CN106188029B - Two and ring class anaplastic lymphoma kinase inhibitor - Google Patents

Two and ring class anaplastic lymphoma kinase inhibitor Download PDF

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CN106188029B
CN106188029B CN201510224442.9A CN201510224442A CN106188029B CN 106188029 B CN106188029 B CN 106188029B CN 201510224442 A CN201510224442 A CN 201510224442A CN 106188029 B CN106188029 B CN 106188029B
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CN106188029A (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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Abstract

The invention belongs to pharmaceutical technology fields, and in particular to two and ring class anaplastic lymphoma kinase inhibitor, its pharmaceutically acceptable salt, ester, solvate or its stereoisomer shown in general formula (I), wherein R1、R2、R3、R4、R5, n, X and Y be defined as in the description.The invention further relates to the preparation methods of these compounds, the application of pharmaceutical preparation and pharmaceutical composition and the compound, its pharmaceutically acceptable salt, ester, solvate or its stereoisomer containing these compounds in preparing treatment and/or preventing the drug of the cancer-related diseases mediated by anaplastic lymphoma kinase.

Description

Two and ring class anaplastic lymphoma kinase inhibitor
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to two and ring class anaplastic lymphoma kinase inhibitor, its pharmacy Upper acceptable salt, ester, solvate or its stereoisomer, the preparation method of these compounds contain these compounds Pharmaceutical preparation and pharmaceutical composition and the compound, its pharmaceutically acceptable salt, ester, solvate or its alloisomerism Application of the body in preparing treatment and/or preventing the drug of the cancer-related diseases mediated by anaplastic lymphoma kinase.
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, and cell metabolism and growth are adjusted.Between become Property lymphom kinase is found in primary cutaneous type (Anaplastic large cell lymphoma, ALCL) earliest In, found also there is high expression in non-small cell lung cancer (NSCLC) later.Unconventionality expressions of the ALK in certain ALCL/NSCLC From different chromosome translocations.These chromosome translocations can generate corresponding fusion protein.To these fusions point Analysis shows that they all contain the gene order in the end of ALK gene 3 ' coding intracellular kinase area, and the genetic fragment merged with ALK is equal The sequence that itself dimerization is mediated containing promoter element and coding, so as to cause the intracellular fusion egg with ALK kinase activity White high expression and excessive activation, cause the vicious transformation of cell.So the active and corresponding signal in ALK intracellular kinases area passes The approach of leading is the important molecule mechanism for causing ALCL to be formed.
Therefore, research and development can effectively reduce the ALK gene of mutation to downstream albumen for the micromolecular inhibitor of ALK Influence, and then influence the effects such as tumor cell invasion, proliferation, the final growth for influencing tumour cell is played antitumor Effect.There is gram azoles of Pfizer successfully to be listed for Buddhist nun (Crizotinib) at present, but has had an a large amount of clinical proof generation ALK inhibitor C rizotinib, easy to produce drug resistance, therefore, design and screen to the active little molecules in inhibiting of ALK mutation Agent and the physicochemical property for making great efforts to improve compound improve druggability (bioavilability as improved compound), have significant Clinical meaning.
Invention content
The present invention has been invented and has been mediated to treating and/or preventing ALK to develop the micromolecular inhibitor for being directed to ALK as target Cancer-related diseases have good result two and ring class anaplastic lymphoma kinase inhibitor.Specific technical solution is such as Under：
General formula 1. (I) compound represented, its pharmaceutically acceptable salt, ester, solvate or its stereoisomer：
Wherein,
R1Selected from hydrogen atom, hydroxyl, amino, cyano, nitro, carboxyl, halogen atom, C1-6Alkyl, hydroxyl C1-6Alkyl, halogen For C1-6Alkyl, C1-6Alkoxy, hydroxyl C1-6Alkoxy, halogenated C1-6Alkoxy, C2-8Alkenyl, C2-8Alkynyl, C1-6Alkyl amino or (C1-6Alkyl)2Amino；
R2、R4、R5Separately it is selected from hydrogen atom, halogen atom, nitro, cyano, amino, hydroxyl, carboxyl, C1-6Alkane Base, hydroxyl C1-6Alkyl, halogenated C1-6Alkyl, amino C1-6Alkyl, sulfonyl C1-6Alkyl, C1-6Alkoxy, hydroxyl C1-6Alkoxy, Halogenated C1-6Alkoxy, C2-8Alkenyl, C2-8Alkynyl, C1-6Alkyl sulfenyl, C1-6Alkyl-carbonyl, C1-6Alkyl carbonyl epoxide, C1-6Alkyl Sulfonamido, C1-6Alkyl amino sulfonyl, (C1-6Alkyl)2Amino-sulfonyl or C1-6Alkyl sulphonyl；
R3Selected from optionally by W 5~14 unit's heteroaryls replaced or 3~8 circle heterocyclic ring bases；
Or R2And R33~8 yuan of naphthenic base optionally replaced by W, 3~8 circle heterocyclic ring bases or 5 are formed together with the carbon being attached thereto ~14 unit's heteroaryls；
Or R4And R56~8 yuan of aryl optionally replaced by W, 5~8 unit's heteroaryls or 3~8 are formed together with the carbon being attached thereto Circle heterocyclic ring base；
X, Y is separately selected from-CO- ,-CO2,-SO- ,-SO2, optionally by the W alkylidenes replaced or imino group；
N is selected from 0,1,2 or 3；
W is selected from hydroxyl, halogen atom, amino, nitro, cyano, carboxyl, C1-6Alkyl, C1-6Alkoxy, halogenated C1-6Alkyl, Halogenated C1-6Alkoxy, C1-6Alkyl amino, (C1-6Alkyl)2Amino, C1-6Alkyl-carbonyl, C1-6Alkyl carbonyl epoxide, C1-6Alkyl Sulfonyl, C1-6Alkyl sulfonyl amino, C1-6Alkoxy C1-6Alkyl, hydroxyl C1-6Alkyl amino, hydroxyl C1-6Alkoxy, amino sulphur Acyl group, aminosulfonyl amino, amino-sulfonyl C1-6Alkyl, aminosulfonyl amino C1-6Alkyl, 5~6 unit's heteroaryls, 5~6 yuan it is miscellaneous Ring group or 3~8 yuan of naphthenic base.
2. compound as described in technical solution 1, its pharmaceutically acceptable salt, ester, solvate or its alloisomerism Body, wherein
R1Selected from hydrogen atom, halogen atom, nitro, cyano, amino, hydroxyl, carboxyl, C1-6Alkyl, hydroxyl C1-6Alkyl or Halogenated C1-6Alkyl；
R2、R4、R5Separately it is selected from hydrogen atom, halogen atom, nitro, cyano, amino, hydroxyl, carboxyl, C1-6Alkane Base, hydroxyl C1-6Alkyl, halogenated C1-6Alkyl, amino C1-6Alkyl, C1-6Alkoxy, hydroxyl C1-6Alkoxy or halogenated C1-6Alcoxyl Base；
R3Selected from optionally by W 5~8 unit's heteroaryls replaced or 4~6 circle heterocyclic ring bases；
Or R2And R3It is formed optionally by W 5~8 unit's heteroaryls replaced or 4~6 circle heterocyclic ring bases together with the carbon being attached thereto；
Or R4And R5It is formed optionally by W 5~6 unit's heteroaryls replaced or 4~6 circle heterocyclic ring bases together with the carbon being attached thereto；
X, Y is separately selected from-CO- ,-CO2,-SO- ,-SO2, the C that is optionally replaced by W1-6Alkylidene or imino group；
N is selected from 0 or 1；
W is selected from hydroxyl, halogen atom, amino, nitro, carboxyl, cyano, C1-6Alkyl, C1-6Alkoxy, halogenated C1-6Alkyl, Halogenated C1-6Alkoxy or C1-6Alkyl amino.
3. compound as described in technical solution 2, its pharmaceutically acceptable salt, ester, solvate or its alloisomerism Body, wherein
R1Selected from hydrogen atom, halogen atom, nitro, cyano, amino, hydroxyl, carboxyl or C1-6Alkyl；
R2、R4、R5Separately it is selected from hydrogen atom, halogen atom, nitro, cyano, amino, hydroxyl, carboxyl, C1-6Alkane Base, hydroxyl C1-6Alkyl, halogenated C1-6Alkyl, amino C1-6Alkyl, C1-6Alkoxy, hydroxyl C1-6Alkoxy or halogenated C1-6Alcoxyl Base；
R3Selected from 5~6 unit's heteroaryls or 5~6 circle heterocyclic ring bases containing 1~2 N atom optionally replaced by W；
Or R2And R35~6 circle heterocyclic ring bases containing 1~2 N atom optionally replaced by W are formed together with the carbon being attached thereto；
Or R4And R5It is miscellaneous that 5~6 yuan containing 1~2 O and/or S atom optionally replaced by W are formed together with the carbon being attached thereto Ring group；
X, Y is separately selected from-SO- ,-SO2, the C that is optionally replaced by W1-6Alkylidene or imino group；
N is selected from 0 or 1；
W is selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atom, C1-6Alkyl, C1-6Alkoxy or C1-6Alkyl ammonia Base.
4. compound as described in technical solution 3, its pharmaceutically acceptable salt, ester, solvate or its alloisomerism Body, wherein
X, Y is separately selected from-SO2Or the C optionally replaced by W1-6Alkylidene, wherein X, Y cannot be to be taken by W simultaneously The C in generation1-6Alkylidene.
5. compound as described in technical solution 3, its pharmaceutically acceptable salt, ester, solvate or its alloisomerism Body, wherein
R1Selected from hydrogen atom, halogen atom, nitro, cyano, amino, hydroxyl, carboxyl or C1-4Alkyl；
R2、R4、R5Separately it is selected from hydrogen atom, halogen atom, C1-4Alkyl, hydroxyl C1-4Alkyl, amino C1-4Alkyl, Halogenated C1-4Alkyl, C1-4Alkoxy, halogenated C1-4Alkoxy or hydroxyl C1-4Alkoxy；
R3Selected from optionally replaced by W pyridyl group, dihydropyridine base, tetrahydro pyridyl, pyrrole radicals, pyrrolin base, four Hydrogen pyrrole radicals, piperidyl, piperazinyl or morpholinyl；
X, Y is separately selected from-SO2Or the C optionally replaced by W1-4Alkylidene；
N is selected from 0 or 1；
W is selected from hydroxyl, halogen atom, amino, nitro or C1-4Alkyl.
