CN102532042A - Aryl urea compound as well as intermediate and application thereof - Google Patents
Aryl urea compound as well as intermediate and application thereof Download PDFInfo
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- CN102532042A CN102532042A CN2010106194159A CN201010619415A CN102532042A CN 102532042 A CN102532042 A CN 102532042A CN 2010106194159 A CN2010106194159 A CN 2010106194159A CN 201010619415 A CN201010619415 A CN 201010619415A CN 102532042 A CN102532042 A CN 102532042A
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- 0 **1C=C=*(*)/C(/Nc2c(c(*)c(*)c(*)c3*)c3nc(*)n2)=C\C=C1 Chemical compound **1C=C=*(*)/C(/Nc2c(c(*)c(*)c(*)c3*)c3nc(*)n2)=C\C=C1 0.000 description 3
- PQTDLSOUXCSWBX-UHFFFAOYSA-N CN(C=Nc1cc(OCCCO)ccc11)C1=O Chemical compound CN(C=Nc1cc(OCCCO)ccc11)C1=O PQTDLSOUXCSWBX-UHFFFAOYSA-N 0.000 description 1
- MLDQJTXFUGDVEO-UHFFFAOYSA-N CNC(c1nccc(Oc(cc2)ccc2NC(Nc(cc2)cc(C(F)(F)F)c2Cl)=O)c1)=O Chemical compound CNC(c1nccc(Oc(cc2)ccc2NC(Nc(cc2)cc(C(F)(F)F)c2Cl)=O)c1)=O MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 description 1
- VBZLRVSRTGORCZ-UHFFFAOYSA-N ClCCCOc1cc2ncnc(Cl)c2cc1 Chemical compound ClCCCOc1cc2ncnc(Cl)c2cc1 VBZLRVSRTGORCZ-UHFFFAOYSA-N 0.000 description 1
- KCORZHJVTZIZFD-UHFFFAOYSA-N O=C1NC=Nc2cc(F)ccc12 Chemical compound O=C1NC=Nc2cc(F)ccc12 KCORZHJVTZIZFD-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
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- 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
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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
- C07C275/40—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 an aryl urea compound disclosed in a formula I, or pharmaceutically acceptable salt, polymorphic substance, solvate or stereoisomer thereof and an intermediate and application thereof. The aryl urea compound I disclosed by the invention has protein kinase inhibitory activity and activity of resisting tumor and angiogenesis.
Description
Technical field
The present invention relates to a kind of aryl urea compounds, its midbody and application thereof particularly.
Background technology
Signal transduction between cell interior and the cell (signal transduction) is being regulated and control the every aspect of cell function.Cell signalling be the molecular basis of the complicated causes of disease of a lot of diseases unusually.Most signal transduction pathways are mediated by protein kinase (protein kinase).The phosphorylation of human protein kinase catalytic serine, Threonine or tyrosine residues is being brought into play important effect in growth, metabolism, differentiation and the apoptosis of cell.The protein kinase imbalance can cause comprising a series of diseases of tumour, mellitus, autoimmune disorder, nerve degenerative diseases and inflammation.Therefore, kinases inhibitor becomes an important channel of the above-mentioned many human major diseases of treatment.
The human kinase protein group membership surpasses 500 kinds of (.Science such as Manning G, 2002,298 (5600): 1912-1934), comprise Tyrosylprotein kinase and serine/threonine kinase.Some important protein kinases as drug targets are exemplified below: HER kinases (like EGFR and HER-2), VEGFR kinases (like VEGFR-1, VEGFR-2 and VEGFR-3), PDGFR kinases (like PDGFR α, PDGFR β, c-KIT, CSF1R and FLT-3), SRC kinases (like SRC, LCK, FYN and HCK), ALK, BCR-ABL, c-MET, TIE-2, FGFR1, RAF kinases (like BRAF and CRAF), Aurora kinases (like AuroraA and Aurora B), and above-mentioned kinase whose mutant strain (like BCR-ABL T315I and BRAF V600E).
Angiogenesis (angiogenesis) is meant from the existing brand-new blood vessel of angiogenesis.Normal angiogenesis is a normal physiological processes that receives tight regulation and control, betides fetal development, wound healing and menstrual cycle.Angiogenesis is in case imbalance possibly cause multiple diseases such as diabetic retinopathy, rheumatoid arthritis, senile macular degeneration, arteriosclerosis and tumour.
Angiogenesis is the lifeline of maintaining tumour existence and progress, and the solid tumor height relies on angiogenesis and continues to obtain nutrition and oxygen.Therefore, the newborn compound of target vascular therapy becomes a big focus of antitumor drug research, and expects that it possibly have advantage aspect security and the resistance.Many SU11752 Xarelto, Sutent and the Pa Zuopani of listing all have the anti-angiogenic rebirth activity at present.
The target of anti-angiogenic rebirth comprises growth factor (like VEGF, platelet derived growth factor receptor, fibroblast growth factor and Urogastron), receptor tyrosine kinase, transcription factor (like hypoxia inducible factor (hypoxia inducible factor)) at present, and the molecule of participating in MAPK and PI3K signal transduction pathway.Wherein the protein kinase target mainly comprises VEGFR, FGFR, PDGFR, c-KIT, FLT-3 and TIE-2 etc.
The urea structure type compound has received extensive and deep research in recent years as kinases inhibitor.(.Current Opinion in Drug Discovery & Development such as Dumas J, 2004,7 (5): 600-616.)
1, Xarelto:
Xarelto (sorafenib) is first by the many SU11752 of selectivity of drugs approved by FDA listing, and its chemical structure characteristic is diaryl urea (diaryl urea).Xarelto is to the Raf-1 (IC in the RAF/MEK/ERK signal transduction pathway
50, 6nM), wild-type BRAF (IC
50, 22nM), V599E anomaly BRAF (IC
50, 38nM) all have remarkable inhibiting activity.In addition, Xarelto also can be imitated by force and suppressed the multiple receptor tyrosine kinase significant to angiogenesis (RTK): 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 retardance tumor cell proliferation both, and target VEGFR-2/PDGFR-signal transductory cascade suppresses neonate tumour blood vessel again.(.Cancer Research such as Wilhelm SM, 2004,64 (19): 7099-7109)
2, the analog of Xarelto:
(.Journal of Medicinal Chemistry such as Potashman MH such as the Potashman of Amgen company; 2007; 50:4351-4373.) be the amino benzoglyoxaline of corresponding 2-with the Xarelto cyclization, through further structure of modification, obtain the amino benzo oxazoline compound 2 ' of 2-.Compound 2 ' is for imitating optionally VEGFR-2 suppressor factor (Ki 3nM) by force, to the IC of HUVEC
50Be 15nM.
The Hasegawa of GlaxoSmithKline PLC etc. (.Journal of Medicinal Chemistry such as Hasegawa M, 2007,50:4453-4470.) reported to be the TIE-2 and the dual tyrosine kinase inhibitor (IC of VEGFR-2 of representative with compound 3 '
50Be respectively 4.9nM and 1.5nM), solubleness is about 200 μ g/mL in PBS (phosphate buffered saline (PBS)).
(.Journal of Medicinal Chemistry such as Ramurthy S such as the Ramurthy of Novartis; 2008; 51 (22): 7049-7052.) report condenses through the phenyl ring with the urea fragment of Xarelto and next door and obtains a series of 2-aryl benzimidazoles RAF suppressor factor with Orally active, therefrom filters out RAF265 and gets into and treat melanomatous clinical trial.
(.Journal of Medicinal Chemistry such as Niculescu-Duvaz D such as Niculescu-Duvaz; 2009; 52 (8): 2255-2264.) adopt bicyclic pyridine and imidazolidone, imitated the B-RAF inhibitors 4 by force ' (IC as the hinge area binding fragment
5012nM).
3, other urea structure kinases inhibitors:
It is clinical that Tandutinib (MLN-518) is in II phase of acute myelocytic leukemia (AML).It is receptor kinase FLT-3, c-KIT and platelet derived growth factor receptor (PDGFR) potent inhibitor (IC
50170～220nM), for p38 kinases, VEGFR-2 and FGFR high selectivity (IC is arranged all
50＞30 μ M).(.Current Opinion in Drug Discovery & Development such as Dumas J, 2004,7 (5): 600-616.)
Boehringer Ingelheim was once developed the clinical trial that di-aryl urea compounds BIRB796 gets into the treatment autoimmune disorder.BIRB796 is a p38 α map kinase inhibitor.(.Journal of Medicinal Chemistry such as Regan J, 2003,46 (22): 4676-4686.)
The isothiazole compounds CP-547632 of Pfizer's report is strong VEGFR-2 of effect and bFGF suppressor factor, IC
50Be respectively 11 and 9nM, demonstrate selectivity with respect to EGFR, PDGFR β and other associated kinases.CP-547632 has the double activity of angiogenesis inhibiting and tumor cell proliferation: the strong effect suppressed VEGFR and FGF inductive angiogenesis in the model in vivo; In the athymic mouse of lotus people xenotransplantation knurl, oral administration can suppress 85% tumor growth.(.Cancer Research such as Beebe JS, 2003,63 (21): 7301-7309.)
(the .Journal of Medicinal Chemistry such as Dai YJ of Abbott Laboratories; 2007; 50 (7): 1584-1597.) in order to seek novel many kinases receptors Tyrosylprotein kinase (RTK) suppressor factor; Extensive structure activity study through in the Aminoindazole series compound has been found ABT-869, is carrying 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 has 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 midbody, with and use.Aryl urea compounds of the present invention is in the biology test; Inhibition for the multiple protein kinases has in various degree is active, and shows respectively that in external anti-human tumor cell line and the test of Human umbilical vein endothelial cells proliferation activity the antitumor cell growth and the anti-angiogenic rebirth that have in various degree are active.
Therefore the present invention relates to a kind of suc as formula the aryl urea compounds shown in the I or its pharmacy acceptable salt, polymorphic form, solvate or steric isomer;
Wherein, R
1aBe hydrogen, R
1For replacing or unsubstituted C
1～C
8Alkyl (preferred C
1～C
6Alkyl is like n-propyl, sec.-propyl, isobutyl-, the tertiary butyl or n-hexyl), replacement or unsubstituted C
3～C
9Naphthenic base (preferred C
3～C
8Naphthenic base is like cyclohexyl), replacement or unsubstituted C
6～C
14Aryl (preferred C
6～C
10Aryl is like phenyl or naphthyl), replacement or unsubstituted C
1～C
13Heteroaryl (preferred C
3～C
9Heteroaryl, further preferred C
3～C
5Heteroaryl, further preferred again thiazolyl is like thiazol-2-yl); Substituting group in the substituted alkyl is 4～9 yuan of (preferred 4～6 yuan) saturated heterocyclyls, and the heteroatoms number of said saturated heterocyclyl is 1～4, and heteroatoms is nitrogen, oxygen or sulphur, like tetramethyleneimine-1-base; Substituting group in the substituted naphthenic base is halogen, C
1～C
3Alkyl or C
1～C
3Alkoxyl group; Substituting group in substituted aryl or the substituted heteroaryl is halogen (like fluorine, chlorine, bromine or iodine), cyanic acid, C
1～C
3Haloalkyl (like trifluoromethyl), C
1～C
3Alkyl, C
1～C
3Alkoxyl group, C
2～C
3Thiazolinyl and C
2～C
3In the alkynyl one or more, every kind of substituent number is 0,1 or a plurality of, and substituent position can be commutable optional position on aryl or the heteroaryl, and when aryl was phenyl ring, substituent position was ortho position, a position or the contraposition of urea side chain; Heteroatoms in the heteroaryl is nitrogen, oxygen or sulphur, and the heteroatoms number is 1～5;
Perhaps R
1, R
1aAnd and R
1, R
1aThe nitrogen-atoms that links to each other Cheng Huanwei together replaces or unsubstituted 4～9 yuan (preferred 5～7 yuan) saturated heterocyclics (like the morpholine ring), and said saturated heterocyclic can extraly contain 1～3 heteroatoms, and said heteroatoms is nitrogen, oxygen or sulphur; Wherein, the substituting group in described substituted 4～9 yuan of saturated heterocyclics is halogen, C
1～C
3Alkyl or C
1～C
3Alkoxyl group;
R
2Be hydrogen, the substituted C of substituted-amino
1～C
6(preferred C
1～C
3) alkoxyl group, wherein the substituting group on the substituted-amino forms 4～9 yuan of replacements or unsubstituted saturated heterocyclic with the amino nitrogen atom cyclization; Can extraly comprise 1～2 heteroatoms in the described saturated heterocyclic, heteroatoms is nitrogen, oxygen or sulphur (preferred nitrogen or oxygen), if the extra packet nitrogen atom, does not then have on this nitrogen-atoms and replaces or further by C
1～C
6(preferred C
1～C
3) the alkyl replacement; Substituting group in the described substituted saturated heterocyclic is C
1～C
3Alkyl, C
1～C
3Alkoxyl group, halogen, amino or hydroxyl;
Perhaps, R
2Be C
1～C
6(preferred C
1～C
3) the substituted C of alkoxyl group
1～C
6(preferred C
1～C
3) alkoxyl group, substituted C
6～C
10Aryl, substituted C
3～C
9Heteroaryl (preferred furyl); Wherein, the substituting group in substituted aryl or the substituted heteroaryl is (to connect C
1～C
3The C of alkyl sulphonyl
1～C
3Alkylamino) substituted C
1～C
3Alkyl, halogen, C
1～C
3Alkyl, C
1～C
3Alkoxyl group, C
2～C
3Thiazolinyl and C
2～C
3In the alkynyl one or more, the heteroatoms in the heteroaryl are nitrogen, oxygen or sulphur, and the heteroatoms number is 1～4; Preferable, the substituting group in substituted aryl or the substituted heteroaryl is (to connect C
1～C
3The C of alkyl sulphonyl
1～C
3Alkylamino) substituted C
1～C
3Alkyl, all the other positions of aryl or heteroaryl do not have and replace or by halogen, C
1～C
3Alkyl, C
1～C
3Alkoxyl group, C
2～C
3Thiazolinyl and C
2～C
3One or more replacements in the alkynyl;
R
3Be hydrogen, C
1～C
3Alkoxyl group, perhaps C
1～C
6(preferred C
1～C
3) the substituted C of alkoxyl group
1～C
6(preferred C
1～C
3) alkoxyl group;
Perhaps R
3Be amino or the substituted C of substituted-amino
1～C
6(preferred C
1～C
3) alkoxyl group; Wherein, Substituting group on the substituted-amino can form 4～9 yuan of (preferred 5～6 yuan) saturated heterocyclics with said amino nitrogen atom cyclization; Can extraly comprise 1～2 heteroatoms in the described saturated heterocyclic, heteroatoms is nitrogen, oxygen or sulphur (preferred nitrogen or oxygen), if the extra packet nitrogen atom; Then there is not replacement on this nitrogen-atoms, or further by C
1～C
6(preferred C
1～C
3) alkyl, perhaps (hydroxyl is substituted) C
1～C
6(preferred C
1～C
3) the alkyl replacement; Perhaps the substituting group on the substituted-amino is (hydroxyl is substituted) C
1～C
6(preferred C
1～C
3) alkyl and/or C
1～C
6(preferred C
1～C
3) alkyl;
Perhaps R
3Be 4～9 yuan of (preferred 5～6 yuan) substituted C of saturated heterocyclic
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 connects, and comprises 1～3 heteroatoms (preferred 1～2) in the described saturated heterocyclic, heteroatoms is nitrogen, oxygen or sulphur (preferred nitrogen or oxygen), if comprise nitrogen-atoms, does not then have on this nitrogen-atoms and replaces or by C
1～C
6(preferred C
1～C
3) the alkyl replacement;
R
4And R
5Be hydrogen, C independently
1～C
3Alkyl, C
1～C
3Alkoxyl group, halogen, amido or cyanic acid;
R
6, R
7, R
8And R
9Be hydrogen, C independently
1～C
3Alkyl, C
1～C
3Alkoxyl group, halogen or cyanic acid;
R
10Be hydrogen, C
1～C
3Alkyl, C
1～C
3Alkoxyl group, halogen, amido or cyanic acid;
R
11Be hydrogen or C
1～C
3Alkyl;
Urea side chain
is connected 2 ', 3 ' or 4 '.
