluminum hydride (320 mg, 8 mmol) and tetrahydrofuran (40 mL) were added to the mL flask. After stirring, 4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-3 was added slowly. A solution of methyl-1H-pyrrole[2,3-d]pyridazine-2-carboxylate 8a (910 mg, 2 mmol) in tetrahydrofuran (100 mL). After completion of the dropwise addition, the mixture was heated under reflux for 3 hours, and ice water was added to quench the reaction. The reaction solution was filtered, extracted with a solution of tetrahydrofuran and saturated sodium chloride, and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate (MgSO4jjjjjjjj Pyrrole [2,3-d]pyridazin-2-yl}-methanol 30a

(828 mg, brownish yellow solid). The yield was 35 %.

MS m/z (ESI): 413 [M+ 1] Step 2

Add o-iodobenzoic acid (746 mg, 2. 66 mmol) and dimethyl sulfoxide (10 mL) to a 50 mL eggplant bottle, and slowly add {4-[3-chloro-4-(3-) after stirring. Fluoro-benzyloxy)-phenylamino]-3-methyl-1H-pyrrole[2,3-d]pyridazin-2-yl}-methanol 30a (733 mg, 1.77 mmol) of dimethyl sulfoxide ( lO mL) solution. After the completion of the dropwise addition, the reaction was carried out at 20 ° C for 1 hour. The reaction solution was poured into water, and a brown solid was precipitated, which was separated by column chromatography to give 4-[3-chloro-4-(3-fluoro-p-oxy)-phenylamino]-3-methyl-1H. Pyrrole [2,3-d]pyridazine-2-carbaldehyde 30b (668 mg, brownish yellow solid). Yield: 92.1 %

MS m/z (ESI): 411 [M+ 1] Step 3,

[3-Chloro-4-(3-fluoro-p-ethoxy)-phenoxy]-{3-methyl-2-[(2-morpholin-4-yl-ethylamino)-methyl]-1Η -pyrrolo[2,3-d]pyridazin-4-yl}-amine

Add 4-[3-chloro-4-(3-fluoro-oxy)-phenylamino]-3-methyl-1H-pyrrole[2,3-d]pyridazine-2- to a 50 mL eggplant-shaped flask Formaldehyde 30b (168 mg, 0.4 mmol), tetrahydrofuran (15 mL) and methanol (15 mL), and then added 2-morpholine-4-ethylamine (79 mg, 0.61 mmol) with stirring and stirring until the mixture became clear. The reaction mixture was stirred at rt. The mixture was washed with sodium bicarbonate, sodium chloride and dried over anhydrous sodium sulfate, filtered, and evaporated to give the crude product which was further purified by column chromatography (dichloromethane: methanol: ammonia = 300: 10: 1.3) -chloro-4-(3-fluoro-benzyloxy)-phenoxy]-{3-methyl-2-[(2-morpholin-4-yl-ethylamino)-methyl]-1H-pyrrole And [2,3-d]pyridazin-4-yl} An 30 (32 mg, yellow solid). Yield: 10%.

MS m/z (ESI): 526 [M+ 1]

^{! ΗΝΜΚ (400ΜΗζ, DMSO-c¾} : 58.78 (s, 1H), 7.88 (s, 1H), 7.79 (s, 1H), 7.47 (m, 2H), 7.31(m, 2H), 7.16(m, 2H), 5.20(s, 2H), 3.84(s, 2H), 3.54(s, 4H), 2.59(ί, 2H), 2.50(t, 2H), 2.39 (m, 4H), 2.31(s, 3H) Example 31

『3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy 1-lH-pyrrolo and 2,3-dl-pyridazine-2-carboxylic acid (2-pyrrolidin-1-yl-B -formamide

first step

5-formyl-1H-pyrrole-2,4-dicarboxylic acid-4-ethyl ester-2-methyl ester In the same manner as described in the first step of Example 1 of the present invention, 5-methyl-1H-pyrrole was used. 2,4-Dicarboxylic acid-4-ethyl ester-2-methyl ester (2.11 g, 10 mmol) 31a was used as a starting material, and the reaction of the starting material with ammonium cerium nitrate was carried out to give the title product 5-formyl-1H-pyrrole. -2,4-Dicarboxylic acid-4-ethyl ester-2-methyl ester 31b (338 mg). The yield was 15%.

MS m/z (ESI): 224 [M-1] Second step

Methyl 4-oxo-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazine-2-carboxylate In the same manner as described in the second step of Example 1 of the present invention, the second The compound 5-formyl-1H-pyrrole-2,4-dicarboxylic acid-4-ethyl ester-2-methyl ester 31b (379 mg, 1.68 mmol) obtained in the step was used as a starting material to carry out the hydration of the starting material with hydrazine ( 99 mg, 1.68 mmol) gave the title product 4-oxo-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid methyl ester 31c (157 mg) . The yield was 29.6%.

MS m/z (ESI): 192 [M-1] Step 3

4-[3-chloro-4-(3-fluorobenzyloxy)-aniline]-1Η-pyrrolo[2,3-d]pyridazine-2-carboxylic acid methyl ester according to Example 1 of the present invention In the same manner as described in the above step, the compound 4-oxo-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid methyl ester 31c obtained in the above second step was used. (308 mg, 1.59 mmol) as a starting material to give the title product 4-[3-chloro-4-(3-fluorobenzyloxy)-aniline]-1H-pyrrolo[2,3-d]pyridazin-2- The methyl carboxylate 31d (1.4 g, white solid) was taken directly to the next product without isolation. MS m/z (ESI): 427 [M+ 1] Step 4

4-[3-chloro-4-(3-fluorobenzyloxy)-aniline]-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid hydrochloride according to the fifth step of Example 1 of the present invention In the same manner, the compound 4-[3-chloro-4-(3-fluorobenzyloxy)-aniline]-1H-pyrrolo[2,3-d]pyridazine obtained in the above third step is used. The title product 4-[3-chloro-4-(3-fluorobenzyloxy)-aniline]-1H-pyrrolo[2,3- d] pyridazine-2-carboxylic acid hydrochloride 31e (237 mg, yellow solid). Yield: 28.2%.

MS m/z (ESI): 450[M+ 1] Step 5

[3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy]-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid (2-pyrrolidin-1-yl- Ethyl)-carboxamide

In the same manner as described in the sixth step of Example 1 of the present invention, the compound 4-[3-chloro-4-(3-fluorobenzyloxy)-aniline]-1H-pyrrolo[4] obtained in the above fourth step was used. 2,3-d]pyridazine-2-carboxylic acid hydrochloride 31e (110 mg, 0.245 nimol) was used as a starting material, and the reaction of the starting material with 2-pyrrole-1-ethylamine was carried out to obtain the title product [3- Chloro-4-(3-fluoro-oxy)-phenoxy]-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid (2-pyrrole-1-yl-ethyl) Formamide 31 (7 mg, yellow solid). Yield: 5.56%.

MS m/z (ESI): 512 [M+ 1]

'HNMR (400MHZ, DMSO-^): δ 7.65(d, 1H), 7.36(t, 1H), 7.30(m, 1H), 7.22(m, 2H), 7.09(m, 2H), 5.12(s, 2H), 3.56(t, 2H), 2.48(m, 2H), 2.42(m, 4H), 1.62(m, 4H) Example 32

4-13-chloro-4-(3-fluorooxy-phenoxy 1-lH-pyrrolo- 2,3-dl-pyridazine-2-carboxylic acid (2-diethylamino-ethyl)-amide

The reaction of the first step to the fourth step of Example 31 of the present invention was repeated, and the compound 4-[3-chloro-4-(3-fluorobenzyloxy)-aniline]-1H-pyrrole obtained in the above fourth step was used. [2,3-d]pyridazine-2-carboxylic acid hydrochloride 31e is used as a starting material, and the reaction of the starting material with diethylethylenediamine is carried out in the same manner as described in the fifth step of Example 31 of the present invention to obtain the title. Product 4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy]-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid (2-diethylamino- Ethyl)-amide 32 (10 mg, yellow solid), yield 8%.

MS m/z (ESI): 509 [M+ 1]

^J HNMR (400 MHZ, DMSO-^): 58.12 (S, IH), 7.64 (d, IH), 7.36 (t, IH), 7.22 (m, 3H), 7.03 (m, IH), 7.08 (m, 1H) ), 5.12(s, 2H), 3.28(t, 2H), 2.54(m, 2H), 2.47(m, 4H), 0.89(m _: 6H) Example 33

4-f3-chloro-4-(-fluoro-benzyloxy)-phenoxy 1-2-3-methoxy-ethyl)-3-methyl-1H-pyrrolof2,3-dlpyridazine-2 -carboxylic acid ethyl ester

First step

1-(2-Methoxy-ethyl)-3,5-dimethyl-1H-pyrrole-2,4-dicarboxylic acid diethyl ester was added to the 2,5-two in a 250 mL eggplant bottle. Diethyl-1H-pyrrole-2,4-dicarboxylate la (8 g, 33 mmol), dimethyl sulfoxide (50 mL) and potassium t-butoxide (4.077 g, 36.3 mmol), with stirring 1-Bromo-2-methoxy-acetamidine (6.3 mL, 43.3 mmol) was added, and the mixture was stirred at room temperature for 5 hours, and the reaction was completed. Ice water (200 mL) was added to the reaction mixture, and ethyl acetate (100 mL EtOAc) was evaporated, evaporated, evaporated, evaporated, evaporated The obtained crude 1-(2-methoxy-ethyl)-3,5-dimethyl-1H-pyrrole-2,4-dicarboxylate 33a was directly subjected to the next reaction.

Second step

5-formyl-1-(2-methoxy-ethyl)-3-methyl-1H-pyrrole-2,4-dicarboxylic acid diethyl ester in the same manner as described in Example 1 of the present invention Using the compound obtained in the above first step, diethyl 1-(2-methoxy-ethyl)-3,5-dimethyl-1H-pyrrole-2,4-dicarboxylate 33a (9.8 g, 3.3 Methanol) The starting material is reacted with ammonium cerium nitrate to give the title product 5-formyl-1-(2-methoxy-ethyl)-3-methyl-1H-pyrrole-2,4- Dicarboxylate 33b (5.287 g, yellow oily liquid). The yield was 51.8%.

MS m/z (ESI): 312 [M+ 1] Step 3

L-(2-Methoxy-ethyl)-3-methyl-4-oxo-4,5-4,5-dihydro-1H-pyrrole[2,3-d]pyridazine-2-carboxylate Methyl ester The compound 5-formyl small (2-methoxy-ethyl)-3-methyl-1H- obtained in the second step above was used in the same manner as described in the second step of Example 1 of the present invention. Pyrrole-2,4-dicarboxylic acid diethyl ester 33b (5,2 g, 16.7 mmol) was used as a starting material to carry out the reaction of the material with hydrazine hydrate (1.5 mL, 25 mmol) to give the title product 1-(2- Methoxy-ethyl)-3-methyl-4-oxo-4,5-4,5-dihydro-1H-pyrrole[2,3-d]pyridazine-2-carboxylic acid methyl ester 33c ( 4.405 g, white solid). Yield: 95.7%. MS m/z (ESI): 280 [M+ 1] Step 4

4-[3-chloro-4-(3-fluoro-benzyloxy)-phenoxy] succinate (2-methoxy-ethyl)-3-methyl-1H-pyrrolo[2,3-d Ethyl pyridazine-2-carboxylate

In the same manner as described in the third and fourth steps of Example 1 of the present invention, the compound 1-(2-methoxy-ethyl)-3-methyl-4-oxo obtained in the above second step was used. 4,5-4,5-Dihydro-1H-pyrrole[2,3-d]pyridazine-2-carboxylic acid methyl ester 33c (1.4 g, 5 mmol) was used as the starting material to give the title product 4-[3- Chloro-4-(3-fluoro-benzyloxy)-phenoxy]-1-(2-methoxy-ethyl)-3-methyl-1H-pyrrolo[2,3-d]pyridazine Ethyl 2-carboxylate 33 (747 mg, yellow solid). Yield: 32%.

MS m/z (ESI): 513 [M+ 1]

¹ H NMR (400 MHz, DMSO-i 3⁄4): 59.15 (d, 2H), 8.49 (s, lH), 7.87 (m, IH), 7.57 (m, 2H), 7.35 (s, 1H), 7.19 (d, 1H) ), 6 52(s, 2H), 5.89(t, 2H), 5.49(q, 2H), 4.49(t, 2H), 3.94(s, 3H): 3.42(s, 3H), 2.50(m, 4H) ), 1.70(t, 3H) Example 34

4-Γ3-chloro-4-(3-fluoro-benzyloxy)-phenoxy-1- -1-(2-methoxy-ethyl)-3-methyl-1H-pyrrole "2,3- Dl-pyridazine-2-carboxylic acid (2-diethylamino-ethyl)-amide

first step

4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-1-(2-methoxyethyl)-3-methyl-1H-pyrrolo[2,3-d Pyridazine- 2-carboxylic acid 4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy]succinimide (2-methoxy-ethyl)-3-methyl-1H was sequentially added to a 100 mL eggplant-shaped flask. -pyrrolo[2,3-d]pyridazine-2-carboxylic acid (2-diethylamino-ethyl)-amide 33 (1.5 g, 2.9 mmol), absolute ethanol (30 mL) and 1N sodium hydroxide Solution (18 mL, 30 mmol). The mixture was heated to reflux for 3 hours and the reaction was completed. The reaction solution was cooled to room temperature, and most of the ethanol was removed under reduced pressure. The pH was adjusted to acidic with 1N hydrochloric acid, and a yellow precipitate was formed and filtered to give 4-[3-chloro-4-(3-fluoro-benzyloxy). -phenylamino]-1-(2-methoxyethyl)-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid 34a

( 1.382 g, yellow solid). Yield: 98.1%.

MS m/z (ESI): 485 [M+ 1] Step 2

₇ _[3-Chloro-4-(3-fluoro-p-ethoxy)-phenoxy]-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid (2-diethylamino-B -amide

In the same manner as described in the sixth step of Example 1 of the present invention, the compound 4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-1- (2-methoxyethyl)-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid 34a (100 mg, 0.21 mmol) as starting material, the starting material and the second The reaction of ethylenediamine gives the title product 7-[3-chloro-4-(3-fluoro-benzyloxy)-phenoxy]-1H-pyrrolo[2,3-d]pyridazine-2 - Carboxylic acid (2-diethylamino-ethyl)-amide 34 (95 mg, yellow solid). Yield: 77.9%.

MS m/z (ESI): 584 [M+ 1]

¹ H NMR (400 MHz, DMSO - 3⁄4): 67.44 (m, 2H), 7.29 (s, lH), 7.25 (m, 1H), 7.18 (m, 2H), 6.94 (s, 1H), 6.86 (d, 1H) ), 5.06(s, 2H), 4.27(t, 2H), 3.67(m, 2H), 3.63(m, 4H), 3.19(s, 3H), 2.87(m, 4H), 2.62(s, 3H) , 1.09(s, 6H) Example 35

4-Γ3-chloro-4-(3-fluoro-benzyloxy)-phenoxy 1- 2 -methoxy-ethyl 3-methyl-1H-pyrrolo "2,3-dlpyridazine-2 -carboxylic acid! ~2-(4-Methyl-piperazin-1-yl)-ethyl 1-amide

The reaction of the first step of Example 34 of the present invention was repeated, using the compound 4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino] small (2-methoxy) obtained in the above first step. Base ethyl)-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid 34a as a starting material, and the raw material is carried out in the same manner as described in the second step of Example 34 of the present invention. -(4- The reaction of methyl-piperazin-1-yl)-ethylamine gives the title product 4-[3-chloro-4-(3-fluoro-hydroxy-oxy)-phenoxy]-1-(2- Oxy-ethyl)-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid [2-(4-methyl-piperazin-1-yl)-ethyl] - Amide 35 (68 mg, yellow solid). The yield was 40%.

