WO2007115473A1 - Pyrrole derivatives inhibitors, their curative uses - Google Patents

Abstract

The present application discloses 2-acetamido-3-carbomethoxy-5-(6,7-dihydro- 6-oxo-4-arylamido pyrrolo[2,3-d]pyrimidine –5-)methylene-1H-pyrrole derivatives of general formula (I),processes for their preparation, the pharmaceutical compositions containing them and their uses as therapeutic agents especially as protein kinase inhibitors. The definitions of substituents in formula (I) are the same as description.

Description

 TECHNICAL FIELD The present invention relates to a novel 2-acetamido-3-carbomethoxy-5(6,7-dihydro-6-oxo-4-aryl) Aminopyrrole[2,3-d]pyrimidin-5-ylidene)methyl-1H-pyrrole derivatives, processes for their preparation and pharmaceutical compositions containing them and their use as therapeutic agents, in particular as protein kinase inhibitors use. BACKGROUND OF THE INVENTION Signal transduction of cells is a basic mechanism of action. During signal transduction, extracellular stimuli are transmitted to the interior of cells, thereby regulating the progression of different cells. These signals regulate a variety of physiological responses, including cell proliferation, differentiation, apoptosis, and exercise, which exist as different types of lytic factors, including growth factors that are predominantly paracrine, autocrine, and endocrine. 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 phosphorylating enzymes 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, a cell can become a cancer cell by converting a portion of its DNA into an oncogene, a growth factor receptor protein encoded by such an oncogene; a tyrosine kinase can also be mutated into an activated form resulting in a variety of Human cell variation, 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 (FTKs) 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 are recognized in human genes, of which about 60 are receptor types and about 30 are non-receptive. The growth factor receptor family 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 Sex receptors (IRR); (3) family 111, 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- Related tyrosine kinase 3 (FIt3) receptor tyrosine kinase and colony hedgehog factor 1 receptor (CSF-1R) 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 ScMessinger and Ullrich, Neuron 1992, 9, 383). A portion of the non-limiting kinases include Abl, ARaf, ATK, ATM, bcr-abl, Blk, BRaf, Brk, Btk, CD 1 , CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CD 9, CHK, AuroraA, AuroraB, AviroraC, cfms, c-fms, c-Kit, c-Met, cRafl, CSF1R, CSK, c-Src, EGFR, ErbB2, ErbB3, ErbB4, ERK, ERK1, ERK2, Fak, fes, FGF 1, FGFR2 , FGFR3, FGFR4, FGFR5, Fgr, FLK-4, Fps, Frk, Fyn, GSK, gsk3a, gsk3b, Hck, Chk, Axl, Pim-1, Plh-1, IGF-1, IKK, IKK1, I K2, IKK3, INS- , Integrin-linked kinase, Jal, JAK1, JAK2, JAK3, JNK, JK, Lck, Lyn, MEK, MEK1, MEK2, p38, PDGFR, PIK, PKBl, PKB2, PKB3, PKC, PKCa, PKCb, PKCd, PKCe, PKCg, PKCl, PKCm, PKCz, PLK1, Polo-like kinase, PYK2, tie _l5 tie ₂ , TrlcA, Trl B, TrkC, UL13, UL97, VEGF-R1, VEGF-R2, Yes and Zap70, and the like. PKs are thought to be associated with central nervous system diseases such as Alzheimer's disease (see Mandelkow, EM et al. FEBS L^tt. 1992, 314, 315; Sengupta, A. et al. Mol. Cell. Biochem. 1997, 167, 99) ^ Pain (See Yashpal, . J. Neurosci. 1995, 15, 3263-72), inflammation such as arthritis (see Badger, J. Pharmn Exp. Titer. 1996, 279, 1453), psoriasis (see Dvir, et al., J. Cell) Biol. 1991, 113, 857), bone diseases such as osteoporosis (see Taka 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) Angiogenic diseases such as angiogenesis (see Strawn et al. Cancer Res. 1996, 56, 3540; Jackson et al J Pharm. Exp. Ther. 1998, 284, 687), autoimmune diseases and transplant rejection (see Bolen and Bmgge) , ^ and. Rev. Immunol 1997, 15, 371), infectious diseases such as viruses (see Littler, E. Nature 199) 2,358,160) is closely related to the target of diseases such as fungal infection (see Lum, RT PCT Int Appl., WO 9805335 Al 980212).

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

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 Determined, can be divided into two categories: (1) there is a catalytic zone substrate (2) no catalytic zone substrate, but can be used as a combination, and related to some 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 receptor The difference in binding is consistent with the difference in substrate phosphorylation. Protein tyrosine kinase function can be determined by expression pattern and ligand availability, and can also be determined 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 kinase, 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 broadness and relevance of tyrosine kinases have been further confirmed by detection of human tumor cells. For example, in human cancers including lung cancer, brain cancer, cervical cancer, gastrointestinal cancer, breast cancer, esophageal cancer, ovarian cancer, uterine cancer, bladder cancer, and thyroid cancer, EGFR tyrosine kinase is mutated and overexpressed.

 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 one of the receptors for HER3 is not enzymatically active, heterodimerization of HER2 with HER3, or HER3 and HER4, can also significantly stimulate 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-associated receptor (IRR). IR, IGF-1R interacts with insulin, IGF-I and IGF-II, resulting from two fully extracellular glycosylated alpha subunits and two tyrosine kinase domain beta subunits that cross the cell membrane Heterotetramer.

The third subgroup of RTK refers to the platelet-derived growth factor receptor (PDGFR) family, including PDGFRct, PDGFR, 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. Broken.

 Platelet-derived growth factor receptors such as PDGFRa and PDGFRp are also transmembrane tyrosine kinase receptors. When they are combined with a ligand, either a homodimer (PDGF-AA, PDGF-BB), or a heterodimer (PDGF-AB) is formed. Subsequent receptor dimerization, tyrosine kinase is activated, signaling downstream regions to promote tumor growth. Mutations in genes are responsible for receptors that are not dependent on binding 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, J. Clin. Oncol. 22 (14S), 9642 (2004)]. GIST is a non-epithelial cell tumor, most of which is found 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's sarcoma have c-Kit expression (see Schutte et al" innovartis 3/ 2001). It is well known that RET (rearranged during transfection;). Proto-oncogene point genetic mutation is tumorigenic, patients with multiple endocrine neoplasia 2 (MEN 2) may cause pheochromocytoma, thyroid marrow Diseases such as 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-1R, Flk-4 and fms-like tyrosine kinase 1 CFlt-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, it is a dimeric glycoprotein, but its biological function is different from that of the target cells in vivo. In particular, VEGFR is involved in angiogenesis and inhibits angiogenesis by inhibiting VEGFRs. It is being used in clinical treatment of tumors and has achieved good results. VEGF is strongly expressed in various malignant solid tumors such as lung cancer, breast cancer, non-Hodgkin's malignant lymphoma, ovarian cancer, pancreatic cancer, malignant pleural mesothelioma, and melanoma, and is associated with the progression of cancer, in white blood cells. Excessive symptoms and lymphoma are also expressed. In addition to its angiogenic activity, VEGFR, VEGF ligands can 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 tumors. Under normal circumstances, the formation of new blood vessels is very important in human physiological processes such as embryo growth, wound healing and female reproduction. However, unanticipated or pathological angiogenesis is associated with a range of conditions of the disease, such as diabetic retinopathy, psoriasis, cancer, rheumatoid arthritis, atheroma, Kaposi's sarcoma and hemangioma. Wait. The production of vascular endothelial cells activates angiogenesis and has been shown to stimulate 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 very important stimulator during angiogenesis and vascular infiltration in both normal and pathological conditions. VEGF can induce vascular sprouting phenotype, which induces endothelial cell proliferation, protease expression and migration to promote capillary formation, thereby forming a super-osmotic, immature vascular network, which is a typical characteristic of 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 I11 family, and has leukemia in adult and young children with acute myeloid leukemia (AML:), acute myeloid leukemia, and myelodysplastic syndrome. In many cases, 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 form of receptor expression are less likely to be cured. 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 closely associated with 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 Factor 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 membrane prion protein 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. W. For the PKT subfamily, Plowman et al. are described in more detail in DN & P 7(6): 334-339 (1994), which 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 most, 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 iBolen, 1993, Oncogen 8: 2025-2031, which is hereby incorporated by reference in its entirety in its entirety in its entirety.

 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 prevalent cytosolic kinases, ie, they function in part of the cytoplasm, not in cytoplasmic organelles. The cytosol is a region within the cell where metabolic and biosynthetic activities occur 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 The present invention relates to novel 2-acetamido-3-carbomethoxy-5(6,7-dihydro-6-oxo-4-arylaminopyrrole[2,3-d]pyrimidine-5- Subunit)methyl-1H-pyrrole derivatives, which are represented by the following formula (I):

 among them:

X is selected from W(CH ₂ ), (CH ₂ )W or W, wherein W is 0, S, SO or S0 ₂ ; or X is -NR ₆ , wherein R ₆ is a hydrogen atom or an alkyl group;

 Y is an oxygen atom or a hydrogen atom;

When X is -NR ₆ and R ₆ is an alkyl group, R ₆ may form a 4 to 8 membered heterocyclic group; wherein the 5 to 8 membered heterocyclic ring may contain one or more atoms of ^, 0 or S, And the 4 to 8 membered heterocyclic ring may be further selected from one or more selected from the group consisting of fluorenyl, halogen, aryl, heteroaryl, haloalkyl, haloalkoxy, hydroxy, amino, alkylamino, amide, aminyl, cyanide Substituted by a substituent of a group, an alkoxy group, an aryloxy group, an amine group, a hydroxyalkyl group, a heterocycloalkyl group, a carboxylic acid, a carboxylic acid ester or -NR ₇ R ₈ ;

Selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an arylalkyl group or a heteroaralkyl group, wherein an alkyl group, a cycloalkyl group, a heterocyclic fluorenyl group, an aryl group, or a heterocyclic group The aryl, arylalkyl or heteroarylalkyl group may be further selected from one or more selected from the group consisting of alkyl, halogen, aryl, hydroxy, amino, guanidino, amide, aminyl, alkoxy, aryloxy, hetero Substituted by a cycloalkyl group, a carboxylic acid, a carboxylic acid ester or a substituent of -NR ₇ R ₈ ; wherein the aryl, heteroaryl, arylalkyl or heteroarylalkyl group may be combined into a bicyclic ring;

Selected from hydrogen atom, alkyl group, cycloalkyl group, heterocycloalkyl group, -(CH ₂ CH ₂ 0) _n , alkenyl group or alkynyl group, -COOR ₇ , -CONR ₇ R ₈ , -C(=S)NR ₇ , -COR ₇ , -SOR ₇ , -S0 ₂ R ₇ , -S0 ₂ NR ₇ R ₈ or -P(=0)(OR ₇ )(OR ₈ ), wherein fluorenyl, cycloalkyl, heterocycloalkane a base, alkenyl or alkynyl group may be further substituted with one or more substituents selected from alkyl, hydroxy, alkoxy, cyano, amino, decylamino, carboxylic acid or carboxylic acid esters;

R _{3 is} selected from a hydrogen atom, a fluorenyl group, an aryl group, a halogen-substituted aryl group or a trifluoromethyl group;

Selected from hydroxy, alkoxy, aryloxy, heterocycloalkoxy, aryloxy, -(OCH ₂ CH ₂ ) _n R ₆ , -N(R ₇ )(CH ₂ ) _n R ₈ , -NR ₇ [CH ₂ CH ₂ 0] _n or -NR ₆ (CH ₂ ) _n [CH(OH)CH ₂ ] _r Z , wherein Z is aryl, heteroaryl, heterocycloalkyl, -NR ₇ R ₈ , -COORe or CONH ₇ R _{8 ;}

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

R ₆ is a hydrogen atom or an alkyl group;

R ₇ and R ₈ are each independently selected from a hydrogen atom, an alkyl 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 heterocyclic fluorenyl group Or an aryl, heteroaryl or heteroaryl group may be further substituted by one or more alkyl, halogen, aryl, hydroxy, amino, alkylamino, amide, aminyl Substituted with a cyano group, a cyano group, an alkoxy group, an aryloxy group, an amine alkyl group, a hydroxyalkyl group, a heterocycloalkyl group, a carboxylic acid, a carboxylic acid ester or -NR ₇ R ₈ ;

Meanwhile, R ₇ 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 or S atoms, and the 4 to 8 membered heterocyclic ring may be further subjected to one or a plurality of alkyl, halogen, aryl, heteroaryl, haloalkyl, haloalkoxy, hydroxy, amino, amide, aminyl, cyano, alkoxy, aryloxy, amidino, hydroxyalkyl Substituted by a heterocycloalkyl group, a carboxylic acid, a carboxylic acid ester or -NR ₇ .

 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 more preferred that X is -NH, a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, An aralkyl or heteroarylalkyl group, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl or heteroaryl group may be further protected by one or more fluorenyl, halogen, aromatic Substituted by a hydroxy group, an amino group, an alkylamino group, an amide group, an aminoacyl group, an alkoxy group, an aryloxy group, a heterocycloalkyl group, a carboxylic acid or a carboxylic acid ester.

 In the compound of the formula (I) of the present invention or a salt thereof, it is preferred that Y is an oxygen atom.

 In the compound of the formula (I) of the present invention or a salt thereof, a hydrogen atom is preferred.

 In the compound of the formula (I) of the present invention or a salt thereof, the compound of the formula I-lc is subjected to selective hydrolysis of a lithium hydroxide solution at room temperature to obtain a compound of the formula I-ld.

 Specifically, the compound of the formula (I) of the present invention or a salt thereof comprises:

 Implementation structure name

_5- [4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrrole[2,3-d]pyrimidine-5-methylene-methyl]-4 -methyl-2-[(3-morpholine-4-yl-propylcarbamoyl)-methyl]-1 Hydrogen-pyrrole-3-carboxylic acid ethyl ester

基甲酰)-甲基] -4-甲基 -1 氢-吡 咯 -3-甲酸乙酯 5-[4-(3-氯 -4-氟 -苯胺）-6-氧代 5-[4-(3-Chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrrole[2,3-d]pyrimidine-5-methylene-methyl]-2 -[(2-diethylenyl-ethylamine)

Carbamoyl)-methyl]-4-methyl-1 Hydrogen-pyrrole-3-carboxylic acid ethyl ester 5-[4-(3-chloro-4-fluoro-aniline)-6-oxo

 -6,7-dihydro-pyrrole[2,3-d]pyrimidine-5-methylene-methyl]-4-methyl-2-[(2-piperidin-1-yl-ethylcarbamoyl) )-Methyl]-hydrogen-pyrrole-3-carboxylate

 5-[4-(3-Chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrrole[2,3-d]pyrimidine-5-methylene-methyl]-2 -[2-(3,5-Dimethyl-piperazin-1-yl)-2-oxo-ethyl]-4-methyl-1 Hydrogen-pyrrole-3-carboxylate

 5-[4-(3-Chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrrole[2,3-d]pyrimidine-5-methylene-methyl]-4 -methyl-2-[(2-pyrrolidin-1-yl-ethylcarbamoyl)-methyl]-1 hydrogen-pyrrole-3-carboxylate

 5-[4-(3-Chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrrole[2,3-d]pyrimidine-5-methylene-methyl]-4 -methyl-2-[(2-morpholin-4-yl-ethylcarbamoyl)-methyl]-hydrogen-pyrrole-3-carboxylate

 5-[4-(3-Chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrrole[2,3-d]pyrimidine-5-methylene-methyl] -4 -Methyl-2-{[3-(2-methyl-piperidin-1-yl)-propylcarbamoyl]-methyl}-1 hydrogen-portion-3-carboxylate ethyl 5-[4 -(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrrole[2,3-d]pyrimidine-5-methylene-methyl]-4-methyl- 2-[2-(4-Methyl-pyrazine-1-yl)-2-oxo-ethyl]-1 Hydrogen-pyrrole-3-carboxylate

5-[4-(3-Chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrrole[2,3-d]pyrimidine-5-methylene-methyl] -4 -methyl-2-[2-(4-?t# -4-yl-piperidin-1-yl)-2-oxo-ethyl]

-1 hydrogen-pyrrole-3-carboxylate 5-[4-(3-chloro-4-fluoro-aniline)-6-oxo

 -6,7-dihydro-pyrrole[2,3-d]pyrimidine-5-methylene-methyl]-4-methyl-2-[2-oxo-2-(2-pyrrolidine-1 -ylmethyl-pyrrolidine small group) -ethyl] -1 hydrogen-pyrrole-3-carboxylic acid ethyl ester

 5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-porto[2,3-d]pyrimidine-5-methylene-methyl] -2-[(2-Diethylamino-ethylcarbamoyl)-methyl]-4-phenyl-1 Hydrogen-pyrrole-3-carboxylic acid ethyl ester

 5-[4-(3-Chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrrole[2,3-d]pyrimidine-5-methylene-methyl]-2 -[(2-diethylamino-ethylcarbamoyl)-methyl]-4-trifluoromethyl-1 hydrogen-portyrrol-3-carboxylate

5-[4-(3-chloro-4-fluoro-phenylamino)-6-oxo-6,7-dihydro-pyrrole[2,3-d]pyrimidin-5-methine]-2-[ 2-(4-hydroxy-4-pyrrolidinyl-1-methyl-piperidin-1-yl)-2-oxo-B

 -4-methyl-1 Hydrogen-pyrrole-3-carboxylic acid ethyl ester

基 -4-羟基-哌啶 -1-基) -2-氧代-乙 基] -4-甲基 -1 氢 -B比咯 -3-羧酸乙 酯 5-[4-(3-氯 -4-氟-苯氨基) -6-氧代 5-[4-(3-chloro-4-fluoro-phenylamino)-6-oxo-6,7-dihydro-pyrrole[2,3-d]pyrimidin-5-methine]-2-[ Ethyl 2-(4-hydroxy-4-piperidin-1-methyl-piperidin-1-yl)-2-oxo-ethyl]-4-methyl-1hydro-pyrrole-3-carboxylate 5-[4-(3-Chloro-4-fluoro-phenylamino)-6-oxo-6,7-dihydro-Ppyr[2,3-d]p pyrimidine-5-methine]- 2-[2-(4-diethylamino)

Ethyl-4-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-4-methyl-1 Hydrogen-B-pyrrol-3-carboxylate 5-[4-(3-chloro-4-fluoro-phenylamino)-6-oxo

 -6,7-dihydro-pyrrole[2,3-d]pyrimidin-5-methine]-4-methyl-2-{[2-(4-methyl-piperazin-1-yl)- Ethyl carbamoyl]-methyl}-1 hydrogen-pyrrole-3-carboxylate

5-[4-P-chloro-4-fluoro-phenylamino)-6-oxo-6,7-dihydro-pyrrole[2,3-d]pyrimidin-5-methine]-2-[2 -(4-hydroxy-4-morpholine-4-methyl-piperidin-1-yl)-2-oxo-ethyl]- ₄ -methyl-hydro-P-pyrrol-3-carboxylate

5-[4-(3-Chloro-4-fluoro-phenylamino)-6-oxo-6,7-dihydro-pyrrole[2,3-d]pyrimidin-5-methine]-4-A Benzyl-2-{[3-(4-methyl-piperazin-1-yl)-propylcarbamoyl]-A

-1 Hydrogen-pyrrole-3-carboxylic acid ethyl ester In another aspect of the invention, a pharmaceutical composition comprising a compound of the formula (I) according to the invention or a pharmaceutically acceptable salt or prodrug thereof And a pharmaceutically acceptable carrier. In another aspect of the invention, a method of modulating protein kinase catalytic activity comprising contacting a protein kinase with a compound of formula (I) or a pharmaceutically acceptable salt of the invention. This protein kinase is selected from the group consisting of a receptor tyrosine kinase, a non-receptor tyrosine kinase, and a serine-threonine kinase. Wherein the pharmaceutically acceptable salt of the present invention is a salt of the compound of the present invention and 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. In another aspect of the invention, a method of treating or preventing a mammal associated with a protein kinase, comprising administering to the mammal a therapeutically effective amount of a pharmaceutical composition of the invention, the composition comprising a compound of the invention or A pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. The disease associated with protein kinases is selected from the group consisting of VEGFR-2, EGFR, HER-2, HER-3, HER-4, PDGFR, 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-Heppd-Lindau's disease, inflammation, Fibrosis disease. With protein kinases The disease 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, melanoma, bladder. Cancer, genitourinary cancer, gastrointestinal cancer, glial cancer, colorectal cancer and ovarian cancer. Preferably, the mammal is a human. Further, the method of the above-mentioned mammal for treating or preventing a protein kinase-related disease, preferably a method of treating a mammal having cancer, comprises simultaneously administering to a mammal in need of treatment a therapeutically effective amount of another selected from the group consisting of taxol Or carboplatin anticancer drugs. The mammal is preferably a human. Another aspect of 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. Wherein the protein kinase-associated disease is selected from the group consisting of a disease associated with VEGFR-2, EGFR, HER-2, HER-3, HER-4, PDGFR, c-Kit, c-Met, FGFR or Flt3; 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 , inflammation or fibrosis; or 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. In another aspect of the invention, there is provided a process for the preparation of a compound of formula (I), which comprises the steps of:

 Using the readily available starting material I-la as a starting material, reacting with sodium nitrite to obtain a compound of the formula I-lb;

 The resulting I-lb compound is subjected to ring formation through Knorr Pyrrole to give a compound of the formula I-lc;

所述 I-lc化合物室温下经碱金属氢氧化物溶液， 优选氢氧化锂溶液的选择 性水解后得到通式 I-ld化合物；

The I-lc compound is subjected to selective hydrolysis of an alkali metal hydroxide solution, preferably a lithium hydroxide solution, at room temperature to obtain a compound of the formula I-ld;

Amidation of the I-ld compound with R ₅ NH ₂ to give a compound of the formula I-le;

 Decarboxylation of an I-le compound under the action of trifluoroacetic acid to give a compound of the formula I-lf;

 The I-lf compound is subjected to formylation with phosphorus oxychloride in an anhydrous system to obtain a compound of the formula I-lg;

