CN103354809B - A kind of aryl urea compounds, its intermediate and application thereof - Google Patents
A kind of aryl urea compounds, its intermediate and application thereof Download PDFInfo
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- CN103354809B CN103354809B CN201180011513.7A CN201180011513A CN103354809B CN 103354809 B CN103354809 B CN 103354809B CN 201180011513 A CN201180011513 A CN 201180011513A CN 103354809 B CN103354809 B CN 103354809B
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- 0 O*=C1NC=NC(C2)C1=CCC2F Chemical compound O*=C1NC=NC(C2)C1=CCC2F 0.000 description 3
- UPAXCRWZTCPAPE-UHFFFAOYSA-N CN1CCC(COC(CC=C23)C=C2N=CN=C3Cl)CC1 Chemical compound CN1CCC(COC(CC=C23)C=C2N=CN=C3Cl)CC1 UPAXCRWZTCPAPE-UHFFFAOYSA-N 0.000 description 1
- WJYDNOOZVOSJMM-UHFFFAOYSA-N CN1CCC(COc(cc2N=CN3)ccc2C3=O)CC1 Chemical compound CN1CCC(COc(cc2N=CN3)ccc2C3=O)CC1 WJYDNOOZVOSJMM-UHFFFAOYSA-N 0.000 description 1
- KCGPVGOFJFVKPF-UHFFFAOYSA-N CN1CCN(CCCOC(CC=C23)C=C2N=CN=C3Cl)CC1 Chemical compound CN1CCN(CCCOC(CC=C23)C=C2N=CN=C3Cl)CC1 KCGPVGOFJFVKPF-UHFFFAOYSA-N 0.000 description 1
- OTDCQIRHAQHLES-UHFFFAOYSA-N CN1CCN(CCCOC(CC=C23)C=C2N=CNC3O)CC1 Chemical compound CN1CCN(CCCOC(CC=C23)C=C2N=CNC3O)CC1 OTDCQIRHAQHLES-UHFFFAOYSA-N 0.000 description 1
- BMQPSEMVBQAIFJ-UHFFFAOYSA-N ClCCCOC(CC=C12)C=C1N=CN=C2Cl Chemical compound ClCCCOC(CC=C12)C=C1N=CN=C2Cl BMQPSEMVBQAIFJ-UHFFFAOYSA-N 0.000 description 1
- YROKQUJKRVXGKT-UHFFFAOYSA-N O=C(C1=CC2)NC=NC1=CC2F Chemical compound O=C(C1=CC2)NC=NC1=CC2F YROKQUJKRVXGKT-UHFFFAOYSA-N 0.000 description 1
- IJGLZSIHCAOGMD-UHFFFAOYSA-N OC1NC=Nc2cc(F)ccc12 Chemical compound OC1NC=Nc2cc(F)ccc12 IJGLZSIHCAOGMD-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/94—Nitrogen atoms
-
- 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
- A61P17/06—Antipsoriatics
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- 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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- 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
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
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- 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
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C275/30—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by halogen atoms, or by nitro or nitroso groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C275/40—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by nitrogen atoms not being part of nitro or nitroso groups
Abstract
The invention discloses a kind of such as formula the aryl urea compounds shown in I or its pharmacy acceptable salt, polymorphic form, solvate or steric isomer, and its intermediate and application.Aryl urea compounds I of the present invention has protein kinase inhibiting activity, and antitumor and anti-angiogenic rebirth activity.
Description
Technical field
The present invention relates to a kind of aryl urea compounds, its intermediate and application thereof particularly.
Background technology
Signal transduction (signaltransduction) between cell interior and cell regulates and controls the every aspect of cell function.The exception of cell signalling is the molecular basis of the complicated cause of disease of a lot of disease.Most signal transduction pathway is mediated by protein kinase (proteinkinase).The phosphorylation of human protein kinase catalytic serine, Threonine or tyrosine residues, plays an important role in the growth of cell, metabolism, differentiation and apoptosis.Disregulated protein kinases can cause a series of diseases comprising tumour, diabetes, autoimmune disorder, nerve degenerative diseases and inflammation.Therefore, kinases inhibitor becomes an important channel for the treatment of above-mentioned many mankind's major diseases.
Human kinase protein group membership is (.Science such as ManningG, 2002,298 (5600): 1912-1934) more than 500 kinds, comprise Tyrosylprotein kinase and serine/threonine kinase.Some important protein kinases as drug targets are exemplified below: HER kinases (as EGFR and HER-2), VEGFR kinases is (as VEGFR-1, VEGFR-2 and VEGFR-3), PDGFR kinases is (as PDGFR α, PDGFR β, c-KIT, CSF1R and FLT-3), SRC kinases is (as SRC, LCK, FYN and HCK), ALK, BCR-ABL, c-MET, TIE-2, FGFR1, RAF kinases (as BRAF and CRAF), Aurora A (as AuroraA and AuroraB), and above-mentioned kinase whose mutant strain (as BCR-ABLT315I and BRAFV600E).
Angiogenesis (angiogenesis) refers to from the brand-new blood vessel of existing angiogenesis.Normal angiogenesis is a normal physiological processes being subject to tight control, betides fetal development, wound healing and menstrual cycle.Angiogenesis is once imbalance may cause the various diseases such as diabetic retinopathy, rheumatoid arthritis, age-related macular degeneration, arteriosclerosis and tumour.
Angiogenesis is the lifeline of maintaining tumour existence and progress, and solid tumor height relies on angiogenesis to be continued to obtain nutrition and oxygen.Therefore, the compound of target vascular therapy new life becomes a large focus of antitumor drug research, and expects that it may have advantage in security and resistance.The multi-kinase inhibitor Xarelto of current listing, Sutent and Pazopanib all have anti-angiogenic rebirth activity.
The target of current anti-angiogenic rebirth comprises somatomedin (as vascular endothelial growth factor, platelet derived growth factor receptor, fibroblast growth factor and Urogastron), receptor tyrosine kinase, transcription factor (as hypoxia inducible factor (hypoxiainduciblefactor)), and participates in the molecule of MAPK and PI3K signal transduction pathway.Wherein protein kinase target mainly comprises VEGFR, FGFR, PDGFR, c-KIT, FLT-3 and TIE-2 etc.
Urea structure type compound receives extensive and deep research in recent years as kinases inhibitor.(the .CurrentOpinioninDrugDiscovery & Development such as DumasJ, 2004,7 (5): 600-616.)
1, Xarelto:
Xarelto (sorafenib) is first selectivity multi-kinase inhibitor gone on the market by U.S. FDA approval, and its chemical structure characteristic is diaryl urea (diarylurea).Xarelto is to the Raf-1 (IC in RAF/MEK/ERK signal transduction pathway
50, 6nM), wild-type BRAF (IC
50, 22nM), V599E anomaly BRAF (IC
50, 38nM) all there is remarkable inhibiting activity.In addition, Xarelto also can the multiple receptor tyrosine kinase significant to angiogenesis (RTK) of potent suppression: VEGFR-2 (IC
50, 90nM), mouse VEGFR-2 (IC
50, 15nM), mouse VEGFR-3 (IC
50, 20nM), mouse PDGFR-β (IC
50, 57nM), c-KIT (IC
50, 68nM) and Flt3 (IC
50, 58nM).In a word, Xarelto is target RAF/MEK/ERK signal transduction pathway blocks tumor cells propagation both, the target VEGFR-2/PDGFR-signal β transductory cascade Tumor suppression angiogenesis (.CancerResearch such as WilhelmSM again, 2004,64 (19): 7099-7109).
2, the analog of Xarelto:
(the .JournalofMedicinalChemistry such as PotashmanMH such as the Potashman of Amgen company, 2007,50:4351-4373.) be corresponding 2-aminobenzimidazole by Xarelto cyclization, by further structure of modification, obtain the amino benzo oxazoline compound 2 ' of 2-.Compound 2 ' is potent optionally VEGFR-2 inhibitor (Ki3nM), to the IC of HUVEC
50for 15nM.
TIE-2 and the VEGFR-2 dual tyrosine kinase inhibitor (IC that it is representative that the Hasegawa of GlaxoSmithKline PLC etc. (.JournalofMedicinalChemistry such as HasegawaM, 2007,50:4453-4470.) report with compound 3 '
50be respectively 4.9nM and 1.5nM), in PBS (phosphate buffered saline (PBS)), solubleness is about 200 μ g/mL.
(the .JournalofMedicinalChemistry such as RamurthyS such as the Ramurthy of Novartis, 2008,51 (22): 7049-7052.) report obtains a series of 2-aryl benzimidazoles RAF inhibitor with Orally active by the urea fragment of Xarelto and the phenyl ring on side being condensed, and therefrom filters out RAF265 and enters the melanomatous clinical trial for the treatment of.
(the .JournalofMedicinalChemistry such as Niculescu-DuvazD such as Niculescu-Duvaz, 2009,52 (8): 2255-2264.) adopt bicyclic pyridine and imidazolidone as hinge area binding fragment, obtain potent B-RAF inhibitors 4 ' (IC
5012nM).
3, other urea structure kinases inhibitors:
The II phase that Tandutinib (MLN-518) is in acute myelocytic leukemia (AML) is clinical.It is receptor kinase FLT-3, c-KIT and platelet derived growth factor receptor (PDGFR) potent inhibitor (IC
50170 ~ 220nM), all there is high selectivity (IC for p38 kinases, VEGFR-2 and FGFR
50> 30 μMs).(the .CurrentOpinioninDrugDiscovery & Development such as DumasJ, 2004,7 (5): 600-616.)
Boehringer Ingelheim once developed the clinical trial that di-aryl urea compounds BIRB796 enters treatment autoimmune disorder.BIRB796 is p 38 alpha map kinase inhibitor.(.JournalofMedicinalChemistry such as ReganJ, 2003,46 (22): 4676-4686.)
The isothiazole compounds CP-547632 of Pfizer's report is potent VEGFR-2 and bFGF inhibitor, IC
50be respectively 11 and 9nM, demonstrate selectivity relative to EGFR, PDGFR β and other associated kinases.CP-547632 has the double activity of angiogenesis inhibiting and tumor cell proliferation: the angiogenesis of potent suppression VEGFR and FGF induction in model in vivo; In the athymic mouse of lotus people xenograft tumor, oral administration can suppress the tumor growth of 85%.(.CancerResearch such as BeebeJS, 2003,63 (21): 7301-7309.)
Abbott Laboratories (the .JournalofMedicinalChemistry such as DaiYJ, 2007,50 (7): 1584-1597.) in order to find novel many kinases receptors Tyrosylprotein kinase (RTK) inhibitor, find ABT-869 by the extensive structure activity study in Aminoindazole series compound, carry out clinical trial.ABT-869 is to the IC of KDR, FLT-3 and c-KIT
50be respectively 4,5 and 16nM.
Summary of the invention
Technical problem to be solved by this invention there is provided a kind of and the diverse aryl urea compounds of prior art or its pharmacy acceptable salt, polymorphic form, solvate or steric isomer, its intermediate, and its application.Aryl urea compounds of the present invention is in biology test, for multiple protein kinases, there is inhibit activities in various degree, and in vitro in human tumor cell lines and human umbilical vein cells test respectively display there is antitumor cell growth in various degree and anti-angiogenic rebirth activity.
Therefore the present invention relates to a kind of such as formula the aryl urea compounds shown in I or its pharmacy acceptable salt, polymorphic form, solvate or steric isomer;
Wherein, R
1afor hydrogen, R
1for substituted or unsubstituted C
1~ C
8alkyl (described C
1~ C
8the preferred C of alkyl
1~ C
6alkyl, as n-propyl, sec.-propyl, isobutyl-, the tertiary butyl or n-hexyl), substituted or unsubstituted C
3~ C
9cycloalkyl (described C
3~ C
9the preferred C of cycloalkyl
3~ C
8cycloalkyl, as cyclohexyl), substituted or unsubstituted C
6~ C
14aryl (described C
6~ C
14the preferred C of aryl
6~ C
10aryl, as phenyl or naphthyl), substituted or unsubstituted C
1~ C
13heteroaryl (described C
1~ C
13heteroaryl is preferably C
1~ C
9heteroaryl, preferred C
3~ C
9heteroaryl, further preferred C
3~ C
5heteroaryl, further preferably thiazolyl, as thiazol-2-yl or 5-methylisoxazole-3-base); Substituting group in the alkyl replaced is 4 ~ 9 yuan of (preferably 4 ~ 6 yuan) saturated heterocyclyls, and the heteroatoms number of described saturated heterocyclyl is 1 ~ 4, and heteroatoms is nitrogen, oxygen or sulphur, as pyrrolidin-1-yl; Substituting group in the cycloalkyl replaced is halogen, C
1~ C
3alkyl or C
1~ C
3alkoxyl group; Replace aryl or replacement heteroaryl in substituting group be halogen (as fluorine, chlorine, bromine or iodine), cyano group, C
1~ C
3haloalkyl (as trifluoromethyl), C
1~ C
3alkyl, C
1~ C
3alkoxyl group, C
2~ C
3thiazolinyl and C
2~ C
3one or more in alkynyl, often kind of substituent number is 0,1 or multiple, and substituent position can be commutable optional position on aryl or heteroaryl, and when aryl is phenyl ring, substituent position is the ortho position of urea side chain, a position or contraposition; Heteroatoms in heteroaryl is nitrogen, oxygen or sulphur, and heteroatoms number is 1 ~ 5;
Or R
1, R
1aand and R
1, R
1anitrogen-atoms Cheng Huanwei substituted or unsubstituted 4 ~ 9 yuan (preferably 5 ~ 7 yuan) saturated heterocyclics (as morpholine ring) be together connected, described saturated heterocyclic additionally can contain 1 ~ 3 heteroatoms, and described heteroatoms is nitrogen, oxygen or sulphur; Wherein, the substituting group in 4 ~ 9 yuan of saturated heterocyclics of described replacement is halogen, C
1~ C
3alkyl or C
1~ C
3alkoxyl group;
R
2for the C that hydrogen, substituted-amino replace
1~ C
6(preferred C
1~ C
3) alkoxyl group, the cyclization together with amino nitrogen atom of the substituting group wherein on substituted-amino forms 4 ~ 9 yuan of substituted or unsubstituted saturated heterocyclics (described saturated heterocyclic can be morpholine or piperazine); Additionally can comprise 1 ~ 2 heteroatoms in described saturated heterocyclic, heteroatoms is nitrogen, oxygen or sulphur (preferred nitrogen or oxygen), if additionally comprise nitrogen-atoms, then on this nitrogen-atoms without replace or by C
1~ C
6(preferred C
1~ C
3) alkyl replacement; Substituting group in the saturated heterocyclic of described replacement is C
1~ C
3alkyl, C
1~ C
3alkoxyl group, halogen, amino or hydroxyl;
Or, R
2for C
1~ C
6(preferred C
1~ C
3) alkoxyl group replace C
1~ C
6(preferred C
1~ C
3) alkoxyl group, replacement C
6~ C
10the C of aryl, replacement
3~ C
9heteroaryl (described C
3~ C
9the preferred furyl of heteroaryl); Wherein, the substituting group in the aryl of replacement or the heteroaryl of replacement is (connect C
1~ C
3the C of alkyl sulphonyl
1~ C
3alkylamino) C that replaces
1~ C
3alkyl, halogen, C
1~ C
3alkyl, C
1~ C
3alkoxyl group, C
2~ C
3thiazolinyl and C
2~ C
3one or more in alkynyl, the heteroatoms in heteroaryl is nitrogen, oxygen or sulphur, and heteroatoms number is 1 ~ 4; Preferably, the substituting group in the aryl of replacement or the heteroaryl of replacement is (connect C
1~ C
3the C of alkyl sulphonyl
1~ C
3alkylamino) C that replaces
1~ C
3alkyl, all the other positions of aryl or heteroaryl are without replacement or by halogen, C
1~ C
3alkyl, C
1~ C
3alkoxyl group, C
2~ C
3thiazolinyl and C
2~ C
3one or more in alkynyl replace;
R
3for hydrogen, C
1~ C
3alkoxyl group, or C
1~ C
6(preferred C
1~ C
3) alkoxyl group replace C
1~ C
6(preferred C
1~ C
3) alkoxyl group;
Or R
3for the C that amino or substituted-amino replace
1~ C
6(preferred C
1~ C
3) alkoxyl group; Wherein, substituting group on substituted-amino cyclization can form 4 ~ 9 yuan of (preferably 5 ~ 6 yuan) saturated heterocyclics together with described amino nitrogen atom, 1 ~ 2 heteroatoms additionally can be comprised in described saturated heterocyclic, heteroatoms is nitrogen, oxygen or sulphur (preferred nitrogen or oxygen), if additionally comprise nitrogen-atoms, then on this nitrogen-atoms, nothing replaces, or by C
1~ C
6(preferred C
1~ C
3) alkyl or (hydroxyl replaces) C
1~ C
6(preferred C
1~ C
3) alkyl replacement; Or the substituting group on described substituted-amino is (hydroxyl replaces) C
1~ C
6(preferred C
1~ C
3) alkyl and/or C
1~ C
6(preferred C
1~ C
3) alkyl;
Or R
3be the C that 4 ~ 9 yuan of (preferably 5 ~ 6 yuan) saturated heterocyclics replace
1~ C
6(preferred C
1~ C
3) alkoxyl group, wherein saturated heterocyclic is with carbon atom and C
1~ C
6(preferred C
1~ C
3) alkoxyl group connect, comprise 1 ~ 3 heteroatoms (preferably 1 ~ 2) in described saturated heterocyclic, heteroatoms is nitrogen, oxygen or sulphur (preferred nitrogen or oxygen), if comprise nitrogen-atoms, then on this nitrogen-atoms without replace or by C
1~ C
6(preferred C
1~ C
3) alkyl replacement;
R
4and R
5be hydrogen, C independently
1~ C
3alkyl, C
1~ C
3alkoxyl group, halogen, amido or cyano group;
R
6, R
7, R
8and R
9be hydrogen, C independently
1~ C
3alkyl, C
1~ C
3alkoxyl group, halogen or cyano group;
R
10for hydrogen, C
1~ C
3alkyl, C
1~ C
3alkoxyl group, halogen, amido or cyano group;
R
11for hydrogen or C
1~ C
3alkyl;
Urea side chain
be connected to 2 ', 3 ' or 4 ' position.
In the present invention, described Compound I is preferably following arbitrary structure:
Wherein, R
1and R
1adefinition ditto described in; Urea side chain is connected to 3 ' or 4 ' position; A is 4-(2-hydroxyethyl) piperazine-1-base, ethyl (2-hydroxyethyl) amido or 2-hydroxyethyl amido.
In the present invention, described Compound I the best be following arbitrary structure:
In the present invention, the pharmacy acceptable salt of described aryl urea compounds is the salt of above-mentioned aryl urea compounds and mineral acid (example hydrochloric acid) or organic acid formation, or the salt of above-mentioned aryl urea compounds and mineral alkali or organic bases formation.
The crystallized form of the formula I in the present invention can be polymorphic, and these crystallized forms are in the present invention involved.In addition, the formula I in the present invention also can form solvate with solvent, as formed hydrate with water, or forms organic solvate with organic solvent, these hydrates and organic solvent compound also in the present invention involved.
Compound of the present invention may contain asymmetric atom, especially chiral carbon atom, therefore all and steric isomer (comprise pure stereoisomers, or the mixture be made up of the steric isomer of various ratio) that is that produce all is regarded as a part of the present invention.
Compound I in the present invention can be prepared by following either method:
(1) each group definition is with described in aforementioned Compound I, but R
2for hydrogen, the C that substituted-amino replaces
1~ C
6alkoxyl group, or C
1~ C
6the C that alkoxyl group replaces
1~ C
6alkoxyl group; R
3for hydrogen, C
1~ C
3alkoxyl group, C
1~ C
6alkoxyl group replace C
1~ C
6alkoxyl group, or R
3for the C that substituted-amino replaces
1~ C
6alkoxyl group, and the substituting group wherein on substituted-amino does not comprise (hydroxyl replaces) C
1~ C
6alkyl; Compound Q and Compound II per are carried out condensation reaction, and adding acidity or basic catalyst can accelerated reaction process;
Wherein, X is halogen, as Cl or Br.Y is R
11nH-, R
11definition ditto described in.The method of described condensation reaction and condition are ordinary method and the condition of this type of reaction.Compound Q commercially availablely can be obtained or be obtained by prior art.
(2) each group definition is with described in aforementioned Compound I, but R
2for hydrogen, the C that substituted-amino replaces
1~ C
6alkoxyl group, or C
1~ C
6the C that alkoxyl group replaces
1~ C
6alkoxyl group; R
3for hydrogen, C
1~ C
3alkoxyl group, C
1~ C
6alkoxyl group replace C
1~ C
6alkoxyl group, or R
3for the C that substituted-amino replaces
1~ C
6alkoxyl group, and the substituting group wherein on substituted-amino does not comprise (hydroxyl replaces) C
1~ C
6alkyl; By compound Q ' and compound R
1r
1anH carries out into urea and reacts, and concrete grammar is isocyanic acid ester process or carbamate method;
Compound Q ' and compound R
1r
1anH commercially availablely can be obtained or be obtained by prior art.
(3) each group definition is with described in aforementioned Compound I, but R
3for the C that amino or substituted-amino replace
1~ C
6alkoxyl group, the cyclization together with described amino nitrogen of the substituting group wherein on substituted-amino forms 4 ~ 9 yuan of saturated heterocyclics, additionally comprises nitrogen-atoms in ring, by (hydroxyl replaces) C on this nitrogen-atoms
1~ C
6alkyl replaces; Or the substituting group on described substituted-amino is (hydroxyl replaces) C
1~ C
6alkyl and/or C
1~ C
6alkyl; By Compound II per ' and the ammonia of ammonia or replacement carry out nucleophilic substitution reaction;
Wherein, R in the substituting group in the ammonia of described replacement and aforesaid compound I
3substituting group in the amino of middle replacement is identical, and X ' is 1 ~ 6 for leavings group (as chlorine), n, represents that the carbonatoms comprised in bracket is 1 ~ 6.The method of described nucleophilic substitution reaction and condition all can be ordinary method and the condition of this type of reaction.
Compound II per ' obtain by following synthetic route:
(4) each group definition is with described in aforementioned Compound I, but R
2for the C replaced
6~ C
10the C of aryl or replacement
3~ C
9heteroaryl, substituting group is (connect C
1~ C
3the C of alkyl sulphonyl
1~ C
3alkylamino) C that replaces
1~ C
3alkyl; Compound 5 and compound 4 are carried out Suzuki (Suzuki) linked reaction, obtains compound 3, then according to the different R in target product
2substituting group, by compound 3 be connected C accordingly
1~ C
3the C of alkyl sulphonyl
1~ C
3alkyl ammonia carries out reductive amination process;
Or, compound 5 and compound 6 are carried out Suzuki (Suzuki) linked reaction, wherein each group definition is with described in aforementioned Compound I, but R
2for the C replaced
6~ C
10the C of aryl or replacement
3~ C
9heteroaryl, substituting group (connects C for removing
1~ C
3the C of alkyl sulphonyl
1~ C
3alkylamino) C that replaces
1~ C
3substituting group outside alkyl.
Wherein, described Suzuki (Suzuki) linked reaction and the method for reductive amination process and condition are ordinary method and the condition of this area this two class reaction.In compound 4 zero represents substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.Compound 4,5 and 6 commercially availablely can be obtained or be obtained by prior art.
According to above-mentioned preparation method disclosed by the invention, those skilled in the art can adopt principle identical with it and method, each particular compound related in obtained general formula compound I of the present invention.
The preparation method of the Compound I in the present invention is exemplified below:
One, the synthesis of Ia, Ib, Ic, Id and Ie series compound
The final step reaction of preparation Ia, Ib, Ic, Id and Ie series compound for: by kind of the quinazoline parent nucleus Q of 5 shown in table 1 and side chain urea U, (namely general formula compound II, Y are R
11nH-, R
11definition ditto described) carry out condensation reaction, prepare target compound.By adding acidity or basic catalyst can accelerate this condensation reaction.
Table 1 quinazoline parent nucleus Q
Note: Q can be base or hydrochloride
(namely general formula compound II, Y are R to side chain urea U
11nH-, R
11definition ditto described), its molecular characterization is the N containing fragrant amido, N '-disubstituted ureas.