MS m/z (ESI): 611 [M+1]

¹ H NMR (400 MHz, DMSO-i3⁄4: 57.63 (s, 1H), 7.59 (s, lH), 7.44 (m, 1H), 7.28 (m, 1H), 7.15 (m, 2H), 6.96 (m, lH) , 6.87(d, 1H), 5.06(s, 2H), 4.4(t, 2H, J= .4Hz), 3.66(t, 4H), 3.5 l(m, 2H), 3.21(s, 3H), 2.56 (s, 3H), 2.44 (m, 4H), 2.21 (s, 3H), 2.19 (m, 4H) Example 36

4-Γ3-chloro-4-(3-fluoro-benzyloxy)-phenoxy 1 methoxy-ethyl)-3-methyl-1H-pyrrole "2,3-dll3⁄4-azine-2-carboxylate Acid "3-(4-methyl-piperazin-1-yl)-propyl 1-amide

The reaction of the first step of Example 34 of the present invention was repeated, using the compound 4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-1-(2-) obtained in the above first step. Methoxyethyl)-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid 34a is used as a starting material, and the starting material is carried out in the same manner as described in the second step of Example 34 of the present invention. Reaction with 3-(4-methyl-piperazin-1-yl)propylamine gives the title product 4-[3-chloro-4-(3-fluoro-benzyloxy)-phenoxy]-1- (2-methoxy-ethyl)-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid [3-(4-methyl-piperazine-1-yl) -propyl]-amide 36 (85 mg, yellow solid). The yield was 76.5%.

MS m/z (ESI): 625 [M+ 1]

^{_{1 HNMR (400MHz, DMSO- tf)}} : 57.46 (m, 2H), 7.29 (s, lH), 7.25 (m, 1H), 7.18 (m, 2H), 6.94 (s, 1H), 6.86 (d, 1H ), 5.06(s, 2H), 4.27(t, 2H), 3.71(m, 4H), 3.56(m, 2H), 3.26(s, 3H), 2.73(s, 3H), 2.57(s, 3H) , 2.52 (m, 4H), 2.32 (m, 4H), 2.24 (s, 3H) Example 37

4-"3-Chloro-4-ί3-fluoro-benzyloxy)-phenoxy 1- 2 -methoxy-ethyl)-3-methyl-1 Η-pyrrolo "2,3-dlazine 2-carboxylic acid (2-pyrrole-1-yl-ethyl)-amide

The reaction of the first step of Example 34 of the present invention was repeated, using the compound 4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino] small (2-methoxy) obtained in the above first step. Base ethyl)-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid 34a as a starting material, and the raw material is carried out in the same manner as described in the second step of Example 34 of the present invention. - a reaction of pyrrolein-1-ethylamine, to give the title product 4-[3-chloro-4-(3-fluoro-benzyloxy)-phenoxy]small (2-methoxy-ethyl) 3-Methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide 37 (95 mg, yellow solid). The yield was 84.3 %.

MS m/z (ESI): 582 [M+ 1]

¹ H NMR (400 MHz, OUSO-d ₆ ): 57.73 (m, 2H), 7.56 (s, lH), 7.39 (m, 1H), 7.28 (m, 2H), 7.05 (s, 1H), 6.95 (d, 1H), 5.16(s, 2H), 4.39(t, 2H), 3.73(m, 4H), 3.29(s, 3H) ₅ 2.81(m, 2H), 2.75(m, 4H), 2.69(s, 3H ), 1.64 (m, 4H) Example 38

4-Γ3-chloro-4-(3-fluoro-benzyloxy)-phenoxy 1 -1-IY2-methoxy-ethoxy)-ethyl 3-methyl-1H-pyrroloindole 2,3 -(11-oxazine-2-carboxylic acid ethyl ester

First step

1-[(2-Methoxy-ethoxy)-ethyl]-3,5-dimethyl-1H-pyrrole-2,4-dicarboxylate in a 250 mL eggplant bottle Add 3,5-dimethyl-1H-pyrrole-2,4-dicarboxylate la (5.742 g, 24 mmol), dimethyl sulfoxide (40 mL) and potassium t-butoxide (2.963 g, 26.4 mmol), 1-bromo-2-(2-methoxy-ethoxy)-ethane (5.706 g, 31 mmol) was added with stirring, and stirred at room temperature for 5 hr. Ice water (200 mL) was added to the reaction mixture, and the mixture was evaporated, evaporated, evaporated, evaporated, evaporated. The resulting crude product 1-[(2-methoxy-ethoxy)-ethyl]-3,5-dimethyl-1H-pyrrole-2,4-dicarboxylic acid diethyl ester 38a (8 g, yellow Solid), proceed directly to the next reaction.

MS m/z (ESI): 342 [M+ 1]

'Second step

5-formyl small [(2-methoxy-ethoxy)-ethyl]-3-methyl-1H-pyrrole-2,4-dicarboxylic acid diethyl ester according to the first step of Example 1 of the present invention In the same manner, the compound 1-[(2-methoxy-ethoxy)-ethyl]-3,5-dimethyl-1H-pyrrole-2,4- obtained in the above first step was used. Dicarboxylic acid diethyl ester 38a (8.2 g, 24 mmol) was used as a raw material to carry out the reaction of the starting material with ammonium cerium nitrate to obtain 5-formyl-1-[(2-methoxy-ethoxy)-B. Diethyl 3-methyl-1H-pyrrole-2,4-dicarboxylate 38b (5.551 g, yellow oily liquid). The yield was 65%.

MS m/z (ESI): 356[M+ 1] Step 3 '

1-[(2-methoxy-ethoxy)-ethyl]-3-methyl-4-oxo-4,5-4,5-dihydro-1H-pyrrole [2,3-d] Methyl pyridazine-2-carboxylate

In the same manner as described in the second step of Example 1 of the present invention, the compound 5-formylsuccini[(2-methoxy-ethoxy)-ethyl]-3-methyl obtained in the above second step was used. -1H-pyrrole-2,4-dicarboxylic acid diethyl ester 38b (4.29 g, 12 mmol) was used as a starting material to give the titled product (1,2-methoxy-ethoxy)-ethyl] Methyl 4-oxo-4,5-4,5-dihydro-1H-pyrrole[2,3-d]pyridazine-2-carboxylic acid methyl ester 38c (4.651 g, white solid) The next step is to react.

MS m/z (ESI): 280 [M+ 1] Step 4

4-[3-Chloro(3-fluoro-benzyloxy)-phenoxy]-1-[(2-methoxy-ethoxy)-ethyl]-3-methyl-1H-pyrrole [2,3-d]pyridazine-2-carboxylic acid ethyl ester

In the same manner as described in the third and fourth steps of Example 1 of the present invention, the compound 1-[(2-methoxy-ethoxy)-ethyl]-3-methyl obtained in the above third step was used. 4-Oxo-4,5-4,5-dihydro-1H-pyrrole[2,3-d]pyridazine-2-carboxylic acid methyl ester 38c (324 mg, 1 mmol) as a starting material Product 4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy]min[(2-methoxy-ethoxy)-ethyl]-3-methyl-1H-pyrrole And [2,3-d] oxazine-2-carboxylic acid ethyl ester 38 (2.83 g, yellow solid). Yield: 41.8 %.

MS m/z (ESI): 558 [M+ 1]

lH NMR: (DMSO-D ₆ , 400 MHz) δ Example 39

_4- Γ3 - chloro hopper (3-fluoro ^ phenoxypropionic 1-1-- "(2-methoxy - ethoxy) - ethyl 1-3- methyl-pyrrolo Γ2,3- -1Η- Pyridazine-2-carboxylic acid (2-diethylamino-ethyl)-amide

first step

4-[3-Chloro-4-(3-fluorobenzyloxy)-phenylamino]-l-[2-(2-methoxyethoxy)-ethyl]-3-methyl-1H-pyrrole And [2,3-d]pyridazine-2-carboxylic acid

In the same manner as described in the fifth step of Example 1 of the present invention, the compound 44-[3-chloro-4-(3-fluoro-benzyloxy)-phenoxy] small [(2) obtained in Example 38 was used. -Methoxy-ethoxy)ethyl-ethyl]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylate 38 as the starting material to give the title product 4-[ 3-Chloro-4-(3-fluorobenzyloxy)-phenylamino]-1-[2-(2-methoxyethoxy)-ethyl]-3-methyl-1H-pyrrolo[2 , 3-d] pyridazine-2-carboxylic acid 38a (45 mg, yellow solid). Yield: 23.7%.

MS m/z (ESI): 529 [M+ 1] Step 2

In the same manner as described in the sixth step of Example 1 of the present invention, the compound 4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino] small [2-] obtained in the above first step was used. (2-methoxyethoxy)-ethyl]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid 38a as a starting material to give the title product 4-[3 -chloro-4-(3-fluorooxy)-phenoxy]-1-[(2-methoxy-ethoxy)-ethyl]-3-methyl-1H-pyrrolo[2, 3-d] pyridazine-2-carboxylic acid (2-diethylamino-ethyl)-amide 39 (35 mg, yellow solid). Yield: 29.7 %.

MS m/z (ESI): 628 [M+ 1]

^L HNMR (400MHz, DMSO-d6): 57.90 (d, 2H), 7.56 (q, 1H), 7.45 (t, 1H), 7.30 (t, 2H), 7.17 (m, 2H), 5.22 (s, 2H) ), 4.49(t, 2H), 3.66(s, 3H), 3.40(m, 4H), 3.32(m, 4H), 3.15(s, 3H), 2,57(s, 4H), 1.23(t, 6H) Example 40

4-Γ3-chloro-4-(3-fluoro-benzyloxy)-phenoxy 1 -1-IT2-methoxy-ethoxy)-ethyl 1-3-methyl-1-(2- Morpholine-4-yl-ethyl 1H-pyrrolo "2,3-dlpyridazine-2-carboxylic acid ethyl ester

The first "~

In the same manner as described in the first step of Example 38 of the present invention, using 3,5-dimethyl-1?-pyrrole-2,4-dicarboxylic acid diethyl la (5,742 g, 24 mmol) as a raw material, Reaction of the starting material with 1-bromo-2-(2-methoxy-ethoxy)-ethane (5.706 g, 31 mmol) afforded the title product 3,5-dimethyl-1-(2- Morpholine- ₄ -ethyl) -1H-pyrrole-2,4-dicarboxylic acid diethyl ester 40a (8 g, yellow solid) was taken directly to the next step. '

MS m/z (ESI): 353 [M+ 1] Step 2

5-formyl 3-dimethyl small (2-morpholine-4-ethyl)-1H-pyrrole-2,4-dicarboxylic acid diethyl ester in the same manner as described in the first step of Example 1 of the present invention, Using the compound obtained in the above first step, diethyl 3,5-dimethyl small (2-morpholine-4-ethyl)-1H-pyrrole-2,4-dicarboxylate 40a (11.7 g, 33 Methyl) as a starting material, the reaction of the starting material with ammonium cerium nitrate, and the thiazole IJ gives 5-formyl-3-dimethyl small (2-morpholine- ₄ -yl-)-H-pyrrole-2,4-di Dicarboxylate 40b (2.043 g, yellow solid). The yield was 13.9%.

MS m/z (ESI): 367[M+ 1] Step 3

3-methyl-1 -(2-morpholine-4-ethyl)-4-oxo-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid The ester was obtained in the same manner as described in the second step of Example 1 of the present invention, using the compound 5-formyl-3-dimethyl small (2-morpholine-4-ethyl)-1H- obtained in the above second step. Pyrrole-2,4-dicarboxylic acid diethyl ester 40b (0.84 g, 2.3 mmol) was used as a starting material, and the title compound (3-methyl-1-) was obtained. (2-morpholine-4-ethyl)-4-oxo-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazine Ethyl 2-carboxylate 40c (0.55 g, yellow solid) was taken directly to the next step.

MS m/z (ESI): 335 [M+ 1]

4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy]-l-[(2-methoxy-ethoxy)-ethyl]-3-methyl-l- (2-morpholin-4-yl-ethyl)-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid ethyl ester

In the same manner as described in the fourth step of Example 40 of the present invention, the compound 3-methyl-1-(2-morphofolin-4-ethyl)-4-oxo-4 obtained in the above third step was used. , 5-dihydro-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid ethyl ester 40c (334 mg, 1 mmol) as a starting material to give the title product 4-[3-chloro-4- (3-Fluoro-benzyloxy)-phenoxy]-1-[(2-methoxy-ethoxy)-ethyl]-3-methyl-1-(2-morpholin-4-yl) -ethyl) -1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid ethyl ester 40 (257 mg, yellow solid). Yield: 45.3 %.

MS m/z (ESI): 568 [M+ 1]

¹ HMMR (400MHz, DMSO-d6): 58.08(s, 1H), 7.88(s, 1H), 7.54(m, 1H), 7.47(m, 1H), 7.31(m,2H), 7.16(m, 2H) ), 5.23(s, 2H), 4.63(t, 2H), 4.39(q, 2H), 3.46(m, 4H), 3.28 (s, 3H), 2.73(s, 3H), 2.56(m, 2H) , 2.36 (m, 4H) Example 41

4-"3-Chloro-(3-fluoro-benzyloxy)-phenoxy-1- -1-(2-methoxy-ethoxy)-ethyl 1-3-trifluoromethyl-1H- Pyrrole and 2,3-dl-pyridazine-2-carboxylic acid ethyl ester,

41 first step

4,4,4-trifluoro-2-indenyl 3-carbonyl-butyric acid ethyl ester

Add 4,4,4-trifluoro-3-carbonyl-butyric acid ethyl ester 41a (3.822 g, 20.75 mmol) and glacial acetic acid (6 mL) to a 100 mL round bottom flask under ice-cooling, stir An aqueous solution of sodium nitrite (1.43 g, 20.75 mmol dissolved in 4 mL of water) was added dropwise, and the reaction temperature was controlled to 0 to 5 ° C throughout the process. After the addition was completed, water (1 mL) was added thereto. After reacting for half an hour in an ice water bath, the ice water bath was removed, and the reaction was continued at room temperature for about 3 hours. The spot was traced until the starting material disappeared, and the reaction was completed to obtain the title product 4,4,4-trifluoro-2-indolyl 3-carbonyl- Ethyl butyrate 4ib m was directly injected into the next reaction. Second step

5-methyl-3-trifluoromethyl-1hydrogen-pyrrole-2,4dicarboxylic acid-4-tert-butyl ester-2-ethyl ester

Take a 100 mL three-necked flask equipped with a thermometer and a dropping funnel, weigh 3-carbonyl-butyric acid-tert-butyl ester (3.28 g, 20.75 mmol), glacial acetic acid (9.3 mL) in a three-necked flask, stir. The temperature was raised to 65 °C, and the zinc powder (2.7 g, 41.5 mmol) was weighed. The reaction liquid 41b of the first step reaction was added dropwise with a dropping funnel, and the zinc powder was added in multiple portions. The temperature of the water bath control system was maintained at 75 °C. Left and right, react for 2 hours, then lower the temperature to 40~45 Ό and react overnight. The reaction was completed by the spotting, and water (30 mL) and ethyl acetate (50 mL) were added to the mixture, and the mixture was stirred for 15 minutes, and then the mixture was extracted with ethyl acetate (50 mL×3). The organic phase was combined and washed with water (50 mL EtOAc), EtOAc (EtOAc) Concentration by pressure, the residue was recrystallized from toluene-n-hexane to give the title product 5-methyl-3-trifluoromethyl-1 hydrogen-pyrrole-2,4dicarboxylic acid-4-tert-butyl ester-2- Ester 41c (3.66 g, white flocculent solid), Yield: 55%.

MS m/z (ESI): 320[M-1] NMR NMR ( 400 MHz, CDCl ₃ -i/ ): 54.37 (q, J = 7.2 Hz, 2H), 2.45 (s, 3H), 1.56 (s, 9H), 1.37 (t, J = 7.2 Hz, 3H) . third step

5-Hydroxymethyl-3-trifluoromethyl-1H-pyrrole-2,4-dicarboxylic acid 4-tert-butyl ester 2-ethyl ester in a 250 mL eggplant-shaped flask with 5-methyl-3-trifluoro Methyl-1H-pyrrole-2,4dicarboxylic acid-4-tert-butyl ester-2-ethyl ester 41c (6 g, 18.6 mmol), tetrahydrofuran (120 mL), acetic acid (20 mL) and water (20 mL The mixture was stirred at room temperature, ammonium cerium nitrate (42 g, 76.2 mmol) was added, and the reaction mixture was stirred at room temperature overnight, and a precipitate formed. The solid was filtered under reduced pressure and washed with EtOAc EtOAc EtOAcjjjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH Trifluoromethyl-1H-pyrrole-2,4-dicarboxylic acid 4-tert-butyl ester 2-ethyl ester 41d ( 1.14 g, yellow solid), yield: 18.2%.

