CN104876914B - Pyrimidine derivative type anaplastic lymphoma kinase inhibitor - Google Patents

Pyrimidine derivative type anaplastic lymphoma kinase inhibitor Download PDF

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CN104876914B
CN104876914B CN201510045202.2A CN201510045202A CN104876914B CN 104876914 B CN104876914 B CN 104876914B CN 201510045202 A CN201510045202 A CN 201510045202A CN 104876914 B CN104876914 B CN 104876914B
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alkyl
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cancer
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CN104876914A (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
    • 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
    • C07D403/14—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 three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Abstract

The invention belongs to the field of a medical technology and specifically relates to a pyrimidine derivative type anaplastic lymphoma kinase inhibitor as shown in the general formula (I) or its stereisomer, or its pharmaceutically acceptable salt, ester or solvate, wherein R1, R2, R3, R4, R5 and A ring are as defined in the specification. The invention also relates to a preparation method of the compounds, a pharmaceutic preparation and a pharmaceutical composition containing the compounds and an application of the compound or its stereisomer, or its pharmaceutically acceptable salt, ester or solvate in the preparation of medicines for treating and/or preventing diseases related to anaplastic lymphoma kinase-mediated cancer.

Description

Pyrimidine derivates species anaplastic lymphoma kinase inhibitor
Technical field
The invention belongs to pharmaceutical technology field, 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 contains 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 the medicine for the treatment of and/or the cancer-related diseases for preventing to be mediated by anaplastic lymphoma kinase In application.
Background technology
Anaplastic lymphoma kinase (Anaplastic lymphoma kinase, ALK) is receptor tyrosine kinase family Member, can raise downstream albumen by autophosphorylation, and then express specific gene, adjust cell metabolism and growth.Anaplasia Property lymphom kinase is found in earliest primary cutaneous type (Anaplastic large cell lymphoma, ALCL) In, found also there is high expression in non-small cell lung cancer (NSCLC) later.
The micromolecular inhibitor of ALK can affect the growth of tumour cell, play antineoplastic action, but face in a large number Bed proves generation ALK inhibitor C rizotinib, easily produces drug resistance, therefore, design and screen to Crizotinib generations The patient of resistance also has two generation ALK inhibitor of good curative effect, with significant clinical meaning.
The ALK inhibitor being currently known include Crizotinib (Pfizer), Alectinib (i.e. CH5424802, Roche), Ceritinib (i.e. LDK378, Novartis), AZD-3463 (AstraZeneca).
Therefore, modified by compound structure and find new compound structure, effort improves the physicochemical property of compound, carries High druggability, the bioavilability for such as improving compound is mutated activated micromolecular inhibitor to find to ALK, for facing The treatment of the disease caused because of ALK mutation on bed, has great importance.
The content of the invention
The present invention has been invented to treating and/or preventing ALK mediations with developing the micromolecular inhibitor for ALK as target Cancer-related diseases there is the pyrimidine derivates species anaplastic lymphoma kinase inhibitor of good result.Specific technical scheme For as follows：
1. the compound or its stereoisomer or its pharmaceutically acceptable salt, ester or solvation shown in formula (I) Thing：
Wherein,
R1Selected from hydrogen, hydroxyl, amino, cyano group, nitro, halogen atom, C1-6Alkyl, hydroxyl C1-6Alkyl, halo C1-6Alkane Base, C1-6Alkoxyl, hydroxyl C1-6Alkoxyl, halo C1-6Alkoxyl, C2-8Thiazolinyl, C2-8Alkynyl, C1-6Alkyl amino, (C1-6Alkane Base)2Amino, sulfonyl C1-6Alkyl or 3～8 yuan of cycloalkyl；
R2And R3Separately it is selected from hydrogen, hydroxyl, amino, cyano group, nitro, halogen atom, C1-6Alkyl, hydroxyl C1-6Alkane Base, amino C1-6Alkyl, halo 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, C1-6Alkoxyl, halo C1-6Alkoxyl, C1-6Alkoxy C1-6Alkoxyl, hydroxyl C1-6Alkoxyl, C2-8Thiazolinyl, carboxyl C2-8Thiazolinyl, hydroxyl C2-8Thiazolinyl, C2-8Alkynyl, hydroxyl C2-8Alkynyl or carboxyl C2-8Alkynyl；
R4Selected from hydrogen or C1-6Alkyl；
R5Selected from hydrogen, hydroxyl, carboxyl, amino, cyano group, nitro, C1-6Alkyl, C1-6Alkoxyl, halo C1-6Alkyl, halo C1-6Alkoxyl, C2-8Thiazolinyl, C2-8Alkynyl, C1-6Alkyl amino or (C1-6Alkyl)2Amino；
A rings form the circle heterocycles base of benzo 3～8 together with the phenyl ring being attached thereto, and 3～8 described circle heterocycles bases can optionally by 1 ～3 q1Replace, wherein q1Selected from hydroxyl, amino, carboxyl, cyano group, nitro, halogen atom, C1-6Alkyl, C1-6Alkoxyl, C1-6 Alkyl amino, (C1-6Alkyl)2Amino, halo C1-6Alkyl, halo C1-6Alkoxyl, C1-6Alkoxy C1-6Alkyl, C1-6Alkyl oxycarbonyl Base, C2-8Thiazolinyl, C2-8Alkynyl or 3～8 circle heterocycles bases.
2. compound as described in technical scheme 1 or its stereoisomer or its pharmaceutically acceptable salt, ester or molten Agent compound, wherein,
R1Selected from hydrogen, hydroxyl, amino, cyano group, nitro, halogen atom, C1-4Alkyl, hydroxyl C1-4Alkyl, halo C1-4Alkane Base, C1-4Alkoxyl, hydroxyl C1-4Alkoxyl, halo C1-4Alkoxyl, C2-6Thiazolinyl, C2-6Alkynyl, C1-4Alkyl amino, (C1-4Alkane Base)2Amino, sulfonyl C1-4Alkyl or 3～6 yuan of cycloalkyl；
R2And R3Separately it is selected from hydrogen, hydroxyl, amino, cyano group, nitro, halogen atom, C1-4Alkyl, hydroxyl C1-4Alkane Base, amino C1-4Alkyl, halo 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, C1-4Alkoxyl, halo C1-4Alkoxyl, C1-4Alkoxy C1-4Alkoxyl, hydroxyl C1-4Alkoxyl, C2-6Thiazolinyl, carboxyl C2-6Thiazolinyl, hydroxyl C2-6Thiazolinyl, C2-6Alkynyl, hydroxyl C2-6Alkynyl or carboxyl C2-6Alkynyl；
R4Selected from hydrogen or C1-4Alkyl；
R5Selected from hydrogen, hydroxyl, carboxyl, amino, cyano group, nitro, C1-4Alkyl, C1-4Alkoxyl, halo C1-4Alkyl, halo C1-4Alkoxyl, C2-6Thiazolinyl, C2-6Alkynyl, C1-4Alkyl amino or (C1-4Alkyl)2Amino；
A rings form the circle heterocycles base of benzo 3～8 together with the phenyl ring being attached thereto, and 3～8 described circle heterocycles bases can optionally by 1 ～2 q1Replace, wherein q1Selected from hydroxyl, amino, carboxyl, cyano group, nitro, halogen atom, C1-4Alkyl, C1-4Alkoxyl, C1-4 Alkyl amino, (C1-4Alkyl)2Amino, halo C1-4Alkyl, halo C1-4Alkoxyl, C1-4Alkoxy C1-4Alkyl, C1-4Alkyl oxycarbonyl Base, C2-6Thiazolinyl, C2-6Alkynyl or 3～6 circle heterocycles bases.
3. compound as described in technical scheme 2 or its stereoisomer or its pharmaceutically acceptable salt, ester or molten Agent compound, wherein,
R1Selected from hydrogen, hydroxyl, cyano group, halogen atom or C1-4Alkyl；
R2Selected from hydrogen or C1-4Alkyl；
R3Selected from hydrogen, hydroxyl, C1-4Alkyl, C1-4Alkoxyl, halo C1-4Alkoxyl, C1-4Alkoxy C1-4Alkoxyl or hydroxyl Base C1-4Alkoxyl；
R4Selected from hydrogen or C1-4Alkyl；
R5Selected from hydrogen or C1-4Alkyl；
A rings form the circle heterocycles base of benzo 4～7 together with the phenyl ring being attached thereto, and 4～7 described circle heterocycles bases can optionally by 1 ～2 q1Replace, wherein q1Selected from C1-4Alkoxyl, C1-4Alkyl amino, C1-4Alkoxy C1-4Alkyl or C1-4Alkyl-carbonyl.
4. compound as described in technical scheme 3 or its stereoisomer or its pharmaceutically acceptable salt, ester or molten Agent compound, wherein,
R1Selected from halogen atom；
R2Selected from hydrogen or C1-4Alkyl；
R3Selected from C1-4Alkoxyl；
R4Selected from hydrogen or C1-4Alkyl；
R5Selected from hydrogen or C1-4Alkyl；
A rings form the circle heterocycles base of benzo 5～6 together with the phenyl ring being attached thereto, and 5～6 described circle heterocycles bases can optionally by 1 ～2 q1Replace, wherein q1Selected from C1-4Alkoxy C1-4Alkyl or C1-4Alkyl-carbonyl.