Wherein, Y is R
11nH-, R
11definition ditto described in; R
1, R
1a, R
6, R
7, R
8and R
9definition the same; Urea side chain can be connected to 2 ', 3 ' or 4 ' position.Table 2 lists some Compound of Example of side chain urea U.
Table 2 side chain urea U illustrates
The preparation method of quinazoline parent nucleus Q can be as described below:
Q1 is according to the document (.W02004024703A1 such as GildayJP; Diao is round. Chinese Journal of Pharmaceuticals, 2008,39 (6): 401-403) and preparation.
The preparation of Q2: morpholinyl third-1-alcohol and 60% sodium hydride act as sodium salt, then obtain Q2T with the condensation of 7-fluquinconazole quinoline-4 (3H)-one, under DMF catalysis, obtain Q2 hydrochloride through sulfur oxychloride chlorination.Morpholinyl third-1-alcohol is according to document preparation .JournalofMedicinalChemistry such as (, 2004,47 (4): 871-887) PlePA.7-fluquinconazole quinoline-4 (3H)-one is obtained by 2-amino-4-fluorobenzoic acid and methane amide cyclization.
Reaction conditions: (a) HCONH
2, 150 DEG C; (b) morpholinyl third-1-alcohol, 60%NaH, DMF; (c) SOCl
2, DMF, backflow.
The preparation of Q3: 3-(4-methylpiperazine-1-yl) third-1-alcohol and 60% sodium hydride act as sodium salt, then obtain Q3T with the condensation of 7-fluquinconazole quinoline-4 (3H)-one, under DMF catalysis, obtain Q3 hydrochloride through sulfur oxychloride chlorination.3-(4-methylpiperazine-1-yl) third-1-alcohol is according to document .US2006142570A1 such as () HerzT preparation.
Reaction conditions: (a) 3-(4-methylpiperazine-1-yl) third-1-alcohol, 60%NaH, DMF; (b) SOCl
2, DMF, backflow.
The preparation of Q4: (1-methyl piperidine-4-base) methyl alcohol and 60% sodium hydride act as sodium salt, then obtain Q4T with the condensation of 7-fluquinconazole quinoline-4 (3H)-one, obtain Q4 hydrochloride under DMF catalysis through sulfur oxychloride chlorination.(1-methyl piperidine-4-base) methyl alcohol is commercially available.
Reaction conditions: (a) (1-methyl piperidine-4-base) methyl alcohol, 60%NaH, DMF; (b) SOCl
2, DMF, backflow.
Q5 is commercially available.
Two, the preparation of If series compound
The preparation of If series compound adopts synthetic route as follows.7-fluquinconazole quinoline-4 (3H)-one and 1, ammediol O-alkylation under sodium hydride exists obtains intermediate 7, sulfur oxychloride chlorination again through DMF catalysis obtains two muriate 8, reflux with side chain urea U condensation again in the aqueous isopropanol of hydrogenchloride, finally in N-Methyl pyrrolidone (NMP) with the various amine A containing hydroxyl respectively condensation obtain If series compound.
Reaction conditions: (a) 1,3-PD, 60%NaH; (b) SOCl
2, DMF; (c) side chain U, HCl aqueous isopropanol, backflow; (d) AH, NMP, 50 DEG C. wherein, described in the definition ditto of A.
Therefore, the invention still further relates to following midbody compound: 1-(the chloro-4-fluorophenyl of 3-)-3-(3-(7-(3-chlorine propoxy-) quinazoline-4-base amido) phenyl) urea (D52-1-0),
1-(the chloro-3-of 4-(trifluoromethyl) phenyl)-3-(3-(7-(3-chlorine propoxy-) quinazoline-4-base amido) phenyl) urea (D52-3-0),
1-(3-(7-(3-chlorine propoxy-) quinazoline-4-base amido) phenyl)-3-(3-fluorophenyl) urea (D52-9-0),
1-(3-(7-(3-chlorine propoxy-) quinazoline-4-base amido) phenyl)-3-(5-methylisoxazole-3-base) urea (D52-20-0),
Or 1-(3-(7-(3-chlorine propoxy-) quinazoline-4-base amido) phenyl)-3-(4-(pyrrolidin-1-yl) butyl) urea (D52-18-0).
Three, the preparation of Ig series compound
The preparation of Ig series compound adopts synthetic route as follows:
2-amino-5-iodine benzonitrile and N; after dinethylformamide dimethylacetal (DMFDMA) condensation; carry out Dimroth again to reset obtain compound III with side chain urea U; carry out Suzuki (Suzuki) linked reaction with 5-formylfuran-2-boric acid again, last and 2-(methylsulfonyl) ethamine carries out reduction amination and obtains Ig series compound target compound.Under intermediate III also can be refluxed in the aqueous isopropanol of hydrogenchloride by 4-chloro-6-iodine quinazoline and side chain urea U, condensation obtains its hydrochloride.
Reaction conditions: (a) DMF.DMA, backflow; (b) side chain U, HOAc, backflow; (c) side chain U, HCl aqueous isopropanol, backflow; (d) 5-formylfuran-2-boric acid, Pd/C, Et
3n, DME-MeOH, 50 DEG C; (e) 2-(methylsulfonyl) ethamine, then NaBH (OAc)
3, THF, room temperature.
Therefore, the invention still further relates to arbitrary midbody compound of following preparation Compound I:
1-(the chloro-4-fluorophenyl of 3-)-3-(3-(6-iodine quinazoline-4-base amido) phenyl) urea hydrochloride (L-3-1),
1-(the chloro-4-fluorophenyl of 3-)-3-(3-(6-(5-formylfuran-2-base) quinazoline-4-base amido) phenyl) urea (L-4-1),
1-(the chloro-3-of 4-(trifluoromethyl) phenyl)-3-(3-(6-iodine quinazoline-4-base amido) phenyl) urea (L-3-3),
1-(the chloro-3-of 4-(trifluoromethyl) phenyl)-3-(3-(6-(5-formylfuran-2-base) quinazoline-4-base amido) phenyl) urea (L-4-3),
1-(3,5-bis-(trifluoromethyl) phenyl)-3-(3-(6-iodine quinazoline-4-base amido) phenyl) urea hydrochloride (L-3-14),
1-(3,5-bis-(trifluoromethyl) phenyl)-3-(3-(6-(5-formylfuran-2-base) quinazoline-4-base amido) phenyl) urea (L-4-14),
1-(2,5-difluorophenyl)-3-(3-(6-iodine quinazoline-4-base amido) phenyl) urea hydrochloride (L-3-15),
1-(2,5-difluorophenyl)-3-(3-(6-(5-formylfuran-2-base) quinazoline-4-base amido) phenyl) urea (L-4-15),
1-(2-methyl-5-fluorophenyl)-3-(3-(6-iodine quinazoline-4-base amido) phenyl) urea hydrochloride (L-3-16),
Or 1-(2-methyl-5-fluorophenyl)-3-(3-(6-(5-formylfuran-2-base) quinazoline-4-base amido) phenyl) urea (L-4-16).
Four, the preparation of side chain urea U
(namely general formula compound II, Y are R to side chain urea U
11nH-, R
11definition ditto described) molecular characterization be N containing fragrant amido, N '-disubstituted ureas.
Therefore, the invention still further relates to the N with following general formula I I, N '-disubstituted ureas
Wherein, Y is R
11nH-or nitro, R
11definition ditto described in; R
1, R
1a, R
6, R
7, R
8and R
9definition the same; Urea side chain can be connected to 2 ', 3 ' or 4 ' position.
Preferably, Compounds of formula II is following structure: 1-(3-aminophenyl)-3-(the chloro-3-of 4-(trifluoromethyl) phenyl) urea (J-3), 1-(4-aminophenyl)-3-(3-cyano-phenyl) urea (P-4), 1-(3-aminophenyl)-3-(3-cyano-phenyl) urea (J-4), 1-(3-aminophenyl)-3-(3-fluorophenyl) urea (J-9), N-(3-aminophenyl) morpholine-4-methane amide (J-12), 1-(3-aminophenyl)-3-aminomethyl phenyl urea (J-13), 1-(3-aminophenyl)-3-(3,5-bis-(trifluoromethyl) phenyl) urea (J-14), 1-(3-aminophenyl)-3-(2,5-difluorophenyl) urea (J-15), 1-(3-aminophenyl)-3-(2-methyl-5-fluorophenyl) urea (J-16), 1-(4-aminophenyl)-3-(thiazol-2-yl) urea (P-17), 1-(3-aminophenyl)-3-(thiazol-2-yl) urea (J-17), 1-(4-aminophenyl)-3-(4-(pyrrolidin-1-yl) butyl) urea (P-18), 1-(3-aminophenyl)-3-(4-(pyrrolidin-1-yl) butyl) urea (J-18), 1-isobutyl--3-(4-aminophenyl) urea (P-19), 1-isobutyl--3-(3-aminophenyl) urea (J-19), 1-(the chloro-4-fluorophenyl of 3-)-3-(3-nitrophenyl) urea (JX-1), 1-(3-nitrophenyl)-3-(3-cyano-phenyl) urea (JX-4), N-(3-nitrophenyl) morpholine-4-methane amide (JX-12), 1-(3-nitrophenyl)-3-(2-methyl-5-fluorophenyl) urea (JX-16), 1-(3-nitrophenyl)-3-(thiazol-2-yl) urea (JX-17), 1-(3-nitrophenyl)-3-(4-(pyrrolidin-1-yl) butyl) urea (JX-18), 1-isobutyl--3-(3-nitrophenyl) urea (JX-19).
The method preparing Compound II per can be divided into isocyanic acid ester process and carbamate method two class.
First introduce and adopt isocyanic ester legal system for Compound II per.
Traditional isocyanic ester synthesis is based on phosgenation.Phosgene is hypertoxic gas, be difficult to storage and transport, and logical phosgene process contamination is serious, all brings immense pressure to environmental protection and labour protection.The invention provides a kind of two (trichloromethyl) ester (hereinafter referred to as triphosgene) one kettle way of carbonic acid that uses and prepare general formula I I (R
1afor H) shown in N, N ' short-cut method of-disubstituted ureas.
Therefore the invention further relates to the preparation method of above-mentioned general formula compound II, it is any one in following method:
Method one: first reaction under tertiary amine exists generates corresponding isocyanic ester IV by compound V and triphosgene, then directly carries out into urea reaction with compound VI or VI ' under tertiary amine exists under one kettle way condition, obtains midbody compound II; Wherein, described in the definition ditto of each group, but R
1afor H; Synthetic route is as follows:
Method two: first reaction under tertiary amine exists generates corresponding isocyanic ester VII by compound VI and triphosgene, then directly carries out into urea reaction with compound V under tertiary amine exists under one kettle way condition, obtains midbody compound II; Wherein, described in the definition ditto of each group; Synthetic route is as follows:
In method one, the present invention is following method and condition particularly preferably: in solvent, first under the existence of tertiary amine, compound V and triphosgene reaction are generated corresponding isocyanic ester IV, then under one kettle way condition, directly under tertiary amine exists, carry out into urea reaction with compound VI or VI ', obtain midbody compound II.
Wherein, described preferred solvents be organic solvent to isocyanic ester inertia, can be one or more in hydrocarbon (as toluene, dimethylbenzene, methylene dichloride or chlorobenzene etc.), ether (as tetrahydrofuran (THF), 2-methyltetrahydrofuran, methyl tertiary butyl ether or glycol dimethyl ether etc.), ketone (as methyl ethyl ketone or methyl iso-butyl ketone (MIBK) etc.) and ester (as ethyl acetate or isobutyl acetate etc.), one or more in preferred 2-methyltetrahydrofuran, methylene dichloride and ethyl acetate.Described tertiary amine is the compound that three hydrogen in ammonia on nitrogen are all substituted rear formation, the carbon atom be wherein connected with nitrogen and nitrogen can form singly-bound or double bond, described tertiary amine preferably comprise in pyridine, triethylamine, diisopropyl ethyl amine, N-methylmorpholine, imidazoles and dimethyl aminopyridine one or more.In the reaction of described generation isocyanic ester, the molar ratio of triphosgene and compound V is preferably 0.3 ~ 2: 1, preferably 0.33 ~ 1: 1, more preferably 0.35 ~ 0.5: 1; Temperature of reaction is preferably-5 DEG C of reflux temperatures to reaction solvent, preferably 0 ~ 50 DEG C, more preferably 20 ~ 40 DEG C; The molar ratio of compound V and tertiary amine is preferably 1: 1 ~ 6, preferably 1: 1 ~ 3, more preferably 1: 1 ~ 1.5.In the reaction of described one-tenth urea, temperature of reaction is preferably 10 DEG C of reflux temperatures to reaction solvent, preferably 15 ~ 60 DEG C, more preferably 20 ~ 50 DEG C; Compound VI or VI ' are preferably 1: 1 ~ 6 with the molar ratio of tertiary amine, preferably 1: 1 ~ 3, more preferably 1: 1 ~ 1.5.The molar ratio of compound V and compound VI or VI ' is preferably 1: 0.6 ~ 3, preferably 1: 0.8 ~ 2, more preferably 1: 0.9 ~ 1.2.
In method two, the present invention is following method and condition particularly preferably: in solvent, first under the existence of tertiary amine, compound VI and triphosgene reaction are generated corresponding isocyanic ester VII, then under one kettle way condition, directly under the existence of tertiary amine, carry out into urea reaction with compound V, obtain midbody compound II.
Wherein, described preferred solvents be organic solvent to isocyanic ester inertia, can be one or more in hydrocarbon (as toluene, dimethylbenzene, methylene dichloride or chlorobenzene etc.), ether (as tetrahydrofuran (THF), 2-methyltetrahydrofuran, methyl tertiary butyl ether or glycol dimethyl ether etc.), ketone (as methyl ethyl ketone or methyl iso-butyl ketone (MIBK) etc.) and ester (as ethyl acetate or isobutyl acetate etc.), one or more in preferred 2-methyltetrahydrofuran, methylene dichloride and ethyl acetate.Described tertiary amine is the compound that three hydrogen in ammonia on nitrogen are all substituted rear formation, the carbon atom be wherein connected with nitrogen and nitrogen can form singly-bound or double bond, described tertiary amine preferably comprise in pyridine, triethylamine, diisopropyl ethyl amine, N-methylmorpholine, imidazoles and dimethyl aminopyridine one or more.In the reaction of described generation isocyanic ester, the molar ratio of triphosgene and compound VI is preferably 0.3 ~ 2: 1, preferably 0.33 ~ 1: 1, more preferably 0.35 ~ 0.5: 1; Temperature of reaction is preferably-5 DEG C of reflux temperatures to reaction solvent, preferably 0 ~ 50 DEG C, more preferably 20 ~ 40 DEG C; The molar ratio of compound VI and tertiary amine is preferably 1: 1 ~ 6, preferably 1: 1 ~ 3, more preferably 1: 1 ~ 1.5.In the reaction of described one-tenth urea, temperature of reaction is preferably 10 DEG C of reflux temperatures to reaction solvent, preferably 15 ~ 60 DEG C, more preferably 20 ~ 50 DEG C; The molar ratio of compound V and tertiary amine is preferably 1: 1 ~ 6, preferably 1: 1 ~ 3, more preferably 1: 1 ~ 1.5.The molar ratio of compound VI and compound V is preferably 1: 0.6 ~ 3, preferably 1: 0.8 ~ 2, more preferably 1: 0.9 ~ 1.2.
In aforesaid method one and method two, Compound II per (Y is nitro) can obtain Compound II per (Y is for amino) by the method for the reduction nitro of this area routine.
Aforesaid method one and method two can be described in further detail below:
Preparation method of the present invention is divided into two stages.First stage: first triphosgene be dissolved in suitable solvent, then add the first amine R
1-NH
2(V) with the solution of a kind of tertiary amine in a kind of suitable solvent, the solution containing the corresponding isocyanic ester of the first amine (IV) is obtained by reacting, without the need to separation and purification; Subordinate phase: in first stage gained reaction solution, add the second amine VI (as 3-N-methyl-p-nitroaniline, 4-N-methyl-p-nitroaniline) or VI ' (as 1,4-Ursol D) and the solution of a kind of tertiary amine in suitable solvent, obtain N, N '-disubstituted ureas II.II (Y is nitro) obtains II (Y is for amino) through reduction.Synthetic route sees above.
In the first phase, triphosgene and the first amine R
1-NH
2(V) molar ratio is 0.3 ~ 2: 1, preferably 0.33 ~ 1: 1, more preferably 0.35 ~ 0.5: 1, the first amine R
1-NH
2(V) can be 1: 1 ~ 6 with the molar ratio of tertiary amine, preferably 1: 1 ~ 3, more preferably 1: 1 ~ 1.5.Described suitable solvent is the organic solvent to isocyanic ester inertia, can be hydrocarbon (toluene, dimethylbenzene, methylene dichloride, chlorobenzene etc.), ether (tetrahydrofuran (THF), 2-methyltetrahydrofuran, methyl tertiary butyl ether, glycol dimethyl ether etc.), ketone (methyl ethyl ketone, methyl iso-butyl ketone (MIBK) etc.), ester (ethyl acetate, isobutyl acetate etc.), or its mixture.Preferred 2-methyltetrahydrofuran, methylene dichloride, ethyl acetate, or its mixture.Described tertiary amine, comprises pyridine, triethylamine, diisopropyl ethyl amine, N-methylmorpholine, imidazoles, dimethyl aminopyridine and composition thereof.Temperature of reaction can be-5 DEG C of reflux temperatures to reaction solvent, preferably 0 ~ 50 DEG C, more preferably 20 ~ 40 DEG C.
In subordinate phase, described suitable solvent and tertiary amine same first stage.Temperature of reaction can be 10 DEG C of reflux temperatures to reaction solvent, preferably 15 ~ 60 DEG C, more preferably 20 ~ 50 DEG C.The molar ratio of the first amine of first stage (V) and subordinate phase the second amine (VI or VI ') can be 1: 0.6 ~ 3, and preferably 1: 0.8 ~ 2, more preferably 1: 0.9 ~ 1.2.The second amine (VI or VI ') can be 1: 1 ~ 6 with the molar ratio of tertiary amine, and preferably 1: 1 ~ 3, more preferably 1: 1 ~ 1.5.
N, N of the present invention '-disubstituted ureas (II) preparation method also can adopt another feeding sequence.First stage: first triphosgene is dissolved in suitable solvent, then the second amine (as 3-N-methyl-p-nitroaniline, 4-N-methyl-p-nitroaniline) and the solution of a kind of tertiary amine in a kind of suitable solvent is added, be obtained by reacting the solution containing the corresponding isocyanic ester of the second amine, without the need to separation and purification; Subordinate phase: in first stage gained reaction solution, adds the first amine and the solution of a kind of tertiary amine in suitable solvent, is obtained by reacting N, N '-disubstituted ureas (II).Synthetic route sees above.
This synthesis technique is easy and simple to handle, and the reaction times is short, and without the need to separating reaction intermediate, without the need to specific installation and condition, yield is high.The triphosgene adopted is crystalline stable phosgene substitute (fusing point 80 DEG C, boiling point 206 DEG C; Even if also only have when seething with excitement and be degraded to phosgene on a small quantity), be easy to transport and storage, be convenient to the metering (.AngewandteChemie-InternationalEditioninEnglish such as EckertH, 1987,26 (9): 894-895), there is the advantage that safe green is easy to get.
Prepared N, N '-disubstituted ureas (II) (Y is nitro) can be amino by reduction nitro, obtains corresponding side chain urea U (II, Y are amino).Method of reducing can be any usability methods, comprises catalytic hydrogenation, catalytic transfer hydrogenation, chemical reduction (as iron powder/ammonium chloride, zinc powder/glacial acetic acid etc.) etc.
In addition, above-mentioned midbody compound II also obtains by following carbamate method.
The method can be exemplified below:
First, compound VI (as 3-N-methyl-p-nitroaniline, 4-N-methyl-p-nitroaniline) and haloformate class (as chloroformic acid 4-nitro phenyl ester, phenyl chloroformate) are reacted and generates corresponding amido formate, then with
(R
1, R
1adefinition with general formula compound I) unsymmetrical urea that condensation obtains containing nitro, the nitro that finally reduces obtains required side chain urea U (II, Y be amino).As follows with the concrete example of the preparation of J-12:
The invention still further relates to the midbody compound N preparing above-mentioned formula I
1-(7-methoxyl group-6-(morpholinyl propoxy-) quinazoline-4-base) benzene-Isosorbide-5-Nitrae-diamines (intermediate of preparation D1-20), 7-(3-chlorine propoxy-)-N-(3-oil of mirbane) quinazoline-4-amine (intermediate of preparation D52-20-4) or N
1-(7-(3-chlorine propoxy-) quinazoline-4-base) benzene-1,3-diamines (intermediate of preparation D52-20-4).
The invention still further relates to above-mentioned formula I or its pharmacy acceptable salt, polymorphic form, solvate or steric isomer preparation treatment Mammals particularly the lack of proper care with protein kinase mediated signal transduction pathway of people, or the application in the medicine of the newborn disease of being correlated with of abnormal vascular.Described disease includes but not limited to tumour, diabetes, autoimmune disorder, nerve degenerative diseases, diabetic retinopathy, age-related macular degeneration, arteriosclerosis, psoriatic and inflammation.Described tumour includes but not limited to the tumour of skin, brain, lung, lymphocyte, kidney, liver, stomach, colon, rectum, bladder, head, neck, mammary gland, Tiroidina, oesophagus, pancreas, prostate gland and Obstetric and Gynecologic Department, and malignant hematologic disease (as leukemia).
Described protein kinase comprises Tyrosylprotein kinase and serine/threonine kinase, and the various saltant types of foregoing kinases.Wherein, described Tyrosylprotein kinase is preferably EGFR, HER-2, VEGFR-1, VEGFR-2, VEGFR-3, PDGFR α, PDGFR β, c-KIT, CSF1R, FLT-3, c-MET, TIE-2, SRC, LCK, FYN or HCK; Described serine/threonine kinase is preferably BRAF, CRAF, AuroraA or AuroraB; Described saltant type kinases is preferably BRAFV600E.
The present invention relates to above-claimed cpd I or its pharmacy acceptable salt, polymorphic form, solvate or steric isomer and prepare the application had in the medicine of people's tumor xenograft knurl inhibit activities.Wherein, described people's tumor xenograft knurl is preferably for transplanting the A549 people's lung cancer in nude mice.
The invention still further relates to above-claimed cpd I or its pharmacy acceptable salt, polymorphic form, solvate or steric isomer and there is in preparation application in the medicine of A549 human lung carcinoma cell, HCT116 people's colon-cancer cell, CEM human leukemia cell or MCA-MB-435 human melanoma cell inhibit activities.
The invention still further relates to described Compound I or its pharmacy acceptable salt, polymorphic form, solvate or steric isomer have the application in the medicine of Human umbilical vein endothelial cells (HUVEC) inhibit activities in preparation.
Aryl urea formula I of the present invention or its pharmacy acceptable salt, polymorphic form, solvate or steric isomer can make various forms of pharmaceutical composition with pharmaceutically acceptable carrier.Described pharmaceutically acceptable carrier includes but not limited to various common medicinal supplementary material (as thinner, lubricant, disintegrating agent, tackiness agent and vehicle etc.).According to therapeutic purpose, pharmaceutical composition can be made various types of administration unit dosage, as tablet, capsule, pill, pulvis, solution, suspension, emulsion agent, ointment, syrup, granule, suppository and injection (solution and suspension) etc.
In order to make the pharmaceutical composition of tablet form be shaped, any known and widely used vehicle in this area can be used.Such as, carrier, as lactose, white sugar, sodium-chlor, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose and silicic acid etc.; Tackiness agent, as water, ethanol, propyl alcohol, common syrup, glucose solution, starch solution, penetrating judgment solution, carboxymethyl cellulose, lac, methylcellulose gum and potassiumphosphate, polyvinylpyrrolidone etc.; Disintegrating agent, as dry starch, sodiun alginate, agar powder and Kelp Powder, the fatty acid ester of sodium bicarbonate, calcium carbonate, polyethylene sorbitan, sodium lauryl sulphate, stearic acid monoglycerides, starch and lactose etc.; Disintegration inhibitor, as white sugar, tristearin, Oleum Cocois and winterized stearin; Adsorption enhancer, as quaternary amine alkali and sodium lauryl sulphate etc.; Wetting agent, as glycerine, starch etc.; Sorbent material, as starch, lactose, kaolin, wilkinite and colloid silicic acid etc.; And lubricant, as pure talcum, stearate, boric acid powder and polyoxyethylene glycol etc.If necessary, tablet can also be made as sugar coated tablet, be coated with gelatin film tablet, enteric coated tablets, film coated tablets, duplicature tablet and multilayer tablet with common painting stain material.
