CN104892585B - Pyrimidine derivates species anaplastic lymphoma kinase inhibitor - Google Patents

Pyrimidine derivates species anaplastic lymphoma kinase inhibitor Download PDF

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CN104892585B
CN104892585B CN201410079234.XA CN201410079234A CN104892585B CN 104892585 B CN104892585 B CN 104892585B CN 201410079234 A CN201410079234 A CN 201410079234A CN 104892585 B CN104892585 B CN 104892585B
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alkyl
cancer
compound
pharmaceutically acceptable
base
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CN104892585A (en
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吴永谦
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Xuanzhu Biopharmaceutical Co Ltd
Shandong Xuanzhu Pharma Co Ltd
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Shandong Xuanzhu Pharma Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring

Abstract

The invention belongs to pharmaceutical technology fields, and in particular to pyrimidine derivates species anaplastic lymphoma kinase inhibitor or its stereoisomer or its pharmaceutically acceptable salt, ester or solvate shown in general formula (I), wherein R1、R2、R3、R4、R5It is defined as in the description with A rings.The invention further relates to the preparation methods of these compounds, the application of pharmaceutical preparation and pharmaceutical composition and the compound or its stereoisomer or its pharmaceutically acceptable salt, ester or solvate containing these compounds in preparing treatment and/or preventing the drug of cancer-related diseases mediated by anaplastic lymphoma kinase.

Description

Pyrimidine derivates species anaplastic lymphoma kinase inhibitor
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to pyrimidine derivates species anaplastic lymphoma kinase inhibitor or its Stereoisomer or its pharmaceutically acceptable salt, ester or solvate, the preparation method of these compounds contain these The pharmaceutical preparation and pharmaceutical composition of compound and the compound or its stereoisomer or its is pharmaceutically acceptable Salt, ester or solvate are preparing treatment and/or are preventing the drug of cancer-related diseases mediated by anaplastic lymphoma kinase In application.
Background technology
Anaplastic lymphoma kinase (Anaplastic lymphoma kinase, ALK) is receptor tyrosine kinase family Member can be raised downstream albumen by autophosphorylation, and then express specific gene, adjust cell metabolism and growth.Between become Property lymphom kinase is found in primary cutaneous type (Anaplastic large cell lymphoma, ALCL) earliest In, it found later in non-small cell lung cancer（NSCLC）In also have high expression.
The micromolecular inhibitor of ALK can influence the growth of tumour cell, play antineoplastic action, but have and largely face Bed proves generation ALK inhibitor C rizotinib, easily generates drug resistance, therefore, designs and screens to Crizotinib generations Drug resistant patient also has the two generation ALK inhibitor of the effect of good, has significant clinical meaning.
The ALK inhibitor being currently known includes crizotinib（Pfizer）、CH5424802（Roche）、LDK378 （Novartis）、AZD-3463（AstraZeneca）.
Therefore, new compound structure is found by compound structure modification, makes great efforts to improve the physicochemical property of compound, carry High druggability such as improves the bioavilability of compound, active micromolecular inhibitor is mutated to ALK to find, for facing The treatment of the disease caused by ALK is mutated, has great importance on bed.
Invention content
The present invention is directed to the micromolecular inhibitor of ALK to develop as target, has invented to treating and/or preventing ALK mediations Cancer-related diseases have good result pyrimidine derivates species anaplastic lymphoma kinase inhibitor.Specific technical solution It is as follows：
1. general formula（Ⅰ）Compound represented or its stereoisomer or its pharmaceutically acceptable salt, ester or solvation Object：
Wherein,
R1Selected from hydrogen, hydroxyl, amino, cyano, nitro, halogen atom, C1-6Alkyl, hydroxyl C1-6Alkyl, halogenated C1-6Alkane Base, C1-6Alkoxy, hydroxyl C1-6Alkoxy, halogenated C1-6Alkoxy, C2-8Alkenyl, C2-8Alkynyl, C1-6Alkyl amino, (C1-6Alkane Base)2Amino, sulfonyl C1-6Alkyl or 3~8 yuan of cycloalkyl；
R2And R3Separately selected from hydrogen, hydroxyl, amino, cyano, nitro, halogen atom, C1-6Alkyl, hydroxyl C1-6Alkane Base, amino C1-6Alkyl, halogenated C1-6Alkyl, C1-6Alkyl amino, C1-6Alkyl-carbonyl, C1-6Alkyl sulfenyl, C1-6Alkylsulfonylamino group Base, C1-6Alkyl amino sulfonyl, (C1-6Alkyl)2Amino-sulfonyl, C1-6Alkyl amino C1-6Alkyl sulphonyl, (C1-6Alkyl)2 Amino C1-6Alkyl sulphonyl, C1-6Alkoxy, halogenated C1-6Alkoxy, C1-6Alkoxy C1-6Alkoxy, hydroxyl C1-6Alkoxy, C2-8Alkenyl, carboxyl C2-8Alkenyl, hydroxyl C2-8Alkenyl, C2-8Alkynyl, carboxyl C2-8Alkynyl, hydroxyl C2-8Alkynyl, carboxyl C2-8Alkynyl or 3~8 circle heterocyclic ring bases, 3~8 circle heterocyclic ring bases can be optionally by 1~3 q1Substitution,
Or R2And R33~8 circle heterocyclic ring base of benzo is formed together with the phenyl ring being attached thereto, 3~8 circle heterocyclic ring bases can Optionally by 1~3 q1Substitution；
R4Selected from hydrogen or C1-6Alkyl；
R5Selected from hydrogen, hydroxyl, carboxyl, amino, cyano, nitro, C1-6Alkyl, C1-6Alkoxy, halogenated C1-6It is alkyl, halogenated C1-6Alkoxy, C2-8Alkenyl, C2-8Alkynyl, C1-6Alkyl amino or (C1-6Alkyl)2Amino；
A rings form 3~8 circle heterocyclic ring base of benzo together with the phenyl ring being attached thereto, and 3~8 circle heterocyclic ring bases can be optionally by 1 ~3 q1Substitution；
q1Selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atom, C1-6Alkyl, C1-6Alkoxy, C1-6Alkyl ammonia Base, (C1-6Alkyl)2Amino, halogenated C1-6Alkyl, halogenated C1-6Alkoxy, C1-6Alkoxy C1-6Alkyl, C2-8Alkenyl, C2-8Alkynyl Or 3~8 circle heterocyclic ring base.
