WO2009012647A1 - Procédés de préparation de dérivés de quinazoline et leurs utilisations pharmaceutiques - Google Patents

Procédés de préparation de dérivés de quinazoline et leurs utilisations pharmaceutiques Download PDF

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WO2009012647A1
WO2009012647A1 PCT/CN2008/001307 CN2008001307W WO2009012647A1 WO 2009012647 A1 WO2009012647 A1 WO 2009012647A1 CN 2008001307 W CN2008001307 W CN 2008001307W WO 2009012647 A1 WO2009012647 A1 WO 2009012647A1
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group
compound
aryl
carboxylic acid
heteroaryl
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PCT/CN2008/001307
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English (en)
Chinese (zh)
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Peng Cho Tang
Jun Feng
Feng Feng
Lei Zhang
Jingquan Ye
Lin Wang
Zhicheng Song
Qianfeng Zhang
Yaxian Dang
Yeying Lu
Ling Zong
Chiqiong Jing
Jie Zang
Ying Zhou
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Shanghai Hengrui Pharmaceutical Co., Ltd.
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Priority claimed from CN 200810127622 external-priority patent/CN101367794B/zh
Application filed by Shanghai Hengrui Pharmaceutical Co., Ltd. filed Critical Shanghai Hengrui Pharmaceutical Co., Ltd.
Publication of WO2009012647A1 publication Critical patent/WO2009012647A1/fr

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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems

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 kinase inhibitor. Background technique
  • Cellular signaling is a fundamental mechanism of action. During signal transduction, 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, which exist as different types of lytic factors, including growth factors that are predominantly paracrine, autocrine, and endocrine. By binding to specific transmembrane receptors, growth factor ligands transmit extracellular signals to the intracellular 'signaling pathway', causing individual cells to respond to extracellular signals. Many signaling processes are reversible processes that utilize ⁇ white phosphorylation, involving specific protein kinases and phosphorylating enzymes.
  • Protein kinase is an enzyme that catalyzes 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, leading to abnormalities in signal transduction. Abnormal differentiation, transformation and growth of cells.
  • a cell can become a cancer cell by converting a portion of its DNA into an oncogene, a growth factor receptor protein encoded by such an oncogene; a tyrosine kinase can also be mutated into an activated form resulting in a variety of Variations in human cells, it can be said that over-expressed normal tyrosine kinases 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 are recognized in human genes, of which about 60 are receptor types and about 30 are non-receptive.
  • the growth factor receptor family can be further divided into 20 receptor tyrosine kinase subfamilies and 10 non-receptor tyrosine kinase subfamilies (Robinson et al, Oncogene. 2000, 19, 5548-5557).
  • the RTKs subfamily includes the following: (1) EGF families, such as EGF, TGFa, Neu and erbB; (2) insulin family, including insulin receptor, insulin-like growth factor I receptor (IGF1) and insulin receptor-related Sexual receptors (IRR); (3) Type III families, such as platelet-derived growth factor receptors (PDGF, including PDGFa and PDGFp receptors), stem cell factor RTKs (SCF RTK', commonly referred to as c-Kit), z ° ⁇ 3 3 ⁇ 4 ⁇ ⁇ w ⁇ ⁇ ⁇ 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3
  • the function of the white tyrosine kinase can be determined by expression pattern and ligand availability, and can also be determined by the downstream region signaling pathway activated by a particular receptor.
  • 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.
  • EGFR tyrosine kinases are mutated and overexpressed.
  • the "HER” or "Erb” receptor tyrosine kinase subfamily includes EGFR, HER2, HER3 and HER4. These subfamilies consist of an extracellular glycosylation ligand binding domain, a transmembrane domain, and an intracellular cytoplasmic catalytic domain that phosphorylates the tyrosine sequence on the protein.
  • the receptor tyrosine kinase catalytic activity can be activated by receptor overexpression or ligand-mediated dimerization.
  • the HER2 family of polymers has both homodimers and heterodimers.
  • 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
  • Polymerization can be accelerated by binding to the heregulin (also known as neyregulin) family of ligands.
  • the heregulin also known as neyregulin
  • one of the receptors for HER3 has no enzymatic activity, heterodimerization of HER2 with HER3, or HER3 and HER4, also significantly stimulates tyrosine kinase receptor dimerization.
  • 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 phosphatidylcholines Alcohol (-3) kinase (PI3 kinase) is also activated, and activation of these signaling pathways promotes cell proliferation and inhibits cell apoptosis.
  • MAP kinases microtubule-associated protein kinases
  • PI3 kinase phosphatidylcholines Alcohol
  • RTK insulin receptor
  • IGF-1 R insulin-like growth factor-1 receptor
  • IRR insulin receptor-related receptor
  • IGF-1 R interacts with insulin, IGF-I and IGF-II, resulting from two completely extracellular glycosylated alpha subunits and two tyrosine kinase domain beta subunits that cross the cell membrane Heterotetramer.
  • the third subgroup of RTK refers to the platelet-derived growth factor receptor (PDGFR) family, including 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.
  • PDGFR platelet-derived growth factor receptor
  • 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. Gene mutations are the reason why receptors are activated independent of binding to ligands, and are also tumors. The driving force generated.
  • 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, J. Clin. Oncol. 22 (14S), 9642 (2004)].
  • GIST is a non-epithelial cell tumor, most of which is found in the stomach, a few in the small intestine, rarely in the esophagus, but also in the liver, peritoneal cavity and other parts.
  • GIST is derived from Cajal interstitial cells (ICC), which forms part of the intestinal autonomic nervous system and is involved 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.
  • ICC Cajal interstitial cells
  • c-Kit expression can also be detected, and c-Kit expression is also found in acute AML and malignant lymphoma, in small cells. Bronchial carcinoma, seminoma, dysgerminoma, testis, intraepithelial neoplasia, melanoma, breast cancer, neuroblastoma, Ewing's sarcoma have c-Kit expression (see Schutte et al., innovartis 3) /2001). It is well known that RET (rearranged during transfection).
  • Proto-oncogene genetic mutations are tumorigenic, and patients with multiple endocrine neoplasias MEN 2) may cause pheochromocytoma, medullary thyroid carcinoma, and parathyroid adenoma and hyperplasia (see Huang et al., Cancer Res. 60, 6223-6 (2000)).
  • Hk 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-1R, 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 cycloglycosylation 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 is strongly expressed in various malignant solid tumors such as lung cancer, breast cancer, non-Hodgkin's malignant lymphoma, ovarian cancer, pancreatic cancer, malignant pleural mesothelioma, and melanoma, and is associated with the progression of cancer, in white blood cells. Excessive symptoms and lymphoma are also expressed.
  • VEGFR vascular endothelial growth factor
  • VEGF ligands can also promote tumor growth by directly pro-survival properties in tumor cells
  • 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 has been shown to stimulate the production of vascular endothelial cells in vivo.
  • Some peptides have been identified, including acidic, basic fibroblast growth factor (aFGF and bFGF) and vascular endothelial growth factor.
  • 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 very important stimulator 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 form 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 closely associated with tumorigenesis, cell motility, invasion and metastasis (see Ma, PC et al. (2003b). Cancer Metastasis Rev, 22, 309-25; Mau!ik, G. et al. (2002b). Cytokine Growth Factor Rev, 13, 41-59). Overexpression or mutation in various tumors, including small cell lung cancer (SCLC), activates c-MET (HGFR) (see Ma, P.C. et al. (2003a). Cancer Res, 63, 6272-6281).