MS m/z (ESI): 338[M+1] Step 4

5-formyl-3-trifluoromethyl-1H-pyrrole-2,4-dicarboxylic acid 4-tert-butyl ester 2-ethyl ester In a 100 mL eggplant-shaped flask, pyridine trioxide (969 mg, 4.39 mmol) was added. ), dichloromethane (15 mL), sodium acetate (200 mg, 2.3 mmol), the mixture was stirred at room temperature, and gradually added 5-hydroxymethyl-3-methyl-1H-pyrrole-2,4-dicarboxylate A solution of 4-tert-butyl ester 2-ethyl ester 41d ( 1.14 g, 3.38 mmol) in dichloromethane (20 mL). After the dropwise addition was completed, the reaction solution was stirred at room temperature overnight, and a precipitate formed. The solid was filtered under reduced pressure and washed with ethyl acetate (EtOAc) (EtOAc) -1H-pyrrole-2,4-dicarboxylic acid 4-tert-butyl ester 2-ethyl ester 41e (490 mg), Yield: 43.3%.

MS m/z (ESI): 334 [M-1]

1H NMR (400 MHz, CDC1 ₃ - : 59.937 (s, lH), 4.37 (q, J = 7.2 Hz, 2H), 1.53 (s, 9H), 1.33 (t, J = 7.2 Hz, 3H)

the fifth step

Ethyl 3-trifluoromethyl-4-oxo-4,5-dihydro-1H-pyrrole[2,3-d]pyridazine-2-carboxylate 5-A in a 10 mL eggplant-shaped bottle Acyl-3-trifluoromethyl-1H-pyrrole-2,4-dicarboxylic acid 4-tert-butyl ester 2-ethyl ester 41e (200 mg, 0.6 mmol), acetic acid (2 mL), hydrazine hydrate (0.07 mL, 1.2 mmol), the reaction was completed after heating for three hours. A large amount of solid was precipitated after cooling to room temperature, and filtered to give ethyl 3-trifluoromethyl- 4-oxo-4,5-dihydro-1H-pyrrole[2,3-d]pyridazine-2-carboxylate 41f ( 120 mg), Yield: 72.7%. MS m/z (ESI): 274[M-1] Step 6 4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy]sodium[(2-methoxy-ethoxy)-ethyl]-3-trifluoromethyl-m- Pyrrolo[2,3-d]pyridazine-2-carboxylic acid ethyl ester

Add 3-trifluoromethyl-4-oxo-4,5-dihydro-1H-pyrrole[2,3-d]pyridazine-2-carboxylic acid ethyl ester 41f (420 mg) in a 50 mL eggplant-shaped flask , 1.53 mmol), anhydrous acetonitrile (10 mL), phosphorus oxychloride (0.72 mL, 7.65 mmol) was added under nitrogen, and the reaction mixture was heated to reflux for 2 hr. Chloro-4-(4-fluoro-benzyloxy)-aniline (111 mg, 0.44 mmol), isopropyl alcohol (2 mL), triethylamine (0.08 mL, 0.53 mmol). The reaction solution is cooled in an ice water bath, and the pH is adjusted to be alkaline by adding ammonia water, and a solid precipitates and is passed through an alkal to obtain 4-[3-chloro-4-(3-fluoro-p-oxy)-phenoxy]-1 -[(2-Methoxy-ethoxy)-ethyl]-3-trifluoromethyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid ethyl ester 41 (302 mg, White solid). Yield: 3έ.9%. ·

MS m/z (ESI): 509 [M+ 1]

¹ H NMR (400MHz, DMSO-d): 58.32 (s, 1H), 7.43 (m, 2H), 7.32 (m, 2H), 7.19 (m, 3H), 5.22 (s, 2H), 4.29 (q, 2H) ), 1.31 (m, 4H) Example 42

4-Γ3-chloro-4-fluoro-benzyloxy)-phenoxy-1- -1-((2-methoxy-ethoxy)-ethyl 3-trifluoromethyl-1H-pyrrole" 2,3-dl-pyridazine-2-carboxylic acid benzyl ester

first step

5-methyl-3-trifluoromethyl-1H-pyrrole-2,4-dicarboxylic acid-2-benzyl ester-4-ethyl ester in the same manner as described in the first and second steps of Example 41 of the present invention Using benzyl malonate 42a (2.22 mg, 10 mmol) as the starting material, the title product 5-methyl-3-trifluoromethyl-1H-pyrrole-2,4-dicarboxylic acid-2- Benzyl ester-4-ethyl ester 42b (100 mg, yellow solid). The yield was 45%.

MS m/z (ESI): 356[M+ 1] Step 2

5-Hydroxymethyl-3-trifluoromethyl-1H-pyrrole-.2,4-dicarboxylic acid-2-carboxylate-4-ethyl ester was used in the same manner as described in the third step of Example 41 of the present invention. The compound obtained in the above step, 5-methyl-1H-pyrrole-2,4-dicarboxylic acid-2-benzyl ester-4-ethyl ester 42b (2.0 g, 5.63 mmol) was used as a starting material to carry out the starting material and ammonium cerium nitrate. Reaction of the title product 5-hydroxymethyl-3-trifluoromethyl-1H-pyrrole-2,4-dicarboxylic acid 2-benzyl ester-4-ethyl ester 42c (635 mg, yellow solid). The yield was 30.4%. '

MS m/z (ESI): 372[M+ 1] Step 3

5-formyl-3-trifluoromethyl-1 Η-pyrrole-2,4-dicarboxylic acid-2-benzyl ester-4-ethyl ester. In the same manner as described in the fourth step of Example 41 of the present invention, The compound obtained in the second step is 5-hydroxymethyl-3-trifluoromethyl-1H-pyrrole-2,4-dicarboxylic acid-2-benzyl ester-4-ethyl ester 42c (2.065 g, 5.56 mmol). Starting material, the raw material and pyridine trichromate are obtained to obtain the title product 5-formyl-3-trifluoromethyl-1H-pyrrole-2,4-dicarboxylic acid-2-ester-4-ethyl ester 42d ( 2.945 g), the obtained solid was directly subjected to the next reaction without purification.

MS m/z (ESI): 370[M+ 1] Step 4

3-trifluoromethyl-4-oxo-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid benzyl ester according to the fifth aspect of Example 41 of the present invention In the same manner, using the compound obtained in the above third step, 5-formyl-3-trifluoromethyl-1H-pyrrole-2,4-dicarboxylic acid-2-benzyl ester-4-ethyl ester 42d (2.05 g , 5.56 mmol) as a starting material, the reaction of the material with hydrazine hydrate (0.56 g, 11 mmol) afforded the title product 3-trifluoromethyl-4-oxo-4,5-dihydro-1H-pyrrole [2,3-d] Benzazine-2-carboxylic acid benzyl ester 42e (1.52 g, yellow solid).

MS m/z (ESI): 338[M+ 1] Step 5 4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy]sodium [(2-methoxy-ethoxy)-ethyl]-3-trifluoromethyl-1H- Pyrrolo[2,3-d]pyridazine-2-carboxylic acid benzyl ester

In the same manner as described in the third and fourth steps of Example 1 of the present invention, the compound 3-trifluoromethyl-4-oxo-4,5-dihydro-1H-pyrrole obtained in the above third step was used. [2,3-d] Benzazine-2-carboxylic acid benzyl ester 42e (200 mg, 0.6 mmol) was used as the starting material to give the title product 4-[3-chloro-4-(3-fluoro-benzyloxy)- Phenoxy]-1-[(2-methoxy-ethoxy)-ethyl]-3-trifluoromethyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid benzyl Ester 42 (100 mg, pale yellow solid). Yield: 29.5%.

MS m/z (ESI): 571 [M+1]

^{1 HNMR (400MHz, DMSO-d6} ): 88.18 (s, 1H), 7.67 (m, 1H), 7.65 (m, 2H), 7.48 (m, 2H), 7.25 (m, 3H), 7.18 (m, 2H ), 7.31 (m, lH), 6.86 (s, lH) 5.01 (s, 2H), 3.49 (s, 2H) Example 43

4-Γ3-chloro-4-(3-fluoro-benzyloxyphenoxy 1 -1-[(2-methoxy-ethoxy-ethyl1-3-trifluoromethyl-1Η-pyrrole) 『2,3-dl-pyridazine-2-carboxylic acid (2-diethylamino-ethyl V amide)

First step

4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-3-trifluoromethyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid 4 -[3-chloro-4-(3-fluoro-p-ethoxy)-phenoxy]-1-[(2-methoxy-ethoxy)-ethyl]-3-trifluoromethyl-1H -pyrrolo[2,3-d]pyridazine-2-carboxylic acid benzyl ester 42 (120 mg, 0.21 mmol) dissolved in dichloromethane (10 mL) Trifluoroacetic acid (5 mL) was quickly added under stirring, and the reaction was completed after heating under reflux for 8 hours. The reaction solution was neutralized by adding a saturated sodium hydrogencarbonate solution to pH 7.8. The reaction mixture was extracted, and the combined organic layer was evaporated, evaporated, evaporated Amino]-3-trifluoromethyl-1H-pyrrolo[2,3-d]indole-2-carboxylic acid 43a (100 mg, yellow solid) was taken directly to the next reaction without isolation.

MS m/z (ESI): 481 [M+ 1] Step 2

4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy]sodium [(2-methoxy-ethoxy)-ethyl]-3-trifluoromethyl-1H- Pyrrolo[2,3-d]indole-2-carboxylic acid (2-diethylamino-ethyl)-amide in the same manner as described in the sixth step of Example 1 of the present invention, with 4-[3-chloro 4-(3-Fluoro-benzyloxy)-phenylamino]-3-trifluoromethyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid 43a as raw material, with hydrazine, hydrazine - the reaction of diethylethane-1,2-diamine gives the title product 4-[3-chloro-4-(3-fluorooxy)-phenoxy]-1-[(2-A) Oxy-ethoxy)-ethyl]-3-trifluoromethyl-1Η-pyrrolo[2,3-d]pyridazine-2-carboxylic acid (2-diethylamino-ethyl)-amide 43 (25 mg, white solid), yield 21%.

MS m/z (ESI): 579 [M+ 1]

'HNMR (400MHZ, DMSO-d6): 58.18 (s, 1H), 7.44 (m, 2H), 7.32 (m, 2H), 7.19 (m, 3H), 5.01 (s, 2H), 3.47 (t, 2H) ), 2.73(t, 2H), 2.50(m, 4H), 0.99(t, 6H) Example 44

4-Γ3-chloro-4-(3-fluorooxy)-phenoxy 1-1-anthracene (2-methoxy-ethoxy)-ethyl 1-3-trifluoromethyl-1H- Pyrrolo-C2,3-dl-pyridazine-2-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide-1

The reaction of the first step and the second step of Example 43 of the present invention was repeated, except that the starting material 4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-3 was obtained in the first step. -Trifluoromethyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid 43a, the starting material and 2-pyrrolidine-1-B were carried out in the same manner as in the sixth step of Example 1. Reaction of the amine gave the title compound 4-[3-chloro-4-(3-fluoro-p-oxy)-phenoxy]sodium[(2-methoxy-ethoxy)-ethyl]-3- Trifluoromethyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid (2-pyrrole-1-yl-ethyl)-amide 44 (25 mg, 18.4), yellow solid.

MS m/z (ESI): 577.7 [M+ 1] 'HNMR (400MHz, OMSO-d6): 58.33(s, 1H), 7.44(m, 2H), 7.32(m, 2H), 7.19(m, 3H), 5.21(s, 2H), 2.76(m, 4H ), 1.91 (m, 4H), 1.22 (m, 4H) Example 45

-Γ2-(5-diethylamino

45 first step

5-formyl-3-methyl-1Η-pyrrole-2,4-dicarboxylic acid-2-tert-butyl ester-4-ethyl ester In the same manner as described in the first step of Example 1 of the present invention, 3,5 was used. -Dimethyl-1Η-pyrrole-2,4-dicarboxylic acid-2-tert-butyl ester-4-ethyl ester 45a (10 g, 37.4 mmol) as a raw material, and reacting the starting material with cerium ammonium nitrate to obtain The title product 5-formyl-3-methyl-1H-pyrrole-2,4-dicarboxylic acid-2-tert-butyl ester-4-ethyl ester 45b (7.4 g, yellow solid). The yield was 70.5 %.

MS m/z (ESI): 280 [M-1]

Second step 5-formyl-3-methyl-1H-pyrrole-2,4-dicarboxylic acid-4-ethyl ester In a 100 mL three-necked flask, the starting material 45b (2.81 g, lOmmol) and the second obtained in the above first step were added. Chloroformamide (40 mL), after dissolving, was cooled to 0 to 5 Torr in an ice bath, and trifluoroacetic acid (20 mL) was slowly added to maintain the temperature at 0 to 5 °C. After the completion of the dropwise addition, the temperature was raised to 10 to 2 (TC, and the reaction was completed after stirring for 4 hours. The reaction liquid was poured into ice water, and solid was precipitated. The mixture was filtered under reduced pressure, washed with water, and dried under vacuum to give the title product 5- Formyl-3-methyl-1H-pyrrole-2,4-dicarboxylic acid-4-ethyl ester 45c (2.19 g, yellow solid), yield: 97.3%.

MS m/z (ESI) _: 224 [M-1] Step 3

Ethyl 2-formyl-5-iodo-4-methyl-1H-pyrrole-3-carboxylate The compound obtained in the above step was added 5-formyl-3-methyl-1H-pyrrole-2 in a 100 mL flask. 4-Dicarboxylic acid-4-ethyl ester 45c (3.2 g, 14.2 mmol) and dichloromethane (140 mL). The whole system was divided into two layers. The solution was brown. A mixed solution of potassium iodide (7.1 g), iodine (3.96 g) and water (71 mL) was added with vigorous stirring, and the mixture was heated to 45 ° C, and the reaction was completed after 2 hours. After the reaction mixture was cooled to room temperature, it was extracted with methylene chloride (200 mL), and the combined organic phase was washed with saturated sodium chloride (100 mL), dried over anhydrous sodium sulfate, filtered and evaporated to dryness Purified by column chromatography (n-hexane: ethyl acetate = 10:1) to give the title product 2-formyl-5-iodo-4-methyl-1H-pyrrole-3-carboxylic acid g, yellow solid), Yield: 26.7%.

MS m/z (ESI): 306 [M-1]

the fourth step

2-iodo-3-methyl-1,5-dihydro-pyrrolo[2,3-d]pyridazine-4-one

In the same manner as described in the second step of Example 1 of the present invention, the compound 2-formyl-5-iodo-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester 45d obtained in the above third step was used. 307mg, 1mmol) was used as the starting material, and the reaction of the starting material with hydrazine hydrate (75 mg, 1.5 mmol) gave the title product 2-iodo-3-methyl-1,5-dihydro-porto[2, 3-d]pyridazin-4-one 45e (65 mg, yellow solid). The yield was 47.4%.

MSm/z(ESI): 276[M+1] Step 5

2-(5-Diethylaminomethyl-furan-2-yl)-3-methyl-1,5-dihydro-pyrrolo[2,3-d]pyridazin-4-one in 200 mL of eggplant 2-(5-Diethylaminomethyl-furan-2-yl)-3-methyl-1,5-dihydro-indolepyr-[2,3-d]pyridazine-4 was added sequentially to the vial. -ketone 45e (390 mg, 1.4 mmol), 90% 5-(diethylaminomethyl)furan-2-boronic acid (355 mg, 1.4 mmol) in water, sodium bicarbonate (517 mg, 3.7 mmol), Ν, Ν - dimethylformamide (10 mL) and water (10 mL). The mixture was added with tetratriphenylbenzene under nitrogen. Palladium phosphinate (59 mg, 0.05 mmol). The reactant was heated to reflux to 110, and the reaction was completed after four hours. The reaction mixture was evaporated to dryness crystalljjjjjjjjjjjjjjj Benzyl)-3-methyl-1,5-dihydro-pyrrolo[2,3-d]pyridazin-4-one 45f (251 mg, yellow solid). Yield: 41.7%.

MS m/z (ESI): 276 [M+ 1] Step 6

[3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy]-[2-(5-diethylaminomethyl-furan-2-yl 3-methyl-1H-pyrrolo[2 ,3-d]pyridazin-4-yl]amide

In the same manner as described in the third and fourth steps of Example 1 of the present invention, the compound 2-(5-diethylaminomethyl-furan-2-yl)-3-methyl- obtained in the above fifth step was used. 1,5-Dihydro-pyrrolo[2,3-d]pyridazin-4-one 45f as a starting material to give [3-chloro-4-(3-fluoro-benzyloxy)-phenoxy]-[ 2-(5-Diethylaminomethyl-furan-2-yl)-3-methyl-1H-pyrrolo[2,3-d]pyridazin-4-yl]amide 45 (1.642 g, white solid) . The yield was 79.7 %.