Among the present invention, what described compound I was preferable is following structure:
Wherein, R
1And R
1aDefinition ditto said; The urea side chain is connected 3 ' or 4 '; A is 4-(2-hydroxyethyl) piperazine-1-base, ethyl (2-hydroxyethyl) amido or 2-hydroxyethyl amido.
Among the present invention, what described compound I was best is following arbitrary structure:
Among the present invention, the pharmacy acceptable salt of described aryl urea compounds is the salt of above-mentioned aryl urea compounds and mineral acid or organic acid formation, the salt that perhaps above-mentioned aryl urea compounds and mineral alkali or organic bases form.
The crystallized form of the formula I compound among the present invention can be polymorphic, and these crystallized forms are in the present invention involved.In addition, the formula I compound among the present invention also can form solvate with solvent, as forming hydrate with water, perhaps forms organic solvate with organic solvent, and these hydrates and organic solvent compound are also in the present invention involved.
Compound of the present invention possibly contain asymmetric atom, chiral carbon atom especially, and therefore and the steric isomer (comprising pure stereoisomers, the mixture of perhaps being made up of the steric isomer of various ratios) that produces all is regarded as a part of the present invention all.
Compound I among the present invention can prepare by following arbitrary method:
(1) each group definition is with described in the aforementioned compound I, but R
2Be hydrogen, the substituted C of substituted-amino
1～C
6Alkoxyl group, perhaps C
1～C
6The substituted C of alkoxyl group
1～C
6Alkoxyl group; R
3Be hydrogen, C
1～C
3Alkoxyl group, C
1～C
6The substituted C of alkoxyl group
1～C
6Alkoxyl group, perhaps R
3Be the substituted C of substituted-amino
1～C
6Alkoxyl group, and wherein the substituting group on the substituted-amino does not comprise (hydroxyl is substituted) C
1～C
6Alkyl; Compound Q and compound I I are carried out condensation reaction get final product, add acid or basic catalyst can the accelerated reaction process;
Wherein, X is a halogen, like Cl or Br.Y is R
11NH-, R
11Definition ditto said.The method of described condensation reaction and condition are the ordinary method and the condition of this type of reaction.Compound Q can commercially availablely obtain or make through prior art.
(2) each group definition is with described in the aforementioned compound I, but R
3Be amino or the substituted C of substituted-amino
1～C
6Alkoxyl group, wherein the substituting group on the substituted-amino forms 4～9 yuan of saturated heterocyclics with said amino nitrogen cyclization, extra packet nitrogen atom in the ring, on this nitrogen-atoms by (hydroxyl is substituted) C
1～C
6Alkyl replaces; Substituting group on the perhaps said substituted-amino is (hydroxyl is substituted) C
1～C
6Alkyl and/or C
1～C
6Alkyl; Compound I I ' and ammonia or substituted ammonia are carried out nucleophilic substitution reaction, get final product;
Wherein, R among substituting group in the described substituted ammonia and the aforesaid compound I
3In substituting group in the substituted amino identical, X ' is leavings group (like a chlorine), n is 1～6, the carbonatoms that comprises in the expression bracket is 1～6.The method of described nucleophilic substitution reaction and condition all can be the ordinary method and the condition of this type of reaction.Compound I I ' can commercially availablely obtain or make through prior art.
(3) each group definition is with described in the aforementioned compound I, but R
2Be substituted C
6～C
10Aryl or substituted C
3～C
9Heteroaryl, substituting group are (to connect C
1～C
3The C of alkyl sulphonyl
1～C
3Alkylamino) substituted C
1～C
3Alkyl; Compound 5 and compound 4 are carried out Suzuki (Suzuki) linked reaction, obtain compound 3, again according to the different R in the title product
2Substituting group is with compound 3 and the corresponding C that is connected
1～C
3The C of alkyl sulphonyl
1～C
3Alkyl ammonia carries out reductive amination process, gets final product;
Perhaps, compound 5 and compound 6 are carried out Suzuki (Suzuki) linked reaction, get final product, wherein each group definition is with described in the aforementioned compound I, but R
2Be substituted C
6～C
10Aryl or substituted C
3～C
9Heteroaryl, substituting group (connects C for removing
1～C
3The C of alkyl sulphonyl
1～C
3Alkylamino) substituted C
1～C
3The substituting group that alkyl is outer.
Wherein, the method for described Suzuki (Suzuki) linked reaction and reductive amination process and condition are the ordinary method and the condition of these two types of reactions of this area.
expression in the compound 4 replaces or unsubstituted aryl or replacement or unsubstituted heteroaryl.Compound 4,5 and 6 can commercially availablely obtain or make through prior art.
According to above-mentioned preparation method disclosed by the invention, those skilled in the art can adopt identical with it principle and method, make each particular compound that relates among the general formula compound I of the present invention.
The preparation method of the compound I among the present invention is exemplified below:
One, Ia, Ib, Ic, Id and Ie series compound is synthetic
The final step reaction of preparation Ia, Ib, Ic, Id and Ie series compound is: 5 kinds of quinazoline parent nucleus Q by shown in the table 1 carry out condensation reaction with side chain urea U, prepare target compound.Can quicken this condensation reaction through adding acid perhaps basic catalyst.
Table 1 quinazoline parent nucleus Q
Annotate: Q can be base or hydrochloride
(be general formula compound II, Y is R to side chain urea U
11NH-, R
11Definition ditto said), its molecular characterization is the N that contains fragrant amido, N '-disubstituted ureas.
Wherein, Y is R
11NH-, R
11Definition ditto said; R
1, R
1a, R
6, R
7, R
8And R
9Definition the same; The urea side chain can be connected 2 ', 3 ' or 4 '.Table 2 has been enumerated some instantiation compounds of side chain urea U.
Table 2 side chain urea U for example
The preparation method of quinazoline parent nucleus Q can be described below:
Q1 is according to document (.WO2004024703A1 such as Gilday JP; Diao is round etc. Chinese Journal of Pharmaceuticals, 2008,39 (6): 401-403) preparation.
The preparation of Q2: morpholinyl third-1-alcohol acts as sodium salt with 60% sodium hydride, obtains Q2T with 7-fluquinconazole quinoline-4 (3H)-ketone condensation again, under DMF catalysis, obtains the Q2 hydrochloride through the sulfur oxychloride chlorination.Morpholinyl third-1-alcohol is according to document preparation (.Journal of Medicinal Chemistry such as Ple PA, 2004,47 (4): 871-887).7-fluquinconazole quinoline 4 (3H)-ketone are obtained by 2-amino-4-fluorobenzoic acid and methane amide cyclization.
Reaction conditions: (a) HCONH
2, 150 ℃; (b) morpholinyl third-1-alcohol, 60%NaH, DMF; (c) SOCl
2, DMF refluxes.
The preparation of Q3: 3-(4-N-METHYL PIPERAZINE-1-yl) third-1-alcohol acts as sodium salt with 60% sodium hydride, obtains Q3T with 7-fluquinconazole quinoline-4 (3H)-ketone condensation again, under DMF catalysis, obtains the Q3 hydrochloride through the sulfur oxychloride chlorination.3-(4-N-METHYL PIPERAZINE-1-yl) third-1-alcohol is according to document .US2006142570A1 such as () Herz T preparation.
Reaction conditions: (a) 3-(4-N-METHYL PIPERAZINE-1-yl) third-1-alcohol, 60%NaH, DMF; (b) SOCl
2, DMF refluxes.
The preparation of Q4: (1-methyl piperidine-4-yl) methyl alcohol and 60% sodium hydride act as sodium salt, obtain Q4T with 7-fluquinconazole quinoline-4 (3H)-ketone condensation again, under DMF catalysis, obtain the Q4 hydrochloride through the sulfur oxychloride chlorination.(1-methyl piperidine-4-yl) methyl alcohol is commercially available.
Reaction conditions: (a) (1-methyl piperidine-4-yl) methyl alcohol, 60%NaH, DMF; (b) SOCl
2, DMF refluxes.
Q5 is commercially available.
Two, the preparation of If series compound
Synthetic route as follows is adopted in the preparation of If series compound.7-fluquinconazole quinoline-4 (3H)-ketone and 1; Ammediol O-alkylation in the presence of sodium hydride obtains midbody 7; Obtain two muriates 8 through the catalytic sulfur oxychloride chlorination of DMF again; Again in the aqueous isopropanol of hydrogenchloride with side chain urea U backflow condensation, at last in N-Methyl pyrrolidone (NMP) with the various amine A that contain hydroxyl respectively condensation obtain the If series compound.
Reaction conditions: (a) 1, ammediol, 60%NaH; (b) SOCl
2, DMF; (c) side chain U, the HCl aqueous isopropanol refluxes; (d) AH, NMP, 50 ℃. wherein, the definition of A is ditto said.
Therefore, the invention still further relates to following midbody compound: 1-(3-chloro-4-fluorophenyl)-3-(3-(7-(3-chlorine propoxy-) quinazoline-4-base amido) phenyl) urea (D52-1-0),
1-(4-chloro-3-(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),
Perhaps 1-(3-(7-(3-chlorine propoxy-) quinazoline-4-base amido) phenyl)-3-(4-(tetramethyleneimine-1-yl) butyl) urea (D52-18-0).
Three, the preparation of Ig series compound
Synthetic route as follows is adopted in the preparation of Ig series compound:
2-amino-5-iodine benzonitrile and N; After dinethylformamide dimethylacetal (DMFDMA) condensation; Carry out the Dimroth rearrangement with side chain urea U again and obtain compound III; 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.Condensation obtained its hydrochloride under intermediate III also can be refluxed in the aqueous isopropanol of hydrogenchloride by 4-chloro-6-iodine quinazoline and side chain urea U.
Reaction conditions: (a) DMFDMA, reflux; (b) side chain U, HOAc refluxes; (c) side chain U, the HCl aqueous isopropanol refluxes; (d) 5-formylfuran-2-boric acid, Pd/C, Et
3N, DME-MeOH, 50 ℃; (e) 2-(methylsulfonyl) ethamine, NaBH (OAc) then
3, THF, room temperature.
Therefore, the invention still further relates to following midbody compound:
1-(3-chloro-4-fluorophenyl)-3-(3-(6-iodine quinazoline-4-base amido) phenyl) urea hydrochloride (L-3-1),
1-(3-chloro-4-fluorophenyl)-3-(3-(6-(5-formylfuran-2-yl) quinazoline-4-base amido) phenyl) urea (L-4-1),
1-(4-chloro-3-(trifluoromethyl) phenyl)-3-(3-(6-iodine quinazoline-4-base amido) phenyl) urea (L-3-3),
1-(4-chloro-3-(trifluoromethyl) phenyl)-3-(3-(6-(5-formylfuran-2-yl) quinazoline-4-base amido) phenyl) urea (L-4-3),
1-(3,5-two (trifluoromethyl) phenyl)-3-(3-(6-iodine quinazoline-4-base amido) phenyl) urea hydrochloride (L-3-14),
1-(3,5-two (trifluoromethyl) phenyl)-3-(3-(6-(5-formylfuran-2-yl) quinazoline-4-base amido) phenyl) urea (L-4-14),
1-(2, the 5-difluorophenyl)-3-(3-(6-iodine quinazoline-4-base amido) phenyl) urea hydrochloride (L-3-15),
1-(2, the 5-difluorophenyl)-3-(3-(6-(5-formylfuran-2-yl) 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),
Perhaps 1-(2-methyl-5-fluorophenyl)-3-(3-(6-(5-formylfuran-2-yl) quinazoline-4-base amido) phenyl) urea (L-4-16).
Four, the preparation of side chain urea U
(be general formula compound II, Y is R to side chain urea U
11NH-, R
11Definition ditto said) molecular characterization be the N that contains fragrant amido, N '-disubstituted ureas.
Therefore, the invention still further relates to N, N '-disubstituted ureas with following general formula I I
Wherein, Y is R
11NH-or nitro, R
11Definition ditto said; R
1, R
1a, R
6, R
7, R
8And R
9Definition the same; The urea side chain can be connected 2 ', 3 ' or 4 '.
Preferable; General formula I I compound is following structure: 1-(3-aminophenyl)-3-(4-chloro-3-(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-two (trifluoromethyl) phenyl) urea (J-14), 1-(3-aminophenyl)-3-(2, the 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-(tetramethyleneimine-1-yl) butyl) urea (P-18), 1-(3-aminophenyl)-3-(4-(tetramethyleneimine-1-yl) butyl) urea (J-18), 1-isobutyl--3-(4-aminophenyl) urea (P-19), 1-isobutyl--3-(3-aminophenyl) urea (J-19), 1-(3-chloro-4-fluorophenyl)-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-(tetramethyleneimine-1-yl) butyl) urea (JX-18), 1-isobutyl--3-(3-nitrophenyl) urea (JX-19).
The method for preparing compound I I can be divided into two types of isocyanic ester method and carbamate methods.
At first introduce and adopt the isocyanic ester legal system to be equipped with compound I I.
Traditional isocyanic ester is synthetic to be main with phosgenation.Phosgene is hypertoxic gas, be difficult to storage and transportation, and logical phosgene process is seriously polluted, all brings immense pressure for environmental protection and labour protection.The invention provides two (trichloromethyl) ester (hereinafter to be referred as the TRIPHOSGENE 99.5) one kettle ways of a kind of use carbonic acid and prepare general formula I I (R
1aBe H) shown in N, the short-cut method of N '-disubstituted ureas.
Therefore the invention further relates to the preparation method of above-mentioned general formula compound II, it is in the following method any one:
Method one: at first compound V and TRIPHOSGENE 99.5 are reacted in the presence of tertiary amine and generate corresponding isocyanate IV, react directly in the presence of tertiary amine, being carried out to urea under the one kettle way condition then, obtain midbody compound II with compound VI or VI '; Wherein, the definition of each group is ditto said, but R
1aBe H; Synthetic route is following:
Method two: at first compound VI and TRIPHOSGENE 99.5 are reacted generation corresponding isocyanate VII in the presence of tertiary amine, in the presence of tertiary amine, be carried out to the urea reaction at direct under the one kettle way condition and compound V then, obtain midbody compound II; Wherein, the definition of each group is ditto said; Synthetic route is following:
In the method one; Preferred especially following method of the present invention and condition: in the solvent; At first in the presence of tertiary amine, compound V and TRIPHOSGENE 99.5 reaction are generated corresponding isocyanate IV; React directly in the presence of tertiary amine, being carried out to urea under the one kettle way condition then, obtain midbody compound II with compound VI or VI '.