  • 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
  • Src Frk, Btk, Csk, Abl, Zap70, Fes/Fps, Fak, Jak, Ack and LIMK. So far, the number of Src subfamily CTKs seems to be the most, including Src, Yes,.
  • 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 prevalent cytosolic kinases, ie, they function in part of the cytoplasm, not in cytoplasmic organelles.
  • the cytosol is a region within the cell where metabolic and biosynthetic activities occur in most cells; for example, proteins are synthesized on cytosol ribosomes.
  • R 1 is selected from a decyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, wherein the fluorenyl group, the heterocycloalkyl group, the aryl group or the heteroaryl group may be further selected from one or more selected from the group consisting of an alkyl group, a halogen group, and an aryl group.
  • R 1 is a structural formula:
  • the hydrazine is selected from aryl or heteroaryl, wherein the aryl or heteroaryl group may be further selected from one or more selected from the group consisting of alkyl, halogen, aryl, hydroxy, amino, alkynyl, alkenyl, cyano, nitro, Substituted by a substituent of a trifluoromethyl group, a halobenzyl group, a heterocycloalkyl group, a carboxylic acid or a carboxylic acid ester;
  • ⁇ is selected from -0(CH 2 )r-, -N(CH 2 )r- or -S(CH 2 )r ;
  • L is selected from aryl or heteroaryl, wherein the aryl or heteroaryl may be further substituted by one or more halogen or alkyl;
  • R 2 is selected from the group consisting of a hydrogen atom, an alkyl group, a cyclodecyl group, a trifluoromethyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an aralkyl group, wherein an alkyl group, a cycloalkyl group, a heterocyclic fluorenyl group, an aryl group , a heteroaryl group, an aryl fluorenyl group further further substituted by one or more substituents selected from the group consisting of an alkyl group, an aryl group, a hydroxyl group, a halogen, an amino group, a cyano group, a decyloxy group, a carboxylic acid, a carboxylic acid ester or -NR 6 R 7 Replaced
  • -NR 6 R 7 substituted with a carboxylic acid or a carboxylic acid ester;
  • R 6 and R 7 are each independently selected from a hydrogen atom, an alkyl group, an alkenyl group, a cyclodecyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, wherein a fluorenyl group, an alkenyl group, a cycloalkyl group, a heterocycloalkyl group, or an aromatic group.
  • n is. ⁇ 6;
  • the present invention includes a compound represented by the following formula (I) or a salt thereof:
  • R 1 is selected from a decyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, wherein the fluorenyl group, heterocycloalkyl group, aryl group or heteroaryl group may be further selected from one or more selected from the group consisting of a fluorenyl group, a halogen group, and an aryl group.
  • the hydrazine is selected from aryl or heteroaryl, wherein the aryl or heteroaryl group may be further selected from one or more selected from the group consisting of alkyl, halogen, aryl, hydroxy, amino, alkynyl, alkenyl, cyano, nitro, Substituted by a substituent of a trifluoromethyl group, a halobenzyl group, a heterocyclic fluorenyl group, a carboxylic acid or a carboxylic acid ester;
  • ⁇ selected from -0(CH 2 )r -, -N(CH 2 )r- or -S(CH 2 )r;
  • L is selected from aryl or heteroaryl, wherein the aryl or heteroaryl group may be further substituted with one or more halogen or alkyl groups;
  • R 2 is selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, a trifluoromethyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an aralkyl group, wherein a fluorenyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group , a heteroaryl group, an aralkyl group further substituted by one or more substituents selected from alkyl, aryl, hydroxy, halogen, amino, cyano, alkoxy, carboxylic acid, carboxylic acid ester or -NR 6 R 7 Replaced
  • R 3 and R 4 together form a 4 to 8 membered ring group; wherein the 5 to 8 membered heterocyclic ring contains one or more 1, 0, S atoms, and the 4 to 8 membered heterocyclic ring is further subjected to one or a plurality selected from the group consisting of fluorenyl, halogen, aryl, heteroaryl, halodecyl, halodecyloxy, hydroxy, alkoxy, aryloxy, carbonyl, heterocycloalkyl, carboxylic acid, carboxylic acid ester Substituted by a substituent of -N-OR 6 or -NR 6 R 7 ;
  • R 6 and R 7 are each independently selected from the group consisting of a hydrogen atom, a decyl group, an alkenyl group, a cyclodecyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, wherein a fluorenyl group, an alkenyl group, a cycloalkyl group, a heterocycloalkyl group, or an aromatic group.
  • n 0 ⁇ 6
  • the present invention includes a compound represented by the following formula ( ⁇ ) or a salt thereof:
  • R 1 is selected from an alkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, wherein the indenyl group, the heterocycloalkyl group, the aryl group or the heteroaryl group may be further selected from one or more selected from the group consisting of an alkyl group, a halogen group, and an aryl group.
  • the base or heteroaryl group may be combined into a bicyclic ring which may be further substituted by a benzyl group or a halobenzyl group;
  • R 1 is a structural formula: Z ⁇
  • B is selected from aryl or heteroaryl, wherein the aryl or heteroaryl group may be further selected from one or more selected from the group consisting of fluorenyl, halogen, aryl, hydroxy, amino, alkynyl, alkenyl, cyano, nitro, Substituted by a substituent of a trifluoromethyl group, a halobenzyl group, a heterocycloalkyl group, a carboxylic acid or a carboxylic acid ester;
  • T is selected from -0(CH 2 )r-, -N(CH 2 )r- or -S(CH 2 )r;
  • L is selected from aryl or heteroaryl, wherein the aryl or heteroaryl group may be further substituted with one or more halogen or alkyl groups;
  • R 2 is selected from the group consisting of a hydrogen atom, an alkyl group, a cyclodecyl group, a trifluoromethyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, an aryl fluorenyl group, wherein a fluorenyl group, a cyclodecyl group, a heterocyclic fluorenyl group, an aryl group a heteroaryl group, an aralkyl group further substituted with one or more substituents selected from the group consisting of a fluorenyl group, an aryl group, a hydroxyl group, a halogen, an amino group, a cyano group, a decyloxy group, a carboxylic acid, a carboxylic acid ester or -NR 6 R 7 Replaced
  • R 5 is selected from a hydrogen atom, a fluorenyl group, a cycloalkyl group or a -C(O)0R 6 , wherein the fluorenyl or cycloalkyl hydrazine is one step or more selected from the group consisting of an alkyl group, a hydroxyl group, an alkoxy group, and a cyano group. Substituting a substituent of -NR 6 R 7 , a carboxylic acid or a carboxylic acid ester;
  • R 6 and R 7 are each independently selected from a hydrogen atom, an alkyl group, an alkenyl group, a cycloalkyl group, a heterocyclic fluorenyl group, an aryl group or a heteroaryl group, wherein an alkyl group, an alkenyl group, a cycloalkyl group, a heterocyclic fluorenyl group, and an aromatic group are used.
  • n 0 ⁇ 6
  • the present invention includes a compound represented by the following formula (III) or a salt thereof: among them-
  • R 1 is selected from an alkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, wherein the alkyl group, heterocycloalkyl group, aryl group or heteroaryl group may be further selected from one or more selected from the group consisting of an alkyl group, a halogen group, and an aryl group.