MS m/z (ESI): 535 [M+ 1]

^{] HNMR (400MHz, DMSO-c¾} ): 58.34 (s, 1H), 7.85 (s, 1H), 7.50 (m, 2H), 7.46 (m, 2H), 7.28 (m, 2H), 6.86 (d, 1H , J=3.2Hz), 6.50(d, 1H, J=2.4Hz), 5.2 l(s, 2H), 3.75(s, 2H), 2.63(m, 4H), 2.33(s, 3H), 1.01( m, 6H)

Example 46

-chloro-4-(3-fluoro-benzyloxy)-phenoxy 1 -|~2-(3-diethylaminomethyl-methyl)-3-methyl-1H-pyrrole

"2.3-dl pyridazine-4-yl 1 amide

first step

2-(3-Diethylaminomethylphenyl)-3-methyl-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one according to the fourth step of Example 45 of the present invention In the manner described, the compound 2-(5-diethylaminomethyl-furan-2-yl)-3-methyl-1,5-dihydro-pyrrolo[2,3-d]pyridazine-4- The ketone 45e (206 mg, 0.75 mmol) and 3-diethylaminomethylbenzeneboronic acid (186 mg, 0.90 mmol) were obtained from the title compound 2-(3-diethylaminomethylphenyl)-3- Base-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one 45a (110 mg, white solid). Yield: 35.5 %.

MS m/z (ESI): 311 [M+ 1]

[3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy]-[2-(3-diethylaminomethyl-methyl)-3-methyl-1H-pyrrolo[2, 3-d]pyridazin-4-yl]amide

In the same manner as described in the third and fourth aspects of the present invention, the compound 2-(3-diethylaminomethylphenyl)-3-methyl-1,5- obtained in the above fifth step was used. Dihydropyrrolo[2,3-d]pyridazin-4-one 45a is used as a starting material to give [3-chloro-4-(3-fluoro-benzyloxy)-phenoxy]-[2-(3- Diethylaminomethyl-methyl>3-methyl-1H-pyrrolo[2,3-d]pyridazin-4-yl]amide 46 (15 mg, white solid).

MS m/z (ESI): 545 [M+ 1]

Example 47

_7- [3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy 1 -1H-pyrrolo- 2,3-dl-pyridazine-2-carboxylic acid (2-diethylamino-B

First step

1H-pyrrole-2,5-dicarboxylic acid dimethyl ester

Adding pyrrole-1,2,5-tricarboxylic acid 1-tert-butyl ester 2,5-dimethyl ester 47a in a 10 mL eggplant vial under nitrogen protection. Dissolved in (200 mg, 0.71 mmol), dichloro Methane (2 mL), trifluoroacetic acid (2 mL) was stirred at room temperature for 1 hour and the reaction was completed. After evaporating most of the solvent under reduced pressure, a solid solid was poured from ice water (2 mL), stirring was continued for 0.5 hr, filtered and washed, and the obtained solid was further separated by column chromatography (hexane: ethyl acetate = 8:1). Purification afforded 1H-pyrrole-2,5-dicarboxylic acid dimethyl ester 47b (60 mg, yellow solid), yield 46.5%.

MS m/z (ESI): 182 [M-1]

Second step

3-formyl-1H-pyrrole-2,5-dicarboxylic acid dimethyl ester

Dichloromethane (2 mL), hydrazine, Ν'-dimethylformamide (0.06 mL, 0.83 mmol) was added to a 50 mL three-necked flask, and the mixture was cooled to 30 Torr with a dry ice-ethanol bath. After stirring for 10 minutes, oxyphosphorus (0.06 mL, 0.66 mmol) was added to a solution of 1H-pyrrole-2,5-dicarboxylate 47b (60 mg, 0.33 mmol) in dichloromethane (1 mL). After 100 hours, the reaction was completed after 3 hours. Add ice water (10 mL) and saturated sodium bicarbonate solution to pH=8~9, and combine the organic phase with ethyl acetate (10 mL×3) and wash with saturated sodium chloride (10 mL) The residue was dried over anhydrous sodium sulfate, filtered, and evaporated. Dimethyl carboxylic acid 47c (62 mg, yellow solid), Yield: 21.4%. third step Methyl 7-oxo-6,7-dihydro-1H-pyrrole[2,3-d]pyridazine-2-carboxylate was added to a 10 mL eggplant vial under argon to add 3-formyl- 1H-Pyrrol-2,5-dicarboxylic acid dimethyl ester 47c (44 mg, 0.21 mmol), dry ethanol (2 mL) and hydrazine hydrate (0.025 mL, .042 mmol). After cooling to room temperature, a solid precipitated and filtered to give methyl 7-oxo-6,7-dihydro-1H-pyrrole[2,3-d]pyridazine-2-carboxylate 47d (17 mg, white solid) , 43.9%.

MS m/z (ESI): 194 [M+ 1]

the fourth step

7-[3-Chloro-4-(4-fluoro-oxy)-phenylamino]-1,4-indole-pyrrole [2,3-d]pyridazine-2-carboxylic acid methyl ester in 10 mL eggplant-shaped flask Add 7-oxo-6,7-dihydro-1H-pyrrole [2,3-d]pyridazine-2-carboxylic acid methyl ester 47d (100 mg, 0.438 mmol), dry acetonitrile (2 mL) Phosphorus oxychloride (0.09 mL, 0.97 mmol) was added under a nitrogen atmosphere, and the reaction mixture was heated under reflux for 3 hr. (111 mg, 0.44 mmol), isopropanol (2 mL), triethylamine (0.08 mL, 0.53 mmol). The reaction solution was cooled in an ice water bath, and aqueous ammonia was added to adjust the pH to be alkaline. A solid precipitated and filtered to give 7-[3-chloro-4-(4-fluoro-benzyloxy)-phenylamino]-1H- Methyl pyrrole [2,3-d]pyridazine-2-carboxylate 47e (63 mg, white solid), yield: 33.8%. MS m/z (ESI): 427 [M+ 1] Step 5

Add 7-[3-chloro-4-(4-fluoro-oxy)-phenylamino]-1H-pyrrole[2,3-d]pyridazine-2-carboxylic acid to a 10 mL eggplant-shaped bottle (72 mg, 1.26 mmol) in water (2 mL), gradually adding 7-[3-chloro-4-(4-fluoro-hydroxy)-phenylamino]-1H-pyrrole [2,3-d] Pyridazine-2-carboxylic acid methyl ester 47e

(134 mg, 0.315 mmol) in ethanol (2 mL). After the completion of the dropwise addition, the mixture was heated under reflux for 1 hour, and the reaction was completed. The reaction solution was cooled to room temperature, and most of the ethanol was removed under reduced pressure. The pH was adjusted to be acidic with a 1N hydrochloric acid solution. A yellow precipitate was formed and filtered, and the residue obtained was further purified by column chromatography (dichloromethane: methanol = 15:1) Purified by isolation to give 7-[3-chloro-4-(4-fluoro-benzyloxy)-phenylamino]-1H-pyrrole [2,3-d]pyridazine-2-carboxylic acid 47f (110 mg, Yellow solid). Yield: 85.3 %. Step 6

₇ _[3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy]-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid (2-diethylamino-B -amide

Add 7-[3-chloro-4-(4-fluoro-benzyloxy)-phenylamino]-1H-pyrrole [2,3-d]pyridazine-2-carboxylic acid 47f to a 10 mL eggplant-shaped flask ( 130 mg, 0.27 mmol), monohydroxybenzotriazole (56 mg, 0.27 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (79) Mg, 0.41 mmol), triethylamine (0.1 mL, 0.675 mmol). After stirring for 15 min, N*1*, N*1*-diethylethane-1,2-diamine was added and stirred at room temperature overnight. The reaction is completed. The reaction solution was poured into water (20 mL), and a large amount of solid precipitated. Filtration gave the title product 7-[3-chloro-4-(3-fluoro-benzyloxy)-phenoxy]-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid (2- Diethylamino-ethyl)-amide 47 (105 mg, yellow solid). Yield: 76.6% ₀

MS m/z (ESI): 512 [M+ 1]

'HNMR (400MHZ, DMSO-C3⁄4): 58.33 (S, lH), 7.66 (m, 1H), 7.47 (m, 2H), 7.32 (m, 1H), 7.25 (m, 1H), 7.18 (m, 2H) ), 6.90(s, 1H), 5.23(s, 2H), 3.47(t, 2H), 2.73(t, 2H), 2.50(m, 4H), 0.99(t, 6H) Example 48

₇ - "3-Chloro-4-(3-fluoro-p-ethoxy)-phenoxy 1 -1H-pyrrolo "2,3-dlpyridazine-2-carboxylic acid (2-2-pyrrole-1) -yl-ethyl)-amide

The reaction of the first step to the fifth step of Example 47 of the present invention was repeated, using the compound obtained in the fifth step, 4-[3-chloro-4-(4-fluoro-benzyloxy)-phenylamino]-1H-pyrrole [ 2,3-d]pyridazine-2-carboxylic acid 47f is used as a starting material, and the reaction of the starting material with 2-pyrrolidine-1-ethylamine is carried out in the same manner as in the sixth step of Example 47 of the present invention to give the title compound. 7-[3-Chloro-4-(3-fluoro-oxy)-phenoxy]-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid (2-2-pyrrolidine-1 -yl-ethyl)-amide 48 (90 mg, yellow solid). Yield: 84.9%.

MS m/z (ESI): 509 [M+ 1]

'HNMR (400MHZ, DMSO-ί/ό): S8.33(s, 1H), 7.67(m, 1H), 7.49(m, 1H), 7.4 l(m, 2H), 7.26(m, 1H), 7.17(m, 2H), 6.82(s, 1H), 5.23(s, 2H), 3.47(m, 2H), 2.73(m, 2H), 2.50(m, 4H), 1.71(m, 4H) 49

₇ - "3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy 1 -1 Η-pyrrolo "2,3-dl oxazin-2-carboxylic acid (2-morpholin-4-yl) -ethyl)-amide

The reaction of the first step to the fifth step of Example 47 of the present invention was repeated, and the compound obtained in the fifth step was used 4-[3-chloro-4-(4-fluoro-oxy-oxy)-phenylamino]-1H-pyrrole [ 2,3-d]pyridazine-2-carboxylic acid 47f is used as a starting material, and the starting material is reacted with 2-morpholin-4-ethylamine in the same manner as described in the sixth step of Example 47 of the present invention to give the title compound. 7-[3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy]-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid (2-morpholin-4- Base-ethyl)-amide 49 (88 mg, yellow solid). Yield: 80%. - S m/z (ESI): 525[M+ 1]

¹ H MR (400MHz, DMSO-c3⁄4): 58.33(s, 1H), 7.67(m, 1H), 7.49(m, 1H), 7.41(m, 2H), 7.26(m, 1H), 7.17(m, 2H), 6.94(s, 1H), 5.23(s, 2H), 3.58(m, 4H), 3.45(m, 2H), 2.89(m, 2H), 2.45(m, 4H) Example 50

7-"3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy 1- 1 Η-pyrrolo "2,3-dl-pyridazine-2-carboxylic acid (3-morpholin-4-yl) -propyl V amide

The reaction of the first step to the fifth step of Example 47 of the present invention was repeated, using the compound obtained in the fifth step, 4-[3-chloro-4-(4-fluoro-benzyloxy)-phenylamino]-1H-pyrrole [ 2,3-d]pyridazine-2-carboxylic acid 47f is used as a starting material, and the starting material is reacted with 3-morpholin-4-ethylamine in the same manner as in the sixth step of Example 47 of the present invention to give the title compound. 7-[3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy]-IH-pyrrolo[2,3-d]pyridazine-2-carboxylic acid (3-morpholin-4- Base-propyl)-amide 50 (70 mg, yellow solid). Yield: 61.9%.

MS m/z (ESI): 540 [M+ 1]

^{! HNMR (400MHz, DMSO 6)} : 58.33 (s, 1H), 7.67 (m, 1H), 7.49 (m, 1H), 7.41 (m, 2H), 7.26 (m, 1H), 7.17 (m, 2H) , 6.94(s, 1H), 5.23(s, 2H), 3.58(m, 4H), 3.34(m, 4H), 2.34(m, 4H), 2.21(m, 2H) Example 51

7-[3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy 1 -1Η-pyrrolo and 2,3-dlpyridazine-2-carboxylic acid (2-piperidin-1-yl) -ethyl)-amide

The reaction of the first step to the fifth step of Example 47 of the present invention was repeated, and the compound obtained in the fifth step was used 4-[3-chloro-4-(4-fluoro-benzyloxy)-phenylamino]-1H-pyrrole [ 2,3-d]indole-2-carboxylic acid 47 hydrazine is used as a starting material, and the starting material is reacted with 2-piperidine-1-ethylamine in the same manner as described in the sixth step of Example 47 of the present invention to give the title compound. 7-[3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy]-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid (2-piperidin-1- Base-ethyl)-amide 51 (88 mg, yellow solid). Yield: 80.7%

MS m/z (ESI): 524 [M+ 1]

'HNMR (400MHZ, DMSO-d6): 58.33 (s, 1H), 7.68 (m, 1H), 7.48 (m, 1H), 7.34 (m, 2H), 7.26 (m, 1H), 7.17 (m, 2H) ), 6.86(s, 1H), 5.23(s, 2H), 3.49(m, 2H), 3.15(m, 2H), 2.4 l(m, 2H), 2.33(m, 2H), 1.69(m, 4H) ), 1.65 (m, 2H) Example 52

743-chloro-4-(3-fluoro-benzyloxy)-phenoxy 1 -1H-pyrrolo "2,3-dloxazin-2-carboxylic acid f3-(4-methyl-piperazine-1 -yl)-propyl 1-amide

The reaction of the first step to the fifth step of Example 47 of the present invention was repeated, and the compound obtained in the fifth step was used 4-[3-chloro-4-(4-fluoro-benzyloxy)-phenylamino]-1H-pyrrole [ 2,3-d]pyridazine-2-carboxylic acid 47f is used as a starting material, and the starting material is 3-(4-methyl-piperazin-1-yl) in the same manner as described in the sixth step of Example 47 of the present invention. - propylamine reaction to give the title compound 7-[3-chloro-4-(3-fluoro-benzyloxy)-phenoxy]-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid [3-(4-Methyl-piperazin-1-yl)-propyl]-amide 52 (74 mg, yellow solid). Yield: 64.3 %. MS m/z (ESI): 553 [M+ 1]

1HNMR (400MHz, DMSO-d6): S8.33 (s, 1H), 7.67 (m, 1H), 7.46 (m, 1H), 7.34 (m, 2H), 7.26 (m, 1H), 7.17 (m, 2H), 6.94(s, 1H), 5.23(s, 2H), 3.35(m, 4H), 3.10(m, 2H), 2.41 (m, 4H), 2.33(m, 4H), 1.96(s, 3H ) Example 53,

7-Γ3-chloro-4-(3-fluoro-oxy)-phenoxy 1 -1H-pyrrolo[2,3-dl哒嗉-2-carboxylic acid 2-(4-methyl-piperazine small -ethyl 1-amide

The reaction of the first step to the fifth step of Example 47 of the present invention was repeated, and the compound obtained in the fifth step was used 4-[3-chloro-4-(4-fluoro-benzyloxy)-phenylamino]-1H-pyrrole [ 2,3-d]pyridazine-2-carboxylic acid 47f is used as a starting material, and the starting material is 3-(4-methyl-piperazin-1-yl) in the same manner as described in the sixth step of Example 47 of the present invention. -ethylamine reaction to give the title compound 7-[3-chloro-4-(3-fluoro-benzyloxy)-phenoxy]-1H-pyrrolo[2,3-d]pyridazine-2-carboxylate 2-(4-Methyl-piperazin-1-yl)-ethyl]-amide 53 (88 mg, yellow solid). Yield: 78.6%. MS m/z (ESI): 538 [M+ 1]

¹ H MR (400MHz, DMSO-d6): 58.33(s, 1H), 7.67(m, 1H), 7.48(m, 1H), 7.34(m, 2H), 7.25(m, 1H), 7.18(m, 2H), 6.86(s, 1H), 5.23(s, 2H), 3.47(m, 2H), 3.15(m, 2H), 2.41(m, 4H), 2.18(m,4H), 1.68(s, 3H) Example 54

4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenyl 1 -7-methyl-6H-pyrrolof3,4-dl piperazine-5-carboxylate

first step

Diethyl 4-formyl-5-methyl-1H-pyrrole-2,3-dicarboxylate In a 100 mL eggplant-shaped flask, add 5-methyl-1H-pyrrole-2,3-dicarboxylic acid diethyl Ethyl ester (4.51 g, 20 mmol) and hydrazine, Ν'-dimethylformamide (25 mL). After dissolved, phosphorus oxychloride (3.8 mL, 40 mmol) was added and the mixture was heated to 100 ° C and refluxed for 2 hours. The reaction is completed. Ice water (100 mL) was added to the reaction solution, and 1N sodium hydroxide solution was added to adjust the pH to be alkaline. A large amount of yellow solid was precipitated, filtered, and dried to give 4-formyl-5-methyl-1H-pyrrole- Diethyl 2,3-dicarboxylate (3.905 g, yellow solid). Yield: 77.2%. MS m/z (ESI): 254 [M+ 1] Step 2,

Ethyl 7-methyl-4-oxo-4,6-dihydro-3indole-pyrrolo[3,4-d]pyridazine-5-carboxylate was added to a 50 mL eggplant bottle under nitrogen. Diethyl 4-formyl-5-methyl-1H-pyrrole-2,3-dicarboxylate (2.532 g, 10 mmol), ethanol (20 mL) and hydrazine hydrate (0.9 mL, 15 mraoD o mixture heated to 90 C, reflux for 3 hours, complete. Cool the reaction solution to room temperature, a large amount of solid precipitated, suction filtration, and dried to give 7-methyl-4-oxo-4,6-dihydro-3H-pyrrole [ 3,4-d]ethyl oxazine-5-carboxylate ( 1.732 g, yellow solid). Yield: 71.9%.

