WO2009012647A1 - Preparation methods of quinazoline derivatives and their pharmaceutical uses - Google Patents

Preparation methods of quinazoline derivatives and their pharmaceutical uses Download PDF

Info

Publication number
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
Authority
WO
WIPO (PCT)
Prior art keywords
group
compound
aryl
carboxylic acid
heteroaryl
Prior art date
Application number
PCT/CN2008/001307
Other languages
French (fr)
Chinese (zh)
Inventor
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
Original Assignee
Shanghai Hengrui Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from CN 200810127622 external-priority patent/CN101367794B/en
Application filed by Shanghai Hengrui Pharmaceutical Co., Ltd. filed Critical Shanghai Hengrui Pharmaceutical Co., Ltd.
Publication of WO2009012647A1 publication Critical patent/WO2009012647A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • 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 %
  • the city of the city is called by the i lake 3 ⁇ 4* ⁇ 3 ⁇ 4 ek ⁇ : (1) ⁇ 9 ( ⁇ inch H) £------- ----- o
  • 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.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Diabetes (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Cardiology (AREA)
  • Endocrinology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Immunology (AREA)
  • Neurosurgery (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Preparation methods of quinazoline derivatives and their pharmaceutical uses. In another word, quinazoline compounds represented by general formulae I,II,III, tautomers, enantiomers, diastereomers, racemes and pharmaceutically acceptable salts thereof as well as metabolites, metabolic precursor or prodrug thereof. Their uses as therapeutical agents especially protein kinase inhibitors. The definitions of substituents of general formulae I,II,III are as same as those in the description.

