WO2007082470A1 - Pyrrolo-pyridazine derivatives,their preparation methods and uses - Google Patents
Pyrrolo-pyridazine derivatives,their preparation methods and uses Download PDFInfo
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- WO2007082470A1 WO2007082470A1 PCT/CN2007/000176 CN2007000176W WO2007082470A1 WO 2007082470 A1 WO2007082470 A1 WO 2007082470A1 CN 2007000176 W CN2007000176 W CN 2007000176W WO 2007082470 A1 WO2007082470 A1 WO 2007082470A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the present invention relates to a novel pyrrolopyridazine derivative, a process for the preparation thereof, and a pharmaceutical composition containing the same and its use as a therapeutic agent, particularly as a tyrosine acid inhibitor.
- Cellular signaling is a fundamental mechanism of action in which extracellular stimuli are transmitted to the interior of the cell, which in turn regulates the progression of different cells. These signals regulate a variety of physiological responses, including cell proliferation, differentiation, apoptosis, and exercise, in the form of different types of lytic factors, including growth factors that are dominated by paracrine, autocrine, and endocrine factors. By binding to specific transmembrane receptors, growth factor ligands transmit extracellular signals to intracellular signaling pathways, causing individual cells to respond to extracellular signals. Many signaling processes are reversible processes that utilize protein phosphorylation involving specific protein kinases and phosphorylating enzymes.
- Protein kinases are enzymes that catalyze the phosphorylation of hydroxyl groups on tyrosine, serine, and threonine residues of proteins.
- the reverse mechanism of protein kinases and phosphorylases balances and regulates signal flow during signaling.
- a protein phosphorylation state can affect its conformation, enzyme activity, cell localization, and the corresponding roles of protein kinases and phosphatases are modified.
- Phosphorylation is an important regulatory mechanism in signal transduction, and abnormalities during signal transduction. Lead to abnormal differentiation, transformation and growth of cells.
- cells can become cancer cells by converting part of their DNA into oncogenes, which are the growth factor receptor proteins encoded by such carcinogenic S; tyrosine kinases can also be mutated into activated forms leading to more A variation of human cells, it can be said that over-expressed normal tyrosine kinase can cause abnormal cell proliferation. '
- Tyrosine kinases can be conveniently divided into two classes: protein tyrosine kinases (PTKs) and serine-threonine kinases (STKs). PTKs phosphorylate tyrosine residues on proteins, and STKs phosphorylate serine and threonine residues on proteins. Tyrosine kinases can be not only receptor type (including extracellular domain, intracellular domain and transmembrane cell domain) but also non-receptor type (including all intracellular domains). A major aspect of PTK activity is that they are involved as cell surface protein growth factor receptors.
- RTKs receptor tyrosine kinases
- 90 tyrosine kinases in human genes are distinguished by i, of which about 60 are receptor types, about 30 species.
- Non-receptor type these growth factor receptor families can be further divided into 20 receptor tyrosine kinase subfamilies and 10 non-receptor tyrosine kinase subfamilies (Robinson et al, Oncogene, 2000, 19, 5548-5557 ).
- the RTKs subfamily includes the following: (1) EGF families, such as EGF, TGFa, Neu and erbB; (2) Insulin family, including insulin receptor, insulin-like growth factor I receptor (IGF1) and insulin receptor-related Sexual receptor (IRF); (3) Chuan-type family, such as platelet-derived growth factor receptor (PDGF, Including PDGFa and PDGFp receptors, stem cell factor RTKs (SCF RTK, commonly referred to as c-Kit), fms-associated tyrosine kinase 3 (Flt3) receptor tyrosine kinase, and colony stimulating factor 1 receptor (CSF) -1 R) Tyrosine kinase and the like.
- EGF families such as EGF, TGFa, Neu and erbB
- Insulin family including insulin receptor, insulin-like growth factor I receptor (IGF1) and insulin receptor-related Sexual receptor (IRF)
- IRF insulin receptor-related Sexual receptor
- Chuan-type family such as platelet-derived
- a portion of the non-limiting kinases include Abl, ARaf, ATK, ATM, bcr-abi, Blk, BRaf, Brk, Btk, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CHK, AuroraA, AuroraB, AuroraC, cfms, c-fms, c-Kit, c-Met, cRafl, CSF1 R, CSK, c-Src, EGFR, ErbB2, ErbB3, ErbB4, ERK, ERK1, ERK2, Fak, fes, FGFR1, FGFR2, FGFR3 , FGFR4, FGFR5, Fgr, FLK-4, Fps, Fr
- PKs are thought to be associated with central nervous system diseases such as Alzheimer's disease (see Mandelkow, EM et al. FEBS Lett. 1992, 314, 315; Sengupta, A. et al. Mol. Cell. Biochem. 1997, 167, 99), pain (see Yashpal, KJ Neurosci. 1995, 15, 3263-72), inflammation such as arthritis (see Badger, J. Pharmn Exp. Then 1996, 279, 1453), psoriasis (see Dvir, et al, J. Cell Biol.
- bone diseases such as osteoporosis (see Tanaka et al, Nature, 1996, 383, 528), cancer (see Hunter and Pines, Cell 1994, 79, 573), atherosclerosis (see Hajjar and Pomerantz, FASEB) J. 1992, 6, 2933), thrombosis (see Salari, FEBS 1990, 263, 104), metabolic disorders such as diabetes (see Borthwick, AC et al. Biochem. Biophys. Res. Commun. 1995, 210, 738), vascular proliferative Diseases such as angiogenesis (see Strawn et al. C8ticer Res. 1996, 56, 3540; Jackson et al. Pharm. Exp. Ther.
- angiogenesis see Strawn et al. C8ticer Res. 1996, 56, 3540; Jackson et al. Pharm. Exp. Ther.
- PTKs signaling specific growth factors (ligands) interact extracellularly, followed by receptor dimerization, which activates the intrinsic activity of protein kinases in an instant and undergoes phosphorylation.
- the binding site of the internal signaling molecule is generated to form a complex with the cytoplasmic signaling molecule, promoting various cellular responses such as cell division (proliferation), expression of extracellular microenvironment metabolism, and the like.
- the binding site for phosphorylation of the receptor tyrosine kinase is also a binding site with a high affinity for the SH2 (synchronous to src) domain of the signaling molecule.
- SH2 synchronous to src domain of the signaling molecule.
- Many intracellular substrate proteins associated with receptor tyrosine kinases have been identified and can be divided into two categories: (1) substrate with catalytic domain (2) substrate without catalytic region, but can be used as a combination, And related to certain catalytically active molecules.
- the specificity of the interaction of a receptor or protein with the substrate SH2 domain is determined by the amino acid sequence near the phosphorylated tyrosine residue, the amino acid sequence surrounding the SH2-domain and the phosphorylated tyrosine sequence, and the specific The difference in bulk binding is consistent with the difference in substrate phosphorylation.
- Protein tyrosine kinase function can be determined by expression pattern and ligand availability, as well as by downstream region signaling pathways activated by specific receptors. Thus, phosphorylation provides an important, regulatable step that determines the selectivity of signaling and the differentiation factor receptor that is activated by a particular receptor. Abnormal expression or mutation of a receptor tyrosine kinase may result in uncontrolled cell proliferation (such as malignant tumor growth) or loss of key developmental processes.
- Tyrosine kinases in most human tumors, such as leukemia, breast cancer, prostate cancer, non-small cell lung cancer (including adenocarcinoma, lung squamous cell carcinoma), gastrointestinal cancer (including colon cancer, rectal cancer, and gastric cancer) In cancers such as bladder cancer, esophageal cancer, ovarian cancer, and pancreatic cancer, mutations or overexpression may occur.
- cancers such as bladder cancer, esophageal cancer, ovarian cancer, and pancreatic cancer
- mutations or overexpression may occur.
- the ubiquity and association of tyrosine kinases have been further confirmed by detection of human tumor cells.
- - EGFR tyrosine kinases are mutated and overexpressed in human cancers including lung, brain, neck, gastrointestinal, breast, esophageal, ovarian, uterine, bladder and thyroid cancers.
- the "HER” or "Erb” receptor tyrosine kinase subfamily includes EGFR, HER2, HER3 and HER4. These subfamilies consist of an extracellular glycosylation ligand binding domain, a transmembrane domain, and an intracellular cytoplasmic catalytic domain that phosphorylates the tyrosine sequence on the protein.
- the receptor tyrosine kinase catalytic activity can be activated by receptor overexpression or ligand-mediated dimerization.
- the HER2 family of polymers has both homodimers and heterodimers.
- 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.
- EGF EGF family ligands
- the heterodimerization can be accelerated by binding to the heregulin (also known as neuregulin) family of ligands.
- HER No one receptor activity but HER2 and HER3, or a HER3 and HER4 profiled dimerization also significantly stimulated tyrosine kinase receptor dimerization. In various cell types, receptor overexpression activates the activity of HER2 kinase.
- MAP kinases microtubule-associated protein kinases
- PI3 kinase phosphatidylinosides Alcohol
- RTK insulin receptor
- IGF-1R insulin-like growth factor-1 receptor
- IRR insulin receptor-related receptor
- IGF-1 R interacts with insulin, IGF-I and IGF-II to form two completely extracellular glycosylated alpha subunits and two tyrosine kinase domain beta subunits Heterotetramer.
- the third subgroup of RTK refers to the platelet-derived growth factor receptor (PDGFR) family, including PDGFRa, PDGFRp, CSFIR, c-Kit and c-fms. These receptors are composed of a variety of immunoglobulin-like cyclic glycosylated extracellular domains and an extracellular domain in which the tyrosine kinase domain in the intracellular domain is blocked by an unrelated amino acid sequence. Platelet-derived growth factor receptors such as PDGFRa and PDGFRP are also transmembrane tyrosine kinase receptors.
- PDGF-AA When they are combined with a ligand, either form a homodimer (PDGF-AA, PDGF-BB), or a heterodimer (PDGF-AB). Subsequent receptor dimerization, tyrosine kinase is activated, signaling downstream regions to promote tumor growth. Mutations in genes are responsible for the receptor's inability to bind to ligands and are a driving force for tumorigenesis.
- c-Kit is a member of the PDGF receptor family and is activated when it binds to the ligand SCF (stem cell factor).
- 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., ⁇ Clin. Oncol. 22(14S), 9642 (2004)].
- GIST is a non-epithelial cell tumor, most of which is present in the stomach, a few in the small intestine, rarely in the esophagus, but also in the liver, peritoneal cavity and other parts.
- GIST is derived from Cajal interstitial cells (ICC), which can form part of the intestinal autonomic nervous system and participate in the control of gastric motility. Most (50 ⁇ 80%) GIST production is due to mutation of c-Kit gene. In the digestive tract, c-Kit/CD117 staining is generally GIST, and c-Kit mutation can make it independent of SCF activation. c-Kit function, resulting in increased cell division rate, leading to instability of the genome. In the cases of distorted mast cell tumor, mast cell proliferative disease, myeloproliferative syndrome, urticaria and other diseases, c-Kit expression can also be detected, and c-Kit expression is also found in acute AML and malignant lymphoma, in small cells.
- ICC Cajal interstitial cells
- Bronchial carcinoma, seminoma, dysgerminoma, testis, intraepithelial neoplasia, melanoma, breast cancer, neuroblastoma, Ewing sarcoma have c-Kit expression (see Schdtte et al., innovartis) 3/2001).
- RET rearranged during transfection.
- Proto-oncogene genetic mutations are tumorigenic, and patients with multiple endocrine neoplasia 2 (MEN 2) may cause pheochromocytoma, medullary thyroid carcinoma, and parathyroid adenoma and hyperplasia ( See Huang et al., Cancer Res. 60, 6223-6 (2000)).
- Flk fetal liver kinase receptor subfamily
- PDGFR fetal liver kinase receptor subfamily
- This subfamily consists of a kinase-containing insertion domain-receptor fetal liver kinase-1 (KDR/FLK-1, VEGFR2), Flk-1 R, Flk-4 and fms-like tyrosine kinase 1 (Flt-1).
- FGF fibroblast growth factor
- 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.
- VEGF vascular endothelial growth factor receptor subfamily
- VEGF vascular endothelial growth factor receptor subfamily
- VEGFR is involved in angiogenesis, inhibits angiogenesis by inhibiting VEGFRs, and is being used in clinical treatment of tumors, and has achieved good therapeutic effects.
- VEGF in various malignant Solid tumors such as lung cancer, breast cancer, non-Hodgkin's lymphoma, ovarian cancer, pancreatic cancer, malignant pleural mesothelioma, and melanoma are strongly expressed and associated with the progression of cancer, in leukemia and lymphoid There are also expressions in the tumor.
- VEGFR In addition to its angiogenic activity, VEGFR.
- VEGF ligands also promote tumor growth by directly pro-survival properties in tumor cells, and PDGF also has an angiogenic effect. The process of neovascularization plays a key role in the continued growth of the tumor.
- vascular endothelial cells activates angiogenesis and stimulates the production of vascular endothelial cells in vivo - some peptides have been identified, including acidic, basic fibroblast growth factors (aFGF and bFGF) and vascular endothelial growth factor.
- aFGF and bFGF basic fibroblast growth factors
- VEGF Due to the restricted expression of the VEGF receptor, its growth factor activity is relatively specific to endothelial cells compared to aFGF and bFGF activity. Recent evidence suggests that VEGF is a frequently important stimulant during angiogenesis and vascular infiltration in both normal and pathological conditions. VEGF induces a vascular sprouting phenotype that induces endothelial cell proliferation, protease expression and migration to promote capillary formation, thereby forming a super-osmotic, immature vascular network, which is typical of typical pathological angiogenesis. It is expected that antagonizing VEGF activity can be of value in the treatment of diseases associated with angiogenesis or vascular permeability, such as tumors, particularly tumor growth inhibition.
- FLT3 Fms-like tyrosine kinase
- PTK tyrosine kinase
- AML acute myeloid leukemia
- AML acute myeloid leukemia
- myelodysplastic syndrome In the case of the disease, the FLT3 gene is abnormally expressed.
- 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.
- FLT3 The tyrosine kinase activity of FLT3 is activated, resulting in the presence of a signal and proliferation in the absence of a ligand. According to the study, patients with mutant forms of receptor expression have a reduced chance of cure. In conclusion, in human leukemia and myelodysplastic syndromes, FLT3 mutations are associated with tumorigenesis.
- Hepatocyte growth factor (HGF) receptor (c-MET or HGFR) tyrosine kinases have been shown to be involved in tumorigenesis, cell motility, invasion and metastasis (see Ma, PC et al. (2003b). Cancer Metastasis Rev, 22, 309-25; Maulik, G. et al. (2002b). Cytokine Growth Fsctor Rev, 13, 41-59). Overexpression or mutation in various tumors, including small cell lung cancer (SCLC), activates c-MET (HGFR) (see Ma, P.C. et al. (2003a). Cancer Res, 63, 6272-6281).
- SCLC small cell lung cancer
- the proto-oncogene c-Met encodes a hepatocyte growth factor receptor, which is a cell membrane glycoprotein with tyrosine kinase activity, which has important physiological regulation effects on various cell proliferation and differentiation.
- the c-met gene has been used in many malignant tumors. Expression is an important factor in the carcinogenesis of thyroid follicular epithelial cells and is closely related to the pathological stage, invasion and metastasis of thyroid cancer.
- CTK receptor tyrosine kinase inhibitors
- STKs serine-threonine kinases or STKs are dominant in the cell, although there are only a few STK-type receptor kinases.
- STKs are the most common cytosolic kinases, that is, they perform their functions in part of the cytoplasm, not in cytoplasmic organelles.
- the cytosol is a region within the cell where the metabolism and biosynthesis activity occurs in most cells; for example, proteins are synthesized on cytosol ribosomes.
- X is selected from W(C3 ⁇ 4), (CH 2 )W, or W, wherein W is 0, S, SO, S0 2; or -N 8 (wherein R 8 is a hydrogen atom or an alkyl group);
- R 8 When X is - 8 and R 8 is an alkyl group, it may form a 4 to 8 membered heterocyclic group with R1; wherein the 5 to 8 membered heterocyclic ring may contain one or more N, 0, S atoms, and 4 ⁇
- the 8-membered heterocyclic ring may be further substituted with one or more fluorenyl groups, halogen, aryl, heteroaryl, halofluorenyl, halodecyloxy, hydroxy, amino, alkylamino, amide, aminyl, Cyano, alkoxy, aryloxy, aminyl, hydroxyalkyl, heterocycloalkyl, carboxylic acid, carboxylic acid ester or substituted with -5 ;
- aryl, arylfluorenyl or heteroarylalkyl group may be further substituted by one or more alkyl, halogen, aryl, hydroxy, amino, alkynyl, alkylamino, amide, aminyl, decyloxy, aryloxy, a heterocyclic fluorenyl group, a carboxylic acid, a carboxylic acid ester or a substituent of -NR 5 ; wherein an aryl group, a heteroaryl group, an arylalkyl group or a heteroaralkyl group may be combined into a bicyclic ring;
- R 2 is selected from the group consisting of a hydrogen atom, a fluorenyl group, a trifluoromethyl group, a cyclodecyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an aralkyl group or a heteroarylalkyl group, wherein an alkyl group, a cycloalkyl group, a heterocyclic ring
- An anthracenyl group, an aryl group, a heteroaryl group, an indenyl group or a heteroaryl group may further be one or more fluorenyl groups, a halogen, an aryl group, a hydroxy group, an amino group, a decylamino group, an amide group, an amino group, a decyl group, Substituted with an aryloxy group, a heterocycloalkyl group, a carboxylic acid, a carboxylic acid ester or -NR 5 R
- R 5 and each selected from the group consisting of a hydrogen atom, a fluorenyl group, a cyclodecyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group or a heteroarylalkyl group, respectively, wherein an indenyl group, a cyclodecyl group, a heterocycloalkyl group, or an aromatic group Base, heteroaryl or heteroaralkyl Further one or more alkyl, halogen, aryl, hydroxy, amino, decylamino, amide, aminyl, cyano, alkoxy, aryloxy, aminyl, hydroxyalkyl, heterocycloalkane Substituted by a carboxylic acid or a carboxylic acid ester;
- R 5 and may form a 4-8 membered heterocyclic group; wherein the 5 to 8 membered heterocyclic ring may contain one or more N, 0, S atoms, and the 4 to 8 membered heterocyclic ring may be further subjected to a Or a plurality of alkyl, halogen, aryl, heteroaryl, alkyl, methoxy, hydroxy, amino, amide, aminyl, cyano, alkoxy, aryloxy, amidino, Substituted with hydroxymethyl, heterocycloalkyl, carboxylic acid, carboxylic acid ester or -NR 5 R6;
- R 7 is selected from the group consisting of hydroxy, decyloxy, aryloxy, heterocycloalkoxy, aryloxy, -N(R 8 )(CH 2 ) n R 9 , -N 8 [CH 2 CH 2 0] n R 8 , -NR 5 or -N (CH 2 ) n [CH(OH)C3 ⁇ 4] r Z (wherein Z is aryl, heteroaryl, heterocycloalkyl, -NR 5 , -COOR 8 or CON 5 R6 );
- R 9 is selected from - R 5 R6, hydroxy, aryl, heteroaryl, alkoxy, -S(0) 2 CH 3 , -O ⁇ C3 ⁇ 4CH 2 0] r R 8 , -1 ⁇ (0-)3 ⁇ 43 ⁇ 4 , -N(OH)R 5 , -Li. (0).
- - COR 10 wherein R w is a fluorenyl group, a halogenated fluorenyl group or a aryl group);
- R 10 is an embankment, haloalkyl or aryl alkyl with
- n 0 ⁇ 6
- r is 1 to 2.
- the present invention includes a compound represented by the following formula (I) or a salt thereof:
- X is selected from W(CH 2 ), (CH 2 )W, or W, wherein W is 0, S, SO, S0 2 ; or -N (wherein R 8 is a hydrogen atom or an alkyl group);
- R 8 may form a 4 to 8 membered heterocyclic group with R1; wherein the 5 to 8 membered heterocyclic ring may contain one or more N, 0, S atoms, and
- the 4 to 8 membered heterocyclic ring may be further substituted with one or more fluorenyl groups, halogen, aryl, heteroaryl, haloalkyl, haloalkoxy, hydroxy, amino, alkylamino > amide, aminyl, cyano, Alkoxy, aryloxy, aminyl, hydroxyalkyl, heterocycloalkyl, carboxylic acid, carboxylic acid ester or - ⁇ 3 ⁇ 4 substituted;
- R4 is selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, -(CH 2 CH 2 0) n R 8 , an alkenyl group or an alkynyl group, wherein a fluorenyl group, a cyclodecyl group, a heterocycloalkyl group, an alkene group Or alkynyl may be further substituted by one or more mercapto, hydroxy, decyloxy, cyano, amino, decylamino, -NR 5 3 ⁇ 4, carboxylic acid or carboxylic acid ester;
- the heteroaryl or heteroarylalkyl group may be further substituted by one or more of fluorenyl, halogen, aryl, hydroxy, amino, decylamino, amide, aminyl, cyano, decyloxy, aryloxy, amidoxime Substituted with a hydroxy group, a heterocycloalkyl group, a carboxylic acid or a carboxylic acid ester;
- a 4 to 8 membered heterocyclic group may be formed; wherein the 5 to 8 membered heterocyclic ring may contain one or more N, 0, S atoms, and the 4 to 8 membered heterocyclic ring may be further subjected to one or more Sulfhydryl, halogen, aryl, heteroaryl, alkyl, methoxy, hydroxy, amino, amide, amino, cyano, methoxy, aryloxy, alkoxy, hydroxyalkyl Substituted by a heterocyclic fluorenyl group, a carboxylic acid, a carboxylic acid ester or -NR 5 R6;
- R 7 is selected from the group consisting of hydroxy, decyloxy, aryloxy, heterocycloalkoxy, aralkyloxy, -N(R 8 )(CH 2 ) n R 9 , - R 8 [CH 2 CH 2 0] n R 8 , -N 5 R6 or -NR 8 (CH 2 ) n [CH(OH)C3 ⁇ 4] r Z (wherein Z is aryl, heteroaryl, heterocycloalkyl, -NR 5 R 6 , -COOR 8 Or CONR 5 R6);
- R 9 is selected from -NR 5 R6, hydroxy, aryl, heteroaryl, decyloxy, -S(0) 2 C3 ⁇ 4, -0[CH 2 CH 2 0] r R 8 , - (0') , - N(OH)R 5 , -NHC(0)R 1G or -COR 10 (wherein R 10 is alkyl, haloalkyl or aryl fluorenyl);
- R 10 is an alkyl group, a halogenated fluorenyl group or an aralkyl group
- n 0 ⁇ 6
- r is 1 to 2.
- the present invention includes a compound represented by the following formula ( ⁇ ) or a salt thereof:
- X is selected from W(CH 2 ), (CH 2 )W, or W, wherein W is 0, S, SO, S0 2 ; or -N (wherein R 8 is a hydrogen atom or a fluorenyl group);
- a 4 to 8 membered heterocyclic group may be formed with R1; wherein the 5 to 8 membered heterocyclic ring may contain one or more N, 0, S atoms, and 4 ⁇
- the 8-membered heterocyclic ring may be further substituted with one or more alkyl, halogen, aryl, heteroaryl, halodecyl, halodecyloxy, hydroxy, amino, decylamino, amide, aminyl, cyanide a group, a methoxy group, an aryloxy group, an aminoalkyl group, a hydroxyalkyl group, a heterocyclic fluorenyl group, a carboxylic acid, a carboxylic acid ester or a substituted group of R 5 ;
- aryl, aralkyl or heteroarylalkyl group may be further substituted by one or more fluorenyl, halogen, aryl, hydroxy, amino, alkynyl, alkylamino, amide, aminyl, alkoxy, aryloxy, a heterocyclic fluorenyl group, a carboxylic acid, a carboxylic acid ester or a substituted group; wherein the aryl group, the heteroaryl group, the aryl fluorenyl group or the heteroaryl fluorenyl group may be combined into a bicyclic ring;
- alkyl, cyclodecyl, heterocycloalkyl, -(C3 ⁇ 4CH 2 0) n R 8 alkenyl or alkynyl, wherein alkyl, cycloalkyl, heterocycloalkyl, alkenyl or alkyne
- the group may be further substituted by one or more alkyl, hydroxy, alkoxy, cyano, amino, alkylamino, -NR 5 , carboxylic acid or carboxylic acid esters;
- R 6 are each independently selected from the group consisting of a hydrogen atom, a fluorenyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group or a heteroarylalkyl group, wherein the alkyl group, the cycloalkyl group, the heterocycloalkyl group, and the aryl group a heteroaryl or heteroarylalkyl group which may be further substituted by one or more of fluorenyl, halogen, aryl, hydroxy, amino, alkylamino, amide, aminyl, cyano, alkoxy, aryloxy, Acridine, hydroxyalkyl, heterocycloalkyl, carboxylic acid or carboxylic acid ester Meanwhile, R 5 and Re may form a 4 to 8 membered heterocyclic group; wherein the 5 to 8 membered heterocyclic ring may contain one or more N, 0, S atoms, and the 4 to 8 member
- R 7 is selected from the group consisting of hydroxy, alkoxy, aryloxy, heterocycloalkoxy, aralkyloxy, -N(R 8 ; CH 2 ) n R 9 , - 8 [CH 2 CH 2 0] n R 8 , -NRsRfi or - NR s (C3 ⁇ 4) n [CH(OH)CH 2 ] r Z (wherein Z is aryl, heteroaryl, heterocycloalkyl, -NRsR ⁇ , -COOR 8 or CON 5R6);
- R 9 is selected from -NR 5 R6, hydroxy, aryl, heteroaryl, decyloxy, -S(0) 2 CH 3 , -O[CH 2 CH 2 0] r R 8 , - ⁇ (0-) 3 ⁇ 43 ⁇ 4, -N(OH)R 5 , -NHC(0)R 1() or - COR 10 (wherein R 10 is a fluorenyl group, a haloalkyl group or an aryl fluorenyl group);
- R 1 () is a fluorenyl group, a halogenated fluorenyl group or an aryl group
- n 0 ⁇ 6
- r is 1 to 2.
- the present invention includes a compound represented by the following formula (III) or a salt thereof:
- X is selected from W(CH 2 ), (CH 2 )W, or W, wherein W is 0, S, SO, S0 2 ; or -NR 8 (wherein a hydrogen atom or a sulfhydryl group);
- R 8 When X is -NR 8 and R 8 is a fluorenyl group, R 8 may form a 4 to 8 membered heterocyclic group with R1; wherein the 5 to 8 membered heterocyclic ring may contain one or more 0, S atoms, and 4
- the ⁇ 8 membered heterocyclic ring may be further substituted with one or more alkyl groups, halogen, aryl, heteroaryl, haloalkyl, haloalkoxy, hydroxy, amino, alkylamino, amide, aminyl, cyano , alkoxy, aryloxy, aminyl, hydroxyalkyl, heterocycloalkyl, carboxylic acid, carboxylic acid ester or substituted with -5 ;
- aryl, aralkyl or heteroarylalkyl group may be further substituted by one or more fluorenyl, halogen, aryl, hydroxy, amino, alkynyl, decylamino, amide, aminyl, alkoxy, aryloxy, a heterocycloalkyl group, a carboxylic acid, a carboxylic acid ester or a substituted group of - R 5 ; a heteroaryl group, an arylalkyl group or a heteroaralkyl group may be combined into a bicyclic ring;
- R 2 is selected from the group consisting of a hydrogen atom, a fluorenyl group, a trifluoromethyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an aryl fluorenyl group or a heteroaryl group, wherein a fluorenyl group, a cycloalkyl group, a heterocyclic ring Alkyl, aryl, heteroaryl, aralkyl or heteroaryl can be further protected by one or more fluorenyl, aryl, aryl, hydroxy, amino, alkylamino, amide, aminyl, alkoxy, An aryloxy group, a heterocycloalkyl group, a carboxylic acid, a carboxylic acid ester or a substituted group of -> 3 ⁇ 4 5 ;
- R 5 and Re are each independently selected from the group consisting of a hydrogen atom, a fluorenyl group, a cyclodecyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group or a heteroarylalkyl group, wherein an alkyl group, a cycloalkyl group, a heterocyclic fluorenyl group, Aryl, heteroaryl or heteroarylalkyl may be further substituted by one or more alkyl, halo, aryl, hydroxy, amino, decylamino, amide, aminyl, cyano, decyloxy, aryloxy Substituted with an amidino group, a hydroxyalkyl group, a heterocyclic fluorenyl group, a carboxylic acid or a carboxylic acid ester;
- R 5 and may form a 4 to 8 membered heterocyclic group; wherein the 5 to 8 membered heterocyclic ring may contain one or more N, 0, S atoms, and the 4 to 8 membered heterocyclic ring may be further subjected to a Or a plurality of alkyl, halogen, aryl, heteroaryl, alkyl, methoxy, hydroxy, amino, amide, aminyl, cyano, methoxy, aryloxy, amidino, Substituted by a hydroxyalkyl group, a heterocycloalkyl group, a carboxylic acid, a carboxylic acid ester or -NR 5 ;
- R 7 is selected from the group consisting of hydroxy, alkoxy, aryloxy, heterocycloalkoxy, aryloxy, -N(R 8 )(C3 ⁇ 4) n R 9 , -NR 8 [CH 2 C3 ⁇ 40] n R 8 , -NR 5 or -NR 8 (C3 ⁇ 4) n [CH(OH)C3 ⁇ 4] r Z (wherein Z is aryl, heteroaryl, heterocycloalkyl, -NR 5 R6, -COOR 8 or CO RsRe);
- R 8 is selected from a hydrogen atom or an alkyl group
- R 9 is selected from the group consisting of - sRi, hydroxy, aryl, heteroaryl, decyloxy, -S(0) 2 CH 3 , -0[CH 2 CH 2 0] r R 8 , -] ⁇ "(0-) 3 ⁇ 4]3 ⁇ 4, -N(0H)R 5 , -NHC(0)R 1() or - CORw (wherein Rio is an alkyl group, a halogenated fluorenyl group or a aryl group);
- R 1 () is an alkyl group, a haloalkyl group or an aryl group
- n 0 ⁇ 6
- r is 1 to 2.
- X is hydrazine (wherein a hydrogen atom or a ⁇ 3 ⁇ 4 alkyl group).
- R2 is a methyl group or a trifluoromethyl group.
- the compound of the formula (I) or a salt thereof includes:
- the salt is a salt of a compound of the above formula and an acid selected from the group consisting of malic acid, lactic acid, maleic acid, hydrochloric acid, methanesulfonic acid, sulfuric acid, phosphoric acid, citric acid, tartaric acid, acetic acid or trifluoroacetic acid. .
- a pharmaceutical composition comprising a compound, a salt or a prodrug of the formula (1), (II) or (III) and a pharmaceutically acceptable carrier or excipient.
- a method of modulating the catalytic activity of a protein kinase comprises contacting a protein kinase with a compound or salt of formula (1), (II) or ( ⁇ ).
- This protein kinase is selected from the group consisting of a receptor tyrosine kinase, a non-receptor tyrosine kinase, and a serine-threonine kinase.
- a method of treating a mammal having and preventing a protein kinase-associated disease in a mammal the method comprising administering to the mammalian organism a therapeutically effective dose of the present invention Inventive pharmaceutical composition.
- the protein kinase-related diseases are selected from the group consisting of EGFR, HER-2, HER-3, HER-4, PDGFR, VEGFR-2, c-Kit, c-Met, FGFR, Flt3 related diseases.
- Diseases associated with protein kinases can also be leukemia, diabetes, autoimmune diseases, hyperproliferative diseases, psoriasis, osteoarthritis, rheumatoid arthritis, angiogenesis, cardiovascular disease, Von-Heppel-Lindau's disease, inflammation, Fibrosis disease.
- Protein kinase-related diseases can also be squamous cell carcinoma, renal cell carcinoma, Kaposi sarcoma, non-small cell lung cancer, small cell lung cancer, lymphoma, thyroid cancer, breast cancer, head and neck cancer, uterine cancer, esophageal cancer, melanin. Cancer, bladder cancer, genitourinary cancer, gastrointestinal cancer, glial cancer, colorectal cancer and ovarian cancer.
- the mammals treated by these methods can be human.
- an anti-cancer drug such as taxol or carboplatin
- the invention relates to the use of a compound of the invention in the manufacture of a medicament for the treatment of a disease associated with a protein kinase.
- the protein kinase-associated disease is selected from the group consisting of EGFR, HER-2, HER-3, a disease associated with HER-4, PDGFR, VEGFR-2, c-Kit, c-Met, FGFR or Flt3; wherein the protein kinase-related disease is selected from the group consisting of leukemia, diabetes, autoimmune disease, hyperproliferative disease, psoriasis, Osteoarthritis, rheumatoid arthritis, angiogenesis, cardiovascular disease, Von-Heppel-Lindau's disease, inflammatory or fibrotic disease; wherein the protein kinase-related disease is cancer, selected from squamous cell carcinoma, Renal cell carcinoma, Kaposi sarcoma, non-small cell lung cancer, small cell lung cancer, lymphoma
- the present invention relates to a compound which discriminates the catalytic activity of a protein kinase, which contacts a cell expressing the protein kinase with a compound or salt of the present invention, and then detects the effect on the cell.
- the present invention also relates to a compound which discriminates the catalytic activity of a protein kinase by contacting an artificially recombinant synthetic kinase protein with a compound or salt of the present invention, and then detecting the effect on the kinase activity by the Elisa method.
- a compound which discriminates the catalytic activity of a protein kinase by contacting an artificially recombinant synthetic kinase protein with a compound or salt of the present invention, and then detecting the effect on the kinase activity by the Elisa method.
- Mercapto refers to a saturated aliphatic hydrocarbon group including straight chain and branched chain groups of 1 to 20 carbon atoms. Preference is given to medium-sized mercapto groups having 1 to 10 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, pentyldenyl. More preferred are lower fluorenyl groups having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl or t-butyl groups and the like.
- the alkyl group may be substituted or unsubstituted, and when substituted, preferred groups are halogen, hydroxy, lower decyloxy, aryl, aryloxy, heteroaryl, heterocyclic fluorenyl, C(0)R 7 , R 5 R 6 and C(0)N 5 R 6 .
- Cyclopentyl means a 3 to 8 membered all-carbon monocyclic, all-carbon 5/6 or 6/6 fused or polycyclic fused ring
- fused ring system means each in the system
- the rings share an adjacent pair of carbon atoms) groups with other rings in the system, wherein one or more of the rings may contain one or more double bonds, and none of the rings have a fully conjugated pi-electron system.
- Examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclopentene, cyclohexanyl, cyclohexadiene, adamantane, cycloheptane, cycloheptatriene and the like.
- the cycloalkyl group can be substituted or unsubstituted.
- the substituent is preferably one or more substituents independently selected from the group consisting of lower fluorenyl, trihaloalkyl, halogen, hydroxy, lower decyloxy, aryl (optionally selected from one or more groups) a group substituted, the substituents are independently of each other a halogen, a hydroxyl group, a lower alkyl group or a lower alkoxy group), an aryloxy group (which may be selected by one or more groups, and the substituents are independently of each other a halogen, a hydroxyl group, a lower fluorenyl or lower alkoxy group, a 6-membered heteroaryl group having 1 to 3 nitrogen atoms in the ring, the carbon in the ring being optionally substituted by one or more groups, the substituents being independently of each other halogen, a hydroxy, lower alkyl or lower decyloxy), 5-
- Alkenyl means a fluorenyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond. Representative examples include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, and the like.
- Alkynyl means a fluorenyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond. Representative examples include, but are not limited to, ethynyl, 1-propynyl, 2-propyn'yl, 1-, 2- or 3-butynyl, and the like.
- Aryl means a group having at least one aromatic ring structure, that is, an aromatic ring having a conjugated ⁇ -electron system, including a carbocyclic aryl group, a heteroaryl group, and a biaryl group.
- the aryl group may be optionally substituted by one or more substituents selected from the group consisting of halogen, trihalomethyl, hydroxy, SR, nitro, cyano, decyloxy, alkyl and R 5 R 6 .
- Heteroaryl means an aryl group having from 1 to 3 heteroatoms as ring atoms, the remaining ring atoms being carbon, and heteroatoms including oxygen, sulfur and nitrogen.
- the ring may be a 5- or 6-membered ring.
- the heterocyclic aryl group include a furyl group, a thienyl group, a pyridyl group, a pyrrole, an N-fluorenylpyrrolyl group, a pyrimidinyl group, a pyrazinyl group, an imidazolyl group and the like.
- Heterocyclic fluorenyl is a monocyclic or fused ring radical having 5 to 9 ring atoms in the ring, wherein one or two ring atoms are selected from nitrogen, oxygen or S(0)n (where n is An integer of 0 to 2) of a hetero atom whose anthracene ring is carbon. These rings may also have one or more double bonds, however, these rings do not have a fully conjugated pi-electron system.
- Unsubstituted heterocycloalkyl group includes, but is not limited to, pyrrolidinyl, piperidino, piperazino, morpholinyl, thiomorpholinyl, piperazine, etc., heterocyclic fluorenyl may be substituted or Unsubstituted.
- the substituents are preferably one or more, more preferably one, two or three, and still more preferably one or two, independently selected from lower alkyl, trihalofluorenyl, halogen, hydroxy, lower Alkoxy, fluorenyl, (lower fluorenyl) thio, cyano, acyl, thioacyl, 0-carbamoyl, fluorenyl-carbamoyl, 0-thiocarbamoyl, hydrazine-thiocarbamoyl , C-amido, oxime-amido, nitro, oxime-sulfonylamino, S-sulfonylamino, R 5 S(0)-, R 5 S(0) 2 , -C(0)OR 5 , A group consisting of R 5 C(0)O- and NR 5 R 6 , and R 5 and R 6 are as defined above.
- the heteroaryl group may be selected from one or two substituents, and the substituents are independently selected from halogen, lower fluorenyl, trihaloalkyl, hydroxy, decyl, cyano, N-acylamino, mono or di Alkylamino, carboxy or N-sulfonylamino.
- Haldroxy means an -OH group.
- Alkoxy means -0-(fluorenyl) and -0- (unsubstituted fluorenyl). Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like.
- Haloalkoxy means -0-(haloalkyl). Representative examples include, but are not limited to, trifluoromethoxy, tribromomethoxy, and the like. 07 000176
- Aryloxy means -o-aryl and -0-heteroaryl, and aryl and heteroaryl are as defined above. Representative examples include, but are not limited to, phenoxy, pyridyloxy, furanoxy, thienyloxy, pyrimidinyloxy, pyrazinyloxy, and the like, and derivatives thereof.
- “Indolyl” refers to -0-(indenyl) and -0-(unsubstituted cycloalkyl). Representative examples include, but are not limited to, methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, and the like.
- Arylthio means -S-aryl and -S-heteroaryl, and aryl and heteroaryl are as defined above. Representative examples include, but are not limited to, phenylthio, pyridylthio, furanthio, thiophenothionyl, pyrimidinyl, and the like, and derivatives thereof,
- Acyl means a -C(0)-R” group, wherein R" is selected from hydrogen, lower alkyl, trihalomethyl, unsubstituted cycloalkyl, aryl (optionally one or more, Preferably one, two or three substituents are selected from the group consisting of lower alkyl, trihalomethyl, lower decyloxy, halogen and -NR 5 R 6 ), heteroaryl (via ring carbon bonding) (optionally one or more, preferably one, two or three substituents selected from the group consisting of lower alkyl, trihalomethyl, lower alkoxy, halogen and -NR 5 R 6 And a heteroalicyclic group (bonded by a ring carbon) (optionally substituted by one or more, preferably one, two or three substituents selected from lower alkyl, trihalomethyl, a group consisting of a lower alkoxy group, a halogen and a -KR 5 R 6 ).
- Representative acyl groups include
- Thioxo refers to a -C(S)-R" group, wherein R" is as defined above.
- Halogen means fluoro, chloro, bromo or iodo, preferably fluoro or chloro.
- Trihalomethyl means -C3 ⁇ 4, 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.
- “optionally substituted with a fluorenyl group” means that the fluorenyl group may, but need not be, the case where the heterocyclic group is substituted by a thiol group and the case where the heterocyclic group is not substituted by a thiol group.
- “Pharmaceutical composition” means a mixture of one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, with other chemical components, such as a physiological/pharmaceutically acceptable carrier. And excipients.
- the purpose of the pharmaceutical composition is to facilitate the administration of the compound to the organism.
- Method for synthesizing the compound of the present invention In order to accomplish the object of the present invention, the present invention adopts the following technical scheme - a method for preparing the compound of the present invention (I) or a salt thereof, comprising the following steps:
- the method for preparing the compound of the formula (I) or a salt thereof of the present invention comprises the following steps:
- a method for preparing a compound of the formula (II) or a salt thereof according to the present invention comprising the following steps
- the invention is further described in the following examples, but these examples are not intended to limit the scope of the invention.
- the structure of the example compounds was determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS).
- the NMR shift ( ⁇ ) is given in parts per million (ppm).
- the NMR was measured by a Bruker AVANCE-400 nuclear magnetic apparatus.
- the solvent was deuterated chloroform (CDC1 3 ), deuterated dimethyl sulfoxide (DMSO-D 6 ), and the internal standard was trimethylsilyl (TMS). shifts are 10- 6 (ppm) given as a unit.
- the MS was measured using a FINMGAN LCQAd (ESI) mass spectrometer.
- Kinase inhibition rate and IC 5 The value is determined by NovoStar microplate reader (BMG, Germany). Thin layer of silica gel is used in Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
- DMSO-D 6 deuterated dimethyl sulfoxide
- Ethyl 5-formyl-3-methyl-1 ⁇ -pyrrole-2,4-dicarboxylate ethyl 3,5-dimethyl-1H-pyrrole-2,4-dicarboxylate la (4.79 g, 20 mmol) was dissolved in tetrahydrofuran (100 mL), and then a mixed solvent of acetic acid (120 mL) and water (100 mL) was added, and ammonium cerium nitrate (44.4 g, 81 mmol) was added in one portion at room temperature for 1.5 hours.
- Ethyl methyl-1H-pyrrole-2,4-dicarboxylate lb (2.544 g, 10 mmol, ) was dissolved in acetic acid (43 mL), and 85% hydrazine hydrate solution (0.65 mL, 11 mmol) was added with stirring. A yellow precipitate formed, stirring was continued, and the mixture was heated to 100 Torr for 2 hours. The reaction solution was cooled to room temperature and allowed to stand overnight.
- This step can also be purified.
- the solid is placed in a 50 mL eggplant-shaped flask, added to tetrahydrofuran (8 mL), stirred at room temperature for 30 minutes, and filtered to give the title product 3-methyl-4-chloro-3a, 4 , 5,7 a - tetrahydro -1H- pyrrolo [2,3-d] pyridazine -2-carboxylate as a yellow solid Id (569 mg, pale yellow solid), yield: 94.9%.
- Ethyl 5-formyl-3-methyl-1-methyl-pyrrole-2,4-dicarboxylate The compound obtained in the above first step was used in the same manner as described in the first step of Example 1 of the present invention.
- 1,3,5-trimethyl-pyrrole-2,4-dicarboxylic acid ethyl ester 15a is used as a raw material, and the reaction of the starting material with ammonium cerium nitrate is carried out to obtain the title product 5-formyl-3-methyl-1.
- Methyl-pyrrole-2,4-dicarboxylic acid ethyl ester 15b (5.283 g). The yield is 45 %.
- Example 8 of the present invention The reaction of the first step to the second step of Example 8 of the present invention was repeated, and the compound 4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamine]-3-methyl obtained in the above second step was used.
- the base-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid 8b is used as a starting material, and the starting material is 2-(4-methyl-piperazine) in the same manner as described in the sixth step of the present invention.
- the compound 4-[3-chloro-4-(pyridin-2-methoxy)-phenylamino]-1 obtained in the above second step is used.
- Example 34 of the present invention The reaction of the first step of Example 34 of the present invention was repeated, using the compound 4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-1-(2-) obtained in the above first step.
- Methoxyethyl)-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid 34a is used as a starting material, and the starting material is carried out in the same manner as described in the second step of Example 34 of the present invention.
- Example 38 the compound 44-[3-chloro-4-(3-fluoro-benzyloxy)-phenoxy] small [(2) obtained in Example 38 was used.
- reaction solution is cooled in an ice water bath, and the pH is adjusted to be alkaline by adding ammonia water, and a solid precipitates and is passed through an alkal to obtain 4-[3-chloro-4-(3-fluoro-p-oxy)-phenoxy]-1 -[(2-Methoxy-ethoxy)-ethyl]-3-trifluoromethyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid ethyl ester 41 (302 mg, White solid). Yield: 3 ⁇ .9%. ⁇
- 5-Hydroxymethyl-3-trifluoromethyl-1H-pyrrole-.2,4-dicarboxylic acid-2-carboxylate-4-ethyl ester was used in the same manner as described in the third step of Example 41 of the present invention.
- the compound obtained in the above step, 5-methyl-1H-pyrrole-2,4-dicarboxylic acid-2-benzyl ester-4-ethyl ester 42b (2.0 g, 5.63 mmol) was used as a starting material to carry out the starting material and ammonium cerium nitrate.
- reaction solution was neutralized by adding a saturated sodium hydrogencarbonate solution to pH 7.8.
- the reaction mixture was extracted, and the combined organic layer was evaporated, evaporated, evaporated Amino]-3-trifluoromethyl-1H-pyrrolo[2,3-d]indole-2-carboxylic acid 43a (100 mg, yellow solid) was taken directly to the next reaction without isolation.
- Methyl 7-oxo-6,7-dihydro-1H-pyrrole[2,3-d]pyridazine-2-carboxylate was added to a 10 mL eggplant vial under argon to add 3-formyl- 1H-Pyrrol-2,5-dicarboxylic acid dimethyl ester 47c (44 mg, 0.21 mmol), dry ethanol (2 mL) and hydrazine hydrate (0.025 mL, .042 mmol).
- Ethyl 7-methyl-4-oxo-4,6-dihydro-3indole-pyrrolo[3,4-d]pyridazine-5-carboxylate was added to a 50 mL eggplant bottle under nitrogen. Diethyl 4-formyl-5-methyl-1H-pyrrole-2,3-dicarboxylate (2.532 g, 10 mmol), ethanol (20 mL) and hydrazine hydrate (0.9 mL, 15 mraoD o mixture heated to 90 C, reflux for 3 hours, complete.
- Ethyl 4-chloro-7-methyl-6H-pyrrolo[3,4-d]pyridazine-5-carboxylate was added to a 100 mL eggplant vial under nitrogen to add 7-methyl-4-oxo Generation of 4-,6-dihydro-3H-pyrrolo[3,4-d]pyridazine-5-carboxylic acid ethyl ester (1.736 g, 7.85 mmol), anhydrous acetonitrile (40 mL) and phosphorus oxychloride ( 1.5 mL, 15.7 mmol). The mixture was heated to 90 Torr and refluxed for 5 hours.
- the compound 2-(5-diethylaminomethyl-furan-2-yl)-3-methyl-1,5-dihydro-porto [2,3-d]oxazin-4-one 45e (330 mg, 1.2 mmol) and 5-(2-methanesulfonylethylaminomethyl)furan-2-boronic acid (280 mg, 1.2 mmol).
- Stop reaction buffer 50 mM EDTA, pH 8.0
- DELFIA® Streptavidin 96-well yellow plate (PerkinElmer Life Sciences #AAAND-0005)
- g. Recombinant human VEGF-R2 kinase (50 mM Tris-HCl (pH 8.0), 100 mM NaCl, 5 mM DTT, 15 mM glutamyl Cysteinyl glycine and 20% glycerol (Cell signaling technology #7787)
- h. lO mM ATP solution Cell signaling technology #9804
- test compound Dilute the test compound to the desired final concentration in DMSO, adding 1 ⁇ of the test compound, one negative control, and a blank control in each test (all do not accept any test compound);
- reaction stop buffer 50 mM EDTA, pH 8.0
- the IC 50 value is calculated from the IR values at a range of concentration concentrations of the test compound.
- the in vitro cell assay described below can determine the anti-angiogenic activity and the proliferative activity of the test compound against EGFR-expressing tumor cells, the activity of which can be expressed by the IC 5D value.
- the general protocol for such an experiment is as follows: first select human tumor cells with high expression of EGFR, inoculate them in 96-well culture plates at a suitable cell concentration (exp 5000 cells/ml medium), and then culture the cells in a carbon dioxide incubator. When they grow to 85% confluence, the medium is changed to a medium containing a series of concentration (usually 6 to 7 concentrations) of the test compound solution, and the plate is returned to the incubator for 72 hours.
- test compound was tested for its ability to inhibit cell proliferation using the sulforhodamine B (SRB) method.
- SRB sulforhodamine B
- DMEM/F12 cell culture medium (Gibco, catalog 12400-024)
- Acetic acid (Sinophma chemical reagent company, catalog T20060508) 1. Trichloroacetic acid (Sinophma chemical reagent company, catalogue T20060305) m. Tris base (Amresco, catalog No. 0826)
- 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;
- a growth medium DMEM/F12 + 10% fetal bovine serum as a medium
- test compound 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 ⁇ , 2 ⁇ , 0.2 ⁇ ;
- the medium was changed to a new medium supplemented with DMEM/F12 +10% fetal bovine serum, and 180 ⁇ l of the medium and 20 ⁇ M were added to each well.
- the test compound solution prepared in the fifth step.
- 20 ⁇ l of the culture medium containing 0.5% DMSO was added, so that the final concentration of A431 cells exposed to the test compound solution was 100 ⁇ , 10 ⁇ , 5 ⁇ , 1 ⁇ , 0.1 ⁇ , 0.01 ⁇ , and 0.001.
- 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. ;
- the absorbance values are the absorbance at 565 nm minus the background absorbance at 96 nm for 690 nm;
- IR ⁇ (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.
- the biochemical activity of the compound of the present invention is determined by the above test.
- EXAMPLE 3 Determination of EGFR kinase activity
- reaction stop buffer 50 mM EDTA, pH 8.0.
- DELFIA® Streptavidin 96-well yellow plate (PerkinElmer Life Sciences #AAAND-0005)
- EGFR kinase 50 mM Tris-HCl (pH 8.0), 100 mM NaCl, 5 mM DTT, 15 mM glutamylcysteinylglycine And 20 ° /. Glycerin, Cell signaling technology #7908)
- PTPIB Tetinylated protein
- test compound 1 ⁇ of test compound, negative control and blank control (no test compound was accepted) were added to each test, and only 1 l of DMSO was added;
- dH 2 01 l diluted 6 ⁇ substrate proteins (Tyr589), and added to 15 ⁇ each test;
- Stop the reaction by adding 30 ⁇ l of Stop Reaction Buffer (50 mM EDTA, pH 8.0) to each test;
- the IC 50 value can be calculated from the ratio of inhibition rates at different concentrations of the test compound.
- 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.
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Abstract
The present application discloses pyrrolo-pyridazine derivatives of formula (I), (II), (III), their preparation methods, pharmaceutical compositions containing the same and their uses of acting as therapeutic agents especially tyrosine kinase inhibitors. The definitions of substituents of formula (I)-(III) are the same as description.
Description
吡咯并哒嗪类衍生物及其制备方法和用途 技术领域 Pyrrolopyridazine derivatives and preparation method and use thereof
本发明涉及一种新的吡咯并哒嗪类衍生物、其制备方法及含有该衍生物的药 物组合物以及其作为治疗剂特别是作为酪氨酸激酸抑制剂的用途。 背景技术 The present invention relates to a novel pyrrolopyridazine derivative, a process for the preparation thereof, and a pharmaceutical composition containing the same and its use as a therapeutic agent, particularly as a tyrosine acid inhibitor. Background technique
细胞的信号传导是一种基础的作用机制, 在信号传导过程中, 来自细胞 外的刺激被传递到细胞内部,进而调节不同细胞的进程。这些信号可调节多种生 理响应, 包括细胞增殖、 分化、 凋亡和运动等, 它们以不同种类溶解因子形式存 在, 包括以旁分泌因子、 自分泌因子和内分泌因子为主的生长因子。通过与特定 跨膜受体结合, 生长因子配体将细胞外信号传递到细胞内信号途径,从而引起个 体细胞对细胞外信号的反应。 很多信号传递过程是利用蛋白磷酸化的可逆过程, 涉及到特定蛋白激酶和磷酰化酶。 Cellular signaling is a fundamental mechanism of action in which extracellular stimuli are transmitted to the interior of the cell, which in turn regulates the progression of different cells. These signals regulate a variety of physiological responses, including cell proliferation, differentiation, apoptosis, and exercise, in the form of different types of lytic factors, including growth factors that are dominated by paracrine, autocrine, and endocrine factors. By binding to specific transmembrane receptors, growth factor ligands transmit extracellular signals to intracellular signaling pathways, causing individual cells to respond to extracellular signals. Many signaling processes are reversible processes that utilize protein phosphorylation involving specific protein kinases and phosphorylating enzymes.
蛋白激酶 (PKs)是对蛋白质的酪氨酸、丝氨酸、苏氨酸残基上的羟基的磷酸 化起催化作用的酶。在信号传导过程中, 蛋白激酶和磷酰化酶的反向机制能够平 衡和调节信号流。 一个蛋白质磷酸化状态能影响其构象、 酶的活性、 细胞定位, 蛋白激酶和磷酸酶的相应作用被修改,磷酰化在信号传导中是一个重要的调节机 制, 在信号传导过程中的异常会导致细胞的非正常分化、 转化和生长。 例如, 细 胞可通过将其一部分 DNA转化为致癌基因而成为癌细胞,酪氨酸激酶就是这样 的致癌 S因所编码的生长因子受体蛋白;酪氨酸激酶还可以突变为活化形式而导 致多种人类细胞的变异, 也可以说,过度表达的正常酪氨酸激酶可以引起不正常 细胞增殖。 ' Protein kinases (PKs) are enzymes that catalyze the phosphorylation of hydroxyl groups on tyrosine, serine, and threonine residues of proteins. The reverse mechanism of protein kinases and phosphorylases balances and regulates signal flow during signaling. A protein phosphorylation state can affect its conformation, enzyme activity, cell localization, and the corresponding roles of protein kinases and phosphatases are modified. Phosphorylation is an important regulatory mechanism in signal transduction, and abnormalities during signal transduction. Lead to abnormal differentiation, transformation and growth of cells. For example, cells can become cancer cells by converting part of their DNA into oncogenes, which are the growth factor receptor proteins encoded by such carcinogenic S; tyrosine kinases can also be mutated into activated forms leading to more A variation of human cells, it can be said that over-expressed normal tyrosine kinase can cause abnormal cell proliferation. '
酪氨酸激酶 (PKs) 可以方便地分成两类: 蛋白酪氨酸激酶 (PTKs)和丝 氨酸一苏氨酸激酶 (STKs) 。 PTKs使蛋白质上的酪氨酸残基磷酸化, STKs 使蛋白质上的丝氨酸、苏氨酸残基磷酸化。酪氨酸激酶不仅可以是受体型(包括 细胞外域、 细胞内域和跨膜细胞域)还可以是非受体型 (包括全部细胞内域) 。 PTK 活性的一个主要方面是它们涉及到作为细胞表面蛋白生长因子受体。 具有 PTK 活性的生长因子受体被称为受体酪氨酸激酶 ("RTKs"), 在人类基因中 90 种酪氨酸激酶被 i只别, 其中约 60种是受体型, 约 30种是非受体型, 这些生长 因子受体家族可进一步分为 20种受体酪氨酸激酶亚族和 10种非受体酪氨酸激 酶亚族 (Robinson 等, Oncogene, 2000, 19, 5548-5557)。 Tyrosine kinases (PKs) can be conveniently divided into two classes: protein tyrosine kinases (PTKs) and serine-threonine kinases (STKs). PTKs phosphorylate tyrosine residues on proteins, and STKs phosphorylate serine and threonine residues on proteins. Tyrosine kinases can be not only receptor type (including extracellular domain, intracellular domain and transmembrane cell domain) but also non-receptor type (including all intracellular domains). A major aspect of PTK activity is that they are involved as cell surface protein growth factor receptors. Growth factor receptors with PTK activity are called receptor tyrosine kinases ("RTKs"), and 90 tyrosine kinases in human genes are distinguished by i, of which about 60 are receptor types, about 30 species. Non-receptor type, these growth factor receptor families can be further divided into 20 receptor tyrosine kinase subfamilies and 10 non-receptor tyrosine kinase subfamilies (Robinson et al, Oncogene, 2000, 19, 5548-5557 ).
RTKs亚族包括以下几种: (1 ) EGF族, 如 EGF, TGFa, Neu 和 erbB等; (2) 胰岛素家族, 包括胰岛素受体、 胰岛素样生长因子 I受体(IGF1 ) 和胰岛 素受体相关性受体(IRF ) ; (3〉川型家族,如血小板衍生生长因子受体(PDGF,
包括 PDGFa和 PDGFp受体)、干细胞因子 RTKs(SCF RTK,通常称作 c-Kit)、 fms-相关酪氨酸激酶 3 ( Flt3)受体酪氨酸激酶和集落剌激因子 1受体(CSF-1 R) 酪氨酸激酶等。它们在控制细胞生长及分化方面起着关键的作用, 也是导致产生 生长因子和细胞因子的细胞信号的关键传递者 (参见 Schlessinger and Ullrich, Neuron 1992, 9, 383)。一部分非限制性激酶包括 Abl, ARaf, ATK, ATM, bcr-abi, Blk, BRaf, Brk, Btk, CDK1 , CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CHK, AuroraA, AuroraB, AuroraC, cfms, c-fms, c-Kit, c-Met, cRafl , CSF1 R, CSK, c-Src, EGFR, ErbB2, ErbB3, ErbB4, ERK, ERK1 , ERK2, Fak, fes, FGFR1 , FGFR2, FGFR3, FGFR4, FGFR5, Fgr, FLK-4, Fps, Frk, Fyn, GSK, gsk3a, gsk3b, Hck, Chk, Axl, Pim-1 , Plh-1 , IGF-IR, IKK, IKK1 , IKK2, IKK3, INS-R, Integrin-linked kinase, Jak, JAK1 , JAK2, JAK3, JNK, JNK, Lck, Lyn, MEK, MEK1 , MEK2, p38, PDGFR, PIK, PKB1 , PKB2, PKB3, PKC, P Ca, PKCb, PKCd, PKCe, PKCg, PKC1 , PKCm, PKCz, PLK1 , Polo-like kinase, PYK2, tiei, tie2, TrkA, TrkB, TrkC, UL13, UL97, VEGF-R1 , VEGF-R2, Yes 和 Zap70等。人们认为 PKs与中枢神经系统疾病如老年痴呆症 (参见 Mandelkow, E. M. 等. FEBS Lett. 1992, 314, 315; Sengupta, A. 等. Mol. Cell. Biochem. 1997, 167,99)、 痛感 (参见 Yashpal, K. J. Neurosci. 1995, 15, 3263-72)、 炎症例如关 节炎 (参见 Badger, J. Pharmn Exp. Then 1996, 279, 1453)、 牛皮癣 (参见 Dvir, 等, J. Cell Biol. 1991 , 1 13, 857)、 骨骼疾病例如骨质疏松 (参见 Tanaka等, Nature, 1996, 383, 528)、 癌症 (参见 Hunter and Pines, Cell 1994, 79, 573)、 动脉硬化症 (参见 Hajjar and Pomerantz, FASEB J. 1992, 6, 2933)、 血栓症(参 见 Salari, FEBS 1990,263, 104)、 代谢紊乱如糖尿病 (参见 Borthwick, A. C. 等. Biochem. Biophys. Res. Commun. 1995,210,738)、血管增生性疾病如血管生成 (参见 Strawn 等 C8ticer Res. 1996, 56, 3540; Jackson 等 Pharm. Exp. Ther. 1998, 284, 687)、 自身免疫疾病和移植排斥反应 (参见 Bolen and Brugge, \ 7/?. Rev. Immunol. 1997, 15, 371)、 传染病如病毒 (参见 Littler, E. Nature 1992,358, 160)和真菌感染 (参见 Lum, R. T. PCT Int Appl., WO 9805335 A1 980212)等疾病的靶点有密切的联系。 The RTKs subfamily includes the following: (1) EGF families, such as EGF, TGFa, Neu and erbB; (2) Insulin family, including insulin receptor, insulin-like growth factor I receptor (IGF1) and insulin receptor-related Sexual receptor (IRF); (3) Chuan-type family, such as platelet-derived growth factor receptor (PDGF, Including PDGFa and PDGFp receptors, stem cell factor RTKs (SCF RTK, commonly referred to as c-Kit), fms-associated tyrosine kinase 3 (Flt3) receptor tyrosine kinase, and colony stimulating factor 1 receptor (CSF) -1 R) Tyrosine kinase and the like. They play a key role in controlling cell growth and differentiation and are key players in cell signaling leading to the production of growth factors and cytokines (see Schlessinger and Ullrich, Neuron 1992, 9, 383). A portion of the non-limiting kinases include Abl, ARaf, ATK, ATM, bcr-abi, Blk, BRaf, Brk, Btk, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CHK, AuroraA, AuroraB, AuroraC, cfms, c-fms, c-Kit, c-Met, cRafl, CSF1 R, CSK, c-Src, EGFR, ErbB2, ErbB3, ErbB4, ERK, ERK1, ERK2, Fak, fes, FGFR1, FGFR2, FGFR3 , FGFR4, FGFR5, Fgr, FLK-4, Fps, Frk, Fyn, GSK, gsk3a, gsk3b, Hck, Chk, Axl, Pim-1, Plh-1, IGF-IR, IKK, IKK1, IKK2, IKK3, INS -R, Integrin-linked kinase, Jak, JAK1, JAK2, JAK3, JNK, JNK, Lck, Lyn, MEK, MEK1, MEK2, p38, PDGFR, PIK, PKB1, PKB2, PKB3, PKC, P Ca, PKCb, PKCd , PKCe, PKCg, PKC1, PKCm, PKCz, PLK1, Polo-like kinase, PYK2, tiei, tie 2 , TrkA, TrkB, TrkC, UL13, UL97, VEGF-R1, VEGF-R2, Yes and Zap70. PKs are thought to be associated with central nervous system diseases such as Alzheimer's disease (see Mandelkow, EM et al. FEBS Lett. 1992, 314, 315; Sengupta, A. et al. Mol. Cell. Biochem. 1997, 167, 99), pain (see Yashpal, KJ Neurosci. 1995, 15, 3263-72), inflammation such as arthritis (see Badger, J. Pharmn Exp. Then 1996, 279, 1453), psoriasis (see Dvir, et al, J. Cell Biol. 1991, 1 13, 857), bone diseases such as osteoporosis (see Tanaka et al, Nature, 1996, 383, 528), cancer (see Hunter and Pines, Cell 1994, 79, 573), atherosclerosis (see Hajjar and Pomerantz, FASEB) J. 1992, 6, 2933), thrombosis (see Salari, FEBS 1990, 263, 104), metabolic disorders such as diabetes (see Borthwick, AC et al. Biochem. Biophys. Res. Commun. 1995, 210, 738), vascular proliferative Diseases such as angiogenesis (see Strawn et al. C8ticer Res. 1996, 56, 3540; Jackson et al. Pharm. Exp. Ther. 1998, 284, 687), autoimmune diseases and transplant rejection (see Bolen and Brugge, \ 7/?. Rev. Immunol. 1997, 15, 371), infectious diseases such as viruses (see Littler, E. Nature 1992, 358, 160) is closely related to the targets of diseases such as fungal infections (see Lum, RT PCT Int Appl., WO 9805335 A1 980212).
PTKs信号传导过程中, 特定生长因子 (配体) 之间在细胞外相互作用, 随 后受体二聚, 瞬间内激活蛋白激酶的内在活性, 并进行磷酰化。 内部信号传导分 子的结合位点产生,生成了与细胞质信号分子的复合物,促进各种细胞应答例如 细胞分裂 (增殖), 对胞外微环境代谢作用的表达等。 During PTKs signaling, specific growth factors (ligands) interact extracellularly, followed by receptor dimerization, which activates the intrinsic activity of protein kinases in an instant and undergoes phosphorylation. The binding site of the internal signaling molecule is generated to form a complex with the cytoplasmic signaling molecule, promoting various cellular responses such as cell division (proliferation), expression of extracellular microenvironment metabolism, and the like.
受体酪氨酸激酶磷酰化的结合位点也是与信号传导分子 SH2 (与 src同源) 域具有高度亲和力的结合位点。很多与受体酪氨酸激酶相关的细胞内底物蛋白已 被确定, 可分为两类: (1 )有催化区底物(2)无催化区底物, 但可作为结合体,
且与某些有催化活性的分子相关。 受体或蛋白与底物 SH2域相互作用的特异性 是通过靠近磷酰化酪氨酸残基的氨基酸序列来确定的, SH2 -域与磷酰化酪氨酸 序列周围的氨基酸序列与特定受体结合的差异性与底物磷酰化的差异性是一致 的。蛋白酪氨酸激酶机能可通过表达模式和配体可用性来确定, 也可由特定受体 激活的下游区信号传导路径来确定。因此,磷酰化提供了一个重要可调节的步骤, 此歩骤可确定由特定受体激活的信号传导的选择性和分化因子受体。受体酪氨酸 激酶的非正常表达或突变可能导致不可控制的细胞增殖(如恶性肿瘤生长)或关 键发展过程的缺失等。 The binding site for phosphorylation of the receptor tyrosine kinase is also a binding site with a high affinity for the SH2 (synchronous to src) domain of the signaling molecule. Many intracellular substrate proteins associated with receptor tyrosine kinases have been identified and can be divided into two categories: (1) substrate with catalytic domain (2) substrate without catalytic region, but can be used as a combination, And related to certain catalytically active molecules. The specificity of the interaction of a receptor or protein with the substrate SH2 domain is determined by the amino acid sequence near the phosphorylated tyrosine residue, the amino acid sequence surrounding the SH2-domain and the phosphorylated tyrosine sequence, and the specific The difference in bulk binding is consistent with the difference in substrate phosphorylation. Protein tyrosine kinase function can be determined by expression pattern and ligand availability, as well as by downstream region signaling pathways activated by specific receptors. Thus, phosphorylation provides an important, regulatable step that determines the selectivity of signaling and the differentiation factor receptor that is activated by a particular receptor. Abnormal expression or mutation of a receptor tyrosine kinase may result in uncontrolled cell proliferation (such as malignant tumor growth) or loss of key developmental processes.
酪氨酸激酶, 在大部分人类肿瘤, 如白血病、 乳腺癌、前列腺癌、 非小细胞 肺癌 (包括腺癌、 肺鳞状上皮细胞癌)、 胃肠癌 (包括结肠癌、 直肠癌和胃癌)、 膀胱癌、 食管癌、 卵巢癌、 胰腺癌等癌症中, 都会出现突变或过度表达。通过对 人类肿瘤细胞进行检测, 酪氨酸激酶广泛性与关联性进一步得到了确认。例如- 在人类癌症包括肺癌、脑癌、颈癌、 胃肠癌、乳腺癌、食管癌、 卵巢癌、子宫癌、 膀胱癌和甲状腺癌中, EGFR酪氨酸激酶会发生突变和过度表达。 Tyrosine kinases, in most human tumors, such as leukemia, breast cancer, prostate cancer, non-small cell lung cancer (including adenocarcinoma, lung squamous cell carcinoma), gastrointestinal cancer (including colon cancer, rectal cancer, and gastric cancer) In cancers such as bladder cancer, esophageal cancer, ovarian cancer, and pancreatic cancer, mutations or overexpression may occur. The ubiquity and association of tyrosine kinases have been further confirmed by detection of human tumor cells. For example - EGFR tyrosine kinases are mutated and overexpressed in human cancers including lung, brain, neck, gastrointestinal, breast, esophageal, ovarian, uterine, bladder and thyroid cancers.
"HER" 或 "Erb" 受体酪氨酸激酶亚族包括 EGFR,HER2,HER3和 HER4。 这些亚族由胞外糖基化配体结合域、跨膜域及可将蛋白质上的酪氨酸序列进行磷 酰化的胞内细胞质催化域所组成。受体酪氨酸激酶催化活性可通过受体过度表达 或配体介导二聚合被激活。 HER2家族聚合体有同型二聚体和异型二聚体两种形 式。同型二聚化的一个例子是 HER1 (EGFR)与 EGF家族配体(包括 EGF, 转 化生长因子 a, betacellulin, 与肝磷脂结合的 EGF, epiregulin) 的聚合, 四种 HER酪氨酸激酶之间的异型二聚合可通过与 heregulin (也叫 neuregulin)家族 配体的结合被加速。虽然 HER?:的受体之一没有酶活性,但 HER2 与 HER3, 或 HER3 与 HER4 的异型二聚也可显著地刺激酪氨酸激酶受体二聚合。 在各种类 型细胞中, 受体过度表达可激活 HER2激酶的活性。 受体同型二聚体和异型二 聚体的激活可将受体和其他细胞内蛋白质酪氨酸序列进行磷酰化,随后细胞内信 号途径如微管相关蛋白激酶 (MAP激酶) 和磷脂酰肌醇 (-3) 激酶 (PI3激酶) 也被激活, 这些信号途径的激活促使细胞增殖, 抑制细胞调亡。 The "HER" or "Erb" receptor tyrosine kinase subfamily includes EGFR, HER2, HER3 and HER4. These subfamilies consist of an extracellular glycosylation ligand binding domain, a transmembrane domain, and an intracellular cytoplasmic catalytic domain that phosphorylates the tyrosine sequence on the protein. The receptor tyrosine kinase catalytic activity can be activated by receptor overexpression or ligand-mediated dimerization. The HER2 family of polymers has both homodimers and heterodimers. An example of homodimerization is the polymerization of HER1 (EGFR) with EGF family ligands (including EGF, transforming growth factor a, betacellulin, heparin-binding EGF, epiregulin), between four HER tyrosine kinases. The heterodimerization can be accelerated by binding to the heregulin (also known as neuregulin) family of ligands. Although HER:? No one receptor activity but HER2 and HER3, or a HER3 and HER4 profiled dimerization also significantly stimulated tyrosine kinase receptor dimerization. In various cell types, receptor overexpression activates the activity of HER2 kinase. Activation of receptor homodimers and heterodimers phosphorylates receptors and other intracellular protein tyrosine sequences, followed by intracellular signaling pathways such as microtubule-associated protein kinases (MAP kinases) and phosphatidylinosides Alcohol (-3) kinase (PI3 kinase) is also activated, and activation of these signaling pathways promotes cell proliferation and inhibits cell apoptosis.