Wherein, Described preferred solvents be to the isocyanic ester organic solvent inert; Can be in hydrocarbon (like toluene, YLENE, methylene dichloride or chlorobenzene etc.), ether (like THF, 2-methyltetrahydrofuran, MTBE or glycol dimethyl ether etc.), ketone (like methyl ethyl ketone or MIBK etc.) and the ester (like ETHYLE ACETATE or isobutyl acetate etc.) one or more, one or more in preferred 2-methyltetrahydrofuran, methylene dichloride and the ETHYLE ACETATE.Described tertiary amine is that three hydrogen on the nitrogen all are substituted the compound that the back forms in the ammonia; Carbon atom that wherein links to each other with nitrogen and nitrogen can form singly-bound or two key, and said tertiary amine is preferable comprises in pyridine, triethylamine, diisopropyl ethyl amine, N-methylmorpholine, imidazoles and the dimethyl aminopyridine one or more.In the reaction of described generation isocyanic ester, what the molar ratio of TRIPHOSGENE 99.5 and compound V was preferable is 0.3～2: 1, preferred 0.33～1: 1, more preferably 0.35～0.5: 1; What temperature of reaction was preferable is-5 ℃ of reflux temperatures to reaction solvent, preferred 0～50 ℃, and more preferably 20～40 ℃; What the molar ratio of compound V and tertiary amine was preferable is 1: 1～6, preferred 1: 1～3, more preferably 1: 1～1.5.In described one-tenth urea reaction, what temperature of reaction was preferable is 10 ℃ of reflux temperatures to reaction solvent, preferred 15～60 ℃, and more preferably 20～50 ℃; What the molar ratio of compound VI or VI ' and tertiary amine was preferable is 1: 1～6, preferred 1: 1～3, more preferably 1: 1～1.5.What the molar ratio of compound V and compound VI or VI ' was preferable is 1: 0.6～3, preferred 1: 0.8～2, more preferably 1: 0.9～1.2.
In the method two; Preferred especially following method of the present invention and condition: in the solvent; At first in the presence of tertiary amine; Compound VI and TRIPHOSGENE 99.5 reaction are generated corresponding isocyanate VII, in the presence of tertiary amine, be carried out to the urea reaction at direct under the one kettle way condition and compound V then, obtain midbody compound II.
Wherein, Described preferred solvents be to the isocyanic ester organic solvent inert; Can be in hydrocarbon (like toluene, YLENE, methylene dichloride or chlorobenzene etc.), ether (like THF, 2-methyltetrahydrofuran, MTBE or glycol dimethyl ether etc.), ketone (like methyl ethyl ketone or MIBK etc.) and the ester (like ETHYLE ACETATE or isobutyl acetate etc.) one or more, one or more in preferred 2-methyltetrahydrofuran, methylene dichloride and the ETHYLE ACETATE.Described tertiary amine is that three hydrogen on the nitrogen all are substituted the compound that the back forms in the ammonia; Carbon atom that wherein links to each other with nitrogen and nitrogen can form singly-bound or two key, and said tertiary amine is preferable comprises in pyridine, triethylamine, diisopropyl ethyl amine, N-methylmorpholine, imidazoles and the dimethyl aminopyridine one or more.In the reaction of described generation isocyanic ester, what the molar ratio of TRIPHOSGENE 99.5 and compound VI was preferable is 0.3～2: 1, preferred 0.33～1: 1, more preferably 0.35～0.5: 1; What temperature of reaction was preferable is-5 ℃ of reflux temperatures to reaction solvent, preferred 0～50 ℃, and more preferably 20～40 ℃; What the molar ratio of compound VI and tertiary amine was preferable is 1: 1～6, preferred 1: 1～3, more preferably 1: 1～1.5.In described one-tenth urea reaction, what temperature of reaction was preferable is 10 ℃ of reflux temperatures to reaction solvent, preferred 15～60 ℃, and more preferably 20～50 ℃; What the molar ratio of compound V and tertiary amine was preferable is 1: 1～6, preferred 1: 1～3, more preferably 1: 1～1.5.What the molar ratio of compound VI and compound V was preferable is 1: 0.6～3, preferred 1: 0.8～2, more preferably 1: 0.9～1.2.
In aforesaid method one and the method two, compound I I (Y is a nitro) can obtain compound I I (Y is for amino) through the method for the conventional reduction nitro in this area.
Aforesaid method one can describe in further detail as follows with method two:
Preparing method of the present invention is divided into two stages.Fs: at first TRIPHOSGENE 99.5 is dissolved in the The suitable solvent, adds first kind of amine R then
1-NH
2(V) with the solution of a kind of tertiary amine in a kind of The suitable solvent, reaction obtains containing the solution of first kind of amine corresponding isocyanate (IV), need not separation and purification; Subordinate phase: in fs gained reaction solution, add second kind of amine VI (like 3-N-methyl-p-nitroaniline, 4-N-methyl-p-nitroaniline) or VI ' (as 1, the 4-Ursol D) and the solution of a kind of tertiary amine in The suitable solvent, obtain N, N '-disubstituted ureas II.II (Y is a nitro) obtains II (Y is for amino) through reduction.Synthetic route is seen before.
In the fs, TRIPHOSGENE 99.5 and first kind of amine R
1-NH
2(V) molar ratio is 0.3～2: 1, preferred 0.33～1: 1, and more preferably 0.35～0.5: 1, the first kind of amine R
1-NH
2(V) can be 1: 1 with the molar ratio of tertiary amine～6, preferred 1: 1～3, more preferably 1: 1～1.5.Said The suitable solvent is to the isocyanic ester organic solvent inert; Can be hydrocarbon (toluene, YLENE, methylene dichloride, chlorobenzene etc.), ether (THF, 2-methyltetrahydrofuran, MTBE, glycol dimethyl ether etc.), ketone (methyl ethyl ketone, MIBK etc.), ester (ETHYLE ACETATE, isobutyl acetate etc.), perhaps its mixture.Preferred 2-methyltetrahydrofuran, methylene dichloride, ETHYLE ACETATE, perhaps its mixture.Said tertiary amine comprises pyridine, triethylamine, diisopropyl ethyl amine, N-methylmorpholine, imidazoles, dimethyl aminopyridine and composition thereof.Temperature of reaction can be-5 ℃ of reflux temperatures to reaction solvent, preferred 0～50 ℃, more preferably 20～40 ℃.
In subordinate phase, the same fs of said The suitable solvent and tertiary amine.Temperature of reaction can be 10 ℃ of reflux temperatures to reaction solvent, preferred 15～60 ℃, more preferably 20～50 ℃.The molar ratio of fs first kind of amine (V) and second kind of amine of subordinate phase (VI or VI ') can be 1: 0.6～and 3, preferred 1: 0.8～2, more preferably 1: 0.9～1.2.The molar ratio of second kind of amine (VI or VI ') and tertiary amine can be 1: 1～and 6, preferred 1: 1～3, more preferably 1: 1～1.5.
N of the present invention, N '-disubstituted ureas (II) preparation method also can adopt other a kind of feeding sequence.Fs: at first TRIPHOSGENE 99.5 is dissolved in the The suitable solvent; Add second kind of amine (like 3-N-methyl-p-nitroaniline, 4-N-methyl-p-nitroaniline) and the solution of a kind of tertiary amine in a kind of The suitable solvent then; Reaction obtains containing the solution of second kind of amine corresponding isocyanate, need not separation and purification; Subordinate phase: in fs gained reaction solution, add first kind of amine and the solution of a kind of tertiary amine in The suitable solvent, reaction obtains N, N '-disubstituted ureas (II).Synthetic route is seen before.
This synthesis technique is easy and simple to handle, and the reaction times is short, need not separating reaction property midbody, need not specific installation and condition, and yield is high.The TRIPHOSGENE 99.5 that is adopted is crystalline stable phosgene substitute (80 ℃ of fusing points, 206 ℃ of a boiling point; Even if when boiling, also having only small amount of degradation is phosgene); Be easy to transportation and storage, be convenient to metering (.Angewandte Chemie-International Edition in English such as Eckert H, 1987; 26 (9): 894-895), have the advantage that safe green is easy to get.
Prepared N, N '-disubstituted ureas (II) (Y is a nitro) can be amino through the 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 (like iron powder/ammonium chloride, zinc powder/glacial acetic acid etc.) etc.
In addition, above-mentioned midbody compound II also can make through following carbamate method.
This method can be exemplified below:
At first, make the reaction of compound VI (like 3-N-methyl-p-nitroaniline, 4-N-methyl-p-nitroaniline) and haloformate class (like chloroformic acid 4-nitro phenyl ester, phenyl chloroformate) generate corresponding amido formate, again with
(R
1, R
1aDefinition with general formula compound I) condensation obtains containing the unsymmetrical urea of nitro, the nitro that reduces at last obtains required side chain urea U (II, Y are amino).Following with the concrete example of the preparation of J-12:
The invention still further relates to above-mentioned formula I compound or its pharmacy acceptable salt, polymorphic form, solvate or steric isomer in particularly the people and the protein kinase mediated signal transduction pathway imbalance of preparation treatment Mammals, the perhaps application in the medicine of the newborn disease of being correlated with of abnormal vascular.Described disease includes but not limited to tumour, mellitus, autoimmune disorder, nerve degenerative diseases, diabetic retinopathy, senile 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 (like white blood disease).
Described protein kinase comprises Tyrosylprotein kinase and serine/threonine kinase, and aforementioned kinase whose various wild-types and mutant.That wherein, described Tyrosylprotein kinase is preferable is 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; That described serine/threonine kinase is preferable is BRAF, CRAF, AuroraA or Aurora B; That described mutant kinases is preferable is BRAF V600E.
Aryl urea formula I compound of the present invention or its pharmacy acceptable salt, polymorphic form, solvate or steric isomer can be processed various forms of pharmaceutical compositions with pharmaceutically acceptable carrier.Said pharmaceutically acceptable carrier includes but not limited to various common medicinal supplementary material (like thinner, lubricant, disintegrating agent, tackiness agent and vehicle etc.).According to therapeutic purpose; Can pharmaceutical composition be processed various types of administration unit dosage, like tablet, capsule, pill, pulvis, solution, suspension-s, emulsion agent, ointment, syrup, granule, suppository and injection (solution and suspension-s) etc.
For the pharmaceutical composition that makes tablet form is shaped, can use any known and widely used vehicle in this area.For example, carrier is like lactose, white sugar, sodium-chlor, glucose, urea, starch, lime carbonate, kaolin, crystalline cellulose and silicic acid etc.; Tackiness agent is like water, ethanol, propyl alcohol, common syrup, glucose solution, starch solution, penetrating judgment solution, CMC 99.5, lac, methylcellulose gum and potassiumphosphate, Vinylpyrrolidone polymer etc.; Disintegrating agent, like dry starch, sodiun alginate, agar powder and sea-tangle powder, fatty ester, sodium lauryl sulphate, stearic acid monoglycerides, starch and the lactose etc. of sodium hydrogencarbonate, lime carbonate, Vilaterm anhydro sorbitol; The disintegration suppressor factor is like white sugar, tristearin, Oleum Cocois and winterized stearin; Adsorption enhancer is like quaternary amine alkali and sodium lauryl sulphate etc.; Wetting agent is like glycerine, starch etc.; Sorbent material is like starch, lactose, kaolin, wilkinite and colloid silicic acid etc.; And lubricant, like purified talcum, stearate, boric acid powder and polyoxyethylene glycol etc.If necessary, can also with common be coated with the stain material make tablet as sugar coated tablet, be coated with gelatin film tablet, enteric coated tablets, film coated tablets, duplicature tablet and multilayer tablet.
For the pharmaceutical composition that makes pill is shaped, can use any known and widely used excipient in this area, for example, and carrier, like lactose, starch, Oleum Cocois, hardened vegetable oils, kaolin and talcum etc.; Tackiness agent, like gum arabic powder, yellow work rubber powder, gelatin and ethanol etc.; Disintegrating agent is like agar and sea-tangle powder etc.
For the pharmaceutical composition that makes suppository form is shaped, can use any known and widely used excipient in this area, for example, 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, can solution and suspension-s be sterilized, and preferably add proper amount of sodium chloride, glucose or glycerine etc. are processed and the isotonic injection of blood.When the preparation injection, also can use any carrier commonly used in this area.For example, water, ethanol, Ucar 35, the isooctadecanol of ethoxylation, the fatty ester of the isooctadecanol of polyoxyization and Vilaterm anhydro sorbitol etc.In addition, also can add common solvating agent, buffer reagent and pain killer etc.As required, during treatment schizophrenia, also can add tinting material, sanitas, spices, seasonings, sweetening agent and other medicines etc.
Compound shown by formula I of the present invention and pharmacy acceptable salt thereof the content in pharmaceutical composition does not have particular restriction, can in very wide scope, select, and can be mass percent 1～70% usually, and preferable is mass percent 1～30%.
Among the present invention, the medication of described pharmaceutical composition does not have particular restriction.Can select the preparation administration of various formulations according to patient age, sex and other condition and symptom.For example, tablet, pill, solution, suspension-s, emulsion, granule and capsule are oral administrations; Suppository is for being administered into rectum; Injection can be individually dosed, perhaps carries liquid (like saline water, glucose solution and amino acid solution) to be mixed into the row vein injection with injection, if necessary can be merely carries out injecting in muscle, intracutaneous, the subcutaneous or abdomen with injection.
Therefore, the invention still further relates to the pharmaceutical composition that comprises above-mentioned aryl urea compounds I or its pharmacy acceptable salt, polymorphic form, solvate or steric isomer.
Except as otherwise noted, the following term that in specification sheets of the present invention and claims, occurs has following implication:
Mean at " alkyl " of this use and to comprise the having radical of saturated aliphatic alkyl of specifying carbonatoms purpose straight chain and side chain.For example, " C
1-C
10Alkyl " be defined as and be included in the group that has 1,2,3,4,5,6,7,8,9 or 10 carbon atom in straight chain or the branched structure.For example, " 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 or the like.
Term " naphthenic base " is meant saturated or the unsaturated monocycle of part, many rings or bridge joint carbocyclic ring substituting group.Ring with 3-20 carbon atom can be expressed as C
3-C
20Naphthenic base; Ring with 5-15 carbon atom can be expressed as C
5-C
15Naphthenic base; Ring with 3-8 carbon atom can be expressed as C
3-C
8Naphthenic base, or the like.This term includes but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, 1H-indenyl, 2,3-indanyl, 1,2,3; 4-tetrahydrochysene-naphthyl, 5,6,7; 8-tetrahydrochysene-naphthyl, 8,9-dihydro-7H-benzocyclohepta alkene-6-base, 6,7; 8,9-tetrahydrochysene-5H-benzocyclohepta thiazolinyl, 5,6; 7,8,9; 10-six hydrogen-benzo cyclooctene base, fluorenyl, two ring [2.2.1] heptyl, two ring [2.2.1] heptenyls, two ring [2.2.2] octyl groups, two ring [3.1.1] heptyl, two ring [3.2.1] octyl groups, two ring [2.2.2] octenyl, two ring [3.2.1] octenyl, adamantyl, octahydro-4,7-methylene radical-1H-indenyl and octahydro-2,5-methylene radical-pentalene base or the like.Naphthenic substituent can be connected on the central element through any suitable carbon atom, and when allowing, can further replace it.
Term " alkoxyl group " expression has said carbonatoms purpose ring-type or a non-annularity alkyl through what oxo bridge connected.Thus, " alkoxyl group " comprises the definition of above alkyl and naphthenic base.
Term " thiazolinyl " is meant and contains straight chain, side chain or the ring-type non-aromatic hydrocarbon base that specifies number carbon atom and at least one carbon-carbon double bond.Carbon-carbon double bond of preferred existence, and can have non-fragrant carbon-carbon double bond up to four.Thus, " C
2-C
10Thiazolinyl " be meant thiazolinyl with 2-10 carbon atom." C
2-C
6Thiazolinyl " be meant thiazolinyl with 2-6 carbon atom, comprise vinyl, propenyl, crotonyl, 2-methyl butene base and cyclohexenyl.The straight chain of thiazolinyl, side chain or loop section can contain two keys, and if be indicated as substituted alkenyl, can be substituted so.