2. compound as described in technical solution 1 or its stereoisomer or its pharmaceutically acceptable salt, ester or molten Agent compound, wherein,
R1Selected from hydrogen, hydroxyl, amino, cyano, nitro, halogen atom, C1-4Alkyl, hydroxyl C1-4Alkyl, halogenated C1-4Alkane Base, C1-4Alkoxy, hydroxyl C1-4Alkoxy, halogenated C1-4Alkoxy, C2-6Alkenyl, C2-6Alkynyl, C1-4Alkyl amino, (C1-4Alkane Base)2Amino, sulfonyl C1-4Alkyl or 3~6 yuan of cycloalkyl；
R2And R3Separately selected from hydrogen, hydroxyl, amino, cyano, nitro, halogen atom, C1-4Alkyl, hydroxyl C1-4Alkane Base, amino C1-4Alkyl, halogenated C1-4Alkyl, C1-4Alkyl amino, C1-4Alkyl-carbonyl, C1-4Alkyl sulfenyl, C1-4Alkylsulfonylamino group Base, C1-4Alkyl amino sulfonyl, (C1-4Alkyl)2Amino-sulfonyl, C1-4Alkyl amino C1-4Alkyl sulphonyl, (C1-4Alkyl)2 Amino C1-4Alkyl sulphonyl, C1-4Alkoxy, halogenated C1-4Alkoxy, C1-4Alkoxy C1-4Alkoxy, hydroxyl C1-4Alkoxy, C2-6Alkenyl, carboxyl C2-6Alkenyl, hydroxyl C2-6Alkenyl, C2-6Alkynyl, carboxyl C2-6Alkynyl, hydroxyl C2-6Alkynyl, carboxyl C2-6Alkynyl or 3~8 circle heterocyclic ring bases, 3~8 circle heterocyclic ring bases can be optionally by 1~3 q1Substitution,
Or R2And R33~8 circle heterocyclic ring base of benzo is formed together with the phenyl ring being attached thereto, 3~8 circle heterocyclic ring bases can Optionally by 1~2 q1Substitution；
R4Selected from hydrogen or C1-4Alkyl；
R5Selected from hydrogen, hydroxyl, carboxyl, amino, cyano, nitro, C1-4Alkyl, C1-4Alkoxy, halogenated C1-4It is alkyl, halogenated C1-4Alkoxy, C2-6Alkenyl, C2-6Alkynyl, C1-4Alkyl amino or (C1-4Alkyl)2Amino；
A rings form 3~8 circle heterocyclic ring base of benzo together with the phenyl ring being attached thereto, and 3~8 circle heterocyclic ring bases can be optionally by 1 ~2 q1Substitution；
q1Selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atom, C1-4Alkyl, C1-4Alkoxy, C1-4Alkyl ammonia Base, (C1-4Alkyl)2Amino, halogenated C1-4Alkyl, halogenated C1-4Alkoxy, C1-4Alkoxy C1-4Alkyl, C2-6Alkenyl, C2-6Alkynyl Or 3~6 circle heterocyclic ring base.
3. compound as described in technical solution 2 or its stereoisomer or its pharmaceutically acceptable salt, ester or molten Agent compound, wherein,
R1Selected from hydrogen, hydroxyl, cyano, halogen atom or C1-4Alkyl；
R2Selected from hydrogen or C1-4Alkyl；
R3Selected from 4~7 circle heterocyclic ring bases, 4~7 circle heterocyclic ring bases can be optionally by 1~2 q1Substitution；
A rings form 4~7 circle heterocyclic ring base of benzo together with the phenyl ring being attached thereto, and 4~7 circle heterocyclic ring bases can be optionally by 1 ~21q；
q1Selected from C1-4Alkyl.
4. compound as described in technical solution 3 or its stereoisomer or its pharmaceutically acceptable salt, ester or molten Agent compound, wherein,
R3Selected from 5~6 circle heterocyclic ring bases；
A rings form following group together with the phenyl ring being attached thereto：
5. compound as described in technical solution 2 or its stereoisomer or its pharmaceutically acceptable salt, ester or molten Agent compound, wherein,
R1Selected from hydrogen, hydroxyl, cyano, halogen atom or C1-4Alkyl；
R2And R34~7 circle heterocyclic ring base of benzo is formed together with the phenyl ring being attached thereto, 4~7 circle heterocyclic ring bases can be optional By 1~2 q1；
R5Selected from hydrogen or C1-4Alkyl；
A rings form 4~7 circle heterocyclic ring base of benzo together with the phenyl ring being attached thereto, and 4~7 circle heterocyclic ring bases can be optionally by 1 ~21q；
q1Selected from C1-4Alkyl.
6. compound as described in technical solution 5 or its stereoisomer or its pharmaceutically acceptable salt, ester or molten Agent compound, wherein,
R1Selected from hydrogen, hydroxyl, cyano, halogen atom or C1-4Alkyl；
R2And R35~6 circle heterocyclic ring base of benzo is formed together with the phenyl ring being attached thereto；
R5Selected from hydrogen or C1-4Alkyl；
A rings form 5~6 circle heterocyclic ring base of benzo together with the phenyl ring being attached thereto.
7. compound as described in technical solution 6 or its stereoisomer or its pharmaceutically acceptable salt, ester or molten Agent compound, wherein,
R2And R3Following group is formed together with the phenyl ring being attached thereto：
8. compound as described in technical solution 7 or its stereoisomer or its pharmaceutically acceptable salt, ester or molten Agent compound, wherein,
A rings form following group together with the phenyl ring being attached thereto：
9. compound as described in technical solution 1 or its stereoisomer or its pharmaceutically acceptable salt, ester or molten Agent compound, the compound are selected from：
10. such as technical solution 1-9 any one of them compound or its stereoisomer or its is pharmaceutically acceptable The pharmaceutical composition of salt, ester or solvate and one or more pharmaceutical carriers and/or diluent, can be made can pharmaceutically connect Any dosage form received.
11. pharmaceutical composition as described in technical solution 10, it is characterised in that can also contain one or more antitumor agents And immunosuppressor, the antitumor agent and immunosuppressor are selected from methotrexate (MTX), capecitabine, gemcitabine, deoxidation fluorine Uridine, pemetrexed disodium, pazopanib, Imatinib, Erlotinib, Lapatinib, Gefitinib, Vande Thani, He Sai Spit of fland, bevacizumab, Rituximab, Herceptin, taxol, vinorelbine, docetaxel, Doxorubicin, hydroxy-camptothecin Alkali, mitomycin, epirubicin, pirarubicin, bleomycin, Letrozole, tamoxifen, fulvestrant, music score of Chinese operas Rayleigh, fluorine he Amine, Leuprorelin, Anastrozole, ifosfamide, busulfan, cyclophosphamide, Carmustine, Nimustine, Semustine, nitrogen Mustard, melphalan, chlorambucil, carboplatin, cis-platinum, oxaliplatin, network platinum, Topotecan, camptothecine, topotecan, everolimus, west Luo Mosi, special cancer are fitted, Ismipur, 6- thioguanines, imuran, rhzomorph D, daunorubicin, adriamycin, mitoxantrone, Bleomycin, plicamycin or aminoglutethimide.
12. such as technical solution 1-9 any one of them compound or its stereoisomer or its is pharmaceutically acceptable Salt, ester or solvate prepare for treat and/or prevent ALK mediation proliferative disease or cancer-related diseases drug In application, the relevant disease of cancer be selected from brain tumor, lung cancer in non-cellule type, dermoid cancer, carcinoma of urinary bladder, stomach Cancer, oophoroma, peritoneal cancer, cancer of pancreas, breast cancer, head and neck cancer, cervix cancer, carcinoma of endometrium, the carcinoma of the rectum, liver cancer, liver are female thin Born of the same parents' knurl, papillary renal cell knurl, incidence squamous cytoma, the nephroblastoma, kidney, adenocarcinoma of esophagus, esophageal squamous cell carcinoma, Female reproductive tract cancer, carcinoma in situ, lymthoma, neuroblastoma, neurofibromatosis, thyroid cancer, osteocarcinoma, cutaneum carcinoma, knot Intestinal cancer, carcinoma of testis, Small Cell Lung Cancer, gastrointestinal stromal tumor, tumor of prostate, mast cell tumor, Huppert's disease, black Plain knurl or glioma.
The part of compounds of the present invention
Detailed description of the invention
" halogen atom " of the present invention includes fluorine atom, chlorine atom, bromine atoms and iodine atom etc..
" C of the present invention1-6Alkyl " represents the alkyl containing 1-6 carbon atom of linear chain or branch chain, including for example “C1-4Alkyl ", " C1-3Alkyl " etc., specific example includes but not limited to：Methyl, ethyl, n-propyl, isopropyl, normal-butyl, 2- Methyl-propyl, 1- methyl-propyls, 1,1- dimethyl ethyls, n-pentyl, 3- methyl butyls, 2- methyl butyls, 1- methyl butyls, 1- Ethyl propyl, n-hexyl, 4- methyl amyls, 3- methyl amyls, 2- methyl amyls, 1- methyl amyls, 3,3- dimethylbutyls, 2, 2- dimethylbutyls, 1,1- dimethylbutyls, 1,2- dimethylbutyls, 1,3- dimethylbutyls, 2,3- dimethylbutyls, 2- second Base butyl, 1,2- dimethyl propyls etc..