RTK另一个亚族包括胰岛素受体 (IR),胰岛素样生长因子 -1受体 (IGF-1R), 胰岛素受体相关受体 (IRR) 。 IR, IGF-1 R与胰岛素, IGF-I 和 IGF-II相互作 用,生成了由两种完全胞外糖基化 α亚基和两个穿过细胞膜且含有酪氨酸激酶域 β亚基构成的异四聚体。 Another subfamily of RTK includes the insulin receptor (IR), the insulin-like growth factor-1 receptor (IGF-1R), and the insulin receptor-related receptor (IRR). IR, IGF-1 R interacts with insulin, IGF-I and IGF-II to form two completely extracellular glycosylated alpha subunits and two tyrosine kinase domain beta subunits Heterotetramer.
RTK 第三个亚族是指血小板源生长因子受体 (PDGFR) 族, 其中包括 PDGFRa, PDGFRp, CSFIR, c-Kit和 c-fms。这些受体由含有各种免疫球蛋白样 环糖基化胞外域和一个胞外域所组成,其中胞内域中酪氨酸激酶区被不相关的氨 基酸序列阻断。
血小板源生长因子受体, 如 PDGFRa和 PDGFRP等也是跨膜酪氨酸激酶 受体。 当它们与配体相结合时, 或形成同型二聚物 (PDGF-AA, PDGF-BB), 或异型二聚物 (PDGF-AB) 。 随后受体二聚, 酪氨酸激酶被活化, 向下游区发 信号来促进肿瘤生长。基因突变是受体不依赖于与配体结合而被激活的原因,也 是肿瘤生成的驱动力。在多种不同的肿瘤细胞株内, 特别是乳房癌、 结肠癌、 卵 巢癌、前列酰癌、 肉瘤和胶质瘤的细胞中, 都发现能够激活 PDGFR生长因子一 PDGF的表达, 其中脑瘤, 前列腺癌(包括腺癌和骨转移癌)恶性神经胶质过多 症研究数据有研究价值。 The third subgroup of RTK refers to the platelet-derived growth factor receptor (PDGFR) family, including PDGFRa, PDGFRp, CSFIR, c-Kit and c-fms. These receptors are composed of a variety of immunoglobulin-like cyclic glycosylated extracellular domains and an extracellular domain in which the tyrosine kinase domain in the intracellular domain is blocked by an unrelated amino acid sequence. Platelet-derived growth factor receptors such as PDGFRa and PDGFRP are also transmembrane tyrosine kinase receptors. When they are combined with a ligand, either form a homodimer (PDGF-AA, PDGF-BB), or a heterodimer (PDGF-AB). Subsequent receptor dimerization, tyrosine kinase is activated, signaling downstream regions to promote tumor growth. Mutations in genes are responsible for the receptor's inability to bind to ligands and are a driving force for tumorigenesis. It is found to activate PDGFR growth factor-PDGF expression in a variety of different tumor cell lines, particularly breast cancer, colon cancer, ovarian cancer, prodramide, sarcoma and glioma cells, of which brain tumors, The research data of malignant gliosis in prostate cancer (including adenocarcinoma and bone metastases) has research value.
c-Kit是 PDGF受体家族的成员, 当其与配体 SCF (干细胞因子) 相结合时, 活性被激活。在各种不同的实体瘤中对 c-Kit表达模式进行了研究, 在肉瘤, 胃肠 道胶质瘤(GIST), 精原细胞瘤和类癌瘤中, c-Kit有过量表达。 [参见 Weber等, 丄 Clin. Oncol. 22(14S), 9642 (2004)]。 GIST是一种非上皮细胞瘤, 大多数存在 于胃部, 少数分布于小肠, 在食道中存在很少, 也有分布在肝、 腹膜腔等部位。 c-Kit is a member of the PDGF receptor family and is activated when it binds to the ligand SCF (stem cell factor). The c-Kit expression pattern was studied in various solid tumors, and c-Kit was overexpressed in sarcoma, gastrointestinal glioma (GIST), seminoma and carcinoid tumors. [See Weber et al., 丄 Clin. Oncol. 22(14S), 9642 (2004)]. GIST is a non-epithelial cell tumor, most of which is present in the stomach, a few in the small intestine, rarely in the esophagus, but also in the liver, peritoneal cavity and other parts.
GIST源于 Cajal 间质细胞 (ICC), ICC可部分形成肠自主神经系统, 参与控制 胃动力。 大多数 (50〜 80%) GIST产生是由于 c-Kit基因发生突变, 在消化道 内, c-Kit/CD117染色阳性的一般都为 GIST, c-Kit突变能够使其不依赖于 SCF激 活便具有 c-Kit机能, 从而使细胞分裂率增加, 导致基因组的不稳定。在畸变肥大 细胞瘤、 肥大细胞增生病、骨髓增生综合征、荨麻疹等疾病中, 也可检测到 c-Kit 的表达, 在急性 AML和恶性淋巴瘤中也有 c-Kit的表达, 在小细胞支气管癌、精原 细胞瘤、 无性细胞瘤、 睾丸、 *上皮内瘤样变、 黑素瘤、 乳房癌、 成神经细胞瘤、 尤因肉瘤都有 c-Kit表达 (参见 Schdtte et al., innovartis 3/2001)。众所周知, RET ( rearranged during transfection ) 。 原癌基因点遗传突变是致瘤的, 患有多发 性内分泌腺瘤病 2 (MEN 2) 病人可能会导致患有嗜铬细胞瘤、甲状腺髓样癌和甲 状旁腺腺瘤和增生等病症 (见 Huang et al., Cancer Res. 60, 6223-6 (2000))。 GIST is derived from Cajal interstitial cells (ICC), which can form part of the intestinal autonomic nervous system and participate in the control of gastric motility. Most (50~80%) GIST production is due to mutation of c-Kit gene. In the digestive tract, c-Kit/CD117 staining is generally GIST, and c-Kit mutation can make it independent of SCF activation. c-Kit function, resulting in increased cell division rate, leading to instability of the genome. In the cases of distorted mast cell tumor, mast cell proliferative disease, myeloproliferative syndrome, urticaria and other diseases, c-Kit expression can also be detected, and c-Kit expression is also found in acute AML and malignant lymphoma, in small cells. Bronchial carcinoma, seminoma, dysgerminoma, testis, intraepithelial neoplasia, melanoma, breast cancer, neuroblastoma, Ewing sarcoma have c-Kit expression (see Schdtte et al., innovartis) 3/2001). As we all know, RET (rearranged during transfection). Proto-oncogene genetic mutations are tumorigenic, and patients with multiple endocrine neoplasia 2 (MEN 2) may cause pheochromocytoma, medullary thyroid carcinoma, and parathyroid adenoma and hyperplasia ( See Huang et al., Cancer Res. 60, 6223-6 (2000)).
因胎肝激酶(Flk)受体亚族与 PDGFR亚族很相似, 有时被归于该族。此亚 族由含激酶插入域-受体胎肝激酶 -1 (KDR/FLK-1 , VEGFR2)、 Flk-1 R, Flk-4和 fms样酪氨酸激酶 1 (Flt-1)所组成。 Because the fetal liver kinase (Flk) receptor subfamily is very similar to the PDGFR subfamily, it is sometimes attributed to this family. This subfamily consists of a kinase-containing insertion domain-receptor fetal liver kinase-1 (KDR/FLK-1, VEGFR2), Flk-1 R, Flk-4 and fms-like tyrosine kinase 1 (Flt-1).
酪氨酸激酶生长因子受体家族的另外一个成员是成纤维细胞生长因子 ( FGF) 受体亚族。 此亚族由四个受体, FGFR1-4、 七个配体和 FGF1 -7组成。 虽然目前尚未确定,但这些受体是由包含各种免疫球蛋白样环糖基化的一个胞外 域和一个其中酪氨酸激酶序列被不相关的氨基酸序列所阻断的细胞内域组成。 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.
酪氨酸激酶生长因子受体家族的另外一个成员是血管内皮生长因子 (VEGF) 受体亚族。 与 PDGF相似, VEGF是二聚糖蛋白, 但生物学功能和体 内靶细胞特异性不同。 特别是, VEGFR与血管生成有关, 通过抑制 VEGFRs来 抑制血管生成, 正应用于临床治疗肿瘤, 且取得了较好疗效。 VEGF在各种恶性
实体肿瘤中, 如肺癌、 乳腺癌、 非霍奇金恶性淋巴瘤、 卵巢癌、 胰腺癌、 恶性胸 膜间皮瘤和黑素瘤有强烈表达,且与癌变进程相关,在白血球过多症和淋巴瘤中 也有表达。 除了其血管生成活性, VEGFR. VEGF配体也可以通过在肿瘤细胞内 直接通过 pro-survival性质促进肿瘤生长, PDGF也具有血管生成作用。新生血管 生成的过程对于肿瘤持续生长起着关键作用, 正常情况下,新生血管的生成在人 的生理过程如胚胎生长、伤口愈合和女性生殖的各个过程都是非常重要的。然而, 非预料或者病理学上的血管生成却与疾病的一系列状态相关, 如糖尿病视网膜 病、 牛皮癣、癌症、类风湿性关节炎、动脉粥样化、卡波济 (氏)肉瘤和血管瘤等。 血管内皮细胞的生成激活血管生成,具有刺激体内血管内皮细胞中的的生成活性 —些多肽已经被确认,包括酸性、碱性的成纤维细胞生长因子 (aFGF and bFGF) 和血管内皮生长因子。 由于 VEGF受体的限制表达, 其生长因子的活性与 aFGF and bFGF活性相比,对内皮细胞相对来讲具有特异性。最近的证据表明, VEGF 在正常情况和病理学情况下的血管生成和血管渗透过程中,都是 常重要的剌激 剂。 VEGF能够诱导血管萌芽表型, 它诱导内皮细胞增殖、 蛋白酶的表达和迁移 来促进毛细血管生成, 从而形成超渗透、 不成熟的血管网络, 这是典型的病理学 血管生成的典型特征。人们期望拮抗 VEGF活性在治疗与血管生成作用或者血管 渗透性相关的疾病如肿瘤特别是抑制肿瘤生长能够有应用的价值。 Another member of the tyrosine kinase growth factor receptor family is the vascular endothelial growth factor (VEGF) receptor subfamily. Similar to PDGF, VEGF is a dimeric glycoprotein, but its biological function is different from that of in vivo target cells. In particular, VEGFR is involved in angiogenesis, inhibits angiogenesis by inhibiting VEGFRs, and is being used in clinical treatment of tumors, and has achieved good therapeutic effects. VEGF in various malignant Solid tumors, such as lung cancer, breast cancer, non-Hodgkin's lymphoma, ovarian cancer, pancreatic cancer, malignant pleural mesothelioma, and melanoma are strongly expressed and associated with the progression of cancer, in leukemia and lymphoid There are also expressions in the tumor. In addition to its angiogenic activity, VEGFR. VEGF ligands also promote tumor growth by directly pro-survival properties in tumor cells, and PDGF also has an angiogenic effect. The process of neovascularization plays a key role in the continued growth of the tumor. Under normal circumstances, the formation of new blood vessels is very important in the various processes of human physiological processes such as embryo growth, wound healing and female reproduction. However, unanticipated or pathological angiogenesis is associated with a range of conditions, such as diabetic retinopathy, psoriasis, cancer, rheumatoid arthritis, atheroma, Kaposi's sarcoma, and hemangioma. Wait. The production of vascular endothelial cells activates angiogenesis and stimulates the production of vascular endothelial cells in vivo - some peptides have been identified, including acidic, basic fibroblast growth factors (aFGF and bFGF) and vascular endothelial growth factor. Due to the restricted expression of the VEGF receptor, its growth factor activity is relatively specific to endothelial cells compared to aFGF and bFGF activity. Recent evidence suggests that VEGF is a frequently important stimulant during angiogenesis and vascular infiltration in both normal and pathological conditions. VEGF induces a vascular sprouting phenotype that induces endothelial cell proliferation, protease expression and migration to promote capillary formation, thereby forming a super-osmotic, immature vascular network, which is typical of typical pathological angiogenesis. It is expected that antagonizing VEGF activity can be of value in the treatment of diseases associated with angiogenesis or vascular permeability, such as tumors, particularly tumor growth inhibition.
FLT3 ( Fms样酪氨酸激酶) 是酪氨酸激酶 (PTK) III型家族成员, 在成人 和幼儿急性髓细胞样白血病(AML) 、急性髓细胞样白血病、骨髓增生异常综合 征等白血球过多症中, FLT3基因非正常表达。 35 %的急性髓细胞样白血病病人 的 FLT3突变被激活且预后不良,大多数的突变都有在近膜域的结构内复制的现 象, 5— 10 %的病人天冬酰氨 835发生点突变, FLT3的酪氨酸激酶活性被激活, 致使在配体缺失的情况下也有信号存在且发生增殖。据研究,有突变形式受体表 达的患者治愈的几率降低。 总之, 在人白血球过多症和骨髓增生异常综合征中, FLT3突变都与肿瘤的发生相关。 FLT3 (Fms-like tyrosine kinase) is a member of the tyrosine kinase (PTK) type III family, and has excessive white blood cells in adult and young children with acute myeloid leukemia (AML), acute myeloid leukemia, and myelodysplastic syndrome. In the case of the disease, the FLT3 gene is abnormally expressed. In 35 % of patients with acute myeloid leukemia, FLT3 mutations are activated and the prognosis is poor. Most of the mutations have intrastructural replication in the proximal membrane domain, and 5-10% of patients have a point mutation in asparagine 835. The tyrosine kinase activity of FLT3 is activated, resulting in the presence of a signal and proliferation in the absence of a ligand. According to the study, patients with mutant forms of receptor expression have a reduced chance of cure. In conclusion, in human leukemia and myelodysplastic syndromes, FLT3 mutations are associated with tumorigenesis.
经证实肝细胞生长因子 (HGF) 受体 (c-MET或 HGFR)酷氨酸激酶与肿 瘤生成、增强细胞运动性、侵袭和转移密切相关 (参见 Ma, P.C等 (2003b). Cancer Metastasis Rev, 22, 309-25; Maulik, G.等 (2002b). Cytokine Growth Fsctor Rev, 13, 41-59)。 各种肿瘤包括小细胞肺癌 (SCLC) 中的过度表达或突变可激 活 c-MET ( HGFR) (参见 Ma, P.C.等 (2003a). Cancer Res, 63, 6272-6281 )。 Hepatocyte growth factor (HGF) receptor (c-MET or HGFR) tyrosine kinases have been shown to be involved in tumorigenesis, cell motility, invasion and metastasis (see Ma, PC et al. (2003b). Cancer Metastasis Rev, 22, 309-25; Maulik, G. et al. (2002b). Cytokine Growth Fsctor Rev, 13, 41-59). Overexpression or mutation in various tumors, including small cell lung cancer (SCLC), activates c-MET (HGFR) (see Ma, P.C. et al. (2003a). Cancer Res, 63, 6272-6281).
原癌基因 c-Met编码肝细胞生长因子受体,是具有酪氨酸激酶活性的细胞膜 糖蛋白,对多种细胞增殖、 分化具有重要的生理调节作用. c-met基因在许多恶性 肿瘤中过表达,是甲状腺滤泡上皮细胞癌变的重要因素,并与甲状腺癌的病理分 期、 侵袭及转移密切相关。 The proto-oncogene c-Met encodes a hepatocyte growth factor receptor, which is a cell membrane glycoprotein with tyrosine kinase activity, which has important physiological regulation effects on various cell proliferation and differentiation. The c-met gene has been used in many malignant tumors. Expression is an important factor in the carcinogenesis of thyroid follicular epithelial cells and is closely related to the pathological stage, invasion and metastasis of thyroid cancer.
关于 PKT亚族, Plowman 等在 DN&P 7(6): 334-339 (1994)中有更为详细
描述, 该文献作为一整体通过引用结合到本文中。 For the PKT subfamily, Plowman et al. are more detailed in DN&P 7(6): 334-339 (1994). Description, the document is incorporated herein by reference in its entirety.
除了 PTKs以外, 还存在另外的细胞酶家族, 称作受体酪氨酸激酶抑制剂, 并在此使用后一名称, 缩写为 "CTK"。 CTKs本身缺少细胞外域和跨膜域。 目前, 已经在 11个亚族 (Src, Frk, Btk, Csk, Abl, Zap70, Fes/Fps, Fak, Jak, Ack和 LIMK) 中已经鉴定超过 24种 CTKs。 在目前为止, Src亚族 CTKs数目似乎最 多, 包括 Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr和 Yrk, 且 Src亚族酶与肿瘤生 成有关。 关于 CTKs 更为详尽的描述, 可参见 旧 olen, 1993, Oncogen 8: 2025-2031 , 其全文包括任何附图作为一整体提出, 通过引用结合到本文中。 In addition to PTKs, there are additional families of cellular enzymes called receptor tyrosine kinase inhibitors, and the latter name is used here, abbreviated as "CTK". CTKs themselves lack the extracellular domain and the transmembrane domain. Currently, more than 24 CTKs have been identified in 11 subfamilies (Src, Frk, Btk, Csk, Abl, Zap70, Fes/Fps, Fak, Jak, Ack and LIMK). So far, the number of Src subfamily CTKs seems to be the highest, including Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk, and Src subfamily enzymes are involved in tumorigenesis. For a more detailed description of CTKs, see Old olen, 1993, Oncogen 8: 2025-2031, the entire disclosure of which is incorporated herein by reference in its entirety in its entirety herein.
与 CTKs相类似, 丝氨酸-苏氨酸激酶或 STKs, 在细胞内占据主导地位, 虽 然仅有几种 STK型受体激酶。 STKs是最普遍的细胞溶质激酶, 即它发挥其功 能在部分细胞质中, 而不是在胞质细胞器中。胞质溶胶是细胞内一个区域, 在此 大多数细胞中间代谢和生物合成活性发生;如蛋白质是在胞质溶胶核糖体上进行 合成的。 Similar to CTKs, serine-threonine kinases or STKs are dominant in the cell, although there are only a few STK-type receptor kinases. STKs are the most common cytosolic kinases, that is, they perform their functions in part of the cytoplasm, not in cytoplasmic organelles. The cytosol is a region within the cell where the metabolism and biosynthesis activity occurs in most cells; for example, proteins are synthesized on cytosol ribosomes.
与过度增殖相关疾病如癌症等的特征之一是对细胞传导途径进行破坏,细胞 传导途径通过细胞周期来控制进程。在真核细胞中, 细胞周期与蛋白质的磷酰化 有序的级联反应密切相关,在信号传导的机制中, PKs很多家族似乎在细胞分裂 周期级联中都起着关键的作用。 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.
关于癌症, 提出两个主要的假设解释过度细胞增殖, 该增殖驱动与已知由 PK调节的功能相关的肿瘤发展。 即, 人们觉得恶性肿瘤生长是由于控制细胞分 裂或增殖的机制被破坏引起的。原癌基因蛋白质产物能够干扰调节细胞生长和增 殖的信号传导途径, 这些原癌基因的蛋白质产物包括上面讨论的细胞外生长因 子,跨膜生长因子 PTK受体(RTKs) ,细胞质 PTKs (CTKs)和细胞溶质 STKs。 人们期待着能够合成具有抗肿瘤细胞增殖活性的抑制剂, 希望能够抑制 PTKs、 CTKs或者 STKs中的一种或者多种, 有效地治疗和改善由 PTKs、 CTKs或者 STKs以及血管生成作用介导的超增殖生理紊乱。 发明内容 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
为了克服现有技术的不足之处, 本发明的目的在于提供一种通式 I, II和 III 所示的新的吡咯并哒嗪类化合物, 以及它们的互变异构体、 对映体、 非对映体、 消旋体和药学上可接受的盐, 以及代谢产物和代谢前体或前药。
In order to overcome the deficiencies of the prior art, it is an object of the present invention to provide novel pyrrolopyridazines of the formulae I, II and III, as well as their tautomers, enantiomers, Diastereomers, racemates and pharmaceutically acceptable salts, as well as metabolites and metabolic precursors or prodrugs.
上式中: In the above formula:
X选自 W(C¾), (CH2)W, 或 W, 其中 W是 0, S, SO, S02; 或 -N 8 (其中 R8是氢原子或烷基); X is selected from W(C3⁄4), (CH 2 )W, or W, wherein W is 0, S, SO, S0 2; or -N 8 (wherein R 8 is a hydrogen atom or an alkyl group);
当 X是 - 8, R8是烷基,则 可以和 R1形成一个 4〜8元杂环基;其中 5〜 8元杂环内可以含有一个或多个 N, 0, S原子, 并且 4〜8元杂环上可以进一歩 被一个或多个的垸基, 卤素, 芳基, 杂芳基, 卤代垸基, 卤代垸氧基, 羟基, 氨 基, 烷氨基, 酰胺基, 胺酰基, 氰基, 烷氧基, 芳氧基, 胺垸基, 羟烷基, 杂环 垸基, 羧酸, 羧酸酯或 - 5 所取代; When X is - 8 and R 8 is an alkyl group, it may form a 4 to 8 membered heterocyclic group with R1; wherein the 5 to 8 membered heterocyclic ring may contain one or more N, 0, S atoms, and 4~ The 8-membered heterocyclic ring may be further substituted with one or more fluorenyl groups, halogen, aryl, heteroaryl, halofluorenyl, halodecyloxy, hydroxy, amino, alkylamino, amide, aminyl, Cyano, alkoxy, aryloxy, aminyl, hydroxyalkyl, heterocycloalkyl, carboxylic acid, carboxylic acid ester or substituted with -5 ;
选自氢原子, 烷基, 环烷基, 杂环垸基, 芳基, 杂芳基, 芳垸基或杂芳烷 基, 其中垸基, 环烷基, 杂环烷基, 芳基, 杂芳基, 芳焼基或杂芳垸基可以进一 步被一个或多个烷基, 卤素, 芳基, 羟基, 氨基, 炔基, 烷氨基, 酰胺基, 胺酰 基, 垸氧基, 芳氧基, 杂环垸基, 羧酸, 羧酸酯或 -NR5 所取代; 其中芳基, 杂芳基, 芳垸基或杂芳烷基可以并成双环; ' Selected from hydrogen atom, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, wherein fluorenyl, cycloalkyl, heterocycloalkyl, aryl, hetero The aryl, arylfluorenyl or heteroarylalkyl group may be further substituted by one or more alkyl, halogen, aryl, hydroxy, amino, alkynyl, alkylamino, amide, aminyl, decyloxy, aryloxy, a heterocyclic fluorenyl group, a carboxylic acid, a carboxylic acid ester or a substituent of -NR 5 ; wherein an aryl group, a heteroaryl group, an arylalkyl group or a heteroaralkyl group may be combined into a bicyclic ring;
R2选自氢原子, 垸基, 三氟甲基, 环垸基, 杂环烷基, 芳基, 杂芳基, 芳烷 基或杂芳垸基, 其中烷基, 环烷基, 杂环垸基, 芳基, 杂芳基, 芳垸基或杂芳垸 基可以进一步被一个或多个垸基, 卤素, 芳基, 羟基, 氨基, 垸氨基, 酰胺基, 胺酰基, 垸氧基, 芳氧基, 杂环烷基, 羧酸, 羧酸酯或 -NR5R6所取代; R 2 is selected from the group consisting of a hydrogen atom, a fluorenyl group, a trifluoromethyl group, a cyclodecyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an aralkyl group or a heteroarylalkyl group, wherein an alkyl group, a cycloalkyl group, a heterocyclic ring An anthracenyl group, an aryl group, a heteroaryl group, an indenyl group or a heteroaryl group may further be one or more fluorenyl groups, a halogen, an aryl group, a hydroxy group, an amino group, a decylamino group, an amide group, an amino group, a decyl group, Substituted with an aryloxy group, a heterocycloalkyl group, a carboxylic acid, a carboxylic acid ester or -NR 5 R6;
选自氢原子, 烷基, 芳基, 杂芳基, 杂芳氧基, -C(=0)R7, -C(=S)R7, -NC(=0)R7, -(CH2)nO(C=0)R7, -(CH2)nO(C=S)R7, -(CH2)nR7, -(CH2CH20)nR8 ; 其中芳基, 杂芳基, 杂芳氧基, -(C¾)nR7可以进一步被一个或多个垸基, -(CH2)nR7, =C(0), 卤素, 三氟甲基, 羧酸, 羧酸酯所取代; Selected from a hydrogen atom, an alkyl group, an aryl group, a heteroaryl group, a heteroaryloxy group, -C(=0)R 7 , -C(=S)R 7 , -NC(=0)R 7 , -(CH 2 ) n O(C=0)R 7 , -(CH 2 ) n O(C=S)R 7 , -(CH 2 ) n R 7 , -(CH 2 CH 2 0) n R 8 ; , heteroaryl, heteroaryloxy, -(C3⁄4) n R 7 may be further protected by one or more thiol groups, -(CH 2 ) n R 7 , =C(0), halogen, trifluoromethyl, Substituted by a carboxylic acid, a carboxylic acid ester;
选自氢原子, 垸基, 环烷基, 杂环烧基, -(C¾CH20)nR8, 烯基或炔基, 其中烷基,环垸基,杂环烷基,烯基或炔基可以进一步被一个或多个烷基,羟基, 垸氧基, 氰基, 氨基, 烷氨基, -NR5 , 羧酸或羧酸酯所取代; Selected from hydrogen atom, fluorenyl, cycloalkyl, heterocycloalkyl, -(C3⁄4CH 2 0) n R 8 , alkenyl or alkynyl, wherein alkyl, cyclodecyl, heterocycloalkyl, alkenyl or alkyne The group may be further substituted by one or more alkyl, hydroxy, decyloxy, cyano, amino, alkylamino, -NR 5 , carboxylic acid or carboxylic acid esters;
R5和 分别选自分别选自氢原子, 垸基, 环垸基, 杂环垸基, 芳基, 杂芳 基或杂芳烷基, 其中焼基, 环垸基, 杂环烷基, 芳基, 杂芳基或者杂芳烷基可以
进一步被一个或多个的烷基, 卤素, 芳基, 羟基, 氨基, 垸氨基, 酰胺基, 胺酰 基, 氰基, 烷氧基, 芳氧基, 胺烷基, 羟垸基, 杂环烷基, 羧酸或者羧酸酯所取 代; R 5 and each selected from the group consisting of a hydrogen atom, a fluorenyl group, a cyclodecyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group or a heteroarylalkyl group, respectively, wherein an indenyl group, a cyclodecyl group, a heterocycloalkyl group, or an aromatic group Base, heteroaryl or heteroaralkyl Further one or more alkyl, halogen, aryl, hydroxy, amino, decylamino, amide, aminyl, cyano, alkoxy, aryloxy, aminyl, hydroxyalkyl, heterocycloalkane Substituted by a carboxylic acid or a carboxylic acid ester;
同时, R5和 可以形成一个 4~8元杂环基; 其中 5〜8元杂环内可以含有 —个或多个 N, 0, S原子,并且 4〜8元杂环上可以进一步被一个或多个的烷基, 卤素, 芳基, 杂芳基, 代烷基, 代垸氧基, 羟基, 氨基, 酰胺基, 胺酰基, 氰基, 烷氧基, 芳氧基, 胺垸基, 羟垸基, 杂环烷基, 羧酸, 羧酸酯或 -NR5R6 所取代; Meanwhile, R 5 and may form a 4-8 membered heterocyclic group; wherein the 5 to 8 membered heterocyclic ring may contain one or more N, 0, S atoms, and the 4 to 8 membered heterocyclic ring may be further subjected to a Or a plurality of alkyl, halogen, aryl, heteroaryl, alkyl, methoxy, hydroxy, amino, amide, aminyl, cyano, alkoxy, aryloxy, amidino, Substituted with hydroxymethyl, heterocycloalkyl, carboxylic acid, carboxylic acid ester or -NR 5 R6;
R7选自羟基, 垸氧基, 芳氧基, 杂环烷氧基, 芳垸氧基, -N(R8)(CH2)nR9, -N 8[CH2CH20]nR8, -NR5 或者 -N (CH2)n[CH(OH)C¾]rZ (其中 Z是芳基, 杂 芳基, 杂环垸基, -NR5 , -COOR8或 CON 5R6); R 7 is selected from the group consisting of hydroxy, decyloxy, aryloxy, heterocycloalkoxy, aryloxy, -N(R 8 )(CH 2 ) n R 9 , -N 8 [CH 2 CH 2 0] n R 8 , -NR 5 or -N (CH 2 ) n [CH(OH)C3⁄4] r Z (wherein Z is aryl, heteroaryl, heterocycloalkyl, -NR 5 , -COOR 8 or CON 5 R6 );
选自氢原子或烷基; Selected from a hydrogen atom or an alkyl group;
R9选自 - R5R6,羟基,芳基,杂芳基,烷氧基, -S(0)2CH3 , -O〖C¾CH20]rR8, -1^(0-)¾¾, -N(OH)R5, -丽。(0) 。或- COR10 (其中 Rw是垸基, 卤代垸基或芳 院基); R 9 is selected from - R 5 R6, hydroxy, aryl, heteroaryl, alkoxy, -S(0) 2 CH 3 , -O 〖C3⁄4CH 2 0] r R 8 , -1^(0-)3⁄43⁄4 , -N(OH)R 5 , -Li. (0). Or - COR 10 (wherein R w is a fluorenyl group, a halogenated fluorenyl group or a aryl group);
R10是垸基, 卤代烷基或芳垸基 R 10 is an embankment, haloalkyl or aryl alkyl with
n是 0〜6; n is 0~6;
r是 1〜2。 具体地, 本发明包括下述通式 (I)表示的化合物或其盐: r is 1 to 2. Specifically, the present invention includes a compound represented by the following formula (I) or a salt thereof:
X选自 W(CH2), (CH2)W, 或 W, 其中 W是 0, S, SO, S02; 或- N (其中 R8是氢原子或烷基); X is selected from W(CH 2 ), (CH 2 )W, or W, wherein W is 0, S, SO, S0 2 ; or -N (wherein R 8 is a hydrogen atom or an alkyl group);
当 X是 -N , Rs是垸基,则 R8可以和 R1形成一个 4〜8元杂环基;其中 5〜 8元杂环内可以含有一个或多个 N, 0, S原子, 并且 4〜8元杂环上可以进一步 被一个或多个的垸基, 卤素, 芳基, 杂芳基, 卤代烷基, 卤代烷氧基, 羟基, 氨 基, 烷氨基 > 酰胺基, 胺酰基, 氰基, 垸氧基, 芳氧基, 胺垸基, 羟烷基, 杂环 垸基, 羧酸, 羧酸酯或 -Ν¾ 所取代; When X is -N and R s is a fluorenyl group, R 8 may form a 4 to 8 membered heterocyclic group with R1; wherein the 5 to 8 membered heterocyclic ring may contain one or more N, 0, S atoms, and The 4 to 8 membered heterocyclic ring may be further substituted with one or more fluorenyl groups, halogen, aryl, heteroaryl, haloalkyl, haloalkoxy, hydroxy, amino, alkylamino > amide, aminyl, cyano, Alkoxy, aryloxy, aminyl, hydroxyalkyl, heterocycloalkyl, carboxylic acid, carboxylic acid ester or -Ν3⁄4 substituted;
选自氢原子, 烷基, 环烷基, 杂环綜基, 芳基, 杂芳基, 芳烷基或杂芳垸 基, 其中烷基, 环垸基, 杂环垸基, 芳基, 杂芳基, 芳烷基或杂芳烷基可以进一
步被一个或多个院基, 素, 芳基, 羟基, 氨基, 炔基, 垸氨基, 酰胺基, 胺酰 基, 烷氧基, 芳氧基, 杂环垸基, 羧酸, 羧酸酯或 -NR5R6所取代; 其中芳基, 杂芳基, 芳烷基或杂芳垸基可以并成双环; Selected from hydrogen atom, alkyl, cycloalkyl, heterocyclic heptyl, aryl, heteroaryl, aralkyl or heteroaryl, wherein alkyl, cyclodecyl, heterocycloalkyl, aryl, hetero Aryl, aralkyl or heteroaralkyl can be further Step by one or more of the formula, aryl, aryl, hydroxy, amino, alkynyl, decylamino, amido, aminyl, alkoxy, aryloxy, heterocycloalkyl, carboxylic acid, carboxylic acid ester or Substituted by -NR 5 R6; wherein the aryl, heteroaryl, aralkyl or heteroaryl group may be combined into a bicyclic ring;
选自氢原子, 垸基, 三氟甲基, 环垸基, 杂环垸基, 芳基, 杂芳基, 芳烷 基或杂芳烷基, 其中垸基, 环垸基, 杂环垸基, 芳基, 杂芳基, 芳垸基或杂芳烷 基可以进一步被一个或多个烷基, 卤素, 芳基, 羟基, 氨基, 垸氨基, 酰胺基, 胺酰基, 垸氧基, 芳氧基, 杂环烷基, 羧酸, 羧酸酯或 -NR5 所取代; Selected from hydrogen atom, fluorenyl, trifluoromethyl, cyclodecyl, heterocycloalkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl, wherein fluorenyl, cyclodecyl, heterocycloalkyl , aryl, heteroaryl, arylalkyl or heteroarylalkyl may be further substituted by one or more alkyl, halo, aryl, hydroxy, amino, decylamino, amide, aminyl, decyloxy, aryloxy Substituted by a heterocycloalkyl group, a carboxylic acid, a carboxylic acid ester or -NR 5 ;
R3选自氢原子, 垸基, 芳基, 杂芳基, 杂芳氧基, -C(=0)R7, -C(=S)R7, -NC(=0)R7, -(CH2)nO(C=0)R7, -(CH2)nO(C=S)R7, -(CH2)„R7, -(CH2CH20)nRg; 其中芳基, 杂芳基, 杂芳氧基, -(CH2)nR7可以进一步被一个或多个烷基, -(CH2)nR7, =C(0), , 三氟甲基, 羧酸, 羧酸酯所取代; R 3 is selected from the group consisting of a hydrogen atom, a fluorenyl group, an aryl group, a heteroaryl group, a heteroaryloxy group, -C(=0)R 7 , -C(=S)R 7 , -NC(=0)R 7 , (CH 2 ) n O(C=0)R 7 , -(CH 2 ) n O(C=S)R 7 , -(CH 2 )„R 7 , -(CH 2 CH 2 0) n R g ; Wherein aryl, heteroaryl, heteroaryloxy, -(CH 2 ) n R 7 may be further substituted by one or more alkyl groups, -(CH 2 ) n R 7 , =C(0), , trifluoromethyl Substituted by a carboxylic acid, a carboxylic acid ester;
R4选自氢原子, 烷基, 环烷基, 杂环烷基, -(CH2CH20)nR8, 烯基或炔基, 其中垸基,环垸基,杂环烷基,烯基或炔基可以进一步被一个或多个垸基,羟基, 垸氧基, 氰基, 氨基, 垸氨基, -NR5¾, 羧酸或羧酸酯所取代; R4 is selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, -(CH 2 CH 2 0) n R 8 , an alkenyl group or an alkynyl group, wherein a fluorenyl group, a cyclodecyl group, a heterocycloalkyl group, an alkene group Or alkynyl may be further substituted by one or more mercapto, hydroxy, decyloxy, cyano, amino, decylamino, -NR 5 3⁄4, carboxylic acid or carboxylic acid ester;
和 分别选自分别选自氢原子, 垸基, 环烷基, 杂环垸基, 芳基, 杂芳 基或杂芳垸基, 其中垸基, 环烷基, 杂环嫁基, 芳基, 杂芳基或者杂芳烷基可以 进一步被一个或多个的垸基, 卤素, 芳基, 羟基, 氨基, 垸氨基, 酰胺基, 胺酰 基, 氰基, 垸氧基, 芳氧基, 胺垸基, 羟垸基, 杂环烷基, 羧酸或者羧酸酯所取 代; And each selected from the group consisting of a hydrogen atom, a fluorenyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group or a heteroaryl group, wherein a fluorenyl group, a cycloalkyl group, a heterocyclic group, an aryl group, The heteroaryl or heteroarylalkyl group may be further substituted by one or more of fluorenyl, halogen, aryl, hydroxy, amino, decylamino, amide, aminyl, cyano, decyloxy, aryloxy, amidoxime Substituted with a hydroxy group, a heterocycloalkyl group, a carboxylic acid or a carboxylic acid ester;
同时, 和 可以形成一个 4〜8元杂环基; 其中 5〜8元杂环内可以含有 一个或多个 N, 0, S原子,并且 4~8元杂环上可以进一步被一个或多个的垸基, 卤素, 芳基, 杂芳基, 代烷基, 代垸氧基, 羟基, 氨基, 酰胺基, 胺酰基, 氰基, 垸氧基, 芳氧基, 胺烷基, 羟烷基, 杂环垸基, 羧酸, 羧酸酯或 -NR5R6 所取代; Meanwhile, a 4 to 8 membered heterocyclic group may be formed; wherein the 5 to 8 membered heterocyclic ring may contain one or more N, 0, S atoms, and the 4 to 8 membered heterocyclic ring may be further subjected to one or more Sulfhydryl, halogen, aryl, heteroaryl, alkyl, methoxy, hydroxy, amino, amide, amino, cyano, methoxy, aryloxy, alkoxy, hydroxyalkyl Substituted by a heterocyclic fluorenyl group, a carboxylic acid, a carboxylic acid ester or -NR 5 R6;
R7选自羟基, 垸氧基, 芳氧基, 杂环烷氧基, 芳烷氧基, -N(R8)(CH2)nR9, - R8[CH2CH20]nR8, -N 5R6或者 -NR8(CH2)n[CH(OH)C¾]rZ (其中 Z是芳基, 杂 芳基, 杂环烷基, -NR5R6, -COOR8或 CONR5R6); R 7 is selected from the group consisting of hydroxy, decyloxy, aryloxy, heterocycloalkoxy, aralkyloxy, -N(R 8 )(CH 2 ) n R 9 , - R 8 [CH 2 CH 2 0] n R 8 , -N 5 R6 or -NR 8 (CH 2 ) n [CH(OH)C3⁄4] r Z (wherein Z is aryl, heteroaryl, heterocycloalkyl, -NR 5 R 6 , -COOR 8 Or CONR 5 R6);
选自氢原子或烷基; Selected from a hydrogen atom or an alkyl group;
R9选自 -NR5R6,羟基,芳基,杂芳基,垸氧基, -S(0)2C¾, -0[CH2CH20]rR8, - (0') , -N(OH)R5, -NHC(0)R1G或 -COR10 (其中 R10是烷基, 卤代烷基或芳 焼基); R 9 is selected from -NR 5 R6, hydroxy, aryl, heteroaryl, decyloxy, -S(0) 2 C3⁄4, -0[CH 2 CH 2 0] r R 8 , - (0') , - N(OH)R 5 , -NHC(0)R 1G or -COR 10 (wherein R 10 is alkyl, haloalkyl or aryl fluorenyl);
R10是烷基, 卤代垸基或芳烷基 R 10 is an alkyl group, a halogenated fluorenyl group or an aralkyl group
n是 0〜6; n is 0~6;
r是 1〜2。
进一步, 本发明包括下述通式 (π)表示的化合物或其盐: r is 1 to 2. Further, the present invention includes a compound represented by the following formula (π) or a salt thereof:
其中: among them:
X选自 W(CH2), (CH2)W, 或 W, 其中 W是 0, S, SO, S02; 或 -N (其中 R8是氢原子或垸基); ' X is selected from W(CH 2 ), (CH 2 )W, or W, wherein W is 0, S, SO, S0 2 ; or -N (wherein R 8 is a hydrogen atom or a fluorenyl group);
当 X是 -N , R8是烷基,则 可以和 R1形成一个 4〜8元杂环基;其中 5〜 8元杂环内可以含有一个或多个 N, 0, S原子, 并且 4〜8元杂环上可以进一步 被一个或多个的烷基, 卤素, 芳基, 杂芳基, 卤代垸基, 卤代垸氧基, 羟基, 氨 基, 垸氨基, 酰胺基, 胺酰基, 氰基, 垸氧基, 芳氧基, 胺烷基, 羟烷基, 杂环 垸基, 羧酸, 羧酸酯或 - R5 所取代; When X is -N and R 8 is an alkyl group, a 4 to 8 membered heterocyclic group may be formed with R1; wherein the 5 to 8 membered heterocyclic ring may contain one or more N, 0, S atoms, and 4~ The 8-membered heterocyclic ring may be further substituted with one or more alkyl, halogen, aryl, heteroaryl, halodecyl, halodecyloxy, hydroxy, amino, decylamino, amide, aminyl, cyanide a group, a methoxy group, an aryloxy group, an aminoalkyl group, a hydroxyalkyl group, a heterocyclic fluorenyl group, a carboxylic acid, a carboxylic acid ester or a substituted group of R 5 ;
选自氢原子, 烷基, 环垸基, 杂环烧基, 芳基, 杂芳基, 芳烷基或杂芳烷 基, 其中烷基, 环烷基, 杂环垸基, 芳基, 杂芳基, 芳烷基或杂芳垸基可以进一 步被一个或多个垸基, 卤素, 芳基, 羟基, 氨基, 炔基, 烷氨基, 酰胺基, 胺酰 基, 烷氧基, 芳氧基, 杂环垸基, 羧酸, 羧酸酯或 所取代; 其中芳基, 杂芳基, 芳垸基或杂芳垸基可以并成双环; Selected from hydrogen atom, alkyl, cyclodecyl, heterocycloalkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl, wherein alkyl, cycloalkyl, heterocycloalkyl, aryl, hetero The aryl, aralkyl or heteroarylalkyl group may be further substituted by one or more fluorenyl, halogen, aryl, hydroxy, amino, alkynyl, alkylamino, amide, aminyl, alkoxy, aryloxy, a heterocyclic fluorenyl group, a carboxylic acid, a carboxylic acid ester or a substituted group; wherein the aryl group, the heteroaryl group, the aryl fluorenyl group or the heteroaryl fluorenyl group may be combined into a bicyclic ring;
选自氢原子, 垸基, 三氟甲基, 环垸基, 杂环烷基, 芳基, 杂芳基, 芳烷 基或杂芳烷基, 其中烷基, 环烷基, 杂环垸基, 芳基, 杂芳基, 芳垸基或 ^芳烷 基可以进一步被一个或多个垸基, 卤素, 芳基, 羟基, 氨基, 垸氨基, 酰胺基, 胺酰基, 垸氧基, 芳氧基, 杂环垸基, 羧酸, 羧酸酯或 -NR5 所取代; Selected from hydrogen atom, fluorenyl, trifluoromethyl, cyclodecyl, heterocycloalkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl, wherein alkyl, cycloalkyl, heterocycloalkyl , aryl, heteroaryl, arylalkyl or aralkyl may be further substituted by one or more fluorenyl, halogen, aryl, hydroxy, amino, hydrazine, amide, aminyl, decyloxy, aryloxy Substituted by a heterocyclic fluorenyl group, a carboxylic acid, a carboxylic acid ester or -NR 5 ;
R3选自氢原子, 烷基, 芳基, 杂芳基, 杂芳氧基, -C(=0)R7, -C(=S)R7, -NC(=0)R7, -(CH2)nO(C=0)R7, -(CH2)nO(C=S)R7, -(CH2)nR7, -(CH2CH20)nR8; 其中芳基, 杂芳基, 杂芳氧基, -(CH2)nR7可以进一步被一个或多个烷基, -(CH2)n 7, =C(0), > 三氟甲基, 羧酸, 羧酸酯所取代; R 3 is selected from the group consisting of a hydrogen atom, an alkyl group, an aryl group, a heteroaryl group, a heteroaryloxy group, -C(=0)R 7 , -C(=S)R 7 , -NC(=0)R 7 , (CH 2 ) n O(C=0)R 7 , -(CH 2 ) n O(C=S)R 7 , -(CH 2 ) n R 7 , -(CH 2 CH 2 0) n R 8 ; Wherein aryl, heteroaryl, heteroaryloxy, -(CH 2 ) n R 7 may be further substituted by one or more alkyl groups, -(CH 2 ) n 7 , =C(0), > trifluoromethyl Substituted by a carboxylic acid or a carboxylic acid ester;
选自氢原子, 烷基, 环垸基, 杂环烷基, -(C¾CH20)nR8, 烯基或炔基, 其中烷基,环烷基,杂环垸基,烯基或炔基可以进一步被一个或多个烷基,羟基, 烷氧基, 氰基, 氨基, 烷氨基, -NR5 , 羧酸或羧酸酯所取代; Selected from hydrogen atom, alkyl, cyclodecyl, heterocycloalkyl, -(C3⁄4CH 2 0) n R 8 , alkenyl or alkynyl, wherein alkyl, cycloalkyl, heterocycloalkyl, alkenyl or alkyne The group may be further substituted by one or more alkyl, hydroxy, alkoxy, cyano, amino, alkylamino, -NR 5 , carboxylic acid or carboxylic acid esters;
和 R6分别选自分别选自氢原子, 垸基, 环烷基, 杂环垸基, 芳基, 杂芳 基或杂芳垸基, 其中烷基, 环烷基, 杂环烷基, 芳基, 杂芳基或者杂芳烷基可以 进一步被一个或多个的垸基, 卤素, 芳基, 羟基, 氨基, 烷氨基, 酰胺基, 胺酰 基, 氰基, 烷氧基, 芳氧基, 胺垸基, 羟烷基, 杂环烷基, 羧酸或者羧酸酯所取
同时, R5和 Re可以形成一个 4〜8元杂环基; 其中 5〜8元杂环内可以含有 一个或多个 N, 0, S原子,并且 4〜8元杂环上可以进一步被一个或多个的垸基, 卤素, 芳基, 杂芳基, 卤代烷基, 卤代垸氧基, 羟基, 氨基, 酰胺基, 胺酰基, 氰基, 烷氧基, 芳氧基, 胺烷基, 羟垸基, 杂环垸基, 羧酸, 羧酸酯或 - R5R6 所取代; And R 6 are each independently selected from the group consisting of a hydrogen atom, a fluorenyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group or a heteroarylalkyl group, wherein the alkyl group, the cycloalkyl group, the heterocycloalkyl group, and the aryl group a heteroaryl or heteroarylalkyl group which may be further substituted by one or more of fluorenyl, halogen, aryl, hydroxy, amino, alkylamino, amide, aminyl, cyano, alkoxy, aryloxy, Acridine, hydroxyalkyl, heterocycloalkyl, carboxylic acid or carboxylic acid ester Meanwhile, R 5 and Re may form a 4 to 8 membered heterocyclic group; wherein the 5 to 8 membered heterocyclic ring may contain one or more N, 0, S atoms, and the 4 to 8 membered heterocyclic ring may be further subjected to a Or a plurality of fluorenyl groups, halogen, aryl, heteroaryl, haloalkyl, halomethoxy, hydroxy, amino, amide, aminyl, cyano, alkoxy, aryloxy, alkoxy Substituted with hydroxyindenyl, heterocycloalkyl, carboxylic acid, carboxylic acid ester or -R 5 R6;
R7选自羟基, 烷氧基, 芳氧基, 杂环烷氧基, 芳烷氧基, -N(R8; CH2)nR9, - 8[CH2CH20]nR8, -NRsRfi或者- NRs(C¾)n[CH(OH)CH2]rZ (其中 Z是芳基, 杂 芳基, 杂环垸基, -NRsR^, -COOR8或 CON 5R6); R 7 is selected from the group consisting of hydroxy, alkoxy, aryloxy, heterocycloalkoxy, aralkyloxy, -N(R 8 ; CH 2 ) n R 9 , - 8 [CH 2 CH 2 0] n R 8 , -NRsRfi or - NR s (C3⁄4) n [CH(OH)CH 2 ] r Z (wherein Z is aryl, heteroaryl, heterocycloalkyl, -NRsR^, -COOR 8 or CON 5R6);
选自氢原子或垸基; Selected from a hydrogen atom or a sulfhydryl group;
R9选自 -NR5R6,羟基,芳基,杂芳基,垸氧基, -S(0)2CH3, -O[CH2CH20]rR8, -^(0-)¾¾, -N(OH)R5, -NHC(0)R1()或- COR10 (其中 R10是垸基, 卤代烷基或芳 垸基); R 9 is selected from -NR 5 R6, hydroxy, aryl, heteroaryl, decyloxy, -S(0) 2 CH 3 , -O[CH 2 CH 2 0] r R 8 , -^(0-) 3⁄43⁄4, -N(OH)R 5 , -NHC(0)R 1() or - COR 10 (wherein R 10 is a fluorenyl group, a haloalkyl group or an aryl fluorenyl group);
R1()是垸基, 卤代垸基或芳垸基 R 1 () is a fluorenyl group, a halogenated fluorenyl group or an aryl group
n是 0〜6; n is 0~6;
r是 1〜2。 进一步, 本发明包括下述通式 (III)表示的化合物或其盐: r is 1 to 2. Further, the present invention includes a compound represented by the following formula (III) or a salt thereof:
X选自 W(CH2), (CH2)W, 或 W, 其中 W是 0, S, SO, S02; 或 -NR8(其中 是氢原子或垸基); X is selected from W(CH 2 ), (CH 2 )W, or W, wherein W is 0, S, SO, S0 2 ; or -NR 8 (wherein a hydrogen atom or a sulfhydryl group);
当 X是 -NR8,R8是垸基,则 R8可以和 R1形成一个 4〜8元杂环基;其中 5〜 8元杂环内可以含有一个或多个 0, S原子, 并且 4〜8元杂环上可以进一步 被一个或多个的烷基, 卤素, 芳基, 杂芳基, 卤代垸基, 卤代烷氧基, 羟基, 氨 基, 烷氨基, 酰胺基, 胺酰基, 氰基, 垸氧基, 芳氧基, 胺垸基, 羟垸基, 杂环 垸基, 羧酸, 羧酸酯或 -^5 所取代; When X is -NR 8 and R 8 is a fluorenyl group, R 8 may form a 4 to 8 membered heterocyclic group with R1; wherein the 5 to 8 membered heterocyclic ring may contain one or more 0, S atoms, and 4 The ~8 membered heterocyclic ring may be further substituted with one or more alkyl groups, halogen, aryl, heteroaryl, haloalkyl, haloalkoxy, hydroxy, amino, alkylamino, amide, aminyl, cyano , alkoxy, aryloxy, aminyl, hydroxyalkyl, heterocycloalkyl, carboxylic acid, carboxylic acid ester or substituted with -5 ;
选自氢原子, 烷基, 环烷基, 杂环烧基, 芳基, 杂芳基, 芳垸基或杂芳烷 基, 其中烷基, 环烷基, 杂环垸基, 芳基, 杂芳基, 芳烷基或杂芳烷基可以进一 步被一个或多个垸基, 卤素, 芳基, 羟基, 氨基, 炔基, 垸氨基, 酰胺基, 胺酰 基, 烷氧基, 芳氧基, 杂环烷基, 羧酸, 羧酸酯或 - R5 所取代; 其中芳基,
杂芳基, 芳垸基或杂芳烷基可以并成双环; Selected from hydrogen atom, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, wherein alkyl, cycloalkyl, heterocycloalkyl, aryl, hetero The aryl, aralkyl or heteroarylalkyl group may be further substituted by one or more fluorenyl, halogen, aryl, hydroxy, amino, alkynyl, decylamino, amide, aminyl, alkoxy, aryloxy, a heterocycloalkyl group, a carboxylic acid, a carboxylic acid ester or a substituted group of - R 5 ; a heteroaryl group, an arylalkyl group or a heteroaralkyl group may be combined into a bicyclic ring;
R2选自氢原子, 垸基, 三氟甲基, 环烷基, 杂环烷基, 芳基, 杂芳基, 芳垸 基或杂芳院基, 其中垸基, 环烷基, 杂环烷基, 芳基, 杂芳基, 芳烷基或杂芳垸 基可以进一步被一个或多个垸基, 素, 芳基, 羟基, 氨基, 烷氨基, 酰胺基, 胺酰基, 烧氧基, 芳氧基, 杂环烷基, 羧酸, 羧酸酯或 ->¾5 所取代; R 2 is selected from the group consisting of a hydrogen atom, a fluorenyl group, a trifluoromethyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an aryl fluorenyl group or a heteroaryl group, wherein a fluorenyl group, a cycloalkyl group, a heterocyclic ring Alkyl, aryl, heteroaryl, aralkyl or heteroaryl can be further protected by one or more fluorenyl, aryl, aryl, hydroxy, amino, alkylamino, amide, aminyl, alkoxy, An aryloxy group, a heterocycloalkyl group, a carboxylic acid, a carboxylic acid ester or a substituted group of -> 3⁄4 5 ;
选自氢原子, 烷基, 芳基, 杂芳基, 杂芳氧基, -C(=0)R7, -C(=S)R7, -NC(=0)R7, -(CH2)nO(C=0)R7, -(CH2)nO(C=S)R7, -(CH2)„R7, -(CH2CH20)nR8; 其中芳基, 杂芳基, 杂芳氧基, -(C¾)nR7可以进一步被一个或多个垸基, -(CH2)nR7, =C(0), 卤素, 三氟甲基, 羧酸, 羧酸酯所取代; Selected from a hydrogen atom, an alkyl group, an aryl group, a heteroaryl group, a heteroaryloxy group, -C(=0)R 7 , -C(=S)R 7 , -NC(=0)R 7 , -(CH 2 ) n O(C=0)R 7 , -(CH 2 ) n O(C=S)R 7 , -(CH 2 )„R 7 , -(CH 2 CH 2 0) n R 8 ; , heteroaryl, heteroaryloxy, -(C3⁄4) n R 7 may be further protected by one or more thiol groups, -(CH 2 ) n R 7 , =C(0), halogen, trifluoromethyl, Substituted by a carboxylic acid, a carboxylic acid ester;
选自氢原子, 垸基, 环垸基, '杂环烷基, -(CH2CH20)nR8, 烯基或炔基, 其中烷基, 环垸基, 杂环垸基,烯基或炔基可以进一步被一个或多个烷基,羟基, 垸氧基, 氰基, 氨基, 烷氨基, - RjF , 羧酸或羧酸酯所取代; Selected from hydrogen atom, fluorenyl, cyclodecyl, 'heterocycloalkyl, -(CH 2 CH 2 0) n R 8 , alkenyl or alkynyl, wherein alkyl, cyclodecyl, heterocycloalkyl, alkene Or alkynyl may be further substituted by one or more alkyl, hydroxy, decyloxy, cyano, amino, alkylamino, -RjF, carboxylic acid or carboxylic acid esters;
R5和 Re分别选自分别选自氢原子, 垸基, 环垸基, 杂环烷基, 芳基, 杂芳 基或杂芳焼基, 其中烷基, 环烷基, 杂环垸基, 芳基, 杂芳基或者杂芳烷基可以 进一步被一个或多个的烷基, 卤素, 芳基, 羟基, 氨基, 垸氨基, 酰胺基, 胺酰 基, 氰基, 垸氧基, 芳氧基, 胺垸基, 羟烷基, 杂环垸基, 羧酸或者羧酸酯所取 代; R 5 and Re are each independently selected from the group consisting of a hydrogen atom, a fluorenyl group, a cyclodecyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group or a heteroarylalkyl group, wherein an alkyl group, a cycloalkyl group, a heterocyclic fluorenyl group, Aryl, heteroaryl or heteroarylalkyl may be further substituted by one or more alkyl, halo, aryl, hydroxy, amino, decylamino, amide, aminyl, cyano, decyloxy, aryloxy Substituted with an amidino group, a hydroxyalkyl group, a heterocyclic fluorenyl group, a carboxylic acid or a carboxylic acid ester;
同时, R5和 可以形成一个 4〜8元杂环基; · 其中 5〜8元杂环内可以含有 一个或多个 N, 0, S原子,并且 4〜8元杂环上可以进一步被一个或多个的烷基, 卤素, 芳基, 杂芳基, 代烷基, 代浣氧基, 羟基, 氨基, 酰胺基, 胺酰基, 氰基, 垸氧基, 芳氧基, 胺垸基, 羟烷基, 杂环烷基, 羧酸, 羧酸酯或 -NR5 所取代; Meanwhile, R 5 and may form a 4 to 8 membered heterocyclic group; wherein the 5 to 8 membered heterocyclic ring may contain one or more N, 0, S atoms, and the 4 to 8 membered heterocyclic ring may be further subjected to a Or a plurality of alkyl, halogen, aryl, heteroaryl, alkyl, methoxy, hydroxy, amino, amide, aminyl, cyano, methoxy, aryloxy, amidino, Substituted by a hydroxyalkyl group, a heterocycloalkyl group, a carboxylic acid, a carboxylic acid ester or -NR 5 ;
R7选自羟基, 烷氧基, 芳氧基, 杂环烷氧基, 芳垸氧基, -N(R8)(C¾)nR9, -NR8[CH2C¾0]nR8, -NR5 或者 -NR8(C¾)n[CH(OH)C¾]rZ (其中 Z是芳基, 杂 芳基, 杂环垸基, -NR5R6, -COOR8或 CO RsRe); R 7 is selected from the group consisting of hydroxy, alkoxy, aryloxy, heterocycloalkoxy, aryloxy, -N(R 8 )(C3⁄4) n R 9 , -NR 8 [CH 2 C3⁄40] n R 8 , -NR 5 or -NR 8 (C3⁄4) n [CH(OH)C3⁄4] r Z (wherein Z is aryl, heteroaryl, heterocycloalkyl, -NR 5 R6, -COOR 8 or CO RsRe);
R8选自氢原子或烷基; R 8 is selected from a hydrogen atom or an alkyl group;
R9选自 - sRi,羟基,芳基,杂芳基,垸氧基, -S(0)2CH3, -0[CH2CH20]rR8, -]^"(0-)¾]¾, -N(0H)R5, -NHC(0)R1()或- CORw (其中 Rio是烷基, 卤代垸基或芳 院基); R 9 is selected from the group consisting of - sRi, hydroxy, aryl, heteroaryl, decyloxy, -S(0) 2 CH 3 , -0[CH 2 CH 2 0] r R 8 , -]^"(0-) 3⁄4]3⁄4, -N(0H)R 5 , -NHC(0)R 1() or - CORw (wherein Rio is an alkyl group, a halogenated fluorenyl group or a aryl group);
R1()是烧基, 卤代烷基或芳垸基 R 1 () is an alkyl group, a haloalkyl group or an aryl group
n是 0~6; n is 0~6;
r是 1〜2。 在本发明的通式 (I)所述的化合物或其盐中, 优选的是 X是 Ν , (其中 是氢原子或 ~¾烷基)。
在本发明的通式 (I)所述的化合物或其盐中,优选的是 R2是甲基或三氟甲基。 具体地, 通式 (I)所述的化合物或其盐包括: r is 1 to 2. In the compound of the formula (I) of the present invention or a salt thereof, it is preferred that X is hydrazine (wherein a hydrogen atom or a ~3⁄4 alkyl group). In the compound of the formula (I) of the present invention or a salt thereof, it is preferred that R2 is a methyl group or a trifluoromethyl group. Specifically, the compound of the formula (I) or a salt thereof includes:
4-(3-氯 -4-氟-苯胺) -3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-(4- (吗啡啉 -4-基) -哌啶基) 甲酰胺 4-(3-chloro-4-fluoro-aniline)-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-(4-(morpholine-4-yl)-piperidinyl Carboxamide
4-(3-氯 -4-氟-苯胺) -3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-(2-二乙胺基乙基)甲酰胺 4-(3-氯 -4-氟-苯胺) -3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-(2-吗啡啉 -4基-乙基)甲酰 胺 4-(3-chloro-4-fluoro-aniline)-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-(2-diethylaminoethyl)carboxamide 4-( 3-chloro-4-fluoro-aniline)-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-(2-morphinolin-4-yl-ethyl)carboxamide
4-(3-炔基-苯胺) -3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-(2-二乙胺基乙基)甲酰胺 4-(3-炔基-苯胺) -3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-(4- (吗啡啉 -4-基) -哌啶基)甲 酰胺 · 4-(3-ynyl-aniline)-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-(2-diethylaminoethyl)carboxamide 4-(3-yne -Benzylamine)-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-(4-(morphinolin-4-yl)-piperidinyl)carboxamide
4-(3-炔基-苯胺) -3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-(2-吡咯啶小基) -乙基)甲酰 胺 4-(3-ynyl-aniline)-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-(2-pyrrolidinyl)-ethyl)formamide
4-(3-炔基-苯胺) -3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-(2-吗啡啉 -4-基) -乙基)甲酰 胺 4-(3-ynyl-aniline)-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-(2-morphinolin-4-yl)-ethyl)formamide
4-[3-氯 -4-(3-氟苄氧) -苯胺 ]-3-甲基 -1H-吡咯并 [2,3-d]哒嗉 -2-(2-吡咯啶 -1-基) - 乙基)甲酰胺 4-[3-Chloro-4-(3-fluorobenzyloxy)-aniline]-3-methyl-1H-pyrrolo[2,3-d]indole-2-(2-pyrrolidin-1-yl) ) - ethyl)carboxamide
4-[3-氯 -4-(3-氟苄氧) -苯胺 ]-3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-(3-吗啡啉 -4-基- 丙基)甲酰胺 4-[3-Chloro-4-(3-fluorobenzyloxy)-aniline]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-(3-morphocolin-4-yl) - propyl) formamide
4-[3-氯 -4-(3-氟苄氧) -苯胺 ]-3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-(2-二乙胺基-乙基) 甲酰胺 4-[3-Chloro-4-(3-fluorobenzyloxy)-aniline]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-(2-diethylamino-B Formamide
4-[3-氯 -4-(3-氟苄氧) -苯胺 ]-3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-(2-吡咯啶 -1基-甲 基-吡咯啶 -1-基)甲酰胺 4-[3-Chloro-4-(3-fluorobenzyloxy)-aniline]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-(2-pyrrolidin-1yl- Methyl-pyrrolidin-1-yl)carboxamide
' 4-[3-氯 -4-(3-氟苄氧) -苯胺 ]-3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-(4- (吗啡啉 -4-基) - 哌啶基)甲酰胺 '4-[3-Chloro-4-(3-fluorobenzyloxy)-aniline]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-(4-(morpholine-4) -yl)-piperidinyl)carboxamide
4-[3-氯 -4-(3-氟苄氧) -苯胺 ]-3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-(2-吗啡啉 -4-基- 乙基)甲酰胺 4-[3-Chloro-4-(3-fluorobenzyloxy)-aniline]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-(2-morphinolin-4-yl) - ethyl)carboxamide
4-[3-氯 -4-(3-氟苄氧) -苯胺 ]-3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-基-二乙胺基甲酸 甲酯 4-[3-Chloro-4-(3-fluorobenzyloxy)-aniline]-3-methyl-1H-pyrrolo[2,3-d]pyridazin-2-yl-diethylaminocarbamate
4-[3-氯 -4-(3-氟苄氧) -苯胺 ]-3-甲基 -1-甲基-吡咯并 [2,3-d]哒嗪 -2-(2-二乙胺基- 乙基)甲酰胺 4-[3-Chloro-4-(3-fluorobenzyloxy)-aniline]-3-methyl-1-methyl-pyrrolo[2,3-d]pyridazine-2-(2-diethylamine) Base-ethyl)formamide
4-[3-氯 -4-(3-氟苄氧) -苯胺 ]-3-甲基 -1-甲基-吡咯并 [2,3-d]哒嗪 -2-(2-吡咯啶 -1- 基-乙基)甲酰胺 4-[3-Chloro-4-(3-fluorobenzyloxy)-aniline]-3-methyl-1-methyl-pyrrolo[2,3-d]pyridazine-2-(2-pyrrolidine- 1-yl-ethyl)carboxamide
4-[3-氯 -4-(3-氟苄氧) -苯胺 ]-1, 3-二甲基 -P比咯并 [2,3-d]哒嗪 -2 (2-吗啡啉 -4-基 -乙基) -甲酰胺 4-[3-chloro-4-(3-fluorobenzyloxy)-aniline]-1,3-dimethyl-P-pyrolo[2,3-d]pyridazine-2 (2-morpholine-4 -yl-ethyl)-carboxamide
4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] - 3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸 [2-(4-
甲基 -哌嗪 -1-基) -乙基〗 -甲酰胺 4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid [2-( 4- Methyl-piperazin-1-yl)-ethyl-formamide
4-[3-氯 -4-(3-氟- 氧基) -苯氨基] - 3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸 [2-(4- 甲基 -哌嗪小基) -丙基] -甲酰胺 4-[3-chloro-4-(3-fluoro-oxy)-phenylamino]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid [2-(4 - methyl-piperazine small group)-propyl]-carboxamide
4-[1-(3-氟苄基 )-1Η-吲唑 -5-氨基] -3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -(2-甲氧乙基) 甲酰胺 4-[1-(3-fluorobenzyl)-1Η-carbazole-5-amino]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-(2-methoxyethyl) Formamide
4-[1-(3-氟苄基) -1H-吲唑 -5-氨基] -3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-(2-二乙胺 基-乙基)甲酰胺 4-[1-(3-fluorobenzyl)-1H-indazole-5-amino]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-(2-diethylamine) Base-ethyl) formamide
4-[3-氯 -4- (吡啶 -2-甲氧基) -苯胺 ]-3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-(2-二乙胺基 -乙基)甲酰胺 4-[3-Chloro-4-(pyridine-2-methoxy)-aniline]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-(2-diethylamino) -ethyl)formamide
4-[3-氯 -4- (吡啶 -2-甲氧基) -苯胺 ]-3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-[(2-吡咯啶 -1-基) -乙基]甲酰胺 4-[3-chloro-4-(pyridine-2-methoxy)-aniline]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-[(2-pyrrolidine- 1-yl)-ethyl]carboxamide
4-[3-氯 -4-(P比啶 -2-甲氧基) -苯胺 ]-3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-[(2-吗啡啉 -4-基) -乙基]甲酰胺 4-[3-chloro-4-(P-pyridyl-2-methoxy)-aniline]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-[(2-morphine) Phenyl-4-yl)-ethyl]carboxamide
4-[3-氯 -4- (吡啶 -2-甲氧基) -苯胺 ]-3-甲基 -1H-吡咯并 [2,3-d]哒嗉 -2-[(3-吗啡啉 -4-基) -乙基]甲酰胺 4-[3-Chloro-4-(pyridine-2-methoxy)-aniline]-3-methyl-1H-pyrrolo[2,3-d]indole-2-[(3-morpholine- 4-yl)-ethyl]carboxamide
4-[3-氯 -4- (吡啶 -2-甲氧基) -苯胺 ]- 1, 3-二甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-[(2-乙 氨基) -乙基]甲酰胺 4-[3-chloro-4-(pyridine-2-methoxy)-aniline]- 1, 3-dimethyl-1H-pyrrolo[2,3-d]pyridazine-2-[(2- Ethylamino)-ethyl]carboxamide
4_[3-氯 -4- (吡啶 -2-甲氧基) -苯胺] - 1, 3-二甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-[(2-吡 咯啶 -1-基) -乙基]甲酰胺 4 _[3-chloro-4-(pyridine-2-methoxy)-aniline]-1,3-dimethyl-1H-pyrrolo[2,3-d]pyridazine-2-[(2- Pyrrolidin-1-yl)-ethyl]carboxamide
4_[3_氯 _4- (吡啶 -2-甲氧基) -苯胺] - 1, 3-二甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-[(3-吗 啡啉 -4-基) -乙基]甲酰胺 4 _[ 3 _Chloro_4-(pyridine-2-methoxy)-aniline] - 1, 3-dimethyl-1H-pyrrolo[2,3-d]pyridazine-2-[(3- Morpholinolin-4-yl)-ethyl]carboxamide
4-[3-氯 -4- (吡啶 -2-甲氧基) -苯胺 ]- 1, 3-二甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-[(2-吗 啡啉 -4-基) -乙基]甲酰胺 4-[3-chloro-4-(pyridine-2-methoxy)-aniline]- 1, 3-dimethyl-1H-pyrrolo[2,3-d]pyridazine-2-[(2- Morpholinolin-4-yl)-ethyl]carboxamide
[3一氯 _4_(3-氟-苄氧基) -苯氧基 ]-{3-甲基 -2-[(2-吗啉 -4-基-乙氨基) -甲基] -1H-吡 咯并 [2,3-d]哒嗪 -4- 基 胺 [3-chloro-4 _ _ (3 - fluoro - benzyloxy) - phenoxy] - {3-methyl-2 - [(2-morpholin-4-yl - ethylamino) - methyl] -1H -pyrrolo[2,3-d]pyridazin-4-ylamine
[3_氯 _4_(3-氟-苄氧基) -苯氧基] -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸(2-吡咯烷 -1-基- 乙基 甲酰胺 , [ 3 _Chloro- 4 _(3-fluoro-benzyloxy)-phenoxy] -1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid (2-pyrrolidin-1-yl- Ethylformamide,
4-[3-氯 -4-(3-氟-苄氧基) -苯氧基] -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸 (2-二乙氮基- 乙基) -酰胺 4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy]-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid (2-diethyl)- Ethyl)-amide
4-[3-氯 -4-(3-氟-苄氧基) -苯氧基] -1-(2-甲氧基 -乙基 )-3-甲基 -1H-吡咯并 [2,3-d] 哒嗪 -2-羧酸乙酯 4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy]-1-(2-methoxy-ethyl)-3-methyl-1H-pyrrolo[2,3 -d] pyridazine-2-carboxylic acid ethyl ester
4_[3_氯 _4-(3-氟-苄氧基) -苯氧基 小(2-甲氧基 -乙基 )-3-甲基 -1H-吡咯并 [2,3-d] 哒嗪 -2-羧酸 (2-二乙氨基-乙基) -酰胺 4 _[ 3 _Chloro_4-(3-fluoro-benzyloxy)-phenoxy small (2-methoxy-ethyl)-3-methyl-1H-pyrrolo[2,3-d] Pyridazine-2-carboxylic acid (2-diethylamino-ethyl)-amide
4-[3-氯 -4-(3-氟-苄氧基) -苯氧基] -1-(2-甲氧基 -乙基 )-3-甲基 -1H-吡咯并 [2,3-d] 哒嗪 -2-羧酸 [2-(4-甲基 -哌嗪 -1-基) -乙基] -酰胺
4-[3-氯 -4-(3-氟-苄氧基) -苯氧基]小 (2-甲氧基 -乙基 )-3-甲基 -1H-吡咯并 [2,3-d] 哒嗪 -2-羧酸 [3-(4-甲基 -哌嗪 -1-基) -丙基] -酰胺 4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy]-1-(2-methoxy-ethyl)-3-methyl-1H-pyrrolo[2,3 -d] pyridazine-2-carboxylic acid [2-(4-methyl-piperazin-1-yl)-ethyl]-amide 4-[3-chloro-4-(3-fluoro-benzyloxy)-phenoxy]sodium(2-methoxy-ethyl)-3-methyl-1H-pyrrolo[2,3-d Pyridazine-2-carboxylic acid [3-(4-methyl-piperazin-1-yl)-propyl]-amide
4-[3-氯 -4-(3-氟-苄氧基) -苯氧基] -1-(2-甲氧基 -乙基 )-3-甲基 -1H-吡咯并 [2,3-d〗 哒嗪 -2-羧酸 (2-吡咯垸 -1-基-乙基) -酰胺 4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy]-1-(2-methoxy-ethyl)-3-methyl-1H-pyrrolo[2,3 -d 哒pyridazine-2-carboxylic acid (2-pyrrole-1-yl-ethyl)-amide
4-[3-氯 -4-(3-氟-节氧基) -苯氧基 ]小[(2-甲氧基-乙氧基) -乙基 ]-3-甲基 -1H-吡咯 并 [2,3-d]哒嗪 -2- 羧酸乙酯 4-[3-Chloro-4-(3-fluoro-p-ethoxy)-phenoxy]sodium[(2-methoxy-ethoxy)-ethyl]-3-methyl-1H-pyrrole [2,3-d]pyridazine-2-carboxylic acid ethyl ester
4-[3-氯 -4-(3-氟-节氧基) -苯氧基] -1-[(2-甲氧基-乙氧基) -乙基 ]-3-甲基 -1H-吡咯 并 [2,3-d]哒嗪 -2-羧酸 (2-二乙氨基-乙基) -酰胺 4-[3-Chloro-4-(3-fluoro-p-ethoxy)-phenoxy]-1-[(2-methoxy-ethoxy)-ethyl]-3-methyl-1H- Pyrrolo[2,3-d]pyridazine-2-carboxylic acid (2-diethylamino-ethyl)-amide
4-[3-氯 -4-(3-氟-节氧基) -苯氧基] -1-[(2-甲氧基-乙氧基) -乙基 ]-3-甲基 -1-(2-吗 啉 -4-基-乙基) -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸乙酯 4-[3-Chloro-4-(3-fluoro-p-ethoxy)-phenoxy]-1-[(2-methoxy-ethoxy)-ethyl]-3-methyl-1- (2-morpholin-4-yl-ethyl)-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid ethyl ester
4-[3-氯 -4-(3-氟-苄氧基) -苯氧基] -1-[(2-甲氧基-乙氧基) -乙基 ]-3-三氟甲基 -1H- 吡咯并 [2,3-d]哒嗪 -2-羧酸乙酯 4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy]-1-[(2-methoxy-ethoxy)-ethyl]-3-trifluoromethyl- 1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid ethyl ester
4-[3-氯 -4-(3-氟-苄氧基) -苯氧基 ]-1-[(2-甲氧基-乙氧基) -乙基 ]-3-三氟甲基 -1H- 吡咯并 [2,3-d]哒嗪 -2-羧酸苄酯 4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy]-1-[(2-methoxy-ethoxy)-ethyl]-3-trifluoromethyl- 1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid benzyl ester
4-[3-氯 -4-(3-氟-苄氧基) -苯氧基] -1-[(2-甲氧基-乙氧基) -乙基 ]-3-三氟甲基 -1H- 吡咯并 [2,3-d]哒嗪 -2-羧酸 (2-二乙胺基-乙基) -酰胺 4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy]-1-[(2-methoxy-ethoxy)-ethyl]-3-trifluoromethyl- 1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid (2-diethylamino-ethyl)-amide
4-[3-氯 -4-(3-氟-苄氧基) -苯氧基] -1-[(2-甲氧基-乙氧基) -乙基 ]-3-三氟甲基 -1H- 吡咯并 [2,3-d]哒嗪 -2-羧酸 (2-吡咯烷 -1-基-乙基) -酰胺 4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy]-1-[(2-methoxy-ethoxy)-ethyl]-3-trifluoromethyl- 1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide
[3-氯 -4-(3-氟-苄氧基) -苯氧基] -[2-(5-二乙氨基甲基 -呋喃 -2-基) -3-甲基 -1H-吡 咯并 [2,3-d]哒嗪 -4-基]酰胺 [3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy]-[2-(5-diethylaminomethyl-furan-2-yl)-3-methyl-1H-pyrrole [2,3-d]oxazin-4-yl]amide
[3-氯 -4-(3-氟-苄氧基) -苯氧基 ]-[2-(3-二乙氨基甲基 -甲基 )-3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -4,基]酰胺 [3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy]-[2-(3-diethylaminomethyl-methyl)-3-methyl-1H-pyrrolo[2, 3-d]pyridazine-4,yl]amide
7-[3-氯 -4-(3-氟- 氧基) -苯氧基]- 1H-吡咯并 [2,3-d]哒嗪 -2-羧酸 (2-二乙氨基- 乙基) -酰胺 7-[3-Chloro-4-(3-fluoro-oxy)-phenoxy]-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid (2-diethylamino-ethyl ) - amide
7-[3-氯 -4-(3-氟- 氧基) -苯氧基 ]-1Η-吡咯并 [2,3-d]哒嗪 -2-羧酸 (2-2-吡咯烷 -1- 基-乙基) -酰胺 7-[3-Chloro-4-(3-fluoro-oxy)-phenoxy]-1Η-pyrrolo[2,3-d]pyridazine-2-carboxylic acid (2-2-pyrrolidine-1 -yl-ethyl)-amide
7-[3-氯 -4-(3-氟-苄氧基) -苯氧基] -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸 (2-吗啉 -4-基- 乙基) -酰胺 7-[3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy]-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid (2-morpholin-4- Base-ethyl)-amide
7-[3-氯 -4-(3-氟-苄氧基) -苯氧基] -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸 (3-吗啉 -4-基- 丙基) -酰胺 7-[3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy]-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid (3-morpholin-4- Base-propyl)-amide
7-[3-氯 -4-(3-氟-节氧基) -苯氧基] -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸 (2-哌啶 -1-基- 乙基) -酰胺 7-[3-Chloro-4-(3-fluoro-p-ethoxy)-phenoxy]-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid (2-piperidin-1- Base-ethyl)-amide
7-[3-氯 -4-(3-氟-苄氧基) -苯氧基] -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸 [3-(4-甲基-哌 嗪小基) -丙基] -酰胺 7-[3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy]-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid [3-(4-methyl) -piperazine small group)-propyl]-amide
7-[3-氯 -4-(3-氟-苄氧基) -苯氧基] -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸 -2-(4-甲基-哌
嗪 -1-基) -乙基] -酰胺 7-[3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy]-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid-2-(4-methyl -piper Pyrazin-1-yl)-ethyl]-amide
4-[3-氯 -4-(3-氟- 氧基) -苯基 ]-7-甲基 -6H-吡咯并 [3,4-d]哌嗪 -5-羧酸乙酯 4-[3-Chloro-4-(3-fluoro-oxy)-phenyl]-7-methyl-6H-pyrrolo[3,4-d]piperazine-5-carboxylate
[3-氯 (3-氟-苄氧基) -苯基 ]-(5-甲基 -6H-吡咯并 [3,4-d]哌嗪 -1-基) -乙胺 [3-Chloro(3-fluoro-benzyloxy)-phenyl]-(5-methyl-6H-pyrrolo[3,4-d]piperazine-1-yl)-ethylamine
4-[1-(3-氟苄基) -1H-吲唑 -5-氨基] -3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-[(2-吡咯啶 4-[1-(3-fluorobenzyl)-1H-indazole-5-amino]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-[(2-pyrrolidine)
-1-基) -乙基]甲酰胺 -1-yl)-ethyl]carboxamide
4-[1-(3-氟苄基) -1H-吲唑 -5-氨基 ]-3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-[(2-吗啡啉 -4-基) -乙基]甲酰胺 4-[1-(3-fluorobenzyl)-1H-indazole-5-amino]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-[(2-morpholine) -4-yl)-ethyl]carboxamide
[3-氯 -4-(3-氟苄氧基) -苯基 ]-(2-{3-[(2-甲磺酰基乙氨基) -甲基] -苯基 }-3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -4-基) -胺 [3-Chloro-4-(3-fluorobenzyloxy)-phenyl]-(2-{3-[(2-methanesulfonylethylamino)-methyl]-phenyl}-3-methyl- 1H-pyrrolo[2,3-d]pyridazin-4-yl)-amine
[3_氯 -4-(3-氟苄氧基) -苯基 ]-(2-{5-[(2-甲磺酰基乙氨基) -甲基] -呋喃 -2-基}-3- 甲基 -1H-吡咯并 [2,3-d]哒嗪 -4-基) -胺 [ 3 _Chloro-4-(3-fluorobenzyloxy)-phenyl]-(2-{5-[(2-methanesulfonylethylamino)-methyl]-furan-2-yl}-3- Methyl-1H-pyrrolo[2,3-d]pyridazin-4-yl)-amine
或其药学上可接受的盐。 Or a pharmaceutically acceptable salt thereof.