In order to make the pharmaceutical composition of pill be shaped, any known and widely used excipient in this area can be used, such as, carrier, as lactose, starch, Oleum Cocois, hardened vegetable oils, kaolin and talcum etc.; Tackiness agent, as gum arabic powder, yellow work rubber powder, gelatin and ethanol etc.; Disintegrating agent, as agar and Kelp Powder etc.
In order to make the pharmaceutical composition of suppository form be shaped, any known and widely used excipient in this area can be used, such as, polyoxyethylene glycol, Oleum Cocois, higher alcohols, the ester of higher alcohols, gelatin and semisynthetic glyceryl ester etc.
In order to prepare the pharmaceutical composition of injection form, by solution and suspension sterilization, and can preferably add appropriate sodium-chlor, glucose or glycerine etc., making the isotonic injection with blood.When preparing injection, any conventional carrier in this area also can be used.Such as, water, ethanol, propylene glycol, the isooctadecanol of ethoxylation, the isooctadecanol of polyoxy and the fatty acid ester etc. of polyethylene sorbitan.In addition, also common solvating agent, buffer reagent and pain killer etc. can be added.As required, during treatment schizophrenia, also tinting material, sanitas, spices, seasonings, sweetening agent and other medicines etc. can be added.
Of the present invention such as formula the compound shown in I and pharmacy acceptable salt thereof the content in pharmaceutical composition without particular restriction, can select in very wide scope, usually can be mass percent 1 ~ 70%, be preferably mass percent 1 ~ 30%.
In the present invention, the medication of described pharmaceutical composition is not particularly limited.According to patient age, sex and other condition and symptom, the preparation administration of various formulation can be selected.Such as, tablet, pill, solution, suspension, emulsion, granule and capsule are oral administrations; Suppository is for being administered into rectum; Injection can be individually dosed, or and injection conveying liquid (as physiological saline, glucose solution and amino acid solution) be mixed into row vein injection, can carry out injecting in muscle, intracutaneous, subcutaneous or abdomen by simple injection if necessary.
Therefore, the invention still further relates to the pharmaceutical composition comprising above-mentioned aryl urea compounds I or its pharmacy acceptable salt, polymorphic form, solvate or steric isomer.
Except as otherwise noted, the following term occurred in specification sheets of the present invention and claims has following implication:
" alkyl " means to comprise the radical of saturated aliphatic alkyl having and specify carbonatoms object straight chain and side chain as used herein.Such as, " C
1-C
10alkyl " be defined as the group being included in and there is in straight chain or branched structure 1,2,3,4,5,6,7,8,9 or 10 carbon atom.Such as, " C
1-c
10alkyl " specifically comprise methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, 2-methyl amyl, n-hexyl, n-heptyl, n-octyl, n-nonyl and positive decyl etc.
Term " cycloalkyl " refers to the unsaturated monocycle of saturated or part, many rings or bridge joint carbocyclic ring substituting group.The ring with 3-20 carbon atom can be expressed as C
3-C
20cycloalkyl; The ring with 5-15 carbon atom can be expressed as C
5-C
15cycloalkyl; The ring with 3-8 carbon atom can be expressed as C
3-C
8cycloalkyl, etc.This term includes but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, 1H-indenyl, 2, 3-indanyl, 1, 2, 3, 4-tetrahydro-naphthalenyl, 5, 6, 7, 8-tetrahydro-naphthalenyl, 8, 9-dihydro-7H-benzo ring heptene-6-base, 6, 7, 8, 9-tetrahydrochysene-5H-benzocyclohepta thiazolinyl, 5, 6, 7, 8, 9, 10-six hydrogen-benzo ring octenyl, fluorenyl, two rings [2.2.1] heptyl, two rings [2.2.1] heptenyl, two rings [2.2.2] octyl group, two rings [3.1.1] heptyl, two rings [3.2.1] octyl group, two rings [2.2.2] octenyl, two rings [3.2.1] octenyl, adamantyl, octahydro-4, 7-methylene radical-1H-indenyl and octahydro-2, 5-methylene radical-pentalene base etc.Naphthenic substituent can be connected on central element through any suitable carbon atom, and can replace further it when permitted.
What term " alkoxyl group " expression was connected by oxo bridge has described carbonatoms object ring-type or acyclic alkyl groups.Thus, " alkoxyl group " comprises the definition of above alkyl and cycloalkyl.
Term " thiazolinyl " refers to containing the straight chain specifying number carbon atom and at least one carbon-carbon double bond, side chain or the non-aromatic alkyl of ring-type.Preferred existence carbon-carbon double bond, and can exist up to four non-aromatic carbon-carbon double bonds.Thus, " C
2-C
10thiazolinyl " refer to the thiazolinyl with 2-10 carbon atom." C
2-C
6thiazolinyl " refer to the thiazolinyl with 2-6 carbon atom, comprise vinyl, propenyl, butenyl, 2-methyl butene base and cyclohexenyl.The straight chain of thiazolinyl, side chain or loop section can contain double bond, and if be indicated as substituted alkenyl, so can be substituted.
Term " alkynyl " refers to containing the straight chain specifying number carbon atom and at least one carbon carbon triple bond, side chain or cyclic hydrocarbon group.Wherein can exist up to three carbon carbon triple bonds.Thus, " C
2-C
10alkynyl " refer to the alkynyl with 2-10 carbon atom." C
2-C
6alkynyl " refer to the alkynyl with 2-6 carbon atom, comprise ethynyl, proyl, butynyl and 3-methylbutynyl etc.
" aryl " refers to any stable can to comprise in each ring up to the monocycle of 7 atoms, dicyclo or three ring carbocyclic rings as used herein, and wherein at least one ring is aromatic nucleus.The example of above-mentioned aryl unit comprises phenyl, naphthyl, tetralyl, 2,3-indanyls, xenyl, phenanthryl, anthryl or acenaphthenyl (acenaphthyl).Be appreciated that at aryl substituent be two ring substituents, and one of them ring is in the situation of non-aromatic ring, connection is undertaken by aromatic ring.
Represent in each ring can up to the stable monocycle of 7 atoms, dicyclo or three rings for term " heteroaryl " as used herein, and wherein at least one ring is aromatic nucleus and is selected from the heteroatoms of O, N and S containing 1-4.Heteroaryl in this range of definition includes but not limited to: acridyl, carbazyl, cinnolines base, quinoxalinyl, pyrazolyl, indyl, benzotriazole base, furyl, thienyl, benzothienyl, benzofuryl, quinolyl, isoquinolyl, oxazolyl, isoxazolyl, indyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidyl, pyrryl, tetrahydroquinoline.As the definition of following heterocycle, " heteroaryl " it should also be understood that to be the N-oxide derivative comprising any nitrogen-containing hetero aryl.Heteroaryl substituent is two ring substituents and ring is non-aromatic ring or under not comprising heteroatomic situation wherein, is appreciated that to connect and carries out respectively by aromatic ring or by the heteroatoms comprising ring.
Term " heterocycle " or " heterocyclic radical " represent the heteroatomic 5-10 unit fragrance or the nonaromatic heterocycles that are selected from O, N and S containing 1-4 as used herein, and comprise bicyclic groups.Therefore, " heterocyclic radical " comprises above-mentioned heteroaryl and its dihydro or tetrahydrochysene analogue.Other example of " heterocyclic radical " includes but not limited to following: benzimidazolyl-, benzofuryl, benzofuraxan base, benzopyrazoles base, benzotriazole base, benzothienyl, benzoxazolyl, carbazyl, carbolinyl, cinnolines base, furyl, imidazolyl, indolinyl, indyl, indazolyl, isobenzofuran-base, pseudoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthalene pyrimidyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxygen cyclobutyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridine base, pyridazinyl, pyridyl, pyrimidyl, pyrryl, quinazolyl, quinolyl, quinoxalinyl, THP trtrahydropyranyl, tetrazyl, tetrazolo pyridyl, thiadiazolyl group, thiazolyl, thienyl, triazolyl, azetidinyl, Isosorbide-5-Nitrae-alkyl dioxin, six hydrogen azatropylidene bases, piperazinyl, piperidyl, pyrrolidyl, morpholinyl, thio-morpholinyl, dihydrobenzo imidazolyl, dihydro benzo furyl, dihydrobenzo thienyl, Er hydrogen benzoxazolyl, dihydrofuran base, glyoxalidine base, indolinyl, dihydro-isoxazole base, dihydro isothiazolyl, Er Qing oxadiazolyl, dihydro-oxazole base, dihydro pyrazinyl, pyrazoline base, dihydropyridine base, dihydro-pyrimidin base, pyrrolin base, dihydroquinoline base, dihydro tetrazyl, thiodiazoline base, dihydro-thiazolyl, dihydro-thiophene base, dihydro triazolyl, dihydro azetidinyl, methylenedioxyphenyl formyl radical, tetrahydrofuran base and tetrahydro-thienyl and N-oxide compound thereof.Heterocyclyl substituent can connect through carbon atom or heteroatoms.
Term " halogen " represents fluorine, chlorine, bromine, iodine, astatine.
Term " haloalkyl " represents the alkyl that halogen optional position replaces.Thus, " haloalkyl " comprises the definition of above halogen and alkyl.
Term " saturated heterocyclyl " represents that containing 1-4 is selected from O, N or S heteroatomic 4-9 unit nonaromatic heterocycles base, and comprises bicyclic groups, and wherein do not comprise unsaturated double-bond, saturated heterocyclyl substituting group can connect through carbon atom or heteroatoms.Nitrogen wherein, sulfur heteroatom can be oxidized arbitrarily, and nitrogen heteroatom can also by quaternary ammoniated arbitrarily.Such as, Pyrrolidine base, piperazinyl, morpholinyl, piperidyl, tetrahydrofuran base, THP trtrahydropyranyl, thio-morpholinyl, imidazolidine base, thiazolidine base, oxidation piperazinyl, oxyl base, thiomorpholine sulfoxide or thiomorpholine sulfone etc.
In the present invention, without prejudice to the field on the basis of common sense, above-mentioned each preferred feature can arbitrary combination, obtains each preferred embodiments of the present invention.
Except specified otherwise, the raw material that the present invention relates to and reagent are all commercially.
Positive progressive effect of the present invention is: present invention finds a class such as formula the brand-new aryl urea compounds shown in I, it possesses stronger antitumor cell growth and anti-angiogenic rebirth activity, and it has stronger inhibit activities for the protein kinase relevant to various diseases.
Embodiment
Further illustrate the present invention by embodiment below, but the present invention is not limited.
First part's Chemical Example
Nuclear magnetic resonance analyser is Varian company INOVA-400, measures hydrogen spectrum under 400MHz; Mass spectrograph is Waters company MicromassQ-Tofmicro, electron spray ionisation (ESI).Elemental analyser is ThermoSCIENTIFICFLASH2000OrganicElementalAnalyzer.
The synthesis of midbody compound II
The preparation of isocyanic acid ester process: J series side chain urea
Embodiment 11-(the chloro-4-fluorophenyl of 3-)-3-(3-nitrophenyl) urea (JX-1)
By triphosgene (4.40g; 14.8mmol) be dissolved in anhydrous methylene chloride (80mL); at nitrogen protection and 31 ~ 34 DEG C; drip the chloro-4-fluoroaniline of 3-(5.82g; 40mmol) with DIEA (6.20g; anhydrous methylene chloride (40mL) solution 48mmol), stirs 0.5h.Then the mixed solution of 3-N-methyl-p-nitroaniline (5.52g, 40mmol), DIEA (6.20g, 48mmol) and anhydrous methylene chloride (70mL) is added, stirring at room temperature 1h.After gained reaction solution uses 10% aqueous potassium hydrogen sulfate, 5% sodium bicarbonate aqueous solution and saturated common salt water washing successively, anhydrous sodium sulfate drying, concentrating under reduced pressure, obtains JX-1 through ethyl acetate-light petrol (1: 4) making beating, for yellow orange solid (10.46g, 84%):
1h-NMR (DMSO-d
6) δ 9.24 (s, 1H), 8.98 (s, 1H), 8.52 (s, 1H), 7.73-7.84 (m, 3H), 7.57 (t, J=2.0Hz, 1H), 7.33-7.35 (m, 2H).
Embodiment 21-(the chloro-4-fluorophenyl of 3-)-3-(3-aminophenyl) urea (J-1)
By JX-1 (10.22g, 33mmol), through the reduced iron powder (11.06g of 1mol/L hydrochloric acid activation, 198mmol), ammonium chloride (1.77g, 33mmol) drops into stirring and refluxing 1.5h in the mixed solvent be made up of 95% ethanol (450mL), THF (150mL) and water (60mL).By diatomite filtered while hot, concentrating under reduced pressure filtrate, adds water and acetic acid ethyl dissolution gained residue, is 9 with liquid ammonia alkalinization to pH.Divide and get organic layer, water layer extracts by ethyl acetate again, and merge organic phase, anhydrous sodium sulfate drying, concentrating under reduced pressure obtains near-white crystalline solid J-1 (7.65g, 83%):
1h-NMR (DMSO-d
6) δ 8.68 (s, 1H), 8.36 (s, 1H), 7.78 (dd, J=2.0,6.8Hz, 1H), 7.28 (m, 2H), 6.90 (t, J=8.0Hz, 1H), 6.76 (s, 1H), 6.56 (d, J=7.6Hz, 1H), 6.22 (d, J=7.6Hz, 1H), 4.95 (s, 2H)
Embodiment 31-(3-nitrophenyl)-3-(3-(trifluoromethyl)-4-chloro-phenyl-) urea (JX-3)
By triphosgene (2.20g; 7.4mmol) be dissolved in methylene dichloride (40mL); at nitrogen protection and 30 ~ 35 DEG C; drip 3-N-methyl-p-nitroaniline (2.76g; 20mmol) with DIEA (3.10g; suspension 24mmol) in methylene dichloride (84mL), stirs 0.5h after dripping off again.Then methylene dichloride (20mL) solution of 3-(trifluoromethyl)-4-chloroaniline (3.91g, 20mmol) and DIEA (3.10g, 24mmol) is added, stirring at room temperature 1h.By gained reaction solution concentrating under reduced pressure, after gained residue with Ethyl acetate dissolves, after using 10% aqueous potassium hydrogen sulfate, 5% sodium bicarbonate aqueous solution and saturated common salt water washing successively, anhydrous sodium sulfate drying, concentrating under reduced pressure, gained residue obtains JX-3 through ethyl acetate-light petrol (1: 4) making beating, is yellow solid (6.20g, 86%):
1h-NMR (DMSO-d
6) δ 9.33 (s, 1H), 9.27 (s, 1H), 8.51 (t, J=2.0Hz, 1H), 8.09 (d, J=2.4Hz, 1H), 7.85-7.86 (m, 1H), 7.83-7.84 (m, 1H), 7.67-7.70 (m, 1H), 7.56-7.63 (m, 2H).
Embodiment 41-(3-aminophenyl)-3-(the chloro-3-of 4-(trifluoromethyl) phenyl) urea (J-3)
Replace JX-1 with JX-3, adopt the method being similar to J-1 to prepare J-3, obtain Light yellow crystals (yield 94%):
1h-NMR (DMSO-d
6) δ 8.97 (s, 1H), 8.44 (s, 1H), 8.11 (s, 1H), 7.58 (d, J=1.6Hz, 2H), 6.90 (t, J=8.0Hz, 1H), (6.80 t, J=2.0Hz, 1H), 6.54-6.56 (m, 1H), 6.22-6.24 (m, 1H), 4.97 (s, 2H).
Embodiment 51-(3-nitrophenyl)-3-(3-cyano-phenyl) urea (JX-4)
Replace the chloro-4-fluoroaniline of 3-with 3-cyano-aniline, adopt the method being similar to JX-1 to prepare JX-4, obtain yellow solid (yield 84%):
1h-NMR (DMSO-d
6) δ 9.32 (s, 1H), 9.12 (s, 1H), 8.53 (m, 1H), 7.96-7.98 (m, 1H), 7.83-7.86 (m, 1H), 7.71-7.76 (m, 2H), 7.56-7.60 (m, 1H), 7.50-7.53 (m, 1H), 7.43-7.46 (m, 1H).
Embodiment 61-(3-aminophenyl)-3-(3-cyano-phenyl) urea (J-4)
Replace JX-1 with JX-4, adopt the method being similar to J-1 to prepare J-4, obtain light yellow solid (yield 62%):
1h-NMR (DMSO-d
6) δ 8.84 (s, 1H), 8.44 (s, 1H), 7.94 (m, 1H), 7.61-7.64 (m, 1H), 7.44-7.49 (m, 1H), 7.38 (d, J=7.6Hz, 1H), 6.88-6.92 (m, 1H), 6.75 (m, 1H), 6.55-6.57 (m, 1H), 6.22-6.24 (m, 1H), 4.95 (brs, 2H).
Embodiment 71-(3-nitrophenyl)-3-(3-fluorophenyl) urea (JX-9)
Replace 3-(trifluoromethyl)-4-chloroaniline with 3-fluoroaniline, adopt the method being similar to JX-3 to prepare JX-9, obtain light yellow solid (yield 92%):
1h-NMR (DMSO-d
6) δ 9.23 (s, 1H), 9.02 (s, 1H), 8.54 (m, 1H), 7.83-7.86 (m, 1H), 7.73-7.75 (m, 1H), 7.58 (t, J=8.0Hz, 1H), 7.49 (dt, J=2.4,12Hz, 1H), 7.33 (dd, J=7.6,14.4Hz, 1H), 7.18 (dd, J=1.2,8.0Hz, 1H), 6.82 (dt, J=2.0,8.4Hz, 1H).
Embodiment 81-(3-aminophenyl)-3-(3-fluorophenyl) urea (J-9)
Replace JX-1 with JX-9, adopt the method being similar to J-1 to prepare J-9, obtain light yellow solid (yield 95%):
1h-NMR (DMSO-d
6) δ 8.72 (s, 1H), 8.35 (s, 1H), 7.46 (dt, J=2.4,12Hz, 1H), 7.24-7.30 (m, 1H), 7.06-7.08 (m, 1H), 6.89 (t, J=8.0Hz, 1H), 6.72-6.77 (m, 1H), 6.54 (ddd, J=0.8,2.0,8.0Hz, 1H), 6.19-6.22 (m, 1H), 4.96 (s, 2H).
Embodiment 91-cyclohexyl-3-(3-nitrophenyl) urea (JX-11)
Replace the chloro-4-fluoroaniline of 3-with hexahydroaniline, adopt the method being similar to JX-1 to prepare JX-11, obtain light yellow solid:
1h-NMR (DMSO-d
6) δ 8.79 (s, 1H), 8.48-8.49 (m, 1H), 7.71-7.74 (m, 1H), 7.58-7.61 (m, 1H), 7.49 (t, J=8.0Hz, 1H), 4.73 (d, J=7.6Hz, 1H), 3.46-3.53 (m, 1H), 1.80-1.84 (m, 2H), 1.64-1.69 (m, 2H), 1.52-1.56 (m, 1H), 1.15-1.37 (m, 5H).
Embodiment 101-cyclohexyl-3-(3-aminophenyl) urea (J-11)
Replace JX-1 with JX-11, adopt the method being similar to J-1 to prepare J-11, obtain near-white solid (yield 86%):
1h-NMR (DMSO-d
6) δ 7.91 (s, 1H), 6.82 (t, J=8.0Hz, 1H), 6.66 (t, J=2.0Hz, 1H), 6.48-6.50 (m, 1H), 6.10-6.12 (m, 1H), (5.90 d, J=7.6Hz, 1H), 4.83 (s, 2H), 3.39-3.44 (m, 1H), 1.77-1.81 (m, 2H), 1.63-1.67 (m, 2H), 1.50-1.54 (m, 1H), 1.10-1.35 (m, 5H).
Embodiment 111-(3-nitrophenyl)-3-aminomethyl phenyl urea (JX-13)
Replace the chloro-4-fluoroaniline of 3-with 3-monomethylaniline, adopt the method being similar to JX-1 to prepare JX-13, obtain yellow solid (yield 87%):
1h-NMR (DMSO-d
6) δ 9.18 (s, 1H), 8.72 (s, 1H), 8.55 (m, 1H), 7.80-7.82 (m, 1H), 7.69-7.72 (m, 1H), 7.56 (t, J=8.4Hz, 1H), 7.15-7.32 (m, 3H), 6.83 (d, J=7.2Hz, 1H), 2.29 (s, 3H).
Embodiment 121-(3-aminophenyl)-3-aminomethyl phenyl urea (J-13)
Replace JX-1 with JX-13 (1.71g, 6.3mmol), adopt the method being similar to J-1 to prepare J-13, obtain near-white solid (yield 85%):
1h-NMR (DMSO-d
6) δ 8.41 (s, 1H), 8.27 (s, 1H), 7.28 (s, 1H), 7.12-7.22 (m, 2H), 6.89 (t, J=8.0Hz, 1H), 6.77 (t, J=2.0Hz, 2H), 6.55 (dd, J=1.2,7.6Hz, 1H), 6.20 (dd, J=1.2,8.0Hz, 1H), 4.94 (s, 2H), 2.28 (s, 3H).
Embodiment 131-(3-nitrophenyl)-3-(3,5-bis-(trifluoromethyl) phenyl) urea (JX-14)
Replace 3-(trifluoromethyl)-4-chloroaniline with 3,5-bis-(trifluoromethyl) aniline, adopt the method being similar to JX-3 to prepare JX-14, obtain apricot solid (yield 83%):
1h-NMR (DMSO-d
6) δ 9.50 (s, 1H), 9.46 (s, 1H), 8.53 (t, J=2.0Hz, 1H), 8.16 (s, 2H), 7.86-7.88 (m, 1H), 7.79-7.82 (m, 1H), 7.66 (s, 1H), (7.59 t, J=8.0Hz, 1H).
Embodiment 141-(3-aminophenyl)-3-(3,5-bis-(trifluoromethyl) phenyl) urea (J-14)
Replace JX-1 with JX-14, adopt the method being similar to J-1 to prepare J-14, obtain near-white solid (yield 74%):
1h-NMR (DMSO-d
6) δ 9.20 (s, 1H), 8.57 (s, 1H), 8.10 (s, 2H), 7.59 (s, 1H), 6.92 (t, J=8.0Hz, 1H), 6.83 (m, 1H), 6.55-6.57 (m, 1H), 6.23-6.26 (m, 1H), 4.99 (s, 2H).
Embodiment 151-(3-nitrophenyl)-3-(2,5-difluorophenyl) urea (JX-15)
Replace 3-(trifluoromethyl)-4-chloroaniline with 2,5-difluoroaniline, adopt the method being similar to JX-3 to prepare JX-15, obtain bright yellow solid (yield 86%):
1h-NMR (DMSO-d
6) δ 9.57 (s, 1H), 8.81 (s, 1H), 8.54 (t, J=2.0Hz, 1H), 8.00 (m, 1H), 7.85 (dt, J=1.2,8.0Hz, 1H), 7.67-7.69 (m, 1H), 7.59 (t, J=8.0Hz, 1H), 7.26-7.33 (m, 1H), 6.85 (m, 1H).
Embodiment 161-(3-aminophenyl)-3-(2,5-difluorophenyl) urea (J-15)
Replace JX-1 with JX-15, adopt the method being similar to J-1 to prepare J-15, obtain near-white solid (yield 93%):
1h-NMR (DMSO-d
6) δ 8.82 (s, 1H), 8.61 (s, 1H), 8.04 (m, 1H), 7.25 (m, 1H), 6.86-6.93 (m, 1H), 6.75-6.80 (m, 2H), 6.55 (t, J=6.8Hz, 1H), 6.21 (ddd, J=1.6,7.6,19.6Hz, 1H), 4.98 (brs, 2H).