Term " alkynyl " is meant to contain and specifies number carbon atom and at least one carbon carbon triple-linked straight chain, side chain or cyclic hydrocarbon group.Wherein can exist up to three carbon carbon triple bonds.Thus, " C
2-C
10Alkynyl " be meant alkynyl with 2-10 carbon atom." C
2-C
6Alkynyl " be meant alkynyl with 2-6 carbon atom, comprise ethynyl, proyl, butynyl and 3-methyl butynyl or the like.
" aryl " in this use is meant that any stable monocycle, the dicyclo or three that in each ring, can comprise up to 7 atoms encircle carbocyclic rings, and wherein at least one ring is an aromatic nucleus.The instance of above-mentioned aryl unit comprises phenyl, naphthyl, tetralyl, 2,3-indanyl, 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 carried out through aromatic ring.
Can be in each ring of term " heteroaryl " expression of this use up to stable monocycle, dicyclo or three rings of 7 atoms, wherein at least one ring is aromatic nucleus and contains 1-4 heteroatoms that is selected from O, N and S.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 following heterocyclic definition, " heteroaryl " it should also be understood that to be the N-oxide derivative that comprises any nitrogenous heteroaryl.The heteroaryl substituting group is that two ring substituents and ring are non-aromatic rings or do not comprise under the heteroatomic situation therein, is appreciated that connection is respectively through aromatic ring or carry out through the heteroatoms that comprises ring.
The term " heterocycle " of this use perhaps " heterocyclic radical " expression contain 1-4 heteroatomic 5-10 unit's fragrance or nonaromatic heterocycles that is selected from O, N and S, and comprise bicyclic groups.Therefore, " heterocyclic radical " comprise above-mentioned heteroaryl with and dihydro or tetrahydrochysene analogue.Other instance of " heterocyclic radical " includes but not limited to following: benzimidazolyl-, benzofuryl, benzo furazan base, benzopyrazoles base, benzotriazole base, benzothienyl, benzoxazolyl, carbazyl, carbolinyl, cinnolines base, furyl, imidazolyl, indolinyl, indyl, indazolyl, isobenzofuran-base, pseudoindolyl, isoquinolyl, isothiazolyl 、 isoxazolyl, naphthalene pyrimidyl 、 oxadiazole Ji 、 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, 1,4-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 oxadiazole base, dihydro-oxazole base, dihydro pyrazinyl, pyrazoline base, dihydropyridine base, dihydro-pyrimidin base, pyrrolin base, EEDQ 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.The heterocyclic radical substituting group can connect through carbon atom or heteroatoms.
Term " halogen " expression fluorine, chlorine, bromine, iodine, astatine.
The substituted alkyl in term " haloalkyl " expression halogen optional position.Thus, " haloalkyl " comprises the definition of above halogen and alkyl.
Term " saturated heterocyclyl " expression contains 1-4 and is selected from the heteroatomic 4-9 of O, N or S unit nonaromatic heterocycles base, and comprises bicyclic groups, does not wherein comprise unsaturated double-bond, and the saturated heterocyclyl substituting group can connect through carbon atom or heteroatoms.Nitrogen wherein, sulfur heteroatom can be by any oxidations, and nitrogen heteroatom can also be by quaternary ammoniated arbitrarily.For example, Pyrrolidine base, piperazinyl, morpholinyl, piperidyl, tetrahydrofuran base, THP trtrahydropyranyl, thio-morpholinyl, imidazolidine base, thiazolidine base, oxidation piperazinyl, oxidation piperidyl, thiomorpholine sulfoxide or thiomorpholine sulfone or the like.
Among the present invention, on the basis of this area general knowledge, but above-mentioned each preferred feature arbitrary combination promptly gets each preferred embodiments of the present invention.
Except that specified otherwise, raw material that the present invention relates to and reagent are all commercially available to be got.
Positive progressive effect of the present invention is: the present invention has found one type suc as formula the brand-new aryl urea compounds shown in the I; It is active that it possesses stronger antitumor cell growth and anti-angiogenic rebirth, and it has stronger inhibition activity for the protein kinase with multiple disease-related.
Embodiment
Further specify the present invention with embodiment below, but the present invention is not limited.
The chemistry embodiment of first part
NMR is the INOVA-400 of Varian company, under 400MHz, measures the hydrogen spectrum; Mass spectrograph is the Micromass Q-Tofmicro of Waters company, electron spray ionisation (ESI).
Midbody compound II's is synthetic
The preparation of isocyanic ester method: J series side chain urea
Embodiment 11-(3-chloro-4-fluorophenyl)-3-(3-nitrophenyl) urea (JX-1)
(4.40g 14.8mmol) is dissolved in the anhydrous methylene chloride (80mL), and under nitrogen protection and 31～34 ℃, (5.82g is 40mmol) with DIEA (6.20g, anhydrous methylene chloride 48mmol) (40mL) solution, stirring 0.5h to drip 3-chloro-4-fluoroaniline with TRIPHOSGENE 99.5.Add then the 3-N-methyl-p-nitroaniline (5.52g, 40mmol), DIEA (6.20g, 48mmol) and the mixed solution of anhydrous methylene chloride (70mL), stirring at room 1h.After the gained reaction solution is used 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 ETHYLE ACETATE-sherwood oil (1: 4) making beating; Be 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-(3-chloro-4-fluorophenyl)-3-(3-aminophenyl) urea (J-1)
With JX-1 (10.22g; 33mmol), through the reduced iron powder (11.06g of 1mol/L hydrochloric acid activation; 198mmol), (1.77g 33mmol) drops into stirring and refluxing 1.5h in the mixed solvent of being made up of 95% ethanol (450mL), THF (150mL) and water (60mL) to ammonium chloride.Through the zeyssatite filtered while hot, concentrating under reduced pressure filtrating adds water and acetic acid ethyl dissolution gained residue, use ammoniacal liquor alkalize to pH be 9.Obtain organic layer, water layer is used ethyl acetate extraction again, merges organic phase, and anhydrous sodium sulfate drying, concentrating under reduced pressure obtain 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)
(2.20g 7.4mmol) is dissolved in the methylene dichloride (40mL), under nitrogen protection and 30～35 ℃ with TRIPHOSGENE 99.5; Drip 3-N-methyl-p-nitroaniline (2.76g; 20mmol) and DIEA (3.10g, the 24mmol) suspension in methylene dichloride (84mL) drip off back restir 0.5h.Add then 3-(trifluoromethyl)-4-chloroaniline (3.91g, 20mmol) and DIEA (3.10g, methylene dichloride 24mmol) (20mL) solution, stirring at room 1h.With gained reaction solution concentrating under reduced pressure; The gained residue with acetic acid ethyl dissolution after, use 10% aqueous potassium hydrogen sulfate, 5% sodium bicarbonate aqueous solution and saturated common salt water washing successively after, anhydrous sodium sulfate drying; Concentrating under reduced pressure; The gained residue obtains JX-3 through ETHYLE ACETATE-sherwood oil (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-(4-chloro-3-(trifluoromethyl) phenyl) urea (J-3)
Replace JX-1 with JX-3, adopt the method that is similar to J-1 to prepare J-3, get light yellow crystallization (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 3-chloro-4-fluoroaniline with the 3-cyano-aniline, adopt the method that is similar to JX-1 to prepare JX-4, get 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 that is similar to J-1 to prepare J-4, get 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 (br s, 2H).
Embodiment 71-(3-nitrophenyl)-3-(3-fluorophenyl) urea (JX-9)
Replace 3-(trifluoromethyl)-4-chloroaniline with the 3-fluoroaniline, adopt the method that is similar to JX-3 to prepare JX-9, get 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 that is similar to J-1 to prepare J-9, get 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 3-chloro-4-fluoroaniline with hexahydroaniline, adopt the method that is similar to JX-1 to prepare JX-11, get 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 that is similar to J-1 to prepare J-11, get 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), and 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 3-chloro-4-fluoroaniline with the 3-monomethylaniline, adopt the method that is similar to JX-1 to prepare JX-13, get 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)
With JX-13 (1.71g 6.3mmol) replaces JX-1, adopts the method that is similar to J-1 to prepare J-13, 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), 2.24 (s, 3H).
Embodiment 131-(3-nitrophenyl)-3-(3,5-two (trifluoromethyl) phenyl) urea (JX-14)
With 3,5-two (trifluoromethyl) aniline replaces 3-(trifluoromethyl)-4-chloroaniline, adopts the method that is similar to JX-3 to prepare JX-14, gets 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-two (trifluoromethyl) phenyl) urea (J-14)
Replace JX-1 with JX-14, adopt the method that is similar to J-1 to prepare J-14, get 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, the 5-difluorophenyl) urea (JX-15)
With 2, the 5-difluoroaniline replaces 3-(trifluoromethyl)-4-chloroaniline, adopts the method that is similar to JX-3 to prepare JX-15, gets glassy 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, the 5-difluorophenyl) urea (J-15)
Replace JX-1 with JX-15, adopt the method that is similar to J-1 to prepare J-15, get 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 (br s, 2H).
Embodiment 171-(3-nitrophenyl)-3-(2-methyl-5-fluorophenyl) urea (JX-16)
Replace 3-(trifluoromethyl)-4-chloroaniline with 5-fluoro-2-aminotoluene, adopt the method that is similar to JX-3 to prepare JX-16, get 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 that is similar to J-1 to prepare J-16, get 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 (br s, 2H), 2.15 (s, 3H).
Embodiment 191-(3-nitrophenyl)-3-(thiazol-2-yl) urea (JX-17)
Replace 3-chloro-4-fluoroaniline with thiazolamine, adopt the method that is similar to JX-1 to prepare JX-17, get yellow solid (yield 70%):
1H-NMR (DMSO-d
6) δ 10.78 (br s, 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 that is similar to J-1 to prepare J-17, get light yellow crystalline powder (yield 100%): MS-ESI m/z 235 (M+H)
+
Embodiment 211-(3-nitrophenyl)-3-(4-(tetramethyleneimine-1-yl) butyl) urea (JX-18)
Replace 3-(trifluoromethyl)-4-chloroaniline with 4-(tetramethyleneimine-1-yl) butane-1-amine, adopt the method that is similar to JX-3 to prepare JX-18, get 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-(tetramethyleneimine-1-yl) butyl) urea (J-18)
Replace JX-1 with JX-18, adopt the method that is similar to J-1 to prepare J-18, get 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 3-chloro-4-fluoroaniline with isobutylamine, adopt the method that is similar to JX-1 to prepare JX-19, get 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 (br s, 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 that is similar to J-1 to prepare J-18, get light yellow solid (yield 93%): MS-ESI m/z 208 (M+H)
+
The preparation of isocyanic ester method: P series side chain urea
Embodiment 251-(3-chloro-4-fluorophenyl)-3-(4-aminophenyl) urea (P-1)
(0.72g 2.4mmol) is dissolved in the methylene dichloride (10mL) with TRIPHOSGENE 99.5.In the cooling of nitrogen protection and ice-water bath down, drip 3-chloro-4-fluoroaniline (0.87g, 6mmol) and DIEA (0.93g, methylene dichloride 7.2mmol) (20mL) solution, stirring 0.5h.Add Ursol D (0.66g, 6mmol), DIEA (0.93g, methylene dichloride 7.2mmol) (20mL) solution, stirring at room 24h, concentrating under reduced pressure reaction solution.With ETHYLE ACETATE (60mL) dissolving gained oily residue, successively with 10% aqueous potassium hydrogen sulfate, 5% sodium bicarbonate aqueous solution and the washing of half saturated salt solution, anhydrous magnesium sulfate drying, concentrating under reduced pressure obtains light yellow solid.Through column chromatography purification (alkali alumina, ETHYLE ACETATE: sherwood oil 3: 5～3: 0) obtain white solid P-1 (yield 39%):
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 3-chloro-4-fluoroaniline with 3-(trifluoromethyl)-4-chloroaniline, adopt the method that is similar to P-1 to prepare P-3, get the 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 3-chloro-4-fluoroaniline with the 3-cyano-aniline, adopt the method that is similar to P-1 to prepare P-4, get 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 (br s, 2H).
Embodiment 281-cyclohexyl-3-(4-aminophenyl) urea (P-11)
Replace 3-chloro-4-fluoroaniline with hexahydroaniline, adopt the method that is similar to P-1 to prepare P-4, get the lightpink 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 (br s, 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 3-chloro-4-fluoroaniline with the 3-monomethylaniline, adopt the method that is similar to P-1 to prepare P-4, get the lightpink solid:
1H-NMR (DMSO-d
6) δ 8.32 (s, 1H), 8.05 (s, 1H), 8.25 (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-(tetramethyleneimine-1-yl) butyl) urea (P-18)
Replace 3-chloro-4-fluoroaniline with 4-(tetramethyleneimine-1-yl) butane-1-amine, adopt the method that is similar to P-1 to prepare P-18, get light gray solid:
1H-NMR (DMSO-d
6) δ 7.80 (s, 1H), 6.99 (d, 2H, J=8.4Hz), 6.46 (d, 2H, J=8.8Hz), 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-ESI m/z 208 (M+H)
+
Embodiment 311-isobutyl--3-(4-aminophenyl) urea (P-19)
Replace 3-chloro-4-fluoroaniline with isobutylamine, adopt the method that is similar to P-1 to prepare P-19, get the 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)
(1.63g 10.5mmol) is dissolved in the acetonitrile (12mL) with TRIPHOSGENE 99.5.Under nitrogen protection and ice-water bath cooling, drip 4-N-methyl-p-nitroaniline (1.07g, acetonitrile 11mmol) (20mL) solution.Stirring at room 1h, backflow 18h, cooling back concentrating under reduced pressure gets yellow solid.The adding morpholine (1.01g, acetonitrile 11mmol) (10mL) solution, stirring at room 5h, concentrating under reduced pressure, the making beating that adds methylene chloride 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)
With above-mentioned product P X-12 (1.55g 6mmol), is added to ethanol: water (2: 1) (54mL) in, (1.64g, 27.3mmol), refluxing adds the activatory reduced iron powder down (1.38g 24.7mmol), continues backflow 1h to add glacial acetic acid.Be cooled to 35 ℃, regulate pH to 9-10, suction filtration with strong aqua.Filtrate decompression is concentrated, and the gained residue adds the ETHYLE ACETATE making beating and obtains lightpink 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 (br s, 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 that is similar to PX-12 to prepare PX-17, get yellow solid (yield 99%):
1H-NMR (DMSO-d
6) δ 10.78 (br s, 1H), 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 that is similar to P-12 to prepare P-17, get 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 (br s, 2H).
The carbamate method:
Embodiment 36N-(3-nitrophenyl) morpholine-4-methane amide (JX-12)
With p-nitrophenyl chloroformate ester (1.02g 5.5mmol) is dissolved among the THF (20mL), under nitrogen protection 0 ℃ drip the 3-N-methyl-p-nitroaniline (0.68g, THF 5mmol) (5mL) solution, add then triethylamine (0.55g, 5.5mmol), restir 0.5h.Add morpholine (0.44g, 5.5mmol) and triethylamine (0.55g, 5.5mmol), backflow 4h.The concentrating under reduced pressure reactant, the extraction residue that adds methylene chloride, water, 1mol/L hydrochloric acid, saturated sodium bicarbonate aqueous solution and the washing of 5% sodium-chlor successively, anhydrous sodium sulfate drying, concentrating under reduced pressure obtains yellow solid.Silica gel column chromatography (ETHYLE ACETATE: sherwood oil: methylene dichloride 4: 5: 3) purifying is after the Virahol recrystallization obtains yellow crystals (0.35g, 28%):
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 that is similar to J-1 to prepare J-12, get 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).