  • the fluorene is selected from an aryl or heteroaryl group, wherein the aryl or heteroaryl group may be further selected from one or more selected from the group consisting of an alkyl group, a halogen, an aryl group, a hydroxyl group, an amino group, an alkynyl group, an alkenyl group, a cyano group, and a nitro group. Substituted by a trifluoromethyl group, a dentate benzyl group, a heterocycloalkyl group, a carboxylic acid or a carboxylic acid ester;
  • ⁇ selected from -0(CH 2 )r -, -N(CH 2 )r- or -S(CH 2 )r;
  • L is selected from aryl or heteroaryl, wherein the aryl or heteroaryl group may be further substituted with one or more halogen or alkyl groups;
  • n 0 ⁇ 6
  • Typical compounds of the invention include, but are not limited to, the following compounds or pharmaceutically acceptable salts thereof.
  • the salt is a salt of the above compound with an acid selected from the group consisting of malic acid, lactic acid, maleic acid, hydrochloric acid, methanesulfonic acid, p-toluenesulfonic acid, sulfuric acid, phosphoric acid, citric acid, tartaric acid, acetic acid or Trifluoroacetate.
  • a pharmaceutical composition comprising a compound of the formula (1), ( ⁇ ) or (III), a salt thereof or a prodrug thereof, and a pharmaceutically acceptable carrier or excipient .
  • a method of modulating the catalytic activity of a protein kinase comprising contacting a protein kinase with a compound or salt of formula (1), ( ⁇ ) or (III).
  • 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 process for the preparation of a compound or salt of the formula (1), ( ⁇ ) or (III) comprises the steps of:
  • Alkyl means a saturated aliphatic hydrocarbon group including straight chain and branched chain groups of 1 to 20 carbon atoms. Preference is given to alkyl groups having 1 to 10 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, pentyl and the like. More preferred are lower alkyl groups having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl or t-butyl groups and the like.
  • Cycloalkyl means a 3 to 8 membered all-carbon monocyclic, all-carbon 5/6 or 6/6 fused ring or a 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, but none of the rings have a fully conjugated pi-electron system.
  • cyclodecyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclopentene, cyclohexane, cyclohexadiene, adamantane, cycloheptadene, cycloheptatriene and the like.
  • the cycloalkyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more, independently selected from the group consisting of lower alkyl, halogen, trihaloalkyl, hydroxy, lower alkoxy, hydroxyalkyl.
  • alkenyl refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond. Representative examples include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, and the like.
  • the alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more, independently selected from the group consisting of halogen, trihalofluorenyl, hydroxy, lower alkoxy, aryl, aryloxy.
  • Alkynyl means a fluorenyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond.
  • 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.
  • 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-alkylpyrrolyl group, a pyrimidinyl group, a pyrazinyl group, an imidazolyl group and the like.
  • Heterocycloalkyl means a monocyclic or fused ring radical having from 5 to 9 ring atoms in the ring wherein one or two ring atoms are selected from nitrogen, oxygen or S(0)n (where n is an integer) From 0 to 2), the remaining ring atoms are carbon. These rings may also have one or more double bonds. However, these rings do not have a fully conjugated ⁇ -electron system.
  • Unsubstituted heterocycloalkyl includes, but is not limited to, pyrrolidinyl, piperidino, piperazino, morpholinyl, thiomorpholinyl, homopiperazine, etc., heterocycloalkyl may be substituted or Unsubstituted.
  • the alkynyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more, independently selected from the group consisting of halogen, lower alkyl, hydroxyalkyl, trihalofluorenyl, hydroxy, aryl, aryl.
  • Haldroxy means an -OH group.
  • Alkoxy means -0-(alkyl) and -0-(unsubstituted cycloalkyl). Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • the alkoxy group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more, independently selected from the group consisting of a fluorenyl group, a halogen, a trihalofluorenyl group, a hydroxyl group, a lower alkoxy group, and an aryl group.
  • Aryloxy means -o-aryl and -o-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.
  • Benzyl means -CH 2 - (aryl).
  • Halogen means fluoro, chloro, bromo or iodo, preferably fluoro or chloro.
  • Haloalkyl means that the fluorenyl group is replaced by a halogen. Representative examples include, but are not limited to, trifluoromethyl, tribromomethyl, and the like.
  • Hydroalkyl means an alkyl group substituted by a hydroxy group.
  • Amine alkyl means an alkyl group substituted with an amino group.
  • Haloalkoxy means - ⁇ -(halofluorenyl). Representative examples include, but are not limited to, trifluoromethoxy, tribromomethoxy, and the like.
  • Heterocycloalkoxy means -0-(heterocyclic fluorenyl).
  • Halobenzyl means -CH 2 - (haloaryl).
  • Trifluoromethyl means -CF 3 .
  • Neitro means -N0 2 .
  • Amino means -NH 2 .
  • Optional or “optionally” means that the event or environment described subsequently may, but need not, occur, i2 ⁇ 4 indicates where the event or environment occurs or does not occur.
  • “optionally substituted with a fluorenyl group to a heterocyclic group” means that an alkyl group may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with 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.
  • the preparation method of the compound of the formula (I) or a salt thereof of the present invention comprises the following steps -
  • the preparation method of the compound of the formula (III) or a salt thereof of the present invention comprises the following steps:
  • the structure of the example compounds was determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS).
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • the NMR shift ( ⁇ ) is given in parts per million (ppm).
  • NMR was measured using a Bruker AVANCE-400 nuclear magnetic apparatus.
  • the solvent was deuterated chloroform (CDC1 3 ), deuterated dimethyl sulfoxide (DMSO-D 6 ), internal standard tetramethylsilane (TMS), chemical shift. is 10- 6 (ppm) given as a unit.
  • the MS was measured using a FIN GAN LCQAd (ESI) mass spectrometer.
  • the average inhibition rate of the kinase VEGFR was measured using an HTScan microplate reader (Cell Signaling).
  • the average inhibition rate of the kinase EGFR/HER-2 was measured using a NovoStar plate reader (BMG, Germany).
  • Thin layer silica gel is used in Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
  • the spare intermediate was dissolved in 400 mL of isopropyl alcohol under nitrogen atmosphere, and then 3-chloro-4-(3-fluoro-benzyl)-phenylamine hydrochloride lc (12 g, 50.4 mmol). The thin layer analysis was followed until the disappearance of the starting material, the reaction solution was cooled to room temperature, and filtered under reduced pressure. The obtained solid was dissolved in a mixed solvent of 100 mL of ethyl acetate and 30 mL of aqueous ammonia, stirred at room temperature for 30 minutes, filtered under reduced pressure, and dried under vacuum.
  • the compound 2-methanesulfonyl-ethylamine hydrochloride 2b (70 mg, 0.4 mmol) obtained in the first step of Example 2 of the present invention was added to a 50 mL eggplant flask under a nitrogen atmosphere, and 5 mL of tetrahydrofuran and 5 were added.
  • reaction was purified by silica gel column chromatography toiel -yl ⁇ -111-pyrrol-2-ylmethyl)-indole, ⁇ '-diethyl-1,2-ethanediamine 3 (50 mg, pale yellow solid). Yield: 16.5%.