At last,

among them

X is selected from W(CH ₂ ), (CH ₂ )W or W, wherein W is 0, S, SO or S0 ₂ ; or X is -NR ₆ ; wherein is a hydrogen atom or an alkyl group;

When X is -NR ₆ and R ₆ is a fluorenyl group, R ₆ may form a 4 to 8 membered heterocyclic group; wherein the 5 to 8 membered heterocyclic ring may contain one or more N, 0 or S atoms, and The 4 to 8 membered heterocyclic ring may be further substituted with one or more alkyl groups, halogens, aryl groups, heteroaryl groups, haloalkyl groups, haloalkoxy groups, hydroxyl groups, Substituted with amino, alkylamino, amido, aminoacyl, cyano, alkoxy, aryloxy, aminalkyl, hydroxyalkyl, heterocycloalkyl, carboxylic acid, carboxylic acid ester or -NR ₇ R ₈ ;

Selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an arylalkyl group or a heteroarylalkyl group, wherein an alkyl group, a cyclodecyl group, a heterocyclic fluorenyl group, an aryl group, or a heterocyclic group The aryl, aralkyl or heteroarylalkyl group may be further substituted by one or more alkyl, halogen, aryl, hydroxy, amino, alkylamino, amide, aminoacyl, alkoxy, aryloxy, heterocycloalkane Substituted with a carboxylic acid, a carboxylic acid ester or -NR ₇ R ₈ ; wherein the aryl, heteroaryl, aralkyl or heteroarylalkyl group may be combined into a bicyclic ring;

Selected from hydrogen atom, alkyl group, cycloalkyl group, heterocycloalkyl group, -(CH ₂ CH ₂ 0) _n R6, alkenyl group or alkynyl group, -COOR ₇ , -CONR ₇ R ₈ , -C(=S) NR ₇ R ₈ , -COR ₇ , -SOR ₇ , -S0 ₂ R ₇ -S0 ₂ NR ₇ or -P(=0)(OR ₇ )(OR ₈ ), wherein a fluorenyl group, a cycloalkyl group, a heterocyclic ring a base, alkenyl or alkynyl group may be further substituted by one or more alkyl, hydroxy, alkoxy, cyano, amino, alkylamino, carboxylic acid or carboxylic acid esters;

R _{3 is} selected from a hydrogen atom, a fluorenyl group, an aryl group, a halogen-substituted aryl group or a trifluoromethyl group;

Selected from hydroxy, alkoxy, aryloxy, heterocycloalkoxy, aralkyloxy, -(OCH ₂ CH ₂ ) _n R ₆ , -N(R ₇ )(CH ₂ ) _n R _s , -NR ₇ [CH ₂ C3⁄40] _n R _s or -NR ₆ (C3⁄4) _n [CH(OH)CH ₂ ] _r Z ; wherein Z is aryl, heteroaryl, heterocycloalkyl, -NR ₇ R ₈ , - COOR ₆ or CONR ₇ R _{8 ;}

R _{5 is} selected from a hydroxyl group, an alkoxy group, an aryloxy group, a heterocyclic methoxy group, an aralkyloxy group, -NCR ₇ ) CH ₂ ) _n R ₈ , -NR ₇ 〖CH ₂ CH ₂ 0] _n or -NR ₆ (CH ₂ ) _n [CH(OH)CH ₂ ] _r Z ; wherein Z is aryl, heteroaryl, heterocycloalkyl, -NR ₇ R ₈ , -COOR ₆ or CONR ₇ R ₈ ;

R ₆ is a hydrogen atom or a fluorenyl group;

R ₇ and R ₈ are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group or a heteroarylalkyl group, wherein a fluorenyl group, a cycloalkyl group, a heterocycloalkyl group , aryl, heteroaryl or heteroarylalkyl may be further substituted by one or more alkyl, halogen, aryl, hydroxy, amino, alkylamino, amide, aminoacyl, cyano, decyloxy, aryloxy Substituted with an amino group, an aminoalkyl group, a hydroxymethyl group, a heterocyclic fluorenyl group, a carboxylic acid, a carboxylic acid ester or -NR ₇ R ₈ ;

Meanwhile, 1 ₇ 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 or S atoms, and the 4 to 8 membered heterocyclic ring may be further subjected to one or a plurality of fluorenyl, halogen, aryl, heteroaryl, haloalkyl, haloalkoxy, hydroxy, amino, amide, aminyl, cyano, alkoxy, aryloxy, aminyl, hydroxyalkyl Substituted by a heterocycloalkyl group, a carboxylic acid, a carboxylic acid ester or -NR ₇ R ₈ .

 n is 0~6;

 r is 1 to 2. .

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 measures the effect on the cell. The present invention also relates to a compound for identifying a catalytic activity of a protein kinase, which allows artificially recombinant synthesis of a kinase protein and The compound or salt of the present invention is contacted, and then the effect on kinase activity is examined 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 alkyl 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 thiol group may be substituted or unsubstituted, and when substituted, preferred groups are halogen, hydroxy, lower alkoxy, aryl, aryloxy, heteroaryl, heterocycloalkyl, -COOR ₇ , - CONR ₇ R ₈ , -C(=S)NR ₇ R ₈ , -COR ₇ , -SOR ₇ , -S0 ₂ R ₇ , -S0 ₂ NR ₇ R ₈ and -P(=0)(OR ₇ )(OR ₈ ).

"Cycloalkyl" 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, cyclohexane, 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 lower alkyl, trihaloalkyl, halogen, hydroxy, lower alkoxy, 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 fluorenyl group or a lower decyloxy 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, Lower alkyl or lower alkoxy), 6-membered heteroaryl (having from 1 to 3 nitrogen atoms in the ring, the carbon in the ring is optionally substituted by one or more groups, the substituents being independently of each other halogen, a hydroxy, lower alkyl or lower alkoxy), 5-membered heteroaryl (having 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 by a group, the substituents are, independently of each other, halogen, hydroxy, lower decyl or lower alkoxy), or 5 or 6 membered heterocycloalkyl (having from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, The carbon and nitrogen atoms of the group, if any, are optionally substituted by one or more groups, the substituents being each other Site is halogen, hydroxy, lower alkyl or lower alkoxy group), a mercapto group, (lower alkyl) thio, cyano, nitro, carboxylic acid, carboxylic _{ester, -OR 8, -NR 8 R 9} , - COR ₈ , -NR ₈ COR ₉ and -S0 ₂ NR ₈ .

"Alkenyl" refers to an alkyl 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. The alkenyl group may be optionally substituted by one or more substituents selected from the group consisting of halogen, trihalomethyl, hydroxy, nitro, cyano, alkoxy, alkyl, carboxylic acid, carboxylic acid esters. , -CONR ₇ R ₈ , -C(=S)NR ₇ R ₈ , -COR ₇ , -SOR ₇ , -S0 ₂ R ₇ , -S0 ₂ NR ₇ R ₈ and -P(=0)(OR ₇ ) (OR ₈ ).

"Alkynyl" means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond. Generation Illustrative examples include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, and the like. The alkynyl group may be optionally substituted by one or more substituents selected from the group consisting of halogen, trihalomethyl, hydroxy, nitro, cyano, decyloxy, decyl, carboxylic acid, carboxylic acid ester, -CONR ₇ R ₈ , -C(=S)NR ₇ R ₈ , -COR ₇ , -SOR ₇ , -S0 ₂ R ₇ , -S0 ₂ R ₇ R ₈ and -P(=0)(OR ₇ )( OR ₈ ).

"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, nitro, cyano, alkoxy, alkyl, carboxylic acid, carboxylic acid ester, -CONR ₇ R ₈ , -C(=S)NR ₇ R ₈ , -COR?, -SOR ₇ , -S0 ₂ R ₇ , -S0 ₂ NR ₇ R ₈ and

"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. The heteroaryl group may be optionally substituted by one or more substituents selected from the group consisting of halogen, trihalomethyl, hydroxy, nitro, cyano, decyloxy, alkyl, carboxylic acid, carboxylic acid esters. , -CONR ₇ R ₈ , -C(=S)NR ₇ R _S , -COR ₇ , -SOR ₇ , -S0 ₂ R ₇ , -S0 ₂ NR ₇ R ₈ and -P(=0)(OR ₇ ) (OR ₈ ).

"Heterocycloalkyl" means a monocyclic or fused ring radical having from 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) From 0 to 2), the remaining ring atoms are 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 includes, but is not limited to, pyrrolidinyl, piperidino, piperazino, morpholinyl, thiomorpholinyl, homopiperazine, etc., heterocycloalkyl can be substituted or Unsubstituted. When substituted, the substituent is preferably one or more substituents selected from the group consisting of: halogen, trihalomethyl, hydroxy, nitro, cyano, alkoxy, alkyl, carboxylic acid, carboxylic acid Ester, -CONR ₇ R ₈ , -C(=S)NR ₇ R ₈ , -COR ₇ , -SOR ₇ , -S0 ₂ R ₇ , -S0 ₂ NR ₇ R ₈ and -P(=0) (OR ₇ ) (OR ₈ ).

 "Hydroxy" means an -OH group.

"Alkoxy" means -◦-(alkyl) and -O- (unsubstituted cycloalkyl). Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like. The alkoxy group may be optionally substituted by one or more substituents selected from the group consisting of halogen, trihalomethyl, hydroxy, nitro, cyano, alkoxy, alkyl, carboxylic acid, carboxylic acid ester , -CONR ₇ R ₈ , -C(=S)NR ₇ R ₈ , -COR ₇ , -SOR ₇ , -S0 ₂ R ₇ , -S0 ₂ NR ₇ R ₈ and -P(=0)(OR ₇ ) (OR ₈ ).

 "Halooxyl," means -O-(haloalkyl). Representative examples include, but are not limited to, trifluoromethoxy, tribromomethoxy, and the like.

"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. The aryloxy group may be optionally substituted by one or more substituents selected from the group consisting of halogen, trihalomethyl, hydroxy, nitro, cyano, alkoxy, alkyl, carboxylic acid, carboxylic acid esters. , -CONR ₇ R ₈ , -C(=S)NR ₇ R ₈ , -COH ₇ , -SOR ₇ , -S0 ₂ R ₇ , -S0 ₂ NR ₇ R ₈ and -P(=0)(OR ₇ )(OR ₈ ).

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

"Trihalomethyl" means -CX ₃ wherein X is a halogen 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 an alkyl group to a heterocyclic group" means that a 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 an alkyl 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 solutions:

 The compounds of the invention can be synthesized by methods known in the art. Suitable synthetic methods for these compounds are provided in the Examples. Generally, these compounds can be prepared according to the following synthetic scheme:

以易得的原料 I-la为起始原料，与亚硝酸钠反应得到通式 I-lb化合物；所得 I-l 化合物经过 Knorr Pyrrole成环得到通式 I-lc化合物， I-lc化合物室温下经 碱金属氢氧化物溶液， 优选氢氧化锂溶液的选择性水解后得到通式 I-ld化合物， I-ld化合物不同的胺进行酰胺化反应得到通式 I-le化合物， I-le化合物经在三氟 醋酸作用下的脱羧得到通式 I-lf化合物， i-if化合物在无水体系中， 与三氯氧磷 经甲酰化反应得到通式 I-lg化合物， 通式 I-lg化合物最后与不同的酮缩合即得 到通式 I所示的目标化合物， 其中以氢氧化锂选择性水解底物 I-ld的效果相当 好， 而且能除去原料中含有的少量 Κηοιτ Pyrrole成环反应中产生的副产物。 其中， 通式 (I)分子中双键的构型为 Z构型 (顺式)， 这一点通过核磁数据可以 推断。 通常在吡咯环上 NH的化学位移为 9ppm左右， 而得到的化合物中吡咯环 上的 NH在 14ppm左右， 主要原因是吡咯环上的 NH与临近的吲哚酮羰基的氧 有分子内氢键作用， 导致 NH 的化学位移移向低场。 这一点在专利 WOO 160814(Su- 11248)中也进行了描述。

Starting from the readily available starting material I-la, reacting with sodium nitrite to obtain a compound of the formula I-lb; the obtained compound I is cyclized by Knorr Pyrrole to obtain a compound of the formula I-lc, and the I-lc compound is subjected to a base at room temperature. The metal hydroxide solution, preferably a lithium hydroxide solution, is selectively hydrolyzed to obtain a compound of the formula I-ld, and the amine of the I-ld compound is amidated to give a compound of the formula I-le, and the compound of the formula I-le is obtained in three Decarboxylation under the action of fluoroacetic acid gives a compound of the formula I-lf. The i-if compound is subjected to a formylation reaction with phosphorus oxychloride in an anhydrous system to obtain a compound of the formula I-lg, and the compound of the formula I-lg is finally The condensation of different ketones gives the target compound of the formula I, wherein the effect of selectively hydrolyzing the substrate I-ld with lithium hydroxide is equivalent. Preferably, it is possible to remove a by-product produced in the ring-forming reaction of a small amount of Κηοιτ Pyrrole contained in the raw material. Among them, the configuration of the double bond in the molecule of the general formula (I) is the Z configuration (cis), which can be inferred from the nuclear magnetic data. Usually, the chemical shift of NH on the pyrrole ring is about 9 ppm, and the NH on the pyrrole ring in the obtained compound is about 14 ppm, mainly because the NH on the pyrrole ring has an intramolecular hydrogen bond with the oxygen of the adjacent fluorenone carbonyl. , causing the chemical shift of NH to shift to the lower field. This is also described in the patent WOO 160814 (Su-11248).

 The present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention or a salt thereof and a pharmaceutical carrier.

 Further, the present invention relates to the use of a compound of the formula (I) or a salt thereof for the preparation of a tyrosine kinase inhibitor drug. In other words, the present invention also provides a composition comprising the above compound in an effective amount, and the use of the compound and/or a pharmaceutical composition containing the same in the preparation of a tyrosine kinase inhibitor.

The invention is further described below in conjunction with the 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 tetramethylsilyl (TMS). shifts are 10- ⁶ (ppm) given as a unit.

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

 The average inhibition rate of the kinase VEGFR was measured using an HTScan microplate reader (Cell Signaling). The average inhibition rate of the kinase EGFR/HER-2 was measured using a NovoStar plate reader (BMG, Germany). Thin layer 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; Preparation Example:

 Example 1

5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-P than [2,3-d]pyrimidine-5-methylene-methyl] Preparation of ethyl 4-methyl-2-[(3-morphinolin-4-yl-propylcarbamoyl)-methyl]-hydrogen-pyrrole-3-carboxylate 1

Preparation of 2-mercapto-3-carbonyl-butyric acid tert-butyl ester lb

 Under ice-cooling conditions, in a 250 ml three-necked flask, 3-carbonyl-butyric acid tert-butyl ester la (32 g, 0.2 mol) was dissolved in 60 ml of glacial acetic acid with stirring, and sodium nitrite solution was added dropwise with stirring. (20 ml, 10 mol/L, 0.2 mol), and the reaction temperature was controlled to 0 to 5 °C. After the completion of the dropwise addition, the mixture was reacted in an ice water bath for 1 hour, and the ice water bath was thoroughly removed. The reaction was continued at room temperature for about 3 hours, and the substrate was traced until the basic reaction of the starting material was completed. The reaction was completed to obtain the title product 2-mercapto-3-carbonyl. A solution of tert-butyl butyrate lb is directly administered to the next reaction.

Preparation of 5-ethoxycarbonylmethyl-3-methyl-1 hydrogen-pyrrole-2,4-dicarboxylic acid-2-tert-butyl ester-4-ethyl ester lc to a 250 equipped with a thermometer and a dropping funnel In a three-necked flask of ml, dissolve diethyl 3-carbonyl-glutarate (40 g, 0.2 mmol) in 90 ml of glacial acetic acid with stirring, and warm to 65 ° C with stirring, and add 1/8 of zinc powder. (; a total of 26 g, 0.4 mmol), add 1 / 8 amount of the first reaction solution lb, the temperature of the water bath control system can not rise too fast, after the temperature is lower than 65 ,, then add 1 / 8 amount of zinc powder And 1/8 amount of the first reaction solution. This is repeated until the zinc powder and the first reaction liquid lb are all added. The temperature was raised to 75 ° C, and the reaction was completed after about 2 hours. Under stirring, the reaction solution was poured into 100 ml of ice water, stirring was continued to room temperature, unreacted zinc powder was removed by filtration, and the reaction liquid was extracted with ethyl acetate (100 ml×3), and the organic phases were combined, followed by water (100 ml×3). The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness crystals crystalssssssssssssssss Hydrogen-pyrrole-2,4-dicarboxylic acid-2-tert-butyl ester-4-ethyl ester lc (60 _g , oily product), yield 88.5 %.

 MS: 340.3 (M + 1).

Preparation of 5-carboxymethyl-3-methyl-1 hydrogen-pyrrole-2,4-dicarboxylic acid-2-tert-butyl ester-4-ethyl ester Id in a 1000 ml single-mouth bottle, 5-ethoxycarbonyl Methyl-3-methyl-1 hydrogen-pyrrole-2,4-dicarboxylic acid-2-tert-butyl ester-4-ethyl ester lc (30 g, 0.088 mol) was dissolved in 268 ml of tetrahydrofuran (268 ml) and 134 Methanol, aqueous lithium hydroxide solution (134 ml, 2.36 mol/L, 0.316 mol) was added under stirring, and the reaction was carried out at room temperature for 1.5 hours, and the spot was traced until the starting material completely disappeared. After the reaction mixture was concentrated under reduced pressure to remove most of tetrahydrofuran and methanol, water (200 ml) was added to the concentrate, and then the mixture was extracted with diethyl ether (100 ml x 5), and the aqueous phase was transferred to a 1000 ml single-mouth bottle, and the mixture was added dropwise with stirring in an ice bath. 20% hydrochloric acid to a pH of 1 to 3, a large amount of a pale yellow precipitate precipitated, suction filtered, and the solid was washed with diethyl ether and dried in vacuo to give the title product 5-carboxymethyl-3-methyl-1 hydrogen-pyrrole- 2,4-Dicarboxylic acid-2-tert-butyl ester-4-ethyl ester ld (20 g, pale yellow solid), yield 7.23 %.

3-methyl-5-[(3-morpholine-4-yl-propylcarbamoyl)-methyl]-1hydro-pyrrole-2,4-dicarboxylic acid-2-tert-butyl ester-4-ethyl ester Preparation of le

 Dissolve 5-carboxymethyl-3-methyl-1 hydrogen-pyrrole-2,4-dicarboxylic acid-2-tert-butyl ester-4-ethyl ester ld (2.18 g, 7 mmol) in 35 ml of dichloromethane In a mixed solvent of 3.5 ml of N'N-dimethylformamide, the mixture was cooled in an ice bath, and 3-morpholine-4-yl-propylamine (1.1 g, 7.7 mmol), N-ethyl-N, - (Dimethylaminopropyl)-carbodiimide (2.67 g, 14 mmol) and 1-hydroxybenzotriazole (0.945 g, 7 mmol). The reaction was allowed to warm to room temperature and stirred overnight. After the next day, the material Id completely disappeared, and cold water (40 ml) was added to the reaction mixture under vigorous stirring. The liquid was separated, and the reaction liquid was extracted with dichloromethane (50 ml×3). The organic phase was combined and the organic phase was saturated with water. The potassium carbonate solution (50 ml), water (50 ml×1) and saturated sodium chloride solution (50 ml×l) was evaporated. -5-[(3-morpholine-4-yl-propylcarbamoyl)-methyl]-1 Hydrogen-pyrrole-2,4-dicarboxylic acid-2-tert-butyl ester-4-ethyl ester le (4.49 g , brown oil), the crude product is directly put into the next reaction.

 MS m/z (ESI): 438.5 (M+1).

Preparation of ethyl 4-methyl-2-[(3-morpholine-4-yl-propylcarbamoyl)-methyl]-hydrogen-pyrrole-3-carboxylate If prepared under a argon atmosphere, 3-methyl -5-[(3-morpholine-4-yl-propylcarbamoyl)-methyl]-1 hydrogen-P-pyrrol-2,4-dicarboxylic acid-2-tert-butyl ester-4-ethyl ester le ( 4.49 g, 7 mmol) was dissolved in 224 ml of dichloromethane and 56 ml of trifluoroacetic acid under stirring. The mixture was heated under reflux for 2 hours. The oil bath was removed and stirring was continued at room temperature for 2 hours. After cooling in an ice bath, slowly add 30% aqueous sodium hydroxide solution to the pH of the reaction solution under vigorous stirring, and let stand, and separate the liquid. The aqueous phase is extracted with dichloromethane (100 ml×4), and the organic phase is combined with organic phase. Wash with saturated sodium chloride solution (25 mlxl), dichloromethane layer dried over anhydrous sodium sulfate, filtered, filtrate Concentration under reduced pressure gave the title product 4-methyl-2-[(3-morphinolin-4-yl-propylcarbamoyl)-methyl]-1-hydro-pyrrole-3-carboxylic acid ethyl ester lf (2.01 g, Tan viscous solid). The crude product is directly put into the next reaction.

 MS m/z (ESI): 338·5 (Μ +1).

Preparation of 5-formyl-4-methyl-2-[(3-morpholine-4-yl-propylcarbamoyl)-methyl]-1hydro-pyrrole-3-carboxylate lg

Under an argon atmosphere, anhydrous N'N-dimethylformamide (0.12 ml, 1.25 mmol) was added to a 25 ml single-mouth bottle, cooled to 0 ° C in an ice bath, and phosphorus oxychloride was slowly added dropwise with stirring. 0.05 ml, 0.55 mmol), after completion of the dropwise addition, stir at room temperature for 15 minutes, then continue cooling in an ice salt bath, and add 4-methyl-2-[(3-morpholine-4-yl-propyl) to the reaction flask. Anhydrous N'N-dimethylformamide solution of carbamoyl)-methyl]-hydrogen-pyrrole-3-carboxylate If (169 mg, 0.5 mmol, dissolved in 0.6 ml of N'N-dimethyl In the formamide, keep the reaction temperature at 0 ° C for 2 hours, follow the trace to the disappearance of the raw materials, add ice water (15 ml) to the reaction solution, quench the reaction, stir for 5 minutes, and then use 30% hydrogen. The sodium oxide solution was adjusted to a pH of 12. The reaction mixture was extracted with EtOAc EtOAc (EtOAc m. 5-formyl-4-methyl-2-[(3-morphinolin-4-yl-propylcarbamoyl)-methyl]-hydrogen-pyrrole-3-carboxylate 1 _g (0.192 g, red The brown viscous solid), the crude product is directly put into the next reaction.