Synthesizing of Ia, Ib, Ic, Id and Ie series compound
Embodiment 384-(3-(4-chloro-7-methoxyl group quinazoline-6-base oxygen) propyl group) morpholine hydrochloride (Q1)
(3.19g 10mmol), sulfur oxychloride (50mL) and dry DMF (1mL) refluxing and stirring 2h, is chilled to room temperature, adds toluene and revolves and steam band residual chloride sulfoxide to the greatest extent, gets the yellow solid residue with 7-methoxyl group-6-(morpholinyl propoxy-) quinazoline-4-alcohol.Add Virahol (15mL) room temperature making beating 2h, suction filtration, vacuum-drying get 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) refluxing and stirring 3h.Be chilled to room temperature, add entry (10mL), methylene dichloride (50mL) and methyl alcohol (10mL) dissolving gained reactant, transfer pH to 7.5, use dichloromethane extraction again with the 1mol/L aqueous sodium hydroxide solution.Merge organic layer, through brine wash, anhydrous sodium sulfate drying, revolve steam bullion.Gained bullion silica gel column chromatography, use ETHYLE ACETATE: ethanol: triethylamine (300: 100: 1) wash-out, after recrystallizing methanol, vacuum-drying (50 ℃, 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-ESI m/z 547 (M+H)
+
Embodiment 401-(3-chloro-4-fluorophenyl)-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 that is similar to D2-9 to prepare D1-1, get 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-ESI m/z 581 (M+H)
+
Embodiment 411-(4-chloro-3-(trifluoromethyl) phenyl)-3-(4-(7-methoxyl group-6-(morpholinyl propoxy-) quinazoline-4-base amido) phenyl) urea (D1-3)
Replace J-9 with P-3, adopt the method that is similar to D2-9 to prepare D1-3, get 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-ESI m/z 631 (M+H)
+
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 that is similar to D2-9 to prepare D1-4, get 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-ESI m/z 554 (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 that is similar to D2-9 to prepare D1-11, get 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), and 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-ESI m/z 535 (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 that is similar to D2-9 to prepare D1-12, get 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-ESI m/z 523 (M+H)
+
Tolyl-3-between embodiment 451-(4-(7-methoxyl group-6-(morpholinyl propoxy-) quinazoline-4-base amido) phenyl) urea (D1-13)
Replace J-9 with P-13, adopt the method that is similar to D2-9 to prepare D1-13, get 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-ESI m/z 543 (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 that is similar to D2-9 to prepare D1-17, get near-white solid (yield 86%):
1HNMR (DMSO-d
6) δ 10.78 (br s, 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-ESI m/z 536 (M+H)
+
Embodiment 471-(4-(7-methoxyl group-6-(morpholinyl propoxy-) quinazoline-4-base amido) phenyl)-3-(4-(tetramethyleneimine-1-yl) butyl) urea (D1-18)
Replace J-9 with P-18, adopt the method that is similar to D2-9 to prepare D1-18, get 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-ESI m/z 578 (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 that is similar to D2-9 to prepare D1-19, get 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-ESI m/z 509 (M+H)
+
Embodiment 491-(3-chloro-4-fluorophenyl)-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 that is similar to D2-9 to prepare D2-1, get 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-ESI m/z 581 (M+H)
+
Embodiment 501-(4-chloro-3-(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 that is similar to D2-9 to prepare D2-3, get 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-ESI m/z 631 (M+H)
+
Embodiment 511-(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 that is similar to D2-9 to prepare D2-4, get 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-ESI m/z 552 (M-H)
-
Embodiment 521-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 that is similar to D2-9 to prepare D2-11, get 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-ESI m/z 535 (M+H)
+
Embodiment 53N-(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 that is similar to D2-9 to prepare D2-12, get 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-ESI m/z523 (M+H)
+
Tolyl-3-between embodiment 541-(3-(7-methoxyl group-6-(morpholinyl propoxy-) quinazoline-4-base amido) phenyl) urea (D2-13)
Replace J-9 with J-13, adopt the method that is similar to D2-9 to prepare D2-13, get 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, and 3H) 2.02 (m, 2H); MS-ESI m/z 543 (M+H)
+
Embodiment 551-(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 that is similar to D2-9 to prepare D2-17, get near-white solid (yield 36%):
1HNMR (DMSO-d
6) δ 10.44 (br s, 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-ESI m/z 536 (M+H)
+
Embodiment 561-(3-(7-methoxyl group-6-(morpholinyl propoxy-) quinazoline-4-base amido) phenyl)-3-(4-(tetramethyleneimine-1-yl) butyl) urea (D2-18)
Replace J-9 with J-18, adopt the method that is similar to D2-9 to prepare D2-18, get 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-ESI m/z 578 (M+H)
+
Embodiment 571-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 that is similar to D2-9 to prepare D2-19, get 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-ESI m/z 509 (M+H)
+
Embodiment 587-fluquinconazole quinoline-4 (3H)-ketone
Under nitrogen protection, (30g 190mmol) and methane amide (240mL), rises to 150 ℃ of insulated and stirred 6h in reaction flask, to add 2-amino-4-fluorobenzoic acid.The gained reactant is chilled to about 100 ℃, and the mixture of ice and water (2L) under impouring is stirred stirs the 1h after-filtration.After the filter cake washing, vacuum-drying (50 ℃ 9h) get tawny solid 52 (24.5g, 77%):
1HNMR (DMSO-d6) δ 12.27 (br s, 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 597-(morpholinyl propoxy-) quinazoline-4 (3H)-ketone (Q2T)
A) morpholinyl third-1-alcohol
With the 3-bromopropyl alcohol (70g 0.5mol) is dissolved in toluene (300mL), room temperature drip morpholine (87g, 1mol).Rise to 80 ℃ of insulated and stirred 4h after dripping off.Be chilled to room temperature, filter the gained suspension liquid, filter cake is used toluene wash.Merge diafiltration liquid and revolve steaming, underpressure distillation gained residue is collected 96～98 ℃/5mmHg of bp cut, gets colourless liquid (61.7g, 85%).
B) 7-(morpholinyl propoxy-) quinazoline-4 (3H)-ketone (Q2T)
With morpholinyl third-1-alcohol (14.52g; 100mmol) be dissolved in dry DMF (20mL), be chilled to 0 ℃ drop in batches 60% sodium hydride (4g, 100mmol); Add 7-fluquinconazole quinoline-4 (3H)-ketone (51) (2.74g then in batches; 17mmol), rise to 60 ℃, 90 ℃ each insulated and stirred 30min, 100min, rise to 110 ℃ of insulated and stirred 3h again.The gained reactant is chilled to room temperature, and the mixture of ice and water under impouring is stirred behind concentrated hydrochloric acid accent pH to 6, is used dichloromethane extraction.United extraction liquid revolves steaming behind washing, anhydrous sodium sulfate drying.In the gained residue, add the ether making beating, suction filtration is used the ether washing leaching cake, vacuum-drying (50 ℃ 4h) get jade green sand property solid Q2T (2.8g, 57%):
1HNMR (DMSO-d
6) δ 11.99 (br s, 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-ESI m/z 289 (M+H)
+
Embodiment 604-(3-(4-chloro-quinazoline-7-base oxygen) propyl group) morpholine hydrochloride (Q2)
With Q2T (1.4g, 4.8mmol), (0.35g, 4.8mmol) refluxing and stirring 2h is chilled to room temperature, adds toluene and revolves and steam band residual chloride sulfoxide to the greatest extent for sulfur oxychloride (22mL) and dry DMF.The gained residue is with Virahol (10mL) making beating 2h, and suction filtration, vacuum-drying get yellow solid Q2 (1.51g, 92%).
Embodiment 671-(3-chloro-4-fluorophenyl)-3-(3-(7-(morpholinyl propoxy-) quinazoline-4-base amido) phenyl) urea (D4-1)
With Q2 (0.34g, 1mmol), (0.35g 1.25mmol), Virahol (8mL) and hydrogenchloride Virahol saturated solution (2mL) refluxing and stirring 4h, is chilled to room temperature to J-1, revolves steaming.In the gained residue, add water (10mL), transfer pH to 9～10., extract with methylene chloride-methanol (v/v, 3: 1) with the 1mol/L aqueous sodium hydroxide solution.United extraction liquid revolves steaming behind washing, anhydrous sodium sulfate drying.With gained residue silica gel column chromatography twice, use ETHYLE ACETATE: ethanol: triethylamine (90: 10: 0.5) wash-out gets nearly 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-ESI m/z 601 (M+H)
+
Embodiment 681-(4-chloro-3-(trifluoromethyl) phenyl)-3-(3-(7-(morpholinyl propoxy-) quinazoline-4-base amido) phenyl) urea (D4-3)
Replace J-1 with J-3, adopt the method that is similar to D4-1 to prepare D4-3, get light yellow crystallization (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-ESI m/z 601 (M+H)
+
Embodiment 691-(4-(7-(morpholinyl propoxy-) quinazoline-4-base amido) phenyl)-3-(4-(tetramethyleneimine-1-yl) butyl) urea (D3-18)
Replace J-1 with P-18, adopt the method that is similar to D4-1 to prepare D3-18, get 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-ESI m/z 548 (M+H)
+
Embodiment 701-(3-(7-(morpholinyl propoxy-) quinazoline-4-base amido) phenyl)-3-(4-(tetramethyleneimine-1-yl) butyl) urea (D4-18)
Replace J-1 with J-18, adopt the method that is similar to D4-1 to prepare D4-18, get 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-ESI m/z 548 (M+H)
+
Embodiment 717-(3-(4-N-METHYL PIPERAZINE-1-yl) propoxy-) quinazoline-4 (3H)-ketone (Q3T)
A) 3-(4-N-METHYL PIPERAZINE-1-yl) third-1-alcohol
Under nitrogen, with N-METHYL PIPERAZINE (31.6g 0.32mol) is dissolved in toluene (150mL), room temperature drip the 3-bromopropyl alcohol (20.8g, 0.15mol).Rise to 80 ℃ of insulated and stirred 2h after dripping off.Be chilled to room temperature, filter the gained suspension liquid, filter cake is used toluene wash.Merge diafiltration liquid and revolve steaming, underpressure distillation gained residue is collected bp100 ℃/1mmHg cut, gets light yellow oil (18.27g, 77%):
1H-NMR (DMSO-d
6) δ 4.80 (br s, 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-N-METHYL PIPERAZINE-1-yl) propoxy-) quinazoline-4 (3H)-ketone (Q3T)
Replace morpholinyl third-1-alcohol with 3-(4-N-METHYL PIPERAZINE-1-yl) third-1-alcohol, adopt the method that is similar to Q2T to prepare Q3T, get light yellow crystallization (1.78g, 40%):
1H-NMR (DMSO-d
6) δ 11.99 (br s, 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).
Embodiment 724-chloro-7-(3-(4-N-METHYL PIPERAZINE-1-yl) propoxy-) quinazoline hydrochloride (Q3)
Replace Q2T with Q3T, adopt the method that is similar to Q2 to prepare Q3, get khaki color solid (yield 100%).
Embodiment 731-(3-chloro-4-fluorophenyl)-3-(3-(7-(3-(4-N-METHYL PIPERAZINE-1-yl) propoxy-) quinazoline-4-base amido) phenyl) urea (D8-1)
Replace Q2 with Q3, adopt the method that is similar to D4-1 to prepare D8-1, get 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-ESI m/z 564 (M+H)
+
Embodiment 741-(4-chloro-3-(trifluoromethyl) phenyl)-3-(3-(7-(3-(4-N-METHYL PIPERAZINE-1-yl) propoxy-) quinazoline-4-base amido) phenyl) urea (D8-3)
Replace Q2 with Q3, replace J-1, adopt the method that is similar to D4-1 to prepare D8-3, get light gray solid (yield 8%) with J-3:
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-ESI m/z614 (M+H)
+
Embodiment 751-(3-(7-(3-(4-N-METHYL PIPERAZINE-1-yl) propoxy-) quinazoline-4-base amido) phenyl)-3-(4-(tetramethyleneimine-1-yl) butyl) urea (D8-18)
Replace Q2 with Q3, replace J-1, adopt the method that is similar to D4-1 to prepare D8-18, get near-white solid (yield 10%) with J-18:
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-ESI m/z 561 (M+H)
+
Embodiment 76 7-((1-methyl piperidine-4-yl) methoxyl group) quinazoline-4 (3H)-ketone (Q4T)
With (1-methyl piperidine-4-yl) methyl alcohol) replace morpholinyl third-1-alcohol, adopt the method that is similar to Q2T to prepare Q4T, get near-white crystallization (yield 40%):
1H-NMR (DMSO-d
6) δ 12.00 (br s, 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/z 274 (M+H)
+
Embodiment 774-chloro-7-((1-methyl piperidine-4-yl) methoxyl group) quinazoline hydrochloride (Q4)
Replace Q2T with Q4T, adopt the method that is similar to Q2 to prepare Q4, get khaki color solid (yield 100%).
Embodiment 781-(3-chloro-4-fluorophenyl)-3-(3-(7-((1-methyl piperidine-4-yl) methoxyl group) quinazoline-4-base amido) phenyl) urea (D10-1)
Replace Q2 with Q4, adopt the method that is similar to D4-1 to prepare D10-1, get 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/z 535 (M+H)
+
Embodiment 791-(4-chloro-3-(trifluoromethyl) phenyl)-3-(3-(7-((1-methyl piperidine-4-yl) methoxyl group) quinazoline-4-base amido) phenyl) urea (D10-3)
Replace Q2 with Q4, replace J-1, adopt the method that is similar to D4-1 to prepare D10-3, get near-white solid (yield 14%) with J-3:
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/z 585 (M+H)
+
Embodiment 801-(3-fluorophenyl)-3-(3-(7-((1-methyl piperidine-4-yl) methoxyl group) quinazoline-4-base amido) phenyl) urea (D10-9)
Replace Q2 with Q4, replace J-1, adopt the method that is similar to D4-1 to prepare D10-9, get near-white solid (yield 7%) with J-9:
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-ESI m/z 501 (M+H)
+
Embodiment 811-(3-(6,7-two (2-methoxy ethoxy) quinazoline-4-base amido) phenyl)-3-(3-chloro-4-fluorophenyl) urea (D6-1)
With Q5 (0.31g, 1mmol), J-1 (0.35g, 1.25mmol), Virahol (5mL) and hydrogenchloride Virahol saturated solution (3mL) refluxing and stirring 4h.Revolve and steam the gained reactant, in the gained residue, add water (10mL), with 1mol/L aqueous sodium hydroxide solution accent pH to 9～10., extract with methylene chloride-methanol (v/v, 3: 1).United extraction liquid revolves steaming behind washing, anhydrous sodium sulfate drying.With gained residue silica gel column chromatography, use ETHYLE ACETATE: ethanol: triethylamine (v/v, 200: 10: 0～70: 10: 1) gradient elution, use ETHYLE ACETATE at last: sherwood oil (v/v, 1: 8) making beating, filtration drying gets 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-ESI m/z 556 (M+H)
+
Embodiment 821-(3-(6,7-two (2-methoxy ethoxy) quinazoline-4-base amido) phenyl)-3-(4-chloro-3-(trifluoromethyl) phenyl) urea (D6-3)
Replace J-1 with J-3, adopt the method that is similar to D6-1 to prepare D6-3, get near-white solid (yield 31%):
1H-NMR (DMSO-d
6) δ 9.41 (br s, 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-ESI m/z 606 (M+H)
+
Embodiment 831-(3-(6,7-two (2-methoxy ethoxy) quinazoline-4-base amido) phenyl)-3-(3-fluorophenyl) urea (D6-9)
Replace J-1 with J-9, adopt the method that is similar to D6-1 to prepare D6-9, get 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/z 522 (M+H)
+
Embodiment 841-(4-(6,7-two (2-methoxy ethoxy) quinazoline-4-base amido) phenyl)-3-(4-(tetramethyleneimine-1-yl) butyl) urea (D5-18)
Replace J-1 with P-18, adopt the method that is similar to D6-1 to prepare D5-18, get 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-ESI m/z 553 (M+H)
+
Embodiment 851-(3-(6,7-two (2-methoxy ethoxy) quinazoline-4-base amido) phenyl)-3-(4-(tetramethyleneimine-1-yl) butyl) urea (D6-18)
Replace J-1 with J-18, adopt the method that is similar to D6-1 to prepare D6-18, get 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-ESI m/z 553 (M+H)
+
Synthesizing of If series compound
Embodiment 867-(3-hydroxyl propoxy-) quinazoline-4 (3H)-ketone (7)
With 1, (13.9g 183mmol) is dissolved in DMF (20mL) to ammediol in the 100mL three-necked bottle; Be chilled to 0 ℃ and drop into 60% sodium hydride (7.3g in batches; 183mmol), add then in batches 7-fluquinconazole quinoline-4 (3H)-ketone (5g, 30.5mmol); Rise to 50 ℃ and 90 ℃ of each insulated and stirred 1h, rise to 120 ℃ of insulated and stirred 3h again.The gained reactant is chilled to 25 ℃, and the mixture of ice and water (280mL) under impouring is stirred is transferred pH to 6 with concentrated hydrochloric acid, the solid that the filter collection is separated out.Filter cake is water and ether washing successively, vacuum-drying (50 ℃ 6h) get light brown solid 7 (6.27g, 93%):
1H-NMR (DMSO-d
6) δ 11.94 (br s, 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).