  • Example 2 of the present invention The reaction of the second step of Example 2 of the present invention was repeated, and the compound 1- ⁇ 4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazole obtained in the above second step was used.
  • the compound is reacted with 2-morpholin-4-yl-ethylamine in the same manner as described in the third step of Example 2 of the present invention, using porphyrin-6-yl ⁇ -111-pyrrole-2-carbaldehyde 2c as a starting material.
  • Oxalyl chloride (7.24 g, 46.7 mmol) was dissolved in 240 mL of dichloromethane at 0 ° C under nitrogen atmosphere, and ⁇ , dimethyl-dimethylformamide (4.6 g, 63 mmol) '5 mE was added dropwise with stirring.
  • Dichloromethane solution stirred at TC for 20 minutes.
  • Dissolve the spare intermediate in 10 mL of dichloromethane quickly drip into the reaction solution, reflux at 60 ° C for 30 minutes, cool to 0 ° C, under nitrogen atmosphere Filtered, the solid was washed with diethyl ether and dried in vacuo.
  • Example 8 of the present invention The compound [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1 ⁇ -pyrrole-2) obtained in Example 8 of the present invention was added to a 10 mL eggplant-shaped flask under an argon atmosphere.
  • -yl)-quinazolin-4-yl]-amine 8 dissolved in 2 mL of N,N-dimethylformamide, sodium hydride (8 mg, 0.337 mmol), stirred at room temperature for 1 hour, iodine Methane (32 mg, 0.225 mmol) was stirred at room temperature overnight. Thin layer analysis was performed until the disappearance of the starting material.
  • Phenyl-4-yl)-amine lg (4.31 g, 8.53 mmol), followed by 6,7-dihydro-2H-pyrano[3,4-c]pyrrol-4-one 10b (1.52 g, 11.68 mmol) , cuprous iodide (840 mg, 4.26 mmol) and potassium phosphate (5.43 g, 25.58 mmol), dissolved in 80 mL of N,N-dimethylformamide, and added with hydrazine, ⁇ '-dimethyl- 1,2-Ethylenediamine (0.5 mL, 4.26 mmol), heated to 68 ° C and stirred overnight. The thin layer analysis was followed until the disappearance of the starting material.
  • -yl]-amine 8 (1.02 g, 2.30 mmol), dissolved in 10 mL of hydrazine, hydrazine-dimethylformamide, and stirred at -15 ° C, and added phosphorus oxychloride (0.3 mL, 3.45 mmol) at room temperature Stir overnight.
  • hydrochloride salt is recrystallized from ethyl acetate to give the title compound [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6- ⁇ 3-[(2- Morpholin-4-yl-ethylamino)-methyl]-P-pyrrol-1-yl ⁇ -quinazolin-4-yl)-amine 15 (20 mg, yellow solid). Yield: 50%.
  • Example 10 of the present invention The reaction of the first to second steps of Example 10 of the present invention was repeated, using the compound 2- ⁇ 4-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl obtained in the above second step.
  • - quinazolin-6-yl ⁇ -6,7-dihydro-2H-pyrano[3,4-c]pyrrol-4-one 10 as a starting material, which is carried out in the same manner as described in Example 13 of the present invention.
  • Raw material and 2-(4-methyl- The reaction of the piperazine-1-yl)-ethylamine is purified by silica gel column chromatography to give the title product 1- ⁇ 4-[3-chloro-4-(3-fluoro-benzyloxy)-benzene.
  • Example 26 of the present invention The compound [1- ⁇ 4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl ⁇ -4-(2-hydroxyl) obtained in Example 26 of the present invention was used. -ethyl) -1H-pyrrol-3-yl]-pyrrolidin-1-yl-methanone 26
  • the reaction of the starting material with lithium aluminum hydride was carried out in the same manner as described in Example 28 of the present invention, using silica gel column chromatography.
  • Example 27 of the present invention [1- ⁇ 4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl ⁇ -4-(2-hydroxyl -ethyl) -1H-pyrrol-3-yl]-morpholin-4-yl-methanone 27
  • the reaction of the starting material with lithium aluminum hydride was carried out in the same manner as described in Example 28 of the present invention, using silica gel column chromatography.
  • the obtained residue was purified to give the title product 2-(1- ⁇ 4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl ⁇ -4-? Polin-4-ylmethyl-1H-pyrrol-3-yl)-ethanol 30 (115 mg, pale yellow solid). Yield: 58.9%.
  • reaction mixture was purified by silica gel column chromatography toield - phenylamino]-quinazolin-6-yl ⁇ -4-(2-trans-ethyl-ethyl)-1H-pyrrole-3-carboxylic acid-(2-pyrrolidin-1-yl-ethyl)- Amine 31 (420 mg, tan solid). Yield: 38.5 %
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  • the spare intermediate was dissolved in 250 mL of isopropanol under a nitrogen atmosphere, and 1-(3-fluorobenzyl)-1 - oxazole-5-amine 43a ( 8.85 g, 36.7 mmol) was added and the mixture was heated to reflux overnight.
  • Example 1 of the present invention The reaction of the first to fourth steps of Example 1 of the present invention was repeated, and the compound 6-iodo-3H-quinazoline-4-one If (5 g, 18.3 mmol) obtained in the fourth step was dissolved in 50 mL of dichloro. In a mixed solvent of sulfoxide and 0.5 mL of N,N-dimethyl 'formamide, the mixture was heated to reflux until the reaction liquid was transparent. After stirring for 6 hours, thin layer analysis followed the disappearance of the starting material, and the thionyl chloride was distilled off and used.
  • the spare intermediate was dissolved in 160 mL of isopropyl alcohol under nitrogen atmosphere, and then 3-chloro-4-(pyridine-2-methoxy)-aniline 44b (4.25 g, 18.2 mmol).
  • the thin layer analysis traced to the disappearance of the raw materials the reaction solution was cooled to room temperature, filtered under reduced pressure, and the obtained solid was dissolved and diluted with 5 mL of methanol, and then ammonia water (200 mL, volume ratio of 1:1) was added to adjust the pH to 8 9.
  • reaction was completed and the reaction mixture was dark red.
  • the obtained reaction liquid is poured into a saturated aqueous solution of sodium chloride, and a solid is precipitated, and the resulting solid is dried under vacuum, and further purified by column chromatography to obtain W 200 title product [3-chloro-4-(pyridine- 2 -yloxy)-phenyl]-(6-pyrrole-yl-quinazolin-2-yl)-amine 4 5 ( 1.15 g, yellow solid ), the yield was 68%.
  • 4-yl)-amine 48a (2 g, 5 mmol), potassium phosphate (3.18 g, 15 mmol), cuprous iodide (0.95 g, 5 mmol) dissolved in 40 mL of N,N-dimethylformamide, mixture Under stirring, hydrazine, ⁇ '-dimethyl-1,2-ethanediamine (0.55 mL, 5 mmol) was added, and the mixture was heated to 65 ° C and stirred overnight. The reaction liquid was poured into 600 mL of water, and a yellow-green solid was precipitated, and filtered, and the obtained solid was purified by column chromatography to give the title product (3-chloro-4-fluorophenyl)-(6-pyrrole-1). - quinazolin-4-yl)-amine 48 (0.9 g yellow solid), yield 53%.