Description

喹唑啉类衍生物的制备方法及其在医药上的应用 ' 技术领域  Preparation method of quinazoline derivatives and its application in medicine
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酶抑制剂的用途。 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 kinase 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 ΐί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. 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 ΐί white 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 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 致癌基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 kinase (PKS) 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. For example, a cell can become a cancer cell by converting a portion of its DNA into an oncogene, a growth factor receptor protein encoded by such an oncogene; a tyrosine kinase can also be mutated into an activated form resulting in a variety of Variations in human cells, it can be said that over-expressed normal tyrosine kinases 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—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 被识别， 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 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).
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（IRR) ) ； (3) III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)、 z ° 璲一著 ¾ ^ ^ w綱驗啄 著 导 伞¾¾¾ ¾¾¾i ^國 ¾ί 奢¾
Figure imgf000004_0001
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 ° 璲 3 3⁄4 ^ ^ w 啄 导 导 导 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
Figure imgf000004_0001
(MM OJS ZHS士^^ ^^ 著^^ ¾ 飆凝 (MM OJS ZHS士^^ ^^ 着^^ 3⁄4 飙凝
-i^^ ^ a m^m^ 纏凝 3¾¾凝¥1¾1棚 二 -i^^ ^ a m^m^ 凝凝 33⁄43⁄4凝¥13⁄41 shed two
sf¾ 互 ¾Η现睇 ¾te、l (：#¾) ^ R^^Ifs^id  Sf3⁄4 互 3⁄4te, l (:#3⁄4) ^ R^^Ifs^id
° ¾ 暴^  ° 3⁄4 暴^
攀^翁 (21^2086 V 9εε9086 ΟΛΛ ' |dd 丄 Od 1 Ή 'ωηη ¾f ) ^ff疆簟 ¾ (091-'89ε'2661- e琴 Ν '3 'J9|W!1 ¾¾ίΠ$¾ί¾ 、（LZS '91· 'Z661- Ί υηωωι ςζ -uuv 's66 g pue uspg ¾f#) WS^ M a ^^ ^ 、(Z89 82 '8661· '^θΐ/Ι dx3 匿 yd T uos|OBp '.opg£ 'gg '966 SQ^ Qoueo ^ UMBJIS  攀^翁(21^2086 V 9εε9086 ΟΛΛ ' |dd 丄Od 1 Ή 'ωηη 3⁄4f ) ^ff江簟3⁄4 (091-'89ε'2661- e琴Ν'3 'J9|W!1 3⁄43⁄4ίΠ$3⁄4ί3⁄4 , ( LZS '91· 'Z661- Ί υηωωι ςζ -uuv 's66 g pue uspg 3⁄4f#) WS^ M a ^^ ^ , (Z89 82 '8661· '^θΐ/Ι dx3 yd T uos|OBp '.opg£ 'gg '966 SQ^ Qoueo ^ UMBJIS
If ）^ ^葛 ^攀^ ' ^鼻 ί暴 、（8SZ'01^'S66t unLULUOQ setJ sAqdoig If )^ ^葛 ^攀^ ' ^鼻 ί暴 , (8SZ'01^'S66t unLULUOQ setJ sAqdoig
i o!g o v '。 ¾Γ ) ¾ί¾Ί|Πί IS 、（WH'S9S'066L  i o!g o v '. 3⁄4Γ ) 3⁄4ί3⁄4Ί|Πί IS , (WH'S9S'066L
S93=/ '!JBies ¾i # ) ^ (££6Z '9 '3661· 33SV=I 'ziuejsujod 0Z pue JBffBH (ε 9 '61 ' ββΙ ΙΙ^θ 'ssu!d pue J8junH ¾f#) ¾ i 、(8 S 'εδε '9661· '9零 N '翁 ^euei ¾f毒) ¾¾?¾r兽^^攀^璣善 (Z98 'ει^ ^66t Ί !3Ι/ΘΟ 'J!Aa ¾Γ#) 、(£S1^ '61Ζ '9661. · 丄 "d g画 ec/d  S93=/ '!JBies 3⁄4i # ) ^ (££6Z '9 '3661· 33SV=I 'ziuejsujod 0Z pue JBffBH (ε 9 '61 ' ββΙ ΙΙ^θ 'ssu!d pue J8junH 3⁄4f#) 3⁄4 i , ( 8 S 'εδε '9661· '9零N '翁^euei 3⁄4f毒) 3⁄43⁄4?3⁄4r beast ^^攀^玑善(Z98 'ει^ ^66t Ί !3Ι/ΘΟ 'J!Aa 3⁄4Γ#) , (£ S1^ '61Ζ '9661. · 丄"dg draw ec/d
T 'jeBpBgii )
Figure imgf000004_0002
'SL '9661· f SomsN T X '|edqseA¾f 攀)灘 、(66' ipo!g //3。 '剛 V 'Bidn6u9s ' Ζ 'ΖββΙ Π T 'jeBpBgii )
Figure imgf000004_0002
'SL '9661· f SomsN TX '|edqseA3⁄4f Climb) Beach, (66' ipo!g //3. 'Just V 'Bidn6u9s ' Ζ 'ΖββΙ Π
'ΙΛΙ ·3 'MO i|spuB|A| ^^ ^^W ^^M^ s ld ¥ 丫 ° O dez tl ss人 '^-d03A'm-d93A 'Ζ61Π 'εΠΠ '〇 !·"丄 ' Ι 丄 ' θ!ϊ '2>Ι人 d '9SBUi>| θ^ϋ-oiod >nd 'zC Hd ' JQMd 'I0>ld '6〇 1d '30>ld'ΙΛΙ ·3 'MO i|spuB|A| ^^ ^^W ^^M^ s ld ¥ 丫° O dez tl ss人'^-d03A'm-d93A 'Ζ61Π 'εΠΠ '〇!·"丄' Ι ' θ!ϊ '2>Ι人 d '9SBUi>| θ^ϋ-oiod >nd 'zC Hd ' JQMd 'I0>ld '6〇1d '30>ld
'po id 'qo>id 'e〇>id 'o id 'ea>id ' a>id a>id ' id 'ddoad 'ssd 'z^an'po id 'qo>id 'e〇>id 'o id 'ea>id ' a>id a>id ' id 'ddoad 'ssd 'z^an
' 1-Ή3ΙΛΙ '>13ΙΛΙ 'u入， '蕭 'ΉΝΓ 'SWr '2 「 ' W ' Γ '9seui> ps)u!|-u!j63}U| oi' 1-Ή3ΙΛΙ '>13ΙΛΙ 'u, '萧'ΉΝΓ 'SWr '2 ' ' W ' Γ '9seui> ps)u!|-u!j63}U| oi
'y-sNi 'ε>ι>ιι 'Ζ ΙΉΙ >I>U 'ΉΉΙ ' i-d〇i ' -md Ίχν ' MO 'ΨΗ 'qe^sB 'B SB '>ISO 'uAj '>iJd 'sdj ->ιυ 'JBJ 'gyjod yd9d 'cydOJ ' ddOd '^JOJ 's ">IBJ
Figure imgf000004_0003
'[.>ΙΗ3 'Myg aqj3 'ΒΘΨΞ 'ZQQJB ' JOB OJS-O 'HSO ' IJSO 'y-sNi 'ε>ι>ιι 'Ζ ΙΉΙ >I>U 'ΉΉΙ ' id〇i ' -md Ίχν ' MO 'ΨΗ 'qe^sB 'B SB '>ISO 'uAj '>iJd 'sdj -> Υυ 'JBJ 'gyjod yd9d 'cydOJ ' ddOd '^JOJ 's ">IBJ
Figure imgf000004_0003
'[.>ΙΗ3 'Myg aqj3 'ΒΘΨΞ 'ZQQJB ' JOB OJS-O 'HSO ' IJSO
'"eyo
Figure imgf000004_0004
'ΉΗΟ '6>{00'"eyo
Figure imgf000004_0004
'ΉΗΟ '6>{00
'8»αο Υ>ιαο '9>ιαο '9Ήαο Ήαο 'ε»αο '3>ιαο >ιαο ¾a '^a '^yg 旧 ς'8»αο Υ>ιαο '9>ιαο '9Ήαο Ήαο 'ε»αο '3>ιαο >ιαο 3⁄4a '^a '^yg Old ς
'i e-Joq 'lAliV '>LLV 'IQV 飆凝 ¾陴 11非^^― ° '6 'Ζ661· uojnsN 'i e-Joq 'lAliV '>LLV 'IQV 飙凝3⁄4陴 11非^^― ° '6 'Ζ661· uojnsN
' ο ΐΙΠ pue 」s6u!sss|L s 1Γ#) 夥^^ ^ K睇^ 爾晦 tt H^^  ' ο ΐΙΠ pue 》s6u!sss|L s 1Γ#) 伙^^ ^ K睇^ 尔晦 tt H^^
( ikjso) I· H凝陣: ¾奪！ ¾賴凝邈g§i ^ (εϊυ) ε纏凝邈 ^邇^ & -SL^ ( ikjso) I· H Condensation: 3⁄4 win! 3⁄4赖凝邈g§i ^ (εϊυ) ε wrapped in 邈 ^迩^ & -SL^
Z.0£l00/800iN3/X3d Z.f9ZlO/600i OAV 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， 此步 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。 Z.0£l00/800iN3/X3d Z.f9ZlO/600i OAV 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. 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^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. Through the detection of human tumor cells, the broadness and relevance of tyrosine kinases have been further confirmed. For example: In human cancers including lung cancer, brain cancer, cervical cancer, gastrointestinal cancer, breast cancer, esophageal cancer, ovarian cancer, uterine cancer, bladder cancer, and thyroid cancer, EGFR tyrosine kinases are mutated and overexpressed.
"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：!聚合可通过与 heregulin (也叫 neyregulin) 家族配体的 结合被加速。虽然 HER3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. Heterotypes:! Polymerization can be accelerated by binding to the heregulin (also known as neyregulin) family of ligands. Although 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. 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 phosphatidylcholines 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-1 R) , 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-1 R), and the insulin receptor-related receptor (IRR). IR, 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.
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。  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.
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。 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. 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, prodryolyzed carcinoma, sarcoma and glioma cells, of which brain tumors, Prostate cancer (including adenocarcinoma and bone metastases) Research data on malignant gliosis 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， J. 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。 GIST源于 Cajal 间质细胞 （ICC) , 1CC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 Schutte 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^ 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))。  c-Kit is a member of the PDGF receptor family and is activated when it binds to the ligand SCF (stem cell factor). The c-Kit expression pattern was studied in various solid tumors, and c-Kit was overexpressed in sarcoma, gastrointestinal glioma (GIST), seminoma and carcinoid tumors. [See Weber et al, J. Clin. Oncol. 22 (14S), 9642 (2004)]. GIST is a non-epithelial cell tumor, most of which is found in the stomach, a few in the small intestine, rarely in the esophagus, but also in the liver, peritoneal cavity and other parts. GIST is derived from Cajal interstitial cells (ICC), which 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. In the cases of distorted mast cell tumor, mast cell proliferative disease, myeloproliferative syndrome, urticaria and other diseases, c-Kit expression can also be detected, and c-Kit expression is also found in acute AML and malignant lymphoma, in small cells. Bronchial carcinoma, seminoma, dysgerminoma, testis, intraepithelial neoplasia, melanoma, breast cancer, neuroblastoma, Ewing's sarcoma have c-Kit expression (see Schutte et al., innovartis 3) /2001). It is well known that RET (rearranged during transfection). Proto-oncogene 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)).
因胎肝激酶（Hk)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-1R, Flk-4和 fms 样酪氨酸激酶 1 (Flt-1)所组成。  Because the fetal liver kinase (Hk) receptor subfamily is very similar to the PDGFR subfamily, it is sometimes attributed to this family. This subfamily consists of a kinase-containing insertion domain-receptor fetal liver kinase-1 (KDR/FLK-1, VEGFR2), Flk-1R, Flk-4 and fms-like tyrosine kinase 1 (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 cycloglycosylation 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， 具有剌激体内血管内皮细胞中的的生成活性一些多肽已经被确认， 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，都是非常重要的刺激剂。 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 is strongly expressed in various malignant solid tumors such as lung cancer, breast cancer, non-Hodgkin's malignant lymphoma, ovarian cancer, pancreatic cancer, malignant pleural mesothelioma, and melanoma, and is associated with the progression of cancer, in white blood cells. Excessive symptoms and lymphoma are also expressed. In addition to its angiogenic activity, VEGFR, VEGF ligands can also promote tumor growth by directly pro-survival properties in tumor cells, and PDGF also has an angiogenic effect. The process of neovascularization plays a key role in the continued growth of the tumor. Under normal circumstances, the formation of new blood vessels in human physiological processes such as embryo growth, The various processes of wound healing and female reproduction are very important. However, unanticipated or pathological angiogenesis is associated with a range of conditions of the disease, such as diabetic retinopathy, psoriasis, cancer, rheumatoid arthritis, atheroma, Kaposi's sarcoma and hemangioma. Wait. The production of vascular endothelial cells activates angiogenesis, and has been shown to stimulate the production of vascular endothelial cells in vivo. Some peptides have been identified, including acidic, basic fibroblast growth factor (aFGF and bFGF) and vascular endothelial growth factor. Due to the restricted expression of the VEGF receptor, its growth factor activity is relatively specific to endothelial cells compared to aFGF and bFGF activity. Recent evidence suggests that VEGF is a very important stimulator during angiogenesis and vascular infiltration in both normal and pathological conditions. VEGF 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 form 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)酪氨酸激酶与肿瘤 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; Mau!ik, G.等（2002b). Cytokine Growth Factor 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 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).
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 D/V&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。  With regard to the PKT subfamily, Plowman et al. are described in more detail in D/V & P 7(6): 334-339 (1994), which 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 iBolen, 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 most, including Src, Yes,. Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk, and Src subfamily enzymes and tumorigenesis have turn off. For a more detailed description of CTKs, see iBolen, 1993, Oncogen 8: 2025-2031, the entire disclosure of which is incorporated herein by reference in its entirety herein in
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 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.
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 process 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中的一种或考多种，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), and 'cytoplasmic PTKs (CTKs). And cytosol 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 treating and improving mediated by PTKs, CTKs or STKs and angiogenesis. Hyperproliferative 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 示的新的喹唑啉类化合物， 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 quinazoline compounds of the formulae I, II and III, and their tautomers, enantiomers, non- Enantiomers, racemates and pharmaceutically acceptable salts, as well as metabolites and metabolic precursors or prodrugs.
Figure imgf000008_0001
其中-
Figure imgf000008_0001
among them-
R1选自垸基、 杂环烷基、 芳基或杂芳基、 其中垸基、 杂环烷基、 芳基或杂芳 基可以进一步被一个或多个选自烷基、 卤素、 芳基、 羟基、 氨基、 炔基、 烯基、 氰基、 硝基、 三氟甲基、 卤代苄基、 杂环烷基、 羧酸或羧酸酯的取代基所取代； 其中芳基或杂芳基可以并成双环， 此双环可以进一步被苄基或卤代苄基所取代； 或者 R1为结构式：
Figure imgf000009_0001
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. Substituted with a substituent of a hydroxy, amino, alkynyl, alkenyl, cyano, nitro, trifluoromethyl, halobenzyl, heterocycloalkyl, carboxylic acid or carboxylic acid ester; Wherein the aryl or heteroaryl group may be combined into a bicyclic ring which may be further substituted by a benzyl or halobenzyl group; or R 1 is a structural formula:
Figure imgf000009_0001
其中- among them-
Β选自芳基或杂芳基， 其中芳基或杂芳基可以进一步被一个或多个选自烷基、 卤素、 芳基、 羟基、 氨基、 炔基、 烯基、 氰基、 硝基、 三氟甲基、 卤代苄基、 杂 环烷基、 羧酸或羧酸酯的取代基所取代； 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;
Τ选自 -0(CH2)r-， -N(CH2)r-或 -S(CH2)r; Τ is selected from -0(CH 2 )r-, -N(CH 2 )r- or -S(CH 2 )r ;
L选自芳基或杂芳基， 其中芳基或杂芳基可以进一步被一个或多个卤素或烷基 所取代； '  L is selected from aryl or heteroaryl, wherein the aryl or heteroaryl may be further substituted by one or more halogen or alkyl;
R2选自氢原子、 烷基、 环垸基、 三氟甲基、 杂环烷基、 芳基、 杂芳基、 芳烷 基， 其中烷基、 环烷基、 杂环垸基、 芳基、 杂芳基、 芳垸基进一步被一个或多个 选自烷基、 芳基、 羟基、 卤素、 氨基、 氰基、 垸氧基、 羧酸、 羧酸酯或 -NR6R7的 取代基所取代； 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
R3和 R4各自独立地选自氢原子、 烷基、 三氟甲基、 环烷基、 杂环烷基、 芳基、 羧酸酯、 -S02R6、 -CH2C(=0)NR6R7、 -C(=0)NR6R7、 -(CH2)nNR6R7或 -NC (=0) R6, 其中垸基、 环垸基、 杂环烷基进一步被一个或多个选自烷基、 卤素、 三氟甲基、 芳基、 羟基、 烷氧基、 芳氧基、 环烷基、 杂环烷基、 杂芳基、 杂环烷氧基、 氰基、 羧酸、 羧酸酉旨、 -S02R6、 或 -(C¾)n R6R7的取代基所取代； R 3 and R 4 are each independently 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 carboxylic acid ester, -S0 2 R 6 , -CH 2 C (=0 NR 6 R 7 , -C(=0)NR 6 R 7 , -(CH 2 )nNR 6 R 7 or -NC (=0) R 6 , wherein fluorenyl, cyclodecyl, heterocycloalkyl is further One or more selected from the group consisting of alkyl, halogen, trifluoromethyl, aryl, hydroxy, alkoxy, aryloxy, cycloalkyl, heterocycloalkyl, heteroaryl, heterocycloalkoxy, cyano Substituting a carboxylic acid, a carboxylic acid, a substituent of -S0 2 R 6 , or -(C3⁄4)n R 6 R 7 ;
同时， R3和 R4—起形成一个 4〜8元环基； 其中 5〜8元杂环内含有一个或多 个>1、 0、 S原子， 并且 4〜8元杂环上进一步被一个或多个选自烷基、 卤素、 芳 基、 杂芳基、 卤代烷基、 卤代烷氧基、 羟基、 烷氧基、 芳氧基、 羰基、 杂环烷基、 羧酸、 羧酸酯、 =N-OR6或 -NR6R7的取代基所取代； Meanwhile, 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 of >1, 0, S atoms, and the 4 to 8 membered heterocyclic ring is further subjected to a Or a plurality selected from the group consisting of alkyl, halogen, aryl, heteroaryl, haloalkyl, haloalkoxy, hydroxy, alkoxy, aryloxy, carbonyl, heterocycloalkyl, carboxylic acid, carboxylic acid ester, =N Substituted by a substituent of -OR 6 or -NR 6 R 7 ;
R5选自氢原子、 烷基、 环烷基、 -C(=0)OR6， 其中烷基或环烷基进一步被一个 或多个选自烷基、 羟基、 垸氧基、 氰基、 -NR6R7、 羧酸或羧酸酯所取代； R 5 is selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, -C(=0)OR 6 , wherein the alkyl group or the cycloalkyl group is further further selected from one or more selected from the group consisting of an alkyl group, a hydroxyl group, a decyloxy group, and a cyano group. -NR 6 R 7 , substituted with a carboxylic acid or a carboxylic acid ester;
R6和 R7分别选自氢原子、 烷基、 烯基、 环垸基、 杂环烷基、 芳基或杂芳基， 其中垸基、 烯基、 环烷基、 杂环烷基、 芳基或者杂芳基进一步被一个或多个选自 烷基、环烷基、卤素、芳基、羟基、氨基、垸氧基、烯基、杂环垸基、羟烷基、 -S02R6, -C(=0) 6, 羧酸、 羧酸酯或 - NR6R7的取代基所取代； 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. Further, the hetero or heteroaryl group is further selected from one or more selected from the group consisting of alkyl, cycloalkyl, halogen, aryl, hydroxy, amino, decyloxy, alkenyl, heterocycloalkyl, hydroxyalkyl, -S0 2 R 6 , -C(=0) 6 , substituted with a carboxylic acid, a carboxylic acid ester or a substituent of -NR 6 R 7 ;
同时， R6和 R7—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选自烷基、 卤素、 芳基、 杂芳基、 卤代芳基、 卤代垸氧基、 氨基、 羟基、 氰基、 烷氧基、 芳氧基、 胺烷基、羟烷基、环烷基、杂环烷基、羰基、羧酸、羧酸酯、 -C(=0)NR6R7, -NC (=0) R6、 -S02R6、 或 -NR6R7的取代基所取代； Meanwhile, R 6 and R 7 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 a Or a plurality selected from the group consisting of alkyl, halogen, aryl, heteroaryl, haloaryl, halomethoxy, amino, hydroxy, cyano, alkoxy, aryloxy, alkoxyalkyl, hydroxyalkyl , cycloalkyl, heterocycloalkyl, carbonyl, carboxylic acid, carboxylic acid ester, -C(=0)NR 6 R 7 , -NC (=0) R 6 , -S0 2 R 6 , or -NR 6 R Substituted by a substituent of 7 ;
n是。〜 6;  n is. ~ 6;
r是 0〜2。 具体地， 本发明包括下述通式 (I)表示的化合物或其盐: r is 0~2. Specifically, the present invention includes a compound represented by the following formula (I) or a salt thereof:
Figure imgf000010_0001
Figure imgf000010_0001
(I)  (I)
其中-among them-
R1选自垸基、 杂环烷基、 芳基或杂芳基， 其中垸基、 杂环垸基、 芳基或杂芳 基可以进一步被一个或多个选自垸基、 卤素、 芳基、 羟基、 氨基、 炔基、 烯基、 氰基、 硝基、 三氟甲基、 卤代苄基、 杂环烷基、 羧酸或羧酸酯的取代基所取代； 其中芳基或杂芳基可以并成双环， 此双环可以进一步被一个苄基或卤代苄基所取 代； 或者 R1为结构式： T 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. Substituted by a substituent of a hydroxy, amino, alkynyl, alkenyl, cyano, nitro, trifluoromethyl, halobenzyl, heterocycloalkyl, carboxylic acid or carboxylic acid ester; wherein aryl or heteroaryl The base may be combined into a bicyclic ring which may be further substituted by a benzyl or halobenzyl group; or R 1 is a structural formula: T
其中：  among them:
Β选自芳基或杂芳基， 其中芳基或杂芳基可以进一步被一个或多个选自烷基、 卤素、 芳基、 羟基、 氨基、 炔基、 烯基、 氰基、 硝基、 三氟甲基、 卤代苄基、 杂 环垸基、 羧酸或羧酸酯的取代基所取代；  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;
Τ选自 -0(CH2)r -， -N(CH2)r-或 -S(CH2)r; Τ selected from -0(CH 2 )r -, -N(CH 2 )r- or -S(CH 2 )r;
L选自芳基或杂芳基，其中芳基或杂芳基可以进一步被一个或多个卤素或烷基 所取代；  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;
R2选自氢原子、 烷基、 环烷基、 三氟甲基、 杂环烷基、 芳基、 杂芳基、 芳烷 基、 其中垸基、 环烷基、 杂环烷基、 芳基、 杂芳基、 芳烷基进一步被一个或多个 选自烷基、 芳基、 羟基、 卤素、 氨基、 氰基、 烷氧基、 羧酸、 羧酸酯或 -NR6R7的 取代基所取代； 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
R3和 R4各自独立地选自氢原子、烷基、 三氟甲基、 环烷基、 杂环烷基、 芳基、 羧酸酯、 -S02R6、 -CH2C(=0)NR6R7 -C(-0)NR6R7 -(CH2)nNR6R7或 -NC (=0) R6， 其中烷基、 环烷基、 杂环垸基进一步被一个或多个选自烷基、 卤素、 三氟甲基、 芳基、 羟基、 烷氧基、 芳氧基、 环烷基、 杂环烷基、 杂芳基、 杂环烷氧基、 氰基、 羧酸、 羧酸酯、 -S02R6、 或 -(CH2)nNR6R7的取代基所取代； R 3 and R 4 are each independently 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 carboxylic acid ester, -S0 2 R 6 , -CH 2 C (=0 ) NR 6 R 7 -C (-0 ) NR 6 R 7 - (CH 2) nNR 6 R 7 , or -NC (= 0) R 6, wherein the alkyl, cycloalkyl, heterocyclyl group is further substituted with one or embankment a plurality selected from the group consisting of alkyl, halogen, trifluoromethyl, aryl, hydroxy, alkoxy, aryloxy, cycloalkyl, heterocycloalkyl, heteroaryl, heterocycloalkoxy, cyano, carboxy Substituted by a substituent of an acid, a carboxylic acid ester, -S0 2 R 6 , or -(CH 2 )nNR 6 R 7 ;
同时， R3和 R4—起形成一个 4〜8元环基； 其中 5〜8元杂环内含有一个或多 个 1、 0、 S原子， 并且 4〜8元杂环上进一步被一个或多个选自垸基、 卤素、 芳 基、 杂芳基、 卤代垸基、 卤代垸氧基、 羟基、 烷氧基、 芳氧基、 羰基、 杂环烷基、 羧酸、 羧酸酯、 -N-OR6或 -NR6R7的取代基所取代； Meanwhile, 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 ;
R6和 R7分别选自氢原子、 垸基、 烯基、 环垸基、 杂环烷基、 芳基或杂芳基， 其中垸基、 烯基、 环烷基、 杂环烷基、 芳基或者杂芳基进一步被一个或多个选自 烷基、环烷基、卤素、芳基、羟基、氨基、烷氧基、烯基、杂环烷基、羟烷基、 -S02R6、 -C(=0) R 羧酸、 羧酸酯或 - NR 7的取代基所取代； 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. Or a heteroaryl group further selected from one or more selected from the group consisting of alkyl, cycloalkyl, halogen, aryl, hydroxy, amino, alkoxy, alkenyl, heterocycloalkyl, hydroxyalkyl, -S0 2 R 6 , -C(=0)R substituted with a carboxylic acid, a carboxylic acid ester or a substituent of -NR 7 ;
同时， R6和 R7—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选自烷基、 卤素、 芳基、 杂芳基、 卤代芳基、 卤代垸氧基、 氨基、 羟基、 氰基、 烷氧基、 芳氧基、 胺烷基、羟烷基、环烷基、杂环烷基、羰基、羧酸、羧酸酯、 -C(=0)NR6R7, -NC (=0) R6、 -S02R6、 或 -NR6R7的取代基所取代； Meanwhile, R 6 and R 7 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 a Or a plurality selected from the group consisting of alkyl, halogen, aryl, heteroaryl, haloaryl, halomethoxy, amino, hydroxy, cyano, alkoxy, aryloxy, alkoxyalkyl, hydroxyalkyl , cycloalkyl, heterocycloalkyl, carbonyl, carboxylic acid, carboxylic acid ester, -C(=0)NR 6 R 7 , -NC (=0) R 6 , -S0 2 R 6 , or -NR 6 R Substituted by a substituent of 7 ;
n是 0〜6；  n is 0~6;
r是 0〜2。 进一步， 本发明包括下述通式 (Π)表示的化合物或其盐:  r is 0~2. Further, the present invention includes a compound represented by the following formula (Π) or a salt thereof:
Figure imgf000011_0001
Figure imgf000011_0001
其中:  among them:
R1选自烷基、 杂环烷基、 芳基或杂芳基， 其中垸基、 杂环烷基、 芳基或杂芳 基可以进一步被一个或多个选自烷基、 卤素、 芳基、 羟基、 氨基、 炔基、 烯基、 氰基.、 硝基、.三氟甲基、..卤代苄基、 杂环烷基、 羧酸或羧酸酯的取代基所取代； 其中芳基或杂芳基可以并成双环， 此双环可以进一步被苄基或卤代苄基所取代； 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. Substituted by a substituent of a hydroxyl group, an amino group, an alkynyl group, an alkenyl group, a cyano group, a nitro group, a trifluoromethyl group, a halogenated benzyl group, a heterocycloalkyl group, a carboxylic acid or a carboxylic acid ester; 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;
B L  B L
或者 R1为结构式： Z ^ Or R 1 is a structural formula: Z ^
B选自芳基或杂芳基， 其中芳基或杂芳基可以进一步被一个或多个选自垸基、 卤素、 芳基、 羟基、 氨基、 炔基、 烯基、 氰基、 硝基、 三氟甲基、 卤代苄基、 杂 环烷基、 羧酸或羧酸酯的取代基所取代； 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选自 -0(CH2)r-， -N(CH2)r-或 -S(CH2)r; T is selected from -0(CH 2 )r-, -N(CH 2 )r- or -S(CH 2 )r;
L选自芳基或杂芳基，其中芳基或杂芳基可以进一步被一个或多个卤素或烷基 所取代；  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;
R2选自氢原子、 烷基、 环垸基、 三氟甲基、 杂环烷基、 芳基、 杂芳基、 芳垸 基， 其中垸基、 环垸基、 杂环垸基、 芳基、 杂芳基、 芳烷基进一步被一个或多个 选自垸基、 芳基、 羟基、 卤素、 氨基、 氰基、 垸氧基、 羧酸、 羧酸酯或 -NR6R7的 取代基所取代； 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
R3选自选自氢原子、烷基、三氟甲基、环垸基、杂环烷基、芳基、羧酸酯、 -S02R6、 -C¾C(=0)NR6R7、 -C(=0)NR6R7、 -(CH2)nNR6R7或 -NC (=0) R6， 其中烷基、 环烷 基、 杂环垸基进一步被一个或多个选自烷基、 卤素、 三氟甲基、 芳基、 羟基、 烷 氧基、 芳氧基、 环烷基、 杂环垸基、 杂芳基、 杂环烷氧基、 氰基、 羧酸、 羧酸酯、 -S02R6、 或 -(CH2)nNR6R7的取代基所取代； R 3 is selected from the group consisting of a hydrogen atom, an alkyl group, a trifluoromethyl group, a cyclodecyl group, a heterocycloalkyl group, an aryl group, a carboxylic acid ester, -S0 2 R 6 , -C3⁄4C(=0)NR 6 R 7 , -C(=0)NR 6 R 7 , -(CH 2 )nNR 6 R 7 or -NC (=0) R 6 , wherein the alkyl group, the cycloalkyl group, the heterocyclic fluorenyl group are further selected from one or more selected from Alkyl, halogen, trifluoromethyl, aryl, hydroxy, alkoxy, aryloxy, cycloalkyl, heterocycloalkyl, heteroaryl, heterocycloalkoxy, cyano, carboxylic acid, carboxylic acid ester, Substituted with a substituent of -S0 2 R 6 or -(CH 2 )nNR 6 R 7 ;
R5选自氢原子、 垸基、 环烷基或 -C(O)0R6， 其中垸基或环烷基迸一步被一个 或多个选自烷基、 羟基、 烷氧基、 氰基、 -NR6R7、 羧酸或羧酸酯的取代基所取代；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;
R6和 R7分别选自氢原子、 烷基、 烯基、 环烷基、 杂环垸基、 芳基或杂芳基， 其中烷基、 烯基、 环烷基、 杂环垸基、 芳基或者杂芳基进一步被一个或多个选自 烷基、环烷基、卤素、芳基、羟基、氨基、烷氧基、烯基、杂环烷基、羟垸基、 -S02R6 -C(=0) R6、 羧酸、 羧酸酯或 - NR6R7的取代基所取代； 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. Or a heteroaryl group further selected from one or more selected from the group consisting of alkyl, cycloalkyl, halogen, aryl, hydroxy, amino, alkoxy, alkenyl, heterocycloalkyl, hydroxydecyl, -S0 2 R 6 -C(=0)R 6 , substituted by a carboxylic acid, a carboxylic acid ester or a substituent of -NR 6 R 7 ;
同时， R6和 R7—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选自烷基、 卤素、 芳基、 杂芳基、 卤代芳基、 卤代烷氧基、 氨基、 羟基、 氰基、 烷氧基、 芳氧基、 胺烷基、羟烷基、环烷基、杂环烷基、羰基、羧酸、羧酸酯、 -C(=0)NR6R7、 -NC (=0) R6、 -S02R6、 或 -NR6R7的取代基所取代； Meanwhile, R 6 and R 7 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 a Or a plurality selected from the group consisting of alkyl, halogen, aryl, heteroaryl, haloaryl, haloalkoxy, amino, hydroxy, cyano, alkoxy, aryloxy, aminalkyl, hydroxyalkyl, ring Alkyl, heterocycloalkyl, carbonyl, carboxylic acid, carboxylic acid ester, -C(=0)NR 6 R 7 , -NC (=0) R 6 , -S0 2 R 6 , or -NR 6 R 7 Substituted by a substituent;
n是 0〜6；  n is 0~6;
r是 0〜2。 进一步， 本发明包括下述通式 (III)表示的化合物或其盐:
Figure imgf000012_0001
其中-r is 0~2. Further, the present invention includes a compound represented by the following formula (III) or a salt thereof:
Figure imgf000012_0001
among them-
R1选自烷基、 杂环烷基、 芳基或杂芳基， 其中烷基、 杂环烷基、 芳基或杂芳 基可以进一步被一个或多个选自烷基、 卤素、 芳基、 羟基、 氨基、 炔基、 烯基、 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 或杂芳基可以并成双环， 此双环可以进一步被苄基或卤代苄基所取代； 或者 R1为结构式： T 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. Substituted by a hydroxyl group, an amino group, an alkynyl group, an alkenyl group, a cyano group, a nitro group, a trifluoromethyl group, a halogenated benzyl group, a heterocycloalkyl group, a carboxylic acid or a carboxylic acid ester; wherein an aryl group or a heteroaryl group may be combined In the form of a bicyclic ring, the bicyclic ring may be further substituted by a benzyl or halobenzyl group; or R 1 is a structural formula: T
其中- among them-
Β选自芳基或杂芳基， 其中芳基或杂芳基可以进一步被一个或多个选自烷基、 卤素、 芳基、 羟基、 氨基、 炔基、·烯基、 氰基、 硝基、 三氟甲基、 齒代苄基、 杂 环烷基、 羧酸或羧酸酯所取代； 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;
Τ选自 -0(CH2)r -、 -N(CH2)r-或 -S(CH2)r; Τ selected from -0(CH 2 )r -, -N(CH 2 )r- or -S(CH 2 )r;
L选自芳基或杂芳基，其中芳基或杂芳基可以进一步被一个或多个卤素或烷基 所取代；  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;
R3和 R4各自独立地选自氢原子、 烷基、 三氟甲基、 环垸基、 杂环垸基、 芳基、 羧酸酯、 -S02R6、 -CH2C(=0)NR6R7、 -C(=0)NR6R7、 -(CH2)nNR6R7或 -NC (=0) R6， 其中烷基、 环烷基、 杂环烷基进一步被一个或多个选自烷基、 卤素、 三氟甲基、 芳基、 羟基、 垸氧基、 芳氧基、 环烷基、 杂环烷基、 杂芳基、 杂环垸 基、 氰基、 羧酸、 羧酸酯、 -S02R6、 或 -(CH2)nNR6R7的取代基所取代； R 3 and R 4 are each independently selected from the group consisting of a hydrogen atom, an alkyl group, a trifluoromethyl group, a cyclodecyl group, a heterocyclic fluorenyl group, an aryl group, a carboxylic acid ester, -S0 2 R 6 , -CH 2 C (=0 )NR 6 R 7 , -C(=0)NR 6 R 7 , -(CH 2 )nNR 6 R 7 or -NC (=0) R 6 , Wherein alkyl, cycloalkyl or heterocycloalkyl is further selected from one or more selected from the group consisting of alkyl, halogen, trifluoromethyl, aryl, hydroxy, decyloxy, aryloxy, cycloalkyl, heterocycloalkane Substituted with a substituent of a heteroaryl group, a heterocyclic fluorenyl group, a cyano group, a carboxylic acid, a carboxylic acid ester, -S0 2 R 6 , or -(CH 2 )nNR 6 R 7 ;
同时， R3和 R4—起形成一个 4〜8元环基； 其中 5〜8元杂环内含有一个或多 个 、 0、 S原子， 并且 4〜8元杂环上进一步被一个或多个选自烷基、 卤素、 芳 基、 杂芳基、 卤代垸基、 卤代烷氧基、 羟基、 垸氧基、 芳氧基、 羰基、 杂环烷基、 羧酸、 羧酸酯、 =N-OR6或 -NR6R7的取代基所取代； Meanwhile, 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, 0, S atoms, and the 4 to 8 membered heterocyclic ring is further subjected to one or more Selected from alkyl, halogen, aryl, heteroaryl, halodecyl, haloalkoxy, hydroxy, decyloxy, aryloxy, carbonyl, heterocycloalkyl, carboxylic acid, carboxylic acid ester, =N Substituted by a substituent of -OR 6 or -NR 6 R 7 ;
R6和 R7分别选自氢原子、 烷基、 烯基、 环烷基、 杂环烷基、 芳基或杂芳基， 其中烷基、 烯基、 环烷基、 杂环垸基、 芳基或者杂芳基进一步被一个或多个选自 烷基、环烷基、卤素、芳基、羟基、氨基、垸氧基、烯基、杂环垸基、羟垸基、 -S02R6、 -C(=0) R6、 羧酸、 羧酸酯或 - NR6R7的取代基所取代； R 6 and R 7 are each independently selected from a hydrogen atom, an alkyl group, an alkenyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, wherein alkyl group, alkenyl group, cycloalkyl group, heterocyclic fluorenyl group, aryl group Further, the hetero or heteroaryl group is further selected from one or more selected from the group consisting of alkyl, cycloalkyl, halogen, aryl, hydroxy, amino, decyloxy, alkenyl, heterocycloalkyl, hydroxydecyl, -S0 2 R 6 Substituting -C(=0)R 6 , a carboxylic acid, a carboxylic acid ester or a substituent of -NR 6 R 7 ;
同时， R6和 R7—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选自垸基、 卤素、 芳基、 杂芳基、 卤代芳基、 卤代垸氧基、 氨基、 羟基、 氰基、 烷氧基、 芳氧基、 胺垸基、羟烷基、环烷基、杂环垸基、羰基、羧酸、羧酸酯、 -C(=0)NR6R7, -NC (=0) R6、 -S02R6、 或 -NR6R7的取代基所取代； Meanwhile, R 6 and R 7 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 a Or a plurality selected from the group consisting of fluorenyl, halogen, aryl, heteroaryl, haloaryl, halomethoxy, amino, hydroxy, cyano, alkoxy, aryloxy, amidino, hydroxyalkyl , cycloalkyl, heterocycloalkyl, carbonyl, carboxylic acid, carboxylic acid ester, -C(=0)NR 6 R 7 , -NC (=0) R 6 , -S0 2 R 6 , or -NR 6 R Substituted by a substituent of 7 ;
n是 0〜6；  n is 0~6;
r是 0〜2。 ― ―  r is 0~2. ― ―
本发明的典型化合物包括如下化合物或它们药学上可接受的盐， 但不限于这 些.  Typical compounds of the invention include, but are not limited to, the following compounds or pharmaceutically acceptable salts thereof.
Figure imgf000013_0001
Figure imgf000014_0001
T/CN2008/001307
Figure imgf000013_0001
Figure imgf000014_0001
T/CN2008/001307
Figure imgf000015_0001
T/CN2008/001307
Figure imgf000015_0001
T/CN2008/001307
Figure imgf000016_0001
Figure imgf000017_0001
Figure imgf000018_0001
Figure imgf000019_0001
Figure imgf000020_0001
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0001
甲
Figure imgf000016_0001
Figure imgf000017_0001
Figure imgf000018_0001
Figure imgf000019_0001
Figure imgf000020_0001
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0001
A
二
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
W two
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
W
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
其中， 所述的盐为上述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、 对甲苯磺酸、 硫酸、 磷酸、 柠檬酸、 酒石酸、 乙酸或三氟 乙酸。
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Wherein 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.
在本发明的另一个方面是一种药物组合物，含有通式 (1)、（Π)或 (III)所示的化合 物、 其盐或其前药和药学上可以接受的载体或赋形剂。  In another aspect of the invention, a pharmaceutical composition comprising a compound of the formula (1), (Π) or (III), a salt thereof or a prodrug thereof, 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)、 （Π)或 (III) 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。  In another aspect of the invention is a method of modulating the catalytic activity of a protein kinase comprising contacting a protein kinase with a compound or salt of formula (1), (Π) 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.
在本发明的另一个方面是通式 (1)、 （Π)或 (III) 的化合物或盐的制备方法， 包括 以下步骤：  In another aspect of the invention, a process for the preparation of a compound or salt of the formula (1), (Π) or (III) comprises the steps of:
一种通式 （I)化合物的制备方法， 该方法包括以下歩骤：  A method of preparing a compound of formula (I), the method comprising the steps of:
(1)
Figure imgf000046_0001
Figure imgf000046_0002
(1)
Figure imgf000046_0001
Figure imgf000046_0002
(Id)
Figure imgf000046_0003
(Id)
Figure imgf000046_0003
Figure imgf000047_0001
种通式 （III)化合物的制备方法， 该方法包括以下步骤:
Figure imgf000047_0001
A method for preparing a compound of the formula (III), the method comprising the steps of:
Figure imgf000048_0001
发明的详细说明
Figure imgf000048_0001
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。 Unless otherwise stated, the following terms used in the specification and claims have the following meanings.
"烷基 "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个碳原子的烷基， 例如甲基、 乙基、 丙基、 2-丙基、 正丁基、 异丁 基、 叔丁基、 戊基等。 更优选的是含有 1至 4个碳原子的低级烷基， 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， 独立地选自卤素、 三卤垸基、 羟基、 低 级烷氧基、 芳基、 芳氧基、 杂芳基、 杂环烷基、 杂芳基、 杂环烷氧基、 氰基、 硝 基、 -C(=0)R6、 -C(=0)NR6R7、 -(C¾)nNR6R7、 - NC (=0) R6R7或 - S02R6。 "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. The alkyl 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, Heteroaryl, heterocycloalkyl, heteroaryl, heterocycloalkoxy, cyano, nitro, -C(=0)R 6 , -C(=0)NR 6 R 7 , -(C3⁄4)nNR 6 R 7 , - NC (=0) R 6 R 7 or - S0 2 R 6 .
"环烷基"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， 但没有一个环具有完全 共轭的 π电子系统。 环垸基的实例有环丙基、 环丁基、 环戊基、 环戊烯、 环己烷、 环己二烯、 金刚烷、 环庚垸、 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， 独立地选自低级烷基、 卤素、 三卤烷基、 羟 基、 低级烷氧基、 羟烷基、 芳基、 芳氧基、 杂芳基、 杂环垸基、 杂环烷氧基、 氰 基、硝基、 -C(=0)R6、 -C(=0)OR6、 -C(=0)NR6 \ -(C¾)nNR6R7、 - NC (=0) R6R7 或 -S02R6。 "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. Examples of 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. , aryl, aryloxy, heteroaryl, heterocycloalkyl, heterocycloalkoxy, cyano, nitro, -C(=0)R 6 , -C(=0)OR 6 , -C( =0) NR 6 \ - (C3⁄4) nNR 6 R 7 , - NC (=0) R 6 R 7 or -S0 2 R 6 .
"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烷基。 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。 烯 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， 独立地选 自为卤素、 三卤垸基、 羟基、 低级烷氧基、 芳基、 芳氧基、 杂芳基、 杂环烷基、 杂芳基、杂环烷基、氰基、硝基、杂环垸氧基、氰基、硝基、 -C(=0)R6、 -C(=0)OR6、 -C(=0)NR6R7、 -(C¾)nNR6R7、 - NC (=0) R6R7或 -S02R6。 "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。 炔 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， 独立地选 自卤素、 三卤烷基、 羟基、 低级烷氧基、 芳基、 芳氧基、 杂芳基、 杂环烷基、 杂 芳基、杂环烷基、杂环烷氧基、氰基、硝基、 -C(=0)R6、 -C(=0)OR6、 -C(=0)NR6R7、 -(CH2)nNR6R7、 - NC (=0) R6R7或 -S02R6。 "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. , heteroaryl, heterocycloalkyl, heteroaryl, heterocycloalkyl, cyano, nitro, heterocyclomethoxy, cyano, nitro, -C(=0)R 6 , -C(= 0) OR 6 , -C(=0)NR 6 R 7 , -(C3⁄4)nNR 6 R 7 , - NC (=0) R 6 R 7 or -S0 2 R 6 . "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-propynyl, 1-, 2- or 3-butynyl, and the like. 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, trihaloalkyl, hydroxy, lower alkoxy, aryl, aryloxy, Heteroaryl, heterocycloalkyl, heteroaryl, heterocycloalkyl, heterocycloalkoxy, cyano, nitro, -C(=0)R 6 , -C(=0)OR 6 , -C (=0) NR 6 R 7 , -(CH 2 )nNR 6 R 7 , - NC (=0) R 6 R 7 or -S0 2 R 6 .
"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、 杂芳基和联芳基。 炔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， 独立地选自卤素、 三卤烷基、 羟基、 硝基、 氰基、 低 级垸氧基、 羟烷基、 垸基、 杂芳基、 杂环烷基、 羧基、 羧酸酯、 杂环烷氧基、 氰 基、硝基、 -C(=0)R6、 -C(=0)OR6、 -C(=0)NR6R7、 -(CH2)nNR6R7、 - NC (=0) R6R7 或 -S02R6。 "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-烷基吡咯基、 嘧啶基、 吡嗪基、 咪唑 基等。 杂芳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， 独立地选自卤素、 三卤烷基、 羟基、 硝基、 氰基、 低级烷氧基、 羟烷基、 烷基、 芳基、杂环烷基、羧基、羧酸酯、杂环烷氧基、氰基、硝基、 -C(=0)R6、 -C(=0)OR6、 -C(=0)NR6R7、 -(CH2)nNR6R7、 - NC (=0) R6R7或 -S02R6。 "杂环烷基"指单环或 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， 其余环原子为碳。 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 包括但不限于吡咯烷基、 哌啶子基、 哌嗪子基、 吗啉基、 硫代吗啉基、 高哌嗪其 等、 杂环垸基可以是取代的或未取代的。 炔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， 独立地选自卤素、 低级烷基、 羟烷基、 三卤垸 基、羟基、芳基、芳氧基、杂芳基、杂环烷基、羧基、羧酸酯、氰基、硝基、 -C(=0)R6、 -C(=0)OR6、 -C(=0)NR6R7、 -(CH2)nNR6R7、 - NC (=0) R6R7或- S02R6。 "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 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, trihaloalkyl, hydroxy, nitro, cyano, lower decyloxy, hydroxy Alkyl, fluorenyl, heteroaryl, heterocycloalkyl, carboxy, carboxylic acid ester, heterocycloalkoxy, cyano, nitro, -C(=0)R 6 , -C(=0)OR 6 -C(=0)NR 6 R 7 , -(CH 2 )nNR 6 R 7 , - NC (=0) R 6 R 7 or -S0 2 R 6 . "Heteroaryl" means an aryl group having from 1 to 3 heteroatoms as ring atoms, the remaining ring atoms being carbon, and heteroatoms including oxygen, sulfur and nitrogen. The ring may be a 5- or 6-membered ring. Examples of the heterocyclic aryl group include a furyl group, a thienyl group, a pyridyl group, a pyrrole, an N-alkylpyrrolyl group, a pyrimidinyl group, a pyrazinyl group, an imidazolyl group and the like. The heteroaryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more, independently selected from the group consisting of halogen, trihaloalkyl, hydroxy, nitro, cyano, lower alkoxy, Hydroxyalkyl, alkyl, aryl, heterocycloalkyl, carboxy, carboxylic acid ester, heterocycloalkoxy, cyano, nitro, -C(=0)R 6 , -C(=0)OR 6 -C(=0)NR 6 R 7 , -(CH 2 )nNR 6 R 7 , - NC (=0) R 6 R 7 or -S0 2 R 6 . "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 π-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. Oxy, heteroaryl, heterocycloalkyl, carboxy, carboxylic acid ester, cyano, nitro, -C(=0)R 6 , -C(=0)OR 6 , -C(=0)NR 6 R 7 , -(CH 2 )nNR 6 R 7 , - NC (=0) R 6 R 7 or - S0 2 R 6 .
"羟基"指 -OH基团。  "Hydroxy" means an -OH group.
"垸氧基"指 -0- (烷基）和 -0- (未取代的环垸基）。 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。 烷氧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， 独立地选自为垸基、 卤素、 三卤垸基、 羟基、 低级烷氧基、 芳基、 芳氧基、 杂芳 基、 杂环烷基、 杂芳基、 杂环垸基、 氰基、 硝基、 -C(=0)R6、 -C(=0)0R6、 -C(=0)NR6R7、 -(C¾)nNR6R7、 - NC (=0) R6R7或 -S02R6。 "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, heteroaryl, heterocycloalkyl, heteroaryl, heterocyclic fluorenyl, cyano, nitro, -C(=0)R 6 , -C(=0)0R 6 , -C( =0) NR 6 R 7 , -(C3⁄4)nNR 6 R 7 , - NC (=0) R 6 R 7 or -S0 2 R 6 .
"芳氧基"指 -o-芳基和 -o-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。 "苄基"指 -CH2- (芳基）。 "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).
"卤素"指氟、 氯、 溴或碘， 优选氟或氯。  "Halogen" means fluoro, chloro, bromo or iodo, preferably fluoro or chloro.
"卤代垸基"指垸基被卤素取代。 代表性实例包括但不限于三氟甲基、 三溴 甲基等。  "Haloalkyl" means that the fluorenyl group is replaced by a halogen. Representative examples include, but are not limited to, trifluoromethyl, tribromomethyl, and the like.
"羟烷基"指烷基被羟基取代。  "Hydroxyalkyl" means an alkyl group substituted by a hydroxy group.
"胺烷基"指烷基被氨基取代。  "Amine alkyl" means an alkyl group substituted with an amino group.
"卤代烷氧基"指 -◦- (卤代垸基）。代表性实例包括但不限于三氟甲氧基、三 溴甲氧基等。  "Haloalkoxy" means -◦-(halofluorenyl). Representative examples include, but are not limited to, trifluoromethoxy, tribromomethoxy, and the like.
"杂环烷氧基"指 -0- (杂环垸基）。  "Heterocycloalkoxy" means -0-(heterocyclic fluorenyl).
"卤代苄基"指- CH2- (卤代芳基）。 "Halobenzyl" means -CH 2 - (haloaryl).
"三氟甲基"指 -CF3。 "Trifluoromethyl" means -CF 3 .
"硝基"指 -N02。 "Nitro" means -N0 2 .
"氰基"指 -CN。  "Cyano" means -CN.
"氨基"指 -NH2。 "Amino" means -NH 2 .
"羰基"指 -C(=0)- "carbonyl" means -C(=0)-
"羧酸"指 （垸基） C(=0)OH "Carboxylic acid" means (mercapto) C(=0)OH
"羧酸酯"指 （烷基） C(=0)0 (烷基）  "Carboxylic ester" means (alkyl) C(=0)0 (alkyl)
"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， i¾ 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" 意味着烷基可以但不必存在， 该说明包括杂环基团被烷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, i2⁄4 indicates where the event or environment occurs or does not occur. For example, "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.
"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：  "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. Methods of Synthesizing the Compounds of the Invention In order to accomplish the objectives of the present invention, the present invention employs the following technical solutions:
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-
Figure imgf000051_0001
The preparation method of the compound of the formula (I) or a salt thereof of the present invention comprises the following steps -
Figure imgf000051_0001
IBX, DMSO  IBX, DMSO
Figure imgf000051_0002
Figure imgf000051_0003
Figure imgf000051_0002
Figure imgf000051_0003
Figure imgf000051_0004
Figure imgf000051_0004
(W) (W)
Figure imgf000052_0001
Figure imgf000052_0001
50 50
Figure imgf000053_0001
Figure imgf000053_0001
(lib)  (lib)
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:  The preparation method of the compound of the formula (III) or a salt thereof of the present invention comprises the following steps:
Figure imgf000053_0002
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)， 内标为四甲基硅烷 (TMS)， 化学位移是以 10—6(ppm)作为单位给出。
Figure imgf000053_0002
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). 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.
MS的测定用 FIN GAN LCQAd (ESI)质谱仪。  The MS was measured using a FIN GAN LCQAd (ESI) mass spectrometer.
激酶 VEGFR平均抑制率的测定使用 HTScan酶标仪 (Cell Signaling公司）。 激酶 EGFR/HER— 2平均抑制率的测定用 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。  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.
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 a carrier.
DMSO-D6: 氘代二甲基亚砜； CDC13: 氘代氯仿; 制备实施例： 实施例 1 DMSO-D 6 : deuterated dimethyl sulfoxide; CDC1 3 : deuterated chloroform; Preparation Example: Example 1
「3-氯 -4-(3-氟-苄氧基) -苯基 1-(6-吡咯 -1-基-喹唑啉 -4-基) -胺  "3-Chloro-4-(3-fluoro-benzyloxy)-phenyl 1-(6-pyrrol-1-yl-quinazolin-4-yl)-amine
Figure imgf000054_0001
Figure imgf000054_0001
1 第一步  1 first step
2-氯 -1-(3-氟-苄氧基) -4-硝基-苯  2-chloro-1-(3-fluoro-benzyloxy)-4-nitro-benzene
室温下在 250 mL茄形瓶中加入 2-氯 -4-硝基 -苯酚 la (20.0 g， 115 mmol), 用 120 mLN,N-二甲基甲酰胺溶解原料，搅拌下加入无水碳酸钾（32.0 g， 230 mmol), 10分钟后加入间氟氯苄（24 g， 126 mmol), 加热至 90°C反应 1.5小时。 薄层分析 跟踪至原料消失， 将反应液冷却至室温， 倒入 1000 mL水中搅拌 30分钟， 减压抽 滤，用少量水洗固体，真空干燥， 得到标题产物 2-氯 -1-(3-氟-苄氧基) -4-硝基-苯 lb (32.3 g, 淡黄色固体)。 产率； 99.5 %。  Add 2-chloro-4-nitro-phenol la (20.0 g, 115 mmol) to a 250 mL eggplant bottle at room temperature, dissolve the material with 120 mL of N,N-dimethylformamide, and add anhydrous potassium carbonate with stirring. (32.0 g, 230 mmol), 10 minutes later, m-chlorobenzyl chloride (24 g, 126 mmol) was added and heated to 90 ° C for 1.5 hours. The thin layer analysis was followed until the disappearance of the starting material, the reaction solution was cooled to room temperature, poured into 1000 mL of water and stirred for 30 minutes, filtered under reduced pressure, and the solid was washed with a small amount of water and dried in vacuo to give the title product 2-chloro-1-(3-fluoro -benzyloxy)-4-nitro-benzenelb (32.3 g, pale yellow solid). Yield; 99.5 %.
MS m/z (ESI): 282[M+1] MS m/z (ESI): 282 [M+1]
第二步  Second step
3-氯 -4-(3-氟-苄氧基) -苯胺盐酸盐  3-chloro-4-(3-fluoro-benzyloxy)-aniline hydrochloride
在 1000 mL三口瓶中加入 2-氯小 (3-氟-苄氧基) -4-硝基-苯 lb (38.6 g， 136.9 mmol), 用 300 mL甲醇溶解原料， 搅拌下加入 100 mL水， 再加入铁粉（32.2 g， 575 mmol)和氯化铵（62.4 g， 1.15 mol) , 加热回流 6小时。 薄层分析跟踪至原料 消失，将反应液冷却至室温，用硅藻土减压抽滤,减压浓縮，用二氯甲烷（100 mLx3 ) 萃取， 合并有机相， 用 50 mL饱和氯化钠溶液洗涤， 二氯甲烷层用无水硫酸镁干 燥， 减压浓缩， 得到标题产物 3-氯 -4-(3-氟-苄氧基) -苯胺盐酸盐 lc (33.2 g， 白色固 体)。 产率： 84.3 %。 Add 2-chloros(3-fluoro-benzyloxy)-4-nitro-benzenelb (38.6 g, 136.9 mmol) to a 1000 mL three-necked flask, dissolve the material in 300 mL of methanol, and add 100 mL of water with stirring. Add iron powder (32.2 g, 575 mmol) and ammonium chloride (62.4 g, 1.15 mol), heated to reflux for 6 hours. Thin layer analysis was performed until the disappearance of the starting material. The reaction solution was cooled to room temperature, filtered with celite under reduced pressure, concentrated under reduced pressure, and extracted with dichloromethane (100 mL×3). The solution was washed with EtOAc EtOAc m. Yield: 84.3 %.
MS m/z (ESI): 252[M+1]  MS m/z (ESI): 252 [M+1]
第三步  third step
2-氨基 -5-碘 -苯甲酸甲酯  2-amino-5-iodo-benzoic acid methyl ester
在 500 mL茄形瓶中加入 2-氨基 -苯甲酸甲酯 Id (23.3 g, 154 mmol), 用盐 酸溶液（浓盐酸 16 mL，水 200 mL)溶解原料，在 10Ό搅拌下滴加氯化碘（25 g， 154 mmol) 的盐酸溶液（浓盐酸 28 mL， 水 lOO mL), 室温搅拌 1小时， 减压抽 滤， 固体真空干燥，得到标题产物 2-氨基 -5-碘 -苯甲酸甲酯 le (29 g，淡黄色固体)。 产率： 69.0%。  Add 2-amino-benzoic acid methyl ester Id (23.3 g, 154 mmol) to a 500 mL eggplant-shaped flask, dissolve the raw material with a hydrochloric acid solution (concentrated hydrochloric acid 16 mL, water 200 mL), and add iodine chloride dropwise with stirring at 10 Torr. (25 g, 154 mmol) of a solution of hydrochloric acid (28 mL of concentrated hydrochloric acid, EtOAc, EtOAc, EtOAc) Le (29 g, pale yellow solid). Yield: 69.0%.
MS m/z (ESI): 278 [M+ 1] MS m/z (ESI): 278 [M+ 1]
第四步  the fourth step
6-碘 -3H-喹唑啉 -4-酮  6-iodo-3H-quinazolin-4-one
氮气氛下在 250 mL茄形瓶中加入 2-氨基 -5-碘 -苯甲酸甲酯 le ( 13.5 g, 48.7 mmol)和甲酸铵 （3.5 g， 55 mmol), 溶于 75 mL甲酰胺中， 搅拌下加热至 180°C 反应 1.2小时。 TLC跟踪至原料消失， 将反应液冷却至室温， 放入冰箱冷冻， 减压 抽滤， 分别用 15 mL甲酰胺和 50 mL正己垸洗涤， 真空千燥， 得到标题产物 6-碘 -3H-喹唑啉 -4-酮 lf (12 g， 白色固体)。 产率： 90.9%。  2-amino-5-iodo-benzoic acid methyl ester le ( 13.5 g, 48.7 mmol) and ammonium formate (3.5 g, 55 mmol) were dissolved in 75 mL formamide in a 250 mL eggplant flask under nitrogen atmosphere. The mixture was heated to 180 ° C with stirring for 1.2 hours. After the TLC traced to the disappearance of the starting material, the reaction solution was cooled to room temperature, placed in a freezer, vacuum filtered, washed with 15 mL of formamide and 50 mL of hexanes, and dried in vacuo to give the title product 6-iodo-3H-quine. Oxazolin-4-one lf (12 g, white solid). Yield: 90.9%.
MS m/z (ESI): 273[M+ 1] MS m/z (ESI): 273 [M+ 1]
第五步  the fifth step
[3-氯 -4-(3-氟-苄氧基) -苯基 ]-(6-碘-喹唑啉 -4-基) -胺  [3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-iodo-quinazolin-4-yl)-amine
氮气氛下在 500 mL茄形瓶中加入 6-碘 -3H-喹唑啉 -4-酮 If (25 g, 91.9 mmol), 溶于 300 mL二氯亚砜和 5 mL Ν,Ν-二甲基甲酰胺的混合溶剂中， 加热回流至反应 液透明。 TLC跟踪至原料消失， 蒸出二氯亚砜， 备用。  6-iodo-3H-quinazolin-4-one If (25 g, 91.9 mmol) was added to a 500 mL eggplant bottle under nitrogen, dissolved in 300 mL of thionyl chloride and 5 mL of hydrazine, hydrazine-dimethyl In a mixed solvent of carbamide, it is heated to reflux until the reaction liquid is transparent. The TLC traced to the disappearance of the starting material, and the thionyl chloride was distilled off and used.
氮气氛下将备用中间体溶于 400 mL异丙醇中， 加入 3-氯 -4-(3-氟-苄基) -苯胺 盐酸盐 lc ( 12 g， 50.4 mmol), 加热回流 3小时。 薄层分析跟踪至原料消失， 将反 应液冷却至室温，减压抽滤，将所得固体用 100 mL乙酸乙酯和 30 mL氨水的混合 溶剂溶解， 室温搅拌 30分钟， 减压抽滤， 真空干燥， 得到标题产物 [3-氯 -4-(3-氟- 苄氧基) -苯基 ]-(6-碘-喹唑啉 -4-基) -胺 lg (12 g， 类白色固体)。 产率： 51.7%。 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 title product [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-iodo-quinazolin-4-yl)-amine 1 g (12 g, white solid) . Yield: 51.7%.
MS m/z (ESI): 506[M+ 1]  MS m/z (ESI): 506 [M+ 1]
第六步  Step 6
[3-氯 -4-(3-氟-苄氧基) -苯基 ]-(6-吡咯 -1-基-喹唑啉 -4-基) -胺  [3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-pyrrole-1-yl-quinazolin-4-yl)-amine
氮气氛下在 250 mL茄形瓶中加入 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-(6-碘-喹唑啉 -4- 基) -胺 lg (600 mg， 1.12 mmol), 无水碳酸钾（650 mg， 4.7 mmol), 碘化亚铜（100 mg, 0.5 mmol)和吡咯（3 g， 44 mmol), 用 25 mL甲苯溶解， 搅拌下滴加 Ν,Ν'- 二甲基 -1,2-乙二胺 （140 mg， 1.6 mmol), 加热回流搅拌过夜。 薄层分析跟踪至原 料消失， 加入 20 mL水和 100 mL乙酸乙酯， 硅藻土过滤， 用 2N盐酸溶液调 pH 至 7，分液，有机相依次用水 (50 mLX 2)洗涤，再用无水硫酸镁干燥，减压抽滤， 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 [3-氯 -4-(3-氟 -苄氧 基) -苯基 ]-(6-吡咯 -1-基-喹唑啉 -4-基) -胺 1 (500 mg， 淡黄色固体)。 产率： 95.0%。 MS m/z (ESI): 445 [M+l] [3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-iodo-quinazolin-4-) was added to a 250 mL eggplant flask under nitrogen atmosphere -) lg (600 mg, 1.12 mmol), anhydrous potassium carbonate (650 mg, 4.7 mmol), cuprous iodide (100 mg, 0.5 mmol) and pyrrole (3 g, 44 mmol), with 25 mL of toluene After dissolving, hydrazine, Ν'-dimethyl-1,2-ethanediamine (140 mg, 1.6 mmol) was added dropwise with stirring, and the mixture was stirred under reflux overnight. The thin layer analysis was followed until the disappearance of the raw materials. Add 20 mL of water and 100 mL of ethyl acetate, filter with celite, adjust the pH to 7 with 2N hydrochloric acid solution, separate the liquid, and wash the organic phase with water (50 mL×2), then use no The title compound [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-((3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-() was obtained. 6-Pyrrol-1-yl-quinazolin-4-yl)-amine 1 (500 mg, pale yellow solid). Yield: 95.0%. MS m/z (ESI): 445 [M+l]
1HNMR (400MHz, DMSO-^): δ 9.73(s, 1H), 8.59(t, 2H), 8.14(dd, 1H, J=9.2), 8.03 (d, 1H, J-2.4), 7.87(d, 1H, J=8.8), 7.76(dd, 1H, J=8.8), 7.56(t, 2H), 7.48(q, 1H), 7.32(q, 3H), 7.18(m, 1H), 6.39(t, 2H), 5.27(s, 2H) 实施例 2 1 HNMR (400MHz, DMSO- ^) : δ 9.73 (s, 1H), 8.59 (t, 2H), 8.14 (dd, 1H, J = 9.2), 8.03 (d, 1H, J-2.4), 7.87 (d , 1H, J=8.8), 7.76(dd, 1H, J=8.8), 7.56(t, 2H), 7.48(q, 1H), 7.32(q, 3H), 7.18(m, 1H), 6.39(t , 2H), 5.27(s, 2H) Example 2
「3-氯 氟-苄氧基) -苯基 1-(6-ί2-[(2-甲磺酰基-乙氨基) -甲基 1-吡咯 -1-基 喹 " 3 -Chlorofluoro-benzyloxy)-phenyl 1-(6-ί2-[(2-methanesulfonyl-ethylamino)-methyl-1-pyrrol-1-ylquina
Figure imgf000056_0001
Figure imgf000056_0001
第一步  First step
2-甲磺酰 -乙胺盐酸盐  2-methanesulfonyl-ethylamine hydrochloride
氮气氛下在 100 mL三口瓶中加入硼垸（40 mL， 1.0 mol/L), 室温搅拌下滴加 甲磺酰乙腈 2a， 室温搅拌过夜。 薄层分析跟踪至原料消失， 向反应液中滴加甲醇 至无气泡产生为止， 减压浓缩除去甲醇。 加入 30 mL饱和的氯化氢甲醇溶液， 加 热回流 1小时， 用 30 mL二氯甲烷稀释， 减压抽滤， 固体真空干燥， 得到标题产 物 2-甲磺酰 -乙胺盐酸盐 2b ( 1.53 g， 白色固体）。 产率： 67.4%。  Boron (40 mL, 1.0 mol/L) was added to a 100 mL three-necked flask under a nitrogen atmosphere, and methanesulfonylacetonitrile 2a was added dropwise with stirring at room temperature, and stirred at room temperature overnight. The thin layer analysis was followed until the disappearance of the starting material, and methanol was added dropwise to the reaction liquid until no bubbles were generated, and methanol was concentrated under reduced pressure. The title product 2-methanesulfonyl-ethylamine hydrochloride 2b (1.53 g, was obtained from the titled product. White solid). Yield: 67.4%.
MS m/z (ESI): 124[M+1] MS m/z (ESI): 124 [M+1]
第二步  Second step
1-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基}-111-吡咯 -2-甲醛 氮气氛下，在 500 mL三口瓶中加入本发明实施例 1第五步中所得到的化合物 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-(6-碘-喹唑啉 -4-基) -胺 lg (1.6 g, 3.17 mmol), 再加入 无水碳酸钾 ( 1.7 g, 13 mmol) , 碘化亚铜 ( 910 mg, 4.76 mmol) , 吡咯 -2-甲醛 ( 1 g， 10.5 mmol) ,用 200 mL甲苯溶解，搅拌下滴加 Ν,Ν'-二甲基 -1，2-乙二胺（560 mg, 6.34 mmol) , 加热回流搅拌 24小时。 薄层分析跟踪至原料消失， 将反应液冷却至 室温， 硅藻土过滤， 用少量水洗涤有机相， 减压浓缩， 用硅胶柱色谱法纯化所得 残余物， 得到标题产物 1-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基}-111-吡咯 -2-甲醛 2c (500 mg， 淡黄色固体)。 产率： 33.4 % 0 1-{4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-111-pyrrole-2-carbaldehyde in a nitrogen atmosphere at 500 mL three The compound obtained in the fifth step of the first embodiment of the present invention is added to the bottle. [3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-iodo-quinazolin-4-yl)-amine 1 g (1.6 g, 3.17 mmol), then anhydrous Potassium carbonate (1.7 g, 13 mmol), cuprous iodide (910 mg, 4.76 mmol), pyrrole-2-carbaldehyde (1 g, 10.5 mmol), dissolved in 200 mL of toluene, and added dropwise with stirring, Ν'- Dimethyl-1,2-ethanediamine (560 mg, 6.34 mmol) was stirred under reflux for 24 hours. The thin layer analysis was carried out until the disappearance of the starting material, the reaction mixture was cooled to room temperature, filtered over Celite, and the organic phase was washed with a little water, and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title product 1-{4-[ 3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-111-pyrrole-2-carbaldehyde 2c (500 mg, pale yellow solid). Yield: 33.4 % 0
MS m/z (ESI): 472[M+1] MS m/z (ESI): 472 [M+1]
1HNMR (400MHz, OMSO-d6): δ 9.80(s, 1H), 9.60(s, 1H), 8.74(s, 1H), 8.63(m, 1H), 8.05(m, 1H), 7.93(dd, 1H, J=8.8), 7.88(m, 1H), 7.76(d, 1H, J= 8.8), 7.60(m, 1H), 7.50(m, 1H), 7.35(m, 4H)， 7.2 l(m, 1H), 6.57(m, 1H), 5.26(s, 2H) 第三步 1 H NMR (400MHz, OMSO-d 6 ): δ 9.80 (s, 1H), 9.60 (s, 1H), 8.74 (s, 1H), 8.63 (m, 1H), 8.05 (m, 1H), 7.93 (dd , 1H, J=8.8), 7.88(m, 1H), 7.76(d, 1H, J= 8.8), 7.60(m, 1H), 7.50(m, 1H), 7.35(m, 4H), 7.2 l( m, 1H), 6.57(m, 1H), 5.26(s, 2H) Step 3
[3-氯 -4-(3-氟-苄氧基) -苯基 ]-(6-{2-[(2-甲磺酰基-乙氨基) -甲基] -吡咯 -1-基} -喹 唑啉 -4-基) -胺  [3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-{2-[(2-methanesulfonyl-ethylamino)-methyl]-pyrrol-1-yl} Quinazolin-4-yl)-amine
氮气氛下在 50 mL茄形瓶中加入本发明实施例 2第一步中所得到的化合物 2- 甲磺酰 -乙胺盐酸盐 2b (70 mg, 0.4 mmol), 加入 5 mL四氢呋喃和 5 mL甲醇的混 合溶剂， 搅拌下加入三乙胺 （0.2 mL， 0.6 mmol ), 再加入 1-{4-[3-氯 -4-(3-氟 -苄氧 基) -苯氨基] -喹唑啉 -6-基}-111-吡咯 -2-甲酸 2c ( 120 mg， 0.25 mmol) , 室温搅拌 30 分钟。 薄层分析跟踪至原料消失， 分批加入硼氢化钠 （40 mg, 1 mmol) , 室温搅 拌 30分钟。 薄层分析跟踪至原料消失， 将反应液减压浓缩， 倒入 50 mL水中， 用 100 mL乙酸乙酯萃取， 有机相用水洗， 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 [3-氯 -4-(3-氟-苄氧基) -苯 基 ]-(6-{2-[(2-甲磺酰基 -乙氨基)-甲基] -吡咯 -1-基 喹唑啉 -4-基) -胺 2(120 mg, 淡黄 色固体)。 产率： 50 %。  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. Add a solution of methanol in methanol, add triethylamine (0.2 mL, 0.6 mmol) with stirring, then add 1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazole Bromo-6-yl}-111-pyrrole-2-carboxylic acid 2c (120 mg, 0.25 mmol) was stirred at room temperature for 30 min. Thin layer analysis was followed until the starting material disappeared, sodium borohydride (40 mg, 1 mmol) was added portionwise and stirred at room temperature for 30 min. The thin layer analysis was carried out until the disappearance of the starting material. The reaction mixture was concentrated under reduced pressure. EtOAc was evaporated, evaporated, evaporated, evaporated. The residue obtained was purified by chromatography to give the title product [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-{2-[(2-methanesulfonyl-ethylamino)-- And pyrrole-1-ylquinazolin-4-yl)-amine 2 (120 mg, pale yellow solid). Yield: 50%.
MS m/z (ESI): 580[M+1] MS m/z (ESI): 580 [M+1]
!HNMR (400MHz, DMSO-t¾): δ 9.80(s, 1H), 8.64(s, 1H), 8.57(d, 1H, J=1.6), 8.06 (m, 2H), 7.88(d, 1H, J= 8.8), 7.76(dd, 1H, J=9.0), 7.48(q, 1H), 7.32(m， 3H), 7.18(m, 1H), 7.08(s, 1H), 6.26(m, 2H), 5.27(s, 2H), 3.75(s, 2H)， 3.17(t, 2H)， 2.89(d, 5H) 实施例 3 ! HNMR (400MHz, DMSO-t¾ ): δ 9.80 (s, 1H), 8.64 (s, 1H), 8.57 (d, 1H, J = 1.6), 8.06 (m, 2H), 7.88 (d, 1H, J = 8.8), 7.76 (dd, 1H, J=9.0), 7.48(q, 1H), 7.32(m, 3H), 7.18(m, 1H), 7.08(s, 1H), 6.26(m, 2H), 5.27(s, 2H), 3.75(s, 2H), 3.17(t, 2H), 2.89(d, 5H) Example 3
N-(l- -「3-氯 -4-(3-氟-苄氧基) -苯氨基 1-喹唑啉 -6-基 }-m-吡咯 -2-基甲 N -(l- -"3-chloro-4-(3-fluoro-benzyloxy)-phenylamino-1-quinazolin-6-yl}-m-pyrrol-2-yl
基) -Ν',Ν'-二乙基 -1,2-乙二胺
Figure imgf000058_0001
Base) -Ν',Ν'-diethyl-1,2-ethanediamine
Figure imgf000058_0001
重复本发明实施例 2 第二步的反应， 使用上述第二步中所得到的化合物 1_{4-[3-氯 -4-(3-氟-节氧基) -苯氨基] -喹唑啉- 6-基}-111-吡咯 -2-甲醛 2c作原料， 按照 本发明实施例 2第三步所述相同方式进行该原料与 Ν,Ν-二乙基 -1,2-乙二胺的反应， 用硅胶柱色谱法纯化所得残余物， 则得到标题产物 N-(l-{4-[3-氯 -4-(3-氟-苄氧基) - 苯氨基] -喹唑啉 -6-基}-111-吡咯 -2-基甲基) -Ν',Ν'-二乙基 -1,2-乙二胺 3 (50 mg， 浅黄 色固体)。 产率： 16.5%。  The reaction of the second step of Example 2 of the present invention is repeated, and the compound 1_{4-[3-chloro-4-(3-fluoro-p-hydroxy)-phenylamino]-quinazoline obtained in the above second step is used. -6-yl}-111-pyrrole-2-carbaldehyde 2c as a starting material, the starting material and hydrazine, hydrazine-diethyl-1,2-ethylenediamine were carried out in the same manner as described in the third step of Example 2 of the present invention. The reaction was purified by silica gel column chromatography toiel -yl}-111-pyrrol-2-ylmethyl)-indole, Ν'-diethyl-1,2-ethanediamine 3 (50 mg, pale yellow solid). Yield: 16.5%.
MS m/z (ESI): 573[M+ 1] MS m/z (ESI): 573 [M+ 1]
'HNMR (400MHZ, DMSO-C¾: δ 9.80(s, 1H)， 8.64(s， 1H), 8.60(d, 1H, J=1.6), 8.08 (m, 2H), 7.88(d, 1H, J-9.2), 7.77(dd, 1H, J=9.0), 7.48 (q, 1H), 7.31(m,-3H), 7.18(m, 1H), 7.06(t, 1H), 6.22(d, 2H, J=2.0), 5.26(s, 2H), 3.71(s, 2H), 2.46(m, 2H), 2.3 l(m, 5H), 1.91(s, 1H), 1.24(t, 6H) 实施例 4  'HNMR (400MHZ, DMSO-C3⁄4: δ 9.80(s, 1H), 8.64(s, 1H), 8.60(d, 1H, J=1.6), 8.08 (m, 2H), 7.88(d, 1H, J- 9.2), 7.77 (dd, 1H, J=9.0), 7.48 (q, 1H), 7.31(m,-3H), 7.18(m, 1H), 7.06(t, 1H), 6.22(d, 2H, J =2.0), 5.26(s, 2H), 3.71(s, 2H), 2.46(m, 2H), 2.3 l(m, 5H), 1.91(s, 1H), 1.24(t, 6H) Example 4
Γ3-氯 -4-(3-氟-苄氧基 苯基 1-(6-ί2-ΙΪ2-吗啉 -4-基-乙氨基) -甲基 1-吡咯 -1-基 μ喹 唑啉 -4-基) -胺  3-Chloro-4-(3-fluoro-benzyloxyphenyl 1-(6-ί2-ΙΪ2-morpholin-4-yl-ethylamino)-methyl 1-pyrrol-1-ylpyrazoline- 4-yl)-amine
Figure imgf000058_0002
Figure imgf000058_0002
重复本发明实施例 2 第二步的反应， 使用上述第二步中所得到的化合物 1-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基}-111-吡咯 -2-甲醛 2c作原料， 按照 本发明实施例 2第三步所述相同方式进行该原料与 2-吗啉 -4-基-乙胺的反应，用硅 胶柱色谱法纯化所得残余物， 则得到标题产物 [3-氯 -4-(3-氟-苄氧基) -苯 基] -(6-{2-[(2-吗啉 -4-基-乙氨基) -甲基] -吡咯 -1-基}-喹唑啉 -4-基) -胺 4 (50 mg， 浅黄 色固体)。 产率： 23.8 %。  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. The obtained residue was purified to silica gel column chromatography toield]]]]]]]]]]]]]]]]]]]]]] -ethylamino)-methyl]-pyrrol-1-yl}-quinazolin-4-yl)-amine 4 (50 mg, pale yellow solid). Yield: 23.8 %.
MS m/z (ESI): 586[M+ 1] MS m/z (ESI): 586 [M+ 1]
1H MR (400MHz, OMSO-d6): δ 9.86(s, 1H), 8.65(s, 2H), 8.05(m, 2H), 7.87(m, 1H)， 7.75(dd, 1H, J=8.8), 7.45(q, 1H), 7.30(m, 3H), 7.18(m, 1H), 7.13(s, 1H), 6.38(s, 1H), 6.27(s, 1H), 5.27(s, 2H)， 3.93(m, 2H), 3.40(m, 4H), 2.87(m, 2H), 2.35(t, 2H, J=2.0), 2.23(s, 4H) 实施例 「3-氯 -4-(3-氟-苄氧基 苯基 〔6-{3-「〔2-甲磺酰基-乙氨基) -甲基 1-P比咯 -1-基} -喹 唑啉 -4-基) -胺
Figure imgf000059_0001
1H MR (400MHz, OMSO-d 6 ): δ 9.86(s, 1H), 8.65(s, 2H), 8.05(m, 2H), 7.87(m, 1H), 7.75(dd, 1H, J=8.8) , 7.45(q, 1H), 7.30(m, 3H), 7.18(m, 1H), 7.13(s, 1H), 6.38(s, 1H), 6.27(s, 1H), 5.27(s, 2H), 3.93(m, 2H), 3.40(m, 4H), 2.87(m, 2H), 2.35(t, 2H, J=2.0), 2.23(s, 4H) Example "3-Chloro-4-(3-fluoro-benzyloxyphenyl[6-{3-"[2-methanesulfonyl-ethylamino)-methyl 1-Ppyrrol-1-yl}-quinazole Phenyl-4-yl)-amine
Figure imgf000059_0001
Figure imgf000059_0002
Figure imgf000059_0002
第一步  First step
1H-吡咯 -3-甲醛  1H-pyrrole-3-carbaldehyde
氮气氛 0°C下在 250 mL茄形瓶中加入氢化钠（1.51 g， 57 mmol)，溶解于 80 mL 四氢呋喃中， 搅拌下滴加吡咯 5a (4 g， 59 mmol), 室温下搅拌 30分钟， 0°C搅拌 下滴加三异丙基氯硅烷（10 g， 52 mmol) , 反应 45分钟。 薄层分析跟踪至原料消 失，将反应液减压浓缩，加入 lOO mL水和 100 mL乙酸乙酯， 乙酸乙酯层用 50 mL 水洗。 减压浓缩， 备用。  Add sodium hydride (1.51 g, 57 mmol) to a 250 mL eggplant flask at 0 ° C, dissolve in 80 mL of tetrahydrofuran, add pyrrole 5a (4 g, 59 mmol) with stirring, and stir at room temperature for 30 minutes. Triisopropylchlorosilane (10 g, 52 mmol) was added dropwise with stirring at 0 ° C for 45 minutes. The thin layer analysis was followed until the starting material was lost. The reaction mixture was concentrated under reduced pressure. <RTI ID=0.0>> Concentrate under reduced pressure and set aside.
氮气氛 0°C下将草酰氯 （7.24 g， 46.7 mmol) 溶解于 240 mL二氯甲烷中， 搅 拌下滴加 Ν,Ν-二甲基甲酰胺 （4.6 g， 63 mmol) '的' 5 mE二氯甲烷溶液， （TC下搅 拌 20分钟。将备用中间体溶于 10 mL二氯甲垸中， 快速滴入反应液中， 60°C下回 流 30分钟， 冷却至 0°C， 氮气氛下过滤， 固体用乙醚洗涤， 真空干燥备用。  Oxalyl chloride (7.24 g, 46.7 mmol) was dissolved in 240 mL of dichloromethane at 0 ° C under nitrogen atmosphere, and Ν, 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.
将上述备用中间体溶于氢氧化钠溶液（50 mL， 5 % ) 中， 室温下搅拌 4小时。 薄层分析跟踪至原料消失， 用二氯甲烷萃取（100 mIX3)， 合并有机相， 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， 则得到标题 产物 1H-吡咯 -3-甲醛 5b ( 1.20 g, 褐色固体）。 产率： 31.6% 第二步  The above-mentioned alternate intermediate was dissolved in a sodium hydroxide solution (50 mL, 5 %) and stirred at room temperature for 4 hours. The thin layer analysis was carried out until the disappearance of the starting material, which was extracted with methylene chloride (100 mIX3), and the organic phase was combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. 1H-pyrrole-3-carbaldehyde 5b ( 1.20 g, brown solid). Yield: 31.6% Second step
1-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基}- -吡咯 -3-甲-醒 使用本发明实施例 1第五步中所得到的化合物 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-(6- 碘-喹唑啉 -4-基) -胺 ^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 1H-吡咯 -3-甲醛 5b的反应， 用硅胶柱色谱法纯化所得残余物， 则得到标题产 物 1-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基}-111-吡咯 -3-甲醛 5c (250 mg， 浅黄色固体)。 产率： 47.0%。  1-{4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-pyrrole-3-methyl-wake using the first embodiment of the present invention The compound [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-iodo-quinazolin-4-yl)-amine obtained in the five steps is used as a raw material according to the present invention. The reaction of the starting material with 1H-pyrrole-3-carbaldehyde 5b was carried out in the same manner as described in the first step of Example 1, and the obtained residue was purified by silica gel column chromatography to give the title product 1-{4-[3-chloro-4. -(3-Fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-111-pyrrole-3-carbaldehyde 5c (250 mg, pale yellow solid). Yield: 47.0%.
MS m/z (ESI): 473 [M+ 1] 第三步 MS m/z (ESI): 473 [M+ 1] Step 3
[3-氯 -4-(3-氟-苄氧基) -苯基 ]-(6-{3-[(2-甲磺酰基-乙氨基) -甲基] -吡咯 -1-基} -喹 唑啉 -4-基) -胺 [3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-{3-[(2-methanesulfonyl-ethylamino)-methyl]-pyrrol-1-yl} - Quino Oxazolin-4-yl)-amine
氮气氛下在 100 mL茄形瓶中加入 1-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基}-111-吡咯 -3-甲醛 5c (50 mg, 0.1 mmol)和 2-甲磺酰 -乙胺盐酸盐（40 mg， 0.3 mmol),溶于 10 mL四氢呋喃和 0.2 mL甲醇的混合溶剂中，再加入三乙胺（0.2 mL, 10 mmol), 室温搅拌 30分钟， 加入氰基硼氢化钠（40 mg， 0.6 mmol) , 室温 搅拌 4小时。 薄层分析跟踪至原料消失， 加入 30 mL乙酸乙酯和 30 mL水， 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，则得到标题产物 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-(6-{3-[(2-甲磺酰基 -乙氨基)-甲基] - 吡咯 -1-基 喹唑啉 -4-基) -胺 5 (20 mg, 淡黄色固体）， 产率： 34.5 %。  1-{4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-111-pyrrole was added to a 100 mL eggplant flask under nitrogen atmosphere. 3-formaldehyde 5c (50 mg, 0.1 mmol) and 2-methanesulfonyl-ethylamine hydrochloride (40 mg, 0.3 mmol), dissolved in a mixture of 10 mL of tetrahydrofuran and 0.2 mL of methanol, then triethylamine (0.2 mL, 10 mmol), stirred at room temperature for 30 min, then sodium succinamine (40 mg, 0.6 mmol). The thin layer analysis was carried out until the disappearance of the starting material. The residue was purified by silica gel column chromatography. Product [3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-{3-[(2-methanesulfonyl-ethylamino)-methyl]-pyrrol-1-ylquina Oxazolin-4-yl)-amine 5 (20 mg, pale yellow solid), Yield: 34.5 %.
MS m/z (ESI): 580[M+ 1] MS m/z (ESI): 580 [M+ 1]
iHNMR (400MHz, DMSO-t¾: δ 9.81(s, 1H)， 8.59(t, 2H), 8.12(dd，' 1H, J=9.0), 8.30 (d, 1H, J=2.8), 7.86(d, 1H, J=9.2), 7.77(dd, 1H, J=8.8), 7.50(m, 3H), 7.33(m， 3H), 7.19(m, 1H), 6.35(s, 1H), 5.28(s, 2H), 3.68(s, 2H), 3.34(m, 7H) 实施例 6 iHNMR (400MHz, DMSO-t3⁄4: δ 9.81 (s, 1H), 8.59 (t, 2H), 8.12 (dd, '1H, J=9.0), 8.30 (d, 1H, J=2.8), 7.86 (d, 1H, J=9.2), 7.77 (dd, 1H, J=8.8), 7.50(m, 3H), 7.33(m, 3H), 7.19(m, 1H), 6.35(s, 1H), 5.28(s, 2H), 3.68(s, 2H), 3.34(m, 7H) Example 6
l-{4-「3-氯 -4-(3-氟-苄氧基 苯氨基 1-喹唑啉 -6-基 4-三氟甲基 -1H-吡咯 -3-羧酸  L-{4-"3-Chloro-4-(3-fluoro-benzyloxyphenylamino-1-quinazolin-6-yl 4-trifluoromethyl-1H-pyrrole-3-carboxylic acid
Figure imgf000060_0001
第一步
Figure imgf000060_0001
first step
4-三氟甲基 -1H-吡咯 -3-羧酸乙酯  4-trifluoromethyl-1H-pyrrole-3-carboxylic acid ethyl ester
氮气氛下， 将对甲苯磺酰基甲基异腈（0.975 g， 5 mmol)和 (E)-4,4,4-三氟丁 烯酸乙酯 （0.84 g， 5 mmol)溶于 8 mL二甲亚砜和 16 mL乙醚的混合溶剂中， 室 温搅拌下将其滴加入氢化钠（240 mg， 6 mmol)的 6 mL乙醚悬浊液中， 室温搅拌 15分钟。 薄层分析跟踪至原料消失， 加入 30 mL水， 用乙醚萃取（30 mLx3)， 合 并有机相， 用无水硫酸镁干燥， 过滤， 滤液减压浓縮， 用硅胶柱色谱法纯化所得 残余物，则得到标题产物 4-三氟甲基 -1H-吡咯 -3-羧酸乙酯 6b(640 mg，浅黄色固体)。 产率： 61.8%。 Under a nitrogen atmosphere, p-toluenesulfonylmethyl isocyanide (0.975 g, 5 mmol) and (E)-4,4,4-trifluorobutenoic acid ethyl ester (0.84 g, 5 mmol) were dissolved in 8 mL. In a mixed solvent of sulfoxide and 16 mL of diethyl ether, it was added dropwise to a suspension of sodium hydride (240 mg, 6 mmol) in 6 mL of diethyl ether with stirring at room temperature, and stirred at room temperature. 15 minutes. The thin layer analysis was carried out until the disappearance of the starting material, and the residue was purified by silica gel column chromatography, eluting with ethyl acetate (30 mL). The title product 4-trifluoromethyl-1H-pyrrole-3-carboxylic acid ethyl ester 6b (640 mg, pale yellow solid) was obtained. Yield: 61.8%.
MS m/z (ESI): 206[M- 1] MS m/z (ESI): 206[M-1]
第二步  Second step
使用本发明实施例 1第五步中所得到的化合物 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-(6- 碘-喹唑啉—4-基) -胺 lg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 4-三氟甲基 -1H-吡咯 -3-羧酸乙酯 6b的反应，得到标题化合物 1-{4-[3-氯 -4-(3- 氟-苄氧基) -苯氨基] -喹唑啉 -6-基}-4-三氟甲基 -1H-吡咯 -3-羧酸乙酯 6 (30 mg， 浅黄 色固体)。 产率： 51.4%。  The compound [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-iodo-quinazolin-4-yl)-amine obtained in the fifth step of Example 1 of the present invention was used. Using lg as a starting material, the reaction of the starting material with ethyl 4-trifluoromethyl-1H-pyrrole-3-carboxylate 6b was carried out in the same manner as described in the sixth step of Example 1 to obtain the title compound 1-{4- [3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-4-trifluoromethyl-1H-pyrrole-3-carboxylic acid ethyl ester 6 (30 Mg, light yellow solid). Yield: 51.4%.
MS m/z (ESI): 585[M+ 1] MS m/z (ESI): 585 [M+ 1]
1HNMR (400MHz, DMSO- 6): δ 8.77(s, 2H), 8.32(s， 1H), 8.27(s, 1H)， 8.19(s, 1H), 8.00(d, 1H， J=4.0), 7.90(s, 1H), 7.72(dd, 1H, J=8.8), 7.48(q, 1H), 7.3 l(m, 3H) , 7.18(t, 1H), 5.26 (s, 2H), 4.28(q, 2H), 1.31(t, 3H) 实施例 7 1 H NMR (400MHz, DMSO- 6 ): δ 8.77 (s, 2H), 8.32 (s, 1H), 8.27 (s, 1H), 8.19 (s, 1H), 8.00 (d, 1H, J = 4.0), 7.90(s, 1H), 7.72(dd, 1H, J=8.8), 7.48(q, 1H), 7.3 l(m, 3H) , 7.18(t, 1H), 5.26 (s, 2H), 4.28(q , 2H), 1.31(t, 3H) Example 7
2-{443-氯 -4-(3-氟-苄氧基 苯氨基 1-喹唑啉 -6-基 吡咯 -1-羧酸叔丁酯 2- ( 4-43-Chloro-4-(3-fluoro-benzyloxyphenylamino-1-quinazolin-6-ylpyrrole-1-carboxylic acid tert-butyl ester)
Figure imgf000061_0001
Figure imgf000061_0001
第一歩  First
吡咯 -1-羧酸叔丁酯  Pyrrole-1-carboxylic acid tert-butyl ester
在 100 mL茄形瓶中加入吡咯（6.71 g， 100 mmol),二碳酸二叔丁酯（26.20 g， 130 mmol)和 4-二甲胺基吡啶（4.89 g， 40 mmol), 用 50 mL乙腈溶解， 室温搅拌 过夜。 薄层分析跟踪至原料消失， 减压浓缩， 用硅胶柱色谱法纯化所得残余物， 则得到标题产物吡咯 -1-羧酸叔丁酯 7a ( 12.5 g， 无色液体）。 产率： 85.7%。 Add pyrrole (6.71 g, 100 mmol), di-tert-butyl dicarbonate (26.20 g, 130 mmol) and 4-dimethylaminopyridine (4.89 g, 40 mmol) in a 100 mL eggplant vial with 50 mL acetonitrile Dissolved and stirred at room temperature overnight. The thin layer analysis was followed until the disappearance of the starting material, concentration under reduced pressure, and the residue obtained was purified by silica gel column chromatography. The title product, tert-butyl pyrrol-1-carboxylate 7a (12.5 g, colorless liquid) was obtained. Yield: 85.7%.
第 ^ -iy  The first ^ -iy
1-羧酸叔丁酯 -2-吡咯硼酸  1-carboxylic acid tert-butyl ester -2-pyrrole boronic acid
氩气氛下， 在 250 mL三口瓶中加入吡咯 -1-羧酸叔丁酯 7a ( 10.47 g, 62.6 mmol), 溶于 100 mL四氢呋喃中， -78Ό搅拌下滴加二异丙基氨基锂 （34 mL， 四 氢呋喃溶液， 2.0 mol/L), -78°C反应 2小时，滴加硼酸三甲酯 (9 mL, 81.4 mmol), -78Ό反应 1小时， 升温至 -40°C反应 30分钟。 薄层分析跟踪至原料消失， 将反应 液倒入 100 mL冰水中， 用 1N盐酸调 pH至 1， 用乙酸乙酯萃取（100 mLx3 )， 合 并有机相，有机相用 200 mL饱和氯化钠溶液洗涤，乙酸乙酯层用无水硫酸镁干燥， 过滤， 滤液减压浓缩， 加入 50 mL正己烷， 放入冰箱冷冻， 减压抽滤， 真空干燥， 则得到标题产物 1-羧酸叔丁酯 -2-吡咯硼酸 7b (6.94 g, 淡黄色固体）。 产率： 52.6 %。  Under a argon atmosphere, add pyrrole-1-carboxylic acid tert-butyl ester 7a (10.47 g, 62.6 mmol) in a 250 mL three-necked flask, dissolve in 100 mL of tetrahydrofuran, add -diisopropylamide lithium dropwise with -78 Torr. The mixture was reacted at -78 ° C for 2 hours, trimethyl borate (9 mL, 81.4 mmol) was added dropwise, and the reaction was carried out for 1 hour at -78 ° C, and the temperature was raised to -40 ° C for 30 minutes. The thin layer analysis was followed until the disappearance of the starting material. The reaction solution was poured into 100 mL of ice water, adjusted to pH 1 with 1N hydrochloric acid, extracted with ethyl acetate (100 mL×3), and the organic phase was combined. The title compound, 1-carboxylic acid tert-butyl ester, was obtained. EtOAcjjjjjjjjj -2-pyrrole boronic acid 7b (6.94 g, pale yellow solid). Yield: 52.6%.
iHNMR (400MHz, DMSO- ): δ 8.02(s, 2Η), 7.33(dd, 1H， J=2.8), 6.43(dd, IH, J=3.2), 6.22(t, IH), 1.55(s, 9H) ' iHNMR (400MHz, DMSO-): δ 8.02(s, 2Η), 7.33(dd, 1H, J=2.8), 6.43(dd, IH, J=3.2), 6.22(t, IH), 1.55(s, 9H ) '
第三步  third step
2-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基} -吡咯 -1-羧酸叔丁酯 重复实施例 1第一步至第五步的反应， 将得到的化合物 [3-氯 -4-(3-氟-苄氧基) - 苯基] -(6-碘-喹唑啉 -4-基) -胺 lg (2.02 g， 4 mmol), 1- (叔丁氧基羰基) -1H-吡咯 -2-硼 酸（l.lg， 5.2mmol)，四三苯基膦化钯（0.23g， 0.2mmol),碳酸钾（1.38g， lOmmol) 溶于 25 mL Ν,Ν-二甲基甲酰胺和 6 mL水的混合溶剂中， 得到的混合物加热到 70 V， 2小时后反应完毕。 将反应液冷却至室温， 倒入 300mL冰水中， 析出白色固 体， 搅拌十分钟后， 抽滤， 产物在真空下干燥， 得到的固体进一步通过柱层析， 得到标题产物 2-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基} -吡咯 -1-羧酸叔丁 酉旨 7 (1.86 g， 浅黄色固体)。 产率： 85.7%。 2-{ 4 -[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-pyrrole-1-carboxylic acid tert-butyl ester Step to the reaction of the fifth step, the obtained compound [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-iodo-quinazolin-4-yl)-amine lg ( 2.02 g, 4 mmol), 1-(tert-butoxycarbonyl)-1H-pyrrole-2-boronic acid (1. lg, 5.2 mmol), tetratriphenylphosphine palladium (0.23 g, 0.2 mmol), potassium carbonate (1.38 g, lOmmol) Dissolved in 25 mL of a mixed solvent of hydrazine, hydrazine-dimethylformamide and 6 mL of water, the mixture was heated to 70 V, and the reaction was completed after 2 hours. The reaction solution was cooled to room temperature, poured into 300 mL of ice water, and a white solid was precipitated. After stirring for ten minutes, the mixture was filtered under suction, and the product was dried under vacuum. -Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-pyrrole-1-carboxylic acid tert-butyl hydrazine 7 (1.86 g, pale yellow solid). Yield: 85.7%.
MS m/z (ESI): 545[M+ 1] MS m/z (ESI): 545 [M+ 1]
iHNMR (400MHz, DMSO- )： δ 9.78(s, IH), 8.61(s, 1H)， 8.58(s, IH), 8.07(d, IH, J=2.0), 7.85(dd, IH, J=8.6), 7.78(s, ,1H), 7.76(d, IH), 7.46(m, 2H), 7.3 l(m, 3H), 7.18 (t, IH), 6.45(m, IH), 6.38(t, IH), 5.26(s, 2H), 1.30(s, 9H) 实施例 8 iHNMR (400MHz, DMSO-): δ 9.78 (s, IH), 8.61 (s, 1H), 8.58 (s, IH), 8.07 (d, IH, J = 2.0), 7.85 (dd, IH, J = 8.6 ), 7.78(s, ,1H), 7.76(d, IH), 7.46(m, 2H), 7.3 l(m, 3H), 7.18 (t, IH), 6.45(m, IH), 6.38(t, IH), 5.26(s, 2H), 1.30(s, 9H) Example 8
Γ3-氯 -4-(3-氟-苄氧基) -苯基 1-「6-αΗ-吡咯 -2-基) -喹唑啉 -4-基 1-胺  Γ3-Chloro-4-(3-fluoro-benzyloxy)-phenyl 1-"6-αΗ-pyrrole-2-yl)-quinazoline-4-yl 1-amine
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000062_0001
Figure imgf000063_0001
在 100 mL茄形瓶中， 加入本发明实施例 7第三步中所得到的化合物 2-{4-[3- 氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基} -吡咯 -1-羧酸叔丁酯 7 ( 1.18 g， 2.17 mmol), 溶于 50 mL四氢呋喃中， 加入甲醇钠（936 mg， 8.66 mmol), 室温搅拌过 夜。薄层分析跟踪至原料消失，将反应液倒入 100 mL冰水中，用乙酸乙酯萃取（50 mLx3 ), 合并有机相， 用无水硫酸钠千燥， 过滤， 滤液减压浓缩， 加入 20 mL正 己烷，放入冰箱冷冻，减压抽滤，真空干燥，则得到标题产物 [3-氯 -4-(3-氟-苄氧基) - 苯基] -[6-(1Η-吡咯 -2-基) -喹唑啉 -4-基] -胺 8 (0.65 g， 淡绿色固体）。 产率： 80.0%。 MS m/z (ESI): 445[M+ 1]  In a 100 mL eggplant-shaped flask, the compound 2-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazole obtained in the third step of Example 7 of the present invention was added. tert-Butyl 6-yl}-pyrrole-l-carboxylate 7 ( 1.18 g, 2.17 mmol) was dissolved in 50 mL EtOAc. Thin layer analysis was performed until the disappearance of the starting material. The reaction solution was poured into 100 mL of ice water and extracted with ethyl acetate (50 mL×3). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Hexane, which was placed in a freezer, chilled, vacuum filtered, and dried in vacuo to give the title product [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1Η-pyrrole-2 -yl)-quinazolin-4-yl]-amine 8 (0.65 g, pale green solid). Yield: 80.0%. MS m/z (ESI): 445 [M+ 1]
iHNMR (400MHz, DMSO-i¾： 8.64(d, 1H, J-2.0), 8.53(s, 1H), 8.14(dd, 1H, J=8.4), 8.05(d, 1H, J=2.8), 7.77(dd, 2H, J=9.0), 7.49(q, 1H), 7.33(m, 4H), 7.19(m, 1H), 6.97(s, 1H), 6.78(s, 1H), 6.22(s, 1H), 5.27(s, 2H)  iHNMR (400MHz, DMSO-i3⁄4: 8.64 (d, 1H, J-2.0), 8.53 (s, 1H), 8.14 (dd, 1H, J = 8.4), 8.05 (d, 1H, J = 2.8), 7.77 ( Dd, 2H, J=9.0), 7.49(q, 1H), 7.33(m, 4H), 7.19(m, 1H), 6.97(s, 1H), 6.78(s, 1H), 6.22(s, 1H) , 5.27(s, 2H)
Figure imgf000063_0002
氩气氛下， 在 10 mL茄形瓶中加入本发明实施例 8所得的化合物 [3-氯 -4-(3- 氟-苄氧基) -苯基 ]-[6-(1Η-吡咯 -2-基) -喹唑啉 -4-基] -胺 8，溶于 2 mL N,N-二甲基甲酰 胺，搅拌下加入氢化钠（8 mg， 0.337 mmol),室温搅拌 1小时，加入碘甲烷（32 mg， 0.225 mmol), 室温搅拌过夜。 薄层分析跟踪至原料消失， 将反应液倒入 20 mL水 中， 用乙酸乙酯萃取（25 mLx3)， 合并有机相， 用 25 mL饱和氯化钠溶液洗涤， 乙酸乙酯层用无水硫酸镁干燥。 过滤， 滤液减压浓縮， 用硅胶柱色谱法纯化所得 残余物， 则得到标题产物 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-[6-(1-甲基 -1H-吡咯 -2-基) -喹 唑啉 -4-基] -胺 9 (35 mg, 淡黄色固体）。 产率： 34.0%。
Figure imgf000063_0002
The compound [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1Η-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. The reaction solution was poured into 20 mL of water and extracted with ethyl acetate (25 mL×3). The organic phase was combined and washed with 25 mL of saturated sodium chloride. dry. Filtration, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography The residue obtained the title product [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1-methyl-1H-pyrrol-2-yl)-quinazoline- 4-yl]-amine 9 (35 mg, pale yellow solid). Yield: 34.0%.
MS m/z (ESI): 459[M+ 1] MS m/z (ESI): 459 [M+ 1]
XHNMR (400MHz, OMSO-d6): 9.78(s, 1H), 8.59(s, 1H), 8.53(s, 1H), 8.04(d, 1H, J=2.4): 7.94(dd, 1H, J-8.4), 7.8 l(d, 1H, J=8.4), 7.76(dd, 1H, J=9.0), 7.49(q, 1H), 7.3 l(m, 3H), 7.19(t, 1H), 6.95(s, 1H), 6.35(s, 1H), 6.15(s, 1H), 5.27(s, 2H), 3.75(s, 3H) 实施例 10 X HNMR (400MHz, OMSO-d 6 ): 9.78 (s, 1H), 8.59 (s, 1H), 8.53 (s, 1H), 8.04 (d, 1H, J=2.4) : 7.94 (dd, 1H, J -8.4), 7.8 l(d, 1H, J=8.4), 7.76(dd, 1H, J=9.0), 7.49(q, 1H), 7.3 l(m, 3H), 7.19(t, 1H), 6.95 (s, 1H), 6.35(s, 1H), 6.15(s, 1H), 5.27(s, 2H), 3.75(s, 3H) Example 10
2-ί4-Γ3-氯 -4-(3-氟-苄氧基 苯氨基 1-喹唑啉 -6-基 6,7-二氢 -2H-吡喃「3，4-clP比  2-ί4-Γ3-chloro-4-(3-fluoro-benzyloxyphenylamino-1-quinazoline-6-yl 6,7-dihydro-2H-pyran "3,4-clP ratio
Figure imgf000064_0001
Figure imgf000064_0001
10  10
第一步  First step
6,7-二氢 -2H-吡喃 [3,4-c]吡咯 -4-酮  6,7-Dihydro-2H-pyran [3,4-c]pyrrole-4-one
在 lOO mL三口瓶中， 加入对甲苯磺酰基甲基异腈（5.48 g， 28.05 mmol), 溶 于 20 mL四氢呋喃中， 0°C搅拌下滴加 1,8-二氮双环 [5.4.0]十一碳 -7-烯 （4.2 mL， 28.05 mmol), 15分钟后加入 5,6-二氢吡喃酮 10a (2.5 g， 25.5 mmol) 的 20 mL四 氢呋喃溶液， 室温搅拌 2小时。 薄层分析跟踪至原料消失， 倒入 150 mL饱和氯化 钠溶液中， 室温搅拌过夜。减压浓缩除去四氢呋喃， 用乙酸乙酯萃取（50 mLx5 ) , 合并有机相， 用无水硫酸镁干燥。 过滤， 滤液减压浓縮， 用 15 mL乙酸乙酯重结 晶， 得到标题产物 6,7-二氢 -2H-吡喃 [3,4-c]吡咯 -4-酮 10b (2.20 g, 黄色固体）。 产 率： 76.3 °  In a 100 mL three-necked flask, p-toluenesulfonylmethyl isocyanide (5.48 g, 28.05 mmol) was added, dissolved in 20 mL of tetrahydrofuran, and 1,8-diazabicyclo[5.4.0] was added dropwise with stirring at 0 °C. Eleven-carbon-7-ene (4.2 mL, 28.05 mmol) was added to a solution of 5,6-dihydropyranone 10a (2.5 g, 25.5 mmol) in 20 mL THF over 15 min. The thin layer analysis was followed until the disappearance of the starting material, poured into 150 mL of saturated sodium chloride solution, and stirred at room temperature overnight. The organic layer was combined and dried over anhydrous magnesium sulfate (MgSO4). Filtration, the filtrate was concentrated under reduced pressure and crystallised eluted eluted eluted elut elut elut elut elut elut elut elut elut elut ). Productivity: 76.3 °
1HNMR (400MHz, DMSO-^): δ 11.70(s, 1Η), 7.16(dd, 1H, J=2.8), 6.64(d, 1H, J=0.8), 2.80(t, 2H), 2.7 l(t, 2H) 第二步 1 H NMR (400 MHz, DMSO-^): δ 11.70 (s, 1 Η), 7.16 (dd, 1H, J = 2.8), 6.64 (d, 1H, J = 0.8), 2.80 (t, 2H), 2.7 l ( t, 2H) Second step
2-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基}-6,7-二氢 -2H-吡喃 [3，4-c]吡 咯 -4-酮  2-{4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-6,7-dihydro-2H-pyran [3,4 -c]pyrrol-4-one
氩气氛下在 250 mL茄形瓶中加入本发明实施例 1第五步所得的化合物 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-(6-碘-喹唑啉 -4-基) -胺 lg (4.31 g， 8.53 mmol), 再加入 6,7- 二氢 -2H-吡喃 [3,4-c]吡咯 -4-酮 10b(1.52 g， 11.68 mmol), 碘化亚铜 （840 mg， 4.26 mmol)和磷酸钾 （5.43 g， 25.58 mmol), 溶于 80 mL N,N-二甲基甲酰胺中， 搅拌 下加入 Ν,Ν'-二甲基 -1,2-乙二胺 （0.5 mL， 4.26 mmol), 加热至 68°C搅拌过夜。 薄 层分析跟踪至原料消失，将反应液倒入 800 mL水中，搅拌下析出固体，减压抽滤， 固体用水洗涤（50 mLx2)，真空干燥，则得到标题产物 2-{4-[3-氯 -4-(3-氟-苄氧基) - 苯氨基] -喹唑啉 -6-基}-6,7-二氢 -2H-吡喃 [3,4-c]吡咯 -4-酮 10 (3.57 g,黄绿色固体）。 产率： 81.3 %。  The compound [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-iodo-quinazoline) obtained in the fifth step of Example 1 of the present invention was added to a 250 mL eggplant-shaped flask under an argon atmosphere. 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, Ν'-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. The reaction solution was poured into 800 mL of water, and the solid was separated by stirring. The solid was filtered under reduced pressure. The solid was washed with water (50 mL×2) and dried in vacuo to give the title product 2-{4-[3- Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-6,7-dihydro-2H-pyrano[3,4-c]pyrrol-4-one 10 (3.57 g, yellow-green solid). Yield: 81.3%.
MS m/z (ESI): 515[M+ 1] MS m/z (ESI): 515 [M+ 1]
iHNMR (400MHz, DMSO-t¾): δ 9.81(s, 1H), 8.74(d, 1H, J=2.0), 8.61(s, 1H), 8.26(d, 1H, J=2.0), 8.23(dd, 1H, J=9.0), 8.02(d, 1H, J=2.8), 7.90(d, 1H, J=8.8), 7.74(dd, 1H, J-8.8), 7.53(s, 1H), 7.48(q, 1H), 7.34(m, 3H), 7.19(t, 1H), 5.28(s, 2H), 4.49(t, 2H, J=5.8), 2.91(t, 2H, J=5.8) 实施例 11 iHNMR (400MHz, DMSO-t3⁄4): δ 9.81 (s, 1H), 8.74 (d, 1H, J = 2.0), 8.61 (s, 1H), 8.26 (d, 1H, J = 2.0), 8.23 (dd, 1H, J=9.0), 8.02(d, 1H, J=2.8), 7.90(d, 1H, J=8.8), 7.74(dd, 1H, J-8.8), 7.53(s, 1H), 7.48(q , 1H), 7.34(m, 3H), 7.19(t, 1H), 5.28(s, 2H), 4.49(t, 2H, J=5.8), 2.91(t, 2H, J=5.8) Example 11
N— ( -{4—「3-氯 (3_氟-苄氧基 苯氨基 1-喹唑啉 -6-基 }-1Η-吡咯 -2-基甲 N — ( -{ 4 — "3-Chloro(3_fluoro-benzyloxyphenylamino-1-quinazolin-6-yl}-1Η-pyrrole-2-yl)
基) -Ν',Ν'-二乙基 -1,2-乙二胺  Base) -Ν',Ν'-diethyl-1,2-ethanediamine
Figure imgf000065_0001
Figure imgf000065_0001
第一步  First step
5-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基]-喹唑啉 -6-基 }-1Η-吡咯 -2-甲醛 氩气氛下在 50 mL茄形瓶中加入本发明实施例 8所得的化合物 [3-氯 -4-(3-氟- 苄氧基) -苯基 ]-[6-(1Η-吡咯 -2-基) -喹唑啉 -4-基] -胺 8( 1.02 g，2.30 mmol)，溶于 10 mL Ν,Ν-二甲基甲酰胺中， -15°C搅拌下， 加入三氯氧磷 （0.3 mL, 3.45 mmol), 室温 搅拌过夜。 薄层分析跟踪至原料消失， 加入 10 mL冰水， 用 1N氢氧化钠溶液调 pH至 11， 过滤， 固体真空干燥， 则得到标题产物 5-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨 基] -喹唑啉 _6-基) -1Η-吡咯 -2-甲醛 11a (0.686 g， 墨绿色固体）粗产品。产率： 63.15-{4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-1Η-pyrrole-2-carbaldehyde in an argon atmosphere at 50 mL eggplant The compound [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1Η-pyrrol-2-yl)-quinazoline-4 obtained in Example 8 of the present invention was added to the bottle. -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. The thin layer analysis was followed until the disappearance of the starting material, 10 mL of ice water was added, the pH was adjusted to 11 with 1N sodium hydroxide solution, filtered, and the solid was dried in vacuo to give the title product 5-{4-[3-chloro-4-(3- Fluoro-benzyloxy)-benzene ammonia -] quinazoline-6-yl) -1 Η-pyrrole-2-carbaldehyde 11a (0.686 g, dark green solid) crude product. Yield: 63.1
%。 %.
MS m/z (ESI): 473 [M+ l]  MS m/z (ESI): 473 [M+ l]
1HNMR (400MHz, DMSO- 6): δ 12.44(s, 1H), 9.76(s, 1H), 9.56(s， 1H), 8.90(s, 1H), 8.59(s, 1H), 8.40(d, 1H, J=9.2), 8.04(s， 1H), 7.8 l(d, 1H, J=8.8), 7.75(dd, 1H, J=8.8), 7.46(m, 1H), 7.33(m, 3H), 7.20(m, 2H)， 7.02(s, 1H), 5.28(s, 2H) 1 HNMR (400MHz, DMSO- 6) : δ 12.44 (s, 1H), 9.76 (s, 1H), 9.56 (s, 1H), 8.90 (s, 1H), 8.59 (s, 1H), 8.40 (d, 1H, J=9.2), 8.04(s, 1H), 7.8 l(d, 1H, J=8.8), 7.75(dd, 1H, J=8.8), 7.46(m, 1H), 7.33(m, 3H) , 7.20(m, 2H), 7.02(s, 1H), 5.28(s, 2H)
第二步  Second step
N-(5-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基]-喹唑啉 -6-¾}-1Η-吡咯 -2-基甲  N-(5-{4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-3⁄4}-1Η-pyrrole-2-yl group
-基) -Ν',Ν'-二乙基 -1,2-乙二胺  -yl) -Ν',Ν'-diethyl-1,2-ethanediamine
100 mL茄形瓶中加入 5-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基}-111-吡 咯 -2-甲醛 11a (294 mg， 0.62 mmol)和 Ν,Ν-二乙基 -1,2-乙二胺（139 mg， 1.2 mmol)， 溶于 10 mL四氢呋喃和 0.2 mL甲醇的混合溶剂中， 室温搅拌 30分钟， 加入氰基 硼氢化钠（80 mg， 1.2 mmol) , 室温搅拌 4小时。薄层分析跟踪至原料消失， 加入 50 mL水， 用乙酸乙酯萃取（50x3)， 合并有机相， 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，则得到标题产物 N-(5-{4-[3- 氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基 }- 1 H-吡咯 -2-基甲基) -Ν',Ν'-二乙基 - 1 ,2-乙 二胺 11 (35 mg， 黄色固体)。 产率： 10.2%。  Add 5-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-111-pyrrole-2-carbaldehyde 11a to a 100 mL eggplant flask (294 mg, 0.62 mmol) and hydrazine, hydrazine-diethyl-1,2-ethanediamine (139 mg, 1.2 mmol), dissolved in 10 mL of tetrahydrofuran and 0.2 mL of methanol, stirred at room temperature for 30 min. Sodium cyanoborohydride (80 mg, 1.2 mmol) was added and stirred at room temperature for 4 h. Thin layer analysis was carried out until the disappearance of the starting material, 50 mL of water was added, and the mixture was extracted with ethyl acetate (50×3), and the organic phase was combined. The ethyl acetate layer was dried over anhydrous magnesium sulfate. The obtained residue obtained the title product N-(5-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}- 1 H-pyrrole -2-ylmethyl)-Ν', Ν'-diethyl-1,2-ethanediamine 11 (35 mg, yellow solid). Yield: 10.2%.
MS m/z (ESI): 573 [M+ l] MS m/z (ESI): 573 [M+ l]
1HNMR (400MHz, DMSO-^): δ 11.82(s, 1H), 9.84(s, 1H), 9.10(s, 1H), 8.55(s, 1H), 8.26(s, 1H), 8.14(d, 1H, J=8.4), 7.98(d, 1H, J=8.4), 7.75(d, 1H, J=8.4), 7.47(m, 1H), 7.33(m, 3H) , 7.19(t, 1H), 6.73(s, 1H), 6.19(s, 1H), 5.26(s, 2H), 2.84(dd, 4H, J=13.8), 2.73(d, 4H, J=6.8), 1.36(s, 1H), 1.26(s, 1H), 1.06(t, 6H， J=6.6) 实施例 12 1 H NMR (400MHz, DMSO-^): δ 11.82 (s, 1H), 9.84 (s, 1H), 9.10 (s, 1H), 8.55 (s, 1H), 8.26 (s, 1H), 8.14 (d, 1H, J=8.4), 7.98(d, 1H, J=8.4), 7.75(d, 1H, J=8.4), 7.47(m, 1H), 7.33(m, 3H), 7.19(t, 1H), 6.73(s, 1H), 6.19(s, 1H), 5.26(s, 2H), 2.84(dd, 4H, J=13.8), 2.73(d, 4H, J=6.8), 1.36(s, 1H), 1.26(s, 1H), 1.06(t, 6H, J=6.6) Example 12
Γ3-氯 -4-(3-氟-苄氧基) -苯基 1-(6-i5-f(2-甲磺酰基-乙氨基) -甲基 1-lH-吡咯 -2-基  Γ3-Chloro-4-(3-fluoro-benzyloxy)-phenyl 1-(6-i5-f(2-methanesulfonyl-ethylamino)-methyl 1-lH-pyrrole-2-yl
' 喹唑啉 -4-基 -胺  'quinazoline-4-yl-amine
Figure imgf000066_0001
重复本发明实施例 11第一步至第二步的反应， 使用上述第一步中所得到的化 合物 5-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基}-11¾-吡咯 -2-甲醛 11a作原料， 按照本发明实施例 11第二歩所述相同方式进行该原料与 2-甲磺酰 -乙胺盐酸盐 2b 的反应， 用硅胶柱色谱法纯化所得残余物， 则得到标题产物 [3-氯 -4-(3-氟- 氧基) - 苯基] -(6-{5-[(2-甲磺酰基 -乙氨基)-甲基] -1H-吡咯 -2-基 喹唑啉 -4-基) -胺 12 (21 mg， 黄色固体)。 产率： 9.1 %。 S m/z (ESI): 580[M+ 1]
Figure imgf000066_0001
The reaction of the first step to the second step of Example 11 of the present invention was repeated, using the compound 5-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino group obtained in the above first step. - quinazoline-6-yl}-113⁄4-pyrrole-2-carbaldehyde 11a as a starting material, the starting material and 2-methanesulfonyl-ethylamine hydrochloride were carried out in the same manner as in the second step of Example 11 of the present invention. The reaction of 2b was purified by silica gel column chromatography toield toield of the title product [3-chloro-4-(3-fluoro-oxy)-phenyl]-(6-{5-[(2-methane) Acyl-ethylamino)-methyl]-1H-pyrrol-2-ylquinazolin-4-yl)-amine 12 (21 mg, yellow solid). Yield: 9.1%. S m/z (ESI): 580 [M+ 1]
1HNMR (400MHz, DMSO-t¾: δ 11.90(s, IH), 9.86(s, IH), 8.93(s, IH), 8.57(s, IH), 8.14(d, 2H), 7.83(m, 2H), 7.48(q, IH), 7.32(q, 3H), 7.20(t, IH), 6.82(s, IH), 6.40(s, 1H): 5.28(s, 2H), 4.27(s, 2H), 3.57(m, 2H), 3.39(m, 2H), 3.15(s, 3H) 实施例 13 1 H NMR (400 MHz, DMSO-t3⁄4: δ 11.90 (s, IH), 9.86 (s, IH), 8.93 (s, IH), 8.57 (s, IH), 8.14 (d, 2H), 7.83 (m, 2H) ), 7.48(q, IH), 7.32(q, 3H), 7.20(t, IH), 6.82(s, IH), 6.40(s, 1H): 5.28(s, 2H), 4.27(s, 2H) , 3.57(m, 2H), 3.39(m, 2H), 3.15(s, 3H) Example 13
l-{4-「3-氯—4-(3-氟-苄氧基) -苯氨基 1-喹唑啉 -6-基 }-4-(2-羟基 -乙基 IH-吡咯 -3- 羧酸 -(2-二乙氨基-乙基) -胺 L-{4-" 3 -Chloro-4-(3-fluoro-benzyloxy)-phenylamino-1-quinazolin-6-yl}-4-(2-hydroxy-ethyl IH-pyrrole-3- Carboxylic acid-(2-diethylamino-ethyl)-amine
Figure imgf000067_0001
氩气氛下在 25 mL 茄形瓶中加入本发明实施例 10 第二步所得的化合物 2-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基}-6,7-二氢 -2H-吡喃 [3,4-c]吡咯 -4- 酮 10 (500 mg， 0.971 mmol), 溶于 2 mL N,N-二乙基 - 1,2-乙二胺中， 加热至 85°C 搅拌过夜。 薄层分析跟踪至原料消失， 将反应液减压浓缩， 用硅胶柱色谱法纯化 所得残余物，再用 2 mL乙酸乙酯重结晶，则得到标题产物 1-{4-[3-氯 -4-(3-氟 -苄氧 基) -苯氨基]-喹唑啉 -6-基 }-4-(2-羟基-乙基) -1H-吡咯 -3-羧酸 -(2-二乙氨基-乙基) -胺 13 (274 mg, 淡黄色固体）。 产率： 44.7%。
Figure imgf000067_0001
The compound 2-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazole obtained in the second step of the present invention was added to a 25 mL eggplant-shaped flask under an argon atmosphere. Phenyl-6-yl}-6,7-dihydro-2H-pyrano[3,4-c]pyrrol-4-one 10 (500 mg, 0.971 mmol) in 2 mL of N,N-diethyl - 1,2-ethylenediamine, heated to 85 ° C and stirred overnight. The thin layer analysis was carried out until the disappearance of the starting material, and the reaction mixture was evaporated to dryness. -(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-4-(2-hydroxy-ethyl)-1H-pyrrole-3-carboxylic acid-(2-diethylamino) -ethyl)-amine 13 (274 mg, pale yellow solid). Yield: 44.7%.
MS m/z (ESI): 631[M+ 1] MS m/z (ESI): 631 [M+ 1]
tHNMR (400MHz, DMSO-c¾: δ 9.85(s, IH), 8.62(d, 1H， J=2.0), 8.59(s, IH), 8.09 (dd, IH, J=9.0), 8.00(dd, 2H, J=9.0), 7.89(m, 2H), 7.74(dd, IH, J=9.0), 7.48(q, IH) , 7.39(d, IH, J=2.0), 7.33(q， 3H), 7.19(t, IH), 5.27(s, 2H), 4.82(s, IH), 3.66(s, 2H), 3.30(m, 3H), 2.90(t, 2H, J-6.8), 2.53(m, 5H), 0.99(t, 6H, J=7.2) 实施例 14 tHNMR (400MHz, DMSO-c3⁄4: δ 9.85 (s, IH), 8.62 (d, 1H, J=2.0), 8.59 (s, IH), 8.09 (dd, IH, J=9.0), 8.00 (dd, 2H) , J=9.0), 7.89(m, 2H), 7.74(dd, IH, J=9.0), 7.48(q, IH) , 7.39(d, IH, J=2.0), 7.33(q, 3H), 7.19 (t, IH), 5.27(s, 2H), 4.82(s, IH), 3.66(s, 2H), 3.30(m, 3H), 2.90(t, 2H, J-6.8), 2.53(m, 5H ), 0.99 (t, 6H, J = 7.2) Example 14
Ν_α_{4_「3_氯 -4-(3-氟-苄氧基) -苯氨基 喹唑啉 _6-基 μ1Η_吡咯 _3-基甲 Ν _ α _ {4 _ "_ 3 chloro - 4 - (3 - fluoro - benzyloxy) - phenylamino quinazoline _6- yl pyrrolidin μ 1Η _ _ 3 - group A
基) -Ν',Ν'-二乙基 -1,2-乙二胺
Figure imgf000068_0001
重复本发明实施例 5第一歩至第二步的反应， 使用上述第二步中所得到的化 合物 [3-氯斗 (3_氟—苄氧基)—苯氨基]—喹唑啉 基 ！^吡咯 -3-甲醛 5c作原料， 按照本发明实施例 5第三步所述相同方式进行该原料与 Ν,Ν-二乙基 -1,2-乙二胺的 反应，用乙酸乙酯和正己烷重结晶，则得到标题产物 N-(l-{4-[3-氯 -4-(3-氟-苄氧基) - 苯氨基]-喹唑啉 -6-基 }-1Η-吡咯 -3-基甲基) -Ν',Ν'-二乙基 -1,2-乙二胺 14 ( 60 mg， 黄 色固体）。 产率： 43.8 %。 Base) -Ν',Ν'-diethyl-1,2-ethanediamine
Figure imgf000068_0001
The reaction of the first to the second step of Example 5 of the present invention was repeated, and the compound [3 - chloropipe ( 3 - fluoro-benzyloxy)-phenylamino]-quinazoline group obtained in the above second step was used! Pyrrole-3-carbaldehyde 5c is used as a starting material, and the reaction of the starting material with hydrazine, hydrazine-diethyl-1,2-ethylenediamine is carried out in the same manner as described in the third step of Example 5 of the present invention, using ethyl acetate and Recrystallization from n-hexane gave the title product N-(l-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-1Η-pyrrole -3-ylmethyl)-Ν', Ν'-diethyl-1,2-ethanediamine 14 (60 mg, yellow solid). Yield: 43.8 %.
MS m/z (ESI): 573 [M+1] MS m/z (ESI): 573 [M+1]
!HNMR (400MHz, DMSO-^): δ 8.60(s, 1H)， 8.58(s, 1H), 8.10(dd, 1H, J-2.2), 8.19(d, 1H, J=2.4), 7.89(d, 1H, J=8.8), 7.60(dd, 1H， J-2.4), 7.62(s, 1H), 7.56(s, 1H), 7.48(q, 1H), 7.32(m, 3H), 7.18(t, 1H), 6.5 l (s, 1H), 5.27(s, 2H), 3.88(s, 2H), 2.85(s, 2H), 2.68(s, 4H), 2.5 l(s, 2H), 1.00(t, 6H) 实施 15 ! HNMR (400MHz, DMSO- ^) : δ 8.60 (s, 1H), 8.58 (s, 1H), 8.10 (dd, 1H, J-2.2), 8.19 (d, 1H, J = 2.4), 7.89 (d , 1H, J=8.8), 7.60(dd, 1H, J-2.4), 7.62(s, 1H), 7.56(s, 1H), 7.48(q, 1H), 7.32(m, 3H), 7.18(t , 1H), 6.5 l (s, 1H), 5.27(s, 2H), 3.88(s, 2H), 2.85(s, 2H), 2.68(s, 4H), 2.5 l(s, 2H), 1.00( t, 6H) Implementation 15
「3-氯 -4-(3-氟-苄氧基) -苯基 1-(6-{3-「(2-吗啉 -4-基 -乙基氨基) -甲基 1-吡咯小基 喹唑啉 -4-基 -胺  "3-Chloro-4-(3-fluoro-benzyloxy)-phenyl 1-(6-{3-"(2-morpholin-4-yl-ethylamino)-methyl-1-pyrrole small group Quinazolin-4-yl-amine
Figure imgf000068_0002
Figure imgf000068_0002
重复本发明实施例 5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 1-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基}-111-吡咯 -3-甲醛 5c作原料， 按照本发明实施例 5第三步所述相同方式进行该原料与 2-吗啉 -4-基-乙胺盐酸盐的 反应， 用乙酸乙酯重结晶所得固体， 则得到标题产物 [3-氯 -4-(3-氟-苄氧基) -苯 基] -(6-{3-[(2-吗啉 -4-基 -乙基氨基) -甲基] -P比咯 -1-基}-喹唑啉 -4-基) -胺 15 (20 mg，黄 色固体)。 产率： 50%。  The reaction of the first step to the second step of Example 5 of the present invention was repeated, and the compound 1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino group obtained in the above second step was used. - quinazolin-6-yl}-111-pyrrole-3-carbaldehyde 5c as a starting material, the starting material and 2-morpholin-4-yl-ethylamine are carried out in the same manner as described in the third step of Example 5 of the present invention. The 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%.
MS mJz (ESI): 587[M+ 1] MS mJz (ESI): 587[M+ 1]
xmMK (400MHz, DMSO-c¾): δ 8.60(d, 1H， J=1.6)， 8.55(s, 1H)， 8.09(dd, 1H, J=9.2), 8.02(d, 1H, J=2.0), 7.84(d, 1H, J=9.2), 7.76(dd, 1H, J=8.8), 7.56(d, 2H), 7.46(q, 1H), 7.30(m, 3H), 7.18(t， 1H), 6.39(s, 1H), 5.24(s， 2H), 3.56(s, 4H), 2.77(t, 2H), 2.46(t, 2H), 2.35(s, 4H), 1.82(s, 2H) 实施例 16 xmMK (400MHz, DMSO-c3⁄4): δ 8.60(d, 1H, J=1.6), 8.55(s, 1H), 8.09(dd, 1H, J=9.2), 8.02(d, 1H, J=2.0), 7.84(d, 1H, J=9.2), 7.76(dd, 1H, J=8.8), 7.56(d, 2H), 7.46(q, 1H), 7.30(m, 3H), 7.18(t, 1H), 6.39(s, 1H), 5.24(s, 2H), 3.56(s, 4H), 2.77(t, 2H), 2.46(t, 2H), 2.35(s, 4H), 1.82(s, 2H) 16
2-{4-「3-氯 -4-G-氟- 氧某 苯氨基 1-喹唑啉 -6-基 5,6-二氢 -2H-环戊垸「cl吡咯
Figure imgf000069_0001
第一步 2-{4-"3-Chloro-4-G-fluoro-oxy-phenylamino-1-quinazolin-6-yl 5,6-dihydro-2H-cyclopentanium "cl pyrrole
Figure imgf000069_0001
first step
5,6-二氢 -2H-环戊烷 [c]吡咯 -4-酮  5,6-dihydro-2H-cyclopentane [c]pyrrole-4-one
在 0°C下于 50 mL三口瓶中加入对甲苯磺酰基异乙腈 （2.56 g， 13.1 mmol), 溶于 12 mL 四氢呋喃， 滴加入 1,8-二氮杂二环 [5,4,0;H ^—碳 -7-烯 （2.0 g， 13.4 mmol), (TC搅拌 15分钟。 滴加入环戊烯 -2-酮 16a ( 1.0 g， 11.9 mmol), 室温搅拌 2小时。薄层分析跟踪至原料消失， 倒入 50 mL水中， 搅拌过夜， 减压浓缩蒸除四 氢呋喃， 用乙酸乙酯萃取（50x3 )， 合并有机相， 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， 则得到标题产物 5,6-二氢 -2H-环戊垸 [c]吡咯 -4-酮 16b (749 mg, 白色固体）。 产率： 52%。  Add p-toluenesulfonyl isoacetonitrile (2.56 g, 13.1 mmol) in a 50 mL three-necked flask at 0 ° C, dissolve in 12 mL of tetrahydrofuran, and add 1,8-diazabicyclo[5,4,0 dropwise; H^-Carbon-7-ene (2.0 g, 13.4 mmol), (TC stirred for 15 min. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; The material disappeared, and poured into 50 mL of water, and the mixture was stirred overnight. The residue was evaporated to drynesshhhhHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH The residue was purified to give the title compound 5,6-dihydro-2H-cyclopentan[c]pyrrol-4-one 16b (749 mg, white solid).
MS m/z (ESI): 122[M+1] MS m/z (ESI): 122[M+1]
iHNMR (400MHz, DMSO-i¾: 6 11.70(s, 1H), 7.16(dd, 1H, J=2.8), 6.64(d, 1H, J=0.8), 2.80(t, 2H), 2.7 l(t, 2H) iHNMR (400MHz, DMSO-i3⁄4: 6 11.70(s, 1H), 7.16 (dd, 1H, J=2.8), 6.64 (d, 1H, J=0.8), 2.80(t, 2H), 2.7 l(t, 2H)
第二步  Second step
2-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基}-5,6-二氢 -2H-环戊烷 [c]吡咯  2-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-5,6-dihydro-2H-cyclopentane [c] Pyrrole
-4-酮  -4-ketone
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 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-(6-碘-喹唑啉 -4-基) -胺 ^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 5,6-二氢 -2H-环戊垸 [c]吡咯 -4-酮 16b的 反应， 用二氯甲烷重结晶， 则得到标题产物 2-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹 唑啉 -6-基}-5,6-二氢 -2H-环戊垸 [c]吡咯 -4-酮 16 (211 mg， 白色固体)。产率： 42.3 %。 MS m/z (ESI): 499[M+1]  The reaction of the first step to the fifth step of Example 1 of the present invention was repeated, and the compound [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6- obtained in the above fifth step was used. Iodine-quinazolin-4-yl)-amine is used as a starting material, and the starting material and 5,6-dihydro-2H-cyclopentanyl[c]pyrrole are carried out in the same manner as described in the sixth step of Example 1 of the present invention. The reaction of 4-ketone 16b is recrystallized from dichloromethane to give the title product 2-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6- 5-5,6-Dihydro-2H-cyclopentanyl[c]pyrrol-4-one 16 (211 mg, white solid). Yield: 42.3 %. MS m/z (ESI): 499 [M+1]
!HNMR (400MHz, DMSO-i¾)： δ 9.79(s, 1H), 8.75(d, 1H, J=2.4), 8.62(s, 1H), 8.22(dd, 1H, J=9.0), 8.02(d, 2H), 7.90(d, 1H), 7.75(dd, 1H, J=8.8), 7.50(m, 2H), 7.35(m, 3H), 7.18(t, 1H)， 5.28(s, 2H), 2.97(t, 2H), 2.83(q, 2H) 实施例 17 ! HNMR (400MHz, DMSO-i¾ ): δ 9.79 (s, 1H), 8.75 (d, 1H, J = 2.4), 8.62 (s, 1H), 8.22 (dd, 1H, J = 9.0), 8.02 (d , 2H), 7.90(d, 1H), 7.75(dd, 1H, J=8.8), 7.50(m, 2H), 7.35(m, 3H), 7.18(t, 1H), 5.28(s, 2H), 2.97(t, 2H), 2.83(q, 2H) Example 17
「1-ί4-[3-氯 -4-(3-氟 -苄氧基)-苯氨基 1-喹唑啉 -6-基 4-(2-羟基-乙基) -1H-吡咯 -3- 基】— (4_甲基 -哌嗪小基) -甲酮 "1-ί4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino-1-quinazolin-6-yl 4-(2-hydroxy-ethyl)-1H-pyrrole-3- Base— (4 _methyl-piperazine small group)-ketone
Figure imgf000070_0001
Figure imgf000070_0001
重复本发明实施例 10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 2-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基]-喹唑啉 -6-基}-6,7-二氢 -2H-吡喃 [3,4-c]吡 P各 -4-酮 10作原料， 按照本发明实施例 13所述相同方式进行该原料与 1-甲基 -哌嗪 的反应， 用硅胶柱色谱法纯化所得残余物， 得到标题产物 [1-{4-[3-氯 -4-(3-氟 -苄氧 基) -苯氨基] -喹唑啉 -6-基}-4-(2-羟基-乙基) -1H-吡咯 -3-基] -(4-甲基 -哌嗪 -1-基) -甲酮 17 (366 mg, 浅黄色固体)。 产率： 77.7%。  The reaction of the first step to the second step of Example 10 of the present invention was repeated, and the compound 2-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino group obtained in the above second step was used. ]-quinazolin-6-yl}-6,7-dihydro-2H-pyran[3,4-c]pyridin-4-one 10 as starting material, in the same manner as described in Example 13 of the present invention The reaction of the starting material with 1-methyl-piperazine was carried out, and the obtained residue was purified to silica gel column chromatography to afford the title product [1-{4-[3-chloro-4-(3-fluoro-benzyloxy)- Phenylamino]-quinazolin-6-yl}-4-(2-hydroxy-ethyl)-1H-pyrrol-3-yl]-(4-methyl-piperazin-1-yl)-methanone 17 (366 mg, pale yellow solid). Yield: 77.7%.
MS m/z (ESI): 615[M+1] MS m/z (ESI): 615 [M+1]
1HNMR (400MHz, DMSO-^): δ 9.77(s, 1H), 8.58(s, 2H), 8.16(dd, 1H, J=9.0), 8.0 l(d, 1H， J=2.8), 7.86(d, 1H, J=8.8), 7.73(dd, 1H, J=9.0), 7.66(d, 1H, J=2.0), 7.48(q, 2H), 7.34(q, 3H), 7.19(t, 1H), 5.28(s, 2H), 4.69(t, 1H, J=1.2), 3.58(t, 6H), 2.69(t, 2H， J=3.2), 2.33(s, 4H), 2.2 l(s, 3H) 实施例 18 1 HNMR (400MHz, DMSO- ^) : δ 9.77 (s, 1H), 8.58 (s, 2H), 8.16 (dd, 1H, J = 9.0), 8.0 l (d, 1H, J = 2.8), 7.86 ( d, 1H, J=8.8), 7.73(dd, 1H, J=9.0), 7.66(d, 1H, J=2.0), 7.48(q, 2H), 7.34(q, 3H), 7.19(t, 1H ), 5.28(s, 2H), 4.69(t, 1H, J=1.2), 3.58(t, 6H), 2.69(t, 2H, J=3.2), 2.33(s, 4H), 2.2 l(s, 3H) Example 18
1- -Π3-氯 -4-(3-氟-苄氧基) -苯氨基 1-喹唑啉 -6-基 }-4-(2-羟基-乙基) -1H-吡咯 -3- 羧酸 -(2-吗啉 -4-基-乙基) -胺  1--indole-3-chloro-4-(3-fluoro-benzyloxy)-phenylamino-1-quinazolin-6-yl}-4-(2-hydroxy-ethyl)-1H-pyrrole-3-carboxylate Acid-(2-morpholin-4-yl-ethyl)-amine
Figure imgf000070_0002
Figure imgf000070_0002
重复本发明实施例 10第一歩至第二步的反应， 使用上述第二步中所得到的化 合物 2-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基}-6，7-二氢 -2H-吡喃 [3,4-c]吡 咯 -4-酮 10作原料，按照本发明实施例 13所述相同方式进行该原料与 2-吗啉 -4-基- 乙胺的反应， 用硅胶柱色谱法纯化所得残余物， 则得到标题产物 1-{4-[3-氯 -4-(3- 氟-苄氧基) -苯氨基] -喹唑啉 -6-基 }-4-(2-羟基-乙基) -1H-吡咯 -3-羧酸 -(2-吗啉 -4-基-乙 基) -胺 18 (50 mg, 淡黄色固体）。 产率： 13.3 %。 MS m/z (ESI): 645 [M+ l] The reaction of the first to second steps of Example 10 of the present invention was repeated, and the compound 2-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino group obtained in the above second step was used. - quinazolin-6-yl}-6,7-dihydro-2H-pyran[3,4-c]pyrrol-4-one 10 as a starting material, in the same manner as described in Example 13 of the present invention The reaction mixture was purified by silica gel column chromatography toield -Phenylamino]-quinazolin-6-yl}-4-(2-hydroxy-ethyl)-1H-pyrrole-3-carboxylic acid-(2-morpholin-4-yl-ethyl)-amine 18 (50 mg, light yellow solid). Yield: 13.3%. MS m/z (ESI): 645 [M+ l]
!HNMR (400MHz, DMSO-^): 8 9.87(s,lH), 8.64(d, IH, J=1.6), 8.59(s， IH), 8.10(d, IH), 8.02(d, 2H), 7.92(m, 2H), 7.75(dd, IH, J=8.8), 7.48(q, 1H)， 7.4 l(s, IH), 7.33(q, 3H), 7.19(t, IH), 5.27(s, 2H), 4.83(s, IH), 3.65(t, 2H), 3.60(t, 4H), 3.38(m, 2H), 2.90(t, 2H)， 2.45(m, 6H) 实施例 19 ! HNMR (400MHz, DMSO- ^) : 8 9.87 (s, lH), 8.64 (d, IH, J = 1.6), 8.59 (s, IH), 8.10 (d, IH), 8.02 (d, 2H), 7.92(m, 2H), 7.75(dd, IH, J=8.8), 7.48(q, 1H), 7.4 l(s, IH), 7.33(q, 3H), 7.19(t, IH), 5.27(s , 2H), 4.83(s, IH), 3.65(t, 2H), 3.60(t, 4H), 3.38(m, 2H), 2.90(t, 2H), 2.45(m, 6H) Example 19
Γ6-(3-Π ,4Ί双哌啶基 -Γ-基甲基 -吡咯 -1-基 喹唑啉 -4-基 1-Γ3-氯 -4- 3-氟-苄氧基 苯基 1-胺  6-(3-Π , 4Ί bispiperidinyl-fluorenyl-methyl-pyrrol-1-ylquinazolin-4-yl 1-indole-3-chloro-4-trifluoro-benzyloxyphenyl 1- Amine
Figure imgf000071_0001
Figure imgf000071_0001
重复本发明实施例 5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 1 -{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基 }- 1Η-吡咯 -3-甲醛 5c作原料， 按照本发明实施例 5第三步所述相同方式进行该原料与 4-哌啶基哌啶的反应， 用 乙酸乙酯重结晶所得固体， 则得到标题产物 [6-(3-[1 ,4']双哌啶基 -Γ-基甲基 -吡咯 -1 - 基) -喹唑啉 -4-基] -[3-氯 -4-(3-氟-苄氧基) -苯基] -胺 19 (60 mg， 浅褐色固体)。 产率： 60.1 %。  The reaction of the first step to the second step of Example 5 of the present invention was repeated, and the compound 1 -{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino group obtained in the above second step was used. - quinazolin-6-yl}- 1 Η-pyrrole-3-carbaldehyde 5c as a starting material, the reaction of the starting material with 4-piperidylpiperidine is carried out in the same manner as described in the third step of Example 5 of the present invention. The solid obtained by recrystallization from ethyl acetate gave the title product [6-(3-[1,4'] bispiperidinyl-indole-methyl-pyrrole-1-yl)-quinazolin-4-yl] -[3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-amine 19 (60 mg, light brown solid). Yield: 60.1%.
MS m/z (ESI): 625[M+ 1]  MS m/z (ESI): 625 [M+ 1]
'HNMR (400MHZ, DMSO-^): δ 8.61(d, IH, J=2.0), 8.55(s, IH), 8.12(dd, IH, J=8.8), 8.03(d, IH, J=2.8), 7.85(d, IH, J=9.2), 7.76(dd, IH, J=8.8), 7.50(m, 3H), 7.32(q, 3H), 7.18(t, IH), 6.3 l(s, IH), 5.26(s， 2H), 3.43(s， 2H), 2.50(m, 5H), 1.70(m， 4H), 1.40(m, 10H) 实施例 20  'HNMR (400MHZ, DMSO-^): δ 8.61 (d, IH, J=2.0), 8.55 (s, IH), 8.12 (dd, IH, J=8.8), 8.03 (d, IH, J=2.8) , 7.85(d, IH, J=9.2), 7.76(dd, IH, J=8.8), 7.50(m, 3H), 7.32(q, 3H), 7.18(t, IH), 6.3 l(s, IH ), 5.26(s, 2H), 3.43(s, 2H), 2.50(m, 5H), 1.70(m, 4H), 1.40(m, 10H) Example 20
Γ3-氯 -4-(3-氟-苄氧基) -苯基 l-(6-{3-f(2-哌啶小基 -乙基氨基) -甲基 1-P比咯 -1-基 喹唑啉 -4-基) -胺  Γ3-Chloro-4-(3-fluoro-benzyloxy)-phenyl 1-(6-{3-f(2-piperidinyl-ethylamino)-methyl 1-Ppyrrol-1- Riquiazolin-4-yl)-amine
Figure imgf000071_0002
Figure imgf000071_0002
重复本发明实施例 5第一步至第二步的反应， 使用上述第二歩中所得到的化 合物 1-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基 吡咯 -3-甲醛 5c作原料， 按照本发明实施例 5第三步所述相同方式进行该原料与 2-哌.啶 -1-基-乙胺的反应， 用乙酸乙酯重结晶所得固体， 则得到标题产物 [3-氯 -4-(3-氟-苄氧基) -苯 基] -(6-{3-[(2-哌啶 -1-基 -乙基氨基) -甲基] -吡咯 -1-基}-喹唑啉 -4-基) -胺 20 (48 mg，黄 色固体)。 产率： 46.7%。 The reaction of the first step to the second step of Example 5 of the present invention was repeated, using the compound 1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino group obtained in the above second hydrazine. - quinazolin-6-ylpyrrole-3-carbaldehyde 5c as a starting material, the reaction of the starting material with 2-piperidin-1-yl-ethylamine is carried out in the same manner as described in the third step of Example 5 of the present invention. The obtained solid was recrystallized from ethyl acetate to give the title product [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-{3-[(2-piperidin-1-yl) -ethylamino)-methyl]-pyrrol-1-yl}-quinazolin-4-yl)-amine 20 (48 mg, yellow Color solid). Yield: 46.7%.
MS m/z (ESI): 585[M+1] MS m/z (ESI): 585 [M+1]
iHNMR (400MHz, DMSO- )： δ 8.58(t, 2H), 8.11(dd, 1H, J=8.8), 8.02(d, 1H, J=2.4), 7.86(d， 1H, J=9.2), 7.76(dd, 1H, J=8.8), 7.52(m, 2H), 7.46(t, 1H), 7.32(q, 3H), 7.18(t, 1H), 6.36(s, 1H), 5.26(s, 2H), 3.70(s, 2H), 2.70(t, 2H), 2.35(m, 6H), 1.50(m, 6H) 实施例 21 iHNMR (400MHz, DMSO-): δ 8.58 (t, 2H), 8.11 (dd, 1H, J = 8.8), 8.02 (d, 1H, J = 2.4), 7.86 (d, 1H, J = 9.2), 7.76 (dd, 1H, J=8.8), 7.52(m, 2H), 7.46(t, 1H), 7.32(q, 3H), 7.18(t, 1H), 6.36(s, 1H), 5.26(s, 2H ), 3.70(s, 2H), 2.70(t, 2H), 2.35(m, 6H), 1.50(m, 6H) Example 21
「3-氯 _4-( -氟-苄氧基) -苯基 1-Γ6-(3-二乙基氨基甲基-吡咯 -1-基) -喹唑啉 -4-基 1- "3 - chloro _ 4 - (- fluoro - benzyloxy) - phenyl-1- Γ 6- (3- diethylaminomethyl - pyrrol-1-yl) - quinolin-4-yl 1-
Figure imgf000072_0001
Figure imgf000072_0001
重复本发明实施例 5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 1-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基}-111-吡咯 -3-甲醛 5c作原料， 按照本发明实施例 5第三步所述相同方式进行该原料与二乙基胺的反应， 用乙酸 乙酯重结晶所得固体， 则得到标题产物 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-(6-{3-[(2-哌啶 -1-基 -乙基氨基) -甲基] -吡咯 -1-基 喹唑啉 -4-基) -胺 21 (50 mg， 黄色固体)。 产率： 63.1 %。  The reaction of the first step to the second step of Example 5 of the present invention was repeated, and the compound 1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino group obtained in the above second step was used. - quinazolin-6-yl}-111-pyrrole-3-carbaldehyde 5c as a starting material, the reaction of the starting material with diethylamine is carried out in the same manner as described in the third step of Example 5 of the present invention, using ethyl acetate The solid obtained was recrystallized to give the title product [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-{3-[(2-piperidin-1-yl-ethylamino) ) -Methyl]-pyrrol-1-ylquinazolin-4-yl)-amine 21 (50 mg, yellow solid). Yield: 63.1%.
MS m/z (ESI): 630[M+ 1]  MS m/z (ESI): 630 [M+ 1]
ιΉΝΜΚ (400MHz, DMSO-^): δ 8.63(s, 1H), 8.58(s, 1H), 8.14(dd, 1H, J=9.2), 8.04(d, 1H), 7.88(d, 1H, J=8.8), 7.77(dd, 1H, J=8.8), 7.64(s, 1H), 7.57(s, 1H), 7.48(q, 1H), 7.32(m, 3H), 7.18(t, 1H), 6.42(s, 1H), 5.27(s, 2H), 3.84(s, 2H), 2.79(d, 3H, J=5.2), 1.92(s, 1H), 1.12(m, 6H) 实施例 22 ΉΝΜΚ (400MHz, DMSO-^): δ 8.63(s, 1H), 8.58(s, 1H), 8.14(dd, 1H, J=9.2), 8.04(d, 1H), 7.88(d, 1H, J= 8.8), 7.77 (dd, 1H, J=8.8), 7.64(s, 1H), 7.57(s, 1H), 7.48(q, 1H), 7.32(m, 3H), 7.18(t, 1H), 6.42 (s, 1H), 5.27(s, 2H), 3.84(s, 2H), 2.79(d, 3H, J=5.2), 1.92(s, 1H), 1.12(m, 6H) Example 22
2-Γ1- -Γ3-氯 -4-(3-氟-苄氧基) -苯氨基 1-喹唑啉 -6-基) -4-(4-甲基 -哌嗉 -1-基甲 基) -1H-吡咯 -3-基 乙醇  2-Γ1--Γ3-chloro-4-(3-fluoro-benzyloxy)-phenylamino-1-quinazolin-6-yl)-4-(4-methyl-piperazin-1-ylmethyl ) -1H-pyrrol-3-ylethanol
Figure imgf000072_0002
在 50 mL茄形瓶中加入四氢铝锂 （26 mg， 0.68 mmol), 溶于 6 mL四氢呋喃 中， 搅拌下滴加 [1-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基 }-4-(2-羟基-乙 基) -1H-吡咯 -3-基] -(4-甲基 -哌嗪小基) -甲酮 17 ( 166 mg， 0.27 mmol) 的 5 mL四氢 呋喃溶液， 加热回流 4小时。 薄层分析跟踪至原料消失， 将反应液冷却至室温， 加入 I mL无水甲醇， 过滤， 滤液减压浓缩， 用硅胶柱色谱法纯化所得残余物， 则 得到标题产物 2-[1-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基}-4-(4-甲基 -哌嗪 小基甲基) -1H-吡咯 -3-基] -乙醇 22 (72 mg， 黄色固体)。 产率： 45 %。
Figure imgf000072_0002
Add lithium tetrahydrogenate (26 mg, 0.68 mmol) to a 50 mL eggplant bottle, dissolve in 6 mL of tetrahydrofuran, and add [1-{4-[3-chloro-4-(3-fluoro-benzyl) dropwise with stirring. Oxyphenyl)-phenylamino]-quinazolin-6-yl}-4-(2-hydroxy-ethyl)-1H-pyrrol-3-yl]-(4-methyl-piperazine small group)-A A solution of ketone 17 (166 mg, 0.27 mmol) in 5 mL EtOAc The thin layer analysis was followed until the disappearance of the starting material, the reaction mixture was cooled to room temperature, and 1 mL of anhydrous methanol was added, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography to give the title product 2-[1-{4 -[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-4-(4-methyl-piperazinemethylidenemethyl)-1H-pyrrole -3-yl]-ethanol 22 (72 mg, yellow solid). Yield: 45 %.
MS m/z (ESI): 601 [M+1] MS m/z (ESI): 601 [M+1]
1HNMR (400MHz, DMSO-t¾): δ 9.76(s, 1H), 8.52(d, 2H), 8.11(d, 1H, J=8.4), 8.01(s, 1H), 7.83(d, 1H, J=8.8), 7.74(d, 1H, J=8.0), 7.40(m, 6H), 7.19(t, 1H), 5.27(s, 2H), 5.03(s, 1H), 3.61 (s, 2H), 3.32(m, 2H), 2.67(s, 2H)， 2.35(m, 8H), 2.21(s, 3H) 实施例 23 1 H NMR (400MHz, DMSO-t3⁄4): δ 9.76 (s, 1H), 8.52 (d, 2H), 8.11 (d, 1H, J = 8.4), 8.01 (s, 1H), 7.83 (d, 1H, J =8.8), 7.74(d, 1H, J=8.0), 7.40(m, 6H), 7.19(t, 1H), 5.27(s, 2H), 5.03(s, 1H), 3.61 (s, 2H), 3.32(m, 2H), 2.67(s, 2H), 2.35(m, 8H), 2.21(s, 3H) Example 23
Ν-(1- -Γ3-氯 -4-ί3-氟-苄氧基) -苯氨基 1-喹唑啉 -6-基 }-4-三氟甲基 -1H-吡咯 -3- 基甲基) -Ν',Ν'-二乙基 -U-乙二胺  Ν-(1- -Γ3-chloro-4-ί3-fluoro-benzyloxy)-phenylamino-1-quinazolin-6-yl}-4-trifluoromethyl-1H-pyrrol-3-ylmethyl ) -Ν',Ν'-diethyl-U-ethylenediamine
Figure imgf000073_0001
Figure imgf000073_0001
第一步  First step
(1-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基}-4-三氟甲基 -1Η-吡咯 -3-基) - 甲醇  (1-{4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-4-trifluoromethyl-1Η-pyrrol-3-yl ) - Methanol
在 50 mL茄形瓶加入 1-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基}-4-三氟 甲基 -1H-吡咯 -3-羧酸乙酯 6 (250 mg, 0.40 mmol), 溶于 15 mL四氢呋喃中， 搅拌 下滴加入四氢铝锂 （40 mg， l .mmol) 的 5 mL四氢呋喃溶液， 40°C搅拌过夜。 薄 层分析跟踪至原料消失， 加入 I mL无水甲醇， 过滤， 滤液减压浓缩， 用硅胶柱色 谱法纯化所得残余物，则得到标题产物 (1-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基}-4-三氟甲基 -1H-吡咯 -3-基) -甲醇 23a ( 177 mg,黄色固体）。 产率： 76.3 %。 MS m/z (ESI): 543 [M+1] 第二步 Add 1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-4-trifluoromethyl-1H to a 50 mL eggplant flask - Pyrrole-3-carboxylate ethyl ester 6 (250 mg, 0.40 mmol), dissolved in 15 mL of tetrahydrofuran, a solution of lithium tetrahydroaluminum (40 mg, l.mmol) in 5 mL of tetrahydrofuran, 40 ° C Stir overnight. The thin layer analysis was followed until the disappearance of the starting material, and 1 mL of anhydrous methanol was added, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title product (1-{4-[3-chloro-4-( 3-Fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-4-trifluoromethyl-1H-pyrrol-3-yl)-methanol 23a (177 mg, yellow solid). Yield: 76.3 %. MS m/z (ESI): 543 [M+1] Second step
(l-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基]-喹唑啉 -6-基}-4-三氟甲基 -IH-吡咯 -3-基) - 甲醛  (l-{4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-4-trifluoromethyl-IH-pyrrol-3-yl ) - Formaldehyde
在 100 mL茄形瓶加入邻碘酰苯甲酸（185 mg， 0.66 mmol), 溶于 10 mL二甲 亚砜中， 滴加入 (1-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基}-4-三氟甲基 -1H- 吡咯 -3-基) -甲醇 23a ( 177 mg, 0.33 mmol)的 5 mL二甲亚砜溶液， 室温搅拌过夜。 薄层分析跟踪至原料消失， 将反应液倒入 30 mL冰水中， 减压抽滤， 固体用二氯 甲垸重结晶， 则得到标题产物 (1-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基 }-4- 三氟甲基 -1H-吡咯 -3-基) -甲醛 23b ( 119 mg,黄色固体）。 产率： 70.0%。  Add o-iodobenzoic acid (185 mg, 0.66 mmol) to a 100 mL eggplant flask, dissolve in 10 mL of dimethyl sulfoxide, and add (1-{4-[3-chloro-4-(3-fluoro-) Benzyloxy)-phenylamino]-quinazolin-6-yl}-4-trifluoromethyl-1H-pyrrol-3-yl)-methanol 23a (177 mg, 0.33 mmol) in 5 mL of dimethyl sulfoxide The solution was stirred at room temperature overnight. The thin layer analysis was followed until the disappearance of the starting material, and the reaction solution was poured into 30 mL of ice water, filtered under reduced pressure, and the solid was recrystallized from methylene chloride to give the title product (1-{4-[3-chloro-4-( 3-Fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-4-trifluoromethyl-1H-pyrrol-3-yl)-carbaldehyde 23b (119 mg, yellow solid). Yield: 70.0%.
MS m/z (ESI): 541 [M+l] MS m/z (ESI): 541 [M+l]
第三步  third step
N-(1_{4_[3_氯 _4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基}-4-三氟甲基 -IH-吡咯 -3- 基甲基) -Ν',Ν'-二乙基 -1,2-乙二胺 N - (1 _{ 4 _[3_Chloro- 4- (3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-4-trifluoromethyl-IH-pyrrole-3 -ylmethyl)-Ν',Ν'-diethyl-1,2-ethanediamine
在 25 mL茄形瓶加入 (1-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基}-4-三氟 甲基- 1H-吡咯 -3-基) -甲醛 23b (40 mg, 0.075 mmol)和 Ν,Ν-二乙基 -1，2-乙二胺（ 10 mg, 0.08 mmol), 溶于 5 mL二氯甲烷中， 反应 3小时后， 加入三乙酰氧基硼氢化 钠 （32 mg， 0.15 mmol)。 室温搅拌 3天。 薄层分析跟踪至原料消失， 加入 20 mL 饱和氯化钠溶液， 用二氯甲烷萃取（20 mLx3)， 合并有机相， 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，则得到标题产物 N-(l-{4-[3- 氯 -4-(3-氟-苄氧基) -苯氨基]-喹唑啉 -6-基 }-4-三氟甲基 -1H-吡咯 -3-基甲基)- Ν',Ν'-二 乙基 -1,2-乙二胺 23 (22 mg,黄色固体）。 产率： 51.2%。  Add (1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-4-trifluoromethyl- in a 25 mL eggplant-shaped flask 1H-pyrrol-3-yl)-carboxaldehyde 23b (40 mg, 0.075 mmol) and hydrazine, hydrazine-diethyl-1,2-ethanediamine (10 mg, 0.08 mmol), dissolved in dichloromethane After reacting for 3 hours, sodium triacetoxyborohydride (32 mg, 0.15 mmol) was added. Stir at room temperature for 3 days. Thin layer analysis was performed until the disappearance of the starting material, and 20 mL of a saturated sodium chloride solution was added, and the mixture was extracted with dichloromethane (20 mL×3). The organic phase was combined, dried over anhydrous magnesium sulfate, filtered, The obtained residue was purified to give the title product N-(l-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-4- Fluoromethyl-1H-pyrrol-3-ylmethyl)-indole, Ν'-diethyl-1,2-ethanediamine 23 (22 mg, yellow solid). Yield: 51.2%.
MS m/z (ESI): 641 [M+l] MS m/z (ESI): 641 [M+l]
lHNMR (400MHz, DMSO-^): δ 9.85(s, IH), 8.70(s, IH), 8.60(s, IH), 8.20(d, IH, J=8.8), 8.03(d, 2H, J=15.2), 7.89(d, IH, J=8.0), 7.75(d, IH, J=7.2), 7.65(s, IH), 7.49(m, IH), 7.30(m, 3H), 7.19(t, IH), 5.27(s, 2H), 3.74(s, 2H), 2.67(d, 2H, J=5.6)， 2.55(s， 4H), 1.23(s, 2H), 0.95(t, 6H) 实施例 24 lHNMR (400MHz, DMSO-^): δ 9.85(s, IH), 8.70(s, IH), 8.60(s, IH), 8.20(d, IH, J=8.8), 8.03(d, 2H, J= 15.2), 7.89(d, IH, J=8.0), 7.75(d, IH, J=7.2), 7.65(s, IH), 7.49(m, IH), 7.30(m, 3H), 7.19(t, IH), 5.27(s, 2H), 3.74(s, 2H), 2.67(d, 2H, J=5.6), 2.55(s, 4H), 1.23(s, 2H), 0.95(t, 6H) twenty four
l_{4-「3-氯 -4-(3-氟-苄氧基) -苯氨基 1-喹唑啉 -6-基 4-(2-羟基-乙基) -IH-吡咯 -3- 羧酸 -「2-(4-甲基 -哌嗪 -1-基) -乙基 1-胺
Figure imgf000074_0001
L_{4-"3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino-1-quinazolin-6-yl 4-(2-hydroxy-ethyl)-IH-pyrrole-3-carboxylate Acid-"2-(4-methyl-piperazin-1-yl)-ethyl 1-amine
Figure imgf000074_0001
重复本发明实施例 10第一歩至第二步的反应， 使用上述第二步中所得到的化 合物 2-{4-[3-氯 -4-(3-氟-苄氧基) -苯 基] -喹唑啉 -6-基}-6,7-二氢 -2H-吡喃 [3,4-c]吡 咯 -4-酮 10作原料， 按照本发明实施例 13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，用硅胶柱色谱法纯化所得残余物，则得到标题产物 1-{4-[3- 氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基 }-4-(2-羟基-乙基) -1H-吡咯 -3-羧酸 -[2-(4-甲 基 -哌嗪 -1-基) -乙基] -胺 24 (512 mg, 淡黄色固体）。 产率： 50.4%。 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. Amino]-quinazolin-6-yl}-4-(2-hydroxy-ethyl)-1H-pyrrole-3-carboxylic acid-[2-(4-methyl-piperazin-1-yl)-B Base] -amine 24 (512 mg, pale yellow solid). Yield: 50.4%.
MS m/z (ESI): 658[M+ 1] MS m/z (ESI): 658 [M+ 1]
^MR (400MHz, DMSO- i): δ 9.86(s, IH), 8.63(s, IH), 8.59(s, IH), 8.10(dd, IH, J=9.2), 8.01 (dd, 2H, J=8.0), 7.89(m, 2H), 7.75(dd, IH, J=9.0), 7.48(q, IH), 7.40(d, IH), 7.33(q, 3H), 7.19(t, IH), 5.28(s, 2H)， 4.82(s, IH), 3.66(t, 2H), 3.35(2H), 2.90(t, 2H), 2.40(m, 10H),2.16(s, 3H) 实施例 25  ^MR (400MHz, DMSO-i): δ 9.86(s, IH), 8.63(s, IH), 8.59(s, IH), 8.10(dd, IH, J=9.2), 8.01 (dd, 2H, J =8.0), 7.89(m, 2H), 7.75(dd, IH, J=9.0), 7.48(q, IH), 7.40(d, IH), 7.33(q, 3H), 7.19(t, IH), 5.28(s, 2H), 4.82(s, IH), 3.66(t, 2H), 3.35(2H), 2.90(t, 2H), 2.40(m, 10H), 2.16(s, 3H) Example 25
Γ1- -「3-氯 -4-(3-氟 -苄氧基)-苯氨基 1-喹唑啉 -6-基 4-(2-羟基-乙基) -IH-吡咯 -3- 基 1-哌啶 -1-基 -甲酮
Figure imgf000075_0001
Γ 1- - "3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino-1-quinazolin-6-yl 4-(2-hydroxy-ethyl)-IH-pyrrol-3-yl 1 -piperidin-1-yl-ketone
Figure imgf000075_0001
重复本发明实施例 10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 2-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基}-6,7-二氢 -2H-吡喃 [3,4-c]吡 咯 -4-酮 10作原料，按照本发明实施例 13所述相同方式进行该原料与哌啶的反应， 用硅胶柱色谱法纯化所得残余物， 则得到标题产物 [1-{4-[3-氯 -4-(3-氟-苄氧基) -苯 氨基] -喹唑啉 -6-基}-4-(2-羟基-乙基) -1H-吡咯 -3-基] -哌啶小基 -甲酮 25 ( 150 mg，淡 黄色固体）。 产率： 16.3 %。  The reaction of the first step to the second step of Example 10 of the present invention was repeated, and the compound 2-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino group obtained in the above second step was used. - quinazolin-6-yl}-6,7-dihydro-2H-pyran[3,4-c]pyrrol-4-one 10 as a starting material, in the same manner as described in Example 13 of the present invention The reaction mixture was purified by silica gel column chromatography to afford the title product [1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazole Phenyl-6-yl}-4-(2-hydroxy-ethyl)-1H-pyrrol-3-yl]-piperidinyl-ketone 25 (150 mg, pale yellow solid). Yield: 16.3 %.
MS m/z (ESI): 600[M+ 1] MS m/z (ESI): 600[M+ 1]
^MR (400MHz, DMSO-i¾: δ 8.57(s, 2H), 8.15(dd, IH, J=9.2), 8.01(d, IH, J=2.8), 7.86(d, IH, J=9.2), 7.73(dd, IH, J=9.0), 7.63(d, IH, J=2.4), 7.46(m, 2H), 7.32(m, 3H), 7.18(t, 1H)， 5.27(s, 2H), 3.58(m, 6H), 2.67(t, 2H), 1.64(d, 2H), 1.51(s, 4H) 实施例 26  ^MR (400MHz, DMSO-i3⁄4: δ 8.57(s, 2H), 8.15(dd, IH, J=9.2), 8.01(d, IH, J=2.8), 7.86(d, IH, J=9.2), 7.73(dd, IH, J=9.0), 7.63(d, IH, J=2.4), 7.46(m, 2H), 7.32(m, 3H), 7.18(t, 1H), 5.27(s, 2H), 3.58(m, 6H), 2.67(t, 2H), 1.64(d, 2H), 1.51(s, 4H) Example 26
Π-{4_「3-氯 -4-(3-氟-苄氧基 苯氨基 1-喹唑啉 -6-基}-4-(2-羟基 -乙基 IH-吡咯 -3- 基 1-吡咯烷 -1-基 -甲酮 Π-{ 4 _" 3 -Chloro-4-(3-fluoro-benzyloxyphenylamino-1-quinazolin-6-yl}-4-(2-hydroxy-ethyl IH-pyrrol-3-yl 1 -pyrrolidin-1-yl-ketone
Figure imgf000075_0002
重复本发明实施例 10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 2-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基}-6,7-二氢 -2H-吡喃 [3,4-c]吡 咯 _4-酮 10作原料， 按照本发明实施例 13所述相同方式进行该原料与吡咯烷的反 应，用硅胶柱色谱法纯化所得残余物，则得到标题产物 [1-{4-[3-氯 -4-(3-氟-节氧基) - 苯氨基 ]-喹唑啉 -6-基 }-4_(2-羟基-乙基) -1H-吡咯 -3-基] -吡咯烷 -1-基 -甲酮 26 ( 596 mg, 淡黄色固体）。 产率： 52.4%。
Figure imgf000075_0002
The reaction of the first step to the second step of Example 10 of the present invention was repeated, and the compound 2-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino group obtained in the above second step was used. - quinazolin-6-yl}-6,7-dihydro-2H-pyrano[3,4-c]pyrrole-4-one 10 as a starting material, in the same manner as described in Example 13 of the present invention The opposite of the raw material and pyrrolidine The residue obtained is purified by silica gel column chromatography to give the title product [1-{4-[3-chloro-4-(3-fluoro-ethoxy)-phenylamino]-quinazoline-6-yl. }-4_(2-Hydroxy-ethyl)-1H-pyrrol-3-yl]-pyrrolidin-1-yl-methanone 26 (596 mg, pale yellow solid). Yield: 52.4%.
MS m/z (ESI): 586[M+ 1] MS m/z (ESI): 586 [M+ 1]
1HNMR (400MHz, DMSO-^): δ 9.76(s, IH), 8.58(s, 2H), 8.18(dd, IH, J=9.2), 8.0 l(d, IH, J=2.4), 7.87(d, IH, J=8.8), 7.8 l(d, IH, J=2.0), 7.73(dd, IH, J=6.4), 7.48(q, IH), 7.43 (s, IH), 7.33(q, 3H), 7.18(t, IH), 5.28(s, 2H), 4.79(t, IH), 3.62(m, 4H), 3.47(m, 2H): 2.80(t, 2H), 1.88(s, 4H) 实施例 27 1 H NMR (400 MHz, DMSO-^): δ 9.76 (s, IH), 8.58 (s, 2H), 8.18 (dd, IH, J = 9.2), 8.0 l (d, IH, J = 2.4), 7.87 ( d, IH, J=8.8), 7.8 l(d, IH, J=2.0), 7.73(dd, IH, J=6.4), 7.48(q, IH), 7.43 (s, IH), 7.33(q, 3H), 7.18(t, IH), 5.28(s, 2H), 4.79(t, IH), 3.62(m, 4H), 3.47(m, 2H): 2.80(t, 2H), 1.88(s, 4H Example 27
Γ1-ί443-氯 -4-Γ3-氟-苄氧基 苯氨基 1-喹唑啉 -6-基 4-(2-羟基-乙基) -IH-吡咯 -3- 基 1-吗啉 -4-基 -甲酮
Figure imgf000076_0001
Γ1-ί443-Chloro-4-indole-3-fluoro-benzyloxyphenylamino-1-quinazolin-6-yl 4-(2-hydroxy-ethyl)-IH-pyrrol-3-yl 1-morpholine-4 -keto-ketone
Figure imgf000076_0001
重复本发明实施例 10第一步至第二步的反应， 使用上述第二歩中所得到的化 合物 2-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基 }-6,7-二氢 -2H-吡喃 [3，4-c]吡 咯 -4-酮 10作原料，按照本发明实施例 13所述相同方式进行该原料与吗啉的反应， - 用硅胶柱色谱法纯化所得残余物， 则得到标题产物 [1-{4-[3-氯 -4-(3-氟-苄氧基) -苯 氨基] -喹唑啉 -6-基 }-4-(2-羟基-乙基) -1H-吡咯 -3-基] -吗啉 -4-基 -甲酮 27 (695 mg,淡 黄色固体）。 产率： 59.5%。  The reaction of the first step to the second step of Example 10 of the present invention was repeated, using the compound 2-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino group obtained in the above second hydrazine. - quinazolin-6-yl}-6,7-dihydro-2H-pyran[3,4-c]pyrrol-4-one 10 as a starting material, in the same manner as described in Example 13 of the present invention The reaction of the starting material with morpholine, the residue obtained by silica gel column chromatography to give the title product [1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quin Oxazolin-6-yl}-4-(2-hydroxy-ethyl)-1H-pyrrol-3-yl]-morpholin-4-yl-methanone 27 (695 mg, pale yellow solid). Yield: 59.5%.
MS m/z (ESI): 602[M+ 1] MS m/z (ESI): 602 [M+ 1]
toMR (400MHz, DMSO-i¾: δ 9.77(s, IH), 8.66(s, 2H), 8.17(s， IH), 8.02(d, 2H, J-2.4), 7.74(dd, IH, J=8.8), 7.69(d, IH, J=2.4), 7.48(m, 2H), 7.33(q, 3H), 7.20(t, IH), 5.28(s, 2H), 4.69(t, 2H), 3.59(s, 4H), 2.70(t, 4H), 1.99(s, 2H) 实施例 28 toMR (400MHz, DMSO-i3⁄4: δ 9.77(s, IH), 8.66(s, 2H), 8.17(s, IH), 8.02(d, 2H, J-2.4), 7.74(dd, IH, J=8.8 ), 7.69(d, IH, J=2.4), 7.48(m, 2H), 7.33(q, 3H), 7.20(t, IH), 5.28(s, 2H), 4.69(t, 2H), 3.59( s, 4H), 2.70(t, 4H), 1.99(s, 2H) Example 28
2-(l-{4-「3-氯 -4-(3-氟-苄氧基) -苯氨基 1-喹唑啉 -6-基 }-4-哌啶 -1-基甲基 -IH-吡咯  2-(l-{4-"3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino-1-quinazolin-6-yl}-4-piperidin-1-ylmethyl-IH -pyrrole
-3-基) -乙醇
Figure imgf000076_0002
Figure imgf000077_0001
氩气分下在 10mL茄形瓶中加入 2 mL四氢呋喃，再加入四氢铝锂（16 mg， 0.42 mmol ) , 室温搅拌下滴加入 [1-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6- 基}-4-(2-羟基-乙基) -1H-吡咯 -3-基] -哌啶 -1-基 -甲酮 25 ( 50 mg， 0.08 mmol)的 2 mL 四氢呋喃溶液， 加热回流搅拌 3 小时。 薄层分析跟踪至原料消失， 加入含水四氢 呋喃猝灭反应， 减压浓缩， 用硅胶柱色谱法纯化所得残余物， 则得到标题产物 2_(1_{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基}-4-哌啶 -1-基甲基 -1H-吡咯 -3- 基) -乙醇 28 ( 32 mg, 淡黄色固体）。 产率： 65.6 %。 -3-yl)-ethanol
Figure imgf000076_0002
Figure imgf000077_0001
Add 2 mL of tetrahydrofuran to a 10 mL eggplant vial under argon, add lithium tetrahydrogenate (16 mg, 0.42 mmol), and add [1-{4-[3-chloro-4-(3-) at room temperature with stirring. Fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-4-(2-hydroxy-ethyl)-1H-pyrrol-3-yl]-piperidin-1-yl-methanone 25 (50 mg, 0.08 mmol) in 2 mL of tetrahydrofuran, stirred under reflux for 3 h. TLC analysis to trace the disappearance of starting material, quench the reaction was added aqueous tetrahydrofuran, concentrated under reduced pressure, purified by silica gel column chromatography resulting residue was _ 2 to give the title product (1_ {4- [3-chloro-4- (3- Fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-4-piperidin-1-ylmethyl-1H-pyrrol-3-yl)-ethanol 28 (32 mg, pale yellow solid) . Yield: 65.6 %.
MS m/z (ESI): 586[M+ 1] MS m/z (ESI): 586 [M+ 1]
!HNMR (400MHz, DMSO-c¾: δ 10.12(s, IH), 8.81(s, IH), 8.57(s, IH), 8.11(d, 2H), 7.86(t, 2H), 7.76(s， IH), 7.55(s, IH), 7.47(q, IH), 7.33(m, 3H), 7.19(t, IH), 5.27(s, 2H), 3.97(s, 2H), 3.68(t, 2H), 2.73(t, 2H), 1.71(s, 4H)， 1.52(s, 2H), 1.24(s, 4H) 实施例 29 ! HNMR (400MHz, DMSO-c¾ : δ 10.12 (s, IH), 8.81 (s, IH), 8.57 (s, IH), 8.11 (d, 2H), 7.86 (t, 2H), 7.76 (s, IH ), 7.55(s, IH), 7.47(q, IH), 7.33(m, 3H), 7.19(t, IH), 5.27(s, 2H), 3.97(s, 2H), 3.68(t, 2H) , 2.73(t, 2H), 1.71(s, 4H), 1.52(s, 2H), 1.24(s, 4H) Example 29
2-α-Μ-「3-氯 -4-(3-氟-苄氧基 苯氨基 喹唑啉 -6-基 4-吡咯烷 -1-基甲基 -IH-吡 咯 -3-基 乙醇  2-α-Μ-"3-chloro-4-(3-fluoro-benzyloxyphenylaminoquinazolin-6-yl 4-pyrrolidin-1-ylmethyl-IH-pyrrole-3-ylethanol
Figure imgf000077_0002
Figure imgf000077_0002
29  29
使用本发明实施例 26所得化合物 [1-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基 }-4-(2-羟基-乙基) -1H-吡咯 -3-基] -吡咯烷 -1-基 -甲酮 26按照本发明实施例 28 所述相同方式进行该原料与四氢铝锂的反应， 用硅胶柱色谱法纯化所得残余物， 则得到标题产物 2-(1-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基 }-4-吡咯烷 -1- 基甲基 -1H-吡咯 -3-基) -乙醇 29 (55 mg， 淡黄色固体)。 产率： 28.2 %。  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. The obtained residue was purified to give the title product 2-(1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-4-pyrrole. Alkyl-1-ylmethyl-1H-pyrrol-3-yl)-ethanol 29 (55 mg, pale yellow solid). Yield: 28.2%.
MS m/z (ESI): 572[M+ 1] MS m/z (ESI): 572 [M+ 1]
toMR (400MHz, OMSO-dg): δ 10.09(s, IH), 8.75(s, IH), 8.56(s, IH), 8.10(m, 2H), 7.84(m, 2H), 7.67(s, IH), 7.48(m, 2H), 7.32(m, 3H), 7.18(t5 IH), 5.27(s, 2H), 3.80(s, 2H), 3.64(t, 2H), 2.89(s, 4H), 2.71(q, 2H), 1.82(s, 4H) 实施例 30 toMR (400MHz, OMSO-dg): δ 10.09(s, IH), 8.75(s, IH), 8.56(s, IH), 8.10(m, 2H), 7.84(m, 2H), 7.67(s, IH ), 7.48(m, 2H), 7.32(m, 3H), 7.18(t 5 IH), 5.27(s, 2H), 3.80(s, 2H), 3.64(t, 2H), 2.89(s, 4H) , 2.71(q, 2H), 1.82(s, 4H) Example 30
2-(ΐ- -Π3-氯 -4-(3-氟-苄氧基 -苯氨基 1-喹唑啉 -6-基 4-吗啉 -4-基甲基 -IH-吡咯  2-(ΐ- -Π3-chloro-4-(3-fluoro-benzyloxy-phenylamino-1-quinazolin-6-yl 4-morpholin-4-ylmethyl-IH-pyrrole
-3-基) -乙醇
Figure imgf000078_0001
-3-yl)-ethanol
Figure imgf000078_0001
使用本发明实施例 27所得化合物 [1-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基}-4-(2-羟基-乙基) -1H-吡咯 -3-基] -吗啉 -4-基 -甲酮 27按照本发明实施例 28所述 相同方式进行该原料与四氢铝锂的反应， 用硅胶柱色谱法纯化所得残余物， 则得 到标题产物 2-(1- {4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基}-4-吗啉 -4-基甲基 -1H-吡咯 -3-基) -乙醇 30 (115 mg， 淡黄色固体)。 产率： 58.9%。  Using the compound obtained in 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%.
MS m/z (ESI): 588[M+ 1〗 MS m/z (ESI): 588 [M+ 1]
'HNMR (400MHz, DMSO-^): δ 9.93(s, 1H)， 8.63(s, IH), 8.55(s, IH), 8.09(d, IH, J=9.2), 8.05(d, IH, J-2.4), 7.83(d, IH, J=8.8), 7.79(dd, IH, J=9.0), 7.53(s, IH), 7.46(m, 2H), 7.32(m, 3H), 7.19(t, IH), 5.26(s, 2H), 3.65(m, 6H), 3.53(s, 2H), 2.70(t, 2H, J=2.6), 2.59(s, 4H) 实施例 31  'HNMR (400MHz, DMSO-^): δ 9.93(s, 1H), 8.63(s, IH), 8.55(s, IH), 8.09(d, IH, J=9.2), 8.05(d, IH, J -2.4), 7.83(d, IH, J=8.8), 7.79(dd, IH, J=9.0), 7.53(s, IH), 7.46(m, 2H), 7.32(m, 3H), 7.19(t , IH), 5.26(s, 2H), 3.65(m, 6H), 3.53(s, 2H), 2.70(t, 2H, J=2.6), 2.59(s, 4H) Example 31
1- {4-「3-氯 -4-( -氟-苄氧基) -苯氨基 喹唑啉 -6-基 4-(2-羟基-乙基) -IH-吡咯 -3- 羧酸 -(2-吡咯烷 -1-基-乙基) -胺  1-{4-"3-Chloro-4-(-fluoro-benzyloxy)-phenylaminoquinazolin-6-yl 4-(2-hydroxy-ethyl)-IH-pyrrole-3-carboxylic acid- (2-pyrrolidin-1-yl-ethyl)-amine
Figure imgf000078_0002
Figure imgf000078_0002
重复本发明实施例 10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 2-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基}-6,7-二氢 -2H-吡喃 [3,4-c]吡 咯 -4-酮 10作原料， 按照本发明实施例 13所述相同方式进行该原料与 2-吡咯烷 -1- 基-乙胺的反应，用硅胶柱色谱法纯化所得残余物，则得到标题产物 1-{4-[3-氯 -4-(3- 氟 -节氧基) -苯氨基] -喹唑啉 -6-基}-4-(2-经基-乙基) -1H-吡咯 -3-羧酸 -(2-吡咯烷 -1-基- 乙基) -胺 31 (420 mg, 黄褐色固体）。 产率： 38.5 %  The reaction of the first step to the second step of Example 10 of the present invention was repeated, and the compound 2-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino group obtained in the above second step was used. - 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. The 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 %
MS m/z (ESI): 629[M+1] MS m/z (ESI): 629 [M+1]
XHNMR (400MHz, DMSO-^):5 9.75(s, IH), 8.63(s, IH), 8.56(s, 1H)， 8.09(dd, IH, J=9.2), 8.02(d, 2H, J=1.6), 7.91(m, 2H), 7.74(dd, 1H， J=8.8), 7.48(q, 1H)， 7.40(d, IH, J=2.0), 7.33(q, 3H), 7.19(t, IH), 5.28(s, 2H), 4.70(s, IH), 3.64(m, 2H), 3.35(m, 2H), 2.90(t, 2H), 2.55(m, 6H)， 1.68(m, 4H) 实施例 32 X HNMR (400MHz, DMSO-^): 5 9.75 (s, IH), 8.63 (s, IH), 8.56 (s, 1H), 8.09 (dd, IH, J = 9.2), 8.02 (d, 2H, J =1.6), 7.91(m, 2H), 7.74(dd, 1H, J=8.8), 7.48(q, 1H), 7.40(d, IH, J=2.0), 7.33(q, 3H), 7.19(t , IH), 5.28(s, 2H), 4.70(s, IH), 3.64(m, 2H), 3.35(m, 2H), 2.90(t, 2H), 2.55(m, 6H), 1.68(m, 4H) Example 32
1-{4-「3-氯 -4-(3-氟-苄氧基 苯氨基 1-喹唑啉 -6-基 }-4-(2-羟基-乙基) -1H-吡咯 -3- 羧酸 -(2-哌啶小基-乙基) -胺 O震 iiAVυ/:ϋ1£ /-οεϊο 1-{4-"3-Chloro-4-(3-fluoro-benzyloxyphenylamino-1-quinazolin-6-yl}-4-(2-hydroxy-ethyl)-1H-pyrrole-3- Carboxylic acid-(2-piperidinyl-ethyl)-amine O shock iiAVυ/:ϋ1£ /-οεϊο
Figure imgf000079_0001
Figure imgf000079_0001
蝴城糊域被 i湖¾*^喊¾ ek≡：(1)Ηΐ9(ε寸H)£- —----- ----- o The city of the city is called by the i lake 3⁄4*^ 3⁄4 ek≡: (1) Ηΐ 9 (ε inch H) £------- ----- o
W 200 氟甲基-吡咯 -1-基)-喹唑啉 -4-基 胺 W 200 fluoromethyl-pyrrol-1-yl)-quinazoline-4-ylamine
Figure imgf000080_0001
Figure imgf000080_0001
重复本发明实施例 23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 (H4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基}-4-三氟甲基 -1H-吡咯 -3-基) - 甲醛 23b作原料， 按照本发明实施例 23第三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， 用硅胶柱色谱法纯化所得残余物， 则得到标题产物 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-[6-(3-{[2-(4-甲基 -哌嗪 -1-基) -乙氨基] -甲基 }-4-三氟甲 基-吡咯 -1-基) -喹唑啉 -4-基] -胺 34 ( 88 mg, 淡黄色固体）。 产率： 71.5 %。  The reaction of the first step to the second step of Example 23 of the present invention was repeated, using the compound obtained in the above second step (H4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]- The quinazolin-6-yl}-4-trifluoromethyl-1H-pyrrol-3-yl)-formaldehyde 23b is used as a starting material, and the starting material and 2-(2) are carried out in the same manner as described in the third step of Example 23 of the present invention. The reaction of 4-methyl-piperazine-1 -yl)-ethylamine is purified by silica gel column chromatography to afford the title product [3-chloro-4-(3-fluoro-benzyloxy)-benzene ]-[6-(3-{[2-(4-methyl-piperazin-1-yl)-ethylamino]-methyl}-4-trifluoromethyl-pyrrol-1-yl)-quin Oxazolin-4-yl]-amine 34 (88 mg, pale yellow solid). Yield: 71.5 %.
MS m/z (ESI): 668[M+ 1] MS m/z (ESI): 668 [M+ 1]
'HNMR (400MHZ, DMSO-^): δ 9.87(s, IH), 8.73(s, IH), 8.61(s, IH), 8.18(dd, IH, J=8.8), 8.07(s, IH), 8.03(s, IH), 7.9 l(d, IH, J=8.8), 7.77(d, IH, J=2.8), 7.71(s, IH), 7.48(m, IH), 7.3 l(m, 3H), 7.18(t, IH), 5.28(s, 2H), 3.83(s, 2H), 3.83(s, 2H), 2.44(m， 6H), 2.20(s, 3H), 2.09(s, 4H) 实施例 35 'HNMR (400MHZ, DMSO-^): δ 9.87 (s, IH), 8.73 (s, IH), 8.61 (s, IH), 8.18 (dd, IH, J = 8.8), 8.07 (s, IH), 8.03(s, IH), 7.9 l(d, IH, J=8.8), 7.77(d, IH, J=2.8), 7.71(s, IH), 7.48(m, IH), 7.3 l(m, 3H ), 7.18(t, IH), 5.28(s, 2H), 3.83(s, 2H), 3.83(s, 2H), 2.44(m, 6H), 2.20(s, 3H), 2.09(s, 4H) Example 35
「3-氯 -4-0-氟-苄氧基 )-苯 |^6 '-「(2-哌啶 -1-基-乙氨基) -甲基 1-4-三氟甲基-吡 咯 -1-基 喹唑啉 -4-基 胺  "3-Chloro-4-0-fluoro-benzyloxy)-benzene|^6 '-"(2-piperidin-1-yl-ethylamino)-methyl1-4-trifluoromethyl-pyrrole- 1- quinazolin-4-ylamine
Figure imgf000080_0002
Figure imgf000080_0002
重复本发明实施例 23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 (1-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基 ]-喹唑啉 -6-基 }-4-三氟甲基 -1H-吡咯 -3-基) - 甲醛 23b作原料，按照本发明实施例 23第三步所述相同方式进行该原料与 2-哌啶 -1-基-乙胺的反应， 用硅胶柱色谱法纯化所得残余物， 则得到标题产物 [3-氯 -4-(3- 氟-苄氧基) -苯基 ]-(6-{3-[(2-哌啶 -1-基-乙氨基) -甲基 ]-4-三氟甲基 -吡咯 -1-基 喹唑 啉 -4-基) -胺 35 (86 mg，. 淡黄色固体）。 产率： 71.7% 0 The reaction of the first step to the second step of Example 23 of the present invention was repeated, and the compound (1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-benzene) obtained in the above second step was used. Amino]-quinazolin-6-yl}-4-trifluoromethyl-1H-pyrrol-3-yl)-formaldehyde 23b is used as a starting material, and the starting material is carried out in the same manner as described in the third step of Example 23 of the present invention. The reaction of 2-piperidin-1-yl-ethylamine is purified by silica gel column chromatography to give the title product [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]- ( 6-{3-[(2-piperidin-1-yl-ethylamino)-methyl]-4-trifluoromethyl-pyrrol-1-ylquinazolin-4-yl)-amine 35 (86 mg ,. Light yellow solid). Yield: 71.7% 0
MS m/z (ESI): 653[M+ 1] MS m/z (ESI): 653 [M+ 1]
^MR (400MHz, DMSO- ): δ 9.86(s, IH), 8.74(s, IH), 8.62(s, IH), 8.17(dd, IH, J=8.4), 8.08(s, IH), 8.04(m, IH), 7.92(d, IH, J=9.2), 7.76(m, 2H), 7.47(q， IH), 7.32(q, 3H)， 7.19(t, IH), 5.28(s, 2H), 3.84(s, 2H), 2.87(s, 2H), 2.66(m, 6H), 1.61(s, 4H)， 1.44(s, 2H) 实施例 36 Γ3-氯 -4- 3-氟-苄氧基 苯基 W6-{3-IT2-甲氧基-乙氨基) -甲基 1-4-三氟甲基 -吡咯 ^MR (400MHz, DMSO-): δ 9.86(s, IH), 8.74(s, IH), 8.62(s, IH), 8.17(dd, IH, J=8.4), 8.08(s, IH), 8.04 (m, IH), 7.92(d, IH, J=9.2), 7.76(m, 2H), 7.47(q, IH), 7.32(q, 3H), 7.19(t, IH), 5.28(s, 2H ), 3.84(s, 2H), 2.87(s, 2H), 2.66(m, 6H), 1.61(s, 4H), 1.44(s, 2H) Example 36 Γ3 -Chloro-4-trifluoro-benzyloxyphenyl W6-{3-IT2-methoxy-ethylamino)-methyl1-4-trifluoromethyl-pyrrole
-1-基 μ喹唑啉 -4-基) -胺  -1-yl μ quinazolin-4-yl)-amine
Figure imgf000081_0001
Figure imgf000081_0001
重复本发明实施例 23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 (1-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基]-喹唑啉 -6-基 }-4_三氟甲基 -1Η-吡咯 -3-基) - 甲醛 23b作原料，按照本发明实施例 23第三步所述相同方式进行该原料与 2-甲氧 基-乙胺的反应， 用硅胶柱色谱法纯化所得残余物， 则得到标题产物 [3-氯 -4-(3-氟- 苄氧基)—苯基] -(6-{3-[(2-甲氧基-乙氨基) -甲基 ]-4-三氟甲基 -吡咯 -1-基}-喹唑啉 - 4- 基) -胺 36 (78 mg, 淡黄色固体）。 产率： 70.3 %。  The reaction of the first step to the second step of Example 23 of the present invention was repeated, and the compound (1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-benzene) obtained in the above second step was used. Amino]-quinazolin-6-yl}-4-trifluoromethyl-1Η-pyrrol-3-yl)-formaldehyde 23b is used as a starting material, and the starting material is carried out in the same manner as described in the third step of Example 23 of the present invention. The reaction of the 2-methoxy-ethylamine was purified by silica gel column chromatography to afford the title product [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-{ 3-[(2-Methoxy-ethylamino)-methyl]-4-trifluoromethyl-pyrrol-1-yl}-quinazoline-4-yl)-amine 36 (78 mg, pale yellow solid ). Yield: 70.3 %.
MS m/z (ESI): 600[M+ 1] MS m/z (ESI): 600[M+ 1]
1HNMR (400MHz, DMSO-i¾: δ 8.66(d， 1H), 8.59(s， 1H), 8.17(dd, 1H, J=9.0), 8.03(s, 1H), 8.00(d, 1H, J=2.8), 7.89(d, 1H, J=8.8), 7.73(dd, 1H, J=8.8), 7.64(s, 1H), 7.46(q, 1H), 7.3 l(q, 3H), 7.18(t, 1H), 5.26(s, 2H), 3.76(s, 2H), 3.45(s, 2H), 3.25(s, 3H), 2.78(t, 2H) 实施例 37  1H NMR (400MHz, DMSO-i3⁄4: δ 8.66 (d, 1H), 8.59 (s, 1H), 8.17 (dd, 1H, J = 9.0), 8.03 (s, 1H), 8.00 (d, 1H, J = 2.8 ), 7.89(d, 1H, J=8.8), 7.73(dd, 1H, J=8.8), 7.64(s, 1H), 7.46(q, 1H), 7.3 l(q, 3H), 7.18(t, 1H), 5.26(s, 2H), 3.76(s, 2H), 3.45(s, 2H), 3.25(s, 3H), 2.78(t, 2H) Example 37
Γ3-氯 -4-(3-氟-苄氧基) -苯基 1-(6-{3-「(2-甲磺酰基-乙氨基) -甲基 1-4-三氟甲基 1-吡 咯 -1-基 喹唑啉 -4-基) -胺  Γ3-Chloro-4-(3-fluoro-benzyloxy)-phenyl 1-(6-{3-"(2-methanesulfonyl-ethylamino)-methyl1-4-trifluoromethyl-1- Pyrrol-1-ylquinazolin-4-yl)-amine
Figure imgf000081_0002
Figure imgf000081_0002
重复本发明实施例 23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 (1-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基 }-4-三氟甲基 -1H-吡咯 -3-基) - 甲醛 23b作原料，按照本发明实施例 23第三歩所述相同方式进行该原料与 2-甲磺 酰基-乙胺的反应， 用硅胶柱色谱法纯化所得残余物， 则得到标题产物 [3-氯 -4-(3- 氟-苄氧基) -苯基 ]-(6-{3-[(2-甲磺酰基-乙氨基) -甲基 ]-4-三氟.甲基 1-吡咯 -1-基 喹唑 啉 -4-基) -胺 37 (50 mg, 淡黄色固体）。 产率： 41.7%。  The reaction of the first step to the second step of Example 23 of the present invention was repeated, and the compound (1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-benzene) obtained in the above second step was used. Amino]-quinazolin-6-yl}-4-trifluoromethyl-1H-pyrrol-3-yl)-formaldehyde 23b is used as a starting material, and the starting material is carried out in the same manner as described in the third step of Example 23 of the present invention. The reaction of the 2-methanesulfonyl-ethylamine was purified by silica gel column chromatography to give the title product [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-{ 3-[(2-Methanesulfonyl-ethylamino)-methyl]-4-trifluoromethyl-1-pyrrol-1-ylquinazolin-4-yl)-amine 37 (50 mg, pale yellow solid ). Yield: 41.7%.
MS m/z (ESI): 648[M+ 1] MS m/z (ESI): 648 [M+ 1]
iHNMR (400MHz, DMSO-c¾): δ 8.66(d, 1H), 8.60(s, 1H), 8.17(dd, 1H, J=8.8), 8.04(s, 1H), 8.0 l(d, 1H, J=2.4), 7.90(d, 1H, J=8.8), 7.73(dd, 1H, J=9.0), 7.63(s, 1H), 7.47(q, 1H), 7.3 l(m, 3H), 7.18(t, 1H), 5.26(s, 2H), 3.74(s, 2H), 3.42(s, 2H), 3.29(t, 2H, J=2.8), 3.01(t, 3H) iHNMR (400MHz, DMSO-c3⁄4): δ 8.66(d, 1H), 8.60(s, 1H), 8.17(dd, 1H, J=8.8), 8.04(s, 1H), 8.0 l(d, 1H, J =2.4), 7.90(d, 1H, J=8.8), 7.73(dd, 1H, J=9.0), 7.63(s, 1H), 7.47(q, 1H), 7.3 l(m, 3H), 7.18( t, 1H), 5.26(s, 2H), 3.74(s, 2H), 3.42(s, 2H), 3.29(t, 2H, J=2.8), 3.01(t, 3H)
实施例 38 Γ3-氯 -4-(3-氟-苄氧基) -苯基 (6-{3-Γ(3-吗啉 -4-基-丙氨基)-甲基卜 4-三氟甲基-吡 咯 -1-基 μ喹唑啉 -4-基) -胺 Example 38 Γ3-Chloro-4-(3-fluoro-benzyloxy)-phenyl (6-{3-Γ(3-morpholin-4-yl-propylamino)-methylbu 4-trifluoromethyl-pyrrole -1-ylpyroxazolin-4-yl)-amine
Figure imgf000082_0001
Figure imgf000082_0001
重复本发明实施例 23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 (1-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基}-4-三氟甲基 -1Η-吡咯 -3-基) - 甲醛 23b作原料，按照本发明实施例 23第三步所述相同方式进行该原料与 3-吗啉 -4-基-丙胺的反应， 用硅胶柱色谱法纯化所得残余物， 则得到标题产物 [3-氯 -4-(3- 氟-苄氧基) -苯基 ]-(6-{3-[(3-吗啉 -4-基-丙氨基) -甲基 ]-4-三氟甲基 -吡咯 -1-基} -喹唑 啉 -4-基) -胺 38 (70 mg, 淡黄色固体）。 产率： 56.9%。  The reaction of the first step to the second step of Example 23 of the present invention was repeated, and the compound (1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-benzene) obtained in the above second step was used. Amino]-quinazolin-6-yl}-4-trifluoromethyl-1Η-pyrrol-3-yl)-formaldehyde 23b is used as a starting material, and the starting material is carried out in the same manner as described in the third step of Example 23 of the present invention. The reaction of 3-morpholin-4-yl-propylamine is purified by silica gel column chromatography to afford the title product [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]- (6) -{3-[(3-morpholin-4-yl-propylamino)-methyl]-4-trifluoromethyl-pyrrol-1-yl}-quinazolin-4-yl)-amine 38 (70 Mg, light yellow solid). Yield: 56.9%.
MS m/z (ESI): 669[M+ 1] MS m/z (ESI): 669 [M+ 1]
^MR (400MHz, DMSO-i¾): δ 9.94(s, 1H), 8.78(s, 1H)， 8.62(s, 1H)， 8.17(dd, 1H, J=8.8), 8.13(s, 1H), 8.05(m, 1H), 7.92(d, 1H, J=9.2), 7.84(s, 1H), 7.77(m, 1H)， 7.48(q, 1H), 7.32(q, 3H), 7.19(t, 1H), 5.26(s, 2H), 3.92(s, 2H), 3.54(t， 4H), 2.84(s, 2H), 2.37(t, 6H), 1.72(t, 2H)  ^MR (400MHz, DMSO-i3⁄4): δ 9.94(s, 1H), 8.78(s, 1H), 8.62(s, 1H), 8.17(dd, 1H, J=8.8), 8.13(s, 1H), 8.05(m, 1H), 7.92(d, 1H, J=9.2), 7.84(s, 1H), 7.77(m, 1H), 7.48(q, 1H), 7.32(q, 3H), 7.19(t, 1H), 5.26(s, 2H), 3.92(s, 2H), 3.54(t, 4H), 2.84(s, 2H), 2.37(t, 6H), 1.72(t, 2H)
- 实施例 39 - Example 39
「3-氯 -4-(3-氟-苄氧基 苯基 l-(6-i3-f(2-吡咯垸 -1-基-乙氨基 甲基 1-4-三氟甲基- 吡咯 -1-基}-喹唑啉 -4-基) -胺
Figure imgf000082_0002
"3-Chloro-4-(3-fluoro-benzyloxyphenyl-l-(6-i3-f(2-pyrrole-1-yl-ethylaminomethyl)1-4-trifluoromethyl-pyrrole- 1-yl}-quinazolin-4-yl)-amine
Figure imgf000082_0002
重复本发明实施例 23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 (1-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基 }-4-三氟甲基 -1H-吡咯 -3-基) - 甲醛 23b作原料，按照本发明实施例 23第三步所述相同方式进行该原料与 2-吡咯 垸 -1-基-乙胺的反应，用硅胶柱色谱法纯化所得残余物，则得到标题产物 [3-氯 -4-(3- 氟-苄氧基) -苯基 ]-(6-{3-[(2-吡咯烷 -1-基-乙氨基) -甲基 ]-4-三氟甲基 -吡咯 -1-基 喹 唑啉 -4-基) -胺 39 (60 mg, 淡黄色固体）。 产率： 50.4%。 . ·  The reaction of the first step to the second step of Example 23 of the present invention was repeated, and the compound (1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-benzene) obtained in the above second step was used. Amino]-quinazolin-6-yl}-4-trifluoromethyl-1H-pyrrol-3-yl)-formaldehyde 23b is used as a starting material, and the starting material is carried out in the same manner as described in the third step of Example 23 of the present invention. The reaction of 2-pyrrole-1-yl-ethylamine is purified by silica gel column chromatography to give the title product [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]- ( 6-{3-[(2-Pyrrolidin-1-yl-ethylamino)-methyl]-4-trifluoromethyl-pyrrol-1-ylquinazolin-4-yl)-amine 39 (60 mg , light yellow solid). Yield: 50.4%. ·
MS m/z (ESI): 639[M+ 1] MS m/z (ESI): 639 [M+ 1]
1HNMR (400MHz, DMSO-*): S10.01(s， 1H), 8.84(s, 1H), 8.61(s, 1H)， 8.21(d, 1H, J=8.8), 8.10(m, 2H), 7.87(m, 3H), 7.47(q, 1H), 7.32(m, 3H), 7.2 l(t, 1H), 5.27(s, 2H), 3.80(s, 2H), 2.89(m, 8H), 1.84(m, 4H) 实施例 40 1-ΙΪΜ4-Γ3-氯 -4-(3-氟-苄氧基) -苯氨基 1-喹唑啉 -6-基 M-三氟甲基 -IH-吡咯 -3- 基甲基) -氨基 1-3-吗啉 -4-基-丙 -2-醇
Figure imgf000083_0001
 1 H NMR (400MHz, DMSO-*): S10.01 (s, 1H), 8.84 (s, 1H), 8.61 (s, 1H), 8.21 (d, 1H, J = 8.8), 8.10 (m, 2H) , 7.87(m, 3H), 7.47(q, 1H), 7.32(m, 3H), 7.2 l(t, 1H), 5.27(s, 2H), 3.80(s, 2H), 2.89(m, 8H) , 1.84 (m, 4H) Example 40 1-ΙΪΜ4-Γ3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino-1-quinazolin-6-yl M-trifluoromethyl-IH-pyrrol-3-ylmethyl)-amino 1-3-morpholin-4-yl-propan-2-ol
Figure imgf000083_0001
重复本发明实施例 23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 (1-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基]-喹唑啉 -6-基}-4-三氟甲基 -1H-吡咯 -3-基) - 甲醛 23b作原料，按照本发明实施例 23第三步所述相同方式进行该原料与 1-氨基 -3-吗啉 -4-基-丙 -2-醇的反应， 用硅胶柱色谱法纯化所得残余物， 则得到标题产物 1_[(1_{4_[3_氯— 4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基 }斗三氟甲基 -1H-吡咯 -3-基甲 基) -氨基] -3-吗啉 -4-基-丙 -2-醇 40 (70 mg, 淡黄色固体）。 产率： 55.1 %。 The reaction of the first step to the second step of Example 23 of the present invention was repeated, and the compound (1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-benzene) obtained in the above second step was used. Amino]-quinazolin-6-yl}-4-trifluoromethyl-1H-pyrrol-3-yl)-formaldehyde 23b is used as a starting material, and the starting material is carried out in the same manner as described in the third step of Example 23 of the present invention. The reaction of 1-amino-3-morpholin-4-yl-propan-2-ol is purified by silica gel column chromatography to give the title product 1_[(1_{ 4 _[ 3 _ chloro-4-( 3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}trifluoromethyl-1H-pyrrol-3-ylmethyl)-amino]-3-morpholin-4-yl- Propan-2-ol 40 (70 mg, pale yellow solid). Yield: 55.1%.
MS m/z (ESI): 685 [M+ 1] MS m/z (ESI): 685 [M+ 1]
JHNMR (400MHz, DMSO-^): 59.98(s, IH), 8.80(s, IH), 8.61(s, IH), 8.17(m, 2H)， 8.06(s, IH), 7.91(d， IH, J=8.8), 7.79(m, 2H), 7.48(q, IH), 7.32(m, 3H)， 7.19(t， IH), 5.27(s, 2H), 4.80(s, IH), 3.87(s, 3H), 3.53(m, 4H), 2.84(m, IH), 2.67(m, IH), 2.33-2.42(m, 6H) 实施例 41 J HNMR (400MHz, DMSO-^): 59.98 (s, IH), 8.80 (s, IH), 8.61 (s, IH), 8.17 (m, 2H), 8.06 (s, IH), 7.91 (d, IH) , J=8.8), 7.79(m, 2H), 7.48(q, IH), 7.32(m, 3H), 7.19(t, IH), 5.27(s, 2H), 4.80(s, IH), 3.87( s, 3H), 3.53 (m, 4H), 2.84 (m, IH), 2.67 (m, IH), 2.33-2.42 (m, 6H) Example 41
4-{Γ(1-ί4-「3-氯 -4-(3-氟-苄氧基) -苯氨基 1-喹唑啉 -6-基 4-三氟甲基 -IH-吡咯 -3- 基甲基) -氨基 1-甲基 U-二氧 -六氢 -1λ*6*-噻喃 -4-醇  4-{Γ(1-ί4-"3-chloro-4-(3-fluoro-benzyloxy)-phenylamino-1-quinazolin-6-yl 4-trifluoromethyl-IH-pyrrole-3- Methyl)-amino 1-methyl U-dioxo-hexahydro-1λ*6*-thiopyran-4-ol
Figure imgf000083_0002
Figure imgf000083_0002
重复本发明实施例 23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 (1-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基}-4-三氟甲基 -1Η-吡咯 -3-基) - 甲醛 23b作原料，按照本发明实施例 23第三步所述相同方式进行该原料与 4-氨基 甲基 -1,1-二氧 -六氢 -1λ*6*-噻喃 -4-醇的反应， 用硅胶柱色谱法纯化所得残余物， 则 得到标题产物 4-{[(1-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基 }-4-三氟甲基 -1Η-吡咯 -3-基甲基) -氨基] -甲基 }-1,1-二氧 -六氢 -1λ*6*-噻喃 -4-醇 41 ( 107 mg, 淡黄 色固体）。 产率： 82.3 %。  The reaction of the first step to the second step of Example 23 of the present invention was repeated, and the compound (1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-benzene) obtained in the above second step was used. Amino]-quinazolin-6-yl}-4-trifluoromethyl-1Η-pyrrol-3-yl)-formaldehyde 23b is used as a starting material, and the starting material is carried out in the same manner as described in the third step of Example 23 of the present invention. The reaction of 4-aminomethyl-1,1-dioxo-hexahydro-1λ*6*-thiopyran-4-ol is purified by silica gel column chromatography to give the title product 4-{[(1) -{4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-4-trifluoromethyl-1Η-pyrrol-3-ylmethyl -Amino]-methyl}-1,1-dioxo-hexahydro-1λ*6*-thiopyran-4-ol 41 (107 mg, pale yellow solid). Yield: 82.3 %.
MS m/z (ESI): 704[M+ 1] MS m/z (ESI): 704 [M+ 1]
1HNMR (400MHz, DMSO-i¾)： 69.84(s, IH), 8.69(s, IH), 8.61(s, IH), 8.20(dd, IH, J=8.8), 8.06(s, IH), 8.02(d, IH, J=2.8), 7.90(d, IH, J=9.2), 7.73(dd, IH, J=8.8), 7.65(s, IH), 7.48(m, IH), 7.33(q, 3H), 7.20(t, IH), 5.28(s, 2H), 4.78(s, IH), 3.76(s, 2H), 3.18(m, 2H), 2.95(m, 2H), 2.60(s, 2H), 1.98(m, 4H) 实施例 42 1 H NMR (400MHz, DMSO-i3⁄4): 69.84 (s, IH), 8.69 (s, IH), 8.61 (s, IH), 8.20 (dd, IH, J = 8.8), 8.06 (s, IH), 8.02 (d, IH, J=2.8), 7.90(d, IH, J=9.2), 7.73(dd, IH, J=8.8), 7.65(s, IH), 7.48(m, IH), 7.33(q, 3H), 7.20(t, IH), 5.28(s, 2H), 4.78(s, IH), 3.76(s, 2H), 3.18(m, 2H), 2.95(m, 2H), 2.60(s, 2H ), 1.98(m, 4H) Example 42
『3-氯 -4-(3-氟-苄氧基 苯基 146-(1H-吡咯 -3-基 喹唑啉 -4-基 1-胺 『3-Chloro- 4- ( 3-fluoro-benzyloxyphenyl 146-(1H-pyrrol-3-ylquinazolin-4-yl 1-amine)
Figure imgf000084_0001
氮气氛下在 50 mL茄形瓶中， 将 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-(6-碘-喹唑啉 -4- 基) -胺 lg ( 255 mg, 0.505 mmol), 1- (三异丙基硅 )-1Η-吡咯 -3-硼酸（269 mg， 1.01 mmol) , 四三苯基膦化钯（2.3 mg， 0.02 mmol), 碳酸钾 （138 mg， 1 mmol)溶于 6 mL N,N-二甲基甲酰胺和 1.5 mL水的混合溶剂中， 得到的混合物加热到 70°C， 2 小时后反应完毕。 将反应液冷却至室温， 倒入 lOOmL冰水中， 析出白色固体， 搅 拌十分钟后， 抽滤， 产物在真空下干燥， 得到的固体进一步通过柱层析， 得到标 题产物 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-[6-(1Η-吡咯 -3-基)-喹唑啉 -4-基] -胺 42 (138 mg， 黄色固体)。 产率： 61.7 %。 ·
Figure imgf000084_0001
[3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-iodo-quinazolin-4-yl)-amine lg (in a 50 mL eggplant-shaped flask under nitrogen atmosphere) 255 mg, 0.505 mmol), 1-(triisopropylsilyl)-1Η-pyrrole-3-boronic acid (269 mg, 1.01 mmol), tetratriphenylphosphine palladium (2.3 mg, 0.02 mmol), potassium carbonate ( 138 mg, 1 mmol) was dissolved in a mixed solvent of 6 mL of N,N-dimethylformamide and 1.5 mL of water, and the mixture was heated to 70 ° C, and the reaction was completed after 2 hours. The reaction liquid was cooled to room temperature, poured into 100 mL of ice water, and a white solid was precipitated. After stirring for ten minutes, the mixture was filtered under suction, and the product was dried in vacuo. (3-Fluoro-benzyloxy)-phenyl]-[6-(1Η-pyrrol-3-yl)-quinazolin-4-yl]-amine 42 (138 mg, yellow solid). Yield: 61.7 %. ·
MS m/z (ESI): 445[M+ 1] MS m/z (ESI): 445 [M+ 1]
'HNMR (400MHZ, DMSO-i¾): δ 11.09(s, IH), 9.68(s, 1H)， 8.56(d, IH, J=1.2), 8.50 (s， 1H)， 8.09(dd, IH, J=7.6) , 8.03(d, 1H， J=2.8)， 7.77 (dd， IH, J-8.8), 7.70(d, IH, J=8.8) , 7.46(m, 2H), 7.33 (m, 3H), 7.19(t, IH), 6.98(m, IH), 6.70(d, IH, 1=1.6), 5.27(s, 2H)  'HNMR (400MHZ, DMSO-i3⁄4): δ 11.09(s, IH), 9.68(s, 1H), 8.56(d, IH, J=1.2), 8.50 (s, 1H), 8.09(dd, IH, J =7.6) , 8.03(d, 1H, J=2.8), 7.77 (dd, IH, J-8.8), 7.70(d, IH, J=8.8) , 7.46(m, 2H), 7.33 (m, 3H) , 7.19(t, IH), 6.98(m, IH), 6.70(d, IH, 1=1.6), 5.27(s, 2H)
' 实施例 43 'Example 43
Γ 3-氟苄基 )- 1Η-吲唑 -5-基 l-(6-吡咯 -1-基-喹唑啉 -4-基) -胺  Γ 3-fluorobenzyl)- 1 Η-carbazole -5-yl l-(6-pyrrol-1-yl-quinazolin-4-yl)-amine
Figure imgf000084_0002
Figure imgf000084_0002
第一步  First step
[1-(3-氟苄基) -1H-吲唑 -5-基] -(6-碘喹唑啉 -4-基) -胺 重复本发明实施例 1第一步至第四歩的反应，将第四步所得的化合物 6-碘 -3H- 喹唑啉 -4-酮 If ( 10 g, 36.7 mmol), 在氮气氛下加入到 500 mL茄形瓶中， 溶于 100 mL二氯亚砜和 3 mL Ν,Ν-二甲基甲酰胺的混合溶剂中， 加热回流至反应液透 明。 搅拌 6小时后， 薄层分析跟踪原料消失， 蒸出二氯亚砜， 备用。 [1-(3-Fluorobenzyl)-1H-indazol-5-yl]-(6-iodoquinazolin-4-yl)-amine The reaction of the first step to the fourth step of Example 1 of the present invention was repeated, and the compound 6-iodo-3H-quinazolin-4-one If (10 g, 36.7 mmol) obtained in the fourth step was added under a nitrogen atmosphere. In a 500 mL eggplant bottle, dissolve in 100 mL of thionyl chloride and 3 mL of a mixture of hydrazine and dimethylformamide, and heat to reflux until the reaction solution is transparent. After stirring for 6 hours, the thin layer analysis traced the disappearance of the starting material, and the thionyl chloride was distilled off and used.
氮气氛下将备用中间体溶于 250 mL异丙醇中， 加入 1-(3-氟苄基 )-1Η-吲唑 -5- 胺 43a ( 8.85 g， 36.7 mmol) , 加热回流过夜。 薄层分析跟踪至原料消失， 将反应 液冷却至室温， 减压抽滤， 将所得固体用 50 mL乙酸乙酯洗涤， 将滤饼加入到氨 水 （200 mL, lOOmL氨水加 lOOmL水）和乙酸乙酯的混合溶剂中溶解， 室温搅 拌 10分钟， 减压抽滤， 真空干燥， 得到标题产物 [1-(3-氟苄基) -1H-吲唑 -5-基] -(6- 碘喹唑啉 -4-基) -胺 43b (13 g， 类白色固体)。 产率： 71.8 %。  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. The thin layer analysis was followed until the disappearance of the starting material, the reaction solution was cooled to room temperature, suction filtered under reduced pressure, and the obtained solid was washed with 50 mL of ethyl acetate, and the filter cake was added to aqueous ammonia (200 mL, 100 mL of ammonia water and 100 mL of water) and acetic acid The ester was dissolved in a mixed solvent, stirred at room temperature for 10 minutes, filtered under reduced pressure and dried in vacuo to give the title product [1-(3-fluorobenzyl)-1H-indazol-5-yl]-(6-iodoquinazole) Phenyl-4-yl)-amine 43b (13 g, off-white solid). Yield: 71.8 %.
MS m/z (ESI): 496[M+ 1] MS m/z (ESI): 496 [M+ 1]
第二步  Second step
[3-氯 -4- (吡啶 -2-甲氧基) -苯基 ]-(6-吡咯 -1-基-喹唑啉 -4-基) -胺 氮气氛下在 100 mL茄形瓶中加入 [1-(3-氟苄基) -1H-吲唑 -5-基] -(6-碘喹唑啉 -4- 基) -胺 43b (100 mg， 0.2 mmol), 磷酸钾 （127 mg， 0.6 mmol), 碘化亚铜（57 mg， 0.3mmol)和吡咯（20 mg， 0.3 mmol), 用 5 mL Ν,Ν-二甲基甲酰胺溶解， 搅拌下 滴加 Ν,Ν'-二甲基 -1,2-乙二胺（26 mg， 0.29 mmol), 加热回流搅拌过夜。 薄层分析 跟踪至原料消失， 倒入 50 mL冰水中， 过滤， 得到墨绿色固体进一步通过柱层析 分离纯化得到标题产物 [3-氯 -4- (吡啶 -2-甲氧基)-苯基] -(6-吡咯 -1-基-喹唑啉 -4-基) - 胺 43 (30 mg， 淡黄色固体)。 产率： 30%。  [3-Chloro-4-(pyridine-2-methoxy)-phenyl]-(6-pyrrol-1-yl-quinazolin-4-yl)-amine in a 100 mL eggplant-shaped flask under nitrogen atmosphere Add [1-(3-fluorobenzyl)-1H-indazol-5-yl]-(6-iodoquinazolin-4-yl)-amine 43b (100 mg, 0.2 mmol), potassium phosphate (127 mg , 0.6 mmol), cuprous iodide (57 mg, 0.3 mmol) and pyrrole (20 mg, 0.3 mmol), dissolved in 5 mL hydrazine, hydrazine-dimethylformamide, and stirred under stirring, Ν'- Methyl-1,2-ethanediamine (26 mg, 0.29 mmol) was stirred and stirred under reflux overnight. The thin layer analysis was followed until the disappearance of the starting material, poured into 50 mL of ice water, and filtered to give a dark green solid which was further purified by column chromatography to give the title product [3-chloro-4-(pyridine-2-methoxy)-phenyl. -(6-Pyrrol-1-yl-quinazolin-4-yl)-amine 43 (30 mg, pale yellow solid). Yield: 30%.