Embodiment 874-chloro-7-(3-chlorine propoxy-) quinazoline (8)
With 7 (6g, 27mmol), sulfur oxychloride (60mL) and DMF (0.57g, 7.8mmol) refluxing and stirring 2h.Be chilled to room temperature, revolve with toluene and steam band sulfur oxychloride to the greatest extent.With methylene dichloride (80mL) dissolving gained residue,, carry with methylene dichloride is counter again with the saturated sodium bicarbonate aqueous solution washing.Merge organic layer, add SODIUM SULPHATE ANHYDROUS 99PCT and gac and stir, revolve steaming after the filtration.In the gained residue, add ether, the solid that filtering is separated out revolves steaming and does near, adds the sherwood oil after-filtration, vacuum-drying (50 ℃ 2.5h) get tawny 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 881-(4-chloro-3-(trifluoromethyl) phenyl)-3-(3-(7-(3-chlorine propoxy-) quinazoline-4-base amido) phenyl) urea (D52-3-0)
With 53 (0.55g, 2mmol), J-3 (0.66g, 2mmol), Virahol (9mL) and hydrogenchloride Virahol saturated solution (2mL) refluxing and stirring 3h.Be chilled to room temperature, transfer pH to 6～7 with the 1mol/L aqueous sodium hydroxide solution.Use methyl alcohol: methylene dichloride (3: 1) and methylene dichloride extract successively, merge organic layer, behind brine wash, anhydrous sodium sulfate drying, revolve steaming.Crystallization gained residue in methyl alcohol filters, vacuum-drying (50 ℃ 6h) get near-white flake-like crystal (0.83g, 75%):
1HNMR (DMSO-d
6) δ 10.87 (br s, 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/z 550 (M+H)
+
Embodiment 891-(3-chloro-4-fluorophenyl)-3-(3-(7-(3-chlorine propoxy-) quinazoline-4-base amido) phenyl) urea (D52-1-0)
Replace J-3 with J-1, adopt the method that is similar to D52-3-0 to prepare D52-1-0, get near-white solid (yield 60%):
1HNMR (DMSO-d
6) δ 9.70 (br s, 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-ESI m/z500 (M+H)
+
Embodiment 901-(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 that is similar to D52-3-0 to prepare D52-9-0, get near-white solid (yield 48%):
1HNMR (DMSO-d
6) δ 11.22 (br s, 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-ESI m/z 466 (M+H)
+
Embodiment 911-(3-(7-(3-chlorine propoxy-) quinazoline-4-base amido) phenyl)-3-(4-(tetramethyleneimine-1-yl) butyl) urea (D52-18-0)
Replace J-3 with J-18, adopt the method that is similar to D52-3-0 to prepare D52-18-0, get colourless needle (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-ESI m/z 519 (M+H)
+
Embodiment 921-(4-chloro-3-(trifluoromethyl) phenyl)-3-(3-(7-(3-(4-(2-hydroxyethyl) piperazine-1-yl) propoxy-) quinazoline-4-base amido) phenyl) urea (D52-3-1)
With D52-3-0 (0.15g, 0.28mmol), potassiumiodide (0.09g, 0.56mmol), 2-(piperazine-1-yl) ethanol (0.15g, 1.12mmol) and N-Methyl pyrrolidone (NMP) (2mL) 50 ℃ of shadings stir 32h.Be chilled to room temperature; The gained reactant is directly gone up the appearance silica gel column chromatography; Use ETHYLE ACETATE: ethanol: triethylamine gradient elution (300: 100: 1.5～100: 100: 1.5); After methyl alcohol: ETHYLE ACETATE (6: 1) recrystallization, vacuum-drying (50 ℃, 6h) light yellow solid (0.07g, 39%):
1HNMR (DMSO-d
6) δ 11.40 (br s, 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-ESI m/z 644 (M+H)
+
Embodiment 931-(3-chloro-4-fluorophenyl)-3-(3-(7-(3-(4-(2-hydroxyethyl) piperazine-1-yl) propoxy-) quinazoline-4-base amido) phenyl) urea (D52-1-1)
Replace D52-3-0 with D52-1-0, adopt the method that is similar to D52-3-1 to prepare D52-1-1, get 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-ESI m/z 594 (M+H)
+
Embodiment 941-(3-fluorophenyl)-3-(3-(7-(3-(4-(2-hydroxyethyl) piperazine-1-yl) propoxy-) quinazoline-4-base amido) phenyl) urea (D52-9-1)
Replace D52-3-0 with D52-9-0, adopt the method that is similar to D52-3-1 to prepare D52-9-1, get yellow crystal (yield 19%):
1H-NMR (DMSO-d
6) δ 10.59 (br s, 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 (br s, 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-ESI m/z 560 (M+H)
+
Embodiment 951-(3-(7-(3-(4-(2-hydroxyethyl) piperazine-1-yl) propoxy-) quinazoline-4-base amido) phenyl)-3-(4-(tetramethyleneimine-1-yl) butyl) urea (D52-18-1)
Replace D52-3-0 with D52-18-0, adopt the method that is similar to D52-3-1 to prepare D52-18-1, get 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 (br s; 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-ESI m/z 519 (M+H)
+
Embodiment 961-(3-(7-(3-(ethyl (2-hydroxyethyl) amido) propoxy-) quinazoline-4-base amido) phenyl)-3-(3-fluorophenyl) urea (D52-9-4)
With D52-9-0 (0.13g, 0.28mmol), potassiumiodide (0.09g, 0.56mmol), 2-(ethylamino-) ethanol (0.1g, 1.12mmol) and 50 ℃ of shadings of NMP (1mL) stir 30h.Be chilled to room temperature, revolve steaming.With appearance silica gel column chromatography on the gained residue, use ETHYLE ACETATE: ethanol: triethylamine gradient elution (900: 100: 1～300: 100: 1), after absolute ethyl alcohol: re-crystallizing in ethyl acetate, vacuum-drying get 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 (br s, 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-ESI m/z 519 (M+H)
+
Embodiment 971-(3-chloro-4-fluorophenyl)-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 that is similar to D52-9-4 to prepare D52-1-4, get 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 (br s, 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-ESI m/z 553 (M+H)
+
Embodiment 981-(4-chloro-3-(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 that is similar to D52-9-4 to prepare D52-3-4, get 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 (br s, 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-ESI m/z 603 (M+H)
+
Embodiment 991-(3-(7-(3-(ethyl (2-hydroxyethyl) amido) propoxy-) quinazoline-4-base amido) phenyl)-3-(4-(tetramethyleneimine-1-yl) butyl) urea (D52-18-4)
Replace D52-9-0 with D52-18-0, adopt the method that is similar to D52-9-4 to prepare D52-18-4, get 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 (br s; 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-ESI m/z 519 (M+H)
+
Embodiment 1001-(3-fluorophenyl)-3-(3-(7-(3-(2-hydroxyethyl amido) propoxy-) quinazoline-4-base amido) phenyl) urea (D52-9-5)
With D52-9-0 (0.13g, 0.28mmol), potassiumiodide (0.09g, 0.56mmol), thanomin (0.07g, 1.12mmol) and N-Methyl pyrrolidone (NMP) (1mL) 50 ℃ of shadings stir 32h.Revolve the steaming reactant, in the gained residue, add entry, use methylene dichloride: methyl alcohol (3: 1) extracts.United extraction liquid revolves steaming.The gained residue is through preparation silica gel thin-layer chromatography (ETHYLE ACETATE: ethanol: triethylamine, 300: 100: 1) purifying, and vacuum-drying gets near-white crystalline solid (yield 29%):
1H-NMR (DMSO-d
6) δ 9.72 (br s, 1H), 9.67 (s, 1H), 9.41 (br s, 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 (br s, 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-ESI m/z 491 (M+H)
+
Embodiment 1011-(4-chloro-3-(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 that is similar to D52-9-5 to prepare D52-3-5, get near-white solid (yield 38%):
1H-NMR (DMSO-d
6) δ 10.14 (br s, 2H), 9.66 (br s, 1H), 9.56 (br s, 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 (br s, 1H); MS-ESI m/z 575 (M+H)
+
Synthesizing of Ig series compound
The preparation of L-3
Embodiment 1021-(4-chloro-3-(trifluoromethyl) phenyl)-3-(3-(6-iodine quinazoline-4-base amido) phenyl) urea (L-3-3)
Under nitrogen protection, with 2-amino-5-iodobenzene formonitrile HCN (1g, 4mmol) and DMF-DMA (1.93g, 16mmol) stirring and refluxing 1h in toluene (10mL), be chilled to revolve after the room temperature steam oily matter.Add J-3 (1.32g, 4mmol) and glacial acetic acid (10mL) stirring and refluxing 1h, revolve steam brownish black oily matter.Add ETHYLE ACETATE and saturated sodium bicarbonate aqueous solution, obtain organic layer after the filtration, through anhydrous sodium sulfate drying, revolve steam bullion, through silica gel column chromatography and absolute ethyl alcohol pull an oar brown solid L-3-3 (0.53g, 23%):
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-ESI m/z 584 (M+H)
+
Embodiment 1031-(4-chloro-3-(trifluoromethyl) phenyl)-3-(3-(6-(5-formylfuran-2-yl) quinazoline-4-base amido) phenyl) urea (L-4-3)
In reaction flask, drop into L-3-3 (0.58g, 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 ℃ of insulated and stirred 16h.Through zeyssatite suction filtration gained reactant while hot, revolve and steam filtrating.In the gained residue, add ETHYLE ACETATE (90mL) and saturated sodium bicarbonate aqueous solution (10mL), obtain organic layer after the stirring.Organic layer revolves steaming behind saturated brine washing, anhydrous sodium sulfate drying, vacuum-drying gets 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-ESI m/z 552 (M+H)
+
Embodiment 1041-(4-chloro-3-(trifluoromethyl) phenyl)-3-(3-(6-(5-((2-(methylsulfonyl) ethylamino-) methyl) furans-2-yl) quinazoline-4-base amido) phenyl) urea (L-3)
(0.28g 0.5mmol) is dissolved in the anhydrous tetrahydro furan (4.4mL), adds diisopropyl ethyl amine (DIEA) (0.13g with L-4-3; 1mmol), hydrochloric acid 2-(methylsulfonyl) ethamine (0.13g; 0.84mmol) and Virahol (0.08g), under nitrogen protection, stirring at room 3h.After adding anhydrous tetrahydro furan (4.3mL) dilution gained reactant, gradation add sodium triacetoxy borohydride (0.2g, 0.95mmol), stirring at room 2h then.Careful Dropwise 5 mol/L aqueous sodium hydroxide solution (1.25mL) in the gained reactant, restir 10min after-filtration.In filtrating, add ETHYLE ACETATE (60mL) and water (10mL), obtain organic layer behind the stirring 15min.Organic layer revolves steaming behind saturated brine washing, anhydrous sodium sulfate drying, vacuum-drying gets yellow L-3 bullion, through silica gel column chromatography (ETHYLE ACETATE: 100: 5 wash-outs of absolute ethyl alcohol) purifying gets beige solid L-3 (yield 24%):
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-ESI m/z 659 (M+H)
+
The preparation of L-1
Embodiment 1051-(3-chloro-4-fluorophenyl)-3-(3-(6-iodine quinazoline-4-base amido) phenyl) urea hydrochloride (L-3-1)
Replace J-3 with J-1, adopt the method that is similar to L-3-3 to prepare L-3-1, get light yellow crystallization (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).
Embodiment 1061-(3-chloro-4-fluorophenyl)-3-(3-(6-(5-formylfuran-2-yl) quinazoline-4-base amido) phenyl) urea (L-4-1)
Replace L-3-3 with L-3-1, adopt the method that is similar to L-4-3 to prepare L-4-1, get orange crystallization (yield 71%):
1HNMR (DMSO-d
6) δ 10.10 (br s, 1H), 9.69 (s, 1H), 9.22 (br s, 1H), 9.17 (br s, 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-ESI m/z 552 (M+H)
+
Embodiment 1071-(3-chloro-4-fluorophenyl)-3-(3-(6-(5-((2-(methylsulfonyl) ethylamino-) methyl) furans-2-yl) quinazoline-4-base amido) phenyl) urea (L-1)
Replace L-4-3 with L-4-1, adopt the method that is similar to L-3 to prepare L-1, get 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-ESI m/z 609 (M+H)
+
The preparation of L-14
Embodiment 1084-chloro-6-iodine quinazoline
In reaction flask, drop into 6-iodine quinazoline-4-one (5.44g, 20mmol), Phosphorus Oxychloride (3.68g, 24mmol) and dry toluene (16mL).Under nitrogen protection, and the dropping triethylamine (2.43g, 24mmol).Rise to 77 ℃ of insulated and stirred 2.5h after dripping off.With the gained reactant be chilled to 2 ℃ stir 1h after, suction filtration.Filter cake with washing with acetone after, room temperature making beating 30min in 1mol/L aqueous sodium hydroxide solution (26mL) again.Suction filtration, behind water and the washing with acetone, vacuum-drying gets beige crystalline solid (5.11g, 88%) successively:
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).
Embodiment 1091-(3,5-two (trifluoromethyl) phenyl)-3-(3-(6-iodine quinazoline-4-base amido) phenyl) urea hydrochloride (L-3-14)
Under nitrogen protection, with 4-chloro-6-iodine quinazoline (0.58g, 2mmol) and J-14 (0.73g, 2mmol) stirring and refluxing 2h in Virahol (15mL) slowly is chilled to the room temperature after-filtration, washed with isopropyl alcohol obtains tawny solid L-3-14 (0.94g, 76%):
1HNMR (DMSO-d
6) δ 11.36 (br s), 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).
Embodiment 1101-(3,5-two (trifluoromethyl) phenyl)-3-(3-(6-(5-formylfuran-2-yl) quinazoline-4-base amido) phenyl) urea (L-4-14)
Replace L-3-3 with L-3-14, adopt the method that is similar to L-4-3 to prepare L-4-14, get 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).