MS m/z (ESI): 220[M-1] Step 3

Ethyl 4-chloro-7-methyl-6H-pyrrolo[3,4-d]pyridazine-5-carboxylate was added to a 100 mL eggplant vial under nitrogen to add 7-methyl-4-oxo Generation of 4-,6-dihydro-3H-pyrrolo[3,4-d]pyridazine-5-carboxylic acid ethyl ester (1.736 g, 7.85 mmol), anhydrous acetonitrile (40 mL) and phosphorus oxychloride ( 1.5 mL, 15.7 mmol). The mixture was heated to 90 Torr and refluxed for 5 hours. The reaction solution was cooled to room temperature, a large amount of solid was precipitated, suction filtered, and dried to give crude 4-chloro-7-methyl-6-pyrrolo[3,4-d]pyridazin-5-carboxylic acid ethyl ester (1.71 g) , yellow solid), proceed directly to the next reaction. the fourth step

Ethyl 4-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-7-methyl-6H-pyrrolo[3,4-d]piperazine-5-carboxylate in nitrogen Under the protection, a crude 4-chloro-7-methyl-6H-pyrrolo[3,4-d]pyridazine-5-carboxylic acid ethyl ester (1.71 g) was added to a 100 mL eggplant bottle, isopropanol ( 50 mL) and 3-chloro-4-(3-fluoro-oxy)-aniline (1.6 g, 6.6 mmoD o mixture heated to 90 ° C, reflux for 7 hours, finished. Cool the reaction solution to room temperature, there are a lot The solid was precipitated, suction filtered and dried to give the title product 4-[3-chloro-4-(3-fluoro-p-oxy)-phenyl]-7-methyl-6H-pyrrolo[3,4-d] Ethyl piperazine-5-carboxylate 54 ( 1.474 g, yellow solid). Yield: 50.8%. MS m/z (ESI): 455 [M+ 1]

'HNMR (400MHZ, DMSO-d6): 59.03 (s, 1H), 8.32 (s, 1H), 7.56 (m, 1H), 7.45 (m, 1H), 7.32(m, 2H), 7.26(m, IH), 7.17(m, IH), 5.23(s, 2H), 4.45(q, 2H), 2.63(s, 3H), 1.43(s _: 3H) 55

3-Chloro-4-[3-fluoro-benzyloxy)-phenyl 1-(5-methyl-6H-pyrrolo[3,4-dlpiperazin-1-yl)-ethylamine

first step

4-formyl 5-methyl-1H-pyrrole-3-carboxylic acid ethyl ester

Add 5-methyl-1H-pyrrole-3-carboxylic acid ethyl ester 55a (306 mg, 2 mmol), 1,2-dichloroethane (5 mL) and nitroformamidine to a 25 mL three-necked flask ( 5 mL), add aluminum trichloride (800 mg) under argon, cool the mixture to 20 Torr, and quickly add dichloromethoxymethyl 1,2-dichloroethane (2.4 mmol, 2 mL) After the dropwise addition was completed, the reaction solution was reacted at 20 ° C for 3 hours. After the reaction is completed, the reaction mixture is poured into water, the organic layer is separated, the aqueous layer is extracted with ethyl acetate, and the organic phase is combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by column chromatography gave 4-formyl-5-methyl-1H-pyrrole-3-carboxylic acid ethyl ester 55b (334 mg,yel. Yield: 92.2%

MS m/z (ESI): 455 [M+ 1]

1H NMR ( 400 MHz, CDC1 ₃ -^): 510.503 (s, 1H), 7.28 (t, IH), 4.32 (q, 2H, J- 6.8 Hz), 2.58 (s, 3H), 1.35 (t, 3H) , J = 6.8 Hz). Second step

5-methyl-2,6-dihydropyrrolo[3,4-d]pyridazine ketone was added to a 10 mL eggplant vial under the protection of nitrogen to form 44-formyl-5-methyl-1H-pyrrole Ethyl 3-carboxylate 55b (91 mg, 0.5 mmol), ethanol (1 mL) and hydrazine hydrate (35μl, 0.6 mmol). The mixture was heated to 90 ° C and refluxed for 4 hours, and the reaction was completed. The reaction solution was cooled to room temperature, a large amount of solid was precipitated, suction filtered, and dried to give 5-methyl-2,6-dihydropyrrolo[3,4-d]pyridazin-1-one 55c (28 mg, yellow solid ). Yield: 39%.

MS m/z (ESI): 150[M+1] Step 3

1-chloro-5-methyl-6H-pyrrolo[3,4-d]pyridazine

5-methyl-2,6-dihydropyrrolo[3,4-d]pyridazin-1-one 55c (150 mg, 1 mmol), anhydrous acetonitrile was added to a 10 mL eggplant flask under nitrogen. (2 mL) and phosphorus oxychloride (0.5 mL, 5 mmol). The mixture was heated to 90 ° C and refluxed for 3 hours, and the reaction was completed. The reaction solution was cooled to room temperature, a large amount of solid was precipitated, suction filtered, and dried to give crude 1-chloro-5-methyl-6H-pyrrolo[3,4-d]pyridazine 55d (170 mg). .

MSm/z(ESI) _: 168[M+1] Step 4

Ethyl 4-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-7-methyl-6H-pyrrolo[3,4-d]piperazine-5-carboxylate in nitrogen Under the protection, add the crude 4-chloro-7-methyl-6H-pyrrolo[3,4-d]pyridazine-5-carboxylic acid ethyl ester (170 mg) to isopropanol (5 niL) in a 100 mL eggplant flask. And the mixture of 3-chloro-4-(3-fluoro-benzyloxy)-phenylamine (176 mg, 0.7 mmol) was heated to 9 (TC, reflux for 7 hours, the reaction was completed. The reaction mixture was cooled to room temperature, and there was a large amount of solid Precipitation, suction filtration, drying to give 4-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-7-methyl-6H-pyrrolo[3,4-d]piperazine- Ethyl 5-carboxylate (72 mg, yellow solid). Yield: 27%.

MSm/z (ESI): 383 [M+1]

1H NMR (400 MHz, COCl d ): S7.493~7.437 (m, 3H), 7.3 l (t, 2H), 7.28 (s, 1H), 7.21~7.15 (m, 2H), 5.20 (s, 2H) ), 4.32 (q, 2H, J = 6.8 Hz), 2.5 l (s, 3H). Example 56

4-Γ1--fluorobenzyl)-1Η-carbazole-5-amino1-3-methyl-1H-pyrrolo-[2,3-dl-pyridazine-2-IY2-pyrrolidin-1-yl) Ethyl 1 carboxamide

The reaction of the first step to the second step of Example 20 of the present invention was repeated, using the compound 4-[1-(3-fluorobenzyl)-1H-indazole-5-amino]-3 obtained in the above second step. -Methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid 20b as a starting material, and the starting material and 2-(pyrrolidine-1) were carried out in the same manner as described in the sixth step of Example 1 of the present invention. -yl)-ethylamine reaction, the title product 4-[1-(3-fluorobenzyl)-1Η-indazole-5-amino]-3-methyl-1H-pyrrolo[2,3- d] pyridazine-2-[(2-pyrrolidin-1-yl)-ethyl]carboxamide 56 (58 mg, yellow solid). The yield was 9%.

MS m/z (ESI): 513 [M+ 1]

1H MR (400MHz, DMSO-^): 58.07(s, 2H), 7.65(m, 2H), 7.33(m, 1H), 7.09(m, 1H), 7.04(m, 2H), 5.67(s, 2H ), 2.68 (m, 4H), 2.34 (m, 4H), 2.41 (s, 3H), 1.72 (m, 4H) Example 57

4-Γ1-(3-fluorobenzyl)-1Η-carbazole-5-amino-3-methyl-IH-pyrrolo-[2,3-dloxazin-2-indole-2-morpholine-4-yl)- Ethyl 1 carboxamide

The reaction of the first step to the second step of Example 18 of the present invention was repeated, using the compound 4-[1-(3-fluorobenzyl)-1H-indazole-5-amino]-3 obtained in the above second step. -Methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid 18b as a starting material, the starting material and 2-morpholine-4- are carried out in the same manner as described in the sixth step of Example 1 of the present invention. The reaction of the base-ethylamine gives the title product 4-[1-(3-fluorobenzyl)-1Η-indazole-5-amino]-3-methyl-1H-pyrrolo[2,3-d] Pyridazin-2-[(2-morphinolin-4-yl)-ethyl]carboxamide 57 (50 m _g , yellow solid). The yield was 58.6 %.

MS m/z (ESI): 529 [M+ 1]

¹ H NMR (400MHz, OMSO-d ₆ ): 58.07(s, 2H), 7.64 (m, 1H), 7.55 (m, 1H), 7.35 (m, 1H), 7.08 (m, 1H), 7.03 (m, 2H), 5.67(s, 2H), 3.59(m, 4H), 3.42(m, 2H), 3.34(m, 2H), 2.40(s, 3H)

Example 58

Π3-Chloro-4- ₍₃ -fluorobenzyloxy)-phenyl W ₂ _n-f(2-methanesulfonylethylamino-methyl 1-phenyl1-3-methyl-1H-pyrrole "2 , 3-dloxazin-4-yl)-amine

first step

2-{3-[(2-Methanesulfonylethylamino)-methyl]-phenyl}-3-methyl-1,5-dihydro-pyrrolo[2,3-d]pyridazine-4- The ketone is in the manner described in the fourth step of Example 45 of the present invention, using the compound 2-(5-diethylaminomethyl-furan-2-yl)-3-methyl-1,5-dihydro-pyrrolo[ 2,3-d]oxazin-4-one 45e (220 mg, 0.8 mmol) and 3-(2-methyl-cyanoethylaminomethyl)benzeneboronic acid (186 mg, 0.8 mmol) 2-{3-[(2-methanesulfonylethylamino)-methyl]-phenyl 3-methyl-1,5-dihydro-pyrrolo[2,3-d]pyridazin-4-one 58a (162 mg, white solid). Yield: 57.8 %.

MS m/z (ESI): 351 [M+ l] Step 2

[3-Chloro-4-(3-fluorobenzyloxy)-phenyl]-(2-{3-[(2-methanesulfonylethylamino)methyl]-phenyl}-3-methyl-1 H-pyrrolo[2,3-d]pyridazin-4-yl)-amine

In the same manner as described in the third and fourth steps of Example 1 of the present invention, the compound 2-{3-[(2-methanesulfonylethylamino)-methyl]-phenyl} obtained in the above fifth step was used. 3-methyl-1,5-dihydro-pyrrolo[2,3-d]pyridazine-4-one 58a as a starting material to give [3-chloro-4-(3-fluorobenzyloxy)-benzene ]-(2-{3-[(2-Methanesulfonylethylamino)-methyl]-phenyl 3-methyl-1H-pyrrolo[2,3-d]pyridazin-4-yl)- Amine 58 (15 mg, white solid). The yield was 44.1%.

MS m/z (ESI): 595 [M+ l]

^{! HNM (400MHz, DMSO-c¾} : 57.94 (m, 2H), 7.54 (m, 3H), 7.46 (m, 2H), 7.32, (m, 3H), 7.18 (m, 2H), 5.22 (s, 2H ), 4.25(d, 2H, J=9Hz), 3.28(s, 3H), 3.03(m, 2H), 2.67(m, 2H), 2.94(s, 3H)

Example 59

_Γ3 -Chloro- _4- _(3- fluorobenzyloxy)-phenyl"l-( _2- {5-"(2-methanesulfonylethylamino)-methyl-1-furan-2-yl 3-methyl -1H-pyrrolo and 2,3-dloxazin-4-yl V amine

first step

2-{5-[(2-methanesulfonyl-ethylamino)methyl]-furan-2-yl}-3-methyl-1,5-dihydro-B than s-[2,3-d] Pyridazin-4-one

According to the method described in the fourth step of Example 45 of the present invention, the compound 2-(5-diethylaminomethyl-furan-2-yl)-3-methyl-1,5-dihydro-porto [2,3-d]oxazin-4-one 45e (330 mg, 1.2 mmol) and 5-(2-methanesulfonylethylaminomethyl)furan-2-boronic acid (280 mg, 1.2 mmol). The title compound 2-{5-[(2-methanesulfonyl-ethylamino)methyl]-furan-2-yl}-3-methyl-1,5-dihydro-P is obtained as the title compound [2, 3-d] pyridazine _4-ketone 59a (162 mg, white solid). Yield: 57.8%.

MS m/z (ESI): 351[M+ 1] Step 2

[3-Chloro-4-(3-fluorobenzyloxy)-phenyl]-(2-{5-[(2-methanesulfonylethylamino)-methyl]-furan-2-yl}-3- Methyl-1H-pyrrolo[2,3-d]pyridazin-4-yl)-amine

In the same manner as described in the third and fourth steps of Example 1 of the present invention, the compound 2-{5-[(2-methanesulfonyl-ethylamino)methyl]-furan-2 obtained in the above fifth step was used. -yl}-3-methyl-1,5-dihydro-pyrrolo[2,3-d]pyridazin-4-one 59a as a starting material to give [3-chloro-4-(3-fluorobenzyloxy) -Phenyl]-(2-{5-[(2-methanesulfonylethylamino)-methyl]-furan-2-ylbu 3-methyl-1H-pyrrolo[2,3-d]哒Pyrazin-4-yl)-amine 59 (15 mg, white solid). The yield was 44.1%.