6. compound as described in technical solution 3, its pharmaceutically acceptable salt, ester, solvate or its alloisomerism Body, wherein
R1Selected from hydrogen atom, halogen atom, nitro, cyano, amino, hydroxyl, carboxyl or C1-4Alkyl；
R2And R35~6 circle heterocyclic ring bases containing 1~2 N atom optionally replaced by W are formed together with the carbon being attached thereto；
R4、R5Separately it is selected from hydrogen atom, C1-4Alkyl or C1-4Alkoxy；
X, Y is separately selected from-SO2Or the C optionally replaced by W1-4Alkylidene；
N is selected from 0 or 1；
W is selected from hydroxyl, halogen atom, amino, nitro or C1-4Alkyl.
7. compound as described in technical solution 6, its pharmaceutically acceptable salt, ester, solvate or its alloisomerism Body, wherein
R2And R3The 6 circle heterocyclic ring bases containing 1~2 N atom optionally replaced by W are formed together with the carbon being attached thereto；
W is selected from hydroxyl, halogen atom, amino, nitro or C1-4Alkyl.
8. compound as described in technical solution 6, its pharmaceutically acceptable salt, ester, solvate or its alloisomerism Body, wherein
R2And R35~6 circle heterocyclic ring bases containing 1 N atom optionally replaced by W are formed together with the carbon being attached thereto；
W is selected from hydroxyl, halogen atom, amino, nitro or C1-4Alkyl.
9. compound as described in technical solution 3, its pharmaceutically acceptable salt, ester, solvate or its alloisomerism Body, wherein
R1Selected from hydrogen atom, halogen atom, nitro, cyano, amino, hydroxyl, carboxyl or C1-4Alkyl；
R2Selected from hydrogen atom, halogen atom, C1-4Alkyl, hydroxyl C1-4Alkyl, amino C1-4Alkyl, C1-4Alkoxy or hydroxyl C1-4Alkoxy；
R3Selected from optionally replaced by W pyridyl group, dihydropyridine base, tetrahydro pyridyl, pyrrole radicals, pyrrolin base, four Hydrogen pyrrole radicals, piperidyl, piperazinyl or morpholinyl；
R4And R5It is miscellaneous that 5~6 yuan containing 1~2 O and/or S atom optionally replaced by W are formed together with the carbon being attached thereto Ring group；
X, Y is separately selected from-SO2Or the C optionally replaced by W1-4Alkylidene；
N is selected from 0 or 1；
W is selected from hydroxyl, halogen atom, amino, nitro or C1-4Alkyl.
10. compound as described in technical solution 9, its pharmaceutically acceptable salt, ester, solvate or its alloisomerism Body, wherein
R4And R56 circle heterocyclic rings containing 1~2 O and/or S atom optionally replaced by W are formed together with the carbon being attached thereto Base；
W is selected from hydroxyl, halogen atom, amino, nitro or C1-4Alkyl.
11. compound as described in technical solution 10, its pharmaceutically acceptable salt, ester, solvate or its solid are different Structure body, wherein
R4And R55~6 circle heterocyclic rings containing 2 O and/or S atom optionally replaced by W are formed together with the carbon being attached thereto Base；
W is selected from hydroxyl, halogen atom, amino, nitro or C1-4Alkyl.
12. compound as described in technical solution 2, its pharmaceutically acceptable salt, ester, solvate or its alloisomerism Body, wherein
R1Selected from hydrogen atom, halogen atom, nitro, cyano, amino, hydroxyl, carboxyl or C1-6Alkyl；
R2、R4、R5Separately it is selected from hydrogen atom, C1-6Alkyl, hydroxyl C1-6Alkyl, halogenated C1-6Alkyl, amino C1-6Alkane Base, C1-6Alkoxy, hydroxyl C1-6Alkoxy or halogenated C1-6Alkoxy；
R3Selected from 5~6 circle heterocyclic ring bases optionally replaced by W；
Or R2And R35~6 circle heterocyclic ring bases optionally replaced by W are formed together with the carbon being attached thereto；
Or R4And R55~6 circle heterocyclic ring bases are formed together with the carbon being attached thereto, 5~6 circle heterocyclic ring bases can optionally be taken by W Generation；
X, Y is separately selected from-SO2Or the C optionally replaced by W1-6Alkylidene；
N is selected from 0 or 1；
W is selected from hydroxyl, halogen atom, amino, nitro, carboxyl, cyano, C1-6Alkyl or C1-6Alkoxy.
13. the compound, its pharmaceutically acceptable salt, ester, solvate or its solid as described in technical solution 12 are different Structure body, wherein
R1Selected from hydrogen atom, halogen atom, nitro, cyano, amino, hydroxyl, carboxyl or C1-6Alkyl；
R2、R4、R5Separately it is selected from hydrogen atom, C1-6Alkyl, hydroxyl C1-6Alkyl, halogenated C1-6Alkyl, amino C1-6Alkane Base, C1-6Alkoxy, hydroxyl C1-6Alkoxy or halogenated C1-6Alkoxy；
R3Selected from the 6 yuan of saturated heterocyclyls containing 1~2 N atom optionally replaced by W；
Or R2And R3The 5 yuan of saturated heterocyclyls containing 1~2 N atom optionally replaced by W are formed together with the carbon being attached thereto；
Or R4And R5The 6 yuan of saturations containing 1~2 O and/or S atom optionally replaced by W are formed together with the carbon being attached thereto Heterocycle；
W is selected from hydroxyl, halogen atom, amino, nitro, carboxyl, cyano, C1-6Alkyl or C1-6Alkoxy.
14. the compound, its pharmaceutically acceptable salt, ester, solvate or its solid as described in technical solution 12 are different Structure body, wherein
R1Selected from hydrogen atom, halogen atom, nitro, cyano, amino, hydroxyl, carboxyl or C1-6Alkyl；
R2、R4、R5Separately it is selected from hydrogen atom, C1-6Alkyl, hydroxyl C1-6Alkyl, halogenated C1-6Alkyl, amino C1-6Alkane Base, C1-6Alkoxy, hydroxyl C1-6Alkoxy or halogenated C1-6Alkoxy；
R3Selected from 5~6 yuan of saturated heterocyclyls containing 1 N atom optionally replaced by W；
Or R2And R35~6 yuan of saturated heterocyclyls containing 1 N atom optionally replaced by W are formed together with the carbon being attached thereto；
Or R4And R55~6 yuan of saturations containing 2 O and/or S atom optionally replaced by W are formed together with the carbon being attached thereto Heterocycle；
W is selected from hydroxyl, halogen atom, amino, nitro, carboxyl, cyano, C1-6Alkyl or C1-6Alkoxy.
15. compound as described in technical solution 2, its pharmaceutically acceptable salt, ester, solvate or its alloisomerism Body, wherein
R1Selected from hydrogen atom, halogen atom, nitro, cyano, amino, hydroxyl, carboxyl or C1-6Alkyl；
R3Selected from optionally replaced by W pyridyl group, dihydropyridine base, tetrahydro pyridyl, pyrrole radicals, pyrrolin base, four Hydrogen pyrrole radicals, piperidyl, piperazinyl or morpholinyl；
R2、R4、R5Separately it is selected from hydrogen atom, halogen atom, nitro, cyano, amino, hydroxyl, carboxyl, C1-6Alkane Base, hydroxyl C1-6Alkyl, halogenated C1-6Alkyl, amino C1-6Alkyl, C1-6Alkoxy, hydroxyl C1-6Alkoxy or halogenated C1-6Alcoxyl Base；
Or R2And R3Together with the carbon being attached thereto formed the pyrrole radicals optionally replaced by W, pyrrolin base, nafoxidine base, Pyrazolyl, imidazole radicals, thiazolyl, oxazolyl, pyridyl group, dihydropyridine base, tetrahydro pyridyl, pyrimidine radicals, pyrazinyl, piperidines Base, piperazinyl or morpholinyl；
Or R4And R51,4- dioxanes base, the 1,3- dioxas optionally replaced by W is formed together with the carbon being attached thereto Cyclohexyl, 1,3- dioxolane base, 1,4- Dioxins base, tetrahydrofuran base, THP trtrahydropyranyl, 4,5- bis- Hydrogen thiazolyl, morpholinyl, oxazolyl, 4,5- dihydro-oxazoles base, 4,5- dihydro-isoxazoles base, thiapyran base or thiazolyl；
X, Y is separately selected from-SO- ,-SO2, the C that is optionally replaced by W1-6Alkylidene or imino group；
N is equal to 0 or 1；
W is selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atom, C1-6Alkyl, C1-6Alkoxy or C1-6Alkyl ammonia Base.
16. the compound, its pharmaceutically acceptable salt, ester, solvate or its solid as described in technical solution 15 are different Structure body, wherein
R1Selected from hydrogen atom, halogen atom, nitro, cyano, amino, hydroxyl, carboxyl or C1-6Alkyl；
R3Selected from optionally replaced by W pyridyl group, dihydropyridine base, tetrahydro pyridyl, pyrrole radicals, pyrrolin base, four Hydrogen pyrrole radicals, piperidyl, piperazinyl or morpholinyl；
R2、R4、R5Separately it is selected from hydrogen atom, halogen atom, nitro, cyano, amino, hydroxyl, carboxyl, C1-6Alkane Base, hydroxyl C1-6Alkyl, halogenated C1-6Alkyl, amino C1-6Alkyl, C1-6Alkoxy, hydroxyl C1-6Alkoxy or halogenated C1-6Alcoxyl Base；
W is selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atom, C1-6Alkyl, C1-6Alkoxy or C1-6Alkyl ammonia Base.