Embodiment 1111-(3,5-two (trifluoromethyl) phenyl)-3-(3-(6-(5-((2-(methylsulfonyl) ethylamino-) methyl) furans-2-yl) quinazoline-4-base amido) phenyl) urea (L-14)
Replace L-4-3 with L-4-14, adopt the method that is similar to L-3 to prepare L-14, get 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-ESI m/z 693 (M+H)
+
The preparation of L-15
Embodiment 1121-(2, the 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 that is similar to L-3-14 to prepare L-3-15, get yellow solid (yield 84%):
1HNMR (DMSO-d
6) δ 11.23 (br s), 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).
Embodiment 1131-(2, the 5-difluorophenyl)-3-(3-(6-(5-formylfuran-2-yl) quinazoline-4-base amido) phenyl) urea (L-4-15)
Replace L-3-3 with L-3-15, adopt the method that is similar to L-4-3 to prepare L-4-15, get 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).
Embodiment 1141-(2, the 5-difluorophenyl)-3-(3-(6-(5-((2-(methylsulfonyl) ethylamino-) methyl) furans-2-yl) quinazoline-4-base amido) phenyl) urea (L-15)
Replace L-4-3 with L-4-15, adopt the method that is similar to L-3 to prepare L-15, get 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-ESI m/z 593 (M+H)
+
The preparation of L-16
Embodiment 1151-(2-methyl-5-fluorophenyl)-3-(3-(6-iodine quinazoline-4-base amido) phenyl) urea hydrochloride (L-3-16)
For J-14, adopt the method that is similar to L-3-14 to prepare L-3-16 with J-16, get tawny solid (yield 93%):
1HNMR (DMSO-d
6) δ 11.42 (br s), 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).
Embodiment 1161-(2-methyl-5-fluorophenyl)-3-(3-(6-(5-formylfuran-2-yl) quinazoline-4-base amido) phenyl) urea (L-4-16)
Replace L-3-3 with L-3-16, adopt the method that is similar to L-4-3 to prepare L-4-16, get light yellow crystallization (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).
Embodiment 1171-(2-methyl-5-fluorophenyl)-3-(3-(6-(5-((2-(methylsulfonyl) ethylamino-) methyl) furans-2-yl) quinazoline-4-base amido) phenyl) urea (L-16)
Replace L-4-3 with L-4-16, adopt the method that is similar to L-3 to prepare L-16, get 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/z 589 (M+H)
+
Second section biology embodiment
Embodiment 118 external anti-human tumor cell lines and the test of Human umbilical vein endothelial cells proliferation activity
1.1 materials and methods
Sample preparation: after DMSO (Merck) dissolving, add solution or uniform suspension that PBS (-) is made into 1000 μ g/ml, then with PBS (-) dilution that contains 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 by pharmacologically active test center of Shanghai Institute of Pharmaceutical Industry frozen with go down to posterity.
Nutrient solution: HUVEC is that DMEM+10～15%FBS+ is two anti-; All the other are that DMEM+10%NBS+ is two anti-, DMEM+10%FBS+ is two anti-.
Full-automatic ELIASA: model: WellscanMK-2, production firm: Labsystems.
TP: mtt assay.It is 1 * 10 that the every hole of 96 well culture plates adds concentration
5The HUVEC of individual/ml or concentration are 4-5 * 10
4Other cell suspensions 100 μ l of individual/ml put 37 ℃, 5%CO
2In the incubator.Behind the 24h, add sample liquid, two multiple holes are established in 10 μ l/ holes, and 37 ℃, 5%CO
2Effect 72h.Every hole adds the MTT solution 20 μ l of 5mg/ml, adds lysate behind the effect 4h, and put in the incubator in 100 μ l/ holes, and 570nm OD value is surveyed with the full-automatic ELIASA of WellscanMK-2 in the dissolving back.
Mtt assay.It is 1 * 10 that the every hole of 96 orifice plates adds concentration
5The cell suspension 100 μ l of individual/ml put 37 ℃, 5%CO
2In the incubator.Behind the 24h, add sample liquid, two multiple holes are established in 10 μ l/ holes, and 37 ℃, 5%CO
2Effect 48h.Every hole adds the MTT solution 20 μ l of 5mg/ml, adds lysate behind the effect 4h, and put in the incubator in 100 μ l/ holes, and 570nm OD value is surveyed with the full-automatic ELIASA of MK-2 in the dissolving back.
1.2 test-results
Test-results is seen table 1.
The concrete formula I compound of table 1 is to the in-vitro multiplication restraining effect of human tumor cells
Embodiment 119 external protein kinase inhibition tests
Adopt Caliper mobility shift assay (referring to .Journal of Biomolecular Screening such as Card A, 2009,14 (1): 31-42.) carry out the protein kinase inhibition test.The positive control that detects is not for adding the blank control group of sample, and negative control is the EDTA group, and reference compound is Staurosporine.Test item be 20 formula I compounds under 3 concentration such as 10,1 and 0.1 μ M, under ATP Km concentration for 10 kinase whose inhibition percentage such as ALK, AuroraA, EGFR, FGFR1, FLT-3, VEGFR-2, c-KIT, c-MET, PDGFR β and TIE-2.Used instrument is Caliper EZ Reader II.Kinase reaction condition and test-results are seen table 2, table 3 and table 4 respectively.
Table 2 kinase reaction condition
| Kinases | Kinases concentration (nM) | ATP concentration (μ M) | Have or not MnCl 2 | Reaction times |
| ALK | 0.8 | 82 | Do not have | 1h |
| AuroraA | 3.5 | 33 | Do not have | 1h |
| EGFR | 8 | 2.3 | Have | 1h |
| FGFR1 | 6 | 262 | Do not have | 1h |
| FLT-3 | 0.45 | 97 | Do not have | 1h |
| VEGFR-2 | 1.8 | 92 | Do not have | 1h |
| c-KIT | 12 | 87 | Do not have | 40min |
| c-MET | 4.5 | 75 | Do not have | 1h |
| PDGFRβ | 6 | 38 | Do not have | 5h |
| TIE-2 | 6 | 157 | Do not have | 1h |
[0429]Table 320 a formula I compound is to the percent inhibition (%) of protein kinase
Table 420 a formula I compound to the percent inhibition (continuing) of protein kinase (%)
Claims (30)
1. one kind suc as formula the aryl urea compounds shown in the I, its pharmacy acceptable salt, polymorphic form, solvate or steric isomer;
Wherein, R
1aBe hydrogen, R
1For replacing or unsubstituted C
1～C
8Alkyl, replacement or unsubstituted C
3～C
9Naphthenic base, replacement or unsubstituted C
6～C
14Aryl, replacement or unsubstituted C
1～C
13Heteroaryl; Substituting group in the described substituted alkyl is 4～9 yuan of saturated heterocyclyls, and the heteroatoms number of said saturated heterocyclyl is 1～4, and heteroatoms is nitrogen, oxygen or sulphur; Substituting group in the described substituted naphthenic base is halogen, C
1～C
3Alkyl or C
1～C
3Alkoxyl group; Substituting group in described substituted aryl or the substituted heteroaryl is halogen, cyanic acid, C
1～C
3Haloalkyl, C
1～C
3Alkyl, C
1～C
3Alkoxyl group, C
2～C
3Thiazolinyl and C
2～C
3In the alkynyl one or more, every kind of substituent number is 0,1 or a plurality of, and substituent position is commutable optional position on aryl or the heteroaryl, and when aryl was phenyl ring, substituent position was ortho position, a position or the contraposition of urea side chain; Heteroatoms in the heteroaryl is nitrogen, oxygen or sulphur, and the heteroatoms number is 1～5;
Perhaps R
1, R
1aAnd and R
1, R
1aThe nitrogen-atoms that links to each other Cheng Huanwei together replaces or unsubstituted 4～9 yuan of saturated heterocyclics, and said saturated heterocyclic can extraly contain 1～3 heteroatoms, and said heteroatoms is nitrogen, oxygen or sulphur; Wherein, the substituting group in described substituted 4～9 yuan of saturated heterocyclics is halogen, C
1～C
3Alkyl or C
1～C
3Alkoxyl group;
R
2Be hydrogen, the substituted C of substituted-amino
1～C
6Alkoxyl group, wherein the substituting group on the substituted-amino forms 4～9 yuan of replacements or unsubstituted saturated heterocyclic with the amino nitrogen atom cyclization; Can extraly comprise 1～2 heteroatoms in the described saturated heterocyclic, heteroatoms is nitrogen, oxygen or sulphur, if the extra packet nitrogen atom, does not then have on this nitrogen-atoms and replaces or further by C
1～C
6Alkyl replaces; Substituting group in the described substituted saturated heterocyclic is C
1～C
3Alkyl, C
1～C
3Alkoxyl group, halogen, amino or hydroxyl;
Perhaps, R
2Be C
1～C
6The substituted C of alkoxyl group
1～C
6Alkoxyl group, substituted C
6～C
10Aryl, substituted C
3～C
9Heteroaryl; Wherein, the substituting group in substituted aryl, the substituted heteroaryl is (to connect C
1～C
3The C of alkyl sulphonyl
1～C
3Alkylamino) substituted C
1～C
3Alkyl, halogen, C
1～C
3Alkyl, C
1～C
3Alkoxyl group, C
2～C
3Thiazolinyl and C
2～C
3In the alkynyl one or more, the heteroatoms in the heteroaryl are nitrogen, oxygen or sulphur, and the heteroatoms number is 1～4;
R
3Be hydrogen, C
1～C
3Alkoxyl group, perhaps C
1～C
6The substituted C of alkoxyl group
1～C
6Alkoxyl group;
Perhaps R
3Be amino or the substituted C of substituted-amino
1～C
6Alkoxyl group; Wherein, Substituting group on the substituted-amino can form 4～9 yuan of saturated heterocyclics with said amino nitrogen atom cyclization, can extraly comprise 1～2 heteroatoms in the described saturated heterocyclic, and heteroatoms is nitrogen, oxygen or sulphur; If the extra packet nitrogen atom, do not have on the then said nitrogen-atoms and replace or further by C
1～C
6Alkyl, perhaps (hydroxyl is substituted) C
1～C
6Alkyl replaces; Perhaps the substituting group on the substituted-amino is (hydroxyl is substituted) C
1～C
6Alkyl and/or C
1～C
6Alkyl;
Perhaps R
3Be 4～9 yuan of substituted C of saturated heterocyclic
1～C
6Alkoxyl group, wherein saturated heterocyclic is with carbon atom and C
1～C
6Alkoxyl group connects, and comprises 1～3 heteroatoms in the described saturated heterocyclic, and heteroatoms is nitrogen, oxygen or sulphur, if comprise nitrogen-atoms, does not have on the then said nitrogen-atoms and replaces or by C
1～C
6Alkyl replaces;
R
4And R
5Be hydrogen, C independently
1～C
3Alkyl, C
1～C
3Alkoxyl group, halogen, amido or cyanic acid;
R
6, R
7, R
8And R
9Be hydrogen, C independently
1～C
3Alkyl, C
1～C
3Alkoxyl group, halogen or cyanic acid;
R
10Be hydrogen, C
1～C
3Alkyl, C
1～C
3Alkoxyl group, halogen, amido or cyanic acid;
R
11Be hydrogen or C
1～C
3Alkyl;
Urea side chain
is connected 2 ', 3 ' or 4 '.
2. aryl urea compounds I as claimed in claim 1 or its pharmacy acceptable salt, polymorphic form, solvate or steric isomer is characterized in that: work as R
1Be substituted C
1～C
8During alkyl, the substituting group of said alkyl is 4～6 yuan of saturated heterocyclyls.
3. aryl urea compounds I as claimed in claim 2 or its pharmacy acceptable salt, polymorphic form, solvate or steric isomer is characterized in that: work as R
1Be 4～6 yuan of substituted C of saturated heterocyclyl
1～C
8During alkyl, described 4～6 yuan of saturated heterocyclyls are tetramethyleneimine-1-base.
4. aryl urea compounds I as claimed in claim 1 or its pharmacy acceptable salt, polymorphic form, solvate or steric isomer is characterized in that: work as R
1For replacing or unsubstituted C
6～C
14During aryl, described C
6～C
14Aryl is C
6～C
10Aryl.
5. aryl urea compounds I as claimed in claim 1 or its pharmacy acceptable salt, polymorphic form, solvate or steric isomer is characterized in that: work as R
1For replacing or unsubstituted C
6～C
14Aryl or C
1～C
13Heteroaryl, when the substituting group on aryl or the heteroaryl was halogen, described halogen was fluorine, chlorine, bromine or iodine.
6. aryl urea compounds I as claimed in claim 1 or its pharmacy acceptable salt, polymorphic form, solvate or steric isomer is characterized in that: work as R
1For replacing or unsubstituted C
6～C
14Aryl or C
1～C
13Heteroaryl, the substituting group on aryl or the heteroaryl are C
1～C
3Haloalkyl the time, described haloalkyl is a trifluoromethyl.
7. aryl urea compounds I as claimed in claim 1 or its pharmacy acceptable salt, polymorphic form, solvate or steric isomer is characterized in that: work as R
1For replacing or unsubstituted C
1～C
8During alkyl, described C
1～C
8Alkyl is C
1～C
6Alkyl; Work as R
1For replacing or unsubstituted C
3～C
9During naphthenic base, described C
3～C
9Naphthenic base is C
3～C
8Naphthenic base; Work as R
1For replacing or unsubstituted C
1～C
13During heteroaryl, described C
1～C
13Heteroaryl is C
1～C
9Heteroaryl; Work as R
1And R
1aAnd and R
1, R
1aThe nitrogen-atoms that links to each other Cheng Huanwei together replaces or during unsubstituted 4～9 yuan of saturated heterocyclics, described saturated heterocyclic is 5～7 yuan of saturated heterocyclics; Substituent definition on described alkyl, naphthenic base, aryl, heteroaryl and the saturated heterocyclic such as claim 1,2,3,5 or 6 said.
8. aryl urea compounds I as claimed in claim 7 or its pharmacy acceptable salt, polymorphic form, solvate or steric isomer is characterized in that: work as R
1For replacing or unsubstituted C
3～C
8During naphthenic base, described naphthenic base is a cyclohexyl; Work as R
1Be C
1～C
9During heteroaryl, described C
1～C
9Heteroaryl is C
3～C
9Heteroaryl; Work as R
1And R
1aAnd and R
1, R
1aDuring 5～7 yuan of saturated heterocyclics of Cheng Huanwei, described 5～7 yuan of saturated heterocyclics are the morpholine ring to the nitrogen-atoms that links to each other together.
9. aryl urea compounds I as claimed in claim 8 or its pharmacy acceptable salt, polymorphic form, solvate or steric isomer is characterized in that: work as R
1Be C
3～C
9During heteroaryl, described C
3～C
9Heteroaryl is C
3～C
5Heteroaryl.
10. aryl urea compounds I as claimed in claim 9 or its pharmacy acceptable salt, polymorphic form, solvate or steric isomer is characterized in that: work as R
1Be C
3～C
5During heteroaryl, described C
3～C
5Heteroaryl is a thiazol-2-yl.