Embodiment 171-(3-nitrophenyl)-3-(2-methyl-5-fluorophenyl) urea (JX-16)
Replace 3-(trifluoromethyl)-4-chloroaniline with 5-fluoro-2-methylbenzene amine, adopt the method being similar to JX-3 to prepare JX-16, obtain apricot solid (yield 94%):
1h-NMR (DMSO-d
6) δ 9.16 (s, 1H), 8.87 (s, 1H), 8.52 (t, J=2.0Hz, 1H), 7.81-7.83 (m, 1H), 7.71-7.73 (m, 1H), 7.56 (t, J=8.0Hz, 1H), 7.41 (dd, J=2.0,12.4Hz, 1H), 7.18 (t, J=8.8Hz, 1H), 7.07 (dd, J=2.0,8.4Hz, 1H), 2.17 (s, 3H)
Embodiment 181-(3-aminophenyl)-3-(2-methyl-5-fluorophenyl) urea (J-16)
Replace JX-1 with JX-16, adopt the method being similar to J-1 to prepare J-16, obtain near-white solid (yield 95%):
1h-NMR (DMSO-d
6) δ 8.59 (s, 1H), 8.31 (s, 1H), 7.40 (dd, J=1.6,12.8Hz, 1H), (7.13 t, J=8.8Hz, 1H), 6.98 (dd, J=2.0,8.0Hz, 1H), 6.89 (t, J=8.0Hz, 1H), 6.76 (m, 1H), 6.54 (dd, J=1.2,8.0Hz, 1H), 6.20 (dd, J=0.8,8.0Hz, 1H), 4.98 (brs, 2H), 2.15 (s, 3H).
Embodiment 191-(3-nitrophenyl)-3-(thiazol-2-yl) urea (JX-17)
Replace the chloro-4-fluoroaniline of 3-with thiazolamine, adopt the method being similar to JX-1 to prepare JX-17, obtain yellow solid (yield 70%):
1h-NMR (DMSO-d
6) δ 10.78 (brs, 1H), 9.44 (s, 1H), 8.57 (m, 1H), 7.87-7.90 (m, 1H), 7.79-7.81 (m, 1H), (7.61 t, J=8.4Hz, 1H), (7.40 d, J=3.6Hz, 1H), (7.13 d, J=3.6Hz, 1H).
Embodiment 201-(3-aminophenyl)-3-(thiazol-2-yl) urea (J-17)
Replace JX-1 with JX-17, adopt the method being similar to J-1 to prepare J-17, obtain Light yellow crystals powder (yield 100%): MS-ESIm/z235 (M+H)
+.
Embodiment 211-(3-nitrophenyl)-3-(4-(pyrrolidin-1-yl) butyl) urea (JX-18)
Replace 3-(trifluoromethyl)-4-chloroaniline with 4-(pyrrolidin-1-yl) butane-1-amine, adopt the method being similar to JX-3 to prepare JX-18, obtain apricot solid (yield 90%):
1h-NMR (DMSO-d
6) δ 9.50 (s, 1H), 8.50 (t, J=2.0Hz, 1H), 7.72 (ddd, J=0.8,2.4,8.4Hz, 1H), 7.66 (ddd, J=0.8,2.0,8.0Hz, 1H), 7.48 (t, J=8.4Hz, 1H), 6.70 (t, J=6.0Hz, 1H), 3.29 (m, 2H), 3.11 (m, 6H), 1.93 (m, 4H), 1.66-1.74 (m, 2H), 1.49-1.54 (m, 2H).
Embodiment 221-(3-aminophenyl)-3-(4-(pyrrolidin-1-yl) butyl) urea (J-18)
Replace JX-1 with JX-18, adopt the method being similar to J-1 to prepare J-18, obtain near-white solid (yield 54%):
1h-NMR (DMSO-d
6) δ 8.02 (s, 1H), 6.82 (t, J=8.0Hz, 1H), 6.68 (s, 1H), 6.48 (d, J=8.4Hz, 1H), 6.11 (d, J=9.2Hz, 1H), 5.99 (t, J=5.6Hz, 1H), 4.88 (s, 2H), 3.06 (m, 2H), 2.39 (m, 6H), 1.66 (m, 4H), 1.43 (m, 4H).
Embodiment 231-isobutyl--3-(3-nitrophenyl) urea (JX-19)
Replace the chloro-4-fluoroaniline of 3-with isobutylamine, adopt the method being similar to JX-1 to prepare JX-19, obtain light yellow solid (yield 42%):
1h-NMR (DMSO-d
6) δ 8.88 (s, 1H), 8.48 (t, J=2.0Hz, 1H), 7.71-7.73 (m, 1H), 7.60-7.62 (m, 1H), 7.48 (t, J=8.0Hz, 1H), 6.30 (brs, 1H), 2.94 (t, J=6.4Hz, 1H), 1.71 (m, 1H), 0.88 (s, 3H), 0.86 (s, 3H).
Embodiment 241-isobutyl--3-(3-aminophenyl) urea (J-19)
Replace JX-1 with JX-19, adopt the method being similar to J-1 to prepare J-18, obtain light yellow solid (yield 93%): MS-ESIm/z208 (M+H)
+.
The preparation of isocyanic acid ester process: P series side chain urea
Embodiment 251-(the chloro-4-fluorophenyl of 3-)-3-(4-aminophenyl) urea (P-1)
Triphosgene (0.72g, 2.4mmol) is dissolved in methylene dichloride (10mL).Under nitrogen protection and ice-water bath cooling, drip methylene dichloride (20mL) solution of the chloro-4-fluoroaniline (0.87g, 6mmol) of 3-and DIEA (0.93g, 7.2mmol), stir 0.5h.Add methylene dichloride (20mL) solution of Ursol D (0.66g, 6mmol), DIEA (0.93g, 7.2mmol), stirring at room temperature 24h, concentrating under reduced pressure reaction solution.Dissolve gained oily residue by ethyl acetate (60mL), use 10% aqueous potassium hydrogen sulfate, 5% sodium bicarbonate aqueous solution and half saturated brine It successively, anhydrous magnesium sulfate drying, concentrating under reduced pressure obtains light yellow solid.White solid P-1 (yield 39%) is obtained through column chromatography purification (alkali alumina, ethyl acetate: sherwood oil 3: 5 ~ 3: 0):
1h-NMR (DMSO-d
6) δ: 8.62 (s, 1H), 8.14 (s, 1H), 7.76-7.78 (m, 1H), 7.25-7.28 (m, 2H), 7.06 (d, J=8.8Hz, 2H), 6.52 (d, J=8.8Hz, 2H), 4.73 (s, 2H).
Embodiment 261-(4-aminophenyl)-3-(3-(trifluoromethyl)-4-chloro-phenyl-) urea (P-3)
Replace the chloro-4-fluoroaniline of 3-with 3-(trifluoromethyl)-4-chloroaniline, adopt the method being similar to P-1 to prepare P-3, obtain near-white solid:
1h-NMR (DMSO-d
6) δ 8.91 (s, 1H), 8.23 (s, 1H), 8.07 (d, J=2.4Hz, 1H), 7.55-7.61 (m, 2H), 7.07 (d, J=8.8Hz, 2H), 6.53 (d, J=8.8Hz, 2H), 4.76 (s, 2H).
Embodiment 271-(4-aminophenyl)-3-(3-cyano-phenyl) urea (P-4)
Replace the chloro-4-fluoroaniline of 3-with 3-cyano-aniline, adopt the method being similar to P-1 to prepare P-4, obtain yellow solid:
1h-NMR (DMSO-d
6) δ 8.79 (s, 1H), 8.23 (s, 1H), 7.92 (m, 1H), 7.60-7.63 (m, 1H), 7.45 (m, 1H), 7.35 (m, 1H), 7.06 (d, J=8.8Hz, 2H), 6.52 (d, J=8.8Hz, 2H), 4.73 (brs, 2H).
Embodiment 281-cyclohexyl-3-(4-aminophenyl) urea (P-11)
Replace the chloro-4-fluoroaniline of 3-with hexahydroaniline, adopt the method being similar to P-1 to prepare P-4, obtain light pink solid:
1h-NMR (DMSO-d
6) δ 7.69 (s, 1H), 6.98 (d, J=8.4Hz, 2H), 6.46 (d, J=8.8Hz, 2H), 5.75 (d, J=8.0Hz, 1H), 4.58 (brs, 1H), 3.41-3.43 (m, 1H), 1.76-1.80 (m, 2H), 1.63-1.66 (m, 2H), 1.51-1.54 (m, 1H), 1.25-1.34 (m, 2H), 1.08-1.21 (m, 3H).
Embodiment 291-(4-aminophenyl)-3-aminomethyl phenyl urea (P-13)
Replace the chloro-4-fluoroaniline of 3-with 3-monomethylaniline, adopt the method being similar to P-1 to prepare P-4, obtain light pink solid:
1h-NMR (DMSO-d
6) δ 8.32 (s, 1H), 8.05 (s, 1H), 7.25 (s, 1H), 7.19 (d, J=8.4Hz, 1H), 7.12 (t, J=8.0Hz, 1H), 7.06 (d, J=8.8Hz, 2H), 6.75 (d, J=7.2Hz, 1H), 6.52 (d, J=8.8Hz, 2H), 4.69 (s, 2H), 2.26 (s, 3H).
Embodiment 301-(4-aminophenyl)-3-(4-(pyrrolidin-1-yl) butyl) urea (P-18)
Replace the chloro-4-fluoroaniline of 3-with 4-(pyrrolidin-1-yl) butane-1-amine, adopt the method being similar to P-1 to prepare P-18, obtain light gray solid:
1h-NMR (DMSO-d
6) δ 7.80 (s, 1H), 6.99 (d, J=8.4Hz, 2H), 6.46 (d, J=8.8Hz, 2H), 5.86 (t, J=5.2Hz, 1H), 4.63 (s, 2H), 3.04 (d, 2H, J=5.6Hz), 2.39 (m, 6H), 1.67 (m, 4H), 1.43 (m, 4H); MS-ESIm/z208 (M+H)
+.
Embodiment 311-isobutyl--3-(4-aminophenyl) urea (P-19)
Replace the chloro-4-fluoroaniline of 3-with isobutylamine, adopt the method being similar to P-1 to prepare P-19, obtain near-white solid:
1h-NMR (DMSO-d
6) δ 7.81 (s, 1H), 7.00 (d, 2H, J=8.4Hz), 6.47 (d, 2H, J=8.4Hz), 5.90 (t, J=5.6Hz, 1H), 4.63 (s, 2H), 2.88 (t, J=6.4Hz, 2H), (1.66 m, 1H), 0.86 (s, 3H), 0.85 (s, 3H).
Embodiment 32N-(4-nitrophenyl) morpholine-4-methane amide (PX-12)
Triphosgene (1.63g, 10.5mmol) is dissolved in acetonitrile (12mL).Under nitrogen protection and ice-water bath cooling, drip acetonitrile (20mL) solution of 4-N-methyl-p-nitroaniline (1.07g, 11mmol).Stirring at room temperature 1h, backflow 18h, after cooling, concentrating under reduced pressure obtains yellow solid.Add acetonitrile (10mL) solution of morpholine (1.01g, 11mmol), stirring at room temperature 5h, concentrating under reduced pressure, add methylene chloride making beating, obtains PX-12, is yellow solid (1.55g, 56%):
1h-NMR (DMSO-d
6) δ 9.26 (s, 1H), 8.14 (d, J=9.2Hz, 2H), 7.75 (d, J=9.2Hz, 2H), 3.62 (m, 4H), 3.48 (m, 4H).
Embodiment 33N-(4-aminophenyl) morpholine-4-methane amide (P-12)
By above-mentioned product P X-12 (1.55g, 6mmol), be added to ethanol: in water (2: 1) (54mL), add glacial acetic acid (1.64g, 27.3mmol), add the reduced iron powder (1.38g, 24.7mmol) of activation under backflow, continue backflow 1h.Be cooled to 35 DEG C, regulate pH to 9-10 with strong aqua, suction filtration.By filtrate reduced in volume, gained residue adds ethyl acetate making beating and obtains light pink solid P-12 (0.57g, 42%):
1h-NMR (DMSO-d
6) δ 8.03 (s, 1H), 7.03 (d, J=8.4Hz, 2H), 6.48 (d, J=8.8Hz, 2H), 4.68 (brs, 2H), 3.59 (m, 4H), 3.36 (m, 4H).
Embodiment 341-(4-nitrophenyl)-3-(thiazol-2-yl) urea (PX-17)
Replace morpholine with thiazolamine, adopt the method being similar to PX-12 to prepare PX-17, obtain yellow solid (yield 99%):
1h-NMR (DMSO-d
6) δ 9.99 (s, 1H), 8.21 (d, J=9.2Hz, 1H), 7.75 (d, J=9.2Hz, 1H), 7.40 (d, J=3.6Hz, 1H), 7.14 (d, J=4.0Hz, 1H).
Embodiment 351-(4-aminophenyl)-3-(thiazol-2-yl) urea (P-17)
Replace PX-12 with PX-17, adopt the method being similar to P-12 to prepare P-17, obtain light gray solid (yield 100%):
1h-NMR (DMSO-d
6) δ 9.06 (s, 1H), 7.31 (d, J=3.6Hz, 1H), 7.10-7.12 (m, 2H), 7.01 (d, J=3.6Hz, 1H), 6.51-6.54 (m, 2H), 4.78 (brs, 2H).
Carbamate method:
Embodiment 36N-(3-nitrophenyl) morpholine-4-methane amide (JX-12)
By p-nitrophenyl chloroformate ester (1.02g; 5.5mmol) be dissolved in THF (20mL); 0 DEG C drips 3-N-methyl-p-nitroaniline (0.68g under nitrogen protection; THF (5mL) solution 5mmol); then triethylamine (0.55g is added; 5.5mmol), then stir 0.5h.Add morpholine (0.44g, 5.5mmol) and triethylamine (0.55g, 5.5mmol), backflow 4h.Concentrating under reduced pressure reactant, add methylene chloride extraction residue, and use water, 1mol/L hydrochloric acid, saturated sodium bicarbonate aqueous solution and 5% NaCl successively, anhydrous sodium sulfate drying, concentrating under reduced pressure obtains yellow solid.Yellow crystals (0.35g, 28%) is obtained through recrystallisation from isopropanol after silica gel column chromatography (ethyl acetate: sherwood oil: methylene dichloride 4: 5: 3) purifying:
1h-NMR (DMSO-d
6) δ 8.97 (s, 1H), 8.47 (m, 1H), 7.88-7.90 (m, 1H), 7.77-7.80 (m, 1H), 7.52 (t, J=8.0Hz, 1H), 3.62 (m, 4H), 3.46 (m, 4H).
Embodiment 37N-(3-aminophenyl) morpholine-4-methane amide (J-12)
Replace JX-1 with JX-12, adopt the method being similar to J-1 to prepare J-12, obtain light gray solid (yield 99%):
1h-NMR (DMSO-d
6) δ 8.16 (s, 1H), 6.84 (t, J=8.0Hz, 1H), 6.76 (t, J=2.0Hz, 1H), 6.56-6.59 (m, 1H), 6.16-6.19 (m, 1H), 3.57 (m, 4H), 3.40 (m, 4H).
The synthesis of Ia, Ib, Ic, Id and Ie series compound
Embodiment 384-(3-(the chloro-7-methoxyquinazoline hydrochloride of 4--6-base oxygen) propyl group) morpholine hydrochloride (Q1)
By 7-methoxyl group-6-(morpholinyl propoxy-) quinazoline-4-alcohol (3.19g, 10mmol), sulfur oxychloride (50mL) and dry DMF (1mL) return stirring 2h, be chilled to room temperature, add toluene and revolve steaming band residual chloride sulfoxide to the greatest extent, obtain yellow solid residue.Add Virahol (15mL) room temperature making beating 2h, suction filtration, vacuum-drying obtain light yellow solid Q1 (3.36g, 90%).
Embodiment 391-(3-fluorophenyl)-3-(3-(7-methoxyl group-6-(morpholinyl propoxy-) quinazoline-4-base amido) phenyl) urea (D2-9)
Get Q1 (0.15g, 0.4mmol) and J-9 (0.1g, 0.4mmol), Virahol (4mL) and hydrogenchloride Virahol saturated solution (1mL) return stirring 3h.Be chilled to room temperature, add water (10mL), methylene dichloride (50mL) and methyl alcohol (10mL) and dissolve gained reactant, adjust pH to 7.5 with 1mol/L aqueous sodium hydroxide solution, then use dichloromethane extraction.Merge organic layer, through salt water washing, anhydrous sodium sulfate drying, revolve and steam to obtain crude product.Gained crude product silica gel column chromatography, by ethyl acetate: ethanol: triethylamine (300: 100: 1) wash-out, finally by recrystallizing methanol, vacuum-drying (50 DEG C, 5h) light yellow solid (yield 14%):
1hNMR (DMSO-d
6) δ 9.43 (s, 1H), 8.84 (s, 1H), 8.74 (s, 1H), 8.45 (s, 1H), 7.97 (t, J=2.0Hz, 1H), 7.87 (s, 1H), 7.43-7.52 (m, 2H), 7.27-7.34 (m, 2H), 7.19 (m, 2H), 7.13 (m, 1H), 6.76-6.80 (m, 1H), 4.21 (t, J=6.4Hz, 2H), 3.94 (s, 3H), 3.58 (m, 4H), 2.41-2.54 (m, 6H), 1.99 (m, 2H); MS-ESIm/z547 (M+H)
+.
Embodiment 401-(the chloro-4-fluorophenyl of 3-)-3-(4-(7-methoxyl group-6-(morpholinyl propoxy-) quinazoline-4-base amido) phenyl) urea (D1-1)
Replace J-9 with P-1, adopt the method being similar to D2-9 to prepare D1-1, obtain white solid (yield 27%):
1hNMR (DMSO-d
6) δ 9.37 (s, 1H), 8.80 (s, 1H), 8.68 (s, 1H), 8.40 (s, 1H), 7.80-7.83 (m, 2H), 7.67 (dd, J=2,6.8Hz, 2H), 7.46 (dd, J=2,6.8Hz, 2H), 7.31-7.33 (m, 2H), 7.17 (s, 1H), 4.19 (t, J=6.4Hz, 2H), 3.93 (s, 3H), 3.59 (t, J=4.4Hz, 4H), 2.47 (m, 2H), 2.40 (t, J=6.4Hz, 4H), 1.99 (m, 2H); MS-ESIm/z581 (M+H)
+.
The preparation of embodiment 411-(the chloro-3-of 4-(trifluoromethyl) phenyl)-3-(4-(7-methoxyl group-6-(morpholinyl propoxy-) quinazoline-4-base amido) phenyl) urea (D1-3) and hydrochloride thereof
A () replaces J-9 with P-3, adopt the method being similar to D2-9 to prepare D1-3, obtain near-white solid (yield 18%):
1hNMR (DMSO-d
6) δ 9.39 (s, 1H), 9.10 (s, 1H), 8.77 (s, 1H), (8.39 s, 1H), 8.11 (d, J=2Hz, 1H), 7.82 (s, 1H), 7.61-7.68 (m, 4H), (7.47 m, 2H), 7.16 (s, 1H) 4.19 (m, 2H), 3.92 (s, 3H), 3.57-3.59 (m, 4H), (2.46 m, 2H), 2.40 (m, 4H), 1.99 (m, 2H); MS-ESIm/z631 (M+H)
+.
B () becomes hydrochloride
Get D1-3 (0.15g, 0.24mmol) backflow 0.5h in methyl alcohol (8ml), add 0.1mol/L hydrochloric acid (2.6ml, 0.26mmol).By gained solution stirring 1h, then cooling crystallization 2h.Suction filtration, vacuum-drying (110 DEG C, 4h), obtains D1-3 hydrochloride, is yellow solid (0.08g, 48%): ultimate analysis (C
30h
30clF
3n
6o
4hCI2H
2o) C, H, N, calculated value 51.22,5.01,11.95, measured value 51.12,4.69,11.80.
Embodiment 421-(3-cyano-phenyl)-3-(4-(7-methoxyl group-6-(morpholinyl propoxy-) quinazoline-4-base amido) phenyl) urea (D1-4)
Replace J-9 with P-4, adopt the method being similar to D2-9 to prepare D1-4, obtain near-white solid (yield 9%):
1hNMR (DMSO-d
6) δ 10.21 (s, 1H), 9.77 (s, 1H), 9.48 (s, 1H), 8.39 (s, 1H), 8.01 (s, 1H), 7.91 (s, 1H), 7.67-7.70 (m, 3H), 7.48 (t, J=8.4Hz, 3H), 7.36 (d, J=7.6Hz, 1H), 7.15 (s, 1H), 4.21 (t, J=6.4Hz, 2H), 3.93 (s, 3H), 3.58 (t, J=4.4Hz, 4H), 2.47 (m, 2H), 2.39 (t, J=4.4Hz, 4H), 1.98 (m, 2H); MS-ESIm/z554 (M+H)
+.
Embodiment 431-cyclohexyl-3-(4-(7-methoxyl group-6-(morpholinyl propoxy-) quinazoline-4-base amido) phenyl) urea (D1-11)
Replace J-9 with P-11, adopt the method being similar to D2-9 to prepare D1-11, obtain near-white solid (yield 27%):
1hNMR (DMSO-d
6) δ 9.31 (s, 1H), 8.37 (s, 1H), 8.23 (s, 1H), 7.82 (s, 1H), 7.57 (d, J=8.8Hz, 2H), 7.38 (d, J=8.8Hz, 2H), 7.15 (s, 1H), 6.00 (d, J=7.6Hz, 1H), 4.18 (t, J=6.4Hz, 2H), 3.93 (s, 3H), 3.59 (t, J=4.4Hz, 4H), 3.48 (m, 1H), 2.50 (m, 2H), 2.41 (m, 4H), 1.99 (m, 2H), 1.80-1.83 (m, 2H), 1.65-1.69 (m, 2H), 1.53-1.56 (m, 1H), 1.28-1.34 (m, 2H), 1.14-1.24 (m, 2H), MS-ESIm/z535 (M+H)
+.
Embodiment 44N-(4-(7-methoxyl group-6-(morpholinyl propoxy-) quinazoline-4-base amido) phenyl) morpholine-4-methane amide (D1-12)
Replace J-9 with P-12, adopt the method being similar to D2-9 to prepare D1-12, obtain white solid (yield 49%):
1hNMR (DMSO-d
6) δ 9.41 (s, 1H), 8.55 (s, 1H), 8.47 (s, 1H), 7.91 (s, 1H), (7.69 dd, J=2.0,6.8Hz, 2H), 7.55 (dd, J=2.0,6.8Hz, 2H), 7.24 (s, 1H), 4.27 (t, J=6.4Hz, 2H), (4.01 s, 3H), 3.65-3.70 (m, 8H), 3.52 (m, 4H), (2.55 m, 2H), 2.48 (m, 4H), 2.07 (m, 2H); MS-ESIm/z523 (M+H)
+.
Tolyl-3-(4-(7-methoxyl group-6-(morpholinyl propoxy-) quinazoline-4-base amido) phenyl) urea (D1-13) between embodiment 451-
Replace J-9 with P-13, adopt the method being similar to D2-9 to prepare D1-13, obtain light yellow solid (yield 14%):
1hNMR (DMSO-d
6) δ 9.37 (s, 1H), 8.60 (s, 1H), 8.54 (s, 1H), 8.40 (s, 1H), 7.84 (s, 1H), 7.66 (dd, J=2, 6.8Hz, 2H), 7.46 (dd, J=2, 6.8Hz, 2H), 7.31 (m, 1H), 7.24 (d, J=8.8Hz, 1H), 7.14-7.18 (m, 2H), 6.79 (d, J=8.0Hz, 1H), 4.20 (t, J=6.4Hz, 2H), 3.94 (s, 3H), 3.60 (m, 4H), 2.52 (m, 2H), 2.43 (m, 4H), 2.29 (s, 3H), 2.01 (m, 2H), MS-ESIm/z543 (M+H)
+.
Embodiment 461-(thiazol-2-yl)-3-(4-(7-methoxyl group-6-(morpholinyl propoxy-) quinazoline-4-base amido) phenyl) urea (D1-17)
Replace J-9 with P-17, adopt the method being similar to D2-9 to prepare D1-17, obtain near-white solid (yield 86%):
1hNMR (DMSO-d
6) δ 10.78 (brs, 1H), 9.71 (s, 1H), 9.49 (s, 1H), 8.40 (s, 1H), 7.90 (s, 1H), 7.72 (d, J=8.8Hz, 2H), 7.49 (d, J=8.8Hz, 2H), 7.35 (d, J=3.2Hz, 2H), 7.16 (s, 1H), 7.07 (d, J=3.2Hz, 2H), 4.21 (m, 2H), 3.93 (s, 3H), 3.58 (t, J=4.4Hz, 4H), (2.47 m, 2H), 2.39 (m, 4H), 1.98 (m, 2H); MS-ESIm/z536 (M+H)
+.