其中,所述的盐为上述通式化合物与选自以下的酸形成的盐:苹果酸、乳酸、 马来酸、 盐酸、 甲磺酸、 硫酸、 磷酸、 柠檬酸、 酒石酸、 乙酸或三氟乙酸。 Wherein the salt is a salt of a compound of the above formula and an acid selected from the group consisting of malic acid, lactic acid, maleic acid, hydrochloric acid, methanesulfonic acid, sulfuric acid, phosphoric acid, citric acid, tartaric acid, acetic acid or trifluoroacetic acid. .
在本发明的另一个方面, 是一种药物组合物, 含有通式 (1)、 (II)或 (III)的化合 物、 盐或前药和药学上可以接受的载体或赋形剂。 In another aspect of the invention, there is provided a pharmaceutical composition comprising a compound, a salt or a prodrug of the formula (1), (II) or (III) and a pharmaceutically acceptable carrier or excipient.
在本发明的另一个方面, 是蛋白激酶催化活性的调节方法, 包括使蛋白激酶 与通式 (1)、 (II)或 (ΠΙ) 的化合物或盐接触。 此蛋白激酶选自受体酪氨酸激酶、 非 受体酪氨酸激酶和丝氨酸-苏氨酸激酶。 在本发明的另一个方面, 是一种治疗患有和预防哺乳动物中与蛋白质激酶有 关的疾病的哺乳动物的方法,所述方法包括对该所述哺乳动物有机体施用给药治 疗有效剂量的本发明药物组合物。 其中, 与蛋白质激酶有关的疾病选自 EGFR, HER-2, HER-3, HER-4, PDGFR, VEGFR-2, c-Kit, c-Met, FGFR, Flt3相关的疾 病。与蛋白质激酶有关的疾病还可以是白血病,糖尿病, 自免疫病,过度增生病, 牛皮癣, 骨关节炎,类风湿性关节炎,血管生成, 心血管病, Von-Heppel-Lindau 氏病, 炎症, 纤维变性病。 与蛋白质激酶有关的疾病还可以是鳞状细胞癌, 肾细 胞癌, Kaposi肉瘤, 非小细胞肺癌, 小细胞肺癌, 淋巴癌, 甲状腺癌, 乳腺癌, 头颈癌, 子宫癌, 食道癌, 黑素癌, 膀胱癌, 生殖泌尿癌, 胃肠癌, 神经胶质癌, 结肠直肠癌和卵巢癌。 这些方法治疗的哺乳动物可以是人。 In another aspect of the invention, a method of modulating the catalytic activity of a protein kinase comprises contacting a protein kinase with a compound or salt of formula (1), (II) or (ΠΙ). This protein kinase is selected from the group consisting of a receptor tyrosine kinase, a non-receptor tyrosine kinase, and a serine-threonine kinase. In another aspect of the invention, a method of treating a mammal having and preventing a protein kinase-associated disease in a mammal, the method comprising administering to the mammalian organism a therapeutically effective dose of the present invention Inventive pharmaceutical composition. Among them, the protein kinase-related diseases are selected from the group consisting of EGFR, HER-2, HER-3, HER-4, PDGFR, VEGFR-2, c-Kit, c-Met, FGFR, Flt3 related diseases. Diseases associated with protein kinases can also be leukemia, diabetes, autoimmune diseases, hyperproliferative diseases, psoriasis, osteoarthritis, rheumatoid arthritis, angiogenesis, cardiovascular disease, Von-Heppel-Lindau's disease, inflammation, Fibrosis disease. Protein kinase-related diseases can also be squamous cell carcinoma, renal cell carcinoma, Kaposi sarcoma, non-small cell lung cancer, small cell lung cancer, lymphoma, thyroid cancer, breast cancer, head and neck cancer, uterine cancer, esophageal cancer, melanin. Cancer, bladder cancer, genitourinary cancer, gastrointestinal cancer, glial cancer, colorectal cancer and ovarian cancer. The mammals treated by these methods can be human.
在本发明的另一个方面是治疗癌症的方法, 该方法包括同时向需要治疗的患 者给药一种抗癌药物, 如紫杉酚或卡铂。 In another aspect of the invention is a method of treating cancer comprising administering to a patient in need of treatment an anti-cancer drug, such as taxol or carboplatin, simultaneously.
在本发明的另一个方面, 是制备通式 (1)、 (Π)或 (III)的化合物的方法。 In another aspect of the invention, a process for the preparation of a compound of formula (1), (Π) or (III).
另一方面, 本发明涉及本发明化合物在制备治疗与蛋白质激酶有关的疾病的 药物中的用途。 其中所述与蛋白质激酶有关的疾病选自 EGFR, HER-2, HER-3,
HER-4, PDGFR, VEGFR-2, c-Kit, c-Met, FGFR或 Flt3相关的疾病; 其中所述 与蛋白激酶有关的疾病选自白血病, 糖尿病, 自免疫病, 过度增生病, 牛皮癣, 骨关节炎, 类风湿性关节炎, 血管生成, 心血管病, Von-Heppel-Lindau氏病, 炎症或纤维变性病; 其中所述与蛋白激酶有关的疾病是癌症, 选自鳞状细胞癌, 肾细胞癌, Kaposi 肉瘤, 非小细胞肺癌, 小细胞肺癌, 淋巴癌, 甲状腺癌, 乳 腺癌, 头颈癌, 子宫癌, 食道癌, 黑素癌, 膀胱癌, 生殖泌尿癌, 胃肠癌, 神经 胶质癌, 结肠直肠癌或卵巢癌。 In another aspect, the invention relates to the use of a compound of the invention in the manufacture of a medicament for the treatment of a disease associated with a protein kinase. The protein kinase-associated disease is selected from the group consisting of EGFR, HER-2, HER-3, a disease associated with HER-4, PDGFR, VEGFR-2, c-Kit, c-Met, FGFR or Flt3; wherein the protein kinase-related disease is selected from the group consisting of leukemia, diabetes, autoimmune disease, hyperproliferative disease, psoriasis, Osteoarthritis, rheumatoid arthritis, angiogenesis, cardiovascular disease, Von-Heppel-Lindau's disease, inflammatory or fibrotic disease; wherein the protein kinase-related disease is cancer, selected from squamous cell carcinoma, Renal cell carcinoma, Kaposi sarcoma, non-small cell lung cancer, small cell lung cancer, lymphoma, thyroid cancer, breast cancer, head and neck cancer, uterine cancer, esophageal cancer, melanoma, bladder cancer, genitourinary cancer, gastrointestinal cancer, nerve Glial cancer, colorectal cancer or ovarian cancer.
本发明涉及鉴别蛋白激酶催化活性的化合物, 使表达该蛋白激酶的细胞与本 发明化合物或盐接触, 然后检测对细胞的效果。 The present invention relates to a compound which discriminates the catalytic activity of a protein kinase, which contacts a cell expressing the protein kinase with a compound or salt of the present invention, and then detects the effect on the cell.
本发明还涉及鉴别蛋白激酶催化活性的化合物, 使人工重组合成激酶蛋白与 本发明化合物或盐接触, 然后用 Elisa方法检测对激酶活性的影响。 发明的详细说明 The present invention also relates to a compound which discriminates the catalytic activity of a protein kinase by contacting an artificially recombinant synthetic kinase protein with a compound or salt of the present invention, and then detecting the effect on the kinase activity by the Elisa method. Detailed description of the invention
除非有相反陈述, 下列用在说明书和权利要求书中的术语具有下述含义。 "垸基"指饱和的脂族烃基团, 包括 1至 20个碳原子的直链和支链基团。 优选含有 1至 10个碳原子的中等大小垸基, 例如甲基、 乙基、 丙基、 2-丙基、 正丁基、异丁基、叔丁基、戊基登。更优选的是含有 1至 4个碳原子的低级垸基, 例如甲基、 乙基、 丙基、 2-丙基、 正丁基、 异丁基或叔丁基等。 烷基可以取代的 或未取代的, 当被取代时, 优选的基团为卤素、 羟基、 低级垸氧基、 芳基、 芳氧 基、 杂芳基、 杂环垸基、 C(0)R7, R5R6和 C(0)N 5R6。 Unless otherwise stated, the following terms used in the specification and claims have the following meanings. "Mercapto" refers to a saturated aliphatic hydrocarbon group including straight chain and branched chain groups of 1 to 20 carbon atoms. Preference is given to medium-sized mercapto groups having 1 to 10 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, pentyldenyl. More preferred are lower fluorenyl groups having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl or t-butyl groups and the like. The alkyl group may be substituted or unsubstituted, and when substituted, preferred groups are halogen, hydroxy, lower decyloxy, aryl, aryloxy, heteroaryl, heterocyclic fluorenyl, C(0)R 7 , R 5 R 6 and C(0)N 5 R 6 .
"环垸基"指 3至 8元全碳单环、 全碳 5元 /6元或 6元 /6元稠合环或多环稠 合环 ("稠合"环系意味着系统中的每个环与体系中的其他环共享毗邻的一对碳 原子)基团, 其中一个或多个环可以含有一个或多个双键, 单没有一个环具有完 全共轭的 π电子系统。 环烷基的实例有环丙基、 环丁基、 环戊基、 环戊烯、环己 垸、 环己二烯、 金刚烷、 环庚烷、 环庚三烯等。 环垸基可以是取代或未取代的。 当被取代时, 取代基优选为一个或多个取代基, 独立地选自由低级垸基、三卤烷 基、 卤素、 羟基、 低级垸氧基、 芳基(可选自被一个或多个基团取代, 取代基是 彼此独立地是卤素、 羟基、 低级烷基或低级烷氧基)、 芳氧基 (可选自被一个或 多个基团取代, 取代基彼此独立地是卤素、 羟基、 低级垸基或低级烷氧基)、 6 元杂芳基 (环中具有 1至 3个氮原子, 环中的碳可选地被一个或多个基团取代, 取代基彼此独立地是卤素、羟基、 低级烷基或低级垸氧基)、 5元杂芳基(具有 1 至 3个选自氮、氧和硫的杂原子,该基团的碳和氮原子可选地被一个或多个基团 取代, 取代基彼此独立地是卤素、 羟基、 低级烧基或低级烷氧基)、 或 5或 6元 杂环烷基(具有 1至 3个选自氮、氧和硫地杂原子, 该基团地碳和氮原子(如果 有的话), 可选地被一个或多个基团取代, 取代基彼此独立地是卤素、 羟基、 低
级垸基或低级垸氧基)、巯基、 (低级垸基)硫基、 芳硫基(可选地被一个或多个 基团取代, 取代基彼此独立地是卤素、 羟基、 低级烷基或低级院氧基)、 氰基。 酰基、 硫代酰基、 0-氨基甲酰基、 N-氨基甲酰基、 O-硫代氨基甲酰基、 N-硫代 氨基甲酰基、 C-酰氨基、 N-酰氨基、 硝基、 N-磺酰氨基、 S-磺酰氨基、 R5S(0)-、 R5S(0)2、 -C(0)OR5。 "Cyclopentyl" means a 3 to 8 membered all-carbon monocyclic, all-carbon 5/6 or 6/6 fused or polycyclic fused ring ("fused" ring system means each in the system The rings share an adjacent pair of carbon atoms) groups with other rings in the system, wherein one or more of the rings may contain one or more double bonds, and none of the rings have a fully conjugated pi-electron system. Examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclopentene, cyclohexanyl, cyclohexadiene, adamantane, cycloheptane, cycloheptatriene and the like. The cycloalkyl group can be substituted or unsubstituted. When substituted, the substituent is preferably one or more substituents independently selected from the group consisting of lower fluorenyl, trihaloalkyl, halogen, hydroxy, lower decyloxy, aryl (optionally selected from one or more groups) a group substituted, the substituents are independently of each other a halogen, a hydroxyl group, a lower alkyl group or a lower alkoxy group), an aryloxy group (which may be selected by one or more groups, and the substituents are independently of each other a halogen, a hydroxyl group, a lower fluorenyl or lower alkoxy group, a 6-membered heteroaryl group having 1 to 3 nitrogen atoms in the ring, the carbon in the ring being optionally substituted by one or more groups, the substituents being independently of each other halogen, a hydroxy, lower alkyl or lower decyloxy), 5-membered heteroaryl (having from 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, the carbon and nitrogen atoms of which are optionally one or more Substituted, the substituents are, independently of each other, halogen, hydroxy, lower alkyl or lower alkoxy), or 5 or 6 membered heterocycloalkyl (having 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, The carbon and nitrogen atoms of the group, if any, optionally taken by one or more groups Substituents are each independently halogen, hydroxy, lower a fluorenyl or lower decyloxy group, a fluorenyl group, a (lower fluorenyl) thio group, an arylthio group (optionally substituted by one or more groups, the substituents being independently of one another halogen, hydroxy, lower alkyl or Low-grade alkoxy), cyano. Acyl, thioacyl, 0-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-acylamino, nitro, N-sulfonate Amido, S-sulfonylamino, R 5 S(0)-, R 5 S(0) 2 , -C(0)OR 5 .
"链烯基"指由至少两个碳原子和至少一个碳-碳双键组成的如上述定义的垸 基。 代表性实例包括但不限于乙烯基、 1-丙烯基、 2-丙烯基、 1-, 2-或 3-丁烯基 等。 "Alkenyl" means a fluorenyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond. Representative examples include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, and the like.
"炔基"指至少两个碳原子和至少一个碳-碳三键组成的如上所定义的垸基。 代表性实例包括但不限于乙炔基、 1-丙炔基、 2-丙炔'基、 1-, 2-或 3-丁炔基等。 "Alkynyl" means a fluorenyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond. Representative examples include, but are not limited to, ethynyl, 1-propynyl, 2-propyn'yl, 1-, 2- or 3-butynyl, and the like.
"芳基"指具有至少一个芳环结构的基团,即具有共轭的 π电子体系的芳环, 包括碳环芳基、杂芳即和联芳基。所述的芳基可以由一个或多个选自以下的取代 机任选取代: 卤素、 三卤甲基、羟基、 SR、硝基、氰基、垸氧基、烷基和 R5R6。 "Aryl" means a group having at least one aromatic ring structure, that is, an aromatic ring having a conjugated π-electron system, including a carbocyclic aryl group, a heteroaryl group, and a biaryl group. The aryl group may be optionally substituted by one or more substituents selected from the group consisting of halogen, trihalomethyl, hydroxy, SR, nitro, cyano, decyloxy, alkyl and R 5 R 6 .
"杂芳基"指具有 1至 3个杂原子作为环原子, 其余的环原子为碳的芳基, 杂原子包括氧、硫和氮。所述环可以是 5元或 6元环。 杂环芳基基团的实例包括 呋喃基、 噻吩基、 吡啶基、 吡咯、 N-浣基吡咯基、 嘧啶基、 吡嗪基、 咪唑基等。 "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.
"杂环垸基" ί旨单环或稠环基团, 在环中, 具有 5至 9个环原子, 其中一个 或两个环原子选自氮、 氧或 S(0)n (其中 n是整数 0至 2) 的杂原子, 其佘环原 子为碳。 这些环还可以具有一个或多个双键、 不过, 这些环不具有完全共轭的 π 电子系统。 未取代的杂环烷基包括但不限于吡咯垸基、 哌啶子基、哌嗪子基、 吗 啉基、 硫代吗啉基、 髙哌嗪其等、 杂环垸基可以是取代的或未取代的。 当被取代 时, 取代基优选为一个或多个, 更优选一个、 两个或三个, 进而更优选一个或两 个, 独立地选自由低级烷基、 三卤垸基、 卤素、 羟基、 低级垸氧基、 巯基、 (低 级垸基) 硫基、 氰基、 酰基、 硫代酰基、 0-氨基甲酰基、 Ν-氨基甲酰基、 0-硫 代氨基甲酰基、 Ν-硫代氨基甲酰基、 C-酰氨基、 Ν-酰氨基、 硝基、 Ν-磺酰氨基、 S-磺酰氨基、 R5S(0)-、 R5S(0)2、 -C(0)OR5、 R5C(0)O-和 NR5R6组成的组, R5 和 R6定义同上。 优选地, 杂芳基可选自被一个或两个取代基取代, 取代基独立 地选自卤素、 低级焼基、 三卤烷基、 羟基、 巯基、 氰基、 N-酰氨基、 单或二烷基 氨基、 羧基或 N-磺酰氨基。 "Heterocyclic fluorenyl" is a monocyclic or fused ring radical having 5 to 9 ring atoms in the ring, wherein one or two ring atoms are selected from nitrogen, oxygen or S(0)n (where n is An integer of 0 to 2) of a hetero atom whose anthracene ring is carbon. These rings may also have one or more double bonds, however, these rings do not have a fully conjugated pi-electron system. Unsubstituted heterocycloalkyl group includes, but is not limited to, pyrrolidinyl, piperidino, piperazino, morpholinyl, thiomorpholinyl, piperazine, etc., heterocyclic fluorenyl may be substituted or Unsubstituted. When substituted, the substituents are preferably one or more, more preferably one, two or three, and still more preferably one or two, independently selected from lower alkyl, trihalofluorenyl, halogen, hydroxy, lower Alkoxy, fluorenyl, (lower fluorenyl) thio, cyano, acyl, thioacyl, 0-carbamoyl, fluorenyl-carbamoyl, 0-thiocarbamoyl, hydrazine-thiocarbamoyl , C-amido, oxime-amido, nitro, oxime-sulfonylamino, S-sulfonylamino, R 5 S(0)-, R 5 S(0) 2 , -C(0)OR 5 , A group consisting of R 5 C(0)O- and NR 5 R 6 , and R 5 and R 6 are as defined above. Preferably, the heteroaryl group may be selected from one or two substituents, and the substituents are independently selected from halogen, lower fluorenyl, trihaloalkyl, hydroxy, decyl, cyano, N-acylamino, mono or di Alkylamino, carboxy or N-sulfonylamino.
"羟基"指 -OH基团。 "Hydroxy" means an -OH group.
"烷氧基"指 -0- (垸基) 和 -0- (未取代地环垸基)。 代表性实例包括但不 限于甲氧基、 乙氧基、 丙氧基、 丁氧基、 环丙氧基、 环丁氧基、 环戊氧基、 环己 氧基等。 "Alkoxy" means -0-(fluorenyl) and -0- (unsubstituted fluorenyl). Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like.
"卤代烷氧基" 指 -0- (卤代烷基)。 代表性实例包括但不限于三氟甲氧基、 三溴甲氧基等。
07 000176 "Haloalkoxy" means -0-(haloalkyl). Representative examples include, but are not limited to, trifluoromethoxy, tribromomethoxy, and the like. 07 000176
"芳氧基"指 -o-芳基和 -0-杂芳基, 芳基和杂芳基定义同上。 代表性实例包 括但不限于苯氧基、 吡啶氧基、 呋喃氧基、 噻吩氧基、 嘧啶氧基、 吡嗪氧基等及 其衍生物。 "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.
"巯基"指 -SH基团。 "Mercapto" refers to the -SH group.
"垸硫基"指 -0- (垸基)和 -0- (未取代的环烷基)。 代表性实例包括但不限 于甲硫基、 乙硫基、 丙硫基、 丁硫基、 环丙硫基、 环丁硫基、 环戊硫基、 环己硫 基等。 "Indolyl" refers to -0-(indenyl) and -0-(unsubstituted cycloalkyl). Representative examples include, but are not limited to, methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, and the like.
"芳硫基"指 -S-芳基和 -S-杂芳基, 芳基和杂芳基定义同上。 代表性实例包 括但不限于苯硫基、 吡啶硫基、 呋喃硫基、 噻吩硫基、 嘧啶硫基等及其衍生物、 "Arylthio" means -S-aryl and -S-heteroaryl, and aryl and heteroaryl are as defined above. Representative examples include, but are not limited to, phenylthio, pyridylthio, furanthio, thiophenothionyl, pyrimidinyl, and the like, and derivatives thereof,
"酰基"指 -C(0)-R"基团, 其中 R"选自由氢、 低级烷基、 三卤甲基、 未取 代的环烷基、 芳基(可选地被一个或多个, 优选一个、 两个或三个取代基, 取代 基选自由低级烷基、 三卤甲基、 低级垸氧基、 卤素和 -NR5R6组成的组)、 杂芳基 (通过环碳键合的) (可选地被一个或多个, 优选一个、 两个或三个取代基, 取 代基选自由低级烷基、 三卤甲基、 低级烷氧基、 卤素和 -NR5R6组成的组) 和杂 脂环基 (通过环碳键合的) (可选地被一个或多个, 优选一个、 两个或三个取代 基取代, 取代基选自由低级烷基、 三卤甲基、 低级烷氧基、 卤素和 -KR5R6组成 的组)。 代表性酰基包括但不限于乙酰基、 三氟乙酰基、 苯甲酰基等。 "Acyl" means a -C(0)-R" group, wherein R" is selected from hydrogen, lower alkyl, trihalomethyl, unsubstituted cycloalkyl, aryl (optionally one or more, Preferably one, two or three substituents are selected from the group consisting of lower alkyl, trihalomethyl, lower decyloxy, halogen and -NR 5 R 6 ), heteroaryl (via ring carbon bonding) (optionally one or more, preferably one, two or three substituents selected from the group consisting of lower alkyl, trihalomethyl, lower alkoxy, halogen and -NR 5 R 6 And a heteroalicyclic group (bonded by a ring carbon) (optionally substituted by one or more, preferably one, two or three substituents selected from lower alkyl, trihalomethyl, a group consisting of a lower alkoxy group, a halogen and a -KR 5 R 6 ). Representative acyl groups include, but are not limited to, acetyl, trifluoroacetyl, benzoyl, and the like.
"硫代酰基"指 -C (S) -R"基团, 其中 R"的定义同上。 "Thioxo" refers to a -C(S)-R" group, wherein R" is as defined above.
"乙酰基"指 -C (0) CH3基团。 "Acetyl" means -C (0) CH 3 group.
"卤素"指氟、 氯、 溴或碘, 优选氟或氯。 "Halogen" means fluoro, chloro, bromo or iodo, preferably fluoro or chloro.
"三卤甲基"指 -C¾, 其中 X是如上所定义的卤素。 "Trihalomethyl" means -C3⁄4, wherein X is a halogen as defined above.
"三卤甲磺酰基"指 ¾CS(=0)2基.团, 其中 X定义同上 "Trihalomethylsulfonyl" means a 3⁄4CS(=0)2 group. wherein X is as defined above.
"可选"或 "可选地"意味着随后所描述地事件或环境可以但不必发生, 该 说明包括该事件或环境发生或不发生地场合。 例如, "可选被垸基取代地杂环基 团"意味着垸基可以但不必存在,该说明包括杂环基团被垸基取代的情形和杂环 基团不被垸基取代的情形。 "Optional" or "optionally" means that the event or environment described subsequently may, but need not, occur, including where the event or environment occurs or does not occur. For example, "optionally substituted with a fluorenyl group" means that the fluorenyl group may, but need not be, the case where the heterocyclic group is substituted by a thiol group and the case where the heterocyclic group is not substituted by a thiol group.
"药物组合物"表示一种或多种本文所述化合物或其生理学上 /药学上可接 受的盐或前体药物与其他化学组分的混合物, 其他组分例如生理学 /药学上可接 受的载体和赋形剂。 药物组合物的目的是促进化合物对生物体的给药。 本发明化合物的合成方法 为了完成本发明的目的, 本发明采用如下技术方案 - 本发明通式 (I)所述的化合物或其盐的制备方法, 包括以下步骤:
本发明通式 (I)所述的化合物或其盐的制备方法, 包括以下步骤:
"Pharmaceutical composition" means a mixture of one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, with other chemical components, such as a physiological/pharmaceutically acceptable carrier. And excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to the organism. Method for synthesizing the compound of the present invention In order to accomplish the object of the present invention, the present invention adopts the following technical scheme - a method for preparing the compound of the present invention (I) or a salt thereof, comprising the following steps: The method for preparing the compound of the formula (I) or a salt thereof of the present invention comprises the following steps:
本发明通式 (II)所述的化合物或其盐的制备方法, 包括以下步骤
A method for preparing a compound of the formula (II) or a salt thereof according to the present invention, comprising the following steps
11-2 本发明通式 (III)所述的化合物或其盐的制备方法, 包括以下步骤-
11-2 A method for producing a compound of the formula (III) or a salt thereof according to the present invention, comprising the following steps -
具体实施方式 detailed description
以下结合实施例用于进一步描述本发明, 但这些实施例并非限制着本发明的 范围。 实施例 化合物的结构是通过核磁共振 (NMR)或质谱 (MS)来确定的。 NMR位移 (δ)以 百万分之一 (ppm)的单位给出。 NMR的测定是用 Bruker AVANCE-400核磁仪, 测定溶剂为氘代氯仿 (CDC13)、 氘代二甲基亚砜 (DMSO-D6), 内标为三甲基硅垸 (TMS), 化学位移是以 10—6(ppm)作为单位给出。 The invention is further described in the following examples, but these examples are not intended to limit the scope of the invention. The structure of the example compounds was determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). The NMR shift (δ) is given in parts per million (ppm). The NMR was measured by a Bruker AVANCE-400 nuclear magnetic apparatus. The solvent was deuterated chloroform (CDC1 3 ), deuterated dimethyl sulfoxide (DMSO-D 6 ), and the internal standard was trimethylsilyl (TMS). shifts are 10- 6 (ppm) given as a unit.
MS的测定用 FINMGAN LCQAd (ESI)质谱仪。 The MS was measured using a FINMGAN LCQAd (ESI) mass spectrometer.
激酶平均抑制率及 IC5。值的测定用 NovoStar酶标仪 (德国 BMG公司) 薄层硅胶使用烟台黄海 HSGF254或青岛 GF254硅胶板 Kinase inhibition rate and IC 5 . The value is determined by NovoStar microplate reader (BMG, Germany). Thin layer of silica gel is used in Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
柱层析一般使用烟台黄海硅胶 200~300目硅胶为载体。 Column chromatography generally uses Yantai Huanghai silica gel 200~300 mesh silica gel as the carrier.
DMSO-D6: 氘代二甲基亚砜; DMSO-D 6 : deuterated dimethyl sulfoxide;
CDC13: 氘代氯仿; 实施例 1 CDC1 3 : deuterated chloroform; Example 1
4-(3-氯 -4-氟 -苯胺 3-甲基 -1H-吡咯并「2,3-dl哒嗉 -2-(4- (吗啡啉 -4-基 -哌啶基)甲酰 4-(3-Chloro-4-fluoro-aniline 3-methyl-1H-pyrrolo- 2,3-dl哒嗉 -2-(4-(morpholine-4-yl-piperidinyl)formyl
第一步 First step
5-甲酰基 -3-甲基 -1Η-吡咯 -2,4-二羧酸乙酯 将 3,5-二甲基 -1H-吡咯 -2,4-二羧酸乙酯 la (4.79 g, 20 mmol)溶于四氢呋喃 (100 mL)中, 再加入乙酸 (120 mL)及水 (100 mL)的混合溶剂, 室温搅拌下一次性 加入硝酸铈铵 (44.4 g, 81 mmol), 反应 1.5 小时后, 向体系中补加水 (200 mL), 用二氯甲烷萃取反应液 (100 mLX 3), 合并有机相, 有机相用饱和碳酸氢钠溶液 清洗至 pH值为偏碱性, 再用饱和氯化钠溶液洗 (25 mLX l), 二氯甲烷层用无水 硫酸镁干燥, 过滤, 滤液减压浓缩, 用硅胶柱色谱法纯化所得残余物, 得到标题 产物 5-甲酰基 -3-甲基 -1H-吡咯 -2,4-二羧酸乙酯 lb (2.544 g, 白色固体)。 产率: 65.09%。 Ethyl 5-formyl-3-methyl-1Η-pyrrole-2,4-dicarboxylate ethyl 3,5-dimethyl-1H-pyrrole-2,4-dicarboxylate la (4.79 g, 20 mmol) was dissolved in tetrahydrofuran (100 mL), and then a mixed solvent of acetic acid (120 mL) and water (100 mL) was added, and ammonium cerium nitrate (44.4 g, 81 mmol) was added in one portion at room temperature for 1.5 hours. Add water (200 mL) to the system, extract the reaction solution with dichloromethane (100 mL×3), combine the organic phases, wash the organic phase with saturated sodium bicarbonate solution until the pH is alkaline, and then use saturated chlorination. The sodium solution was washed (25 mL EtOAc), EtOAcjjjjjjjjjjj Ethyl 1H-pyrrole-2,4-dicarboxylate lb (2.544 g, white solid). Yield: 65.09%.
MS m/z (ESI): 254[M- 1] MS m/z (ESI): 254 [M-1]
'HNMR (400MHZ, CDCI3- ): 510.27(s, 1H), 4.39(m, 4H), 2.60(s, 3H), 1.37(q, 6H) 第二步 'HNMR (400MHZ, CDCI3-): 510.27(s, 1H), 4.39(m, 4H), 2.60(s, 3H), 1.37(q, 6H)
3-甲基 -4-羰基 -3a,4,5,7a-四氢 -1H-吡咯并 [2,3-d]哒嗪 -2羧酸乙酯 室温下,将 5-甲酰基 -3-甲基 -1H-吡咯 -2,4-二羧酸乙酯 lb (2.544 g, 10 mmol, ) 溶解于乙酸 (43 mL)中, 搅拌下加入 85%的水合肼溶液 (0.65 mL, 11 mmol), 有 黄色沉淀生成, 继续搅拌, 加热至 100Ό反应 2小时, 将反应液冷却至室温, 静 置过夜。 次日, 减压抽滤, 固体干燥, 得到标题产物 3-甲基 -4-羰基 -3a, 4, 5, 7a- 四氢 -1H-吡咯并 [2,3-d]哒嗪 -2羧酸乙酯 lc (1.74 g,黄色粉末状固体)。产率: 78.73 %。 Ethyl 3-methyl-4-carbonyl-3a,4,5,7a-tetrahydro-1H-pyrrolo[2,3-d]pyridazine-2carboxylate 5-formyl-3- at room temperature Ethyl methyl-1H-pyrrole-2,4-dicarboxylate lb (2.544 g, 10 mmol, ) was dissolved in acetic acid (43 mL), and 85% hydrazine hydrate solution (0.65 mL, 11 mmol) was added with stirring. A yellow precipitate formed, stirring was continued, and the mixture was heated to 100 Torr for 2 hours. The reaction solution was cooled to room temperature and allowed to stand overnight. The next day, suction filtration under reduced pressure and solid dried to give the title product 3-methyl-4-carbonyl-3a, 4, 5, 7a-tetrahydro-1H-pyrrolo[2,3-d]pyridazine-2carboxylate Ethyl ester lc (1.74 g, yellow powdery solid). Yield: 78.73%.
MS m/z (ESI): 222[M+ 1] MS m/z (ESI): 222 [M+ 1]
1HNMR (400MHz, D SO-^): 58.09(s, 1H), 4.34(q, 2H, J=7.2 Hz), 2.63(s, 3H),
1.35(t, 3H, J=7.2 Hz) 第三步 1HNMR (400MHz, D SO-^): 58.09(s, 1H), 4.34 (q, 2H, J = 7.2 Hz), 2.63 (s, 3H), 1.35(t, 3H, J=7.2 Hz) Step 3
3-甲基 -4-氯 -3a,4,5,7a-四氢 -1H-吡咯并 [2,3-d]哒嗪 -2羧酸乙酯 在氮气氛下, 在 100 mL 的三颈瓶中, 将 3-甲基 -4-羰基 -3a,4,5,7a-四氢 -1H- 吡咯并 [2,3-d]哒嗪 -2羧酸乙酯 lc (553 mg, 2.5 mmol)溶解于无水乙腈 (15mL), 室 温搅拌下缓慢滴加无水三氯氧磷 (0.465 mL, 5 mmol), 滴加完毕后, 加热回流至 黄色固体 lc逐渐反应溶解为黄色溶液,继续回流 0.5 小时。将反应液移至 100 mL 的茄形瓶中, 减压旋蒸除去乙腈, 再向反应体系中加入正己烷 (10 mL), 减压旋 干,重复三次 (去除残余三氯氧磷)。得到标题产物 3-甲基 -4-氯 -3a,4,5,7a-四氢 -1H- 吡咯并 [2,3-d]哒嗪 -2羧酸乙酯 Id (黄色固体), 备用, 直接做下一步。 Ethyl 3-methyl-4-chloro-3a,4,5,7a-tetrahydro-1H-pyrrolo[2,3-d]pyridazine-2carboxylate under nitrogen atmosphere at 100 mL three neck In the flask, ethyl 3-methyl-4-carbonyl-3a,4,5,7a-tetrahydro-1H-pyrrolo[2,3-d]pyridazine-2carboxylate lc (553 mg, 2.5 mmol Dissolve in anhydrous acetonitrile (15 mL), slowly add anhydrous phosphorus oxychloride (0.465 mL, 5 mmol) with stirring at room temperature. After the addition is completed, heat to reflux to a yellow solid lc gradually dissolve to a yellow solution and continue to reflux. 0.5 hours. The reaction solution was transferred to a 100 mL eggplant-shaped flask, and acetonitrile was distilled off under reduced pressure. Then, n-hexane (10 mL) was added to the reaction mixture, and the mixture was evaporated to dryness and dried three times (removing residual phosphorus oxychloride). The title product 3-methyl-4-chloro-3a,4,5,7a-tetrahydro-1H-pyrrolo[2,3-d]pyridazine-2carboxylate Id (yellow solid) was obtained, Do the next step directly.
此步也可纯化, 将此固体置于 50 mL的茄形瓶中, 加入四氢呋喃 (8 mL), 室 温条件下搅拌 30 分钟, 过滤, 得标题产物 3-甲基 -4-氯 -3a,4,5,7a-四氢 -1H-吡咯 并 [2,3-d]哒嗪 -2羧酸乙酯黄色固体 Id (569 mg, 浅黄色固体), 产率: 94.9%。 MS m/z (ESI): 240[M+ 1] This step can also be purified. The solid is placed in a 50 mL eggplant-shaped flask, added to tetrahydrofuran (8 mL), stirred at room temperature for 30 minutes, and filtered to give the title product 3-methyl-4-chloro-3a, 4 , 5,7 a - tetrahydro -1H- pyrrolo [2,3-d] pyridazine -2-carboxylate as a yellow solid Id (569 mg, pale yellow solid), yield: 94.9%. MS m/z (ESI): 240 [M+ 1]
!HNMR (400MHz, DMSO-i¾): 69.5 l(s, 1H), 4.43(q, 2H, J=7.2 Hz), 2.77(s, 3H), 1.39(t, 3H, J=7.2 Hz) ! HNMR (400MHz, DMSO-i¾ ): 69.5 l (s, 1H), 4.43 (q, 2H, J = 7.2 Hz), 2.77 (s, 3H), 1.39 (t, 3H, J = 7.2 Hz)
, 第四步 ' , the fourth step '
4-(3-氯 -4-氟-苯胺) -3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸乙酯盐酸盐 在第三步盛有 3-甲基 氯 -3a,4,5,7a-四氢 -1H-吡咯并 [2,3-d]哒嗪 -2羧酸乙酯 黄色固体 Id 的茄形瓶中搅拌下直接加入异丙醇 (15 mL)和 3-氯 -4-氟 -苯胺 (546 mg, 3.75 mmol), 加热回流, 点板跟踪至原料消失。 将反应液冷却至室温, 继续 用冰水浴冷却并搅拌, 有黄色固体产生, 减压抽滤, 固体用少量乙酸乙酯洗涤, 真空干燥,得到标题产物 4-(3-氯 -4-氟-苯胺) -3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸 乙酯盐酸盐 le (440 mg, 黄色固体)。 产率: 50.4%。 4-(3-Chloro-4-fluoro-aniline)-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid ethyl ester hydrochloride in the third step 3- Methyl chloride-3a,4,5,7a-tetrahydro-1H-pyrrolo[2,3-d]pyridazine-2carboxylic acid ethyl ester Yellow solid Id in an eggplant-shaped flask, directly added with isopropanol under stirring ( 15 mL) and 3-chloro-4-fluoro-aniline (546 mg, 3.75 mmol), heated to reflux, and the spot was traced until the starting material disappeared. The reaction solution was cooled to room temperature, then cooled with EtOAc EtOAc EtOAc (EtOAc) Aniline)-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid ethyl ester hydrochloride (440 mg, yellow solid). Yield: 50.4%.
MS m/z (ESI): 349[M+ 1] 第五步 MS m/z (ESI): 349[M+ 1] Step 5
4-(3-氯 -4-氟-苯胺) -3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-甲酸 在 100 mL茄形瓶中, 将 4-(3-氯 -4-氟-苯胺) -3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2- 羧酸乙酯 le (440 mg, 1.26 mmol)搅拌下溶解于乙醇 (30 mL)中, 再加入氢氧化钠 溶液 (5 mL, 1 mol/L), 加热回流, 点板跟踪至原料消失, 将反应液冷却至室温过 夜, 减压旋蒸除去乙醇, 搅拌下用 1 N盐酸溶液调 pH值至 2, 有大量固体析出。 减压抽滤,固体用蒸馏水洗漆,干燥,得到标题产物 4-(3-氯 -4-氟-苯胺) -3-甲基 -1H-
吡咯并 [2,3-d]哒嗪 -2-甲酸 lf(367 mg, 黄色固体)。 产率: 91 %。 4-(3-chloro-4-fluoro-aniline)-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid in a 100 mL eggplant-shaped flask, 4-(3- Chloro-4-fluoro-aniline) 3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid ethyl ester (440 mg, 1.26 mmol) dissolved in ethanol (30 mL) In addition, add sodium hydroxide solution (5 mL, 1 mol / L), heat to reflux, point plate tracking until the disappearance of the raw materials, the reaction solution was cooled to room temperature overnight, and the ethanol was evaporated under reduced pressure, and 1 N hydrochloric acid was stirred with stirring. The solution was adjusted to pH 2 and a large amount of solid precipitated. Filtration under reduced pressure, the solid was washed with distilled water and dried to give the title product 4-(3-chloro-4-fluoro-aniline)-3-methyl-1H- Pyrrolo[2,3-d]pyridazine-2-carboxylic acid lf (367 mg, yellow solid). Yield: 91%.
4-(3-氯 -4-氟-苯胺) -3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-(4- (吗啡啉 -4-基) -哌啶基)甲酰 胺 4-(3-chloro-4-fluoro-aniline)-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-(4-(morpholine-4-yl)-piperidinyl Carboxamide
向一个 100 mL的茄形瓶中加入 4-(3-氯 -4-氟-苯胺) -3-甲基 -1H-吡咯并 [2,3-d] 哒嗪 -2-甲酸 If (320 mg, 1 mmol), N-乙基 -N,- (二甲氨基丙基) -碳二亚胺 (288 mg, 1.5 mmol)、 卜羟基苯并噻唑 (203 mg, 1.5 mmo) 和 N'N-二甲基甲酰胺 (30mL), 搅拌至溶解后, 加入三乙胺 (0.35 mL, 2.5 mmol), 搅拌 5分钟后加入 4- (吗啡啉 -4-基) -哌啶 (255 mg, 1.5 mmol), 室温下搅拌过夜, 点板监测至原料消失, 将反 应液倒入冰水 (200 mL)中, 用乙酸乙酯萃取反应液 (80 mLX 4), 合并有机相, 有 机相用饱和氯化钠溶液洗 (25 mL), 乙酸乙酯层用无水硫酸镁干燥, 过滤, 滤液 减压浓缩,用硅胶柱色谱法纯化所得残余物,得到标题产物 4-(3-氯 -4-氟-苯胺) -3- 甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-(4- (吗啡啉 -1-基) -哌啶基)甲酰胺 1 (43 mg, 黄色固 体)。 产率: 9%。 Add 4-(3-chloro-4-fluoro-aniline)-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid If (320 mg) to a 100 mL eggplant-shaped flask , 1 mmol), N-ethyl-N,-(dimethylaminopropyl)-carbodiimide (288 mg, 1.5 mmol), hydroxybenzothiazole (203 mg, 1.5 mmo) and N'N- Dimethylformamide (30 mL), after stirring until dissolved, was added triethylamine (0.35 mL, 2.5 mmol). After stirring for 5 min, 4-(morpholinolin-4-yl)-piperidine (255 mg, 1.5 mmol) After stirring at room temperature overnight, the plate was monitored until the disappearance of the starting material. The reaction solution was poured into ice water (200 mL), and the reaction mixture was extracted with ethyl acetate (80 mL×4), and the organic phase was combined. The sodium solution was washed (25 mL), EtOAcjjjjjjjjjjjjjj Benzene)-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-(4-(morphinolin-1-yl)-piperidinyl)carboxamide 1 (43 mg, yellow solid) . Yield: 9%.
MS m/z (ESI): 473[M+1] MS m/z (ESI): 473[M+1]
1HNMR (400MHz, DMSO-i¾): δ 8.89(s, 1H), 7.99 (d, 1H), 7.62(t, 1H), 7.34 (q, 1H), 3.57(s, 4H), 3.45(s, 9H), 2.47(s, 3H), 1.84 (m, 2H),1.36(m, 2H) 实施例 2 1HNMR (400MHz, DMSO-i3⁄4): δ 8.89 (s, 1H), 7.99 (d, 1H), 7.62 (t, 1H), 7.34 (q, 1H), 3.57 (s, 4H), 3.45 (s, 9H) ), 2.47(s, 3H), 1.84 (m, 2H), 1.36 (m, 2H) Example 2
4-(3-氯 -4-氟-苯胺 3-甲基 -1H-吡咯并 f2,3-dl哒嗪 -2-(2-二乙胺基乙基)甲酰胺 4-(3-Chloro-4-fluoro-aniline 3-methyl-1H-pyrrolof2,3-dloxazin-2-(2-diethylaminoethyl)carboxamide
重复本发明实施例 1第一步至第五步的反应, 使用上述第五步中所得到的化 合物 4-(3-氯 -4-氟-苯胺) -3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-甲酸 If作原料, 按照本 发明实施例 1第六步所述相同方式进行该原料与二乙基乙二胺的反应,则得到标 题产物 4-(3-氯 -4-氟-苯胺) -3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-(2-二乙胺基乙基)甲酰 胺 2 (239 mg, 黄色固体)。 产率: 38%。 The reaction of the first step to the fifth step of Example 1 of the present invention was repeated, using the compound 4-(3-chloro-4-fluoro-aniline)-3-methyl-1H-pyrrole obtained in the above fifth step. 2,3-d]pyridazine-2-carboxylic acid If as a starting material, the reaction of the starting material with diethylethylenediamine is carried out in the same manner as described in the sixth step of the present invention, to obtain the title product 4-(3). -chloro-4-fluoro-aniline)-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-(2-diethylaminoethyl)carboxamide 2 (239 mg, yellow solid ). Yield: 38%.
MS m/z (ESI): 419[M+ 1] MS m/z (ESI): 419 [M+ 1]
'HNMR (400MHZ, DMSO-C¾: δ 8.91 (s, 1H), 7.98(d, 1H), 9.60(d5 1H), 7.34(t, 1H),
3.39(t, 2H), 2.71(s, 3H), 2.64(t, 2H), 2.57(m, 4H), 1.00(t, 6H) 实施例 3 'HNMR (400MHZ, DMSO-C3⁄4: δ 8.91 (s, 1H), 7.98 (d, 1H), 9.60 (d 5 1H), 7.34 (t, 1H), 3.39(t, 2H), 2.71(s, 3H), 2.64(t, 2H), 2.57(m, 4H), 1.00(t, 6H) Example 3
4-(3-氯 -4-氟 -苯胺 )-3-甲基 -1H-吡咯并『2,3-dl哒嗪 -2-(2-吗啡啉 -4基-乙基)甲酰胺 4-(3-Chloro-4-fluoro-aniline)-3-methyl-1H-pyrrolo-2,3-dloxazin-2-(2-morpholine-4-yl-ethyl)carboxamide
3 重复本发明实施例 1第一步至第五步的反应, 使用上述第五步中所得到的化 合物 4-(3-氯 -4-氟-苯胺) -3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-甲酸 If作原料, 按照本 发明实施例 1第六步所述相同方式进行该原料与吗啡啉 -4基-乙二胺的反应, 则 得到标题产物 4-(3-氯 -4-氟-苯胺) -3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-(2-吗啡啉 -4基- 乙基)甲酰胺 3 (248 mg, 黄色固体)。 产率: 38.4%。 3 Repeat the reaction of the first step to the fifth step of the first embodiment of the present invention, using the compound 4-(3-chloro-4-fluoro-aniline)-3-methyl-1H-pyrrole obtained in the above fifth step. [2,3-d]pyridazine-2-carboxylic acid If as a starting material, the reaction of the starting material with morpholine-4-yl-ethylenediamine is carried out in the same manner as described in the sixth step of the present invention, to obtain the title product. 4-(3-chloro-4-fluoro-aniline)-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-(2-morphinolin-4-yl-ethyl)carboxamide 3 (248 mg, yellow solid). Yield: 38.4%.
MS m/z (ESI): 433[M+ 1] MS m/z (ESI): 433 [M+ 1]
1H MR (400MHz, DMSO-^): δ 8.92(s, 1H), 7.99(d, 1H), 7.62(d, 1H), 7.34 (t, 1H), 3.59(t, 4H), 3.43(t, 2H), 2.71(s, 3H), 2.50(t, 2H), 2.44(s, 4H) 实施例 4 1H MR (400MHz, DMSO-^): δ 8.92(s, 1H), 7.99(d, 1H), 7.62(d, 1H), 7.34 (t, 1H), 3.59(t, 4H), 3.43(t, 2H), 2.71(s, 3H), 2.50(t, 2H), 2.44(s, 4H) Example 4
4-Π-炔基-苯胺) -3-甲基 -1H-吡咯并 f2,3-dl哒嗪 -2-ί2-二乙胺基乙基)甲酰胺 4-Π-alkynyl-aniline)-3-methyl-1H-pyrrolof2,3-dlpyridazine-2-ί2-diethylaminoethylformamide
4-(3-炔基-苯胺) -3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸乙酯盐酸盐 按照实施例 1第三、 四步所述相同方法, 氮气氛下, 100 mL的三颈瓶中, 将 3-甲基 -4-羰基 -3a,4,5,7a-四氢 -1H-吡咯并 [2,3-d]哒嗪 -2羧酸乙酯 lc (1.549 g, 7 mmol)溶解于无水乙腈 (50 mL)中, 室温搅拌下缓慢滴加无水三氯氧磷 (1.3 mL), 滴加完毕后, 加热回流至黄色固体 lc逐渐反应溶解为橙红色溶液, 继续回流 30 分钟。 将反应液移至 150 mL的茄形瓶中, 减压旋蒸除去乙腈, 再向反应体系中 加入正己垸 (10 mL), 减压旋干, 重复三次 (去除残余三氯氧磷)。 得到 3-甲基 -4- 氯 -3a,4,5,7a-四氢 -1H-吡咯并 [2,3-d]哒嗪 -2羧酸乙酯 Id (黄色固体), 在此茄形瓶 中直接加入异丙醇 (35 mL)和间乙炔基苯胺 (0.9 g, 7.7 mmol), 加热回流 3小时, 点板跟踪至原料消失。将反应液冷却至室温, 继续用冰水浴冷却并搅拌, 有黄色 固体产生, 减压抽滤, 固体用少量的乙酸乙酯和乙醇洗涤, 红外干燥, 得到标题 产物 4-(3-炔基-苯胺) -3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸乙酯盐酸盐 4a (1.194 g, 黄色固体)。 产率: 44.22%。 4-(3-ynyl-aniline)-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid ethyl ester hydrochloride as described in Example 1, third and fourth steps In the same way, in a 100 mL three-necked flask under a nitrogen atmosphere, 3-methyl-4-carbonyl-3a,4,5,7a-tetrahydro-1H-pyrrolo[2,3-d]pyridazine- 2 Carboxylic acid ethyl ester lc (1.549 g, 7 mmol) was dissolved in anhydrous acetonitrile (50 mL), and anhydrous phosphorus oxychloride (1.3 mL) was slowly added dropwise with stirring at room temperature. After the addition was completed, the mixture was heated to reflux. The solid lc gradually reacted to dissolve into an orange-red solution and continued to reflux for 30 minutes. The reaction solution was transferred to a 150 mL eggplant-shaped flask, and acetonitrile was removed by vacuum distillation under reduced pressure. Then, hexane (10 mL) was added to the reaction mixture, and the mixture was evaporated to dryness and dried three times (removing residual phosphorus oxychloride). Obtaining 3-methyl-4-chloro-3a,4,5,7a-tetrahydro-1H-pyrrolo[2,3-d]pyridazine-2carboxylic acid ethyl ester Id (yellow solid), in the shape of eggplant Isopropanol (35 mL) and m-ethynylaniline (0.9 g, 7.7 mmol) were added directly to the flask, and the mixture was heated under reflux for 3 hours, and the spot was traced until the starting material disappeared. The reaction solution was cooled to room temperature, cooled with ice-cooled water and stirred, and then evaporated, evaporated, evaporated, evaporated, evaporated. Aniline)-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid ethyl ester hydrochloride 4a (1.194 g, yellow solid). Yield: 44.22%.
MS m/z (ESI): 321 [M+ l] 第二步' MS m/z (ESI): 321 [M+ l] Step 2
4-(3-炔基-苯胺) -3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-甲酸 按照本发明实施例 1第五步所述相同方式, 使用 4-(3-块基-苯胺) -3-甲基 -1H- 吡咯并 [2,3-d]哒嗪 -2-羧酸乙酯盐酸盐 4a作原料, 制得本标题产物 4-(3-炔基-苯 胺) -3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-甲酸 4b (970 mg, 黄色固体)。 4-(3-ynyl-aniline)-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid In the same manner as described in the fifth step of Example 1 of the present invention, 4- (3-blockyl-aniline)-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid ethyl ester hydrochloride 4a as a starting material, the title product 4-(3) - alkynyl-aniline)-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid 4b (970 mg, yellow solid).
MS m/z (ESI): 219[M+ 1] 第三步 MS m/z (ESI): 219 [M+ 1] Step 3
4-(3-炔基-苯胺) -3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-(2-二乙胺基乙基)甲酰胺 按照本发明实施例 1第六步所述相同方式, 使用 4-(3-炔基-苯胺) -3-甲基 -1H- 吡咯并 [2,3-d]哒嗪 -2-甲酸 4b作原料, 进行该原料与二乙基乙二胺的反应, 则得 到标题产物 4-(3-炔基-苯胺) -3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-(2-二乙胺基乙基)甲 酰胺 4 (253mg, 白色固体)。 产率: 43.2%。 4-(3-ynyl-aniline)-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-(2-diethylaminoethyl)carboxamide according to Example 1 of the present invention In the same manner as described in the sixth step, 4-(3-ynyl-aniline)-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid 4b is used as a raw material to carry out the raw material and The reaction of diethylethylenediamine gives the title product 4-(3-ynyl-aniline)-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-(2-diethyl) Aminoethyl)carboxamide 4 (253 mg, white solid). Yield: 43.2%.
MS m/z (ESI): 391 [M+ l] MS m/z (ESI): 391 [M+ l]
1HNMR (400MHz, DMSO-^): 58.913(s, 1H), 7.884(s, 1H), 7.660(d, 1H), 7.311(t, 1H), 7.068(d, 1H), 4.082(s, 1H), 3.373(t, 2H), 2.696(s, 3H), 2.596(t, 2H), 2.579〜2.513(m, 4H), 0.987(t, 6H) 实施例 5
4-( -炔基-苯胺) -3-甲基 -1H-吡咯并 r2,3-d|哒嗪 -2-(4- (吗啡啉 -4-基) -哌啶基) 1 H NMR (400MHz, DMSO-^): 58.913 (s, 1H), 7.884 (s, 1H), 7.660 (d, 1H), 7.311 (t, 1H), 7.068 (d, 1H), 4.082 (s, 1H) ), 3.373(t, 2H), 2.696(s, 3H), 2.596(t, 2H), 2.579~2.513(m, 4H), 0.987(t, 6H) Example 5 4-(-alkynyl-aniline)-3-methyl-1H-pyrrolo-r2,3-d|pyridazine-2-(4-(morpholine-4-yl)-piperidinyl)
重复本发明实施例 4第一步至第二步的反应, 使用上述第二步中所得到的化 合物 4-(3-炔基-苯胺) -3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-甲酸 4b作原料, 按照本发 明实施例 1第六步所述相同方式进行该原料与 4- (吗啡啉 -4-基) -哌啶的反应, 则 得到标题产物 4-(3-炔基-苯胺) -3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-(4- (吗啡啉 -4-基) - 哌啶基)甲酰胺 5 (122 mg, 橙黄色固体)。 产率: 20 %。 The reaction of the first step to the second step of Example 4 of the present invention was repeated, using the compound 4-(3-ynyl-aniline)-3-methyl-1H-pyrrolo[2,3 obtained in the above second step. -d]pyridazine-2-carboxylic acid 4b as a starting material, the reaction of the starting material with 4-(morpholinolin-4-yl)-piperidine is carried out in the same manner as described in the sixth step of the present invention, to obtain the title product. 4-(3-ynyl-aniline)-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-(4-(morphinolin-4-yl)-piperidinyl)carboxamide 5 (122 mg, orange-yellow solid). Yield: 20%.
MS m/z (ESI) : 445[M+ 1] MS m/z (ESI) : 445 [M+ 1]
JHNMR (400MHz, DMSO-^): δ 8.89(s, 1H), 7.84(s, 1H), 7.67(d, 1H), 7.32(t, 1H, -ArH), 7.07(d, 1H), 4.10(s, 1H) , 3.58(s, 4H), 3.47(s, 9H), 2.46(s, 3H), 1.87 (m, 2H),1.36(m, 2H) 实施例 6 J HNMR (400MHz, DMSO-^): δ 8.89 (s, 1H), 7.84 (s, 1H), 7.67 (d, 1H), 7.32 (t, 1H, -ArH), 7.07 (d, 1H), 4.10 (s, 1H), 3.58(s, 4H), 3.47(s, 9H), 2.46(s, 3H), 1.87 (m, 2H), 1.36 (m, 2H) Example 6
4-(3-炔基 -苯胺 > -甲基 -1H-吡咯并「2,3-dl哒嗪 -2-(2-吡咯啶 -1-基)-乙基)甲酰胺 4-(3-ynyl-aniline > -methyl -1H-pyrrolo "2,3-dloxazin-2-(2-pyrrolidin-1-yl)-ethyl)carboxamide
重复本发明实施例 4第一步至第二步的反应, 使用上述第二步中所得到的化 合物 4-(3-炔基-苯胺) -3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-甲酸 4b作原料, 按照本发 明实施例 1第六步所述相同方式进行该原料与 2- (吡咯啶 -1-基) -乙胺的反应, 则 得到标题产物 4-(3-炔基-苯胺) -3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-(2-吡咯啶 -1-基) - 乙基)甲酰胺 6 (405 mg, 浅黄色固体)。 产率: 57.9 % The reaction of the first step to the second step of Example 4 of the present invention was repeated, using the compound 4-(3-ynyl-aniline)-3-methyl-1H-pyrrolo[2,3 obtained in the above second step. -d]pyridazine-2-carboxylic acid 4b as a starting material, the reaction of the starting material with 2-(pyrrolidin-1-yl)-ethylamine is carried out in the same manner as described in the sixth step of the present invention, to obtain the title product. 4-(3-ynyl-aniline)-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-(2-pyrrolidin-1-yl)-ethyl)carboxamide 6 ( 405 mg, pale yellow solid). Yield: 57.9 %
MS m/z (ESI): 389[M+ 1] MS m/z (ESI): 389 [M+ 1]
1HNMR (400MHz, OMSO-d6): δ 8.96(s, 1H), 7.84(s, 1H), 7.66(d, 1H), 7.33(t, 1H), 7.09(d, 1H), 4.12(s, 1H), 3.65(t, 2H), 3.35(t, 2H), 2.73(s, 3H), 2.51 (m, 4H), 2.00(m, 4H)
实施例 Ί 1 H NMR (400MHz, OMSO-d 6 ): δ 8.96(s, 1H), 7.84(s, 1H), 7.66(d, 1H), 7.33(t, 1H), 7.09(d, 1H), 4.12(s , 1H), 3.65(t, 2H), 3.35(t, 2H), 2.73(s, 3H), 2.51 (m, 4H), 2.00(m, 4H) Example
4-(3-炔基-笨胺) -3-甲基 -1Η-吡咯并「2,3-dl哒嗪 -2- 2-吗啡啉 -4-基) -乙基)甲酰胺 4-(3-ynyl-phenylamine)-3-methyl-1Η-pyrrolo-[2,3-dlpyridazine-2- 2-morpholine-4-yl)-ethyl)carboxamide
重复本发明实施例 4第一步至第二步的反应, 使用上述第二步中所得到的化 合物 4-(3-炔基-苯胺) -3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-甲酸 4b作原料, 按照本发 明实施例 1第六步所述相同方式进行该原料与 (2-吗啡啉 -4-基) -乙胺的反应,则得 到标题产物 4-(3-炔基-苯胺) -3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-(2-吗啡啉 -4-基) -乙 基)甲酰胺 7 (139 mg, 黄色固体)。 产率: 23 %。 The reaction of the first step to the second step of Example 4 of the present invention was repeated, using the compound 4-(3-ynyl-aniline)-3-methyl-1H-pyrrolo[2,3 obtained in the above second step. -d]pyridazine-2-carboxylic acid 4b as a starting material, the reaction of the starting material with (2-morphocolin-4-yl)-ethylamine is carried out in the same manner as described in the sixth step of the present invention, to obtain the title product. 4-(3-ynyl-aniline)-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-(2-morphinolin-4-yl)-ethyl)carboxamide 7 ( 139 mg, yellow solid). Yield: 23%.