" C of the present invention2-8Alkenyl " refers to the linear chain or branch chain that the carbon atom number containing at least one double bond is 2-8 Or cricoid alkenyl, including such as " C2-6Alkenyl ", " C2-4Alkenyl ", " C2-3Alkenyl ", " C3-6Cycloalkenyl group " etc., specific example includes But it is not limited to：Vinyl, 1- acrylic, 2- acrylic, 2- cyclobutenyls, 3- cyclobutenyls, 2- methyl-1-propylenes base, 1- methyl -2- Acrylic, 1- pentenyls, 2- pentenyls, 3- pentenyls, 2-methyl-1-butene alkenyl, 3-methyl-1-butene base, 2- methyl -3- fourths Alkenyl, 1,1- dimethyl -2- acrylic, 1- ethyl -2- acrylic, 2- hexenyls, 3- hexenyls, 2- methyl-1-pentenes alkenyl, 3- Methyl-1-pentene alkenyl, 1- methyl -2- pentenyls, 3- methyl -2- pentenyls, 2- methyl-3-pentenyls, 1- methyl -4- amylenes Base, 3- methyl -4- pentenyls, 1,1- dimethyl -3- cyclobutenyls, 1,2- dimethyl -3- cyclobutenyls, 1,3- dimethyl -2- butylene Base, 2,2- dimethyl -3- cyclobutenyls, 2,3- dimethyl -2- cyclobutenyls, 2,3- dimethyl -1- cyclobutenyls, 2- ethyl -1- butylene Base, 2- ethyl -3- cyclobutenyls, 2- heptenyls, 3- heptenyls, 4- heptenyls, 1- octenyls, 3- octenyls, 4- octenyls, 1,3- Butadienyl, 2,4- pentadienyls, 1,4- hexadienyls, 2,4- hexadienyls, 1,5- heptadiene base, 2,5- heptadiene base, 2, 6- octadienyls, cyclopentenyl, 1,3- cyclopentadienyl groups, cyclohexenyl group, 1,4- cyclohexadienyls, cycloheptenyl, 1,4- cycloheptyls Dialkylene, cyclo-octene base etc..
" C of the present invention2-8Alkynyl " refers to the alkynyl for the linear chain or branch chain that the carbon atom number containing three keys is 2-8, Include such as " C2-6Alkynyl ", " C2-4Alkynyl ", " C2-3Alkynyl " etc., specific example includes but not limited to：Acetenyl, 1- propine Base, 2- butynyls, 1- methyl -2-propynyl, valerylene base, 3- pentynyls, 1- methyl -2- butynyls, 2- methyl -3- butine Base, 1,1- dimethyl -2-propynyl, 1- ethyls -2-propynyl, 2- hexin bases, 3- hexin bases, 1- methyl-valerylene base, 1- first Base -3- pentynyls, 2- methyl -3- pentynyls, 1,1- dimethyl -3- butynyls, 2- ethyl -3- butynyls, 2- heptynyls, 3- heptan Alkynyl, 4- methyl -2- hexin bases, 5- methyl -2- hexin bases, 2- methyl -3- hexin bases, 5- methyl -3- hexin bases, 2- methyl - 4- hexin base 4- methyl -5- hexin bases, 2- octynyls, 3- octynyls, 4- octynyls, 4- methyl -2- heptynyls, 5- methyl -3- Heptynyl, 6- methyl -3- heptynyls, 2- methyl -4- heptynyls, 2- methyl -5- heptynyls, 3- methyl -6- heptynyls etc..
" C of the present invention1-6Alkoxy, C1-6Alkyl amino, (C1-6Alkyl)2Amino, C1-6Alkyl sulfenyl, C1-6Alkyl Carbonyl, C1-6Alkyl sulfonyl amino, C1-6Alkyl amino sulfonyl, (C1-6Alkyl)2Amino-sulfonyl, C1-6Alkyl sulphonyl " is Refer to C1-6Alkyl-O-, C1-6Alkyl-NH-, (C1-6Alkyl)2-N-、C1-6Alkyl-S-, C1-6Alkyl-C (O)-, C1-6Alkyl- SO2NH-、C1-6Alkyl-NHSO2-、(C1-6Alkyl)2-NHSO2-、C1-6Alkyl-SO2The group that mode is formed, wherein " C1-6Alkane Described in base " text as defined above.
" C of the present invention1-4Alkoxy, C1-4Alkyl amino, (C1-4Alkyl)2Amino, C1-4Alkyl sulfenyl, C1-4Alkyl Carbonyl, C1-4Alkyl sulfonyl amino, C1-4Alkyl amino sulfonyl, (C1-4Alkyl)2Amino-sulfonyl, C1-4Alkyl sulphonyl " is Refer to C1-4Alkyl-O-, C1-4Alkyl-NH-, (C1-4Alkyl)2-N-、C1-4Alkyl-S-, C1-4Alkyl-C (O)-, C1-4Alkyl- SO2NH-、C1-4Alkyl-NHSO2-、(C1-4Alkyl)2-NHSO2-、C1-4Alkyl-SO2The group that mode is formed, wherein " C1-4Alkane Described in base " text as defined above.
" halogenated C of the present invention1-6Alkyl, hydroxyl C1-6Alkyl, amino C1-6Alkyl, sulfonyl C1-6Alkyl, C1-6Alkane Oxygroup C1-6Alkyl, hydroxyl C2-8Alkenyl, carboxyl C2-8Alkenyl, hydroxyl C2-8Alkynyl, carboxyl C2-8Alkynyl, halogenated C1-6Alkoxy, hydroxyl Base C1-6Alkoxy, C1-6Alkoxy C1-6Alkoxy, hydroxyl C1-6Alkyl amino " refers to one or more, for example, 1~4,1~3 A, 1~2 halogen atom, hydroxyl, amino, sulfonyl, carboxyl, C1-6Alkoxy replaces C respectively1-6Alkyl, C2-8Alkenyl, C2-8 Alkynyl, C1-6Alkoxy, C1-6The group that hydrogen atom in alkyl amino is formed.
" halogenated C of the present invention1-4Alkyl, hydroxyl C1-4Alkyl, amino C1-4Alkyl, sulfonyl C1-4Alkyl, C1-4Alkane Oxygroup C1-4Alkyl, hydroxyl C2-6Alkenyl, carboxyl C2-6Alkenyl, hydroxyl C2-6Alkynyl, carboxyl C2-6Alkynyl, halogenated C1-4Alkoxy, hydroxyl Base C1-4Alkyl, hydroxyl C1-4Alkoxy, C1-4Alkoxy C1-4Alkoxy, hydroxyl C1-4Alkyl amino " refers to one or more, such as 1 ~4,1~3,1~2 halogen atom, hydroxyl, amino, sulfonyl, carboxyl, C1-4Alkoxy replaces C respectively1-4Alkyl, C2-6Alkenyl, C2-6Alkynyl, C1-4Alkoxy, C1-4The group that hydrogen atom in alkyl amino is formed.
" C of the present invention1-6Alkyl amino C1-6Alkyl sulphonyl, (C1-6Alkyl)2Amino C1-6Alkyl sulphonyl " is Refer to C1-6Alkyl amino or (C1-6Alkyl)2Amino replaces C1-6The group that hydrogen atom in alkyl sulphonyl is formed.