MS m/z (ESI): 585 [M+ 1] '

¹ H NMR (400 MHz, DMSO-): 58.02 (s, 1H), 7.87 (s, 1H), 7.49 (m, 2H), 7.30 (d, 2H), 7.20 (m, 2H), 7.15 (m, 2H) , 6.87(d, 2H, J=3.2Hz), 6.51(d, 1H, J=3.2Hz), 5.22(s, 2H), 3.83(s, 2H), 3.28(q, 2H, J=6.8Hz) , 3.02(s, 3H), 2.97(d, 2H), 2.64(s, 3H). Biological Evaluation Example 1: Determination of VEGF-R2 Kinase Activity

In this experiment, the in vitro kinase activity of recombinant human VEGF-R2 protein was determined by enzyme-linked immunosorbent assay (ELISA). Materials and reagents - a. Wash buffer (PBS-T buffer): lx PBS (137 mM NaCl, 2.7 mM KCK 4.3 mM Na ₂ HP0 ₄ 1.4 mM KH ₂ P0 ₄ , adjusted to pH 7.2) and 0.05% Tween-20

b. 1% bovine serum albumin (BSA, Calbiochem #136593) PBS-T buffer

c. Stop reaction buffer: 50 mM EDTA, pH 8.0

d. DELFIA® 铕 labeled anti-mouse IgG (PerkinElmer Life Sciences #AD0124)

e. DELFIA® Signal Multiplier (PerkinElmer Life Sciences #1244-105)

f. DELFIA® Streptavidin 96-well yellow plate (PerkinElmer Life Sciences #AAAND-0005) g. Recombinant human VEGF-R2 kinase (50 mM Tris-HCl (pH 8.0), 100 mM NaCl, 5 mM DTT, 15 mM glutamyl Cysteinyl glycine and 20% glycerol (Cell signaling technology #7787) h. lO mM ATP solution (Cell signaling technology #9804)

i. Biotin-Gastrin Precursor (Tyr87) Peptide (Cell signaling technology #1310) j. Phospho-Tyrosine Mouse mAb (P-Tyr-100) (Cell signaling technology #9411) k. HTScanTM Tyrosine Kinase Buffer (4x )

Lx kinase buffer -

60 mM HEPES

5 mM MgCl ₂

5 mM MnCl ₂

3 μΜ Ν ₃ νθ

(Cell signaling technology #9805)

1. 1.25 M DTT (lOOOOx) (Cell signaling technology)

Program:

Experiment with the following scenario:

1. Dilute the test compound to the desired final concentration in DMSO, adding 1 μΐ of the test compound, one negative control, and a blank control in each test (all do not accept any test compound);

2. Dilute 6 μΜ substrate protein (Tyr87) with dH ₂ 01:1 and add 15 μM to each test;

3. Transfer the VEGF-R2 enzyme from -80. C is directly transferred to ice, and the enzyme is thawed on ice;

4. Take 2.2 g of VEGF-R2 enzyme into each test;

5. Add 10 μΐ DTT (1.25 M) to 2.5 ml 4x HTScanTM tyrosine kinase buffer (240 mM HEPES pH 7.5, 20 mM MgCI ₂ , 20 mM MnCI ₂ , 12 μΜ Na ₃ V0 ₄ ). DTT/kinase buffer;

6. Transfer 0.75 ml DTT/kinase buffer to each of each test to prepare a 4x reaction mixture and add 7.5 μL of reaction solution to each test;

7. Add 2 μl ΑΤΡ (10 ηιΜ) to 498 μ1 άΗ ₂ 0 and add 7.5 μΐ to each test; The final test conditions for the 30 μΐ reaction are:

60 mM HEPES pH 7.5

5 mM MgCl ₂

5 mM MnCl ₂

1.25 mM DTT

10 μΜΑΤΡ

I.5 μΜ polypeptide substrate

22 ng VEGF-R2 kinase

8. Incubate the reaction tube for 30 minutes at 25 °C;

9. Stop the reaction by adding 30 μΐ reaction stop buffer (50 mM EDTA, pH 8.0) to each *| test.

10. Add 25 μM reaction solution and 75 μΐ dH ₂ 0 to each well of a 96-well streptavidin coated plate, and shake at room temperature for 60 minutes;

II. Wash each well with 20 (^1 PBS-T buffer 3 times, tap on a paper towel to remove the remaining liquid;

12. Dilute the primary antibody Phospho-tyrosine mAb (P-Tyr-100) with 1% bovine serum albumin PBS-T buffer 1:1000 and add 100 μM diluted p-Tyr-100 antibody to each well. ;

13. Incubate for 60 minutes at room temperature;

14. Wash as described in step 11;

15. Dilute the labeled anti-mouse IgG with 1:500 in 1% bovine serum albumin PBS-T buffer and add 100 μl of diluted antibody to each well;

16. Incubate for 30 minutes at room temperature;

17. Wash each well 5 times with PBS-T buffer 200 μM and pat on a paper towel to remove any remaining liquid;

18. Add 100 DELFIA® signal multiplier to each well;

19. Incubate for 5 minutes at room temperature;

20. At a wavelength of 615 nm, read the fluorescence intensity with a suitable time-resolving pull reader.

Calculate the inhibition ratio: IR (%) =100- 100*(X-B)/ (N-B)

X = absorbance of test compound

N=yang's control

B=blank

The IC ₅₀ value is calculated from the IR values at a range of concentration concentrations of the test compound. Activity of the compounds of the invention

The biochemical activity of the compounds of the present invention was determined by the above test, and the measured IC ₅ o values are shown in the following table. Example No. IC ₅₀ (VEGFR/bio) M)

31 >1

32 0.52

43 >1

44 >1

45 >1

46 >1

57 >1 case 2 inhibition cell proliferation test

The following in vitro assays were used to determine the proliferative activity of the compounds of the invention against cell lines with high expression of human tumor cell A431 EGFR.

The in vitro cell assay described below can determine the anti-angiogenic activity and the proliferative activity of the test compound against EGFR-expressing tumor cells, the activity of which can be expressed by the IC _5D value. The general protocol for such an experiment is as follows: first select human tumor cells with high expression of EGFR, inoculate them in 96-well culture plates at a suitable cell concentration (exp 5000 cells/ml medium), and then culture the cells in a carbon dioxide incubator. When they grow to 85% confluence, the medium is changed to a medium containing a series of concentration (usually 6 to 7 concentrations) of the test compound solution, and the plate is returned to the incubator for 72 hours. After 72 hours, the test compound was tested for its ability to inhibit cell proliferation using the sulforhodamine B (SRB) method. The IC _5Q value can be calculated from the inhibition values of the test compound for the cells at a range of different concentrations. Materials and Method:

a. dimethyl sulfoxide (Sinophma chemical reagent company, catalogue T20050806) b. A431 cells in the Institute of biochemistry and cell biology)

c. Falcon 100 mm Cell Culture Plate (Baton Dickison Labware, Baton Dickison and company, Catalog No. 18677)

d. Corning 96-well culture plate (Corning Incorporated, catalogue 3599)

e. Fisher pipette (Fisher scientific, catalogue 03-692-164)

f. DMEM/F12 cell culture medium (Gibco, catalog 12400-024)

g. Australian fetal bovine serum (Gibco, catalogue 10099-141)

h. Phosphate buffered saline (Gibco, catalogue 10010-072)

i. 0.25 % insulin - EDTA (Gibco, catalog 25200-056)

j. Sulforhodamine B (Sigma, Table of Contents 3520-42-1)

k. Acetic acid (Sinophma chemical reagent company, catalog T20060508) 1. Trichloroacetic acid (Sinophma chemical reagent company, catalogue T20060305) m. Tris base (Amresco, catalog No. 0826)

n. II · Grade A/B3 Biological Safety Work Cabinet (ThermoForma Catalogue. HB005 ³ _03)

0. Series II water jacketed carbon dioxide incubator (ThermoForma model: 3111)

p. Centrifuge (Fisher Scientific Marathon 8 k, Catalogue 0027-02)

q. Novastar Board Reader (BMG Labtech, Catalog 700-00S1)

r. Orbital shaker (Qilinbeier, catalog TS-1)

The following test program to test the compounds of the invention for inhibition of A431 cell proliferation IC _5C value.

1. A431 cells were cultured in a 100 mm corning plate in a growth medium (DMEM/F12 + 10% fetal bovine serum as a medium) (37 ° C, 5 % C0 ₂ ) until the cells were fully confluent;

2. Wash A431 cells with fetal bovine serum in a 100 mm plate, digest the cells with Tyrpsin, and inoculate the cells on a comping 96-well cell culture plate at a concentration of 50000 cells/ml, 6 wells per plate. As a control well.

3. Incubate the cells in 96-well plates at 37 ° C, 5 % C0 ₂ until approximately 85% confluence is reached;

4. Dissolve the test compound in DMSO, dispose the 20 mM mother liquor, and dilute the mother liquor with DMSO to obtain a series of solutions of the test compound, ie 2 mM, 1 mM, 0.2 mM, 20 μΜ, 2 μΜ, 0.2 μΜ;

5. Dilute the compound solution configured above using cell culture medium (DMEM/F12 +10% fetal bovine serum as the culture medium). Each DMSO series concentration compound solution was diluted 20 times, and 5 μl DMSO compound solution and 95 μl culture solution were added to the cell culture medium each time to ensure that the concentration of A431 cells exposed to DMSO solution did not exceed 0.5%, and vortexed;

6. When the A431 cells adhered to the 85% confluence, the medium was changed to a new medium supplemented with DMEM/F12 +10% fetal bovine serum, and 180 μl of the medium and 20 μM were added to each well. The test compound solution prepared in the fifth step. In the negative control cell group, 20 μl of the culture medium containing 0.5% DMSO was added, so that the final concentration of A431 cells exposed to the test compound solution was 100 μΜ, 10 μΜ, 5 μΜ, 1 μΜ, 0.1 μΜ, 0.01 μΜ, and 0.001. Μ

7. Place the culture plate in an incubator and continue to culture for 72 hours at 37 °C, 5 % C0 ₂ ;

8. After 72 hours, transfer the plate from the incubator to the sterile studio;

9. Add reagent grade pure water to TCA to prepare fixative (50% trichloroacetic acid -TCA), and slowly layer the cells in 50 μL cold TCA solution;

10. Incubate for 1 hour at 4 ,, and then wash several times with water to remove TCA, serum protein, and the like. The plate is dried in air and stored for later use. The blank background optical density value is determined by incubating the culture in a medium without cell growth.

11. Prepare 0.4% Sulforhodamine B solution in 10% acetic acid solution and add 50 μΐ to each well. Sulforhodamine B solution;

12. Cell staining for 30 minutes;

13. Prepare a 10% acetic acid wash solution. When the coloring is about to be completed, the coloring agent is discarded and the cells are quickly rinsed with a 10% acetic acid solution. The above operation is repeated until the coloring agent is washed, and the number of rinsing is minimized to reduce the desorption of the protein-bound coloring agent. After the rinsing is completed, the plate is dried in the air;

14. The mixed colorant is dissolved in a volume of Sulforhodamine B. The solubilizing solution (10 mM Tris) is the same as the original volume of the medium. The plate is allowed to stand at room temperature for 5 minutes, and the mixture is slowly stirred with a shaker to accelerate the mixing with the dye. ;

15. Using a spectrophotometric measurement, read the absorbance at a wavelength of 565 nm. The absorbance values are the absorbance at 565 nm minus the background absorbance at 96 nm for 690 nm;

16. Calculate the inhibition ratio using the following method: '

IR= ιοοχ (absorbance value of the control group - absorbance value of the drug group) / absorbance value of the control group %.

The IC ₅₀ value can be calculated from the ratio of compound inhibition rates at different concentrations. Activity of the compounds of the invention

The biochemical activity of the compound of the present invention is determined by the above test.

Example No. IC ₅₀ (EGFR/A431)^M)

8 0.14

9 11.22

10 1.16

11 5.81

12 18.79

14 11.44

15 1.74

16 6.68

17 3.38

18 0.25

19 0.98

21 8.10

22 5.26

23 9.9

24 . 0.87

26 1.62

27 11.02 28 0.22

29 0.23

30 12.02

31 1.6

32 0.54

33 1.92

34 16.15

35 8.05

36 6.78

39 9.91

40 5.34

42 3.01

43 4.44

45 0.77

46 0.48

52 8.42

55 1.21

56 11.71

EXAMPLE 3: Determination of EGFR kinase activity

In vitro EGFR kinase activity was tested by the following method. Materials and reagents - a. Wash buffer (PBS-T buffer): lx PBS (137 mM NaCl, 2.7 mM KCl, 4.3 mM Na ₂ HP0 ₄ , 1.4 mM KH ₂ P0 ₄ , adjusted to pH 7.2) and 0.05% Tween-20

b. 1% bovine serum albumin (BSA, Calbiochem #136593) PBS-T buffer

c. Reaction stop buffer: 50 mM EDTA, pH 8.0.

d. DELFIA® 铕 labeled anti-mouse IgG (PerkinElmer Life Sciences #AD0124)

e. DELFIA® Signal Multiplier (PerkinElmer Life Sciences #1244-105)

f. DELFIA® Streptavidin 96-well yellow plate (PerkinElmer Life Sciences #AAAND-0005) g. EGFR kinase (50 mM Tris-HCl (pH 8.0), 100 mM NaCl, 5 mM DTT, 15 mM glutamylcysteinylglycine And 20 ° /. Glycerin, Cell signaling technology #7908)

h. 10 mM ATP solution (Cell signaling technology #9804).

i. PTPIB (Tyr66) biotinylated protein (Cell signaling technology #1325).

j, Phospho-tyrosine mouse mAb (P-Tyr-100) (Cell signaling technology #9411)· k. HTScanTM Tyrosine Kinase Buffer (1⁄2)

l Kinase Buffer -

60 mM HEPES

5 mM MgCl ₂

5 mM MnCl ₂

(Cell signaling technology #9805).

1. 1.25 M DTT (lOOOOx) (Cell signaling technology).

Use the following scenario to test:

1. Dilute the test compound to the final concentration with DMSO;

1 μΐ of test compound, negative control and blank control (no test compound was accepted) were added to each test, and only 1 l of DMSO was added;

2. dH ₂ 01: l diluted 6 μΜ substrate proteins (Tyr589), and added to 15 μΐ each test;

3. Transfer the enzyme directly from -80 ° C to ice, and EGFR enzyme is thawed on ice;

4. Take 3 EGFR enzymes into each test;

6. Transfer 0.75 ml DTT/kinase buffer to each of each test to prepare a 4x reaction mixture and add 7.5 μΐ 4χ reaction solution to each test;

7. Add 2 μΙ ΑΤΡ (10 mM) to 496 μΐ d3⁄40 and add 7.5 μΐ to each test; 30 μΐ reaction The final test conditions are:

60 mM HEPES pH 7.5

5 mM MgCl ₂

5 mM MnCl ₂

3 μΜ Ν ₃ νθ ₄

1.25 mM DTT

20 μΜΑΤΡ

1.5 μΜ peptide substrate

30 ng EGFR kinase

8. Incubate the reaction tube for 45 minutes at 25 °C;

9. Stop the reaction by adding 30 μl of Stop Reaction Buffer (50 mM EDTA, pH 8.0) to each test;

10. Add 25 μM reaction solution and 75 μΐ d3⁄40 to each well of a 96-well streptavidin-coated plate. Warm down and shake for 60 minutes;

11. Wash each well 3 times with 200 μΐ PBS-T buffer and pat on a paper towel to remove the remaining liquid;

12. Dilute the antibody Phospho-tyrosine mAb (P-Tyr-100) with 1% bovine serum albumin in PBS-T buffer 1:1000, and add 100 μM diluted antibody to each well;

13. Incubate for 60 minutes at room temperature with shaking;

14. Wash as described in step 11;

15. Dilute the anti-mouse IgG with 1:5% dilution of 1% bovine serum albumin in PBS-T buffer and add 100 μl of diluted antibody to each well;

16. Incubate for 30 minutes at room temperature with shaking;

18. Add 100 DELFIA® signal multiplier to each well;

19. Incubate for 5 minutes at room temperature with shaking;

20. At 615 nm, read the fluorescence intensity with a suitable time-resolving plate reader. .

Calculate the inhibition ratio: IR (%) =100- 100*(X-B)/ (N-B)

X = fluorescence value of test compound

N-negative control

B=blank

The IC ₅₀ value can be calculated from the ratio of inhibition rates at different concentrations of the test compound. Activity of the compounds of the invention

The biochemical activity of the compounds of the present invention was determined by the above test, and the measured IC50 values are shown in the following table.