MS m/z (ESI): 435 [M+1] MS m/z (ESI): 435 [M+1]
^MR (400MHz, DMSO-i¾)： δ 9.98(s, 1Η)， 8.71(s, 1Η)， 8.53(s, 1Η)， 8.25(s, 1Η)， 8.18(s, 1Η), 8.17(dd, 1H, J=9.2), 7.87(d, 1H, J=9.2), 7.79(d, 1H, J=8.8), 7.74(m, 1H), 7.6 l(m, 2H), 7.38(m, 1H), 7.11(m, 3H), 6.38(m, 2H) 实施例 44  ^MR (400MHz, DMSO-i3⁄4): δ 9.98(s, 1Η), 8.71(s, 1Η), 8.53(s, 1Η), 8.25(s, 1Η), 8.18(s, 1Η), 8.17(dd, 1H, J=9.2), 7.87(d, 1H, J=9.2), 7.79(d, 1H, J=8.8), 7.74(m, 1H), 7.6 l(m, 2H), 7.38(m, 1H) , 7.11(m, 3H), 6.38(m, 2H) Example 44
Γ3-氯 -4- (吡啶 -2-甲氧基 -苯基 l-(6-吡咯 -1-基-喹唑啉 -4-基 -胺
Figure imgf000085_0001
Γ3-Chloro-4-(pyridine-2-methoxy-phenyl-l-(6-pyrrol-1-yl-quinazolin-4-yl-amine)
Figure imgf000085_0001
44
Figure imgf000086_0001
第一步 44
Figure imgf000086_0001
first step
3-氯 -4- (吡啶 -2-甲氧基) -苯胺  3-chloro-4-(pyridine-2-methoxy)-aniline
在 250mL茄形瓶中加入 2-(2-氯 -4-硝基-苯氧基甲基) -吡啶 44a ( 9.5g, 35.9mmol), lOO mL甲醇， 氯化铵（19.17g， 359mmol)和 50 mL 7 ， 所得的混合 物加热回流 3 小时后反应完毕。 冷却反应液至室温， 过滤， 母液减压下浓縮， 得 到的残留物加入 80 mL水，用二氯甲烷萃取所得混合液（100 mLx3)，有机相用无 水硫酸钠干燥，过滤，滤液浓縮后得到本标题产物 3-氯 -4- (吡啶 -2-甲氧基) -苯胺 44b ( 8.7 g, 黄色固体）， 100%。 纯度： 98.13 %。  Add 2-(2-chloro-4-nitro-phenoxymethyl)-pyridine 44a (9.5 g, 35.9 mmol), 100 mL methanol, ammonium chloride (19.17 g, 359 mmol) and a 250 mL eggplant flask. 50 mL of 7 , the resulting mixture was heated to reflux for 3 hours and the reaction was completed. The reaction mixture was cooled to room temperature, filtered, and the residue was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. The title product, 3-chloro-4-(pyridine-2-methoxy)-phenylamine 44b (8.7 g, yellow solid). Purity: 98.13 %.
第二步  Second step
[3-氯 -4- (吡啶 -2-甲氧基) -苯基 ]-(6-碘喹唑啉 -4-基 1)-胺  [3-Chloro-4-(pyridine-2-methoxy)-phenyl]-(6-iodoquinazolin-4-yl 1)-amine
重复本发明实施例 1第一歩至第四步的反应，将第四步所得的化合物 6-碘 -3H- 喹唑啉—4-酮 If (5 g， 18.3 mmol)溶于 50 mL二氯亚砜和 0.5 mL N,N-二甲基 '甲酰 胺的混合溶剂中， 加热回流至反应液透明。 搅拌 6小时后， 薄层分析跟踪原料消 失， 蒸出二氯亚砜， 备用。  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.
氮气氛下将备用中间体溶于 160 mL异丙醇中， 加入 3-氯 -4- (吡啶 -2-甲氧基) - 苯胺 44b (4.25 g， 18.2 mmol), 加热回流过夜。 薄层分析跟踪至原料消失， 将反 应液冷却至室温，减压抽滤，将所得固体用 5 mL甲醇溶解稀释后加入氨水 (200 mL, 体积比为 1 : 1)， 调节 pH值至 8— 9， 冰水浴冷却后抽滤得到标题产物 [3-氯 -4- (吡 啶 -2-甲氧基)-苯基] -(6-碘喹唑啉 -4-基 1)-胺 44c (8 g， 类白色固体)。 产率： 89.6%。 MS m/z (ESI): 489[M+ 1]  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. After cooling in an ice water bath, suction filtration gave the title product [3-chloro-4-(pyridine-2-methoxy)-phenyl]-(6-iodoquinazolin-4-yl 1)-amine 44c (8 g, off-white solid). Yield: 89.6%. MS m/z (ESI): 489 [M+ 1]
1HNMR (400MHz, DMSO-Jd): δ 9.78(s, 1H), 8.60(d, 3H)， 8.16(d, 1H, J=9.2), 8.04(m, 1H)， 7.89(m, 2H), 7.76(d, 1H, J=9.2), 7.59(m, 3H), 7.38(t, 1H), 7.3 l(d, 1H, J==8.8), 6.38(s, 2H), 5.31(s, 2H) 1 H NMR (400 MHz, DMSO-J d ): δ 9.78 (s, 1H), 8.60 (d, 3H), 8.16 (d, 1H, J = 9.2), 8.04 (m, 1H), 7.89 (m, 2H) , 7.76(d, 1H, J=9.2), 7.59(m, 3H), 7.38(t, 1H), 7.3 l(d, 1H, J==8.8), 6.38(s, 2H), 5.31(s, 2H)
第三步  third step
[3-氯 -4- (吡啶 -2-甲氧基) -苯基] -(6-吡咯 -1-基-喹唑啉 -2-基) -胺 氮气氛下在 100 mL茄形瓶中加入 [3-氯 -4- (吡啶 -2-甲氧基) -苯基 ]-(6-碘喹唑啉 -4-基 1)-胺 44c (1.95 g， 4 mmol), 磷酸钾 （2.55 g， 12 mmol), 碘化亚铜 （2.28 g， 12 mmol)和吡咯（ll mL， 160 mmol) , 用 25 mLN,N-二甲基甲酰胺溶解， 搅拌下 滴加 Ν,Ν'-二甲基 -1,2-乙二胺 （1.3 mL, 12 mmol), 加热回流搅拌 4小时后反应完 毕。 将反应液冷却至室温， 倒入 lOO mL冰水中， 过滤， 得到黑色固体， 进一步通 过柱层析分离纯化， 得到标题产物 [3-氯 -4- (吡啶 -2-甲氧基) -苯基] -(6-吡咯 -1-基-喹 唑啉 -2-基) -胺 44 (1.3 g， 白色固体)。 产率： 76%。 [3-Chloro-4-(pyridine-2-methoxy)-phenyl]-(6-pyrrol-1-yl-quinazolin-2-yl)-amine in a 100 mL eggplant-shaped flask under nitrogen atmosphere Add [3-chloro-4-(pyridine-2-methoxy)-phenyl]-(6-iodoquinazolin-4-yl 1)-amine 44c (1.95 g, 4 mmol), potassium phosphate (2.55 g, 12 mmol), cuprous iodide (2.28 g, 12 mmol) and pyrrole (ll mL, 160 mmol), dissolved in 25 mL of N,N-dimethylformamide, and stirred under stirring, Ν'- Methyl-1,2-ethanediamine (1.3 mL, 12 mmol) was stirred and stirred under reflux for 4 h. The reaction solution was cooled to room temperature, poured into 100 mL of ice water, and filtered to give a black solid. Purification by column chromatography to give the title product [3-chloro-4-(pyridine-2-methoxy)-phenyl]-(6-pyrrol-1-yl-quinazolin-2-yl)-amine 44 (1.3 g, white solid). Yield: 76%.
MS m/z (ESI): 428[M+1] MS m/z (ESI): 428 [M+1]
iHNMR (400MHz, DMSO-c¾: δ 9.78(s, 1H)， 8.60(d, 3H), 8.16(d, 1H, J=9.2), 8.04(m, 1H), 7.89(m, 2H)， 7.76(d, 1H, J=9.2), 7.59(m, 3H), 7.38(t, 1H), 7.3 l(d, 1H, J=8.8), 6.38(s, 2H), 5.31(s, 2H) 实施例 45 iHNMR (400MHz, DMSO-c3⁄4: δ 9.78 (s, 1H), 8.60 (d, 3H), 8.16 (d, 1H, J = 9.2), 8.04 (m, 1H), 7.89 (m, 2H), 7.76 ( d, 1H, J=9.2), 7.59(m, 3H), 7.38(t, 1H), 7.3 l(d, 1H, J=8.8), 6.38(s, 2H), 5.31(s, 2H) 45
Γ3-氯 -4- (吡啶 -2-甲氧基 苯基 1 -〔6-吡咯 -1-基-喹唑啉 -2-基) -胺  Γ3-Chloro-4-(pyridine-2-methoxyphenyl 1-[6-pyrrole-1-yl-quinazolin-2-yl)-amine
Figure imgf000087_0001
Figure imgf000087_0001
第一步  First step
2-{4-[3-氯 -4- (吡啶 -2-甲氧基) -苯氨基] -喹唑啉 -6-基} -吡咯 -1-羧酸叔丁酯 重复实施例 44第一步至第二步的反应， 将得到的化合物 [3-氯 -4- (吡啶 -2-甲氧 基) -苯基 ]-(6-碘喹唑啉 -4-基 1)-胺 44c (1.95 g， 4 mmol)， 1-(叔丁氧基羰基)-111-吡咯 -2-硼酸 7b ( 1.1 g， 5.2纖 ol)， 四三苯基膦化钯 (0.23 g, 0.2匪 ol)，碳酸钾 ( 1.38 g， lO nimol)溶于 25 niL N，N-二甲基甲酰胺和 6 mL水的混合溶剂中， 得到的混合 物加热到 70°C， 2小时后反应完毕。 将反应液冷却至室温， 倒入 300 mL冰水中， 析出白色固体， 搅拌十分钟后， 抽滤， 产物 真空下干燥， 得到的固体进一步通 过柱层析， 得到标题产物 2-{4-[3-氯 -4- (吡啶 -2-甲氧基) -苯氨基] -喹唑啉 -6-基} -吡咯 -1-羧酸叔丁酯 45a (2.0g, 黄色固体）， 产率： 95 %。  2-{4-[3-Chloro-4-(pyridine-2-methoxy)-phenylamino]-quinazolin-6-yl}-pyrrole-1-carboxylic acid tert-butyl ester Step to the reaction of the second step, the obtained compound [3-chloro-4-(pyridine-2-methoxy)-phenyl]-(6-iodoquinazolin-4-yl 1)-amine 44c ( 1.95 g, 4 mmol), 1-(tert-butoxycarbonyl)-111-pyrrole-2-boronic acid 7b (1.1 g, 5.2 OL), tetratriphenylphosphine palladium (0.23 g, 0.2 匪ol), Potassium carbonate (1. 38 g, lO nimol) was dissolved in a mixed solvent of 25 niL of N,N-dimethylformamide and 6 mL of water, and the resulting mixture was heated to 70 ° C, and the reaction was completed after 2 hours. The reaction solution was cooled to room temperature, poured into 300 mL of ice water, and a white solid was precipitated. After stirring for ten minutes, the mixture was filtered under suction, and the product was dried under vacuum. The obtained solid was further subjected to column chromatography to give the title product 2-{4-[3 -Chloro-4-(pyridine-2-methoxy)-phenylamino]-quinazolin-6-yl}-pyrrole-1-carboxylic acid tert-butyl ester 45a (2.0 g, yellow solid), yield: 95 %.
MS m/z (ESI): 529[M+1] MS m/z (ESI): 529 [M+1]
第二步  Second step
[3-氯 -4- (吡啶 -2-甲氧基) -苯基] -(6-吡咯 -1-基-喹唑啉 -2-基) -胺 将上述步骤得到的化合物 2-{4-[3-氯 -4- (吡啶 -2-甲氧基) -苯氨基] -喹唑啉 -6-基 吡咯 -1-羧酸叔丁酯 45a溶解于 55 mL无水四氢呋喃中， 得到的黄色溶液用冰水浴 冷却至 0°C， 加入甲醇钠 （ 1.728 g， 16 mmol)，将反应液逐渐升至室温， 3小时后 反应完毕， 反应液呈深红色。 将得到的反应液倒入饱和氯化钠水溶液中， 析出固 体， 过滤， 得到的黄色固体在真空下干燥后， 进一步通过柱层析分离纯化， 得到 W 200 标题产物 [3-氯- 4- (吡啶 _2_甲氧基) -苯基] -(6-吡咯- 基-喹唑啉 -2-基) -胺 45 ( 1.15 g， 黄色固体）， 产率 68%。 [3-chloro-4-(pyridine-2-methoxy)-phenyl]-(6-pyrrol-1-yl-quinazolin-2-yl)-amine The compound obtained in the above step 2-{4 -[3-Chloro-4-(pyridine-2-methoxy)-phenylamino]-quinazolin-6-ylpyrrole-1-carboxylic acid tert-butyl ester 45a was dissolved in 55 mL of anhydrous tetrahydrofuran. The yellow solution was cooled to 0 ° C with an ice water bath, sodium methoxide (1 728 g, 16 mmol) was added, and the mixture was gradually warmed to room temperature. After 3 hours, the 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%.
MS m/z (ESI): 428[M+1] MS m/z (ESI): 428 [M+1]
'H MR (400MHZ, DMSO- ): δ 11.38(s, IH), 9.67(s, IH), 8.65(s, IH), 8.6 l(d, IH), 8.53(s, IH), 8.14(d, IH, J=9.2), 8.06(m, IH), 7.88(t, IH), 7.76(m, 2H), 7.60(d, IH, J=7.6), 7.38(t, IH), 7.3 l(d, IH, J=9.2), 6.97(s, 1H)， 6.77(s， IH) , 6.22(s, IH) , 5.3 l(s, 2H) 实施例 46  'H MR (400MHZ, DMSO- ): δ 11.38(s, IH), 9.67(s, IH), 8.65(s, IH), 8.6 l(d, IH), 8.53(s, IH), 8.14(d , IH, J=9.2), 8.06(m, IH), 7.88(t, IH), 7.76(m, 2H), 7.60(d, IH, J=7.6), 7.38(t, IH), 7.3 l( d, IH, J=9.2), 6.97(s, 1H), 6.77(s, IH), 6.22(s, IH), 5.3 l(s, 2H) Example 46
Γ3-氯 -4- (吡啶 -2-甲氧基) -苯基 1-(6-· 5-Γί2-甲磺酰基-乙氨基) -甲基 IH-吡咯 -2- 基 喹唑啉 -4-基) -胺  Γ3-Chloro-4-(pyridine-2-methoxy)-phenyl 1-(6-· 5-Γί2-methanesulfonyl-ethylamino)-methyl IH-pyrrol-2-ylquinazoline-4 -yl)-amine
Figure imgf000088_0001
Figure imgf000088_0001
第一步  First step
5-{4-[3-氯 -4- (吡啶 -2-甲氧基) -苯氨基] -喹唑啉 -6-基 }-1Η-吡咯 -2-甲醛 氮气氛下， 将 10 mL Ν,Ν-二甲基甲酰胺用冰浴冷却至 0°C， 加入三氯氧膦 (0.085mL, 0.98mmol), 混合液升至室温， 搅拌半小时。 得到的溶液冷却至 0°C , 加入实施例 45所得到的化合物 [3-氯 -4- (吡啶 -2-甲氧基) -苯基] -(6-吡咯 -1-基-喹唑啉 -2-基) -胺 45， 混合液在室温下搅拌 4小时反应完毕后， '加入 10mL冰水， 并用 1N 氢氧化钠溶液调节 pH=l l。用二氯甲烷和甲醇混合溶剂 ( 60 mLx5 )进行萃取。 有 机相在减压下浓缩， 所得的残留物在室温下放置过夜， 有黄色固体析出， 过滤， 得到标题产物 5-{4-[3-氯 -4- (吡啶 -2-甲氧基) -苯氨基] -喹唑啉 -6-基 }-m-吡咯 -2-甲醛 46a ( 120 mg, 黄色固体）， 产率 40 %。  5-{4-[3-Chloro-4-(pyridine-2-methoxy)-phenylamino]-quinazolin-6-yl}-1Η-pyrrole-2-carboxaldehyde under nitrogen atmosphere, 10 mL Ν The hydrazine-dimethylformamide was cooled to 0 ° C with an ice bath, and phosphorus oxychloride (0.085 mL, 0.98 mmol) was added, and the mixture was warmed to room temperature and stirred for half an hour. The resulting solution was cooled to 0 ° C, and the compound [3-chloro-4-(pyridine-2-methoxy)-phenyl]-(6-pyrrol-1-yl-quinazoline) obtained in Example 45 was added. 2-yl)-amine 45, the mixture was stirred at room temperature for 4 hours, and after completion of the reaction, '10 mL of ice water was added, and pH = 11 was adjusted with a 1 N sodium hydroxide solution. Extraction was carried out with a mixed solvent of dichloromethane and methanol (60 mL x 5 ). The organic phase was concentrated under reduced pressure. EtOAcjjjjjjjj Phenylamino]-quinazolin-6-yl}-m-pyrrole-2-carbaldehyde 46a (120 mg, yellow solid), yield 40%.
MS m/z (ESI): 456[M+1] MS m/z (ESI): 456 [M+1]
iHNMR (400MHz, OMSO-d6): δ 12.59(s, IH), 11.20(s, IH), 9.60(s, IH), 9.25(s, IH), 8.86(s, IH), 8.62(d, IH, J=4.4), 8.58(d, IH, J=8.8), 8.00(s, IH), 7.9 l(m, 2H), 7.72(d, IH, J=8.8), 7.61(d, IH, J=7.6), 7.38(m, 2H), 7.20(s, 1H)， 7.14(s, IH), 5.36(s, 2H) iHNMR (400MHz, OMSO-d 6 ): δ 12.59(s, IH), 11.20(s, IH), 9.60(s, IH), 9.25(s, IH), 8.86(s, IH), 8.62(d, IH, J=4.4), 8.58(d, IH, J=8.8), 8.00(s, IH), 7.9 l(m, 2H), 7.72(d, IH, J=8.8), 7.61(d, IH, J=7.6), 7.38(m, 2H), 7.20(s, 1H), 7.14(s, IH), 5.36(s, 2H)
第二步  Second step
[3-氯 -4- (吡啶 -2-甲氧基) -苯基 ]-(6-{5-[(2-甲磺酰基-乙氨基) -甲基 ]-1Η-吡咯 -2- 基}-喹唑啉 -4-基) -胺 将 2-甲磺酰 -乙胺盐酸盐 2b (30 mg, 0.186 mmol), 三乙胺（0.038 ml, 0.275 mmol)溶于 5mL二氯甲烷中， 完全溶解后加入上述步骤所得的化合物 5-{4-[3-氯 -4- (吡啶 -2-甲氧基) -苯氨基] -喹唑啉 -6-基}-111-吡咯 -2-甲醛 46a(50 mg, 0.11 mmol) , 搅拌 6小时后， 加入三乙酰氧基硼氢化钠（61 mg， 0.286 mmol)。所得的混合液在 室温下搅拌过夜， 反应完毕。 用 TLC色谱分离产物， 得到标题产物 [3-氯 -4- (吡啶 -2-甲氧基) -苯基 ]-(6-{5-[(2-甲磺酰基-乙氨基) -甲基 ]-1Η-吡咯 -2-基}-喹唑啉 -4-基) - 胺 46 (46 mg, 黄色固体）， 产率 74.0%。 [3-Chloro-4-(pyridine-2-methoxy)-phenyl]-(6-{5-[(2-methanesulfonyl-ethylamino)-methyl]-1Η-pyrrole-2-yl }-quinazolin-4-yl)-amine 2-Methanesulfonyl-ethylamine hydrochloride 2b (30 mg, 0.186 mmol), triethylamine (0.038 ml, 0.275 mmol) was dissolved in 5 mL of dichloromethane, and then dissolved. {4-[3-Chloro-4-(pyridine-2-methoxy)-phenylamino]-quinazolin-6-yl}-111-pyrrole-2-carbaldehyde 46a (50 mg, 0.11 mmol), stirring After 6 hours, sodium triacetoxyborohydride (61 mg, 0.286 mmol) was added. The resulting mixture was stirred at room temperature overnight and the reaction was completed. The product was isolated by TLC to give the title product [3-chloro-4-(pyridine-2-methoxy)-phenyl]-(6-{5-[(2-methylsulfonyl-ethylamino)-methyl ]-1Η-pyrrol-2-yl}-quinazolin-4-yl)-amine 46 (46 mg, yellow solid), yield 74.0%.
MS m/z (ESI): 564[M+1] MS m/z (ESI): 564[M+1]
'HNMR (400MHZ, DMSO-i¾): δ 11.92(s, 1H), 9.84(s, 1H), 9.04(s, 1H), 8.61(s, 1H), 8.55(s, 1H), 8.23(s, 1H), 8.15(d, 1H, J-8.8), 7.90(m, 2H), 7.77(d, 1H, J=8.4), 7.61 (d, 1H, J=7.6), 7.38(t, 1H), 7.30(d, 1H, J=9.2), 6.77(s, 1H), 6.29(s, 1H), 5.36(s, 2H), 4.12(s, 2H), 3.5 l(t, 2H), 3.11(s, 3H), 3.06(t, 2H) 实施例 47  'HNMR (400MHZ, DMSO-i3⁄4): δ 11.92(s, 1H), 9.84(s, 1H), 9.04(s, 1H), 8.61(s, 1H), 8.55(s, 1H), 8.23(s, 1H), 8.15(d, 1H, J-8.8), 7.90(m, 2H), 7.77(d, 1H, J=8.4), 7.61 (d, 1H, J=7.6), 7.38(t, 1H), 7.30(d, 1H, J=9.2), 6.77(s, 1H), 6.29(s, 1H), 5.36(s, 2H), 4.12(s, 2H), 3.5 l(t, 2H), 3.11(s , 3H), 3.06(t, 2H) Example 47
2-{4-Γ3-氯 -4- (吡啶 -2-甲氧基) -苯氨基 1-喹唑啉 -6-基 6,7-二氢 -2H-吡喃「3,4-cl  2-{4-Γ3-chloro-4-(pyridine-2-methoxy)-phenylamino-1-quinazoline-6-yl 6,7-dihydro-2H-pyran "3,4-cl
Figure imgf000089_0001
Figure imgf000089_0001
10b 47  10b 47
在 100 mL茄形瓶中， 依次加入 [3-氯 -4- (吡啶 -2-甲氧基) -苯基 ]-(6-碘喹唑 啉 -4-基 1)-胺 44c ( 1.95 g， 4 mmol) , 6，7-二氢 -2H-吡喃并 [3,4-c]吡咯 -4-酮 10b (713 mg, 5.2 mmol), 磷酸钾（2.55 g， 12 mmol) , 碘化亚铜（0.76 g， 4 mmol)和 25 mL Ν,Ν-二甲基甲酰胺， 混合物在搅拌下加入 Ν,Ν'-二甲基 -1,2-乙二胺 （0.44 mL, 4 mmol), 加热反应液到 70°C， 搅拌过夜。 冷却反应液， 倒入 100 ml冰水中， 有墨 绿色固体析出， 抽滤， 得到的固体通过柱层析分离提纯， 得到的标题产物 2-{4-[3- 氯 -4- (吡啶 -2-甲氧基) -苯氨基]-喹唑啉 -6-基}-6，7-二氢 -2H-吡喃 [3,4-c]吡咯 -4-酮 47 (0.9 g， 类白色固体）， 产率 45.2%。  In a 100 mL eggplant-shaped flask, [3-chloro-4-(pyridine-2-methoxy)-phenyl]-(6-iodoquinazolin-4-yl 1)-amine 44c ( 1.95 g) was added in sequence. , 4 mmol), 6,7-dihydro-2H-pyrano[3,4-c]pyrrol-4-one 10b (713 mg, 5.2 mmol), potassium phosphate (2.55 g, 12 mmol), iodide Cuprous (0.76 g, 4 mmol) and 25 mL of hydrazine, hydrazine-dimethylformamide, mixture of hydrazine, Ν'-dimethyl-1,2-ethanediamine (0.44 mL, 4 mmol) The reaction solution was heated to 70 ° C and stirred overnight. The reaction solution was cooled, poured into 100 ml of ice water, and a dark green solid was precipitated, and filtered, and the obtained solid was purified by column chromatography to give the title product 2-{4-[3-chloro-4-(pyridine-2). -methoxy)-phenylamino]-quinazolin-6-yl}-6,7-dihydro-2H-pyrano[3,4-c]pyrrol-4-one 47 (0.9 g, white solid) ), the yield was 45.2%.
MS m/z (ESI): 498 [M+ 1] MS m/z (ESI): 498 [M+ 1]
^MR (400MHz, DMSO-ί/ί): δ 9.83(s, 1Η), 8.75(s, 1H), 8.61 (m, 2H), 8.24(t, 2H), 8.03(s, 1H), 7.89(m, 2H), 7.73(d, 1H, J=8.8), 7.60(d, 1H， J=7.6), 7.54(s, 1H), 7.38(t, 1H), 7.32(d, 1H, J=8.8), 5.32(s, 2H) , 4.48(t, 2H), 2.9 l(t, 2H) 实施例 48 ^MR (400MHz, DMSO-ί/ί): δ 9.83(s, 1Η), 8.75(s, 1H), 8.61 (m, 2H), 8.24(t, 2H), 8.03(s, 1H), 7.89( m, 2H), 7.73(d, 1H, J=8.8), 7.60(d, 1H, J=7.6), 7.54(s, 1H), 7.38(t, 1H), 7.32(d, 1H, J=8.8 ), 5.32(s, 2H) , 4.48(t, 2H), 2.9 l(t, 2H) Example 48
(3-氯 -4-氟苯基 )-〔6-吡咯 -1-喹唑啉 -4-基) -胺  (3-chloro-4-fluorophenyl)-[6-pyrrole-1-quinazolin-4-yl)-amine
Figure imgf000090_0001
Figure imgf000090_0001
第一步  First step
(3-氯 -4-氟苯基 )-(6-碘-喹唑啉 -4-基) -胺  (3-chloro-4-fluorophenyl)-(6-iodo-quinazolin-4-yl)-amine
重复本发明实施例 1第五所述的实验步骤， 不同的是以实施例 1第四步所得 的化合物 6-碘 -3H-喹唑啉 -4-酮 If作原料， 按照本发明实施例 1第五步所述的相同 方式使得该原料与 3-氯 -4-氟-苯胺的反应， 得到标题化合物 (3-氯 -4-氟苯基 )-(6-碘- 喹唑啉 -4-基) -胺 48a ( 15 mg, 黄色固体）， 产率 56%。  The experimental procedure described in the fifth embodiment of the present invention is repeated, except that the compound 6-iodo-3H-quinazolin-4-one If obtained in the fourth step of the first embodiment is used as a raw material, according to the embodiment 1 of the present invention. The title compound (3-chloro-4-fluorophenyl)-(6-iodo-quinazolin-4-) was obtained from the title compound (3-chloro-4-fluorophenyl)- -) 48a (15 mg, yellow solid), yield 56%.
MS m/z (ESI): 400 [M+ 1] MS m/z (ESI): 400 [M+ 1]
― 第二步 ' (3-氯 -4-氟苯基 )-(6-吡咯 -1-喹唑啉 -4-基) -胺  ― Second step '(3-Chloro-4-fluorophenyl)-(6-pyrrole-1-quinazolin-4-yl)-amine
在 100 mL茄形瓶中， 将上述步骤所得的化合物 (3-氯 -4-氟苯基 )-(6-碘-喹唑啉 The compound obtained in the above step (3-chloro-4-fluorophenyl)-(6-iodo-quinazoline) in a 100 mL eggplant-shaped flask
-4-基) -胺 48a (2 g, 5 mmol)，磷酸钾（3.18 g， 15mmol) ,碘化亚铜（0.95g， 5mmol) 溶解于 40 mLN,N-二甲基甲酰胺中， 混合物在搅拌下加入 Ν,Ν'-二甲基 -1,2-乙二胺 (0.55 mL, 5 mmol) ,加热反应液到 65°C，搅拌过夜。将反应液倒入 600 mL水中， 有黄绿色固体析出， 抽滤， 得到的固体通过柱层析分离提纯， 得到的标题产物 (3- 氯 -4-氟苯基 )-(6-吡咯 -1-喹唑啉 -4-基) -胺 48 (0.9 g黄色固体）， 产率 53 %。 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, Ν'-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%.
MS m/z (ESI): 339 [M+ 1] MS m/z (ESI): 339 [M+ 1]
1HNMR (400MHz, DMSO-^): δ 9.89(s, 1H), 8.64(d, 2H), 8.19(m, 2H), 7.91(d, 1H, J=9.2), 7.85(m, 1H), 7.59(t, 2H), 7.50(m, 1H)， 6.39(t, 2H) 实施例 49 1 HNMR (400MHz, DMSO- ^) : δ 9.89 (s, 1H), 8.64 (d, 2H), 8.19 (m, 2H), 7.91 (d, 1H, J = 9.2), 7.85 (m, 1H), 7.59(t, 2H), 7.50(m, 1H), 6.39(t, 2H) Example 49
(3-氯 -4-氟 -苯基 「6-(1H-吡咯 -2-基 喹唑啉 -4-基 Ί-胺  (3-Chloro-4-fluoro-phenyl "6-(1H-pyrrol-2-ylquinazolin-4-ylindole-amine)
Figure imgf000090_0002
Figure imgf000091_0001
Figure imgf000090_0002
Figure imgf000091_0001
第一步  First step
2-{4-[3-氯 -4-氟-苯氨基] -喹唑啉 -6-基 吡咯 -1-羧酸叔丁酯  2-{4-[3-Chloro-4-fluoro-phenylamino]-quinazoline-6-ylpyrrole-1-carboxylic acid tert-butyl ester
重复实施例 48第一步的反应，将得到的化合物 (3-氯 -4-氟苯基 )-(6-碘-喹唑啉 -4_ 基) -胺 48a ( 1.60 g, 4 mmol), 1- (叔丁氧基羰基) -1H-吡咯 -2-硼酸 7b ( 1.1 g， 5.2 mmol), 四三苯基膦化钯 （0.23 g， 0.2 mmol)， 碳酸钾 （1.38 g， lO mmol) 溶于 25 mLN,N-二甲基甲酰胺和 6 mL水的混合溶剂中， 得到的混合物加热到 70°C , 2 小时后反应完毕。 将反应液冷却至室温， 倒入 300 mL冰水中， 析出白色固体， 搅 拌十分钟后， 抽滤， 产物在真空下干燥， 得到的固体进一步通过柱层析， 得到标 题产物 2-{4-[3-氯 -4-氟-苯氨基] -喹唑啉 -6-基 吡咯 -1-羧酸叔丁酯 49a ( 1.49g，黄色 固体）产率： 85 %。 '  The reaction of the first step of Example 48 was repeated, and the obtained compound (3-chloro-4-fluorophenyl)-(6-iodo-quinazolin-4-yl)-amine 48a ( 1.60 g, 4 mmol), 1 -(tert-Butoxycarbonyl)-1H-pyrrole-2-boronic acid 7b (1.1 g, 5.2 mmol), tetrakistriphenylphosphine palladium (0.23 g, 0.2 mmol), potassium carbonate (1.38 g, 10 mmol) The mixture obtained was heated to 70 ° C in a mixed solvent of 25 mL of N,N-dimethylformamide and 6 mL of water, and the reaction was completed after 2 hours. The reaction solution was cooled to room temperature, poured into 300 mL of ice water, and a white solid was precipitated. After stirring for ten minutes, the mixture was filtered, and the product was dried under vacuum. The obtained solid was further subjected to column chromatography to give the title product 2-{4-[ 3-Chloro-4-fluoro-phenylamino]-quinazolin-6-ylpyrrole-1-carboxylic acid tert-butyl ester 49a ( 1.49 g, yellow solid) Yield: 85 %. '
MS m/z (ESI): 439[M+1]  MS m/z (ESI): 439 [M+1]
一少  One less
[(3-氯 -4-氟-苯基) -[6-(1Η-吡咯 -2-基)-喹唑啉 -4-基] -胺  [(3-Chloro-4-fluoro-phenyl)-[6-(1Η-pyrrole-2-yl)-quinazolin-4-yl]-amine
将上述步骤得到的化合物 2-{4-[3-氯 -4-氟-苯氨基] -喹唑啉 -6-基} -吡咯 -1-羧酸 . 叔丁酯 49a溶解于 55 mL无水四氢呋喃中，得到的黄色溶液用冰水浴冷却至 0°C， 加入甲醇钠 （1.46 g， 13 mmol) ，将反应液逐渐升至室温， 3小时后反应完毕， 反 应液呈深红色。 将得到的反应液倒入饱和氯化钠水溶液中， 析出固体， 过滤， 得 到的黄色固体在真空下干燥后， 进一步通过柱层析分离纯化， 得到标题化合物 (3- 氯 -4-氟-苯基) -[6-(1Η-吡咯 -2-基) -喹唑啉 -4-基] -胺 49 (767 mg, 淡黄色固体）， 产率 67%。 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. The obtained 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-(1Η-pyrrol-2-yl)-quinazolin-4-yl]-amine 49 (767 mg, pale yellow solid), yield 67%.
MS m/z (ESI): 339[M+ 1]  MS m/z (ESI): 339 [M+ 1]
!HNMR (400MHz, DMSO-^): δ 11.41(s, 1H), 9.79(s, 1H), 8.65(s, 1H), 8.58(s5 1H), 8.21(d, 1H, J=6.8), 8.15(d, 1H, J=8.0), 7.86(m, 1H), 7.80(d, 1H, J=8.8), 7.48(t, 1H), 6.98(s, 1H), 6.78(t, 1H)， 6.24(q, 1H) 实施例 50 ! HNMR (400MHz, DMSO- ^) : δ 11.41 (s, 1H), 9.79 (s, 1H), 8.65 (s, 1H), 8.58 (s 5 1H), 8.21 (d, 1H, J = 6.8), 8.15(d, 1H, J=8.0), 7.86(m, 1H), 7.80(d, 1H, J=8.8), 7.48(t, 1H), 6.98(s, 1H), 6.78(t, 1H), 6.24 (q, 1H) Example 50
Γ3-氯 -4-(3-氟-苄氧基) -苯基 l-(6- -「(2-吗啉 -4-乙氨基) -甲基 1-lH-吡咯 -2-基 喹 唑啉 -4-基) -胺  3-chloro-4-(3-fluoro-benzyloxy)-phenyl-l-(6--(2-morpholin-4-ethylamino)-methyl 1-lH-pyrrol-2-ylquinazole Phenyl-4-yl)-amine
Figure imgf000091_0002
Figure imgf000091_0002
Figure imgf000092_0001
第 ^ "步
Figure imgf000092_0001
Step ^ "step
[3-氯 -4-(3-氟苄氧基) -苯基 ]-[6-(l-三异丙基硅基 -1Η-吡咯 -2-基) -喹唑啉 -4-基] - 胺  [3-Chloro-4-(3-fluorobenzyloxy)-phenyl]-[6-(l-triisopropylsilyl-1Η-pyrrol-2-yl)-quinazolin-4-yl] - Amine
将本发明实施 8所得的化合物 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-[6-(1Η-吡咯 -2-基) - 喹唑啉 -4-基] -胺 8 (225 mg, 0.5 mmol)溶解于 10 mL四氢呋喃中， 溶解后在干冰 浴冷却至一 78°C， 加入二异丙基胺锂 （0.5 mL, 0.5 mol), 搅拌 20分钟后升至室 温反应 10分钟后，继续冰浴冷却至一 78 Ό，加入三异丙基硅氯（195 mg, 1 mmol), 1小时后反应完毕。在反应液中加水猝灭反应， 减压下蒸出四氢呋喃， 残留物用乙 酸乙酯（100 mL X 3 )萃取反应液， 合并的有机相用无水硫酸钠干燥， 过滤， 滤液 减压下浓缩， 残留物进一步通过柱层析分离纯化， 得到本标题产物 [3-氯 -4-(3-氟苄 氧基) -苯基 ]-[6-(1-三异丙基硅烷基 -1H-吡咯 -2-基) -喹唑啉 -4-基] -胺 50a ( 145 mg, 黄色固体）， 产率： 48.3 %。  The compound obtained in the practice of the present invention 8 [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1Η-pyrrol-2-yl)-quinazolin-4-yl] -Amine 8 (225 mg, 0.5 mmol) was dissolved in 10 mL of THF, dissolved in a dry ice-bath to </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; After reacting for 10 minutes at room temperature, the mixture was cooled to a temperature of 78 Torr, and triisopropylsilyl chloride (195 mg, 1 mmol) was added. After 1 hour, the reaction was completed. The reaction mixture was quenched with EtOAc (EtOAc)EtOAc. The residue is further purified by column chromatography to give the title product [3-chloro-4-(3-fluorobenzyloxy)-phenyl]-[6-(1-triisopropylsilyl-1H- Pyrrrol-2-yl)-quinazolin-4-yl]-amine 50a (145 mg, yellow solid), Yield: 48.3 %.
MS m/z (ESI): 601 [M+ 1] MS m/z (ESI): 601 [M+ 1]
第二步  Second step
5-{4-[3-氯 -4-(3-氟苄氧基) -苯氨基]-喹唑啉 -6-基 }小三异丙基硅基 -1H-吡咯 -3- 甲醛  5-{4-[3-Chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazoline-6-yl}tris-triisopropylsilyl-1H-pyrrole-3-carbaldehyde
将 5 mL N,N-二甲基甲酰胺在冰浴条件下，冷却至 0°C后，加入三氯氧磯（26 mg, 0.17 mmol), 升温至室温， 搅拌 1小时后再冷却至 0°C， 加入上述步骤所得的 化合物 [3-氯 -4-(3-氟苄氧基) -苯基 ]-[6-(1-三异丙基硅烷基 -1H-吡咯 -2-基)-喹唑啉 -4- 基] -胺 50a (67 mg, 0.11 mmol), 所得的混合物在室温下搅拌过夜， 反应完毕。 反 应液中滴加 5 %氢氧化钠溶液， 调节 pH= ll， 用乙酸乙酯 ( 100 mL X 3 )萃取反应 液， 合并的有机相用无水硫酸钠干燥， 过滤， 滤液减压下浓缩， 所得的残留物通 过柱层析进一步分离纯化， 得到本标题产物 5-{4-[3-氯 -4-(3-氟苄氧基) -苯氨基] -喹 唑啉 -6-基}-1-三异丙基硅基 -1H-吡咯 -3-甲醛 50b (36 mg, 黄色固体）， 产率： 68 %。  After 5 mL of N,N-dimethylformamide was cooled to 0 ° C in an ice bath, triclosan (26 mg, 0.17 mmol) was added, and the mixture was warmed to room temperature, stirred for 1 hour and then cooled to 0. °C, adding the compound obtained in the above step [3-chloro-4-(3-fluorobenzyloxy)-phenyl]-[6-(1-triisopropylsilyl-1H-pyrrol-2-yl) - quinazolin-4-yl]-amine 50a (67 mg, 0.11 mmol). The obtained mixture was stirred at room temperature overnight and the reaction was completed. The reaction solution was added dropwise with a 5% aqueous solution of sodium hydroxide, and the mixture was adjusted to pH ll. The mixture was extracted with ethyl acetate (100 mL EtOAc). The residue obtained is further purified by column chromatography to give the title product 5-{4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazoline-6-yl}- 1-Triisopropylsilyl-1H-pyrrole-3-carbaldehyde 50b (36 mg, yellow solid), Yield: 68%.
MS m/z (ESI): 473 [M+ 1]  MS m/z (ESI): 473 [M+ 1]
第三步  third step
[3-氯 -4-(3-氟-苄氧基) -苯基 ]-(6-{4-[(2-吗啉 -4-乙氨基) -甲基] -1H-吡咯 -2-基} -喹 唑啉 -4-基) -胺 [3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-{4-[(2-morpholin-4-ethylamino)-methyl]-1H-pyrrole-2- - quin Oxazolin-4-yl)-amine
将上述步骤所得的化合物 5-{4-[3-氯 -4-(3-氟苄氧基) -苯氨基] -喹唑啉 -6-基 }-1- 三异丙基硅基 -1H-吡咯 -3-甲醛 50b (36 mg， 0.076 mmol)溶解于 5 mL四氢呋喃中， 搅拌下滴加 2-吗啉 -4-基 -乙胺 （15 mg， 0.114 mmol), 分批加入三乙酰氧基硼氢化 钠 （127 mg， 0.6 mmol), 所得的混合物液加热回流 3小时后反应完毕。 反应液在 减压下蒸干， 所得的残留物进一步通过柱层析分离纯化， 得到标题产物 [3-氯 -4-(3- 氟-苄氧基) -苯基 ]-(6-{4-[(2-吗啉 -4-乙氨基) -甲基 ]-1Η-吡咯 -2-基}-喹唑啉 -4-基) -胺 50 (37 mg, 黄色固体）， 产率： 83.1 %。  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. The reaction mixture was evaporated to drynessmjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj -[(2-morpholin-4-ethylamino)-methyl]-1Η-pyrrol-2-yl}-quinazolin-4-yl)-amine 50 (37 mg, yellow solid), Yield: 83.1 %.
MS m/z (ESI): 587 [M+ 1] MS m/z (ESI): 587 [M+ 1]
iHNMR (400MHz, CDC13): δ 10.17(s, IH), 8.67(s, IH), 8.09(s, IH), 7.96(d, IH, J=8.8), 7.89(s, 1H)， 7.82(m, 2H), 7.64(d, IH, J=8.8), 7.35(m, IH), 7.25(m, 2H), 7.02(m, IH), 6.96(d, IH, J=8.8), 6.13(s, IH), 6.12(s, IH), 5.14(s, 2H), 3.91(s, 2H), 3.64(t, 4H), 2.80(t 2H), 2.50(t, 2H), 2.20(t, 4H) . 实施例 51 iHNMR (400MHz, CDC1 3 ): δ 10.17(s, IH), 8.67(s, IH), 8.09(s, IH), 7.96(d, IH, J=8.8), 7.89(s, 1H), 7.82( m, 2H), 7.64(d, IH, J=8.8), 7.35(m, IH), 7.25(m, 2H), 7.02(m, IH), 6.96(d, IH, J=8.8), 6.13( s, IH), 6.12(s, IH), 5.14(s, 2H), 3.91(s, 2H), 3.64(t, 4H), 2.80(t 2H), 2.50(t, 2H), 2.20(t, 4H) . Example 51
Γ3-氯 -4-(3-氟-苄氧基) -苯基 1-{6-Γ1-(2-二乙氨基乙基) -IH-吡咯 -3-基卜喹唑啉 -4- 基 }-胺
Figure imgf000093_0001
将本发明实施 42所得的化合物 [3-氯 -4-(3-氟-节氧基) -苯基 ]-[6-(1Η-吡咯 -3-基) - 喹唑啉 -4-基] -胺 42 (70 mg, 0.157mmol)溶解于 5 mLN，N—二甲基甲酰胺中， 溶 液在冰浴冷却下， 加入氢化钠 （16 mg, 0.4 mmol) , 混合液升至室温， 搅拌 30分 钟后， 加入（2-溴乙基） -二乙胺氢溴酸盐 （62 mg， 0.236 mmol), 加热反应液至 60°C， 搅拌 2小时后反应完毕， 加水猝灭反应。 反应液用乙酸乙酯 （100 mL X 3 ) 萃取， 合并的有机相用无水硫酸钠干燥， 过滤， 滤液减压下浓缩所得的残留物进 一步通过柱层析分离纯化， 得到本标题产物 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-{6-[1-(2- 二乙氨基乙基 )-1Η-吡咯 -3-基]-喹唑啉 -4-基} -胺 51 (40 mg,黄色固体），产率： 46.8 %。 3-Chloro-4-(3-fluoro-benzyloxy)-phenyl 1-{6-indole 1-(2-diethylaminoethyl)-IH-pyrrol-3-ylquinazolin-4-yl }-amine
Figure imgf000093_0001
The compound obtained by carrying out 42 of the present invention [3-chloro-4-(3-fluoro-p-hydroxy)-phenyl]-[6-(1Η-pyrrol-3-yl)-quinazolin-4-yl] -Amine 42 (70 mg, 0.157 mmol) was dissolved in 5 mL of N-N-dimethylformamide. The solution was cooled in ice-cooled, sodium hydride (16 mg, 0.4 mmol) was added and the mixture was warmed to room temperature and stirred 30 After a minute, (2-bromoethyl)-diethylamine hydrobromide (62 mg, 0.236 mmol) was added, and the reaction mixture was heated to 60 ° C, stirred for 2 hours, and then the reaction was completed, and the mixture was quenched with water. The reaction mixture was extracted with ethyl acetate (100 mL EtOAc). -chloro-4-(3-fluoro-benzyloxy)-phenyl]-{6-[1-(2-diethylaminoethyl)-1Η-pyrrol-3-yl]-quinazoline-4- Base -amine 51 (40 mg, yellow solid), yield: 46.8 %.
MS m/z (ESI): 544 [M+ 1] MS m/z (ESI) : 544 [M+ 1]
lH MR (400MHz, CD3OD): δ 8.40(s, IH), 7.85(d, IH), 7.70(s, IH), 7.34(d, IH, J=8.8): 7.27(m, IH), 7.11(m, 4H), 7.03(m, 3H)， 6.70(s, IH), 6.48(s, 1H)， 4.72(s, 2H), 4.02(t, 2H), 2.63(t, 2H), 2.42(q, 4H), 0.79(t, 6H) 实施例 52 lH MR (400MHz, CD 3 OD): δ 8.40(s, IH), 7.85(d, IH), 7.70(s, IH), 7.34(d, IH, J=8.8) : 7.27(m, IH), 7.11(m, 4H), 7.03(m, 3H), 6.70(s, IH), 6.48(s, 1H), 4.72(s, 2H), 4.02(t, 2H), 2.63(t, 2H), 2.42 (q, 4H), 0.79(t, 6H) Example 52
Γ6-(5-「1，4'1二哌啶基 -1'-甲基 -IH-吡咯 -3-基) -喹唑啉 -4-基 l-「3-氯 -4-(3-氟 -苄氧 基) -1-胺 6-(5-"1,4'1 Dipiperidinyl-1'-methyl-IH-pyrrol-3-yl)-quinazolin-4-yl-"3-chloro-4-(3- Fluoro-benzyloxy Base-1-amine
Figure imgf000094_0001
第一步
Figure imgf000094_0001
first step
3-{4-[3-氯 -4-(3-氟苄氧基) -苯氨基] -喹唑啉 -6-基 }-1-三异丙基硅 -1H-吡咯 -2-甲 醛  3-{4-[3-Chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazoline-6-yl}-1-triisopropylsilyl-1H-pyrrole-2-carbaldehyde
重复本发明实施例 50第二步所述的实验步骤， 不同的是以上述第一步所得的 化合物 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-[6-(1Η-吡咯 -3-基) -喹唑啉 -4-基] -胺 42a作为原 料， 以实施例 50第二步所述的方式，进行该原料与三氯氧磷和 Ν,Ν-二甲基甲酰胺 的反应， 得到本标题产物 3-{4-[3-氯 -4-(3-氟苄氧基) -苯氨基] -喹唑啉 -6-基 }-1-三异 丙基硅 -1Η-吡咯 -2-甲醛 52a (35 mg, 黄色固体）， 产率： 56.0%。  The experimental procedure described in the second step of Example 50 of the present invention is repeated, except that the compound obtained in the first step described above is [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6- (1Η-pyrrol-3-yl)-quinazolin-4-yl]-amine 42a as a starting material, in the manner described in the second step of Example 50, the starting material and phosphorus oxychloride and ruthenium, osmium-two The reaction of methylformamide gives the title product 3-{4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazolin-6-yl}-1-triisopropyl Base silyl-1 Η-pyrrole-2-carbaldehyde 52a (35 mg, yellow solid), Yield: 56.0%.
MS m/z (ESI): 473 [M+ 1] MS m/z (ESI): 473 [M+ 1]
第二步  Second step
重复本发明实施例 50第三步所述的实验步骤， 不同的是以上述实验所得的化 合物 3-{4-[3-氯 -4-(3-氟苄氧基) -苯氨基]-喹唑啉 -6-基 }-1-三异丙基硅 -1H-吡咯 -2-甲 醛 52a作原料，按照本发明实施例 50第三步所述的相同方式使得该原料与 [1,4']二 哌啶的反应，得到标题化合物 [6-(5-[1,4']二哌啶基 -Γ-甲基 -1H-吡咯 -3-基) -喹唑啉 -4- 基] -[3-氯 -4-(3-氟-苄氧基) -] -胺 52 ( 100 mg， 白色固体）， 产率 68.0%。  The experimental procedure described in the third step of Example 50 of the present invention is repeated, except that the compound obtained in the above experiment is 3-{4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-quin Oxazolin-6-yl}-1-triisopropylsilyl-1H-pyrrole-2-carbaldehyde 52a is used as a starting material to make the starting material and [1, 4' in the same manner as described in the third step of Example 50 of the present invention. Reaction of dipiperidine to give the title compound [6-(5-[1,4']dipiperidinyl-indole-methyl-1H-pyrrol-3-yl)-quinazolin-4-yl]- [3-Chloro-4-(3-fluoro-benzyloxy)-]-amine 52 (100 mg, white solid), yield 68.0%.
MS m/z (ESI): 625 [M+ 1] MS m/z (ESI): 625 [M+ 1]
ifiNMR (400MHz, DMSO- ): δ 11.12(s, IH), 9.91(s, IH), 8.62(s, IH), 8.59(s, IH), 8.18(d, IH, J=8.8), 8.14(s, IH), 7.86(d, IH, J=8.8), 7.80(d, IH, J=8.8), 7.55(m, IH), 7.40(m, 2H), 7.25(t, IH), 6.85(s, IH), 6.60(s, IH), 5.33(s, 2H)， 3.65(s, 2H), 2.96(m, 2H); 2.74(m, 2H), 2.05(m, IH), 2.02(m, 2H), 1.82(m, 2H), 1.30-1.60(m, 10H) 实施例 53 IfiNMR (400MHz, DMSO-): δ 11.12(s, IH), 9.91(s, IH), 8.62(s, IH), 8.59(s, IH), 8.18(d, IH, J=8.8), 8.14( s, IH), 7.86(d, IH, J=8.8), 7.80(d, IH, J=8.8), 7.55(m, IH), 7.40(m, 2H), 7.25(t, IH), 6.85( s, IH), 6.60(s, IH), 5.33(s, 2H), 3.65(s, 2H), 2.96(m, 2H) ; 2.74(m, 2H), 2.05(m, IH), 2.02(m , 2H), 1.82 (m, 2H), 1.30-1.60 (m, 10H) Example 53
l-{4-「3-氯 -4- (吡啶 -2-甲氧基) -苯氨基 1-喹唑啉 -6-基 }-4-(2-羟基) -IH-吡咯 -3-羧 酸 -(2-二乙氨基乙基)-甲酰胺 L-{4-"3-Chloro-4-(pyridine-2-methoxy)-phenylamino-1-quinazolin-6-yl}-4-(2-hydroxy)-IH-pyrrole-3-carboxylate Acid-(2-diethylaminoethyl)-carboxamide
Figure imgf000095_0001
将 2-{4-[3-氯 -4- (吡啶 -2-甲氧基) -苯氨基]-喹唑啉 -6-基}-6,7-二氢 -2H-吡喃 [3,4-c] 吡咯 -4-酮 47 ( 100 mg， 0.2 mmol)和 1 mLN,N-二乙基 -1,2-乙二胺加入 10 mL茄 形瓶中， 混合物加热至 90Ό， 搅拌过夜， 反应完毕。 反应液在减压下浓缩， 得到 的残留物用乙酸乙酯溶解后， 再加入环己烷， 有大量白色固体析出， 过滤， 得到 的固体用少量甲醇溶解， 用 TLC板进一步分离提纯， 得到黄色固体， 真空干燥得 到标题产物 1-{4-[3-氯 -4- (吡啶 -2-甲氧基) -苯氨基] -喹唑啉 -6-基 }-4-(2-羟基) -1Η-吡 咯 -3-羧酸 -(2-二乙氨基乙基) -甲酰胺 53 ( HO mg, 黄色固体）， 产率： 89.5 %。 MS m/z (ESI): 615 [M+ 1]
Figure imgf000095_0001
2-{4-[3-Chloro-4-(pyridine-2-methoxy)-phenylamino]-quinazolin-6-yl}-6,7-dihydro-2H-pyran [3, 4-c] Pyrrole-4-one 47 (100 mg, 0.2 mmol) and 1 mL of N,N-diethyl-1,2-ethanediamine were added to a 10 mL eggplant-shaped flask, and the mixture was heated to 90 Torr and stirred overnight. The reaction is completed. The reaction mixture was concentrated under reduced pressure. EtOAc was evaporated. mjjjjjjjjjjjjjjjjj Solid, dried under vacuum to give the title product 1-{4-[3-chloro-4-(pyridine-2-methoxy)-phenylamino]-quinazolin-6-yl}-4-(2-hydroxy)- 1Η-pyrrole-3-carboxylic acid-(2-diethylaminoethyl)-carboxamide 53 (HO mg, yellow solid), Yield: 89.5 %. MS m/z (ESI): 615 [M+ 1]
iHNMR (400MHz, DMSO-^): δ 10.25(s, 1H), 8.91(s, 1H), 8.61(m, 2H), 8.42(s, 2H), 8.13(d, 2H, J=7.2), 7.89(m, 3H), 7.60(d, 1H, J=7.6), 7.53(s, 1H), 7.38(m, 1H), 7.30(d, 1H, J=8.8), 5.31(s, 2H), 4.70(s, 1H)， 3.64(m, 4H), 3.22(m, 6H), 2.9 l(t, 2H), 1.27(t, 6H) 实施例 54 iHNMR (400MHz, DMSO-^): δ 10.25 (s, 1H), 8.91 (s, 1H), 8.61 (m, 2H), 8.42 (s, 2H), 8.13 (d, 2H, J = 7.2), 7.89 (m, 3H), 7.60(d, 1H, J=7.6), 7.53(s, 1H), 7.38(m, 1H), 7.30(d, 1H, J=8.8), 5.31(s, 2H), 4.70 (s, 1H), 3.64(m, 4H), 3.22(m, 6H), 2.9 l(t, 2H), 1.27(t, 6H) Example 54
l-{4-「3-氯 (吡啶 -2-甲氧基) -苯氨基 1-喹唑啉 -6-基 4--4-(2-羟基 MH-吡咯 -3- 羧酸 吗啉 -4-乙基) -甲酰胺  L-{4-"3-Chloro(pyridine-2-methoxy)-phenylamino-1-quinazolin-6-yl 4--4-(2-hydroxyMH-pyrrole-3-carboxylic acid morpholine- 4-ethyl)-carboxamide
Figure imgf000095_0002
Figure imgf000095_0002
重复本发明实施例 53第一步所述的实验步骤， 不同的是以实施例 47所得的 化合物 2-{4-[3-氯 -4- (吡啶 -2-甲氧基) -苯氨基] -喹唑啉 -6-基}-6,7-二氢 -2H-吡喃 [3,4-c] 吡咯 _4-酮 47作原料， 按照本发明实施例 53第一步所述的相同方式使得该原料与 2-吗啉 -4-基-乙胺的反应， 得到标题化合物 1-{4-[3-氯 -4- (吡啶 -2-甲氧基) -苯氨基] - 喹唑啉 -6-基}-4-(2-羟基) -1H-吡咯 -3-羧酸 -(2-吗啉 -4-乙基) -甲酰胺 54 ( 110 mg， 黄 色固体）， 产率： 87.3 %。 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 %.
MS m/z (ESI): 629 [M+ l] MS m/z (ESI): 629 [M+ l]
'HNMR (400MHZ, DMSO-^): δ 9.97(s, 1H), 8.74(s, 1H), 8.60(m, 2H), 8.09(m, 3H), 7.89(m, 3H), 7.79(d, 1H, J=8.8), 7.60(d, 1H, J=8.0), 7.45(s5 1H), 7.38(t, 1H), 7.30(d, 1R J=8.8), 5.3 l(s, 2H), 4.81(s, 1H), 3.64(m, 8H), 3.17(m, 6H), 2.89(t, 2H) 实施例 55 'HNMR (400MHZ, DMSO-^): δ 9.97 (s, 1H), 8.74 (s, 1H), 8.60 (m, 2H), 8.09 (m, 3H), 7.89 (m, 3H), 7.79 (d, 1H, J=8.8), 7.60(d, 1H, J=8.0), 7.45(s 5 1H), 7.38(t, 1H), 7.30(d, 1R J=8.8), 5.3 l(s, 2H), 4.81(s, 1H), 3.64(m, 8H), 3.17(m, 6H), 2.89(t, 2H) Example 55
{4-「3-氯 -4- (吡啶 -2-甲氧基)-苯氨基 1-喹唑啉 -6-基 4--4-(2-羟基 1H-吡咯 -3- {4-"3-Chloro-4-(pyridine-2-methoxy)-phenylamino-1-quinazoline-6-yl 4--4-(2-hydroxy 1H-pyrrole-3-
' 羧酸 -(2-甲氧基乙基) -甲酰胺 'carboxylic acid -(2-methoxyethyl)-carboxamide
Figure imgf000096_0001
Figure imgf000096_0001
重复本发明实施例 53第一步所述的实验步骤， 不同的是以实施例 47所得的 化合物 2-{4-[3-氯 -4- (吡啶 -2-甲氧基) -苯氨基] -喹唑啉 -6-基}-6,7-二氢 -2H-吡喃 [3,4-c] 吡咯 -4-酮 47作原料， 按照本发明实施例 53第一步所述的相同方式使得该原料与 2-甲氧基乙胺的反应， 得到标题化合物 1-{4-[3-氯 -4- (吡啶 -2-甲氧基) -苯氨基] -喹唑 啉 -6-基}-4-(2-轻基) -1H-吡咯 -3-羧酸 -(2-甲氧基乙基) -甲酰胺 55 ( 110 mg, 黄色固 体）， 产率： 87.3 %。  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).
MS m/z (ESI): 571 [M— 1] MS m/z (ESI): 571 [M-1]
!HNMR (400MHz, DMSO-^): δ 10.00(s, 1H), 8.72(s, 1H), 8.68(d, 2H), 8.18(d, 1H, J=9.2), 8.13(s, 1H), 8.09(m, 2H), 8.00(m, 2H), 7.97(d, 1H， J=8.0), 7.67(d, 1H, J=8.0), 7.46(m, 2H), 7.39(d, 1H, J=9.2), 5.39(s, 2H), 4.85(s, 1H), 3.72(t， 2H), 3.52(m, 2H), 3.47(m, 2H), 3.37(s, 3H), 2.97(t， 2H) 实施例 56 ! HNMR (400MHz, DMSO- ^) : δ 10.00 (s, 1H), 8.72 (s, 1H), 8.68 (d, 2H), 8.18 (d, 1H, J = 9.2), 8.13 (s, 1H), 8.09(m, 2H), 8.00(m, 2H), 7.97(d, 1H, J=8.0), 7.67(d, 1H, J=8.0), 7.46(m, 2H), 7.39(d, 1H, J =9.2), 5.39(s, 2H), 4.85(s, 1H), 3.72(t, 2H), 3.52(m, 2H), 3.47(m, 2H), 3.37(s, 3H), 2.97(t, 2H) Example 56
1-ί4-|~3-氯 -4- (吡啶 -2-甲氧基) -苯氨基 Ί-喹唑啉 -6-基 M--4-(2-羟基) -1H-吡咯 -3- 羧酸 -「2-(4-甲基 -哌嗪 -1-基 乙基 1-酰胺  1-ί4-|~3-chloro-4-(pyridine-2-methoxy)-phenylaminopurine-quinazolin-6-yl M--4-(2-hydroxy)-1H-pyrrole-3- Carboxylic acid - "2-(4-methyl-piperazin-1-ylethyl 1-amide)
Figure imgf000096_0002
重复本发明实施例 53第一步所述的实验步骤， 不同的是以实施例 47所得的 化合物 2-{4-[3-氯 -4- (吡啶 -2-甲氧基) -苯氨基] -喹唑啉 -6-基}-6,7-二氢 -2H-吡喃 [3,4-c] 吡咯 -4-酮 47作原料， 按照本发明实施例 53第一步所述的相同方式使得该原料与 2-(4-甲基-哌嗪 -1-基)-乙胺的反应， 得到标题化合物 1-{4-[3-氯 -4- (吡啶 -2-甲氧基) - 苯氨基 ]-喹唑啉 -6-基 }-4-(2-羟基) -1H-吡咯 -3-羧酸 -[2-(4-甲基 -哌嗪 -1-基) -乙基] -酰 胺 56 ( 90 mg， 黄色固体）， 产率： 88 %。
Figure imgf000096_0002
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. Compound 1-{4-[3-Chloro-4-(pyridine-2-methoxy)-phenylamino]-quinazolin-6-yl}-4-(2-hydroxy)-1H-pyrrole-3- Carboxylic acid-[2-(4-methyl-piperazin-1-yl)-ethyl]-amide 56 (90 mg, yellow solid), yield: 88%.
MS m/z (ESI): 643 [M+ 1] MS m/z (ESI): 643 [M+ 1]
!H MR (400MHz, DMSO-^): δ 10.1 l(s, IH), 8.89(s, IH), 8.06(m, 2H), 8.25(s, IH), 8.13(m, 2H), 7.90(m, 4H), 7.60(d, IH, J=7.6), 7.49(s, IH), 7.37(t, IH), 7.26(d, IH, J=9.2), 5.3 l(s, 2H), 4.82(s, IH), 3.65(t, 2H), 3.26(m, 2H), 2.89(t, 2H), 2.67(m, 10H), 2.4 l(s, 3H) 实施例 57 ! H MR (400MHz, DMSO- ^ ): δ 10.1 l (s, IH), 8.89 (s, IH), 8.06 (m, 2H), 8.25 (s, IH), 8.13 (m, 2H), 7.90 ( m, 4H), 7.60(d, IH, J=7.6), 7.49(s, IH), 7.37(t, IH), 7.26(d, IH, J=9.2), 5.3 l(s, 2H), 4.82 (s, IH), 3.65(t, 2H), 3.26(m, 2H), 2.89(t, 2H), 2.67(m, 10H), 2.4 l(s, 3H) Example 57
1-ί4-「3-氯 -4- (吡啶 -2-甲氧基) -苯氨基 1-喹唑啉 -6-基 4--4-(2-羟基) -IH-吡咯 -3-  1-ί4-"3-Chloro-4-(pyridine-2-methoxy)-phenylamino-1-quinazoline-6-yl 4--4-(2-hydroxy)-IH-pyrrole-3-
Figure imgf000097_0001
重复本发明实施例 53第一步所述的实验步骤， 不同的是以实施例 47所得的 化合物 2-{4-[3-氯 -4- (吡啶 -2-甲氧基) -苯氨基] -喹唑啉 -6-基}-6,7-二氢 -2H-吡喃 [3,4-c] 吡咯 -4-酮 47作原料， 按照本发明实施例 53第一步所述的相同方式使得该原料与 3-吗啉 -4-基-丙胺的反应， 得到标题化合物 1-{4-[3-氯 -4- (吡啶 -2-甲氧基) -苯氨基] - 喹唑啉 -6-基}-4-(2-羟基) -1H-吡咯 -3-羧酸 -(3-吗啉 -4-丙基) -酰胺 57 ( 90 mg, 黄色固 体）， 产率 88 %。
Figure imgf000097_0001
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%.
MS m/z (ESI): 640 [M- 1]  MS m/z (ESI): 640 [M-1]
1H MR (400MHz, DMSO-t¾): 6 10.10(s, IH), 8.84(s, IH), 8.59(d, 2H), 8.21(s, IH), 8.10(m, 2H), 8.02(s, IH), 7.88(m, 2H), 7.83(d, IH, J=8.0), 7.60(d, IH, J=7.6), 7.49(s, 1H)， 7.38(t, IH), 7.29(d, IH, J=8.8)， 5.3 l(s, 2H), 4.86(s, IH), 3.62(m, 6H), 3.36(m, 2H), 3.25(m, 2H), 2.89(t, 2H), 2.2 l(m, 4H)， 1.71(m, 2H) 实施例 58  1H MR (400MHz, DMSO-t3⁄4): 6 10.10(s, IH), 8.84(s, IH), 8.59(d, 2H), 8.21(s, IH), 8.10(m, 2H), 8.02(s, IH), 7.88(m, 2H), 7.83(d, IH, J=8.0), 7.60(d, IH, J=7.6), 7.49(s, 1H), 7.38(t, IH), 7.29(d, IH, J=8.8), 5.3 l(s, 2H), 4.86(s, IH), 3.62(m, 6H), 3.36(m, 2H), 3.25(m, 2H), 2.89(t, 2H), 2.2 l(m, 4H), 1.71(m, 2H) Example 58
1-ί4-「3-氯 -4-ί吡啶 -2-甲氧基) -苯氨基 1-喹唑啉 -6-基 }-4 4- 2-羟基) -IH-吡咯 -3- 基 1_吗啉 -4-甲酮
Figure imgf000098_0001
1-ί4-"3-Chloro-4-isopropylpyridine-2-methoxy)-phenylamino-1-quinazolin-6-yl}-4 4- 2-hydroxy)-IH-pyrrol-3-yl 1 _morpholine-4-ketone
Figure imgf000098_0001
58  58
重复本发明实施例 53第一步所述的实验步骤， 不同的是以实施例 47所得的 化合物 2-{4-[3-氯 -4- (吡啶 -2-甲氧基) -苯氨基] -喹唑啉 -6-基 }-6，7-二氢 -2H-吡喃 [3,4-c] 吡咯 -4-酮 47作原料， 按照本发明实施例 53第一步所述的相同方式使得该原料与 吗啉的反应， 得到标题化合物 1-{4-[3-氯 -4- (吡啶 -2-甲氧基) -苯氨基] -喹唑啉 -6- 基}-4-(2-羟基) -1H-吡咯 -3-基] -吗啉 -4-甲酮 58 (230 mg, 白色固体）， 产率： 98.2%。 MS m/z (ESI): 584 [M- 1] 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]
tHNMR (400MHz, DMSO- )： 6 9.77(s, 1Η), 8.59(m, 3H), 8.17(d, 1H, J=10.4), 8.02(s, 1H), 7.88(m, 2H), 7.73(d, 1H, J=8.0), 7.68(s, 1H), 7.60(d, 1H, J=7.2), 7.45(s, 1H), 7.38(t, 1H), 7.32(d, 1H, J=9.2), 5.3 l(s, 2H), 4.69(t, 1H), 3.57(m, 8H), 3.17(m, 2H), 2.70(t, 2H) 实施例 59 tHNMR (400MHz, DMSO-): 6 9.77 (s, 1 Η), 8.59 (m, 3H), 8.17 (d, 1H, J = 10.4), 8.02 (s, 1H), 7.88 (m, 2H), 7.73 ( d, 1H, J=8.0), 7.68(s, 1H), 7.60(d, 1H, J=7.2), 7.45(s, 1H), 7.38(t, 1H), 7.32(d, 1H, J=9.2 ), 5.3 l(s, 2H), 4.69(t, 1H), 3.57(m, 8H), 3.17(m, 2H), 2.70(t, 2H) Example 59
l- -「3-氯 -4- (吡啶 -2-甲氧基)-苯氨基 1-喹唑啉 -6-基 4-(2-羟基) -1H-吡咯 -3- 基卜(4-甲基 -哌嗪 -1-基) -甲酮  L--"3-Chloro-4-(pyridine-2-methoxy)-phenylamino-1-quinazolin-6-yl 4-(2-hydroxy)-1H-pyrrol-3-yl b (4- Methyl-piperazin-1-yl)-methanone
Figure imgf000098_0002
重复本发明实施例 53第一步所述的实验步骤， 不同的是以实施例 47所得的 化合物 2-{4-[3-氯 -4- (吡啶 -2-甲氧基) -苯氨基] -喹唑啉 -6-基}-6,7-二氢 -2H-吡喃 [3,4-c] 吡咯 -4-酮 47作原料， 按照本发明实施例 53第一步所述的相同方式使得该原料与 1 -甲基哌嗪的反应， 得到标题化合物 1-{4-[3-氯 -4- (吡啶 -2-甲氧基) -苯氨基] -喹唑啉 -6_基}_4-(2-羟基) -1H-吡咯 -3-基] -(4-甲基 -哌嗪 - 1-基) -甲酮 59 ( 100 mg， 棕色油状 物）， 产率： 95 %。
Figure imgf000098_0002
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%.
MS m/z (ESI): 599 [M+ 1] MS m/z (ESI): 599 [M+ 1]
'HNMR (400MHZ, DMSO-^): δ 9.77(s, 1H), 8.60(m, 3H), 8.17(d, 1H, J-8.8), 8.02(s, 1H), 7.88(m, 2H), 7.73(d, 1H, 3=6.4), 7.65(s, 1H), 7.60(d, 1H, J=8.0), 7.45(s, 1H), 7.38(t, 1H), 7.32(d, 1H, J=9.2), 5.3 l(s, 2H), 4.69(s, 1H), 3.60(m, 6H), 2.69(t, 2H), 2.33(t, 4H), 2.2 l(s, 3H) 实施例 60  'HNMR (400MHZ, DMSO-^): δ 9.77 (s, 1H), 8.60 (m, 3H), 8.17 (d, 1H, J-8.8), 8.02 (s, 1H), 7.88 (m, 2H), 7.73(d, 1H, 3=6.4), 7.65(s, 1H), 7.60(d, 1H, J=8.0), 7.45(s, 1H), 7.38(t, 1H), 7.32(d, 1H, J = 9.2), 5.3 l(s, 2H), 4.69(s, 1H), 3.60(m, 6H), 2.69(t, 2H), 2.33(t, 4H), 2.2 l(s, 3H) Example 60
1-ί4-「3-氯 -4-Qi比啶 -2-甲氧某 苯氨基 1-喹唑啉 -6-基 -4-(2-羟基) -1H-吡咯 -3-基 1-
Figure imgf000099_0001
1-ί4-"3-Chloro-4-Qi-pyridyl-2-methoxy-phenylamino-1-quinazolin-6-yl-4-(2-hydroxy)-1H-pyrrol-3-yl 1-
Figure imgf000099_0001
重复本发明实施例 53第一步所述的实验步骤， 不同的是以实施例 47所得的 化合物 2-{4-[3-氯 -4- (吡啶 -2-甲氧基) -苯氨基] -喹唑啉 -6-基}-6,7-二氢 -2H-吡喃 [3,4- c] 吡咯 -4-酮 47作原料， 按照本发明实施例 53第一步所述的相同方式使得该原料与 吡咯烷的反应， 得到标题化合物 1-{4-[3-氯 -4- (吡啶 -2-甲氧基) -苯氨基] -喹唑啉 -6- 基 }-4-(2-羟基) -1H-吡咯 -3-基] -吡咯烷 -1-甲酮 60 ( 170 mg， 灰色固体）， 产率 95 %。 MS m/z (ESI): 570 [M+ 1]  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%. MS m/z (ESI): 570 [M+ 1]
'HNMR (400MHZ, DMSO-C¾: δ 9.78(s, 1H), 8.59(m, 3H), 8.18(d, 1H, J=8.4), 8.01(s, 1H), 7.89(t, 2H), 7.8 l(s, 1H)， 7.72(d, 1H, J=7.2), 7.60(d, 1H, J=7.6), 7.42(s, 1H), 7.36(t, 1H), 7.32(d, 1H, J=8.8), 5.3 l(s, 2H), 4.78(s, 1H), 3.62(t, 4H), 3.52(t, 2H), 2.79(t, 2H), 1.88(s, 4H) 实施例 61  'HNMR (400 MHZ, DMSO-C3⁄4: δ 9.78 (s, 1H), 8.59 (m, 3H), 8.18 (d, 1H, J = 8.4), 8.01 (s, 1H), 7.89 (t, 2H), 7.8 l(s, 1H), 7.72(d, 1H, J=7.2), 7.60(d, 1H, J=7.6), 7.42(s, 1H), 7.36(t, 1H), 7.32(d, 1H, J = 8.8), 5.3 l(s, 2H), 4.78(s, 1H), 3.62(t, 4H), 3.52(t, 2H), 2.79(t, 2H), 1.88(s, 4H) Example 61
2-Γ1-ί4-Γ3-氯 -4- (吡啶 -2-甲氧基) -苯氨基 1 -喹唑啉 -6-基 }-4-(4-甲基 -哌嗪 -1-甲 基 1H-吡咯 -3-基 1-乙醇  2-Γ1-ί4-Γ3-chloro-4-(pyridine-2-methoxy)-phenylamino-1-quinazoline-6-yl}-4-(4-methyl-piperazine-1-methyl 1H-pyrrol-3-yl 1-ethanol
Figure imgf000099_0002
Figure imgf000099_0002
第一步  First step
在 25 mL茄形瓶中加入氢化铝锂 （44 mg， 1.16mmol)和 4mL四氢呋喃， 室 温下搅拌， 逐渐滴加化合物 1-{4-[3-氯 -4- (吡啶 -2-甲氧基) -苯氨基] -喹唑啉 -6- 基 }-4-(2-羟基) -1H-吡咯 -3-基]— (4-甲基 -哌嗪 -1-基) -甲酮 59 ( 130 mg, 0.385 mmol) 的 3 mL四氢呋喃溶液， 溶液中有大量气泡产生， 并有粘稠状固体产生， 反应液呈 黄色。 将反应液加热至 50°C， 搅拌 2小时后反应完毕， 用冰浴冷却反应液， 慢慢 滴加甲醇， 反应液呈澄清透明。 用减压柱冲洗， 浓缩反应液， 得到的固体进一步 通过 TLC板分离纯化， 得到标题产物 2-[1-{4-[3-氯 -4- (吡啶 -2-甲氧基) -苯氨基] -喹 唑啉 _6_基 }_4-(4-甲基 -哌嗪 -1-甲基) -1H-吡咯 -3-基] -乙醇 61 (70 mg, 黄色固体）， 产 率： 55.6%。 MS m/z (ESI): 585 [M+ l] Lithium aluminum hydride (44 mg, 1.16 mmol) and 4 mL of tetrahydrofuran were added to a 25 mL eggplant flask, stirred at room temperature, and the compound 1-{4-[3-chloro-4-(pyridine-2-methoxy) was gradually added dropwise. -Phenylamino]-quinazolin-6-yl}-4-(2-hydroxy)-1H-pyrrol-3-yl]-(4-methyl-piperazin-1-yl)-methanone 59 ( 130 mg, 0.385 mmol) in 3 mL of tetrahydrofuran solution. A large amount of bubbles were formed in the solution, and a viscous solid was produced. The reaction solution was yellow. The reaction solution was heated to 50 ° C, stirred for 2 hours, and the reaction was completed. The reaction solution was cooled with an ice bath, and methanol was slowly added dropwise, and the reaction mixture was clear and transparent. The title compound (2-[1-chloro-4-(pyridin-2-yloxy)-phenylamino) was obtained by chromatography. - quinazoline _ 6 _ yl} 4-(4-methyl-piperazin-1-methyl)-1H-pyrrol-3-yl]-ethanol 61 (70 mg, yellow solid), Yield: 55.6 %. MS m/z (ESI): 585 [M+ l]
iHNMR (400MHz, DMSO-c¾)： δ 9.99(s, IH), 8.6 l(m, 3H), 8.05(d, 2H), 7.88(t, 1H): 7.8 l(t, 2H), 7.59(d5 IH, J=7.6), 7.46(d, 2H), 7.39(t, IH), 7.29(d, IH, J-9.2), 5.30(s， 2H): 3.78(m, 4H), 2.73(t, 2H), 2.23(m, 8H), 2.11(s, 3H) 实施例 62 iHNMR (400MHz, DMSO-c3⁄4): δ 9.99(s, IH), 8.6 l(m, 3H), 8.05(d, 2H), 7.88(t, 1H): 7.8 l(t, 2H), 7.59(d 5 IH, J=7.6), 7.46(d, 2H), 7.39(t, IH), 7.29(d, IH, J-9.2), 5.30(s, 2H) : 3.78(m, 4H), 2.73(t , 2H), 2.23 (m, 8H), 2.11 (s, 3H) Example 62
Γ3-氯 -4-(3-氟苄氧基) -苯基 l-(6-{5-「(2-甲磺酰基-乙氨基) -甲基 1-lH-吡咯 -3-基 喹唑啉 -4-基) -胺  3-Chloro-4-(3-fluorobenzyloxy)-phenyl-l-(6-{5-"(2-methanesulfonyl-ethylamino)-methyl 1-lH-pyrrol-3-ylquinazole Phenyl-4-yl)-amine
Figure imgf000100_0001
Figure imgf000100_0001
重复本发明实施例 52第二步所述的实验步骤， 不同的是以上述实验所得的化 合物 3-{4-[3-氯 -4-(3-氟苄氧基) -苯氨基] -喹唑啉 -6-基 三异丙基硅 -1H-吡咯 -2-甲 醛 52a作原料， 按照本发明实施例 52第二步所述的相同方式使得该原料与 2-甲磺 酰基乙胺的反应， 得到标题化合物 [3-氯 -4-(3-氟苄氧基) -苯基 ]-(6-{5-[(2-甲磺酰基- 乙氨基)-甲基] -1H-吡咯 -3-基 喹唑啉 -4-基) -胺 62 ( 10 mg，黄色固体），产率 8.5 %。 MS m/z (ESI): 580 [M+ l]  The experimental procedure described in the second step of Example 52 of the present invention was repeated, except that the compound obtained in the above experiment was 3-{4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinuc Oxazolin-6-yltriisopropylsilane-1H-pyrrole-2-carbaldehyde 52a is used as a starting material to react the starting material with 2-methanesulfonylethylamine in the same manner as described in the second step of Example 52 of the present invention. , the title compound [3-chloro-4-(3-fluorobenzyloxy)-phenyl]-(6-{5-[(2-methanesulfonyl-ethylamino)-methyl]-1H-pyrrole- 3-Hydroxyquinazolin-4-yl)-amine 62 (10 mg, yellow solid), yield 8.5%. MS m/z (ESI): 580 [M+ l]
iHNMR (400MHz, DMSO-*): δ 11.15(s, IH), 9.91(s, IH), 8.70(s, IH), 8.49(s, IH), 8.08(d, IH, J=8.8), 7.83(d, IH, J=9.2), 7.69(d, IH, J=8.8), 7.5 l(s, IH), 7.47(t, IH), 7.32(m, 3H), 7.20(t, IH), 6.88(s, IH), 6.74(s, IH), 5.26(s, 2H), 3.86(s, 2H), 3.24(t, 2H), 2.95(s, 3H), 2.92(t, 2H) 实施例 63 iHNMR (400MHz, DMSO-*): δ 11.15(s, IH), 9.91(s, IH), 8.70(s, IH), 8.49(s, IH), 8.08(d, IH, J=8.8), 7.83 (d, IH, J=9.2), 7.69(d, IH, J=8.8), 7.5 l(s, IH), 7.47(t, IH), 7.32(m, 3H), 7.20(t, IH), 6.88(s, IH), 6.74(s, IH), 5.26(s, 2H), 3.86(s, 2H), 3.24(t, 2H), 2.95(s, 3H), 2.92(t, 2H) 63
Γ3-氯 -4-(3-氟-苄氧基) -苯基 1-(6-ί5-「(3-吗啡林 -4-丙氨基) -甲基 1-lH-吡咯 -3-基} - 喹唑啉 -4-基) -胺  3-chloro-4-(3-fluoro-benzyloxy)-phenyl 1-(6-ί5-"(3-morphinyl-4-propylamino)-methyl 1-lH-pyrrol-3-yl} - quinazolin-4-yl)-amine
Figure imgf000100_0002
Figure imgf000100_0002
重复本发明实施例 52第二步所 的实验步骤， 不同的是以上述实验所得的化 合物 3-{4-[3-氯 -4-(3-氟苄氧基) -苯氨基] -喹唑啉 -6-基 }-1_三异丙基硅 -1H-吡咯 -2-甲 醛 52a作原料， 按照本发明实施例 52第二步所述的相同方式使得该原料与 3-吗啉 -4-基-丙胺的反应，得到标题化合物 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-(6-{5-[(3-吗啡林 -4- 丙氨基)-甲基] -1H-吡咯 -3-基}-喹唑啉 -4-基) -胺 63 (20 mg， 黄色固体 ,)， 产率 35.0  The experimental procedure of the second step of Example 52 of the present invention was repeated, except that the compound obtained in the above experiment was 3-{4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazoline Porphyrin-6-yl}-1_triisopropylsilyl-1H-pyrrole-2-carbaldehyde 52a as a starting material, the starting material and 3-morpholine-4 were obtained in the same manner as described in the second step of Example 52 of the present invention. Reaction of -yl-propylamine to give the title compound [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-{5-[(3-morphinyl-4-propylamino)- Methyl]-1H-pyrrol-3-yl}-quinazolin-4-yl)-amine 63 (20 mg, yellow solid), yield 35.0
MS m/z (ESI): 601 [M+ l] 'HNMR (400MHZ, DMSO-C¾): δ 11.10(s, 1H), 9.90(s, 1H), 8.53(d, 2H), 8.08(s, 1H), 8.10(d3 1H, J=8.4), 7.81(d, 1H), 7.73 (d, 1H, J=8.4), 7.47(m, 1H), 7.30(m, 3H), 7.18(t, 1H), 6.80(s, 1H)， 6.46(s, 1H)， 5.26(s, 2H), 3.86(s, 2H), 3.59(t, 2H)， 3.48(t, 2H), 2.33(t, 4H), 2.24(t, 4H), 1.57(m, 2H) 实施例 64MS m/z (ESI): 601 [M+ l] 'HNMR (400MHZ, DMSO-C3⁄4): δ 11.10(s, 1H), 9.90(s, 1H), 8.53(d, 2H), 8.08(s, 1H), 8.10(d 3 1H, J=8.4), 7.81(d, 1H), 7.73 (d, 1H, J=8.4), 7.47(m, 1H), 7.30(m, 3H), 7.18(t, 1H), 6.80(s, 1H), 6.46(s, 1H), 5.26(s, 2H), 3.86(s, 2H), 3.59(t, 2H), 3.48(t, 2H), 2.33(t, 4H), 2.24(t, 4H), 1.57(m, 2H Embodiment 64
-氯 -4-(3-氟-苄氧基）苯基 1-ί6-Π-(2-吡咯烷 -1-基-乙基 1H-吡咯 -3-基 1-喹唑 啉 -4-基 μ胺  -Chloro-4-(3-fluoro-benzyloxy)phenyl 1-ί6-indole-(2-pyrrolidin-1-yl-ethyl 1H-pyrrol-3-yl-1-quinazolin-4-yl Μamine
Figure imgf000101_0001
Figure imgf000101_0001
重复本发明实施 51所述的实验步骤， 不同的是以实施例 42所得的化合物 [3- 氯 -4- (吡啶 -2-甲氧基) -苯基 ]-(6-吡咯 -1-基-喹唑啉 -4-基) -胺 42作为原料， 按照实施 例 51所述的方式， 进行该原料与 1-(2-氯乙基) -吡咯垸的反应， 得到本标题产物 [3- 氯 -4-(3-氟-苄氧基)苯基 ]-{6-[1-(2-吡咯垸 -1-基-乙基) -1Η-吡咯 -3-基] -喹唑啉 -4-基} - 胺 (30 mg, 黄色固体）， 产率： 35.9%  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)-1Η-pyrrol-3-yl]-quinazoline- 4-yl}-amine (30 mg, yellow solid), Yield: 35.9%
MS m/z (ESI): 542[M+ 1] MS m/z (ESI): 542 [M+ 1]
1HNMR (400MHz, DMSO-^): δ 8.65(s, 1Ή), 8.02(m, 2H), 7.9 l(d, 1H, J=8.4), 7.8 l(m, 2H), 7.52(d, 1H, J=8.8), 7.32(m, 1H), 7.20(m, 2H), 7.04(m, 2H), 6.90(d, 1H, J=9.2), 6.70(s, 1H), 6.49(s, 1H)， 5.09(s, 2H)， 4.0 l(t, 2H), 2.86(t, 2H), 2.54(m, 4H), 1.77(m, 4H) 实施例 65 1 H NMR (400 MHz, DMSO-^): δ 8.65 (s, 1 Ή), 8.02 (m, 2H), 7.9 l (d, 1H, J = 8.4), 7.8 l (m, 2H), 7.52 (d, 1H) , J=8.8), 7.32(m, 1H), 7.20(m, 2H), 7.04(m, 2H), 6.90(d, 1H, J=9.2), 6.70(s, 1H), 6.49(s, 1H ), 5.09(s, 2H), 4.0 l(t, 2H), 2.86(t, 2H), 2.54 (m, 4H), 1.77 (m, 4H) Example 65
-3-基 喹唑啉 -4-基 1-胺
Figure imgf000101_0002
重复本发明实施 51所述的实验步骤， 不同的是以实施例 42所得的化合物 [3- 氯 -4- (吡啶 -2-甲氧基)-苯基] -(6-吡咯 -1-基-喹唑啉 -4-基) -胺 42作为原料， 按照实施 例' 51所述的方式， 进行该原料与 1-(3-氯苯基 )-4-(3-氯丙基)-哌嗪的反应， 得到本 标题产物 [3-氯 -4-(3-氟苄氧基) -苯基 ]-[6-(1-{3-[4-(3-氯苯基) -哌嗪 -1-基] -丙基 }-1Η- 吡咯 -3-基) -喹唑啉 -4-基] -胺 （32 mg， 黄色固体）， 产率： 20.9%。 -3-ylquinazolin-4-yl 1-amine
Figure imgf000101_0002
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}-1Η-pyrrol-3-yl)-quinazolin-4-yl]-amine (32 mg, yellow solid), Yield: 20.9%.
MS m/z (ESI): 681 [M+ 1] MS m/z (ESI): 681 [M+ 1]
!HNMR (400MHz, OMSO-d6): δ 9.67(s, 1H), 8.52(d, 2H), 8.03(m, 2H), 7.70(d, 1H, J 8.8), 7.46(d, 1H, J=10.8), 7.34(m, 2H), 7.29(m, 3H), 7.19(m, 2H), 6.92(m, 3H), 6.77(d, IH, J=6.4), 6.67(s, IH), 5.2 l(s, 2H)， 4.0 l(t, 2H), 3.28(t, 4H), 3.20(t, 4H), 2.33(t, 2H), 1.98(t, 2H) !HNMR (400MHz, OMSO-d 6 ): δ 9.67(s, 1H), 8.52(d, 2H), 8.03(m, 2H), 7.70(d, 1H, J 8.8), 7.46(d, 1H, J = 10.8), 7.34 (m, 2H), 7.29 (m, 3H), 7.19 (m, 2H), 6.92 (m, 3H), 6.77(d, IH, J=6.4), 6.67(s, IH), 5.2 l(s, 2H), 4.0 l(t, 2H), 3.28(t, 4H), 3.20(t, 4H), 2.33( t, 2H), 1.98(t, 2H)
实施例 66  Example 66
4-(2-羟乙基 )-1- -Γ3-甲基 -4-(6-甲基吡啶 -3-氧基) -苯氨基 1-喹唑啉 -6-基 IH-吡 咯 -3-羧酸 -(2-吡咯烷 -1-基-乙基) -酰胺  4-(2-Hydroxyethyl)-1- -indol-3-methyl-4-(6-methylpyridin-3-yloxy)-phenylamino-1-quinazolin-6-yl IH-pyrrole-3- Carboxylic acid-(2-pyrrolidin-1-yl-ethyl)-amide
Figure imgf000102_0001
第一步
Figure imgf000102_0001
first step
(6-碘-喹唑啉 -4-基) -[3-甲基 -4-(6-甲基-吡啶 -3-氧代) -苯基] -胺 重复本发明实施例 1第五步所述的实验步骤， 不同的是以实施例 1第四步所 得的化合物 6-碘 -3H-喹唑啉 -4-酮 If作原料， 按照本发明实施例 1第五步所述的相 同方式使得该原料与 3-甲基 -4-(6-甲基 -吡啶 -3-氧代) -苯胺的反应，得到标题化合物 (6_碘-喹唑啉 _4-基) -[3-甲基 -4-(6-甲基 -P比啶 -3-氧代) -苯基] -胺 66a ( 10 g， 灰白色固 体）， 产率 65 %。 (6-iodo-quinazolin-4-yl)-[3-methyl-4-(6-methyl-pyridin-3-oxo)-phenyl]-amine repeats the fifth step of Example 1 of the present invention The experimental procedure is the same as the compound 6-iodo-3H-quinazolin-4-one If obtained in the fourth step of the first embodiment, in the same manner as described in the fifth step of the first embodiment of the present invention. The reaction of the starting material with 3-methyl-4-(6-methyl-pyridin-3-oxo)-phenylamine gives the title compound (6- iodo-quinazoline-4-yl)-[3- 4-(6-Methyl-P-pyridin-3-oxo)-phenyl]-amine 66a (10 g, off-white solid), yield 65%.
MS m/z (ESI): 469[M+ 1] MS m/z (ESI): 469 [M+ 1]
第二步  Second step
2-{4-[3-甲基 -4-(6-甲基-吡啶 -3-氧代) -苯氨基] -喹唑啉 -6-基}-6,7-二氢 -2H-吡喃 并 [3,4-c]吡咯 -4-酮  2-{4-[3-Methyl-4-(6-methyl-pyridin-3-oxo)-phenylamino]-quinazolin-6-yl}-6,7-dihydro-2H-pyridyl Cyclo[3,4-c]pyrrol-4-one
在 250 mL茄形瓶中， 将上述步骤所得的化合物 (6-碘-喹唑啉 -4-基) -[3-甲基 -4-(6-甲基 -吡啶 -3-氧代) -苯基] -胺 66a ( 11.7 g， 25mmol), 6,7-二氢 -2H-吡喃并 [3,4-c] 吡咯 -4-酮 47b ( 3.6g, 26.25 mmol), 磷酸钾 ( 15.92 g, 25龜 ol)， 碘化亚铜 (4.775 g， 25mmol)溶解于 80 mL N,N-二甲基甲酰胺中， 混合物在搅拌下滴加 Ν,Ν'-二甲 基 -1,2-乙二胺（2.18 g， 25 mmol), 加热反应液到 80°C， 搅拌过夜。 将反应液倒入 250 mL冰水中， 有黄色固体析出， 抽滤， 得到的固体用 300 mL甲醇洗涤， 得到 的固体在真空下干燥， 得到本标题产物 2-{4-[3-甲基 -4-(6-甲基-吡啶 -3-氧代) -苯氨 基] -喹唑啉 -6-基}-6,7-二氢 -2H-吡喃并 [3,4-c]吡咯 -4-酮 66b ( 11.59 g， 黄色固体）， 产率 97.06%。 In a 250 mL eggplant-shaped flask, the compound obtained in the above step (6-iodo-quinazolin-4-yl)-[3-methyl-4-(6-methyl-pyridin-3-oxo)- Phenyl]-amine 66a (11.7 g, 25 mmol), 6,7-dihydro-2H-pyrano[3,4-c]pyrrol-4-one 47b (3.6 g, 26.25 mmol), potassium phosphate ( 15.92 g, 25 turtle ol), cuprous iodide (4.775 g, 25 mmol) was dissolved in 80 mL of N,N-dimethylformamide, and the mixture was added dropwise with stirring, Ν'-dimethyl-1,2 Ethylenediamine (2.18 g, 25 mmol), the reaction was heated to 80 ° C and stirred overnight. The reaction solution was poured into 250 mL of ice water, and a yellow solid was precipitated, which was filtered, and the obtained solid was washed with 300 mL of methanol, and the obtained solid was dried under vacuum to give the title product 2-{4-[3-methyl- 4-(6-methyl-pyridin-3-oxo)-phenylamine - quinazolin-6-yl}-6,7-dihydro-2H-pyrano[3,4-c]pyrrol-4-one 66b ( 11.59 g, yellow solid), yield 97.06%.
MS m/z (ESI): 478 [M+ l]  MS m/z (ESI): 478 [M+ l]
第三步  third step
4-(2-羟乙基 )-l-{4-[3-甲基 -4-(6-甲基吡啶 -3-氧基) -苯氨基] -喹唑啉 -6-基}-1 吡 咯 -3-羧酸（2-吡咯垸 -1-基-乙基:) -酰胺  4-(2-Hydroxyethyl)-l-{4-[3-methyl-4-(6-methylpyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-1 Pyrrole-3-carboxylic acid (2-pyrrole-1-yl-ethyl:)-amide
将 2-{4-[3-甲基 -4-(6-甲基 -吡啶 -3-氧) -苯氨基]-喹唑啉 -6-基}-6,7-二氢 -2H-吡 喃并 [3，4-c]吡咯 -4-酮 66b ( 120 mg， 0.25 mmol)和 2 mL 2-吡咯烷基小基-乙胺加 入 lO mL茄形瓶中， 混合物加热至 90°C， 搅拌过夜， 反应完毕。 反应液在减压下 浓缩， 得到的残留物用乙酸乙酯溶解后， 再加入环己烷， 有大量白色固体析出， 过滤， 得到的固体用少量甲醇溶解， 用 TLC板分离提纯， 得到黄色固体， 真空干 燥得到标题产物 4-(2-羟乙基 )-1-{4-[3-甲基 -4-(6-甲基吡啶 -3-氧基) -苯氨基] -喹唑啉 -6-基 }-1Η-吡咯 -3-羧酸 -(2-吡咯烷 -1-基-乙基) -酰胺 66 ( 17 mg，浅黄色固体），产率- 97.0%。  2-{4-[3-Methyl-4-(6-methyl-pyridin-3-oxo)-phenylamino]-quinazolin-6-yl}-6,7-dihydro-2H-pyridyl Methyl [3,4-c]pyrrol-4-one 66b (120 mg, 0.25 mmol) and 2 mL of 2-pyrrolidinoyl-ethylamine were added to a 10 mL jar-shaped flask, and the mixture was heated to 90 ° C. Stir overnight and the reaction is complete. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. The title product 4-(2-hydroxyethyl)-1-{4-[3-methyl-4-(6-methylpyridin-3-yloxy)-phenylamino]-quinazoline- 6-yl}-1 Η-pyrrole-3-carboxylic acid-(2-pyrrolidin-1-yl-ethyl)-amide 66 (17 mg, pale yellow solid), yield - 97.0%.
MS m/z (ESI): 592 [M+ l] MS m/z (ESI): 592 [M+ l]
1HNMR (400MHz, DMSO-t¾: δ 9.89(s, IH), 8.68(s, IH), 8.58(s, IH), 8.19(s, IH), 8.09(m, 3H), 7.9 l(d, IH, J=8.8), 7.78(s, IH), 7.73 (dd, IH, J=8.4), 7.42(s, IH), 7.24(m, 2H), 6.99(d, IH, J=8.8), 4.85(s, IH), 3.65(t, 2H), 3.41(m, 2H), 2.90(t, 2H), 2.67(m, 6H), 2.45(s, 3H), 2.23(s, 3H), 1.74(m, 4H) 实施例 67 1 H NMR (400 MHz, DMSO-t3⁄4: δ 9.89 (s, IH), 8.68 (s, IH), 8.58 (s, IH), 8.19 (s, IH), 8.09 (m, 3H), 7.9 l (d, IH, J=8.8), 7.78(s, IH), 7.73 (dd, IH, J=8.4), 7.42(s, IH), 7.24(m, 2H), 6.99(d, IH, J=8.8), 4.85(s, IH), 3.65(t, 2H), 3.41(m, 2H), 2.90(t, 2H), 2.67(m, 6H), 2.45(s, 3H), 2.23(s, 3H), 1.74 (m, 4H) Example 67
Ν-Π- -Γ3-氯 -4-(3-氟苄氧基) -苯氨基 喹唑啉 -6-基 M-三氟甲基 -IH-吡咯 -3- 基 2-甲基-丙烯酰胺  Ν-Π--Γ3-chloro-4-(3-fluorobenzyloxy)-phenylaminoquinazolin-6-yl M-trifluoromethyl-IH-pyrrol-3-yl 2-methyl-acrylamide
Figure imgf000103_0001
Figure imgf000103_0001
Figure imgf000104_0001
第一步
Figure imgf000104_0001
first step
4,4,4-三氟-丁 -2-烯酸  4,4,4-trifluoro-but-2-enoic acid
在 100 mL茄形瓶中加入 4,44-三氟-丁 -2-烯酸乙酯 67a (56 g, 0.33 ol 甲酸（46g lmmol)和 lmL浓硫酸， 得到的混合液加热至 80°C， 搅拌过 '夜， 反 应完毕。停止加热， 在常温下蒸馏， 收集 40 8(TC的馏分， 得到本标题产物 4,4,4- 三氟-丁 -2-烯酸 67b (24 g, 白色固体）， 产率 51.9%  4,44-trifluoro-but-2-enoic acid ethyl ester 67a (56 g, 0.33 ol formic acid (46 g lmmol) and 1 mL of concentrated sulfuric acid was added to a 100 mL eggplant flask, and the resulting mixture was heated to 80 ° C. After stirring for 'night', the reaction was completed. The heating was stopped, and distillation was carried out at room temperature, and 40 8 (TC fraction was collected to obtain the title product 4,4,4-trifluoro-but-2-enoic acid 67b (24 g, white solid) ), the yield is 51.9%
MSm/z(ESI): 139 [M~l] MSm/z(ESI): 139 [M~l]
第二步  Second step
4,4,4-三氟-丁 -2-烯酸苄酯  Benzyl 4,4,4-trifluoro-but-2-enoate
在 1000 mL茄形瓶中加入 4,4,4-三氟-丁 -2-烯酸 67b (26.5 g, 0.18 mol), 1-(3- 二甲氨基丙基 )-3-乙基碳二亚胺盐酸盐（54 g 0.27 mol), 1-羟基苯并三唑（3.85 g 0.27mol), 三乙胺 （46 g, 0.45mol), 和 400 mL四氢呋喃， 所得的混合物在室温 下搅拌 1小时后加入苄醇（29.2 g 0.27mol), 搅拌过夜， 反应完毕。 在反应液中 加入冰水猝灭反应， 用乙酸乙酯 （400mLX3) 萃取， 有机相用无水硫酸钠干燥， 过滤，滤液浓缩，得到的残留物进一步通过柱层析分离纯化，得到本标题产物 4,4,4- 三氟-丁 -2-烯酸苄酯 67c (2.95 g, 黄色油状液体）， 产率： 7.7%  Add 4,4,4-trifluoro-but-2-enoic acid 67b (26.5 g, 0.18 mol), 1-(3-dimethylaminopropyl)-3-ethylcarbamate to a 1000 mL eggplant vial Imine hydrochloride (54 g 0.27 mol), 1-hydroxybenzotriazole (3.85 g 0.27 mol), triethylamine (46 g, 0.45 mol), and 400 mL of tetrahydrofuran, the mixture was stirred at room temperature 1 After an hour, benzyl alcohol (29.2 g 0.27 mol) was added and stirred overnight to complete the reaction. The reaction mixture was quenched with EtOAc (EtOAc)EtOAc. 4,4,4-Trifluoro-but-2-enoic acid benzyl ester 67c (2.95 g, yellow oily liquid), Yield: 7.7%
MSm/z(ESI): 579 [M—1] MSm/z (ESI): 579 [M-1]
第三步  third step
4-三氟甲基 -1H-吡咯 -3-甲酸苄酯  4-trifluoromethyl-1H-pyrrole -3-carboxylic acid benzyl ester
将对甲苯磺酰甲基异腈 （2.73g H.lmmol) 溶解于 25 mL四氢呋喃中， 冰浴 冷却至 0°C， 氮气氛下， 加入二环 [54,0]-1,8-二氮 -7-壬烯（2.15 g H.lmmol), 搅 02 拌 30分钟后加入 4,4,4-三氟-丁 -2-浠酸苄酯 67c (2.95g 12.7mmol), 得到的混合 物搅拌过夜， 反应完毕。 在反应液中加入 40 mL 冰水猝灭反应， 用二氯甲垸 ( 100mLx3 )萃取， 合并的有机相用无水硫酸镁干燥， 过滤， 浓缩， 得到的残留. 物进一步通过柱层析分离纯化， 得到本标题产物 4-三氟甲基 -1H-吡咯 -3-甲酸苄酯 67d ( 1.938 g， 黄色固体）， 产率： 56.7% 0 The p-toluenesulfonylmethyl isocyanide (2.73 g H.lmmol) was dissolved in 25 mL of tetrahydrofuran, cooled to 0 ° C in an ice bath, and added to the bicyclo[54,0]-1,8-diazepine under nitrogen atmosphere. -7-pinene (2.15 g H.lmmol), stirred 02 After stirring for 30 minutes, 4,4,4-trifluoro-butan-2-carboxylic acid benzyl ester 67c (2.95 g of 12.7 mmol) was added, and the obtained mixture was stirred overnight and the reaction was completed. The reaction mixture was quenched by the addition of 40 mL of ice water, and extracted with dichloromethane (100 mL×3). The combined organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated to give residue. , to give the title product 4-trifluoromethyl--1H- pyrrole-3-carboxylic acid benzyl ester 67d (1.938 g, yellow solid), yield: 56.7% 0
MS m/z (ESI): 268 [M— 1] MS m/z (ESI): 268 [M-1]
第四步  the fourth step
4-三氟甲基 -1H-吡咯 -3-甲酸  4-trifluoromethyl-1H-pyrrole-3-carboxylic acid
在 25 mL茄形瓶中，冰浴条件下，加入上述步骤所得的化合物 4-三氟甲基 -1H- 吡咯 -3-甲酸苄酯 67d ( 120 mg 0.445mmol)和 3 mL三氟醋酸， 搅拌 30分钟后撤 去冰浴， 室温下搅拌过夜， 反应完毕。 将反应液倒入 50 mL冰水中， 用乙酸乙酯 (200 ml X 3 )萃取， 有机相用无水硫酸钠干燥， 过滤， 滤液浓缩， 得到的残留物 进一步通过柱层析分离纯化，得到本标题产物 4-三氟甲基 -1H-吡咯 -3-甲酸 67e(3.39 g， 黄色固体）， 产率： 52.6% '  In a 25 mL eggplant-shaped flask, the compound 4-trifluoromethyl-1H-pyrrole-3-carboxylic acid benzyl ester 67d (120 mg 0.445 mmol) obtained in the above step and 3 mL of trifluoroacetic acid were added and stirred under ice bath. After 30 minutes, the ice bath was removed, and the mixture was stirred at room temperature overnight, and the reaction was completed. The reaction mixture was poured into 50 mL of ice water, and extracted with ethyl acetate (200 ml X 3 ). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Title product 4-trifluoromethyl-1H-pyrrole-3-carboxylic acid 67e (3.39 g, yellow solid), yield: 52.6%
MS m/z (ESI): 180 [M+ l] 第五步 MS m/z (ESI): 180 [M+ l] Step 5
l-{4-[3-氯 -4-(3-氟苄氧基) -苯氨基]-喹唑啉 -6-基}-4-三氟甲基 -1H-吡咯 -3-甲酸 将上述步骤所得的化合物 4-三氟甲基 -1H-吡咯 -3-甲酸（2.14 g 12 mmol) , [3-氯 -4-(3-氟-节氧基) -苯基 ]-(6-碘-喹唑啉 -4-基) -胺 lg (6.07 g 12 mmol), 磷酸钾 ( 10.19 g 48 mmol), 碘化亚铜 ( 3.44 g, 18 mmol )和 4-三氟甲基 -1H-吡咯 -3-甲 酸（2.14 g 12 mmol)和 5 mL N,N-二甲基甲酰胺溶解， 搅拌下滴加 Ν,Ν'-二甲基 -1,2-乙二胺（1.6 g 18 mmol), 加热回流搅拌过夜。 将反应液加入到 150 mL冰水 中，有黄色固体析出，抽滤,得到的黄色固体不经分离直接进行下一步反应 (500 mg, 淡黄色固体)。  1-{4-[3-Chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazolin-6-yl}-4-trifluoromethyl-1H-pyrrole-3-carboxylic acid The compound obtained in the step 4-trifluoromethyl-1H-pyrrole-3-carboxylic acid (2.14 g 12 mmol), [3-chloro-4-(3-fluoro-p-oxy)-phenyl]-(6-iodine -quinazolin-4-yl)-amine lg (6.07 g 12 mmol), potassium phosphate (10.19 g 48 mmol), cuprous iodide (3. 44 g, 18 mmol) and 4-trifluoromethyl-1H-pyrrole 3-carboxylic acid (2.14 g 12 mmol) and 5 mL of N,N-dimethylformamide were dissolved, and hydrazine was added dropwise with stirring, Ν'-dimethyl-1,2-ethanediamine (1.6 g 18 mmol) Heat and reflux to stir overnight. The reaction solution was poured into 150 mL of ice water, and a yellow solid was precipitated, and filtered, and the obtained yellow solid was directly subjected to the next reaction (500 mg, pale yellow solid).
MS m/z (ESI): 445[M+1]  MS m/z (ESI): 445 [M+1]
第六步  Step 6
1_{4_[4_(3_氟苄氧基) _3_氯苯氨基] -喹唑啉 _6_基}_4_三氟甲基- 1H_吡咯 _3_叠氮 基 -甲酮 1_{ 4 _[4_ (3 _fluorobenzyloxy) _ 3 _chlorophenylamino]-quinazoline _ 6 _ yl}_ 4 _trifluoromethyl- 1H _pyrrole _ 3 _ azido-methanone
将上述步骤所得的化合物 1-{4-[3-氯 -4-(3-氟苄氧基) -苯氨基] -喹唑啉 -6-基}-4-三 氟甲基 -1H-吡咯 -3-甲酸 67f (278 mg 0.5mmol) , 三乙胺 (76 mg, 0.75 ol)溶 解于 2 mL四氢呋喃中， 搅拌下加入叠氮基憐酸二苯酯 （151 mg 0.55mmol), 所 得的混合物在室温下搅拌 7小时后反应完毕。反应液用乙酸乙酯（30mLx3 )萃取， 合并的有机相依次用 70 mL水， 30 mL饱和食盐水洗涤， 无水硫酸钠干燥， 过滤， 减压下浓缩有机相， 所得的残留物进一步通过柱层析分离纯化， 得到本标题产物 1-{4-[4-(3-氟苄氧基) -3-氯苯氨基] -喹唑啉 -6-基}-4-三氟甲基 -1H-吡咯 -3-叠氮基-甲 03 酮 67g ( 101 mg, 黄色固体）， 产率： 35%。 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 combined organic layer was washed with EtOAc (EtOAc) Purification by chromatography to give the title product 1-{4-[4-(3-fluorobenzyloxy)-3-chlorophenylamino]-quinazolin-6-yl}-4-trifluoromethyl-1H -pyrrole-3-azido-methyl 03 Ketone 67g (101 mg, yellow solid), Yield: 35%.
MS m/z (ESI): 581 [M+ l] MS m/z (ESI): 581 [M+ l]
第七步  Seventh step
(l-{4-[3-氯 -4-(3-氟苄氧基) -苯氨基] -喹唑啉 -6-基 }-4-三氟甲基 -IH-吡咯 -3-基) - 氨基甲酸叔丁酯  (l-{4-[3-Chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazolin-6-yl}-4-trifluoromethyl-IH-pyrrol-3-yl) - tert-butyl carbamate
将上述歩骤所得的化合物 1-{4-[4-(3-氟苄氧基) -3-氯苯氨基] -喹唑啉 -6-基}-4- 三氟甲基 -1H-吡咯 -3-叠氮基 -甲酮 67g ( 1.37 g， 2.35mmol)溶于 75 mL甲苯， 在外 浴温度为 130°C下， 加热所得的黄色混悬液， 3 小时后加入叔丁醇 （15 mL, 159 mmol),继续回流 2小时后，在 45Ό下搅拌过夜，蒸干反应液，所得的残留物 (1-{4-[3- 氯 -4-(3-氟苄氧基) -苯氨基]-喹唑啉 -6-基}-4-三氟甲基 -1H-吡咯 -3-基)-氨基甲酸叔丁 酯 67h ( 1.6 g, 黄色固体） 不经分离直接进行下一步反应。  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. , 159 mmol), after refluxing for 2 hours, stirring at 45 ° C overnight, evaporation of the reaction mixture, and the obtained residue (1-{4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino ]-Quinazolin-6-yl}-4-trifluoromethyl-1H-pyrrol-3-yl)-carbamic acid tert-butyl ester 67h (1.6 g, yellow solid).
MS m/z (ESI): 628 [M+ l] MS m/z (ESI): 628 [M+ l]
第八步  Eighth step
[6-(3-氨基 -4-三氟甲基 -吡咯 -1-基)-喹唑啉 -4-基] -[3-氯 -4-(3-氟苄氧基)-苯基] -胺 氮气氛下， 在 50 mL茄形瓶中， 将上述步骤所得的化合物 (1-{4-[3-氯 -4-(3-氟 苄氧基) -苯氨基] -喹唑啉 -6-基 }-4-三氟甲基 -1H-吡咯 -3-基) -氨基甲酸叔丁酯 67h (219 mg, 0.35 mmol)溶解于 20 mL二氯甲烷， 得到的溶液在冰浴冷却下逐渐滴 加 5 mL三氟醋酸， 室温下搅拌 1.5小时后反应完毕。 将反应液在减压下浓缩蒸去 溶剂，得到的固体在干燥皿中干燥，得到本标题产物 [6-(3-氨基 -4-三氟甲基 -吡咯 -1- 基) -喹唑啉 -4-基 ]-[3-氯 -4-(3-氟苄氧基) -苯基] -胺 67i ( lOO mg, 黄色固体）， 产率： 54.3 %  [6-(3-Amino-4-trifluoromethyl-pyrrol-1-yl)-quinazolin-4-yl]-[3-chloro-4-(3-fluorobenzyloxy)-phenyl] The compound obtained in the above step (1-{4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazoline-in a 50 mL eggplant-shaped flask under an amine nitrogen atmosphere 6-Butyl}-4-trifluoromethyl-1H-pyrrol-3-yl)-carbamic acid tert-butyl ester 67h (219 mg, 0.35 mmol) was dissolved in 20 mL of dichloromethane. 5 mL of trifluoroacetic acid was gradually added dropwise, and the reaction was completed after stirring at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure and evaporated to dryness. 4-yl]-[3-chloro-4-(3-fluorobenzyloxy)-phenyl]-amine 67i (100 mg, yellow solid), Yield: 54.3 %
MS m/z (ESI): 528 [M+ l]  MS m/z (ESI): 528 [M+ l]
第九步  Step 9
N_(1_{4-[3-氯 -4-(3-氟苄氧基) -苯氨基]-喹唑啉 -6-基}-4-三氟甲基 -1H-吡咯 -3- 基) -2-甲基-丙烯酰胺 N _ (1 _{ 4 -[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazolin-6-yl}-4-trifluoromethyl-1H-pyrrole-3- -2-methyl-acrylamide
将上述步骤所得的化合物 [6-(3-氨基 -4-三氟甲基-吡咯 -1-基) -喹唑啉 -4-基] -[3- 氯 -4-(3-氟苄氧基)-苯基] -胺 67K200 mg, 0.379 mmol),三乙胺（0.4 mL， 0.758 mmol) 溶解于 15 mL二氯甲烷中， 混合物在丙酮干冰浴冷却下加入 2-甲基-丁 -3-烯酰氯 (0.1 mL, 0.379 mmol), 搅拌 4小时后有固体析出。 所得的固体通过 TLC板进行 分离纯化， 用乙酸乙酯进行冲洗， 得到本标题产物 N-(l-{4-[3-氯 -4-(3-氟苄氧基) - 苯氨基]-喹唑啉 -6-基}-4-三氟甲基 -1H-吡咯 -3-基) -2-甲基-丙烯酰胺（49 mg，黄色固 体）， 产率 21.7%。  The compound obtained in the above step [6-(3-amino-4-trifluoromethyl-pyrrol-1-yl)-quinazolin-4-yl]-[3-chloro-4-(3-fluorobenzyloxy) Base)-phenyl]-amine 67K200 mg, 0.379 mmol), triethylamine (0.4 mL, 0.758 mmol) dissolved in 15 mL of dichloromethane. -Aroyl chloride (0.1 mL, 0.379 mmol), solidified after stirring for 4 hr. The obtained solid was separated and purified by EtOAc (EtOAc) elute Oxazolin-6-yl}-4-trifluoromethyl-1H-pyrrol-3-yl)-2-methyl-acrylamide (49 mg, yellow solid), yield 21.7%.
MS m/z (ESI): 596[M+ 1] MS m/z (ESI): 596 [M+ 1]
1蘭 MR (400MHz, DMSO-i¾)： δ 9.87(s, IH), 9.25(s, IH), 8.69(s, IH), 8.62(s, IH), 8.24(d, IH, J=8.8), 8.10(s, IH), 8.0 l(s, IH), 7.9 l(d, IH, J=8.8), 7.85(s, IH), 7.73(d, IH, J=8.8), 7.48(q, IH), 7.33(m, 3H)， 7.20(t, IH), 5.82(s, 1H)， 5.52(s, IH), 5.28(s, 2H), 1.97(s, 3H) 实施例 68 1 blue MR (400MHz, DMSO-i3⁄4): δ 9.87(s, IH), 9.25(s, IH), 8.69(s, IH), 8.62(s, IH), 8.24(d, IH, J=8.8) , 8.10(s, IH), 8.0 l(s, IH), 7.9 l(d, IH, J=8.8), 7.85(s, IH), 7.73(d, IH, J=8.8), 7.48(q, IH), 7.33(m, 3H), 7.20(t, IH), 5.82(s, 1H), 5.52(s, IH), 5.28(s, 2H), 1.97(s, 3H) Example 68
Π-ί4-「3-氯 -4-ί吡啶 -2-甲氧基) -苯氨基 1-喹唑啉 -6-基 羟乙基 )-1Η-吡咯 -3- 基 1-哌啶 -1-甲酮  Π-ί4-"3-Chloro-4-isopropylpyridine-2-methoxy)-phenylamino-1-quinazolin-6-ylhydroxyethyl)-1Η-pyrrol-3-yl 1-piperidine-1 -ketone
Figure imgf000107_0001
Figure imgf000107_0001
重复本发明实施例 53第一步所述的实验步骤， 不同的是以实施例 47所得的 化合物 2-{4-[3-氯 -4- (吡啶 -2-甲氧基) -苯氯基] -喹唑啉 -6-基}-6,7-二氢 -2H-吡喃 [3,4-c] 吡咯 -4-酮 47作原料， 按照本发明实施例 53第一步所述的相同方式使得该原料与 哌啶的反应， 得到标题化合物 [1-{4-[3-氯 -4- (吡啶 -2-甲氧基) -苯氨基 ]-喹唑啉 -6- 基}-4-(2-羟乙基) -1H-吡咯 -3-基] -哌啶 -1-甲酮 68 ( 100 mg，灰色固体），产率 95 %。 MS m/z (ESI): 584 [M+ 1]  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]
JHNMR (400MHz, DMSO-t¾): δ 9.88(s, 1H), 8.61(m, 3H), 8.17(d, 1H, J=8.8), 8.05(s, 1H), 7.88(m, 2H), 7.76(d, 1H, J=8.8)， 7.67(s, 1H), 7.60(d, 1H, J=7.6), 7.48(s, 1H), 7.38(t, 1H), 7.3 l(d, 1H, J=8.4), 5.3 l(s, 2H), 4.71(s, 1H), 3.56(m, 6H), 2.68(t, 2H), 1.52-1.64(m, 6H) 实施例 69 J HNMR (400MHz, DMSO-t3⁄4): δ 9.88 (s, 1H), 8.61 (m, 3H), 8.17 (d, 1H, J = 8.8), 8.05 (s, 1H), 7.88 (m, 2H), 7.76(d, 1H, J=8.8), 7.67(s, 1H), 7.60(d, 1H, J=7.6), 7.48(s, 1H), 7.38(t, 1H), 7.3 l(d, 1H, J=8.4), 5.3 l(s, 2H), 4.71(s, 1H), 3.56(m, 6H), 2.68(t, 2H), 1.52-1.64(m, 6H) Example 69
2-(l-{4-[3-氯 -4- (吡啶 -2-甲氧基) -苯氨基] -喹唑啉 -6-基 4-哌啶 -1-甲基 -1H-吡咯  2-(l-{4-[3-Chloro-4-(pyridine-2-methoxy)-phenylamino]-quinazoline-6-yl 4-piperidine-1-methyl-1H-pyrrole
-3-基) -乙醇  -3-yl)-ethanol
Figure imgf000107_0002
Figure imgf000107_0002
重复本发明实施例 61第一步所述的实验歩骤， 不同的是以实施例 68所得的 化合物 [1-{4-[3-氯 -4- (吡啶 -2-甲氧基) -苯氨基]-喹唑啉 -6-基}-4-(2-羟乙基) -1H-吡咯 -3-基] -哌啶 -1-甲酮 68作原料， 按照本发明实施例 61第一步所述的相同方式使得 该原料与氢化铝锂反应，得到标题化合物 2-(1-{4-[3-氯 -4- (吡啶 -2-甲氧基) -苯氨基] - 喹唑啉 -6-基 4-哌啶 -1-甲基 -1H-吡咯 -3-基) -乙醇 69 ( 150 mg, 棕色固体）， 产率： 40%。 .  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. Amino]-quinazolin-6-yl}-4-(2-hydroxyethyl)-1H-pyrrol-3-yl]-piperidin-1-one 78 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-piperidin-1-methyl-1H-pyrrol-3-yl)-ethanol 69 (150 mg, brown solid), yield: 40%. .
MS m/z (ESI): 570 [M+ 1] MS m/z (ESI): 570 [M+ 1]
1HNMR (400MHz, DMSO-t¾): δ 10.07(s, 1H), 8.79(s, 1H), 8.60(t, 2H), 8.10(q, 2H), 7.90(t, 2H), 7.80(t, 2H), 7.59(t, 2H), 7.38(t, 1H), 7.30(d, 1H, J=8.8), 5.3 l(s, 2H), 4.14(s, 2H), 3.69(t, 2H), 3.00(t, 4H), 2.75(t, 2H), 1.66(m, 6H) 实施例 70 1 HNMR (400MHz, DMSO-t¾ ): δ 10.07 (s, 1H), 8.79 (s, 1H), 8.60 (t, 2H), 8.10 (q, 2H), 7.90 (t, 2H), 7.80 (t, 2H), 7.59(t, 2H), 7.38(t, 1H), 7.30(d, 1H, J=8.8), 5.3 l(s, 2H), 4.14(s, 2H), 3.69(t, 2H), 3.00(t, 4H), 2.75(t, 2H), 1.66(m, 6H) Example 70
4-U(l- -「3-氯 -4-(3-氟-苄氧基 苯氨基 喹唑啉 -6-基 1H-吡咯 -3-甲基 氨基 甲基 U-二氧代 -六氢 -1λ*6*-噻喃 -4-醇  4-U(l- -"3-chloro-4-(3-fluoro-benzyloxyphenylaminoquinazolin-6-yl 1H-pyrrole-3-methylaminomethyl U-dioxo-hexahydro -1λ*6*-thiopyran-4-ol
Figure imgf000108_0001
Figure imgf000108_0001
重复本发明实施例 5第一步至第三步所述的实验步骤， 不同的是以实施例 5 第二步所得的化合物 1-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基}-111-吡咯 -3- 甲醛 5c作原料， 按照本发明实施例 5第三步所述的相同方式使得该原料与 4-氨甲 基 -U-二氧代- 六氢 -1λ*6*-噻喃 -4-醇反应， 得到本标题产物 4-{[(1-{4-[3-氯 -4-(3- 氟-苄氧基) -苯氨基]-喹唑啉 -6-基}-111- '|咯 -3-甲基) -氨基] -甲基 }-1,1-二氧代 -六氢 -1λ*6*-噻喃 -4-醇 70 (90 mg, 黄色固体）， 产率： 67.2%  The experimental procedure described in the first step to the third step of Example 5 of the present invention is repeated, except that the compound 1-{4-[3-chloro-4-(3-fluoro-benzyl) obtained in the second step of Example 5 is used. Oxyphenyl)-phenylamino]-quinazolin-6-yl}-111-pyrrole-3-carbaldehyde 5c is used as a starting material, and the starting material is 4-aminocarb in the same manner as described in the third step of Example 5 of the present invention. Reaction of thio-U-dioxo-hexahydro-1λ*6*-thiopyran-4-ol to give the title product 4-{[(1-{4-[3-chloro-4-(3-fluoro-) Benzyloxy)-phenylamino]-quinazolin-6-yl}-111- '|pyr-3-methyl)-amino]-methyl}-1,1-dioxo-hexahydro-1λ* 6*-thiopyran-4-ol 70 (90 mg, yellow solid), Yield: 67.2%
MS m/z (ESI): 637[M+1] MS m/z (ESI): 637[M+1]
!HNMR (400MHz, DMSO-t¾: δ 9.42 (s, IH), 8.99 (s, IH), 8.92(s, IH), 8.38(dd, IH, J=8.8), 8.05(d, IH, J=9.2), 8.01 (d, IH, J-2.4), 7.94(s, IH), 7.85(t, IH), 7.79(dd, IH, J=9.2), 7.48(m, IH), 7.35(m, 3H), 7.20(t, IH), 6.62(s, IH), 5.25(s, 2H), 4.09(s, 2H), 3.19(m, 2H), 3.07(m, 4H), 2.06(m, 4H) 实施例 71 !HNMR (400MHz, DMSO-t3⁄4: δ 9.42 (s, IH), 8.99 (s, IH), 8.92 (s, IH), 8.38 (dd, IH, J=8.8), 8.05 (d, IH, J= 9.2), 8.01 (d, IH, J-2.4), 7.94(s, IH), 7.85(t, IH), 7.79(dd, IH, J=9.2), 7.48(m, IH), 7.35(m, 3H), 7.20(t, IH), 6.62(s, IH), 5.25(s, 2H), 4.09(s, 2H), 3.19(m, 2H), 3.07(m, 4H), 2.06(m, 4H) Example 71
4-(2-羟乙基 )-14443-甲基 -4-(6-甲基吡啶 -3-氧基) -苯氨基 1-喹唑啉 -6-基 IH-吡 咯 -3-羧酸 -(2-甲氧基乙基) -酰胺  4-(2-Hydroxyethyl)-14443-methyl-4-(6-methylpyridin-3-yloxy)-phenylamino-1-quinazolin-6-yl IH-pyrrole-3-carboxylic acid- (2-methoxyethyl)-amide
Figure imgf000108_0002
重复本发明实施例 66第一步至第三步的实验步骤， 不同的是以第二步所得的 化合物将 2-{4-[3-甲基 -4-(6-甲基 -吡啶 -3-氧代) -苯氨基] -喹唑啉 -6-基}-6,7-二氢 -2H- 吡喃并 [3,4-c]吡咯 -4-酮 66b作原料， 按照本发明实施例 66第三步所述的相同方式 使得该原料与 2-甲氧基乙胺的反应， 得到标题化合物 4-(2-羟乙基)小{4-[3-甲基 -4-(6-甲基吡啶 -3-氧基) -苯氨基] -喹唑啉 -6-基}-111-吡咯 -3-羧酸 (2-甲氧基乙基) -酰胺 71 ( 15 mg, 黄色固体）， 产率： 8%。
Figure imgf000108_0002
The experimental steps of the first step to the third step of Example 66 of the present invention are repeated, except that the compound obtained in the second step is 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, according to the invention The reaction of the starting material with 2-methoxyethylamine afforded the title compound 4-(2-hydroxyethyl -methylpyridin-3-oxy)-phenylamino]-quinazolin-6-yl}-111-pyrrole-3-carboxylic acid (2-methoxyethyl)-amide 71 (15 mg, yellow solid ), Yield: 8%.
MS m/z (ESI): 553 [M+1] W MS m/z (ESI): 553 [M+1] W
'HNM (400MHz, DMSO-^): δ 9.86(s, 1H), 8.69(s, 1H), 8.58(s, 1H), 8.19(s, 1H): 8.08(t, 2H), 8.00(s, 1H), 7.9 l(d, 1H, J=8.4), 7.78(s, 1H), 7.7 l(d, 1H, J=8.4), 7.4 l(s, 1H): 7.25(m, 2H), 7.00(d, 1H, J=8.4), 4.80(t, 1H), 3.66(q, 2H), 3.44(t, 2H), 3.39(t, 2H): 3.29(s, 3H), 2.90(t, 2H), 2.45(s， 3H), 2.24(s, 3H) 实施例 72 'HNM (400MHz, DMSO-^): δ 9.86(s, 1H), 8.69(s, 1H), 8.58(s, 1H), 8.19(s, 1H) : 8.08(t, 2H), 8.00(s, 1H), 7.9 l(d, 1H, J=8.4), 7.78(s, 1H), 7.7 l(d, 1H, J=8.4), 7.4 l(s, 1H) : 7.25(m, 2H), 7.00 (d, 1H, J=8.4), 4.80(t, 1H), 3.66(q, 2H), 3.44(t, 2H), 3.39(t, 2H) : 3.29(s, 3H), 2.90(t, 2H ), 2.45(s, 3H), 2.24(s, 3H) Example 72
「1，4Ί二哌啶基 -1'-基- (5-{4-「3-氯 -4-(3-氟苄氧基) -苯氨基 喹唑啉 -6-基 1H-吡 咯 -2-基) -甲酮  "1,4ΊDipiperidinyl-1'-yl-(5-{4-"3-chloro-4-(3-fluorobenzyloxy)-phenylaminoquinazolin-6-yl 1H-pyrrole-2 -yl)-ketone
Figure imgf000109_0001
第一步
Figure imgf000109_0001
first step
5-{4-[3-氯 -4-(3-氟苄氧基) -苯氨基] -喹唑啉 -6-基}-111-吡咯 -2-羧酸 重复本发明实施 11第一步的实验步骤，·将实施例 11第一步所得的化合物 5-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基]-喹唑啉 -6-基 }-1Η-吡咯 -2-甲醛 11a (283 mg， 0.6 mmol)溶解于 5 mL四氢呋喃中， 分批加入 6 mL 1.5N高锰酸钾溶液， 搅拌 5小时 后反应完毕。在反应液中加入饱和亚硫酸钠溶液，过滤，滤液用乙酸乙酯（100 mL X 3 )萃取， 合并的有机相依次用 50 mL饱和氯化钠溶液洗涤， 无水硫酸钠干燥， 过滤， 滤液减压下浓缩， 得到本标题产物 5-{4-[3-氯 -4-(3-氟苄氧基) -苯氨基] -喹唑 啉 -6-基 }-1Η-吡咯 -2-羧酸 72a (265 mg, 黄色固体）， 产率 90.4%。  5-{4-[3-Chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazolin-6-yl}-111-pyrrole-2-carboxylic acid repeats the first step of the practice of the present invention Experimental procedure, the compound obtained in the first step of Example 11 5-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}- 1Η-pyrrole-2-carbaldehyde 11a (283 mg, 0.6 mmol) was dissolved in 5 mL of tetrahydrofuran, and 6 mL of 1.5 N potassium permanganate solution was added in portions, and the reaction was completed after stirring for 5 hours. A saturated sodium sulfite solution was added to the reaction mixture, the mixture was filtered, and the filtrate was extracted with ethyl acetate (100 mL EtOAc). The combined organic phase was washed with 50 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and filtered. Concentration to give the title product 5-{4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazolin-6-yl}-1Η-pyrrole-2-carboxylic acid 72a (265 mg, yellow solid), yield 90.4%.
MS m/z (ESI): 489 [M+ 1] MS m/z (ESI): 489 [M+ 1]
第二歩  Second
5-{4-[3-氯 -4-(3-氟苄氧基) -苯氨基] -喹唑啉 -6基 }-1Η-吡咯 -2-羧酸 (2-吗啉 -4-乙 基) -酰胺  5-{4-[3-Chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazolin-6-yl}-1Η-pyrrole-2-carboxylic acid (2-morpholin-4-B -amide
将上述实验所得的化合物 5-{4-[3-氯 -4-(3-氟苄氧基) -苯氨基] -喹唑啉 -6- 基}-111-吡咯 -2-羧酸 72a (49 mg, O.lmmol) , 二氯亚砜（60 mg， 0.5 mmol) 溶解 于 5 mL二氯甲烷中， 加热回流 1小时后冷却至室温， 加入 [1,4']二哌啶 （33.6 mg， 0.2 mmol)的 5 mL二氯甲垸溶液，所得的混合液在室温下搅拌 2小时后反应完毕。 减压下浓縮溶剂， 得到的残留物通过 TLC板分离纯化， 得到本标题产物 5-{4-[3- 氯 -4-(3-氟苄氧基) -苯氨基] -喹唑啉 -6基 }-1Η-吡咯 -2-羧酸 (2-吗啉 -4-¾基) -酰胺 72 ( 12 mg， 白色固体）， 产率： 18.8%。  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. The solvent was concentrated under reduced pressure, and the residue was purified mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 6-based}-1 Η-pyrrole-2-carboxylic acid (2-morpholin-4-yl)-amide 72 (12 mg, white solid), yield: 18.8%.
MS m/z (ESI): 639 [M+ 1] 1HNMR (400MHz, CDC13): δ 9.20(s, 1H), 8.71(s, 1H), 7.92(d, 3H, J=9.2), 7.85(m, 2H)， 7.53(d, 1H, J=8.8), 7.35(m, 1H), 7.22(m, 2H), 7.02(t， 1H), 6.96(d, 1H, J=8.8), 6.88(s, 1H), 6.38(s, 1H), 5.16(s, 2H)， 2.53(m, 4H), 2.19(m, 4H), 2.00(m, 1H), 1.48(m， 8H), 1.34(m, 2H) 实施例 73 MS m/z (ESI): 639 [M+ 1] 1 H NMR (400MHz, CDC1 3 ): δ 9.20(s, 1H), 8.71(s, 1H), 7.92(d, 3H, J=9.2), 7.85(m, 2H), 7.53(d, 1H, J= 8.8), 7.35(m, 1H), 7.22(m, 2H), 7.02(t, 1H), 6.96(d, 1H, J=8.8), 6.88(s, 1H), 6.38(s, 1H), 5.16 (s, 2H), 2.53 (m, 4H), 2.19 (m, 4H), 2.00 (m, 1H), 1.48 (m, 8H), 1.34 (m, 2H) Example 73
4-(2-羟乙基 )-l- -「3-甲基 -4-(6-甲基吡啶- 3-氧基 苯氨基 1-喹唑啉 -6-基 1H-吡 咯 3-羧酸（2-哌啶 -1-乙基 V酰胺  4-(2-hydroxyethyl)-l--"3-methyl-4-(6-methylpyridine-3-oxyphenylamino-1-quinazolin-6-yl 1H-pyrrole 3-carboxylic acid (2-piperidin-1-ethyl V amide
Figure imgf000110_0001
Figure imgf000110_0001
重复本发明实施例 66第一步至第三步所述的实验步骤，不同的是以实施例 66 所得的化合物 2-{4-[3-甲基 -4-(6-甲基-吡啶 -3-氧代) -苯氨基] -喹唑啉 -6-基}-6,7-二氢 -2H-吡喃并 [3,4-c]吡咯 -4-酮 66b作原料， 按照本发明实施例 66第三步所述的相同 方式使得该原料与 2-哌啶 -1-基-乙胺的反应，得到标题化合物 4-(2-羟乙基 )-1-{4-[3- 甲基—4_(6_甲基吡啶 _3-氧基) -苯氨基] -喹唑啉 -6-基}-111-吡咯 -3-羧酸 （2-哌啶 -1-乙 基) -酰胺 73— (42mg， 黄色固体）， 产率： 15.7%。 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 The title compound 4-(2-hydroxyethyl)-1-{4-[3- Methyl- 4 (6-methylpyridine-3-oxy)-phenylamino]-quinazolin-6-yl}-111-pyrrole-3-carboxylic acid (2-piperidin-1-ethyl) - Amide 73 - (42 mg, yellow solid), Yield: 15.7%.
MS m/z (ESI): 604 [M- 1] MS m/z (ESI): 604 [M-1]
1HNMR (400MHz, DMSO-i¾): δ 9.93(s, 1H), 8.73(s， 1H), 8.58(s, 1H)， 8.19(s, 1H), 8.11(s, 1H), 8.09(m, 1H), 7.90(m, 2H), 7.76(s, 1H), 7.75(dd, 1H, J=8.8), 7.44(s, 1H), 7.23 (m, 2H), 7.00(d, 1H, J=8.8), 3.66(t, 2H), 3.58(q, 2H), 2.89(t, 2H), 2.45(m, 6H), 2.34(m, 2H), 2.27(m, 4H), 1.50(m, 6H) 实施例 74 1 H NMR (400 MHz, DMSO-i3⁄4): δ 9.93 (s, 1H), 8.73 (s, 1H), 8.58 (s, 1H), 8.19 (s, 1H), 8.11 (s, 1H), 8.09 (m, 1H), 7.90(m, 2H), 7.76(s, 1H), 7.75(dd, 1H, J=8.8), 7.44(s, 1H), 7.23 (m, 2H), 7.00(d, 1H, J= 8.8), 3.66(t, 2H), 3.58(q, 2H), 2.89(t, 2H), 2.45(m, 6H), 2.34(m, 2H), 2.27(m, 4H), 1.50(m, 6H) Example 74
l-{4-「3-氯 -4- (吡啶 -2-甲氧基) -苯氨基 1-喹唑啉 -6-基 M-4-(2-羟乙基) -1H-吡咯  L-{4-"3-Chloro-4-(pyridine-2-methoxy)-phenylamino-1-quinazoline-6-yl M-4-(2-hydroxyethyl)-1H-pyrrole
-3-羧酸 (2-吡咯垸 -1-基 -乙基 V酰胺  3-carboxylic acid (2-pyrrole-1-yl-ethyl Vamide
Figure imgf000110_0002
Figure imgf000110_0002
重复本发明实施例 53第一步所述的实验步骤， 不同的是以实施例 47所得的 化合物 2-{4-[3-氯 -4- (吡啶 -2-甲氧基) -苯氨基]-喹唑啉 -6-基 }-6,7-二氢 -2H-吡喃 [3,4-c] 吡咯 -4-酮 47作原料， 按照本发明实施例 53第一步所述的相同方式使得该原料与 2-吡咯烧 -1-基-乙胺的反应，得到标题化合物 1-{4-[3-氯 -4- (吡啶 -2-甲氧基) -苯氨基] - 喹唑啉 -6-基}-4-4-(2-羟乙基) -1H-吡咯 -3-羧酸 (2-吡咯烷 -1-基-乙基) -酰胺 74 ( 140 mg， 黄色固体）， 产率 40.0%。 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 Phenyl-6-yl}-4-4-(2-hydroxyethyl)-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide 74 (140 Mg, yellow solid), yield 40.0%.
MS m/z (ESI): 611 [M—l] MS m/z (ESI): 611 [M—l]
^MR (400MHz, DMSO-^): δ 9.99(d, IH, J-12.8), 8.85(d, IH, J=12.8), 8.61(d, 2H: J=6.0), 8.44(m, IH), 8.3 l(s, IH), 8.13(t, 2H), 7.88(t, 3H), 7.60(d, 1H， J=8.0), 7.50(d, IH, J=5.2), 7.38(t, IH), 7.30(d, IH, J=9.2), 5.31(s, 2H), 4.73(s, IH), 3.58(m, 6H)， 3.09(m, 4H)， 2.91(t, 2H), 1.96(m, 4H) 实施例 75 ^MR (400MHz, DMSO-^): δ 9.99(d, IH, J-12.8), 8.85(d, IH, J=12.8), 8.61(d, 2H : J=6.0), 8.44(m, IH) , 8.3 l(s, IH), 8.13(t, 2H), 7.88(t, 3H), 7.60(d, 1H, J=8.0), 7.50(d, IH, J=5.2), 7.38(t, IH ), 7.30(d, IH, J=9.2), 5.31(s, 2H), 4.73(s, IH), 3.58(m, 6H), 3.09(m, 4H), 2.91(t, 2H), 1.96( m, 4H) Example 75
l-{4-[3-氯 -4- (吡啶 - 2-甲氧基) -苯氨基]-喹唑啉 -6-基}-4-(2-羟乙基) -IH-吡咯 -3- 羧酸（2-哌啶 -1-乙基) -酰胺  L-{4-[3-Chloro-4-(pyridine-2-methoxy)-phenylamino]-quinazolin-6-yl}-4-(2-hydroxyethyl)-IH-pyrrole-3 - Carboxylic acid (2-piperidin-1-ethyl)-amide
Figure imgf000111_0001
Figure imgf000111_0001
重复本发明实施例 53第一步所述的实验步骤， 不同的是以实施例 47所得的 化合物 2-{4-[3-氯 -4- (吡啶 -2-甲氧基) -苯氨基]-喹唑啉 -6-基}-6,7-二氢 -2H-吡喃 [3,4-c] 吡咯 -4-酮 47作原料， 按照本发明实施例 53第一步所述的相同方式使得该原料与 2-哌啶 -1-基-乙胺的反应， 得到标题化合物 1-{4-[3-氯 -4- (吡啶 -2-甲氧基) -苯氨基] - 喹唑啉 _6-基}-4-(2-羟乙基 )-1Η-吡咯 -3-羧酸 （2-哌啶 -1-乙基) -酰胺 75 (70 mg, 棕色 固体）， 产率 56.0%。  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)-1Η-pyrrole-3-carboxylic acid (2-piperidin-1-ethyl)-amide 75 (70 mg, brown solid), yield 56.0 %.
MS m/z (ESI): 625 [M—l] MS m/z (ESI): 625 [M—l]
1HNMR (400MHz, DMSO-c¾)： 5 10.07(s, IH), 8.89(s, IH), 8.60(d, IH, J=7.6), 8.29-8.45(m, 2H), 8.14(m, 2H), 7.89(t, 3H), 7.60(d, IH, J=8.0), 7.52(d, IH), 7.37(t, IH), 7.30(d, IH, J=9.2), 5.31(s, 2H), 4.74(s, IH), 3.65(m, 4H), 2.98-3.16(m, 4H), 2.91 (t, 4H), 2.78(m, 6H) 实施例 76 1 H NMR (400MHz, DMSO-c3⁄4): 5 10.07 (s, IH), 8.89 (s, IH), 8.60 (d, IH, J = 7.6), 8.29-8.45 (m, 2H), 8.14 (m, 2H) ), 7.89(t, 3H), 7.60(d, IH, J=8.0), 7.52(d, IH), 7.37(t, IH), 7.30(d, IH, J=9.2), 5.31(s, 2H ), 4.74(s, IH), 3.65(m, 4H), 2.98-3.16(m, 4H), 2.91 (t, 4H), 2.78(m, 6H) Example 76
2-(1- -Γ3-氯 -4-Q1比啶 -2-甲氧基) -苯氨基 1-喹唑啉 -6-基 4-吡咯垸 -1-甲基 -1H-吡 咯 -3-基 V乙醇  2-(1- -Γ3-chloro-4-Q1pyridin-2-methoxy)-phenylamino-1-quinazolin-6-yl 4-pyrrole-1-yl-1H-pyrrole-3- Base V ethanol
Figure imgf000111_0002
Figure imgf000111_0002
重复本发明实施例 61第一步所述的实验步骤， 不同的是以实施例 60所得的 化合物 -{4-[3-氯 -4- (吡啶 -2-甲氧基) -苯氨基] -喹唑啉 -6-基}-4--4-(2-羟基) -1H-吡咯 -3- 基]-吡咯烷 -1-甲酮 60作原料，按照本发明实施例 61第一步所述的相同方式使得该 原料与氢化铝锂反应， 得到标题化合物 2-(1-{4-[3-氯 -4- (吡啶 -2-甲氧基) -苯氨基] - 喹唑啉 -6-基 }-4-吡咯烷小甲基 -1Η-吡咯 -3-基) -乙醇 76 (30 mg, 棕色固体）， 产率： 44 % 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-1Η-pyrrol-3-yl)-ethanol 76 (30 mg, brown solid), Yield: 44 %
MS m/z (ESI) : 556 [M+ 1]  MS m/z (ESI) : 556 [M+ 1]
1HNMR (400MHz, OMSO-d6): δ 9.88(s, 1H), 8.58(d, 3H), 8.11(d, 1H, J=7.6), 8.04(s, 1H), 7.88(m, 2H), 7.76(d, 1H J=6.8), 7.60(d, 2H), 7.44(s, 1H), 7.37(t, 1H), 7.3 l(d, 1H, J=9.2), 5.31(s, 2H), 3.85(s, 2H), 3.65(t, 2H), 2.90(m 4H), 2.7 l(t, 2H), 1.83(m, 4H) 实施例 77 1 H NMR (400MHz, OMSO-d 6 ): δ 9.88 (s, 1H), 8.58 (d, 3H), 8.11 (d, 1H, J = 7.6), 8.04 (s, 1H), 7.88 (m, 2H) , 7.76(d, 1H J=6.8), 7.60(d, 2H), 7.44(s, 1H), 7.37(t, 1H), 7.3 l(d, 1H, J=9.2), 5.31(s, 2H) , 3.85(s, 2H), 3.65(t, 2H), 2.90(m 4H), 2.7 l(t, 2H), 1.83(m, 4H) Example 77
ί4-(2-羟乙基 )-1-「4-α-苯乙氨基)-喹唑啉 -6-基 1-lH-吡咯 -3-基 哌啶 -1-甲酮  4-4-(2-Hydroxyethyl)-1-"4-α-phenethylamino)-quinazoline-6-yl 1-lH-pyrrole-3-ylpiperidine-1-one
Figure imgf000112_0001
Figure imgf000112_0001
- . - + 第一步 、 - . - + first step,
(6-碘-喹唑啉 -4-基) -(1-苯乙基) -胺  (6-iodo-quinazolin-4-yl)-(1-phenylethyl)-amine
重复本发明实施例 1第五所述的实验步骤， 不同的是以实施例 1第四步所得 的化合物 6-碘 -3Η-喹唑啉 -4-酮 If作原料， 按照本发明实施例 1第五步所述的相同 方式使得该原料与 1-苯基乙胺的反应，得到标题化合物 (6-碘-喹唑啉- 4-基)- (1-苯乙 基) -胺 77a ( 9 g， 黄色固体）， 产率 66 %  The experimental procedure described in the fifth embodiment of the present invention is repeated, except that the compound 6-iodo-3Η-quinazolin-4-one If obtained in the fourth step of the first embodiment is used as a raw material, according to the embodiment 1 of the present invention. The title compound (6-iodo-quinazolin-4-yl)-(1-phenylethyl)-amine 77a (9) was obtained in the same manner as described in the fifth step. g, yellow solid), yield 66 %
MS m/z (ESI): 376[M+ 1] MS m/z (ESI): 376 [M+ 1]
第二步  Second step
2-[4-(1-苯乙氨基)-喹唑啉 -6-基] -6,7-二氢 -2H-吡喃并 [3,4-c]吡咯 -4-酮 在 100 mL茄形瓶中，将上述步骤所得的化合物 (6-碘-喹唑啉 -4-基) -(1-苯乙基) - 胺 77a ( 2.3 g 6.13 mmol) , 6,7-二氢 -2H-吡喃并 [3,4-c]吡咯 -4-酮 10b ( 1.093g 7.97 mmol ),磷酸钾（3.9 g 18.4 ol)，碘化亚铜 (2.33 g, 10.26 mmol )溶解于 25 mL Ν,Ν-二甲基甲酰胺中，搅拌下滴加 Ν,Ν'-二甲基 -1,2-乙二胺（0.897 g 10.26 mmol) , 加热反应液到 70°C， 搅拌过夜。 将反应液倒入 100 mL冰水中， 有白色固体析出， 抽滤， 得到的固体用 300 mL 甲醇洗涤， 固体在真空下干燥， 得到本标题产物 2-[4-(1-苯乙氨基) -喹唑啉 -6-基] -6 7-二氢 -2H-吡喃并 [3 4-c]吡咯 -4-酮 77b ( 2.2 g，黄 色固体）， 产率 95.7 %  2-[4-(1-Phenylethylamino)-quinazolin-6-yl]-6,7-dihydro-2H-pyrano[3,4-c]pyrrol-4-one in 100 mL eggplant In the flask, the compound obtained in the above step (6-iodo-quinazolin-4-yl)-(1-phenylethyl)-amine 77a (2.3 g 6.13 mmol), 6,7-dihydro-2H- Pyrido[3,4-c]pyrrol-4-one 10b ( 1.093g 7.97 mmol), potassium phosphate (3.9 g 18.4 ol), cuprous iodide (2.33 g, 10.26 mmol) dissolved in 25 mL Ν, Ν In dimethylformamide, hydrazine, Ν'-dimethyl-1,2-ethanediamine (0.897 g, 10.26 mmol) was added dropwise with stirring, and the reaction mixture was heated to 70 ° C and stirred overnight. The reaction mixture was poured into 100 mL of ice water, and a white solid was precipitated, and filtered, and the obtained solid was washed with 300 mL of methanol, and the solid was dried under vacuum to give the title product 2-[4-(1-phenylethylamino)- Quinazoline-6-yl]-6 7-dihydro-2H-pyrano[3 4-c]pyrrol-4-one 77b (2.2 g, yellow solid), yield 95.7 %
MS m/z (ESI): 385 [M+ 1] MS m/z (ESI): 385 [M+ 1]
第三步 {4-(2-羟乙基 )-l-[4-(l-苯乙氨基)-喹唑啉 -6-基] -1H-吡咯 -3-基} -哌啶 -1-甲酮 将 2-[4-(1-苯乙氨基) -喹唑啉 -6-基] -6,7-二氢 -2H-吡喃并 [3,4-c]吡咯 -4-酮 77b (300 mg, 0.78 mmol)和 3 mL哌啶加入至 10 mL茄形瓶中，混合物加热至 65Ό， 搅拌过夜， 反应完毕。 反应液在减压下浓缩， 得到的残留物用乙酸乙酯溶解后， 再加入环己烷，有大量白色固体析出，过滤，得到的固体用少量甲醇溶解，用 TLC 板分离提纯， 得到黄色固体， 真空干燥得到标题产物 {4-(2-羟乙基 )-1-[4-(1-苯乙氨 基) -喹唑啉 -6-基] -1Η-吡咯 -3-基} -哌啶 -1-甲酮 77 (360 mg, 浅黄色固体）， 产率： third step {4-(2-Hydroxyethyl)-l-[4-(l-phenylethylamino)-quinazolin-6-yl]-1H-pyrrol-3-yl}-piperidin-1-one 2-[4-(1-Phenylethylamino)-quinazolin-6-yl]-6,7-dihydro-2H-pyrano[3,4-c]pyrrol-4-one 77b (300 mg , 0.78 mmol) and 3 mL of piperidine were added to a 10 mL eggplant-shaped flask, and the mixture was heated to 65 Torr, stirred overnight, and the reaction was completed. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. The title product {4-(2-hydroxyethyl)-1-[4-(1-phenylethylamino)-quinazolin-6-yl]-1Η-pyrrol-3-yl}-piperidine was obtained by vacuum drying. 1-ketone 77 (360 mg, pale yellow solid), Yield:
MS m/z (ESI): 470 [M+ l]MS m/z (ESI): 470 [M+ l]
HNMR (400MHz, DMSO-t¾: δ 8.56(s, 1H), 8.48(d, 2H, 3=6.8), 8.07(s, 1H), 7.83(s, 1H), 7.78(s, 1H), 7.44(m, 3H), 7.33(t, 2H), 7.23(t, 1H), 5.64(m, 1H), 4.7 l(s, 1H)， 3.68(m, 6H), 2.67(t, 2H), 1.63(d, 3H, J=6.4), 1.24(t, 6H) 实施例 78  HNMR (400MHz, DMSO-t3⁄4: δ 8.56 (s, 1H), 8.48 (d, 2H, 3 = 6.8), 8.07 (s, 1H), 7.83 (s, 1H), 7.78 (s, 1H), 7.44 ( m, 3H), 7.33(t, 2H), 7.23(t, 1H), 5.64(m, 1H), 4.7 l(s, 1H), 3.68(m, 6H), 2.67(t, 2H), 1.63( d, 3H, J=6.4), 1.24(t, 6H) Example 78
{4-(2-羟乙基 )小[4-(1-苯乙氨基 喹唑啉 -6-基 1-m-吡咯 -3-基}-吡咯垸 -1-甲酮  {4-(2-Hydroxyethyl) small [4-(1-phenylethylaminoquinazolin-6-yl 1-m-pyrrole-3-yl}-pyrrole-1-one
Figure imgf000113_0001
重复本发明实施例 77第一步至第三歩所述的实验步骤，不同的是以实施例 77 所得的化合物 2-[4-(1-苯乙氨基) -喹唑啉 -6-基] -6,7-二氢- 2H-吡喃并 [3,4-c]吡咯 -4-酮 77b作原料， 按照本发明实施例 77第三步所述的相同方式使得该原料与吡咯烷的 反应， 得到标题化合物 {4-(2-羟乙基 )-1-[4-(1-苯乙氨基) -喹唑啉 -6-基] -1H-吡咯 -3- 基 }-吡咯垸 -1-甲酮 78 (42mg, 黄色固体）， 产率： 95 %。
Figure imgf000113_0001
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 The title compound {4-(2-hydroxyethyl)-1-[4-(1-phenylethylamino)-quinazolin-6-yl]-1H-pyrrol-3-yl}-pyrrole- 1-Mextone 78 (42 mg, yellow solid), Yield: 95%.
MS m/z (ESI): 456 [M+ l] MS m/z (ESI): 456 [M+ l]
]HNMR (400MHz, DMSO-c¾): δ 8.65(s, 2H), 8.40(s, 1H), 8.琴， 1H, J=8.4), 7.83(s, 1H), 7.76(d, 1H, J=8.4), 7.46(m, 3H), 7.32(t, 2H), 7.2 l(t, 1H), 5.64(m, 1H), 4.8 l(s, 1H), 3.61(m, 4H), 3.46(m, 2H), 2.78(t, 2H), 1.86(m, 4H), 1.64(d, 3H, J=6.8) 实施例 79 ' ] HNMR (400MHz, DMSO-c¾ ): δ 8.65 (s, 2H), 8.40 (s, 1H), 8. Qin, 1H, J = 8.4), 7.83 (s, 1H), 7.76 (d, 1H, J =8.4), 7.46(m, 3H), 7.32(t, 2H), 7.2 l(t, 1H), 5.64(m, 1H), 4.8 l(s, 1H), 3.61(m, 4H), 3.46( m, 2H), 2.78(t, 2H), 1.86(m, 4H), 1.64(d, 3H, J=6.8) Example 79 '
4-(2-羟乙基 )小|~4-(1-苯基-乙氨基) -喹唑啉 -6-基 1-lH-吡咯 -3-羧酸 (7-二乙氨基  4-(2-hydroxyethyl) small|~4-(1-phenyl-ethylamino)-quinazoline-6-yl 1-lH-pyrrole-3-carboxylic acid (7-diethylamino)
乙―基 V酰胺
Figure imgf000114_0001
E-based V amide
Figure imgf000114_0001
重复本发明实施例 77第一步至第三歩所述的实验步骤，不同的是以实施例 77 所得的化合物 2-[4-(1-苯乙氨基) -喹唑啉 -6-基] -6,7-二氢 -2H-吡喃并 [3,4-c]吡咯 -4-酮 77b作原料，按照本发明实施例 77第三步所述的相同方式使得该原料 Ν,Ν-二乙基 -1 ,2-乙二胺的反应， 得到标题化合物 {4-(2-羟乙基) - 1 -[4-(1 -苯基-乙氨基)-喹唑啉 -6- 基] -1Η-吡咯 -3-羧酸 (2-二乙氨基乙基) -酰胺 79 (50 mg, 黄色固体）， 产率： 26%。 MS m/z (ESI): 501 [M+ 1]  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. Reaction of diethyl-1,2-ethanediamine gives the title compound {4-(2-hydroxyethyl)-1-[4-(1-phenyl-ethylamino)-quinazoline-6-yl -1Η-pyrrole-3-carboxylic acid (2-diethylaminoethyl)-amide 79 (50 mg, yellow solid), Yield: 26%. MS m/z (ESI): 501 [M+ 1]
^MR (400MHz, DMSO-c¾)： δ 8.82(s, IH), 8.75(d, IH, J=7.2), 8.41(m, 3H), 8.03(d, IH, J=8.8), 7.78(d, IH, J=8.8), 7.50(m, 3H), 7.32(t, 2H), 7.2 l(t, IH), 5.64(m, 1H)， 4.76(s, IH), 3.64(t, 2H), 3.58(m, 2H), 3.13(m, 6H), 2.91 (t, 2H), 1.66(d, 3H, J=7.2), 1.24(t, 6H) 实施例 80  ^MR (400MHz, DMSO-c3⁄4): δ 8.82(s, IH), 8.75(d, IH, J=7.2), 8.41(m, 3H), 8.03(d, IH, J=8.8), 7.78(d , IH, J=8.8), 7.50(m, 3H), 7.32(t, 2H), 7.2 l(t, IH), 5.64(m, 1H), 4.76(s, IH), 3.64(t, 2H) , 3.58(m, 2H), 3.13(m, 6H), 2.91 (t, 2H), 1.66(d, 3H, J=7.2), 1.24(t, 6H) Example 80
Γ3-氯 -4-(3-氟苄氧基) -苯基 1-Γ6-(3-ί「(1，1-二氧 -六氢 -1λ*6*-噻喃 -4-甲基) -氨基 1- 甲基 吡咯 -1-基) -喹唑啉 -4-基 1-胺  Γ3-Chloro-4-(3-fluorobenzyloxy)-phenyl 1-indole-6-(3-ί"(1,1-dioxo-hexahydro-1λ*6*-thiopyran-4-methyl) -amino 1-methylpyrrol-1-yl)-quinazolin-4-yl 1-amine
Figure imgf000114_0002
Figure imgf000114_0002
重复本发明实施例 5第一步至第三歩所述的实验步骤， 不同的是以实施例 5 第二步所得的化合物 1-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基}-111-吡咯 -3- 甲醛 5c作原料，按照本发明实施例 5第三步所述的相同方式使得该原料与 C-(l,l- 二氧代 -六氢 -1λ*6*-噻喃 -4-基) -甲胺的反应， 得到标题化合物 [3-氯 -4-(3-氟苄氧基) - 苯基] -[6-(3-{[(1，1-二氧 -六氢 -1λ*6*-噻喃 -4-甲基) -氨基] -甲基 吡咯 -1-基) -喹唑啉 -4-基] -胺 80 (53 mg, 黄色固体）， 产率 40.7%。  The experimental procedure described in the first step to the third step of Example 5 of the present invention was repeated, except that the compound obtained in the second step of Example 5 was 1-{4-[3-chloro-4-(3-fluoro-benzyl). Oxyphenyl)-phenylamino]-quinazolin-6-yl}-111-pyrrole-3-carbaldehyde 5c is used as a starting material to make the starting material and C-(l) in the same manner as described in the third step of Example 5 of the present invention. Reaction of l-dioxo-hexahydro-1λ*6*-thiopyran-4-yl)-methylamine gave the title compound [3-chloro-4-(3-fluorobenzyloxy)-phenyl] -[6-(3-{[(1,1-dioxo-hexahydro-1λ*6*-thiopyran-4-methyl)-amino]-methylpyrrol-1-yl)-quinazoline- 4-yl]-amine 80 (53 mg, yellow solid), yield 40.7%.
MS m/z (ESI): 621 [M+ l] MS m/z (ESI): 621 [M+ l]
^MR (400MHz, DMSO-ί ί): δ 9.85(s, IH), 8.62(s, IH), 8.57(s, IH), 8.12(dd, IH, J=8.8), 8.04(d, IH, J=2.4), 7.86(d, IH, J=8.8), 7.77(dd, IH, J=8.8), 7.54(s, 2H), 7.47(q, IH), 7.32(m, 3H), 7.19(t, IH), 6.39(s, IH), 5.27(s, 2H), 3.71(s, 2H), 3.08(m, 4H), 2.58(m, 2H), 2.11(m, 2H), 1.80(m, IH), 1.62(m, 2H) 实施例 81 氯 _4-氟苯氨基) -喹唑啉 -6-基 l-4-〔2-羟基-乙基) -1Η-吡咯 -3-羧酸（2 ^MR (400MHz, DMSO-ίί): δ 9.85(s, IH), 8.62(s, IH), 8.57(s, IH), 8.12(dd, IH, J=8.8), 8.04(d, IH, J=2.4), 7.86(d, IH, J=8.8), 7.77(dd, IH, J=8.8), 7.54(s, 2H), 7.47(q, IH), 7.32(m, 3H), 7.19( t, IH), 6.39(s, IH), 5.27(s, 2H), 3.71(s, 2H), 3.08(m, 4H), 2.58(m, 2H), 2.11(m, 2H), 1.80(m , IH), 1.62 (m, 2H) Example 81 Chloro-4-fluorophenylamino)-quinazolin-6-yl l-4-[2-hydroxy-ethyl)-1Η-pyrrole-3-carboxylic acid (2
-吡咯垸 -1-乙基) -酰胺  -pyrrole -1-ethyl)-amide
Figure imgf000115_0001
Figure imgf000115_0001
第一步  First step
2-[4-(3-氯 -4-氟-苯氨基) -喹唑啉 -6-基] -6,7-二氢 -2H-吡喃 [3,4-c]吡咯 -4-酮 在 100 mL茄形瓶中，依次加入 (3-氯 -4-氟苯基 )-(6-碘-喹唑啉 -4-基) -胺 lg ( 100 mg， 0.25mmol), 6,7-二氢 -2H-吡喃并 [3,4-c]吡咯 -4-酮 10b (44.6 mg， 0.33 mmol), 磷酸钾（ 159.2 mg， 0.75 mmol), 碘化亚铜（57.1mg， 0.3 mmol)溶解于 2 mLN,N- 二甲基甲酰胺中， 搅拌下滴加 Ν,Ν'-二甲基 -1,2-乙二胺 （26.3 mg， 0.3 mmol), 加 热反应液到 70°C， 搅拌过夜。 将反应液倒入 40 mL冰水中， 有白色固体析出， 抽 滤，得到的固体用 300 mL 甲醇洗涤，固体在真空下干燥，得到本标题产物 2-[4-(3- 氯 -4-氟-苯氨基) -喹唑啉 -6-基] -6,7-二氢 -2H-吡喃 [3,4-c]吡咯 -4-酮 81a ( 102.2 g， 黄 色固体）， 产率 100%。  2-[4-(3-Chloro-4-fluoro-phenylamino)-quinazolin-6-yl]-6,7-dihydro-2H-pyrano[3,4-c]pyrrol-4-one In a 100 mL eggplant-shaped flask, (3-chloro-4-fluorophenyl)-(6-iodo-quinazolin-4-yl)-amine lg (100 mg, 0.25 mmol), 6,7- Dihydro-2H-pyrano[3,4-c]pyrrol-4-one 10b (44.6 mg, 0.33 mmol), potassium phosphate (159.2 mg, 0.75 mmol), cuprous iodide (57.1 mg, 0.3 mmol) Dissolve in 2 mL of N,N-dimethylformamide, add hydrazine, Ν'-dimethyl-1,2-ethanediamine (26.3 mg, 0.3 mmol), and heat the reaction solution to 70 °C. Stir overnight. The reaction solution was poured into 40 mL of ice water, and a white solid was separated, filtered, filtered, and the obtained solid was washed with 300 mL of methanol, and the solid was dried under vacuum to give the title product 2-[4-(3-chloro-4-fluoro) -Phenylamino)-quinazolin-6-yl]-6,7-dihydro-2H-pyrano[3,4-c]pyrrol-4-one 81a (102.2 g, yellow solid), yield 100% .
MS m/z (ESI): 409 [M+ 1] MS m/z (ESI): 409 [M+ 1]
第二步  Second step
1-[4-(3-氯 -4-氟苯氨基)-喹唑啉 -6-基] -4-(2-羟基-乙基) -1H-吡咯 -3-羧酸（2  1-[4-(3-Chloro-4-fluorophenylamino)-quinazoline-6-yl]-4-(2-hydroxy-ethyl)-1H-pyrrole-3-carboxylic acid (2
-吡咯烷 -1-乙基) -酰胺  -pyrrolidine-1-ethyl)-amide
将 2-[4-(3-氯 -4-氟 -苯氨基)-喹唑啉 -6-基] -6,7-二氢 -2H-吡喃 [3,4-c]吡咯 -4-酮 81a ( 110 mg， 0.25 mmol)和 2-吡咯烷 -1-基 -乙胺（0.6 mL, 0.25 mmol)加入至 10 mL 茄形瓶中， 混合物加热至 90°C， 搅拌过夜， 反应完毕。 反应液在减压下浓缩， 得 到的残留物用乙酸乙酯溶解后， 再加入环己烷， 有大量白色固体析出， 过滤， 得 到的固体用少量甲醇溶解， 用 TLC板分离提纯， 得到黄色固体， 真空干燥得到标 题产物 1-[4-(3-氯 -4-氟苯氨基) -喹唑啉 -6-基] -4-(2-羟基-乙基) -1H-吡咯 -3-羧酸 -(2-口比 咯烷 -1-乙基) -酰胺 81 (25 mg， 黄色固体）， 产率： 31.87%。  2-[4-(3-Chloro-4-fluoro-phenylamino)-quinazolin-6-yl]-6,7-dihydro-2H-pyrano[3,4-c]pyrrole-4- Ketone 81a (110 mg, 0.25 mmol) and 2-pyrrolidin-1-yl-ethylamine (0.6 mL, 0.25 mmol) were added to a 10 mL eggplant-shaped flask, and the mixture was heated to 90 ° C, stirred overnight, and the reaction was completed. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. Drying in vacuo gave the title product 1-[4-(3-chloro-4-fluorophenylamino)-quinazolin-6-yl]-4-(2-hydroxy-ethyl)-1H-pyrrole-3-carboxy Acid-(2-portpyrrol-1-yl)-amide 81 (25 mg, yellow solid), Yield: 31.87%.
MS m/z (ESI): 524 [M+ 1] MS m/z (ESI): 524 [M+ 1]
1HNMR (400MHz, DMSO-^): δ 10.24(s, 1H), 8.97(s, 1H), 8.64(s, 1H), 8.56(s, 1H), 8.35(m, 2H), 8.15(d, 1H, J=8.8), 8.06(m, 1H), 7.92(d, 1H, J=9.2), 7.56(s, 1H), 7.47(t5 1H), 4.73(s, 1H), 3.71(t, 2H),3.63(q, 2H), 3.43(m, 2H), 2.9 l(t, 2H), 2.50(m, 4H), 1.85(m, 4H) 实施例 82 1 H NMR (400 MHz, DMSO-^): δ 10.24 (s, 1H), 8.97 (s, 1H), 8.64 (s, 1H), 8.56 (s, 1H), 8.35(m, 2H), 8.15(d, 1H, J=8.8), 8.06(m, 1H), 7.92(d, 1H, J=9.2), 7.56(s, 1H), 7.47(t 5 1H), 4.73(s, 1H), 3.71(t, 2H), 3.63(q, 2H), 3.43(m, 2H), 2.9 l(t, 2H), 2.50(m, 4H), 1.85(m, 4H) Example 82
4-(2-羟乙基 l-M-「3-甲基 -4-(6-甲基 -吡啶 -3-氧基) -苯氨基 1-喹唑啉 - 6-基 }-m- 吡咯 -3-羧酸 -ί3-吗啉 -4-丙基 酰胺  4-(2-Hydroxyethyl lM-"3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino-1-quinazoline-6-yl}-m-pyrrole-3 -carboxylic acid-ί3-morpholin-4-propylamide
Figure imgf000116_0001
Figure imgf000116_0001
重复本发明实施例 66第一步至第三步的实验步骤， 不同的是以第二步所得的 化合物将 2-{4-[3-甲基 -4-(6-甲基-吡啶 -3-氧代) -苯氨基] -喹唑啉 -6-基}-6,7-二氢 -2Η- 吡喃并 [3,4-c]吡咯 -4-酮 66b作原料， 按照本发明实施例 66第三步所述的相同方式 使得该原料与 3-吗啉 -4-丙胺的反应， 得到标题化合物 4-(2-羟乙基 )-1-{4-[3-甲基 -4-(6-甲基吡啶 -3-氧基) -苯氨基] -喹唑啉 -6-基 }-1Η-吡咯 -3-羧酸 -(3-吗啉 -4-丙基) -酰 胺 82 (20 mg， 黄色固体）， 产率： 8.6%。  The experimental steps of the first step to the third step of Example 66 of the present invention are repeated, except that the compound obtained in the second step is 2-{4-[3-methyl-4-(6-methyl-pyridine-3). -Oxo)-phenylamino]-quinazolin-6-yl}-6,7-dihydro-2-indole-pyrano[3,4-c]pyrrol-4-one 66b as starting material, according to the invention Reaction of the starting material with 3-morpholin-4-propanamine in the same manner as described in the third step of Example 66 gave the title compound 4-(2-hydroxyethyl)-1-{4-[3-methyl-4. -(6-methylpyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-1Η-pyrrole-3-carboxylic acid-(3-morpholin-4-propyl)-amide 82 (20 mg, yellow solid), Yield: 8.6%.
MS m/z (ESI).- 621 [M+ l] MS m/z (ESI).- 621 [M+ l]
1HNMR (400MHz, DMSOi¾): δ 9.87(s, 1H), 8.69(s, 1H), 8.58(s, 1H), 8.19(s, 1H)， 8.10(d, 1H, J=8.8), 8.00(m, 2H), 7.9 l(d, 1H, J=8.8), 7.78(s, 1H), 7.72(d, 1H, J=8.8), 7.42(s, 1H), 7.25(m, 2H), 7.00(d, 1H, J=8.8), 4.84(t, 1H), 3.58-3.66(m, 8H), 2.89(t, 2H), 2.45(s, 3H)5 2.36(s, 6H), 2.24(s, 3H)， 2.14(t, 2H) 实施例 83 1 H NMR (400MHz, DMSOi3⁄4): δ 9.87 (s, 1H), 8.69 (s, 1H), 8.58 (s, 1H), 8.19 (s, 1H), 8.10 (d, 1H, J = 8.8), 8.00 ( m, 2H), 7.9 l(d, 1H, J=8.8), 7.78(s, 1H), 7.72(d, 1H, J=8.8), 7.42(s, 1H), 7.25(m, 2H), 7.00 (d, 1H, J=8.8), 4.84(t, 1H), 3.58-3.66(m, 8H), 2.89(t, 2H), 2.45(s, 3H) 5 2.36(s, 6H), 2.24(s , 3H), 2.14(t, 2H) Example 83
4-(2-羟乙基 )-1- -Γ3-甲基 -4-(6-甲基 -吡啶 -3-氧基) -苯氨基 喹唑啉 -6-基 -1H- 吡咯 -3-羧酸 -(2-吗啉 -4-乙基) -酰胺  4-(2-Hydroxyethyl)-1- -indol-3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylaminoquinazolin-6-yl-1H-pyrrole-3- Carboxylic acid-(2-morpholin-4-ethyl)-amide
Figure imgf000116_0002
Figure imgf000116_0002
重复本发明实施例' 66第一歩至第三步的实验步骤， 不同的是以第二步所得的 化合物将 2-{4-[3-甲基 -4-(6-甲基 -吡啶 -3-氧代) -苯氨基] -喹唑啉 -6-基}-6,7-二氢 -2H- 吡喃并 [3,4-c]吡咯 -4-酮 66b作原料， 按照本发明实施例 66第三步所述的相同方式 使得该原料与 2-吗啉 -4-基-乙胺的反应，得到标题化合物 4-(2-轻乙基 )-1-{4-[3-甲基 -4-(6-甲基吡啶 -3-氧基) -苯氨基] -喹唑啉 -6-基}-111-吡咯 -3-羧酸 -(2-吗啉 -4-乙基) -酰 胺 83 ( lO mg, 黄色固体）， 产率： 5.4%。 The experimental procedure of the first to third steps of the embodiment of the invention '66 is repeated, except that the compound obtained in the second step is 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 The title compound 4-(2-light ethyl)-1-{4-[3- Methyl-4-(6-methylpyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-111-pyrrole-3-carboxylic acid-(2-morpholin-4-ethyl ) - acyl Amine 83 (10 mg, yellow solid), Yield: 5.4%.
MS m/z (ESI): 608 [M+ l] MS m/z (ESI): 608 [M+ l]
]HNMR (400MHz, DMSO-i¾: δ 9.85(s, IH), 8.66(s, IH), 8.58(s, IH), 8.19(s, IH), 8.09(d, IH, J=9.2), 8.00(s, IH), 7.9 l(m, 2H), 7.77(s, IH), 7.72(d, IH, J=9.2), 7.41 (s, IH), 7.25(m, 2H), 7.00(d, IH, J=8.8), 4.82(t, IH), 3.58-3.66(m, 8H), 2.90(t, 2H), 2.45 (m, 9H), 2.24(s, 3H) 实施例 84 ] HNMR (400MHz, DMSO-i¾ : δ 9.85 (s, IH), 8.66 (s, IH), 8.58 (s, IH), 8.19 (s, IH), 8.09 (d, IH, J = 9.2), 8.00 (s, IH), 7.9 l(m, 2H), 7.77(s, IH), 7.72(d, IH, J=9.2), 7.41 (s, IH), 7.25(m, 2H), 7.00(d, IH, J=8.8), 4.82(t, IH), 3.58-3.66(m, 8H), 2.90(t, 2H), 2.45 (m, 9H), 2.24(s, 3H) Example 84
4-(2-羟乙基 )-1-{4-Γ3-甲基 -4-(6-甲基 -吡啶 -3-氧基) -苯氨基 1-喹唑啉 -6-基 }-lH-  4-(2-Hydroxyethyl)-1-{4-Γ3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamino-1-quinazolin-6-yl}-lH -
Figure imgf000117_0001
Figure imgf000117_0001
84  84
重复本发明实施例 66第一步至第三步的实验步骤， 不同的是以第二步所得的 化合物将 2-{4-[3-甲基 -4-(6-甲基 -Β比啶 -3-氧) -苯氨基] -喹唑啉 -.6-基 }-6,7-二氢 -2Η-吡 喃并 [3,4-c]吡咯 -4-酮 66b作原料， 按照本发明实施例 66第三步所述的相同方式使 得该原料与 Ν,Ν-二乙基 -1,2-乙二胺的反应， 得到标题化合物 4-(2-羟乙基 )小{4-[3- 甲基 -4-(6-甲基吡啶 -3-氧基) -苯氨基]-喹唑啉 -6-基 }-1Η-吡咯 -3-羧酸 -(2-乙氨基乙 基) -酰胺 84 (36 mg, 黄色固体）， 产率： 15 %。  The experimental steps of the first step to the third step of Example 66 of the present invention are repeated, except that the compound obtained in the second step is 2-{4-[3-methyl-4-(6-methyl-indenylpyridinium). -3-Oxo)-phenylamino]-quinazoline-.6-yl}-6,7-dihydro-2-indole-pyrano[3,4-c]pyrrol-4-one 66b as a starting material, according to the present The reaction of the starting material with hydrazine, hydrazine-diethyl-1,2-ethanediamine was carried out in the same manner as described in the third step of the invention to give the title compound 4-(2-hydroxyethyl). [3-methyl-4-(6-methylpyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-1Η-pyrrole-3-carboxylic acid-(2-ethylaminoethyl - amide 84 (36 mg, yellow solid), Yield: 15%.
MS m/z (ESI): 592 [M- l] MS m/z (ESI): 592 [M- l]
1HNMR (400MHz, DMSO-^): S 9.98(s, IH), 8.81(s, IH), 8.58(s, IH), 8.09-8.19(m, 4H)， 7.78-7.91(m, 3H), 7.48(s, 1H)， 7.24(s, 2H), 6.99(d, IH, J=8.0), 4.79(s, IH), 3.65(t, 2H), 3.40(t, 2H), 2.74-2.90(m, 8H), 2.45(s, 3H), 2.23(s, 3H), 1.08(t, 6H) 实施例 85 1 HNMR (400MHz, DMSO- ^) : S 9.98 (s, IH), 8.81 (s, IH), 8.58 (s, IH), 8.09-8.19 (m, 4H), 7.78-7.91 (m, 3H), 7.48(s, 1H), 7.24(s, 2H), 6.99(d, IH, J=8.0), 4.79(s, IH), 3.65(t, 2H), 3.40(t, 2H), 2.74-2.90( m, 8H), 2.45(s, 3H), 2.23(s, 3H), 1.08(t, 6H) Example 85
「3-氯 -4-(3-氟苄氧基) -苯基 1-{6-「1-(2-甲氧基乙基 MH-吡咯 -3-基 1-喹唑啉 -4- 基 胺  "3-Chloro-4-(3-fluorobenzyloxy)-phenyl 1-{6-"1-(2-methoxyethyl-MH-pyrrol-3-yl-1-quinazolin-4-yl) Amine
Figure imgf000117_0002
Figure imgf000117_0002
重复本发明实施 51所述的实验步骤， 不同的是以实施例 42所得的化合物 [3- 氯 -4- (吡啶 -2-甲氧基) -苯基 ]-(6-吡咯 -1-基-喹唑啉 -4-基) -胺 42作为原料， 按照实施 例 51所述的方式， 进行该原料与 1-氯 -2-甲氧基乙烷的反应， 得到本标题产物 [3- 氯 -4-(3-氟苄氧基) -苯基 ]-{6-[1-(2-甲氧基乙基) -1H-吡咯 -3-基] -喹唑啉 -4-基 胺 85 ( lOO mg, 黄色固体）， 产率： 20% 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%
MS m/z (ESI): 503[M+ 1] MS m/z (ESI): 503 [M+ 1]
'HNMR (400MHZ, DMSO-d6): 69.87(s, 1H), 8.65(s, 1H), 8.49(s, 1H)， 8.07(s, 1H), 8.04(d, 1H, J=8.8), 7.80(d, 1H), 7.69(d, 1H, J=8.8), 7.48(m, 2H), 7.3 l(m, 3H), 7.18(t, 1H), 6.89(t, 1H), 6.70(s, 1H), 5.27(s, 2H), 4.10(t, 2H), 3.66(t, 2H), 3.28(s, 3H) 实施例 86  'HNMR (400MHZ, DMSO-d6): 69.87 (s, 1H), 8.65 (s, 1H), 8.49 (s, 1H), 8.07 (s, 1H), 8.04 (d, 1H, J = 8.8), 7.80 (d, 1H), 7.69(d, 1H, J=8.8), 7.48(m, 2H), 7.3 l(m, 3H), 7.18(t, 1H), 6.89(t, 1H), 6.70(s, 1H), 5.27(s, 2H), 4.10(t, 2H), 3.66(t, 2H), 3.28(s, 3H) Example 86
Γ3-氯 -4-(3-氟苄氧基) -苯基 l-{6-fl-(2-吗啉 -4-乙基) -1H-吡咯 -3-基 1 -喹唑啉 -4- 基 胺  3-chloro-4-(3-fluorobenzyloxy)-phenyl 1-{6-fl-(2-morpholin-4-ethyl)-1H-pyrrol-3-yl-1-quinazoline-4 - alkamine
Figure imgf000118_0001
Figure imgf000118_0001
重复本发明实施 51所述的实验歩骤， 不同的是以实施例 42所得的化合物 [3- 氯 -4- (吡啶 -2-甲氧基) -苯基 ]-(6-B比咯 -1-基-喹唑啉 -4-基) -胺 42作为原料， 按照实施 例 51所述的方式， 进行该原料与 1-(2-氯乙基) -吗啉盐酸盐的反应， 得到本标题产 物 [3-氯 -4-P-氟苄氧基) -苯基 ]-{6-[1-(2-吗啉 -4-乙基) -1H-吡咯 -3-基] -喹唑啉 -4-基 胺 （6 mg， 黄色固体） 86， 产率： 7.2%。  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. The title product [3-chloro-4-P-fluorobenzyloxy)-phenyl]-{6-[1-(2-morpholin-4-ethyl)-1H-pyrrol-3-yl]-quin Oxazolin-4-ylamine (6 mg, yellow solid) 86, Yield: 7.2%.
MS m/z (ESI): 559 [M+ 1] MS m/z (ESI): 559 [M+ 1]
ifiNMR (400MHz, CDC13): 88.70(s, 1H), 7.92(d, 1H), 7.83(m, 3H), 7.54(m, 2H), 7.34(m, 1H), 7.23(m, 2H), 7.09(s, 1H), 6.99(m, 2H), 6.77(m, 1H), 6.52(m, 1H), 5.14(s, 2H), 4.03(t, 2H), 3.71(t, 4H), 2.75(t, 2H), 2.49(t, 4H) 实施例 87 IfiNMR (400MHz, CDC13): 88.70(s, 1H), 7.92(d, 1H), 7.83(m, 3H), 7.54(m, 2H), 7.34(m, 1H), 7.23(m, 2H), 7.09 (s, 1H), 6.99(m, 2H), 6.77(m, 1H), 6.52(m, 1H), 5.14(s, 2H), 4.03(t, 2H), 3.71(t, 4H), 2.75( t, 2H), 2.49(t, 4H) Example 87
5-{4-|~3-氯 -4-(3-氟苄氧基) -苯氨基 1-喹唑啉 -6基 μΐΗ-吡咯 -2-羧酸 -(2-吗啉 -4- 乙基) -酰胺  5-{4-|~3-chloro-4-(3-fluorobenzyloxy)-phenylamino-1-quinazolin-6-ylpyrrole-pyrrole-2-carboxylic acid-(2-morpholin-4-ethyl -amide
Figure imgf000118_0002
Figure imgf000118_0002
重复本发明实施例 72第一步至第二步的实验歩骤， 不同的是以实施例 72第 一步所得的化合物 5-{4-[3-氯 -4-(3-氟苄氧基) -苯氨基] -喹唑啉 -6-基}-111-吡咯 -2-羧 酸 72a作为原料， 按照实施例 72第二步所述的方式， 进行该原料与 2-吗啉 -4-基- 乙胺的反应，得到本标题产物 5-{4-[3-氯 -4-(3-氟苄氧基) -苯氨基]-喹唑啉 -6基}-111- 吡咯 -2-羧酸 -(2-吗啉 -4-乙基) -酰胺 87 (20 mg， 白色固体）， 产率： 33 %。 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%.
MS mix (ESI): 601 [M+ l] MS mix (ESI): 601 [M+ l]
1HNMR (400MHz, DMSO- d6): 5ll.85(s, IH), 9.91 (s, IH), 8.64(s, IH), 8.56(s, IH), 8.04(s, IH), 7.93(d, IH, J=8.4), 7.78(m, 2H), 7.47(q, IH), 7.30(m, 3H)， 7.18(t, IH), 7.06(s, IH), 6.98(s, IH), 6.36(s, IH), 5.26(s, 2H), 3.26(t, 2H), 3.20(s, 4H), 2.29(t, 2H), 2.21(s, 4H) 实施例 88 1H NMR (400MHz, DMSO-d 6 ): 5ll.85 (s, IH), 9.91 (s, IH), 8.64 (s, IH), 8.56 (s, IH), 8.04 (s, IH), 7.93 (d , IH, J=8.4), 7.78(m, 2H), 7.47(q, IH), 7.30(m, 3H), 7.18(t, IH), 7.06(s, IH), 6.98(s, IH), 6.36(s, IH), 5.26(s, 2H), 3.26(t, 2H), 3.20(s, 4H), 2.29(t, 2H), 2.21(s, 4H) Example 88
2-(1-ί4-Γ3-氯 -4- (吡啶 -2-甲氧基)-苯氨基 1-喹唑啉 -6-基 4-吗啉 -4-甲基 -IH-吡咯  2-(1-ί4-Γ3-chloro-4-(pyridine-2-methoxy)-phenylamino-1-quinazoline-6-yl 4-morpholine-4-methyl-IH-pyrrole
-3-基) -乙醇  -3-yl)-ethanol
Figure imgf000119_0001
Figure imgf000119_0001
重复本发明实施例 61第一步所述的实验歩骤， 不同的是以实施例 58所得的 化合物 1-{4-[3-氯 -4- (吡啶 -2-甲氧基) -苯氨基] -喹唑啉 -6-基}-4--4-(2-羟基) -1H-吡咯 -3-基] -吗啉 -4-甲酮 58作原料， 按照本发明实施例 61第一步所述的相同方式使得 该原料与氢化铝锂反应，得到标题化合物 2-(1-{4-[3-氯 -4- (吡啶 -2-甲氧基) -苯氨基] - 喹唑啉 -6-基 4-吗啉 -4-甲基 -1H-吡咯 -3-基) -乙醇 88 (30 mg, 棕色固体）， 产率： 44%。  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%.
MS m/z (ESI): 556 [M+ l]  MS m/z (ESI): 556 [M+ l]
^MR (400MHz, DMSO- d6): δ 9.82(s, IH), 8.61(d, IH, J=4.4), 8,54(s, 2H), 8.11(d， IH, J=8.8), 8.02(s, IH), 7.89(t, IH), 7.83(d, IH, J=8.8), 7.74(d, IH, J=8.8), 7.60(d, 1H， J=7.6), 7.44(s, IH), 7.38(m, 2H), 7.31(d, IH, J=8.8), 5.3 l(s, 2H), 3.63(t, 2H), 3.58(s, 4H), 3.36(s, 2H), 2.68(t, 3H), 2.42 (s, 4H) 实施例 89 ^MR (400MHz, DMSO-d 6 ): δ 9.82(s, IH), 8.61(d, IH, J=4.4), 8,54(s, 2H), 8.11(d, IH, J=8.8), 8.02(s, IH), 7.89(t, IH), 7.83(d, IH, J=8.8), 7.74(d, IH, J=8.8), 7.60(d, 1H, J=7.6), 7.44(s , IH), 7.38(m, 2H), 7.31(d, IH, J=8.8), 5.3 l(s, 2H), 3.63(t, 2H), 3.58(s, 4H), 3.36(s, 2H) , 2.68(t, 3H), 2.42 (s, 4H) Example 89
{4-(2-羟乙基 )-1-Γ4-(1-苯乙氨基 喹唑啉 -6-基 1-lH-吡咯 -3-基 吗啉 -4-甲酮  {4-(2-Hydroxyethyl)-1-indol-4-(1-phenylethylaminoquinazolin-6-yl 1-lH-pyrrole-3-ylmorpholine-4-methanone
Figure imgf000119_0002
Figure imgf000119_0002
重复本发明实施例 77第一步至第三步所述的实验步骤，不同的是以实施例 77 所得的化合物 2-[4-(1-苯乙氨基) -喹唑啉 -6-基] -6,7-二氢 -2H-吡喃并 [3,4-c]吡咯 -4-酮 77b作原料， 按照本发明实施例 77第三步所述的相同方式使得该原料与吗啉的反 应， 得到标题化合物 {4-(2-羟乙基 )-1-[4-(1-苯乙氨基) -喹唑啉 -6-基] -1H-吡咯 -3-基 吗啉—4_甲酮 89 ( HO mg, 黄色固体）， 产率： 30%。 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. Reaction to give the title compound {4-(2-hydroxyethyl)-1-[4-(1-phenylethylamino)-quinazolin-6-yl]-1H-pyrrol-3-yl Morpholine-4-methanone 89 (HO mg, yellow solid), Yield: 30%.
MS m/z (ESI): 472[M+ 1] MS m/z (ESI): 472 [M+ 1]
1HNMR (400MHz, DMSO- d6): δ 8.57(s, IH), 8.5 l(d, IH, J=7.6), 8.40(s, IH), 8.08(d, IH, J=8.4), 7.77(d, IH, J=8.8), 7.67(s, IH), 7.45(m, 3H), 7.33(t, 2H), 7.23(t, IH), 5.64(m, IH), 4.70(t, IH), 3.60(s, 10H), 2.69(t, 2H), 1.63(d, 3H, J=6.8) 实施例 90 ■1H NMR (400MHz, DMSO-d 6 ): δ 8.57 (s, IH), 8.5 l (d, IH, J = 7.6), 8.40 (s, IH), 8.08 (d, IH, J = 8.4), 7.77 ( d, IH, J=8.8), 7.67(s, IH), 7.45(m, 3H), 7.33(t, 2H), 7.23(t, IH), 5.64(m, IH), 4.70(t, IH) , 3.60(s, 10H), 2.69(t, 2H), 1.63(d, 3H, J=6.8) Example 90 ■
-(2-羟乙基 )-1-Γ4-(1-苯乙氨基 )-喹唑啉 -6-基 1 -1Η-吡咯 -3-基 }-(4-甲基 -哌嗪 -1- 基) -甲酮  -(2-hydroxyethyl)-1-indol-4-(1-phenylethylamino)-quinazolin-6-yl-1 -1indole-pyrrol-3-yl}-(4-methyl-piperazin-1- Ketone
Figure imgf000120_0001
Figure imgf000120_0001
重复本发明实施例 77第一步至第三步所述的实验步骤，不同的是以实施例 77 所得的化合物 2-[4-(1-苯乙氨基) -喹唑啉 -6-基] -6,7-二氢 -2Η-吡喃并 [3,4-c]吡咯 -4-酮 77b作原料， 按照本发明实施例 77第三步所述的相同方式使得该原料与 1-甲基哌 嗪的反应，得到标题化合物 {4-(2-羟乙基 )-1-[4-(1-苯乙氨基)-喹唑啉 -6-基] -1H-吡咯 -3-基 }- (4-甲基 -哌嗪小基) -甲酮 90 ( 130 mg, 黄色固体）， 产率： 34%。  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%.
MS m/z (ESI): 485[M+ 1] MS m/z (ESI): 485 [M+ 1]
^MR (400MHz, DMSO- d6): 6 8.62(s, IH), 7.89(s, IH), 7.87(d, IH), 7.69(dd, IH, J=8.8), 7.48(d, 2H), 7.35(t, 2H), 7.28(d, IH), 7.15(s, IH), 7.03(s, IH), 6.61(s, IH), 5.70(m, IH), 3.78(m, 6H), 3.48(s, IH), 2.80(t, 2H), 2.48(t, 4H), 2.33(s, 3H), 1.73(d, 3H, J=6.8) 实施例 91 ^MR (400MHz, DMSO-d 6 ): 6 8.62(s, IH), 7.89(s, IH), 7.87(d, IH), 7.69(dd, IH, J=8.8), 7.48(d, 2H) , 7.35(t, 2H), 7.28(d, IH), 7.15(s, IH), 7.03(s, IH), 6.61(s, IH), 5.70(m, IH), 3.78(m, 6H), 3.48(s, IH), 2.80(t, 2H), 2.48(t, 4H), 2.33(s, 3H), 1.73(d, 3H, J=6.8) Example 91
2-Π-Γ4-α -苯乙氨基) -喹唑啉 -6-基 1-4-哌啶 -1 -甲基 -1Η-吡咯 -3-基} -乙醇  2-Π-Γ4-α-phenethylamino)-quinazoline-6-yl 1-4-piperidine-1-1-methyl-1Η-pyrrole-3-yl}-ethanol
Figure imgf000120_0002
Figure imgf000120_0002
在 25 mL茄形瓶中加入氢化铝锂 （36 mg， 0.957 mmol)和 3 mL四氢呋喃， 室温下搅拌， 逐渐滴加化合物 {4-(2-羟乙基 )-1-[4-(1-苯乙氨基) -喹唑啉 -6-基] -IH-吡 咯 -3-基} -哌啶 -1-甲酮 77 ( 150 mg， 0.319 mmol)的 3 mL四氢呋喃溶液， 溶液中有 大量气泡产生， 并有粘稠状固体产生， 反应液呈黄色。 将反应液加热至 50°C， 搅 拌 4小时后反应完毕， 用冰浴冷却反应液， 慢慢滴加甲醇， 反应液呈澄清透明。 用减压柱冲洗， 浓縮反应液， 得到的固体进一步通过 TLC板分离纯化， 得到标题 产物 2-{1-[4-(1-苯乙氨基) -喹唑啉 -6-基] -4-哌啶 -1-甲基 -1H-吡咯 -3-基} -乙醇 91 (40 mg， 黄色固体）， 产率： 27.5 %。 Add lithium aluminum hydride (36 mg, 0.957 mmol) and 3 mL of tetrahydrofuran to a 25 mL eggplant bottle. Stir at room temperature, gradually add the compound {4-(2-hydroxyethyl)-1-[4-(1-phenylethylamino)-quinazolin-6-yl]-IH-pyrrol-3-yl} Piperidine-1-ketone 77 (150 mg, 0.319 mmol) in 3 mL of tetrahydrofuran. A large amount of bubbles were formed in the solution, and a viscous solid was produced. The reaction mixture was yellow. The reaction solution was heated to 50 ° C, stirred for 4 hours, and the reaction was completed. The reaction solution was cooled with an ice bath, and methanol was slowly added dropwise, and the reaction mixture was clear and transparent. The mixture was washed with a vacuum column, and the mixture was evaporated. mjjjjjjjjjjjjjjjjjjjjjj - piperidin-1-methyl-1H-pyrrol-3-yl}-ethanol 91 (40 mg, yellow solid), yield: 27.5 %.
MS m/z (ESI): 456[M+ 1]  MS m/z (ESI): 456 [M+ 1]
'HNMR (400MHZ, DMSO- d6): δ 8.79(s, IH), 8.75(s, IH), 8.39(s, IH), 8.01(d, IH, J=8.4), 7.78(d, 2H, J=6.8), 7.50(m, 3H), 7.3 l(t, 2H), 7.22(t, IH), 5.64(m, IH), 4.07(s: 2H), 3.67(q, 2H), 3.17(m, 4H), 3.11(t, 2H), 1.74(s, 4H), 1.65(d， 3H, J-6.8), 1.43(m, 2H) 实施例 92 'HNMR (400MHZ, DMSO- d 6 ): δ 8.79 (s, IH), 8.75 (s, IH), 8.39 (s, IH), 8.01 (d, IH, J = 8.4), 7.78 (d, 2H, J=6.8), 7.50(m, 3H), 7.3 l(t, 2H), 7.22(t, IH), 5.64(m, IH), 4.07(s : 2H), 3.67(q, 2H), 3.17( m, 4H), 3.11(t, 2H), 1.74(s, 4H), 1.65 (d, 3H, J-6.8), 1.43 (m, 2H) Example 92
2—Π-Γ4-α-苯乙氨基) -喹唑啉 -6-基 1-4-吡咯垸 -1-甲基 -IH-吡咯 -3-基 乙醇  2-Π-Γ4-α-phenethylamino)-quinazoline-6-yl 1-4-pyrrole-1-methyl-IH-pyrrole-3-ylethanol
Figure imgf000121_0001
Figure imgf000121_0001
重复本发明实施例 91第一步所述的实验步骤， 不同的是以实施例 78所得的 化合物 {4-(2-羟乙基 )小[4-(1-苯乙氨基) -喹唑啉 -6-基] -ΊΗ-吡咯 -3-基 吡咯垸 -1-甲 酮 78作原料， 按照本发明实施例 90第一步所述的相同方式使得该原料与氢化铝 锂反应， 得到标题化合物 2-{1-[4-(1-苯乙氨基)-喹唑啉 -6-基] -4-吡咯烷 -1-甲基 -1H- 吡咯 -3-基} -乙醇 92 (60 mg， 黄色固体）， 产率： 31 %。  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. 2-{1-[4-(1-Phenylethylamino)-quinazolin-6-yl]-4-pyrrolidin-1-yl-1H-pyrrol-3-yl}-ethanol 92 (60 mg, Yellow solid), Yield: 31%.
MS m/z (ESI): 442 [M+ 1] MS m/z (ESI): 442 [M+ 1]
1HNMR (400MHz, DMSO- d6): δ 8.91(s, IH), 8.82(s, IH), 8.34(s, 1H)， 8.00(dd, IH, J=8.8), 7.88(s, IH), 7.77(d, IH, J=8.8), 7.5 l(m, 3H), 7.3 l(t, 2H), 7.2 l(t, IH), 5.64(m, IH), 4.20(s, 2H), 3.66(t, 2H), 3.29(m, 4H), 2.74(t, 2H), 1.94(s, 4H), 1.66(d, 3H, J=6.8) 实施例 93 1 H NMR (400 MHz, DMSO-d 6 ): δ 8.91 (s, IH), 8.82 (s, IH), 8.34 (s, 1H), 8.00 (dd, IH, J = 8.8), 7.88 (s, IH) , 7.77(d, IH, J=8.8), 7.5 l(m, 3H), 7.3 l(t, 2H), 7.2 l(t, IH), 5.64(m, IH), 4.20(s, 2H), 3.66(t, 2H), 3.29(m, 4H), 2.74(t, 2H), 1.94(s, 4H), 1.66(d, 3H, J=6.8) Example 93
4-(2-羟乙基 )-l-「4-(l-苯乙氨基) -喹唑啉 -6-基 1-lH-吡咯 -3-羧酸 -(2-B比咯垸 -1-基- 乙基 V酰胺  4-(2-hydroxyethyl)-l-"4-(l-phenylethylamino)-quinazolin-6-yl 1-lH-pyrrole-3-carboxylic acid-(2-B ratio 垸-1 -yl-ethyl V amide
Figure imgf000121_0002
Figure imgf000121_0002
重复本发明实施例 77第一步至第三步所述的实验步骤，不同的是以实施例 77 所得的化合物 2-[4-(1 -苯乙氨基) -喹唑啉 -6-基] -6,7-二氢 -2H-吡喃并 [3,4-c]吡咯 -4-酮 77b作原料， 按照本发明实施例 77第三步所述的相同方式使得该原料与 2-吡咯垸 基 -1-基-乙胺的反应， 得到标题化合物 4-(2-羟乙基 )-1-[4-(1-苯乙氨基)-喹唑啉 -6- 基] -1H-吡咯 -3-羧酸 -(2-吡咯烷 -1-基-乙基) -酰胺 93 ( 50 mg, 黄色固体）， 产率： 32The experimental steps described in the first step to the third step of the embodiment 77 of the present invention are repeated, except that the embodiment 77 is The obtained compound 2-[4-(1-phenylethylamino)-quinazolin-6-yl]-6,7-dihydro-2H-pyrano[3,4-c]pyrrol-4-one 77b The starting material was reacted with 2-pyrrolidino-1-yl-ethylamine in the same manner as described in the third step of Example 77 to give the title compound 4-(2-hydroxyethyl)-1. -[4-(1-phenylethylamino)-quinazolin-6-yl]-1H-pyrrole-3-carboxylic acid-(2-pyrrolidin-1-yl-ethyl)-amide 93 (50 mg, Yellow solid), Yield: 32
%。 %.
MS m/z (ESI): 490[M+ 1]  MS m/z (ESI): 490 [M+ 1]
'HNMR (400MHz, DMSO- d6): δ 8.8 l(m, 2H), 8.40(m, 3H), 8.04(d, IH, J=8.8), 7.78(d, IH, J=8.8), 7.48(m, 3H)， 7.32(t, 2H), 7.22(t, IH), 5.64(m, IH), 4.75(s, IH), 3.64(t, 2H), 3.57(q, 2H), 3.22(m, 6H), 2.90(t， 2H), 1.93(s, 4H), 1.65(d, 3H, J=7.2) 实施例 94 'HNMR (400MHz, DMSO-d 6 ): δ 8.8 l (m, 2H), 8.40 (m, 3H), 8.04 (d, IH, J = 8.8), 7.78 (d, IH, J = 8.8), 7.48 (m, 3H), 7.32(t, 2H), 7.22(t, IH), 5.64(m, IH), 4.75(s, IH), 3.64(t, 2H), 3.57(q, 2H), 3.22( m, 6H), 2.90 (t, 2H), 1.93 (s, 4H), 1.65 (d, 3H, J = 7.2) Example 94
4-f2-羟乙基 )-l-「4- ( 苯乙氨基)-喹唑啉 -6-基 1-m-吡咯 -3-羧酸 -(2-哌啶 -1-乙基) - 酰胺  4-f2-hydroxyethyl)-l-"4-(phenylethylamino)-quinazolin-6-yl 1-m-pyrrole-3-carboxylic acid-(2-piperidin-1-ethyl)- Amide
Figure imgf000122_0001
Figure imgf000122_0001
一 重复本发明实施例 77第一步至第三步所述的实验步骤，不同的是以实施例 77 所得的化合物 2-[4-(1-苯乙氨基)-喹唑啉 -6-基] -6,7-二氢 -2H-吡喃并 [3,4-c]吡咯 -4-酮 77b作原料， 按照本发明实施例 77第三步所述的相同方式使得该原料与 2-哌啶基 -1-基-乙胺的反应， 得到标题化合物 4-(2-羟乙基 )-1 -[4-(1 -苯乙氨基)-喹唑啉 -6- 基] -1H-吡咯 -3-羧酸 -(2-哌啶 -1-乙基) -酰胺 94 ( 50 mg, 黄色固体）， 产率： 25 %。 MS m/z (ESI): 513[M+ 1]  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. Reaction of piperidinyl-1-yl-ethylamine to give the title compound 4-(2-hydroxyethyl)-1 -[4-(1-phenylethylamino)-quinazolin-6-yl]-1H- Pyrrole-3-carboxylic acid-(2-piperidin-1-ethyl)-amide 94 (50 mg, yellow solid), Yield: 25 %. MS m/z (ESI): 513 [M+ 1]
1HNMR (400MHz, DMSO- d6): δ 8.82(s, IH), 8.76(d, IH, J-6.0), 8.45(m, 3H), 8.04(d, IH, J=7.6), 7.79(d, IH, J=8.0), 7.5 l(m, 3H), 7.3 l(t, 2H), 7.22(t, IH), 5.64(m, IH), 4.75(s, IH), 3.64(t, 4H), 3.49(m, 2H), 3.20(t, 2H), 2.90(t, 4H), 1.82(m, 4H), 1.66(d 3H, 1=6.0), 1.23(m, 2H) 实施例 95 1 H NMR (400 MHz, DMSO-d 6 ): δ 8.82 (s, IH), 8.76 (d, IH, J-6.0), 8.45 (m, 3H), 8.04 (d, IH, J = 7.6), 7.79 ( d, IH, J=8.0), 7.5 l(m, 3H), 7.3 l(t, 2H), 7.22(t, IH), 5.64(m, IH), 4.75(s, IH), 3.64(t, 4H), 3.49 (m, 2H), 3.20 (t, 2H), 2.90 (t, 4H), 1.82 (m, 4H), 1.66 (d 3H, 1 = 6.0), 1.23 (m, 2H) Example 95
4-(2-羟乙基 )小「4-(1-苯乙氨基) -喹唑啉 -6-基 1-lH-吡咯 -3-羧酸 -(2-甲氧基乙基) - 酰胺  4-(2-hydroxyethyl) small "4-(1-phenylethylamino)-quinazolin-6-yl 1-lH-pyrrole-3-carboxylic acid-(2-methoxyethyl)-amide
Figure imgf000122_0002
重复本发明实施例 77第一步至第三步所述的实验步骤，不同的是以实施例 77 所得的化合物 2-[4-(1-苯乙氨基) -喹唑啉 -6-基] -6,7-二氢 -2H-吡喃并 [3,4-c]吡咯 -4-酮 77b作原料， 按照本发明实施例 77第三步所述的相同方式使得该原料与 2-甲氧基 乙胺的反应， 得到标题化合物 4-(2-羟乙基 )-1-[4-(1-苯乙氨基) -喹唑啉 -6-基] -1H-吡 咯 -3-羧酸 -(2-甲氧基乙基) -酰胺 95 (50 mg, 黄色固体）， 产率： 28%。
Figure imgf000122_0002
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%.
MS m/z (ESI): 460[M+ 1] MS m/z (ESI): 460 [M+ 1]
1HNMR (400MHz, DMSO- d6): δ 8.76(d, IH, J=7.2), 8.68(s, IH), 8.44(s, IH), 8.09(s, IH), 8.02(t, 2H), 7.8 l(d, IH, J=8.8), 7.47(d, 2H, J=7.6), 7.40(s, 1H)， 7.33(t, 2H), 7.23(t, IH), 5.66(m, IH), 4.80(s, IH), 3.64(t, 2H), 3.45(t, 2H), 3.39(t, 2H), 3.27(s, 3H), 2.89(t，. 2H)， 1.64(d, 3H, J=6.8) 实施例 96 1HNMR (400MHz, DMSO- d 6) : δ 8.76 (d, IH, J = 7.2), 8.68 (s, IH), 8.44 (s, IH), 8.09 (s, IH), 8.02 (t, 2H), 7.8 l(d, IH, J=8.8), 7.47(d, 2H, J=7.6), 7.40(s, 1H), 7.33(t, 2H), 7.23(t, IH), 5.66(m, IH) , 4.80(s, IH), 3.64(t, 2H), 3.45(t, 2H), 3.39(t, 2H), 3.27(s, 3H), 2.89(t,. 2H), 1.64(d, 3H, J = 6.8) Example 96
4-(2-羟乙基 )-1-「4-(1-苯乙氨基)-喹唑啉 -6-基 1-lH-吡咯 -3-羧酸 -(2-吗啉 -4-乙基) - 酰胺  4-(2-hydroxyethyl)-1-"4-(1-phenylethylamino)-quinazolin-6-yl 1-lH-pyrrole-3-carboxylic acid-(2-morpholin-4-ethyl Base) - amide
Figure imgf000123_0001
Figure imgf000123_0001
重复本发明实施例 77第一步至第三步所述的实验步骤，不同的是以实施例 77 所得的化合物 2-[4-(1-苯乙氨基)-喹唑啉 -6-基] -6,7-二氢 -2H-吡喃并 [3,4-c]吡咯 -4-酮 77b作原料， 按照本发明实施例 77第三步所述的相同方式使得该原料与的 2-吗啉 -4-基 -乙胺反应，得到标题化合物 4-(2-羟乙基 )-1-[4-(1-苯乙氨基)-喹唑啉 -6-基] -1H- 吡咯 -3-羧酸 -(2-吗啉 -4-乙基) -酰胺 96 (85 mg, 黄色固体）， 产率： 42.5%。  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%.
MS m/z (ESI): 515[M+ 1] MS m/z (ESI): 515 [M+ 1]
iHNMR (400MHz, DMSO- d6): δ 8.66(m, 2H), 8.41(s, IH), 8.00(m, 3H), 7.76(d, IH), 7.47(d, 2H， J=7.6), 7.39(s, IH), 7.33(t, 2H), 7.19(t, IH), 5.62(m, IH), 4.70(s, IH), 3.64(m， 8H), 2.89(t, 2H), 2.54(m， 6H), 1.64(d, 3H, J=6.8) 实施例 97 iHNMR (400MHz, DMSO- d 6) : δ 8.66 (m, 2H), 8.41 (s, IH), 8.00 (m, 3H), 7.76 (d, IH), 7.47 (d, 2H, J = 7.6), 7.39(s, IH), 7.33(t, 2H), 7.19(t, IH), 5.62(m, IH), 4.70(s, IH), 3.64(m, 8H), 2.89(t, 2H), 2.54 (m, 6H), 1.64 (d, 3H, J = 6.8) Example 97
4-(2-羟乙基 )-1-「4-α-苯乙氨基)-喹唑啉 -6-基 1-lH-吡咯 -3-羧酸 - 3-吗啉 -4-丙基) - 酰胺 01307 4-(2-Hydroxyethyl)-1-"4-α-phenethylamino)-quinazolin-6-yl 1-lH-pyrrole-3-carboxylic acid-3-morpholine-4-propyl) - amide 01307
Figure imgf000124_0001
Figure imgf000124_0001
重复本发明实施例 77第一歩至第三步所述的实验步骤，不同的是以实施例 77 所得的化合物 2-[4-(1-苯乙氨基)-喹唑啉 -6-基] -6,7-二氢 -2H-吡喃并 [3，4-c]吡咯- 4-酮 77b作原料， 按照本发明实施例 77第三步所述的相同方式使得该原料与的 2-吗啉 -4-基 -丙胺反应，得到标题化合物 4-(2-羟乙基 )-1-[4-(1-苯乙氨基) -喹唑啉 -6-基] -1H- 吡咯 -3-羧酸 -(2-吗啉 -4-丙基) -酰胺 97 ( 86 mg, 黄色固体）， 产率： 42%。  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%.
MS m/z (ESI): 529[M+ 1] MS m/z (ESI): 529 [M+ 1]
lBNMR (400MHz, DMSO- d6): δ 8.88(s, 2H), 8.39(s, 2H), 8.12(s, IH), 8.04(d, IH, J=8.4), 7.77(d, 1H， J=8.8), 7.5 l(m, 3H), 7.3 l(t, 2H), 7.2 l(t, IH), 5.64(m, IH), 4.83(s, IH), 3.70(m, 6H), 3.33(m, 2H), 2.89(m, 6H), 2.54(m, 2H), 1.84(m, 2H), 1.67(d， 3H, J=6.8) 实施例 98 lBNMR (400MHz, DMSO- d 6) : δ 8.88 (s, 2H), 8.39 (s, 2H), 8.12 (s, IH), 8.04 (d, IH, J = 8.4), 7.77 (d, 1H, J = 8.8), 7.5 l(m, 3H), 7.3 l(t, 2H), 7.2 l(t, IH), 5.64(m, IH), 4.83(s, IH), 3.70(m, 6H), 3.33 (m, 2H), 2.89 (m, 6H), 2.54 (m, 2H), 1.84 (m, 2H), 1.67 (d, 3H, J = 6.8) Example 98
2-{4-C4甲基哌嗪 -1-甲基 ΐ-Γ4-(1-苯乙氨基) -喹唑啉 -6-基 1-m-吡咯 -3-基} -乙醇  2-{4-C4methylpiperazine-1-methylindole-indole 4-(1-phenylethylamino)-quinazoline-6-yl 1-m-pyrrole-3-yl}-ethanol
Figure imgf000124_0002
Figure imgf000124_0002
重复本发明实施例 91第一步所述的实验步骤， 不同的是以实施例 90所得的 化合物 {4-(2-羟乙基 )-1-[4-(1-苯乙氨基)-喹唑啉 -6-基] -1H-吡咯 -3-基 }-(4-甲基 -哌嗪 -1-基) -甲酮 90作原料，按照本发明实施例 91第一步所述的相同方式使得该原料与 氢化铝锂反应， 得到标题化合物 2-{4-(4甲基哌嗪 -1-甲基) -1-[4-(1-苯乙氨基) -喹唑 啉 -6-基] -1H-吡咯 -3-基} -乙醇 98 (90 mg, 黄色固体）， 产率： 91 %。  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%.
MS m/z (ESI): 471 [M+ 1] MS m/z (ESI): 471 [M+ 1]
!HNMR (400MHz, DMSO- d6): δ 8.68(s, IH), 8.62(s, IH), 8.37(s, IH), 8.01 (dd, IH, J=8.8), 7.73(d, IH, J-8.8), 7.47(m, 4H), 7.32(t, 2H), 7.22(t, IH), 5.64(m, IH), 3.63(t, 2H), 3.52(s, 2H), 2.85(m, 4H), 2.67(m, 6H), 1.65(d， 3H, J=6.8) 实施例 99 !HNMR (400MHz, DMSO-d 6 ): δ 8.68(s, IH), 8.62(s, IH), 8.37(s, IH), 8.01 (dd, IH, J=8.8), 7.73(d, IH, J-8.8), 7.47(m, 4H), 7.32(t, 2H), 7.22(t, IH), 5.64(m, IH), 3.63(t, 2H), 3.52(s, 2H), 2.85(m , 4H), 2.67 (m, 6H), 1.65 (d, 3H, J = 6.8) Example 99
Γ1,4Ί二哌啶基 -Γ-基 -Π-ί4-Γ3-氯 -4- (吡啶 -2-甲氧基) -苯氨基 1-喹唑啉 -6-基 4-(2- 羟乙基 MH-吡咯 -3-yH-甲酮
Figure imgf000125_0001
Γ1,4ΊDipiperidinyl-fluorenyl-yl-Π-ί4-Γ3-chloro-4-(pyridin-2-methoxy)-phenylamino-1-quinazolin-6-yl 4-(2-hydroxyethyl MH-pyrrole-3-yH-methanone
Figure imgf000125_0001
重复本发明实施例 53第一步所述的实验步骤， 不同的是以实施例 47所得的 化合物 2-{4-[3-氯 -4- (吡啶 -2-甲氧基) -苯氨基]-喹唑啉 -6-基}-6,7-二氢 -2H-吡喃 [3,4-c] 吡咯 -4-酮 47作原料， 按照本发明实施例 53第一步所述的相同方式使得该原料与 [1,4']二哌啶的反应， 得到标题化合物 [1,4']二哌啶基 -Γ-基 -[1-{4-[3-氯 -4- (吡啶 -2-甲 氧基) -苯氨基]-喹唑啉 -6-基}-4-(2-羟乙基 )-1Η-吡咯 -3- yl]-甲酮 99 ( 120 mg， 黄色固 体）， 产率： 43 %。  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)-1Η-pyrrole-3-yl]-methanone 99 (120 mg, yellow solid) , Yield: 43%.
MS m/z (ESI): 667[M+ 1] MS m/z (ESI): 667 [M+ 1]
!HNMR (400MHz, DMSO- d6): δ 10.20(s, IH), 8.90(s, IH), 8.61(d, 1H， J-4.4), 8.58(s, IH), 8.15(m, 2H), 7.88(m, 4H), 7.60(d, IH, J=8.0), 7.55(s, IH), 7.38(t, IH), 7.29(d, IH, J=8.8), 5.3 l(s, 2H), 4.7 l(t, IH), 3.60(q, 2H), 3.39(m, 4H)， 2.93 (m, 5H), 2.69(t， 2H), 1.82(m, 6H), 1.69(m, 4H) 实施例 100 ! HNMR (400MHz, DMSO- d 6 ): δ 10.20 (s, IH), 8.90 (s, IH), 8.61 (d, 1H, J-4.4), 8.58 (s, IH), 8.15 (m, 2H) , 7.88(m, 4H), 7.60(d, IH, J=8.0), 7.55(s, IH), 7.38(t, IH), 7.29(d, IH, J=8.8), 5.3 l(s, 2H ), 4.7 l(t, IH), 3.60(q, 2H), 3.39(m, 4H), 2.93 (m, 5H), 2.69(t, 2H), 1.82(m, 6H), 1.69(m, 4H) Embodiment 100
2-M-吗啉 -4-甲基小 Γ4-ί1-苯乙氨基)-喹唑啉 -6-基 1-1H-吡咯 -3-基 乙醇  2-M-morpholine -4-methyl oxime 4-ί1-phenethylamino)-quinazoline-6-yl 1-1H-pyrrole-3-ylethanol
Figure imgf000125_0002
Figure imgf000125_0002
重复本发明实施例 91第一步所述的实验歩骤， 不同的是以实施例 89所得的 化合物 {4-(2-羟乙基 )-1-[4-(1-苯乙氨基) -喹唑啉 -6-基] -1H-吡咯 -3-基 吗啉 -4-甲酮 89作原料，按照本发明实施例 91第一步所述的相同方式使得该原料与氢化铝锂反 应， 得到标题化合物 2-{4-吗啉 -4-甲基 -1-[4-(1-苯乙氨基) -喹唑啉 -6-基] -1H-吡咯 -3- 基 乙醇 100 ( 95mg， 黄色固体）， 产率： 85 %。  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. The title compound 2-{4-morpholin-4-methyl-1-[4-(1-phenylethylamino)-quinazolin-6-yl]-1H-pyrrol-3-ylethanol 100 (95 mg, Yellow solid), Yield: 85 %.
MS m/z (ESI): 458 [M+ l] MS m/z (ESI): 458 [M+ l]
1HNMR (400MHz, DMSO- d6): δ 8.79(s, 1H)， 8.70(s, IH), 8.41(s, IH), 8.01(d, IH, J=8.8), 7.77(d, IH, J=8.8), 7.69(s, IH), 7.49(d, 3H), 7.32(t, 2H), 7.22(t, IH), 5.65(m, IH), 3.97(s, 2H), 3.78(m, 4H), 3.66(t, 2H), 3.02(m, 4H), 2.74(t, 2H), 1.65(d， 3H, 1=6.0) 实施例 101 1 H NMR (400 MHz, DMSO-d 6 ): δ 8.79 (s, 1H), 8.70 (s, IH), 8.41 (s, IH), 8.01 (d, IH, J = 8.8), 7.77 (d, IH, J=8.8), 7.69(s, IH), 7.49(d, 3H), 7.32(t, 2H), 7.22(t, IH), 5.65(m, IH), 3.97(s, 2H), 3.78(m 4H), 3.66(t, 2H), 3.02(m, 4H), 2.74(t, 2H), 1.65(d, 3H, 1=6.0) Example 101
1-Γ4-(3-氯 -4-氟-苯氨基) -喹唑啉 -6-基 l-4-(2-羟乙基 MH-吡咯 -3-羧酸 -(2-甲氧基 乙基) -酰胺
Figure imgf000126_0001
1-Γ4-(3-chloro-4-fluoro-phenylamino)-quinazolin-6-yl-1-(2-hydroxyethyl MH-pyrrole-3-carboxylic acid-(2-methoxyethyl) -amide
Figure imgf000126_0001
重复本发明实施例 81第一步至第二步所述的实验步骤，不同的是以实施例 81 第一步所得的化合物 2-[4-(3-氯 -4-氟-苯氨基) -喹唑啉 -6-基] -6,7-二氢 -2H-吡喃 [3,4-c] 吡咯 -4-酮 81a作原料，按照本发明实施例 81第二步所述的相同方式使得该原料与 2-甲氧基乙胺的反应， 得到标题化合物 1-[4-(3-氯 -4-氟-苯氨基) -喹唑啉 -6-基] -4-(2- 羟乙基) -1H-吡咯 -3-羧酸 -(2-甲氧基乙基) -酰胺 101 ( 130 mg, 黄色固体）， 产率： 60 %。  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 the second step of Example 81 of the present invention The reaction of the starting material with 2-methoxyethylamine afforded the title compound 1-[4-(3-chloro-4-fluoro-phenylamino)-quinazolin-6-yl]-4-(2-hydroxyl Ethyl) -1H-pyrrole-3-carboxylic acid-(2-methoxyethyl)-amide 101 (130 mg, yellow solid), yield: 60%.
MS m/z (ESI): 484[M+ 1]  MS m/z (ESI): 484 [M+ 1]
iHNMR (400MHz, DMSO- d6): δ 10.14(s, IH), 8.79(s, IH), 8.25(dd, IH, J=6.8), 8.19(d, IH, J=2.0), 8.10(d, IH, J=9.2), 8.01(t, 1H)， 7.89-7.94(m, 2H), 7.45(m, 2H), 4.80(s, IH), 3.67(t, 2H), 3.46(t, 2H), 3.40(m, 2H), 3.29(s, 3H), 2.90(t, 2H) 实施例 102 iHNMR (400MHz, DMSO- d 6) : δ 10.14 (s, IH), 8.79 (s, IH), 8.25 (dd, IH, J = 6.8), 8.19 (d, IH, J = 2.0), 8.10 (d , IH, J=9.2), 8.01(t, 1H), 7.89-7.94(m, 2H), 7.45(m, 2H), 4.80(s, IH), 3.67(t, 2H), 3.46(t, 2H ), 3.40 (m, 2H), 3.29 (s, 3H), 2.90 (t, 2H) Example 102
1-Γ4-(3-氯 -4-氟-苯氨基) -喹唑啉 -6-基 l-4-(2-羟乙基) -IH-吡咯 -3-羧酸 -(2-二乙氨 基乙基) -酰胺  1-Γ4-(3-chloro-4-fluoro-phenylamino)-quinazolin-6-yl-1-(2-hydroxyethyl)-IH-pyrrole-3-carboxylic acid-(2-diethyl) Aminoethyl)-amide
Figure imgf000126_0002
Figure imgf000126_0002
重复本发明实施例 81第一步至第二步所述的实验步骤，不同的是以实施例 81 第一步所得的化合物 2-[4-(3-氯 -4-氟-苯氨基) -喹唑啉 -6-基] -6,7-二氢 -2H-吡喃 [3,4-c] 吡咯 -4-酮 81a作原料，按照本发明实施例 81第二步所述的相同方式使得该原料与 Ν,Ν-二乙基 -1,2-乙二胺的反应，得到标题化合物 1-[4-(3-氯 -4-氟 -苯氨基)-喹唑啉 -6- 基] -4-(2-羟乙基 )-1Η-吡咯 -3-羧酸 -(2-二乙氨基乙基) -酰胺 102 ( 100 mg，黄色固体）， 产率： 43.29%  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 the second step of Example 81 of the present invention The title compound 1-[4-(3-chloro-4-fluoro-phenylamino)-quinazoline-6-yl is obtained by the reaction of m.p. 4-(2-hydroxyethyl)-1Η-pyrrole-3-carboxylic acid-(2-diethylaminoethyl)-amide 102 (100 mg, yellow solid), Yield: 43.29%
MS m/z (ESI): 526[M+ 1] MS m/z (ESI): 526 [M+ 1]
1HNMR (400MHz, DMSO- d6): δ 10.16(s, IH), 8.89(s, IH), 8.64(s, IH), 8.46(s, IH), 8.32(m, 2H), 8.13(d, IH, J=8.0), 8.02(m, IH), 7.92(d, IH, J=8.8), 7.52(s, IH), 7.4 l(t, IH), 4.74(s, IH), 3.65(m, 4H), 3.17(m, 4H), 2.9 l(t, 4H), 1.53- 1.80(m, 6H) 实施例 103 1 H NMR (400 MHz, DMSO-d 6 ): δ 10.16 (s, IH), 8.89 (s, IH), 8.64 (s, IH), 8.46 (s, IH), 8.32 (m, 2H), 8.13 (d) , IH, J=8.0), 8.02(m, IH), 7.92(d, IH, J=8.8), 7.52(s, IH), 7.4 l(t, IH), 4.74(s, IH), 3.65( m, 4H), 3.17 (m, 4H), 2.9 l(t, 4H), 1.53- 1.80 (m, 6H) Example 103
l_「4-(3-氯 -4-氟-苯氨基) -喹唑啉 -6-基 l-4-(2-羟乙基 )-lH-吡咯 -3-羧酸 -(2-哌啶 -1- 乙基) -酰胺
Figure imgf000127_0001
L_"4-(3-Chloro-4-fluoro-phenylamino)-quinazolin-6-yl l-4-(2-hydroxyethyl)-lH-pyrrole-3-carboxylic acid-(2-piperidine -1-ethyl)-amide
Figure imgf000127_0001
重复本发明实施例 81第一步至第二步所述的实验步骤，不同的是以实施例 81 第一步所得的化合物 2-[4-(3-氯 -4-氟-苯氨基) -喹唑啉 -6-基] -6,7-二氢 -2H-吡喃 [3,4-c] 吡咯 -4-酮 81a作原料，按照本发明实施例 81第二歩所述的相同方式使得该原料与 2-哌啶 -1-乙胺的反应， 得到标题化合物 1-[4-(3-氯 -4-氟-苯氨基) -喹唑啉 -6-基] -4- (2- 羟乙基 )-1Η-吡咯 -3-羧酸 -(2-哌啶 -1-乙基) -酰胺 103 ( 154 mg， 黄色固体）， 产率： 65.14%。  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. 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 Η-pyrrole-3-carboxylic acid-(2-piperidin-1-ethyl)-amide 103 (154 mg, yellow solid), yield: 65.14%.
MS m/z (ESI): 537[M+ 1]  MS m/z (ESI): 537 [M+ 1]
IHNMR (400MHz, DMSO- d6): δ 10.16(s, 1H), 8.91(s, 1H), 8.61(s, 1H), 8.50(s, 1H), 8.39(t, 1H), 8.31(dd, 1H, J=6.8), 8.10(dd, 1H, J=8.8), 8.01(m, 1H)， 7.87(d, 1H, J=9.2), 7.54(s, 1H), 7.42(t, 1H), 4.80(s, 1H), 3.67(t, 2H), 3.60(q, 2H), 3.19(m, 6H), 2.91(t, 2H)， 1.25(t, 6H) 实施例 104 I H NMR (400MHz, DMSO-d 6 ): δ 10.16 (s, 1H), 8.91 (s, 1H), 8.61 (s, 1H), 8.50 (s, 1H), 8.39 (t, 1H), 8.31 (dd , 1H, J=6.8), 8.10(dd, 1H, J=8.8), 8.01(m, 1H), 7.87(d, 1H, J=9.2), 7.54(s, 1H), 7.42(t, 1H) , 4.80(s, 1H), 3.67(t, 2H), 3.60(q, 2H), 3.19(m, 6H), 2.91(t, 2H), 1.25(t, 6H) Example 104
1-Γ4-(3-氯 -4-氟-苯氨基) -喹唑啉 -6-基 l-4-(2-羟乙基 )-lH-吡咯 -3-羧酸 -(2-吗啉 -4- 乙基) -酰胺  1-Γ4-(3-chloro-4-fluoro-phenylamino)-quinazolin-6-yl-1-(2-hydroxyethyl)-lH-pyrrole-3-carboxylic acid-(2-morpholine -4-ethyl)-amide
Figure imgf000127_0002
Figure imgf000127_0002
重复本发明实施例 81第一步至第二歩所述的实验步骤，不同的是以实施例 81 第一步所得的化合物 2-[4-(3-氯 -4-氟-苯氨基) -喹唑啉 -6-基] -6,7-二氢 -2H-吡喃 [3,4-c] 吡咯 -4-酮 81a作原料，按照本发明实施例 81第二步所述的相同方式使得该原料与 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 the second step of Example 81 of the present invention Make the raw material
2_吗啉 _4-基-乙胺的反应， 得到标题化合物 1-[4-(3-氯 -4-氟-苯氨基) -喹唑啉 -6- 基] -4-(2-羟乙基) -1H-吡咯 -3-羧酸 -(2-吗啉 -4-乙基) -酰胺 104 ( 128 mg, 黄色固体）， 产率： 53.92%。 Reaction of 2- morpholine-4-yl-ethylamine gave the title compound 1-[4-(3-chloro-4-fluoro-phenylamino)-quinazolin-6-yl]-4-(2-hydroxyl) Ethyl) -1H-pyrrole-3-carboxylic acid-(2-morpholin-4-ethyl)-amide 104 (128 mg, yellow solid), yield: 53.92%.
MS m/z (ESI): 540[M+ 1]  MS m/z (ESI): 540 [M+ 1]
1HNMR (400MHz, DMSO- d6): δ 10.14(s, 1H)， 8.82(s, 1H), 8.63(s, 1H)， 8.28(dd, 1H,1H NMR (400MHz, DMSO-d 6 ): δ 10.14 (s, 1H), 8.82 (s, 1H), 8.63 (s, 1H), 8.28 (dd, 1H,
J=6.8), 8.22(s, 1H), 8.12(dd, 1H, J-5.2), 8.02(s, 1H), 7.94(m, 2H), 7.46(t, 2H), 4.81(s,J=6.8), 8.22(s, 1H), 8.12(dd, 1H, J-5.2), 8.02(s, 1H), 7.94(m, 2H), 7.46(t, 2H), 4.81(s,
1H), 3.66(m, 6H), 3.42(m, 4H), 2.90(t, 2H), 2.50(m, 4H) 实施例 105 1H), 3.66(m, 6H), 3.42(m, 4H), 2.90(t, 2H), 2.50(m, 4H) Example 105
1-Γ4-(3-氯 -4-氟-苯氨基) -喹唑啉 -6-基 l-4-(2-羟乙基 IH-吡咯 -3-羧酸 -「2-(4甲基 哌嗪 -1 -基 乙基 1-酰胺  1-Γ4-(3-chloro-4-fluoro-phenylamino)-quinazolin-6-yl-1-(2-hydroxyethyl IH-pyrrole-3-carboxylic acid-"2-(4 methyl) Piperazine-1-ylethyl 1-amide
Figure imgf000128_0001
Figure imgf000128_0001
重复本发明实施例 81第一步至第二步所述的实验步骤，不同的是以实施例 81 第一步所得的化合物 2-[4-(3-氯 -4-氟 -苯氨基)-喹唑啉 -6-基] -6,7-二氢 -2H-吡喃 [3,4-c] 吡咯 -4-酮 81a作原料，按照本发明实施例 81第二步所述的相同方式使得该原料与 2_(4-甲基 -哌嗪 -1 -基) -乙胺的反应，得到标题化合物 1-[4-(3-氯 -4-氟-苯氨基) -喹唑啉 -6-基] -4- (2-羟乙基 )-1Η-吡咯 -3-羧酸 -[2-(4甲基哌嗪小基) -乙基] -酰胺 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 the second step of Example 81 of the present invention Reaction of the starting material with 2 -(4-methyl-piperazin-1 -yl)-ethylamine afforded the title compound 1-[4-(3-chloro-4-fluoro-phenylamino)-quinazoline- 6-yl]-4-(2-hydroxyethyl)-1Η-pyrrole-3-carboxylic acid-[2-(4methylpiperazine)-ethyl]-amide
105 (90 mg, 黄色固体）， 产率： 69.4% 105 (90 mg, yellow solid), Yield: 69.4%
MS m/z (ESI): 553[M+ 1] MS m/z (ESI): 553 [M+ 1]
'HNMR (400MHZ, DMSO- d6): δ 10.05(s, 1H), 8.72(s, 1H), 8.64(s, 1H), 8.22(dd, 1H, J=6.8), 8.13(dd, 1H, J=5.2), 8.07(s, 1H), 7.90(m, 3H), 7.49(t, 1H), 7.43(s, 1H), 4.8 l(s, 1H), 3.65(t, 2H), 3.35(m, 12H), 2.89(t 2H), 2.30(t, 3H) 实施例 106 'HNMR (400MHZ, DMSO- d 6 ): δ 10.05 (s, 1H), 8.72 (s, 1H), 8.64 (s, 1H), 8.22 (dd, 1H, J = 6.8), 8.13 (dd, 1H, J=5.2), 8.07(s, 1H), 7.90(m, 3H), 7.49(t, 1H), 7.43(s, 1H), 4.8 l(s, 1H), 3.65(t, 2H), 3.35( m, 12H), 2.89 (t 2H), 2.30 (t, 3H) Example 106
Γ1 -Γ4-(3-氯 -4-氟 -苯氨基)-喹唑啉 -6-基 l-4-(2-羟乙基) -1H-吡咯 -3-基 1-吗啉 -4-甲  Γ1 -Γ4-(3-chloro-4-fluoro-phenylamino)-quinazolin-6-yl l-4-(2-hydroxyethyl)-1H-pyrrol-3-yl 1-morpholin-4- A
Figure imgf000128_0002
Figure imgf000128_0002
重复本发明实施例 81第一步至第二步所述的实验步骤，不同的是以实施例 81 第一步所得的化合物 2-[4-(3-氯 -4-氟-苯氨基) -喹唑啉 -6-基] -6,7-二氢 -2H-吡喃 [3,4-c] 吡咯 -4-酮 81a作原料，按照本发明实施例 81第二步所述的相同方式使得该原料与 吗啉的反应， 得到标题化合物 [1 -[4-(3-氯 -4-氟-苯氨基) -喹唑啉 -6-基] -4-(2-羟乙 基) -1H-吡咯 -3-基] -吗啉 -4-甲酮 106 ( 158 mg， 黄色固体）， 产率： 72.3 %。  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 the second step of Example 81 of the present invention The reaction of the starting material with morpholine gives the title compound [1 -[4-(3-chloro-4-fluoro-phenylamino)-quinazolin-6-yl]-4-(2-hydroxyethyl)- 1H-Pyrrol-3-yl]-morpholine-4-methanone 106 (158 mg, yellow solid), Yield: 7.23.
MS m/z (ESI): 496[M+ 1] MS m/z (ESI): 496 [M+ 1]
'HNMR (400MHZ, DMSO- d6): δ 10.07(s, 1H), 8.67(d, 2H), 8.21 (s, 2H), 7.90(t, 2H), 7.73(s, 1H), 7.49(s, 2H), 4.68(s, 1H), 3.22(m, 10H), 2.70(t, 2H) 实施例 107 'HNMR (400MHZ, DMSO- d 6 ): δ 10.07 (s, 1H), 8.67 (d, 2H), 8.21 (s, 2H), 7.90 (t, 2H), 7.73 (s, 1H), 7.49 (s , 2H), 4.68(s, 1H), 3.22(m, 10H), 2.70(t, 2H) Example 107
「1-Γ4-(3-氯 -4-氟-苯氨基) -喹唑啉 -6-基 l-4-(2-羟乙基) -1H-吡咯 -3-基 l-(4-甲基哌 嗪 -1-基 甲酮 "1-Γ4-(3-Chloro-4-fluoro-phenylamino)-quinazolin-6-yl l-4-(2-hydroxyethyl)-1H-pyrrol-3-yl 1-(4-A Kipi Pyrazin-1-yl ketone
Figure imgf000129_0001
Figure imgf000129_0001
107  107
重复本发明实施例 81第一步至第二步所述的实验步骤，不同的是以实施例 81 第一步所得的化合物 2-[4-(3-氯 -4-氟-苯氨基) -喹唑啉 -6-基] -6,7-二氢 -2H-吡喃 [3，4-c] 吡咯 -4-酮 81a作原料，按照本发明实施例 81第二步所述的相同方式使得该原料与 4-甲基-哌嗪的反应， 得到标题化合物 [1-[4-(3-氯 -4-氟-苯氨基) -喹唑啉 -6-基] -4-(2- 羟乙基 )-1Η-吡咯 -3-基] -(4-甲基哌嗪 -1-基) -甲酮 107 ( 184 mg, 黄色固体）， 产率： 82.08 %。  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 the second step of Example 81 of the present invention The reaction of the starting material with 4-methyl-piperazine gave the title compound [1-[4-(3-chloro-4-fluoro-phenylamino)-quinazolin-6-yl]-4-(2- Hydroxyethyl)-1Η-pyrrol-3-yl]-(4-methylpiperazin-1-yl)-methanone 107 (184 mg, yellow solid), yield: 82.08 %.
MS m/z (ESI): 509[M+ 1]  MS m/z (ESI): 509 [M+ 1]
iHNMR (400MHz, DMSO- d6): δ 9.97(s, IH), 8.64(d, 2H), 8.18(d, 2H, J=9.2), 7.89(d, 2H， J=8.8), 7.70(s, IH), 7.48(m, 2H), 4.69(s, IH), 3.63(m, 6H), 2.70(t, 2H), 2.44(m, 4H), 2.28(s, 3H) 实施例 108 iHNMR (400MHz, DMSO- d 6) : δ 9.97 (s, IH), 8.64 (d, 2H), 8.18 (d, 2H, J = 9.2), 7.89 (d, 2H, J = 8.8), 7.70 (s , IH), 7.48 (m, 2H), 4.69 (s, IH), 3.63 (m, 6H), 2.70 (t, 2H), 2.44 (m, 4H), 2.28 (s, 3H) Example 108
Γ1-Γ4-(3-氯 -4-氟-苯氨基) -喹唑啉 -6-基 l-4-(2-羟乙基 IH-吡咯 -3-羧酸 -(3 啉  Γ1-Γ4-(3-Chloro-4-fluoro-phenylamino)-quinazoline-6-yl l-4-(2-hydroxyethyl IH-pyrrole-3-carboxylic acid -(3 porphyrin)
Figure imgf000129_0002
Figure imgf000129_0002
重复本发明实施例 81第一步至第二步所述的实验步骤，不同的是以实施例 81 第一步所得的化合物 2-[4-(3-氯 -4-氟-苯氨基) -喹唑啉 -6-基] -6,7-二氢 -2H-吡喃 [3,4-c] 吡咯 -4-酮 81a作原料，按照本发明实施例 81第二步所述的相同方式使得该原料与 3-吗啉 -4-基-丙胺的反应， 得到标题化合物 [1-[4-(3-氯 -4-氟-苯氨基) -喹唑啉 -6- 基 ]_4-(2-羟乙基) -1H-吡咯 -3-羧酸 -(3-吗啉 -4-丙基) -酰胺 108 ( 146 mg， 黄色固体）， 产率: 59.9%。  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 the second step of Example 81 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-fluoro-phenylamino)-quinazolin-6-yl]-4-( 2-Hydroxyethyl)-1H-pyrrole-3-carboxylic acid-(3-morpholin-4-propyl)-amide 108 (146 mg, yellow solid), yield: 59.9%.
MS m/z (ESI): 554[M+ 1] MS m/z (ESI): 554[M+ 1]
iHNMR (400MHz, DMSO- d6): δ 10.13(s, IH), 8.82(s, IH), 8.62(s, IH), 8.26(d, IH, J=4.8), 8.20(s, IH), 8.11(d, IH, J=8.8), 8.02(m, IH), 7.92(m, 2H), 7.45(t, 2H), 4.80(s, IH), 3.74(m, 6H), 3.27(m, 4H), 2.87(t, 2H), 2.6 l(m, 4H), 1.76(m, 2H) 实施例 109 Γ1-Γ4-(3-氯 -4-氟-苯氨基) -喹唑啉 -6-基 l-4-(2-羟乙基) -IH-吡咯 -3-基 1-吡咯烷 -1- 甲酮 iHNMR (400MHz, DMSO- d 6) : δ 10.13 (s, IH), 8.82 (s, IH), 8.62 (s, IH), 8.26 (d, IH, J = 4.8), 8.20 (s, IH), 8.11(d, IH, J=8.8), 8.02(m, IH), 7.92(m, 2H), 7.45(t, 2H), 4.80(s, IH), 3.74(m, 6H), 3.27(m, 4H), 2.87(t, 2H), 2.6 l(m, 4H), 1.76(m, 2H) Example 109 Γ1-Γ4-(3-Chloro-4-fluoro-phenylamino)-quinazolin-6-yl l-4-(2-hydroxyethyl)-IH-pyrrol-3-yl 1-pyrrolidine-1- Ketone
Figure imgf000130_0001
Figure imgf000130_0001
重复本发明实施例 81第一步至第二步所述的实验步骤，不同的是以实施例 81 第一步所得的化合物 2-[4-(3-氯 -4-氟-苯氨基) -喹唑啉 -6-基] -6,7-二氢 -2H-吡喃 [3,4-c] 吡咯 -4-酮 81a作原料，按照本发明实施例 81第二步所述的相同方式使得该原料与 吡咯烷的反应， 得到标题化合物 [1-[4-(3-氯 -4-氟-苯氨基)-喹唑啉 -6-基] -4-(2-羟乙 基) -1H-吡咯 -3-基] -吡咯烷小甲酮 109 ( 190 mg, 黄色固体）， 产率： 67.4%。  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 the second step of Example 81 of the present invention The title compound [1-[4-(3-chloro-4-fluoro-phenylamino)-quinazolin-6-yl]-4-(2-hydroxyethyl)- 1H-Pyrrol-3-yl]-pyrrolidine dimethyl ketone 109 (190 mg, yellow solid), Yield: 67.4%.
MS m/z (ESI): 480[M+ 1] MS m/z (ESI): 480 [M+ 1]
1HNMR (400MHz, DMSO- d6): δ 10.12(s, 1H), 8.75(s, 1H), 8,63(s， 1H), 8.23(nr, 2H), 7.89(m, 3H)， 7.48(t, 2H), 4.80(s, 1H), 3.65(m, 4H), 3.48(m, 2H), 2.79(t, 2H), 1.87(m, 4H) 实施例 110 1 H NMR (400MHz, DMSO-d 6 ): δ 10.12 (s, 1H), 8.75 (s, 1H), 8,63 (s, 1H), 8.23 (nr, 2H), 7.89 (m, 3H), 7.48 (t, 2H), 4.80 (s, 1H), 3.65 (m, 4H), 3.48 (m, 2H), 2.79 (t, 2H), 1.87 (m, 4H) Example 110
Γ1-Γ4-(3-氯 -4-氟 -苯氨基)-喹唑啉 -6-基 l-4-(2-羟乙基 )-1Η-吡咯 -3-基 1-哌啶小甲  Γ1-Γ4-(3-Chloro-4-fluoro-phenylamino)-quinazoline-6-yl l-4-(2-hydroxyethyl)-1Η-pyrrole-3-yl 1-piperidine
Figure imgf000130_0002
Figure imgf000130_0002
重复本发明实施例 81第一步至第二步所述的实验步骤，不同的是以实施例 81 '第一步所得的化合物 2-[4-(3-氯 -4-氟-苯氨基) -喹唑啉 -6-基] -6，7-二氢 -2H-吡喃 [3,4-c] 吡咯 -4-酮 81a作原料，按照本发明实施例 81第二步所述的相同方式使得该原料与 哌啶的反应， 得到标题化合物 [1-[4-(3-氯 -4-氟-苯氨基) -喹唑啉 -6-基] -4-(2-羟乙 基) -1H-吡咯 -3-基] -哌啶 -1-甲酮 110 (200 mg, 黄色固体）， 产率： 68.9%。  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). -quinazolin-6-yl]-6,7-dihydro-2H-pyrano[3,4-c]pyrrol-4-one 81a as a starting material, the same as described in the second step of Example 81 of the present invention The reaction of the starting material with piperidine afforded the title compound [1-[4-(3-chloro-4-fluoro-phenylamino)-quinazolin-6-yl]-4-(2-hydroxyethyl) -1H-pyrrol-3-yl]-piperidin-1-one 110 (200 mg, yellow solid), Yield: 68.9%.
MS m/z (ESI): 494[M+ 1] MS m/z (ESI): 494 [M+ 1]
iHNMR (400MHz, DMSO- d6): δ 9.91(s, 1H), 8.63(s, 2H), 8.19(m, 2H), 7.89(m, 2H), 7.65(s, 1H), 7.48(m, 2H), 4.69(t, 1H)， 3.57(m, 6H), 2.68(t, 2H), 1.64(m, 2H), 1.53(m, 4H) 实施例 111 iHNMR (400MHz, DMSO- d 6) : δ 9.91 (s, 1H), 8.63 (s, 2H), 8.19 (m, 2H), 7.89 (m, 2H), 7.65 (s, 1H), 7.48 (m, 2H), 4.69(t, 1H), 3.57(m, 6H), 2.68(t, 2H), 1.64(m, 2H), 1.53(m, 4H) Example 111
4-二甲氨基-丁 -2-烯酸 -(1-ί4-「3-氯 -4-(3-氟-苄氧基) -苯氨基 1-喹唑啉 -6-基 4-三 氟甲某 -1H-吡咯 -3-基) -酰胺
Figure imgf000131_0001
4-Dimethylamino-but-2-enoic acid-(1-ί4-"3-chloro-4-(3-fluoro-benzyloxy)-phenylamino-1-quinazolin-6-yl 4-trifluoro A-1H-pyrrol-3-yl)-amide
Figure imgf000131_0001
重复本发明实施例 67第一步至第八步所述的实验步骤， 不同的是将第八步所 得的化合物 [6- (3-氨基 -4-三氟甲基 -吡咯 -1-基)-喹唑啉 -4-基] -[3-氯 -4-(3-氟苄氧基) - 苯基] -胺 67i ( 150 mg， 0.284 mmol), 0.2 mL二异丙基乙胺， 双（2-氧代- 3-恶唑垸 基）次磷酰氯（86.74 mg， 0.341 mmol), 4-二甲氨基-丁 -2-烯酸（52 mg， 0.312 mmol) 溶于 25 mL二氯甲垸中， 室温下搅拌过夜， 反应完毕。 用 TLC色谱分离产物， 得到标题产物 4-二甲氨基-丁 -2-烯酸 -(1-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基}-4-三氟甲基 -1H-吡咯- 3-基) -酰胺 111 (32 mg， 黄色固体）， 产率： 17.6%。 MS m/z (ESI): 640[M+ 1]  The experimental procedure described in the first step to the eighth step of Example 67 of the present invention is repeated, except that the compound obtained in the eighth step [6-(3-amino-4-trifluoromethyl-pyrrol-1-yl) is used. -quinazolin-4-yl]-[3-chloro-4-(3-fluorobenzyloxy)-phenyl]-amine 67i (150 mg, 0.284 mmol), 0.2 mL of diisopropylethylamine, double (2-oxo-3-oxazolylhydrazyl)phosphoryl chloride (86.74 mg, 0.341 mmol), 4-dimethylamino-but-2-enoic acid (52 mg, 0.312 mmol) dissolved in 25 mL of dichloromethane The mixture was stirred at room temperature overnight and the reaction was completed. The product was isolated by TLC to give the title product 4-dimethylamino-but-2-enoic acid-(1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quin Oxazolin-6-yl}-4-trifluoromethyl-1H-pyrrole-3-yl)-amide 111 (32 mg, yellow solid), yield: 17.6%. MS m/z (ESI): 640 [M+ 1]
lHNMR (400MHz, DMSO- d6): δ 10.05(s, 1H), 9.7 l(s, 1H), 8.79(s, 1H), 8.60(s, 1H), 8.21(dd, 1H, J=8.8), 8.12(d, 2H, J=9.6), 8.04(s, 1H), 7.90(d, 1H, J=8.8), 7.77(dd, 1H, J=9.2), 7.48(q, 1H), 7.32(m, 3H), 7.19(m, 1H), 6.78(m， 1H), 6.63(d, 1H), 5.27(s, 2H), 3.55(m, 2H), 2.47(s, 6H) lHNMR (400MHz, DMSO- d 6) : δ 10.05 (s, 1H), 9.7 l (s, 1H), 8.79 (s, 1H), 8.60 (s, 1H), 8.21 (dd, 1H, J = 8.8) , 8.12(d, 2H, J=9.6), 8.04(s, 1H), 7.90(d, 1H, J=8.8), 7.77(dd, 1H, J=9.2), 7.48(q, 1H), 7.32( m, 3H), 7.19(m, 1H), 6.78(m, 1H), 6.63(d, 1H), 5.27(s, 2H), 3.55(m, 2H), 2.47(s, 6H)
- . -实施例 112 -- . - Example 112 -
{6-「3,4-二- (二乙氨基甲基 吡咯 -1-基 1-喹唑啉 -4-基 「3-氯 -4-(3-氟-苄氧基) -苯 基 胺 {6-"3,4-Di-(diethylaminomethylpyrrol-1-yl-1-quinazolin-4-yl"3-chloro-4-(3-fluoro-benzyloxy)-phenylamine
Figure imgf000131_0002
第一步
Figure imgf000131_0002
first step
i— -P-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基}-111-吡咯 -3,4-二羧基二乙酯 在 250 mL茄形瓶中， 依次加入实施例 1第五步所得化合物 [3-氯 -4-(3-氟 - 氧 基) -苯基 ]-(6-碘-喹唑啉 -4-基) -胺 lg (7.10 g, 0.014 mol), 1H-吡咯 -3 ,4-二甲酸二乙酯 (2.97 g， 0.014 mol),磷酸钾 ( 8.92 g， 0.042 mol),碘化亚铜 (2.76 g， 0.014 mol), Ν, Ν'-二甲基 -1,2-乙二胺 ( 1.23 g, 0.014 mol)和 100 mLN,N-二甲基甲酰胺， 所得 的混合液在氮气保护下加热至 70Ό，搅拌过夜，反应完毕。将反应液倒入 1000 mL 水中， 搅拌， 过滤， 固体进一步通过柱层析分离纯化， 得到本标题产物 1-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基]-喹唑啉 -6-基}-1 吡咯 -3,4-二羧基二乙酯 112a ( 3.3g， 黄 色固体）， 产率： 40%。 i--P-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-111-pyrrole-3,4-dicarboxydiethyl ester in 250 mL eggplant In the bottle, the compound obtained in the fifth step of Example 1 was sequentially added [3-chloro-4-(3-fluoro-oxygen) -phenyl]-(6-iodo-quinazolin-4-yl)-amine lg (7.10 g, 0.014 mol), diethyl 1H-pyrrole-3,4-dicarboxylate (2.97 g, 0.014 mol ), potassium phosphate ( 8.92 g, 0.042 mol), cuprous iodide (2.76 g, 0.014 mol), hydrazine, Ν'-dimethyl-1,2-ethanediamine (1.23 g, 0.014 mol) and 100 mLN , N-dimethylformamide, the resulting mixture was heated to 70 Torr under a nitrogen atmosphere, stirred overnight, and the reaction was completed. The reaction solution was poured into 1000 mL of water, stirred, and filtered, and the solid was further purified by column chromatography to give the title product 1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino ]-quinazoline-6-yl}-1pyrrole-3,4-dicarboxydiethyl ester 112a (3.3 g, yellow solid), Yield: 40%.
MS m/z (ESI): 588[M- 1] MS m/z (ESI): 588 [M-1]
第二步  Second step
(1-{4-[3-氯 -4-(3-氟苄氧基) -苯氨基] -喹唑啉 -6-基}-4-羟基甲基 -1H-吡咯 -3-基) - 甲醇  (1-{4-[3-Chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazolin-6-yl}-4-hydroxymethyl-1H-pyrrol-3-yl) - Methanol
在 250 mL茄形瓶中， 将氢化铝锂（581 mg, 15.3mmol)溶解于 75 mL四氢呋 喃中， 所得的溶液在冰浴条件下， 冷却至 0°C， 搅拌下加入上述步骤所得化合物 1-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基}-111-吡咯 -3,4-二羧基二乙酯 112a ( 1.5 g, 2.55 mniol), 保持冰浴反应 2小时后反应完毕。 在反应液中滴加 7.5 mL 水， 7.5 mL IN氢氧化钠溶液，搅拌下加入 100 mL乙酸乙酯，硅藻土过滤，用 200 mL乙酸乙酯洗涤，-滤液依次用饱和氯化钠溶液洗涤， 无水硫酸钠干燥， 过滤， 滤 液减压下浓缩， 得到本化合物 (1-{4-[3-氯 -4-(3-氟苄氧基) -苯氨基] -喹唑啉 -6-基 }-4- 羟基甲基 -1H-吡咯 -3-基) -甲醇 112b (黄色固体）不经分离直接进行下一步反应。 MS m/z (ESI): 503 [M- 1]  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. 7.5 mL of water and 7.5 mL of IN sodium hydroxide solution were added dropwise to the reaction solution, and 100 mL of ethyl acetate was added thereto with stirring, and the mixture was filtered through Celite, washed with 200 mL of ethyl acetate, and the filtrate was washed successively with saturated sodium chloride Drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to give the compound (1-{4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazoline-6- The benzyl}-4-hydroxymethyl-1H-pyrrol-3-yl)-methanol 112b (yellow solid) was directly subjected to the next reaction without isolation. MS m/z (ESI): 503 [M-1]
第三步  third step
1-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基}-111-吡咯 -3,4-二甲醛 在 250 mL茄形瓶中，将邻碘酰苯甲酸 （2.86 g， 10.2mmol))溶解于 50 mL二 甲基亚砜中， 搅拌下加入上述步骤所得的化合物 (1-{4-[3-氯 -4-(3-氟苄氧基) -苯氨 基]-喹唑啉 -6-基}-4-羟基甲基 -1H-吡咯 -3-基) -甲醇 112b ( 1.287g， 2.55mmol) 的 25 mL二甲基亚砜溶液， 所得的混合液在室温下搅拌 2小时， 反应完毕。将反应液倒 入 500 mL冰水中， 用乙酸乙酯 (250 mL X 4 )萃取， 有机相用饱和碳酸氢钠溶液 洗涤， 饱和氯化钠溶液洗涤， 无水硫酸钠干燥， 过滤， 减压下浓缩， 得到的残留 物通过柱层析进一步分离纯化， 得到本标题产物 1-{4-[3-氯 -4-0氟-苄氧基) -苯氨 基] -喹唑啉 -6-基 }-1Η-吡咯 -3,4-二甲醛 112c (760 mg， 黄色固体）， 产率： 59.4%。 MS m/z (ESI): 499[M- 1]  1-{4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-111-pyrrole-3,4-dicarbaldehyde in 250 mL eggplant In the flask, o-iodobenzoic acid (2.86 g, 10.2 mmol) was dissolved in 50 mL of dimethyl sulfoxide, and the compound obtained in the above step (1-{4-[3-chloro-4-() was added with stirring. 3-fluorobenzyloxy)-phenylamino]-quinazolin-6-yl}-4-hydroxymethyl-1H-pyrrol-3-yl)-methanol 112b ( 1.287 g, 2.55 mmol) in 25 mL of dimethyl The sulfoxide solution was stirred at room temperature for 2 hours, and the reaction was completed. The reaction solution was poured into 500 mL of ice water, and extracted with ethyl acetate (250 mL X 4 ). The organic phase was washed with saturated sodium hydrogen carbonate solution, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated Concentration, the obtained residue was further purified by column chromatography to give the title product 1-{4-[3-chloro-4-0-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl} -1 Η-pyrrole-3,4-dicarbaldehyde 112c (760 mg, yellow solid), Yield: 59.4%. MS m/z (ESI): 499 [M-1]
第四歩  Fourth
{6-[3,4-二- (二乙氨基甲基) -吡咯 -1-基]-喹唑啉 -4-基 }-[3-氯 -4-(3-氟-苄氧基) -苯 基] -胺  {6-[3,4-di-(diethylaminomethyl)-pyrrol-1-yl]-quinazolin-4-yl}-[3-chloro-4-(3-fluoro-benzyloxy) -phenyl]-amine
将上述步骤所得的化合物 1-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6- 基 }-1Η-吡咯 -3,4-二甲醛 112c ( 100 mg， 0.2 mmol)溶解于 5 mL二氯甲烷中， 搅拌 下加入二乙胺（44 mg， 0.6 mmol),继续搅拌 6小时后，加入三乙酰氧基硼氢化（170 mg, O.S mmol) , 搅拌过夜， 反应完毕。在反应液中加入 5 mL饱和氯化钠溶液， 1 mL饱和碳酸氢钠溶液， 二氯甲垸（20 mL X 3 )萃取， 有机相用饱和氯化钠溶液洗 涤， 无水硫酸钠干燥， 过滤， 浓缩， 得到的残留物进一步通过 TLC板分离纯化， 得到本标题产物 {6-[3,4-二- (二乙氨基甲基) -吡咯 -1-基] -喹唑啉 -4-基 }-[3-氯 -4-(3-氟- 苄氧基) -苯基] -胺 112 ( 73 mg, 黄色固体）， 产率： 59.4% The compound obtained in the above step is 1-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-1Η-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. Add 5 mL of saturated sodium chloride solution, 1 mL of saturated sodium bicarbonate solution, dichloromethane (20 mL X 3 ), and wash the organic phase with saturated sodium chloride solution, dry over anhydrous sodium sulfate, and filter. The residue was purified by EtOAc (EtOAc) elute }-[3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-amine 112 (73 mg, yellow solid), yield: 59.4%
MS m/z (ESI): 615[M+ 1] MS m/z (ESI): 615 [M+ 1]
1H NMR (400MHz, DMSO- d6): δ 10.04(s, 1H), 8.78(s, 1H), 8.59(s, 1H)， 8.14(dd, 1H, J=8.8), 8.07(d, 1H, J=2.4), 7.90(d, 1H, J=9.2), 7.83(m, 3H), 7.47(q, 1H)， 7.32(m, 3H), 7.19(t, 1H), 5.27(s, 2H), 3.93(s, 4H), 2.9 l(q, 8H), 1.14(t, 12H) 实施例 113 1H NMR (400MHz, DMSO- d 6 ): δ 10.04 (s, 1H), 8.78 (s, 1H), 8.59 (s, 1H), 8.14 (dd, 1H, J = 8.8), 8.07 (d, 1H, J=2.4), 7.90(d, 1H, J=9.2), 7.83(m, 3H), 7.47(q, 1H), 7.32(m, 3H), 7.19(t, 1H), 5.27(s, 2H) , 3.93(s, 4H), 2.9 l(q, 8H), 1.14(t, 12H) Example 113
Γ6-(3,4-二 -吗啉 -4-甲基吡咯 -1-基 喹唑啉 -4-基 「3-氯 -4-(3-氟-苄氧基) -苯基 1-胺  6-(3,4-Di-morpholin-4-methylpyrrol-1-ylquinazolin-4-yl "3-chloro-4-(3-fluoro-benzyloxy)-phenyl 1-amine
Figure imgf000133_0001
Figure imgf000133_0001
重复本发明实施例 112第一步至第四步所述的实验步骤， 不同的是以第三步 所得的化合物 1-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基 }-1Η-吡咯 -3,4-二甲 醛 112c作原料， 按照本发明实施例 112第四步所述的相同方式使得该原料与吗啉 的反应，得到标题化合物 [6-(3,4-二 -吗啉 -4-甲基吡咯 -1-基) -喹唑啉 -4-基] -[3-氯 -4-(3- 氟-苄氧基) -苯基] -胺 113 (73 mg, 黄色固体）， 产率： 59.4%。  The experimental procedure described in the first step to the fourth step of the embodiment 112 of the present invention is repeated, except that the compound 1-{4-[3-chloro-4-(3-fluoro-benzyloxy) obtained in the third step is obtained. -Phenylamino]-quinazolin-6-yl}-1Η-pyrrole-3,4-dicarbaldehyde 112c as a starting material, which reacts the starting material with morpholine in the same manner as described in the fourth step of Example 112 of the present invention. , the title compound [6-(3,4-di-morpholin-4-methylpyrrol-1-yl)-quinazolin-4-yl]-[3-chloro-4-(3-fluoro-benzyl) Oxyphenyl)-phenyl]-amine 113 (73 mg, yellow solid), yield: 59.4%.
MS m/z (ESI): 616[M+ 1] MS m/z (ESI): 616 [M+ 1]
1H NMR (400MHz, DMSO- d6): δ 9.78(s, 1H), 8.54(m, 2H), 8.14(dd, 1H, J=9.2), 8.00(d, 1H, J=2.4), 7.83(d, 1H, J=8.8), 7.73(dd, 1H, J=8.8), 7.47(m, 3H), 7.33(m, 3H), 7.19(t, 1H), 5.28(s, 2H), 3.58(s， 8H), 3.44(s, 4H), 2.41(s, 8H) . 实施例 114 1H NMR (400MHz, DMSO- d 6 ): δ 9.78 (s, 1H), 8.54 (m, 2H), 8.14 (dd, 1H, J = 9.2), 8.00 (d, 1H, J = 2.4), 7.83 ( d, 1H, J=8.8), 7.73(dd, 1H, J=8.8), 7.47(m, 3H), 7.33(m, 3H), 7.19(t, 1H), 5.28(s, 2H), 3.58( s, 8H), 3.44(s, 4H), 2.41(s, 8H) . Example 114
6—(3,4-二-哌啶小甲基吡咯 -1-基 喹唑啉 -4-基 l-「3-氯 -4-(3-氟苄氧基) -苯基 胺  6-(3,4-di-piperidinylmethylpyrrole-1-ylquinazolin-4-yl l-"3-chloro-4-(3-fluorobenzyloxy)-phenylamine
Figure imgf000133_0002
Figure imgf000133_0002
重复本发明实施例 112第一步至第四步所述的实验步骤， 不同的是以第三步 所得的化合物 1-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基}-111-吡咯 -3,4-二甲 醛 112c作原料， 按照本发明实施例 112第四步所述的相同方式使得该原料与哌啶
Figure imgf000134_0001
寸-釉 ¾a-z)j-H¾-9-柳^ ¾ t -ε)-ΐ7-ϋ- 寸 H}-z The experimental procedure described in the first step to the fourth step of the embodiment 112 of the present invention is repeated, except that the compound 1-{4-[3-chloro-4-(3-fluoro-benzyloxy) obtained in the third step is obtained. -Phenylamino]-quinazolin-6-yl}-111-pyrrole-3,4-dicarbaldehyde 112c as a starting material, the starting material and piperidine are obtained in the same manner as described in the fourth step of Example 112 of the present invention.
Figure imgf000134_0001
Inch-glaze 3⁄4a-z)j-H3⁄4-9-柳^ 3⁄4 t -ε)-ΐ7-ϋ- inch H}-z
9u ^  9u ^
(ΗΠ 's)99 XB 's)8乙 \UZ £s)A3'S '(HI ¾9ΓΖ, '(Η£ '∞)Ϊ£·Λ '(HI OZ VL '(8-8=f 'Ηΐ 'Ρ)Ι6·Λ '(8"8=f 'Ηΐ 'ΡΡ)Α6·Α UZ 's)g0'8 '(8'8=f 'HI 'PP)W8 VZ=£ 'HI 'V)ZZ'2 '(HI 's)09'8 '(Ηΐ 's) 6 '(HI 's)6SOI S -(9P -OS 勵 O )環 N (ΗΠ 's)99 XB 's)8B\UZ £ s)A3'S '(HI 3⁄49ΓΖ, '(Η£ '∞)Ϊ£·Λ '(HI OZ VL '(8-8=f 'Ηΐ 'Ρ )Ι6·Λ '(8"8=f 'Ηΐ 'ΡΡ)Α6·Α UZ 's)g0'8 '(8'8=f 'HI 'PP)W8 VZ=£ 'HI 'V)ZZ'2 '(HI 's)09'8 '(Ηΐ 's) 6 '(HI 's)6SOI S -( 9 P -OS excitation O ) ring N
[l+W] 09S :(IS3)Z/UIS [l+W] 09S :(IS3)Z/UIS
°%Δ·ςε
Figure imgf000134_0002
- (¾¾ -ε)-Η -εΗ¾ -柳¾ -[¾-1-^ (¾ώ¾^¾ώ二) -二 -ΐ7'ε]-9}啄 齄^ g ' ^ & si °%Δ·ςε
Figure imgf000134_0002
- (3⁄43⁄4 -ε)-Η -εΗ3⁄4 -柳3⁄4 -[3⁄4-1-^ (3⁄4ώ3⁄4^3⁄4ώ二) -二-ΐ7'ε]-9}啄齄^ g ' ^ & si
Figure imgf000134_0003
Figure imgf000134_0003
1FT¾ oi  1FT3⁄4 oi
(U 's)£S'I '(H8 's)e9'l £(H8 '^)£S'Z Xm 's)98'£ '(IK ^)ί ζ '(HI ¾6ΓΑ '(Η£ ^)££·ί '(Ηΐ ^)SVL '(Η£ ^)ZLL '0'8=f 'HI 'Ρ)88·Δ '(Ηΐ 's)go'8 '(8"8=£ (U 's) £S'I '(H8 's)e9'l £ (H8 '^)£S'Z Xm 's)98'£ '(IK ^)ί ζ '(HI 3⁄46ΓΑ '(Η£ ^)££·ί '(Ηΐ ^)SVL '(Η£ ^)ZLL '0'8=f 'HI 'Ρ)88·Δ '(Ηΐ 's)go'8 '(8"8=£
'Ηΐ 'ΡΡ)£Γ8 '(HI 's)8S-8 '(HI ^)ZL '(HI 's)00 I 9 -(9P "OS iO ^ΗΙ^ΟΟ^) Ή ΝΗ^ 'Ηΐ 'ΡΡ) £Γ8 '(HI 's)8S-8 '(HI ^)ZL '(HI 's)00 I 9 -( 9 P "OS iO ^ΗΙ^ΟΟ^) Ή ΝΗ^
ίι+ν o 9 :(isa)z/∞si Ίι+ν o 9 : (isa)z/∞si
-£)-H -£]-[¾-i7-柳; f禪 ¾-ι-¾Η¾¾ώ-ι-¾ι¾ιίι-:Γ-ΐ7'ε)-9 导 W齄^ fii¾ 'W'S^ .0CT00/800ZN3/X3d -£)-H -£]-[3⁄4-i7-柳; f禅3⁄4-ι-3⁄4Η3⁄43⁄4ώ-ι-3⁄4ι3⁄4ιίι-:Γ-ΐ7'ε)-9 Guide W齄^ fii3⁄4 'W'S^ .0CT00/800ZN3/ X3d
Figure imgf000135_0001
第一步
Figure imgf000135_0001
first step