" 3~8 yuan of cycloalkyl " refers to that the paraffin section of 3~8 carbon atoms removes monocyclic ring-type derived from a hydrogen atom Alkyl, including such as " 3~6 yuan of cycloalkyl ", " 4~6 yuan of cycloalkyl " etc..The example includes but not limited to：Cyclopropane base, ring fourth Alkyl, pentamethylene base, cyclohexyl, cycloheptyl alkyl, cyclooctane base, methyl cyclopropane base, dimethylcyclopropane base, methyl ring fourth Alkyl, dimethylcyclobutane base, methyl cyclopentane base, dimethylcyclopentane base, methyl cyclohexane alkyl, dimethyleyelohexane alkyl Deng.
" hetero atom " of the present invention refers to N, O, C (O), S, SO and/or SO2Deng, preferably N, O, S, more preferable N, O.
" 3~8 circle heterocyclic ring base " refers to containing 3~8 annular atoms and contains at least one hetero atom（Such as 1,2,3,4 or 5 hetero atoms）The monocyclic heterocyclic compound of Non-aromatic heterocyclic compound remove the obtained group of a hydrogen atom, including such as " 3 ~7 circle heterocyclic ring bases ", " 3~6 circle heterocyclic ring base ", " 4~7 circle heterocyclic ring base ", " 4~6 circle heterocyclic ring base ", " 5~6 circle heterocyclic ring base " etc..Tool Body example includes but are not limited to：Aziridine base, 2H- aziridine base, diazacyclo propyl, 3H- diazacyclos Acrylic, azetidinyl, 1,4- dioxanes base, 1,3- dioxanes base, 1,3- dioxolane base, 1,4- Dioxins base, tetrahydrofuran base, pyrrolin base, pyrrolidinyl, imidazolidinyl, 4,5- glyoxalidine base, Pyrazolidinyl, 4,5- pyrazolines base, 2,5- dihydro-thiophenes base, tetrahydro-thienyl, 4,5- dihydro-thiazolyls, piperidyl, piperazine Base, morpholinyl, 4,5- dihydro-oxazoles base, 4,5- dihydro-isoxazoles base, 2,3- dihydro-isoxazoles base, 2H-1,2- oxazinyls, 6H- 1,3- oxazinyls, 4H-1,3- thiazinyls, 6H-1,3- thiazinyls, 2H- pyranoses, 2H- pyran-2-ones base, 3,4- dihydros -2H- Pyranose etc., preferably " 5-6 circle heterocyclic rings base ".
The present invention also provides two preparation methods of above compound, but following methods are not limited only to, reaction equation It is as follows：
The preparation method referenced patent 201410072908.3 of intermediate 8.
The preparation of step 1 intermediate 1
Buy or prepare respectively intermediate 1.
The preparation of step 2 intermediate 2
Intermediate 1 is dissolved in appropriate solvent（Such as N,N-dimethylformamide）, add in appropriate（Such as 2 equivalent）N- bromo ambers Amber acid imide, heating（Such as 55 DEG C）It is stirred overnight, is cooled to room temperature, water quenching is added to go out reaction, organic solvent（Such as acetic acid second Ester）Extraction, concentration, through proper method（Such as silica gel column chromatography）Purifying obtains intermediate 2.
The preparation of step 3 intermediate 3
Intermediate 2 is dissolved in appropriate solvent（Such as ethyl alcohol), acetic acid is added in,（Such as at 70 DEG C）Reduced iron is added portionwise Powder, heating（Such as 80 DEG C）Stirring（Such as 3 hours）, solid is filtered out, water quenching is added to go out reaction, organic solvent（Such as ethyl acetate） Extraction, concentration, through proper method（Such as silica gel column chromatography）Purifying obtains intermediate 3.
The preparation of step 4 intermediate 4
Intermediate 3 is dissolved in toluene and acetic acid, is added at room temperature appropriate（Such as 1.5 equivalent）N- iodos succinyl is sub- Amine, stirring（Such as 2 hours）, water quenching is added to go out reaction, organic solvent（Such as ethyl acetate）Extraction, concentration, through proper method（Example Such as silica gel column chromatography）Purifying obtains intermediate 4.
The preparation of step 5 intermediate 5
By intermediate 4 and R3Boric acid is dissolved in solvent（Such as dioxane）, add in metal palladium catalyst（Such as [1,1'- Bis- (diphenylphosphine) ferrocene] palladium chloride）, add in appropriate（Such as 1.5 equivalent）Inorganic base（Such as potassium carbonate）, nitrogen protection Lower heating（Such as 80 DEG C）Overnight, it filters, filtrate organic solvent（Such as ethyl acetate）Extraction, the organic phase of merging is through appropriate Method（Such as silica gel column chromatography）Purifying obtains intermediate 5.
The preparation of step 6 intermediate 6
Intermediate 5 is dissolved in appropriate solvent（Such as methanol）, add in palladium carbon（10%）, it is passed through hydrogen at room temperature, it is stirred Night, filtering, filtrate are concentrated to give intermediate 6.
The preparation of step 8 intermediate 8
The preparation method referenced patent 201410072908.3 of intermediate 8.
The preparation of step 7 intermediate 7
Intermediate 6 is dissolved in appropriate solvent, adds in alkali（Such as sodium hydrogen）, R is added at room temperature4- X, room temperature or heating stirring, Water quenching is added to go out reaction, organic solvent（Such as ethyl acetate）Extraction, concentration, through proper method（Silica gel column chromatography）During purifying obtains Mesosome 7.
Step 8 general formula of the present invention（I）The preparation of compound
Intermediate 7 and intermediate 8 are dissolved in solvent（Such as dioxane）, add in metal palladium catalyst（Such as [1,1'- Bis- (diphenylphosphine) ferrocene] palladium chloride）, add in appropriate（Such as 1.5 equivalent）Inorganic base（Such as cesium carbonate）, nitrogen protection Lower heating（Such as 90 DEG C）Overnight, it filters, filtrate organic solvent（Such as ethyl acetate）Extraction, the organic phase of merging is through appropriate Method（Such as silica gel column chromatography）Purifying obtains general formula of the present invention（I）Compound.
In reaction equation, R1、R2、R3、R4、R5With A rings as defined hereinabove, X represents fluorine atom, chlorine atom, bromine atoms And iodine atom.
Formula（I）" stereoisomer " of compound refers to work as formula（I）Compound is there are during asymmetric carbon atom, meeting Enantiomter is generated, when compound is there are when carbon-carbon double bond or cyclic structure, cis-trans-isomer can be generated, when compound exists When ketone or oxime, tautomer, all formulas can be generated（I）The enantiomter of compound, diastereoisomer, racemization isomery Body, cis-trans-isomer, tautomer, geometric isomer, epimer and its mixture, are included in the scope of the invention In.
The general formula of the present invention（I）If the raceme that shown any compound synthesis obtains, required enantiomer-pure Compound can be obtained by the method for chiral resolution：The chromatography with chiral stationary phase can be passed through（Image height compacting is standby Liquid chromatogram, supercritical fluid chromatography）.Chirality padding includes but not limited to：Chiralcel OJ-H, Chiralpak AD-H, Chiralpak IA, Chiralpak AS-H.
The general formula of the present invention（I）Shown any compound pharmaceutically acceptable salt refer to by it is pharmaceutically acceptable, Salt prepared by non-toxic alkali or acid, including acylate, inorganic acid salt, organic alkali salt, inorganic base salts.