5. compound as described in technical scheme 4 or its stereoisomer or its pharmaceutically acceptable salt, ester or molten Agent compound, wherein,
A rings form the member heterocyclic ring containing nitrogen base of benzo 5～6,5～6 described member heterocyclic ring containing nitrogen bases together with the phenyl ring being attached thereto Can optionally by 1 q1Replace, wherein q1Selected from C1-4Alkoxy C1-4Alkyl or C1-4Alkyl-carbonyl.
6. compound as described in technical scheme 5 or its stereoisomer or its pharmaceutically acceptable salt, ester or molten Agent compound, wherein,
A rings form 5～6 yuan of heterocyclic radicals containing 1～2 nitrogen-atoms of benzo together with the phenyl ring that is attached thereto, and described 5～6 Heterocyclic radical of the unit containing 1～2 nitrogen-atoms can optionally by 1 q1Replace, wherein q1Selected from C1-4Alkoxy C1-4Alkyl or C1-4Alkyl Carbonyl.
7. compound as described in technical scheme 6 or its stereoisomer or its pharmaceutically acceptable salt, ester or molten Agent compound, wherein,
A rings form 5～6 yuan of heterocyclic radicals containing 1 nitrogen-atoms of benzo together with the phenyl ring being attached thereto, and described 5～6 yuan contain The heterocyclic radical of 1 nitrogen-atoms can optionally by 1 q1Replace, wherein q1Selected from C1-4Alkoxy C1-4Alkyl or C1-4Alkyl-carbonyl.
8. compound as described in technical scheme 5 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 scheme 1 or its stereoisomer or its pharmaceutically acceptable salt, ester or molten Agent compound, wherein,
R1Selected from chlorine atom；
R2Selected from hydrogen or C1-6Alkyl；
R3Selected from isopropoxy；
R4Selected from hydrogen or C1-6Alkyl；
R5Selected from hydrogen or C1-6Alkyl；
A rings form the circle heterocycles base of benzo 4～7 together with the phenyl ring being attached thereto.
10. compound as described in technical scheme 1 or its stereoisomer or its pharmaceutically acceptable salt, ester or Solvate, wherein,
A rings form following group together with the phenyl ring being attached thereto：
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 atomic iodine etc..
" C of the present invention1-6Alkyl " represents the alkyl containing 1-6 carbon atom of straight or branched, including for example “C1-4Alkyl ", " C1-3Alkyl " etc., instantiation is included but is 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 invention2-8Thiazolinyl " refers to the straight or branched that the carbon number containing at least one double bond is 2-8 Or the thiazolinyl of ring-type, including such as " C2-6Thiazolinyl ", " C2-4Thiazolinyl ", " C2-3Thiazolinyl ", " C3-6Cycloalkenyl group " etc., instantiation includes But it is not limited to：Vinyl, 1- acrylic, 2- acrylic, 2- cyclobutenyls, 3- cyclobutenyls, 2- methyl-1-propylene bases, 1- methyl -2- Acrylic, 1- pentenyls, 2- pentenyls, 3- pentenyls, 2-methyl-1-butene thiazolinyl, 3-methyl-1-butene base, 2- methyl -3- fourths Thiazolinyl, 1,1- dimethyl -2- acrylic, 1- ethyl -2- acrylic, 2- hexenyls, 3- hexenyls, 2- methyl-1-pentene thiazolinyls, 3- Methyl-1-pentene thiazolinyl, 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 bases, 2,5- heptadiene bases, 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 of the straight or branched that the carbon number containing three keys is 2-8, its Include such as " C2-6Alkynyl ", " C2-4Alkynyl ", " C2-3Alkynyl " etc., instantiation is included but is 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 invention1-6Alkoxyl, 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 Base " text as defined above is described.
" C of the present invention1-4Alkoxyl, 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 Base " text as defined above is described.
" halo C of the present invention1-6Alkyl, hydroxyl C1-6Alkyl, amino C1-6Alkyl, sulfonyl C1-6Alkyl, C1-6Alkane Epoxide C1-6Alkyl, hydroxyl C2-8Thiazolinyl, carboxyl C2-8Thiazolinyl, hydroxyl C2-8Alkynyl, carboxyl C2-8Alkynyl, halo C1-6Alkoxyl, hydroxyl Base C1-6Alkoxyl, C1-6Alkoxy C1-6Alkoxyl, hydroxyl C1-6Alkyl amino " refers to one or more, such as 1～4,1～3 Individual, 1～2 halogen atom, hydroxyl, amino, sulfonyl, carboxyl, C1-6Alkoxyl replaces respectively C1-6Alkyl, C2-8Thiazolinyl, C2-8 Alkynyl, C1-6Alkoxyl, C1-6The group that hydrogen atom in alkyl amino is formed.
" halo C of the present invention1-4Alkyl, hydroxyl C1-4Alkyl, amino C1-4Alkyl, sulfonyl C1-4Alkyl, C1-4Alkane Epoxide C1-4Alkyl, hydroxyl C2-6Thiazolinyl, carboxyl C2-6Thiazolinyl, hydroxyl C2-6Alkynyl, carboxyl C2-6Alkynyl, halo C1-4Alkoxyl, hydroxyl Base C1-4Alkoxyl, C1-4Alkoxy C1-4Alkoxyl, hydroxyl C1-4Alkyl amino " refers to one or more, such as 1～4,1～3 Individual, 1～2 halogen atom, hydroxyl, amino, sulfonyl, carboxyl, C1-4Alkoxyl replaces respectively C1-4Alkyl, C2-6Thiazolinyl, C2-6 Alkynyl, C1-4Alkoxyl, 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.
" C of the present invention1-4Alkyl amino C1-4Alkyl sulphonyl, (C1-4Alkyl)2Amino C1-4Alkyl sulphonyl " is Refer to C1-4Alkyl amino or (C1-4Alkyl)2Amino replaces C1-4The group that hydrogen atom in alkyl sulphonyl is formed.
" 3～8 yuan of cycloalkyl ", the paraffin section for referring to 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 is included but is 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 preferred N, O, S, more preferably N, O.
" 3～8 circle heterocycles base " refer to containing 3～8 annular atoms and containing 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 group that obtains of a hydrogen atom, including such as " 3 ～7 circle heterocycles bases ", " 3～6 circle heterocycles base ", " 4～7 circle heterocycles base ", " 4～6 circle heterocycles base ", " 5～6 circle heterocycles base ", " 5～ 6 member heterocyclic ring containing nitrogen bases ", " 5～6 yuan of heterocyclic radicals containing 1～2 nitrogen-atoms ", " 5～6 yuan of heterocyclic radicals containing 1 nitrogen-atoms " etc.. Instantiation is included but are not limited to：Aziridine base, 2H- aziridine bases, diazacyclo propyl, 3H- diazas Cyclopropanyl, azetidinyl, 1,4- dioxane bases, 1,3- dioxane bases, 1,3- dioxolane Base, 1,4- Dioxin bases, tetrahydrofuran base, pyrrolin base, pyrrolidinyl, imidazolidinyl, 4,5- glyoxalidine Base, pyrazolidinyl, 4,5- pyrazoline bases, 2,5- dihydro-thiophene bases, tetrahydro-thienyl, 4,5- dihydro-thiazolyls, piperidyl, piperazine Piperazine base, morpholinyl, 4,5- dihydro-oxazole bases, 4,5- dihydro-isoxazole bases, 2,3- dihydro-isoxazole bases, 2H-1,2- oxazinyls, 6H-1,3- oxazinyls, 4H-1,3- thiazinyls, 6H-1,3- thiazinyls, 2H- pyranoses, 2H- pyran-2-one bases, 3,4- dihydros- 2H- pyranoses etc..
Present invention also offers three preparation methods of above-claimed cpd, but following methods are not limited only to, reaction equation It is as follows：
Preparation method 1：
Reactions steps：
The preparation of step 1 intermediate 1
Raw material 1 is dissolved in solvent (such as DMF), potassium hydroxide and iodine, stirring (such as 30 is added Minute) after, potassium hydroxide and paratoluensulfonyl chloride are added, (such as 2 hours) are stirred at room temperature, add water and be quenched, during suction filtration is obtained Mesosome 1.
The preparation of step 2 intermediate 2
Intermediate 1 is dissolved in solvent (such as dioxane), adds 4,4,5,5- tetramethyl -1, the boron of 3,2- dioxane penta Alkane and suitable palladium catalyst (such as tetra-triphenylphosphine palladium) add alkali (such as triethylamine), the lower heating (such as 80 of nitrogen protection DEG C) overnight, cool down (such as room temperature), add water and be quenched, organic solvent (such as ethyl acetate) extraction, concentration, purified (such as silicon Plastic column chromatography) obtain intermediate 2.