2-(l-{4-[3-氯 -4-(3-氟 氧基) -苯氨基]-喹唑啉 -6-基 }-4-羟甲基 -1H-吡咯 -3-基) - 乙醇  2-(l-{4-[3-Chloro-4-(3-fluorooxy)-phenylamino]-quinazolin-6-yl}-4-hydroxymethyl-1H-pyrrol-3-yl) - Ethanol
" 在 500 mL单口烧瓶中， 将氢化铝锂（1.48 g， 38.8mmol)溶解于 150 mL四氢 呋喃中， 将反应液在冰浴条件下， 冷却至 0〜5°C， 搅拌下分批加入实施例 10所得 的化合物 2-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基}-6,7-二氢 -2H-吡喃 [3,4-c] 吡咯 -4-酮 10 ( 10 g， 19.4mmol),所得的混合液在室温下搅拌下 3小时后反应完毕。 用 100 mL四氢呋喃和 50 mL水的混合溶剂猝灭反应。 将反应液中倒入 150 mL水 和 150 mL乙酸乙酯中进行分液， 用乙酸乙酯 （100 mLX 3 )进一步萃取水层， 合 并的有机相依次用饱和氯化钠溶液洗涤， 无水硫酸钠干燥， 过滤， 滤液减压下浓 缩， 得到的固体用 5 mL乙酸乙酯洗涤， 得到本标题产物 2-(1-{4-[3-氯 -4-(3-氟苄氧 基)-苯氨基 ]-喹唑啉 -6-基}-4-羟甲基 -1H-吡咯 -3-基) -乙醇 116a (5.23g， 灰色固体）， 产率： 52.1 %。  In a 500 mL single-necked flask, lithium aluminum hydride (1.48 g, 38.8 mmol) was dissolved in 150 mL of tetrahydrofuran, and the reaction solution was cooled to 0 to 5 ° C under ice bath, and the mixture was added in portions under stirring. 10 obtained compound 2-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-6,7-dihydro-2H-pyran [3,4-c]pyrrol-4-one 10 (10 g, 19.4 mmol), the resulting mixture was stirred at room temperature for 3 hours and then the reaction was completed. The reaction mixture was quenched with a mixture solvent of 100 mL of tetrahydrofuran and 50 mL of water. The reaction mixture was poured into 150 mL of water and 150 mL of ethyl acetate, and the aqueous layer was further extracted with ethyl acetate (100 mL X 3 ). The combined organic phases were washed successively with saturated sodium chloride The organic layer was dried (MgSO4), filtered, evaporated. -Phenylamino]-quinazolin-6-yl}-4-hydroxymethyl-1H-pyrrol-3-yl)-ethanol 116a (5.23 g, m.p.).
MS m/z (ESI): 519[M+ 1]  MS m/z (ESI): 519 [M+ 1]
第二步  Second step
1-{4-[3-氯 -4-(3-氟苄氧基) -苯氨基]-喹唑啉 -6-基}-4-(2-羟乙基) -1H-吡咯 -3-甲 醛  1-{4-[3-Chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazolin-6-yl}-4-(2-hydroxyethyl)-1H-pyrrole-3- Formaldehyde
在 50 mL单口烧瓶中， 将邻碘酰基苯甲酸（540 mg， 1.93mniol)溶解于 5 mL 二甲基亚砜中， 搅拌下逐滴加入将上述步骤所得的化合物 2-(1-{4-[3-氯 -4-(3-氟苄 氧基) -苯氨基] -喹唑啉 -6-基}-4-羟甲基 -1H-吡咯 -3-基) -乙醇 116a ( lg， 1.93 mmol) 的 3 mL二甲基亚砜溶液， 所得的反应液在室温下搅拌 1小时后， 反应完毕。 将反 应液加入到 150 mL 5 %碳酸氢钠溶液中， 有固体析出， 过滤， 真空下干燥， 得到 本标题产物 1-{4-[3-氯 -4-(3-氟苄氧基) -苯氨基] -喹唑啉 -6-基}-4-(2-羟乙基) -1H-吡咯 -3-甲醛 116b ( l.lg, 土黄色固体） 粗产品， 不经分离直接进行下一歩反应。  In a 50 mL single-necked flask, o-iodobenzoic acid (540 mg, 1.93mniol) was dissolved in 5 mL of dimethyl sulfoxide, and the compound 2-(1-{4-) obtained in the above step was added dropwise with stirring. [3-Chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazolin-6-yl}-4-hydroxymethyl-1H-pyrrol-3-yl)-ethanol 116a ( lg, 1.93 A solution of 3 mL of dimethyl sulfoxide in mmol) was stirred at room temperature for 1 hour and then the reaction was completed. The reaction mixture was poured into 150 mL of 5% sodium hydrogen carbonate solution, and solid was precipitated, filtered and dried in vacuo to give the title product 1-{4-[3-chloro-4-(3-fluorobenzyloxy)- Phenylamino]-quinazolin-6-yl}-4-(2-hydroxyethyl)-1H-pyrrole-3-carbaldehyde 116b (1.lg, khaki solid) crude product, directly reaction.
MS m/z (ESI): 518[M+ 1] 第三步 MS m/z (ESI): 518 [M+ 1] third step
2一 - -P-氯 _4-(3-氟苄氧基) -苯氨基] -喹唑啉 -6-基 }-4-[(2-吗啉 -4-乙氨基) -甲 基] -1H-吡咯 -3-基 乙醇  2-(-P-chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazolin-6-yl}-4-[(2-morpholin-4-ethylamino)-methyl] -1H-pyrrol-3-ylethanol
将上述步骤所得的粗品 1-{4-[3-氯 -4-(3-氟苄氧基) -苯氨基] - 喹唑啉 -6- 基}-4-(2-羟乙基 )-1Η-吡咯 -3-甲醛 116b (500 mg， 0.71 mmol)溶解于 20 mL二氯 甲烷中， 搅拌下加入 2-吗啉 -4-基 -乙胺 （185 mg， 1.42 mmol), 室温下搅拌 3小时 后加入三乙酰氧基硼氢化钠（300 mg， 1.42mmol), 所得的混合液在室温下搅拌过 夜，反应完毕。在反应液中加入 5 mL饱和碳酸氢钠溶液和 5 mL饱和氯化钠溶液， 用二氯甲烷（100 mLX 3 )萃取反应液， 合并的有机相用饱和氯化钠溶液洗涤， 无 水硫酸钠干燥， 过滤， 滤液减压浓缩， 得到的固体进一步通过 TLC板进行分离纯 化，得到本标题产物 2-{1-{4-[3-氯 -4-(3-氟苄氧基) -苯氨基] -喹唑啉 -6-基}-4-[(2-吗啉 -4-乙氨基) -甲基] -1H-吡咯 -3-基} -乙醇 116 (90 mg, 黄色固体）， 产率： 20%。  The crude product obtained in the above step was 1-{4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazolin-6-yl}-4-(2-hydroxyethyl)- 1Η-pyrrole-3-carbaldehyde 116b (500 mg, 0.71 mmol) was dissolved in 20 mL of dichloromethane, and 2-morpholin-4-yl-ethylamine (185 mg, 1.42 mmol) was added with stirring, stirring at room temperature 3 After a while, sodium triacetoxyborohydride (300 mg, 1.42 mmol) was added, and the resulting mixture was stirred at room temperature overnight, and the reaction was completed. 5 mL of saturated sodium bicarbonate solution and 5 mL of saturated sodium chloride solution were added to the reaction mixture, and the reaction mixture was extracted with dichloromethane (100 mL×3), and the combined organic phases were washed with saturated sodium chloride Drying, filtration, and concentrating the filtrate under reduced pressure, and the obtained solid was further purified by chromatography to afford the title product 2-{1-{4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino - quinazolin-6-yl}-4-[(2-morpholin-4-ethylamino)-methyl]-1H-pyrrol-3-yl}-ethanol 116 (90 mg, yellow solid) Rate: 20%.
MS m/z (ESI): 632[M+ 1] MS m/z (ESI): 632 [M+ 1]
1H NMR (400MHz, DMSO- d6): δ 9.75(s, 1H), 8.52(s, 1H), 8.48(s, 1H), 8.06(d, 1H), 7.99(s, 1H), 7.8 l(d, 1H, J=8.8), 7.7 l(d, 1H), 7.45(m, 2H), 7.3 l(m, 4H), 7.15(t, 1H), 5.25(s, 2H), 3.60(s, 4H), 3.54(t, 4H), 2.65(m, 4H), 2.39(t, 2H), 2.33(t, 4H) 实施例 117 1H NMR (400MHz, DMSO- d 6 ): δ 9.75 (s, 1H), 8.52 (s, 1H), 8.48 (s, 1H), 8.06 (d, 1H), 7.99 (s, 1H), 7.8 l ( d, 1H, J=8.8), 7.7 l(d, 1H), 7.45(m, 2H), 7.3 l(m, 4H), 7.15(t, 1H), 5.25(s, 2H), 3.60(s, 4H), 3.54 (t, 4H), 2.65 (m, 4H), 2.39 (t, 2H), 2.33 (t, 4H) Example 117
Γ3-氯 -4-(3-氟苄氧基) -苯基 l-(6-{54(2-甲氧基-乙氨基) -甲基 1-lH-吡咯 -3-基} -喹 唑啉 -4-基) -胺  3-chloro-4-(3-fluorobenzyloxy)-phenyl 1-(6-{54(2-methoxy-ethylamino)-methyl 1-lH-pyrrol-3-yl}-quinazole Phenyl-4-yl)-amine
Figure imgf000136_0001
Figure imgf000136_0001
重复本发明实施例 52第一步至第二步所述的实验步骤，不同的是以实施例 52 第一步所得的化合物 3-{4-[3-氯 -4-(3-氟苄氧基) -苯氨基] -喹唑啉 -6-基}-1-三异丙基 硅 -1H-吡咯 -2-甲醛 52a作原料， 按照本发明实施例 52第二步所述的相同方式使得 该原料与 2-甲氧基乙胺的反应， 得到标题化合物 [3-氯 -4-(3-氟苄氧基) -苯 基] -(6-{5-[(2-甲氧基-乙氨基) -甲基] -1H-吡咯 -3-基}-喹唑啉 -4-碁) -胺 117 (55 mg,黄 色固体）， 产率 51.8%。  The experimental procedure described in the first step to the second step of Example 52 of the present invention was repeated, except that the compound obtained in the first step of Example 52 was 3-{4-[3-chloro-4-(3-fluorobenzyloxy). -Phenylamino]-quinazolin-6-yl}-1-triisopropylsilyl-1H-pyrrole-2-carbaldehyde 52a as a starting material, in the same manner as described in the second step of Example 52 of the present invention Reaction of the starting material with 2-methoxyethylamine gave the title compound [3-chloro-4-(3-fluorobenzyloxy)-phenyl]-(6-{5-[(2-methoxy-) Ethylamino)-methyl]-1H-pyrrol-3-yl}-quinazolin-4-indole-amine 117 (55 mg, yellow solid), yield 51.8%.
MS m/z (ESI): 532 [M+ 1] MS m/z (ESI): 532 [M+ 1]
1H NMR (400MHz, DMSO- d6): 610.94(s, 1H), 9.67(s, 1H), 8.54(s, 1H), 8.44(s, 1H), 8.03(m, 2H), 7.75(m, 2H), 7.47(m, 1H), 7.3 l(m, 3H), 7.20(m, 1H), 6.80(t, 1H), 6.44(t, 1H), 5.27(s, 2H), 3.87(s, 2H), 3.39(t, 2I-I), 3.19(s, 3H), 2.68(t, 2H) 实施例 118 「3-氯 -4-G-氟苄氧基 苯基 1-(6-ί5-ΙΪ2-吗啉 -4-乙氨基) -甲基 1-lH-吡咯 -3-基 μ喹 1H NMR (400MHz, DMSO- d 6 ): 610.94 (s, 1H), 9.67 (s, 1H), 8.54 (s, 1H), 8.44 (s, 1H), 8.03 (m, 2H), 7.75 (m, 2H), 7.47(m, 1H), 7.3 l(m, 3H), 7.20(m, 1H), 6.80(t, 1H), 6.44(t, 1H), 5.27(s, 2H), 3.87(s, 2H), 3.39(t, 2I-I), 3.19(s, 3H), 2.68(t, 2H) Example 118 "3-Chloro-4-G-fluorobenzyloxyphenyl 1-(6-ί5-ΙΪ2-morpholin-4-ethylamino)-methyl 1-lH-pyrrol-3-yl-hypoquine
唑啉 -4-基) -胺  Oxazoline-4-yl)-amine
Figure imgf000137_0001
Figure imgf000137_0001
52a 118  52a 118
重复本发明实施例 52第一步至第二步所述的实验步骤，不同的是以实施例 52 第一步所得的化合物 3-{4-[3-氯 -4-C3-氟苄氧基) -苯氨基] -喹唑啉 -6-基 }-1-三异丙基 硅 -1H-吡咯 -2-甲醛 52a作原料， 按照本发明实施例 52第二步所述的相同方式使得 该原料与 2-吗啉 -4-基-乙胺的反应， 得到标题化合物 [3-氯 -4-(3-氟苄氧基) -苯 基] -(6-{5-[(2-吗啉 -4-乙氨基) -甲基 ]-1Η-吡咯 -3-基}-喹唑啉 -4-基) -胺 118 (26 mg,黄 色固体）， 产率： 48.5 %。  The experimental procedure described in the first step to the second step of Example 52 of the present invention was repeated, except that the compound obtained in the first step of Example 52 was 3-{4-[3-chloro-4-C3-fluorobenzyloxy. - phenylamino]-quinazolin-6-yl}-1-triisopropylsilyl-1H-pyrrole-2-carbaldehyde 52a as a starting material, in the same manner as described in the second step of Example 52 of the present invention Reaction of the starting material with 2-morpholin-4-yl-ethylamine gave the title compound [3-chloro-4-(3-fluorobenzyloxy)-phenyl]-(6-{5-[(2-? Phenyl-4-ethylamino)-methyl]-1Η-pyrrol-3-yl}-quinazolin-4-yl)-amine 118 (26 mg, yellow solid), yield: 48.5 %.
MS m/z (ESI): 587[M+ 1] MS m/z (ESI): 587 [M+ 1]
1H NMR (400MHz, CDC13): 510.60(s, IH), 8.61(s, IH), 7.7 l(m, 4H), 7.44(d, IH, J=8.8), 7.33(m, IH), 7.20(m, 2H), 7.16(m, IH), 6.87(d, IH, J=8.8), 6.76(s, IH), 6.28(s, 1H)， 5.07(s, 2H), 3.87(s, 2H), 3.7 l(t, 4H), 2.50(m, 8H) 实施例 119  1H NMR (400MHz, CDC13): 510.60 (s, IH), 8.61 (s, IH), 7.7 l (m, 4H), 7.44 (d, IH, J = 8.8), 7.33 (m, IH), 7.20 ( m, 2H), 7.16(m, IH), 6.87(d, IH, J=8.8), 6.76(s, IH), 6.28(s, 1H), 5.07(s, 2H), 3.87(s, 2H) , 3.7 l(t, 4H), 2.50 (m, 8H) Example 119
Figure imgf000137_0002
Figure imgf000137_0002
化合物 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-[6-(1Η-吡咯 -3-基) -喹唑啉 -4-基] -胺 42作原料， 按照本发明实施例 51所述的相同方式使得该原料与甲磺酰氯的反应， 得到标题化 合物 [3-氯 -4-(3-氟苄氧基) -苯基 ]-[6-(1-甲磺酰基 -1Η-吡咯 -3-基) -喹唑啉 -4-基] -胺 119The compound [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1Η-pyrrol-3-yl)-quinazolin-4-yl]-amine 42 is used as a starting material, The reaction of the starting material with methanesulfonyl chloride in the same manner as described in Example 51 of the present invention afforded the title compound [3-chloro-4-(3-fluorobenzyloxy)-phenyl]-[6-(1- Sulfonyl-1Η-pyrrol-3-yl)-quinazolin-4-yl]-amine 119
(26 mg, 黄色固体）， 产率： 48.5 %。 (26 mg, yellow solid), Yield: 48.5 %.
MS m/z (ESI): 523 [M+ l] Ή NMR (400MHz, DMSO- d6): 610.24(s, IH), 9.04(s, IH), 8.94(s, IH), 8.19(d, IH J=8.8), 8.14(s, IH), 7.86(s, IH), 7.75(d, IH, J=8.4), 7.48(d, IH, 3=6.0), 7.39(m, IH): 7.30(m, 5H), 7.8 l(m, IH), 5.27(s, 2H), 3.55(s， 3H) 实施例 120 MS m/z (ESI): 523 [M+ l] Ή NMR (400MHz, DMSO- d 6 ): 610.24 (s, IH), 9.04 (s, IH), 8.94 (s, IH), 8.19 (d, IH J = 8.8), 8.14 (s, IH), 7.86 (s, IH), 7.75 (d, IH, J = 8.4), 7.48 (d, IH, 3 = 6.0), 7.39 (m, IH): 7.30 (m, 5H), 7.8 l (m, IH), 5.27(s, 2H), 3.55(s, 3H) Example 120
2-η-「4-(3-氯 -4-氟苯氨基)-喹唑啉 -6-基 1-4-吗啉 -4-甲基 -IH-吡咯 -3-基 乙醇  2-η-"4-(3-Chloro-4-fluorophenylamino)-quinazoline-6-yl 1-4-morpholine-4-methyl-IH-pyrrole-3-ylethanol
Figure imgf000138_0001
Figure imgf000138_0001
第一步  First step
在 25 mL茄形瓶中加入氢化铝锂（50 mg， 1.31 mmol)和 3 mL四氢呋喃， 冰 浴冷却下逐渐滴加化合物 [1-[4-(3-氯 -4-氟-苯氨基) -喹唑啉 -6-基] -4-(2-羟乙基 )-1Η- 吡咯 -3-基] -吗啉 -4-甲鮞 106 ( 150 mg， ' 0.319 mmol) 的 3 mL四氢呋喃溶液。 将反 应液在室温下搅拌 4小时后反应完毕， 慢慢滴加甲醇， 反应液在减压下浓缩， 得 到的残留物用 TLC板进行分离纯化， 得到标题产物 2-{1-[4-(3-氯 -4-氟苯氨基) -喹 唑啉 -6-基] -4-吗啉 -4-甲基 -1H-吡咯 -3-基} -乙醇 120 (54 mg，黄色固体），产率： 85.54 %。  Lithium aluminum hydride (50 mg, 1.31 mmol) and 3 mL of tetrahydrofuran were added to a 25 mL eggplant flask, and the compound [1-[4-(3-chloro-4-fluoro-phenylamino)] was gradually added dropwise under ice cooling. A solution of quinazolin-6-yl]-4-(2-hydroxyethyl)-1Η-pyrrol-3-yl]-morpholin-4-carboindole 106 (150 mg, '0.319 mmol) in 3 mL THF. After the reaction mixture was stirred at room temperature for 4 hours, the reaction was completed, and methanol was slowly added dropwise, and the reaction mixture was concentrated under reduced pressure, and the obtained residue was purified and purified to afford the title product 2-{1-[4-( 3-chloro-4-fluorophenylamino)-quinazolin-6-yl]-4-morpholin-4-methyl-1H-pyrrol-3-yl}-ethanol 120 (54 mg, yellow solid) Rate: 85.54%.
MS m/z (ESI): 482[M+ 1]  MS m/z (ESI): 482 [M+ 1]
1H NMR (400MHz, DMSO- d6): δ 9.88(s, IH), 8.60(s, 1H)， 8.53(s, IH), 8.18(m, 2H)， 7.86(d, 2H, J=8.4), 7.49(m, IH), 7.42(d, 2H), 4.90(s, IH), 3.62(m, 6H), 3.37(m, 2H), 2.69(t, 2H), 2.43(m, 4H) 实施例 121 1H NMR (400MHz, DMSO- d 6 ): δ 9.88 (s, IH), 8.60 (s, 1H), 8.53 (s, IH), 8.18 (m, 2H), 7.86 (d, 2H, J = 8.4) , 7.49(m, IH), 7.42(d, 2H), 4.90(s, IH), 3.62(m, 6H), 3.37(m, 2H), 2.69(t, 2H), 2.43(m, 4H) Example 121
2-Π-「4-(3-氯 -4-氟苯氨基 喹唑啉 -6-基 1-4-哌啶 -1-甲基 -IH-吡咯 -3-基 1-乙醇 2- Π-"4-(3-Chloro-4-fluorophenylaminoquinazolin-6-yl1-4-piperidin-1-methyl-IH-pyrrol-3-yl 1-ethanol
Figure imgf000138_0002
Figure imgf000138_0002
重复本发明实施例 120第一步所述的实验步骤， 不同的是以实施例 110最终 所得的化合物 [1-[4-(3-氯 -4-氟-苯氨基) -喹唑啉 -6-基] -4-(2-羟乙基 )-1Η-吡咯 -3-基] - 哌啶 -1-甲酮 110作原料， 按照本发明实施例 120第一步所述的相同方式使得该原 料与氢化铝锂的反应， 得到标题化合物 2-{1-[4-(3-氯 -4-氟苯氨基) -喹唑啉 -6-基] -4- 哌啶 -1-甲基 -1H-吡咯 -3-基} -乙醇 121 (57 mg, 黄色固体）， 产率： 78.13 % , MS m/z (ESI): 480[M+ 1] The experimental procedure described in the first step of Example 120 of the present invention was repeated, except that the compound [1-[4-(3-chloro-4-fluoro-phenylamino)-quinazoline-6 finally obtained in Example 110 was obtained. -yl]-4-(2-hydroxyethyl)-1Η-pyrrol-3-yl] - Piperidine-1-methyl ketone 110 was used as a starting material, and the title compound was obtained from the title compound 2-{1-[4-(3-chloro) in the same manner as described in the first step of Example 120. 4-fluorophenylamino)-quinazolin-6-yl]-4-piperidin-1-methyl-1H-pyrrol-3-yl}-ethanol 121 (57 mg, yellow solid), yield: 78.13 % , MS m/z (ESI): 480[M+ 1]
1H NMR (400MHz, DMSO- d6): δ 9.90(s, IH), 8.55(d, 2H), 8.15(m, 2H), 7.83(d, 2H, J=8.8), 7.46(t， 1H)， 7.39(d, 2H, J=10.0), 5.20(s, IH), 3.62(m, 2H), 3.29(s, 2H), 2.67(t, 2H), 2.38(m, 4H), 1.49(m, 4H), 1.41(m, 2H) 实施例 122 1H NMR (400MHz, DMSO-d 6 ): δ 9.90 (s, IH), 8.55 (d, 2H), 8.15 (m, 2H), 7.83 (d, 2H, J = 8.8), 7.46 (t, 1H) , 7.39(d, 2H, J=10.0), 5.20(s, IH), 3.62(m, 2H), 3.29(s, 2H), 2.67(t, 2H), 2.38(m, 4H), 1.49(m , 4H), 1.41 (m, 2H) Example 122
2-Γ1-Γ4-(ϊ3-氯 -4-氟苯氨基) -喹唑啉 -6-基 l-4-(4-甲基哌嗪小甲基) -IH-吡咯 -3- 基 乙醇  2-Γ1-Γ4-(ϊ3-chloro-4-fluorophenylamino)-quinazoline-6-yl l-4-(4-methylpiperazine small methyl)-IH-pyrrole-3-ylethanol
Figure imgf000139_0001
Figure imgf000139_0001
重复本发明实施例 120第一步所述的实验步骤， 不同的是以实施例 107最终 所得的化合物 [1-[4-(3-氯 -4-氟-苯氨基) -喹唑啉 -6-基] -4-(2-羟乙基) -1H-吡咯 -3- 基] -(4-甲基哌嗪 -1-基) -甲酮 107作原料，按照本发明实施例 120第一步所述的相同 方式使得该原料与氢化铝锂的反应， 得到标题化合物 2-[1-[4-((3-氯 -4-氟苯氨基) - 喹唑啉 -6-基] -4-(4-甲基哌嗪 -1-甲基) -1H-吡咯 -3-基] -乙醇 122 (40 mg, 黄色固体）， 产率: 45.7%。  The experimental procedure described in the first step of Example 120 of the present invention was repeated, except that the compound [1-[4-(3-chloro-4-fluoro-phenylamino)-quinazoline-6 finally obtained in Example 107 was obtained. -yl]-4-(2-hydroxyethyl)-1H-pyrrol-3-yl]-(4-methylpiperazin-1-yl)-methanone 107 as starting material, according to Example 120 of the present invention The title compound 2-[1-[4-((3-chloro-4-fluorophenylamino)-quinazolin-6-yl]-4 was obtained in the same manner as described above. -(4-Methylpiperazin-1-methyl)-lH-pyrrol-3-yl]-ethanol 122 (40 mg, yellow solid), yield: 45.7%.
MS m/z (ESI): 480[M+ 1]  MS m/z (ESI): 480 [M+ 1]
1H NMR (400MHz, DMSO- d6): δ 9.90(s, IH), 8.59(d, 2H)， 8.18(d, 2H), 8.13(d, IH, 1H NMR (400MHz, DMSO- d 6 ): δ 9.90 (s, IH), 8.59 (d, 2H), 8.18 (d, 2H), 8.13 (d, IH,
J=8.8), 7.86(d, 2H, J=8.8), 7.48(t, 1H)， 7.38(d, 2H), 5.00(s, IH), 3.62(s, 2H), 3.33(s,J=8.8), 7.86(d, 2H, J=8.8), 7.48(t, 1H), 7.38(d, 2H), 5.00(s, IH), 3.62(s, 2H), 3.33(s,
2H), 2.67(t, 2H), 2.42(m, 8H), 2.15(s, 3H) 实施例 123 2H), 2.67(t, 2H), 2.42(m, 8H), 2.15(s, 3H) Example 123
2-(i- -「3-氯 -4-C3-氟苄氧基) -苯氨基 Ί-喹唑啉 -6-基 4-二乙氨基甲基 -IH-吡咯  2-(i- - "3-chloro-4-C3-fluorobenzyloxy)-phenylaminopurine-quinazoline-6-yl 4-diethylaminomethyl-IH-pyrrole
-3-基) -乙醇  -3-yl)-ethanol
Figure imgf000139_0002
Figure imgf000139_0002
重复本发明实施例 116第一步至第三步所述的实验步骤， 不同的是以实施例 116第二步所得的化合物 1-{4-[3-氯 -4-(3--氟苄氧基) -苯氨基] - 喹唑啉 -6-基 }-4-(2- 羟乙基) -lH-吡咯 -3-甲醛 116b作原料，按照本发明实施例 116第三步所述的相同方 式使得该原料与二乙胺的反应，得到标题化合物 2-(1-{4-[3-氯 -4-(3-氟苄氧基) -苯氨 基]-喹唑啉 -6-基 }-4-二乙氨基甲基 -1H-吡咯 -3-基) -乙醇 123 ( 14 mg, 黄色固体）， 产率： 5 % o The experimental procedure described in the first step to the third step of Example 116 of the present invention was repeated, except that the compound obtained in the second step of Example 116 was 1-{4-[3-chloro-4-(3--fluorobenzyl). Oxy)phenylamino]-quinazolin-6-yl}-4-(2- The hydroxyethyl)-lH-pyrrole-3-carbaldehyde 116b is used as a starting material to react the starting material with diethylamine in the same manner as described in the third step of Example 116 of the present invention to give the title compound 2-(1-{4 -[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazolin-6-yl}-4-diethylaminomethyl-1H-pyrrol-3-yl)-ethanol 123 ( 14 mg, yellow solid), Yield: 5 % o
MS m/z (ESI): 674[M+1]  MS m/z (ESI): 674 [M+1]
'H NMR (400MHZ, DMSO- d6): δ 9.77(s, 1H), 8.54(s, 1H), 8.50(s, 1H), 8.11(dd, 1H， J=8.8), 8.01(s, 1H)， 7.83(d, 1H, J=8.8), 7.74(dd3 1H, J=8.8), 7.47(m, 1H), 7.42(s, 1H), 7.35(m, 4H), 7.19(t, 1H), 5.27(s, 2H), 3.62(t, 2H), 3.42(s, 2H), 2.68(t， 2H), 2.53(q, 4H), 1.02(t, 6H) " 实施例 124 'H NMR (400 MHZ, DMSO-d 6 ): δ 9.77 (s, 1H), 8.54 (s, 1H), 8.50 (s, 1H), 8.11 (dd, 1H, J = 8.8), 8.01 (s, 1H) ), 7.83(d, 1H, J=8.8), 7.74(dd 3 1H, J=8.8), 7.47(m, 1H), 7.42(s, 1H), 7.35(m, 4H), 7.19(t, 1H) ), 5.27(s, 2H), 3.62(t, 2H), 3.42(s, 2H), 2.68(t, 2H), 2.53(q, 4H), 1.02(t, 6H) "Example 124
2-α-ί4-「3-氯 -4-(3-氟苄氧基) -苯氨基 喹唑啉 -6-基 }-4-二甲氨基甲基 -lH-吡咯  2-α-ί4-"3-Chloro-4-(3-fluorobenzyloxy)-phenylaminoquinazoline-6-yl}-4-dimethylaminomethyl-lH-pyrrole
-3-基) -乙醇  -3-yl)-ethanol
Figure imgf000140_0001
Figure imgf000140_0001
重复本发明实施例 116第 步至第三步所述的实验步骤， 不同的是以实施例 Repeat the experimental steps described in the first step to the third step of the embodiment 116 of the present invention, except that the embodiment is
116第二步所得的化合物 1-{4-[3-氯 -4-(3--氟苄氧基) -苯氨基] -喹唑啉 -6-基}-4-(2- 羟乙基 1H-吡咯 -3-甲醛 116b作原料，按照本发明实施例 116第三步所述的相同方 式使得该原料与二甲胺的反应，得到标题化合物 2-(1-{4-[3-氯 -4-(3-氟苄氧基) -苯氨 基]—喹唑啉 _6-基}-4-二甲氨基甲基 -1H-吡咯 -3-基) -乙醇 124 ( 122 mg, 黄色固体）， 产率： 38.5 %。 Compound 1-{4-[3-chloro-4-(3--fluorobenzyloxy)-phenylamino]-quinazolin-6-yl}-4-(2-hydroxyethyl) obtained in the second step 1H-pyrrole-3-carbaldehyde 116b is used as a starting material to react the starting material with dimethylamine in the same manner as described in the third step of Example 116 of the present invention to give the title compound 2-(1-{4-[3-chloro 4-(3-fluorobenzyloxy)-phenylamino]-quinazoline-6-yl}-4-dimethylaminomethyl-1H-pyrrol-3-yl)-ethanol 124 ( 122 mg, yellow solid ), Yield: 38.5 %.
MS m/z (ESI): 546[M+ 1]  MS m/z (ESI): 546 [M+ 1]
1H NMR (400MHz, DMSO- d6): δ 9.77(s, 1H), 8.54(s, 1H), 8.51(d, 1H， J=2.4), 8.10(dd, 1H), 8.01 (d, 1H, J=2.4)， 7.83(d, 1H, J=8.8), 7.74(dd, 1H, J=8.8), 7.48(m， 1H), 7.43 (d, 1H), 7.35(m, 4H), 7.29(t, 1H), 5.27(s, 2H), 5.10(s, 1H), 3.61 (t, 2H), 3.28(s, 2H), 2.66(t, 2H), 2.19(s, 6H) 实施例 125 1H NMR (400MHz, DMSO- d 6 ): δ 9.77 (s, 1H), 8.54 (s, 1H), 8.51 (d, 1H, J = 2.4), 8.10 (dd, 1H), 8.01 (d, 1H, J=2.4), 7.83(d, 1H, J=8.8), 7.74(dd, 1H, J=8.8), 7.48(m, 1H), 7.43 (d, 1H), 7.35(m, 4H), 7.29( t, 1H), 5.27(s, 2H), 5.10(s, 1H), 3.61 (t, 2H), 3.28(s, 2H), 2.66(t, 2H), 2.19(s, 6H) Example 125
4- Π-ί4-「3-氯 -4- 3-氟苄氧基) -苯氨基 1-喹唑啉 -6-基 4-( -羟基乙基) -lH-吡咯  4- Π-ί4-"3-Chloro-4- 3-fluorobenzyloxy)-phenylamino 1-quinazoline-6-yl 4-(-hydroxyethyl)-1H-pyrrole
-3-甲基 1-氨基 甲基) -1,1-二氧代 -六氢 -1λ*6*-噻喃 -4-醇  -3-methyl 1-aminomethyl)-1,1-dioxo-hexahydro-1λ*6*-thiopyran-4-ol
Figure imgf000140_0002
重复本发明实施例 116第一步至第三步所述的实验歩骤， 不同的是以实施例 116第二歩所得的化合物 1-{4-[3-氯 -4-(3--氟苄氧基) -苯氨基] -喹唑啉 -6-基}-4-(2- 羟乙基 )-1Η-吡咯 -3-甲醛 116b作原料，按照本发明实施例 116第三步所述的相同方 式使得该原料与 4-氨甲基 -1,1-二氧代 -六氢 -1λ*6*-噻喃 -4-醇的反应，得到标题化合 物 4-({[1-{4-[3-氯 -4-(3-氟苄氧基) -苯氨基]-喹唑啉 -6-基}-4-(2-羟基乙基) -1Η-吡咯 -3-甲基] -氨基 }-甲基) -U-二氧代 -六氢 -1λ*6*-噻喃 -4-醇 125 ( 103 mg， 黄色固体）， 产率： 31.3 %。
Figure imgf000140_0002
The experimental procedure described in the first step to the third step of the embodiment 116 of the present invention is repeated, except that the compound obtained in the second step of the embodiment 116 is 1-{4-[3-chloro-4-(3--fluoro). Benzyloxy)-phenylamino]-quinazolin-6-yl}-4-(2-hydroxyethyl)-1Η-pyrrole-3-carbaldehyde 116b as a starting material, according to the third step of Example 116 of the present invention The reaction of the starting material with 4-aminomethyl-1,1-dioxo-hexahydro-1λ*6*-thiopyran-4-ol in the same manner gave the title compound 4-({[1-{4 -[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazolin-6-yl}-4-(2-hydroxyethyl)-1Η-pyrrole-3-methyl] - Amino}-methyl)-U-dioxo-hexahydro-1λ*6*-thiopyran-4-ol 125 (103 mg, yellow solid), yield: 31.3%.
MS m/z (ESI): 680[M+ 1] MS m/z (ESI): 680 [M+ 1]
1H NMR (400MHz, DMSO- d6): δ 9.77(s, 1H), 8.55(s, 1H), 8.50(s, 1H), 8.10(d, 1H, J=9.6), 8.01(s, 1H), 7.84(d, 1H, J=8.8), 7.75(dd, 1H, J=8.8), 7.49(m, 1H), 7.43(s, 1H), 7.36(m, 4H), 7.20(m, 1H), 5.27(s, 2H), 3.64(t, 2H), 3.58(s, 2H), 3.10(m, 4H), 2.67(t, 2H), 2.50(m, 2H)， 2.10(m, 2H), 1.60(m, 2H) 实施例 126 1H NMR (400MHz, DMSO- d 6 ): δ 9.77 (s, 1H), 8.55 (s, 1H), 8.50 (s, 1H), 8.10 (d, 1H, J = 9.6), 8.01 (s, 1H) , 7.84(d, 1H, J=8.8), 7.75(dd, 1H, J=8.8), 7.49(m, 1H), 7.43(s, 1H), 7.36(m, 4H), 7.20(m, 1H) , 5.27(s, 2H), 3.64(t, 2H), 3.58(s, 2H), 3.10(m, 4H), 2.67(t, 2H), 2.50(m, 2H), 2.10(m, 2H), 1.60 (m, 2H) Example 126
2-(1- -「3-氯 -4-(3-氟苄氧基) -苯氨基卜喹唑啉 -6-基 }-4-ί「α,1-二氧代 -六氢 -1λ*6*-噻喃 -4甲基) -氨基 1-甲基 吡咯 -3-基) -乙醇  2-(1- -"3-Chloro-4-(3-fluorobenzyloxy)-phenylaminobuquinazoline-6-yl}-4-ί"α,1-dioxo-hexahydro-1λ *6*-thiopyran-4-methyl)-amino 1-methylpyrrol-3-yl)-ethanol
Figure imgf000141_0001
Figure imgf000141_0001
重复本发明实施例 116第一步至第三步所述的实验步骤， 不同的是以实施例 116第二步所得的化合物 1-{4-[3-氯 -4-(3--氟苄氧基) -苯氨基] -喹唑啉 -6-基 }-4-(2- 羟乙基) -1H-吡咯 -3-甲醛 116b作原料，按照本发明实施例 116第三步所述的相同方 式使得该原料与 C-(l,l-二氧代 -六氢 -1λ*6*4噻喃 -4-基) -甲胺的反应， 得到标题化 合物 2-(1-{4-[3-氯 -4-(3-氟苄氧基) -苯氨基]-喹唑啉 -6-基 }-4-{[(1,1-二氧代 -六氢 -1λ*6*-噻喃 -4甲基) -氨基] -甲基 }-1Η-吡咯 -3-基) -乙醇 126 ( 115 mg， 黄色固体）， 产率： 35.8%。  The experimental procedure described in the first step to the third step of Example 116 of the present invention was repeated, except that the compound obtained in the second step of Example 116 was 1-{4-[3-chloro-4-(3--fluorobenzyl). Oxyphenyl)-phenylamino]-quinazolin-6-yl}-4-(2-hydroxyethyl)-1H-pyrrole-3-carbaldehyde 116b as a starting material, according to the third step of Example 116 of the present invention The reaction of the starting material with C-(l,l-dioxo-hexahydro-1λ*6*4-thiopyran-4-yl)-methylamine affords the title compound 2-(1-{4-[ 3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazolin-6-yl}-4-{[(1,1-dioxo-hexahydro-1λ*6*-thiophene M--4-methyl)-amino]-methyl}-1Η-pyrrol-3-yl)-ethanol 126 (115 mg, yellow solid), yield: 35.8%.
MS m/z (ESI): 664[M+ 1] MS m/z (ESI): 664 [M+ 1]
1H NMR (400MHz, DMSO- d6): δ 9.82(s， 1H)， 8.55(m, 2H), 8.10(d, 1H, J=8.8), 8.03(d, 1H, J=2.4), 7.86(d, 1H, J=8.8), 7.77(dd, 1H, J=7.2), 7.53(m, 2H), 7.39(s, 1H), 7.35(m, 3H), 7.19(m, 1H)， 5.27(s, 2H), 3.74(s, 2H), 3.66(t, 2H), 3.18(m, 3H), 2.97(d, 2H), 2.71(m, 4H), 2.00(m, 4H) 实施例 127 1H NMR (400MHz, DMSO-d 6 ): δ 9.82 (s, 1H), 8.55 (m, 2H), 8.10 (d, 1H, J = 8.8), 8.03 (d, 1H, J = 2.4), 7.86 ( d, 1H, J=8.8), 7.77 (dd, 1H, J=7.2), 7.53(m, 2H), 7.39(s, 1H), 7.35(m, 3H), 7.19(m, 1H), 5.27( s, 2H), 3.74(s, 2H), 3.66(t, 2H), 3.18(m, 3H), 2.97(d, 2H), 2.71(m, 4H), 2.00(m, 4H) Example 127
2_d-{4_「3-氯 -4— (3-氟苄氧基 苯氨基 1-喹唑啉 -6-基 4-「Q-甲磺酰基乙氨基) -甲 基 1-1H-吡咯 -3-基 乙醇
Figure imgf000142_0001
 2 _d-{ 4 _" 3 -Chloro- 4 - ( 3 -fluorobenzyloxyphenylamino 1-quinazolin-6-yl 4-"Q-methylsulfonylethylamino) -methyl 1-1H-pyrrole -3-ylethanol
Figure imgf000142_0001
重复本发明实施例 116第一歩至第三步所述的实验步骤， 不同的是以实施例 116第二步所得的化合物 1-{4-[3-氯 -4-(3--氟苄氧基) -苯氨基] -喹唑啉 -6-基 }-4-(2- 羟乙基 )-1Η-吡咯 -3-甲醛 116b作原料，按照本发明实施例 116第三步所述的相同方 式使得该原料与 2-甲磺酰基乙胺的反应， 得到标题化合物 2-(1-{4-[3-氯 -4-(3-氟苄 氧基) -苯氨基]-喹唑啉 -6-基}-4-[(2-甲磺酰基乙氨基) -甲基] -1H-吡咯 -3-基} -乙醇 127 The experimental procedure described in the first to third steps of Example 116 of the present invention was repeated, except that the compound 1-{4-[3-chloro-4-(3--fluorobenzyl) obtained in the second step of Example 116 was used. Oxyphenyl)-phenylamino]-quinazolin-6-yl}-4-(2-hydroxyethyl)-1Η-pyrrole-3-carbaldehyde 116b as a starting material, according to the third step of Example 116 of the present invention The title compound 2-(1-{4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazoline was obtained in the same manner. -6-yl}-4-[(2-methanesulfonylethylamino)-methyl]-1H-pyrrol-3-yl}-ethanol 127
(97 mg, 黄色固体）， 产率： 32.1 %。 (97 mg, yellow solid), Yield: 32.1 %.
MS m/z (ESI): 624[M+ 1] MS m/z (ESI): 624 [M+ 1]
1H NMR (400MHz, DMSO- d6): δ 9.77(s, IH), 8.55(m, IH), 8.51(s, IH), 8.10(dd, IH, J=9.6), 8.01(d, IH, J=2.8), 7.85(d, IH, J-8.8), 7.76(dd, IH, J=8.8), 7.49(m, 2H), 7.37(m: 4H), 7.19(m, IH), 5.27(s, 2H), 3.65(t, 4H), 3.28(m, 2H), 3.02(m, 2H), 2.68(t, 2H), 2.5 l(t, 3H) 实施例 128 1H NMR (400MHz, DMSO- d 6 ): δ 9.77 (s, IH), 8.55 (m, IH), 8.51 (s, IH), 8.10 (dd, IH, J = 9.6), 8.01 (d, IH, J=2.8), 7.85(d, IH, J-8.8), 7.76(dd, IH, J=8.8), 7.49(m, 2H), 7.37(m : 4H), 7.19(m, IH), 5.27( s, 2H), 3.65(t, 4H), 3.28(m, 2H), 3.02(m, 2H), 2.68(t, 2H), 2.5 l(t, 3H) Example 128
「1- -C3-氯 -4-(3-氟苄氧基) -苯氨基 1-喹唑啉 -6-基 4-(2-吗啉 -4-乙基) -IH-吡咯  "1--C3-Chloro-4-(3-fluorobenzyloxy)-phenylamino-1-quinazoline-6-yl 4-(2-morpholin-4-ethyl)-IH-pyrrole
-3-基 1-吗啉 -4-甲酮  -3-yl 1-morpholine-4-methanone
Figure imgf000142_0002
第一步
Figure imgf000142_0002
first step
甲磺酸 2-[1-{4-[3-氯 -4-(3-氟苄氧基) -苯氨基] -喹唑啉 -6-基}-4- (吗啉 -4-羰 基) -1H-吡咯 -3-基] -乙酯 在 50 mL 茄形瓶中， 将 [1-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6- 基}-4-(2-羟基-乙基) -1H-吡咯 -3-基] -吗啉 -4-基 -甲酮 27 (500 mg， 0.83 mmol)溶解 于 20 mL四氢呋喃中， 搅拌下加入 0.23 mL三乙胺， 所得的混合液在冰浴冷却下 逐渐滴加甲磺酰氯（190 mg， 1.66mmol)的 5 mL四氢呋喃溶液， 反应液在室温下 搅拌 1小时后反应完毕。 将反应液加入到 50 mL水中， 有黄色固体析出， 过滤， 得到的固体在真空下干燥， 得到本标题产物甲磺酸 2-[1-{4-[3-氯 -4-(3-氟苄氧基) - 苯氨基] -喹唑啉 -6-基}-4- (吗啉 -4-羰基) -1H-吡咯 -3-基] -乙酯 128a (500 mg， 黄色固 体）， 产率： 90%。 2-[1-{4-[3-Chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazolin-6-yl}-4-(morpholin-4-carbonyl) methanesulfonate -1H-pyrrol-3-yl]-ethyl ester [1-{4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-4-(2- in a 50 mL eggplant-shaped flask Hydroxy-ethyl)-1H-pyrrol-3-yl]-morpholin-4-yl-methanone 27 (500 mg, 0.83 mmol) was dissolved in 20 mL of tetrahydrofuran, and 0.23 mL of triethylamine was added with stirring. The mixture was gradually added dropwise with a solution of methanesulfonyl chloride (190 mg, 1.66 mmol) in 5 mL of tetrahydrofuran, and the reaction mixture was stirred at room temperature for 1 hour. The reaction solution was added to 50 mL of water, and a yellow solid was precipitated and filtered, and the obtained solid was dried under vacuo to give the title product 2-[1-{4-[3-chloro-4-(3-fluoro). Benzyloxy)-phenylamino]-quinazolin-6-yl}-4-(morpholin-4-carbonyl)-1H-pyrrol-3-yl]-ethyl ester 128a (500 mg, yellow solid) Rate: 90%.
MS m/z (ESI): 681 [M+ 1] MS m/z (ESI): 681 [M+ 1]
第二歩  Second
[l-{4-[3-氯 -4-(3-氟苄氧基) -苯氨基]-喹唑啉 -6-基}-4-(2-吗啉 -4-乙基) -1H-吡咯  [l-{4-[3-Chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazolin-6-yl}-4-(2-morpholin-4-ethyl)-1H -pyrrole
-3-基] -吗啉 -4-甲酮  -3-yl]-morpholine-4-methanone
在 25 mL茄形瓶中， 将上述步骤所得的化合物甲磺酸 2-[1-{4-[3-氯 -4-(3-氟苄 氧基) -苯氨基]-喹唑啉 -6-基 }-4- (吗啉 -4-羰基) -1H-吡咯 -3-基] -乙酯 128a ( 80 mg， 0.118 mmol)溶解于 2 mL [1,4]二氧六环中， 混合液在搅拌下加入 1 mL吗啉， 加 热反应液至 70Ό， 反应 4小时后反应完毕。 反应液冷却至室温， 滴加到 50 mL水 中， 析出白色固体， 过滤， 所得的粗品进一步通过 TLC板进行分离纯化， 得到本 标题产物 [1-{4-[3-氯 -4-(3-氟苄氧基) -苯氨基]-喹唑啉 -6-基}-4-(2-吗啉 -4-乙基) -1H- 吡咯 -3-基] -吗啉 -4-甲酮 128 ( 50 mg, 黄色固体）， 产率： 64%。  In the 25 mL eggplant-shaped flask, the compound obtained in the above step was 2-[1-{4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazoline-6. -yl}-4-(morpholine-4-carbonyl)-1H-pyrrol-3-yl]-ethyl ester 128a (80 mg, 0.118 mmol) dissolved in 2 mL [1,4] dioxane, mixed The solution was added with 1 mL of morpholine under stirring, and the reaction solution was heated to 70 Torr. After 4 hours of reaction, the reaction was completed. The reaction solution was cooled to room temperature, added dropwise to 50 mL of water, and the white solid was separated, filtered, and the obtained crude product was further purified and purified by TLC to give the title product [1-{4-[3-chloro-4-(3- Fluorobenzyloxy)-phenylamino]-quinazolin-6-yl}-4-(2-morpholin-4-ethyl)-1H-pyrrol-3-yl]-morpholin-4-methanone 128 (50 mg, yellow solid), Yield: 64%.
MS m/z (ESI): 672[M+ 1] MS m/z (ESI): 672 [M+ 1]
1H NMR (400MHz, DMSO- d6): δ 9.80(s, 1H), 9.00(s, 1H), 8.60(s, 1H), 8.20(d, 2H), 7.90(m, 3H), 7.80(s, 1H), 7.47(m, 1H), 7.32 (m, 3H), 7.19 (m, 1H), 5.28(s, 2H), 3.97(s, 2H), 3.81(s, 2H), 3.67(s, 8H), 3.48(s, 2H), 3.40(s, 2H), 3.14(s, 2H), 3.04(s, 2H) 实施例 129 1H NMR (400MHz, DMSO- d 6 ): δ 9.80 (s, 1H), 9.00 (s, 1H), 8.60 (s, 1H), 8.20 (d, 2H), 7.90 (m, 3H), 7.80 (s , 1H), 7.47(m, 1H), 7.32 (m, 3H), 7.19 (m, 1H), 5.28(s, 2H), 3.97(s, 2H), 3.81(s, 2H), 3.67(s, 8H), 3.48(s, 2H), 3.40(s, 2H), 3.14(s, 2H), 3.04(s, 2H) Example 129
Γ1- -Γ3-氯 -4-(3-氟苄氧基) -苯氨基 1-喹唑啉 -6-基 }-4-(2-甲氧基乙基) -1H-吡咯  Γ1- -Γ3-chloro-4-(3-fluorobenzyloxy)-phenylamino-1-quinazoline-6-yl}-4-(2-methoxyethyl)-1H-pyrrole
-3-基 1-吗啉 -4-甲酮  -3-yl 1-morpholine-4-methanone
Figure imgf000143_0001
Figure imgf000143_0001
重复本发明实施例 128第一步至第二步所述的实验步骤， 不同的是以实施例 128第一歩所得的化合物甲磺酸 2-[1-{4-[3-氯 -4-(3-氟苄氧基) -苯氨基] -喹唑啉 -6- 基 }_4- (吗啉 -4-羰基) -1H-吡咯 -3-基] -乙酯 128a作原料，按照本发明实施例 128第二 步所述的相同方式使得该原料与甲醇钠的反应， 得到标题化合物 [1-{4-[3-氯 -4-(3- 氟苄氧基) -苯氨基] -喹唑啉 -6-基 4-(2-甲氧基乙基) -1H-吡咯 -3-基] -吗啉 -4-甲酮 129 (25mg, 黄色固体）， 产率： 32%。 The experimental procedure described in the first step to the second step of Example 128 of the present invention was repeated, except that the compound obtained in the first step of Example 128 was 2-[1-{4-[3-chloro-4-methanesulfonate. (3-Fluorobenzyloxy)-phenylamino]-quinazolin-6-yl}_4-(morpholin-4-carbonyl)-1H-pyrrol-3-yl]-ethyl ester 128a as a starting material, according to the invention The title compound [1-{4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinidine was obtained in the same manner as described in the second step of Example 128. Oxazolin-6-yl 4-(2-methoxyethyl)-1H-pyrrol-3-yl]-morpholine-4-ketone 129 (25 mg, yellow solid), Yield: 32%.
MS m/z (ESI): 617[M+ 1] MS m/z (ESI) : 617 [M+ 1]
1H NMR (400MHz, DMSO- d6): δ 10.10(s, 1H), 8.80(s, 1H), 8.57(s, 1H), 8.18(d, 1H): 8.09(s, 1H), 7.84(m, 3H), 7.50(m, 2H), 7.30(m, 3H), 7.18(t, 1H), 5.27(s, 2H)， 3.62(s: 8H), 3.53(t, 2H), 3.27(s, 3H), 2.78(t, 2H) 实施例 130 1H NMR (400MHz, DMSO- d 6 ): δ 10.10 (s, 1H), 8.80 (s, 1H), 8.57 (s, 1H), 8.18 (d, 1H): 8.09 (s, 1H), 7.84 (m , 3H), 7.50(m, 2H), 7.30(m, 3H), 7.18(t, 1H), 5.27(s, 2H), 3.62(s : 8H), 3.53(t, 2H), 3.27(s, 3H), 2.78(t, 2H) Example 130
Γ1-ί4-「3-氯 -4-(3-氟苄氧基) -苯氨基 1-喹唑啉 -6-基 4-(2-二乙氨基乙基 IH-吡 咯 -3-基 1-吗啉 -4-甲酮  Γ1-ί4-"3-Chloro-4-(3-fluorobenzyloxy)-phenylamino-1-quinazolin-6-yl 4-(2-diethylaminoethyl IH-pyrrol-3-yl 1- Morpholine-4-methanone
Figure imgf000144_0001
Figure imgf000144_0001
重复本发明实施例 128第一步至第二步所述的实验步骤， 不同的是以实施例 128第一步所得的化合物甲磺酸 2-[1-{4-[3-氯 -4-(3-氟苄氧基) -苯氨基] -喹唑啉 -6- 基 }-4- (吗啉 -4-羰基) -1H-吡咯 -3-基] -乙酯 128a作原料，按照本发明实施例 128第二 步所述的相同方式使得该原料与二乙胺的反应， 得到标题化合物 [1-{4-[3-氯 -4-(3- 氟苄氧基) -苯氨基] -喹唑啉 -6-基 }-4-(2-二乙氨基乙基) -1H-吡咯 -3-基] -吗啉 -4-甲酮 130 (40 mg， 黄色固体）， 产率： 48 %。  The experimental procedure described in the first step to the second step of the embodiment 128 of the present invention is repeated, except that the compound obtained in the first step of the embodiment 128 is 2-[1-{4-[3-chloro-4- (3-Fluorobenzyloxy)-phenylamino]-quinazolin-6-yl}-4-(morpholin-4-carbonyl)-1H-pyrrol-3-yl]-ethyl ester 128a as a starting material, according to the present The title compound [1-{4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino] was obtained in the same manner as described in the second step of the invention. -quinazolin-6-yl}-4-(2-diethylaminoethyl)-1H-pyrrol-3-yl]-morpholin-4-methanone 130 (40 mg, yellow solid), yield: 48%.
MS m/z (ESI): 657[M+ 1] MS m/z (ESI): 657 [M+ 1]
1H NMR (400MHz, DMSO- d6): δ 9.80(s, 1H), 9.00(s, 1H), 8.62(s, 1H), 8.20(d, 1H, J=10.0), 8.14(s, 1H)， 7.92(m, 3H), 7.90(s, 1H), 7.47(m, 1H)， 7.32 (m, 3H), 7.19 (m, 1H), 5.28 (s, 2H), 3.67(s, 8H), 3.50(t, 2H), 3.19(q, 4H), 2.96(t, 2H), 1.26(t, 6H) 实施例 131 1H NMR (400MHz, DMSO- d 6 ): δ 9.80 (s, 1H), 9.00 (s, 1H), 8.62 (s, 1H), 8.20 (d, 1H, J = 10.0), 8.14 (s, 1H) , 7.92(m, 3H), 7.90(s, 1H), 7.47(m, 1H), 7.32 (m, 3H), 7.19 (m, 1H), 5.28 (s, 2H), 3.67(s, 8H), 3.50(t, 2H), 3.19(q, 4H), 2.96(t, 2H), 1.26(t, 6H) Example 131
Γ1-ί4-「3-氯 -4-(3-氟苄氧基 苯氨基 Ί-喹唑啉 -6-基 4-(2-二甲氨基乙基) -1H-吡 咯 -3-基 1-吗啉 -4-甲酮  Γ1-ί4-"3-Chloro-4-(3-fluorobenzyloxyphenylaminopurine-quinazolin-6-yl 4-(2-dimethylaminoethyl)-1H-pyrrol-3-yl 1- Morpholine-4-methanone
Figure imgf000144_0002
Figure imgf000144_0002
重复本发明实施例 128第一步至第二步所述的实验步骤， 不同的是以实施例 128第一歩所得的化合物甲磺酸 2-[1-{4-[3-氯 -4-(3-氟苄氧基) -苯氨基] -喹唑啉 -6- 基}_4- (吗啉 -4-羰基) -1H-吡咯 -3-基] -乙酯 128a作原料，按照本发明实施例 128第二 步所述的相同方式使得该原料与二甲胺的反应， 得到标题化合物 [1-{4-[3-氯 - P氟苄氧基) -苯氨基] -喹唑啉 -6-基 }-4-(2-二甲氨基乙基) -1H-吡咯 -3-基] -吗啉 -4-甲酮 131 ( 180 mg, 黄色固体）， 产率： 65 %。 MS m/z (ESI): 630[M+ 1] The experimental procedure described in the first step to the second step of Example 128 of the present invention was repeated, except that the compound obtained in the first step of Example 128 was 2-[1-{4-[3-chloro-4-methanesulfonate. (3-Fluorobenzyloxy)-phenylamino]-quinazolin-6-yl}_4-(morpholin-4-carbonyl)-1H-pyrrol-3-yl]-ethyl ester 128a as a starting material, according to the invention The title compound [1-{4-[3-chloro-P-fluorobenzyloxy)-phenylamino]-quinazoline- was obtained in the same manner as described in the second step of Example 128. 6-yl}-4-(2-dimethylaminoethyl)-1H-pyrrol-3-yl]-morpholin-4-methanone 131 (180 mg, yellow solid), yield: 65 %. MS m/z (ESI): 630 [M+ 1]
1H NMR (400MHz, DMSO- d6): 8 9.80(s, 1H), 8.60(d, 2H, J=9.2), 8.13(dd, 1H, J=9.2); 8.00(d, 1H, J=2.0), 7.84(d, 1H, J-8.8), 7.73(dd, 1H, J=8.8), 7.66(d, 1H, J=1.6), 7.46(m, 2H), 7.30(m, 3H), 7.18(t, 1H), 5.26(s, 2H), 3.60(s, 8H), 2.66(t, 2H), 2.44(t, 2H), 2.17(s, 6H) 实施例 132 1H NMR (400MHz, DMSO-d 6 ): 8 9.80 (s, 1H), 8.60 (d, 2H, J = 9.2), 8.13 (dd, 1H, J = 9.2) ; 8.00 (d, 1H, J = 2.0 ), 7.84(d, 1H, J-8.8), 7.73(dd, 1H, J=8.8), 7.66(d, 1H, J=1.6), 7.46(m, 2H), 7.30(m, 3H), 7.18 (t, 1H), 5.26(s, 2H), 3.60(s, 8H), 2.66(t, 2H), 2.44(t, 2H), 2.17(s, 6H) Example 132
「 ^^^氟苄基^；^-吲唑 -氨基^！-喹唑啉 基 ^-羟乙基^；^-吡咯  〔^^^fluorobenzyl^;^-carbazole-amino^!-quinazolinyl^-hydroxyethyl^;^-pyrrole
基 1-吗啉 -4-甲酮  1-morpholine-4-ketone
Figure imgf000145_0001
第一步
Figure imgf000145_0001
first step
[1 -(4-氟苄基) -1H-吲唑 -5基] -(6-碘-喹唑啉 -4-基) -胺  [1-(4-fluorobenzyl)-1H-indazole-5-yl]-(6-iodo-quinazolin-4-yl)-amine
重复本发明实施例 1第五步所述的实验步骤， 不同的是以实施例 1第四步所 得的化合物 6-碘 -3H-喹唑啉 -4-酮 If作原料， 按照本发明实施例 1第五步所述的相 同方式使该原料与 1-(4-氟苄基) -1H-吲唑 -5-胺的反应， 得到标题化合物 [1-(4-氟苄 基) -1H-吲唑 -5-基] -(6-碘-喹唑啉 -4-基) -胺 132a ( 13 g， 灰白色固体）， 产率 71.8 %。  The experimental procedure described in the fifth step of the first embodiment of the present invention is repeated, except that the compound 6-iodo-3H-quinazolin-4-one If obtained in the fourth step of the first embodiment is used as a raw material, according to an embodiment of the present invention. Reaction of the starting material with 1-(4-fluorobenzyl)-1H-indazole-5-amine in the same manner as described in the above step to give the title compound [1-(4-fluorobenzyl)-1H- Oxazol-5-yl]-(6-iodo-quinazolin-4-yl)-amine 132a (13 g, off-white solid), yield 71.
MS m/z (ESI): 496[M+ 1]  MS m/z (ESI): 496 [M+ 1]
第二步  Second step
2-(4-{3-[2-(4-氟苄基 1)-4-乙烯基 -2H-吡唑 -3-基] -烯丙氨基 喹唑啉 -6-基) -6,7- 二氢 -2H-吡喃 [3,4-c]吡咯 -4-酮  2-(4-{3-[2-(4-fluorobenzyl 1)-4-vinyl-2H-pyrazol-3-yl]-allylaminoquinazolin-6-yl)-6,7 - Dihydro-2H-pyrano[3,4-c]pyrrol-4-one
在 250 mL茄形瓶中， 将上述步骤所得的化合物 [1-(4-氟苄基 )-1Η-吲唑 -5- 基 ]_(6-碘-喹唑啉 -4-基) -胺 132a ( 5 g， lO mmol), 6,7-二氢 -2H-吡喃并 [3,4-c]吡咯 -4- 酮 10b ( 1.78 g， 13 mmol),磷酸钾（6.37 g， 30 mmol),碘化亚铜（2.86 g， 15mmol) 溶解于 50 mLN,N-二甲基甲酰胺中， 混合物在搅拌下加入 Ν,Ν'-二甲基 -1,2-乙二胺 ( 1.32 g, 15 mmol), 加热反应液到 65°C， 搅拌过夜。 将反应液倒入 250 mL冰水 中， 有墨绿色固体析出， 抽滤， 得到的固体用 300 mL 甲醇洗涤， 固体在真空下干 燥， 得到本标题产物 2-(4-{3-[2-(4-氟苄基 1)-4-乙烯基 -2H-吡唑 -3-基] -烯丙氨基 } -喹 唑啉 -6-基) -6,7-二氢 -2H-吡喃 [3,4-c]吡咯 -4-酮 132b (5.1 g， 墨绿色固体）， 不经分 离直接进行下一歩反应。 The compound obtained in the above step [1-(4-fluorobenzyl)-1Η-indazol-5-yl]-(6-iodo-quinazolin-4-yl)-amine was obtained in a 250 mL eggplant-shaped flask. 132a (5 g, lO mmol), 6,7-dihydro-2H-pyrano[3,4-c]pyrrole-4- Ketone 10b ( 1.78 g, 13 mmol), potassium phosphate (6.37 g, 30 mmol), cuprous iodide (2.86 g, 15 mmol) dissolved in 50 mL of N,N-dimethylformamide, and the mixture was stirred under stirring. , Ν '-Dimethyl-1,2-ethanediamine ( 1.32 g, 15 mmol), and the reaction mixture was heated to 65 ° C and stirred overnight. The reaction liquid was poured into 250 mL of ice water, and a dark green solid was precipitated. The solid was washed with 300 mL of methanol, and the solid was dried under vacuum to give the title product 2-(4-{3-[2-( 4-fluorobenzyl 1)-4-vinyl-2H-pyrazol-3-yl]-allylamino}-quinazolin-6-yl)-6,7-dihydro-2H-pyran[3 , 4-c]pyrrol-4-one 132b (5.1 g, dark green solid), the next reaction was carried out without isolation.
MS m/z (ESI): 478 [M+ 1] MS m/z (ESI): 478 [M+ 1]
第三歩  Third
[1-{4-[1-(4-氟苄基 )-1Η-吲唑 -5-氨基] -喹唑啉 -6-基}-4-(2-羟乙基) -1H-吡咯 -3- 基] -吗啉 -4-甲酮  [1-{4-[1-(4-Fluorobenzyl)-1Η-indazol-5-amino]-quinazolin-6-yl}-4-(2-hydroxyethyl)-1H-pyrrole- 3-yl]-morpholine-4-ketone
将 2-(4-{3-[2-(4-氟 基 1)-4-乙烯基 -2H-吡唑 -3-基] -烯丙氨基 }-喹唑啉 -6- 基) -6,7-二氢 -2H-吡喃 [3,4-c]吡咯 -4-酮 132b ( 150 mg, 0.3 mmol)和 1 mL吗啉加 入 10 mL茄形瓶中， 混合物加热至 12(TC， 搅拌过夜， 反应完毕。反应液在减压下 浓縮， 得到的残留物用二氯甲烷萃取， 有机相在减压下浓缩， 得到的固体进一步 通过 TLC板分离提纯， 得到黄色固体， 真空干燥得到标题产物 [1-{4-[1-(4-氟苄 基) -1H-吲唑 -5-氨基] -喹唑啉 -6-基}-4-(2-羟乙基) -1H-吡咯 -3-基] -吗啉 -4-甲酮 132(27 mg, 浅黄色固体）， 产率： 15%。  2-(4-{3-[2-(4-Fluoro1)-4-vinyl-2H-pyrazol-3-yl]-allylamino}-quinazolin-6-yl)-6 , 7-Dihydro-2H-pyrano[3,4-c]pyrrol-4-one 132b (150 mg, 0.3 mmol) and 1 mL of morpholine were added to a 10 mL eggplant-shaped flask, and the mixture was heated to 12 (TC, After stirring overnight, the reaction was completed. The reaction mixture was evaporated. mjjjjjjjjjjjjjjjjjjjj The title product [1-{4-[1-(4-fluorobenzyl)-1H-indazole-5-amino]-quinazolin-6-yl}-4-(2-hydroxyethyl)-1H- Pyrrol-3-yl]-morpholin-4-methanone 132 (27 mg, pale yellow solid), Yield: 15%.
MS m/z (ESI): 592 [M+ 1] MS m/z (ESI): 592 [M+ 1]
Ή NMR (400MHz, DMSO- d6): δ 10.49(s, 1H), 9.06(m, 1H), 8.5 l(s, 1H), 8.3 l(s, 1H), 8.18(dd, 2H, J=8.8), 7.92(s, 1H), 7.88(m, 2H), 7.76(d, 1H, J=8.8), 7.63(s, 1H), 7.38(m, 1H), 7.10(m, 3H), 5.72(s, 2H), 4.77(s, 1H), 3.62(m, 10H), 2.71(t, 2H) 实施例 133 NMR NMR (400MHz, DMSO-d 6 ): δ 10.49(s, 1H), 9.06(m, 1H), 8.5 l(s, 1H), 8.3 l(s, 1H), 8.18(dd, 2H, J= 8.8), 7.92(s, 1H), 7.88(m, 2H), 7.76(d, 1H, J=8.8), 7.63(s, 1H), 7.38(m, 1H), 7.10(m, 3H), 5.72 (s, 2H), 4.77(s, 1H), 3.62(m, 10H), 2.71(t, 2H) Example 133
l-{441-(4-氟苄基 )-1Η吲唑 -5-氨基 1-喹唑啉 -6-基 4-(2-羟乙基 MH-吡咯 -3- 基 W4-甲基 -哌嗪 -1-基) -甲酮  L-{441-(4-Fluorobenzyl)-1oxazol-5-amino-1-quinazolin-6-yl 4-(2-hydroxyethyl MH-pyrrol-3-yl W4-methyl-piperidin Pyrazin-1-yl)-methanone
Figure imgf000146_0001
Figure imgf000146_0001
重复本发明实施例 132第一步至第三步的实验步骤， 不同的是以第二步所得 的化合物将 2-(4-{3-[2-(4-氟苄基 1)-4-乙烯基 -2H-吡唑 -3-基] -烯丙氨基 喹唑啉 -6- 基) -6，7-二氢 -2H-吡喃 [3,4-c]吡咯 -4-酮 132b作原料， 按照本发明实施例 132第三步 所述的相同方式使得该原料与 1-甲基哌嗪的反应，得到标题化合物 1-{4-[1-(4-氟苄 基) -1H Π引唑 -5-氨基]-喹唑啉 -6-基}-4-(2-羟乙基 )-1Η-吡咯 -3-基] -(4-甲基 -哌嗪 -1-基) - 甲酮 133 ( lO mg, 黄色固体）， 产率： 5.5%。 MS m/z (ESI): 605 [M+ l] The experimental steps of the first step to the third step of the embodiment 132 of the present invention are repeated, except that the compound obtained in the second step is 2-(4-{3-[2-(4-fluorobenzyl 1)-4- Vinyl-2H-pyrazol-3-yl]-allylaminoquinazolin-6-yl)-6,7-dihydro-2H-pyrano[3,4-c]pyrrol-4-one 132b The starting material was reacted with 1-methylpiperazine in the same manner as described in the third step of Example 132 to give the title compound 1-{4-[1-(4-fluorobenzyl)-1H? Bora-5-amino]-quinazolin-6-yl}-4-(2-hydroxyethyl)-1Η-pyrrol-3-yl]-(4-methyl-piperazin-1-yl)- Methyl ketone 133 (10 mg, yellow solid), Yield: 5.5%. MS m/z (ESI): 605 [M+ l]
1H NMR (400MHz, DMSO- d6): δ 10.30(s, IH), 8.75(s, IH), 8.52(s, IH), 8.3 l(s, 1H): 8.12(m, 2H), 7.86(m, IH), 7.76(m, 3H), 7.52(s, IH), 7.49(m, IH), 7.07(m, 3H), 5.72(s: 2H), 4.76(s, IH), 3.59(m, 6H), 2.70(s, 2H)， 2.5 l(m, 4H), 2.2 l(m, 3H) 实施例 134 1H NMR (400MHz, DMSO-d 6 ): δ 10.30 (s, IH), 8.75 (s, IH), 8.52 (s, IH), 8.3 l (s, 1H) : 8.12 (m, 2H), 7.86 ( m, IH), 7.76(m, 3H), 7.52(s, IH), 7.49(m, IH), 7.07(m, 3H), 5.72(s : 2H), 4.76(s, IH), 3.59(m , 6H), 2.70(s, 2H), 2.5 l(m, 4H), 2.2 l(m, 3H) Example 134
(4-氟苄基 )— 1H-吲唑 -5-氨基 1-喹唑啉 -6-基}-4-(2-羟乙基 )-1Η-吡咯 -3-羧 酸 -(2-二乙氨基乙基) -酰胺 (4 - fluorobenzyl) - IH - indazol-5-amino-l-quinolin-6-yl} -4- (2-hydroxyethyl) -1Η- pyrrole-3-carboxylic acid - (2- Ethylaminoethyl)-amide
Figure imgf000147_0001
Figure imgf000147_0001
重复本发明实施例 132第一步至第三步的实验步骤， 不同的是以第二步所得 的化合物将 2-(4-{3-[2-(4-氟苄基 1)-4-乙烯基 -2H-吡唑 -3-基] -烯丙氨基 喹唑啉 -6- 基) -6,7-二氢 -2H-吡喃 [3,4-c]吡咯 -4-酮 132b作原料， 按照本发明实施例 132第三步 所述的相同方式使得该原料与 Ν,Ν-二乙基 -1,2-乙二胺的反应， 得到标题化合物 1一{4-[1-(4-氟苄基 )-1Η-吲唑 -5-氨基] -喹唑啉 -6-基}-4-(2-羟乙基) -1Η-吡咯 -3-羧酸 -(2- 二乙氨基乙基) -酖胺 134 (40 mg, 黄色固体）， 产率： 21.5 %。  The experimental steps of the first step to the third step of the embodiment 132 of the present invention are repeated, except that the compound obtained in the second step is 2-(4-{3-[2-(4-fluorobenzyl 1)-4- Vinyl-2H-pyrazol-3-yl]-allylaminoquinazolin-6-yl)-6,7-dihydro-2H-pyrano[3,4-c]pyrrol-4-one 132b The starting material is reacted with hydrazine, hydrazine-diethyl-1,2-ethanediamine in the same manner as described in the third step of Example 132 of the present invention to give the title compound 1-{4-[1-( 4-fluorobenzyl)-1Η-indazole-5-amino]-quinazolin-6-yl}-4-(2-hydroxyethyl)-1Η-pyrrole-3-carboxylic acid-(2-diethyl Aminoethyl)-guanamine 134 (40 mg, yellow solid), Yield: 21.5 %.
MS m/z (ESI): 621 [M+ l] MS m/z (ESI): 621 [M+ l]
1H NMR (400MHz, DMSO- d6): δ 10.28(s, IH), 9.00(s, IH), 8.54(s, IH), 8.33(m, IH), 8.32(s, IH), 8.17(m, IH), 8.13(dd, IH, J=9.2), 7.89(m, 2H), 7.77(d, IH, J=9.2), 7.59(s, IH), 7.38(m, IH), 7.11(m, 3H), 5.72(s, 2H), 4.80(s, IH), 3.66(t, 2H), 3.45(t, 2H), 2.91(m, 8H), 1.10(s, 6H) 实施例 135 1H NMR (400MHz, DMSO- d 6 ): δ 10.28 (s, IH), 9.00 (s, IH), 8.54 (s, IH), 8.33 (m, IH), 8.32 (s, IH), 8.17 (m , IH), 8.13(dd, IH, J=9.2), 7.89(m, 2H), 7.77(d, IH, J=9.2), 7.59(s, IH), 7.38(m, IH), 7.11(m , 3H), 5.72(s, 2H), 4.80(s, IH), 3.66(t, 2H), 3.45(t, 2H), 2.91(m, 8H), 1.10(s, 6H) Example 135
l- -「l-(4-氟苄基 MH-吲唑 -5-氨基 1-喹唑啉 -6-基 }-4-(2-羟乙基 MH-吡咯 -3-羧 酸 -(3-吗啉 -4-丙基 酰胺  L--"1-Fluorobenzyl MH-carbazole-5-amino-1-quinazolin-6-yl}-4-(2-hydroxyethyl MH-pyrrole-3-carboxylic acid-(3 -morpholine-4-propylamide
Figure imgf000147_0002
Figure imgf000147_0002
重复本发明实施例 132第一步至第三步的实验步骤， 不同的是以第二歩所得 的化合物将 2-(4-{3-[2-(4-氟苄基 1)-4-乙烯基 -2H-吡唑 -3-基] -烯丙氨基 }-喹唑啉 -6- 基) -6，7-二氢 -2H-B比喃 [3,4-c]吡咯 -4-酮 132b作原料， 按照本发明实施例 132第三歩 所述的相同方式使得该原料与 3-吗啉 -4-丙胺的反应， 得到标题化合物 1-{4-[1-(4- 氟苄基 )-1Η-吲唑 -5-氨基] -喹唑啉 -6-基}-4-(2-羟乙基) -1H-吡咯 -3-羧酸 (3-吗啉 -4-丙 基) -酰胺 135 (20 mg, 黄色固体）， 产率： 10.3 %。 The experimental steps of the first step to the third step of the embodiment 132 of the present invention are repeated, except that the compound obtained by the second oxime is 2-(4-{3-[2-(4-fluorobenzyl 1)-4- Vinyl-2H-pyrazol-3-yl]-allylamino}-quinazolin-6-yl)-6,7-dihydro-2H-Bpyrano[3,4-c]pyrrole-4- Ketone 132b as a raw material, according to Example 132 of the present invention The reaction of the starting material with 3-morpholine-4-propylamine in the same manner as described gave the title compound 1-{4-[1-(4-fluorobenzyl)-1?-indazole-5-amino]-quin. Oxazolin-6-yl}-4-(2-hydroxyethyl)-1H-pyrrole-3-carboxylic acid (3-morpholin-4-propyl)-amide 135 (20 mg, yellow solid), yield : 10.3 %.
MS m/z (ESI): 649 [M+ 1] MS m/z (ESI): 649 [M+ 1]
1H NMR (400MHz, DMSO- d6): δ 10.19(s, 1H), 8.90(s, 1H)， 8.35(s, 1H), 8.26(s, 1H), 8.17(s, 1H), 7.98(s, 1H), 7.96(dd, 1H, J=8.8), 7.74(m, 2H), 7.58(d, 1H, J=8.8), 7.4 l(s, 1H), 7.19(m, 1H), 6.92(m, 3H), 5.54(s, 2H), 4.69(s, 1H), 3.48(m, 8H), 3.07(m, 2H), 2.71 (m, 2H), 2.20(m, 6H) 实施例 136 . 1H NMR (400MHz, DMSO- d 6 ): δ 10.19 (s, 1H), 8.90 (s, 1H), 8.35 (s, 1H), 8.26 (s, 1H), 8.17 (s, 1H), 7.98 (s , 1H), 7.96 (dd, 1H, J=8.8), 7.74(m, 2H), 7.58(d, 1H, J=8.8), 7.4 l(s, 1H), 7.19(m, 1H), 6.92( m, 3H), 5.54 (s, 2H), 4.69 (s, 1H), 3.48 (m, 8H), 3.07 (m, 2H), 2.71 (m, 2H), 2.20 (m, 6H).
1-Μ-Π-(4-氟苄基 MH-吲唑 -5-氨基 1-喹唑啉 -6-基 羟乙基 )-lH-吡咯 -3-羧 酸 -(2-哌啶 -1-乙基) -酰胺  1-Μ-Π-(4-fluorobenzyl MH-carbazole-5-amino-1-quinazolin-6-ylhydroxyethyl)-lH-pyrrole-3-carboxylic acid-(2-piperidine-1 -ethyl)-amide
Figure imgf000148_0001
Figure imgf000148_0001
重复本发明实施例 132第一步至第三步的实验步骤， 不同的是以第二步所得 的化合物将 2-(4-{3-[2-(4-氟 基 1)-4-乙烯基 -2H-吡唑 -3-基] -烯丙氨基 喹唑啉 -6- 基) -6,7-二氢 -2H-吡喃 [3,4-c]吡咯 -4-酮 132b作原料， 按照本发明实施例 132第三步 所述的相同方式使得该原料与 2-哌啶 -1-乙胺的反应， 得到标题化合物 1-{4-[ (4- 氟苄基) -1H-吲唑 -5-氨基]-喹唑啉 -6-基}- 4-(2-羟乙基) -1H-吡咯 -3-羧酸（2-哌啶 -1-乙 基) -酰胺 136 ( 17 mg， 黄色固体）， 产率： 8 %。  The experimental steps of the first step to the third step of the embodiment 132 of the present invention are repeated, except that the compound obtained in the second step is 2-(4-{3-[2-(4-fluoroyl))-4-ethene. Benzyl-2H-pyrazol-3-yl]-allylaminoquinazolin-6-yl)-6,7-dihydro-2H-pyrano[3,4-c]pyrrol-4-one 132b The title compound 1-{4-[(4-fluorobenzyl)-1H- Oxazol-5-amino]-quinazolin-6-yl}- 4-(2-hydroxyethyl)-1H-pyrrole-3-carboxylic acid (2-piperidin-1-ethyl)-amide 136 ( 17 mg, yellow solid), Yield: 8 %.
MS m/z (ESI): 633 [M+ 1] MS m/z (ESI): 633 [M+ 1]
1H NMR (400MHz, DMSO- d6): δ 10.07(s, 1H), 8.80(s, 1H), 8.54(s, 1H), 8.26(s, 2H), 8.17(m, 1H), 8.11(dd, 1H, J=8.8), 7.9 l(d, 1H， J=8.8), 7.76(s, 2H), 7.47(s, 1H), 7.38(m, 1H), 7.11(m, 3H), 5.72(s, 2H), 4.80(s, 1H)， 3.67(t, 2H), 3.55(m, 2H), 3.10(m, 4H), 2.92(m, 4H), 1.72(s, 4H), 1.44(m, 2H) 实施例 137 1H NMR (400MHz, DMSO- d 6 ): δ 10.07 (s, 1H), 8.80 (s, 1H), 8.54 (s, 1H), 8.26 (s, 2H), 8.17 (m, 1H), 8.11 (dd , 1H, J=8.8), 7.9 l(d, 1H, J=8.8), 7.76(s, 2H), 7.47(s, 1H), 7.38(m, 1H), 7.11(m, 3H), 5.72( s, 2H), 4.80(s, 1H), 3.67(t, 2H), 3.55(m, 2H), 3.10(m, 4H), 2.92(m, 4H), 1.72(s, 4H), 1.44(m , 2H) Example 137
l- -「l-(4-氟苄基 H-吲唑 -5-氨基 1-喹唑啉 -6-基 4-(2-羟乙基) -1H-吡咯 -3-羧 酸 -(2-吡 P各院 -1-基-乙基) -酰胺  L--"1-Fluorobenzyl H-indazole-5-amino-1-quinazolin-6-yl 4-(2-hydroxyethyl)-1H-pyrrole-3-carboxylic acid-(2 -pyridinyl-1-1-yl-ethyl)-amide
Figure imgf000148_0002
重复本发明实施例 132第一步至第三步的实验步骤， 不同的是以第二步所得 的化合物将 2-(4-{3-[2-(4-氟苄基 1)-4-乙烯基 -2H-吡唑 -3-基]-烯丙氨基}-喹唑啉 -6- 基) -6,7-二氢 -2H-吡喃 [3,4-c]吡咯 -4-酮 132b作原料， 按照本发明实施例 132第三步 所述的相同方式使得该原料与 2-吡咯垸 -1-基-乙胺的反应， 得到标题化合物 1- {4-[1-(4-氟苄基) -1H-吲唑 -5-氨基]-喹唑啉 -6-基}-4-(2-轻乙基 )-1Η-吡咯 -3-羧酸 -(2- 吡咯烷 -1-基-乙基) -酰胺 137 ( 16 mg, 黄色固体）， 产率： 8.6%。
Figure imgf000148_0002
The experimental steps of the first step to the third step of the embodiment 132 of the present invention are repeated, except that the compound obtained in the second step is 2-(4-{3-[2-(4-fluorobenzyl 1)-4- Vinyl-2H-pyrazol-3-yl]-allylamino}-quinazolin-6-yl)-6,7-dihydro-2H-pyrano[3,4-c]pyrrol-4-one Using 132b as a starting material, the starting material is reacted with 2-pyrrole-1-yl-ethylamine in the same manner as described in the third step of Example 132 of the present invention to give the title compound 1- {4-[1-(4- Fluorobenzyl)-1H-indazole-5-amino]-quinazolin-6-yl}-4-(2-lightethyl)-1Η-pyrrole-3-carboxylic acid-(2-pyrrolidine-1 -yl-ethyl)-amide 137 (16 mg, yellow solid), Yield: 8.6%.
MS m/z (ESI): 619 [M+ 1] MS m/z (ESI): 619 [M+ 1]
1H NMR (400MHz, DMSO- d6): δ 10.08(s, 1H), 8.84(s, 1H), 8.54(s, 1H), 8.28(s, 1H), 8.18(s, 1H), 8.10(m, 1H), 7.9 l(d, 1H), 7.78(m, 2H), 7.48(s, 1H), 7.39(s, 1H)， 7.39(m, 1H), 7.11(m, 3H), 5.72(s, 2H), 4.80(s, 1H), 3.67(m， 2H), 3.54(m, 2H), 3.10(m, 4H), 2.93(m, 4H), 1.91(m, 4H) 实施例 138 1H NMR (400MHz, DMSO- d 6 ): δ 10.08 (s, 1H), 8.84 (s, 1H), 8.54 (s, 1H), 8.28 (s, 1H), 8.18 (s, 1H), 8.10 (m , 1H), 7.9 l(d, 1H), 7.78(m, 2H), 7.48(s, 1H), 7.39(s, 1H), 7.39(m, 1H), 7.11(m, 3H), 5.72(s , 2H), 4.80 (s, 1H), 3.67 (m, 2H), 3.54 (m, 2H), 3.10 (m, 4H), 2.93 (m, 4H), 1.91 (m, 4H) Example 138
l-(3- -「3-氯 -4-(3-氟苄氧基)-苯氨基 1 -喹唑啉 -6-基 吡咯小基) -3-吗啉 -4-丙 -2-  L-(3- -"3-Chloro-4-(3-fluorobenzyloxy)-phenylamino 1-quinazoline-6-ylpyrrole small)-3-morpholine-4-prop-2-
Figure imgf000149_0001
Figure imgf000149_0001
第一步  First step
[3-氯 -4-(3-氟苄氧基)-苯基] -[6-(1-环氧乙烷基甲基 -1H-吡咯 -3-基)-喹唑啉 -4-基] -胺 将本发明实施 42所得的化合物 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-[6-(1Η-吡咯 -3-基) - 喹唑啉 -4-基] -胺 42 (447 mg, 1.007 mmol)溶解于 5 mLN,N—二甲基甲酰胺中， 溶 液在冰浴冷却下， 加入氢化钠 （16 mg， 0.4 mmol), 混合液升至室温， 搅拌 30分 钟后， 加入 2-氯甲基环氧乙垸（125 mg， 1.351 mmol), 加热反应液至 60°C， 搅拌 2小时后反应完毕， 加水猝灭反应。 反应液用乙酸乙酯 （100 mLX 3 )萃取， 合并 的有机相用无水硫酸钠干燥， 过滤， 滤液减压下浓缩， 所得的残留物进一歩通过 柱层析分离纯化， 得到本标题产物 [3-氯 -4-(3-氟苄氧基) -苯基 ]-[6-(1-环氧乙烷基甲 基 -1H-吡咯 -3-基) -喹唑啉 -4-基] -胺 138a (200 mg, 黄色固体）， 产率： 39.8%。 MS m/z (ESI): 501 [M+ 1]  [3-Chloro-4-(3-fluorobenzyloxy)-phenyl]-[6-(1-oxiranylmethyl-1H-pyrrol-3-yl)-quinazolin-4-yl -Amine The compound obtained in the practice of the present invention 42 [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1Η-pyrrol-3-yl)-quinazoline-4 -yl]-amine 42 (447 mg, 1.007 mmol) was dissolved in 5 mL of N,N-dimethylformamide. The solution was cooled in ice-cooled, sodium hydride (16 mg, 0.4 mmol) was added and the mixture was warmed to room temperature After stirring for 30 minutes, 2-chloromethyloxirane (125 mg, 1.351 mmol) was added, and the reaction mixture was heated to 60 ° C, stirred for 2 hours, and then the reaction was completed, and the mixture was quenched with water. The reaction mixture was extracted with ethyl acetate (100 mL EtOAc). 3-Chloro-4-(3-fluorobenzyloxy)-phenyl]-[6-(1-oxiranylmethyl-1H-pyrrol-3-yl)-quinazolin-4-yl] -amine 138a (200 mg, yellow solid), yield: 39.8%. MS m/z (ESI): 501 [M+ 1]
第二步  Second step
l-(3-{4-[3-氯 -4-(3-M苄氧基) -苯氨基] -喹唑啉 -6-基}-吡咯 -1-基) -3-吗啉 -4-丙 -2-醇 将吗啉（35 mg， 0.402 mmol)溶解于 0.5 mLN,N-二甲基甲酰胺， 在冰浴条件 下， 冷却至 0°C， 加入氢化钠 （7 mg， 0.175 mmol), 室温下搅拌 20分钟后加入上 述歩骤所得的化合物 [3-氯 -4-(3-氟苄氧基) -苯基 ]-[6-(1-环氧乙垸基甲基 -1H-吡咯 -3- 基) -喹唑啉 -4-基] -胺 138a (68 mg， 0.136 mmol) 的 0.5 mLN,N-二甲基甲酰胺的溶 液， 室温下搅拌过夜， 所得的混合液通过 TLC板进一步分离纯化， 得到本标题产 物 [3-氯 -4-(3-氟苄氧基) -苯基 ]-[6-(1-环氧乙烷基甲基 -1H-吡咯 -3-基) -喹唑啉 -4-基] - 胺 138 (36 mg, 黄色固体）， 产率： 45 %。 L-(3-{4-[3-Chloro-4-(3-Mbenzyloxy)-phenylamino]-quinazolin-6-yl}-pyrrol-1-yl)-3-morpholine-4 -propan-2-ol The morpholine (35 mg, 0.402 mmol) was dissolved in 0.5 mL of N,N-dimethylformamide, cooled to 0 ° C under ice-cooling, sodium hydride (7 mg, 0.175 mmol), and stirred at room temperature 20 After a minute, the compound [3-chloro-4-(3-fluorobenzyloxy)-phenyl]-[6-(1-epoxyethylidenemethyl-1H-pyrrol-3-yl) was added. a solution of - quinazolin-4-yl]-amine 138a (68 mg, 0.136 mmol) in 0.5 mL of N-N-dimethylformamide, stirred at room temperature overnight, and the obtained mixture was further purified by TLC. The title product [3-chloro-4-(3-fluorobenzyloxy)-phenyl]-[6-(1-oxiranylmethyl-1H-pyrrol-3-yl)-quinazoline is obtained. 4-yl]-amine 138 (36 mg, yellow solid), Yield: 45 %.
MS m/z (ESI): 588 [M+ 1] MS m/z (ESI): 588 [M+ 1]
Ή NMR (400MHz, DMSO- d6): δ 9.70(s, 1H), 8.50(s, 1H), 8.02(s, 1H), 7.71(m, 2H), 7.42(m, 1H), 7.40(t， 1H), 7.33(m, 3H), 7.19(t, 2H), 6.87(m, 2H), 6.64(m, 1H), 5.27(s, 2H), 4.10(m, 1H), 4.00(m, 1H), 3.85(m, 1H), 3.61(m, 4H), 2.40(m, 2H), 2.19(m, 4H) 实施例 139 Ή NMR (400MHz, DMSO- d 6 ): δ 9.70 (s, 1H), 8.50 (s, 1H), 8.02 (s, 1H), 7.71 (m, 2H), 7.42 (m, 1H), 7.40 (t , 1H), 7.33(m, 3H), 7.19(t, 2H), 6.87(m, 2H), 6.64(m, 1H), 5.27(s, 2H), 4.10(m, 1H), 4.00(m, 1H), 3.85 (m, 1H), 3.61 (m, 4H), 2.40 (m, 2H), 2.19 (m, 4H) Example 139
2-Π-「4-〔3-氯 -4-氟苯氨基) -喹唑啉 -6-基 1-4-吡咯垸 -1-甲基 -1H-吡咯 -3-基 乙醇  2-Π-"4-[3-Chloro-4-fluorophenylamino)-quinazoline-6-yl 1-4-pyrrole-1-methyl-1H-pyrrole-3-ylethanol
Figure imgf000150_0001
Figure imgf000150_0001
重复本发明实施例 120第一步所述的实验步骤， 不同的是以实施例 109最终 所得的化合物 [1-[4-(3-氯 -4-氟-苯氨基) -喹唑啉 -6-基] -4-(2-羟乙基 H-吡咯 -3-基] - 吡咯烷 -1-甲酮 109作原料， 按照本发明实施例 120第一步所述的相同方式使得该 原料与氢化铝锂的反应， 得到标题化合物 2-{1-[4-(3-氯 -4-氟苯氨基) -喹唑啉 -6- 基] -4-吡咯烷 -1-甲基 -1H-吡咯 -3-基} -乙醇 139 (62 mg，黄色固体），产率： 71.16%。 MS m/z (ESI): 466[M+ 1]  The experimental procedure described in the first step of Example 120 of the present invention was repeated, except that the compound [1-[4-(3-chloro-4-fluoro-phenylamino)-quinazoline-6 finally obtained in Example 109 was obtained. -yl]-4-(2-hydroxyethyl H-pyrrol-3-yl)-pyrrolidin-1-one ketone 109 as a starting material, in the same manner as described in the first step of Example 120 of the present invention Reaction of lithium aluminum hydride to give the title compound 2-{1-[4-(3-chloro-4-fluorophenylamino)-quinazolin-6-yl]-4-pyrrolidin-1-methyl-1H- Pyrrol-3-yl}-ethanol 139 (62 mg, yellow solid), yield: 71.16%. MS m/z (ESI): 466[M+ 1]
'HNMR (400MHZ, DMSO- d6): δ 9.90(s, 1H), 8.52(d, 2H), 8.14(d, 2H), 7.80(m, 2H), 7.46(m, 1H), 7.42(s, 1H), 7.33(s, 1H), 5.10(s, 1H), 3.61(t, 2H), 3.46(s, 2H), 2.66(t, 2H)， 2.50(m, 4H), 1.70(s, 4H) 实施例 140 'HNMR (400MHZ, DMSO- d 6 ): δ 9.90 (s, 1H), 8.52 (d, 2H), 8.14 (d, 2H), 7.80 (m, 2H), 7.46 (m, 1H), 7.42 (s , 1H), 7.33(s, 1H), 5.10(s, 1H), 3.61(t, 2H), 3.46(s, 2H), 2.66(t, 2H), 2.50(m, 4H), 1.70(s, 4H) Example 140
2-Π-Γ4-(3-氯 -4-氟苯氨基) -喹唑啉 -6-基 1-4-二甲氨基甲基 -1H-吡咯 -3-基 乙醇  2-Π-Γ4-(3-chloro-4-fluorophenylamino)-quinazoline-6-yl 1-4-dimethylaminomethyl-1H-pyrrole-3-ylethanol
Figure imgf000150_0002
Figure imgf000150_0002
Figure imgf000151_0001
第一步
Figure imgf000151_0001
first step
2-{l-[4-(3-氯 -4-氟苯氨基)-喹唑啉 -6-基] -4-羟甲基 -1H-吡咯 -3-基 乙醇 在 50 mL茄形瓶中， 将 20 mL四氢呋喃冰浴条件下冷却至 0〜5°C， 搅拌下加 入氢化铝锂（18.6 mg， 0.49 mmol), 随后分批加入实施例 81第一步所得的产物 2-[4-(3-氯 -4-氟-苯氨基) -喹唑啉 -6-基] -6,7-二氢 -2H-吡喃 [3,4-c]吡咯 -4-酮 81a ( 100 - mg， 0.245 mmol)，在冰浴条件下继续搅拌 30分钟后反应完毕。在溶液中加入 O.lmL 水和 O.l mL 20%氢氧化钠溶液， 抽滤， 依次用 50 mL四氢呋喃洗涤滤饼， 滤液中 加入 20 mL二氯甲烷有固体析出，抽滤，固体真空干燥，得到本标题产物 2-{1-[4-(3- 氯 -4-氟苯氨基)-喹唑啉 -6-基] -4-羟甲基 -1H-吡咯 -3-基} -乙醇 140a (65 mg, 黄色固 体）， 产率： 64.1 %。  2-{l-[4-(3-chloro-4-fluorophenylamino)-quinazolin-6-yl]-4-hydroxymethyl-1H-pyrrol-3-ylethanol in 50 mL eggplant-shaped flask The mixture was cooled to 0 to 5 ° C under 20 mL of tetrahydrofuran, and lithium aluminum hydride (18.6 mg, 0.49 mmol) was added under stirring, and then the product obtained in the first step of Example 81 was added in portions 2-[4-( 3-chloro-4-fluoro-phenylamino)-quinazolin-6-yl]-6,7-dihydro-2H-pyrano[3,4-c]pyrrol-4-one 81a (100-mg, 0.245 mmol), stirring was continued for 30 minutes under ice bath conditions and the reaction was completed. O.lmL water and Ol mL 20% sodium hydroxide solution were added to the solution, suction filtration, and the filter cake was washed successively with 50 mL of tetrahydrofuran. 20 mL of dichloromethane was added to the filtrate to precipitate a solid, which was suction filtered and dried in vacuo to give a solid. The title product 2-{1-[4-(3-chloro-4-fluorophenylamino)-quinazolin-6-yl]-4-hydroxymethyl-1H-pyrrol-3-yl}-ethanol 140a ( 65 mg, yellow solid), Yield: 64.1%.
MS m/z (ESI): 413[M+ 1]  MS m/z (ESI): 413 [M+ 1]
第二步  Second step
1-[4-(3-氯 -4-氟苯氨基) -喹唑啉 -6-基] -4-(2-羟基-乙基) -1H-吡咯 -3-甲醛 将邻碘酰基苯甲酸（44.1 mg， 0.157 mmol)溶解于 3 mL二甲亚砜中， 搅拌下 加入上述歩骤所得的化合物 2-{1-[4-(3-氯 -4-氟苯氨基) -喹唑啉 -6-基] -4-羟甲基 -1H- 吡咯 -3-基} -乙醇 140a ( 65 mg, 0.157 mmol), 室温下搅拌 2小时后反应完毕。 将 反应液倒入 100 mL 5 %碳酸氢钠溶液中， 搅拌 5分钟后， 用乙酸乙酯（ 100 ml 3 ) 萃取反应液， 合并的有机相在减压下浓缩， 得到的残留物进一歩通过柱层析分离 纯化， 得到本标题产物 1-[4-(3-氯 -4-氟苯氨基)-喹唑啉 -6-基] -4-(2-羟基-乙基) -1H- 吡咯 -3-甲醛 140b (32 mg, 黄色固体）， 产率： 51.9%。  1-[4-(3-chloro-4-fluorophenylamino)-quinazolin-6-yl]-4-(2-hydroxy-ethyl)-1H-pyrrole-3-carbaldehyde o-iodobenzoic acid (44.1 mg, 0.157 mmol) was dissolved in 3 mL of dimethyl sulfoxide, and the compound 2-{1-[4-(3-chloro-4-fluorophenylamino)-quinazoline obtained above was added with stirring. 6-yl]-4-hydroxymethyl-1H-pyrrol-3-yl}-ethanol 140a (65 mg, 0.157 mmol). The reaction solution was poured into 100 mL of a 5% sodium hydrogencarbonate solution, and the mixture was stirred for 5 minutes, and then the mixture was extracted with ethyl acetate (100 ml 3 ), and the combined organic phases were concentrated under reduced pressure. Purification by column chromatography to give the title product 1-[4-(3-chloro-4-fluorophenylamino)-quinazolin-6-yl]-4-(2-hydroxy-ethyl)-1H-pyrrole -3-Formaldehyde 140b (32 mg, yellow solid), Yield: 51.9%.
MS m/z (ESI): 411 [M+ 1]  MS m/z (ESI): 411 [M+ 1]
第三步  third step
2-{ 1-[4-(3-氯 -4-氟苯氨基) -喹唑啉 -6-基] -4-二甲氨基甲基 -1Η-吡咯 -3-基 乙醇 在 50 mL茄形瓶中将上述步骤所得的化合物 1-[4-(3-氯 -4-氟苯氨基) -喹唑啉 2-{ 1-[4-(3-chloro-4-fluorophenylamino)-quinazolin-6-yl]-4-dimethylaminomethyl-1Η-pyrrol-3-ylethanol in 50 mL eggplant The compound obtained in the above step was 1-[4-(3-chloro-4-fluorophenylamino)-quinazoline
-6-基] -4-(2-羟基-乙基) -1H-吡咯 -3-甲醛 140b ( 80 mg, 0.195 mmol)溶解于 5 mL二 氯甲烷中，搅拌下加入二甲胺（0.2 mL， 0.389 mmol)和三乙酰氧基硼氢化钠（165 mg, 0.389 mmol) , 所得的混合液在室温下搅拌过夜， 反应完毕。 将反应液中加入 5 mL碳酸氢钠和 5 mL饱和氯化钠水溶液，分层后，水层用二氯甲垸（50 mL X 3 ) 萃取， 合并的有机相用无水硫酸钠干燥， 过滤， 滤液减压下浓缩， 得到的残留物 进一步通过 TLC板进行分离纯化， 得到本标题产物 2-{1-[4-(3-氯 -4-氟苯氨基) -喹 唑啉 -6-基] -4-二甲氨基甲基 -1H-吡咯 -3-基} -乙醇 140 (70 mg, 黄色固体）， 产率： 40.9%。 -6-yl]-4-(2-hydroxy-ethyl)-1H-pyrrole-3-carbaldehyde 140b (80 mg, 0.195 mmol) was dissolved in 5 mL of dichloromethane and dimethylamine (0.2 mL) , 0.389 mmol) and sodium triacetoxyborohydride (165 mg, 0.389 mmol). The obtained mixture was stirred at room temperature overnight and the reaction was completed. The reaction solution was added with 5 mL of sodium hydrogencarbonate and 5 mL of a saturated aqueous solution of sodium chloride, and the layers were separated. The combined organic phase is dried over anhydrous sodium sulfate, filtered, and the filtrate is evaporated, evaporated, mjjjjjjjjjjjjjj 4-fluorophenylamino)-quinazolin-6-yl]-4-dimethylaminomethyl-1H-pyrrol-3-yl}-ethanol 140 (70 mg, yellow solid), yield: 40.9%.
MS m/z (ESI): 438[M- 1]  MS m/z (ESI): 438 [M-1]
lENMR (400MHz, DMSO- d6): δ 9.00(s, IH), 8.62(s, IH), 8.35(m, IH), 8.12(m, IH), 8.05(m, IH), 7.92(m, 2H), 7.65(d, 2H), 7.44(t, IH), 5.10(s， IH), 4.17(s, 2H), 3.67(t, 2H); 2.78(s, 6H), 2.72(t, 2H) 实施例 141 lENMR (400MHz, DMSO- d 6) : δ 9.00 (s, IH), 8.62 (s, IH), 8.35 (m, IH), 8.12 (m, IH), 8.05 (m, IH), 7.92 (m, 2H), 7.65(d, 2H), 7.44(t, IH), 5.10(s, IH), 4.17(s, 2H), 3.67(t, 2H) ; 2.78(s, 6H), 2.72(t, 2H Example 141
2-{ l-「4 3-氯 -4-氟苯氨基)-喹唑啉 -6-基 l-4-「(2-甲磺酰基-乙氨基) -甲基 1-lH-吡 咯 -3-基 乙醇 2-{ l-" 4 3-chloro-4-fluorophenylamino)-quinazolin-6-yl l-4-"(2-methanesulfonyl-ethylamino)-methyl 1-lH-pyrrole-3 -based ethanol
Figure imgf000152_0001
Figure imgf000152_0001
重复本发明实施例 140第一步至第三步的实验步骤， 不同的是以第二步所得 的化合物 1-[4-(3-氯 -4-氟苯氨基) -喹唑啉 -6-基] -4-(2-羟基-乙基) -1H-吡咯 -3-甲醛 140b作为原料，进行该原料与 2-甲磺酰基乙胺的反应，得到本标题产物 2-{1-[4-((3- 氯 -4-氟苯氨基) -喹唑啉 -6-基] -4-[(2-甲磺酰基-乙氨基) -甲基] -1H-吡咯 -3-基} -乙醇 141 ( 67 mg, 黄色固体）， 产率： 33.3 %。  The experimental steps of the first step to the third step of the embodiment 140 of the present invention are repeated, except that the compound obtained in the second step is 1-[4-(3-chloro-4-fluorophenylamino)-quinazoline-6- 4-(2-hydroxy-ethyl)-1H-pyrrole-3-carbaldehyde 140b is used as a starting material to carry out the reaction of the starting material with 2-methanesulfonylethylamine to give the title product 2-{1-[4 -((3-chloro-4-fluorophenylamino)-quinazolin-6-yl]-4-[(2-methanesulfonyl-ethylamino)-methyl]-1H-pyrrol-3-yl} Ethanol 141 (67 mg, yellow solid), Yield: 33.3 %.
MS m/z (ESI): 518[M+ 1] MS m/z (ESI): 518 [M+ 1]
1H NMR (400MHz, DMSO- d6): δ 10.24(s, IH), 8.90(s, IH), 8.6 l(s, IH), 8.29(m, IH), 8.11(m, IH), 7.98(m, IH), 7.90(m, IH), 7.70(s, IH), 7.53(m, IH), 7.49(m, IH), 3.90(s, 2H), 3.66(t, 2H), 3.50(m, 2H), 3.25(m, 2H), 3.10(s, 3H)， 2.70(m, 2H) 实施例 142 1H NMR (400MHz, DMSO-d 6 ): δ 10.24 (s, IH), 8.90 (s, IH), 8.6 l (s, IH), 8.29 (m, IH), 8.11 (m, IH), 7.98 ( m, IH), 7.90(m, IH), 7.70(s, IH), 7.53(m, IH), 7.49(m, IH), 3.90(s, 2H), 3.66(t, 2H), 3.50(m , 2H), 3.25(m, 2H), 3.10(s, 3H), 2.70(m, 2H) Example 142
4-(m-「4-(3-氯 -4-氟苯氨基) -喹唑啉 -6-基 l-4-(2-羟乙基 1H-吡咯 -3-甲基 1-氨 基 甲基) -U-二氧代 -六氢 -1λ*6*-噻喃 -4-醇  4-(m-"4-(3-Chloro-4-fluorophenylamino)-quinazolin-6-yl-l-4-(2-hydroxyethyl 1H-pyrrole-3-methyl 1-aminomethyl -U-dioxo-hexahydro-1λ*6*-thiopyran-4-ol
Figure imgf000152_0002
Figure imgf000152_0002
uz 'i)\L m ¾)90-£ Xm '^)6ΐτ \nz 'i i uz cs)80 '(HI '(HI 'ί)6νιUz 'i)\L m 3⁄4)90-£ Xm '^)6ΐτ \nz 'ii uz c s)80 '(HI '(HI 'ί)6νι
'(HI '^)9ζ'ί '(Ηΐ ¾ι)08·乙 '(Ζ·6=ί ¾I 'V)\&L '(Hi '∞)00·8 '(Γ6=Γ ¾ΐ 'ΡΡ)ζΓ8 \Υ9=ί 5Ζ 'HI 'ΡΡ)1£·8 '(ΗΪ 's)i79'8 '(HI 's)S8'8 '(HI ^)6Z0l 8 -i9P -OS I ' m) ¾WNHl '(HI '^)9ζ'ί '(Ηΐ 3⁄4ι)08·乙'(Ζ·6=ί 3⁄4I 'V)\&L '(Hi '∞)00·8 '(Γ6=Γ 3⁄4ΐ 'ΡΡ)ζΓ8 \ Υ9=ί 5Ζ 'HI 'ΡΡ)1£·8 '(ΗΪ 's)i79'8 '(HI 's)S8'8 '(HI ^)6Z0l 8 -i 9 P -OS I ' m) 3⁄4WNH l
[I+W]8SS :(lS3)z/ra S1A[ [I+W]8SS : (lS3)z/ra S1A[
° rii ：隶^ '( M^M- 's∞w) 耷 愛籩- (愛由寸- 翁° rii : Lie ^ '( M^M- ' s ∞w) 耷爱笾- (Love by inch - Weng
-*9*ΎΙ-霄 卞 [愛 -9-雜;iiiti-(¾¾¾¾t¾-£)寸 H ^ mn^ oz '^ί¾^翘 ώ- (愛寸 -¾¾-*9*Ύΐ-¾ -¾:τ-π)- ^ ^ ^m^^pi 颢 ώ-ε-¾ι ϋ-Ηί- (愛 2-¾¾ -乙) - ¾-9-脚 耷葛 ¾寸-鶩 -£) ]-1-*9*ΎΙ-霄卞[爱-9-杂;iiiti-(3⁄43⁄43⁄43⁄4t3⁄4-£) inch H ^ mn^ oz '^ί3⁄4^ ώ ώ - (爱寸-3⁄43⁄4-*9*Ύΐ-3⁄4 -3⁄4: Τ-π)- ^ ^ ^m^^pi 颢ώ-ε-3⁄4ι ϋ-Ηί- (Love 2-3⁄43⁄4 - B) - 3⁄4-9-Foot Ge 3⁄4 inch-鹜-£) ]-1
^~mr^ u± '蘊^ ^^ ^?三^ ^?一^ on m ^^ w  ^~mr^ u± '蕴^ ^^ ^?三^ ^?一^ on m ^^ w
Figure imgf000153_0001
Figure imgf000153_0001
載 2-(¾_£, -Ηί-{¾ -頃焉-
Figure imgf000153_0002
Figure imgf000153_0003
Load 2-(3⁄4_£, -Ηί-{3⁄4 - 焉 -
Figure imgf000153_0002
Figure imgf000153_0003
'ίηζ ^ILZ Km '∞)90·ε XH 'ra)6re Xuz 'i i '(HZ CS)SO '(HI 's)srs £(HI ¾6i7 oi'ίηζ ^ILZ Km '∞)90·ε XH 'ra)6re Xuz 'ii '(HZ C S)SO '(HI 's)srs £ (HI 3⁄46i7 oi
:(Hl '^)9S'L '(Ηΐ '∞)08·乙 '( 6=ί 'HI cV)l6'L '(HI )00·8 \Ζ6=ί 'ΗΪ 'ΡΡ)Π·8 Υ9=ί : (Hl '^)9S'L '(Ηΐ '∞)08·乙'( 6=ί 'HI c V)l6'L '(HI )00·8 \Ζ6= ί 'ΗΪ 'ΡΡ)Π·8 Υ9=ί
Ήΐ 'PP)I£"8 '(Ηί ^9'8 '(HI ^)92S ΚΙ ^)6 01 S -(9P -QSVia ^HWOO ) ¾ΗΝΗ, Ήΐ 'PP)I£"8 '(Ηί ^9'8 '(HI ^)92S ΚΙ ^)6 01 S -( 9 P -QSVia ^HWOO ) 3⁄4ΗΝΗ,
°%8· ：
Figure imgf000153_0004
<Sra 9D ζη ϋ -駒難-*9* 1-霄 二 -Π- (愛 ώ-{耷葛- [ ώ 8· :
Figure imgf000153_0004
<Sra 9D ζη ϋ -驹难-*9* 1-霄二-Π- (爱ώ-{耷葛- [ ώ
-ε-^φ-ΗΙ-ί^^ξ^) - [養 -9-棚¾¾-(¾^*¾ -：)$-£)-17]-1]}) 嗨：^ 1Ιώ-£ ¾ϋ-Ηΐ-(¾ ¾5^- H-[¾-9-#i ia-(¾^¾B-l7-»-£H]-T 啄 -ε-^φ-ΗΙ-ί^^ξ^) - [养-9-棚3⁄43⁄4-(3⁄4^*3⁄4 -:)$-£)-17]-1]}) 嗨:^ 1Ιώ-£ 3⁄4ϋ -Ηΐ-(3⁄4 3⁄45^- H-[3⁄4-9-#i ia-(3⁄4^3⁄4B-l7-»-£H]-T 啄
Figure imgf000153_0005
Figure imgf000153_0005
Ζ.0εΐ00/800ΖΝ3/Χ3<1 .^9ΖΐΟ/600ί OAV
Figure imgf000154_0001
Ζ.0εΐ00/800ΖΝ3/Χ3<1 .^9ΖΐΟ/600ί OAV
Figure imgf000154_0001
重复本发明实施例 140第一步至第三步的实验步骤， 不同的是以第二步所得 的化合物 1-[4-(3-氯 -4-氟苯氨基) -喹唑啉 -6-基] -4-(2-羟基-乙基) -1H-吡咯 -3-甲醛 140b作为原料， 进行该原料与二乙胺的反应， 得到本标题产物 2-{1-[4-(3-氯 4-氟- 苯氨基)-喹唑啉 -6-基] -4-二乙氨基甲基 -1H-吡咯 -3-基} -乙醇 144(98 mg，黄色固体）， 产率： 54.9%。  The experimental steps of the first step to the third step of the embodiment 140 of the present invention are repeated, except that the compound obtained in the second step is 1-[4-(3-chloro-4-fluorophenylamino)-quinazoline-6- -4-(2-hydroxy-ethyl)-1H-pyrrole-3-carbaldehyde 140b is used as a starting material to carry out the reaction of the starting material with diethylamine to obtain the title product 2-{1-[4-(3- Chloro-4-fluoro-phenylamino)-quinazolin-6-yl]-4-diethylaminomethyl-1H-pyrrol-3-yl}-ethanol 144 (98 mg, yellow solid), yield: 54.9% .
MS m/z (ESI): 468[M+1] MS m/z (ESI): 468 [M+1]
!HNMR (400MHz, DMSO- d6): δ 10.63(s, IH), 9.13(s, IH), 8.62(s, IH), 8.40(m, IH), 8.14(m, 2H), 8.10(s, IH), 7.90(d, IH, J=8.8), 7.68(s, IH), 7.46(t, IH), 4.14(s, 2H), 3.70(t, 2H), 3.19(m, 4H), 2.73(t, 2H), 1.32(m, 6H) 实施例 145 ! HNMR (400MHz, DMSO- d 6 ): δ 10.63 (s, IH), 9.13 (s, IH), 8.62 (s, IH), 8.40 (m, IH), 8.14 (m, 2H), 8.10 (s , IH), 7.90(d, IH, J=8.8), 7.68(s, IH), 7.46(t, IH), 4.14(s, 2H), 3.70(t, 2H), 3.19(m, 4H), 2.73(t, 2H), 1.32(m, 6H) Example 145
2—Π— {4—「3_氯 K吡啶 -2-甲氧基) -苯氨基 1-喹唑啉 -6-基 M-「(2-甲磺酰基 -乙氨  2-—Π—{4—“3_Chloro Kpyridine-2-methoxy)-phenylamino-1-quinazoline-6-yl M-((2-methanesulfonyl-ethylamine)
基 V甲基 1-1H-吡咯 -3-基 乙醇  V methyl 1-1H-pyrrol-3-ylethanol
Figure imgf000154_0002
第一步
Figure imgf000154_0002
first step
2-(1-{4-[3-氯 -4- (吡啶 -2-甲氧基) -苯氨基] -喹唑啉 -6-基}-4-轻甲基 -1H-吡咯 -3- 基) -乙醇  2-(1-{4-[3-Chloro-4-(pyridine-2-methoxy)-phenylamino]-quinazolin-6-yl}-4-light methyl-1H-pyrrole-3- Base) - ethanol
在 50 mL茄形瓶中， 将氢化铝锂（220 mg， 5.86 mmol)溶解于 15 mL四氢呋 喃中， 所得的溶液在冰浴条件下， 冷却至一 5°C， 搅拌下分批加入实施例 47所得 的最终化合物 2-{4-[3-氯 -4- (吡啶 -2-甲氧基) -苯氨基]-喹唑啉 -6-基}-6,7-二氢 -2H-吡 喃 [3,4-c]吡咯 -4-酮 47 ( 1.45 g, 2.93 mmol), 搅拌 30分钟后反应完毕。 在反应液 中加入 1 mL水， 1 mL饱和氢氧化钠溶液， 过滤反应液， 母液在减压下浓缩， 得 到本标题产物 2-(1-{4-[3-氯 -4- (吡啶 -2-甲氧基) -苯氨基] -喹唑啉 -6-基 }-4_羟甲基 -1H- 吡咯 -3-基) -乙醇 145a (381 mg, 黄色固体）， 产率： 33 %。 Dissolve lithium aluminum hydride (220 mg, 5.86 mmol) in 15 mL of tetrahydrofuran in a 50 mL eggplant bottle In the middle, the obtained solution was cooled to a temperature of 5 ° C under ice-cooling, and the final compound 2-{4-[3-chloro-4-(pyridine-2-methoxy) obtained in Example 47 was added portionwise with stirring. -Phenylamino]-quinazolin-6-yl}-6,7-dihydro-2H-pyrano[3,4-c]pyrrol-4-one 47 ( 1.45 g, 2.93 mmol), stirred 30 The reaction is completed in minutes. 1 mL of water and 1 mL of a saturated sodium hydroxide solution were added to the reaction mixture, and the reaction mixture was filtered, and the residue was concentrated under reduced pressure to give the title product 2-(1-{4-[3-chloro-4-(pyridine- 2-methoxy)-phenylamino]-quinazolin-6-yl}-4-hydroxymethyl-1H-pyrrol-3-yl)-ethanol 145a (381 mg, yellow solid), Yield: 33 % .
MS m/z (ESI): 502[M+ 1] MS m/z (ESI): 502 [M+ 1]
第二步  Second step
2-(1-{4-[3-氯- 4- (吡啶 -2-甲氧基) -苯氨基] -喹唑啉 -6-基}-4-(2-羟乙基) -1H-吡咯  2-(1-{4-[3-Chloro-4-(pyridine-2-methoxy)-phenylamino]-quinazolin-6-yl}-4-(2-hydroxyethyl)-1H- Pyrrole
-3-甲醛  -3-formaldehyde
在 25 mL茄形瓶中， 将邻碘酰基苯甲酸（93 mg, 0.32 mmol)溶解于 5 mL二 甲基亚砜中， 搅拌下逐滴加入上述步骤所得的化合物 2-(1-{4-[3-氯 -4- (吡啶 -2-甲氧 基) -苯氨基] -喹唑啉 -6-基}-4-羟甲基 -1H-吡咯 -3-基) -乙醇 145a ( 147 mg, 0.29mmol) 的 2 mL二甲基亚砜溶液， 搅拌过夜， 反应完毕。 将反应液倒入 100 mL水中， 有 固体生成，抽滤，得到本标题产物 2-(1-{4-[3-氯 -4- (吡啶 -2-甲氧基) -苯氨基] -喹唑啉 -6-基}-4-(2-羟乙基 )-1Η-吡咯 -3-甲醛 145b ( 80 mg, 黄色固体）， 产率： 55 %。  In a 25 mL eggplant-shaped flask, o-iodobenzoic acid (93 mg, 0.32 mmol) was dissolved in 5 mL of dimethyl sulfoxide, and the compound 2-(1-{4-) obtained in the above step was added dropwise with stirring. [3-Chloro-4-(pyridine-2-methoxy)-phenylamino]-quinazolin-6-yl}-4-hydroxymethyl-1H-pyrrol-3-yl)-ethanol 145a ( 147 mg , 0.29 mmol) in 2 mL of dimethyl sulfoxide solution, stirred overnight, and the reaction was completed. The reaction solution was poured into 100 mL of water, and solid was formed and filtered to give the title product 2-(1-{4-[3-chloro-4-(pyridine-2-methoxy)-phenylamino]-quin. Oxazolin-6-yl}-4-(2-hydroxyethyl)-1Η-pyrrole-3-carbaldehyde 145b (80 mg, yellow solid), yield: 55 %.
MS m/z (ESI): 500[M+ 1] MS m/z (ESI): 500 [M+ 1]
第二步  Second step
2-{1-{4-[3-氯 -4- (吡啶 -2-甲氧基) -苯氨基]-喹唑啉 -6-基}-4-[(2-甲磺酰基 -乙氨 基)-甲基] -m-吡咯 -3-基 乙醇  2-{1-{4-[3-Chloro-4-(pyridine-2-methoxy)-phenylamino]-quinazolin-6-yl}-4-[(2-methanesulfonyl-ethylamino) )-methyl]-m-pyrrol-3-ylethanol
将上述步骤所得的化合物 2-(1-{4-[3-氯 -4- (吡啶 -2-甲氧基) -苯氨基] -喹唑啉 -6- 基}-4-(2-羟乙基 )-1Η-吡咯 -3-甲醛 145b (30 mg, 0.06 mmol)溶解于 10 mL甲醇中， 搅拌下加入 2-甲磺酰基乙胺盐酸盐 （19 mg， 0.12 mmol), 室温下搅拌 3小时后加 入三乙酰氧基硼氢化钠（25.4 mg， 0.12 mmol), 所得的混合液在室温下搅拌过夜， 反应完毕。 反应液在减压下浓缩， 得到的固体进一步通过 TLC板进行分离纯化， 得到本标题产物 2-{1-{4-[3-氯 -4- (吡啶 -2-甲氧基) -苯氨基] -喹唑啉 -6-基 }-4-[(2-甲磺 酰基 -乙氨基)-甲基] -1H-吡咯 -3-基} -乙醇 145 ( 50 mg, 黄色固体）， 产率： 31 %。 MS m/z (ESI): 608[M+ 1]  The compound obtained in the above step is 2-(1-{4-[3-chloro-4-(pyridine-2-methoxy)-phenylamino]-quinazoline-6-yl}-4-(2-hydroxyl Ethyl)-1Η-pyrrole-3-carbaldehyde 145b (30 mg, 0.06 mmol) was dissolved in 10 mL of methanol, and then added with methanesulfonylethylamine hydrochloride (19 mg, 0.12 mmol). After 3 hours, sodium triacetoxyborohydride (25.4 mg, 0.12 mmol) was added, and the obtained mixture was stirred at room temperature overnight, and the reaction was completed. The reaction mixture was concentrated under reduced pressure, and the obtained solid was further purified by TLC. , the title product 2-{1-{4-[3-chloro-4-(pyridine-2-methoxy)-phenylamino]-quinazolin-6-yl}-4-[(2-A) Sulfonyl-ethylamino)-methyl]-1H-pyrrol-3-yl}-ethanol 145 (50 mg, yellow solid), yield: 31%. MS m/z (ESI): 608 [M+ 1]
JHNMR (400MHz, DMSO-^): δ 10.17(s, IH), 8.80(s, IH), 8.61(d, IH, J=4.4), 8.55(s, IH), 8.13(s， 1H)， 8.07(d, IH, J=9.2), 7.88(m, 3H), 7.67(s, 1H)， 7.60(d， IH, J=7.6), 7.53 (s, IH), 7.37 (t, IH), 7.30 (d, IH, J=8.8 ), 5.30 (s, 2H), 3.81(s, 2H), 3.65(t, 2H), 3.44(t, 2H), 3.15(t, 2H), 3.09(s, 3H), 2.69(t, 2H) 实施例 146 J HNMR (400MHz, DMSO-^): δ 10.17(s, IH), 8.80(s, IH), 8.61(d, IH, J=4.4), 8.55(s, IH), 8.13(s, 1H), 8.07(d, IH, J=9.2), 7.88(m, 3H), 7.67(s, 1H), 7.60(d, IH, J=7.6), 7.53 (s, IH), 7.37 (t, IH), 7.30 (d, IH, J=8.8), 5.30 (s, 2H), 3.81(s, 2H), 3.65(t, 2H), 3.44(t, 2H), 3.15(t, 2H), 3.09(s, 3H), 2.69(t, 2H) Example 146
甲磺酰基-乙氨基 甲基 1-Γ4-Π-苯乙氨基) -喹唑啉 -6-基 1-1H-吡咯 -3- 基} -乙醇 Methanesulfonyl-ethylaminomethyl 1-indole 4-indole-phenylethylamino)-quinazolin-6-yl-1H-pyrrol-3-yl}-ethanol
Figure imgf000156_0001
第一步
Figure imgf000156_0001
first step
2-{4-羟甲基小[4-(1-苯乙氨基) -喹唑啉 -6-基] -1H-吡咯 -3-基} -乙醇 在 50 mL茄形瓶中， 将氢化铝锂（ 197 mg， 5.2 mmol)溶解于 15 mL四氢呋 喃中， 所得的溶液在冰浴条件下， 冷却至一 5Ό， 搅拌下分批加入实施例 77第二 步所得的化合物 2-{4-[3-氯 -4- (吡啶 -2-甲氧基) -苯氨基]-喹唑啉 -6-基 6,7-二氢 -2Η- 吡喃 [3,4-c]吡咯 -4-酮 77b ( 1 g, 26 mmol), 搅拌 30分钟后反应完毕。 在反应液中 加入 l mL水， l mL饱和氢氧化钠溶液， 过滤反应液， 母液在减压下浓缩， 得到 本标题产物 2-{4-羟甲基 -1-[4-(1-苯乙氨基) -喹唑啉 -6-基] -1H-吡咯 -3-基} -乙醇 146a (480mg, 类白色固体）， 产率： 47%。  2-{4-Hydroxymethyl small [4-(1-phenylethylamino)-quinazolin-6-yl]-1H-pyrrol-3-yl}-ethanol in a 50 mL eggplant-shaped flask, aluminum hydride Lithium (197 mg, 5.2 mmol) was dissolved in 15 mL of tetrahydrofuran, and the resulting solution was cooled to a temperature of 5 Torr under ice bath, and the compound 2-{4-[3] obtained in the second step of Example 77 was added portionwise with stirring. -Chloro-4-(pyridine-2-methoxy)-phenylamino]-quinazolin-6-yl 6,7-dihydro-2Η-pyrano[3,4-c]pyrrol-4-one 77b (1 g, 26 mmol), the reaction was completed after stirring for 30 minutes. 1 mL of water and 1 mL of saturated sodium hydroxide solution were added to the reaction mixture, and the reaction liquid was filtered, and the mother liquid was concentrated under reduced pressure to give the title product 2-{4-hydroxymethyl-1-[4-(1-benzene) Ethylamino)-quinazolin-6-yl]-lH-pyrrol-3-yl}-ethanol 146a (480 mg, off-white solid), Yield: 47%.
MS m/z (ESI): 389[M+ 1] MS m/z (ESI): 389 [M+ 1]
第二步  Second step
4-(2-羟乙基 1)小[4-(1-苯基-乙氨基) -喹唑啉 -6-基] -1H-吡咯 -3-甲醛 在 25 mL茄形瓶中， 将邻碘酰基苯甲酸（415 mg， 1.48 mmol)溶解于 5 mL 二甲基亚砜中，搅拌下逐滴加入上述步骤所得的化合物 2-{4-羟甲基 -1-[4-(1-苯乙氨 基) -喹唑啉 -6-基] -1H-吡咯 -3-基} -乙醇 146a (480 mg, 1.23 mmol) 的 4 mL二甲基 亚砜溶液，搅拌过夜， 反应完毕。将反应液倒入 100 mL水中，.有固体生成，抽滤， 得到本标题产物 4-(2-羟乙基 )-1-[4-(1-苯基-乙氨基) -喹唑啉 -6-基] -1H-吡咯 -3-甲醛 146b (400 mg, 黄色固体）， 产率： 84%。  4-(2-hydroxyethyl 1) small [4-(1-phenyl-ethylamino)-quinazolin-6-yl]-1H-pyrrole-3-carbaldehyde in a 25 mL eggplant-shaped bottle, adjacent Iodosylbenzoic acid (415 mg, 1.48 mmol) was dissolved in 5 mL of dimethyl sulfoxide, and the compound 2-{4-hydroxymethyl-1-[4-(1-benzene) obtained in the above step was added dropwise with stirring. A solution of ethylamino)-quinazolin-6-yl]-lH-pyrrol-3-yl}-ethanol 146a (480 mg, 1.23 mmol) in 4 mL of dimethyl sulfoxide was stirred overnight and the reaction was completed. The reaction solution was poured into 100 mL of water, and a solid was formed and filtered to give the title product 4-(2-hydroxyethyl)-1-[4-(1-phenyl-ethylamino)-quinazoline- 6-yl]-1H-pyrrole-3-carbaldehyde 146b (400 mg, yellow solid), yield: 84%.
MS m/z (ESI): 387[M+ 1] MS m/z (ESI): 387 [M+ 1]
第二步  Second step
2-{4-[(2-甲磺酰基-乙氨基) -甲基 ]小[4-(1-苯乙氨基) -喹唑啉 -6-基] -1H-吡咯 -3- 基} -乙醇  2-{4-[(2-Methanesulfonyl-ethylamino)-methyl]sodium [4-(1-phenylethylamino)-quinazolin-6-yl]-1H-pyrrol-3-yl} Ethanol
将上述步骤所得的化合物 4-(2-羟乙基 )-1-[4-(1-苯基-乙氨基) -喹唑啉 -6-基] -1H- 吡咯 -3-甲醛 146b (90 mg, 0.233 mmol)溶解于 20 mL二氯甲烷中， 搅拌下加入 2-甲磺酰基乙胺盐酸盐 (74 mg, 0.466 mmol) , 三乙胺 ( 0.066 mL, 0.466 mmol), 室温下搅拌 4小时后加入三乙酰氧基硼氢化钠（99 mg， 0.466 mmol),所得的混合 液在室温下搅拌过夜， 反应完毕。 反应液在减压下浓缩， 得到的固体进一步通过 TLC板进行分离纯化， 得到本标题产物 2-{4-[(2-甲磺酰基-乙氨基) -甲基 ]-1-[4-(1- 苯乙氨基) -喹唑啉 -6-基] -1H-吡咯 -3-基} -乙醇 146 ( 30 mg, 黄色固体）， 产率： 26 %。 The compound obtained in the above step is 4-(2-hydroxyethyl)-1-[4-(1-phenyl-ethylamino)-quinazolin-6-yl]-1H- Pyrrole-3-carbaldehyde 146b (90 mg, 0.233 mmol) was dissolved in 20 mL of dichloromethane. EtOAc (EtOAc, m. After stirring at room temperature for 4 hours, sodium triacetoxyborohydride (99 mg, 0.466 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the obtained solid was further purified and purified to afford the title product 2-{4-[(2-methylsulfonyl-ethylamino)-methyl]-1-[4-( 1-Phenylethylamino)-quinazolin-6-yl]-1H-pyrrol-3-yl}-ethanol 146 (30 mg, yellow solid), yield: 26%.
MS ni/z (ESI): 494[M+ 1]  MS ni/z (ESI): 494[M+ 1]
lH MR (400MHz, DMSO- d6): δ 8.80(s, IH), 8.70(s, IH), 8.4(s, IH), 7.98(d, IH, J=9.2), 7.80(d, 2H, J=8.8), 7.50(d, 3H, J=6.8), 7.32(t, 2H), 7.23 (t, IH), 5.65 (m, IH), 4.09(s, 2H), 3.67(t, 4H), 3.41(t, 2H), 3.15(s, 3H), 2.74(t, 2H), 1.65(d, 3H, 3=72) 实施例 147 lH MR (400MHz, DMSO-d 6 ): δ 8.80(s, IH), 8.70(s, IH), 8.4(s, IH), 7.98(d, IH, J=9.2), 7.80(d, 2H, J=8.8), 7.50(d, 3H, J=6.8), 7.32(t, 2H), 7.23 (t, IH), 5.65 (m, IH), 4.09(s, 2H), 3.67(t, 4H) , 3.41(t, 2H), 3.15(s, 3H), 2.74(t, 2H), 1.65(d, 3H, 3=72) Example 147
2-ί4-二乙氨基甲基 -1-「4-Π-苯乙氨基) -喹唑啉 -6-基 1-lH-吡咯 -3-基 乙酉】  2-ί4-diethylaminomethyl-1-"4-indolyl-phenylethylamino)-quinazoline-6-yl-1-lH-pyrrole-3-ylethylidene]
Figure imgf000157_0001
Figure imgf000157_0001
重复本发明实施例 146第一步至第三步所述的实验步骤， 不同的是以实施例 146 ·第二步化合物 4-(2-羟乙基 )-1-[4-(1-苯基 -乙氨基)-喹唑啉 -6-基] -1Η-吡咯 -3-甲醛 146b作原料， 按照本发明实施例 146第三步所述的相同方式使得该原料与二乙胺 的反应， 得到标题化合物 2-{4-二乙氨基甲基 -1-[4-(1-苯乙氨基) -喹唑啉 -6-基] -1H- 吡咯 -3-基} -乙醇 147 (35 mg, 黄色固体）， 产率： 74%。  The experimental procedure described in the first step to the third step of the embodiment 146 of the present invention is repeated, except that the compound of the second step is 4-(2-hydroxyethyl)-1-[4-(1-benzene). The base-ethylamino)-quinazolin-6-yl]-l-pyridyl-3-carbaldehyde 146b is used as a starting material to react the starting material with diethylamine in the same manner as described in the third step of Example 146 of the present invention. The title compound 2-{4-diethylaminomethyl-1-[4-(1-phenylethylamino)-quinazolin-6-yl]-1H-pyrrol-3-yl}-ethanol 147 (35 mg , yellow solid), Yield: 74%.
MS m/z (ESI): 444 [M+ 1] MS m/z (ESI): 444 [M+ 1]
1HNMR (400MHz, DMSO- d6): δ 10.00(s, IH), 8.93(s, IH), 8.43(s, IH), 8.04(d, 1H， J=9.2), 7.93(s, IH), 7.80(d, IH, J=8.8), 7:60(s, IH), 7.53(d, 2H, J=7.2), 7.3 l(t, 2H), 7.22(m, IH), 5.65(m, IH), 5.50(s, IH), 4.16(s, 2H), 3.67(t, 2H), 3.16(s, 4H), 2.72(t, 2H): 1.67(d, 3H, J=7.2), 1.30(q, 6H) 实施例 148 1 H NMR (400 MHz, DMSO-d 6 ): δ 10.00 (s, IH), 8.93 (s, IH), 8.43 (s, IH), 8.04 (d, 1H, J = 9.2), 7.93 (s, IH) , 7.80(d, IH, J=8.8), 7:60(s, IH), 7.53(d, 2H, J=7.2), 7.3 l(t, 2H), 7.22(m, IH), 5.65(m , IH), 5.50(s, IH), 4.16(s, 2H), 3.67(t, 2H), 3.16(s, 4H), 2.72(t, 2H) : 1.67(d, 3H, J=7.2), 1.30 (q, 6H) Example 148
3- -Π3-氯 -4-(3-氟苄氧基 苯氨基 1-喹唑啉 -6-基 -吡咯 -1-基 3-「(U-二氧代- 六氢 -1λ*6*-噻喃 -4-甲基 氨基 1-丙 -2-醇  3--indole 3-chloro-4-(3-fluorobenzyloxyphenylamino-1-quinazolin-6-yl-pyrrol-1-yl 3-"(U-dioxo-hexahydro-1λ*6* -thiopyran-4-methylamino 1-propan-2-ol
Figure imgf000157_0002
重复本发明实施例 138第一步至第二步的实验步骤， 不同的是以实施例 138 第一歩所得的化合物 [3-氯 -4-(3-氟苄氧基) -苯基 ]-[6-(1-环氧乙烷基甲基 -1H-吡咯 -3- 基) -喹唑啉 -4-基] -胺 138a作为原料， 按照实施例 138第二歩所述的实验方式， 进 行该原料与 C-(l,l-二氧 -六氢 -1λ*6*-噻喃 -4-基) -甲胺的反应， 得到本标题产物 1-(3-{4-[3-氯 -4-(3-氟苄氧基) -苯氨基] -喹唑啉 -6-基}-吡咯 -1-基) -3-[(1，1-二氧代 -六氢 -1λ*6*-噻喃 -4-甲基) -氨基] -丙 -2-醇 148 (34 mg, 黄色固体）， 产率： 52.3%。
Figure imgf000157_0002
The experimental procedure of the first step to the second step of Example 138 of the present invention was repeated, except that the compound obtained in the first step of Example 138 [3-chloro-4-(3-fluorobenzyloxy)-phenyl]- [6-(1-oxiranylmethyl-1H-pyrrol-3-yl)-quinazolin-4-yl]-amine 138a as a starting material, according to the experimental procedure described in the second example of Example 138, The reaction of the starting material with C-(l,l-dioxy-hexahydro-1λ*6*-thiopyran-4-yl)-methylamine is carried out to give the title product 1-(3-{4-[3- Chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazolin-6-yl}-pyrrol-1-yl)-3-[(1,1-dioxo-hexahydro-1λ* 6*-thiopyran-4-methyl)-amino]-propan-2-ol 148 (34 mg, yellow solid), yield: 52.3%.
MS m/z (ESI): 664[M+ 1] MS m/z (ESI): 664 [M+ 1]
'HNMR (400MHZ, DMSO- d6): δ 9.80(s, 1H), 8.6 l(s, 1H), 8.49(s, 1H), 8.05(m, 2H), 7.80(dd, 1H), 7.7 l(d, 1H, J=8.8)， 7.45(m, 2H)， 7.33(m, 3H)， 7.28(t5 1H), 6.89(t, 1H)， 6.70(t, 1H), 5.60(s, 1H), 5.27(s, 2H), 4.10(d, 2H), 3.98(m, 1H), 3.03(m, 4H), 2.70(m, 4H), 1.70(m, 1H), 1.30(m, 4H) 实施例 149 'HNMR (400MHZ, DMSO-d 6 ): δ 9.80 (s, 1H), 8.6 l (s, 1H), 8.49 (s, 1H), 8.05 (m, 2H), 7.80 (dd, 1H), 7.7 l (d, 1H, J=8.8), 7.45(m, 2H), 7.33(m, 3H), 7.28(t 5 1H), 6.89(t, 1H), 6.70(t, 1H), 5.60(s, 1H ), 5.27(s, 2H), 4.10(d, 2H), 3.98(m, 1H), 3.03(m, 4H), 2.70(m, 4H), 1.70(m, 1H), 1.30(m, 4H) Example 149
2-α-ί443-氯 -4-Qi比啶 -2-甲氧基) -苯氨基 1-喹唑啉 -6-基 4-二乙氨基甲基 -1H-吡 咯 -3-基) -乙醇  2-α-ί443-chloro-4-Qipyridin-2-methoxy)-phenylamino-1-quinazolin-6-yl 4-diethylaminomethyl-1H-pyrrol-3-yl)-ethanol
Figure imgf000158_0001
Figure imgf000158_0001
重复本发明实施例 145 第一步至第三步所述的实验步骤， 不同的是以实施例 145第二步化合物 2-(1-{4-[3-氯 -4- (吡啶 -2-甲氧基) -苯氦基] -喹唑啉 -6-基}-4-(2-羟乙 基) -1H-吡咯 -3-甲醛 145b作原料， 按照本发明实施例 145第三步所述的相同方式 使得该原料与二乙胺的反应， 得到标题化合物 2-(1-{4-[3-氯 -4- (：吡啶 -2-甲氧基) -苯 氨基]-喹唑啉 -6-基}-4-二乙氨基甲基 -1H-吡咯 -3-基) -乙醇 149 (50 mg, 黄色固体）， 产率： 30%。  The experimental procedure described in the first step to the third step of Example 145 of the present invention was repeated, except that the compound of the second step of Example 145 was 2-(1-{4-[3-chloro-4-(pyridine-2-) Methoxy)-phenylhydrazino]-quinazolin-6-yl}-4-(2-hydroxyethyl)-1H-pyrrole-3-carbaldehyde 145b as a starting material, according to the third step of Example 145 of the present invention The title compound 2-(1-{4-[3-chloro-4-(:pyridine-2-methoxy)-phenylamino]-quinazoline was obtained in the same manner as described above. -6-yl}-4-diethylaminomethyl-1H-pyrrol-3-yl)-ethanol 149 (50 mg, yellow solid), yield: 30%.
MS m/z (ESI): 559[M+ 1]  MS m/z (ESI): 559 [M+ 1]
lm K (400MHz, DMSO- d6): δ 11.12(s, 1H), 10.08(s, 1H), 8.72(s, 1H), 8.48(s, 1H), 8.23(s, 1H), 8.17(s, 1H), 8.11(d, 1H, J=8.4), 7.72(m, 3H), 7.49(s, 1H), 7.37(q, 1H)， 7.10(m, 3H), 6.89(s, 1H), 6.74(s, 1H), 5.72(s, 2H) 实施例 150 Lm K (400MHz, DMSO-d 6 ): δ 11.12(s, 1H), 10.08(s, 1H), 8.72(s, 1H), 8.48(s, 1H), 8.23(s, 1H), 8.17(s , 1H), 8.11(d, 1H, J=8.4), 7.72(m, 3H), 7.49(s, 1H), 7.37(q, 1H), 7.10(m, 3H), 6.89(s, 1H), 6.74(s, 1H), 5.72(s, 2H) Example 150
Γ1-(3-氟苄基 MH-吲唑 -5-基 1-[6-αΗ-吡咯 -3-基) -喹唑啉 -4-基 1-胺 1-(3-fluorobenzyl MH-indazol-5-yl 1-[6-αΗ-pyrrol-3-yl)-quinazolin-4-yl 1-amine
Figure imgf000159_0001
氮气氛下在 50 mL茄形瓶中， 将 [1-(3-氟苄基 )-1Η-吲唑 -5-基]- (6-碘喹唑啉 -4- 基) -胺 43b (250 mg， 0.505 mmol), 1- (三异丙基硅 )-1Η-吡咯 -3-硼酸（269 mg， 1.01 mmol), 四三苯基膦化钯（2.3 mg， 0.02 mmol), 碳酸钾 （138 mg, 1 mmol)溶于 6 mL N,N-二甲基甲酰胺和 1.5 mL水的混合溶剂中， 得到的混合物加热到 70°C， 2 小时后反应完毕。 将反应液冷却至室温， 倒入 lOOmL冰水中， 析出白色固体， 搅 拌十分钟后， 抽滤， 产物在真空下干燥， 得到的固体进一步通过柱层析， 得到标 题产物 [1-(3-氟苄基) -1H-吲唑 -5-基 ]-[6-(m-吡咯 -3-基) -喹唑啉 -4-基] -胺 150 ( 130 mg, 黄色固体）， 产率： 59.3 %。
Figure imgf000159_0001
[1-(3-Fluorobenzyl)-1Η-oxazol-5-yl]-(6-iodoquinazolin-4-yl)-amine 43b (250) in a 50 mL eggplant-shaped flask under nitrogen atmosphere Mg, 0.505 mmol), 1-(triisopropylsilyl)-1Η-pyrrole-3-boronic acid (269 mg, 1.01 mmol), tetrakistriphenylphosphine palladium (2.3 mg, 0.02 mmol), potassium carbonate (138 Mg, 1 mmol) was dissolved in a mixed solvent of 6 mL of N,N-dimethylformamide and 1.5 mL of water, and the mixture was heated to 70 ° C, and the reaction was completed after 2 hours. The reaction liquid was cooled to room temperature, poured into 100 mL of ice water, and a white solid was precipitated. After stirring for ten minutes, the mixture was filtered under suction, and the product was dried in vacuo to give the title compound. Benzyl)-1H-indazol-5-yl]-[6-(m-pyrrol-3-yl)-quinazolin-4-yl]-amine 150 (130 mg, yellow solid), yield: 59.3 %.
MS m/z (ESI): 435[M+1] MS m/z (ESI): 435 [M+1]
'HNMR (400MHZ, DMSO- d6): δ 10.27(s, 1H), 8.86(s, 1H), 8.5 l(s, 1H), 8.27(s, 1H)， 8.17(s, lH), 8.07(d, m, J=8.8), 7.87(m, 1H), 7.76(s, 3H), 7.56(s, 1H)， 7.39(q, 1H), 7.07(m, 3H), 5.71(s, 2H), 3.99(s, 2H), 3.67(m, 2H)， 2.73(m, 2H), 2.62(m, 6H) 实施例 151 'HNMR (400MHZ, DMSO-d 6 ): δ 10.27(s, 1H), 8.86(s, 1H), 8.5 l(s, 1H), 8.27(s, 1H), 8.17(s, lH), 8.07( d, m, J=8.8), 7.87(m, 1H), 7.76(s, 3H), 7.56(s, 1H), 7.39(q, 1H), 7.07(m, 3H), 5.71(s, 2H) , 3.99(s, 2H), 3.67(m, 2H), 2.73(m, 2H), 2.62(m, 6H) Example 151
2-(4- n,l-二氧代 -六氢 -1λ*6*-噻喃 -4-甲基) -氨基 1-甲基 }小 -Γ 3-氟苄 基) -1Η-吲唑 -5-氨基 1-喹唑啉 -6-基 }-1Η-吡咯 -3-基) -乙醇  2-(4-n,l-dioxo-hexahydro-1λ*6*-thiopyran-4-methyl)-amino-1-methyl}small-oxime 3-fluorobenzyl)-1-indole-carbazole -5-amino-1-quinazolin-6-yl}-1Η-pyrrol-3-yl)-ethanol
Figure imgf000159_0002
Figure imgf000159_0002
Figure imgf000160_0001
Figure imgf000160_0001
151  151
第一步  First step
2-(1-{4-[1-(3-氟苄基 )-1Η-吲唑 -5-氨基] -喹唑啉 -6-基 }-4-轻甲基 -1H-吡咯 -3-基) -乙醇 在 250 mL茄形瓶中， 将氢化铝锂（340 mg， 5.2 mmol)溶解于 50 mL四氢呋 喃中， 所得的溶液在冰浴条件下， 冷却至一 5°C， 搅拌下分批加入实施例 132第二 步所得的化合物 2-(4-{3-[2-(4-氟苄基 1)-4-乙烯基 -2H-吡唑 -3-基]-烯丙氨基}-喹唑啉 -6-基) -6,7-二氢 -2H-吡喃 [3,4-c]吡咯 -4-酮 132b (2.26 g, 4.48 mmol), 搅拌 3小时后 反应完毕。 在反应液中加入 50 mL四氢呋喃和水（体积比为 1 : 1 )的混合溶剂猝 灭反应， 加入 lOO mL乙酸乙酯， 搅拌， 有固体生成， 硅藻土过滤， 滤液用乙酸乙 酯（100 mL X 3 )萃取，合并的有机相在减压下蒸干，得到本标题产物 2-(1-{4-[1-(3- 氟苄基) -1H-吲唑 -5-氨基]-喹唑啉 -6-基}-4-羟甲基 -1H-吡咯 -3-基) -乙醇 151a ( 1.713 g， 黄色固体）， 产率： 75.19%。  2-(1-{4-[1-(3-fluorobenzyl)-1Η-oxazol-5-amino]-quinazolin-6-yl}-4-light methyl-1H-pyrrole-3- Base) - Ethanol In a 250 mL eggplant-shaped flask, lithium aluminum hydride (340 mg, 5.2 mmol) was dissolved in 50 mL of tetrahydrofuran, and the resulting solution was cooled to 5 ° C in an ice bath, and batched under stirring. The compound obtained in the second step of Example 132 was added 2-(4-{3-[2-(4-fluorobenzyl 1)-4-vinyl-2H-pyrazol-3-yl]-allylamino}- Quinazoline-6-yl)-6,7-dihydro-2H-pyrano[3,4-c]pyrrol-4-one 132b (2.26 g, 4.48 mmol). The reaction mixture was quenched by adding 50 mL of a mixed solvent of tetrahydrofuran and water (1:1 by volume), and 100 mL of ethyl acetate was added thereto, stirred, solid formed, filtered through Celite, and filtrated ethyl acetate (100) Extraction of the combined organic phase with EtOAc (3 mL) Quinazoline-6-yl}-4-hydroxymethyl-1H-pyrrol-3-yl)-ethanol 151a ( 1.713 g, yellow solid), Yield: 75.19%.
第二步  Second step
1-{4-[1-(3-氟苄基) -1H-吲唑 -5-氨基] -喹唑啉 -6-基 }-4-(2-羟乙基 )-1Η-吡咯 -3-甲醛 在 50 mL茄形瓶中， 将邻碘酰基苯甲酸（990 mg， 3.54 mmol)溶解于 20 mL 二甲基亚砜中， 搅拌下逐滴加入上述步骤所得的化合物 2-(1-{4-[1-(3-氟苄基 )-1Η- 吲唑 -5-氨基] -喹唑啉 -6-基 }-4-羟甲基 -1H-吡咯 -3-基) -乙醇 151a( 1.713 g， 3.37 mmol) 的 5 mL二甲基亚砜溶液， 搅拌过夜， 反应完毕。将反应液倒入 100 mL 5 %碳酸氢 钠溶液和 50 mL乙酸乙酯， 有固体生成， 抽滤， 得到本标题产物 1-{4-[1-(3-氟苄 基) -1H-吲唑 -5-氨基] -喹唑啉 -6-基}-4-(2-羟乙基) -1H-吡咯 -3-甲醛 151b (4.5 g，黄色 固体）， 产物不经分离直接进行下一步反应。  1-{4-[1-(3-Fluorobenzyl)-1H-indazole-5-amino]-quinazolin-6-yl}-4-(2-hydroxyethyl)-1Η-pyrrole-3 - Formaldehyde In a 50 mL eggplant-shaped flask, o-iodobenzoic acid (990 mg, 3.54 mmol) was dissolved in 20 mL of dimethyl sulfoxide, and the compound 2-(1-{) obtained in the above step was added dropwise with stirring. 4-[1-(3-fluorobenzyl)-1Η-oxazol-5-amino]-quinazolin-6-yl}-4-hydroxymethyl-1H-pyrrol-3-yl)-ethanol 151a ( A solution of 1.713 g, 3.37 mmol) in 5 mL of dimethyl sulfoxide was stirred overnight and the reaction was completed. The reaction solution was poured into 100 mL of 5% sodium hydrogencarbonate solution and 50 mL of ethyl acetate. A solid was formed and filtered to give the title product 1-{4-[1-(3-fluorobenzyl)-1H-indole. Imidazole-5-amino]-quinazolin-6-yl}-4-(2-hydroxyethyl)-1H-pyrrole-3-carbaldehyde 151b (4.5 g, yellow solid). reaction.
MS m/z (ESI): 507[M+ 1] MS m/z (ESI): 507 [M+ 1]
第三步  third step
2-(4-{[(1，1-二氧代 -六氢 -1λ*6*-噻喃 -4-甲基) -氨基] -甲基 }-1-{4-[1-(3-氟苄 基) -1Η-吲唑 -5-氨基] -喹唑啉 -6-基 }-1Η-吡咯 -3-基) -乙醇 将上述步骤所得的化合物 1-{4-[1-(3-氟苄基) -1H-吲唑 -5-氨基] -喹唑啉 -6- 基}-4-(2-羟乙基) -1H-吡咯 -3-甲醛 151b (500 mg， 0.493 mmol)溶解于 20 mL二氯 甲烷中， 搅拌下加入 C-(l,l-二氧 -六氢 -1λ*6*-噻喃 -4-基) -甲胺 （161 mg, 0.987 mmol), 室温下搅拌 4小时后加入三乙酰氧基硼氢化钠 （209 mg， 0.987 mmol), 所得的混合液在室温下搅拌过夜， 反应完毕。 反应液在减压下浓缩， 得到的固体 进一步通过 TLC板进行分离纯化，得到本标题产物 2-(4-{[(1,1-二氧代 -六氢 -1λ*6*- 噻喃 -4-甲基) -氨基] -甲基 }-1-{4-[1-(3-氟苄基) -1Η-吲唑 -5-氨基] -喹唑啉 -6-基 }-m-吡 咯 -3-基) -乙醇 151 (80 mg, 黄色固体）， 产率： 24.9%。 2-(4-{[(1,1-dioxo-hexahydro-1λ*6*-thiopyran-4-methyl)-amino]-methyl}-1-{4-[1-(3 -fluorobenzyl)-1Η-indazole-5-amino]-quinazolin-6-yl}-1Η-pyrrol-3-yl)-ethanol The compound obtained in the above step 1-{4-[1-( 3-fluorobenzyl)-1H-indazole-5-amino]-quinazoline-6- }}-4-(2-hydroxyethyl)-1H-pyrrole-3-carbaldehyde 151b (500 mg, 0.493 mmol) was dissolved in 20 mL of dichloromethane, and then added to C-(l,l-diox) Hexahydro-1λ*6*-thiopyran-4-yl)-methylamine (161 mg, 0.987 mmol), stirred at room temperature for 4 h then sodium triacetoxyborohydride (209 mg, 0.987 mmol). The mixture was stirred at room temperature overnight and the reaction was completed. The reaction mixture was concentrated under reduced pressure, and the obtained solid was further purified and purified to afford the title product 2-(4-{[(1,1-dioxo-hexahydro-1λ*6*-thiopyran)- 4-methyl)-amino]-methyl}-1-{4-[1-(3-fluorobenzyl)-1(indolyl-5-amino)-quinazolin-6-yl}-m- Pyrrol-3-yl)-ethanol 151 (80 mg, yellow solid), Yield: 24.9%.
MS m/z (ESI): 654[M+ 1] MS m/z (ESI): 654 [M+ 1]
!HNMR (400MHz, DMSO- d6): δ 11.10(s, 1H), 9.80(s, 1H), 8.56(d, 2H), 8.21 (dd, 1H, J =6.8), 8.11(d, 1H, J=8.8), 7.87(m, 1H), 7.73(d, 1H, J=8.4), 7.47(m, 2H), 6.91(s， 1H), 6.7 l(s, 1H) 实施例 152 ! HNMR (400MHz, DMSO- d 6 ): δ 11.10 (s, 1H), 9.80 (s, 1H), 8.56 (d, 2H), 8.21 (dd, 1H, J = 6.8), 8.11 (d, 1H, J = 8.8), 7.87 (m, 1H), 7.73 (d, 1H, J = 8.4), 7.47 (m, 2H), 6.91 (s, 1H), 6.7 l (s, 1H) Example 152
2-(4-二甲氨基甲基 -1 -Μ-Γ1-(3-氟苄基) -1H-吲唑 -5-氨基 1-喹唑啉 -6-基 1H-吡咯  2-(4-Dimethylaminomethyl-l-indole-indole 1-(3-fluorobenzyl)-1H-indazole-5-amino-1-quinazoline-6-yl 1H-pyrrole
-3-基) -乙醇  -3-yl)-ethanol
Figure imgf000161_0001
Figure imgf000161_0001
重复本发明实施例 151 第一步至第三步所述的实验步骤， 不同的是以实施例 151 第二步化合物 1-{4-[1-(3-氟苄基) -1H-吲唑 -5-氨基] -喹唑啉 -6-基}-4-(2-羟乙 基) -1H-吡咯 -3-甲醛 151b作原料， 按照本发明实施例 151第三步所述的相同方式 使得该原料与二甲胺的反应， 得到标题化合物 2-(4-二甲氨基甲基 -1-{4-[1-(3-氟苄 基) -1H-吲唑 -5-氨基] -喹唑啉 -6-基}-1：«-吡咯 -3-基) -乙醇 152 (60 mg, 黄色固体）， 产率： 35%。  The experimental procedure described in the first step to the third step of Example 151 of the present invention was repeated, except that the compound of the second step of Example 151 was 1-{4-[1-(3-fluorobenzyl)-1H-carbazole. -5-Amino]-quinazolin-6-yl}-4-(2-hydroxyethyl)-1H-pyrrole-3-carbaldehyde 151b as a starting material, in the same manner as described in the third step of Example 151 of the present invention The reaction of the starting material with dimethylamine gave the title compound 2-(4-dimethylaminomethyl-1-{4-[1-(3-fluorobenzyl)-1H-indazole-5-amino]- Quinazoline-6-yl}-1: «-pyrrol-3-yl)-ethanol 152 (60 mg, yellow solid), yield: 35%.
MS m/z (ESI): 536[M+ 1]  MS m/z (ESI): 536 [M+ 1]
!HNMR (400MHz, DMSO- d6): δ 10.27(s, 1H), 8.86(s, 1H), 8.51(s, 1H)， 8.27(s, 1H), 8.17(s， 1H), 8.07(d, 1H, J=8.8), 7.87(m, 1H), 7.76(s, 3H)， 7.56(s, 1H), 7.39(q, 1H), 7.07(m, 3H), 5.71(s, 2H)， 3.99(s， 2H)， 3.67(m, 2H), 2.73(m, 2H), 2.62(m, 6H) 实施例 153 ! HNMR (400MHz, DMSO- d 6 ): δ 10.27 (s, 1H), 8.86 (s, 1H), 8.51 (s, 1H), 8.27 (s, 1H), 8.17 (s, 1H), 8.07 (d , 1H, J=8.8), 7.87(m, 1H), 7.76(s, 3H), 7.56(s, 1H), 7.39(q, 1H), 7.07(m, 3H), 5.71(s, 2H), 3.99(s, 2H), 3.67(m, 2H), 2.73(m, 2H), 2.62(m, 6H) Example 153
2-Π- -Γ1-(3-氟苄基 H-吲唑 -5-氨基 1-喹唑啉 -6-基 4-IY2-甲磺酰基 -乙氨基)- 甲基 1-1H-吡咯 -3-基} -乙醇 091 2-Π--Γ1-(3-fluorobenzyl H-indazole-5-amino-1-quinazolin-6-yl 4-IY2-methanesulfonyl-ethylamino)-methyl1-1H-pyrrole- 3-yl}-ethanol 091
Wz^ WWz Wz^ WWz
- ¾¾ϋώ-ζ-ε- (愛 -1 ^ - ¾-9-柳¾¾ ¾¾-(¾¾ 簿-£)寸-鶩-£_|-17 -£)-1  - 3⁄43⁄4ϋώ-ζ-ε- (Love -1 ^ - 3⁄4-9-柳3⁄43⁄4 3⁄43⁄4-(3⁄43⁄4 书-£) inch-鹜-£_|-17 -£)-1
(HI 's) '9(HI 's) '9
'(HI 's)I6'9 XUZ
Figure imgf000162_0001
'(HI 's)I6'9 XUZ
Figure imgf000162_0001
Γ 'HI 'PP)lZ-8 HZ 'P)9S'8 '(HI 's)08'6 '(HI '5)0ΓΠ § ·'(9Ρ "OSNQ 'ZHWOOt) ¾ ^NHr Γ 'HI 'PP)lZ-8 HZ 'P)9S'8 '(HI 's)08'6 '(HI '5)0ΓΠ § ·'( 9 Ρ "OSNQ 'ZHWOOt) 3⁄4 ^NH r
[\+n]6££ :(isa)z∞sw[\+n]6££ : (isa)z∞sw
。％0ΐ 5Z) ¾-[¾-l7-雜 OZ ft 耷 -ε- ^物 -m)-9]- (愛 蔦 -ε) :^ '^i 邈 »—ε- α¾ι-Η ¾. %0ΐ 5Z) 3⁄4-[3⁄4-l7-Miscellaneous OZ ft 耷 -ε-^物-m)-9]- (Love 茑 -ε) :^ '^i 邈 »—ε- α3⁄4ι-Η 3⁄4
¾ ≡)-t n m ' ^ ς\ im '- ^ kSP 3⁄4 ≡)-tnm ' ^ ς\ im '- ^ k SP
Figure imgf000162_0002
Figure imgf000162_0002
(RZ(RZ
'1)69'Z m 's)80'£ '(HZ 'i)9YZ '(HZ 'l)WZ '(IK ¾S9"£ ΉΖ 'S)08'£ Xm 'S) 'S '(H£ '∞)Ζ ·Λ '(HI ) '(Ηΐ
Figure imgf000162_0003
m ' )。8' '(HI 'Ρ)90·8 '(HI es)9f8 '(ΗΪ 'S)Z '8 '(HI £s)05"8 '(HI 's)£8'8 '(Ηΐ '^ ΟΙ 9 -(9P -OS Q ^UWOO ) ¾[WNHl ίι+γύ i9 :dsa)z/∞sw
Figure imgf000162_0004
'1)69'Z m 's)80'£ '(HZ 'i)9YZ '(HZ 'l)WZ '(IK 3⁄4S9"£ ΉΖ 'S)08'£ Xm 'S) 'S '(H£ '∞)Ζ ·Λ '(HI ) '(Ηΐ
Figure imgf000162_0003
m '). 8''(HI'Ρ)90·8'(HI e s)9f8 '(ΗΪ ' S )Z '8 '(HI £ s)05"8 '(HI 's)£8'8 '(Ηΐ ' ^ ΟΙ 9 -( 9 P -OS Q ^UWOO ) 3⁄4[WNH l ίι+γύ i9 : dsa)z/∞sw
Figure imgf000162_0004
£Si ϋΙ -{¾-ε-¾ -Ηΐ-[¾ώ-( ϋτ -¾¾^ώ-ζ)]-ΐ7-{¾-9-#ι ΐΰ- [愛篱 £Si ϋ Ι -{3⁄4-ε-3⁄4 -Ηΐ-[3⁄4ώ-( ϋ τ -3⁄43⁄4^ώ-ζ)]-ΐ7-{3⁄4-9-#ι ΐΰ- [Love fence
Figure imgf000162_0005
Figure imgf000162_0005
Ζ.0εΐ00/800ΖΜ3/Χ3<1 而 600Z OAV
Figure imgf000163_0001
Ζ.0εΐ00/800ΖΜ3/Χ3<1 and 600Z OAV
Figure imgf000163_0001
重复本发明实施例 138第一步至第二步的实验步骤， 不同的是以实施例 138 第一步所得的化合物 [3-氯 -4-(3-氟苄氧基) -苯基 ]-[6-(1-环氧乙烷基甲基 -1H-吡咯 -3- 基) -喹唑啉 -4-基] -胺 138a作为原料， 按照实施例 138第二步所述的实验方式， 进 行该原料与 2-甲磺酰基乙胺的反应，得到本标题产物 1-(3-{4-[3-氯 -4-(3-氟苄氧基) - 苯氨基] -喹唑啉 -6-基} -吡咯 1-基) -3-(2-甲磺酰基-乙氨基) -丙 -2-醇 155 ( 17 mg，黄色 固体）， 产率： 27.9%。  The experimental procedure of the first step to the second step of Example 138 of the present invention was repeated, except that the compound obtained in the first step of Example 138 [3-chloro-4-(3-fluorobenzyloxy)-phenyl]- [6-(1-oxiranylmethyl-1H-pyrrol-3-yl)-quinazolin-4-yl]-amine 138a as a starting material, according to the experimental procedure described in the second step of Example 138, The reaction of the starting material with 2-methanesulfonylethylamine afforded the title product 1-(3-{4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazoline- 6-yl}-pyrrole 1-yl)-3-(2-methanesulfonyl-ethylamino)-propan-2-ol 155 (17 mg, yellow solid), yield: 27.9%.
MS m/z (ESI): 624[M+ 1] MS m/z (ESI): 624 [M+ 1]
1HNMR (400MHz, DMSO- d6): δ 9.69(s, IH), 8.52(d, 2H), 8.02(d, 2H), 7.78(dd, IH), 7.70(d, IH, J=8.8), 7.49(q, IH), 7.41(s, IH), 7.32(m, 3H), 7.19(t, IH), 6.88(s, IH), 6.66(s, IH), 5.27(s, 2H)， 5.10(d, IH), 4.03 (d, 2H), 3.80(m, IH), 3.23(m, 2H), 3.15(t, 2H)， 3.02(s, 3H), 2.95 (t, 2H) 实施例 156 1 H NMR (400 MHz, DMSO-d 6 ): δ 9.69 (s, IH), 8.52 (d, 2H), 8.02 (d, 2H), 7.78 (dd, IH), 7.70 (d, IH, J = 8.8) , 7.49(q, IH), 7.41(s, IH), 7.32(m, 3H), 7.19(t, IH), 6.88(s, IH), 6.66(s, IH), 5.27(s, 2H), 5.10(d, IH), 4.03 (d, 2H), 3.80(m, IH), 3.23(m, 2H), 3.15(t, 2H), 3.02(s, 3H), 2.95 (t, 2H) 156
2-{4-「3-氯 -4-(3-氟苄氧基) -苯氨基 1-喹唑啉 -6-基 }-5，6-二氢 -2H-环戊烷并「(；1吡 咯 -4-酮 -0-(2-二乙氨基乙基) -肟  2-{4-"3-Chloro-4-(3-fluorobenzyloxy)-phenylamino-1-quinazolin-6-yl}-5,6-dihydro-2H-cyclopentane" (; 1 pyrrole-4-one-0-(2-diethylaminoethyl)-indole
Figure imgf000163_0002
Figure imgf000163_0002
第一步  First step
5，6-二氢 -2H-环戊垸并 [c]吡咯 -4-酮 -0-(2-二乙氨基乙基) -肟  5,6-dihydro-2H-cyclopenta[c]pyrrole-4-one -0-(2-diethylaminoethyl)-indole
在 50 mL茄形瓶中， 将 5,6-二氢 -2H-环戊垸 [c]吡咯 -4-酮 16b (200 mg, 1.65 mmol), 0-(2-二乙氨基乙基) -羟胺盐酸盐 （474 mg, 2.31mmol) 溶解于 20 mL乙 醇中， 搅拌下加入醋酸钠 （406 mg， 4.95 mmol), 所得的混合液加热回流 4小时， 反应完毕。 溶液冷却至室温， 过滤， 滤液减压下浓缩， 得到的残留物通过柱层析 进一步分离纯化， 得到本标题产物 5,6-二氢 -2H-环戊烷并 [c]吡咯 -4-酮 -0-(2-二乙氨 基乙基) -肟 156a ( 155 mg, 黄色固体）， 产率： 40% In a 50 mL eggplant-shaped flask, 5,6-dihydro-2H-cyclopentanyl[c]pyrrol-4-one 16b (200 mg, 1.65 mmol), 0-(2-diethylaminoethyl)- Hydroxylamine hydrochloride (474 mg, 2.31 mmol) was dissolved in 20 mL of ethanol, sodium acetate (406 mg, 4.95 mmol) was added with stirring, and the mixture was refluxed for 4 hr. The reaction is completed. The solution was cooled to room temperature, filtered, and the filtrate was evaporated, evaporated, evaporated, mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj -0-(2-Diethylaminoethyl)-indole 156a ( 155 mg, yellow solid), Yield: 40%
MS m/z (ESI): 254[M+ 1] MS m/z (ESI): 254 [M+ 1]
第二步  Second step
2-{4-[3-氯 -4-(3-氟苄氧基) -苯氨基] -喹唑啉 -6-基}-5,6-二氢 -2H-环戊烷并 [c]吡 咯 -4-酮- 0-(2-二乙氨基乙基) -肟  2-{4-[3-Chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazolin-6-yl}-5,6-dihydro-2H-cyclopentane[c] Pyrrole-4-one- 0-(2-diethylaminoethyl)-indole
在 50 mL茄形瓶中，依次加入上述步骤所得的化合物 5,6-二氢 -2H-环戊烷并 [c] 吡咯 -4-酮 0-(2-二乙氨基乙基) -肟 156a (70 mg， 0.3mmol)， （3-氯 -4-氟苯基 )-(6-碘 -喹唑啉 -4-基) -胺 lg ( 152 mg， 0.3mmol)， 磷酸钾（191 mg， 0.9 mmol), 碘化亚铜 (57mg， 0.3 mmol), Ν,Ν'-二甲基 -1,2-乙二胺（26 mg， 0.3mmol)溶解于 3mL N,N- 二甲基甲酰胺中， 混合物在氮气保护下， 加热到 70。C， 搅拌过夜。 将反应液倒入 100 mL冰水中， 用乙酸乙酯 （30 mLX 3 )萃取， 合并的有机相依次用饱和氯化钠 洗涤， 无水硫酸钠干燥， 过滤， 滤液减压下浓缩， 得到的残'留物用 TLC板， 固体 在真空下干燥， 得到本标题产物 2-{4-[3-氯 -4-(3-氟苄氧基) -苯氨基] -喹唑啉 -6- 基}-5,6-二氢 -2H-环戊烷并 [c]吡咯 -4-酮 -0-(2-二乙氨基乙基) -肟（46 mg，黄色固体）， 产率： 25.3 %。  In a 50 mL eggplant-shaped flask, the compound obtained in the above step was sequentially added with 5,6-dihydro-2H-cyclopenta[c]pyrrole-4-one 0-(2-diethylaminoethyl)-indole 156a. (70 mg, 0.3 mmol), (3-chloro-4-fluorophenyl)-(6-iodo-quinazolin-4-yl)-amine lg (152 mg, 0.3 mmol), potassium phosphate (191 mg, 0.9 mmol), cuprous iodide (57 mg, 0.3 mmol), hydrazine, Ν'-dimethyl-1,2-ethanediamine (26 mg, 0.3 mmol) dissolved in 3 mL of N,N-dimethylformamide The mixture was heated to 70 under nitrogen. C, stir overnight. The reaction mixture was poured into 100 mL of ice water and extracted with ethyl acetate (30 mL×3). The combined organic phases were washed sequentially with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, 'Residue was dried on a TLC plate, and the solid was obtained in vacuo to give the title product 2-{4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazoline-6-yl} -5,6-Dihydro-2H-cyclopenta[c]pyrrol-4-one-0-(2-diethylaminoethyl)-indole (46 mg, yellow solid), yield: 25.3%.
MS m/z (ESI): 614[M+ 1] MS m/z (ESI): 614 [M+ 1]
^MR (400MHz, DMSO- d6): δ 10.13(s， 1H), 8.92(s, 1H), 8.60(s, 1H), 8.17(m, 3H), 7.88(d, 2H, J =9.2), 7.47(m, 1H), 7.43(s, 1H)， 7.32(m, 2H), 7.28(d, 1H, J=9.2), 7.19(t, 1H), 5.27(s, 2H), 4.40(t, 2H), 3.14(m, 2H), 3.05(q, 2H), 2.90(t, 2H), 1.26(m, 10H) 实施例 157 ^MR (400MHz, DMSO-d 6 ): δ 10.13(s, 1H), 8.92(s, 1H), 8.60(s, 1H), 8.17(m, 3H), 7.88(d, 2H, J =9.2) , 7.47(m, 1H), 7.43(s, 1H), 7.32(m, 2H), 7.28(d, 1H, J=9.2), 7.19(t, 1H), 5.27(s, 2H), 4.40(t , 2H), 3.14(m, 2H), 3.05(q, 2H), 2.90(t, 2H), 1.26(m, 10H) Example 157
(Z) -2- -Γ3-氯 -{4-「3-氯- 4-(3-氟苄氧基)-苯氨基 1-喹唑啉 -6-基 }-5,6-二氢 -2H- 环戊烷并「cl吡咯 -4-酮 -0-(2-吗啉 -4-乙基) -肟  (Z)-2-(Γ3-Chloro-{4-"3-chloro-4-(3-fluorobenzyloxy)-phenylamino-1-quinazolin-6-yl}-5,6-dihydro- 2H-cyclopentane and "clpyrrol-4-one-0-(2-morpholin-4-ethyl)-oxime
Figure imgf000164_0001
第一步
Figure imgf000164_0001
first step
5,6-二氢 -2H-环戊烷并 [c]吡咯 -4-酮 -0-(2-吗啉 -4-乙基) -肟  5,6-dihydro-2H-cyclopenta[c]pyrrole-4-one -0-(2-morpholin-4-ethyl)-indole
在 50 mL茄形瓶中， 将 5,6-二氢 -2H-环戊烷 [c]吡咯 -4-酮 16b (200 mg， 1.65 mmol) , 0-(2-吗啉 -4-乙基) -羟胺盐酸盐（507mg， 2.31mmol)溶解于 20 mL乙醇中， 搅拌下加入醋酸钠（406 mg， 4.95 mmol), 所得的混合液加热回流 6小时， 反应完 毕。 溶液冷却至室温， 过滤， 减压下浓缩， 得到的残留物通过柱层析进一步分离 纯化， 得到本标题产物 5，6-二氢 -2H-环戊烷并 [c]吡咯 -4-酮 -0-(2-吗啉 -4-乙基) -肟 157a (328 mg， 白色固体）， 产率： 80%  5,6-Dihydro-2H-cyclopentane [c]pyrrol-4-one 16b (200 mg, 1.65 mmol), 0-(2-morpholin-4-ethyl) in a 50 mL eggplant-shaped flask - Hydroxylamine hydrochloride (507 mg, 2.31 mmol) was dissolved in 20 mL of ethanol, and sodium acetate (406 mg, 4.95 mmol) was added with stirring, and the mixture was heated under reflux for 6 hr. The solution was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue obtained was purified and purified by column chromatography to give the title product 5,6-dihydro-2H-cyclopentane[c]pyrrol-4-one- 0-(2-morpholin-4-ethyl)-indole 157a (328 mg, white solid), Yield: 80%
MS m/z (ESI): 250[M+ 1] MS m/z (ESI): 250 [M+ 1]
第二步  Second step
(Z) 2-{4-[3-氯 -4-(3-氟苄氧基) -苯氨基] -喹唑啉 -6-基}-5,6-二氢 -2H-环戊烷并 [c] 吡咯 -4-酮 -0-O吗啉 -4-乙基) -肟  (Z) 2-{4-[3-Chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazolin-6-yl}-5,6-dihydro-2H-cyclopentane [c] Pyrrol-4-one-0-Omorpholin-4-ethyl)-肟
在 50 mL茄形瓶中，依次加入上述步骤所得的化合物 5,6-二氢 -2H-环戊烷并 [c] 吡咯 -4-酮 -0-(2-吗啉 -4-乙基) -肟 157a ( 100 mg， 0.4 mmol), (3-氯 -4-氟苯基 )-(6- 碘-喹唑啉 -4-基) -胺 lg (203 mg， 0.4 mmol), 磷酸钾（255 mg， 1.2 mmol), 碘化 亚铜（76 mg， 0.4mmol), Ν,Ν'-二甲基 -1,2-乙二胺（35 mg， 0.4mmol)溶解于 3 mL Ν,Ν-二甲基甲酰胺中， 混合物在氮气保护下， 加热到 70°C， 搅拌 20小时后反应完 毕。将反应液倒入 100 mL冰水中， 用乙酸乙酯 . ( 30 mL X 3 )萃取， 合并的有机相 依次用饱和氯化钠洗涤， 无水硫酸钠干燥， 过滤， 减压下浓缩， 得到的残留物用 HPLC进一步分离纯化， 得到本标题产物 （Z) 2-{4-[3-氯 -4-(3-氟苄氧基) -苯氨基] - 喹唑啉 -6-基}-5,6-二氢 -2H-环戊垸并 [c]吡咯 -4-酮 -0-(2-吗啉 -4-乙基) -肟 157( 80 mg， 黄色固体）， 产率： 32%。  In a 50 mL eggplant-shaped flask, the compound obtained in the above step, 5,6-dihydro-2H-cyclopenta[c]pyrrole-4-one-0-(2-morpholin-4-ethyl) was added in order. - 肟157a (100 mg, 0.4 mmol), (3-chloro-4-fluorophenyl)-(6-iodo-quinazolin-4-yl)-amine lg (203 mg, 0.4 mmol), potassium phosphate ( 255 mg, 1.2 mmol), cuprous iodide (76 mg, 0.4 mmol), hydrazine, Ν'-dimethyl-1,2-ethanediamine (35 mg, 0.4 mmol) dissolved in 3 mL Ν, Ν- In dimethylformamide, the mixture was heated to 70 ° C under a nitrogen atmosphere, and the reaction was completed after stirring for 20 hours. The reaction mixture was poured into 100 mL of ice water, EtOAc (30 mL EtOAc). The residue was further purified by HPLC to give the title product (Z) 2-{4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazoline-6-yl}-5 ,6-Dihydro-2H-cyclopenta[c]pyrrol-4-one-0-(2-morpholin-4-ethyl)-indole 157 (80 mg, yellow solid), Yield: 32% .
MS m/z (ESI): 628[M+ 1] MS m/z (ESI): 628 [M+ 1]
!HNMR (400MHz, DMSO- d6): δ 9.82(s, 1H), 8.62(d, 2H), 8.13(d, 1H, J=8.4), 8.02(s, 1H)， 7.87(d, 1H, J -=9.2), 7.74(d, 2H, J=8.0), 7.46(q, 1H), 7.30(m, 4H), 7.18(t, 1H), 5.26(s, 2H), 4.19(t, 2H), 3.55(t, 4H), 3.03(t, 2H), 2.89(t, 2H), 2.67(t, 2H), 2.48(m, 4H) 实施例 158 ! HNMR (400MHz, DMSO- d 6 ): δ 9.82 (s, 1H), 8.62 (d, 2H), 8.13 (d, 1H, J = 8.4), 8.02 (s, 1H), 7.87 (d, 1H, J -=9.2), 7.74(d, 2H, J=8.0), 7.46(q, 1H), 7.30(m, 4H), 7.18(t, 1H), 5.26(s, 2H), 4.19(t, 2H ), 3.55(t, 4H), 3.03(t, 2H), 2.89(t, 2H), 2.67(t, 2H), 2.48(m, 4H) Example 158
(E) -2-ί4-Γ3-氯 -i4-「3-氯 -4-(3-氟苄氧基) -苯氨基 1-喹唑啉 -6-基 }-5,6-二氢 -2H- 环戊烷并「(；1吡咯 -4-酮 -0-(2-吗啉 -4-乙基 -肟  (E) -2-ί4-Γ3-chloro-i4-"3-chloro-4-(3-fluorobenzyloxy)-phenylamino-1-quinazolin-6-yl}-5,6-dihydro- 2H-cyclopentane and "(;1 pyrrole-4-one-0-(2-morpholin-4-ethyl-oxime)
Figure imgf000165_0001
重复本发明实施例 157第一步至第二步的实验步骤， 对第二步的粗产品进行 HPLC制备分离得到本标题产物（E) -2-{4-[3-氯 -{4-[3-氯 -4-(3-氟苄氧基) -苯氨基] - 喹唑啉 -6-基 }-5,6-二氢 -2H-环戊烷并 [c]吡咯 -4-酮 -0-(2-吗啉 -4-乙基) -肟 158(60 mg， 黄色固体）， 产率 24%。
Figure imgf000165_0001
The experimental procedure of the first step to the second step of the embodiment 157 of the present invention is repeated, and the crude product of the second step is subjected to HPLC separation to obtain the title product (E) -2-{4-[3-chloro-{4-[ 3-Chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazolin-6-yl}-5,6-dihydro-2H-cyclopenta[c]pyrrol-4-one- 0-(2-morpholin-4-ethyl)-indole 158 (60 mg, yellow solid), yield 24%.
MS m/z (ESI): 628[M+ 1] MS m/z (ESI): 628 [M+ 1]
XHNMR (400MHz, DMSO- d6): δ 9.69(s, 1H), 8.59(d, 2H), 8.14(d, 1H, J=8.8), 8.01(s, 1H), 7.82(d, 1H, J=8.8), 7.74(s, 2H)， 7.47(q, 1H), 7.33(m, 4H), 7.18(t, 1H), 5.25(s， 2H), 4.16(t, 2H), 3.58(t, 4H), 3.04(t, 2H), 2.82(t, 2H), 2.61 (t, 2H), 2.50(m, 4H) 实施例 159 X H NMR (400MHz, DMSO-d 6 ): δ 9.69 (s, 1H), 8.59 (d, 2H), 8.14 (d, 1H, J = 8.8), 8.01 (s, 1H), 7.82 (d, 1H, J=8.8), 7.74(s, 2H), 7.47(q, 1H), 7.33(m, 4H), 7.18(t, 1H), 5.25(s, 2H), 4.16(t, 2H), 3.58(t , 4H), 3.04(t, 2H), 2.82(t, 2H), 2.61 (t, 2H), 2.50 (m, 4H) Example 159
Γ3-甲基 -4-(6-甲基-吡啶 -3-氧代 苯基 1-Γ6-αΗ-吡咯 -3-基) -喹唑啉 -4-基 胺  Γ3-Methyl-4-(6-methyl-pyridine-3-oxophenyl 1-Γ6-αΗ-pyrrole-3-yl)-quinazolin-4-ylamine
Figure imgf000166_0001
Figure imgf000166_0001
重复本发明实施例 150 的实验步骤,不同的是以 (6-碘-喹唑啉 -4-基) -[3-甲基 -4-(6-甲基 -吡啶 -3-氧代) -苯基] -胺 66a作为原料， 按照实施例 150所述的方式， 进 行该原料与 1 -(三异丙基硅) -1H-吡咯 -3-硼酸的反应， 得到本标题产物 (3-氯 -4-氟苯 基) -[6-(1Η-吡咯 -3-基) -喹唑啉 -4-基] -胺 159 ( 30 mg, 棕色固体）， 产率： 21 %。 MS m/z (ESI): 408[M+ 1]  The experimental procedure of Example 150 of the present invention was repeated except that (6-iodo-quinazolin-4-yl)-[3-methyl-4-(6-methyl-pyridin-3-oxo)- The phenyl]-amine 66a was used as a starting material, and the material was reacted with 1-(triisopropylsilyl)-1H-pyrrole-3-boronic acid in the manner described in Example 150 to give the title product (3-chloro 4-fluorophenyl)-[6-(1Η-pyrrol-3-yl)-quinazolin-4-yl]-amine 159 (30 mg, brown solid), yield: 21%. MS m/z (ESI): 408 [M+ 1]
1HNMR (400MHZ, DMSO- d6): δ 8.51(s, 1H), 8.41(s， 1H), 8.10(m, 2H), 7.70(d, 1H, J = 8.8)， 7.67(s, 1H), 7.59(dd, 1H, J= 8.8), 7.35(s, 1H), 7.27(m, 2H), 7.98(d, 1H, J= 8.8), 6.84(t, 1H), 6.70(t, 1H), 2.49(s, 3H), 2.25(s, 3H) 实施例 160 1HNMR (400MHZ, DMSO- d 6) : δ 8.51 (s, 1H), 8.41 (s, 1H), 8.10 (m, 2H), 7.70 (d, 1H, J = 8.8), 7.67 (s, 1H), 7.59 (dd, 1H, J= 8.8), 7.35(s, 1H), 7.27(m, 2H), 7.98(d, 1H, J= 8.8), 6.84(t, 1H), 6.70(t, 1H), 2.49(s, 3H), 2.25(s, 3H) Example 160
N-f2— (3-{4-「3-氯 -4-(3-氟苄氧基) -苯氨基 1 -喹唑啉 -6-基 }-吡咯小基 V乙基 1 -甲 磺酰胺 N -f 2 —(3-{4-"3-Chloro-4-(3-fluorobenzyloxy)-phenylamino-1-quinazoline-6-yl}-pyrrole small group Vethyl 1-methane Amide
Figure imgf000166_0002
Figure imgf000166_0002
重复本发明实施 51所述的实验步骤， 不同的是以实施例 42所得的化合物 [3- 氯 -4- (吡啶 -2-甲氧基) -苯基 ]-(6-吡咯 -1-基-喹唑啉 -4-基) -胺 42作为原料， 按照实施 例 51所述的方式， 进行该原料与 N-(2-溴-乙基)-甲磺酰胺的反应， 得到本标题产 物 N-[2-(3-{4-[3-氯 -4-(3-氟苄氧基) -苯氨基] -喹唑啉 -6-基}-吡咯 -1-基) -乙基] -甲磺 酰胺 160 ( 114 mg， 黄色固体）， 产率： 44%。 MS m/z (ESI): 566[M+ 1] 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 N-(2-bromo-ethyl)-methanesulfonamide as described in Example 51 to give the title product N -[2-(3-{4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazolin-6-yl}-pyrrol-1-yl)-ethyl] - Methanesulfonamide 160 (114 mg, yellow solid), Yield: 44%. MS m/z (ESI): 566 [M+ 1]
!HNMR (400MHz, DMSO-d6): δ 9.76(s, 1H), 8.55(s, 1H), 8.51(s， 1H), 8.04(m, 2H): 7.74(m, 2H), 7.48(m, 2H), 7.3 l(m, 4H), 7.20(t, 1H), 6.95(t, 1H), 6.69(t, 1H), 5.28(s: 2H), 4.04(t， 2H), 3.38(t, 2H), 2.83(s, 3H) 实施例 161 !HNMR (400MHz, DMSO-d6): δ 9.76 (s, 1H), 8.55 (s, 1H), 8.51 (s, 1H), 8.04 (m, 2H) : 7.74 (m, 2H), 7.48 (m, 2H), 7.3 l(m, 4H), 7.20(t, 1H), 6.95(t, 1H), 6.69(t, 1H), 5.28(s : 2H), 4.04(t, 2H), 3.38(t, 2H), 2.83(s, 3H) Example 161
4-{f3-(3-i4-D-氯 -4-(3-氟苄氧基) -苯氨基 喹唑啉 -6-基 }-吡咯 -1-基) -2-羟基-丙 胺基 1-甲基 U-二氧代 -六氢 -1λ*6*-噻喃 -4-醇 4- {f3-(3-i4-D-chloro-4-(3-fluorobenzyloxy)-phenylaminoquinazolin-6-yl}-pyrrol-1-yl)-2-hydroxy-propylamino 1 -methyl U-dioxo-hexahydro-1λ*6*-thiopyran-4-ol
Figure imgf000167_0001
Figure imgf000167_0001
重复本发明实施例 138第一步至第二步的实验步骤， 不同的是以实施例 138 第一步所得的化合物 [3-氯 -4-(3-氟苄氧基) -苯基 ]-[6-(1-环氧乙烷基甲基 -1Η-吡咯 -3- 基)-喹唑啉 -4-基] -胺 138a作为原料， 按照实施例 138第二步所述的实验方式， 进 行该原料与 C-(l,l-二氧 -六氢 -1λ*6*-噻喃 -4-基) -甲胺的反应， 得到本标题产物 4-{[3-(3-{4-[3-氯 -4-(3-氟苄氧基) -苯氨基] -喹唑啉 -6-基 吡咯 -1-基 2-羟基-丙胺基] - 甲基 }-1,1-二氧代 -六氢 -1λ*6*-噻喃 -4-醇 161 (30 mg, 黄色固体）， 产率： 44.2%。 MS m/z (ESI): 680[M+ 1]  The experimental procedure of the first step to the second step of Example 138 of the present invention was repeated, except that the compound obtained in the first step of Example 138 [3-chloro-4-(3-fluorobenzyloxy)-phenyl]- [6-(1-oxiranylmethyl-1Η-pyrrol-3-yl)-quinazolin-4-yl]-amine 138a as a starting material, according to the experimental procedure described in the second step of Example 138, The reaction of the starting material with C-(l,l-dioxo-hexahydro-1λ*6*-thiopyran-4-yl)-methylamine is carried out to give the title product 4-{[3-(3-{4 -[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazolin-6-ylpyrrolidin-1-yl 2-hydroxy-propylamino]-methyl}-1,1-di Oxo-hexahydro-1λ*6*-thiopyran-4-ol 161 (30 mg, yellow solid), Yield: 44.2% MS m/z (ESI): 680 [M+ 1]
iHNMR (400MHz, DMSO- d6): δ 9.77(s, 1H), 8.59(s, 1H)， 8.50(s, 1H), 8.04(m, 2H), 7.76(m, 2H), 7.48(m, 2H), 7.33(m, 3H), 7.19(t, 1H), 6.90(m, 2H), 6.63(s, 1H)， 5.27(s, 2H), 4.06(m, 4H), 3.79(m, 1H), 3.23(m, 2H), 3.18(m, 4H), 2.0 l(m, 4H) 实施例 162 iHNMR (400MHz, DMSO- d 6) : δ 9.77 (s, 1H), 8.59 (s, 1H), 8.50 (s, 1H), 8.04 (m, 2H), 7.76 (m, 2H), 7.48 (m, 2H), 7.33(m, 3H), 7.19(t, 1H), 6.90(m, 2H), 6.63(s, 1H), 5.27(s, 2H), 4.06(m, 4H), 3.79(m, 1H ), 3.23 (m, 2H), 3.18 (m, 4H), 2.0 l (m, 4H) Example 162
4-(Ul-「4-「3-氯 -4-(3-氟苄氧基)-苯氨基 1-喹唑啉 -6-基 l-4-(2-羟乙基) -1H-吡咯 -3- 甲基 1-氨基 甲基) -U-二氧代 -六氢 -1λ*6*-噻喃 -4-醇  4-(Ul-"4-"3-Chloro-4-(3-fluorobenzyloxy)-phenylamino-1-quinazolin-6-yl l-4-(2-hydroxyethyl)-1H-pyrrole -3-methyl 1-aminomethyl)-U-dioxo-hexahydro-1λ*6*-thiopyran-4-ol
Figure imgf000167_0002
Figure imgf000167_0002
重复本发明实施例 151 第一歩至第三步所述的实验步骤， 不同的是以实施例 151 第二步化合物 1-{4-[1-(3-氟苄基) -1Η-吲唑 -5-氨基] -喹唑啉 -6-基 }-4-(2-羟乙 基) -1Η-吡咯 -3-甲醛 151b作原料， 按照本发明实施例 151第三步所述的相同方式 使得该原料与 4-氨甲基 -1,1-二氧 -六氢 -1λ*6*-噻喃 -4-醇的反应， 得到标题化合物 4-({[1—[4-[3-氯 -4-(3-氟苄氧基) -苯氨基]-喹唑啉 -6-基] -4-(2-羟乙基 )-1Η-吡咯 -3-甲 基] -氨基 } -甲基 )-1,1-二氧代 -六氢 -1λ*6*-噻喃 -4-醇 162 ( 125 mg，黄色固体），产率 : 37.8%。 The experimental procedure described in the first to third steps of Example 151 of the present invention was repeated, except that the compound of the second step of Example 151 was 1-{4-[1-(3-fluorobenzyl)-1?-carbazole. -5-Amino]-quinazolin-6-yl}-4-(2-hydroxyethyl)-1?-pyrrole-3-carbaldehyde 151b as a starting material, in the same manner as described in the third step of Example 151 of the present invention The reaction of the starting material with 4-aminomethyl-1,1-dioxo-hexahydro-1λ*6*-thiopyran-4-ol gives the title compound 4-({[1 -[4-[3- Chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazolin-6-yl]-4-(2-hydroxyethyl)-1Η-pyrrole-3-A Alkyl]-amino}-methyl)-1,1-dioxo-hexahydro-1λ*6*-thiopyran-4-ol 162 (125 mg, yellow solid), yield : 37.8%.
MS m/z (ESI): 670 [M+ 1]  MS m/z (ESI): 670 [M+ 1]
iHNMR (400MHz, DMSO- d6): δ 9.89(s, IH), 8.56(s, 1H)， 8.49(s, IH), 8.21(s, 1H): 8.17(s, IH), 8.10(dd, IH), 7.83(m, IH), 7.76(m, IH), 7.72(dd, IH), 7.45(s, IH), 7.38(m: 2H), 7.07(m, 3H), 5.72(s, 2H)， 4.75(s, 2H), 3.63(t, 4H), 3.15(m, 2H), 2.94(m, 2H): 2.67(t, 2H), 2.59(s, 2H), 1.98(m, 4H) 实施例 163 iHNMR (400MHz, DMSO- d 6) : δ 9.89 (s, IH), 8.56 (s, 1H), 8.49 (s, IH), 8.21 (s, 1H): 8.17 (s, IH), 8.10 (dd, IH), 7.83(m, IH), 7.76(m, IH), 7.72(dd, IH), 7.45(s, IH), 7.38(m : 2H), 7.07(m, 3H), 5.72(s, 2H ), 4.75(s, 2H), 3.63(t, 4H), 3.15(m, 2H), 2.94(m, 2H) : 2.67(t, 2H), 2.59(s, 2H), 1.98(m, 4H) Example 163
(3-乙炔基苯基) -「6-(1Η-吡咯 -3-基) -喹唑啉 -4-基 1-胺  (3-ethynylphenyl)-"6-(1Η-pyrrole-3-yl)-quinazoline-4-yl 1-amine
Figure imgf000168_0001
Figure imgf000168_0001
163a 163  163a 163
第一步  First step
(3-乙炔基 -苯基 )-(6-碘-喹唑啉 -4-基) -胺  (3-ethynyl-phenyl)-(6-iodo-quinazolin-4-yl)-amine
重复本发明实施例 1第五步所述的实验步骤， 不同的是以实施例 1第四步所 得的化合物 6-碘 -3H-喹唑啉 -4-酮 If作原料， 按照本发明实施例 1第五歩所述的相 同方式使得该原料与 3-乙炔基-苯胺的反应， 得到标题化合物 (3-乙炔基 -苯基 )-(6- 碘-喹唑啉—4-基) -胺 163a (2 g， 灰白色固体）， 产率 65 %。  The experimental procedure described in the fifth step of the first embodiment of the present invention is repeated, except that the compound 6-iodo-3H-quinazolin-4-one If obtained in the fourth step of the first embodiment is used as a raw material, according to an embodiment of the present invention. The title compound (3-ethynyl-phenyl)-(6-iodo-quinazolin-4-yl)-amine is obtained by the reaction of the title compound with 3- ethynyl-phenylamine. 163a (2 g, off-white solid), yield 65%.
MS m/z (ESI): 372[M+ 1] MS m/z (ESI): 372 [M+ 1]
第二步  Second step
(3-乙炔基 -苯基 )-[6-(1Η-吡咯 -3-基) -喹唑啉 -4-基] -胺  (3-ethynyl-phenyl)-[6-(1Η-pyrrole-3-yl)-quinazolin-4-yl]-amine
重复本发明实施例 150的实验步骤，不同的是以 (6-碘-喹唑啉 -4-基) - (3-乙炔基 苯基) -胺 163a作为原料，按照实施例 150所述的方式，进行该原料与 1- (三异丙基 硅) -1H-吡咯 -3-硼酸的反应， 得到本标题产物 (3-乙炔基 -苯基 )-[6-(1Η-吡咯 -3-基) -喹 唑啉 -4-基] -胺 163 ( lO mg, 白色固体）， 产率： 5.7%。  The experimental procedure of Example 150 of the present invention was repeated except that (6-iodo-quinazolin-4-yl)-(3-ethynylphenyl)-amine 163a was used as a starting material in the manner described in Example 150. The reaction of the starting material with 1-(triisopropylsilyl)-1H-pyrrole-3-boronic acid afforded the title product (3-ethynyl-phenyl)-[6-(1Η-pyrrol-3-yl). - quinazolin-4-yl]-amine 163 (10 mg, white solid), Yield: 5.7%.
MS m/z (ESI): 311[M+ 1] MS m/z (ESI): 311 [M+ 1]
1HNMR (400MHZ, DMSO- d6): δ 8.51(s, IH), 8.44(s， IH), 8.09(d, IH, J=8.8), 7.95(s, IH), 7.80(d, IH, J= 8.4), 7.7 l(d, IH, J= 8.4), 7.38(t, 2H), 7.27(d, IH, 3=7.6), 6.83(s, IH), 6.70(s, IH), 3.30(s, IH) 实施例 164 4-ί「(4-Μ-Π-(3-氟-苄基) -1H-吲唑 -5-基氨基 1-喹唑啉 -6-基 IH-吡咯 -2-基甲基) -氨 基 1-甲基 }-U-二氧 -六氢 -1λ*6*-噻喃 -4-醇 1HNMR (400MHZ, DMSO- d 6) : δ 8.51 (s, IH), 8.44 (s, IH), 8.09 (d, IH, J = 8.8), 7.95 (s, IH), 7.80 (d, IH, J = 8.4), 7.7 l(d, IH, J= 8.4), 7.38(t, 2H), 7.27(d, IH, 3=7.6), 6.83(s, IH), 6.70(s, IH), 3.30( s, IH) Example 164 4-ί"(4-Μ-Π-(3-fluoro-benzyl)-1H-indazol-5-ylamino-1-quinazolin-6-yl IH-pyrrol-2-ylmethyl)-amino 1-methyl}-U-dioxy-hexahydro-1λ*6*-thiopyran-4-ol
Figure imgf000169_0001
Figure imgf000169_0001
164e 164  164e 164
第一步  First step
4-溴 -1H-吡咯 -2-甲醛  4-bromo-1H-pyrrole-2-carbaldehyde
氩气氛下， 将 1H-吡咯 -2-甲醛 164a (3.04g， 32 mmol)溶于 150 mL四氢呋喃 中， 干冰-丙酮浴冷却至 -70 °C， 分批加入 N-溴琥珀酰亚胺（5.62 g， 32 mmol), 保 持 -78°C搅拌 1小时反应完毕。 加入 100 mL水和 100 mL正己垸， 温度升至室温， 抽滤，滤液水相通过正己烷（100 mLx3)萃取，合并的有机相依次用饱和氯化钠溶 液洗涤， 无水硫酸钠干燥， 过滤， 减压下浓缩， 残留物中加入 30 mL正己烷和四 氢呋喃的混合溶剂（正己垸： 四氢呋喃 =20: 1)， 在室温下搅拌 1小时， 有固体析 出， 过滤， 滤饼用正己烷洗涤 3次， 得到 4-溴 -1H-吡咯 -2-甲醛 164b (2.2 g， 棕色 固体)， 产率： 40%。  1H-pyrrole-2-carbaldehyde 164a (3.04 g, 32 mmol) was dissolved in 150 mL of tetrahydrofuran under argon atmosphere, cooled to -70 °C in dry ice-acetone bath, and N-bromosuccinimide (5.62) was added portionwise. g, 32 mmol), stirring at -78 ° C for 1 hour. After adding 100 mL of water and 100 mL of hexane, the temperature was raised to room temperature, and suction filtration was performed. The aqueous phase of the filtrate was extracted with n-hexane (100 mL×3), and the combined organic phases were washed successively with saturated sodium chloride solution, dried over anhydrous sodium sulfate and filtered. After concentration under reduced pressure, 30 mL of a mixed solvent of n-hexane and tetrahydrofuran (n-hexane: tetrahydrofuran = 20:1) was added to the residue, and the mixture was stirred at room temperature for 1 hour, and solids were precipitated, filtered, and the filter cake was washed with n-hexane. Then, 4-bromo-1H-pyrrole-2-carbaldehyde 164b (2.2 g, brown solid) was obtained. Yield: 40%.
MS m/z (ESI): 174[M+1] MS m/z (ESI): 174 [M+1]
第二步  Second step
4-溴 -2-甲酰基吡咯- 1 -甲酸叔丁酯  4-bromo-2-formylpyrrole-1 -carboxylic acid tert-butyl ester
将 4-溴 -1H-吡咯 -2-甲醛 164b (1 g， 5.78 mmol)溶于 50 mL乙腈中， 搅拌下依 次加入二碳酸二叔丁酯 (1.89g， 8.67 mmol)和 4-二甲氨基吡啶 (353 mg， 2.89 mmol), 溶液在室温下搅拌 30分钟反应完毕。 反应液在减压下浓缩， 残留物中加入 50 mL 正己烷和四氢呋喃混合溶剂（正己垸： 四氢呋喃 =20: 1)和 50 mL 7_K， 分液， 有机 相依次用水， 饱和氯化钠溶液溶液洗涤， 无水硫酸钠干燥， 过滤， 减压下浓缩， 得到 4-溴 -2-甲酰基吡咯 -1-甲酸叔丁酯 164c (1.2 g， 棕黄色固体)， 产率： 76%。 MS m/z (ESI): 274[M+1] 4-Bromo-1H-pyrrole-2-carbaldehyde 164b (1 g, 5.78 mmol) was dissolved in 50 mL of acetonitrile, and di-tert-butyl dicarbonate (1.89 g, 8.67 mmol) and 4-dimethylamino group were sequentially added with stirring. Pyridine (353 mg, 2.89 mmol), The solution was stirred at room temperature for 30 minutes and the reaction was completed. The reaction solution was concentrated under reduced pressure, and 50 mL of a mixture solvent of n-hexane and tetrahydrofuran (n-hexane: tetrahydrofuran = 20:1) and 50 mL of 7_K were added to the residue, and the organic phase was washed successively with water and saturated sodium chloride solution. The residue was dried over anhydrous sodium sulfate, filtered, and evaporated. MS m/z (ESI): 274 [M+1]
第三步  third step
2-甲酰基 -4-(4,4,5，5-四甲基 -[1,3,2]二氧硼戊环 -2-基) -吡咯 -1-甲酸叔丁酯 氩气氛下，将 4-溴 -2-甲酰基吡咯 -1-甲酸叔丁酯 164c (200 mg， 0.73 mmol),联 硼酸频那醇酯 (280 mg， 1.1 mmol), 四 (三苯基)膦钯 (60 mg， 0.073 mmol), 醋酸钾 (216 mg, 2.2 mmol)溶于 10 mL四氢呋喃中， 混合液加热至 80°C， 回流过夜。反应 液在减压下浓缩， 所得的残留物通过硅胶柱层析进行分离纯化， 得到 2-甲酰基 — 4-(4,4,5，5-四甲基 -[1,3,2]二氧硼戊环 -2-基) -吡咯小甲酸叔丁酯 164d (45 mg, 黄色 固体)， 产率： 19%。  2-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrrole-1-carboxylic acid tert-butyl ester under argon atmosphere 4-Bromo-2-formylpyrrole-1-carboxylic acid tert-butyl ester 164c (200 mg, 0.73 mmol), boranoic acid pinacol ester (280 mg, 1.1 mmol), tetrakis(triphenyl)phosphine palladium (60 Mg, 0.073 mmol), potassium acetate (216 mg, 2.2 mmol) was dissolved in 10 mL of THF. The mixture was warmed to <RTIgt; The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to afford 2-formyl 4-(4,4,5,5-tetramethyl-[1,3,2] Butyl oxopenta-2-yl)-pyrrole carboxylic acid 164d (45 mg, yellow solid), yield: 19%.
MS m/z (ESI): 322 [M+1] MS m/z (ESI): 322 [M+1]
第四歩  Fourth
4-{4-[1-(3-氟苄基) -1H-吲唑 -5-基氨基] -喹唑啉 -6-基}-111-吡咯 -2-甲醛 在 100 mL茄形瓶中， 加入化合物 2-甲酰基 -4-(4，4,5,5-四甲基 -[1,3,2]二氧硼戊环 -2-基) -吡咯 -1:甲酸叔丁酯 164d (584 mg， 1.82mmol), [1-(4-氟苄基 )-1Η-吲唑 -5- 基]— (6-碘-喹唑啉 -4-基) -胺 132a (500 mg, 1.82 mmol),碳酸钾 (lg， 4.56mtnol), 30 mL Ν,Ν-二甲基甲酰胺和 7mL水的混合溶剂，氮气保护下加入四 (三苯基)膦钯 (310mg， 0.182mmol),混合液加热至 70〜75 °C，用薄层色谱跟踪反应进程， 4小时后反应完 毕。 将反应液倒入 250 mL冰水中， 有固体析出， 抽滤， 滤饼通过硅胶柱层析进一 步分离纯化， 得到 4-{4-[1-(3-氟苄基 )-1Η-吲唑 -5-基氨基]-喹唑啉 -6- ¾}-1Η-吡咯 -2- 甲醛 164e (168 mg， 黄色固体)， 产率 20%。 4-{4-[1-(3-fluorobenzyl)-1H-indazol-5-ylamino]-quinazolin-6-yl}-111-pyrrole-2-carbaldehyde in a 100 mL eggplant-shaped flask Add the compound 2-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrrole-1 : tert-butyl formate 164d (584 mg, 1.82 mmol), [1-(4-fluorobenzyl)-1Η-indazol-5-yl]-(6-iodo-quinazolin-4-yl)-amine 132a (500 mg, 1.82 Methyl acetate (lg, 4.56 mtnol), 30 mL of a mixed solvent of hydrazine, hydrazine-dimethylformamide and 7 mL of water, and added tetrakis(triphenyl)phosphine palladium (310 mg, 0.182 mmol) under nitrogen. The liquid was heated to 70 to 75 ° C, and the progress of the reaction was followed by thin layer chromatography, and the reaction was completed after 4 hours. The reaction solution was poured into 250 mL of ice water, and a solid was precipitated, suction filtered, and the filter cake was further separated and purified by silica gel column chromatography to obtain 4-{4-[1-(3-fluorobenzyl)-1 oxime-carbazole- 5-Aminoamino]-quinazoline-6- 3⁄4}-1 Η-pyrrole-2-carbaldehyde 164e (168 mg, yellow solid), yield 20%.
MS m/z (ESI): 322 [M+1] MS m/z (ESI): 322 [M+1]
!HNMR (400MHz, CD30D-^):512.48(s,lH), 9.89(s,lH), 9.60(s,lH), 8.82(s,lH), 8. ! HNMR (400MHz, CD30D - ^ ): 512.48 (s, lH), 9.89 (s, lH), 9.60 (s, lH), 8.82 (s, lH), 8.
48(s,lH), 8.20(m,3H), 7.96(s,lH), 7.75(m,3H), 7.64(s,lH), 7.35(m,lH), 7.06(m,3H),48(s,lH), 8.20(m,3H), 7.96(s,lH), 7.75(m,3H), 7.64(s,lH), 7.35(m,lH), 7.06(m,3H),
5.72(s,2H) 5.72(s, 2H)
第五步  the fifth step
4-{[(4-{4-[l-(3-氟-节基) -1H-吲唑 -5-基氨基]-喹唑啉 -6-基}-111-吡咯 -2-基甲基) -氨 基] -甲基 二氧 -六氢 -1λ*6*-噻喃 -4-醇  4-{[(4-{4-[l-(3-fluoro-]-yl)-1H-indazol-5-ylamino]-quinazolin-6-yl}-111-pyrrol-2-yl-methyl -amino]-methyldioxy-hexahydro-1λ*6*-thiopyran-4-ol
氮气氛下， 在 100 mL茄形瓶中加入 4-{4-[1-(3-氟苄基 )-1Η-吲唑 -5-基氨基] -喹 唑啉 -6-基}-111-吡咯 -2-甲醛 164e (120 mg, 0.259 mmol)和 4-氨甲基 -1,1-二氧 -六氢 -1λ*6*-噻喃 -4-醇 (84 mg， 0.466 mmol), 溶于 6 mL二氯甲烷中， 室温搅拌 6小时 后加入三 (乙酰氧基)硼氢化钠（165 mg, 0.78 mmol), 室温搅拌过夜。 在反应液中 加入 5 mL饱和碳酸氢钠溶液， 萃取， 分层， 有机相减压下浓缩， 得到的残留物进 一步通过硅胶柱层析（二氯甲烷： 甲醇 =10 : 1)分离纯化， 得到本标题产物 4-{[(4-{4-[1-(3-氟-苄基) -1H-吲唑 -5-基氨基] -喹唑啉 -6-基 HH-吡咯 -2-基甲基) -氨 基] -甲基 }-U-二氧 -六氢 -1λ*6*-噻喃 -4-醇； I64 (25 mg， 黄色固体)， 产率： 15.4%。 4-{4-[1-(3-Fluorobenzyl)-1Η-oxazol-5-ylamino]-quinazolin-6-yl}-111- was added to a 100 mL eggplant flask under nitrogen atmosphere Pyrrole-2-carbaldehyde 164e (120 mg, 0.259 mmol) and 4-aminomethyl-1,1-dioxo-hexahydro-1λ*6*-thiopyran-4-ol (84 mg, 0.466 mmol), dissolved After stirring at room temperature for 6 hours in 6 mL of dichloromethane, sodium tris(acetoxy)borohydride (165 mg, 0.78 mmol) was added and stirred at room temperature overnight. 5 mL of saturated sodium bicarbonate solution was added to the reaction solution, extracted, layered, and the organic phase was concentrated under reduced pressure to give residue. The product was isolated and purified by silica gel column chromatography (dichloromethane: methanol = 10:1) to give the title product 4-{[(4-{4-[1-(3-fluoro-benzyl)-1H-carbazole -5-ylamino]-quinazolin-6-ylHH-pyrrol-2-ylmethyl)-amino]-methyl}-U-dioxy-hexahydro-1λ*6*-thiopyran-4- Alcohol; I64 (25 mg, yellow solid), Yield: 15.4%.
MS tn/z (ESI): 626[M+ 1] MS tn/z (ESI): 626 [M+ 1]
1HNMR (400MHz, CD30D- )： 511.15(s,lH), 9.93(s,lH), 8.69(s,lH), 8.44 (s, 1H), 8.25(s,lH), 8.17(s,lH), 8.06(d,lH,J-8.8Hz), 7.76(s,lH), 7.69(d,lH,J=8.8Hz), 1 H NMR (400MHz, CD30D- ): 511.15 (s, lH), 9.93 (s, lH), 8.69 (s, lH), 8.44 (s, 1H), 8.25 (s, lH), 8.17 (s, lH) , 8.06 (d, lH, J-8.8Hz), 7.76 (s, lH), 7.69 (d, lH, J = 8.8 Hz),
7.48(s,lH), 7.38(m,lH), 7.08(m,3H), 6.75(s,lH), 5.72(s,2H)5 3.91(s,2H), 3.52(m,lH), 3.19(m,4H), 3.00(m,2H), 2.02(m,4H) 实施例 165 7.48(s,lH), 7.38(m,lH), 7.08(m,3H), 6.75(s,lH), 5.72(s,2H) 5 3.91(s,2H), 3.52(m,lH), 3.19 (m, 4H), 3.00 (m, 2H), 2.02 (m, 4H) Example 165
[l-(3-氟- 基) -1H-吲唑 -5-基] -(6-{5-[(2-甲磺酰基-乙氨基) -甲基 ]-1Η-吡咯 -3-基} -喹 唑啉 -4-基) -胺  [l-(3-Fluoro-yl)-1H-indazol-5-yl]-(6-{5-[(2-methanesulfonyl-ethylamino)-methyl]-1Η-pyrrol-3-yl }-quinazolin-4-yl)-amine
Figure imgf000171_0001
Figure imgf000171_0001
氮气氛下， 在 100 mL茄形瓶中加入 4-{4-[1-(3-氟苄基 )-1Η-吲唑 -5-基氨基] -喹 唑啉 -6-基}-111-吡咯 -2-甲醛 164e (100 mg， 0.216 mmol), 2-甲磺酰基乙胺盐酸盐 (100 mg, 0.43 mmol)和三乙胺 (0.2 mL， 5 mmol), 溶于 6 mL二氯甲垸中， 室温搅 拌 6小时后加入三 (乙酰氧基)硼氢化钠 （137 mg， 0.648 mmol), 室温搅拌过夜。在 反应液中加入 5 mL饱和碳酸氢钠溶液， 萃取， 分层， 有机相减压下浓缩， 得到的 残留物进一步通过硅胶柱层析 (二氯甲烷： 甲醇 =10: 1)分离纯化， 得到本标题产物 [1-(3-氟-苄基) -1H-吲唑 -5-基] -(6-{5-[(2-甲磺酰基 -乙氨基)-甲基] -1H-吡咯 -3-基 喹 唑啉 -4-基) -胺 165 (30 mg， 黄色固体)， 产率： 24.4%。  4-{4-[1-(3-Fluorobenzyl)-1Η-oxazol-5-ylamino]-quinazolin-6-yl}-111- was added to a 100 mL eggplant flask under nitrogen atmosphere Pyrrole-2-carbaldehyde 164e (100 mg, 0.216 mmol), 2-methanesulfonylethylamine hydrochloride (100 mg, 0.43 mmol) and triethylamine (0.2 mL, 5 mmol), dissolved in 6 mL of dichloromethane After stirring at room temperature for 6 hours, sodium tris(acetoxy)borohydride (137 mg, 0.648 mmol) was added and stirred at room temperature overnight. 5 mL of a saturated sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was separated, and the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane: methanol = 10:1). The title product [1-(3-fluoro-benzyl)-1H-indazol-5-yl]-(6-{5-[(2-methanesulfonyl-ethylamino)-methyl]-1H-pyrrole -3-ylquinazolin-4-yl)-amine 165 (30 mg, yellow solid), Yield: 24.4%.
MS m/z (ESI): 570[M+ 1] MS m/z (ESI): 570 [M+ 1]
1HNMR (400MHz, CD30D-i¾: 511.32(s,lH), 10.05(s,lH), 8.71(s,lH), 8.45(s,lH), 8.26(s,lH), 8.17(s,lH), 8.05(d,lH,J=8.8Hz), 7.77(s,lH), 7.70(d,lH,J=8.8Hz), 1 H NMR (400 MHz, CD30D-i3⁄4: 511.32 (s, lH), 10.05 (s, lH), 8.71 (s, lH), 8.45 (s, lH), 8.26 (s, lH), 8.17 (s, lH) , 8.05 (d, lH, J = 8.8 Hz), 7.77 (s, lH), 7.70 (d, lH, J = 8.8 Hz),
7.56(s,lH), 7.37(s,lH), 7.07(m,3H), 6.80(s,lH), 5.72(s,2H), 4.04(s,2H), 3.20(s,2H), 3.10(s,3H), 3.05(m,2H) 实施例 166 7.56(s,lH), 7.37(s,lH), 7.07(m,3H), 6.80(s,lH), 5.72(s,2H), 4.04(s,2H), 3.20(s,2H), 3.10 (s, 3H), 3.05 (m, 2H) Example 166
「6-(5-{「(1,1-二氧-六氢-1 *6*-噻喃-4-基甲基)-氨基1-甲基 111-吡咯-3-基)-喹唑啉-4- 基 l-fl-(3-氟 -苄基 1H-吲唑 -5-基 1-胺
Figure imgf000172_0001
"6-(5-{"(1,1-dioxo-hexahydro-1 *6*-thiopyran-4-ylmethyl)-amino 1-methyl 111-pyrrol-3-yl)-quinazole啉-4-yl l-fl-(3-fluoro-benzyl 1H-indazol-5-yl 1-amine
Figure imgf000172_0001
氮气氛下， 在 100 mL茄形瓶中加入 4-{4-[1-(3-氟苄基 )-1Η-吲唑 -5-基氨基] -喹 唑啉 -6-基 }-1Η-吡咯 -2-甲醛 164e (200 mg， 0.46 mmol) 和 C-(l,l-二氧代 -六氢 -1λ*6*-噻喃 -4-基) -甲胺盐酸盐（180 mg， 0.90 mmol), 溶于 10 mL二氯甲垸中， 室 温搅拌 6小时后加入三 (乙酰氧基)硼氢化钠 （275 mg， 1.3 mmol), 室温搅拌过夜。 在反应液中加入 5 mL饱和碳酸氢钠溶液， 萃取， 分层， 有机相减压下浓缩， 得到 的残留物通过硅胶柱层析进一步分离纯化 (二氯甲烷： 甲醇 =15: 1)， 得到本标题产 物 [1-(3-氟-苄基) -1H-吲唑 -5-基] -(6-{5-[(2-甲磺酰基-乙氨基) -甲基 ]-1Η-吡咯 -3-基} - 喹唑啉 -4-基) -胺 166 (58 mg， 黄色固体)， 产率： 22%。  4-{4-[1-(3-Fluorobenzyl)-1Η-indazol-5-ylamino]-quinazolin-6-yl}-1Η- was added to a 100 mL eggplant flask under nitrogen atmosphere Pyrrole-2-carbaldehyde 164e (200 mg, 0.46 mmol) and C-(l,l-dioxo-hexahydro-1λ*6*-thiopyran-4-yl)-methylamine hydrochloride (180 mg, The mixture was stirred at room temperature for 6 hours, then sodium tris(acetoxy)borohydride (275 mg, 1.3 mmol) was added and stirred at room temperature overnight. 5 mL of a saturated sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was separated, and the organic layer was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (dichloromethane:methanol = 15:1). The title product [1-(3-fluoro-benzyl)-1H-indazol-5-yl]-(6-{5-[(2-methanesulfonyl-ethylamino)-methyl]-1Η-pyrrole -3-yl}-quinazolin-4-yl)-amine 166 (58 mg, yellow solid), yield: 22%.
MS m/z (ESI): 610[M+ 1]  MS m/z (ESI): 610 [M+ 1]
toMR (400MHz, CD30D-^):511.25(s,lH), 9.92(s,lH), 8.69(s,lH), 8.45(s，lH), 8.24(s,lH), 8.17(s,lH), 8.06(d,lH,J=8.8Hz), 7.75(s,lH), 7.71(d,lH,J-8.8Hz),  toMR (400MHz, CD30D-^): 511.25(s,lH), 9.92(s,lH), 8.69(s,lH), 8.45(s,lH), 8.24(s,lH), 8.17(s,lH) , 8.06 (d, lH, J = 8.8 Hz), 7.75 (s, lH), 7.71 (d, lH, J-8.8 Hz),
7.53(s,lH), 7.38(m,lH), 7.08(m,3H), 6.80(s,lH), 5.72(s,2H)， 4.02(s,2H), 3.10(m,4H), 2.75(m，2H), 2.15(m,2H), 2.02(m,lH), 1.682(m,2H) 实施例 167  7.53(s,lH), 7.38(m,lH), 7.08(m,3H), 6.80(s,lH), 5.72(s,2H), 4.02(s,2H), 3.10(m,4H), 2.75 (m, 2H), 2.15 (m, 2H), 2.02 (m, lH), 1.682 (m, 2H) Example 167
4- -「3-氯 -4-(3-氟-苄氧基 苯氨基 1-喹唑啉 -6-基 1- (甲苯基 -4-磺酰基 1H-吡咯 -2-  4--"3-Chloro-4-(3-fluoro-benzyloxyphenylamino-1-quinazolin-6-yl 1-(methylphenylsulfonyl 1H-pyrrole-2-
笫六歩笫六歩
Figure imgf000172_0002
Figure imgf000172_0002
第一步  First step
2，2,2-三氯 -1-(1H-吡咯 -2-基) -乙酮 将吡咯 (1.4 mL， 20mmol)和三氯乙酰氯 (2.4 mL， 21.4mmol)分别溶于 12 mL乙 醚中， 搅拌下将吡咯的乙醚溶液滴加至三氯乙酖氯的乙醚溶液中， 室温下搅拌 1 小时后， 反应完毕。在反应液中加入 30 mL10 %碳酸钾溶液， 分液，有机相在减压 下浓缩， 得到的粗品通过硅胶柱层析进一步分离纯化， 得到 2,2,2-三氯 -1-GH-吡咯 -2-基) -乙酮 167a (3.79g， 灰色固体)， 产率： 89.6%。 2,2,2-trichloro-1-(1H-pyrrol-2-yl)-ethanone Pyrrole (1.4 mL, 20 mmol) and trichloroacetyl chloride (2.4 mL, 21.4 mmol) were dissolved in 12 mL of diethyl ether, respectively, and the solution of pyrrole in diethyl ether was added dropwise to a solution of trichloroethyl chlorochloride in diethyl ether at room temperature. After stirring for 1 hour, the reaction was completed. 30 mL of 10% potassium carbonate solution was added to the reaction mixture, and the organic phase was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give 2,2,2-trichloro-1-GH-pyrrole. 2-yl)-ethanone 167a (3.79 g, gray solid), Yield: 89.6%.
MS m/z (ESI): 213[M+ 1] MS m/z (ESI): 213 [M+ 1]
第二步  Second step
2,2，2-三氯- 1 -(4-碘 - 1 H-吡咯 -2-基) -乙酮  2,2,2-trichloro-1 -(4-iodo-1 H-pyrrol-2-yl)-ethanone
将氯化碘 (0.91 mL， 18.2mmol)溶于 15 mL二氯甲烷中， 缓慢滴加到 2,2，2-三 氯 -1-(1Η-吡咯 -2-基) -乙酮 167a (3.79g， 17.8mmol)的 30 mL二氯甲烷溶液中， 室温 下搅拌 2小时， 加入 10%碳酸钠溶液淬灭反应， 分液， 有机相依次通过水， 饱和 氯化钠溶液洗涤， 无水硫酸钠干燥， 过滤， 减压下浓缩， 得到的残留物用乙酸乙 酯和正己垸重结晶， 得到 2,2,2-三氯小 (4-碘 -1H-吡咯 -2-基) -乙酮 167b (5.152g, 灰 色固体)， 产率： 85.5 %。  Iodine chloride (0.91 mL, 18.2 mmol) was dissolved in 15 mL of dichloromethane and slowly added dropwise to 2,2,2-trichloro-1-(1Η-pyrrol-2-yl)-ethanone 167a (3.79 g, 17.8 mmol) in 30 mL of dichloromethane solution, stirring at room temperature for 2 hours, adding 10% sodium carbonate solution to quench the reaction, liquid separation, the organic phase was washed successively with water, saturated sodium chloride solution, anhydrous sodium sulfate Drying, filtration, and concentrating under reduced pressure. EtOAc m. m. (5.152 g, gray solid), Yield: 85.5 %.
MS m/z (ESI): 339[M+ 1] MS m/z (ESI): 339 [M+ 1]
第三步  third step
4-碘 -1H-吡咯 -2-羧酸甲酯  4-iodo-1H-pyrrole-2-carboxylic acid methyl ester
将甲醉钠 (436 mg， 8.07mmol)溶于 10 mL甲醇中， 所得的溶液逐渐滴加到 2,2,2-三氯 -1-(4-碘 -1H-吡咯 -2-基) -乙酮 167b (2.276g, 6.72mmol)15 mL甲醇中， 室 温下搅拌 1小时后反应完毕。 将反应液减压下浓缩， 加入 100 mL水和 100 mL甲 基叔丁基醚， 分液， 有机相依次通过水， 饱和氯化钠溶液洗涤， 无水硫酸钠干燥， 过滤， 减压下浓缩， 得到 4-碘 -1H-吡咯 -2-羧酸甲酯 167c (1.353 g， 灰色固体)， 产 率： 80.2%。 Sodium agaridine ( 436 mg , 8.07 mmol) was dissolved in 10 mL of methanol, and the resulting solution was gradually added dropwise to 2,2,2-trichloro-1-(4-iodo-1H-pyrrol-2-yl)- Ethyl ketone 167b (2.276 g, 6.72 mmol) in 15 mL of methanol was stirred at room temperature for 1 hour and then the reaction was completed. The reaction solution was concentrated under reduced pressure. EtOAc (EtOAc)EtOAc. Methyl 4-iodo-1H-pyrrole-2-carboxylate 167c (1.353 g, m.p.).
MS m/z (ESI): 252[M+ 1]  MS m/z (ESI): 252 [M+ 1]
第四步  the fourth step
4-碘 - 1 - (甲苯 -4-磺酰基) - 1 H-吡咯 -2-羧酸甲酯 将 4-碘 -1H-吡咯 -2-羧酸甲酯 167c (1.353 g， 5.4mmol)溶于 5 mL二氯甲烷中， 搅拌下依次加入三乙胺 (1.65 mL， 11.88mmol), 4-二甲氨基吡啶 (62 mg， 0.5mmol) 和对甲苯磺酰氯 (1.13 g， 5.94mmol), 混合液在室温下搅拌 16小时， 反应完毕。加 入 1N HC1淬灭反应， 分液， 有机相依次用饱和碳酸氢钠 (100 ml 3)洗涤， 饱和氯 化钠溶液 (100 mLx3)洗涤， 无水硫酸钠干燥， 过滤， 减压下浓缩， 得到的粗品进一 步通过甲基叔丁基醚重结晶， 得到 4-碘 -1- (甲苯 -4-磺酰基) -1H-吡咯 -2-羧酸甲酯 4-iodo-1 - (toluene-4-sulfonyl) - 1 H-pyrrole-2-carboxylic acid methyl ester 4-11-Iodo-1H-pyrrole-2-carboxylic acid methyl ester 167c (1.353 g, 5.4 mmol) Triethylamine (1.65 mL, 11.88 mmol), 4-dimethylaminopyridine (62 mg, 0.5 mmol) and p-toluenesulfonyl chloride (1.13 g, 5.94 mmol) were added in a mixture of 5 mL of dichloromethane. The solution was stirred at room temperature for 16 hours and the reaction was completed. The reaction was quenched by the addition of 1N EtOAc. EtOAc (EtOAc m. The crude product was further recrystallized from methyl tert-butyl ether to give methyl 4-iodo-1-(toluene-4-sulfonyl)-1H-pyrrole-2-carboxylate
167d (1.834 g, 淡黄色固体)， 产率： 83.9%。 167d (1.834 g, pale yellow solid), Yield: 83.9%.
MS m/z (ESI): 406[M+ 1] 第五步 4-(4,4,5,5-四甲基 -[1,3,2]二氧硼戊环 -2-基) -1- (甲苯 -4-磺酰基 )-1Η-吡咯 -2-羧酸甲酯 将 4-碘 -1- (甲苯 -4-磺酰基 )-1Η-吡咯 -2-羧酸甲酯 167d (288 mg， 0.7mmol), 双联 频哪醇硼酸酯 (235 mg， 0.91mmol)和醋酸钾 (210 mg， 2.1mmol)溶于 Ν,Ν-二甲基甲 酰胺中， 搅拌下加入二氯 [Ι,Γ-二茂铁磷酸]钯的 lmL二氯甲垸溶液中， 混合液加 热至 80°C , 18小时后反应完毕。将反应液中加入 lOO mL水和 100 mL乙醚，过滤， 分液， 有机相依次用 100 mL水， 100 mL饱和氯化钠溶液洗涤， 无水硫酸钠干燥， 过滤， 减压下浓缩， 得到的残留物通过硅胶柱层析进一步分离纯化， 得到标题产 物 4-(4,4,5,5-四甲基 -[1,3,2]二氧硼戊环 -2-基) -1- (甲苯 -4-磺酰基) -1H-吡咯 -2-羧酸甲 酯 167e (105 mg， 无色固体)， 产率： 37%。 MS m/z (ESI): 406 [M+ 1] Step 5 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl)-1Η-pyrrole-2- Methyl carboxylate 4-111-iodo-1-(toluene-4-sulfonyl)-1Η-pyrrole-2-carboxylic acid methyl ester 167d (288 mg, 0.7 mmol), bis-pinacol borate (235 mg , 0.91mmol) and potassium acetate (210 mg, 2.1mmol) are dissolved in hydrazine, hydrazine-dimethylformamide, and 1 mL of dichloroformamidine solution of dichloro[Ι,Γ-ferrocenephosphoric acid]palladium is added with stirring. The mixture was heated to 80 ° C and the reaction was completed after 18 hours. The reaction solution was added with 100 mL of water and 100 mL of diethyl ether, filtered, and separated. The organic phase was washed successively with 100 mL of water, 100 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was further purified by silica gel column chromatography to give the title product 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-( Methyl toluene-4-sulfonyl)-1H-pyrrole-2-carboxylate 167e (105 mg, colorless solid), yield: 37%.
MS m/z (ESI): 406[M+ 1]MS m/z (ESI): 406 [M+ 1]
Figure imgf000174_0001
Figure imgf000174_0001
4-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基 }-1- (甲苯基 -4-磺酰基) -1Η-吡咯 -2- 羧酸甲酯  4-{4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-1-(tolyl-4-sulfonyl)-1Η-pyrrole -2-carboxylic acid methyl ester
将 4-(4,4,5,5-四甲基 -[1 ,3,2]二氧硼戊环 -2-基) -1 - (甲苯 -4-磺酰基 )-1Η-吡咯 -2-羧酸 甲酯 167e(105 mg， 0.26mmol), [3-氯 -4-(3-氟-苄氧基) -苯基 ]-(6-碘-喹唑啉 -4-基) -胺 lg(130 mg, 0.26mmol) , 碳酸钾 (93.9 mg， 0.65mmol)和四三苯基膦钯 (45 mg， 0.026mmol)溶于 6 mL Ν,Ν-二甲基甲酰胺和 2 mL水的混合溶剂中， 反应液加热至 55 °C搅拌过夜。 过滤反应液， 滤液用乙酸乙酯萃取， 合并的有机相依次通过水， 饱和氯化钠溶液洗涤， 无水硫酸钠干燥， 过滤， 减压下浓缩， 得到的残留物通过 硅胶柱层析进一步分离纯化， 得到 4-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6- 基}-1- (甲苯基 -4-磺酰基 )-1Η-吡咯 -2-羧酸甲酯 167 (58 mg,浅黄色固体)，产率： 32.8 %。  4-(4,4,5,5-Tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-1 -(toluene-4-sulfonyl)-1Η-pyrrole-2 -Methylcarboxylate 167e (105 mg, 0.26 mmol), [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-iodo-quinazolin-4-yl)-amine Lg (130 mg, 0.26 mmol), potassium carbonate (93.9 mg, 0.65 mmol) and tetrakistriphenylphosphine palladium (45 mg, 0.026 mmol) dissolved in 6 mL hydrazine, hydrazine-dimethylformamide and 2 mL water In the mixed solvent, the reaction solution was heated to 55 ° C and stirred overnight. The reaction mixture was filtered, and the filtrate was evaporated, evaporated, evaporated, evaporated Purification afforded 4-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-1-(tolyl-4-sulfonyl)- Methyl 1 Η-pyrrole-2-carboxylate 167 (58 mg, pale yellow solid), yield: 32.8 %.
MS m/z (ESI): 657[M+ 1]  MS m/z (ESI): 657 [M+ 1]
1H NMR (400 MHz, CDC1-3): δ8.72 (s, 1H), 8.09 (d， J = 2.4Hz, 1H), 8.06 (s, 1H), 7.93 (d, J = 2.0Hz, 2H), 7.91 (s, 2H), 7.89 (d, J = 2.4Hz, 1H), 7.81 (s, 1H), 7.60 (dd, J = 1.6Hz, 1H), 7.41 (d, J = 2.0Hz, 1H), 7.34 (br， 3H), 7.23 (br, 2H), 7.00 (m, 2H), 5.15 (s, 2H), 3.74 (s, 3H), 2.43 (s, 3H)  1H NMR (400 MHz, CDC 1-3): δ 8.72 (s, 1H), 8.09 (d, J = 2.4 Hz, 1H), 8.06 (s, 1H), 7.93 (d, J = 2.0 Hz, 2H) , 7.91 (s, 2H), 7.89 (d, J = 2.4Hz, 1H), 7.81 (s, 1H), 7.60 (dd, J = 1.6Hz, 1H), 7.41 (d, J = 2.0Hz, 1H) , 7.34 (br, 3H), 7.23 (br, 2H), 7.00 (m, 2H), 5.15 (s, 2H), 3.74 (s, 3H), 2.43 (s, 3H)
实施例 168  Example 168
4-G-i4-「3-氯 -4-(3-氟-苄氧基) -苯氨基 喹唑啉 -6-基}-吡咯 -1-基甲基 U-二氧 -六氢  4-G-i4-"3-chloro-4-(3-fluoro-benzyloxy)-phenylaminoquinazoline-6-yl}-pyrrole-1-ylmethyl U-dioxo-hexahydro
-1λ*6*-噻喃 -4-醇  -1λ*6*-thiopyran-4-ol
Figure imgf000174_0002
Figure imgf000174_0002
Figure imgf000175_0001
第一步
Figure imgf000175_0001
first step
1-氧代 -6-硫代-螺 [2.5]辛烷  1-oxo-6-thio-spiro [2.5]octane
氮气氛下，在冰浴冷却下，将三甲基氧硫化碘 (13.5 g, 61 mmol)和氢化钠 （2.46 g， 6.15 mmol)溶于 60 mL二甲基亚砜中， 混合液在室温下搅拌 1小时后， 滴加四 氢噻喃 -4-酮 168a (6.79 g， 60 mmol)的 80 mL二甲基亚砜溶液，温度控制不高于 15 V，搅拌 10分钟后自然升至室温， 3小时后反应完毕。把反应液倒入 350 mL冰水 中， 用乙醚萃取 (400 mL X 3)， 合并的有机相依次通过饱和氯化钠溶液洗涤， 无水 硫酸钠干燥， 过滤， 减压下浓缩， 得到 1-氧代 -6-硫代-螺 [2.5]辛烷 168b (7.09 g， 白 色固体)， 产率： 92 %。  Under nitrogen atmosphere, trimethyloxysulfide iodine (13.5 g, 61 mmol) and sodium hydride (2.46 g, 6.15 mmol) were dissolved in 60 mL of dimethyl sulfoxide under ice cooling, and the mixture was at room temperature. After stirring for 1 hour, a solution of tetrahydrothiopyran-4-one 168a (6.79 g, 60 mmol) in 80 mL of dimethyl sulfoxide was added dropwise, the temperature was controlled not higher than 15 V, and the mixture was naturally warmed to room temperature after stirring for 10 minutes. The reaction was completed after 3 hours. The reaction mixture was poured into 350 mL of ice water, and extracted with diethyl ether (400 mL X 3). The combined organic phases were washed sequentially with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated Generation-6-thio-spiro[2.5]octane 168b (7.09 g, white solid), yield: 92%.
MS m/z (ESI): 131 [M+ 1] '  MS m/z (ESI): 131 [M+ 1] '
第二步  Second step
1-氧代 -6-硫代-螺 [2.5] 辛烷 6，6-二氧滑物  1-oxo-6-thio-spiro [2.5] octane 6,6-dioxoslide
将 1-氧代 -6-硫代-螺 [2.5]辛烷 168b (7 g， 53.8 mmol)溶于 100 mL乙腈中， 搅拌 下加入 50 mL水，搅拌 5分钟后依次加入臭氧 (99 g, 161 mmol)和碳酸钠 (51 g， 0.48 mol), 室温下搅拌 1小时后反应完毕。在反应液中加入 300 mL二氯甲烷， 搅拌 30 分钟， 过滤， 滤饼用二氯甲烷洗涤 (150mLX 2)， 滤液在减压下浓缩， 得到粗品 1- 氧代 -6-硫代-螺 [2.5] 辛烷 6,6-二氧化物 168c (7.48 g， 黄色固体)， 产物不经分离直 接进行下一步反应。  1-Oxo-6-thio-spiro[2.5]octane 168b (7 g, 53.8 mmol) was dissolved in 100 mL of acetonitrile, and 50 mL of water was added with stirring. After stirring for 5 minutes, ozone (99 g, 161 mmol) and sodium carbonate (51 g, 0.48 mol) were stirred at room temperature for 1 hour and the reaction was completed. 300 mL of dichloromethane was added to the reaction mixture, and the mixture was stirred for 30 minutes, filtered, and the filter cake was washed with dichloromethane (150 mL×2), and the filtrate was concentrated under reduced pressure to give crude 1-oxo-6-thio-spiral [ 2.5] Octane 6,6-dioxide 168c (7.48 g, yellow solid). The product was taken to the next step without isolation.
MS m/z (ESI): 163[M+ 1]  MS m/z (ESI): 163 [M+ 1]
第三步  third step
4-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基}-吡咯 -1-基甲基 )-1,1-二氧 -六氢  4-(3-{4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-pyrrol-1-ylmethyl)-1,1 -dioxy-hexahydrogen
-1λ*6*-噻喃 -4-醇  -1λ*6*-thiopyran-4-ol
将 [3-氯 -4-(3-氟- 氧基) -苯基 ]-[6-(1Η-吡咯 -3-基)-喹唑啉 -4-基] -胺 42(89 mg, [3-Chloro-4-(3-fluoro-oxy)-phenyl]-[6-(1Η-pyrrole-3-yl)-quinazolin-4-yl]-amine 42 (89 mg,
0.2 mmol)和氢化钠 (24 mg， 0.6 mmol)溶于 2 mLN,N-二甲基甲酰胺中，室温下搅 拌 30分钟后加入 1-氧代 -6-硫代-螺 [2.5] 辛垸 6,6-二氧化物 168c (40 mg, 0.24 mmol), 室温下搅拌 1.5小时后反应完毕。 在反应液中加入 100 mL水， 水相用乙 酸乙酯 (100 mL X 3)萃取， 合并的有机相依次通过饱和氯化钠溶液洗涤， 无水硫酸 钠干燥， 过滤， 减压下浓缩， 得到的残留物通过硅胶柱层析进一步分离纯化， 得 到标题产物 4-(3-{4-[3-氯 -4-P-氟-苄氧基) -苯氨基] -喹唑啉 -6-基 吡咯 -1-基甲 基) -U-二氧 -六氢 -1λ*6*-噻喃 -4-醇 168 (40 mg， 黄色固体)， 产率： 33 %。 0.2 mmol) and sodium hydride (24 mg, 0.6 mmol) were dissolved in 2 mL of N,N-dimethylformamide, stirred at room temperature for 30 min and then added 1-oxo-6-thio-spiro[2.5] 6,6-dioxide 168c (40 mg, 0.24 mmol) was stirred at room temperature for 1.5 hours and then the reaction was completed. 100 mL of water was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (100 mL X 3 ). The combined organic phases were washed successively with saturated sodium chloride The residue was dried over EtOAc (EtOAc m.). Phenylamino]-quinazolin-6-ylpyrrol-1-ylmethyl)-U-dioxo-hexahydro-1λ*6*-thiopyran-4-ol 168 (40 mg, yellow solid), yield : 33%.
MS m/z (ESI): 608[M+ 1] MS m/z (ESI): 608 [M+ 1]
1H NMR (400 MHz , DMSO-d6)： 69.726 (s, 1H) ,8.535 (s, 1H) , 8.503 (s,lH) ,8.031 (d, J = 8.4 Hz, 2H),7.726 (t,J=8.4Hz,2H),7.484 (d, J = 6.4Hz, 1H),7.407(S,1H),7.322 (m,3H),7.190(s,lH),6.907(s,lH),6.679(s,lH),5.274(s,2H),5.256(s,lH),3.994(s,2H),3.18 l(m,2H),3.008 (d,J=12.8Hz,2H),2.005(d,J=7.6Hz,2H),1.831 (d,J=13.6Hz,2H) 实施例 169  1H NMR (400 MHz, DMSO-d6): 69.726 (s, 1H), 8.535 (s, 1H), 8.503 (s, lH), 8.031 (d, J = 8.4 Hz, 2H), 7.726 (t, J = 8.4 Hz, 2H), 7.484 (d, J = 6.4 Hz, 1H), 7.407 (S, 1H), 7.322 (m, 3H), 7.190 (s, lH), 6.907 (s, lH), 6.679 (s, lH), 5.274 (s, 2H), 5.256 (s, lH), 3.994 (s, 2H), 3.18 l (m, 2H), 3.008 (d, J = 12.8 Hz, 2H), 2.005 (d, J = 7.6 Hz, 2H), 1.831 (d, J = 13.6 Hz, 2H). Example 169
{6-「1-(2-二乙氨基-乙基) -1H-吡咯 -3-基 1-喹唑啉 -4-基 「l-(3-氟苄基) -m-吲唑 -5-基  {6-"1-(2-Diethylamino-ethyl)-1H-pyrrol-3-yl-1-quinazolin-4-yl "l-(3-fluorobenzyl)-m-indazole-5 -base
Figure imgf000176_0001
将 {6-[1-(2-二乙氨基-乙基) -1H-吡咯 -3-基]-喹唑啉 -4-基 }-[1-(3-氟苄基) -1H-吲 唑 -5-基] -胺 150 (434 mg， lmmol)溶于 6 mL的 Ν,Ν-二甲基甲酰胺中， 冰浴冷却至 0°C， 加入氢化钠 (200 mg， 5 mmol), 搅拌 30分钟。
Figure imgf000176_0001
{6-[1-(2-Diethylamino-ethyl)-1H-pyrrol-3-yl]-quinazolin-4-yl}-[1-(3-fluorobenzyl)-1H-indole Oxazol-5-yl]-amine 150 (434 mg, 1 mmol) was dissolved in 6 mL of hydrazine, hexane-dimethylformamide, cooled to 0 ° C, and sodium hydride (200 mg, 5 mmol). Stir for 30 minutes.
另取 2-溴 -Ν,Ν-二乙基乙胺氢溴酸盐 (287 mg， 1.1 mmol)的 2 mL N,N-二甲基甲 酰胺溶液， 加入氢化钠 (44 mg， 1.83 mmol), 在 0Ό下搅拌 30分钟后， 将溶液加入 上述放入反应液中， 所得的溶液在 0°C下搅拌 30分钟后反应完毕。 将反应液倒入 40 mL冰水中， 分液， 水层用乙酸乙酯 (25 mLx4)萃取， 合并的有机相依次通过饱 和氯化钠溶液 (10 mLx2)洗涤， 无水硫酸钠干燥， 过滤， 减压下浓缩， 得到的残留 物通过薄层层析制备板分离纯化， 得到标题产物 {6-[1-(2-二乙氨基-乙基) -1H-吡咯 -3-基] -喹唑啉 -4-基 }-[1-(3-氟苄基) -1H-吲唑 -5-基] -胺 169(300 mg， 黄色固体)， 产率 56.3 %。  A solution of 2-bromo-indole, hydrazine-diethylethylamine hydrobromide (287 mg, 1.1 mmol) in 2 mL of N,N-dimethylformamide, and sodium hydride (44 mg, 1.83 mmol) After stirring at 0 °C for 30 minutes, the solution was added to the above reaction solution, and the resulting solution was stirred at 0 ° C for 30 minutes and the reaction was completed. The reaction mixture was poured into 40 mL of ice water, and the aqueous layer was separated, ethyl acetate (25 mL×4), and the combined organic phase was washed successively with saturated sodium chloride solution (10 mL×2), dried over anhydrous sodium sulfate and filtered. Concentration under reduced pressure, the obtained residue was purified and purified by silica gel chromatography to afford the title product (6-[1-(2-diethylamino-ethyl)-1H-pyrrol-3-yl]-quinazole Phenyl-4-yl}-[1-(3-fluorobenzyl)-1H-indazol-5-yl]-amine 169 (300 mg, yellow solid).
MS m/z (ESI): 534[M+ 1]  MS m/z (ESI): 534 [M+ 1]
1腿 MR (400MHz, DMSO- d6): δ 9.84(s， 1H), 8.82(s, 1H), 8.46(s, 1H), 8.25(s, 1H), 8.18(s, 1H), 8.05(d, 1H, J =8.4), 7.75(s, 2H), 7.72(d, 1H, J=8.4), 7.47(s, 1H), 7.40(dd, 1H, J=7.2, J= 14), 7.13(dd, 3H, J=8.4, J= 19.2), 6.93(s, 1H), 6.69(s, 1H), 5.72(s, 2H), 4.01(br s， 2H), 2.81(br s, 2H), 2.55(br s, 4H), 0.97(s, 6H) 实施例 170 1 leg MR (400MHz, DMSO-d6): δ 9.84(s, 1H), 8.82(s, 1H), 8.46(s, 1H), 8.25(s, 1H), 8.18(s, 1H), 8.05(d , 1H, J = 8.4), 7.75(s, 2H), 7.72(d, 1H, J=8.4), 7.47(s, 1H), 7.40(dd, 1H, J=7.2, J= 14), 7.13( Dd, 3H, J=8.4, J= 19.2), 6.93(s, 1H), 6.69(s, 1H), 5.72(s, 2H), 4.01 (br s, 2H), 2.81 (br s, 2H), 2.55 (br s, 4H), 0.97 (s, 6H) Example 170
[3-氯 -4- (3-氟- 氧基) -苯基 M6- R,8aRVl-i六氢吡咯并「2j-cin,41噁嗪基 -3-某甲 基) -1H-吡咯 -3-基 1-喹唑啉 -4-基 μ胺  [3-Chloro-4-(3-fluoro-oxy)-phenyl M6-R, 8aRVl-i hexahydropyrrolo "2j-cin, 41oxazinyl-3-methyl"-1H-pyrrole- 3-yl 1-quinazolin-4-yl-imamide
Figure imgf000177_0001
Figure imgf000177_0001
第一步  First step
(3R,8aR)-3- (氯甲基) -六氢- 1 H-吡咯 [2, 1 -c] [1 ,4]噁嗪 - 将环氧氯丙烷 170a (157 ml, 2 mol)加入干燥的圆底烧瓶中， 冰浴冷却 20分钟 后滴加 D-脯氨醇 170b (20 g, 0.2 mol), 在 40Ό反应 0. 5小时。 蒸掉过量环氧氯丙 烷。 冰浴下滴加浓硫酸 (60 ml) , 在 150-180°C下反应 1.5小时。 将反应液倒入冰水 (200 ml)中以淬灭反应，用氨水调节溶液 pH值为 8，正己烧 /乙酸乙酯 (1/1， 300 ml) 萃取， 水相用乙酸乙酯 (200 ml X 3)萃取， 合并有机相， 用饱和氯化钠溶液 (100 ml) 洗涤有机相， 用无水硫酸镁干燥， 过滤， 减压浓缩滤液， 用硅胶柱色谱法纯化所 得残余物， 得到标题产物 (3R,8aR)-3- (氯甲基) -六氢 -1H-吡咯 [2,l-c][l,4]噁嗪 170c (6.882 g, 棕色油状液体)， 产率 19.8 %。  (3R,8aR)-3-(Chloromethyl)-hexahydro-1H-pyrrole[2,1-c] [1 ,4]oxazine - Add Epichlorohydrin 170a (157 ml, 2 mol) 5小时。 The reaction was carried out in a 40 ° hr. Excess epoxy propylene chloride was distilled off. Concentrated sulfuric acid (60 ml) was added dropwise under ice bath and reacted at 150-180 ° C for 1.5 hours. The reaction solution was poured into ice water (200 ml) to quench the reaction, and the pH of the solution was adjusted to 8 with aqueous ammonia, and extracted with hexane/ethyl acetate (1/1, 300 ml). The organic phase was washed with a saturated aqueous solution of sodium chloride (100 ml), dried over anhydrous magnesium sulfate, filtered and evaporated. Product (3R,8aR)-3-(Chloromethyl)-hexahydro-1H-pyrrole[2, lc][l,4]oxazine 170c (6.882 g, brown oily).
MS m/z (ESI): 585 [M+ 1] MS m/z (ESI): 585 [M+ 1]
第二步  Second step
[3-氯 -4-(3-氟- 氧基) -苯基 ]-{6-[(3R,8aR)- 1- (六氢吡咯并 [2,l-c][l，4]噁嗪基 -3-基甲 基) -1H-吡咯 -3-基] -喹唑啉 -4-基} -胺  [3-chloro-4-(3-fluoro-oxy)-phenyl]-{6-[(3R,8aR)-1-(hexahydropyrrolo[2,lc][l,4]oxazinyl -3-ylmethyl)-1H-pyrrol-3-yl]-quinazolin-4-yl}-amine
在 25 mL的单口烧瓶中，将 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-[6-(1Η-吡咯 -3-基) -喹唑 啉— 4-基] -胺 42 (444 mg， 1 mmol)溶于 6 mL N，N-二甲基甲酰胺中，在冰浴条件下， 冷却至 0°C， 加入氢化钠 (120 mg， 3 mmol), 搅拌 30分钟后加入 (3R,8aR)-3- (氯甲 基) -六氢 -1H-吡咯 [2,l-c][l,4]噁嗪 170c (211 mg， 1.2 mmol), 室温下搅拌 4小时反 应完毕。 反应液减压下浓缩， 得到的残留物通过硅胶柱层析进一步分离纯化 (二氯 甲烷：甲醇 =40: 1)，得到本标题产物 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-{6-[(3R,8aR)-l- (六 氢吡咯并 [2,l-c][l,4]噁嗪基 -3-基甲基 )-1Η-吡咯 -3-基] -喹唑啉 -4-基 } 安 170 (5 mg, 黄色固体)， 产率： 6.5 %。 [3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1Η-pyrrol-3-yl)-quinazolin-4-yl in a 25 mL single-necked flask - Amine 42 (444 mg, 1 mmol) was dissolved in 6 mL of N,N-dimethylformamide, cooled to 0 ° C under ice bath, sodium hydride (120 mg, 3 mmol) After 30 minutes, (3R,8aR)-3-(chloromethyl)-hexahydro-1H-pyrrole[2,lc][l,4]oxazine 170c (211 mg, 1.2 mmol) was added and stirred at room temperature for 4 hours. The reaction is completed. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified and purified by silica gel column chromatography. Methane:methanol = 40: 1) gave the title product [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-{6-[(3R,8aR)-l- (hexahydropyrrole) And [2, lc][l,4]oxazin-3-ylmethyl)-1Η-pyrrol-3-yl]-quinazolin-4-yl} An 170 (5 mg, yellow solid), Rate: 6.5 %.
MS m/z (ESI): 585[M+ 1] MS m/z (ESI): 585 [M+ 1]
1H NMR(400 MHz ,DMSO-d6): 59.67(S,1H),8.8(S,1H),8.5(S,1H),  1H NMR (400 MHz, DMSO-d6): 59.67 (S, 1H), 8.8 (S, 1H), 8.5 (S, 1H),
8.03(d,J=8.8Hz,2H),7.76(dd,J=2Hz,lH),7.70(d,J=8.4Hz,lH),7.5(m,2H),7.36(m,3H), 7.2(s,lH),6.93(s3lH),6.60(s3lH),5.27(s,2H),4.0 (m,lH),3.62 ( =12Hz52H),3.51 (s,2H),3.0 (br,lH),2. 31(m,lH),2.1(br,3H),1.4-1.6 (m,2H),1.1237(m,2H) 实施例 171 8.03 (d, J = 8.8 Hz, 2H), 7.76 (dd, J = 2 Hz, lH), 7.70 (d, J = 8.4 Hz, lH), 7.5 (m, 2H), 7.36 (m, 3H), 7.2 (s, lH), 6.93 (s 3 lH), 6.60 (s 3 lH), 5.27 (s, 2H), 4.0 (m, lH), 3.62 (=12Hz 5 2H), 3.51 (s, 2H), 3.0 (br, lH), 2. 31 (m, lH), 2.1 (br, 3H), 1.4-1.6 (m, 2H), 1.1237 (m, 2H) Example 171
「3_氯 _4_(3-氟-苄氧基 苯基 1-(6-Π-「2-(1-甲基-吡咯垸 -2-基) -乙基 1-lH-吡咯 -3-基 喹 唑啉 -4-基) -胺 "3_Chloro- 4" -( 3 -fluoro-benzyloxyphenyl 1-(6-indole-"2-(1-methyl-pyrrole-2-yl)-ethyl 1-lH-pyrrole-3 - quinazolin-4-yl)-amine
Figure imgf000178_0001
Figure imgf000178_0001
在 25 mL的单口烧瓶中， 将 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-[6-(1Η-吡咯 -3-基) -喹 唑啉 -4-基] -胺 42 (100 mg， 0.22 mmol)溶于 6 mLN,N-二甲基甲酰胺中， 在冰浴条 件下， 冷却至 0°C， 加入氢化钠 (27 mg， 1.13 mmol), 搅拌 30分钟后加入 2-(2-氯 乙基) -1-甲基吡咯烷盐酸盐（50 mg， 0.27 mmol), 室温下搅拌 4小时反应完毕。 反 应液减压下浓缩， 得到的残留物通过硅胶柱层析进一步分离纯化 (二氯甲烷： 甲醇 =40： 1)， 得到本标题产物 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-(6-{1-[2-(1-甲基 -B比咯烷 -2- 基) -乙基] -1H-吡咯 -3-基}-喹唑啉 -4-基) -胺 171 (27 mg， 淡黄色固体)， 产率： 78%。 MS m/z (ESI): 558[M+ 1]  [3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1Η-pyrrol-3-yl)-quinazolin-4-yl in a 25 mL single-necked flask - Amine 42 (100 mg, 0.22 mmol) was dissolved in 6 mL of N-N-dimethylformamide, cooled to 0 ° C under ice bath, sodium hydride (27 mg, 1.13 mmol). After a minute, 2-(2-chloroethyl)-1-methylpyrrolidine hydrochloride (50 mg, 0.27 mmol) was added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjjj -phenyl]-(6-{1-[2-(1-methyl-B-pyrrolidin-2-yl)-ethyl]-1H-pyrrol-3-yl}-quinazoline-4- - 171 (27 mg, pale yellow solid), Yield: 78%. MS m/z (ESI): 558 [M+ 1]
1H NMR(400 MHz ,DMSO-d6)： δ 9.67 (s,lH), 8.8(s,lH),8.5 (s,lH), 8.03(d,  1H NMR (400 MHz, DMSO-d6): δ 9.67 (s,lH), 8.8 (s,lH), 8.5 (s,lH), 8.03 (d,
J=8.8Hz,2H), 7.76(dd， J=2Hz, 1H), 7.70(d,J=8.4Hz,lH),7.5(m,2H), 7.36(m,3H), 7.2(s，lH)， 6.93(s,lH), 6.60(s,lH), 5.27(s,2H), 3.97(m,2H) , 2.08(m,3H), 1.66(m,2H), 1.24-1.30(m,7H) 实施例 172 J = 8.8 Hz, 2H), 7.76 (dd, J = 2 Hz, 1H), 7.70 (d, J = 8.4 Hz, lH), 7.5 (m, 2H), 7.36 (m, 3H), 7.2 (s, lH) ), 6.93(s,lH), 6.60(s,lH), 5.27(s,2H), 3.97(m,2H) , 2.08(m,3H), 1.66(m,2H), 1.24-1.30(m, 7H) Example 172
4-(3-{4-「3-氯 -4-(3-氟 -苄氧基)-苯氨基 1-喹唑啉 -6-基 吡咯 -1-基甲基) -哌啶 -4-醇 4-(3-{4-"3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino-1-quinazolin-6-ylpyrrol-1-ylmethyl)-piperidin-4- alcohol
Figure imgf000179_0001
Figure imgf000179_0001
第一步  First step
1-氧代 -6-氮杂-螺 [2.5]辛烷 -6-羧酸叔丁酯  1-oxo-6-aza-spiro [2.5]octane-6-carboxylic acid tert-butyl ester