 MS m/z (ESI): 364.3 (M + 1).

_5- [4-(3-Chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrrole[2,3-d]pyrimidine-5-methylene-methyl]-4 -Methyl 2-[(3-morpholine-4-yl-propylcarbamoyl)-methyl]-1hydro-pyrrole-3-carboxylic acid ethyl ester 1 was prepared under an argon atmosphere in a 10 ml single port In the bottle, 5-formyl-4-methyl-2-[(3-morphinolin-4-yl-propylcarbamoyl)-methyl]-1 hydrogen-pyrrole-3-carboxylic acid ethyl ester lg was added in sequence ( 0.183 g, 0.5 mmol), 4-(3-chloro-4-fluoro-aniline)-5,7-dihydro-pyrrole[2,3-d]pyrimidin-6-one (0.139 g, 0.5 mniol) (Bioorganic & Medicinal Chemistry letters 2002, 12(16), 2153-2157. ), piperidine (0.125 ml, 1.25 mmol) and ethanol (1.5 ml), heated under reflux for 1.5 hours, point plated to 4-(3-chloro-4) -Fluoro-aniline) -5,7-dihydro-pyrrole[2,3-d]pyrimidin-6-one completely disappeared, the reaction solution was naturally cooled to room temperature, a large amount of solid was produced, and filtered under reduced pressure to give the title product. 5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-P than [2,3-d]pyrimidine-5-methylene-methyl] Ethyl 4-methyl-2-[(3-morphinolin-4-yl-propylcarbamoyl)-methyl]-l-hydrogen-pyrrole-3-carboxylate 1 (0.129 g, yellow solid), yield 41.3%.

 MS m/z (ESI): 626.4 (M + 1).

1H NMR (DMSO-D ₆ , 400MHz) 58.324 (s, 1H, -CH=N), 7.704 (dd, 1H, -ArH), 7.389~7.337 (m, 3H, -ArH; -CH=C), 4.237 ; 4.184(q, 2H, -C0 ₂ CH ₂ -), 3.540(t, 4H, 2x-OCH ₂ -), 3.289(s, 2H, -CH ₂ CON-), 3.108(t, 2H, -CONCH ₂ -), 2.363(s, 3H, -ArCH ₃ ) _: 2.320~2.266(m, 6H, 3 -NCH ₂ -,), 1.628-1.560(m, 2H, -CH ₂ -), 1.273(t, 3H, -CH ₃ ). Example 2

_5- [4- ₍₃ -chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrrole[2,3-d]pyrimidine-5-methylene-methyl]-2 -[(2-Diethylamino-ethylcarbamoyl)-methyl]-4-methyl-1hydro-pyrrole-3-carboxylic acid ethyl ester 2

5-[(2-Diethylamino-ethylcarbamoyl)-methyl]-3-methyl-1hydrogen-pyrrole-2,4-dicarboxylic acid-2-tert-butyl ester-4-ethyl ester

 Preparation of 2a

 5-Carboxymethyl-3-methyl-1hydro-P-pyrrol-2,4-dicarboxylic acid-2-tert-butyl ester-4-ethyl ester ld (125 mg, 0.4 ml) was dissolved in 2 with stirring In a mixed solvent of dichloromethane and 0.2 ml of N'N-dimethylformamide, it was cooled in an ice bath, and N,N-diethylethylenediamine (60 ul, 0.44 mmol), N-ethyl- N,-(dimethylaminopropyl)-carbodiimide (154 mg, 0.8 mmol) and 1-hydroxybenzotriazole (56 mg, 0.4 mrnol). The reaction was allowed to warm to room temperature and stirred overnight. After the next day the plate to the raw material Id disappeared completely, cold water (5 ml) was added to the reaction solution under vigorous stirring, and the solution was allowed to stand for separation. The reaction solution (50 ml×3) was extracted with dichloromethane, and the organic phase was combined. The saturated potassium carbonate solution (5 ml×1), water (5 ml×l) and saturated sodium chloride solution (25 ml×l) was washed, and the methylene chloride layer was dried over anhydrous sodium sulfate and filtered. 2-diethylamino-ethylcarbamoyl)-methyl]-3-methyl-1hydro-pyrrole-2,4-dicarboxylic acid-2-tert-butyl ester-4-ethyl ester 2a (136 mg, light Yellow mucilage), yield 83%.

Preparation of ethyl 2-[(2-diethylamino-ethylcarbamoyl)-methyl]-4-methyl-1 hydrogen-pyrrole-3-carboxylate 2b. Under an argon atmosphere, 5-[(2- Diethylamino-ethylcarbamoyl)-methyl]-3-methyl-1hydro-pyrrole-2,4-dicarboxylic acid-2-tert-butyl ester-4-ethyl ester 2a (420 mg, 1 mmol) Dissolve in 40 ml of dichloromethane and 10 ml of trifluoroacetic acid with stirring, heat under reflux for 2 hours, remove the oil bath, continue stirring at room temperature for 2 hours, and trace the plate to the original. The material disappeared completely. After cooling in an ice bath, slowly add 30% aqueous sodium hydroxide solution to the pH of the reaction solution under vigorous stirring, add 30 ml of ice water, settle for separation, and extract the aqueous phase with dichloromethane (30 ml×4). The organic phase was washed with a saturated aqueous solution of sodium chloride (25 ml), and the methylene chloride layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated to give the title product 2-[(2-diethylamino)- Ethylcarbamoyl)-methyl]-4-methyl-1 Hydrogen-pyrrole-3-carboxylic acid ethyl ester 2b (300 mg, gray mucilage). The yield was 95%.

 MS m/z (ESI): 310.5 (M+1).

Preparation of 2-[(2-diethylamino-ethylcarbamoyl)-methyl]-5-formyl-4-methyl-1hydrogen-pyrrole-3-carboxylate 2c

 Under an argon atmosphere, anhydrous N'N-dimethylformamide (0.3 ml) was added to a 25 ml single-mouth bottle, cooled to 0 ° C in an ice bath, and phosphorus oxychloride (112 ul) was slowly added dropwise with stirring. 1.1 mmol), after the addition was completed, stir at room temperature for 15 minutes, continue to cool in an ice salt bath, and add 2-[(2-diethylamino-ethylcarbamoyl)-methyl]-4- to the reaction flask. A solution of methyl-1H-pyrrole-3-carboxylate 2b in anhydrous N'N-dimethylformamide (309 mg, 1 mmol, dissolved in 0.6 ml of N'N-dimethylformamide). The reaction temperature was maintained at 0 ° C for 2 hours, the spot was traced until the starting material disappeared, and ice water (4 ml) was added to the reaction solution to quench the reaction, stirred for 5 minutes, and then adjusted to pH 12 with 30% sodium hydroxide solution. . The reaction mixture was extracted with EtOAc EtOAc (EtOAc m. 2-[(2-Diethylamino-ethylcarbamoyl)-methyl]-5-formyl-4-methyl-1hydro-P-pyrrol-3-carboxylate 2c (283 mg, off-white solid ), the yield was 84%.

 MS m/z (ESI): 338·7 (Μ +1).

5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrrole[2,3-d]pyrimidine-5-methylene-methyl]-2 Preparation of 2-[(2-diethylamino-ethylcarbamoyl)-methyl]-4-methyl-1 hydrogen-pyrrole-3-carboxylate 2 in an argon atmosphere in a 10 ml single-mouth bottle , 2-[(2-Diethylamino-ethylcarbamoyl)-methyl]-5-formyl-4-methyl-1 hydrogen-pyrrole-3-carboxylic acid ethyl ester 2c (0.077 g, 0.23) Methyl), 4-(3-chloro-4-fluoro-aniline)-5,7-dihydro-pyrrole[2,3-d]pyrimidin-6-one (0.056 g, 0.2 mmol), piperidine (0.05 ml , 0.5 mmol) and ethanol (0.5 ml), heated under reflux for 1.5 hours, and traced to 4-(3-chloro-4-fluoro-aniline)-5,7-dihydro-pyrrole [2,3-d]pyrimidine The -6-ketone disappeared completely, the reaction solution was naturally cooled to room temperature, and a large amount of solid was produced, which was filtered under reduced pressure to give the title product 5-[4-(3-chloro-4-fluoro-aniline)-6-oxo- 6,7-Dihydro-P than [2,3-d]pyrimidine-5-methylene-methyl]-2-[(2-diethylamino-ethylcarbamoyl)-methyl] 4-Methyl-1 Hydrogen-pyrrole-3-carboxylate 2 (0.049 g, yellow solid), yield 41%.

 MS m/z (ESI): 598.3 (M+1).

1H NMR (DMSO-D ₆ , 400MHz) 58.323 (s, 1H, -CH=N), 7.686 (dd, 1H, -ArH), 7.394~7.360 (m, 3H, -ArH; -CH=C) ₅ 4.187 (q, 2H, -C0 ₂ CH ₂ -), 3.474(s, 2H, -CH2CON-), 3.188(t, 2H, -CONCH2-), 2.351~2.329(m, 9H, 3 -NCH ₂ -; ArCH ₃ ), 1.486-1.358 (m, 6H, 2x-CH ₃ ), 1.275 (t, 3H, -CH ₃ ). Example 3

 5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrrole[2,3-d]pyrimidine-5-methylene-methyl] -4 -Preparation of methyl 2-[(2-piperidinyl-ethylcarbamoyl)-methyl]-hydrogen-pyrrole-3-carboxylate 3

3-methyl-5-[(2-piperidin-1-yl-ethylcarbamoyl)-methyl]-1 hydrogen-P-pyrrol-2,4-dicarboxylic acid-2-tert-butyl ester-4- Ethyl ester

 Preparation of 3a

 Dissolve 5-carboxymethyl-3-methyl-1 hydrogen-pyrrole-2,4-dicarboxylic acid-2-tert-butyl ester-4-ethyl ester ld ( 4.351 g, 14 mmol:) in 70 ml with stirring Dichloromethane and 7 ml of N'N-dimethylformamide in a mixed solvent, cooled in an ice bath, and then added 2-piperidin-1-yl-ethylamine (1.971 g, 154 mmol), N-ethyl - Ν'-(Dimethylaminopropyl)-carbodiimide (5.351 g, 28 mmol) and 1-hydroxybenzotriazole (1.891 g, 14 mmol). The reaction was allowed to warm to room temperature and stirred overnight. After the next day the plate to the raw material Id disappeared completely, cold water (40 ml) was added to the reaction solution under vigorous stirring, and the mixture was allowed to stand for separation. The reaction liquid was extracted with dichloromethane (50 ml×3), and the organic phase was combined, and the organic phase was sequentially saturated. The potassium carbonate solution (50 ml×1), water (50 ml×1), and saturated sodium chloride solution (50 ml×l) was evaporated. 5-[(2-piperidin-1-yl-ethylcarbamoyl)-methyl]-1 hydrogen-pyrrole-2,4-dicarboxylic acid-2-tert-butyl ester-4-ethyl ester 3a (4.818 g, Brown viscous liquid), the crude product is directly put into the next reaction.

 MS m/z (ESI): 422·3 (Μ +1).

Preparation of ethyl 4-methyl-2-[( ² -piperidinyl-ethylcarbamoyl)-methyl]-1hydro-pyrrole-3-carboxylate 3b. 3-methyl- ⁵ under argon atmosphere -[(2-piperidinyl-ethylcarbamoyl)-methyl]-1 hydrogen-pyrrole-2,4-dimethyl Acid-2-tert-butyl ester-4-ethyl ester 3a (4.81 g, 11.4 mmol) was dissolved in 365 ml of dichloromethane and 68 ml of trifluoroacetic acid, heated under reflux for 2 hrs, the oil bath was removed, and stirring was continued at room temperature for 2 hours. , the point plate is tracked until the material disappears completely. After cooling in an ice bath, slowly add 30% aqueous sodium hydroxide solution to the pH of the reaction solution under vigorous stirring, and let stand, partition, and extract the aqueous phase with dichloromethane (100 ml×4), combine the organic phase, organic phase. Washed with a saturated sodium chloride solution (25 ml, EtOAc) -ethylcarbamoyl)-methyl]-1 Hydrogen-pyrrol-3-carboxylate 3b (2.39 g, tan viscous liquid), the crude product was directly taken to the next reaction.

 MS m/z (ESI): 322·5 (Μ +1).

Preparation of 5-formyl-4-methyl-2-[(2-piperidinyl-ethylcarbamoyl)-methyl]-1hydro-pyrrole-3-carboxylate 3c

 Under an argon atmosphere, anhydrous N'N-dimethylformamide (0.58 ml, 7.5 mmol) was added to a 25 ml single-mouth bottle, cooled to 0 ° C in an ice bath, and phosphorus oxychloride was slowly added dropwise with stirring. 0.307 ml, 3.3 mmol), after the addition was completed, stir at room temperature for 15 minutes, then continue cooling in an ice salt bath, and add 4-methyl-2-[(2-piperidinyl-ethylamino) to the reaction flask. A solution of ethyl acyl-methyl]-hydrogen-pyrrole-3-carboxylate 3b in anhydrous N'N-dimethylformamide (0.963 mg, 3 mmol, dissolved in 3.6 ml N'N-dimethyl In the amide), keep the reaction temperature at 0 ° C for 2 hours, follow the trace to the disappearance of the raw materials, add ice water (15 ml) to the reaction solution, quench the reaction, stir for 5 minutes, and then use 30% sodium oxychloride. The solution was adjusted to a pH of 12. The reaction mixture was extracted with EtOAc EtOAc (EtOAc m. 5-formyl-4-methyl-2-[(2-piperidin-1-yl-ethylcarbamoyl)-methyl]-1 hydrogen-B-pyrrol-3-carboxylate 3c (0.952 g, The orange-yellow solid), the crude product is directly put into the next reaction.

 MS m/z (ESI): 350.4 (M + 1).

5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrrole[23-d]pyrimidine-5-methylene-methyl]-4-methyl Preparation of ethyl-2-[(2-piperidin-1-yl-ethylcarbamoyl)-methyl]-1hydro-pyrrole-3-carboxylate 3 in an argon atmosphere in a 10 ml single-mouth bottle Add 5-formyl-4-methyl-2-[(2-piperidin-1-yl-ethylcarbamoyl)-methyl]-1hydro-pyrrole-3-carboxylic acid ethyl ester 3c (0.233 g) , 0.66 mmol), 4-(3-chloro-4-fluoro-aniline)-5,7-dihydro-indolepyr[2,3-d]pyrimidin-6-one (0.169 g, 0.6 mmol), Pyridine (0.15 ml, 1.5 mmol) and ethanol (1.5 ml), heated under reflux for 1.5 hours, and traced to 4-(3-chloro-4-fluoro-aniline)-5,7-dihydro-pyrrole [2,3 -d] Pyrimidine-6-one completely disappeared, the reaction solution was naturally cooled to room temperature, and a large amount of solid was produced, which was filtered under reduced pressure to give the title product 5-[4-(3-chloro-4-fluoro-aniline)-6 -oxo- 6,7-dihydro-pyrrole[2,3-d]pyrimidine-5-methylene-methyl]-4-methyl-2-[(2-piperidin-1-yl-B Carbamate)-Methyl]-1 Hydrogen-pyrrole-3-carboxylic acid ethyl ester 3 (0.289 g, yellow solid), yield 79%.

MS m/z (ESI): 610·6 (Μ +1). 1H NMR (DMSO-D ₆ , 400MHz) 58.318 (s, 1H, -CH-N), 7.687 (dd, 1H, -ΑιΉ), 7.405~7.333 (m, 3H, -ΑιΉ; -CH=C), 4.183 (q, 2H, -C0 ₂ CH ₂ -), 3.482(s, 2H _: -CH ₂ CON-), 3.139(t, 2H, -CONCH ₂ -), 2.491~2.438 (m, 6H, 3 -NCH ₂ -), 2.348 (s, 3H: -Ai-CH ₃ ), 1.273 (t, 3H, -CH ₃ ), 0.915 (t, 6H, 3x-CH ₂ -). Example 4

 5-[4-(3-Chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrrole[2,3-d]pyrimidine-5-methylene-methyl]-2 -[2-(3,5-Dimethyl-piperazin-1-yl)-2-oxo-ethyl]-4-methyl-1hydro-pyrrole-3-carboxylic acid ethyl ester 4

5-[2-(3,5-Dimethyl-piperazin-1-yl)-2-oxo-ethyl]-3-methyl-1chloro-pyrrole-2,4-dicarboxylic acid-2- Tert-butyl ester

 Preparation of -4-ethyl ester 4a

Dissolve 5-carboxymethyl-3-methyl-1 hydrogen-pyrrole-2,4-dicarboxylic acid-2-tert-butyl ester-4-ethyl ester ld (0.933 g, 3 mmol) in 15 ml of dichloromethane And 1.5 ml of N'N-dimethylformamide in a mixed solvent, cooled in an ice bath, and (2S, 6R)-2,6-dimethyl-piperazine (0.377 g, 3.3 mmol), N- Ethyl-N,-(dimethylaminopropyl)-carbodiimide (1.146 g, 6 mmol) and 1-hydroxybenzotriazole (0.405 g, 3 mmol). The reaction was allowed to warm to room temperature and stirred overnight. . After the next day the plate to the raw material Id completely disappeared, 40 ml of cold water was added to the reaction solution under vigorous stirring, and the solution was allowed to stand for separation. The reaction liquid was extracted with dichloromethane (50 ml×3), and the organic phase was combined, and the organic phase was sequentially saturated potassium carbonate. The solution (50 ml×1), water (50 ml×1), EtOAc (EtOAc) ,5-dimethyl-piperazine small group)-2-oxo-ethyl]-3-methyl-1 hydrogen-pyrrole-2,4-dicarboxylic acid-2-tert-butyl Ester-4-ethyl ester 4a (0.710 g, tan viscous liquid), the crude product was directly put into the next reaction.

 MS m/z (ESI): weight .4 (M+1).

Preparation of 2-[2-(3,5-dimethyl-piperazin-1-yl)-2-oxo-ethyl]-4-methyl-1hydro-pyrrole-3-carboxylate 4b 5-[2-(3,5-Dimethyl-piperazin-1-yl)-2-oxo-ethyl]-3-methyl-1hydro-pyrrole-2,4-di 2-tert-Butyl ester-4-ethyl formate 4a (0.710 g, 1.7 mmol) was dissolved in 55.8 ml of dichloromethane (55.8 ml) and 7 ml of trifluoroacetic acid, and the mixture was heated to reflux for 2 hours, and the oil bath was removed. Stirring was continued for 2 hours at room temperature, and the spot was traced until the starting material completely disappeared. After cooling in an ice bath, slowly add 30% aqueous sodium hydroxide solution to the pH of the reaction solution with vigorous stirring, and let stand, and separate the liquid. The aqueous phase is extracted with dichloromethane (100 ml×4), and the organic phase is combined with the organic phase. Washed with a saturated sodium chloride solution (25 ml, EtOAc) (mjjjjjjjjj Ethyl 1-[2-oxo-ethyl]-4-methyl-1 -hydropyrrole-3-carboxylate 4b (0.309 g, tan viscous liquid), the crude product was taken directly to the next reaction.

 MS m/z (ESI): 308.4 (M+1).

2-[2-(3,5-Dimethyl-piperazin-1-yl)-2-oxo-ethyl]-5-formyl-4-methyl-1hydro-pyrrole-3-carboxylic acid Ester

 Preparation of 4c

 Under an argon atmosphere, anhydrous N'N-dimethylformamide (0.2 ml, 2.5 mmol) was added to a 25 ml single-mouth bottle, cooled to 0 ° C in an ice bath, and phosphorus oxychloride was slowly added dropwise with stirring. 0.1 ml, 1.1 mmol), after the addition was completed, stir at room temperature for 15 minutes, continue cooling in an ice salt bath, and add 2-[2-(3,5-dimethyl-piperazine small group) to the reaction flask. a solution of ethyl 2-oxo-ethyl]-4-methyl-1hydro-pyrrole-3-carboxylate 4b in anhydrous N'N-dimethylformamide (0.309 g, 1 mmol, dissolved in 1.2 ml N'N-dimethylformamide), the reaction temperature was maintained at 0 ° C for 2 hours, the spot plate was traced until the disappearance of the starting material, and ice water (15 ml) was added to the reaction solution to quench the reaction, and the mixture was stirred for 5 minutes. The pH was adjusted to 12 with a 30% sodium hydroxide solution. The reaction mixture was extracted with EtOAc EtOAc (EtOAc m. 2-[2-(3,5-Dimethyl-piperazin-1-yl)-2-oxo-ethyl]-5-formyl-4-methyl-1hydro-pyrrole-3-carboxylic acid Ester 4c (0.329 g, deep wine red viscous liquid), the crude product was directly put into the next reaction.

 MS m/z (ESI): 336.4 (M + 1).

5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrrole[2,3-d]pyrimidine-5-methylene-methyl]-2 -[2-(3,5-Dimethyl-piperazinyl)-2-oxo-ethyl]-4-methyl-1hydro-pyrrole-3-carboxylic acid ethyl ester 4 was prepared under an argon atmosphere In a 10 ml single-mouth bottle, 2-[2-(3,5-dimethyl-piperazine-l-yl)-2-oxo-ethyl]-5-formyl-4-yl was added sequentially Ethyl 1-hydrogen-pyrrole-3-carboxylate 4c (0.114 g, 0.34 mmol), 4-(3-chloro-4-fluoro-aniline)-5,7-dihydro-pyrrole [2,3-d] Pyrimidine-6-one (0.086 g, 0.3 mmol), piperidine (0.08 ml, 0.8 mmol) and ethanol (0.8 ml), heated under reflux for 1.5 hours, and traced to 4-(3-chloro-4-fluoro-aniline)-5,7-dihydro-pyrrole [2,3-d]pyrimidine- The 6-ketone disappeared completely, the reaction solution was naturally cooled to room temperature, and a large amount of solid was produced, which was filtered under reduced pressure to give the title product 5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6. ,7-Dihydro-pyrrole[2,3-d]pyrimidine-5-methylene-methyl]-2-[2-(3,5-dimethyl-piperazin-1-yl)-2- Ethyl-ethyl]-4-methyl-1hydro-pyrrole-3-carboxylic acid ethyl ester 4 (0.049 g, yellow solid), yield 27.4%.

