CN103965119A - Zinc binding group-containing irreversible EGFR tyrosine kinase inhibitor - Google Patents

Zinc binding group-containing irreversible EGFR tyrosine kinase inhibitor Download PDF

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CN103965119A
CN103965119A CN201310042025.3A CN201310042025A CN103965119A CN 103965119 A CN103965119 A CN 103965119A CN 201310042025 A CN201310042025 A CN 201310042025A CN 103965119 A CN103965119 A CN 103965119A
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thiazolinyl
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CN103965119B (en
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吴永谦
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Beijing Ao He Research Institute Co Ltd
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Tonghua Jida Pharmaceutical Co Ltd
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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

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Abstract

Belonging to the technical field of medicine, the invention in particular relates to a zinc binding group-containing irreversible EGFR (epidermal growth factor receptor) tyrosine kinase inhibitor shown as general formula (I), its deuterated compounds, pharmaceutically acceptable salts or stereoisomers, wherein R1, R2, R3, R4, R5, R6, R7, W, X, L, T, and n are defined as the specification. The invention also relates to a preparation method of the compounds, pharmaceutical preparations containing the compounds, and application of the compounds in preparation of drugs treating and/or preventing tumors. (formula I).

Description

The irreversible EGFR tyrosine kinase inhibitor that contains zinc binding moiety
Technical field
The invention belongs to medical technical field, be specifically related to the irreversible EGFR tyrosine kinase inhibitor, its deuterated thing, its pharmacy acceptable salt or its steric isomer that contain zinc binding moiety, the preparation method of these compounds, the pharmaceutical preparation that contains these compounds, and these compounds treat and/or prevent the purposes in the medicine of tumour in preparation.
Background technology
Protein tyrosine kinase is a class is transferred to phosphate group the tyrosine residues that is positioned at protein substrate enzyme from ATP catalysis, and it works in normal cell growth.Many growth factor receptor proteins work by Tyrosylprotein kinase, and by this process influence signal, and then regulate Growth of Cells.But under certain conditions, these acceptors or sudden change or overexpression, become abnormal, causes that cell proliferation is uncontrolled, causes tumor growth, final disease---the cancer of knowing that causes.Growth factor receptor protein tyrosine kinase inhibitor is by suppressing above-mentioned phosphorylation process, plays treatment cancer and other and be characterized as the disease of uncontrolled or abnormal cell growth.
EGF-R ELISA (epidermal growth factor receptor, EGFR) be a kind of multi-functional glycoprotein being distributed widely on the each cell membranes in tissue of human body, it is birds EBL virus (avian erythroblasticleukemia viral, v-erb-b) oncogene autoploid.Human epidermal growth factor receptor/HER1/ErbB-1 and HER2 (human epidermalgrowth factor receptor-2)/ErbB-2/Teu/p185, HER3/ErbB-3, HER4/ErbB-4 etc. are included into HER/ErbB family, belong to protein tyrosine kinase (PTKs).Clinical study shows, EGFR etc. are in the tumour of epithelial origin, as crossed expression in the kinds of tumors such as squamous cell carcinoma of the head and neck, mammary cancer, the rectum cancer, ovarian cancer, prostate cancer, nonsmall-cell lung cancer.Pan-HER tyrosine kinase inhibitor by with the kinase catalytic site of ATP competitive binding intracellular region, the autophosphorylation of tyrosine in blocker molecule, blocking-up tyrosine-kinase enzyme activation, suppresses HER family and activates, thereby suppresses cell cycle progression, acceleration apoptosis performance therapeutic action.
The medicine of listing comprises selectivity EGFR tyrosine kinase inhibitor Gefitinib (gefitinb at present; Iressa; ZD1839), erlotinib (erlotinib; Tarceva; and EGFR/HER2 double inhibitor lapatinibditosylate (Lapatinib OSI-774); Tykerb, GW572016), above three medicines are reversibility EGF receptor tyrosine phosphorylated kinase inhibitor.Research discovery, some tumour initially produces good therapeutic response to it, but occurs again progression of disease after treatment some months, produces natural or Secondary cases resistance.
European patent 520722A1,566226A1,635498A1 and 602851A1, WO95/19774, WO95/15758 all relate to 4-phenylamino quinazoline derivant class reversibility EGFR tyrosine phosphorus acylase kinase inhibitor; some of them compound has very high EGFR tyrosine-kinase enzyme inhibition activity, but their activity on animal pathological model is lower.Because being catalysis phosphate, the physiological function of protein tyrosine kinase (PTK) transfers to the catalyzer of this biological process protein-tyrosine residue from ATP, above-mentioned reversibility EGFR tyrosine kinase inhibitor and ATP are competing the combination with EGFR Tyrosylprotein kinase, and due to the concentration of ATP in cell higher (mM level), make vitro test show highly active reversibility EGFR tyrosine kinase inhibitor and be difficult on animal pathological model effective.And the EGF receptor tyrosine kinase inhibitors of irreversible does not become competitive relation with ATP, thereby can expection can there is good activity in vivo.
The United States Patent (USP) 97/05778 of 1997 discloses the irreversible EGFR tyrosine kinase inhibitor of a class, this class inhibitor is introduced a Michael acceptor in the 6-position of quinazoline, make it with EGFR tyrosine kinase activity central pocket wall on halfcystine (Cys773) on-there is Michael addition reaction in SH.And, the activity of this class inhibitor with they with on halfcystine-Michael addition reaction occurs SH complexity becomes positively related structure activity relationship.Therefore, Wyeth Pharmaceuticals of the U.S., Pfizer company and Boehringer Ingelheim drugmaker all select hyperergy-highly active two high type EGFR tyrosine kinase irreversible inhibitor further to develop, and existing medicine enters the clinical study stage at present.Wherein Neratinib (HKI-272), PF-00299804 and Afatinib (BIBW-2992) are all in clinical three phase conceptual phases, and structure is as follows:
Research shows, Pan-HER tyrosine kinase irreversible inhibitor is except effective inhibition EGFR, also inhibited to HER2/4, this all have the medicine of Irreversible inhibition except having improved pharmaceutical activity to HER/ErbB family, also reduced the generation of resistance.
HDAC inhibitor is novel antineoplastic target medicine, it is a kind of epigenetic regulation agent, relate to the each side that tumour occurs and develops, comprise inducing apoptosis of tumour cell, inhibition tumor cell cycle, inducing tumor cell differentiation, suppress vasculogenesis, suppress metastases and regulate function of immune system etc.Can be used for the treatment of multiple blood tumor and solid tumor.The hdac inhibitor of listing has Vorinostat (Vorinostat, SAHA, Zolinza) and Romidepsin (FK-228, Istodax) at present.Research discovery, hdac inhibitor and tyrosine kinase inhibitor all have synergistic function with arbitrary proportion coupling.
CUDC-101 is many target spots of unit molecule reversible EGFR/HER2/HDAC inhibitor of being researched and developed by Curis company, studies at present, for the treatment of liver cancer, mammary cancer, nonsmall-cell lung cancer, cancer of the stomach and head and neck cancer in the clinical Ib phase.Preclinical study shows that it all has good anti-tumor activity in vivo and in vitro, compared with tyrosine kinase inhibitor, has improved drug effect, has overcome the generation of resistance.
The medicine that the present invention has good antitumor action simultaneously and reduces resistance generation taking exploitation, as target, has been found the inhibiting compound of the many target spots of irreversible EGFR/HER2/HDAC.
Summary of the invention
Concrete technical scheme of the present invention is as follows:
Compound shown in general formula (I), its deuterated thing, its pharmacy acceptable salt or its steric isomer:
Wherein,
R 1for hydrogen atom, or be not substituted or by 1 ~ 3 identical or different Q 1the following group replacing:
C 1-6alkyl, C 2-6thiazolinyl, C 2-6alkynyl, 3-8 unit cycloalkyl, the cycloalkyl C of 3-8 unit 1-6alkyl, 6-10 unit cyclic group, 6-10 unit cyclic group C 1-6alkyl, 7-12 unit volution base, the volution base C of 7-12 unit 1-6alkyl, 7-12 unit's bridged ring base or the bridged ring base C of 7-12 unit 1-6alkyl, and carbon atom in described 3-8 unit cycloalkyl, 6-10 unit cyclic group, 7-12 unit's volution base or 7-12 unit bridged ring base can be by 1 ~ 3 identical or different O, CO, S, SO, SO 2, N or NR creplace R crepresent hydrogen atom or C 1-6alkyl,
Q 1for halogen atom, hydroxyl, amino, carboxyl, cyano group, formamyl, amino-sulfonyl, C 1-6alkyl, C 1-6alkoxyl group, C 1-6alkylamino, C 1-6alkyl-carbonyl, two (C 1-6alkyl) amino, C 1-6alkyl carbonyl oxy, C 1-6alkoxy carbonyl, C 1-6alkyl amido, C 1-6alkyl sulphonyl, C 1-6alkyl sulphinyl, C 1-6alkyl sulfonyl amino or 3-8 unit cycloalkyl;
R 2for hydrogen atom, halogen atom, hydroxyl, cyano group, nitro, formamyl, amino-sulfonyl, C 1-6alkyl, C 2-6thiazolinyl, C 2-6alkynyl, C 1-6alkoxyl group, halo C 1-6alkyl, halo C 1-6alkoxyl group, C 1-6alkylamino, two (C 1-6alkyl) amino, C 1-6alkylthio, C 1-6alkyl-carbamoyl, C 1-6alkyl-carbonyl, C 1-6alkoxy carbonyl, C 1-6alkyl carbonyl oxy, C 1-6alkyl amido, C 1-6alkyl sulphonyl, C 1-6alkyl sulphinyl, C 1-6alkyl sulfonyl amino, phenyl, pyridyl, furyl, thiazolyl, imidazolyl or thienyl, described phenyl, pyridyl, furyl, thiazolyl, imidazolyl or thienyl can optionally be replaced by 1 ~ 2 identical or different following substituting group: halogen atom, hydroxyl, amino, cyano group, C 1-6alkyl, C 1-6alkoxyl group, C 1-6alkylamino or two (C 1-6alkyl) amino;
R 3, R 4and R 5be hydrogen atom independently respectively, halogen atom, C 1-6alkyl, C 1-6alkoxyl group, halo C 1-6alkyl, halo C 1-6alkoxyl group, C 1-6alkylamino or two (C 1-6alkyl) amino;
R 6and R 7be hydrogen atom independently respectively, C 1-6alkyl or C 1-6alkyl-carbonyl;
X is the methyne that N atom or cyano group replace;
W is not for being substituted or by R athe C replacing 1-6alkyl, C 2-6thiazolinyl, C 2-6alkynyl, 6-14 unit aryl, 3-14 unit heterocyclic radical, the aryl C of 6-14 unit 1-6alkyl, the heterocyclic radical C of 3-14 unit 1-6alkyl, C 1-6alkyl 3-14 unit heterocyclic radical, C 2-6thiazolinyl 6-14 unit aryl, C 2-6thiazolinyl 3-14 unit heterocyclic radical, C 2-6alkynyl 6-14 unit aryl, C 2-6alkynyl 3-14 unit heterocyclic radical, C 2-6alkynyl 3-8 unit cycloalkyl, C 1-6the aryl C of alkyl 6-14 unit 1-6alkyl, C 1-6the aryl C of alkyl 6-14 unit 2-6thiazolinyl, C 2-6the heterocyclic radical C of thiazolinyl 3-14 unit 1-6alkyl, the heterocyclic radical-3-14 heterocyclic radical C of unit of 3-14 unit 1-6alkyl, and described C 1-6alkyl, C 2-6thiazolinyl, C 2-6carbon atom in alkynyl can be by O, S, S (O), SO 2, NR bor CO replaces,
R afor hydrogen atom, halogen atom, hydroxyl, amino, carboxyl, cyano group, formamyl, amino-sulfonyl, C 1-6alkyl, C 1-6alkoxyl group, C 1-6alkylamino, two (C 1-6alkyl) amino, C 1-6alkyl carbonyl oxy, C 1-6alkoxy carbonyl, C 1-6alkyl amido, C 1-6alkyl sulphonyl, C 1-6alkyl sulphinyl, C 1-6alkyl sulfonyl amino, 3-8 unit's cycloalkyl or 3-8 unit heterocyclic radical,
R bfor hydrogen atom, be not substituted or at least by 1 Q 3the C replacing 1-6alkyl, 3-8 unit's cycloalkyl or 3-8 unit heterocyclic radical,
Q 3for halogen atom, carboxyl, hydroxyl, amino, cyano group, nitro, C 1-6alkoxyl group, halo C 1-6alkoxyl group, C 1-6alkylamino, two (C 1-6alkyl) amino, C 1-6alkyl-carbonyl, C 1-6alkyl-carbonyl oxygen base, C 1-6alkoxy carbonyl, formamyl, C 1-6alkyl-carbamoyl, two (C 1-6alkyl) formamyl, amino-sulfonyl, C 1-6alkyl amino sulfonyl, two (C 1-6alkyl) amino-sulfonyl, C 1-6alkyl sulfonyl amino, C 1-6alkyl sulphonyl, C 1-6alkyl-carbonyl-amino, guanidine radicals, 3-8 unit cycloalkyl, 3-8 unit's heterocyclic radical or 6-14 unit aryl;
L is key ,-O-,-S-,-SO-,-SO 2-,-NH-,-N (CH 3)-,-C (O)-or do not exist;
T is key ,-C (O)-or-C (R ' R ' ')-, R ' and R ' ' are respectively hydrogen or C 1-6alkyl;
N is 1,2 or 3, and n=2 or 3 o'clock, R 2can be identical or different.