在冰盐浴冷却下， 将 100 mL二甲基亚砜逐渐滴加到三甲基氧硫化碘 (40g， 0.18 mol)和氢化钠 (7.48 g， 0.18 mol)的混合物中， 滴加过程中， 保持温度在 0〜5 °C， 搅 拌下滴加 4-氧代 -哌啶 -1-羧酸叔丁酯 172a (34.1g, 0.17 mol)的 100 mL二甲基亚砜 溶液， 滴加完毕后逐渐升至室温， 在室温下搅拌 3 小时， 反应完毕。 将反应液倒 入 lOO mL冰水中， 用乙醚萃取， 合并的有机相依次用无水硫酸钠干燥， 过滤， 减 压下浓缩，得到化合物 1-氧代 -6-氮杂-螺 [2.5]辛垸 -6-羧酸叔丁酯 172b(32g，黄色固 体)， 产率： 83.4%。  100 mL of dimethyl sulfoxide was gradually added dropwise to a mixture of trimethyloxysulfide iodine (40 g, 0.18 mol) and sodium hydride (7.48 g, 0.18 mol) under cooling in an ice salt bath, during the dropwise addition. While maintaining the temperature at 0~5 °C, a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester 172a (34.1 g, 0.17 mol) in 100 mL of dimethyl sulfoxide was added dropwise with stirring. The temperature was gradually raised to room temperature, and the mixture was stirred at room temperature for 3 hours, and the reaction was completed. The reaction solution was poured into 100 mL of ice water, and extracted with diethyl ether. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 1-oxo-6-aza-spiro[2.5] tert-Butyl-carboxylic acid tert-butyl ester 172b (32 g, yellow solid), Yield: 83.4%.
MS m/z (ESI): 214[M+ 1] MS m/z (ESI): 214 [M+ 1]
第二步  Second step
4-(3-{4-[3-氯 -4-(3-氟- 氧基) -苯氨基] -喹唑啉 -6-基} -吡咯 -1-基甲基 )-4-羟基 -哌啶  4-(3-{4-[3-Chloro-4-(3-fluoro-oxy)-phenylamino]-quinazolin-6-yl}-pyrrol-1-ylmethyl)-4-hydroxy- Piperidine
-1-羧酸叔丁酯  Tert-butyl-1-carboxylate
在 50 mL的烧瓶中， 将 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-[6-(1Η-吡咯 -3-基) -喹唑啉 -4-基] -胺 42 (223 mg， 0.5 mmol)溶于 10 mL干燥的 Ν,Ν-二甲基甲酰胺中， 在冰浴 条件下， 冷却至 0°C， 加入氢化钠 (60 mg， 1.5 mmol), 搅拌 30分钟后加入 1-氧代 -6-氮杂-螺 [2.5]辛烷 -6-羧酸叔丁酯 172b (50 mg， 0.27 mmol), 室温下搅拌 1小时反 应完毕。 反应液减压下浓缩， 得到的残留物通过硅胶柱层析进一步分离纯化 (二氯 甲烷： 甲醇 =40: 1)， 得到本标题产物 4-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑 啉 _6-基 吡咯 -1-基甲基 )-4-羟基 -哌啶 -1-羧酸叔丁酯 172c (193 mg， 淡黄色固体)， 产率： 58.7%  [3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1Η-pyrrol-3-yl)-quinazolin-4-yl] in a 50 mL flask -Amine 42 (223 mg, 0.5 mmol) was dissolved in 10 mL dry EtOAc EtOAc (EtOAc) After stirring for 30 minutes, 1-oxo-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester 172b (50 mg, 0.27 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjj (3-Fluoro-benzyloxy)-phenylamino]-quinazoline-6-ylpyrrol-1-ylmethyl)-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester 172c (193 mg, light Yellow solid), Yield: 58.7%
MS m/z (ESI): 659[M+ 1] MS m/z (ESI): 659 [M+ 1]
第三步  third step
4-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基} -吡咯 -1-基甲基) -哌啶 -4-醇 将 4— (3— {4— [3—氯 -4_(3_氟-苄氧基)—苯氨基]—喹唑啉 _6-基 吡咯 -1-基甲基 )-4-羟基- 哌啶 -1-羧酸叔丁酯 172c (90 mg， 0.137 mmol)溶于 25 mL二氯甲烷中，在冰浴条件 下， 冷却至 0°C， 逐渐滴加三氟乙酸 (25 mL， 1.38mol)， 升至室温， 搅拌 40分钟后 反应完毕。 将反应液在减压下浓缩， 得到的残留物通过硅胶柱层析进一步分离纯 化，得到标题产物 4-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基 吡咯 -1-基甲 基) -哌啶 -4-醇三氟乙酸盐 172 (92 mg， 黄绿色固体)， 产率： 100%。 4-(3-{4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-pyrrol-1-ylmethyl)-piperidine- 4-alcohol 4-(3-{ 4- [3-Chloro-4_(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-ylpyrrolidin-1-ylmethyl)-4-hydroxy-piperidin tert-Butyl-1-carboxylic acid tert-butyl ester 172c (90 mg, 0.137 mmol) was dissolved in dichloromethane (25 mL), cooled to 0 ° C under ice-cooling, and then trifluoroacetic acid (25 mL, 1.38 mol) ), warmed to room temperature, stirred for 40 minutes and the reaction was completed. The reaction mixture was concentrated under reduced pressure. EtOAc m. m. Phenylamino]-quinazolin-6-ylpyrrol-1-ylmethyl)-piperidin-4-ol trifluoroacetate 172 (92 mg, yellow-brown solid). Yield: 100%.
MS m/z (ESI): 559[M+ 1] MS m/z (ESI): 559 [M+ 1]
1H NMR(400 MHz , DMSO-d6)： 510.742 (s,lH) , 8.733 (s, 1H) , 8.687(s,lH), 1H NMR (400 MHz, DMSO-d 6 ): 510.742 (s,lH), 8.733 (s, 1H), 8.687 (s,lH),
8.598(d,J=12Hz,lH), 8.340(d,J=9.2Hz,lH), 8.194(d,J=8.8Hz,lH), 7.942(s,lH), 8.598 (d, J = 12 Hz, lH), 8.340 (d, J = 9.2 Hz, lH), 8.194 (d, J = 8.8 Hz, lH), 7.942 (s, lH),
7.784(d,J=8.4Hz,lH), 7.690(t,J-4.4z,lH),7.491(m,3H), 7.201(t,J=8.8Hz,lH), 7.784 (d, J = 8.4 Hz, lH), 7.690 (t, J-4.4z, lH), 7.491 (m, 3H), 7.201 (t, J = 8.8 Hz, lH),
6.926(s,lH), 5.308(s,lH), 5.173(d,J=12Hz,lH), 3.059(d,J=4.8Hz,2H), 6.926(s,lH), 5.308(s,lH), 5.173(d,J=12Hz,lH), 3.059(d,J=4.8Hz,2H),
1.708(t,J=l 1.4Hz,2H), 1.584(d, J=13.6Hz,4H), 1.342(s,2H) 实施例 173 1.708 (t, J = l 1.4 Hz, 2H), 1.584 (d, J = 13.6 Hz, 4H), 1.342 (s, 2H) Example 173
Γ3-氯 -4-(3-氟-苄氧基 苯基 1-{6-「1-(3-哌啶 -1-基 -丙基 1H-吡咯 -3-基 1-喹唑啉 -4-基  3-chloro-4-(3-fluoro-benzyloxyphenyl 1-{6-"1-(3-piperidin-1-yl-propyl 1H-pyrrol-3-yl 1-quinazolin-4 -base
Figure imgf000180_0001
Figure imgf000180_0001
将化合物 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-[6-(1Η-吡咯 -3-基) -喹唑啉 -4-基] -胺 42 (111 mg， 0.25 mmol)和氢化钠 (65.3 mg， 1.25 mmol)溶于 5 mLN,N-二甲基甲酰胺中， 室温下搅拌 30分钟后加入 1-(3-氯丙基) -哌啶盐酸盐 (70.5 mg， 0.3 mmol), 加热至 50°C， 2小时后反应完毕。在反应液中加入 100 mL水和 100 mL， 分液， 水相用乙 酸乙酯 (100 mLX 3)萃取， 合并的有机相依次通过饱和氯化钠溶液洗涤， 无水硫酸 钠干燥， 过滤， 减压下浓縮， 得到的残留物通过硅胶柱层析进一步分离纯化， 得 到标题产物 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-{6-[1-(3-哌啶 -1-基-丙基) -1H-吡咯 -3-基] -喹 唑啉 _4-基} -胺 173(30 mg， 红色固体)， 产率： 21.1 %。  The compound [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1Η-pyrrol-3-yl)-quinazolin-4-yl]-amine 42 (111 mg , 0.25 mmol) and sodium hydride (65.3 mg, 1.25 mmol) dissolved in 5 mL of N,N-dimethylformamide, stirred at room temperature for 30 min then added 1-(3-chloropropyl)-piperidine hydrochloride (70.5 mg, 0.3 mmol), heated to 50 ° C, and the reaction was completed after 2 hours. 100 mL of water and 100 mL were added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (100 mL×3). The combined organic phases were washed sequentially with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and reduced The residue was concentrated and purified by silica gel column chromatography to give the title product [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-{6-[1-(3 -piperidin-1-yl-propyl)-1H-pyrrol-3-yl]-quinazoline-4-yl}-amine 173 (30 mg, red solid), Yield: 21.1%.
MS m/z (ESI): 570[M+ 1] MS m/z (ESI): 570 [M+ 1]
1H NMR(400 MHz, DMSO-d6): δ 9.68 (s, 1H), 8.53 (s, 1H), 8.50 (s, 1H), 8.05 (s, 1H), 8.03 (d, J = 8.8Hz, 1H), 7.76 (d, J = 8.8Hz, 1H), 7.70 (d, J = 8.8Hz, 1H), 7.50 (t, J - 8.8Hz, 1H), 7.43 (s, 1H), 7.33 (m, 3H), 7.19 (t, J = 8.8Hz, 1H), 6.89 (s, 1H), 6.66 (s, 1H), 5.27 (s, 2H), 3.96 (t, J = 6.8Hz, 2H), 2.33 (br, 4H), 2.23 (br, 2H), 1.92 (m, 2H): 1.52 (br, 4H), 1.31 (br, 2H) 实施例 174 1H NMR (400 MHz, DMSO-d 6 ): δ 9.68 (s, 1H), 8.53 (s, 1H), 8.50 (s, 1H), 8.05 (s, 1H), 8.03 (d, J = 8.8 Hz, 1H), 7.76 (d, J = 8.8Hz, 1H), 7.70 (d, J = 8.8Hz, 1H), 7.50 (t, J - 8.8Hz, 1H), 7.43 (s, 1H), 7.33 (m, 3H), 7.19 (t, J = 8.8Hz, 1H), 6.89 (s, 1H), 6.66 (s, 1H), 5.27 (s, 2H), 3.96 (t, J = 6.8Hz, 2H), 2.33 (br, 4H), 2.23 (br, 2H), 1.92 (m, 2H) : 1.52 (br, 4H), 1.31 (br, 2H) Example 174
Γ1-(3-氟 -苄基 1H-吲唑 -5-基 l-i6-fl-i2-吗啉 -4-基 -乙基 1H-吡咯 -3-基 1-喹唑啉 -4- 基 胺  1-(3-Fluoro-benzyl 1H-indazol-5-yl-i-6-fl-i2-morpholin-4-yl-ethyl 1H-pyrrol-3-yl-1-quinazolin-4-yl Amine
Figure imgf000181_0001
Figure imgf000181_0001
将 {6-[1-(2-二乙氨基-乙基) -1H-吡咯 -3-基] -喹唑啉 -4-基 }-[1_(3-氟苄基) -1H-吲 唑 -5-基] -胺 150 (434 mg， 1 mmol)溶于 6 mL的 Ν,Ν-二甲基甲酰胺中， 冰浴冷却 至 0Ό， 加入氢化钠 (200 mg， 5 mmol), 搅拌 30分钟。  {6-[1-(2-Diethylamino-ethyl)-1H-pyrrol-3-yl]-quinazolin-4-yl}-[1_(3-fluorobenzyl)-1H-carbazole -5-yl]-amine 150 (434 mg, 1 mmol) was dissolved in 6 mL of hydrazine, hexane-dimethylformamide, cooled to 0 EtOAc, EtOAc (EtOAc, EtOAc minute.
另取 4-(2-溴乙基 1)-吗啉氢溴酸盐 (302 mg， 1.1 mmol)的 2 mL Ν,Ν-二甲基甲酰 胺溶液， 加入氢化钠 （44 mg， 1.83 mmol), 在 0°C下搅拌 30分钟后， 将溶液加入 上述放入反应液中， 所得的溶液在 0Ό下搅拌 2小时后反应完毕。 将反应液倒入 100 mL冰水中， 分液， 水层用乙酸乙酯 (25 mLx4)萃取， 合并的有机相依次通过饱 和氯化钠溶液洗涤， 无水硫酸钠千燥， 过滤， 减压下浓缩， 得到的残留物通过薄 层层析制备板分离纯化， 得到标题产物 [1-(3-氟-苄基) -1H-吲唑 -5-基 ]-{6-[1-(2-吗啉 -4-基-乙基) -1H-吡咯 -3-基] -喹唑啉 -4-基 胺 174 (300mg， 黄色固体)， 产率 54.8%。 MS m/z (ESI): 548[M+ 1]  A solution of 4-(2-bromoethyl 1)-morpholine hydrobromide (302 mg, 1.1 mmol) in 2 mL EtOAc EtOAc (EtOAc) After stirring at 0 ° C for 30 minutes, the solution was added to the above reaction solution, and the resulting solution was stirred at 0 ° C for 2 hours, and the reaction was completed. The reaction solution was poured into 100 mL of ice water, and the aqueous layer was separated with ethyl acetate (25 mL×4). The combined organic phases were washed successively with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated After concentration, the obtained residue was purified by a thin layer chromatography chromatography to give the title product [1-(3-fluoro-benzyl)-1H-carbazol-5-yl]-{6-[1-(2- Morpholin-4-yl-ethyl)-1H-pyrrol-3-yl]-quinazolin-4-ylamine 174 (300 mg, yellow solid), yield 54.8%. MS m/z (ESI): 548 [M+ 1]
iHNMR (400MHz, CD30D - )： 89.84(s,lH), 8.61(s,lH), 8.45(s,lH), 8.23(s,lH), 8.17(s,lH), 8.05(d,lH,J=8.8Hz), 7.75(s,2H), 7.71(d,lH,J=8.8Hz), 7.46(s,lH), iHNMR (400MHz, CD30D - ): 89.84(s,lH), 8.61(s,lH), 8.45(s,lH), 8.23(s,lH), 8.17(s,lH), 8.05(d,lH,J =8.8Hz), 7.75(s,2H), 7.71(d,lH,J=8.8Hz), 7.46(s,lH),
7.38(m,lH), 7.08(m,3H), 6.93(s，lH), 6.68(s,lH), 5.72(s,2H), 4.07(m,2H), 3.58(m,4H), 2.71(m,2H), 2.45(m,4H) 实施例 175 7.38(m,lH), 7.08(m,3H), 6.93(s,lH), 6.68(s,lH), 5.72(s,2H), 4.07(m,2H), 3.58(m,4H), 2.71 (m, 2H), 2.45 (m, 4H) Example 175
Γ1-(3-氟-苄基) -1H-吲唑 -5-基 1-ί6-「 2-吡咯垸 -1-基-乙基) -1H-吡咯 -3-基 1-喹唑啉 -4- 基 -胺 1-(3-Fluoro-benzyl)-1H-indazol-5-yl 1-ί6-"2-pyrrolidin-1-yl-ethyl)-1H-pyrrol-3-yl-1-quinazoline- 4-yl-amine
Figure imgf000182_0001
将 {6-[1-(2-二乙氨基-乙基) -1H-吡咯 -3-基]-喹唑啉 -4-基 }-[1-(3-氟苄基 )-1Η-吲 唑 -5-基] -胺 150 (434 mg, 1 mmol)溶于 6 mL的 Ν,Ν-二甲基甲酰胺中， 冰浴冷却 至 0Ό， 加入氢化钠 (200 mg， 5 mmol), 搅拌 30分钟后， 加入 1-(2-氯乙基) -吡咯 烷盐酸盐 (187 mg， 1.1 mmol), 室温下搅拌 30分钟后， 加热至 50Ό , 1.5小时后反 应完毕。 将反应液倒入 100 mL冰水中， 有固体析出， 过滤， 将滤饼溶于 100 mL 乙酸乙酯中， 通过无水硫酸钠干燥， 过滤浓缩， 得到的残留物进一步通过 HPLC 制备色谱分离， 得到标题产物 [1-(3-氟-苄基) -1H-吲唑 -5-基 ]-{6-[1-(2-吡咯烷 -1-基- 乙基) 吡咯 -3-基] -喹唑啉 -4-基} -胺 175 (700 mg, 淡黄色固体)， 产率 40%。 MS m/z (ESI): 532[M+ 1]
Figure imgf000182_0001
{6-[1-(2-Diethylamino-ethyl)-1H-pyrrol-3-yl]-quinazolin-4-yl}-[1-(3-fluorobenzyl)-1Η-吲Oxazol-5-yl]-amine 150 (434 mg, 1 mmol) was dissolved in 6 mL of hydrazine, hexane-dimethylformamide, cooled to 0 EtOAc, EtOAc (EtOAc) After 30 minutes, 1-(2-chloroethyl)-pyrrolidine hydrochloride (187 mg, 1.1 mmol) was added, and the mixture was stirred at room temperature for 30 minutes, and then heated to 50 Torr. The reaction solution was poured into 100 mL of ice water, and a solid was precipitated. The mixture was filtered, and the filtered cake was dissolved in ethyl acetate (100 mL), dried over anhydrous sodium sulfate, and concentrated by filtration. The title product [1-(3-fluoro-benzyl)-1H-indazol-5-yl]-{6-[1-(2-pyrrolidin-1-yl-ethyl)pyrrol-3-yl]- Quinazolin-4-yl}-amine 175 (700 mg, pale yellow solid), yield 40%. MS m/z (ESI): 532 [M+ 1]
XHNMR (400MHz, CD30D - )： S9.87(s,lH), 8.65(s,lH), 8.45(s,lH), 8.24(s,lH), 8.17(s,lH), 8.03(d,lH,J-8.8Hz), 7.75(s,2H), 7.71(d，lH,J=8.8Hz), 7.51(s,lH), X HNMR (400MHz, CD30D - ): S9.87(s,lH), 8.65(s,lH), 8.45(s,lH), 8.24(s,lH), 8.17(s,lH), 8.03(d, lH, J-8.8Hz), 7.75(s,2H), 7.71(d,lH,J=8.8Hz), 7.51(s,lH),
7.38(m,lH), 7.08(m,3H), 6.96(s,lH), 6.72(s,lH)， 5.72(s,2H), 4.18(m,2H), 3.10(m,2H), 2.75(m,4H), 1.77(m,4H) 实施例 176 7.38(m,lH), 7.08(m,3H), 6.96(s,lH), 6.72(s,lH), 5.72(s,2H), 4.18(m,2H), 3.10(m,2H), 2.75 (m, 4H), 1.77 (m, 4H) Example 176
Γ3-氯 -4-(3-氟-苄氧基) -苯基 1-{6-「1-(2-甲磺酰基-乙基) -1H-吡咯 -3-基 1-喹唑啉 -4- 基} -胺  3-chloro-4-(3-fluoro-benzyloxy)-phenyl 1-{6-"1-(2-methanesulfonyl-ethyl)-1H-pyrrol-3-yl-1-quinazoline- 4-yl}-amine
Figure imgf000182_0002
Figure imgf000182_0002
176a
Figure imgf000183_0001
第一步 176a
Figure imgf000183_0001
first step
甲磺酸 2-甲磺酰基乙酯  Methanesulfonic acid 2-methanesulfonyl ethyl ester
将 2-甲磺酰基乙醇 (248 mg， 2 mmol)溶于 10 mL千燥的二氯甲垸中，搅拌下加 入吡啶 (316 mg， 4 mmol), 将溶液冷却至 0°C， 加入甲磺酰氯 (344 mg， 3 mmol), 混合液升至室温， 撹拌 2小时反应完毕。 将反应液减压下浓缩， 在残留物中加入 15 mL水， 用乙酸乙酯萃取， 合并的有机相依次通过饱和氯化钠溶液洗涤 (10 mL X 2)，无水硫酸钠干燥，过滤，减压下浓缩，得到甲磺酸 2-甲磺酰基乙酯 176a (240 mg， 淡黄色固体)， 产率： 60%。  2-Methanesulfonylethanol (248 mg, 2 mmol) was dissolved in 10 mL of dry dichloromethane, pyridine (316 mg, 4 mmol) was added with stirring, and the solution was cooled to 0 ° C. The acid chloride (344 mg, 3 mmol) was added to the mixture at room temperature and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. Concentration under reduced pressure gave 2-methanesulfonyl methanesulfonate 176a (240 mg, pale yellow solid).
MS m/z (ESI): 203[M+ 1] MS m/z (ESI): 203 [M+ 1]
第二步  Second step
[3-氯 -4-(3-氟-苄氧基) -苯基 ]-{6-[1-(2-甲磺酰基-乙基) -1H-吡咯 -3-基] -喹唑啉 -4-基 胺  [3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-{6-[1-(2-methanesulfonyl-ethyl)-1H-pyrrol-3-yl]-quinazoline -4-ylamine
在 25 mL的单口烧瓶中，将 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-[6-(1Η-吡咯 -3-基) -喹唑 啉 -4-基] -胺 42 (89 mg， 0.2 mmol)溶于 3 mLN,N-二甲基甲酰胺中，在冰浴条件下， 冷却至 0°C，· 加入氢化钠 (24 mg, 1 mmol), 搅拌 30分钟后逐渐滴加甲磺酸 2-甲磺 酰基乙酯（49 mg， 0.24 mmol),室温下搅拌 4小时反应完毕。反应液中加入 10 mL 水， 用乙酸乙酯萃取 (10 mLX4)， 合并的有机相依次通过饱和氯化钠溶液洗涤， 无 水硫酸钠干燥， 过滤， 减压下浓缩， 得到的残留物通过硅胶柱层析进一步分离纯 化 (二氯甲烷： 甲醇 =5: 2), 得到本标题产物 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-{6-[1-(2- 甲磺酰基-乙基) -1H-吡咯 -3-基] -喹唑啉 -4-基 胺 176 (60 mg， 淡黄色固体)， 产率： 54%。  [3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1Η-pyrrol-3-yl)-quinazolin-4-yl in a 25 mL single-necked flask - Amine 42 (89 mg, 0.2 mmol) was dissolved in 3 mL of N-N-dimethylformamide, cooled to 0 ° C under ice-cooling, and sodium hydride (24 mg, 1 mmol) was added and stirred After 30 minutes, 2-methanesulfonyl methanesulfonate (49 mg, 0.24 mmol) was gradually added dropwise, and the mixture was stirred at room temperature for 4 hours. 10 ml of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL EtOAc). Further separation and purification by column chromatography (dichloromethane:methanol = 5: 2) gave the title product [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-{6-[1-( 2-Methanesulfonyl-ethyl)-1H-pyrrol-3-yl]-quinazolin-4-ylamine 176 (60 mg, pale yellow solid), yield: 54%.
MS m/z (ESI): 551[M+ 1]  MS m/z (ESI): 551 [M+ 1]
1H NMR(400 MHz ,DMSO-d6): 59.70(s, lH),8.55(s, lH),8.50(s， lH),8.05(m, 1H), 8.02(m, lH),7.73(m, 2H),7.52(m, 2H),7.34(m, 3H),7.19(m, lH),7.01(s, lH),6.72(s, lH),5.27(s, 2H),4.40(t, 2H),3.72(t, 2H),2.82(s, 3H) 实施例 177 1H NMR (400 MHz, DMSO-d 6 ): 59.70 (s, lH), 8.55 (s, lH), 8.50 (s, lH), 8.05 (m, 1H), 8.02 (m, lH), 7.73 (m) , 2H), 7.52 (m, 2H), 7.34 (m, 3H), 7.19 (m, lH), 7.01 (s, lH), 6.72 (s, lH), 5.27 (s, 2H), 4.40 (t, 2H), 3.72 (t, 2H), 2.82 (s, 3H). Example 177
「3-氯 -4-(3-氟-苄氧基 -苯基 l- -U-「2- (四氢呋喃 -2-基氧基) -乙基 1-lH-吡咯 -3-基 喹唑啉 -4-基) -胺 "3-Chloro-4-(3-fluoro-benzyloxy-phenyll--U-"2-(tetrahydrofuran-2-yloxy)-ethyl 1-lH-pyrrol-3-ylquinazoline -4-yl)-amine
Figure imgf000184_0001
将 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-[6-(1Η-吡咯 -3-基) -喹唑啉 -4-基] -胺 42 (120 mg， 0.27 mmol)和氢化钠 (32.4 mg， 0.81 mmol)溶于 10 mLN,N-二甲基甲酰胺中， 室温 下搅拌 30分钟后加入 2-(2-溴乙氧基) -四氢吡喃 (70 mg， 0.3 mmol), 室温下搅拌 30 分钟后反应完毕。在反应液中加入 100 mL饱和氯化钠溶液淬灭反应， 用乙酸乙酯 萃取 (100 mLX 3)， 合并的有机相用无水硫酸钠干燥， 过滤， 减压下浓缩， 得到的 残留物通过硅胶柱层析进一步分离纯化， 得到标题产物 [3-氯 -4-(3-氟-苄氧基) -苯 基] -(6-{1-[2- (四氢呋喃 -2-基氧基)-乙基] -1H-吡咯 -3-基}-喹唑啉 -4-基) -胺 177(190 mg， 黄色固体)， 产率： 55.2%。
Figure imgf000184_0001
[3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1Η-pyrrol-3-yl)-quinazolin-4-yl]-amine 42 (120 mg, 0.27 mmol) and sodium hydride (32.4 mg, 0.81 mmol) were dissolved in 10 mL of N,N-dimethylformamide, stirred at room temperature for 30 min and then added 2-(2-bromoethoxy)-tetrahydropyran ( 70 mg, 0.3 mmol), the reaction was completed after stirring at room temperature for 30 minutes. The reaction mixture was quenched with aq. EtOAc (EtOAc) (EtOAc) Further separation and purification by silica gel column chromatography gave the title product [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-{1-[2-(tetrahydrofuran-2-yloxy) -ethyl]-1H-pyrrol-3-yl}-quinazolin-4-yl)-amine 177 (190 mg, yellow solid), yield: 55.2%.
MS m/z (ESI): 573 [M+ 1] MS m/z (ESI): 573 [M+ 1]
1H NMR (400 MHz, DMSO-d6): δ 9.69 (s, IH), 8.54 (s, IH), 8.50 (s, IH), 8.05 (s, IH), 8.03 (d, J = 8.8Hz, IH), 7.76 (d, J = 8.8Hz, IH), 7.70 (d, J = 8.8Hz, IH), 7.50 (t, J = 8.8Hz, IH), 7.43 (s， IH), 7.33 (m, 3H), 7.19 (t， J = 8.8Hz, IH), 6.93 (s, IH), 6.67 (s, IH), 5.27 (s, 2H), 4.57 (br, 1H)， 4.14 (br, 2H), 3.90 (br, IH), 3.70 (br, IH), 3.57 (m, 2H); 2.90 (br, IH), 2.74 (br, IH), 1.38 (br, 4H) 实施例 178 1H NMR (400 MHz, DMSO-d6): δ 9.69 (s, IH), 8.54 (s, IH), 8.50 (s, IH), 8.05 (s, IH), 8.03 (d, J = 8.8 Hz, IH ), 7.76 (d, J = 8.8Hz, IH), 7.70 (d, J = 8.8Hz, IH), 7.50 (t, J = 8.8Hz, IH), 7.43 (s, IH), 7.33 (m, 3H) ), 7.19 (t, J = 8.8Hz, IH), 6.93 (s, IH), 6.67 (s, IH), 5.27 (s, 2H), 4.57 (br, 1H), 4.14 (br, 2H), 3.90 (br, IH), 3.70 (br, IH), 3.57 (m, 2H) ; 2.90 (br, IH), 2.74 (br, IH), 1.38 (br, 4H) Example 178
1-(3-{4-「1-(3-氟-苄基) -IH-吲唑 -5-基氨基 1-喹唑啉 -6-基 吡咯 -1-基) -3-吗啉 -4-基-丙  1-(3-{4-"1-(3-Fluoro-benzyl)-IH-indazol-5-ylamino-1-quinazolin-6-ylpyrrol-1-yl)-3-morpholine- 4-base-propyl
-2-醇  -2-ol
Figure imgf000184_0002
Figure imgf000184_0002
Figure imgf000185_0001
第一步
Figure imgf000185_0001
first step
[l-(3-氟-苄基) -1H-吲唑 -5-基] -[6-(1-环氧乙基甲基 -1H-吡咯 -3-基) -喹唑啉 -4-基] -胺 在 100 mL茄形瓶中， 将 {6-[1-(2-二乙氨基-乙基) -1H-吡咯 -3-基]-喹唑啉 -4- 基}-[1-(3-氟苄基 )-1Η-吲唑 -5-基] -胺 150 (1.3 g, 3 mmol)溶于 30 mL的 Ν,Ν-二甲基 甲酰胺中， 冰浴冷却至 0°C， 加入氢化钠 (1 g， 6.6 mmol), 搅拌 30分钟后， 室温 下加入环氧氯丙烷 (0.42 mL, 5.35 mmol), 2小时后反应完毕。将反应液倒入 100 mL 冰水中， 有固体析出， 得到 [1-(3-氟-苄基) -1H-吲唑 -5-基] -[6-(1-环氧乙基甲基 -1H- 吡咯 -3-基)-喹唑啉 -4-基] -胺 178a (1.8 g，黄色固体)，产物不经分离直接进行下一步 反应。  [l-(3-Fluoro-benzyl)-1H-indazol-5-yl]-[6-(1-Epoxyethylmethyl-1H-pyrrol-3-yl)-quinazoline-4- {6-[1-(2-diethylamino-ethyl)-1H-pyrrol-3-yl]-quinazolin-4-yl}-[1] in a 100 mL eggplant-shaped flask -(3-Fluorobenzyl)-1Η-indazol-5-yl]-amine 150 (1.3 g, 3 mmol) dissolved in 30 mL of hydrazine, dimethyl-dimethylformamide, cooled to 0 ° C. After adding sodium hydride (1 g, 6.6 mmol), and stirring for 30 minutes, epichlorohydrin (0.42 mL, 5.35 mmol) was added at room temperature, and the reaction was completed after 2 hours. The reaction solution was poured into 100 mL of ice water, and a solid precipitated to give [1-(3-fluoro-benzyl)-1H-indazol-5-yl]-[6-(1-epoxyethylmethyl- 1H-Pyrrol-3-yl)-quinazolin-4-yl]-amine 178a (1.8 g, yellow solid).
MS m/z (ESI): 491 [M+ 1]  MS m/z (ESI): 491 [M+ 1]
!ΗΝΜΚ (400MHz, CD30D- )： 58.68(s,lH), 8.16(s,lH), 8.10(s,lH), 8.06(s,2H), 7.99(d,lH,J=8.8Hz), 7.90(d,lH,J=8.8Hz), 7.65(d,lH,J=8.8Hz), 7.39(d,lH,J=8.8Hz), 7.34(m,lH), 7.20(s,lH), 7.02(m,2H), 6.92(d,lH,J=9.6Hz), 6.80(s,lH), 6.62(s,lH), 5.63(s,2H), 4.29(m,lH), 3.98(m,lH), 3.33(m,lH), 2.90(m,lH), 2.56(m,lH) ! 400 (400MHz, CD30D- ): 58.68(s,lH), 8.16(s,lH), 8.10(s,lH), 8.06(s,2H), 7.99(d,lH,J=8.8Hz), 7.90 (d, lH, J = 8.8 Hz), 7.65 (d, lH, J = 8.8 Hz), 7.39 (d, lH, J = 8.8 Hz), 7.34 (m, lH), 7.20 (s, lH), 7.02 (m, 2H), 6.92 (d, lH, J = 9.6 Hz), 6.80 (s, lH), 6.62 (s, lH), 5.63 (s, 2H), 4.29 (m, lH), 3.98 (m, lH), 3.33(m,lH), 2.90(m,lH), 2.56(m,lH)
第二步  Second step
1-(3-{4-[1-(3-氟-苄基) -1H-吲唑 -5-基氨基]-喹唑啉 -6-基 吡咯 -1-基) -3-吗啉 -4-基-丙  1-(3-{4-[1-(3-Fluoro-benzyl)-1H-indazol-5-ylamino]-quinazolin-6-ylpyrrol-1-yl)-3-morpholine- 4-base-propyl
-2-醇  -2-ol
, 在 100 mL茄形瓶中， 将 [1-(3-氟-苄基) -1H-吲唑 -5-基] -[6-(1-环氧乙基甲基 -1H- 吡咯 -3-基) -喹唑啉 -4-基] -胺 178a (1.8 g， 3.67mmol)溶于 40 mL甲醇中， 搅拌下加 入吗啉 (510 mg， 5.87mmol), 反应液加热回流过夜。将反应液在减压下浓缩， 得到 的残留物通过硅胶柱层析进一歩分离纯化， 得到本标题产物 1-(3-{4-[1-(3-氟-苄 基) -1H-吲唑 -5-基氨基] -喹唑啉 -6-基 吡咯小基 )-3-吗啉 -4-基-丙 -2-醇 178(600 mg， 黄色固体） ， 产率： 35.3 %。  , [1-(3-Fluoro-benzyl)-1H-indazol-5-yl]-[6-(1-epoxyethylmethyl-1H-pyrrole-3) in a 100 mL eggplant-shaped flask Methyl- quinazolin-4-yl]-amine 178a (1.8 g, 3.67 mmol) was dissolved in 40 mL MeOH. The reaction mixture was concentrated under reduced pressure. EtOAc mjjjjjjjjj Zyrid-5-ylamino]-quinazolin-6-ylpyrrole small)-3-morpholin-4-yl-propan-2-ol 178 (600 mg, yellow solid), yield: 35.3 %.
MS m/z (ESI): 578[M+ 1]  MS m/z (ESI): 578 [M+ 1]
^MR (400MHz, CD30D-4): 59.82(s,lH), 8.60(s,lH), 8.44(s,lH), 8.23(s,lH), 8.17(s,lH), 8.03(d,lH,J=8.8Hz),7.73(m,3H), 7.43(s,lH), 7.38(m,lH), 7.10(m,3H), 6.88(s,lH), 6.67(s,lH), 5.72(s,2H), 4.96(s,lH), 3.97(m,3H), 3.61(m,4H), 2.43(m,4H), 2.26(m，2H) 实施例 179^MR (400MHz, CD30D-4): 59.82(s,lH), 8.60(s,lH), 8.44(s,lH), 8.23(s,lH), 8.17(s,lH), 8.03(d,lH , J = 8.8 Hz), 7.73 (m, 3H), 7.43 (s, lH), 7.38 (m, lH), 7.10 (m, 3H), 6.88 (s, lH), 6.67 (s, lH), 5.72 (s, 2H), 4.96 (s, lH), 3.97 (m, 3H), 3.61 (m, 4H), 2.43 (m, 4H), 2.26 (m, 2H) Example 179
3-{4-「1-(3-氟-苄基) -1H-吲唑 -5-基氨基 1-喹唑啉 -6-基 吡咯 -1-基 -3-(2-甲磺酰基- 乙氨基) -丙 -2-醇  3-{4-"1-(3-Fluoro-benzyl)-1H-indazol-5-ylamino-1-quinazolin-6-ylpyrrolidin-1-yl-3-(2-methanesulfonyl- Ethylamino)-propan-2-ol
Figure imgf000186_0001
Figure imgf000186_0001
在 100 mL茄形瓶中， 将 [1-(3-氟-苄基) -1H-吲唑 -5-基] -[6-(1-环氧乙基甲基 -1H- 吡咯 -3-基) -喹唑啉 -4-基] -胺 178a (134 g， 0.27 mmol)溶于 10 mL甲醇中， 搅拌下 加入 2-甲磺酰基乙胺盐酸盐 (66 mg, 0.47mmol)和 0.3 mL三乙胺， 反应液加热回流 过夜。 将反应液在减压下浓缩， 得到的残留物通过硅胶柱层析进一步分离纯化， 得到本标题产物 1-(3-{4-[1-(3-氟-苄基) -1H-吲唑 -5-基氨基] -喹唑啉 -6-基}-吡咯 -1- 基) -3-(2-甲磺酰基-乙氨基) -丙 -2-醇 179 (29 mg， 黄色固体） ， 产率： 17.5 %。  [1-(3-Fluoro-benzyl)-1H-indazol-5-yl]-[6-(1-epoxyethylmethyl-1H-pyrrole-3- in a 100 mL eggplant-shaped flask - quinazolin-4-yl]-amine 178a (134 g, 0.27 mmol) was dissolved in 10 mL of methanol, and then added with 2-methanesulfonylethylamine hydrochloride (66 mg, 0.47 mmol) and 0.3 In a solution of mL triethylamine, the reaction mixture was heated to reflux overnight. The reaction mixture was concentrated under reduced pressure. EtOAc m m m m m -5-ylamino]-quinazolin-6-yl}-pyrrol-1-yl)-3-(2-methanesulfonyl-ethylamino)-propan-2-ol 179 (29 mg, yellow solid) Yield: 17.5 %.
MS m/z (ESI): 614[M+ 1] MS m/z (ESI): 614 [M+ 1]
^MR (400MHz, CD30D-t 6): 59.96(s,lH), 8.69(s,lH), 8.44(s,lH), 8.24(s,lH), 8.17(s,lH), 8.04(d,lH,J=8.8Hz), 7.76(s,2H), 7.69(d,lH,J=8.8Hz), 7.48(s,lH), ^MR (400MHz, CD30D-t 6 ): 59.96(s,lH), 8.69(s,lH), 8.44(s,lH), 8.24(s,lH), 8.17(s,lH), 8.04(d, lH, J=8.8Hz), 7.76(s,2H), 7.69(d,lH,J=8.8Hz), 7.48(s,lH),
7.38(m,lH), 7.08(m,3H), 6.90(s,lH), 6.72(s,lH), 5.72(s,2H), 4.10(m,3H), 3.39(m,4H), 3.12(m,3H), 2.91(m,2H) 实施例 180 7.38(m,lH), 7.08(m,3H), 6.90(s,lH), 6.72(s,lH), 5.72(s,2H), 4.10(m,3H), 3.39(m,4H), 3.12 (m, 3H), 2.91 (m, 2H) Example 180
3-(3_{4-「3-氯 _4-( _氟-苄氧基 苯氨基 1-喹唑啉 -6-基 吡咯 -1-基) -丙烷 -1,2-二醇三氟 乙酸盐 3- (3_{ 4 -"3-Chloro- 4 -(-fluoro-benzyloxyphenylamino-1-quinazolin-6-ylpyrrol-1-yl)-propane-1,2-diol trifluoroethyl Acid salt
Figure imgf000186_0002
Figure imgf000187_0001
在 100 mL茄形瓶中， 将 [1-(3-氟- 基) -1H-吲唑 -5-基] -[6-(1-环氧乙基甲基 -1Η- 吡咯 -3-基) -喹唑啉 -4-基] -胺 178a (130 g， 0.25 mmol)溶于 10 mL二氧六环中， 搅 拌下加入 1 mL三氟醋酸和 1 mL水， 将反应液加热至 80°C， 2小时后反应完毕。 将反应液在减压下浓缩，得到的残留物通过硅胶柱层析进一步分离纯化 (二氯甲烷: 甲醇 =20: 1)， 得到本标题产物 3-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基]-喹唑啉 -6- 基}-吡咯小基) -丙烷 -1,2-二醇三氟乙酸盐 180 (158 mg， 黄色固体） ， 产率： 100%。 MS m/z (ESI): 519[M+ 1]
Figure imgf000186_0002
Figure imgf000187_0001
[1-(3-Fluoro-yl)-1H-indazol-5-yl]-[6-(1-epoxyethylmethyl-1Η-pyrrol-3-yl) in a 100 mL eggplant-shaped flask - quinazolin-4-yl]-amine 178a (130 g, 0.25 mmol) dissolved in 10 mL of dioxane, 1 mL of trifluoroacetic acid and 1 mL of water were added with stirring, and the reaction was heated to 80 ° C, the reaction was completed after 2 hours. The reaction mixture was concentrated under reduced pressure. EtOAc mjjjjjjj 4-(3-Fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-pyrroleyl)-propane-1,2-diol trifluoroacetate 180 (158 mg, yellow solid ), Yield: 100%. MS m/z (ESI): 519 [M+ 1]
1HNMR (400 MHz, CD30D-^): δ 8.60 (s, 1H), 8.58 (s, 1H), 8.19 (d, 1H), 7.71 (d, 1H): 7.60 (d, 1H), 7.41 (m, 1H), 7.32 (d, 1H), 7.29 (m, 1H), 7.15 (d, 1H), 7.05 (m, 1H)6.86 (s, 1H), 6.80 (s, 1H), 5.24 (s, 2H), 4.15 (d, 1H), 3.95 (d, 1H), 3.90 (m,lH), 3.66 (s， 1H),3.51 (d, 2H) 实施例 181  1HNMR (400 MHz, CD30D-^): δ 8.60 (s, 1H), 8.58 (s, 1H), 8.19 (d, 1H), 7.71 (d, 1H): 7.60 (d, 1H), 7.41 (m, 1H), 7.32 (d, 1H), 7.29 (m, 1H), 7.15 (d, 1H), 7.05 (m, 1H) 6.86 (s, 1H), 6.80 (s, 1H), 5.24 (s, 2H) , 4.15 (d, 1H), 3.95 (d, 1H), 3.90 (m, lH), 3.66 (s, 1H), 3.51 (d, 2H) Example 181
「3-氯 -4-(3-氟-苄氧基) -苯基 1-{6-「1-(2-哌啶小基-乙基) -1H-吡咯 -3-基 1-喹唑啉 -4-基 "3-Chloro-4-(3-fluoro-benzyloxy)-phenyl 1-{6-"1-(2-piperidinyl-ethyl)-1H-pyrrol-3-yl-1-quinazole Porphyrin-4-yl
Figure imgf000187_0002
将 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-[6-(1Η-吡咯 -3-基) -喹唑啉 -4-基] -胺 42 (230 mg， 0. 5 mmol)和氢化钠 (113 mg， 2.5 mmol)溶于 10 mL N,N-二甲基甲酰胺中， 室 温下搅拌 30分钟后加入 1-(2-氯乙基) -哌啶盐酸盐 (70.5 mg， 0.3 mmol), 加热至 50 °C， 2小时后反应完毕。在反应液中加入 200 mL水和 200 mL, 分液， 水相用乙酸 乙酯 (200 mLX 3)萃取， 合并的有机相依次通过饱和氯化钠溶液洗涤， 无水硫酸钠 干燥， 过滤， 减压下浓缩， 得到的残留物通过硅胶柱层析进一步分离纯化， 得到 标题产物 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-{6-[1-(3-哌啶 -1-基-丙基) -1H-吡咯 -3-基] -喹唑 啉 -4-基} -胺 181(65 mg， 桔黄色固体)， 产率： 21 %。 MS m/z (ESI): 557[M+ 1]
Figure imgf000187_0002
[3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1Η-pyrrol-3-yl)-quinazolin-4-yl]-amine 42 (230 mg, 0. 5 mmol) and sodium hydride (113 mg, 2.5 mmol) dissolved in 10 mL of N,N-dimethylformamide, stirred at room temperature for 30 min then added 1-(2-chloroethyl)-piperidine salt The acid salt (70.5 mg, 0.3 mmol) was heated to 50 ° C and the reaction was completed after 2 hours. Add 200 mL of water and 200 mL to the reaction solution, and separate the liquid. The aqueous phase is extracted with ethyl acetate (200 mL×3). The combined organic phases are washed sequentially with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, reduced Concentration under reduced pressure, and the residue obtained was purified by silica gel column chromatography to give the title product [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-{6-[1-(3- Piperidin-1-yl-propyl)-1H-pyrrol-3-yl]-quinazolin-4-yl}-amine 181 (65 mg, orange solid). Yield: 21%. MS m/z (ESI): 557 [M+ 1]
1H NMR (400 MHz, CD30D-^): δ 9.68 (s, 1H), 8.53 (s， 1H), 8.50 (s, 1H), 8.05 (s, 1H); 8.02 (d, J = 8.8Hz, 1H), 7.85 (d, J = 8.8Hz, 1H), 7.69 (d, J = 8.8Hz, 1H), 7.54 (t, J = 8.8Hz, 1H), 7.42 (s, 1H), 7.32 (m, 3H), 7.19 (t, J = 8.8Hz, 1H), 6.92 (s, 1H), 6.65 (s, 1H)， 5.27 (s, 2H), 3.96 (br, 2H), 2.70 (br, 2H), 2.42 (br, 4H), 1.51 (m, 4H), 1.20 (m, 2H) 实施例 182 1H NMR (400 MHz, CD30D-^): δ 9.68 (s, 1H), 8.53 (s, 1H), 8.50 (s, 1H), 8.05 (s, 1H) ; 8.02 (d, J = 8.8Hz, 1H ), 7.85 (d, J = 8.8Hz, 1H), 7.69 (d, J = 8.8Hz, 1H), 7.54 (t, J = 8.8Hz, 1H), 7.42 (s, 1H), 7.32 (m, 3H) ), 7.19 (t, J = 8.8Hz, 1H), 6.92 (s, 1H), 6.65 (s, 1H), 5.27 (s, 2H), 3.96 (br, 2H), 2.70 (br, 2H), 2.42 (br, 4H), 1.51 (m, 4H), 1.20 (m, 2H) Example 182
Γ3-氯 -4-(3-氟-苄氧基 苯基 1-ί6-Γ1-(3-吗啉 -4-基-丙基 1H-吡咯 -3-基 1-喹唑啉 -4-基  Γ3-Chloro-4-(3-fluoro-benzyloxyphenyl 1-ί6-Γ1-(3-morpholin-4-yl-propyl 1H-pyrrol-3-yl-1-quinazolin-4-yl
Figure imgf000188_0001
将化合物 [3-氯 -4-( 氟-苄氧基) -苯基 ]-|;6-(lH-吡咯 -3-基) -喹唑啉 -4-基] -胺 42 (654 mg, 1.48 mmol)溶于 5 mLN,N-二甲基甲酰胺中， 在干冰乙醇浴冷却下加入氢 化钠 (176 mg， 4.43 mmol), 搅拌 30分钟后加入 4-(3-溴丙基) -吗啉（367 mg， 1.77 mmol), 升至室温搅拌过夜。 反应液在减压下浓缩， 得到的残留物通过硅胶柱层析 进一步分离纯化， 得到标题产物 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-{6-[1-(3-吗啉 -4-基-丙 基) -1H-吡咯 -3-基] -喹唑啉 -4-基} -胺 182(110 mg， 淡黄色固体)， 产率： 13 %。
Figure imgf000188_0001
The compound [3-chloro-4-(fluoro-benzyloxy)-phenyl]-|; 6-(lH-pyrrol-3-yl)-quinazolin-4-yl]-amine 42 (654 mg, 1.48 mmol) was dissolved in 5 mL of N,N-dimethylformamide. Sodium hydride (176 mg, 4.43 mmol) was added in a dry ice ethanol bath. After stirring for 30 minutes, 4-(3-bromopropyl)-? The porphyrin (367 mg, 1.77 mmol) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. -(3-morpholin-4-yl-propyl)-lH-pyrrol-3-yl]-quinazolin-4-yl}-amine 182 (110 mg, pale yellow solid), yield: 13%.
MS m/z (ESI): 572[M+1]  MS m/z (ESI): 572 [M+1]
1H NMR (400 MHz, CD30D-^): δ 9.67 (s,lH), 8.8(s,lH),8.5 (s,lH), 8.03(d, J=8.8Hz, 2H), 7.76(dd,J=2Hz,lH), 7.70(d,J=8.4Hz,lH), 7.5(m， 2H), 7.36(m,3H), 7.2(s,lH), 6.93(s,lH), 6.60(s,lH),5.27(s,2H), 4.0(t,J=14Hz,2H), 3.67(m,4H), 2.51(m,4H),  1H NMR (400 MHz, CD30D-^): δ 9.67 (s, lH), 8.8 (s, lH), 8.5 (s, lH), 8.03 (d, J = 8.8 Hz, 2H), 7.76 (dd, J =2 Hz, lH), 7.70 (d, J = 8.4 Hz, lH), 7.5 (m, 2H), 7.36 (m, 3H), 7.2 (s, lH), 6.93 (s, lH), 6.60 (s, lH), 5.27 (s, 2H), 4.0 (t, J = 14 Hz, 2H), 3.67 (m, 4H), 2.51 (m, 4H),
2.27(m,2H),1.9(m,2H) 实施例 183  2.27 (m, 2H), 1.9 (m, 2H) Example 183
2-(3-i4-D-氯 -4-(3-氟-苄氧某 苯氨基 1-喹唑啉 -6-基 吡咯 -1-基 I- 吗啉 基 -乙酮  2-(3-i4-D-chloro-4-(3-fluoro-benzyloxy)phenylamino-1-quinazolin-6-ylpyrrole-1-yl I-morpholinyl-ethanone
Figure imgf000188_0002
Figure imgf000189_0001
将 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-[6-(1Η-吡咯 -3-基) -喹唑啉 -4-基] -胺 42 (100 mg, 0.225 mmol)和氢化钠 （27 mg， 0.675 mmol)溶于 10 mL N,N-二甲基甲酰胺 中， 室温下搅拌 30分钟后加入 2-氯 -1-吗啉 -4-基 -乙酮（44 mg， 0.27 mmol), 搅拌 30分钟后反应完毕。在反应液中加入 100 mL饱和氯化钠溶液淬灭反应，水相用乙 酸乙酯萃取 (100 mL X 3)， 合并的有机相依次通过水 (100 mL X 3)洗涤， 饱和氯化钠 溶液洗涤， 无水硫酸钠干燥， 过滤， 减压下浓缩， 得到的残留物通过硅胶柱层析 进一歩分离纯化， 得到标题产物 2-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6- 基} -吡咯 -1-基) -1-吗啉 -4-基 -乙酮 183(50 mg， 黄色固体)， 产率： 38.9 %。
Figure imgf000188_0002
Figure imgf000189_0001
[3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1Η-pyrrol-3-yl)-quinazolin-4-yl]-amine 42 (100 mg, 0.225 mmol) and sodium hydride (27 mg, 0.675 mmol) dissolved in 10 mL of N,N-dimethylformamide, stirred at room temperature for 30 min, then added 2-chloro-1-morpholin-4-yl-ethanone (44 mg, 0.27 mmol), the reaction was completed after stirring for 30 minutes. The reaction mixture was quenched by the addition of 100 mL of saturated sodium chloride solution. The aqueous phase was extracted with ethyl acetate (100 mL X 3), and the combined organic phases were washed sequentially with water (100 mL X 3), saturated sodium chloride solution The organic layer was dried (MgSO4jjjjjjjjjjjj Fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-pyrrol-1-yl)-1-morpholin-4-yl-ethanone 183 (50 mg, yellow solid), yield: 38.9 %.
MS m/z (ESI): 573[M+ 1] MS m/z (ESI): 573 [M+ 1]
1H NMR (400 MHz, CD30D-t¾)： δ 9.69(s , 1Η) , 8.53(s， 1H) δ 8.50(s , 1Η), 8.03 (d , J=8.8Hz , 2H) , 7.76(d , J=2Hz , 1Η) , 7.70(d , J=8.4Hz , 1Η) , 7.47(m, 2Η) , 7.32(m , 3Η) , 7.19(m , 1Η) , 6.94(s , 1Η) , 6.66(s , 1Η) , 5.27(s , 2Η) , 4.06(m， 2Η) , 3.58(m , 4Η) , 2.45(br , 4Η) 实施例 184  1H NMR (400 MHz, CD30D-t3⁄4): δ 9.69 (s, 1 Η), 8.53 (s, 1H) δ 8.50 (s , 1 Η), 8.03 (d , J = 8.8 Hz , 2H) , 7.76 (d , J =2Hz , 1Η) , 7.70(d , J=8.4Hz , 1Η) , 7.47(m, 2Η) , 7.32(m , 3Η) , 7.19(m , 1Η) , 6.94(s , 1Η) , 6.66(s , 1Η) , 5.27(s , 2Η) , 4.06(m, 2Η) , 3.58(m , 4Η) , 2.45(br , 4Η) Example 184
4-{4-「3-氯 -4-(3-氟-苄氧基 苯氨基 1-喹唑啉 -6-基 }-1Η-吡咯 -2-羧酸（2-甲磺酰基-乙  4-{4-"3-Chloro-4-(3-fluoro-benzyloxyphenylamino-1-quinazolin-6-yl}-l-pyrrole-2-carboxylic acid (2-methanesulfonyl-B
Figure imgf000189_0002
Figure imgf000190_0001
第一步
Figure imgf000189_0002
Figure imgf000190_0001
first step
2,2,2-三氟- 1 -( 1 H-吡咯 -2-基)-甲酮  2,2,2-trifluoro-1 -( 1 H-pyrrol-2-yl)-methanone
将吡咯 (23.8 mL， 345 mmol)溶于 lOO mL乙醚中，用恒压滴液漏斗缓慢滴加到 氯乙酰氯 (41.9 mL， 375 mmol)的 lOO mL乙醚溶液中， 滴加过程中有热量放出， 用 冰浴冷却， 滴加完毕后， 反应液在室温下搅拌 1.5 小时后， 用恒压滴液漏斗滴加 80 mL碳酸钾 (30 g， 217 mmol)溶液， 有大量气泡冒出。 滴加完毕后， 有机相通过 无水硫酸钠干燥， 减压下蒸掉溶剂， 残留物用正己垸溶解， 过滤， 得到 2,2,2-三氟 -1-(1H-吡咯 -2-基) -甲酮 184a (55.4g， 灰白色固体)， 产率： 75.6%。  The pyrrole (23.8 mL, 345 mmol) was dissolved in 100 mL of diethyl ether, and slowly added dropwise to a solution of chloroacetyl chloride (41.9 mL, 375 mmol) in 100 mL of diethyl ether using a constant pressure dropping funnel, and heat was released during the dropwise addition. After cooling with an ice bath, the reaction mixture was stirred at room temperature for 1.5 hours, and then a solution of 80 mL of potassium carbonate (30 g, 217 mmol) was added dropwise with a constant pressure dropping funnel, and a large amount of air bubbles appeared. After the completion of the dropwise addition, the organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in n-hexane and filtered to give 2,2,2-trifluoro-1-(1H-pyrrol-2-yl) - ketone 184a (55.4 g, off-white solid), Yield: 75.6%.
第二步  Second step
2,2,2-三氟 - 1 -(4-碘- 1 H-吡咯 -2-基) -甲酮  2,2,2-trifluoro-1 -(4-iodo-1 H-pyrrol-2-yl)-methanone
将 2,2,2-三氟 -1-(1H-吡咯 -2-基) -甲酮 184a (32.1 g， 151 mmol)溶于 150 mL重蒸 的二氯甲烷中， 搅拌下滴加氯化碘 (25 g， 153.8 mmol)的 80 mL二氯甲垸溶液中， 滴加完毕后， 反应液在室温下搅拌 2小时后， 加入 100 mL 10%碳酸钾溶液淬灭反 应， 分液， 有机相依次用 100 mL 1 N亚硫酸钠溶液和 100 mL水和饱和氯化钠溶 液洗涤， 无水硫酸钠干燥， 过滤， 减压下浓缩， 得到粗品 2,2,2-三氟 -1-(4-碘 -1H- 吡咯 -2-基) -甲酮 184b (50.78g， 白色固体)， 产物不经分离直接进行下一步反应。  Dissolve 2,2,2-trifluoro-1-(1H-pyrrol-2-yl)-methanone 184a (32.1 g, 151 mmol) in 150 mL of re-distilled dichloromethane and add chlorination with stirring Iodine (25 g, 153.8 mmol) in 80 mL of dichloromethane solution, after the addition was completed, the reaction solution was stirred at room temperature for 2 hours, then added with 100 mL of 10% potassium carbonate solution to quench the reaction, liquid separation, organic phase-dependent It was washed with 100 mL of 1 N sodium sulfite solution and 100 mL of water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude 2,2,2-trifluoro-1-(4- -1H-pyrrol-2-yl)-methanone 184b (50.78 g, white solid).
第三步  third step
4-碘 -1H-吡咯 -2-甲酸甲酯  4-iodo-1H-pyrrole-2-carboxylic acid methyl ester
将粗品 2,2,2-三氟小 (4-碘- 1H-吡咯 -2-基) -甲酮 184b (50.78g)溶于 250 mL甲醇 中， 搅拌下滴加甲醇钠 (9.857g， 180 mmol)的 40 mL甲醇溶液， 滴加完毕后， 在室 温下搅拌 1 小时反应完毕。 将反应液在减压下浓缩， 残留物用甲基叔丁醚和水分 液， 有机相依次通过 50 mL水和饱和氯化钠溶液洗涤， 无水硫酸钠干燥， 过滤， 减压下浓缩， 得到粗品 4-碘 -1H-吡咯 -2-甲酸甲酯 184c (29.435g， 灰白色固体)， 产 物不经分离直接进行下一步反应。  The crude 2,2,2-trifluoromethane (4-iodo-1H-pyrrol-2-yl)-methanone 184b (50.78 g) was dissolved in methanol (250 mL), and sodium methoxide (9.857 g, 180) was added dropwise with stirring. Methyl) 40 mL of methanol solution, after completion of the dropwise addition, the reaction was completed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. EtOAc EtOAc m. Crude 4-iodo-1H-pyrrole-2-carboxylic acid methyl ester 184c (29.435 g, off-white solid).
第四步  the fourth step
4-碘小 (甲苯 _4—磺酰基 )_1H-吡咯 -2-甲酸甲酯 将粗品 4-碘 -1H-吡咯 -2-甲酸甲酯 184c (29.4g)溶于 180 mL二氯甲垸中， 搅拌 下依次加入三乙胺 (26 g， 258 mmol), 4-二甲氨基吡啶 (1.43g， 11.7 mmol)和对甲基 苯磺酰氯 (24.6 g， 129 mmol), 混合液在室温下搅拌过夜。 在反应液中加入 1N盐 酸溶液淬灭反应， 有机相依次通过饱和碳酸氢钠溶液， 饱和氯化钠溶液洗涤， 无 水硫酸钠干燥， 过滤， 减压下浓缩， 得到的残留物用硅胶柱层析分离纯化 (正己烷 和乙酸乙酯 =4: 1)，得到 4-碘 -1- (甲苯 -4-磺酰基) -1H-吡咯 -2-甲酸甲酯 184d (22.87g, 白色固体)。 4 -Iodo small (methyl toluene- 4 -sulfonyl)_1H-pyrrole-2-carboxylate The crude 4-iodo-1H-pyrrole-2-carboxylic acid methyl ester 184c (29.4 g) was dissolved in 180 mL of dichloromethane. Triethylamine (26 g, 258 mmol), 4-dimethylaminopyridine (1.43 g, 11.7 mmol) and p-toluenesulfonyl chloride (24.6 g, 129 mmol) were added successively with stirring, and the mixture was stirred at room temperature. overnight. The reaction mixture was quenched by the addition of 1N aqueous hydrochloric acid. The organic phase was washed with saturated sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Separation and purification (n-hexane And ethyl acetate = 4: 1) gave methyl 4-iodo-1-(toluene-4-sulfonyl)-1H-pyrrole-2-carboxylate 184d (22.87 g, white solid).
MS m/z (ESI): 405 [M+ l]  MS m/z (ESI): 405 [M+ l]
第五歩  Fifth
4-(4,4,5,5-四甲基 -[1 ,3,2]二氧硼戊环 -2-基) -1 -(甲苯 -4-磺酰基) -1H-吡咯 -2-甲酸甲酯 将 4-碘 -1- (甲苯 -4-磺酰基 )-1Η-吡咯 -2-甲酸甲酯 184d (4.05 g， 10 mmol), 双联 频那醇硼酸酯 (3.43 g， 13 mmol), 二氯 [1 , 1 '-二茂铁磷酸]钯 (746 mg， 1 mmol)和醋 酸钾 (3 g， 30 mmol)溶于 30 mL N,N-二甲基甲酰胺中， 用氩气氛下， 加入 l mL重 蒸的二氯甲烷中， 将反应液加热至 80°C， 搅拌 18小时后反应完毕。将反应液在减 压下浓缩， 得到的残渣用乙醚溶解， 过滤， 除去不溶物， 有机相依次通过 1 N盐 酸溶液，'水和饱和氯化钠溶液洗涤， 无水硫酸钠干燥， 过滤， 减压下浓缩， 得到 的残留物通过硅胶柱层析进一步分离纯化 (正己垸： 乙酸乙酯 = 10 : 1)， 得到 4-(4,4，5,5-四甲基 -[1,3,2]二氧硼戊环 -2-基) -1- (甲苯 -4-磺酰基) -1H-吡咯 -2-甲酸甲酯 184e (3.03 g, 白色固体)， 产率： 74.7%。  4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-1 -(toluene-4-sulfonyl)-1H-pyrrole-2- Methyl 4-formo-1-(toluene-4-sulfonyl)-1Η-pyrrole-2-carboxylic acid methyl ester 184d (4.05 g, 10 mmol), bis-pinacol borate (3.43 g, 13 Methyl) [dichloro [1 , 1 '-ferrocene phosphate] palladium (746 mg, 1 mmol) and potassium acetate (3 g, 30 mmol) in 30 mL of N,N-dimethylformamide Under an argon atmosphere, 1 mL of re-distilled dichloromethane was added, and the reaction liquid was heated to 80 ° C, and the reaction was completed after stirring for 18 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was evaporated, evaporated, evaporated, evaporated The mixture was concentrated under reduced pressure, and the obtained residue was purified and purified by silica gel column chromatography (yield: ethyl acetate = 10:1) to give 4-(4,4,5,5-tetramethyl-[1,3, 2] Dioxaborolan-2-yl)-1-(toluene-4-sulfonyl)-1H-pyrrole-2-carboxylic acid methyl ester 184e (3.03 g, white solid), yield: 74.7%.
MS m/z (ESI): 406[M+ 1] MS m/z (ESI): 406 [M+ 1]
第六歩  Sixth
4-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基 (甲苯基 -4-甲磺酰基) -1H-吡咯  4-{4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl (tolyl-4-methylsulfonyl)-1H-pyrrole
-2-甲酸甲酉旨  -2-carboxylic acid formazan
将 4-(4,4,5,5-四甲基 -[1，3，2]二氧硼戊环 -2-基) -1- (甲苯 -4-磺酰基) -1H-吡咯 -2-甲酸 甲酯 184e (2.91 g， 7.1 mmol)和 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-(6-碘-喹唑啉 -4-基) -胺 lg (3.53 g，7.1 mmol)溶于 30 mL N,N-二甲基甲酰胺中，搅拌下加入三苯基膦钯 (0.82 g， 0.71 mmol)和碳酸钾 (2.59 g， 17.75 mmol), 加入 10 mL水， 有白色不溶物析出， 加热反应液至 60 °C， 24小时后反应完毕。反应液中加入 100 mL水和 100 mL乙酸 乙酯， 分液， 有机相依次用水洗涤，' 饱和氯化钠溶液洗涤， 无水硫酸钠干燥， 过 滤， 减压下浓缩， 得到的残留物通过硅胶柱层析进一步分离纯化 (正己烷： 乙酸乙 酯 = 1 : 1)， 得到 4-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基 }-1- (甲苯基 -4-甲 磺酰基 )-1Η-吡咯 -2-甲酸甲酯 184f (3.45 g， 黄色固体)， 产率： 73.9%。  4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl)-1H-pyrrole-2 - methyl formate 184e (2.91 g, 7.1 mmol) and [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-iodo-quinazolin-4-yl)-amine lg (3.53 g, 7.1 mmol) was dissolved in 30 mL of N,N-dimethylformamide, and triphenylphosphine palladium (0.82 g, 0.71 mmol) and potassium carbonate (2.59 g, 17.75 mmol) were added with stirring. In the mL water, white insoluble matter was precipitated, and the reaction solution was heated to 60 ° C. After 24 hours, the reaction was completed. 100 mL of water and 100 mL of ethyl acetate were added to the reaction mixture, and the organic phase was washed with water, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Further separation and purification by column chromatography (n-hexane: ethyl acetate = 1 : 1) gave 4-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline- Methyl 6-yl}-1-(methylphenyl-4-methylsulfonyl)-l-pyrrole-2-carboxylate 184f (3.45 g, yellow solid), yield: 73.9%.
MS m/z (ESI): 657[M+ 1] MS m/z (ESI): 657 [M+ 1]
第七步  Seventh step
4-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基}-111-吡咯 -2-甲酸 将 4-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基}-1- (甲苯基 -4-甲磺酰 基) -1H-吡咯 -2-甲酸甲酯 184f (350 mg， 0.53 mmol)和一水合氢氧化锂 (224 mg， 5.3 mmol)加入到微波反应瓶中， 加入 4 mL甲醇和 2 mL 7 ， 100°C下， 微波反应 2小 时。 将反应液倒入 10 mL水中， 用 1 N盐酸调节 pH值 =6, 过滤， 得到 4-{4-[3- 氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基}-111-吡咯 -2-甲酸 184g (248 mg， 黄色固 体)， 产率： 95 %。 MS m/z (ESI): 489[M+ 1] 4-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-111-pyrrole-2-carboxylic acid 4-{4-[3 -Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-1-(methylphenyl-4-methylsulfonyl)-1H-pyrrole-2-carboxylic acid methyl ester 184f (350 mg, 0.53 mmol) and lithium hydroxide monohydrate (224 mg, 5.3 mmol) were added to a microwave reaction flask, and 4 mL of methanol and 2 mL of 7 were added at 100 ° C for 2 hours under microwave. The reaction solution was poured into 10 mL of water, adjusted to pH = 6 with 1 N hydrochloric acid, and filtered to give 4-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazole Benzyl-6-yl}-111-pyrrole-2-carboxylic acid 184 g (248 mg, yellow solid), yield: 95%. MS m/z (ESI): 489 [M+ 1]
1H NMR (400MHz ,DMSO-d6): 512.09(S,1H)511.90(S,1H),9.63(S,1H),8.62(S, 1H), 8.5 l(s, lH),8.37(s,lH)58.04(m,2H),7.79(m,lH),7.60(m, lH),7.49(m, 1H),7.32 (m, 4H), 7.19(m, lH),5.27(s, 2H) 1H NMR (400MHz, DMSO-d6): 512.09 (S, 1H) 5 11.90 (S, 1H), 9.63 (S, 1H), 8.62 (S, 1H), 8.5 l (s, lH), 8.37 (s, lH) 5 8.04 (m, 2H), 7.79 (m, lH), 7.60 (m, lH), 7.49 (m, 1H), 7.32 (m, 4H), 7.19 (m, lH), 5.27 (s, 2H) )
第八步  Eighth step
4-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基]-喹唑啉 -6-基}-11 -吡咯 -2-羧酸（2-甲磺酰基-乙 基) -酰胺  4-{4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-11-pyrrole-2-carboxylic acid (2-methanesulfonyl- Ethyl)-amide
将 4-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基}-111-吡咯 -2-甲酸 184g (49 mg， 0.1 mmol)和 2-甲磺酰基乙胺盐酸盐 (103 mg， 0.8 mmol)溶于 8 mL无水二氯甲 烷中， 搅拌下加入 Ν,Ν-二异丙基乙胺 (103 mg， 0.8 mmol)和双 (二氧代 -3-噁唑烷) 次磷酰氯 (102 mg, 0.4 mmol), 室温下 2小时反应完毕。 将反应液在减压下浓缩， 得到的残留物通过硅胶柱层析进一步分离纯化 (二氯甲烷： 甲醇 =8: 1)， 得到标题 产物 4-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基}-111-吡咯 -2-羧酸（2-甲磺酰 基-乙基)-酰胺 184 (21 mg， 黄色固体)， 产率： 35.4%。  4-{4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-111-pyrrole-2-carboxylic acid 184 g (49 mg, 0.1 mmol And 2-methanesulfonylethylamine hydrochloride (103 mg, 0.8 mmol) dissolved in 8 mL of dry methylene chloride, and stirred with hydrazine, bis-diisopropylethylamine (103 mg, 0.8 mmol) And bis(dioxo-3-oxazolidine)phosphoryl chloride (102 mg, 0.4 mmol), the reaction was completed at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. EtOAc m. m. -fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-111-pyrrole-2-carboxylic acid (2-methanesulfonyl-ethyl)-amide 184 (21 mg, yellow solid) Yield: 35.4%.
MS m/z (ESI): 595[M+ 1] MS m/z (ESI): 595 [M+ 1]
1H NMR (400 MHz, CD30D-i¾)： δ 11.86(s, lH),9.74(s, lH),8.65(s, lH),8.53(s, 1H), 8.37(s, lH),8.04(m, 2H),7.76(m, 2H),7.60(m, lH),7.49(m, lH),7.32(m, 4H),7.19(m, lH),5.27(s, 2H),3.68(t, J=6.8Hz, 2H),3.38(t, J=6.8Hz, 2H),3.06(s, 3H) 实施例 185  1H NMR (400 MHz, CD30D-i3⁄4): δ 11.86 (s, lH), 9.74 (s, lH), 8.65 (s, lH), 8.53 (s, 1H), 8.37 (s, lH), 8.04 (m) , 2H), 7.76 (m, 2H), 7.60 (m, lH), 7.49 (m, lH), 7.32 (m, 4H), 7.19 (m, lH), 5.27 (s, 2H), 3.68 (t, J = 6.8 Hz, 2H), 3.38 (t, J = 6.8 Hz, 2H), 3.06 (s, 3H). Example 185
(S -(3-M-「3-氯 -4-(3-氟-苄氧基) -苯氨基 1-喹唑啉 -6-基 吡咯 -1-基) -3-吗啉 -4-基-  (S-(3-M-"3-chloro-4-(3-fluoro-benzyloxy)-phenylamino-1-quinazolin-6-ylpyrrolidin-1-yl)-3-morpholin-4- Base -
Figure imgf000192_0001
第 ~ "步
Figure imgf000192_0001
No. ~ "step
(S)-[3-氯 -4-(3-氟-苄基) -苯基]- [6-(1-环氧乙基甲基 -1H-吡咯 -3-基) -喹唑啉 -4-基] -胺 在 100 mL茄形瓶中，将 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-[6-(1Η-吡咯 -3-基) -喹唑啉 -4-基] -胺 42 (459 mg, 1.034 mmol)溶于 5 mL的 Ν,Ν-二甲基甲酰胺中， 冰浴冷却 至 0°C， 加入氢化钠 (96 mg， 2.4 mmol), 搅拌 30分钟后， 室温下加入 (R)-2-氯甲基 环氧乙烷 (148 mg, 1.6 mmol)， 1小时后反应完毕。 将反应液倒入 100 mL冰水中， 用乙酸乙酯 (100 mL X 3)萃取， 合并的有机相依次通过水 (100 mL X 3)洗涤， 饱和氯 化钠溶液 (100 mL)洗涤， 无水硫酸钠千燥， 过滤， 减压下浓缩， 得到的残留物通过 硅胶柱层析进一步分离纯化 (梯度洗脱： 二氯甲烷： 甲醇 = 150: 1， 100： 1)， 得到 (S)-[3-氯 -4-(3-氟-苄基) -苯基 ]-[6-(1-环氧乙基甲基 -1H-吡咯 -3-基) -喹唑啉 -4-基] -胺 185a (240 mg, 黄色固体)， 产率： 70%。  (S)-[3-Chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-epoxyethylmethyl-1H-pyrrol-3-yl)-quinazoline- 4-yl]-amine in a 100 mL eggplant-shaped flask, [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1Η-pyrrol-3-yl)-quin Oxazolin-4-yl]-amine 42 (459 mg, 1.034 mmol) was dissolved in 5 mL of hydrazine, dimethyl-dimethylformamide, cooled to 0 ° C in ice bath, and sodium hydride (96 mg, 2.4 mmol After stirring for 30 minutes, (R)-2-chloromethyloxirane (148 mg, 1.6 mmol) was added at room temperature, and the reaction was completed after 1 hour. The reaction solution was poured into 100 mL of ice water and extracted with ethyl acetate (100 mL X 3). The combined organic phases were washed sequentially with water (100 mL X 3 ) and washed with saturated sodium chloride (100 mL) The sodium sulfate was dried, filtered, and concentrated under reduced pressure. The residue obtained was purified and purified by silica gel column chromatography (gradient elution: methylene chloride: methanol = 150: 1, 100: 1) to give (S)-[ 3-Chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-epoxyethylmethyl-1H-pyrrol-3-yl)-quinazolin-4-yl] - Amine 185a (240 mg, yellow solid), Yield: 70%.
MS m/z (ESI): 501 [M+ 1] MS m/z (ESI): 501 [M+ 1]
1H NMR(400 MHz , DMSO-i/6): 511.100(s, 1H)， 8.319(s, IH), 7.902(s, IH), 7.846 (s, IH), 7.539 (s, IH ), 7.480 (s, IH), 7.323 (m, 2H), 7. 251(s, IH), 7.115(s， 2H), 7.020 (s, IH), 6.838(s, IH), 6.497(s, IH), 5.209(s, 2H), 4.492(d, J=12.8Hz, IH), 4.118(m, IH), 3.189(s, IH), 2.837(s, IH), 2.65 l(s, IH)  1H NMR (400 MHz, DMSO-i/6): 511.100 (s, 1H), 8.319 (s, IH), 7.902 (s, IH), 7.846 (s, IH), 7.539 (s, IH), 7.480 ( s, IH), 7.323 (m, 2H), 7. 251(s, IH), 7.115(s, 2H), 7.020 (s, IH), 6.838(s, IH), 6.497(s, IH), 5.209 (s, 2H), 4.492 (d, J = 12.8Hz, IH), 4.118(m, IH), 3.189(s, IH), 2.837(s, IH), 2.65 l(s, IH)
第二歩  Second
(S)-l-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基} -吡咯 -1-基) -3-吗啉 -4-基-丙  (S)-l-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-pyrrol-1-yl)-3 -morpholin-4-yl-propyl
-2-醇  -2-ol
在 100 mL茄形瓶中， 将 (S)-[3-氯 -4-(3-氟-苄基) -苯基 ]-[6-(1-环氧乙基甲基 -1H- 吡咯 -3-基) -喹唑啉 -4-基] -胺 185a (240 mg， 0.48 mmol)和吗啉 (69 mg， 0.793 mmol) 溶于 10 mL无水甲醇中， 加热回流过夜。 将反应液在减压下浓缩， 得到的残留物 通过硅胶柱层析进一步分离纯化 (梯度洗脱： 二氯甲烷： 甲醇 =60: 1， 50： 1， 40： 1)， 得到本标题产物 (S)-l-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基 比咯 小基) -3-吗啉 -4-基-丙 -2-醇 185(170 mg， 黄色固体） ， 产率： 60.3 %。  In a 100 mL eggplant-shaped flask, (S)-[3-chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-epoxyethylmethyl-1H-pyrrole- 3-Based)-quinazolin-4-yl]-amine 185a (240 mg, 0.48 mmol) and morpholine (69 mg, 0.793 mmol). The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjj S)-l-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylpyrrolidine)-3-morpholine- 4-Base-propan-2-ol 185 (170 mg, yellow solid), Yield: 60.3 %.
MS m/z (ESI): 588[M+ 1] MS m/z (ESI): 588 [M+ 1]
1H NMR (400 MHz, CD30D-^): δ 9.70(s, 1H)， 8.54(s, IH), 8.50(s, IH), 8.05(s, IH), 8.02(s, IH), 7.76(dd, J=8.8Hz 2.4Hz, IH), 7.70(d, J=8.8Hz, IH), 7.49(m, IH), 7.42(s, IH), 7.32(m, 3H), 7.19(t, J=8.4Hz, IH), 6.88(s,lH), 6.66(s, IH), 5.27(s, 2H), 4.06(dd, J-13.6Hz 3.6Hz， IH), 3.96(m,lH), 3.87(m, IH), 3.61(m, 4H), 2.42(m, 4H), 2.28(m, 2H) 实施例 186  1H NMR (400 MHz, CD30D-^): δ 9.70 (s, 1H), 8.54 (s, IH), 8.50 (s, IH), 8.05 (s, IH), 8.02 (s, IH), 7.76 (dd , J=8.8Hz 2.4Hz, IH), 7.70(d, J=8.8Hz, IH), 7.49(m, IH), 7.42(s, IH), 7.32(m, 3H), 7.19(t, J= 8.4Hz, IH), 6.88(s,lH), 6.66(s, IH), 5.27(s, 2H), 4.06(dd, J-13.6Hz 3.6Hz, IH), 3.96(m,lH), 3.87( m, IH), 3.61 (m, 4H), 2.42 (m, 4H), 2.28 (m, 2H).
qp小 (3-i4-「3-氯 -4-(3-氟 -苄氧基)-苯氨基 1-喹唑啉 -6-基 吡咯 -1-基 3-吗啉 -4-基-丙 Qp small (3-i4-"3-chloro-4-(3-fluoro-benzyloxy)-phenylamino-1-quinazolin-6-ylpyrrolidin-1-yl 3-morpholin-4-yl-propanoid
-2-醇
Figure imgf000193_0001
-2-ol
Figure imgf000193_0001
Figure imgf000194_0001
第一步
Figure imgf000194_0001
first step
(R)-[3-氯 -4-(3-氟-苄基) -苯基 ]- [6-(l-环氧乙基甲基 -IH-吡咯 -3-基) -喹唑啉 -4-基] -胺 在 100 mL茄形瓶中，将 [3-氯 -4-(3-氟- 氧基) -苯基 ]-[6-(1Η-吡咯 -3-基) -喹唑啉 -4-基] -胺 42 (561 mg， 1.264 mmol)溶于 5 mL的 Ν,Ν-二甲基甲酰胺中， 冰浴冷却 至 0°C， 加入氢化钠 （112 mg， 2.8 mmol), 搅拌 30分钟后， 室温下加入 (S)-2-氯甲 基环氧乙烷 (190 mg， 2.054 mmol), 1小时后反应完毕。将反应液倒入 100 mL冰水 中， 用乙酸乙酯 (100 mL X 3)萃取， 合并的有机相依次通过水洗涤， 饱和氯化钠溶 液洗涤， 无水硫酸钠干燥， 过滤， 减压下浓缩， 得到的残留物通过硅胶柱层析进 —步分离纯化 (梯度洗脱： 二氯甲烷： 甲醇 = 150: 1， 100： 1)， 得到 (R)-[3-氯 -4-(3- 氟-苄基)—苯基] -[6-(1-环氧乙基甲基 -1H-吡咯 -3-基) -喹唑啉 -4-基] -胺 186a (317 mg, 黄色固体)， 产率： 50.2%。  (R)-[3-chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-oxiranylmethyl-IH-pyrrol-3-yl)-quinazoline- 4-[3-]-amine in a 100 mL eggplant-shaped flask, [3-chloro-4-(3-fluoro-oxy)-phenyl]-[6-(1Η-pyrrol-3-yl)-quinazoline Phenyl-4-yl]-amine 42 (561 mg, 1.264 mmol) was dissolved in 5 mL of hydrazine, hexane-dimethylformamide, cooled to 0 ° C, and sodium hydride (112 mg, 2.8 mmol) After stirring for 30 minutes, (S)-2-chloromethyloxirane (190 mg, 2.054 mmol) was added at room temperature, and the reaction was completed after 1 hour. The reaction mixture was poured into 100 mL of ice water and extracted with ethyl acetate (100 mL EtOAc). The residue obtained is purified by silica gel column chromatography (gradient elution: methylene chloride: methanol = 150: 1, 100: 1) to give (R)-[3-chloro-4-(3- Fluoro-benzyl)-phenyl]-[6-(1-epoxyethylmethyl-1H-pyrrol-3-yl)-quinazolin-4-yl]-amine 186a (317 mg, yellow solid) , Yield: 50.2%.
MS m/z (ESI): 501 [M+ l] MS m/z (ESI): 501 [M+ l]
1H NMR (400 MHz , DMSO- 6): 511.100(s, IH), 8.319(s, IH), 7.902(s, IH), 7.846 (s, 1H)， 7.539 (s, IH ), 7.480 (s, IH), 7.323 (m, 2H), 7. 251(s, IH), 7.115(s, 2H), 7.020 (s, IH), 6.838(s, IH), 6.497(s, IH), 5.209(s, 2H), 4.492(d, J=12.8Hz, IH), 4.118(m, IH), 3.189(s, IH), 2.837(s, IH), 2.65 l(s, IH)  1H NMR (400 MHz, DMSO-6): 511.100 (s, IH), 8.319 (s, IH), 7.902 (s, IH), 7.846 (s, 1H), 7.539 (s, IH), 7.480 (s, IH), 7.323 (m, 2H), 7. 251(s, IH), 7.115(s, 2H), 7.020 (s, IH), 6.838(s, IH), 6.497(s, IH), 5.209(s , 2H), 4.492(d, J=12.8Hz, IH), 4.118(m, IH), 3.189(s, IH), 2.837(s, IH), 2.65 l(s, IH)
第二步  Second step
(R)_l_(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基} -吡咯 -1-基) -3-吗啉 -4-基-丙 ( R) _l_(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-pyrrol-1-yl)-3- Phenyl-4-yl-propyl
-2-醇  -2-ol
在 100 mL茄形瓶中， 将 (R)-[3-氯 -4-(3-氟-苄基) -苯基 ]-[6-(1-环氧乙基甲基 -1H- 吡咯 -3-基)-喹唑啉 -4-基] -胺 186a (315 mg, 0.702 mmol)和吗啉 (87 mg, 1 mmol)溶 于 10 mL无水甲醇中， 加热回流过夜。 将反应液在减压下浓缩， 得到的残留物通 过硅胶柱层析进一步分离纯化 (梯度洗脱： 二氯甲垸： 甲醇 =60: 1， 40： 1)， 得到 本标题产物 (R)-l-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基 吡咯 -1-基) -3- 吗啉 -4-基-丙 -2-醇 186(271 mg， 黄色固体） ， 产率： 65.8 %。  In a 100 mL eggplant-shaped flask, (R)-[3-chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-epoxyethylmethyl-1H-pyrrole- 3-Methyl)-quinazolin-4-yl]-amine 186a (315 mg, 0.702 mmol) and morpholine (87 mg, 1 mmol) were dissolved in 10 mL anhydrous methanol. The reaction mixture was concentrated under reduced pressure. EtOAc m. L-(3-{4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylpyrrolidin-1-yl)-3-morpholine-4- Base-propan-2-ol 186 (271 mg, yellow solid), Yield: 65.8 %.
MS m/z (ESI): 588[M+ 1] MS m/z (ESI): 588 [M+ 1]
1H NMR (400 MHz, CD30D-i¾): δ 9.70(s, 1H)， 8.54(s, IH), 8.50(s, IH), 8.05(s, IH), 8.02(s, IH), 7.76(dd, J=8.8Hz 2.4Hz, 1H)， 7.70(d, J=8.8Hz, IH), 7.49(m, IH), 7.42(s, 1H), 7.32(m, 3H), 7.19(t, J=8.4Hz， 1H), 6.88(s,lH), 6.66(s, 1H), 5.27(s, 2H), 4.06(dd, J=13.6Hz 3.6Hz, 1H), 3.96(m,lH), 3.87(m, 1H), 3.61(m, 4H), 2.42(m, 4H)， 2.28(m, 2H) 实施例 1871H NMR (400 MHz, CD30D-i3⁄4): δ 9.70 (s, 1H), 8.54 (s, IH), 8.50 (s, IH), 8.05 (s, IH), 8.02 (s, IH), 7.76 (dd , J=8.8Hz 2.4Hz, 1H), 7.70(d, J=8.8Hz, IH), 7.49(m, IH), 7.42(s, 1H), 7.32(m, 3H), 7.19(t, J=8.4Hz, 1H), 6.88(s,lH), 6.66(s, 1H), 5.27(s, 2H), 4.06(dd, J=13.6 Hz 3.6 Hz, 1H), 3.96 (m, lH), 3.87 (m, 1H), 3.61 (m, 4H), 2.42 (m, 4H), 2.28 (m, 2H) Example 187
3-{4-「3-氯 -4-(3-氟-苄氧基) -苯氨基 1-喹唑啉 -6-基 吡咯小基 3-(2，5-二氢吡咯 -1-  3-{4-"3-chloro-4-(3-fluoro-benzyloxy)-phenylamino-1-quinazoline-6-ylpyrrole small 3-(2,5-dihydropyrrole-1-
Figure imgf000195_0001
第一步
Figure imgf000195_0001
first step
[3-氯 -4-(3-氟-苄基) -苯基 ]- [6-(1-环氧乙基甲基 -1H-吡咯 -3-基) -喹唑啉 -4-基] -胺 在 100 mL茄形瓶中，将 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-[6-(1Η-吡咯 -3-基) -喹唑啉 -4-基] -胺 42 (890 mg， 2 mmol)溶于 10 mLN,N-二甲基甲酰胺中， 冰浴冷却至 0°C， 加入氢化钠 (176 mg， 4.4 mmol), 搅拌 30分钟后， 室温下加入 2-氯甲基环氧乙烷 (300 mg, 3.2 mmol), 1小时后反应完毕。 将反应液倒入 100 mL冰水中， 用乙酸乙 酯 (100 mLX 3)萃取， 合并的有机相依次通过有机相依次通过水 (100 mLX 3)洗涤， 饱和氯化钠溶液 (100 mLX 3)洗涤， 无水硫酸钠干燥， 过滤， 减压下浓縮， 得到的 残留物通过硅胶柱层析进一步分离纯化，得到 [3-氯 -4-(3-氟-苄基) -苯基] - [6-G-环氧 乙基甲基 -1H-吡咯 -3-基) -喹唑啉 -4-基] -胺 187a (700 mg, 黄色固体)， 产率： 70%。 MS m/z (ESI): 501 [M+ l]  [3-Chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-epoxyethylmethyl-1H-pyrrol-3-yl)-quinazolin-4-yl] -Amine in a 100 mL eggplant-shaped flask, [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1Η-pyrrol-3-yl)-quinazoline-4 -Alkyl-amine 42 (890 mg, 2 mmol) was dissolved in 10 mL of N-N-dimethylformamide, cooled to 0 ° C in ice-cooled, sodium hydride (176 mg, 4.4 mmol), and stirred for 30 min. 2-Chloromethyloxirane (300 mg, 3.2 mmol) was added at room temperature, and the reaction was completed after 1 hour. The reaction solution was poured into 100 mL of ice water and extracted with ethyl acetate (100 mL×3). The combined organic phases were washed sequentially with water (100 mL×3) and saturated sodium chloride solution (100 mL×3). The residue was dried over anhydrous sodium sulfate (MgSO4). 6-G-Epoxyethylmethyl-1H-pyrrol-3-yl)-quinazolin-4-yl]-amine 187a (700 mg, yellow solid), yield: 70%. MS m/z (ESI): 501 [M+ l]
1H NMR (400 MHz, DMSO-i¾): 511.100(s, 1H), 8.319(s, 1H), 7.902(s, 1H), 7.846 (s, 1H), 7.539 (s, 1H ), 7.480 (s, 1H)， 7.323 (m, 2H)， 7. 251(s, 1H)， 7.115(s, 2H), 7.020 (s, 1H), 6.838(s, 1H), 6.497(s, 1H), 5.209(s, 2H), 4.492(d, J=12.8Hz， 1H), 4.118(m， 1H), 3.189(s, 1H)， 2.837(s, 1H), 2.65 l(s, 1H) 1H NMR (400 MHz, DMSO-i3⁄4): 511.100 (s, 1H), 8.319 (s, 1H), 7.902 (s, 1H), 7.846 (s, 1H), 7.539 (s, 1H), 7.480 (s, 1H), 7.323 (m, 2H), 7. 251(s, 1H), 7.115(s, 2H), 7.020 (s, 1H), 6.838(s, 1H), 6.497(s, 1H), 5.209(s , 2H), 4.492 (d, J = 12.8Hz, 1H), 4.118(m, 1H), 3.189(s, 1H), 2.837(s, 1H), 2.65 l(s, 1H)
第二歩  Second
l-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基]-喹唑啉 -6-基}-吡咯 -1-基) -3-(2,5-二氢吡咯 -1- 基) -丙 -2-醇 L-(3-{4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-pyrrol-1-yl)-3-(2, 5-dihydropyrrole-1-yl)-propan-2-ol
在 100 mL茄形瓶中，将 [3-氯 -4-(3-氟-苄基) -苯基]- [6-(1-环氧乙基甲基 -1H-吡咯 -3-基) -喹唑啉 -4-基] -胺 187a (1.8 g, 3.67mmol)和 2,5-二氢 -1H-吡咯 (41.5 mg， 0.6 mmol)溶于 10 mL无水甲醇中， 加热回流 3小时后， 反应完毕。将反应液在减压下 浓缩，得到的残留物通过硅胶柱层析进一步分离纯化，得到本标题产物 1-(3-{4-[3- 氯 -4-(3-氟-苄氧基) -苯氨基]-喹唑啉 -6-基} -吡咯 -1-基) -3-(2,5-二氢吡咯 -1-基) -丙 -2- 醇 187(110 mg， 黄色固体） ， 产率： 64.4% [3-Chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-epoxyethylmethyl-1H-pyrrol-3-yl) in a 100 mL eggplant-shaped flask -quinazolin-4-yl]-amine 187a (1.8 g, 3.67 mmol) and 2,5-dihydro-1H-pyrrole (41.5 mg, 0.6 mmol) were dissolved in 10 mL anhydrous methanol and heated to reflux for 3 h. After that, the reaction is completed. The reaction mixture was concentrated under reduced pressure. Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-pyrrol-1-yl)-3-(2,5-dihydropyrrole-1-yl) Prop-2-propanol 187 (110 mg, yellow solid), Yield: 64.4%
MS m/z (ESI): 570[M+ 1] MS m/z (ESI): 570 [M+ 1]
1H NMR (400 MHz, CD30D-c 6): 59.704 (s,lH) ,8.544(s,lH),8.496(s,m),8.035(t, J=6.4Hz,2H),7.763(m,lH) ,7.704(d,J=13.6Hz,lH) ,7.475(t,J=7Hz,lH) ,7.421(s,lH) ,7.3 22(m，3H),7.205(d,J=9.6Hz,lH)，6.880(s,lH)，6.656(s，lH)，5.813(s,2H)，5.274(s,2H),4.997 (d,J=4.4Hz,lH)54.08(d,J=13.6Hz,lH)53.884(m,2H),3.492(m,4H),2.557(d,J=5.6Hz,2H) 实施例 1881H NMR (400 MHz, CD30D-c 6 ): 59.704 (s, lH), 8.544 (s, lH), 8.496 (s, m), 8.035 (t, J = 6.4 Hz, 2H), 7.763 (m, lH) ), 7.704 (d, J = 13.6 Hz, lH), 7.745 (t, J = 7 Hz, lH), 7.421 (s, lH), 7.3 22 (m, 3H), 7.205 (d, J = 9.6 Hz, lH) ), 6.880 (s, lH), 6.656 (s, lH), 5.813 (s, 2H), 5.274 (s, 2H), 4.997 (d, J = 4.4 Hz, lH) 5 4.08 (d, J = 13.6 Hz) , lH) 5 3.884 (m, 2H), 3.492 (m, 4H), 2.557 (d, J = 5.6 Hz, 2H) Example 188
3_{4-「3-氯 -4-(3-氟-苄氧基) -苯氨基 1-喹唑啉 _6-基 吡咯 -1-基) -3-哌啶 -1-基-丙 -2- 3_ {4 -" 3 -Chloro-4-( 3 -fluoro-benzyloxy)-phenylamino-1-quinazoline-6-ylpyrrolidin-1-yl)-3-piperidin-1-yl-propane- 2-
Figure imgf000196_0001
Figure imgf000196_0001
在 100 mL茄形瓶中， 将 [3-氯 -4-(3-氟-节基)-苯基] - [6-(1-环氧乙基甲基 -1H-吡 咯 -3-基)-喹唑啉 -4-基] -胺 187b (150 mg, 0.3 mmol)和哌啶 (51.1 mg， 0.6 mmol)溶 于 10 mL无水甲醇中， 加热回流 3小时反应完毕。 将反应液在减压下浓缩，'得到 的残留物通过硅胶柱层析进一步分离纯化， 得到本标题产物 1-(3-{4-[3-氯 -4-(3-氟- 苄氧基) -苯氨基] -喹唑啉 -6-基 吡咯小基 )-3-哌啶 -1-基-丙 -2-醇 188(135 mg，黄色固 体） ， 产率： 77%。  [3-Chloro-4-(3-fluoro-)-phenyl]-[6-(1-epoxyethylmethyl-1H-pyrrol-3-yl) in a 100 mL eggplant-shaped flask -Quinazolin-4-yl]-amine 187b (150 mg, 0.3 mmol) and piperidine (51.1 mg, 0.6 mmol) were dissolved in 10 mL anhydrous methanol and refluxed for 3 hours. The reaction mixture was concentrated under reduced pressure. &lt;RTI ID=0.0&gt;&gt; - phenylamino]-quinazolin-6-ylpyrrole small)-3-piperidin-1-yl-propan-2-ol 188 (135 mg, yellow solid), yield: 77%.
MS m/z (ESI): 586[M+ 1] MS m/z (ESI): 586 [M+ 1]
1H NMR (400 MHz, CD30D-i¾)： δ 9.700 (s, IH) ,8.536 (s, IH) , 8.496 (s,lH) ,8.037 (m, 2H),7.765 (m, IH )，7.703 (d, J - 8.8Hz, 1H),7.484 (s,lH),7.413 (s, IH), 7.322(m, 3H),7.193 (t, J - 8.6 Hz, IH) ,6.870(s,lH),6.653(s,lH), 5.273(s,2H),4.863(s,lH), 4.042(m,lH),3.930(s,lH),3.852(m,lH)32.377(s,4H),2.208(m,2H),1.522(m,4H),1.393 (m,2H) 实施例 189 1H NMR (400 MHz, CD30D-i3⁄4): δ 9.700 (s, IH) , 8.536 (s, IH) , 8.496 (s, lH) , 8.037 (m, 2H), 7.765 (m, IH ), 7.703 (d , J - 8.8Hz, 1H), 7.484 (s, lH), 7.413 (s, IH), 7.322 (m, 3H), 7.193 (t, J - 8.6 Hz, IH) , 6.870 (s, lH), 6.653 (s, lH), 5.273 (s, 2H), 4.863 (s, lH), 4.042 (m, lH), 3.930 (s, lH), 3.852 (m, lH) 3 2.377 (s, 4H), 2.208 ( m, 2H), 1.522 (m, 4H), 1.393 (m, 2H) Example 189
l- 3-M-f3-氯 -4-Π-氟-苄氧基) -苯氨基 1-喹唑啉 -6-基 吡咯 -1-基) -3-二乙氨基-丙 -2- 1-(3-M-f3-Chloro-4-indole-fluoro-benzyloxy)-phenylamino-1-quinazolin-6-ylpyrrolidin-1-yl)-3-diethylamino-propan-2-
Figure imgf000197_0001
在 100 mL茄形瓶中， 将 [3-氯 -4-(3-氟- 基) -苯基 ]- [6-(1-环氧乙基甲基 -1H-吡 咯 -3-基) -喹唑啉 -4-基] -胺 187b (150 mg， 0.3 mmol)和乙二胺（43.9 mg， 0.6 mmol) 溶于 10 mL无水甲醇中， 加热回流 3小时反应完毕。 将反应液在减压下浓缩， 得 到的残留物通过硅胶柱层析进一步分离纯化， 得到本标题产物 1-(3-{4-[3-氯 -4- (3- 氟-苄氧基) -苯氨基] -喹唑啉 -6-基} -吡咯 -1-基) -3-二乙氨基-丙 -2-醇 189 (120 mg, 黄 色固体） ， 产率： 70%。
Figure imgf000197_0001
In a 100 mL eggplant-shaped flask, [3-chloro-4-(3-fluoro-yl)-phenyl]-[6-(1-epoxyethylmethyl-1H-pyrrol-3-yl)- The quinazolin-4-yl]-amine 187b (150 mg, 0.3 mmol) and ethylenediamine (43.9 mg, 0.6 mmol) were dissolved in 10 mL of anhydrous methanol and refluxed for 3 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjj -Phenylamino]-quinazolin-6-yl}-pyrrol-1-yl)-3-diethylamino-propan-2-ol 189 (120 mg, yellow solid), yield: 70%.
MS m/z (ESI): 574[M+ 1] MS m/z (ESI): 574 [M+ 1]
1H NMR (400 MHz, CD30D-rf6): 69.699 (s,lH) ,8.539(s,lH),8.495(s,lH),8.034(t, J=6.4Hz,2H),7J52(m,lH),7.703(d,J=8.8Hz,lH),7.485(d,J=7.2Hz,lH),7.426(s,lH),7.32 3(m,3H),7.194(s,lH),6.884(s,lH),6.656(s,lH),5.274(s,2H),4.078(d,J=12Hz,lH),3.829(s ,2H), 2.509(br,4H),2.351(s, 2H),0.968(t, J = 7.2Hz, 6H) 实施例 190 1H NMR (400 MHz, CD30D-rf 6 ): 69.699 (s, lH), 8.539 (s, lH), 8.495 (s, lH), 8.034 (t, J = 6.4 Hz, 2H), 7J52 (m, lH) ), 7.703 (d, J = 8.8 Hz, lH), 7.485 (d, J = 7.2 Hz, lH), 7.426 (s, lH), 7.32 3 (m, 3H), 7.194 (s, lH), 6.084 ( s,lH), 6.656(s,lH), 5.274(s,2H),4.078(d,J=12Hz,lH),3.829(s,2H), 2.509(br,4H),2.351(s, 2H) , 0.968 (t, J = 7.2 Hz, 6H) Example 190
1-「1,4'1二哌啶基-1'-基-2-(3-{4-「3-氯-4-(3-氟-苄氧基)-苯氨基 喹唑啉-6-基}-吡咯-1- 基) -乙酮  1-"1,4'1 Dipiperidinyl-1'-yl-2-(3-{4-"3-chloro-4-(3-fluoro-benzyloxy)-phenylaminoquinazoline-6 -yl}-pyrrol-1-yl)-ethanone
Figure imgf000197_0002
第一歩 1-[1，4']二哌啶基 -Γ-基 -2-氯 -乙酮
Figure imgf000197_0002
First 1-[1,4']dipiperidinyl-fluorenyl-2-chloro-ethanone
将 4-哌啶基哌啶 (90 mg, 0.54 mmol)溶于 10 mL四氢呋喃中，加入三乙胺 (108 mg， 1.07 mmol), 冰浴冷却至 0°C， 搅拌下加入氯乙酰氯 (67 mg， 0.59 mmol), 搅 拌 30分钟后反应完毕。在反应液中加入 10 mL水， 减压下蒸去四氢呋喃， 得到的 溶液用乙酸乙酯萃取 (50 mLX 3),合并的有机相依次通过水洗涤，无水硫酸钠干燥， 过滤， 减压下浓缩， 得到的残留物通过硅胶柱层析进一步分离纯化 (二氯甲烷： 甲 醇 = 1 : 1)， 得到化合物 1-[1,4']二哌啶基 -Γ-基 -2-氯 -乙酮 (65 mg， 黄色油状液体)， 产率： 50%  4-Piperidylpiperidine (90 mg, 0.54 mmol) was dissolved in 10 mL of THF, triethylamine (108 mg, 1.07 mmol) was added, cooled to 0 ° C with ice-cooling, and chloroacetyl chloride (67) was added with stirring. Mg, 0.59 mmol), the reaction was completed after stirring for 30 minutes. To the reaction mixture, 10 mL of water was added, and the mixture was evaporated to dryness. After concentration, the residue obtained was further purified by silica gel column chromatography (dichloromethane:methanol = 1:1) to give compound 1-[1,4']dipiperidinyl-indole-yl-2-chloro-B Ketone (65 mg, yellow oily liquid), Yield: 50%
MS m/z (ESI): 245[M+ 1]  MS m/z (ESI): 245 [M+ 1]
第二步  Second step
1-[1,4']二哌啶基 -Γ-基 -2-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基]-喹唑啉 -6-基}-吡咯 -1- 基) -乙酮  1-[1,4']dipiperidinyl-fluorenyl-2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline- 6-yl}-pyrrol-1-yl)-ethanone
将化合物 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-[6-(1Η-吡咯 -3-基) -喹唑啉 -4-基] -胺 42 (80 mg, 0.18 mmol)和氢化钠 （21.6 mg， 0.54 mmol)溶于 10 mLN,N-二甲基甲酰 胺中， 室温下搅拌 30分钟后加入 1-[1,4']二哌啶基 -Γ-基 -2-氯 -乙酮 190a (53 mg, 0.216 mmol), 搅拌 30分钟后反应完毕。 在反应液中加入 100 mL饱和氯化钠溶液 淬灭反应， 水相用乙酸乙酯萃取 (100 mLX 3)， 合并的有机相依次通过水 (100 mL X 3)洗涤， 饱和氯化钠溶液洗涤 (100 mLX 3), 无水硫酸钠干燥， 过滤， 减压下浓. 缩， 得到的残留物通过硅胶柱层析进一歩分离纯化， 得到标题产物 1-[1,4']二哌啶 基 -Γ-基 -2-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基}-吡咯 -1-基) -乙酮 190(40 mg, 黄色固体)， 产率： 34%。  The compound [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1Η-pyrrol-3-yl)-quinazolin-4-yl]-amine 42 (80 mg , 0.18 mmol) and sodium hydride (21.6 mg, 0.54 mmol) were dissolved in 10 mL of N,N-dimethylformamide, and stirred at room temperature for 30 min, then 1-[1,4']dipiperidinyl-indole- The base 2-chloro-ethanone 190a (53 mg, 0.216 mmol) was stirred for 30 minutes and then the reaction was completed. The reaction mixture was quenched by the addition of 100 mL of saturated sodium chloride solution. The aqueous phase was extracted with ethyl acetate (100 mL×3), and the combined organic phases were washed with water (100 mL X 3 ) and washed with saturated sodium chloride (100 mL X 3 ), dried over anhydrous sodium sulfate, EtOAcjjjjjjjjjj -Γ-yl-2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-pyrrol-1-yl) - Ethyl ketone 190 (40 mg, yellow solid), Yield: 34%.
MS m/z (ESI): 653 [M+ l] MS m/z (ESI): 653 [M+ l]
1H NMR (400 MHz, CD30D-t¾): δ 9.71(s , IH) , 8.54(s , lH)5=8.50(s ， IH)， 5=8.02(m,2H) , 7.77(dd , J=2.4Hz , IH) , 7.71(d , J=8.4Hz , IH)， 7.48(m , IH)， 7.3 l(m , 4H) , 7.19(m , IH) , 6.82(s , IH) , 6.66(s , IH) , 5.27(s , 2H) , 4.95(d , J=4Hz , 2H) , 4.14(d , J=12.8Hz , IH) , 3.83(d , J=13.6Hz , IH) , 3.15(m , 3H) , 2.84(t， J=10.8Hz， IH) , 2.24(br , IH) , 1.86(t , J=12.4Hz , 2H) , 1.68(br , 4H) , 1.39(m , 3H) 实施例 191  1H NMR (400 MHz, CD30D-t3⁄4): δ 9.71 (s , IH) , 8.54 (s , lH) 5 = 8.50 (s , IH ) , 5 = 8.02 (m, 2H) , 7.77 (dd , J = 2.4 Hz , IH) , 7.71 (d , J = 8.4 Hz , IH ) , 7.48 ( m , IH ) , 7.3 l (m , 4H ) , 7.19 ( m , IH ) , 6.82 ( s , IH ) , 6.66 ( s , IH) , 5.27(s , 2H) , 4.95(d , J=4Hz , 2H) , 4.14(d , J=12.8Hz , IH) , 3.83(d , J=13.6Hz , IH) , 3.15(m , 3H ), 2.84 (t, J = 10.8 Hz, IH), 2.24 (br, IH), 1.86 (t, J = 12.4 Hz, 2H), 1.68 (br, 4H), 1.39 (m, 3H) Example 191
(SM3-氯 -4-(3-氟-苄氧基) -苯基 1-「6-α-吗啉 -3-基甲基 -IH-吡咯 -3-基)-喹唑啉 -4-基 1-  (SM3-Chloro-4-(3-fluoro-benzyloxy)-phenyl 1-"6-α-morpholin-3-ylmethyl-IH-pyrrol-3-yl)-quinazoline-4- Base 1
Figure imgf000198_0001
Figure imgf000198_0001
Figure imgf000199_0001
Figure imgf000199_0001
Figure imgf000199_0002
第一步
Figure imgf000199_0002
first step
2-苄氨基 -3-羟基丙酸  2-benzylamino-3-hydroxypropionic acid
在 100 mL的三口烧瓶中， 加入 L-丝氨酸 (4.1 g， 40 mmol)和 2M氢氧化钠溶液 (20 mL, 1.6g)， 搅拌下滴加苯甲醛 (8.3 g， 80 mmol), 搅拌 15分钟后， 冰浴冷却至 5Ό , 加入硼氢化钠 (0.86 g， 22 mmol), 室温下搅拌 2小时反应完毕。 用乙醚洗涤 反应液， 在冰浴冷却下， 用浓盐酸调节 pH=6.5， 抽滤， 得到 2-苄氨基 -3-羟基丙 酸 191a(4.05 g， 白色固体)， 产率： 51.9%。 In a 100 mL three-necked flask, add L-serine (4.1 g, 40 mmol) and 2M sodium hydroxide solution (20 mL, 1.6 g ), add benzaldehyde (8.3 g, 80 mmol), and stir for 15 minutes with stirring. Thereafter, the mixture was cooled to 5 Torr in an ice bath, sodium borohydride (0.86 g, 22 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with diethyl ether. EtOAc (EtOAc m.)
MS m/z (ESI): 196[M+ 1] MS m/z (ESI): 196 [M+ 1]
第二步  Second step
4-苄基 -5-氧代 -吗啉 -3-甲酸  4-benzyl-5-oxo-morpholine-3-carboxylic acid
将 2-苄氨基 -3-羟基丙酸 191a (7.2 g， 36 mmol)溶于 50 mL四氢呋喃中， 冰浴 冷却至 0°C， 加入 5 °C的饱和碳酸钠溶液 (15.4 g， 11 mmol), 滴加完毕后加入氯乙 酰氯 (7.2 mL， 60 mmol), 搅拌 3小时反应完毕。 反应液中加入 10 mL 50%氢氧化 钠溶液， 搅拌 10分钟后用正己垸萃取 (20 mL X 2)， 水相冷却至 0°C， 浓盐酸调节 pH<2, 在一 20°C下放置 6小时， 过滤， 得到的固体真空干燥， 得到 4-节基 -5-氧代 -吗啉 -3-甲酸 191b(6.6 g， 白色固体)， 产率： 76%。  2-Benzylamino-3-hydroxypropionic acid 191a (7.2 g, 36 mmol) was dissolved in 50 mL of tetrahydrofuran, cooled to 0 ° C in an ice bath, and a saturated sodium carbonate solution (15.4 g, 11 mmol) at 5 ° C was added. After the addition was completed, chloroacetyl chloride (7.2 mL, 60 mmol) was added, and the reaction was completed after stirring for 3 hours. Add 10 mL of 50% sodium hydroxide solution to the reaction solution, stir for 10 minutes, then extract with hexamethylene hydride (20 mL X 2), cool the aqueous phase to 0 ° C, adjust the pH to <2 with concentrated hydrochloric acid, and place at 20 ° C. After 6 hours, the resulting solid was dried in vacuo to give 4- <RTI ID=0.0># </RTI> 5- oxo-morpholine-3-carboxylic acid 191b (6.6 g, white solid).
MS m/z (ESI): 234[M- 1] MS m/z (ESI): 234 [M-1]
第三步  third step
(R)-(4-苄基吗啉 -3-基) -甲醇  (R)-(4-benzylmorpholine-3-yl)-methanol
将 4-苄基 -5-氧代 -吗啉 -3-甲酸 191b(10 g， 42.5 mmol)溶于 10 mL甲苯中， 氩气 氛下， 冰浴冷却下加入红铝溶液 (65 mL， 0.21 mol), 反应液在室温下搅拌 24小时 反应完毕。 在反应液中滴加乙醇， 直至无气泡生成， 用 2M氢氧化钠溶液调节 pH = 12, 加入 100 mL水， 分液， 水相用 2N盐酸溶液洗涤三次， 用 2M氢氧化钠溶 液调节 pH=8， 用乙酸乙酯萃取 (50 mLX 3)， 合并的有机相用无水硫酸钠干燥， 过 滤， 减压下浓缩， 得到 (R)-(4-节基吗啉 -3-基:) -甲醇 191c (8 g, 黄色油状液体)， 产 率： 86.9%。 4-Benzyl-5-oxo-morpholine-3-carboxylic acid 191b (10 g, 42.5 mmol) was dissolved in 10 mL of toluene. Under a argon atmosphere, a red aluminum solution (65 mL, 0.21 mol) was added under ice cooling. The reaction solution was stirred at room temperature for 24 hours and the reaction was completed. Ethanol was added dropwise to the reaction solution until no bubbles were formed, and the pH was adjusted with 2M sodium hydroxide solution. = 12, add 100 mL of water, separate the liquid, wash the aqueous phase three times with 2N hydrochloric acid solution, adjust pH=8 with 2M sodium hydroxide solution, extract with ethyl acetate (50 mL X 3), and combine the organic phase with anhydrous sulfuric acid The sodium was dried, filtered, and concentrated under reduced pressure to give (D)-(4-pyridylmorpholin-3-yl:)-methanol 191c (8 g, yellow oily liquid), yield: 86.9%.
MS m/z (ESI): 208[M+ 1] MS m/z (ESI): 208 [M+ 1]
第四步  the fourth step
(S)-(4-苄基吗啉 -3-基)-甲磺酸甲酯  (S)-(4-benzylmorpholine-3-yl)-methanesulfonate
将 (R)-(4-苄基吗啉 -3-基) -甲醇 191c (1.035 g， 5 mmol)和吡啶 (790 mg, 10 mmol) 溶于 20 mL二氯甲烷中， 在冰浴条件下， 冷却至 0°C， 逐渐滴加甲磺酰氯 (859 mg， 7.5 mmol), 室温下搅拌过夜。 将反应液中加入 50 mL水， 减压下旋干溶剂， 乙酸 乙酯萃取 (50 mLX 3)，合并的有机相依次通过饱和氯化钠溶液洗涤，无水硫酸钠干 燥， 过滤， 减压下浓缩， 得到的残留物通过硅胶柱层析进一步分离纯化 (正己垸： 乙酸乙酯二 1 : 1)， 得到 (S)-(4-苄基吗啉 -3-基) -甲磺酸甲酯 191d (1.4 g， 无色油状液 体)， 产率： 98%  (R)-(4-Benzylmorpholin-3-yl)-methanol 191c (1.035 g, 5 mmol) and pyridine (790 mg, 10 mmol) were dissolved in 20 mL dichloromethane. Cool to 0 ° C, gradually add methanesulfonyl chloride (859 mg, 7.5 mmol), and stir at room temperature overnight. The reaction solution was added to 50 mL of water, and the solvent was evaporated, evaporated, evaporated, evaporated, evaporated. After concentration, the residue obtained was further purified by silica gel column chromatography (hexanes: ethyl acetate: 1:1) to give (S)-(4-benzylmorpholin-3-yl)-methanesulfonic acid methyl ester. 191d (1.4 g, colorless oily liquid), Yield: 98%
MS m/z (ESI): 286[M+ 1] MS m/z (ESI): 286 [M+ 1]
第五步  the fifth step
(S)-(吗啉 -3_基) -甲磺酸甲酯 (S)-(morpholine- 3 _yl)-methyl methanesulfonate
将 (S)-(4-苄基吗啉 -3-基) -甲磺酸甲酯 191d (285 mg, 1 mmol)溶于 15 mL乙醇 中， 加入 50 mg Pd/C， 抽真空， 充入氢气， 室温下搅拌 2小时反应完毕。 过滤反 应液， 滤液在减压下浓缩， 得到 (S)-(吗啉 -3-基) -甲磺酸甲酯 191e (185 mg， 淡黄色 油状液体)， 产率： 95 %。 (S)-(4-Benzylmorpholin-3-yl)-methanesulfonate methyl ester 191d (285 mg, 1 mmol) was dissolved in 15 mL ethanol, 50 mg Pd/C was added, vacuum was applied, and charged Hydrogen was stirred at room temperature for 2 hours and the reaction was completed. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, to give (S) - (morpholin-3-yl) - methyl methanesulfonate 191e (185 mg, as a pale yellow oily liquid), Yield: 95%.
MS m/z (ESI): 195[M+ 1] MS m/z (ESI): 195 [M+ 1]
第六步  Step 6
(R)-[3-氯 -4-(3-氟- 氧基) -苯基 ]-[6-(1-吗啉 -3-基甲基 -1H-吡咯 -3-基)-喹唑啉 -4-基] - 胺  (R)-[3-chloro-4-(3-fluoro-oxy)-phenyl]-[6-(1-morpholin-3-ylmethyl-1H-pyrrol-3-yl)-quinazole Phenyl-4-yl]-amine
将 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-[6-(1Η-吡咯 -3-基) -喹唑啉 -4-基] -胺 42 (222 mg, 0.5 mmol)和氢化钠 (60 mg, 2.5mmol)溶于 6 mL Ν,Ν-二甲基甲酰胺中， 搅拌 30分 钟后加入 (S)-(吗啉 -3-基) -甲磺酸甲酯 191e (116 mg， 0.6 mmol), 反应液在室温下搅 拌 2小时反应完毕。 在反应液中加入 15 mL水和 20 mL乙酸乙酯， 水相用乙酸乙 酯萃取 (20 mL X 3)，合并的有机相依次通过饱和氯化钠溶液洗涤，无水硫酸钠干燥， 过滤， 减压下浓縮， 得到的残留物通过硅胶柱层析进一歩分离纯化 (梯度洗脱： 二 氯甲烷： 甲醇 =40: 1， 20： 1)， 得到 (R)-| 氯 -4-(3-氟-苄氧基) -苯基 ]-[6-(1-吗啉 -3- 基甲基 -1H-吡咯 -3-基) -喹唑啉 -4-基] -胺 191 (105 mg， 淡黄色固体)， 产率： 89%。 MS m/z (ESI): 544[M+ 1]  [3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1Η-pyrrol-3-yl)-quinazolin-4-yl]-amine 42 (222 mg, 0.5 mmol) and sodium hydride (60 mg, 2.5 mmol) were dissolved in 6 mL of hydrazine, hydrazine-dimethylformamide, and stirred for 30 minutes, then (S)-(morpholin-3-yl)-methanesulfonic acid The ester 191e (116 mg, 0.6 mmol) was stirred at room temperature for 2 hours. 15 mL of water and 20 mL of ethyl acetate were added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (20 mL EtOAc). Concentration under reduced pressure, the residue obtained was purified by silica gel column chromatography ( gradient eluting: methylene chloride: methanol = 40:1, 20:1) to give (R)-|chloro-4-( 3-fluoro-benzyloxy)-phenyl]-[6-(1-morpholin-3-ylmethyl-1H-pyrrol-3-yl)-quinazolin-4-yl]-amine 191 (105 Mg, light yellow solid), Yield: 89%. MS m/z (ESI): 544 [M+ 1]
1H NMR (400 MHz, CD30D- ): δ 9.69(s, lH),8.54(s, lH),8.50(s, lH),8.04(m, 2H),7.75(m, 2H),7.47(m, lH),7.40(m, lH),7.30(m, 3H),7.19(m, IH), 6.88(s, IH), 6.68(s: 08 001307 lH),5.27(s, 2H),3.88(m5 2H),3.62(m, 2H),3.36(m, 1H), 3.13(m, lH),3.03(m: lH),2.80(m, lH),2.72(m, 1H) 实施例 192 1H NMR (400 MHz, CD30D-): δ 9.69 (s, lH), 8.54 (s, lH), 8.50 (s, lH), 8.04 (m, 2H), 7.75 (m, 2H), 7.47 (m, lH), 7.40 (m, lH), 7.30 (m, 3H), 7.19 (m, IH), 6.88 (s, IH), 6.68 (s : 08 001307 lH), 5.27 (s, 2H), 3.88 (m 5 2H), 3.62 (m, 2H), 3.36 (m, 1H), 3.13 (m, lH), 3.03 (m : lH), 2.80 (m) , lH), 2.72 (m, 1H) Example 192
2-(3-M-「3-氯 -4-( -氟- 氧基) -苯氨基 1-喹唑啉 -6-基 吡咯 -1-基 )-l-(4-甲基 -哌嗪 -1- 基) -乙酮  2-(3-M-"3-Chloro-4-(-fluoro-oxy)-phenylamino-1-quinazolin-6-ylpyrrol-1-yl)-l-(4-methyl-piperazine -1-yl)-ethanone
Figure imgf000201_0001
第一步
Figure imgf000201_0001
first step
2—氯小 (4-甲基 -哌嗪 -1-基） -乙酮  2-chloro small (4-methyl-piperazin-1-yl)-ethanone
将 1-甲基哌嗪 (2 g， 20 mmol)溶于 60 mL四氢呋喃中， 在干冰乙醇浴冷却至一 70°C， 搅拌下逐渐滴加氯乙酰氯 (2.26 g, 30 mmol), 滴加完毕在冰浴冷却下搅拌 30分钟后反应完毕。 在反应液中加入 20 mL水， 减压下蒸去四氢呋喃， 得到的溶 液用二氯甲烷萃取 (100 mLX 3)，合并的有机相依次通过水洗涤，无水硫酸钠干燥， 过滤， 减压下浓缩， 得到的残留物通过硅胶柱层析进一步分离纯化 (二氯甲烷： 甲 醇 = 1 : 1)， 得到 2-氯 -1-(4-甲基 -哌嗪 -1-基） -乙酮 192a (500 mg， 黄色固体)， 产率： 14.2%。  Dissolve 1-methylpiperazine (2 g, 20 mmol) in 60 mL of tetrahydrofuran, cool to 70 ° C in a dry ice ethanol bath, and gradually add chloroacetyl chloride (2.26 g, 30 mmol) dropwise with stirring. After completion of stirring for 30 minutes under ice cooling, the reaction was completed. To the reaction mixture, 20 mL of water was added, and the mixture was evaporated to dryness, and then evaporated, evaporated, evaporated, evaporated, evaporated. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 1:1) to give 2-chloro-1-(4-methyl-piperazin-1-yl)-ethanone 192a (500 mg, yellow solid), Yield: 14.2%.
MS m/z (ESI): 177[M+ 1]  MS m/z (ESI): 177 [M+ 1]
第二步  Second step
2-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基}-吡咯 -1-基)小 (4-甲基 -哌嗪 -1- 基) -乙酮  2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-pyrrol-1-yl) small (4-methyl -piperazin-1-yl)-ethanone
将化合物 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-[6-(1Η-吡咯 -3-基) -喹唑啉 -4-基] -胺 42 (200 mg, 0.45 mmol)和氢化钠 （54 mg， 1.35 mmol)溶于 10 mLN,N-二甲基甲酰 胺中，室温下搅拌 30分钟后加入 2-氯 -1-(4-甲基 -哌嗪 -1-基） -乙酮 192a (95 mg, 0.54 mmol), 反应液加热至 50°C， 2小时后反应完毕。 在反应液中加入 100 mL饱和氯 化钠溶液淬灭反应， 水相用乙酸乙酯萃取 (100 mLX 3)， 合并的有机相依次通过水 (100 mLX 3)洗涤， 饱和氯化钠溶液洗涤 (100 mLX 3)， 无水硫酸钠干燥， 过滤， 减 压下浓缩， 得到的残留物通过硅胶柱层析进一步分离纯化， 得到标题产物 The compound [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1Η-pyrrol-3-yl)-quinazolin-4-yl]-amine 42 (200 mg , 0.45 mmol) and sodium hydride (54 mg, 1.35 mmol) dissolved in 10 mL of N,N-dimethylformamide, stirred at room temperature for 30 min then added 2-chloro-1-(4-methyl-piperazine- 1-yl)-ethanone 192a (95 mg, 0.54 mmol). The reaction mixture was heated to 50 ° C. The reaction mixture was quenched by adding 100 mL of saturated sodium chloride solution, and the aqueous phase was extracted with ethyl acetate (100 mL×3). (100 mL×3), washed with a saturated sodium chloride solution (100 mL×3), dried over anhydrous sodium sulfate, filtered, evaporated.
2— (3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基} -吡咯 -1-基) -1-(4-甲基 -哌嗪 -1- 基) -乙酮 192(85 mg， 黄色固体)， 产率： 32.3 %。 2- (3- {4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-pyrrol-1-yl)-1-(4- Methyl-piperazin-1-yl)-ethanone 192 (85 mg, yellow solid), yield: 303.
MS m/z (ESI): 586[M+1] MS m/z (ESI): 586 [M+1]
1HNMR (400 MHz, CD30D-i¾)： δ 9.70(s,lH), 8.54(s,lH), 8.49(s,lH),  1HNMR (400 MHz, CD30D-i3⁄4): δ 9.70 (s, lH), 8.54 (s, lH), 8.49 (s, lH),
8.03(d,J-8Hz,2H), 7.76(d, J=8.4Hz,lH), 7.70(d,J=8.8Hz,lH), 7.48(m,lH),7.41(s,lH), 7.33(m,3H),7.19(t3J=8Hz,lH),6.88(s,lH),6.65(s,lH),5.27(s,2H),4.97(s,2H),3.49(m, 4H),2.36(m,2H),2.29(m,2H),2.21(s,3H) 实施例 193 8.03 (d, J-8Hz, 2H), 7.76 (d, J = 8.4 Hz, lH), 7.70 (d, J = 8.8 Hz, lH), 7.48 (m, lH), 7.41 (s, lH), 7.33 (m,3H), 7.19 (t 3 J=8 Hz, lH), 6.88 (s, lH), 6.65 (s, lH), 5.27 (s, 2H), 4.97 (s, 2H), 3.49 (m, 4H) ), 2.36 (m, 2H), 2.29 (m, 2H), 2.21 (s, 3H). Example 193
氯 -4-( _氟-苄氧基) -苯氨基 喹唑啉 _6-基} -吡咯 基 3-(4_甲基-哌嗪小 基) -丙 -2-醇 Chloro- 4 -(-fluoro-benzyloxy)-phenylaminoquinazolin- 6 -yl } -pyrrolyl- 3- (4 -methyl-piperazine small)-propan-2-ol
Figure imgf000202_0001
将 [3-氯 -4-(3-氟-苄基) -苯基 ]-[6-(1-环氧乙基甲基 -1H-吡咯 -3-基)-喹唑啉 -4-基] - 胺 187a (153 mg, 0.306 mmol)溶于 15 mL甲醇中，搅拌下加入 1-甲基哌嗪 (48 mg， 0.48 mmol), 加热回流 7小时后反应完毕。 反应液在减压下浓缩， 得到的残留物通 过硅胶柱层析进一歩分离纯化 (梯度洗脱： 二氯甲垸： 甲醇二 50: 1， 20： 1)， 得到 本标题产物 1-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基 吡咯 -1-基) - 3-(4-甲基 -哌嗪 -1-基) -丙 -2-醇 193 (120 mg， 黄色固体)， 产率： 65.2%。
Figure imgf000202_0001
[3-Chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-epoxyethylmethyl-1H-pyrrol-3-yl)-quinazolin-4-yl - Amine 187a (153 mg, 0.306 mmol) was dissolved in 15 mL MeOH. &lt;RTI ID=0.0&gt;&gt; The reaction mixture was concentrated under reduced pressure. EtOAc mjjjjjjj -{4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylpyrrol-1-yl)-3-(4-methyl-piperazine- 1-yl)-propan-2-ol 193 (120 mg, yellow solid), Yield: 65.2%.
MS m/z (ESI): 601 [M+ 1] MS m/z (ESI): 601 [M+ 1]
1H NMR (400 MHz, CD30D-t¾: δ 9.68(s, 1H), 8.52(s, 1H), 8.48(s, 1H), 8.02(m, 2H), 7.75(d, J-8.8Hz, 1H), 7.69(d, J=8.8Hz, 1H), 7.47(q, J=7.2Hz, 1H)， 7.39(s, 1H), 7.3 l(m, 3H), 7.18(t, J=8.4Hz, 1H), 6.85(s,lH), 6.64(s, 1H), 5.26(s, 2H), 4.89(s, 1H), 4.02(m, 1H), 3.92(m,lH), 3.84(m， 1H), 2.41 (dr, 4H), 2.33(dr, 4H), 2.22(m, 5H) 实施例 194  1H NMR (400 MHz, CD30D-t3⁄4: δ 9.68 (s, 1H), 8.52 (s, 1H), 8.48 (s, 1H), 8.02 (m, 2H), 7.75 (d, J-8.8Hz, 1H) , 7.69(d, J=8.8Hz, 1H), 7.47(q, J=7.2Hz, 1H), 7.39(s, 1H), 7.3 l(m, 3H), 7.18(t, J=8.4Hz, 1H ), 6.85(s,lH), 6.64(s, 1H), 5.26(s, 2H), 4.89(s, 1H), 4.02(m, 1H), 3.92(m,lH), 3.84(m, 1H) , 2.41 (dr, 4H), 2.33 (dr, 4H), 2.22 (m, 5H) Example 194
(RVl-G- -「3-氯 -4-(3-氟-苄氧基) -苯氨基 1-喹唑啉 -6-基 -吡咯小基) -3-「4-〔2-甲磺酰 基-乙氨基) -哌啶 -1-基 1-丙 -2-醇
Figure imgf000203_0001
(RVl-G--"3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino-1-quinazolin-6-yl-pyrroleyl)-3-"4-[2-methanesulfonate Acyl-ethylamino)-piperidin-1-yl 1-propan-2-ol
Figure imgf000203_0001
第一歩  First
4-(2-甲磺酰基 1-乙氨基) -哌啶 -1-甲酸叔丁酯 将 2-甲磺酰基乙胺盐酸盐 (527 mg， 3.25 mmol)溶于重蒸的四氢呋喃溶液中，加 入 4 mL三乙胺，室温下搅拌 1小时后加入 4-氧代 -哌啶 -1-甲酸叔丁酯 194a (525 mg， 2.5 mmol), 继续搅拌 1小时后加入三 (乙酰氧基)硼氢化钠 (1.96 g， 15 mmol), 室温 下搅拌 1小时后反应完毕。 将反应液中加入 30 mL水淬灭反应， 减压下蒸掉四氢 呋喃，水相用乙酸乙酯萃取 (50 mLX 3)，合并的有机相通过无水硫酸钠干燥，过滤， 减压下浓缩，得到的残留物通过硅胶柱层析进一步分离纯化 (正己烷：乙酸乙酯 = 1 : 1)， 得到 4-(2-甲磺酰基 1-乙氨基) -哌啶 -1-甲酸叔丁酯 194b (567 mg， 类白色固体)， 产率： 73.9%。  4-(2-Methanesulfonyl 1-ethylamino)-piperidine-1-carboxylic acid tert-butyl ester 2-Methanesulfonylethylamine hydrochloride (527 mg, 3.25 mmol) was dissolved in EtOAc (EtOAc) After adding 4 mL of triethylamine and stirring at room temperature for 1 hour, 4-tert-piperidine-1-carboxylic acid tert-butyl ester 194a (525 mg, 2.5 mmol) was added, and stirring was continued for 1 hour, then tris(acetoxy)boron was added. Sodium hydride (1.96 g, 15 mmol) was stirred at room temperature for 1 hour. The reaction mixture was quenched with EtOAc (3 mL). The residue obtained was further purified by silica gel column chromatography (hexane: ethyl acetate = 1:1) to give 4-(2-methylsulfonyl 1-ethylamino)-piperidine-1-carboxylic acid tert-butyl ester 194b (567 mg, off-white solid), Yield: 73.9%.
MS m/z (ESI): 307[M+] MS m/z (ESI): 307 [M + ]
第二步  Second step
(2-甲磺酰基-乙基) -哌啶 -4-基胺三氟乙酸盐 将 4-(2-甲磺酰基 1-乙氨基) -哌啶 -1-甲酸叔丁酯 194b (567 mg， 1.85 mmol)溶于 15 mL二氯甲烷中， 搅拌下滴加 6 mL三氟乙酸， 室温下搅拌 1小时， 反应完毕。 将反应液在减压下浓缩，残留物通过硅胶柱层析分离纯化 (乙酸乙酯： 甲醇 =3: 1)， 得到 (2-甲磺酰基-乙基) -哌啶 -4-基胺三氟乙酸盐 194c(835 mg, 黄色固体)， 产率- 91 %。  (2-Methanesulfonyl-ethyl)-piperidin-4-ylamine trifluoroacetate 4-(2-methanesulfonyl 1-ethylamino)-piperidine-1-carboxylic acid tert-butyl ester 194b (567 The mg, 1.85 mmol) was dissolved in 15 mL of dichloromethane, and 6 mL of trifluoroacetic acid was added dropwise with stirring, and the mixture was stirred at room temperature for 1 hour, and the reaction was completed. The reaction mixture was concentrated under reduced pressure and purified (mjjjjjjjjjjjjjjjjjjj Fluoroacetate 194c (835 mg, yellow solid), yield - 91%.
MS m/z (ESI): 208 [M+ 1]  MS m/z (ESI): 208 [M+ 1]
第二步  Second step
(R)-l-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基 比咯 -1-基) -3-[4-(2-甲磺酰 基-乙氨基) -哌啶 - 1 -基] -丙 -2-醇 在 100 mL茄形瓶中， 将 (R)-[3-氯 -4-(3-氟-苄基) -苯基 ]-[6-(1-环氧乙基甲基 -1H- 吡咯 -3-基) -喹唑啉 -4-基] -胺 186a (244 mg， 0.5 mmol)溶于 30 mL甲醇中， 搅拌下 依次加入三乙胺 (0.5 mL,2.5 mmol)和 (2-甲磺酰基-乙基) -哌啶 -4-基胺三氟乙酸盐 194c (432 mg， 1 mmol), 混合液加热回流反应过夜。 将反应液在减压下浓缩， 得 到的残留物通过硅胶柱层析进一步分离纯化 (： 二氯甲垸： 甲醇 = 8 : 1)， 得到本标 题产物 (R)-l-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基} -吡咯 -1-基) -3-[4-(2- 甲磺酰基-乙氨基) -哌啶小基] -丙 -2-醇 194 (186 mg, 黄色固体） ， 产率： 29 %。 MS m/z (ESI): 707[M+] (R)-l-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylpyrrol-1-yl)-3- [4-(2-Methanesulfonyl-ethylamino)-piperidine-1-yl]-propan-2-ol In a 100 mL eggplant-shaped flask, (R)-[3-chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-epoxyethylmethyl-1H-pyrrole- 3-yl)-quinazolin-4-yl]-amine 186a (244 mg, 0.5 mmol) was dissolved in 30 mL of methanol and then added triethylamine (0.5 mL, 2.5 mmol) and (2-methane) Acyl-ethyl)-piperidin-4-ylamine trifluoroacetate 194c (432 mg, 1 mmol). The reaction mixture was concentrated under reduced pressure, and the residue obtained was purified and purified by silica gel column chromatography (:dichloromethane:methanol = 8:1) to give the title product (R)-l-(3-{4 -[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-pyrrol-1-yl)-3-[4-(2-methanesulfonyl- Ethylamino)-piperidinyl]-propan-2-ol 194 (186 mg, yellow solid), Yield: 29%. MS m/z (ESI): 707 [M + ]
1H NMR (400 MHz, CO30O-d6): δ 9.72 (s， 1H), 8.55 (s， 1H)， 8.50 (s， 1H), 8.05 (s, 1H): 8.03 (d, J = 8.8Hz, 1H), 7.77 (d, J - 8.8Hz, 1H), 7.71 (d, J = 8.8Hz, 1H), 7.48 (t, J = 8.8Hz, 1H), 7.42 (s, 1H), 7.31 (m, 3H), 7.19 (t, J = 8.8Hz, 1H), 6.89 (s, 1H), 6.68 (s, 1H), 5.27 (s, 2H), 4.06 (t, J = 12.8Hz, 1H), 3.94 (s, 1H), 3.85 (m,lH), 3.08 (br， 9H), 2.57 (br, 1H), 2.40 (br, 5H), 1.18 (t, J = 7.2Hz, 4H) 实施例 195 1H NMR (400 MHz, CO30O-d 6 ): δ 9.72 (s, 1H), 8.55 (s, 1H), 8.50 (s, 1H), 8.05 (s, 1H) : 8.03 (d, J = 8.8 Hz, 1H), 7.77 (d, J - 8.8Hz, 1H), 7.71 (d, J = 8.8Hz, 1H), 7.48 (t, J = 8.8Hz, 1H), 7.42 (s, 1H), 7.31 (m, 3H), 7.19 (t, J = 8.8Hz, 1H), 6.89 (s, 1H), 6.68 (s, 1H), 5.27 (s, 2H), 4.06 (t, J = 12.8Hz, 1H), 3.94 ( s, 1H), 3.85 (m, lH), 3.08 (br, 9H), 2.57 (br, 1H), 2.40 (br, 5H), 1.18 (t, J = 7.2 Hz, 4H) Example 195
1-二乙氨基 -3-(3- -fl-(3-氟 -苄基 IH-吲唑 -5-基氨基 1-喹唑啉 -6-基 }-吡咯小基 丙  1-Diethylamino-3-(3--fl-(3-fluoro-benzyl IH-indazole-5-ylamino-1-quinazolin-6-yl}-pyrrole small group C
-2-1?  -2-1?
Figure imgf000204_0001
在 100 mL茄形瓶中， 加入 2 mL二乙胺和 2 mL甲醇， 搅拌下加入 [1-(3-氟-苄 基) -1H-吲唑 -5-基 ]-[6-(1-环氧乙基甲基 -1H-吡咯 -3-基)-喹唑啉 -4-基] -胺 178a (150 mg, 0.283 mmol), 将反应液加热至 50°C反应过夜。将反应液在减压下浓缩， 得到 的残留物通过薄层制备板进行分离纯化， 得到本标题产物 1-二乙氨基 -3-(3-{4-[1-(3-氟-苄基) -1H-吲唑 -5-基氨基 ]-喹唑啉 -6-基} -吡咯 -1-基) -丙 -2-醇 195(92 mg, 黄色固体） ， 产率： 56.8 %。
Figure imgf000204_0001
In a 100 mL eggplant-shaped flask, add 2 mL of diethylamine and 2 mL of methanol, and add [1-(3-fluoro-benzyl)-1H-indazole-5-yl]-[6-(1- Epoxyethylmethyl-1H-pyrrol-3-yl)-quinazolin-4-yl]-amine 178a (150 mg, 0.283 mmol). The reaction mixture was heated to 50 ° C overnight. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified and purified to afford the title product 1-diethylamino-3-(3-{4-[1-(3-fluoro-benzyl) -1H-indazol-5-ylamino]-quinazolin-6-yl}-pyrrol-1-yl)-propan-2-ol 195 (92 mg, yellow solid), yield: 56.8 %.
MS m/z (ESI): 564[M+ 1] MS m/z (ESI): 564 [M+ 1]
!HNMR (400MHz, CD30D- ): S9.91(s,lH), 8.71(s,lH), 8.45(s，lH), 8.25(s，lH), 8.17(s,lH), 8.03(d,lH,J=8.8Hz), 7.76(s,2H), 7.70(d,lH,J=8.8Hz), 7.52(s,lH),  !HNMR (400MHz, CD30D-): S9.91(s,lH), 8.71(s,lH), 8.45(s,lH), 8.25(s,lH), 8.17(s,lH), 8.03(d, lH, J=8.8Hz), 7.76(s,2H), 7.70(d,lH,J=8.8Hz), 7.52(s,lH),
7.38(m，lH), 7.08(m,3H),6.93(s,lH), 6.74(s,lH), 5.72(s,2H), 4.08(m,3H), 3.18(m,4H), 3.00(m,2H), 1.22(m,6H) 实施例 196 7.38(m,lH), 7.08(m,3H), 6.93(s,lH), 6.74(s,lH), 5.72(s,2H), 4.08(m,3H), 3.18(m,4H), 3.00 (m, 2H), 1.22 (m, 6H) Example 196
4-M43-氯 -4-(3-氟-苄氧基) -苯氨基 1-喹唑啉 -6-基 }-1Η-吡咯 e-2-羧酸（U-二氧 -六氢  4-M43-Chloro-4-(3-fluoro-benzyloxy)-phenylamino-1-quinazoline-6-yl}}-1Η-pyrrole e-2-carboxylic acid (U-dioxo-hexahydro)
-1λ*6*-噻喃 -4-基甲基) -酰胺  -1λ*6*-thiopyran-4-ylmethyl)-amide
Figure imgf000205_0001
将 4-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基}-11€-吡咯 -2-甲酸 184g (122 mg， 0.25 mmol)和 C-(l,l-二氧 -六氢 -1λ*6*-噻喃 -4-基) -甲胺盐酸盐 (75 mg, 0.375 mmol)溶于 10 mL无水二氯甲烷中， 搅拌下加入 Ν,Ν-二异丙基乙胺 (129 mg， 1 mmol)和双 (二氧代 -3-噁唑烷)次磷酰氯 (127 mg， 0.5 mmol), 室温下反应 2小时。 将反应液在减压下浓縮，得到的残留物通过硅 柱层析进一步分离纯化 (；梯度洗脱： 二氯甲烷： 甲醇 =50: 1， 30： 1)， 得到标题产物 4-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨 基] -喹唑啉 -6-基 }-1Η -吡咯 e-2-羧酸（1,1-二氧 -六氢 -1λ*6*-噻喃 -4-基甲基) -酰胺 196 (12 mg, 黄色固体)， 产率： 7.6%。
Figure imgf000205_0001
4-{4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-11 €-pyrrole-2-carboxylic acid 184 g (122 mg, 0.25 mmol) and C-(l,l-dioxo-hexahydro-1λ*6*-thiopyran-4-yl)-methylamine hydrochloride (75 mg, 0.375 mmol) dissolved in 10 mL anhydrous dichloride In methane, hydrazine, hydrazine-diisopropylethylamine (129 mg, 1 mmol) and bis(dioxo-3-oxazolidine)phosphoryl chloride (127 mg, 0.5 mmol) were added with stirring at room temperature. 2 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified and purified by silica gel chromatography ( gradient elution: methylene chloride:methanol = 50:1, 30:1) to give the title product 4-{4 -[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-1Η-pyrrole e-2-carboxylic acid (1,1-dioxo-hexahydro) -1λ*6*-thiopyran-4-ylmethyl)-amide 196 (12 mg, yellow solid), yield: 7.6%.
MS m/z (ESI): 634[M+ 1] MS m/z (ESI): 634 [M+ 1]
^ ΝΜΪ θΟ ΜΗζ, CD30D- )： δ 11.93(s, lH),9.68(s, lH),8.63(s, lH),8.48(s, lH),8.13(d,J=9.2Hz,lH),8.0(s, lH),7.70(m, 2H),7.60(s, lH),7.45(m, lH),7.28(m, 4H),7.16(m, lH),5.25(s, 2H),3.21(m, 2H),3.10(m, 4H),2.05(m, 2H),1.80(m, lH)1.68(m, 2H) 实施例 197  ^ Ο θΟ ΜΗζ, CD30D- ): δ 11.93(s, lH), 9.68(s, lH), 8.63(s, lH), 8.48(s, lH), 8.13(d, J=9.2Hz, lH), 8.0 (s, lH), 7.70 (m, 2H), 7.60 (s, lH), 7.45 (m, lH), 7.28 (m, 4H), 7.16 (m, lH), 5.25 (s, 2H), 3.21. (m, 2H), 3.10 (m, 4H), 2.05 (m, 2H), 1.80 (m, lH) 1.68 (m, 2H).
Γ3-氯 -4-(3-氟-苄氧基) -苯基 l-(6-il-「2-(4-甲基 -哌嗪 -1-基) -乙基 1-lH-吡咯 -3-基 喹唑 啉 -4-基) -胺  3-chloro-4-(3-fluoro-benzyloxy)-phenyl 1-(6-il-"2-(4-methyl-piperazin-1-yl)-ethyl 1-lH-pyrrole- 3-ylquinazolin-4-yl)-amine
Figure imgf000205_0002
Figure imgf000206_0001
将 1-二乙氨基 -3-(3-{4-[l-(3-氟-苄基) -1Η-吲唑 -5-基氨基] -喹唑啉 -6-基}-吡咯 -1- 基) -丙 -2-醇 195(197 mg, 0.337 mmol)溶于 10 mL四氢呋喃中， 冰浴冷却至 0°C， 加入氢化铝锂 (38 mg， 1 mmol), 搅拌 10分钟后反应完毕。在反应液中加入十水合 硫酸钠淬灭反应， 过滤反应液， 滤饼用甲醇洗涤， 滤液在减压下浓缩， 得到的残 留物通过硅胶柱层析进一步分离纯化 (二氯甲烷： 甲醇： 氨水 = 10: 1： Id), 得到 标题产物 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-(6-{1-[2-(4-甲基 -哌嗪 -1-基) -乙基] -1H-吡咯 -3-基}-喹唑啉 -4-基) -胺 197(55mg， 黄色固体)， 产率： 26%。
Figure imgf000205_0002
Figure imgf000206_0001
1-Diethylamino-3-(3-{4-[l-(3-fluoro-benzyl)-1Η-indazol-5-ylamino]-quinazolin-6-yl}-pyrrole-1 -yl)-propan-2-ol 195 (197 mg, 0.337 mmol) was dissolved in 10 mL of tetrahydrofuran, cooled to 0 ° C in an ice-bath, and lithium aluminum hydride (38 mg, 1 mmol) was added and stirred for 10 min. . The reaction mixture was quenched by the addition of sodium sulfate decahydrate, and the reaction mixture was filtered. The filtrate was washed with methanol, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (dichloromethane: methanol: ammonia = 10: 1: Id), the title product [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-{1-[2-(4-methyl-piperazine)- 1-yl)-ethyl]-1H-pyrrol-3-yl}-quinazolin-4-yl)-amine 197 (55 mg, yellow solid), yield: 26%.
MS m/z (ESI): 572[M+1] MS m/z (ESI): 572 [M+1]
】H NMR (400 MHz, CD30D-^): δ 9.70(s,lH),8.54(s,lH), 8.49(s,lH), H NMR (400 MHz, CD30D-^): δ 9.70 (s, lH), 8.54 (s, lH), 8.49 (s, lH),
8.03(d,J=8Hz,2H), 7.76(d,J=8.4Hz,lH), 7.70 (d,J=8.8Hz,lH), 7.48(m,lH),7.41(s,lH), 7.33(m,3H), 7.19(t,J=8Hz,lH), 6.88(s,lH),6.65(s,lH),5.27(s,2H),4.04(m,2H),  8.03 (d, J = 8 Hz, 2H), 7.76 (d, J = 8.4 Hz, lH), 7.70 (d, J = 8.8 Hz, lH), 7.48 (m, lH), 7.41 (s, lH), 7.33 (m, 3H), 7.19 (t, J = 8 Hz, lH), 6.88 (s, lH), 6.65 (s, lH), 5.27 (s, 2H), 4.04 (m, 2H),
2.68(m,2H), 3.46(m,4H),2.32(m,4H),3.15(s,3H) 实施例 198 2.68 (m, 2H), 3.46 (m, 4H), 2.32 (m, 4H), 3.15 (s, 3H) Example 198
ί6-Γ1-(2-Γ1,4Ί二哌啶基 -Γ-基-乙基) -1H-吡咯 -3-基 1-喹唑啉 -4-基 「3-氯 -4-(3-氟 - 氧 基) -苯基 1-胺 66-Γ1-(2-Γ1,4ΊDipiperidinyl-fluorenyl-ethyl)-1H-pyrrol-3-yl-1-quinazolin-4-yl "3-chloro-4-(3-fluoro - oxy)-phenyl 1-amine
Figure imgf000206_0002
Figure imgf000206_0002
将 1-[1,4']二哌啶基 -Γ-基 -2-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基 吡咯 -1-基) -乙酮 190(220 mg， 0.337 mmol)溶于 10 mL四氢呋喃中， 冰浴冷却至 0 V， 加入氢化铝锂 (38 mg， 1 mmol), 搅拌 10分钟后反应完毕。在反应液中加入十 水合碳酸钠淬灭反应， 过滤反应液， 滤饼用甲醇洗涤， 滤液在减压下浓缩， 得到 的残留物通过硅胶柱层析进一步分离纯化 (二氯甲烷： 甲醇： 氨水 = 10: 1： Id), 得到标题产物 {6-[1-(2-[1,4']二哌啶基 -Γ-基-乙基) -1H-吡咯 -3-基] -喹唑啉 -4-基 }-[3- 氯 -4-(3-氟-苄氧基) -苯基] -胺 198(72 mg， 黄色固体)， 产率： 33.5 %。 MS m/z (ESI): 640[M+ 1] 1-[1,4']Dipiperidinyl-fluorenyl-2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline -6-Pyryrrol-1-yl)-ethanone 190 (220 mg, 0.337 mmol) was dissolved in 10 mL of THF, cooled to 0 EtOAc. After the reaction is completed. The reaction mixture was quenched by the addition of sodium carbonate decahydrate, and the reaction mixture was filtered. The filtrate was washed with methanol, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol: ammonia = 10: 1: Id), the title product {6-[1-(2-[1,4']dipiperidinyl-indolyl-ethyl)-1H-pyrrol-3-yl]-quinazole Phenyl-4-yl}-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-amine 198 (72 mg, yellow solid), yield: 33.5 %. MS m/z (ESI): 640 [M+ 1]
'H NMR (400 MHz, CD30D- ): δ 9.69(s,lH),8.53(s,lH),8.50(s,lH),8.03(m,2H), 7.77(dd,J=2.4Hz,lH),7.70(d,J=8.4Hz,lH),7.43(m,2H)，7.30(m,3H),7.19(m,lH),6.91(s,l H),6.65(s,lH),5.27(s,2H)34.03(t,J=6.8Hz,2H),2.96(d,J=6.4Hz,2H)32.66(t,J=6.4Hz,2H),2 .44(br,4H),2.21 (br,lH), 1.98(m,2H), 1.69(d,J=6.0Hz,2H), 1.44(m,8H) 实施例 199 'H NMR (400 MHz, CD30D-): δ 9.69 (s, lH), 8.53 (s, lH), 8.50 (s, lH), 8.03 (m, 2H), 7.77 (dd, J = 2.4 Hz, lH ), 7.70 (d, J = 8.4 Hz, lH), 7.43 (m, 2H), 7.30 (m, 3H), 7.19 (m, lH), 6.91 (s, l H), 6.65 (s, lH), 5.27(s,2H) 3 4.03(t,J=6.8Hz,2H),2.96(d,J=6.4Hz,2H) 3 2.66(t,J=6.4Hz,2H),2.44(br,4H ), 2.21 (br, lH), 1.98 (m, 2H), 1.69 (d, J = 6.0 Hz, 2H), 1.44 (m, 8H) Example 199
Γ1-(3-氟-苄基) -1H-吲唑 -5-基 1-(6-Π-「2- (四氢呋喃 -2-基氧基) -乙基 1-lH-吡咯 -3-基 喹唑啉 -4-基) -胺  1-(3-Fluoro-benzyl)-1H-indazol-5-yl 1-(6-indole-"2-(tetrahydrofuran-2-yloxy)-ethyl 1-lH-pyrrol-3-yl Quinazolin-4-yl)-amine
Figure imgf000207_0001
将 {6-[1-(2-二乙氨基-乙基) -1H-吡咯 -3-基] -喹唑啉 -4-基 }-[1-(3-氟苄基 )-1Η-吲唑 -5-基] -胺 150 (119 g, 0.276 mmol)溶于 1 mLN,N-二甲基甲酰胺中，冰浴冷却至 0°C， 加入氢化钠 (lOO mg, 0.8mmol),搅拌 30分钟后，加入 2-(2-溴乙氧基)-四氢呋喃 (25 mg， 0.359mmol), 30分钟后反应完毕。将反应液倒入 50 mL冰水中，有固体析出， 过滤， 滤饼通过硅胶柱层析分离纯化， 得到标题产物 [1-(3-氟-苄基) -1H-吲唑 -5- 基 ]-(6-{1-[2-(四氢呋喃 -2-基氧基) -乙基 ]-1Η-吡咯 -3-基 喹唑啉 -4-基）-胺 199(86.9mg, 黄色固体)， 产率： 56%。
Figure imgf000207_0001
{6-[1-(2-Diethylamino-ethyl)-1H-pyrrol-3-yl]-quinazolin-4-yl}-[1-(3-fluorobenzyl)-1Η-吲Oxazol-5-yl]-amine 150 (119 g, 0.276 mmol) was dissolved in 1 mL of N,N-dimethylformamide, cooled to 0 ° C in ice, and sodium hydride (100 mg, After 30 minutes, 2-(2-bromoethoxy)-tetrahydrofuran (25 mg, 0.359 mmol) was added and the reaction was completed after 30 min. The reaction liquid was poured into 50 mL of ice water, and a solid was precipitated, which was filtered, and the filter cake was purified by silica gel column chromatography to give the title product [1-(3-fluoro-benzyl)-1H-indazole-5-yl] -(6-{1-[2-(Tetrahydrofuran-2-yloxy)-ethyl]-1Η-pyrrol-3-ylquinazolin-4-yl)-amine 199 (86.9 mg, yellow solid) Yield: 56%.
MS m/z (ESI): 563[M+ 1] MS m/z (ESI): 563 [M+ 1]
^MR (400MHz, CD30D-i¾)： 59.86(s,lH), 8.62(s,lH), 8.46(s,lH), 8.23(s,lH), 8.18(s,lH), 8.04(d,lH,J=8.8Hz), 7.73(m,3H), 7.46(s,lH), 7.38(m,lH), 7.09(m,3H), 6.93(s,lH), 6.69(s,lH), 5.72(s,2H), 4.57(m,lH), 4.14(m,2H), 3.91(m,lH), 3.71(m,lH), 3.59(m,lH), 3.39(m,lH), 1.63(m,6H) 实施例 200 ^MR (400MHz, CD30D-i3⁄4): 59.86(s,lH), 8.62(s,lH), 8.46(s,lH), 8.23(s,lH), 8.18(s,lH), 8.04(d,lH , J=8.8Hz), 7.73(m,3H), 7.46(s,lH), 7.38(m,lH), 7.09(m,3H), 6.93(s,lH), 6.69(s,lH), 5.72 (s, 2H), 4.57 (m, lH), 4.14 (m, 2H), 3.91 (m, lH), 3.71 (m, lH), 3.59 (m, lH), 3.39 (m, lH), 1.63 ( m, 6H) Example 200
1-Γ3-(3-ί4-「3-氯 -4-(3-氟-苄氧基) -苯氨基 1-喹唑啉 -6-基 比咯 -1-基) -丙基 1-哌啶 -4-醇  1-Γ3-(3-ί4-"3-chloro-4-(3-fluoro-benzyloxy)-phenylamino-1-quinazolin-6-ylpyrrol-1-yl)-propyl 1-piperidyl Pyridin-4-ol
Figure imgf000207_0002
Figure imgf000207_0002
Figure imgf000208_0001
第一步
Figure imgf000208_0001
first step
4-羟基 -哌啶 -1-羧酸叔丁酯  4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester
将化合物 4-氧代 -哌啶 -1-羧酸叔丁酯 200a (10g, 0.05mmol)溶于 30 mL甲醇中， 搅拌下加入二氯化钴溶液 (6.53g， 0.05mmol), 分批加入硼氢化钠 (3.8g， O.lmmol), 搅拌 1 小时后反应完毕。 过滤反应液， 滤液在减压下浓缩， 得到的残留物通过硅 胶柱层析进一步分离纯化， 得到化合物 4-轻基 -哌啶 -1-羧酸叔丁酯 200b(9g， 淡黄 色固体)， 产率： 90%。  The compound 4-oxo-piperidine-1-carboxylic acid tert-butyl ester 200a (10 g, 0.05 mmol) was dissolved in 30 mL of methanol, and a solution of cobalt dichloride (6.53 g, 0.05 mmol) was added with stirring. Sodium borohydride (3.8 g, 0.1 mmol) was stirred for 1 hour and then the reaction was completed. The reaction mixture was filtered, and the filtrate was evaporated. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Yield: 90%.
MS m/z (ESI): 202[M+ 1] MS m/z (ESI): 202 [M+ 1]
第二步  Second step
哌啶 -4-醇三氟醋酸盐  Piperidine-4-ol trifluoroacetate
将化合物 4-羟基 -哌啶 -1-羧酸叔丁酯 200b (lg， 4.98mmol)溶于 15 mL三氟乙酸 溶液中， 冰浴冷却至 0°C， 搅拌 2小时后反应完毕。减压下浓缩反应液， 所得的产 物哌啶 -4-醇三氟醋酸盐 200c (500 mg， 黄色固体)不经分离直接进行下一步反应。  The compound 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester 200b (lg, 4.98 mmol) was dissolved in 15 mL of trifluoroacetic acid solution, cooled to 0 ° C in an ice bath, and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and the obtained product was obtained from the the the the the the the the
第三步  third step
1-(3-溴丙基) -哌啶 -4-醇  1-(3-bromopropyl)-piperidin-4-ol
将化合物哌啶 -4-醇三氟醋酸盐 200c (500 mg, 2.33mmol)溶于 10 mL二氯甲烷 中， 搅拌下加入 1,3-二溴丙烷 (2.82g， 13.95mmol), 冰浴冷却至 0°C， 逐滴加入三 乙胺 (705mg， 6.98mmol), 搅拌 1小时后反应完毕， 有固体生成。 过滤反应液， 滤 液在减压下浓縮， 得到的残留物通过硅胶柱层析进一步分离纯化 (二氯甲烷： 甲醇 =40： 1)， 得到化合物 -(3-溴丙基) -哌啶 -4-醇 200d (672 mg， 淡黄色油状液体)， 产 物不经分离直接进行下一步反应。  The compound piperidin-4-ol trifluoroacetate 200c (500 mg, 2.33 mmol) was dissolved in 10 mL of dichloromethane and 1,3-dibromopropane (2.82 g, 13.95 mmol) was added with stirring, ice bath After cooling to 0 ° C, triethylamine (705 mg, 6.98 mmol) was added dropwise, and after stirring for 1 hour, the reaction was completed and solid formed. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (dichloromethane:methanol = 40:1) to give compound-(3-bromopropyl)-piperidine- 4-Alcohol 200d (672 mg, light yellow oily liquid), product was taken directly to the next reaction without isolation.
MS m/z (ESI): 222[M+ 1] MS m/z (ESI): 222 [M+ 1]
第四步  the fourth step
1-[3-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基}-吡咯 -1-基) -丙基] -哌啶 -4-醇 在 25 mL的单口烧瓶中， 将 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-[6-(1Η-吡咯 -3-基) -喹 唑啉 -4-基] -胺 42 (445 mg， 1 mmol)溶于 6 mL N,N-二甲基甲酰胺中， 在冰浴条件 下， 冷却至 0°C， 加入氢化钠 (72 mg， 3 mmol), 搅拌 30分钟后逐渐滴加 1-(3-溴丙 基) -哌啶 -4-醇（672 mg， 2 mmol)的 lmL三乙胺溶液，室温下搅拌 4小时反应完毕。 反应液减压下浓缩， 得到的残留物通过硅胶柱层析进一步分离纯化 (二氯甲烷： 甲 醇 =4: 1)，得到本标题产物 1-[3-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基 ]-喹唑啉 -6-基} - 吡咯 -1-基)-丙基] -哌啶 -4-醇 200 (10 mg， 淡黄色固体)， 产率： 1.7%。 1-[3-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-pyrrol-1-yl)-propyl ]-piperidin-4-ol [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1Η-pyrrol-3-yl) in a 25 mL single-necked flask -quinazolin-4-yl]-amine 42 (445 mg, 1 mmol) dissolved in 6 mL of N,N-dimethylformamide, cooled to 0 ° C under ice-cooling, 72 mg, 3 mmol), after stirring for 30 minutes, gradually add 1-(3-bromopropyl) A solution of piperidin-4-ol (672 mg, 2 mmol) in 1 mL of triethylamine was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjjjj 4-(3-Fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-pyrrol-1-yl)-propyl]-piperidin-4-ol 200 (10 mg, light yellow Solid), Yield: 1.7%.
MS m/z (ESI): 587[M+ 1] MS m/z (ESI): 587 [M+ 1]
1HNMR (400 MHz, CD30D-^): δ 9.67 (s,lH), 8.8(s,lH),8.5 (s,lH),  1HNMR (400 MHz, CD30D-^): δ 9.67 (s, lH), 8.8 (s, lH), 8.5 (s, lH),
8.03(d,J=8.8Hz,2H)57.76(dd,J=2Hz,lH),7.70(d,J=8.4Hz,lH),7.5(m52H),7.36(m,3H), 7.2(s,lH),6.93(s,lH)36.60(s,lH),5.27(s,2H),4.08(m,lH),3.89(m,4H),3.50(m,4H),1.2 (m,6H) 实施例 201 8.03 (d, J = 8.8 Hz, 2H) 5 7.76 (dd, J = 2 Hz, lH), 7.70 (d, J = 8.4 Hz, lH), 7.5 (m 5 2H), 7.36 (m, 3H), 7.2 (s, lH), 6.93 (s, lH) 3 6.60 (s, lH), 5.27 (s, 2H), 4.08 (m, lH), 3.89 (m, 4H), 3.50 (m, 4H), 1.2 ( m, 6H) Example 201
0 143-(3-ί4-「3-氯 -4-(3-氟-苄氧基 苯氨基 1-喹唑啉 -6-基 吡咯 -1-基 2-羟基-丙 基 1-哌啶 -4-醇  0 143-(3-ί4-"3-Chloro-4-(3-fluoro-benzyloxyphenylamino-1-quinazolin-6-ylpyrrolidin-1-yl 2-hydroxy-propyl 1-piperidine- 4-alcohol
Figure imgf000209_0001
在 100 mL茄形瓶中， 将 (R)-[3-氯 -4-(3-氟-苄基) -苯基 ]-[6-(1-环氧乙基甲基 -1H- 吡咯 -3-基)-喹唑啉 -4-基] -胺 186a (250 mg, 0.5 mmol)和 4-羟基哌啶 (50 nig， 0.5 mmol)溶于 lO mL无水甲醇中， 加热回流过夜。将反应液在减压下浓缩， 得到的残 留物通过硅胶柱层析进一步分离纯化 (梯度洗脱： 二氯甲烷： 甲醇 = 10: 1), 得到 本标题产物 (R)-l-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基} -吡咯 -1-基) -3- 吗啉 _4-基-丙 -2-醇 201 (105 mg， 黄色固体） ， 产率： 35%。
Figure imgf000209_0001
In a 100 mL eggplant-shaped flask, (R)-[3-chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-epoxyethylmethyl-1H-pyrrole- 3-Methyl)-quinazolin-4-yl]-amine 186a (250 mg, 0.5 mmol) and 4-hydroxypiperidine (50 nig, 0.5 mmol) were dissolved in 10 mL of dry methanol and then evaporated. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjj {4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-pyrrol-1-yl)-3-morpholine-4-yl-propion -2-Alcohol 201 (105 mg, yellow solid), Yield: 35%.
MS m/z (ESI): 602[M+ 1] MS m/z (ESI): 602 [M+ 1]
1H NMR (400 MHz, CD30D-^): δ 9.67 (s,lH), 8.8(s,lH)，8.5 (s，lH),  1H NMR (400 MHz, CD30D-^): δ 9.67 (s, lH), 8.8 (s, lH), 8.5 (s, lH),
8.03(d,J=8.8Hz,2H),7.76(dd,J=2Hz,lH),7.70(d,J=8.4Hz,lH),7.5(m,2H),7.36(m,3H), 7.2(s,lH),6.93(s,lH),6.60(s,lH),5.27(s,2H)55.0(br,lH),3.9-4.4(m,3H),3.5(m,lH),3.4(m, lH),3.1(m,2H),1.9(br,2H)，1.7(br,2H),1.26(m,4H) 实施例 202 8.03 (d, J = 8.8 Hz, 2H), 7.76 (dd, J = 2 Hz, lH), 7.70 (d, J = 8.4 Hz, lH), 7.5 (m, 2H), 7.36 (m, 3H), 7.2 (s, lH), 6.93 (s, lH), 6.60 (s, lH), 5.27 (s, 2H) 5 5.0 (br, lH), 3.9-4.4 (m, 3H), 3.5 (m, lH), 3.4 (m, lH), 3.1 (m, 2H), 1.9 (br, 2H), 1.7 (br, 2H), 1.26 (m, 4H) Example 202
(RVl-(3-(4-(3-氯 -4-(3-氟苄氧基苯氨基)喹唑啉 -6-基) -1H-吡咯小基 3-"S~)-2- (羟甲 基)吡咯烷 -1-基)丙 -2-醇 (RVl-(3-(4-(3-chloro-4-(3-fluorobenzyloxyphenylamino)quinazolin-6-yl)-1H-pyrrole small group 3-"S~)-2- ( Hydroxymethyl)pyrrolidin-1-yl)propan-2-ol
Figure imgf000210_0001
Figure imgf000210_0001
Figure imgf000210_0002
第一步
Figure imgf000210_0002
first step
(S)-2-羟甲基-吡咯烷 -1-甲酸叔丁酯  (S)-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester
将氢化铝锂 (759 mg, 20 mmol)溶于 20 mL四氢呋喃溶液中， 加热回流 15分钟 后冷却至室温， 加入 L-脯氨酸 (1.15 g， 10 mmol)的 10 mL四氢呋喃溶液， 加热回 流 3小时后反应结束。 反应液降至室温， 加入 30 mL饱和氯化铵溶液， 水相用乙 酸乙酯萃取 (20 mL X 3)，合并的有机相通过饱和氯化钠溶液洗涤，无水硫酸钠干燥， 过滤， 减压下浓缩， 残渣中加入碳酸氢钠 (840 mg， 10 mmol)搅拌 5分钟后加入二 碳酸二叔丁酯 (3.485 g， 16 mmol), 混合液在室温下搅拌 24小时反应完毕。将反应 液用 2N盐酸调节 pH二 7， 水相用乙酸乙酯萃取 (20 mL X 3)， 合并的有机相通过饱 和氯化钠溶液洗涤， 无水硫酸钠干燥， 过滤， 减压下浓缩， 得到 (S)-2-羟甲基 -吡咯 垸 -1-甲酸叔丁酯 202a (2.57 g， 无色油状液体)。  Lithium aluminum hydride (759 mg, 20 mmol) was dissolved in 20 mL of tetrahydrofuran solution, heated to reflux for 15 min, then cooled to room temperature, then a solution of L-valine (1.15 g, 10 mmol) in 10 mL of THF. The reaction is completed after an hour. The reaction solution was cooled to room temperature, 30 mL of a saturated ammonium chloride solution was added, and the aqueous phase was extracted with ethyl acetate (20 mL X 3). The combined organic phases were washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure. sodium hydrogen carbonate (840 mg, 10 mmol) was added to the residue and stirred for 5 minutes, then di-tert-butyl dicarbonate (3.485 g, 16 mmol) was added, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was adjusted to pH 2 with 2N EtOAc. EtOAc (EtOAc)EtOAc. (S)-2-Hydroxymethyl-pyrrole-1-carboxylic acid tert-butyl ester 202a (2.57 g, colorless oily liquid).
MS m/z (ESI): 202[M+ 1] MS m/z (ESI): 202 [M+ 1]
第二步  Second step
(S)-吡咯烷 -2-基甲醇  (S)-pyrrolidine-2-ylmethanol
在 50 mL三口烧瓶中，加入 (S)-2-羟甲基-吡咯烷 -1-甲酸叔丁酯 202a (100.6 mg， 0.5 mmol)溶于 20 mL二氯甲烷中， 冰浴冷却至 0°C， 加入三氟乙酸 (2.2 mL, 28 mmol), 室温下搅拌 1.5小时， 反应完毕。将反应液在减压下浓缩， 得到化合物 (S)- 吡咯烷 -2-基甲醇 202b不经分离直接进行下一步反应。  In a 50 mL three-necked flask, (S)-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester 202a (100.6 mg, 0.5 mmol) was dissolved in 20 mL of dichloromethane and cooled to 0 ° in ice. C, trifluoroacetic acid (2.2 mL, 28 mmol) was added, and stirred at room temperature for 1.5 hr. The reaction solution was concentrated under reduced pressure to give Compound (S)-pyrrolidine-2-ylmethanol 202b.
MS m/z (ESI): 102[M+ 1] MS m/z (ESI): 102[M+ 1]
(R)-l-(3-(4-(3-氯 -4-(3-氟苄氧基)苯氨基)喹唑啉 -6-基) -1Η-吡咯 -1-基) -3-((S)-2- (羟甲 基)吡咯焼 -1-基)丙 -2-醇 在 100 mL茄形瓶中， 将 (R)-[3-氯 -4-(3-氟-苄基) -苯基 ]-[6-(1-环氧乙基甲基 -1H- 吡咯 -3-基) -喹唑啉 -4-基] -胺 186a (150 mg, 0.3 mmol)和 (S)-吡咯垸 -2-基甲醇 202b (25.3mg, 0.25 mmol)溶于 12 mL无水甲醇中，加入 1 mL三乙胺加热回流 6小时反 应完毕。将反应液在减压下浓缩，得到的残留物通过硅胶柱层析进一歩分离纯化 (梯 度洗脱： 二氯甲烷： 甲醇 = 50: 1), 得到本标题产物 (R)-l-(3-(4-(3-氯 -4-(3-氟苄氧 基）苯氨基）喹唑啉 -6-基) -1H-吡咯 -1-基) -3-((S)-2- (羟甲基）吡咯烷 -1-基）丙 -2-醇 202(28 mg, 黄色固体） ， 产率： 18.6%。 (R)-l-(3-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)-1Η-pyrrol-1-yl)-3- ((S)-2-(hydroxymethyl)pyrrolidin-1-yl)propan- 2 -ol In a 100 mL eggplant-shaped flask, (R)-[3-chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-epoxyethylmethyl-1H-pyrrole- 3-yl)-quinazolin-4-yl]-amine 186a (150 mg, 0.3 mmol) and (S)-pyrrole-2-ylmethanol 202b (25.3 mg, 0.25 mmol) dissolved in 12 mL anhydrous methanol In the middle, 1 mL of triethylamine was added and heated to reflux for 6 hours. The reaction mixture was concentrated under reduced pressure. EtOAc mjjjjjjjjj -(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)-1H-pyrrol-1-yl)-3-((S)-2- ( Hydroxymethyl)pyrrolidin-1-yl)propan-2-ol 202 (28 mg, yellow solid), Yield: 18.6%.
MS m/z (ESI): 602[M+ 1]  MS m/z (ESI): 602 [M+ 1]
lH NMR (400 MHz, CD30D-*): δ 9.935 (s,lH) ,8.686(s,lH),8.483(s,lH),8.094(s, lH),8.035(d,J=8.8Hz,lH),7.830(d,J=8.4Hz,lH),7.685(d,J=8.4Hz ,lH),7.480(m,2H),7.3 17(m,3H),7.190(t,J=8.4Hz,lH),6.870(s,lH),6.707(s,lH),5.271(s,2H),5.048(s,lH),4.606( s,lH),4.118(d3J==12.8Hz,lH),3.795(m,2H),3.417(t,J=5.2Hz,2H),2.717(m5lH),2.456(d,J- 6Hz,2H),2.316(m,lH),2.221(t, J=8.4Hz,lH), 1.792(m,lH),1.629(t, J=24Hz, lH NMR (400 MHz, CD30D-*): δ 9.935 (s, lH), 8.686 (s, lH), 8.843 (s, lH), 8.094 (s, lH), 8.035 (d, J = 8.8 Hz, lH ), 7.830 (d, J = 8.4 Hz, lH), 7.685 (d, J = 8.4 Hz, lH), 7.480 (m, 2H), 7.3 17 (m, 3H), 7.190 (t, J = 8.4 Hz, lH), 6.870 (s, lH), 6.707 (s, lH), 5.271 (s, 2H), 5.048 (s, lH), 4.606 (s, lH), 4.118 (d 3 J = = 12.8 Hz, lH) , 3.795 (m, 2H), 3.417 (t, J = 5.2 Hz, 2H), 2.718 (m 5 lH), 2.456 (d, J-6 Hz, 2H), 2.316 (m, lH), 2.221 (t, J =8.4 Hz, lH), 1.792 (m, lH), 1.629 (t, J = 24 Hz,
2H),1.536(d, J = 6Hz ,lH) 实施例 203  2H), 1.536 (d, J = 6 Hz, lH) Example 203
O小! ~3—0— {4_f3_氯 (3-氟―苄氧基) -苯氨基 ·]_喹唑啉— 6_基 _吡咯小基 2—羟-丙基 哌啶 -4-醇盐酸盐 O small! ~3—0— {4 _f 3 _Chloro (3 -fluoro-benzyloxy)-phenylamino·]_quinazoline- 6 _yl-pyrrole small 2 -hydroxy-propyl piperidine-4 -alcohol hydrochloride
Figure imgf000211_0001
Figure imgf000211_0001
在 100 mL茄形瓶中， 将 (S)-[3-氯 -4-(3-氟-苄基) -苯基 ]-[6-(1-环氧乙基甲基 -1H- 吡咯 -3-基)-喹唑啉 -4-基] -胺 185a (250 mg, 0.5 mmol)和 4-羟基哌啶 (50 mg, 0.5 mmol)溶于 10 mL无水甲醇中， 加热回流过夜。将反应液在减压下浓缩， 得到的残 留物通过硅胶柱层析进一步分离纯化 (梯度洗脱： 二氯甲烷： 甲醇 = 10: 1), 得到 本标题产物 (S)-l-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基]-喹唑啉 -6-基 吡咯 -1-基) -3- 吗啉 -4-基-丙 -2-醇 203a (105 mg， 黄色固体） ， 产率： 35 %。  In a 100 mL eggplant-shaped flask, (S)-[3-chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-epoxyethylmethyl-1H-pyrrole- 3-Methyl)-quinazolin-4-yl]-amine 185a (250 mg, 0.5 mmol) and 4-hydroxypiperidine (50 mg, 0.5 mmol) were dissolved in 10 mL anhydrous methanol and then evaporated. The reaction mixture was concentrated under reduced pressure. EtOAc mjjjjjjj {4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylpyrrol-1-yl)-3-morpholin-4-yl-propane-2 - alcohol 203a (105 mg, yellow solid), Yield: 35 %.
MS m/z (ESI): 602[M+ 1]  MS m/z (ESI): 602 [M+ 1]
1H NMR (400 MHz, CD30D-c¾: δ 9.67 (s,lH), 8.8(s,lH),8.5 (s,lH),  1H NMR (400 MHz, CD30D-c3⁄4: δ 9.67 (s, lH), 8.8 (s, lH), 8.5 (s, lH),
8.03(d,J-8.8Hz,2H),7.76(dd,J=2Hz,lH),7.70(d,J=8.4Hz,lH),7.5(m,2H),7.36(m,3H),7.2 (s,lH)，6.93(s,lH),6.60(s,lH),5.27(s,2H),4.1(m,2H),3.9(br，lH),3.55(s,lH),3.4(m，lH),3. 05(s,4H),2.5(m,2H),1.85(br,2H),1.55(br,2H) 实施例 204 8.03 (d, J-8.8 Hz, 2H), 7.76 (dd, J = 2 Hz, lH), 7.70 (d, J = 8.4 Hz, lH), 7.5 (m, 2H), 7.36 (m, 3H), 7.2 (s, lH), 6.93 (s, lH), 6.60 (s, lH), 5.27 (s, 2H), 4.1 (m, 2H), 3.9 (br, lH), 3.55 (s, lH), 3.4 ( m, lH), 3. 05(s, 4H), 2.5 (m, 2H), 1.85 (br, 2H), 1.55 (br, 2H) Example 204
(S)-l-(3- -「3-氯 -4-(3-氟-苄氧基) -苯氨基 1-喹唑啉 -6-基 }-吡咯小基) -3-环丙基氨基-  (S)-l-(3- -"3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino-1-quinazolin-6-yl}-pyrroleyl)-3-cyclopropyl Amino-
Figure imgf000212_0001
在 100 mL茄形瓶中， 将 (S)-[3-氯 -4-(3-氟-苄基) -苯基 ]-[6-(1-环氧乙基甲基 -1H- 吡咯 -3-基) -喹唑啉 -4-基] -胺 185a (216 mg, 0.4 mmol)和环丙胺 (0.1 mL， 0.8 mmol) 溶于 20 mL无水甲醇中， 加热回流过夜。 将反应液在减压下浓縮， 得到的残留物 通过硅胶柱层析进一歩分离纯化 (梯度洗脱： 二氯甲垸： 甲醇 = 10: 1)， 得到本标 题产物 (S)-l-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基 吡咯 -1-基) -3-环丙 基氨基-丙 -2-醇 204a (202 mg， 黄色固体） ， 产率： 83.8 %。
Figure imgf000212_0001
In a 100 mL eggplant-shaped flask, (S)-[3-chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-epoxyethylmethyl-1H-pyrrole- The 3-yl)-quinazolin-4-yl]-amine 185a (216 mg, 0.4 mmol) and cyclopropylamine (0.1 mL, 0.8 mmol) were dissolved in 20 mL anhydrous methanol The reaction mixture was concentrated under reduced pressure. EtOAc mjjjjjjj (3-{4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylpyrrol-1-yl)-3-cyclopropylamino-propan- 2-alcohol 204a (202 mg, yellow solid), Yield: 83.8 %.
MS m/z (ESI): 558[M+ 1] MS m/z (ESI): 558 [M+ 1]
1H NMR (400 MHz, CD30D-i¾): δ 9.74 (s, 1H), 8.56 (s, 1H), 8.49 (s, 1H), 8.03 (s, 1H): 8.02 (d, J - 8.8Hz, 1H), 7.77 (d, J = 8.8Hz, 1H), 7.70 (d, J = 8.8Hz, 1H), 7.48 (t, J = 8.8Hz, 1H), 7.43 (s, 1H)， 7.33 (m, 3H), 7.16 (t, J = 8.8Hz, 1H), 6.88 (s， 1H), 6.71 (s, 1H), 5.27 (s, 2H), 4.06 (t, J = 12.8Hz, 1H), 3.94 (s, 1H), 3.85 (m, 1H), 2.69 (m, 2H), 2.23 (br, 1H), 0.43 (m, 4H) 实施例 205  1H NMR (400 MHz, CD30D-i3⁄4): δ 9.74 (s, 1H), 8.56 (s, 1H), 8.49 (s, 1H), 8.03 (s, 1H): 8.02 (d, J - 8.8Hz, 1H ), 7.77 (d, J = 8.8Hz, 1H), 7.70 (d, J = 8.8Hz, 1H), 7.48 (t, J = 8.8Hz, 1H), 7.43 (s, 1H), 7.33 (m, 3H) ), 7.16 (t, J = 8.8Hz, 1H), 6.88 (s, 1H), 6.71 (s, 1H), 5.27 (s, 2H), 4.06 (t, J = 12.8Hz, 1H), 3.94 (s , 1H), 3.85 (m, 1H), 2.69 (m, 2H), 2.23 (br, 1H), 0.43 (m, 4H) Example 205
(R)-l-「3-(3-i4-「3-氯 -4-(3-氟-苄氧基) -苯氨基 1-喹唑啉 -6-基 μ吡咯小基) -2-羟-丙 基 1-4-羟甲基 -哌啶 -4-醇 (R)-l-"3-(3-i4-"3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino-1-quinazolin-6-ylpyrroleyl)-2- Hydroxy-propyl 1-4-hydroxymethyl-piperidin-4-ol
Figure imgf000213_0001
第一步
Figure imgf000213_0001
first step
1-氧 -6-氮杂螺 [2.5]辛垸三氟乙酸盐  1-oxo-6-azaspiro[2.5]octyltrifluoroacetate
将 1-氧 -6-氮杂-螺 [2.5]辛烷 -6-甲酸叔丁酯 205a (509 mg, 2.39 mmol)溶于 200 mL二氯甲烷中， 在冰浴条件下， 冷却至 0°C， 加入 5 mL三氟乙酸， 室温下搅拌 30分钟， 反应完毕。 将反应液在减压下浓縮， 得到无色油状液体粗品 1-氧代 -6-氮 杂螺 [2.5]辛垸三氟乙酸盐 205b， 产物不经分离直接进行下一步反应。  1-Oxo-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester 205a (509 mg, 2.39 mmol) was dissolved in dichloromethane (200 mL) and cooled to 0. C, 5 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 30 minutes, and the reaction was completed. The reaction solution was concentrated under reduced pressure to give a crude oily product, 1- chloro -6-azaspiro[2.5] octyltrifluoroacetate 205b, and the product was subjected to the next reaction without isolation.
第二歩  Second
(R)-l-[3-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基]-喹唑啉 -6-基}-吡咯 -1-基) -2-羟-丙  (R)-l-[3-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-pyrrol-1-yl ) -2-hydroxy-propyl
. 基] -4-羟甲基 -哌啶 -4-醇  . -4-hydroxymethyl-piperidin-4-ol
在 100 mL茄形瓶中，将 (R)-[3-氯 -4-(3-氟-苄基) -苯基 ]-[6-(1-环氧乙基甲基 -1H- 吡咯 -3-基) -喹唑啉 -4-基] -胺 186a (154 mg， 0.3 mmol)溶于 25 mL甲醇中， 搅拌下 依次加入 1-氧 -6-氮杂螺 [2.5]辛垸三氟乙酸盐 205b(0.1 mL， 0.8 mmol)和碳酸钾 (41.4 mg， 0.3mmol), 加热回流 4小时， 反应完毕。 将反应液在减压下浓缩， 得到的残 留物通过硅胶柱层析进一步分离纯化 (梯度洗脱： 二氯甲烷： 甲醇 =20: 1)， 得到 本标题产物 (R)-l-[3-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基 吡咯 -1- 基) -2-羟-丙基] -4-羟甲基 -哌啶 -4-醇 205 (632. mg， 黄色固体） ， 产率： 41.2%。 . MS m/z (ESI): 632[M+ 1]  (R)-[3-chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-epoxyethylmethyl-1H-pyrrole- in a 100 mL eggplant-shaped flask 3-yl)-quinazolin-4-yl]-amine 186a (154 mg, 0.3 mmol) was dissolved in 25 mL of methanol, and then 1-oxy-6-azaspiro[2.5]octyltrifluoride was added sequentially with stirring. Acetate 205b (0.1 mL, 0.8 mmol) and potassium carbonate (41.4 mg, 0.3 mmol) were refluxed for 4 hr. The reaction mixture was concentrated under reduced pressure. EtOAc mjjjjjjjj (3-{4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylpyrrole-1-yl)-2-hydroxy-propyl] -4 -Hydroxymethyl-piperidin-4-ol 205 (632. mg, yellow solid), Yield: 41.2%. MS m/z (ESI): 632 [M+ 1]
1H NMR (400 MHz, CD30D-i¾)： δ 9.76 (s, 1H), 8.56 (s, 1H), 8.49 (s, 1H), 8.04 (s, 1H), 8.02 (d， J = 8.8Hz, 1H), 7.78 (d, J = 8.8Hz, 1H), 7.70 (d， J = 8.8Hz, 1H), 7.47 (t, J = 8.8Hz, 1H)， 7.45 (s, 1H), 7.32 (m, 3H), 7.20 (t， J - 8.8Hz, 1H), 6.87 (s, 1H), 6.66 (s, 1H), 5.27 (s, 2H), 4.56 (br, 1H) 4.06 (t, J = 12.8Hz, 1H), 3.94 (s, 1H), 3.85 (m, 1H), 3.52 (s, 2H), 3.43 (br, 4H), 3.18 (t, J = 6.0Hz, 2H), 1.38 (d, J = 12.8Hz, 2H), 1.25 (d， J = 9.6Hz, 2H) 实施例 206 1H NMR (400 MHz, CD30D-i3⁄4): δ 9.76 (s, 1H), 8.56 (s, 1H), 8.49 (s, 1H), 8.04 (s, 1H), 8.02 (d, J = 8.8Hz, 1H ), 7.78 (d, J = 8.8Hz, 1H), 7.70 (d, J = 8.8Hz, 1H), 7.47 (t, J = 8.8Hz, 1H), 7.45 (s, 1H), 7.32 (m, 3H) ), 7.20 (t, J - 8.8Hz, 1H), 6.87 (s, 1H), 6.66 (s, 1H), 5.27 (s, 2H), 4.56 (br, 1H) 4.06 (t, J = 12.8Hz, 1H), 3.94 (s, 1H), 3.85 (m, 1H), 3.52 (s, 2H), 3.43 (br, 4H), 3.18 (t, J = 6.0Hz, 2H), 1.38 (d, J = 12.8 Hz, 2H), 1.25 (d, J = 9.6Hz, 2H) Example 206
(RVl-(l- -「3-氯 -4-G-氟-苄氧基) -苯氨基 喹唑啉 -6-基 吡咯小基) -3-甲氧基-丙 -2-  (RVl-(l- -"3-chloro-4-G-fluoro-benzyloxy)-phenylaminoquinazoline-6-ylpyrrole small)-3-methoxy-prop-2-
Figure imgf000214_0001
Figure imgf000214_0001
在 100 mL茄形瓶中， 将 (S)-[3-氯 -4-(3-氟- 基) -苯基 ]-[6-(1-环氧乙基甲基 -1H- 吡咯 -3-基)-喹唑啉 -4-基] -胺 185a (150 mg, 0.3 mmol)和 4-甲基 -哌嗪 -1-基胺（38 mg， 0.33 mmol)溶于 20 mL无水甲醇中， 加热回流反应 3小时。 将反应液在减压 下浓缩， 得到的残留物通过硅胶柱层析进一步分禽 化 (二氯甲烷： 甲醇 = 50: 1)； 得到本标题产物 (R)-l-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基]-喹唑啉 -6-基 吡咯 -1- 基) -3-甲氧基-丙 -2-醇 206 (76 mg， 黄色固体） ， 产率： 47.6%。  (S)-[3-Chloro-4-(3-fluoro-yl)-phenyl]-[6-(1-epoxyethylmethyl-1H-pyrrole-3) in a 100 mL eggplant-shaped flask -yl)-quinazolin-4-yl]-amine 185a (150 mg, 0.3 mmol) and 4-methyl-piperazin-1-ylamine (38 mg, 0.33 mmol) dissolved in 20 mL anhydrous methanol The reaction was heated to reflux for 3 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was crystallized from silica gel column chromatography (dichloromethane:methanol = 50:1) to give the title product (R)-l-(3-{4- [3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylpyrrole-1-yl)-3-methoxy-propan-2-ol 206 (76 mg , yellow solid), Yield: 47.6%.
MS m/z (ESI): 533 [M+ 1] MS m/z (ESI): 533 [M+ 1]
1H NMR (400 MHz, CD30D-^): δ 9.69 (s, 1Η), 8.54 (s, 1H), 8.50 (s, 1H), 8.05 (s, 1H): 8.03 (d, J = 8.8Hz, 1H), 7.77 (d, J = 8.8Hz, 1H), 7.70 (d, J = 8.8Hz， 1H), 7.50 (t, J = 8.8Hz, 1H), 7.43 (s, 1H), 7.33 (m, 3H), 7.19 (t, J = 8.8Hz, 1H), 6.87 (s, 1H), 6.66 (s, 1H), 5.27 (s, 2H), 5.20 (d, J = 4.8Hz, 1H)， 4.06 (t, J = 12.8Hz, 1H), 3.94 (s, 1H), 3.85 (m,lH), 3.31 (s， 3H),3.36(m,2H) 实施例 207  1H NMR (400 MHz, CD30D-^): δ 9.69 (s, 1Η), 8.54 (s, 1H), 8.50 (s, 1H), 8.05 (s, 1H): 8.03 (d, J = 8.8Hz, 1H ), 7.77 (d, J = 8.8Hz, 1H), 7.70 (d, J = 8.8Hz, 1H), 7.50 (t, J = 8.8Hz, 1H), 7.43 (s, 1H), 7.33 (m, 3H) ), 7.19 (t, J = 8.8Hz, 1H), 6.87 (s, 1H), 6.66 (s, 1H), 5.27 (s, 2H), 5.20 (d, J = 4.8Hz, 1H), 4.06 (t , J = 12.8 Hz, 1H), 3.94 (s, 1H), 3.85 (m, lH), 3.31 (s, 3H), 3.36 (m, 2H) Example 207
(S)-l-「l,4'l二哌啶基 -Γ-基 -3-(3- -「3-氯 -4-(3-氟-苄氧基) -苯氨基 1-喹唑啉 -6-基 吡 咯 -1-基 -丙 -2-醇  (S)-l-"l,4'l Dipiperidinyl-fluorenyl-3-(3--"3-chloro-4-(3-fluoro-benzyloxy)-phenylamino-1-quinazoline Porphyrin-6-ylpyrrolidin-1-yl-propan-2-ol
Figure imgf000214_0002
Figure imgf000215_0001
Figure imgf000214_0002
Figure imgf000215_0001
207  207
在 100 mL茄形瓶中， 将 (S)-[3-氯 -4-(3-氟-苄基) -苯基 ]-[6-(1-环氧乙基甲基 -1H- 吡咯 -3-基) -喹唑啉 -4-基] -胺 185a (100 mg， 0.2 mmol)和 4-哌啶基哌啶 (43 mg， 0.4 mmol)溶于 20 mL无水甲醇中，加热回流 5小时后反应完毕。将反应液在减压下浓 缩， 得到的残留物通过硅胶柱层析进一步分离纯化 (梯度洗脱： 二氯甲烷： 甲醇 = 50： 1， 5： 1)， 得到本标题产物 (S)-l-[l,4']二哌啶基 -Γ-基 -3-(3-{4-[3-氯 -4-(3-氟-苄 氧基) -苯氨基]-喹唑啉 -6-基}-吡咯 -1-基) -丙 -2-醇 207 (73 mg， 淡黄色固体） ， 产率： 54%。  In a 100 mL eggplant-shaped flask, (S)-[3-chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-epoxyethylmethyl-1H-pyrrole- 3-yl)-quinazolin-4-yl]-amine 185a (100 mg, 0.2 mmol) and 4-piperidylpiperidine (43 mg, 0.4 mmol) dissolved in 20 mL anhydrous methanol and heated to reflux 5 The reaction is completed after an hour. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjjj -[l,4']dipiperidinyl-fluorenyl-3-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6 -yl}-pyrrol-1-yl)-propan-2-ol 207 (73 mg, pale yellow solid), yield: 54%.
MS m/z (ESI): 669[M+ 1]  MS m/z (ESI): 669 [M+ 1]
1H NMR (400 MHz, CD30D-^): δ 9.70(s, 1 H),8.54(s, 1 Η)δ-8.49(s, 1 H), S=8.03(d, J=8Hz,2H), 7.76(d,J=8.4Hz,lH), 7.70(d,J-8.8Hz,lH), 7.48(m,lH), 7.41(s,lH), 1H NMR (400 MHz, CD30D-^): δ 9.70 (s, 1 H), 8.54 (s, 1 Η) δ-8.49 (s, 1 H), S = 8.03 (d, J = 8 Hz, 2H), 7.76 (d, J = 8.4 Hz, lH), 7.70 (d, J-8.8 Hz, lH), 7.48 (m, lH), 7.41 (s, lH),
7.33(m,3H), 7.19(t, J=8Hz, 1 H),6.88(s, 1 H), 6.65(s,lH),5.27(s,2H), 4.88(m,lH), 7.33(m,3H), 7.19(t, J=8Hz, 1 H), 6.88(s, 1 H), 6.65(s,lH), 5.27(s,2H), 4.88(m,lH),
4.02(m, 1 H), 3.87(m,2H),2.90(m,2H),2.42(m,4H),2.21 (m,3H), 1.94(m,2H), 4.02(m, 1 H), 3.87 (m, 2H), 2.90 (m, 2H), 2.42 (m, 4H), 2.21 (m, 3H), 1.94 (m, 2H),
1.64(m,2H),1.36(m,6H) . 实施例 208 1.64 (m, 2H), 1.36 (m, 6H). Example 208
l-(3-M-「3-氯 -4-(3-氟-苄氧基) -苯氨基 1-喹唑啉 -6-基 吡咯 -1-基 )-3-Γ4-(2-羟乙基) -哌 嗪 -1-基 1-丙 -2-醇 1-(3-M-"3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino-1-quinazolin-6-ylpyrrole-1-yl)-3-indole 4-(2-hydroxyl Ethyl)-piperazin-1-yl 1-propan-2-ol
Figure imgf000215_0002
Figure imgf000215_0002
187a  187a
将 [3-氯 -4-(3-氟-苄基) -苯基] - [6-(1-环氧乙基甲基 -1H-吡咯 -3-基) -喹唑啉 -4- 基] -胺 187a (200 mg， 0.4mmol)溶于 10 mL甲醇中， 依次搅拌下加入 2 mL三乙胺 和 2-哌嗪 -1-基 -乙醇 (0.06 mL， 0.44 mmol), 反应液加热回流， 4小时后反应完毕。 将反应液在减压下浓缩，得到的残留物通过硅胶柱层析进一步分离纯化 (二氯甲烷: 甲醇 = 10: 1)， 得到本标题产物 1-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6- 基 } 比咯 -1-基) -3-[4-(2-羟乙基) -哌嗪 -1-基] -丙 -2-醇 208 (156 mg， 黄色固体)， 产率： 60%。 [3-Chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-epoxyethylmethyl-1H-pyrrol-3-yl)-quinazolin-4-yl -Amine 187a (200 mg, 0.4 mmol) was dissolved in 10 mL of methanol, and then 2 mL of triethylamine and 2-piperazin-1-yl-ethanol (0.06 mL, 0.44 mmol) were added with stirring. After 4 hours, the reaction was completed. The reaction mixture was concentrated under reduced pressure. Methanol = 10: 1), the title product 1-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl} -1-yl)-3-[4-(2-hydroxyethyl)-piperazin-1-yl]-propan-2-ol 208 (156 mg, yellow solid), yield: 60%.
MS m/z (ESI): 631 [M+ 1]  MS m/z (ESI): 631 [M+ 1]
1H NMR (400 MHz, CD30D-^): δ 9.71 (s, 1H), 8.54 (s, 1H), 8.50 (s, 1H), 8.04 (s, 1H): 8.02 (d, J = 8.8Hz, 1H), 7.85 (d, J = 8.8Hz, 1H), 7.69 (d, J = 8.8Hz, 1H), 7.54 (t, J = 8.8Hz, 1H)， 7.42 (s, 1H), 7.32 (m, 3H), 7.19 (t, J = 8.8Hz, 1H), 6.87 (s, 1H), 6.65 (s, 1H), 5.27 (s, 2H), 4.90 (d, J = 4.0Hz, 1H), 4.35 (m, 1H) 4.06 (t, J = 12.8Hz, 1H), 3.94 (br, 1H), 3.85 (m, 1H), 3.49 (m, 2H), 2.35 (br, 10H), 2.20 (m, 2H) 实施例 209  1H NMR (400 MHz, CD30D-^): δ 9.71 (s, 1H), 8.54 (s, 1H), 8.50 (s, 1H), 8.04 (s, 1H): 8.02 (d, J = 8.8Hz, 1H ), 7.85 (d, J = 8.8Hz, 1H), 7.69 (d, J = 8.8Hz, 1H), 7.54 (t, J = 8.8Hz, 1H), 7.42 (s, 1H), 7.32 (m, 3H) ), 7.19 (t, J = 8.8Hz, 1H), 6.87 (s, 1H), 6.65 (s, 1H), 5.27 (s, 2H), 4.90 (d, J = 4.0Hz, 1H), 4.35 (m , 1H) 4.06 (t, J = 12.8Hz, 1H), 3.94 (br, 1H), 3.85 (m, 1H), 3.49 (m, 2H), 2.35 (br, 10H), 2.20 (m, 2H) Example 209
l-(3-{4-「3-氯 _4-(3_氟-苄氧基 苯氨基 1—喹唑啉 _6-基 吡咯小基) -3-(4-甲磺酰基-哌 L-(3-{4-" 3 -Chloro-4-( 3 -fluoro-benzyloxyphenylamino-1-quinazoline-6-ylpyrroleyl)-3-(4-methanesulfonyl-piperidinyl)
Figure imgf000216_0001
Figure imgf000216_0001
、 第一步 First step
1-甲磺酰基哌嗪  1-methanesulfonylpiperazine
将哌嗪 (1.72g， 20 mmol)溶于 10 mL二氯甲垸中， 搅姅下加入三乙胺 (2 mL， 40mmol), 冰浴冷却下， 加入甲磺酰氯 (5.55 mL， 24mmol), 混合液在室温下搅拌 1 小时反应完毕。 反应液在减压下浓缩， 得到的残留物通过硅胶柱层析进一步分离 纯化， 得到化合物 1-甲磺酰基哌嗪二 209a (2g， 白色固体)， 产率 : ' 64%。  The piperazine (1.72 g, 20 mmol) was dissolved in 10 mL of dichloromethane, and then triethylamine (2 mL, 40 mmol). The mixture was stirred at room temperature for 1 hour and the reaction was completed. The reaction mixture was concentrated under reduced pressure. EtOAc m.
MS m/z (ESI): 165[M+ 1] MS m/z (ESI): 165 [M+ 1]
第二步  Second step
1_(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基 吡咯 -1-基) -3-(4-甲磺酰基-哌 嗪 -1-基) -丙 -2-醇 1-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylpyrrol-1-yl)-3-(4-methanesulfonyl) -piper Pyrazin-1-yl)-propan-2-ol
1-甲磺酰基哌嗪 209a (66 mg， 0.4mmol)溶于 10 mL甲醇中， 依次搅拌下加入 2 mL三乙胺和 [3-氯 -4-(3-氟-苄基) -苯基 ]- [6-(1-环氧乙基甲基 -1H-吡咯 -3-基) -喹唑 啉 -4-基] -胺 187a (200 mg， 0.4mmol), 混合液加热回流 2小时后反应完毕。 反应液 在减压下浓缩， 得到的残留物通过硅胶柱层析进一步分离纯化 (二氯甲烷： 甲醇二 10： 1)， 得到本标题产物 1-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉- 6-基}-吡咯 小基) -3-(4-甲磺酰基 -哌嗪 -1-基) -丙 -2-醇 209 (19 mg， 白色固体)， 产率： 7.2%。 MS m/z (ESI): 665[M+ 1]  1-Methanesulfonylpiperazine 209a (66 mg, 0.4 mmol) was dissolved in 10 mL of methanol and then added 2 mL of triethylamine and [3-chloro-4-(3-fluoro-benzyl)-phenyl. ]-[6-(1-Epoxyethylmethyl-1H-pyrrol-3-yl)-quinazolin-4-yl]-amine 187a (200 mg, 0.4 mmol). The reaction is completed. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjj -(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl}-pyrroleyl)-3-(4-methanesulfonyl-piperazin-1-yl)-propan-2- Alcohol 209 (19 mg, white solid), Yield: 7.2%. MS m/z (ESI): 665 [M+ 1]
1H NMR (400 MHz, CD30D-t¾: δ 9.67 (s,lH), 8.8(s,lH),8.5 (s,lH),  1H NMR (400 MHz, CD30D-t3⁄4: δ 9.67 (s, lH), 8.8 (s, lH), 8.5 (s, lH),
8.03(d,J=8.8Hz,2H),7.76(dd,J=2Hz,lH),7.70(d,J=8.4Hz,lH),7.5(m,2H),7.36(m,3H), 7.2(s,lH),6.93(s,lH),6.60(s,lH),5.27(s,2H),5.0(s,lH),4.0(m,3H),3.15(t,J=17.6Hz,4H),2. 9(s,3H),2.6(m,4H),2.3(s,2H) 实施例 210 8.03 (d, J = 8.8 Hz, 2H), 7.76 (dd, J = 2 Hz, lH), 7.70 (d, J = 8.4 Hz, lH), 7.5 (m, 2H), 7.36 (m, 3H), 7.2 (s, lH), 6.93 (s, lH), 6.60 (s, lH), 5.27 (s, 2H), 5.0 (s, lH), 4.0 (m, 3H), 3.15 (t, J = 17.6 Hz, 4H), 2. 9 (s, 3H), 2.6 (m, 4H), 2.3 (s, 2H) Example 210
「3-氯 -4-(3-氟-苄氧基) -苯基 146-「l-(2-吡啶 -2-基-乙基) -m-吡咯 -3-基 1-喹唑啉 -4-基 "3-Chloro-4-(3-fluoro-benzyloxy)-phenyl 146-"1-(2-pyridin-2-yl-ethyl)-m-pyrrol-3-yl 1-quinazoline- 4-base
膣  膣
Figure imgf000217_0001
第一步
Figure imgf000217_0001
first step
甲磺酸 ( 2-吡啶 -4-基)乙酯  Methanesulfonic acid (2-pyridin-4-yl)ethyl ester
将 2-吡啶 -2-基 -乙醇 (2.4 g， 20 mmol)溶于 20 mL二氯甲垸中， 在冰浴条件下， 冷却至 0°C， 依次加入三乙胺 (5.5 mL， 40 mmol)和甲磺酰氯 (2.3 mL， 30 mmol), 室温下搅拌 2小时， 反应完毕。 将反应液中加入 30 mL水， 减压下蒸掉二氯甲烷， 用乙酸乙酯萃取 (60 mL X 3)，合并的有机相依次通过饱和氯化钠溶液洗涤，无水硫 酸钠干燥， 过滤， 减压下浓缩， 得到的残留物通过硅胶柱层析进一步分离纯化 (正 己垸： 乙酸乙酯 =3 : 1)， 得到甲磺酸（2-吡啶 -2-基)乙酯 210a (3.9 g， 黄色油状液 体)， 产率： 97%。 2-Pyridin-2-yl-ethanol (2.4 g, 20 mmol) was dissolved in 20 mL of dichloromethane, cooled to 0 ° C under ice-cooling, and then triethylamine (5.5 mL, 40 mmol) And methanesulfonyl chloride (2.3 mL, 30 mmol), stirred at room temperature for 2 hours, and the reaction was completed. The reaction solution was added with 30 mL of water, and the dichloromethane was evaporated under reduced pressure and extracted with ethyl acetate (60 mL EtOAc). The organic layer was dried (MgSO4). Ester 210a (3.9 g, yellow oily liquid), Yield: 97%.
MS m/z (ESI): 202[M+ 1] MS m/z (ESI): 202 [M+ 1]
第二歩  Second
在 50 mL的烧瓶中，将 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-[6-(1Η-吡咯 -3-基) -喹唑啉 -4- 基] -胺 42 (222 mg， 0.5 mmol)溶于 6 mL千燥的 Ν,Ν-二甲基甲酰胺中， 在冰浴条件 下， 冷却至 0Ό， 加入氢化钠 (60 mg， 1.5 mmol), 搅拌 20分钟后加入甲磺酸（ 2- 吡啶 -2-基)乙酯 210a (151 mg， 0.75 mmol), 室温下搅拌 2小时反应完毕。 反应液 减压下浓缩，得到的残留物通过硅胶柱层析进一步分离纯化 (二氯甲垸： 甲醇 = 60: 1)， 得到本标题产物 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-{6-[1-(2-吡啶 -2-基-乙基) -1H-吡咯 -3-基] -喹唑啉 -4-基 } 安 210 (235 mg， 黄色固体)， 产率： 85.6%。  [3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1Η-pyrrol-3-yl)-quinazolin-4-yl] in a 50 mL flask -Amine 42 (222 mg, 0.5 mmol) was dissolved in 6 mL of dry EtOAc EtOAc (EtOAc (EtOAc) After 20 minutes, (2-pyridin-2-yl)ethyl methanesulfonate 210a (151 mg, 0.75 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjjj -phenyl]-{6-[1-(2-pyridin-2-yl-ethyl)-1H-pyrrol-3-yl]-quinazolin-4-yl} An 210 (235 mg, yellow Solid), Yield: 85.6%.
MS m/z (ESI): 550[M+ 1] MS m/z (ESI): 550 [M+ 1]
1H NMR (400 MHz, CD30D-i¾): S9.69(s, lH),8.53(m, 3H),8.02(m, 2H),7.75(m, 1H), 7.70(m, 2H),7.48(m, lH),7.42(s, lH),7.25(m， 6H), 6.85(s, 1H), 6.62(s, lH),5.27(s, 2H),4.35(t, J=7.2Hz, 2H),3.26(t, J=7.2Hz, 2H) 实施例 211  1H NMR (400 MHz, CD30D-i3⁄4): S9.69 (s, lH), 8.53 (m, 3H), 8.02 (m, 2H), 7.75 (m, 1H), 7.70 (m, 2H), 7.48 ( m, lH), 7.42 (s, lH), 7.25 (m, 6H), 6.85 (s, 1H), 6.62 (s, lH), 5.27 (s, 2H), 4.35 (t, J = 7.2 Hz, 2H ), 3.26 (t, J = 7.2 Hz, 2H) Example 211
1-(3-ί4-「3-氯 -4-f3-氟-苄氧基 苯氨基 1-喹唑啉 -6-基}-吡咯 -1-基 3-(U-二氧 -六氢  1-(3-ί4-"3-chloro-4-f3-fluoro-benzyloxyphenylamino-1-quinazoline-6-yl}-pyrrole-1-yl 3-(U-dioxo-hexahydro)
Figure imgf000218_0001
Figure imgf000218_0001
187a  187a
211  211
将 1,1-二氧 -六氢 -1λ*6*-噻喃 -4-基胺盐酸盐（103 mg， 0.56 mmol)和 [3-氯 -4-(3- 氟-苄基) -苯基 ]- [6-(1-环氧乙基甲基 -1H-吡咯 -3-基) -喹唑啉 -4-基] -胺 187a (163 mg, 0.33 mmol)溶于 10 mL甲醇中， 搅拌下加入三乙胺 (82 mg， 0.81 mmol), 加热回流 过夜。 反应液在减压下浓缩， 得到的残留物通过硅胶柱层析进一步分离纯化 (二氯 甲烷： 甲醇 =40: 1)， 得到本标题产物 1-(3-{4-[3-氯 -4-(3-氟- 氧基) -苯氨基] -喹唑 啉 _6-基 吡咯 -1-基) -3-CU-二氧 -六氢 -1λ*6*-噻喃 -4-基氨基) -丙 -2-醇 211 (92 mg,黄 色固体)， 产率： 21.7%。 1,1-Dioxo-hexahydro-1λ*6*-thiopyran-4-ylamine hydrochloride (103 mg, 0.56 mmol) and [3-chloro-4-(3-fluoro-benzyl)- Phenyl]-[6-(1-epoxyethylmethyl-1H-pyrrol-3-yl)-quinazolin-4-yl]-amine 187a (163 mg, 0.33 mmol) dissolved in 10 mL of methanol Triethylamine (82 mg, 0.81 mmol) was added with stirring and heated to reflux overnight. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjj -(3-fluoro-oxy)-phenylamino]-quinazoline-6-ylpyrrolidin-1-yl)-3-CU-dioxy-hexahydro-1λ*6*-thiopyran-4-ylamino ) - propan-2-ol 211 (92 mg, yellow Color solid), Yield: 21.7%.
MS m/z (ESI): 650[M+ 1] MS m/z (ESI): 650 [M+ 1]
1H NMR (400 MHz, CD30D-c¾: S8.55(s, 1H), 8.50(s, 1H), 8.04(m, 2H), 7.77(d, J=9.2Hz, 1H), 7.70(d, J=8.4Hz， 1H), 7.48(m, 1H), 7.43(s, 1H), 7.32(m, 3H), 7.19(t, J=8.8Hz, 1H), 6.89(s,lH), 6.66(s, 1H), 5.27(s, 2H), 5.07(s, 1H), 4.05(m, 1H), 3.88(m, 2H), 3.13(dr, 4H), 3.01(m， 2H), 2.72(m, 2H), 1.24(m, 4H) 实施例 212  1H NMR (400 MHz, CD30D-c3⁄4: S8.55 (s, 1H), 8.50 (s, 1H), 8.04 (m, 2H), 7.77 (d, J = 9.2 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.48 (m, 1H), 7.43 (s, 1H), 7.32 (m, 3H), 7.19 (t, J = 8.8 Hz, 1H), 6.89 (s, lH), 6.66 (s , 1H), 5.27(s, 2H), 5.07(s, 1H), 4.05(m, 1H), 3.88(m, 2H), 3.13(dr, 4H), 3.01(m, 2H), 2.72(m, 2H), 1.24 (m, 4H) Example 212
Γ3-氯 -4-(3-氟-苄氧基) -苯基 1-「6-α-吡啶 -2-基甲基 -1H-吡咯 -3-基) -喹唑啉 -4-基 1-胺  Γ3-Chloro-4-(3-fluoro-benzyloxy)-phenyl 1-"6-α-pyridin-2-ylmethyl-1H-pyrrol-3-yl)-quinazolin-4-yl 1 -amine
Figure imgf000219_0001
Figure imgf000219_0001
第一步  First step
甲磺酸 ( 2-吡啶 -2-基)甲酯 (2-pyridyl- 2 -yl)methyl methanesulfonate
将 2-吡啶 -4-基 -甲醇 (2.18 g， 20 mmol)溶于 30 mL二氯甲烷中，在冰浴条件下， 冷却至 0°C， 依次加入三乙胺 (5.5 mL， 40 mmol)和甲磺酰氯 (2.4 mL， 30 mmol), 室温下搅拌 2小时， 反应完毕。 将反应液中加入 30 mL水， 减压下蒸掉二氯甲烷， 用乙酸乙酯萃取 (30 mLX 3)， 合并的有机相依次通过无水硫酸钠干燥， 过滤， 减压 下浓縮，残留物通过硅胶柱层析分离纯化 (二氯甲烷：甲醇 = 10: 1)，得到甲磺酸（2- 吡啶 -2-基)甲酯 212a (2.3 g， 红褐色固体)， 产率： 61.5 %。  2-Pyridin-4-yl-methanol (2.18 g, 20 mmol) was dissolved in dichloromethane (30 mL), cooled to 0 ° C, and then triethylamine (5.5 mL, 40 mmol) Methanesulfonyl chloride (2.4 mL, 30 mmol) was stirred at room temperature for 2 hours and the reaction was completed. The reaction mixture was added with water (30 mL), EtOAc (EtOAc m. Purification by silica gel column chromatography (dichloromethane:methanol = 10:1) afforded (2-pyridin-2-yl)methyl methanesulfonate 212a (2.3 g, red brown solid), yield: 61.5 % .
MS m/z (ESI): 188[M+ 1] 第二步 MS m/z (ESI): 188[M+ 1] Step 2
[3-氯 -4-(3-氟-苄氧基) -苯基 ]-[6-(1-吡啶 -4-基甲基 -1H-吡咯 -3-基)-喹唑啉 -4-基] -胺 在 50 mL的烧瓶中，将 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-[6-(1Η-吡咯 -3-基) -喹唑啉 -4- 基] -胺 42 (222 mg， 0.5 mmol)溶于 6 mL干燥的 Ν,Ν-二甲基甲酰胺中， 在冰浴条件 下， 冷却至 0°C， 加入氢化钠 (60 mg， 1.5 mmol), 搅拌 20分钟后加入甲磺酸（ 2- 吡啶 -2-基)甲酯 212a (136 mg， 0.73 mmol), 室温下搅拌 2小时反应完毕。 反应液 减压下浓缩，得到的残留物通过硅胶柱层析进一步分离纯化 (二氯甲烷： 甲醇 =60: 1)， 得到本标题产物 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-[6-(1-吡啶 -2-基甲基 -1H-吡咯 -3- 基) -喹唑啉 -4-基] -胺 212 (22 mg， 黄色固体)， 产率： 84%。 [3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1-pyridin-4-ylmethyl-1H-pyrrol-3-yl)-quinazoline-4- [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1Η-pyrrol-3-yl)-quinazoline- in a 50 mL flask 4-Alkyl]-Amine 42 (222 mg, 0.5 mmol) dissolved in 6 mL of dry hydrazine, s-dimethylformamide, in ice bath After cooling to 0 ° C, sodium hydride (60 mg, 1.5 mmol) was added, and after stirring for 20 minutes, (2-pyridin-2-yl)methyl methanesulfonate 212a (136 mg, 0.73 mmol) was stirred at room temperature. The reaction was completed in 2 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjjj -Phenyl]-[6-(1-pyridin-2-ylmethyl-1H-pyrrol-3-yl)-quinazolin-4-yl]-amine 212 (22 mg, yellow solid), yield : 84%.
MS m/z (ESI): 536[M+ 1] MS m/z (ESI): 536 [M+ 1]
1H NMR (400 MHz, CD30D-Jd): 59.69(s, lH),8.57(m, 2H),8.50(s, lH),8.01(m, 2H),7.76(m, 3H)， 7.49(m, 2H),7.33(m, 4H)，7.16(m， 2H),7.02(s, 1H), 6.73(s， lH),5.27(m: 4H) 实施例 2131H NMR (400 MHz, CD30D- J d): 59.69 (s, lH), 8.57 (m, 2H), 8.50 (s, lH), 8.01 (m, 2H), 7.76 (m, 3H), 7.49 (m , 2H), 7.33 (m, 4H), 7.16 (m, 2H), 7.02 (s, 1H), 6.73 (s, lH), 5.27 (m : 4H) Example 213
— 1-(3_ -「 3-氟-苄基) -IH-吲唑 -5-基氨基 1-喹唑啉 -6-基 吡咯小基) -3-吗啉 -4- 基-丙 -2-醇  — 1-(3_ -"3-Fluoro-benzyl)-IH-indazol-5-ylamino-1-quinazolin-6-ylpyrroleyl)-3-morpholin-4-yl-propane-2 - alcohol
Figure imgf000220_0001
Figure imgf000220_0001
第一步  First step
(R)_4-环氧乙基甲基吗啉 ( R) _4-Epoxyethylmethylmorpholine
在 100 mL茄形瓶中， 将吗啉 (5 g, 57mmol)溶于 2.5 mL叔丁醇中， 在氩气氛 下， 将反应液冷却至 0°C， 缓慢滴加 (R)-2-氯甲基环氧乙垸 213a (5.4g， 59mmol), 保持 (TC搅拌 30分钟后， 升至室温反应过夜。 在冰浴冷却下， 保持 15°C以下， 滴 加 30 mL叔丁醇钾 (6.3g， 56mmol)的四氢呋喃溶液，滴加完毕后，在此温度下反应 2小时后反应完毕。将反应液倒入 100 mL冰水中， 用二氯甲烷 (50 mLx3)萃取， 合 并的有机相依次通过饱和氯化钠溶液洗涤， 无水硫酸钠干燥， 过滤， 减压下浓缩， 得到的残留物通过硅胶柱层析进一步分离纯化， 得到化合物 (R)-4-环氧乙基甲基吗 啉 213b (5.65g， 黄色油状液体)， 产率： 69.2%。  In a 100 mL eggplant-shaped flask, morpholine (5 g, 57 mmol) was dissolved in 2.5 mL of tert-butanol, and the reaction solution was cooled to 0 ° C under argon atmosphere, and (R)-2-chloro was slowly added dropwise. Methyl oxirane 213a (5.4 g, 59 mmol), kept (TC stirred for 30 minutes, allowed to react to room temperature overnight. Under ice cooling, keep below 15 ° C, add 30 mL of potassium t-butoxide (6.3 g, 56 mmol) of tetrahydrofuran solution, after completion of the dropwise addition, the reaction was completed after 2 hours at this temperature. The reaction solution was poured into 100 mL of ice water, extracted with dichloromethane (50 mL×3), and the combined organic phases were passed sequentially. The mixture was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and evaporated. (5.65 g, yellow oily liquid), Yield: 69.2%.
MS m/z (ESI): 144[M+ 1] MS m/z (ESI): 144 [M+ 1]
第二步 (R)-l-(3-{4-[l-(3-氟- 基) -1H-吲唑 -5-基氨基] -喹唑啉 -6-基} -吡咯 -1-基) -3-吗啉 -4- 基-丙 -2-醇 Second step (R)-l-(3-{4-[l-(3-Fluoro-yl)-1H-indazol-5-ylamino]-quinazolin-6-yl}-pyrrol-1-yl)- 3-morpholin-4-yl-propan-2-ol
将 {6-[1-(2-二乙氨基-乙基) -1H-吡咯 -3-基] -喹唑啉 -4-基 }-[1-(3-氟苄基) -1H-吲唑 -5-基] -胺 150 (200 mg， 0.46mmol)溶于 4 mLN,N-二甲基甲酰胺中， 0°C下加入氢化 钠 (150 mg， 3.75mmol),搅拌 30分钟后，加入 (R)-4-环氧乙基甲基吗啉 213b (98 mg， 0.69mmol), 反应液在室温下搅拌过夜。 将反应液倒入 100 mL冰水中， 用乙酸乙 酯 (40 mLx4)萃取， 合并有机相， 依次用饱和氯化钠溶液洗涤， 无水硫酸钠干燥， 过滤， 减压下浓缩， 得到的残留物通过硅胶柱层析进一步分离纯化， 得到标题产 物 (R)-l-(3-{4-[l-(3-氟-苄基) -1H-吲唑 -5-基氨基]-喹唑啉 -6-基}-吡咯 -1-基) -3-吗啉 -4-基-丙 -2-醇 213 (56 mg， 淡黄色固体)， 产率： 21.1 %。  {6-[1-(2-Diethylamino-ethyl)-1H-pyrrol-3-yl]-quinazolin-4-yl}-[1-(3-fluorobenzyl)-1H-indole The oxazol-5-yl]-amine 150 (200 mg, 0.46 mmol) was dissolved in 4 mL of N,N-dimethylformamide, sodium hydride (150 mg, 3.75 mmol) was added at 0 ° C and stirred for 30 min. (R)-4-Epoxyethylmethylmorpholine 213b (98 mg, 0.69 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into 100 mL of ice water, and extracted with ethyl acetate (40 mL×4), and the organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Further separation and purification by silica gel column chromatography gave the title product (R)-l-(3-{4-[l-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-quinazoline -6-yl}-pyrrol-1-yl)-3-morpholin-4-yl-propan-2-ol 213 (56 mg, pale yellow solid), yield: 21.1%.
MS m/z (ESI): 578[M+ 1] MS m/z (ESI): 578 [M+ 1]
lBNMR (400MHz, CD30D-i¾): 59.82(s,lH), 8.60(s,lH), 8.44(s，lH), 8.23(s,lH), 8.17(s,lH), 8.03(d,lH,J=8.8Hz), 7.73(m,3H), 7.43(s,lH), 7.38(m,lH), 7.10(m,3H), 6.88(s,lH), 6.67(s,lH), 5.72(s,2H), 4.96(s,lH), 3.97(m,3H), 3.61(m,4H), 2.43(m,4H), 2.26(m,2H) 实施例 214 lBNMR (400MHz, CD30D-i3⁄4): 59.82(s,lH), 8.60(s,lH), 8.44(s,lH), 8.23(s,lH), 8.17(s,lH), 8.03(d,lH, J=8.8Hz), 7.73(m,3H), 7.43(s,lH), 7.38(m,lH), 7.10(m,3H), 6.88(s,lH), 6.67(s,lH), 5.72( s, 2H), 4.96 (s, lH), 3.97 (m, 3H), 3.61 (m, 4H), 2.43 (m, 4H), 2.26 (m, 2H).
(S)-l-(3-i4-「l-(3-氟-苄基) -1H-吲唑 -5-基氨基 1-喹唑啉 -6-基 }-吡咯 -1-基) -3-吗啉 -4-基  (S)-l-(3-i4-"1-(3-Fluoro-benzyl)-1H-indazol-5-ylamino-1-quinazolin-6-yl}-pyrrol-1-yl) - 3-morpholin-4-yl
-丙 -2-醇  -propan-2-ol
Figure imgf000221_0001
Figure imgf000221_0001
第一步  First step
(S)-4-环氧乙基甲基吗啉  (S)-4-epoxyethylmethylmorpholine
在 100 mL茄形瓶中， 将吗啉 (5 g, 57mmol)溶于 2.5 mL叔丁醇中， 在氩气氛 下， 将反应液冷却至 0°C， 缓慢滴加 (S)-2-氯甲基环氧乙烷 214a (5.4g， 59mmol), 保持 0°C搅拌 30分钟后， 升至室温反应过夜。 在冰浴冷却下， 保持 15°C以下， 滴 加 30 mL叔丁醇钾 (6.3g， 56mmol)的四氢呋喃溶液，滴加完毕后，在此温度下反应 2小时后反应完毕。将反应液倒入 100 mL冰水中， 用二氯甲烷 (50 mLx4)萃取， 合 并的有机相依次通过饱和氯化钠溶液洗涤， 无水硫酸钠干燥， 过滤， 减压下浓缩， 得到的残留物通过硅胶柱层析进一步分离纯化， 得到化合物 (S)-4-环氧乙基甲基吗 啉 214b (6.3g， 黄色油状液体)， 产率： 69.2%。 In a 100 mL eggplant-shaped flask, morpholine (5 g, 57 mmol) was dissolved in 2.5 mL of tert-butanol, and the reaction solution was cooled to 0 ° C under argon atmosphere, and (S)-2-chloro was slowly added dropwise. Methyl oxirane 214a (5.4 g, 59 mmol) was stirred at 0 ° C for 30 minutes and then allowed to warm to room temperature overnight. Under ice cooling, keep below 15 ° C, add 30 mL of potassium t-butoxide (6.3 g, 56 mmol) in tetrahydrofuran solution, after the addition is completed, react at this temperature. The reaction was completed after 2 hours. The reaction solution was poured into 100 mL of ice water, and extracted with dichloromethane (50 mL×4). The combined organic phases were washed successively with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Further separation and purification by silica gel column chromatography gave Compound (S)-4-Epoxyethylmethylmorpholine 214b (6.3 g, yellow oily liquid). Yield: 69.2%.
MS m/z (ESI): 144[M+ 1] MS m/z (ESI): 144 [M+ 1]
笛―上!^  Flute - on!^
(S)-l-(3-{4-[l-(3-氟-苄基) -1H-吲唑 -5-基氨基] -喹唑啉 -6-基}-吡咯 -1-基) -3-吗啉 -4-基  (S)-l-(3-{4-[l-(3-Fluoro-benzyl)-1H-indazol-5-ylamino]-quinazolin-6-yl}-pyrrol-1-yl) -3-morpholin-4-yl
-丙 -2-醇  -propan-2-ol
将 {6-[1-(2-二乙氨基-乙基) -1H-吡咯 -3-基]-喹唑啉 -4-基 }-[1-(3-氟苄基) -1H-吲唑 -5-基] -胺 150 (200 mg， 0.46mmol)溶于 4 mLN，N-二甲基甲酰胺中， 0°C下加入氢化 钠 (150 mg， 3.75mmol),搅拌 30分钟后，加入 (S)-4-环氧乙基甲基吗啉 214b (98 mg， 0.69mmol), 反应液在室温下搅拌过夜， 反应完毕。 将反应液倒入 100 mL冰水中， 用乙酸乙酯 (40 mLx4)萃取， 合并有机相， 依次用饱和氯化钠溶液洗涤， 无水硫酸 钠干燥， 过滤， 减压下浓缩， 得到的残留物通过硅胶柱层析进一步分离纯化， 得 到标题产物 (S)-l-(3-{4-[l-(3-氟-苄基) -1H-吲唑 -5-基氨基] -喹唑啉 -6-基} -吡咯 -1- 基 )_3-吗啉 -4-基-丙 -2-醇 214 (70 mg， 淡黄色固体)， 产率： 35.1 %。  {6-[1-(2-Diethylamino-ethyl)-1H-pyrrol-3-yl]-quinazolin-4-yl}-[1-(3-fluorobenzyl)-1H-indole The oxazol-5-yl]-amine 150 (200 mg, 0.46 mmol) was dissolved in 4 mL of N,N-dimethylformamide, sodium hydride (150 mg, 3.75 mmol) was added at 0 ° C and stirred for 30 min. (S)-4-Epoxyethylmethylmorpholine 214b (98 mg, 0.69 mmol) was added, and the reaction mixture was stirred at room temperature overnight, and the reaction was completed. The reaction mixture was poured into 100 mL of ice water, and extracted with ethyl acetate (40 mL×4), and the organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure Further separation and purification by silica gel column chromatography gave the title product (S)-l-(3-{4-[l-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-quinazoline -6-yl}-pyrrol-1-yl)-3-morpholin-4-yl-propan-2-ol 214 (70 mg, pale yellow solid), yield: 35.1.
MS m/z (ESI): 578[M+ 1] 实施例 215 MS m/z (ESI): 578 [M+ 1] EXAMPLE 215
2-(3-M-「3-氯 -4-(3-氟-苄氧基) -苯氨基 1-喹唑啉 -6-基 吡咯 -1-基)小哌啶 -1-基 -乙酮  2-(3-M-"3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino-1-quinazolin-6-ylpyrrol-1-yl)piperidine-1-yl-B Ketone
Figure imgf000222_0001
第一步
Figure imgf000222_0001
first step
2-氯 -1-哌啶 -1-基 -乙酮  2-chloro-1-piperidin-1-yl-ethanone
将哌啶 (850 mg， 10 mmol)溶于 40 mL二氯甲垸中，加入三乙胺 (2.02 g， 20 mmol), 冰浴冷却至 -78Ό， 搅拌下加入氯乙酰氯 (1.13 g， 10 mmol), 搅拌 30分钟后反应完 毕。 在反应液中加入 10 mL冰水， 减压下蒸去二氯甲垸， 残渣用乙酸乙酯萃取 (20 mLX 3), 合并的有机相通过水洗涤， 无水硫酸钠干燥， 过滤， 减压下浓缩， 得到 的残留物通过硅胶柱层析进一歩分离纯化 (二氯甲烷： 甲醇 = 1 : 1)， 得到化合物 2- 氯 -1-哌啶 -1-基 -乙酮 215a (1.52 g， 红褐色油状液体)， 产率： 94.4%。  Piperidine (850 mg, 10 mmol) was dissolved in 40 mL of dichloromethane, triethylamine (2.02 g, 20 mmol) was added, and the mixture was cooled to -78 Torr in an ice bath, and chloroacetyl chloride (1.13 g, 10) was added with stirring. Mmmol), the reaction was completed after stirring for 30 minutes. To the reaction mixture, 10 mL of ice water was added, and dichloromethane was evaporated, and the residue was evaporated to ethyl acetate. The residue was concentrated and purified by silica gel column chromatography (dichloromethane:methanol = 1:1) to give the compound 2-chloro-1-piperidin-1-yl-ethanone 215a (1.52 g, Reddish brown oily liquid), Yield: 94.4%.
MS m/z (ESI): 162[M+ 1] MS m/z (ESI): 162 [M+ 1]
第二步  Second step
2—(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基]-喹唑啉 -6-基}-吡咯 -1-基) -1-哌啶 -1-基 -乙酮 在 50 mL的烧瓶中， 将 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-[6-(1Η-吡咯 -3-基) -喹唑啉 -4-基] -胺 42 (222 mg, 0.5 mmol)溶于 4 mL Ν,Ν-二甲基甲酰胺中， 在冰浴条件下， 冷却至 0°C， 加入氢化钠 (60 mg， 1.5 mmol), 搅拌 20分钟后加入 2-氯 -1-哌啶 -1- 基 -乙酮 215a (121 mg, 0.75 mmol), 室温下搅拌 1.5小时反应完毕。 反应液减压下 浓缩， 得到的残留物通过硅胶柱层析进一歩分离纯化 (二氯甲烷： 甲醇 = 30: 1)， 得到本标题产物 2-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基 吡咯 -1-基) -1- 哌啶 -1-基 -乙酮 215 (101 mg, 黄色固体)， 产率： 35.4%。  2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-pyrrol-1-yl)-1-piperidine- 1-methyl-ethanone [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1Η-pyrrol-3-yl)-quinazole in a 50 mL flask Phenyl-4-yl]-amine 42 (222 mg, 0.5 mmol) was dissolved in 4 mL EtOAc EtOAc (EtOAc) 1.5 mmol), after stirring for 20 minutes, 2-chloro-1-piperidin-1-yl-ethanone 215a (121 mg, 0.75 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjjj -(3-Fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylpyrrolidin-1-yl)-1-piperidin-1-yl-ethanone 215 (101 mg, yellow solid) Rate: 35.4%.
MS m/z (ESI): 570[M+ 1] MS m/z (ESI): 570 [M+ 1]
1H NMR (400 MHz, CD30D-i¾: 59.71(s, lH),8.54(s, lH),8.50(s, lH),8.03(m, 2H), 7.75(m, 2H), 7.47(m, lH),7.31(m, 4H),7.19(m, 1H), 6.82(s, 1H), 6.65(s, lH),5.27(s, 2H), 4.94(s, 2H), 3.46(t, J=5.2Hz, 4H), 3.3 l(m, 1H), 1.46-1.61(br, 6H) 1H NMR (400 MHz, CD30D-i3⁄4: 59.71 (s, lH), 8.54 (s, lH), 8.50 (s, lH), 8.03 (m, 2H), 7.75 (m, 2H), 7.47 (m, lH) ), 7.31 (m, 4H), 7.19 (m, 1H), 6.82 (s, 1H), 6.65 (s, lH), 5.27 (s, 2H), 4.94 (s, 2H), 3.46 (t, J = 5.2 Hz, 4H), 3.3 l(m, 1H), 1.46-1.61 (br, 6H)
实施例 216 Example 216
2—(3-{4-「3-氯 -4-( -氟-苄氧基) -苯氨基 1-喹唑啉 -6-基 吡咯 -1-基 -Ν,Ν-二乙基 -乙酰  2-(3-{4-"3-chloro-4-(-fluoro-benzyloxy)-phenylamino-1-quinazolin-6-ylpyrrol-1-yl-indole, hydrazine-diethyl-acetyl
Figure imgf000223_0001
Figure imgf000224_0001
Figure imgf000223_0001
Figure imgf000224_0001
第一步  First step
2-氯 -Ν,Ν-二乙基乙酰胺  2-chloro-indole, hydrazine-diethylacetamide
将二乙胺 (11.6 g， 159 mmol)溶于 60 mL四氢呋喃中， 在干冰乙醇浴冷却至一 78°C， 搅拌下逐渐滴加氯乙酰氯 (6 g， 53 mmol), 滴加完毕在冰浴冷却下搅拌 30 分钟， 反应完毕。 在反应液中加入 20 mL水， 减压下蒸去四氢呋喃， 得到的溶液 用乙酸乙酯萃取 (100 mL X 3)， 合并的有机相依次通过水洗涤， 无水硫酸钠干燥， 过滤，减压下浓缩，得到粗品 2-氯 -Ν,Ν-二乙基乙酰胺 216a (6.2 g，黄色油状液体)， 产物不经分离直接进行下一步反应。  Diethylamine (11.6 g, 159 mmol) was dissolved in 60 mL of tetrahydrofuran, cooled to 78 ° C in a dry ice ethanol bath, and gradually added with chloroacetyl chloride (6 g, 53 mmol) with stirring. The mixture was stirred for 30 minutes under cooling, and the reaction was completed. To the reaction mixture, 20 mL of water was added, and the mixture was evaporated to dryness, and the mixture was evaporated to ethyl ether (ethyl acetate). Concentration gave the crude 2-chloro-indole, hydrazine-diethylacetamide 216a (6.2 g, yellow oily).
MS m/z (ESI): 150[M+ 1] MS m/z (ESI): 150 [M+ 1]
第二步  Second step
2-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基}-吡咯 -1-基) -Ν,Ν-二乙基 -乙酰 胺  2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-pyrrol-1-yl)-indole, fluorene-di Ethyl-acetamide
将化合物 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-[6-(1Η-吡咯 -3-基) -喹唑啉 -4-基] -胺 42 (500 mg， 1.12 mmol)和氢化钠 （134 mg, 3.36 mmol)溶于 10 mLN,N-二甲基甲酰 胺中， 室温下搅拌 30分钟后加入 2-氯 -Ν,Ν-二乙基乙酰胺 216a (184 mg， 1.23 mmol),室温下搅拌 30分钟后反应完毕。在反应液中加入 100 mL饱和氯化钠溶液 淬灭反应， 水相用乙酸乙酯萃取 (100 mL X 3)， 合并的有机相依次通过水 (100 mL X 3)洗涤， 饱和氯化钠溶液洗涤 (100 mL X 3), 无水硫酸钠干燥， 过滤， 减压下浓 縮， 得到的残留物通过硅胶柱层析进一步分离纯化 (乙酸乙酯： 正己烷 = 1 : 1)， 得 到标题产物 2-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基 吡咯 -1-基) -Ν,Ν- 二乙基-乙酰胺 216(385 mg， 黄色固体)， 产率： 57.4%。  The compound [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1Η-pyrrol-3-yl)-quinazolin-4-yl]-amine 42 (500 mg , 1.12 mmol) and sodium hydride (134 mg, 3.36 mmol) dissolved in 10 mL of N,N-dimethylformamide, stirred at room temperature for 30 min, then added 2-chloro-indole, Ν-diethylacetamide 216a ( 184 mg, 1.23 mmol), the reaction was completed after stirring at room temperature for 30 minutes. The reaction mixture was quenched by the addition of 100 mL of saturated sodium chloride solution. The aqueous phase was extracted with ethyl acetate (100 mL X 3), and the combined organic phases were washed sequentially with water (100 mL X 3), saturated sodium chloride solution After washing (100 mL of X3), EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 2-(3-{4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylpyrrol-1-yl)-indole, fluorene-diethyl - acetamide 216 (385 mg, yellow solid), Yield: 57.4%.
MS m/z (ESI): 558[M+ 1] MS m/z (ESI): 558 [M+ 1]
1H NMR (400 MHz, CD30D-i¾): 59.72(s , 1H) , 8.55(s， 1H)， 8.50(s , 1H) , 8.03(d , J=8.8Hz , 2H) , 7.76(dd , J=2Hz , 1H) , 7.71(d , J=8.4Hz , 1H) , 7.47(m , 1H) , 7.3 l(m , 4H)， 7.19(m , 1H) , 6.84(s , 1H) , 6.66(s , 1H) , 5.27(s , 2H) , 4.93(s , 2H) , 3.39(m , 4H)， U8(t , J=6.8Hz , 3H) , 1.06(t , J=1.2Hz , 3H) 实施例 217 2-( -ί4-「3-氯 -4-(3-氟- 氧基 苯氨基 Ί-喹唑啉 -6-基 吡咯 -1-基 N-环 1H NMR (400 MHz, CD30D-i3⁄4): 59.72 (s, 1H), 8.55 (s, 1H), 8.50 (s, 1H), 8.03 (d, J = 8.8 Hz, 2H), 7.76 (dd, J = 2Hz , 1H) , 7.71(d , J=8.4Hz , 1H) , 7.47(m , 1H) , 7.3 l(m , 4H), 7.19(m , 1H) , 6.84(s , 1H) , 6.66(s , 1H), 5.27(s, 2H), 4.93(s, 2H), 3.39(m, 4H), U8(t, J=6.8Hz, 3H), 1.06(t, J=1.2Hz, 3H) Example 217 2-( -ί4-"3-chloro-4-(3-fluoro-oxyphenylaminopurine-quinazolin-6-ylpyrrolidin-1-yl N-ring
Figure imgf000225_0001
第 ^ "歩
Figure imgf000225_0001
The first ^ "歩
2-氯 -N-环丙基-乙酰胺  2-chloro-N-cyclopropyl-acetamide
将氯乙酰氯 (2.26 g， 20 mmol)溶于 30 mL乙醚中， 在冰浴条件下， 冷却至 0°C， 缓慢滴加环丙基胺 (2.28 g， 40 mmol), 1小时后滴加完毕，有固体析出。加入 30 mL 氯仿， 搅拌 15分钟， 过滤， 滤液在减压下浓缩， 得到的白色固体用 50 mL二氯甲 烷溶解， 用水洗涤 (50 mL X 3)， 有机相通过无水硫酸钠干燥， 过滤， 减压下浓缩， 得到的 2-氯 -N-环丙基-乙酰胺 217a (1.32 g, 白色固体)， 产率： 50%  Dissolve chloroacetyl chloride (2.26 g, 20 mmol) in 30 mL of diethyl ether, cool to 0 ° C under ice-cooling, slowly add cyclopropylamine (2.28 g, 40 mmol), and add 1 hour later. At the end, a solid precipitated. After adding 30 mL of chloroform, the mixture was stirred for 15 minutes, and the filtrate was evaporated. EtOAcjjjjjjjjjjjj Concentration under reduced pressure gave 2-chloro-N-cyclopropyl-acetamide 217a (1.32 g, white solid), yield: 50%
MS m/z (ESI): 134[M+ 1] 第二步 MS m/z (ESI): 134[M+ 1] Step 2
2-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基]-喹唑啉 -6-基}-吡咯 -1-基) -N-环丙基-乙酰胺 在 50 mL的烧瓶中，将 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-[6-(1Η-吡咯 -3-基) -喹唑啉 -4- 基] -胺 42 (167 mg， 0.375 mmol)溶于 2.5 mL干燥的 Ν,Ν-二甲基甲酰胺中， 在冰浴 条件下，冷却至 0°C，加入氢化钠 (45 mg， 1.13 mmol),搅拌 20分钟后加入 2-氯 -N- 环丙基-乙酰胺 217a (60 mg， 0.45 mmol), 室温下搅拌 3小时反应完毕。 在反应液 中加入 50 mL水， 用乙酸乙酯萃取反应液 (50 mL X 3)， 合并的有机相依次通过无 水硫酸钠干燥， 过滤， 减压下浓缩， 得到的残留物通过硅胶柱层析进一步分离纯 化 (二氯甲烷： 甲醇 = 10: 1)， 得到本标题产物 2-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨 基] -喹唑啉 -6-基} -吡咯 -1-基) -N-环丙基-乙酰胺 217 (110 mg， 黄色固体)， 产率： 54 %。 MS m/z (ESI): 541 [M+ l] 2-(3-{4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-pyrrol-1-yl)-N-cyclopropyl - acetamide in a 50 mL flask, [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1Η-pyrrol-3-yl)-quinazoline-4 -yl]-amine 42 (167 mg, 0.375 mmol) dissolved in 2.5 mL of dry hydrazine, dimethyl-dimethylformamide, cooled to 0 ° C under ice-bath, and sodium hydride (45 mg, 1.13) After stirring for 20 minutes, 2-chloro-N-cyclopropyl-acetamide 217a (60 mg, 0.45 mmol) was added, and the mixture was stirred at room temperature for 3 hours. 50 mL of water was added to the reaction mixture, and the reaction mixture was extracted with ethyl acetate (50 mL EtOAc). Further separation and purification (dichloromethane: methanol = 10:1) gave the title product 2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quin. Oxazolin-6-yl}-pyrrol-1-yl)-N-cyclopropyl-acetamide 217 (110 mg, yellow solid), yield: 54%. MS m/z (ESI) : 541 [M+ l]
1H NMR (400 MHz, CD30D- ): 59.710 (s,lH) ,8.546(s,lH),8.495(s,lH),8.230(d, J=3.2Hz,lH),8.028(t,J=4.8Hz，2H),7.754(m,lH),7.705(d，J=6.8Hz,lH)，7.469(t,J=5.4Hz,l H),7.322(m,4H),7.197(t,J=3.8Hz,lH),6.833(t,J=1.6Hz,lH),6.665(d,J=1.2Hz,lH),5.266( s,2H),4.540(s,lH),2.670(m,lH),0.649(m,2H),0.448(m,2H) 实施例 218  1H NMR (400 MHz, CD30D-): 59.710 (s, lH), 8.546 (s, lH), 8.495 (s, lH), 8.230 (d, J = 3.2 Hz, lH), 8.082 (t, J = 4.8) Hz, 2H), 7.754 (m, lH), 7.705 (d, J = 6.8 Hz, lH), 7.469 (t, J = 5.4 Hz, l H), 7.322 (m, 4H), 7.197 (t, J = 3.8 Hz, lH), 6.833 (t, J = 1.6 Hz, lH), 6.665 (d, J = 1.2 Hz, lH), 5.266 (s, 2H), 4.540 (s, lH), 2.670 (m, lH) , 0.649 (m, 2H), 0.448 (m, 2H). Example 218
4-Γ(4- -「3-氯 -4-(3-氟-苄氧基) -苯氨基 1-喹唑啉 -6-基 }-lH-吡咯 -2-基甲基) -氨基 哌  4-Γ(4--"3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino-1-quinazolin-6-yl}-lH-pyrrol-2-ylmethyl)-aminopiper
Figure imgf000226_0001
第一步 .
Figure imgf000226_0001
first step.
4-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基]-喹唑啉 -6-基}-111-吡咯 -2-甲醛 将 30 mL N,N-二甲基甲酰胺， 在冰浴条件下， 冷却至 0°C， 加入三氯氧磷 (825 mg， 5.392 mmol),反应升至室温搅拌 1小时后，冷却反应液至 0Ό ,加入 [3-氯 -4-(3- 氟-苄氧基) -苯基 ]-[6-(1Η-吡咯 -3-基) -喹唑啉 -4-基] -胺 42(1.565 g， 3.525 mmol)室温 搅拌 3 小时后反应完毕。 将反应液中加入 50 mL水， 用 2N氢氧化钠溶液调节 ρΗ>11 , 加入 50 mL四氢呋喃， 水相用乙酸乙酯萃取 (50 mLX 3)， 合并的有机相通 过无水硫酸钠干燥， 过滤， 减压下浓缩， 得到的残留物通过硅胶柱层析进一步分 离纯化 (正己烷： 乙酸乙酯 =2: 1)， 得到 4-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑 啉 -6-基}-111-吡咯 -2-甲醛 218a (424 mg， 黄色固体)， 产率： 25.5%。 第二步 4-{4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-111-pyrrole-2-carbaldehyde 30 mL N,N-II Methylformamide, cooled to 0 ° C in an ice bath, added phosphorus oxychloride (825 mg, 5.392 mmol), the reaction was allowed to warm to room temperature and stirred for 1 hour, then the reaction mixture was cooled to 0 Ό, and then added. 4-(3-Fluoro-benzyloxy)-phenyl]-[6-(1Η-pyrrol-3-yl)-quinazolin-4-yl]-amine 42 (1.565 g, 3.525 mmol) stirred at room temperature The reaction was completed after 3 hours. Add 50 mL of water to the reaction solution, adjust ρΗ>11 with 2N sodium hydroxide solution, add 50 mL of tetrahydrofuran, and extract the aqueous phase with ethyl acetate (50 mL×3). The residue was concentrated and purified by silica gel column chromatography (hexane: ethyl acetate = 2:1) to afford 4-{4-[3-chloro-4-(3-fluoro-benzyl) Oxy)phenylamino]-quinazolin-6-yl}-111-pyrrole-2-carbaldehyde 218a (424 mg, yellow solid), yield: 25.5%. Second step
4-[(4-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基 }-m-吡咯 -2-基甲基) -氨基] - 哌啶 -1-甲酸叔丁酯 4 -[(4-{4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-m-pyrrol-2-ylmethyl) - Amino] - piperidine-1-carboxylic acid tert-butyl ester
将 4-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基}-111-吡咯 -2-甲醛 218a (424 mg, 黄色固体)和 4-氨基 -哌啶小甲酸叔丁酯 (133 mg， 0.67 mmol)溶于 20 mL二氯 甲垸中，在室温下搅拌 2小时后加入三 (乙酰氧基)硼氢化钠 (313 mg， 1.476 mmol), 混合液在室温下搅拌过夜。 将反应液中加入 50 mL水， 减压下蒸掉二氯甲烷， 水 相用乙酸乙酯萃取 (50 mLX 3)， 合并的有机相通过无水硫酸钠干燥， 过滤， 减压下 浓缩， 得到的残留物通过 Combi Flash分离， 得到标题产物 4-[(4-{4-[3-氯 -4-(3-氟- 苄氧基) -苯氨基] -喹唑啉 -6-基 }-1Η-吡咯 -2-基甲基) -氨基] -哌啶 -1-甲酸叔丁酯 218 (132 mg, 黄色固体)， 产率： 62.6%。  4-{4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-111-pyrrole-2-carbaldehyde 218a (424 mg, yellow solid And 4-amino-piperidine-succinic acid tert-butyl ester (133 mg, 0.67 mmol) dissolved in 20 mL of dichloromethane, stirred at room temperature for 2 hours, then added sodium tris(acetoxy)borohydride (313 mg) , 1.476 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was combined with 50 mL of EtOAc (EtOAc m. The residue was isolated by Combi Flash to give the title product 4-[(4-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl}- tert-Butyl 218 (132 mg, yellow solid), Yield: 62.6%.
MS m/z (ESI): 657[M+ 1] MS m/z (ESI): 657 [M+ 1]