17. the compound, its pharmaceutically acceptable salt, ester, solvate or its solid as described in technical solution 15 are different Structure body, wherein
R1Selected from hydrogen atom, halogen atom, nitro, cyano, amino, hydroxyl, carboxyl or C1-6Alkyl；
R4、R5Separately it is selected from hydrogen atom, halogen atom, nitro, cyano, amino, hydroxyl, carboxyl, C1-6Alkyl, hydroxyl Base C1-6Alkyl, halogenated C1-6Alkyl, amino C1-6Alkyl, C1-6Alkoxy, hydroxyl C1-6Alkoxy or halogenated C1-6Alkoxy；
R2And R3The pyrrole radicals optionally replaced by W, pyrrolin base, nafoxidine base, pyrrole are formed together with the carbon being attached thereto Oxazolyl, imidazole radicals, thiazolyl, oxazolyl, pyridyl group, dihydropyridine base, tetrahydro pyridyl, pyrimidine radicals, pyrazinyl, piperidyl, Piperazinyl or morpholinyl；
W is selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atom, C1-6Alkyl, C1-6Alkoxy or C1-6Alkyl ammonia Base.
18. the compound, its pharmaceutically acceptable salt, ester, solvate or its solid as described in technical solution 15 are different Structure body, wherein
R1Selected from hydrogen atom, halogen atom, nitro, cyano, amino, hydroxyl, carboxyl or C1-6Alkyl；
R3Selected from optionally replaced by W pyridyl group, dihydropyridine base, tetrahydro pyridyl, pyrrole radicals, pyrrolin base, four Hydrogen pyrrole radicals, piperidyl, piperazinyl or morpholinyl；
R2Selected from hydrogen atom, halogen atom, nitro, cyano, amino, hydroxyl, carboxyl, C1-6Alkyl, hydroxyl C1-6Alkyl, halogen For C1-6Alkyl, amino C1-6Alkyl, C1-6Alkoxy, hydroxyl C1-6Alkoxy or halogenated C1-6Alkoxy；
R4And R51,4- dioxanes base, the 1,3- dioxanes optionally replaced by W is formed together with the carbon being attached thereto Hexyl, 1,3- dioxolane base, 1,4- Dioxins base, tetrahydrofuran base, THP trtrahydropyranyl, 4,5- dihydros Thiazolyl, morpholinyl, oxazolyls, 4,5- dihydro-oxazoles base, 4,5- dihydro-isoxazoles base, thiapyran base or thiazolyl；
W is selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atom, C1-6Alkyl, C1-6Alkoxy or C1-6Alkyl ammonia Base.
19. compound as described in technical solution 2, its pharmaceutically acceptable salt, ester, solvate or its alloisomerism Body, wherein
X, Y is separately selected from-CO- ,-CO2,-SO- ,-SO2, the C that is optionally replaced by W1-6Alkylidene or imino group, And representative-a CO- ,-CO in X, Y2,-SO- or-SO2, another represents the C optionally replaced by W1-6Alkylidene or imido Base；
W is selected from hydroxyl, halogen atom, amino, nitro, carboxyl, cyano, C1-6Alkyl, C1-6Alkoxy, halogenated C1-6Alkyl, Halogenated C1-6Alkoxy or C1-6Alkyl amino.
The part of compounds of the present invention
Detailed description of the invention
In the description and claims of this application, compound is in accordance with chemical structural formula and names, if It indicates that the name of compound is not inconsistent with chemical structural formula when same compound, is subject to chemical structural formula or chemical equation.
" halogen atom " of the present invention includes fluorine atom, chlorine atom, bromine atom and iodine atom etc..
" C of the present invention1-6Alkyl " indicates the alkyl containing 1-6 carbon atom of linear chain or branched chain, including for example “C1-4Alkyl ", " C1-3Alkyl " etc., specific example include 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 branched 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 include 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 etc..
" C of the present invention2-8Alkynyl " refers to the alkynyl for the linear chain or branched chain that the carbon atom number containing three keys is 2-8, Include such as " C2-6Alkynyl ", " C2-4Alkynyl ", " C2-3Alkynyl " etc., specific example include 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 carbonyl epoxide, C1-6Alkyl sulphonyl, C1-6Alkyl sulfonyl amino, C1-6Alkyl amino sulfonyl, (C1-6Alkane Base)2Amino-sulfonyl " refers to C1-6Alkyl-O-, C1-6Alkyl-NH-, (C1-6Alkyl)2-N-、C1-6Alkyl-S-, C1-6Alkyl-C (O)-、C1-6Alkyl-C (O)-O-, C1-6Alkyl-SO2-、C1-6Alkyl-SO2-NH-、C1-6Alkyl-NH-SO2-、(C1-6Alkyl)2- NH-SO2The group that mode is formed, wherein " C1-6Described in alkyl " text as defined above.
" C of the present invention1-4Alkoxy, C1-4Alkyl amino, (C1-4Alkyl)2Amino, C1-4Alkyl sulfenyl, C1-4Alkyl Carbonyl, C1-4Alkyl carbonyl epoxide, C1-4Alkyl sulphonyl, C1-4Alkyl sulfonyl amino, C1-4Alkyl amino sulfonyl, (C1-4Alkane Base)2Amino-sulfonyl " refers to C1-4Alkyl-O-, C1-4Alkyl-NH-, (C1-4Alkyl)2-N-、C1-4Alkyl-S-, C1-4Alkyl-C (O)-、C1-4Alkyl-C (O)-O-, C1-4Alkyl-SO2-、C1-4Alkyl-SO2-NH-、C1-4Alkyl-NH-SO2-、(C1-4Alkyl)2- NH-SO2The group that mode is formed, wherein " C1-4Described in alkyl " text as defined above.
" halogenated C of the present invention1-6Alkyl, hydroxyl C1-6Alkyl, amino C1-6Alkyl, sulfonyl C1-6Alkyl, amino sulphur Acyl group C1-6Alkyl, aminosulfonyl amino C1-6Alkyl, C1-6Alkoxy C1-6Alkyl, halogenated C1-6Alkoxy, hydroxyl C1-6Alkoxy " Refer to one or more, such as 1~4,1~3,1~2 halogen atom, hydroxyl, amino, sulfonyl, amino-sulfonyl, ammonia Ylsulfonylamino, C1-6Alkoxy replaces C respectively1-6Alkyl, C1-6Hydrogen atom in alkoxy is formed by group.
" halogenated C of the present invention1-4Alkyl, hydroxyl C1-4Alkyl, amino C1-4Alkyl, sulfonyl C1-4Alkyl, amino sulphur Acyl group C1-6Alkyl, aminosulfonyl amino C1-6Alkyl, C1-4Alkoxy C1-4Alkyl, halogenated C1-4Alkoxy, hydroxyl C1-4Alkoxy " Refer to one or more, such as 1~4,1~3,1~2 halogen atom, hydroxyl, amino, sulfonyl, amino-sulfonyl, ammonia Ylsulfonylamino, C1-4Alkoxy replaces C respectively1-4Alkyl, C1-4Hydrogen atom in alkoxy is formed by group.
" 3~8 yuan of naphthenic base " of the present invention refers to that paraffin section one hydrogen atom of removal of 3~8 carbon atoms spreads out Raw monocycle cyclic alkyl, including for example " 3~6 yuan of naphthenic base ", " 4~7 yuan of naphthenic base ", " 4~8 yuan of naphthenic base ", " 4~6 yuan Naphthenic base ", " 5~6 yuan of naphthenic base " etc..The example includes but not limited to：Cyclopropane base, cyclobutane base, pentamethylene base, hexamethylene Base, cycloheptyl alkyl, cyclooctane base, methyl cyclopropane base, dimethylcyclopropane base, methyl cyclobutane base, dimethylcyclobutane base, Methyl cyclopentane base, dimethylcyclopentane base, methyl cyclohexane alkyl, dimethyleyelohexane alkyl etc..
" 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 " of the present invention refer to containing 3~8 annular atoms and containing it is at least one (such as 1, 2,3,4 or 5) monocyclic heterocyclic compound of heteroatomic saturation or fractional saturation removes the obtained group of a hydrogen atom, packet Include such as " 3~7 circle heterocyclic ring base ", " 3~6 circle heterocyclic ring base ", " 4~7 circle heterocyclic ring base ", " 4~6 circle heterocyclic ring base ", " 5~6 circle heterocyclic rings Base ", " 5~6 member heterocyclic ring containing nitrogen base ", " 5 member heterocyclic ring containing nitrogen base ", " 6 member heterocyclic ring containing nitrogen base ", " 5 yuan of saturated heterocyclyls ", " 6 yuan full And heterocycle ", 5~6 circle heterocyclic ring bases of 1~2 N atom " contain ", " the 5 circle heterocyclic ring bases for containing 1~2 N atom ", " contain 1~2 N 6 circle heterocyclic ring bases of atom ", " 5~6 circle heterocyclic ring bases containing 1~2 O and/or S atom ", " 6 containing 1~2 O and/or S atom Circle heterocyclic ring base ", " the 5 circle heterocyclic ring bases containing 1~2 O and/or S atom ", " 5~6 yuan of saturations containing 1~2 O, S and/or N atom Heterocycle ", " 5~6 yuan of saturated heterocyclyls containing 1~2 O and/or S atom ", " 5~6 yuan of saturations containing 1~2 N atom are miscellaneous Ring group ", " 5 yuan of saturated heterocyclyls containing 1~2 O and/or S atom ", " 6 yuan of saturated heterocyclics containing 1~2 O and/or S atom Base ", 5 yuan of saturated heterocyclyls of 1~2 N atom " contain ", " 6 yuan of saturated heterocyclyls for containing 1~2 N atom ", " containing 2 O and/ Or 5~6 yuan of saturated heterocyclyls of S atom ", " 5~6 circle heterocyclic ring bases containing 2 O and/or S atom ", " contain the 5~6 of 1 N atom Circle heterocyclic ring base ", " 5~6 yuan of saturated heterocyclyls for containing 1 N atom " etc..Specific example includes but are not limited to：Aziridine Base, 2H- aziridine base, diazacyclo propyl, 3H- diazacyclos acrylic, azetidinyl, 1,4- dioxanes Hexyl, 1,3- dioxanes base, 1,3- dioxolane base, 1,4- Dioxins base, tetrahydrofuran base, THP trtrahydropyranyl, pyrrolin base, pyrrolidinyl, imidazolidinyl, 4,5- glyoxalidine base, pyrazolidinyl, 4,5- pyrazolines Base, 2,5- dihydrothiophenes, tetrahydro-thienyl, 4,5- dihydro-thiazolyls, piperidyl, piperazinyl, 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- thiazines Base, 6H-1,3- thiazinyls, 2H- pyranoses, 2H- pyran-2-ones base, 3,4- dihydro -2H- pyranoses etc..