The optimal technical scheme of the compound shown in general formula (I), its deuterated thing, its pharmacy acceptable salt or its steric isomer is:
Wherein,
R 1for hydrogen atom, or be not substituted or by 1 ~ 3 identical or different Q 1the following group replacing:
C 1-4alkyl, C 2-4thiazolinyl, C 2-4alkynyl, 3-8 unit cycloalkyl, the cycloalkyl C of 3-8 unit 1-4alkyl, 6-10 unit cyclic group, 6-10 unit cyclic group C 1-4alkyl, 7-12 unit volution base, the volution base C of 7-12 unit 1-4alkyl, 7-12 unit's bridged ring base or the bridged ring base C of 7-12 unit 1-4alkyl, and carbon atom in described 3-8 unit cycloalkyl, 6-10 unit cyclic group, 7-12 unit's volution base or 7-12 unit bridged ring base can be by 1 ~ 3 identical or different O, CO, S, N or NR creplace R crepresent hydrogen atom or C 1-4alkyl,
Q 1for halogen atom, hydroxyl, amino, carboxyl, cyano group, formamyl, amino-sulfonyl, C 1-4alkyl, C 1-4alkoxyl group, C 1-4alkylamino, C 1-6alkyl-carbonyl, two (C 1-4alkyl) amino, C 1-4alkyl carbonyl oxy, C 1-4alkoxy carbonyl, C 1-4alkyl amido, C 1-4alkyl sulphonyl, C 1-4alkyl sulphinyl, C 1-4alkyl sulfonyl amino or 3-6 unit cycloalkyl;
R 2for hydrogen atom, halogen atom, hydroxyl, cyano group, nitro, formamyl, amino-sulfonyl, C 1-4alkyl, C 2-4thiazolinyl, C 2-4alkynyl, C 1-4alkoxyl group, halo C 1-4alkyl, halo C 1-4alkoxyl group, C 1-4alkylamino, two (C 1-4alkyl) amino, C 1-4alkylthio, C 1-4alkyl-carbamoyl, C 1-4alkyl-carbonyl, C 1-4alkoxy carbonyl, C 1-4alkyl carbonyl oxy, C 1-4alkyl amido, C 1-4alkyl sulphonyl, C 1-4alkyl sulphinyl, C 1-4alkyl sulfonyl amino, phenyl, pyridyl, furyl, thiazolyl, imidazolyl or thienyl, described phenyl, pyridyl, furyl, thiazolyl, imidazolyl or thienyl can optionally be replaced by 1 ~ 2 identical or different following substituting group: halogen atom, hydroxyl or C 1-6alkyl;
R 3, R 4and R 5be hydrogen atom independently respectively, halogen atom, C 1-4alkyl, C 1-4alkoxyl group, halo C 1-4alkyl, halo C 1-4alkoxyl group, C 1-4alkylamino or two (C 1-4alkyl) amino;
R 6and R 7be hydrogen atom independently respectively, C 1-4alkyl or C 1-4alkyl-carbonyl;
X is the methyne that N atom or cyano group replace;
W is not for being substituted or by R athe C replacing 1-6alkyl, C 2-6thiazolinyl, 6-10 unit aryl, 3-8 unit heterocyclic radical, the aryl C of 6-10 unit 1-6alkyl, the heterocyclic radical C of 3-8 unit 1-6alkyl, C 1-6alkyl 3-8 unit heterocyclic radical, C 2-6thiazolinyl 6-10 unit aryl, C 2-6thiazolinyl 3-8 unit heterocyclic radical, C 1-6the aryl C of alkyl 6-10 unit 1-6alkyl, C 1-6the aryl C of alkyl 6-10 unit 2-6thiazolinyl, C 2-6the heterocyclic radical C of thiazolinyl 3-8 unit 1-6alkyl, or the heterocyclic radical-3-8 heterocyclic radical C of unit of 3-8 unit 1-6alkyl, and described C 1-6alkyl, C 2-6carbon atom in thiazolinyl can be by O, S, NR bor CO replaces,
R afor hydrogen atom, halogen atom, hydroxyl, amino, carboxyl, cyano group, formamyl, amino-sulfonyl, C 1-4alkyl, C 1-4alkoxyl group, C 1-4alkylamino, two (C 1-4alkyl) amino, C 1-4alkyl carbonyl oxy, C 1-4alkoxy carbonyl, C 1-4alkyl amido, C 1-4alkyl sulphonyl, C 1-4alkyl sulphinyl, C 1-4alkyl sulfonyl amino, 3-6 unit's cycloalkyl or 3-6 unit heterocyclic radical,
R bfor hydrogen atom, be not substituted or at least by 1 Q 3the C replacing 1-4alkyl, 3-6 unit's cycloalkyl or 3-6 unit heterocyclic radical,
Q 3for halogen atom, carboxyl, hydroxyl, amino, cyano group, nitro, C 1-4alkoxyl group, halo C 1-4alkoxyl group, C 1-4alkylamino, two (C 1-4alkyl) amino, C 1-4alkyl-carbonyl, C 1-4alkyl-carbonyl oxygen base, C 1-4alkoxy carbonyl, formamyl, C 1-4alkyl-carbamoyl, two (C 1-4alkyl) formamyl, amino-sulfonyl, C 1-4alkyl amino sulfonyl, two (C 1-4alkyl) amino-sulfonyl, C 1-4alkyl sulfonyl amino, C 1-4alkyl sulphonyl, C 1-4alkyl-carbonyl-amino, guanidine radicals, 3-6 unit cycloalkyl, 3-6 unit's heterocyclic radical or phenyl;
L is key ,-O-,-S-,-NH-or do not exist;
T be key or-C (R ' R ' ')-, R ' and R ' ' are respectively hydrogen or C 1-4alkyl;
N is 1,2 or 3, and n=2 or 3 o'clock, R 2can be identical or different.
The optimal technical scheme of the compound shown in general formula (I), its deuterated thing, its pharmacy acceptable salt or its steric isomer is:
Wherein,
R 1for hydrogen atom, or be not substituted or by 1 ~ 3 identical or different Q 1the following group replacing:
C 1-4alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, azetidinyl, tetrahydrofuran base, THP trtrahydropyranyl, pyrrolidyl, piperidyl, morpholinyl, piperazinyl, cyclopropyl C 1-4alkyl, cyclobutyl C 1-4alkyl, cyclopentyl C 1-4alkyl, cyclohexyl C 1-4alkyl, suberyl C 1-4alkyl, azetidinyl C 1-4alkyl, tetrahydrofuran base C 1-4alkyl, THP trtrahydropyranyl C 1-4alkyl, pyrrolidyl C 1-4alkyl, piperidyl C 1-4alkyl, morpholinyl C 1-4alkyl, piperazinyl C 1-4alkyl, 6-10 unit cyclic group, 6-10 unit cyclic group methyl, 6-10 unit cyclic group ethyl, 7-10 unit volution base, 7-10 unit volution ylmethyl, 7-10 unit volution base ethyl, 7-10 unit bridged ring base, 7-10 unit's bridged ring ylmethyl or 7-10 unit bridged ring base ethyl, and described cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, azetidinyl, tetrahydrofuran base, THP trtrahydropyranyl, pyrrolidyl, piperidyl, morpholinyl, piperazinyl, 6-10 unit cyclic group, 7-10 unit volution base, carbon atom in 7-10 unit bridged ring base can be by 1 ~ 3 identical or different O, CO, S, N or NR creplace R crepresent hydrogen atom, methyl or ethyl, Q 1for halogen atom, hydroxyl, amino, C 1-4alkyl, C 1-4alkoxyl group, C 1-4alkylamino, two (C 1-4alkyl) amino, C 1-4alkyl carbonyl oxy, C 1-4alkyl amido or C 1-4alkyl sulfonyl amino,
R 2for halogen atom, cyano group, nitro, C 1-4alkyl, C 2-4thiazolinyl, C 2-4alkynyl, C 1-4alkoxyl group, fluoro C 1-4alkyl, fluoro C 1-4alkoxyl group, C 1-4alkyl-carbamoyl, C 1-4alkyl-carbonyl, C 1-4alkoxy carbonyl, C 1-4alkyl carbonyl oxy, C 1-4alkyl amido, C 1-4alkyl sulfonyl amino, phenyl, pyridyl or thiazolyl;
R 3, R 4and R 5be hydrogen atom independently respectively, halogen atom, C 1-4alkyl, C 1-4alkoxyl group, fluoro C 1-4alkyl, fluoro C 1-4alkoxyl group, C 1-4alkylamino or two (C 1-4alkyl) amino;
R 6and R 7be hydrogen atom independently respectively, C 1-4alkyl or C 1-4alkyl-carbonyl;
X is the methyne that N atom or cyano group replace;
W is not for being substituted or by R athe C replacing 2-6alkyl, C 2-6thiazolinyl, phenyl, 5-6 unit heterocyclic radical, phenyl C 1-4alkyl, the heterocyclic radical C of 5-6 unit 1-4alkyl, C 1-4alkyl 5-6 unit heterocyclic radical, C 2-6thiazolinyl phenyl, C 2-6thiazolinyl 5-6 unit heterocyclic radical, C 2-6thiazolinyl phenyl C 1-6alkyl, C 2-6the heterocyclic radical C of thiazolinyl 5-6 unit 1-4alkyl, the heterocyclic radical-5-6 heterocyclic radical C of unit of 5-6 unit 1-4alkyl, and described C 2-6alkyl, C 2-6thiazolinyl, C 1-6carbon atom in alkyl can be by O, S, NR bor CO replaces,
R afor halogen atom, hydroxyl, amino, carboxyl, cyano group, C 1-4alkyl, C 1-4alkoxyl group or 3-6 unit cycloalkyl,
R bfor hydrogen atom, be not substituted or at least by 1 Q 3the C replacing 1-4alkyl,
Q 3for halogen atom, carboxyl, hydroxyl, amino, cyano group, nitro, C 1-4alkoxyl group, fluoro C 1-4alkoxyl group, C 1-4alkylamino, two (C 1-4alkyl) amino, C 1-4alkyl-carbonyl, formamyl, amino-sulfonyl or C 1-4alkyl sulphonyl;
L is key ,-O-,-S-or do not exist;
T be key or-C (R ' R ' ')-, R ' and R ' ' are respectively hydrogen or methyl;
N is 1,2 or 3, and n=2 or 3 o'clock, R 2can be identical or different.
The optimal technical scheme of the compound shown in general formula (I), its deuterated thing, its pharmacy acceptable salt or its steric isomer is:
Wherein,
R 1for hydrogen atom, be not substituted or by 1 ~ 3 identical or different Q 1the following group replacing: methyl, ethyl,
Q 1for halogen atom, hydroxyl, amino, methyl, ethyl, methoxyl group, oxyethyl group, methylamino-, ethylamino, dimethylamino or diethylamino;
R 2for halogen atom, cyano group, nitro, methyl, ethyl, vinyl, ethynyl, methoxyl group, trifluoromethyl, trifluoromethoxy, ethanoyl, methoxycarbonyl, acetoxyl group, kharophen, sulfonyloxy methyl amino, phenyl, pyridyl or thiazolyl;
R 3, R 4and R 5be respectively hydrogen atom;
R 6and R 7be hydrogen atom independently respectively, methyl, ethyl or ethanoyl;
X is the methyne that N atom or cyano group replace;
W is not for being substituted or by R athe C replacing 2-6alkyl, C 2-6thiazolinyl, 5-6 unit heterocyclic radical, methyl 5-6 unit heterocyclic radical, ethyl 5-6 unit's heterocyclic radical or C 2-6thiazolinyl phenyl C 1-6alkyl, and described C 2-6alkyl, C 2-6thiazolinyl, C 1-6carbon atom in alkyl can be by NR binstitute replaces,
R afor halogen atom, hydroxyl, amino, carboxyl, cyano group, C 1-4alkyl or C 1-4alkoxyl group,
R bfor hydrogen atom or C 1-4alkyl;
L is for-O-or do not exist;
T is key;
N is 1,2 or 3, and n=2 or 3 o'clock, R 2can be identical or different.
The optimal technical scheme of the compound shown in general formula (I), its deuterated thing, its pharmacy acceptable salt or its steric isomer is:
Wherein,
R 1for hydrogen atom, be not substituted or by 1 ~ 3 identical or different Q 1the following group replacing: methyl, ethyl,
Q 1for halogen atom, hydroxyl, amino, methyl, ethyl, methoxy or ethoxy;
R 2for fluorine atom, chlorine atom, bromine atoms, methyl, vinyl, ethynyl, phenyl or pyridyl;
R 3, R 4, R 5, R 6and R 7be respectively hydrogen atom;
X is the methyne that N atom or cyano group replace;
W is not for being substituted or by R athe C replacing 2-6alkyl, C 2-6thiazolinyl, C 2-6thiazolinyl phenyl C 1-6alkyl, and described C 2-6alkyl, C 2-6thiazolinyl, C 1-6carbon atom in alkyl can be by NR binstitute replaces,
R afor halogen atom, hydroxyl, amino, carboxyl, cyano group, C 1-4alkyl or C 1-4alkoxyl group,
R bfor hydrogen atom, methyl, ethyl or sec.-propyl;
L is for-O-or do not exist;
T is key;
N is 1,2 or 3, and n=2 or 3 o'clock, R 2can be identical or different.
The optimal technical scheme of the compound shown in general formula (I), its deuterated thing, its pharmacy acceptable salt or its steric isomer is:
Wherein, R 1for hydrogen atom, be not substituted or by 1 ~ 3 identical or different Q 1the following group replacing: methyl,
Q 1for fluorine atom, chlorine atom, hydroxyl, amino, methyl or ethyl;
R 2for fluorine atom, chlorine atom, methyl, ethynyl, phenyl or pyridyl;
R 3, R 4, R 5, R 6and R 7be respectively hydrogen atom;
X is the methyne that N atom or cyano group replace;
W is not for being substituted or by R athe C replacing 2-6alkyl, C 2-6thiazolinyl or C 2-6thiazolinyl phenyl C 1-6alkyl, and described C 2-6alkyl, C 2-6thiazolinyl, C 1-6carbon atom in alkyl can be by NR binstitute replaces,
R afor fluorine atom, chlorine atom, hydroxyl, amino, carboxyl, cyano group, methyl, ethyl or methoxyl group,
R bfor hydrogen atom, methyl, ethyl or sec.-propyl;
L is for-O-or do not exist;
T is key;
N is 1,2 or 3, and n=2 or 3 o'clock, R 2can be identical or different.