1H NMR (400 MHz, CD30D-t¾: 511.18(dr, 1H), 9.85(s, 1H), 8.58(m, 2H), 8.08(s, 1H): 7.95(d, J=8.8Hz, 1H), 7.8 l(m, 2H), 7.48(m, 1H), 7.3 l(m, 3H), 7.19(m, 1H), 7.01(s,lH), 6.44(s, 1H), 5.27(s, 2H), 4.22(dr, 2H), 3.90(m, 2H), 3.18(m, 1H), 2.68(dr, 2H), 1.92(m, 4H), 1.37(s, 9H) 实施例 219 1H NMR (400 MHz, CD30D-t3⁄4: 511.18 (dr, 1H), 9.85 (s, 1H), 8.58 (m, 2H), 8.08 (s, 1H) : 7.95 (d, J = 8.8 Hz, 1H), 7.8 l(m, 2H), 7.48(m, 1H), 7.3 l(m, 3H), 7.19(m, 1H), 7.01(s,lH), 6.44(s, 1H), 5.27(s, 2H) 4.22(dr, 2H), 3.90(m, 2H), 3.18(m, 1H), 2.68(dr, 2H), 1.92(m, 4H), 1.37(s, 9H) Example 219
l-(3- -「3-氯 -4-(3-氟-苄氧基 苯氨基 1-喹唑啉 -6-基 μ吡咯 -1-基 3-(2-哌啶 -1-基-乙 氨基) -丙 -2-醇  L-(3- -"3-Chloro-4-(3-fluoro-benzyloxyphenylamino-1-quinazolin-6-ylpyrrol-1-yl-3-(2-piperidin-1-yl-) Ethylamino)-propan-2-ol
Figure imgf000227_0001
将 [3-氯 -4-(3-氟-苄基) -苯基 ]-[6-(1-环氧乙基甲基 -1H-吡咯 -3-基)-喹唑啉 -4-基] - 胺 187a (150 mg, 0.3 mmol)溶于 10 mL甲醇中，依次搅拌下加入 2-哌啶 -1-基 -乙胺 (42.3 mg, 0.33 mmol), 混合液加热回流 3小时后反应完毕。反应液在减压下浓缩， 得到的残留物通过硅胶柱层析进一步分离纯化 (二氯甲垸： 甲醇 = 50: 1)， 得到本 标题产物 l-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基]-喹唑啉 -6-基 吡咯 -1-基) -3-(2-哌啶 -1-基-乙氨基) -丙 -2-醇 219 (22 mg， 黄色固体)， 产率： 11.7%。
Figure imgf000227_0001
[3-Chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-epoxyethylmethyl-1H-pyrrol-3-yl)-quinazolin-4-yl - Amine 187a (150 mg, 0.3 mmol) was dissolved in 10 mL of MeOH. &lt;EMI ID&gt;&gt;&gt; 2-piperidin-1-yl-ethylamine (42.3 mg, 0.33 mmol). . The reaction solution was concentrated under reduced pressure, and the obtained residue was purified and purified by silica gel column chromatography (dichloromethane:methanol = 50:1) The title product l-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylpyrrol-1-yl)-3-(2- Piperidin-1-yl-ethylamino)-propan-2-ol 219 (22 mg, yellow solid), yield: 11.7%.
MS m/z (ESI): 629[M+1] MS m/z (ESI): 629 [M+1]
1H NMR (400 MHz, CD30D-t¾): S9.70(s，lH),8.54(s,lH)S=8.49(s,lH),  1H NMR (400 MHz, CD30D-t3⁄4): S9.70 (s, lH), 8.54 (s, lH) S = 8.49 (s, lH),
8=8.03(d,J=8Hz,2H),7.76(d,J=8.4Hz,lH),7.70(d,J=8.8Hz,lH),7.48(m,lH),7.41(s,lH),7. 33(m,3H),7.19(t,J=8Hz,lH),6.88(s,lH),6.65(s,lH),5.27(s，2H),4.01(m,lH)，3.88(m,2H),3 .51(m,2H)52.60(t, J =6.6Hz,2H),2.35(m,6H),1.47(br,4H)1.36(m,2H) 实施例 220 8=8.03 (d, J=8 Hz, 2H), 7.76 (d, J=8.4 Hz, lH), 7.70 (d, J=8.8 Hz, lH), 7.48 (m, lH), 7.41 (s, lH) , 7. 33 (m, 3H), 7.19 (t, J = 8 Hz, lH), 6.88 (s, lH), 6.65 (s, lH), 5.27 (s, 2H), 4.01 (m, lH), 3.88 (m, 2H), 3. 51 (m, 2H) 5 2.60 (t, J = 6.6 Hz, 2H), 2.35 (m, 6H), 1.47 (br, 4H) 1.36 (m, 2H) Example 220
1_(3-ί4-Γ3-氯 -4-(3-氟 -苄氧基)-苯氨基 1-喹唑啉 -6-基 吡咯 -1-基) -3-(2-甲氧基 -乙氨 基) -丙 -2-醇  1_(3-ί4-Γ3-chloro-4-(3-fluoro-benzyloxy)-phenylamino-1-quinazolin-6-ylpyrrol-1-yl)-3-(2-methoxy-B Amino)-propan-2-ol
Figure imgf000228_0001
Figure imgf000228_0001
187a  187a
220  220
将 [3-氯 -4-(3-氟-苄基)-苯基] -[6-(1-环氧乙基甲基 -1H-吡咯 -3-基) -喹唑啉 -4-基] - 胺 187a (150 mg， 0.3 mmol)溶于 20 mL异丙醇和 1,2-二氯乙烷 (1： 1)的混合溶剂中， 搅拌下加入 2-甲氧基乙胺 (67.5 mg， 0.9 mmol),混合液加热回流过夜。反应液在减 压下浓缩， 得到的残留物通过硅胶柱层析进一步分离纯化 (二氯甲烷： 甲醇 = 15: 1)， 得到本标题产物 1-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基}-吡咯 -1- 基) -3-(2-甲氧基-乙氨基) -丙 -2-醇 220 (90 mg， 黄色固体)， 产率： 52.3 %。  [3-Chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-epoxyethylmethyl-1H-pyrrol-3-yl)-quinazolin-4-yl - Amine 187a (150 mg, 0.3 mmol) was dissolved in a mixture of 20 mL isopropanol and 1,2-dichloroethane (1:1), and 2-methoxyethylamine (67.5 mg, 0.9 mmol), the mixture was heated to reflux overnight. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjj -(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-pyrrol-1-yl)-3-(2-methoxy-ethylamino)-propan-2-ol 220 (90 mg, yellow solid), Yield: 52.3%.
MS m/z (ESI): 586[M+1] MS m/z (ESI): 586 [M+1]
1H NMR (400 MHz, CD30D-c¾: 59.70(s,lH) , 8.54(s,lH) , 8.49(s,lH) , 8.03  1H NMR (400 MHz, CD30D-c3⁄4: 59.70 (s, lH), 8.54 (s, lH), 8.49 (s, lH), 8.03
(d,J=8Hz,2H)， 7.76 (d,J=8.4Hz,lH) , 7.70 (d,J=8.8Hz,lH) , 7.48 (m,lH) , 7.41 (s,lH) , 7.33 (m,3H) , 7.19 (t,J=8Hz,lH) , 6.88 (s,lH) , 6.65 (s,lH) , 5.27 (s,2H)， 5.05 (br,lH) , 4.01 (m,lH) , 3.88(m,2H) , 3.51 (m,2H) , 3.26 (br,2H) , 3.25 (s,3H) , 2.67 (t,J=5.6Hz,2H) 实施例 221 (d, J = 8 Hz, 2H), 7.76 (d, J = 8.4 Hz, lH), 7.70 (d, J = 8.8 Hz, lH), 7.48 (m, lH), 7.41 (s, lH), 7.33 ( m,3H) , 7.19 (t,J=8Hz,lH) , 6.88 (s,lH) , 6.65 (s,lH) , 5.27 (s,2H), 5.05 (br,lH) , 4.01 (m,lH) , 3.88 (m, 2H), 3.51 (m, 2H), 3.26 (br, 2H), 3.25 (s, 3H), 2.67 (t, J = 5.6 Hz, 2H) Example 221
l-(3_{4-「3-氯 -4-(3-氟-苄氧基) -苯氨某 喹唑啉 -6-基 }-吡咯小基) -3-哌嗪 -1-基-丙 -2- m L-( 3 _{4-"3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino quinazolin-6-yl}-pyrroleyl)-3-piperazin-1-yl -prop-2- m
Figure imgf000229_0001
将 [3-氯 -4-(3-氟-苄基)-苯基] - [6-(1-环氧乙基甲基 -1H-吡咯 -3-基) -喹唑啉 -4-基] - 胺 187a (150 mg, 0.3 mmol)溶于 20 mL异丙醇中， 搅拌下加入无水哌嗪 (80 mg， 0.9 mmol), 混合液加热回流过夜。 反应液在减压下浓缩， 得到的残留物通过硅胶 柱层析进一歩分离纯化 (二氯甲烷： 甲醇 =20: 1)， 得到本标题产物 1-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基} -吡咯 -1-基) -3-哌嗪 -1-基-丙 -2-醇 221 (140 mg, 黄色固体)， 产率： 70%。
Figure imgf000229_0001
[3-Chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-epoxyethylmethyl-1H-pyrrol-3-yl)-quinazolin-4-yl - Amine 187a (150 mg, 0.3 mmol) was dissolved in 20 mL of isopropyl alcohol. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjj 4-(3-Fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-pyrrol-1-yl)-3-piperazin-1-yl-propan-2-ol 221 (140 mg , yellow solid), Yield: 70%.
MS m/z (ESI): 587[M+ 1] MS m/z (ESI): 587 [M+ 1]
1H NMR (400 MHz, CD30O-d6): 59.70 (s,lH) , 8.54 (s,lH) , 8.49 (s,lH), 5=8.03(d,J=8Hz,2H), 7.76 (d,J=8.4Hz,lH), 7.70 (d,J=8.8Hz,lH) , 7.48 (m,lH) , 7.41 (s,lH) , 7.33 (m,3H) , 7.19 (t,J=8Hz,lH) , 6.88(s,lH) , 6.65 (s,lH) , 5.27 (s,2H) , 4.88 (br,lH) , 4.09 (m,lH) , 3.94 (br,lH)， 3.84 (m,lH) , 2.68 (m,4H) , 2.33 (br,4H) , 2.25 (t,J=2.8Hz，2H) 实施例 222 1H NMR (400 MHz, CD30O-d 6 ): 59.70 (s, lH), 8.54 (s, lH), 8.49 (s, lH), 5 = 8.03 (d, J = 8 Hz, 2H), 7.76 (d, J = 8.4 Hz, lH), 7.70 (d, J = 8.8 Hz, lH), 7.48 (m, lH), 7.41 (s, lH), 7.33 (m, 3H), 7.19 (t, J = 8 Hz, lH ), 6.88(s,lH) , 6.65 (s,lH) , 5.27 (s,2H) , 4.88 (br,lH) , 4.09 (m,lH) , 3.94 (br,lH), 3.84 (m,lH) , 2.68 (m, 4H) , 2.33 (br, 4H) , 2.25 (t, J = 2.8 Hz, 2H) Example 222
4-Γ3-(3-{443-氯 -4-(3-氟-苄氧基) -苯氨基 1-喹唑啉 -6-基 吡咯 -1-基 2-羟 -丙基氨基  4-Γ3-(3-{443-chloro-4-(3-fluoro-benzyloxy)-phenylamino-1-quinazoline-6-ylpyrrole-1-yl 2-hydroxy-propylamino
Figure imgf000229_0002
Figure imgf000229_0002
222
Figure imgf000230_0001
222
Figure imgf000230_0001
4-氨基环己醇盐酸盐 (75.8 mg， 0.5 mmol, Alfa)溶于 10 mL甲醇中， 依次搅 拌下加入 2 mL三乙胺和 [3-氯 -4-(3-氟-苄基) -苯基 ]-[6-(1-环氧乙基甲基 -1H-吡咯 -3- 基) -喹唑啉 -4-基] -胺 187a (200 mg， 0.4 mmol),混合液加热回流 2小时后反应完毕。 反应液在减压下浓缩， 得到的残留物通过硅胶柱层析进一步分离纯化 (二氯甲烷： 甲醇 = 10: 1)，得到本标题产物 4-[3-(3-{4-[3-氯 -4-(3-氟- 氧基) -苯氨基] -喹唑啉 -6- 基 吡咯小基 )-2-羟-丙基氨基]-环己醇 222 (94 mg, 黄色固体)， 产率： 38.3 %。 MS m/z (ESI): 616[M+1] 4-Aminocyclohexanol hydrochloride (75.8 mg, 0.5 mmol, Alfa) was dissolved in 10 mL of methanol, and 2 mL of triethylamine and [3-chloro-4-(3-fluoro-benzyl) were added with stirring. -Phenyl]-[6-(1-epoxyethylmethyl-1H-pyrrol-3-yl)-quinazolin-4-yl]-amine 187a (200 mg, 0.4 mmol). The reaction was completed after 2 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjjj Chloro-4-(3-fluoro-oxy)-phenylamino]-quinazolin-6-ylpyrroleyl)-2-hydroxy-propylamino]-cyclohexanol 222 (94 mg, yellow solid) Yield: 38.3 %. MS m/z (ESI): 616 [M+1]
1H NMR (400 MHz, CD30D- ): 59.67 (s,lH)， 8.8(s,lH),8.5 (s,lH), 8.03(d,  1H NMR (400 MHz, CD30D- ): 59.67 (s, lH), 8.8 (s, lH), 8.5 (s, lH), 8.03 (d,
J=8.8Hz,2H)37.76(dd,J=2Hz,lH),7.70(d,J=8.4Hz,lH),7.5(m,2H),7.36(m,3H),7.2(s,lH), 6.93(s,lH),6.60(s,lH),5.27(s,2H),4.5(s,lH),4.05(m,lH),3.95(m,2H), 2.7(m,lH), 2.55(s,l H),2.5(m,2H),2.2(m, 1 H), 1.8(m,4H), 1.25(m,4H) J = 8.8 Hz, 2H) 3 7.76 (dd, J = 2 Hz, lH), 7.70 (d, J = 8.4 Hz, lH), 7.5 (m, 2H), 7.36 (m, 3H), 7.2 (s, lH ), 6.93 (s, lH), 6.60 (s, lH), 5.27 (s, 2H), 4.5 (s, lH), 4.05 (m, lH), 3.95 (m, 2H), 2.7 (m, lH) , 2.55(s,l H),2.5(m,2H),2.2(m, 1 H), 1.8(m,4H), 1.25(m,4H)
― . 实施例 223 - η-Γ2-(3- -「3-氯 -4-(3-氟-苄氧基 苯氨基 1-喹唑啉 -6-基 吡咯 -1-基) -乙基 1-吡咯烷 ― Example 223 - η-Γ2-(3- -"3-chloro-4-(3-fluoro-benzyloxyphenylamino-1-quinazolin-6-ylpyrrol-1-yl)-ethyl 1 -pyrrolidine
-2-基 ^甲醇  -2-yl^methanol
Figure imgf000230_0002
Figure imgf000230_0002
Figure imgf000231_0001
Figure imgf000231_0001
223 第一步  223 first step
2-氯小(2-羟甲基-吡咯垸 -1-基) -乙酮  2-chloro small (2-hydroxymethyl-pyrrole-1-yl)-ethanone
将 2-轻甲基吡咯垸（505 mg， 5 mmol)溶于 10 mL四氢呋喃中， 在丙酮 -干冰 浴条件下，冷却至一 78Ό，加入 1 mL三乙胺，搅拌 15小时后，滴加氯乙酰氯 (0.38 mL, 5 mmol), 搅拌 1小时后反应完毕。 反应物在减压下浓缩， 残留物通过硅胶柱 层析进行分离纯化 (二氯甲烷： 甲醇 = 15 : 1)， 得到无色油状液体粗品 2-氯 -1-(2-羟 甲基-吡咯垸 -1-基) -乙酮 223a， 产物不经分离直接进行下一步反应。  2-light methylpyrrole (505 mg, 5 mmol) was dissolved in 10 mL of tetrahydrofuran, cooled to a temperature of 78 Torr in acetone-dry ice bath, 1 mL of triethylamine was added, stirred for 15 hours, and chlorine was added dropwise. Acetyl chloride (0.38 mL, 5 mmol) was stirred for 1 hour and the reaction was completed. The reaction mixture was concentrated under reduced pressure. EtOAc mjjjjjjj垸-1-yl)-ethanone 223a, the product was directly subjected to the next reaction without isolation.
MS m/z (ESI): 178[M+ 1] MS m/z (ESI): 178 [M+ 1]
第二步  Second step
2-(3-{4-[3-氯 -4-(3-氟苄氧基) -苯氨基] -喹唑啉 -6-基 吡咯 -1-基) -1-(2-羟甲基-吡咯烷  2-(3-{4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazolin-6-ylpyrrol-1-yl)-1-(2-hydroxymethyl) -pyrrolidine
-1-基) -乙酮  -1-yl)-ethanone
在 50 mL的烧瓶中， 将 [3-氯 -4-(3-氟-节氧基) -苯基 ]-[6-(1Η-吡咯 -3-基) -喹唑啉 -4-基] -胺 42 (444 mg， 1 mmol)溶于 10 mL干燥的 Ν,Ν-二甲基甲酰胺中， 在冰浴 条件下，冷却至 0°C，加入氢化钠 （72 mg， 3 mmol)，搅拌 30分钟后加入 2-氯 -1-(2- 羟甲基-吡咯垸 -1-基) -乙酮 223a (213 mg， 1.2 mmol), 室温下搅拌 1小时反应完毕。 反应液减压下浓缩， 得到的残留物通过硅胶柱层析进一歩分离纯化 (二氯甲烷： 甲 醇 = 8 : 1)，得到 2-(3-{4-[3-氯 -4-(3-氟苄氧基) -苯氨基] -喹唑啉 -6-基 比咯 -1-基) -1-(2- 羟甲基-吡咯垸 -1-基) -乙酮 223b (70 mg， 淡黄色固体)， 产率： 10%。  [3-Chloro-4-(3-fluoro-p-ethoxy)-phenyl]-[6-(1Η-pyrrol-3-yl)-quinazolin-4-yl] in a 50 mL flask -Amine 42 (444 mg, 1 mmol) was dissolved in 10 mL dry EtOAc EtOAc (EtOAc) After stirring for 30 minutes, 2-chloro-1-(2-hydroxymethyl-pyrrole-1-yl)-ethanone 223a (213 mg, 1.2 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjjjjjjjjj -fluorobenzyloxy)-phenylamino]-quinazolin-6-ylpyrrol-1-yl)-1-(2-hydroxymethyl-pyrrole-1-yl)-ethanone 223b (70 mg, Light yellow solid), Yield: 10%.
MS m/z (ESI): 587[M+ 1] MS m/z (ESI): 587 [M+ 1]
第三步  third step
{1_[2-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基}-吡咯 -1-基) -乙基] -吡咯烷  {1_[2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-pyrrol-1-yl)-ethyl -pyrrolidine
-2-基} -甲醇 将 2-(3-{4-[3-氯 -4-(3-氟苄氧基) -苯氨基] -喹唑啉 -6-基 吡咯 -1-基) -l-(2-羟甲基- 吡咯垸 -1-基) -乙酮 223b (190 mg， 0.29 mmol)溶于 20 mL四氢呋喃中， 搅拌下加 入氢化铝锂 (32.6 mg， 0.86 mmol), 3小时后反应完毕。 在反应液中加入甲醇淬灭 反应， 减压下浓縮， 得到的残留物通过硅胶柱层析进一步分离纯化， 得到标题产 物 {1-[2-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基 吡咯 -1-基) -乙基] -吡咯 烷 -2-基} -甲醇 223 (40 mg， 黄色固体)， 产率： 24%。 -2-yl}-methanol 2-(3-{4-[3-Chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazolin-6-ylpyrrol-1-yl)-l-(2-hydroxyl) The benzyl-pyrrolidin-1-yl)-ethanone 223b (190 mg, 0.29 mmol) was dissolved in 20 mL of THF, and lithium aluminum hydride (32.6 mg, 0.86 mmol) was added with stirring, and the reaction was completed after 3 hours. The reaction mixture was quenched with EtOAc (EtOAc) (EtOAc). -(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylpyrrol-1-yl)-ethyl]-pyrrolidin-2-yl}-methanol 223 (40 mg, yellow solid) , Yield: 24%.
MS m/z (ESI): 573 [M+ 1] MS m/z (ESI): 573 [M+ 1]
1H NMR (400 MHz, CD30D-i¾)： 69.67 (s，lH)， 8.8(s,lH),8.5 (s,lH), 8.03(d, J=8.8Hz, 2H)37.76(dd,J=2Hz,lH),7.70(d,J=8.4Hz,lH),7.5(m,2H),7.36(m,3H),7.2(s,lH),6.93 (s,lH),6.60(s,lH),5.27(s,2H),4.4(m,2H),4.05(m,2H),3.45(m,5H),2.33(br,lH),1.82(br,l H),1.62(m,2H),1.55(br,lH) 实施例 224 1H NMR (400 MHz, CD30D-i3⁄4): 69.67 (s, lH), 8.8 (s, lH), 8.5 (s, lH), 8.03 (d, J = 8.8 Hz, 2H) 3 7.76 (dd, J = 2 Hz, lH), 7.70 (d, J = 8.4 Hz, lH), 7.5 (m, 2H), 7.36 (m, 3H), 7.2 (s, lH), 6.93 (s, lH), 6.60 (s, lH) ), 5.27 (s, 2H), 4.4 (m, 2H), 4.05 (m, 2H), 3.45 (m, 5H), 2.33 (br, lH), 1.82 (br, l H), 1.62 (m, 2H) ), 1.55 (br, lH) Example 224
Γ3-氯 -4-(3-氟- 氧基) -苯基 146-Γ1-(2-吡啶 -4-基-乙基) -1H-吡咯 -3-基 1-喹唑啉 -4-基  3-chloro-4-(3-fluoro-oxy)-phenyl 146-indole 1-(2-pyridin-4-yl-ethyl)-1H-pyrrol-3-yl-1-quinazolin-4-yl
Figure imgf000232_0001
第一步
Figure imgf000232_0001
first step
甲磺酸（2-吡啶 -4-基)乙酯  (2-pyridin-4-yl)ethyl methanesulfonate
将 2-吡啶 -4-基 -乙醇 (174 mg， 1.42 mmol)溶于 20 mL二氯甲垸中，在冰浴条件 下， 冷却至 0°C， 依次加入三乙胺 (352 mg， 3.5 mmol)和甲磺酰氯 (200 mg, 1.75 mmol), 室温下搅拌 1小时， 反应完毕。将反应液中加入 50 mL水， 减压下蒸掉二 氯甲烷， 用乙酸乙酯萃取 (100 mLX 3)， 合并的有机相依次通过无水硫酸钠干燥， 过滤， 减压下浓缩， 得到的粗品甲磺酸（2-吡啶 -4-基)乙酯 224a (266 mg， 粉色油状 液体)不经分离直接进行下一步反应。 2-Pyridin-4-yl-ethanol (174 mg, 1.42 mmol) was dissolved in 20 mL of dichloromethane, cooled to 0 ° C, and then triethylamine (352 mg, 3.5 mmol) And methanesulfonyl chloride (200 mg, 1.75 mmol), stirred at room temperature for 1 hour, and the reaction was completed. The reaction mixture was added with 50 mL of EtOAc (EtOAc m. Crude (2-pyridin-4-yl)ethyl methanesulfonate 224a (266 mg, pink oil Liquid) The next reaction is carried out without isolation.
MS m/z (ESI): 202[M+ 1]  MS m/z (ESI): 202 [M+ 1]
第二歩  Second
在 50 mL的烧瓶中，将 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-[6-(1Η-吡咯 -3-基) -喹唑啉 -4- 基] -胺 42 (225 mg， 0.51 mmol)溶于 3 mL干燥的 Ν,Ν-二甲基甲酰胺中， 在冰浴条 件下，冷却至 0°C，加入氢化钠 (45 mg， 1.13 mmol),搅拌 20分钟后加入甲磺酸（ 2- 吡啶 -4-基)乙酯 224a (266 mg， 1.32 mmol), 室温下搅拌 1.5小时反应完毕。 反应液 减压下浓缩，得到的残留物通过硅胶柱层析进一步分离纯化 (二氯甲烷： 甲醇 =60: 1)， 得到本标题产物 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-{6-[1-(2-吡啶 -4-基-乙基) -1H-吡咯 -3-基]-喹唑啉 -4-基 胺 224 (5 mg， 黄色固体)， 产率： 1.8 %。  [3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1Η-pyrrol-3-yl)-quinazolin-4-yl] in a 50 mL flask -Amine 42 (225 mg, 0.51 mmol) was dissolved in 3 mL dry EtOAc EtOAc (EtOAc) After stirring for 20 minutes, (2-pyridin-4-yl)ethyl methanesulfonate 224a (266 mg, 1.32 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjjj -phenyl]-{6-[1-(2-pyridin-4-yl-ethyl)-1H-pyrrol-3-yl]-quinazolin-4-ylamine 224 (5 mg, yellow solid) , Yield: 1.8%.
MS m/z (ESI): 550[M+ 1] MS m/z (ESI): 550 [M+ 1]
1H NMR (400 MHz, CD30D-c¾: δ 9.68(s, IH), 8.49(m, 4H), 8.01(m, 2H), 7.75(m, 1H); 7.70(d, J=8.4Hz, IH), 7.49(m, IH), 7.43(s, IH), 7.32(m, 3H), 7.24(m, 2H), 7.19(m, IH): 6.87(s, IH), 6.64(s, IH), 5.27(s, 2H), 4.25(t, J=7.2Hz, 2H), 3.14(t, J=7.2Hz, 2H) 实施例 225 1H NMR (400 MHz, CD30D-c3⁄4: δ 9.68 (s, IH), 8.49 (m, 4H), 8.01 (m, 2H), 7.75 (m, 1H) ; 7.70 (d, J = 8.4 Hz, IH) , 7.49(m, IH), 7.43(s, IH), 7.32(m, 3H), 7.24(m, 2H), 7.19(m, IH): 6.87(s, IH), 6.64(s, IH), 5.27(s, 2H), 4.25(t, J=7.2Hz, 2H), 3.14(t, J=7.2Hz, 2H) Example 225
2-(3-ί4-「3-氯 -4-(3-氟-苄氧基) -苯氨基 1-喹唑啉 -6-基 吡咯 -1-基 N-(U-二氧 -六氢  2-(3-ί4-"3-chloro-4-(3-fluoro-benzyloxy)-phenylamino-1-quinazolin-6-ylpyrrolidin-1-yl N-(U-dioxo-hexahydro
Figure imgf000233_0001
Figure imgf000233_0001
225a  225a
Figure imgf000233_0002
Figure imgf000233_0002
2-氯 -N-(U-二氧代 -六氢 -1λ*6*-噻喃 -4-基) -乙酰胺  2-Chloro-N-(U-dioxo-hexahydro-1λ*6*-thiopyran-4-yl)-acetamide
将 1,1-二氧代 -六氢 -1λ*6*-噻喃 -4-基胺盐酸盐（32 mg， 0.173 mmol)溶于 5 mL 四氢呋喃中， 在冰浴条件下， 冷却至 0°C， 加入三乙胺 (37 mg， 0.366 mmol), 搅拌 下加入氯乙酰氯 (32 mg， 0.283 mmol), 0°C下搅拌 2小时后反应完毕。 反应物在减 压下浓缩， 残留物用二氯甲烷洗涤， 得到化合物 2-氯 -N-(l,l-二氧代 -六氢 -1λ*6*- 噻喃 -4-基) -乙酰胺 225a， 产物不经分离直接进行下一歩反应。 Dissolve 1,1-dioxo-hexahydro-1λ*6*-thiopyran-4-ylamine hydrochloride (32 mg, 0.173 mmol) in 5 mL of tetrahydrofuran and cool to 0 in ice bath °C, add triethylamine (37 mg, 0.366 mmol), stir Chloroacetyl chloride (32 mg, 0.283 mmol) was added, and the reaction was completed after stirring at 0 ° C for 2 hours. The reaction was concentrated under reduced pressure and the residue was purified eluting with methylene chloride to afford compound 2-chloro-N-(l,l-dioxo-hexahydro-1λ*6*-thiopyran-4-yl)-B Amide 225a, the product was directly subjected to the next reaction without isolation.
第二步  Second step
2-(3-{4-[3-氯 -4-(3-氟- 氧基) -苯氨基] -喹唑啉 -6-基 吡咯 -1-基) -N-(l,l-二氧 -六氢  2-(3-{4-[3-chloro-4-(3-fluoro-oxy)-phenylamino]-quinazolin-6-ylpyrrol-1-yl)-N-(l,l-di Oxygen-hexahydrogen
-1λ*6*-噻喃 -4-基)-乙酰胺  -1λ*6*-thiopyran-4-yl)-acetamide
在 50 mL的烧瓶中，将 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-[6-(1Η-吡咯 -3-基) -喹唑啉 -4- 基] -胺 42 (52 mg， 0.117 mmol)溶于 1 mL N,N-二甲基甲酰胺中， 在冰浴条件下， 冷却至 0°C， 加入氢化钠 （29 mg， 0.725 mmol), 搅拌 30分钟后加入 2-氯 -N-(l,l- 二氧代 -六氢 -1λ*6*-噻喃 -4-基) -乙酰胺 225a (39 mg， 0.173 mmol)的 1 mLN,N-二甲 基甲酰胺溶液，室温下搅拌 1.5小时反应完毕。反应液加入 50 mL水， 乙酸乙酯萃 取 (50 mL X 3)， 合并的有机相通过无水硫酸钠干燥， 过滤， 减压下浓缩， 得到的残 留物通过硅胶柱层析进一步分离纯化 (梯度洗脱： 二氯甲烷： 甲醇 = 100: 1， 60： 1)， 得到 2-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基]-喹唑啉 -6-基}-吡咯 -1-基) -N-(l,l-二 氧 -六氢 -1λ*6*-噻喃 -4-基) -乙酰胺 225 (15 mg， 黄色固体)， 产率： 20.3 %。  [3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1Η-pyrrol-3-yl)-quinazolin-4-yl] in a 50 mL flask -Amine 42 (52 mg, 0.117 mmol) was dissolved in 1 mL EtOAc (EtOAc) After a minute, 2-chloro-N-(l,l-dioxo-hexahydro-1λ*6*-thiopyran-4-yl)-acetamide 225a (39 mg, 0.173 mmol) in 1 mL of N,N- The dimethylformamide solution was stirred at room temperature for 1.5 hours and the reaction was completed. The reaction mixture was added with 50 mL of water, EtOAc (EtOAc (EtOAc)EtOAc. Elution: methylene chloride: methanol = 100: 1, 60: 1) to give 2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazole Phenyl-6-yl}-pyrrol-1-yl)-N-(l,l-dioxo-hexahydro-1λ*6*-thiopyran-4-yl)-acetamide 225 (15 mg, yellow solid) , Yield: 20.3 %.
MS m/z (ESI): 634[M+ 1] MS m/z (ESI): 634 [M+ 1]
1H NMR (400 MHz, CD30D-i¾): 69.72(s, IH), 8.55(s, IH), 8.5 l(s, IH), 8.3 l(d, J=7.2Hz IH), 8.03(m, 2H), 7.76(d, J=8.8Hz, IH), 7.7 l(d, J=8.0Hz, IH), 7.49(m, IH), 7.34(m, 3H), 7.18(m, IH), 6.86(s,lH), 6.68(s, IH), 5.28(s, 2H), 4.62(s, 2H), 4.02(m, IH), 3.13(m,4H), 1.31(m, 4H)  1H NMR (400 MHz, CD30D-i3⁄4): 69.72 (s, IH), 8.55 (s, IH), 8.5 l (s, IH), 8.3 l (d, J = 7.2 Hz IH), 8.03 (m, 2H) ), 7.76 (d, J = 8.8 Hz, IH), 7.7 l (d, J = 8.0 Hz, IH), 7.49 (m, IH), 7.34 (m, 3H), 7.18 (m, IH), 6.86 ( s,lH), 6.68(s, IH), 5.28(s, 2H), 4.62(s, 2H), 4.02(m, IH), 3.13(m,4H), 1.31(m, 4H)
实施例 226  Example 226
Γ3-氯 -4-(3-氟-苄氧基) -苯基 1-「6-(1-环丙基甲基 -IH-吡咯 -3-基) -喹唑啉 -4-基 1-胺  3-Chloro-4-(3-fluoro-benzyloxy)-phenyl 1-"6-(1-cyclopropylmethyl-IH-pyrrol-3-yl)-quinazolin-4-yl 1- Amine
Figure imgf000234_0001
第一步
Figure imgf000234_0001
first step
甲磺酸环丙基甲酯  Cyclopropyl methyl sulfonate
将环丙基甲醇 (720 g， lO mmol)溶于 20 mL乙醚中，在冰浴条件下，冷却至 0 。C , 依次加入三乙胺 (2.8 mL， 20 mmol)和甲磺酰氯 (1.2 mL， 15 mmol), 室温下搅 拌 2小时， 反应完毕。 过滤反应液， 滤饼用乙醚洗涤， 滤液在减压下旋干， 得到 甲磺酸环丙基甲酯 226a (1.49 g， 无色油状液体)， 产率： 99.3 % .  Cyclopropylmethanol (720 g, 10 mmol) was dissolved in 20 mL of diethyl ether and cooled to 0 in ice bath. C. Triethylamine (2.8 mL, 20 mmol) and methanesulfonyl chloride (1.2 mL, 15 mmol) were added successively and stirred at room temperature for 2 hr. The reaction solution was filtered, and the filtered cake was washed with diethyl ether, and the filtrate was evaporated to dryness to give the m.p.
MS m/z (ESI): 151 [M+ 1] MS m/z (ESI): 151 [M+ 1]
第二步  Second step
[3-氯 -4-(3-氟-苄氧基) -苯基 ]-[6-(1-吡啶 -4-基甲基 -1H-吡咯 -3-基) -喹唑啉 -4-基] -胺 在 50 mL的烧瓶中，将 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-[6-(1Η-吡咯 -3-基) -喹唑啉 -4- 基] -胺 42 (146 mg， 0.33 mmol)溶于 4 mL干燥的 Ν,Ν-二甲基甲酰胺中， 搅拌下加 入氢化钠 (40 mg， 0.99 mmol), 30分钟后加入甲磺酸环丙基甲酯 226a (74 mg， 0.5 mmol), 在 55°C下搅拌 2小时反应完毕。 反应液加入 30 mL冰水， 用乙酸乙酯萃 取 (30 mLX 4)， 合并的有机相依次通过饱和氯化钠溶液洗涤 (30 mLX 2)， 无水硫酸 钠干燥， 过滤， 减压下浓缩， 得到的残留物通过硅胶柱层析进一步分离纯化 (二氯 甲烷： 甲醇 =60: 1)， 得到本标题产物 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-[6-(1-环丙基甲 基 -1H-吡咯 -3-基)-喹唑啉 -4-基] -胺 226 (81 mg， 黄色固体)， 产率： 49.6%。  [3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1-pyridin-4-ylmethyl-1H-pyrrol-3-yl)-quinazoline-4- [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1Η-pyrrol-3-yl)-quinazoline- in a 50 mL flask 4-Alkyl]-Amine 42 (146 mg, 0.33 mmol) was dissolved in 4 mL dry EtOAc EtOAc (EtOAc (EtOAc) The acid cyclopropylmethyl ester 226a (74 mg, 0.5 mmol) was stirred at 55 ° C for 2 hours. The reaction mixture was added with 30 mL of EtOAc (EtOAc)EtOAc. The residue obtained was further purified by silica gel column chromatography (dichloromethane:methanol=60:1) to give the title product [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[ 6-(1-Cyclopropylmethyl-1H-pyrrol-3-yl)-quinazolin-4-yl]-amine 226 (81 mg, yellow solid), yield: 49.
MS m/z (ESI): 499[M+ 1] MS m/z (ESI): 499 [M+ 1]
1H NMR (400 MHz, CD30D-i¾: 59.69(s, lH),8.53(s, lH),8.50(s, lH),8.04(m, 2H),7.75(m, 1H), 7.70(m, lH),7.49(m, 2H), 7.28(m, 3H),7.19(m, 1H), 6.95(s, 1H), 6.67(s, lH),5.27(s, 2H),3.81(d. J=7.2Hz, 2H),1.24(m, lH),0.56(m, 2H),0.39(m, 2H) 实施例 227  1H NMR (400 MHz, CD30D-i3⁄4: 59.69 (s, lH), 8.53 (s, lH), 8.50 (s, lH), 8.04 (m, 2H), 7.75 (m, 1H), 7.70 (m, lH) ), 7.49 (m, 2H), 7.28 (m, 3H), 7.19 (m, 1H), 6.95 (s, 1H), 6.67 (s, lH), 5.27 (s, 2H), 3.81 (d. J = 7.2 Hz, 2H), 1.24 (m, lH), 0.56 (m, 2H), 0.39 (m, 2H).
2-(3-ί4-「3-氯 -4-(3-氟-苄氧基) -苯氨基 1-喹唑啉 -6-基 吡咯 -1-基) -N-「ar,4r - (4-羟-环 己基 1-乙酰胺  2-(3-ί4-"3-chloro-4-(3-fluoro-benzyloxy)-phenylamino-1-quinazolin-6-ylpyrrol-1-yl)-N-"ar,4r - ( 4-hydroxy-cyclohexyl 1-acetamide
Figure imgf000235_0001
第一步
Figure imgf000235_0001
first step
2-氯 -N-[(k,4r 4-羟基-环己基] -乙酰胺  2-chloro-N-[(k,4r 4-hydroxy-cyclohexyl]-acetamide
将 (lr,4r)-4-氨基环己醇盐酸盐 (115 mg, 0.6 mmol)溶于 10 mL干燥的二氯甲 垸中， 加入三乙胺 (8.3 mL， 60 mmol), 在丙酮-干冰浴条件下， 冷却至—78°C， 滴 加氯乙酰氯 (0.38 mL， 5 mmol), 搅拌 1小时后反应完毕。 反应物在减压下浓缩， 加入 50 mL 乙酸乙酯，过滤，滤饼用 30 mL乙酸乙酯洗涤，有机相在减压下浓缩， 得到化合物 2-氯 -N-(4-羟基-环己基) -乙酰胺 227a (3.55 g，红褐色固体)，产率： 92.7 %  (lr,4r)-4-Aminocyclohexanol hydrochloride (115 mg, 0.6 mmol) was dissolved in 10 mL of dry methylene chloride and triethylamine (8.3 mL, 60 mmol) Under dry ice bath conditions, it was cooled to -78 ° C, and chloroacetyl chloride (0.38 mL, 5 mmol) was added dropwise. After stirring for 1 hour, the reaction was completed. The reaction was concentrated under reduced pressure. EtOAc (EtOAc)EtOAc. - acetamide 227a (3.55 g, reddish brown solid), yield: 92.7 %
MS m/z (ESI): 192[M+ 1]  MS m/z (ESI): 192 [M+ 1]
第二步  Second step
2-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基}-吡咯 -1-基) -N-[(lr,4r)- (4-羟-环 己基]-乙酰胺  2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-pyrrol-1-yl)-N-[(lr , 4r)-(4-hydroxy-cyclohexyl)-acetamide
在 50 mL的烧瓶中，将 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-[6-(1Η-吡咯 -3-基) -喹唑啉 -4- 基] -胺 42 (222 mg， 0.5 mmol)溶于 10 mL干燥的 Ν,Ν-二甲基甲酰胺中， 在冰浴条 件下，冷却至 0°C，加入氢化钠（80 mg, 3.3 mmol),搅拌 30分钟后加入 2-氯 -N-(4- 羟基-环己基) -乙酰胺 227a (115 mg， 0.6 mmol), 室温下搅拌 6小时反应完毕。 将 反应液中加入 50 mL冰水淬灭反应， 有乙酸乙酯萃取 (50 mL X 3), 合并的有机相 通过饱和氯化钠溶液洗涤， 无水硫酸钠干燥， 过滤， 减压下浓缩， 得到的残留物 通过硅胶柱层析进一步分离纯化 (二氯甲烷： 甲醇 =20: 1)，得到 2-(3-{4-[3-氯 P氟-苄氧基) -苯氨基] -喹唑啉 -6-基 吡咯 -1-基) -N-[(lr,4r)- (4-羟 -环己基]-乙酰胺 227 (35 mg, 黄色固体)， 产率： 11.7%。  [3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1Η-pyrrol-3-yl)-quinazolin-4-yl] in a 50 mL flask -Amine 42 (222 mg, 0.5 mmol) was dissolved in 10 mL dry EtOAc EtOAc (EtOAc) After stirring for 30 minutes, 2-chloro-N-(4-hydroxy-cyclohexyl)acetamide 227a (115 mg, 0.6 mmol) was added, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was quenched with EtOAc (EtOAc) (EtOAc) The residue obtained is further purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to give 2-(3-{4-[3-chloro-P-fluoro-benzyloxy)-phenylamino]-quine Oxazolin-6-ylpyrrolidin-1-yl)-N-[(lr,4r)-(4-hydroxy-cyclohexyl]-acetamide 227 (35 mg, yellow solid), yield: 11.7%.
MS m/z (ESI): 600[M+ 1] MS m/z (ESI): 600[M+ 1]
1H NMR (400 MHz, CD30D-i¾): 59.71(s, lH)，8.55(s, lH),8.50(s, lH),8.02(m, 3H), 7.75(m, 1H), 7.70(m, lH),7.47(m, lH),7.30(m, 3H),7.19(m, 1H), 6.83(s, 1H)， 6.67(s, lH),5.27(s, 2H), 4.56(s, 2H), 3.51(m, 1H), 3.38(m, 1H), 1.81(m, 4H) 1.2(m, 4H)  1H NMR (400 MHz, CD30D-i3⁄4): 59.71 (s, lH), 8.55 (s, lH), 8.50 (s, lH), 8.02 (m, 3H), 7.75 (m, 1H), 7.70 (m, lH), 7.47 (m, lH), 7.30 (m, 3H), 7.19 (m, 1H), 6.83 (s, 1H), 6.67 (s, lH), 5.27 (s, 2H), 4.56 (s, 2H) ), 3.51(m, 1H), 3.38(m, 1H), 1.81(m, 4H) 1.2(m, 4H)
实施例 228 Example 228
2-(3_{443-氯 -4-0氟-苄氧基) -苯氨基]_喹唑啉 _6-基 }-吡咯小基 4-吡咯垸 -1-基- 哌啶小基) -乙酮 2- (3_{443-chloro-4-0fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl}-pyrrole small 4-pyrrole-1-yl-piperidine small group) - Ethyl ketone
Figure imgf000236_0001
Figure imgf000236_0001
228 228
Figure imgf000237_0001
Figure imgf000237_0001
228  228
第一步  First step
2-氯小(4-吡咯烷 -1-基 -哌啶小基) -乙酮  2-Chloro(4-pyrrolidin-1-yl-piperidinyl)-ethanone
将 4-吡咯垸基哌啶 (350 mg, 2.27 mmol)溶于 60 mL四氢呋喃中， 在干冰乙醇 浴冷却至一 78°C， 搅拌下逐渐滴加氯乙酰氯 (6 g， 53 nrniol), 滴加完毕在冰浴冷却 下搅拌 30分钟， 反应完毕。 在反应液中加入 20 mL水， 减压下蒸去四氢呋喃， 得 到的溶液用乙酸乙酯萃取 (100 mL X 3)， 合并的有机相依次通过水洗涤 (100 mL X 2)， 无水硫酸钠干燥， 过滤， 减压下浓缩， 得到的残留物通过硅胶柱层析进一步分 离纯化 (二氯甲烷： 甲醇 = 10: 1)， 得到本标题产物 2-氯 -1- (4-吡咯烷 -1-基 -哌啶 -1- 基) -乙酮 228a (225 mg， 棕色固体)， 产率： 13 %。  Dissolve 4-pyrrolidinopiperidine (350 mg, 2.27 mmol) in 60 mL of tetrahydrofuran, cool to 78 ° C in a dry ice ethanol bath, and gradually add chloroacetyl chloride (6 g, 53 nrniol) with stirring. After the addition was completed, the mixture was stirred under ice cooling for 30 minutes, and the reaction was completed. 20 mL of water was added to the reaction mixture, and tetrahydrofuran was evaporated under reduced pressure. The obtained mixture was evaporated to ethyl acetate (100 mL EtOAc). The mixture was dried, filtered, and evaporated tolulujjjjjjjjjjj -yl-piperidin-1-yl)-ethanone 228a (225 mg, brown solid), yield: 13%.
MS m/z (ESI): 231 [M+ 1] MS m/z (ESI): 231 [M+ 1]
第二步  Second step
2-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基}-吡咯 -1-基)小(4-吡咯烷 -1-基- 哌啶 -1-基) -乙酮 2- (3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-pyrrol-1-yl)small (4-pyrrolidine) -1-yl-piperidin-1-yl)-ethanone
将化合物 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-[6-(1Η-吡咯 -3-基) -喹唑啉 -4-基] -胺 42 The compound [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1Η-pyrrole-3-yl)-quinazolin-4-yl]-amine 42
(300 mg, 0.67 mmol)和氢化钠（80 mg， 2 mmol)溶于 10 mL Ν,Ν-二甲基甲酰胺 中， 室温下搅拌 30分钟后加入 2-氯 -1-(4-吡咯垸小基 -哌啶 -1-基) -乙酮 228a (190 mg， 0.8 mπlol)的l mL N,N-二甲基甲酰胺溶液， 室温下搅拌 30分钟后反应完毕。 在反应液中加入 100 mL饱和氯化钠溶液淬灭反应， 水相用乙酸乙酯萃取 (100 mL X 3), 合并的有机相依次通过水， 饱和氯化钠溶液洗涤， 无水硫酸钠干燥， 过滤， 减压下浓缩，得到的残留物通过硅胶柱层析进一步分离纯化 (二氯甲烷： 甲醇 = 1Ό: 1)， 得到标题产物 2-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基 吡咯 -1- 基)小 (4-吡咯烷 -1-基 -哌啶小基) -乙酮 228(190 mg， 黄色固体)， 产率： 44%。 (300 mg, 0.67 mmol) and sodium hydride (80 mg, 2 mmol) dissolved in 10 mL of hydrazine, dimethyl-dimethylformamide, stirred at room temperature for 30 min, then 2-chloro-1-(4-pyrrole) A solution of the small base-piperidin-1-yl)-ethanone 228a (190 mg, 0.8 mπlol) in 1 mL of N,N-dimethylformamide was stirred at room temperature for 30 min. The reaction mixture was quenched by the addition of 100 mL of saturated sodium chloride solution. The aqueous phase was extracted with ethyl acetate (100 mL EtOAc). The residue was purified by silica gel column chromatography (dichloromethane:methanol = 1 : : :) to give the title product 2-(3-{4-[3-chloro-4- (3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylpyrrolidin-1-yl)small (4-pyrrolidin-1-yl-piperidine small)-ethanone 228 (190 mg , yellow solid), Yield: 44%.
MS m/z (ESI): 639[M+ 1] MS m/z (ESI): 639 [M+ 1]
1H NMR (400 MHz, CD30D-i¾: 59.74 (s, 1H), 8.55 (s, 1H), 8.50 (s, 1H), 8.03 (s, 2H), 7.76 (d, J = 8.8Hz, 1H), 7.70 (d, J = 8.8Hz, 1H), 7.50 (t, J = 8.8Hz, 1H), 7.43 (s, 1H), 7.33 (m， 3H), 7.19 (t, J = 8.8Hz, 1H), 6.83 (s, 1H), 6.66 (s, 1H), 5.27 (s, 2H), 4.95 (m, 2H), 4.14 (d, J = 13.2Hz, 1H), 3.83 (d, J = 12.0Hz, 1H), 3.14 (m, 1H), 2.84 (m, 1H), 2.50 (m, 4H), 2.34 (br, 1H), 1.68 (m, 4H), 1.41 (m, lH),1.28(m, 1H) 实施例 229 1H NMR (400 MHz, CD30D-i3⁄4: 59.74 (s, 1H), 8.55 (s, 1H), 8.50 (s, 1H), 8.03 (s, 2H), 7.76 (d, J = 8.8Hz, 1H), 7.70 (d, J = 8.8 Hz, 1H), 7.50 (t, J = 8.8 Hz, 1H), 7.43 (s, 1H), 7.33 (m, 3H), 7.19 (t, J = 8.8 Hz, 1H), 6.83 (s, 1H), 6.66 (s, 1H), 5.27 (s, 2H), 4.95 (m, 2H), 4.14 (d, J = 13.2Hz, 1H), 3.83 (d, J = 12.0Hz, 1H ), 3.14 (m, 1H), 2.84 (m, 1H), 2.50 (m, 4H), 2.34 (br, 1H), 1.68 (m, 4H), 1.41 (m, lH), 1.28 (m, 1H) Example 229
Γ3-氯斗(3-氟- 氧基) -苯基 W6-「l-(2-环丙基氨基-乙基) -1Η-吡咯 -3-基 1-喹唑啉 -4- 基 胺 Γ3 -Chlorine ( 3-fluoro-oxy)-phenyl W6-"1-(2-cyclopropylamino-ethyl)-l-pyridin-3-yl 1-quinazolin-4-ylamine
Figure imgf000238_0001
将 2-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基 吡咯 -1-基) 环丙基- 乙酰胺 217 (54 mg， 0.1 mmol)溶于 3 mL四氢呋喃中， 搅拌下加入氢化铝锂 (11.4 mg， 0.3 mmol), 3小时后反应完毕。 加入甲醇淬灭反应， 减压下浓缩， 得到的残 留物通过硅胶柱层析进一步分离纯化 (二氯甲垸： 甲醇 = 10: 1)， 得到标题产物 [3- 氯 -4-(3-氟-苄氧基) -苯基 ]-{6-[1-(2-环丙基氨基-乙基) -1H-吡咯 -3-基] -喹唑啉 -4-基 胺 229 (8 mg， 淡黄色固体)， 产率： 15.2%
Figure imgf000238_0001
2-(3-{4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylpyrrolidin-1-yl)cyclopropyl-acetamide 217 (54 mg, 0.1 mmol) was dissolved in 3 mL of tetrahydrofuran, and lithium aluminum hydride (11.4 mg, 0.3 mmol) was added with stirring, and the reaction was completed after 3 hours. The reaction mixture was quenched with EtOAc (EtOAc)EtOAc. -benzyloxy)-phenyl]-{6-[1-(2-cyclopropylamino-ethyl)-1H-pyrrol-3-yl]-quinazolin-4-ylamine 229 (8 mg, Light yellow solid), Yield: 15.2%
MS m/z (ESI): 528[M+ 1] MS m/z (ESI): 528 [M+ 1]
1H NMR (400 MHz, CO30O-d6): 58.467(s,lH), 8.445(s,lH), 8.057(d, J=8.4Hz,lH), 7.920(d,J=2Hz,lH),7.729(d, J=8.8Hz,lH),7.637(t,J=4.2Hz,lH),7.436(m,lH), 1H NMR (400 MHz, CO30O-d 6 ): 58.467 (s, lH), 8.445 (s, lH), 8.057 (d, J = 8.4 Hz, lH), 7.920 (d, J = 2 Hz, lH), 7.729 (d, J = 8.8 Hz, lH), 7.663 (t, J = 4.2 Hz, lH), 7.436 (m, lH),
7.319(m,3H),7.165(d,J=8.8Hz,lH),7.085(t,J=7.8Hz,lH),6.865(s,lH),6.708(s,lH),5.229( s32H),4.124(t,J=6.4Hz,2H),3.134(m,2H),2.213(m,lH),0.532(m,2H),0.394(m,2H) 实施例 230 7.319(m,3H), 7.165(d,J=8.8Hz,lH),7.085(t,J=7.8Hz,lH),6.865(s,lH),6.708(s,lH),5.229(s 3 2H ), 4.124 (t, J = 6.4 Hz, 2H), 3.134 (m, 2H), 2.213 (m, lH), 0.532 (m, 2H), 0.394 (m, 2H).
Γ3-氯 -4-(3-氟-苄氧基) -苯基 W6-(l-吡啶 -4-基甲基 -1H-吡咯 -3-基) -喹唑啉 -4-基 1-胺  3-Chloro-4-(3-fluoro-benzyloxy)-phenyl W6-(l-pyridin-4-ylmethyl-1H-pyrrol-3-yl)-quinazolin-4-yl 1-amine
Figure imgf000238_0002
Figure imgf000238_0002
Figure imgf000239_0001
Figure imgf000239_0001
Figure imgf000239_0002
第一歩
Figure imgf000239_0002
First
甲磺酸 ( 2-吡啶 -4-基)甲酯  Methanesulfonic acid (2-pyridin-4-yl)methyl ester
将 2-吡啶 -4-基 -甲醇 (536 mg， 4.92 mmol)溶于 40 mL二氯甲烷中，在冰浴条件 下， 冷却至 0°C， 依次加入三乙胺 (1.1 mg， 10.83 mmol)和甲磺酰氯 (668 mg， 5.83 mmol), 室温下搅拌 1小时， 反应完毕。将反应液中加入 50 mL水， 减压下蒸掉二 氯甲垸， 用乙酸乙酯萃取 (100 mLX 3)， 合并的有机相依次通过无水硫酸钠干燥， 过滤， 减压下浓縮， 残留物通过硅胶柱层析分离纯化 (二氯甲烷： 甲醇 = 10: 1), 得到甲磺酸（2-吡啶 -4-基)甲酯 230a (246 mg， 白色固体)， 产率： 26.7%。  2-Pyridin-4-yl-methanol (536 mg, 4.92 mmol) was dissolved in 40 mL of dichloromethane and then cooled to 0 ° C, then triethylamine (1.1 mg, 10.83 mmol) Methanesulfonyl chloride (668 mg, 5.83 mmol) was stirred at room temperature for 1 hour and the reaction was completed. The reaction mixture was added with 50 mL of water, EtOAc (EtOAc m. The residue was purified by silica gel column chromatography (dichlorohexane:methanol = 10:1) toield (2-pyridin-4-yl)methyl methanesulfonate 230a (246 mg, white solid), yield: 26.7% .
MS m/z (ESI): 188[M+ 1] MS m/z (ESI): 188 [M+ 1]
第二步  Second step
[3-氯 -4-(3-氟-苄氧基) -苯基 ]-[6-(1-吡啶 -4-基甲基 -1H-吡咯 -3-基) -喹唑啉 -4-基] -胺 在 50 mL的烧瓶中，将 [3-氯 -4-(3-氟- 氧基) -苯基 ]-[6-(1Η-吡咯 -3-基) -喹唑啉 -4- 基] -胺 42 (203 mg， 0.46 mmol)溶于 2 mL干燥的 Ν,Ν-二甲基甲酰胺中， 在冰浴条 件下，冷却至 0Ό，加入氢化钠 (46 mg， 1.15 mmol),搅拌 20分钟后加入甲磺酸（ 2- 吡啶 -4-基)甲酯 230a (136 mg， 0.73 mmol), 室温下搅拌 1.5小时反应完毕。反应液 减压下浓缩，得到的残留物通过硅胶柱层析进一步分离纯化 (二氯甲垸： 甲醇 =60: 1)， 得到本标题产物 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-[6-(1-吡啶 -4-基甲基 -1H-吡咯 -3- 基)-喹唑啉 -4-基] -胺 230 (22 mg， 黄色固体)， 产率： 84%。  [3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1-pyridin-4-ylmethyl-1H-pyrrol-3-yl)-quinazoline-4- [3-chloro-4-(3-fluoro-oxy)-phenyl]-[6-(1Η-pyrrol-3-yl)-quinazoline-4 in a 50 mL flask -Alkyl-amine 42 (203 mg, 0.46 mmol) was dissolved in 2 mL dry EtOAc EtOAc (EtOAc m. After stirring for 20 minutes, (2-pyridin-4-yl)methyl methanesulfonate 230a (136 mg, 0.73 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjjj -phenyl]-[6-(1-pyridin-4-ylmethyl-1H-pyrrol-3-yl)-quinazolin-4-yl]-amine 230 (22 mg, yellow solid) Rate: 84%.
MS m/z (ESI): 536[M+ 1] MS m/z (ESI): 536 [M+ 1]
1H NMR (400 MHz, CD30D- ): 69.71(s, IH), 8.56(m， 3H), 8.51(s, IH), 8.06(d, J=8.4Hz, IH), 8.0 l(d, J=2.0Hz, IH), 7.74(m, 2H), 7.49(m, 2H), 7.32(m, 3H), 7.21 (m, 3H), 7.03(s, IH), 6.77(s, IH), 5.27(s, 4H) 实施例 231  1H NMR (400 MHz, CD30D-): 69.71 (s, IH), 8.56 (m, 3H), 8.51 (s, IH), 8.06 (d, J = 8.4 Hz, IH), 8.0 l (d, J = 2.0Hz, IH), 7.74(m, 2H), 7.49(m, 2H), 7.32(m, 3H), 7.21 (m, 3H), 7.03(s, IH), 6.77(s, IH), 5.27( s, 4H) Example 231
2-(3-{4-「3-氯 -4-( -氟-苄氧基) -苯氨基 1-喹唑啉 -6-基 吡咯 -1-基 N-哌啶 -4-基 -乙酰  2-(3-{4-"3-Chloro-4-(-fluoro-benzyloxy)-phenylamino-1-quinazolin-6-ylpyrrolidin-1-yl N-piperidin-4-yl-acetyl
腔 Cavity
Figure imgf000240_0001
第一步
Figure imgf000240_0001
first step
N-(l -苄基 -哌啶 -4-基) -2-氯-乙酰胺  N-(l-benzyl-piperidin-4-yl)-2-chloro-acetamide
将 1-苄基 -哌啶 -4-基胺 231a(2.1 mL， 10 mmol, Aldrich)溶于 25 mL四氢呋喃中， 用干冰-丙酮浴冷却至 -78°C， 滴加氯乙酰氯 (0.91 mL, 12 mmol), 保持此温度， 1 小时后反应完毕。 将反应液中加入 50 mL水和 50 mL乙酸乙酯， 分液， 睡相用乙 酸乙酯萃取 (50 mLX2)，合并的有机相通过饱和氯化钠溶液洗涤，无水硫酸钠干燥， 过滤，减压下浓缩，得到 N-(l-苄基 -哌啶 -4-基) -2-氯-乙酰胺 231b (2.5 g，粉色固体)， 产率： 91.4%  1-Benzyl-piperidin-4-ylamine 231a (2.1 mL, 10 mmol, Aldrich) was dissolved in 25 mL of tetrahydrofuran, cooled to -78 ° C with dry ice-acetone bath, and chloroacetyl chloride (0.91 mL) was added dropwise. , 12 mmol), maintain this temperature, and the reaction is completed after 1 hour. The reaction mixture was combined with 50 mL of water and 50 mL of EtOAc. Concentration under reduced pressure gave N-(l-benzyl-piperidin-4-yl)-2-chloro-acetamide 231b (2.5 g, pink solid), yield: 91.4%
MS m/z (ESI): 267[M+ 1]  MS m/z (ESI): 267 [M+ 1]
第二步  Second step
N-(l-苄基 -哌啶 -4-基) -2-(3-{4-[3-氯 -4-(3-氟苄氧基) -苯氨基] -喹唑啉 -6-基 吡咯 -1- 基)-乙酰胺 .  N-(l-benzyl-piperidin-4-yl)-2-(3-{4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazoline-6- Pyryrrol-1-yl)-acetamide.
将 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-[6-(1Η-吡咯 -3-基) -喹唑啉 -4-基] -胺 42 (445mg, [3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1Η-pyrrole-3-yl)-quinazolin-4-yl]-amine 42 (445 mg,
1 mmol)溶于 10 mL干燥的 Ν,Ν-二甲基甲酰胺中， 在冰浴条件下， 冷却至 0°C， 加 入氢化钠 (140 mg， 3 mmol), 搅拌 30分钟后加入 N-(l-苄基 -哌啶 -4-基) -2-氯 -乙酰 胺 231b (316 mg， 1.2 mmol), 室温下搅拌 1小时反应完毕。 反应液减压下浓缩， 得到的残留物通过硅胶柱层析进一步分离纯化 (二氯甲垸： 甲醇 =25: 1), 得到本 标题产物 2-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基]-喹唑啉 -6-基 吡咯 -1-基) -N-哌啶 -4-基-乙酰胺 231c (478 mg， 淡黄色固体)， 产率： 70.9%。 1 mmol) dissolved in 10 mL of dry hydrazine, hydrazine-dimethylformamide, cooled to 0 ° C under ice-cooling, sodium hydride (140 mg, 3 mmol), and stirred for 30 min. (l-Benzyl-piperidin-4-yl)-2-chloro-acetamide 231b (316 mg, 1.2 mmol). The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjjjj -(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylpyrrolidin-1-yl)-N-piperidine 4-yl-acetamide 231c (478 mg, pale yellow solid), Yield: 70.9%.
MS m/z (ESI): 675[M+1] MS m/z (ESI): 675 [M+1]
第三步  third step
2-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基]-喹唑啉 -6-基 吡咯 -1-基) -N-哌啶 -4-基 -乙酰 胺  2-(3-{4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylpyrrolidin-1-yl)-N-piperidine-4- Acetylamine
将 2-(3-{4-[3-氯 -4-(3-氟-节氧基) -苯氨基] -喹唑啉 -6-基 吡咯 -1-基) -N-哌啶 -4-基 -乙酰胺 231c (429 mg， 0.64 mmol)溶于 5 mL二氯甲垸和 5 mL甲醇的混合溶剂中， 加入 Pd/C(45 mg， 0.1 mmol), 在 3atm的氢气压下反应过夜。过滤反应液， 滤液在 减压下浓缩， 得到的残留物通过硅胶柱层析进一步分离纯化 (二氯甲烷： 甲醇 =2: 1)， 得到标题产物 2-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基}-吡咯 -1- 基) -N-哌啶 -4-基-乙酰胺 231(78 mg， 黄绿色固体)， 产率： 39.3 %。  2-(3-{4-[3-Chloro-4-(3-fluoro-p-hydroxy)-phenylamino]-quinazolin-6-ylpyrrol-1-yl)-N-piperidine-4 -Base-acetamide 231c (429 mg, 0.64 mmol) was dissolved in a mixture of 5 mL of dichloromethane and 5 mL of methanol. Pd/C (45 mg, 0.1 mmol) was added and reacted under hydrogen at 3 atm overnight. . The reaction mixture was filtered, and the filtrate was evaporated. mjjjjjjjjjjjjjjj 4-(3-Fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-pyrrol-1-yl)-N-piperidin-4-yl-acetamide 231 (78 mg, yellow Green solid), Yield: 39.3 %.
MS m/z (ESI): 585[M+1] MS m/z (ESI): 585 [M+1]
1H NMR (400 MHz, CD30D-^): 59.73 (s, 1H), 8.56 (s, 1H)， 8.50 (s, 1H), 8.09 (s, 1H), 8.07 (d, J = 8.8Hz, 1H), 8.03 (s, 1H), 7.85 (d, J = 8.8Hz, 1H), 7.69 (d， J = 8.8Hz, 1H), 7.54 (t, J = 8.8Hz, 1H), 7.42 (s, 1H), 7.32 (m, 3H), 7.19 (t, J = 8.8Hz, 1H), 6.85 (s, 1H), 6.67 (s, 1H), 5.27 (s， 2H),4.58 (s， 2H), 4.09 (s, 1H), 3.62 (m, 1H), 3.18 (s, 2H), 2.93 (d, J = 12.4Hz, 2H), 1.71 (d, J = 9.6Hz, 2H), 1.32 (m, 2H) 实施例 232  1H NMR (400 MHz, CD30D-^): 59.73 (s, 1H), 8.56 (s, 1H), 8.50 (s, 1H), 8.09 (s, 1H), 8.07 (d, J = 8.8Hz, 1H) , 8.03 (s, 1H), 7.85 (d, J = 8.8Hz, 1H), 7.69 (d, J = 8.8Hz, 1H), 7.54 (t, J = 8.8Hz, 1H), 7.42 (s, 1H) , 7.32 (m, 3H), 7.19 (t, J = 8.8Hz, 1H), 6.85 (s, 1H), 6.67 (s, 1H), 5.27 (s, 2H), 4.58 (s, 2H), 4.09 ( s, 1H), 3.62 (m, 1H), 3.18 (s, 2H), 2.93 (d, J = 12.4Hz, 2H), 1.71 (d, J = 9.6Hz, 2H), 1.32 (m, 2H) Example 232
(S)-「3-氯 -4-(3-氟-苄氧基) -苯基 1-Γ6-α-吡咯烷 -3-基甲基 -1H-吡咯 -3-基 喹唑啉  (S)-"3-Chloro-4-(3-fluoro-benzyloxy)-phenyl 1-indole-6-α-pyrrolidin-3-ylmethyl-1H-pyrrole-3-ylquinazoline
-4-基卜胺  -4- benzylamine
Figure imgf000241_0001
Figure imgf000241_0001
232 232
Figure imgf000242_0001
第一步
Figure imgf000242_0001
first step
(S)-3-轻甲基-吡咯烷 -1-甲酸叔丁酯  (S)-3-light methyl-pyrrolidine-1-carboxylic acid tert-butyl ester
将 (S)-3-羟甲基-吡咯烷 (5.05g， 50mmol)溶于 150mL二氯甲烷中， 氩气保护， 冰浴冷却至 0°C， 加入二碳酸二叔丁酯 (11.44 g， 52.5 mmol), 室温下搅拌 6小时， 反应完毕。将反应液用饱和碳酸氢钠洗涤， 水相用乙酸乙酯萃取 (50mLX3)， 合并 的有机相依次通过饱和氯化钠溶液洗涤， 无水硫酸钠干燥， 过滤， 减压下浓缩， 得到的残留物通过硅胶柱层析进一步分离纯化 (正己烷： 乙酸乙酯 =1: 1)， 得到 (S)-3-羟甲基-吡咯烷 -1-甲酸叔丁酯 232a(9.29g， 黄色油状液体)， 产率： 92.4%。 MSm/z(ESI): 201[M+1]  (S)-3-Hydroxymethyl-pyrrolidine (5.05 g, 50 mmol) was dissolved in 150 mL of dichloromethane, argon-protected, cooled to 0 ° C in ice-bath, and di-tert-butyl dicarbonate (11.44 g, 52.5 mmol), stirred at room temperature for 6 hours, and the reaction was completed. The reaction mixture was washed with EtOAc EtOAc (EtOAc m. The product was further separated and purified by silica gel column chromatography (hexane: ethyl acetate = 1 : 1) to afford (S) 3-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester 232a (9.29 g, yellow oily liquid ), Yield: 92.4%. MSm/z (ESI): 201[M+1]
第二步  Second step
(S)-3-甲磺酰氧甲基-吡咯烷 -1-甲酸叔丁酯  (S)-3-methanesulfonyloxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester
将 (S)-3-羟甲基-吡咯烷 -1-甲酸叔丁酯 232a(2.01 g， 10 mmol)溶于 50 mL二氯甲 烷中， 氩气氛下加入三乙胺 (5.6 mL， 40 mmol), 搅拌 10分钟后加入甲磺酰氯 (1.55 mL, 20 mmol), 室温下搅拌 1小时， 反应完毕。 将反应液用饱和碳酸氢钠洗涤， 水相用乙酸乙酯萃取 (50mLX3)，合并的有机相依次通过饱和氯化钠溶液洗涤，无 水硫酸钠干燥， 过滤， 减压下浓缩， 得到的残留物通过硅胶柱层析进一步分离纯 化 (：正己垸： 乙酸乙酯 =4: 1), 得到 (S)-3-甲磺酰氧甲基-吡咯烷 -1-甲酸叔丁酯 232b(2.47 g, 黄色油状液体)， 产率： 88.5%。 第三步  (S)-3-Hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester 232a (2.01 g, 10 mmol) was dissolved in 50 mL of dichloromethane and triethylamine (5.6 mL, 40 mmol After stirring for 10 minutes, methanesulfonyl chloride (1.55 mL, 20 mmol) was added, and the mixture was stirred at room temperature for 1 hour, and the reaction was completed. The reaction mixture was washed with EtOAc EtOAc (EtOAc m. The product was further separated and purified by silica gel column chromatography (: hexanes: ethyl acetate = 4:1) to give (S)-3-methanesulfonyloxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester 232b (2.47 g). , yellow oily liquid), Yield: 88.5%. third step
(S)-3-(3-{4-[3-氯 -4-(3-氟- 氧基) -苯氧基] -喹唑啉 -6-基}-吡咯 -1-基甲基)-吡咯烷 -1- 甲酸叔丁酯  (S)-3-(3-{4-[3-chloro-4-(3-fluoro-oxy)-phenoxy]-quinazolin-6-yl}-pyrrol-1-ylmethyl) -pyrrolidine-1-carboxylic acid tert-butyl ester
将 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-[6-(1Η-吡咯 -3-基)-喹唑啉 -4-基] -胺 42 (220 mg， 0.49 mmol)溶于 10 mLN,N-二甲基甲酰胺中，搅拌下加入氢化钠 (60 mg， 1.47 mmol) 和 (S)-3-甲磺酰氧甲基-吡咯烷小甲酸叔丁酯 232b(198 mg, 0.74 mmol)的 5 mL N,N- 二甲基甲酰胺溶液， 混合加热至 80°C， 3 小时后反应完毕。 将反应液用水洗涤， 乙酸乙酯萃取 ('50 mL X 3)，合并的有机相依次通过饱和氯化钠溶液洗涤，无水硫酸 钠干燥， 过滤， 减压下浓缩， 得到的残留物通过硅胶柱层析进一步分离纯化 (二氯 甲烷： 四氢呋喃 =20: 1)，得到 (S)-3-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6- 基 吡咯 -1-基甲基) -吡咯垸 -1-甲酸叔丁酯 232c(lll mg,黄色油状液体)，产率： 36.1 %。 [3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1Η-pyrrol-3-yl)-quinazolin-4-yl]-amine 42 (220 mg, 0.49 mmol) dissolved in 10 mL of N,N-dimethylformamide and sodium hydride (60 mg, 1.47 mmol) And (S)-3-methanesulfonyloxymethyl-pyrrolidine carboxylic acid tert-butyl ester 232b (198 mg, 0.74 mmol) in 5 mL of N,N-dimethylformamide, mixed and heated to 80 ° C, The reaction was completed after 3 hours. The reaction mixture was washed with water, EtOAc (EtOAc m. Further separation and purification by column chromatography (dichloromethane: tetrahydrofuran = 20:1) gave (S)-3-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino - quinazoline-6-ylpyrrol-1-ylmethyl)-pyrroleium-1-carboxylic acid tert-butyl ester 232c (111 mg, yellow oily liquid), yield: 36.1%.
MS m/z (ESI): 629[M+ 1]  MS m/z (ESI): 629 [M+ 1]
第四步 the fourth step
(S)-[3-氯 -4-(3-氟-苄氧基) -苯基 ]-[6-(1-吡咯烷 -3-基甲基 -1H-吡咯 -3-基) -喹唑啉  (S)-[3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1-pyrrolidin-3-ylmethyl-1H-pyrrol-3-yl)-quin Oxazoline
-4-基] -胺  -4-yl]-amine
将 (S)-3-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基}-吡咯 -1-基甲基) -吡 咯烷 -1-甲酸叔丁酯 232c (110 mg， 0.175 mmol)溶于 10 mL二氯甲烷中， 搅拌下加 入 3 mL盐酸甲醚溶液， 室温下搅拌 1小时反应完毕。 将反应液在减压下浓缩， 得 '到的残留物通过硅胶柱层析进一步分离纯化 (梯度洗脱： 二氯甲烷： 甲醇二 20: 1， 二氯甲烷： 甲醇： 氨水 =20: 1： Id), 得到 (S)-[3-氯 -4-(3-氟-苄氧基) -苯基 ]-[6-(1- 吡咯烷 -3-基甲基 -1H-吡咯 -3-基) -喹唑啉 -4-基] -胺 232 (30 mg， 淡黄色固体)， 产率： 32.6%  (S)-3-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-pyrrol-1-ylmethyl - Pyrrolidine-1-carboxylic acid tert-butyl ester 232c (110 mg, 0.175 mmol) was dissolved in 10 mL of dichloromethane, and 3 mL of a methyl ether hydrochloride solution was added under stirring, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give purified crystals crystals. Id), (S)-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1-pyrrolidin-3-ylmethyl-1H-pyrrole-3- - quinazolin-4-yl]-amine 232 (30 mg, pale yellow solid), Yield: 32.6%
MS m/z (ESI): 529[M+ 1]  MS m/z (ESI): 529 [M+ 1]
1H NMR (400 MHz, CD30D-i¾: 59.70 (s,lH)， 8.54 (s,lH), 8.50 (s,lH), 8.04 (s,2H) , 7.72 (dd , J=2.0Hz, 1H) , 7.71(d , J= 8.4Hz, 1H) , 7.48 (m , 2H) , 7.32 (m , 3H) , 7.19 (m , 1H) ,6.91 (s , 1H) , 6.66 (s , 1H) , 5.27 (s , 2H) , 4.04 (m, 1H) , 3.84 (m , 2H) , 3.35 (m , 1H), 2.81 (m , 2H) , 1.69 (m , 3H) , 1.38 (m , 1H) 实施例 233  1H NMR (400 MHz, CD30D-i3⁄4: 59.70 (s, lH), 8.54 (s, lH), 8.50 (s, lH), 8.04 (s, 2H), 7.72 (dd, J = 2.0 Hz, 1H), 7.71(d , J= 8.4Hz, 1H) , 7.48 (m , 2H) , 7.32 (m , 3H) , 7.19 (m , 1H) , 6.91 (s , 1H) , 6.66 (s , 1H) , 5.27 (s , 2H) , 4.04 (m, 1H), 3.84 (m , 2H) , 3.35 (m , 1H), 2.81 (m , 2H) , 1.69 (m , 3H) , 1.38 (m , 1H) Example 233
2-(3-{4-「3-氯 -4-(3-氟-苄氧基) -苯氨基 1-喹唑啉 -6-基 -吡咯小基-l-「4-(2-羟乙基 哌 嗪 -1-基 乙酮  2-(3-{4-"3-chloro-4-(3-fluoro-benzyloxy)-phenylamino-1-quinazolin-6-yl-pyrroleyl-l-"4-(2-hydroxyl) Ethyl piperazine-1-ketoethyl ketone
Figure imgf000243_0001
Figure imgf000243_0001
Figure imgf000244_0001
第一歩
Figure imgf000244_0001
First
2-氯小 [4-(2-羟乙基) -哌嗪小基] -乙酮  2-chlorosodium [4-(2-hydroxyethyl)-piperazine small group]-ethanone
将 2-哌嗪 -1-基 -乙醇（1.302 g， lO mmol)溶于 20 mL四氢呋喃中， 在丙酮-干 冰浴条件下， 冷却至一 78°C， 加入 2 mL三乙胺， 搅拌 15小时后， 滴加氯乙酰氯 (0.75 mL， lO mmol), 搅拌 1小时后反应完毕。 反应物在减压下浓缩， 残留物通过 硅胶柱层析进行分离纯化 (二氯甲垸： 甲醇 = 15: 1)， 得到无色油状液体粗品 2-氯 -1-[4-(2-羟乙基) -哌嗪 -1-基] -乙酮 233a， 产物不经分离直接进行下一步反应。  Dissolve 2-piperazin-1-yl-ethanol (1.302 g, 10 mmol) in 20 mL of tetrahydrofuran, cool to a temperature of 78 ° C under acetone-dry ice bath, add 2 mL of triethylamine, stir for 15 hours After that, chloroacetyl chloride (0.75 mL, 10 mmol) was added dropwise, and the reaction was completed after stirring for 1 hour. The reactant was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 15:1) Ethyl)-piperazin-1-yl]-ethanone 233a, the product was directly subjected to the next reaction without isolation.
MS m/z (ESI): 207[M+ 1] MS m/z (ESI): 207 [M+ 1]
第二步  Second step
2-(3-{4-[3-氯 -4-(3-氟苄氧基) -苯氨基]-喹唑啉 -6-基 } 比咯 -1-基) -l-[4-(2-羟乙基) -哌 嗪 -1-基 1]-乙酮  2-(3-{4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazolin-6-yl}pyr-1-yl)-l-[4-( 2-hydroxyethyl)-piperazin-1-yl 1]-ethanone
在 50 mL的烧瓶中， 将 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-[6-(1Η-吡咯 -3-基) -喹唑啉 -4-基] -胺 42 (444 mg， 1 mmol)溶于 10 mL干燥的 Ν,Ν-二甲基甲酰胺中， 在冰浴 条件下，冷却至 0°C，加入氢化钠 （72 mg， 3 mmol)，搅拌 30分钟后加入 2-氯 -1-[4-(2- 羟乙基) -哌嗪小基] -乙酮 233a (206 mg， 1 mmol), 室温下搅拌 1小时反应完毕。反 应液减压下浓缩， 得到的残留物通过硅胶柱层析进一步分离纯化 (二氯甲烷： 甲醇 = 8： 1)， 得到 2-(3-{4-[3-氯 -4-(3-氟苄氧基) -苯氨基] -喹唑啉 -6-基} -吡咯 -1- 基 )_1_[4_(2-羟乙基) -哌嗪 -1-基 1]-乙酮 233 (215 mg, 淡黄色固体)， 产率： 34.9%。 MS m/z (ESI): 586[M+ 1] [3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1Η-pyrrol-3-yl)-quinazolin-4-yl] in a 50 mL flask -Amine 42 (444 mg, 1 mmol) was dissolved in 10 mL dry EtOAc EtOAc (EtOAc) After stirring for 30 minutes, 2-chloro-1-[4-(2-hydroxyethyl)-piperazine small group]-ethanone 233a (206 mg, 1 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjj Fluorobenzyloxy)-phenylamino]-quinazolin-6-yl}-pyrrol-1-yl)_1_[ 4 _(2-hydroxyethyl)-piperazin-1-yl 1]-ethanone 233 ( 215 mg, pale yellow solid), Yield: 34.9%. MS m/z (ESI): 586 [M+ 1]
1H NMR (400 MHz, D30O-d6): 59.67 (s,lH), 8.8(s,lH),8.5 (s，lH)， 1H NMR (400 MHz, D30O-d 6 ): 59.67 (s,lH), 8.8 (s,lH), 8.5 (s,lH),
8.03(d,J=8.8Hz,2H),7.76(dd,J=2Hz,lH),7.70(d,J=8.4Hz,lH),7.5(m,2H),7.36(m53H),8.03 (d, J = 8.8 Hz, 2H), 7.76 (dd, J = 2 Hz, lH), 7.70 (d, J = 8.4 Hz, lH), 7.5 (m, 2H), 7.36 (m 5 3H),
7.2(s5lH),6.93(s,lH),6.60(s,lH),5.27(s,2H),5.0(s,2H),3.5(m,8H),2.4(U=12Hz,4H) 实施例 234 7.2 (s 5 lH), 6.93 (s, lH), 6.60 (s, lH), 5.27 (s, 2H), 5.0 (s, 2H), 3.5 (m, 8H), 2.4 (U = 12 Hz, 4H) Example 234
l-(3-{4-「3-氯 -4-(3-氟-苄氧基 苯氨基 1-喹唑啉 -6-基 吡咯小基) -3-(4-吡咯烷小基- 哌啶小基) -丙 -2-醇 L- (3 -{4-"3-Chloro-4-(3-fluoro-benzyloxyphenylamino-1-quinazolin-6-ylpyrroleyl)-3-(4-pyrrolidinyl-piperidine) Pyridyl)-propan-2-ol
Figure imgf000245_0001
Figure imgf000245_0001
4-吡咯烷小基 -哌啶 (69 mg, 0.45mmol, Alfa) 和 [3-氯 -4-(3-氟-苄基)-苯基] - [6-(1-环氧乙基甲基 -1H-吡咯 -3-基) -喹唑啉 -4-基] -胺 187a (150 mg, 0.3 mmol)溶于 10 mL甲醇中，混合液加热回流过夜。反应液在减压下浓缩，得到的残留物通过硅 胶柱层析进一步分离纯化 (二氯甲烷： 甲醇 = 10: 1)， 得到本标题产物 1-(3-{4-[3- 氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基}-吡咯 -1-基) -3-(4-吡咯烷 -1-基 -哌啶 -1-基) - 丙 -2-醇 234 (35 mg， 黄色固体)， 产率： 15 %。 4-pyrrolidinyl-piperidine (69 mg, 0.45 mmol, Alfa) and [3-chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-epoxyethyl-methyl) The yl-1H-pyrrol-3-yl)-quinazolin-4-yl]-amine 187a (150 mg, 0.3 mmol) was dissolved in 10 mL MeOH. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjjj -(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-pyrrol-1-yl)-3-(4-pyrrolidin-1-yl-piperidin-1-yl) - Propan-2-ol 234 (35 mg, yellow solid), Yield: 15%.
MS m/z (ESI): 655 [M+1] MS m/z (ESI): 655 [M+1]
1H NMR (400 MHz, CD30D- ): 59.713 (s,lH) ,8.546 (s,lH),8.494 (s,lH),8.0341H NMR (400 MHz, CD30D- ): 59.713 (s, lH) , 8.546 (s, lH), 8.494 (s, lH), 8.034
(t,J-5 Hz,2H),7J64(t,J-5.6Hz,lH),7J03(d,J=8.4Hz,lH),7.484(m,lH),7.417(s,lH),7.3 19(m,3H),7.193(t,J=8.6Hz,lH),6.868(s,lH),6.655(s,lH),5.274(s,2H),4.896(s,lH),4.030( d,J=13.6Hz,lH),3.877(m,2H),3.486(s52H),3.427(m,lH),2.848(m,2H),2.652(m,2H),2.24 5(d,J=17.6Hz,2H),2.000(t,J=11.6Hz52H),1.815(m,2H),1.501(m,2H),1.254(m, 4H) 实施例 235 (t, J-5 Hz, 2H), 7J64 (t, J-5.6Hz, lH), 7J03 (d, J = 8.4 Hz, lH), 7.484 (m, lH), 7.417 (s, lH), 7.3 19(m,3H),7.193(t,J=8.6Hz,lH),6.868(s,lH),6.655(s,lH), 5.274(s,2H),4.896(s,lH),4.030(d) , J = 13.6 Hz, lH), 3.877 (m, 2H), 3.486 (s 5 2H), 3.427 (m, lH), 2.848 (m, 2H), 2.652 (m, 2H), 2.24 5 (d, J =17.6 Hz, 2H), 2.000 (t, J = 11.6 Hz 5 2H), 1.815 (m, 2H), 1.501 (m, 2H), 1.254 (m, 4H) Example 235
β-氯 -4-D-氟-苄氧基) -苯基 l-(6-{l-「2-(U-二氧 -六氢 -1λ*6*-噻喃 -4-基氨基) -乙 基 1H-吡咯 -3-基 喹唑啉 -4-基) -胺  β-chloro-4-D-fluoro-benzyloxy)-phenyl-l-(6-{l-"2-(U-dioxo-hexahydro-1λ*6*-thiopyran-4-ylamino) -ethyl 1H-pyrrol-3-ylquinazolin-4-yl)-amine
Figure imgf000245_0002
将 2-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基}-吡咯 -1-基) -N-(l,l-二氧 -六氢 -1λ*6*-噻喃 -4-基) -乙酰胺 225 (54 mg， 0.1 mmol)溶于 3 mL四氢呋喃中， 搅 拌下加入氢化铝锂 (11.4 mg， 0.3 mmol), 3小时后反应完毕。 加入甲醇淬灭反应， 减压下浓缩，得到的残留物通过硅胶柱层析进一步分离纯化 (二氯甲烷： 甲醇 = 10: 1)， 得到标题产物 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-{6-[1-(2-环丙基氨基-乙基) -1H-吡咯 -3-基] -喹唑啉 -4-基 胺 229 (8 mg， 淡黄色固体)， 产率： 15.2%。
Figure imgf000245_0002
2-(3-{4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-pyrrol-1-yl)-N-(l ,l-Dioxo-hexahydro-1λ*6*-thiopyran-4-yl)-acetamide 225 (54 mg, 0.1 mmol) was dissolved in 3 mL of THF, and lithium aluminum hydride (11.4 mg, 0.3 Mmmol), the reaction was completed after 3 hours. The reaction mixture was quenched with EtOAc (EtOAc m.). Benzyloxy)-phenyl]-{6-[1-(2-cyclopropylamino-ethyl)-1H-pyrrol-3-yl]-quinazolin-4-ylamine 229 (8 mg, light Yellow solid), Yield: 15.2%.
MS m/z (ESI): 528[M+ 1] MS m/z (ESI): 528 [M+ 1]
1H NMR (400 MHz, CD30D-^): 59.68(s, 1H), 8.53(s, 1H), 8.50(s, 1H), 8.03(m, 2H), 7.76(dd, J=8.8Hz 2.4Hz, 1H), 7.70(d, J=8.8Hz, 1H), 7.48(m, 1H), 7.45(s， 1H), 7.32(m, 3H), 7.19(m, 1H), 6.93(s,lH), 6.67(s, 1H), 5.27(s, 2H), 3.99(m, 2H), 3.10(m, 2H)， 2.98(m, 2H), 2.90(m, 2H)， 2.79(m, 1H), 1.24(m, 4H) 实施例 236  1H NMR (400 MHz, CD30D-^): 59.68 (s, 1H), 8.53 (s, 1H), 8.50 (s, 1H), 8.03 (m, 2H), 7.76 (dd, J = 8.8 Hz 2.4 Hz, 1H), 7.70 (d, J=8.8Hz, 1H), 7.48(m, 1H), 7.45(s, 1H), 7.32(m, 3H), 7.19(m, 1H), 6.93(s,lH), 6.67(s, 1H), 5.27(s, 2H), 3.99(m, 2H), 3.10(m, 2H), 2.98(m, 2H), 2.90(m, 2H), 2.79(m, 1H), 1.24 (m, 4H) Example 236
ί4-Γ3-(3-ί4-「3-氯 -4-(3-氟-苄氧基 苯氨基 1-喹唑啉 -6-基 吡咯 -1-基) -2-羟 -丙基 1-哌  Γ4-Γ3-(3-ί4-"3-Chloro-4-(3-fluoro-benzyloxyphenylamino-1-quinazolin-6-ylpyrrol-1-yl)-2-hydroxy-propyl 1- Piper
Figure imgf000246_0001
Figure imgf000246_0001
第一步  First step
环丙基 -哌嗪 -1-基 -甲酮  Cyclopropyl-piperazine-1-yl-ketone
氩气氛下，将哌嗪 -1-甲酸叔丁酯 (1.86 g， 10 mmol)和碳酸钾 (4.15 g， 30 mmol) 溶于 100 mL二氯甲垸中， 搅拌下加入环丙基甲酰氯 (1.17 g， 11.2 mmol), 混合液 在室温下搅拌过夜。 将反应液倒入 30 mL水中， 乙酸乙酯萃取 (30 mL X 3)， 合并 的有机相通过无水硫酸钠干燥， 过滤， 减压下浓缩， 得到环丙基 -哌嗪 -1-基 -甲酮 236a (2.5 g, 白色固体)， 产率： 99%。  Piperazine-1-carboxylic acid tert-butyl ester (1.86 g, 10 mmol) and potassium carbonate (4.15 g, 30 mmol) were dissolved in 100 mL of dichloromethane under argon, and cyclopropylcarbonyl chloride was added with stirring. 1.17 g, 11.2 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water (30 mL), EtOAc (EtOAc (EtOAc) Methyl ketone 236a (2.5 g, white solid), Yield: 99%.
MS m/z (ESI): 255 [M+ 1] 第二步 MS m/z (ESI): 255 [M+ 1] Second step
环丙基 -哌嗪 -1-基 -甲酮  Cyclopropyl-piperazine-1-yl-ketone
4-环丙基羰基 -哌嗪 -1-甲酸叔丁酯 236a (2.1 g, 8 mmol)溶于 10 mL干燥的二氯 甲烷中，搅拌下加入三氟醋酸 (14.28 g， 125 mmol),室温下搅拌 2小时后反应完毕。 将反应液在减压下浓缩， 加入 20 mL饱和碳酸钠溶液， 分液， 浓缩水相， 得到的 残渣加入 20 mL甲醇， 搅拌， 过滤， 滤饼用甲醇洗涤三次， 滤液通过无水硫酸钠 干燥， 过滤， 减压下浓缩， 得到环丙基 -哌嗪 -1-基 -甲酮 236b (1.5 g， 白色固体)， 产率： 99%。  tert-Butyl 4-cyclopropylcarbonyl-piperazine-l-carboxylate 236a (2.1 g, 8 mmol) was dissolved in 10 mL of dry methylene chloride. Trifluoroacetic acid (14.28 g, 125 mmol) After stirring for 2 hours, the reaction was completed. The reaction solution was concentrated under reduced pressure. 20 mL of saturated sodium carbonate solution was added, and the mixture was separated, and the aqueous phase was concentrated. The obtained residue was added to 20 mL of methanol, stirred, filtered, and the filter cake was washed three times with methanol, and the filtrate was dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure gave cyclopropyl-piperazin-1-yl-methanone 236b (1.5 g, white solid).
MS m/z (ESI): 155[M+ 1]  MS m/z (ESI): 155 [M+ 1]
. 第三步  . third step
{4-[3-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基 吡咯 -1-基) -2-羟-丙基] -哌 嗪 -1-基}-环丙基 -甲酮  {4-[3-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylpyrrol-1-yl)-2-hydroxy -propyl]-piperazin-1-yl}-cyclopropyl-ketone
将环丙基-哌嗪小基 -甲酮 236b (51 mg, 0.33 mmol)和 [3-氯 -4-(3-氟-苄基) -苯 基]- [6-(1-环氧乙基甲基 -1H-吡咯 -3-基)-喹唑啉 -4-基] -胺 187a (150 mg， 0.3 mmol) 溶于 50 mL甲醇中， 混合液加热回流过夜。 反应液在减压下浓缩， 得到的残留物 通过硅胶柱层析进一步分离纯化 (二氯甲烷： 甲醇 =40: 1)， 得到本标题产物 {4-[3-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基]-喹唑啉 -6-基}-吡咯 -1-基) -2-羟-丙基] -哌 嗪 -1-基}-环丙基 -甲酮 236 (21 mg， 黄色固体)， 产率： 10.7%。  Cyclopropyl-piperazine small-ketone 236b (51 mg, 0.33 mmol) and [3-chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-epoxyethyl) Methyl-1H-pyrrol-3-yl)-quinazolin-4-yl]-amine 187a (150 mg, 0.3 mmol) was dissolved in 50 mL MeOH. The reaction mixture was concentrated under reduced pressure. EtOAc mjjjjjjjj -chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-pyrrol-1-yl)-2-hydroxy-propyl]-piperazin-1-yl} -cyclopropyl-methanone 236 (21 mg, yellow solid), yield: 10.7%.
MS m/z (ESI): 655[M+ 1] MS m/z (ESI): 655 [M+ 1]
1H NMR (400 MHz, CD30D-c 6): 58.468(s,H), 8.446(s,H),8.079(d,J=8.8Hz,lH), 7.921 (s,lH),7.731(dJ=8.8Hz,lH),7.640(d5J=9.2Hz,lH),7.431(t,J=7Hz,lH), 1H NMR (400 MHz, CD30D-c 6 ): 58.468 (s, H), 8.446 (s, H), 8.079 (d, J = 8.8 Hz, lH), 7.921 (s, lH), 7.731 (dJ = 8.8 Hz, lH), 7.640 (d 5 J = 9.2 Hz, lH), 7.431 (t, J = 7 Hz, lH),
7.352(t,J=8.6Hz,2H),7.290(d,J=9.2Hz,lH),7.178(d,J=9.2Hz,lH),7.091(t,J=8.6Hz,lH),6. 74(s,lH),6.696(s,lH),5.242(s,2H),4.122(m,2H),4.013(t,J=7.2Hz,lH),3.593(m,2H),3.81 6(br,2H),3.650(br,2H),2.605(br,2H),2.431(d,J=6Hz,2H),2.253(s,lH),1.322(s,lH) 实施例 237 7.352 (t, J = 8.6 Hz, 2H), 7.290 (d, J = 9.2 Hz, lH), 7.178 (d, J = 9.2 Hz, lH), 7.091 (t, J = 8.6 Hz, lH), 6. 74 (s, lH), 6.696 (s, lH), 5.242 (s, 2H), 4.122 (m, 2H), 4.013 (t, J = 7.2 Hz, lH), 3.593 (m, 2H), 3.81 6 ( Br, 2H), 3.650 (br, 2H), 2.605 (br, 2H), 2.431 (d, J = 6 Hz, 2H), 2.253 (s, lH), 1.322 (s, lH) Example 237
l-(3- -「3-氯 -4-(3-氟-苄氧基 苯氨基 1-喹唑啉 -6-基 吡咯小基) -3-(4-环丙基甲基- 哌嗪 -1-基 丙 -2-醇  L-(3- -"3-Chloro-4-(3-fluoro-benzyloxyphenylamino-1-quinazolin-6-ylpyrroleyl)-3-(4-cyclopropylmethyl-piperazine) -1-ylpropan-2-ol
Figure imgf000247_0001
Figure imgf000247_0001
Figure imgf000248_0001
Figure imgf000248_0001
Figure imgf000248_0002
Figure imgf000248_0002
187a  187a
237  237
第一步  First step
l-环丙基甲基 -哌嗪  L-cyclopropylmethyl-piperazine
将甲磺酸环丙基甲酯 226a (1.49 g， 10 mmol)和哌嗪 (1.77g，20 mmol)溶于 30 mL 乙腈中， 搅拌下加入碳酸钾 (2.07g， 15 mmol), 混合液加热回流， 反应过夜。 将反 应液倒入 30 mL水中， 分液， 有机相通过无水硫酸钠干燥， 过滤， 减压下浓缩， 得到的残留物通过硅胶柱层析进一步分离纯化 (二氯甲烷： 甲醇 =5 : 1)， 得到 1- 环丙基甲基 -哌嗪 237a (373 mg， 黄色油状液体)， 产率： 26.8%。  Dissolve cyclopropylmethyl methanesulfonate 226a (1.49 g, 10 mmol) and piperazine (1.77 g, 20 mmol) in 30 mL of acetonitrile, add potassium carbonate (2.07 g, 15 mmol) with stirring, and heat the mixture. Reflow and reaction overnight. The reaction solution was poured into 30 mL of water, and the organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated. ), 1-cyclopropylmethyl-piperazine 237a (373 mg, yellow oily liquid) was obtained. Yield: 26.8%.
MS m/z (ESI): 141 [M+ l] 第二步 MS m/z (ESI): 141 [M+ l] Step 2
将 1-环丙基甲基 -哌嗪 237a (57 mg, 0.42 mmol)和 [3-氯 -4-(3-氟-苄基) -苯基] - [6-(1-环氧乙基甲基 -1H-吡咯 -3-基) -喹唑啉 -4-基] -胺 187a (140 mg, 0.3 mmol)溶于 25 mL甲醇中，混合液加热回流过夜。反应液在减压下浓缩，得到的残留物通过硅 胶柱层析进一步分离纯化 (二氯甲烷： 甲醇 =40: 1), 得到本标题产物 1-(3-{4-[3- 氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基 吡咯 -1-基) -3-(4-环丙基甲基 -哌嗪 -1-基) - 丙 -2-醇 237(116 mg， 黄色固体)， 产率： 30.1 %。  1-Cyclopropylmethyl-piperazine 237a (57 mg, 0.42 mmol) and [3-chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-epoxyethyl) Methyl-1H-pyrrol-3-yl)-quinazolin-4-yl]-amine 187a (140 mg, 0.3 mmol) was dissolved in 25 mL MeOH. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjj -(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylpyrrol-1-yl)-3-(4-cyclopropylmethyl-piperazin-1-yl)-propane- 2-alcohol 237 (116 mg, yellow solid), Yield: 30.1%.
MS m/z (ESI): 641 [M+ l] MS m/z (ESI): 641 [M+ l]
1H NMR (400 MHz, CD30D- )： 59.72 (s, 1H), 8.54 (s, 1H), 8.50 (s， 1H), 8.04 (s, 1H), 8.02 (d， J = 8.8Hz, 1H), 7.77 (d, J = 8.8Hz, 1H), 7.69 (d, J = 8.8Hz, 1H), 7.54 (t, J = 8.8Hz, 1H)， 7.42 (s, 1H), 7.32 (m, 3H), 7.19 (t, J = 8.8Hz, 1H), 6.87 (s, 1H), 6.65 (s, 1H), 5.27 (s, 2H), 4.92 (d， J = 4.0Hz, 1H)， 4.06 (t, J = 12.8Hz, 1H), 3.94 (s, 1H), 3.85 (m, 1H), 2.48 (br, 8H), 2.25 (br, 2H), 2.19 (br， 2H), 0.80 (m, 1H), 0.45 (d， J = 6.8Hz, 2H), 0.06 (d, J = 4.4Hz, 2H) 实施例 238  1H NMR (400 MHz, CD30D-): 59.72 (s, 1H), 8.54 (s, 1H), 8.50 (s, 1H), 8.04 (s, 1H), 8.02 (d, J = 8.8Hz, 1H), 7.77 (d, J = 8.8 Hz, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.54 (t, J = 8.8 Hz, 1H), 7.42 (s, 1H), 7.32 (m, 3H), 7.19 (t, J = 8.8Hz, 1H), 6.87 (s, 1H), 6.65 (s, 1H), 5.27 (s, 2H), 4.92 (d, J = 4.0Hz, 1H), 4.06 (t, J = 12,8 Hz, 1H), (d, J = 6.8 Hz, 2H), 0.06 (d, J = 4.4 Hz, 2H) Example 238
2-(3- -「3-氯 -4-(3-氟-苄氧基 苯氨基 1-喹唑啉 -6-基 吡咯小基 I- 哌嗪 -1-基 -乙酮 2-(3- -"3-chloro-4-(3-fluoro-benzyloxyphenylamino-1-quinazolin-6-ylpyrrolidinyl I-piperazin-1-yl-ethanone
Figure imgf000249_0001
第一步
Figure imgf000249_0001
first step
4-(2-氯乙酰基) -哌嗪小甲酸叔丁酯  4-(2-chloroacetyl)-piperazine-less-tert-butyl formate
将哌嗪 -1-甲酸叔丁酯 (1 g， 5.38 mmol)溶于 10 mL四氢呋喃中， 搅拌下加入三 乙胺 (651 mg， 6.45 mmol), 反应液在丙酮-干冰浴冷却至 -78 °C， 滴加氯乙酰氯 (0.8 mL， 6.45 mmol), 反应液在室温下搅拌 24小时， 反应完毕。 将反应液在减压下浓 缩， 残留物加入 50 mL水， 用乙酸乙酯萃取 (50 mL X 3)， 合并的有机相通过无水 硫酸钠干燥，过滤，减压下浓缩，得到的残留物通过硅胶柱层析进一步分离纯化 (：正 己烷： 乙酸乙酯 = 1 : 1)， 得到 4-(2-氯乙酰基) -哌嗪 -1-甲酸叔丁酯 238a (U g， 黄 色固体)， 产率： 70%。  tert-Butyl piperazine-1-carboxylate (1 g, 5.38 mmol) was dissolved in 10 mL of tetrahydrofuran, triethylamine (651 mg, 6.45 mmol) was added with stirring, and the reaction was cooled to -78 ° in acetone-dry ice bath. C, Chloroacetyl chloride (0.8 mL, 6.45 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 24 hours, and the reaction was completed. The reaction mixture was concentrated under reduced pressure. EtOAc m. Further separation and purification by silica gel column chromatography (:hexane: ethyl acetate = 1:1) afforded 4-(2-chloroacetyl)-piperazine-1-carboxylic acid tert-butyl ester 238a (U g, yellow solid) , Yield: 70%.
MS m/z (ESI): 264[M+ 1] MS m/z (ESI): 264 [M+ 1]
第二步  Second step
4-[2-(3-{4-[3-氯 -4-(3-氟苄氧基) -苯氨基] -喹唑啉 -6-基}-吡咯 -1-基) -乙酰基] -哌嗪 -1- 甲酸叔丁酯  4-[2-(3-{4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazolin-6-yl}-pyrrol-1-yl)-acetyl] - piperazine-1-carboxylic acid tert-butyl ester
在 50 mL的烧瓶中，将 [3-氯 -4-(3-氟 - 氧基) -苯基 ]-[6-(1Η-吡咯 -3-基) -喹唑啉 -4- 基] -胺 42 (444 mg, 1 mmol)溶于 10 mL干燥的 Ν,Ν-二甲基甲酰胺中， 在冰浴条件 下，冷却至 0°C，加入氢化钠 (72 mg， 3 mmol),搅拌 30分钟后加入 4-(2-氯乙酰基) - 哌嗪 -1-甲酸叔丁酯 238a (263 mg， 1 mmol), 室温下搅拌 1小时反应完毕。 在反应 液中加入饱和氯化钠溶液， 乙酸乙酯萃取 (100 mL X 3)， 合并的有机相通过无水硫 酸钠干燥， 过滤， 减压下浓缩， 得到的残留物通过硅胶柱层析进一歩分离纯化 (二 氯甲烷：甲醇 =40: 1)，得到 4-[2-(3-{4-[3-氯 -4-(3-氟苄氧基)-苯氨基] -喹唑啉 -6-基 吡咯 -1-基) -乙酰基] -哌嗪 -1-甲酸叔丁酯 238b (300 mg， 淡黄色固体)， 产率： 51 %。 MS m/z (ESI): 671[M+ 1] [3-Chloro-4-(3-fluoro-oxy)-phenyl]-[6-(1Η-pyrrol-3-yl)-quinazolin-4-yl]- in a 50 mL flask Amine 42 (444 mg, 1 mmol) was dissolved in 10 mL dry EtOAc EtOAc (EtOAc) After 30 minutes, 4-(2-chloroacetyl)-piperazine-1-carboxylic acid tert-butyl ester 238a (263 mg, 1 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Add saturated sodium chloride solution to the reaction solution, extract with ethyl acetate (100 mL X 3), and combine the organic phase with anhydrous sulfur The sodium salt was dried, filtered, and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (dichloromethane:methanol = 40:1) to give 4-[2-(3-{4-[3 -Chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazolin-6-ylpyrrol-1-yl)-acetyl]-piperazine-1-carboxylic acid tert-butyl ester 238b (300 mg, Light yellow solid), Yield: 51%. MS m/z (ESI): 671 [M+ 1]
第三步  third step
2-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基 }-吡咯 -1-基) -1-哌嗪 -1-基 -乙酮 将 4-[2-(3-{4-[3-氯 -4-(3-氟苄氧基) -苯氨基] -喹唑啉 -6-基 吡咯- 1-基) -乙酰基] -哌 嗪 -1-甲酸叔丁酯 238b(400 mg, 0.6 mmol)溶于 10 mL二氯甲垸中，搅拌下加入 3 mL 三氟醋酸， 室温下搅拌 2小时后反应完毕。 将反应液中加入饱和碳酸氢钠溶液， 调节 pH=8，用乙酸乙酯萃取 (100 mLX 3)， 合并的有机相通过无水硫酸钠干燥， 过 滤， 减压下浓缩， 残留物通过硅胶柱层析进一步分离纯化 (二氯甲垸： 甲醇 = 10: 2-(3-{4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-pyrrol-1-yl)-1-piperazine- 4-[2-(3-{4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazolin-6-ylpyrrole-1-yl - acetyl]-piperazine-1-carboxylic acid tert-butyl ester 238b (400 mg, 0.6 mmol) was dissolved in 10 mL of dichloromethane, and 3 mL of trifluoroacetic acid was added with stirring, and the reaction was completed after stirring at room temperature for 2 hours. . The reaction mixture was added with a saturated aqueous solution of sodium bicarbonate, and the mixture was adjusted to pH=8, and ethyl acetate (100 mL EtOAc). Further separation and purification by chromatography (dichloromethane: methanol = 10:
1)， 得到标题产物 2-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基}-吡咯 -1- 基)小哌嗪 -1 -基 -乙酮 238(270 mg， 黄色固体)， 产率： 79%。 1), the title product 2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-pyrrol-1-yl) Small piperazine-1-yl-ethanone 238 (270 mg, yellow solid), yield: 79%.
MS m/z (ESI): 571 [M+ l] MS m/z (ESI): 571 [M+ l]
1H NM (400 MHz, CO30O-d6): 59.70 (s,lH) , 8.54 (s,lH), 8.49 (s,lH),8.03 (d,1H NM (400 MHz, CO30O-d 6 ): 59.70 (s,lH) , 8.54 (s,lH), 8.49 (s,lH),8.03 (d,
J=8Hz,2H) , 7.76 (d,J=8.4Hz,lH) , 7.70 (d,J=8.8Hz,lH) , 7.48 (m,lH), 7.41 (s,lH), 7.33 (m,3H)， 7.19 (t,J=8Hz,lH) , 6.88 (s，lH) , 6.65 (s，lH) , 5.27 (s,2H)， 4.95 (s,2H) , 3.44 (br,4H) , 2.72 (m,4H) 实施例 239 J=8Hz, 2H), 7.76 (d, J=8.4Hz, lH), 7.70 (d, J=8.8Hz, lH), 7.48 (m,lH), 7.41 (s,lH), 7.33 (m,3H ), 7.19 (t, J=8Hz, lH), 6.88 (s, lH), 6.65 (s, lH), 5.27 (s, 2H), 4.95 (s, 2H), 3.44 (br, 4H), 2.72 ( m, 4H) Example 239
N_{ 143-(3_{4-「3-氯 -4-(3-氟 -苄氧基)-苯氨基 1-喹唑啉 -6-基 }-吡咯 -1-基) -2-羟 -丙基 1- N _ { 1 4 3 - (3 _ {4 -"3-chloro-4-(3-fluoro-benzyloxy)-phenylamino-1-quinazolin-6-yl}-pyrrol-1-yl) - 2-hydroxy-propyl 1-
Figure imgf000250_0001
第一步 N-哌啶 -4-基-乙酰胺乙酸盐
Figure imgf000250_0001
first step N-piperidin-4-yl-acetamide acetate
将哌啶 -4-基胺（0.52 mL， 5 mmol)溶于 20 mL乙醚中， 逐渐滴加醋酸酐 (0.57 mL, 6 mmol)的 20 mL乙醚溶液， 滴加完毕后， 室温下搅拌 1小时， 反映完毕。 过滤反应液， 滤饼用乙醚洗涤， 滤液在减压下浓缩， 得到 N-哌啶 -4-基 -乙酰胺乙酸 盐 239a (962 mg， 白色固体)， 产率： 95.7%。  Dissolve piperidin-4-ylamine (0.52 mL, 5 mmol) in 20 mL of diethyl ether and gradually add acetic anhydride (0.57 mL, 6 mmol) in 20 mL of diethyl ether. After the dropwise addition, stir at room temperature for 1 hour. , the reflection is complete. The reaction mixture was filtered, and then filtered and evaporated, mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
第二步  Second step
N -哌啶 _4—基-乙酰胺 N-piperidin- 4 -yl-acetamide
将 N-哌啶 -4-基-乙酰胺乙酸盐 239a (500 mg, 2.48 mmol)溶于 10 mL甲醇中， 滴加 20 mL饱和碳酸钾的甲醇溶液， 室温下搅拌 1小时， 反应完毕。 将反应液在 减压下浓缩， 得到的残留物用乙酸乙酯萃取 (100 mLX 3)， 所得的残留物通过硅胶 柱层析分离纯化 (二氯甲烷：甲醇 = 10: 1),得到 N-哌啶 -4-基-乙酰胺 239b (224 mg， 无色油状液体)， 产率： 63.7%。  N-Piperidin-4-yl-acetamide acetate 239a (500 mg, 2.48 mmol) was dissolved in 10 mL of methanol, and 20 mL of saturated potassium carbonate in methanol was added dropwise and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. Piperidin-4-yl-acetamide 239b (224 mg, colorless oily). Yield: 63.7%.
MS m/z (ESI): 143 [M+ l] MS m/z (ESI): 143 [M+ l]
第三步  third step
Ν-{ 1-[3-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基 比咯 -1-基) -2-羟-丙基] - 哌啶 -4-基 乙酰胺 Ν-{ 1-[3-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylpyrrol-1-yl) - 2-hydroxy-propyl]-piperidin-4-ylacetamide
将 N-哌啶 -4-基-乙酰胺 239b (60 mg, 0.42 mmol)和 [3-氯 -4-(3-氟-苄基) -苯基 ]- [6-(1-环氧乙基甲基 -1H-吡咯 -3-基) -喹唑啉 -4-基] -胺 187a (165 mg, 0.33 mmol)溶于 30 mL甲醇中，混合液加热回流过夜。反应液在减压下浓缩， 得到的残留物通过硅 胶柱层析进一步分离纯化（二氯甲烷： 甲醇 = 50 : 1)， 得到本标题产物 Ν-{1-[3-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基}-吡咯 -1-基) -2-羟-丙基] - 哌啶 -4-基}-乙酰胺 239 (33 mg， 黄色固体)， 产率： 22.9%。  N-piperidin-4-yl-acetamide 239b (60 mg, 0.42 mmol) and [3-chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-epoxyethyl) The benzyl-1H-pyrrol-3-yl)-quinazolin-4-yl]-amine 187a (165 mg, 0.33 mmol) was dissolved in 30 mL MeOH. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified and purified by silica gel column chromatography (dichloromethane:methanol = 50:1) to give the title product Ν-{1-[3-(3-{4- [3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-pyrrol-1-yl)-2-hydroxy-propyl]-piperidin-4- }--acetamide 239 (33 mg, yellow solid), Yield: 22.9%.
MS m/z (ESI): 643[M+ 1] MS m/z (ESI): 643 [M+ 1]
1H NMR (400 MHz, CD30D-^): 610.00 (s, IH), 8.72 (s, IH), 8.48 (s， 1H)， 8.11 (s, IH), 8.02 (d, J = 8.8Hz, IH), 7.85 (d, J = 8.8Hz, IH), 7.69 (d, J = 8.8Hz, IH), 7.54 (t, J = 8.8Hz, IH), 7.42 (s, IH), 7.32 (m; 3H)， 7.19 (t, J = 8.8Hz, IH), 6.86 (s, IH), 6.73 (s, IH), 5.27 (s, 2H), 5.17 (br, IH), 4.14 (d, J = 12.4Hz, IH), 4.06 (t, J = 12.8Hz, IH), 3.94 (s, IH), 3.85 (m, IH), 3.72 (d, J = 13.2Hz, IH), 3.34 (s, IH), 3.04 (t, J = 11.6Hz, IH), 2.70 (t, J = 10.8Hz, IH), 2.60 (m, 2'H), 1.97 (s, 3H), 1.74 (br, 2H), 1.15 (m, 2H) 实施例 240 1H NMR (400 MHz, CD30D-^): 610.00 (s, IH), 8.72 (s, IH), 8.48 (s, 1H), 8.11 (s, IH), 8.02 (d, J = 8.8Hz, IH) , 7.85 (d, J = 8.8Hz, IH), 7.69 (d, J = 8.8Hz, IH), 7.54 (t, J = 8.8Hz, IH), 7.42 (s, IH), 7.32 (m ; 3H) , 7.19 (t, J = 8.8Hz, IH), 6.86 (s, IH), 6.73 (s, IH), 5.27 (s, 2H), 5.17 (br, IH), 4.14 (d, J = 12.4Hz, IH), 4.06 (t, J = 12.8Hz, IH), 3.94 (s, IH), 3.85 (m, IH), 3.72 (d, J = 13.2Hz, IH), 3.34 (s, IH), 3.04 ( t, J = 11.6Hz, IH), 2.70 (t, J = 10.8Hz, IH), 2.60 (m, 2'H), 1.97 (s, 3H), 1.74 (br, 2H), 1.15 (m, 2H) Embodiment 240
Γ3-氯 -4-(3-氟-苄氧基 苯基 1-· 6-「 2-哌嗪 -1-基 -乙基 1H-吡咯 -3-基 1-喹唑啉 -4-基  Γ3-Chloro-4-(3-fluoro-benzyloxyphenyl 1-·6-"2-piperazin-1-yl-ethyl 1H-pyrrole-3-yl-1-quinazolin-4-yl
膣 膣
Figure imgf000252_0001
将 2-(3-{4-[3-氯 -4-(3-氟- 氧基) -苯氨基] -喹唑啉 -6-基} -吡咯小基) -1-哌嗪 -1 -基 -乙酮 238(120 mg， 0.21 mmol)溶于 10 mL四氢呋喃中， 在氩气保护下， 加入氢化 铝锂 (40 mg， 2.1 mmol), 室温下搅拌 1小时反应完毕。 将反应液在减压下浓缩， 得到的残留物通过硅胶柱层析进一步分离纯化 (二氯甲垸： 甲醇 = 15 : 1)， 得到 [3- 氯 -4-(3-氟-苄氧基) -苯基 ]-{6-[1-(2-哌嗪 -1-基-乙基) -1H-吡咯 -3-基] -喹唑啉 -4-基} -胺 (44 mg, 黄色固体)， 产率： 37.6%。
Figure imgf000252_0001
2-(3-{4-[3-Chloro-4-(3-fluoro-oxy)-phenylamino]-quinazolin-6-yl}-pyrroleyl)-1-piperazine-1 The ketone ketone 238 (120 mg, 0.21 mmol) was dissolved in 10 mL of tetrahydrofuran. Lithium aluminum hydride (40 mg, 2.1 mmol) was added under argon, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified and purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to give [3-chloro-4-(3-fluoro-benzyloxy) -phenyl]-{6-[1-(2-piperazin-1-yl-ethyl)-1H-pyrrol-3-yl]-quinazolin-4-yl}-amine (44 mg, yellow Solid), Yield: 37.6%.
MS m/z (ESI): 557[M+ 1] MS m/z (ESI): 557 [M+ 1]
1H NMR (400 MHz, CD30D-t¾): 59.70 (s,lH)， 8.54 (s,lH), 8.49 (s，lH)， 8.03 (d, J=8Hz, 2H) , 7.76 (d,J=8.4Hz,lH) , 7.70 (d,J=8.8Hz,lH) , 7.48(m,lH) , 7.41 (s，lH)， 7.33 (m,3H) , 7.19 (t,J=8Hz，lH) , 6.88 (s,lH) , 6.65 (s,lH) , 5.27 (s,2H) , 4.05 1H NMR (400 MHz, CD30D-t3⁄4): 59.70 (s,lH), 8.54 (s,lH), 8.49 (s,lH), 8.03 (d, J=8Hz, 2H), 7.76 (d, J=8.4 Hz, lH), 7.70 (d, J = 8.8 Hz, lH), 7.48 (m, lH), 7.41 (s, lH), 7.33 (m, 3H), 7.19 (t, J = 8 Hz, lH), 6.88 (s,lH) , 6.65 (s,lH) , 5.27 (s,2H) , 4.05
(t,J=8Hz,2H)， 2.92 (m,4H) , 2.72 (m，2H) , 2.53 (br,4H) 实施例 241 (t, J = 8 Hz, 2H), 2.92 (m, 4H), 2.72 (m, 2H), 2.53 (br, 4H) Example 241
1-(3-{4-「1-(3-氟 -苄基 IH-吲唑 -5-基氨基 1-喹唑啉 -6-基 }-吡咯小基) -3-(4-甲基 -哌嗪  1-(3-{4-"1-(3-Fluoro-benzyl IH-indazol-5-ylamino-1-quinazolin-6-yl}-pyrroleyl)-3-(4-methyl -Piperazine
-1-基)-丙-2-醇  -1-yl)-propan-2-ol
Figure imgf000252_0002
Figure imgf000253_0001
在 100 mL茄形瓶中， 将 [1-(3-氟-苄基) -1Η-吲唑 -5-基 ]-[6-(1-环氧乙基甲基 -1H- 吡咯 -3-基) -喹唑啉 -4-基] -胺 178a (565 mg， 1.15 mmol)溶于 30 mL甲醇中，氩气保 护下加入 1-甲基哌嗪 (461 mg， 4.6 mmol), 反应液加热回流过夜。 将反应液在减压 下浓缩， 得到的残留物通过薄层层析板进一步分离纯化 (二氯甲烷： 甲醇 =7: 1)， 得到本标题产物 1-(3-{4-[1-(3-氟-苄基) -1H-吲唑 -5-基氨基 ]-喹唑啉 -6-基 吡咯 -1- 基) -3-(4-甲基 -哌嗪 -1-基) -丙 -2-醇 241 (296 mg， 黄色固体） ， 产率： 43.5 %。
Figure imgf000252_0002
Figure imgf000253_0001
[1-(3-Fluoro-benzyl)-1Η-indazol-5-yl]-[6-(1-epoxyethylmethyl-1H-pyrrole-3- in a 100 mL eggplant-shaped flask - quinazolin-4-yl]-amine 178a (565 mg, 1.15 mmol) was dissolved in 30 mL of methanol, and 1-methylpiperazine (461 mg, 4.6 mmol) was added under argon. Reflux overnight. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified (yield: methylene chloride: methanol = 7:1) to afford the title product 1-(3-{4-[1-( 3-fluoro-benzyl)-1H-indazol-5-ylamino]-quinazolin-6-ylpyrrolidin-1-yl)-3-(4-methyl-piperazin-1-yl)-propane 2-Alcohol 241 (296 mg, yellow solid), Yield: 43.5 %.
MS m/z (ESI): 591[M+ 1] MS m/z (ESI): 591 [M+ 1]
'HNMR (400MHZ, DMSO-i¾): δ 9.83(s,lH)58.61 (S,1H),8.44(S,1H),8.23 (s,lH), 8.17(s,lH),8.04(d,lH,J = 8.8 Hz ),7.75(m,3H),7.41 (m,2H), 7.14(m,3H), 6.87(s,lH),'HNMR (400MHZ, DMSO-i3⁄4): δ 9.83(s,lH) 5 8.61 (S,1H), 8.44 (S,1H), 8.23 (s,lH), 8.17 (s,lH), 8.04 (d, lH, J = 8.8 Hz ), 7.75 (m, 3H), 7.41 (m, 2H), 7.14 (m, 3H), 6.87 (s, lH),
6.67 (s，lH),5.72 (s,2H),4.94(br s，lH)，4.04 (m,2H),3.94(m, 1 H),3.88(m, 1 H),3.18 (d,2H, J = 3.6 Hz),2.47(m,5H),2.27 (m,5H) 实施例 242 6.67 (s, lH), 5.72 (s, 2H), 4.94 (br s, lH), 4.04 (m, 2H), 3.94 (m, 1 H), 3.88 (m, 1 H), 3.18 (d, 2H) , J = 3.6 Hz), 2.47 (m, 5H), 2.27 (m, 5H) Example 242
2-(3-ί4-Γ3-氯 -4-( -氟-苄氧基) -苯氨基 1-喹唑啉 -6-基 吡咯 -1-基) -l-(T3S，5R)-3,5-二 甲基 -哌嗪 -1-基 V乙酮  2-(3-ί4-Γ3-chloro-4-(-fluoro-benzyloxy)-phenylamino-1-quinazolin-6-ylpyrrol-1-yl)-1 -(T3S,5R)-3, 5-dimethyl-piperazin-1-yl V ethyl ketone
Figure imgf000253_0002
Figure imgf000253_0002
第一步 zvz first step Zvz
Figure imgf000254_0001
Figure imgf000254_0001
B¾¾  B3⁄43⁄4
-(愛 ¾ ^-篤 -ε) -霄 -£_1-¾-17-柳¾畢-1¾-£-^ -m- (愛 2-¾-i-ii¾¾¾- HJ-w ςζ -(爱3⁄4 ^-笃 -ε) -霄 -£_1-3⁄4-17-柳3⁄4毕-13⁄4-£-^ -m- (Love 2-3⁄4-i-ii3⁄43⁄43⁄4- HJ-w ςζ
(Η9 'ra)66 '(HI
Figure imgf000254_0002
'Ρ)9//£ '(Ηΐ 'ΖΗ8·乙 ΐ=Γ ^ΖΖ XUZ ' V9l ΖΗ0ΤΑ=Γ 'ΡΡ)96 ΗΖ '^ίΖ '(HI 'S)99'9 '(HI 'S)38"9 '(Ηΐ ^)6YL \ '(HI ^) YL '(Ηΐ ¾8-8=1 'Ρ)ΐΓΑ '(Ηΐ ¾8'8=1 'Ρ)9 //乙 (Η9 'ra)66 '(HI
Figure imgf000254_0002
'Ρ'9//£ '(Ηΐ 'ΖΗ8·乙ΐ=Γ ^ΖΖ XUZ 'V9l ΖΗ0ΤΑ=Γ 'ΡΡ)96 ΗΖ '^ίΖ '(HI 'S)99'9 '(HI 'S)38" 9 '(Ηΐ ^)6YL \ '(HI ^) YL '(Ηΐ 3⁄48-8=1 'Ρ)ΐΓΑ '(Ηΐ 3⁄48'8=1 'Ρ)9 //B
'(Η3 '∞)£0·8 '(Ηΐ 's)0S'8 '(HI '(HI ^ \L69, ^9P-( OZQ ^UVi OOV) ¾WMHT '(Η3 '∞)£0·8 '(Ηΐ 's)0S'8 '(HI '(HI ^ \L69, ^ 9 P-( OZQ ^UVi OOV) 3⁄4WMH T
[l+IAl]66S :(lSH)zA«SFi 03 °%6Ί9 ：拿:^ 'Sm LZ) ZfZ 醒 2- (耷个翻 二 £- ¾ ))十(¾十^物- {¾-9-擁^ - 驚 輋^ -― ¾
Figure imgf000254_0003
'翳士 邈 氺 π¾目 [l+IAl]66S : (lSH)zA«SFi 03 °%6Ί9 : Take: ^ ' Sm LZ) ZfZ Wake up 2 (耷 翻 2 £ - 3⁄4 )) 10 (3⁄4 十^物 - {3⁄4- 9 -拥^ - Thriller ^ -― 3⁄4
Figure imgf000254_0003
'翳士邈氺π3⁄4目
4(εχΊ∞
Figure imgf000254_0004
 4 (εχΊ∞
Figure imgf000254_0004
^丄遝 ； '(ioraui 9 29ε) ^ZPZ ¾¾° ffitz-[g-i-fairci-¾!i!~-si£-(¾s's£)]-t- zp^ 丄遝; '(i oraui 9 29ε) ^ZPZ 3⁄43⁄4° ffi t z-[gi-fairci-3⁄4!i!~-s i £-(3⁄4s's£)]-t- zp
Figure imgf000254_0005
os ¾
Figure imgf000254_0005
Os 3⁄4
醒2-(¾十峯 11逝 - ώ οι 二 -S'£-(WS£))-I-(¾-I-^ S-9-糊 - -ε) -鶩 -ε]-ΐ/}-ε  Wake up 2-(3⁄4十峰11逝- ώ οι 二-S'£-(WS£))-I-(3⁄4-I-^ S-9-糊- -ε) -鹜-ε]-ΐ/} -ε
^二蚩 '  ^二蚩'
[ι+Μ]ΐ6ΐ :(isa)z/∞si^[ι+Μ]ΐ6ΐ : (isa)z/∞si^
00ΐ : ^ 00ΐ : ^
'Sui 9ς ) ^ZPZ ¾邈' 醒 2-1¾-1-翁¾(0-¾*二 -S'£-(WS£)H-¾-20ί 5 士 簟 蔦二^鎏丄 3? ¾¾^ ¾ '^Ί^ 01 Υ ϋϊ^ίΦ^ S '(iouixu^i '§ra^^) 綱 2鹙 γ1¾止 凝 'aSZr^d ^土^醒 'Sui 9 ς ) ^ZPZ 3⁄4邈' Wake 2-13⁄4-1-Weng 3⁄4 (0-3⁄4*二-S'£-(WS£)H-3⁄4-20ί 5 士簟茑二^鎏丄3? 3⁄43⁄4 ^ 3⁄4 '^Ί^ 01 Υ ϋϊ^ίΦ^ S '(iouixu^i '§ra^^) Outline 2鹙γ13⁄4 Stop condensing 'aSZr^d ^ soil awake
d ¾¾¾ 'Φ^ώϋ- Ί∞ Οΐ -ίΜ (ΐ0画 Ζ 'Sui 6 )fd|ftl¾i:-9 -(¾9'SZ;) d ¾¾¾ 'Φ ^ ώϋ- Ί∞ Οΐ -ίΜ (ΐ 0 Videos Ζ' Sui 6) fd | ftl¾i : -9 - (¾9'SZ;)
邈^腿2-[¾-1-¾¾|-¾-由二 -S'£-(WS£)]-I-:)$-乙  邈^腿2-[3⁄4-1-3⁄43⁄4|-3⁄4- by two -S'£-(WS£)]-I-:)$-B
Z.0CT00/800∑N3/X3d 9簡 600Z OAV Z.0CT00/800∑N3/X3d 9 Jane 600Z OAV
Figure imgf000255_0001
Figure imgf000255_0001
. 第一步 The first step
甲磺酸 2-氮杂环庚小基 -乙酯  Methanesulfonic acid 2-azetidinyl-ethyl ester
将 2-氮杂环庚- 1-基 -乙醇 (1.43 g， lO mmol)溶于 10 mL二氯甲垸中， 在冰浴条 件下，冷却至 0°C，依次加入三乙胺 (2.02 g， 20 mmol)和甲磺酰氯 (1.7 g， 15 mmol), 室温下搅拌 1小时， 反应完毕。 将反应液中加入 20 mL水淬灭反应， 将旋干二氯 甲烷， 水相用乙酸乙酯萃取 (30 mLX 3), 合并的有机相通过饱和氯化钠溶液洗涤， 无水硫酸钠干燥， 过滤， 减压下浓缩， 得到的残留物通过硅胶柱层析进一步分离 纯化， 得到甲磺酸 2-氮杂环庚 -1-基 -乙酯 243a (2.1 g， 黄色油状液体)， 产率： 95 %。  2-Azepan-1-yl-ethanol (1.43 g, 10 mmol) was dissolved in 10 mL of dichloromethane, cooled to 0 ° C under ice-cooling, and then triethylamine (2.02 g) 20 mmol) and methanesulfonyl chloride (1.7 g, 15 mmol) were stirred at room temperature for 1 hour and the reaction was completed. The reaction mixture was quenched with EtOAc (EtOAc) (EtOAc) Filtration and concentrating under reduced pressure, and the residue obtained was purified by silica gel column chromatography to give 2-azul-heptan-1-yl-ethyl ester 243a (2.1 g, yellow oily liquid). 95%.
MS m/z (ESI): 222[M+ 1]  MS m/z (ESI): 222 [M+ 1]
第二步  Second step
{6-[1-(2-氮杂环庚 -1-基-乙基) -1H-吡咯 -3-基]-喹唑啉 -4-基 }-[3-氯 -4-(3-氟-苄氧基) - 苯基] -胺  {6-[1-(2-Azepan-1-yl-ethyl)-1H-pyrrol-3-yl]-quinazolin-4-yl}-[3-chloro-4-(3- Fluoro-benzyloxy)-phenyl]-amine
在 50 mL的烧瓶中，将 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-[6-(1Η-吡咯 -3-基) -喹唑啉 -4- 基] -胺 42 (222 mg， 0.5 mmol)溶于 6 mL干燥的 N，N-二甲基甲酰胺中， 搅拌下加入 氢化钠 (60 mg， 2.5 mmol), 30分钟后加入甲磺酸 2-氮杂环庚小基 -乙酯 243a (166 mg， 0.75 mmol), 室温下搅拌 1小时反应完毕。 反应液加入 20 mL冰水， 用乙酸 乙酯萃取 (30 mLX 4)，合并的有机相依次通过饱和氯化钠溶液洗涤，无水硫酸钠干 燥，过滤， 减压下浓缩，得到的残留物通过硅胶柱层析进一步分离纯化 (二氯甲烷: 甲醇 = 10: 1)， 得到本标题产物 {6-[1-(2-氮杂环庚 -1-基-乙基) -1H-吡咯 -3-基] -喹唑 啉 -4-基 }-[3-氯 -4-(3-氟-苄氧基) -苯基] -胺 243 (230 mg， 黄色固体)， 产率： 81 %。 MS m/z (ESI): 570[M+ 1]  [3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1Η-pyrrol-3-yl)-quinazolin-4-yl] in a 50 mL flask -Amine 42 (222 mg, 0.5 mmol) was dissolved in 6 mL of dry N-N-dimethylformamide and sodium hydride (60 mg, 2.5 mmol) was added with stirring. Heterocyclic heptyl-ethyl ester 243a (166 mg, 0.75 mmol) was stirred at room temperature for 1 hour. The reaction mixture was poured into 20 mL of ice water and extracted with ethyl acetate (30 mL×4). The combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Further separation and purification by silica gel column chromatography (dichloromethane:methanol = 10:1) afforded the title product (6-[1-(2-azephhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhhh -yl]-quinazolin-4-yl}-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-amine 243 (230 mg, yellow solid), yield: 81%. MS m/z (ESI): 570 [M+ 1]
1H NMR (400 MHz, CD30D-^): S9.68(s, lH),8.52(s, lH),8.50(s, lH),8.02(m, 2H), 7.76(m, 1H), 7.70(m, 1H), 7.47(m, 2H)，7.32(m, 3H),7.19(m, 1H), 6.92(s, 1H), 6.65(s, lH),5.27(s， 2H), 4.00(t, J=6.0Hz, 2H), 2.86(m, 2H), 2.67(m, 4H), 1.56(m, 8H) 实施例 244  1H NMR (400 MHz, CD30D-^): S9.68 (s, lH), 8.52 (s, lH), 8.50 (s, lH), 8.02 (m, 2H), 7.76 (m, 1H), 7.70 ( m, 1H), 7.47 (m, 2H), 7.32 (m, 3H), 7.19 (m, 1H), 6.92 (s, 1H), 6.65 (s, lH), 5.27 (s, 2H), 4.00 (t , J = 6.0 Hz, 2H), 2.86 (m, 2H), 2.67 (m, 4H), 1.56 (m, 8H). Example 244
2-(3-M-[3-氯 -4-(3-氟-苄氧基) -苯氨基 1-喹唑啉 -6-基 吡咯小基 N- f4-羟 -1 , 1 -二氧- 六氢 -1λ*6*-噻喃 -4-基甲基) -乙酰胺 2-(3-M-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino-1-quinazolin-6-ylpyrrole small group N-f4-hydroxy-1 , 1-dioxy - Hexahydro-1λ*6*-thiopyran-4-ylmethyl)-acetamide
Figure imgf000256_0001
Figure imgf000256_0001
42  42
244  244
第一步  First step
2-氯 -Ν-(4-羟基 -1,1-二氧 -六氢 -1λ*6*-噻喃 -4-基甲基) -乙酰胺 将 4-氨甲基 -1,1-二氧代 -六氢 -1λ*6*-噻喃 -4-醇（358 mg， 2 mmol)溶于 10 mL 二氯甲烷中， 搅拌下三乙胺 (0.55 mL， 4 mmol), 加入在干冰一丙酮浴条件下， 冷 却至 -78Ό , 氩气氛下， 加入和氯乙酰氯 (226 mg， 2 mmol), 温度升至 -30°C下搅拌 1小时， 反应完毕。 反应液减压下旋干溶剂， 加入 20 mL乙酸乙酯， 过滤， 滤液在 减压下浓缩，得到 2-氯 -N-(4-羟基 -1,1-二氧 -六氢 -1λ*6*-噻喃 -4-基甲基)-乙酰胺 244a (430 mg， 红褐色固体)， 产率： 84.3 %。  2-Chloro-indole-(4-hydroxy-1,1-dioxo-hexahydro-1λ*6*-thiopyran-4-ylmethyl)-acetamide 4-aminomethyl-1,1-di Oxo-hexahydro-1λ*6*-thiopyran-4-ol (358 mg, 2 mmol) was dissolved in 10 mL of dichloromethane, stirring triethylamine (0.55 mL, 4 mmol) Under an acetone bath condition, it was cooled to -78 Torr, and chloroacetyl chloride (226 mg, 2 mmol) was added under an argon atmosphere, and the mixture was stirred at -30 ° C for 1 hour, and the reaction was completed. The solvent was evaporated to dryness under reduced pressure. ethyl acetate (20 mL), filtered, and the filtrate was concentrated under reduced pressure to give 2-chloro-N-(4-hydroxy-1,1-dioxo-hexahydro-1 λ*6 *-thiopyran-4-ylmethyl)-acetamide 244a (430 mg, reddish brown solid), Yield: EtOAc.
MS m/z (ESI): 256[M+ 1] MS m/z (ESI): 256 [M+ 1]
第二步  Second step
2-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氣基] -喹唑啉 -6-基}-吡咯 -1-基) -N-(4-羟 -1,1-二氧- 六氢 -1λ*6*-噻喃 -4-基甲基) -乙酰胺  2-(3-{4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylyl]-quinazolin-6-yl}-pyrrol-1-yl)-N-(4 -hydroxy-1,1-dioxo-hexahydro-1λ*6*-thiopyran-4-ylmethyl)-acetamide
在 50 mL的烧瓶中， 将 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-[6-(1Η-吡咯 -3-基) -喹唑啉 -4-基] -胺 42 (222 mg， 0.5 mmol)溶于 8 mL干燥的四氢呋喃中， 氩气氛下， 加入叔 丁醇钾 (224 mg, 2 mmol), 30分钟后加入 2-氯 -N-(4-轻基 -1,1-二氧 -六氢 -1λ*6*-噻 喃 _4-基甲基) -乙酰胺 244a (192 mg， 0.75 mmol), 室温下搅拌 3小时反应完毕。 反 应液加入 20 mL甲醇， 减压下浓缩， 得到的残留物通过硅胶柱层析进一步分离纯 化 (二氯甲烷： 甲醇 =30: 1)， 得到本标题产物 2-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨 基] -喹唑啉 -6-基} -吡咯小基) -N-(4-羟 -1,1-二氧 -六氢 -1λ*6*-噻喃 -4-基甲基) -乙酰胺 244 (92 mg, 黄色固体)， 产率： 49%。  [3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1Η-pyrrol-3-yl)-quinazolin-4-yl] in a 50 mL flask -Amine 42 (222 mg, 0.5 mmol) was dissolved in 8 mL of dry THF. EtOAc (t. The group-1,1-dioxo-hexahydro-1λ*6*-thiopyran-4-ylmethyl)-acetamide 244a (192 mg, 0.75 mmol) was stirred at room temperature for 3 hours. The reaction mixture was added to 20 mL of MeOH (mjjjjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH -chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-pyrrole small group -N-(4-hydroxy-1,1-dioxo-hexahydro- 1λ*6*-thiopyran-4-ylmethyl)-acetamide 244 (92 mg, yellow solid), yield: 49%.
MS m/z (ESI): 664[M+ 1] Ή NMR (400 MHz, CD30D-c¾: 59.71 (s, lH),8.55(s, lH),8.50(s, lH),8.13(m, 1H): 8.03(m, 2H), 7.74(m, 2H), 7.49(m, lH),7.33(m, 4H),7.19(m, 1H), 6.86(s, 1H), 6.68(s: lH),5.27(s， 2H), 4.68(s, 2H), 3.18(m, 4H), 2.98(m, 2H), 1.93(m, 4H) 实施例 245 MS m/z (ESI): 664 [M+ 1] NMR NMR (400 MHz, CD30D-c3⁄4: 59.71 (s, lH), 8.55 (s, lH), 8.50 (s, lH), 8.13 (m, 1H): 8.03 (m, 2H), 7.74 (m, 2H) ), 7.49(m, lH), 7.33(m, 4H), 7.19(m, 1H), 6.86(s, 1H), 6.68(s : lH), 5.27(s, 2H), 4.68(s, 2H) , 3.18(m, 4H), 2.98(m, 2H), 1.93(m, 4H) Example 245
1-ί3-ί4-|~3-氯 -4- 3-氟-苄氧基 苯氨基 1-喹唑啉 -6-基} -吡咯 -1-基) -3-(2-甲磺酰基-乙  1-ί3-ί4-|~3-chloro-4-trifluoro-benzyloxyphenylamino-1-quinazolin-6-yl}-pyrrol-1-yl)-3-(2-methanesulfonyl- B
Figure imgf000257_0001
在 100 mL茄形瓶中， 将碳酸铯274 mg， 0.84 mmol)溶于 Ν,Ν-二甲基甲酰胺 中， 搅拌下加入 [3-氯 -4-(3-氟-苄基) -苯基 ]-[6-(1-环氧乙基甲基 -1Η-吡咯 -3-基) -喹唑 啉 -4-基] -胺 178a (140 mg， 0.28 mmol)和 2-甲磺酰基乙醇（104 mg， 0.84 mmol)溶 于 10 mL无水甲醇中， 加热回流过夜。 将反应液加入 lOO mL水， 用乙酸乙酯 (100 mLX 3)萃取， 合并的有机相依次通过无水硫酸钠干燥， 过滤， 减压下浓缩， 得到 的残留物通过硅胶柱层析进一步分离纯化 (二氯甲烷： 甲醇 =50: 1)， 得到本标题 产物 μρ-^-ρ-氯 -4-(3-氟-苄氧基) -苯氨基]-喹唑啉 -6-基} -吡咯 -1-基) -3-(2-甲磺酰基 -乙氧基) -丙 -2-醇 245 (42 mg， 黄色固体)， 产率： 24%。
Figure imgf000257_0001
In a 100 mL eggplant-shaped flask, cesium carbonate 274 m g , 0.84 mmol) was dissolved in hydrazine, hydrazine-dimethylformamide, and [3-chloro-4-(3-fluoro-benzyl)- Phenyl]-[6-(1-epoxyethylmethyl-1Η-pyrrol-3-yl)-quinazolin-4-yl]-amine 178a (140 mg, 0.28 mmol) and 2-methanesulfonyl Ethanol (104 mg, 0.84 mmol) was dissolved in 10 mL anhydrous methanol and heated to reflux overnight. The reaction mixture was poured into 100 mL of water and extracted with ethyl acetate (100 mL×3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. (Dichloromethane: methanol = 50: 1) gave the titled product, p-[pi]-[rho]-[pi] -1-yl)-3-(2-methanesulfonyl-ethoxy)-propan-2-ol 245 (42 mg, yellow solid), yield: 24%.
MS m/z (ESI): 625 [M+ 1] MS m/z (ESI): 625 [M+ 1]
1H NMR (400 MHz, CD30D-c¾): 59.67 (s,lH), 8.8(s,lH),8.5 (s,lH), 8.03(d, J=8.8Hz, 2H),7.76(dd,J-2Hz,lH),7.70(d,J=8.4Hz,lH),7.5(m,2H),7.36(m,3H)57.2(s,lH),6.93(s,lH ),6.60(s,lH),5.27(s,2H),4.01(m,lH),3.90(m,lH),3.80(m,2H),3.50(m,3H),3.39(m,2H)33. 02(s,3H),1.98(br,lH) 实施例 246 1H NMR (400 MHz, CD30D-c3⁄4): 59.67 (s, lH), 8.8 (s, lH), 8.5 (s, lH), 8.03 (d, J = 8.8 Hz, 2H), 7.76 (dd, J- 2 Hz, lH), 7.70 (d, J = 8.4 Hz, lH), 7.5 (m, 2H), 7.36 (m, 3H) 5 7.2 (s, lH), 6.93 (s, lH), 6.60 (s, lH) ), 5.27 (s, 2H), 4.01 (m, lH), 3.90 (m, lH), 3.80 (m, 2H), 3.50 (m, 3H), 3.39 (m, 2H) 3 3. 02 (s, 3H), 1.98 (br, lH) Example 246
Ν-{1-「2-(3-ί4-Γ3-氯 -4-(3-氟-苄氧基) -苯氨基 1-喹唑啉 -6-基 吡咯 -1-基) -乙酰基 1-哌 啶 -4-基 乙酰胺 2008/001307 Ν-{1-"2-(3-ί4-Γ3-chloro-4-(3-fluoro-benzyloxy)-phenylamino-1-quinazolin-6-ylpyrrol-1-yl)-acetyl 1 -piperidin-4-ylacetamide 2008/001307
Figure imgf000258_0001
第一步
Figure imgf000258_0001
first step
N-[l-(2-氯-乙酰基) -哌啶 -4-基] -乙酰胺  N-[l-(2-chloro-acetyl)-piperidin-4-yl]-acetamide
将 N-哌啶 -4-基-乙酰胺 239b (150 mg， 1.05 mmol)溶于 15 mL二氯甲烷中， 加 入三乙胺 (l mL， 2.1 mmol),反应液在丙酮-干冰浴冷却至 -78°C，滴加氯乙酰氯 (119 mg, 1.05 mriiol), 搅拌 1小时反应完毕。 反应液中加入 50 mL水和 50 mL乙酸乙 酯， 分液， 水相用乙酸乙酯萃取 (100 mLX2)， 合并的有机相通过无水硫酸钠干燥， 过滤， 减压下浓缩， 得到的残留物通过硅胶柱层析进一步分离纯化 (二氯甲烷： 甲 醇 =50: 1)， 得到本标题产物 Ν-{1-[2-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基]-喹唑啉 -6-基}-吡咯 -1-基) -乙酰基] -哌啶 -4-基}-乙酰胺 246a (27 mg， 黄色油状液体)， 产率： 12%。  N-piperidin-4-yl-acetamide 239b (150 mg, 1.05 mmol) was dissolved in 15 mL dichloromethane, triethylamine (1 mL, 2.1 mmol). Chloroacetyl chloride (119 mg, 1.05 mriiol) was added dropwise at -78 ° C, and the reaction was completed by stirring for 1 hour. 50 ml of water and 50 mL of ethyl acetate were added to the reaction mixture, and the mixture was evaporated. EtOAcjjjjjjjjjjjjjjj The product was further purified by silica gel column chromatography (dichloromethane:methanol = 50:1) to give the title product Ν-{1-[2-(3-{4-[3-chloro-4-(3-fluoro) -benzyloxy)-phenylamino]-quinazolin-6-yl}-pyrrol-1-yl)-acetyl]-piperidin-4-yl}-acetamide 246a (27 mg, yellow oily) Yield: 12%.
MS m/z (ESI): 219[M+ 1]  MS m/z (ESI): 219 [M+ 1]
第二步  Second step
Ν-{1-[2-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基}-吡咯 -1-基) -乙酰基] -哌 啶 -4-基 乙酰胺  Ν-{1-[2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-pyrrol-1-yl) -acetyl]-piperidin-4-ylacetamide
在 50 mL的烧瓶中， 将 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-[6-(m-吡咯 -3-基)-喹唑啉 -4-基] -胺 42 (59 mg, 0.11 mmol)溶于 10 mL干燥的 Ν,Ν-二甲基甲酰胺中， 在冰浴 条件下，冷却至 0°C，加入氢化钠 (16 mg， 0.33 mmol),搅拌 30分钟后加入 N-[l-(2- 氯-乙酰基) -哌啶 -4-基]-乙酰胺 246a (27 mg, 0.12 mmol),室温下搅拌 1小时反应完 毕。反应液中加入 50 mL水和 50 mL乙酸乙酯，分液，水相用乙酸乙酯萃取 (100 mL X 2)， 合并的有机相通过无水硫酸钠干燥， 过滤， 减压下浓缩， 得到的残留物通过 硅胶柱层析进一步分离纯化（二氯甲烷： 甲醇 = 50 : 1)， 得到本标题产物 Ν-{1-[2-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基}-吡咯 -1-基) -乙酰基] -哌 啶 -4-基}-乙酰胺 246 (18 mg， 淡黄色固体)， 产率： 26.1 %。 MS m/z (ESI): 627[M+ 1] [3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(m-pyrrol-3-yl)-quinazolin-4-yl] in a 50 mL flask - Amine 42 (59 mg, 0.11 mmol) was dissolved in 10 mL dry EtOAc EtOAc (EtOAc) After stirring for 30 minutes, N-[l-(2-chloro-acetyl)-piperidin-4-yl]-acetamide 246a (27 mg, 0.12 mmol) was added, and the mixture was stirred at room temperature for 1 hour. 50 mL of water and 50 mL of ethyl acetate were added to the reaction mixture, and the mixture was evaporated. The residue was further purified by silica gel column chromatography (dichloromethane:methanol = 50:1) to give the title product Ν-{1-[2-(3-{4-[3-chloro-4-(3) -fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-pyrrol-1-yl)-acetyl]-piperidin-4-yl}-acetamide 246 (18 mg, pale yellow solid ), Yield: 26.1%. MS m/z (ESI): 627 [M+ 1]
1H NMR (400 MHz, CD30D-c¾: 510.05 (s, 1H), 8.76 (s, 1H), 8.53 (s, 1H), 8.50 (s, 1H), 8.11 (s， 1H), 8.02 (d, J = 8.8Hz, 1H), 7.85 (d, J = 8.8Hz, 1H), 7.69 (d, J = 8.8Hz, 1H), 7.54 (t, J = 8.8Hz, 1H), 7.42 (s, 1H), 7.32 (m, 3H), 7.19 (t, J = 8.8Hz, 1H), 6.85 (s: 1H), 6.76 (s, 1H), 5.27 (s， 2H), 4.63 (s, 2H), 4.17 (d, J = 12.8Hz, 1H), 3.79 (br, 2H), 3.14 (t, J = 11.6Hz, 1H), 2.79 (t, J = 11.4Hz, 1H), 2.00 (s, 3H), 1.77 (m, 2H), 1.30 (m, 2H) 实施例 247  1H NMR (400 MHz, CD30D-c3⁄4: 510.05 (s, 1H), 8.76 (s, 1H), 8.53 (s, 1H), 8.50 (s, 1H), 8.11 (s, 1H), 8.02 (d, J = 8.8Hz, 1H), 7.85 (d, J = 8.8Hz, 1H), 7.69 (d, J = 8.8Hz, 1H), 7.54 (t, J = 8.8Hz, 1H), 7.42 (s, 1H), 7.32 (m, 3H), 7.19 (t, J = 8.8Hz, 1H), 6.85 (s: 1H), 6.76 (s, 1H), 5.27 (s, 2H), 4.63 (s, 2H), 4.17 (d , J = 12.8Hz, 1H), 3.79 (br, 2H), 3.14 (t, J = 11.6Hz, 1H), 2.79 (t, J = 11.4Hz, 1H), 2.00 (s, 3H), 1.77 (m , 2H), 1.30 (m, 2H) Example 247
(RV 3- 43-氯 -4-(3-氟-苄氧基 苯氨基 1-喹唑啉 -6-基 吡咯小基 3- HV2-吡咯 烷 -1 -基甲基-吡咯烷- 1 -基 1-丙 -2-醇  (RV 3-43-chloro-4-(3-fluoro-benzyloxyphenylamino-1-quinazolin-6-ylpyrrole small group 3- HV2-pyrrolidin-1-ylmethyl-pyrrolidine-1 - 1-propan-2-ol
Figure imgf000259_0001
第一步
Figure imgf000259_0001
first step
(S)- 3-羟甲基-吡咯烷 -1-甲酸叔丁酯  (S)- 3-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester
将 (S)-3-羟甲基-吡咯垸 (5.05 g， 50 mmol)溶于 150 mL二氯甲烷中， 在冰浴条件 • 下， 冷却至 0°C， 加入乙酸酑 (11.44 g， 52.5 mmol), 反应液在室温下搅拌过夜。 将 反应液用饱和碳酸氢钠洗涤， 乙酸乙酯萃取 (50 mLX 3)，合并的有机相通过饱和氯 化钠溶液洗涤， 无水硫酸钠干燥， 过滤， 减压下浓缩， 得到的残留物通过硅胶柱 层析进一步分离纯化 (正己垸： 乙酸乙酯 =3 : 1)， 得到 (S)-3-羟甲基-吡咯烷 -1-甲酸 叔丁酯 247a (9.54 g， 黄色油状液体)， 产率： 94.9%。  (S)-3-Hydroxymethyl-pyrroleium (5.05 g, 50 mmol) was dissolved in 150 mL of dichloromethane, cooled to 0 ° C under ice-bath conditions, and acetonitrile (11.44 g, 52.5 (mmol), the reaction was stirred at room temperature overnight. The reaction mixture was washed with EtOAc EtOAc EtOAc (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH Further separation and purification by silica gel column chromatography (n-hexane: ethyl acetate = 3:1) afforded (S) 3-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester 247a (9.54 g, yellow oily liquid). Yield: 94.9%.
MS m/z (ESI): 202[M+ 1]  MS m/z (ESI): 202 [M+ 1]
第二步 (S)-3-甲磺酰氧甲基-吡咯垸 -1-甲酸叔丁酯 Second step (S)-3-Methanesulfonyloxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester
将 (S)-3-羟甲基-吡咯垸小甲酸叔丁酯 247a(5 g， 24.8 mmol)溶于 100 mL二氯 甲烷中， 在氩气氛下， 滴加三乙胺 (13.8 mL， 100 mmol), 冰浴冷却至 0°C， 加入甲 磺酰氯 (3.9 mL， 49.6 mmol), 反应液在室温下搅拌 1小时反应完毕。将反应液用饱 和碳酸氢钠洗涤， 乙酸乙酯萃取 (50 mLX 3)，合并的有机相通过水和饱和氯化钠溶 液洗涤， 无水硫酸钠干燥， 过滤， 减压下浓缩， 得到的残留物通过硅胶柱层析进 一步分离纯化 (正己烷： 乙酸乙酯 =4: 1)， 得到 (S)-3-甲磺酰氧甲基-吡咯烷 -1-甲酸 叔丁酯 247b(6.14 g， 黄色油状液体)， 产率： 88.7 %。  (S)-3-Hydroxymethyl-pyrrolidinic acid tert-butyl ester 247a (5 g, 24.8 mmol) was dissolved in 100 mL of dichloromethane, and triethylamine (13.8 mL, 100) was added dropwise under an argon atmosphere. (mmol), cooled to 0 ° C in an ice-bath, methanesulfonyl chloride (3.9 mL, 49.6 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was washed with EtOAc EtOAc EtOAc. The product was further separated and purified by silica gel column chromatography (hexane: ethyl acetate = 4:1) to afford (S)-3-methanesulfonyloxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester 247b (6.14 g, Yellow oily liquid), Yield: 88.7 %.
MS m/z (ESI): 280[M+ 1] MS m/z (ESI): 280 [M+ 1]
第三歩  Third
(R)-3-吡咯烷 -1-基甲基-吡咯烷 -1-甲酸叔丁酯  (R)-3-pyrrolidin-1-ylmethyl-pyrrolidine-1-carboxylic acid tert-butyl ester
(S)-3-甲磺酰氧甲基 -P比咯烷 -1-甲酸叔丁酯 247b(1.5 g， 5.37 mmol)和吡咯烷 (0.49 mL, 5.9 mmol)溶于 55 mL乙醇和四氢呋喃 (10: 1)的混合溶剂中， 搅拌下加 入碳酸钾 (1.11 g， 8.05 mmol), 加热回流反应过夜。 将反应液在减压下浓缩， 残留 物通过硅胶柱层析进一步分离纯化 (正己烷： 乙酸乙酯 = 1 : 1), 得到 (R)-3-吡咯烷 -1-基甲基 -P比咯垸 -1-甲酸叔丁酯 247c(215 mg， 黄色油状液体)， 产率： 13.4%。 MS m/z (ESI): 255 [M+ 1]  (S)-3-Methanesulfonyloxymethyl-P-terrolidine-1-carboxylic acid tert-butyl ester 247b (1.5 g, 5.37 mmol) and pyrrolidine (0.49 mL, 5.9 mmol) were dissolved in 55 mL of ethanol and tetrahydrofuran ( To a mixed solvent of 10:1), potassium carbonate (1.11 g, 8.05 mmol) was added under stirring, and the mixture was heated to reflux overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified and purified to silica gel column chromatography (hexane: ethyl acetate = 1:1) to give (R)-3-pyrrolidin-1-ylmethyl-P ratio垸 垸-1-carboxylic acid tert-butyl ester 247c (215 mg, yellow oily liquid), Yield: 13.4%. MS m/z (ESI): 255 [M+ 1]
第四步  the fourth step
(S)-l- (吡咯烷 -3-基甲基)吡咯烷盐酸盐  (S)-l-(pyrrolidin-3-ylmethyl)pyrrolidine hydrochloride
将 ( )-3-吡咯烷小基甲基-吡咯垸小甲酸叔丁酯 247c(215 mg, 0.98 mmol)溶于 Dissolve ( )-3-pyrrolidinylmethyl-pyrrolidine carboxylic acid tert-butyl ester 247c (215 mg, 0.98 mmol)
10 mL二氯甲垸中， 搅拌下加入 10 mL 4N甲醚-氯化氢溶液， 室温下搅拌 3小时， 反应完毕。将反应液在减压下浓缩， 得到的残留物用乙酸乙酯洗涤 (50 mLX 3)， 得 到 (S)-l- (吡咯烷 -3-基甲基)吡咯烷盐酸盐 (lOO mg, 灰白色固体)， 产率: 67.6%。 In 10 mL of dichloromethane, 10 mL of 4N methyl ether-hydrogen chloride solution was added under stirring, and the mixture was stirred at room temperature for 3 hours, and the reaction was completed. The reaction mixture was concentrated under reduced pressure. EtOAc mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Off-white solid), Yield: 67.6%.
第五步  the fifth step
(R)-l-(3-{4-[3-氯 -4-(3-氟-节氧基) -苯氨基] -喹唑啉 -6-基} -吡咯 -1-基) -3-(2-吡咯烷 -1- 基甲基-吡咯烷 -1-基) -丙 -2-醇 (R)-l-(3-{4-[3-chloro-4-(3-fluoro-p-hydroxy)-phenylamino]-quinazolin-6-yl}-pyrrol-1-yl)-3 -(2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-propan-2-ol
(R)-[3-氯 -4-(3-氟-苄基)-苯基] -[6-(1-环氧乙基甲基 -1H-吡咯 -3-基) -喹唑啉 -4- 基] -胺 186a (170 mg, 0.35 mmol)溶于 30 mL 甲醇中， 氩气氛下， 搅拌下加入 (S)-l- (吡咯烷 -3-基甲基)吡咯烷盐酸盐 (101 mg， 0.52 mmol)和碳酸钾 (0.071 g， 0.52 mmol), 混合物加热回流过夜。将反应液在减压下浓缩， 得到的残留物通过硅胶柱 层析进一步分离纯化 (二氯甲垸： 甲醇 =40: 1 , 30： 1， 15： 1， 10： 1)， 得到标题 产物 (R)-l-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基}-吡咯 -1-基) -3-(2-吡咯 烷 -1-基甲基-吡咯焼 -1-基) -丙 -2-醇 247(35 mg， 黄色固体)， 产率： 24.1 %。  (R)-[3-chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-epoxyethylmethyl-1H-pyrrol-3-yl)-quinazoline- 4-yl]-amine 186a (170 mg, 0.35 mmol) was dissolved in 30 mL of methanol, and (S)-l-(pyrrolidin-3-ylmethyl)pyrrolidine hydrochloride was added with stirring under argon ( 101 mg, 0.52 mmol) and potassium carbonate (0.071 g, 0.52 mmol). The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified and purified by silica gel column chromatography (dichloromethane:methanol = 40:1, 30:1, 15:1, 10:1) R)-l-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-pyrrol-1-yl)-3- (2-Pyrrolidin-1-ylmethyl-pyrrole-1-yl)-propan-2-ol 247 (35 mg, yellow solid), Yield: 24.1%.
MS m/z (ESI): 656 [M+ 1] MS m/z (ESI): 656 [M+ 1]
1H NMR (400 MHz, CD30D- ): 69.70 (s,lH), 8.54 (s,lH)， 8.50 (s,lH), 8.03 (m , 2H) , 7.76 (d , J=8.8Hz , IH) , 7.70 (d , J=8.8Hz , IH) , 7.47 (m , IH)， 7.42 (s , IH) , 7.36 (m： 3H) , 7.19 (m， 1H) , 6.88 (s , 1H) , 6.65 (s , 1H)， 5.27(s , 2H) , 3.98 (m , 1Η) , 3.85 (m： 2H) , 3.12 (m , 1H)， 2.64(m , 1H) , 2.59 (m , 1H)， 2.41 (br , 6H) , 2.27 (m , 2Η)， 1.85 (m , 1H) , 1.66 (br , 6H) , 1.45 (m , 1Η) 实施例 248 1H NMR (400 MHz, CD30D-): 69.70 (s, lH), 8.54 (s, lH), 8.50 (s, lH), 8.03 (m, 2H), 7.76 (d, J = 8.8 Hz, IH), 7.70 (d , J=8.8Hz , IH) , 7.47 (m , IH), 7.42 (s , IH) , 7.36 (m: 3H) , 7.19 (m, 1H), 6.88 (s , 1H) , 6.65 (s , 1H), 5.27 (s , 2H) , 3.98 (m , 1Η ) , 3.85 (m: 2H) , 3.12 (m , 1H ) ), 2.64(m , 1H) , 2.59 (m , 1H), 2.41 (br , 6H) , 2.27 (m , 2Η), 1.85 (m , 1H) , 1.66 (br , 6H) , 1.45 (m , 1Η) Example 248
1-Γ3-(3-{4-「1-(3-氟 -苄基 1H-吲唑 -5-基氨基 1-喹唑啉 -6-基 吡咯 -1-基 2-羟-丙基  1-Γ3-(3-{4-"1-(3-Fluoro-benzyl 1H-indazole-5-ylamino-1-quinazoline-6-ylpyrrole-1-yl 2-hydroxy-propyl
Figure imgf000261_0001
Figure imgf000261_0001
178a  178a
248  248
在 100 mL茄形瓶中， 将 [1-(3-氟-苄基) -1H-吲唑 -5-基] -[6-(1-环氧乙基甲基 -1H- 吡咯 -3-基)-喹唑啉 -4-基] -胺 178a (225 g， 0.46 mmol)溶于 25 mL甲醇中， 搅拌下 加入 4-羟基哌啶 (186 mg， 1.84 mmol), 反应液加热回流过夜。 将反应液在减压下 浓缩， 得到的残留物通过硅胶柱层析进一步分离纯化 (二氯甲烷： 甲醇 = 10: 1), 得到本标题产物 1-[3-(3-{4-[1-(3-氟-苄基) -1H-吲唑 -5-基氨基] -喹唑啉 -6-基 } 比咯 -1-基) -2-羟-丙基] -哌啶 -4-醇 248 (29 mg， 黄棕色固体） ， 产率： 48%。  [1-(3-Fluoro-benzyl)-1H-indazol-5-yl]-[6-(1-epoxyethylmethyl-1H-pyrrole-3- in a 100 mL eggplant-shaped flask The base quinazolin-4-yl]-amine 178a (225 g, 0.46 mmol) was dissolved in EtOAc (MeOH) (EtOAc) The reaction mixture was concentrated under reduced pressure. -(3-fluoro-benzyl)-1H-indazol-5-ylamino]-quinazolin-6-yl}pyrrol-1-yl)-2-hydroxy-propyl]-piperidin-4- Alcohol 248 (29 mg, yellow-brown solid), Yield: 48%.
MS m/z (ESI): 592[M+ 1] MS m/z (ESI): 592 [M+ 1]
'HNMR (400MHZ, DMSO-i¾): 69.86(s, 1H)， 8.63(s, 1H), 8.45(s, 1H), 8.23(s, 1H), 8.17(s, 1H), 8.03(d, 1H， J = 8.8Hz), 7.77(s, 2H), 7.70(d, 1H, J = 8.8Hz), 7.45(s, 1H), 7.38(m, 1H), 7.08(m, 3H), 6.68(s, 1H)， 6.70(s,lH), 5.72(s, 2H), 4.56(m, 1H), 4.06(m, 2H), 3.91(m, 2H), 3.50(m, 1H)， 3.18(m, 2H), 2.90(m, 1H), 2.74(m, 1H), 2.5 l(m, 2H), 1.78(m, 2H), 1.52(m, 2H) 实施例 249  'HNMR (400MHZ, DMSO-i3⁄4): 69.86(s, 1H), 8.63(s, 1H), 8.45(s, 1H), 8.23(s, 1H), 8.17(s, 1H), 8.03(d, 1H) , J = 8.8Hz), 7.77(s, 2H), 7.70(d, 1H, J = 8.8Hz), 7.45(s, 1H), 7.38(m, 1H), 7.08(m, 3H), 6.68(s , 1H), 6.70(s,lH), 5.72(s, 2H), 4.56(m, 1H), 4.06(m, 2H), 3.91(m, 2H), 3.50(m, 1H), 3.18(m, 2H), 2.90 (m, 1H), 2.74 (m, 1H), 2.5 l (m, 2H), 1.78 (m, 2H), 1.52 (m, 2H) Example 249
1-(U-二氧 -六氢 -1λ*6*-噻喃 -4-基氨基 )-3-(3-M-「l-(3-氟-苄基) -1H-吲唑 -5-基氨基 1- 喹唑啉 -6-基 }-吡咯 -1-基) -丙 -2-醇 1-(U-Dioxo-hexahydro-1λ*6*-thiopyran-4-ylamino)-3-(3-M-"1-(3-fluoro-benzyl)-1H-indazole-5 -ylamino-1-quinazolin-6-yl}-pyrrol-1-yl)-propan-2-ol
Figure imgf000262_0001
Figure imgf000262_0001
178a  178a
249  249
在 100 mL茄形瓶中， 将 1,1-二氧 -六氢 -1λ*6*-噻喃 -4-基胺盐酸盐（302 mg， 1.63 mmol)溶于 20 mL甲醇中， 加入三乙胺 (165 mg， 1.63 mmol), 搅拌 30分钟后 加入 [1-(3-氟-苄基) -1H-吲唑 -5-基 ]-[6-(1-环氧乙基甲基 -1H-吡咯 -3-基) -喹唑啉 -4- 基] -胺 178a (200 g， 0.41 mmol) ， 反应液加热回流过夜。 将反应液在减压下浓缩， 得到的残留物通过薄层层析制备板分离纯化 (二氯甲烷： 甲醇 = 10: 1), 得到本标 题产物 1-(1,1-二氧 -六氢 -1λ*6*-噻喃 -4-基氨基 )-3-(3-{4-[1-(3-氟-苄基) -1H-吲唑 -5- 基氨基]-喹唑啉 -6-基}-吡咯 -1-基) -丙 -2-醇 249 (45 mg， 黄棕色固体） ， 产率： 17.3 0 In a 100 mL eggplant-shaped flask, 1,1-dioxo-hexahydro-1λ*6*-thiopyran-4-ylamine hydrochloride (302 mg, 1.63 mmol) was dissolved in 20 mL of methanol. Ethylamine (165 mg, 1.63 mmol), after stirring for 30 minutes, [1-(3-fluoro-benzyl)-1H-indazol-5-yl]-[6-(1-epoxyethylmethyl- 1H-Pyrrol-3-yl)-quinazolin-4-yl]-amine 178a (200 g, 0.41 mmol). The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified (yield: methylene chloride:methanol = 10:1) to give the title product 1-(1,1-dioxy-hexahydro). -1λ*6*-thiopyran-4-ylamino)-3-(3-{4-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-quinazoline- 6-yl}-pyrrol-1-yl)-propan-2-ol 249 (45 mg, yellow-brown solid), Yield: 17.3 0
MS m/z (ESI): 640[M+ 1]  MS m/z (ESI): 640 [M+ 1]
lBNMR (400MHz, DMSO-t¾: 59.88(s, IH), 8.63(s, IH), 8.44(s, IH), 8.23(s, IH), 8.18(s, IH), 8.03(d, IH, J = 8.8Hz), 7.76(s, 2H), 7.72(d, IH, J = 8.8Hz), 7.45(s, IH), 7.39(m, 1H)， 7.09(m, 3H), 6.90(s, IH), 6.70(s, IH), 5.72(s, 2H), 4.06(m, 2H), 3.92(m, IH), 3.06(m, 9H), 2.13(m, 2H), 1.92(m, 2H) 实施例 250 lBNMR (400MHz, DMSO-t3⁄4: 59.88(s, IH), 8.63(s, IH), 8.44(s, IH), 8.23(s, IH), 8.18(s, IH), 8.03(d, IH, J = 8.8Hz), 7.76(s, 2H), 7.72(d, IH, J = 8.8Hz), 7.45(s, IH), 7.39(m, 1H), 7.09(m, 3H), 6.90(s, IH ), 6.70(s, IH), 5.72(s, 2H), 4.06(m, 2H), 3.92(m, IH), 3.06(m, 9H), 2.13(m, 2H), 1.92(m, 2H) Example 250
1-「1,4Ί二哌啶基 -Γ-基 -3-(3-ί4-「1-(3-氟-苄基) -IH-吲唑 -5-基氨基-喹唑啉 -6-基 吡 咯小基 V丙 -2-醇  1-"1,4ΊDipiperidinyl-fluorenyl-3-(3-ί4-"1-(3-fluoro-benzyl)-IH-indazol-5-ylamino-quinazoline-6- Pyryryl small group V propan-2-ol
Figure imgf000262_0002
Figure imgf000263_0001
在 100 mL茄形瓶中， 将 [1-(3-氟-节基) -1Η-吲唑 -5-基 ]-[6-(1-环氧乙基甲基 -1Η- 吡咯 -3-基) -喹唑啉 -4-基] -胺 178a (200 g, 0.41 mmol)溶于 20 mL甲醇中， 搅拌下 加入 4-哌啶基哌啶 （274 mg， 1.63 mmol), 反应液加热回流过夜。将反应液在减压 下浓缩， 得到的残留物通过薄层层析制备板分离纯化 (二氯甲垸： 甲醇 = 10: 1)， 得到本标题产物 1-[1,4']二哌啶基 -Γ-基 -3-(3-{4-[1-(3-氟-苄基) -1H-吲唑 -5-基氨基] - 喹唑啉 -6-基}-吡咯小基) -丙 -2-醇 250 (109 mg， 黄棕色固体） ， 产率： 41 %。
Figure imgf000262_0002
Figure imgf000263_0001
[1-(3-Fluoro-nodal)-1 Η-indazol-5-yl]-[6-(1-epoxyethylmethyl-1Η-pyrrole-3- in a 100 mL eggplant-shaped flask - quinazolin-4-yl]-amine 178a (200 g, 0.41 mmol) was dissolved in 20 mL of MeOH. &lt;RTI ID=0.0&gt;&gt; overnight. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified (yield: methylene chloride: methanol = 10:1) to afford the title product 1-[1,4']dipiperidine. Base-fluorenyl-3-(3-{4-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-quinazolin-6-yl}-pyrrole small group) -propan-2-ol 250 (109 mg, yellow-brown solid), Yield: 41%.
MS m/z (ESI): 659[M+ 1] MS m/z (ESI): 659 [M+ 1]
1HNMR (400MHz, DMSO-c¾): 59.89(s, 1H)， 8.65(s, 1H), 8.45(s, 1H), 8.23(s, 1H), 8.17(s, 1H), 8.03(d, 1H, J = 8.8Hz), 7.75(s, 1H), 7.70(d, 2H, J = 8.8Hz), 7.45(s, 1H), 7.37(m, 1H), 7.06(m, 3H), 6.88(s, 1H), 6.69(s, 1H), 5.72(s, 2H), 3.96(m, 3H), 3.01(m, 5H), 2.29(m, 3H), 1.98(m, 4H), 1.70(m, 6H), 1.44(m, 4H) 实施例 251  1HNMR (400MHz, DMSO-c3⁄4): 59.89 (s, 1H), 8.65 (s, 1H), 8.45 (s, 1H), 8.23 (s, 1H), 8.17 (s, 1H), 8.03 (d, 1H, J = 8.8 Hz), 7.75 (s, 1H), 7.70 (d, 2H, J = 8.8 Hz), 7.45 (s, 1H), 7.37 (m, 1H), 7.06 (m, 3H), 6.88 (s, 1H), 6.69(s, 1H), 5.72(s, 2H), 3.96(m, 3H), 3.01(m, 5H), 2.29(m, 3H), 1.98(m, 4H), 1.70(m, 6H) ), 1.44 (m, 4H) Example 251
1-环丙基氨基 -3-(3-{4-「l-(3-氟 -苄基 IH-吲唑 -5-基氨基 1-喹唑啉 -6-基 }-吡咯小基) -  1-cyclopropylamino-3-(3-{4-"1-fluoro-benzyl-IH-indazol-5-ylamino-1-quinazolin-6-yl}-pyrrole small group) -
Figure imgf000263_0002
在 100 mL茄形瓶中， 将 [1-(3-氟-苄基) -1H-吲唑 -5-基] -[6-(1-环氧乙基甲基 -1H- 吡咯 -3-基) -喹唑啉 -4-基] -胺 178a (200 g, 0.41 mmol)溶于 20 mL甲醇中， 搅拌下 加入环丙基胺（93 mg， 1.63 mmol), 反应液加热回流过夜。 将反应液在减压下浓 缩， 得到的残留物通过薄层层析制备板分离纯化 (二氯甲烷： 甲醇 = 10: 1), 得到 本标题产物 1-环丙基氨基 -3-(3-{4-[1-(3-氟-苄基) -1H-吲唑 -5-基氨基] -喹唑啉 -6-基 吡咯 -1-基) -丙 -2-醇 251 (95 mg， 黄棕色固体） ， 产率： 41 %。
Figure imgf000263_0002
[1-(3-Fluoro-benzyl)-1H-indazol-5-yl]-[6-(1-epoxyethylmethyl-1H-pyrrole-3- in a 100 mL eggplant-shaped flask The quinazolin-4-yl]-amine 178a (200 g, 0.41 mmol) was dissolved in 20 mL MeOH. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified (yield: methylene chloride: methanol = 10:1). The title product 1-cyclopropylamino-3-(3-{4-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-quinazolin-6-ylpyrrole- 1-yl)-propan-2-ol 251 (95 mg, yellow-brown solid), Yield: 41%.
MS m/z (ESI): 548[M+1] MS m/z (ESI): 548 [M+1]
1丽 MR (400MHz, CD30D- )： 58.47(s, IH), 8.43(s, IH), 8.11(s, IH), 8.09(s, IH), 8.07(d, IH, J = 8.8Hz), 7.74(s, IH), 7.70(d, 2H, J = 8.8Hz), 7.43(s, IH), 7.30(m, IH), 6.97(m, 3H), 6.79(s, IH), 6.63(s, IH), 5.62(s, 2H), 4.02(m, 3H), 2.87(m, IH), 2.74(m, IH), 2.28(m, IH), 0.57(m, 4H) 实施例 252 1丽 MR (400MHz, CD30D- ): 58.47(s, IH), 8.43(s, IH), 8.11(s, IH), 8.09(s, IH), 8.07(d, IH, J = 8.8Hz), 7.74(s, IH), 7.70(d, 2H, J = 8.8Hz), 7.43(s, IH), 7.30(m, IH), 6.97(m, 3H), 6.79(s, IH), 6.63(s , IH), 5.62 (s, 2H), 4.02 (m, 3H), 2.87 (m, IH), 2.74 (m, IH), 2.28 (m, IH), 0.57 (m, 4H) Example 252
l-(3- -「3-氯 -4-(3-氟 -苄氧基)-苯氨基 1-喹唑啉 -6-基 吡咯小基) -3-『4-环丙基 -哌嗪  L-(3- -"3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino-1-quinazolin-6-ylpyrroleyl)-3-"4-cyclopropyl-piperazine
-1-基) -丙 -2-醇  -1-yl)-propan-2-ol
Figure imgf000264_0001
第一步
Figure imgf000264_0001
first step
1-环丙基 -哌嗪  1-cyclopropyl-piperazine
将 4-环丙基 -哌嗪小甲酸叔丁酯 252a (500 mg， 2.2 mmol)溶于 20 mL二氯甲烷 中， 搅拌下滴加 3 mL三氟乙酸， 室温下搅拌 1小时， 反应完毕。 将反应液在减压 下浓缩， 得到的残留物溶于 15 mL甲醇中， 用饱和碳酸钠溶液调节 pH=8〜9， 浓 缩反应液， 得到的残留物通过硅胶柱层析进一步分离纯化 (二氯甲垸： 甲醇： 氨水 =20： 2： Id), 得到 1-环丙基 -哌嗪 252b(277 mg， 白色固体)， 产率： 100%。 MS m/z (ESI): 127[M+1]  4-tert-propyl-piperazine-formic acid tert-butyl ester 252a (500 mg, 2.2 mmol) was dissolved in 20 mL of dichloromethane, and 3 mL of trifluoroacetic acid was added dropwise with stirring, and the mixture was stirred at room temperature for 1 hour, and the reaction was completed. The reaction mixture was concentrated under reduced pressure, and the obtained residue was dissolved in 15 mL of methanol. The mixture was adjusted to pH=8~9 with saturated sodium carbonate solution, and the residue was concentrated and purified by silica gel column chromatography. Chloroformamide: Methanol: Ammonia water = 20: 2: Id) gave 1-cyclopropyl-piperazine 252b (277 mg, white solid). Yield: 100%. MS m/z (ESI): 127 [M+1]
第二步  Second step
1-(3-{4-[3-氯 -4-(3-氟- 氧基) -苯氨基] -喹唑啉 -6-基}-吡咯 -1-基) -3-(4-环丙基 -哌嗪  1-(3-{4-[3-chloro-4-(3-fluoro-oxy)-phenylamino]-quinazolin-6-yl}-pyrrol-1-yl)-3-(4-cyclo Propyl-piperazine
-1-基) -丙 -2-醇 将 1-环丙基 -哌嗪 252b (61 mg, 0.48 mmol)溶于 25 mL甲醇中，搅拌下加入 [3- 氯 -4-(3-氟-苄基) -苯基] - [6-(1-环氧乙基甲基 -1H-吡咯 -3-基) -喹唑啉 -4-基]-胺 187a (200 mg, 0.4 mmol), 混合液加热回流过夜。 反应液在减压下浓缩， 得到的残留物 通过硅胶柱层析进一歩分离纯化 (梯度洗脱： 二氯甲烷： 甲醇 =50: 1， 25： 1)， 得 到本标题产物 1-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基}-吡咯 -1-基) -3-(4- 环丙基 -哌嗪 -1-基) -丙 -2-醇 252 (46 mg， 黄色固体)， 产率： 29.7%。 -1-yl)-propan-2-ol 1-Cyclopropyl-piperazine 252b (61 mg, 0.48 mmol) was dissolved in 25 mL of methanol and [3-chloro-4-(3-fluoro-benzyl)-phenyl]-[6- (1-Epoxyethylmethyl-1H-pyrrol-3-yl)-quinazolin-4-yl]-amine 187a (200 mg, 0.4 mmol). The reaction mixture was concentrated under reduced pressure. EtOAc mjjjjjjj {4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-pyrrol-1-yl)-3-(4-cyclopropyl-piperidin Pyrazin-1-yl)-propan-2-ol 252 (46 mg, yellow solid), yield: 29.7%.
MS m/z (ESI): 627[M+] MS m/z (ESI): 627 [M + ]
1H NMR (400 MHz, CD30D-^): 59.70 (s,lH), 8.54 (s,lH), 8.38 (s , IH) , 8.04 (m， 2H) , 7.77 (dd , J=2.4Hz , IH) , 7.71 (d , J=8.4Hz， IH) , 7.48 (m , IH) , 7.41 (s , IH) , 7.32 (m , 3H) , 7.19 (m , IH) , 6.87 (s , IH) , 6.65 (s , IH) , 5.27 (s , 2H) , 4.03 (m , IH)： 3.88 (br , IH) , 3.81 (m， IH)， 2.57 (br , 4H) , 2.40 (br , 4H) , 2.23 (br , 2H) , 1.58 (br , IH) , 0.39 (m , 2H) , 0.27 (m , 2H) 实施例 253  1H NMR (400 MHz, CD30D-^): 59.70 (s,lH), 8.54 (s,lH), 8.38 (s, IH), 8.04 (m, 2H), 7.77 (dd, J=2.4Hz, IH) , 7.71 (d, J=8.4Hz, IH), 7.48 (m , IH) , 7.41 (s , IH) , 7.32 (m , 3H) , 7.19 (m , IH) , 6.87 (s , IH ) , 6.65 ( s , IH ) , 5.27 (s , 2H) , 4.03 ( m , IH ) : 3.88 (br , IH ) , 3.81 (m, IH), 2.57 (br , 4H) , 2.40 (br , 4H) , 2.23 (br , 2H), 1.58 (br , IH) , 0.39 (m , 2H) , 0.27 (m , 2H) Example 253
2-(3- -「3-氯 -4-(3-氟-苄氧基) -苯氨基 1-喹唑啉 -6-基 吡咯小基 )小(4-环丙基甲基-  2-(3- -"3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino-1-quinazoline-6-ylpyrrole small) Small (4-cyclopropylmethyl-
Figure imgf000265_0001
Figure imgf000265_0001
第一步 First step
2-氯 -1-(4-环丙基甲基哌嗪 -1-基) -乙酮  2-chloro-1-(4-cyclopropylmethylpiperazine-1-yl)-ethanone
将 1-环丙基甲基哌嗪 237a (200 mg, 1.05 mmol)溶于 10 mL二氯甲垸和 10 mL 四氢呋喃的混合溶剂中， 加入三乙胺 (1 mL, 2.1 mmol), 反应液在丙酮-干冰浴冷 却至 -78Γ , 滴加氯乙酰氯 (0.2 mL， 1.43 mmol), 搅拌 1小时后反应完毕。 反应液 中加入 50 mL水和 50 mL乙酸乙酯， 分液， 水相用乙酸乙酯萃取 (100 mLX 2)， 合 并的有机相通过无水硫酸钠干燥， 过滤， 减压下浓缩， 得到 2-氯 -1-(4-环丙基甲基 哌嗪小基) -乙酮 253a (151 mg， 棕色油状液体)， 产率： 48.8 %。 Dissolve 1-cyclopropylmethylpiperazine 237a (200 mg, 1.05 mmol) in 10 mL of a mixture of dichloromethane and 10 mL of tetrahydrofuran, and add triethylamine (1 mL, 2.1 mmol). The acetone-dry ice bath was cooled to -78 Torr, and chloroacetyl chloride (0.2 mL, 1.43 mmol) was added dropwise. After stirring for 1 hour, the reaction was completed. 50 mL of water and 50 mL of ethyl acetate were added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (100 mL×2). The organic phase was dried over anhydrous sodium sulfate, filtered and evaporatedEtOAcjjjjjjjjjjjjjjjjjjjjjjjjj , Yield: 48.8 %.
MS m/z (ESI): 239[M+23] MS m/z (ESI): 239 [M+23]
第二步  Second step
2-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基]-喹唑啉 -6-基 } l比咯 -1-基) -1-(4-环丙基甲基- 哌嗪 -1-基) -乙酮  2-(3-{4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl} lpyr-1-yl)-1-(4) -cyclopropylmethyl-piperazin-1-yl)-ethanone
在 50 mL的烧瓶中，将 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-[6-(1Η-吡咯 -3-基) -喹唑啉 -4- 基] -胺 42 (335 mg， 0.7 mmol)溶于 20 mL干燥的 N，N-二甲基甲酰胺中， 在冰浴条 件下，冷却至 0°C ,加入氢化钠 (108 mg， 2.1 mmol),搅拌 30分钟后加入 2-氯 -1-(4- 环丙基甲基哌嗪 -1-基) -乙酮 253a (150 mg， 0.7 mmol),室温下搅拌 3小时反应完毕。 反应液中加入 50 mL水和 50 mL乙酸乙酯， 分液， 水相用乙酸乙酯萃取 (100 mL X2), 合并的有机相通过无水硫酸钠干燥， 过滤， 减压下浓缩， 得到的残留物通过 硅胶柱层析进一歩分离纯化 (二氯甲垸： 甲醇 =25 : 1)，得到本标题产物 2-(3-{4-[3- 氯 -4-(3-氟-苄氧基) -苯氨基]-喹唑啉 -6-基 吡咯 -1-基) -1-(4-环丙基甲基 -哌嗪 -1-基) - 乙酮 253 (215 mg， 黄色固体)， 产率： 49%。  [3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1Η-pyrrol-3-yl)-quinazolin-4-yl] in a 50 mL flask -Amine 42 (335 mg, 0.7 mmol) was dissolved in 20 mL of dry N-N-dimethylformamide, cooled to 0 ° C under ice bath and sodium hydride (108 mg, 2.1 mmol). After stirring for 30 minutes, 2-chloro-1-(4-cyclopropylmethylpiperazin-1-yl)-ethanone 253a (150 mg, 0.7 mmol) was added, and the mixture was stirred at room temperature for 3 hours. 50 ml of water and 50 mL of ethyl acetate were added to the reaction mixture, and the mixture was evaporated. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 25:1) to give the title product 2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy) -Phenylamino]-quinazolin-6-ylpyrrol-1-yl)-1-(4-cyclopropylmethyl-piperazin-1-yl)-ethanone 253 (215 mg, yellow solid) , Yield: 49%.
MS m/z (ESI): 625[M+ 1] MS m/z (ESI): 625 [M+ 1]
1H NMR (400 MHz, CD30D- ): δΐθ.00 (s, 1H), 8.72 (s, 1H), 8.49 (s, 1H), 8.10 (s, 1H), 8.02 (d, J = 8.8Hz, 1H), 7.85 (d, J - 8.8Hz, 1H), 7.69 (d， J = 8.8Hz, 1H), 7.54 (t， J = 8.8Hz, 1H), 7.42 (s, 1H), 7.32 (m, 3H), 7.19 (t, J = 8.8Hz, 1H), 6.80 (s, 1H), 6.74 (s， 1H)， 5.27 (s, 2H), 4.96 (s, 2H), 3.51 (br, 4H), 2.51 (br, 2H), 2.43 (br, 2H), 2.22 (d, J = 6.0Hz, 2H), 0.85 (m, 1H), 0.47 (m, 2H), 0.09 (m, 2H) 实施例 254  1H NMR (400 MHz, CD30D- ): δ ΐ θ.00 (s, 1H), 8.72 (s, 1H), 8.49 (s, 1H), 8.10 (s, 1H), 8.02 (d, J = 8.8Hz, 1H ), 7.85 (d, J - 8.8Hz, 1H), 7.69 (d, J = 8.8Hz, 1H), 7.54 (t, J = 8.8Hz, 1H), 7.42 (s, 1H), 7.32 (m, 3H) ), 7.19 (t, J = 8.8Hz, 1H), 6.80 (s, 1H), 6.74 (s, 1H), 5.27 (s, 2H), 4.96 (s, 2H), 3.51 (br, 4H), 2.51 (br, 2H), 2.43 (br, 2H), 2.22 (d, J = 6.0 Hz, 2H), 0.85 (m, 1H), 0.47 (m, 2H), 0.09 (m, 2H) Example 254
l-CH4-「l-(3-氟 -节基 1H-吲唑 -5-基氨基 1-喹唑啉 -6-基}-吡咯小基-3-「4-(2-羟乙 基) -哌啶 -1-基 1-丙 -2-醇  l-CH4-"1-Fluoro-benzyl 1H-carbazol-5-ylamino-1-quinazolin-6-yl}-pyrroleyl-3-"4-(2-hydroxyethyl) -piperidin-1-yl 1-propan-2-ol
Figure imgf000266_0001
在 100 mL茄形瓶中， 将 [1-(3-氟-苄基) -1H-吲唑 -5-基 ]-[6-(1-环氧乙基甲基 -1H- 吡咯 -3-基) -喹唑啉 -4-基] -胺 178a (100 g， 0.204 mmol)溶于 20 mL甲醇中， 搅拌下 加入 2-哌啶 -4-基乙醇（79 mg， 0.61 mmol), 反应液加热回流过夜。 将反应液在减 压下浓缩， 得到的残留物通过薄层层析制备板分离纯化 (二氯甲烷： 甲醇 = 10: 1)， 得到本标题产物 1-(3-{4-[1-(3-氟-苄基) -1H-吲唑 -5-基氨基] -喹唑啉 -6-基}-吡咯 -1- 基 )_3-[4-(2-羟乙基) -哌啶小基] -丙 -2-醇 254 (105 mg， 黄棕色固体） ， 产率： 83 %。 MS m/z (ESI): 620[M+ 1]
Figure imgf000266_0001
[1-(3-Fluoro-benzyl)-1H-indazol-5-yl]-[6-(1-epoxyethylmethyl-1H-pyrrole-3- in a 100 mL eggplant-shaped flask - quinazolin-4-yl]-amine 178a (100 g, 0.204 mmol) dissolved in 20 mL of methanol, and then added 2-piperidin-4-ylethanol (79 mg, 0.61 mmol). Heat to reflux overnight. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified (yield: methylene chloride: methanol = 10:1) to afford the title product 1-(3-{4-[1-( 3-fluoro-benzyl)-1H-indazol-5-ylamino]-quinazolin-6-yl}-pyrrol-1-yl)-3-[4-(2-hydroxyethyl)-piperidine -propan-2-ol 254 (105 mg, yellow-brown solid), Yield: 83%. MS m/z (ESI): 620 [M+ 1]
iHNMR (400MHz, DMSO-^): 59.85(s, IH), 8.63(s, IH), 8.45(s, IH), 8.23(s, IH), 8.17(s, IH), 8.03(d, IH, J = 8.8Hz), 7.74(m, 3H), 7.44(s, IH), 7.38(m, IH), 7.08(m, 3H): 6.89(s, IH), 6.70(s, IH), 5.72(s, 2H), 4.36(m, IH), 4.04(m, 3H), 3.91(m, IH), 3.44(m, 2H), 2.5 l(m, 6H), 1.70(m, 2H), 1.24(m, 5H) 实施例 255 iHNMR (400MHz, DMSO-^): 59.85 (s, IH), 8.63 (s, IH), 8.45 (s, IH), 8.23 (s, IH), 8.17 (s, IH), 8.03 (d, IH, J = 8.8 Hz), 7.74 (m, 3H), 7.44 (s, IH), 7.38 (m, IH), 7.08 (m, 3H): 6.89 (s, IH), 6.70 (s, IH), 5.72 ( s, 2H), 4.36(m, IH), 4.04(m, 3H), 3.91(m, IH), 3.44(m, 2H), 2.5 l(m, 6H), 1.70(m, 2H), 1.24( m, 5H) Example 255
1-ί3-ί4-「1-(3-氟 -苄基 MH-吲唑 -5-基氨基 1-喹唑啉 -6-基 吡咯 -1-基) -3-f4-(2-羟乙 基) -哌嗪小基 丙 -2-醇  1-ί3-ί4-"1-(3-Fluoro-benzyl-MH-indazol-5-ylamino-1-quinazolin-6-ylpyrrolidin-1-yl)-3-f4-(2-hydroxyethyl) -piperazine small propan-2-ol
Figure imgf000267_0001
Figure imgf000267_0001
在 100 mL茄形瓶中， 将 [1-(3-氟-苄基) -1H-吲唑 -5-基] -[6-(1-环氧乙基甲基 -1H- 吡咯 -3-基) -喹唑啉 -4-基] -胺 178a (150 g， 0.306 mmol)溶于 20 mL甲醇中， 搅拌下 加入 2-呃嗪 -1-基乙醇（79 mg， 0.61 mmol), 反应液加热回流过夜。 将反应液在减 压下浓缩， 得到的残留物通过薄层层析制备板分离纯化 (二氯甲烷： 甲醇 = 10: 1)， 得到本标题产物 1_(3-{4-[1-(3-氟-苄基) -1H-吲唑 -5-基氨基]-喹唑啉 -6-基}-吡咯 -1- 基) -3-[4-(2-羟乙基) -哌嗪小基] -丙 -2-醇 255 (95 mg， 黄棕色固体） , 产率： 50%。 MS m/z (ESI): 621 [M+1] [1-(3-Fluoro-benzyl)-1H-indazol-5-yl]-[6-(1-epoxyethylmethyl-1H-pyrrole-3- in a 100 mL eggplant-shaped flask - quinazolin-4-yl]-amine 178a (150 g, 0.306 mmol) was dissolved in 20 mL of methanol, and 2-pyridazin-1-ylethanol (79 mg, 0.61 mmol) was added with stirring. Heat to reflux overnight. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified (yield: methylene chloride:methanol = 10:1) to afford the title product 1_(3-{4-[1-(3) -fluoro-benzyl)-1H-indazol-5-ylamino]-quinazolin-6-yl}-pyrrol-1-yl)-3-[4-(2-hydroxyethyl)-piperazine -propan-2-ol 255 (95 mg, yellow-brown solid), Yield: 50%. MS m/z (ESI): 621 [M+1]
ΉΝΜΚ (400MHz, DMSO-^): 59.84(s, 1H)， 8.62(s， IH), 8.45(s, IH), 8.23(s, IH), ΉΝΜΚ (400MHz, DMSO-^): 59.84(s, 1H), 8.62(s, IH), 8.45(s, IH), 8.23(s, IH),
8.17(s, IH), 8.03(d, IH, J = 8.8Hz), 7.73(m, 3H), 7.43(s, IH), 7.38(m, IH), 7.12(m, 3H): 6.87(s, IH), 6.67(s, IH), 5.72(s, 2H), 4.94(m, IH), 4.45(m， IH), 4.07(m, 2H), 4.03(m, 1H), 3.87(m, 1H), 3.52(m, 2H)3 3.18(m, 2H), 2.33(m, 9H) 实施例 256 8.17(s, IH), 8.03(d, IH, J = 8.8Hz), 7.73(m, 3H), 7.43(s, IH), 7.38(m, IH), 7.12(m, 3H): 6.87(s , IH), 6.67(s, IH), 5.72(s, 2H), 4.94(m, IH), 4.45(m, IH), 4.07(m, 2H), 4.03(m, 1H), 3.87 (m, 1H), 3.52 (m, 2H) 3 3.18 (m, 2H), 2.33 (m, 9H) Example 256
l-(3- -「l- (3-氟 -苄基 H-吲唑 -5-基氨基 1-喹唑啉 -6-基 吡咯小基) -3-fi2-羟乙基)- 甲基 -氨基 1-丙 -2-醇  1-(3--"1-(3-Fluoro-benzyl H-indazol-5-ylamino-1-quinazolin-6-ylpyrroleyl)-3-fi2-hydroxyethyl)-methyl -amino 1-propan-2-ol
Figure imgf000268_0001
Figure imgf000268_0001
在 100 mL茄形瓶中， 将 [1-(3-氟-苄基) -1H-吲唑 -5-基 ]-[6-(1-环氧乙基甲基 -1H- 吡咯 -3-基)-喹唑啉 -4-基] -胺 178a (150 g， 0.306 mmol)溶于 20 mL甲醇中， 搅拌下 加入 2-甲氨基乙醇（92 mg， 1.224 mmol), 反应液加热回流过夜。 将反应液在减压 下浓缩， 得到的残留物通过薄层层析制备板分离纯化 (二氯甲垸： 甲醇 = 10: 1), 得到本标题产物 1-(3-{4-[1-(3-氟-苄基) -1H-吲唑 -5-基氨基]-喹唑啉 -6-基 吡咯 -1- 基) -3-[(2-羟乙基) -甲基-氨基] -丙 -2-醇 256 (49 mg， 黄棕色固体） ， 产率： 30%。 MS m/z (ESI): 566[M+ 1]  [1-(3-Fluoro-benzyl)-1H-indazol-5-yl]-[6-(1-epoxyethylmethyl-1H-pyrrole-3- in a 100 mL eggplant-shaped flask The quinazolin-4-yl]-amine 178a (150 g, 0.306 mmol) was dissolved in 20 mL MeOH. EtOAc (EtOAc) The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified (yield: methylene chloride:methanol = 10:1) to afford the title product 1-(3-{4-[1- (3-fluoro-benzyl)-1H-indazol-5-ylamino]-quinazolin-6-ylpyrrolidin-1-yl)-3-[(2-hydroxyethyl)-methyl-amino] -propan-2-ol 256 (49 mg, yellow-brown solid), Yield: 30%. MS m/z (ESI): 566 [M+ 1]
!HNMR (400MHz, CD30D - )： 58.48(s, 1H), 8.23(s, 1H), 7.97(s, 1H), 7.88(s, 1H), 7.73(d, 1H,J = 8.8Hz), 7.65(m, 1H), 7.53(m, 1H), 7.16(m, 2H), 7.05(s, 1H), 6.87(m, 2H), 6.77(d, 1H， J = 8.8Hz), 6.57(s, 1H), 6.38(s, 1H), 5.42(s, 2H), 3.96(m, 2H), 3.69(m, 3H), 2.6 l(m, 1H), 2.52(m, 1H), 2.38(m, 2H). 2.26(s, 3H) 实施例 257 !HNMR (400MHz, CD30D - ): 58.48(s, 1H), 8.23(s, 1H), 7.97(s, 1H), 7.88(s, 1H), 7.73(d, 1H, J = 8.8Hz), 7.65 (m, 1H), 7.53(m, 1H), 7.16(m, 2H), 7.05(s, 1H), 6.87(m, 2H), 6.77(d, 1H, J = 8.8Hz), 6.57(s, 1H), 6.38(s, 1H), 5.42(s, 2H), 3.96(m, 2H), 3.69(m, 3H), 2.6 l(m, 1H), 2.52(m, 1H), 2.38(m, 2H). 2.26(s, 3H) Example 257
l-(3-{4-fl-(3-氟 -苄基 IH-吲唑 -5-基氨基 1-喹唑啉 -6-基 吡咯小基 3-哌嗪 -1-基-丙 1-(3-{4-fl-(3-Fluoro-benzyl IH-carbazole-5-ylamino-1-quinazolin-6-ylpyrrole small 3-piperazin-1-yl-propane
-2-醇 -2-ol
Figure imgf000269_0001
在 100 mL茄形瓶中， 将 [1-(3-氟-苄基) -1H-吲唑 -5-基] -[6-(1-环氧乙基甲基 -1H- 吡咯 -3-基) -喹唑啉 -4-基] -胺 178a (150 g， 0.306 mmol)溶于 20 mL甲醇中， 搅拌下 加入哌嗪（105 mg， 1.224 mmol), 反应液加热回流过夜。 将反应液在减压下浓缩， 得到的残留物通过薄层层析制备板分离纯化 (二氯甲垸： 甲醇二 10: 1)， 得到本标 题产物 1-(3-{4-[1-(3-氟-苄基) -1H-吲唑 -5-基氨基] -喹唑啉 -6-基}-吡咯 -1-基) -3-哌嗪 -1-基-丙 -2-醇 257 (20 mg， 黄棕色固体） ， 产率： 12%。
Figure imgf000269_0001
[1-(3-Fluoro-benzyl)-1H-indazol-5-yl]-[6-(1-epoxyethylmethyl-1H-pyrrole-3- in a 100 mL eggplant-shaped flask The quinazolin-4-yl]-amine 178a (150 g, 0.306 mmol) was dissolved in 20 mL MeOH. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified (yield: methylene chloride:methanol: 10:1) to afford the title product 1-(3-{4-[1- (3-fluoro-benzyl)-1H-indazol-5-ylamino]-quinazolin-6-yl}-pyrrol-1-yl)-3-piperazin-1-yl-propan-2-ol 257 (20 mg, yellow-brown solid), Yield: 12%.
MS m/z (ESI): 577[M+ 1] MS m/z (ESI): 577 [M+ 1]
iHNMR (400MHz, CD30D- )： 68.49(s, 1H), 8.38(s， 1H), 8.10(s, 1H), 8.06(s, 1H), 7.97(d, 1H, J = 8.8Hz), 7.76(d， 1H, J = 8.8Hz), 7.67(d, 1H, J = 8.8Hz), 7.37(s, 1H), 7.29(m, 2H), 6.96(m, 2H), 6.86(d, 1H), 6.76(s, 1H)， 6.61(s5 1H), 5.60(s, 2H), 4.03(m, 2H), 3.93(m, 1H), 3.07(m, 4H), 2.68(m, 4H), 2.42(m, 2H) 实施例 258 iHNMR (400MHz, CD30D-): 68.49(s, 1H), 8.38(s, 1H), 8.10(s, 1H), 8.06(s, 1H), 7.97(d, 1H, J = 8.8Hz), 7.76( d, 1H, J = 8.8Hz), 7.67(d, 1H, J = 8.8Hz), 7.37(s, 1H), 7.29(m, 2H), 6.96(m, 2H), 6.86(d, 1H), 6.76(s, 1H), 6.61(s 5 1H), 5.60(s, 2H), 4.03(m, 2H), 3.93(m, 1H), 3.07(m, 4H), 2.68(m, 4H), 2.42 (m, 2H) Example 258
l-(3- -「l-(3-氟 -苄基 1H-吲唑 -5-基氨基 1-喹唑啉 -6-基 吡咯 -1-基 3-(4-吗啉 -4-基- 1-(3--"1-(3-Fluoro-benzyl-1H-indazol-5-ylamino-1-quinazolin-6-ylpyrrolidin-1-yl 3-(4-morpholin-4-yl) -
Figure imgf000269_0002
在 100 mL茄形瓶中， 将 [1-(3-氟-节基) -1H-吲唑 -5-基] -[6-(1-环氧乙基甲基 -1H- 吡咯 -3-基) -喹唑啉 -4-基] -胺 178a (100 g， 0.203 mmol)溶于 20 mL甲醇中， 搅拌下 加入 4-哌啶 -4-基 -吗啉（104 mg， 0.609 mmol), 反应液加热回流过夜。 将反应液在 减压下浓缩， 得到的残留物通过薄层层析制备板分离纯化 (二氯甲烷： 甲醇 = 10: 1)， 得到本标题产物 1-(3-{4-[1-(3-氟- 基) -1H-吲唑 -5-基氨基] -喹唑啉 -6-基 }-吡咯 -1-基)- 3-(4-吗啉 -4-基 -哌啶小基) -丙 -2-醇 258 (21 mg， 黄棕色固体） ， 产率： 16%。 MS m/z (ESI): 661 [M+l]
Figure imgf000269_0002
[1-(3-Fluoro-nodal)-1H-indazol-5-yl]-[6-(1-epoxyethylmethyl-1H-pyrrole-3- in a 100 mL eggplant-shaped flask - quinazolin-4-yl]-amine 178a (100 g, 0.203 mmol) was dissolved in 20 mL MeOH. &lt;RTI ID=0.0&gt;&gt; The reaction solution was heated to reflux overnight. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified (yield: methylene chloride: methanol = 10:1) to afford the title product 1-(3-{4-[1-( 3-fluoro-yl)-1H-indazol-5-ylamino]-quinazolin-6-yl}-pyrrol-1-yl)-3-(4-morpholin-4-yl-piperidine small group - propan-2-ol 258 (21 mg, yellow-brown solid), Yield: 16%. MS m/z (ESI): 661 [M+l]
iHNMR (400MHz, CD30D- )： S8.50(s, IH), 8.36(s, IH), 8.11(s， 1H)， 8.06(s, IH), 7.96(d, IH, J = 8.8Hz), 7.76(d, IH, J = 8.8Hz), 7.67(d, IH, J = 8.8Hz), 7.37(s, IH), 7.28(s, 2H), 6.98(s, 2H), 6.86(s, IH), 6.76(s, IH), 6.61(s, IH), 5.60(s, 2H), 3.95(m, 3H), 3.73(m, 4H), 3.09(m, 2H), 2.56(m, 4H), 2.46(m, 2H), 2.36(m, IH), 2.24(m, 2H), 1.90(m, 2H), 1.61(m, 2H) 实施例 259 iHNMR (400MHz, CD30D-): S8.50(s, IH), 8.36(s, IH), 8.11(s, 1H), 8.06(s, IH), 7.96(d, IH, J = 8.8Hz), 7.76(d, IH, J = 8.8Hz), 7.67(d, IH, J = 8.8Hz), 7.37(s, IH), 7.28(s, 2H), 6.98(s, 2H), 6.86(s, IH ), 6.76(s, IH), 6.61(s, IH), 5.60(s, 2H), 3.95(m, 3H), 3.73(m, 4H), 3.09(m, 2H), 2.56(m, 4H) , 2.46(m, 2H), 2.36(m, IH), 2.24(m, 2H), 1.90(m, 2H), 1.61(m, 2H) Example 259
l-(4-氨基 -哌啶小基) -3-(3- -「3-氯 -4-(3-氟-苄氧基) -苯氨基 1-喹唑啉 -6-基 吡咯- 1-  1-(4-Amino-piperidinyl)-3-(3--"3-chloro-4-(3-fluoro-benzyloxy)-phenylamino-1-quinazolin-6-ylpyrrole-1 -
Figure imgf000270_0001
Figure imgf000270_0001
第一步  First step
(1 -节基 -哌啶 -4-基) -氨基甲酸叔丁酯  (1-N-based-piperidin-4-yl)-tert-butyl carbamate
将醋酸酐 (2.43 g， 11 mmol)溶于 20 mL二氯甲烷中，用恒压滴液漏斗缓慢滴加 1-苄基 -哌啶 -4-基胺 259a (2.05 mL 10 mraol, Aldrich)的 20 mL二氯甲烷溶液中， 滴加完毕后， 室温下搅拌过夜。 将反应液在减压下浓縮， 得到的残留物通过硅胶 柱层析进一步分离纯化 (二氯甲烷： 甲醇 =25: 1), 得到 (1-苄基 -哌啶 -4-基 )-氨基甲 酸叔丁酯 259b (2.91g， 白色固体)， 产率： 100% Acetic anhydride (2.43 g, 11 mmol) was dissolved in 20 mL of dichloromethane and slowly added dropwise using a constant pressure dropping funnel. 1-Benzyl-piperidin-4-ylamine 259a (2.05 mL of 10 mraol, Aldrich) in 20 mL of dichloromethane was added and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified mjjjjjjjjjjjj Tert-butyl formate 259b (2.91 g, white solid), Yield: 100%
MS m/z (ESI): 291 [M+ 1] MS m/z (ESI): 291 [M+ 1]
第二步  Second step
哌啶 -4-基-氨基甲酸叔丁酯  Piperidine-4-yl-carbamic acid tert-butyl ester
将 (1-苄基 -哌啶 -4-基) -氨基甲酸叔丁酯 259b (2.9 g 10 ol)溶于 150 mL甲醇 中， 搅拌下加入 Pd/C， 用氢气置换空气， 4次后， 在 3(TC下催化加氢， 24小时后 反应完毕。过滤反应液,减压下浓缩滤液，得到哌啶 -4-基-氨基甲酸叔丁酯 259c (1.96 g， 白色固体)， 产率： 98 %  (1-Benzyl-piperidin-4-yl)-carbamic acid tert-butyl ester 259b (2.9 g 10 ol) was dissolved in 150 mL of methanol, Pd/C was added with stirring, and the air was replaced with hydrogen for 4 times. Catalytic hydrogenation at 3 (TC), the reaction was completed after 24 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound: </RTI> <RTIgt; 98%
MS m/z (ESI): 201 [M+ 1] MS m/z (ESI): 201 [M+ 1]
第三歩  Third
{1_[3-(3-{4-[3-氯 -4-(3-氟- 氧基) -苯氨基] -喹唑啉 -6-基}-吡咯 -1-基) -2-羟基-丙基] - 哌啶 -4-基} -氨基甲酸叔丁酯  {1_[3-(3-{4-[3-chloro-4-(3-fluoro-oxy)-phenylamino]-quinazolin-6-yl}-pyrrol-1-yl)-2-hydroxyl -propyl]-piperidin-4-yl}-tert-butyl carbamate
将 [3-氯 -4-(3-氟-苄基) -苯基]- [6-(1-环氧乙基甲基 -1H-吡咯 -3-基) -喹唑啉 -4-基] - 胺 187a (200 mg 0.4 mmol)溶于 20 mL甲醇中， 搅拌下加入哌啶 -4-基-氨基甲酸 叔丁酯 259c (118 mg 0.5 6 mmol), 混合液加热回流过夜。 反应液在减压下浓缩， 得到的残留物通过硅胶柱层析进一步分离纯化 (二氯甲烷： 甲醇 = 25 : 1)， 得到 {1-[3-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基]-喹唑啉 -6-基}-吡咯 -1-基) -2-羟基-丙基] - 哌啶 -4-基} -氨基甲酸叔丁酯 259d (178 mg， 黄色固体)， 产率： 74.2%  [3-Chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-epoxyethylmethyl-1H-pyrrol-3-yl)-quinazolin-4-yl - Amine 187a (200 mg 0.4 mmol) was dissolved in 20 mL MeOH. &lt;EMI ID=9.1&gt;&gt; The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified and purified by silica gel column chromatography (dichloromethane:methanol = 25:1) to give {1-[3-(3-{4-[3-chloro- 4-(3-Fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-pyrrol-1-yl)-2-hydroxy-propyl]-piperidin-4-yl}-carbamic acid tert-Butyl ester 259d (178 mg, yellow solid), Yield: 74.2%
MS m/z (ESI): 701 [M+ 1] MS m/z (ESI): 701 [M+ 1]
第四步  the fourth step
1-(4-氨基 -哌啶 -1-基) -3-(3-{4-[3-氯 -4-(3-氟- 氧基) -苯氨基] -喹唑啉 -6-基} -吡咯 -1- 基) -丙 -2-醇  1-(4-Amino-piperidin-1-yl)-3-(3-{4-[3-chloro-4-(3-fluoro-oxy)-phenylamino]-quinazoline-6-yl }-pyrrole-1-yl)-propan-2-ol
将 {1-[3-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基}-吡咯 -1-基) -2-羟基- 丙基] -哌啶 -4-基} -氨基甲酸叔丁酯 259d (58.6 mg 0.09 mmol)溶于 15 mL二氯甲烷 中， 在冰浴条件下， 冷却至 0°C， 加入 3 mL三氟乙酸， 保持此温度搅拌 3小时后 反应完毕。 将反应液中加入饱和碳酸氢钠溶液， 调节 pH=8， 加入 50 mL乙酸乙 酯和 50 mL四氢呋喃，.分液， 水相用乙酸乙酯萃取 (50 mLX 3), 合并的有机相通 过无水硫酸钠干燥， 过滤， 减压下浓缩， 得到的残留物通过硅胶柱层析进一步分 离纯化 (甲醇： 氯水 =50: 1)， 得到 1-(4-氨基 -哌啶 -1-基) -3-(3-{4-[3-氯 -4-(3-氟 -苄氧 基) -苯氨基]-喹唑啉 -6-基 吡咯 -1-基) -丙 -2-醇 259(35 mg，淡黄色固体)，产率： 69.7 %  {1-[3-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-pyrrol-1-yl)- 2-Hydroxy-propyl]-piperidin-4-yl}-carbamic acid tert-butyl ester 259d (58.6 mg 0.09 mmol) dissolved in 15 mL of dichloromethane, cooled to 0 ° C under ice bath, 3 mL of trifluoroacetic acid was stirred at this temperature for 3 hours and the reaction was completed. The reaction solution was added to a saturated aqueous solution of sodium hydrogencarbonate, and the mixture was adjusted to pH=8, 50 mL of ethyl acetate and 50 mL of tetrahydrofuran were added, and the mixture was separated, and the aqueous phase was extracted with ethyl acetate (50 mL×3). The organic layer was dried over sodium sulfate, filtered, and evaporated, evaporated,462462462462462462462462462462462462462462462462462462462462462462462 -3-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylpyrrol-1-yl)-propan-2-ol 259 (35 mg, pale yellow solid), yield: 69.7 %
MS m/z (ESI): 601 [M+ 1] ' MS m/z (ESI): 601 [M+ 1] '
1H NMR (400 MHz, CD30D-^): S9.71 (s, 1H), 8.55 (s, 1H)， 8.50 (s, 1H), 8.11 (s， 1H), 8.02 (d， J = 8.8Hz, 1H), 7.85 (d, J = 8.8Hz, 1H)， 7.69 (d, J = 8.8Hz, 1H), 7.54 (t, J = 8.8Hz, 1H), 7.42 (s, 1H), 7.32 (m, 3H), 7.19 (t, J = 8.8Hz, 1H), 6.87 (s, 1H), 6.65 (s, 1H), 5.27 (s, 2H), 4.40 (br, 1H), 4.06 (t， J = 12.8Hz, 1H), 3.94 (s, 1H), 3.85 (m, 1H), 3.18 (d, J = 3.2Hz, 2H), 2.78 (br, 2H), 2.49 (br, 2H), 2.19 (m, 3H), 1.66 (br, 2H), 1.28 (br, 2H) 实施例 260 1H NMR (400 MHz, CD30D-^): S9.71 (s, 1H), 8.55 (s, 1H), 8.50 (s, 1H), 8.11 (s, 1H), 8.02 (d, J = 8.8Hz, 1H), 7.85 (d, J = 8.8Hz, 1H), 7.69 (d, J = 8.8Hz, 1H), 7.54 (t, J = 8.8Hz, 1H), 7.42 ( s, 1H), 7.32 (m, 3H), 7.19 (t, J = 8.8Hz, 1H), 6.87 (s, 1H), 6.65 (s, 1H), 5.27 (s, 2H), 4.40 (br, 1H ), 4.06 (t, J = 12.8Hz, 1H), 3.94 (s, 1H), 3.85 (m, 1H), 3.18 (d, J = 3.2Hz, 2H), 2.78 (br, 2H), 2.49 (br , 2H), 2.19 (m, 3H), 1.66 (br, 2H), 1.28 (br, 2H) Example 260
2-(3-{4-「3-氯 -4-(3-氟 -苄氧基)-苯氨基 1-喹唑啉 -6-基 比咯小基)- 1-吡咯垸小基-乙 2- (3-{4-"3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino-1-quinazolin-6-ylpyrrolidine)- 1-pyrrolidinyl-B
Figure imgf000272_0001
将 2-(3-{4-[3-氯 -4-(3-氟- 氧基) -苯氨基] -喹唑啉 -6-基}-吡咯 -1-基) -1-(4-环丙基 甲基 -哌嗪小基) -乙酮 253 (53 mg， 0.08 mmol)溶于 10 mL四氢呋喃中，搅拌下加入 氢化铝锂 (40 mg， 0.08 mmol), 室温下搅拌 30分钟后反应完毕。 反应液用甲醇淬 灭， 减压下浓缩， 得到的残留物通过硅胶柱层析进一歩分离纯化 (二氯甲烷： 甲醇 =25： 1)， 得到标题产物 2-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基}-吡咯 -1-基)小吡咯垸小基 -乙酮 (8 mg， 黄色固体)， 产率： 15.4%。
Figure imgf000272_0001
2-(3-{4-[3-Chloro-4-(3-fluoro-oxy)-phenylamino]-quinazolin-6-yl}-pyrrol-1-yl)-1-(4- Cyclopropylmethyl-piperazine small base)-ethanone 253 (53 mg, 0.08 mmol) was dissolved in 10 mL of tetrahydrofuran, and lithium aluminum hydride (40 mg, 0.08 mmol) was added with stirring, and the mixture was stirred at room temperature for 30 minutes. Finished. The reaction mixture was quenched with EtOAc (EtOAc) (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH -Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-pyrrol-1-yl)pyrrolidinyl-ethanone (8 mg, yellow solid), Yield: 15.4%.
MS m/z (ESI): 611 [M+ 1]  MS m/z (ESI): 611 [M+ 1]
1H NMR (400 MHz, CD30D-c¾)： 58.64 (s, 1H), 8.41 (s, 1H), 7.97 (d, J = 2.8Hz, 1H), 7.90 (d， J = 8.8Hz， 1H), 7.84 (d, J = 8.8Hz, 1H), 7.70 (m, 1H), 7.34 (m, 1H), 7.22 (m5 3H), 7.02 (m, 1H), 6.94 (d, J = 8.8Hz, 1H), 6.69 (d， J = 2.0Hz, 1H), 6.56 (d, J = 1.6Hz, 1H), 5.13 (s, 2H), 4.02 (t, J = 6.0Hz, 3H), 2.90 (m, 5H), 2.80 (s, 4H), 2.59 (d, J = 6.8Hz, 2H), 0.88 (m, 1H), 0.62 (m, 2H), 0.24 (m, 2H) 实施例 261 1H NMR (400 MHz, CD30D-c3⁄4): 58.64 (s, 1H), 8.41 (s, 1H), 7.97 (d, J = 2.8Hz, 1H), 7.90 (d, J = 8.8Hz, 1H), 7.84 (d, J = 8.8Hz, 1H), 7.70 (m, 1H), 7.34 (m, 1H), 7.22 (m 5 3H), 7.02 (m, 1H), 6.94 (d, J = 8.8Hz, 1H) , 6.69 (d, J = 2.0Hz, 1H), 6.56 (d, J = 1.6Hz, 1H), 5.13 (s, 2H), 4.02 (t, J = 6.0Hz, 3H), 2.90 (m, 5H) , 2.80 (s, 4H), 2.59 (d, J = 6.8 Hz, 2H), 0.88 (m, 1H), 0.62 (m, 2H), 0.24 (m, 2H) Example 261
2-(3-{4-「3-氯 -4-(3-氟-苄氧基 苯氨基 1-喹唑啉 -6-基 吡咯 -1-基)小吡咯垸 -1-基-乙  2-(3-{4-"3-Chloro-4-(3-fluoro-benzyloxyphenylamino-1-quinazolin-6-ylpyrrole-1-yl)pyrrolidin-1-yl-B
酮 ketone
Figure imgf000273_0001
第一步
Figure imgf000273_0001
first step
2-氯小吡咯烷小基 -乙酮  2-chloropyrrolidine small group-ethyl ketone
将吡咯 (71 mg, 1 mmol)溶于 10 mL二氯甲烷中， 溶液在冰浴下冷却至 0°C， 搅拌下加入氯乙酰氯 (170 mg， 1.5 mmol), 室温下搅拌 1小时反应完毕。 反应液中 加入 50 mL水， 二氯甲烷萃取 (50 mL X 3)， 合并的有机相依次通过水， 饱和氯化 钠溶液洗涤， 无水硫酸钠干燥， 过滤， 减压下浓缩， 得到 2-氯 -1-吡咯垸 -1-基 -乙酮 261a (115 mg, 白色固体)， 产率： 78%  The pyrrole (71 mg, 1 mmol) was dissolved in 10 mL of dichloromethane, and the solution was cooled to 0 ° C under ice-cooling. chloroacetyl chloride (170 mg, 1.5 mmol) was added with stirring, and the mixture was stirred at room temperature for 1 hour. . The reaction mixture was added with 50 mL of water and dichloromethane (50 mL X 3). The combined organic phases were washed sequentially with water Chloro-1-pyrrole-1-yl-ethanone 261a (115 mg, white solid), Yield: 78%
第二步  Second step
2_(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基]-喹唑啉 -6-基 吡咯 -1-基)小吡咯垸 -1-基-乙 酮 2 _ (3 -{4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylpyrrol-1-yl)pyrrolidin-1-yl- Ethyl ketone
在 50 mL的烧瓶中，将 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-[6-(1Η-吡咯 -3-基) -喹唑啉 -4- 基] -胺 42 (111 mg, 0.25 mmol)溶于 10 mL干燥的 Ν,Ν-二甲基甲酰胺中， 在冰浴 条件下，冷却至 0°C， 加入氢化钠 (30 mg, 0.75 mmol), 搅拌 30分钟后加入 2-氯 -1- 吡咯垸 -1-基 -乙酮 261a (55 mg， 0.375 mmol), 室温下搅拌 1小时反应完毕。 反应 液加入 50 mL水， 二氯甲烷萃取 (50 mLX 3)， 合并的有机相通过无水硫酸钠干燥， 过滤， 减压下浓缩， 得到的残留物通过硅胶柱层析进一步分离纯化 (正己垸： 乙酸 乙酯 =2: 1)，得到本标题产物 2-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基 吡咯 -1-基)小吡咯烷 -1-基 -乙酮 261 (72 mg, 黄色固体)， 产率： 51.9%。  [3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1Η-pyrrol-3-yl)-quinazolin-4-yl] in a 50 mL flask -Amine 42 (111 mg, 0.25 mmol) was dissolved in 10 mL dry EtOAc EtOAc (EtOAc) After stirring for 30 minutes, 2-chloro-1-pyrrole-1-yl-ethanone 261a (55 mg, 0.375 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was extracted with 50 mL of water and EtOAc (EtOAc (EtOAc) (EtOAcjjjjjjjjj : ethyl acetate = 2: 1) to give the title product 2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl Pyrrol-1-yl)pyrrolidin-1-yl-ethanone 261 (72 mg, yellow solid), Yield: 51.9%.
MS m/z (ESI): 556[M+ 1] MS m/z (ESI): 556 [M+ 1]
1H NMR (400 MHz, CD30D-^): 69.713 (s,lH) ,8.545 (d,J=1.2Hz,lH),8.499 (s,lH), 8.027(m,2H),7J59(m,lH),7.708(d,J=8.8Hz,lH),7.479(m,lH),7.323(m54H),7.192(m,lH ),6.282(t,J=2.4Hz,lH),6.056(m,lH),5.268(s,2H),4.853(s,2H),3.500(t,J=6.8Hz,2H)53.345 (t,J=7.2Hz,2H), 1.925(m,2H), 1.810(m,2H) 实施例 262 1H NMR (400 MHz, CD30D-^): 69.713 (s, lH), 8.545 (d, J = 1.2 Hz, lH), 8.499 (s, lH), 8.027 (m, 2H), 7J59 (m, lH) , 7.708 (d, J = 8.8 Hz, lH), 7.479 (m, lH), 7.323 (m 5 4H), 7.192 (m, lH), 6.282 (t, J = 2.4 Hz, lH), 6.056 (m, lH), 5.268 (s, 2H), 4.853 (s, 2H), 3.500 (t, J = 6.8 Hz, 2H) 5 3.345 (t, J = 7.2 Hz, 2H), 1.925 (m, 2H), 1.810 ( m, 2H) Example 262
Γ3-氯 -4-(3-氟-苄氧基) -苯基 M6-「5- (哌啶 -4-基氨基) -1H-吡咯 -3-基 1-喹唑啉 -4-基 μ  3-chloro-4-(3-fluoro-benzyloxy)-phenyl M6-"5-(piperidin-4-ylamino)-1H-pyrrol-3-yl-1-quinazolin-4-yl
Figure imgf000274_0001
Figure imgf000274_0001
在氩气氛下， 将 4-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基]-喹唑啉 -6-基 }-m-吡咯 -2- 甲醛 218a (94.4 mg， 0.2 mmol)和哌啶 -4-基胺 （26 mg， 0.26 mmol)溶于 20 mL二氯 甲烷中， 在室温下搅拌 30分钟后， 加入三 (乙酰氧基)硼氢化钠 (212 mg， 1 mmol), 混合液在室温下搅拌过夜。 将反应液中加入 50 mL水， 减压下蒸掉二氯甲烷， 水 相用乙酸乙酯萃取 (50 mLX 3)， 合并的有机相通过无水硫酸钠干燥， 过滤， 减压下 浓缩， 得到的残留物通过硅胶柱层析进一步分离纯化 (二氯甲垸： 甲醇 =5: 1)， 得 到标题产物 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-{6-[5- (哌啶 -4-基氨基) -1H-吡咯 -3-基] - 喹 唑啉 -4-基} -胺 262 (8 mg， 黄色固体)， 产率： 71.4%。  4-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-m-pyrrole-2-carbaldehyde 218a (under argon) 94.4 mg, 0.2 mmol) and piperidin-4-ylamine (26 mg, 0.26 mmol) were dissolved in 20 mL dichloromethane. After stirring at room temperature for 30 min, sodium tris(acetoxy)borohydride (212) Mg, 1 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was combined with 50 mL of EtOAc (EtOAc m. The residue was further purified by silica gel column chromatography (dichloromethane:methanol = 5:1) to give the title product [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-{6 -[5-(piperidin-4-ylamino)-lH-pyrrol-3-yl]-quinazolin-4-yl}-amine 262 (8 mg, yellow solid), yield: 71.4%.
MS m/z (ESI): 557[M+ 1] MS m/z (ESI): 557 [M+ 1]
1H NMR (400 MHz, CD30D-t¾: δΐθ.919 (s,lH)，9.684(s，lH), 8.533(s,lH),  1H NMR (400 MHz, CD30D-t3⁄4: δ ΐ θ.919 (s, lH), 9.684 (s, lH), 8.533 (s, lH),
8.441(d,J=12Hz,lH),8.143(d，J=8.4Hz,lH),8.044(s,lH),7.740(m,2H),7.461(br，lH),7.282 (m,3H),7.179(m,lH),6.791 (s, 1 H),6.452(d,J=20.8Hz, 1 H)，5.244(s,2H),3.864(s, 1H),3.480 (m,2H),3.327(br,4H),1.913(br,2H), 1.264(br,2H) 实施例 263 8.441 (d, J = 12 Hz, lH), 8.143 (d, J = 8.4 Hz, lH), 8.044 (s, lH), 7.740 (m, 2H), 7.461 (br, lH), 7.282 (m, 3H) , 7.179 (m, lH), 6.791 (s, 1 H), 6.452 (d, J = 20.8 Hz, 1 H), 5.244 (s, 2H), 3.864 (s, 1H), 3.480 (m, 2H), 3.327 (br, 4H), 1.913 (br, 2H), 1.264 (br, 2H) Example 263
(RV「3-氯 -4-(3-氟 - 氧基) -苯基 W6-(l-环氧丙垸基 -2-基甲基 -1H-吡咯 -3-基) -喹唑啉  (RV "3-chloro-4-(3-fluoro-oxy)-phenyl W6-(l-glycidyl-2-ylmethyl-1H-pyrrole-3-yl)-quinazoline
-4-基 胺  -4-ylamine
Figure imgf000274_0002
Figure imgf000275_0001
在 50 mL的烧瓶中，将 [3-氯 -4-(3-氟- 氧基) -苯基 ]-[6-(1Η-吡咯 -3-基) -喹唑啉 -4- 基] -胺 42 (223 mg, 0.5 mmol)溶解于 10 mL干燥的 Ν,Ν-二甲基甲酰胺中， 在冰浴 条件下， 冷却至 0°C , 加入氢化钠 (60 mg， 2.5 mmol), 搅拌 30分钟后加入 (S)-2-(2- 氯乙基)环氧乙烷（80 mg， 0.75 mmol), 室温下搅拌 1小时反应完毕。 反应液减压 下浓缩， 得到的残留物进一步通过柱层析分离纯化 (二氯甲垸： 甲醇 = 10: 1)， 得 到本标题产物 (R)-[3-氯 -4-(3-氟-苄氧基) -苯基 ]-[6-(1-环氧丙烷基 -2-基甲基 -1H-吡咯 _3-基) -喹唑啉—4-基] -胺 263 (40 mg， 淡黄色固体)， 产率： 19.32%。
Figure imgf000274_0002
Figure imgf000275_0001
[3-Chloro-4-(3-fluoro-oxy)-phenyl]-[6-(1Η-pyrrol-3-yl)-quinazolin-4-yl]- in a 50 mL flask Amine 42 (223 mg, 0.5 mmol) was dissolved in 10 mL dry EtOAc EtOAc (EtOAc (EtOAc) After 30 minutes, (S)-2-(2-chloroethyl)oxirane (80 mg, 0.75 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. EtOAc m. -benzyloxy)-phenyl]-[6-(1-epoxypropenyl-2-ylmethyl-1H-pyrrole-3-yl)-quinazoline-4-yl]-amine 263 (40 mg , pale yellow solid), Yield: 19.32%.
MS m/z (ESI): 515[M+ 1] MS m/z (ESI): 515 [M+ 1]
1H NMR (400 MHz, CD30D-^): 59.710 (s,lH) ,8.552 (s,lH), 8.056(s,lH), 8.026(s,lH): 7.762(d,J=8.8Hz,lH), 7.709(d,J=9.2Hz,lH),7.484 (m,2H), 7.323 (m,3H),7.192(m,lH), 933(s,lH), 6.696 (s,lH),5.274(s,2H),4.989 (m,lH),4.518(m,lH),4.336(m，lH), 1H NMR (400 MHz, CD30D-^): 59.710 (s, lH), 8.552 (s, lH), 8.056 (s, lH), 8.026 (s, lH) : 7.762 (d, J = 8.8 Hz, lH) , 7.709 (d, J = 9.2 Hz, lH), 7.484 (m, 2H), 7.323 (m, 3H), 7.192 (m, lH), 933 (s, lH), 6.696 (s, lH), 5.274 ( s, 2H), 4.989 (m, lH), 4.518 (m, lH), 4.336 (m, lH),
4.186(m,2H),2.666(m,lH),2.364(m,2H) 实施例 264 4.186 (m, 2H), 2.666 (m, lH), 2.364 (m, 2H) Example 264
1-(3- -Γ3-氯 -4-(3-氟-苄氧基 苯氨基 1-喹唑啉 -6-基}-吡咯小基 )-3-((3S,5R)-3,5-二 甲基 -哌嗪 -1-基)-丙 -2-醇  1-(3- -Γ3-chloro-4-(3-fluoro-benzyloxyphenylamino-1-quinazolin-6-yl}-pyrroleyl)-3-((3S,5R)-3,5 -Dimethyl-piperazin-1-yl)-propan-2-ol
Figure imgf000275_0002
Figure imgf000275_0002
(2S，6R)-2，6-二甲基哌嗪 (68 mg, 0.6 mmol, ABCR)溶解于 25 mL异丙醇中， 搅拌下依次加入 2 mL 1,2-二氯乙烷和 [3-氯 -4-(3-氟-苄基) -苯基] - [6-(1-环氧乙基甲 基 -1H-吡咯 -3-基) -喹唑啉 -4-基] -胺 187a (200 mg, 0.4 mmol),混合液在 65°C加热回 流过夜。反应液在减压下浓缩，得到的残留物通过硅胶柱层析分离纯化 (二氯甲烷: 甲醇 = 10: 1), 得到本标题产物 1-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6- 基 吡咯小基 )-3-((3S,5R)-3，5-二甲基-哌嗪小基) -丙 -2-醇 264 (211 mg, 黄色固体)， 产率： 86.1 %。 (2S,6R)-2,6-Dimethylpiperazine (68 mg, 0.6 mmol, ABCR) was dissolved in 25 mL of isopropanol, and 2 mL of 1,2-dichloroethane and [3] were added sequentially with stirring. -chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-epoxyethylmethyl-1H-pyrrol-3-yl)-quinazolin-4-yl]-amine 187a (200 mg, 0.4 mmol), and the mixture was heated to reflux at 65 ° C overnight. The reaction mixture was concentrated under reduced pressure. Methanol = 10: 1), the title product 1-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylpyrrole is obtained. -3-((3S,5R)-3,5-dimethyl-piperazine small)-propan-2-ol 264 (211 mg, yellow solid), yield: 86.1%.
MS m/z (ESI): 616[M+ 1] MS m/z (ESI): 616 [M+ 1]
1H NMR(400 MHz， DMSO- d): 59.70(s, 1H), 8.55(s， 1H), 8.50(s, 1H), 8.05(m, 1H), 8.02(m, 1H), 7.73(m, 2H)， 7.52(m, 2H), 7.34(m, 3H), 7.19(m， 1H)， 7.01(s, 1H)， 6.72(s, 1H), 5.27(s, 2H), 4.91(br, 1H), 4.03 (m, 3H), 2.87(br, 2H)， 2.77(m, 2H), 2.22(m, 2H), 1.61(m, 2H), 0.96(t, J=6Hz, 6H) 1H NMR (400 MHz, DMSO-d): 59.70 (s, 1H), 8.55 (s, 1H), 8.50 (s, 1H), 8.05 (m, 1H), 8.02 (m, 1H), 7.73 (m, 2H), 7.52(m, 2H), 7.34(m, 3H), 7.19(m, 1H), 7.01(s, 1H), 6.72(s, 1H), 5.27(s, 2H), 4.91(br, 1H) ), 4.03 (m, 3H), 2.87 (br, 2H), 2.77 (m, 2H), 2.22 (m, 2H), 1.61 (m, 2H), 0.96 (t, J = 6 Hz, 6H)
实施例 265 Example 265
2-(3-{4-「3-氯 -4-(3-氟-苄氧基 苯氨基 1-喹唑啉 -6-基 吡咯小基 l-(4-环丙基 -哌嗪 小基) -乙酮  2-(3-{4-"3-Chloro-4-(3-fluoro-benzyloxyphenylamino-1-quinazolin-6-ylpyrrole small group 1-(4-cyclopropyl-piperazine small group) )-Ethyl ketone
Figure imgf000276_0001
Figure imgf000276_0001
42  42
第一步  First step
2-氯小 (4-环丙基 -哌嗪小基) -乙酮  2-chloro small (4-cyclopropyl-piperazine small group)-ethyl ketone
将 1-环丙基 -哌嗪 252b (l g， 7.94 mmol)溶于 10 mL二氯甲烷中， 溶液在丙酮 -干冰浴下冷却至 -78°C， 搅拌下加入 1 mL三乙胺和氯乙酰氯 (1.2 g， 11.9 mmol), 维持此温度搅拌 40分钟反应完毕。 反应液中加入 50 mL水， 二氯甲烷萃取 (50 mL X 3)， 合并的有机相依次通过水， 饱和氯化钠溶液洗涤， 无水硫酸钠干燥， 过滤， 减压下浓缩， 得到 2-氯 -1-(4-环丙基 -哌嗪 -1-基) -乙酮 265a (115 mg， 白色固体)， 产 物不经分离直接进行下一步反应。  1-Cyclopropyl-piperazine 252b (lg, 7.94 mmol) was dissolved in 10 mL of dichloromethane. The solution was cooled to -78 ° C in acetone-dry ice bath and 1 mL triethylamine and chloroethyl The acid chloride (1.2 g, 11.9 mmol) was stirred at this temperature for 40 minutes and the reaction was completed. The reaction mixture was added with 50 mL of water and dichloromethane (50 mL X 3). The combined organic phases were washed sequentially with water Chloro-1-(4-cyclopropyl-piperazin-1-yl)-ethanone 265a (115 mg, white solid).
MS m/z (ESI): 203[M+ 1] 2-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基}-吡咯 -1-基) -l-(4-环丙基 -哌嗪 MS m/z (ESI): 203 [M+ 1] 2-(3-{4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-pyrrol-1-yl)-l-(4- Cyclopropyl-piperazine
-1-基) -乙酮  -1-yl)-ethanone
在 50 mL的烧瓶中，将 [3-氯 -4-P-氟-苄氧基) -苯基 ]-[6-(1Η-吡咯 -3-基) -喹唑啉 -4- 基] -胺 42 (257 mg, 0.58 mmol)溶于 10 mL干燥的 Ν,Ν-二甲基甲酰胺中， 在冰浴 条件下，冷却至 0°C，加入氢化钠 (69 mg， 2.9 mmol),搅拌 30分钟后加入 2-氯小 (4- 环丙基 -哌嗪小基) -乙酮 265a (140 mg, 0.69 mmol), 室温下搅拌 1小时反应完毕。 反应液加入 50 mL水， 用乙酸乙酯萃取 (50 mLX 3), 合并的有机相通过无水硫酸 钠干燥， 过滤， 减压下浓缩， 得到的残留物通过硅胶柱层析进一步分离纯化 (二氯 甲烷： 甲醇 =40: 1)， 得到本标题产物 2-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑 啉 -6-基 }-吡咯小基 )小(4-环丙基 -哌嗪小基) -乙酮 265 (148 mg， 黄色固体)， 产率： 35.2%。  [3-Chloro-4-P-fluoro-benzyloxy)-phenyl]-[6-(1Η-pyrrol-3-yl)-quinazolin-4-yl]- in a 50 mL flask Amine 42 (257 mg, 0.58 mmol) was dissolved in 10 mL dry EtOAc EtOAc (EtOAc m. After 30 minutes, 2-chlorosodium (4-cyclopropyl-piperazine small group)-ethanone 265a (140 mg, 0.69 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was added to 50 mL of water, EtOAc (EtOAc) (EtOAc) Methyl chloride: Methanol = 40: 1) gave the title product 2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6-yl }-pyrrole small group) small (4-cyclopropyl-piperazine small group)-ethanone 265 (148 mg, yellow solid), yield: 35.2%.
MS m/z (ESI): 611[M+ 1]  MS m/z (ESI): 611 [M+ 1]
¾ΝΜΚ(400 MHz , DMSO- 6): 69.74(s, 1H), 8.65(s, 1H), 8.53(s, 1H), 8.37(s, 1H), 8.04(m, 2H), 7.76(m, 2H), 7.60(m, 1H), 7.49(m, 1H), 7.32(m, 4H), 7.19(m, 1H), 5.27(s, 2H), 4.96(s, 2H), 3.45(br, 4H), 2.57(br, 4H)， 1.64(m, 1H), 0.45(m, 2H), 0.35(m, 2H) 实施例 266  3⁄4ΝΜΚ(400 MHz, DMSO-6): 69.74(s, 1H), 8.65(s, 1H), 8.53(s, 1H), 8.37(s, 1H), 8.04(m, 2H), 7.76(m, 2H ), 7.60 (m, 1H), 7.49 (m, 1H), 7.32 (m, 4H), 7.19 (m, 1H), 5.27 (s, 2H), 4.96 (s, 2H), 3.45 (br, 4H) 2.57(br, 4H), 1.64(m, 1H), 0.45(m, 2H), 0.35(m, 2H) Example 266
氯 -4-(3-氟 -苄氧基)-苯氨基 1-喹唑啉 -6-基 HH-吡咯 -2-甲酸（2-二乙氨基-乙 基) -酰胺  Chloro-4-(3-fluoro-benzyloxy)-phenylamino 1-quinazoline-6-yl HH-pyrrole-2-carboxylic acid (2-diethylamino-ethyl)-amide
Figure imgf000277_0001
Figure imgf000277_0001
将双 (2-氧代 -3-恶唑垸基)次磷酰氯 (191 mg, 0.75 mmol)溶于 10 mL无水二氯甲 烷中， 搅拌下加入三乙胺 (0.1 mL， 0.75 mmol), 室温下搅拌 15分钟后， 依次加入 4-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基}-111-吡咯 -2-甲酸 184g (244 mg, 0.5 mmol)和 N*1*,N*1*-二乙基乙烷 -1,2-二胺 (58 mg, 0.5 mmol), 室温下搅拌 1小 时反应完毕。 将反应液在减压下浓缩， 残渣中加入 20 mL水， 用乙酸乙酯萃取 (50 mLX 3), 合并的有机相依次通过无水硫酸钠干燥， 过滤， 减压下浓缩， 得到的残 留物通过硅胶柱层析进一步分离纯化 (二氯甲烷： 甲醇 = 15 : 1), 得到标题产物 4-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基]-喹唑啉 -6-基 HH-吡咯 -2-甲酸 （2-二乙氨基-乙 基) -酰胺 266 (115 mg， 黄色固体)， 产率： 39.2%。 Bis(2-oxo-3-oxazolyl)phosphoryl chloride (191 mg, 0.75 mmol) was dissolved in 10 mL of dry dichloromethane and triethylamine (0.1 mL, 0.75 mmol). After stirring at room temperature for 15 minutes, 4-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-111-pyrrole-2- Formic acid 184 g (244 mg, 0.5 mmol) and N*1*, N*1*-diethylethane-1,2-diamine (58 mg, 0.5 mmol) were stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure. EtOAc was evaporated. The combined organic phase was dried over anhydrous sodium sulfate (MgSO4), EtOAcjjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 4-{4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl HH-pyrrole-2-carboxylic acid (2-diethylamino-ethyl) - amide 266 (115 mg, yellow solid), Yield: 39.2%.
MS m/z (ESI): 587[M+ 1]  MS m/z (ESI): 587 [M+ 1]
Ή NMR(400 MHz , DMSO-c¾)： S=11.97(s, 1H), 9.85(s， 1H), 8.75(s, 1H), 8.52(s, 1H): 8.05(m, 2H), 7.80(m, 2H) 7.68(s, 1H), 7.47(m, 2H)， 7.3 l(m, 3H), 7.19 (m, 1H)， 6.98(s, 1H), 6.86(s, 1H), 5.27(s, 2H), 3.62(m, 2H), 3.33(m, 2H), 3.17(m, 2H), 3.05(m, 2H), 1.12(m, 6H) 实施例 267 NMR NMR (400 MHz, DMSO-c3⁄4): S = 11.97 (s, 1H), 9.85 (s, 1H), 8.75 (s, 1H), 8.52 (s, 1H) : 8.05 (m, 2H), 7.80 ( m, 2H) 7.68(s, 1H), 7.47(m, 2H), 7.3 l(m, 3H), 7.19 (m, 1H), 6.98(s, 1H), 6.86(s, 1H), 5.27(s , 2H), 3.62 (m, 2H), 3.33 (m, 2H), 3.17 (m, 2H), 3.05 (m, 2H), 1.12 (m, 6H) Example 267
(4-氨基 -哌啶 -1-基 )-(4-ί4-Γ3-氯 -4-ί3-氟苄氧基) -苯氨基 1-喹唑啉 -6-基 }-lH-吡咯 -2- 基) -甲酮  (4-Amino-piperidin-1-yl)-(4-ί4-Γ3-chloro-4-ί3-fluorobenzyloxy)-phenylamino-1-quinazolin-6-yl}-lH-pyrrole-2 - base) - ketone
Figure imgf000278_0001
Figure imgf000278_0001
第一步  First step
[1-(4-{4-[3-氯 -4-(3-氟苄氧基) -苯氨基] -喹唑啉 -6- }-1Η-吡咯 -2-羰基) -哌啶 -4-基] - 氨基甲酸叔丁酯  [1-(4-{4-[3-Chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazoline-6- }-1Η-pyrrole-2-carbonyl)-piperidin-4 -yl] - tert-butyl carbamate
将双 (2-氧代 -3-恶唑烷基)次磷酰氯 (191 mg, 0.75 mmol)溶于 10 mL无水二氯甲 烷中， 搅拌下加入三乙胺 (0.1 mL， 0.75 mmol)， 室温下搅拌 15分钟后， 依次加入 4-{4-[3-氯 -4-(3-氟- 氧基) -苯氨基] -喹唑啉 -6-基 }-1Η-吡咯 -2-甲酸 184g (244 mg, 0.5 mmol)和哌啶 -4-基-氨基甲酸叔丁酯 (100 mg, 0.5 mmol), 室温下搅拌 1小时反 应完毕。 将反应液在减压下浓缩， 残渣中加入 20 mL水， 用乙酸乙酯萃取 (50 niL X 3), 合并的有机相依次通过无水硫酸钠干燥， 过滤， 减压下浓缩， 得到的残留物 通过硅胶柱层析进一歩分离纯化（二氯甲烷： 甲醇 = 30 : 1)， 得到标题产物 [1-(4- {4-[3-氯 -4-(3-氟苄氧基) -苯氨基] -喹唑啉 -6-基}-1&吡咯 -2-羰基) -哌啶 -4-基] - 氨基甲酸叔丁酯 267a(225 mg， 黄色固体)， 产率： 67.2%。 The bis(2-oxo-3-oxazolidinyl)phosphoryl chloride (191 mg, 0.75 mmol) was dissolved in 10 mL of dry dichloromethane and triethylamine (0.1 mL, 0.75 mmol). After stirring at room temperature for 15 minutes, 4-{4-[3-chloro-4-(3-fluoro-oxy)-phenylamino]-quinazolin-6-yl}-1Η-pyrrole-2-carboxylic acid was sequentially added. 184g (244 mg, 0.5 mmol) and tert-butyl piperidin-4-yl-carbamate (100 mg, 0.5 mmol), stirred at room temperature for 1 h Should be completed. The reaction mixture was concentrated under reduced pressure. EtOAc was evaporated, evaporated, evaporated, evaporated. The product was purified by silica gel column chromatography (dichloromethane:methanol = 30:1) to give the title product [1-(4-{4-[3-chloro-4-(3-fluorobenzyloxy)) Phenylamino]-quinazolin-6-yl}-1&pyrrole-2-carbonyl)-piperidin-4-yl]-tert-butyl carbamate 267a (225 mg, yellow solid), yield: 67.2%.
MS m/z (ESI): 671 [M+ 1] MS m/z (ESI): 671 [M+ 1]
第二步  Second step
(4-氨基 -哌啶 -1-基) -(4-{4-[3-氯 -4-(3-氟苄氧基) -苯氨基] -喹唑啉 -6-基}-111-吡咯 -2- 基) -甲酮  (4-Amino-piperidin-1-yl)-(4-{4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazoline-6-yl}-111- Pyrrol-2-yl)-methanone
将 [1-(4-{4-[3-氯 -4-(3-氟苄氧基) -苯氨基] -喹唑啉 -6-基 }-m-吡咯 -2-羰基) -哌啶[1-( 4 -{4-[3-Chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazolin-6-yl}-m-pyrrole-2-carbonyl)-piperidine
-4-基] -氨基甲酸叔丁酯 267a (215 mg， 0.32 mmol)溶于 10 mL二氯甲烷中， 搅拌下 加入 10 mL三氟乙酸， 室温下搅拌 2小时反应完毕。 反应液在减压下浓缩， 加入 30 mL饱和碳酸氢钠溶液， 乙酸乙酯萃取 (50 mLX3)， 合并的有机相依次通过饱和 氯化钠溶液洗涤， 无水硫酸钠干燥， 过滤， 减压下浓缩， 得到的残留物通过碱性 氧化铝柱层析分离纯化 (二氯甲垸： 甲醇 =30: 1)， 得到本标题产物 (4-氨基 -哌啶 -1- 基 )-(4-{4-[3-氯 -4-(3-氟苄氧基) -苯氨基] -喹唑啉 -6-基 1H-吡咯 -2-基) -甲酮 267 (125 mg， 黄色固体)， 产率： 65.4%。 4--4-]-tert-butyl carbamate 267a (215 mg, 0.32 mmol) was dissolved in 10 mL of dichloromethane, and 10 mL of trifluoroacetic acid was added under stirring, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. Concentration and purification of the residue obtained by EtOAc (m.j. 4-[3-Chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazolin-6-yl 1H-pyrrol-2-yl)-methanone 267 (125 mg, yellow solid) Rate: 65.4%.
MS m/z (ESI): 571 [M+ 1] MS m/z (ESI): 571 [M+ 1]
1H NMR(400 MHz, DMSO- 6):511.78(s, 1H), 9.67(s, 1H), 8.63(s, 1H), 8.52(s, 1H), 8.18(s， 1H), 8.03(d, J=2.4Hz, 1H), 7.75(m, 2H) 7.60(m, 1H), 7.50(m, 1H)， 7.3 l(m, 3H), 7.19(m, 1H), 7.08(s, 1H), 5.27(s, 2H), 4.38(m, 2H), 3.59(m, 1H), 3.14(m, 2H), 1.84(m, 2H), 1.40(m, 2H) 实施例 268  1H NMR (400 MHz, DMSO-6): 511.78 (s, 1H), 9.67 (s, 1H), 8.63 (s, 1H), 8.52 (s, 1H), 8.18 (s, 1H), 8.03 (d, J=2.4Hz, 1H), 7.75(m, 2H) 7.60(m, 1H), 7.50(m, 1H), 7.3 l(m, 3H), 7.19(m, 1H), 7.08(s, 1H), 5.27(s, 2H), 4.38(m, 2H), 3.59(m, 1H), 3.14(m, 2H), 1.84(m, 2H), 1.40(m, 2H) Example 268
(3R)-l-「3-(3-i4-P-氯 -4-(3-氟苄氧基) -苯氨基 1-喹唑啉 -6-基 吡咯 -1-基) -2-羟基-丙 基 1-吡咯垸 -3-醇  (3R)-l-"3-(3-i4-P-chloro-4-(3-fluorobenzyloxy)-phenylamino-1-quinazolin-6-ylpyrrol-1-yl)-2-hydroxyl -propyl 1-pyrrole-3-ol
Figure imgf000279_0001
(R)-吡咯垸 -3-醇（30 mg, 0.34 mmol)溶解于 10 mL甲醇中， 搅拌下加入 [3- 氯 -4-(3-氟-苄基)-苯基] -[6-(1-环氧乙基甲基 -1H-吡咯 -3-基)-喹唑啉 -4-基] -胺 187a (100 mg, 0.2 mmol), 混合液加热回流 3小时后反应完毕。 反应液在减压下浓缩， 得到的残留物通过硅胶柱层析分离纯化 (二氯甲烷： 甲醇 = 10: 1)， 得到本标题产 物 (3R)-l-[3-(3-{4-[3-氯 -4-(3-氟苄氧基) -苯氨基] -喹唑啉 -6-基} -吡咯 -1-基) -2-羟基- 丙基] -吡咯烷 -3-醇 268 (85 mg， 黄色固体)， 产率： 43 %。
Figure imgf000279_0001
(R)-pyrrole-3-ol (30 mg, 0.34 mmol) was dissolved in 10 mL of methanol and [3-chloro-4-(3-fluoro-benzyl)-phenyl]-[6- (1-Epoxyethylmethyl-1H-pyrrol-3-yl)-quinazolin-4-yl]-amine 187a (100 mg, 0.2 mmol). The reaction mixture was concentrated under reduced pressure, and then purified, mjjjjjjjjjjjjjjjjjj [3-Chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazolin-6-yl}-pyrrol-1-yl)-2-hydroxy-propyl]-pyrrolidin-3-ol 268 (85 mg, yellow solid), Yield: 43%.
MS m/z (ESI): 588[M+ 1] MS m/z (ESI): 588 [M+ 1]
1H NMR(400 MHz , DMSO-d6): S10.026(s, 1H), 8.760(s, 1H), 8.491(s, 1H), 8.124 (s, 1H), 8.034(s, 1H), 7.863(s, 1H), 7.699(s, 1H), 7.510(s, 2H), 7.263(m, 3H), 6.874(s, 1H), 6.748(s, 1H), 5.267(s, 2H), 4.252(s, 1H), 3.981(m, 2H), 3.387(s, 2H), 2.642(s, 2H)， 2.008(s， 2H), 1.655 (s, 2H) 1 H NMR (400 MHz, DMSO-d6): S10.026 (s, 1H), 8.760 (s, 1H), 8.491 (s, 1H), 8.124 (s, 1H), 8.034 (s, 1H), 7.863 (s, 1H), 7.699(s, 1H), 7.510(s, 2H), 7.263(m, 3H), 6.874(s, 1H), 6.748(s, 1H), 5.267(s, 2H), 4.252( s, 1H), 3.981(m, 2H), 3.387(s, 2H), 2.642(s, 2H), 2.008(s, 2H), 1.655 (s, 2H)
实施例 269 Example 269
2-(3_{4-f3_氯— 4_( _氟-苄氧基) -苯氨基卜喹唑啉 -6_基 吡咯小基 N-G-P比咯烷小基- 2- (3_{4-f3_Chloro- 4 _(-fluoro-benzyloxy)-phenylaminobuquinazoline- 6 -ylpyrrole small group NGPpyrrolidine small group-
Figure imgf000280_0001
Figure imgf000280_0001
第一步  First step
2-氯 -N-(2-吡咯垸小基-乙基) -甲酰胺  2-chloro-N-(2-pyrrolidinyl-ethyl)-carboxamide
2-吡咯烷小基 -乙胺 (228 mg， 2 mmol)溶于 15 mL四氢呋喃中， 在丙酮-干冰浴 冷却下冷却至 -78°C ,搅拌下依次加入三乙胺 (0.83 mL, 6 mmol)和氯乙酰氯 (0.48 mL, 6 mmol), 混合液在 -78°C下搅拌 1小时后反应完毕。 将反应液在减压下浓缩， 得到 2-氯 -N-(2-吡咯垸 -1-基-乙基) -甲酰胺 310 (290 mg， 黄色固体)， 产物不经分离 直接进行下一歩反应。 MS m/z (ESI): 291 [M+ l] 2-Pyrrolidinyl-ethylamine (228 mg, 2 mmol) was dissolved in 15 mL of tetrahydrofuran, cooled to -78 ° C under ice-dry ice-cooling, and then triethylamine (0.83 mL, 6 mmol) And chloroacetyl chloride (0.48 mL, 6 mmol), the mixture was stirred at -78 ° C for 1 hour and the reaction was completed. The reaction mixture was concentrated under reduced pressure to give 2-chloro-N-(2-pyrrolidin-1-yl-ethyl)-carboxamide 310 (290 mg,yield yellow solid). . MS m/z (ESI): 291 [M+ l]
第二歩  Second
2-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基 吡咯 -1-基) -N-(2-吡咯垸 -1-基- 乙基) -乙酰胺  2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylpyrrol-1-yl)-N-(2-pyrrole -1-yl-ethyl)-acetamide
将 [3-氯 -4-(3-氟-节氧基) -苯基 ]-[6-(1Η-吡咯 -3-基) -喹唑啉 -4-基] -胺 42 (177 mg, [3-Chloro-4-(3-fluoro-p-ethoxy)-phenyl]-[6-(1Η-pyrrole-3-yl)-quinazolin-4-yl]-amine 42 (177 mg,
0.4 mmol)溶解于 10 mL干燥的 N，N-二甲基甲酰胺中，在冰浴条件下，冷却至 0°C， 加入氢化钠 (112 mg, 2.8 mmol),搅拌 30分钟后加入 2-氯 -N-(2-吡咯烷 -1-基-乙基) - 甲酰胺 310 (290 mg)， 室温下搅拌 1小时反应完毕。将反应液在减压下浓缩， 残渣 通过水洗涤，二氯甲烷萃取 (100 mLx3)，合并的有机相通过无水硫酸钠干燥，过滤， 减压下浓缩， 得到的残留物通过柱层析进一步分离纯化 (二氯甲烷： 甲醇 = 50: 1), 得到 2-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基]-喹唑啉 -6-基}-吡咯 -1-基) -N-(2-吡咯烷 小基-乙基) -乙酰胺 310 (45 mg， 黄色固体)， 产率： 18.8%。 0.4 mmol) was dissolved in 10 mL of dry N,N-dimethylformamide, cooled to 0 ° C under ice-cooling, sodium hydride (112 mg, 2.8 mmol), and stirred for 30 min. Chloro-N-(2-pyrrolidin-1-yl-ethyl)-carboxamide 310 (290 mg) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. EtOAc EtOAc m. Separation and purification (dichloromethane: methanol = 50: 1) to give 2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6- }}-pyrrol-1-yl)-N-(2-pyrrolidinyl-ethyl)-acetamide 310 (45 mg, yellow solid), Yield: 18.8%.
MS m/z (ESI): 599[M+ 1] MS m/z (ESI): 599 [M+ 1]
1H NMR(400 MHz , DMSO- 6): 59.722(s, 1H), 8.563(d, J=1.6Hz , 1H), 8.504(s, 1H), 8.051(s, 1H), 7.766(m, 1H), 7.713(d, J=8.8Hz, 1H), 7.474(m, 1H), 7.344(m, 3H), 7.190(m, 1H), 6.868(m, 2H), 6.687(s, 1H)， 6.633(s, 1H), 5.273(s, 2H), 4.622(s, 2H), 3.607(m, 2H), 3.243(m, 2H)， 2.191(s, 2H), 1.765(s, 2H), 1.679(s, 4H) 实施例 270  1H NMR (400 MHz, DMSO-6): 59.722 (s, 1H), 8.563 (d, J = 1.6 Hz, 1H), 8.504 (s, 1H), 8.051 (s, 1H), 7.766 (m, 1H) , 7.713(d, J=8.8Hz, 1H), 7.474(m, 1H), 7.344(m, 3H), 7.190(m, 1H), 6.868(m, 2H), 6.687(s, 1H), 6.633( s, 1H), 5.273(s, 2H), 4.622(s, 2H), 3.607(m, 2H), 3.243(m, 2H), 2.191(s, 2H), 1.765(s, 2H), 1.679(s , 4H) Example 270