  • the compound obtained in the above step is 2- ⁇ 4-[ 3 -chloro- 4 -fluoro-phenylamino]-quinazoline- 6 -yl ⁇ -pyrrole-1-carboxylic acid.
  • Tert-butyl ester 49a is dissolved in 55 mL of anhydrous In tetrahydrofuran, the obtained yellow solution was cooled to 0 ° C with ice-water bath, sodium methoxide (1.46 g, 13 mmol) was added, and the reaction mixture was gradually warmed to room temperature. After 3 hours, the reaction was completed and the reaction mixture was dark red.
  • reaction liquid was poured into a saturated aqueous solution of sodium chloride, and the solid was precipitated, and filtered, and the obtained solid was dried in vacuo and purified by column chromatography to give the title compound (3-chloro-4-fluoro-benzene -[6-(1 ⁇ -pyrrol-2-yl)-quinazolin-4-yl]-amine 49 (767 mg, pale yellow solid), yield 67%.
  • the compound obtained in the above step is 5- ⁇ 4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazolin-6-yl ⁇ -1-triisopropylsilyl-1H - Pyrrole-3-carbaldehyde 50b (36 mg, 0.076 mmol) was dissolved in 5 mL of tetrahydrofuran, and 2-morpholin-4-yl-ethylamine (15 mg, 0.114 mmol) was added dropwise with stirring. Sodium borohydride (127 mg, 0.6 mmol) was obtained.
  • reaction mixture was evaporated to drynessmjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
  • Example 47 The experimental procedure described in the first step of Example 53 of the present invention was repeated, except that the compound obtained in Example 47 was 2- ⁇ 4-[3-chloro-4-(pyridine-2-methoxy)-phenylamino] -quinazolin-6-yl ⁇ -6,7-dihydro-2H-pyrano[3,4-c]pyrrole-4-one 47 as starting material, the same as described in the first step of Example 53 of the present invention
  • the reaction of the starting material with 2-morpholin-4-yl-ethylamine afforded the title compound 1- ⁇ 4-[3-chloro-4-(pyridine-2-methoxy)-phenylamino]-quinazole
  • Phenyl-6-yl ⁇ -4-(2-hydroxy)-1H-pyrrole-3-carboxylic acid-(2-morpholin-4-ethyl)-carboxamide 54 (110 mg, yellow Color solid), Yield: 87.3 %.
  • Example 47 The experimental procedure described in the first step of Example 53 of the present invention was repeated, except that the compound obtained in Example 47 was 2- ⁇ 4-[3-chloro-4-(pyridine-2-methoxy)-phenylamino] -quinazolin-6-yl ⁇ -6,7-dihydro-2H-pyrano[3,4-c]pyrrolidin-4-one 47 as the starting material, the same as described in the first step of Example 53 of the present invention
  • the reaction of the starting material with 2-methoxyethylamine afforded the title compound 1- ⁇ 4-[3-chloro-4-(pyridine-2-methoxy)-phenylamino]-quinazoline-6- 4-(2-light-based)-1H-pyrrole-3-carboxylic acid-(2-methoxyethyl)-carboxamide 55 (110 mg, yellow solid).
  • Example 47 The experimental procedure described in the first step of Example 53 of the present invention was repeated, except that the compound obtained in Example 47 was 2- ⁇ 4-[3-chloro-4-(pyridine-2-methoxy)-phenylamino] -quinazolin-6-yl ⁇ -6,7-dihydro-2H-pyran [3,4-c] Pyrrole-4-one 47 was used as a starting material, and the title compound was reacted with 2-(4-methyl-piperazin-1-yl)-ethylamine in the same manner as in the first step of Example 53 to obtain the title.
  • Example 47 The experimental procedure described in the first step of Example 53 of the present invention was repeated, except that the compound obtained in Example 47 was 2- ⁇ 4-[3-chloro-4-(pyridine-2-methoxy)-phenylamino] -quinazolin-6-yl ⁇ -6,7-dihydro-2H-pyrano[3,4-c]pyrrolidin-4-one 47 as the starting material, the same as described in the first step of Example 53 of the present invention
  • the reaction of the starting material with 3 -morpholin-4-yl-propylamine afforded the title compound 1- ⁇ 4-[3-chloro-4-(pyridine-2-methoxy)-phenylamino]-quinazoline -6-yl ⁇ -4-(2-hydroxy)-1H-pyrrole-3-carboxylic acid-(3-morpholin-4-propyl)-amide 57 (90 mg, yellow solid), yield 88%.
  • Example 47 The experimental procedure described in the first step of Example 53 of the present invention was repeated, except that the compound obtained in Example 47 was 2- ⁇ 4-[3-chloro-4-(pyridine-2-methoxy)-phenylamino] -quinazolin-6-yl ⁇ -6,7-dihydro-2H-pyrano[3,4-c]pyrrolidin-4-one 47 as the starting material, the same as described in the first step of Example 53 of the present invention
  • the reaction of the starting material with morpholine gave the title compound 1- ⁇ 4-[3-chloro-4-(pyridine-2-methoxy)-phenylamino]-quinazolin-6-yl ⁇ -4- (2-Hydroxy)-1H-pyrrol-3-yl]-morpholin-4-methanone 58 (230 mg, white solid), yield: 98.2%.
  • MS m/z (ESI) 584 [M-1]
  • Example 47 The experimental procedure described in the first step of Example 53 of the present invention was repeated, except that the compound obtained in Example 47 was 2- ⁇ 4-[3-chloro-4-(pyridine-2-methoxy)-phenylamino] -quinazolin-6-yl ⁇ -6,7-dihydro-2H-pyrano[3,4-c]pyrrolidin-4-one 47 as the starting material, the same as described in the first step of Example 53 of the present invention
  • the reaction of the starting material with 1-methylpiperazine gave the title compound 1- ⁇ 4-[3-chloro-4-(pyridine-2-methoxy)-phenylamino]-quinazoline- 6 -yl ⁇ _4-(2-Hydroxy)-1H-pyrrol-3-yl]-(4-methyl-piperazine-1-yl)-methanone 59 (100 mg, brown oil), yield: 95%.
  • Example 47 The experimental procedure described in the first step of Example 53 of the present invention was repeated, except that the compound obtained in Example 47 was 2- ⁇ 4-[3-chloro-4-(pyridine-2-methoxy)-phenylamino] -quinazolin-6-yl ⁇ -6,7-dihydro-2H-pyrano[3,4-c]pyrrolidin-4-one 47 as the starting material, the same as described in the first step of Example 53 of the present invention
  • the reaction of the starting material with pyrrolidine afforded the title compound 1- ⁇ 4-[3-chloro-4-(pyridine-2-methoxy)-phenylamino]-quinazoline-6-yl ⁇ -4- (2-Hydroxy)-1H-pyrrol-3-yl]-pyrrolidin-1-one 60 (170 mg, gray solid), yield 95%.