Detailed Description Of The Invention:
" C of the present invention 1-6alkyl " represent the alkyl that contains 1-6 carbon atom of straight or branched, as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, isopentyl, 2-methyl butyl, neo-pentyl, 1-ethyl propyl, n-hexyl, isohexyl, 4-methyl amyl, 3-methyl amyl, 2-methyl amyl, 1-methyl amyl, 3, 3-dimethylbutyl, 2, 2-dimethylbutyl, 1, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2, 3-dimethylbutyl, 2-ethyl-butyl, 1-methyl-2-methyl-propyl, n-heptyl, 2-methyl hexyl, 3-methyl hexyl, 2, 4-dimethyl amyl group, n-octyl, 2-methylheptyl, 3-methylheptyl, 4-methylheptyl, 2, 4-dimethyl hexyl etc." C of the present invention 1-4alkyl " refer to the specific examples that contains 1-4 carbon atom in above-mentioned example.
" C of the present invention 2-6thiazolinyl " refer to straight or branched that the carbonatoms that contains two keys is 2-6 or the thiazolinyl of ring-type, as vinyl, 1-propenyl, 2-propenyl, 1-methyl ethylene, 1-butylene base, crotyl, 3-butenyl, 1-methyl-1-propylene base, 2-methyl-1-propylene base, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl isophthalic acid-butenyl, 2-methyl-1-butene thiazolinyl, 3-methyl-1-butene base, 1-methyl-2-butene base, 2-methyl-2-butene base, 3-methyl-2-butene base, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentene thiazolinyl, 2-methyl-1-pentene thiazolinyl, 3-methyl-1-pentene thiazolinyl, 4-methyl-1-pentene base, 1-methyl-pentenyl, 2-methyl-pentenyl, 3-methyl-pentenyl, 4-methyl-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-crotyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-1-butylene base, 1,2-dimethyl-crotyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-1-butylene base, 1,3-dimethyl-crotyl, 1,3-dimethyl-crotyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-1-butylene base, 2,3-dimethyl-crotyl, 2,3-dimethyl-3-butenyl, 3,3-dimethyl-1-butylene base, 3,3-dimethyl-crotyl, 1-ethyl-1-butylene base, 1-ethyl-crotyl, 1-ethyl-3-butenyl, 2-ethyl-1-butylene base, 2-ethyl-crotyl, 2-ethyl-3-butenyl, 1,1,2-trimethylammonium-2-propenyl, 1-ethyl-1-methyl-2-propenyl, 1-Ethyl-2-Methyl-1-propenyl, 1-Ethyl-2-Methyl-2-propenyl, 1,3-butadiene, 1,3-pentadiene, Isosorbide-5-Nitrae-pentadiene, Isosorbide-5-Nitrae-hexadiene, cyclopentenyl, 1，3-cyclopentadiene base, cyclohexenyl, 1，4-cyclohexadiene base etc." C of the present invention 2-4thiazolinyl " refer to " C 2-6thiazolinyl " in contain 2-4 carbon atom specific examples.
" C of the present invention 2-6alkynyl " refer to the alkynyl of the straight or branched that the carbonatoms that contains triple bond is 2-6, as ethynyl, 2-propynyl, 2-butyne base, 3-butynyl, 1-methyl-2-propynyl, valerylene base, 3-pentynyl, 4-pentynyl, 1-methyl-2-butyne base, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1, 1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 2-hexin base, 3-hexin base, 4-hexin base, 5-hexin base, 1-methyl-valerylene base, 1-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3-methyl-4-pentynyl, 4-methyl-valerylene base, 1, 1-dimethyl-2-butyne base, 1, 1-dimethyl-3-butynyl, 1, 2-dimethyl-3-butynyl, 2, 2-dimethyl-3-butynyl, 1-ethyl-2-butyne base, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl, 1-ethyl-1-methyl-2-propynyl etc." C of the present invention 2-4alkynyl " refer to " C 2-6alkynyl " in contain 2-4 carbon atom specific examples.
" C of the present invention 1-6alkoxyl group " refer to C 1-6the group that alkyl-O-mode connects, C 1-6alkyl as hereinbefore defined.As methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, tert.-butoxy, sec-butoxy, pentyloxy, neopentyl oxygen, hexyloxy etc." C of the present invention 1-4alkoxyl group " refer to the specific examples that contains 1-4 carbon atom in above-mentioned example.
" C of the present invention 1-6alkylthio " refer to C 1-6the group that alkyl-S-mode connects, C 1-6alkyl as hereinbefore defined." C of the present invention 1-4alkylthio " refer to C 1-4the group that alkyl-S-mode connects, C 1-4alkyl as hereinbefore defined.
" C of the present invention 1-6alkylamino ", " two (C 1-6alkyl) amino ", " C 1-6alkyl carbonyl oxy ", " C 1-6alkoxy carbonyl ", " C 1-6alkyl-carbonyl ", " C 1-6alkyl sulphonyl ", " C 1-6alkyl sulphinyl ", " C 1-6alkyl sulfonyl amino ", " C 1-6alkyl amido ", " C 1-6alkyl-carbamoyl " refer to C 1-6alkyl-NH-, (C 1-6alkyl) 2n-, C 1-6alkyl-C (O)-O-, C 1-6alkyl-O-C (O)-, C 1-6alkyl-C (O)-, C 1-6alkyl-SO 2-, C 1-6alkyl-SO-, C 1-6alkyl-SO 2-NH-, C 1-6alkyl-C (O)-NH-, C 1-6the group that alkyl-NH-C (O)-mode connects, wherein " C 1-6alkyl " as defined above.
" C of the present invention 1-4alkylamino ", " two (C 1-4alkyl) amino ", " C 1-4alkyl carbonyl oxy ", " C 1-4alkoxy carbonyl ", " C 1-4alkyl-carbonyl ", " C 1-4alkyl sulphonyl ", " C 1-4alkyl sulphinyl ", " C 1-4alkyl sulfonyl amino ", " C 1-4alkyl amido ", " C 1-4alkyl-carbamoyl " refer to C 1-4alkyl-NH-, (C 1-4alkyl) 2n-, C 1-4alkyl-C (O)-O-, C 1-4alkyl-O-C (O)-, C 1-4alkyl-C (O)-, C 1-4alkyl-SO 2-, C 1-4alkyl-SO-, C 1-4alkyl-SO 2-NH-, C 1-4alkyl-C (O)-NH-, C 1-4the group that alkyl-NH-C (O)-mode connects, wherein " C 1-4alkyl " as defined above.
" halogen atom " of the present invention refers to fluorine atom, chlorine atom, bromine atoms, iodine atom etc.
" halo C of the present invention 1-6alkyl " refer to that " halogen atom " replaces above-mentioned " C 1-6alkyl " on one or more hydrogen atoms, and the group being connected with other structures by alkyl." halo C of the present invention 1-4alkyl " refer to that " halogen atom " replaces above-mentioned " C 1-4alkyl " on one or more hydrogen atoms, and the group being connected with other structures by alkyl.Described " halogen atom " and " C 1-4alkyl " as defined above.
" halo C of the present invention 1-6alkoxyl group " refer to one or more " halogen atom " replacement " C 1-6alkoxyl group " derivative group." halo C of the present invention 1-4alkoxyl group " refer to one or more " halogen atom " replacement " C 1-4alkoxyl group " derivative group, described " halogen atom ", " C 1-6alkoxyl group " and " C 1-4alkoxyl group " as defined above.
" 3-8 unit cycloalkyl " of the present invention refers to paraffin section removal a cyclic alkyl that hydrogen atom is derivative, such as cyclopropane base, tetramethylene base, pentamethylene base, cyclohexyl, suberane, cyclooctane, methyl cyclopropane, dimethylcyclopropane, methyl cyclobutane, dimethyl tetramethylene, methylcyclopentane, dimethylcyclopentane, methylcyclohexane, the dimethyl cyclohexane etc. of 3-8 carbon atom.Preferably " 3-6 unit cycloalkyl ", refers to the specific examples that contains 3-6 carbon atom in above-mentioned example, as cyclopropane base, tetramethylene base, pentamethylene base, cyclohexyl etc.
" 6-10 unit ring " of the present invention refer to a class by two or more ring texturees share each other two adjacent atoms couple together form contain 6-10 carbon atom and/or heteroatomic condensed ring structure, described heteroatoms has nitrogen, oxygen and sulphur etc." 6-10 unit ring " comprises " the first saturated and ring of 6-10 ", " 6-10 unit's fractional saturation ring " and " the first unsaturated and ring of 6-10 ".Specific examples includes but are not limited to: dicyclo [3.1.0] hexyl, 3-azabicyclo [3.1.0] hexyl, dicyclo [3.2.0] heptane base, 3-azabicyclo [3.2.0] heptane base, octahydro pentalene base, octahydro cyclopenta [c] pyrryl, octahydro pyrrolo-[3,4-c] pyrryl, dicyclo [4.2.0] octyl, 3-azabicyclo [4.2.0] octyl, dicyclo [4.1.0] heptane base, octahydro-1H-indenyl, octahydro-1H-pseudoindoyl, naphthane base, Decahydroisoquinolinpreparation base, 5,6-glyoxalidine [1.2-a] pyrazine-7 (8H)-Ji, 5,6-dihydro-1,7-naphthyridines-7 (8H)-Ji, 5H-pyrroles [3.4-b] pyridine-6 (7H)-Ji, 7,8-dihydropyridine [4.3-d] pyrimidine-6 (5H)-Ji, 2,3,6,7-tetrahydrochysene-1H-pyrazoles [4.3-c] pyridine-5 (4H)-Ji, 6,7-thiazoline [5.4-c] pyridine-5 (4H)-Ji, 3-methyl-6,7-dihydro-3H-pyrazoles [4.5-c] pyridine-5 (4H)-Ji, 2-methyl six hydrogen cyclopentano [c] pyrroles-5-bases etc.
7-12 unit bridged ring base, what refer to that any two rings share that two non-conterminous atoms form contains 7-12 carbon atom or/and heteroatomic ring texture, and described heteroatoms is selected from N, S, O, CO, SO and/or SO 2deng.Comprising for example " 7-10 unit bridged ring base ", " 7-9 unit bridged ring base ", " 7-8 unit bridged ring base " etc.The example for example includes but not limited to:
7-12 unit volution base, refer to have that two rings share that atoms form at least contain 7-12 carbon atom or/and heteroatomic ring texture, described heteroatoms is selected from N, S, O, CO, SO and/or SO 2deng.Comprising for example " 7-10 unit volution base ", " 7-9 unit volution base ", " 7-8 unit volution base " etc.The example for example includes but are not limited to:
" 6-14 unit aryl " of the present invention refers to the ring-type aromatic group that contains 6-14 carbon atom, comprises 6-8 unit's aryl and 7-14 unit aryl.
6-8 unit aryl refers to the undersaturated aryl that contains 6-8 carbon atom, such as phenyl, cyclooctatetraenyl etc.
7-14 unit aryl refers to and is shared each other by two or more ring texturees that two adjacent carbon atoms form, have the condensed ring group that a ring is whole undersaturated aromatic nucleus at least, comprise the whole unsaturated aryl of 7-14 unit, such as naphthalene, phenanthrene etc., also comprise 7-14 unit fractional saturation aryl, for example benzo 3-8 unit saturated cyclic alkyls, benzo 3-8 unit fractional saturation cycloalkyl, specific examples is as 2,3-dihydro-1H-indenyl, 1H-indenyl, 1,2,3,4-tetralyl, Isosorbide-5-Nitrae-dihydro naphthyl etc.
" 6-10 unit aryl " of the present invention refers to the ring-type aromatic group that contains 6-10 carbon atom, comprises 6-8 unit's monocyclic aryl and 9-10 unit fused ring aryl.
" 3-14 unit heterocyclic radical " of the present invention refers to and contains the first cyclic group of one or more heteroatomic 3-14, comprise 3-8 unit's heterocyclic radical and 6-14 unit heterocyclic radical.
3-8 unit heterocyclic radical, refers to and contains 3-8 the annular atoms heterocyclic radical of (wherein at least containing a heteroatoms).Specific examples includes but are not limited to 2,5-dihydro-thiophene base, 4,5-pyrazoline base, 3,4-dihydro-2H-pyranyl, 5,6-dihydro-4H-1,3-oxazinyl, ethylenimine base, azetidinyl, Thietane base, tetrahydrofuran base, Pyrrolidine base, imidazolidyl, pyrazolidyl, tetrahydrofuran base, Isosorbide-5-Nitrae-dioxane base, 1,3-dioxane base, 1,3-dithian base, morpholinyl, piperazinyl etc.
6-14 unit heterocyclic radical, refer to that containing 6-14 annular atoms (wherein at least containing a heteroatoms) shares each other two adjacent atoms by two or more ring texturees and couple together the condensed ring structure forming, as the structure of benzo 3-8 unit heterocyclic radical formation, the structure that 3-8 unit's heterocyclic radical 3-8 unit heterocyclic radical form etc., specific examples includes but not limited to: , replace etc. ring texture the group that any commutable hydrogen atom forms.
" 3-8 unit heterocyclic radical " of the present invention, " 5-10 unit heterocyclic radical ", " 5-6 unit heterocyclic radical " refer to that above-mentioned " 3-14 unit heterocyclic radical " middle annular atoms number is respectively the specific examples of 3-8 unit, 5-10 unit, 5-6 unit.