 MS m/z (ESI): 5%·6 (Μ +1).

1H NMR (DMSO-D ₆ , 400MHz) 58.324 (s, 1H, -CH=N), 7.713 (dd, 1H, -ArH), 7.409-7.341 (m, 3H, -ArH; -CH=C), 4.166 (q, 2H, -C0 ₂ CH ₂ -), 3.434~3.377 (m, 6H, -CH2CON-; 2 -CONCH ₂ -), 2.668~2.563 (ra, 2H, 2x-NCHR-), 2.378(s, 3H, -ArCH ₃ ), 1.255(t, 3H, -CH ₃ ), 0.964 (d, 6H, 2x-CH ₃ ). Example 5

 5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrrole[2,3-d]pyrimidine-5-methylene-methyl]-4 -Preparation of methyl 2-[(2-pyrrole-1-yl-ethylcarbamoyl)-methyl]-1hydro-pyrrole-3-carboxylate 5

3-methyl-5-[(2-pyrrolidinyl-ethylcarbamoyl)-methyl]-1hydro-P-pyrrol-2,4-dicarboxylic acid-2-tert-butyl ester-4-ethyl ester Preparation of 5a

Dissolve 5-carboxymethyl-3-methyl-1 hydrogen-pyrrole-2,4-dicarboxylic acid-2-tert-butyl ester-4-ethyl ester ld (2.8 g, 9 mmol) in 45 ml of dichloromethane In a mixed solvent of 4.5 ml of N'N-dimethylformamide, it was cooled in an ice bath, and 2-pyrrole-1-yl-ethylamine (1.13 _g , 909 mmol), N-ethyl-Ν' - (Dimethylaminopropyl)-carbodiimide (3.44 g, 18 mmol) and 1-hydroxybenzotriazole (1.22 g, 9 mmol). The reaction was allowed to warm to room temperature and stirred overnight. After the next day, the plate is completely disappeared after the raw material Id disappears. 40 ml of cold water was added to the solution, and the solution was separated, and the reaction mixture was extracted with dichloromethane (50 ml×3). The organic phase was combined, and the organic phase was successively saturated with potassium carbonate (50 ml×l), water (50 ml×l) and saturated chlorination The sodium solution (50 ml×1) was evaporated. -Methyl]-1 Hydrogen-pyrrole-2,4-dicarboxylic acid-2-tert-butyl ester-4-ethyl ester 5a (4.48 g, tan viscous liquid), the crude product was directly put into the next reaction.

 MS m/z (ESI): 408.3 (M+1).

Preparation of ethyl 4-methyl-2-[(2-pyrrolidin-1-yl-ethylcarbamoyl)-methyl]-1hydro-pyrrole-3-carboxylate 5b

 3-methyl-5-[(2-pyrrolidinyl-ethylcarbamoyl)-methyl]-l-hydrogen-pyrrole-2,4-dicarboxylic acid-2-tert-butyl ester-4 under argon atmosphere - Ethyl ester 5a (4.48 g, 9 nimol) was dissolved in 288 ml of dichloromethane and 54 ml of trifluoroacetic acid, stirred under reflux for 2 hours, the oil bath was removed, stirring was continued for 2 hours at room temperature, and the material was completely traced until the material disappeared. . After cooling in an ice bath, slowly add 30% aqueous sodium hydroxide solution to the pH of the reaction solution under vigorous stirring, and let stand, and separate the liquid. The aqueous phase is extracted with dichloromethane (100 ml×4), and the organic phase is combined. The mixture was washed with a saturated aqueous solution of sodium chloride (25 ml.). -ethylcarbamoyl)-methyl]-1 hydrogen-pyrrole-3-carboxylic acid ethyl ester 5b (1.68 g, tan viscous liquid), the crude product was directly put into the next reaction.

 MS m/z (ESI): 308.4 (M+1).

Preparation of ethyl 5-formyl-4-methyl-2-[(2-Ppyrrolidine-ylcarbamoyl)-methyl]-1hydro-pyrrole-3-carboxylate 5c

 Under an argon atmosphere, anhydrous N'N-dimethylformamide (0.4 ml, 5.0 mmol) was added to a 25 ml single-mouth bottle, cooled to 0 ° C in an ice bath, and phosphorus oxychloride was slowly added dropwise with stirring. 0.2 ml, 2.2 mmol), after the addition was completed, stir at room temperature for 15 minutes, continue cooling in an ice salt bath, and add 4-methyl-2-[(2-pyrrole-1-yl-B) to the reaction flask. A solution of carbamoyl)-methyl]-hydrogen-pyrrole-3-carboxylate 5b in anhydrous N'N-dimethylformamide (0.614 g, 2 mmol, dissolved in 2.4 ml of N'N-dimethyl In the formamide, keep the reaction temperature at 0 ° C for 2 hours, follow the trace to the disappearance of the starting material, add ice water (15 ml) to the reaction solution to quench the reaction, stir for 5 minutes, then use 30% hydrogen The sodium oxide solution was adjusted to a pH of 12. The reaction mixture was extracted with EtOAc EtOAc (EtOAc m. 5-formyl-4-methyl-2-[(2-pyrrole-1-yl-ethylcarbamoyl)-methyl]-1hydro-pyrrole-3-carboxylic acid ethyl ester 5c (0.517 g, brown solid ), the yield was 77%.

 MS nVz (ESI): 336·6 (Μ +1).

5-[4-(3-Chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrrole[2,3-d]pyrimidine-5-methylene-methyl]-4 -methyl-2 -[(2-Pyrrolidinyl-ethylcarbamoyl)-methyl]-1hydro-pyrrole-ethyl 3-carboxylate 5 Preparation of argon in a 10 ml single-mouth bottle, sequentially added 5- Formyl-4-methyl-2-[(2-pyrrolidin-1-yl-ethylcarbamoyl)-methyl]-hydrogen-pyrrole-3-carboxylate 5c (0.26 g, 0.782 mmol), 4-(3-chloro-4-fluoro-aniline)-5,7-dihydro-pyrrole[2,3-d]pyrimidin-6-one (0.112 g, 0.403 mmol), piperidine (0.15 ml, 1.5 mmol And ethanol (1.5 ml), heating under reflux for 1.5 hours, point plate tracking to 4-(3-chloro-4-fluoro-aniline)-5,7-dihydro-pyrrole [2,3-d]pyrimidine-6- The ketone disappeared completely, the reaction solution was naturally cooled to room temperature, and a large amount of solid was produced, which was filtered under reduced pressure to give the title product 5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7 -dihydro-pyrrole[2,3-d]pyrimidine-5-methylene-methyl]-4-methyl-2-[(2-pyrrolidinyl-ethylcarbamoyl)-methyl]- 1 Hydrogen-pyrrol-3-carboxylate 5 (39 mg, tan solid), yield 16.3 %.

 MS m/z (ESI): 596·4 (Μ +1).

1H NMR (DMSO-D ₆ , 400MHz) 58.320 (s, 1H, -CH=N), 7.684 (dd, 1H, -ArH), 7.392~7.356 (m, 3H, -ArH; -CH=C), 4.185 (q, 2H, -C0 ₂ CH ₂ -), 3.478(s, 2H, -CH2CON-), 3.200(t, 2H, -CONCH2-), 2.567(t ₅ 2H, -NCH ₂ -), 2.475~2.408 (m, 4H, 2x-NCH ₂ - ), 2.350 (s, 3H, -Ai H ₃ ), 1.660 (q, 4H, 2x-CH ₂ - ), 1.274 (t, 3H, -CH ₃ ). Example 6

 5-[4-(3-Chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrrole[2,3-d]pyrimidine-5-methylene-methyl]-4 -Preparation of methyl 2-[(2-morpholin-4-yl-ethylcarbamoyl)-methyl]-hydrogen-pyrrole-3-carboxylate 6

3-methyl-5-[(2-morpholin-4-yl-ethylcarbamoyl)-methyl]-1 hydrogen-pyrrole-2,4-dicarboxylic acid-2-tert-butyl ester-4-ethyl ester

 Preparation of 6a

5-carboxymethyl-3-methyl-1 hydrogen-pyrrole-2,4-dicarboxylic acid-2-tert-butyl ester-4-ethyl ester ld (10.9 g, 35 Ment) dissolved in a mixed solvent of 175 ml of dichloromethane and 17.5 ml of N'N-dimethylformamide, cooled in an ice bath, and then added 2-morpholin-4-yl-ethylamine (5.0 g, 38.5 mmol). ), N-ethyl-Ν'-(dimethylaminopropyl)-carbodiimide (13.37 g, 70 mmol) and 1-hydroxybenzotriazole (4.73 g, 35 mmol), the reaction system naturally rose to Stir at room temperature overnight. After the next day the plate to the raw material Id disappeared completely, 35 ml of cold water was added to the reaction solution under vigorous stirring, and the liquid was allowed to stand for separation. The reaction liquid was extracted with dichloromethane (50 ml×3), and the organic phase was combined, and the organic phase was sequentially saturated with potassium carbonate. The solution (50 ml×1), water (50 ml×1), EtOAc (EtOAc) [(2-morpholin-4-yl-ethylcarbamoyl)-methyl]-1 hydrogen-pyrrole-2,4-dicarboxylic acid-2-tert-butyl ester-4-ethyl ester 6a (12.88 g, tan The viscous liquid), the crude product is directly put into the next reaction.

 MS m/z (ESI): 424.4 (M + 1).

Preparation of ethyl 4-methyl-2-[(2-morpholin-4-yl-ethylcarbamoyl)-methyl]-1 hydrogen-pyrrole-3-carboxylate 6b 3-methyl group under argon atmosphere -5-[(2-morpholin-4-yl-ethylcarbamoyl)-methyl]-1hydro-pyrrole-2,4-dicarboxylic acid-2-tert-butyl ester-4-ethyl ester 6a (4.23 g , 10 mmol) was dissolved in 320 ml of dichloromethane and 60 ml of trifluoroacetic acid with stirring, heated under reflux for 2 hours, the oil bath was removed, stirring was continued for 2 hours at room temperature, and the spot was traced until the starting material disappeared completely. After cooling in an ice bath, slowly add 30% aqueous sodium hydroxide solution to the pH of the reaction solution under vigorous stirring, and let stand, and separate the liquid. The aqueous phase is extracted with dichloromethane (100 ml×4), and the organic phase is combined with organic phase. Washed with a saturated sodium chloride solution (25 ml, EtOAc), m. -ethylcarbamoyl)-methyl]-hydrogen-pyrrole-3-carboxylate 6b (2.35 g, tan viscous liquid:), the crude product was directly taken to the next reaction.

 MS m/z (ESI): 324·3 (Μ +1).

Preparation of 5-formyl-4-methyl-2-[(2-morpholin-4-yl-ethylcarbamoyl)-methyl]-1hydro-pyrrole-3-carboxylate 6c

Under an argon atmosphere, anhydrous N'N-dimethylformamide (1.6 ml, 20 mmol) was added to a 25 ml single-mouth bottle, cooled to 0 ° C in an ice bath, and phosphorus oxychloride was slowly added dropwise with stirring. 0.75 ml, 8.0 mmol), after completion of the dropwise addition, stir at room temperature for 15 minutes, continue cooling in an ice salt bath, and add 4-methyl-2-[(2-morpholine-4-yl-ethylamino) to the reaction flask. A solution of the formyl)-methyl]-hydrogen-B than the ethyl 3-carboxylate 6b in anhydrous N,N-dimethylformamide (2.346 mg, 7.26 mmol, dissolved in 8.7 ml N'N- Methylformamide), keep the reaction temperature at 0 ° C for 2 hours, follow the trace to the disappearance of the raw materials, add ice water (15 ml) to the reaction solution to quench the reaction, stir for 5 minutes and then use 30% hydrogen. The sodium oxide solution was adjusted to a pH of 12. The reaction mixture was extracted with EtOAc EtOAc (EtOAc m. 5-formyl-4-methyl-2-[(2-morpholin-4-yl-ethylcarbamoyl)-methyl]-1hydro-pyrrole-3-carboxylic acid ethyl ester 6c (1.105 g, tan Viscous liquid), yield 43.3%. MS m/z (ESI): 352.5 (M+1).

5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-P than [2,3-d]pyrimidine-5-methylene-methyl] Preparation of 4-methyl-2-[2-(2-morpholin-4-yl-ethylcarbamoyl)-methyl]-hydrogen-pyrrole-3-carboxylate 6 in an argon atmosphere at 10 ml In a single-mouth bottle, 5-formyl-4-methyl-2-[(2-morpholin-4-yl-ethylcarbamoyl)-methyl]-hydrogen-pyrrole-3-carboxylate was added in sequence. 6c (0.253 g, 0.72 mmol), 4-(3-chloro-4-fluoro-aniline)-5,7-dihydro-pyrrole[2,3-d]pyrimidin-6-one (0.169 g, 0.6 mmol) Piperidine (0.15 ml, 1.5 mmol) and ethanol (3 ml), heated under reflux for 1.5 hours, and traced to 4-(3-chloro-4-fluoro-aniline)-5,7-dihydro-P ratio [2,3-d]pyrimidin-6-one completely disappeared, the reaction solution was cooled to room temperature, and a large amount of solid was obtained, which was filtered under reduced pressure to give the title product 5-[4-(3-chloro-4-fluoro- Aniline)-6-oxo-6,7-dihydro-pyrrole[2,3-d]pyrimidine-5-methylene-methyl]-4-methyl-2-[(2-morpholin-4 Ethyl-ethylcarbamoyl-methyl-1-hydrogen-pyrrole-3-carboxylate 6 (0.204 g, yellow solid), yield 54.8%.

 MS m/z (ESI): 612·2 (Μ +1).

1H NMR (DMSO-D ₆ , 400MHz): S8.325 (s, 1H, -CH=N), 7.685 (dd, 1H, -ΑιΉ), 7.394~7.359 (m, 3H, -ArH; -CH=C ), 4.190(q, 2H, -C0 ₂ CH ₂ -), 3.541(t, 4H, 2x-OCH ₂ -) ₅ 3.476(s, 2H, -C3⁄4CON-), 3.213(t, 2H, -CONC3⁄4-) , 2.404~2.334(m, 9H, 3 -NCH ₂ - ₅ -ArCH ₃ ), 1.276(t, 3H, - C3⁄4). Example 7

 5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-P than [2,3-d]pyrimidine-5-methylene-methyl] Preparation of 4-methyl-2-{[3-(2-methyl-piperidinyl)-propylcarbamoyl]-methyl}-1hydro-pyrrole-3-carboxylic acid ethyl ester

3-甲基 -5-{[3-(2-甲基 -哌啶 -1-基) -丙氨基甲酰] -甲基 }-l氢 -吡咯 -2,4-二甲酸 -2- 叔丁酯 -4-乙酯 7a的制备

3-methyl-5-{[3-(2-methyl-piperidin-1-yl)-propylcarbamoyl]-methyl}-l-hydrogen-pyrrole-2,4-dicarboxylic acid-2-un Preparation of butyl ester-4-ethyl ester 7a

 Dissolve 5-carboxymethyl-3-methyl-1 hydrogen-pyrrole-2,4-dicarboxylic acid-2-tert-butyl ester-4-ethyl ester ld (4.35 g, 14 mmol) in 70 ml of dichloromethane And 7 ml of N'N-dimethylformamide in a mixed solvent, cooled in an ice bath, and (2R)-3-(2-methyl-piperidinyl)-propylamine (2.41 g, 15.4 mmol) , N-ethyl-Ν'-(dimethylaminopropyl)-carbodiimide (5.35 g, 28 mmol) and 1-hydroxybenzotriazole (1.89 g, 14 mmol), the reaction system naturally rose to room temperature , stir overnight. After the next day the plate to the raw material Id completely disappeared, 40 ml of cold water was added to the reaction solution under vigorous stirring, and the mixture was allowed to stand for separation. The reaction liquid was extracted with dichloromethane (50 ml×3), and the organic phase was combined, and the organic phase was sequentially saturated potassium carbonate. The solution (50 mix 1), water (50 ml×1), EtOAc (EtOAc) -{[3-(2-methyl-piperidin-1-yl)-propylcarbamoyl]-methyl}-1 Hydrogen-pyrrole-2,4-dicarboxylic acid-2-tert-butyl ester-4-B Ester 7a (6.617 g, tan oil), the crude product was taken directly to the next reaction.

 MS m/z (ESI): 450·3 (Μ +1).

Preparation of ethyl 4-methyl-2-{[3-(2-methyl-piperidinyl)-propylcarbamoyl]-methyl}-1 hydrogen-pyrrole-3-carboxylate 7b

 3-methyl-5-{[3-(2-methyl-piperidin-1-yl)-propylcarbamoyl]-methyl}-1 hydrogen was added sequentially to a 500 ml three-necked flask under an argon atmosphere. - Pyrrole-2,4-dicarboxylic acid-2-tert-butyl ester-4-ethyl ester 7a (63 g, 14 mmol) was dissolved in 450 ml of dichloromethane and 84 ml of trifluoroacetic acid with stirring, and heated under reflux for 2 hours. The oil bath was removed and stirring was continued for 2 hours at room temperature, and the spot was traced until the material completely disappeared. After cooling in an ice bath, slowly add 30% aqueous sodium hydroxide solution to the pH of the reaction solution with vigorous stirring, and let stand, partition, and extract the aqueous phase with methylene chloride (100 ml×4), combine organic phase, organic The phase was washed with a saturated aqueous solution of sodium chloride (25 ml.). Ethyl piperidin-1-yl)-propylcarbamoyl]-methyl}-1 Hydrogen-pyrrole-3-carboxylate 7b (3.348 g, white solid).

 MS m/z (ESI): 350.4 (M + 1).

5-formyl- ⁴ -methyl-2-{{3-(2-methyl-piperidin-1-yl)-propylcarbamoyl]-methyl}-1 hydrogen-pyrrole-3-carboxylate Preparation of 7c

Under an argon atmosphere, anhydrous N'N-dimethylformamide (0.66 ml, 8.25 mmol) was added to a 25 ml single-mouth bottle, cooled to 0 ° C in an ice bath, and phosphorus oxychloride was slowly added dropwise with stirring. 0.3 ml, 3.3 mmol), after the addition was completed, stir at room temperature for 15 minutes, continue cooling in an ice salt bath, and add 4-methyl-2-{[3-(2-methyl-piperidine) to the reaction flask. -1-yl)-propylcarbamoyl]-methyl}-1 Hydrogen-pyrrole-3-carboxylic acid ethyl ester 7b anhydrous N'N-dimethylformamide solution (1.048 mg, 3 mmol, dissolved in 3.6 ml of N'N-dimethylformamide), kept at a reaction temperature of 0 ° C for 2 hours, traced to the disappearance of the starting material Thereafter, ice water (15 ml) was added to the reaction mixture to quench the reaction, and the mixture was stirred for 5 minutes, and then adjusted to pH 12 with a 30% sodium hydroxide solution. The reaction mixture was extracted with EtOAc EtOAc (EtOAc m. 5-formyl-4-methyl-2-{[3-(2-methyl-piperidin-1-yl)-propylcarbamoyl]-methyl)-1 hydrogen-pyrrole-3-carboxylate 7c (1.422 g, brown solid), the crude product was taken directly to the next reaction.

 MS m/z (ESI): 378.5 (M+1).

5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrrole[2,3-d]pyrimidine-5-methylene-methyl] -4 -methyl-2 -{[3-(2-methyl-piperidinyl)-propanylmethyl]-methyl}-1 hydrogen-pyrrole-3-carboxylic acid ethyl ester 7 prepared under argon atmosphere In a 10 ml single-mouth bottle, 5-formyl-4-methyl-2-{[3-(2-methyl-piperidinyl)-propylcarbamoyl]-methyl}-1 hydrogen was added in sequence. -pyrrole-3-carboxylate ethyl ester 7c (0.226 g, 0.6 mmol), 4-(3-chloro-4-fluoro-aniline)-5,7-dihydro-pyrrole[2,3-d]pyrimidine-6- Ketone (0.167 g, 0.6 mmol), piperidine (0.15 ml, 1.5 mmol) and ethanol (1.5 ml), heated to reflux for 1.5 h, and the pad was traced to 4-(3-chloro-4-fluoro-aniline)-5. 7-Dihydro-pyrrole [2,3-d]pyrimidin-6-one completely disappeared, and the reaction solution was naturally cooled to room temperature, and a large amount of solid was produced, which was filtered under reduced pressure to give the title product 5-[4-(3- Chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrrole[2,3-d]pyrimidine-5-methylene-methyl]-4-methyl-2-{[ Ethyl 3-(2-methyl-piperidin-1-yl)-propylcarbamoyl]-methyl}-1-hydro-pyrrole-3-carboxylate 7 (102 mg, yellow solid).

 MS m/z (ESI): 639.3 (M+1).