Acylate includes formic acid, acetic acid, trifluoroacetate, benzene sulfonic acid, benzoic acid, p-methyl benzenesulfonic acid, camphorsulfonic acid, lemon It is lemon acid, methanesulfonic acid, ethanesulfonic acid, propane sulfonic acid, fumaric acid, gluconic acid, glutamic acid, isethionic acid, lactic acid, maleic acid, malic acid, flat The salt of peach acid, glactaric acid, pamoic acid, pantothenic acid, succinic acid, tartaric acid etc..
Inorganic acid salt includes the salt of hydrobromic acid, hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid etc..
Organic alkali salt includes primary, secondary and tertiary amine, is substituted amine and includes naturally occurring substitution amine, cyclammonium and basic ion exchange Resin, selected from glycine betaine, caffeine, choline, N, N '-dibenzyl-ethylenediamin, diethylamine, 2- Diethylaminoethanols, 2- dimethylamine Base ethyl alcohol, ethanol amine, ethylenediamine, N- ethyl-morpholines, N-ethylpiperidine, meglumine, Glucosamine, Hai Baming, isopropyl Amine, methylglucosamine, morpholine, piperazine, piperidines, procaine, purine, theobromine, triethylamine, trimethylamine, tripropyl amine (TPA), ammonia fourth three The salt of alcohol etc..Native amino hydrochlorate for example glycine, alanine, valine, leucine, isoleucine, nor-leucine, tyrosine, Cystine, cysteine, methionine, proline, hydroxy-proline, histidine, ornithine, lysine, arginine, serine etc. Salt.
Inorganic base salts include the salt of ammonium and lithium, sodium, potassium, calcium, magnesium, zinc, barium, aluminium, iron, ketone, ferrous iron, manganese, bivalent manganese etc..
Formula（I）" ester " of compound refers to, works as formula（I）Compound can be esterified there are during carboxyl with alcohol The ester for reacting and being formed, works as formula（I）Compound can be esterified anti-there are during hydroxyl with generations such as organic acid, inorganic acid, acylates The ester answered and formed.Under the conditions of existing for acid or alkali the corresponding acid of hydrolysis generation or alcohol can occur for ester.
General formula (I) compound represented, its pharmaceutically acceptable salt, its stereoisomer or its ester can be solvations Object form.In the case that if solvate is hydrate, aquation can be completed in preparation process or can utilize original The hygroscopicity without aquatic products that begins gradually carries out.
Further requirement protection of the present invention includes above-mentioned formula（I）Shown any compound, its is pharmaceutically acceptable The pharmaceutical composition of salt, its stereoisomer, its ester or its solvate and one or more pharmaceutical carriers and/or diluent, Pharmaceutically acceptable any dosage form can be made.Being applied in a manner of oral, parenteral, rectum or transpulmonary administration etc. needs this The patient of kind treatment.During for being administered orally, conventional solid pharmaceutical preparation, such as tablet, capsule, pill, granule can be made into； It may be made as oral liquid, such as oral solution, oral suspensions, syrup.When oral preparation is made, it can add in Suitable filler, adhesive, disintegrant, lubricant etc..During for parenteral administration, can be made into injection, including parenteral solution, Injection sterile powder and concentrated solution for injection.When injection is made, the conventional method production in existing pharmaceutical field can be used, When preparing injection, additives can be added without, suitable additives can be also added according to the property of drug.For rectally When, it can be made into suppository etc..During for transpulmonary administration, inhalant or spray etc. can be made into.
Further requirement protection of the present invention includes formula recited above（I）Any compound, its pharmaceutically acceptable salt, Its stereoisomer, its ester or its solvate and other one or more antitumor agents and the pharmaceutical composition of immunosuppressor Object.The antitumor agent and immunosuppressor, including but not limited to methotrexate (MTX), capecitabine, gemcitabine, deoxidation fluorine urine Glycosides, pemetrexed disodium, pazopanib, Imatinib, Erlotinib, Lapatinib, Gefitinib, Vande Thani, Trastuzumab, Bevacizumab, Rituximab, Herceptin, taxol, vinorelbine, docetaxel, Doxorubicin, hydroxycamptothecin, Mitomycin, epirubicin, pirarubicin, bleomycin, Letrozole, tamoxifen, fulvestrant, music score of Chinese operas Rayleigh, Flutamide, Leuprorelin, Anastrozole, ifosfamide, busulfan, cyclophosphamide, Carmustine, Nimustine, Semustine, mustargen, Melphalan, chlorambucil, carboplatin, cis-platinum, oxaliplatin, network platinum, Topotecan, camptothecine, topotecan, everolimus, western sieve Mo Si, special cancer are fitted, Ismipur, 6- thioguanines, imuran, rhzomorph D, daunorubicin, adriamycin, mitoxantrone, are striven Light mycin, plicamycin or aminoglutethimide.
The present invention also provides formulas（I）Compound represented, its pharmaceutically acceptable salt, its alloisomerism The application of body, its ester or its solvate in the drug of cancer-related diseases for the treatment of and/or prevention ALK mediations is prepared, institute It states the relevant disease of cancer and is selected from brain tumor, lung cancer in non-cellule type, dermoid cancer, carcinoma of urinary bladder, gastric cancer, oophoroma, abdomen Film cancer, cancer of pancreas, breast cancer, head and neck cancer, cervix cancer, carcinoma of endometrium, the carcinoma of the rectum, liver cancer, hepatoblastoma, mamillary kidney Cytoma, incidence squamous cytoma, the nephroblastoma, kidney, adenocarcinoma of esophagus, esophageal squamous cell carcinoma, female reproductive tract cancer, Carcinoma in situ, lymthoma, neuroblastoma, neurofibromatosis, thyroid cancer, osteocarcinoma, cutaneum carcinoma, the cancer of the brain, colon cancer, testis Cancer, Small Cell Lung Cancer, gastrointestinal stromal tumor, tumor of prostate, mast cell tumor, Huppert's disease, melanoma or god Through glioma.
The compounds of this invention has the following advantages：
（1）Formula（I）Compound or its stereoisomer or its pharmaceutically acceptable salt, ester or solvation Object has excellent ALK inhibitory activity；
（2）Formula（I）Compound or its stereoisomer or its pharmaceutically acceptable salt, ester or solvation Object shows good biological stability, and effect is more longlasting, and bioavilability is high；
（3）The compounds of this invention preparation process is simple, and drug purity is high, stable quality, is easy to carry out large-scale industry life Production.
Below by way of external zymetology inhibitory activity experiment the present invention is further explained compound advantageous effect, but should not be by this Being interpreted as the compounds of this invention only has following advantageous effect.
The external zymetology activity experiment of 1 the compounds of this invention of experimental example
Test sample：The trifluoroacetate of the compounds of this invention 1, chemical name and preparation method are shown in 1 trifluoro second of compound The preparation embodiment of hydrochlorate.
Comparison medicine：LDK378 makes by oneself (preparation of referenced patent WO2008/073687A2 preparation methods).
Meaning representated by the abbreviation of following middle experiments is as follows：
DMSO：Dimethyl sulfoxide (DMSO)
DTT：Dithiothreitol (DTT)
SEB：Enzyme catalyst buffer solution
ATP：Adenosine triphyosphate
ALK：Anaplastic lymphoma kinase
SA-XL665：The donor of marked by streptavidin
2.5 ×, 5 ×, 10 × "×" therein：Times
Experimental method：
ALK kinase buffer liquids are prepared：
The SEB, 40 μ L mother liquors that MgCl2,40 μ L mother liquid concentrations that 20 μ L mother liquid concentrations are 1000mM are 2500nM are taken respectively 5 × enzyme buffer liquid of the DTT of a concentration of 100mM, 800 μ L are added in the ultra-pure water of 3100 μ L, mixing.
2.5 × test solution is prepared：
The 1mM storing solutions of comparison medicine are prepared：Comparison medicine 1.48mg is weighed, adds in appropriate DMSO dissolvings, mixing is spare.