  • Example 51 The experimental procedure described in Example 51 of the present invention was repeated, except that the compound obtained in Example 42 [3-chloro-4-(pyridine-2-methoxy)-phenyl]-(6-pyrrol-1-yl) - quinazolin-4-yl)-amine 42 as a starting material, the reaction of the starting material with 1-(2-chloroethyl)-pyrrole in the manner described in Example 51 afforded the title product. Chloro-4-(3-fluoro-benzyloxy)phenyl]- ⁇ 6-[1-(2-pyrrole-1-yl-ethyl)-1 ⁇ -pyrrol-3-yl]-quinazoline- 4-yl ⁇ -amine (30 mg, yellow solid), Yield: 35.9%
  • Example 51 of the present invention The experimental procedure described in Example 51 of the present invention was repeated, except that the compound obtained in Example 42 [3-chloro-4-(pyridine-2-methoxy)-phenyl]-(6-pyrrol-1-yl) -quinazolin-4-yl)-amine 42 as a starting material, the starting material and 1-(3-chlorophenyl)-4-(3-chloropropyl)-peri Reaction of the azine to give the title product [3-chloro-4-(3-fluorobenzyloxy)-phenyl]-[6-(1- ⁇ 3-[4-(3-chlorophenyl)-piperazine -1-yl]-propyl ⁇ -1 ⁇ -pyrrol-3-yl)-quinazolin-4-yl]-amine (32 mg, yellow solid), Yield: 20.9%.
  • the compound obtained in the above step is 1- ⁇ 4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazolin-6-yl ⁇ -4-trifluoromethyl-1H-pyrrole 3-carboxylic acid 67f (278 mg 0.5 mmol), triethylamine (76 mg, 0.75 ol) was dissolved in 2 mL of tetrahydrofuran, and azide diphenyl diphenyl ester (151 mg 0.55 mmol) was added with stirring. After stirring at room temperature for 7 hours, the reaction was completed. The reaction mixture was extracted with ethyl acetate (30 mL ⁇ 3).
  • the compound obtained by the above-mentioned step is 1- ⁇ 4-[4-(3-fluorobenzyloxy)-3-chlorophenylamino]-quinazolin-6-yl ⁇ -4-trifluoromethyl-1H-pyrrole 3-azido-methanone 67g ( 1.37 g, 2.35 mmol) was dissolved in 75 mL of toluene. The resulting yellow suspension was heated at an external bath temperature of 130 ° C. After 3 hours, tert-butanol (15 mL) was added.
  • Example 53 of the present invention The experimental procedure described in the first step of Example 53 of the present invention was repeated, except that the compound obtained in Example 47 was 2- ⁇ 4-[3-chloro-4-(pyridine-2-methoxy)-phenyl chloride. - quinazolin-6-yl ⁇ -6,7-dihydro-2H-pyrano[3,4-c]pyrrolidin-4-one 47 as a starting material, according to the first step of Example 53 of the present invention
  • the reaction of the starting material with piperidine gave the title compound [1- ⁇ 4-[3-chloro-4-(pyridine-2-methoxy)-phenylamino]-quinazoline-6-yl ⁇ - 4-(2-Hydroxyethyl)-1H-pyrrol-3-yl]-piperidin-1-one 78 (100 mg, m. MS m/z (ESI): 584 [M+ 1]
  • Example 61 of the present invention The experimental procedure described in the first step of Example 61 of the present invention was repeated, except that the compound [1- ⁇ 4-[3-chloro-4-(pyridine-2-methoxy)-benzene obtained in Example 68 was obtained.
  • the starting material was reacted with lithium aluminum hydride in the same manner as described to give the title compound 2-(1- ⁇ 4-[3-chloro-4-(pyridine-2-methoxy)-phenylamino]-quinazoline.
  • -6-yl 4-piperidin-1-methyl-1H-pyrrol-3-yl)-ethanol 69 (150 mg, brown solid), yield: 40%. .
  • the compound obtained in the above experiment was 5- ⁇ 4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazolin-6-yl ⁇ -111-pyrrole-2-carboxylic acid 72a ( 49 mg, O.lmmol), dichlorosulfoxide (60 mg, 0.5 mmol) dissolved in 5 mL of dichloromethane, heated to reflux for 1 hour, cooled to room temperature, then [1,4']dipiperidine (33.6 mg) , 0.2 mmol) of 5 mL of dichloromethane solution, the resulting mixture was stirred at room temperature for 2 hours and the reaction was completed.
  • Example 66 The experimental procedure described in the first step to the third step of Example 66 of the present invention was repeated, except that the compound obtained in Example 66 was 2- ⁇ 4-[3-methyl-4-(6-methyl-pyridine- 3-oxo)-phenylamino]-quinazolin-6-yl ⁇ -6,7-dihydro-2H-pyrano[3,4-c]pyrrol-4-one 66b as starting material, in accordance with the invention
  • Example 47 The experimental procedure described in the first step of Example 53 of the present invention was repeated, except that the compound obtained in Example 47 was 2- ⁇ 4-[3-chloro-4-(pyridine-2-methoxy)-phenylamino] -quinazolin-6-yl ⁇ -6,7-dihydro-2H-pyrano[3,4-c]pyrrolidin-4-one 47 as the starting material, the same as described in the first step of Example 53 of the present invention
  • the reaction of the starting material with 2-pyrrole-1-yl-ethylamine afforded the title compound 1- ⁇ 4-[3-chloro-4-(pyridine-2-methoxy)-phenylamino]-quinazole
  • Example 47 The experimental procedure described in the first step of Example 53 of the present invention was repeated, except that the compound obtained in Example 47 was 2- ⁇ 4-[3-chloro-4-(pyridine-2-methoxy)-phenylamino] -quinazolin-6-yl ⁇ -6,7-dihydro-2H-pyrano[3,4-c]pyrrolidin-4-one 47 as the starting material, the same as described in the first step of Example 53 of the present invention
  • the reaction of the starting material with 2-piperidin-1-yl-ethylamine afforded the title compound 1- ⁇ 4-[3-chloro-4-(pyridine-2-methoxy)-phenylamino]-quinazoline ——6-yl ⁇ -4-(2-hydroxyethyl)-1 ⁇ -pyrrole-3-carboxylic acid (2-piperidin-1-ethyl)-amide 75 (70 mg, brown solid), yield 56.0 %.
  • Example 61 of the present invention The experimental procedure described in the first step of Example 61 of the present invention was repeated, except that the compound obtained in Example 60- ⁇ 4-[3-chloro-4-(pyridine-2-methoxy)-phenylamino]- Quinazoline-6-yl ⁇ -4--4-(2-hydroxy)-1H-pyrrol-3-yl]-pyrrolidin-1-one 60 as a starting material, according to the first step of Example 61 of the present invention
  • the starting material is reacted with lithium aluminum hydride in the same manner to give the title compound 2-(1- ⁇ 4-[3-chloro-4-(pyridine-2-methoxy)-phenylamino]- Quinazoline-6-yl ⁇ -4-pyrrolidine small methyl-1 ⁇ -pyrrol-3-yl)-ethanol 76 (30 mg, brown solid), Yield: 44 %
  • Example 77 The experimental procedure described in the first step to the third step of Example 77 of the present invention was repeated, except that the compound obtained in Example 77 was 2-[4-(1-phenylethylamino)-quinazolin-6-yl] -6,7-Dihydro-2H-pyrano[3,4-c]pyrrol-4-one 77b as a starting material, in the same manner as described in the third step of Example 77 of the present invention, the starting material and pyrrolidine
  • Example 77 The experimental procedure described in the first step to the third step of Example 77 of the present invention was repeated, except that the compound obtained in Example 77 was 2-[4-(1-phenylethylamino)-quinazolin-6-yl] -6,7-Dihydro-2H-pyrano[3,4-c]pyrrol-4-one 77b is used as a starting material in the same manner as described in the third step of Example 77 of the present invention.