Example No. ICso (EGF 谨 ο) (μΜ)

8 0.78

10 1.28

20 2.53

Claims

Claim

A compound represented by the general formulae (1), (Π) and (III) or a salt thereof:

among them-

X is selected from W(CH ₂ ), (CH ₂ )W or W, wherein W is 0, S, SO, S0 _{2 ;} or -NR ₈ , wherein is a hydrogen atom or an alkyl group;

When X is -NR ₈ and R ₈ is a fluorenyl group, then R _s may form a 4 to 8 membered heterocyclic group with Rj; wherein the 5 to 8 membered heterocyclic ring contains one or more N, 0, S atoms, And a 4 to 8 membered heterocyclic ring further substituted with one or more fluorenyl, halogen, aryl, heteroaryl, haloalkyl, haloalkoxy, hydroxy, amide, aminyl, cyano, decyloxy , aryloxy, aminoalkyl, hydroxyalkyl, heterocycloalkyl, carboxylic acid, carboxylic acid ester or substituted with -R ₅ R6;

Selected from hydrogen atom, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl, wherein alkyl, cyclodecyl, heterocycloalkyl, aryl, hetero Aryl, arylalkyl or heteroaryl fluorenyl is further protected by one or more alkyl, aryl, aryl, hydroxy, amino, alkynyl, alkenyl, hydroxyalkyl, alkylamino, N-homoyl, N , N-2 (alkyl formyl), cyano, nitro, trifluoromethyl, halobenzyl, heterocycloalkyl, carboxylic acid or carboxylic acid ester substituted; wherein aryl, heteroaryl, aromatic A fluorenyl or heteroarylalkyl group is bicyclic, wherein the bicyclic ring may be further substituted by a benzyl or halobenzyl group; or a structural formula: ^Τ

among them-

The hydrazine is selected from the group consisting of aryl, heteroaryl, aralkyl or heteroaryl, wherein the aryl, heteroaryl, arylalkyl or heteroaryl group may be further substituted by one or more alkyl, aryl, aryl, Hydroxy, amino, alkynyl, alkenyl, hydroxymethyl, hydrazino, N-alkylformyl, N,N-2 (alkyl), cyano, nitro, trifluoromethyl, halobenzyl Substituted by a heterocycloalkyl group, a carboxylic acid or a carboxylic acid ester; wherein the aryl, heteroaryl, aralkyl or heteroaryl group is bicyclic, wherein the bicyclic ring may be further substituted by a benzyl or halobenzyl group. Replace

T is selected from: -0(C3⁄4)r-, -N(C3⁄4)r- or -S(C3⁄4)r;

L is selected from the group consisting of: fluorenyl, aryl, heteroaryl, haloaryl; R _{2 is} selected from the group consisting of a hydrogen atom, a fluorenyl group, a trifluoromethyl group, a cyclodecyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an aryl fluorenyl group or a heteroaryl fluorenyl group, wherein a fluorenyl group, a cycloalkyl group, a heterocyclic group Alkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl further substituted by one or more alkyl, halo, aryl, hydroxy, amide, aminyl, alkoxy, aryloxy, heterocycle Substituted by an alkyl group, a carboxylic acid, a carboxylic acid ester or -NR ₅ ;

Selected from hydrogen atom, fluorenyl, aryl, heteroaryl, heteroaryloxy, -C(=0)R ₇ , -C(=S)R ₇ ,

-(CH ₂ ) _n O(CS)R ₇ , -(CH ₂ ) _n R ₇ , -(CH ₂ CH ₂ 0) _n R ₈ ; wherein aryl, heteroaryl, heteroaryloxy, -(CH ₂ ) _n R _{7 is} further substituted by one or more alkyl groups, -(C3⁄4) _n R ₇ , =C(0), halogen, trifluoromethyl, carboxylic acid or carboxylic acid ester;

R4 is selected from the group consisting of a hydrogen atom, a fluorenyl group, a cycloalkyl group, a heterocyclic fluorenyl group, -(CH ₂ CH ₂ 0) _n R ₈ , an alkenyl group or an alkynyl group, wherein an alkyl group, a cycloalkyl group, a heterocyclic fluorenyl group, an alkene group Or alkynyl is further substituted by one or more thiol, hydroxy, alkoxy, cyano, -NRsRe, carboxylic acid or carboxylic acid ester;

R ₅ and each independently selected from the group consisting of a hydrogen atom, a fluorenyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group or a heteroarylalkyl group, wherein an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, and a heterocyclic group Aryl or heteroaryl fluorenyl is further substituted by one or more alkyl, halo, aryl, hydroxy, amino, decylamino, amide, aminyl, cyano, decyloxy, aryloxy, aminalkyl, a hydroxyalkyl group, a carboxylic acid, a carboxylic acid ester or a _-5 substituent;

Meanwhile, R ₅ and together form a 4 to 8 membered heterocyclic group; wherein the 5 to 8 membered heterocyclic ring contains one or more N, 0, S atoms, and the 4 to 8 membered heterocyclic ring is further subjected to one or more Alkyl, halogen, aryl, heteroaryl, haloalkyl, methoxy, hydroxy, amide, aminyl, cyano, graftoxy, aryloxy, amidino, hydroxyalkyl, a heterocycloalkyl group, a carboxylic acid, a carboxylic acid ester, -(CH ₂ ) _n R ₇ or -NR ₅ substituted;

R _{7 is} selected from the group consisting of hydroxy, decyloxy, aryloxy, heterocycloalkoxy, aryloxy, -N(R ₈ )(CH ₂ ) _n R ₉ , - R ₈ [CH ₂ CH ₂ 0] _n R ₈ , -NR5R6 or -N3⁄4(C3⁄4) _n [CH(OH)CH ₂ ] _r Z (wherein Z is aryl, heteroaryl, heterocycloalkyl, ₅ , 00 or .0>3⁄4 ₅ ) _;

Selected from a hydrogen atom or a sulfhydryl group;

R _{9 is} selected from -NR ₅ , hydroxy, aryl, heteroaryl, decyloxy, -S(0) ₂ C3⁄4, -0[CH ₂ CH ₂ 0] _r R ₈ , -!^(0 )1 ₅ , -N(OH)R ₅ , -NHC(O)R _]0 3⁄4 -COR ₁₀ , wherein R _w is fluorenyl, haloalkyl or aryl;

R ₁₍₎ is a fluorenyl group, a halogenated fluorenyl group or an aralkyl group

n is. ~ 6;

r is Bu 2.

The compound according to claim 1 or a salt thereof, wherein the compound is a compound represented by the general formula (I):

among them-

X is selected from W(CH ₂ ), (CH ₂ )W or W, wherein W is 0, S, SO, S0 ₂ ; or - R ₈ , wherein R ₈ is a hydrogen atom or an alkyl group;

When X is -N and R ₈ is a fluorenyl group, a 4 to 8 membered heterocyclic group may be formed; wherein the 5 to 8 membered heterocyclic ring contains one or more N, 0, S atoms, and 4 to 8 a heterocyclic ring having one or more alkyl groups, halogen, aryl, heteroaryl, haloalkyl, haloalkoxy, hydroxy, amide, aminyl, cyano, decyloxy, aryloxy , aminyl, hydroxyalkyl, heterocycloalkyl, carboxylic acid, carboxylic acid ester or substituted with -R ₅ R6;

Selected from hydrogen atom, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, wherein alkyl, cycloalkyl, heterocycloalkyl, aryl, hetero Aryl, arylalkyl or heteroaryl is further substituted by one or more alkyl, halo, aryl, hydroxy, amino, alkynyl, alkenyl, hydroxyalkyl, alkylamino, N-heteroyl, N , N-2 (n-ylformyl), cyano, nitro, trifluoromethyl, benzyl, heterocycloalkyl, carboxylic acid or carboxylic acid ester substituted; wherein aryl, heteroaryl, aralkyl Or a heteroarylalkyl group which is bicyclic, wherein the bicyclic ring may be further substituted by a benzyl or halobenzyl group; or Ri is a structural formula: Z ^

among them: '

A is selected from aryl, heteroaryl, arylalkyl or heteroarylalkyl, wherein the aryl, heteroaryl, aralkyl or heteroarylalkyl group may be further protected by one or more sulfhydryl groups, halogens, aryl groups, Hydroxy, amino, alkynyl, alkenyl, hydroxyalkyl, decylamino, N-alkylformyl, N,N-2(alkylformyl), cyano, nitro, trifluoromethyl, halobenzyl Substituted by a heterocyclic fluorenyl group, a decanoic acid or a carboxylic acid ester; wherein the aryl group, the heteroaryl group, the aralkyl group or the heteroarylalkyl group is bicyclic, wherein the bicyclic ring may be further substituted by a benzyl or halobenzyl group. Replace

T is selected from: -0(CH ₂ )r -, -N(C3⁄4)r- or -S(CH ₂ )r-;

L is selected from the group consisting of: an alkyl group, an aryl group, a heteroaryl group, an it-substituted aryl group;

Selected from hydrogen atom, fluorenyl, trifluoromethyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl or heteroaryl, wherein fluorenyl, cycloalkyl, heterocycloalkyl , aryl, heteroaryl, aralkyl or heteroarylalkyl further substituted by one or more fluorenyl, aryl, aryl, hydroxy, amide, aminyl, alkoxy, aryloxy, heterocycloalkyl , carboxylic acid, carboxylic acid ester or -^! ^! Replaced by ^;

R _{3 is} selected from the group consisting of a hydrogen atom, an alkyl group, an aryl group, a heteroaryl group, a heteroaryloxy group, -C(=0)R ₇ , -C(-S)R ₇ , -NC(=0)R ₇ , (CH ₂ ) _n O(C=0)R ₇ , -(CH ₂ ) _n O(C=S)R ₇ , -(C3⁄4) _n R ₇ , -(CH ₂ CH ₂ 0) _n R ₈ Wherein aryl, heteroaryl, heteroaryloxy, -(C3⁄4) _n R _{7 is} further protected by one or more fluorenyl groups, -(C3⁄4) _n R ₇ , =C(0), halogen, trifluoromethyl, Substituted by a carboxylic acid or a carboxylic acid ester;

Selected from hydrogen atom, alkyl, cycloalkyl, heterocycloalkyl, -(CH ₂ CH ₂ 0) _n R ₈ , alkenyl or alkynyl, wherein alkyl, cycloalkyl, heterocycloalkyl, alkenyl Or an alkynyl group is further substituted by one or more mercapto, hydroxy, alkoxy, cyano, ruthenium, carboxylic acid or carboxylic acid;

R ₅ and each independently selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group or a heteroarylalkyl group, wherein alkyl, cyclodecyl, heterocycloalkyl, aryl, hetero An aryl or heteroarylalkyl group further substituted by one or more fluorenyl, halogen, aryl, hydroxy, amino, alkylamino, amide, aminyl, cyano, alkoxy, aryloxy, alkoxyalkyl, a hydroxyalkyl group, a carboxylic acid, a carboxylic acid ester or a _-5 substituent;

At the same time, a 4-8 membered heterocyclic group is formed together; wherein the 5 to 8 membered heterocyclic ring contains one or more N, 0, S atoms, and the 4 to 8 membered heterocyclic ring is further subjected to one or more Halogen, aryl, heteroaryl, haloalkyl, halomethoxy, hydroxy, amide, aminyl, cyano, hexyloxy, aryloxy, alkoxyalkyl, hydroxyalkyl, hetero embankment cycloalkyl group, a carboxylic acid, _{_{carboxylate, - (CH 2) n R}} 7 or -NR ₅ substituted;

R _{7 is} selected from the group consisting of hydroxy, alkoxy, aryloxy, heterocyclomethoxy, aryloxy, -N(R ₈ )(CH ₂ ) _n R ₉ , -N ₈ [CH ₂ CH ₂ 0] _n R ₈ , -NR ₅ or -NR _s (CH2) _n [CH(OH)CH ₂ ] _r Z, wherein Z is aryl, heteroaryl, heterocycloalkyl, -Ν, 003⁄4 or. 01^ _{5 ;}

Selected from a hydrogen atom or a sulfhydryl group;

R _{9 is} selected from -3⁄4 , hydroxy, aryl, heteroaryl, alkoxy, -S(0) ₂ CH ₃ , -O[CH ₂ CH ₂ 0] _r R ₈ , -N^CORsR^ -N( OH)R ₅ , —NHC(0)R ₁₍₎ or — COR ₁₍₎ , wherein R ₁₍₎ is an indenyl group, a haloalkyl group or an aryl group;

ο is 'yl, haloalkyl or aralkyl

n is 0~6;

r is 1 to 2.

The compound according to claim 1 or a salt thereof, wherein the compound is a compound represented by the formula (Π):

among them:

X is selected from W(C3⁄4), (CH ₂ )W or W, wherein W is 0, S, SO, S0 _2; or -NR ₈ , wherein Is a hydrogen atom or a burnt group;

When X is -N and R ₈ is a fluorenyl group, a 4 to 8 membered heterocyclic group may be formed; wherein the 5 to 8 membered heterocyclic ring contains one or more N, 0, S atoms, and 4 to 8 a heterocyclic ring having one or more alkyl groups, halogen, aryl, heteroaryl, haloalkyl, haloalkoxy, hydroxy, amide, aminyl, cyano, alkoxy, aryloxy, amine An alkyl group, a hydroxyalkyl group, a heterocycloalkyl group, a carboxylic acid, a carboxylic acid ester or a hydrazine;

Selected from hydrogen atom, alkyl, cyclodecyl, heterocycloalkyl, aryl, heteroaryl, aralkyl or heteroaryl, wherein alkyl, cyclodecyl, heterocycloalkyl, aryl, hetero Aryl, aralkyl or heteroaryl fluorenyl is further substituted by one or more alkyl, halogen, aryl, hydroxy, amino, alkynyl, alkenyl, hydroxyalkyl, decylamino, fluorenyl-alkylformyl, hydrazine , Ν-2(fluorenyl), cyano, nitro, trifluoromethyl, halobenzyl, heterocycloalkyl, carboxylic acid or carboxylic acid ester substituted; wherein aryl, heteroaryl, aromatic An alkyl or heteroaryl fluorenyl group which is bicyclic, wherein the bicyclic ring may be further substituted by a benzyl or halobenzyl group; or a structural formula: ζ ^

among them-

The hydrazine is selected from the group consisting of aryl, heteroaryl, aralkyl or heteroarylalkyl, wherein the aryl, heteroaryl, arylalkyl or heteroarylalkyl group may be further protected by one or more fluorenyl groups, halogens, aryl groups, Hydroxy, amino, alkynyl, alkenyl, hydroxyalkyl, alkylamino, N-alkyl formyl, N, N-2 (heteroyl), cyano, nitro, trifluoromethyl, halogenated Substituted by a heterocyclic fluorenyl group, a carboxylic acid or a carboxylic acid ester; wherein the aryl group, the heteroaryl group, the aryl fluorenyl group or the heteroaryl fluorenyl group is bicyclic, and the ¹ Φ bicyclic ring may be further substituted by a benzyl group or a halogenated benzyl group. Substituted by

T is selected from: -0(CH ₂ )r -, -N(C3⁄4)r- or -S(C3⁄4)r-;

L is selected from the group consisting of: an alkyl group, an aryl group, a heteroaryl group, a halogenated aryl group;

R _{2 is} selected from the group consisting of a hydrogen atom, an alkyl group, a trifluoromethyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an arylsulfonyl group or a heteroarylalkyl group, wherein an alkyl group, a cyclodecyl group, a heterocyclic ring Alkyl, aryl, heteroaryl, arylalkyl or heteroaryl is further substituted by one or more alkyl, halo, aryl, hydroxy, amide, aminyl: decyloxy, aryloxy, heterocyclic Substituted by an alkyl group, a carboxylic acid, a carboxylic acid ester or -NR ₅ ;

R _{3 is} selected from the group consisting of a hydrogen atom, a fluorenyl group, an aryl group, a heteroaryl group, a heteroaryloxy group, -C(=0)R ₇ , -C(=S)R ₇ , -NC(=0)R ₇ , (CH ₂ ) _n O(C=0)R ₇ , -(CH ₂ ) _n O(C=S)R ₇ ', -(CH ₂ ) _n R ₇ , -(CH ₂ CH ₂ 0) „ ₈ ; Wherein aryl, heteroaryl, heteroaryloxy, -(CH ₂ ) _n R _{7 is} further substituted by one or more alkyl groups, -(CH ₂ ) _n R ₇ , =C(0), halogen, trifluoromethyl Substituted by a carboxylic acid or a carboxylic acid ester;

R4 is selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, -(CH ₂ CH ₂ 0) _n R ₈ , an alkenyl group or an alkynyl group, wherein an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an alkene group Or alkynyl is further substituted by one or more alkyl, hydroxy, alkoxy, cyano, ₅ R6, carboxylic acid or carboxylic acid esters;

And each selected from the group consisting of a hydrogen atom, a fluorenyl group, a cyclodecyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group or a heteroarylalkyl group, wherein an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group Or a heteroaryl group further substituted by one or more alkyl, halogen, aryl, hydroxy, amino, alkylamino, amide, aminyl, cyano, alkane Oxyl, aryloxy, aminoalkyl, hydroxyalkyl, carboxylic acid, carboxylic acid ester or ₅ substituted;

Meanwhile, R ₅ and together form a 4 to 8 membered heterocyclic group; wherein the 5 to 8 membered heterocyclic ring contains one or more N, 0, S atoms, and the 4 to 8 membered heterocyclic ring is further subjected to one or more Sulfhydryl, halogen, aryl, heteroaryl, hydrazino, halomethoxy, hydroxy, amide, aminyl, cyano, alkoxy, aryloxy, alkoxy, hydroxyalkyl, Substituted by a heterocyclic fluorenyl group, a carboxylic acid, a carboxylic acid ester, -(CH ₂ ) _n R ₇ or -NR ₅ ;

R _{7 is} selected from the group consisting of hydroxyl, alkoxy, aryloxy, heterocyclomethoxy, aryloxy, -N(R ₈ )(CH ₂ ) _n R ₉ ,

-NR ₈ [CH ₂ CH ₂ 0] _n R ₈ , - ₅ R6 or -N ₈ (CH ₂ ) _n [CH(OH)CH ₂ ] _r Z (wherein Z is an aryl group, a heteroaryl group, a heterocycloalkane Base, -NR ₅ R6, -COOR ₈ or CONRsRe);

R _{8 is} selected from a hydrogen atom or an alkyl group; '

R _{9 is} selected from -NR ₅ , hydroxy, aryl, heteroaryl, alkoxy, -S(0) ₂ CH ₃ , -O[C3⁄4CH ₂ 0] _r R _g ,

Or -COR ₁₍₎ , wherein R ₁₀ is alkyl, haloalkyl or aryl I

Rio is an alkyl group, a halogenated fluorenyl group or an aralkyl group.

n is 0~6;

r is 1 to 2.