(3-{4-「3-氯 -4-(3-氟-苄氧基) -苯氨基 1-喹唑啉 -6-基)-吡咯小基) -乙腈  (3-{4-"3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino-1-quinazoline-6-yl)-pyrroleyl)-acetonitrile
Figure imgf000281_0001
Figure imgf000281_0001
在 50 mL的烧瓶中，将 [3-氯 -4-(3-氟-节氧基) -苯基 ]-[6-(lH-吡咯 -3-基) -喹唑啉 -4- 基] -胺 42 (400 mg, 0.9 mmol)溶解于 10 mL干燥的 Ν,Ν-二甲基甲酰胺中， 在冰浴 条件下， 冷却至 0°C， 加入氢化钠 (60 mg， 1.5 mmol), 搅拌 30分钟后加入氯 -乙腈 (82 mg, 1.08 mmol), 室温下搅拌 1小时反应完毕。 反应液减压下浓缩， 得到的残 留物进一步通过柱层析分离纯化 (二氯甲烷：甲醇 =40: 1)，得到本标题产物 (3-{4-[3- 氯 _4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基 } 1比咯 -1-基) -乙腈 270 (70 mg, 淡黄色固 体)， 产率： 16 %。 [3-Chloro-4-(3-fluoro-p-ethoxy)-phenyl]-[6-(lH-pyrrol-3-yl)-quinazolin-4-yl] in a 50 mL flask -Amine 42 (400 mg, 0.9 mmol) was dissolved in 10 mL dry EtOAc EtOAc (EtOAc) After stirring for 30 minutes, chloro-acetonitrile (82 mg, 1.08 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjjj Fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl} 1pyrrol-1-yl)-acetonitrile 270 (70 mg, light yellow solid Body), Yield: 16%.
MS m/z (ESI): 484[M+] MS m/z (ESI): 484 [M+]
'H NMR(400 MHZ , DMSO- 6): δ9.67 (s, 1H), 8.5 (s, 2H), 8.0 (s, 2H), 7.7 (s, 1H), 7.69(m, 1H), 7.5(m, 2H), 7.36(m, 3H), 7.2(m, 1H), 6.93(m, 1H), 6.60(s, 1H), 5.34(s: 2H), 5.27(s, 2H) 实施例 271 'H NMR (400 MHZ, DMSO-6): δ 9.67 (s, 1H), 8.5 (s, 2H), 8.0 (s, 2H), 7.7 (s, 1H), 7.69 (m, 1H), 7.5 (m, 2H), 7.36 (m, 3H), 7.2 (m, 1H), 6.93 (m, 1H), 6.60 (s, 1H), 5.34 (s : 2H), 5.27 (s, 2H) Example 271
l-(3- -[3-氯 -4-(3-氟-苄氧基) -苯氨基 1-喹唑啉 -6-基 μ吡咯 -1-基) -3-ΙΪ2-羟基-乙基) - 甲基 -氨基 1-丙 -2-醇  1-(3--[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino-1-quinazolin-6-ylpyrrol-1-yl)-3-indole-2-hydroxy-ethyl ) - Methyl-amino 1-propan-2-ol
Figure imgf000282_0001
Figure imgf000282_0001
2-甲氨基 -乙醇（22.5 mg， 0.3 mmol, Aldrich)溶解于 10 mL甲醇中， 搅拌下加 入 [3-氯 -4-(3-氟-苄基) -苯基]- [6-(1-环氧乙基甲基 -1H-吡咯 -3-基) -喹唑啉 -4-基] -胺 187a (150 mg, 0.3 mmol), 混合液加热回流过夜。 反应液在减压下浓缩， 得到的残 留物通过硅胶柱层析分离纯化 (二氯甲烷： 甲醇 = 10: 1)， 得到 1-(3-{4-[3-氯 -4-(3- 氟-苄氧基) -苯氨基]—喹唑啉 -6-基 }-吡咯小基 )-3-[(2-羟基-乙基) -甲基-氨基] -丙 -2-醇 271(140 mg, 黄色固体)， 产率： 81.2%。 2-Methylamino-ethanol (22.5 mg, 0.3 mmol, Aldrich) was dissolved in 10 mL of methanol, and [3-chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1) was added with stirring. Epoxyethylmethyl-1H-pyrrol-3-yl)-quinazolin-4-yl]-amine 187a (150 mg, 0.3 mmol). The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified (jjjjjjjjjjj Fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-pyrroleyl)-3-[(2-hydroxy-ethyl)-methyl-amino]-propan- 2 -ol 271 ( 140 mg, yellow solid), Yield: 81.2%.
MS m/z (ESI): 576[M+ 1] MS m/z (ESI): 576 [M+ 1]
1H NMR(400 MHz , DMSO- d): 69.67 (s, 1H), 8.5 (s, 2H), 8.0 (s, 2H), 7.7 (s, 1H)， 7.69(m, 1H), 7.5(m, 2H), 7.36(m, 3H), 7.2(m, 1H), 6.93(m, 1H), 6.60(s， 1H), 5.27(s, 2H), 4.9(S, 1H), 4.44(m, 1H), 4.07(m， 1H), 3.87(m, 2H), 3.49(m, 2H), 2.49(m, 2H), 2.32(d, J 5.6Hz, 2H), 2.26(s, 3H) 实施例 272 1H NMR (400 MHz, DMSO-d): 69.67 (s, 1H), 8.5 (s, 2H), 8.0 (s, 2H), 7.7 (s, 1H), 7.69 (m, 1H), 7.5 (m, 2H), 7.36 (m, 3H), 7.2 (m, 1H), 6.93 (m, 1H), 6.60 (s, 1H), 5.27 (s, 2H), 4.9 (S, 1H), 4.44 (m, 1H) ), 4.07(m, 1H), 3.87(m, 2H), 3.49(m, 2H), 2.49(m, 2H), 2.32(d, J 5.6Hz, 2H), 2.26(s, 3H) Example 272
3-{4-「3-氯 -4-(3-氟 -苄氧基)-苯氨基 1-喹唑啉 -6-基 吡咯小基 )-3-(4-吗啉 -4-基-哌 啶 -1-基) -丙 -2-醇 3-{4-"3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino-1-quinazolin-6-ylpyrroleyl)-3-(4-morpholin-4-yl- Piperidin-1-yl)-propan-2-ol
Figure imgf000283_0001
第一步
Figure imgf000283_0001
first step
1_(3— {4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基} -吡咯 -1-基) -3-(4-吗啉 -4-基-哌 啶 -1-基) -丙 -2-醇 1_ (3 — {4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-pyrrol-1-yl)-3-(4-? Polin-4-yl-piperidin-1-yl)-propan-2-ol
4-(1-甲基-哌啶-4-基)-吗啉(54.8 1¾，0.32
Figure imgf000283_0002
1^^11)溶解于 10 mL甲醇中， 搅拌下加入 [3-氯 -4-(3-氟-苄基) -苯基]- [6-(1-环氧乙基甲基 -1H-吡咯 -3-基) -喹唑啉 -4-基] -胺 187a (160 mg， 0.32 mmol),混合液加热回流过夜。反应液在减压下浓缩， 得到的残留物通过硅胶柱层析分离纯化 (二氯甲烷： 甲醇 = 10: 1)， 得到本标题产 物 1-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基}-吡咯 -1-基) -3-(4-吗啉 -4-基- 哌啶 -1-基) -丙 -2-醇 272 (123 mg， 黄色固体)， 产率： 57.4%。 4-(1-methyl-piperidin-4-yl)-morpholine (54.8 13⁄4, 0.32
Figure imgf000283_0002
1^^11) Dissolved in 10 mL of methanol, and [3-chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-epoxyethylmethyl-1H-) was added with stirring. Pyrrol-3-yl)-quinazolin-4-yl]-amine 187a (160 mg, 0.32 mmol). The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjj (3-Fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-pyrrol-1-yl)-3-(4-morpholin-4-yl-piperidin-1-yl)- Propan-2-ol 272 (123 mg, yellow solid), Yield: 57.4%.
MS m/z (ESI): 671 [M+ 1] MS m/z (ESI): 671 [M+ 1]
1H NMR(400 MHz , DMSO-i 6): 59.67 (s, 1H), 8.5 (s, 2H), 8.0 (s， 2H), 7.7 (s, 1H), 7.69(m, 1H)， 7.5(m, 2H), 7.36(m, 3H), 7.2(m, 1H), 6.93(m, 1H), 6.60(s, 1H), 5.27(s, 2H), 4.9(s, 1H), 4.05(m, 1H), 3.89(m, 2H), 3.54(m, 4H), 2.88(m, 2H), 2.42(S, 4H), 2.2 l(t, J=4.8, 3H), 2.08(t, J=10.8, 1H), 1.95(t, J=10.4, 2H), 1.72(d, J=11.2, 2H), 1.42(m, 2H) 实施例 273  1H NMR (400 MHz, DMSO-i 6): 59.67 (s, 1H), 8.5 (s, 2H), 8.0 (s, 2H), 7.7 (s, 1H), 7.69 (m, 1H), 7.5 (m) , 2H), 7.36(m, 3H), 7.2(m, 1H), 6.93(m, 1H), 6.60(s, 1H), 5.27(s, 2H), 4.9(s, 1H), 4.05(m, 1H), 3.89(m, 2H), 3.54(m, 4H), 2.88(m, 2H), 2.42(S, 4H), 2.2 l(t, J=4.8, 3H), 2.08(t, J=10.8 , 1H), 1.95 (t, J = 10.4, 2H), 1.72 (d, J = 11.2, 2H), 1.42 (m, 2H) Example 273
Γ3-氯 -4-(3-氟-苄氧基) -苯基 1-{6-「1-(3-乙基-环氧丙垸 -3-基甲基) -lH-吡咯 -3-基 1-喹唑 啉 -4-基} -胺  Γ3-Chloro-4-(3-fluoro-benzyloxy)-phenyl 1-{6-"1-(3-ethyl-epoxypropion-3-ylmethyl)-lH-pyrrole-3- 1-quinazolin-4-yl}-amine
Figure imgf000283_0003
Figure imgf000283_0003
Figure imgf000284_0001
第一步
Figure imgf000284_0001
first step
甲磺酸 (3-乙基-环氧丙烷 -3-基)甲酯  Methanesulfonic acid (3-ethyl-epoxypropan-3-yl)methyl ester
将 (3-乙基-环氧丙烷 -3-基) -甲醇 (580 mg， 5 mmol)溶于 15 mL二氯甲垸中， 搅 拌下加入三乙胺 (758 mg， 7.6 mmol), 将反应液在冰浴下冷却至 0°C， 逐渐加入甲 磺酰氯 (687 mg， 6 mmol), 室温下搅拌 30分钟， 反应完毕。 将反应液在减压下浓 缩， 加入 20 mL水， 乙酸乙酯萃取 (40 mLX 3)， 合并的有机相依次通过饱和氯化 钠溶液洗涤， 无水硫酸钠干燥， 过滤， 减压下浓缩， 得到的残留物通过硅胶柱层 析进一步分离纯化 (二氯甲垸： 甲醇 =40: 1)， 得到甲磺酸 (3-乙基-环氧丙烷 -3-基) 甲酯 273a (945 mg， 无色油状液体)， 产率： 97.4%。  (3-Ethyl-epoxypropan-3-yl)-methanol (580 mg, 5 mmol) was dissolved in 15 mL of dichloromethane, and triethylamine (758 mg, 7.6 mmol) was added with stirring. The solution was cooled to 0 ° C in an ice-bath, and then methanesulfonyl chloride (. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc)EtOAc. The residue obtained was further separated and purified by silica gel column chromatography (dichloromethane:methanol = 40:1) to afford (3-ethyl- propylene oxide-3-yl) methyl ester 273a (945 mg, Colorless oily liquid), Yield: 97.4%.
MS m/z (ESI): 195[M+ 1] MS m/z (ESI): 195 [M+ 1]
第二歩  Second
[3—氯 _4-(3-氟-苄氧基) -苯基 ]-{6-[1-(3-乙基-环氧丙烷 -3-基甲基) -1H-吡咯 -3-基] -喹唑 啉 -4-基} -胺 [ 3 -Chloro- 4- (3-fluoro-benzyloxy)-phenyl]-{6-[1-(3-ethyl-epoxypropan-3-ylmethyl)-1H-pyrrole-3- -quinazolin-4-yl}-amine
在 50 mL的烧瓶中，将 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-[6-(1Η-吡咯 -3-基) -喹唑啉 -4- 基] -胺 42 (223 mg， 0.5 mmol)溶解于 10 mL干燥的 Ν,Ν-二甲基甲酰胺中， 在冰浴 条件下， 冷却至 0Ό， 加入氢化钠 (60 mg， 2.5 mmol), 搅拌 30分钟后加入甲磺酸 (3-乙基-环氧丙烷 -3-基)甲酯 273a (145 mg， 0.75 mmol), 室温下搅拌 1小时反应完 毕。 反应液加入 20 mL水， 乙酸乙酯萃取 (40 mLX 3)， 合并的有机相依次通过饱 和氯化钠溶液洗涤， 无水硫酸钠干燥， 过滤， 减压下浓缩， 得到的残留物通过硅 胶柱层析进一步分离纯化 (二氯甲烷： 甲醇 =40: 1)， 得到本标题产物 [3-氯 -4-(3- 氟-苄氧基) -苯基 ]-{6-[1-(3-乙基-环氧丙烷 -3-基甲基) -1H-吡咯 -3-基] -喹唑啉 -4-基 胺 273 (125 mg， 淡黄色固体)， 产率： 46.1 %。  [3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1Η-pyrrol-3-yl)-quinazolin-4-yl] in a 50 mL flask -Amine 42 (223 mg, 0.5 mmol) was dissolved in 10 mL dry EtOAc EtOAc (EtOAc) After a minute, (3-ethyl-epoxypropan-3-yl)methyl sulfonate 273a (145 mg, 0.75 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water (20 mL), EtOAc (EtOAc (EtOAc) Further separation and purification by chromatography (dichloromethane:methanol = 40:1) gave the title product [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-{6-[1-(3 -ethyl-epoxypropan-3-ylmethyl)-1H-pyrrol-3-yl]-quinazolin-4-ylamine 273 (125 mg, pale yellow solid), yield: 46.1.
MS m/z (ESI): 543 [M+ 1] MS m/z (ESI): 543 [M+ 1]
1H NMR(400 MHz， DMSO-^d):5-9.68(s, 1H), 8.53(s, 1H), 8.50(s, 1H), 8.06(d, J=8.8Hz, 1H), 8.02(m, 1H), 7.75(m, 2H), 7.47(m, 1H), 7.41(m, 1H), 7.3 l(m, 3H), 7.19(m, 1H), 6.91(s, 1H)， 6.70(s, 1H), 5.27(s， 2H), 4.55(d， J=6.0Hz, 2H), 4.3 l(d, J-6.0Hz, 2H), 4.20(s, 2H), 1.54(m, 2H), 0.96 (t, J=7.2Hz, 3H) 实施例 274 </ RTI><RTIgt; , 1H), 7.75(m, 2H), 7.47(m, 1H), 7.41(m, 1H), 7.3 l(m, 3H), 7.19(m, 1H), 6.91(s, 1H), 6.70(s , 1H), 5.27(s, 2H), 4.55(d, J=6.0Hz, 2H), 4.3 l(d, J-6.0Hz, 2H), 4.20(s, 2H), 1.54(m, 2H), 0.96 (t, J=7.2Hz, 3H) Example 274
μθ- -Ρ—氯— 4_(3_氟-苄氧基 苯氨基 喹唑啉 -6_基—吡咯小基 3_ (RV3-二甲基氨 基-吡咯垸小基) -丙 -2-醇 Θθ- -Ρ-chloro- 4 _ (3 _fluoro-benzyloxyphenylaminoquinazolin-6-yl-pyrrole small 3 _ (RV3-dimethylamino-pyrrolidinyl)-propan-2- alcohol
Figure imgf000285_0001
Figure imgf000285_0001
(R)-N,N-二甲基吡咯烷 -3-胺（52 mg， 0.46 mmol)溶解于 30 mL甲醇中， 搅拌 下加入 [3-氯 -4-(3-氟-苄基) -苯基 ]- [6-(1-环氧乙基甲基 -1H-吡咯 -3-基)-喹唑啉 -4- 基] -胺 187a (152 mg， 0.3 mmol), 混合液加热回流过夜。 反应液在减压下浓缩， 得 - . 到的残留物通过硅胶柱层析分离纯化 (二氯甲烷： 甲醇 = 10: 1), 得到本标题产物0 1-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基]-喹唑啉 -6-基}-吡咯 -1-基) -3-((R)-3-二甲基氨 基-吡咯烷小基) -丙 -2-醇 274 (80 mg， 黄色固体)， 产率： 54.3 %。  (R)-N,N-Dimethylpyrrolidin-3-amine (52 mg, 0.46 mmol) was dissolved in 30 mL of methanol and [3-chloro-4-(3-fluoro-benzyl)- Phenyl]-[6-(1-epoxyethylmethyl-1H-pyrrol-3-yl)-quinazolin-4-yl]-amine 187a (152 mg, 0.3 mmol). . The reaction mixture was concentrated under reduced pressure to dryness crystall Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-pyrrol-1-yl)-3-((R)-3-dimethylamino-pyrrolidine Small base) - propan-2-ol 274 (80 mg, yellow solid), yield: 54.3 %.
MS m/z (ESI): 616[M+ 1]  MS m/z (ESI): 616 [M+ 1]
1H NMR(400 MHz , DMSO-ifd): 59.69(s, 1H)， 8.54(s, 1H), 8.50(s, 1H), 8.04(m, 2H), 7.75(m, 2H), 7.47(m, 1H), 7.40(m, 1H), 7.30(m, 3H), 7.19(m, 1H)， 6.88(s, 1H), 6.68(s,5 1H), 5.27(s, 2H), 5.09(br, 1H), 3.82(m, 3H), 2.67 (m, 4H), 2.5 l(m, 3H), 2.16(s, 6H), 1.87(m, 1H), 1.65(m, 1H) 实施例 275  1H NMR (400 MHz, DMSO-ifd): 59.69 (s, 1H), 8.54 (s, 1H), 8.50 (s, 1H), 8.04 (m, 2H), 7.75 (m, 2H), 7.47 (m, 1H), 7.40(m, 1H), 7.30(m, 3H), 7.19(m, 1H), 6.88(s, 1H), 6.68(s,5 1H), 5.27(s, 2H), 5.09(br, 1H), 3.82 (m, 3H), 2.67 (m, 4H), 2.5 l (m, 3H), 2.16 (s, 6H), 1.87 (m, 1H), 1.65 (m, 1H) Example 275
2-(344-「3-氯 -4-(3-氟-苄氧基 苯氨基卜喹唑啉 -6-基 吡咯 -1-基 N-α-环丙基 -哌啶0 -4-基) -乙酰胺  2-(344-"3-Chloro-4-(3-fluoro-benzyloxyphenylaminobuquinazolin-6-ylpyrrolidin-1-yl N-α-cyclopropyl-piperidine 0-4-yl) ) -acetamide
Figure imgf000285_0002
Figure imgf000285_0002
275 275
Figure imgf000286_0001
第一步
Figure imgf000286_0001
first step
(1 -环丙基 -哌啶 -4-基) -甲酸叔丁酯  (1-cyclopropyl-piperidin-4-yl)-carboxylic acid tert-butyl ester
将哌啶 _4_基—甲酸叔丁酯 (l.2 g， 5 mmol)溶于 40 mL甲醇中，搅泮下依次加 入 (1-乙氧基小甲基-丙氧基) -三甲基硅烷 (1.52 mL， 7.5 mmol), 氰基硼氢化钠 (1.26 g， 20 mmol)和乙酸 (2.86 mL, 50 mmol), 混合液加热回流反应过夜。 将反应液在 减压下浓缩， 得到的残渣中加入 20 mL乙酸乙酯， 搅拌下加入饱和氢氧化钠溶液， 调节 pH为碱性，用乙酸乙酯萃取 (50 mLX 3)，合并的有机相通过无水硫酸钠干燥， 过滤， 减压下浓缩， 得到的残留物用硅胶柱层析分离纯化 (二氯甲烷： 甲醇 =50. 1),得到 (1-环丙基 -哌啶 -4-基) -甲酸叔丁酯 275a (1.12 g， 白色固体)，产率： 80.4%。 MS m/z (ESI): 241 [M+ 1] _ _ Piperidine 4-yl - carboxylic acid tert-butyl ester (. L 2 g, 5 mmol ) was dissolved in 40 mL of methanol, were added under stirring Pan (1-ethoxy-methyl small - propoxy) - trimethoxysilane The silane (1.52 mL, 7.5 mmol), sodium cyanoborohydride (1.26 g, 20 mmol) and acetic acid (2.86 mL, 50 mmol). The reaction mixture was concentrated under reduced pressure. EtOAc was evaporated. EtOAc EtOAc EtOAc. The residue was dried over anhydrous sodium sulfate (MgSO4). Base) - tert-butyl formate 275a (1.12 g, white solid), yield: 80.4%. MS m/z (ESI): 241 [M+ 1]
第二歩  Second
1-环丙基 -哌啶 -4-基胺  1-cyclopropyl-piperidin-4-ylamine
将 (1-环丙基 -哌啶 -4-基) -甲酸叔丁酯 275a (1 g, 4.16 mmol)溶于 50 mL二氯甲 垸中， 搅拌下加入 10 mL三氟乙酸， 室温下搅拌 2小时反应完毕。 将反应液在减 压下浓缩， 得到的残渣加入 5 mL甲醇， 加入无水碳酸钾， 调节 pH=8， 旋干， 得 到的残留物用硅胶柱层析分离纯化 (二氯甲垸： 甲醇 =20: 1), 得到 1-环丙基 -哌啶 -4-基胺 275b (1.317 g， 白色固体)， 产率： 80.4%。  (1-Cyclopropyl-piperidin-4-yl)-carboxylic acid tert-butyl ester 275a (1 g, 4.16 mmol) was dissolved in 50 mL of dichloromethane, and 10 mL of trifluoroacetic acid was added with stirring, stirring at room temperature The reaction was completed in 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was evaporated to ethylamine (5 mL), EtOAc (EtOAc) 20: 1), 1-cyclopropyl-piperidin-4-ylamine 275b (1.317 g, white solid).
MS m/z (ESI): 141 [M+ 1] MS m/z (ESI): 141 [M+ 1]
第三步  third step
1—氯 _N-(1_环丙基 -哌啶—4-基)-乙酰胺 1-chloro- N- (1_cyclopropyl-piperidine-4-yl)-acetamide
将 1-环丙基 -哌啶 -4-基胺 275b (350 mg, 2.5 mmol)溶于 10 mL四氢呋喃中， 溶液在丙酮-干冰浴下冷却至 -78°C，搅拌下加入 0.7 mL三乙胺和氯乙酰氯 (339 mg, 3 mmol), 维持此温度搅拌 40分钟反应完毕。 反应液中加入 20 mL四氢呋喃， 有 白色固体析出， 过滤， 滤液在减压下浓缩， 得到的残留物通过硅胶柱层析分离纯 化 (二氯甲烷： 甲醇 = 10: 1), 得到 1-氯 -N-(l-环丙基 -哌啶 -4-基) -乙酰胺 275c (297 mg, 白色固体)， 产率： 51 %。 MS m/z (ESI): 217[M+ 1] 1-Cyclopropyl-piperidin-4-ylamine 275b (350 mg, 2.5 mmol) was dissolved in 10 mL of tetrahydrofuran. The solution was cooled to -78 ° C in acetone-dry ice bath and 0.7 mL of triethyl The amine and chloroacetyl chloride (339 mg, 3 mmol) were stirred at this temperature for 40 minutes. 20 mL of tetrahydrofuran was added to the reaction mixture, and a white solid was precipitated, which was filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (dichloromethane: methanol = 10:1) to give 1-chloro- N-(l-Cyclopropyl-piperidin-4-yl)-acetamide 275c (297 mg, white solid). MS m/z (ESI): 217 [M+ 1]
第四歩  Fourth
2-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基 吡咯 -1-基) -N-(l-环丙基 -哌啶  2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylpyrrol-1-yl)-N-(l-cyclopropane Base-piperidine
-4-基) -乙酰胺  -4-yl)-acetamide
在 50 mL的烧瓶中，将 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-[6-(1Η-吡咯 -3-基) -喹唑啉 -4- 基] -胺 42 (338 mg, 0.76 mmol)溶于 10 mL干燥的 Ν,Ν-二甲基甲酰胺中， 在冰浴 条件下，冷却至 0°C，加入氢化钠 (91 mg, 3.8 mmol),搅拌 30分钟后加入 1-氯 -N-(l- 环丙基 -哌啶 -4-基) -乙酰胺 275c (297 mg, 0.91 mmol),室温下搅拌 1小时反应完毕。 反应液加入 50 mL水， 用乙酸乙酯萃取 (50 mLX 3)， 合并的有机相通过无水硫酸 钠干燥， 过滤， 减压下浓縮， 得到的残留物通过硅胶柱层析进一步分离纯化 (二氯 甲烷： 甲醇 =20: 1)， 得到本标题产物 2-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑 啉 -6-基 吡咯 -1-基) -N-(l-环丙基 -哌啶 -4-基)-乙酰胺 275 (397 mg,黄色固体)，产率： 46.3 %。  [3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1Η-pyrrol-3-yl)-quinazolin-4-yl] in a 50 mL flask -Amine 42 (338 mg, 0.76 mmol) was dissolved in 10 mL dry EtOAc EtOAc (EtOAc) After stirring for 30 minutes, 1-chloro-N-(l-cyclopropyl-piperidin-4-yl)-acetamide 275c (297 mg, 0.91 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was added to 50 mL of EtOAc (EtOAc)EtOAc. Dichloromethane: methanol = 20: 1) gave the title product 2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline-6- Pyrrrol-1-yl)-N-(l-cyclopropyl-piperidin-4-yl)-acetamide 275 (397 mg, yellow solid), yield: 46.
MS m/z (ESI): 625[M+ 1]  MS m/z (ESI): 625 [M+ 1]
1H NMR(400 MHz , DMSO-ί/ό): S9.69(s, 1H), 8.54(s, 1H), 8.50(s, 1H), 8.04(m, 2H), 7.75(m, 2H), 7.47(m, 1H), 7.40(m, 1H), 7.30(m, 3H), 7.19(m, 1H), 6.88(s, 1H), 6.68(s, 1H), 5.27(s, 2H), 4.59(s, 2H), 3.80(m, 1H), 3.57(m， 2H), 2.88(m, 2H), 2.25(m, 2H)， 1.73(m, 2H), 1.58(br, 1H), 0.39(m, 2H), 0.27(br, 2H) 1H NMR (400 MHz, DMSO-ί/ό): S9.69 (s, 1H), 8.54 (s, 1H), 8.50 (s, 1H), 8.04 (m, 2H), 7.75 (m, 2H), 7.47(m, 1H), 7.40(m, 1H), 7.30(m, 3H), 7.19(m, 1H), 6.88(s, 1H), 6.68(s, 1H), 5.27(s, 2H), 4.59 (s, 2H), 3.80(m, 1H), 3.57(m, 2H), 2.88(m, 2H), 2.25(m, 2H), 1.73(m, 2H), 1.58(br, 1H), 0.39( m, 2H), 0.27(br, 2H)
实施例 276 Example 276
1-(3-{4-「3-氯-4-(3-氟-苄氧基)-苯氨基1-喹唑啉-6-基}-吡咯-1-基)-3-(1,1-二-1 *6*-噻 1- (3 -{4-"3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino-1-quinazolin-6-yl}-pyrrol-1-yl)-3-(1, 1-two-1 *6*-thiazide
Figure imgf000287_0001
硫吗啉 1,1-二氧化物（54 mg， 0.4 mmol, Aldrich)溶解于 10 mL甲醇中， 搅拌 下加入 [3-氯 -4-(3-氟-苄基) -苯基] - [6-(1-环氧乙基甲基 -1H-吡咯 -3-基) -喹唑啉 -4- 基] -胺 187a (200 mg， 0.4 mmol), 混合液加热回流过夜。 反应液在减压下浓缩， 得 到的残留物通过硅胶柱层析分离纯化 (二氯甲烷： 甲醇 = 10: 1), 得到标题产物 1-(3_{4_[3_氯 _4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基 吡咯 -1-基) -3-(1,1-二 -1λ*6*-噻 吗啉 -4-基) -丙 -2-醇 276 (20 mg， 黄色固体)， 产率： 7.9%。
Figure imgf000287_0001
Thiomorpholine 1,1-dioxide (54 mg, 0.4 mmol, Aldrich) was dissolved in 10 mL of methanol and [3-chloro-4-(3-fluoro-benzyl)-phenyl]-[ 6-(1-Epoxyethylmethyl-1H-pyrrol-3-yl)-quinazolin-4-yl]-amine 187a (200 mg, 0.4 mmol). The reaction solution is concentrated under reduced pressure to give The residue obtained was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to give the title product 1-( 3 _{ 4 _[ 3 _ chloro- 4-(3-fluoro-benzyloxy) -phenylamino]-quinazolin-6-ylpyrrol-1-yl)-3-(1,1-di-1λ*6*-thiamorpholin-4-yl)-propan-2-ol 276 (20 Mg, yellow solid), Yield: 7.9%.
MS m/z (ESI): 636[M+ 1] MS m/z (ESI): 636 [M+ 1]
1H NMR(400 MHz， DMSO-i/6): 59.67 (s, IH), 8.5 (s, 2H), 8.0 (s, 2H), 7.7 (s, IH), 7.69(m, IH), 7.5(m, 2H), 7.36(m, 3H), 7.2(m, IH), 6.93(m, 1H)， 6.60(s, IH), 5.27(s, 2H), 5.05(s, IH), 4.06(d, J=11.2, IH), 3.89(m, 2H), 3.13(s, 4H), 2.96(s, 4H), 2.43(d, J=4.8, 2H) 实施例 277  </ RTI> <RTIgt; m, 2H), 7.36(m, 3H), 7.2(m, IH), 6.93(m, 1H), 6.60(s, IH), 5.27(s, 2H), 5.05(s, IH), 4.06(d , J = 11.2, IH), 3.89 (m, 2H), 3.13 (s, 4H), 2.96 (s, 4H), 2.43 (d, J = 4.8, 2H) Example 277
1-(3-Μ-Γ3-氯 -4-(3-氟-苄氧基 苯氨基 1-喹唑啉 -6-基 吡咯小基 )-3-((RV3-氟 -P比咯烷  1-(3-Μ-Γ3-chloro-4-(3-fluoro-benzyloxyphenylamino-1-quinazolin-6-ylpyrroleyl)-3-((RV3-fluoro-P-rrolidine)
Figure imgf000288_0001
(R)-3-氟吡咯烷盐酸盐（50.4 mg, 0.4 mmol)溶解于 10 mL甲醇中， 依次搅拌 下加入 2 mL三乙胺和 [3-氯 -4-(3-氟-苄基) -苯基 ]-[6-(1-环氧乙基甲基 -1H-吡咯 -3- 基) -喹唑啉 -4-基] -胺 187a (200 mg， 0.4mmol), 混合液加热回流 2小时后反应完毕。 反应液在减压下浓缩， 得到的残留物通过硅胶柱层析分离纯化 (二氯甲烷： 甲醇 = 10： 1)， 得到本标题产物 1-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基}-吡咯 小基) -3-((R)-3-氟-吡咯焼小基) -丙 -2-醇 277 (110 mg， 黄色固体)， 产率： 46.7%。 MS m/z (ESI): 590[M+ 1]
Figure imgf000288_0001
(R)-3-fluoropyrrolidine hydrochloride (50.4 mg, 0.4 mmol) was dissolved in 10 mL of methanol, and then added 2 mL of triethylamine and [3-chloro-4-(3-fluoro-benzyl) with stirring -Phenyl]-[6-(1-epoxyethylmethyl-1H-pyrrol-3-yl)-quinazolin-4-yl]-amine 187a (200 mg, 0.4 mmol), heated in a mixture The reaction was completed after refluxing for 2 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjj (3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-pyrroleyl)-3-((R)-3-fluoro-pyrroleinyl)-propan-2-ol 277 (110 mg, yellow solid), Yield: 46.7%. MS m/z (ESI): 590 [M+ 1]
1H NMR(400 MHz , DMSO-c¾)： δ9·67 (s, IH), 8.5 (s， 2H)， 8.0 (s, 2H), 7.7 (s, IH), 7.69(m, IH), 7.5(m, 2H), 7.36(m, 3H), 7.2(m, IH), 6.93(m, IH), 6.60(s, IH), 5.27(s, 2H)， 5.05 (s， IH), 4.06(m, 1H)， 3.89(m, 2H), 2.88(m, 2H), 2.42(m, 3H)， 2.22(m, IH), 1.89(m, IH), 1.23(m, 2H)  1H NMR (400 MHz, DMSO-c3⁄4): δ9·67 (s, IH), 8.5 (s, 2H), 8.0 (s, 2H), 7.7 (s, IH), 7.69 (m, IH), 7.5 ( m, 2H), 7.36 (m, 3H), 7.2 (m, IH), 6.93 (m, IH), 6.60 (s, IH), 5.27 (s, 2H), 5.05 (s, IH), 4.06 (m) , 1H), 3.89 (m, 2H), 2.88 (m, 2H), 2.42 (m, 3H), 2.22 (m, IH), 1.89 (m, IH), 1.23 (m, 2H)
实施例 278 1-(3-ί4-「3-氯 -4-(3-氟-苄氧基) -苯氨基卜喹唑啉 -6-基 吡咯小基 )-3-噻唑烷 -3-基-丙 Example 278 1-(3-ί4-"3-chloro-4-(3-fluoro-benzyloxy)-phenylaminobuquinazolin-6-ylpyrroleyl)-3-thiazol-3-yl-propan
-2-醇  -2-ol
Figure imgf000289_0001
Figure imgf000289_0001
在 100 mL茄形瓶中， 将 [1-(3-氟-苄基) -1H-吲唑 -5-基] -[6-(1-环氧乙基甲基 -1H- 吡咯 -3-基)-喹唑啉 -4-基] -胺 178a (200 mg, 0.41 mmol)溶解于 25 mL甲醇中，搅拌 下加入噻唑烷 (43 mg， 0.48 mmol),反应液加热回流过夜。将反应液在减压下浓缩， 得到的残留物通过硅胶柱层析分离纯化 (二氯甲烷： 甲醇 =60: 1)， 得到本标题产 物 1-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基]-喹唑啉 -6-基} -吡咯 -1-基) -3-噻唑烷 -3-基- 丙 -2-醇 278 (152 mg, 黄色固体） ， 产率： 54%。  [1-(3-Fluoro-benzyl)-1H-indazol-5-yl]-[6-(1-epoxyethylmethyl-1H-pyrrole-3- in a 100 mL eggplant-shaped flask The hydrazinolin-4-yl]-amine 178a (200 mg, 0.41 mmol) was dissolved in 25 mL MeOH. The reaction mixture was concentrated under reduced pressure and purified purified m.jjjjjjjjjjj -(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-pyrrol-1-yl)-3-thiazolidin-3-yl-propan-2-ol 278 (152 mg, Yellow solid), Yield: 54%.
MS m/z (ESI): 590[M+ 1] MS m/z (ESI): 590 [M+ 1]
1H NMR(400 MHz, DMSO-c 6): 59.69(s, 1H), 8.54(s, 1H), 8.50(s, 1H), 8.04(m, 2H), 7.75(m, 2H)， 7.47(m, 1H), 7.40(m， 1H), 7.30(m, 3H), 7.19(m, 1H), 6.88(s, 1H), 6.68(s, 1H), 5.27(s, 2H), 5.15(s, 1H), 4.13(m, 3H), 3.89(m, 2H)， 3.05(m, 2H), 2.79(m, 2H), 2.27(m, 2H) 实施例 279  1H NMR (400 MHz, DMSO-c 6): 59.69 (s, 1H), 8.54 (s, 1H), 8.50 (s, 1H), 8.04 (m, 2H), 7.75 (m, 2H), 7.47 (m) , 1H), 7.40(m, 1H), 7.30(m, 3H), 7.19(m, 1H), 6.88(s, 1H), 6.68(s, 1H), 5.27(s, 2H), 5.15(s, 1H), 4.13(m, 3H), 3.89(m, 2H), 3.05(m, 2H), 2.79(m, 2H), 2.27(m, 2H) Example 279
「3-氯 -4-(3-氟- 氧基) -苯基 1-(6-{1-「2-(4-环丙基 -哌嗪小基) -乙基 "l-m-吡咯 -3-基 }-喹 唑啉 _4-基) -胺  "3-Chloro-4-(3-fluoro-oxy)-phenyl 1-(6-{1-"2-(4-cyclopropyl-piperazine small)-ethyl "lm-pyrrole-3" -yl}-quinazoline-4-yl)-amine
Figure imgf000289_0002
Figure imgf000290_0001
将 2-(3-{4-[3-氯 -4-(3-氟-节氧基) -苯氨基]-喹唑啉 -6-基}-吡咯 -1-基) -l-(4-环丙基 -哌嗪 -1-基) -乙酮 265 (50 mg， 0.082 mmol)溶于 10 mL四氢呋喃中， 搅拌下加入氢 化铝锂 (31.4 mg， 0.82 mmol), 室温下搅拌过夜。 将反应液在减压下浓缩， 得到的 残留物通过硅胶柱层析分离纯化 (二氯甲烷： 甲醇 =20: 1), 得到本标题产物 [3-氯 -4-(3-氟- 氧基) -苯基 ]-(6-{1-[2-(4-环丙基 -哌嗪 -1-基) -乙基] -1H-吡咯 -3-基}-喹唑啉 -4-基) -胺 279 (48 mg， 黄色固体） ， 产率： 97.9%。
Figure imgf000289_0002
Figure imgf000290_0001
2-(3-{4-[3-Chloro-4-(3-fluoro-pethoxy)-phenylamino]-quinazolin-6-yl}-pyrrol-1-yl)-l-(4 -cyclopropyl-piperazin-l-yl)-ethanone 265 (50 mg, 0.082 mmol) was dissolved in 10 mL of THF. EtOAc (3. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjj -phenyl]-(6-{1-[2-(4-cyclopropyl-piperazin-1-yl)-ethyl]-1H-pyrrol-3-yl}-quinazolin-4-yl - Amine 279 (48 mg, yellow solid), Yield: 97.9%.
MS m/z (ESI): 597[M+ 1] MS m/z (ESI): 597 [M+ 1]
1H NMR(400 MHz, DMSO-t¾): 59.69(s, 1H), 8.54(s， 1H), 8.50(s, 1H), 8,04(m, 2H), 7.75(m, 2H), 7.47(m, 1H), 7.40(m, 1H), 7.30(ra, 3H), 7.19(m， 1H)， 6.88(s, 1H), 6.68(s, 1H), 5.27(s, 2H), 4.05(m, 2H), 2.67(m, 2H), 2.54(br, 4H), 2A2(br, 4H), 1.59(br, 1H), 0.38(m, 2H), 0.27(m, 2H)  </ RTI> <RTIgt; m, 1H), 7.40(m, 1H), 7.30(ra, 3H), 7.19(m, 1H), 6.88(s, 1H), 6.68(s, 1H), 5.27(s, 2H), 4.05(m , 2H), 2.67(m, 2H), 2.54(br, 4H), 2A2(br, 4H), 1.59(br, 1H), 0.38(m, 2H), 0.27(m, 2H)
实施例 280  Example 280
1-Γ3-(3-ί4-「3-氯 -4-(3-氟苄氧基) -苯氨基 1-喹唑啉 -6-基 吡咯 -1-基 2-羟基-丙基 哌 啶 4-甲酰胺  1-Γ3-(3-ί4-"3-Chloro-4-(3-fluorobenzyloxy)-phenylamino-1-quinazolin-6-ylpyrrolidin-1-yl 2-hydroxy-propylpiperidine 4 -formamide
Figure imgf000290_0002
Figure imgf000290_0002
哌啶 -4-甲酰胺（80 mg， 0.63 mmol)溶解于 20 mL甲醇中， 搅拌下加入 [3-氯 -4-(3-氟-苄基) -苯基 ]-[6-(1-环氧乙基甲基 -1H-吡咯 -3-基) -喹唑啉 -4-基] -胺 187a (260 mg, 0.52 mmol), 混合液加热回流过夜。 反应液在减压下浓缩， 得到的残留物通 过硅胶柱层析分离纯化 (二氯甲垸： 甲醇 =5: 1), 得到本标题产物 1-[3-(3-{4-[3-氯 -4-(3-氟苄氧基) -苯氨基] -喹唑啉 -6-基 吡咯 -1-基) -2-羟基-丙基] -哌啶 -4-甲酰胺 280 (222 mg, 黄色固体)， 产率： 67.9%。  Piperidine-4-carboxamide (80 mg, 0.63 mmol) was dissolved in 20 mL of methanol and [3-chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1- Epoxyethylmethyl-1H-pyrrol-3-yl)-quinazolin-4-yl]-amine 187a (260 mg, 0.52 mmol). The reaction mixture was concentrated under reduced pressure, and the residue was purified mjjjjjjjjjjj Chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazolin-6-ylpyrrol-1-yl)-2-hydroxy-propyl]-piperidine-4-carboxamide 280 (222 mg , yellow solid), Yield: 67.9%.
MS m/z (ESI): 629[M+] Ή NMR(400 MHz , DMSO- 6):59.72(s, IH), 8.56(s, 1H)， 8.55(s， IH), 8.05(m, 2H)， 7.78(d, J-6Hz, IH), 7.69(d, J=6.8Hz, IH), 7.5 l(m, IH), 7.41 (s, IH), 7.3 l(m, 3H), 7.2 l(m, 2H), 6.88(m, IH), 6.65(m， 2H)， 5.27(s, 2H), A.9\(br, IH), 4.08(m, IH), 3.94(6/'， IH), 3.85(m, IH), 2.91 (m, 2H), 2.24(br, 2H), 1.98(m, 3H), 1.63(m, 4H) MS m/z (ESI): 629 [M + ] NMR (400 MHz, DMSO-6): 59.72 (s, IH), 8.56 (s, 1H), 8.55 (s, IH), 8.05 (m, 2H), 7.78 (d, J-6Hz, IH), 7.69(d, J=6.8Hz, IH), 7.5 l(m, IH), 7.41 (s, IH), 7.3 l(m, 3H), 7.2 l(m, 2H), 6.88(m, IH), 6.65(m, 2H), 5.27(s, 2H), A.9\(br, IH), 4.08(m, IH), 3.94(6/', IH), 3.85(m, IH), 2.91 (m , 2H), 2.24(br, 2H), 1.98(m, 3H), 1.63(m, 4H)
■ 实施例 281 ■ Example 281
l-((3S，5R)-3,5-二甲基 -哌嗪 -1-基) -3-β- -Γ 3-氟-苄基) -IH-吲唑 -5-基氨基 喹唑啉 L-((3S,5R)-3,5-Dimethyl-piperazin-1-yl)-3-β--indole 3-fluoro-benzyl)-IH-indazole-5-ylaminoquinazole Porphyrin
-6-基 }-吡咯 -1-基 V丙 -2-醇  -6-yl}-pyrrole-1-yl-V-propan-2-ol
Figure imgf000291_0001
在 100 mL茄形瓶中， 将 [1-(3-氟-苄基) -1H-吲唑 -5-基] -[6-(1-环氧乙基甲基 -1H- 吡咯 -3-基;) -喹唑啉 -4-基] -胺 178a (200 mg， 0.41 mmol)溶解于 25 mL甲醇中，搅拌 下加入 C2S,6R 2,6-二甲基哌嗪 C140 mg， 1.22 mmol) , 反应液加热回流过夜。 将反 应液在减压下浓缩， 得到的残留物通过薄层色谱板分离纯化 (二氯甲烷： 甲醇 =8: 1)， 得到本标题产物 l-((3S,5R)-3,5-二甲基 -哌嗪 -1-基) -3-(3-{4-[1-(3-氟-苄基) -1H- 吲唑 -5-基氨基]-喹唑啉 -6-基 }-吡咯 -1-基) -丙 -2-醇 281 (53 mg， 黄色固体） ， 产率： 21 %。
Figure imgf000291_0001
[1-(3-Fluoro-benzyl)-1H-indazol-5-yl]-[6-(1-epoxyethylmethyl-1H-pyrrole-3- in a 100 mL eggplant-shaped flask ;) - quinazolin-4-yl]-amine 178a (200 mg, 0.41 mmol) was dissolved in 25 mL of methanol and added with stirring C2S, 6R 2,6-dimethylpiperazine C 140 mg, 1.22 mmol) The reaction solution was heated to reflux overnight. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified (yield: methylene chloride: hexane = 8:1) to give the title product l-((3S,5R)-3,5- Methyl-piperazin-1-yl)-3-(3-{4-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-quinazoline-6-yl} - pyrrol-1-yl)-propan-2-ol 281 (53 mg, yellow solid), Yield: 21%.
MS m/z (ESI) : 605 [M+ 1]  MS m/z (ESI) : 605 [M+ 1]
1HNMR (400MHz, DMSO-i/6): 69.90(s, IH), 8.66(s, IH), 8.45(s, IH), 8.24(s, IH),1HNMR (400MHz, DMSO-i/6): 69.90 (s, IH), 8.66 (s, IH), 8.45 (s, IH), 8.24 (s, IH),
8.17(s, IH), 8.02(m, IH), 7.75(s， 2H)， 7.70(m IH), 7.47(s, lH),7.39(m,lH),7.13(m, 3H): 6.88(s, IH), 6.69(s, IH), 5.72(s, 2H), 5.03(m, lH),3.98(m,, 3H)， 3.26(m, 2H), 2.96(m, 2H), 2.29(m, 2H), 2.02(m, 2H), 1.20(m, 6H) 实施例 282 8.17(s, IH), 8.02(m, IH), 7.75(s, 2H), 7.70(m IH), 7.47(s, lH), 7.39(m,lH),7.13(m, 3H) : 6.88( s, IH), 6.69(s, IH), 5.72(s, 2H), 5.03(m, lH), 3.98(m,, 3H), 3.26(m, 2H), 2.96(m, 2H), 2.29( m, 2H), 2.02 (m, 2H), 1.20 (m, 6H). Example 282
4-Γ3-(3-{4-「1-(3-氟 -苄基 1H-吲唑 -5-基氨基 1-喹唑啉 -6-基 吡咯小基 )-2-羟基-丙 基] -哌嗪 -1-甲酸乙酯 4-Γ3-(3-{4-"1-(3-Fluoro-benzyl 1H-indazol-5-ylamino-1-quinazolin-6-ylpyrroleyl)-2-hydroxy-propyl] - piperazine-1-carboxylate
Figure imgf000292_0001
在 100 mL茄形瓶中， 将 [1-(3-氟-苄基) -1H-吲唑 -5-基] -[6-(1-环氧乙基甲基 -1Η- 吡咯 -3-基)-喹唑啉 -4-基] -胺 178a (200 mg， 0.41 mmol)溶解于 25 mL甲醇中，搅拌 下加入哌嗪 -1-甲酸乙酯 （194 mg， 1.22 mmol), 反应液加热回流过夜。将反应液在 减压下浓缩， 得到的残留物通过薄层色谱板分离纯化 (二氯甲烷： 甲醇 = 10: 1)， 得到本标题产物 4-[3-(3-{4-[1-(3-氟-苄基) -1H-吲唑 -5-基氨基] -喹唑啉 -6-基} -吡咯 -1-基) -2-羟基-丙基] -哌嗪 -1-甲酸乙酯 282 (80 mg， 黄色固体） ， 产率： 30%。
Figure imgf000292_0001
[1-(3-Fluoro-benzyl)-1H-indazol-5-yl]-[6-(1-epoxyethylmethyl-1Η-pyrrole-3- in a 100 mL eggplant-shaped flask Base quinazolin-4-yl]-amine 178a (200 mg, 0.41 mmol) was dissolved in 25 mL of MeOH. EtOAc EtOAc EtOAc Reflux overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified (yield: methylene chloride:methanol = 10:1) to afford the title product 4-[3-(3-{4-[1- (3-fluoro-benzyl)-1H-indazol-5-ylamino]-quinazolin-6-yl}-pyrrol-1-yl)-2-hydroxy-propyl]-piperazine-1-carboxylic acid Ethyl ester 282 (80 mg, yellow solid), Yield: 30%.
MS m/z (ESI): 649[M+1] MS m/z (ESI): 649 [M+1]
!HNMR (400MHz, DMSO- 6): 59.84(s, 1H)， 8.61 (s, 1H), 8.45(s, 1H), 8.24(s, 1H), 8.17(s, 1H), 8.04(m, 1H), 7.75(s, 2H), 7.70(m 1H), 7.44(s, 1H), 7.40(m, 1H), 7.08(m, 3H)， 6.88(s, 1H), 6.67(s, 1H)， 5.73(s, 2H), 4.99(s, 1H), 4.05(m, 2H), 3.90(m, 3H)， 3.39(m, 4H), 2.4 l(m, 4H), 2.28(m, 2H), 1.18(m, 3H) ! HNMR (400MHz, DMSO- 6) : 59.84 (s, 1H), 8.61 (s, 1H), 8.45 (s, 1H), 8.24 (s, 1H), 8.17 (s, 1H), 8.04 (m, 1H ), 7.75(s, 2H), 7.70(m 1H), 7.44(s, 1H), 7.40(m, 1H), 7.08(m, 3H), 6.88(s, 1H), 6.67(s, 1H), 5.73(s, 2H), 4.99(s, 1H), 4.05(m, 2H), 3.90(m, 3H), 3.39(m, 4H), 2.4 l(m, 4H), 2.28(m, 2H), 1.18(m, 3H)
实施例 283 Example 283
1-(3-ί4-「1-(3-氟-苄基) -1H-吲唑 -5-基氨基 1-喹唑啉 -6-基 吡咯 -1-基) -3-(2-甲氧基-乙  1-(3-ί4-"1-(3-Fluoro-benzyl)-1H-indazol-5-ylamino-1-quinazolin-6-ylpyrrol-1-yl)-3-(2-A oxy-B
Figure imgf000292_0002
Figure imgf000293_0001
在 100 mL茄形瓶中， 将 [1-(3-氟-节基) -1H-吲唑 -5-基] -[6-(1-环氧乙基甲基 -1Η- 吡咯 -3-基) -喹唑啉 -4-基] -胺 178a (200 mg， 0.41 mmol)溶解于 25 mL甲醇中，搅拌 下加入 2-甲氧基乙胺（92 mg， 1.22 mmol), 反应液加热回流过夜。 将反应液在减 压下浓缩， 得到的残留物通过薄层色谱板分离纯化 (二氯甲烷： 甲醇 =8: 1), 得到 本标题产物 1-(3-{4-[1-(3-氟-苄基) -1H-吲唑 -5-基氨基] -喹唑啉 -6-基 吡咯 -1- 基) -3-(2-甲氧基-乙氨基) -丙 -2-醇 283 (100 mg， 黄色固体） ， 产率： 43 %。
Figure imgf000292_0002
Figure imgf000293_0001
[1-(3-Fluoro-nodal)-1H-indazol-5-yl]-[6-(1-epoxyethylmethyl-1Η-pyrrole-3- in a 100 mL eggplant-shaped flask - quinazolin-4-yl]-amine 178a (200 mg, 0.41 mmol) was dissolved in 25 mL of methanol. EtOAc (EtOAc, m. overnight. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified (yield: methylene chloride:methanol = 8:1) to afford the title product 1-(3-{4-[1-(3- Fluoro-benzyl)-1H-indazol-5-ylamino]-quinazolin-6-ylpyrrolidin-1-yl)-3-(2-methoxy-ethylamino)-propan-2-ol 283 (100 mg, yellow solid), Yield: 43%.
MS m/z (ESI): 566[M+ 1] MS m/z (ESI): 566 [M+ 1]
iHNMR (400MHz, DMSO-i/d): S9.86(s， 1H), 8.63(s, 1H)， 8.45(s, 1H), 8.23(s; 1H), 8.17(s, 1H), 8.04(m, 1H), 7.78(s, 2H), 7.70(m 1H), 7.44(m, 1H), 7.37(m, 1H), 7.08(m, 3H), 6.89(s, 1H), 6.69(s, 1H), 5.72(s, 2H), 4.09(m, 3H), 3.92(m, 2H), 3.18(m, 3H), 2.59(m, 4H) iHNMR (400MHz, DMSO-i/d): S9.86 (s, 1H), 8.63 (s, 1H), 8.45 (s, 1H), 8.23 (s ; 1H), 8.17 (s, 1H), 8.04 ( m, 1H), 7.78(s, 2H), 7.70(m 1H), 7.44(m, 1H), 7.37(m, 1H), 7.08(m, 3H), 6.89(s, 1H), 6.69(s, 1H), 5.72(s, 2H), 4.09(m, 3H), 3.92(m, 2H), 3.18(m, 3H), 2.59(m, 4H)
… .―. . 实施例 284 ... .. . . Example 284
Ν4(3Ι -1-「3-(3-{4-「1-(3-氟-苄基) -1H-吲唑 -5-基氨基 "I-喹唑啉 -6-基 }-吡咯 -1-基) -2- 羟基 -丙基 1-吡咯垸 -3-基 乙酰胺  Ν4(3Ι -1-"3-(3-{4-"1-(3-Fluoro-benzyl)-1H-indazol-5-ylamino"I-quinazolin-6-yl}-pyrrole- 1-yl)-2-hydroxy-propyl 1-pyrrole-3-ylacetamide
Figure imgf000293_0002
在 100 mL茄形瓶中， 将 [1-(3-氟-苄基) -1H-吲唑 -5-基] -[6-(1-环氧乙基甲基 -1H- 吡咯 -3-基) -喹唑啉 -4-基] -胺 178a (200 mg， 0.41 mmol)溶解于 25 mL甲醇中，搅拌 下加入 (R)-N- (卩比咯烷 -3-基)乙酰胺 (174 mg， 1.22 mmol), 反应液加热回流过夜。 将反应液在减压下浓缩， 得到的残留物通过薄层色谱板分离纯化 (二氯甲垸： 甲醇 =8： 1)， 得到本标题产物 N-{(3R)-l-[3-(3-{4-[l-(3-氟-苄基) -1H-吲唑 -5-基氨基] -喹 唑啉 -6-基} -吡咯 -1-基) -2-羟基-丙基] -吡咯烷 -3-基 乙酰胺 284 (50 mg,黄色固体） ， 产率: 20%
Figure imgf000293_0002
[1-(3-Fluoro-benzyl)-1H-indazol-5-yl]-[6-(1-epoxyethylmethyl-1H-pyrrole-3- in a 100 mL eggplant-shaped flask - quinazolin-4-yl]-amine 178a (200 mg, 0.41 mmol) was dissolved in 25 mL of methanol and (R)-N-(p-pyrrolidin-3-yl)acetamide was added with stirring. 174 mg, 1.22 mmol), and the reaction was heated to reflux overnight. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified (yield). =8: 1), the title product N-{(3R)-l-[3-(3-{4-[l-(3-fluoro-benzyl)-1H-indazol-5-ylamino] is obtained. -quinazolin-6-yl}-pyrrol-1-yl)-2-hydroxy-propyl]-pyrrolidin-3-ylacetamide 284 (50 mg, yellow solid), yield: 20%
MS m/z (ESI): 619[M+1]  MS m/z (ESI): 619 [M+1]
JHNMR (400MHz, DMSO-c/6): 59.87(s, 1H), 8.64(s, 1H), 8.45(s, 1H), 8.23(s, 1H), 8.17(s, 1H), 8.04(m, 1H)， 7.75(m, 3H), 7.41(s, 1H), 7.37(m, 1H), 7.08(m, 3H), 6.89(s, 1H), 6.69(s, 1H), 5.72(s, 2H), 4.04(m, 2H), 3.98(m, 1H), 3.53(m, 2H), 3.28(m, 3H), 3.00(m, 2H), 2.50(m, 3H), 1.83(m, 2H) 实施例 285 J HNMR (400MHz, DMSO-c/6): 59.87 (s, 1H), 8.64 (s, 1H), 8.45 (s, 1H), 8.23 (s, 1H), 8.17 (s, 1H), 8.04 (m) , 1H), 7.75(m, 3H), 7.41(s, 1H), 7.37(m, 1H), 7.08(m, 3H), 6.89(s, 1H), 6.69(s, 1H), 5.72(s, 2H), 4.04(m, 2H), 3.98(m, 1H), 3.53(m, 2H), 3.28(m, 3H), 3.00(m, 2H), 2.50(m, 3H), 1.83(m, 2H Example 285
l-(3- -「l-(3-氟 -苄基 1H-吲唑 -5-基氨基卜喹唑啉 -6-基 吡咯小基) -3-「l，2，31三唑  L-(3- -"1-(3-Fluoro-benzyl 1H-indazole-5-ylaminobuquinazoline-6-ylpyrrole small)-3-"l,2,31 triazole
-1-基-丙 -2-醇  -1-yl-propan-2-ol
Figure imgf000294_0001
Figure imgf000294_0001
在 100 mL茄形瓶中， 将 [1-(3-氟-苄基) -1H-吲唑- 5-基] -[6-(1-环氧乙基甲基 -1H- 吡咯 -3-基) -喹唑啉 -4-基] -胺 178a (100 mg, 0.23 mmol)溶解于 5 mL干燥的 Ν,Ν- 二甲基甲酰胺中， 在冰浴条件下， 冷却至 0°C， 加入氢化钠 (22 mg， 0.92 mmol), 搅拌 30分钟后加入 [1,2,3]三唑 (43 mg, 0.63 mmol), 加热至 50°C搅拌过夜。 反应 液中加入 20 mL冰水和 20 mL二氯甲烷， 分液， 水相用二氯甲垸萃取 (20 mLX 3)， 合并的有机相通过无水硫酸钠干燥， 过滤， 减压下浓缩， 得到的残留物进一步通 过薄层色谱板分离纯化 (二氯甲垸： 甲醇 = 10: 1)， 得到本标题产物 1-(3-{4-[1-(3- 氟-苄基) -1H-吲唑 -5-基氨基]-喹唑啉 -6-基 吡咯 -1-基) -3-[1,2,3]三唑 -1-基-丙 -2-醇 285(19 mg, 黄色固体） ， 产率： 15 %。  [1-(3-Fluoro-benzyl)-1H-indazole-5-yl]-[6-(1-epoxyethylmethyl-1H-pyrrole-3- in a 100 mL eggplant-shaped flask - quinazolin-4-yl]-amine 178a (100 mg, 0.23 mmol) was dissolved in 5 mL of dry hydrazine, s-dimethylformamide, and cooled to 0 ° C under ice bath. Sodium hydride (22 mg, 0.92 mmol) was added, and after stirring for 30 min, [1,2,3]triazole (43 mg, 0.63 mmol) was added and the mixture was stirred at 50 ° C overnight. 20 mL of ice water and 20 mL of dichloromethane were added to the reaction mixture, and the aqueous layer was separated with methylene chloride (20 mL EtOAc). The obtained residue was further purified by a thin layer chromatography (dichloromethane:methanol = 10:1) to give the title product 1-(3-{4-[1-(3-fluoro-benzyl)-1H. -carbazol-5-ylamino]-quinazolin-6-ylpyrrol-1-yl)-3-[1,2,3]triazol-1-yl-propan-2-ol 285 (19 mg, Yellow solid), Yield: 15%.
MS m/z (ESI): 560[M+ 1] MS m/z (ESI): 560 [M+ 1]
1H MR (400MHz, DMSO- 6): 59.93(s, 1H), 8.68(s, 1H), 8.44(s, 1H), 8.24(s, 1H), 8.17(s, 1H), 8.11(s, 1H), 8.05(m, 1H), 7.74(m, 4H)， 7.49(s, 1H), 7.37(m, 1H), 7.08(m, 3H), 6.89(s, 1H), 6.74(s, 1H), 5.72(s， 2H), 4.49(m, 1H), 4.35(m, 1H), 4.22 (m, 1H), 4.09(m, 1H)， 3.94(m, 1H) 实施例 286 1H MR (400MHz, DMSO-6): 59.93(s, 1H), 8.68(s, 1H), 8.44(s, 1H), 8.24(s, 1H), 8.17(s, 1H), 8.11(s, 1H) ), 8.05(m, 1H), 7.74(m, 4H), 7.49(s, 1H), 7.37(m, 1H), 7.08(m, 3H), 6.89(s, 1H), 6.74(s, 1H) , 5.72(s, 2H), 4.49(m, 1H), 4.35(m, 1H), 4.22 (m, 1H), 4.09 (m, 1H), 3.94 (m, 1H) Example 286
1-( -Μ-Π-(3-氟-苄基) -m-吲唑 -5-基氨基 1-喹唑啉 -6-基 吡咯小基 3- (2-吗啉 -4-基- 乙氨基) -丙 -2-醇  1-(-Μ-Π-(3-fluoro-benzyl)-m-carbazol-5-ylamino-1-quinazolin-6-ylpyrrole small 3-(2-morpholin-4-yl- Ethylamino)-propan-2-ol
Figure imgf000295_0001
Figure imgf000295_0001
在 100 mL茄形瓶中， 将 [1-(3-氟-苄基) -1H-吲唑 -5-基] -[6-(1-环氧乙基甲基 -1H- 吡咯 -3-基) -喹唑啉 -4-基] -胺 178a (250 mg， 0.51 mmol)溶解于 30 mL甲醇中，搅拌 下加入 2-吗啉 -4-基 -乙胺（199 mg， 1.53 mmol), 反应液加热回流过夜。 将反应液 在减压下浓缩， 得到的残留物通过薄层色谱板分离纯化 (二氯甲垸： 甲醇 = 10: 1)， 得到本标题产物 1-(3-{4-[1-(3-氟-苄基) -1H-吲唑 -5-基氨基] -喹唑啉 -6-基 吡咯 -1- 基) -3-(2-吗啉 -4-基-乙氨基) -丙 -2-醇 286 (54 mg， 黄色固体） ， 产率： 17%。  [1-(3-Fluoro-benzyl)-1H-indazol-5-yl]-[6-(1-epoxyethylmethyl-1H-pyrrole-3- in a 100 mL eggplant-shaped flask - quinazolin-4-yl]-amine 178a (250 mg, 0.51 mmol) was dissolved in 30 mL of methanol and 2-morpholin-4-yl-ethylamine (199 mg, 1.53 mmol). The reaction solution was heated to reflux overnight. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified (yield: methylene chloride:methanol = 10:1) to afford the title product 1-(3-{4-[1-(3) -fluoro-benzyl)-1H-indazol-5-ylamino]-quinazolin-6-ylpyrrolidin-1-yl)-3-(2-morpholin-4-yl-ethylamino)-propane- 2-alcohol 286 (54 mg, yellow solid), Yield: 17%.
MS m/z (ESI): 619[M+ 1] MS m/z (ESI): 619 [M+ 1]
JHNMR (400MHz, DMSO- 6): S9.99(s, 1H), 8.73(s, 1H)， 8.45(s, 1H), 8.27(s, 1H), 8.17(s, 1H), 8.04(m, 1H), 7.76(m, 3H), 7.51(s， 1H), 7.37(m, 1H), 7.08(m, 3H), 6.92(s, 1H), 6.75(s, 1H), 5.72(s, 2H)， 4.23(m, 1H), 4.07(m, 2H), 3.56(m， 4H), 3.18 (s, 1H), 2.84(m, 1H), 2.60(m, 4H), 2.39(m, 4H) 实施例 287 JHNMR (400MHz, DMSO-6): S9.99(s, 1H), 8.73(s, 1H), 8.45(s, 1H), 8.27(s, 1H), 8.17(s, 1H), 8.04(m, 1H), 7.76(m, 3H), 7.51(s, 1H), 7.37(m, 1H), 7.08(m, 3H), 6.92(s, 1H), 6.75(s, 1H), 5.72(s, 2H) ), 4.23(m, 1H), 4.07(m, 2H), 3.56(m, 4H), 3.18 (s, 1H), 2.84(m, 1H), 2.60(m, 4H), 2.39(m, 4H) Example 287
Γ 3-氟-苄基) -1H-吲唑 -5-基 W6-「l-(3-吗啉 -4-基-丙基) -1H-吡咯 -3-基 1-喹唑啉 -4- 基 胺  Γ 3-Fluoro-benzyl)-1H-indazole-5-yl W6-"1-(3-morpholin-4-yl-propyl)-1H-pyrrol-3-yl-1-quinazoline-4 - alkamine
Figure imgf000295_0002
Figure imgf000295_0002
Figure imgf000296_0001
第一步
Figure imgf000296_0001
first step
4-(3-溴-丙基) -吗啉  4-(3-bromo-propyl)-morpholine
将吗啉 (4 mL， 49.36 mmol), 1,3-二溴丙基 (25 mL， 245 mmol)溶于三乙胺 (27.5 mL， 197 mmol)中， 室温下搅拌过夜， 有白色固体生成， 加入 2 mL甲醇溶解， 混 合物通过硅胶柱层析进一步分离纯化 (洗脱剂： 乙酸乙酯)，得到 4-(3-溴-丙基) -吗啉 287a(1.2 g, 淡黄色固体)， 产率： 12%。  The morpholine (4 mL, 49.36 mmol), 1,3-dibromopropyl (25 mL, 245 mmol) was dissolved in triethylamine (27.5 mL, 197 mmol). After adding 2 mL of methanol, the mixture was separated and purified by silica gel column chromatography (eluent: ethyl acetate) to give 4-(3-bromo-propyl)-morpholine 287a (1.2 g, pale yellow solid). Rate: 12%.
第二步  Second step
[1-(3-氟-苄基) -1H-吲唑 -5-基] -{6-[1-(3-吗啉 -4-基-丙基) -1H-吡咯 -3-基] -喹唑啉 -4- 基} -胺  [1-(3-Fluoro-benzyl)-1H-indazol-5-yl]-{6-[1-(3-morpholin-4-yl-propyl)-1H-pyrrol-3-yl] -quinazolin-4-yl}-amine
在 100 mL茄形瓶中， 将 [1-(3-氟-苄基) -1H-吲唑 -5-基] -[6-(1-环氧乙基甲基 -1H- 吡咯 -3-基) -喹唑啉斗基] -胺 178a (100 mg， 0.23 mmol)溶解于 5 mL干燥的 Ν,Ν- 二甲基甲酰胺中， 在冰浴条件下， 冷却至 0°C， 加入氢化钠 (22 mg， 0.92 mmol), 搅拌 30分钟后加入 4-(3-溴-丙基) -吗啉 287a (79 mg， 0.38 mmol),室温下搅拌 3小 时反应完毕。 反应液中加入 20 mL冰水和 20 mL二氯甲垸， 分液， 水相用二氯甲 烷萃取 (20 mLX 3)， 合并的有机相通过无水硫酸钠干燥， 过滤， 减压下浓缩， 得到 的残留物进一步通过薄层色谱板分离纯化 (二氯甲垸： 甲醇 = 10: 1)， 得到本标题 产物 1-(3-{4-[1-(3-氟-苄基) -1H-吲唑 -5-基氨基] -喹唑啉 -6-基}-吡咯 -1-基) -3-[1,2，3] 三唑 _1-基-丙 _2-醇 287(19 mg， 黄色固体） ， 产率： 15 %。  [1-(3-Fluoro-benzyl)-1H-indazol-5-yl]-[6-(1-epoxyethylmethyl-1H-pyrrole-3- in a 100 mL eggplant-shaped flask - quinazoline sulfo]-amine 178a (100 mg, 0.23 mmol) dissolved in 5 mL of dry hydrazine, hydrazine-dimethylformamide, cooled to 0 ° C under ice-cooling, hydrogenation Sodium (22 mg, 0.92 mmol), stirred for 30 min, then added 4-(3-bromo-propyl)-morpholine 287a (79 mg, 0.38 mmol). 20 mL of ice water and 20 mL of dichloromethane were added to the reaction mixture, and the aqueous layer was extracted with dichloromethane (20 mL EtOAc). The obtained residue was further purified by a thin layer chromatography (dichloromethane:methanol = 10:1) to give the title product 1-(3-{4-[1-(3-fluoro-benzyl)-1H. -carbazol-5-ylamino]-quinazolin-6-yl}-pyrrol-1-yl)-3-[1,2,3]triazol-1-yl-propan-2-ol 287 (19 Mg, yellow solid), Yield: 15%.
MS m/z (ESI): 562[M+ 1] MS m/z (ESI): 562 [M+ 1]
'HNMR (400MHZ, DMSO-^6): 59.82(S, lH), 8.61(S, lH), 8.45(S, lH), 8.247(S, lH), 8.17(s, 1H), 8.05(m, 1H), 7.77(m, 3H), 7.44(m, 2H), 7.14(m, 3H), 6.91(s, 1H)， 6.68(s, 1H), 5.72(s, 2H), 4.00(m, 2H), 3.60(m, 4H), 2.50(m, 6H), 1.94(m, 2H) 实施例 288  'HNMR (400MHZ, DMSO-^6): 59.82(S, lH), 8.61(S, lH), 8.45(S, lH), 8.247(S, lH), 8.17(s, 1H), 8.05(m, 1H), 7.77 (m, 3H), 7.44 (m, 2H), 7.14 (m, 3H), 6.91 (s, 1H), 6.68 (s, 1H), 5.72 (s, 2H), 4.00 (m, 2H) ), 3.60 (m, 4H), 2.50 (m, 6H), 1.94 (m, 2H) Example 288
4-「3-(3- -β-氯 -4-(3-氟苄氧基 苯氨基 1-喹唑啉 -6-基}-吡咯 -1-基 2-羟基 -丙基 1-哌 嗪 -2-酮 4-"3-(3--β-Chloro-4-(3-fluorobenzyloxyphenylamino-1-quinazolin-6-yl}-pyrrol-1-yl 2-hydroxy-propyl 1-piperazine) 2-ketone
Figure imgf000297_0001
Figure imgf000297_0001
187a  187a
哌嗪 -2-酮（60 mg, 0.6 mmol)溶解于 30 mL甲醇中， 搅拌下加入 [3-氯 -4-(3- 氟-苄基)-苯基] -[6-(1-环氧乙基甲基 -1H-吡咯 -3-基) -喹唑啉 -4-基] -胺 187a (250 mg, 0.51 mmol), 混合液加热回流过夜。 反应液在减压下浓缩， 得到的残留物通过硅胶 柱层析分离纯化 (二氯甲烷： 甲醇 =30: 1)， 得到本标题产物 : 1-[3-(3-{4-[3-氯 -4-(3- 氟苄氧基) -苯氨基] -喹唑啉 -6-基 吡咯小基 )-2-轻基-丙基] -哌嗪 -2-酮 288 (72 mg, 黄色固体)， 产率： 40.1 %。  Piperazine-2-one (60 mg, 0.6 mmol) was dissolved in 30 mL of methanol and [3-chloro-4-(3-fluoro-benzyl)-phenyl]-[6-(1-cyclo) was added with stirring. Oxyethylmethyl-1H-pyrrol-3-yl)-quinazolin-4-yl]-amine 187a (250 mg, 0.51 mmol). The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjj Chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazolin-6-ylpyrrole small)-2-light-propyl]-piperazin-2-one 288 (72 mg, yellow Solid), Yield: 40.1%.
MS m/z (ESI): 601[M+] MS m/z (ESI): 601 [M + ]
1H NMR(400 MHz, DMSO-t¾):S 9.69(s, IH), 8.54(s, 1H)， 8.50(s, 1H)， 8.04(m, 2H), 7.75(m, 2H), 7.47(m, IH), 7.40(m, IH), 7.30(m, 3H), 7.19(m, IH), 6.88(s, IH), 6.68(s, IH), 5.27(s, 2H), 5.05(br, IH), 3.98(m, 3H), 3.19(m, 2H), 2.64(m, 2H), 2.35(m, 2H), 1.23(m, 2H) 实施例 289  </ RTI> <RTIgt; , IH), 7.40(m, IH), 7.30(m, 3H), 7.19(m, IH), 6.88(s, IH), 6.68(s, IH), 5.27(s, 2H), 5.05(br, IH), 3.98 (m, 3H), 3.19 (m, 2H), 2.64 (m, 2H), 2.35 (m, 2H), 1.23 (m, 2H) Example 289
{6-[5-(4-氨基 -哌啶 -1-基甲基 H-吡咯 -3-基 1-喹唑啉 -4-基}-「3-氯 -4-(3-氟-苄氧基) - 苯基 1-胺  {6-[5-(4-Amino-piperidin-1-ylmethylH-pyrrol-3-yl-1-quinazolin-4-yl}-"3-chloro-4-(3-fluoro-benzyl) Oxy)-phenyl 1-amine
Figure imgf000297_0002
Figure imgf000297_0002
Figure imgf000298_0001
Figure imgf000298_0001
第一步  First step
(1-苄基 -哌啶 -4-基) -氨基甲酸叔丁酯  (1-benzyl-piperidin-4-yl)-carbamic acid tert-butyl ester
将 1-苄基 -哌啶 -4-基胺 (2.05 mL， 10 mmol)溶于 20 mL二氯甲烷中，用恒压滴液 漏斗缓慢滴加二碳酸二叔丁酯 (2.43 g， 11 mmol)的 20 mL二氯甲垸溶液，室温下搅 拌过夜。将反应液在减压下浓缩，得到的残留物通过硅胶柱层析进一步分离纯化 (二 氯甲烷： 甲醇 =25: 1)， 得到 (1-苄基 -哌啶 -4-基) -氨基甲酸叔丁酯 289a(2.91 g， 白 色固体)， 产率： 100%。  1-Benzyl-piperidin-4-ylamine (2.05 mL, 10 mmol) was dissolved in dichloromethane (20 mL), and di-tert-butyl dicarbonate (2.43 g, 11 mmol) was slowly added dropwise using a constant pressure dropping funnel. A 20 mL solution of dichloromethane was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified and purified (jjjjjjjjjjj tert-Butyl ester 289a (2.91 g, white solid), Yield: 100%.
MS m/z (ESI): 291 [M+ 1] MS m/z (ESI): 291 [M+ 1]
第二步  Second step
哌啶 -4-基-氣基甲酸叔丁酯  Piperidine-4-yl-carbamic acid tert-butyl ester
将 (1-苄基 -哌啶 -4-基) -氨基甲酸叔丁酯 289a(2.9 g， 10 mmol)溶于 150 mL甲醇 中， 搅拌下加入 Pd/C(0.4 g)， 用氢气置换空气 4次， 在 30 C下催化加氢反应 24小 时。过滤， 减压下浓缩滤液， 得到哌啶 -4-基-氨基甲酸叔丁酯 289b (1.96 g， 白色固 体)， 产率： 98 %。  (1-Benzyl-piperidin-4-yl)-carbamic acid tert-butyl ester 289a (2.9 g, 10 mmol) was dissolved in 150 mL of methanol, and Pd/C (0.4 g) was added with stirring. 4 times, the catalytic hydrogenation reaction was carried out at 30 C for 24 hours. Filtration and concentration of the filtrate under reduced pressure afforded </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt;
MS m/z (ESI): 201[M+ 1]  MS m/z (ESI): 201 [M+ 1]
第三步  third step
4-{4-[3-氯 -4-(3-氟苄氧基) -苯氨基] -喹唑啉 -6-基 }-1Η-吡咯 -2-甲醛 将 30 mL干燥的 Ν,Ν-二甲基甲酰胺，冰浴下冷却至 0Ό，加入三氯氧磷 (918 mg， 6 mmol),搅拌 1小时后， 0Ό下加入 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-[6-(1Η-吡咯 -3-基) - 喹唑啉 -4-基] -胺 42 (1.776 g， 4 mmol), 室温下搅拌 3小时反应完毕。 加入 10 mL 水淬灭反应， 乙酸乙酯萃取（100 mLX 3)， 合并的有机相通过无水硫酸钠干燥， 过 滤， 减压下浓缩， 得到的残留物通过硅胶主层析进一歩分离纯化 (正己垸： 乙酸乙 酯 =2: 1)， 得到 4-{4-[3-氯 -4-(3-氟苄氧基) -苯氨基] -喹唑啉 -6-基}-111-吡咯 -2-甲醛 289c (300 mg, 黄色固体)， 产率： 15.9%。 4-{4-[3-Chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazolin-6-yl}-1Η-pyrrole-2-carbaldehyde 30 mL of dry mash, Ν- Dimethylformamide was cooled to 0 Torr in an ice bath, and phosphorus oxychloride (918 mg, 6 mmol) was added. After stirring for 1 hour, [3-chloro-4-(3-fluoro-benzyloxy) was added at 0 Torr. -Phenyl]-[6-(1Η-pyrrol-3-yl)-quinazolin-4-yl]-amine 42 (1.776 g, 4 mmol). The reaction was quenched by the addition of 10 mL EtOAc (EtOAc)EtOAc. Filtration, concentrating under reduced pressure, and the obtained residue was purified by chromatography on silica gel chromatography (ethyl hexane: ethyl acetate = 2: 1) to give 4-{4-[3-chloro-4-(3-fluoro) Benzyloxy)-phenylamino]-quinazolin-6-yl}-111-pyrrole-2-carbaldehyde 289c (300 mg, yellow solid), yield: 15.9%.
MS m/z (ESI): 473[M+ 1] MS m/z (ESI): 473 [M+ 1]
第四步  the fourth step
[1-(4-{4-[3-氯 -4-(3-氟苄氧基) -苯氨基] -喹唑啉 -6-基}-111-吡咯 -2-基甲基) -哌啶 -4- 基] -氨基甲酸叔丁酯  [1-(4-{4-[3-Chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazolin-6-yl}-111-pyrrol-2-ylmethyl)-piperidin Butyl-4-yl]-carbamic acid tert-butyl ester
将 4-{4-[3-氯 -4-(3-氟苄氧基) -苯氨基] -喹唑啉 -6-基}-111-吡咯 -2-甲醛 289c (216 mg, 0.46 mmol), 哌啶 -4-基-氨基甲酸叔丁酯 (183 mg， 0.92 mmol)和三 (乙酰氧基) 硼氢化钠 (1.94 g， 9.2 mmol)溶于 20 mL二氯甲垸中， 在 35°C下搅拌过夜。 将反应 液中加入 20 mL饱和碳酸氢钠溶液淬灭反应， 二氯甲烷萃取（100 mL X 3)， 合并的 有机相通过无水硫酸钠干燥， 过滤， 减压下浓缩， 得到的残留物通过硅胶主层析 进一步分离纯化 (二氯甲烷： 甲醇 = 100: 1)， 得到 [1-(4-{4-[3-氯 -4-(3-氟苄氧基) -苯 氨基] -喹唑啉 -6-基}-111-吡咯 -2-基甲基) -哌啶 -4-基] -氨基甲酸叔丁酯 289d (210 mg, 黄色固体)， 产率： 70%。  4-{4-[3-Chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazolin-6-yl}-111-pyrrole-2-carbaldehyde 289c (216 mg, 0.46 mmol) , piperidin-4-yl-carbamic acid tert-butyl ester (183 mg, 0.92 mmol) and tris(acetoxy)sodium borohydride (1.94 g, 9.2 mmol) dissolved in 20 mL of dichloromethane, at 35 ° Stir overnight at C. The reaction mixture was quenched with EtOAc EtOAc (EtOAc (EtOAcMeOHMeOHMeOHMeOH Further separation and purification by silica gel chromatography (dichloromethane: methanol = 100: 1) gave [1-(4-{4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-quine Tazobutyl oxazol-6-yl}-111-pyrrol-2-ylmethyl)-piperidin-4-yl]-carbamic acid 289d (210 mg, yellow solid), yield: 70%.
MS m/z (ESI): 657[M+ 1] MS m/z (ESI): 657 [M+ 1]
第五步  the fifth step
{6-[5-(4-氨基 -哌啶 -1-基甲基 )-1Η-吡咯 -3_-華] -喹唑啉 -4-基 }-[3-氯 -4-(3-氟-苄氧基) - 苯基] -胺  {6-[5-(4-Amino-piperidin-1-ylmethyl)-1Η-pyrrole-3_-hua]-quinazolin-4-yl}-[3-chloro-4-(3-fluoro -benzyloxy)-phenyl]-amine
将 [1_(4-{4-[3-氯 -4-(3-氟苄氧基) -苯氨基] -喹唑啉 -6-基}-111-吡咯 -2-基甲基) -哌 啶 -4-基] -氨基甲酸叔丁酯 289d (210 mg， 0.32 mmol)溶于 10 mL二氯甲烷中， 搅拌 下加入 1.05 mL三氟乙酸， 室温下搅拌 1小时反应完毕。将反应液中加入氨水，使 溶液呈碱性， 分出有机层， 水相用二氯甲烷萃取 (100 mLX 3)， 合并的有机相通过 无水硫酸钠干燥， 过滤， 减压下浓缩， 得到的残留物通过硅胶主层析进一歩分离 纯化 (二氯甲烷： 甲醇 = 100: 1)， 得到标题产物 {6-[5-(4-氨基 -哌啶 -1-基甲基 )-1Η- 吡咯 -3-基] -喹唑啉 -4-基 }-[3-氯 -4-(3-氟-苄氧基) -苯基] -胺 289(170 mg, 黄色固体)， 产率： 95 %。  [1_(4-{4-[3-Chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazolin-6-yl}-111-pyrrol-2-ylmethyl)-peri tert-Butyl-4-yl]-carbamic acid tert-butyl ester 289d (210 mg, 0.32 mmol) was dissolved in 10 mL of dichloromethane, and 1.05 mL of trifluoroacetic acid was added with stirring, and the mixture was stirred at room temperature for 1 hour. Aqueous ammonia was added to the reaction solution to make the solution alkaline, and the organic layer was separated. The aqueous phase was extracted with dichloromethane (100 mL×3), and the combined organic phases were dried over anhydrous sodium sulfate. The residue was purified by chromatography on silica gel eluting elut elut elut elut elut elut Pyrrol-3-yl]-quinazolin-4-yl}-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-amine 289 (170 mg, yellow solid), yield: 95%.
MS m/z (ESI): 557[M+ 1]  MS m/z (ESI): 557 [M+ 1]
1HNMR(400 MHz , CD30D-J6): 58.746(s, 1H), 8.677(s, 1H), 8.296(d, J=1.2Hz, 1H), 7.94(S, 1H), 7.823(d, J=9.2Hz, 1H), 7.66 l(m, 1H), 7.465(m, 2H), 7.398(m, 1H), 7.266(s, 1H), 7.237(s, 1H), 7.089(m, 1H), 6.968(s, 1H)， 5.282(s, 2H), 4.399(s, 2H), 3.645(d, J=12.8Hz, 2H), 3.161(m, 2H), 2.309(d, J=12.0Hz, 2H), 2.018(m, 2H) 实施例 290  1H NMR (400 MHz, CD30D-J6): 58.746 (s, 1H), 8.677 (s, 1H), 8.296 (d, J = 1.2 Hz, 1H), 7.94 (S, 1H), 7.823 (d, J = 9.2 Hz, 1H), 7.66 l(m, 1H), 7.465(m, 2H), 7.398(m, 1H), 7.266(s, 1H), 7.237(s, 1H), 7.089(m, 1H), 6.968( s, 1H), 5.282(s, 2H), 4.399(s, 2H), 3.645(d, J=12.8Hz, 2H), 3.161(m, 2H), 2.309(d, J=12.0Hz, 2H), 2.018 (m, 2H) Example 290
2-(3-{4-「3-氯 -4-(3-氟-苄氧基 苯氨基 1-喹唑啉 -6-基 }-吡咯小基 I-噻唑垸 -3-基-乙  2-(3-{4-"3-Chloro-4-(3-fluoro-benzyloxyphenylamino-1-quinazolin-6-yl}-pyrrole small group I-thiazolium-3-yl-B
酮 ketone
Figure imgf000300_0001
Figure imgf000300_0001
Figure imgf000300_0002
第一步
Figure imgf000300_0002
first step
2-氯 -1-噻唑烷 -3-基 -乙酮  2-chloro-1-thiazolidine-3-yl-ethanone
将噻唑烷 (332 mg, 3.73 mmol)溶于 10 mL二氯甲烷中，溶液在丙酮-干冰浴下 冷却至 -78Ό , 搅拌下加入 1 it^L三乙胺和氯乙酰氯 (505 mg， 4.47 mmol), 维持此 温度搅拌 40分钟反应完毕。 反应液在减压下浓缩， 得到的残留物通过硅胶柱层析 分离纯化 (；二氯甲烷： 甲醇 = 10: 1) ， 得到 2-氯- 噻唑垸 -3-基 -乙酮 290a (338 mg, 无色油状液体)， 产率： 54.6%。  The thiazolidine (332 mg, 3.73 mmol) was dissolved in 10 mL of dichloromethane, and the solution was cooled to -78 Torr in acetone-dry ice bath, and 1 s. Mmmol), maintain this temperature and stir for 40 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified (jjjjjjjjjjj , colorless oily liquid), Yield: 54.6%.
MS m/z (ESI): 167[M+ 1] MS m/z (ESI): 167 [M+ 1]
第二步  Second step
2-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基 吡咯 -1-基)小噻唑烷 -3-基-乙 酮  2-(3-{4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylpyrrol-1-yl)thiathiazol-3-yl- Ethyl ketone
在 50 mL的烧瓶中，将 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-[6-(1Η-吡咯 -3-基) -喹唑啉 -4- 基] -胺 42 (500 mg, 1.12 mmol)溶于 10 mL干燥的 Ν,Ν-二甲基甲酰胺中， 在冰浴 条件下， 冷却至 0Ό， 加入氢化钠 (134 mg， 5.62 mmol), 搅拌 30分钟后加入 2-氯 -1-噻唑烷 -3-基 -乙酮 290a (224 mg, 1.35 mmol), 室温下搅拌 2小时反应完毕。 反 应液加入 50 mL水， 用乙酸乙酯萃取 (50 mL X 4)， 合并的有机相通过无水硫酸钠 干燥， 过滤， 减压下浓縮， 得到的残留物通过硅胶柱层析进一步分离纯化 (二氯甲 垸： 甲醇 =40: 1)， 得到本标题产物 2-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基 比咯 -1-基) -1-噻唑烷 -3-基 -乙酮 290 (442 mg， 黄色固体)， 产率： 60%。 MS m/z (ESI): 574[M+ 1]  [3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1Η-pyrrol-3-yl)-quinazolin-4-yl] in a 50 mL flask -Amine 42 (500 mg, 1.12 mmol) was dissolved in 10 mL dry EtOAc EtOAc EtOAc (EtOAc) After a minute, 2-chloro-1-thiazolidin-3-yl-ethanone 290a (224 mg, 1.35 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was added to 50 mL of EtOAc (EtOAc)EtOAc. (Dichloromethane: methanol = 40: 1), the title product 2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline- 6-Methylpyr-1-yl)-1-thiazolidin-3-yl-ethanone 290 (442 mg, yellow solid), Yield: 60%. MS m/z (ESI): 574 [M+ 1]
1H NMR(400 MHz, DMSO-i¾)： S9.69(s, 1H), 8.54(s, 1H), 8.50(s, 1H), 8.04(m, 2H), 7.75(m, 2H), 7.47(m, 1H), 7.40(m, 1H), 7.30(m, 3H), 7.19(m, 1H), 6.88(s, 1H), 6.68(s, IH), 5.27(s, 2H), 4.98(s, 2H)， 4.65(s5 IH), 4.5 l(s, IH), 3.82(m, IH), 3.71(m, IH): </ RTI><RTIgt; m, 1H), 7.40(m, 1H), 7.30(m, 3H), 7.19(m, 1H), 6.88(s, 1H), 6.68(s, IH), 5.27(s, 2H), 4.98(s, 2H), 4.65(s 5 IH), 4.5 l(s, IH), 3.82(m, IH), 3.71(m, IH):
3.18(m, lH), 3.04(m, IH) 实施例 291 3.18(m, lH), 3.04(m, IH) Example 291
1-Γ3-( - -「3-氯 -4-(3-氟苄氧基) -苯氨基 1-喹唑啉 -6-基 吡咯小基 )-2-羟基-丙基 哌  1-Γ3-( - -"3-chloro-4-(3-fluorobenzyloxy)-phenylamino-1-quinazoline-6-ylpyrrole small)-2-hydroxy-propyl
Figure imgf000301_0001
哌啶 -3-甲酸乙酯（61.6 mg， 0.39 mmol, Alfa)溶解于 10 mL甲醇中， 搅拌下 加入 [3-氯 -4-(3-氟-苄基) -苯基] - [6-(1-环氧乙基甲基 -1H-吡咯 -3-基) -喹唑啉 -4-基] - 胺 187a (196 mg， 0.39 mmol), 混合液加热回流过夜。 反应液在减压下浓缩， 得到 的残留物通过硅胶柱层析分离纯化 (二氯甲烷： 甲醇 = 10 : 1) , 得到标题产物
Figure imgf000301_0001
Ethyl piperidine-3-carboxylate (61.6 mg, 0.39 mmol, Alfa) was dissolved in 10 mL of methanol and [3-chloro-4-(3-fluoro-benzyl)-phenyl]-[6- (1-Epoxyethylmethyl-1H-pyrrol-3-yl)-quinazolin-4-yl]-amine 187a (196 mg, 0.39 mmol). The reaction mixture was concentrated under reduced pressure.
1- [3-(3-{4-[3-氯 -4-(3-氟苄氧基) -苯氨基] -喹唑啉 -6-基} -吡咯 -1-基) -2-羟基-丙基] -哌 啶 -3-甲酸乙酯 291 (220 mg， 黄色固体)， 产率- 85.4%。 1-[3-(3-{4-[3-Chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazolin-6-yl}-pyrrol-1-yl)-2-hydroxyl Ethyl-propyl]-piperidine-3-carboxylate 291 (220 mg, yellow solid), yield - 85.4%.
MS m/z (ESI): 658[M+ 1] MS m/z (ESI): 658 [M+ 1]
1H MR(400 MHz , DMSO-i/6): 59.67 (s, IH), 8.5 (s, 2H), 8.0 (s, 2H), 7.7 (s, IH), 7.69(m, IH), 7.5(m, 2H), 7.36(m, 3H)， 7.2(m, IH), 6.93 (m, 1H)， 6.60(s, IH), 5.27(s, 2H), 5.05(s, IH), 4.06(m, IH), 3.89(m, 2H), 2.83(m, IH), 2.62 (m, 2H), 2.27(m, 4H), 1.76(m, 2H), 1.50(m, 2H), 1.44(m, 2H), 1.24(m, 3H) 实施例 292 1 H MR (400 MHz, DMSO-i/6): 59.67 (s, IH), 8.5 (s, 2H), 8.0 (s, 2H), 7.7 (s, IH), 7.69 (m, IH), 7.5 (m, 2H), 7.36 (m, 3H), 7.2 (m, IH), 6.93 (m, 1H), 6.60 (s, IH), 5.27 (s, 2H), 5.05 (s, IH), 4.06 ( m, IH), 3.89 (m, 2H), 2.83 (m, IH), 2.62 (m, 2H), 2.27 (m, 4H), 1.76 (m, 2H), 1.50 (m, 2H), 1.44 (m) , 2H), 1.24(m, 3H) Example 292
2— (3_ -「3-氯 -4-(3-氟-苄氧基) -苯氨基 喹唑啉 -6-基 吡咯 -l-V U-二氧 -1λ*6*-噻 2 — (3_ -"3-Chloro-4-(3-fluoro-benzyloxy)-phenylaminoquinazolin-6-ylpyrrole-lV U-dioxo-1λ*6*-thiazide
Figure imgf000301_0002
08 001307
Figure imgf000301_0002
08 001307
Figure imgf000302_0001
第一歩
Figure imgf000302_0001
First
2-氯小(1,1-二氧代 -1λ*6*-噻吗啉 -4-基) -乙酮  2-chloro small (1,1-dioxo-1λ*6*-thiamorpholin-4-yl)-ethanone
将噻吗啉 1,1-二氧化物 (150 mg， 1.11 mmol)溶于 20 mL四氢呋喃中， 在干冰 乙醇浴冷却至一 78°C，搅拌下逐渐滴加三乙胺 (0.14 mL, 1.11 mmol)和氯乙酰氯 (126 mg, 1.11 mmol),滴加完毕在冰浴冷却下搅拌 2小时反应完毕。反应液在减压下浓 缩， 得到的残留物通过硅胶柱层析进一步分离纯化 (二氯甲烷： 甲醇 = 1 : 1)， 得到 2-氯 -1-(1,1-二氧代 -1λ*6*-噻吗啉 -4-基) -乙酮 192a， 产物不经分离直接进行下一歩 反应。  The thiamorpholine 1,1-dioxide (150 mg, 1.11 mmol) was dissolved in 20 mL of tetrahydrofuran, cooled to a temperature of 78 ° C in a dry ice ethanol bath, and triethylamine (0.14 mL, 1.11 mmol) was gradually added dropwise with stirring. And chloroacetyl chloride (126 mg, 1.11 mmol), after completion of the dropwise addition, the reaction was completed by stirring in an ice bath for 2 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified and purified by silica gel column chromatography (dichloromethane: methanol = 1:1) to give 2-chloro-1-(1,1-dioxo-1? 6*-Thiomorpholin-4-yl)-ethanone 192a, the product was directly subjected to the next reaction without isolation.
- ^ . -第二步  - ^ . -Step 2
2-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基) -吡咯 -1-)-1-(1,1-二氧 -1λ*6*-噻 吗啉 -4-基) -乙酮  2-(3-{4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl)-pyrrole-1-)-1-(1,1 -Dioxo-1λ*6*-thiamorpholin-4-yl)-ethanone
将化合物 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-[6-(1Η-吡咯 -3-基)-喹唑啉 -4-基] -胺 42 (444 mg, l mmol)和氢化钠 （120 mg， 5 mmol)溶于 10 mLN,N-二甲基甲酰胺中， 室温下搅拌 30分钟后加入 2-氯 -1-(1,1-二氧代 -1λ*6*-噻吗啉 -4-基) -乙酮 292a (235 mg, 1.11 mmol), 反应液加热至 50°C， 2小时后反应完毕。 反应液在减压下浓缩， 得到的残留物通过硅胶柱层析进一步分离纯化 (二氯甲烷： 甲醇 =50: 1)， 得到标 题产物 2-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基}-吡咯 -1- -(1,1-二氧 -1λ*6*-噻吗啉 -4-基) -乙酮 292(15 mg， 黄色固体)， 产率： 5.1 %。  The compound [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1Η-pyrrol-3-yl)-quinazolin-4-yl]-amine 42 (444 mg , l mmol) and sodium hydride (120 mg, 5 mmol) dissolved in 10 mL of N,N-dimethylformamide, stirred at room temperature for 30 min, then added 2-chloro-1-(1,1-dioxo- 1λ*6*-thiamorpholin-4-yl)-ethanone 292a (235 mg, 1.11 mmol), the reaction mixture was heated to 50 ° C, and the reaction was completed after 2 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjj (3-Fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-pyrrole-1-(1,1-dioxo-1λ*6*-thiamorpholin-4-yl)- Ethyl ketone 292 (15 mg, yellow solid), Yield: 5.1%.
MS m/z (ESI): 620[M+ 1] MS m/z (ESI): 620 [M+ 1]
1H NMR(400 MHz , DMSO-Jd): 59.67 (s, IH), 8.5 (s， 2H), 8.0 (s, 2H), 7.7 (s, IH), 7.69(m, IH), 7.5(m， 2H), 7.36(m， 3H), 7.2(m, IH), 6.93(m, IH), 6.60(s, IH), 5.27(s, 2H), 3.92(s, 4H), 3.15(s, 2H) 实施例 293  1H NMR (400 MHz, DMSO-Jd): 59.67 (s, IH), 8.5 (s, 2H), 8.0 (s, 2H), 7.7 (s, IH), 7.69 (m, IH), 7.5 (m, 2H), 7.36(m, 3H), 7.2(m, IH), 6.93(m, IH), 6.60(s, IH), 5.27(s, 2H), 3.92(s, 4H), 3.15(s, 2H) Example 293
2-(3-{4-D-氯 -4-(3-氟-苄氧基 苯氨基 1-喹唑啉 -6-基 吡咯 -1-基) -l-(4-吗啉 -4-基-哌 啶 -1-基)-乙酮 2- ( 3- {4-D-chloro-4-(3-fluoro-benzyloxyphenylamino-1-quinazolin-6-ylpyrrolidin-1-yl)-l-(4-morpholin-4- Base-piperidin-1-yl)-ethanone
Figure imgf000303_0001
第一步
Figure imgf000303_0001
first step
2-氯 -l-{4- [乙基 -(2-甲氧基-乙基)-氨基] -哌啶 -1-基} -乙酮  2-Chloro-l-{4- [ethyl-(2-methoxy-ethyl)-amino]-piperidin-1-yl}-ethanone
将乙基 -(2-甲氧基-乙基) -哌啶 4-基-胺 (176 mg, 1.03 mmol)溶于 20 mL四氢呋 喃中， 在干冰乙醇浴冷却至一 78 °C， 搅拌下依次加入三乙胺 (0.13 mL， 1.03 mmol) 和氯乙酰氯 (115 mg, 1.02 mmol), 滴加完毕在冰浴冷却下搅拌 2小时反应完毕。 反应液在减压下浓缩， 得到的残留物通过硅胶柱层析进一步分离纯化 (二氯甲烷： 甲醇 = 1 : 1)， 得到 2-氯 -1-{4- [乙基 -(2-甲氧基-乙基) -氨基] -哌啶 -1-基} -乙酮 293a， 产物不经分离直接进行下一步反应。  Ethyl-(2-methoxy-ethyl)-piperidin-4-yl-amine (176 mg, 1.03 mmol) was dissolved in 20 mL of tetrahydrofuran, cooled to a 78 ° C in dry ice ethanol bath, stirring Triethylamine (0.13 mL, 1.03 mmol) and chloroacetyl chloride (115 mg, 1.02 mmol) were added, and the mixture was stirred under ice-cooling for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified and purified by silica gel column chromatography (dichlorobenzene:methanol = 1:1) to give 2-chloro-1-{4-[ethyl-(2- Oxy-ethyl)-amino]-piperidin-1-yl}-ethanone 293a, the product was directly subjected to the next reaction without isolation.
第二步  Second step
2-(3-{4-[3-氯 -4-(3-氟- 氧基) -苯氨基] -喹唑啉 -6-基}-吡咯 -1-基 >1-(4-吗啉 -4-基-哌 啶 -1-基) -乙酮  2-(3-{4-[3-chloro-4-(3-fluoro-oxy)-phenylamino]-quinazolin-6-yl}-pyrrol-1-yl>1-(4-morpholine) -4-yl-piperidin-1-yl)-ethanone
将化合物 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-[6-(1Η-吡咯 -3-基) -喹唑啉 -4-基] -胺 42 (444 mg, 1 mmol)和氢化钠 （120 mg， 5 mmol)溶于 10 mLN，N-二甲基甲酰胺中， 室温下搅拌 30分钟后加入 2-氯 -1-{4- [乙基 -(2-甲氧基-乙基)-氨基] -哌啶 -1-基} -乙酮 293a (252 mg, 1.02 mmol), 反应液加热至 50°C， 2小时后反应完毕。 反应液在减 压下浓缩， 得到的残留物通过硅胶柱层析进一步分离纯化 (二氯甲垸： 甲醇 =50: 1) , 得到标题产物 2-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基} -吡咯 -1-)-1-(1,1-二氧 -1λ*6*-噻吗啉 -4-基) -乙酮 292(240 mg， 黄色固体)， 产率： 36.7%。 MS m/z (ESI): 655[M+ 1]  The compound [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1Η-pyrrol-3-yl)-quinazolin-4-yl]-amine 42 (444 mg , 1 mmol) and sodium hydride (120 mg, 5 mmol) dissolved in 10 mL of N,N-dimethylformamide, stirred at room temperature for 30 min then added 2-chloro-1-{4- [ethyl-(2) -Methoxy-ethyl)-amino]-piperidin-1-yl}-ethanone 293a (252 mg, 1.02 mmol). The reaction mixture was heated to 50 ° C. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjj -(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-pyrrole-1-)-1-(1,1-dioxo-1λ*6*-thiamorpholin-4 -yl)-ethanone 292 (240 mg, yellow solid), Yield: 36.7%. MS m/z (ESI): 655 [M+ 1]
1H MR(400 MHz， DMSO-i 6): 59.67 (s, IH), 8.5 (s, 2H), 8.0 (s, 2H), 7.7 (s, IH), 7.69(m, IH), 7.5(m, 2H), 7.36(m, 3H), 7.2(m, IH), 6.93(m, 1H)， 6.60(s, 1H)， 5.27(s, 2H)， 4.96(m, 2H), 4.34(d5 J=8, IH), 3.92(d, J=13.6, IH), 3.56(d, J=4, 4H), 3.18(d, J=5.2; IH), 3.06(t, J=12， IH), 2.67(t, J=12.8, 1H)， 2.47(m, 4H), 1.8(s, 2H)1.3(m, 2H) 实施例 294 1H MR (400 MHz, DMSO-i 6): 59.67 (s, IH), 8.5 (s, 2H), 8.0 (s, 2H), 7.7 (s, IH), 7.69 (m, IH), 7.5 (m) , 2H), 7.36(m, 3H), 7.2(m, IH), 6.93(m, 1H), 6.60(s, 1H), 5.27(s, 2H), 4.96(m, 2H), 4.34(d 5 J=8, IH), 3.92(d, J=13.6, IH), 3.56(d, J=4, 4H), 3.18(d, J=5.2 ; IH), 3.06(t, J=12, IH) , 2.67(t, J=12.8, 1H), 2.47(m, 4H), 1.8(s, 2H)1.3(m, 2H) Example 294
「l-(3-氟 -苄基 1H-吲唑 -5-基 l-「6-(l-吗啉 -2-基甲基 -1H-吡咯 -3-基) -喹唑啉 -4-基 1-胺  "1-(3-Fluoro-benzyl 1H-indazol-5-yl-l-"6-(l-morpholin-2-ylmethyl-1H-pyrrol-3-yl)-quinazoline-4- Base 1-amine
Figure imgf000304_0001
Figure imgf000304_0001
在 50 mL茄形瓶中，将硫酸单 -(2-氨基乙基）酯 (150 mg， 1 mmol)和氢氧化钠 (40 mg， 1 mmol)溶于 1 mL zR中， 搅拌 15分钟后依次加入 [1-(3-氟-苄基) -1H-吲唑 -5- 基] -[6-(1-环氧乙基甲基 -1H-吡咯 -3-基) -喹唑啉 -4-基] -胺 178a (157 mg， 0.32 mmol) 的 2 mL二甲基亚砜溶液和 20 mL甲醇，反应液加热回流过夜。将反应液在减压下 浓缩， 加入 15 mL 40%氢氧化钠溶液， 继续加热回流反应过夜。 将反应液冷却至 室温， 调节 pH= 12， 用乙酸乙酯和甲醇的混合溶剂萃取， 合并的有机相通过饱和 氯化钠溶液洗涤， 无水硫酸钠干燥， 过滤， 减压下浓缩， 得到的残留物通过薄层 色谱板进一歩分离纯化 (二氯甲烷： 甲醇： 氨水 = 120: 10： Id), 得到本标题产物 [1-(3-氟-苄基) -1H-吲唑 -5-基] -[6-(1-吗啉 -2-基甲基 -1H-吡咯 -3-基) -喹唑啉 -4-基] -胺 294 (92 mg, 黄色固体） ， 产率： 29.3 %。  In a 50 mL eggplant bottle, mono-(2-aminoethyl) sulfate (150 mg, 1 mmol) and sodium hydroxide (40 mg, 1 mmol) were dissolved in 1 mL of zR and stirred for 15 minutes. Add [1-(3-Fluoro-benzyl)-1H-indazol-5-yl]-[6-(1-epoxyethylmethyl-1H-pyrrol-3-yl)-quinazoline-4 -Alkyl]-Amine 178a (157 mg, 0.32 mmol) in 2 mL of dimethyl sulfoxide and 20 mL of methanol. The reaction solution was concentrated under reduced pressure, and 15 mL of 40% sodium hydroxide solution was added, and the mixture was heated and refluxed overnight. The reaction mixture was cooled to room temperature, adjusted to pH = 12, and extracted with a mixed solvent of ethyl acetate and methanol. The combined organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography (dichloromethane:methanol:methanol = 120: 10: Id) to give the title product [1-(3-fluoro-benzyl)-1H-carbazole-5- -[6-(1-morpholin-2-ylmethyl-1H-pyrrol-3-yl)-quinazolin-4-yl]-amine 294 (92 mg, yellow solid), yield: 29.3 %.
MS m/z (ESI): 534[M+ 1] MS m/z (ESI): 534 [M+ 1]
ιΉ ΜΚ (400MHz, DMSO- d): 59.81(s,lH), 8.59(s,lH), 8.45(s，lH)， 8.23(s,lH), 8.17(s,lH), 8.03(d,lH,J=8.8Hz), 7.73(m,3H), 7.38(m;2H), 7.10(m,3H), 6.87(s,lH), 6.67(s,lH)， 5.72(s,2H), 3.94(m,2H), 3.76(d,lH,J=11.2Hz), 3.65(m,lH)， 3.42(m,lH), 2.76(d,lH,J=11.2Hz), 2.66(m,2H), 2.37(m,lH) 实施例 295 Ή ΜΚ (400MHz, DMSO-d): 59.81(s,lH), 8.59(s,lH), 8.45(s,lH), 8.23(s,lH), 8.17(s,lH), 8.03(d,lH , J = 8.8 Hz), 7.73 (m, 3H), 7.38 (m ; 2H), 7.10 (m, 3H), 6.87 (s, lH), 6.67 (s, lH), 5.72 (s, 2H), 3.94 (m, 2H), 3.76 (d, lH, J = 11.2 Hz), 3.65 (m, lH), 3.42 (m, lH), 2.76 (d, lH, J = 11.2 Hz), 2.66 (m, 2H) , 2.37 (m, lH) Example 295
1-Γ2-(3-{4-「3-氯 -4-(3-氟苄氧基) -苯氨基 1-喹唑啉 -6-基 吡咯 -1-基) -乙酰基 1-哌啶 -4- 甲酸乙酯  1-Γ2-(3-{4-"3-Chloro-4-(3-fluorobenzyloxy)-phenylamino-1-quinazolin-6-ylpyrroli-1-yl)-acetyl-1-piperidine -4- ethyl formate
Figure imgf000304_0002
Figure imgf000304_0002
Figure imgf000305_0001
第一步
Figure imgf000305_0001
first step
1 -(2-氯乙酰基) -哌啶 -4-甲酸乙酯  Ethyl 1-(2-chloroacetyl)-piperidine-4-carboxylate
将哌啶 -4-甲酸乙酯 (895 mg， 5.7 mmol)溶于 20 mL四氢呋喃中，搅拌下加入三 乙胺 (2 mL, 6.3 mmol),在干冰乙醇浴冷却至一 78 °C，搅拌下逐渐滴加氯乙酰氯 (0.78 mL, 6.3 mmol), 滴加完毕， 室温下搅拌 3小时反应完毕。 在反应液中加入 20 mL 水， 减压下蒸去四氢呋喃， 得到的溶液用乙酸乙酯萃取 (100 mLX 3)， 合并的有机 相依次通过水洗涤 (100 mLX 2)， 无水硫酸钠干燥， 过滤， 减压下浓缩， 得到的残 留物通过硅胶柱层析进一步分离纯化 (二氯甲烷： 甲醇 = 10: 1)， 得到 1-(2-氯乙酰 基) -哌啶 -4-甲酸乙酯 295a (1.168 g， 黄色油状液体)， 产率： 87.6%。  Ethyl piperidine-4-carboxylate (895 mg, 5.7 mmol) was dissolved in 20 mL of tetrahydrofuran. Triethylamine (2 mL, 6.3 mmol) was added with stirring. Chloroacetyl chloride (0.78 mL, 6.3 mmol) was gradually added dropwise, and the addition was completed, and the reaction was completed by stirring at room temperature for 3 hours. To the reaction mixture, 20 mL of water was added, and the mixture was evaporated to dryness, and the mixture was evaporated to ethyl acetate (100 mL). Filtration and concentrating under reduced pressure, and the residue obtained was purified by silica gel column chromatography (dichloromethane: methanol = 10:1) to give ethyl 1-(2-chloroacetyl)-piperidine-4-carboxylate. 295a (1.168 g, yellow oily liquid), Yield: 87.6%.
MS m/z (ESI): 235[M+ 1] MS m/z (ESI): 235 [M+ 1]
第二步  Second step
1_[2-(3-{4-[3-氯 -4-(3-氟苄氧基) -苯氨基] -喹唑啉 -6-基} -吡咯 -1-基) -乙酰基] -哌啶 -4- 甲酸乙酯  1_[2-(3-{4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazolin-6-yl}-pyrrol-1-yl)-acetyl] - Ethyl piperidine-4-carboxylate
将化合物 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-[6-(1Η-吡咯 -3-基)-喹唑啉 -4-基] -胺 42 The compound [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1Η-pyrrole-3-yl)-quinazolin-4-yl]-amine 42
(227 mg, 0.5 mmol)和氢化钠（78 mg， 3.25 mmol)溶于 10 mL N,N-二甲基甲酰胺 中， 室温下搅拌 30分钟后加入 1-(2-氯乙酰基) -哌啶 -4-甲酸乙酯 295a (140 mg， 0.6 mmol)的 1 mL N,N-二甲基甲酰胺溶液， 室温下搅拌 3小时反应完毕。 在反应液中 加入 100 mL乙酸乙酯和 100 mL水， 分液， 水相用乙酸乙酯萃取 (100 mL X 3)， 合 并的有机相依次通过水， 饱和氯化钠溶液洗涤， 无水硫酸钠千燥， 过滤， 减压下 浓缩， 得到的残留物通过硅胶柱层析进一步分离纯化 (二氯甲烷： 甲醇 =50: 1)， 得到标题产物 1-[2-(3-{4-[3-氯 -4-(3-氟 氧基) -苯氨基]-喹唑啉 -6-基} -吡咯 -1-基) -乙 酰基] -哌啶 -4-甲酸乙酯 295(190 mg， 黄色固体)， 产率： 44%。 (227 mg, 0.5 mmol) and sodium hydride (78 mg, 3.25 mmol) were dissolved in 10 mL of N,N-dimethylformamide, and stirred at room temperature for 30 min then added 1-(2-chloroacetyl)-piper A solution of ethyl pyridine-4-carboxylate 295a (140 mg, 0.6 mmol) in 1 mL of N,N-dimethylformamide was stirred at room temperature for 3 hours. 100 mL of ethyl acetate and 100 mL of water were added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (100 mL×3). The combined organic phases were washed sequentially with water and saturated sodium chloride. The sodium was dried, filtered, and concentrated under reduced pressure. EtOAcjjjjjjjj Ethyl 3-chloro-4-(3-fluorooxy)-phenylamino]-quinazolin-6-yl}-pyrrol-1-yl)-acetyl]-piperidine-4-carboxylate 295 (190 mg , yellow solid), Yield: 44%.
MS m/z (ESI): 643 [M+ l] MS m/z (ESI): 643 [M+ l]
1H NMR(400 MHz , DMSO-i¾)： 59.71 (s, IH), 8.55(m, IH), 8.50(m, IH), 8.03(m.2H), 7.76(m. lH), 7.7 l(d, J=8.8Hz , IH), 7.47(m, IH), 7.3 l(m, IH), 7.18(m, IH), 6.82(m, IH), 6.66(m, IH), 5.27(s, 2H)， 4.96(m, 2H), 4.22(s, lH)4.08(m, 2H), 3.85(m, 1H)， 3.17(m, IH), 2.77(m, 1H)， 6.63(m, IH), 1.87(m, 2H), 1.58(m, 2H), 1.22(t, J=7.2 Hz, 3H) 实施例 296 1H NMR (400 MHz, DMSO-i3⁄4): 59.71 (s, IH), 8.55 (m, IH), 8.50 (m, IH), 8.03 (m.2H), 7.76 (m. lH), 7.7 l (d , J=8.8Hz, IH), 7.47(m, IH), 7.3 l(m, IH), 7.18(m, IH), 6.82(m, IH), 6.66(m, IH), 5.27(s, 2H ), 4.96(m, 2H), 4.22(s, lH)4.08(m, 2H), 3.85(m, 1H), 3.17(m, IH), 2.77(m, 1H), 6.63(m, IH), 1.87(m, 2H), 1.58(m, 2H), 1.22(t, J=7.2 Hz, 3H) Example 296
1-Γ2-(3- -「3-氯 -4-(3-氟苄氧基) -苯氨基 1-喹唑啉 -6-基 吡咯小基)-乙酰基 1-哌啶 -4-  1-Γ2-(3--"3-Chloro-4-(3-fluorobenzyloxy)-phenylamino-1-quinazoline-6-ylpyrrolidinyl)-acetyl 1-piperidine-4-
Figure imgf000306_0001
Figure imgf000306_0001
第一步  First step
1-(2-氯-乙酰基) -哌啶 -4-甲酰胺  1-(2-chloro-acetyl)-piperidine-4-carboxamide
将哌啶 -4-甲酰胺 252b (150 mg， 1.17 mmol)溶于 10 mL四氢呋喃中， 溶液在 丙酮-干冰浴下冷却至 -78°C， 搅拌下加入 1 mL三乙胺和氯乙酰氯 (159 mg, 1.41 mmol), 维持此温度搅拌 40分钟反应完毕。 过滤反应液， 得到的残留物通过硅胶 柱层析分离纯化 (二氯甲烷：甲醇 =30: 1)，得到 1-(2-氯-乙酰基) -哌啶 -4-甲酰胺 296a (115 mg, 白色固体)， 产率： 85.4%。  Piperidine-4-carboxamide 252b (150 mg, 1.17 mmol) was dissolved in 10 mL of tetrahydrofuran. The solution was cooled to -78 ° C in acetone-dry ice bath and 1 mL triethylamine and chloroacetyl chloride were added with stirring. 159 mg, 1.41 mmol), maintained at this temperature and stirred for 40 minutes. The reaction solution was filtered, and the obtained residue was purified (jjjjjjjjjj , white solid), Yield: 85.4%.
MS m/z (ESI): 205[M+ 1] MS m/z (ESI): 205 [M+ 1]
第二歩 .  The second one .
1-[2-(3-{4-[3-氯 -4-(3-氟苄氧基) -苯氨基] -喹唑啉 -6-基 吡咯 -1-基) -乙酰基] -哌啶 -4- 甲酰胺  1-[2-(3-{4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazolin-6-ylpyrrol-1-yl)-acetyl]-piperidin Pyridin-4-carboxamide
在 50 mL的烧瓶中，将 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-[6-(1Η-吡咯 -3-基) -喹唑啉 -4- 基] -胺 42 (327 mg, 0.74 mmol)溶于 10 mL干燥的 Ν,Ν-二甲基甲酰胺中， 在冰浴 条件下， 冷却至 0°C， 加入氢化钠 (88 mg， 3.7 mmol), 搅拌 30分钟后加入 1-(2-氯 -乙酰基) -哌啶 -4-甲酰胺 296a (180 mg， 0.88 mmol), 室温下搅拌 2小时反应完毕。 反应液力卩入 50 mL水， 用乙酸乙酯萃取 (50 mLX 3)， 合并的有机相通过无水硫酸 钠干燥， 过滤， 减压下浓缩， 得到的残留物通过硅胶柱层析进一步分离纯化 (二氯 甲烷： 甲醇 =40: 1)， 得到本标题产物 1-[2-(3-{4-[3-氯 -4-(3-氟苄氧基) -苯氨基] -喹 唑啉 -6-基} -吡咯 -1-基) -乙酰基] -哌啶 -4-甲酰胺 296 (100 mg，黄色固体)，产率： 18.5 %。 MS m/z (ESI): 613[M+ 1] [3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1Η-pyrrol-3-yl)-quinazolin-4-yl] in a 50 mL flask -Amine 42 (327 mg, 0.74 mmol) was dissolved in 10 mL dry EtOAc EtOAc (EtOAc) After stirring for 30 minutes, 1-(2-chloro-acetyl)-piperidine-4-carboxamide 296a (180 mg, 0.88 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into 50 mL of water and extracted with ethyl acetate (50 mL×3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. (Dichloromethane: methanol = 40: 1) gave the title product 1-[2-(3-{4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazoline -6-yl}-pyrrol-1-yl)-acetyl]-piperidine-4-carboxamide 296 (100 mg, yellow solid), yield: 18.5%. MS m/z (ESI): 613 [M+ 1]
Ή NMR(400 MHz, DMSO-^6):610.00(s, IH), 8.73(s, IH), 8.48(s, IH), 8.10(d, 1H): 8.00(m, IH), 7.84(m, IH), 7.48(m, IH), 7.29(m, 4H), 7.16(m, IH), 6.79(s, 2H), 6.74(m: IH), 5.27(s, 2H), 4.95(m, 2H), 4.30(m, IH), 2.92(m, IH), 3.32(m, IH), 3.09(m, 1H): 2.67(m, IH), 1.77(m, 2H), 1.55(m， IH), 1.41(m, IH) NMR (400 MHz, DMSO-^6): 610.00 (s, IH), 8.73 (s, IH), 8.48 (s, IH), 8.10 (d, 1H): 8.00 (m, IH), 7.84 (m) , IH), 7.48(m, IH), 7.29(m, 4H), 7.16(m, IH), 6.79(s, 2H), 6.74(m : IH), 5.27(s, 2H), 4.95(m, 2H), 4.30(m, IH), 2.92(m, IH), 3.32(m, IH), 3.09(m, 1H): 2.67(m, IH), 1.77(m, 2H), 1.55(m, IH ), 1.41(m, IH)
实施例 297 Example 297
N- RVl-「3-(3-{4-「氯 -4-(3-氟苄氧基) -苯氨基 1-喹唑啉 -6-基 U-吡咯 -1-基 2-羟基- 丙基 吡咯焼 -3-基 甲酰胺  N- RVl-"3-(3-{4-"chloro-4-(3-fluorobenzyloxy)-phenylamino-1-quinazolin-6-yl U-pyrrol-1-yl 2-hydroxy-propyl Pyryrrole-3-ylformamide
Figure imgf000307_0001
Figure imgf000307_0001
187a  187a
297  297
在 100 mL茄形瓶中， 将 [1-(3-氟-苄基) -1H-吲唑 -5-基 ]-[6-(1-环氧乙基甲基 -1H- 吡咯 -3-基) -喹唑啉 -4-基] -胺 178a (200 mg, 0.41 mmol)溶解于 25 mL甲醇中，搅拌 下加入 (R)-N-(l-甲基吡咯烷 -3-基)乙酰胺（61.4 mg, 0.48 mmol), 反应液加热回流 过夜。将反应液在减压下浓缩，得到的残留物通过硅胶柱层析分离纯化 (二氯甲烷: 甲醇 =20: 1),得到本标题产物 N-{(3R)-l -[3-(3-{4- [氯 -4-(3-氟苄氧基) -苯氨基]-喹 唑啉 -6-基 1}-吡咯 -1-基) -2-羟基-丙基] -P比咯烷 -3-基}-甲酰胺 297(122 mg, 淡黄色固 体） ， 产率： 40.5 %。  [1-(3-Fluoro-benzyl)-1H-indazol-5-yl]-[6-(1-epoxyethylmethyl-1H-pyrrole-3- in a 100 mL eggplant-shaped flask - quinazolin-4-yl]-amine 178a (200 mg, 0.41 mmol) was dissolved in 25 mL of methanol and (R)-N-(l-methylpyrrolidin-3-yl) The amide (61.4 mg, 0.48 mmol) was heated to reflux overnight. The reaction mixture was concentrated under reduced pressure and purified residue purified mjjjjjjjjjjjj -{4-[Chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazolin-6-yl 1}-pyrrol-1-yl)-2-hydroxy-propyl]-P ratio Alkyl-3-yl}-carboxamide 297 (122 mg, pale yellow solid), yield: 40.5.
MS m/z (ESI): 629[M+ 1] MS m/z (ESI): 629 [M+ 1]
1H NMR(400 MHz, DMSO- 6):59.69(s, IH), 8.54(s, IH), 8.50(s, IH), 8.04(m, 2H), 7.75(m, 2H), 7.47(m, IH), 7.40(m, IH), 7.30(m, 3H), 7.19(m, IH), 6.88(s, IH), 6.68(s， IH), 5.27(s， 2H), 4.95(br, 1H)， 4.06(m, IH), 3.86(m, 2H), 2.68(m, 2H), 2.36(m, 4H), 2.08(m, 1H)， 1.79(s, 3H), 1.54(m, IH) 实施例 298  1H NMR (400 MHz, DMSO-6): 59.69 (s, IH), 8.54 (s, IH), 8.50 (s, IH), 8.04 (m, 2H), 7.75 (m, 2H), 7.47 (m, IH), 7.40(m, IH), 7.30(m, 3H), 7.19(m, IH), 6.88(s, IH), 6.68(s, IH), 5.27(s, 2H), 4.95(br, 1H) ), 4.06(m, IH), 3.86(m, 2H), 2.68(m, 2H), 2.36(m, 4H), 2.08(m, 1H), 1.79(s, 3H), 1.54(m, IH) Example 298
1— Γ3-(3-{4-「3-氯 -4-(3-氟-苄氧基 苯氨基 1-喹唑啉 -6-基 吡咯小基 2-羟基丙基 1-哌 啶 -4-甲酸乙酯 1-—3-(3-{4-"3-Chloro-4-(3-fluoro-benzyloxyphenylamino-1-quinazolin-6-ylpyrroleyl-2-hydroxypropyl 1-piperidine-4 -ethyl formate
Figure imgf000308_0001
Figure imgf000308_0001
187a  187a
哌嗪 -4-甲酸乙酯（94 mg， 0.6 mmol， Alfa)溶解于 30 mL无水乙醇中，搅拌下 加入 [3-氯 -4-(3-氟-苄基) -苯基 ]-[6-(1-环氧乙基甲基 -1H-吡咯 -3-基) -喹唑啉 -4-基] - 胺 187a (250 mg, 0.5 mmol)， 混合液加热回流过夜。 反应液在减压下浓缩， 得到 的残留物通过硅胶柱层析分离纯化 (二氯甲烷： 甲醇 = 60: 1)， 得到本标题产物 i^—p- -O氯- 4-(3-氟-苄氧基) -苯氨基]-喹唑啉 -6-基 吡咯 -1-基) -2-羟基丙基] -哌 啶 -4-甲酸乙酯 299 (260 mg, 黄色固体)， 产率： 79%。  Ethyl piperazine-4-carboxylate (94 mg, 0.6 mmol, Alfa) was dissolved in 30 mL of absolute ethanol and [3-chloro-4-(3-fluoro-benzyl)-phenyl]-[ 6-(1-Epoxyethylmethyl-1H-pyrrol-3-yl)-quinazolin-4-yl]-amine 187a (250 mg, 0.5 mmol). The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjj -benzyloxy)-phenylamino]-quinazolin-6-ylpyrrol-1-yl)-2-hydroxypropyl]-piperidine-4-carboxylic acid ethyl ester 299 (260 mg, yellow solid), yield : 79%.
MS m/z (ESI): 658[M+] MS m/z (ESI): 658 [M + ]
Ή NMR(400 MHz, DMSO-i d):59.69(s, IH), 8.54(s, 1H)， 8.50(s, IH), 8.04(m, 2H), 7.75(m, 2H), 7.47(m, IH), 7.40(m, IH), 7.30(m, 3H), 7.19(m, IH), 6.88(s, IH), 6.68(s, IH), 5.27(s, 2H), 4.90(s, IH), 4.05(m, 3H), 3.89(m, 2H), 2.8 l(m, 2H), 2.30(m, 3H), 2.06(m, 2H), 1.81(m, 2H), 1.64(m, 2H), 1.17(t, J=6.8Hz, 3H)  NMR (400 MHz, DMSO-i d): 59.69 (s, IH), 8.54 (s, 1H), 8.50 (s, IH), 8.04 (m, 2H), 7.75 (m, 2H), 7.47 (m) , IH), 7.40(m, IH), 7.30(m, 3H), 7.19(m, IH), 6.88(s, IH), 6.68(s, IH), 5.27(s, 2H), 4.90(s, IH), 4.05(m, 3H), 3.89(m, 2H), 2.8 l(m, 2H), 2.30(m, 3H), 2.06(m, 2H), 1.81(m, 2H), 1.64(m, 2H), 1.17(t, J=6.8Hz, 3H)
实施例 299 Example 299
1-(3-ί4-「1-ί3-氟苄基 MH-吲唑 -5-基氨基 1-喹唑啉 -6-基 吡咯 -1-基) -3-(4-吡啶 -4-基  1-(3-ί4-"1-ί3-fluorobenzyl MH-indazol-5-ylamino-1-quinazolin-6-ylpyrrol-1-yl)-3-(4-pyridin-4-yl)
Figure imgf000308_0002
Figure imgf000308_0002
178a 在 100 mL茄形瓶中， 将 [1-(3-氟-苄基)- 1Η-吲唑 -5-基] -[6-(1-环氧乙基甲基 -1H- 吡咯 -3-基)-喹唑啉 -4-基] -胺 178a (225 mg, 0.46 mmol)溶解于 20 mL甲醇中， 搅 拌下加入 1-吡啶 -4-基甲基 -哌嗪 (163 mg， 0.92 mmol), 反应液加热回流过夜。 将 反应液在减压下浓縮，得到的残留物通过薄层色谱板分离纯化 (二氯甲 ： 甲醇 = 10： 1)， 得到本标题产物 1-(3-{4-[1-(3-氟 基) -1H-吲唑 -5-基氣基] -喹唑啉- 6-基 吡咯 -1-基) -3-(4-吡啶 -4-基甲基 -哌嗪 -1-基) -丙 -2-醇 299 (100 mg, 黄棕色固体） ， 产率： 33 %。 178a [1-(3-Fluoro-benzyl)- 1Η-indazol-5-yl]-[6-(1-epoxyethylmethyl-1H-pyrrole-3- in a 100 mL eggplant-shaped flask Base quinazolin-4-yl]-amine 178a (225 mg, 0.46 mmol) was dissolved in 20 mL MeOH. &lt;RTI ID=0.0&gt;&gt; The reaction solution was heated to reflux overnight. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified (yield: chloroform:methanol = 10:1) to give the title product 1-(3-{4-[1-(3) -fluoro))-1H-indazol-5-ylyl]-quinazoline-6-ylpyrrol-1-yl)-3-(4-pyridin-4-ylmethyl-piperazin-1-yl ) - propan-2-ol 299 (100 mg, yellow-brown solid), Yield: 33%.
MS m/z (ESI): 668[M+ 1] MS m/z (ESI): 668 [M+ 1]
1HNMR (400MHz, OMSO-d6): 69.8 l(s, 1H), 8.59(s， 1H), 8.5 l(m, 2H), 8.44(s, 1H), 8.22(s, 1H), 8.17(s, 1H), 8.03(m, 1H), 7.73 (m, 3H), 7.42(s, 1H), 7.39(m, 1H), 7.3 l(m, 2H), 7.11 (m， 3H), 6.87(s, 1H), 6.66(s, 1H), 5.72(s, 2H), 4.93(m, 1H), 4.06(m, 3H), 3.51(s, 2H), 2.44(m, 7H), 2.36(m, 3H) 1 H NMR (400MHz, OMSO-d6): 69.8 l(s, 1H), 8.59(s, 1H), 8.5 l(m, 2H), 8.44(s, 1H), 8.22(s, 1H), 8.17(s , 1H), 8.03(m, 1H), 7.73 (m, 3H), 7.42(s, 1H), 7.39(m, 1H), 7.3 l(m, 2H), 7.11 (m, 3H), 6.87(s , 1H), 6.66(s, 1H), 5.72(s, 2H), 4.93(m, 1H), 4.06(m, 3H), 3.51(s, 2H), 2.44(m, 7H), 2.36(m, 3H)
. 实施例 300 Example 300
1-(3-{4-Π-(3-氟苄基 -1H-吲唑 -5-基氨基 1-喹唑啉 -6-基) -吡咯 -1 -基) -3-(4-吡啶 -3-基 甲基 -哌嗪 -1-基) -丙 -2-醇  1-(3-{4-Π-(3-fluorobenzyl-1H-indazol-5-ylamino-1-quinazolin-6-yl)-pyrrole-1 -yl)-3-(4-pyridine -3-ylmethyl-piperazin-1-yl)-propan-2-ol
Figure imgf000309_0001
在 100 mL茄形瓶中， 将 [1- (3-氟-苄基) -1H-吲唑 -5-基] -[6-(1-环氧乙基甲基 -1H- 吡咯 -3-基) -喹唑啉 -4-基] -胺 178a (225 mg, 0.46 mmol)溶解于 20 mL甲醇中，搅拌 下加入 2-吗啉 -3-基 -乙胺（163 mg， 0.92 mmol) , 反应液加热回流过夜。 将反应液 在减压下浓缩， 得到的残留物通过薄层色谱板分离纯化 (二氯甲烷： 甲醇 = 10: 1), 得到本标题产物 1-(3-{4-[1-(3-氟苄基 )-1Η-吲唑 -5-基氨基] -喹唑啉 -6-基} -吡咯 -1- 基) -3-(4-吡啶 -3-基甲基 -哌嗪小基) -丙 -2-醇 300 (92 mg， 黄色固体） ， 产率： 36 %。 MS m/z (ESI): 668[M+ 1]
Figure imgf000309_0001
[1-(3-Fluoro-benzyl)-1H-indazol-5-yl]-[6-(1-epoxyethylmethyl-1H-pyrrole-3- in a 100 mL eggplant-shaped flask - quinazolin-4-yl]-amine 178a (225 mg, 0.46 mmol) was dissolved in 20 mL of methanol and then added 2-morpholin-3-yl-ethylamine (163 mg, 0.92 mmol). The reaction solution was heated to reflux overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified (yield: methylene chloride:methanol = 10:1) to give the title product 1-(3-{4-[1-(3- Fluorobenzyl)-1Η-indazol-5-ylamino]-quinazolin-6-yl}-pyrrol-1-yl)-3-(4-pyridin-3-ylmethyl-piperazine small group) -propan-2-ol 300 (92 mg, yellow solid), Yield: 36%. MS m/z (ESI): 668 [M+ 1]
lHNMR (400MHz, DMSO- 6): 59.81(s, 1H), 8.59(s, 1H), 8.5 l(m, 2H), 8.44(s, 1H), 8.22(s, 1H), 8.17(s, 1H), 8.03(m, 1H)， 7.73(m, 3H), 7.42(s, 1H), 7.39(m, 1H), 7.3 l(m, 2H), 7.11(m， 3H), 6.87(s, 1H), 6.66(s, 1H), 5.72(s, 2H), 4.93(m, 1H), 4.06(m, 3H), .51(s, 2H), 2.44(m, 7H), 2.36(m, 3H) 实施例 301 lHNMR (400MHz, DMSO-6): 59.81 (s, 1H), 8.59 (s, 1H), 8.5 l (m, 2H), 8.44 (s, 1H), 8.22 (s, 1H), 8.17 (s, 1H) ), 8.03(m, 1H), 7.73(m, 3H), 7.42(s, 1H), 7.39(m, 1H), 7.3 l(m, 2H), 7.11(m, 3H), 6.87(s, 1H ), 6.66(s, 1H), 5.72(s, 2H), 4.93(m, 1H), 4.06(m, 3H), .51(s, 2H), 2.44(m, 7H), 2.36(m, 3H) Example 301
(S)-l-二乙氨基 -3-(3-{4-「l-(3-氟-苄基) -IH-吲唑 -5-基氨基 1-喹唑啉 -6-基 吡咯 -1- 基) -丙 -2-醇  (S)-l-Diethylamino-3-(3-{4-"1-(3-fluoro-benzyl)-IH-indazol-5-ylamino-1-quinazolin-6-ylpyrrole- 1-yl)-propan-2-ol
Figure imgf000310_0001
第一步
Figure imgf000310_0001
first step
(S)-[l-(3-氟-苄基) -1H-吲唑 -5-基] - [6-(1-环氧乙基甲基 -1H-吡咯 -3-基) -喹唑啉 -4-基] - 胺  (S)-[l-(3-Fluoro-benzyl)-1H-indazol-5-yl]-[6-(1-Epoxyethylmethyl-1H-pyrrol-3-yl)-quinazole Phenyl-4-yl]-amine
在 100 mL茄形瓶中， 将 [l-O氟 -苄基 H-吲唑 -5-基 )-[6-(1Η-吡咯 -3-基) -喹唑啉- 基] -胺 150 (300 mg， 0.69mmol)溶于 5 mL的 N，N-二甲基甲酰胺中， 冰浴冷却至 0°C， 加入氢化钠 (60 mg， 2.76 mmol), 搅拌 30分钟后， 室温下加入 (R)-2-氯甲基 环氧乙烷 (148 mg， 1.6 mmol), 1小时后反应完毕。 将反应液倒入 100 mL冰水中， 用乙酸乙酯 (100 mLX 3)萃取， 合并的有机相依次通过有机相依次通过水洗涤， 饱 和氯化钠溶液洗涤， 无水硫酸钠干燥， 过滤， 减压下浓缩， 得到的粗品 (S)-[l-(3- 氟-苄基) -1H-吲唑 -5-基 ]-[6-(1-环氧乙基甲基 -1H-吡略 -3-基:) -喹唑啉 -4-基] -胺 301a (黄色固体)， 产物不经分离直接进行下一步反应。  In a 100 mL eggplant-shaped flask, [lOfluoro-benzyl H-carbazol-5-yl)-[6-(1Η-pyrrol-3-yl)-quinazolinyl]-amine 150 (300 mg , 0.69mmol) was dissolved in 5 mL of N,N-dimethylformamide, cooled to 0 ° C in ice-bath, sodium hydride (60 mg, 2.76 mmol) was added, stirred for 30 minutes, then added at room temperature (R) 2-Chloromethyloxirane (148 mg, 1.6 mmol), the reaction was completed after 1 hour. The reaction solution was poured into 100 mL of ice water and extracted with ethyl acetate (100 mL×3). The combined organic phases were washed sequentially with water, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and reduced. Concentration under pressure, the obtained crude product (S)-[l-(3-fluoro-benzyl)-1H-indazol-5-yl]-[6-(1-epoxyethylmethyl-1H-pyrrol 3-yl:)-quinazolin-4-yl]-amine 301a (yellow solid), the product was directly subjected to next reaction without isolation.
第二步  Second step
(S)小二乙氨基 -3-(3-{4-[1-(3-氟-苄基) -1H-吲唑 -5-基氨基] -喹唑啉 -6-基}-吡咯 -1- 基) -丙 -2-醇  (S) Small diethylamino-3-(3-{4-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-quinazolin-6-yl}-pyrrole- 1-yl)-propan-2-ol
将上述步骤所得的粗品 (S)-[l-(3-氟-苄基) -1H-吲唑 -5-基] -[6-(1-环氧乙基甲基 -1H-吡咯 -3-基) -喹唑啉 -4-基] -胺 301a溶于 25 mL甲醇中， 搅拌下加入二乙胺 （152 mg， 2.07 nraiol), 反应液加热回流过夜。 将反应液在减压下浓缩， 得到的残留物 通过薄层色谱板分离纯化，得到标题产物 (S)-l-二乙氨基 -3-(3-{4-[1-(3-氟-节基) -1H- 吲唑 -5-基氨基] -喹唑啉 -6-基}-吡咯 -1-基) -丙 -2-醇 301 (60 mg, 黄棕色固体)， 产率: 15 %。 The crude product obtained in the above step (S)-[l-(3-fluoro-benzyl)-1H-indazol-5-yl]-[6-(1-epoxyethylmethyl) -1H-pyrrol-3-yl)-quinazolin-4-yl]-amine 301a was dissolved in 25 mL of methanol, and diethylamine (152 mg, 2.07 nraiol) was added with stirring, and the reaction mixture was heated to reflux overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified mjjjjjjjjjjjjj -1H-carbazol-5-ylamino]-quinazolin-6-yl}-pyrrol-1-yl)-propan-2-ol 301 (60 mg, yellow-brown solid), yield: 15 %.
MS m/z (ESI): 564[M+ 1]  MS m/z (ESI): 564 [M+ 1]
!HNMR (400MHz, DMSO- 6): 59.93(s, 1H), 8.69(s, 1H), 8.45(s, 1H), 8.24(s, 1H)， 8.17(s， 1H), 8.04(m, 1H), 7.75(m, 3H), 7.51(s, 1H), 7.41 (m, 1H), 7.09(m, 3H), 6.93(s, 1H)， 6.74(s， 1H), 5.72(s, 2H), 4.25(m, 1H)， 4.11(m, 1H)， 3.98(m, 1H), 3.03(m, 6H), 1.24(m, 6H) 实施例 302 ! HNMR (400MHz, DMSO- 6) : 59.93 (s, 1H), 8.69 (s, 1H), 8.45 (s, 1H), 8.24 (s, 1H), 8.17 (s, 1H), 8.04 (m, 1H ), 7.75(m, 3H), 7.51(s, 1H), 7.41 (m, 1H), 7.09(m, 3H), 6.93(s, 1H), 6.74(s, 1H), 5.72(s, 2H) 4.25(m, 1H), 4.11(m, 1H), 3.98(m, 1H), 3.03(m, 6H), 1.24(m, 6H) Example 302
1-二乙氨基 -3-(3-ί4-「1-(3-氟苄基) -1H-吲唑 -5-基氨基 1-喹唑啉 -6-基 吡咯 -1-基) -丙  1-Diethylamino-3-(3-ί4-"1-(3-fluorobenzyl)-1H-indazol-5-ylamino-1-quinazolin-6-ylpyrrol-1-yl)-propane
-2-醇  -2-ol
Figure imgf000311_0001
第一步
Figure imgf000311_0001
first step
(R)-[l-(3-氟- 基) -1Η-吲唑 -5-基] - [6-(1-环氧乙基甲基 -1Η-吡咯 -3-基) -喹唑啉 -4- 基] -胺  (R)-[l-(3-Fluoro-yl)-1Η-indazol-5-yl]-[6-(1-Epoxyethylmethyl-1Η-pyrrol-3-yl)-quinazoline -4-yl]-amine
在 100 mL茄形瓶中， 将 [1-(3-氟 -苄基 H-吲唑 -5-基) -[6-(1Η-吡咯 -3-基) -喹唑啉- 基] -胺 150 (300 mg, 0.69mmol)溶于 5 mL的 Ν,Ν-二甲基甲酰胺中， 冰浴冷却至 0°C， 加入氢化钠 (60 mg， 2.76 mmol), 搅拌 30分钟后， 室温下加入 (S)-2-氯甲基环 氧乙垸 (148 mg, 1.6 mmol), 1小时后反应完毕。 将反应液倒入 100 mL冰水中， 用 乙酸乙酯 (100 mLX 3)萃取， 合并的有机相依次通过有机相依次通过水洗涤， 饱和 氯化钠溶液洗涤， 无水硫酸钠干燥， 过滤， 减压下浓缩， 得到的粗品 (R)-[l-(3-氟- 苄基) -1H-吲唑 -5-基] -[6-(1-环氧乙基甲基 -1H-吡咯 -3-基)-喹唑啉 -4-基] -胺 302a (黄色 固体)， 产物不经分离直接进行下一步反应。 [1-(3-Fluoro-benzyl H-indazol-5-yl)-[6-(1Η-pyrrol-3-yl)-quinazolinyl]-amine in a 100 mL eggplant-shaped flask 150 (300 mg, 0.69 mmol) dissolved in 5 mL of hydrazine, hydrazine-dimethylformamide, cooled to ice bath After adding sodium hydride (60 mg, 2.76 mmol) at 0 ° C, stirring for 30 minutes, (S)-2-chloromethyloxirane (148 mg, 1.6 mmol) was added at room temperature, and the reaction was completed after 1 hour. The reaction solution was poured into 100 mL of ice water and extracted with ethyl acetate (100 mL×3). The combined organic phases were washed sequentially with water, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and reduced. Concentration under pressure gave the crude product (R)-[l-(3-fluoro-benzyl)-1H-indazol-5-yl]-[6-(1-epoxyethylmethyl-1H-pyrrole- 3-yl)-quinazolin-4-yl]-amine 302a (yellow solid), the product was taken directly to the next step without isolation.
第二步  Second step
(R)-l-二乙氨基 -3-(3-{4-[1-(3-氟-苄基) -1H-吲唑 -5-基氨基] -喹唑啉 -6-基} -吡咯 -1- 基) -丙 -2-醇  (R)-l-Diethylamino-3-(3-{4-[1-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-quinazolin-6-yl} Pyrrol-1-yl)-propan-2-ol
将上述步骤所得的粗品 (R)-[l-(3-氟-苄基) -1H-吲唑 -5-基] -[6-(1-环氧乙基甲基 The crude product obtained in the above step (R)-[l-(3-fluoro-benzyl)-1H-indazole-5-yl]-[6-(1-epoxyethylmethyl)
-1H-吡咯 -3-基) -喹唑啉 -4-基] -胺 302a溶于 25 mL甲醇中， 搅拌下加入二乙胺（152 mg， 2.07 mmol), 反应液加热回流过夜。 将反应液在减压下浓缩， 得到的残留物 通过薄层色谱板分离纯化， 得到标题产物 (R)-l-二乙氨基 -3-(3-{4-[1-(3-氟-苄 基) -1H-吲唑 -5-基氨基 ]-喹唑啉 -6-基} -吡咯 -1-基) -丙 -2-醇 302 (35 mg,黄棕色固体)， 产率： 10%。 -1H-pyrrolidin-3-yl)-quinazolin-4-yl]-amine 302a was dissolved in 25 mL of methanol and diethylamine (152 mg, 2.07 mmol). The reaction mixture was concentrated under reduced pressure, and the residue was purified mjjjjjjjjj Benzyl)-1H-indazol-5-ylamino]-quinazolin-6-yl}-pyrrol-1-yl)-propan-2-ol 302 (35 mg, yellow-brown solid), Yield: 10 %.
MS m/z (ESI): 564 [M+ 1]  MS m/z (ESI): 564 [M+ 1]
^MR (400MHz, DMSO-ί/ό): 59.93(s, 1H), 8.69(s, 1H), 8.45(s, 1H), 8.24(s, 1H), 8.17(s, 1H)， 8.04(m, 1H), 7.75(m, 3H), 7.5 l(s, 1H), 7.41 (m, 1H), 7.09(m, 3H), 6.93 (s, 1H), 6.74(s, 1H), 5.72(s, 2H), 4.25(m, 1H), 4.11(m, 1H), 3.98(m, 1H), 3.03(m, 6H), 1.24(m, 6H) 实施例 303  ^MR (400MHz, DMSO-ί/ό): 59.93(s, 1H), 8.69(s, 1H), 8.45(s, 1H), 8.24(s, 1H), 8.17(s, 1H), 8.04(m , 1H), 7.75(m, 3H), 7.5 l(s, 1H), 7.41 (m, 1H), 7.09(m, 3H), 6.93 (s, 1H), 6.74(s, 1H), 5.72(s , 2H), 4.25 (m, 1H), 4.11 (m, 1H), 3.98 (m, 1H), 3.03 (m, 6H), 1.24 (m, 6H) Example 303
Γ3-氯 -4-(3-氟苄氧基) -苯基 W6-fl-(2-甲氨基 -乙基 )-1Η-吡咯 -3-基卜喹唑啉 -4-基 胺  Γ3-Chloro-4-(3-fluorobenzyloxy)-phenyl W6-fl-(2-methylamino-ethyl)-1Η-pyrrole-3-ylbuquinazoline-4-ylamine
Figure imgf000312_0001
Figure imgf000312_0001
303 303
Figure imgf000313_0001
第一步
Figure imgf000313_0001
first step
甲磺酸 2- (叔丁氧羰基-甲氨基) -乙酯  Methanesulfonic acid 2-(tert-butoxycarbonyl-methylamino)-ethyl ester
将 2-甲氨基-乙醇溶于 10 mL四氢呋喃和 1 mL水的混合溶剂中， 搅拌下依次 加入碳酸氢钠 (840 mg， 10 mmol)和二碳酸二叔丁酯 (2.18 g， 10 mmol), 室温下搅 拌过夜。 将反应液在减压下浓缩， 残渣中加入 50 mL乙酸乙酯， 得到的混合液依 次通过水洗涤， 饱和氯化钠溶液洗涤， 无水硫酸钠干燥， 过滤， 减压下浓缩， 得 到的残渣 (1.7 g)备用。  2-Methylamino-ethanol was dissolved in a mixed solvent of 10 mL of tetrahydrofuran and 1 mL of water, and sodium hydrogencarbonate (840 mg, 10 mmol) and di-tert-butyl dicarbonate (2.18 g, 10 mmol) were sequentially added under stirring. Stir at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and ethyl acetate (50 mL) was evaporated. The mixture was washed with water, and the mixture was washed with water, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. (1.7 g) spare.
将上述步骤的残渣溶于 20 mL二氯甲烷中， 搅拌下加入三乙胺 (2.1 mL, 15 mmol), 将反应液在冰浴下冷却至 0°C， 逐渐加入甲磺酰氯 (981 mg， 12 mmol), 室 温下搅拌 30分钟， 反应完毕。 将反应液在减压下浓缩， 加入 50 mL乙酸乙酯， 得 到的溶液依次通过水洗涤， 饱和氯化钠溶液洗涤， 无水硫酸钠干燥， 过滤， 减压 下浓缩， 得到的残留物通过硅胶柱层析进一步分离纯化 (二氯甲烷： 甲醇 = 15 : 1)， 得到甲磺酸 2- (叔丁氧羰基-甲氨基) -乙酯 303a (2.4 g， 黄色油状液体)， 产率： 94.8 %。  The residue of the above step was dissolved in 20 mL of dichloromethane, and triethylamine (2.1 mL, 15 mmol) was added with stirring. The reaction solution was cooled to 0 ° C in an ice bath, and then methanesulfonyl chloride (981 mg, 12 mmol), stirred at room temperature for 30 minutes, and the reaction was completed. The reaction mixture was concentrated under reduced pressure and ethyl acetate (50 mL) was evaporated. EtOAcjjjjjjjjjjjjj Further separation and purification by column chromatography (dichloromethane:methanol = 15:1) gave 2-(t-butoxycarbonyl-methylamino)ethyl ester methanesulfonate 303a (2.4 g, yellow oily liquid), yield: 94.8 %.
MS m/z (ESI): 254[M+ 1]  MS m/z (ESI): 254 [M+ 1]
第二步  Second step
[2_(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基]-喹唑啉 -6-基}-吡咯 -1-基)-乙基] -甲基 -氨基 甲酸叔丁酯 [ 2 _(3-{4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-pyrrol-1-yl)-ethyl] - Methyl-carbamic acid tert-butyl ester
在 50 mL的烧瓶中，将 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-[6-(1Η-吡咯 -3-基)-喹唑啉 -4- 基] -胺 42 (223 mg, 0.5 mmol)溶解于 25 mL干燥的 Ν,Ν-二甲基甲酰胺中， 在冰浴 条件下， 冷却至 0°C , 加入氢化钠 (80 mg， 3.3 mmol), 搅拌 30分钟后加入甲磺酸 2- (叔丁氧羰基-甲氨基) -乙酯 303a (190 mg， 0.75 mmol), 室温下搅拌 3小时反应完 毕。 反应液加入 20 mL水， 乙酸乙酯萃取 (30 mLX 3)， 合并的有机相依次通过饱 和氯化钠溶液洗涤， 无水硫酸钠干燥， 过滤， 减压下浓缩， 得到的残留物通过硅 胶柱层析进一步分离纯化 (二氯甲烷： 甲醇 = 10: 1)， 得到 [2-(3-{4-[3-氯 -4-(3-氟- 苄氧基) -苯氨基] -喹唑啉 -6-基 吡咯 -1-基) -乙基] -甲基-氨基甲酸叔丁酯 303b (285 mg， 黄色固体)， 产率： 95%。 [3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1Η-pyrrol-3-yl)-quinazolin-4-yl] in a 50 mL flask -Amine 42 (223 mg, 0.5 mmol) was dissolved in EtOAc (EtOAc (EtOAc:EtOAc) After stirring for 30 minutes, 2-(tert-butoxycarbonyl-methylamino)-ethyl sulfonate 303a (190 mg, 0.75 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was added with 20 mL of water, extracted with ethyl acetate (30 mL×3), and the combined organic phases were passed through The mixture was washed with a sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated. -{4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-ylpyrrol-1-yl)-ethyl]-methyl-carbamic acid tert-butyl Ester 303b (285 mg, yellow solid), Yield: 95%.
MS m/z (ESI): 602[M+ 1]  MS m/z (ESI): 602 [M+ 1]
第三歩  Third
[3-氯 -4-(3-氟苄氧基)-苯基] -{6- [1-(2-甲氨基-乙基) -1H-吡咯 -3-基] -喹唑啉 -4-基} -胺 将 [2-(3-{4-[3-氯 -4-(3-氟-节氧基) -苯氨基] -喹唑啉 -6-基} -吡咯 -1-基)-乙基] -甲基- 氨基甲酸叔丁酯 303b (285 mg， 0.47 mmol)溶于 5 mL二氯甲烷中，搅拌下加入 5 mL 三氟乙酸， 室温下搅拌 2小时反应完毕。 反应液在减压下浓缩， 加入 30 mL饱和 碳酸氢钠溶液， 乙酸乙酯萃取 (50 mLX 3)，合并的有机相依次通过饱和氯化钠溶液 洗涤， 无水硫酸钠干燥， 过滤， 减压下浓缩， 得到的粗品通过乙酸乙酯重结晶， 得到本标题产物 [J-氯 -4-(3-氟苄氧基) -苯基 ]-{6-[1-(2-甲氨基-乙基) -1H-吡咯 -3-基] - 喹唑啉 _4-基} -胺 303 (195 mg， 黄色固体)， 产率： 83 %。  [3-chloro-4-(3-fluorobenzyloxy)-phenyl]-{6-[1-(2-methylamino-ethyl)-1H-pyrrol-3-yl]-quinazoline-4 -yl}-amine [2-(3-{4-[3-chloro-4-(3-fluoro-p-oxy)-phenylamino]-quinazolin-6-yl}-pyrrol-1-yl -ethyl]-methyl-carbamic acid tert-butyl ester 303b (285 mg, 0.47 mmol) was dissolved in 5 mL of dichloromethane, and 5 mL of trifluoroacetic acid was added under stirring, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc)EtOAc. Concentration, the obtained crude product was crystallized from ethyl acetate to give the title product [J-chloro-4-(3-fluorobenzyloxy)-phenyl]-{6-[1-(2-methylamino-B -1H-pyrrol-3-yl]-quinazoline-4-yl}-amine 303 (195 mg, yellow solid), yield: 83%.
MS m/z (ESI): 502[M+ 1]  MS m/z (ESI): 502 [M+ 1]
'H NMR(400MHz, DMSO-C?(5):510.18(S, lH), 8.91(S,1H), 8.49(S, lH), 8.18(d，  'H NMR (400MHz, DMSO-C?(5): 510.18(S, lH), 8.91(S,1H), 8.49(S, lH), 8.18(d,
J=2.4Hz, 1H), 8.03(d, J=8.8Hz, 1H), 7.92(m, 1H), 7.70(m, 2H)， 7.47(m, 1H),  J=2.4Hz, 1H), 8.03(d, J=8.8Hz, 1H), 7.92(m, 1H), 7.70(m, 2H), 7.47(m, 1H),
7.3 l(m, 3H), 7.17(m, 1H), 6.98(s, 1H), 6.86(s, 1H), 5.27(s, 2H), 4.35(d, J=6.4Hz, 2H), 3.32(d, J=6.4Hz, 2H), 2.47(s, 3H) 实施例 304  7.3 l(m, 3H), 7.17(m, 1H), 6.98(s, 1H), 6.86(s, 1H), 5.27(s, 2H), 4.35(d, J=6.4Hz, 2H), 3.32( d, J = 6.4 Hz, 2H), 2.47 (s, 3H) Example 304
(6-Π-「4-(2-二乙氨基-乙基) -吗啉 -2-基甲基 1-lH-吡咯 -3-基 }-喹唑啉 -4-基 M 3-氟- 苄基) -1H-吲唑 -5-基 1-胺  (6-Π-"4-(2-Diethylamino-ethyl)-morpholin-2-ylmethyl 1-lH-pyrrol-3-yl}-quinazolin-4-yl M 3-fluoro- Benzyl)-1H-indazole-5-yl 1-amine
Figure imgf000314_0001
Figure imgf000314_0001
将 [1-(3-氟-苄基) -1H-吲唑 -5-基] -[6-(1-吗啉 -2-基甲基 -1H-吡咯 -3-基) -喹唑啉 -4- 基] -胺 294 (100 mg， 0.19 mmol)溶于 2 mL二甲基亚砜， 氩气保护下， 加入氢氧化 钾 (100 mg， 1.8 mmol), 室温下搅拌 30分钟后加入 (2-溴-乙基) -二乙基-胺 (59 mg, 0.23 mmol), 25 °C下搅拌 3小时反应完毕。将反应液倒入 50 mL冰水中， 乙酸乙酯 萃取 (50 mLX 4)， 合并的有机相依次通过无水硫酸钠干燥， 过滤， 减压下浓缩， 得 到的残留物通过硅胶柱层析分离纯化 (二氯甲垸： 甲醇 = 10: 1), 得到本标题产物 (6-{ 1-[4- (2-二乙氨基-乙基) -吗啉 -2-基甲基] -1H-吡咯 -3-基 喹唑啉 -4-基) -[1-(3-氟- 苄基) -1H-吲唑 -5-基] -胺 304(30 mg， 淡黄色固体)， 产率： 24.9%。 [1-(3-Fluoro-benzyl)-1H-indazol-5-yl]-[6-(1-morpholin-2-ylmethyl-1H-pyrrol-3-yl)-quinazoline -4- -Amine 294 (100 mg, 0.19 mmol) was dissolved in 2 mL of dimethyl sulfoxide under argon. Potassium hydroxide (100 mg, 1.8 mmol) was added and stirred at room temperature for 30 min. -ethyl)-Diethyl-amine (59 mg, 0.23 mmol), stirred at 25 ° C for 3 hours. The reaction mixture was poured into 50 mL of ice water and extracted with ethyl acetate (50 mL×4). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated. (Chlorochloroformamide: Methanol = 10: 1) gave the title product (6-{ 1-[4-(2-diethylamino-ethyl)-morpholin-2-ylmethyl]-1H-pyrrole -3-ylquinazolin-4-yl)-[1-(3-fluoro-benzyl)-1H-indazol-5-yl]-amine 304 (30 mg, pale yellow solid), Yield: 24.9 %.
MS m/z (ESI): 633[M+ 1] MS m/z (ESI): 633 [M+ 1]
' HNMR (400MHZ, OMSO-d6): 69.85(s,lH), 8.62(s,lH), 8.45(s,lH)， 8.23(s,lH), 8.17(s,lH), 8.03(d,lH,J=8.8Hz), 7.74(m,3H), 7.39(m,2H), 7.08(m,3H),  'HNMR (400MHZ, OMSO-d6): 69.85(s,lH), 8.62(s,lH), 8.45(s,lH), 8.23(s,lH), 8.17(s,lH), 8.03(d,lH , J=8.8Hz), 7.74(m,3H), 7.39(m,2H), 7.08(m,3H),
6.88(s,lH),6.68(s,lH), 5.72(s,2H), 4.00(m,2H), 3.82(d,lH,J=11.2Hz), 3.75(m,lH), 3.49(m,lH), 2.80(d,lH,J=11.2Hz), 2.70(m,lH), 2.55(m，3H)， 2.42(m,3H),  6.88(s,lH), 6.68(s,lH), 5.72(s,2H), 4.00(m,2H), 3.82(d,lH,J=11.2Hz), 3.75(m,lH), 3.49(m , lH), 2.80 (d, lH, J = 11.2 Hz), 2.70 (m, lH), 2.55 (m, 3H), 2.42 (m, 3H),
2.06(t,2H,J=10.4Hz), 1.83(t,2H,J=10.4Hz), 0.98(m,6H) 2.06(t,2H,J=10.4Hz), 1.83(t,2H,J=10.4Hz), 0.98(m,6H)
实施例 305 Example 305
(4- -D-氯 -4-(3-氟苄氧基) -苯氨基 1-喹唑啉 -6-基 }-1Η-吡咯 -2-基) -甲醇  (4--D-Chloro-4-(3-fluorobenzyloxy)-phenylamino-1-quinazoline-6-yl}-1Η-pyrrole-2-yl)-methanol
Figure imgf000315_0001
Figure imgf000315_0001
将 4-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基] -喹唑啉 -6-基 }-1_ (甲苯基 -4-磺酰基 )-1Η- 吡咯 -2-羧酸甲酯 167 (1 g， 1.5 mmol)溶于 30 mL四氢呋喃中， 冰浴冷却至 0°C， 搅 拌下分批加入氢化铝锂 (470 mg， 7.5 mmol), 保持 0°C搅拌 1小时反应完毕。 加入 5 mL甲醇淬灭反应， 反应液在减压下浓缩， 得到的残留物通过硅胶柱层析进一步 分离纯化 (二氯甲烷： 甲醇 = 50: 1)， 得到标题产物 (4-{4-[3-氯 -4-(3-氟苄氧基) -苯氨 基] -喹唑啉 -6-基}-111-吡咯 -2-基) -甲醇 305 (300 mg, 黄色固体)， 产率： 42.2%。 MS m/z (ESI): 475[M+ 1]  4-{4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-1_(tolyl-4-sulfonyl)-1Η-pyrrole Methyl 2-carboxylate 167 (1 g, 1.5 mmol) was dissolved in 30 mL of tetrahydrofuran, cooled to 0 ° C with ice-cooling, and lithium aluminum hydride (470 mg, 7.5 mmol) was added portionwise with stirring, maintaining 0 ° C The reaction was completed by stirring for 1 hour. The reaction was quenched by the addition of 5 mL of EtOAc (EtOAc) (EtOAc) 3-Chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazolin-6-yl}-111-pyrrol-2-yl)-methanol 305 (300 mg, yellow solid), yield: 42.2%. MS m/z (ESI): 475 [M+ 1]
lHNMR (400MHz, DMSO- <5): 511.02(s, 1H), 9.69(m, 1H), 8.55(m, 1H), 8.49(m, 1H), 8.05(m,2H), 7.78(m,lH), 7.69(d, J=8.0Hz5 1H)， 7.47(m, 1H), 7.3 l(m, 4H), 7.17(m, lH),6.60(m, lH),5.27(s, 2H),4.45(d, J=5.2Hz, 2H) 实施例 306 lHNMR (400MHz, DMSO- <5): 511.02 (s, 1H), 9.69 (m, 1H), 8.55 (m, 1H), 8.49 (m, 1H), 8.05 (m, 2H), 7.78 (m, lH) ), 7.69 (d, J = 8.0 Hz 5 1H), 7.47 (m, 1H), 7.3 l (m, 4H), 7.17 (m, lH), 6.60 (m, lH), 5.27 (s, 2H), 4.45 (d, J = 5.2 Hz, 2H) Example 306
2-(3-{4-「3-氯 -4-(3-氟-苄氧基) -苯氨基 1-喹唑啉 -6-基 -吡咯 -1-基) -乙醇  2-(3-{4-"3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino-1-quinazoline-6-yl-pyrrole-1-yl)-ethanol
Figure imgf000316_0001
Figure imgf000316_0001
将 2-(3-{4-[3-氯 -4-(3-氟-节氧基) -苯氨基] -喹唑啉 -6-基 吡咯 -1-基) -N，N-二乙基 -乙酰胺 216(116 mg, 0.2 mmol)溶于 5 mL四氢呋喃中， 冰浴冷却至 0°C， 搅拌下 分批加入三乙基硼氢化锂四氢呋喃溶液 (2 mL， 2 mmol), 室温下搅拌过夜。 加入 5 mL甲醇淬灭反应， 反应液在减压下浓缩， 得到的残留物通过硅胶柱层析进一步分 离纯化 (二氯甲垸： 甲醇 =50: 1), 得到标题产物 2-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯 氨基] -喹唑啉 -6-基} -吡咯 -1-基) -乙醇 306(26 mg， 黄色固体)， 产率： 26.6%。  2-(3-{4-[3-Chloro-4-(3-fluoro-p-hydroxy)-phenylamino]-quinazolin-6-ylpyrrol-1-yl)-N,N-diethyl Base-acetamide 216 (116 mg, 0.2 mmol) was dissolved in 5 mL of THF, cooled to 0 ° C in ice-cooled, and a solution of lithium triethyl borohydride (2 mL, 2 mmol) Stir overnight. The reaction mixture was quenched by the addition of 5 mL of EtOAc (EtOAc) (EtOAc (EtOAc) 4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-pyrrol-1-yl)-ethanol 306 (26 mg, yellow solid) Rate: 26.6%.
MS m/z (ESI): 544[M+ 1] MS m/z (ESI): 544 [M+ 1]
1H NMR(400 MHz , DMSO-t¾)： 59.70(s, IH), 8.52(m, 2H), 8.04(m, 2H), 7.73(m, 2H), 7.49(m, 2H), 7.34(m, 2H), 7.29(m, IH), 7.19(m, IH), 6.90(m, 1H)， 6.66(m, IH), 5.27(s, 2H), 4.97(t， J=4.8Hz, IH), 3.99(m, 2H), 3.72(m, 2H) 实施例 307  1H NMR (400 MHz, DMSO-t3⁄4): 59.70 (s, IH), 8.52 (m, 2H), 8.04 (m, 2H), 7.73 (m, 2H), 7.49 (m, 2H), 7.34 (m, 2H), 7.29(m, IH), 7.19(m, IH), 6.90(m, 1H), 6.66(m, IH), 5.27(s, 2H), 4.97(t, J=4.8Hz, IH), 3.99 (m, 2H), 3.72 (m, 2H) Example 307
(R)-2-(3-{4-「3-氯 -4-(3-氟-苄氧基 苯氨基 喹唑啉 -6-基 吡咯 -1-基 3-二甲基氨 基-吡咯垸 -1-基) -乙酮  (R)-2-(3-{4-"3-Chloro-4-(3-fluoro-benzyloxyphenylaminoquinazolin-6-ylpyrrole-1-yl3-dimethylamino-pyrrole -1-yl)-ethanone
Figure imgf000316_0002
Figure imgf000316_0002
Figure imgf000317_0001
第一步
Figure imgf000317_0001
first step
(R)-2-氯- 1 -(3- (二甲氨基)吡咯烷- 1 -基)乙酮  (R)-2-chloro-1 -(3-(dimethylamino)pyrrolidine-1-yl)ethanone
将 (R)-N,N-二甲氨基吡咯烷 -3-胺（52 mg， 0.46 mmol)溶于 10 mL二氯甲烷中， 溶液在丙酮-干冰浴下冷却至 -78°C， 搅拌下加入 1 mL三乙胺和氯乙酰氯 (60 mg, 0.55 mmol), 维持此温度搅拌 40分钟反应完毕。 反应液在减压下浓缩， 得到的残 留物通过硅胶柱层析分离纯化 (二氯甲烷： 甲醇 = 10: 1)， 得到无色油状液体 (R)-2- 氯 -1-(3- (二甲氨基)吡咯烷 -1-基)乙酮 307a， 产物不经分离直接进行下一步反应。 MS m/z (ESI): 167[M+ 1] 第二步  (R)-N,N-Dimethylaminopyrrolidin-3-amine (52 mg, 0.46 mmol) was dissolved in 10 mL of dichloromethane. The solution was cooled to -78 ° C in acetone-dry ice bath and stirred. Add 1 mL of triethylamine and chloroacetyl chloride (60 mg, 0.55 mmol), and maintain the temperature for 40 minutes. The reaction mixture was concentrated under reduced pressure. EtOAc mjjjjjjjjj Dimethylamino)pyrrolidin-1-yl)ethanone 307a, the product was directly subjected to the next reaction without isolation. MS m/z (ESI): 167[M+ 1] Step 2
(R)-2-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯氨基]-喹唑啉 -6-基}-吡咯 -1-基) -l-(3-二甲基氨 基-吡咯垸 -1-基) -乙酮  (R)-2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-pyrrol-1-yl)-l -(3-dimethylamino-pyrrole-1-yl)-ethanone
在 50 mL的烧瓶中，将 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-[6-(1Η-吡咯 -3-基) -喹唑啉 -4- 基] -胺 42 (260 mg, 0.58 mmol)溶于 10 mL干燥的 N，N-二甲基甲酰胺中， 在冰浴 条件下， 冷却至 0°C， 加入氢化钠 (101 mg， 3.48 mmol), 搅拌 30分钟后加入 (R)-2- 氯 -1-(3- (二甲氨基)吡咯垸小基)乙酮 307a (133 mg, 0.7 mmol), 室温下搅拌 3小时 反应完毕。 反应液加入 50 mL水， 用乙酸乙酯萃取 (50 mLX 3)， 合并的有机相通 过无水硫酸钠干燥， 过滤， 减压下浓缩， 得到的残留物通过硅胶柱层析进一步分 离纯化 (二氯甲烷： 甲醇 = 40: 1)， 得到本标题产物 (R)-2-(3-{4-[3-氯 -4-(3-氟 -苄氧 基) -苯氨基] -喹唑啉 -6-基 吡咯 -1-基)小(3-二甲基氨基-吡咯烷 -1-基) -乙酮 307 (80 mg, 黄色固体)， 产率： 19%。  [3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1Η-pyrrol-3-yl)-quinazolin-4-yl] in a 50 mL flask -Amine 42 (260 mg, 0.58 mmol) was dissolved in 10 mL of dry N-N-dimethylformamide, cooled to 0 ° C under ice bath and sodium hydride (101 mg, 3.48 mmol). After stirring for 30 minutes, (R)-2-chloro-1-(3-(dimethylamino)pyrrolidinyl)acetone 307a (133 mg, 0.7 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was added to 50 mL of water, EtOAc (EtOAc) (EtOAc) Methyl chloride: methanol = 40: 1), the title product (R)-2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazoline -6-Pyryrrol-1-yl)small (3-dimethylamino-pyrrolidin-1-yl)-ethanone 307 (80 mg, yellow solid), yield: 19%.
MS m/z (ESI): 599[M+ 1] MS m/z (ESI): 599 [M+ 1]
1H NMR(400 MHz, DMSO-c/6):5= 9.69(s, IH), 8.54(s， IH), 8.50(s, IH), 8.04(m, 2H), 7.75(m, 2H), 7.47(m, IH), 7.40(m, IH), 7.30(m, 3H), 7.19(m, IH), 6.88(s, IH), 6.68(s, IH), 5.27(s, 2H), 4.85(m, 2H), 3.65(m, 4H), 3.25(m, IH), 2.68(m, IH), 2.17(s, 6H)， 1.72(m, IH) 实施例 308 (R)-N-{ l-「2-(3-[4-「3-氯 -4-(3-氟苄氧基) -苯氨基 1-喹唑啉 -6-基 吡咯 -1-基 乙酰基 1- 吡咯垸 -3-基 乙酰胺 1H NMR (400 MHz, DMSO-c/6): 5 = 9.69 (s, IH), 8.54 (s, IH), 8.50 (s, IH), 8.04 (m, 2H), 7.75 (m, 2H), 7.47(m, IH), 7.40(m, IH), 7.30(m, 3H), 7.19(m, IH), 6.88(s, IH), 6.68(s, IH), 5.27(s, 2H), 4.85 (m, 2H), 3.65 (m, 4H), 3.25 (m, IH), 2.68 (m, IH), 2.17 (s, 6H), 1.72 (m, IH) Example 308 (R)-N-{ l-"2-(3-[4-"3-Chloro-4-(3-fluorobenzyloxy)-phenylamino-1-quinazolin-6-ylpyrrole-1-yl Acetyl 1-pyrrole-3-ylacetamide
Figure imgf000318_0001
第一步
Figure imgf000318_0001
first step
(R)-N-[l-(2-氯-乙酰基) -吡咯烷 -3-基] -乙酰胺 将 (R)-N-吡咯烷 -3-基-乙酰胺 (200 mg, 1.56 mmol)溶于 20 mL四氢呋喃中， 溶 液在丙酮-干冰浴下冷却至 -78 °C，搅拌下加入 1 mL三乙胺和氯乙酰氯 (212 mg， 1.88 mmol), 维持此温度搅拌 1小时反应完毕。 过滤反应液， 滤液在减压下浓缩， 得到 的残留物通过硅胶柱层析分离纯化 (二氯甲烷： 甲醇 =40: 1), 得到 （R)-N-[l-(2- 氯-乙酰基) -吡咯垸 -3-基] -乙酰胺 308a (205 mg， 淡黄色油状液体)， 产率： 21.4%。 MS m/z (ESI): 205 [M+] 第二步 (R)-N-[l-(2-chloro-acetyl)-pyrrolidin-3-yl]-acetamide (R)-N-pyrrolidin-3-yl-acetamide (200 mg, 1.56 mmol Dissolve in 20 mL of tetrahydrofuran, cool the solution to -78 °C in acetone-dry ice bath, add 1 mL of triethylamine and chloroacetyl chloride (212 mg, 1.88 mmol) with stirring, and maintain the temperature for 1 hour. . The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. EtOAcjjjjjjjjjjjjjj -Pyrrolidin-3-yl]-acetamide 308a (205 mg, light yellow oily). Yield: 21.4%. MS m/z (ESI): 205 [M + ] Step 2
(R)-N-{l-[2-(3-{4-[3-氯 -4-(3-氟苄氧基) -苯氨基] -喹唑啉 -6-基} -吡咯 -1-基) -乙酰基] - 吡咯烷 -3-基 乙酰胺 (R)-N-{l-[2-(3-{4-[3-chloro-4-(3-fluorobenzyloxy)-phenylamino]-quinazolin-6-yl}-pyrrole-1 -yl)-acetyl]-pyrrolidin-3-ylacetamide
在 50 mL的烧瓶中，将 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-[6-(1Η-吡咯 -3-基) -喹唑啉 -4- 基] -胺 42 (472 mg， 1.06 mmol)溶于 10 mL干燥的 Ν,Ν-二甲基甲酰胺中， 在冰浴 条件下， 冷却至 0°C， 加入氢化钠 (127 mg， 5.3 mmol) , 搅拌 30 分钟后加入 (1 )-1^-[1-(2-氯-乙酰基)-吡咯垸-3-基]-乙酷胺3083 (261 1¾， 1.27 mmol), 室温下搅 拌 2小时反应完毕。 反应液加入 50 mL水， 用乙酸乙酯萃取 (50 mL X 3)， 合并的 有机相通过无水硫酸钠干燥， 过滤， 减压下浓缩， 得到的残留物通过硅胶柱层析 进一步分离纯化 (二氯甲烷： 甲醇 =20: 1)， 得到本标题产物 (R)-N-{ l-[2-(3-{4-[3- 氯 -4-(3-氟苄氧基) -苯氨基]-喹唑啉 -6-基} -吡咯 -1-基) -乙酰基] -吡咯烷 -3-基 乙酰胺 7 [3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1Η-pyrrol-3-yl)-quinazolin-4-yl] in a 50 mL flask -Amine 42 (472 mg, 1.06 mmol) was dissolved in 10 mL dry EtOAc EtOAc (EtOAc) After stirring for 30 minutes, (1)-1^-[1-(2-chloro-acetyl)-pyrrole-3-yl]-acetamide 3083 (261 13⁄4, 1.27 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Finished. The reaction mixture was added to 50 mL of EtOAc (EtOAc)EtOAc. Dichloromethane: methanol = 20: 1), the title product (R)-N-{ l-[2-(3-{4-[3-chloro-4-(3-fluorobenzyloxy)-benzene Amino]-quinazolin-6-yl}-pyrrol-1-yl)-acetyl]-pyrrolidin-3-ylacetamide 7
308 (302 mg, 黄色固体)， 产率： 39%。 308 (302 mg, yellow solid), Yield: 39%.
MS m/z (ESI): 615[M+ 1]  MS m/z (ESI): 615 [M+ 1]
1H NMR(400 MHz , DMSO-i¾):S= 9.69(s, IH), 8.54(s, IH), 8.50(s, IH), 8.04(m, 2H), 7.75(m, 2H), 7.47(m, 1H)， 7.40(m, IH), 7.30(m, 3H), 7.19(m, IH), 6.88(s, IH), 6.68(s, IH), 5.27(s， 2H), 4.85(m, 2H), 3.61(m, 3H), 3.28(s, 3H), 1.19(m, 4H) 实施例 309  1H NMR (400 MHz, DMSO-i3⁄4): S = 9.69 (s, IH), 8.54 (s, IH), 8.50 (s, IH), 8.04 (m, 2H), 7.75 (m, 2H), 7.47 ( m, 1H), 7.40(m, IH), 7.30(m, 3H), 7.19(m, IH), 6.88(s, IH), 6.68(s, IH), 5.27(s, 2H), 4.85(m , 2H), 3.61 (m, 3H), 3.28 (s, 3H), 1.19 (m, 4H) Example 309
l-(3-氨基 -哌啶 -1-基) -2-(3-{4-「3-氯 -4-(3-氟-苄氧基) -苯基氨基卜喹唑啉 -6-基 吡咯  L-(3-Amino-piperidin-1-yl)-2-(3-{4-"3-chloro-4-(3-fluoro-benzyloxy)-phenylaminobuquinazoline-6- Kipyrrole
-1-基) -乙酮  -1-yl)-ethanone
Figure imgf000319_0001
Figure imgf000319_0001
第一步  First step
(S)- [1-(2-氯-乙酰基) -哌啶 -3-基] -氨基甲酸叔丁酯  (S)- [1-(2-Chloro-acetyl)-piperidin-3-yl]-carbamic acid tert-butyl ester
(S)-哌啶 -3-基氨基甲酸叔丁酯 (200 mg， 1 mmol)溶于 30 mL四氢呋喃中， 在丙 酮-干冰浴冷却下冷却至 -78°C，搅拌下依次加入三乙胺 (0.42 mL, 3 mmol)和氯乙酰 氯 (0.1 mL， 1.2 mmol), 混合液在 -78 °C下搅拌 1小时后反应完毕。将反应液在减压 下浓缩，残渣通过水洗涤， 乙酸乙酯萃取 (100 mLx3)，合并的有机相通过无水硫酸 钠干燥， 过滤， 减压下浓缩， 得到 (S)-[l-(2-氯-乙酰基) -哌啶 -3-基] -氨基甲酸叔丁酯 309a (271 mg, 灰色固体)， 产率： 98 %。  (S)-tert-butyl piperidin-3-ylcarbamate (200 mg, 1 mmol) was dissolved in 30 mL of tetrahydrofuran, cooled to -78 ° C under ice-dry ice-cooling, and then triethylamine was added with stirring. (0.42 mL, 3 mmol) and chloroacetyl chloride (0.1 mL, 1.2 mmol), and the mixture was stirred at -78 °C for one hour and then the reaction was completed. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjjjjj 2-Chloro-acetyl)-piperidin-3-yl]-carbamic acid tert-butyl ester 309a (271 mg, m.p.).
MS m/z (ESI): 276[M+] 第二步 MS m/z (ESI): 276 [M + ] Second step
(S)-{l-[2-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯基氨基] -喹唑啉 -6-基} -吡咯 -1-基) -乙酰 基] -哌啶 -3-基} -氨基甲酸叔丁酯  (S)-{l-[2-(3-{4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-pyrrole-1 -yl)-acetyl]-piperidin-3-yl}-carbamic acid tert-butyl ester
将 [3-氯 -4-(3-氟-苄氧基) -苯基 ]-[6-(1Η-吡咯 -3-基) -喹唑啉 -4-基] -胺 42 (317 mg, 0.71 mmol)溶解于 10 mL千燥的 Ν,Ν-二甲基甲酰胺中， 在冰浴条件下， 冷却至 0 °C， 加入氢化钠 (86 mg, 3.6 mmol), 搅拌 30分钟后加入 (S)-[l-(2-氯-乙酰基) -哌啶 -3-基] -氨基甲酸叔丁酯 309a (271 mg, 0.98 mmol), 室温下搅拌 1小时反应完毕。 将反应液在减压下浓缩， 残渣通过水洗涤， 乙酸乙酯萃取 (100 mLx3)，合并的有机 相通过无水硫酸钠干燥， 过滤， 减压下浓缩， 得到的残留物通过柱层析进一步分 离纯化 (二氯甲烷： 甲醇 = 50: 1)， 得到 (S)-{ l-[2-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯基 氨基] -喹唑啉 -6-基} -吡咯 -1-基) -乙酰基] -哌啶 -3-基 氨基甲酸叔丁酯 309b (100 mg, 棕黄色固体)， 产率： 38.5 %。  [3-Chloro-4-(3-fluoro-benzyloxy)-phenyl]-[6-(1Η-pyrrol-3-yl)-quinazolin-4-yl]-amine 42 (317 mg, 0.71 mmol) was dissolved in 10 mL of dry hydrazine, hydrazine-dimethylformamide, cooled to 0 ° C under ice-cooling, sodium hydride (86 mg, 3.6 mmol) was added, stirred for 30 minutes and then added ( S)-[1-(2-Chloro-acetyl)-piperidin-3-yl]-carbamic acid tert-butyl ester 309a (271 mg, 0.98 mmol). The reaction mixture was concentrated under reduced pressure. EtOAc EtOAc m. Separation and purification (dichloromethane: methanol = 50: 1) gave (S)-{ l-[2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl Amino]-quinazolin-6-yl}-pyrrol-1-yl)-acetyl]-piperidin-3-ylcarbamic acid tert-butyl ester 309b (100 mg, brownish yellow solid), yield: 38.5 %.
MS ni/z (ESI): 685 [M+] MS ni/z (ESI): 685 [M + ]
第三步 '  third step '
(S)-l-(3-氨基 -哌啶 -1-基) -2-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯基氨基] -喹唑啉 -6-基 }-吡 咯小基) -乙酮 (S)-l-(3-Amino-piperidin-1-yl)-2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quin Oxazolin-6-yl}-pyrrole small group)-acetone
将 (S)-{l-[2-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯基氨基]-喹唑啉 -6-基} -吡咯 -1-基) - 乙酰基] -哌啶 -3-基} -氨基甲酸叔丁酯 309b (100 mg, 0.15 mmol)溶于 20 mL二氯甲 烷中， 搅拌下加入 5 mL三氟乙酸， 室温下搅拌 2小时反应完毕。 反应液在减压下 浓缩， 加入 30 mL饱和碳酸氢钠溶液， 乙酸乙酯萃取 (50 mLX 3)， 合并的有机相 依次通过饱和氯化钠溶液洗涤， 无水硫酸钠干燥， 过滤， 减压下浓缩， 得到的残 留物通过碱性氧化铝柱层析分离纯化 (二氯甲烷： 甲醇 = 50: 1)， 得到本标题产物 (S)-l-(3-氨基 -哌啶 -1-基) -2-(3-{4-[3-氯 -4-(3-氟-苄氧基) -苯基氨基] -喹唑啉 -6-基 } 比 咯小基) -乙酮 309 (60 mg， 黄色固体)， 产率： 70.6%  (S)-{l-[2-(3-{4-[3-Chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}-pyrrole- 1-yl)-acetyl]-piperidin-3-yl}-carbamic acid tert-butyl ester 309b (100 mg, 0.15 mmol) dissolved in 20 mL of dichloromethane, 5 mL of trifluoroacetic acid was added with stirring, at room temperature The reaction was completed after stirring for 2 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. The residue was purified by column chromatography (methanol:methanol: 50:1) to afford the title product (S)-l-(3-amino-piperidin-1-yl. -2-(3-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-quinazolin-6-yl}pyrrolidyl)-ethanone 309 ( 60 mg, yellow solid), Yield: 70.6%
MS m/z (ESI): 585[M+] MS m/z (ESI): 585 [M + ]
1H NMR(400 MHz, DMSO-^(5):59.69(s, 1H), 8.73(s, 1H), 8.48(s, 1H), 8.10(m, 1H), 8.00(m, 1H), 7.84(m, 1H), 7.48(m, 1H), 7.29(m, 4H), 7.16(m, 1H), 6.79(s, 2H), 6.74(m, 1H), 5.27(s， 2H)， 4.95(s, 2H), 3.72(m, 1H), 2.99(m, 1H), 2.88(m, 1H), 2.72(m, 1H), 2.40(m, 1H), 1.73(m, 4H) 实施例 310  </ RTI> <RTIgt; m, 1H), 7.48(m, 1H), 7.29(m, 4H), 7.16(m, 1H), 6.79(s, 2H), 6.74(m, 1H), 5.27(s, 2H), 4.95(s , 2H), 3.72 (m, 1H), 2.99 (m, 1H), 2.88 (m, 1H), 2.72 (m, 1H), 2.40 (m, 1H), 1.73 (m, 4H) Example 310
氟-苄基 -1H-吲唑 -5-基 1-ί6-Π44-(2-吗啡啉 -4-基-乙基)-吗啡啉 -2-基甲基 1-lH- 吡咯 -3-基 喹唑啉 -4-基) -胺
Figure imgf000321_0001
Fluoro-benzyl-1H-indazole-5-yl 1-ί6-Π44-(2-morphinolin-4-yl-ethyl)-morphinolin-2-ylmethyl 1-lH-pyrrol-3-yl Quinazolin-4-yl)-amine
Figure imgf000321_0001
310a  310a
Figure imgf000321_0002
第 ~ ^步
Figure imgf000321_0002
Step ~ ^
甲磺酸 (2-吗啉 -4-基) -乙酯  Methanesulfonic acid (2-morpholin-4-yl)-ethyl ester
将 2-吗啉 -4-基 -乙醇 (0.036 mL， 0.3 mmol)溶于 5 mL二氯甲烷中， 搅拌下加入 三乙胺 (0.05 mL， 0.36 mmol), 混合液在丙酮-干冰浴冷却至 -78 °C， 氩气保护下， 加入甲磺酰氯 (0.06 mL， 0.33 mmol), 保持 -78°C下反应 1小时， 薄层色谱跟踪， 显 示反应完毕， 有甲磺酸 (2-吗啉 -4-基) -乙酯 310a生成， 反应液不经处理直接进行下 一步反应。  2-morpholin-4-yl-ethanol (0.036 mL, 0.3 mmol) was dissolved in dichloromethane (5 mL), triethylamine (0.05 mL, 0.36 mmol) At -78 °C, under argon atmosphere, add methanesulfonyl chloride (0.06 mL, 0.33 mmol), and keep at -78 °C for 1 hour. Trace by thin layer chromatography, the reaction is complete, there is methanesulfonic acid (2-morpholine) The -4-yl)-ethyl ester 310a was formed, and the reaction liquid was directly subjected to the next reaction without being treated.
MS m/z (ESI): 210[M+ 1] MS m/z (ESI): 210 [M+ 1]
第二步  Second step
1-(3-氟-苄基) -1H-吲唑 -5-基] -(6-{1-[4-(2-吗啡啉 -4-基-乙基) -吗啡啉 -2-基甲基 ]-1Η- 吡咯 -3-基 喹唑啉 -4-基) -胺  1-(3-Fluoro-benzyl)-1H-indazol-5-yl]-(6-{1-[4-(2-morphinolin-4-yl-ethyl)-morpholin-2-yl Methyl]-1Η-pyrrol-3-ylquinazolin-4-yl)-amine
在上述步骤的反应液中加入 [1-(3-氟-苄基) -1H-吲唑 -5-基] -[6-(1-吗啉 -2-基甲基 -1H-吡咯 -3-基)-喹唑啉 -4-基] -胺 294 (80 mg, 0.15 mmol), 加热回流 40小时。 在反 应液中加入 50 mL二氯甲烷中， 用饱和碳酸氢钠洗涤， 饱和氯化钠溶液洗涤， 无 7_K硫酸钠干燥， 过滤， 减压下浓缩， 得到的残留物通过薄层层析板分离纯化 (二氯 甲烷： 甲醇： 氨水 = 15 : 1： Id) , 得到本标题产物 1-(3-氟-苄基) -1H-吲唑 -5- 基 ]_(6-{1-[4-(2-吗啡啉 -4-基-乙基) -吗啡啉 -2-基甲基 ]-1Η-吡咯 -3-基 喹唑啉 -4-基) - 胺 310(35 mg， 淡黄色固体)， 产率： 36.1 %。  In the reaction solution of the above step, [1-(3-fluoro-benzyl)-1H-indazol-5-yl]-[6-(1-morpholin-2-ylmethyl-1H-pyrrole-3) was added. -yl)-quinazolin-4-yl]-amine 294 (80 mg, 0.15 mmol). Add 50 mL of dichloromethane to the reaction mixture, wash with saturated sodium bicarbonate, wash with saturated sodium chloride solution, dry with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification (dichloromethane: methanol: aqueous ammonia = 15 : 1: Id) gave the title product 1-(3-fluoro-benzyl)-1H-carbazol-5-yl]-(6-{1-[4 -(2-morpholine-4-yl-ethyl)-morpholine-2-ylmethyl]-1Η-pyrrol-3-ylquinazolin-4-yl)-amine 310 (35 mg, pale yellow solid ), Yield: 36.1%.
MS m/z (ESI): 647[M+ 1] MS m/z (ESI): 647[M+ 1]
^MR (400MHz, DMSO-c 6): 59.81(s,lH), 8.60(s,lH), 8.45(s,lH), 8.23(s,lH), 8.17 (s,lH), 8.03(d,lH,J=8.8Hz), 7.73(m,3H), 7.39(m,2H), 7.11(m，3H), 6.88(s,lH),  ^MR (400MHz, DMSO-c 6): 59.81(s,lH), 8.60(s,lH), 8.45(s,lH), 8.23(s,lH), 8.17 (s,lH), 8.03(d, lH, J=8.8Hz), 7.73(m,3H), 7.39(m,2H), 7.11(m,3H), 6.88(s,lH),
6.67(s,lH), 5.72(s,2H), 4.00(m，2H), 3.81(d,lH,J=11.2Hz), 3.74(m,lH), 3.54(m,5H), 08 0013076.67(s,lH), 5.72(s,2H), 4.00(m,2H), 3.81(d,lH,J=11.2Hz), 3.74(m,lH), 3.54(m,5H), 08 001307
2.80(d,lH,J=11.2Hz), 2.71(d,lH,J=11.2Hz), 2.41 (m,4H), 2.37(m,4H); 2.80 (d, lH, J = 11.2 Hz), 2.71 (d, lH, J = 11.2 Hz), 2.41 (m, 4H), 2.37 (m, 4H) ;
2.06(t,lH,J=10.4Hz), 1.82(t,lH,J=10.4Hz) 实施例 311 2.06 (t, lH, J = 10.4 Hz), 1.82 (t, lH, J = 10.4 Hz) Example 311
Γ 3-氟 -苄某 IH-吲唑 -5-基 1-ί6-「1-ί4-甲磺酰基-吗啡啉 -2-基甲基) -1H-吡咯 -3-基 1- 喹唑啉 _4-基). -胺  Γ 3-Fluoro-benzyl IH-carbazole-5-yl 1-ί6-"1-ί4-methanesulfonyl-morpholine-2-ylmethyl)-1H-pyrrol-3-yl 1-quinazoline _4-base). -amine
Figure imgf000322_0001
Figure imgf000322_0001
294 313  294 313
将 [1-(3-氟-苄基) -1H-吲唑 -5-基] -[6-(1-吗啉 -2-基甲基 -1H-吡咯 -3-基)-喹唑啉 -4- 基] -胺 294 (100 mg， 0.19 mmol)溶于 5 mL二氯甲烷中， 搅拌下加入三乙胺 (0.033 mL, 0.23 mmol), 混合液在丙酮-干冰浴冷却至 -78 °C， 氩气保护下， 加入甲磺酰氯 (0.017 mL, 0.21 mmol), 保持 -78°C下反应 3小时反应完毕。 将反应液加入 50 mL 二氯甲垸中， 依次通过饱和碳酸氢钠洗涤， 饱和氯化钠溶液洗涤， 无水硫酸钠干 燥， 过滤， 减压下浓缩， 残留物通过薄层层析板分离纯化 (二氯甲烷： 甲醇 = 15: 1)，得到本标题产物 [1-(3-氟-苄基) -1H-吲唑 -5-基] -{6-[1-(4-甲磺酰基-吗啡啉 -2-基甲 基) -1H-吡咯 -3-基]-喹唑啉 -4-基 胺 311(50 mg， 淡黄色固体)， 产率： 43 %。  [1-(3-Fluoro-benzyl)-1H-indazol-5-yl]-[6-(1-morpholin-2-ylmethyl-1H-pyrrol-3-yl)-quinazoline -4-yl]-amine 294 (100 mg, 0.19 mmol) was dissolved in 5 mL of dichloromethane, then triethylamine (0.033 mL, 0.23 mmol) was added with stirring, and the mixture was cooled to -78 ° in acetone-dry ice bath C. Under argon atmosphere, methanesulfonyl chloride (0.017 mL, 0.21 mmol) was added, and the reaction was completed at -78 ° C for 3 hours. The reaction mixture was poured into 50 mL of dichloromethane, washed successively with saturated sodium hydrogen carbonate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. (Dichloromethane: methanol = 15:1) gave the title product [1-(3-fluoro-benzyl)-1H-indazol-5-yl]-{6-[1-(4-methylsulfonyl) - morpholine-2-ylmethyl)-1H-pyrrol-3-yl]-quinazolin-4-ylamine 311 (50 mg, pale yellow solid), yield: 43%.
MS m/z (ESI): 612[M+ 1] MS m/z (ESI): 612 [M+ 1]
1HNMR (400MHz, DMSO- <5): 59.84(s,lH), 8.61(s,lH), 8.46(s,lH)， 8.23(s,lH), 1 H NMR (400 MHz, DMSO- <5): 59.84 (s,lH), 8.61 (s,lH), 8.46 (s,lH), 8.23 (s,lH),
8.17(s,lH), 8.03(d,lH,J=8.8Hz), 7.72(m,3H), 7.44(s,lH), 7.39(m,lH), 8.17(s,lH), 8.03(d,lH,J=8.8Hz), 7.72(m,3H), 7.44(s,lH), 7.39(m,lH),
7.11(m,3H),6.92(s,lH), 6.69(s,lH), 5.72(s,2H), 4.12(m,3H), 3.83(m,lH), 3.55(m,2H), 3.35(m,lH), 2.92(s,3H), 2.84(t,lH,J=11.2Hz), 2.59(m,lH) 实施例 312 7.11(m,3H), 6.92(s,lH), 6.69(s,lH), 5.72(s,2H), 4.12(m,3H), 3.83(m,lH), 3.55(m,2H), 3.35 (m, lH), 2.92 (s, 3H), 2.84 (t, lH, J = 11.2 Hz), 2.59 (m, lH).
「l-(3-氟 -苄基 MH-吲唑 -5-基 〔6-{ 1-Γ4-(2-甲磺酰基-乙基) -吗啡啉 -2-基甲基卜 1Η-吡 咯 -3-基 喹唑啉 -4-基) -胺 "1-(3-Fluoro-benzyl-MH-oxazol-5-yl[6-{1-indol-4-(2-methanesulfonyl-ethyl)-morphinolin-2-ylmethylpyridinium-pyrrole- 3-ylquinazolin-4-yl)-amine
Figure imgf000323_0001
第一步
Figure imgf000323_0001
first step
甲磺酸 (2-甲磺酰基:) -乙酯  Methanesulfonic acid (2-methanesulfonyl:)-ethyl ester
将 2-甲磺酰基 -乙醇 (47 mg， 0.38 mmol)溶于 5 mL二氯甲烷中， 撹拌下加入三 2-Methanesulfonyl-ethanol (47 mg, 0.38 mmol) was dissolved in 5 mL of dichloromethane.
- 乙胺 (0.065· mL， 0.46 mmol), 混合液在丙酮-干冰浴冷却至 -78°C， 氩气保护下， 加 入甲磺酰氯 (0.027 mL, 0.34 mmol),升至室温反应 1小时。将反应液在减压下浓缩， 得到的粗品甲磺酸 (2-甲磺酰基) -乙酯 312a不经分离直接进行下一步反应。 - Ethylamine (0.065·mL, 0.46 mmol). The mixture was cooled to -78 ° C in acetone-dry ice bath, and methanesulfonyl chloride (0.027 mL, 0.34 mmol) was added under argon, and allowed to react to room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the obtained crude methanesulfonic acid (2-methanesulfonyl)-ethyl ester 312a was directly subjected to the next reaction without isolation.
MS m/z (ESI): 203[M+1]  MS m/z (ESI): 203 [M+1]
第二步  Second step
[l-(3-氟-苄基) -1H-吲唑 -5-基] -(6-{1-[4-(2-甲磺酰基-乙基) -吗啡啉 -2-基甲基 ]-1Η-吡 咯 -3-基}-喹唑啉 -4-基) -胺  [l-(3-Fluoro-benzyl)-1H-indazol-5-yl]-(6-{1-[4-(2-methanesulfonyl-ethyl)-morpholine-2-ylmethyl ]-1Η-pyrrol-3-yl}-quinazolin-4-yl)-amine
将粗品甲磺酸 (2-甲磺酰基) -乙酯溶于 5 mL 乙腈中， 搅拌下加入 [1-(3-氟-苄 基) -1H-吲唑 -5-基] -[6-(1-吗啉 -2-基甲基 -1H-吡咯 -3-基) -喹唑啉 -4-基] -胺 294 (100 mg， 0.19 mmol)和碳酸钾 (105 mg, 0.76 mmol), 加热回流反应过夜。 在反应液中 加入 50 mL二氯甲垸中， 抽滤， 滤液在减压下浓缩， 得到的残留物通过薄层层析 板分离纯化 (二氯甲垸： 甲醇 = 12: 1)， 得到本标题产物 1-(3-氟-苄基) -1H-吲唑 -5- 基] -(6-{1-[4-(2-吗啡啉 -4-基-乙基) -吗啡啉 -2-基甲基] -1H-吡咯 -3-基 喹唑啉 -4-基) - B 312(75 mg, 淡黄色固体)， 产率： 61.7%。  The crude methanesulfonic acid (2-methanesulfonyl)-ethyl ester was dissolved in 5 mL of acetonitrile, and [1-(3-fluoro-benzyl)-1H-indazole-5-yl]-[6- (1-morpholin-2-ylmethyl-1H-pyrrol-3-yl)-quinazolin-4-yl]-amine 294 (100 mg, 0.19 mmol) and potassium carbonate (105 mg, 0.76 mmol), The reaction was heated to reflux overnight. 50 mL of dichloromethane was added to the reaction mixture, and the mixture was filtered with suction. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by chromatography (dichloromethane:methanol = 12:1). The title product 1-(3-fluoro-benzyl)-1H-indazol-5-yl]-(6-{1-[4-(2-morphinolin-4-yl-ethyl)-morpholine-2 -ylmethyl]-1H-pyrrol-3-ylquinazolin-4-yl)-B 312 (75 mg, pale yellow solid), yield: 61.7%.
MS m/z (ESI): 640[M+ 1]  MS m/z (ESI): 640 [M+ 1]
lWMR (400MHz, DMSO-c/6): 59.81(s,lH), 8.60(s,lH), 8.45(s,lH), 8.23(s,lH), 8.17(s,lH), 8.03(d,lH,J=8.8Hz), 7.73(m,3H), 7.38(m,2H), 7.08(m,3H), 6.88(s,lH), 6.67(s,lH), 5.72(s,2H), 4.02(m,2H), 3.79(m,2H), 3.49(m，lH), 3.28(m,2H), 3.03(s,3H), 2.75(m,4H), 2.07(t,lH,J=10.4Hz), 1.88(t,lH,J=10.4Hz) 实施例 313 lWMR (400MHz, DMSO-c/6): 59.81(s,lH), 8.60(s,lH), 8.45(s,lH), 8.23(s,lH), 8.17(s,lH), 8.03(d, lH, J=8.8Hz), 7.73(m,3H), 7.38(m,2H), 7.08(m,3H), 6.88(s,lH), 6.67(s,lH), 5.72(s,2H), 4.02(m,2H), 3.79(m,2H), 3.49(m,lH), 3.28(m,2H), 3.03(s,3H), 2.75(m,4H), 2.07(t,lH,J= 10.4Hz), 1.88(t,lH,J=10.4Hz) Example 313
-(3-氟- 基) -1H-吲唑 -5-基 1-(6-Π-Γ4-(3-甲氧基-丙基)-吗啡啉 -2-基甲基 1-1H-吡咯  -(3-fluoro-yl)-1H-indazol-5-yl 1-(6-indole-indolyl 4-(3-methoxy-propyl)-morphinolin-2-ylmethyl1-1H-pyrrole
-3-基 奎唑啉 -4-基) -胺  -3-ylquinazoline-4-yl)-amine
Figure imgf000324_0001
Figure imgf000324_0001
第一步  First step
甲磺酸 3-甲氧基丙酯  3-methoxypropyl methanesulfonate
将 3-甲氧基-丙小醇（34 mg， 0.38 mmol)溶于 5 mL二氯甲烷中， 搅拌下加入 三乙胺 (0.065 mL， 0.46 mmol), 混合液在丙酮-干冰浴冷却至 -78Ό， 氩气保护下， 加入甲磺酰氯 (0.027 mL， 0.34 mmol),升至室温反应 1小时。将反应液在减压下浓 缩， 得到的粗品甲磺酸 3-甲氧基丙酯 313a不经分离直接进行下一步反应。  3-Methoxy-propanol (34 mg, 0.38 mmol) was dissolved in 5 mL of dichloromethane, and triethylamine (0.065 mL, 0.46 mmol) was added with stirring, and the mixture was cooled in acetone-dry ice bath - 78 Ό, under argon, methanesulfonyl chloride (0.027 mL, 0.34 mmol) was added and the mixture was allowed to react to room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the obtained crude 3-methoxypropyl methanesulfonate 313a was directly subjected to the next reaction without isolation.
MS m/z (ESI): 203 [M+ 1] MS m/z (ESI): 203 [M+ 1]
第二步  Second step
[1-(3-氟-苄基) -1H-吲唑 -5-基 ]-(6-{ 1-[4-(3-甲氧基-丙基) -吗啡啉 -2-基甲基 ]-1Η-吡咯  [1-(3-Fluoro-benzyl)-1H-indazol-5-yl]-(6-{ 1-[4-(3-methoxy-propyl)-morpholine-2-ylmethyl ]-1Η-pyrrole
-3-基}-喹唑啉 -4-基) -胺  -3-yl}-quinazolin-4-yl)-amine
将粗品甲磺酸 3-甲氧基丙酯 313a溶于 5 mL乙腈中， 搅拌下加入 [1 -(3-氟- 基) -1H-吲唑 -5-基] -[6-(1-吗琳 -2-基甲基 -1H-吡咯 -3-基) -喹唑啉 -4-基] -胺 294 (100 mg， 0.19 mmol)和碳酸钾 (105 mg， 0.76 mmol), 加热回流反应过夜。 在反应液中 加入 50 mL二氯甲烷中， 抽滤， 滤液在减压下浓缩， 得到的残留物通过薄层层析 板分离纯化 (二氯甲垸： 甲醇二 12: 1)， 得到本标题产物 [1-(3-氟- 基) -1H-吲唑 -5- 基 ]-(6_{ [ (3_甲氧基-丙基) -吗啡 p林 _2_基甲基] -1H-吡咯 -3-基} -喹唑啉 -4-基) -胺 313(40 mg, 淡黄色固体)， 产率： 34.8 %。 The crude 3-methoxypropyl methanesulfonate 313a was dissolved in 5 mL of acetonitrile, and [1-(3-fluoro-yl)-1H-indazol-5-yl]-[6-(1-吗林-2-ylmethyl-1H-pyrrol-3-yl)-quinazolin-4-yl]-amine 294 (100 mg, 0.19 mmol) and potassium carbonate (105 mg, 0.76 mmol). overnight. 50 ml of dichloromethane was added to the reaction mixture, and the mixture was filtered with suction, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by chromatography (dichloromethane:methanol: 12:1). Product [1-(3-Fluoro-yl)-1H-indazol-5-yl]-( 6 _{ [ (3 _methoxy-propyl)-morphine p-lin _ 2 _ylmethyl] -1H -pyrrol-3-yl}-quinazolin-4-yl)-amine 313 (40 mg, pale yellow solid), yield: 34.8 %.
MS m/z (ESI): 606[M+ 1] MS m/z (ESI): 606 [M+ 1]
iHNMR (400MHz, DMSO- 6): 59.81(s,lH)， 8.59(s，lH), 8.45(s，lH)， 8.23(s,lH), 8.17(s,lH), 8.03(d,lH,J=8.8Hz), 7.73(m,3H), 7.39(m,2H), 7.06(m,3H), 6.88(s,lH), .67(s,lH)， 5.72(s,2H), 4.02(m,2H), 3.82(d,l¾J=10.4Hz), 3.74(m,lH), 3.50(m,lH .33(m,2H), 3.21(s,3H), 2.75(d，lH,J=10.4Hz), 2.67(d,lH,J=10.4Hz), 2.30(m,2H), .00(m,lH), 1.75(t,lH,J=10.4Hz), 1.66(m,2H) 实施例 3 iHNMR (400MHz, DMSO-6): 59.81 (s, lH), 8.59 (s, lH), 8.45 (s, lH), 8.23 (s, lH), 8.17 (s, lH), 8.03 (d, lH, J=8.8Hz), 7.73(m,3H), 7.39(m,2H), 7.06(m,3H), 6.88(s,lH), .67(s,lH), 5.72(s,2H), 4.02(m,2H), 3.82(d,l3⁄4J=10.4Hz), 3.74(m,lH), 3.50(m,lH .33(m,2H) ), 3.21(s,3H), 2.75(d,lH,J=10.4Hz), 2.67(d,lH,J=10.4Hz), 2.30(m,2H), .00(m,lH), 1.75( t, lH, J = 10.4 Hz), 1.66 (m, 2H) Example 3
2_「2—(3_{4-「l_(3-氟 -苄基 IH-吲唑 -5-基氨基 1-喹唑啉 -6-基 }-吡咯 -1-基甲基 吗啡啉 2 _"2-(3_{4-"l_( 3 -fluoro-benzyl IH-carbazol-5-ylamino-1-quinazolin-6-yl}-pyrrol-1-ylmethylmorpholine
-4-基 乙醇  -4-yl alcohol
Figure imgf000325_0001
Figure imgf000325_0001
第一步  First step
2- (叔丁基-二甲基-硅氧基) -乙醇  2-(tert-butyl-dimethyl-siloxy)-ethanol
将氢化钠 (800 mg， 20 mmol)溶于 20 mL四氢呋喃中， 氩气保护下， 冰浴冷却 至 0t：， 滴加乙二醇 (1.24 g， 20 mmol), 室温下搅拌 1小时反应完毕。 将反应液倒 入 lOO mL冰水中， 乙酸乙酯萃取 (50 mLX 3)， 合并的有机相依次通过饱和碳酸氢 钠溶液洗涤， 饱和氯化钠溶液洗涤， 无水硫酸钠干燥， 过滤， 减压下浓缩， 得到 粗品 2- (叔丁基 -二甲基-硅氧基) -乙醇 314a (3.8 g，无色油状液体)，产物不经分离直 接进行下一步反应。  Sodium hydride (800 mg, 20 mmol) was dissolved in 20 mL of tetrahydrofuran under argon. The mixture was cooled to EtOAc EtOAc (EtOAc:EtOAc) The reaction mixture was poured into 100 mL of ice water and extracted with ethyl acetate (50 mL×3). The combined organic phases were washed sequentially with saturated sodium hydrogen carbonate solution, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, Concentration gave the crude 2-(tert-butyl-dimethyl-siloxy)-ethanol 314a (3.8 g, m.
第二步  Second step
甲磺酸 2- (叔丁基 -二甲基-硅氧基) -乙酯 将粗品 2- (叔丁基 -二甲基-硅氧基) -乙醇 314a (3.8 g)溶于 30 mL二氯甲垸中， 搅拌下加入三乙胺 (4 g， 30 mmol), 混合液在丙酮-干冰浴冷却至 -78 °C， 氩气保护 下， 加入甲磺酰氯 (3.4 g， 30 mmol), 升至室温反应 1小时。 将反应液倒入 100 mL 冰水中，乙酸乙酯萃取 (50 mLX 3)，合并的有机相依次通过饱和碳酸氢钠溶液洗涤， 饱和氯化钠溶液洗涤， 无水硫酸钠干燥， 过滤， 减压下浓縮， 残留物通过硅胶柱 层析分离纯化 (正己烷： 乙酸乙酯 =4: 1)， 得到甲磺酸 2- (叔丁基 -二甲基-硅氧基) - 乙酉旨 314b (3.5 g， 无色油状液体)， 产率： 68.8% 2-(tert-butyl-dimethyl-siloxy)-ethyl methanesulfonate The crude 2-(tert-butyl-dimethyl-silanoxy)-ethanol 314a (3.8 g) was dissolved in 30 mL of dichloromethane, and triethylamine (4 g, 30 mmol) was added with stirring. After cooling to -78 °C in an acetone-dry ice bath, methanesulfonyl chloride (3.4 g, 30 mmol) was added and the mixture was allowed to react to room temperature for 1 hour. The reaction solution was poured into 100 mL of ice water, and extracted with ethyl acetate (50 mL×3). The combined organic phases were washed with saturated sodium hydrogen carbonate solution, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated. The residue was concentrated and purified by silica gel column chromatography (hexane: ethyl acetate = 4:1) to give 2-(t-butyl-dimethyl-silyloxy)-methanesulfonate as 314b ( 3.5 g, colorless oily liquid), Yield: 68.8%
MS m/z (ESI): 255[M+ 1] MS m/z (ESI): 255 [M+ 1]
第二步  Second step
[6-(l-{4-[2- (叔丁基-二甲基 -硅氧基)-乙基] -吗啉 -2-基甲基). -1H-吡咯 -3-基) -喹唑啉 斗基] -[1-(3-氟苄基 )-1Η-吲唑 -5-基] -胺  [6-(l-{4-[2-(tert-Butyl-dimethyl-siloxy)-ethyl]-morpholin-2-ylmethyl). -1H-pyrrol-3-yl) - Quinazoline]-[1-(3-fluorobenzyl)-1Η-indazol-5-yl]-amine
将甲磺酸 2- (叔丁基-二甲基-硅氧基) -乙酯 314b (84 mg, 0.33 mmol)溶于 5 mL 乙腈中， 搅拌下加入 [1-(3-氟-苄基) -1H-吲唑 -5-基] -[6-(1-吗啉 -2-基甲基 -1H-吡咯 -3- 基)-喹唑啉 -4-基] -胺 294 (60 mg， 0.11 mmol)和碳酸钾 (61 mg， 0.44 mmol), 加热回 流反应过夜。 在反应液中加入 20 mL二氯甲烷中， 抽滤， 滤液在减压下浓縮， 得 到的残留物通过薄层层析板分离纯化 (二氯甲烷：甲醇 = 12: 1),得到 [6-(1-{4-[2- (叔 丁基-二甲基 -硅氧基)-乙塞] -吗啉 -2-基甲基 HH-吡咯 -3-基) -喹唑啉 -4-基] -[1-(3-氟 苄基) -1H-吲唑 -5-基] -胺 314c (40 mg， 淡黄色固伴)， 产率： 39.4%。  2-(tert-Butyl-dimethyl-silanoxy)-ethyl sulfonate 314b (84 mg, 0.33 mmol) was dissolved in 5 mL of acetonitrile and [1-(3-fluoro-benzyl) was added with stirring. -1H-carbazol-5-yl]-[6-(1-morpholin-2-ylmethyl-1H-pyrrol-3-yl)-quinazolin-4-yl]-amine 294 (60 mg , 0.11 mmol) and potassium carbonate (61 mg, 0.44 mmol). After adding 20 mL of dichloromethane to the reaction mixture, the mixture was filtered with suction, and the filtrate was evaporated, evaporated, mjjjjjjjj -(1-{4-[2-(tert-butyl-dimethyl-siloxy)-ethion]-morpholin-2-ylmethylHH-pyrrol-3-yl)-quinazoline-4 -yl]-[1-(3-fluorobenzyl)-1H-indazol-5-yl]-amine 314c (40 mg, pale yellow solid), Yield: 39.4%.
MS m/z (ESI): 692[M+ 1] MS m/z (ESI): 692 [M+ 1]
第四步  the fourth step
2-[2-(3-{4-[l-(3-氟-苄基) -1H-吲唑 -5-基氨基] -喹唑啉 -6-基}-吡咯 -1-基甲基) -吗啡啉  2-[2-(3-{4-[l-(3-fluoro-benzyl)-1H-indazol-5-ylamino]-quinazolin-6-yl}-pyrrol-1-ylmethyl ) - morpholine
-4-基] -乙醇  -4-yl]-ethanol
将 [6-(1-{4-[2- (叔丁基-二甲基 -硅氧基)- 乙基] -吗啉 -2-基甲基 }-1Η-吡咯 -3-基) -喹 唑啉 -4-基] -[1-(3-氟苄基) -1H-吲唑 -5-基] -胺 314c (30 mg, 0.043 mmol)溶于 2 mL四 氢呋喃中， 搅拌下加入四丁基氟化铵 (50 mg， 0.16 mmol), 室温下搅拌 1小时反应 完毕。将反应液倒入 20 mL冰水中， 加入 2 mL饱和碳酸氢钠溶液， 乙酸乙酯萃取 (20 mLX 3)，合并的有机相依次通过饱和碳酸氢钠溶液洗涤，饱和氯化钠溶液洗涤， 无水硫酸钠干燥， 过滤，减压下浓缩， 残留物通过薄层层析板分离纯化 (二氯甲烷- 甲醇 = 10: 1)， 得到 2-[2-(3-{4-[1-(3-氟-苄基) -1H-吲唑 -5-基氨基] -喹唑啉 -6-基 吡 咯小基甲基) -吗啡啉 -4-基] -乙醇 314 (19 mg， 淡黄色固体)， 产率： 76.5 %。  [6-(1-{4-[2-(tert-Butyl-dimethyl-siloxy)-ethyl]-morpholin-2-ylmethyl}-1Η-pyrrol-3-yl)- Quinazolin-4-yl]-[1-(3-fluorobenzyl)-1H-indazol-5-yl]-amine 314c (30 mg, 0.043 mmol) was dissolved in 2 mL of THF. Ammonium butyl fluoride (50 mg, 0.16 mmol) was stirred at room temperature for 1 hour. Pour the reaction solution into 20 mL of ice water, add 2 mL of saturated sodium bicarbonate solution, and extract with ethyl acetate (20 mL×3). The combined organic phases are washed sequentially with saturated sodium hydrogen carbonate solution and washed with saturated sodium chloride solution. The organic layer was dried over sodium sulfate, filtered, evaporated, evaporated, evaporated, evaporated, evaporated 3-fluoro-benzyl)-1H-indazol-5-ylamino]-quinazolin-6-ylpyrroleylmethyl)-morpholine-4-yl]-ethanol 314 (19 mg, pale yellow solid ), Yield: 76.5 %.
MS m/z (ESI): 578[M+ 1] MS m/z (ESI): 578 [M+ 1]
1HNMR (400MHz, DMSO-c½): S9.81(s,lH), 8.60(s,lH), 8.45(s,lH), 8.23(s,lH), 8.17(s. lH), 8.03(d,lH,J=8.8Hz), 7.73(m,3H), 7.38(m,2H), 7.08(m,3H), 6.88(s,lH), 6.67(s,lH), 5.72(s,2H), 4.40(t,lH,J=5.2Hz), 4.00(m,2H), 3.83(m,2H), 3.51(m,3H), 2.79(d,lH,J=10.4Hz), 2.70(d,lH,J=10.4Hz), 2.39(m,2H), 2.08(t,lH,J=10.4Hz), 1.85(t,lH,J=10.4Hz) 实验例: 1 HNMR (400MHz, DMSO-c½ ): S9.81 (s, lH), 8.60 (s, lH), 8.45 (s, lH), 8.23 (s, lH), 8.17 (. S lH), 8.03 (d , lH, J=8.8Hz), 7.73(m,3H), 7.38(m,2H), 7.08(m,3H), 6.88(s,lH), 6.67(s,lH), 5.72(s,2H) , 4.40 (t, lH, J = 5.2 Hz), 4.00 (m, 2H), 3.83 (m, 2H), 3.51 (m, 3H), 2.79 (d, lH, J = 10.4 Hz), 2.70 (d, lH, J = 10.4 Hz), 2.39 (m, 2H), 2.08 (t, lH, J = 10.4 Hz), 1.85 (t, lH, J = 10.4 Hz) Experimental example:
生物学评价 例 1 EGFR抑制细胞增殖测试  Biological evaluation Example 1 EGFR 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 inhibitory activity of the compounds of the invention against human tumor cell A431 EGFR-expressing cell lines.
下面所述的体外细胞试验可确定受试化合物的对高表达 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 IC5G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介质）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，可用磺酰罗丹明 B (SRB)方法进行测试化合物对于抑制细胞增殖活性。 IC50 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- a. 二甲基亚砜 (Sinophma chemical reagent company, 目录 T20050806号) b. A431 细胞（购于 Institute of biochemistry and cell biology) The in vitro cell assay described below can determine the anti-angiogenic activity and the proliferative activity of the test compound against tumor cells highly expressing EGFR, the activity of which can be expressed by the IC 5G value. The general protocol for such an experiment is as follows: First, human tumor cells with high expression of EGFR are selected, seeded in 96-well culture plates at a suitable cell concentration (exp 5000 cells/ml medium), and then the cells are cultured in a carbon dioxide incubator. When they grow to 85% confluence, the medium is changed to a medium containing a series of concentration (usually 6 to 7 concentrations) of the test compound solution, and the plate is returned to the incubator for 72 hours. After 72 hours, the test compound was tested for its ability to inhibit cell proliferation using the sulforhodamine B (SRB) method. The IC 50 value can be calculated from the inhibition values of the test compound for the cells at a range of different concentrations. Materials and Methods - a. Sodium sulfoxide (Sinophma chemical reagent company, catalogue T20050806) b. A431 cells (purchased in 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. 康宁 （corning) 96孔培养板 (Corning Incorporated, 目录 3599号） d. Corning 96-well culture plate (Corning Incorporated, catalogue 3599)
e. 费氏移液管（Fisher scientific, 目录 03-692-164号） e. Fisher's 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. 磺酰罗丹明 B (Sigma, 目录 3520-42-1号） j. Sulfonhodamine B (Sigma, Table of Contents 3520-42-1)
k. 醋酸（Sinophma chemical reagent company, 目录 T20060508号） k. Acetic acid (Sinophma chemical reagent company, catalog T20060508)
1. 三氯醋酸（Sinophma chemical reagent company, 目录 T20060305号）  1. Trichloroacetic acid (Sinophma chemical reagent company, catalogue T20060305)
m. Tris碱（Amresco, 目录 0826号） m. Tris base (Amresco, catalogue 0826)
n. II级 A/B3 型生物学安全工作橱 (ThermoForma目录. HB0053-03号） n. Class II A/B3 Biological Safety Work Cabinet (ThermoForma Catalogue. HB0053-03)
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 700-0081号） q. Novastar Board Reader (BMG Labtech, Catalog 700-0081)
r. 定轨摇床（Qilinbeier, 目录 TS-1号） 方案： r. Orbital shaker (Qilinbeier, catalog TS-1) Program:
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 IC5Q值。The following protocol was used to test the inhibitory cell proliferation IC 5Q values of the test compounds of the invention against A431 cells.
I. 将 A431细胞殖于 lOOmra康宁 培养板在生长基（以 DMEM/ 2+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； I. A431 cells were cultured in a lOOmra Corning plate in a growth medium (DMEM/2+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， 以胰蛋白酶消化细胞后， 再 将细胞接种在康宁 96孔细胞培养板上， 浓度为 50000细胞 /ml,每个板空 6孔， 作 为对照孔.； 2. Wash A431 cells with fetal bovine serum in a 100 mm culture plate, trypsinize the cells, and inoculate the cells on a Corning 96-well cell culture plate at a concentration of 50,000 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, configure 20 mM mother liquor, and then dilute the mother liquor with DMSO to obtain a series of solutions of the test compound, ie 2 mM, 1 mM, 0.2 mM, 20 μΜ, 2 μΜ, 0.2 μΜ;
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 of DMSO compound solution and 95 μl of the culture solution were added to the cell culture medium each time to ensure that the concentration of A431 cells exposed to the DMSO solution did not exceed 0.5%, and the mixture was 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 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 culture medium and 20 μM were added to each well. The test compound solution prepared in the fifth step. In the negative control cell group, 20 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 4°C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。 空白被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 at 4 ° C for 1 hour, and then wash several times with water to remove TCA, serum protein, and the like. The plates are dried in air and stored for later use. The measurement of the optical density value of the blank is the value obtained by incubating the culture in a medium without cell growth.
I I.用 10 %醋酸溶液制备 0.4 %磺酰罗丹明 B溶液， 并向每孔中加入 50 μΐ磺酰 罗丹明 Β溶液；  I I. Prepare 0.4% sulforhodamine B solution with 10% acetic acid solution, and add 50 μM sulfonyl rhodamine solution to each well;
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%的醣酸溶 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 complete, discard the colorant and rinse the cells quickly with 10% sugar 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磺酰罗丹明 Β中， 增溶溶液（lO 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 certain volume of sulforhodamine, the solubilizing solution (10 mM Tris) is the same as the original volume of the medium, and the plate is allowed to stand at room temperature for 5 minutes, and slowly stirred with a shaker to accelerate Mixing of dyes;
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 mn下吸 光度减去 690 nm下 96孔板被景吸光度所得的数值； 15. Using a spectrophotometric measurement, read the absorbance at a wavelength of 565 nm. Absorbance value is 565 mn lower suction The luminosity minus the value obtained by the absorbance of the 96-well plate at 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， 测得的 ic5G值见下表。 The biochemical activity of the compound of the present invention was measured by the above test, and the measured ic 5G value is shown in the following table.
实施  Implementation
Figure imgf000329_0001
2ZZ
Figure imgf000329_0001
2ZZ
Figure imgf000330_0001
/:/:i O z-0200800si>l£ z-sozAV
Figure imgf000330_0001
/:/:i O z-0200800si>l£ z-sozAV
Figure imgf000331_0001
Figure imgf000331_0001
Figure imgf000332_0001
Figure imgf000332_0001
/:/:i O z-0200800si>l£ z-sozAV
Figure imgf000333_0001
/:/:i O z-0200800si>l£ z-sozAV
Figure imgf000333_0001
Figure imgf000333_0002
Figure imgf000333_0003
Figure imgf000333_0002
Figure imgf000333_0003
90舊£ 90 old £
〇ε 308 0.626 〇ε 308 0.626
309 0.729  309 0.729
310 1.3  310 1.3
311 0.243  311 0.243
312 0.572  312 0.572
313 0.832  313 0.832
314 0.477 例 2. EGFR激酶活性测定  314 0.477 cases 2. 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：  In vitro EGFR kinase activity was tested by the following method. Materials and reagents:
a.洗涤缓冲液（PBS-T缓冲液)： lx PBS (137 mM NaCl, 2.7 mM KC1, 4.3 mM Na2HP04; 1.4 mM KH2P04,调 pH至 7.2)和 0.05 %吐温 -20 a. Wash buffer (PBS-T buffer): lx PBS (137 mM NaCl, 2.7 mM KC1, 4.3 mM Na 2 HP0 4; 1.4 mM KH 2 P0 4 , adjusted to pH 7.2) and 0.05% Tween-20
b. 1 %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％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 package perforated yellow plate (PerkinElmer Life Sciences #AAAND-0005) g. EGFR kinase (50 mM Tris-HCl (pH 8.0), 100 mM NaCl, 5 mM DTT, 15 mM glutamylcysteinylglycine And 20% glycerol, Cell signaling technology #7908)
h. 10 mM ATP溶液（Cell signaling technology #9804). h. 10 mM ATP solution (Cell signaling technology #9804).
i. PTP1B (Tyr66)生物素酰化蛋白 （Cell signaling technology #1325). i. PTP1B (Tyr66) biotinylated protein (Cell signaling technology #1325).
j.磷-酪氨酸鼠 mAb (P-Tyr-100) (Cell signaling technology #9411). j. Phosphorus-tyrosine mouse mAb (P-Tyr-100) (Cell signaling technology #9411).
k. HTScanTM酪氨酸激酶缓冲液（4x) k. HTScanTM Tyrosine Kinase Buffer (4x)
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
3 μΜ Ν 3νθ4 3 μΜ Ν 3 νθ 4
(细胞信号转导技术 #9805).  (Cell Signal Transduction Technology #9805).
1. 1.25 M DTT (ΙΟΟΟχ) (细胞信号转导技术). 方案： 1. 1.25 M DTT (ΙΟΟΟχ) (Cell Signal Transduction Technology). Protocol:
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 with DMSO to a final concentration;
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 test compound, negative control and blank control were added to each test (no test compound was accepted) ()), only 1 l 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. Dilute 6 μΜ substrate protein (Tyr589) with dH 2 01:1 and add 15 μΐ to 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. M 3 μg EGFR酶到每个测试中；  4. M 3 μg EGFR 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 μ14χ反应液；  6. Transfer 0.75 ml of DTT/kinase buffer to each of each test to prepare a 4x reaction mixture and add 7.5 μl of reaction solution to each test;
7.加入 2 μΙ ΑΤΡ (10 mM)至 496 μΐ d¾0中，并在每个测试中加入 7.5 μΐ; 7. Add 2 μΙ ΑΤΡ (10 mM) to 496 μΐ d3⁄40 and add 7.5 μΐ to each test;
30 μΐ反应最终测试条件为：  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
Figure imgf000335_0001
Figure imgf000335_0001
1.25 mM DTT  1.25 mM DTT
20 μΜΑΤΡ  20 μΜΑΤΡ
I.5 μΜ多肽底物  I.5 μΜ polypeptide 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 at 25 ° C for 45 minutes;
9.每个测试中加入 30 μΐ中止反应缓冲液 (50 mM EDTA, pH 8.0)中止反应； 9. Stop the reaction by adding 30 μΐ stop reaction buffer (50 mM EDTA, pH 8.0) in each test.
10.在 96孔链亲和素包被的培养板每孔中加入 25 μΐ反应液和 75 μΐ dH20，在室温 下， 并振摇 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 at room temperature and shake for 60 minutes;
II.每孔用 200 ^ PBS-T缓冲液洗涤 3次， 在纸巾上轻拍以除去剩余的液体； 12. 用 1 %牛血清白蛋白 PBS-T缓冲液 1:1000稀释抗体磷-酪氨酸 mAb (P-Tyr-100), 在每孔中加入 100 μΐ稀释的抗体；  II. Wash each well 3 times with 200 ^ PBS-T buffer, tap on a paper towel to remove the remaining liquid; 12. Dilute the antibody phosphorus-tyrosine with 1% bovine serum albumin PBS-T buffer 1:1000 Acid mAb (P-Tyr-100), 100 μM diluted antibody was added 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% bovine serum albumin in PBS-T buffer 1:500 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 N=阴性对照 X = fluorescence value of test compound 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 IC5Q值见下表。 The biochemical activity of the compound of the present invention was measured by the above test, and the measured IC 5Q value is shown in the following table.
Figure imgf000336_0001
Figure imgf000337_0001
Figure imgf000336_0001
Figure imgf000337_0001
Figure imgf000338_0001
Figure imgf000338_0001
Figure imgf000339_0001
Figure imgf000339_0001
Figure imgf000340_0001
Figure imgf000340_0001
246 0.102 246 0.102
247 0.095 247 0.095
248 0.024248 0.024
251 0.012251 0.012
252 0.117252 0.117
253 0.443253 0.443
260 0.094260 0.094
285 0.058285 0.058
299 0.598299 0.598
300 0.282300 0.282
301 0.038301 0.038
302 0.071302 0.071
303 0.073303 0.073
304 0.248304 0.248
306 0.052306 0.052
307 0.133307 0.133
308 0.129308 0.129
309 0.038309 0.038
310 0.276310 0.276
311 0.257311 0.257
312 0.236312 0.236
313 0.291313 0.291
314 0.205 例 3: HER-2激酶抑制剂活性测定 314 0.205 Example 3: Determination of HER-2 kinase inhibitor activity
本试验用酶联免疫吸附测定法 (ELISA)来测定体外 HER-2激酶抑制剂活性。 材料与试剂：  In this assay, the activity of HER-2 kinase inhibitor in vitro was determined by enzyme-linked immunosorbent assay (ELISA). Materials and reagents:
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,调节 pH7.2)和 0.05 % 吐温 -20 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 pH 7.2) and 0.05 % Tween-20
b. 1 %牛血清蛋白 （BSA, Calbiochem #136593) PBS-T缓冲液 b. 1% bovine serum albumin (BSA, Calbiochem #136593) PBS-T buffer
c.封闭缓冲液： 50 mM EDTA , pH 8.0 c. Blocking 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® Streptavidi包 96孔黄板（PerkinElmer Life Sciences #AAAND-0005). g. HER-2/ErbB2激酶（Invitrogen corporation #PV3366).f. DELFIA® Streptavidi 96-well yellow plate (PerkinElmer Life Sciences #AAAND-0005). g. HER-2/ErbB2 kinase (Invitrogen corporation #PV3366).
. 10 mM ATP溶液 (Cell signaling technology #9804).  10 mM ATP solution (Cell signaling technology #9804).
i. FLT3 (Tyr589)生物素酰化蛋白蛋白 （Cell signaling technology #1305). i. FLT3 (Tyr589) biotinylated protein protein (Cell signaling technology #1305).
j.磷-酪氨酸鼠 mAb (P-Tyr-100) (Cell signaling technology #9411). j. Phosphorus-tyrosine mouse mAb (P-Tyr-100) (Cell signaling technology #9411).
k. HTScan™酪氨酸激酶缓冲液（4x) 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 3νθ4 3 μΜ Ν 3 νθ 4
(细胞信号转导技术 #9805).  (Cell Signal Transduction Technology #9805).
1. 1.25 M DTT (ΙΟΟΟχ) (细胞信号转导技术). 方案： 1. 1.25 M DTT (ΙΟΟΟχ) (Cell Signal Transduction Technology). Protocol:
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 with DMSO to a final concentration;
在每个试验中加入 1 μΐ受试化合物、 阴性对照（不接受任何受试化合物)，和 1 μΐ DMSO; 1 μΐ of test compound, negative control (no test compound received), and 1 μΐ DMSO were added to each test;
2.用 d¾0稀释 1:16 μΜ底物蛋白 (Tyr87), 并在每个测试中加入 15 μΐ;  2. Dilute 1:16 μΜ substrate protein (Tyr87) with d3⁄40 and add 15 μΐ to each test;
3. 将 HER-2酶从 -80°C直接转移到冰上， HER-2酶解冻在冰上； 3. Transfer the HER-2 enzyme directly from -80 °C to ice, and thresh the HER-2 enzyme on ice;
4.取 4.5 HER-2酶到酶管中； 4. Take 4.5 HER-2 enzyme into the enzyme tube;
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/激酶缓冲液到每个酶管中， 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 enzyme tube to make 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;  7. Add 2 μΙ ΑΤΡ (10 mM) to 496 μΐ d3⁄40 and add 7.5 μΐ to each test;
30 μΐ反应最终试验条件为： 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
Figure imgf000342_0001
Figure imgf000342_0001
1.25 mM DTT  1.25 mM DTT
20 μΜΑΤΡ  20 μΜΑΤΡ
1.5 μΜ底物蛋白  1.5 μΜ substrate protein
45 ng HER-2激酶  45 ng HER-2 kinase
8. 在 25°C下， 将反应管温育 60分钟； 9. 每个测试中加入 30 μΐ封闭缓冲液 (50 mM EDTA, pH 8.0)终止反应； 8. Incubate the reaction tube for 60 minutes at 25 °C; 9. Stop the reaction by adding 30 μΐ blocking buffer (50 mM EDTA, pH 8.0) to each test;
10.在 96孔链亲和素包被的培养板每孔中加入 25 μΐ反应液和 75 μΐ d¾0,在室温 下， 并伴随振摇 60分钟；  10. Add 25 μM reaction solution and 75 μΐ d3⁄40 to each well of a 96-well streptavidin-coated plate at room temperature with shaking 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过量的液体； 12. 用 1 %牛血清白蛋白 PBS-T 缓冲液 1:1000稀释主要抗体磷-酪氨酸 mAb (P-Tyr-100), 并在每孔中加入 100 μΐ稀释的主要抗体；  11. Wash each well with 200 μΐ PBS-T buffer 3 times, pat on a paper towel to remove excess liquid; 12. Dilute the main antibody phosphorus-case with 1% bovine serum albumin PBS-T buffer 1:1000 Amino acid mAb (P-Tyr-100), and 100 μM diluted primary antibody was added to each well;
13.室温下， 伴随振摇下温育 60分钟；  13. Incubate for 60 minutes at room temperature with shaking;
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 μM diluted antibody to each well;
16.室温下， 伴随振摇下温育 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过量的液体； 17. Wash each well 5 times with PBS-T buffer 200 μM and pat on a paper towel to remove excess 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， 伴随振摇下温育 5分钟；  19. Incubate for 5 minutes at room temperature with shaking;
20.在波长 615 nm下， 用合适的时间分辨板读取器读取吸光度。 计算抑制率比值： IR (%) =100- 100*(X-B)/ (N-B) 20. Read the absorbance at a wavelength of 615 nm using a suitable time-resolving plate reader. 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
The IC5o值可通过受试化合物不同剃度浓度下的抑制率比值计算得到 ( 本发明化合物的活性 The IC 5 o value can be calculated from the inhibition ratio of the test compound at different concentration concentrations ( the activity of the compound 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 The biochemical activity of the compound of the present invention is determined by the above test, and the measured IC 5 o value is shown in the following table.
Figure imgf000343_0001
Figure imgf000344_0001
Figure imgf000343_0001
Figure imgf000344_0001
Figure imgf000345_0001
Figure imgf000345_0001
/:/:-0200800si>l£-3ίϊο /:/:-0200800si>l£-3ίϊο
Figure imgf000346_0001
Figure imgf000346_0001
Figure imgf000347_0001
Figure imgf000347_0001
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 SK-BR-3 HER-2高表达的细胞株抑制增殖活性。 The following in vitro assays were used to determine the inhibitory activity of the compounds of the invention against a cell line in which human tumor cells SK-BR-3 HER-2 is highly expressed.
下面所述的体外细胞试验可确定受试化合物的对高度表达 HER-2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 IC5c值来表示。 此类试验的一般 方案如下： 首先选择高度表达 HER-2的人类肿瘤细胞， 以适宜细胞浓度下接种在 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 60%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 96个小时。 96小时后， 可用磺酰罗 丹明 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 tumor cells highly expressing HER-2, the activity of which can be expressed by the IC 5 c value. The general protocol for such an assay is as follows: First select human tumor cells that highly express HER-2, inoculate them in 96-well culture plates at the appropriate cell concentration, and then culture the cells in a carbon dioxide incubator as they grow to 60%. 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 96 hours. After 96 hours, the test compound can be 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. SK-BR-3 细胞（购于 Institute of biochemistry and cell biology) a dimethyl sulfoxide (Sinophma chemical reagent company, catalog T20050806) b. SK-BR-3 cells (purchased from 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.康宁 96孔培养板（Corning Incorporated, 目录 3599号） d. Corning 96-well culture plate (Corning Incorporated, catalogue 3599)
e. 费^液管（Fisher scientific, 目录 03-692-164号） e. Fees for liquid management (Fisher scientific, catalogue 03-692-164)
f. RPMI1640细胞培养基（Gibco, 目录 12400-021号） f. RPMI1640 Cell Culture Medium (Gibco, Catalog 12400-021)
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. 磺酰罗丹明 B (Sigma, 目录 3520-42-1号） j. Sulfonhodamine B (Sigma, Table of Contents 3520-42-1)
k. 醋酸（Sinophma chemical reagent company, 目录 T20060508号） k. Acetic acid (Sinophma chemical reagent company, catalog T20060508)
1. 三氯醋酸（Sinophma chemical reagent company, 目录 T20060305号） 1. Trichloroacetic acid (Sinophma chemical reagent company, catalogue T20060305)
m. Tris碱（Amresco, 目录 0826号） m. Tris base (Amresco, catalogue 0826)
n. II级 A/B3 型生物学安全工作橱 (ThermoForma目录. HB0053-03号） n. Class II A/B3 Biological Safety Work Cabinet (ThermoForma Catalogue. HB0053-03)
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 700-0081号） q. Novastar Board Reader (BMG Labtech, Catalog 700-0081)
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 SK-BR-3细胞的抑制细胞增殖 IC5o值。 1. 将 SK-BR-3细胞殖于 100mm康宁 培养板在生长基（以 RPMI 1640+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； 2. 在 100 111111培养板中用胎牛血清洗涤31^-81 -3细胞， 以胰蛋白酶 消化细胞后， 再将细胞接种在康宁 96孔细胞培养板上， 浓度为 50000细胞 /ml,每个板空 6孔， 作为对照孔.； The following protocol was used to test the inhibitory cell proliferation IC 5 o values of the test compounds of the present invention against SK-BR-3 cells. 1. Incubate SK-BR-3 cells in a 100 mm Corning plate in a growth medium (RPMI 1640 + 10% fetal bovine serum) (37 °C, 5 % C0 2 ) until the cells are fully confluent ; 2. Wash 31^-81 -3 cells with fetal bovine serum in 100 111111 culture plates, trypsinize the cells, and inoculate the cells on Corning 96-well cell culture plates at a concentration of 50000 cells/ml, each 6 holes in the plate, as a control hole.;
3. 在 37 V, 5 % C02条件下， 将细胞在 96孔板中培养， 直至达到约 60 %汇合； 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 —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;3. Incubate the cells in a 96-well plate at 37 V, 5 % C0 2 until approximately 60% confluence; 4. Dissolve the test compound in DMSO, dispose the 20 mM stock solution, and dilute the mother solution with DMSO to obtain - a solution of a series of test compounds, ie 2 mM, 1 mM, 0.2 mM, 20 μΜ, 2 μΜ, 0.2 μΜ;
5. 使用细胞培养基 （RPMI1640 +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， 保 SK-BR-3细胞暴露在 DMSO溶液中的 浓度不超过 0.5 %， 用涡旋混合； I 5. Dilute the compound solution configured above using cell culture medium (RPMI1640 +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, and the concentration of SK-BR-3 cells exposed to DMSO solution was not more than 0.5%, and vortex was used. Mixed; I
6. 当 SK-BR-3细胞贴壁，生长达到 60°/。汇合后，将培养基换为加有 RPMI164(H10 %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 μΐ培养液， 这样 SK-BR-3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 SK-BR-3 cells are attached, the growth reaches 60°/. After confluence, the medium was changed to a new medium supplemented with RPMI164 (H10% fetal bovine serum culture solution, and 180 μl of the culture medium and 20 μM of the test compound solution prepared in the fifth step were added to each well. Negative control In the cell group, 20 μL of culture medium containing 0.5% DMSO was added, so that the final concentration of SK-BR-3 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 μΜ;
7. 将培养板放入恒温箱内， 在 37 °C, 5 % C02条件下， 连续培养 96小时；7. Place the culture plate in an incubator and continue to culture for 96 hours at 37 °C, 5 % C0 2 ;
8. %小时后， 将培养板从恒温箱中转移到无菌工作室； 8. After the hour, 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。 空白被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 plates are dried in air and stored for later use. The measurement of the optical density value of the blank is the value obtained by incubating the culture in a medium without cell growth.
11.用 10 %醋酸溶液制备 0.4 %磺酰罗丹明 B溶液， 并向每孔中加入 50 μΐ磺酰 罗丹明 Β溶液；  11. Prepare a 0.4% sulforhodamine B solution with 10% acetic acid solution, and add 50 μM sulfonyl rhodamine solution to each well;
12.细胞着色 30分钟； , 12. Cell coloring 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磺酰罗丹明 Β中， 增溶溶液（lO 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 certain volume of sulforhodamine, the solubilizing solution (10 mM Tris) is the same as the original volume of the medium, and the plate is allowed to stand at room temperature for 5 minutes, and slowly stirred with a shaker to accelerate Mixing of dyes;
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孔板被景吸光度^?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 absorbance of the 96-well plate at 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， 测得的 IC5Q值见下表: The biochemical activity of the compounds of the present invention was determined by the above test, and the measured IC 5Q values are shown in the following table:
实施 Ι-3)(μΜ)  Implementation Ι-3)(μΜ)
Figure imgf000350_0001
6Π
Figure imgf000350_0001
6Π
Figure imgf000351_0001
.0CT00/800ZN3/X3d /:/:i O z-0200800si>l£ z-sozAV
Figure imgf000351_0001
.0CT00/800ZN3/X3d /:/:i O z-0200800si>l£ z-sozAV
Figure imgf000352_0001
Figure imgf000352_0001
6S 6S
/:/:i O z-0200800si>l£ z-sozAV /:/:i O z-0200800si>l£ z-sozAV
8寸 Γ0 8 inch Γ0
Figure imgf000353_0001
Figure imgf000353_0001
寸 090,  Inch 090,
Figure imgf000353_0002
Figure imgf000353_0003
Figure imgf000353_0002
Figure imgf000353_0003
9£寸0.  9 £0.
寸 ss Inch ss
6寸寸0. 6 inch inch 0.
/ OV¾o6A/u/DfsosoosiId-o / OV3⁄4o6A/u/DfsosoosiId-o
Figure imgf000354_0001
Figure imgf000354_0001
Figure imgf000355_0001
.0C100/800ZN3/X3d
Figure imgf000355_0001
.0C100/800ZN3/X3d