  • Example 51 The experimental procedure described in Example 51 of the present invention was repeated, except that the compound obtained in Example 42 [3-chloro-4-(pyridine-2-methoxy)-phenyl]-(6-pyrrol-1-yl) - quinazolin-4-yl)-amine 42 as a starting material, the material was reacted with 1-chloro-2-methoxyethane in the manner described in Example 51 to give the title product [3-chloro] 4-(3-fluorobenzyloxy)-phenyl]- ⁇ 6-[1-(2-methoxyethyl)-1H-pyrrol-3-yl]-quinazolin-4-ylamine 85 ( lOO mg, yellow solid), Yield: 20%
  • Example 51 of the present invention The experimental procedure described in Example 51 of the present invention was repeated, except that the compound obtained in Example 42 [3-chloro-4-(pyridine-2-methoxy)-phenyl]-(6-B ratio- 1-Base-quinazolin-4-yl)-amine 42 was used as a starting material, and the reaction of the material with 1-(2-chloroethyl)-morpholine hydrochloride was carried out in the same manner as described in Example 51.
  • Example 72 The experimental procedure of the first step to the second step of Example 72 of the present invention was repeated, except that the compound obtained in the first step of Example 72 was 5- ⁇ 4-[3-chloro-4-(3-fluorobenzyloxy). - phenylamino]-quinazolin-6-yl ⁇ -111-pyrrole-2-carboxylic acid 72a as a starting material, the starting material and 2-morpholin-4- in the manner described in the second step of Example 72 base- Reaction of ethylamine to give the title product 5- ⁇ 4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazolin-6-yl ⁇ -111-pyrrole-2-carboxylic acid -(2-morpholin-4-ethyl)-amide 87 (20 mg, white solid), Yield: 33%.
  • Example 61 of the present invention The experimental procedure described in the first step of Example 61 of the present invention was repeated, except that the compound obtained in Example 58 was 1- ⁇ 4-[3-chloro-4-(pyridine-2-methoxy)-phenylamino. - quinazolin-6-yl ⁇ -4--4-(2-hydroxy)-1H-pyrrol-3-yl]-morpholin-4-methanone 58 as a starting material, according to Example 61 of the present invention The starting material was reacted with lithium aluminum hydride in the same manner as described to give the title compound 2-(1- ⁇ 4-[3-chloro-4-(pyridine-2-methoxy)-phenylamino]-quinazoline. -6-yl 4-morpholin-4-methyl-1H-pyrrol-3-yl)-ethanol 88 (30 mg, brown solid), yield: 44%.
  • Example 77 The experimental procedure described in the first step to the third step of Example 77 of the present invention was repeated, except that the compound obtained in Example 77 was 2-[4-(1-phenylethylamino)-quinazolin-6-yl] -6,7-Dihydro-2H-pyrano[3,4-c]pyrrol-4-one 77b is used as a starting material to make the starting material and morpholine in the same manner as described in the third step of Example 77 of the present invention.
  • Example 77 The experimental procedure described in the first step to the third step of Example 77 of the present invention was repeated, except that the compound obtained in Example 77 was 2-[4-(1-phenylethylamino)-quinazolin-6-yl] -6,7-Dihydro-2-indole-pyrano[3,4-c]pyrrol-4-one 77b as a starting material, in the same manner as described in the third step of Example 77 of the present invention, the starting material and 1-A Reaction of the piperazine gives the title compound ⁇ 4-(2-hydroxyethyl)-1-[4-(1-phenylethylamino)-quinazolin-6-yl]-1H-pyrrol-3-yl ⁇ - (4-methyl-piperazine small group)-methanone 90 (130 mg, yellow solid), Yield: 34%.
  • Example 91 of the present invention The experimental procedure described in the first step of Example 91 of the present invention was repeated, except that the compound obtained in Example 78 was ⁇ 4-(2-hydroxyethyl) small [4-(1-phenylethylamino)-quinazoline. -6-yl]-indolyl-pyrrol-3-ylpyrrole-1-one 78 as a starting material, which was reacted with lithium aluminum hydride in the same manner as described in the first step of Example 90 of the present invention to give the title compound.
  • Example 77 The experimental procedure described in the first step to the third step of Example 77 of the present invention was repeated, except that the compound obtained in Example 77 was 2-[4-(1-phenylethylamino)-quinazolin-6-yl. -6,7-Dihydro-2H-pyrano[3,4-c]pyrrol-4-one 77b as a starting material, which is obtained in the same manner as described in the third step of Example 77 of the present invention.
  • Example 77 The experimental procedure described in the first step to the third step of Example 77 of the present invention was repeated, except that the compound obtained in Example 77 was 2-[4-(1-phenylethylamino)-quinazolin-6-yl] -6,7-Dihydro-2H-pyrano[3,4-c]pyrrol-4-one 77b as a starting material, in the same manner as described in the third step of Example 77 of the present invention, the starting material and 2-A Reaction of oxyethylamine to give the title compound 4-(2-hydroxyethyl)-1-[4-(1-phenylethylamino)-quinazolin-6-yl]-1H-pyrrole-3-carboxylic acid -(2-methoxyethyl)-amide 95 (50 mg, yellow solid), Yield: 28%.
  • Example 77 The experimental procedure described in the first step to the third step of Example 77 of the present invention was repeated, except that the compound obtained in Example 77 was 2-[4-(1-phenylethylamino)-quinazolin-6-yl] -6,7-Dihydro-2H-pyrano[3,4-c]pyrrol-4-one 77b as a starting material, in the same manner as described in the third step of Example 77 of the present invention, the starting material is 2- Reaction with morpholin-4-yl-ethylamine gave the title compound 4-(2-hydroxyethyl)-1-[4-(1-phenylethylamino)-quinazolin-6-yl]-1H-pyrrole- 3-carboxylic acid-(2-morpholin-4-ethyl)-amide 96 (85 mg, yellow solid), yield: 42.5%.
  • Example 77 of the present invention The experimental procedure described in the first to third steps of Example 77 of the present invention was repeated, except that the compound obtained in Example 77 was 2-[4-(1-phenylethylamino)-quinazolin-6-yl] -6,7-Dihydro-2H-pyrano[3,4-c]pyrrole-4-one 77b as a starting material, in the same manner as described in the third step of Example 77 of the present invention, the starting material is 2- Reaction with morpholin-4-yl-propylamine gave the title compound 4-(2-hydroxyethyl)-1-[4-(1-phenylethylamino)-quinazolin-6-yl]-1H-pyrrole-3 -carboxylic acid-(2-morpholin-4-propyl)-amide 97 (86 mg, yellow solid), yield: 42%.
  • Example 91 of the present invention The experimental procedure described in the first step of Example 91 of the present invention was repeated, except that the compound obtained in Example 90 was ⁇ 4-(2-hydroxyethyl)-1-[4-(1-phenylethylamino)-quinaline.