The preparation of step 3 intermediate 3
Intermediate 2 and raw material 2 are dissolved in into appropriate solvent (such as dioxane and water), suitable palladium catalyst (example is added Such as [1,1'- double (diphenylphosphine) ferrocene] palladium chloride), add appropriate (such as 2.5 equivalents) alkali (such as cesium carbonate), nitrogen The lower heating (such as 80 DEG C) of protection is overnight, cold to go (such as to room temperature) to add water to be quenched, organic solvent (such as ethyl acetate) extraction, Concentration, purified (such as silica gel column chromatography) obtains intermediate 3.
The preparation of step 4 intermediate 5
Intermediate 4 is dissolved in into trifluoroacetic acid, appropriate (such as 1 equivalent) natrium nitrosum is added, is stirred at room temperature that (such as 1 is little When), concentration, purifying obtains intermediate 5.
The preparation of step 5 intermediate 6
Intermediate 5 is dissolved in into suitable solvent (such as ethyl acetate), palladium carbon (10% palladium carbon) is added, hydrogen, room temperature is passed through It is stirred overnight, filters palladium carbon, is concentrated to give intermediate 6.
The preparation of step 6 intermediate 7
Intermediate 6 and intermediate 3 are dissolved in into solvent (such as dioxane), metal palladium catalyst (such as [1,1'- is added Double (diphenylphosphine) ferrocene] palladium chloride), add appropriate (such as 1.5 equivalents) inorganic base (such as cesium carbonate), nitrogen protection Overnight, suction filtration, filtrate is extracted with ethyl acetate lower heating (such as 80 DEG C), and concentration, Jing proper methods (for example prepare efficient liquid phase Chromatography) purifying obtain intermediate 7.
The preparation of the logical formula (I) compound of step 7 present invention
Intermediate 7 is dissolved in into solvent (such as ethanol), adds inorganic base (such as cesium carbonate) to be stirred overnight at room temperature, suction filtration, Filtrate concentrates, and purifying obtains the logical formula (I) compound of the present invention.
Preparation method 2：
The preparation of step 1 intermediate 1
Raw material 1 is dissolved in appropriate solvent, adds appropriate (such as 1 equivalent) sodium hydrogen, low temperature (such as 0 DEG C) to stir (such as 10 points Clock), add R5- X is stirred overnight, and adds water and is quenched, and is extracted with organic solvent (such as ethyl acetate), the organic phase concentration of merging, Purified (silica gel column chromatography) obtains intermediate 1.
The preparation of step 2 intermediate 2
Intermediate 1 is dissolved in into solvent (such as DMF), alkali (such as potassium hydroxide) and iodine, room temperature is added Stirring 3 hours, adds water and is quenched, ethyl acetate extraction, and the organic phase concentration of merging, Jing silica gel column chromatographies purifying obtains intermediate 2.
The preparation of step 3 intermediate 3
Intermediate 2 is dissolved in solvent (such as dioxane) and adds 4,4,5,5- tetramethyl -1,3,2- dioxaborolanes Alkali (such as triethylamine), the lower heating (such as 80 DEG C) of nitrogen protection are added with suitable palladium catalyst (such as tetra-triphenylphosphine palladium) Overnight, cooling adds water and is quenched (such as to room temperature), organic solvent (such as ethyl acetate) extraction, concentration, Jing proper method (examples Such as silica gel column chromatography) purifying obtains intermediate 3.
The preparation of step 4 intermediate 4
Raw material 2 and intermediate 3 are dissolved in into appropriate solvent (such as dioxane and water), suitable palladium catalyst (example is added Such as [1,1'- double (diphenylphosphine) ferrocene] palladium chloride), add alkali (such as 2.5 equivalent of cesium carbonate), the lower heating of nitrogen protection (such as 80 DEG C) overnight, are cooled down (such as to room temperature), are added water and are quenched, and organic solvent (such as ethyl acetate) extraction, concentration, Jing is fitted When method (such as silica gel column chromatography) purifying obtains intermediate 4.
The preparation of step 5 intermediate 5
Raw material 3 is dissolved in into solvent (such as trifluoroacetic acid), appropriate (such as 1 equivalent) natrium nitrosum is added, (example is stirred at room temperature Such as 1 hour), concentration, Jing proper methods (such as silica gel column chromatography) purifying obtains intermediate 5.
The preparation of step 6 intermediate 6
Intermediate 5 is dissolved in into suitable solvent (such as ethyl acetate), 10% palladium carbon is added, hydrogen is passed through, was stirred at room temperature At night, palladium carbon is filtered, be concentrated to give intermediate 6.
The preparation of step 7 intermediate 7
Intermediate 6 is dissolved in into appropriate solvent, alkali (such as sodium hydrogen) is added, R4-X, room temperature or heating stirring is added under room temperature, Add water and reaction is quenched, organic solvent (such as ethyl acetate) extraction, concentration, during Jing proper methods (silica gel column chromatography) purifying is obtained Mesosome 7.
The preparation of the logical formula (I) compound of step 8 present invention
Intermediate 7 and intermediate 4 are dissolved in into solvent (such as dioxane), metal palladium catalyst (such as [1,1'- is added Double (diphenylphosphine) ferrocene] palladium chloride), add appropriate (such as 1.5 equivalents) inorganic base (such as cesium carbonate), nitrogen protection Overnight, suction filtration, filtrate is extracted lower heating (such as 80 DEG C) with organic solvent (such as ethyl acetate), and organic phase Jing of merging is appropriate Method (such as silica gel column chromatography) purifying obtains the logical formula (I) compound of the present invention.
Preparation method 3：
The preparation of step 1 intermediate 1
Raw material 1 is dissolved in into solvent (such as DMF), adds alkali (such as potassium hydroxide) and iodine, room temperature to stir (such as 0.5-3.5 hours) is mixed, is added water and is quenched, ethyl acetate extraction, the organic phase concentration of merging, anhydrous sodium sulfate drying is removed Solvent is gone to obtain intermediate 1.
The preparation of step 2 intermediate 2
Intermediate 2 is dissolved in solvent (such as dichloromethane), adds di-tert-butyl dicarbonate and alkali (such as triethylamine), room temperature Lower stirring (such as 8-16 hours), adds water and is quenched, and organic solvent (such as ethyl acetate) extraction, concentration obtains intermediate 2.
The preparation of step 3 intermediate 3
Triethyl borate is dissolved in into appropriate solvent (such as tetrahydrofuran), -78 DEG C of dropwise addition n-BuLis, stirring (such as 20 - 1 hour minute), the iodo- 1H- indoles -1- formic acid esters of tert-butyl group 3- is added, it is warmed to room temperature, stir (such as 1-3 hours), add water It is quenched, organic solvent (such as ethyl acetate) extraction, concentration obtains intermediate 3.
The preparation of step 4 intermediate 4
Raw material 2 and intermediate 3 are dissolved in into appropriate solvent (such as dioxane and water), suitable palladium catalyst (example is added Such as [1,1'- double (diphenylphosphine) ferrocene] palladium chloride), add alkali (such as 1-3.5 equivalent of cesium carbonate), nitrogen protection it is lower plus Hot (such as 80 DEG C -95 DEG C) overnight, are cooled down (such as to room temperature), are added water and are quenched, organic solvent (such as ethyl acetate) extraction, dense Contracting, Jing proper methods (such as silica gel column chromatography) purifying obtains intermediate 4.
The preparation of step 5 intermediate 5
Raw material 3 is dissolved in into solvent (such as dichloromethane), appropriate (such as 1-2 equivalents) acetic anhydride is added, (example is stirred at room temperature Such as 1-3 hours), add water and be quenched, organic solvent (such as dichloromethane) extraction, concentration, Jing proper methods (such as silica gel column layer Analysis) purifying obtain intermediate 5.
The preparation of step 6 intermediate 6
Intermediate 5 is dissolved in into suitable solvent (such as second alcohol and water), aqueous ammonium chloride solution and zinc powder, 70 DEG C of reactions are added (such as 2-4 hours), room temperature is filtered, and is added water and is quenched, organic solvent (such as ethyl acetate) extraction, concentration, Jing proper method (examples Such as silica gel column chromatography) purifying obtains intermediate 6.
The preparation of the logical formula (I) compound of step 7 present invention
Intermediate 6 and intermediate 4 are dissolved in into solvent (such as sec-amyl alcohol), p-methyl benzenesulfonic acid, the lower heating of nitrogen protection is added (such as 80 DEG C -120 DEG C) overnight, suction filtration, filtrate is extracted with organic solvent (such as ethyl acetate), and organic phase Jing of merging is appropriate Method (such as silica gel column chromatography) purifying obtains the logical formula (I) compound of the present invention.
In reaction equation, R1、R2、R3、R4、R5With A rings as defined hereinabove, X represents fluorine atom, chlorine atom, bromine atoms And atomic iodine.
" stereoisomer " of formula (I) compound of the present invention referred to when formula (I) compound has asymmetric carbon atom, meeting Enantiomter is produced, when compound has carbon-carbon double bond or circulus, cis-trans-isomer can be produced, when compound is present When ketone or oxime, dynamic isomer, enantiomter, diastereoisomer, the racemization isomery of all formula (I) compounds can be produced Body, cis-trans-isomer, dynamic isomer, geometric isomer, epimer and its mixture, are included in the scope of the invention In.