Embodiment 471-(4-(7-methoxyl group-6-(morpholinyl propoxy-) quinazoline-4-base amido) phenyl)-3-(4-(pyrrolidin-1-yl) butyl) urea (D1-18)
Replace J-9 with P-18, adopt the method being similar to D2-9 to prepare D1-18, obtain light yellow solid (yield 35%):
1hNMR (DMSO-d
6) δ 9.33 (s, 1H), 8.39 (s, 1H), 8.37 (s, 1H), 7.82 (s, 1H), 7.59 (d, 2H, J=9.2Hz), 7.41 (d, 2H, J=8.8Hz), 7.15 (s, 1H), 6.12 (m, 1H), 4.17 (t, 2H, J=6.4Hz), 3.92 (s, 3H), (3.57 m, 4H), 3.11 (m, 2H), 2.39-2.49 (m, 12H), (1.95-2.00 m, 2H), 1.65 (m, 4H), 1.46 (m, 4H); MS-ESIm/z578 (M+H)
+.
Embodiment 481-isobutyl--3-(4-(7-methoxyl group-6-(morpholinyl propoxy-) quinazoline-4-base amido) phenyl) urea (D1-19)
Replace J-9 with P-19, adopt the method being similar to D2-9 to prepare D1-19, obtain white solid (yield 51%):
1hNMR (DMSO-d
6) δ 9.36 (s, 1H), 9.07 (s, 1H), 8.36 (s, 1H), 7.83 (s, H), 7.54 (dd, 2H, J=2, 9.2Hz), 7.43 (dd, 2H, J=2, 6.8Hz), 7.14 (s, H), 6.86 (m, 1H), 4.18 (t, 2H, J=6.4Hz), 3.92 (s, 3H), 3.58 (t, 4H, J=4.8Hz), 2.91 (t, 2H, J=6.4Hz), 2.39 (t, 4H, J=4.8Hz), 1.98 (m, 2H), 1.70 (m, 1H), 1.64 (s, 2H), 0.89 (s, 3H), 0.88 (s, 3H), MS-ESIm/z509 (M+H)
+.
The preparation of embodiment 491-(4-(7-methoxyl group-6-(morpholinyl propoxy-) quinazoline-4-base amido) phenyl)-3-(5-methylisoxazole-3-base) urea (D1-20) and hydrochloride thereof
(a) N
1-(7-methoxyl group-6-(morpholinyl propoxy-) quinazoline-4-base) benzene-Isosorbide-5-Nitrae-diamines
By 7-methoxyl group-6-(morpholinyl propoxy-)-N-(4-oil of mirbane) quinazoline-4-amine (7.09g, 16.14mmol) be dissolved in methyl alcohol (100ml), add 10% palladium charcoal (0.72g), stir 5h at 1.40MPa hydrogen pressure, at 50 DEG C.Let cool, filtering palladium charcoal, filtrate evaporate to dryness.With acetone recrystallization gained residue, vacuum-drying (40 DEG C, 2h), obtains N
1-(7-methoxyl group-6-(morpholinyl propoxy-) quinazoline-4-base) benzene-Isosorbide-5-Nitrae-diamines, faint yellow solid (5.56g, 84%).
(b) 1-(4-(7-methoxyl group-6-(morpholinyl propoxy-) quinazoline-4-base amido) phenyl)-3-(5-methylisoxazole-3-base) urea (D1-20)
3-amino-5-methylisoxazole (0.34g, 3.46mmol) is dissolved in methylene dichloride (10ml), methylene dichloride (2ml) solution of 0 DEG C of dropping phenyl chloroformate (0.54g, 3.46mmol).Stirring at room temperature 2h, adularescent solid is separated out.Add triethylamine (0.35g, 3.46mmol), solution is clarified.Add N successively
1-(7-methoxyl group-6-(morpholinyl propoxy-) quinazoline-4-base) benzene-Isosorbide-5-Nitrae-diamines (0.89g, 2.18mmol), triethylamine (1.40g, 17.70mmol), backflow 3h, has solid to separate out.Filtered while hot, filter cake vacuum-drying (35 DEG C, 2h), obtains Off-white solid D1-20 (0.33g, 28%): mp218-221 DEG C;
1h-NMR (DMSO-d
6) δ 9.38 (s, 1H), 9.36 (s, 1H), 8.78 (s, 1H), 8.40 (s, 1H), 7.83 (s, 1H), 7.68 (d, J=8.8Hz, 2H), 7.46 (d, J=8.8Hz, 2H), 7.17 (s, 1H), 6.53 (s, 1H), 4.19 (t, J=8.8Hz, 2H), 3.93 (s, 3H), 3.59 (t, J=4.4Hz, 4H), (2.47 m, 2H), 2.40 (t, J=4.4Hz, 4H), 2.37 (s, 3H), 1.99 (m, 2H); MS-ESIm/z534 (M+H)
+.
C () becomes hydrochloride
Get D1-20 (0.24g, 0.45mmol) and be dissolved in methyl alcohol (20ml), backflow 0.5h, adds 0.1mol/L hydrochloric acid (5.0ml, 0.5mmol).By gained solution stirring 1h, then cooling crystallization 2h, filter, obtain D1-20 hydrochloride, be yellow solid (0.1g, 37%): ultimate analysis (C
27h
31n
7o
5hCl, 1.5H
2o) C, H, N, calculated value 54.32,5.91,16.42, measured value 54.12,5.77,16.27.
Embodiment 501-(the chloro-4-fluorophenyl of 3-)-3-(3-(7-methoxyl group-6-(morpholinyl propoxy-) quinazoline-4-base amido) phenyl) urea (D2-1)
Replace J-9 with J-1, adopt the method being similar to D2-9 to prepare D2-1, obtain near-white solid (yield 11%):
1hNMR (DMSO-d
6) δ 9.44 (s, 1H), 8.82 (s, 1H), 8.77 (s, 1H), 8.47 (s, 1H), 7.82-7.98 (m, 3H), 7.21-7.47 (m, 6H), 4.23 (m, 2H), 3.96 (s, 3H), 3.61 (m, 4H), 2.52 (m, 2H), 2.43 (m, 4H), 2.02 (m, 2H); MS-ESIm/z581 (M+H)
+.
Embodiment 511-(the chloro-3-of 4-(trifluoromethyl) phenyl)-3-(3-(7-methoxyl group-6-(morpholinyl propoxy-) quinazoline-4-base amido) phenyl) urea (D2-3)
Replace J-9 with J-3, adopt the method being similar to D2-9 to prepare D2-3, obtain light yellow solid (yield 61%):
1hNMR (DMSO-d
6) δ 9.48 (s, 1H), 9.19 (s, 1H), 8.91 (s, 1H), 8.49 (s, 1H), 8.17 (d, J=2.0Hz, 1H), 8.02 (s, 1H), 7.92 (s, 1H), 7.63-7.66 (m, 2H), 7.52 (d, J=8.4Hz, 1H), 7.33 (t, J=7.6H, 1H), 7.23-7.24 (m, 2H), 4.26 (t, J=6.4H, 2H), 3.98 (s, 3H), 3.65 (m, 4H), (2.53 m, 2H), 2.48 (m, 4H), 2.06 (m, 2H); MS-ESIm/z631 (M+H)
+.
Embodiment 521-(3-cyano-phenyl)-3-(3-(7-methoxyl group-6-(morpholinyl propoxy-) quinazoline-4-base amido) phenyl) urea (D2-4)
Replace J-9 with J-4, adopt the method being similar to D2-9 to prepare D2-4, obtain near-white solid (yield 14%):
1hNMR (DMSO-d
6) δ 9.42 (s, 1H), 8.97 (s, 1H), 8.84 (s, 1H), 8.44 (s, 1H), 7.96-7.98 (m, 2H), 7.86 (m, 1H), 7.66-7.68 (m, 1H), 7.47-7.51 (m, 1H), 7.39-7.45 (m, 2H), 7.29 (t, J=8.0Hz, 1H), 7.20-7.22 (m, 1H), 7.18 (s, 1H), 4.20 (t, J=6.4Hz, 2H), 3.93 (s, 3H), 3.58 (t, J=4.8Hz, 4H), 2.47 (m, 2H), 2.40 (m, 4H), 1.99 (m, 2H), MS-ESIm/z552 (M-H)
-.
Embodiment 531-cyclohexyl-3-(3-(7-methoxyl group-6-(morpholinyl propoxy-) quinazoline-4-base amido) phenyl) urea (D2-11)
Replace J-9 with J-11, adopt the method being similar to D2-9 to prepare D2-11, obtain light yellow solid (yield 18%):
1hNMR (DMSO-d
6) δ 9.39 (s, 1H), 8.43 (s, 1H), 8.33 (s, 1H), 7.87 (d, J=7.6Hz, 2H), 7.32 (d, J=8.0Hz, 1H), 7.18-7.22 (m, 2H), 7.11 (d, J=8.0Hz, 1H), 6.06 (d, J=8Hz, 1H), 4.21 (m, 2H), (3.93 s, 3H), 3.63 (m, 4H), 3.48 (m, 1H), (2.57 m, 6H), 2.05 (m, 2H), 1.13-1.82 (m, 10H); MS-ESIm/z535 (M+H)
+.
Embodiment 54N-(3-(7-methoxyl group-6-(morpholinyl propoxy-) quinazoline-4-base amido) phenyl) morpholine-4-methane amide (D2-12)
Replace J-9 with J-12, adopt the method being similar to D2-9 to prepare D2-12, obtain light yellow solid (yield 15%):
1hNMR (DMSO-d
6) δ 9.40 (s, 1H), 8.53 (s, 1H), 8.44 (s, 1H), 7.91 (s, 1H), 7.88 (s, 1H), 7.41 (d, J=8.0Hz, 1H), 7.18-7.26 (m, 3H), 4.21 (t, J=5.6Hz, 2H), 3.94 (s, 3H), 3.62 (m, 8H), 3.44 (m, 4H), 2.57 (m, 6H), 2.02 (m, 2H); MS-ESIm/z523 (M+H)
+.
Tolyl-3-(3-(7-methoxyl group-6-(morpholinyl propoxy-) quinazoline-4-base amido) phenyl) urea (D2-13) between embodiment 551-
Replace J-9 with J-13, adopt the method being similar to D2-9 to prepare D2-13, obtain light yellow solid (yield 38%):
1hNMR (DMSO-d
6) δ 9.42 (s, 1H), 8.66 (s, 1H), 8.54 (s, 1H), 8.45 (m, 1H), (7.96 s, 1H), 7.88 (s, 1H), 7.43 (d, J=7.6Hz, 1H), 7.14-7.30 (m, 6H), 6.79 (d, J=7.2Hz, 1H), 4.22 (t, J=6.4Hz, 2H), (3.94 s, 3H), 3.60 (m, 4H), 2.41 (m, 6H), 2.28 (s, 3H) 2.02 (m, 2H); MS-ESIm/z543 (M+H)
+.
Embodiment 561-(thiazol-2-yl)-3-(3-(7-methoxyl group-6-(morpholinyl propoxy-) quinazoline-4-base amido) phenyl) urea (D2-17)
Replace J-9 with J-17, adopt the method being similar to D2-9 to prepare D2-17, obtain near-white solid (yield 36%):
1hNMR (DMSO-d
6) δ 10.44 (brs, 1H), 9.46 (s, 1H), 9.01 (s, 1H), 8.46 (s, 1H), 7.98 (s, 1H), 7.88 (s, 1H), 7.55 (d, J=8.8Hz, 1H), 7.30-7.38 (m, 2H), 7.19 (m, 2H), 7.10 (d, J=3.2Hz, 1H), 4.21 (t, J=6.4Hz, 2H), 3.94 (s, 3H), 3.59 (m, 4H), (2.48 m, 2H), 2.41 (m, 4H), 2.00 (m, 2H); MS-ESIm/z536 (M+H)
+.
Embodiment 571-(3-(7-methoxyl group-6-(morpholinyl propoxy-) quinazoline-4-base amido) phenyl)-3-(4-(pyrrolidin-1-yl) butyl) urea (D2-18)
Replace J-9 with J-18, adopt the method being similar to D2-9 to prepare D2-18, obtain white solid (yield 30%):
1hNMR (DMSO-d
6) δ 9.36 (s, 1H), 8.42 (s, 1H), 8.38 (s, 1H), 7.85 (s, 2H), 7.32 (d, 1H, J=8.4Hz), 7.14-7.23 (m, 3H), 6.11 (m, 1H), 4.20 (t, 2H, J=6.4Hz), (3.93 s, 3H), 3.57 (m, 6H), 3.10 (d, 2H, J=5.2Hz), 2.40 (m, 10H), (1.99 m, 2H), 1.66 (m, 4H), 1.46 (m, 4H); MS-ESIm/z578 (M+H)
+.
Embodiment 581-isobutyl--3-(3-(7-methoxyl group-6-(morpholinyl propoxy-) quinazoline-4-base amido) phenyl) urea (D2-19)
Replace J-9 with J-19, adopt the method being similar to D2-9 to prepare D2-19, obtain khaki color solid (yield 19%):
1hNMR (DMSO-d
6) δ 9.33 (s, 1H), 8.43 (s, 1H), 8.35 (s, 1H), 7.86 (m, 2H), 7.33 (d, J=8.0Hz, 1H), 7.13-7.23 (m, 3H), 6.12 (m, 1H), 4.21 (t, 2H, J=6.4Hz), 3.94 (s, 3H), 3.59 (t, 4H, J=4.4Hz), (2.92-2.96 m, 2H), 2.42 (m, 6H), 1.98-2.01 (m, 2H), (1.72 m, 1H), 0.90 (s, 3H), 0.88 (s, 3H); MS-ESIm/z509 (M+H)
+.
Embodiment 597-fluquinconazole quinoline-4 (3H)-one
Under nitrogen protection, in reaction flask, add 2-amino-4-fluorobenzoic acid (30g, 190mmol) and methane amide (240mL), rise to 150 DEG C of insulated and stirred 6h.Gained reactant is chilled to about 100 DEG C, the mixture of ice and water (2L) under impouring stirring, filters after stirring 1h.After filter cake washing, vacuum-drying (50 DEG C, 9h) obtains Tan solid 52 (24.5g, 77%):
1hNMR (DMSO-d6) δ 12.27 (brs, 1H), 8.19 (dd, J=8.8,6.4Hz, 1H), 8.11 (s, 1H), 7.43 (dd, J=10.4,2.4Hz, 1H), 7.38 (td, J=8.8,3.2Hz, 1H).
Embodiment 607-(morpholinyl propoxy-) quinazoline-4 (3H)-one (Q2T)
(a) morpholinyl third-1-alcohol
3-bromopropyl alcohol (70g, 0.5mol) is dissolved in toluene (300mL), drips morpholine (87g, 1mol) in room temperature.80 DEG C of insulated and stirred 4h are risen to after dripping off.Be chilled to room temperature, filter gained suspension liquid, filter cake toluene wash.Merge diafiltration liquid and revolve steaming, underpressure distillation gained residue, collect bp96 ~ 98 DEG C/5mmHg cut, obtain colourless liquid (61.7g, 85%).
(b) 7-(morpholinyl propoxy-) quinazoline-4 (3H)-one (Q2T)
By morpholinyl third-1-alcohol (14.52g, 100mmol) be dissolved in dry DMF (20mL), be chilled to 0 DEG C and drop into 60% sodium hydride (4g in batches, 100mmol), then add 7-fluquinconazole quinoline-4 (3H)-one (51) (2.74g in batches, 17mmol), rise to 60 DEG C, 90 DEG C each insulated and stirred 30min, 100min, then rise to 110 DEG C of insulated and stirred 3h.Gained reactant is chilled to room temperature, the mixture of ice and water under impouring stirring, after adjusting pH to 6 with concentrated hydrochloric acid, uses dichloromethane extraction.United extraction liquid, revolves steaming after washing, anhydrous sodium sulfate drying.In gained residue, add ether making beating, suction filtration, uses washed with diethylether filter cake, and vacuum-drying (50 DEG C, 4h) obtains jade green sand solid Q2T (2.8g, 57%):
1hNMR (DMSO-d
6) δ 11.99 (brs, 1H), 8.02 (s, 1H), 8.00 (d, J=5.2Hz, 1H), 7.06-7.09 (m, 2H), 4.16 (t, J=6.4Hz, 2H), 3.57 (t, J=4.8Hz, 4H), 2.43 (t, J=6.8Hz, 2H), 2.37 (t, J=4.8Hz, 4H), 1.91 (m, 2H); MS-ESIm/z289 (M+H)
+.
Embodiment 614-(3-(4-chloro-quinazoline-7-base oxygen) propyl group) morpholine hydrochloride (Q2)
By Q2T (1.4g, 4.8mmol), sulfur oxychloride (22mL) and dry DMF (0.35g, 4.8mmol) return stirring 2h, be chilled to room temperature, add toluene and revolve steaming band residual chloride sulfoxide to the greatest extent.Gained residue Virahol (10mL) is pulled an oar 2h, and suction filtration, vacuum-drying obtain yellow solid Q2 (1.51g, 92%).
Embodiment 621-(the chloro-4-fluorophenyl of 3-)-3-(3-(7-(morpholinyl propoxy-) quinazoline-4-base amido) phenyl) urea (D4-1)
By Q2 (0.34g, 1mmol), J-1 (0.35g, 1.25mmol), Virahol (8mL) and hydrogenchloride Virahol saturated solution (2mL) return stirring 4h, be chilled to room temperature, revolve steaming.Add water in gained residue (10mL), adjust pH to 9 ~ 10. with 1mol/L aqueous sodium hydroxide solution, extract with methylene chloride-methanol (v/v, 3: 1).United extraction liquid, revolves steaming after washing, anhydrous sodium sulfate drying.By gained residue silica gel column chromatography twice, by ethyl acetate: ethanol: triethylamine (90: 10: 0.5) wash-out obtains yellow solid D4-1 (0.06g, 11%):
1hNMR (DMSO-d
6) δ 9.60 (s, 1H), 8.80 (s, 1H), 8.74 (s, 1H), 8.52 (s, 1H), 8.49 (d, J=9.2Hz, 1H), 7.99 (s, 1H), 7.81-7.82 (m, 1H), 7.49 (d, J=8.0Hz, 1H), 7.22-7.33 (m, 5H), 7.17 (d, J=2.4Hz, 1H), 4.20 (t, J=6.4Hz, 2H), (3.59 m, 4H), 2.46-2.47 (m, 2H), 2.40 (t, J=4.4Hz, 4H), 1.95 (m, 2H); MS-ESIm/z601 (M+H)
+.
Embodiment 631-(the chloro-3-of 4-(trifluoromethyl) phenyl)-3-(3-(7-(morpholinyl propoxy-) quinazoline-4-base amido) phenyl) urea (D4-3)
Replace J-1 with J-3, adopt the method being similar to D4-1 to prepare D4-3, obtain Light yellow crystals (yield 13%):
1hNMR (DMSO-d
6) δ 9.61 (s, 1H), 9.12 (s, 1H), 8.85 (s, 1H), 8.52 (s, 1H), 8.48 (d, J=9.6Hz, 1H), 8.13 (d, J=2.0Hz, 1H), 8.01 (m, 1H), 7.61-7.62 (m, 2H), 7.53 (d, J=8.0Hz, 1H), 7.28 (t, J=8.0Hz, 1H), 7.21-7.24 (m, 2H), 7.17 (d, J=2.4Hz, 1H), 4.20 (t, J=6.4Hz, 2H), 3.60 (m, 4H), 2.49 (m, 2H), 2.42 (m, 4H), 1.95-1.98 (m, 2H), MS-ESIm/z601 (M+H)
+.
Embodiment 641-(4-(7-(morpholinyl propoxy-) quinazoline-4-base amido) phenyl)-3-(4-(pyrrolidin-1-yl) butyl) urea (D3-18)
Replace J-1 with P-18, adopt the method being similar to D4-1 to prepare D3-18, obtain near-white solid (yield 11%):
1hNMR (DMSO-d
6) δ 9.48 (s, 1H), 8.43 (s, 1H), 8.40 (d, J=9.2Hz, 1H), 8.30 (s, 1H), 7.61 (d, J=8.8Hz, 2H), 7.37 (d, J=8.8Hz, 2H), 7.19 (dd, J=2.4, 9.2Hz, 1H), 7.12 (d, J=2.4Hz, 1H), 6.06 (m, 1H), 4.18 (t, J=6.4Hz, 2H), 3.58 (t, J=4.8Hz, 4H), 3.09 (m, 2H), 2.39 (m, 12H), 1.94 (m, 2H), 1.66 (m, 4H), 1.46 (m, 4H), MS-ESIm/z548 (M+H)
+.
Embodiment 651-(3-(7-(morpholinyl propoxy-) quinazoline-4-base amido) phenyl)-3-(4-(pyrrolidin-1-yl) butyl) urea (D4-18)
Replace J-1 with J-18, adopt the method being similar to D4-1 to prepare D4-18, obtain light yellow solid (yield 7%):
1hNMR (DMSO-d
6) δ 9.54 (s, 1H), 8.49 (s, 1H), 8.47 (d, J=8.8Hz, 1H), 8.37 (s, 1H), 7.88 (s, 1H), 7.37 (d, J=7.6Hz, 1H), 7.16-7.23 (m, 4H), 6.10 (m, 1H), 4.20 (t, J=6.4Hz, 2H), (3.59 m, 4H), 3.09 (m, 2H), 2.40 (m, 12H), (1.95 m, 2H), 1.67 (m, 4H), 1.47 (m, 4H); MS-ESIm/z548 (M+H)
+.
Embodiment 667-(3-(4-methylpiperazine-1-yl) propoxy-) quinazoline-4 (3H)-one (Q3T)
(a) 3-(4-methylpiperazine-1-yl) third-1-alcohol
Under a nitrogen, methylpiperazine (31.6g, 0.32mol) is dissolved in toluene (150mL), drips 3-bromopropyl alcohol (20.8g, 0.15mol) in room temperature.80 DEG C of insulated and stirred 2h are risen to after dripping off.Be chilled to room temperature, filter gained suspension liquid, filter cake toluene wash.Merge diafiltration liquid and revolve steaming, underpressure distillation gained residue, collect bp100 DEG C/1mmHg cut, obtain light yellow oil (18.27g, 77%):
1h-NMR (DMSO-d
6) δ 4.80 (brs, 1H), 3.75 (t, J=5.6Hz, 2H), 2.57 (td, J=6.0,2.4Hz, 2H), 2.53 (m, 4H), 2.42 (m, 4H), 2.25 (s, 3H), 1.66-1.71 (m, 2H).
(b) 7-(3-(4-methylpiperazine-1-yl) propoxy-) quinazoline-4 (3H)-one (Q3T)
Replace morpholinyl third-1-alcohol with 3-(4-methylpiperazine-1-yl) third-1-alcohol, adopt the method being similar to Q2T to prepare Q3T, obtain Light yellow crystals (1.78g, 40%):
1h-NMR (DMSO-d
6) δ 11.99 (brs, 1H), 8.00-8.02 (m, 2H), 7.07-7.10 (m, 2H), 4.14 (t, J=6.4Hz, 2H), 2.43 (t, J=6.8Hz, 2H), 2.38 (m, 4H), (2.31 m, 4H), 2.15 (s, 3H), 1.36 (m, 2H).
The chloro-7-of embodiment 674-(3-(4-methylpiperazine-1-yl) propoxy-) quinazoline hydrochloride (Q3)
Replace Q2T with Q3T, adopt the method being similar to Q2 to prepare Q3, obtain khaki color solid (yield 100%).