" 5~14 unit's heteroaryl " of the present invention refers to that (wherein at least one annular atom is containing 5~14 annular atoms Hetero atom, such as nitrogen-atoms, oxygen atom or sulphur atom) the cyclic group with armaticity.Including such as " 5~10 yuan of heteroaryls Base ", " 5~8 unit's heteroaryl ", " 5~6 unit's heteroaryl ", " 6~12 unit's heteroaryl " etc..Specific example includes but are not limited to furan Mutter base, thienyl, pyrrole radicals, thiazolyl, isothiazolyl, thiadiazolyl group, oxazolyl, isoxazolyl, oxadiazolyls, imidazole radicals, Pyrazolyl, 1,2,3- triazolyls, 1,2,4- triazolyls, 1,2,3- oxadiazolyls, 1,2,4- oxadiazolyls, 1,2,5- oxadiazoles Base, 1,3,4- oxadiazolyls, pyridyl group, 2- pyriconyls, 4- pyriconyls, pyrimidine radicals, 1,4- Dioxins base, 2H-1,2- oxazinyls, 4H-1,2- oxazinyls, 6H-1,2- oxazinyls, 4H-1,3- oxazinyls, 6H-1,3- oxazinyls, 4H-1,4- Oxazinyl, pyridazinyl, pyrazinyl, 1,2,3- triazine radicals, cyanuro 1,3,5,1,2,4,5- tetrazines base, azepine cycloheptatriene base, 1,3- diazas cycloheptatriene base, azepine cyclooctatetraenyl etc.." 5~6 unit's heteroaryl " refers to containing in 5~14 unit's heteroaryls There is the specific example of 5~6 annular atoms.
" 6~8 yuan of aryl " of the present invention refers to the monocyclic aryl containing 6~8 ring carbon atoms, the example include but It is not limited to：Phenyl, cyclooctatetraenyl etc..
The present invention also provides two preparation methods of above compound, but are not limited only to following methods, reaction equation It is as follows：
Preparation method one：
Reaction step：
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, then raw material 1, reaction mixture room temperature is added in 0 DEG C of addition sodium hydride, stirring It stirs (such as 1-12h), water quenching is added to go out, organic solvent (such as ethyl acetate) extraction, concentration, purified (such as silica gel column layer Analysis) obtain intermediate 2.
The preparation of the logical formula (I) compound of step 3 present invention
Intermediate 2 and intermediate 3 are dissolved in appropriate solvent (such as Isosorbide-5-Nitrae-dioxane), under nitrogen protection, heat (example Such as 70 DEG C -120 DEG C) reaction (such as 4-16 hours), it filters, is diluted with water, organic solvent (such as ethyl acetate) extraction is done Dry, concentration obtains the logical formula (I) compound of the present invention through proper method (such as silica gel column chromatography).
Preparation method two：
Reaction step：
The preparation of step 1 intermediate 1
Raw material 1 and raw material 2 are dissolved in appropriate solvent (such as n,N-Dimethylformamide), react at room temperature (such as 0.5-5 hours), 0 DEG C adds water quenching to go out, organic solvent (such as ethyl acetate) extraction, and concentration is purified (such as silica gel column chromatography) Obtain intermediate 1.
The preparation of step 2 intermediate 2
Intermediate 1 is dissolved in appropriate solvent (such as tetrahydrofuran), is stirred at room temperature (such as 6-16 hours), 0 DEG C plus water quenching It goes out, organic solvent (such as ethyl acetate) extraction, concentration, purified (such as silica gel column chromatography) obtains intermediate 2.
The preparation of the logical formula (I) compound of step 3 present invention
Intermediate 2 and intermediate 3 are dissolved in appropriate solvent (such as Isosorbide-5-Nitrae-dioxane), under nitrogen protection, heat (example Such as 70 DEG C -120 DEG C) reaction (such as 4-16 hours), it filters, is diluted with water, organic solvent (such as ethyl acetate) extraction is done Dry, concentration obtains the logical formula (I) compound of the present invention through proper method (such as silica gel column chromatography).
In reaction equation, R1、R2、R3、R4、R5, n, X and Y as defined hereinabove, it is former that M represents fluorine atom, chlorine atom, bromine Son and iodine atom.
" stereoisomer " of formula (I) compound of the present invention refers to the meeting when formula (I) compound is there are when asymmetric carbon atom Enantiomter is generated, when compound is there are when carbon-carbon double bond or cyclic structure, will produce cis-trans-isomer, when compound exists When ketone or oxime, tautomer, the enantiomter of all formula (I) compounds, diastereoisomer, racemization isomery will produce Body, cis-trans-isomer, tautomer, geometric isomer, epimer and its mixture, are included in the scope of the invention In.
If the raceme that any compound synthesis obtains shown in the logical formula (I) of the present invention, required enantiomer-pure Compound can be obtained by the method for chiral resolution：It can (image height be suppressed standby by chromatography with chiral stationary phase Liquid chromatogram, supercritical fluid chromatography).Chirality padding includes but not limited to：Chiralcel OJ-H, Chiralpak AD-H, Chiralpak IA, Chiralpak AS-H.
The present invention logical formula (I) shown in 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, and substituted amine includes that naturally occurring substitution amine, cyclammonium and basic ion exchange Resin, selected from glycine betaine, caffeine, choline, N, N '-dibenzyl-ethylenediamins, 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..
" ester " of formula (I) compound of the present invention refer to, when formula (I) compound is there are when carboxyl, can be esterified with alcohol Reaction and the ester formed can be esterified anti-with generations such as organic acid, inorganic acid, acylates when formula (I) compound is there are when hydroxyl The ester answered and formed.Under the conditions of ester is existing for acid or alkali, hydrolysis can occur and generate corresponding acid or alcohol.
Logical formula (I) compound represented, its pharmaceutically acceptable salt, ester or its stereoisomer can be solvates Form.If in the case that solvate is hydrate, aquation can be completed in preparation process or can be utilized original The hygroscopicity of no aquatic products gradually carries out.
Further requirement of the present invention protection includes any compound shown in above-mentioned formula (I), its is pharmaceutically acceptable The pharmaceutical composition of salt, ester, solvate or its stereoisomer and one or more pharmaceutical carriers and/or diluent, can be with Pharmaceutically acceptable any dosage form is made.It is applied in a manner of oral, parenteral, rectum or transpulmonary administration etc. and needs this control The patient for the treatment of.When for being administered orally, conventional solid pharmaceutical preparation, such as tablet, capsule, pill, granule can be made into；Also may be used Oral liquid, such as oral solution, oral suspensions, syrup is made.When oral preparation is made, it is suitable to be added Filler, adhesive, disintegrant, lubricant etc..When for parenteral administration, injection, including injection, injection can be made into With aseptic powdery and concentrated solution for injection.When injection is made, the conventional method production in existing pharmaceutical field can be used, prepare When injection, additives can be added without, suitable additives can also be added according to the property of drug.When for rectally, It can be made into suppository etc..When for transpulmonary administration, inhalant or spray etc. can be made into.
Further requirement of the present invention protection include any compound of formula recited above (I), its pharmaceutically acceptable salt, The pharmaceutical composition of ester, solvate or its stereoisomer and other one or more antitumor agents and immunosuppressor.Institute The antitumor agent and immunosuppressor stated are antimetabolite, including but not limited to capecitabine, gemcitabine, pemetrexed two Sodium；For growth factor receptor inhibitors, including but not limited to pazopanib, Imatinib, Erlotinib, Lapatinib, Gefitinib, Vande Thani；For antibody, including but not limited to Trastuzumab, bevacizumab；For mitotic inhibitor, it is selected from taxol, Changchun Rui Bin, docetaxel, Doxorubicin；For antitumor steroids, including but not limited to Letrozole, tamoxifen, fulvestrant, fluorine His amine, Triptorelin；For alkylating agents, including but not limited to cyclophosphamide, mustargen, melphalan, chlorambucil, Carmustine；For Metal platinum class, including but not limited to carboplatin, cis-platinum, oxaliplatin；For immunosupress class, including but not limited to everolimus, west Luo Mosi, special cancer are suitable；For purine analogue, including but not limited to Ismipur, 6- thioguanines, imuran；For antibiosis Plain class, including but not limited to rhzomorph D, daunorubicin, adriamycin, mitoxantrone, bleomycin, plicamycin；For platinum complex, Including but not limited to cis-platinum, Kapo Platinum；For adrenal cortex inhibitor class, including but not limited to aminoglutethimide；For enzyme inhibitor, Including but not limited to SAHA, it cytarabine, methotrexate (MTX), hydroxycarbamide, Hydroxycamptothecin, Topotecan, topotecan, replaces according to vertical Health.