If the raceme that the arbitrary compound synthesis shown in the logical formula (I) of the present invention are obtained, required enantiomer-pure Compound can be obtained by the method for chiral resolution：Can (image height be suppressed standby by chromatography with chiral stationary phase Liquid chromatogram, supercritical fluid chromatography).Chirality padding is included but is not limited to：Chiralcel OJ-H, Chiralpak AD-H, Chiralpak IA, Chiralpak AS-H.
The present invention logical formula (I) shown in arbitrary 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, ethyl sulfonic 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, butanedioic 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, and being substituted amine includes that naturally occurring replacement amine, cyclammonium and basic ion are exchanged Resin, selected from glycine betaine, caffeine, choline, N, N '-dibenzyl-ethylenediamin, diethylamine, 2- Diethylaminoethanols, 2- dimethylamine Base ethanol, monoethanolamine, 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..
" ester " of formula (I) compound of the present invention is referred to, when formula (I) compound has carboxyl, can be esterified with alcohol The ester for reacting and being formed, when formula (I) compound has hydroxyl, can occur esterification anti-with organic acid, inorganic acid, acylate etc. The ester answered and formed.Ester can occur hydrolysis and generate corresponding acid or alcohol under conditions of acid or alkali are present.
Compound, its pharmaceutically acceptable salt, its stereoisomer or its ester shown in formula (I) can be solvation Thing form.If in the case that solvate is hydrate, aquation can complete in preparation process or can be using original The hygroscopicity without aquatic products that begins gradually is carried out.
Further requirement of the present invention protection includes arbitrary compound shown in above-mentioned formula (I), its is pharmaceutically acceptable Salt, its stereoisomer, the pharmaceutical composition of its ester or its solvate and one or more pharmaceutical carrier and/or diluent, Pharmaceutically acceptable arbitrary formulation can be made.Being applied in modes such as oral, parenteral, rectum or transpulmonary administrations needs this The patient for planting treatment.During for being administered orally, conventional solid pharmaceutical preparation, such as tablet, capsule, pill, granule are can be made into； May be made as oral liquid, such as oral solution, oral suspensions, syrup.When making oral formulations, can add Suitable filler, adhesive, disintegrant, lubricant etc..During for parenteral, injection is can be made into, including parenteral solution, Injection sterile powder and concentrated solution for injection.When making injection, the conventional method production in existing pharmaceutical field can be adopted, When preparing injection, additives can be added without, also dependent on the property of medicine suitable additives are added.For rectally When, can be made into suppository etc..During for transpulmonary administration, inhalant or spray etc. are can be made into.
Further requirement of the present invention protection include the arbitrary compound of formula recited above (I), its pharmaceutically acceptable salt, The drug regimen of its stereoisomer, its ester or its solvate and other one or more antitumor agents and immunodepressant Thing.Described antitumor agent and immunodepressant, including but not limited to methotrexate (MTX), capecitabine, gemcitabine, deoxygenate fluorine urine Glycosides, pemetrexed disodium, pazopanib, Imatinib, Erlotinib, Lapatinib, Gefitinib, ZD6474, Trastuzumab, Bevacizumab, Rituximab, Herceptin, taxol, vinorelbine, docetaxel, Doxorubicin, HCPT, Mitomycin, epirubicin, THP, bleomycin, Letrozole, tamoxifen, fulvestrant, music score of Chinese operas Rayleigh, Flutamide, Leuprorelin, Anastrozole, ifosfamide, busulfan, endoxan, BCNU, Nimustine, Semustine, mustargen, Melphalan, chlorambucil, carboplatin, cis-platinum, oxaliplatin, network platinum, Topotecan, camptothecine, TPT, everolimus, western sieve Mo Si, special cancer are suitable, Ismipur, 6- thioguanines, imuran, rhzomorph D, daunorubicin, adriamycin, mitoxantrone, strive Light mycin, plicamycin or aminoglutethimide.
Present invention also offers compound, its pharmaceutically acceptable salt, its alloisomerism shown in formula (I) of the present invention The application of body, its ester or its solvate in the medicine of the cancer-related diseases for preparing treatment and/or preventing ALK to mediate, institute State the related disease of cancer and be selected from brain tumor, lung cancer in non-cellule type, dermoid cancer, carcinoma of urinary bladder, cancer of the stomach, 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, ED-SCLC, gastrointestinal stromal tumor, tumor of prostate, mast cell tumor, Huppert's disease, melanoma or god Jing gliomas.
The compounds of this invention has advantages below：
(1) formula (I) compound of the present invention or its stereoisomer or its pharmaceutically acceptable salt, ester or solvation Thing has excellent ALK inhibitory activity；
(2) formula (I) compound of the present invention or its stereoisomer or its pharmaceutically acceptable salt, ester or solvation Thing shows good biological stability, acts on more longlasting, and bioavilability is high；
(3) the compounds of this invention preparation process is simple, medicine purity is high, steady quality, it is easy to carry out large-scale industry life Produce.
The compounds of this invention beneficial effect is expanded on further below by way of external zymetology and the experiment of cytology inhibitory activity, but This should not be interpreted as the compounds of this invention and only there is following beneficial effect.
The external zymetology activity experiment of the compounds of this invention of experimental example 1
Test sample：The trifluoroacetate of the compounds of this invention 1, compound 2 and compound 4, its chemical name and preparation side Method is shown in the preparation embodiment of the trifluoroacetate of compound 1, compound 2 and compound 4.
Comparison medicine ceritinib, makes by oneself (preparation of referenced patent WO2008/073687A2 preparation method).
Implication representated by the abbreviation of following middle experiments is as follows：
DMSO：Dimethyl sulfoxide (DMSO)
DTT：Dithiothreitol (DTT)
SEB：Enzyme catalyst cushioning liquid
ATP：Adenosine triphyosphate
ALK：Anaplastic lymphoma kinase
SA-XL665：The donor of marked by streptavidin
2.5 ×, 5 ×, 10 × "×" therein：Times
Experimental technique：
ALK kinase buffer liquids are prepared：
DTT, the 5 × enzyme buffer liquid of SEB, 100mM of MgCl2,2500nM that appropriate mother liquid concentration is 1000mM are taken respectively, In being added to ultra-pure water so that ultimate density is respectively：5mM, 25nM, 1mM, 1 × enzyme buffer liquid, mix, stand-by.
2.5 × need testing solution is prepared：
The 1mM storing solutions of comparison medicine are prepared：Comparison medicine (1.48mg) is weighed, appropriate DMSO dissolvings are added, is mixed, it is standby.
The 1mM storing solutions of compound are prepared：Respectively Weigh Compound is appropriate (concrete sample weighting amount please see the table below), adds appropriate DMSO dissolves, and mixes, standby.
1mM storing solutions are taken respectively, the solution that concentration is 200 μM are made with DMSO dilutions, as mother liquor.Will be above-mentioned with DMSO Mother liquor three times stepwise dilution makes a series of solution of concentration, and then each concentration dilutes 80 times with ALK kinase buffer liquids respectively, Each 2.5 × need testing 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 is prepared respectively with ALK kinase buffer liquids, It is standby.
ALK zymetologys are reacted：
1) it is separately added into 2.5 × need testing solution, 2 μ L that 4 μ L prepare in hole corresponding in 384 orifice plates to prepare 5 × ALK kinase solutions, 25 DEG C are incubated 10 minutes.
2) corresponding Kong Zhongzai is separately added into 5 × substrate solution that 2 μ L prepare and 5 × ATP that 2 μ L are prepared is molten Liquid, starts enzyme reaction, and 25 DEG C are incubated 30 minutes.
Zymetology is detected：
The SA-XL665 of desired concn is prepared with detection buffer solution (detection buffer), then with isopyknic junket Histidine kinase antibody is mixed, and this antibody-solutions that 10 μ L are prepared, terminating reaction are separately added in corresponding hole.25 DEG C of incubations 1h。
ELIASA 665nm/615nm read plates.
IC50：Inhibiting rate (%)=(maximum-sample value)/(maximum-minimum of a value) × 100 are calculated, using Graph Prisim softwares carry out curve fitting, and draw IC50Value.
Maximum：It is not added with the positive control of compound, minimum of a value：Not enzyme-added negative control.
Experimental result and conclusion：
The external zymetology inhibitory activity of the compounds of this invention of table 1.
The external zymetology inhibitory activity of the compounds of this invention of table 2.
The external zymetology inhibitory activity of the compounds of this invention of table 3.
From table 1, table 2 and table 3, the compounds of this invention has good inhibitory activity to ALK kinases, can be used to treat The kinase mediated illness of the disease related to kinases, particularly ALK or the patient's condition, with significant clinical meaning.
The cell in vitro activity experiment of the compounds of this invention of experimental example 2
Test sample：The trifluoroacetate and compound 2 of the compounds of this invention 1, its chemical name and preparation method are shown in chemical combination The trifluoroacetate of thing 1 and the preparation embodiment of compound 2.
Comparison medicine 1Ceritinib, makes by oneself (preparation of referenced patent WO2008/073687A2 preparation method), and its structural formula is such as Described in background technology.