Embodiment 681-(the chloro-4-fluorophenyl of 3-)-3-(3-(7-(3-(4-methylpiperazine-1-yl) propoxy-) quinazoline-4-base amido) phenyl) urea (D8-1)
Replace Q2 with Q3, adopt the method being similar to D4-1 to prepare D8-1, obtain near-white solid (yield 11%):
1h-NMR (DMSO-d
6) δ 9.59 (s, 1H), 8.82 (s, 1H), 8.75 (s, 1H), 8.46-8.51 (m, 2H), 7.98 (s, 1H), 7.81 (d, J=7.2Hz, 1H), 7.48 (d, J=7.2Hz, 1H), 7.15-7.32 (m, 6H), 4.18 (m, 2H), 2.39 (m, 10H), 2.18 (s, 3H), 1.92-1.97 (m, 2H); MS-ESIm/z564 (M+H)
+.
Embodiment 691-(the chloro-3-of 4-(trifluoromethyl) phenyl)-3-(3-(7-(3-(4-methylpiperazine-1-yl) propoxy-) quinazoline-4-base amido) phenyl) urea (D8-3)
Replace Q2 with Q3, replace J-1 with J-3, adopt the method being similar to D4-1 to prepare D8-3, obtain light gray solid (yield 8%):
1h-NMR (DMSO-d
6) δ 9.62 (s, 1H), 9.31 (s, 1H), 8.98 (s, 1H), 8.48-8.51 (m, 2H), 8.14 (m, 1H), 7.99 (s, 1H), 7.53-7.62 (m, 3H), 7.15-7.30 (m, 4H), 4.19 (t, J=6.4Hz, 2H), 2.40 (m, 10H), 2.19 (s, 3H), 1.92-1.96 (m, 2H); MS-ESIm/z614 (M+H)
+.
Embodiment 701-(3-(7-(3-(4-methylpiperazine-1-yl) propoxy-) quinazoline-4-base amido) phenyl)-3-(4-(pyrrolidin-1-yl) butyl) urea (D8-18)
Replace Q2 with Q3, replace J-1 with J-18, adopt the method being similar to D4-1 to prepare D8-18, obtain near-white solid (yield 10%):
1h-NMR (DMSO-d
6) δ 9.76 (s, 1H), 8.70 (s, 1H), 8.45-8.56 (m, 3H), 7.86 (m, 2H), (7.54 d, J=9.6Hz, 1H), (7.14-7.34 m, 5H), 6.43 (m, 1H), 4.32 (t, J=6.0Hz, 2H), 2.40 (m, 14H), (2.32 m, 4H), 2.14 (s, 3H), 1.95 (m, 2H), (1.66 m, 3H), 1.59 (m, 2H), 1.46 (m, 3H); MS-ESIm/z561 (M+H)
+.
Embodiment 717-((1-methyl piperidine-4-base) methoxyl group) quinazoline-4 (3H)-one (Q4T)
With (1-methyl piperidine-4-base) methyl alcohol) replace morpholinyl third-1-alcohol, adopt the method being similar to Q2T to prepare Q4T, obtain near-white crystallization (yield 40%):
1h-NMR (DMSO-d
6) δ 12.00 (brs, 1H), 7.99-8.02 (m, 2H), 7.07-7.09 (m, 2H), 3.97 (d, J=5.6Hz, 2H), 2.81 (d, J=11.6Hz, 2H), (2.19 s, 3H), 1.93 (t, J=11.6Hz, 2H), 1.74-1.76 (m, 3H), 1.36 (m, 2H); MS-ESI:m/z274 (M+H)
+.
The chloro-7-of embodiment 724-((1-methyl piperidine-4-base) methoxyl group) quinazoline hydrochloride (Q4)
Replace Q2T with Q4T, adopt the method being similar to Q2 to prepare Q4, obtain khaki color solid (yield 100%).
Embodiment 731-(the chloro-4-fluorophenyl of 3-)-3-(3-(7-((1-methyl piperidine-4-base) methoxyl group) quinazoline-4-base amido) phenyl) urea (D10-1)
Replace Q2 with Q4, adopt the method being similar to D4-1 to prepare D10-1, obtain near-white solid (yield 7%):
1h-NMR (DMSO-d
6) δ 9.59 (s, 1H), 8.80 (s, 1H), 8.74 (s, 1H), 8.51 (s, 1H), (8.48 d, J=8.8Hz, 1H), 7.98 (s, 1H), 7.81 (d, J=6.8Hz, 1H), (7.48 d, J=7.2Hz, 1H), 7.22-7.32 (m, 5H), 7.15 (s, 1H), 4.01 (d, J=5.2Hz, 2H), 2.79 (d, J=10.4Hz, 2H), 2.16 (s, 3H), 1.89 (t, J=11.2Hz, 2H), 1.76-1.78 (m, 3H), 1.37 (m, 2H); MS-ESI:m/z535 (M+H)
+.
Embodiment 741-(the chloro-3-of 4-(trifluoromethyl) phenyl)-3-(3-(7-((1-methyl piperidine-4-base) methoxyl group) quinazoline-4-base amido) phenyl) urea (D10-3)
Replace Q2 with Q4, replace J-1 with J-3, adopt the method being similar to D4-1 to prepare D10-3, obtain near-white solid (yield 14%):
1h-NMR (DMSO-d
6) δ 9.61 (s, 1H), 9.09 (s, 1H), 8.83 (s, 1H), 8.52 (s, 1H), 8.48 (d, J=9.6Hz, 1H), 8.13 (d, J=1.2Hz, 1H), 8.01 (s, 1H), 7.61 (m, 2H), 7.53 (d, J=7.6Hz, 1H), 7.28 (t, J=8.0Hz, 1H), 7.22-7.25 (m, 2H), 7.16 (d, J=2.4Hz, 1H), 4.01 (d, J=5.6Hz, 2H), 2.80 (d, J=11.2Hz, 2H), 2.17 (s, 3H), 1.89 (t, J=11.2Hz, 2H), 1.76-1.79 (m, 3H), 1.38 (m, 2H), MS-ESI:m/z585 (M+H)
+.
Embodiment 751-(3-fluorophenyl)-3-(3-(7-((1-methyl piperidine-4-base) methoxyl group) quinazoline-4-base amido) phenyl) urea (D10-9)
Replace Q2 with Q4, replace J-1 with J-9, adopt the method being similar to D4-1 to prepare D10-9, obtain near-white solid (yield 7%):
1h-NMR (DMSO-d
6) δ 9.68 (s, 1H), 9.21 (s, 1H), 9.02 (s, 1H), (8.52-8.54 m, 2H), 7.98 (s, 1H), 7.49-7.53 (m, 2H), (7.12-7.33 m, 6H), 6.77-6.79 (m, 1H), 4.10 (m, 2H), (2.99 m, 2H), 2.75 (s, 3H), 2.11 (m, 2H), 2.00 (m, 3H), 1.65 (m, 2H); MS-ESIm/z501 (M+H)
+.
Embodiment 761-(3-(6,7-bis-(2-methoxy ethoxy) quinazoline-4-base amido) phenyl)-3-(the chloro-4-fluorophenyl of 3-) urea (D6-1)
By Q5 (0.31g, 1mmol), J-1 (0.35g, 1.25mmol), Virahol (5mL) and hydrogenchloride Virahol saturated solution (3mL) return stirring 4h.Revolve and steam gained reactant, add water in gained residue (10mL), adjust pH to 9 ~ 10. with 1mol/L aqueous sodium hydroxide solution, extract with methylene chloride-methanol (v/v, 3: 1).United extraction liquid, revolves steaming after washing, anhydrous sodium sulfate drying.By gained residue silica gel column chromatography, by ethyl acetate: ethanol: triethylamine (v/v, 200: 10: 0 ~ 70: 10: 1) gradient elution, finally use ethyl acetate: sherwood oil (v/v, 1: 8) pull an oar, filtration drying obtains light yellow solid D6-1 (0.25g, 45%):
1hNMR (DMSO-d
6) δ 9.41 (s, 1H), 8.81 (s, 1H), 8.75 (s, 1H), (8.45 s, 1H), 7.96 (s, 1H), 7.90 (s, 1H), (7.80-7.82 m, 1H), 7.44 (d, J=8.4Hz, 1H), 7.27-7.33 (m, 3H), 7.20-7.22 (m, 2H), (4.28-4.32 m, 4H), 3.75-3.80 (m, 4H), 3.38 (s, 3H), 3.36 (s, 3H); MS-ESIm/z556 (M+H)
+.
Embodiment 771-(3-(6,7-bis-(2-methoxy ethoxy) quinazoline-4-base amido) phenyl)-3-(the chloro-3-of 4-(trifluoromethyl) phenyl) urea (D6-3)
Replace J-1 with J-3, adopt the method being similar to D6-1 to prepare D6-3, obtain near-white solid (yield 31%):
1h-NMR (DMSO-d
6) δ 9.41 (brs, 1H), 9.08 (s, 1H), 8.83 (s, 1H), 8.45 (s, 1H), 8.13 (d, J=2.0Hz, 1H), 7.98 (s, 1H), 7.90 (s, 1H), (7.59-7.63 m, 2H), 7.47 (d, J=8.0Hz, 1H), 7.30 (t, J=8.4Hz, 1H), 7.21 (m, 2H), 4.28-4.32 (m, 4H), (3.75-3.80 m, 4H), 3.39 (s, 3H), 3.38 (s, 3H); MS-ESIm/z606 (M+H)
+.
Embodiment 781-(3-(6,7-bis-(2-methoxy ethoxy) quinazoline-4-base amido) phenyl)-3-(3-fluorophenyl) urea (D6-9)
Replace J-1 with J-9, adopt the method being similar to D6-1 to prepare D6-9, obtain near-white solid (yield 31%):
1h-NMR (DMSO-d
6) δ 9.41 (s, 1H), 8.84 (s, 1H), 8.74 (s, 1H), 8.45 (s, 1H), 7.97 (s, 1H), 7.90 (s, 1H), (7.43-7.51 m, 2H), 7.27-7.33 (m, 2H), 7.20-7.21 (m, 2H), (7.13 d, J=7.6Hz, 1H), 6.78 (dt, J=2.4,8.8Hz, 1H), 4.28 (m, 4H), (3.76 m, 4H), 3.38 (s, 3H), 3.36 (s, 3H); MS-ESI:m/z522 (M+H)
+.
Embodiment 791-(4-(6,7-bis-(2-methoxy ethoxy) quinazoline-4-base amido) phenyl)-3-(4-(pyrrolidin-1-yl) butyl) urea (D5-18)
Replace J-1 with P-18, adopt the method being similar to D6-1 to prepare D5-18, obtain near-white solid (yield 24%):
1h-NMR (DMSO-d
6) δ 9.29 (s, 1H), 8.38 (s, 1H), 8.31 (s, 1H), 7.85 (s, 1H), (7.58 d, J=8.8Hz, 2H), 7.39 (d, J=8.8Hz, 2H), 7.18 (s, 1H), (6.07 t, J=5.6Hz, 1H), 4.28 (t, J=4.8Hz, 4H), 3.74-3.79 (m, 4H), (3.37 s, 3H), 3.36 (s, 3H), 3.10 (m, 2H), (2.41 m, 6H), 1.66 (m, 4H), 1.46 (m, 4H); MS-ESIm/z553 (M+H)
+.
Embodiment 801-(3-(6,7-bis-(2-methoxy ethoxy) quinazoline-4-base amido) phenyl)-3-(4-(pyrrolidin-1-yl) butyl) urea (D6-18)
Replace J-1 with J-18, adopt the method being similar to D6-1 to prepare D6-18, obtain yellow solid (yield 27%):
1h-NMR (DMSO-d
6) δ 9.34 (s, 1H), 8.43 (s, 1H), 8.37 (s, 1H), 7.85-7.89 (m, 2H), 7.31-7.34 (m, 1H), 7.18-7.23 (m, 2H), (7.13-7.15 m, 1H), 6.09 (t, J=5.6Hz, 1H), 4.27-4.31 (m, 4H), 3.74-3.79 (m, 4H), (3.37 s, 3H), 3.36 (s, 3H), 3.10 (m, 2H), (2.40 m, 6H), 1.67 (m, 4H), 1.47 (m, 4H); MS-ESIm/z553 (M+H)
+.
The synthesis of If series compound
Embodiment 817-(3-hydroxy propyloxy group) quinazoline-4 (3H)-one (7)
By 1 in 100mL three-necked bottle, ammediol (13.9g, 183mmol) be dissolved in DMF (20mL), be chilled to 0 DEG C and drop into 60% sodium hydride (7.3g in batches, 183mmol), then add 7-fluquinconazole quinoline-4 (3H)-one (5g, 30.5mmol) in batches, rise to 50 DEG C and 90 DEG C of each insulated and stirred 1h, then rise to 120 DEG C of insulated and stirred 3h.Gained reactant is chilled to 25 DEG C, and the mixture of ice and water (280mL) under impouring stirring, adjusts pH to 6 with concentrated hydrochloric acid, the solid that filter collection is separated out.Filter cake uses water and washed with diethylether successively, and vacuum-drying (50 DEG C, 6h) obtains brown solid 7 (6.27g, 93%):
1h-NMR (DMSO-d
6) δ 11.94 (brs, 1H), 7.96 (m, 2H), (7.04 dd, J=2.4,6.0Hz, 2H), 4.48 (t, J=5.2Hz, 1H), 4.13 (t, J=6.4Hz, 2H), 3.53 (dd, J=6.0,11.2Hz, 2H), 1.86 (m, 2H).
The chloro-7-of embodiment 824-(3-chlorine propoxy-) quinazoline (8)
By 7-(3-hydroxy propyloxy group) quinazoline-4 (3H)-one (7) (6g, 27mmol), sulfur oxychloride (60mL) and DMF (0.57g, 7.8mmol) return stirring 2h.Be chilled to room temperature, revolve with toluene and steam band sulfur oxychloride to the greatest extent.Dissolve gained residue with methylene dichloride (80mL), with saturated sodium bicarbonate aqueous solution washing, then carry with methylene dichloride is counter.Merge organic layer, add anhydrous sodium sulphate and gac stirring, after filtration, revolve steaming.In gained residue, add ether, the solid of filtering precipitation, revolve and steam near dry, filter after adding sherwood oil, vacuum-drying (50 DEG C, 2.5h) obtains Tan solid 8 (4.49g, 64%):
1hNMR (DMSO-d
6) δ 8.97 (s, 1H), 8.18 (d, J=8.8Hz, 1H), 7.48-7.51 (m, 2H), 4.36 (t, J=6.0Hz, 2H), 3.83 (t, J=6.4Hz, 2H), 2.27 (m, 2H).
Embodiment 831-(the chloro-3-of 4-(trifluoromethyl) phenyl)-3-(3-(7-(3-chlorine propoxy-) quinazoline-4-base amido) phenyl) urea (D52-3-0)
By chloro-for 4-7-(3-chlorine propoxy-) quinazoline (8) (0.55g, 2mmol), J-3 (0.66g, 2mmol), Virahol (9mL) and hydrogenchloride Virahol saturated solution (2mL) return stirring 3h.Be chilled to room temperature, adjust pH to 6 ~ 7 with 1mol/L aqueous sodium hydroxide solution.With methyl alcohol: methylene dichloride (3: 1) and methylene dichloride extract successively, merge organic layer, after salt water washing, anhydrous sodium sulfate drying, revolve steaming.Crystallization gained residue in methyl alcohol, filters, and vacuum-drying (50 DEG C, 6h) obtains near-white flake-like crystal (0.83g, 75%):
1hNMR (DMSO-d
6) δ 10.87 (brs, 1H), 9.49 (s, 1H), 9.20 (s, 1H), 8.76 (s, 1H), 8.65 (d, J=9.2Hz, 1H), 8.14 (d, J=1.6Hz, 1H), 7.96 (s, 1H), 7.62 (m, 2H), 7.44 (dd, J=2.4,9.2Hz, 2H), 7.36 (t, J=8.0Hz, 1H), 7.25-7.30 (m, 2H), 4.33 (t, J=6.4Hz, 2H), 3.85 (t, J=6.4Hz, 2H), 2.29 (dd, J=6.4,12.4Hz, 2H); MS-ESIm/z550 (M+H)
+.
Embodiment 841-(the chloro-4-fluorophenyl of 3-)-3-(3-(7-(3-chlorine propoxy-) quinazoline-4-base amido) phenyl) urea (D52-1-0)
Replace J-3 with J-1, adopt the method being similar to D52-3-0 to prepare D52-1-0, obtain near-white solid (yield 60%):
1hNMR (DMSO-d
6) δ 9.70 (brs, 1H), 8.84 (s, 1H), 8.76 (s, 1H), 8.55 (s, 1H), 8.52 (d, J=9.2Hz, 1H), 8.00 (s, 1H), 7.81-7.83 (m, 1H), 7.49 (d, J=8.0Hz, 1H), 7.20-7.36 (m, 6H), 4.30 (m, 2H), 3.87 (t, J=6.8Hz, 2H), 2.27 (m, 2H); MS-ESIm/z500 (M+H)
+.
Embodiment 851-(3-(7-(3-chlorine propoxy-) quinazoline-4-base amido) phenyl)-3-(3-fluorophenyl) urea (D52-9-0)
Replace J-3 with J-9, adopt the method being similar to D52-3-0 to prepare D52-9-0, obtain near-white solid (yield 48%):
1hNMR (DMSO-d
6) δ 11.22 (brs, 1H), 9.28 (s, 1H), 9.21 (s, 1H), (8.85 s, 1H), 8.71 (d, J=9.6Hz, 1H), 7.92 (s, 1H), 7.48-7.52 (m, 2H), (7.27-7.41 m, 4H), 7.11-7.14 (m, 1H), 6.77 (dt, J=2.4,8.8Hz, 1H), 4.34 (m, 2H), 3.85 (t, J=6.4Hz, 2H), 2.22 (m, 2H); MS-ESIm/z466 (M+H)
+.
Embodiment 861-(3-(7-(3-chlorine propoxy-) quinazoline-4-base amido) phenyl)-3-(4-(pyrrolidin-1-yl) butyl) urea (D52-18-0)
Replace J-3 with J-18, adopt the method being similar to D52-3-0 to prepare D52-18-0, obtain colorless needles (yield 16%):
1hNMR (DMSO-d
6) δ 9.60 (s, 1H), 8.64 (s, 1H), (8.49 m, 2H), 7.87 (s, 1H), 7.34-7.37 (m, 1H), (7.18-7.25 m, 4H), 6.37 (t, J=5.6Hz, 1H), 4.28 (t, J=5.6Hz, 2H), 3.83 (t, J=6.4Hz, 2H), 3.12 (m, 8H), 2.23-2.28 (m, 2H), (1.93 m, 4H), 1.65-1.71 (m, 2H), 1.48-1.53 (m, 2H); MS-ESIm/z519 (M+H)
+.
Embodiment 871-(the chloro-3-of 4-(trifluoromethyl) phenyl)-3-(3-(7-(3-(4-(2-hydroxyethyl) piperazine-1-base) propoxy-) quinazoline-4-base amido) phenyl) urea (D52-3-1)
By D52-3-0 (0.15g, 0.28mmol), potassiumiodide (0.09g, 0.56mmol), 32h is stirred in 2-(piperazine-1-base) ethanol (0.15g, 1.12mmol) and N-Methyl pyrrolidone (NMP) (2mL) 50 DEG C of shadings.Be chilled to room temperature, by direct for gained reactant loading silica gel column chromatography, by ethyl acetate: ethanol: triethylamine gradient wash-out (300: 100: 1.5 ~ 100: 100: 1.5), finally by methyl alcohol: ethyl acetate (6: 1) recrystallization, vacuum-drying (50 DEG C, 6h) obtain light yellow solid (0.07g, 39%):
1hNMR (DMSO-d
6) δ 11.40 (brs, 1H), 9.81 (s, 1H), 9.54 (s, 1H), 8.86 (s, 1H), 8.74 (d, J=8.8Hz, 1H), 8.15 (s, 1H), 7.93 (s, 1H), 7.60 (dd, J=8.8,22.4Hz, 2H), 7.49 (d, J=9.2Hz, 1H), (7.33-7.41 m, 4H), 4.34 (m, 2H), 3.66-3.81 (m, 10H), (3.40 m, 2H), 3.33 (m, 2H), 2.30 (m, 2H); MS-ESIm/z644 (M+H)
+.
Embodiment 881-(the chloro-4-fluorophenyl of 3-)-3-(3-(7-(3-(4-(2-hydroxyethyl) piperazine-1-base) propoxy-) quinazoline-4-base amido) phenyl) urea (D52-1-1)
Replace D52-3-0 with D52-1-0, adopt the method being similar to D52-3-1 to prepare D52-1-1, obtain khaki color solid (yield 41%):
1h-NMR (DMSO-d
6) δ 9.69 (s, 1H), 9.18 (s, 1H), 9.00 (s, 1H), (8.53 s, 1H), 8.51 (d, J=10.0Hz, 1H), 7.97 (s, 1H), 7.80-7.82 (m, 1H), 7.51 (d, J=8.0Hz, 1H), (7.19-7.33 m, 6H), 4.23 (m, 2H), 3.55-3.71 (m, 10H), (3.31 m, 2H), 3.22 (m, 2H), 1.99 (m, 2H); MS-ESIm/z594 (M+H)
+.
Embodiment 891-(3-fluorophenyl)-3-(3-(7-(3-(4-(2-hydroxyethyl) piperazine-1-base) propoxy-) quinazoline-4-base amido) phenyl) urea (D52-9-1)
Replace D52-3-0 with D52-9-0, adopt the method being similar to D52-3-1 to prepare D52-9-1, obtain yellow crystal (yield 19%):
1h-NMR (DMSO-d
6) δ 10.59 (brs, 1H), 9.34 (s, 1H), 9.20 (s, 1H), 8.71 (s, 1H), 8.65 (d, J=9.2Hz, 1H), 7.94 (s, 1H), 7.27-7.51 (m, 7H), 7.13 (d, J=8.0Hz, 1H), 6.78 (t, J=8.4Hz, 1H), 5.09 (brs, 1H), 4.27 (t, J=6.4Hz, 2H), 3.73 (m, 2H), (3.31 m, 8H), 3.18 (t, J=5.2Hz, 2H), 2.91 (m, 2H), 2.10 (m, 2H); MS-ESIm/z560 (M+H)
+.
Embodiment 901-(3-(7-(3-(4-(2-hydroxyethyl) piperazine-1-base) propoxy-) quinazoline-4-base amido) phenyl)-3-(4-(pyrrolidin-1-yl) butyl) urea (D52-18-1)
Replace D52-3-0 with D52-18-0, adopt the method being similar to D52-3-1 to prepare D52-18-1, obtain light yellow solid (yield 12%):
1h-NMR (DMSO-d
6) δ: 9.66 (s, 1H), 9.02 (s, 1H), 8.54 (d, J=9.2Hz, 1H), 8.46 (s, 1H), 7.83 (s, 1H), 7.39 (d, J=6.4Hz, 1H), 7.13-7.18 (m, 4H), 6.74 (m, 1H), 4.47 (brs, 1H), 4.18 (t, J=6.0Hz, 2H), 3.93 (m, 2H), 3.63 (m, 8H), 3.33-3.53 (m, 6H), 2.98-3.14 (m, 6H), (1.81-1.95 m, 6H), 1.63 (m, 2H), 1.46 (m, 2H); MS-ESIm/z519 (M+H)
+.
Embodiment 911-(3-(7-(3-(ethyl (2-hydroxyethyl) amido) propoxy-) quinazoline-4-base amido) phenyl)-3-(3-fluorophenyl) urea (D52-9-4)
30h is stirred in D52-9-0 (0.13g, 0.28mmol), potassiumiodide (0.09g, 0.56mmol), 2-(ethylamino-) ethanol (0.1g, 1.12mmol) and NMP (1mL) 50 DEG C of shadings.Be chilled to room temperature, revolve steaming.By gained residue loading silica gel column chromatography, by ethyl acetate: ethanol: triethylamine gradient wash-out (900: 100: 1 ~ 300: 100: 1), finally by dehydrated alcohol: re-crystallizing in ethyl acetate, vacuum-drying obtain light yellow solid (0.05g, 34%):
1h-NMR (DMSO-d
6) δ 9.66 (s, 1H), 8.92 (s, 1H), 8.79 (s, 1H), 8.50-8.53 (m, 2H), 8.01 (s, 1H), 7.50 (dd, J=0.8,9.6Hz, 2H), 7.11-7.33 (m, 6H), 6.78 (dt, J=2.4,8.4Hz, 1H), 5.30 (brs, 1H), 4.27 (t, J=5.6Hz, 2H), (3.76 m, 2H), 3.18-3.30 (m, 6H), 2.21 (m, 2H), 1.25 (t, J=6.8Hz, 3H); MS-ESIm/z519 (M+H)
+.