Claims

权利要求书  Claim
1. 一种由通式 (1)、 （Π)和 (III)表示的化合物或盐: A compound or salt represented by the general formulae (1), (Π) and (III):
Figure imgf000356_0001
Figure imgf000356_0001
R1选自烷基、 杂环烷基、 芳基或杂芳基， 其中垸基、 杂环烷基、 芳基或杂芳 基进一步被一个或多个选自烷基、 卤素、 芳基、 羟基、 氨基、 炔基、 烯基、 氰基、 硝基、 三氟甲基、 卤代苄基、 杂环烷基、 羧酸或羧酸酯的取代基所取代； 其中芳 基或杂芳基进一步并成双环， 此双环进一步被一个苄基或卤代苄基所取代； R 1 is selected from alkyl, heterocycloalkyl, aryl or heteroaryl, wherein the indenyl, heterocycloalkyl, aryl or heteroaryl group is further further selected from one or more selected from the group consisting of alkyl, halogen, aryl, Substituted by a substituent of a hydroxy, amino, alkynyl, alkenyl, cyano, nitro, trifluoromethyl, halobenzyl, heterocycloalkyl, carboxylic acid or carboxylic acid ester; wherein an aryl or heteroaryl group Further forming a bicyclic ring, the bicyclic ring is further substituted by a benzyl or halobenzyl group;
β L  β L
或者 R1为结构式： Ζ ^ Or R 1 is a structural formula: Ζ ^
其中- among them-
Β选自芳基或杂芳基，其中芳基或杂芳基进一步被一个或多个选自烷基、卤素、 芳基、 羟基、 氨基、 炔基、 烯基、 氰基、 硝基、 三氟甲基、 代苄基、 杂环烷基、 羧酸或羧酸酯的取代基所取代； The oxime is selected from aryl or heteroaryl, wherein the aryl or heteroaryl is further selected from one or more selected from the group consisting of alkyl, halogen, aryl, hydroxy, amino, alkynyl, alkenyl, cyano, nitro, tri Substituted by a substituent of a fluoromethyl group, a benzyl group, a heterocycloalkyl group, a carboxylic acid or a carboxylic acid ester;
Τ选自 -0(CH2)r -， -N(CH2)r-或 -S(CH2)r; Τ selected from -0(CH 2 )r -, -N(CH 2 )r- or -S(CH 2 )r;
L选自芳基或杂芳基，其中该芳基或杂芳基进一步被一个或多个卤素或烷基所 取代；  L is selected from aryl or heteroaryl, wherein the aryl or heteroaryl is further substituted by one or more halogen or alkyl;
R2选自氢原子、 烷基、 环烷基、 三氟甲基、 杂环烷基、 芳基、 杂芳基或芳烷 基， 其中烷基、 环烷基、 杂环烷基、 芳基、 杂芳基、 芳烷基进一步被一个或多个 选自烷基、 芳基、 羟基、 卤素、 氨基、 氰基、 烷氧基、 羧酸、 羧酸酯或 -NR6R7的 基团所取代； R 2 is selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a trifluoromethyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group or an aralkyl group, wherein an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group a heteroaryl group, an aralkyl group further further comprising one or more groups selected from the group consisting of alkyl, aryl, hydroxy, halogen, amino, cyano, alkoxy, carboxylic acid, carboxylic acid ester or -NR 6 R 7 Replaced
R3和 R4各自独立地选自氢原子、 烷基、 三氟甲基、 环烷基、 杂环烷基、 芳基、 羧酸酯、 -S02R6、 -CH2C(=0)NR6R7、 -C(0)NR6R7、 -(C¾)nNR6R7或 -NC (=0) R6， 其中烷基、 环烷基、 杂环垸基进一步被一个或多个选自烷基、 卤素、 三氟甲基、 芳基、 羟基、 烷氧基、 芳氧基、 环垸基 Λ 杂环烷基、 杂芳基、 杂环烷氧基、 氰基、 羧酸、 羧酸酯、 -S02R6或- (CH2;>nNR6R7的取代基所取代； R 3 and R 4 are each independently 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 carboxylic acid ester, -S0 2 R 6 , -CH 2 C (=0 )NR 6 R 7 , -C(0)NR 6 R 7 , -(C3⁄4)nNR 6 R 7 or -NC (=0) R 6 , wherein the alkyl group, the cycloalkyl group, the heterocyclic group is further one or a plurality selected from the group consisting of alkyl, halogen, trifluoromethyl, aryl, hydroxy, alkoxy, aryloxy, cyclodecyl 杂环 heterocycloalkyl, heteroaryl, heterocycloalkoxy, cyano, carboxy Substituted by a substituent of an acid, a carboxylic acid ester, -S0 2 R 6 or -(CH 2 ;>nNR 6 R 7 ;
同时， R3和 R4—起形成一个 4〜8元环基； 其中 5〜8元杂环内含有一个或多 个 ^、 0、 S原子， 并且 4〜8元杂环上进一步被一个或多个选自烷基、 卤素、 芳 基、 杂芳基、 卤代烷基、 卤代烷氧基、 '轻基、 垸氧基、 芳氧基、 羰基、 杂环垸基、 羧酸、 羧酸酯、 =N-OR6或 -NR6R7的取代基所取代； Meanwhile, 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 a ^, 0, S atom, and a 4 to 8 membered heterocyclic ring further further selected from one or more selected from the group consisting of alkyl, halogen, aryl, heteroaryl, haloalkyl, haloalkoxy, 'light, decyloxy Substituted with an aryloxy group, a carbonyl group, a heterocyclic fluorenyl group, a carboxylic acid, a carboxylic acid ester, a substituent of =N-OR 6 or -NR 6 R 7 ;
R5选自氢原子、 烷基、 环烷基、 -。0<))ΟΙ δ， 其中垸基或环垸基进一步被一个 或多个选自垸基、 羟基、 烷氧基、 氰基、 -NR6R7、 羧酸或羧酸酯的取代基所取代；R 5 is selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, and -. 0<)) ΟΙ δ , wherein the fluorenyl or cyclodecyl group is further substituted by one or more substituents selected from the group consisting of fluorenyl, hydroxy, alkoxy, cyano, -NR 6 R 7 , carboxylic acid or carboxylic acid esters Replace
1 6和 1 7分别选自氢原子、 垸基、 烯基、 环烷基、 杂环烷基、 芳基或杂芳基， 其中烷基、 烯基、 环烷基、 杂环烷基、 芳基或者杂芳基进一步被一个或多个选自 烷基、环烷基、卤素、芳基、羟基、氨基、烷氧基、烯基、杂环烷基、羟烷基、 -S02R6, -C(=0) R6、 羧酸、 羧酸酯或 - NR6R7的取代基所取代； 1 6 and 17 are respectively selected from a hydrogen atom, a decyl group, an alkenyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, wherein an alkyl group, an alkenyl group, a cycloalkyl group, a heterocycloalkyl group, or an aromatic group Or a heteroaryl group further selected from one or more selected from the group consisting of alkyl, cycloalkyl, halogen, aryl, hydroxy, amino, alkoxy, alkenyl, heterocycloalkyl, hydroxyalkyl, -S0 2 R 6 , -C(=0) R 6 , substituted by a carboxylic acid, a carboxylic acid ester or a substituent of -NR 6 R 7 ;
同时， R6和 R7—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选自烷基、 卤素、 芳基、 杂芳基、 卤代芳基、 卤代垸氧基、 氨基、 羟基、 氰基、 烷氧基、 芳氧基、 胺烷基、羟垸基、环垸基、杂环烷基、羰基、羧酸、羧酸酯、 -C(=0)NR6R7、 -NC (=0) R6、 -S02R6、 或 -NR6R7的取代基所取代； Meanwhile, R 6 and R 7 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 a Or a plurality selected from the group consisting of alkyl, halogen, aryl, heteroaryl, haloaryl, halomethoxy, amino, hydroxy, cyano, alkoxy, aryloxy, alkoxyalkyl, hydroxyalkyl , cyclodecyl, heterocycloalkyl, carbonyl, carboxylic acid, carboxylic acid ester, -C(=0)NR 6 R 7 , -NC (=0) R 6 , -S0 2 R 6 , or -NR 6 R Substituted by a substituent of 7 ;
n是 0〜6；  n is 0~6;
r是 0〜2。  r is 0~2.
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： The compound according to claim 1 or a salt thereof, wherein the compound is a compound represented by the formula (I):
Figure imgf000357_0001
Figure imgf000357_0001
(I)  (I)
其中： among them:
R1选自烷基、 杂环烷基、 芳基或杂芳基， 其中烷基、 杂环垸基、 芳基或杂芳 基进一步被一个或多个选自烷基、 卤素、 芳基、 羟基、 氨基、 炔基、 烯基、 氰基、 硝基、 三氟甲基、 卤代苄基、 杂环烷基、 羧酸或羧酸酯的取代基所取代； 其中芳 基或杂芳基进一步并成双环， 此双环进一步被苄基或卤代苄基所取代； R 1 is selected from alkyl, heterocycloalkyl, aryl or heteroaryl, wherein alkyl, heterocycloalkyl, aryl or heteroaryl is further selected from one or more selected from the group consisting of alkyl, halogen, aryl, Substituted by a substituent of a hydroxy, amino, alkynyl, alkenyl, cyano, nitro, trifluoromethyl, halobenzyl, heterocycloalkyl, carboxylic acid or carboxylic acid ester; wherein an aryl or heteroaryl group Further forming a bicyclic ring, the bicyclic ring is further substituted by a benzyl group or a halobenzyl group;
β L  β L
或者 R1为结构式： Ζ ^ Or R 1 is a structural formula: Ζ ^
其中：  among them:
Β选自芳基或杂芳基，其中芳基或杂芳基进一步被一个或多个选自垸基、卤素、 芳基、 羟基、 氨基、 炔基、 烯基、 氰基、 硝基、 三氟甲基、 卤代苄基、 杂环烷基、 羧酸或羧酸酯的取代基所取代；  The oxime is selected from aryl or heteroaryl, wherein the aryl or heteroaryl is further selected from one or more selected from the group consisting of fluorenyl, halogen, aryl, hydroxy, amino, alkynyl, alkenyl, cyano, nitro, tri Substituted by a substituent of a fluoromethyl group, a halobenzyl group, a heterocycloalkyl group, a carboxylic acid or a carboxylic acid ester;
Τ选自 -0(CH2)r-， -N(CH2)r-或 -S(C¾)r; Τ selected from -0(CH 2 )r-, -N(CH 2 )r- or -S(C3⁄4)r ;
L选自芳基或杂芳基，其中芳基或杂芳基进一步被一个或多个卤素或烷基所取 代； L is selected from aryl or heteroaryl, wherein the aryl or heteroaryl is further taken up by one or more halo or alkyl Generation
R2选自氢原子、 烷基、 环烷基、 三氟甲基、 杂环烷基、 芳基、 杂芳基、 芳烷 基， 其中烷基、 环烷基、 杂环烷基、 芳基、 杂芳基、 芳垸基进一步被一个或多个 选自烷基、 芳基、 羟基、 卤素、 氨基、 氰基、 垸氧基、 羧酸、 羧酸酯或 -NR6R7的 取代基所取代； 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 an alkyl group, a cycloalkyl group, a heterocycloalkyl 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
R3和 R4各自独立地选自氢原子、 烷基、 三氟甲基、 环烷基、 杂环烷基、 芳基、 羧酸酯、 -S02R6、 -C¾C(=0)NR6R7、 -C(=0)NR6R7、 -(CH2)nNR6R7或 -NC (=0) R6， 其中烷基、 环垸基、 杂环垸基进一步被一个或多个选自垸基、 卤素、 三氟甲基、 芳基、 羟基、 烷氧基、 芳氧基、 环垸基、 杂环烷基、 杂芳基、 杂环烷氧基、 氰基、 羧酸、 羧酸酯、 -S02R6、 或 -(CH2)nNR6R7的取代基所取代； R 3 and R 4 are each independently 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 carboxylic acid ester, -S0 2 R 6 , -C3⁄4C(=0)NR 6 R 7 , —C(=0)NR 6 R 7 , —(CH 2 )nNR 6 R 7 or —NC (=0) R 6 , wherein alkyl, cyclodecyl, heterocyclic fluorenyl is further protected by one or a plurality selected from the group consisting of fluorenyl, halogen, trifluoromethyl, aryl, hydroxy, alkoxy, aryloxy, cyclodecyl, heterocycloalkyl, heteroaryl, heterocycloalkoxy, cyano, carboxy Substituted by a substituent of an acid, a carboxylic acid ester, -S0 2 R 6 , or -(CH 2 )nNR 6 R 7 ;
同时， R3和 R4—起形成一个 4〜8元环基； 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选自烷基、 卤素、 芳 基、 杂芳基、 卤代烷基、 卤代烷氧基、 羟基、 烷氧基、 芳氧基、 羰基、 杂环烷基、 羧酸、 羧酸酯、 =N-OR6或 -NR6R7的 代基所取代； Meanwhile, 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 N, 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 alkyl, halogen, aryl, heteroaryl, haloalkyl, haloalkoxy, hydroxy, alkoxy, aryloxy, carbonyl, heterocycloalkyl, carboxylic acid, carboxylic acid ester, =N- Substituted by a substituent of OR 6 or -NR 6 R 7 ;
R6和 R7分别选自氢原子、 烷基、 烯基、 环烷基、 杂环烷基、 芳基或杂芳基， 其中垸基、 烯基、 环烷基、 杂环烷基、 '芳基或者杂芳基进一步被一个或多个选自 烷基、环烷基、卤素、芳基、羟基、氨基、烷氧基、烯基、杂环垸基、羟烷基、 -S02R6、R 6 and R 7 are each independently selected from a hydrogen atom, an alkyl group, an alkenyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, wherein a fluorenyl group, an alkenyl group, a cycloalkyl group, a heterocycloalkyl group, The aryl or heteroaryl group is further selected from one or more selected from the group consisting of alkyl, cycloalkyl, halogen, aryl, hydroxy, amino, alkoxy, alkenyl, heterocycloalkyl, hydroxyalkyl, -S0 2 R 6 ,
-C(=0) R6、 羧酸、 羧酸酯或 - NR6R7的取代基所取代； -C(=0)R 6 , substituted by a carboxylic acid, a carboxylic acid ester or a substituent of -NR 6 R 7 ;
同时， R6和 R7—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选自烷基、 卤素、 芳基、 杂芳基、 卤代芳基、 卤代烷氧基、 氨基、 羟基、 氰基、 烷氧基、 芳氧基、 胺烷基、羟烷基、环烷基、杂环烷基、羰基、羧酸、羧酸酯、 -C(0)NR6R7、 -NC (=0) R6、 -S02R6 或 -NR6R7的取代基所取代； Meanwhile, R 6 and R 7 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 a Or a plurality selected from the group consisting of alkyl, halogen, aryl, heteroaryl, haloaryl, haloalkoxy, amino, hydroxy, cyano, alkoxy, aryloxy, aminalkyl, hydroxyalkyl, ring Alkyl, heterocycloalkyl, carbonyl, carboxylic acid, carboxylic acid ester, substituent of -C(0)NR 6 R 7 , -NC (=0) R 6 , -S0 2 R 6 or -NR 6 R 7 Replaced
11是 0〜6；  11 is 0~6;
r是 0〜2。  r is 0~2.
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：
Figure imgf000358_0001
The compound according to claim 1 or a salt thereof, wherein the compound is a compound represented by the formula (Π):
Figure imgf000358_0001
(II)  (II)
其中- among them-
R1选自烷基、 杂环烷基、 芳基或杂芳基， 其中烷基、 杂环烷基、 芳基或杂芳 基进一步被一个或多个选自烷基、 卤素、 芳基、 羟基、 氨基、 炔基、 烯基、 氰基、 硝基、 三氟甲基、 卤代苄基、 杂环烷基、 羧酸或羧酸酯的取代基所取代； 其中芳 基或杂芳基进一步并成双环， 此双环进一步被苄基或卤代苄基所取代； 或者 R1为结构式：
Figure imgf000359_0001
R 1 is selected from alkyl, heterocycloalkyl, aryl or heteroaryl, wherein alkyl, heterocycloalkyl, aryl or heteroaryl is further selected from one or more selected from the group consisting of alkyl, halogen, aryl, Substituted by a substituent of a hydroxy, amino, alkynyl, alkenyl, cyano, nitro, trifluoromethyl, halobenzyl, heterocycloalkyl, carboxylic acid or carboxylic acid ester; The base or heteroaryl is further combined into a bicyclic ring which is further substituted by a benzyl or halobenzyl group; or R 1 is a structural formula:
Figure imgf000359_0001
^巾：  ^ towel:
B选自芳基或杂芳基，其中芳基或杂芳基进一步被一个或多个选自烷基、卤素、 芳基、 羟基、 氨基、 炔基、 烯基、 氰基、 硝基、 三氟甲基、 卤代苄基、 杂环烷基、 羧酸或羧酸酯的取代基所取代；  B is selected from aryl or heteroaryl, wherein the aryl or heteroaryl is further selected from one or more selected from the group consisting of alkyl, halogen, aryl, hydroxy, amino, alkynyl, alkenyl, cyano, nitro, tri Substituted by a substituent of a fluoromethyl group, a halobenzyl group, a heterocycloalkyl group, a carboxylic acid or a carboxylic acid ester;
T选自 -0(CH2)r-， -N(CH2)r-或 -S(CH2)r; T is selected from -0(CH 2 )r-, -N(CH 2 )r- or -S(CH 2 )r;
L选自芳基或杂芳基，其中芳基或杂芳基进一步被一个或多个卤素或垸基所取 代；  L is selected from aryl or heteroaryl, wherein the aryl or heteroaryl is further substituted by one or more halogen or sulfhydryl groups;
R2选自氢原子、 烷基、 环烷基、 三氟甲基、 杂环垸基、 芳基、 杂芳基、 芳烷 基， 其中垸基、 环烷基、 杂环烷基、 芳基、 杂芳基、 芳烷基进一步被一个或多个 选自垸基、 芳基、 羟基、 素、 氨基、 氰基、 烷氧基、 羧酸、 羧酸酯或 -NR6R7的 取代基所取代； R 2 is selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, a trifluoromethyl group, a heterocyclic fluorenyl 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 with one or more substituents selected from the group consisting of a fluorenyl group, an aryl group, a hydroxy group, a hydroxy group, an amino group, a cyano group, an alkoxy group, a carboxylic acid, a carboxylic acid ester or -NR 6 R 7 Replaced
R3选自氢原子、烷基、三氟甲基、环烷基、杂环垸基、 芳基、羧酸酯、 -S02R6、 -CH2C(=0)NR6R7、 -C(=0)NR6R7、 -(C¾)nNR6R7或 -NC (=0) R6， 其中烷基、 环烷 基、 杂环烷基进一步被一个或多个选自烷基、 卤素、 三氟甲基、 芳基、 羟基、 烷 氧基、 芳氧基、 环烷基、 杂环垸基、 杂芳基、 杂环烷氧基、 氰基、 羧酸、 羧酸酯、 -S02R6、 或 -(C¾)nNR6R7的取代基所取代； R 3 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 carboxylic acid ester, -S0 2 R 6 , -CH 2 C(=0)NR 6 R 7 , -C(=0)NR 6 R 7 , -(C3⁄4)nNR 6 R 7 or -NC (=0) R 6 , wherein the alkyl group, the cycloalkyl group, the heterocycloalkyl group are further selected from one or more selected from the group consisting of an alkane Base, halogen, trifluoromethyl, aryl, hydroxy, alkoxy, aryloxy, cycloalkyl, heterocycloalkyl, heteroaryl, heterocycloalkoxy, cyano, carboxylic acid, carboxylic acid ester Substituted by a substituent of -S0 2 R 6 or -(C3⁄4)nNR 6 R 7 ;
R5选自氢原子、 烷基、 环烷基或 -C(=0)OR6， 其中烷基或环烷基进一步被一个 或多个选自烷基、 羟基、 烷氧基、 氰基、 -NR6R7、 羧酸或羧酸酯的取代基所取代; R 5 is selected from a hydrogen atom, an alkyl group, a cycloalkyl group or -C(=0)OR 6 , wherein the alkyl group or the cycloalkyl group is further further selected from one 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;
R6和 R7分别选自氢原子、 烷基、 烯基、 环烷基、 杂环垸基、 芳基或杂芳基， 其中烷基、 烯基、 环烷基、 杂环烷基、 芳基或者杂芳基进一步被一个或多个选自 烷基、环烷基、卤素、芳基、羟基、氨基、垸氧基、烯基、杂环垸基、羟烷基、 -S02R6、 -C(=0) R6、 羧酸、 羧酸酯或 - NR6R7的取代基所取代； 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 heterocycloalkyl group, or an aromatic group Further, the hetero or heteroaryl group is further selected from one or more selected from the group consisting of alkyl, cycloalkyl, halogen, aryl, hydroxy, amino, decyloxy, alkenyl, heterocycloalkyl, hydroxyalkyl, -S0 2 R 6 Substituting -C(=0)R 6 , a carboxylic acid, a carboxylic acid ester or a substituent of -NR 6 R 7 ;
同时， R6和 R7—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选自垸基、 卤素、 芳基、 杂芳基、 卤代芳基、 卤代烷氧基、 氨基、 羟基、 氰基、 烷氧基、 芳氧基、 胺烷基、羟烷基、环烷基、杂环烷基、羰基、羧酸、羧酸酯、 -C(=0)NR6R7, -NC (=0) R6、 -S02R6、 或 -NR6R7的取代基所取代； Meanwhile, R 6 and R 7 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 a Or a plurality selected from the group consisting of fluorenyl, halogen, aryl, heteroaryl, haloaryl, haloalkoxy, amino, hydroxy, cyano, alkoxy, aryloxy, aminalkyl, hydroxyalkyl, ring Alkyl, heterocycloalkyl, carbonyl, carboxylic acid, carboxylic acid ester, -C(=0)NR 6 R 7 , -NC (=0) R 6 , -S0 2 R 6 , or -NR 6 R 7 Substituted by a substituent;
n是 0〜 6；  n is 0~6;
r是 0〜2。  r is 0~2.
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：
Figure imgf000360_0001
其中： The compound according to claim 1 or a salt thereof, wherein the compound is a compound represented by the formula (III):
Figure imgf000360_0001
among them:
R1选自烷基、 杂环垸基、 芳基或杂芳基， 其中烷基、 杂环烷基、 芳基或杂芳 基进一步被一个或多个选自烷基、 ^素、 芳基、 羟基、 氨基、 炔基、 烯基、 氰基、 硝基、 三氟甲基、 卤代苄基、 杂环烷基、 羧酸或羧酸酯的取代基所取代； 其中芳 基或杂芳基进一步并成双环， 此双环进一步被苄基或卤代苄基所取代； 或者 R1为结构式：
Figure imgf000360_0002
R 1 is selected from an alkyl group, a heterocyclic fluorenyl group, an aryl group or a heteroaryl group, wherein the alkyl group, heterocycloalkyl group, aryl group or heteroaryl group is further selected from one or more selected from the group consisting of an alkyl group, a aryl group and an aryl group. Substituted by a substituent of a hydroxy, amino, alkynyl, alkenyl, cyano, nitro, trifluoromethyl, halobenzyl, heterocycloalkyl, carboxylic acid or carboxylic acid ester; wherein aryl or heteroaryl Further forming a bicyclic ring, which is further substituted by a benzyl or halobenzyl group; or R 1 is a structural formula:
Figure imgf000360_0002
其中- among them-
B选自芳基或杂芳基，其中芳基或杂芳基进一步被一个或多个选自烷基、卤素、 芳基、 羟基、 氨基、 炔基、 烯基、 氰基、 硝基、 三氟甲基、 卤代苄基、 杂环烷基、 羧酸或羧酸酯的取代基所取代； B is selected from aryl or heteroaryl, wherein the aryl or heteroaryl is further selected from one or more selected from the group consisting of alkyl, halogen, aryl, hydroxy, amino, alkynyl, alkenyl, cyano, nitro, tri Substituted by a substituent of a fluoromethyl group, a halobenzyl group, a heterocycloalkyl group, a carboxylic acid or a carboxylic acid ester;
T选自 -0(CH2)r -、 -N(CH2)r-或 -S(CH2)r; T is selected from -0(CH 2 )r -, -N(CH 2 )r- or -S(CH 2 )r ;
L选自芳基或杂芳基，其中芳基或杂芳基进一步被一个或多个卤素或烷基所取 代；  L is selected from aryl or heteroaryl, wherein the aryl or heteroaryl is further substituted by one or more halo or alkyl;
R3和 R4各自独立地选自氢原子、 烷基、 三氟甲基、 环垸基、 杂环烷基、 芳基、 羧酸酯、 -S02R6、 -CH2C(=0)NR6R7、 -d(=0)NR6R7、 -(C¾)nNR6R7或 -NC (=0) R6， 其中烷基、 环垸基、 杂环垸基进一步被一个或多个选自垸基、 卤素、 三氟甲基、 芳基、 羟基、 烷氧基、 芳氧基、 环垸基、 杂环烷基、 杂芳基、 杂环垸氧基、 氰基、 羧酸、 羧酸酯、 -S02R6、 或 -(CH2)nNR 7的取代基所取代； R 3 and R 4 are each independently selected from the group consisting of a hydrogen atom, an alkyl group, a trifluoromethyl group, a cyclodecyl group, a heterocycloalkyl group, an aryl group, a carboxylic acid ester, -S0 2 R 6 , -CH 2 C (=0 )NR 6 R 7 , -d(=0)NR 6 R 7 , -(C3⁄4)nNR 6 R 7 or -NC (=0) R 6 , wherein the alkyl group, the cycloalkyl group, the heterocyclic fluorenyl group are further Or a plurality selected from the group consisting of fluorenyl, halogen, trifluoromethyl, aryl, hydroxy, alkoxy, aryloxy, cyclodecyl, heterocycloalkyl, heteroaryl, heterocyclomethoxy, cyano, Substituted by a substituent of a carboxylic acid, a carboxylic acid ester, -S0 2 R 6 , or -(CH 2 )nNR 7 ;
同时， R3和 R4—起形成一个 4〜8元环基； 其中 5〜8元杂环内含有一个或多 个>1、 0、 S原子， 并且 4〜8元杂环上进一步被一个或多个选自烷基、 卤素、 芳 基、 杂芳基、 卤代烷基、 卤代烷氧基、 羟基、 垸氧基、 芳氧基、 羰基、 杂环垸基、 羧酸、 羧酸酯、 =N-OR6或 -NR6R7的取代基所取代； Meanwhile, 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 of >1, 0, S atoms, and the 4 to 8 membered heterocyclic ring is further subjected to a Or a plurality selected from the group consisting of alkyl, halogen, aryl, heteroaryl, haloalkyl, haloalkoxy, hydroxy, decyloxy, aryloxy, carbonyl, heterocycloalkyl, carboxylic acid, carboxylic acid ester, =N Substituted by a substituent of -OR 6 or -NR 6 R 7 ;
R6和 R7分别选自氢原子、 垸基、 烯基、 环烷基、 杂环烷基、 芳基或杂芳基， 其中烷基、 烯基、 环烷基、 杂环烷基、 芳基或者杂芳基进一步被一个或多个选自 烷基、环垸基、卤素、芳基、羟基、氨基、垸氧基、烯基、杂环垸基、羟垸基、 -S02R6、 -C(=0) R6、 羧酸、 羧酸酯或 - NR6R7的取代基所取代； R 6 and R 7 are each independently selected from the group consisting of a hydrogen atom, a fluorenyl group, an alkenyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, wherein an alkyl group, an alkenyl group, a cycloalkyl group, a heterocycloalkyl group, or an aromatic group. Further, the hetero or heteroaryl group is further selected from one or more selected from the group consisting of alkyl, cyclodecyl, halogen, aryl, hydroxy, amino, decyloxy, alkenyl, heterocycloalkyl, hydroxydecyl, -S0 2 R 6 Substituting -C(=0)R 6 , a carboxylic acid, a carboxylic acid ester or a substituent of -NR 6 R 7 ;
同时， R6和 R7—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选自烷基、 卤素、 芳基、 杂芳基、 卤代芳基、 卤代垸氧基、 氨基、 羟基、 氰基、 烷氧基、 芳氧基、 胺垸基、羟烷基、环烷基、杂环垸基、羰基、羧酸、羧酸酯、 -C(=0)NR6R7, -NC (=0) R6、 -S02R6、 或 -NR 7的取代基所取代； n是 0—6； Meanwhile, R 6 and R 7 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 a Or a plurality selected from the group consisting of alkyl, halogen, aryl, heteroaryl, haloaryl, halomethoxy, amino, hydroxy, cyano, alkoxy, aryloxy, amidino, hydroxyalkyl , cycloalkyl, heterocycloalkyl, carbonyl, carboxylic acid, carboxylic acid ester, -C(=0)NR 6 R 7 , -NC (=0) R 6 , -S0 2 R 6 , or -NR 7 Substituted by a substituent; n is 0-6;
l '是 0〜2。  l 'is 0~2.
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:
Figure imgf000361_0001
Figure imgf000361_0001
Figure imgf000362_0001
.0CT00/800ZN3/X3d
Figure imgf000362_0001
.0CT00/800ZN3/X3d
Figure imgf000363_0001
.0CT00/800ZN3/X3d Z9
Figure imgf000363_0001
.0CT00/800ZN3/X3d Z9
Figure imgf000364_0001
Figure imgf000364_0001
.0CT00/800ZN3/X3d
Figure imgf000365_0001
.0CT00/800ZN3/X3d
Figure imgf000365_0001
Figure imgf000366_0001
.0CT00/800ZN3/X3d
Figure imgf000366_0001
.0CT00/800ZN3/X3d
Figure imgf000367_0001
.0C100/800ZN3/X3d Ζ^9ΖΪ0/600Ζ ΟΛ\ 99£
Figure imgf000367_0001
.0C100/800ZN3/X3d Ζ^9ΖΪ0/600Ζ ΟΛ\ £99
Figure imgf000368_0001
.0CT00/800ZN3/X3d
Figure imgf000368_0001
.0CT00/800ZN3/X3d
Figure imgf000369_0001
Figure imgf000369_0001
.0CT00/800ZN3/X3d 89£ .0CT00/800ZN3/X3d £89
Figure imgf000370_0001
Figure imgf000370_0001
^oeioo/sooz j/xai ^oeioo/sooz j/xai
Figure imgf000371_0001
.0CT00/800ZN3/X3d
Figure imgf000371_0001
.0CT00/800ZN3/X3d
Figure imgf000372_0001
Figure imgf000372_0001
.0CT00/800ZN3/X3d .0CT00/800ZN3/X3d
Figure imgf000373_0001
Figure imgf000373_0001
6. 根据权利要求 1所述的化合物或其盐， 其中所述的盐为所述化合物与选自以下 的酸形成的盐： 苹果酸、 乳酸、 马来酸、 盐酸、 甲磺酸、 对甲苯磺酸、 硫酸、 磷 酸、 柠檬酸、 酒石酸、 乙酸或三氟乙酸。 7. 一种药用组合物、 其含有治疗有效剂量的根据权利要求 1〜6 中任何一项所述 的化合物或其盐， 及药学上可以接受的载体或赋形剂。 The compound according to claim 1 or a salt thereof, wherein the salt is a salt of the compound with an acid selected from the group consisting of malic acid, lactic acid, maleic acid, hydrochloric acid, methanesulfonic acid, p-toluene Sulfonic acid, sulfuric acid, phosphoric acid, citric acid, tartaric acid, acetic acid or trifluoroacetic acid. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 6 or a salt thereof, and a pharmaceutically acceptable carrier or excipient.
8.一种根据权利要求 2所述的通式（I)化合物的制备方法，该方法包括以下步骤: (1) 8. A process for the preparation of a compound of formula (I) according to claim 2, which process comprises the steps of: (1)
Figure imgf000373_0002
在碘化亚酮和磷酸钾的条件下， 6位喹唑啉碘代物 a与 6,7-二氢 -2H-吡喃 [3,4-c] 吡咯 -4-酮进行偶联，得到吡咯内酯喹唑啉类化合物 b，吡咯内酯喹唑啉类化合物 b 与取代胺反应， 得到通式化合物 (I a), la可与甲磺酰氯、 取代胺反应， 进一步得 到通式化合物 (l b); 同时， 吡咯内酯喹唑啉类化合物 b与氢化铝锂反应，得到二羟 基化合物 c，二羟基化合物 c部分氧化得到的吡咯酸基化合物 d与取代胺和三乙酰 氧基硼氢化钠进行还原氨化得到通式化合物 (I c);
Figure imgf000373_0002
Coupling of the 6-position quinazoline iodide a with 6,7-dihydro-2H-pyran[3,4-c]pyrrole-4-one under the conditions of iodide and potassium phosphate to obtain pyrrole The lactone quinazoline compound b, the pyrrolactone quinazoline compound b is reacted with a substituted amine to obtain a compound of the formula (I a), and la can be reacted with methanesulfonyl chloride or a substituted amine to further obtain a compound of the formula (lb). At the same time, the pyrrolactone quinazoline compound b is reacted with lithium aluminum hydride to obtain a dihydroxy compound c, a pyrrolic acid group compound d obtained by partial oxidation of the dihydroxy compound c with a substituted amine and sodium triacetoxyborohydride. Reductive amination to give a compound of the formula (I c);
(2) (2)
Figure imgf000374_0001
在碘化亚酮和磷酸钾的条件下， 6位喹唑啉碘代物 a与 4-三氟甲基 -1H-吡咯 -3- 甲酸乙酯进行偶联， 得到三氟甲基吡咯甲酸乙酯取代喹唑啉类化合物 e， e与叠氮 磷酸二苯酯反应， 得到叠氮基甲酰基吡咯化合物 f， f与甲醇反应， 然后在三氟醋 酸的条件下， 得到氨基吡咯化合物 g， g与酰氯反应得到通式化合物 (I d); 或者， 化合物 e与氢化铝锂反应， 得到羟基还原产物 h， h部分氧化得到的化合物 i与取 代胺和三乙酰氧基硼氢化钠反应得到通式化合物 (I e);
Figure imgf000374_0001
Coupling of the 6-position quinazoline iodide a with ethyl 4-trifluoromethyl-1H-pyrrole-3-carboxylate under ethyl iodide and potassium phosphate gives ethyl trifluoromethylpyrroleate The substituted quinazoline compound e, e is reacted with diphenyl azide to obtain an azide formylpyrrole compound f, f is reacted with methanol, and then under the condition of trifluoroacetic acid, an aminopyrrole compound g, g and The acid chloride is reacted to obtain the compound of the formula (I d); or the compound e is reacted with lithium aluminum hydride to obtain a hydroxy reduction product h, and the compound i obtained by partial oxidation of h is reacted with a substituted amine and sodium triacetoxyborohydride to obtain a compound of the formula. (I e);
(3) (3)
Figure imgf000374_0002
在碘化亚酮和磷酸钾的条件下， 6位喹唑啉碘代物 a与 3-吡咯甲醛进行偶联， 得到吡咯甲醛喹唑啉类化合物 j， j与取代胺和三乙酰氧基硼氢化钠反应， 得到通 式化合物 (I f); 化合物 a与吡咯进行 Suzuki偶联反应， 得到吡咯取代化合物 k， k 与 Ν,Ν-二甲基甲酰胺和三氯氧磷反应， 得到吡咯甲酰化产物 1， 1还原氨化得到通 式化合物 (I g);
Figure imgf000374_0002
Under the conditions of iodide and potassium phosphate, the 6-position quinazoline iodide a is coupled with 3-pyrrolidine to obtain pyrrolidine quinazoline compound j, j and substituted amine and triacetoxyborohydride. Sodium reaction to obtain the compound of the formula (I f); the compound a and the pyrrole are subjected to a Suzuki coupling reaction to obtain a pyrrole-substituted compound k, k which is reacted with hydrazine, hydrazine-dimethylformamide and phosphorus oxychloride to obtain pyrrole Reductive product 1,1 reductive amination to give the general compound (I g);
(4) (4)
Figure imgf000375_0001
在碘化亚酮和磷酸钾的条件下， 6位喹唑啉碘代物 a与 1H-吡咯 -3，4-二甲酸乙 酯进行偶联， 得到吡咯二甲酸乙酯取代喹唑啉类化合物 m， m与氢化铝锂反应， 吡咯二甲酸乙酯被还原位为吡咯二羟甲基产物 n， n进一步被氧化得到吡咯二甲醛 产物 o， 化合物 0还原氨化得到通式化合物 (I h);
Figure imgf000375_0001
Under the conditions of iodide and potassium phosphate, the 6-position quinazoline iodide a is coupled with 1H-pyrrole-3,4-dicarboxylic acid ethyl ester to obtain ethyl pyrrole dicarboxylate substituted quinazoline compound m. , m is reacted with lithium aluminum hydride, the ethyl pyrrole dicarboxylate is reduced to the pyrrole dimethylol product n, n is further oxidized to obtain the pyrrole dialdehyde product o, and the compound 0 is reductively aminated to obtain the compound of the formula (I h ) ;
(5) (5)
Figure imgf000375_0002
在碘化亚酮和磷酸钾的条件下， 6位喹唑啉碘代物 a与化合物 p进行偶联，得 到吡咯取代喹唑啉类通式化合物 (I i)。
Figure imgf000375_0002
Under the conditions of iodide and potassium phosphate, the 6-position quinazoline iodide a is coupled with the compound p to obtain a pyrrole-substituted quinazoline-based compound (I i).
9. 一种根据权利要求 3所述的通式 qi)化合物的制备方法， 该方法包括以下步 9. A process for the preparation of a compound of the formula qi) according to claim 3, which comprises the following steps
Figure imgf000375_0003
Figure imgf000375_0003
(t) ("a)  (t) ("a)
在碘化亚酮和磷酸钾的条件下， 6位喹唑啉碘代物 a与 2-硼酸吡咯化合物 q 进行 Suzuki偶联， 得到吡咯取代喹唑啉类化合物 r， r在碱性条件下脱去对吡咯 N 保护， 得到 6-吡咯取代的喹唑啉类化合物 s， s与 Ν,Ν—二甲基甲酰胺和三氯氧磷 反应， 进行 Vilsemier反应， 得到 2-醛基取代吡咯化合物 t， t在三乙酰氧基氢化铝 锂和取代胺的条件下进行化合物氨化， 得到通式化合物 (Π a); 6-position quinazoline iodide a and 2-boric acid pyrrole compound q under conditions of iodide and potassium phosphate Suzuki coupling is carried out to obtain a pyrrole-substituted quinazoline compound r, r is deprotected from pyrrole N under basic conditions to obtain a 6-pyrrole-substituted quinazoline compound s, s and hydrazine, hydrazine-dimethyl The formamide is reacted with phosphorus oxychloride to carry out the Vilsemier reaction to obtain a 2-aldehyde-substituted pyrrole compound t, and the compound is aminated under the conditions of lithium triacetoxyaluminum hydride and a substituted amine to obtain a compound of the formula (Π a );
Figure imgf000376_0001
Figure imgf000376_0001
(lib)  (lib)
将 6-吡咯取代的喹唑啉类化合物 s与三异丙基硅氯进行反应，得到的化合物 u 进一步与 Ν,Ν—二甲基甲酰胺和三氯氧磷反应得到吡咯甲酰化产物 ν， V还原氨化 得到通式化合物 (li b：)，化合物 s在强碱氢化钠条件下与 1-卤代垸基如碘甲烷反应， 得到通式化合物 (lie：)。  The 6-pyrrole-substituted quinazoline compound s is reacted with triisopropylsilyl chloride, and the obtained compound u is further reacted with hydrazine, hydrazine-dimethylformamide and phosphorus oxychloride to obtain a pyrrolylated product ν Reductive amination of V to give a compound of the formula (li b:), which is reacted with a 1-haloindenyl group such as methyl iodide under strong sodium hydride to give a compound of the formula (lie:).
10. 一种根据权要求 4所述的通式 （ΙΠ) 化合物的制备方法， 该方法包括以下步 骤： 10. A method of preparing a compound of the formula (ΙΠ) according to claim 4, the method comprising the steps of:
Figure imgf000376_0002
在碳酸鉀和三苯基膦化钯的条件下， 6位喹唑啉碘代物 a与 3-硼酸吡咯化合物 w进行 Suzuki偶联， 得到的吡咯取代喹唑啉化合物 X在氢化钠条件下， 与卤代或 甲磺酰基取代的化合物， 即 R3X或 R3S03CH3反应， 得到通式化合物 (Ilia); 化合 物 x在氢化钠条件下， 也可以与 α-卤代酰胺反应， 得到通式化合物 (IIId)， 酰胺的 羰基也可以进一步被氢化铝锂还原， 得到通式化合物 (Ille); 化合物 X在氢化钠条 件下， 与消旋环氧氯丙烷反应得到通式物 (ΙΠί)， 与 NHR6R7开环反应， 得到通式 物 (IIIg)， 在相同的条件下， 化合物 X与 R型或 S型环氧氯丙烷反应， 进一步开环 反应，对应得到 S型或 R型通式物 (IIIg);化合物 X与 Ν,Ν-二甲基甲酰胺和三氯氧 磷反应， 得到的甲酰化产物 y， 在高锰酸钾的氧化下， 将吡咯醛转化为吡咯羧酸， 进一步与取代胺反应得到通式化合物 (IIIb)， 化合物 y也可以直接被还原氨化得到 通式化合物 (111(0。 11 . 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要求 1〜6中任何一项所述的化合物或盐接触。
Figure imgf000376_0002
Under the conditions of potassium carbonate and palladium triphenylphosphine, the 6-position quinazoline iodide a is subjected to Suzuki coupling with the 3-boronic acid pyrrole compound w, and the obtained pyrrole-substituted quinazoline compound X is obtained under sodium hydride conditions. A halogenated or methanesulfonyl substituted compound, i.e., R 3 X or R 3 S0 3 CH 3 , is obtained to give a compound of the formula (Ilia); The compound x can also be reacted with an α-haloamide under sodium hydride to obtain a compound of the formula (IIId). The carbonyl group of the amide can also be further reduced by lithium aluminum hydride to obtain a compound of the formula (Ille); Reaction with racemic epichlorohydrin under sodium conditions to give the general formula (ΙΠί), ring-opening reaction with NHR 6 R 7 to give the general formula (III g ), under the same conditions, compound X and R or S-type epichlorohydrin reaction, further ring-opening reaction, corresponding to the S-type or R-type general formula (III g ); compound X and hydrazine, hydrazine-dimethylformamide and phosphorus oxychloride, the obtained A The acylated product y, converted to pyrrolecarboxylic acid by oxidation of potassium permanganate, further reacted with a substituted amine to obtain a compound of the formula (IIIb), and the compound y can also be directly reductively aminated to obtain a compound of the formula ( A method for regulating the catalytic activity of a protein kinase, which comprises contacting the protein kinase with the compound or salt according to any one of claims 1 to 6.
12. 根据权利要求 11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。 12. The method of claim 11, 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.
13. 根据权利要求 1-6任一项所述的化合物或其盐在制备治疗与蛋白质激酶有关的 疾病的药物中的用途。 13. Use of a compound according to any one of claims 1 to 6 or a salt thereof for the manufacture of a medicament for the treatment of a disease associated with a protein kinase.
14.根据权利要求 7所述的组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。 14. Use of a composition according to claim 7 in the manufacture of a medicament for the treatment of a disease associated with a protein kinase.
PCT/CN2008/001307 2007-07-20 2008-07-14 Preparation methods of quinazoline derivatives and their pharmaceutical uses WO2009012647A1 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN200710136195 2007-07-20
CN200710136195.2 2007-07-20
CN 200810127622 CN101367794B (en) 2007-07-20 2008-06-30 Preparation method for quinazoline derivants and medical uses thereof
CN200810127622.5 2008-06-30

Publications (1)

Publication Number Publication Date
WO2009012647A1 true WO2009012647A1 (en) 2009-01-29

Family

ID=40280984

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2008/001307 WO2009012647A1 (en) 2007-07-20 2008-07-14 Preparation methods of quinazoline derivatives and their pharmaceutical uses

Country Status (1)

Country Link
WO (1) WO2009012647A1 (en)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011041655A1 (en) * 2009-10-01 2011-04-07 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Quinazolin-4-amine derivatives; and methods of use
WO2011073378A1 (en) 2009-12-18 2011-06-23 Basilea Pharmaceutica Ag Tricyclic antibiotics
WO2012171860A1 (en) 2011-06-17 2012-12-20 Basilea Pharmaceutica Ag Tricyclic antibiotics
JP2013510876A (en) * 2009-11-13 2013-03-28 ジェノスコ Kinase inhibitor
US8916574B2 (en) 2009-09-28 2014-12-23 Qilu Pharmaceutical Co., Ltd. 4-(substituted anilino)-quinazoline derivatives useful as tyrosine kinase inhibitors
EP2740729A4 (en) * 2011-08-01 2015-02-25 Hangzhou Minsheng Inst For Pharma Res Quinazoline derivative, composition having the derivative, and use of the derivative in preparing medicament
CN112479913A (en) * 2020-11-19 2021-03-12 安徽修一制药有限公司 Preparation method of N, N-diethyl chloroacetamide
US11034669B2 (en) 2018-11-30 2021-06-15 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof
WO2022140456A1 (en) * 2020-12-22 2022-06-30 Mekanistic Therapeutics Llc Substituted aminobenzyl heteroaryl compounds as egfr and/or pi3k inhibitors

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998002434A1 (en) * 1996-07-13 1998-01-22 Glaxo Group Limited Fused heterocyclic compounds as protein tyrosine kinase inhibitors
WO1999050264A1 (en) * 1998-03-30 1999-10-07 Kyowa Hakko Kogyo Co., Ltd. Quinazoline derivatives
GB2345486A (en) * 1999-01-11 2000-07-12 Glaxo Group Ltd Heteroaromatic protein tyrosine kinase inhibitors
WO2007056170A2 (en) * 2005-11-02 2007-05-18 Bayer Healthcare Ag Pyrrolo[2,1-f] [1,2,4] triazin-4-ylamines igf-1r kinase inhibitors for the treatment of cancer and other hyperproliferative diseases

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998002434A1 (en) * 1996-07-13 1998-01-22 Glaxo Group Limited Fused heterocyclic compounds as protein tyrosine kinase inhibitors
WO1999050264A1 (en) * 1998-03-30 1999-10-07 Kyowa Hakko Kogyo Co., Ltd. Quinazoline derivatives
GB2345486A (en) * 1999-01-11 2000-07-12 Glaxo Group Ltd Heteroaromatic protein tyrosine kinase inhibitors
WO2007056170A2 (en) * 2005-11-02 2007-05-18 Bayer Healthcare Ag Pyrrolo[2,1-f] [1,2,4] triazin-4-ylamines igf-1r kinase inhibitors for the treatment of cancer and other hyperproliferative diseases

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8916574B2 (en) 2009-09-28 2014-12-23 Qilu Pharmaceutical Co., Ltd. 4-(substituted anilino)-quinazoline derivatives useful as tyrosine kinase inhibitors
WO2011041655A1 (en) * 2009-10-01 2011-04-07 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Quinazolin-4-amine derivatives; and methods of use
JP2013510876A (en) * 2009-11-13 2013-03-28 ジェノスコ Kinase inhibitor
WO2011073378A1 (en) 2009-12-18 2011-06-23 Basilea Pharmaceutica Ag Tricyclic antibiotics
WO2012171860A1 (en) 2011-06-17 2012-12-20 Basilea Pharmaceutica Ag Tricyclic antibiotics
EP2740729A4 (en) * 2011-08-01 2015-02-25 Hangzhou Minsheng Inst For Pharma Res Quinazoline derivative, composition having the derivative, and use of the derivative in preparing medicament
US11034669B2 (en) 2018-11-30 2021-06-15 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof
CN112479913A (en) * 2020-11-19 2021-03-12 安徽修一制药有限公司 Preparation method of N, N-diethyl chloroacetamide
WO2022140456A1 (en) * 2020-12-22 2022-06-30 Mekanistic Therapeutics Llc Substituted aminobenzyl heteroaryl compounds as egfr and/or pi3k inhibitors
US11673876B2 (en) 2020-12-22 2023-06-13 Mekanistic Therapeutics Llc Substituted aminobenzyl heteroaryl compounds as EGFR and/or PI3K inhibitors

Similar Documents

Publication Publication Date Title
WO2009012647A1 (en) Preparation methods of quinazoline derivatives and their pharmaceutical uses
JP5415271B2 (en) Substituted pyrrolo-pyrazole derivatives as kinase inhibitors
JP5342547B2 (en) Pyrrolonitroheterocyclic derivatives, their preparation and pharmaceutical use
KR101580482B1 (en) 4-pyrazolyl-N-arylpyrimidin-2-amines and 4-pyrazolyl-N-heteroarylpyrimidin-2-amines as Janus kinase inhibitors
KR101452520B1 (en) Pyrrolo [3,2-c] pyridine-4-one 2-indolinone protein kinase inhibitors
JP5095626B2 (en) Pyrrolotriazine kinase inhibitor
JP4740878B2 (en) Pyrrotriazine compounds as kinase inhibitors
CN109422755A (en) A kind of nitrogen-containing heterocycle compound, preparation method, intermediate, composition and application
CN101367794B (en) Preparation method for quinazoline derivants and medical uses thereof
WO2007085205A1 (en) Pyrrole substituted 2-indolinone derivatives, the preparation methods and medical uses thereof
TW200300350A (en) C-5 modified indazolylpyrrolotriazines
MXPA06002964A (en) Quinazoline derivatives as tyrosine kinase inhibitors.
WO2014078372A1 (en) Pyrrolidinyl urea, thiourea, guanidine and cyanoguanidine compounds as trka kinase inhibitors
KR20080011199A (en) Nitrogen-containing heterocyclic compound
CA2611378A1 (en) Aminoquinoline and aminoquinazoline kinase modulators
KR20100089090A (en) Pyridine and pyrazine derivatives useful in the treatment of cell proliferative disorders
MXPA06002963A (en) Quinazoline derivatives as tyrosine kinase inhibitors.
JP2007505871A (en) Quinazoline derivatives
RU2643361C2 (en) New triazolopyrasine derivatives and their application
CA2611242A1 (en) Alkylquinoline and alkylquinazoline kinase modulators
EP2203442A1 (en) Substituted pyrrolo-pyrimidine derivatives, process for their preparation and their use as kinase inhibitors
JP2009528335A (en) Quinazoline derivatives
CN117813299A (en) Nitrogen-containing heterocyclic derivative inhibitor, preparation method and application thereof
JP2008545787A (en) Intermediates and related synthetic methods useful in the synthesis of alkylquinolines and alkylquinazoline kinase modulators
AU2006268174A1 (en) Kinase inhibitors

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 08783512

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 08783512

Country of ref document: EP

Kind code of ref document: A1