Comparison medicine 2Alectinib, makes by oneself (preparation of referenced patent CN102459172A preparation method), and its structural formula is as carried on the back Described in scape technology.
Implication 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 technique：
(1) NCI-H3122, Karpas-299 cell：
(1) culture medium is prepared：
Hyclone 10mL, penicillin and streptomysin concentration are taken respectively is respectively the mixed of 10000U/mL and 10000mg/mL Close solution 1mL to be added in 89mLRPMI1640 culture mediums, mix.
(2) cell culture：
In 5%CO2, 37 DEG C of conditions incubator in, two cells of NCI-H3122, Karpas-299 are put into T25 blake bottles The middle medium culture cell prepared in " (1) " is to 80% fusion.
(3) inoculating cell：
With trypsin digestion cell, 1000rpm centrifugation 4min, supernatant is removed, be suspended again with new culture medium, adjust cell Density, takes the cell suspension 90 μ L and is inoculated in 96 orifice plates, obtains final cell density and is：NCI-H3122：3000 thin Born of the same parents/hole；Karpas-299：3000 cells/wells；Then in 5%CO2, cultivate 24h in 37 DEG C of incubators.
(4) test sample is added：
(4.1) need testing solution is prepared
The solution of comparison medicine 1：Weigh comparison medicine 3.02mg, add appropriate DMSO dissolvings and made with DMSO gradient dilutions respectively A series of mother liquor (1000 × control drug solns) of concentration, then dilute the mother liquor 100 with culture medium respectively and obtain 10 × control again Drug solns, take respectively the solution 10 μ L, and in being added to the corresponding hole of 96 orifice plates, obtaining control drug solns ultimate density is：10μM、 2.5μM、625nM、156nM、39nM、9.8nM、2.5nM。
The solution of compound 1：The trifluoroacetate 1.99mg of Weigh Compound 1, adds appropriate DMSO dissolvings and uses respectively DMSO gradient dilutions make a series of mother liquor (solution of 1000 × compound 1) of concentration, then with culture medium dilute the mother liquor respectively 100 times obtain the solution of 10 × compound 1, and the solution 10 μ L are taken respectively, in being added to the corresponding hole of 96 orifice plates, obtain compound 1 Solution ultimate density is：10μM、2.5μM、625nM、156nM、39nM、9.8nM、2.5nM.
The solution of compound 2：Weigh Compound 2.32mg, adds appropriate DMSO dissolving and is made with DMSO gradient dilutions respectively A series of mother liquor (solution of 500 × compound 2) of concentration, then dilute the mother liquor 50 with culture medium respectively and obtain 10 × compound again 2 solution, take respectively the solution 10 μ L, and in being added to the corresponding hole of 96 orifice plates, obtaining the solution ultimate density of compound 2 is：10μM、 2.5μM、625nM、156nM、39nM、9.8nM、2.5nM。
(4.2) control wells are arranged：
Vehicle controls：0.1%DMSO.
Blank：Culture medium, instrument zeroing.
(4.3) 96 orifice plates are put into 37 DEG C, 5%CO272h is cultivated in incubator.
(5) detect：
MTS detection methods：
1. by CellTiterThe hole cell proliferation detecting kit room temperature of single solution 96 places 90min.
2. CellTiter is added in each test hole of 96 orifice platesThe mono- μ L of solution reagent 20 of AQueous.
3. 96 orifice plates are put into 5%CO2, cultivate 2h in 37 DEG C of incubators.
4. ELIASA Detection wavelength 490nm is set, result is read.
(6)IC50Calculate：Cell survival rate (%)=(sample value-blank value)/(maximum-blank value) × 100, adopts Carried out curve fitting with Graph prisim softwares, draw IC50Value.
Maximum：It is not added with the cell controls that compound only adds solvent, blank value：Culture medium is compareed.
(2) NCI-H2228 cells：
(1) culture medium is prepared：
Hyclone 10mL, penicillin and streptomysin concentration are taken respectively is respectively the mixed of 10000U/mL and 10000mg/mL Close solution 1mL to be added in 89mLRPMI1640 culture mediums, mix.
(2) cell culture：
In 5%CO2, 37 DEG C of conditions incubator in, NCI-H2228 cells are put in T25 blake bottles and are prepared with " (1) " Good medium culture cell is to 80% fusion.
(3) inoculating cell：
With trypsin digestion cell, 1000rpm centrifugation 4min, supernatant is removed, be suspended again with new culture medium, adjust cell Density 2 × 104Individual/mL, takes the cell suspension 100 μ L and is inoculated in 96 orifice plates, obtains final cell density and is：2000 thin Born of the same parents/hole.
(4) test sample is added：
(4.1) need testing solution is prepared：
The solution of compound 1 is prepared：The trifluoroacetate 2.39mg of Weigh Compound 1, adds appropriate DMSO, dissolving to mix It is even, by solution DMSO gradient dilutions, a series of solution of concentration is obtained, it is standby.
The solution of compound 2 is prepared：Weigh Compound 2.05mg, adds appropriate DMSO, dissolving to mix, by solution DMSO Gradient dilution, obtains a series of solution of concentration, standby.
The solution of comparison medicine 2 is prepared：Comparison medicine 3.21mg, 2.11mg is weighed respectively, adds appropriate DMSO, dissolving to mix, will Solution DMSO gradient dilutions, obtain a series of solution of concentration, standby.
The preparation of taxol：Taxol 5mg is taken, appropriate DMSO is added, dissolving is mixed, standby.
After inoculating cell 24h, take 99 μ L complete mediums and be added separately in each hole of 96 orifice plates, then take above-mentioned preparation The μ L of solution 1 of good variable concentrations are added in corresponding hole so that the ultimate density of compound 1 and 2 is：10000nM、 3333.33nM、1111.11nM、370.37nM、123.45nM、41.15nM、13.71nM、4.57nM、1.52nM.Comparison medicine 2 Ultimate density is respectively：9800nM、2450nM、612.5nM、153.1nM、38.28nM、9.57nM、2.39nM、0.60nM、 0.15nM and 10000,2500,625,156.25,39.06,9.76,2.44,0.61nM.The ultimate density of taxol is 1000n M。
(4.2) control wells are arranged：
Vehicle controls：0.5%DMSO.
Blank：Culture medium, instrument zeroing.
Taxol control：Add the cell controls of 1000nM taxols.
(4.3) this 96 orifice plate is put into 5%CO2, 37 DEG C of conditions incubator in cultivate 96h.
(5) detect：
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 each test hole of 96 orifice platesThe μ L of reagent 60.
3. 96 orifice plates mix 2min with the vibration of micropore plate oscillator lucifuge, make cell lysis.
4. 96 orifice plate lucifuges are incubated at room temperature into 10min, the optical signal value for making generation is stablized.
5. ELIASA reads result under luminescence patterns.
(6) result treatment：
IC50Computing formula one (compound 1)：Cell inhibitory rate (%)=(ODSolvent- ODCompound)/(ODSolvent- ODlow)× 100, carried out curve fitting using Graph prisim softwares, draw IC50Value.
IC50Computing formula two (compound 2)：Cell inhibitory rate (%)=(ODSolvent-ODCompound)/(ODSolvent-ODIt is blank) × 100, Carried out curve fitting using Graph prisim softwares, draw IC50Value.
ODSolvent：It is not added with the Vehicle controls that compound only adds solvent, ODlow：The cell controls of 1000nM taxols are added, ODIt is blank：Only add the blank of culture medium.
Experimental result and conclusion：
The cell inhibitory activity of the compounds of this invention of table 4.
The cell inhibitory activity of the compounds of this invention of table 5.
The cell inhibitory activity of the compounds of this invention of table 6.
From table 4, table 5 and table 6, the compounds of this invention is to cell NCI-H3122, Karpas-299 and NCI-H2228 Good inhibitory activity is respectively provided with, can be used to treat the kinase mediated illnesss of ALK or the patient's condition, with significant clinical meaning.
Specific embodiment
By the following examples the specific embodiment of form, makees further specifically to the above of the present invention It is bright.But this scope for being interpreted as above-mentioned theme of the invention should not be only limitted to following examples.It is all based on the above of the present invention The technology realized belongs to the scope of the present invention.
It is defined as follows representated by following abbreviations：
DMF：N,N-dimethylformamide
Pd(dppf)Cl2：[double (diphenylphosphine) ferrocene of 1,1'-] palladium chloride
TEA：Triethylamine
TFA：Trifluoroacetic acid
The N- of embodiment 1 (the chloro- 4- of 5- (1H- indol-3-yls) pyrimidine -2-base) -6- isopropoxy isoindoline -5- amine (is changed Compound 1) trifluoroacetate preparation
(1) preparation of the iodo- 1- p-toluenesulfonyls -1H- indoles of 3-
1H- indoles (13g, 110.97mmol) is dissolved in DMF (400mL), under nitrogen protection potassium hydroxide is dividedly in some parts I is added under (18.2g, 324.39mmol), room temperature2(28g, 110.32mmol), stirs 30 minutes, and hydrogen-oxygen is then dividedly in some parts again Change potassium (18.2g, 324.39mmol), then be dividedly in some parts 4- methylbenzenes -1- sulfonic acid chlorides (44.5g, 233.42mmol), mixture room Temperature stirring 3 hours, adds water (400mL) that reaction is quenched, and solid suction filtration, filter cake water (150mL) and n-hexane (100mL) are washed Wash, filtration cakes torrefaction, obtain product (33g, yield 75%).