The present invention also provides formula (I) compound represented of the present invention, its pharmaceutically acceptable salt, ester, solvates Or its stereoisomer is in preparing treatment and/or preventing the drug of cancer-related diseases or non-cancerous disease that ALK is mediated Using the relevant disease of cancer includes but not limited to the cancer of the brain, lung cancer, lung cancer in non-cellule type, dermoid cancer, wing Guang cancer, gastric cancer, oophoroma, peritoneal cancer, cancer of pancreas, breast cancer, head and neck cancer, cervix cancer, carcinoma of endometrium, colorectal cancer, liver Cancer, kidney, the cancer of the esophagus, adenocarcinoma of esophagus, esophageal squamous cell carcinoma, non-Hodgkin lymphoma, brain tumor, central nerve neuroma, Glioma, glioblastoma multiforme, glioma sarcomatosum, prostate cancer, thyroid cancer, female reproductive tract cancer, carcinoma in situ, Lymthoma, histocytic lymphoma, neurofibroma, osteocarcinoma, cutaneum carcinoma, colon cancer, carcinoma of testis, Small Cell Lung Cancer, gastrointestinal tract Mesenchymoma, tumor of prostate, mast cell tumor, Huppert's disease, melanoma, glioma, glioblastoma, star Cytoma, neuroblastoma, sarcoma；The hyperplasia of prostate of proliferative disease, including but not limited to skin or prostate.
The compounds of this invention has the following advantages：
(1) formula (I) compound of the present invention, its pharmaceutically acceptable salt, ester, solvate or its stereoisomer have Excellent ALK inhibitory activity；
(2) formula (I) compound of the present invention, its pharmaceutically acceptable salt, ester, solvate or its stereoisomer are shown Go out good biological stability, 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：Trifluoroacetate, compound 3 and the compound 4 of the compounds of this invention 2, according to the trifluoro second of compound 2 It is prepared by the preparation embodiment of hydrochlorate, compound 3 and compound 4.
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：
It is the MgCl of 1000mM to take appropriate mother liquid concentration respectively2, the DTT of SEB, 100mM of 2500nM, 5 × enzyme buffer liquid, It is added in ultra-pure water so that ultimate density is respectively：5mM, 25nM, 1mM, 1 × enzyme buffer liquid, mixing, for use.
2.5 × test solution is prepared：
The 1mM storing solutions of comparison medicine are prepared：Comparison medicine (1.48mg) is weighed, appropriate DMSO dissolvings are added, mixing is spare.
The 1mM storing solutions of compound are prepared：Weigh Compound is appropriate (specific sample weighting amount is see following table) respectively, is added appropriate DMSO dissolves, and mixing is spare.
1mM storing solutions are taken respectively, a concentration of 200 μM of solution are made with 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 uses ALK kinase buffer liquids to dilute 80 times 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 value)/(maximum value-minimum value) × 100 are calculated, using Graph Prism softwares carry out curve fitting, and obtain IC50Value.
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 the compounds of this invention has good inhibitory activity to ALK kinases, can be used for treating and kinases phase The disease of pass, especially ALK kinase mediated illness or the patient's condition have significant clinical meaning.
Specific implementation mode
The specific implementation mode 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.
1 4- of embodiment (the chloro- 2- of 5- ((2- isopropoxy -5- methyl -4- (piperidin-4-yl) phenyl) amino) pyrimidine -4- Base) -3,4- dihydro -2H- benzos [b] [1,4] thiazine 1,1- dioxide (compound 1) trifluoroacetate preparation
(1) preparation of 2- ((2- chloroethyls) is thio) aniline
In the there-necked flask of a 250mL, 2- aminothiophenols (10g, 79.88mmol), 1,2- dichloroethanes is added (78g,788.3mmol).Reaction mixture is heated to flow back under nitrogen protection, and the methanol solution of sodium methoxide (15g) is then added dropwise, It is added dropwise, is heated to reflux 3 hours.Wait for reaction finish, reaction solution cooling pour into ice water, then use dichloromethane (3 × It 100mL) extracts, merges organic layer, washed with the sodium bicarbonate of saturation, separate organic layer and dried with anhydrous sodium sulfate, is concentrated to give To product (8g, yield 53%).
(2) preparation of N- (2- ((2- chloroethyls) is thio) phenyl) acetamide
In the single port bottle of a 100mL, 2- ((2- chloroethyls) is thio) aniline (7.5g, 40.0mmol), acetic acid is added Acid anhydride (7.5g, 73mmol).Reaction mixture is heated to reflux 2 hours, and reaction solution cooling is poured into ice water, with ethyl acetate (80mL × 3) it extracts, merges organic phase, saturated salt solution washed once, and organic layer is dried with anhydrous sodium sulfate.It is concentrated under reduced pressure, residue Through column chromatography (ethyl acetate:Petroleum ether=1:5) product (5.7g, yield 62%) is obtained.
(3) preparation of 1- (2,3- dihydro -4H- benzos [b] [1,4] thiazine -4- bases) ethyl ketone
In the there-necked flask of a 250mL be added N- (2- ((2- chloroethyls) is thio) phenyl) acetamide (5.4g, 23.5mmol), t-BuOH (50mL) is heated to 45 DEG C, and the t-BuOH (50mL) of t-BuOK (2.7g, 24.1mmol) is then added dropwise Solution.45 DEG C of reaction mixture reacts 1 hour.Reaction solution cooling is poured into ice water, pH=4~5 is adjusted with hydrochloric acid (1M), with two Chloromethanes (50mL × 3) extracts, and merges organic phase, saturated common salt water washing, and anhydrous sodium sulfate drying is concentrated under reduced pressure to give crude product (3.8g)。
(4) preparation of 1- (1,1- dioxos -2,3- dihydro -4H- benzos [b] [1,4] thiazine -4- bases) ethyl ketone
1- (2,3- dihydro -4H- benzos [b] [1,4] thiazine -4- bases) ethyl ketone is added in the there-necked flask of a 250mL (3.8g, 19.66mmol) and methanol (50mL).(NH is added4)2MoO4The aqueous solution (20mL) of (2.7g, 13.78mmol).Then H is added2O2(10mL, 30%).Reaction mixture is stirred overnight at room temperature, and methanol, residual solution ethyl acetate (50mL is removed under reduced pressure × 3) it extracts, merges organic phase, concentration, residue is through column chromatography (ethyl acetate:Petroleum ether=1:5) product (2g, the production of two steps are obtained 38%) rate is.
(5) preparation of 3,4- dihydros -2H- benzos [b] [1,4] thiazine 1,1- dioxide
1- (1,1- dioxos -2,3- dihydro -4H- benzos [b] [1,4] thiazines-are added in the single port bottle of a 100mL 4- yls) ethyl ketone (2g, 8.88mmol), methanol (20mL), concentrated hydrochloric acid (5mL).Reaction mixture is stirred overnight at room temperature, with saturation Sodium bicarbonate adjusts pH value to 8~9, is extracted with ethyl acetate, and merges organic phase, being concentrated to give product, (800mg, yield are 49%).
(6) system of 4- (2,5- dichloro pyrimidine -4- bases) -3,4- dihydro -2H- benzos [b] [1,4] thiazine 1,1- dioxide It is standby
3,4- dihydro -2H- benzos [b] [1,4] thiazine 1,1- dioxide is added in the single port bottle of a 100mL (500mg,2.73mmol)、DMSO(10mL).Then sodium hydride (60%, 126mg, 3.15mmol) is added for 0 DEG C.10 points of stirring Clock.Then 2,4,5- trichloropyrimidines (500mg, 2.73mmol) are added.Reaction mixture is stirred overnight at room temperature.Then water is added (2mL) is quenched, and water (50mL) dilution is added.It is extracted with ethyl acetate (100mL × 2), merges organic phase, use saturated salt solution (100mL × 3) are washed.Organic layer is separated, is dried with anhydrous sodium sulfate, is concentrated under reduced pressure, residue is through column purification (ethyl acetate: Petroleum ether=1:15~1:3) product (200mg, yield 22%) is obtained.
(7) tertiary butyl 4- (4- ((the chloro- 4- of 5- (1,1- dioxide -2,3- dihydro -4H- benzos [b] [1,4] thiazine -4- Base) pyrimidine -2-base) amino) -5- isopropoxy -2- aminomethyl phenyls) piperidines -1- formic acid esters preparation
In the single port bottle of a 100mL be added 4- (2,5- dichloro pyrimidine -4- bases) -3,4- dihydro -2H- benzos [b] [1, 4] thiazine 1,1- dioxide (200mg, 0.61mmol), tertiary butyl 4- (4- amino -5- isopropoxy -2- aminomethyl phenyls) piperazine Pyridine -1- formic acid esters (180mg, 0.52mmol), 1,4- dioxane (20mL), cesium carbonate (400mg, 1.23mmol) and Pd (dppf)Cl2(50mg).Under nitrogen protection, reaction mixture is heated to 80 DEG C of reactions overnight, filtering, filter cake ethyl acetate (50mL) is washed, and filtrate is added water (100mL) and dilutes, and is extracted with ethyl acetate (50mL × 3), merges organic phase, anhydrous slufuric acid Sodium is dried.It is concentrated under reduced pressure, residue purifies (Column through Prep-HPLC:Water Sunfire C18,19x150mm,Phase A:H2O (0.05%TFA), B:CH3CN.25mL/min), component is collected, product (70mg, yield 21%) is concentrated to give.
(8) 4- (the chloro- 2- of 5- ((2- isopropoxy -5- methyl -4- (piperidin-4-yl) phenyl) amino) pyrimidine-4-yl) -3, The preparation of 4- dihydro -2H- benzos [b] [1,4] thiazine 1,1- dioxide trifluoroacetates
Tertiary butyl 4- (4- ((the chloro- 4- of 5- (1,1- dioxide -2,3- dihydros-are added in the single port bottle of a 100mL 4H- benzos [b] [1,4] thiazine -4- bases) pyrimidine -2-base) amino) -5- isopropoxy -2- tolyls) piperidines -1- formic acid esters (70mg, 0.11mmol) and dichloromethane (5mL).Trifluoroacetic acid (0.5mL) is added in room temperature.Reaction mixture was stirred at room temperature Night.Reaction solution is concentrated under reduced pressure, and residue divides water to be dried to obtain final product (61.5mg, yield 86%).