" 3-8 unit cycloalkyl " of the present invention, " 6-10 unit cyclic group ", " 6-14 unit aryl ", " 3-14 unit heterocyclic radical ", 7-12 unit volution base ", " 7-12 unit bridged ring base " can also be by oxo or sulfo-; described oxo is one or more atom quilt-C (the O)-replacement on finger ring; for example 2-pyriconyl, 4-pyriconyl, 2H-pyran-2-one base, 5,6-dihydro-2H-pyran-2-one base, morpholine-3-ketone group etc.Described sulfo-is one or more atom quilt-C (the S)-replacement on finger ring.
Preferred compound of the present invention:
Above-claimed cpd of the present invention can adopt method and/or other technology known to persons of ordinary skill in the art that the present invention describes to synthesize, but is not limited only to following methods:
Reaction equation:
(1) preparation of intermediate 1
Raw material 1 salt of wormwood is suspended in to chamber in raw material 2, adds 50% aqueous sodium hydroxide solution, mixed solution is heated to 70 DEG C and reacts, and reacts complete, and mixed solution is poured water moisture into and fully stirred, filter, and washing, drying under reduced pressure, obtains intermediate 1.
(2) preparation of intermediate 2
Intermediate 1 is dissolved in appropriate tetrahydrofuran (THF), adds the reduction of catalyzer Raney's nickel, filter after completion of the reaction, rotary evaporation, except desolventizing, obtains intermediate 2.
(3) preparation of intermediate 3
The tetrahydrofuran solution of intermediate 2 is dissolved in appropriate methylene dichloride, adds triethylamine, under 0 DEG C of condition, add raw material 3, stirring reaction, after completion of the reaction, with chromatographic separation and purification, obtains intermediate 3.
(4) preparation of intermediate 4
Intermediate 3 is dissolved in appropriate methyl alcohol, adds the aqueous solution of lithium hydroxide, stirring at room temperature, after completion of the reaction, with 1M salt acid for adjusting pH value, to 6-7, concentrating under reduced pressure obtains product (0.4 g, productive rate 85 %).
(5) preparation of general formula (I) compound
Intermediate 4 and chlorine isobutyl carbonate propyl diester are dissolved in appropriate tetrahydrofuran (THF), add triethylamine, stirring at room temperature, mixture is dissolved in appropriate methyl alcohol, adds the methanol solution of raw material 4 and MeONa, under room temperature, stirs, after completion of the reaction, purify by preparation liquid phase, obtain logical formula I compound.
R in upper reaction equation 1, R 2, R 3, R 4, R 5, R 6, R 7, L, W, X, T, n be as defined above, and F in raw material 1 can be replaced by Cl, Br, I.
" pharmacy acceptable salt " of the claimed formula I compound of the present invention, comprises an alkali metal salt, as sodium salt, sylvite, lithium salts etc.; Alkaline earth salt, as calcium salt, magnesium salts etc.; Other metal-salts, as aluminium salt, molysite, zinc salt, mantoquita, nickel salt, cobalt salt etc.; Inorganic base salts, as ammonium salt; Organic alkali salt, as tertiary octyl group amine salt, dibenzyl amine salt, alkylbenzyldimethylasaltsum saltsum, glucosamine salt, phenylglycocoll alkyl ester salt, ethylenediamine salt, N-METHYL-ALPHA-L-GLUCOSAMINE salt, guanidinesalt, diethyl amine salt, triethylamine salt, dicyclohexyl amine salt, N, N '-dibenzyl ethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzyl-styroyl amine salt, piperazine salt, tetramethyl-amine salt, three (methylol) aminomethane salt; Halogen acid salt, as hydrofluoride, hydrochloride, hydrobromate, hydriodate etc.; Inorganic acid salt, as nitrate, perchlorate, vitriol, phosphoric acid salt etc.; Lower alkyl sulfonate, as mesylate, fluoroform sulphonate, esilate etc.; Arylsulphonate, as benzene sulfonate, P-TOLUENE SULFO ACID 99's salt etc.; Organic acid salt, as acetate, malate, fumarate, succinate, Citrate trianion, tartrate, oxalate, maleate etc.; Amino acid salts, as glycinate, Trimethyl glycine salt, arginic acid salt, ornithine salt, glutaminate, aspartate etc.
" steric isomer " of the claimed formula I compound of the present invention, in the time there is one or more unsymmetrical carbon in compound structure, can produce enantiomer; In the time that compound contains thiazolinyl or ring texture, can produce cis/trans isomer; In the time that compound has ketone or oxime, can produce tautomer etc.All these isomer and mixture all belong to category of the present invention.
" the deuterated thing " of the claimed formula I compound of the present invention, when the hydrogen atom in compound is during by the some or all of replacement of its isotropic substance deuterium (symbol is D), the material producing also belongs to category of the present invention.
Formula I compound of the present invention, its deuterated thing, its pharmacy acceptable salt or its steric isomer can be made pharmaceutical preparation with one or more pharmaceutical carriers.Described pharmaceutical preparation refers to the conventional formulation using clinically, can be oral or the mode such as administered parenterally be applied to the patient who needs this treatment.As tablet, particle, capsule, powder, injection, inhalation, sublingual administration preparation, syrup, gel, ointment, suppository, lotion, nasal cavity drop, sprays, preparation capable of permeating skin etc.These preparations can pass through ordinary method, add pharmaceutical carrier and are prepared from as vehicle, tamanori, moistening agent, disintegrating agent, thickening material etc.
The further claimed formula I compound of the present invention, its deuterated thing, its pharmacy acceptable salt or its steric isomer are in the purposes for the preparation for the treatment of and/or preventing in the medicine of tumour.Further abnormality proliferation, differentiation or survival that formula I compound of the present invention can stop cell are (for example, can effectively stop tumor size to increase or stop tumour to reach transfering state), can also stop development or the induced tumor apoptosis of cancer or suppress tumor-blood-vessel growth.
" tumour " of the present invention includes but not limited to
(1) lymph hemopoietic system knurl, comprises acute lymphoblastic leukemia, B cell lymphoma and Burketts lymphoma etc.;
(2) marrow hemopoietic system knurl, comprises acute and chronic myelocytic leukemia and promyelocytic leukemia, myelomatosis etc.;
(3) knurl in interstitial source, comprises fibrosarcoma, rhabdosarcoma, mesothelioma etc.;
(4) other tumours, comprise melanoma, spermocytoma, teratoma, neuroblastoma and neurospongioma etc.
(5) malignant tumour, mainly refer to cancer, comprise bladder cancer, the cancer of the brain, mammary cancer, colon and rectum carcinoma, kidney, liver cancer, lung cancer, ovarian cancer, carcinoma of the pancreas, adrenal carcinoma, prostate cancer, cancer of the stomach, carcinoma of vagina, cervical cancer, carcinoma of endometrium, thyroid carcinoma and skin carcinoma etc.
The compounds of this invention, compared with immediate prior art, has the following advantages:
(1) many target spots of unit molecule EGFR/Her2/HDAC inhibitor of the present invention, all has very strong anti-tumor activity in vivo and in vitro, comprises the tumour cell to tyrosine kinase inhibitor resistance;
(2) the compounds of this invention has reduced the generation of resistance;
(3) the compounds of this invention preparation technology is simple, and physico-chemical property is good, and steady quality is easy to carry out large-scale commercial production.
Further set forth below the beneficial effect of the compounds of this invention by external pharmacology activity experiment, but this should be interpreted as to the compounds of this invention only has following beneficial effect.
the external zymetology activity experiment of experimental example the compounds of this invention
Trial-product: the compounds of this invention, its chemical name, structural formula and preparation are referring to the embodiment of each compound.
Contrast medicine: CUDC-101, compound 12 in patent US7547781, prepares with reference to patent working example 8, and its structural formula is: .
The inhibition determination of activity of experimental technique HDAC enzyme
1. test is prepared with reagent
1 times of damping fluid (50 mM hydroxyethyl piperazine ethanesulfonic acid, pH=7.4,100 mM Repone K, 0.001% tween 20,0.05% bovine serum albumin, 20 μ M Trichloroethyl Phosphates)
2. compound serial dilution
1. the DMSO(dimethyl sulfoxide (DMSO) of 0.15 mM) compound solution: the compound solution 15 μ L of 10 mM join in the 100%DMSO of 985 μ L.
2. serial dilution compound on 96 orifice plates: diluted chemical compound 4 times (the compound 20 μ L of 0.15 mM add the 100%DMSO of 60 μ L) is next hole, and 10 concentration of serial dilution are always on 96 orifice plates.
3. add in 100%DMSO to 2 the blank hole of 100 μ L, the not enzyme-added and compound in hole, as Schwellenwert control wells; Another does not add compound, as maximum value control wells.
4. the DMSO compound solution that shifts 0.15 mM prepared by 6 μ L from former 96 orifice plates, to another 96 orifice plate, adds 1 times of damping fluid of 94 μ L, as intermediate plate.
5. on vibrator, shake 10 minutes.
3. prepare enzyme solution
Prepare enzyme solution with 1 times of damping fluid.The enzyme concn of HDAC1 is 6.25 nM, and the enzyme concn of HDAC6 is 7.6 nM.
4. prepare matrix solution
The substrate of trypsinase and HDAC (Boc-lys (AC)-AMC) is joined in 1 times of buffered soln.The matrix solution of HDAC1 is the trypsinase of 20 μ M and the substrate of 20 μ M, and the matrix solution of HDAC6 is the trypsinase of 20 μ M and the substrate of 8/6 μ M.
5. the compound solution of the each concentration of transferase 45 μ L is to 384 orifice plates.
6. the enzyme solution of transferase 45 μ L is to 384 orifice plates, and 1 times of damping fluid of transferase 45 μ L is to lower concentration control wells.
7. incubated at room 10 minutes.
8. the matrix solution of transferase 45 μ L starts reaction to 384 orifice plates.
Room temperature gently mix 60 seconds.
10. under the collaborative dynamic mode that 355 nm excite and 460 nm launch, read plate.HDAC1 reads plate 30 minutes in incubated at room after 20 minutes, HDAC6 reads plate 45 minutes in incubated at room after 3 minutes.
11. fitting of a curve draws IC 50
Calculate inhibiting rate (%)=(maximum value-sample value)/(maximum value-minimum value) × 100
Adopt Graphpad 5.0 softwares to carry out curve fitting, draw IC 50value.
Experimental result
The external zymetology determination of activity (IC of table 1 part of compounds of the present invention 50)
The external zymetology determination of activity (IC of table 2 part of compounds of the present invention 50)
The external zymetology determination of activity (IC of table 3 part of compounds of the present invention 50)
The external zymetology determination of activity (IC of table 4 part of compounds of the present invention 50)
The external zymetology determination of activity (IC of table 5 part of compounds of the present invention 50)
From table 1-5 experimental result, the compounds of this invention has good inhibition activity to HDAC1 enzyme and HDAC6, and part of compounds of the present invention is with contrast medicine activity suitable, can be used for treating the disease of Tumor-assaciated.
Embodiment
The embodiment of form by the following examples, is described in further detail foregoing of the present invention.But this should be interpreted as to the scope of the above-mentioned theme of the present invention only limits to following examples.All technology realizing based on foregoing of the present invention all belong to scope of the present invention.
embodiment 1 (E)-N 1 -(4-((the chloro-4-fluorophenyl of 3-) amino)-7-methoxyl group quinazoline-6-yl)-N 8 the preparation of-hydroxyl oct-2-ene diamide (compound 1)
(1) preparation of diethyl phosphonyl tert.-butyl acetate
By triethyl-phosphite (1.66g, 10 mmol) and the mixing solutions of bromo-acetic acid tert-butyl (1.93 g, 10mmol), under 100 DEG C of conditions, stir 3 hours, concentrating under reduced pressure obtains product (2.48 g, productive rate 98 %) after completion of the reaction.
(2) preparation of 6-oxo ethyl hexanoate
By pyridinium chlorochromate (21.5 g, 0.1 mol) join 6 hydroxycaproic acid ethyl ester (3.20 g, 20 mmol) methylene dichloride (40 mL) solution in, stirring at room temperature approximately 6 hours, reaction mixture obtains product (2.6 g, productive rate 82 %) with preparative chromatography separation and purification.
(3) preparation of (E)-1-tertiary butyl 8-ethyl oct-2-ene two acid esters
By 6-oxo ethyl hexanoate (1.58 g; 10 mmol) be dissolved in tetrahydrofuran (THF) (20 mL); under nitrogen protection condition, dropwise add diethyl phosphonyl tert.-butyl acetate (2.52 g; 10 mmol) and sodium hydride (60 %; 440 mg, 11 mmol) tetrahydrofuran (THF) (20 mL) mixing solutions.Stirring at room temperature 1 hour, then water slowly dilutes, then uses extracted with diethyl ether twice.Merge organic phase and make siccative with sodium sulfate, rotary evaporation is dry, and crude product obtains product (2.02 g, productive rate 79 %) with preparative chromatography separation and purification.
(4) preparation of (E)-8-oxyethyl group-8-oxo oct-2-ene acid
By (E)-1-tertiary butyl 8-ethyl oct-2-ene two acid esters (2.56 g, 10 mmol) and tosic acid (1.72 g, 10 mmol) be dissolved in toluene (20 mL), back flow reaction 30min, the crude product of reaction solution concentrating under reduced pressure gained obtains product (1.8 g, productive rate 90 %) through preparative chromatography separation and purification.
(5) preparation of the chloro-8-oxo of (E)-8-oct-6-ene acetoacetic ester
By (E)-8-oxyethyl group-8-oxo oct-2-ene acid (1.8 g, 9 mmol) be dissolved in methylene dichloride (20 mL), add DMF (0.2 mL) and oxalyl chloride (1 mL), stir 2 hours.After completion of the reaction, concentrating under reduced pressure obtains product (1.9 g, productive rate 97%).
(6) preparation of N-(the chloro-4-fluorophenyl of 3-)-7-methoxyl group-6-nitro-quinazoline-4-amine
By N-(the chloro-4-fluorophenyl of 3-) the fluoro-6-nitro-quinazoline-4-of-7-amine (6.72 g, 20 mmol) be suspended in methyl alcohol (100 mL), add 50 % aqueous sodium hydroxide solutions (2 mL), mixed solution heats 2 hours under 70 DEG C of conditions, after completion of the reaction, mixed solution is poured into water abundant stirring 30 min, filter, washing, 60 DEG C of vacuum-dryings are spent the night, obtain product (6.2 g, productive rate 89 %).