The 1mM storing solutions of compound 1 are prepared：1 trifluoroacetate 1.54mg of Weigh Compound adds in appropriate DMSO dissolvings, Mixing, it is spare.
1mM storing solutions are taken respectively, a concentration of 200 μM of solution are made of DMSO dilutions, as mother liquor.It will be above-mentioned with DMSO Mother liquor three times dilute a series of solution that concentration are made step by step, and then each concentration dilutes 80 times with ALK kinase buffer liquids respectively, Each 2.5 × test solution is made, concentration is respectively：2500nM、833.33nM、277.78nM、92.59nM、30.86nM、 10.29nM、3.43nM、1.14nM、0.38nM、0.13nM、0.04nM。
Various other preparation of reagents：
Required 5 × ALK kinase solutions, 5 × substrate solution, 5 × ATP solution are prepared respectively with ALK kinase buffer liquids, It is spare.
ALK zymetologys are reacted：
1）It is prepared that the prepared 2.5 × test solutions of 4 μ L, 2 μ L are separately added into 384 orifice plates in corresponding hole 5 × ALK kinase solutions, 25 DEG C are incubated 10 minutes.
2）Corresponding Kong Zhongzai is separately added into the prepared 5 × substrate solutions of 2 μ L and the 2 prepared 5 × ATP of μ L are molten Liquid starts enzyme reaction, and 25 DEG C are incubated 30 minutes.
Zymetology detects：
With detection buffer solution (detection buffer) prepare needed for concentration SA-XL665, then with isometric junket Histidine kinase antibody mixing is separately added into this prepared antibody-solutions of 10 μ L in corresponding hole, terminates reaction.25 DEG C of incubations 1h。
Microplate reader 665nm/615nm read plates.
IC50：Inhibiting rate (%)=(maximum value-sample ratio)/(maximum value-minimum value) × 100 are calculated, using Graph Prisim softwares carry out curve fitting, and obtain IC50 values.
Maximum value：It is not added with the positive control of compound, minimum value：Not enzyme negative control.
Experimental result and conclusion：
The external zymetology inhibitory activity of 1. the compounds of this invention of table
By table 1 as it can be seen that compared with comparison medicine, the compounds of this invention has better inhibitory activity to ALK kinases, can be used for Treatment and the relevant disease of kinases, kinase mediated particularly ALK illness or the patient's condition have significant clinical meaning.
The cell in vitro activity experiment of 2 the compounds of this invention of experimental example
Test sample：The trifluoroacetate of the compounds of this invention 1, chemical name and preparation method are shown in the trifluoro of compound 1 The preparation embodiment of acetate.
Comparison medicine 1LDK-378 makes by oneself (preparation of referenced patent WO2008/073687A2 preparation methods), and structural formula is as carried on the back Described in scape technology.
Comparison medicine 2CH5424802 makes by oneself (preparation of referenced patent CN102459172A preparation methods), and structural formula is as carried on the back Described in scape technology.
Meaning representated by the abbreviation of following middle experiments is as follows：
rpm：Rpm
DMSO：Dimethyl sulfoxide (DMSO)
MTS：Thiazole bromide blue tetrazolium
RPMI1640：1640 culture medium (RPMI:Roswell Park Memorial Institute)
500 ×, 1000 ×, 10 × "×" therein：Times
Experimental method：
（One）NCI-H3122, Karpas-299 cell：
（1）It is prepared by cell：
With containing 10% fetal calf serum, 100U/ml penicillin, 100mg/ml streptomysins RPMI-1640 culture mediums, 5% CO2, 37 DEG C of conditions incubator in, culture cell is spare to 80% fusion.
（2）Inoculating cell：
With trypsin digestion cell, 1000rpm centrifugation 4min remove supernatant, with the RPMI-1640 containing 2.5% fetal calf serum Culture medium is suspended again, adjusts cell density, 90 μ L of the cell suspension is taken to be inoculated into 96 orifice plates, obtains final cell density For 3000/hole；Then in 5%CO2, cultivate for 24 hours in 37 DEG C of incubators.
（3）Add in test sample：
（3.1）Test solution is prepared
1 solution of comparison medicine：Comparison medicine 3.02mg is weighed, appropriate DMSO is added in and dissolves and be made respectively of DMSO gradient dilutions A series of mother liquor of concentration（1000 × control drug solns）, then dilute the mother liquor 100 with culture medium respectively and obtain 10 × control again Drug solns take 10 μ L of the solution, are added in the corresponding hole of 96 orifice plates respectively, obtain control drug solns ultimate density and are：10μM、 2.5μM、625nM、156nM、39nM、9.8nM、2.5nM。
1 solution of compound：The trifluoroacetate 2.09mg of Weigh Compound 1 adds in appropriate DMSO and dissolves and use respectively A series of mother liquor of concentration is made in DMSO gradient dilutions（1000 × compound, 1 solution）, then respectively the mother liquor is diluted with culture medium 100 times obtain 10 × compound, 1 solution, take 10 μ L of the solution respectively, are added in the corresponding hole of 96 orifice plates, obtain compound 1 Solution ultimate density is：10μM、2.5μM、625nM、156nM、39nM、9.8nM、2.5nM.
（3.2）Control wells are set：
Vehicle controls：0.1%DMSO.
Culture medium compares：Inoculating cell, is not added with compound.
Blank control：Culture medium, instrument zeroing.
（3.3）96 orifice plates are put into 37, DEG C 5%CO272h is cultivated in incubator.
（4）Detection:
MTS detection methods：
1. by CellTiterSingle 96 hole cell proliferation detecting kit of solution is placed at room temperature for 90min.
2. add in CellTiter into each test hole of 96 orifice platesThe mono- 20 μ L of solution reagent of AQueous.
3. 96 orifice plates are put into 5%CO2, cultivate 40min in 37 DEG C of incubators.
4. setting microplate reader Detection wavelength 490nm, result is read.
（5）IC50 is calculated：Cell survival rate (%)=(sample value-blank value)/(maximum value-blank value) × 100 uses Graph prisim softwares carry out curve fitting, and obtain IC50 values.
Maximum value：It is not added with the cell controls of compound solubilization matchmaker, blank value：Blank value.
（Two）NCI-H2228 cells：
（1）It is prepared by cell：
With the RPMI-1640 culture mediums containing 10% fetal calf serum, in 5%CO2, 37 DEG C of conditions incubator in, cultivate cell It is spare to 80% fusion.（2）Inoculating cell：
With trypsin digestion cell, 1000rpm centrifugation 4min remove supernatant, with the RPMI-1640 containing 2.5% fetal calf serum Culture medium is suspended again, adjusts 2 × 104/mL of cell density, 100 μ L of the cell suspension is taken to be inoculated into 96 orifice plates, obtains Final cell density is：2000 cells/wells.
（3）Add in test sample：
（3.1）Test solution is prepared：
1 solution of compound is prepared：The trifluoroacetate 2.01mg of Weigh Compound 1 adds in appropriate DMSO, dissolving, mixing, By solution DMSO gradient dilutions, a series of solution of concentration is obtained, it is spare.
2 solution of comparison medicine is prepared：Comparison medicine 3.21mg is weighed, adds in appropriate DMSO, is dissolved, mixing, by solution DMSO Gradient dilution obtains a series of solution of concentration, spare.
After inoculating cell 6h, 99 μ L complete mediums is taken to be added separately in each hole of 96 orifice plates, then take above-mentioned preparation The 1 μ L of solution of good various concentration are added in corresponding hole so that the ultimate density of compound 1 is：10000nM、2500nM、 625nM、156.25nM、39.06nM、9.77nM、2.44nM、0.61nM、0.15nM.The ultimate density of comparison medicine is：9800nM、 2450nM、612.5nM、153.1nM、38.28nM、9.57nM、2.39nM、0.60nM、0.15nM。
（3.2）Control wells are set：
Vehicle controls：0.5%DMSO.