The compound or a salt thereof according to claim 1, wherein the compound is a compound represented by the formula (III) -

X is selected from W(CH ₂ ), (C3⁄4)W or W, wherein W is 0, S, SO, S0 ₂ ; or -NR ₈ , wherein R ₈ is a hydrogen atom or an alkyl group;

When X is -NR ₈ and R ₈ is an alkyl group, a 4 to 8 membered heterocyclic group may be formed; wherein the 5 to 8 membered heterocyclic ring contains one or more N, 0, S atoms, and 4~ The 8-membered heterocyclic ring is further substituted with one or more fluorenyl, aryl, aryl, heteroaryl, hydrazino, halo alkoxy, hydroxy, amide, aminyl, cyano, alkoxy, aryl Oxyl, aminyl, hydroxyalkyl, heterocycloalkyl, carboxylic acid, carboxylic acid ester or -Ν substituted;

Rj is selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an arylsulfonyl group or a heteroarylalkyl group, wherein an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, Heteroaryl, arylalkyl or heteroarylalkyl is further protected by one or more fluorenyl, halogen, aryl, hydroxy, amino, alkynyl, alkenyl, hydroxy, pyridyl, N-alkyl formyl, N,N-2(alkyl formyl), cyano, nitro, trifluoromethyl, halobenzyl, heterocycloalkyl, carboxylic acid or carboxylic acid ester; An aryl, heteroaryl, arylfluorenyl or heteroaryl fluorenyl group which is bicyclic, wherein the bicyclic ring may be further substituted by a benzyl or halobenzyl group; or is a structural formula: z

among them:

The hydrazine is selected from the group consisting of aryl, heteroaryl, aralkyl or heteroaryl, wherein the aryl, heteroaryl, arylalkyl or heteroarylalkyl group may be further substituted by one or more alkyl groups, halogens, aryl groups, Hydroxy, amino, alkynyl, alkenyl, hydroxyalkyl, alkylamino, N-alkylcarbonyl, N,N-2(fluorenyl), cyano, nitro, trifluoromethyl, halobenzyl Substituted by a heterocyclic fluorenyl group, a carboxylic acid or a carboxylic acid ester; wherein the aryl group, the heteroaryl group, the aryl fluorenyl group or the heteroaryl fluorenyl group is bicyclic, wherein the bicyclic ring may be further substituted by a benzyl or halobenzyl group. Replace

T is selected from: -0(CH ₂ )r-, -N(C3⁄4)r- or -S(CH ₂ )r- _;

L is selected from the group consisting of: fluorenyl, aryl, heteroaryl, haloaryl;

Selected from hydrogen atom, alkyl group, trifluoromethyl, cyclodecyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, wherein alkyl, cycloalkyl, heterocyclic , aryl, heteroaryl, aralkyl or heteroarylalkyl further substituted by one or more alkyl, halo, aryl, hydroxy, amide, aminyl, decyloxy, aryloxy, heterocycloalkyl , carboxylic acids, carboxylic acid ester or substituted by -NR ₅ R6;

Selected from hydrogen atom, alkyl group, aryl group, heteroaryl group, heteroaryloxy group, -C( ))R ₇ , -C(=S)R ₇ , -NC(=0)R ₇ , -(CH ₂ _n O(C=0)R ₇ , -(CH ₂ ) _n O(C=S)R ₇ , -(C3⁄4) _n R ₇ , -(CH ₂ CH ₂ 0) _n R _{8 ;} wherein aryl, Heteroaryl, heteroaryloxy, -(CH ₂ ) _n R _{7 is} further protected by one or more fluorenyl groups, -(C3⁄4) _n R ₇ , =C(0), halogen, trifluoromethyl, carboxylic acid or Substituted by a carboxylic acid ester;

R4 is selected from the group consisting of a hydrogen atom, a fluorenyl group, a cycloalkyl group, a heterocyclic fluorenyl group, -(CH ₂ CH ₂ 0) _n R ₈ , an alkenyl group or an alkynyl group, wherein an alkyl group, a cycloalkyl group, a heterocyclic fluorenyl group, an alkene group Or alkynyl is further substituted by one or more alkyl, hydroxy, methoxy, cyano, NR ₅ , carboxylic acid or carboxylic acid esters;

R ₅ and each independently selected from the group consisting of a hydrogen atom, a fluorenyl group, a cyclodecyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group or a heteroarylalkyl group, wherein a fluorenyl group, a cyclodecyl group, a heterocyclic fluorenyl group, an aryl group, a hetero Aryl or heteroaryl fluorenyl is further substituted by one or more alkyl, halo, aryl, hydroxy, amino, decylamino, amide, aminyl, cyano, alkoxy, aryloxy, aminyl, Substituted by a hydroxyalkyl group, a carboxylic acid, a carboxylic acid ester or _-5 ;

Meanwhile, R ₅ and together form a 4 to 8 membered heterocyclic group; wherein the 5 to 8 membered heterocyclic ring contains one or more N, 0, S atoms, and the 4 to 8 membered heterocyclic ring is further subjected to one or more Alkyl, halogen, aryl, heteroaryl, haloalkyl, halomethoxy, hydroxy, amide, aminyl, fluorenyl, alkoxy, aryloxy, alkoxy, hydroxyalkyl , a heterocycloalkyl group, a carboxylic acid, a carboxylic acid ester, substituted with -(CH ₂ ) _n R ₇ or -R ₅ ;

R ₇ is selected from hydroxy, alkoxy, aryloxy, heterocyclic oxy burning, embankment aryloxy _{group, -N (R 8) (CH} 2) n R 9, -NR 8 [CH 2 C¾0] n R 8 , -Ν or -N (C3⁄4) _n [CH(OH)CH ₂ ] _r Z (wherein Z is aryl, heteroaryl, heterocycloalkyl, -NR ₅ R ₆ , -COOR ₈ or CONR ₅ Re) _; R _{8 is} selected from a hydrogen atom or an alkyl group;

R _{9 is} selected from -N R6, hydroxy, aryl, heteroaryl, decyloxy, -S(0) ₂ CH ₃ , -O[CH ₂ CH ₂ 0] _r R ₈ , -N^CORsRs, -N (OH)R ₅ , -NHC(0)R ₁₍₎ or - COR _1Q , wherein R ₁₍₎ is fluorenyl, haloalkyl or

R ₁₀ is a mercapto group, a haloalkyl group or an aralkyl group

n is 0~6;

r is 1 to 2.

The compound according to claim 1 or a salt thereof, wherein X is _-8 and R ₈ is a hydrogen atom or a C,~ fluorenyl group.

The compound according to claim 1 or a salt thereof, wherein R 2 is a hydrogen atom, a methyl group or a trifluoromethyl group.

The compound according to claim 1 or a salt thereof, wherein the compound is selected from the group consisting of:

4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy]-1-(2-methoxy-ethyl)-3-methyl-1Η-pyrrolo[2,3 -d]pyridazine-2-carboxylic acid [2-(4-methyl-piperazine small)-ethyl]-amide

4-[3-chloro-4-(3-fluoro-benzyloxy)-phenoxy]-1-(2-methoxy-ethyl)-3-methyl-m-

>" Pyrrolo[2 3-d]pyridazine-2-carboxylic acid [3-(4-methyl-piperazin-1-yl:)-propyl]-amide

4-[3-chloro-4-(3-fluoro-benzyloxy)-phenoxy]-1-(2-methoxy-ethyl)-3-methyl-1H-pyrrolo[2,3 -d]pyridazine-2-carboxylic acid (2-pyrrolidinyl-ethyl)-amide

4-[3-chloro-4-(3-fluoro-oxy)-phenoxy]min[(2-methoxy-ethoxy)-ethyl]-3-methyl-1H-pyrrolo[ 2 3-d]pyridazine-2-carboxylic acid ethyl ester

?

4-[3-chloro-4-(3-fluoro-benzyloxy)-phenoxy]

,

Small [(2-methoxy-ethoxy)-ethyl]-3-methyl-1H-pyrrole [2,3-d]pyridazine-2-buty. Carboxylic acid (2-diethylamino-ethyl)-amide

4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy] 3⁄46. Small [(2-methoxy-ethoxy)-ethyl]-3-methyl- 1 - (2-morpholin-4-yl-ethyl)-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid ethyl ester

4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy]min[(2-methoxy-ethoxy)-ethyl]-3-trifluoromethyl-1H- Ethyl pyrrolo[2,3-d]pyridazine-2-carboxylate -l-[(2-Methoxy-ethoxy)-ethyl]-3-trifluoromethyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid benzyl ester

4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy]-1-[( ² -methoxy-ethoxy)-ethyl]- ³ -trifluoromethyl- 1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid (2-diethylamino-ethyl)-amide

4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy]-1-[(2-methoxy-ethoxy)-ethyl]-3-trifluoromethyl- 1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid (2-pyrrole-1-yl-ethyl)-amide

-[2-(5-Diethylaminomethyl-furan-2-yl)-3-methyl-1H-pyrrolo[2,3-d]pyridazin-4-yl]amide

[ ³ -Chloro- ⁴ _( ³ -fluoro-benzyloxy)-phenoxy]-[2-(3-diethylaminomethyl-methyl)-3-methyl-1H-pyrrolo[2, 3-d]pyridazin-4-yl]amide

7-[3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy]-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid (2-diethylamino-B -amide

7-[3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy]-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid (2-2-pyrrolidine- 1-yl-ethyl)-amide

7-[3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy]-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid (2-morpholin-4- Base-ethyl)-amide 7-[3-chloro-4-(3-fluoro-benzyloxy)-phenoxy]

50 -1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid (3-morpholin-4-yl-propyl)-amide

7-[3-chloro-4-(3-fluoro-benzyloxy)-phenoxy]

51 -1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid (2-piperidin-1-yl-ethyl)-amide

₇ -[3-chloro-4-(3-fluoro-oxy)-phenoxy]

52 -1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid

[3-(4-Methyl-piperazin-1-yl)-propyl]-amide

7-[3-chloro-4-(3-fluoro-benzyloxy)-phenoxy]

53 -1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid

2-(4-methyl-piperazin-1 -yl)-ethyl]-amide

4-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-indole-

54 methyl-6H-pyrrolo[3,4-d]piperazine-5-carboxylate

[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(5-

55 methyl-6H-pyrrolo[3,4-d]piperazine-1-yl) -

, ethylamine

4-[1-(3-fluorobenzyl)-1Η-carbazole-5-amino]-3-

56-methyl-1H-pyrrolo[2,3-d]pyridazine-2-[(2-pyrrolidin-1-yl)-ethyl]carboxamide

4-[1-(3-fluorobenzyl)-1H-indazole-5-amino]-3-

57-methyl-1H-pyrrolo[2,3-d]pyridazine-2-[(2-morphinolin-4-yl)-ethyl]carboxamide

The compound according to claim 1 or a salt thereof, wherein the salt is a pharmaceutically acceptable salt of a compound with an acid selected from the group consisting of malic acid, lactic acid, maleic acid, hydrochloric acid, methanesulfonic acid , sulfuric acid, phosphoric acid, citric acid, tartaric acid, acetic acid or trifluoroacetic acid.

A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 8, or a salt or prodrug thereof, and a pharmaceutically acceptable carrier or excipient.

10. A process for the preparation of a compound of formula I, which comprises the following steps -

11. A process for the preparation of a compound of formula I, which process comprises the steps of:

12. A process for the preparation of a compound of formula I, which comprises the following steps -

13. A process for the preparation of a compound of formula II, the process comprising the steps of:

EtOOC EtOOC CI

EtOOC EtOOC CHO

POCI. W NH ₂ .NH ₂ .H ₂ Q POCI ₃

N N

EtOOC Fly DMF

N EtOOC C ₂ H ₅ OH CH ₃ CN

14. A process for the preparation of a compound of formula II, the process comprising the steps of:

11-2

15. A process for the preparation of a compound of formula III, the process comprising the steps of:

111-1

A method of modulating the catalytic activity of a protein kinase, which comprises contacting said protein kinase with a compound or salt according to any one of claims 1-8.

17. The method of claim 10, wherein the protein kinase is selected from the group consisting of a receptor tyrosine kinase, a non-receptor tyrosine kinase, or a serine-threonine kinase.

18. A method of treating a mammal having a disease associated with a protein kinase, the method comprising administering to the mammal a therapeutically effective amount of the pharmaceutical composition of claim 9.

19. The method of claim 18, wherein the protein kinase-associated disease is selected from the group consisting of EGFR, HER-2, HER-3, HER-4, PDGFR, VEGFR-2, c-Kit, c-Met, FGFR or Flt3 related diseases.

20. The method of claim 18, wherein the mammal is a human.

The method according to claim 18, wherein the protein kinase-related disease is selected from the group consisting of leukemia, diabetes, autoimmune disease, hyperproliferative disease, psoriasis, osteoarthritis, rheumatoid arthritis, angiogenesis, heart Vascular disease, Von-Heppel-Lindau's disease, inflammation or fibrosis.

The method according to claim 18, wherein the protein kinase-related disease is cancer, selected from the group consisting of squamous cell carcinoma, renal cell carcinoma, Kaposi sarcoma, non-small cell lung cancer, small cell lung cancer, lymphoma, thyroid gland Cancer, breast cancer, head and neck cancer, uterine cancer, esophageal cancer, melanoma, bladder cancer, genitourinary cancer, gastrointestinal cancer, glial cancer, colorectal cancer or ovarian cancer.

23. The method of claim 22, further comprising administering to the patient in need of treatment a therapeutically effective amount of another anti-cancer drug.

24. The method of claim 23, wherein the other anti-cancer drug is selected from the group consisting of taxol or carboplatin.

25. Use of a compound of claim 1 for the manufacture of a medicament for the treatment of a disease associated with a protein kinase.

26. The use according to claim 25, wherein the protein kinase-associated disease is selected from the group consisting of EGFR, HER-2, HER-3, HER-4, PDGFR, VEGFR-2, c-Kit, c-Met, FGFR or Flt3 related diseases.

The use according to claim 25, wherein the protein kinase-related disease is selected from the group consisting of leukemia, diabetes, autoimmune disease, hyperproliferative disease, psoriasis, osteoarthritis, rheumatoid arthritis, angiogenesis, heart Vascular disease, Von-Heppel-Lindau's disease, inflammation or fibrosis.

The use according to claim 25, wherein the protein kinase-related disease is cancer, selected from the group consisting of squamous cell carcinoma, renal cell carcinoma, Kaposi sarcoma, non-small cell lung cancer, small cell lung cancer, lymphoma, thyroid cancer. , breast cancer, head and neck cancer, uterine cancer, esophageal cancer, melanoma, bladder cancer, genitourinary cancer, gastrointestinal cancer, glial cancer, colorectal cancer or ovarian cancer.