Embodiment 921-(the chloro-4-fluorophenyl of 3-)-3-(3-(7-(3-(ethyl (2-hydroxyethyl) amido) propoxy-) quinazoline-4-base amido) phenyl) urea (D52-1-4)
Replace D52-9-0 with D52-1-0, adopt the method being similar to D52-9-4 to prepare D52-1-4, obtain white solid (yield 20%):
1h-NMR (DMSO-d
6) δ 9.65 (s, 1H), 8.91 (s, 1H), (8.82 s, 1H), 8.50-8.53 (m, 2H), 8.00 (s, 1H), (7.80-7.82 m, 1H), 7.50 (d, J=8.4Hz, 1H), 7.19-7.35 (m, 6H), 5.30 (brs, 1H), (4.27 t, J=5.6Hz, 2H), (3.76 m, 2H), 3.20-3.29 (m, 6H), 2.20 (m, 2H), (1.25 t, J=6.8Hz, 3H); MS-ESIm/z553 (M+H)
+.
Embodiment 931-(the chloro-3-of 4-(trifluoromethyl) phenyl)-3-(3-(7-(3-(ethyl (2-hydroxyethyl) amido) propoxy-) quinazoline-4-base amido) phenyl) urea (D52-3-4)
Replace D52-9-0 with D52-3-0, adopt the method being similar to D52-9-4 to prepare D52-3-4, obtain buff powder (yield 82%):
1h-NMR (DMSO-d
6) δ: 9.73 (s, 1H), 9.20 (s, 1H), 8.91 (s, 1H), 8.55 (s, 1H), 8.53 (d, J=9.2Hz, 1H), 8.14 (s, 1H), 8.02 (s, 1H), 7.61 (m, 2H), 7.53 (d, J=8.4Hz, 1H), 7.19-7.32 (m, 4H), 5.32 (brs, 1H), 4.27 (t, J=6.4Hz, 2H), 3.77 (m, 2H), 3.30 (m, 2H), 3.21 (m, 4H), 2.21 (t, J=7.2Hz, 2H), 1.26 (t, J=7.2Hz, 3H), MS-ESIm/z603 (M+H)
+.
Embodiment 941-(3-(7-(3-(ethyl (2-hydroxyethyl) amido) propoxy-) quinazoline-4-base amido) phenyl)-3-(4-(pyrrolidin-1-yl) butyl) urea (D52-18-4)
Replace D52-9-0 with D52-18-0, adopt the method being similar to D52-9-4 to prepare D52-18-4, give light yellow oil (yield 60%):
1h-NMR (DMSO-d
6) δ 9.66 (s, 1H), 9.02 (s, 1H), 8.54 (d, J=9.2Hz, 1H), 8.46 (s, 1H), 7.83 (s, 1H), 7.39 (d, J=6.4Hz, 1H), 7.13-7.18 (m, 4H), 6.74 (m, 1H), 4.47 (brs, 1H), 4.18 (t, J=6.0Hz, 2H), 3.93 (m, 2H), 3.63 (m, 8H), 3.33-3.53 (m, 6H), 2.98-3.14 (m, 6H), 1.81-1.95 (m, 6H), 1.63 (m, 2H), 1.46 (m, 2H): MS-ESIm/z519 (M+H)
+.
Embodiment 951-(3-fluorophenyl)-3-(3-(7-(3-(2-hydroxyethyl amido) propoxy-) quinazoline-4-base amido) phenyl) urea (D52-9-5)
By D52-9-0 (0.13g, 0.28mmol), potassiumiodide (0.09g, 0.56mmol), 32h is stirred in thanomin (0.07g, 1.12mmol) and N-Methyl pyrrolidone (NMP) (1mL) 50 DEG C of shadings.Revolve steaming reactant, in gained residue, add water, with methylene dichloride: methyl alcohol (3: 1) extracts.United extraction liquid, revolves steaming.Gained residue is through preparing silica gel thin-layer chromatography (ethyl acetate: ethanol: triethylamine, 300: 100: 1) purifying, and vacuum-drying obtains near-white crystalline solid (yield 29%):
1h-NMR (DMSO-d
6) δ 9.72 (brs, 1H), 9.67 (s, 1H), 9.41 (brs, 1H), 8.50-8.53 (m, 2H), (7.92 s, 1H), 7.49-7.55 (m, 2H), 7.12-7.31 (m, 6H), 6.75 (t, J=8.4Hz, 1H), (4.44 brs, 1H), 4.21 (t, J=6.4Hz, 2H), 3.48 (m, 2H), 2.73 (t, J=6.8Hz, 2H), 2.62 (t, J=5.6Hz, 2H), 1.93 (m, 2H); MS-ESIm/z491 (M+H)
+.
Embodiment 961-(the chloro-3-of 4-(trifluoromethyl) phenyl)-3-(3-(7-(3-(2-hydroxyethyl amido) propoxy-) quinazoline-4-base amido) phenyl) urea (D52-3-5)
Replace D52-9-0 with D52-3-0, adopt the method being similar to D52-9-5 to prepare D52-3-5, obtain near-white solid (yield 38%):
1h-NMR (DMSO-d
6) δ 10.14 (brs, 2H), 9.66 (brs, 1H), 9.56 (brs, 1H), (8.50 m, 2H), 8.14 (d, J=2.0Hz, 1H), 7.94 (s, 1H), 7.56-7.66 (m, 3H), (7.15-7.28 m, 4H), 4.21 (t, J=6.4Hz, 2H), 3.46 (m, 2H), 2.71 (m, 2H), (2.60 m, 2H), 1.91 (m, 2H), 1.65 (brs, 1H); MS-ESIm/z575 (M+H)
+.
The preparation of embodiment 971-(3-(7-(3-(ethyl (2-hydroxyethyl) amido) propoxy-) quinazoline-4-base amido) phenyl)-3-(5-methylisoxazole-3-base) urea (D52-20-4)
(a) N
1-(7-(3-chlorine propoxy-) quinazoline-4-base) benzene-1,3-diamines
Chloro-for 4-7-(3-chlorine propoxy-) quinazoline (8) (3.00g, 11.7mmol), m-nitraniline (1.61g, 11.7mmol) and DMF (25ml) are stirred 2h at 70 DEG C.Let cool, adjust pH to 9 with ammoniacal liquor, add water (80ml) stirs 30min afterwards.Filter, vacuum-drying (75 DEG C, 2.5h), obtains 7-(3-chlorine propoxy-)-N-(3-oil of mirbane) quinazoline-4-amine, is yellow solid (4.00g, yield 95%).
7-(3-chlorine propoxy-)-N-(3-oil of mirbane) quinazoline-4-amine (1.00g, 2.79mmol) is dissolved in ethanol (10ml), is heated to 50 DEG C, drip SnCl
2.2H
2the 6mol/L hydrochloric acid soln (6.6ml) of O (2.20g, 10mmol), backflow 1.5h.Let cool, regulate pH to 8 with 50% aqueous sodium hydroxide solution, add water (150ml) dilution, is extracted with ethyl acetate 3 times.Merge organic layer, successively with water, saturated sodium-chloride water solution washing, concentrating under reduced pressure after anhydrous sodium sulfate drying.Gained residue, through vacuum-drying (50 DEG C, 2h), obtains N
1-(7-(3-chlorine propoxy-) quinazoline-4-base) benzene-1,3-diamines, is faint yellow solid (0.86g, yield 94%).
(b) 1-(3-(7-(3-(ethyl (2-hydroxyethyl) amido) propoxy-) quinazoline-4-base amido) phenyl)-3-(5-methylisoxazole-3-base) urea (D52-20-4)
3-amino-5-methylisoxazole (0.47g, 4.8mmol) is dissolved in anhydrous methylene chloride (8ml), is added dropwise at 0 DEG C in anhydrous methylene chloride (2ml) solution of phenyl chloroformate (0.76g, 4.8mmol).Stirring at room temperature 2h, adularescent solid is separated out.Add triethylamine (0.49g, 4.8mmol), solution is clarified.Add N successively
1-(7-(3-chlorine propoxy-) quinazoline-4-base) benzene-1,3-diamines (1.00g, 3.0mmol), triethylamine (1.46g, 14.4mmol), backflow 3h.Be cooled to room temperature, under stirring, add water (7ml), 1mol/L aqueous sodium hydroxide solution (1ml).Divide and get organic layer, with saturated sodium-chloride water solution washing, then in ice bath, stir 3h.Filter, vacuum-drying (40 DEG C, 2h), obtain 1-(3-(7-(3-chlorine propoxy-) quinazoline-4-base amido) phenyl)-3-(5-methylisoxazole-3-base) urea (D52-20-0), for Off-white solid (0.74g, yield 54%).
By D52-20-0 (0.40g, 0.88mmol), potassiumiodide (0.29g, 1.7mmol), 2-ethylamino ethanol (0.31g, 3.5mmol) is dissolved in N-Methyl pyrrolidone (NMP) (5ml), and at 80 DEG C, lucifuge stirs 8h.Be cooled to room temperature, add water (50ml) and ethyl acetate (30ml), pull an oar at 70 DEG C 0.5h.Filtered while hot, filter cake vacuum-drying (80 DEG C, 4h), obtains faint yellow solid (0.20g, yield 45%): mp144-146 DEG C,
1h-NMR (DMSO-d
6) δ 9.63 (s, 1H), 9.37 (s, 1H), 8.86 (s, 1H), 8.51 (s, 1H), 8.46 (d, J=9.2Hz, 1H), 7.95 (s, 1H), 7.52 (d, J=8.0Hz, 1H), 7.30 (t, J=8.0Hz, 1H), 7.21-7.24 (m, 2H), 7.16 (d, J=2.0Hz, 1H), 6.52 (s, 1H), 4.35 (brs, 1H), 4.19 (t, J=6.4Hz, 2H), 3.43 (t, J=6.4Hz, 2H), 2.63 (t, J=6.4Hz, 2H), 2.55 (m, 4H), 2.36 (s, 3H), 1.90 (m, 2H), 0.97 (t, J=7.2Hz, 3H).
The synthesis of Ig series compound
The preparation of embodiment 981-(the chloro-3-of 4-(trifluoromethyl) phenyl)-3-(3-(6-(5-((2-(methylsulfonyl) ethylamino-) methyl) furans-2-base) quinazoline-4-base amido) phenyl) urea (L-3)
(a) 1-(the chloro-3-of 4-(trifluoromethyl) phenyl)-3-(3-(6-iodine quinazoline-4-base amido) phenyl) urea (L-3-3)
Under nitrogen protection, the stirring and refluxing 1h in toluene (10mL) by 2-amino-5-iodobenzene formonitrile HCN (1g, 4mmol) and DMF-DMA (1.93g, 16mmol), revolves after being chilled to room temperature and steams to obtain oily matter.Add J-3 (1.32g, 4mmol) and glacial acetic acid (10mL) stirring and refluxing 1h, revolve and steam to obtain brownish black oily matter.Add ethyl acetate and saturated sodium bicarbonate aqueous solution, point get organic layer after filtering, through anhydrous sodium sulfate drying, revolve and steam to obtain crude product, to pull an oar to obtain brown solid L-3-3 (0.53g, 23%) through silica gel column chromatography and dehydrated alcohol:
1hNMR (DMSO-d
6) δ 9.83 (s, 1H), 9.09 (s, 1H), 9.02 (s, 1H), 8.84 (s, 1H), 8.60 (s, 1H), 8.09-8.13 (m, 2H), 8.02 (s, 1H), 7.52-7.64 (m, 4H), 7.30 (t, J=8.0Hz, 1H), 7.23 (d, J=8.0Hz, 1H); MS-ESIm/z584 (M+H)
+.
(b) 1-(the chloro-3-of 4-(trifluoromethyl) phenyl)-3-(3-(6-(5-formylfuran-2-base) quinazoline-4-base amido) phenyl) urea (L-4-3)
L-3-3 (0.58g is dropped in reaction flask; 1mmol), 5-formylfuran-2-boric acid (0.21g; 1.5mmol), 7% palladium charcoal (dry powder; 0.1g), 1; 2-glycol dimethyl ether (DME) (10mL), methyl alcohol (5mL) and triethylamine (0.3g, 3mmol).Be warming up to 50 DEG C of insulated and stirred 16h.By diatomite suction filtration gained reactant while hot, revolve and steam filtrate.In gained residue, add ethyl acetate (90mL) and saturated sodium bicarbonate aqueous solution (10mL), divide after stirring and get organic layer.Organic layer is after saturated brine washing, anhydrous sodium sulfate drying, and revolve steaming, vacuum-drying obtains yellow orange solid L-4-3 (0.47g, 85%):
1hNMR (DMSO-d
6) δ 10.09 (s, 1H), 9.69 (s, 1H), 9.11 (s, 1H), 9.06 (s, 1H), 8.88 (s, 1H), 8.61 (s, 1H), 8.31 (dd, J=1.2, 8.8Hz, 1H), 8.14 (d, J=2.0Hz, 1H), 8.03 (s, 1H), 7.88 (d, J=8.8Hz, 1H), 7.74 (d, J=4.0Hz, 1H), 7.60-7.66 (m, 2H), 7.55 (d, J=8.4Hz, 1H), 7.42 (d, J=4.0Hz, 1H), 7.34 (t, J=8.0Hz, 1H), 7.25 (d, J=8.0Hz, 1H), MS-ESIm/z552 (M+H)
+.
(c) 1-(the chloro-3-of 4-(trifluoromethyl) phenyl)-3-(3-(6-(5-((2-(methylsulfonyl) ethylamino-) methyl) furans-2-base) quinazoline-4-base amido) phenyl) urea (L-3)
By L-4-3 (0.28g; 0.5mmol) be dissolved in anhydrous tetrahydro furan (4.4mL); add diisopropyl ethyl amine (DIEA) (0.13g; 1mmol), hydrochloric acid 2-(methylsulfonyl) ethamine (0.13g; 0.84mmol) with Virahol (0.08g); under nitrogen protection, stirring at room temperature 3h.Add after anhydrous tetrahydro furan (4.3mL) dilutes gained reactant, gradation adds sodium triacetoxy borohydride (0.2g, 0.95mmol), then stirring at room temperature 2h.Careful dropping 5mol/L aqueous sodium hydroxide solution (1.25mL) in gained reactant, then filter after stirring 10min.In filtrate, add ethyl acetate (60mL) and water (10mL), divide after stirring 15min and get organic layer.Organic layer is after saturated brine washing, anhydrous sodium sulfate drying, and revolve steaming, vacuum-drying obtains yellow L-3 crude product, obtains buff white solid L-3 (yield 24%) through silica gel column chromatography (ethyl acetate: dehydrated alcohol 100: 5 wash-out) purifying:
1h-NMR (DMSO-d
6) δ 9.88 (s, 1H), 9.11 (s, 1H), 8.86 (s, 1H), 8.80 (s, 1H), 8.56 (m, 1H), 8.14-8.17 (m, 2H), 8.04 (m, 1H), 7.81 (d, J=8.8Hz, 1H), 7.60-7.66 (m, 2H), 7.54 (d, J=7.6Hz, 1H), 7.33 (t, J=8.0Hz, 1H), 7.26 (d, J=8.0Hz, 1H), 7.06 (d, J=3.6Hz, 1H), 6.50 (d, J=3.2Hz, 1H), 3.86 (s, 2H), 3.26 (t, J=6.8Hz, 2H), 3.26 (m, 1H), 3.02 (s, 3H), 3.02 (t, J=6.8Hz, 2H), MS-ESIm/z659 (M+H)
+.
The preparation of embodiment 991-(the chloro-4-fluorophenyl of 3-)-3-(3-(6-(5-((2-(methylsulfonyl) ethylamino-) methyl) furans-2-base) quinazoline-4-base amido) phenyl) urea (L-1)
(a) 1-(the chloro-4-fluorophenyl of 3-)-3-(3-(6-iodine quinazoline-4-base amido) phenyl) urea hydrochloride (L-3-1)
Replace J-3 with J-1, adopt the method being similar to L-3-3 to prepare L-3-1, obtain Light yellow crystals (yield 37%):
1hNMR (DMSO-d
6) δ 9.83 (s, 1H), 9.03 (m, 1H), 8.81 (s, 1H), 8.76 (s, 1H), 8.61 (s, 1H), 8.11 (dd, J=2.0,8.8Hz, 1H), 8.01 (t, J=2.0Hz, 1H), 7.80-7.82 (m, 1H), 7.56 (d, J=8.4Hz, 1H), 7.50 (d, J=8.8Hz, 1H), 7.23-7.33 (m, 4H).
(b) 1-(the chloro-4-fluorophenyl of 3-)-3-(3-(6-(5-formylfuran-2-base) quinazoline-4-base amido) phenyl) urea (L-4-1)
Replace L-3-3 with L-3-1, adopt the method being similar to L-4-3 to prepare L-4-1, obtain orange crystallization (yield 71%):
1hNMR (DMSO-d
6) δ 10.10 (brs, 1H), 9.69 (s, 1H), 9.22 (brs, 1H), 9.17 (brs, 1H), 9.05 (s, 1H), 8.59 (s, 1H), (8.30 dd, J=0.9,8.8Hz, 1H), 7.99 (s, 1H), 7.87 (d, J=8.8Hz, 1H), 7.83 (dd, J=2.4,6.8Hz, 1H), 7.74 (d, J=4.0Hz, 1H), 7.48 (d, J=7.6Hz, 1H), 7.42 (d, J=4.0Hz, 1H), 7.26-7.36 (m, 4H); MS-ESIm/z552 (M+H)
+.
(c) 1-(the chloro-4-fluorophenyl of 3-)-3-(3-(6-(5-((2-(methylsulfonyl) ethylamino-) methyl) furans-2-base) quinazoline-4-base amido) phenyl) urea (L-1)
Replace L-4-3 with L-4-1, adopt the method being similar to L-3 to prepare L-1, obtain light orange look solid (yield 13%):
1hNMR (DMSO-d
6) δ 9.87 (s, 1H), 8.83 (s, 1H), 8.79 (m, 2H), 8.55 (s, 1H), (8.16 dd, J=2.0,8.8Hz, 1H), 8.01 (m, 1H), 7.80-7.82 (m, 2H), 7.50 (d, J=7.6Hz, 1H), 7.25-7.33 (m, 4H), 7.06 (d, J=3.2Hz, 1H), 6.49 (d, J=3.2Hz, 1H), 3.85 (s, 2H), 3.26 (t, J=6.8Hz, 2H), (3.26 m, 1H), 3.02 (m, 2H), 3.02 (s, 3H); MS-ESIm/z609 (M+H)
+.
The preparation of embodiment 1001-(3,5-bis-(trifluoromethyl) phenyl)-3-(3-(6-(5-formylfuran-2-base) quinazoline-4-base amido) phenyl) urea (L-14)
(a) 4-chloro-6-iodine quinazoline
6-iodine quinazoline-4-one (5.44g, 20mmol), Phosphorus Oxychloride (3.68g, 24mmol) and dry toluene (16mL) is dropped in reaction flask.Under nitrogen protection, triethylamine (2.43g, 24mmol) is dripped.77 DEG C of insulated and stirred 2.5h are risen to after dripping off.After gained reactant being chilled to 2 DEG C of stirring 1h, suction filtration.After filter cake washing with acetone, then at 1mol/L aqueous sodium hydroxide solution (26mL) middle room temperature making beating 30min.Suction filtration, after using water and washing with acetone successively, vacuum-drying obtains beige crystalline solid (5.11g, 88%):
1hNMR (CDCl
3) δ 9.08 (s, 1H), 8.68 (d, J=1.6Hz, 1H), 8.23 (dd, J=2.0,8.8Hz, 1H), 7.82 (d, J=8.8Hz, 1H).
(b) 1-(3,5-bis-(trifluoromethyl) phenyl)-3-(3-(6-iodine quinazoline-4-base amido) phenyl) urea hydrochloride (L-3-14)
Under nitrogen protection; by chloro-for 4-6-iodine quinazoline (0.58g; 2mmol) with J-14 (0.73g; 2mmol) stirring and refluxing 2h in Virahol (15mL); filter after being slowly chilled to room temperature; washed with isopropyl alcohol obtains Tan solid L-3-14 (0.94g, 76%):
1hNMR (DMSO-d
6) δ 11.36 (brs), 10.11 (s, 1H), 9.58 (s, 1H), 9.23 (d, J=3.6Hz, 1H), 8.92 (m, 1H), 8.36 (dd, J=1.2,8.8Hz, 1H), 8.14 (s, 2H), 7.97 (s, 1H), 7.69 (d, J=8.4Hz, 1H), 7.62 (s, 1H), 7.35-7.45 (m, 3H).
(c) 1-(3,5-bis-(trifluoromethyl) phenyl)-3-(3-(6-(5-formylfuran-2-base) quinazoline-4-base amido) phenyl) urea (L-4-14)
Replace L-3-3 with L-3-14, adopt the method being similar to L-4-3 to prepare L-4-14, obtain yellow orange solid (yield 78%):
1hNMR (DMSO-d
6) δ 10.10 (s, 1H), 9.69 (s, 1H), 9.36 (s, 1H), 9.06 (d, J=1.6Hz, 1H), 9.03 (s, 1H), 8.61 (s, 1H), 8.31 (dd, J=2.0, 8.8Hz, 1H), 8.15 (s, 2H), 8.05 (s, 1H), 7.88 (d, J=9.2Hz, 1H), 7.74 (d, J=3.6Hz, 1H), 7.62 (s, 1H), 7.62 (s, 1H), 7.58 (d, J=8.0Hz, 1H), 7.42 (d, J=3.6Hz, 1H), 7.35 (t, J=8.4Hz, 1H), 7.27 (d, J=8.4Hz, 1H).
(d) 1-(3,5-bis-(trifluoromethyl) phenyl)-3-(3-(6-(5-((2-(methylsulfonyl) ethylamino-) methyl) furans-2-base) quinazoline-4-base amido) phenyl) urea (L-14)
Replace L-4-3 with L-4-14, adopt the method being similar to L-3 to prepare L-14, obtain yellow solid (yield 23%):
1h-NMR (DMSO-d
6) δ 9.88 (s, 1H), 9.40 (s, 1H), 9.05 (s, 1H), 8.79 (s, 1H), 8.55 (s, 1H), 8.15-8.16 (m, 3H), 8.05 (s, 1H), 7.80 (d, J=8.8Hz, 1H), 7.62 (s, 1H), 7.56 (d, J=8.0Hz, 1H), 7.33 (t, J=8.0Hz, 1H), 7.25-7.27 (m, 1H), 7.06 (d, J=3.2Hz, 1H), 6.49 (d, J=3.2Hz, 1H), 3.85 (s, 2H), 3.26 (t, J=6.8Hz, 2H), 3.26 (m, 1H), 3.01 (s, 3H), 2.99-3.02 (m, 2H), MS-ESIm/z693 (M+H)
+.
The preparation of embodiment 1011-(2,5-difluorophenyl)-3-(3-(6-(5-((2-(methylsulfonyl) ethylamino-) methyl) furans-2-base) quinazoline-4-base amido) phenyl) urea (L-15)
(a) 1-(2,5-difluorophenyl)-3-(3-(6-iodine quinazoline-4-base amido) phenyl) urea hydrochloride (L-3-15)
Replace J-14 with J-15, adopt the method being similar to L-3-14 to prepare L-3-15, obtain yellow solid (yield 84%):
1hNMR (DMSO-d
6) δ 11.23 (brs), 9.68 (s, 1H), 9.51 (m, 1H), 9.23 (d, J=1.2Hz, 1H), 8.96 (s, 1H), 8.89 (m, 1H), 8.33 (d, J=8.8Hz, 1H), 7.92-8.06 (m, 2H), 7.70 (d, J=8.8Hz, 1H), 7.25-7.44 (m, 4H), 6.79-6.84 (m, 1H).