(7) N 4-(the chloro-4-fluorophenyl of 3-)-7-methoxyl group quinazoline-4, the preparation of 6-diamines
By N-(the chloro-4-fluorophenyl of 3-)-7-methoxyl group-6-nitro-quinazoline-4-amine (7.1 g, 20mmol) be dissolved in tetrahydrofuran (THF) (100 mL), add catalyzer Raney Ni (Raney's nickel) (1.2 g) reduction, filter after completion of the reaction, rotary evaporation obtains product (6.4 g, productive rate 99 %).
(8) preparation of (E)-8-((4-((the chloro-4-fluorophenyl of 3-) amino)-7-methoxyl group quinazoline-6-yl) amino)-8-oxo oct-6-ene acetoacetic ester
By N 4-(the chloro-4-fluorophenyl of 3-)-7-methoxyl group quinazoline-4,6-diamines (3.18 g, 10 mmol) be dissolved in methylene dichloride (50 mL), add triethylamine (2.02 g, 20 mmol), under 0 DEG C of condition, add the chloro-8-oxo of (E)-8-oct-6-ene acetoacetic ester (0.33 g, 15 mmol), stir 2 hours, after completion of the reaction, obtain product (0.36 g, productive rate 71.9 %) with preparative chromatography separation and purification.
(9) preparation of (E)-8-((4-((the chloro-4-fluorophenyl of 3-) amino)-7-methoxyl group quinazoline-6-yl) amino)-8-oxo oct-6-ene acid
By (E)-8-((4-(3-chloro-4-fluorobenzene nitrile) amino)-7-methoxyl group quinazoline-6-yl) amino)-8-oxo oct-6-ene acetoacetic ester (0.5 g, 1 mmol) be dissolved in methyl alcohol (20 mL), add and be dissolved with lithium hydroxide (0.24 g, 10 mmol) the aqueous solution (10 mL), stirred overnight at room temperature, use after completion of the reaction 1M salt acid for adjusting pH value to 6-7, concentrating under reduced pressure obtains product (0.4 g, productive rate 85 %).
(10) preparation of (E)-8-((4-((the chloro-4-fluorophenyl of 3-) amino)-7-methoxyl group quinazoline-6-yl) amino)-8-oxo oct-6-ene acid sec.-propyl anhydride of carbonic acid
By (E)-8-((4-(the chloro-4-fluorophenyl of 3-) amino)-7-methoxyl group quinazoline-6-yl) amino)-8-oxo oct-6-ene acid (0.47 g, 1 mmol) and chlorine isobutyl carbonate propyl diester (0.14 g, 1.1 mmol) be dissolved in tetrahydrofuran (THF) (50 mL), add triethylamine (0.16 g, 1.6mmol), stirring at room temperature 1 hour, purifying is not directly used in next step reaction.
(11) (E)-N 1-(4-((the chloro-4-fluorophenyl of 3-) amino)-7-methoxyl group quinazoline-6-yl)-N 8the preparation of-hydroxyl oct-2-ene diamide
By previous step reaction mixture (0.46 g, 14 mmol) be dissolved in methyl alcohol (15 mL), add azanol (0.33 g, 10 mmol) and MeONa (0.34 g, 6.3 mmol) methanol solution, under room temperature, stir 20 hours, after completion of the reaction, crude product obtains product (42 mg, two-step reaction productive rate 8.6 %) with preparative chromatography separation and purification
Molecular formula: C 23h 23clFN 5o 4molecular weight: 487.91 LC-MS (m/e): 489.1 (M+H)
1H-NMR (400 MHz, DMSO-d 6) δ: 10.34(s, 1H), 9.79 (s,1H), 9.49 -9.40(m, 1H), 8.82 (s, 1H), 8.68 (m, 1H), 8.51(s, 1H), 8.10 (m, 1H), 7.77(m, 1H), 7.42 (t,1H), 7.26(s, 1H), 5.60 (m, 2H), 4.00(s, 3H), 3.30-3.27 (m, 2H), 2.06 (m, 1H), 1.96(m, 3H), 1.58 (m, 2H).
embodiment 2 (R, E)-N 1 -(4-((the chloro-4-fluorophenyl of 3-) amino)-7-((tetrahydrofuran (THF)-3-yl) oxygen base) quinazoline-6-yl)-N 8 the preparation of-hydroxyl oct-6-ene diamide (compound 2)
(1) preparation of (R, E)-8-((4-((the chloro-4-fluorophenyl of 3-) amino)-7-((tetrahydrofuran (THF)-3-yl) oxygen base) quinazoline-6-yl) amino)-8-oxo oct-6-ene acetoacetic ester
By (R)-N 4-(the chloro-4-fluorophenyl of 3-)-7-(tetrahydrofuran (THF)-3-yl) oxygen base) quinazoline-4,6-diamines (3.74 g, 10 mmol) be dissolved in methylene dichloride (50 mL), add triethylamine (2.02 g, 20 mmol), under 0 DEG C of condition, add chloro-8 oxo oct-6-ene acetoacetic ester (3.3 g of (E)-8-, 15 mmol), stir 2 hours, after completion of the reaction, obtain product (1.36 g, productive rate 24 %) with preparative chromatography separation and purification.
(2) preparation of (R, E)-8-((4-((the chloro-4-fluorophenyl of 3-) amino)-7-((tetrahydrofuran (THF)-3-yl) oxygen base) quinazoline-6-yl) amino)-8-oxo oct-6-ene acid
By (R, E)-8-((4-((the chloro-4-fluorophenyl of 3-) amino)-7-((tetrahydrofuran (THF)-3-yl) oxygen base) quinazoline-6-yl) amino)-8-oxo oct-6-ene acetoacetic ester (0.56 g, 1 mmol) be dissolved in methyl alcohol in (20 mL), add and be dissolved with lithium hydroxide (0.24 g, 10 mmol) water (5mL) solution, stirred overnight at room temperature.After completion of the reaction, by reaction solution with 1 M salt acid for adjusting pH value to 6-7, concentrating under reduced pressure obtains product (0.4 g, productive rate 76 %).
(3) preparation of (R, E)-8-((4-((the chloro-4-fluorophenyl of 3-) amino)-7-((tetrahydrofuran (THF)-3-yl) oxygen base) quinazoline-6-yl) amino)-8-oxo oct-6-ene acid sec.-propyl carbonic anhydride
By (R, E)-8-((4-((the chloro-4-fluorophenyl of 3-) amino)-7-((tetrahydrofuran (THF)-3-yl) oxygen base) quinazoline-6-yl) amino)-8-oxo oct-6-ene acid (0.53 g, 1 mmol) and isopropyl chlorocarbonate (0.14 g, 1.1 mmol) be dissolved in tetrahydrofuran (THF) (50 mL), add triethylamine (0.16 g, 1.6mmol), stirring at room temperature 1 hour, is not purifiedly directly used in next step reaction.
(4) (R, E)-N 1-(4-((the chloro-4-fluorophenyl of 3-) amino)-7-((tetrahydrofuran (THF)-3-yl) oxygen base) quinazoline-6-yl)-N 8the preparation of-hydroxyl oct-6-ene diamide
By in previous step reaction mixture, add the methanol solution that is dissolved with azanol (0.46 g, 13.9 mmol) and sodium methoxide (0.34 g, 6.3 mmol), stirring at room temperature 20 h.After completion of the reaction, obtain product (38 mg, productive rate 7 %) with preparative chromatography column separating purification.
Molecular formula: C 26h 27clFN 5o 5molecular weight: 543.97 LC-MS (m/e): 545.1 (M+H)
1H-NMR (400 MHz, DMSO-d 6) δ: 10.34(s, 1H), 9.79 (s,1H), 9.25 (m, 1H), 8.82 (s, 1H), 8.76 (s, 1H), 8.51(s, 1H), 8.11 (m, 1H), 7.75(m, 1H), 7.41 (t, 1H), 7.22(s, 1H), 5.63 (m, 2H), 5.29 (m, 1H), 3.78-4.01 (m, 4H), 3.14-3.38 (m, 3H), 2.31(s, 1H), 1.94-2.11(m, 5H), 1.58 (m, 1H).
the preparation of embodiment 3 (E)-N-(4-((the chloro-4-fluorophenyl of 3-) amino)-7-methoxyl group quinazoline-6-yl)-4-((3-(hydroxyl amino)-3-oxopropyl) (methyl) amino) but-2-enamides (compound 3)
(1) preparation of N-(the chloro-4-fluorophenyl of 3-)-7-methoxyl group-6-nitro-quinazoline-4-amine
By N-(the chloro-4-fluorophenyl of 3-) the fluoro-6-nitro-quinazoline-4-of-7-amine (6.72 g, 20 mmol) be suspended in methyl alcohol (100 mL), add 50 % aqueous sodium hydroxide solutions (2 mL), mixed solution is heated to 70 DEG C of reactions 2 hours.Mixture is poured into water to abundant stirring 30 min, then filters, washing, the drying under reduced pressure product (6.2 g, productive rate 89%) that spends the night to obtain under 60 DEG C of conditions.
(2) N 4-(the chloro-4-fluorophenyl of 3-)-7-methoxyl group quinazoline-4, the preparation of 6-diamines
By N-(the chloro-4-fluorophenyl of 3-)-7-methoxyl group-6-nitro-quinazoline-4-amine (7.1 g, 20mmol) be dissolved in tetrahydrofuran (THF) (100 mL), (1.2 g), and passes into hydrogen and reduce, and stirs 2 hours to add catalyzer Raney Ni.After completion of the reaction, filter, filtrate decompression concentrates to obtain product (6.4 g, 100 %).
(3) preparation of 3-(benzylamino) methyl propionate
By benzylamine (2.14 mL, 20 mmol) be dissolved in anhydrous methylene chloride (50 mL), add and be dissolved with methyl acrylate (2.0 mL, 22 mmol) anhydrous methylene chloride (50mL) solution, reaction solution stir spend the night, then water cancellation, extraction, organic layer anhydrous sodium sulfate drying, concentrating under reduced pressure is removed methylene dichloride and is obtained product (3.7 g, productive rate 96 %).
(4) preparation of 3-(benzyl (methyl) amino) methyl propionate
By 3-(benzylamino) methyl propionate (5.8 g, 30 mmol) be dissolved in acetonitrile (50 mL), add methyl iodide (8.58 g, 60 mmol) and salt of wormwood (8.28 g, 60 mmol), stirring is spent the night, and then obtains product (5 g, yield 80 %) with silica gel column chromatography separating purification.
(5) preparation of 3-(methylamino) methyl propionate
By 3-(benzyl (methyl) amino) methyl propionate (25.1 g, 121 mmol) be dissolved in methyl alcohol (250 mL) and hexanaphthene (125 mL), (7.0 g) to add the palladium carbon of 10 %, mixture reflux 3 hours, filter, concentrating under reduced pressure obtains product (10.9 g, productive rate 77 %).
(6) preparation of (E)-4-((3-methoxyl group-3-oxopropyl) (methyl) amino) but-2-ene acid
By 3-(methylamino) methyl propionate (3.5 g, 30 mmol) be dissolved in methylene dichloride (50 mL), add (E)-4-bromine but-2-ene acid (4.9 g, 30 mmol) and salt of wormwood (8.28g, 60 mmol), stirring is spent the night.Then obtain product (3 g, productive rate 50 %) with silica gel column chromatography separating purification.
(7) preparation of (E)-3-((the chloro-4-oxo but-2-ene-1-of 4-yl) (methyl) amino) methyl propionate
By (E)-4-((3-methoxyl group-3-oxopropyl) (methyl) amino) but-2-ene acid (1.0 g, 5 mmol) be dissolved in methylene dichloride (20 mL), add N, dinethylformamide (0.2 mL) and oxalyl chloride (1 mL), stir 2 hours.After completion of the reaction, concentrating under reduced pressure obtains product, and purifying is not directly used in next step reaction.
(8) preparation of (E)-3-((4-((4-((the chloro-4-fluorophenyl of 3-) amino)-7-methoxyl group quinazoline-6-yl) amino)-4-oxo but-2-ene-1-yl) (methyl) amino) methyl propionate
By N 4-(the chloro-4-fluorophenyl of 3-)-7-methoxyl group quinazoline-4,6-diamines (3.18 g, 10 mmol) be dissolved in methylene dichloride (50 mL), add triethylamine (2.02 g, 20 mmol), under 0 DEG C of condition, add (E)-3-((the chloro-4-oxo of 4-but-2-ene) (methyl) amino) methyl propionate (0.33 g, 15 mmol), stir 2 hours.After completion of the reaction, obtain product (0.4 g, productive rate 8 %) with preparative column chromatographic separation and purification.
(9) preparation of (E)-3-((4-((4-((the chloro-4-fluorophenyl of 3-) amino)-7-methoxyl group quinazoline-6-yl) amino)-4-oxo but-2-ene-1-yl) (methyl) amino) propionic acid
By (E)-3-((4-((4-((the chloro-4-fluorophenyl of 3-) amino)-7-methoxyl group quinazoline-6-yl) amino)-4-oxo but-2-ene-1-yl) (methyl) amino) methyl propionate (0.5 g, 1 mmol) be dissolved in methyl alcohol (20 mL), add the aqueous solution (5 mL) that is dissolved with lithium hydroxide (0.24 g, 10 mmol).Stirred overnight at room temperature, after completion of the reaction, reaction mixture is with 1 M salt acid for adjusting pH value to 6-7, and concentrating under reduced pressure obtains product (0.4 g, productive rate 82 %).