1H NMR (DMSO-D ₆ , 400MHz): 58.324 (s, 1H, -CH=N), 7.684 (dd, 1H, -ΑιΉ), 7.393~7.359 (m, 3H, -ArH; -CH=C), 4.187(q, 2H, -C0 ₂ CH ₂ -), 3.454(s, 2H, -CH2CON-), 3.08 l(t, 2H, -CONCH2-), 2.350~2.334 (m ₅ 6H, -NCH ₂ -, -NCHR-, -ArCH ₃ ), 2.233(t, 2H, -NCH ₂ -), 1.579~1.526(m, 6H, 3 -CH ₂ -), 1.273(t, 3H, -CH ₃ ), 1.204-1.156 (m, 2H, -CH ₂ -), 0.952 (d, 3H, -C3⁄4). Example 8

 5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrrole[2,3-d]pyrimidine-5-methylene-methyl]-4 -Preparation of methyl 2-[2-(4-methyl-pyrazine-1-yl)-2-oxo-ethyl]-hydrogen-pyrrole-3-carboxylate 8

3-methyl-5-[2-(4-methyl-pyrazin-1-yl)-2-oxo-ethyl]-1hydro-pyrrole-2,4-dicarboxylic acid-2-tert-butyl ester -4- Preparation of ethyl ester 8a

 Dissolve 5-carboxymethyl-3-methyl-1 hydrogen-pyrrole-2,4-dicarboxylic acid-2-tert-butyl ester-4-ethyl ester ld (933 mg, 3 mmol) in 15 ml of dichloromethane混合 and 1.5 ml of N'N-dimethylformamide in a mixed solvent, cooled in an ice bath, and then added 1-methyl-pyrazine (331 mg, 3.3 mmol), N-ethyl-Ν'- (two Methylaminopropyl)-carbodiimide (1.146 g, 6 mmol) and 1-hydroxybenzotriazole (405 mg, 3 mmol). The reaction was allowed to warm to room temperature and stirred overnight. After the next day the plate to the raw material Id completely disappeared, 40 ml of cold water was added to the reaction solution under vigorous stirring, and the mixture was allowed to stand for separation. The reaction liquid was extracted with dichloromethane (50 ml×3), and the organic phase was combined, and the organic phase was sequentially saturated potassium carbonate. The solution (50 ml×1), water (50 ml×1), EtOAc (EtOAc) [2-(4-Methyl-pyrazin-1-yl)-2-oxo-ethyl]-1 Hydrogen-pyrrole-2,4-dicarboxylic acid-2-tert-butyl ester-4-ethyl ester 8a ( 676 mg, brown oil), the crude product was taken directly to the next reaction.

 MS m/z (ESI): 394.4 (MI).

Preparation of ethyl 4-methyl-2-[2-(4-methyl-pyrazine-1-yl)-2-oxo-ethyl]-hydrogen-pyrrole-3-carboxylate 8b under argon atmosphere 3-Methyl-5-[2-(4-methyl-pyrazin-1-yl)-2-oxo-ethyl]-1 hydrogen-pyrrole-2,4-dicarboxylic acid-2-tert-butyl Ester-4-ethyl ester 8a (676 mg, 1.7 mmol) was dissolved in 180 ml of dichloromethane and 30 ml of trifluoroacetic acid with stirring, heated under reflux for 2 hours, the oil bath was removed, stirring was continued for 2 hours at room temperature, and the material was traced to the starting material. Completely disappear. After cooling in an ice bath, slowly add 30% aqueous sodium hydroxide solution to the pH of the reaction solution under vigorous stirring, and let stand, and separate the liquid. The aqueous phase is extracted with dichloromethane (100 ml×4), and the organic phase is combined with organic phase. The mixture was washed with a saturated aqueous solution of sodium chloride (25 ml.). Ethyl-1-yl)-2-oxo-ethyl]- 1 Hydrogen-pyrrole-3-carboxylate 8b (504 mg, brown oil).

 MS m/z (ESI): 294.3 (M + 1).

5-formyl-4-methyl-2-[2-(4-methyl-pyrazine)-2-oxo-ethyl]-hydrogen-pyrrole-3-carboxylate 8c Preparation

 Under an argon atmosphere, anhydrous N'N-dimethylformamide (0.37 ml, 4.625 mmol) was added to a 25 ml single-mouth bottle, cooled to 0 ° C in an ice bath, and phosphorus oxychloride was slowly added dropwise with stirring. 0.17 ml, 1.87 mmol), after completion of the dropwise addition, stir at room temperature for 15 minutes, then continue cooling in an ice salt bath, and add 4-methyl-2-[2-(4-methyl-pyrazine-) to the reaction flask. A solution of 1-ethyl)- 2-oxo-ethyl]-hydrogen-pyrrole-3-carboxylate 8b in anhydrous N'N-dimethylformamide (501 mg, 1.7 mmol, dissolved in 2 ml N In 'N-dimethylformamide, keep the reaction temperature at 0 ° C for 2 hours, follow the trace to the disappearance of the starting material, add ice water (15 ml) to the reaction solution, quench the reaction, stir for 5 minutes, then The pH was adjusted to 12 with a 30% sodium hydroxide solution. The reaction mixture was extracted with EtOAc EtOAc (EtOAc m. 5-formyl-4-methyl-2-[2-(4-methyl-pyrazin-1-yl)-2-oxo-ethyl]-1hydro-pyrrole-3-carboxylate 8c ( 404 mg, brown oil), the crude product was taken directly to the next reaction.

 MS m/z (ESI): 324.3 (M + 1).

5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrrole[2,3-d]pyrimidine-5-methylene-methyl] -4 -Methyl-2-[2-(4-methyl-pyrazine-1-yl)-2-oxo-ethyl]-hydrogen-pyrrole-3-carboxylate 8 is prepared under argon atmosphere In a 10 ml single-mouth bottle, 5-formyl-4-methyl-2-[2-(4-methyl-pyrazine small)-2-oxo-ethyl]-1 hydrogen-pyrrole was added in sequence. Ethyl 3-carboxylate 8c (192 mg, 0.6 mmol), 4-(3-chloro-4-fluoro-aniline)-5,7-dihydro-pyrrole[2,3-d]pyrimidin-6-one ( 167 mg, 0.6 mmol), piperidine (0.15 ml, 1.5 mmol) and ethanol (1.5 ml), heated to reflux for 1.5 h, and then traced to 4-(3-chloro-4-fluoro-aniline) -5,7- The dihydro-pyrrole [2,3-d]pyrimidin-6-one completely disappeared, the reaction solution was naturally cooled to room temperature, and a large amount of solid was produced, which was filtered under reduced pressure to give the title product 5-[4-(3-chloro- 4-fluoro-aniline)-6-oxo-6,7-dihydro-P than [2,3-d]pyrimidin-5-methylene-methyl]-4-methyl-2-[2 -(4-Methyl-pyrazinyl)-2-oxo-ethyl]-l-hydro-pyrrole-3-carboxylate 8 (168 mg, yellow solid), yield 48.1%.

 MS m/z (ESI): 582.5 (M + 1).

1H NMR (DMSO-D ₆ , 400MHz): 58.324 (s, 1H, -CH=N), 7.694 (dd, 1H, -ArH), 7.403~7.340 (m, 3H, -ArH; -CH=C), 4.167(q, 2H, -C0 ₂ CH ₂ -) ₅ 3.534~3.477(m, 6H, -CH ₂ CON-; 2x-CONCH ₂ -), 2.366(s, 3H, -ArCH ₃ ), 2.344~2.290( m, 4H, 2 -NCH ₂ -), 2.190 (s, 33⁄4 -NCH ₃ ), 1.257 (t, 3H, -CH ₃ ). Example 9

5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrrole[2,3-d]pyrimidine-5-methylene-methyl]-4 -Preparation of methyl 2-[2-(4-morpholin-4-yl-piperidinyl)-2-oxo-ethyl]-hydrogen-pyrrole-3-carboxylate 9

3-methyl-5-[2-(4-morpholine-4-yl-piperidinyl)-2-oxo-ethyl]-1hydro-pyrrole-2,4-dicarboxylic acid-2-tert Preparation of butyl ester-4-ethyl ester 9a

Dissolve 5-carboxymethyl-3-methyl-1 hydrogen-pyrrole-2,4-dicarboxylic acid-2-tert-butyl ester-4-ethyl ester ld (1.236 g, 3.97 mmol) in 20 ml of dichloromethane混合 and 2 mIN'N-dimethylformamide in a mixed solvent, cooled in an ice bath, and then added 4-piperidin-4-yl-morpholine (0.75 g, 4.4 mmol), N-ethyl-N ,-(Dimethylaminopropyl)-carbodiimide (2 g, 7.94 mmol) and 1-hydroxybenzotriazole (0.6 g, 3.97 mmol). The reaction was allowed to warm to room temperature and stirred overnight. After the next day the plate to the raw material Id completely disappeared, 40 ml of cold water was added to the reaction solution under vigorous stirring, and the mixture was allowed to stand for separation. The reaction liquid was extracted with dichloromethane (50 ml×3), and the organic phase was combined, and the organic phase was sequentially saturated potassium carbonate. solution (50 mlxl), water (50 mlxl) and saturated sodium chloride solution (50 mlxl) was washed with dichloromethane layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title product _ _3-methyl-5 - [2-(4-morpholin-4-yl-piperidin-1-yl)-2-oxo-ethyl]-1 hydrogen-pyrrole-2,4-dicarboxylic acid-2-tert-butyl ester-4- Ethyl ester 9a (1.673 g, tan viscous liquid), yield 90.33%.

 MS m/z (ESI): 464.7 (M+1).

Preparation of ethyl 4-methyl-2-[2-(4-morpholin-4-yl-piperidin-1-yl)-2-oxo-ethyl]-1hydro-pyrrole-3-carboxylate

3-methyl-5-[2-(4-morpholino-4-yl-piperidin-1-yl)-2-oxo-ethyl]-1hydrogen-pyrrole-2,4 under argon -2-tert-Butyl 4-carboxylate diacetate 9a (1.673 g, 3.6 mmol) was dissolved in 113 ml of dichloromethane and 20 ml of trifluoroacetic acid with stirring, heated under reflux for 2 hrs, and the oil bath was removed. Stir for 2 hours and track the plate until the material completely disappeared. After cooling in an ice bath, slowly add 30% aqueous sodium hydroxide solution to the pH of the reaction solution with vigorous stirring, and let stand, partition, and extract the aqueous phase with dichloromethane (100 ml×4), and combine The organic phase was washed with a saturated aqueous solution of sodium chloride (25 ml?). Ethyl 4-(4-morpholin-4-yl-piperidine-1-yl)-2-oxo-ethyl]-1hydro-pyrrole-3-carboxylate 9b (1.141 g, m. The yield was 86.99%.

 MS m/z (ESI): 364.5 (M+1).

5-formyl-4-methyl-2-[2-(4-morpholin-4-yl-piperidin-1-yl)-2-oxo-ethyl]-1 hydrogen-pyrrole-3-carboxylic acid Preparation of ethyl ester 9c

 Under an argon atmosphere, anhydrous N'N-dimethylformamide (0.3 ml, 3.9 mmol) was added to a 25 ml single-mouth bottle, cooled to 0 ° C in an ice bath, and phosphorus oxychloride was slowly added dropwise with stirring. 112 ul, 1.1 mmol), after completion of the dropwise addition, stir at room temperature for 15 minutes, continue to cool in an ice salt bath, and add 4-methyl-2-[2<4-morpholin-4-yl- to the reaction flask. A solution of piperidinyl)-2-oxo-ethyl]-hydrogen-pyrrole-3-carboxylate 9b in anhydrous N,N-dimethylformamide (363 mg, 1 mmol, dissolved in 0.6 ml N'N-dimethylformamide), the reaction temperature was maintained at 0 ° C for 2 hours, the spot plate was traced until the disappearance of the starting material, and ice water (15 ml) was added to the reaction solution to quench the reaction, and the mixture was stirred for 5 minutes. The pH was adjusted to 12 with a 30% sodium hydroxide solution. The reaction mixture was extracted with EtOAc EtOAc (EtOAc m. Product 5-formyl-4-methyl-2-[2-(4-morpholin-4-yl-piperidinyl)-2-oxo-ethyl]-1 hydrogen-pyrrole-3-carboxylate Ester 9c (0.292 g, reddish brown solid), yield 74.68 %.

 MS m/z (ESI): 392.6 (M+1).

5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-B than [2,3-d]pyrimidine-5-methylene-methyl] 4-methyl-2-(2-(4-morpholino-4-yl-piperidin-1-yl)-2-oxo-ethyl]-hydrogen-pyrrole-3-carboxylate 9 Under the argon atmosphere, 5-formyl-4-methyl-2-[2-(4-morpholin-4-yl-piperidinyl)-2-oxo was added sequentially in a 10 ml single-mouth bottle. Ethyl-ethyl]-hydrogen-P-pyrrol-3-carboxylate 9c (0.292 g, 0.75 mmol), 4-(3-chloro-4-fluoro-aniline)-5,7-dihydro-pyrrole [ 2,3-d]pyrimidin-6-one (0.115 g, 0.75 mmol), piperidine (0.15 ml, 1.5 mmol) and ethanol (1.2 ml), heated under reflux for 1.5 hours, and the plate was traced to 4-(3-chloro -4-fluoro-aniline) -5,7-dihydro-pyrrole [2,3-d]pyrimidin-6-one completely disappeared, the reaction solution was naturally cooled to room temperature, a large amount of solid was produced, and filtered under reduced pressure to obtain The title product 5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrrole[2,3-d]pyrimidine-5-methylene-methyl] 4-methyl-2-[2-(4-morpholin-4-yl-piperidin-1-yl)-2-oxo-ethyl]-1 hydrogen _p than carboxy-3-carboxylate 9 (40 mg, brown solid), yield 16.43%.

 MS m/z (ESI): 652·5 (Μ +1).

1H NMR (DMSO-D ₆ , 400MHz) _: 58.321 (s, 1H, -CH=N), 7.692 (dd, 1H, -ArH), 7.425~7.337 (m, 3H, -ArH; -CH=C), 4.165(q, 2H, -C0 ₂ CH ₂ -), 3.529(t, 4H, 2x-OCH ₂ -) ₅ 3.474(s, 2H, -C3⁄4CON-), 3.049(t, 4H, 2x-CONCH ₂ -) , 2.441~2.435(m, 5H, 2x-NCH ₂ -, -NCHR-), 2.346(s, 3H, -ArC3⁄4), 1.798-1.768(m, 4H, 2x-CH ₂ -), 1.273(t, 3H, -C3⁄4). Example 10

 5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrrole[2,3-d]pyrimidine-5-methylene-methyl]-4 -methyl

 -2-[2-oxo-2-(2-pyrrolidin-1-ylmethyl-pyrrole-1-yl)-ethyl]-1 hydrogen

 -Preparation of pyrrole _3-ethyl formate 10

3-methyl-5-[2-oxo-2-(2-pyrrolidin-1-ylmethyl-pyrrole-1-yl)-ethyl]-1hydro-pyrrole-2,4-dicarboxylic acid Preparation of -2-tert-butyl ester-4-ethyl ester 10a

 Dissolve 5-carboxymethyl-3-methyl-1 hydrogen-pyrrole-2,4-dicarboxylic acid-2-tert-butyl ester-4-ethyl ester ld (1.244 g, 4 mmol) in 20 ml of dichloromethane In a mixed solvent of hydrazine and 2 ml of N'N-dimethylformamide, it was cooled in an ice bath, and (s)-2-(pyrrolidin-1-ylmethyl)-pyrrolidine (0.72 ml, 4.4 mmol) was sequentially added with stirring. ), N-ethyl-N,-(dimethylaminopropyl)-carbodiimide (2 g, 8 mmol) and 1-hydroxybenzotriazole (0.6 g, 4 mmol), the reaction system naturally rose to Stir at room temperature overnight. After the next day the plate to the raw material Id completely disappeared, 40 ml of cold water was added to the reaction solution under vigorous stirring, and the mixture was allowed to stand for separation. The reaction liquid was extracted with dichloromethane (50 ml×3), and the organic phase was combined, and the organic phase was sequentially saturated with carbonic acid. The potassium solution (50 ml×1), water (50 ml×1), and saturated sodium chloride solution (50 ml×1) was evaporated. -[2-oxo-2-(2-pyrrolidin-1-ylmethyl-pyrrole-1-yl)-ethyl]-1 hydrogen-P-pyrrol-2,4-dicarboxylic acid-2-tert Butyl ester-4-ethyl ester 10a (1.755 g, brownish yellow oil), yield 98.15%.

MS m/z (ESI): 448.3 (M+1). 4-methyl-2-[2-oxo-2-(2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-ethyl]- 1 Hydrogen-to-Butyl-3-carboxylate Preparation of ester 10b

 3-methyl-5-[2-oxo-2-(2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-ethyl]- 1 Hydrogen-pyrrole-2 under argon atmosphere , 4-tert-butyl 4-carboxylate 4-ethyl ester 10a (1.255 g, 3.93 mmol) was dissolved in 124 ml of dichloromethane and 22 ml of trifluoroacetic acid under stirring, and the mixture was heated to reflux for 2 hours, and the oil bath was removed. Stirring was continued for 2 hours at room temperature, and the plate was tracked until the material completely disappeared. After cooling in an ice bath, slowly add 30% aqueous sodium hydroxide solution to the pH of the reaction solution under vigorous stirring, and let stand, and separate the liquid. The aqueous phase is extracted with dichloromethane (100 ml×4), and the organic phase is combined. After washing with a saturated sodium chloride solution (25 ml×1), the methylene chloride layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated to give the title product 4-methyl-2-[2-oxo-2- 2-Pyrrolidin-1-ylmethyl-pyrrolidine-1-yl)-ethyl]-1 Hydrogen-portoprol-3-carboxylate 10b (0.566 g, brownish yellow oil). The yield was 41.63 %.

 MS m/z (ESI): 348.3 (M+1).

5-formyl-4-methyl-2-[2-oxo-2-(2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-ethyl]-1 hydrogen-pyrrole

 Preparation of ethyl-3-carboxylate 10c

 Under an argon atmosphere, add anhydrous N'N-dimethylformamide (ml, mmol) to a 25 ml single-mouth bottle, cool to 0 °C in an ice bath, and slowly add triclosan (183 ul) with stirring. , 1.8 mmol), after the addition was completed, stir at room temperature for 15 minutes, and then continue to cool in an ice salt bath. 4-methyl-2-[2-oxo-2-(2-pyrrolidine) was added dropwise to the reaction flask. A solution of ethyl 1-methylmethyl-pyrrolidin-1-yl)-ethyl]-hydrogen-pyrrole-3-carboxylate 10b in anhydrous N'N-dimethylformamide (566 mg, 1.63 mmol, dissolved In 2 ml of N'N-dimethylformamide), keep the reaction temperature at 0 ° C for 2 hours, follow the plate until the disappearance of the starting materials, add ice water (15 ml) to the reaction solution, quench the reaction, stir After 5 minutes, the pH was adjusted to 12 with a 30% sodium hydroxide solution. The reaction mixture was extracted with EtOAc EtOAc (EtOAc m. 5-formyl 4-methyl-2-[2-oxo-2-(2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-ethyl]-1 hydrogen-pyrrole-3 Ethyl formate 10c (0.536 g, reddish brown solid), yield 87.72%.

 MS m/z (ESI): 372.

5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-P than [2,3-d]pyrimidine-5-methylene-methyl] 4-methyl-2-[2-oxo-2-(2-pyrrolidin-1ylmethyl-P-pyrrolidin-1-yl)-ethyl]-1hydro-pyrrole-3-carboxylic acid Ester 10 preparation

Under a argon atmosphere, in a 10 ml single-mouth bottle, 5-formyl-4-methyl-2-[2-oxo-2-(2-pyrrolidin-1-ylmethyl-pyrrolidine) was added in sequence. Ethyl)-ethyl]-hydrogen-pyrrole-3-carboxylate 10c (0.2 g, 0.5 mmol), 4-(3-chloro-4-fluoro-aniline)-5,7-dihydro-porto [2,3-d]pyrimidin-6-one (0.14 g, 2.5 mmol), Pyridine (0.1 ml, 1 mmol) and ethanol (1.2 ml), heated under reflux for 1.5 hours, and traced to 4-(3-chloro-4-fluoro-aniline)-5,7-dihydro-pyrrole [2,3 -d] Pyrimidine-6-one completely disappeared, the reaction solution was naturally cooled to room temperature, and a large amount of solid was produced, which was filtered under reduced pressure to give the title product 5-[4-(3-chloro-4-fluoro-aniline)-6 -oxo-6,7-dihydro-pyrrole[2,3-d]pyrimidine-5-methylene-methyl]-4-methyl-2-[2-oxo-2-(2-pyrrole) Ethyl-1 -methyl-P-pyrrolidin-1-yl)-ethyl]-hydrogen-pyrrole-3-carboxylate 10 (0.103 g, yellow solid), yield 37.44%.

 MS m/z (ESI): 636.5 (M+1).

1H NMR (DMSO-D ₆ , 400MHz): S8.323 (s, 1H, -CH=N), 7.710 (dd, 1H, -AxH), 7.398~7.339 (m, 3H, -ΑιΉ; -CH=C ), 4.209~4.063(m, 3H, -C0 ₂ C3⁄4-, -CONCHR-), 3.522(t, 2H, -CONCH2-), 3.291(s, 2H, -CH ₂ CON-), 2.465~2.433(m , 6H, 3x-NCH ₂ -), 2.371(s, 3H, -ArCH ₃ ), 1.944-1.837(m, 4H, 2x-CH ₂ - ), 1.666-1.653(m, 4H, 2x-CH ₂ - ) _: 1.251(t, 3H, -CH ₃ ) o Example 11

_5- [4-(3-Chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrrole[2,3-d]pyrimidine-5-methylene-methyl]-2 -[(2-Diethylamino-ethylcarbamoyl)-methyl]-4-phenyl-1-hydro-pyrrole-3-carboxylate ethyl ester 11

Preparation of ethyl 2-ethoxycarbonylmethyl-4-phenyl-l-hydrogen-pyrrole-3-carboxylate lib

In a 250 ml three-necked flask equipped with a reflux condenser, 2-amino-1-phenyl-ethanone 11a (10.3 g, 0.06 mol) and sodium acetate (9.86 g, 0.12 mol) were added and the pump was pumped to vacuum. After stirring, diethyl 3-carbonyl-glutaric acid (10.9 ml, 0.06 mol) and water (60 ml) were added, and the mixture was heated under reflux for 5 hours, then the mixture was stirred and stirred at room temperature overnight. The next day, the point plate was traced until the raw material disappeared and the reaction was terminated. Reaction solution Ethyl acetate (50 ml×7), EtOAc (EtOAc m. Ethoxycarbonylmethyl 4-phenyl-1-hydro-pyrrole-3-carboxylic acid ethyl ester llb (16.802 g, pale yellow solid), yield 93.03%.