  • Oxazolin-6-yl]-1H-pyrrol-3-yl ⁇ -(4-methyl-piperazin-1-yl)-methanone 90 as the starting material the same as described in the first step of Example 91 of the present invention
  • the starting material was reacted with lithium aluminum hydride to give the title compound 2- ⁇ 4-(4methylpiperazin-1-methyl)-1-[4-(1-phenylethylamino)-quinazoline-6- -1H-pyrrol-3-yl ⁇ -ethanol 98 (90 mg, yellow solid), yield: 91%.
  • Example 47 The experimental procedure described in the first step of Example 53 of the present invention was repeated, except that the compound obtained in Example 47 was 2- ⁇ 4-[3-chloro-4-(pyridine-2-methoxy)-phenylamino] -quinazolin-6-yl ⁇ -6,7-dihydro-2H-pyrano[3,4-c]pyrrolidin-4-one 47 as the starting material, the same as described in the first step of Example 53 of the present invention
  • the reaction of the starting material with [1,4']dipiperidine gave the title compound [1,4']dipiperidinyl-fluorenyl-[1- ⁇ 4-[3-chloro-4-(pyridine) 2-methoxy)-phenylamino]-quinazolin-6-yl ⁇ -4-(2-hydroxyethyl)-1 ⁇ -pyrrole-3-yl]-methanone 99 (120 mg, yellow solid) , Yield: 43%.
  • Example 91 of the present invention The experimental procedure described in the first step of Example 91 of the present invention was repeated, except that the compound obtained in Example 89 was ⁇ 4-(2-hydroxyethyl)-1-[4-(1-phenylethylamino)- Quinazoline-6-yl]-1H-pyrrol-3-ylmorpholine-4-ketone 89 is used as a starting material to react the starting material with lithium aluminum hydride in the same manner as described in the first step of Example 91 of the present invention.
  • Example 81 The experimental procedure described in the first step to the second step of Example 81 of the present invention was repeated, except that the compound obtained in the first step of Example 81 was 2-[4-(3-chloro-4-fluoro-phenylamino)- Quinazoline-6-yl]-6,7-dihydro-2H-pyrano[3,4-c]pyrrolidin-4-one 81a as a starting material in the same manner as described in Example No.
  • Example 81 of Example 81 of the present invention The reaction of the material with 2-piperidine-1-ethylamine afforded the title compound 1-[4-(3-chloro-4-fluoro-phenylamino)-quinazolin-6-yl]-4-(2) - hydroxyethyl)-1 ⁇ -pyrrole-3-carboxylic acid-(2-piperidin-1-ethyl)-amide 103 (154 mg, yellow solid), yield: 65.14%.
  • Lithium aluminum hydride (581 mg, 15.3 mmol) was dissolved in 75 mL of tetrahydrofuran in a 250 mL eggplant-shaped flask, and the resulting solution was cooled to 0 ° C under ice-cooling, and the compound 1- ⁇ 4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl ⁇ -111-pyrrole-3,4-dicarboxydiethyl ester 112a ( 1.5 g , 2.55 mniol), the reaction was completed after 2 hours of keeping the ice bath reaction.
  • the compound obtained in the above step is 1- ⁇ 4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl ⁇ -1 ⁇ -pyrrole-3,4-di Formaldehyde 112c (100 mg, 0.2 mmol) was dissolved in 5 mL of dichloromethane and stirred Diethylamine (44 mg, 0.6 mmol) was added, and stirring was continued for 6 hr. then triacetoxyborohydride (170 mg, OS mmol) was added and stirred overnight.

Abstract

L'invention concerne des procédés de préparation de dérivés de quinazoline et leurs utilisations pharmaceutiques. En d'autres termes, l'invention concerne des composés de quinazoline représentés par les formules générales I,II,III, des tautomères, des énantiomères, des diastéréomères, des racèmes et des sels pharmaceutiquement acceptables de ceux-ci, ainsi que des métabolites, des précurseurs métaboliques ou des promédicaments de ceux-ci. L'invention concerne en outre leurs utilisations en tant qu'agents thérapeutiques et, en particulier, en tant qu'inhibiteurs de protéines kinases. Les définitions des substituants des formules générales I,II,III sont les mêmes que celles données dans la description.
PCT/CN2008/001307 2007-07-20 2008-07-14 Procédés de préparation de dérivés de quinazoline et leurs utilisations pharmaceutiques WO2009012647A1 (fr)

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WO2011041655A1 (fr) * 2009-10-01 2011-04-07 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Dérivés de la quinazolin-4-amine; et méthodes d'utilisation
WO2011073378A1 (fr) 2009-12-18 2011-06-23 Basilea Pharmaceutica Ag Antibiotiques tricycliques
WO2012171860A1 (fr) 2011-06-17 2012-12-20 Basilea Pharmaceutica Ag Antibiotiques tricycliques
JP2013510876A (ja) * 2009-11-13 2013-03-28 ジェノスコ キナーゼ阻害剤
US8916574B2 (en) 2009-09-28 2014-12-23 Qilu Pharmaceutical Co., Ltd. 4-(substituted anilino)-quinazoline derivatives useful as tyrosine kinase inhibitors
EP2740729A4 (fr) * 2011-08-01 2015-02-25 Hangzhou Minsheng Inst For Pharma Res Dérivé de quinazoline, composition pharmaceutique contenant le composé, et utilisation du dérivé dans la préparation d'un médicament
CN112479913A (zh) * 2020-11-19 2021-03-12 安徽修一制药有限公司 一种n,n-二乙基氯代乙酰胺的制备方法
US11034669B2 (en) 2018-11-30 2021-06-15 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof
WO2022140456A1 (fr) * 2020-12-22 2022-06-30 Mekanistic Therapeutics Llc Composés d'hétéroaryle d'aminobenzyle substitués utilisés en tant qu'inhibiteurs d'egfr et/ou de pi3k

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US8916574B2 (en) 2009-09-28 2014-12-23 Qilu Pharmaceutical Co., Ltd. 4-(substituted anilino)-quinazoline derivatives useful as tyrosine kinase inhibitors
WO2011041655A1 (fr) * 2009-10-01 2011-04-07 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Dérivés de la quinazolin-4-amine; et méthodes d'utilisation
JP2013510876A (ja) * 2009-11-13 2013-03-28 ジェノスコ キナーゼ阻害剤
WO2011073378A1 (fr) 2009-12-18 2011-06-23 Basilea Pharmaceutica Ag Antibiotiques tricycliques
WO2012171860A1 (fr) 2011-06-17 2012-12-20 Basilea Pharmaceutica Ag Antibiotiques tricycliques
EP2740729A4 (fr) * 2011-08-01 2015-02-25 Hangzhou Minsheng Inst For Pharma Res Dérivé de quinazoline, composition pharmaceutique contenant le composé, et utilisation du dérivé dans la préparation d'un médicament
US11034669B2 (en) 2018-11-30 2021-06-15 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof
CN112479913A (zh) * 2020-11-19 2021-03-12 安徽修一制药有限公司 一种n,n-二乙基氯代乙酰胺的制备方法
WO2022140456A1 (fr) * 2020-12-22 2022-06-30 Mekanistic Therapeutics Llc Composés d'hétéroaryle d'aminobenzyle substitués utilisés en tant qu'inhibiteurs d'egfr et/ou de pi3k
US11673876B2 (en) 2020-12-22 2023-06-13 Mekanistic Therapeutics Llc Substituted aminobenzyl heteroaryl compounds as EGFR and/or PI3K inhibitors

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