(10) preparation of (E)-3-((4-((4-((the chloro-4-fluorophenyl of 3-) amino)-7-methoxyl group quinazoline-6-yl) amino)-4-oxo but-2-ene-1-yl) (methyl) amino) propionic acid (sec.-propyl carbonic acid) acid anhydrides
By (E)-3-((4-((4-((the chloro-4-fluorophenyl of 3-) amino)-7-methoxyl group quinazoline-6-yl) amino)-4-oxo but-2-ene-1-yl) (methyl) amino) propionic acid (0.49 g, 1 mmol) and isopropyl chlorocarbonate (0.14 g, 1.1 mmol) be dissolved in tetrahydrofuran (THF) (50 mL), add triethylamine (0.16 g, 1.5 mmol), stirring at room temperature 1 hour, purifying is not directly used in next step reaction.
(11) preparation of (E)-N-(4-((the chloro-4-fluorophenyl of 3-) amino)-7-methoxyl group quinazoline-6-yl)-4-((3-(hydroxyl amino)-3-oxopropyl) (methyl) amino) but-2-enamides
By in the reaction mixture of previous step, add azanol (0.46 g, 14 mmol) and sodium methoxide (0.34 g, 6.3 mmol) methanol solution, stirred overnight at room temperature, after completion of the reaction, crude product obtains product (40 mg, two-step reaction productive rate 8 %) with preparative chromatography separation and purification.
Molecular formula: C 23h 24clFN 6o 4molecular weight: 502.93 LC-MS (m/e): 504 (M+H)
1H-NMR (400 MHz, MeOD) δ: 8.91(s, 1H), 8.47 (s, 1H), 8.01(d, 1H), 7.67 (m, 1H), 7.23 (m, 2H), 7.06(m,1H), 6.56 (d, 1H), 4.60 (s, 3H), 4.08 (s, 3H), 2.76(m, 2H), 2.34 (m, 4H).
embodiment 4(E)- n 1 -(4-((the chloro-4-fluorophenyl of 3-) amino)-7-((7-methyl-7-azaspiro [3.5] nonane-2-yl) methoxyl group) quinazoline-6-yl)-N 8 the preparation of-hydroxyl oct-2-ene diamide (compound 4)
(1) preparation of (E)-8-((4-((the chloro-4-fluorophenyl of 3-) amino)-7-((7-methyl-7-azaspiro [3.5] ninth of the ten Heavenly Stems-2-yl) methoxyl group) quinazoline-6-yl) amino)-8-oxo oct-6-ene acid esters
By N 4-(the chloro-4-fluorophenyl of 3-)-7-((7-methyl-7-azaspiro [3.5] ninth of the ten Heavenly Stems-2-yl) methoxyl group) quinazoline-4,6-diamines (0.91 g, 2 mmol) and (E)-8-methoxyl group-8-oxo oct-2-ene acid (0.4 g, 2 mmol) be dissolved in N, in dinethylformamide (30 mL), under 0 DEG C of condition, add 2-(7-azo benzotriazole)-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester (1.14 g, 3 mmol) and triethylamine (0.4 g, 4 mmol), stir 22 hours.After completion of the reaction, obtain product (0.51 g, productive rate 40 %) with silica gel column chromatography separating purification.
(2) preparation of (E)-8-((4-((the chloro-4-fluorophenyl of 3-) amino)-7-((7-methyl-7-azepine [3.5] ninth of the ten Heavenly Stems-2-yl) methoxyl group) quinazoline-6-yl) amino)-8-oxo oct-6-ene acid
By (E)-8-((4-((the chloro-4-fluorophenyl of 3-) amino)-7-((7-methyl-7-azaspiro [3.5] ninth of the ten Heavenly Stems-2-yl) methoxyl group) quinazoline-6-yl) amino)-8-oxo-6-olefin(e) acid ester (0.64 g, 1mmol) be dissolved in methyl alcohol (20 mL), add the aqueous solution (5 mL) that is dissolved with lithium hydroxide (0.24 g, 10 mmol).Stirred overnight at room temperature, after completion of the reaction, uses 1M salt acid for adjusting pH to 6-7 in reaction mixture, concentrating under reduced pressure obtains product (0.5 g, productive rate 82 %).
(3) (E)-N 1-(4-((the chloro-4-fluorophenyl of 3-) amino)-7-((7-methyl-7-azaspiro [3.5] ninth of the ten Heavenly Stems-2-yl) methoxyl group) quinazoline-6-yl)-N 8the preparation of-((tetrahydrochysene-2H-pyrans-2-yl) oxygen base) oct-2-ene diamide
By (E)-8-((4-((the chloro-4-fluorophenyl of 3-) amino)-7-((7-methyl-azaspiro [3.5] ninth of the ten Heavenly Stems-2-yl) methoxyl group) quinazoline-6-yl) amino)-8-oxo oct-6-ene acid (0.6 g, 1 mmol) be dissolved in N, in dinethylformamide (30 mL), add O-(tetrahydrochysene-2H-pyrans-2-yl) azanol (0.12 g, 1.1 mmol), I-hydroxybenzotriazole (0.27 g, 2 mmol), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (0.38 g, 2 mmol) and triethylamine (0.48 g, 4.7 mmol), stirring at room temperature 24 hours, after completion of the reaction, extract by ethyl acetate (50 mL), get organic layer, concentrating under reduced pressure and the dry product (0.2g that to obtain, productive rate 28 %).
(4) (E)-N 1-(4-((the chloro-4-fluorophenyl of 3-) amino)-7-((7-methyl-7-azaspiro [3.5] ninth of the ten Heavenly Stems-2-yl) methoxyl group) quinazoline-6-yl)-N 8the preparation of-hydroxyl oct-2-ene diamide
By (E)-N 1-(4-((the chloro-4-fluorophenyl of 3-) amino)-7-((7-methyl-7-azaspiro [3.5] ninth of the ten Heavenly Stems-2-yl) methoxyl group) quinazoline-6-yl)-N 8-((tetrahydrochysene-2H-pyrans-2-yl) oxygen base) oct-2-ene diamide (0.2 g, 0.3 mmol) be dissolved in tetrahydrofuran (THF) (20 mL), add concentrated hydrochloric acid (2 mL), stirring at room temperature 3 hours, after completion of the reaction, obtain product (25 mg, productive rate 13 %) with preparative chromatography column separating purification.
Molecular formula: C 32h 38clFN 6o 4molecular weight: 625.13 LC-MS (m/e): 625.3 (M+H)
1H-NMR (400 MHz, DMSO-d 6) δ: 8.73(s, 1H), 8.48 (s,1H), 8.02 (m, 1H), 7.65 (m, 1H), 7.24 (m, 2H), 7.06 (m, 1H), 6.28(d, 1H), 4.22(m, 2H), 2.86-3.20 (m,4H), 2.76 (s, 3H), 2.33 (m, 2H), 1.56-2.21 (m, 15H).
embodiment 5 N 1 -(4-(the chloro-4-fluorophenyl of 3-amino)-7-(tetrahydrofuran (THF)-3-base oxygen base) quinazoline-6-yl)-N 8 the preparation of-hydroxyl oct-2-ene diamide (compound 5)
(1) preparation of 7-fluquinconazole quinoline-4-alcohol
2-amino-4-fluorobenzoic acid (92 g, 0.6 mol) is dissolved in 2-methyl cellosolve (50 mL), adds acetic acid carbonamidine (56 g, 0.5mol), mixed-liquor return reaction 18 hours, react cooling after, concentrating under reduced pressure, in resistates, add ammonium hydroxide (0.01 N, the 250 mL) aqueous solution, stir 1 hour, filter suspended substance, wash with water, anhydrous sodium sulfate drying obtains off-white color solid (86 g, productive rate 87 %).
(2) preparation of the fluoro-6-nitro-quinazoline-4-of 7-alcohol
Under 0 DEG C of condition, 7-fluquinconazole quinoline-4-alcohol (86 g, 0.5 mol) is dissolved in the vitriol oil (30mL), in 15 min, dropwise adds while stirring concentrated nitric acid (30 mL).Mixed solution is heated to 100 DEG C of reactions 3 hours, and cool to room temperature, pours in frozen water while stirring, removes by filter throw out, obtains product (25 g, productive rate 24 %) with acetic acid recrystallization
(3) preparation of 7-methoxyl group-6-nitro-quinazoline-4-alcohol
By fluoro-7-6-nitro-quinazoline-4-alcohol (2.1 g, 10 mmol) be suspended in methyl alcohol (100 mL), add 50 % aqueous sodium hydroxide solutions (2 mL), mixed solution, is poured into water after 2 hours 70 DEG C of reactions, fully stirs 30 min, filter, washing, 60 DEG C of drying under reduced pressure product (2 g, productive rate 90 %) that spends the night to obtain.
(4) preparation of 6-amino-7-methoxyl group quinazoline-4-alcohol
By 7-methoxyl group-6-nitro-quinazoline-4-alcohol (6.6 g, 30 mmol) be dissolved in methyl alcohol (50mL) and tetrahydrofuran (THF) (50 mL), add zinc (11.6 g, 177 mmol) and ammonium chloride (9.6 g, 179 mmol), reaction solution refluxes 3 hours, after completion of the reaction, concentrating under reduced pressure obtains crude product, and silica gel column chromatography separating purification obtains crude product (6 g).
(5) preparation of (E)-8-((4-hydroxyl-7-methoxyl group quinazoline-6-yl) amino)-8-oxo oct-6-ene acetoacetic ester
By 6-amino-7-methoxyl group quinazoline-4-alcohol (3.8 g, 20 mmol) and (E)-8-oxyethyl group-8-oxo oct-2-ene acid (4 g, 20 mmol) be dissolved in N, in dinethylformamide (100 mL), under 0 DEG C of condition, add 2-(7-azo benzotriazole)-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester (3.8 g, 10 mmol) and triethylamine (2.02g, 20 mmol), stir 22 hours.After completion of the reaction, obtain product (5 g, productive rate 67 %) with silica gel column chromatography separating purification.
(6) preparation of (E)-8-((the chloro-7-methoxyl group quinazoline-6-of 4-yl) amino)-8-oxo oct-6-ene acetoacetic ester
By (E)-8-((4-hydroxyl-7-methoxyl group quinazoline-6-yl) amino)-8-oxo oct-6-ene acid esters (0.37 g, 1 mmol) be suspended in sulfur oxychloride (100 mL), add DMF (0.2 mL).Mixed solution heats 2 hours at 70 DEG C, reaction solution concentrating under reduced pressure, and purifying is not directly used in next step reaction.
(7) preparation of (E)-8-((4-((3-ethynyl phenyl) amino)-7-methoxyl group quinazoline-6-yl) amino)-8-oxo oct-6-ene acetoacetic ester
By (E)-8-((the chloro-7-methoxyl group quinazoline-6-of 4-yl) amino)-8-oxo oct-6-ene acetoacetic ester (0.39 g,
1 mmol) be dissolved in tetrahydrofuran (THF), add 3-acetylenylaniline (0.12 g, 1 mmol), under 70 DEG C of conditions, stir 3 hours, after completion of the reaction, reaction mixture obtains product (0.15 g, productive rate 32 %) with silica gel column chromatography separating purification.
(8) preparation of (E)-8-((4-((3-ethynyl phenyl) amino)-7-methoxyl group quinazoline-6-yl) amino)-8-oxo oct-6-ene acid
By (E)-8-((4-((3-ethynyl phenyl) amino)-7-methoxyl group quinazoline-6-yl) amino)-8-oxo oct-6-ene acetoacetic ester (0.47 g, 1 mmol) be dissolved in methyl alcohol (12 mL), add and be dissolved with Lithium Hydroxide Monohydrate (0.13 g, 3 mmol) the aqueous solution (3 mL), stirred overnight at room temperature.After completion of the reaction, mixed solution is with 1M salt acid for adjusting pH to 6-7, and concentrating under reduced pressure obtains product (0.4 g, productive rate 90 %).
(9) preparation of (E)-8-((4-((3-ethynyl phenyl) amino)-7-methoxyl group quinazoline-6-yl) amino)-8-oxo oct-6-ene acid (sec.-propyl carbonic acid) acid anhydrides
By (E)-8-((4-((3-ethynyl phenyl) amino)-7-methoxyl group quinazoline-6-yl) amino)-8-oxo oct-6-ene acid (132 mg, 0.3 mmol) be dissolved in tetrahydrofuran (THF) (20 mL), be cooled to 0 DEG C, add triethylamine (60.6 mg, 0.6 mmol), stir half an hour, dropwise add again isopropyl chlorocarbonate (81.6 m g, 0.7 mmol) after molten stirring half an hour, be not purifiedly directly used in next step reaction.