MS m/z (ESI): 405[M+ 1] MS m/z (ESI): 405 [M+ 1]
1HNMR (400MHz, DMSO-rf6): 58.92(s, 1H,), 7.85(s, 1H), 7.67(d, 1H), 7.3 l(t, 1H), 7.07(d,lH), 4.09(s, 1H), 359(t, 4H), 3.42(q, 2H),2.70(s, 3H), 2.51(s, 2H), 2.45(q, 4H) 实施例 8 1 H NMR (400 MHz, DMSO-rf 6 ): 58.92 (s, 1H,), 7.85 (s, 1H), 7.67 (d, 1H), 7.3 l (t, 1H), 7.07 (d, lH), 4.09 ( s, 1H), 359(t, 4H), 3.42(q, 2H), 2.70(s, 3H), 2.51(s, 2H), 2.45(q, 4H) Example 8
4-『3-氯 -4-(3-氟苄氧 笨胺 1-3-甲基 吡咯并 f2,3-dl哒嗪 -2-(2-吡咯啶 -1-基 乙基) 甲酰胺 4- "3-Chloro-4-(3-fluorobenzyloxylamine 1-3-methylpyrrolo-f2,3-dloxazin-2-(2-pyrrolidin-1-ylethyl)carboxamide
4-[3-氯 -4-(3-氟苄氧) -苯胺 ]-3-甲基 -1Η-吡咯并 [2,3-d]哒嗪 -2-羧酸乙酯盐酸盐 按照实施例 1第三、 四步所述相同方式, 氮气氛下, 在一个 50 mL的三颈瓶 中,将 3-甲基 -4-羰基 -3a,4,5,7a-四氢 -1H-吡咯并 [2,3-d]哒嗪 -2羧酸乙酯 lc(443 mg, 2 mmd)溶解于无水乙腈 (15 mL)中, 室温搅拌下缓慢滴加无水三氯氧磷 (0.372 mL, 4 mmol), 滴加完毕后, 加热回流至黄色固体 lc逐渐反应溶解为黄色溶液, 继续回流 30 分钟。 将反应液移至 100 mL的茄形瓶中, 减压旋蒸除去乙腈, 再 向反应体系中加入正己垸 (10 mL), 减压旋干, 重复三次 (去除残余三氯氧磷), 得 到 3-甲基 -4-氯 -3a,4,5,7a-四氢 -1H-吡咯并 [2,3-d]哒嗪 -2羧酸乙酯 Id (黄色固体)。 在此茄形瓶中直接加入异丙醇 (15 mL)和 3-氯 -4-(3-氟苄氧) -苯胺盐酸盐 (0.576 g, 2.0 mmo)以及三乙胺 (0.3 mL, 2.2 mmol), 加热回流 3 小时, 点板跟踪至原料消 失。 将反应液冷却至室温, 继续用冰水浴冷却并搅拌, 有黄色固体产生, 减压抽 滤, 固体用少量的异丙醇洗涤, 干燥, 得到标题产物 4-(3-炔基-苯胺) -3-甲基 -1H- 吡咯并 [2,3-d]哒嗪 -2-羧酸乙酯盐酸盐 8a (0.445 g, 黄色固体)。产率: 45.4%。 将 此固体置于 50 mL茄形瓶中, 加入甲醇 (10 mL), 用浓氨水调节 PH为 9, 室温条 件下搅拌 5 rain, 过滤, 得到 4-[3-氯 -4-(3-氟苄氧) -苯胺 ]-3-甲基 -1H-吡咯并 [2,3-d] 哒嗪 -2-羧酸乙酯 (黄色固体)。 4-[3-Chloro-4-(3-fluorobenzyloxy)-aniline]-3-methyl-1Η-pyrrolo[2,3-d]pyridazine-2-carboxylic acid ethyl ester hydrochloride according to the implementation In the same manner as described in the third and fourth steps of Example 1, 3-methyl-4-carbonyl-3a,4,5,7a-tetrahydro-1H-pyrrole in a 50 mL three-necked flask under nitrogen atmosphere And [2,3-d]pyridazine-2carboxylic acid ethyl ester lc (443 mg, 2 mmd) was dissolved in anhydrous acetonitrile (15 mL), and anhydrous phosphorus oxychloride (0.372 mL) was slowly added dropwise with stirring at room temperature. , 4 mmol), after the completion of the dropwise addition, the mixture was heated to reflux to a yellow solid lc and gradually dissolved to a yellow solution, and reflux was continued for 30 minutes. The reaction solution was transferred to a 100 mL eggplant-shaped flask, and acetonitrile was distilled off under reduced pressure. Then, hexamethylene hydride (10 mL) was added to the reaction system, and the mixture was evaporated to dryness, and then, three times (removal of residual phosphorus oxychloride) was obtained. 3-Methyl-4-chloro-3a,4,5,7a-tetrahydro-1H-pyrrolo[2,3-d]pyridazine-2carboxylic acid ethyl ester Id (yellow solid). Isopropanol (15 mL) and 3-chloro-4-(3-fluorobenzyloxy)-phenylamine hydrochloride (0.576 g, 2.0 mmo) and triethylamine (0.3 mL, 2.2) were added directly to the eggplant flask. Mmmol), heated to reflux for 3 hours, the spot plate was traced until the starting material disappeared. The reaction solution was cooled to room temperature, cooled with ice-water-bath and stirred, and evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. 3-Methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid ethyl ester hydrochloride 8a (0.445 g, yellow solid). Yield: 45.4%. The solid was placed in a 50 mL eggplant-shaped flask, methanol (10 mL) was added, the pH was adjusted to 9 with concentrated aqueous ammonia, stirred at room temperature for 5 min, and filtered to give 4-[3-chloro-4-(3-fluoro Benzyloxy)-aniline]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid ethyl ester (yellow solid).
MS m/z (ESI): 455[M+ 1] 第二步 MS m/z (ESI): 455 [M+ 1] Step 2
4-[3-氯 -4-(3-氟苄氧) -苯胺 ]-3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-甲酸 按照本发明实施例 1第五步所述相同方式, 使用 4-(3-块基-苯胺) -3-甲基 -1H- 吡咯并 [2,3-d]哒嗪 -2-羧酸乙酯盐酸盐 8a作原料, 制得本标题产物 4-[3-氯 -4-(3- 氟苄氧) -苯胺 ]-3-甲基 - 1H-吡咯并 [2,3-d]哒嗪 -2-甲酸 8b。 4-[3-chloro-4-(3-fluorobenzyloxy)-aniline]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid according to Example 1 of the present invention In the same manner as described above, 4-(3-blockyl-aniline)-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid ethyl ester hydrochloride 8a was used as a starting material. The title product 4-[3-chloro-4-(3-fluorobenzyloxy)-aniline]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid 8b was obtained.
MS m/z (ESI): 427[MH- 1] MS m/z (ESI): 427 [MH-1]
第三步 third step
4-[3-氯 -4-(3-氟苄氧)-苯胺] -3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-(2-吡咯啶小基) -乙基) 甲酰胺 4-[3-Chloro-4-(3-fluorobenzyloxy)-aniline]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-(2-pyrrolidinesyl) - Ethyl) formamide
按照本发明实施例 1 第六步所述相同方式, 使用 4-[3-氯 -4-(3-氟苄氧) -苯 胺] -3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-甲酸 8b作原料, 进行该原料与 2-(B比咯啶 -1- 基) -乙胺的反应, 则得到标题产物 4-[3-氯 -4-(3-氟苄氧) -苯胺 ]-3-甲基 _1H-吡咯并 [2,3-d]哒嗪 -2-(2-吡咯啶小基) -乙基)甲酰胺 8 (80 mg, 黄色固体)。 产率: 17.3 %。 In the same manner as described in the sixth step of Example 1 of the present invention, 4-[3-chloro-4-(3-fluorobenzyloxy)-aniline]-3-methyl-1H-pyrrolo[2,3-d was used. The pyridazine-2-carboxylic acid 8b is used as a starting material to carry out the reaction of the starting material with 2-(B-pyrrolidin-1-yl)-ethylamine to give the title product 4-[3-chloro-4-(3-fluoro Benzyloxy)-aniline]-3-methyl_1H-pyrrolo[2,3-d]pyridazine-2-(2-pyrrolidinyl)-ethyl)carboxamide 8 (80 mg, yellow solid) . Yield: 17.3%.
MS m/z (ESI): 523[M+ 1] MS m/z (ESI): 523 [M+ 1]
LC-MS: 98,3 %。 LC-MS: 98,3 %.
'HNMR (400MHZ, DMSO-^): 58.87(S, lH), 7.89(S, 1H), 7.55(d, 1H), 7.45(m, 1H),
7.30(m, 2H), 7.17(m, 2H), 5.22(s, 2H), 3.43(t, 2H), 2.69(s, 3H), 2.63(t, 2H), 2.5 l(m, 4H), 1.71(s, 4H) 实施例 9 'HNMR (400MHZ, DMSO-^): 58.87 (S, lH), 7.89 (S, 1H), 7.55 (d, 1H), 7.45 (m, 1H), 7.30(m, 2H), 7.17(m, 2H), 5.22(s, 2H), 3.43(t, 2H), 2.69(s, 3H), 2.63(t, 2H), 2.5 l(m, 4H), 1.71(s, 4H) Example 9
重复本发明实施例 8第一步至第二步的反应, 使用上述第二步中所得到的化 合物 4-[3-氯 -4-(3-氟苄氧) -苯胺 ]-3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-甲酸 8b作原料, 按照本发明实施例 1 第六步所述相同方式进行该原料与 (3-吗啡啉 -4-基) -丙胺的 反应, 则得到标题产物 4-[3-氯 -4-(3-氟苄氧) -苯胺 ]-3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-(3-吗啡啉 -4-基-丙基)甲酰胺 9 (174 mg, 黄色固体)。 产率: 35%。 The reaction of the first step to the second step of Example 8 of the present invention was repeated, using the compound 4-[3-chloro-4-(3-fluorobenzyloxy)-aniline]-3-methyl obtained in the above second step. -1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid 8b as a starting material, and the starting material and (3-morphocolin-4-yl) are carried out in the same manner as described in the sixth step of the present invention. The reaction of propylamine gives the title product 4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamine]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-( 3-morpholine-4-yl-propyl)carboxamide 9 (174 mg, yellow solid). Yield: 35%.
MS m/z (ESI): 553[M+1] MS m/z (ESI): 553 [M+1]
1HNMR (400MHz, DMSO-t ,ί): 58.86(s, 1H), 7.89(s, 1H), 7.54(d, 1H), 7.46 (m, 1H), 7.30(m, 2H), 7.18(m, 2H), 5.22(s, 2H), 3.36(t, 4H), 3.33(t, 2H), 2.69(s, 3H), 2.34(m, 6H), 1.720(t, 2H) 1 H NMR (400MHz, DMSO-t, ί): 58.86 (s, 1H), 7.89 (s, 1H), 7.54 (d, 1H), 7.46 (m, 1H), 7.30 (m, 2H), 7.18 (m) , 2H), 5.22(s, 2H), 3.36(t, 4H), 3.33(t, 2H), 2.69(s, 3H), 2.34(m, 6H), 1.720(t, 2H)
, 实施例 10 , Example 10
4-Γ3-氯 -4-G-氟苄氧 苯胺 1-3-甲基 -1H-吡咯并 r2,3-dl哒嗪 -2-(2-二乙胺基-乙基)甲 4-Γ3-Chloro-4-G-fluorobenzyloxyaniline 1-3-methyl-1H-pyrrolo 2,3-dlpyridazine-2-(2-diethylamino-ethyl)
重复本发明实施例 8第一步至第二步的反应, 使用上述第二步中所得到的化 合物 4-[3-氯 -4-(3-氟苄氧) -苯胺 ]-3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-甲酸 8b作原料, 按照本发明实施例 1第六步所述相同方式进行该原料与二乙基乙二胺的反应,则 得到标题产物 4-[3-氯 -4-(3-氟苄氧) -苯胺 ]-3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-(2-二乙 胺基-乙基)甲酰胺 10 (234 mg, 浅黄色固体)。 产率: 34.9%。
MS m/z (ESI): 525[M+ 1] The reaction of the first step to the second step of Example 8 of the present invention was repeated, using the compound 4-[3-chloro-4-(3-fluorobenzyloxy)-aniline]-3-methyl obtained in the above second step. -1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid 8b as a starting material, the reaction of the starting material with diethylethylenediamine is carried out in the same manner as described in the sixth step of Example 1 of the present invention, The title product 4-[3-chloro-4-(3-fluorobenzyloxy)-aniline]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-(2-diethylamino) -ethyl)formamide 10 (234 mg, pale yellow solid). Yield: 34.9%. MS m/z (ESI): 525 [M+ 1]
1HNMR (400MHz, DMSO- ): 68.86(s, 1H), 7.88(s, 1H), 7.56(d, 1H), 7.46 (m, 1H), 7.30(m, 2H), 7.17(m, 2H), 5.22(s, 2H), 3.38(t, 2H), 2.70(s, 3H), 2.61(t, 2H), 2.54(m, 4H ), 0.99(t, 6H) 实施例 11 1HNMR (400MHz, DMSO-): 68.86 (s, 1H), 7.88 (s, 1H), 7.56 (d, 1H), 7.46 (m, 1H), 7.30 (m, 2H), 7.17 (m, 2H), 5.22(s, 2H), 3.38(t, 2H), 2.70(s, 3H), 2.61(t, 2H), 2.54(m, 4H), 0.99(t, 6H) Example 11
4-Γ3-氯 -4-(3-氟苄氧) -苯胺 1-3-甲基 -1H-吡咯并 f2,3-dl哒嗪 -2-(2-吡咯啶 -1 基-甲基- 吡咯啶 -1-基甲酰胺 4-Γ3-chloro-4-(3-fluorobenzyloxy)-aniline 1-3-methyl-1H-pyrrolo-f2,3-dl-pyridazine-2-(2-pyrrolidin-1yl-methyl- Pyrrolidin-1-ylformamide
重复本发明实施例 8第一步至第二步的反应, 使用上述第二步中所得到的化 合物 4-[3-氯 -4-(3-氟苄氧) -苯胺 ]-3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-甲酸 8b作原料, 按照本发明实施例 1第六步所述相同方式进行该原料与 2-吡咯啶 -1基-甲基-吡咯 啶的反应, 则得到标题产物 4-[3-氯 -4-(3-氟苄氧) -苯胺 ]-3-甲基 -1H-吡咯并 [2,3-d] 哒嗪 -2-(2-吡咯啶 -1基-甲基-吡咯啶 -1-基)甲酰胺 11 (100 mg,橙黄色固体)。产率: 18%。 The reaction of the first step to the second step of Example 8 of the present invention was repeated, using the compound 4-[3-chloro-4-(3-fluorobenzyloxy)-aniline]-3-methyl obtained in the above second step. -1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid 8b as a starting material, and the starting material and 2-pyrrolidin-1yl-methyl- are carried out in the same manner as described in the sixth step of Example 1 of the present invention. The reaction of pyrrolidine gives the title product 4-[3-chloro-4-(3-fluorobenzyloxy)-aniline]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2- (2-Pyrrolidin-1yl-methyl-pyrrolidin-1-yl)carboxamide 11 (100 mg, orange-yellow solid). Yield: 18%.
MS m/z (ESI): 563[ + 1] MS m/z (ESI): 563[ + 1]
1HNMR (400MHz, DMSO-^): 58.84(s, 1H), 7.90 (s, 1H), 7.55 (d, 1H), 7.46(m, 1H), 7.30(m, 2H), 7.16(m, 2H), 5.22(s, 2H), 3.46〜1.15(m, 20H) 实施例 12 1 H NMR (400MHz, DMSO-^): 58.84 (s, 1H), 7.90 (s, 1H), 7.55 (d, 1H), 7.46 (m, 1H), 7.30 (m, 2H), 7.16 (m, 2H) ), 5.22(s, 2H), 3.46~1.15(m, 20H) Example 12
4_[3-氯 -4-(3-氟苄氧) -苯胺 ]-3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-(4- (吗啡啉 -4-基) -哌 啶基)甲酰胺 4-(3-Chloro-4-(3-fluorobenzyloxy)-aniline]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-(4-(morpholinolin-4-yl) )-piperidinyl)carboxamide
重复本发明实施例 8第一步至第二步的反应, 使用上述第二步中所得到的化
合物 4-[3-氯 -4-(3-氟苄氧) -苯胺 ]-3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-甲酸 8b作原料, 按照本发明实施例 1第六步所述相同方式进行该原料与 4- (吗啡啉 -4-基) -哌啶的 反应, 则得到标题产物 4-[3-氯 -4-(3-氟苄氧) -苯胺 ]-3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2_(4- (吗啡啉 -4-基) -哌啶基)甲酰胺 12 (31 mg, 橙黄色固体)。 产率: Ί%。 Repeat the reaction of the first step to the second step of the embodiment 8 of the present invention, using the chemical obtained in the second step above. 4-[3-chloro-4-(3-fluorobenzyloxy)-aniline]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid 8b as a starting material, according to the present The reaction of the starting material with 4-(morpholinolin-4-yl)-piperidine was carried out in the same manner as in the sixth step of the invention, to give the title product 4-[3-chloro-4-(3-fluorobenzyloxy). - aniline]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2_(4-(morpholine-4-yl)-piperidinyl)carboxamide 12 (31 mg, orange yellow solid). Yield: Ί%.
MS m/z (ESI): 579[M+ 1] MS m/z (ESI): 579 [M+ 1]
!HNMR (400MHz, OMSO-d6): 58.83(s, 1H), 7.88(s, 1H), 7.54(d, 1H), 7.46 (m, 1H), 7.30(m, 2H), 7.16(m, 2H), 5.21(s, 2H), 3.57(s, 4H), 3.45(s, 9H), 2.45(s, 3H), 1.85(s, 2H),1.36(m, 2H) !HNMR (400MHz, OMSO-d 6 ): 58.83(s, 1H), 7.88(s, 1H), 7.54(d, 1H), 7.46 (m, 1H), 7.30(m, 2H), 7.16(m, 2H), 5.21(s, 2H), 3.57(s, 4H), 3.45(s, 9H), 2.45(s, 3H), 1.85(s, 2H), 1.36(m, 2H)
, 实施例 13 . ' ■ , Example 13 . ' ■
4-[3-氯 -4-(3-氟苄氧) -苯胺 ]-3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-(2-吗啡啉 -4-基-乙基) 甲酰胺 4-[3-Chloro-4-(3-fluorobenzyloxy)-aniline]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-(2-morphinolin-4-yl) -ethyl) formamide
重复本发明实施例 8第一步至第二步的反应, 使用上述第二步中所得到的化 合物 4-[3-氯 -4-(3-氟苄氧) -苯胺 ]-3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-甲酸 8b作原料, 按照本发明实施例 1第六步所述相同方式进行该原料与 2-吗啡啉 -4-基-乙胺的反 应, 则得到标题产物 4-[3-氯 -4-(3-氟苄氧) -苯胺 ]-3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-(2-吗啡啉 -4-基-乙基)甲酰胺 13 (176 mg, 黄色固体)。 产率: 30.2%。 The reaction of the first step to the second step of Example 8 of the present invention was repeated, using the compound 4-[3-chloro-4-(3-fluorobenzyloxy)-aniline]-3-methyl obtained in the above second step. -1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid 8b as a starting material, and the starting material and 2-morphinolin-4-yl-ethylamine are carried out in the same manner as described in the sixth step of Example 1 of the present invention. The title product was obtained as the title product 4-[3-chloro-4-(3-fluorobenzyloxy)-aniline]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-(2 - morphinolin-4-yl-ethyl)carboxamide 13 (176 mg, yellow solid). Yield: 30.2%.
MS m/z (ESI): 539[M+ 1] MS m/z (ESI): 539 [M+ 1]
'HNMR (400MHZ, OUSO-d6): 58.87(s, 1H), 7.8937(s, 1H), 7.5547(d, 1H), 7.4 (m, 1H), 7.30(m, 2H), 7.17(m, 2H), 5.22(s, 2H), 3.59(t, 4H -), 3.44(t, 2H), 2.7 l(s, 3H), 2.49 (t, 2H), 2.40 (m, 4H) 实施例 14 'HNMR (400MHZ, OUSO-d 6 ): 58.87 (s, 1H), 7.8937 (s, 1H), 7.5547 (d, 1H), 7.4 (m, 1H), 7.30 (m, 2H), 7.17 (m, 2H), 5.22(s, 2H), 3.59(t, 4H -), 3.44(t, 2H), 2.7 l(s, 3H), 2.49 (t, 2H), 2.40 (m, 4H) Example 14
4_Γ3-氯 _4_〔3-氟苄氧) -苯胺 1-3-甲基 -1H-吡咯并 r2,3-dl哒嗪 -2-基-二乙胺基甲酸甲 4 _ Γ3 - chloro _4_ [3 - fluoro-benzyloxy) - phenylamine Methyl 1-3- -1H- pyrrolo r2,3-dl pyridazin-2-yl - diethylamino carboxylic acid
4-[3-氯 -4-(3-氟苄氧) -苯胺 ]-3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-甲醇 氮气氛下, 将四氢锂铝 (120 mg, 3 mmol)溶解于四氢呋喃 (30 mL)中, 搅拌均 匀,反应体系放出一些气泡,备用。而后将 4-[3-氯 -4-(3-氟苄氧) -苯胺 ]-3-甲基 -1H- 吡咯并 [2,3-d]哒嗪 -2-羧酸乙酯 8a (700 mg, 1.5 mmol)混溶于四氢呋喃 (70 mL)中, 并将此悬浮液慢慢滴加入上述四氧铝锂的四氢呋喃溶液中,反应体系由原来的灰 色浑悬液立刻变为浅绿色浑悬液, 继续回流反应 3.5小时, 可见绿色浑悬液慢慢 变为土黄色浑悬液, 点板跟踪至反应结束。 加水淬灭反应, 饱和食盐水洗涤, 有 机层干燥, 过滤, 滤液减压浓缩, 得标题产品 4-[3-氯 -4-(3-氟苄氧) -苯胺 ]-3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-甲醇 14a (499 mg), 产率 81 %。 4-[3-chloro-4-(3-fluorobenzyloxy)-aniline]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-methanol under nitrogen atmosphere, tetrahydrogen lithium Aluminum (120 mg, 3 mmol) was dissolved in tetrahydrofuran (30 mL), stirred well, and the reaction system released some bubbles for use. Then 4-[3-chloro-4-(3-fluorobenzyloxy)-aniline]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid ethyl ester 8a (700 Mg, 1.5 mmol) was dissolved in tetrahydrofuran (70 mL), and the suspension was slowly added dropwise to the above tetrahydrofuran solution of lithium tetraoxide. The reaction system immediately changed from the original gray sputum suspension to a light green suspension. The liquid was continuously refluxed for 3.5 hours, and it was found that the green sputum suspension slowly turned into a khaki suspension, and the spot was traced until the end of the reaction. The reaction mixture was quenched with EtOAc (EtOAc m.) (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH - Pyrrolo[2,3-d]pyridazine-2-methanol 14a (499 mg), yield 81%.
MS m/z (ESI): 413[M+ 1] MS m/z (ESI): 413 [M+ 1]
1HNMR (400MHz, DMSO-c¾: 68.80(s, 1H), 7.88(s, 1H), 7.52(d, 1H), 7.45 (m, 1H), 7.30(m, 2H), 7, 17(m, 2H), 5.21(s, 2H), 4.62 ( s, 2H), 2.42(s, 3H) 第二步 1 H NMR (400 MHz, DMSO-c3⁄4: 68.80 (s, 1H), 7.88 (s, 1H), 7.52 (d, 1H), 7.45 (m, 1H), 7.30 (m, 2H), 7, 17 (m, 2H), 5.21(s, 2H), 4.62 ( s, 2H), 2.42(s, 3H)
4— [3-氯 -4-(3-氟苄氧) -苯胺 ]-3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-基-二乙胺基甲酸甲 酯 4 — [3-Chloro-4-(3-fluorobenzyloxy)-aniline]-3-methyl-1H-pyrrolo[2,3-d]pyridazin-2-yl-diethylaminocarbamate
在一个 50 mL的茄形瓶中, 将 4-[3-氯 -4-(3-氟苄氧) -苯胺 ]-3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-甲醇 14a (206 mg, 0.5 mmol)搅拌下溶解于 N'N-二甲基甲酰胺 (5 mL)
中, 室温条件下称取 55%~65%氢化钠固体 (26 mg, 0.6 mmol), 慢慢加入预制的 前溶液中, 室温搅拌 5分钟。 而后, 慢慢滴加二乙胺甲酰氯 (82 mg, 0.6 mmol, ) 的 N,N-二甲基甲酰胺溶液 (5 mL), 溶液由黄色变为棕红色, 点板显示此吋原料 已大部分消失, 持续在室温条件下搅拌 3小时。停止反应, 将反应液慢慢倒入冰 水中,有固体产生,继续搅拌 30分钟,过滤,得到标题产物 4-[3-氯 -4-(3-氟苄氧) - 苯胺] -3-甲基 -1H吡咯并 [2,3-d]哒嗪 -2-基 -二乙胺基甲酸甲酯 14 (195 mg, 黄色固 体)。 产率 76 %。 In a 50 mL eggplant-shaped flask, 4-[3-chloro-4-(3-fluorobenzyloxy)-aniline]-3-methyl-1H-pyrrolo[2,3-d]pyridazine- 2-Methanol 14a (206 mg, 0.5 mmol) dissolved in N'N-dimethylformamide (5 mL) The 55%~65% sodium hydride solid (26 mg, 0.6 mmol) was weighed at room temperature and slowly added to the pre-formed pre-solution and stirred at room temperature for 5 minutes. Then, a solution of diethylformyl chloride (82 mg, 0.6 mmol, ) in N,N-dimethylformamide (5 mL) was added dropwise, and the solution changed from yellow to brownish red. Most disappeared and was continuously stirred at room temperature for 3 hours. The reaction was stopped, and the reaction solution was poured slowly into ice water, and a solid was formed, stirring was continued for 30 minutes, and filtered to give the title product 4-[3-chloro-4-(3-fluorobenzyloxy)-aniline]-3- Methyl-1H pyrrolo[2,3-d]pyridazin-2-yl-diethylammoniumcarboxylate 14 (195 mg, yellow solid). The yield was 76%.
MS m/z (ESI): 512[M+1] MS m/z (ESI): 512 [M+1]
'HNMR (400MHZ ,DMSO- ): 58.79(s, 1H), 7.88(s, 1H), 7.521 (d, 1H), 7.45 (m, 1H), 7.30(m, 2H), 7.17(m, 2H), 5.21(s, 2H), 4.62( s, 2H), 2.42(s, 3H) 实施例 15 'HNMR (400MHZ, DMSO-): 58.79 (s, 1H), 7.88 (s, 1H), 7.521 (d, 1H), 7.45 (m, 1H), 7.30 (m, 2H), 7.17 (m, 2H) , 5.21(s, 2H), 4.62( s, 2H), 2.42(s, 3H) Example 15
4_Γ3_氯 _4-(3-氟苄氧) -苯胺 甲基小甲基 -B比咯并 l"2,3-dl哒嗪 -2-(2-二乙胺基-乙基) 甲酰胺 4 _Γ3_Chloro- 4- (3 -fluorobenzyloxy)-anilinemethyl-small methyl-B-pyrrolo-l"2,3-dl-pyridazine-2-(2-diethylamino-ethyl) A Amide
1,3,5-三甲基-吡咯 -2,4-二羧酸乙酯 1,3,5-trimethyl-pyrrole-ethyl 2,4-dicarboxylate
氮气氛下, 在 50 mL茄形瓶中, 将 55%〜65%氢化钠 (240 mg, 5.5 mmol)搅拌
下溶解于 N'N-二甲基甲酰胺 (5 mL),慢慢加入原料 3,5-二甲基 -1H-吡咯 -2,4-二羧 酸乙酯 la (1.196 g, 5 mmol), 室温下搅拌 10分钟, 而后加入碘甲垸 (2.7 mL, 53 mmol), 室温搅拌过夜, 点板跟踪反应结束。 次日, 将反应液倒入水中, 有白色 固体析出, 过滤, 固体红外烘千, 得到标题产物 15a (1.086 g, 白色固体)。 产率 86%。 Stir 55%~65% sodium hydride (240 mg, 5.5 mmol) in a 50 mL eggplant bottle under nitrogen Dissolved in N'N-dimethylformamide (5 mL) and slowly added the crude ethyl 3,5-dimethyl-1H-pyrrole-2,4-dicarboxylate la (1.196 g, 5 mmol) Stir at room temperature for 10 minutes, then add methyl iodide (2.7 mL, 53 mmol), stir at room temperature overnight, and click to stop the reaction. On the next day, the reaction mixture was poured into water, a white solid was evaporated, filtered, and then evaporated to give the title product 15a (1.086 g, white solid). The yield was 86%.
MS m/z (ESI): 254[M- 1] 第二步 MS m/z (ESI): 254 [M-1] second step
5-甲酰基 -3-甲基 -1 -甲基-吡咯 -2,4-二羧酸乙酯 按照本发明实施例 1第一步所述相同方式, 使用上述第一步中所得到的化合 物 1,3,5-三甲基 -吡咯 -2,4-二羧酸乙酯 15a作原料,进行该原料与硝酸铈铵的反应, 则得到标题产物 5-甲酰基 -3-甲基 -1-甲基 -吡咯 -2,4-二羧酸乙酯 15b (5.283 g)。 产 率 45 %。 Ethyl 5-formyl-3-methyl-1-methyl-pyrrole-2,4-dicarboxylate The compound obtained in the above first step was used in the same manner as described in the first step of Example 1 of the present invention. 1,3,5-trimethyl-pyrrole-2,4-dicarboxylic acid ethyl ester 15a is used as a raw material, and the reaction of the starting material with ammonium cerium nitrate is carried out to obtain the title product 5-formyl-3-methyl-1. Methyl-pyrrole-2,4-dicarboxylic acid ethyl ester 15b (5.283 g). The yield is 45 %.
MS m/z (ESI): 268[M+ 1] MS m/z (ESI): 268 [M+ 1]
IHNMR (400MHz, COC\3-d): δ 10.376(s, 1H), 9,915(s, 1H), 4.37(m, 4H), 4.17(s, 3H): 2.49(s, 3H), 1.40(q, 6H) I HNMR (400MHz, COC\ 3 -d): δ 10.376(s, 1H), 9,915(s, 1H), 4.37(m, 4H), 4.17(s, 3H) : 2.49(s, 3H), 1.40( q, 6H)
第三步 third step
3-甲基 -4-羰基 -3a,4,5,7a-四氢 -1-甲基-吡咯并 [2,3-d]哒嗪 -2羧酸乙酯 按照本发明实施例 1第二步所述相同方式,使用上述第二步中所得到的化合 物 5-甲酰基 -3-甲基小甲基 -吡咯 -2,4-二羧酸乙酯 15b (3.24 g, 12 mmol)作原料, 进行该原料与水合肼 (0.72 g, 12 mmol)的反应, 则得到标题产物 3-甲基 -4-羰基 -3a,4,5,7a-四氢小甲基-吡咯并 [2,3-d]哒嗪 -2羧酸乙 15c (2. 272 g)。 产率 79.3 %。 Ethyl 3-methyl-4-carbonyl-3a,4,5,7a-tetrahydro-1-methyl-pyrrolo[2,3-d]pyridazine-2carboxylate according to Example 1 of the present invention In the same manner as described in the above step, the compound 5-formyl-3-methyl small methyl-pyrrole-2,4-dicarboxylate 15b (3.24 g, 12 mmol) obtained in the above second step was used as a starting material. The reaction of the starting material with hydrazine hydrate (0.72 g, 12 mmol) afforded the title product 3-methyl-4-carbonyl-3a,4,5,7a-tetrahydro-s-methyl-pyrrolo[2,3 -d]pyridazine-2carboxylic acid ethyl 15c (2.227 g). The yield was 79.3 %.
MS m/z (ESI): 236[M+ 1] MS m/z (ESI): 236 [M+ 1]
'HNMR (400MHZ, DMSO- ): δ 8.400(s, 1H), 4.341 (q, 2H, J=7.2 Hz), 3.979(s, 3H,), 2.620(s, 3H), 1.351(t, 3H, J=7.2 Hz) 第四步 'HNMR (400MHZ, DMSO-): δ 8.400(s, 1H), 4.341 (q, 2H, J=7.2 Hz), 3.979(s, 3H,), 2.620(s, 3H), 1.351(t, 3H, J=7.2 Hz) Step 4
4-[3-氯 -4-(3-氟苄氧) -苯胺 ]-3-甲基小甲基-吡咯并 [2,3-d]哒嗪 -2-羧酸乙酯盐酸盐 按照本发明实施例 1第三、 四步所述相同方式反应, 使用上述第三步中所得 到的化合物 3-甲基 -4-羰基 -3a,4,5,7a-四氢 -1-甲基-吡咯并 [2,3-d]哒嗪 -2羧酸乙酯 15c 作原料, 得到本标题产物 4-[3-氯 -4-(3-氟苄氧) -苯胺 ]-3-甲基 -1-甲基-吡咯并 [2,3-d]哒嗪 -2-羧酸乙酯盐酸盐 15d (1. 642 g, 白色固体)。 产率 79.7%。 4-[3-chloro-4-(3-fluorobenzyloxy)-aniline]-3-methylsuccinyl-pyrrolo[2,3-d]pyridazine-2-carboxylic acid ethyl ester hydrochloride In the same manner as described in the third and fourth steps of the present invention, the compound obtained in the above third step is 3-methyl-4-carbonyl-3a,4,5,7a-tetrahydro-1-methyl. - pyrrolo[2,3-d]pyridazine-2carboxylic acid ethyl ester 15c as a starting material to give the title product 4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamine]-3-methyl 1-methyl-pyrrolo[2,3-d]pyridazine-2-carboxylic acid ethyl ester hydrochloride 15d (1. 642 g, white solid). The yield was 79.7%.
MS m/z (ESI): 468[M+ 1]
第五步 MS m/z (ESI): 468 [M+ 1] the fifth step
4-[3-氯 -4-(3-氟苄氧) -苯胺 ]-3-甲基小甲基-吡咯并 [2,3-d]哒嗪 -2-羧酸 按照本发明实施例 i第五步所述相同方式反应, 使用上述第四步中所得到的 化合物 4-[3-氯 -4-(3-氟苄氧) -苯胺 ]-3-甲基 -1-甲基-吡咯并 [2,3-d]哒嗪 -2-羧酸乙酯 盐酸盐作原料, 得到本标题产物 4-[3-氯 -4-(3-氟苄氧) -苯胺 ]-3-甲基 -I-甲基-吡咯 并 [2,3-d]哒嗉 -2-羧酸 15e(1.410 g, 黄色固体)。 4-[3-chloro-4-(3-fluorobenzyloxy)-aniline]-3-methylsuccinyl-pyrrolo[2,3-d]pyridazine-2-carboxylic acid according to the present invention i In the same manner as described in the fifth step, the compound 4-[3-chloro-4-(3-fluorobenzyloxy)-aniline]-3-methyl-1-methyl-pyrrole obtained in the above fourth step was used. And [2,3-d]pyridazine-2-carboxylic acid ethyl ester hydrochloride as a starting material, the title product 4-[3-chloro-4-(3-fluorobenzyloxy)-aniline]-3-methyl Base-I-methyl-pyrrolo[2,3-d]indole-2-carboxylic acid 15e (1.410 g, yellow solid).
MS m/z (ESI): 441 [M+1] 第六步 MS m/z (ESI): 441 [M+1] Step 6
4-[3-氯 -4-(3-氟苄氧) -苯胺 ]-3-甲基 -1-甲基-吡咯并 [2,3-d]哒嗪 -2-(2-二乙胺基-乙基) 甲酰胺 4-[ 3 -chloro-4-(3-fluorobenzyloxy)-aniline]-3-methyl-1-methyl-pyrrolo[2,3-d]pyridazine-2-(2-diethylamine) Base-ethyl) formamide
按照本发明实施例 1第六步所述相同方式反应, 使用上述第五步中所得到的 化合物 4-[3-氯- 4-(3-氟苄氧) -苯胺 ]-3-甲基 -1-甲基-吡咯并 [2,3-d]哒嗪 -2-羧酸 15e 作原料,得到本标题产物 4-[3-氯 -4-(3-氟苄氧) -苯胺 ]-3-甲基 -1-甲基-吡咯并 [2,3-d] 哒嗪 -2-(2-二乙胺基-乙基)甲酰胺 15 (41 mg, 黄色固体)。 In the same manner as described in the sixth step of Example 1 of the present invention, the compound 4-[3-chloro-4-(3-fluorobenzyloxy)-aniline]-3-methyl- obtained in the above fifth step was used. 1-methyl-pyrrolo[2,3-d]pyridazine-2-carboxylic acid 15e as a starting material to give the title product 4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamine]-3 Methyl-1-methyl-pyrrolo[2,3-d]pyridazine-2-(2-diethylamino-ethyl)carboxamide 15 (41 mg, yellow solid).
MS m/z (ESI): 539[M+ 1] MS m/z (ESI): 539 [M+ 1]
'HNMR (400MHZ, DMSO- ): 59.06(s, 1H), 7.899(d, 1H), 7.56(dd, 1H), 7.45 (m, 1H), 7.30(m, 2H), 7.17(m, 2H), 5.22(s, 2H), 3.83(s, 3H), 3.39(t, 2H), 2.45(m, 9H), 0.990(t, 6H) 实施例 16 'HNMR (400MHZ, DMSO-): 59.06 (s, 1H), 7.899 (d, 1H), 7.56 (dd, 1H), 7.45 (m, 1H), 7.30 (m, 2H), 7.17 (m, 2H) , 5.22(s, 2H), 3.83(s, 3H), 3.39(t, 2H), 2.45(m, 9H), 0.990(t, 6H) Example 16
4-Γ3-氯 -4-( -氟苄氧) -苯胺】-3-甲基 -1-甲基-吡咯并 f2,3-dl哒壞 -2- 2-吡咯啶 -i-基-乙 基)甲酰胺 ' 4-Γ3-chloro-4-(-fluorobenzyloxy)-aniline]-3-methyl-1-methyl-pyrrolof2,3-dl哒 bad-2- 2-pyrrolidine-i-yl-B Carboxamide
重复本发明实施例 15第一步至第五步的反应, 使用上述第五步中所得到的 化合物 4-[3-氯 -4-(3-氟苄氧) -苯胺 ]-3-甲基 -1-甲基-吡咯并 [2,3-d]哒嗪 -2-羧酸 15e 作原料, 按照本发明实施例 15第六步所述相同方式进行该原料与 2- (吡咯啶 -1- 基) -乙胺的反应,则得到标题产物 4-[3-氯 -4-(3-氟苄氧) -苯胺 ]-3-甲基 -1-甲基-吡咯 并 [2,3-d]哒嗪 -2-(2-吡咯啶 -1-基) -乙基)甲酰胺 16 (24 mg, 黄色固体)。 The reaction of the first step to the fifth step of Example 15 of the present invention was repeated, and the compound 4-[3-chloro-4-(3-fluorobenzyloxy)-aniline]-3-methyl obtained in the above fifth step was used. 1-methyl-pyrrolo[2,3-d]pyridazine-2-carboxylic acid 15e as a starting material, the starting material and 2-(pyrrolidin-1) were carried out in the same manner as described in the sixth step of Example 15 of the present invention. -yl)-ethylamine reaction to give the title product 4-[3-chloro-4-(3-fluorobenzyloxy)-aniline]-3-methyl-1-methyl-pyrrolo[2,3- d] pyridazine-2-(2-pyrrolidin-1-yl)-ethyl)carboxamide 16 (24 mg, yellow solid).
S m/z (ESJ): 537[M+1]
¾ M (400MHz, DMSO-^): 9.07(s, 1H), 7.89(s, 1H), 7.55(m, 1H), 7.45(m, 1H), 7.30(m, 2H), 7.16(m, 2H), 5.22(s, 2H), 3.84(s, 3H), 3.55(ί, 2H), 3.10 (m, 6H), 2.55(s, 3H), U8(s,4H) . 实施例 17 S m/z (ESJ): 537[M+1] 3⁄4 M (400MHz, DMSO-^): 9.07(s, 1H), 7.89(s, 1H), 7.55(m, 1H), 7.45(m, 1H), 7.30(m, 2H), 7.16(m, 2H) ), 5.22(s, 2H), 3.84(s, 3H), 3.55(ί, 2H), 3.10 (m, 6H), 2.55(s, 3H), U8(s, 4H). Example 17
4-|~3-氯 -4- 3-氟苄氧 )-苯胺 1, 3-二甲基-吡咯并「2,3-cH哒嗪 -2 (2-吗啡啉 -4-基-乙 基) -甲酰胺 4-|~3-Chloro-4- 3-fluorobenzyloxy)-aniline 1,3-dimethyl-pyrrolo-2,3-cHpyridazine-2 (2-morpholine-4-yl-ethyl ) -carboxamide
重复本发明实施例 15第一步至第五步的反应, 使用上述第五步中所得到的 化合物 4-[3-氯 -4-(3-氟苄氧) -苯胺 ]-3-甲基 -1-甲基-吡咯并 [2,3-d]哒嗪 -2-羧酸 15e 作原料, 按照本发明实施例 15第六步所述相同方式进行该原料与 2-吗啡啉 -4-基 -乙胺的反应, 则得到标题产物 4-[3-氯 -4-(3-氟苄氧) -苯胺 ]-1 , 3-二甲基-吡咯并 [2,3-d]哒嗪 -2-(2-吗啡啉 -4-基-乙基) -甲酰胺 17 (223 mg, 黄色固体)。产率: 51%。 MS m/z (ESI): 554[M+ 1] The reaction of the first step to the fifth step of Example 15 of the present invention was repeated, using the compound 4-[3-chloro-4-(3-fluorobenzyloxy)-aniline]-3-methyl obtained in the above fifth step. 1-methyl-pyrrolo[2,3-d]pyridazine-2-carboxylic acid 15e as a starting material, the starting material and 2-morpholine-4- are carried out in the same manner as described in the sixth step of Example 15 of the present invention. The reaction of the base-ethylamine gives the title product 4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamine]-1,3-dimethyl-pyrrolo[2,3-d]pyridazine 2-(2-morpholine-4-yl-ethyl)-carboxamide 17 (223 mg, yellow solid). Yield: 51%. MS m/z (ESI): 554[M+ 1]
!HNMR (400MHz, DMSO-c d): 7.90(s, 1H), 7.66(m, 1H), 7.33(m, 2H), 7.20(m, 2H), 7.16(m, 2H), 5.21(s, 2H), 4.23(m, 4H), 3.84(s, 3H), 3.55(t, 2H), 3.10 (m, 4H), 2.53(s, 3H), 2.05(m,4H) 实施例 18 ! HNMR (400MHz, DMSO-c d): 7.90 (s, 1H), 7.66 (m, 1H), 7.33 (m, 2H), 7.20 (m, 2H), 7.16 (m, 2H), 5.21 (s, 2H), 4.23(m, 4H), 3.84(s, 3H), 3.55(t, 2H), 3.10 (m, 4H), 2.53 (s, 3H), 2.05 (m, 4H) Example 18
443-氯 -4-(3-氟-苄氧基 苯氨基 3-甲基 -1H-吡咯并 [2,3-dl哒嗪 -2-羧酸 f2-i4-甲 基-哌嗪小基 V乙基 1-甲酰胺 443-chloro-4-(3-fluoro-benzyloxyphenylamino 3-methyl-1H-pyrrolo[2,3-dloxazin-2-carboxylic acid f2-i4-methyl-piperazine small group V Ethyl 1-carboxamide
重复本发明实施例 8第一步至第二步的反应,使用上述第二步中所得到的化 合物 4-[3-氯 -4-(3-氟苄氧) -笨胺 ]-3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-甲酸 8b作原料, 按照本发明实施例 1第六步所述相同方式进行该原料与 2-(4-甲基 -哌嗪 -1-基) -乙
胺的反应, 则得到标题产物 4-[3-氯 -4-(3-氟-苄氧基) -笨氨基: 1- 3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸 [2-(4-甲基 -呢嗪 -1-基) -乙基] -甲酰胺 18 (90 mg, 浅黄色固体)。 产率: 15%。 The reaction of the first step to the second step of Example 8 of the present invention was repeated, and the compound 4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamine]-3-methyl obtained in the above second step was used. The base-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid 8b is used as a starting material, and the starting material is 2-(4-methyl-piperazine) in the same manner as described in the sixth step of the present invention. -1-base) - B The reaction of the amine gives the title product 4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino: 1- 3-methyl-1H-pyrrolo[2,3-d]pyridazine 2-carboxylic acid [2-(4-methyl-heptazin-1-yl)-ethyl]-carboxamide 18 (90 mg, pale yellow solid). Yield: 15%.
MS m/z (ESI): 553[M+1] MS m/z (ESI): 553 [M+1]
]HNMR (400MHz, DMSO-ί/ί): 7.97(s, 1H), 7.66(m, 1H), 7.54(m, 1H), 7.43(m, 1H), 7.18(m, 2H), 7.15(m, 2H), 5.22(s, 2H), 4.23 (m, 4H), 3.43(q, 2H), 2.71(s, 3H), 2.49 (m, 4H), 2.34(m,2H), 2.16(s, 3H) 实施例 19 ] HNMR (400MHz, DMSO-ί / ί): 7.97 (s, 1H), 7.66 (m, 1H), 7.54 (m, 1H), 7.43 (m, 1H), 7.18 (m, 2H), 7.15 (m , 2H), 5.22(s, 2H), 4.23 (m, 4H), 3.43(q, 2H), 2.71(s, 3H), 2.49 (m, 4H), 2.34(m,2H), 2.16(s, 3H) Example 19
4-Γ3-氯 -4-( -氟-苄氧基) -苯氨基 1- 3-甲基 -1H-吡咯并 r2,3-dl哒嗪 -2-羧酸 Γ2-(4-甲 基-哌嚷小基) -丙基 1-甲酰胺 4-Γ3-chloro-4-(-fluoro-benzyloxy)-phenylamino-1- 3-methyl-1H-pyrrolo-r2,3-dl-pyridazine-2-carboxylic acid hydrazine 2-(4-methyl- Piperidinyl) -propyl 1-carboxamide
重复本发明实施例 8第一步至第二步的反应,使用上述第二步中所得到的化 合物 4-[3-氯 -4-(3-氟苄氧) -苯胺 ]-3-甲基 -1Η-吡咯并 [2,3-d]哒嗪 -2-甲酸 8b作原料, 按照本发明实施例 1第六步所述相同方式进行该原料与 2-(4-甲基 -哌嗪 -1-基) -丙 胺的反应, 则得到标题产物 4-[3-氯斗 (3-氟-节氧基) -苯氨基] - 3-甲§:111-吡咯并 [2,3-d]哒嗪 -2-羧酸 [2-(4-甲基 -哌嗪 -1-基) -丙基] -甲酰胺 19 (214 mg, 浅黄色固 体)。 产率: 35%。 The reaction of the first step to the second step of Example 8 of the present invention was repeated, and the compound 4-[3-chloro-4-(3-fluorobenzyloxy)-aniline]-3-methyl obtained in the above second step was used. -1Η-pyrrolo[2,3-d]pyridazine-2-carboxylic acid 8b as a starting material, the starting material and 2-(4-methyl-piperazine-in the same manner as described in the sixth step of Example 1 of the present invention. The reaction of 1-yl)-propylamine gives the title product 4-[3-Chloro(3-fluoro-hydroxy)-phenylamino]-3-methyl § : 111-pyrrolo[2,3-d] Pyridazine-2-carboxylic acid [2-(4-methyl-piperazin-1-yl)-propyl]-carboxamide 19 (214 mg, pale yellow solid). Yield: 35%.
MS m/z (ESI): 567[M+ 1] MS m/z (ESI): 567[M+ 1]
'HNMR (400MHz, DMSO-i¾: 7.97(s, 1H), 7.56(d, 2H), 7.30(m, 1H), 7.18(m, 2H), 7.15(m, 2H), 5.26(s, 2H), 2.89(s, 3H), 2.38(m, 8H), 2.21(s, 3H), 1.87(m, 4H), 1.26(m, 2H) 'HNMR (400MHz, DMSO-i3⁄4: 7.97(s, 1H), 7.56(d, 2H), 7.30(m, 1H), 7.18(m, 2H), 7.15(m, 2H), 5.26(s, 2H) , 2.89(s, 3H), 2.38(m, 8H), 2.21(s, 3H), 1.87(m, 4H), 1.26(m, 2H)
实施例 20Example 20
-『l-(3-氟苄基) -1H-吲唑 -5-氨基 1-3-甲基 -1H-吡咯并 哒嗪 -(2-甲氧乙基)甲酰
-"1-(3-Fluorobenzyl)-1H-indazole-5-amino1-3-methyl-1H-pyrrolopyridazine-(2-methoxyethyl)formyl
第一步 First step
4-〖l-(3-氟苄基) -1H-吲唑 -5-氨基] -3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸乙酯盐酸 按照实施例 1第三、四步所述方法, 氮气氛下, 在一个 50 mL的三颈瓶中, 将 3-甲基 -4-羰基 -3a,4,5,7a-四氢 -1H-吡咯并 [2,3-d]哒嗪 -2羧酸乙酯 lc(1.264 g, 1.2 mmol)溶解于无水乙腈 (15 mL)中, 室温搅拌下缓慢滴加无水三氯氧磷 (0.223 mL, 2.4 mmol)滴加完毕后, 加热回流至黄色固体 lc逐渐反应溶解为黄色溶液, 继 回流 30分钟。 将反应液移至 100 mL的茄形瓶中, 减压旋蒸除去乙腈, 再向反 应体系中加入正己垸 (10 mL), 减压旋干, 重复三次 (去除残余三氯氧磷)。而后在 此茄形瓶中加入异丙醇 (15 mL)和 1-(3-氟苄基 )-5-氨基 -1H-吲唑 (258 mg, 1.07 mmd)以及三乙胺, 加热回流 3 小时, 点板跟踪反应至原料消失。 将反应液冷却 至室温, 继续用冰水浴冷却并搅拌, 有黄色固体产生, 减压抽滤, 固体用少量的 异丙醇洗涤, 干燥, 得到标题产物 4-[1-(3-氟苄基 )-1Η-吲唑 -5-氨基] -3-甲基 -1H- 吡咯并 [2,3-d]哒嗪 -2-羧酸乙酯盐酸盐 20a (0.329 g, 浅黄色固体)。 产率 66.5 %。 MS m/z (ESI): 445[M+ 1] 4-[1-(3-Fluorobenzyl)-1H-indazole-5-amino]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid ethyl ester hydrochloride Example 1 Method of the third and fourth steps, 3-methyl-4-carbonyl-3a,4,5,7a-tetrahydro-1H-pyrrole in a 50 mL three-necked flask under nitrogen atmosphere And [2,3-d]pyridazine-2carboxylic acid ethyl ester lc (1.264 g, 1.2 mmol) was dissolved in anhydrous acetonitrile (15 mL), and anhydrous phosphorus oxychloride (0.223 mL) was slowly added dropwise with stirring at room temperature. After 2.4 g), the mixture was heated to reflux to a yellow solid lc and gradually dissolved to a yellow solution, followed by reflux for 30 minutes. The reaction solution was transferred to a 100 mL eggplant-shaped flask, and acetonitrile was removed by vacuum distillation under reduced pressure. Then, hexane (10 mL) was added to the reaction system, and the mixture was evaporated to dryness and dried three times (removing residual phosphorus oxychloride). Then, isopropanol (15 mL) and 1-(3-fluorobenzyl)-5-amino-1H-carbazole (258 mg, 1.07 mmd) and triethylamine were added to the eggplant flask, and the mixture was heated under reflux for 3 hours. , the point plate tracks the reaction until the raw material disappears. The reaction solution was cooled to room temperature, cooled with ice-cooled water and stirred, and then evaporated, evaporated, evaporated, evaporated, evaporated. -1 - oxazole-5-amino]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid ethyl ester hydrochloride 20a (0.329 g, pale yellow solid). The yield was 66.5 %. MS m/z (ESI): 445 [M+ 1]
1HNMR (400MHz, DMSO-i¾: S8.83(s, 1Η), 8.09(s, 2H), 7.67(m, 1H), 7.57 (m, 1H), 7.36(m, 1H), 7.06(m, 3H), 5.68(s, 2H), 4.39(q, 2H), 2.69(s, 3H), 1.37(t, 3H) 第二步
4-[l-(3-氟苄基 )-1Η-吲唑 -5-氨基] -3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸 按照本发明实施例 1第五步所述相同方式, 使用 4-[1-(3-氟苄基 )-1Η-吲唑 -5- 氨基] -3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸乙酯盐酸盐作原料, 制得标题产物 4-[1-(3-氟苄基) -1H-吲唑 -5-氨基] -3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸 20b,进行 下一步反应。 1H NMR (400MHz, DMSO-i3⁄4: S8.83 (s, 1 Η), 8.09 (s, 2H), 7.67 (m, 1H), 7.57 (m, 1H), 7.36 (m, 1H), 7.06 (m, 3H) ), 5.68(s, 2H), 4.39(q, 2H), 2.69(s, 3H), 1.37(t, 3H) Step 2 4-[l-(3-Fluorobenzyl)-1Η-indazol-5-amino]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid is practiced in accordance with the invention In the same manner as described in the fifth step of Example 1, 4-[1-(3-fluorobenzyl)-1Η-indazole-5-amino]-3-methyl-1H-pyrrolo[2,3-d] was used. The title product, 4-[1-(3-fluorobenzyl)-1H-indazole-5-amino]-3-methyl-1H-pyrrole, was obtained as the title compound. And [2,3-d]pyridazine-2-carboxylic acid 20b was subjected to the next reaction.
MS m/z (ESI): 517[M+ 1] 第三步 MS m/z (ESI): 517[M+ 1] Step 3
4-[l-(3-氟苄基) -1H-吲唑 -5-氨基] -3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -(2-甲氧乙基)甲酰 胺 4-[l-(3-fluorobenzyl)-1H-indazole-5-amino]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-(2-methoxyethyl) Formamide
按照本发明实施例 1第六步所述相同方式, 使用 4-[1-(3-氟苄基 )-1Η-吲唑 -5- 氨基] -3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸作原料, 进行该原料与 2-甲氧乙基胺 的反应, 则得到标题产物 4-[1-(3-氟苄基) -1H-吲唑 -5-氨基] -3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -(2-甲氧乙基)甲酰胺 20 (45 mg, 黄色固体)。 产率 8 %。 In the same manner as described in the sixth step of Example 1 of the present invention, 4-[1-(3-fluorobenzyl)-1Η-indazole-5-amino]-3-methyl-1H-pyrrolo[2, 3-d]pyridazine-2-carboxylic acid as a starting material, the reaction of the starting material with 2-methoxyethylamine affords the title product 4-[1-(3-fluorobenzyl)-1H-carbazole- 5-Amino]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-(2-methoxyethyl)carboxamide 20 (45 mg, yellow solid). The yield was 8 %.
MS m/z (ESI): 474[M+ 1] MS m/z (ESI): 474 [M+ 1]
1HNMR (400MHz, DMSO- ): S8.84(s, 1H), 8.080(s, 2H), 7.66(m, 1H), 7.57(m, 1H), 7.35(m, 1H), 7.06(m, 3H), 5.68(s, 2H ), 3.50(t, 2H), 2.72(s, 3H), 2.52(t, 2H) 实施例 21 1HNMR (400MHz, DMSO-): S8.84 (s, 1H), 8.080 (s, 2H), 7.66 (m, 1H), 7.57 (m, 1H), 7.35 (m, 1H), 7.06 (m, 3H) ), 5.68(s, 2H ), 3.50(t, 2H), 2.72(s, 3H), 2.52(t, 2H) Example 21
4-Γ1-(3-氟苄基) -1H-吲唑 -5-氨基 1-3-甲基 -1H-吡咯并「2,3-dl哒嗪 -2-(2-二乙胺基-乙 基)甲酰胺 4-Γ1-(3-fluorobenzyl)-1H-indazole-5-amino1-3-methyl-1H-pyrrolo-[2,3-dl-pyridazine-2-(2-diethylamino)- Ethyl)formamide
重复本发明实施例 20第一步至第二步的反应, 使用上述第二步中所得到的 化合物 4-[1 3-氟苄基) -1H-吲唑 -5-氨基] -3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸 20b作原料,按照本发明实施例 1第六步所述相同方式进 该原料与二乙基乙二 胺的反应, 则得到标题产物 4-[1 -(3-氟苄基 )-1Η-吲唑 -5-氨基] -3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-(2-二乙胺基-乙基)甲酰胺 21(90 mg, 浅褐色固体)。 产率 13.5 %。 MS m/z (ESI): 515[M+ 1] The reaction of the first step to the second step of Example 20 of the present invention was repeated, using the compound 4-[1 3-fluorobenzyl)-1H-indazole-5-amino]-3-methyl obtained in the above second step. The base-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid 20b is used as a raw material, and the reaction of the raw material with diethylethylenediamine is carried out in the same manner as described in the sixth step of the first embodiment of the present invention. The title product 4-[1-(3-fluorobenzyl)-1Η-indazol-5-amino]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-(2) was obtained. -Diethylamino-ethyl)carboxamide 21 (90 m g , light brown solid). The yield was 13.5%. MS m/z (ESI): 515 [M+ 1]
1HNMR (400MHZ, OMSO-d6): S8.84(s, 1H), 8.09(s, 2H), 8.07(s, 1H), 7.644(m, 1H),
7.56(m, 1H), 7.35(m, 1H), 7.08(m, 1H), 7.02(m, 2H), 5.68(s, 2H), 3.37(t, 2H), 2.71(s, 3H), 2.55(m, 6H), 0.94(t, 6H) 实施例 22 1HNMR (400MHZ, OMSO-d 6 ): S8.84(s, 1H), 8.09(s, 2H), 8.07(s, 1H), 7.644(m, 1H), 7.56(m, 1H), 7.35(m, 1H), 7.08(m, 1H), 7.02(m, 2H), 5.68(s, 2H), 3.37(t, 2H), 2.71(s, 3H), 2.55 (m, 6H), 0.94 (t, 6H) Example 22
4-Γ3-氯 -4- (吡啶 -2-甲氧基) -苯胺 1-3-甲基 -1H-吡咯并「2.3-dl哒嗪 -2- 2-二乙胺某-乙 基甲酰胺 4-Γ3-chloro-4-(pyridine-2-methoxy)-aniline 1-3-methyl-1H-pyrrolo-2.3-dl-pyridazine-2- 2-diethylamine-ethylformamide
4-[3-氯 -4- (吡啶 -2-甲氧基) -苯胺 ]-3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸乙酯盐酸 盐 4-[3-Chloro-4-(pyridine-2-methoxy)-aniline]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid ethyl ester hydrochloride
按照实施例 1第三、 四步所述方法, 氮气氛下, 在 50 mL的三颈瓶中, 将 3- 甲基 -4-羰基- 3a,4,5,7a-四氢 -1H-吡咯并 [2,3-d]哒嗪 -2羧酸乙酯 lc (1.1 g, 5 mmol) 溶解于无水乙腈 (35 mL),室温搅拌下缓慢滴加无水三氯氧磷 (0.92 mL, 10 mmol, 2eq)滴加完毕后,加热回流至黄色固体逐渐反应溶解为黄色溶液,继续回流 30分 钟。 将反应液移至 100 mL的茄形瓶中, 减压旋蒸除去乙腈, 再向反应体系中加 入正己垸 (10 mL), 减压旋干, 重复三次 (去除残余三氯氧磷)。而后在此茄形瓶中 加入异丙醇 (30 mL)和 3-氯 -4- (吡啶 -2-甲氧基) -苯胺 (1.056 g, 4.5 mmol)以及三乙 胺, 加热回流 12 小时, 点板跟踪至原料消失。 将反应液冷却至室温, 继续用冰 水浴冷却并搅拌,有黄色固体产生,减压抽滤, 固体用少量的异丙醇洗涤,干燥, 得到标题产物 4-[3-氯 -4- (吡啶 -2-甲氧基) -苯胺 ]-3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-
羧酸乙酯盐酸盐 22a (0.939 g, 黄色固体)。 产率 42.9%。 3-methyl-4-carbonyl-3a,4,5,7a-tetrahydro-1H-pyrrole in a 50 mL three-necked flask under nitrogen atmosphere according to the method described in the third and fourth steps of Example 1. And [2,3-d]pyridazine-2carboxylic acid ethyl ester lc (1.1 g, 5 mmol) was dissolved in anhydrous acetonitrile (35 mL), and anhydrous phosphorus oxychloride (0.92 mL) was slowly added dropwise with stirring at room temperature. After completion of the dropwise addition of 10 mmol, 2 eq), the mixture was heated to reflux to a yellow solid and gradually dissolved to a yellow solution, and reflux was continued for 30 minutes. The reaction solution was transferred to a 100 mL eggplant-shaped flask, and acetonitrile was removed by vacuum distillation under reduced pressure. Then, hexane (10 mL) was added to the reaction mixture, and the mixture was evaporated to dryness and dried three times (removing residual phosphorus oxychloride). Then, isopropanol (30 mL) and 3-chloro-4-(pyridine-2-methoxy)-aniline (1.056 g, 4.5 mmol) and triethylamine were added to the eggplant flask, and the mixture was heated under reflux for 12 hours. The point plate is tracked until the material disappears. The reaction solution was cooled to room temperature, then cooled with ice-cooled water and stirred, and evaporated, evaporated, evaporated, evaporated, evaporated. -2-methoxy)-aniline]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2- Ethyl carboxylate hydrochloride 22a (0.939 g, yellow solid). The yield was 42.9%.
4-[3-氯 -4- (吡啶 -2-甲氧基) -苯胺 ]-3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸 按照本发明实施例 1第五步所述相同方式, 使用 4-[3-氯 -4- (吡啶 -2-甲氧基) - 苯胺 ]-3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸乙酯盐酸盐 22a作原料, 制得本标题 产物 4-[3-氯 -4- (吡啶 -2-甲氧基) -苯胺 ]-3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸 22b (0.686g, 黄色固体)。 产率 79.8%。 4-[3-Chloro-4-(pyridine-2-methoxy)-aniline]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid according to an embodiment of the invention In the same manner as described in the fifth step, 4-[3-chloro-4-(pyridine-2-methoxy)-aniline]-3-methyl-1H-pyrrolo[2,3-d]pyridazine was used. The title product 4-[3-chloro-4-(pyridine-2-methoxy)-aniline]-3-methyl-1H-pyrrole is obtained by using 2-carboxylic acid ethyl ester hydrochloride 22a as a starting material. [2,3-d]pyridazine-2-carboxylic acid 22b (0.686 g, yellow solid). The yield was 79.8%.
MS m/z (ESI): 410[M+ 1] 第三步 MS m/z (ESI): 410[M+ 1] Step 3
4-[3-氯 -4- (吡啶 -2-甲氧基) -苯胺 ]-3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-(2-二乙胺基-乙 基)甲酰胺 4-[3-Chloro-4-(pyridine-2-methoxy)-aniline]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-(2-diethylamino) -ethyl)formamide
按照本发明实施例 1第六步所述相同方式, 使用 4-[3-氯 -4- (吡啶 -2-甲氧基) - 苯胺] -3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸 22b作原料, 进行该原料与二乙基乙 二胺的反应,则得到标题产物 4-[3-氯 -4- (吡啶 -2-甲氧基) -苯胺 ]-3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-(2-二乙胺基-乙基)甲酰胺 22 (25 mg, 黄色固体)。 产率 85.1 %。 MS m/z (ESI): 508[M+ 1] In the same manner as described in the sixth step of Example 1 of the present invention, 4-[3-chloro-4-(pyridine-2-methoxy)-aniline]-3-methyl-1H-pyrrolo[2,3 was used. -d]pyridazine-2-carboxylic acid 22b as a starting material, the reaction of the starting material with diethylethylenediamine gives the title product 4-[3-chloro-4-(pyridine-2-methoxy)- Aniline]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-(2-diethylamino-ethyl)carboxamide 22 (25 mg, yellow solid). The yield was 85.1%. MS m/z (ESI): 508 [M+ 1]
1HNMR (400MHz, DMSO-J5): δ 8.89(s, 1H), 8.59(d, 1H), 7.87(m, 2H), 7.58(d, 1H), 7.52(d, 1H), 7.37(m, 1H), 7.2 l(d, 1H), 5.26(s, 2H), 3.64(t, 2H), 2.74(s, 3H), 2.50(m, 6H), 1.20(t, 6H) 实施例 23 1 HNMR (400MHz, DMSO-J 5): δ 8.89 (s, 1H), 8.59 (d, 1H), 7.87 (m, 2H), 7.58 (d, 1H), 7.52 (d, 1H), 7.37 (m , 1H), 7.2 l(d, 1H), 5.26(s, 2H), 3.64(t, 2H), 2.74(s, 3H), 2.50(m, 6H), 1.20(t, 6H) Example 23
4-[3-氯 -4- (吡啶 -2-甲氧基) -苯胺 ]-3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-[(2-吡咯啶 -1- 基) -乙基]甲酰胺 4-[3-chloro-4-(pyridine-2-methoxy)-aniline]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-[(2-pyrrolidine- 1-yl)-ethyl]carboxamide
重复本发明实施例 20第一步至第二步的反应, 使用上述第二步中所得到的 化合物 4-[3-氯 -4- (吡啶 -2-甲氧基) -苯胺 ]-3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸 22b 作原料,按照本发明实施例 1第六步所述相同方式进行该原料与 2- (吡咯啶 -1-基) - 乙胺的反应,则得到标题产物 4-[3-氯- 4- (吡啶 -2-甲氧基) -苯胺 ]-3-甲基 -1H-吡咯并
[2,3-d]哒嗪 -2-[(2-吡咯啶 -1-基) -乙基]甲酰胺 23 (46 mg, 黄色固体)。 产率 56.5 %。 The reaction of the first step to the second step of Example 20 of the present invention was repeated, using the compound 4-[3-chloro-4-(pyridine-2-methoxy)-aniline]-3- obtained in the above second step. Methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid 22b is used as a starting material, and the starting material is 2-(pyrrolidin-1-) in the same manner as described in the sixth step of Example 1 of the present invention. Reaction of ethylamine to give the title product 4-[3-chloro-4-(pyridine-2-methoxy)-aniline]-3-methyl-1H-pyrrole [2,3-d]pyridazine-2-[(2-pyrrolidin-1-yl)-ethyl]carboxamide 23 (46 mg, yellow solid). The yield was 56.5 %.
MS m/z (ESI): 506[M+ 1] MS m/z (ESI): 506 [M+ 1]
'HNMR: (400MHz ,DMSO-i/5) 58.86(s, IH), 8.59(d, IH), 7.87 (m, 2H), 7.58(d, IH), 7.53(d, IH), 7.37(m, IH), 7.19(d, IH), 5.25(s, 2H), 3.42(t, 2H), 2.70(s, 3H), 2.63(t, 2H), 2.51 (m, 4H), 1.70(s, 4H) 实施例 24 'HNMR: (400MHz, DMSO-i/ 5 ) 58.86(s, IH), 8.59(d, IH), 7.87 (m, 2H), 7.58(d, IH), 7.53(d, IH), 7.37(m , IH), 7.19(d, IH), 5.25(s, 2H), 3.42(t, 2H), 2.70(s, 3H), 2.63(t, 2H), 2.51 (m, 4H), 1.70(s, 4H) Example 24
4-[3-氯 -4- (吡啶 -2-甲氧基) -苯胺 ]-3-甲基 -IH-吡咯并 [2,3-d]哒嗪 -2-[(2-吗啡啉 -4- 基) -乙基]甲酰胺 4-[3-chloro-4-(pyridine-2-methoxy)-aniline]-3-methyl-IH-pyrrolo[2,3-d]pyridazine-2-[(2-morpholine- 4-yl)-ethyl]carboxamide
重复本发明实施例 20第一步至第二步的反应, 使用上述第二步中所得到的 化合物 4-[3-氯 -4- (吡啶 -2-甲氧基) -苯胺 ]-3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸 22b 作原料, 按照本发明实施例 1第六步所述相同方式进行该原料与 2-(2-吗啡啉 -4- 基) -乙胺的反应, 则得到标题产物 4-[3-氯 -4- (吡啶 -2-甲氧基)-苯胺] -3-甲基 -1H-吡 咯并 [2,3- d]哒嗪 -2-[(2-吗啡啉 -4-基) -乙基]甲酰胺 24(62 mg,黄色固体)。产率: 10.6 % The reaction of the first step to the second step of Example 20 of the present invention was repeated, using the compound 4-[3-chloro-4-(pyridine-2-methoxy)-aniline]-3- obtained in the above second step. Methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid 22b is used as a starting material, and the starting material and 2-(2-morpholine) are carried out in the same manner as described in the sixth step of Example 1 of the present invention. The reaction of 4-yl)-ethylamine gives the title product 4-[3-chloro-4-(pyridine-2-methoxy)-phenylamine]-3-methyl-1H-pyrrolo[2,3- d] pyridazine-2-[(2-morphinolin-4-yl)-ethyl]carboxamide 24 (62 mg, yellow solid). Yield: 10.6 %
MS m/z (ESI): 523 [M+ l] MS m/z (ESI): 523 [M+ l]
1HNM (400MHz ,DMSO- 6) S8.86(s, IH), 8.59(d, IH), 7.90 (m, 2H), 7.58(d, IH), 7.54(d, IH), 7.37(m, 1H), 7.19(d, IH), 5.28(s, 2H), 3.59(t, 4H), 3.42(t, 4H), 2.72(s, 3H), 2.45 (m, 4H) 实施例 25 1 HNM (400MHz, DMSO- 6 ) S8.86(s, IH), 8.59(d, IH), 7.90 (m, 2H), 7.58(d, IH), 7.54(d, IH), 7.37(m, (H, 4H)
4-Γ3-氯 -4- (吡啶 -2-甲氧基) -苯胺 1-3-甲基 -IH-吡咯并「2,3-dl哒嗪 -2-Γ( -吗啡啉 -4- 基) -乙基 1甲酰胺 4-Γ3-chloro-4-(pyridine-2-methoxy)-aniline 1-3-methyl-IH-pyrrolo and 2,3-dloxazin-2-indole (-morpholinolin-4-yl) ) -ethyl 1 carboxamide
重复本发明实施例 20第一步至第二步的反应, 使用上述第二步中所得到的
化合物 4-[3-氯 -4- (吡啶 -2-甲氧基) -苯胺 ]-3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸 22b 作原料, 按照本发明实施例 1第六步所述相同方式进行该原料与 2-(3-吗啡啉 -4- 基) -乙胺的反应, 则得到标题产物 4-[3-氯 -4- (吡啶 - 2-甲氧基) -苯胺 ]-3-甲基 -1H-吡 咯并 [2,3-d]哒嗪 -2-[(3-吗啡啉 -4-基) -乙基]甲酰胺 25 (66mg, 黄色固体)。 产率 11 Repeating the reaction of the first step to the second step of the embodiment 20 of the present invention, using the method obtained in the second step above The compound 4-[3-chloro-4-(pyridine-2-methoxy)-aniline]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid 22b is used as a raw material. The reaction of the starting material with 2-(3-morphocolin-4-yl)-ethylamine was carried out in the same manner as described in the sixth step of Example 1 to obtain the title product 4-[3-chloro-4-(pyridine. -2-methoxy)-aniline]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-[(3-morphorphyrin-4-yl)-ethyl]carboxamide 25 (66 mg, yellow solid). Yield 11
%。 %.