(2) 3- (4,4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- bases) -1- p-toluenesulfonyl -1H- Yin The preparation of diindyl
By the iodo- 1- p-toluenesulfonyls -1H- indoles (11.8g, 29.71mmol) of 3-, 4,4,5,5- tetramethyl -1,3,2- Dioxaborolanes (5.7g, 44.54mmol), 1,4- dioxane (250mL), tetrakis triphenylphosphine palladium (3.5g, In 3.03mmol) being added to there-necked flask with triethylamine (7.6g, 75.11mmol), lower 80 DEG C of nitrogen protection is reacted 2 hours, is cooled to Room temperature, reactant liquor is diluted with water (500mL), then is extracted with ethyl acetate (3 × 200mL), takes organic layer, uses saturated sodium-chloride water Solution washs (3 × 200mL), anhydrous sodium sulfate drying, filters, and is concentrated under reduced pressure to give crude product (10g), is directly used in next step.
(3) preparation of 3- (2,5- dichloro pyrimidine -4- bases) -1- p-toluenesulfonyl -1H- indoles
By 3- (4,4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- bases) -1- p-toluenesulfonyl -1H- indoles Crude product (10g) be dissolved in the mixed solvent (150/50mL) of dioxane and water, add 2,4,5- trichloropyrimidines (5g, 27.26mmol)、Pd(dppf)Cl2(2g, 2.73mmol) and cesium carbonate (20.4g, 62.61mmol), nitrogen protects lower 80 DEG C instead Overnight inoganic solids should be filtered, filtrate adds water (500mL), is extracted with ethyl acetate (3 × 200mL), merge organic phase, used Saturated sodium-chloride water solution washs (3 × 200mL), reduced pressure concentration, silica gel column chromatography purifying (ethyl acetate：Petroleum ether=1:15- 1:3) product (2.6g, 6.22mmol, two-step reaction yield 21%), is obtained.
(4) preparation of 6- nitros isoindoline -5- alcohol
Isoindoline -5- alcohol (800mg, 5.92mmol) is dissolved in into trifluoroacetic acid (200mL), natrium nitrosum is dividedly in some parts (408mg, 5.91mmol), is stirred at room temperature 1 hour, and LC/MS shows that reaction is complete, reduced pressure concentration.Residue with it is pre-prepared efficiently Liquid chromatogram (mobile phase A：H2O(20mM NH4HCO3), Mobile phase B：CH3CN, 5-10%B, 25mL/min) purifying obtain product (200mg, yield 19%).
(5) preparation of tert-butyl group 5- hydroxyls -6- nitros isoindoline -2- formic acid esters
6- nitros isoindoline -5- alcohol (200mg, 1.11mmol) is dissolved in into dichloromethane (20mL), triethylamine is added (167mg, 1.65mmol), room temperature adds stirring 10 minutes, adds di-tert-butyl dicarbonate (242mg, 1.11mmol), room temperature It is stirred overnight, LC/MS shows that reaction is complete, reduced pressure concentration, residue is with pre-prepared high performance liquid chromatography (mobile phase A：H2O (20mM NH4HCO3), Mobile phase B：CH3CN, 5-10%B, 25mL/min) purifying obtain product (130mg, yield 42%).
(6) preparation of tert-butyl group 5- isopropoxies -6- nitros isoindoline -2- formic acid esters
By tert-butyl group 5- hydroxyls -6- nitros isoindoline -2- formic acid esters (130mg, 0.46mmol), DMF (8mL, cesium carbonate During (451mg, 1.38mmol) and 2- iodopropanes (789mg, 4.64mmol) sequentially add reaction bulb, 80 DEG C are stirred overnight, LC/MS Show that reaction is complete, add water and be quenched, ethyl acetate extraction (3 × 20mL) takes organic phase, and with saturated sodium-chloride water solution (3 are washed × 200mL), anhydrous sodium sulfate drying is concentrated under reduced pressure to give product (120mg, yield 80%).
(7) preparation of tert-butyl group 5- amino -6- isopropoxies isoindoline -2- formic acid esters
Ethyl acetate (20mL), palladium carbon (32mg, 10%w/w) are sequentially added into reaction bulb, tert-butyl group 5- isopropyls are added Epoxide -6- nitros isoindoline -2- formic acid esters (120mg, 0.37mmol), N2Displacement three times, hydrogen (3-5atm) is replaced three times, It is stirred overnight at room temperature, LC/MS shows that reaction is complete, and by mixture suction filtration, filtrate reduced in volume obtains product (100mg, yield 91%).
(8) tert-butyl group 5- ((the chloro- 4- of 5- (1- p-toluenesulfonyl -1H- indol-3-yls) pyrimidine -2-base) amino) -6- is different The preparation of propoxyl group isoindoline -2- formic acid esters
Nitrogen protection under, by 3- (2,5- dichloro pyrimidine -4- bases) -1- p-toluenesulfonyl -1H- indoles (143mg, 0.34mmol) it is dissolved in dioxy six with tert-butyl group 5- amino -6- isopropoxies isoindoline -2- formic acid esters (100mg, 0.34mmol) In ring (5mL), cesium carbonate (112mg, 0.34mmol), Pd (dppf) Cl are sequentially added2.CH2Cl2(28mg, 0.03mmol), 80 React at DEG C overnight, LC/MS shows that reaction is complete, cooling, suction filtration, filtrate concentration, residue (is flowed with preparing efficient liquid phase and purify Dynamic phase A：H2O (0.05%TFA), Mobile phase B：CH3CN, 70-92%B, 20mL/min) obtain product (107mg, yield 46%).
(9) tert-butyl group 5- ((the chloro- 4-1H- indol-3-yls of 5-) pyrimidine -2-base) amino) -6- isopropoxy isoindolines - The preparation of 2- formic acid esters
Tert-butyl group 5- ((the chloro- 4- of 5- (1- p-toluenesulfonyl -1H- indol-3-yls) pyrimidine -2-base) amino) -6- is different Propoxyl group isoindoline -2- formic acid esters (105mg, 0.16mmol) is dissolved in ethanol (20mL), add cesium carbonate (157mg, 0.48mmol), it is stirred overnight at room temperature, LC/MS shows that reaction is complete, suction filtration, filtrate low temperature concentration, residue is used and prepares efficient liquid Phase chromatogram (mobile phase A：H2O (0.05%TFA), Mobile phase B：CH3CN, 85-100%B, 25mL/min) purifying obtain product (30mg, yield 36%).
(10) N- (the chloro- 4- of 5- (1H- indol-3-yls) pyrimidine -2-base) -6- isopropoxy isoindoline -5- amine trifluoro second The preparation of hydrochlorate
By tert-butyl group 5- (the chloro- 4- of 5- (1H- indoles -3- pyrimidine -2- amino) -6- isopropoxies-isoindoline -2- formic acid Ester (30mg, 0.06mmol) is dissolved in dichloromethane (20mL), adds trifluoroacetic acid (0.5mL), is stirred overnight at room temperature, reduced pressure concentration Obtain end-product (17.9mg, yield 58%).
Molecular formula：C25H23ClF3N5O3Molecular weight：533.94 LC-MS(m/z)：420[M+H]+
1H-NMR(300MHz,DMSO-d6)δ:11.93 (s, 1H), 8.49-8.45 (m, 2H), 8.37-8.35 (d, 1H, J= 7.2Hz),8.14-8.07(m,2H),7.52-7.49(m,1H),7.24-7.19(m,1H),7.11-7.07(m,2H),4.63- 4.60(m,1H),4.20(s,2H),4.12(s,2H),1.30-1.28(m,6H).
The N- of embodiment 2 (the chloro- 4- of 5- (1H- indol-3-yls) pyrimidine -2-base) -6- isopropoxy -1,2,3,4- tetrahydrochysenes are different The preparation of quinoline -7- amine (compound 2)
(1) preparation of (the 1H)-formic acid esters of tert-butyl group 6- methoxyl groups -3,4- dihydro-isoquinolines -2
By 6- methoxyl groups -1,2,3,4- four hydrogen isoquinoline hydrochloric acid salts (2.0g, 10mmol) and triethylamine (3.03g, 30mmol) it is dissolved in (100mL) in dichloromethane, adds di-tert-butyl dicarbonate (2.62g, 12mmol), reaction 2 is little under room temperature When.Add water (50mL), and point liquid, water extracts (50mL × 2) with dichloromethane, and organic phase merges, and saturated common salt water washing is anhydrous Sodium sulphate is dried, concentrated in vacuo to obtain crude product (3.0g).