(10) (E)-N 1-(4-((3-ethynyl phenyl) amino)-7-methoxyl group quinazoline-6-yl)-N 8the preparation of-hydroxyl oct-2-ene diamide
By in previous step reaction mixture, add and be dissolved with azanol (0.46 g, 13.9 mmol) methanol solution in, stirring is spent the night, add water and ethyl acetate extraction, organic layer saturated sodium chloride washings, drying under reduced pressure, obtain product (36 mg, productive rate 26%) with preparative chromatography separation and purification
Molecular formula: C 25h 25n 5o 4molecular weight: 459.50 LC-MS (m/e): 460.2 (M+H)
1H-NMR (400 MHz, MeOD) δ: 8.79(m, 1H), 8.43 (s, 1H), 7.88 (s, 1H), 7.72 (m, 1H), 7.34 (t, 1H), 7.24(d, 1H), 7.13 (s, 1H), 6.33(m, 1H), 5.71 (m, 1H), 4.02(s, 3H), 3.35 (s, 1H), 1.68 (m, 4H), 1.30 (m, 2H), 0.93 (m, 2H).
embodiment 6 N 1 -(4-(the chloro-4-fluorophenyl of 3-amino)-7-(tetrahydrofuran (THF)-3-base oxygen base) quinazoline-6-yl)-N 8 the preparation of-hydroxyl oct-2-ene diamide (compound 6)
(1) (E)-N'-(2-cyano group-4-nitrophenyl)-N, N-dimethylamino formyl imines
By 2 cyano 4 nitro aniline (1.00 g, 6.13 mmol) be dissolved in dioxane (25 mL), add DMF dimethylacetal (0.88 g, 7.39 mmol), under 100 DEG C of conditions, stir 2 hours, reaction solution is cooled to room temperature, stored refrigerated, remove by filter precipitation, rinse several times with ether, drying under reduced pressure obtains product (1.3 g, productive rate 97 %)
(2) preparation of N-(3-ethynyl phenyl)-6-nitro-quinazoline-4-amine
By (E)-N'-(2-cyano group-4-nitrophenyl)-N, N-dimethylamino formyl imines (6.0 g, 27 mmol) be dissolved in acetic acid (45 mL), under room temperature condition, add 3-acetylene aniline (3.3 g, 28 mmol), reflux 1 hour.After completion of the reaction, be cooled to room temperature, filter, filter residue rinses to obtain product (6.5 g, productive rate 83 %) with ether
(3) N 4-(3-ethynyl phenyl) quinazoline-4, the preparation of 6-diamines
By N-(3-ethynyl phenyl)-6-nitro-quinazoline-4-amine (7.1 g, 24 mmol) be dissolved in tetrahydrofuran (THF) (100 mL), add catalyzer Raney Ni (1.2 g) reduction, reaction finishes rear filtration, concentrating under reduced pressure obtains product (6.2 g, productive rate 99 %).
(4) preparation of (E)-8-((4-((3-ethynyl phenyl) amino) quinazoline-6-yl) amino)-8-oxo oct-6-ene acetoacetic ester
By N 4-(3-ethynyl phenyl) quinazoline-4,6-diamines (1.04 g, 4 mmol) and (E)-8-oxyethyl group-8-oxo oct-2-ene acid (0.4 g, 2 mmol) be dissolved in tetrahydrofuran (THF) (30 mL), under 0 DEG C of condition, add 2-(7-azo benzotriazole)-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester (2.28 g, 6 mmol) and triethylamine (0.4 g, 4 mmol), stir 22 hours.After completion of the reaction, obtain product (0.8 g, productive rate 90 %) with silica gel column chromatography separating purification.
(5) preparation of (E)-8-((4-((3-ethynyl phenyl) amino) quinazoline-6-yl) amino)-8-oxo oct-6-ene acid
By (E)-8-((4-((3-ethynyl phenyl) amino) quinazoline-6-yl) amino)-8-oxo oct-6-ene acetoacetic ester (0.88 g, 2 mmol) be dissolved in methyl alcohol (20 mL), add and be dissolved with lithium hydroxide (0.24 g, 10 mmol) the aqueous solution (10 mL), stirred overnight at room temperature.After completion of the reaction, mixed solution is with 1M salt acid for adjusting pH value to 6-7, and concentrating under reduced pressure obtains product ((0.7g, productive rate 84 %)).
(6) (E)-N 1-(4-((3-ethynyl phenyl) amino) quinolyl-6-yl)-N 8the preparation of-((tetrahydrochysene-2H-pyrans-2-yl) oxygen base) oct-2-ene diamide
By (E)-8-((4-((3-ethynyl phenyl) amino) quinazoline-6-yl) amino)-8-oxo oct-6-ene acid (0.6 g, 1.4 mmol) be dissolved in tetrahydrofuran (THF) (30 mL), add O-(tetrahydrochysene-2H-pyrans-2-yl) azanol (0.24 g, 2 mmol), I-hydroxybenzotriazole (0.27g, 2 mmol), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (0.38g, 2 mmol) and triethylamine (0.48 g, 4.7 mmol), stirring at room temperature 24 hours.After completion of the reaction, with ethyl acetate (50 mL) extraction, get organic layer, concentrating under reduced pressure is dried to obtain product (0.6 g, productive rate 83 %).
(7) (E)-N 1-(4-((3-ethynyl phenyl) amino) quinazoline-6-yl)-N 8the preparation (page42) of-hydroxyl oct-2-ene diamide
By (E)-N 1-(4-((3-ethynyl phenyl) amino) quinolyl-6-yl)-N 8-((tetrahydrochysene-2H-pyrans-2-yl) oxygen base) oct-2-ene diamide (0.5 g, 1 mmol) is dissolved in tetrahydrofuran (THF) (20mL), adds concentrated hydrochloric acid (2 mL), stirring at room temperature 3 hours.After completion of the reaction, obtain product (84 mg, productive rate 20 %) with preparative chromatography column separating purification
Molecular formula: C 24h 23n 5o 3molecular weight: 429.5 LC-MS (m/e): 430.2 (M+H)
1H-NMR (400 MHz, DMSO-d 6) δ: 10.24(m, 2H), 9.84 (s,1H), 8.68 (m, 2H), 8.54 (s, 1H), 7.99 (s, 1H), 7.86(m, 2H), 7.75 (m, 1H), 7.38(m, 1H), 7.20 (d, 1H), 5.60(m, 1H), 4.18 (s, 1H), 3.12 (m, 1H), 1.97 (m, 3H), 1.57 (m, 2H).
With reference to above-mentioned preparation method, can also prepare following compound:

Claims (9)

1. compound, its deuterated thing, its pharmacy acceptable salt or its steric isomer shown in logical formula I:
Wherein,
R 1for hydrogen atom, or be not substituted or by 1 ~ 3 identical or different Q 1the following group replacing:
C 1-6alkyl, C 2-6thiazolinyl, C 2-6alkynyl, 3-8 unit cycloalkyl, the cycloalkyl C of 3-8 unit 1-6alkyl, 6-10 unit cyclic group, 6-10 unit cyclic group C 1-6alkyl, 7-12 unit volution base, the volution base C of 7-12 unit 1-6alkyl, 7-12 unit's bridged ring base or the bridged ring base C of 7-12 unit 1-6alkyl, and carbon atom in described 3-8 unit cycloalkyl, 6-10 unit cyclic group, 7-12 unit's volution base or 7-12 unit bridged ring base can be by 1 ~ 3 identical or different O, CO, S, SO, SO 2, N or NR creplace R crepresent hydrogen atom or C 1-6alkyl,
Q 1for halogen atom, hydroxyl, amino, carboxyl, cyano group, formamyl, amino-sulfonyl, C 1-6alkyl, C 1-6alkoxyl group, C 1-6alkylamino, C 1-6alkyl-carbonyl, two (C 1-6alkyl) amino, C 1-6alkyl carbonyl oxy, C 1-6alkoxy carbonyl, C 1-6alkyl amido, C 1-6alkyl sulphonyl, C 1-6alkyl sulphinyl, C 1-6alkyl sulfonyl amino or 3-8 unit cycloalkyl;
R 2for hydrogen atom, halogen atom, hydroxyl, cyano group, nitro, formamyl, amino-sulfonyl, C 1-6alkyl, C 2-6thiazolinyl, C 2-6alkynyl, C 1-6alkoxyl group, halo C 1-6alkyl, halo C 1-6alkoxyl group, C 1-6alkylamino, two (C 1-6alkyl) amino, C 1-6alkylthio, C 1-6alkyl-carbamoyl, C 1-6alkyl-carbonyl, C 1-6alkoxy carbonyl, C 1-6alkyl carbonyl oxy, C 1-6alkyl amido, C 1-6alkyl sulphonyl, C 1-6alkyl sulphinyl, C 1-6alkyl sulfonyl amino, phenyl, pyridyl, furyl, thiazolyl, imidazolyl or thienyl, described phenyl, pyridyl, furyl, thiazolyl, imidazolyl or thienyl can optionally be replaced by 1 ~ 2 identical or different following substituting group: halogen atom, hydroxyl, amino, cyano group, C 1-6alkyl, C 1-6alkoxyl group, C 1-6alkylamino or two (C 1-6alkyl) amino;
R 3, R 4and R 5be hydrogen atom independently respectively, halogen atom, C 1-6alkyl, C 1-6alkoxyl group, halo C 1-6alkyl, halo C 1-6alkoxyl group, C 1-6alkylamino or two (C 1-6alkyl) amino;
R 6and R 7be hydrogen atom independently respectively, C 1-6alkyl or C 1-6alkyl-carbonyl;
X is the methyne that N atom or cyano group replace;
W is not for being substituted or by R athe C replacing 1-6alkyl, C 2-6thiazolinyl, C 2-6alkynyl, 6-14 unit aryl, 3-14 unit heterocyclic radical, the aryl C of 6-14 unit 1-6alkyl, the heterocyclic radical C of 3-14 unit 1-6alkyl, C 1-6alkyl 3-14 unit heterocyclic radical, C 2-6thiazolinyl 6-14 unit aryl, C 2-6thiazolinyl 3-14 unit heterocyclic radical, C 2-6alkynyl 6-14 unit aryl, C 2-6alkynyl 3-14 unit heterocyclic radical, C 2-6alkynyl 3-8 unit cycloalkyl, C 1-6the aryl C of alkyl 6-14 unit 1-6alkyl, C 1-6the aryl C of alkyl 6-14 unit 2-6thiazolinyl, C 2-6the heterocyclic radical C of thiazolinyl 3-14 unit 1-6alkyl, the heterocyclic radical-3-14 heterocyclic radical C of unit of 3-14 unit 1-6alkyl, and described C 1-6alkyl, C 2-6thiazolinyl, C 2-6carbon atom in alkynyl can be by O, S, S (O), SO 2, NR bor CO replaces,
R afor hydrogen atom, halogen atom, hydroxyl, amino, carboxyl, cyano group, formamyl, amino-sulfonyl, C 1-6alkyl, C 1-6alkoxyl group, C 1-6alkylamino, two (C 1-6alkyl) amino, C 1-6alkyl carbonyl oxy, C 1-6alkoxy carbonyl, C 1-6alkyl amido, C 1-6alkyl sulphonyl, C 1-6alkyl sulphinyl, C 1-6alkyl sulfonyl amino, 3-8 unit's cycloalkyl or 3-8 unit heterocyclic radical,
R bfor hydrogen atom, be not substituted or at least by 1 Q 3the C replacing 1-6alkyl, 3-8 unit's cycloalkyl or 3-8 unit heterocyclic radical,
Q 3for halogen atom, carboxyl, hydroxyl, amino, cyano group, nitro, C 1-6alkoxyl group, halo C 1-6alkoxyl group, C 1-6alkylamino, two (C 1-6alkyl) amino, C 1-6alkyl-carbonyl, C 1-6alkyl-carbonyl oxygen base, C 1-6alkoxy carbonyl, formamyl, C 1-6alkyl-carbamoyl, two (C 1-6alkyl) formamyl, amino-sulfonyl, C 1-6alkyl amino sulfonyl, two (C 1-6alkyl) amino-sulfonyl, C 1-6alkyl sulfonyl amino, C 1-6alkyl sulphonyl, C 1-6alkyl-carbonyl-amino, guanidine radicals, 3-8 unit cycloalkyl, 3-8 unit's heterocyclic radical or 6-14 unit aryl;
L is key ,-O-,-S-,-SO-,-SO 2-,-NH-,-N (CH 3)-,-C (O)-or do not exist;
T is key ,-C (O)-or-C (R ' R ' ')-, R ' and R ' ' are respectively hydrogen or C 1-6alkyl;
N is 1,2 or 3, and n=2 or 3 o'clock, R 2can be identical or different.