Molecular formula：C29H33ClF3N5O5S molecular weight:656.12LC-MS(m/z):542[M+H]+
1H-NMR(300MHz,DMSO)δ:8.54-8.58(m,1H),8.46(s,1H),8.23(brs.2H),7.77- 7.80 (d, 1H, J=8.1Hz), 7.68 (s, 1H), 7.47 (t, 1H, J=8.1Hz), 7.22 (t, 1H, J=6.9Hz), 6.92 (d, 1H, J=8.1Hz), 6.74 (s, 1H), 4.50-4.58 (m, 1H), 4.35-4.38 (m, 2H), 3.74-3.78 (m, 2H), 3.35-3.39 (m, 2H), 2.95-3.06 (m, 3H), 2.17 (s, 3H), 1.74-1.80 (m, 4H), 1.28 (d, 6H, J= 6.0Hz).
2 3- of embodiment (the chloro- 2- of 5- ((2- isopropoxy -5- methyl -4- (piperidin-4-yl) phenyl) amino) pyrimidine -4- Base) -2,3- dihydrobenzos [d] thiazole 1,1- dioxide (compound 2) trifluoroacetate preparation
(1) preparation of 2- ((2,5- dichloro pyrimidine -4- bases) amino) benzenethiol
2- aminobenzene -1- mercaptan (6g, 47.93mmol), N, N- dimethyl formyls are added in the there-necked flask of a 250mL Amine (100mL), sodium tert-butoxide (5.53g) are then added dropwise 2,4,5- trichloropyrimidines (8.78g, 47.87mmol), are added dropwise, room Temperature stirring 1 hour.0 DEG C is added water quenching in ice-water bath and goes out reaction, and it is 7 to adjust pH value with hydrochloric acid (1M), then uses ethyl acetate (100mL × 3) extract, and merge organic layer and with saturated common salt water washing, separate organic layer and dried with anhydrous sodium sulfate.Decompression removes Solvent, residue is gone to purify (petroleum ether through column chromatography:Ethyl acetate=1:1) product (6.5g, yield 50%) is obtained.
(2) preparation of 3- (2,5- dichloro pyrimidine -4- bases) -2,3- dihydrobenzos [d] thiazole
In the there-necked flask of a 250mL be added 2- ((2,5- dichloro pyrimidine -4- bases) amino) benzenethiol (3.5g, 12.86mmol), tetrahydrofuran (50mL), LiHMDS (1M, in THF) (25.8mL), CH2I2(3.45g, 12.88mmol), instead Mixture is answered to be stirred overnight at room temperature.0 DEG C is added water quenching in ice-water bath and goes out reaction, then uses ethyl acetate (50mL × 3) extraction, Merge organic layer and with saturated common salt water washing, separates organic layer and dried with anhydrous sodium sulfate.Solvent, residue warp is removed under reduced pressure Column chromatography purifies (petroleum ether:Ethyl acetate=5:1) product (550mg, yield 15%) is obtained.
(3) preparation of 3- (2,5- dichloro pyrimidine -4- bases) -2,3- dihydrobenzos [d] thiazole 1,1- dioxide
3- (2,5- dichloro pyrimidine -4- bases) -2,3- dihydrobenzos [d] thiazole is added in the there-necked flask of a 50mL (540mg, 1.90mmol), dichloromethane (10mL), m-CPBA (723mg, 4.19mmol).Reaction mixture was stirred at room temperature Then Na is added in night2S2O3(10%) reaction is quenched in aqueous solution, is extracted with dichloromethane (20mL × 3), merges organic layer simultaneously With saturated common salt water washing, separates organic layer and dried with anhydrous sodium sulfate.Solvent is removed under reduced pressure, residue is purified through column chromatography (petroleum ether:Ethyl acetate=3:1) product (480mg, yield 80%) is obtained.
(4) tertiary butyl 4- (4- ((the chloro- 4- of 5- (1,1- dioxos benzo [d] thiazole -3 (2H)-yl) pyrimidine -2-base) ammonia Base) -5- isopropyl -2- aminomethyl phenyls) piperidines -1- formic acid esters preparation
3- (2,5- dichloro pyrimidine -4- bases) -2,3- dihydrobenzos [d] thiazole 1 is added in the there-necked flask of a 100mL, 1- dioxide (480mg, 1.52mmol), tertiary butyl 4- (4- amino -5- isopropoxy -2- aminomethyl phenyls) piperidines -1- formic acid Ester (529mg, 1.52mmol), 1,4- dioxane (15mL), cesium carbonate (1.47g, 4.51mmol), Pd (dppf) Cl2.CH2Cl2(125mg, 0.15mmol) is warming up to 80 DEG C of reactions under nitrogen protection overnight, is cooled to room temperature, is filtered to remove insoluble Solid.Filter cake, filtrate concentration are washed with acetonitrile.Residue Prep-HPLC purifies (Column:Water Sunfire C18,19x150mm,5um,Phase A:H2O (0.05%TFA), B:CH3CN.B:45-90%, 7min, 25mL/min.), it collects Component is concentrated under reduced pressure to give product (200mg, yield 21%).
(5) 3- (the chloro- 2- of 5- ((2- isopropoxy -5- methyl -4- (piperidin-4-yl) phenyl) amino) pyrimidine-4-yl) -2, The preparation of 3- dihydrobenzos [d] thiazole 1,1- dioxide trifluoroacetates
Tertiary butyl 4- (4- ((the chloro- 4- of 5- (1,1- dioxos benzo [d] thiazoles -3 are added in the there-necked flask of a 100mL (2H)-yl) pyrimidine -2-base) amino) -5- isopropoxy -2- aminomethyl phenyls) piperidines -1- formic acid esters (200mg, 0.32mmol), Dichloromethane (10mL), trifluoroacetic acid (1mL).Reaction mixture is stirred overnight at room temperature, through being concentrated under reduced pressure to give final product (182mg, yield 89%).
Molecular formula：C28H31ClF3N5O5S molecular weight:642.09 LC-MS(m/z):528[M+H]+
1H-NMR(300MHz,DMSO)δ:8.55-8.59(1H,m),8.49(1H,s),8.24-8.27(1H,m),8.19 (1H, s), 7.84-7.86 (1H, d, J=7.2Hz), 7.61-7.66 (1H, t, J=8.4Hz), 7.51-7.57 (2H, m), 7.28-7.33 (1H, t, J=8.4Hz), 6.73 (1H, s), 5.31 (2H, s), 4.47-4.55 (1H, m), 3.35-3.39 (2H, M), 2.93-3.05 (3H, m), 2.07 (3H, s), 1.74-1.81 (4H, m), 1.25-1.27 (6H, d, J=6.0Hz)
3 3- of embodiment (the chloro- 2- of 5- ((7- methyl -8- (piperidin-4-yl) -2,3- dihydrobenzos [b] [1,4] bioxin - 5- yls) amino) -4 base of piperidines) and -2,3- dihydrobenzos [d] thiazole 1,1- dioxide (compound 3) preparation
(1) preparation of 2- methoxyl groups -4- methyl -6- nitrophenols
2- methoxyl group -4- methylphenols (50.0g, 0.362mol) are dissolved in chloroform (1L), are cooled to 0 DEG C, will be sent out Cigarette nitric acid (22.8g, 0.362mol) is dissolved in acetic acid (120mL), is slowly added dropwise in solution, and internal temperature control is at 0 DEG C Hereinafter, being warmed to room temperature, the reaction was continued 0.5 hour.The reaction was complete, and rotary evaporation removes solvent, and methanol (200mL) is added in residue, Filtering, is dried in vacuo to obtain product (30g, yield 45.4%).
(2) preparation of 5- methyl-3-nitros benzene -1,2- glycol
2- methoxyl group -4- methyl -6- nitrophenols (30.0g, 0.164mol) are added to hydrobromic acid (200mL, 80%) In, 20g tetrabutyl ammonium fluorides are added, are heated to 110 DEG C, reaction is overnight.Reaction is completed, and water (1000mL) is added, with acetic acid second Ester (5 × 500mL) extracts, and organic phase merges, saturated salt solution (250mL) washing, anhydrous sodium sulfate drying.Filtering, rotation are steamed Hair removes solvent, and residue is directly used in next step.
(3) 7- methyl-5-nitros -2,3- dihydrobenzos [the b] [preparation of 1,4] bioxin
5- methyl-3-nitro benzene -1,2- glycol (20g, 0.118mol) is dissolved in N,N-dimethylformamide (100mL) In, 1,2- Bromofumes (44.4g, 0.236mol) and potassium carbonate (49.2g, 0.356mol) is added.60 DEG C are heated to, was reacted Night.Reaction is completed, and water (300mL) is added, and is extracted with ethyl acetate (3 × 200mL), and organic phase is merged, and rotary evaporation removes molten Agent, residue is through silica gel column chromatography (petroleum ether:Ethyl acetate=5:1) product (19g, yield 82.6%) is obtained.
(4) 6- bromine-7-methyls -5- nitro -2,3- dihydrobenzos [the b] [preparation of 1,4] bioxin
By 7- methyl-5-nitro -2,3- dihydrobenzos [b], [1,4] bioxin (19g, 0.097mol) are dissolved in N, N- bis- In methylformamide (200mL), N-bromosuccinimide (34.5g, 0.194mol) is added portionwise.60 DEG C are heated to, reaction Overnight.Reaction is completed, and water (300mL) is added, and is extracted with ethyl acetate (3 × 200mL), and organic phase is merged, and rotary evaporation removes Solvent, residue is through silica gel column chromatography (petroleum ether:Ethyl acetate=5:1) product (18g, yield 67.7%) is obtained.
(5) 6- bromine-7-methyls -2,3- dihydrobenzos [the b] [preparation of 1,4] bioxin -5- amine
By 6- bromine-7-methyl -5- nitro -2,3- dihydrobenzos [b], [1,4] bioxin (18g, 65.7mmol) are dissolved in second In alcohol (200mL), acetic acid (20mL) is added, is heated to 70 DEG C, iron powder (36.8g, 657.1mmol) is added portionwise.It is warming up to 80 DEG C, react 3 hours, after the completion of reaction, be cooled to room temperature, filter, water (300mL) is added in filtrate, with ethyl acetate (3 × It 300mL) extracts, merges organic phase, rotary evaporation removes solvent, and residue is through silica gel column chromatography (petroleum ether:Ethyl acetate=2: 1) product (12g, yield 75%) is obtained.