 MS m/z (ESI): 302·2 (Μ +1).

Preparation of 4-phenyl-1hydrogen-pyrrole-3-carboxylic acid ethyl ester-2-carboxylic acid 11c

 Ethyl 2-ethoxycarbonylmethyl-4-phenyl-1hydro-pyrrole-3-carboxylate llb (20.387 g, 0.068 mmol) was dissolved in a mixture of 102 ml of methanol and 102 ml of tetrahydrofuran with stirring under an argon atmosphere. To the solution, a lithium hydroxide aqueous solution (11.38 g, 0.27 mol dissolved in 154 ml of water) was added, and the mixture was reacted at room temperature for 0.5 hour, and then heated to reflux for 2 hours. The spot was traced until the starting material disappeared, the reaction was terminated, and the methanol was removed by vacuum distillation under reduced pressure. Tetrahydrofuran was diluted with water (50 ml), and 20% hydrochloric acid was added dropwise to the reaction solution under ice-cooling to pH 4. At this time, a large amount of white solid was formed, and filtered to give the title product 4-phenyl-1 hydrogen-pyrrole. Ethyl 3-carboxylate-2-carboxylate (18.48 g, white solid), yield 100%.

 MS m/z (ESI): 274 (M+1).

Preparation of ethyl 2-[(2-diethylamino-ethylcarbamoyl)-methyl]-4-phenyl-1 hydrogen-pyrrole-3-carboxylate lid 5-methyl-4-phenyl- 1 Hydrogen-pyrrole-3-carboxylic acid ethyl ester-2-carboxylic acid 11c (18.48 g, 0.068 mol) was dissolved in a mixed solvent of 34 ml of dichloromethane and 34 ml of N'N-dimethylformamide, cooled in an ice bath. N,N-Diethylethylenediamine (10.155 ml, 0.074 mmol), N-ethyl-N,-(dimethylaminopropyl)-carbodiimide (33.85 g, 0.135 mmol) was added sequentially with stirring. And 1-hydroxybenzotriazole (10.188 g, 0.068 mmol), the reaction was allowed to warm to room temperature and stirred overnight. From the next day, the material to the raw material 11c disappeared completely. 50 ml of cold water was added to the reaction solution under vigorous stirring, and the mixture was allowed to stand for separation. The reaction liquid was extracted with dichloromethane (100 ml×3), and the organic phase was combined. The organic phase was sequentially saturated with potassium carbonate solution. (50 mlxl), water (50 mix 1) and saturated sodium chloride solution (50 ml×1), the methylene chloride layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give the title product 2-[(2- Ethyl diethylamino-ethylcarbamoyl)-methyl]-4-phenyl-1 hydrogen-pyrrole-3-carboxylate lld (22.94 g, brown oil), yield: 91.33%.

 MS m/z (ESI): 372 (M+1).

Preparation of 2-[(2-diethylamino-ethylcarbamoyl)-methyl]-5-formyl-4-phenyl-l-hydrogen-pyrrole-3-carboxylate

Under an argon atmosphere, anhydrous N'N-dimethylformamide (0.58 ml, 7.5 mmol) was added to a 25 ml single-mouth bottle, cooled to 0 ° C in an ice bath, and phosphorus oxychloride was slowly added dropwise with stirring. 0.42 ml, 4.5 mmol), after completion of the dropwise addition, stir at room temperature for 15 minutes, continue cooling in an ice salt bath, and add 2-[(2-diethylamino-ethylcarbamoyl)-methyl to the reaction flask. a solution of 4-phenyl-1-hydro-pyrrole-3-carboxylate lid in anhydrous N'N-dimethylformamide (1.113 g, 3 mmol, dissolved in 3.6 ml of N'N-dimethyl In the amide), keep the reaction temperature After reacting at 0 ° C for 2 hours, the spot plate was traced until the disappearance of the starting material, and ice water (25 ml) was added to the reaction solution to quench the reaction, stirred for 5 minutes, and then adjusted to pH 12 with a 30% sodium hydroxide solution. The reaction mixture was extracted with EtOAc EtOAc (EtOAc (EtOAc). 2-[(2-Diethylamino-ethylcarbamoyl)-methyl]-5-formyl-4-phenyl-1 hydrogen-pyrrole-3-carboxylic acid ethyl ester lle (1.19 g, brown oil) , the yield is 99.33%, and the crude product is directly put into the next reaction.

 MS m/z (ESI): 1 (M+1).

_5- [4-(3-Chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrrole[2,3-d]pyrimidine-5-methylene-methyl]-2 -[(2-Diethylamino-ethylcarbamoyl)-methyl]- 4-phenyl-1 hydrogen-pyrrole-ethyl 3-carboxylate 11 was prepared under a argon atmosphere in a 10 ml vial , 2-[(2-Diethylamino-ethylcarbamoyl)-methyl]-5-formyl-4-methyl-1hydro-P-pyrrol-3-carboxylate 2c (0.14 g) , 0.35 mmol), 4-(3-chloro-4-fluoro-aniline)-5,7-dihydro-indolepyr[2,3-d]pyrimidin-6-one (0.097 g, 0.35 mmol), Pyridine (0.07 ml, 0.7 mmol) and ethanol (0.84 ml), heated under reflux for 1.5 hours, and traced to 4-(3-chloro-4-fluoro-aniline)-5,7-dihydro-pyrrole [2,3] -d] Pyrimidine-6-one completely disappeared, the reaction solution was naturally cooled to room temperature, and a large amount of solid was produced, which was filtered under reduced pressure to give the title product 5-[4-(3-chloro-4-fluoro-aniline)-6 -oxo-6,7-dihydro-pyrrole[2,3-d]pyrimidine-5-methylene-methyl]-2-[(2-diethylamino-ethylcarbamoyl)-methyl - 4-Phenyl-1 Hydrogen-pyrrole-3-carboxylic acid ethyl ester 11 (0.041 g, yellow solid), yield 17%.

 MS m/z (ESI): 660.8 (M + 1).

实施例 12 1H NMR (DMSO-D ₆ , 400MHz) 513.70 (s, 1H, NH), 8.84 (s, 1H, -NH), 7.36 (s, 1H, -CH=C), 7.43 (dd, 1H, -ArH) , 7.29-7.35(m, 5H, -ArH), 7.22-7.27(m, 2H, -ArH), 7.16(s, 1H, -ArH), 4.02(t, 2H, -C0 ₂ CH ₂ -), 3.99 (s, 2H, -CH ₂ CON-), 3.19(t, 2H, -CONCH ₂ -), 2.50(t, 2H, -NCH ₂ -), 2.49(q, 4H, 2x-NCH ₂ -), 1.00 (t, 3H, CH ₃ ), 0.95(t,

Example 12

 5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrrole[2,3-d]pyrimidine-5-methylene-methyl]-2 -[(2-Diethylamino-ethylcarbamoyl)-methyl]-4-trifluoromethyl-1hydro-pyrrole-3-carboxylic acid ethyl ester 12

Preparation of tert-butyl 4,4,4-trifluoro-2-indolyl-3-carbonyl-butyrate 12b, tert-butyl 4,4,4-trifluoro-3-carbonyl-butyrate under ice-bath conditions 12a (42.4 g, 0.2 mol) was dissolved in 60 ml of glacial acetic acid, and an aqueous solution of sodium nitrite (20 ml, 10 mol/L, 0.2 mol) was added dropwise with stirring, and the reaction temperature was controlled to 0 to 5 throughout the process. °C. After the completion of the dropwise addition, the mixture was reacted in an ice water bath for 1 hour, 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- A solution of mercapto-3-carbonyl-butyric acid tert-butyl ester 12b was directly subjected to the next reaction.

Preparation of 5-ethoxycarbonylmethyl-3-trifluoromethyl-1hydro-pyrrole-2,4-dicarboxylic acid-2-tert-butyl ester-4-ethyl ester 12c to a thermometer equipped with a dropping funnel In a 250 ml three-necked flask, diethyl 3-carbonyl-glutarate (48.2 g, 0.2 mmol) and glacial acetic acid (90 ml) were added in sequence, and the mixture was heated to 65 Torr with stirring, and the zinc powder was weighed (26 g total, 0.4 mol), add 1/8 amount of zinc powder (3.25 g, 0.05 mmol), add 1/8 amount of the first reaction liquid 12b with a dropping funnel, the temperature of the water bath control system can not rise too fast, wait for the temperature to be low After 65 ° C, add 1/8 of the amount of zinc powder and 1/8 of the first step of the reaction solution. This is repeated until the zinc powder and the first reaction liquid 12b are all added. The temperature was raised to 75 ° C and the reaction was carried out for about 2 hours. Pour the reaction solution into 100 ml of ice water under stirring, continue to stir to room temperature, remove unreacted zinc powder by filtration, extract the reaction solution with ethyl acetate (100 ml×3), combine the organic phases, and then use water (100 ml×3). Washed with saturated sodium bicarbonate (100 ml×4), saturated aqueous sodium chloride (100 ml×l) Filtration and concentration under reduced pressure afforded the title product 5--ethoxycarbonylmethyl-3-trifluoromethyl-1 hydrogen-pyrrole-2,4-dicarboxylic acid-2-tert-butyl ester-4-ethyl ester 12c (67.6 g , white waxy solid), yield 86%.

MS m/z (ESI): 394 (M + 1).

Preparation of 5-carboxymethyl-3-trifluoromethyl-1hydro-pyrrole-2,4-dicarboxylic acid-2-tert-butyl ester-4-ethyl ester 12d 5-Ethoxycarbonylmethyl-3- Trifluoromethyl-1hydro-pyrrole-2,4-dicarboxylic acid-2-tert-butyl ester-4-ethyl ester 12c (34.6 g, 0.088 mol) was dissolved in 268 ml of tetrahydrofuran and 134 ml of methanol and stirred. Aqueous lithium hydroxide solution (134 ml, 2.36 mol/L, 0.316 mol) was reacted at room temperature for 1.5 hours, and the spot was traced until the starting material completely disappeared. After the reaction mixture was concentrated under reduced pressure to remove most of tetrahydrofuran and methanol, water (200 ml) was added to the concentrate, and then the mixture was extracted with diethyl ether (100 ml×5), and the aqueous phase was transferred to a 1000 ml single-mouth bottle, and the mixture was stirred in an ice bath. After adding 20% hydrochloric acid to a pH of 1 to 3, a large amount of a pale yellow precipitate precipitated, suction filtered, and the solid was washed with diethyl ether and dried in vacuo to give the title product 5-carboxymethyl-3-trifluoromethyl-1 hydrogen. -P-pyrrol-2,4-dicarboxylic acid-2-tert-butyl ester 4-ethyl ester 12d (24 g, white solid), yield 74.7%.

MS m/z (ESI): 364 (M-1).

5-[(2-Diethylamino-ethylcarbamoyl)-methyl]-3-trifluoromethyl-1hydro-pyrrole-2,4-dicarboxylic acid-2-tert-butyl ester-4-ethyl ester Preparation of 12e

 Dissolve 5-carboxymethyl-3-trifluoromethyl-1hydro-pyrrole-2,4-dicarboxylic acid-2-tert-butyl ester-4-ethyl ester 12d (146 mg, 0.4 mmol) in 2 ml two In a mixed solvent of methyl chloride and 0.2 ml of N'N-dimethylformamide, it was cooled in an ice bath, and N'N-diethylethylenediamine (60 ul, 0.44 mmol), N-ethyl-N was added in sequence with stirring. ,-(Dimethylaminopropyl)-carbodiimide (154 mg, 0.8 mmol) and 1-hydroxybenzotriazole (56 mg, 0.4 mmol). The reaction was allowed to warm to room temperature and stirred overnight. After the next day the plate to the raw material Id disappeared completely, cold water (5 ml) was added to the reaction solution under vigorous stirring, and the liquid was separated, and the reaction liquid was extracted with dichloromethane (50 ml×3), and the organic phase was combined, and the organic phase was sequentially saturated. The potassium carbonate solution (5 ml×1), water (5 ml×1), and saturated sodium chloride solution (25 ml×l) was washed, and the methylene chloride layer was dried over anhydrous sodium sulfate. 2-diethylamino-ethylcarbamoyl)-methyl]-3-trifluoromethyl-1hydro-pyrrole-2,4-dicarboxylic acid-2-tert-butyl ester-4-ethyl ester 12e (154 mg , light yellow mucilage), yield 83%.

MS m/z (ESI): 464 (M+1).

Preparation of 5-[(2-diethylamino-ethylcarbamoyl)-methyl]-3-trifluoromethyl-lhydro-P-pyrrolidine-2,4-dicarboxylic acid 4-ethyl ester 12f

In a 100 ml three-necked flask, 5-[(2-diethylamino-ethylcarbamoyl)-methyl]-3-trifluoromethyl-1hydro-P-pyrrol-2,4-dicarboxylic acid -2-tert-Butyl ester-4-ethyl ester 12e (5.87 g, 12.67 mmol) was dissolved in dichloromethane (35 ml), trifluoroacetic acid (5 ml, 67.4 mmol) was added and stirred at room temperature for 1.5 hours. Board tracking original The material was substantially disappeared, and the reaction mixture was concentrated under reduced pressure to dryness to dryness crystals crystals 4-ethyl 2,4-dicarboxylate 12f (5.17 g, pale yellow solid), yield 100%. Used directly in the next step.

2-[(2-Diethylamino-ethylcarbamoyl)-methyl]-5-lightylmethyl-4-trifluoromethyl-hydrogen-pyrrole-3-carboxylate

 Preparation of 12g

5-[(2-Diethylamino-ethylcarbamoyl)-methyl]-3-trifluoromethyl-1hydro-pyrrole-2,4- under a nitrogen atmosphere in a 250 ml round bottom flask 4-ethyl dicarboxylate 12f (13.594 g, 33.4 mmol) was dissolved in 20 ml of anhydrous tetrahydrofuran with stirring, and a solution of boron hydride in tetrahydrofuran (100 ml, 1 mol/L, 100 mmol) was added dropwise to the reaction mixture at room temperature. The reaction was overnight. The plate was traced until the starting material disappeared, and cooled to 0 ° C. Dilute hydrochloric acid (50 ml, 1 mol/L) was slowly added dropwise to the reaction solution to quench the reaction. After stirring for 15 minutes, it was neutralized with 10% sodium hydroxide until The reaction mixture was extracted with EtOAc (EtOAc (EtOAc m. Ethyl 2-[(2-diethylamino-ethylcarbamoyl)-methyl]-5-carbomethyl-4-trifluoromethyl-1hydro-pyrrole-3-carboxylate 12 _g (2.94 g , white solid), yield 55%.

MS m/z (ESI): 394 (M + 1).

2-[(2-Diethylamino-ethylcarbamoyl)-methyl]-5-formyl-4-trifluoromethyl-l-hydrogen-pyrrole-3-carboxylate

 12h preparation

Add pyridine trioxide hydrochloride (4.3 g, 20 mmol), sodium acetate (1.0 g, 12.19 mmol) and dichloromethane (50 ml) to a 250 ml round bottom flask and slowly add 2- with stirring [(2-Diethylamino-ethylcarbamoyl)-methyl]-5-hydroxymethyl-4-trifluoromethyl-1 hydrogen-pyrrole-3-carboxylic acid ethyl ester 12 _g dichloromethane suspension The solution (7.14 g, 18.7 mmol, dissolved in 80 ml of dichloromethane) was reacted at room temperature for 5 hours, and the material was almost disappeared by the spotting. The reaction mixture was filtered over EtOAcjjjjjjjjjjjjjjj Ethyl 4-trifluoromethyl-1hydro-pyrrole-3-carboxylate 12h (4.985 g, white solid), yield 70%.

MS m/z (ESI): 399 (MH).

5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-pyrrole[2,3-d]pyrimidine-5-methylene-methyl]-2 -[(2-Diethylamino-ethylcarbamoyl)-methyl]-4-trifluoromethyl-1hydro-pyrrole-3-carboxylic acid ethyl ester 12 was prepared under an argon atmosphere in a 10 ml single port In the flask, 2-[(2-diethylamino-ethylcarbamoyl)-methyl]-5-formyl-4-trifluoromethyl-1hydro-pyrrole-3-carboxylate ethyl ester was added in sequence for 12 h ( 90 mg, 0.23 mmol), 4-(3-chloro-4-fluoro-aniline)-5,7-dihydro-pyrrole[2,3-d]pyrimidin-6-one (56 mg, 0.2 mmol), Pyridine (0.05 ml, 0.5 mmol) and ethanol (0.5 ml), heated under reflux for 1.5 hours, and traced to 4-(3-chloro-4-fluoro-aniline)-5,7-dihydro-pyrrole [2,3 -d]pyrimidine-6-one completely disappeared, the reaction solution was naturally cooled to room temperature, and there was a large amount of solid production. The crude solid was washed with a small amount of ethanol to give the title product 5-[4-(3-chloro-4-fluoro-aniline)-6-oxo-6,7-dihydro-P ratio. [2,3-d]pyrimidine-5-methylene-methyl]-2-[(2-diethylamino-ethylcarbamoyl)-methyl]-4-trifluoromethyl-1 hydrogen - Pyrrole-3-carboxylate ethyl ester 12 (61 mg, yellow solid), yield 41%. MS m/z (ESI): 652 (M+1). Example 13

 5-[4-(3-chloro-4-fluoro-phenylamino)-6-oxo-6,7-dihydro-pyrrole[2,3-d]pyrimidin-5-methine]-2-[ Ethyl 2-(4- -4-pyrrolidinylmethyl-piperidin-1-yl)-2-oxo-ethyl]-4-methyl-1hydro-pyrrole-3-carboxylate 13 Preparation

 13

 2-[2-(4-Hydroxy-4-pyrrolidinyl-1-methyl-piperidin-1-yl)-2-oxo-ethyl]-4-methyl-1 hydrogen-P ratio- Preparation of 3-carboxylate ethyl ester 13b

 Ethyl 2-carboxymethyl-4-methyl-1hydro-pyrrole-3-carboxylate 13a (1.55 g, 7.3 mmol), 4-pyrrolidine small methyl-piperidine under argon atmosphere Pyridin-4-hydroxy (3.29 g, 11 mmol), dichloromethane (37 ml), hydrazine, hydrazine-dimethylformamide (3.7 ml), N-ethyl-N,-(dimethylaminopropyl) - carbodiimide (3.7 g, 14.6 mmol) and 1-hydroxybenzotriazole (U mg, 7.3 mmol), triethylamine (10 ml, 75 mmol) in a 100 ml eggplant-shaped flask, stirred at room temperature overnight . The next day, the reaction to the raw material 13a is completed, and the reaction is quenched by adding ice cubes, and the organic layer is washed successively with a saturated sodium chloride solution (40 ml×5) and a saturated sodium carbonate solution (30 ml <3), anhydrous sodium sulfate. Drying, suction filtration, and concentration of the filtrate under reduced pressure to give the title product 2-[2-(4-hydroxy-4-pyrrolidinylmethylmethyl-piperidinyl)-2-oxo-ethyl]-4- Ethyl 1-hydrogen-pyrrole-3-carboxylate 13b (2 g, brown oil), yield: 74%.

MS m/z (ESI): 378·7 (Μ +1). 5-formyl-2-[2-(4-hydroxy-4-pyrrolidinylmethyl-piperidinyl)-2-oxo-ethyl]-4-methyl-1 hydrogen-pyrrole-3 -Preparation of ethyl carboxylate 13c

 Under an argon atmosphere, 100 ml of anhydrous dichloromethane was added to a 250 ml three-necked flask, cooled in a dry ice-acetone bath, and dimethylformamide (3.9 ml, 0.05 mol) was added thereto, followed by slow dropwise addition of phosphorus oxychloride ( 3.7 ml, 0.04 mol), after stirring for 5 minutes in a dry ice-acetone bath, stirring was continued for 20 minutes at room temperature, at which time the reaction system was a slightly yellow transparent solution. The reaction system was re-cooled in a dry ice-acetone bath to give 2-[2-(4-hydroxy-4-pyrrolidinyl-1-methyl-piperidin-1-yl)-2-oxo-ethyl]- Ethyl 4-methyl-1H-pyrrole-3-carboxylate 13b (2 g, 5.3 imnol) was dissolved in dichloromethane (27 ml) and hydrazine, dimethyl-dimethylformamide (1.1 ml). In the mixed solvent, it was slowly added dropwise to the reaction system. The reaction solution was further reacted in a dry ice-acetone bath for 1.5 hours, reacted in an ice bath for 1.5 hours, and reacted at room temperature for 3 hours. The reaction was traced to the disappearance of the starting material 13b, and the reaction was quenched by adding ice. Under ice bath, adjust the pH of the reaction solution to about 10 with sodium hydroxide, adjust the pH to slightly acidic with hydrochloric acid, extract the reaction solution with ethyl acetate (70 ml×9), dry the organic layer with anhydrous sodium sulfate, suction filtration, filtrate The organic layer was evaporated to dryness crystals crystals crystals crystals crystals 4-pyrrolidinyl-1-methyl-piperidin-1-yl)-2-oxo-ethyl]-4-methyl-1hydro-pyrrole-3-carboxylic acid ethyl ester 13c (1.29 g, brown Oil), Yield: 60%

 MS m/z (ESI): 406.9 (M + 1).