2. compound as claimed in claim 1, its deuterated thing, its pharmacy acceptable salt or its steric isomer:
Wherein,
R 1for hydrogen atom, or be not substituted or by 1 ~ 3 identical or different Q 1the following group replacing:
C 1-4alkyl, C 2-4thiazolinyl, C 2-4alkynyl, 3-8 unit cycloalkyl, the cycloalkyl C of 3-8 unit 1-4alkyl, 6-10 unit cyclic group, 6-10 unit cyclic group C 1-4alkyl, 7-12 unit volution base, the volution base C of 7-12 unit 1-4alkyl, 7-12 unit's bridged ring base or the bridged ring base C of 7-12 unit 1-4alkyl, and carbon atom in described 3-8 unit cycloalkyl, 6-10 unit cyclic group, 7-12 unit's volution base or 7-12 unit bridged ring base can be by 1 ~ 3 identical or different O, CO, S, N or NR creplace R crepresent hydrogen atom or C 1-4alkyl,
Q 1for halogen atom, hydroxyl, amino, carboxyl, cyano group, formamyl, amino-sulfonyl, C 1-4alkyl, C 1-4alkoxyl group, C 1-4alkylamino, C 1-6alkyl-carbonyl, two (C 1-4alkyl) amino, C 1-4alkyl carbonyl oxy, C 1-4alkoxy carbonyl, C 1-4alkyl amido, C 1-4alkyl sulphonyl, C 1-4alkyl sulphinyl, C 1-4alkyl sulfonyl amino or 3-6 unit cycloalkyl;
R 2for hydrogen atom, halogen atom, hydroxyl, cyano group, nitro, formamyl, amino-sulfonyl, C 1-4alkyl, C 2-4thiazolinyl, C 2-4alkynyl, C 1-4alkoxyl group, halo C 1-4alkyl, halo C 1-4alkoxyl group, C 1-4alkylamino, two (C 1-4alkyl) amino, C 1-4alkylthio, C 1-4alkyl-carbamoyl, C 1-4alkyl-carbonyl, C 1-4alkoxy carbonyl, C 1-4alkyl carbonyl oxy, C 1-4alkyl amido, C 1-4alkyl sulphonyl, C 1-4alkyl sulphinyl, C 1-4alkyl sulfonyl amino, phenyl, pyridyl, furyl, thiazolyl, imidazolyl or thienyl, described phenyl, pyridyl, furyl, thiazolyl, imidazolyl or thienyl can optionally be replaced by 1 ~ 2 identical or different following substituting group: halogen atom, hydroxyl or C 1-6alkyl;
R 3, R 4and R 5be hydrogen atom independently respectively, halogen atom, C 1-4alkyl, C 1-4alkoxyl group, halo C 1-4alkyl, halo C 1-4alkoxyl group, C 1-4alkylamino or two (C 1-4alkyl) amino;
R 6and R 7be hydrogen atom independently respectively, C 1-4alkyl or C 1-4alkyl-carbonyl;
X is the methyne that N atom or cyano group replace;
W is not for being substituted or by R athe C replacing 1-6alkyl, C 2-6thiazolinyl, 6-10 unit aryl, 3-8 unit heterocyclic radical, the aryl C of 6-10 unit 1-6alkyl, the heterocyclic radical C of 3-8 unit 1-6alkyl, C 1-6alkyl 3-8 unit heterocyclic radical, C 2-6thiazolinyl 6-10 unit aryl, C 2-6thiazolinyl 3-8 unit heterocyclic radical, C 1-6the aryl C of alkyl 6-10 unit 1-6alkyl, C 1-6the aryl C of alkyl 6-10 unit 2-6thiazolinyl, C 2-6the heterocyclic radical C of thiazolinyl 3-8 unit 1-6alkyl, or the heterocyclic radical-3-8 heterocyclic radical C of unit of 3-8 unit 1-6alkyl, and described C 1-6alkyl, C 2-6carbon atom in thiazolinyl can be by O, S, NR bor CO replaces,
R afor hydrogen atom, halogen atom, hydroxyl, amino, carboxyl, cyano group, formamyl, amino-sulfonyl, C 1-4alkyl, C 1-4alkoxyl group, C 1-4alkylamino, two (C 1-4alkyl) amino, C 1-4alkyl carbonyl oxy, C 1-4alkoxy carbonyl, C 1-4alkyl amido, C 1-4alkyl sulphonyl, C 1-4alkyl sulphinyl, C 1-4alkyl sulfonyl amino, 3-6 unit's cycloalkyl or 3-6 unit heterocyclic radical,
R bfor hydrogen atom, be not substituted or at least by 1 Q 3the C replacing 1-4alkyl, 3-6 unit's cycloalkyl or 3-6 unit heterocyclic radical,
Q 3for halogen atom, carboxyl, hydroxyl, amino, cyano group, nitro, C 1-4alkoxyl group, halo C 1-4alkoxyl group, C 1-4alkylamino, two (C 1-4alkyl) amino, C 1-4alkyl-carbonyl, C 1-4alkyl-carbonyl oxygen base, C 1-4alkoxy carbonyl, formamyl, C 1-4alkyl-carbamoyl, two (C 1-4alkyl) formamyl, amino-sulfonyl, C 1-4alkyl amino sulfonyl, two (C 1-4alkyl) amino-sulfonyl, C 1-4alkyl sulfonyl amino, C 1-4alkyl sulphonyl, C 1-4alkyl-carbonyl-amino, guanidine radicals, 3-6 unit cycloalkyl, 3-6 unit's heterocyclic radical or phenyl;
L is key ,-O-,-S-,-NH-or do not exist;
T be key or-C (R ' R ' ')-, R ' and R ' ' are respectively hydrogen or C 1-4alkyl;
N is 1,2 or 3, and n=2 or 3 o'clock, R 2can be identical or different.
3. compound as claimed in claim 2, its deuterated thing, its pharmacy acceptable salt or its steric isomer:
Wherein,
R 1for hydrogen atom, or be not substituted or by 1 ~ 3 identical or different Q 1the following group replacing:
C 1-4alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, azetidinyl, tetrahydrofuran base, THP trtrahydropyranyl, pyrrolidyl, piperidyl, morpholinyl, piperazinyl, cyclopropyl C 1-4alkyl, cyclobutyl C 1-4alkyl, cyclopentyl C 1-4alkyl, cyclohexyl C 1-4alkyl, suberyl C 1-4alkyl, azetidinyl C 1-4alkyl, tetrahydrofuran base C 1-4alkyl, THP trtrahydropyranyl C 1-4alkyl, pyrrolidyl C 1-4alkyl, piperidyl C 1-4alkyl, morpholinyl C 1-4alkyl, piperazinyl C 1-4alkyl, 6-10 unit cyclic group, 6-10 unit cyclic group methyl, 6-10 unit cyclic group ethyl, 7-10 unit volution base, 7-10 unit volution ylmethyl, 7-10 unit volution base ethyl, 7-10 unit bridged ring base, 7-10 unit's bridged ring ylmethyl or 7-10 unit bridged ring base ethyl, and described cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, azetidinyl, tetrahydrofuran base, THP trtrahydropyranyl, pyrrolidyl, piperidyl, morpholinyl, piperazinyl, 6-10 unit cyclic group, 7-10 unit volution base, carbon atom in 7-10 unit bridged ring base can be by 1 ~ 3 identical or different O, CO, S, N or NR creplace R crepresent hydrogen atom, methyl or ethyl, Q 1for halogen atom, hydroxyl, amino, C 1-4alkyl, C 1-4alkoxyl group, C 1-4alkylamino, two (C 1-4alkyl) amino, C 1-4alkyl carbonyl oxy, C 1-4alkyl amido or C 1-4alkyl sulfonyl amino,
R 2for halogen atom, cyano group, nitro, C 1-4alkyl, C 2-4thiazolinyl, C 2-4alkynyl, C 1-4alkoxyl group, fluoro C 1-4alkyl, fluoro C 1-4alkoxyl group, C 1-4alkyl-carbamoyl, C 1-4alkyl-carbonyl, C 1-4alkoxy carbonyl, C 1-4alkyl carbonyl oxy, C 1-4alkyl amido, C 1-4alkyl sulfonyl amino, phenyl, pyridyl or thiazolyl;
R 3, R 4and R 5be hydrogen atom independently respectively, halogen atom, C 1-4alkyl, C 1-4alkoxyl group, fluoro C 1-4alkyl, fluoro C 1-4alkoxyl group, C 1-4alkylamino or two (C 1-4alkyl) amino;
R 6and R 7be hydrogen atom independently respectively, C 1-4alkyl or C 1-4alkyl-carbonyl;
X is the methyne that N atom or cyano group replace;
W is not for being substituted or by R athe C replacing 2-6alkyl, C 2-6thiazolinyl, phenyl, 5-6 unit heterocyclic radical, phenyl C 1-4alkyl, the heterocyclic radical C of 5-6 unit 1-4alkyl, C 1-4alkyl 5-6 unit heterocyclic radical, C 2-6thiazolinyl phenyl, C 2-6thiazolinyl 5-6 unit heterocyclic radical, C 2-6thiazolinyl phenyl C 1-6alkyl, C 2-6the heterocyclic radical C of thiazolinyl 5-6 unit 1-4alkyl, the heterocyclic radical-5-6 heterocyclic radical C of unit of 5-6 unit 1-4alkyl, and described C 2-6alkyl, C 2-6thiazolinyl, C 1-6carbon atom in alkyl can be by O, S, NR bor CO replaces,
R afor halogen atom, hydroxyl, amino, carboxyl, cyano group, C 1-4alkyl, C 1-4alkoxyl group or 3-6 unit cycloalkyl,
R bfor hydrogen atom, be not substituted or at least by 1 Q 3the C replacing 1-4alkyl,
Q 3for halogen atom, carboxyl, hydroxyl, amino, cyano group, nitro, C 1-4alkoxyl group, fluoro C 1-4alkoxyl group, C 1-4alkylamino, two (C 1-4alkyl) amino, C 1-4alkyl-carbonyl, formamyl, amino-sulfonyl or C 1-4alkyl sulphonyl;
L is key ,-O-,-S-or do not exist;
T be key or-C (R ' R ' ')-, R ' and R ' ' are respectively hydrogen or methyl;
N is 1,2 or 3, and n=2 or 3 o'clock, R 2can be identical or different.
4. compound as claimed in claim 3, its deuterated thing, its pharmacy acceptable salt or its steric isomer:
Wherein,
R 1for hydrogen atom, be not substituted or by 1 ~ 3 identical or different Q 1the following group replacing: methyl, ethyl,
Q 1for halogen atom, hydroxyl, amino, methyl, ethyl, methoxyl group, oxyethyl group, methylamino-, ethylamino, dimethylamino or diethylamino;
R 2for halogen atom, cyano group, nitro, methyl, ethyl, vinyl, ethynyl, methoxyl group, trifluoromethyl, trifluoromethoxy, ethanoyl, methoxycarbonyl, acetoxyl group, kharophen, sulfonyloxy methyl amino, phenyl, pyridyl or thiazolyl;
R 3, R 4and R 5be respectively hydrogen atom;
R 6and R 7be hydrogen atom independently respectively, methyl, ethyl or ethanoyl;
X is the methyne that N atom or cyano group replace;
W is not for being substituted or by R athe C replacing 2-6alkyl, C 2-6thiazolinyl, 5-6 unit heterocyclic radical, methyl 5-6 unit heterocyclic radical, ethyl 5-6 unit's heterocyclic radical or C 2-6thiazolinyl phenyl C 1-6alkyl, and described C 2-6alkyl, C 2-6thiazolinyl, C 1-6carbon atom in alkyl can be by NR binstitute replaces,
R afor halogen atom, hydroxyl, amino, carboxyl, cyano group, C 1-4alkyl or C 1-4alkoxyl group,
R bfor hydrogen atom or C 1-4alkyl;
L is for-O-or do not exist;
T is key;
N is 1,2 or 3, and n=2 or 3 o'clock, R 2can be identical or different.
5. compound as claimed in claim 4, its deuterated thing, its pharmacy acceptable salt or its steric isomer:
Wherein,
R 1for hydrogen atom, be not substituted or by 1 ~ 3 identical or different Q 1the following group replacing: methyl, ethyl,
Q 1for halogen atom, hydroxyl, amino, methyl, ethyl, methoxy or ethoxy;
R 2for fluorine atom, chlorine atom, bromine atoms, methyl, vinyl, ethynyl, phenyl or pyridyl;
R 3, R 4, R 5, R 6and R 7be respectively hydrogen atom;
X is the methyne that N atom or cyano group replace;
W is not for being substituted or by R athe C replacing 2-6alkyl, C 2-6thiazolinyl, C 2-6thiazolinyl phenyl C 1-6alkyl, and described C 2-6alkyl, C 2-6thiazolinyl, C 1-6carbon atom in alkyl can be by NR binstitute replaces,
R afor halogen atom, hydroxyl, amino, carboxyl, cyano group, C 1-4alkyl or C 1-4alkoxyl group,
R bfor hydrogen atom, methyl, ethyl or sec.-propyl;
L is for-O-or do not exist;
T is key;
N is 1,2 or 3, and n=2 or 3 o'clock, R 2can be identical or different.
6. compound as claimed in claim 5, its deuterated thing, its pharmacy acceptable salt or its steric isomer:
Wherein, R 1for hydrogen atom, be not substituted or by 1 ~ 3 identical or different Q 1the following group replacing: methyl,
Q 1for fluorine atom, chlorine atom, hydroxyl, amino, methyl or ethyl;
R 2for fluorine atom, chlorine atom, methyl, ethynyl, phenyl or pyridyl;
R 3, R 4, R 5, R 6and R 7be respectively hydrogen atom;
X is the methyne that N atom or cyano group replace;
W is not for being substituted or by R athe C replacing 2-6alkyl, C 2-6thiazolinyl or C 2-6thiazolinyl phenyl C 1-6alkyl, and described C 2-6alkyl, C 2-6thiazolinyl, C 1-6carbon atom in alkyl can be by NR binstitute replaces,
R afor fluorine atom, chlorine atom, hydroxyl, amino, carboxyl, cyano group, methyl, ethyl or methoxyl group,
R bfor hydrogen atom, methyl, ethyl or sec.-propyl;
L is for-O-or do not exist;
T is key;
N is 1,2 or 3, and n=2 or 3 o'clock, R 2can be identical or different.
7. compound as claimed in claim 6, its deuterated thing, its pharmacy acceptable salt or its steric isomer, wherein compound is selected from:
8. the pharmaceutical preparation that contains compound, its deuterated thing, its pharmacy acceptable salt or its steric isomer described in claim 1～7 any one, is characterized in that comprising one or more pharmaceutical carriers.
9. the compound as described in claim 1～7 any one, its deuterated thing, its pharmacy acceptable salt or its steric isomer are in the purposes for the preparation for the treatment of and/or preventing in the medicine of tumour.
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WO2017107986A1 (en) * 2015-12-25 2017-06-29 山东轩竹医药科技有限公司 Crystals of quinazoline derivative and preparation method therefor
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CN101659658A (en) * 2008-08-29 2010-03-03 北大方正集团有限公司 Quinoline substituted by cyan

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WO2003065995A2 (en) * 2002-02-07 2003-08-14 Supergen, Inc. Method for treating diseases associated with abnormal kinase activity
CN101535279A (en) * 2006-09-11 2009-09-16 柯瑞斯公司 Quinazoline based EGFR inhibitors containing a zinc binding moiety
CN101659658A (en) * 2008-08-29 2010-03-03 北大方正集团有限公司 Quinoline substituted by cyan

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104193746A (en) * 2014-08-09 2014-12-10 刘雪静 Novel synthesis method of 9,5-substituted imidazole [1, 2-c]-quinazoline-3(2H)-ketone thick heterocyclic compound
WO2017107986A1 (en) * 2015-12-25 2017-06-29 山东轩竹医药科技有限公司 Crystals of quinazoline derivative and preparation method therefor
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JP2018538348A (en) * 2015-12-25 2018-12-27 シュアンチュー ファーマ カンパニー，リミティド Quinazoline derivative crystals and method for preparing the same
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CN109265449A (en) * 2018-11-07 2019-01-25 沈阳工业大学 The bis- target spot tyrosine kinase inhibitors of EGFR and HER2 and preparation method and purposes
CN109265449B (en) * 2018-11-07 2021-11-23 沈阳工业大学 EGFR and HER2 double-target tyrosine kinase inhibitor and preparation method and application thereof

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