(b) 1-(2,5-difluorophenyl)-3-(3-(6-(5-formylfuran-2-base) quinazoline-4-base amido) phenyl) urea (L-4-15)
Replace L-3-3 with L-3-15, adopt the method being similar to L-4-3 to prepare L-4-15, obtain yellow orange solid (yield 77%):
1hNMR (DMSO-d
6) δ 10.10 (s, 1H), 9.70 (m, 1H), 9.22 (s, 1H), 9.07 (d, J=1.6Hz, 1H), 8.75 (s, 1H), 8.62 (m, 1H), 8.31 (dd, J=1.6,8.8Hz, 1H), 8.03-8.09 (m, 2H), (7.89 d, J=8.4Hz, 1H), (7.74 d, J=4.0Hz, 1H), (7.54 d, J=8.0Hz, 1H), (7.43 d, J=3.6Hz.1H), 7.26-7.41 (m, 3H), 6.82 (m, 1H).
(c) 1-(2,5-difluorophenyl)-3-(3-(6-(5-((2-(methylsulfonyl) ethylamino-) methyl) furans-2-base) quinazoline-4-base amido) phenyl) urea (L-15)
Replace L-4-3 with L-4-15, adopt the method being similar to L-3 to prepare L-15, obtain yellow solid (yield 23%):
1hNMR (DMSO-d
6) δ 9.89 (s, 1H), 9.26 (s, 1H), 8.80 (s, 1H), 8.80 (s, 1H), 8.57 (s, 1H), 8.17 (dd, J=1.6, 8.8Hz, 1H), 8.04-8.09 (m, 2H), 7.82 (d, J=8.4Hz, 1H), 7.53 (d, J=8.0Hz, 1H), 7.34 (t, J=8.0Hz, 1H), 7.26-7.31 (m, 2H), 7.07 (d, J=3.6Hz, 1H), 6.83 (m, 1H), 6.50 (d, J=3.2Hz, 1H), 3.86 (s, 2H), 3.28 (t, J=6.8Hz, 2H), 3.28 (s, 1H), 3.02 (s, 3H), 3.00-3.04 (m, 2H), MS-ESIm/z593 (M+H)
+.
The preparation of embodiment 1021-(2-methyl-5-fluorophenyl)-3-(3-(6-(5-((2-(methylsulfonyl) ethylamino-) methyl) furans-2-base) quinazoline-4-base amido) phenyl) urea (L-16)
(a) 1-(2-methyl-5-fluorophenyl)-3-(3-(6-iodine quinazoline-4-base amido) phenyl) urea hydrochloride (L-3-16)
With J-16 for J-14, adopt the method being similar to L-3-14 to prepare L-3-16, obtain Tan solid (yield 93%):
1hNMR (DMSO-d
6) δ 11.42 (brs), 9.68 (s, 2H), (9.25 m, 1H), 9.23 (d, J=1.2Hz, 1H), 8.92 (m, 1H), 8.36 (dd, J=2.0,8.8Hz, 1H), 7.92 (m, 1H), 7.71 (d, J=8.8Hz, 1H), 7.35-7.45 (m, 3H), 7.15 (t, J=8.8Hz, 1H), 7.03 (dd, J=2.0,8.4Hz, 1H), 2.16 (s, 3H).
(b) 1-(2-methyl-5-fluorophenyl)-3-(3-(6-(5-formylfuran-2-base) quinazoline-4-base amido) phenyl) urea (L-4-16)
Replace L-3-3 with L-3-16, adopt the method being similar to L-4-3 to prepare L-4-16, obtain Light yellow crystals (yield 49%):
1hNMR (DMSO-d
6) δ 10.09 (s, 1H), 9.69 (s, 1H), 9.06 (s, 1H), 8.74 (s, 2H), 8.60 (s, 1H), 8.31 (dd, J=1.6, 8.8Hz, 1H), 8.00 (s, 1H), 7.87 (d, J=8.4Hz, 1H), 7.73 (d, J=3.6Hz, 1H), 7.49 (d, J=8.4Hz, 1H), 7.42-7.45 (m, 2H), 7.32 (t, J=8.0Hz, 1H), 7.25 (d, J=8.0Hz, 1H), 7.16 (t, J=8.8Hz, 1H), 7.03 (dd, J=2.0, 8.4Hz, 1H), 2.17 (s, 3H).
(c) 1-(2-methyl-5-fluorophenyl)-3-(3-(6-(5-((2-(methylsulfonyl) ethylamino-) methyl) furans-2-base) quinazoline-4-base amido) phenyl) urea (L-16)
Replace L-4-3 with L-4-16, adopt the method being similar to L-3 to prepare L-16, obtain light yellow solid (yield 14%):
1hNMR (DMSO-d
6) δ 9.87 (s, 1H), 8.80 (s, 1H), 8.76 (s, 1H), 8.75 (s, 1H), 8.56 (s, 1H), 8.16 (dd, J=1.6, 8.8Hz, 1H), 8.01 (s, 2H), 7.81 (d, J=8.8Hz, 1H), 7.50 (d, J=8.0Hz, 1H), 7.44 (dd, J=1.6, 12.4Hz, 1H), 7.32 (t, J=8.0Hz, 1H), 7.25 (d, J=8.4Hz, 1H), 7.17 (t, J=8.8Hz, 1H), 7.03-7.07 (m, 2H), 6.50 (d, J=3.2Hz, 1H), 3.86 (s, 2H), 3.30 (t, J=6.8Hz, 2H), 3.30 (s, 1H), 3.02 (s, 3H), 3.00-3.04 (m, 2H), 2.18 (s, 3H), MS-ESI:m/z589 (M+H)
+.
Second section Biological examples
Embodiment 103 In Vitro Anti human tumor cell line and human umbilical vein cells test
1.1 materials and methods
Sample preparation: after dissolving with DMSO (Merck), adds PBS (-) and is made into the solution of 1000 μ g/ml or uniform suspension, then dilute with the PBS (-) containing DMSO.
Cell strain: A549 (human lung carcinoma cell), HCT116 (people's colon-cancer cell), CEM (human leukemia cell) and MCA-MB-435 (human melanoma cell) and HUVEC (Human umbilical vein endothelial cells).Above cell strain is frozen and go down to posterity by pharmacologically active test center of Shanghai Institute of Pharmaceutical Industry.
Nutrient solution: HUVEC is that DMEM+10 ~ 15%FBS+ is dual anti-; All the other are that DMEM+10%NBS+ is dual anti-, DMEM+10%FBS+ is dual anti-.
Full-automatic microplate reader: model: WellscanMK-2, production firm: Labsystems.
Test method: mtt assay.It is 1 × 10 that the 96 every holes of well culture plate add concentration
5the HUVEC of individual/ml or concentration are 4-5 × 10
4other cell suspensions 100 μ l of individual/ml, puts 37 DEG C, 5%CO
2in incubator.After 24h, add sample liquid, 10 μ l/ holes, if duplicate hole, 37 DEG C, 5%CO
2effect 72h.Every hole adds the MTT solution 20ul of 5mg/ml, and add lysate after effect 4h, 100 μ l/ holes, put in incubator, surveys 570nmOD value after dissolving by the full-automatic microplate reader of WellscanMK-2.
Mtt assay.It is 1 × 10 that the 96 every holes of orifice plate add concentration
5the cell suspension 100 μ l of individual/ml, puts 37 DEG C, 5%CO
2in incubator.After 24h, add sample liquid, 10 μ l/ holes, if duplicate hole, 37 DEG C, 5%CO
2effect 48h.Every hole adds the MTT solution 20 μ l of 5mg/ml, and add lysate after effect 4h, 100 μ l/ holes, put in incubator, surveys 570nmOD value after dissolving by the full-automatic microplate reader of MK-2.
1.2 test-results
Test-results is in table 1.
The concrete formula I of table 1 is to the in-vitro multiplication restraining effect of human tumor cells
The external protein kinase inhibition test of embodiment 104
Calipermobilityshiftassay (see .JournalofBiomolecularScreening such as CardA, 2009,14 (1): 31-42.) is adopted to carry out protein kinase inhibition test.The positive control detected is blank group that does not add sample, and negative control is EDTA group, and reference compound is Staurosporine.Test item is 20 formula I under 3 concentration such as 10,1 and 0.1 μMs, for 10 kinase whose inhibition percentages such as ALK, AuroraA, EGFR, FGFR1, FLT-3, VEGFR-2, c-KIT, c-MET, PDGFR β and TIE-2 under ATPKm concentration.Instrument is CaliperEZReaderII.Kinase reaction condition and test-results are respectively in table 2, table 3 and table 4.
Table 2 kinase reaction condition
| Kinases | Kinase concentration (nM) | ATP concentration (μM) | With or without MnCl 2 | Reaction times |
| ALK | 0.8 | 82 | Nothing | 1h |
| AuroraA | 3.5 | 33 | Nothing | 1h |
| EGFR | 8 | 2.3 | Have | 1h |
| FGFR1 | 6 | 262 | Nothing | 1h |
| FLT-3 | 0.45 | 97 | Nothing | 1h |
| VEGFR-2 | 1.8 | 92 | Nothing | 1h |
| c-KIT | 12 | 87 | Nothing | 40min |
| c-MET | 4.5 | 75 | Nothing | 1h |
| PDGFRβ | 6 | 38 | Nothing | 5h |
| TIE-2 | 6 | 157 | Nothing | 1h |
A table 320 formula I is to the percent inhibition (%) of protein kinase
A table 420 formula I is to the percent inhibition (Continued) (%) of protein kinase
The activity test of embodiment 105 anti-tumor in vivo
Select 7 formula I, take Xarelto as positive control, adopt A549 people's lung cancer model of transplanting in nude mice, all with 25mg/kg dosage per os gastric infusion 12 days, being that leading indicator investigates its Anticancer effect in vivo based on the tumor control rate of relative tumour volume (RTV), and by observing its toxic reaction of body weight change preliminary examinations of tested nude mice.Results from vivo experiments is in table 5.
Gross tumor volume calculation formula is: TV=ab
2/ 2, wherein a is tumour major diameter (mm), b is perpendicular tumour minor axis (mm).Relative tumour volume calculation formula is: RTV=Vt/Vo, Vo measure gained gross tumor volume for (d0) during point cage, and Vt is the gross tumor volume of (d4, d8, d12, d16) when measuring each time.
A table 57 formula I is to the tumor-inhibiting action of the A549 Non-small cell lung carcinoma transplanted in nude mice
Compare with blank group (t checks): * P < 0.05, * * P < 0.01.
The activity test of embodiment 106 anti-tumor in vivo
Select 2 formula I (100mg/kg dosage), with Xarelto (50mg/kg dosage) for positive control, adopt A549 people's lung cancer model of transplanting in nude mice, equal per os gastric infusion 14 days, being that leading indicator investigates its Anticancer effect in vivo based on the tumor control rate of relative tumour volume (RTV), and by observing its toxic reaction of body weight change preliminary examinations of tested nude mice.Results from vivo experiments is in table 6.Relative tumour volume, tumor control rate % method of calculation are with embodiment 105.
A table 62 formula I is to the tumor-inhibiting action of the A549 Non-small cell lung carcinoma transplanted in nude mice
Compare with blank group (t checks): * P < 0.05, * * P < 0.01.
Formula I is external has growth inhibitory activity to human tumor cell line and Human umbilical vein endothelial cells (HUVEC).Described human tumor cell line includes but not limited to A549 human lung carcinoma cell, HCT116 people's colon-cancer cell, CEM human leukemia cell and MCA-MB-435 human melanoma cell.
To people's tumor xenograft knurl, there is growth inhibitory activity in formula I body.Described people's tumor xenograft knurl includes but not limited to transplant the A549 people's lung cancer in nude mice.
Claims (18)
1. one kind such as formula the aryl urea compounds shown in I, its pharmacy acceptable salt;
Wherein, R
1afor hydrogen, R
1for substituted or unsubstituted C
1~ C
6the C of alkyl, replacement
6~ C
10aryl, substituted or unsubstituted C
3~ C
5heteroaryl; Described C
6~ C
10aryl is phenyl; Substituting group in the alkyl of described replacement is pyrrolidin-1-yl, and the substituting group in the aryl of described replacement or the heteroaryl of replacement is halogen, cyano group, C
1~ C
3haloalkyl and C
1~ C
3one or more in alkyl, often kind of substituent number is 0,1 or multiple, and substituent position is commutable optional position on aryl or heteroaryl, and when aryl is phenyl ring, substituent position is the ortho position of urea side chain, a position or contraposition; Heteroatoms in heteroaryl is nitrogen, oxygen or sulphur, and heteroatoms number is 1 ~ 5; Described halogen is fluorine, chlorine, bromine or iodine; Described haloalkyl is trifluoromethyl; Described C
3~ C
5heteroaryl is selected from thiazol-2-yl or 5-methylisoxazole-3-base;
Or R
1, R
1aand and R
1, R
1athe nitrogen-atoms Cheng Huanwei morpholine ring be together connected;
Described Compound I is following arbitrary structure, i.e. R
4, R
5, R
6, R
7, R
8, R
9, R
10, R
11be hydrogen;
Wherein, A is 4-(2-hydroxyethyl) piperazine-1-base, ethyl (2-hydroxyethyl) amido or 2-hydroxyethyl amido;
Or, described such as formula the aryl urea compounds shown in I for such as formula the compound shown in D1-11;
2. aryl urea compounds I as claimed in claim 1 or its pharmacy acceptable salt, is characterized in that: described Compound I is following arbitrary structure:
3. one kind such as formula the aryl urea compounds shown in I, its pharmacy acceptable salt; The described structure such as formula the aryl urea compounds shown in I is such as formula shown in D2-11:
4. the aryl urea compounds as described in claim 1 or 3 or its pharmacy acceptable salt, is characterized in that: the pharmacy acceptable salt of described aryl urea compounds I is the salt of aryl urea compounds I and mineral acid or organic acid formation.
5. aryl urea compounds as claimed in claim 4 or its pharmacy acceptable salt, is characterized in that: described mineral acid is hydrochloric acid.
6. following arbitrary midbody compound of the Compound I of preparation described in claim 1 or 3:
1-(the chloro-4-fluorophenyl of 3-)-3-(3-(7-(3-chlorine propoxy-) quinazoline-4-base amido) phenyl) urea,
1-(the chloro-3-of 4-(trifluoromethyl) phenyl)-3-(3-(7-(3-chlorine propoxy-) quinazoline-4-base amido) phenyl) urea,
1-(3-(7-(3-chlorine propoxy-) quinazoline-4-base amido) phenyl)-3-(3-fluorophenyl) urea,
1-(3-(7-(3-chlorine propoxy-) quinazoline-4-base amido) phenyl)-3-(4-(pyrrolidin-1-yl) butyl) urea,
1-(the chloro-4-fluorophenyl of 3-)-3-(3-(6-(5-formylfuran-2-base) quinazoline-4-base amido) phenyl) urea,
1-(the chloro-3-of 4-(trifluoromethyl) phenyl)-3-(3-(6-(5-formylfuran-2-base) quinazoline-4-base amido) phenyl) urea,
1-(3,5-bis-(trifluoromethyl) phenyl)-3-(3-(6-(5-formylfuran-2-base) quinazoline-4-base amido) phenyl) urea,
1-(2,5-difluorophenyl)-3-(3-(6-(5-formylfuran-2-base) quinazoline-4-base amido) phenyl) urea,
1-(2-methyl-5-fluorophenyl)-3-(3-(6-(5-formylfuran-2-base) quinazoline-4-base amido) phenyl) urea,
N
1-(7-methoxyl group-6-(morpholinyl propoxy-) quinazoline-4-base) benzene-Isosorbide-5-Nitrae-diamines,
Or 1-(3-(7-(3-chlorine propoxy-) quinazoline-4-base amido) phenyl)-3-(5-methylisoxazole-3-base) urea.
7. a preparation method of the midbody compound II of the Compound I described in claim 1 or 3, it is following method:
Wherein, R
1, R
6, R
7, R
8and R
9definition as described in any one of Claims 1 to 5, R
1afor hydrogen, Y is R
11nH-, R
11definition as claimed in claim 1; Urea side chain is connected to 3 ' or 4 ' position;
Method one: first the reaction under tertiary amine exists of compound V and triphosgene is generated corresponding isocyanic ester IV, then under one kettle way condition directly with compound VI ' under tertiary amine exists, carry out into urea reaction, obtain midbody compound II;
8. preparation method as claimed in claim 7, is characterized in that: in method one, and the temperature of the reaction of described generation isocyanic ester IV is-5 DEG C of reflux temperatures to reaction solvent; The temperature of described one-tenth urea reaction is 10 DEG C of reflux temperatures to reaction solvent.
9. preparation method as claimed in claim 7, it is characterized in that: in method one, the temperature of the reaction of described generation isocyanic ester IV is 0 ~ 50 DEG C; The temperature of described one-tenth urea reaction is 15 ~ 60 DEG C.
10. preparation method as claimed in claim 9, it is characterized in that: in method one, the temperature of the reaction of described generation isocyanic ester IV is 20 ~ 40 DEG C; The temperature of described one-tenth urea reaction is 20 ~ 50 DEG C.
11. preparation methods as described in any one of claim 7 ~ 10, is characterized in that:
In method one, described method comprises the following step: in solvent, first under the existence of tertiary amine, compound V and triphosgene reaction are generated corresponding isocyanic ester IV, then under one kettle way condition, directly under tertiary amine exists, carry out into urea reaction with VI ', obtain midbody compound II; Wherein, described solvent is one or more in hydrocarbon, methylene dichloride, chlorobenzene, ether, ketone and ester; Described tertiary amine comprise in pyridine, triethylamine, diisopropyl ethyl amine, N-methylmorpholine, imidazoles and dimethyl aminopyridine one or more; In the reaction generating isocyanic ester, the molar ratio of triphosgene and compound V is 0.3 ~ 2:1, and the molar ratio of compound V and tertiary amine is 1:1 ~ 6; In the reaction of one-tenth urea, compound VI ' be 1:1 ~ 6 with the molar ratio of tertiary amine; Compound V and compound VI ' molar ratio be 1:0.6 ~ 3.
12. preparation methods as claimed in claim 11, is characterized in that:
In method one, described hydrocarbon is toluene or dimethylbenzene, and ether is tetrahydrofuran (THF), 2-methyltetrahydrofuran, methyl tertiary butyl ether or glycol dimethyl ether, and ketone is methyl ethyl ketone or methyl iso-butyl ketone (MIBK), and ester is ethyl acetate or isobutyl acetate; In the reaction generating isocyanic ester IV, the molar ratio of triphosgene and compound V is 0.33 ~ 1:1, and the molar ratio of compound V and tertiary amine is 1:1 ~ 3; In the reaction of one-tenth urea, compound VI ' be 1:1 ~ 3 with the molar ratio of tertiary amine.
13. preparation methods as claimed in claim 12, is characterized in that:
In method one, described solvent is one or more in 2-methyltetrahydrofuran, methylene dichloride and ethyl acetate; In the reaction generating isocyanic ester IV, the molar ratio of triphosgene and compound V is 0.35 ~ 0.5:1, and the molar ratio of compound V and tertiary amine is 1:1 ~ 1.5; In the reaction of one-tenth urea, compound VI ' be 1:1 ~ 1.5 with the molar ratio of tertiary amine.
The application in the medicine of the relevant disease of preparation treatment abnormal vascular new life of 14. aryl urea compounds I as described in claim 1 or 3 or its pharmacy acceptable salt; Described disease is tumour, diabetes, autoimmune disorder, nerve degenerative diseases, diabetic retinopathy, age-related macular degeneration, arteriosclerosis, psoriatic or inflammation; Described tumour is the tumour of skin, brain, lung, lymphocyte, kidney, liver, stomach, colon, rectum, bladder, head, neck, mammary gland, Tiroidina, oesophagus, pancreas, prostate gland or Obstetric and Gynecologic Department, or malignant hematologic disease.
15. aryl urea compounds I as described in claim 1 or 3 or its pharmacy acceptable salt are preparing the application had in the medicine of people's tumor xenograft knurl inhibit activities; Described people's tumor xenograft knurl is transplant the A549 people's lung cancer in nude mice.
16. aryl urea compounds I as described in claim 1 or 3 or its pharmacy acceptable salt have the application in the medicine of A549 human lung carcinoma cell, HCT116 people's colon-cancer cell, CEM human leukemia cell or MCA-MB-435 human melanoma cell inhibit activities in preparation.
17. Compound I as described in claim 1 or 3 or its pharmacy acceptable salt are preparing the application had in the medicine of Human umbilical vein endothelial cells inhibit activities.
18. pharmaceutical compositions comprising aryl urea compounds I as described in claim 1 or 3 or its pharmacy acceptable salt.
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| CN2010106194159A Pending CN102532042A (en) | 2010-12-30 | 2010-12-30 | Aryl urea compound as well as intermediate and application thereof |
| CN201180011513.7A Expired - Fee Related CN103354809B (en) | 2010-12-30 | 2011-12-29 | A kind of aryl urea compounds, its intermediate and application thereof |
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| WO (1) | WO2012089137A1 (en) |
Families Citing this family (18)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2011035540A1 (en) | 2009-09-28 | 2011-03-31 | 齐鲁制药有限公司 | 4-(substituted anilino)quinazoline derivatives as tyrosine kinase inhibitors |
| CN103102315B (en) * | 2012-11-01 | 2016-01-20 | 云南大学 | A kind of Quinazoline arylurea and its production and use |
| EP3607821B1 (en) * | 2013-03-15 | 2022-08-03 | EyePoint Pharmaceuticals, Inc. | Compositions, formulations and methods for treating ocular diseases |
| CN103450096B (en) * | 2013-04-27 | 2015-04-29 | 北京师范大学 | Two nitrogen mustard derivatives, as well as preparation method and application therefore in tumor treatment |
| CN104292170B (en) * | 2014-09-22 | 2016-06-29 | 广西师范大学 | There is quinazoline-Arylurea derivatives and the application thereof of antitumor action |
| CN105503836B (en) * | 2015-12-03 | 2018-04-24 | 中国人民解放军***南京总医院 | A kind of novel quinazoline quinoline derivant LU1502 and its preparation method and application |
| CN105541807B (en) * | 2015-12-03 | 2018-04-24 | 中国人民解放军***南京总医院 | A kind of novel quinazoline quinoline derivant LU1506 and its preparation method and application |
| CN105399733B (en) * | 2015-12-03 | 2018-04-24 | 中国人民解放军***南京总医院 | A kind of novel quinazoline quinoline derivant LU1504 and its preparation method and application |
| CN105503835B (en) * | 2015-12-03 | 2018-04-24 | 中国人民解放军***南京总医院 | A kind of novel quinazoline quinoline derivant LU1510 and its preparation method and application |
| CN108530455B (en) * | 2017-03-01 | 2021-01-12 | 北京赛特明强医药科技有限公司 | Urea substituted aromatic ring connecting dioxane and quinazoline compound or medicinal salt or hydrate and application as tyrosine kinase inhibitor |
| US10273227B2 (en) * | 2017-04-27 | 2019-04-30 | Astrazeneca Ab | C5-anilinoquinazoline compounds and their use in treating cancer |
| CN107098863B (en) * | 2017-05-26 | 2020-04-10 | 重庆莱美隆宇药业有限公司 | Preparation method of gefitinib |
| EP3750894B1 (en) | 2018-02-11 | 2024-04-03 | Beijing Scitech-MQ Pharmaceuticals Limited | Urea-substituted aromatic ring-linked dioxazoline compound, preparation method therefor, and uses thereof |
| CN110862398B (en) * | 2018-08-27 | 2021-04-06 | 北京赛特明强医药科技有限公司 | Urea substituted aromatic ring-linked dioxane quinazoline or quinoline compound, composition and application thereof |
| CN110862397A (en) * | 2018-08-27 | 2020-03-06 | 北京赛特明强医药科技有限公司 | Dioxane quinazoline and dioxane quinoline compounds, and preparation method and application thereof |
| CN109553581B (en) * | 2018-09-25 | 2022-01-25 | 广州六顺生物科技股份有限公司 | Substituted urea compounds, pharmaceutically acceptable salts or solvates thereof, uses thereof, medicaments and pharmaceutical compositions |
| CN110357852B (en) * | 2019-06-21 | 2022-06-10 | 中国药科大学 | Benzopyrimidine compounds, preparation method and application |
| CN115677681A (en) * | 2021-07-23 | 2023-02-03 | 上海挚盟医药科技有限公司 | Preparation method of hepatitis B virus nucleocapsid inhibitor |
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- 2011-12-29 WO PCT/CN2011/084887 patent/WO2012089137A1/en active Application Filing
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| CN102532042A (en) | 2012-07-04 |
| WO2012089137A1 (en) | 2012-07-05 |
| CN103354809A (en) | 2013-10-16 |
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