MS m/z (ESI): 537[M+ 1] MS m/z (ESI): 537 [M+ 1]
'HNMR(400MHz ,DMSO-i¾) 58.86(s, 1H), 8.59(d, 1H), 7.90 (m, 2H), 7.58(d, 1H), 7.54(d, 1H), 7.37(m, 1H), 7.19(d, 1H), 5.27(s, 2H), 3.57(t, 4H), 3.37(t, 4H), 2.74(s, 3H), 2.51 (m, 4H), 2.37(m, 2H) 实施例 26 'HNMR (400MHz, DMSO-i3⁄4) 58.86(s, 1H), 8.59(d, 1H), 7.90 (m, 2H), 7.58(d, 1H), 7.54(d, 1H), 7.37(m, 1H) , 7.19(d, 1H), 5.27(s, 2H), 3.57(t, 4H), 3.37(t, 4H), 2.74(s, 3H), 2.51 (m, 4H), 2.37(m, 2H) Example 26
4-f3-氯 -4- (吡啶 -2-甲氧基 苯胺 1-1 , 3-二甲基 -1H-吡咯并「2,3-dl哒嗪 -2-Γ(2-乙氨 基) -乙基 1甲酰胺 4-f3-chloro-4-(pyridine-2-methoxyaniline 1-1, 3-dimethyl-1H-pyrrolo- 2,3-dl-pyridazine-2-indole (2-ethylamino)- Ethyl 1 carboxamide
4-[3-氯 -4- (吡啶 -2-甲氧基) -苯氨基] -1,3-二甲基 -1Η-吡咯并 [2,3-d]哒嗪 -2-羧酸乙酯 按照本发明实施例 1第三、 四步所述相同方式反应, 使用上述第三步中所得 到的化合物 3-甲基 -4-羰基 -3a,4,5,7a-四氢 -1-甲基-吡咯并 [2,3-d]哒嗪 -2羧酸乙酯 15c (2.34 g, lO mmol) 作原料, 得到本标题产物 4-[3-氯 -4-(3-氟苄氧) -苯胺 ] -1,3- 二甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸乙酯 26a (3.39 g, 黄色固体)。产率 75.3 %。
MS m/z (ESI) : 452[M+ 1] 4-[3-Chloro-4-(pyridine-2-methoxy)-phenylamino]-1,3-dimethyl-1Η-pyrrolo[2,3-d]pyridazine-2-carboxylic acid B The ester is reacted in the same manner as described in the third and fourth steps of Example 1 of the present invention, using the compound obtained in the above third step, 3-methyl-4-carbonyl-3a, 4,5,7a-tetrahydro-1- Methyl-pyrrolo[2,3-d]pyridazine-2carboxylic acid ethyl ester 15c (2.34 g, 10 mmol) was used as the starting material to give the title product 4-[3-chloro-4-(3-fluorobenzyloxy). ) - Aniline] -1,3-Dimethyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid ethyl ester 26a (3.39 g, yellow solid). The yield was 75.3%. MS m/z (ESI): 452 [M+ 1]
第二步 , The second step,
4-[3-氯 -4- (吡啶 -2-甲氧基) -苯氨基] -1,3-二甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸 按照本发明实施例 1第五步 ^述相同方式反应, 使用上述第一步中戶万得到的 化合物 4-[3-氯 -4-(3-氟苄氧) -苯胺] -1,3-二甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸乙酯 26a (451 mg, 1 mmol) 作原料, 得到本标题产物 4-[3-氯 -4- (吡啶 -2-甲氧基) -苯 氨基] -1,3-二甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸 26b (150 mg, 黄色固体)。 产率: 35.6 %。 4-[3-chloro-4-(pyridine-2-methoxy)-phenylamino]-1,3-dimethyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid In the fifth step of the first embodiment of the present invention, the reaction of the same manner is used, and the compound 4-[3-chloro-4-(3-fluorobenzyloxy)-aniline]-1,3-di which is obtained by the above-mentioned first step is used. Ethylmethyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylate 26a (451 mg, 1 mmol) was used as the starting material to give the title product 4-[3-chloro-4-(pyridine- 2-Methoxy)-phenylamino]-1,3-dimethyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid 26b (150 mg, yellow solid). Yield: 35.6 %.
MS m/z (ESI): 424[M+ 1] 第三步 MS m/z (ESI): 424 [M+ 1] Step 3
4-[3-氯 -4- (吡啶 -2-甲氧基) -苯胺 ]-1, 3-二甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-[(2-乙氨 基) -乙基]甲酷胺 4-[3-chloro-4-(pyridine-2-methoxy)-aniline]-1,3-dimethyl-1H-pyrrolo[2,3-d]pyridazine-2-[(2- Ethylamino)-ethyl]carbamamine
按照本发明实施例 1第六步所述相同方式反应,使用上述第二步中所得到的 化合物 4-[3-氯 -4- (吡啶 -2-甲氧基) -苯氨基] -1,3-二甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-羧 酸 2 作原料,得到本标题产物 4-[3-氯 -4- (吡啶 -2-甲氧基) -苯胺 ]-1 , 3-二甲基 -1H- 吡咯并 [2,3-d]哒嗪 -2-[(2-乙氨基) -乙基]甲酰胺 26 ( 154 mg, 黄色固体)。产率 27.3 According to the same manner as described in the sixth step of the first embodiment of the present invention, the compound 4-[3-chloro-4-(pyridin-2-methoxy)-phenylamino]-1 obtained in the above second step is used. 3-Dimethyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid 2 as a starting material to give the title product 4-[3-chloro-4-(pyridine-2-methoxy) -aniline]-1,3-dimethyl-1H-pyrrolo[2,3-d]pyridazine-2-[(2-ethylamino)-ethyl]carboxamide 26 (154 mg, yellow solid). Yield 27.3
%。 %.
MS m/z (ESI): 523 [M+ 1] MS m/z (ESI): 523 [M+ 1]
'HNMR(400MHz, OMSO-d6) 58.86(s, 1H), 8.59(d, 1H), 7.90 (m, 3H), 7.55(m, 2H), 7.35(m, 1H), 7.19(d, 1H), 5.26(s, 2H), 3.83(s, 3H), 3.38(m, 2H), 3.29(m, 4H), 2.60(m, 4H), 2.56(s, 3H), 0.98(t, 6H) 实施例 27 'HNMR (400MHz, OMSO-d 6 ) 58.86(s, 1H), 8.59(d, 1H), 7.90 (m, 3H), 7.55(m, 2H), 7.35(m, 1H), 7.19(d, 1H ), 5.26(s, 2H), 3.83(s, 3H), 3.38(m, 2H), 3.29(m, 4H), 2.60(m, 4H), 2.56(s, 3H), 0.98(t, 6H) Example 27
4-f3-氯 -4- (吡啶 -2-甲氧基) -苯胺 VI, 3-二甲基 -1H-吡咯并 Γ2,3-(Γ|哒嗪 -24(2-吡咯啶 小基) -乙基 1甲酰胺 4-f3-chloro-4-(pyridine-2-methoxy)-aniline VI, 3-dimethyl-1H-pyrroloindole 2,3-(indole|pyridazine-24 (2-pyrrolidine small group) -ethyl 1 carboxamide
重复本发明实施例 26第一步至第二步的反应, 使用上述第二步中所得到的 化合物 4-[3-氯 -4- (吡啶 -2-甲氧基) -苯胺 ]-3-甲基 -1Η-吡咯并 [2,3-d]哒嗪 -2-羧酸 26b 作原料, 按照本发明实施例 1第六步所述相同方式进行该原料与 2-(2-吡咯啶 -1- 基) -乙胺的反应, 则得到标题产物 4-[3-氯 -4- (吡啶 -2-甲氧基) -苯胺 ]-1, 3-二甲基
-1H-吡咯并 [2,3-d]哒嗪 -2-[(2-吡咯啶 -1-基) -乙基]甲酰胺 27 (179mg, 黄色固体)。 产率 29.9%。 The reaction of the first step to the second step of Example 26 of the present invention was repeated, using the compound 4-[3-chloro-4-(pyridine-2-methoxy)-aniline]-3- obtained in the above second step. Methyl-1Η-pyrrolo[2,3-d]pyridazine-2-carboxylic acid 26b is used as a starting material, and the starting material and 2-(2-pyrrolidine-) are carried out in the same manner as described in the sixth step of Example 1 of the present invention. Reaction of 1-yl)-ethylamine gives the title product 4-[3-chloro-4-(pyridine- 2 -methoxy)-phenylamine]-1,3-dimethyl -1H-pyrrolo[2,3-d]pyridazine-2-[(2-pyrrolidin-1-yl)-ethyl]carboxamide 27 (179 mg, yellow solid). The yield was 29.9%.
MS m/z (ESI): 521 [M+ 1] MS m/z (ESI): 521 [M+ 1]
1H MR(400MHz ,DMSO-c¾: 59.07(s, 1H), 8.59(d, 1H), 8.49(s,lH), 7.87 (m, 3H), 7.57(m, 2H), 7.36(s, 1H), 7.19(d, 1H), 5.26(s, 2H), 3.82(s, 3H), 3.43(m, 2H), 3.29(m, 2H), 2.54(s, 3H), 2.50(m, 4H), 1.70(m, 4H) 实施例 28 ' 1 H MR (400MHz, DMSO-c3⁄4: 59.07(s, 1H), 8.59(d, 1H), 8.49(s,lH), 7.87 (m, 3H), 7.57(m, 2H), 7.36(s, 1H ), 7.19(d, 1H), 5.26(s, 2H), 3.82(s, 3H), 3.43(m, 2H), 3.29(m, 2H), 2.54(s, 3H), 2.50(m, 4H) , 1.70(m, 4H) Example 28'
4-【3-氯 -4- (吡啶 -2-甲氧基) -苯胺 1 , 3-二甲基 -1H-吡咯并『2,3-dl哒嗉 -2-ΙΪ3-吗啡啉 -4-基) -乙基 1甲酰胺 4-[3-chloro-4-(pyridine-2-methoxy)-aniline 1, 3-dimethyl-1H-pyrrolo-2,3-dl哒嗉-2-indole-3-morpholine-4- -ethyl 1-carboxamide
重复本发明实施例 26第一步至第二步的反应, 使用上述第二步中所得到的 化合物 4-[3-氯 -4- (吡啶 -2-甲氧基) -苯胺 ]-3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸 26b 作原料, 按照本发明实施例 1第六步所述相同方式进行该原料与 2-(3-吗啡啉 -4- 基) -乙胺的反应, 则得到标题产物 4-[3-氯 -4- (吡啶 -2-甲氧基) -苯胺 ]-1, 3-二甲基 -1H-吡咯并 [2,3-d]哒嗉 -2-[(3-吗啡啉 -4-基) -乙基]甲酰胺 28 (68 mg, 黄色固体)。 产率 11.4 %。 The reaction of the first step to the second step of Example 26 of the present invention was repeated, using the compound 4-[3-chloro-4-(pyridine-2-methoxy)-aniline]-3- obtained in the above second step. Methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid 26b was used as a starting material, and the starting material and 2-(3-morpholine) were carried out in the same manner as described in the sixth step of Example 1 of the present invention. 4-yl)-ethylamine reaction gave the title product 4-[3-chloro-4-(pyridine-2-methoxy)-aniline-1,3-dimethyl-1H-pyrrolo[2 , 3-d]indole-2-[(3-morpholine-4-yl)-ethyl]carboxamide 28 (68 mg, yellow solid). The yield was 11.4%.
MS m/z (ESI): 551 [M+ 1] MS m/z (ESI): 551 [M+ 1]
!ΗΝΜΚ(400ΜΗζ ,DMSO-c¾) 59.07(s, 1H), 8.59(d, 1H), 8.60(m,lH), 7.87 (m, 3H), 7.57(m, 2H), 7.34(d, 1H), 7.19(d, 1H), 5.26(s, 2H), 3.81(s, 3H), 3.57(m, 4H), 3.37(m, 2H), 2.53(s, 3H), 2.37(m, 6H), 1.73(m, 2H) ! ΗΝΜΚ (400ΜΗζ, DMSO-c¾ ) 59.07 (s, 1H), 8.59 (d, 1H), 8.60 (m, lH), 7.87 (m, 3H), 7.57 (m, 2H), 7.34 (d, 1H) , 7.19(d, 1H), 5.26(s, 2H), 3.81(s, 3H), 3.57(m, 4H), 3.37(m, 2H), 2.53(s, 3H), 2.37(m, 6H), 1.73 (m, 2H)
实施例 29 Example 29
4-「3-氯 -4- (吡啶 -2-甲氧基) -苯胺 1-1, 3-二甲基 -1H-吡咯并「2,3-dl哒嗪 -24(2-吗啡 啉 -4-基) -乙基 1甲酰胺
重复本发明实施例 26第一步至第二步的反应, 使用上述第二步中所得到的 化合物 4- [3-氯 -4- (吡啶 -2-甲氧基) -苯胺 ]-3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸 26b 作原料, 按照本发明实施例 1第六步所述相同方式进行该原料与 2-(2-吗啡啉 -4- 基) -乙胺的反应, 则得到标题产物 4-[3-氯 -4- (吡啶 -2_甲氧基) -苯胺 ]-1,3-二甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-[(2-吗啡啉 -4-基) -乙基]甲酰胺 29 (58 mg, 黄色固体)。 产率 10 %。 4-"3-Chloro-4-(pyridine-2-methoxy)-aniline 1-1,3-dimethyl-1H-pyrrolo "2,3-dloxazin-24 (2-morpholine- 4-yl)-ethyl 1 carboxamide The reaction of the first step to the second step of Example 26 of the present invention was repeated, using the compound 4-[3-chloro-4-(pyridine-2-methoxy)-aniline]-3- obtained in the above second step. Methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid 26b was used as a starting material, and the starting material and 2-(2-morpholine) were carried out in the same manner as described in the sixth step of Example 1 of the present invention. The reaction of 4-yl)-ethylamine gives the title product 4-[3-chloro-4-(pyridin-2-yloxy)-aniline]-1,3-dimethyl-1H-pyrrolo[2 , 3-d]pyridazine-2-[(2-morphinolin-4-yl)-ethyl]carboxamide 29 (58 mg, yellow solid). The yield was 10%.
MS m/z (ESI): 537[M+ 1] MS m/z (ESI): 537 [M+ 1]
IHNMR(400MHz ,OMSO-d6): 59.07(s, 1H), 8.59(d, 1H), 8.60(m,lH), 7.87 (m, 3H), 7.57(m, 2H), 7.34(d, 1H), 7.19(d, 1H), 5.26(s, 2H), 3.84(s, 3H), 3.58(m, 4H), 3.47(t, 2H), 3.28(t, 2H), 2.57(s, 3H), 2.44(m, 4H), 1.73(m, 2H) 实施例 30 I H NMR (400 MHz, OMSO-d 6 ): 59.07 (s, 1H), 8.59 (d, 1H), 8.60 (m, lH), 7.87 (m, 3H), 7.57 (m, 2H), 7.34 (d, 1H), 7.19(d, 1H), 5.26(s, 2H), 3.84(s, 3H), 3.58(m, 4H), 3.47(t, 2H), 3.28(t, 2H), 2.57(s, 3H ), 2.44 (m, 4H), 1.73 (m, 2H) Example 30
「3-氯 -4-(3-氟-苄氧基) -苯氧基 W3-甲基 -2-Γ(2-吗啉 -4-基-乙氨基) -甲基 1-lH-吡咯并 「2,3-dl哒嗪 -4-基 胺 "3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy W3-methyl-2-indole (2-morpholin-4-yl-ethylamino)-methyl 1-lH-pyrrole "2,3-dloxazin-4-ylamine
{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基 ]-3-甲基 -1H-吡咯 [2,3-d]哒嗪 -2-基} -甲醇 在 250 mL烧瓶中加入氢化铝锂 (320 mg, 8 mmol) 和四氢呋喃 (40 mL), 搅拌后慢慢加入 4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -3-甲基 -1H-吡咯 [2,3-d]哒嗪- 2- 羧酸乙酯 8a ( 910 mg, 2 mmol) 的四氢呋喃 (100 mL) 溶液。 滴加完毕后, 在 加热回流 3小时, 加入冰水猝灭反应。过滤反应液, 用四氢呋喃和饱和氯化钠溶 液萃取, 合并有机相。无水硫酸钠干燥有机相, 过滤, 减压下蒸干, 得到本标题 产物 {4-[3-氯 -4-(3-氟- 氧基) -苯氨基] -3-甲基 -1H-吡咯 [2,3-d]哒嗪 -2-基} -甲醇 30a {4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-3-methyl-1H-pyrrole[2,3-d]pyridazin-2-yl}-methanol at 250 Lithium aluminum hydride (320 mg, 8 mmol) and tetrahydrofuran (40 mL) were added to the mL flask. After stirring, 4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-3 was added slowly. A solution of methyl-1H-pyrrole[2,3-d]pyridazine-2-carboxylate 8a (910 mg, 2 mmol) in tetrahydrofuran (100 mL). After completion of the dropwise addition, the mixture was heated under reflux for 3 hours, and ice water was added to quench the reaction. The reaction solution was filtered, extracted with a solution of tetrahydrofuran and saturated sodium chloride, and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate (MgSO4jjjjjjjj Pyrrole [2,3-d]pyridazin-2-yl}-methanol 30a
( 828 mg, 棕黄色固体)。 产率 35 %。 (828 mg, brownish yellow solid). The yield was 35 %.
MS m/z (ESI): 413[M+ 1] 第二步 MS m/z (ESI): 413 [M+ 1] Step 2
在 50 mL茄形瓶中加入邻碘酰苯甲酸(746 mg, 2. 66 mmol)和二甲亚砜(10 mL) , 搅拌后慢慢加入 {4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -3-甲基 -1H-吡咯 [2,3-d] 哒嗪 -2-基} -甲醇 30a (733 mg, 1.77 mmol) 的二甲亚砜 ( lO mL) 溶液。 滴加完 毕后, 在 20°C反应 1小时。 将反应液倒入水中, 有褐色固体析出, 进一歩通过 柱层析分离,得到 4-[3-氯 -4-(3-氟-节氧基) -苯氨基] -3-甲基 -1H-吡咯 [2,3-d]哒嗪 -2- 甲醛 30b (668 mg, 棕黄色固体)。 产率: 92.1 % Add o-iodobenzoic acid (746 mg, 2. 66 mmol) and dimethyl sulfoxide (10 mL) to a 50 mL eggplant bottle, and slowly add {4-[3-chloro-4-(3-) after stirring. Fluoro-benzyloxy)-phenylamino]-3-methyl-1H-pyrrole[2,3-d]pyridazin-2-yl}-methanol 30a (733 mg, 1.77 mmol) of dimethyl sulfoxide ( lO mL) solution. After the completion of the dropwise addition, the reaction was carried out at 20 ° C for 1 hour. The reaction solution was poured into water, and a brown solid was precipitated, which was separated by column chromatography to give 4-[3-chloro-4-(3-fluoro-p-oxy)-phenylamino]-3-methyl-1H. Pyrrole [2,3-d]pyridazine-2-carbaldehyde 30b (668 mg, brownish yellow solid). Yield: 92.1 %
MS m/z (ESI): 411 [M+ 1] 第三步 , MS m/z (ESI): 411 [M+ 1] Step 3,
[3-氯 -4-(3-氟-节氧基) -苯氧基] -{3-甲基 -2-[(2-吗啉 -4-基-乙氨基) -甲基 ]-1Η-吡咯并 [2,3-d]哒嗪 -4-基} -胺 [3-Chloro-4-(3-fluoro-p-ethoxy)-phenoxy]-{3-methyl-2-[(2-morpholin-4-yl-ethylamino)-methyl]-1Η -pyrrolo[2,3-d]pyridazin-4-yl}-amine
在 50 mL 茄形瓶中加入 4-[3-氯 -4-(3-氟- 氧基) -苯氨基] -3-甲基 -1H-吡咯 [2,3-d]哒嗪 -2-甲醛 30b ( 168 mg, 0.4mmol),四氢呋喃( 15 mL)和甲醇(15 mL), 搅拌下加入 2-吗啉 -4-乙胺 (79 mg, 0.61mmol), 继续搅拌直至混合物变澄清, 继续加入硼氢化钠 (39 mg, 1.03 mmoD o 反应液在室温下搅拌 1.5小时, TLC 显示反应完毕。将有机溶剂在减压下蒸发, 得到的残留物用乙酸乙酯萃取, 合并 的萃取液用饱和碳酸氢钠, 氯化钠洗涤, 无水硫酸钠干燥, 过滤, 浓缩, 得到的 粗品进一步通过柱层析分离 (二氯甲垸: 甲醇: 氨水 = 300: 10: 1.3 ), 得到标 题化合物 [3-氯 -4-(3-氟-苄氧基) -苯氧基] -{3-甲基 -2-[(2-吗啉 -4-基-乙氨基) -甲 基] -1H-吡咯并 [2,3-d]哒嗪 -4-基 } 安 30 (32 mg, 黄色固体)。 产率: 10%。 Add 4-[3-chloro-4-(3-fluoro-oxy)-phenylamino]-3-methyl-1H-pyrrole[2,3-d]pyridazine-2- to a 50 mL eggplant-shaped flask Formaldehyde 30b (168 mg, 0.4 mmol), tetrahydrofuran (15 mL) and methanol (15 mL), and then added 2-morpholine-4-ethylamine (79 mg, 0.61 mmol) with stirring and stirring until the mixture became clear. The reaction mixture was stirred at rt. The mixture was washed with sodium bicarbonate, sodium chloride and dried over anhydrous sodium sulfate, filtered, and evaporated to give the crude product which was further purified by column chromatography (dichloromethane: methanol: ammonia = 300: 10: 1.3) -chloro-4-(3-fluoro-benzyloxy)-phenoxy]-{3-methyl-2-[(2-morpholin-4-yl-ethylamino)-methyl]-1H-pyrrole And [2,3-d]pyridazin-4-yl} An 30 (32 mg, yellow solid). Yield: 10%.
MS m/z (ESI): 526[M+ 1] MS m/z (ESI): 526 [M+ 1]
!ΗΝΜΚ(400ΜΗζ ,DMSO-c¾: 58.78(s, 1H), 7.88(s, 1H), 7.79(s, 1H), 7.47 (m, 2H),
7.31(m, 2H), 7.16(m, 2H), 5.20(s, 2H), 3.84(s, 2H), 3.54(s, 4H), 2.59(ί, 2H), 2.50(t, 2H), 2.39 (m, 4H) , 2.31(s, 3H) 实施例 31 ! ΗΝΜΚ (400ΜΗζ, DMSO-c¾ : 58.78 (s, 1H), 7.88 (s, 1H), 7.79 (s, 1H), 7.47 (m, 2H), 7.31(m, 2H), 7.16(m, 2H), 5.20(s, 2H), 3.84(s, 2H), 3.54(s, 4H), 2.59(ί, 2H), 2.50(t, 2H), 2.39 (m, 4H), 2.31(s, 3H) Example 31
『3-氯 -4-(3-氟-苄氧基) -苯氧基 1-lH-吡咯并「2,3-dl哒嗪 -2-羧酸 (2-吡咯烷 -1-基-乙 基) -甲酰胺 『3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy 1-lH-pyrrolo and 2,3-dl-pyridazine-2-carboxylic acid (2-pyrrolidin-1-yl-B -formamide
5-甲酰基 -1H-吡咯 -2,4-二羧酸 -4-乙酯 -2-甲酯 按照本发明实施例 1第一步所述相同方式, 使用 5-甲基 -1H-吡咯 -2,4-二羧酸 -4-乙酯 -2-甲酯 (2.11g, lO mmol) 31a作原料, 进行该原料与硝酸铈铵的反应, 则得到标题产物 5-甲酰基 -1H-吡咯 -2,4-二羧酸 -4-乙酯 -2-甲酯 31b (338 mg)。产率 15%。 5-formyl-1H-pyrrole-2,4-dicarboxylic acid-4-ethyl ester-2-methyl ester In the same manner as described in the first step of Example 1 of the present invention, 5-methyl-1H-pyrrole was used. 2,4-Dicarboxylic acid-4-ethyl ester-2-methyl ester (2.11 g, 10 mmol) 31a was used as a starting material, and the reaction of the starting material with ammonium cerium nitrate was carried out to give the title product 5-formyl-1H-pyrrole. -2,4-Dicarboxylic acid-4-ethyl ester-2-methyl ester 31b (338 mg). The yield was 15%.
MS m/z (ESI): 224[M- 1]
第二步 MS m/z (ESI): 224 [M-1] Second step
4-氧代 -4,5-二氢 -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸甲酯 按照本发明实施例 1第二步所述相同方式, 使用上述第二步中所得到的化合 物 5-甲酰基 -1H-吡咯 -2,4-二羧酸 -4-乙酯 -2-甲酯 31b (379 mg, 1.68 mmol)作原料, 进行该原料与水合肼 (99 mg, 1.68 mmol) 的反应, 则得到标题产物 4-氧代 -4,5- 二氢 -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸甲酯 31c (157 mg)。 产率 29.6 %。 Methyl 4-oxo-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazine-2-carboxylate In the same manner as described in the second step of Example 1 of the present invention, the second The compound 5-formyl-1H-pyrrole-2,4-dicarboxylic acid-4-ethyl ester-2-methyl ester 31b (379 mg, 1.68 mmol) obtained in the step was used as a starting material to carry out the hydration of the starting material with hydrazine ( 99 mg, 1.68 mmol) gave the title product 4-oxo-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid methyl ester 31c (157 mg) . The yield was 29.6%.
MS m/z (ESI): 192[M— 1] 第三步 MS m/z (ESI): 192 [M-1] Step 3
4-[3-氯 -4-(3-氟苄氧) -苯胺 ]-1Η-吡咯并 [2,3-d]哒嗪 -2-羧酸甲酯 按照本发明实施例 1第三、四步所述相同方式反应,使用上述第二步中所得 到的化合物 4-氧代 -4,5-二氢 -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸甲酯 31c ( 308 mg, 1.59 mmol) 作原料, 得到本标题产物 4-[3-氯 -4-(3-氟苄氧) -苯胺] -1H-吡咯并 [2,3-d]哒 嗪 -2-羧酸甲酯 31d (1.4 g, 白色固体), 产物可不经分离, 直接进行下一步反应。 MS m/z (ESI): 427[M+ 1] 第四步 4-[3-chloro-4-(3-fluorobenzyloxy)-aniline]-1Η-pyrrolo[2,3-d]pyridazine-2-carboxylic acid methyl ester according to Example 1 of the present invention In the same manner as described in the above step, the compound 4-oxo-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid methyl ester 31c obtained in the above second step was used. (308 mg, 1.59 mmol) as a starting material to give the title product 4-[3-chloro-4-(3-fluorobenzyloxy)-aniline]-1H-pyrrolo[2,3-d]pyridazin-2- The methyl carboxylate 31d (1.4 g, white solid) was taken directly to the next product without isolation. MS m/z (ESI): 427 [M+ 1] Step 4
4-[3-氯 -4-(3-氟苄氧) -苯胺] -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸盐酸盐 按照本发明实施例 1第五步所述相同方式反应, 使用上述第三步中所得到的 化合物 4-[3-氯 -4-(3-氟苄氧) -苯胺] -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸甲酯 31d ( 610 mg, 1.43mmol)作原料, 得到本标题产物 4-[3-氯 -4-(3-氟苄氧) -苯胺] -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸盐酸盐 31e (237 mg, 黄色固体)。 产率: 28.2%。 4-[3-chloro-4-(3-fluorobenzyloxy)-aniline]-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid hydrochloride according to the fifth step of Example 1 of the present invention In the same manner, the compound 4-[3-chloro-4-(3-fluorobenzyloxy)-aniline]-1H-pyrrolo[2,3-d]pyridazine obtained in the above third step is used. The title product 4-[3-chloro-4-(3-fluorobenzyloxy)-aniline]-1H-pyrrolo[2,3- d] pyridazine-2-carboxylic acid hydrochloride 31e (237 mg, yellow solid). Yield: 28.2%.
MS m/z (ESI): 450[M+ 1] 第五步 MS m/z (ESI): 450[M+ 1] Step 5
[3-氯 -4-(3-氟-苄氧基) -苯氧基] -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸 (2-吡咯烷 -1-基-乙 基) -甲酰胺 [3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy]-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid (2-pyrrolidin-1-yl- Ethyl)-carboxamide
按照本发明实施例 1第六步所述相同方式反应,使用上述第四步中所得到的 化合物 4-[3-氯 -4-(3-氟苄氧) -苯胺] -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸盐酸盐 31e(110 mg, 0.245 nimol)作原料, 进行该原料与 2-吡咯垸 -1-乙胺的反应, 得到本标题产 物 [3-氯 -4-(3-氟- 氧基) -苯氧基] -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸 (2-吡咯垸 -1-基- 乙基) -甲酰胺 31 (7 mg, 黄色固体)。 产率: 5.56%。 In the same manner as described in the sixth step of Example 1 of the present invention, the compound 4-[3-chloro-4-(3-fluorobenzyloxy)-aniline]-1H-pyrrolo[4] obtained in the above fourth step was used. 2,3-d]pyridazine-2-carboxylic acid hydrochloride 31e (110 mg, 0.245 nimol) was used as a starting material, and the reaction of the starting material with 2-pyrrole-1-ethylamine was carried out to obtain the title product [3- Chloro-4-(3-fluoro-oxy)-phenoxy]-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid (2-pyrrole-1-yl-ethyl) Formamide 31 (7 mg, yellow solid). Yield: 5.56%.
MS m/z (ESI): 512[M+ 1] MS m/z (ESI): 512 [M+ 1]
'HNMR (400MHZ, DMSO-^): δ 7.65(d, 1H), 7.36(t, 1H), 7.30(m, 1H), 7.22(m, 2H), 7.09(m, 2H), 5.12(s, 2H), 3.56(t, 2H), 2.48(m, 2H), 2.42(m, 4H), 1.62(m, 4H)
实施例 32 'HNMR (400MHZ, DMSO-^): δ 7.65(d, 1H), 7.36(t, 1H), 7.30(m, 1H), 7.22(m, 2H), 7.09(m, 2H), 5.12(s, 2H), 3.56(t, 2H), 2.48(m, 2H), 2.42(m, 4H), 1.62(m, 4H) Example 32
4-13-氯 -4-(3-氟^氧基 -苯氧基 1-lH-吡咯并「2,3-dl哒嗪 -2-羧酸 (2-二乙氨基-乙 基) -酰胺 4-13-chloro-4-(3-fluorooxy-phenoxy 1-lH-pyrrolo- 2,3-dl-pyridazine-2-carboxylic acid (2-diethylamino-ethyl)-amide
重复本发明实施例 31第一步至第四步的反应, 使用上述第四步中所得到的 化合物 4-[3-氯 -4-(3-氟苄氧) -苯胺] -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸盐酸盐 31e作原 料, 按照本发明实施例 31第五步所述相同方式进行该原料与二乙基乙二胺的反 应, 则得到标题产物 4-[3-氯 -4-(3-氟-苄氧基) -苯氧基] -1H-吡咯并 [2,3-d]哒嗪 -2-羧 酸 (2-二乙氨基-乙基)-酰胺 32 (10 mg, 黄色固体), 产率 8%。 The reaction of the first step to the fourth step of Example 31 of the present invention was repeated, and the compound 4-[3-chloro-4-(3-fluorobenzyloxy)-aniline]-1H-pyrrole obtained in the above fourth step was used. [2,3-d]pyridazine-2-carboxylic acid hydrochloride 31e is used as a starting material, and the reaction of the starting material with diethylethylenediamine is carried out in the same manner as described in the fifth step of Example 31 of the present invention to obtain the title. Product 4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy]-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid (2-diethylamino- Ethyl)-amide 32 (10 mg, yellow solid), yield 8%.
MS m/z (ESI): 509[M+ 1] MS m/z (ESI): 509 [M+ 1]
JHNMR (400MHZ, DMSO-^): 58.12(S, IH), 7.64(d, IH), 7.36(t, IH), 7.22(m, 3H), 7.03(m, IH), 7.08(m, 1H), 5.12(s, 2H), 3.28(t, 2H), 2.54(m, 2H), 2.47(m, 4H), 0.89(m: 6H) 实施例 33 J HNMR (400 MHZ, DMSO-^): 58.12 (S, IH), 7.64 (d, IH), 7.36 (t, IH), 7.22 (m, 3H), 7.03 (m, IH), 7.08 (m, 1H) ), 5.12(s, 2H), 3.28(t, 2H), 2.54(m, 2H), 2.47(m, 4H), 0.89(m : 6H) Example 33
4-f3-氯 -4-( -氟-苄氧基) -苯氧基 1 - 2-甲氧基 -乙基 )-3-甲基 -1H-吡咯并 f2,3-dl哒 嗪 -2-羧酸乙酯 4-f3-chloro-4-(-fluoro-benzyloxy)-phenoxy 1-2-3-methoxy-ethyl)-3-methyl-1H-pyrrolof2,3-dlpyridazine-2 -carboxylic acid ethyl ester
第一步 First step
l-(2-甲氧基 -乙基 )-3,5-二甲基 -1H-吡咯 -2,4-二羧酸二乙酯 在 250 mL的茄形瓶中依次加入 3,5-二甲基 -1H-吡咯 -2,4-二羧酸二乙酯 la( 8 g, 33 mmol), 二甲基亚砜 ( 50 mL) 和叔丁醇钾 (4.077 g, 36.3 mmol), 搅拌下 加入 1-溴 -2-甲氧基 -乙垸 (6.3 mL, 43.3 mmol), 室温下撿拌 5小时, 反应完毕。 在反应液中加入冰水(200 mL), 并用乙酸乙酯萃取 (100 mL X 3 )有固体析出, 合并的有机相用饱和氯化钠洗涤, 无水硫酸钠干燥, 过滤, 减压下浓縮得到的粗 品 1-(2-甲氧基 -乙基 )-3,5-二甲基 -1H-吡咯 -2,4-二羧酸二乙酯 33a直接进行下一步 反应。 1-(2-Methoxy-ethyl)-3,5-dimethyl-1H-pyrrole-2,4-dicarboxylic acid diethyl ester was added to the 2,5-two in a 250 mL eggplant bottle. Diethyl-1H-pyrrole-2,4-dicarboxylate la (8 g, 33 mmol), dimethyl sulfoxide (50 mL) and potassium t-butoxide (4.077 g, 36.3 mmol), with stirring 1-Bromo-2-methoxy-acetamidine (6.3 mL, 43.3 mmol) was added, and the mixture was stirred at room temperature for 5 hours, and the reaction was completed. Ice water (200 mL) was added to the reaction mixture, and ethyl acetate (100 mL EtOAc) was evaporated, evaporated, evaporated, evaporated, evaporated The obtained crude 1-(2-methoxy-ethyl)-3,5-dimethyl-1H-pyrrole-2,4-dicarboxylate 33a was directly subjected to the next reaction.
第二步 Second step
5-甲酰基 -1-(2-甲氧基 -乙基 )-3-甲基 -1H-吡咯 -2,4-二羧酸二乙酯 按照本发明实施例 1 第一步所述相同方式, 使用上述第一步所得的化合物 1-(2-甲氧基 -乙基 )-3,5-二甲基 -1H-吡咯 -2,4-二羧酸二乙酯 33a (9.8 g, 3.3 mmol) 作原料, 进行该原料与硝酸铈铵的反应, 则得到标题产物 5-甲酰基 -1-(2-甲氧基- 乙基) -3-甲基 -1H-吡咯 -2,4-二羧酸二乙酯 33b (5.287 g,黄色油状液体)。产率 51.8 %。 5-formyl-1-(2-methoxy-ethyl)-3-methyl-1H-pyrrole-2,4-dicarboxylic acid diethyl ester in the same manner as described in Example 1 of the present invention Using the compound obtained in the above first step, diethyl 1-(2-methoxy-ethyl)-3,5-dimethyl-1H-pyrrole-2,4-dicarboxylate 33a (9.8 g, 3.3 Methanol) The starting material is reacted with ammonium cerium nitrate to give the title product 5-formyl-1-(2-methoxy-ethyl)-3-methyl-1H-pyrrole-2,4- Dicarboxylate 33b (5.287 g, yellow oily liquid). The yield was 51.8%.
MS m/z (ESI): 312[M+ 1] 第三步 MS m/z (ESI): 312 [M+ 1] Step 3
l-(2-甲氧基 -乙基 )-3-甲基 -4-氧代 -4,5-4,5-二氢 -1H-吡咯 [2,3-d]哒嗪 -2-羧酸甲酯 按照本发明实施例 1第二步所述相同方式,使用上述第二步中所得到的化合 物 5-甲酰基小(2-甲氧基 -乙基 )-3-甲基 -1H-吡咯 -2,4-二羧酸二乙酯 33b (5,2 g, 16.7 mmol) 作原料, 进行该原料与水合肼(1.5 mL, 25 mmol) 的反应, 则得到 标题产物 1-(2-甲氧基 -乙基 )-3-甲基 -4-氧代 -4,5-4,5-二氢 -1H-吡咯 [2,3-d]哒嗪 -2-羧 酸甲酯 33c (4.405 g, 白色固体)。 产率: 95.7%。
MS m/z (ESI): 280[M+ 1] 第四步 L-(2-Methoxy-ethyl)-3-methyl-4-oxo-4,5-4,5-dihydro-1H-pyrrole[2,3-d]pyridazine-2-carboxylate Methyl ester The compound 5-formyl small (2-methoxy-ethyl)-3-methyl-1H- obtained in the second step above was used in the same manner as described in the second step of Example 1 of the present invention. Pyrrole-2,4-dicarboxylic acid diethyl ester 33b (5,2 g, 16.7 mmol) was used as a starting material to carry out the reaction of the material with hydrazine hydrate (1.5 mL, 25 mmol) to give the title product 1-(2- Methoxy-ethyl)-3-methyl-4-oxo-4,5-4,5-dihydro-1H-pyrrole[2,3-d]pyridazine-2-carboxylic acid methyl ester 33c ( 4.405 g, white solid). Yield: 95.7%. MS m/z (ESI): 280 [M+ 1] Step 4
4-[3-氯 -4-(3-氟-苄氧基) -苯氧基] 小(2-甲氧基 -乙基 )-3-甲基 -1H-吡咯并 [2,3-d]哒 嗪 -2-羧酸乙酯 4-[3-chloro-4-(3-fluoro-benzyloxy)-phenoxy] succinate (2-methoxy-ethyl)-3-methyl-1H-pyrrolo[2,3-d Ethyl pyridazine-2-carboxylate
按照本发明实施例 1第三、四步所述相同方式反应,使用上述第二步中所得 到的化合物 1-(2-甲氧基 -乙基 )-3-甲基 -4-氧代 -4,5-4,5-二氢 -1H-吡咯 [2,3-d]哒嗪 -2- 羧酸甲酯 33c ( 1.4 g, 5 mmol)作原料,得到本标题产物 4-[3-氯 -4-(3-氟-苄氧基) - 苯氧基] -1-(2-甲氧基 -乙基 )-3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸乙酯 33 ( 747 mg, 黄色固体)。 产率: 32%。 In the same manner as described in the third and fourth steps of Example 1 of the present invention, the compound 1-(2-methoxy-ethyl)-3-methyl-4-oxo obtained in the above second step was used. 4,5-4,5-Dihydro-1H-pyrrole[2,3-d]pyridazine-2-carboxylic acid methyl ester 33c (1.4 g, 5 mmol) was used as the starting material to give the title product 4-[3- Chloro-4-(3-fluoro-benzyloxy)-phenoxy]-1-(2-methoxy-ethyl)-3-methyl-1H-pyrrolo[2,3-d]pyridazine Ethyl 2-carboxylate 33 (747 mg, yellow solid). Yield: 32%.
MS m/z (ESI): 513[M+ 1] MS m/z (ESI): 513 [M+ 1]
1HNMR(400MHz,DMSO-i¾): 59.15(d, 2H), 8.49(s,lH), 7.87 (m, IH), 7.57(m, 2H), 7.35(s, 1H), 7.19(d, 1H), 6 52(s, 2H),5.89(t, 2H), 5.49(q, 2H), 4.49(t, 2H), 3.94(s, 3H): 3.42(s, 3H), 2.50(m, 4H), 1.70(t, 3H) 实施例 34 1 H NMR (400 MHz, DMSO-i 3⁄4): 59.15 (d, 2H), 8.49 (s, lH), 7.87 (m, IH), 7.57 (m, 2H), 7.35 (s, 1H), 7.19 (d, 1H) ), 6 52(s, 2H), 5.89(t, 2H), 5.49(q, 2H), 4.49(t, 2H), 3.94(s, 3H): 3.42(s, 3H), 2.50(m, 4H) ), 1.70(t, 3H) Example 34
4-Γ3-氯 -4-(3-氟-苄氧基) -苯氧基 1 -1-(2-甲氧基 -乙基 )-3-甲基 -1H-吡咯并「2,3-dl哒 嗪 -2-羧酸 (2-二乙氨基-乙基) -酰胺 4-Γ3-chloro-4-(3-fluoro-benzyloxy)-phenoxy-1- -1-(2-methoxy-ethyl)-3-methyl-1H-pyrrole "2,3- Dl-pyridazine-2-carboxylic acid (2-diethylamino-ethyl)-amide
4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -1-(2-甲氧基乙基) -3-甲基 -1H-吡咯并 [2,3-d]哒嗪- 2-羧酸
在 lOO mL茄形瓶中依次加入 4-[3-氯 -4-(3-氟-苄氧基) -苯氧基]小(2-甲氧基- 乙基) -3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸 (2-二乙氨基-乙基) -酰胺 33 ( 1.5 g, 2.9mmol), 无水乙醇 (30 mL) 和 1N氢氧化钠溶液 ( 18 mL, 30 mmol)。 混合 物加热回流 3小时, 反应完毕。反应液冷却至室温, 减压下除去大部分乙醇, 用 1N盐酸溶液调节 pH值至酸性, 有黄色沉淀生成, 过滤, 得到 4-[3-氯 -4-(3-氟- 苄氧基) -苯氨基] -1-(2-甲氧基乙基) -3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸 34a4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-1-(2-methoxyethyl)-3-methyl-1H-pyrrolo[2,3-d Pyridazine- 2-carboxylic acid 4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy]succinimide (2-methoxy-ethyl)-3-methyl-1H was sequentially added to a 100 mL eggplant-shaped flask. -pyrrolo[2,3-d]pyridazine-2-carboxylic acid (2-diethylamino-ethyl)-amide 33 (1.5 g, 2.9 mmol), absolute ethanol (30 mL) and 1N sodium hydroxide Solution (18 mL, 30 mmol). The mixture was heated to reflux for 3 hours and the reaction was completed. The reaction solution was cooled to room temperature, and most of the ethanol was removed under reduced pressure. The pH was adjusted to acidic with 1N hydrochloric acid, and a yellow precipitate was formed and filtered to give 4-[3-chloro-4-(3-fluoro-benzyloxy). -phenylamino]-1-(2-methoxyethyl)-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid 34a
( 1.382 g, 黄色固体)。 产率: 98.1 %。 ( 1.382 g, yellow solid). Yield: 98.1%.
MS m/z (ESI): 485[M+ 1] 第二步 MS m/z (ESI): 485 [M+ 1] Step 2
7_[3-氯 -4-(3-氟-节氧基) -苯氧基] -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸 (2-二乙氨基-乙 基) -酰胺 7 _[3-Chloro-4-(3-fluoro-p-ethoxy)-phenoxy]-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid (2-diethylamino-B -amide
按照本发明实施例 1第六步所述相同方式反应,使用上述第一步中所得到的 化合物 4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -1-(2-甲氧基乙基) -3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸 34a ( 100 mg, 0.21 mmol)作原料, 进行该原料与二乙基乙二 胺的反应, 得到本标题产物 7-[3-氯 -4-(3-氟-苄氧基) -苯氧基] -1H-吡咯并 [2,3-d] 哒嗪 -2-羧酸 (2-二乙氨基-乙基) -酰胺 34 ( 95 mg, 黄色固体)。 产率: 77.9%。 In the same manner as described in the sixth step of Example 1 of the present invention, the compound 4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-1- (2-methoxyethyl)-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid 34a (100 mg, 0.21 mmol) as starting material, the starting material and the second The reaction of ethylenediamine gives the title product 7-[3-chloro-4-(3-fluoro-benzyloxy)-phenoxy]-1H-pyrrolo[2,3-d]pyridazine-2 - Carboxylic acid (2-diethylamino-ethyl)-amide 34 (95 mg, yellow solid). Yield: 77.9%.
MS m/z (ESI): 584[M+ 1] MS m/z (ESI): 584 [M+ 1]
1HNMR(400MHz,DMSO- ¾): 67.44(m, 2H), 7.29(s,lH), 7.25 (m, 1H), 7.18(m, 2H), 6.94(s, 1H), 6.86(d, 1H), 5.06(s, 2H), 4.27(t, 2H), 3.67(m,2H), 3.63(m, 4H), 3.19(s, 3H), 2.87(m, 4H), 2.62(s, 3H), 1.09(s, 6H) 实施例 35 1 H NMR (400 MHz, DMSO - 3⁄4): 67.44 (m, 2H), 7.29 (s, lH), 7.25 (m, 1H), 7.18 (m, 2H), 6.94 (s, 1H), 6.86 (d, 1H) ), 5.06(s, 2H), 4.27(t, 2H), 3.67(m, 2H), 3.63(m, 4H), 3.19(s, 3H), 2.87(m, 4H), 2.62(s, 3H) , 1.09(s, 6H) Example 35
4-Γ3-氯 -4-(3-氟-苄氧基) -苯氧基 1 - 2-甲氧基 -乙基 3-甲基 -1H-吡咯并「2,3-dl哒 嗪 -2-羧酸! ~2-(4-甲基 -哌嗪 -1-基) -乙基 1-酰胺 4-Γ3-chloro-4-(3-fluoro-benzyloxy)-phenoxy 1- 2 -methoxy-ethyl 3-methyl-1H-pyrrolo "2,3-dlpyridazine-2 -carboxylic acid! ~2-(4-Methyl-piperazin-1-yl)-ethyl 1-amide
重复本发明实施例 34 第一步的反应, 使用上述第一步中所得到的化合物 4-[3-氯 -4-(3-氟-苄氧基) -苯氨基 ]小(2-甲氧基乙基) -3-甲基 -1H-吡咯并 [2,3-d]哒嗪- 2-羧酸 34a作原料,按照本发明实施例 34第二步所述相同方式进行该原料与 2-(4-
甲基 -哌嗪 -1-基) -乙胺的反应, 则得到标题产物 4-[3-氯 -4-(3-氟-节氧基) -苯氧基] -1-(2-甲氧基 -乙基 )-3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸 [2-(4-甲基 -哌嗪 -1-基) -乙 基] -酰胺 35 (68 mg, 黄色固体)。 产率 40%。 The reaction of the first step of Example 34 of the present invention was repeated, using the compound 4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino] small (2-methoxy) obtained in the above first step. Base ethyl)-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid 34a as a starting material, and the raw material is carried out in the same manner as described in the second step of Example 34 of the present invention. -(4- The reaction of methyl-piperazin-1-yl)-ethylamine gives the title product 4-[3-chloro-4-(3-fluoro-hydroxy-oxy)-phenoxy]-1-(2- Oxy-ethyl)-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid [2-(4-methyl-piperazin-1-yl)-ethyl] - Amide 35 (68 mg, yellow solid). The yield was 40%.
MS m/z (ESI): 611[M+1] MS m/z (ESI): 611 [M+1]
1HNMR(400MHz ,DMSO-i¾: 57.63(s, 1H), 7.59(s,lH), 7.44 (m, 1H), 7.28(m, 1H), 7.15(m, 2H), 6.96(m,lH), 6.87(d, 1H), 5.06(s, 2H), 4.4(t, 2H,J= .4Hz), 3.66(t, 4H), 3.5 l(m, 2H), 3.21(s, 3H), 2.56(s, 3H), 2.44(m, 4H), 2.21(s, 3H),2.19(m,4H) 实施例 36 1 H NMR (400 MHz, DMSO-i3⁄4: 57.63 (s, 1H), 7.59 (s, lH), 7.44 (m, 1H), 7.28 (m, 1H), 7.15 (m, 2H), 6.96 (m, lH) , 6.87(d, 1H), 5.06(s, 2H), 4.4(t, 2H, J= .4Hz), 3.66(t, 4H), 3.5 l(m, 2H), 3.21(s, 3H), 2.56 (s, 3H), 2.44 (m, 4H), 2.21 (s, 3H), 2.19 (m, 4H) Example 36
4-Γ3-氯 -4-(3-氟-苄氧基) -苯氧基 1 甲氧基 -乙基 )-3-甲基 -1H-吡咯并「2,3-dll¾ 嗪 -2-羧酸「3-(4-甲基 -哌嗪 -1-基) -丙基 1-酰胺 4-Γ3-chloro-4-(3-fluoro-benzyloxy)-phenoxy 1 methoxy-ethyl)-3-methyl-1H-pyrrole "2,3-dll3⁄4-azine-2-carboxylate Acid "3-(4-methyl-piperazin-1-yl)-propyl 1-amide
重复本发明实施例 34第一步的反应, 使用上述第一步中所得到的化合物 4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -1-(2-甲氧基乙基) -3-甲基 -1H-吡咯并 [2,3-d]哒嗪- 2-羧酸 34a作原料,按照本发明实施例 34第二步所述相同方式进行该原料与 3-(4- 甲基 -哌嗪 -1-基)丙胺的反应, 则得到标题产物 4-[3-氯 -4-(3-氟-苄氧基) -苯氧基] -1-(2-甲氧基-乙基) -3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸 [3-(4-甲基 -哌嗪 -1 -基) -丙 基] -酰胺 36 (85 mg, 黄色固体)。 产率 76.5%。 The reaction of the first step of Example 34 of the present invention was repeated, using the compound 4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-1-(2-) obtained in the above first step. Methoxyethyl)-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid 34a is used as a starting material, and the starting material is carried out in the same manner as described in the second step of Example 34 of the present invention. Reaction with 3-(4-methyl-piperazin-1-yl)propylamine gives the title product 4-[3-chloro-4-(3-fluoro-benzyloxy)-phenoxy]-1- (2-methoxy-ethyl)-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid [3-(4-methyl-piperazine-1-yl) -propyl]-amide 36 (85 mg, yellow solid). The yield was 76.5%.
MS m/z (ESI): 625[M+ 1] MS m/z (ESI): 625 [M+ 1]
1HNMR(400MHz ,DMSO- tf): 57.46(m, 2H), 7.29(s,lH), 7.25 (m, 1H), 7.18(m, 2H), 6.94(s, 1H), 6.86(d, 1H), 5.06(s, 2H), 4.27(t, 2H), 3.71(m, 4H), 3.56(m, 2H), 3.26(s, 3H), 2.73(s, 3H), 2.57(s, 3H), 2.52(m, 4H), 2.32(m, 4H), 2.24(s, 3H) 实施例 37 1 HNMR (400MHz, DMSO- tf) : 57.46 (m, 2H), 7.29 (s, lH), 7.25 (m, 1H), 7.18 (m, 2H), 6.94 (s, 1H), 6.86 (d, 1H ), 5.06(s, 2H), 4.27(t, 2H), 3.71(m, 4H), 3.56(m, 2H), 3.26(s, 3H), 2.73(s, 3H), 2.57(s, 3H) , 2.52 (m, 4H), 2.32 (m, 4H), 2.24 (s, 3H) Example 37
4-「3-氯 -4-ί3-氟-苄氧基) -苯氧基 1 - 2-甲氧基 -乙基 )-3-甲基 -1Η-吡咯并「2,3-dl哒 嗪 -2-羧酸 (2-吡咯垸 -1-基-乙基) -酰胺
4-"3-Chloro-4-ί3-fluoro-benzyloxy)-phenoxy 1- 2 -methoxy-ethyl)-3-methyl-1 Η-pyrrolo "2,3-dlazine 2-carboxylic acid (2-pyrrole-1-yl-ethyl)-amide
重复本发明实施例 34第一步的反应, 使用上述第一步中所得到的化合物 4-[3-氯 -4-(3-氟-苄氧基) -苯氨基]小(2-甲氧基乙基) -3-甲基 -1H-吡咯并 [2,3-d]哒嗪- 2-羧酸 34a作原料, 按照本发明实施例 34第二步所述相同方式进行该原料与 2- 吡咯垸 -1-乙胺的反应, .则得到标题产物 4-[3-氯 -4-(3-氟-苄氧基) -苯氧基]小(2-甲 氧基-乙基) -3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸 (2-吡咯烷 -1-基-乙基) -酰胺 37(95 mg, 黄色固体)。 产率 84.3 %。 The reaction of the first step of Example 34 of the present invention was repeated, using the compound 4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino] small (2-methoxy) obtained in the above first step. Base ethyl)-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid 34a as a starting material, and the raw material is carried out in the same manner as described in the second step of Example 34 of the present invention. - a reaction of pyrrolein-1-ethylamine, to give the title product 4-[3-chloro-4-(3-fluoro-benzyloxy)-phenoxy]small (2-methoxy-ethyl) 3-Methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide 37 (95 mg, yellow solid). The yield was 84.3 %.
MS m/z (ESI): 582[M+ 1] MS m/z (ESI): 582 [M+ 1]
1HNMR(400MHz ,OUSO-d6): 57.73(m, 2H), 7.56(s,lH), 7.39 (m, 1H), 7.28(m, 2H), 7.05(s, 1H), 6.95(d, 1H), 5.16(s, 2H), 4.39(t, 2H), 3.73(m, 4H), 3.29(s, 3H)5 2.81(m, 2H), 2.75(m, 4H), 2.69(s, 3H), 1.64(m, 4H) 实施例 38 1 H NMR (400 MHz, OUSO-d 6 ): 57.73 (m, 2H), 7.56 (s, lH), 7.39 (m, 1H), 7.28 (m, 2H), 7.05 (s, 1H), 6.95 (d, 1H), 5.16(s, 2H), 4.39(t, 2H), 3.73(m, 4H), 3.29(s, 3H) 5 2.81(m, 2H), 2.75(m, 4H), 2.69(s, 3H ), 1.64 (m, 4H) Example 38
4-Γ3-氯 -4-(3-氟-苄氧基) -苯氧基 1 -1-IY2-甲氧基-乙氧基) -乙基 3-甲基 -1H-吡咯并 Γ2,3-(11哒嗪 -2-羧酸乙酯 4-Γ3-chloro-4-(3-fluoro-benzyloxy)-phenoxy 1 -1-IY2-methoxy-ethoxy)-ethyl 3-methyl-1H-pyrroloindole 2,3 -(11-oxazine-2-carboxylic acid ethyl ester
第一步 First step
l-[(2-甲氧基-乙氧基) -乙基 ]-3,5-二甲基 -1H-吡咯 -2,4-二羧酸二乙酯 在 250 mL的茄形瓶中依次加入 3,5-二甲基 -1H-吡咯 -2,4-二羧酸二乙酯 la (5.742 g, 24 mmol), 二甲基亚砜 (40 mL) 和叔丁醇钾 (2.963 g, 26.4 mmol), 搅拌下加入 1-溴 -2-(2-甲氧基-乙氧基) -乙烷 (5.706 g, 31 mmol), 室温下搅拌 5 小时, 反应完毕。 在反应液中加入冰水 (200 mL), 并用乙酸乙酯萃取 (lOO mL X 3 ) 有固体析出, 合并的有机相用饱和氯化钠洗涤, 无水硫酸钠干燥, 过滤, 减压下浓缩得到的粗品 1-[(2-甲氧基-乙氧基) -乙基 ]-3,5-二甲基 -1H-吡咯 -2,4-二羧 酸二乙酯 38a (8 g, 黄色固体), 直接进行下一步反应。 1-[(2-Methoxy-ethoxy)-ethyl]-3,5-dimethyl-1H-pyrrole-2,4-dicarboxylate in a 250 mL eggplant bottle Add 3,5-dimethyl-1H-pyrrole-2,4-dicarboxylate la (5.742 g, 24 mmol), dimethyl sulfoxide (40 mL) and potassium t-butoxide (2.963 g, 26.4 mmol), 1-bromo-2-(2-methoxy-ethoxy)-ethane (5.706 g, 31 mmol) was added with stirring, and stirred at room temperature for 5 hr. Ice water (200 mL) was added to the reaction mixture, and the mixture was evaporated, evaporated, evaporated, evaporated, evaporated. The resulting crude product 1-[(2-methoxy-ethoxy)-ethyl]-3,5-dimethyl-1H-pyrrole-2,4-dicarboxylic acid diethyl ester 38a (8 g, yellow Solid), proceed directly to the next reaction.
MS m/z (ESI): 342[M+ 1] MS m/z (ESI): 342 [M+ 1]
' 第二步 'Second step
5-甲酰基小[(2-甲氧基-乙氧基) -乙基 ]-3-甲基 -1H-吡咯 -2,4-二羧酸二乙酯 按照本发明实施例 1第一步所述相同方式,使用上述第一步中所得到的化合 物 1-[(2-甲氧基-乙氧基) -乙基 ]-3,5-二甲基 -1H-吡咯 -2,4-二羧酸二乙酯 38a (8.2 g, 24 mmol) 作原料, 进行该原料与硝酸铈铵的反应, 则得到 5-甲酰基 -1-[(2-甲氧 基-乙氧基) -乙基 ]-3-甲基 -1H-吡咯 -2,4-二羧酸二乙酯 38b (5.551g, 黄色油状液 体)。 产率 65%。 5-formyl small [(2-methoxy-ethoxy)-ethyl]-3-methyl-1H-pyrrole-2,4-dicarboxylic acid diethyl ester according to the first step of Example 1 of the present invention In the same manner, the compound 1-[(2-methoxy-ethoxy)-ethyl]-3,5-dimethyl-1H-pyrrole-2,4- obtained in the above first step was used. Dicarboxylic acid diethyl ester 38a (8.2 g, 24 mmol) was used as a raw material to carry out the reaction of the starting material with ammonium cerium nitrate to obtain 5-formyl-1-[(2-methoxy-ethoxy)-B. Diethyl 3-methyl-1H-pyrrole-2,4-dicarboxylate 38b (5.551 g, yellow oily liquid). The yield was 65%.
MS m/z (ESI): 356[M+ 1] 第三步 ' MS m/z (ESI): 356[M+ 1] Step 3 '
1-[(2-甲氧基-乙氧基) -乙基 ]-3-甲基 -4-氧代 -4,5-4,5-二氢 -1H-吡咯 [2,3-d]哒嗪 -2-羧 酸甲酯 1-[(2-methoxy-ethoxy)-ethyl]-3-methyl-4-oxo-4,5-4,5-dihydro-1H-pyrrole [2,3-d] Methyl pyridazine-2-carboxylate
按照本发明实施例 1第二步所述相同方式, 使用上述第二步中所得到的化 合物 5-甲酰基小[(2-甲氧基-乙氧基) -乙基 ]-3-甲基 -1H-吡咯 -2,4-二羧酸二乙酯 38b
(4.29 g, 12 mmol)作原料, 进行该原料与水合肼 (0.72 g, 12 mmol)的反应, 则 得到标题产物 1-[(2-甲氧基-乙氧基) -乙基 ]-3-甲基 -4-氧代 -4,5-4,5-二氢 -1H-吡咯 [2,3-d]哒嗪 -2-羧酸甲酯 38c (4.651 g, 白色固体), 直接进行下一步反应。 In the same manner as described in the second step of Example 1 of the present invention, the compound 5-formylsuccini[(2-methoxy-ethoxy)-ethyl]-3-methyl obtained in the above second step was used. -1H-pyrrole-2,4-dicarboxylic acid diethyl ester 38b (4.29 g, 12 mmol) was used as a starting material to give the titled product (1,2-methoxy-ethoxy)-ethyl] Methyl 4-oxo-4,5-4,5-dihydro-1H-pyrrole[2,3-d]pyridazine-2-carboxylic acid methyl ester 38c (4.651 g, white solid) The next step is to react.
MS m/z (ESI): 280[M+ 1] 第四步 MS m/z (ESI): 280 [M+ 1] Step 4
4-[3-氯斗(3-氟-苄氧基) -苯氧基] -1-[(2-甲氧基-乙氧基) -乙基 ]-3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸乙酯 4-[3-Chloro(3-fluoro-benzyloxy)-phenoxy]-1-[(2-methoxy-ethoxy)-ethyl]-3-methyl-1H-pyrrole [2,3-d]pyridazine-2-carboxylic acid ethyl ester
按照本发明实施例 1第三、 四步所述相同方式反应, 使用上述第三步中所得 到的化合物 1-[(2-甲氧基-乙氧基) -乙基 ]-3-甲基 -4-氧代 -4,5-4,5-二氢 -1H-吡咯 [2,3-d]哒嗪 -2-羧酸甲酯 38c (324 mg, 1 mmol) 作原料, 得到本标题产物 4-[3- 氯 -4-(3-氟-苄氧基) -苯氧基] 小[(2-甲氧基-乙氧基) -乙基 ]-3-甲基 -1H-吡咯并 [2,3-d] 哒嗪 -2-羧酸乙酯 38 (2.83 g, 黄色固体)。 产率: 41.8 %。 In the same manner as described in the third and fourth steps of Example 1 of the present invention, the compound 1-[(2-methoxy-ethoxy)-ethyl]-3-methyl obtained in the above third step was used. 4-Oxo-4,5-4,5-dihydro-1H-pyrrole[2,3-d]pyridazine-2-carboxylic acid methyl ester 38c (324 mg, 1 mmol) as a starting material Product 4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy]min[(2-methoxy-ethoxy)-ethyl]-3-methyl-1H-pyrrole And [2,3-d] oxazine-2-carboxylic acid ethyl ester 38 (2.83 g, yellow solid). Yield: 41.8 %.
MS m/z (ESI): 558[M+ 1] MS m/z (ESI): 558 [M+ 1]
lHNMR: (DMSO-D6, 400MHz) δ 实施例 39 lH NMR: (DMSO-D 6 , 400 MHz) δ Example 39
4-Γ3-氯斗 (3-氟 ^氧基 苯氧基 1 -1-「(2-甲氧基-乙氧基) -乙基 1-3-甲基 -1Η-吡咯并 Γ2,3-ά 嗪 -2-羧酸 (2-二乙氨基-乙基) -酰胺 4- Γ3 - chloro hopper (3-fluoro ^ phenoxypropionic 1-1-- "(2-methoxy - ethoxy) - ethyl 1-3- methyl-pyrrolo Γ2,3- -1Η- Pyridazine-2-carboxylic acid (2-diethylamino-ethyl)-amide
4-[3-氯 -4-(3-氟苄氧基) -苯氨基] -l-[2-(2-甲氧基乙氧基) -乙基 ]-3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸 4-[3-Chloro-4-(3-fluorobenzyloxy)-phenylamino]-l-[2-(2-methoxyethoxy)-ethyl]-3-methyl-1H-pyrrole And [2,3-d]pyridazine-2-carboxylic acid
按照本发明实施例 1第五步所述相同方式反应, 使用实施例 38所得到的化 合物 44-[3-氯 -4-(3-氟-苄氧基) -苯氧基]小[(2-甲氧基-乙氧基) -乙基 ]-3-甲基 -1H-吡 咯并 [2,3-d]哒嗪 -2-羧酸乙酯 38作原料, 得到本标题产物 4-[3-氯 -4-(3-氟苄氧基) - 苯氨基 ]-1-[2-(2-甲氧基乙氧基) -乙基 ]-3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸 38a (45 mg, 黄色固体)。 产率: 23.7%。 In the same manner as described in the fifth step of Example 1 of the present invention, the compound 44-[3-chloro-4-(3-fluoro-benzyloxy)-phenoxy] small [(2) obtained in Example 38 was used. -Methoxy-ethoxy)ethyl-ethyl]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylate 38 as the starting material to give the title product 4-[ 3-Chloro-4-(3-fluorobenzyloxy)-phenylamino]-1-[2-(2-methoxyethoxy)-ethyl]-3-methyl-1H-pyrrolo[2 , 3-d] pyridazine-2-carboxylic acid 38a (45 mg, yellow solid). Yield: 23.7%.
MS m/z (ESI): 529[M+ 1] 第二步 MS m/z (ESI): 529 [M+ 1] Step 2
4-[3-氯 -4-(3-氟-节氧基) -苯氧基] -1-[(2-甲氧基-乙氧基) -乙基 ]-3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸 (2-二乙氨基-乙基) -酰胺 4-[3-Chloro-4-(3-fluoro-p-ethoxy)-phenoxy]-1-[(2-methoxy-ethoxy)-ethyl]-3-methyl-1H- Pyrrolo[2,3-d]pyridazine-2-carboxylic acid (2-diethylamino-ethyl)-amide
按照本发明实施例 1第六步所述相同方式反应,使用上述第一步中所得到的 化合物 4-[3-氯 -4-(3-氟苄氧基) -苯氨基 ]小[2-(2-甲氧基乙氧基) -乙基 ]-3-甲基 -1H- 吡咯并 [2,3-d]哒嗪 -2-羧酸 38a作原料, 得到本标题产物 4-[3-氯 -4-(3-氟^氧基) - 苯氧基] -1-[(2-甲氧基-乙氧基) -乙基 ]-3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸 (2-二 乙氨基-乙基) -酰胺 39 (35 mg, 黄色固体)。 产率: 29.7 %。 In the same manner as described in the sixth step of Example 1 of the present invention, the compound 4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino] small [2-] obtained in the above first step was used. (2-methoxyethoxy)-ethyl]-3-methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid 38a as a starting material to give the title product 4-[3 -chloro-4-(3-fluorooxy)-phenoxy]-1-[(2-methoxy-ethoxy)-ethyl]-3-methyl-1H-pyrrolo[2, 3-d] pyridazine-2-carboxylic acid (2-diethylamino-ethyl)-amide 39 (35 mg, yellow solid). Yield: 29.7 %.