5-[4-(3-chloro-4-fluoro-phenylamino)-6-oxo-6,7-dihydro-pyrrole[2,3-d]pyrimidin-5-methine]-2-[ 2-(4-Hydroxy-4-pyrrolidinyl-1-methyl-piperidin-1-yl)-2-oxo-ethyl]-4-methyl-1hydro-pyrrole-3-carboxylic acid Preparation of ester 13

 5-formyl-2-[2-(4-hydroxy-4-pyrrolidinylmethyl-piperidine)-oxo-oxo was added sequentially in a 10 ml single-mouth vial under argon -ethyl]-4-methyl-1hydro-pyrrole-3-carboxylic acid ethyl ester 13c (0.103 g, 0.255 mmol), 4-(3-chloro-4-fluoro-aniline)-5,7-dihydrogen -Phenol [2,3-d]pyrimidin-6-one (0.071 g, 0.255 mmol) (Bioorganic & Medicinal Chemistry letters., 2002, 12(16), 2153-2157.), piperidine (0.637 ml, 0.637 mmol) and ethanol (0.7 ml), heated under reflux for 1.5 hours, and traced to 4-(3-chloro-4-fluoro-aniline)-5,7-dihydro-pyrrole [2,3-d]pyrimidine- The 6-ketone disappeared completely, the reaction solution was naturally cooled to room temperature, and a large amount of solid was produced, which was filtered under reduced pressure to give the title product 5-[4-(3-chloro-4-fluoro-phenylamino)-6-oxo- 6,7-Dihydro-P is more than [2,3-d]pyrimidin-5-methine]-2-[2-(4-hydroxy-4-pyrrolidinyl-1-methyl-piperidine- Ethyl 1-ethyl)-2-oxo-ethyl]-4-methyl-1hydro-pyrrole-3-carboxylate 14 (78 mg, yellow solid), yield 46.0%.

 MS m/z (ESI): 666.7 (M + 1).

^MR (DMSO-D ₆ ,400MHz) 8.315(s, 1H, -NH), 7.707~7.685(dd, 1H, -ArH), 4.210-4.156(dd, 2H, -CH ₂ ), 2.450~2.414(d , -4H, 2xCH ₂ ), 2.355(s, 3H, -CH ₃ ), 1.484-1.459 (m, 4H, 2><CH ₂ ), 1.281~1.246 (t, 3H, -CH ₃ ). Example 14

5-[4-(3-chloro-4-fluoro-phenylamino)-6-oxo-6,7-dihydro-pyrrole[2,3-d]pyrimidin-5-methine]-2-[ Preparation of ethyl 2-(4-hydroxy- ₄ -pyridiniummethyl-piperidine-1-yl) _-2 -oxo-ethyl]-4-methyl-1hydro-pyrrole-3-carboxylate 14

 2-[2-(4-Hydroxy-4-piperidin-1-methyl-piperidin-1-yl)-2-oxo-ethyl]-4-methyl-1H-pyrrole-3-carboxylic acid Ethyl ester

 Preparation of 14a

 Ethyl 2-carboxymethyl-4-methyl-1 hydrogen-pyrrole-3-carboxylate 13a (316 mg, 1.5 mmol), 4-piperidin-4-yl under argon Base-piperidin-4-hydroxy (707 mg, 2.25 mmol), dichloromethane (7.6 ml), hydrazine, hydrazine-dimethylformamide (0.76 ml), N-ethyl-N,-dimethylamino Propyl)-carbodiimide (748 mg, 2.25 mmol) and 1-hydroxybenzotriazole (304 mg, 2.25 mmol), triethylamine (2.09 ml, 15 mmol) in a 25 ml eggplant bottle, at room temperature Stir overnight. The next day, the reaction to the raw material was completed, and the reaction was quenched by adding ice cubes. The organic layer was washed successively with saturated sodium chloride solution (20 ml×5) and saturated potassium carbonate solution (20 ml×l), dried over anhydrous sodium sulfate and evaporated. Filtration and concentration of the filtrate under reduced pressure afforded the title product 2-[2-(4-hydroxy-4-piperidin-1-methyl-piperidin-1-yl)-2-oxo-ethyl]-4-methyl -1H-pyrrole-3-carboxylic acid ethyl ester 14a (557 mg, brown oil), Yield: 95 %

 MS m/z (ESI): 392·6 (Μ +1).

5-formyl-2-[2-(4-hydroxy-4-piperidin-1-methyl-piperidin-1-yl)-2-oxo-ethyl]-4-methyl-1 hydrogen- Pyrrole

 Preparation of ethyl-3-carboxylate 14b

Under an argon atmosphere, 100 ml of anhydrous dichloromethane was added to a three-necked flask, cooled in a dry ice-acetone bath, and dimethylformamide (3.9 ml, 0.05 mol) was added, followed by slow dropwise addition of phosphorus oxychloride (3.7 ml, After stirring for 5 minutes in a dry ice-acetone bath, stirring was continued at room temperature for 20 minutes, at which time the reaction system was yellowish. Clear solution. The reaction system was re-cooled in a dry ice-acetone bath to give 2-[2-(4-hydroxy-4-piperidin-1-methyl-piperidin-1-yl)-2-oxo-ethyl]-4 -methyl-1H-pyrrole-3-carboxylic acid ethyl ester 14a (7.9 g, 0.02 mol) dissolved in dichloromethane (30 ml) and a mixed solvent of hydrazine, hydrazine-dimethylformamide (1 ml) Medium, slowly added dropwise to the reaction system. The reaction solution was further reacted in a dry ice-acetone bath for 1.5 hours, reacted in an ice bath for 1.5 hours, and reacted at room temperature for 3 hours. The reaction was tracked until the starting material 14a disappeared, and ice cubes were added to quench the reaction. Under ice bath, adjust the pH of the reaction solution to about 10 with sodium hydroxide, adjust the pH to slightly acidic with hydrochloric acid, and extract the reaction solution (dichloromethane: methanol = 10: 1, 100 mlx9), and the organic layer is anhydrous sodium sulfate. Drying, suction filtration, EtOAc~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 2-[2-(4-Hydroxy-4-piperidin-1-methyl-piperidin-1-yl)-2-oxo-ethyl]-4-methyl-1hydro-pyrrole-3-carboxylate Ethyl ester 14b (3.5 g, brown oil), yield: 36.1%.

 MS m/z (ESI): 42.

5-[4-(3-Chloro-4-fluoro-phenylamino)-6-oxo-6,7-dihydro-pyrrole[2,3-d]pyrimidin-5-methine]-2-[ 2-(4-Hydroxy- ₄ piperidinylmethyl-piperidine)- ₂ oxo-ethyl] _ ₄ -methyl- 1H-indolepyr-3-carboxylate ethyl ester 14 Preparation of 5-formyl-2-[2-(4-hydroxy-4-piperidin-1-methyl-piperidin-1-yl)- in a 10 ml single-mouth bottle under argon atmosphere Ethyl 2-oxo-ethyl]-4-methyl-1hydro-pyrrole-3-carboxylate 14b (0.113 g, 0.27 mmol), 4-(3-chloro-4-fluoro-aniline) -5, 7-Dihydro-pyrrole[2,3-d]pyrimidin-6-one (0.075 g, 0.27 mmol) (Bioorganic & Medicinal Chemistry letters., 2002, 12(16), 2153-2157.), piperidine (0.675) Ml, 0.675 mmol) and ethanol (0.8 ml), heated under reflux for 1.5 hours, point plated to 4-(3-chloro-4-fluoro-aniline) -5,7-dihydro-P ratio [2,3- d] Pyrimidine-6-one completely disappeared, the reaction solution was naturally cooled to room temperature, a large amount of solid was produced, and filtered under reduced pressure to give the title product 5-[4-(3-chloro-4-fluoro-phenylamino)-6. -oxo-6,7-dihydro-pyrrole[2,3-d]pyrimidin-5-methine]-2-[2-(4-hydroxy-4-piperidin-1-methyl-piperidine -1-yl)-2-oxo-ethyl]-4-methyl-1 hydrogen-pyridyl 3-carboxylate 14 (0.103 g, yellow solid), yield 56.1%.

 MS m/z (ESI): 680.5 (M + 1).

¹ H NMR (DMSO-D ₆ , 400 MHz) 13.642 (s, 1H, -NH), 9.284 (s, 1H, -NH), 8.334 (s, 1H, -CH), 7.400~7.378 (d, 1H, -ΑιΉ) ), 3.292(s, 2H, -CH ₂ ), 2.431~2.388(t, 4H, 2x-CH ₂ ), 2.190(s, 2H, -CH ₂ ), 1.303-1.267(t, 6H, 2x-CH ₃ ). Example 15

 5-[4-(3-chloro-4-fluoro-phenylamino)-6-oxo-6,7-dihydro-pyrrole[2,3-d]p-pyrimidine-5-methine]-2- [2-(4-Diethylaminomethyl-4-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-4-methyl-1hydro-pyrrole-3-carboxylic acid ethyl ester 15

Preparation

 2-[2-(4-Diethylaminomethyl-4-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-4-methyl-1-hydrogen-P ratio- 3- Preparation of ethyl carboxylate 15a

 Ethyl 2-carboxymethyl-4-methyl-1hydro-pyrrole-3-carboxylate 13a (316 mg, 1.5 mmol), 4-diethylaminomethyl- under argon atmosphere Piperidine-4-hydroxy (420 mg, 2.25 mmol), dichloromethane (8 ml), hydrazine, hydrazine-dimethylformamide (0.76 ml), N-ethyl-N,-(dimethylaminopropyl) - carbodiimide (748 mg, 2.25 mmol) and 1-hydroxybenzotriazole (304 mg, 2.25 mmol), triethylamine (2.09 ml, 15 mmol) in a 25 ml eggplant-shaped flask, stirred at room temperature overnight. The next day, the reaction to the raw material 13a was completed, and the reaction was quenched by adding ice, and the organic layer was washed successively with saturated sodium chloride solution (20 ml×5) and saturated potassium carbonate solution (20 ml×l), and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate under reduced pressure gave the title product 2-[2-(4-diethylaminomethyl-4-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-4- Base-1 hydrogen-pyrrole-3-carboxylic acid ethyl ester

15a (570 mg, brown oil), directly to the next step.

 MS m/z (ESI): 380.7 (M+l) o

2-[2-(4-Diethylaminomethyl-4-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-5-formyl-4-methyl-1 hydrogen-pyrrole Preparation of ethyl-3-carboxylate 15b

Under an argon atmosphere, 17 ml of anhydrous dichloromethane was added to a three-necked flask, cooled in a dry ice-acetone bath, and hydrazine, hydrazine-dimethylformamide (0.77 ml, 10 mmol) was added, and phosphorus oxychloride was slowly added dropwise. After stirring for 10 minutes in a dry ice-acetone bath, stirring was continued at room temperature for 20 minutes, at which time the reaction system was a slightly yellow transparent solution. The reaction system was re-cooled in a dry ice-acetone bath to give 2-[2-(4-diethylaminomethyl-4-carbyl-piperidinyl)-2-oxo-ethyl]-4-methyl Ethyl 1-hydrogen-pyrrole-3-carboxylic acid ethyl ester 15a (1.265 g, 3.34 mmol) was dissolved in a mixed solvent of 5 ml of dichloromethane and 1 ml of N,N-dimethylformamide with stirring, slowly It is added dropwise to the reaction system. The reaction solution was further reacted in a dry ice-acetone bath for 1.5 hours, reacted in an ice bath for 1.5 hours, and reacted at room temperature for 3 hours. The reaction was traced to the disappearance of the starting material 15a, and the reaction was quenched by adding ice. Under ice bath, adjust the pH of the reaction solution to about 10 with sodium hydroxide, adjust the pH to slightly acidic with hydrochloric acid, and extract the reaction solution (dichloromethane: methanol = 10: 1, 100 mlx9), and the organic layer is anhydrous sodium sulfate. The title compound (2-[2-) was obtained. m.jjjjjjjjjjjjjj (4-Diethylaminomethyl-4-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-5-carvedyl-4-methyl-1hydro-pyrrole-3-carboxylate Ethyl ester 15b (297 mg, tan solid), Yield: 21.9%.

MS m/z (ESI): 409.0 (M+1).

₅ _[4-(3-Chloro-4-fluoro-phenylamino)-6-oxo-6,7-dihydro-pyrrole[2,3-d]p-pyrimidine-5-methine]-2- [2-(4-Diethylaminomethyl-4-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-4-methyl-1hydro-pyrrole-3-carboxylic acid ethyl ester 15

 Preparation

 2-[2-(4-Diethylaminomethyl-4-hydroxy-piperidin-1-yl)-2-oxo-ethyl group was added sequentially in a 10 ml single-mouth bottle under argon atmosphere. -5-Formyl-4-methyl-1 Hydrogen-pyrrole-3-carboxylic acid ethyl ester 15b (0.037 g, 0.09 mmol), 4-(3-chloro-4-fluoro-aniline) -5,7- Dihydro-pyrrole[2,3-d]pyrimidin-6-one (0.025 g, 0.09 mmol) (Bioorganic & Medicinal Chemistry letters., 2002, 12(16), 2153-2157.), piperidine (0.225 ml, 0.225 mmol) and ethanol (0.3 ml), heated under reflux for 1.5 hours, and traced to 4-(3-chloro-4-fluoro-aniline)-5,7-dihydro-pyrrole [2,3-d]pyrimidine- The 6-ketone disappeared completely, the reaction solution was naturally cooled to room temperature, and a large amount of solid was produced, which was filtered under reduced pressure to give the title product 5-[4-(3-chloro-4-fluoro-phenylamino)-6-oxo- 6,7-Dihydro-P than [2,3-d]p-pyrimidine-5-methine]-2-[2-(4-diethylaminomethyl-4-hydroxy-piperidine-1 Ethyl- -2-oxo-ethyl]-4-methyl-1hydro-pyrrole-3-carboxylic acid ethyl ester 15 (22 mg, yellow solid), yield 36.6%.

 MS mJz (ESI): 668·7 (Μ +1).

1HNMR (DMSO-D ₆ , 400MHz) 13.623 (s, 1H, -NH), 9.285 (s, 1H, -NH), 8.336 (s, 1H, -CH), 7.740~7.735 (d, 1H, -ArH) , 2.514~2.506(s, 3H, -CH ₃ ), 2.282(s, 2H, -CH ₂ ), 1.462~1.435(dd, 4H, 2x-CH ₂ ), 0.931-0.896 (t, 6H, 2x-CH ₃ ). Example 16

 5-[4-(3-Chloro-4-fluoro-phenylamino)-6-oxo-6,7-dihydro-pyrrole[2,3-d]pyrimidin-5-methine]-4-methyl Preparation of ethyl 2-{[2-(4-methyl-piperazin-1-yl)-ethylcarbamoyl]-methyl}-1 hydrogen-pyrrole-3-carboxylate 16

 4-methyl-2-{[2-(4-methyl-piperazin-1-yl)-ethylcarbamoyl]-methyl }-l hydrogen-pyrrole-3-carboxylic acid ethyl ester

 Preparation of 16a

 Ethyl 2-carboxymethyl-4-methyl-1hydro-pyrrole-3-carboxylate 13a (3 g, 14.2 mmol), 2-(4-methyl-piperidine) under argon atmosphere Pyrazin-1-yl)-ethylamine (2.23 g, 14.2 mmol), dichloromethane (71 ml), N,N-dimethylformamide (7.1 ml), N-ethyl-N, - Aminopropyl)-carbodiimide (5.43 g, 28.4 mmol) and 1-hydroxybenzotriazole (1.92 g, 14.2 mmol) were added to a 25 ml eggplant-shaped flask and stirred at room temperature overnight. The next day, the reaction was completed until the raw material 14a was completely reacted. The reaction was quenched by adding ice, and the organic layer was washed successively with saturated sodium chloride solution (50 ml×5) and saturated potassium carbonate solution (20 ml×l), and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate under reduced pressure afforded the title product 4-methyl-2-{[2-(4-methyl-piperazin-1-yl:)-ethylcarbamoyl]-methyl 1-hydro-pyrrole Ethyl 3-carboxylate 16a (1.2 g, yellow solid), Yield: 25.1%

5-formyl-4-methyl-2-{[2-(4-methyl-piperazin-1-yl)-ethylcarbamoyl]-methyl}-1 hydrogen-pyrrole-3-carboxylic acid Preparation of ethyl ester 16b

Dichloromethane (18 ml, dry) was added to a three-necked flask under argon, cooled in a dry ice-acetone bath, and hydrazine, hydrazine-dimethylformamide (0.7 ml, 8.93 mmol) was added, followed by slow dropwise addition of trichloroox Phosphorus (0.5 ml, 5.36 mmol) was stirred for 5 minutes in a dry ice-acetone bath, and stirring was continued at room temperature for 20 minutes, at which time the reaction system was a slightly yellow transparent solution. The reaction system was re-cooled in a dry ice-acetone bath to give 4-methyl-2-{[2-(4-methyl-piperazin-1-yl)-ethylcarbamoyl]-methyl}-1 hydrogen Ethyl pyrrole-3-carboxylate 16a (1.2 g, 3.57 mmol) was dissolved in 6 ml of dichloromethane with stirring and slowly added dropwise to the reaction mixture. The reaction solution was further reacted in a dry ice-acetone bath for 1.5 hours, reacted in an ice bath for 1.5 hours, and reacted at room temperature for 3 hours. The reaction was traced to the disappearance of the starting material 16a, and the reaction was quenched by adding ice. Under ice bath, the pH of the reaction solution was adjusted to about 11 with sodium hydroxide, and the reaction mixture was extracted (dichloromethane: methanol = 20: 1, 60 ml x 8). The organic layer was dried over anhydrous sodium sulfate, filtered and filtered. The residue was purified to give crystal crystal crystal crystal crystal crystal crystal Ethyl ethylcarbamoyl]-methyl}-1 hydrogen-pyrrole-3-carboxylate 110b (892 mg, yellow solid). Yield: 68.4%. MS: 365.5 (M+l) c

5-[4-(3-Chloro-4-fluoro-phenylamino)-6-oxo-6,7-dihydro-pyrrole[2,3-d]pyrimidin-5-methine]-4-methyl Preparation of ethyl _{2- 2} _{[ ₂ _( ₄ -methyl-piperazine small group)-ethylcarbamoyl]-methyl}-hydrogen-pyrrole-3-carboxylate 16 under an argon atmosphere In a 10 ml single-mouth bottle, 5-formyl-4-methyl-2-{[2-(4-methyl-piperazin-1-yl)-ethylcarbamoyl]-methyl was added in sequence. }-1 Hydrogen-pyrrole-3-carboxylic acid ethyl ester 16b (0.055 g, 0.15 mmol), 4-(3-chloro-4-fluoro-aniline)-5,7-dihydro-pyrrole [2,3-d Pyrimidine-6-one (0.042 g, 0.15 mmol) (Bioorganic & Medicinal Chemistry letters., 2002, 12(16), 2153-2157.), piperidine (0.375 ml, 0.375 mmol) and ethanol (0.5 ml), After heating under reflux for 1.5 hours, the spot plate was traced to 4-(3-chloro-4-fluoro-aniline)-5,7-dihydro-pyrrole [2,3-d]pyrimidin-6-one completely disappeared, and the reaction solution was naturally After cooling to room temperature, a large amount of solid was produced, and filtered under reduced pressure to give the title product 5-[4-(3-chloro-4-fluoro-phenylamino)-6-oxo-6,7-dihydro-pyrrole [2 ,3-d]pyrimidine-5-methine]-4-methyl-2-{[2-(4-methyl-piperazin-1-yl)-ethylcarbamoyl]-methyl}- 1hydro-pyrrole-3-carboxylic acid Ester 16 (44 mg, yellow solid), yield 47.1%.

 MS ni/z (ESI): 625.9 (M+1).

^MR (DMSO-D ₆ ,400MHz) 8.323(s, 1H, -NH), 7.712~7.689(d, 1H, -ArH), 4.238~4.185(q, 2H, -CH ₂ ), 3.219~3.185(t , 2H, -CH ₂ ), 2.445(s, 3H, -CH ₃ ). Example 17

 5-[4-(3-chloro-4-fluoro-phenylamino)-6-oxo-6,7-dihydro-pyrrole[2,3-d]pyrimidin-5-methine]-2-[ 2-(4-hydroxy-4-morpholine-4-methyl-piperidinyl)-2-oxo-ethyl]-4-methyl-1hydro-pyrrole-3-carboxylic acid ethyl ester 17 System

 2-[2-(4-Hydroxy-4-morpholine-4-methyl-piperidin-1-yl)-2-oxo-ethyl]-4-methyl-1hydro-pyrrole-3-carboxylate Preparation of ethyl acetate 17a

 Ethyl 2-carboxymethyl-4-methyl-1hydro-pyrrole-3-carboxylate 13a (638 mg, 3.0 mmol), 4-morpholine-4-methyl under argon atmosphere - piperidin-4-hydroxyl (1.425 g, 4.5 mmol), dichloromethane (15.5 ml), hydrazine, hydrazine-dimethylformamide (1.55 ml), N-ethyl-Ν'- (dimethylaminopropyl) -carbodiimide (1.49 g, 4.5 mmol) and 1-hydroxybenzotriazole (609 mg, 4.5 mmol), triethylamine (4.22 ml, 30 mmol) in a 25 ml eggplant bottle, at room temperature Stir overnight. The next day, the reaction to the raw material 13a was completed. The reaction was quenched by adding ice cubes, and the organic layer was washed successively with saturated sodium chloride solution (40 ml×5) and saturated potassium carbonate solution (40 ml×1), dried over anhydrous sodium sulfate. After suction filtration, the filtrate was concentrated under reduced pressure to give the title product 2-[2-(4-hydroxy-4-morpholine-4-methyl-piperidinyl)-2-oxo-ethyl]-4-methyl -1 Hydrogen-pyrrole-3-carboxylic acid ethyl ester 17a (1.742 g, brown oil) was taken directly to the next step.

 MS m/z (ESI): 394.1 (M+1).