Culture medium compares：Inoculating cell, is not added with compound.
Blank control：Culture medium, instrument zeroing.
（3.3）This 96 orifice plate is put into 5%CO2, 37 DEG C of conditions incubator in cultivate 96h.
（4）Detection：
CTG detection methods：
1. culture medium in the every hole of 96 orifice plates is removed into 80 μ L, equilibrium at room temperature 30min.
2. add in CellTiter- into each test hole of 96 orifice plates60 μ L of reagent.
3. 96 orifice plates are protected from light oscillation mixing 2min with micropore plate oscillator, make cell cracking.
4. 96 orifice plates are protected from light incubation at room temperature 10min, stablize the optical signal value of generation.
5. microplate reader reads result under luminescence patterns.
（5）Result treatment：
IC50 is calculated：Cell inhibitory rate (%)=(ODSolvent- ODCompound)/(ODSolvent- ODpositive) × 100, using Graph Prisim softwares carry out curve fitting, and obtain IC50 values.
ODSolvent：It is not added with the cell controls of compound solubilization matchmaker, ODpositive：Add in the cell pair of 1000nM taxols According to.
Experimental result and conclusion：
The cell inhibitory activity of 2. the compounds of this invention of table
As can be seen from Table 2, compared with comparison medicine, the compounds of this invention is to cell NCI-H3122, Karpas-299 and NCI- H2228 is respectively provided with better inhibitory activity, and the illness or the patient's condition kinase mediated available for treatment ALK have significant clinical meaning Justice.
Specific embodiment
The specific embodiment of form by the following examples makees further specifically the above of the present invention It is bright.But the range that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to following embodiment.It is all to be based on the above of the present invention The technology realized all belongs to the scope of the present invention.
It is defined as follows representated by following abbreviations：
DMF：N,N-dimethylformamide
NBS：N- bromo-succinimides
The chloro- 4- of embodiment 15- (1H- indol-3-yls)-N- (7- methyl -8- (piperidin-4-yl) -2,3- dihydrobenzos [b] [1,4] bioxin -5- bases) pyrimidine -2- amine (compound 1) trifluoroacetate preparation
（1）The preparation of 2- methoxyl group -4- methyl -6- nitrophenols
Under nitrogen protection, 2- methoxyl group -4- methylphenols (11g, 79.62mmol) are dissolved in chloroform (200mL), ice bath item Under part, the acetic acid solution (31mL, 79.62mmol) of fuming nitric aicd is added dropwise, is stirred 2 minutes under condition of ice bath, reaction solution concentration, then With recrystallizing methanol, product (7g, yield 48%) is obtained.
（2）The preparation of 5- methyl-3-nitro -1,2- benzenediols
Under nitrogen protection, 2- methoxyl group -4- methyl -6- nitrophenols (4.5g, 24.57mmol) are dissolved in HBr solution (48%) (80mL), adds in catalyst methyl tricapryl ammonium chloride (4.5g, 11.13mmol), and reaction solution is small in 110 DEG C of stirrings 4 When, LC-MS shows that the reaction was complete, is cooled to room temperature, and water quenching is added to go out, ethyl acetate extraction（3×100mL）, organic phase is taken to use full (3 × 300mL) is washed with sodium-chloride water solution, anhydrous sodium sulfate drying is concentrated under reduced pressure to give crude product (3g, yield 72%).
（3）7- methyl-5-nitro -2,3- dihydrobenzos [the b] [preparation of 1,4] bioxin
Under nitrogen protection, 5- methyl-3-nitros -1,2- benzenediol (4.5g, 26.61mmol) is dissolved in DMF (180mL), 1,2- Bromofume (10g, 53.23mmol) and potassium carbonate (11g, 79.59mmol) are added in there-necked flask, and 55 DEG C are stirred overnight, It is cooled to room temperature, is stirred overnight, LC-MS shows that the reaction was complete, is cooled to room temperature, and water quenching is added to go out, ethyl acetate extraction（3× 200mL）, organic phase is taken to be washed (3 × 300mL) with saturated sodium-chloride water solution, anhydrous sodium sulfate drying is concentrated under reduced pressure, remaining Object purifies (ethyl acetate with silica gel column chromatography：Petroleum ether=1:5) product (4g, yield 77%) is obtained.
（4）6- bromine-7-methyl -5- nitro -2,3- dihydrobenzos [the b] [preparation of the preparation of 1,4] bioxin
Under nitrogen protection, by 7- methyl-5-nitros -2,3- dihydrobenzo [b], [Isosorbide-5-Nitrae] bioxin (4g, 20.49mmol) is molten In n,N-Dimethylformamide (160mL), NBS (7.3g, 41.02mmol) is added in, 55 DEG C are stirred overnight, and are cooled to room temperature, add Water quenching is gone out, and ethyl acetate extraction (3 × 200mL) takes organic phase to be washed (3 × 300mL) with saturated sodium-chloride water solution, anhydrous sulphur Sour sodium drying, after reduced pressure, residue purifies (ethyl acetate through silica gel column chromatography：Petroleum ether=1:5) obtain product (3.5g, Yield 62%).
（5）6- bromine-7-methyl -2,3- dihydrobenzos [the b] [preparation of 1,4] bioxin -5- amine
Nitrogen protection under, by 6- bromine-7-methyl -5- nitros -2,3- dihydrobenzos [b] [Isosorbide-5-Nitrae] bioxin (3.5g, 12.77mmol) be dissolved in ethyl alcohol (70mL), add in acetic acid (14mL), be added portionwise at 70 DEG C reduced iron powder (10.8g, After 192.3mmol), 80 DEG C are stirred 3 hours, filter out solid, and filtrate adds water quenching to go out reaction, and ethyl acetate extracts (2 × 200mL), Organic phase is taken to be washed (3 × 300mL) with saturated sodium-chloride water solution, anhydrous sodium sulfate drying, after reduced pressure, residue is through silicon Gel column chromatography eluting (ethyl acetate：Petroleum ether=1:2) product (2.0g, yield 64%) is obtained.
（6）[the preparation of 1,4] bioxin -5- amine of the iodo- 7- methyl -2,3- dihydrobenzos [b] of the bromo- 8- of 6-
Nitrogen protection under, by 6- bromine-7-methyls -2,3- dihydro-Isosorbide-5-Nitrae-benzo [b] [Isosorbide-5-Nitrae] bioxin -5- amine (2g, 8.19mmol) it is dissolved in toluene (20mL) and acetic acid（In 0.5mL), at room temperature, NIS (2.8g, 12.45mmol) is added in, room temperature is stirred It mixes 2 hours, water quenching is added to go out, ethyl acetate extraction (3 × 200mL), organic phase is successively with sodium hydrogensulfite (2 × 200mL), saturation Sodium-chloride water solution (3 × 300mL) washs, and anhydrous sodium sulfate drying, after reduced pressure, residue is through silica gel column chromatography (acetic acid Ethyl ester：Petroleum ether=1:2) purifying obtains product (1.6g, yield 53%).