MS m/z (ESI): 628[M+ 1] MS m/z (ESI): 628 [M+ 1]
LHNMR (400MHz, DMSO-d6): 57.90(d, 2H), 7.56(q, 1H), 7.45(t, 1H), 7.30(t, 2H), 7.17(m, 2H), 5.22(s, 2H), 4.49(t, 2H), 3.66(s, 3H), 3.40(m, 4H), 3.32(m, 4H), 3.15(s, 3H), 2,57(s, 4H), 1.23(t, 6H) 实施例 40 L HNMR (400MHz, DMSO-d6): 57.90 (d, 2H), 7.56 (q, 1H), 7.45 (t, 1H), 7.30 (t, 2H), 7.17 (m, 2H), 5.22 (s, 2H) ), 4.49(t, 2H), 3.66(s, 3H), 3.40(m, 4H), 3.32(m, 4H), 3.15(s, 3H), 2,57(s, 4H), 1.23(t, 6H) Example 40
4-Γ3-氯 -4-(3-氟-苄氧基 )-苯氧基 1 -1-IT2-甲氧基-乙氧基) -乙基 1-3-甲基 -1-(2-吗啉 -4- 基-乙基 1H-吡咯并「2,3-dl哒嗪 -2-羧酸乙酯 4-Γ3-chloro-4-(3-fluoro-benzyloxy)-phenoxy 1 -1-IT2-methoxy-ethoxy)-ethyl 1-3-methyl-1-(2- Morpholine-4-yl-ethyl 1H-pyrrolo "2,3-dlpyridazine-2-carboxylic acid ethyl ester
第 "~ The first "~
按照本发明实施例 38第一步所述相同方式, 使用 3,5-二甲基 -1Η-吡咯 -2,4- 二羧酸二乙酯 la ( 5.742 g, 24 mmol) 作原料, 进行该原料与 1-溴 -2-(2-甲氧基- 乙氧基) -乙烷 (5.706 g, 31 mmol) 的反应, 则得到本标题产物 3,5-二甲基 -1-(2- 吗啡琳 -4_乙基) -1H-吡咯 -2,4-二羧酸二乙酯 40a ( 8 g, 黄色固体), 直接进行下一 步反应。 ' In the same manner as described in the first step of Example 38 of the present invention, using 3,5-dimethyl-1?-pyrrole-2,4-dicarboxylic acid diethyl la (5,742 g, 24 mmol) as a raw material, Reaction of the starting material with 1-bromo-2-(2-methoxy-ethoxy)-ethane (5.706 g, 31 mmol) afforded the title product 3,5-dimethyl-1-(2- Morpholine- 4 -ethyl) -1H-pyrrole-2,4-dicarboxylic acid diethyl ester 40a (8 g, yellow solid) was taken directly to the next step. '
MS m/z (ESI): 353[M+ 1] 第二步 MS m/z (ESI): 353 [M+ 1] Step 2
5-甲酰基3-二甲基小(2-吗啡啉 -4-乙基) -1H-吡咯 -2,4-二羧酸二乙酯 按照本发明实施例 1第一步所述相同方式,使用上述第一步中所得到的化合 物 3,5-二甲基小 (2-吗啡啉 -4-乙基) -1H-吡咯 -2,4-二羧酸二乙酯 40a ( 11.7 g, 33 mmol)作原料, 进行该原料与硝酸铈铵的反应, 贝 IJ得到 5-甲酰基 - 3-二甲基小(2- 吗啡啉 -4_乙基) -1H-吡咯 -2,4-二羧酸二乙酯 40b (2.043 g, 黄色固体)。 产率 13.9 %。 5-formyl 3-dimethyl small (2-morpholine-4-ethyl)-1H-pyrrole-2,4-dicarboxylic acid diethyl ester in the same manner as described in the first step of Example 1 of the present invention, Using the compound obtained in the above first step, diethyl 3,5-dimethyl small (2-morpholine-4-ethyl)-1H-pyrrole-2,4-dicarboxylate 40a (11.7 g, 33 Methyl) as a starting material, the reaction of the starting material with ammonium cerium nitrate, and the thiazole IJ gives 5-formyl-3-dimethyl small (2-morpholine- 4 -yl-)-H-pyrrole-2,4-di Dicarboxylate 40b (2.043 g, yellow solid). The yield was 13.9%.
MS m/z (ESI): 367[M+ 1] 第三步 MS m/z (ESI): 367[M+ 1] Step 3
3-甲基 - 1 -(2-吗啡啉 -4-乙基) -4-氧代 -4,5-二氢 - 1H-吡咯并 [2,3-d]哒嗪 -2-羧酸乙酯 按照本发明实施例 1第二步所述相同方式,使用上述第二步中所得到的化合 物 5-甲酰基 -3-二甲基小(2-吗啡啉 -4-乙基) -1H-吡咯 -2,4-二羧酸二乙酯 40b (0.84 g, 2.3 mmol) 作原料, 进行该原料与水合肼 (0.23 mL, 3.5 mmol)的反应, 则得 到标题产物 3-甲基 -1-(2-吗啡啉 -4-乙基) -4-氧代 -4,5-二氢 -1H-吡咯并 [2,3-d]哒嗪
-2-羧酸乙酯 40c ( 0.55 g, 黄色固体), 直接进行下一步反应。 3-methyl-1 -(2-morpholine-4-ethyl)-4-oxo-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid The ester was obtained in the same manner as described in the second step of Example 1 of the present invention, using the compound 5-formyl-3-dimethyl small (2-morpholine-4-ethyl)-1H- obtained in the above second step. Pyrrole-2,4-dicarboxylic acid diethyl ester 40b (0.84 g, 2.3 mmol) was used as a starting material, and the title compound (3-methyl-1-) was obtained. (2-morpholine-4-ethyl)-4-oxo-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazine Ethyl 2-carboxylate 40c (0.55 g, yellow solid) was taken directly to the next step.
MS m/z (ESI): 335[M+ 1] 第四歩 MS m/z (ESI): 335 [M+ 1]
4-[3-氯 -4-(3-氟-苄氧基) -苯氧基] -l-[(2-甲氧基-乙氧基) -乙基 ]-3-甲基 -l-(2-吗啉 -4- 基-乙基) -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸乙酯 4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy]-l-[(2-methoxy-ethoxy)-ethyl]-3-methyl-l- (2-morpholin-4-yl-ethyl)-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid ethyl ester
按照本发明实施例 40第四步所述相同方式反应, 使用上述第三步中所得到 的化合物 3-甲基 -1-(2-吗啡啉 -4-乙基) -4-氧代 -4,5-二氢 -1H-吡咯并 [2,3-d]哒嗪 -2- 羧酸乙酯 40c (334 mg, 1 mmol) 作原料, 得到本标题产物 4-[3-氯 -4-(3-氟 -苄氧 基) -苯氧基] -1-[(2-甲氧基-乙氧基) -乙基 ]-3-甲基 -1-(2-吗啉 -4-基-乙基) -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸乙酯 40 (257 mg, 黄色固体)。 产率: 45.3 %。 In the same manner as described in the fourth step of Example 40 of the present invention, the compound 3-methyl-1-(2-morphofolin-4-ethyl)-4-oxo-4 obtained in the above third step was used. , 5-dihydro-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid ethyl ester 40c (334 mg, 1 mmol) as a starting material to give the title product 4-[3-chloro-4- (3-Fluoro-benzyloxy)-phenoxy]-1-[(2-methoxy-ethoxy)-ethyl]-3-methyl-1-(2-morpholin-4-yl) -ethyl) -1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid ethyl ester 40 (257 mg, yellow solid). Yield: 45.3 %.
MS m/z (ESI): 568[M+ 1] MS m/z (ESI): 568 [M+ 1]
1HMMR (400MHz, DMSO-d6): 58.08(s, 1H), 7.88(s, 1H), 7.54(m, 1H), 7.47(m, 1H), 7.31(m,2H), 7.16(m, 2H), 5.23(s, 2H), 4.63(t, 2H), 4.39(q, 2H), 3.46(m, 4H), 3.28 (s, 3H), 2.73(s, 3H), 2.56(m, 2H), 2.36(m, 4H) 实施例 41 1 HMMR (400MHz, DMSO-d6): 58.08(s, 1H), 7.88(s, 1H), 7.54(m, 1H), 7.47(m, 1H), 7.31(m,2H), 7.16(m, 2H) ), 5.23(s, 2H), 4.63(t, 2H), 4.39(q, 2H), 3.46(m, 4H), 3.28 (s, 3H), 2.73(s, 3H), 2.56(m, 2H) , 2.36 (m, 4H) Example 41
4-「3-氯斗(3-氟-苄氧基) -苯氧基 1 -1-Γ(2-甲氧基-乙氧基) -乙基 1-3-三氟甲基 -1H-吡 咯并『2,3-dl哒嗪 -2-羧酸乙酯 , 4-"3-Chloro-(3-fluoro-benzyloxy)-phenoxy-1- -1-(2-methoxy-ethoxy)-ethyl 1-3-trifluoromethyl-1H- Pyrrole and 2,3-dl-pyridazine-2-carboxylic acid ethyl ester,
41 第一步 41 first step
4,4,4-三氟 -2-肟基 3-羰基-丁酸乙酯 4,4,4-trifluoro-2-indenyl 3-carbonyl-butyric acid ethyl ester
在冰浴条件下, 将 4,4,4-三氟 -3-羰基-丁酸乙酯 41a (3.822 g, 20.75 mmol)和 冰醋酸 (6 mL)加入到 100 mL的圆底烧瓶中, 搅拌下逐滴滴加亚硝酸钠的水溶液 (1.43 g, 20.75 mmol溶解在 4 mL水中), 在整个过程中控制反应温度为 0〜5°C, 滴加结束后, 再加水 (l mL), 于冰水浴中反应半小时, 撤去冰水浴, 在室温下继 续反应约 3小时, 点板跟踪至原料消失, 反应结束, 得到标题产物 4,4,4-三氟 -2- 肟基 3-羰基-丁酸乙酯 4ib m, 直接投下一步反应。 第二步 Add 4,4,4-trifluoro-3-carbonyl-butyric acid ethyl ester 41a (3.822 g, 20.75 mmol) and glacial acetic acid (6 mL) to a 100 mL round bottom flask under ice-cooling, stir An aqueous solution of sodium nitrite (1.43 g, 20.75 mmol dissolved in 4 mL of water) was added dropwise, and the reaction temperature was controlled to 0 to 5 ° C throughout the process. After the addition was completed, water (1 mL) was added thereto. After reacting for half an hour in an ice water bath, the ice water bath was removed, and the reaction was continued at room temperature for about 3 hours. The spot was traced until the starting material disappeared, and the reaction was completed to obtain the title product 4,4,4-trifluoro-2-indolyl 3-carbonyl- Ethyl butyrate 4ib m was directly injected into the next reaction. Second step
5-甲基 -3-三氟甲基 -1氢 -吡咯 -2,4二羧酸 -4-叔丁酯 -2-乙酯 5-methyl-3-trifluoromethyl-1hydrogen-pyrrole-2,4dicarboxylic acid-4-tert-butyl ester-2-ethyl ester
取一个配有温度计, 滴液漏斗的 100 mL的三颈烧瓶, 称取 3-羰基-丁酸-叔 丁酯 (3.28g, 20.75mmol), 冰醋酸 (9.3 mL)于三颈瓶中, 搅拌下升温至 65 °C, 称 量锌粉 (2.7 g, 41.5 mmol), 用滴液漏斗滴加第一步反应的反应液 41b, 分多次加 入锌粉,水浴控制体系温度保持在 75°C左右,反应 2小时,然后降低温度到 40〜 45Ό , 反应过夜。 点板跟踪反应结束, 在反应液中加入水 (30 mL)和乙酸乙酯 (50 mL), 搅拌 15分钟后, 用乙酸乙酯 (50 mLx3)萃取反应液。 合并有机相, 依 次用水 (50 mLX 2)、 饱和碳酸氢钠水溶液 (50 mLX 2)、 饱和氯化钠水溶液 (50 mL X 2) 洗涤, 乙酸乙酯层用无水硫酸钠干燥, 过滤, 减压浓缩, 残余物用甲苯-正 I 己垸重结晶得到标题产物 5-甲基 -3-三氟甲基 -1 氢-吡咯 -2,4二羧酸 -4-叔丁酯 -2- 乙酯 41c(3.66 g, 白色絮状固体), 产率: 55%。 Take a 100 mL three-necked flask equipped with a thermometer and a dropping funnel, weigh 3-carbonyl-butyric acid-tert-butyl ester (3.28 g, 20.75 mmol), glacial acetic acid (9.3 mL) in a three-necked flask, stir. The temperature was raised to 65 °C, and the zinc powder (2.7 g, 41.5 mmol) was weighed. The reaction liquid 41b of the first step reaction was added dropwise with a dropping funnel, and the zinc powder was added in multiple portions. The temperature of the water bath control system was maintained at 75 °C. Left and right, react for 2 hours, then lower the temperature to 40~45 Ό and react overnight. The reaction was completed by the spotting, and water (30 mL) and ethyl acetate (50 mL) were added to the mixture, and the mixture was stirred for 15 minutes, and then the mixture was extracted with ethyl acetate (50 mL×3). The organic phase was combined and washed with water (50 mL EtOAc), EtOAc (EtOAc) Concentration by pressure, the residue was recrystallized from toluene-n-hexane to give the title product 5-methyl-3-trifluoromethyl-1 hydrogen-pyrrole-2,4dicarboxylic acid-4-tert-butyl ester-2- Ester 41c (3.66 g, white flocculent solid), Yield: 55%.
MS m/z (ESI): 320[M- 1]
Ή NMR ( 400 MHz, CDCl3-i/ ): 54.37(q, J=7.2Hz, 2H), 2.45(s, 3H), 1.56(s,9H), 1.37(t, J=7.2Hz, 3H)。 第三步 MS m/z (ESI): 320[M-1] NMR NMR ( 400 MHz, CDCl 3 -i/ ): 54.37 (q, J = 7.2 Hz, 2H), 2.45 (s, 3H), 1.56 (s, 9H), 1.37 (t, J = 7.2 Hz, 3H) . third step
5-羟甲基 -3-三氟甲基 -1H-吡咯 -2,4-二羧酸 4-叔丁酯 2-乙酯 在 250 mL茄形瓶中加入 5-甲基 -3-三氟甲基 -1氢 -吡咯 -2,4二羧酸 -4-叔丁酯 -2-乙酯 41c (6 g, 18.6 mmol) ,四氢呋喃(120 mL),醋酸(20 mL)和水(20 mL) , 混合物在室温下搅拌, 加入硝酸铈铵 (42 g, 76.2 mmol), 反应液在室温下搅拌 过夜, 有沉淀生成。 固体在减压下过滤, 用乙酸乙酯 (200 mL) 洗涤, 粗品进 一步通过柱层析 (正己垸: 乙酸乙酯 = 10: 1 ) 进一步分离纯化, 得到本标题化 合物 5-甲酰基 -3-三氟甲基 -1H-吡咯 -2,4-二羧酸 4-叔丁酯 2-乙酯 41d ( 1.14 g, 黄 色固体), 产率: 18.2%。 5-Hydroxymethyl-3-trifluoromethyl-1H-pyrrole-2,4-dicarboxylic acid 4-tert-butyl ester 2-ethyl ester in a 250 mL eggplant-shaped flask with 5-methyl-3-trifluoro Methyl-1H-pyrrole-2,4dicarboxylic acid-4-tert-butyl ester-2-ethyl ester 41c (6 g, 18.6 mmol), tetrahydrofuran (120 mL), acetic acid (20 mL) and water (20 mL The mixture was stirred at room temperature, ammonium cerium nitrate (42 g, 76.2 mmol) was added, and the reaction mixture was stirred at room temperature overnight, and a precipitate formed. The solid was filtered under reduced pressure and washed with EtOAc EtOAc EtOAcjjjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH Trifluoromethyl-1H-pyrrole-2,4-dicarboxylic acid 4-tert-butyl ester 2-ethyl ester 41d ( 1.14 g, yellow solid), yield: 18.2%.
MS m/z (ESI): 338[M+1] 第四步 MS m/z (ESI): 338[M+1] Step 4
5-甲酰基 -3-三氟甲基 -1H-吡咯 -2,4-二羧酸 4-叔丁酯 2-乙酯 在 100 mL茄形瓶中加入吡啶三氧化铬(969 mg, 4.39 mmol),二氯甲烷(15 mL ), 醋酸钠 (200 mg, 2.3 mmol) , 混合物在室温下搅拌, 逐渐滴加 5-羟甲基 -3-甲基 -1H-吡咯 -2,4-二羧酸 4-叔丁酯 2-乙酯 41d ( 1.14 g, 3.38 mmol) 的二氯甲 垸 (20 mL) 溶液。 滴加完毕后, 反应液在室温下搅拌过夜, 有沉淀生成。 固体 在减压下过滤, 用乙酸乙酯 (200 mL)洗涤, 得到黄色固体通过柱层析(正己 烷: 乙酸乙酯 = 10: 1 ) 进一步分离纯化 5-甲酰基 -3-三氟甲基 -1H-吡咯 -2,4-二羧 酸 4-叔丁酯 2-乙酯 41e (490 mg), 产率: 43.3 %。 5-formyl-3-trifluoromethyl-1H-pyrrole-2,4-dicarboxylic acid 4-tert-butyl ester 2-ethyl ester In a 100 mL eggplant-shaped flask, pyridine trioxide (969 mg, 4.39 mmol) was added. ), dichloromethane (15 mL), sodium acetate (200 mg, 2.3 mmol), the mixture was stirred at room temperature, and gradually added 5-hydroxymethyl-3-methyl-1H-pyrrole-2,4-dicarboxylate A solution of 4-tert-butyl ester 2-ethyl ester 41d ( 1.14 g, 3.38 mmol) in dichloromethane (20 mL). After the dropwise addition was completed, the reaction solution was stirred at room temperature overnight, and a precipitate formed. The solid was filtered under reduced pressure and washed with ethyl acetate (EtOAc) (EtOAc) -1H-pyrrole-2,4-dicarboxylic acid 4-tert-butyl ester 2-ethyl ester 41e (490 mg), Yield: 43.3%.
MS m/z (ESI): 334[M- 1] MS m/z (ESI): 334 [M-1]
1H NMR (400 MHz, CDC13- : 59.937 (s,lH), 4.37(q, J=7.2Hz, 2H), 1.53(s, 9H), 1.33(t, J=7.2Hz, 3H) 1H NMR (400 MHz, CDC1 3 - : 59.937 (s, lH), 4.37 (q, J = 7.2 Hz, 2H), 1.53 (s, 9H), 1.33 (t, J = 7.2 Hz, 3H)
第五步 the fifth step
3-三氟甲基 -4-氧代 -4,5-二氢 -1H-吡咯 [2,3-d]哒嗪 -2-羧酸乙酯 在 10 mL的茄形瓶中加入 5-甲酰基 -3-三氟甲基 -1H-吡咯 -2,4-二羧酸 4-叔 丁酯 2-乙酯 41e (200 mg, 0.6mmol) ,醋酸(2 mL),水合胼(0.07 mL, 1.2 mmol) , 加热回流三小时后反应完毕。冷却至室温有大量固体析出,过滤得到 3-三氟甲基 一 4-氧代 -4,5-二氢 -1H-吡咯 [2,3-d]哒嗪 -2-羧酸乙酯 41f ( 120 mg), 产率: 72.7%。 MS m/z (ESI): 274[M- 1] 第六步
4-[3-氯 -4-(3-氟-苄氧基) -苯氧基]小 [(2-甲氧基-乙氧基) -乙基 ]-3-三氟甲基 -m-吡 咯并 [2,3-d]哒嗪 -2-羧酸乙酯 Ethyl 3-trifluoromethyl-4-oxo-4,5-dihydro-1H-pyrrole[2,3-d]pyridazine-2-carboxylate 5-A in a 10 mL eggplant-shaped bottle Acyl-3-trifluoromethyl-1H-pyrrole-2,4-dicarboxylic acid 4-tert-butyl ester 2-ethyl ester 41e (200 mg, 0.6 mmol), acetic acid (2 mL), hydrazine hydrate (0.07 mL, 1.2 mmol), the reaction was completed after heating for three hours. A large amount of solid was precipitated after cooling to room temperature, and filtered to give ethyl 3-trifluoromethyl- 4-oxo-4,5-dihydro-1H-pyrrole[2,3-d]pyridazine-2-carboxylate 41f ( 120 mg), Yield: 72.7%. MS m/z (ESI): 274[M-1] Step 6 4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy]sodium[(2-methoxy-ethoxy)-ethyl]-3-trifluoromethyl-m- Pyrrolo[2,3-d]pyridazine-2-carboxylic acid ethyl ester
在 50 mL茄形瓶中加入 3-三氟甲基 -4-氧代 -4,5-二氢 -1H-吡咯 [2,3-d]哒嗪 -2- 羧酸乙酯 41f (420 mg, 1.53 mmol), 无水乙腈 (10 mL), 在氮气保护下加入三 氯氧磷 (0.72 mL, 7.65 mmol), 反应混合物加热回流 2小时后, 减压下蒸出大 部分溶剂,加入 3-氯 -4-(4-氟-苄氧基) -苯胺(111 mg, 0.44 mmol),异丙醇(2mL), 三乙胺 (0.08 mL, 0.53 mmol), 加热回流 3小时反应完毕。 反应液在冰水浴中 冷却, 加入氨水调节 pH值至碱性, 有固体析出, 过罈, 得到 4-[3-氯 -4-(3-氟-节 氧基) -苯氧基] -1-[(2-甲氧基-乙氧基) -乙基 ]-3-三氟甲基 -1H-吡咯并 [2,3-d]哒嗪 -2- 羧酸乙酯 41 (302 mg, 白色固体)。 产率: 3έ.9%。 · Add 3-trifluoromethyl-4-oxo-4,5-dihydro-1H-pyrrole[2,3-d]pyridazine-2-carboxylic acid ethyl ester 41f (420 mg) in a 50 mL eggplant-shaped flask , 1.53 mmol), anhydrous acetonitrile (10 mL), phosphorus oxychloride (0.72 mL, 7.65 mmol) was added under nitrogen, and the reaction mixture was heated to reflux for 2 hr. Chloro-4-(4-fluoro-benzyloxy)-aniline (111 mg, 0.44 mmol), isopropyl alcohol (2 mL), triethylamine (0.08 mL, 0.53 mmol). The reaction solution is cooled in an ice water bath, and the pH is adjusted to be alkaline by adding ammonia water, and a solid precipitates and is passed through an alkal to obtain 4-[3-chloro-4-(3-fluoro-p-oxy)-phenoxy]-1 -[(2-Methoxy-ethoxy)-ethyl]-3-trifluoromethyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid ethyl ester 41 (302 mg, White solid). Yield: 3έ.9%. ·
MS m/z (ESI): 509[M+ 1] MS m/z (ESI): 509 [M+ 1]
1HNMR (400MHz, DMSO- d): 58.32(s, 1H), 7.43(m, 2H), 7.32(m, 2H), 7.19(m, 3H), 5.22(s, 2H), 4.29(q, 2H), 1.31(m, 4H) 实施例 42 1 H NMR (400MHz, DMSO-d): 58.32 (s, 1H), 7.43 (m, 2H), 7.32 (m, 2H), 7.19 (m, 3H), 5.22 (s, 2H), 4.29 (q, 2H) ), 1.31 (m, 4H) Example 42
4-Γ3-氯 -4- -氟-苄氧基) -苯氧基 1 -1-「(2-甲氧基-乙氧基) -乙基 3-三氟甲基 -1H-吡 咯并「2,3-dl哒嗪 -2-羧酸苄酯 4-Γ3-chloro-4-fluoro-benzyloxy)-phenoxy-1- -1-((2-methoxy-ethoxy)-ethyl 3-trifluoromethyl-1H-pyrrole" 2,3-dl-pyridazine-2-carboxylic acid benzyl ester
5-甲基 -3-三氟甲基 -1H-吡咯 -2,4-二羧酸 -2-苄酯 -4-乙酯 按照本发明实施例 41第一步和第二步所述相同方式, 使用丙二酸苄酯乙酯 42a (2.22 mg, 10 mmol) 作原料, 得到本标题产物 5-甲基 -3-三氟甲基 -1H-吡咯 -2,4-二羧酸 -2-苄酯 -4-乙酯 42b (100 mg, 黄色固体)。 产率 45%。 5-methyl-3-trifluoromethyl-1H-pyrrole-2,4-dicarboxylic acid-2-benzyl ester-4-ethyl ester in the same manner as described in the first and second steps of Example 41 of the present invention Using benzyl malonate 42a (2.22 mg, 10 mmol) as the starting material, the title product 5-methyl-3-trifluoromethyl-1H-pyrrole-2,4-dicarboxylic acid-2- Benzyl ester-4-ethyl ester 42b (100 mg, yellow solid). The yield was 45%.
MS m/z (ESI): 356[M+ 1] 第二步 MS m/z (ESI): 356[M+ 1] Step 2
5-羟甲基 -3-三氟甲基 -1H-吡咯 -.2,4-二羧酸 -2-节酯 -4-乙酯 按照本发明实施例 41第三步所述相同方式,使用上述步骤所得到的化合物 5-甲基 -1H-吡咯 -2,4-二羧酸 -2-苄酯 -4-乙酯 42b (2.0 g, 5.63 mmol) 作原料,进行该 原料与硝酸铈铵的反应,得到本标题产物 5-羟甲基 -3-三氟甲基 -1H-吡咯 -2,4-二羧 酸 _2-苄酯 -4-乙酯 42c (635 mg, 黄色固体)。 产率 30.4%。 ' 5-Hydroxymethyl-3-trifluoromethyl-1H-pyrrole-.2,4-dicarboxylic acid-2-carboxylate-4-ethyl ester was used in the same manner as described in the third step of Example 41 of the present invention. The compound obtained in the above step, 5-methyl-1H-pyrrole-2,4-dicarboxylic acid-2-benzyl ester-4-ethyl ester 42b (2.0 g, 5.63 mmol) was used as a starting material to carry out the starting material and ammonium cerium nitrate. Reaction of the title product 5-hydroxymethyl-3-trifluoromethyl-1H-pyrrole-2,4-dicarboxylic acid 2-benzyl ester-4-ethyl ester 42c (635 mg, yellow solid). The yield was 30.4%. '
MS m/z (ESI): 372[M+ 1] 第三步 MS m/z (ESI): 372[M+ 1] Step 3
5-甲酰基 -3-三氟甲基 -1Η-吡咯 -2,4-二羧酸 -2-苄酯 -4-乙酯 .按照本发明实施例 41第四步所述相同方式, 使用上述第二步所得到的化合 物 5-羟甲基 -3-三氟甲基 -1H-吡咯 -2,4-二羧酸 -2-苄酯 -4-乙酯 42c (2.065 g, 5.56 mmol)作原料, 进行该原料与吡啶三氧化铬, 得到本标题产物 5-甲酰基 -3-三氟 甲基 -1H-吡咯 -2,4-二羧酸 -2-节酯 -4-乙酯 42d (2.945 g), 得到的固体不经纯化, 直 接进行下一步反应。 5-formyl-3-trifluoromethyl-1 Η-pyrrole-2,4-dicarboxylic acid-2-benzyl ester-4-ethyl ester. In the same manner as described in the fourth step of Example 41 of the present invention, The compound obtained in the second step is 5-hydroxymethyl-3-trifluoromethyl-1H-pyrrole-2,4-dicarboxylic acid-2-benzyl ester-4-ethyl ester 42c (2.065 g, 5.56 mmol). Starting material, the raw material and pyridine trichromate are obtained to obtain the title product 5-formyl-3-trifluoromethyl-1H-pyrrole-2,4-dicarboxylic acid-2-ester-4-ethyl ester 42d ( 2.945 g), the obtained solid was directly subjected to the next reaction without purification.
MS m/z (ESI): 370[M+ 1] 第四步 MS m/z (ESI): 370[M+ 1] Step 4
3-三氟甲基 -4-氧代 -4,5-二氢 -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸苄酯 按照本发明实施例 41第五歩所述相同方式, 使用上述第三步中所得到的化 合物 5-甲酰基 -3-三氟甲基 -1H-吡咯 -2,4-二羧酸 -2-苄酯 -4-乙酯 42d (2.05 g, 5.56 mmol)作原料, 进行该原料与水合肼 (0.56 g, 11 mmol) 的反应, 则得到标题产 物 3-三氟甲基 -4-氧代 -4,5-二氢 -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸苄酯 42e (1.52 g, 黄 色固体), 得到的固体不经纯化, 直接进行下一歩反应。 3-trifluoromethyl-4-oxo-4,5-dihydro-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid benzyl ester according to the fifth aspect of Example 41 of the present invention In the same manner, using the compound obtained in the above third step, 5-formyl-3-trifluoromethyl-1H-pyrrole-2,4-dicarboxylic acid-2-benzyl ester-4-ethyl ester 42d (2.05 g , 5.56 mmol) as a starting material, the reaction of the material with hydrazine hydrate (0.56 g, 11 mmol) afforded the title product 3-trifluoromethyl-4-oxo-4,5-dihydro-1H-pyrrole [2,3-d] Benzazine-2-carboxylic acid benzyl ester 42e (1.52 g, yellow solid).
MS m/z (ESI): 338[M+ 1] 第五步
4-[3-氯 -4-(3-氟-苄氧基) -苯氧基]小 [(2_甲氧基-乙氧基) -乙基 ]-3-三氟甲基 -1H-吡 咯并 [2,3-d]哒嗪 -2-羧酸苄酯 MS m/z (ESI): 338[M+ 1] Step 5 4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy]sodium [(2-methoxy-ethoxy)-ethyl]-3-trifluoromethyl-1H- Pyrrolo[2,3-d]pyridazine-2-carboxylic acid benzyl ester
按照本发明实施例 1第三、四步所述相同方式反应,使用上述第三步中所得 到的化合物 3-三氟甲基 -4-氧代 -4,5-二氢 -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸苄酯 42e (200 mg, 0.6 mmol) 作原料, 得到本标题产物 4-[3-氯 -4-(3-氟-苄氧基) -苯氧基] -1-[(2-甲氧基-乙氧基) -乙基 ]-3-三氟甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸苄酯 42 (100 mg, 浅黄色固体)。 产率: 29.5%。 In the same manner as described in the third and fourth steps of Example 1 of the present invention, the compound 3-trifluoromethyl-4-oxo-4,5-dihydro-1H-pyrrole obtained in the above third step was used. [2,3-d] Benzazine-2-carboxylic acid benzyl ester 42e (200 mg, 0.6 mmol) was used as the starting material to give the title product 4-[3-chloro-4-(3-fluoro-benzyloxy)- Phenoxy]-1-[(2-methoxy-ethoxy)-ethyl]-3-trifluoromethyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid benzyl Ester 42 (100 mg, pale yellow solid). Yield: 29.5%.
MS m/z (ESI): 571[M+1] MS m/z (ESI): 571 [M+1]
1HNMR (400MHz, DMSO-d6): 88.18(s, 1H), 7.67(m, 1H), 7.65(m, 2H), 7.48(m, 2H),7.25(m,3H), 7.18(m,2H), 7.31(m,lH), 6.86(s, lH) 5.01(s, 2H), 3.49(s, 2H) 实施例 43 1 HNMR (400MHz, DMSO-d6 ): 88.18 (s, 1H), 7.67 (m, 1H), 7.65 (m, 2H), 7.48 (m, 2H), 7.25 (m, 3H), 7.18 (m, 2H ), 7.31 (m, lH), 6.86 (s, lH) 5.01 (s, 2H), 3.49 (s, 2H) Example 43
4-Γ3-氯 -4-(3-氟-苄氧基 苯氧基 1 -1-[(2-甲氧基-乙氧基 -乙基 1-3-三氟甲基 -1Η-吡 咯并『2,3-dl哒嗪 -2-羧酸 (2-二乙胺基 -乙基 V酰胺 4-Γ3-chloro-4-(3-fluoro-benzyloxyphenoxy 1 -1-[(2-methoxy-ethoxy-ethyl1-3-trifluoromethyl-1Η-pyrrole) 『2,3-dl-pyridazine-2-carboxylic acid (2-diethylamino-ethyl V amide)
第一步 First step
4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -3-三氟甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸 将 4-[3-氯 -4-(3-氟-节氧基) -苯氧基] -1-[(2-甲氧基-乙氧基) -乙基 ]-3-三氟甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸苄酯 42( 120 mg, 0.21mmol)溶于二氯甲烷( 10 mL)
中, 搅拌下迅速加入三氟醋酸 (5 mL), 加热回流 8小时后反应完毕。 加入饱和 碳酸氢钠溶液中和反应液, 至 pH 7.8。萃取反应液, 合并的有机相通过饱和氯化 钠洗搽,无水硫酸钠干燥,过滤,减压下浓缩得到的粗品 4-[3-氯 -4-(3-氟- 氧基) - 苯氨基 ]-3-三氟甲基 -1H-吡咯并 [2,3-d]哒嗉 -2-羧酸 43a ( lOO mg, 黄色固体)不经 分离直接进行下一步的反应。 4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-3-trifluoromethyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid 4 -[3-chloro-4-(3-fluoro-p-ethoxy)-phenoxy]-1-[(2-methoxy-ethoxy)-ethyl]-3-trifluoromethyl-1H -pyrrolo[2,3-d]pyridazine-2-carboxylic acid benzyl ester 42 (120 mg, 0.21 mmol) dissolved in dichloromethane (10 mL) Trifluoroacetic acid (5 mL) was quickly added under stirring, and the reaction was completed after heating under reflux for 8 hours. The reaction solution was neutralized by adding a saturated sodium hydrogencarbonate solution to pH 7.8. The reaction mixture was extracted, and the combined organic layer was evaporated, evaporated, evaporated Amino]-3-trifluoromethyl-1H-pyrrolo[2,3-d]indole-2-carboxylic acid 43a (100 mg, yellow solid) was taken directly to the next reaction without isolation.
MS m/z (ESI): 481 [M+ 1] 第二步 MS m/z (ESI): 481 [M+ 1] Step 2
4-[3-氯 -4-(3-氟-苄氧基) -苯氧基]小[(2-甲氧基-乙氧基) -乙基 ]-3-三氟甲基 -1H-吡 咯并 [2,3-d]哒嗉 -2-羧酸 (2-二乙胺基-乙基) -酰胺 按照本发明实施例 1第六步所述相同方式, 以 4-[3-氯 -4-(3-氟-苄氧基) -苯氨 基] -3-三氟甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸 43a 为原料, 与 Ν,Ν-二乙基乙烷 -1 ,2-二胺的反应, 则得到标题产物 4-[3-氯 -4-(3-氟^氧基) -苯氧基] -1-[(2-甲氧基 -乙氧基) -乙基 ]-3-三氟甲基 -1Η-吡咯并 [2,3-d]哒嗪 -2-羧酸 (2-二乙胺基-乙基) -酰胺 43(25 mg, 白色固体), 产率 21 %。 4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy]sodium [(2-methoxy-ethoxy)-ethyl]-3-trifluoromethyl-1H- Pyrrolo[2,3-d]indole-2-carboxylic acid (2-diethylamino-ethyl)-amide in the same manner as described in the sixth step of Example 1 of the present invention, with 4-[3-chloro 4-(3-Fluoro-benzyloxy)-phenylamino]-3-trifluoromethyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid 43a as raw material, with hydrazine, hydrazine - the reaction of diethylethane-1,2-diamine gives the title product 4-[3-chloro-4-(3-fluorooxy)-phenoxy]-1-[(2-A) Oxy-ethoxy)-ethyl]-3-trifluoromethyl-1Η-pyrrolo[2,3-d]pyridazine-2-carboxylic acid (2-diethylamino-ethyl)-amide 43 (25 mg, white solid), yield 21%.
MS m/z (ESI): 579[M+ 1] MS m/z (ESI): 579 [M+ 1]
'HNMR (400MHZ, DMSO-d6): 58.18(s, 1H), 7.44(m, 2H), 7.32(m, 2H), 7.19(m, 3H), 5.01(s, 2H), 3.47(t, 2H), 2.73(t, 2H), 2.50(m, 4H), 0.99(t, 6H) 实施例 44 'HNMR (400MHZ, DMSO-d6): 58.18 (s, 1H), 7.44 (m, 2H), 7.32 (m, 2H), 7.19 (m, 3H), 5.01 (s, 2H), 3.47 (t, 2H) ), 2.73(t, 2H), 2.50(m, 4H), 0.99(t, 6H) Example 44
4-Γ3-氯 -4-(3-氟^氧基) -苯氧基 1 -1 -Γ(2-甲氧基-乙氧基) -乙基 1-3-三氟甲基 -1H-吡 咯并 C2,3-dl哒嗪 -2-羧酸 (2-吡咯烷 -1 -基-乙基) -酰胺 一 4-Γ3-chloro-4-(3-fluorooxy)-phenoxy 1-1-anthracene (2-methoxy-ethoxy)-ethyl 1-3-trifluoromethyl-1H- Pyrrolo-C2,3-dl-pyridazine-2-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide-1
重复本发明实施例 43第一步和第二步的反应,不同的是以第一步所得的原料 4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -3-三氟甲基 -1H-吡咯并 [2,3-d]哒嗪- 2-羧酸 43a, 按照实施例 1第六步所述的方式, 进行该原料与 2-吡咯烷 -1-乙胺的反应, 得到 标题化合物 4-[3-氯 -4-(3-氟-节氧基) -苯氧基] 小[(2-甲氧基-乙氧基) -乙基 ]-3-三氟 甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸 (2-吡咯焼 -1-基-乙基) -酰胺 44 (25 mg, 18.4 ), 黄色固体。 The reaction of the first step and the second step of Example 43 of the present invention was repeated, except that the starting material 4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-3 was obtained in the first step. -Trifluoromethyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid 43a, the starting material and 2-pyrrolidine-1-B were carried out in the same manner as in the sixth step of Example 1. Reaction of the amine gave the title compound 4-[3-chloro-4-(3-fluoro-p-oxy)-phenoxy]sodium[(2-methoxy-ethoxy)-ethyl]-3- Trifluoromethyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid (2-pyrrole-1-yl-ethyl)-amide 44 (25 mg, 18.4), yellow solid.
MS m/z (ESI): 577.7[M+ 1]
'HNMR (400MHz, OMSO-d6): 58.33(s, 1H), 7.44(m, 2H), 7.32(m , 2H), 7.19(m, 3H), 5.21(s, 2H), 2.76(m, 4H), 1.91(m, 4H), 1.22(m, 4H) 实施例 45 MS m/z (ESI): 577.7 [M+ 1] 'HNMR (400MHz, OMSO-d6): 58.33(s, 1H), 7.44(m, 2H), 7.32(m, 2H), 7.19(m, 3H), 5.21(s, 2H), 2.76(m, 4H ), 1.91 (m, 4H), 1.22 (m, 4H) Example 45
-Γ2-(5-二乙氨基 -Γ2-(5-diethylamino
45 第一步 45 first step
5-甲酰基 -3-甲基 -1Η-吡咯 -2,4-二羧酸 -2-叔丁酯 -4-乙酯 按照本发明实施例 1第一步所述相同方式, 使用 3,5-二甲基 -1Η-吡咯 -2,4-二 羧酸 -2-叔丁酯 -4-乙酯 45a ( 10 g, 37.4 mmol) 作原料, 进行该原料与硝酸铈铵 的反应, 则得到标题产物 5-甲酰基 -3-甲基 -1H-吡咯 -2,4-二羧酸 -2-叔丁酯 -4-乙酯 45b (7.4 g, 黄色固体)。 产率 70.5 %。 5-formyl-3-methyl-1Η-pyrrole-2,4-dicarboxylic acid-2-tert-butyl ester-4-ethyl ester In the same manner as described in the first step of Example 1 of the present invention, 3,5 was used. -Dimethyl-1Η-pyrrole-2,4-dicarboxylic acid-2-tert-butyl ester-4-ethyl ester 45a (10 g, 37.4 mmol) as a raw material, and reacting the starting material with cerium ammonium nitrate to obtain The title product 5-formyl-3-methyl-1H-pyrrole-2,4-dicarboxylic acid-2-tert-butyl ester-4-ethyl ester 45b (7.4 g, yellow solid). The yield was 70.5 %.
MS m/z (ESI): 280[M- 1] MS m/z (ESI): 280 [M-1]
第二步
5-甲酰基 -3-甲基 -1H-吡咯 -2,4-二羧酸 -4-乙酯 在 100 mL的三口烧瓶中加入上述第一步所得的原料 45b (2.81g, lOmmol) 和二氯甲垸(40mL), 溶解后,在冰浴下冷却至 0〜5Ό, 缓慢加入三氟醋酸(20 mL) ,保持温度在 0〜5°C。 滴加完毕后, 升温至 10〜2(TC, 搅拌 4小时后反应 完毕。 将反应液倒入冰水中, 有固体析出。 减压下抽滤, 水洗, 真空下干燥, 得 到本标题产物 5-甲酰基 -3-甲基 -1H-吡咯 -2,4-二羧酸 -4-乙酯 45c (2.19g, 黄色固 体), 产率: 97.3%。 Second step 5-formyl-3-methyl-1H-pyrrole-2,4-dicarboxylic acid-4-ethyl ester In a 100 mL three-necked flask, the starting material 45b (2.81 g, lOmmol) and the second obtained in the above first step were added. Chloroformamide (40 mL), after dissolving, was cooled to 0 to 5 Torr in an ice bath, and trifluoroacetic acid (20 mL) was slowly added to maintain the temperature at 0 to 5 °C. After the completion of the dropwise addition, the temperature was raised to 10 to 2 (TC, and the reaction was completed after stirring for 4 hours. The reaction liquid was poured into ice water, and solid was precipitated. The mixture was filtered under reduced pressure, washed with water, and dried under vacuum to give the title product 5- Formyl-3-methyl-1H-pyrrole-2,4-dicarboxylic acid-4-ethyl ester 45c (2.19 g, yellow solid), yield: 97.3%.
MS m/z(ESI): 224[M-1] 第三步 MS m/z (ESI) : 224 [M-1] Step 3
2-甲酰基 -5-碘 -4-甲基 -1H-吡咯 -3-羧酸乙酯 在 100 mL烧瓶中加入上述步骤所得的化合物 5-甲酰基 -3-甲基 -1H-吡咯 -2,4- 二羧酸 -4-乙酯 45c (3.2 g, 14.2 mmol)和二氯甲垸 (140 mL), 搅拌下加入碳酸 氢钠水溶液 (4.8 g, 71mL)。 整个体系分为两层, 溶液呈棕色, 剧烈搅拌下加入 碘化钾 (7.1 g)、 碘 (3.96 g) 和水 (71 mL)的混合溶液, 加热至 45°C, 继续反应 2小时后反应完毕。 反应液冷却至室温后, 用二氯甲垸萃取 (200mLX2), 合并 的有机相用饱和氯化钠洗涤(100mLX2),无水硫酸钠干燥,过滤,减压下蒸干, 得到的残留物进一步通过柱层析(正己垸: 乙酸乙酯 = 10:1)分离纯化, 得到本 标题产物 2-甲酰基 -5-碘 -4-甲基 -1H-吡咯 -3-羧酸乙酉 ^ 45d (0.8 g, 黄色固体), 产率: 26.7%。 Ethyl 2-formyl-5-iodo-4-methyl-1H-pyrrole-3-carboxylate The compound obtained in the above step was added 5-formyl-3-methyl-1H-pyrrole-2 in a 100 mL flask. 4-Dicarboxylic acid-4-ethyl ester 45c (3.2 g, 14.2 mmol) and dichloromethane (140 mL). The whole system was divided into two layers. The solution was brown. A mixed solution of potassium iodide (7.1 g), iodine (3.96 g) and water (71 mL) was added with vigorous stirring, and the mixture was heated to 45 ° C, and the reaction was completed after 2 hours. After the reaction mixture was cooled to room temperature, it was extracted with methylene chloride (200 mL), and the combined organic phase was washed with saturated sodium chloride (100 mL), dried over anhydrous sodium sulfate, filtered and evaporated to dryness Purified by column chromatography (n-hexane: ethyl acetate = 10:1) to give the title product 2-formyl-5-iodo-4-methyl-1H-pyrrole-3-carboxylic acid g, yellow solid), Yield: 26.7%.
MS m/z(ESI): 306[M-1] MS m/z (ESI): 306 [M-1]
第四步 the fourth step
2-碘 -3-甲基 -1,5-二氢-吡咯并 [2,3-d]哒嗪 -4-酮 2-iodo-3-methyl-1,5-dihydro-pyrrolo[2,3-d]pyridazine-4-one
按照本发明实施例 1第二步所述相同方式,使用上述第三步中所得到的化合 物 2-甲酰基 -5-碘 -4-甲基 -1H-吡咯 -3-羧酸乙酯 45d(307mg, lmmol)作原料,进行 该原料与水合肼 (75 mg, 1.5 mmol)的反应, 则得到标题产物 2-碘 -3-甲基 -1,5-二氢 -口比咯并 [2,3-d]哒嗪 -4-酮 45e (65 mg, 黄色固体)。 产率 47.4%。 In the same manner as described in the second step of Example 1 of the present invention, the compound 2-formyl-5-iodo-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester 45d obtained in the above third step was used. 307mg, 1mmol) was used as the starting material, and the reaction of the starting material with hydrazine hydrate (75 mg, 1.5 mmol) gave the title product 2-iodo-3-methyl-1,5-dihydro-porto[2, 3-d]pyridazin-4-one 45e (65 mg, yellow solid). The yield was 47.4%.
MSm/z(ESI): 276[M+1] 第五步 MSm/z(ESI): 276[M+1] Step 5
2-(5-二乙氨基甲基 -呋喃 -2-基) -3-甲基 -1,5-二氢-吡咯并 [2,3-d]哒嗪 -4-酮 在 200 mL 的茄形瓶中依次加入 2-(5-二乙氨基甲基 -呋喃 -2-基) -3-甲基 -1,5-二氢-卩比咯并 [2,3-d]哒嗪 -4-酮 45e (390 mg, 1.4 mmol), 90%5- (二乙氨基甲 基)呋喃 -2-硼酸 (355 mg, 1.4 mmol) 水溶液, 碳酸氢钠 (517 mg, 3.7 mmol), Ν,Ν-二甲基甲酰胺 (10 mL)和水(10mL〉。 混合物在氮气保护下, 加入四三苯
基膦化钯(59 mg, 0.05 mmol)。 加热回流反应物至 110, 四小时后反应完毕。减 压下蒸干反应液, 得到的残留物进一步通过柱层析 (二氯甲垸: 甲醇 = 5: 1 )分 离纯化得到本标题产物 2-(5-二乙氨基甲基 -呋喃 -2-基) -3-甲基 -1,5-二氢-吡咯并 [2,3-d]哒嗪 -4-酮 45f (251 mg, 黄色固体)。 产率: 41.7%。 2-(5-Diethylaminomethyl-furan-2-yl)-3-methyl-1,5-dihydro-pyrrolo[2,3-d]pyridazin-4-one in 200 mL of eggplant 2-(5-Diethylaminomethyl-furan-2-yl)-3-methyl-1,5-dihydro-indolepyr-[2,3-d]pyridazine-4 was added sequentially to the vial. -ketone 45e (390 mg, 1.4 mmol), 90% 5-(diethylaminomethyl)furan-2-boronic acid (355 mg, 1.4 mmol) in water, sodium bicarbonate (517 mg, 3.7 mmol), Ν, Ν - dimethylformamide (10 mL) and water (10 mL). The mixture was added with tetratriphenylbenzene under nitrogen. Palladium phosphinate (59 mg, 0.05 mmol). The reactant was heated to reflux to 110, and the reaction was completed after four hours. The reaction mixture was evaporated to dryness crystalljjjjjjjjjjjjjjj Benzyl)-3-methyl-1,5-dihydro-pyrrolo[2,3-d]pyridazin-4-one 45f (251 mg, yellow solid). Yield: 41.7%.
MS m/z (ESI): 276[M+ 1] 第六步 MS m/z (ESI): 276 [M+ 1] Step 6
[3-氯 _4-(3-氟-苄氧基) -苯氧基] -[2-(5-二乙氨基甲基 -呋喃 -2-基 3-甲基 -1H-吡咯 并 [2,3-d]哒嗪 -4-基]酰胺 [3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy]-[2-(5-diethylaminomethyl-furan-2-yl 3-methyl-1H-pyrrolo[2 ,3-d]pyridazin-4-yl]amide
按照本发明实施例 1第三、 四步所述相同方式反应, 使用上述第五步中所 得到的化合物 2-(5-二乙氨基甲基 -呋喃 -2-基) -3-甲基 -1,5-二氢-吡咯并 [2,3-d]哒嗪 -4-酮 45f 作原料, 得到 [3-氯 -4-(3-氟-苄氧基) -苯氧基] -[2-(5-二乙氨基甲基 -呋喃 -2-基) -3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -4-基]酰胺 45 (1.642 g, 白色固体)。产率 79.7 %。 In the same manner as described in the third and fourth steps of Example 1 of the present invention, the compound 2-(5-diethylaminomethyl-furan-2-yl)-3-methyl- obtained in the above fifth step was used. 1,5-Dihydro-pyrrolo[2,3-d]pyridazin-4-one 45f as a starting material to give [3-chloro-4-(3-fluoro-benzyloxy)-phenoxy]-[ 2-(5-Diethylaminomethyl-furan-2-yl)-3-methyl-1H-pyrrolo[2,3-d]pyridazin-4-yl]amide 45 (1.642 g, white solid) . The yield was 79.7 %.
MS m/z (ESI): 535[M+ 1] MS m/z (ESI): 535 [M+ 1]
]HNMR (400MHz, DMSO-c¾): 58.34(s, 1H), 7.85(s, 1H), 7.50(m, 2H), 7.46(m, 2H), 7.28(m, 2H), 6.86(d, 1H, J=3.2Hz), 6.50(d, 1H, J=2.4Hz), 5.2 l(s, 2H), 3.75(s, 2H), 2.63(m, 4H), 2.33(s, 3H), 1.01(m, 6H) ] HNMR (400MHz, DMSO-c¾ ): 58.34 (s, 1H), 7.85 (s, 1H), 7.50 (m, 2H), 7.46 (m, 2H), 7.28 (m, 2H), 6.86 (d, 1H , J=3.2Hz), 6.50(d, 1H, J=2.4Hz), 5.2 l(s, 2H), 3.75(s, 2H), 2.63(m, 4H), 2.33(s, 3H), 1.01( m, 6H)
实施例 46 Example 46
-氯 -4-(3-氟-苄氧基) -苯氧基 1 -|~2-(3-二乙氨基甲基-甲基) -3-甲基 -1H-吡咯并 -chloro-4-(3-fluoro-benzyloxy)-phenoxy 1 -|~2-(3-diethylaminomethyl-methyl)-3-methyl-1H-pyrrole
「2.3-dl哒嗪 -4-基 1酰胺 "2.3-dl pyridazine-4-yl 1 amide
2-(3-二乙氨基甲基苯基 )-3-甲基 -1,5-二氢吡咯并 [2,3-d]哒嗪 -4-酮 按照本发明实施例 45第四步所述的方式,以化合物 2-(5-二乙氨基甲基 -呋喃 -2-基) -3-甲基 -1,5-二氢-吡咯并 [2,3-d]哒嗪 -4-酮 45e (206 mg, 0.75 mmol)和 3- 二乙氨基甲基苯硼酸 (186 mg, 0.90 mmol) 为原料, 得到本标题化合物 2-(3-二 乙氨基甲基苯基) -3-甲基 -1,5-二氢吡咯并 [2,3-d]哒嗪 -4-酮 45a ( 110 mg, 白色固 体)。 产率: 35.5 %。 2-(3-Diethylaminomethylphenyl)-3-methyl-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one according to the fourth step of Example 45 of the present invention In the manner described, the compound 2-(5-diethylaminomethyl-furan-2-yl)-3-methyl-1,5-dihydro-pyrrolo[2,3-d]pyridazine-4- The ketone 45e (206 mg, 0.75 mmol) and 3-diethylaminomethylbenzeneboronic acid (186 mg, 0.90 mmol) were obtained from the title compound 2-(3-diethylaminomethylphenyl)-3- Base-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one 45a (110 mg, white solid). Yield: 35.5 %.
MS m/z (ESI): 311 [M+ 1] MS m/z (ESI): 311 [M+ 1]
[3-氯 -4-(3-氟-苄氧基) -苯氧基] -[2-(3-二乙氨基甲基 -甲基 )-3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -4-基]酰胺 [3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy]-[2-(3-diethylaminomethyl-methyl)-3-methyl-1H-pyrrolo[2, 3-d]pyridazin-4-yl]amide
按照本发明实施例 1第三、 四歩所述相同方式反应,使用上述第五步中所得到的 化合物 2-(3-二乙氨基甲基苯基) -3-甲基 -1,5-二氢吡咯并 [2,3-d]哒嗪 -4-酮 45a作原 料, 得到 [3-氯 -4-(3-氟-苄氧基) -苯氧基] -[2-(3-二乙氨基甲基 -甲基 >3-甲基 -1H-吡 咯并 [2,3-d]哒嗪 -4-基]酰胺 46 (15 mg, 白色固体)。 产率 44.1 %。 In the same manner as described in the third and fourth aspects of the present invention, the compound 2-(3-diethylaminomethylphenyl)-3-methyl-1,5- obtained in the above fifth step was used. Dihydropyrrolo[2,3-d]pyridazin-4-one 45a is used as a starting material to give [3-chloro-4-(3-fluoro-benzyloxy)-phenoxy]-[2-(3- Diethylaminomethyl-methyl>3-methyl-1H-pyrrolo[2,3-d]pyridazin-4-yl]amide 46 (15 mg, white solid).
MS m/z (ESI): 545[M+ 1] MS m/z (ESI): 545 [M+ 1]
实施例 47 Example 47
7-【3-氯 -4-(3-氟-苄氧基) -苯氧基 1 -1H-吡咯并「2、3-dl哒嗪 -2-羧酸 (2-二乙氨基-乙 7- [3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy 1 -1H-pyrrolo- 2,3-dl-pyridazine-2-carboxylic acid (2-diethylamino-B
第一步 First step
1H-吡咯 -2,5-二羧酸二甲酯 1H-pyrrole-2,5-dicarboxylic acid dimethyl ester
在氮气保护下, 在 10 mL的茄形瓶中加入吡咯 -1,2,5-三羧酸 1-叔丁酯 2,5-二甲酯 47a溶解于 (200 mg, 0.71 mmol), 二氯甲烷 (2 mL), 三氟醋酸 (2 mL), 室温 下搜拌 1小时, 反应完毕。 减压下蒸发大部分溶剂后, 加入冰水 (2 mL)有固 体析出, 继续搅拌 0.5 小时, 过滤、 洗涤, 得到的固体通过柱层析(正己烷: 乙 酸乙酯 =8: 1 )进一步分离纯化得到 1H-吡咯 -2,5-二羧酸二甲酯 47b (60 mg, 黄 色固体), 产率 46.5%。 Adding pyrrole-1,2,5-tricarboxylic acid 1-tert-butyl ester 2,5-dimethyl ester 47a in a 10 mL eggplant vial under nitrogen protection. Dissolved in (200 mg, 0.71 mmol), dichloro Methane (2 mL), trifluoroacetic acid (2 mL) was stirred at room temperature for 1 hour and the reaction was completed. After evaporating most of the solvent under reduced pressure, a solid solid was poured from ice water (2 mL), stirring was continued for 0.5 hr, filtered and washed, and the obtained solid was further separated by column chromatography (hexane: ethyl acetate = 8:1). Purification afforded 1H-pyrrole-2,5-dicarboxylic acid dimethyl ester 47b (60 mg, yellow solid), yield 46.5%.
MS m/z (ESI): 182[M- 1] MS m/z (ESI): 182 [M-1]
第二步 Second step
3-甲酰基 -1H-吡咯 -2,5-二羧酸二甲酯 3-formyl-1H-pyrrole-2,5-dicarboxylic acid dimethyl ester
在 50 mL的三口烧瓶中加入二氯甲垸(2 mL), Ν,Ν'—二甲基甲酰胺(0.06 mL, 0.83 mmol), 混合物用干冰—乙醇浴冷却至一 30Ό后, 加入三氯氧磷(0.06 mL, 0.66 mmol)后搅拌十分钟后加入 1H-吡咯 -2,5-二羧酸二甲酯 47b (60 mg, 0.33 mmol) 的二氯甲垸溶液 (1 mL), 加热至 100°C, 3小时后反应完毕。 在反 应液中加入冰水 (10 mL) 和饱和碳酸氢钠溶液, 调节 pH=8〜9, 用乙酸乙酯 ( 10 mLX 3 ), 合并有机相, 用饱和氯化钠 (10 mL) 洗漆, 无水硫酸钠干燥, 过滤, 浓缩, 得到的残留物通过柱层析 (正己烷: 乙酸乙酯 =2: ! ) 进一步分离 纯化, 得到 3-甲酰基 -1H-吡咯 -2,5-二羧酸二甲酯 47c (62 mg, 黄色固体), 产率: 21.4%。 第三步
7-氧代 -6,7-二氢 -1H-吡咯 [2,3-d]哒嗪 -2-羧酸甲酯 在氩气保护下, 于 10 mL茄形瓶中加入 3-甲酰基 -1H-吡咯 -2,5-二羧酸二甲酯 47c (44 mg, 0.21 mmol), 无水乙醇 (2 mL)和水合肼(0.025 mL, .042 mmol), 加热回流 1.5小时后反应完毕。冷却至室温,有固体析出,过滤,得到 7-氧代 -6,7- 二氢 -1H-吡咯 [2,3-d]哒嗪 -2-羧酸甲酯 47d ( 17 mg, 白色固体), 43.9%。 Dichloromethane (2 mL), hydrazine, Ν'-dimethylformamide (0.06 mL, 0.83 mmol) was added to a 50 mL three-necked flask, and the mixture was cooled to 30 Torr with a dry ice-ethanol bath. After stirring for 10 minutes, oxyphosphorus (0.06 mL, 0.66 mmol) was added to a solution of 1H-pyrrole-2,5-dicarboxylate 47b (60 mg, 0.33 mmol) in dichloromethane (1 mL). After 100 hours, the reaction was completed after 3 hours. Add ice water (10 mL) and saturated sodium bicarbonate solution to pH=8~9, and combine the organic phase with ethyl acetate (10 mL×3) and wash with saturated sodium chloride (10 mL) The residue was dried over anhydrous sodium sulfate, filtered, and evaporated. Dimethyl carboxylic acid 47c (62 mg, yellow solid), Yield: 21.4%. third step Methyl 7-oxo-6,7-dihydro-1H-pyrrole[2,3-d]pyridazine-2-carboxylate was added to a 10 mL eggplant vial under argon to add 3-formyl- 1H-Pyrrol-2,5-dicarboxylic acid dimethyl ester 47c (44 mg, 0.21 mmol), dry ethanol (2 mL) and hydrazine hydrate (0.025 mL, .042 mmol). After cooling to room temperature, a solid precipitated and filtered to give methyl 7-oxo-6,7-dihydro-1H-pyrrole[2,3-d]pyridazine-2-carboxylate 47d (17 mg, white solid) , 43.9%.
MS m/z (ESI): 194[M+ 1] MS m/z (ESI): 194 [M+ 1]
第四步 the fourth step
7— [3-氯 -4-(4-氟-节氧基) -苯基氨基] -1Η-吡咯 [2,3-d]哒嗪 -2-羧酸甲酯 在 10 mL 茄形瓶中加入 7-氧代 -6,7-二氢 -1H-吡咯 [2,3-d]哒嗪 -2-羧酸甲酯 47d ( 100 mg, 0.438 mmol),无水乙腈(2 mL),在氮气保护下加入三氯氧磷(0.09 mL, 0.97 mmol), 反应混合物加热回流 3小时后, 减压下蒸出大部分溶剂, 加 入 3-氯 -4-(4-氟- 氧基) -苯胺(111 mg, 0.44 mmol),异丙醇(2 mL),三乙胺(0.08 mL, 0.53 mmol), 加热回流 3小时反应完毕。 反应液在冰水浴中冷却, 加入氨 水调节 pH值至碱性, 有固体析出, 过滤, 得到 7-[3-氯 -4-(4-氟-苄氧基) -苯基氨 基】 -1H-吡咯 [2,3-d]哒嗪 -2-羧酸甲酯 47e (63 mg, 白色固体), 产率: 33.8%。 MS m/z (ESI): 427[M+ 1] 第五步 7-[3-Chloro-4-(4-fluoro-oxy)-phenylamino]-1,4-indole-pyrrole [2,3-d]pyridazine-2-carboxylic acid methyl ester in 10 mL eggplant-shaped flask Add 7-oxo-6,7-dihydro-1H-pyrrole [2,3-d]pyridazine-2-carboxylic acid methyl ester 47d (100 mg, 0.438 mmol), dry acetonitrile (2 mL) Phosphorus oxychloride (0.09 mL, 0.97 mmol) was added under a nitrogen atmosphere, and the reaction mixture was heated under reflux for 3 hr. (111 mg, 0.44 mmol), isopropanol (2 mL), triethylamine (0.08 mL, 0.53 mmol). The reaction solution was cooled in an ice water bath, and aqueous ammonia was added to adjust the pH to be alkaline. A solid precipitated and filtered to give 7-[3-chloro-4-(4-fluoro-benzyloxy)-phenylamino]-1H- Methyl pyrrole [2,3-d]pyridazine-2-carboxylate 47e (63 mg, white solid), yield: 33.8%. MS m/z (ESI): 427 [M+ 1] Step 5
7-[3-氯 -4-(4-氟- 氧基) -苯氨基] -1H-吡咯 [2,3-d]哒嗪 -2-羧酸 在 10 mL茄形瓶中加入氢氧化钾 (72 mg, 1.26 mmol)水溶液 (2 mL), 逐渐滴加 7-[3-氯 -4-(4-氟-节氧基) -苯基氨基] -1H-吡咯 [2,3-d]哒嗪 -2-羧酸甲酯 47e Add 7-[3-chloro-4-(4-fluoro-oxy)-phenylamino]-1H-pyrrole[2,3-d]pyridazine-2-carboxylic acid to a 10 mL eggplant-shaped bottle (72 mg, 1.26 mmol) in water (2 mL), gradually adding 7-[3-chloro-4-(4-fluoro-hydroxy)-phenylamino]-1H-pyrrole [2,3-d] Pyridazine-2-carboxylic acid methyl ester 47e
( 134 mg, 0.315 mmol) 的乙醇溶液(2 mL)。 滴加完毕后, 加热回流 1小时, 反应完毕。反应液冷却至室温,减压下除去大部分乙醇,用 1N盐酸溶液调节 pH 值至酸性,有黄色沉淀生成, 过滤,得到的残留物进一步通过柱层析(二氯甲烷: 甲醇 = 15: 1 ) 分离纯化, 得到 7-[3-氯 -4-(4-氟-苄氧基) -苯氨基] -1H-吡咯 [2,3-d] 哒嗪 -2-羧酸 47f ( 110 mg, 黄色固体)。 产率: 85.3 %。 第六步 (134 mg, 0.315 mmol) in ethanol (2 mL). After the completion of the dropwise addition, the mixture was heated under reflux for 1 hour, and the reaction was completed. The reaction solution was cooled to room temperature, and most of the ethanol was removed under reduced pressure. The pH was adjusted to be acidic with a 1N hydrochloric acid solution. A yellow precipitate was formed and filtered, and the residue obtained was further purified by column chromatography (dichloromethane: methanol = 15:1) Purified by isolation to give 7-[3-chloro-4-(4-fluoro-benzyloxy)-phenylamino]-1H-pyrrole [2,3-d]pyridazine-2-carboxylic acid 47f (110 mg, Yellow solid). Yield: 85.3 %. Step 6
7_[3-氯 -4-(3-氟-苄氧基) -苯氧基] -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸 (2-二乙氨基-乙 基) -酰胺 7 _[3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy]-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid (2-diethylamino-B -amide
在 10 mL茄形瓶中加入 7-[3-氯 -4-(4-氟-苄氧基) -苯氨基] -1H-吡咯 [2,3-d]哒 嗪 -2-羧酸 47f ( 130 mg, 0.27 mmol), 1一羟基苯骈三氮唑(56 mg, 0.27 mmol), 1-乙基 -3-(3-二甲基氨基丙基)碳二酰亚胺盐酸盐(79 mg, 0.41 mmol),三乙胺(0.1 mL, 0.675 mmol), 混合物搅拌 15分钟后加入 N*1*,N*1*-二乙基乙烷 -1,2-二胺, 室温搅拌过夜, 反应完毕。将反应液倒入水(20 mL) 中, 有大量固体沉淀生成,
过滤, 得到标题产物 7-[3-氯 -4-(3-氟-苄氧基) -苯氧基] -1H-吡咯并 [2,3-d]哒嗪 -2- 羧酸 (2-二乙氨基-乙基) -酰胺 47 ( 105 mg, 黄色固体)。 产率: 76.6% 0 Add 7-[3-chloro-4-(4-fluoro-benzyloxy)-phenylamino]-1H-pyrrole [2,3-d]pyridazine-2-carboxylic acid 47f to a 10 mL eggplant-shaped flask ( 130 mg, 0.27 mmol), monohydroxybenzotriazole (56 mg, 0.27 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (79) Mg, 0.41 mmol), triethylamine (0.1 mL, 0.675 mmol). After stirring for 15 min, N*1*, N*1*-diethylethane-1,2-diamine was added and stirred at room temperature overnight. The reaction is completed. The reaction solution was poured into water (20 mL), and a large amount of solid precipitated. Filtration gave the title product 7-[3-chloro-4-(3-fluoro-benzyloxy)-phenoxy]-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid (2- Diethylamino-ethyl)-amide 47 (105 mg, yellow solid). Yield: 76.6% 0
MS m/z (ESI): 512[M+ 1] MS m/z (ESI): 512 [M+ 1]
'HNMR (400MHZ, DMSO-C¾): 58.33(S, lH), 7.66(m, 1H), 7.47(m, 2H), 7.32(m, 1H), 7.25(m, 1H), 7.18(m, 2H), 6.90(s, 1H), 5.23(s, 2H), 3.47(t, 2H), 2.73(t, 2H), 2.50(m, 4H), 0.99(t, 6H) 实施例 48 'HNMR (400MHZ, DMSO-C3⁄4): 58.33 (S, lH), 7.66 (m, 1H), 7.47 (m, 2H), 7.32 (m, 1H), 7.25 (m, 1H), 7.18 (m, 2H) ), 6.90(s, 1H), 5.23(s, 2H), 3.47(t, 2H), 2.73(t, 2H), 2.50(m, 4H), 0.99(t, 6H) Example 48
7-「3-氯 -4-(3-氟-节氧基) -苯氧基 1 -1H-吡咯并「2,3-dl哒嗪 -2-羧酸 (2-2-吡咯垸 -1-基- 乙基) -酰胺 7 - "3-Chloro-4-(3-fluoro-p-ethoxy)-phenoxy 1 -1H-pyrrolo "2,3-dlpyridazine-2-carboxylic acid (2-2-pyrrole-1) -yl-ethyl)-amide
重复本发明实施例 47 第一步到第五步的反应, 使用第五步所得的化合物 4-[3-氯 -4-(4-氟-苄氧基) -苯氨基] -1H-吡咯 [2,3-d]哒嗪 -2-羧酸 47f 作原料, 按照本 发明实施例 47第六步所述的相同方式进行该原料与 2-吡咯烷 -1-乙胺的反应, 得 到标题化合物 7-[3-氯 -4-(3-氟- 氧基) -苯氧基] -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸 (2-2- 吡咯烷 -1-基-乙基)-酰胺 48 ( 90 mg, 黄色固体)。 产率: 84.9%。 The reaction of the first step to the fifth step of Example 47 of the present invention was repeated, using the compound obtained in the fifth step, 4-[3-chloro-4-(4-fluoro-benzyloxy)-phenylamino]-1H-pyrrole [ 2,3-d]pyridazine-2-carboxylic acid 47f is used as a starting material, and the reaction of the starting material with 2-pyrrolidine-1-ethylamine is carried out in the same manner as in the sixth step of Example 47 of the present invention to give the title compound. 7-[3-Chloro-4-(3-fluoro-oxy)-phenoxy]-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid (2-2-pyrrolidine-1 -yl-ethyl)-amide 48 (90 mg, yellow solid). Yield: 84.9%.
MS m/z (ESI): 509[M+ 1] MS m/z (ESI): 509 [M+ 1]
'HNMR (400MHZ, DMSO-ί/ό): S8.33(s, 1H), 7.67(m, 1H), 7.49(m, 1H), 7.4 l(m, 2H), 7.26(m, 1H), 7.17(m, 2H), 6.82(s, 1H), 5.23(s, 2H), 3.47(m, 2H), 2.73(m, 2H), 2.50(m, 4H), 1.71(m, 4H) 实施例 49 'HNMR (400MHZ, DMSO-ί/ό): S8.33(s, 1H), 7.67(m, 1H), 7.49(m, 1H), 7.4 l(m, 2H), 7.26(m, 1H), 7.17(m, 2H), 6.82(s, 1H), 5.23(s, 2H), 3.47(m, 2H), 2.73(m, 2H), 2.50(m, 4H), 1.71(m, 4H) 49
7-「3-氯 -4-(3-氟-苄氧基) -苯氧基 1 -1Η-吡咯并「2,3-dl哒嗪 -2-羧酸 (2-吗啉 -4-基-乙 基) -酰胺 7 - "3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy 1 -1 Η-pyrrolo "2,3-dl oxazin-2-carboxylic acid (2-morpholin-4-yl) -ethyl)-amide
重复本发明实施例 47 第一步到第五步的反应, 使用第五步所得的化合物 4-[3-氯 -4-(4-氟-节氧基) -苯氨基] -1H-吡咯 [2,3-d]哒嗪 -2-羧酸 47f 作原料, 按照本 发明实施例 47第六步所述的相同方式, 进行该原料与 2-吗啉 -4-乙胺反应, 得到 标题化合物 7-[3-氯 -4-(3-氟-苄氧基) -苯氧基] -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸 (2-吗 啉 -4-基-乙基) -酰胺 49 ( 88 mg, 黄色固体)。 产率: 80%。 - S m/z (ESI): 525[M+ 1] The reaction of the first step to the fifth step of Example 47 of the present invention was repeated, and the compound obtained in the fifth step was used 4-[3-chloro-4-(4-fluoro-oxy-oxy)-phenylamino]-1H-pyrrole [ 2,3-d]pyridazine-2-carboxylic acid 47f is used as a starting material, and the starting material is reacted with 2-morpholin-4-ethylamine in the same manner as described in the sixth step of Example 47 of the present invention to give the title compound. 7-[3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy]-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid (2-morpholin-4- Base-ethyl)-amide 49 (88 mg, yellow solid). Yield: 80%. - S m/z (ESI): 525[M+ 1]
1H MR (400MHz, DMSO-c¾): 58.33(s, 1H), 7.67(m, 1H), 7.49(m, 1H), 7.41(m, 2H), 7.26(m, 1H), 7.17(m, 2H), 6.94(s, 1H), 5.23(s, 2H), 3.58(m, 4H), 3.45(m, 2H), 2.89(m,2H), 2.45(m, 4H) 实施例 50 1 H MR (400MHz, DMSO-c3⁄4): 58.33(s, 1H), 7.67(m, 1H), 7.49(m, 1H), 7.41(m, 2H), 7.26(m, 1H), 7.17(m, 2H), 6.94(s, 1H), 5.23(s, 2H), 3.58(m, 4H), 3.45(m, 2H), 2.89(m, 2H), 2.45(m, 4H) Example 50
7-「3-氯 -4-(3-氟-苄氧基) -苯氧基 1 -1Η-吡咯并「2,3-dl哒嗪 -2-羧酸 (3-吗啉 -4-基-丙 基 V酰胺 7-"3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy 1- 1 Η-pyrrolo "2,3-dl-pyridazine-2-carboxylic acid (3-morpholin-4-yl) -propyl V amide
重复本发明实施例 47 第一步到第五步的反应, 使用第五步所得的化合物 4-[3-氯 -4-(4-氟-苄氧基) -苯氨基] -1H-吡咯 [2,3-d]哒嗪 -2-羧酸 47f 作原料, 按照本 发明实施例 47第六步所述的相同方式, 进行该原料与 3-吗啉 -4-乙胺反应, 得到 标题化合物 7-[3-氯 -4-(3-氟-苄氧基) -苯氧基] -IH-吡咯并 [2,3-d]哒嗪 -2-羧酸 (3-吗 啉 -4-基-丙基) -酰胺 50 (70 mg, 黄色固体)。 产率: 61.9%。 The reaction of the first step to the fifth step of Example 47 of the present invention was repeated, using the compound obtained in the fifth step, 4-[3-chloro-4-(4-fluoro-benzyloxy)-phenylamino]-1H-pyrrole [ 2,3-d]pyridazine-2-carboxylic acid 47f is used as a starting material, and the starting material is reacted with 3-morpholin-4-ethylamine in the same manner as in the sixth step of Example 47 of the present invention to give the title compound. 7-[3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy]-IH-pyrrolo[2,3-d]pyridazine-2-carboxylic acid (3-morpholin-4- Base-propyl)-amide 50 (70 mg, yellow solid). Yield: 61.9%.