(6) the iodo- 7- methyl -2,3- dihydrobenzos [b] of the bromo- 8- of the 6- [preparation of 1,4] bioxin -5- amine
By 6- bromine-7-methyl -2,3- dihydrobenzos [b], [1,4] bioxin -5- amine (12g, 49.16mmol) are dissolved in toluene In (100mL), acetic acid (5mL) and N-iodosuccinimide (16.6g, 73.78mmol) is added, reacts 3 hours at room temperature.Instead It should complete, water (100mL) is added, be extracted with ethyl acetate (3 × 200mL), merge organic phase, use solution of sodium bisulfite (200mL) is washed, and rotary evaporation removes organic phase, and residue is through silica gel column chromatography (petroleum ether:Ethyl acetate=2:1) it is produced Object (7g, yield 38.5%).
(7) tertiary butyl 4- (the bromo- 6- methyl -2,3- dihydrobenzos [b] of 8- amino -7- [1,4] bioxin -5- bases) -3,6- The preparation of dihydropyridine -1 (2H)-formic acid esters
By the iodo- 7- methyl -2,3- dihydrobenzos [b] of the bromo- 8- of 6- [1,4] bioxin -5- amine (7.0g, 18.92mmol) and Tertiary butyl 4- (4,4,5,5- tetramethyl -1,3,2- dioxy boron pentane -2- bases) -3,6- dihydropyridines -1 (2H)-formic acid esters (5.8g, 18.76mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (100mL), and water (15mL) and [1,1'- bis- (diphenylphosphines) two are added Luxuriant iron] palladium chloride (1.4g, 1.91mmol), potassium carbonate (7.83g, 56.7mmol) is heated to 80 DEG C, reacts 3 hours.Reaction It completes, water (100mL) is added, extracted with dichloromethane (3 × 200mL), merge organic phase, washed with saturated salt solution (100mL) It washs, rotary evaporation removes organic phase, and residue is through silica gel column chromatography (petroleum ether:Ethyl acetate=5:1) product (5g, production are obtained Rate 62.7%).
(8) tertiary butyl 4- (8- amino -6- methyl -2,3- dihydrobenzos [b] [1,4] bioxin -5- bases) piperidines -1- formic acid The preparation of ester
By tertiary butyl 4- (the bromo- 6- methyl -2,3- dihydrobenzos [b] of 8- amino -7- [1,4] bioxin -5- bases) -3,6- two Pyridinium hydroxide -1 (2H)-formic acid esters (5g, 11.76mmol) is dissolved in methanol (150mL), and 4g palladium charcoals are added, are passed through hydrogen, room temperature Lower reaction is overnight.Reaction is completed, and filtering, rotary evaporation removes solvent, obtains product (2.5g, yield 61.1%).
(9) preparation of 2- ((2,5- dichloro pyrimidine -4- bases) amino) benzenethiol
2,4,5- trichloropyrimidines (15.0g, 81.8mmol) are dissolved in n,N-Dimethylformamide (50mL), 2- ammonia is added Base benzenethiol (10.24g, 81.8mmol) and potassium carbonate (2.26g, 16.4mmol) react 3 hours at room temperature.The reaction was complete, adds Enter water (300mL), extracted with ethyl acetate (3 × 200mL), merge organic phase, rotary evaporation removes solvent, and residue is through silica gel Column chromatography (petroleum ether:Ethyl acetate=2:1) product (12g, yield 53.8%) is obtained.
(10) preparation of 3- (2,5- dichloro pyrimidine -4- bases) -2,3- dihydrobenzos [d] thiazole
2- ((2,5- dichloro pyrimidine -4- bases) amino) benzenethiol (12.0g, 44.1mmol) is dissolved in tetrahydrofuran (50mL) In, (trimethyl silicon substrate) lithium amides of 1N bis- (88.2mL, 88.2mmol) are added in solution at 0 DEG C, are stirred 0.5 hour.It will Diiodomethane (11.82g, 44.1mmol) is added dropwise in reaction solution, is stirred overnight at room temperature.Reaction is completed, and water (50mL) is added Reaction is quenched, is extracted with ethyl acetate (3 × 50mL), merges organic phase, rotary evaporation removes solvent, and residue is through silica gel column layer Analyse (petroleum ether:Ethyl acetate=2:1) product (2.0g, yield 16%) is obtained.
(11) preparation of 3- (2,5- dichloro pyrimidine -4- bases) -2,3- dihydrobenzos [d] thiazole 1,1- dioxide
3- (2,5- dichloro pyrimidine -4- bases) -2,3- dihydrobenzos [d] thiazole (2.0g, 7.04mmol) is dissolved in dichloromethane Metachloroperbenzoic acid (3.63g, 21.03mmol) is added portionwise in alkane (50mL), and reaction at room temperature is stayed overnight.Reaction is completed, and is added Hypo solution (30mL), liquid separation, water phase are extracted with dichloromethane (3 × 20mL), merge organic phase, with unsaturated carbonate hydrogen Sodium, sodium chloride solution washing, rotary evaporation remove solvent, and residue is through silica gel column chromatography (petroleum ether:Ethyl acetate=2:1) To product (1.5g, yield 67.4%).
(12) tertiary butyl 4- (8- ((the chloro- 4- of 5- (1,1- dioxos benzo [d] thiazole -3 (2H)-yl) pyrimidine -2-base) ammonia Base) -6- methyl -2,3- dihydrobenzos [b] [1,4] bioxin -5- bases) piperidines -1- carboxylates preparation
By 3- (2,5- dichloro pyrimidine -4- bases) -2,3- dihydrobenzos [d] thiazole 1,1- dioxide (181mg, 0.572mmol) and tertiary butyl 4- (8- amino -6- methyl -2,3- dihydrobenzos [b] [1,4] bioxin -5- bases) piperidines -1- first Acid esters (200mg, 0.574mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (15mL), and [1,1'- bis- (diphenylphosphine) ferrocene] two are added Palladium bichloride (42mg, 0.057mmol), cesium carbonate (560mg, 1.72mmol), is heated to 110 DEG C, overnight.Reaction is completed, filtering, Rotary evaporation removes solvent, and residue is through silica gel column chromatography (dichloromethane:Methanol=20:1) product (80mg, yield are obtained 22.3%).
(13) 3- (the chloro- 2- of 5- ((7- methyl -8- (piperidin-4-yl) -2,3- dihydrobenzos [b] [1,4] bioxin -5- bases) Amino) -4 base of piperidines) -2,3- dihydrobenzos [d] thiazole 1,1- dioxide preparation
By tertiary butyl 4- (8- ((the chloro- 4- of 5- (1,1- dioxos benzo [d] thiazole -3 (2H)-yl) pyrimidine -2-base) ammonia Base) and -6- methyl -2,3- dihydrobenzos [b] [1,4] bioxin -5- bases) piperidines -1- carboxylates (80mg, 0.127mmol) are dissolved in In dichloromethane (10mL), trifluoroacetic acid (2mL) is added, stirs 3 hours at room temperature.Reaction is completed, and rotary evaporation removes solvent, Ethyl acetate (50mL), saturated sodium bicarbonate solution washing is added, rotary evaporation removes organic phase, and residue is through silica gel column chromatography (dichloromethane:Methanol=15:1) final product (40mg, yield 59.7%) is obtained.
Molecular formula:C25H26ClN5O4S molecular weight:528.02 LC-MS(m/z):528.2[M+H]+
1H-NMR(400MHz,DMSO-d6)δ:8.45 (s, 1H), 8.33 (s, 1H), 7.82 (d, J=7.6Hz, 1H), 7.57-7.62 (m, 1H), 7.46 (d, J=8.4Hz, 1H), 7.28 (t, J=7.6Hz, 1H), 7.03 (s, 1H), 5.28 (s, 2H),4.18(s,4H),3.28-3.29(m,2H),2.90-2.99(m,3H),2.32-2.39(m,2H),2.10(s,3H), 1.58-1.61(m,2H).
4 3- of embodiment (the chloro- 2- of 5- ((6- isopropoxy isoindoline -5- bases) amino) pyrimidine-4-yl) -2,3- two The preparation of hydrogen benzo [d] thiazole 1,1- dioxide (compound 4)
(1) preparation of the bromo- 5- methoxyl methyl benzoates of 2-
3- methoxyl methyl benzoates (16.6g, 0.10mol) are dissolved in dichloromethane (150mL), are slowly added under ice bath Enter bromine (16.0g, 0.10mol), after being added dropwise, reacts at room temperature 2 hours.Saturated sodium thiosulfate solution (20mL) is added to quench It goes out reaction, is extracted with dichloromethane (200mL), organic phase is washed with water three times, dry, and rotary evaporation removes solvent, residue Through pillar layer separation (petroleum ether:Ethyl acetate=20:1) product (15.9g, yield 64.9%) is obtained.
(2) preparation of 2- cyano -5- methoxyl methyl benzoates
The bromo- 5- methoxyl methyl benzoates (15.9g, 64.9mmol) of 2-, cuprous cyanide (6.39g, 71.4mmol) are added Enter into N,N-dimethylformamide (150mL).It is heated to 140 DEG C of reaction half an hour.Ethyl acetate (500mL) is added, with full And brine It, organic phase drying, rotary evaporation remove solvent, residue is through column chromatography (petroleum ether:Ethyl acetate=20: 1) product (6.7g, yield 54.0%) is obtained.
(3) preparation of 6- methoxyl groups isoindoline -1- ketone
2- cyano -5- methoxyl methyl benzoates (6.7g, 35.1mmol) are dissolved in methanol (50mL), Raney Ni is added (335mg), replacing hydrogen are stirred at room temperature 2 hours, filter, and filter cake is washed with a small amount of methanol, merging filtrate, and rotary evaporation removes Solvent, residue is through pillar layer separation (DCM:MeOH=10:1) product (4.7g, yield 82%) is obtained.