5-formyl-2-[2-(4-hydroxy-4-morphinphyrin-4-methyl-piperidin-1-yl)-2-oxo-ethyl]-4-methyl-1 hydrogen- Preparation of ethyl bromide-3-carboxylate 17b

Dichloromethane (23 ml, dry) was added to a three-necked flask under argon, cooled in a dry ice-acetone bath, and N,N-dimethylformamide (1.0 ml, 0.012 mol) was added, followed by slow dropwise addition of trichloro Phosphorus (0.83 ml, 8.87 mmol) was stirred for 5 minutes in a dry ice-acetone bath, and stirring was continued at room temperature for 20 minutes, at which time the reaction system was a slightly yellow transparent solution. The reaction system was re-cooled in a dry ice-acetone bath to give 2-[2-(4-hydroxy-4-morpholine-4-methyl-piperidin-1-yl)-2-oxo-ethyl]-4 Ethyl methyl 1-hydro-pyrrole-3-carboxylate 17a (1.742 g, 4.43 mmol) was dissolved in 7 ml of dichloromethane with stirring and slowly added dropwise to the reaction mixture. The reaction solution was further reacted in a dry ice-acetone bath for 1.5 hours, reacted in an ice bath for 1.5 hours, and reacted at room temperature for 3 hours. The reaction was traced to the disappearance of the starting material 17a, and the reaction was quenched by adding ice. Under ice-cooling, the pH of the reaction mixture was adjusted to about 11 with sodium hydroxide, and the reaction mixture was extracted (dichloromethane: methanol 20:1, 60 ml×8), and the organic layer was dried over anhydrous sodium sulfate. The residue was obtained as a dark brown solid, which was purified by silica gel column chromatography (dichlorobenzene: EtOAc: EtOAc: EtOAc: EtOAc Morpholin-4-methyl-4 - piperidinyl - i - yl) -2-oxo - ethyl] _ ₄ - methyl hydrogen _i - pyrrole-3-carboxylic acid ethyl ester 17b (660 mg, Light yellow solid), Yield: 35.3 %.

 MS m/z (ESI): 422.7 (M+l).

5-[4-(3-chloro-4-fluoro-phenylamino)-6-oxo-6,7-dihydro-pyrrole[2,3-d]pyrimidin-5-methine]-2-[ 2-(4-hydroxy-4-4-morpholine-4-methyl-piperidinyl)-2-oxo-ethyl]-4-methyl-1hydro-pyrrole-3-carboxylic acid ethyl ester 17 Preparation

 5-formyl-2-[2-(4-hydroxy-4-morpholine-4-methyl-piperidinyl)-2-oxo was added sequentially in a 10 ml single-mouth vial under argon Ethyl-ethyl]-4-methyl-1hydro-pyrrole-3-carboxylic acid ethyl ester 17b (0.057 g, 0.136 mmol), 4-(3-chloro-4-fluoro-aniline) -5,7-di Hydrogen-pyrrole[2,3-d]pyrimidin-6-one (0.038 g, 0.136 mmol) (Bioorganic & Medicinal Chemistry letters., 2002, 12(16), 2153-2157.), piperidine (0.342 ml, 0.342) Methyl) and ethanol (0.4 ml), heated under reflux for 1.5 hours, and traced to 4-(3-chloro-4-fluoro-aniline)-5,7-dihydro-pyrrole [2,3-d]pyrimidine-6 - The ketone disappears completely, the reaction solution is naturally cooled to room temperature, a large amount of solid is produced, and filtered under reduced pressure to give the title product 5-[4-(3-chloro-4-fluoro-phenylamino:)-6-oxo- 6,7-Dihydro-pyrrole[2,3-d]pyrimidin-5-methine]-2-[2-(4-hydroxy-4-morphinphyrin-4-methyl-piperidin-1-yl Ethyl 2-oxo-ethyl]-4-methyl-1hydro-pyrrole-3-carboxylate 17 (25 mg, yellow solid), yield 26.8%.

 MS m/z (ESI): 682.6 (M + 1).

_{1HNMR (DMSO- D 6, 400MHz)} 13.642 (s, 1H, -NH), 9.284 (s, 1H, -NH), 8.334 (s, 1H, -CH), 7.400 ~ 7.378 (d, 1H, -ArH) , 3.292(s, 2H, -CH ₂ ), 2.431-2.388(t, 4H, 2x-CH ₂ ), 2.190(s, 2H, -CH ₂ ), 1.303-1.267(t, 6H, 2x-CH ₃ ) . Example 18

5-[4-(3-Chloro-4-fluoro-phenylamino)-6-oxo-6,7-dihydro-pyrrole[2,3-d]pyrimidin-5-methine]-4-methyl yl _ ₂ - {[3- (4-methyl - piperazinyl small-yl) - propyl-carbamoyl] - methyl} hydrogen- 1 - pyrrole-3-carboxylate 18

18

 4-methyl-2-{[3-(4-methyl-piperazinyl)-propylcarbamoyl]-methyl }-l hydrogen-Ppyrrol-3-carboxylate

 Preparation of 18a

 Under the argon atmosphere, 2-carboxymethyl-4-methyl-1 hydrogen-P than ethyl-3-carboxylate 13a (2.11 g, 10 mmol), 3-(4-methyl) -piperazin-1-yl)-propylamine (1.73 g, 11 mmol), dichloromethane (50 ml), hydrazine, hydrazine-dimethylformamide (5 ml), N-ethyl-N, - (dimethylaminopropyl)-carbodiimide (3.8 g, 20 mmol) and 1-hydroxybenzotriazole (1.35 g, 10 mmol), triethylamine (3.5 ml, 25 mmol) added to 100 ml of eggplant Stir at room temperature overnight in a vial. The next day, the reaction to the raw material 13a was completed, and the reaction was quenched by adding ice, and the organic layer was washed successively with saturated sodium chloride solution (20 ml×5) and saturated potassium carbonate solution (20 ml×l), and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate under reduced pressure gave the title product 4-methyl-2-{[3-(4-methyl-piperazin-1-yl)-propylcarbamoyl]-methyl}-1 hydrogen- Ethyl pyrrole-3-carboxylate 18a (3 g, brown oil), Yield: 85.7%

 MS m/z (ESI): 351.8 (M+1).

Ethyl 5-formyl-4-methyl-2-{[3-(4-methyl-piperazine)-propylcarbamoyl]-methyl}-1hydro-pyrrole-3-carboxylate Preparation of 18b

Under argon atmosphere, add 44 ml of anhydrous dichloromethane to a 100 ml three-necked flask, cool in a dry ice-acetone bath, add hydrazine, hydrazine-dimethylformamide (1.8 ml, 0.02 mol), and slowly add trichlorochloride. Phosphorus (1.41 ml, 9.43 mmol), after stirring for 5 minutes, the ice-acetone bath was thoroughly removed, and stirring was continued for 20 minutes at room temperature until the reaction system was a yellowish transparent solution. The reaction system was re-cooled in a dry ice-acetone bath to give 4-methyl-2-{[3-(4-methyl-piperazin-1-yl)-propylcarbamoyl]-methyl}-1 hydrogen Ethyl pyrrole-3-carboxylate 18a (3 g, 8.57 mmol) was dissolved in a mixed solvent of 10 ml of dichloromethane and 0.5 ml of N,N-dimethylformamide with stirring, and slowly added dropwise to the reaction system. . The reaction solution was reacted in a thousand ice-acetone bath for 1.5 hours, reacted in an ice bath for 1.5 hours, and reacted at room temperature for 3 hours. The reaction was traced to the disappearance of the starting material 18a, and the reaction was quenched by adding ice. Under ice bath, adjust the pH of the reaction solution to about 11 with 1M sodium hydroxide solution, and extract the reaction solution (dichloromethane: methanol = 10: 1, 50 mlx6). The organic layer was dried over anhydrous sodium sulfate and filtered. Concentration under reduced pressure afforded EtOAc (EtOAc:EtOAc) (4-methyl-piperazine small group)-propylcarbamoyl] - Ethyl methyl}-l-hydropyrrole-3-carboxylate 18b (200 mg, brown oil), yield: 6.1%.

MS m/z (ESI): 379 +1).

₅ _[4-(3-Chloro-4-fluoro-phenylamino)-6-oxo-6,7-dihydro-pyrrole[2,3-d]pyrimidin-5-methine]-4-A Preparation of ethyl 2-{-(3-(4-methyl-piperazine)-propylcarbamoyl]-methyl}-1hydro-pyrrole-3-carboxylic acid ethyl ester 18

 5-formyl-4-methyl-2-{[3-(4-methyl-piperazin-1-yl)-propylcarbamoyl] in a 10 ml vial under argon -Methyl}-1 Hydrogen-pyrrole-3-carboxylic acid ethyl ester 18b (0.049 g, 0.129 mmol), 4-(3-chloro-4-fluoro-aniline)-5,7-dihydro-pyrrole [2, 3-d]pyrimidin-6-one (0.036 g, 0.129 mmol) (Bioorganic & Medicinal Chemistry letters., 2002, 12(16), 2153-2157.) and piperidine (0.322 ml, 0.322 mmol) dissolved in stirring In 0.4 ml of ethanol, heating under reflux for 1.5 hours, the spotting was traced to 4-(3-chloro-4-fluoro-aniline)-5,7-dihydro-pyrrole [2,3-d]pyrimidin-6-one completely disappeared. The reaction solution was naturally cooled to room temperature, and a large solid was produced, which was filtered under reduced pressure to give the title product 5-[4-(3-chloro-4-fluoro-phenylamino)-6-oxo-6,7- Hydrogen-pyrrole[2,3-d]pyrimidin-5-methine]-4-methyl-2-{[3-(4-methyl-piperazin-1-yl)-propylcarbamoyl] Ethylmethyl-1-hydrogen-pyrrole-3-carboxylate 18 (35 mg, yellow solid), yield 42.5.

 MS m/z (ESI): 639.7 (M+l).

lHNMR (DMSO-D ₆ , 400MHz) 13.642(s, 1H, -NH), 9.284(s, 1H, -NH), 8.334(s, 1H, -CH), 7.400~7.378(d, 1H, -ArH) , 3.292(s, 2H, -CH ₂ ), 2.431~2.388(t, 4H, 2x-CH ₂ ), 2.190(s, 2H, -CH ₂ ), 1.303-1.267(t, 6H, 2x-CH ₃ ) .

Determination of kinase inhibitory activity

Example 1: Inhibition of cell proliferation test

 The following in vitro assays were used to determine the inhibitory activity of the compounds of the invention against cell lines with high expression of human tumor cells HUVEC VEGFR.

The in vitro cell assay described below can determine the anti-angiogenic activity and the proliferative activity of the test compound against VEGFR-expressing tumor cells, and the activity can be expressed by the IC _5Q value. The general protocol for such an experiment is as follows: First, human tumor cells with high expression of VEGFR are selected, seeded in 96-well culture plates at a suitable cell concentration (exp 5000 cells/ml medium), and then cultured 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. IC _5Q values can be passed through a range of different concentrations of test compounds for cells The suppression value is calculated. Materials and Method:

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

c. Falcon 100 mm cell culture plate (Baton Dickison Labware, Baton Dicldson and company, catalogue 18677)

d. corning 96孑 L culture plate (Coming Incorporated, catalogue 3599)

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

f. DMEM/F12 cell culture medium (Gibco, catalogue l ² 400-0 ² 4)

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, catalogue 0826)

n. Class II A/B3 Biological Safety Work Cabinet (ThermoForma Catalogue. HB005 ³ -03)

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

ρ· Centrifuge (Fisher Scientific Marathon 8 k, Catalogue 0027-02)

q. Novastar Board Reader (BMG Labtech, Catalog 700-0081)

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

The following protocol was used to test the inhibitory cell proliferation IC ₅ o values of the test compounds of the invention against HUVEC cells.

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

 2. Wash HUVEC cells with fetal bovine serum in 100 mm culture plates, 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. Control hole

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 above configuration using cell culture medium (DMEM/F12 +10% fetal bovine serum as culture medium) Compound solution. 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 HUVEC cells exposed to the DMSO solution did not exceed 0.5%, and mixed with the scramble;

 6. When the HUVEC cells are adherent and the growth reaches 85% confluence, the medium is changed to a new medium supplemented with DMEM/F12 +10% fetal bovine serum, and 180 μl of the culture medium and 20 μM are added to each well. The test compound solution prepared in the fifth step. In the negative control cell group, 20 μL of culture medium containing 0.5% DMSO was added, so that the final concentration of HUVEC 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 at 4 ° C for 1 hour, 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 μM sulforhodamine B solution to each well;

 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 was measured by the above test, and the measured IC50 values are shown in the following table.

IC ₅₀ (VEGFR/HUVEC)^M) 2.4

 4.7

 2.9

 4.2

 3.3 Example 3: Inhibition of 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 tumor cells highly expressing EGFR, the activity of which can be expressed by the IC _5Q value. The general protocol for such an experiment is as follows: First, human tumor cells with high expression of EGFR are selected, seeded in 96-well culture plates at a suitable cell concentration (exp 5000 cells/ml medium), and then the cells are cultured 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:

s. dimethyl sulfoxide (Sinoplima chemical reagent company, catalogue T20050806) t. A431 cells (Beigou in the Institute of biochemistry and cell biology)

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

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

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

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

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

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

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

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

Cc. citric acid (Sinophma chemical reagent company, catalog T20060508)

Dd. Trichloroacetic acid (Sinophma chemical reagent company, catalogue T20060305) ee. Tris base (Amresco, catalogue No. 0826)

Ff. Class II A/B3 Biological Safety Work Cabinet (ThermoForma Catalogue. HB0053-03) Gg. Series II water jacketed carbon dioxide incubator (ThermoForma model: 3111)

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

Ii. Novastar Board Reader (BMG Labtech, Catalog 700-0081)

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

The following protocol was used to test the inhibitory cell proliferation IC _5Q values of the test compounds of the invention against A431 cells.

17. 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;

 18. Wash A431 cells with fetal bovine serum in 100 mm culture plates, 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. Control hole

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

20. Dissolve the test compound in DMSO, dispose the 20 mM mother liquor, and then 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;

21. 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;

 22. 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 culture 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 μM 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

23. The culture plate is placed in an incubator and continuously cultured at 37 ° C, 5 % C0 ₂ for 72 hours;

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

 25. 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;

 26. Incubate at 4 ° C for 1 hour, 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.

 27. Prepare 0.4% Sulforhodamine B solution in 10% acetic acid solution, and add 50 μM sulforhodamine B solution to each well;

 28. Cell staining for 30 minutes;

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

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

 31. Using spectrophotometric measurements, 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;

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

Example number IC _5Q (EGFR/A431)^M)

 2 0.28

3 6.77

4 5.94

7 1.44

10 1.02

11 2.16

14 0.17

15 7.13

17 0.56

18 0.5

EXAMPLE 4: 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 KC1, 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% glycerol, Cell signaling technology #7908)

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

i. PTP1B (Tyr66) biotinylated protein (Cell signaling technology #1325).

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

 (Cell signaling technology #9805).

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

Use the following scenario to test:

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

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

2. Dilute 6 μΜ substrate protein (Tyr589) with dH ₂ 01 :1 and add 15 μΐ to 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;

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 of 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 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

1.25 mM DTT 20 μΜΑΤΡ

 I.5 μΜ polypeptide substrate

30 ng EGFR kinase

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

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

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

 II. Wash each well with 200 l PBS-T buffer 3 times, tap 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 Section 11;

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

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

 17. Wash each well 5 times with PBS-T buffer 200 μM, tap on a paper towel to remove the remaining liquid;

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. IC ₅₍ ) (EGFR/bio)^M)

 2 0.13 15 0.06

17 0.007

18 0.025

Claims

Rights request A compound represented by the following formula (I): or a pharmaceutically acceptable salt thereof:

 among them: X is selected from W(CH ₂ ), (CH ₂ )W, or W, wherein W is 0, S, SO or S0 ₂ ; or X is -NR _6; wherein R ₆ is a hydrogen atom or an alkyl group;  Y is an oxygen atom or a hydrogen atom; When X is -NR ₆ and R ₆ is an alkyl group, R ₆ 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 is further selected from one or more selected from the group consisting of alkyl, halogen, aryl, heteroaryl, haloalkyl, haloalkoxy, hydroxy, amino, alkylamino, amide, aminyl, cyano, alkane Substituted by an oxy group, an aryloxy group, an amine fluorenyl group, a hydroxyalkyl group, a heterocycloalkyl group, a carboxylic acid, a carboxylic acid ester or a substituent of -NR ₇ R ₈ ; Selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an arylalkyl group or a heteroaralkyl group, wherein an alkyl group, a cycloalkyl group, a heterocyclic fluorenyl group, an aryl group, or a heterocyclic group The aryl, aralkyl or heteroarylalkyl group is further selected from one or more selected from the group consisting of alkyl, halogen, aryl, hydroxy, amino, alkylamino, amide, aminoacyl, decyloxy, aryloxy, heterocycle Substituting an alkyl group, a carboxylic acid, a carboxylic acid ester or a substituent of -NR ₇ R ₈ ; wherein the aryl, heteroaryl, aralkyl or heteroarylalkyl group is bicyclic; R _{2 is} selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, -(CH ₂ CH ₂ 0) _n R ₆ , an alkenyl group or an alkynyl group, -C00R ₇ , -CONR ₇ R ₈ , -C( _{= S) NR 7 R 8,} -C0R 7, -S0R 7, -S0 2 R 7, -S0 2 NR 7 R 8 or _{-P (= 0) (oR 7} ) (oR 8), wherein the alkyl, cycloalkyl, An alkyl, heterocycloalkyl, alkenyl or alkynyl group is further substituted with one or more substituents selected from the group consisting of alkyl, hydroxy, decyloxy, cyano, amino, decylamino, carboxylic acid or carboxylic acid esters;  Selected from a hydrogen atom, an alkyl group, an aryl group, a halogen-substituted aryl group or a trifluoromethyl group; FU is selected from the group consisting of hydroxyl, alkoxy, aryloxy, heterocycloalkoxy, aryloxy, -(OCH ₂ CH ₂ ) _n R ₆ , -N(R ₇ )(C3⁄4) _n R ₈ , -NR ₇ [CH ₂ C3⁄40] _n R ₈ or -NR ₆ (C3⁄4) _n [CH(OH)CH ₂ ] _r Z ; wherein Z is aryl, heteroaryl, heterocycloalkyl, -NR ₇ R ₈ , - C00R ₆ or CONR ₇ R _{8 ;} R _{5 is} selected from the group consisting of hydroxyl, alkoxy, aryloxy, heterocycloalkoxy, aryloxy, -N(R ₇ )(CH ₂ ) _n R ₈ , -NR ₇ [C3⁄4CH ₂ 0] _n R ₈ Or -NR ₆ (CH ₂ ) _n [CH(OH)C3⁄4] _r Z ; wherein Z is aryl, heteroaryl, heterocycloalkyl, -NR ₇ R ₈ , -C00R ₆ or C0NR ₇ R _{s ;} R ₆ is a hydrogen atom or an alkyl group; R ₇ and R ₈ are each independently selected from a hydrogen atom, an alkyl 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 heterocyclic fluorenyl group, an aryl group Further, the heteroaryl or heteroarylalkyl group is further selected from one or more selected from the group consisting of alkyl, halogen, aryl, hydroxy, amino, decylamino, amide, aminyl, cyano, alkoxy, aryloxy, amine Substituted by an alkyl group, a hydroxyalkyl group, a heterocyclic fluorenyl group, a carboxylic acid, a carboxylic acid ester or a substituent of -NR ₇ R ₈ ; Meanwhile, R ₇ and R ₈ may form a 4 to ₈ membered heterocyclic group; wherein the 5 to 8 membered heterocyclic ring contains one or more N, 0, and S atoms, and the 4 to 8 membered heterocyclic ring is further subjected to one or more Selected from alkyl, halogen, aryl, heteroaryl, haloalkyl, haloalkoxy, hydroxy, amino, amide, aminyl, cyano, alkoxy, aryloxy, alkoxyalkyl, hydroxyalkyl Substituted by a heterocycloalkyl group, a carboxylic acid, a carboxylic acid ester or a substituent of -NR ₇ R ₈ .  n is 0~6;  r is 1 to 2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein X is -NH, Ri is a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an aromatic group An alkyl or heteroarylalkyl group, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl group is further selected from one or more selected from the group consisting of alkyl, halogen, and aromatic Substituents of a hydroxy group, an amino group, an alkylamino group, an amide group, an aminoacyl group, an alkoxy group, an aryloxy group, a heterocycloalkyl group, a carboxylic acid, or a carboxylic acid ester are substituted. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Y is an oxygen atom. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R ₂ is a hydrogen atom. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is a 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. The compound or a salt thereof according to any one of claims 1 to 5, which comprises -

7. A process for the preparation of a compound of the formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, comprising the steps of:

 Using I-la as a starting material, reacting with sodium nitrite to obtain the formula I-lb compound 3⁄4

 The resulting I-lb compound is subjected to norr Pyrrole to give a compound of the formula I-lc;

 The I-lc compound is subjected to selective hydrolysis of an alkali metal hydroxide solution at room temperature to obtain a compound of the formula I-Id;

Amidation of the I-ld compound with R ₅ NH ₂ to give a compound of the formula I-le;

 Decarboxylation of an I-le compound under the action of trifluoroacetic acid to give a compound of the formula I-lf;

 The I-lf compound is subjected to formylation with phosphorus oxychloride in an anhydrous system to obtain a compound of the formula I-lg; general formula

 The production method according to claim 7, wherein the alkali metal hydroxide solution is a lithium hydroxide solution. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, and a pharmaceutical carrier. A method of modulating the catalytic activity of a protein kinase, which comprises contacting the protein kinase with the compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof. 11. 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. 12. 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. 13. The method of claim 12, wherein the protein kinase-associated disease is selected from the group consisting of VEGFR-2, EGFR, HER-2, HER-3, HER-4, PDGFR, c-Kit, c-Met , FGFR or Flt3 related diseases. 14. The method of claim 12 wherein said mammal is a human. The method according to claim 12, 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. 16. The method according to claim 12, 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. 17. The method of claim 16 further comprising administering to the patient in need of treatment a therapeutically effective amount of another anti-cancer drug. 18. The method of claim 17, wherein the other anti-cancer drug is selected from the group consisting of taxol or carboplatin. 19. Use of a compound of claim 1 for the manufacture of a medicament for the treatment of a disease associated with a protein kinase. The use according to claim 19, wherein the protein kinase-associated disease is selected from the group consisting of VEGFR-2, EGFR, HER-2, HER-3, HER-4, PDGFR, c-Kit, c-Met , FGFR or Flt3 related diseases. The method according to claim 19, 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 19, 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.