11., it is characterized in that: work as R like claim 1～10 each described aryl urea compounds I or its pharmacy acceptable salt, polymorphic form, solvate or steric isomer
2Be the substituted C of substituted-amino
1～C
6Alkoxyl group, when wherein the substituting group on the substituted-amino forms 4～9 yuan of replacements or unsubstituted saturated heterocyclic with the amino nitrogen atom cyclization, described C
1～C
6Alkoxyl group is C
1～C
3Alkoxyl group, described saturated heterocyclic are morpholine or piperazine;
Perhaps, work as R
2Be C
1～C
6The substituted C of alkoxyl group
1～C
6Alkoxyl group or substituted C
3～C
9During heteroaryl; Described C
1～C
6Alkoxyl group is C
1～C
3Alkoxyl group, described substituted C
4～C
9Heteroaryl is substituted furyl; Substituting group in the substituted furyl is R in the claim 1
2Be substituted C
4～C
9Substituting group during heteroaryl.
12., it is characterized in that: work as R like claim 1～10 each described aryl urea compounds I or its pharmacy acceptable salt, polymorphic form, solvate or steric isomer
2Be substituted C
6～C
10Aryl or substituted C
3～C
9During heteroaryl, the substituting group in substituted aryl or the substituted heteroaryl is (to connect C
1～C
3The C of alkyl sulphonyl
1～C
3Alkylamino) substituted C
1～C
3Alkyl, all the other positions of aryl or heteroaryl do not have and replace or by halogen, C
1～C
3Alkyl, C
1～C
3Alkoxyl group, C
2～C
3Thiazolinyl and C
2～C
3One or more replacements in the alkynyl.
13., it is characterized in that: work as R like claim 1～10 each described aryl urea compounds I or its pharmacy acceptable salt, polymorphic form, solvate or steric isomer
3Be C
1～C
6The substituted C of alkoxyl group
1～C
6During alkoxyl group, described C
1～C
6Alkoxyl group is C
1～C
3Alkoxyl group;
Perhaps work as R
3Be the substituted C of substituted-amino
1～C
6During alkoxyl group, described C
1～C
6Alkoxyl group is C
1～C
3Alkoxyl group, wherein, the substituting group on the substituted-amino forms 5～6 yuan of saturated heterocyclics with said amino nitrogen atom cyclization, when in the ring during extra packet nitrogen atom, does not have on this nitrogen-atoms and replaces, perhaps by C
1～C
3The substituted C of alkyl or hydroxyl
1～C
3Alkyl replaces; Perhaps the substituting group on the substituted-amino is (hydroxyl is substituted) C
1～C
3Alkyl and/or C
1～C
3Alkyl;
Perhaps work as R
3Be 4～9 yuan of substituted C of saturated heterocyclic
1～C
6Alkoxyl group, wherein saturated heterocyclic is with carbon atom and C
1～C
6When alkoxyl group connects, described C
1～C
6Alkoxyl group is C
1～C
3Alkoxyl group, described 4～9 yuan of saturated heterocyclics are 5～6 yuan of saturated heterocyclics, comprise 1～2 heteroatoms in the described saturated heterocyclic, in ring when comprising nitrogen-atoms, then do not have on this nitrogen-atoms and replace or by C
1～C
3Alkyl replaces.
14. like claim 1～10 each described aryl urea compounds I or its pharmacy acceptable salt, polymorphic form, solvate or steric isomer, it is characterized in that: described compound I is following arbitrary structure:
Wherein, R
1And R
1aDefinition such as claim 1～10 each is said; The urea side chain is connected 3 ' or 4 '; A is 4-(2-hydroxyethyl) piperazine-1-base, ethyl (2-hydroxyethyl) amido or 2-hydroxyethyl amido.
15. like claim 1～10 each described aryl urea compounds I or its pharmacy acceptable salt, polymorphic form, solvate or steric isomer, it is characterized in that: described compound I is following arbitrary structure:
16. like each described aryl urea compounds of claim 1～10 or its pharmacy acceptable salt, polymorphic form, solvate or steric isomer; It 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, the perhaps salt of aryl urea compounds I and mineral alkali or organic bases formation; Described solvate is the solvate of hydrate or compound I and organic solvent formation.
17. arbitrary midbody compound below the described compound I of preparation claim 1:
1-(3-chloro-4-fluorophenyl)-3-(3-(7-(3-chlorine propoxy-) quinazoline-4-base amido) phenyl) urea,
1-(4-chloro-3-(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-(tetramethyleneimine-1-yl) butyl) urea,
1-(3-chloro-4-fluorophenyl)-3-(3-(6-iodine quinazoline-4-base amido) phenyl) urea hydrochloride,
1-(3-chloro-4-fluorophenyl)-3-(3-(6-(5-formylfuran-2-yl) quinazoline-4-base amido) phenyl) urea,
1-(4-chloro-3-(trifluoromethyl) phenyl)-3-(3-(6-iodine quinazoline-4-base amido) phenyl) urea,
1-(4-chloro-3-(trifluoromethyl) phenyl)-3-(3-(6-(5-formylfuran-2-yl) quinazoline-4-base amido) phenyl) urea,
1-(3,5-two (trifluoromethyl) phenyl)-3-(3-(6-iodine quinazoline-4-base amido) phenyl) urea hydrochloride,
1-(3,5-two (trifluoromethyl) phenyl)-3-(3-(6-(5-formylfuran-2-yl) quinazoline-4-base amido) phenyl) urea,
1-(2, the 5-difluorophenyl)-3-(3-(6-iodine quinazoline-4-base amido) phenyl) urea hydrochloride,
1-(2, the 5-difluorophenyl)-3-(3-(6-(5-formylfuran-2-yl) quinazoline-4-base amido) phenyl) urea,
1-(2-methyl-5-fluorophenyl)-3-(3-(6-iodine quinazoline-4-base amido) phenyl) urea hydrochloride,
1-(2-methyl-5-fluorophenyl)-3-(3-(6-(5-formylfuran-2-yl) quinazoline-4-base amido) phenyl) urea,
1-(3-aminophenyl)-3-(4-chloro-3-(trifluoromethyl) phenyl) urea,
1-(4-aminophenyl)-3-(3-cyano-phenyl) urea,
1-(3-aminophenyl)-3-(3-cyano-phenyl) urea,
1-(3-aminophenyl)-3-(3-fluorophenyl) urea,
N-(3-aminophenyl) morpholine-4-methane amide,
1-(3-aminophenyl)-3-aminomethyl phenyl urea,
1-(3-aminophenyl)-3-(3,5-two (trifluoromethyl) phenyl) urea,
1-(3-aminophenyl)-3-(2, the 5-difluorophenyl) urea,
1-(3-aminophenyl)-3-(2-methyl-5-fluorophenyl) urea,
1-(4-aminophenyl)-3-(thiazol-2-yl) urea,
1-(3-aminophenyl)-3-(thiazol-2-yl) urea,
1-(4-aminophenyl)-3-(4-(tetramethyleneimine-1-yl) butyl) urea,
1-(3-aminophenyl)-3-(4-(tetramethyleneimine-1-yl) butyl) urea,
1-isobutyl--3-(4-aminophenyl) urea,
1-isobutyl--3-(3-aminophenyl) urea,
1-(3-chloro-4-fluorophenyl)-3-(3-nitrophenyl) urea,
1-(3-nitrophenyl)-3-(3-cyano-phenyl) urea,
N-(3-nitrophenyl) morpholine-4-methane amide,
1-(3-nitrophenyl)-3-(2-methyl-5-fluorophenyl) urea,
1-(3-nitrophenyl)-3-(thiazol-2-yl) urea,
1-(3-nitrophenyl)-3-(4-(tetramethyleneimine-1-yl) butyl) urea,
Perhaps 1-isobutyl--3-(3-nitrophenyl) urea.
18. a preparation method who prepares the midbody compound II of the described compound I of claim 1, it is in the following method any one:
Wherein, R
1, R
6, R
7, R
8And R
9Definition such as claim 1～17 each is said, R
1aBe hydrogen, Y is R
11NH-or nitro, R
11Definition according to claim 1; The urea side chain is connected 2 ', 3 ' or 4 ';
Method one: at first compound V and TRIPHOSGENE 99.5 are reacted in the presence of tertiary amine and generate corresponding isocyanate IV, react directly in the presence of tertiary amine, being carried out to urea under the one kettle way condition then, obtain midbody compound II with compound VI or VI ':
Method two: at first compound VI and TRIPHOSGENE 99.5 are reacted generation corresponding isocyanate VII in the presence of tertiary amine, in the presence of tertiary amine, be carried out to the urea reaction at direct under the one kettle way condition and compound V then, obtain midbody compound II;
19. preparation method as claimed in claim 18 is characterized in that: in the method one, the temperature of the reaction of described generation isocyanic ester IV is-5 ℃ of reflux temperatures to reaction solvent; The temperature of described one-tenth urea reaction is 10 ℃ of reflux temperatures to reaction solvent;
In the method two, the temperature of the reaction of described generation isocyanic ester VII is-5 ℃ of reflux temperatures to reaction solvent; The temperature of described one-tenth urea reaction is 10 ℃ of reflux temperatures to reaction solvent.
20. preparation method as claimed in claim 19 is characterized in that: in the method one, the temperature of the reaction of described generation isocyanic ester IV is 0～50 ℃; The temperature of described one-tenth urea reaction is 15～60 ℃;
In the method two, the temperature of the reaction of described generation isocyanic ester VII is 0～50 ℃; The temperature of described one-tenth urea reaction is 15～60 ℃.
21. preparation method as claimed in claim 20 is characterized in that: in the method one, the temperature of the reaction of described generation isocyanic ester IV is 20～40 ℃; The temperature of described one-tenth urea reaction is 20～50 ℃;
In the method two, the temperature of the reaction of described generation isocyanic ester VII is 20～40 ℃; The temperature of described one-tenth urea reaction is 20～50 ℃.
22., it is characterized in that like each described preparation method of claim 18～21:
In the method one; Described method comprises the following step: in the solvent; At first in the presence of tertiary amine, compound V and TRIPHOSGENE 99.5 reaction are generated corresponding isocyanate IV; React directly in the presence of tertiary amine, being carried out to urea under the one kettle way condition then, obtain midbody compound II with compound VI or VI '; Wherein, described solvent is one or more in hydrocarbon, ether, ketone and the ester; Described tertiary amine comprises one or more in pyridine, triethylamine, diisopropyl ethyl amine, N-methylmorpholine, imidazoles and the dimethyl aminopyridine; In the reaction that generates isocyanic ester, the molar ratio of TRIPHOSGENE 99.5 and compound V is 0.3～2: 1, and the molar ratio of compound V and tertiary amine is 1: 1～6; In becoming the urea reaction, compound VI or VI ' are 1: 1～6 with the molar ratio of tertiary amine; The molar ratio of compound V and compound VI or VI ' is 1: 0.6～3;
In the method two; Described method comprises the following step: in the solvent, at first in the presence of tertiary amine, compound VI and TRIPHOSGENE 99.5 reaction are generated corresponding isocyanate VII; Direct then and compound V is carried out to the urea reaction in the presence of tertiary amine, obtain midbody compound II; Wherein, described solvent is one or more in hydrocarbon, ether, ketone and the ester; Described tertiary amine comprises one or more in pyridine, triethylamine, diisopropyl ethyl amine, N-methylmorpholine, imidazoles and the dimethyl aminopyridine; In the reaction that generates isocyanic ester, the molar ratio of TRIPHOSGENE 99.5 and compound VI is 0.3～2: 1, and the molar ratio of compound VI and tertiary amine is 1: 1～6; In becoming the urea reaction, the molar ratio of compound V and tertiary amine is 1: 1～6; The molar ratio of compound VI and compound V is 1: 0.6～3.
23. preparation method as claimed in claim 22 is characterized in that:
In the method one; Described hydrocarbon is toluene, YLENE, methylene dichloride or chlorobenzene; Ether is THF, 2-methyltetrahydrofuran, MTBE or glycol dimethyl ether, and ketone is methyl ethyl ketone or MIBK, and ester is ETHYLE ACETATE or isobutyl acetate; In the reaction that generates isocyanic ester IV, the molar ratio of TRIPHOSGENE 99.5 and compound V is 0.33～1: 1, and the molar ratio of compound V and tertiary amine is 1: 1～3; In becoming the urea reaction, compound VI or VI ' are 1: 1～3 with the molar ratio of tertiary amine; The molar ratio of compound V and compound VI is 1: 0.8～2;
In the method two; Described hydrocarbon is toluene, YLENE, methylene dichloride or chlorobenzene; Ether is THF, 2-methyltetrahydrofuran, MTBE or glycol dimethyl ether, and ketone is methyl ethyl ketone or MIBK, and ester is ETHYLE ACETATE or isobutyl acetate; In the reaction that generates isocyanic ester VII, the molar ratio of TRIPHOSGENE 99.5 and compound VI is 0.33～1: 1, and the molar ratio of compound VI and tertiary amine is 1: 1～3; In becoming the urea reaction, the molar ratio of compound V and tertiary amine is 1: 1～3; The molar ratio of compound VI and compound V is 1: 0.8～2.
24. preparation method as claimed in claim 23 is characterized in that:
In the method one, described solvent is one or more in 2-methyltetrahydrofuran, methylene dichloride and the ETHYLE ACETATE; In the reaction that generates isocyanic ester IV, the molar ratio of TRIPHOSGENE 99.5 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 becoming the urea reaction, compound VI or VI ' are 1: 1～1.5 with the molar ratio of tertiary amine; The molar ratio of compound V and compound VI is 1: 0.9～1.2;
In the method two, described solvent is one or more in 2-methyltetrahydrofuran, methylene dichloride and the ETHYLE ACETATE; In the reaction that generates isocyanic ester VII, the molar ratio of TRIPHOSGENE 99.5 and compound VI is 0.35～0.5: 1, and the molar ratio of compound VI and tertiary amine is 1: 1～1.5; In becoming the urea reaction, the molar ratio of compound V and tertiary amine 1: 1～1.5; The molar ratio of compound VI and compound V is 1: 0.9～1.2.
25. aryl urea compounds I as claimed in claim 1 or its pharmacy acceptable salt, polymorphic form, solvate or steric isomer are in preparation treatment and protein kinase mediated signal transduction pathway imbalance, the application in the medicine of the disease that perhaps abnormal vascular new life is relevant.
26. application as claimed in claim 25 is characterized in that: described disease is tumour, mellitus, autoimmune disorder, nerve degenerative diseases, diabetic retinopathy, senile macular degeneration, arteriosclerosis, psoriatic or inflammation.
27. application as claimed in claim 26; It is characterized in that: 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, perhaps malignant hematologic disease.
28. application as claimed in claim 25 is characterized in that: described protein kinase comprises Tyrosylprotein kinase and serine/threonine kinase, and aforementioned kinase whose various wild-types and mutant.
29. application as claimed in claim 28 is characterized in that: described Tyrosylprotein kinase is 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 BRAF, CRAF, AuroraA or Aurora B; Described mutant kinases is BRAF V600E.
30. comprise the pharmaceutical composition of aryl urea compounds I as claimed in claim 1 or its pharmacy acceptable salt, polymorphic form, solvate or steric isomer.
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| CN2010106194159A CN102532042A (en) | 2010-12-30 | 2010-12-30 | Aryl urea compound as well as intermediate and application thereof |
| CN201180011513.7A CN103354809B (en) | 2010-12-30 | 2011-12-29 | A kind of aryl urea compounds, its intermediate and application thereof |
| PCT/CN2011/084887 WO2012089137A1 (en) | 2010-12-30 | 2011-12-29 | Arylurea compound, intermediate and use thereof |
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2010
- 2010-12-30 CN CN2010106194159A patent/CN102532042A/en active Pending
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2011
- 2011-12-29 CN CN201180011513.7A patent/CN103354809B/en not_active Expired - Fee Related
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| CN103354809B (en) | 2016-01-13 |
| CN103354809A (en) | 2013-10-16 |
| WO2012089137A1 (en) | 2012-07-05 |
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