(2) preparation of (the 1H)-formic acid esters of tert-butyl group 6- methoxyl groups -7- nitro -3,4- dihydro-isoquinolines -2
(1H)-formic acid esters crude product (3.0g, 10mmol) of tert-butyl group 6- methoxyl group -3,4- dihydro-isoquinolines -2 is dissolved in into second In nitrile (50mL), TFAA (10mL) and potassium nitrate (1.21g, 12mmol) are added under ice bath, are reacted 4 hours under ice bath, Methyl alcohol (20mL) is added, solvent is removed under reduced pressure, water (50mL) and ethyl acetate (100mL) is added, point liquid, water mutually uses ethyl acetate Extraction (100mL), organic phase merges, and saturated common salt water washing, anhydrous sodium sulfate drying is concentrated in vacuo, crude product Jing silica gel column layers Analysis (ethyl acetate/petroleum ether=0～1/8) obtains product (1.2g, yield 39%).
(3) preparation of (the 1H)-formic acid esters of tert-butyl group 6- hydroxyls -7- nitro -3,4- dihydro-isoquinolines -2
By the dissolving of (the 1H)-formic acid esters (1.2g, 3.9mmol) of tert-butyl group 6- methoxyl group -7- nitro -3,4- dihydro-isoquinolines -2 In dichloromethane (50mL), Boron tribromide (1.18g, 4.7mmol) is added under ice bath, reacted 1 hour under ice bath, add methyl alcohol (20mL), remove solvent under reduced pressure, add water (50mL) and ethyl acetate (50mL), point liquid, water is mutually extracted with ethyl acetate (50mL × 2), organic phase merges, and saturated common salt water washing, anhydrous sodium sulfate drying is concentrated in vacuo, crude product Jing silica gel column chromatography (acetic acid Ethyl ester/petroleum ether=0～1/3) obtain product (780mg, yield 68.0%).
(4) preparation of (the 1H)-formic acid esters of tert-butyl group 6- isopropoxies -7- nitro -3,4- dihydro-isoquinolines -2
By the dissolving of (the 1H)-formic acid esters (780mg, 2.65mmol) of tert-butyl group 6- hydroxyl -7- nitro -3,4- dihydro-isoquinolines -2 In DMF (20mL), add Iso-Propyl iodide (676mg, 3.98mmol) and cesium carbonate (1.73g, 5.3mmol), react 16 hours at 70 DEG C.Room temperature is cooled to, water (50mL) is added, (80mL × 2) are extracted with ethyl acetate, is had Machine mutually merges, and saturated common salt water washing, anhydrous sodium sulfate drying is concentrated in vacuo, crude product Jing silica gel column chromatographies (ethyl acetate/stone Oily ether=0～1/7) obtain product (700mg, yield 78.6%).
1H-NMR(400MHz,CDCl3)δ:7.58(s,1H),6.83(s,1H),4.60-4.64(m,1H),4.52(s, 2H), 3.64 (t, J=5.6Hz, 2H), 2.84 (t, J=5.6Hz, 2H), 1.49 (s, 9H), 1.38 (d, J=6.0Hz, 6H).
(5) preparation of (the 1H)-formic acid esters of tert-butyl group 7- amino -6- isopropoxy -3,4- dihydro-isoquinolines -2
By (the 1H)-formic acid esters (700mg, 2.08mmol) of tert-butyl group 6- isopropoxy -7- nitro -3,4- dihydro-isoquinolines -2 It is dissolved in (2/1,60mL) in second alcohol and water, adds saturated aqueous ammonium chloride (10mL) and zinc powder (680mg, 10.4mmol), rises React 3 hours to 70 DEG C.Room temperature is cooled to, is filtered by diatomite, filtrate concentration, add water (50mL), ethyl acetate extraction (100mL × 3), organic phase merges, saturated common salt water washing, anhydrous sodium sulfate drying, concentration, crude product Jing silica gel column chromatography (second Acetoacetic ester/petroleum ether=0～1/4) obtain product (550mg, yield 86%).
(6) preparation of the iodo- 1H- indoles of 3-
Indoles (11.72g, 100mmol) and potassium hydroxide (6.73g, 119.9mmol) are dissolved in into N,N-dimethylformamide (200mL) in, elemental iodine (25.4g, 100mmol) is dissolved in DMF (50mL), in instilling reactant liquor, reaction 1 hour, TLC detections raw material reaction completely, added water, and ethyl acetate extraction merges organic phase, and anhydrous sodium sulfate drying, rotation is steamed Send out removing solvent and obtain product (23.1g, yield 95%).
(7) preparation of the iodo- 1H- indoles -1- formic acid esters of tert-butyl group 3-
The iodo- 1H- indoles (23.1g, 95.05mmol) of 3- are dissolved in dichloromethane (200mL), addition triethylamine (24g, 237.6mmol) with di-tert-butyl dicarbonate (20.75g, 95.07mmol), stir 12 hours under room temperature, TLC detection raw materials disappear Lose.Add water, ethyl acetate extraction, merge organic phase, anhydrous sodium sulfate drying, rotary evaporation remove solvent obtain product (27.7g, Yield 85%).
(8) preparation of (1- (tertbutyloxycarbonyl) -1H- indol-3-yls) boric acid
Triethyl borate (2.92g, 20mmol) is dissolved in tetrahydrofuran (20mL), -78 DEG C are cooled to, normal-butyl is added dropwise Lithium (2.4mol/L, 8.33mL, 20mmol), stirs half an hour, the iodo- 1H- indoles -1- formic acid esters of addition tert-butyl group 3- (3.43g, 10mmol), room temperature is slowly increased to, is stirred 2 hours, TLC detection raw materials disappear.Add water, ethyl acetate extraction merges organic phase, Anhydrous sodium sulfate drying, rotary evaporation removes solvent afforded crude material (2.61g), not purified to be directly used in next step.
(9) preparation of tert-butyl group 3- (2,5- dichloro pyrimidine -4- bases) -1H- indoles -1- formic acid esters
(1- (tertbutyloxycarbonyl) -1H- indol-3-yls) crude boronic acid (2.61g, 10mmol) is dissolved in into dioxane (50mL) in, 2,4,5- trichloropyrimidines (1.83g, 10mmol), 1,1'- double Diphenyl phosphino ferrocene palladium chlorides are added (261mg) with cesium carbonate (9.77g, 30mmol), 90 DEG C of reactions are warming up to overnight.Reaction is finished, and filters off insoluble matter, is added water, second Acetoacetic ester is extracted, and merges organic phase, anhydrous sodium sulfate drying, crude product Jing silica gel column chromatography (petroleum ethers：Ethyl acetate=3:1) it is pure Change to obtain product (2g, yield 55%).
(10) N- (the chloro- 4- of 5- (1H- indol-3-yls) pyrimidine -2-base) -6- isopropoxy -1,2,3,4- tetrahydroisoquinolines - It is prepared by 7- amine
By tert-butyl group 3- (2,5- dichloro pyrimidine -4- bases) -1H- indoles -1- formic acid esters (364mg, 1.0mmol) and the tert-butyl group (the 1H)-formic acid esters (306mg, 1.0mmol) of 7- amino -6- isopropoxy -3,4- dihydro-isoquinolines -2 adds sec-amyl alcohol (30mL) In, add p-methyl benzenesulfonic acid (344mg, 2.0mmol), lower 110 DEG C of nitrogen protection to react 16 hours.Room temperature is cooled to, is concentrated, plus Enter saturated sodium bicarbonate solution (30mL), be extracted with ethyl acetate (50mL × 3), organic phase merges, saturated common salt water washing, nothing Aqueous sodium persulfate is dried, and concentration, crude product Jing silica gel column chromatographies (ethanol/methylene=0～1/10, plus 0.05% ammoniacal liquor) obtain end Product (200mg, yield 46%).
Molecular formula：C24H24ClN5O molecular weight：433.94 LC-MS(m/z)：434.2[M+H]+
1H-NMR(400MHz,DMSO-d6)δ:11.9 (brs, 1H), 8.47 (s, 1H), 8.41 (s, 1H), 8.34 (d, J= 8.0Hz, 1H), 8.00 (s, 1H), 7.75 (s, 1H), 7.48 (d, J=8.4Hz, 1H), 7.18-7.22 (m, 1H), 7.05-7.09 (m, 1H), 6.76 (s, 1H), 4.52-4.58 (m, 1H), 3.71 (s, 2H), 2.92 (t, J=5.6Hz, 2H), 2.65 (t, J= 5.6Hz, 2H), 1.25 (d, J=6.0Hz, 6H).
The 1- of embodiment 3 (7- ((the chloro- 4- of 5- (1H- indol-3-yls) pyrimidine -2-base) amino) -6- isopropoxies -3,4- two Hydrogen isoquinoline -2 (1H)-yl) ethyl ketone (compound 4) preparation
(1) preparation of 1- ((the 1H)-yl of 6- methoxyl group -3,4- dihydro-isoquinolines -2) ethyl ketone
By 6- methoxyl groups -1,2,3,4- four hydrogen isoquinoline hydrochloric acid salts (2.0g, 10mmol) and triethylamine (3.03g, 30mmol) it is dissolved in (100mL) in dichloromethane, adds acetic anhydride (1.53g, 15mmol), reacts 2 hours under room temperature.Add water (50mL) liquid, water, is divided to extract (50mL × 2) with dichloromethane, organic phase merges, saturated common salt water washing, anhydrous sodium sulfate It is dried, it is concentrated in vacuo to obtain crude product (2.2g).