（7）Tertiary butyl 4- (the bromo- 6- methyl -2,3- dihydrobenzos [b] of 8- amino -7- [1,4] bioxin -5- bases) -5,6- The preparation of dihydropyridine -1 (2H)-formic acid esters
Nitrogen protection under, by iodo- 7- methyl -2, the 3- dihydrobenzos [b] of the bromo- 8- of 6- [Isosorbide-5-Nitrae] bioxin -5- amine (1.6g, It 4.32mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (30mL), adds dissolved with tert-butyl ester 4- (4,4,5,5- tetramethyls -1,3,2- bis- Oxygen Polymorphs boron -2- bases) -5,6- dihydropyridines -1 (2H)-formic acid esters (1.2g, 3.88mmol) water (6mL) solution in, add in [1,1'- bis- (diphenyl phosphine) ferrocene] palladium chloride (II) (640mg, 0.87mmol) and potassium carbonate (1.8g, 13.02mmol), it reacts 2 hours for 83 DEG C, is cooled to room temperature, water quenching is added to go out, dichloromethane extraction (3 × 100mL), organic phase is dense After contracting, residue purifies (ethyl acetate through silica gel column chromatography：Petroleum ether=1:5) product (900mg, yield 55%) is obtained.
（8）Tertiary butyl 4- (8- amino -6- methyl -2,3- dihydrobenzos [b] [- 5 base of 1,4] bioxin)-piperidines -1- formic acid The preparation of ester
Nitrogen protection under, by tertiary butyl 4- (bromo- 6- methyl -2, the 3- dihydrobenzos [b] of 8- amino -7- [Isosorbide-5-Nitrae] bioxin - 5- yls) -5,6- dihydropyridines -1 (2H)-formic acid esters (900mg, 2.12mmol) is dissolved in methanol (30mL), add palladium carbon (1g), is passed through hydrogen, is stirred overnight at room temperature, and filters out solid, and filtrate decompression is concentrated to give product (300mg, yield 41%).
(9) tertiary butyl 3- (2- ((8- (1- (tertbutyloxycarbonyl) piperidin-4-yl) -7- methyl -2,3- dihydrobenzos [b] [1, 4] bioxin -5- bases) amino) -5- chlorine pyrimidine-4-yl) and -1H- indoles -1- formic acid esters preparation
By tertiary butyl 4- (8- amino -6- methyl -2,3- dihydrobenzos [b] [1,4] bioxin -5- bases)-piperidines -1- formic acid Ester (80mg, 0.23mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (2mL), adds in tertiary butyl 3- (2,5- dichloro pyrimidine -4- bases) -1H- Yin Diindyl -1- formic acid esters (100mg, 0.27mmol, preparation method referenced patent CN201410072908.3), [1,1'- bis- (hexichol Phosphino-) ferrocene] palladium chloride (II) (50mg, 0.06mmol) and cesium carbonate (300mg, 0.92mmol) nitrogen protection it is lower 90 DEG C Stirring 2 hours, room temperature during cooling filter out solid, filtrate concentration, residue through prepare efficient liquid phase purify to obtain product (30mg, Yield 19%).
（10）The chloro- 4- of 5- (1H- indol-3-yls)-N- (7- methyl -8- (piperidin-4-yl) -2,3- dihydrobenzos [b] [1, 4] bioxin -5- bases) pyrimidine -2- amine trifluoroacetates preparation
By tertiary butyl 2- (2- ((8- (1- (tertbutyloxycarbonyl) piperidin-4-yl) -7- methyl -2,3- dihydrobenzos [b] [1, 4] bioxin -5- bases) amino) -5- chlorine pyrimidine-4-yl) -1H- indoles -1- formic acid esters (30mg, 0.04mmol) is dissolved in dichloromethane Alkane (10mL) adds in trifluoroacetic acid (3mL), is stirred at room temperature 3 hours, after concentration, and residue obtains title through preparing efficient liquid phase Compound (19.3mg, yield 74%).
Molecular formula：C28H27ClF3N5O4Molecular weight：590.00LC-MS(m/z):476(M+H+)
1H-NMR(300MHz,CD3OD)δ:8.51(s,1H),8.46-8.49(d,1H,J=7.8Hz),8.34(s,1H), 7.69(s,1H),7.47-7.49(d,1H,J=8.1Hz),7.20-7.25(m,1H),7.07-7.13(m,1H),4.30-4.33 (m,4H),3.51-3.56(m,2H),3.08-3.18(m,3H),2.66-2.73(m,2H),2.29(s,3H),1.84-1.88 (m,2H).

Claims (6)

1. general formula (I) compound represented or its stereoisomer or its pharmaceutically acceptable salt：
Wherein,
R1Selected from hydrogen, hydroxyl, cyano, halogen atom or C1-4Alkyl；
R2Selected from hydrogen or C1-4Alkyl；
R3Selected from 4~7 circle heterocyclic ring bases, 4~7 circle heterocyclic ring bases can be optionally by 1~2 q1Substitution；
R4Selected from hydrogen or C1-4Alkyl；
R5Selected from hydrogen or C1-4Alkyl；
A rings form following group together with the phenyl ring being attached thereto：
q1Selected from C1-4Alkyl.
2. compound as described in claim 1 or its stereoisomer or its pharmaceutically acceptable salt：
Wherein,
R3Selected from 5~6 circle heterocyclic ring bases；
A rings form following group together with the phenyl ring being attached thereto：
3. compound as described in claim 1 or its stereoisomer or its pharmaceutically acceptable salt, the compound It is selected from：
4. compound or its stereoisomer as described in claim 1-3 any claims or its is pharmaceutically acceptable Salt and one or more pharmaceutical carriers and/or diluent pharmaceutical composition, pharmaceutically acceptable any dose can be made Type.
5. pharmaceutical composition as claimed in claim 4, it is characterised in that can also contain one or more antitumor agents and be immunized Inhibitor, the antitumor agent and immunosuppressor are selected from methotrexate (MTX), capecitabine, gemcitabine, doxifluridine, training U.S. bent plug disodium, pazopanib, Imatinib, Erlotinib, Lapatinib, Gefitinib, Vande Thani, Trastuzumab, shellfish are cut down Monoclonal antibody, Rituximab, Herceptin, taxol, vinorelbine, docetaxel, Doxorubicin, hydroxycamptothecin, mitogen Mycin, epirubicin, pirarubicin, bleomycin, Letrozole, tamoxifen, fulvestrant, music score of Chinese operas Rayleigh, Flutamide, bright third Rayleigh, Anastrozole, ifosfamide, busulfan, cyclophosphamide, Carmustine, Nimustine, Semustine, mustargen, Ma Fa Orchid, chlorambucil, carboplatin, cis-platinum, oxaliplatin, network platinum, Topotecan, camptothecine, topotecan, everolimus, Sirolimus, Special cancer is fitted, Ismipur, 6- thioguanines, imuran, rhzomorph D, daunorubicin, adriamycin, mitoxantrone, win honour for it is mould Element, plicamycin or aminoglutethimide.
6. compound or its stereoisomer as described in claim 1-3 any claims or its is pharmaceutically acceptable Salt prepare for treat and/or prevent ALK mediation proliferative disease or cancer-related diseases drug in application, institute It states the relevant disease of cancer and is selected from brain tumor, lung cancer in non-cellule type, dermoid cancer, carcinoma of urinary bladder, gastric cancer, oophoroma, abdomen Film cancer, cancer of pancreas, breast cancer, head and neck cancer, cervix cancer, carcinoma of endometrium, the carcinoma of the rectum, liver cancer, hepatoblastoma, mamillary kidney Cytoma, incidence squamous cytoma, the nephroblastoma, kidney, adenocarcinoma of esophagus, esophageal squamous cell carcinoma, female reproductive tract cancer, It is carcinoma in situ, lymthoma, neuroblastoma, neurofibromatosis, thyroid cancer, osteocarcinoma, cutaneum carcinoma, colon cancer, carcinoma of testis, small Cell lung cancer, gastrointestinal stromal tumor, tumor of prostate, mast cell tumor, Huppert's disease, melanoma or neuroglia Knurl.
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