MS m/z (ESI): 540[M+ 1] MS m/z (ESI): 540 [M+ 1]
!HNMR (400MHz, DMSO 6): 58.33(s, 1H), 7.67(m, 1H), 7.49(m, 1H), 7.41 (m, 2H), 7.26(m, 1H), 7.17(m, 2H), 6.94(s, 1H), 5.23(s, 2H), 3.58(m, 4H), 3.34(m, 4H), 2.34(m, 4H), 2.21(m,2H) 实施例 51 ! HNMR (400MHz, DMSO 6) : 58.33 (s, 1H), 7.67 (m, 1H), 7.49 (m, 1H), 7.41 (m, 2H), 7.26 (m, 1H), 7.17 (m, 2H) , 6.94(s, 1H), 5.23(s, 2H), 3.58(m, 4H), 3.34(m, 4H), 2.34(m, 4H), 2.21(m, 2H) Example 51
7-[3-氯 -4-(3-氟-苄氧基) -苯氧基 1 -1Η-吡咯并「2,3-dl哒嗪 -2-羧酸 (2-哌啶 -1-基-乙 基) -酰胺
重复本发明实施例 47第一步到第五步的反应, 使用第五步所得的化合物 4-[3-氯 -4-(4-氟-苄氧基) -苯氨基] -1H-吡咯 [2,3-d]哒嗉 -2-羧酸 47Ϊ作原料, 按照本 发明实施例 47第六步所述的相同方式, 进行该原料与 2-哌啶 -1-乙胺反应, 得到 标题化合物 7-[3-氯 -4-(3-氟-苄氧基) -苯氧基] -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸 (2-哌 啶 -1-基-乙基) -酰胺 51 ( 88 mg, 黄色固体)。 产率: 80.7% 7-[3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy 1 -1Η-pyrrolo and 2,3-dlpyridazine-2-carboxylic acid (2-piperidin-1-yl) -ethyl)-amide The reaction of the first step to the fifth step of Example 47 of the present invention was repeated, and the compound obtained in the fifth step was used 4-[3-chloro-4-(4-fluoro-benzyloxy)-phenylamino]-1H-pyrrole [ 2,3-d]indole-2-carboxylic acid 47 hydrazine is used as a starting material, and the starting material is reacted with 2-piperidine-1-ethylamine in the same manner as described in the sixth step of Example 47 of the present invention to give the title compound. 7-[3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy]-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid (2-piperidin-1- Base-ethyl)-amide 51 (88 mg, yellow solid). Yield: 80.7%
MS m/z (ESI): 524[M+ 1] MS m/z (ESI): 524 [M+ 1]
'HNMR (400MHZ, DMSO-d6): 58.33(s, 1H), 7.68(m, 1H), 7.48(m, 1H), 7.34(m, 2H), 7.26(m, 1H), 7.17(m, 2H), 6.86(s, 1H), 5.23(s, 2H),3.49(m, 2H), 3.15(m, 2H), 2.4 l(m, 2H), 2.33(m, 2H), 1.69(m, 4H), 1.65(m, 2H) 实施例 52 'HNMR (400MHZ, DMSO-d6): 58.33 (s, 1H), 7.68 (m, 1H), 7.48 (m, 1H), 7.34 (m, 2H), 7.26 (m, 1H), 7.17 (m, 2H) ), 6.86(s, 1H), 5.23(s, 2H), 3.49(m, 2H), 3.15(m, 2H), 2.4 l(m, 2H), 2.33(m, 2H), 1.69(m, 4H) ), 1.65 (m, 2H) Example 52
743-氯 -4-(3-氟-苄氧基) -苯氧基 1 -1H-吡咯并「2,3-dl哒嗪 -2-羧酸 f3-(4-甲基 -哌嗪 -1- 基) -丙基 1-酰胺 743-chloro-4-(3-fluoro-benzyloxy)-phenoxy 1 -1H-pyrrolo "2,3-dloxazin-2-carboxylic acid f3-(4-methyl-piperazine-1 -yl)-propyl 1-amide
重复本发明实施例 47第一步到第五步的反应, 使用第五步所得的化合物 4-[3-氯 -4-(4-氟-苄氧基) -苯氨基] -1H-吡咯 [2,3-d]哒嗪 -2-羧酸 47f 作原料, 按照本 发明实施例 47第六步所述的相同方式,进行该原料与 3-(4-甲基 -哌嗪 -1-基) -丙胺 反应, 得到标题化合物 7-[3-氯 -4-(3-氟-苄氧基) -苯氧基] -1H-吡咯并 [2,3-d]哒嗪 -2- 羧酸 [3-(4-甲基 -哌嗪 -1-基) -丙基] -酰胺 52 (74 mg, 黄色固体)。 产率: 64.3 %。 MS m/z (ESI): 553[M+ 1] The reaction of the first step to the fifth step of Example 47 of the present invention was repeated, and the compound obtained in the fifth step was used 4-[3-chloro-4-(4-fluoro-benzyloxy)-phenylamino]-1H-pyrrole [ 2,3-d]pyridazine-2-carboxylic acid 47f is used as a starting material, and the starting material is 3-(4-methyl-piperazin-1-yl) in the same manner as described in the sixth step of Example 47 of the present invention. - propylamine reaction to give the title compound 7-[3-chloro-4-(3-fluoro-benzyloxy)-phenoxy]-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid [3-(4-Methyl-piperazin-1-yl)-propyl]-amide 52 (74 mg, yellow solid). Yield: 64.3 %. MS m/z (ESI): 553 [M+ 1]
1HNMR (400MHz, DMSO-d6): S8.33(s, 1H), 7.67(m, 1H), 7.46(m, 1H), 7.34(m, 2H), 7.26(m, 1H), 7.17(m, 2H), 6.94(s, 1H), 5.23(s, 2H),3.35(m, 4H), 3.10(m, 2H), 2.41 (m, 4H), 2.33(m, 4H), 1.96(s, 3H)
实施例 53 、 1HNMR (400MHz, DMSO-d6): S8.33 (s, 1H), 7.67 (m, 1H), 7.46 (m, 1H), 7.34 (m, 2H), 7.26 (m, 1H), 7.17 (m, 2H), 6.94(s, 1H), 5.23(s, 2H), 3.35(m, 4H), 3.10(m, 2H), 2.41 (m, 4H), 2.33(m, 4H), 1.96(s, 3H ) Example 53,
7-Γ3-氯 -4-(3-氟- 氧基) -苯氧基 1 -1H-吡咯并【2,3-dl哒嗉 -2-羧酸 2-(4-甲基 -哌嗪小 基) -乙基 1-酰胺 7-Γ3-chloro-4-(3-fluoro-oxy)-phenoxy 1 -1H-pyrrolo[2,3-dl哒嗉-2-carboxylic acid 2-(4-methyl-piperazine small -ethyl 1-amide
重复本发明实施例 47第一步到第五步的反应, 使用第五步所得的化合物 4-[3-氯- 4-(4-氟-苄氧基) -苯氨基] -1H-吡咯 [2,3-d]哒嗪 -2-羧酸 47f 作原料, 按照本 发明实施例 47第六步所述的相同方式,进行该原料与 3-(4-甲基 -哌嗪 -1-基) -乙胺 反应,得到标题化合物 7-[3-氯 -4-(3-氟-苄氧基) -苯氧基] -1H-吡咯并 [2,3-d]哒嗪 -2- 羧酸 2-(4-甲基 -哌嗪 -1-基) -乙基] -酰胺 53 (88 mg, 黄色固体)。 产率: 78.6%。 MS m/z (ESI): 538[M+ 1] The reaction of the first step to the fifth step of Example 47 of the present invention was repeated, and the compound obtained in the fifth step was used 4-[3-chloro-4-(4-fluoro-benzyloxy)-phenylamino]-1H-pyrrole [ 2,3-d]pyridazine-2-carboxylic acid 47f is used as a starting material, and the starting material is 3-(4-methyl-piperazin-1-yl) in the same manner as described in the sixth step of Example 47 of the present invention. -ethylamine reaction to give the title compound 7-[3-chloro-4-(3-fluoro-benzyloxy)-phenoxy]-1H-pyrrolo[2,3-d]pyridazine-2-carboxylate 2-(4-Methyl-piperazin-1-yl)-ethyl]-amide 53 (88 mg, yellow solid). Yield: 78.6%. MS m/z (ESI): 538 [M+ 1]
1H MR (400MHz, DMSO-d6): 58.33(s, 1H), 7.67(m, 1H), 7.48(m, 1H), 7.34(m, 2H), 7.25(m, 1H), 7.18(m, 2H), 6.86(s, 1H), 5.23(s, 2H), 3.47(m, 2H), 3.15(m, 2H), 2.41(m, 4H), 2.18(m,4H), 1.68(s, 3H) 实施例 54 1 H MR (400MHz, DMSO-d6): 58.33(s, 1H), 7.67(m, 1H), 7.48(m, 1H), 7.34(m, 2H), 7.25(m, 1H), 7.18(m, 2H), 6.86(s, 1H), 5.23(s, 2H), 3.47(m, 2H), 3.15(m, 2H), 2.41(m, 4H), 2.18(m,4H), 1.68(s, 3H) Example 54
4-【3-氯 -4-(3-氟-苄氧基) -苯基 1 -7-甲基 -6H-吡咯并 f3,4-dl哌嗪 -5-羧酸乙酯 4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenyl 1 -7-methyl-6H-pyrrolof3,4-dl piperazine-5-carboxylate
4-甲酰基 -5-甲基 -1H-吡咯 -2,3-二羧酸二乙酯 在 lOO mL茄形瓶中加入 5-甲基 -1H-吡咯 -2,3-二羧酸二乙酯(4.51g,20 mmol) 和 Ν,Ν'-二甲基甲酰胺 (25 mL), 溶解后加入三氯氧磷 (3.8 mL, 40 mmol), 混合 物加热至 100°C, 回流 2小时, 反应完毕。 反应液中加入冰水 (100 mL),加入 1N氢氧化钠溶液调节 pH值至碱性, 有大量黄色固体析出, 过滤, 千燥后得到 4-甲酰 -5-甲基 -1H-吡咯 -2,3-二羧酸二乙酯 (3.905 g, 黄色固体)。 收率: 77.2%。 MS m/z (ESI): 254[M+ 1] 第二步 , Diethyl 4-formyl-5-methyl-1H-pyrrole-2,3-dicarboxylate In a 100 mL eggplant-shaped flask, add 5-methyl-1H-pyrrole-2,3-dicarboxylic acid diethyl Ethyl ester (4.51 g, 20 mmol) and hydrazine, Ν'-dimethylformamide (25 mL). After dissolved, phosphorus oxychloride (3.8 mL, 40 mmol) was added and the mixture was heated to 100 ° C and refluxed for 2 hours. The reaction is completed. Ice water (100 mL) was added to the reaction solution, and 1N sodium hydroxide solution was added to adjust the pH to be alkaline. A large amount of yellow solid was precipitated, filtered, and dried to give 4-formyl-5-methyl-1H-pyrrole- Diethyl 2,3-dicarboxylate (3.905 g, yellow solid). Yield: 77.2%. MS m/z (ESI): 254 [M+ 1] Step 2,
7-甲基 _4-氧代 -4,6-二氢 -3Η-吡咯并 [3,4-d]哒嗪 -5-羧酸乙酯 在氮气保护下, 于 50 mL茄形瓶中加入 4-甲酰基 -5-甲基 -1H-吡咯 -2,3-二羧 酸二乙酯 (2.532 g, lO mmol), 乙醇 (20 mL) 和水合肼 (0.9 mL, 15 mraoD o 混合物加热至 90 C, 回流 3小时, 完应完毕。 冷却反应液至室温, 有大量固体 析出, 抽滤,干燥后得到 7-甲基 -4-氧代 -4,6-二氢 -3H-吡咯并 [3,4-d]哒嗪 -5-羧酸乙 酯 ( 1.732 g, 黄色固体)。 产率: 71.9%。 Ethyl 7-methyl-4-oxo-4,6-dihydro-3indole-pyrrolo[3,4-d]pyridazine-5-carboxylate was added to a 50 mL eggplant bottle under nitrogen. Diethyl 4-formyl-5-methyl-1H-pyrrole-2,3-dicarboxylate (2.532 g, 10 mmol), ethanol (20 mL) and hydrazine hydrate (0.9 mL, 15 mraoD o mixture heated to 90 C, reflux for 3 hours, complete. Cool the reaction solution to room temperature, a large amount of solid precipitated, suction filtration, and dried to give 7-methyl-4-oxo-4,6-dihydro-3H-pyrrole [ 3,4-d]ethyl oxazine-5-carboxylate ( 1.732 g, yellow solid). Yield: 71.9%.
MS m/z (ESI): 220[M- 1] 第三步 MS m/z (ESI): 220[M-1] Step 3
4-氯 -7-甲基 -6H-吡咯并 [3,4-d]哒嗪 -5-羧酸乙酯 在氮气保护下, 于 100 mL茄形瓶中加入 7-甲基 -4-氧代 -4,6-二氢 -3H-吡咯并 [3,4-d]哒嗪 -5-羧酸乙酯(1.736 g, 7.85 mmol),无水乙腈(40 mL)和三氯氧磷(1.5 mL, 15.7 mmol)。 混合物加热至 90Ό, 回流 5小时, 完应完毕。 冷却反应液至 室温, 有大量固体析出, 抽滤, 干燥后得到粗品 4-氯 -7-甲基 -6Η-吡咯并 [3,4-d] 哒嗪 -5-羧酸乙酯 (1.71 g, 黄色固体), 直接进行下一步反应。 第四步 Ethyl 4-chloro-7-methyl-6H-pyrrolo[3,4-d]pyridazine-5-carboxylate was added to a 100 mL eggplant vial under nitrogen to add 7-methyl-4-oxo Generation of 4-,6-dihydro-3H-pyrrolo[3,4-d]pyridazine-5-carboxylic acid ethyl ester (1.736 g, 7.85 mmol), anhydrous acetonitrile (40 mL) and phosphorus oxychloride ( 1.5 mL, 15.7 mmol). The mixture was heated to 90 Torr and refluxed for 5 hours. The reaction solution was cooled to room temperature, a large amount of solid was precipitated, suction filtered, and dried to give crude 4-chloro-7-methyl-6-pyrrolo[3,4-d]pyridazin-5-carboxylic acid ethyl ester (1.71 g) , yellow solid), proceed directly to the next reaction. the fourth step
4-[3-氯 -4-(3-氟-苄氧基) -苯基] -7-甲基 -6H-吡咯并 [3,4-d]哌嗪 -5-羧酸乙酯 在氮气保护下, 于 100 mL茄形瓶中加入粗品 4-氯 -7-甲基 -6H-吡咯并 [3,4-d] 哒嗪 -5-羧酸乙酯(1.71 g), 异丙醇(50 mL)和 3-氯 -4-(3-氟- 氧基) -苯胺(1.6 g, 6.6 mmoD o 混合物加热至 90°C, 回流 7小时, 完应完毕。 冷却反应液至室温, 有大量固体析出, 抽滤, 干燥后得到标题产物 4-[3-氯 -4-(3-氟-节氧基) -苯基] -7- 甲基 -6H-吡咯并 [3,4-d]哌嗪 -5-羧酸乙酯 54 ( 1.474 g, 黄色固体)。 收率: 50.8%。 MS m/z (ESI): 455[M+ 1] Ethyl 4-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-7-methyl-6H-pyrrolo[3,4-d]piperazine-5-carboxylate in nitrogen Under the protection, a crude 4-chloro-7-methyl-6H-pyrrolo[3,4-d]pyridazine-5-carboxylic acid ethyl ester (1.71 g) was added to a 100 mL eggplant bottle, isopropanol ( 50 mL) and 3-chloro-4-(3-fluoro-oxy)-aniline (1.6 g, 6.6 mmoD o mixture heated to 90 ° C, reflux for 7 hours, finished. Cool the reaction solution to room temperature, there are a lot The solid was precipitated, suction filtered and dried to give the title product 4-[3-chloro-4-(3-fluoro-p-oxy)-phenyl]-7-methyl-6H-pyrrolo[3,4-d] Ethyl piperazine-5-carboxylate 54 ( 1.474 g, yellow solid). Yield: 50.8%. MS m/z (ESI): 455 [M+ 1]
'HNMR (400MHZ, DMSO-d6): 59.03(s, 1H), 8.32(s, 1H), 7.56(m, 1H), 7.45(m, 1H),
7.32(m, 2H), 7.26(m, IH), 7.17(m, IH), 5.23(s, 2H), 4.45(q, 2H), 2.63(s, 3H), 1.43(s: 3H) 实施例 55 'HNMR (400MHZ, DMSO-d6): 59.03 (s, 1H), 8.32 (s, 1H), 7.56 (m, 1H), 7.45 (m, 1H), 7.32(m, 2H), 7.26(m, IH), 7.17(m, IH), 5.23(s, 2H), 4.45(q, 2H), 2.63(s, 3H), 1.43(s : 3H) 55
『3-氯 -4-〔3-氟-苄氧基) -苯基 1-(5-甲基 -6H-吡咯并 [3,4-dl哌嗪 -1-基) -乙胺 3-Chloro-4-[3-fluoro-benzyloxy)-phenyl 1-(5-methyl-6H-pyrrolo[3,4-dlpiperazin-1-yl)-ethylamine
4-甲酰基 -5-甲基 -1H-吡咯 -3-羧酸乙酯 4-formyl 5-methyl-1H-pyrrole-3-carboxylic acid ethyl ester
在 25 mL的三口烧瓶中加入 5-甲基 -1H-吡咯 -3-羧酸乙酯 55a (306 mg, 2 mmol) , 1,2-二氯乙烷 (5 mL) 和硝基甲垸 (5 mL), 氩气保护下加入三氯化铝 (800 mg), 将混合物冷却到一 20Ό, 迅速加入二氯甲氧基甲基的 1, 2-二氯乙嫁 溶液 (2.4 mmol, 2 mL), 滴加完毕后, 反应液在一 20°C下反应 3小时。 反应完 毕后, 将反应液倒入水中, 分离出有机层, 水层进一步用乙酸乙酯萃取, 合并有 机相, 用饱和氯化钠洗涤, 无水硫酸钠干燥, 过滤, 浓缩得到的残留物进一步通 过柱层析分离纯化, 得到 4-甲酰基 -5-甲基 -1H-吡咯 -3-羧酸乙酯 55b (334 mg, 黄色固体)。 产率: 92.2% Add 5-methyl-1H-pyrrole-3-carboxylic acid ethyl ester 55a (306 mg, 2 mmol), 1,2-dichloroethane (5 mL) and nitroformamidine to a 25 mL three-necked flask ( 5 mL), add aluminum trichloride (800 mg) under argon, cool the mixture to 20 Torr, and quickly add dichloromethoxymethyl 1,2-dichloroethane (2.4 mmol, 2 mL) After the dropwise addition was completed, the reaction solution was reacted at 20 ° C for 3 hours. After the reaction is completed, the reaction mixture is poured into water, the organic layer is separated, the aqueous layer is extracted with ethyl acetate, and the organic phase is combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by column chromatography gave 4-formyl-5-methyl-1H-pyrrole-3-carboxylic acid ethyl ester 55b (334 mg,yel. Yield: 92.2%
MS m/z (ESI): 455[M+ 1] MS m/z (ESI): 455 [M+ 1]
1H NMR ( 400 MHz, CDC13-^): 510.503(s, 1H), 7.28(t, IH), 4.32(q, 2H, J-6.8Hz), 2.58(s, 3H), 1.35(t, 3H, J=6.8Hz)。
第二步 1H NMR ( 400 MHz, CDC1 3 -^): 510.503 (s, 1H), 7.28 (t, IH), 4.32 (q, 2H, J- 6.8 Hz), 2.58 (s, 3H), 1.35 (t, 3H) , J = 6.8 Hz). Second step
5-甲基 -2,6-二氢吡咯并 [3,4-d]哒嗪小酮 在氮气保护下,于 10 mL茄形瓶中加入 44-甲酰基 -5-甲基 -1H-吡咯 -3-羧酸乙 酯 55b (91 mg,0.5mmol), 乙醇 (1 mL)和水合肼 (35μ1, 0.6mmol)。 混合物 加热至 90°C, 回流 4小时, 反应完毕。 冷却反应液至室温, 有大量固体析出, 抽滤, 干燥后得到 5-甲基 -2,6-二氢吡咯并 [3,4-d]哒嗪 -1-酮 55c (28 mg, 黄色固 体)。 产率: 39%。 5-methyl-2,6-dihydropyrrolo[3,4-d]pyridazine ketone was added to a 10 mL eggplant vial under the protection of nitrogen to form 44-formyl-5-methyl-1H-pyrrole Ethyl 3-carboxylate 55b (91 mg, 0.5 mmol), ethanol (1 mL) and hydrazine hydrate (35μl, 0.6 mmol). The mixture was heated to 90 ° C and refluxed for 4 hours, and the reaction was completed. The reaction solution was cooled to room temperature, a large amount of solid was precipitated, suction filtered, and dried to give 5-methyl-2,6-dihydropyrrolo[3,4-d]pyridazin-1-one 55c (28 mg, yellow solid ). Yield: 39%.
MS m/z (ESI): 150[M+1] 第三步 MS m/z (ESI): 150[M+1] Step 3
1-氯 -5-甲基 -6H-吡咯并 [3,4-d]哒嗪 1-chloro-5-methyl-6H-pyrrolo[3,4-d]pyridazine
在氮气保护下, 于 10 mL茄形瓶中加入 5-甲基 -2,6-二氢吡咯并 [3,4-d]哒嗪 -1-酮 55c (150mg, 1 mmol), 无水乙腈 (2mL)和三氯氧磷 (0.5 mL, 5mmol)。 混合物加热至 90°C, 回流 3小时, 反应完毕。 冷却反应液至室温, 有大量固体 析出, 抽滤, 干燥后得到粗品 1-氯 -5-甲基 -6H-吡咯并 [3,4-d]哒嗪 55d (170mg), 直接进行下一步反应。 5-methyl-2,6-dihydropyrrolo[3,4-d]pyridazin-1-one 55c (150 mg, 1 mmol), anhydrous acetonitrile was added to a 10 mL eggplant flask under nitrogen. (2 mL) and phosphorus oxychloride (0.5 mL, 5 mmol). The mixture was heated to 90 ° C and refluxed for 3 hours, and the reaction was completed. The reaction solution was cooled to room temperature, a large amount of solid was precipitated, suction filtered, and dried to give crude 1-chloro-5-methyl-6H-pyrrolo[3,4-d]pyridazine 55d (170 mg). .
MSm/z(ESI): 168[M+1] 第四步 MSm/z(ESI) : 168[M+1] Step 4
4-[3-氯 -4-(3-氟-苄氧基) -苯基 ]-7-甲基 -6H-吡咯并 [3,4-d]哌嗪 -5-羧酸乙酯 在氮气保护下, 于 100 mL茄形瓶中加入粗品 4-氯 -7-甲基 -6H-吡咯并 [3,4-d] 哒嗪 -5-羧酸乙酯 (170mg), 异丙醇(5niL) 和 3-氯 -4-(3-氟-苄氧基) -苯胺(176 mg, 0.7mmol)o 混合物加热至 9(TC, 回流 7小时, 反应完毕。 冷却反应液至室 温, 有大量固体析出, 抽滤, 干燥后得到 4-[3-氯 -4-(3-氟-苄氧基) -苯基] -7-甲基 -6H-吡咯并 [3,4-d]哌嗪 -5-羧酸乙酯 (72 mg,黄色固体)。 收率: 27%。 Ethyl 4-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-7-methyl-6H-pyrrolo[3,4-d]piperazine-5-carboxylate in nitrogen Under the protection, add the crude 4-chloro-7-methyl-6H-pyrrolo[3,4-d]pyridazine-5-carboxylic acid ethyl ester (170 mg) to isopropanol (5 niL) in a 100 mL eggplant flask. And the mixture of 3-chloro-4-(3-fluoro-benzyloxy)-phenylamine (176 mg, 0.7 mmol) was heated to 9 (TC, reflux for 7 hours, the reaction was completed. The reaction mixture was cooled to room temperature, and there was a large amount of solid Precipitation, suction filtration, drying to give 4-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-7-methyl-6H-pyrrolo[3,4-d]piperazine- Ethyl 5-carboxylate (72 mg, yellow solid). Yield: 27%.
MSm/z(ESI): 383[M+1] MSm/z (ESI): 383 [M+1]
1H NMR ( 400 MHz, COCl d ): S7.493〜7.437(m, 3H), 7.3 l(t, 2H), 7.28(s, 1H), 7.21〜7.15(m, 2H), 5.20(s, 2H), 4.32(q, 2H, J=6.8Hz), 2.5 l(s, 3H) 实施例 56 1H NMR (400 MHz, COCl d ): S7.493~7.437 (m, 3H), 7.3 l (t, 2H), 7.28 (s, 1H), 7.21~7.15 (m, 2H), 5.20 (s, 2H) ), 4.32 (q, 2H, J = 6.8 Hz), 2.5 l (s, 3H). Example 56
4-Γ1- -氟苄基 )-1Η-吲唑 -5-氨基 1-3-甲基 -1H-吡咯并「2,3-dl哒嗪 -2-IY2-吡咯啶 -1- 基) -乙基 1甲酰胺
重复本发明实施例 20第一步至第二步的反应, 使用上述第二步中所得到的 化合物 4-[1-(3-氟苄基) -1H-吲唑 -5-氨基] -3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸 20b作原料,按照本发明实施例 1第六步所述相同方式进行该原料与 2- (吡咯啶 -1- 基) -乙胺的反应, 则得到标题产物 4-[1-(3-氟苄基 )-1Η-吲唑 -5-氨基] -3-甲基 -1H- 吡咯并 [2,3-d]哒嗪 -2-[(2-吡咯啶 -1-基) -乙基]甲酰胺 56 (58 mg,黄色固体)。产率 9 %。 4-Γ1--fluorobenzyl)-1Η-carbazole-5-amino1-3-methyl-1H-pyrrolo-[2,3-dl-pyridazine-2-IY2-pyrrolidin-1-yl) Ethyl 1 carboxamide The reaction of the first step to the second step of Example 20 of the present invention was repeated, using the compound 4-[1-(3-fluorobenzyl)-1H-indazole-5-amino]-3 obtained in the above second step. -Methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid 20b as a starting material, and the starting material and 2-(pyrrolidine-1) were carried out in the same manner as described in the sixth step of Example 1 of the present invention. -yl)-ethylamine reaction, the title product 4-[1-(3-fluorobenzyl)-1Η-indazole-5-amino]-3-methyl-1H-pyrrolo[2,3- d] pyridazine-2-[(2-pyrrolidin-1-yl)-ethyl]carboxamide 56 (58 mg, yellow solid). The yield was 9%.
MS m/z (ESI): 513 [M+ 1] MS m/z (ESI): 513 [M+ 1]
1H MR (400MHz, DMSO-^): 58.07(s, 2H), 7.65(m, 2H), 7.33(m, 1H), 7.09(m, 1H), 7.04(m, 2H), 5.67(s, 2H), 2.68(m, 4H), 2.34(m, 4H), 2.41 (s, 3H), 1.72(m, 4H) 实施例 57 1H MR (400MHz, DMSO-^): 58.07(s, 2H), 7.65(m, 2H), 7.33(m, 1H), 7.09(m, 1H), 7.04(m, 2H), 5.67(s, 2H ), 2.68 (m, 4H), 2.34 (m, 4H), 2.41 (s, 3H), 1.72 (m, 4H) Example 57
4-Γ1-(3-氟苄基 )-1Η-吲唑 -5-氨基 3-甲基 -IH-吡咯并「2,3-dl哒嗪 -2-ΙΪ2-吗啡啉 -4- 基) -乙基 1甲酰胺 4-Γ1-(3-fluorobenzyl)-1Η-carbazole-5-amino-3-methyl-IH-pyrrolo-[2,3-dloxazin-2-indole-2-morpholine-4-yl)- Ethyl 1 carboxamide
重复本发明实施例 18第一步至第二步的反应, 使用上述第二步中所得到的 化合物 4-[1 -(3-氟苄基) -1H-吲唑 -5-氨基] -3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸 18b 作原料, 按照本发明实施例 1第六步所述相同方式进行该原料与 2-吗啡啉 -4-基- 乙胺的反应, 则得到标题产物 4-[1-(3-氟苄基 )-1Η-吲唑 -5-氨基] -3-甲基 -1H-吡咯 并 [2,3-d]哒嗪 -2-[(2-吗啡啉 -4-基) -乙基]甲酰胺 57(50 mg, 黄色固体)。 产率 58.6 %。 The reaction of the first step to the second step of Example 18 of the present invention was repeated, using the compound 4-[1-(3-fluorobenzyl)-1H-indazole-5-amino]-3 obtained in the above second step. -Methyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid 18b as a starting material, the starting material and 2-morpholine-4- are carried out in the same manner as described in the sixth step of Example 1 of the present invention. The reaction of the base-ethylamine gives the title product 4-[1-(3-fluorobenzyl)-1Η-indazole-5-amino]-3-methyl-1H-pyrrolo[2,3-d] Pyridazin-2-[(2-morphinolin-4-yl)-ethyl]carboxamide 57 (50 m g , yellow solid). The yield was 58.6 %.
MS m/z (ESI): 529 [M+ 1] MS m/z (ESI): 529 [M+ 1]
1HNMR (400MHz, OMSO-d6): 58.07(s, 2H), 7.64(m, 1H), 7.55(m, 1H), 7.35(m, 1H), 7.08(m, 1H), 7.03(m, 2H), 5.67(s, 2H), 3.59(m, 4H), 3.42(m, 2H), 3.34(m, 2H), 2.40(s,
3H) 1 H NMR (400MHz, OMSO-d 6 ): 58.07(s, 2H), 7.64 (m, 1H), 7.55 (m, 1H), 7.35 (m, 1H), 7.08 (m, 1H), 7.03 (m, 2H), 5.67(s, 2H), 3.59(m, 4H), 3.42(m, 2H), 3.34(m, 2H), 2.40(s, 3H)
实施例 58 Example 58
Π3-氯 -4-(3-氟苄氧基) -苯基 W2_n-f(2-甲磺酰基乙氨基 -甲基 1-苯基 1-3-甲基 -1H- 吡咯并「2,3-dl哒嗪 -4-基) -胺 Π3-Chloro-4- (3 -fluorobenzyloxy)-phenyl W 2 _n-f(2-methanesulfonylethylamino-methyl 1-phenyl1-3-methyl-1H-pyrrole "2 , 3-dloxazin-4-yl)-amine
2-{3-[(2-甲磺酰基乙氨基) -甲基] -苯基 }-3-甲基 -1,5-二氢-吡咯并 [2,3-d]哒嗪 -4-酮 按照本发明实施例 45第四步所述的方式,以化合物 2-(5-二乙氨基甲基 -呋喃 -2-基) -3-甲基 -1,5-二氢-吡咯并 [2,3-d]哒嗪 -4-酮 45e (220 mg, 0.8 mmol) 和 3- (2- 甲橫酰基乙氨基甲基)苯硼酸 (186 mg, 0.8 mmol) 为原料, 得到本标题化合物 2-{3-[(2-甲磺酰基乙氨基) -甲基] -苯基 3-甲基 -1,5-二氢-吡咯并 [2,3-d]哒嗪 -4-酮 58a ( 162 mg, 白色固体)。 产率: 57.8 %。 2-{3-[(2-Methanesulfonylethylamino)-methyl]-phenyl}-3-methyl-1,5-dihydro-pyrrolo[2,3-d]pyridazine-4- The ketone is in the manner described in the fourth step of Example 45 of the present invention, using the compound 2-(5-diethylaminomethyl-furan-2-yl)-3-methyl-1,5-dihydro-pyrrolo[ 2,3-d]oxazin-4-one 45e (220 mg, 0.8 mmol) and 3-(2-methyl-cyanoethylaminomethyl)benzeneboronic acid (186 mg, 0.8 mmol) 2-{3-[(2-methanesulfonylethylamino)-methyl]-phenyl 3-methyl-1,5-dihydro-pyrrolo[2,3-d]pyridazin-4-one 58a (162 mg, white solid). Yield: 57.8 %.
MS m/z (ESI): 351 [M+ l] 第二步 MS m/z (ESI): 351 [M+ l] Step 2
[3-氯 -4-(3-氟苄氧基) -苯基 ]-(2-{3-[(2-甲磺酰基乙氨基)甲基] -苯基 }-3-甲基 -1 H-吡咯并 [2,3-d]哒嗪 -4-基) -胺 [3-Chloro-4-(3-fluorobenzyloxy)-phenyl]-(2-{3-[(2-methanesulfonylethylamino)methyl]-phenyl}-3-methyl-1 H-pyrrolo[2,3-d]pyridazin-4-yl)-amine
按照本发明实施例 1第三、四步所述相同方式反应,使用上述第五步中所得 到的化合物 2-{3-[(2-甲磺酰基乙氨基) -甲基] -苯基 }-3-甲基 -1,5-二氢-吡咯并 [2,3-d] 哒嗪 _4-酮 58a 作原料, 得到 [3-氯 -4-(3-氟苄氧基) -苯基 ]-(2-{3-[(2-甲磺酰基乙氨 基) -甲基] -苯基 3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -4-基) -胺 58 (15 mg, 白色固体)。 产率 44.1 %。 In the same manner as described in the third and fourth steps of Example 1 of the present invention, the compound 2-{3-[(2-methanesulfonylethylamino)-methyl]-phenyl} obtained in the above fifth step was used. 3-methyl-1,5-dihydro-pyrrolo[2,3-d]pyridazine-4-one 58a as a starting material to give [3-chloro-4-(3-fluorobenzyloxy)-benzene ]-(2-{3-[(2-Methanesulfonylethylamino)-methyl]-phenyl 3-methyl-1H-pyrrolo[2,3-d]pyridazin-4-yl)- Amine 58 (15 mg, white solid). The yield was 44.1%.
MS m/z (ESI): 595 [M+ l] MS m/z (ESI): 595 [M+ l]
!HNM (400MHz, DMSO-c¾: 57.94 (m, 2H), 7.54(m, 3H), 7.46(m, 2H), 7.32,(m, 3H), 7.18(m, 2H), 5.22(s, 2H), 4.25(d, 2H, J=9Hz), 3.28(s, 3H), 3.03(m, 2H), 2.67(m, 2H), 2.94(s, 3H) ! HNM (400MHz, DMSO-c¾ : 57.94 (m, 2H), 7.54 (m, 3H), 7.46 (m, 2H), 7.32, (m, 3H), 7.18 (m, 2H), 5.22 (s, 2H ), 4.25(d, 2H, J=9Hz), 3.28(s, 3H), 3.03(m, 2H), 2.67(m, 2H), 2.94(s, 3H)
实施例 59 Example 59
Γ3-氯 _4-(3_氟苄氧基) -苯基 "l-(2-{5-「(2-甲磺酰基乙氨基) -甲基 1-呋喃 -2-基 3-甲基 -1H-吡咯并「2,3-dl哒嗪 -4-基 V胺
第一步 Γ3 -Chloro- 4- (3- fluorobenzyloxy)-phenyl"l-( 2- {5-"(2-methanesulfonylethylamino)-methyl-1-furan-2-yl 3-methyl -1H-pyrrolo and 2,3-dloxazin-4-yl V amine first step
2-{5-[(2-甲磺酰基-乙氨基)甲基] -呋喃 -2-基}-3-甲基 -1,5-二氢 -B比咯并 [2,3-d]哒嗪 -4-酮 2-{5-[(2-methanesulfonyl-ethylamino)methyl]-furan-2-yl}-3-methyl-1,5-dihydro-B than s-[2,3-d] Pyridazin-4-one
按照本发明实施例 45第四步所述的方式, 以化合物 2-(5-二乙氨基甲基-呋 喃 -2-基) -3-甲基 -1,5-二氢-口比咯并 [2,3-d]哒嗪 -4-酮 45e (330 mg, 1.2 mmol )和 5-(2- 甲磺酰基乙氨基甲基)呋喃 -2-硼酸 (280 mg, 1.2 mmol) 为原料, 得到本标题化 合物 2-{5-[(2-甲磺酰基-乙氨基)甲基] -呋喃 -2-基}-3-甲基 -1,5-二氢 -P比咯并 [2,3-d] 哒嗪 _4-酮 59a ( 162 mg, 白色固体)。 产率: 57.8%。 According to the method described in the fourth step of Example 45 of the present invention, the compound 2-(5-diethylaminomethyl-furan-2-yl)-3-methyl-1,5-dihydro-porto [2,3-d]oxazin-4-one 45e (330 mg, 1.2 mmol) and 5-(2-methanesulfonylethylaminomethyl)furan-2-boronic acid (280 mg, 1.2 mmol). The title compound 2-{5-[(2-methanesulfonyl-ethylamino)methyl]-furan-2-yl}-3-methyl-1,5-dihydro-P is obtained as the title compound [2, 3-d] pyridazine _4-ketone 59a (162 mg, white solid). Yield: 57.8%.
MS m/z (ESI): 351[M+ 1] 第二步 MS m/z (ESI): 351[M+ 1] Step 2
[3一氯 _4-(3-氟苄氧基) -苯基 ]-(2-{5-[(2-甲磺酰基乙氨基) -甲基] -呋喃 -2-基}-3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -4-基) -胺 [3-Chloro-4-(3-fluorobenzyloxy)-phenyl]-(2-{5-[(2-methanesulfonylethylamino)-methyl]-furan-2-yl}-3- Methyl-1H-pyrrolo[2,3-d]pyridazin-4-yl)-amine
按照本发明实施例 1第三、四步所述相同方式反应,使用上述第五步中所得 到的化合物 2-{5-[(2-甲磺酰基-乙氨基)甲基] -呋喃 -2-基}-3-甲基 -1,5-二氢-吡咯并 [2,3-d]哒嗪 -4-酮 59a作原料, 得到 [3-氯 -4-(3-氟苄氧基) -苯基 ]-(2-{5-[(2-甲磺酰基 乙氨基) -甲基] -呋喃 -2-基卜 3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -4-基) -胺 59 (15 mg, 白色 固体)。 产率 44.1 %。 In the same manner as described in the third and fourth steps of Example 1 of the present invention, the compound 2-{5-[(2-methanesulfonyl-ethylamino)methyl]-furan-2 obtained in the above fifth step was used. -yl}-3-methyl-1,5-dihydro-pyrrolo[2,3-d]pyridazin-4-one 59a as a starting material to give [3-chloro-4-(3-fluorobenzyloxy) -Phenyl]-(2-{5-[(2-methanesulfonylethylamino)-methyl]-furan-2-ylbu 3-methyl-1H-pyrrolo[2,3-d]哒Pyrazin-4-yl)-amine 59 (15 mg, white solid). The yield was 44.1%.
MS m/z (ESI): 585 [M+ 1] ' MS m/z (ESI): 585 [M+ 1] '
1HNMR (400MHz, DMSO- ): 58.02(s, 1H), 7.87(s, 1H), 7.49(m, 2H), 7.30(d, 2H), 7.20(m, 2H), 7.15(m, 2H), 6.87(d, 2H, J=3.2Hz), 6.51(d, 1H, J=3.2Hz), 5.22(s, 2H), 3.83(s, 2H), 3.28(q, 2H, J=6.8Hz), 3.02(s, 3H), 2.97(d, 2H), 2.64(s, 3H)。 生物学评价 例 1: VEGF-R2激酶活性测定 1 H NMR (400 MHz, DMSO-): 58.02 (s, 1H), 7.87 (s, 1H), 7.49 (m, 2H), 7.30 (d, 2H), 7.20 (m, 2H), 7.15 (m, 2H) , 6.87(d, 2H, J=3.2Hz), 6.51(d, 1H, J=3.2Hz), 5.22(s, 2H), 3.83(s, 2H), 3.28(q, 2H, J=6.8Hz) , 3.02(s, 3H), 2.97(d, 2H), 2.64(s, 3H). Biological Evaluation Example 1: Determination of VEGF-R2 Kinase Activity
本试验采用酶联吸附免疫测定法 (ELISA) 测定重组人类 VEGF-R2蛋白体 外激酶活性。
材料与试剂- a. 洗涤缓冲液 (PBS-T 缓冲液): lx PBS (137 mM NaCl、 2.7 mM KCK 4.3 mMNa2HP04 1.4 mM KH2P04, 调 pH至 7.2)和 0.05 % Tween-20 In this experiment, the in vitro kinase activity of recombinant human VEGF-R2 protein was determined by enzyme-linked immunosorbent assay (ELISA). Materials and reagents - a. Wash buffer (PBS-T buffer): lx PBS (137 mM NaCl, 2.7 mM KCK 4.3 mM Na 2 HP0 4 1.4 mM KH 2 P0 4 , adjusted to pH 7.2) and 0.05% Tween-20
b. 1 %牛血清白蛋白 (BSA, Calbiochem #136593)PBS-T缓冲液 b. 1% bovine serum albumin (BSA, Calbiochem #136593) PBS-T buffer
c. 中止反应缓冲液: 50 mM EDTA , pH 8.0 c. Stop reaction buffer: 50 mM EDTA, pH 8.0
d. DELFIA®铕标记抗鼠 IgG (PerkinElmer Life Sciences #AD0124) d. DELFIA® 铕 labeled anti-mouse IgG (PerkinElmer Life Sciences #AD0124)
e. DELFIA®信号倍增液 (PerkinElmer Life Sciences #1244-105) e. DELFIA® Signal Multiplier (PerkinElmer Life Sciences #1244-105)
f. DELFIA® Streptavidin包 96孔黄板 (PerkinElmer Life Sciences #AAAND-0005) g. 重组人类 VEGF-R2 激酶(50 mM Tris-HCl (pH 8.0), 100 mM NaCl, 5 mM DTT, 15 mM谷酰基胱氨酰甘氨酸和 20 %甘油 (Cell signaling technology #7787) h. lO mM ATP溶液 (Cell signaling technology #9804) f. DELFIA® Streptavidin 96-well yellow plate (PerkinElmer Life Sciences #AAAND-0005) g. Recombinant human VEGF-R2 kinase (50 mM Tris-HCl (pH 8.0), 100 mM NaCl, 5 mM DTT, 15 mM glutamyl Cysteinyl glycine and 20% glycerol (Cell signaling technology #7787) h. lO mM ATP solution (Cell signaling technology #9804)
i. Biotin-Gastrin Precursor (Tyr87) Peptide (Cell signaling technology #1310) j. Phospho-Tyrosine Mouse mAb (P-Tyr-100) (Cell signaling technology #9411) k. HTScan™酪氨酸激酶缓冲液 (4x) i. Biotin-Gastrin Precursor (Tyr87) Peptide (Cell signaling technology #1310) j. Phospho-Tyrosine Mouse mAb (P-Tyr-100) (Cell signaling technology #9411) k. HTScanTM Tyrosine Kinase Buffer (4x )
lx激酶缓冲液-Lx kinase buffer -
60 mM HEPES 60 mM HEPES
5 mM MgCl2 5 mM MgCl 2
5 mM MnCl2 5 mM MnCl 2
3 μΜ Ν 3νθ 3 μΜ Ν 3 νθ
(Cell signaling technology #9805) (Cell signaling technology #9805)
1. 1.25 M DTT (lOOOx) (Cell signaling technology) 1. 1.25 M DTT (lOOOOx) (Cell signaling technology)
方案: Program:
使用如下方案进行试验: Experiment with the following scenario:
1. 用 DMSO稀释受试化合物至所需最终浓度, 在每个试验中加入 1 μΐ待测化合 物、 一个阴性对照和空白对照 (均不接受任何受试化合物); 1. Dilute the test compound to the desired final concentration in DMSO, adding 1 μΐ of the test compound, one negative control, and a blank control in each test (all do not accept any test compound);
2. 用 dH201:l稀释 6 μΜ底物蛋白 (Tyr87), 并在每个测试中加入 15 μΐ; 2. Dilute 6 μΜ substrate protein (Tyr87) with dH 2 01:1 and add 15 μM to each test;
3.将 VEGF-R2酶从- 80。C直接转移到冰上, 酶解冻在冰上; 3. Transfer the VEGF-R2 enzyme from -80. C is directly transferred to ice, and the enzyme is thawed on ice;
4. 取 2.2 g VEGF-R2酶到每个测试中; 4. Take 2.2 g of VEGF-R2 enzyme into each test;
5.加入 10 μΐ DTT (1.25 M) 到 2.5 ml 4x HTScan™酪氨酸激酶缓冲液 (240 mM HEPES pH 7.5, 20 mM MgCI2, 20 mM MnCI2, 12 μΜ Na3V04) 中,制得 DTT/激酶 缓冲液; 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. 转移 0.75 ml DTT/激酶缓冲液到每个每个测试中, 制得 4x 反应混合液,并在 每个测试中加入 7.5 μΗχ反应液; 6. Transfer 0.75 ml DTT/kinase buffer to each of each test to prepare a 4x reaction mixture and add 7.5 μL of reaction solution to each test;
7.加入 2 μ1 ΑΤΡ (10 ηιΜ)至 498 μ1 άΗ20中, 并在每个测试中加入 7.5 μΐ;
30 μΐ反应最终测试条件为: 7. Add 2 μl ΑΤΡ (10 ηιΜ) to 498 μ1 άΗ 2 0 and add 7.5 μΐ to each test; The final test conditions for the 30 μΐ reaction are:
60 mM HEPES pH 7.5 60 mM HEPES pH 7.5
5 mM MgCl2 5 mM MgCl 2
5 mM MnCl2 5 mM MnCl 2
1.25 mM DTT 1.25 mM DTT
10 μΜΑΤΡ 10 μΜΑΤΡ
I.5 μΜ多肽底物 I.5 μΜ polypeptide substrate
22 ng VEGF-R2激酶 22 ng VEGF-R2 kinase
8. 在 25°C下, 将反应管温育 30分钟; 8. Incubate the reaction tube for 30 minutes at 25 °C;
9. 每个 *|试中加入 30 μΐ反应中止缓冲液 (50 mM EDTA, pH 8.0)中止反应; 9. Stop the reaction by adding 30 μΐ reaction stop buffer (50 mM EDTA, pH 8.0) to each *| test.
10. 在 96孔 streptavidin包被培养板每孔中加入 25 μΐ反应液和 75 μΐ dH20,在室 温下, 振摇 60分钟; 10. Add 25 μM reaction solution and 75 μΐ dH 2 0 to each well of a 96-well streptavidin coated plate, and shake at room temperature for 60 minutes;
II. 每孔用 20(^1 PBS-T缓冲液洗涤 3次, 在纸巾上轻拍以除去剩余的液体; II. Wash each well with 20 (^1 PBS-T buffer 3 times, tap on a paper towel to remove the remaining liquid;
12. 用 1 %牛血清白蛋白 PBS-T缓冲液 1:1000稀释主要抗体 Phospho-酪氨酸 mAb (P-Tyr-100), 并在每孔中加入 100 μΐ稀释的 p-Tyr-100抗体; 12. Dilute the primary antibody Phospho-tyrosine mAb (P-Tyr-100) with 1% bovine serum albumin PBS-T buffer 1:1000 and add 100 μM diluted p-Tyr-100 antibody to each well. ;
13. 室温下, 振摇温育 60 分钟; 13. Incubate for 60 minutes at room temperature;
14. 按第 11步所述方法进行洗涤; 14. Wash as described in step 11;
15. 用 1 %牛血清白蛋白 PBS-T缓冲液 1:500稀释铕标记的抗鼠 IgG, 并在每个 孔中加入 100 μΐ稀释的抗体; 15. Dilute the labeled anti-mouse IgG with 1:500 in 1% bovine serum albumin PBS-T buffer and add 100 μl of diluted antibody to each well;
16. 室温下, 振摇温育 30分钟; 16. Incubate for 30 minutes at room temperature;
17. 每孔用 PBS-T缓冲液 200 μΐ洗涤 5次, 在纸巾上轻拍以除去剩余的液体; 17. Wash each well 5 times with PBS-T buffer 200 μM and pat on a paper towel to remove any remaining liquid;
18. 每孔中加入 100 DELFIA®信号倍增液; 18. Add 100 DELFIA® signal multiplier to each well;
19. 室温下, 振摇温育 5分钟; 19. Incubate for 5 minutes at room temperature;
20. 在波长 615 nm下, 用合适的时间分辨扳读取器读取荧光强度。 20. At a wavelength of 615 nm, read the fluorescence intensity with a suitable time-resolving pull reader.
计算抑制率比值: IR (%) =100- 100*(X-B)/ (N-B) Calculate the inhibition ratio: IR (%) =100- 100*(X-B)/ (N-B)
X=受试化合物吸光度 X = absorbance of test compound
N=阳'性对照 N=yang's control
B=空白 B=blank
IC50 值通过受测化合物一系列浓度递度下的 IR值来计算。 本发明化合物的活性 The IC 50 value is calculated from the IR values at a range of concentration concentrations of the test compound. Activity of the compounds of the invention
本发明化合物的生化学活性通过以上的试验进行测定, 测得的 IC5o值见下 表。
实施例编号 IC50 (VEGFR/bio) M)The biochemical activity of the compounds of the present invention was determined by the above test, and the measured IC 5 o values are shown in the following table. Example No. IC 50 (VEGFR/bio) M)
31 >131 >1
32 0.5232 0.52
43 >143 >1
44 >144 >1
45 >145 >1
46 >146 >1
57 >1 例 2 抑制细胞增殖测试 57 >1 case 2 inhibition cell proliferation test
下面的体外试验是用来测定本发明化合物对于人类肿瘤细胞 A431 EGFR高 表达的细胞株抑制增殖活性。 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.
下面所述的体外细胞试验可确定受试化合物的对髙表达 EGFR 的肿瘤细胞 的抗血管生成活性和抑制增殖活性,其活性可用 IC5D值来表示。此类试验的一般 方案如下:首先选择高表达 EGFR的人类肿瘤细胞,以适宜细胞浓度下(exp 5000 个细胞 /ml medium) 接种在 96孔培养板上, 然后将细胞在二氧化碳恒温箱内进 行培养, 当它们生长至 85%汇合, 更换培养基为加有一系列浓度递度 (一般 6 到 7个浓度) 受试化合物溶液的培养基, 将培养板重新放回培养箱, 连续培养 72个小时。 72小时后, 可用 sulforhodamine B (SRB)方法进行测试化合物对于 抑制细胞增殖活性。 IC5Q值可通过一系列不同浓度下, 受试化合物对于细胞的抑 制数值进行计算。 材料和方法: The in vitro cell assay described below can determine the anti-angiogenic activity and the proliferative activity of the test compound against EGFR-expressing tumor cells, the activity of which can be expressed by the IC 5D value. The general protocol for such an experiment is as follows: first select human tumor cells with high expression of EGFR, inoculate them in 96-well culture plates at a suitable cell concentration (exp 5000 cells/ml medium), and then culture the cells in a carbon dioxide incubator. When they grow to 85% confluence, the medium is changed to a medium containing a series of concentration (usually 6 to 7 concentrations) of the test compound solution, and the plate is returned to the incubator for 72 hours. After 72 hours, the test compound was tested for its ability to inhibit cell proliferation using the sulforhodamine B (SRB) method. The IC 5Q value can be calculated from the inhibition values of the test compound for the cells at a range of different concentrations. Materials and Method:
a. 二甲基亚砜 (Sinophma chemical reagent company, 目录 T20050806号) b. A431 细胞 于 Institute of biochemistry and cell biology) a. dimethyl sulfoxide (Sinophma chemical reagent company, catalogue T20050806) b. A431 cells in the Institute of biochemistry and cell biology)
c. Falcon 100 mm细胞培养板 (Baton Dickison Labware, Baton Dickison and company, 目录 18677号) c. Falcon 100 mm Cell Culture Plate (Baton Dickison Labware, Baton Dickison and company, Catalog No. 18677)
d. corning 96孔培养板 (Corning Incorporated, 目录 3599号) d. Corning 96-well culture plate (Corning Incorporated, catalogue 3599)
e. Fisher移液管 (Fisher scientific, 目录 03-692-164号) e. Fisher pipette (Fisher scientific, catalogue 03-692-164)
f. DMEM/F12 细胞培养基 (Gibco, 目录 12400-024号) f. DMEM/F12 cell culture medium (Gibco, catalog 12400-024)
g. 澳大利亚胎牛血清 (Gibco, 目录 10099-141号) g. Australian fetal bovine serum (Gibco, catalogue 10099-141)
h. 磷酸盐缓冲盐水 (Gibco, 目录 10010-072号) h. Phosphate buffered saline (Gibco, catalogue 10010-072)
i. 0.25 %胰岛素 -EDTA (Gibco, 目录 25200-056号) i. 0.25 % insulin - EDTA (Gibco, catalog 25200-056)
j. Sulforhodamine B (Sigma, 目录 3520-42-1号) j. Sulforhodamine B (Sigma, Table of Contents 3520-42-1)
k. 醋酸(Sinophma chemical reagent company, 目录 T20060508号)
1. 三氯醋酸(Sinophma chemical reagent company, 目录 T20060305号) m. Tris碱 (Amresco, 目录 0826号) k. Acetic acid (Sinophma chemical reagent company, catalog T20060508) 1. Trichloroacetic acid (Sinophma chemical reagent company, catalogue T20060305) m. Tris base (Amresco, catalog No. 0826)
n. II ·级 A/B3 型生物学安全工作橱 (ThermoForma目录. HB0053_03号) n. II · Grade A/B3 Biological Safety Work Cabinet (ThermoForma Catalogue. HB005 3 _03)
0. 系列 II水套式二氧化碳培养箱(ThermoForma模型: 3111) 0. Series II water jacketed carbon dioxide incubator (ThermoForma model: 3111)
p. 离心机 (Fisher Scientific Marathon 8 k, 目录 0027-02号) p. Centrifuge (Fisher Scientific Marathon 8 k, Catalogue 0027-02)
q. Novastar板读取器(BMG Labtech, 目录 700-00S1号) q. Novastar Board Reader (BMG Labtech, Catalog 700-00S1)
r. 定轨摇床 (Qilinbeier, 目录 TS-1号) 方案: r. Orbital shaker (Qilinbeier, catalog TS-1)
下面的方案用来测试本发明受试化合物对于 A431细胞的抑制细胞增殖 IC5C值。The following test program to test the compounds of the invention for inhibition of A431 cell proliferation IC 5C value.
1. 将 A431细胞殖于 100mm corning培养板在生长基 (以 DMEM/F12+10%胎牛 血清为培养液)中进行培养 (37 °C, 5 % C02), 直至细胞充分汇合; 1. A431 cells were cultured in a 100 mm corning plate in a growth medium (DMEM/F12 + 10% fetal bovine serum as a medium) (37 ° C, 5 % C0 2 ) until the cells were fully confluent;
2. 在. 100 mm培养板中用胎牛血清洗涤 A431细胞, 以 Tyrpsin消化细胞后, 再 将细胞接种在 coming 96孔细胞培养板上, 浓度为 50000 cells/ml,每个板空 6孔, 作为对照孔.; 2. Wash A431 cells with fetal bovine serum in a 100 mm plate, digest the cells with Tyrpsin, and inoculate the cells on a comping 96-well cell culture plate at a concentration of 50000 cells/ml, 6 wells per plate. As a control well.
3. 在 37 °C, 5 % C02条件下, 将细胞在 96孔板中培养, 直至达到约 85 %汇合;3. Incubate the cells in 96-well plates at 37 ° C, 5 % C0 2 until approximately 85% confluence is reached;
4. 用 DMSO溶解受试化合物, 配置 20 mM母液, 后用 DMSO稀释母液, 得到 一系列浓度的受试化合物的溶液,即 2 mM, 1 mM, 0.2 mM, 20 μΜ, 2 μΜ, 0.2 μΜ;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. 使用细胞培养基 (DMEM/F12 +10 %胎牛血清为培养液)稀释上面所配置的 化合物溶液。每个 DMSO系列浓度化合物溶液稀释 20倍, 每次在细胞培养基中 加入 5μ1 DMSO化合物溶液和 95μ1培养液, 确保 A431细胞暴露在 DMSO溶液 中的浓度不超过 0.5 %, 用涡旋混合,; 5. Dilute the compound solution configured above using cell culture medium (DMEM/F12 +10% fetal bovine serum as the culture medium). Each DMSO series concentration compound solution was diluted 20 times, and 5 μl DMSO compound solution and 95 μl culture solution were added to the cell culture medium each time to ensure that the concentration of A431 cells exposed to DMSO solution did not exceed 0.5%, and vortexed;
6. 当 A431细胞贴壁,生长达到 85%汇合后, 将培养基换为加有 DMEM/F12 +10 %胎牛血清培养液的新培养基, 每孔中再加入 180μ1培养液和 20 μΐ在第五步中 所制备的受试化合物溶液。 阴性对照细胞组, 加入含有 0.5%DMSO的 20 μ1培 养液, 这样 A431细胞暴露在受试化合物溶液中的最终浓度为 100 μΜ, 10 μΜ, 5 μΜ, 1 μΜ, 0.1 μΜ, 0.01 μΜ, and 0.001 μΜ; 6. When the A431 cells adhered to the 85% confluence, the medium was changed to a new medium supplemented with DMEM/F12 +10% fetal bovine serum, and 180 μl of the medium and 20 μM were added to each well. The test compound solution prepared in the fifth step. In the negative control cell group, 20 μl of the culture medium containing 0.5% DMSO was added, so that the final concentration of A431 cells exposed to the test compound solution was 100 μΜ, 10 μΜ, 5 μΜ, 1 μΜ, 0.1 μΜ, 0.01 μΜ, and 0.001. Μ
7. 将培养板放入恒温箱内, 在 37 °C,5 % C02条件下, 连续培养 72小时;7. Place the culture plate in an incubator and continue to culture for 72 hours at 37 °C, 5 % C0 2 ;
8. 72小时后, 将培养板从恒温箱中转移到无菌工作室; 8. After 72 hours, transfer the plate from the incubator to the sterile studio;
9. 将试药级纯水加入到 TCA中制备固定剂 (50 %三氯醋酸 -TCA), 将细胞慢慢 地分层放在 50 μΐ冷 TCA溶液中; 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.在 4Ό下, 培养 1小时, 后用水洗涤数次以除去 TCA、 血清蛋白等。 培养板 在空气中干燥,存储待用。空白背景光学密度值的测定是在没有细胞生长的培养 基中温育培养所得的数值。 10. Incubate for 1 hour at 4 ,, and then wash several times with water to remove TCA, serum protein, and the like. The plate is dried in air and stored for later use. The blank background optical density value is determined by incubating the culture in a medium without cell growth.
11.用 10 %醋酸溶液制备 0.4 % Sulforhodamine B溶液, 并向每孔中加入 50 μΐ
sulforhodamine B溶液; 11. Prepare 0.4% Sulforhodamine B solution in 10% acetic acid solution and add 50 μΐ to each well. Sulforhodamine B solution;
12.细胞着色 30分钟; 12. Cell staining for 30 minutes;
13.制备 10%醋酸洗涤溶液。 当着色将要完毕时, 弃去着色剂, 用 10%的醋酸溶 液快速冲洗细胞。重复上述的操作直至着色剂洗净为止,尽量减少冲洗次数以减 少与蛋白结合的着色剂的去吸附。 冲洗完毕后, 将培养板在空气中干燥; 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.混合的着色剂溶解在一定体积的 Sulforhodamine B中,增溶溶液(10 mM Tris) 与培养基原体积相同,将培养板在室温下放置 5分钟,用摇床缓慢搅拌加快与染 料的混合; 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.用分光光度测量, 在波长 565 nm下读取吸光度值。 吸光度数值为 565 nm下 吸光度减去 690 nm下 96孔板背景吸光度所得的数值; 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.使用如下方法计算抑制率比值: ' 16. Calculate the inhibition ratio using the following method: '
IR= ιοοχ (对照组吸光度值-用药组吸光度值 )/对照组吸光度值%. IR= ιοοχ (absorbance value of the control group - absorbance value of the drug group) / absorbance value of the control group %.
IC50值可通过不同浓度下化合物抑制率比值计算得到。 本发明化合物的活性 The IC 50 value can be calculated from the ratio of compound inhibition rates at different concentrations. Activity of the compounds of the invention
本发明化合物的生化学活性通过以上的试验进行测定, The biochemical activity of the compound of the present invention is determined by the above test.
实施例编号 IC50 (EGFR/A431)^M) Example No. IC 50 (EGFR/A431)^M)
8 0.14 8 0.14
9 11.229 11.22
10 1.1610 1.16
11 5.8111 5.81
12 18.7912 18.79
14 11.4414 11.44
15 1.7415 1.74
16 6.6816 6.68
17 3.3817 3.38
18 0.2518 0.25
19 0.9819 0.98
21 8.1021 8.10
22 5.2622 5.26
23 9.923 9.9
24 . 0.8724 . 0.87
26 1.6226 1.62
27 11.02
28 0.22 27 11.02 28 0.22
29 0.23 29 0.23
30 12.02 30 12.02
31 1.6 31 1.6
32 0.54 32 0.54
33 1.92 33 1.92
34 16.15 34 16.15
35 8.05 35 8.05
36 6.78 36 6.78
39 9.91 39 9.91
40 5.34 40 5.34
42 3.01 42 3.01
43 4.44 43 4.44
45 0.77 45 0.77
46 0.48 46 0.48
52 8.42 52 8.42
55 1.21 55 1.21
56 11.71 56 11.71
EXAMPLE 3: EGFR激酶活性测定 EXAMPLE 3: Determination of EGFR kinase activity
体外 EGFR激酶活性通过以下的方法进行测试。 材料与试剂- a. 洗涤缓冲液(PBS-T缓冲液): lx PBS (137 mM NaCl, 2.7 mM KCl, 4.3 mM Na2HP04, 1.4 mM KH2P04, 调 pH至 7.2)和 0.05 % Tween-20 In vitro EGFR kinase activity was tested by the following method. Materials and reagents - a. Wash buffer (PBS-T buffer): lx PBS (137 mM NaCl, 2.7 mM KCl, 4.3 mM Na 2 HP0 4 , 1.4 mM KH 2 P0 4 , adjusted to pH 7.2) and 0.05% Tween-20
b. 1 %牛血清白蛋白 (BSA, Calbiochem #136593)PBS-T缓冲液 b. 1% bovine serum albumin (BSA, Calbiochem #136593) PBS-T buffer
c. 反应中止缓冲液: 50 mM EDTA , pH 8.0. c. Reaction stop buffer: 50 mM EDTA, pH 8.0.
d. DELFIA®铕标记抗鼠 IgG (PerkinElmer Life Sciences #AD0124) d. DELFIA® 铕 labeled anti-mouse IgG (PerkinElmer Life Sciences #AD0124)
e. DELFIA®信号倍增液 (PerkinElmer Life Sciences #1244-105) e. DELFIA® Signal Multiplier (PerkinElmer Life Sciences #1244-105)
f. DELFIA® Streptavidin包 96孔黄板 (PerkinElmer Life Sciences#AAAND-0005) g. EGFR激酶 (50 mM Tris-HCl (pH 8.0), 100 mM NaCl, 5 mM DTT, 15 mM谷酰 基胱氨酰甘氨酸和 20 °/。甘油, Cell signaling technology #7908) f. DELFIA® Streptavidin 96-well yellow plate (PerkinElmer Life Sciences #AAAND-0005) g. EGFR kinase (50 mM Tris-HCl (pH 8.0), 100 mM NaCl, 5 mM DTT, 15 mM glutamylcysteinylglycine And 20 ° /. Glycerin, Cell signaling technology #7908)
h. 10 mM ATP溶液 (Cell signaling technology #9804). h. 10 mM ATP solution (Cell signaling technology #9804).
i. PTPIB (Tyr66)生物素酰化蛋白 (Cell signaling technology #1325). i. PTPIB (Tyr66) biotinylated protein (Cell signaling technology #1325).
j, Phospho-酪氨酸鼠 mAb (P-Tyr-100) (Cell signaling technology #9411)·
k. HTScan™酪氨酸激酶缓冲液(½) j, Phospho-tyrosine mouse mAb (P-Tyr-100) (Cell signaling technology #9411)· k. HTScanTM Tyrosine Kinase Buffer (1⁄2)
l 激酶缓冲液-l Kinase Buffer -
60 mM HEPES 60 mM HEPES
5 mM MgCl2 5 mM MgCl 2
5 mM MnCl2 5 mM MnCl 2
(Cell signaling technology #9805). (Cell signaling technology #9805).
1. 1.25 M DTT (lOOOx) (Cell signaling technology). 方案: 1. 1.25 M DTT (lOOOOx) (Cell signaling technology).
使用如下方案进行测试: Use the following scenario to test:
1. 用 DMSO稀释受试化合物达到最终浓度值; 1. Dilute the test compound to the final concentration with DMSO;
在每个试验中加入 1 μΐ受试化合物、阴性对照和空白对照(不接受任何受试化合 物) , 只加入 1 l DMSO; 1 μΐ of test compound, negative control and blank control (no test compound was accepted) were added to each test, and only 1 l of DMSO was added;
2. 用 dH201 :l稀释 6 μΜ 底物蛋白 (Tyr589), 并加 15 μΐ到每个测试; 2. dH 2 01: l diluted 6 μΜ substrate proteins (Tyr589), and added to 15 μΐ each test;
3. 将酶从 -80°C直接转移到冰上, EGFR酶解冻在冰上; 3. Transfer the enzyme directly from -80 ° C to ice, and EGFR enzyme is thawed on ice;
4. 取 3 EGFR酶到每个测试中; 4. Take 3 EGFR enzymes into each test;
5. 加入 10 μΐ DTT (1.25 M) 到 2.5 ml 4x HTScan™酪氨酸激酶缓冲液 (240 mM HEPES pH 7.5, 20 mM MgCI2, 20 mM MnCI2, 12 μΜ Na3V04) 中,制得 DTT/激酶 缓冲液; 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. 转移 0.75 ml DTT/激酶缓冲液到每个每个测试中,制得 4x 反应混合液,并在 每个测试中加入 7.5 μΐ 4χ 反应液; 6. Transfer 0.75 ml DTT/kinase buffer to each of each test to prepare a 4x reaction mixture and add 7.5 μΐ 4χ reaction solution to each test;
7. 加入 2 μΙ ΑΤΡ (10 mM) 至 496 μΐ d¾0中,并在每个测试中加入 7.5 μΐ; 30 μΐ反应最终测试条件为: 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 60 mM HEPES pH 7.5
5 mM MgCl2 5 mM MgCl 2
5 mM MnCl2 5 mM MnCl 2
3 μΜ Ν 3νθ4 3 μΜ Ν 3 νθ 4
1.25 mM DTT 1.25 mM DTT
20 μΜΑΤΡ 20 μΜΑΤΡ
1.5 μΜ 多肽底物 1.5 μΜ peptide substrate
30 ng EGFR激酶 30 ng EGFR kinase
8. 在 25°C下, 将反应管温育 45分钟; 8. Incubate the reaction tube for 45 minutes at 25 °C;
9. 每个测试中加入 30 μ1中止反应缓冲液 (50 mM EDTA, pH 8.0)中止反应; 9. Stop the reaction by adding 30 μl of Stop Reaction Buffer (50 mM EDTA, pH 8.0) to each test;
10. 在 96孔 streptavidin包被培养板每孔中加入 25 μΐ反应液和 75 μΐ d¾0,在室
温下, 并振摇 60分钟; 10. Add 25 μM reaction solution and 75 μΐ d3⁄40 to each well of a 96-well streptavidin-coated plate. Warm down and shake for 60 minutes;
11. 每孔用 200 μΐ PBS-T缓冲液洗涤 3次, 在纸巾上轻拍以除去剩余的液体; 11. Wash each well 3 times with 200 μΐ PBS-T buffer and pat on a paper towel to remove the remaining liquid;
12. 用 1 %牛血清白蛋白 PBS-T缓冲液 1:1000稀释抗体 Phospho-酪氨酸 mAb (P-Tyr-100), 在每孔中加入 100 μΐ稀释的抗体; 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. 在室温下, 振摇温育 60分钟; 13. Incubate for 60 minutes at room temperature with shaking;
14. 按第 11步所述方法洗涤; 14. Wash as described in step 11;
15. 用 1 %牛血清白蛋白 PBS-T缓冲液 1:500稀释铕标记抗鼠 IgG, 并在每孔中 加入 100 μΐ稀释抗体; 15. Dilute the anti-mouse IgG with 1:5% dilution of 1% bovine serum albumin in PBS-T buffer and add 100 μl of diluted antibody to each well;
16. 在室温下, 振摇温育 30分钟; 16. Incubate for 30 minutes at room temperature with shaking;
17. 每孔用 PBS-T缓冲液 200 μΐ洗涤 5次, 在纸巾上轻拍以除去剩余的液体; 17. Wash each well 5 times with PBS-T buffer 200 μM and pat on a paper towel to remove any remaining liquid;
18. 每孔中加入 100 DELFIA®信号倍增液; 18. Add 100 DELFIA® signal multiplier to each well;
19. 在室温下, 振摇温育 5分钟; 19. Incubate for 5 minutes at room temperature with shaking;
20. 在 615 nm处, 用合适的时间分辨板读取器读取荧光强度。。 20. At 615 nm, read the fluorescence intensity with a suitable time-resolving plate reader. .