(2) preparation of 1- ((the 1H)-yl of 6- methoxyl group -7- nitro -3,4- dihydro-isoquinolines -2) ethyl ketone
1- ((the 1H)-yl of 6- methoxyl group -3,4- dihydro-isoquinolines -2) ethyl ketone crude product (2.2g, 10mmol) is dissolved in into acetonitrile (50mL) in, TFAA (10mL) and potassium nitrate (1.21g, 12mmol) are added under ice bath, is reacted 4 hours under ice bath, plus Enter methyl alcohol (20mL), remove solvent under reduced pressure, add water (50mL) and ethyl acetate (100mL), point liquid, water is extracted with ethyl acetate Take (100mL × 2), organic phase merges, saturated common salt water washing, anhydrous sodium sulfate drying is concentrated in vacuo, crude product Jing silica gel column layers Analysis (ethyl acetate/petroleum ether=0～1/7) obtains product (1.2g, yield 48%).
(3) preparation of 1- ((the 1H)-yl of 6- hydroxyl -7- nitro -3,4- dihydro-isoquinolines -2) ethyl ketone
1- ((the 1H)-yl of 6- methoxyl group -7- nitro -3,4- dihydro-isoquinolines -2) ethyl ketone (1.2g, 4.8mmol) is dissolved in In dichloromethane (50mL), Boron tribromide (1.33g, 5.3mmol) is added under ice bath, reacted 1 hour under ice bath, add methyl alcohol (20mL), remove solvent under reduced pressure, add water (50mL) and ethyl acetate (100mL), point liquid, water is mutually extracted with ethyl acetate (100mL × 2), organic phase merges, and saturated common salt water washing, anhydrous sodium sulfate drying is concentrated in vacuo, crude product Jing silica gel column chromatographies (ethyl acetate/petroleum ether=0～1/3) obtains product (810mg, yield 71.5%).
(4) preparation of 1- ((the 1H)-yl of 6- isopropoxy -7- nitro -3,4- dihydro-isoquinolines -2) ethyl ketone
1- ((the 1H)-yl of 6- hydroxyl -7- nitro -3,4- dihydro-isoquinolines -2) ethyl ketone (810mg, 3.4mmol) is dissolved in In DMF (20mL), add Iso-Propyl iodide (867mg, 5.1mmol) and cesium carbonate (2.22g, 6.8mmol), react 16 hours at 70 DEG C, add water (50mL), be extracted with ethyl acetate (80mL × 2), organic phase merges, satisfy And brine It, anhydrous sodium sulfate drying is concentrated in vacuo, crude product Jing silica gel column chromatographies (ethyl acetate/petroleum ether=0～1/ 6) product (760mg, yield 80%) is obtained.
(5) preparation of 1- ((the 1H)-yl of 7- amino -6- isopropoxy -3,4- dihydro-isoquinolines -2) ethyl ketone
1- ((the 1H)-yl of 6- isopropoxy -7- nitro -3,4- dihydro-isoquinolines -2) ethyl ketone (760mg, 2.7mmol) is molten In second alcohol and water (2/1,60mL), saturated aqueous ammonium chloride (10mL) and zinc powder (883mg, 13.5mmol) are added, risen to 70 DEG C are reacted 3 hours.Room temperature is cooled to, is filtered by diatomite, filtrate concentration, add water (50mL), ethyl acetate extraction (100mL × 3), organic phase merges, saturated common salt water washing, anhydrous sodium sulfate drying, concentration, crude product Jing silica gel column chromatography (second Acetoacetic ester/petroleum ether=0～1/4) obtain product (500mg, yield 74.6%).
(6) (7- ((the chloro- 4- of 5- (1H- indol-3-yls) pyrimidine -2-base) amino) -6- isopropoxy -3,4- dihydros are different for 1- Quinoline -2 (1H)-yl) ethyl ketone preparation
By tert-butyl group 3- (2,5- dichloro pyrimidine -4- bases) -1H- indoles -1- formic acid esters (preparation method is shown in embodiment 2, (6)～(9) step, 250mg, 0.69mmol) and 1- (7- amino -6- isopropoxy -3,4- dihydro-isoquinolines -2 (1H)-yl) ethyl ketone (171mg, 0.69mmol) is added in sec-amyl alcohol (30mL), p-methyl benzenesulfonic acid (238mg, 1.38mmol) is added, under nitrogen protection 110 DEG C are reacted 16 hours.Room temperature is cooled to, is concentrated, add saturated sodium bicarbonate solution (30mL), be extracted with ethyl acetate (50mL × 3), organic phase merges, saturated common salt water washing, anhydrous sodium sulfate drying, concentration, crude product Jing silica gel column chromatography (first Alcohol/dichloromethane=0～1/10) obtain end-product (100mg, yield 30.5%).
Molecular formula：C26H26ClN5O2Molecular weight：475.98 LC-MS(m/z)：476.2[M+H]+
1H-NMR(400MHz,CDCl3)δ:8.69(s,1H),8.55-8.59(m,1H),8.43-8.45(m,1H),8.38- 8.40(m,1H),8.33-8.35(m,1H),7.76-7.79(m,1H),7.45-7.50(m,1H),7.30-7.33(m,1H), 6.68-6.70(m,1H),4.60-4.65(m,2H),4.47(s,1H),3.67-3.84(m,2H),2.78-2.88(m,2H), 2.05-2.18(m,3H),1.41-1.46(m,6H)。

Claims (7)

1. the compound or its pharmaceutically acceptable salt shown in formula (I)：
Wherein,
R1Selected from halogen atom；
R2Selected from hydrogen or C1-4Alkyl；
R3Selected from C1-4Alkoxyl；
R4Selected from hydrogen or C1-4Alkyl；
R5Selected from hydrogen or C1-4Alkyl；
A rings form the member heterocyclic ring containing nitrogen base of benzo 5～6,5～6 described member heterocyclic ring containing nitrogen Ji Keren together with the phenyl ring being attached thereto Choosing is by 1～2 q1Replace, wherein q1Selected from C1-4Alkyl-carbonyl.
2. compound as claimed in claim 1 or its pharmaceutically acceptable salt：
Wherein,
A rings form 5～6 yuan of heterocyclic radicals containing 1～2 nitrogen-atoms of benzo together with the phenyl ring being attached thereto, and described 5～6 yuan contain 1 The heterocyclic radical of～2 nitrogen-atoms can optionally by 1 q1Replace, wherein q1Selected from C1-4Alkyl-carbonyl.
3. compound as claimed in claim 2 or its pharmaceutically acceptable salt：
Wherein,
A rings form following group together with the phenyl ring being attached thereto：
4. compound as claimed in claim 1 or its pharmaceutically acceptable salt, the compound is selected from：
5. compound as described in claim 1-4 any claim or its pharmaceutically acceptable salt and one or more The pharmaceutical composition of pharmaceutical carrier, can make pharmaceutically acceptable arbitrary formulation.
6. pharmaceutical composition as claimed in claim 5, it is characterised in that can also be containing one or more antitumor agent and immunity Inhibitor, described antitumor agent and immunodepressant is selected from methotrexate (MTX), capecitabine, gemcitabine, doxifluridine, training U.S. bent plug disodium, pazopanib, Imatinib, Erlotinib, Lapatinib, Gefitinib, ZD6474, Trastuzumab, shellfish are cut down Monoclonal antibody, Rituximab, Herceptin, taxol, vinorelbine, docetaxel, Doxorubicin, HCPT, mitogen Mycin, epirubicin, THP, bleomycin, Letrozole, tamoxifen, fulvestrant, music score of Chinese operas Rayleigh, Flutamide, bright third Rayleigh, Anastrozole, ifosfamide, busulfan, endoxan, BCNU, Nimustine, Semustine, mustargen, Ma Fa Orchid, chlorambucil, carboplatin, cis-platinum, oxaliplatin, network platinum, Topotecan, camptothecine, TPT, everolimus, Sirolimus, Special cancer is suitable, Ismipur, 6- thioguanines, imuran, rhzomorph D, daunorubicin, adriamycin, mitoxantrone, win honour for it is mould Element, plicamycin or aminoglutethimide.
7. compound or its pharmaceutically acceptable salt as described in claim 1-4 any claim is being prepared for controlling Treat and/or prevent the proliferative disease of ALK mediations or the application in the medicine of cancer-related diseases, the related disease of the cancer Selected from brain tumor, lung cancer in non-cellule type, dermoid cancer, carcinoma of urinary bladder, cancer of the stomach, oophoroma, peritoneal cancer, cancer of pancreas, mammary gland Cancer, head and neck cancer, cervix cancer, carcinoma of endometrium, the carcinoma of the rectum, liver cancer, hepatoblastoma, papillary renal cell knurl, incidence squama Shape 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, colon cancer, carcinoma of testis, ED-SCLC, stomach and intestine Road mesenchymoma, tumor of prostate, mast cell tumor, Huppert's disease, melanoma or glioma.
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