计算抑制率比值: IR (%) =100- 100*(X-B)/ (N-B) Calculate the inhibition ratio: IR (%) =100- 100*(X-B)/ (N-B)
X=受试化合物荧光值 X = fluorescence value of test compound
N-阴性对照 N-negative control
B=空白 B=blank
IC50值可通过受试化合物不同浓度递度下的抑制率比值计算得到。 本发明化合物的活性 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
本发明化合物的生化学活性通过以上的试验进行测定, 测得的 IC50值见下表。 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.
实施例编号 ICso (EGF謹 ο)(μΜ) Example No. ICso (EGF 谨 ο) (μΜ)
8 0.78 8 0.78
10 1.2810 1.28
20 2.53
20 2.53
Claims
1. 一种由通式 (1)、 (Π)和 (III)表示的化合物或其盐: A compound represented by the general formulae (1), (Π) and (III) or a salt thereof:
X选自 W(CH2), (CH2)W或 W, 其中 W是 0, S, SO, S02 ; 或 -NR8, 其中 是氢原子或烷基; X is selected from W(CH 2 ), (CH 2 )W or W, wherein W is 0, S, SO, S0 2 ; or -NR 8 , wherein is a hydrogen atom or an alkyl group;
当 X是 -NR8, R8是垸基时, 则 Rs可以和 Rj形成一个 4〜8元杂环基; 其中 5〜8元杂环内含有一个或多个 N, 0, S原子, 并且 4〜8元杂环上进一步被一 个或多个的垸基, 卤素, 芳基, 杂芳基, 卤代垸基, 卤代烷氧基, 羟基, 酰胺基, 胺酰基, 氰基, 垸氧基, 芳氧基, 胺烷基, 羟烷基, 杂环烷基, 羧酸, 羧酸酯或 - R5R6所取代; When X is -NR 8 and R 8 is a fluorenyl group, then R s may form a 4 to 8 membered heterocyclic group with Rj; wherein the 5 to 8 membered heterocyclic ring contains one or more N, 0, S atoms, And a 4 to 8 membered heterocyclic ring further substituted with one or more fluorenyl, halogen, aryl, heteroaryl, haloalkyl, haloalkoxy, hydroxy, amide, aminyl, cyano, decyloxy , aryloxy, aminoalkyl, hydroxyalkyl, heterocycloalkyl, carboxylic acid, carboxylic acid ester or substituted with -R 5 R6;
选自氢原子, 烷基, 环烷基, 杂环焼基, 芳基, 杂芳基, 芳烷基或杂芳烷 基, 其中烷基, 环垸基, 杂环烷基, 芳基, 杂芳基, 芳垸基或杂芳垸基进一步被 一个或多个烷基, 素, 芳基, 羟基, 氨基, 炔基, 烯基, 羟垸基, 烷氨基, N-院基甲酰基, N,N-2(烷基甲酰基), 氰基, 硝基, 三氟甲基, 卤代苄基, 杂环 烷基, 羧酸或羧酸酯所取代; 其中芳基, 杂芳基, 芳垸基或杂芳烷基并成双环, 其中双环可以进一步被一个苄基或卤代苄基所取代; 或者 为结构式: Τ Selected from hydrogen atom, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl, wherein alkyl, cyclodecyl, heterocycloalkyl, aryl, hetero Aryl, arylalkyl or heteroaryl fluorenyl is further protected by one or more alkyl, aryl, aryl, hydroxy, amino, alkynyl, alkenyl, hydroxyalkyl, alkylamino, N-homoyl, N , N-2 (alkyl formyl), cyano, nitro, trifluoromethyl, halobenzyl, heterocycloalkyl, carboxylic acid or carboxylic acid ester substituted; wherein aryl, heteroaryl, aromatic A fluorenyl or heteroarylalkyl group is bicyclic, wherein the bicyclic ring may be further substituted by a benzyl or halobenzyl group; or a structural formula: Τ
其中- among them-
Α选自芳基, 杂芳基, 芳烷基或杂芳垸基, 其中芳基, 杂芳基, 芳垸基或杂 芳垸基可以进一步被一个或多个烷基, 素, 芳基, 羟基, 氨基, 炔基, 烯基, 羟垸基, 垸氨基, N-烷基甲酰基, N,N-2(烧基甲酰基), 氰基, 硝基, 三氟甲基, 卤代苄基, 杂环烷基, 羧酸或羧酸酯所取代; 其中芳基, 杂芳基, 芳烷基或杂芳 嫁基并成双环, 其中双环可以进一步被一个苄基或卤代苄基所取代; The hydrazine is selected from the group consisting of aryl, heteroaryl, aralkyl or heteroaryl, wherein the aryl, heteroaryl, arylalkyl or heteroaryl group may be further substituted by one or more alkyl, aryl, aryl, Hydroxy, amino, alkynyl, alkenyl, hydroxymethyl, hydrazino, N-alkylformyl, N,N-2 (alkyl), cyano, nitro, trifluoromethyl, halobenzyl Substituted by a heterocycloalkyl group, a carboxylic acid or a carboxylic acid ester; wherein the aryl, heteroaryl, aralkyl or heteroaryl group is bicyclic, wherein the bicyclic ring may be further substituted by a benzyl or halobenzyl group. Replace
T选自: -0(C¾)r-, -N(C¾)r-或 -S(C¾)r; T is selected from: -0(C3⁄4)r-, -N(C3⁄4)r- or -S(C3⁄4)r;
L选自: 垸基, 芳基, 杂芳基, 卤代芳基;
R2选自氢原子, 垸基, 三氟甲基, 环垸基, 杂环烷基, 芳基, 杂芳基, 芳垸 基或杂芳垸基, 其中垸基, 环烷基, 杂环烷基, 芳基, 杂芳基, 芳垸基或杂芳烷 基进一步被一个或多个烷基, 卤素, 芳基, 羟基, 酰胺基, 胺酰基, 烷氧基, 芳 氧基, 杂环烷基, 羧酸, 羧酸酯或 -NR5 所取代; L is selected from the group consisting of: fluorenyl, aryl, heteroaryl, haloaryl; R 2 is selected from the group consisting of a hydrogen atom, a fluorenyl group, a trifluoromethyl group, a cyclodecyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an aryl fluorenyl group or a heteroaryl fluorenyl group, wherein a fluorenyl group, a cycloalkyl group, a heterocyclic group Alkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl further substituted by one or more alkyl, halo, aryl, hydroxy, amide, aminyl, alkoxy, aryloxy, heterocycle Substituted by an alkyl group, a carboxylic acid, a carboxylic acid ester or -NR 5 ;
选自氢原子, 垸基, 芳基, 杂芳基, 杂芳氧基, -C(=0)R7, -C(=S)R7,
-(CH2)nO(C-S)R7, -(CH2)nR7, -(CH2CH20)nR8; 其中芳基, 杂芳基, 杂芳氧基, -(CH2)nR7进一步被一个或多个烷基, -(C¾)nR7, =C(0), 卤素, 三氟甲基, 羧酸或羧酸酯所取代; Selected from hydrogen atom, fluorenyl, aryl, heteroaryl, heteroaryloxy, -C(=0)R 7 , -C(=S)R 7 , -(CH 2 ) n O(CS)R 7 , -(CH 2 ) n R 7 , -(CH 2 CH 2 0) n R 8 ; wherein aryl, heteroaryl, heteroaryloxy, -(CH 2 ) n R 7 is further substituted by one or more alkyl groups, -(C3⁄4) n R 7 , =C(0), halogen, trifluoromethyl, carboxylic acid or carboxylic acid ester;
R4选自氢原子, 垸基, 环烷基, 杂环垸基, -(CH2CH20)nR8, 烯基或炔基, 其中烷基, 环烷基, 杂环垸基, 烯基或炔基进一步被一个或多个垸基, 羟基, 烷 氧基, 氰基, -NRsRe, 羧酸或羧酸酯所取代; R4 is selected from the group consisting of a hydrogen atom, a fluorenyl group, a cycloalkyl group, a heterocyclic fluorenyl group, -(CH 2 CH 2 0) n R 8 , an alkenyl group or an alkynyl group, wherein an alkyl group, a cycloalkyl group, a heterocyclic fluorenyl group, an alkene group Or alkynyl is further substituted by one or more thiol, hydroxy, alkoxy, cyano, -NRsRe, carboxylic acid or carboxylic acid ester;
R5和 分别选自氢原子, 垸基, 环烷基, 杂环垸基, 芳基, 杂芳基或杂芳 垸基, 其中烷基, 环烷基, 杂环烷基, 芳基, 杂芳基或者杂芳垸基进一步被一个 或多个的烷基, 卤素, 芳基, 羟基, 氨基, 垸氨基, 酰胺基, 胺酰基, 氰基, 垸 氧基, 芳氧基, 胺烷基, 羟烷基, 羧酸, 羧酸酯或 - 5 所取代; R 5 and each independently selected from the group consisting of a hydrogen atom, a fluorenyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group or a heteroarylalkyl group, wherein an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, and a heterocyclic group Aryl or heteroaryl fluorenyl is further substituted by one or more alkyl, halo, aryl, hydroxy, amino, decylamino, amide, aminyl, cyano, decyloxy, aryloxy, aminalkyl, a hydroxyalkyl group, a carboxylic acid, a carboxylic acid ester or a -5 substituent;
同时, R5和 一起形成一个 4〜8元杂环基; 其中 5〜8元杂环内含有一个 或多个 N, 0, S原子, 并且 4〜8元杂环上进一步被一个或多个的烷基, 卤素, 芳基, 杂芳基, 卤代烧基, 代垸氧基, 羟基, 酰胺基, 胺酰基, 氰基, 嫁氧基, 芳氧基, 胺垸基, 羟烷基, 杂环烷基, 羧酸, 羧酸酯, -(CH2)nR7或- NR5 所取 代; Meanwhile, R 5 and together form a 4 to 8 membered heterocyclic group; wherein the 5 to 8 membered heterocyclic ring contains one or more N, 0, S atoms, and the 4 to 8 membered heterocyclic ring is further subjected to one or more Alkyl, halogen, aryl, heteroaryl, haloalkyl, methoxy, hydroxy, amide, aminyl, cyano, graftoxy, aryloxy, amidino, hydroxyalkyl, a heterocycloalkyl group, a carboxylic acid, a carboxylic acid ester, -(CH 2 ) n R 7 or -NR 5 substituted;
R7选自羟基, 垸氧基, 芳氧基, 杂环烷氧基, 芳垸氧基, -N(R8)(CH2)nR9, - R8[CH2CH20]nR8, -NR5R6或者 -N¾(C¾)n[CH(OH)CH2]rZ (其中 Z是芳基, 杂 芳基, 杂环烷基, 5 , 00 或。0>¾5 ); R 7 is selected from the group consisting of hydroxy, decyloxy, aryloxy, heterocycloalkoxy, aryloxy, -N(R 8 )(CH 2 ) n R 9 , - R 8 [CH 2 CH 2 0] n R 8 , -NR5R6 or -N3⁄4(C3⁄4) n [CH(OH)CH 2 ] r Z (wherein Z is aryl, heteroaryl, heterocycloalkyl, 5 , 00 or .0>3⁄4 5 ) ;
选自氢原子或垸基; Selected from a hydrogen atom or a sulfhydryl group;
R9选自 -NR5 ,羟基,芳基,杂芳基,垸氧基, -S(0)2C¾, -0[CH2CH20]rR8, -!^(0 )1 5 , -N(OH)R5, -NHC(O)R]0 ¾ -COR10, 其中 Rw是垸基, 卤代烷基或 芳院基; R 9 is selected from -NR 5 , hydroxy, aryl, heteroaryl, decyloxy, -S(0) 2 C3⁄4, -0[CH 2 CH 2 0] r R 8 , -!^(0 )1 5 , -N(OH)R 5 , -NHC(O)R ]0 3⁄4 -COR 10 , wherein R w is fluorenyl, haloalkyl or aryl;
R1()是垸基, 卤代垸基或芳烷基 R 1() is a fluorenyl group, a halogenated fluorenyl group or an aralkyl group
n是。〜 6; n is. ~ 6;
r是卜 2。 r is Bu 2.
2. 根据权利要求 1所述的化合物或其盐, 其中所述化合物为由通式 (I)表示的化 合物:
其中-The compound according to claim 1 or a salt thereof, wherein the compound is a compound represented by the general formula (I): among them-
X选自 W(CH2), (CH2)W或 W, 其中 W是 0, S, SO, S02; 或 - R8, 其中 R8是氢原子或烷基; X is selected from W(CH 2 ), (CH 2 )W or W, wherein W is 0, S, SO, S0 2 ; or - R 8 , wherein R 8 is a hydrogen atom or an alkyl group;
当 X是 -N , R8是垸基时, 则 可以和 形成一个 4〜8元杂环基; 其中 5〜8元杂环内含有一个或多个 N, 0, S原子, 并且 4〜8元杂环上进一歩被一 个或多个的烷基, 卤素, 芳基, 杂芳基, 卤代垸基, 卤代烷氧基, 羟基, 酰胺基, 胺酰基, 氰基, 垸氧基, 芳氧基, 胺垸基, 羟烷基, 杂环垸基, 羧酸, 羧酸酯或 - R5R6所取代; When X is -N and R 8 is a fluorenyl group, a 4 to 8 membered heterocyclic group may be formed; wherein the 5 to 8 membered heterocyclic ring contains one or more N, 0, S atoms, and 4 to 8 a heterocyclic ring having one or more alkyl groups, halogen, aryl, heteroaryl, haloalkyl, haloalkoxy, hydroxy, amide, aminyl, cyano, decyloxy, aryloxy , aminyl, hydroxyalkyl, heterocycloalkyl, carboxylic acid, carboxylic acid ester or substituted with -R 5 R6;
选自氢原子, 烷基, 环烷基, 杂环垸基, 芳基, 杂芳基, 芳焼基或杂芳烷 基, 其中烷基, 环烷基, 杂环垸基, 芳基, 杂芳基, 芳垸基或杂芳烧基进一步被 一个或多个烷基, 卤素, 芳基, 羟基, 氨基, 炔基, 烯基, 羟烷基, 烷氨基, N-綜基甲酰基, N,N-2(踪基甲酰基), 氰基, 硝基, 三氟甲基, 代苄基, 杂环 烧基, 羧酸或羧酸酯所取代; 其中芳基, 杂芳基, 芳烷基或杂芳烷基并成双环, 其中双环可以进一步被一个苄基或卤代苄基所取代; 或者 Ri为结构式: Z ^ Selected from hydrogen atom, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, wherein alkyl, cycloalkyl, heterocycloalkyl, aryl, hetero Aryl, arylalkyl or heteroaryl is further substituted by one or more alkyl, halo, aryl, hydroxy, amino, alkynyl, alkenyl, hydroxyalkyl, alkylamino, N-heteroyl, N , N-2 (n-ylformyl), cyano, nitro, trifluoromethyl, benzyl, heterocycloalkyl, carboxylic acid or carboxylic acid ester substituted; wherein aryl, heteroaryl, aralkyl Or a heteroarylalkyl group which is bicyclic, wherein the bicyclic ring may be further substituted by a benzyl or halobenzyl group; or Ri is a structural formula: Z ^
其中: ' among them: '
A选自芳基, 杂芳基, 芳垸基或杂芳垸基, 其中芳基, 杂芳基, 芳烷基或杂 芳烷基可以进一步被一个或多个垸基, 卤素, 芳基, 羟基, 氨基, 炔基, 烯基, 羟烷基, 垸氨基, N-烷基甲酰基, N,N-2(烷基甲酰基), 氰基, 硝基, 三氟甲基, 卤代苄基, 杂环垸基, 狻酸或羧酸酯所取代; 其中芳基, 杂芳基, 芳烷基或杂芳 烷基并成双环, 其中双环可以进一步被一个苄基或卤代苄基所取代; A is selected from aryl, heteroaryl, arylalkyl or heteroarylalkyl, wherein the aryl, heteroaryl, aralkyl or heteroarylalkyl group may be further protected by one or more sulfhydryl groups, halogens, aryl groups, Hydroxy, amino, alkynyl, alkenyl, hydroxyalkyl, decylamino, N-alkylformyl, N,N-2(alkylformyl), cyano, nitro, trifluoromethyl, halobenzyl Substituted by a heterocyclic fluorenyl group, a decanoic acid or a carboxylic acid ester; wherein the aryl group, the heteroaryl group, the aralkyl group or the heteroarylalkyl group is bicyclic, wherein the bicyclic ring may be further substituted by a benzyl or halobenzyl group. Replace
T选自: -0(CH2)r -, -N(C¾)r-或 -S(CH2)r-; T is selected from: -0(CH 2 )r -, -N(C3⁄4)r- or -S(CH 2 )r-;
L选自: 烷基, 芳基, 杂芳基, it代芳基; L is selected from the group consisting of: an alkyl group, an aryl group, a heteroaryl group, an it-substituted aryl group;
选自氢原子, 垸基, 三氟甲基, 环烷基, 杂环烷基, 芳基, 杂芳基, 芳烷 基或杂芳垸基, 其中垸基, 环烷基, 杂环烷基, 芳基, 杂芳基, 芳烷基或杂芳烷 基进一步被一个或多个垸基, 素, 芳基, 羟基, 酰胺基, 胺酰基, 烷氧基, 芳 氧基, 杂环烷基, 羧酸, 羧酸酯或 -^!^!^所取代; Selected from hydrogen atom, fluorenyl, trifluoromethyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl or heteroaryl, wherein fluorenyl, cycloalkyl, heterocycloalkyl , aryl, heteroaryl, aralkyl or heteroarylalkyl further substituted by one or more fluorenyl, aryl, aryl, hydroxy, amide, aminyl, alkoxy, aryloxy, heterocycloalkyl , carboxylic acid, carboxylic acid ester or -^! ^! Replaced by ^;
R3选自氢原子, 烷基, 芳基, 杂芳基, 杂芳氧基, -C(=0)R7, -C(-S)R7, -NC(=0)R7, -(CH2)nO(C=0)R7, -(CH2)nO(C=S)R7, -(C¾)nR7, -(CH2CH20)nR8
其中芳基, 杂芳基, 杂芳氧基, -(C¾)nR7进一步被一个或多个垸基, -(C¾)nR7, =C(0), 卤素, 三氟甲基, 羧酸或羧酸酯所取代; R 3 is selected from the group consisting of a hydrogen atom, an alkyl group, an aryl group, a heteroaryl group, a heteroaryloxy group, -C(=0)R 7 , -C(-S)R 7 , -NC(=0)R 7 , (CH 2 ) n O(C=0)R 7 , -(CH 2 ) n O(C=S)R 7 , -(C3⁄4) n R 7 , -(CH 2 CH 2 0) n R 8 Wherein aryl, heteroaryl, heteroaryloxy, -(C3⁄4) n R 7 is further protected by one or more fluorenyl groups, -(C3⁄4) n R 7 , =C(0), halogen, trifluoromethyl, Substituted by a carboxylic acid or a carboxylic acid ester;
选自氢原子, 烷基, 环烷基, 杂环垸基, -(CH2CH20)nR8, 烯基或炔基, 其中烷基, 环烷基, 杂环烷基, 烯基或炔基进一步被一个或多个垸基, 羟基, 烷 氧基, 氰基, Ν¾ , 羧酸或羧酸酷所取代; Selected from hydrogen atom, alkyl, cycloalkyl, heterocycloalkyl, -(CH 2 CH 2 0) n R 8 , alkenyl or alkynyl, wherein alkyl, cycloalkyl, heterocycloalkyl, alkenyl Or an alkynyl group is further substituted by one or more mercapto, hydroxy, alkoxy, cyano, ruthenium, carboxylic acid or carboxylic acid;
R5和 分别选自氢原子, 烷基, 环烷基, 杂环烧基, 芳基, 杂芳基或杂芳 烷基, 其中烷基, 环垸基, 杂环垸基, 芳基, 杂芳基或者杂芳烷基进一步被一个 或多个的垸基, 卤素, 芳基, 羟基, 氨基, 烷氨基, 酰胺基, 胺酰基, 氰基, 烷 氧基, 芳氧基, 胺烷基, 羟烷基, 羧酸, 羧酸酯或 - 5 所取代; R 5 and each independently selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group or a heteroarylalkyl group, wherein alkyl, cyclodecyl, heterocycloalkyl, aryl, hetero An aryl or heteroarylalkyl group further substituted by one or more fluorenyl, halogen, aryl, hydroxy, amino, alkylamino, amide, aminyl, cyano, alkoxy, aryloxy, alkoxyalkyl, a hydroxyalkyl group, a carboxylic acid, a carboxylic acid ester or a -5 substituent;
同时, 和 一起形成一个 4~8元杂环基; 其中 5〜8元杂环内含有一个 或多个 N, 0, S原子, 并且 4〜8元杂环上进一步被一个或多个的垸基, 卤素, 芳基, 杂芳基, 卤代烧基, 卤代垸氧基, 羟基, 酰胺基, 胺酰基, 氰基, 掠氧基, 芳氧基, 胺烷基, 羟烷基, 杂环垸基, 羧酸, 羧酸酯, -(CH2)nR7或 -NR5 所取 代; At the same time, a 4-8 membered heterocyclic group is formed together; wherein the 5 to 8 membered heterocyclic ring contains one or more N, 0, S atoms, and the 4 to 8 membered heterocyclic ring is further subjected to one or more Halogen, aryl, heteroaryl, haloalkyl, halomethoxy, hydroxy, amide, aminyl, cyano, hexyloxy, aryloxy, alkoxyalkyl, hydroxyalkyl, hetero embankment cycloalkyl group, a carboxylic acid, carboxylate, - (CH 2) n R 7 or -NR 5 substituted;
R7选自羟基, 烷氧基, 芳氧基, 杂环垸氧基, 芳垸氧基, -N(R8)(CH2)nR9, -N 8[CH2CH20]nR8, -NR5 或者 -NRs(CH2)n[CH(OH)CH2]rZ, 其中 Z是芳基, 杂 芳基, 杂环烷基, -Ν , 00¾或。01^5 ; R 7 is selected from the group consisting of hydroxy, alkoxy, aryloxy, heterocyclomethoxy, aryloxy, -N(R 8 )(CH 2 ) n R 9 , -N 8 [CH 2 CH 2 0] n R 8 , -NR 5 or -NR s (CH2) n [CH(OH)CH 2 ] r Z, wherein Z is aryl, heteroaryl, heterocycloalkyl, -Ν, 003⁄4 or. 01^ 5 ;
选自氢原子或垸基; Selected from a hydrogen atom or a sulfhydryl group;
R9选自- ¾ ,羟基, 芳基,杂芳基,烷氧基, -S(0)2CH3, -O[CH2CH20]rR8, -N^CORsR^ -N(OH)R5, -NHC(0)R1()或- COR1(), 其中 R1()是垸基, 卤代垸基或 芳烧基;R 9 is selected from -3⁄4 , hydroxy, aryl, heteroaryl, alkoxy, -S(0) 2 CH 3 , -O[CH 2 CH 2 0] r R 8 , -N^CORsR^ -N( OH)R 5 , —NHC(0)R 1() or — COR 1() , wherein R 1() is an indenyl group, a haloalkyl group or an aryl group;
ο是' 基, 卤代烷基或芳烷基 ο is 'yl, haloalkyl or aralkyl
n是 0〜6; n is 0~6;
r是 1〜2。 r is 1 to 2.
3. 根据权利要求 1所述的化合物或其盐,其中所述化合物为由通式 (Π)表示的化 合物: .. The compound according to claim 1 or a salt thereof, wherein the compound is a compound represented by the formula (Π):
X选自 W(C¾), (CH2)W或 W, 其中 W是 0, S, SO, S02; 或 -NR8, 其中
是氢原子或烧基; X is selected from W(C3⁄4), (CH 2 )W or W, wherein W is 0, S, SO, S0 2; or -NR 8 , wherein Is a hydrogen atom or a burnt group;
当 X是 -N , R8是垸基时, 则 可以和 形成一个 4~8元杂环基; 其中 5〜8元杂环内含有一个或多个 N, 0, S原子, 并且 4〜8元杂环上进一歩被一 个或多个的烷基, 卤素, 芳基, 杂芳基, 卤代烷基, 卤代烷氧基, 羟基, 酰胺基, 胺酰基, 氰基, 烷氧基, 芳氧基, 胺烷基, 羟烷基, 杂环烷基, 羧酸, 羧酸酯或 -Ν 所取代; When X is -N and R 8 is a fluorenyl group, a 4 to 8 membered heterocyclic group may be formed; wherein the 5 to 8 membered heterocyclic ring contains one or more N, 0, S atoms, and 4 to 8 a heterocyclic ring having one or more alkyl groups, halogen, aryl, heteroaryl, haloalkyl, haloalkoxy, hydroxy, amide, aminyl, cyano, alkoxy, aryloxy, amine An alkyl group, a hydroxyalkyl group, a heterocycloalkyl group, a carboxylic acid, a carboxylic acid ester or a hydrazine;
选自氢原子, 烷基, 环垸基, 杂环烷基, 芳基, 杂芳基, 芳烷基或杂芳垸 基, 其中烷基, 环垸基, 杂环烷基, 芳基, 杂芳基, 芳烷基或杂芳垸基进一步被 一个或多个烷基, 卤素, 芳基, 羟基, 氨基, 炔基, 烯基, 羟烷基, 垸氨基, Ν-烷基甲酰基, Ν,Ν-2(焼基甲酰基), 氰基, 硝基, 三氟甲基, 卤代苄基, 杂环 垸基, 羧酸或羧酸酯所取代; 其中芳基, 杂芳基, 芳烧基或杂芳垸基并成双环, 其中双环可以进一步被一个苄基或卤代苄基所取代; 或者 为结构式: ζ ^ Selected from hydrogen atom, alkyl, cyclodecyl, heterocycloalkyl, aryl, heteroaryl, aralkyl or heteroaryl, wherein alkyl, cyclodecyl, heterocycloalkyl, aryl, hetero Aryl, aralkyl or heteroaryl fluorenyl is further substituted by one or more alkyl, halogen, aryl, hydroxy, amino, alkynyl, alkenyl, hydroxyalkyl, decylamino, fluorenyl-alkylformyl, hydrazine , Ν-2(fluorenyl), cyano, nitro, trifluoromethyl, halobenzyl, heterocycloalkyl, carboxylic acid or carboxylic acid ester substituted; wherein aryl, heteroaryl, aromatic An alkyl or heteroaryl fluorenyl group which is bicyclic, wherein the bicyclic ring may be further substituted by a benzyl or halobenzyl group; or a structural formula: ζ ^
其中- among them-
Α选自芳基, 杂芳基, 芳烷基或杂芳烷基, 其中芳基, 杂芳基, 芳垸基或杂 芳垸基可以进一步被一个或多个垸基, 卤素, 芳基, 羟基, 氨基, 炔基, 烯基, 羟烷基, 烷氨基, N-烷基甲酰基, N,N-2(綜基甲酰基), 氰基, 硝基, 三氟甲基, 卤代节基, 杂环浣基, 羧酸或羧酸酯所取代; 其中芳基, 杂芳基, 芳垸基或杂芳 垸基并成双环, 其1 Φ双环可以进一步被一个苄基或卤代苄基所取代; The hydrazine is selected from the group consisting of aryl, heteroaryl, aralkyl or heteroarylalkyl, wherein the aryl, heteroaryl, arylalkyl or heteroarylalkyl group may be further protected by one or more fluorenyl groups, halogens, aryl groups, Hydroxy, amino, alkynyl, alkenyl, hydroxyalkyl, alkylamino, N-alkyl formyl, N, N-2 (heteroyl), cyano, nitro, trifluoromethyl, halogenated Substituted by a heterocyclic fluorenyl group, a carboxylic acid or a carboxylic acid ester; wherein the aryl group, the heteroaryl group, the aryl fluorenyl group or the heteroaryl fluorenyl group is bicyclic, and the 1 Φ bicyclic ring may be further substituted by a benzyl group or a halogenated benzyl group. Substituted by
T选自: -0(CH2)r -, -N(C¾)r-或 -S(C¾)r-; T is selected from: -0(CH 2 )r -, -N(C3⁄4)r- or -S(C3⁄4)r-;
L选自: 烷基, 芳基, 杂芳基, 卤代芳基; L is selected from the group consisting of: an alkyl group, an aryl group, a heteroaryl group, a halogenated aryl group;
R2选自氢原子, 烷基, 三氟甲基, 环烷基, 杂环烷基, 芳基, 杂芳基, 芳垸 基或杂芳烷基, 其中烷基, 环垸基, 杂环烷基, 芳基, 杂芳基, 芳垸基或杂芳垸 基进一步被一个或多个烷基, 卤素, 芳基, 羟基, 酰胺基, 胺酰基: 垸氧基, 芳 氧基, 杂环烷基, 羧酸, 羧酸酯或 -NR5 所取代; R 2 is selected from the group consisting of a hydrogen atom, an alkyl group, a trifluoromethyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an arylsulfonyl group or a heteroarylalkyl group, wherein an alkyl group, a cyclodecyl group, a heterocyclic ring Alkyl, aryl, heteroaryl, arylalkyl or heteroaryl is further substituted by one or more alkyl, halo, aryl, hydroxy, amide, aminyl: decyloxy, aryloxy, heterocyclic Substituted by an alkyl group, a carboxylic acid, a carboxylic acid ester or -NR 5 ;
R3选自氢原子, 垸基, 芳基, 杂芳基, 杂芳氧基, -C(=0)R7, -C(=S)R7, -NC(=0)R7, -(CH2)nO(C=0)R7, -(CH2)nO(C=S)R7', -(CH2)nR7, -(CH2CH20)„ 8; 其中芳基, 杂芳基, 杂芳氧基, -(CH2)nR7进一步被一个或多个烷基, -(CH2)nR7, =C(0), 卤素, 三氟甲基, 羧酸或羧酸酯所取代; R 3 is selected from the group consisting of a hydrogen atom, a fluorenyl group, an aryl group, a heteroaryl group, a heteroaryloxy group, -C(=0)R 7 , -C(=S)R 7 , -NC(=0)R 7 , (CH 2 ) n O(C=0)R 7 , -(CH 2 ) n O(C=S)R 7 ', -(CH 2 ) n R 7 , -(CH 2 CH 2 0) „ 8 ; Wherein aryl, heteroaryl, heteroaryloxy, -(CH 2 ) n R 7 is further substituted by one or more alkyl groups, -(CH 2 ) n R 7 , =C(0), halogen, trifluoromethyl Substituted by a carboxylic acid or a carboxylic acid ester;
R4选自氢原子, 烷基, 环烷基, 杂环烷基, -(CH2CH20)nR8, 烯基或炔基, 其中烷基, 环烷基, 杂环垸基, 烯基或炔基进一步被一个或多个烷基, 羟基, 烷 氧基, 氰基, 5R6, 羧酸或羧酸酯所取代; R4 is selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, -(CH 2 CH 2 0) n R 8 , an alkenyl group or an alkynyl group, wherein an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an alkene group Or alkynyl is further substituted by one or more alkyl, hydroxy, alkoxy, cyano, 5 R6, carboxylic acid or carboxylic acid esters;
和 分别选自氢原子, 垸基, 环垸基, 杂环烷基, 芳基, 杂芳基或杂芳 垸基, 其中烷基, 环烷基, 杂环烷基, 芳基, 杂芳基或者杂芳垸基进一步被一个 或多个的烷基, 卤素, 芳基, 羟基, 氨基, 烷氨基, 酰胺基, 胺酰基, 氰基, 烷
氧基, 芳氧基, 胺烷基, 羟烷基, 羧酸, 羧酸酯或 5 所取代; And each selected from the group consisting of a hydrogen atom, a fluorenyl group, a cyclodecyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group or a heteroarylalkyl group, wherein an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group Or a heteroaryl group further substituted by one or more alkyl, halogen, aryl, hydroxy, amino, alkylamino, amide, aminyl, cyano, alkane Oxyl, aryloxy, aminoalkyl, hydroxyalkyl, carboxylic acid, carboxylic acid ester or 5 substituted;
同时, R5和 一起形成一个 4〜8元杂环基; 其中 5〜8元杂环内含有一个 或多个 N, 0, S原子, 并且 4〜8元杂环上进一步被一个或多个的垸基, 卤素, 芳基, 杂芳基, 代垸基, 卤代垸氧基, 羟基, 酰胺基, 胺酰基, 氰基, 烷氧基, 芳氧基, 胺烷基, 羟烷基, 杂环垸基, 羧酸, 羧酸酯, -(CH2)nR7或 -NR5 所取 代; Meanwhile, R 5 and together form a 4 to 8 membered heterocyclic group; wherein the 5 to 8 membered heterocyclic ring contains one or more N, 0, S atoms, and the 4 to 8 membered heterocyclic ring is further subjected to one or more Sulfhydryl, halogen, aryl, heteroaryl, hydrazino, halomethoxy, hydroxy, amide, aminyl, cyano, alkoxy, aryloxy, alkoxy, hydroxyalkyl, Substituted by a heterocyclic fluorenyl group, a carboxylic acid, a carboxylic acid ester, -(CH 2 ) n R 7 or -NR 5 ;
R7选自羟基, 烷氧基, 芳氧基, 杂环垸氧基, 芳垸氧基, -N(R8)(CH2)nR9,R 7 is selected from the group consisting of hydroxyl, alkoxy, aryloxy, heterocyclomethoxy, aryloxy, -N(R 8 )(CH 2 ) n R 9 ,
-NR8[CH2CH20]nR8, - 5R6或者 -N 8(CH2)n〖CH(OH)CH2]rZ (其中 Z是芳基, 杂 芳基, 杂环烷基, -NR5R6, -COOR8或 CONRsRe); -NR 8 [CH 2 CH 2 0] n R 8 , - 5 R6 or -N 8 (CH 2 ) n [CH(OH)CH 2 ] r Z (wherein Z is an aryl group, a heteroaryl group, a heterocycloalkane Base, -NR 5 R6, -COOR 8 or CONRsRe);
R8选自氢原子或烷基; ' R 8 is selected from a hydrogen atom or an alkyl group; '
R9选自 -NR5 ,羟基,芳基,杂芳基,烷氧基, -S(0)2CH3, -O[C¾CH20]rRg,
或 -COR1(), 其中 R10是烷基, 卤代烷基或 芳綜基 i R 9 is selected from -NR 5 , hydroxy, aryl, heteroaryl, alkoxy, -S(0) 2 CH 3 , -O[C3⁄4CH 2 0] r R g , Or -COR 1() , wherein R 10 is alkyl, haloalkyl or aryl I
Rio是烷基, 卤代垸基或芳烷基 Rio is an alkyl group, a halogenated fluorenyl group or an aralkyl group.
n是 0〜6; n is 0~6;
r是 1〜2。 r is 1 to 2.
4. 根据权利要求 1所述的化合物或其盐, 其中所述化合物为由通式 (III)表示的 化合物- The compound or a salt thereof according to claim 1, wherein the compound is a compound represented by the formula (III) -
X选自 W(CH2), (C¾)W或 W, 其中 W是 0, S, SO, S02; 或 -NR8, 其中 R8是氢原子或烷基; X is selected from W(CH 2 ), (C3⁄4)W or W, wherein W is 0, S, SO, S0 2 ; or -NR 8 , wherein R 8 is a hydrogen atom or an alkyl group;
当 X是 -NR8, R8是烷基时, 则 可以和 形成一个 4〜8元杂环基; 其中 5〜8元杂环内含有一个或多个 N, 0, S原子, 并且 4~8元杂环上进一步被一 个或多个的垸基, 素, 芳基, 杂芳基, 代焼基, 卤代烧氧基, 羟基, 酰胺基, 胺酰基, 氰基, 烷氧基, 芳氧基, 胺垸基, 羟烷基, 杂环烷基, 羧酸, 羧酸酯或 -Ν 所取代; When X is -NR 8 and R 8 is an alkyl group, a 4 to 8 membered heterocyclic group may be formed; wherein the 5 to 8 membered heterocyclic ring contains one or more N, 0, S atoms, and 4~ The 8-membered heterocyclic ring is further substituted with one or more fluorenyl, aryl, aryl, heteroaryl, hydrazino, halo alkoxy, hydroxy, amide, aminyl, cyano, alkoxy, aryl Oxyl, aminyl, hydroxyalkyl, heterocycloalkyl, carboxylic acid, carboxylic acid ester or -Ν substituted;
Rj选自氢原子, 烷基, 环烷基, 杂环烷基, 芳基, 杂芳基, 芳垸基或杂芳垸 基, 其中烷基, 环烷基, 杂环烷基, 芳基, 杂芳基, 芳垸基或杂芳烷基进一步被 一个或多个垸基, 卤素, 芳基, 羟基, 氨基, 炔基, 烯基, 羟院基, 垸氨基,
N-烷基甲酰基, N,N-2(烷基甲酰基), 氰基, 硝基, 三氟甲基, 卤代苄基, 杂环 垸基, 羧酸或羧酸酯所取代; 其中芳基, 杂芳基, 芳垸基或杂芳垸基并成双环, 其中双环可以进一步被一个苄基或卤代苄基所取代; 或者 为结构式: z Rj is selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an arylsulfonyl group or a heteroarylalkyl group, wherein an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, Heteroaryl, arylalkyl or heteroarylalkyl is further protected by one or more fluorenyl, halogen, aryl, hydroxy, amino, alkynyl, alkenyl, hydroxy, pyridyl, N-alkyl formyl, N,N-2(alkyl formyl), cyano, nitro, trifluoromethyl, halobenzyl, heterocycloalkyl, carboxylic acid or carboxylic acid ester; An aryl, heteroaryl, arylfluorenyl or heteroaryl fluorenyl group which is bicyclic, wherein the bicyclic ring may be further substituted by a benzyl or halobenzyl group; or is a structural formula: z
其中: among them:
Α选自芳基, 杂芳基, 芳烷基或杂芳烧基, 其中芳基, 杂芳基, 芳垸基或杂 芳烷基可以进一步被一个或多个烷基, 卤素, 芳基, 羟基, 氨基, 炔基, 烯基, 羟烷基, 烷氨基, N-烧基甲酰基, N,N-2(焼基甲酰基), 氰基, 硝基, 三氟甲基, 卤代苄基, 杂环垸基, 羧酸或羧酸酯所取代; 其中芳基, 杂芳基, 芳垸基或杂芳 垸基并成双环, 其中双环可以进一步被一个苄基或卤代苄基所取代; The hydrazine is selected from the group consisting of aryl, heteroaryl, aralkyl or heteroaryl, wherein the aryl, heteroaryl, arylalkyl or heteroarylalkyl group may be further substituted by one or more alkyl groups, halogens, aryl groups, Hydroxy, amino, alkynyl, alkenyl, hydroxyalkyl, alkylamino, N-alkylcarbonyl, N,N-2(fluorenyl), cyano, nitro, trifluoromethyl, halobenzyl Substituted by a heterocyclic fluorenyl group, a carboxylic acid or a carboxylic acid ester; wherein the aryl group, the heteroaryl group, the aryl fluorenyl group or the heteroaryl fluorenyl group is bicyclic, wherein the bicyclic ring may be further substituted by a benzyl or halobenzyl group. Replace
T选自: -0(CH2)r-, -N(C¾)r-或 -S(CH2)r-; T is selected from: -0(CH 2 )r-, -N(C3⁄4)r- or -S(CH 2 )r- ;
L选自: 垸基, 芳基, 杂芳基, 卤代芳基; L is selected from the group consisting of: fluorenyl, aryl, heteroaryl, haloaryl;
选自氢原子, 烷基, 三氟甲基, 环垸基, 杂环浣基, 芳基, 杂芳基, 芳垸 基或杂芳垸基, 其中烷基, 环烷基, 杂环院基, 芳基, 杂芳基, 芳烷基或杂芳烷 基进一步被一个或多个烷基, 卤素, 芳基, 羟基, 酰胺基, 胺酰基, 垸氧基, 芳 氧基, 杂环烷基, 羧酸, 羧酸酯或 -NR5R6所取代; Selected from hydrogen atom, alkyl group, trifluoromethyl, cyclodecyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, wherein alkyl, cycloalkyl, heterocyclic , aryl, heteroaryl, aralkyl or heteroarylalkyl further substituted by one or more alkyl, halo, aryl, hydroxy, amide, aminyl, decyloxy, aryloxy, heterocycloalkyl , carboxylic acids, carboxylic acid ester or substituted by -NR 5 R6;
选自氢原子, 烷基, 芳基, 杂芳基, 杂芳氧基, -C( ))R7, -C(=S)R7, -NC(=0)R7, -(CH2)nO(C=0)R7, -(CH2)nO(C=S)R7, -(C¾)nR7, -(CH2CH20)nR8 ; 其中芳基, 杂芳基, 杂芳氧基, -(CH2)nR7进一步被一个或多个垸基, -(C¾)nR7, =C(0), 卤素, 三氟甲基, 羧酸或羧酸酯所取代; Selected from hydrogen atom, alkyl group, aryl group, heteroaryl group, heteroaryloxy group, -C( ))R 7 , -C(=S)R 7 , -NC(=0)R 7 , -(CH 2 n O(C=0)R 7 , -(CH 2 ) n O(C=S)R 7 , -(C3⁄4) n R 7 , -(CH 2 CH 2 0) n R 8 ; wherein aryl, Heteroaryl, heteroaryloxy, -(CH 2 ) n R 7 is further protected by one or more fluorenyl groups, -(C3⁄4) n R 7 , =C(0), halogen, trifluoromethyl, carboxylic acid or Substituted by a carboxylic acid ester;
R4选自氢原子, 垸基, 环烷基, 杂环垸基, -(CH2CH20)nR8, 烯基或炔基, 其中烷基, 环烷基, 杂环垸基, 烯基或炔基进一步被一个或多个烷基, 羟基,.垸 氧基, 氰基, NR5 , 羧酸或羧酸酯所取代; R4 is selected from the group consisting of a hydrogen atom, a fluorenyl group, a cycloalkyl group, a heterocyclic fluorenyl group, -(CH 2 CH 2 0) n R 8 , an alkenyl group or an alkynyl group, wherein an alkyl group, a cycloalkyl group, a heterocyclic fluorenyl group, an alkene group Or alkynyl is further substituted by one or more alkyl, hydroxy, methoxy, cyano, NR 5 , carboxylic acid or carboxylic acid esters;
R5和 分别选自氢原子, 垸基, 环焼基, 杂环烷基, 芳基, 杂芳基或杂芳 烷基, 其中垸基, 环垸基, 杂环垸基, 芳基, 杂芳基或者杂芳垸基进一步被一个 或多个的烷基, 卤素, 芳基, 羟基, 氨基, 垸氨基, 酰胺基, 胺酰基, 氰基, 烷 氧基, 芳氧基, 胺垸基, 羟烷基, 羧酸, 羧酸酯或 -^5 所取代; R 5 and each independently selected from the group consisting of a hydrogen atom, a fluorenyl group, a cyclodecyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group or a heteroarylalkyl group, wherein a fluorenyl group, a cyclodecyl group, a heterocyclic fluorenyl group, an aryl group, a hetero Aryl or heteroaryl fluorenyl is further substituted by one or more alkyl, halo, aryl, hydroxy, amino, decylamino, amide, aminyl, cyano, alkoxy, aryloxy, aminyl, Substituted by a hydroxyalkyl group, a carboxylic acid, a carboxylic acid ester or -5 ;
同时, R5和 一起形成一个 4〜8元杂环基; 其中 5〜8元杂环内含有一个 或多个 N, 0, S原子, 并且 4〜8元杂环上进一步被一个或多个的烷基, 卤素, 芳基, 杂芳基, 卤代垸基, 卤代垸氧基,羟基, 酰胺基, 胺酰基, 氤基, 烧氧基, 芳氧基, 胺烷基, 羟烷基, 杂环烷基, 羧酸, 羧酸酯, -(CH2)nR7或 - R5 所取 代; Meanwhile, R 5 and together form a 4 to 8 membered heterocyclic group; wherein the 5 to 8 membered heterocyclic ring contains one or more N, 0, S atoms, and the 4 to 8 membered heterocyclic ring is further subjected to one or more Alkyl, halogen, aryl, heteroaryl, haloalkyl, halomethoxy, hydroxy, amide, aminyl, fluorenyl, alkoxy, aryloxy, alkoxy, hydroxyalkyl , a heterocycloalkyl group, a carboxylic acid, a carboxylic acid ester, substituted with -(CH 2 ) n R 7 or -R 5 ;
R7选自羟基, 烷氧基, 芳氧基, 杂环烧氧基, 芳垸氧基, -N(R8)(CH2)nR9, -NR8[CH2C¾0]nR8, -Ν 或者 -N (C¾)n[CH(OH)CH2]rZ (其中 Z是芳基, 杂 芳基, 杂环烷基, -NR5R6, -COOR8或 CONR5Re);
R8选自氢原子或烷基; R 7 is selected from hydroxy, alkoxy, aryloxy, heterocyclic oxy burning, embankment aryloxy group, -N (R 8) (CH 2) n R 9, -NR 8 [CH 2 C¾0] n R 8 , -Ν or -N (C3⁄4) n [CH(OH)CH 2 ] r Z (wherein Z is aryl, heteroaryl, heterocycloalkyl, -NR 5 R 6 , -COOR 8 or CONR 5 Re) ; R 8 is selected from a hydrogen atom or an alkyl group;
R9选自 -N R6,羟基,芳基,杂芳基,垸氧基, -S(0)2CH3, -O[CH2CH20]rR8, -N^CORsRs, -N(OH)R5, -NHC(0)R1()或- COR1Q, 其中 R1()是垸基, 卤代烷基或 R 9 is selected from -N R6, hydroxy, aryl, heteroaryl, decyloxy, -S(0) 2 CH 3 , -O[CH 2 CH 2 0] r R 8 , -N^CORsRs, -N (OH)R 5 , -NHC(0)R 1() or - COR 1Q , wherein R 1() is fluorenyl, haloalkyl or
R10是垸基, 卤代烷基或芳烷基 R 10 is a mercapto group, a haloalkyl group or an aralkyl group
n是 0〜6; n is 0~6;
r是 1〜2。 r is 1 to 2.
5. 根据权利要求 1所述的化合物或其盐,其中 X是 - 8, R8是氢原子或 C,〜 焼基。 The compound according to claim 1 or a salt thereof, wherein X is -8 and R 8 is a hydrogen atom or a C,~ fluorenyl group.
6. 根据权利要求 1所述的化合物或其盐,其中 R2是氢原子, 甲基或三氟甲基。 The compound according to claim 1 or a salt thereof, wherein R 2 is a hydrogen atom, a methyl group or a trifluoromethyl group.
7. 根据权利要求 1所述的化合物或其盐, 其中该化合物选自: The compound according to claim 1 or a salt thereof, wherein the compound is selected from the group consisting of:
4-[3-氯 -4-(3-氟-苄氧基) -苯氧基] -1-(2-甲氧基 -乙基 )-3-甲基 -1Η- 吡咯并 [2,3-d]哒嗪 -2-羧酸 [2-(4- 甲基 -哌嗪小基) -乙基] -酰胺 4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy]-1-(2-methoxy-ethyl)-3-methyl-1Η-pyrrolo[2,3 -d]pyridazine-2-carboxylic acid [2-(4-methyl-piperazine small)-ethyl]-amide
4-[3-氯 -4-(3-氟-苄氧基) -苯氧基] -1-(2-甲氧基 -乙基 )-3-甲基 -m-4-[3-chloro-4-(3-fluoro-benzyloxy)-phenoxy]-1-(2-methoxy-ethyl)-3-methyl-m-
>」 吡咯并 [2 3-d]哒嗪 -2-羧酸 [3-(4- 甲基 -哌嗪 -1-基:) -丙基] -酰胺 >" Pyrrolo[2 3-d]pyridazine-2-carboxylic acid [3-(4-methyl-piperazin-1-yl:)-propyl]-amide
4-[3-氯 -4-(3-氟-苄氧基) -苯氧基] -1-(2-甲氧基 -乙基 )-3-甲基 -1H- 吡咯并 [2,3-d]哒嗪 -2-羧酸 (2-吡咯垸 小基-乙基) -酰胺 4-[3-chloro-4-(3-fluoro-benzyloxy)-phenoxy]-1-(2-methoxy-ethyl)-3-methyl-1H-pyrrolo[2,3 -d]pyridazine-2-carboxylic acid (2-pyrrolidinyl-ethyl)-amide
4-[3-氯 -4-(3-氟 - 氧基) -苯氧基] 小[(2-甲氧基-乙氧基) -乙基 ]-3- 甲基 -1H-吡咯并 [2 3-d]哒嗪 -2- 羧酸乙酯 4-[3-chloro-4-(3-fluoro-oxy)-phenoxy]min[(2-methoxy-ethoxy)-ethyl]-3-methyl-1H-pyrrolo[ 2 3-d]pyridazine-2-carboxylic acid ethyl ester
? ?
4-[3-氯 -4-(3-氟-苄氧基) -苯氧基]4-[3-chloro-4-(3-fluoro-benzyloxy)-phenoxy]
、 ,
小[(2-甲氧基-乙氧基) -乙基 ]-3- 甲基 -1H-吡咯 [2,3-d]哒嗪 -2- 丁。 羧酸 (2-二乙氨基-乙基) -酰胺 Small [(2-methoxy-ethoxy)-ethyl]-3-methyl-1H-pyrrole [2,3-d]pyridazine-2-buty. Carboxylic acid (2-diethylamino-ethyl)-amide
4-[3-氯 -4-(3-氟-苄氧基) -苯氧基] ¾6. 小 [(2-甲氧基-乙氧基) -乙基 ]-3- 甲基 - 1 -(2-吗啉 -4-基-乙基) - 1H- 吡咯并 [2,3-d]哒嗪 -2-羧酸乙酯 4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy] 3⁄46. Small [(2-methoxy-ethoxy)-ethyl]-3-methyl- 1 - (2-morpholin-4-yl-ethyl)-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid ethyl ester
4-[3-氯 -4-(3-氟-苄氧基) -苯氧基] 小[(2-甲氧基-乙氧基) -乙基 ]-3- 三氟甲基 -1H-吡咯并 [2,3-d]哒嗪 -2- 羧酸乙酯
-l-[(2-甲氧基-乙氧基) -乙基 ]-3- 三氟甲基 -1H-吡咯并 [2,3-d]哒嗪 -2- 羧酸苄酯 4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy]min[(2-methoxy-ethoxy)-ethyl]-3-trifluoromethyl-1H- Ethyl pyrrolo[2,3-d]pyridazine-2-carboxylate -l-[(2-Methoxy-ethoxy)-ethyl]-3-trifluoromethyl-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid benzyl ester
4- [3-氯 -4-(3-氟-苄氧基) -苯氧基] -1-[(2-甲氧基-乙氧基) -乙基 ]_3- 三氟甲基 -1H-吡咯并 [2,3-d]哒嗪 -2- 羧酸 (2-二乙胺基-乙基) -酰胺4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy]-1-[( 2 -methoxy-ethoxy)-ethyl]- 3 -trifluoromethyl- 1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid (2-diethylamino-ethyl)-amide
4-[3-氯 -4-(3-氟-苄氧基) -苯氧基] -1-[(2-甲氧基-乙氧基) -乙基 ]-3- 三氟甲基 -1H-吡咯并 [2,3-d]哒嗪 -2- 羧酸 (2-吡咯烧 -1-基-乙基) -酰胺 4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy]-1-[(2-methoxy-ethoxy)-ethyl]-3-trifluoromethyl- 1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid (2-pyrrole-1-yl-ethyl)-amide
-[2-(5-二乙氨基甲基 -呋喃 -2-基) -3- 甲基 - 1 H-吡咯并 [2,3-d]哒嗪 -4-基] 酰胺 -[2-(5-Diethylaminomethyl-furan-2-yl)-3-methyl-1H-pyrrolo[2,3-d]pyridazin-4-yl]amide
[3-氯 _4_(3-氟-苄氧基) -苯氧基] -[2-(3-二乙氨基甲基 -甲基 )-3-甲基 -1H-吡咯并 [2,3-d]哒嗪 -4-基]酰胺 [ 3 -Chloro- 4 _( 3 -fluoro-benzyloxy)-phenoxy]-[2-(3-diethylaminomethyl-methyl)-3-methyl-1H-pyrrolo[2, 3-d]pyridazin-4-yl]amide
7-[3-氯 -4-(3-氟-苄氧基) -苯氧基] -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸 (2-二乙氨基-乙基) -酰胺
7-[3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy]-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid (2-diethylamino-B -amide
7-[3-氯 -4-(3-氟-苄氧基) -苯氧基] -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸 (2-2-吡咯烷 -1-基-乙基) -酰胺 7-[3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy]-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid (2-2-pyrrolidine- 1-yl-ethyl)-amide
7-[3-氯 -4-(3-氟-苄氧基) -苯氧基] -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸 (2- 吗啉 -4-基-乙基) -酰胺
7-[3-氯 -4-(3-氟-苄氧基) -苯氧基]7-[3-Chloro-4-(3-fluoro-benzyloxy)-phenoxy]-1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid (2-morpholin-4- Base-ethyl)-amide 7-[3-chloro-4-(3-fluoro-benzyloxy)-phenoxy]
50 -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸 (3- 吗啉 -4-基-丙基) -酰胺
50 -1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid (3-morpholin-4-yl-propyl)-amide
7-[3-氯 -4-(3-氟-苄氧基) -苯氧基]7-[3-chloro-4-(3-fluoro-benzyloxy)-phenoxy]
51 -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸 (2- 哌啶 -1-基-乙基) -酰胺 51 -1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid (2-piperidin-1-yl-ethyl)-amide
7-[3-氯 -4-(3-氟- 氧基) -苯氧基] 7 -[3-chloro-4-(3-fluoro-oxy)-phenoxy]
52 -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸 52 -1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid
7-[3-氯 -4-(3-氟-苄氧基) -苯氧基]7-[3-chloro-4-(3-fluoro-benzyloxy)-phenoxy]
53 -1H-吡咯并 [2,3-d]哒嗪 -2-羧酸 53 -1H-pyrrolo[2,3-d]pyridazine-2-carboxylic acid
2-(4-甲基 -哌嗪 -1 -基) -乙基] -酰胺 2-(4-methyl-piperazin-1 -yl)-ethyl]-amide
4-[3-氯 -4-(3-氟-苄氧基) -苯基] -Ί-4-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-indole-
54 甲基 -6H-吡咯并 [3,4-d]哌嗪 -5- 羧酸乙酯 54 methyl-6H-pyrrolo[3,4-d]piperazine-5-carboxylate
[3-氯 -4-(3-氟-苄氧基) -苯基 ]-(5-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(5-
55 甲基 -6H-吡咯并 [3,4-d]哌嗪 -1-基) -55 methyl-6H-pyrrolo[3,4-d]piperazine-1-yl) -
, 乙胺 , ethylamine
4-[1-(3-氟苄基 )-1Η-吲唑 -5-氨基] -3-4-[1-(3-fluorobenzyl)-1Η-carbazole-5-amino]-3-
56 甲基 -1H-吡咯并 [2,3-d]哒嗪 -2- [(2-吡咯啶 -1-基) -乙基]甲酰胺 56-methyl-1H-pyrrolo[2,3-d]pyridazine-2-[(2-pyrrolidin-1-yl)-ethyl]carboxamide
4-[1-(3-氟苄基) -1H-吲唑 -5-氨基] -3-4-[1-(3-fluorobenzyl)-1H-indazole-5-amino]-3-
8. 根据权利要求 1所述的化合物或其盐, 其中所述的盐为化合物与选自以下的 酸形成的药学上可以接受的盐: 苹果酸、 乳酸、 马来酸、 盐酸、 甲磺酸、 硫酸、 磷酸、 柠檬酸、 酒石酸、 乙酸或三氟乙酸。 The compound according to claim 1 or a salt thereof, wherein the salt is a pharmaceutically acceptable salt of a compound with an acid selected from the group consisting of malic acid, lactic acid, maleic acid, hydrochloric acid, methanesulfonic acid , sulfuric acid, phosphoric acid, citric acid, tartaric acid, acetic acid or trifluoroacetic acid.
9. 一种药用组合物, 其含有治疗有效剂量的根据权利要求 1〜8 中任何一项所 述的化合物或其盐或前药, 及药学上可以接受的载体或赋形剂。 A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 8, or a salt or prodrug thereof, and a pharmaceutically acceptable carrier or excipient.
10. 一种通式 I化合物的制备方法, 该方法包括以下步骤- 10. A process for the preparation of a compound of formula I, which comprises the following steps -
11.一种通式 I化合物的制备方法, 该方法包括以下步骤:
11. A process for the preparation of a compound of formula I, which process comprises the steps of:
13.一种通式 II化合物的制备方法, 该方法包括以下步骤: 13. A process for the preparation of a compound of formula II, the process comprising the steps of:
EtOOC EtOOC CI EtOOC EtOOC CI
EtOOC EtOOC CHO EtOOC EtOOC CHO
POCI. W NH2.NH2.H2Q POCI3 POCI. W NH 2 .NH 2 .H 2 Q POCI 3
N N N N
EtOOC 飞 DMF EtOOC Fly DMF
N EtOOC C2H5OH CH3CN N EtOOC C 2 H 5 OH CH 3 CN
14.一种通式 II化合物的制备方法, 该方法包括以下步骤: 14. A process for the preparation of a compound of formula II, the process comprising the steps of:
11-2 11-2
15.一种通式 III化合物的制备方法, 该方法包括以下步骤: 15. A process for the preparation of a compound of formula III, the process comprising the steps of:
111-1 111-1
16. 一种调节蛋白激酶催化活性的方法, 其中包括将所述的蛋白激酶与权利 求 1〜8中任何一项所述的化合物或盐接触。 A method of modulating the catalytic activity of a protein kinase, which comprises contacting said protein kinase with a compound or salt according to any one of claims 1-8.
17. 根据权利要求 10所述的方法, 其中所述蛋白激酶选自受体酪氨酸激酶、 非 受体酪氨酸激酶或丝氨酸 -苏氨酸激酶。 17. The method of claim 10, wherein the protein kinase is selected from the group consisting of a receptor tyrosine kinase, a non-receptor tyrosine kinase, or a serine-threonine kinase.
18. 一种治疗患有与蛋白质激酶有关的疾病的哺乳动物的方法, 所述方法包括对 所述哺乳动物给药治疗有效剂量的根据权利要求 9所述的药物组合物。 18. A method of treating a mammal having a disease associated with a protein kinase, the method comprising administering to the mammal a therapeutically effective amount of the pharmaceutical composition of claim 9.
19. 根据权利要求 18所述的方法,其中所述与蛋白质激酶有关的疾病选自 EGFR, HER-2, HER-3, HER-4, PDGFR, VEGFR-2, c-Kit, c-Met, FGFR或 Flt3相关的疾 病。 19. The method of claim 18, wherein the protein kinase-associated disease is selected from the group consisting of EGFR, HER-2, HER-3, HER-4, PDGFR, VEGFR-2, c-Kit, c-Met, FGFR or Flt3 related diseases.
20. 根据权利要求 18所述的方法, 其中所述的哺乳动物是人。
20. The method of claim 18, wherein the mammal is a human.
21.根据权利要求 18所述的方法, 其中所述与蛋白激酶有关的疾病选自白血病, 糖尿病, 自免疫病, 过度增生病, 牛皮癣, 骨关节炎, 类风湿性关节炎, 血管生 成, 心血管病, Von-Heppel-Lindau氏病, 炎症或纤维变性病。 The method according to claim 18, wherein the protein kinase-related disease is selected from the group consisting of leukemia, diabetes, autoimmune disease, hyperproliferative disease, psoriasis, osteoarthritis, rheumatoid arthritis, angiogenesis, heart Vascular disease, Von-Heppel-Lindau's disease, inflammation or fibrosis.
22.根据权利要求 18所述的方法, 其中所述与蛋白激酶有关的疾病是癌症, 选 自鳞状细胞癌, 肾细胞癌, Kaposi肉瘤, 非小细胞肺癌, 小细胞肺癌, 淋巴癌, 甲状腺癌, 乳腺癌, 头颈癌, 子宫癌, 食道癌, 黑素癌, 膀胱癌, 生殖泌尿癌, 胃肠癌, 神经胶质癌, 结肠直肠癌或卵巢癌。 The method according to claim 18, wherein the protein kinase-related disease is cancer, selected from the group consisting of squamous cell carcinoma, renal cell carcinoma, Kaposi sarcoma, non-small cell lung cancer, small cell lung cancer, lymphoma, thyroid gland Cancer, breast cancer, head and neck cancer, uterine cancer, esophageal cancer, melanoma, bladder cancer, genitourinary cancer, gastrointestinal cancer, glial cancer, colorectal cancer or ovarian cancer.
23. 根据权利要求 22所述的方法, 该方法进一步包括同时向需要治疗的患者给 药治疗有效量的其它抗癌药物。 23. The method of claim 22, further comprising administering to the patient in need of treatment a therapeutically effective amount of another anti-cancer drug.
24. 根据权利要求 23所述的方法, 其中所述的其它抗癌药物选自紫杉酚或卡铂。 24. The method of claim 23, wherein the other anti-cancer drug is selected from the group consisting of taxol or carboplatin.
25.一种权利要求 1所述的化合物在制备治疗与蛋白质激酶有关的疾病的药物中 的用途。 25. Use of a compound of claim 1 for the manufacture of a medicament for the treatment of a disease associated with a protein kinase.
26. 根据权利要求 25所述的用途,其中所述与蛋白质激酶有关的疾病选自 EGFR, HER-2, HER-3, HER-4, PDGFR, VEGFR-2, c-Kit, c-Met, FGFR或 Flt3相关的疾 病。 26. The use according to claim 25, wherein the protein kinase-associated disease is selected from the group consisting of EGFR, HER-2, HER-3, HER-4, PDGFR, VEGFR-2, c-Kit, c-Met, FGFR or Flt3 related diseases.
27.根据权利要求 25所述的用途, 其中所述与蛋白激酶有关的疾病选自白血病, 糖尿病, 自免疫病, 过度增生病, 牛皮癣, 骨关节炎, 类风湿性关节炎, 血管生 成, 心血管病, Von-Heppel-Lindau氏病, 炎症或纤维变性病。 The use according to claim 25, wherein the protein kinase-related disease is selected from the group consisting of leukemia, diabetes, autoimmune disease, hyperproliferative disease, psoriasis, osteoarthritis, rheumatoid arthritis, angiogenesis, heart Vascular disease, Von-Heppel-Lindau's disease, inflammation or fibrosis.
28. 根据权利要求 25所述的用途, 其中所述与蛋白激酶有关的疾病是癌症, 选 自鱗状细胞癌, 肾细胞癌, Kaposi肉瘤, 非小细胞肺癌, 小细胞肺癌, 淋巴癌, 甲状腺癌, 乳腺癌, 头颈癌, 子宫癌, 食道癌, 黑素癌, 膀胱癌, 生殖泌尿癌, 胃肠癌, 神经胶质癌, 结肠直肠癌或卵巢癌。
The use according to claim 25, wherein the protein kinase-related disease is cancer, selected from the group consisting of squamous cell carcinoma, renal cell carcinoma, Kaposi sarcoma, non-small cell lung cancer, small cell lung cancer, lymphoma, thyroid cancer. , breast cancer, head and neck cancer, uterine cancer, esophageal cancer, melanoma, bladder cancer, genitourinary cancer, gastrointestinal cancer, glial cancer, colorectal cancer or ovarian cancer.
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2021123297A1 (en) * | 2019-12-18 | 2021-06-24 | Janssen Pharmaceutica Nv | Oga inhibitor compounds |
US12083114B2 (en) | 2018-12-19 | 2024-09-10 | Disarm Therapeutics, Inc. | Inhibitors of SARM1 in combination with neuro-protective agents |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP4403550A1 (en) * | 2021-09-17 | 2024-07-24 | Jiangsu Hengrui Pharmaceuticals Co., Ltd. | Fused bicyclic derivative, pharmaceutically acceptable salt, crystal form thereof and preparation method therefor |
Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1056102A (en) * | 1990-04-27 | 1991-11-13 | 比克·古尔顿·劳姆贝尔格化学化司 | Pyridazines and process for preparing them |
CN1044811C (en) * | 1994-01-19 | 1999-08-25 | 三共株式会社 | Pyrrolopyridazine derivative |
CN1370172A (en) * | 1999-06-15 | 2002-09-18 | 三共株式会社 | Optically active pyrrolopyridazine compound |
CN1422272A (en) * | 2000-02-10 | 2003-06-04 | 三共株式会社 | Pyrrolopyridazine compound |
WO2004006836A2 (en) * | 2002-07-11 | 2004-01-22 | Merck & Co., Inc. | Treatment of neuropathic pain with 6h-pyrrolo[3,4-d]pyridazine compounds |
WO2004029057A1 (en) * | 2002-09-25 | 2004-04-08 | Sankyo Company, Limited | Medicinal composition for treatment for or prevention of visceral pain |
WO2004084899A1 (en) * | 2003-03-24 | 2004-10-07 | Sankyo Company, Limited | Medicinal composition containing pyrrolopyridazine compound |
WO2004089378A1 (en) * | 2003-04-04 | 2004-10-21 | Sankyo Company, Limited | Medicinal composition containing pyrrolopyridazine derivative |
WO2005097800A1 (en) * | 2004-04-02 | 2005-10-20 | Osi Pharmaceuticals, Inc. | 6,6-bicyclic ring substituted heterobicyclic protein kinase inhibitors |
-
2006
- 2006-03-14 CN CNA2006100648490A patent/CN101003537A/en active Pending
-
2007
- 2007-01-17 WO PCT/CN2007/000176 patent/WO2007082470A1/en active Application Filing
Patent Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1056102A (en) * | 1990-04-27 | 1991-11-13 | 比克·古尔顿·劳姆贝尔格化学化司 | Pyridazines and process for preparing them |
CN1044811C (en) * | 1994-01-19 | 1999-08-25 | 三共株式会社 | Pyrrolopyridazine derivative |
CN1370172A (en) * | 1999-06-15 | 2002-09-18 | 三共株式会社 | Optically active pyrrolopyridazine compound |
CN1422272A (en) * | 2000-02-10 | 2003-06-04 | 三共株式会社 | Pyrrolopyridazine compound |
WO2004006836A2 (en) * | 2002-07-11 | 2004-01-22 | Merck & Co., Inc. | Treatment of neuropathic pain with 6h-pyrrolo[3,4-d]pyridazine compounds |
WO2004029057A1 (en) * | 2002-09-25 | 2004-04-08 | Sankyo Company, Limited | Medicinal composition for treatment for or prevention of visceral pain |
WO2004084899A1 (en) * | 2003-03-24 | 2004-10-07 | Sankyo Company, Limited | Medicinal composition containing pyrrolopyridazine compound |
WO2004089378A1 (en) * | 2003-04-04 | 2004-10-21 | Sankyo Company, Limited | Medicinal composition containing pyrrolopyridazine derivative |
WO2005097800A1 (en) * | 2004-04-02 | 2005-10-20 | Osi Pharmaceuticals, Inc. | 6,6-bicyclic ring substituted heterobicyclic protein kinase inhibitors |
Non-Patent Citations (1)
Title |
---|
MEADE E.A. ET AL.: "Synthesis, antiproliferative, and antiviral activity of certain 4-aminopyrrolo[2,3-d]pyridazine nucleosides: an entry into a novel series of adenosine analogs", J. MED. CHEM., vol. 35, no. 3, 1992, pages 526 - 533, XP003015963 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US12083114B2 (en) | 2018-12-19 | 2024-09-10 | Disarm Therapeutics, Inc. | Inhibitors of SARM1 in combination with neuro-protective agents |
WO2021123297A1 (en) * | 2019-12-18 | 2021-06-24 | Janssen Pharmaceutica Nv | Oga inhibitor compounds |
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