(4) preparation of 6- hydroxyls 1-isoindolinone
6- methoxyl group isoindoline -1- ketone (4.7g, 28.8mmol) is added in dry alchlor (30g), To being sufficiently mixed uniformly, nitrogen protection is heated to 120 DEG C and reacts 2 hours, be cooled to room temperature, ethyl acetate (150mL) is added for stirring It stirs evenly, gained suspension filters, organic phase saturated common salt water washing 3 times, anhydrous sodium sulfate drying, through pillar layer separation (DCM:MeOH=20:1) product (1.19g, yield 27.7%) is obtained.
(5) preparation of 6- isopropoxies 1-isoindolinone
6- hydroxyls 1-isoindolinone (1.0g, 6.71mmol) is dissolved in acetonitrile (25mL), potassium carbonate is added (926mg, 6.71mmol), 3- Iso-Propyl iodides (1.14g, 6.71mmol) are heated to 70 DEG C and react 2 hours, and rotary evaporation removes Solvent is removed, saturated solution of sodium bicarbonate (10mL) is added, is extracted with dichloromethane, organic phase is dried with anhydrous sodium sulfate, rotation Evaporation of solvent, through pillar layer separation (petroleum ether:Ethyl acetate=3:1) product (803mg, yield 62.6%) is obtained.
(6) preparation of 6- isopropoxies -5- nitros iso-indoles -1- ketone
By 6- isopropoxies 1-isoindolinone (803mg, 4.20mmol) be dissolved in trifluoroacetic anhydride and acetonitrile (10mL, 1: 1) in mixed solution, it is slowly added to potassium nitrate (424mg, 4.20mmol) under ice bath, is warmed to room temperature reaction 2 hours, is added 50mL saturated solution of sodium bicarbonate is quenched, and is extracted with dichloromethane, and organic phase is dried with anhydrous sodium sulfate, and rotary evaporation removes molten Agent, residue is through pillar layer separation (petroleum ether:Ethyl acetate=5:1) product (612mg, yield 61.7%) is obtained.
(7) preparation of 5- amino -6- isopropoxy 1-isoindolinones
6- isopropoxy -5- nitros 1-isoindolinones (612mg, 2.59mmol) are dissolved in methanol (15mL), are added Palladium carbon (31mg), replacing hydrogen are stirred at room temperature 30 minutes.Reaction solution filters, and rotary evaporation removes solvent and obtains crude product (530mg)。
(8) preparation of 6- isopropoxies isoindoline -5- amine
5- amino -6- isopropoxies 1-isoindolinones (530mg, 2.57mmol) are dissolved in methanol (10mL), in nitrogen The tetrahydrofuran solution (2.57mL, 5.14mmol) of the borane dimethylsulf iotade of 2.0mol/L is added under gas shielded, is heated to flowing back Reaction 8 hours, is cooled to room temperature, is slowly added to the hydrochloric acid solution of the 6mol/L of 2mL, be heated to reflux 1 hour, be cooled to room temperature, directly Rotary evaporation removes solvent, and residue is through pillar layer separation (DCM:MeOH=10:1) product (80mg, yield 16.2%) is obtained.
(9) preparation of tertiary butyl 5- amino -6- isopropoxies isoindoline -2- formic acid esters
6- isopropoxy isoindoline -5- amine (80mg, 0.417mmol) is dissolved in the dichloromethane of 5mL, is added three Ethamine (42mg, 0.416mmol), di-tert-butyl dicarbonate (91mg, 0.417mmol), are stirred at room temperature 2 hours, rotary evaporation removes Remove solvent, pillar layer separation (DCM:MeOH=10:1) product (95mg, yield 78%) is obtained.
(10) preparation of 3- (2,5- dichloro pyrimidine -4- bases) -2,3- dihydrobenzos [d] thiazole 1,1- dioxide
2,3- dihydrobenzos [d] thiazole -1,1- dioxide (507mg, 3.0mmol) is dissolved in 10mL tetrahydrofurans, Under ice bath be added sodium hydride (86.4mg, 3.6mmol), stirring be slow added into after ten minutes 2,4,5- trichloropyrimidines (549mg, 3.0mmol), it is warmed to room temperature stirring 2 hours, 20mL sodium chloride saturated solutions are added, are extracted with dichloromethane, organic phase is with anhydrous Sodium sulphate is dried, and rotary evaporation removes solvent, and residue is through pillar layer separation (petroleum ether:Ethyl acetate=10:1) product is obtained (376mg, yield 39.7%).
(11) tertiary butyl 5- ((the chloro- 4- of 5- (1,1- dioxies benzo [d] thiazole -3 (2H)-yl) pyrimidine -2-base) amino) -6- The preparation of isopropoxy isoindoline -2- formic acid esters
By 3- (2,5- dichloro pyrimidine -4- bases) -2,3- dihydrobenzos [d] thiazole 1,1- dioxide (103mg, 0.326mmol), tertiary butyl 5- amino -6- isopropoxies isoindoline -2- formic acid esters (95mg, 0.325mmol), Pd2 (dba)3(10mg), X-Phos (20mg), cesium carbonate (106mg, 0.326mmol), is added in Isosorbide-5-Nitrae-dioxane of 10mL, Nitrogen protection, 110 DEG C are heated 6 hours.Rotary evaporation removes solvent, and 10mL sodium chloride saturated solutions are added, are extracted with dichloromethane It takes, organic phase is dried with anhydrous sodium sulfate, and rotary evaporation removes solvent, and residue is through pillar layer separation (DCM:MeOH=10:1) Obtain product (82mg, yield 44.0%).
(12) 3- (the chloro- 2- of 5- ((6- isopropoxy isoindoline -5- bases) amino) pyrimidine-4-yl) -2,3- dihydrobenzenes And the preparation of [d] thiazole 1,1- dioxide
Tertiary butyl 5- ((the chloro- 4- of 5- (1,1- dioxies benzo [d] thiazole -3 (2H)-yl) pyrimidine -2-base) amino) -6- is different Propoxyl group isoindoline -2- formic acid esters (82mg, 0.143mmol) is dissolved in the dichloromethane and trifluoroacetic acid mixed solution of 5mL In (1:1) it, is stirred at room temperature 2 hours, rotary evaporation removes solvent, and residue is through pillar layer separation (DCM:MeOH=10:1) it obtains Final product (46mg, yield 68.0%).
Molecular formula：C22H22ClN5O3S molecular weight:471.96 LC-MS(m/z):472.1[M+H]+
1H-NMR(400MHz,CDCl3)δ:8.35 (s, 1H), 7.97 (s, 1H), 7.81 (s, 1H), 7.78 (d, 1H, J= 7.2Hz), 7.56 (d, 1H, J=1.2Hz), 7.46 (d, 1H, J=8.4Hz), 7.31 (t, 1H, J=7.6Hz), 6.79 (s, 1H), 5.04 (s, 2H), 4.54-4.60 (m, 1H), 4.20 (s, 2H), 4.04 (s, 2H), 1.38 (d, 6H, J=6.0Hz).

Claims (12)

  1. General formula 1. (I) compound represented, its pharmaceutically acceptable salt or its stereoisomer：
    Wherein,
    R1Selected from hydrogen atom, hydroxyl, amino, cyano, nitro, carboxyl, halogen atom, C1-6Alkyl, hydroxyl C1-6Alkyl, halogenated C1-6 Alkyl, C1-6Alkoxy, hydroxyl C1-6Alkoxy, halogenated C1-6Alkoxy, C2-8Alkenyl, C2-8Alkynyl, C1-6Alkyl amino or (C1-6 Alkyl)2Amino；
    R2、R4、R5Separately it is selected from hydrogen atom, halogen atom, nitro, cyano, amino, hydroxyl, carboxyl, C1-6Alkyl, hydroxyl Base C1-6Alkyl, halogenated C1-6Alkyl, amino C1-6Alkyl, sulfonyl C1-6Alkyl, C1-6Alkoxy, hydroxyl C1-6It is alkoxy, halogenated C1-6Alkoxy, C2-8Alkenyl, C2-8Alkynyl, C1-6Alkyl sulfenyl, C1-6Alkyl-carbonyl, C1-6Alkyl carbonyl epoxide, C1-6Alkyl sulfonyl Amino, C1-6Alkyl amino sulfonyl, (C1-6Alkyl)2Amino-sulfonyl or C1-6Alkyl sulphonyl；
    R3Selected from optionally by W 5~14 unit's heteroaryls replaced or 3~8 circle heterocyclic ring bases；
    Or R2And R33~8 yuan of naphthenic base optionally replaced by W, 3~8 circle heterocyclic ring bases or 5~14 are formed together with the carbon being attached thereto Unit's heteroaryl；
    Or R4And R5It is miscellaneous that 6~8 yuan of aryl optionally replaced by W, 5~8 unit's heteroaryls or 3~8 yuan are formed together with the carbon being attached thereto Ring group；
    X, Y is separately selected from-SO2, or the C that is optionally replaced by W1-4Alkylidene；
    N is selected from 0,1,2 or 3；
    W is selected from hydroxyl, halogen atom, amino, nitro, cyano, carboxyl, C1-6Alkyl, C1-6Alkoxy, halogenated C1-6It is alkyl, halogenated C1-6Alkoxy, C1-6Alkyl amino, (C1-6Alkyl)2Amino, C1-6Alkyl-carbonyl, C1-6Alkyl carbonyl epoxide, C1-6Alkyl sulfonyl Base, C1-6Alkyl sulfonyl amino, C1-6Alkoxy C1-6Alkyl, hydroxyl C1-6Alkyl amino, hydroxyl C1-6Alkoxy, amino-sulfonyl, Aminosulfonyl amino, amino-sulfonyl C1-6Alkyl, aminosulfonyl amino C1-6Alkyl, 5~6 unit's heteroaryls, 5~6 circle heterocyclic ring bases Or 3~8 yuan of naphthenic base.
  2. 2. compound as described in claim 1, its pharmaceutically acceptable salt or its stereoisomer：
    Wherein,
    R1Selected from hydrogen atom, halogen atom, nitro, cyano, amino, hydroxyl, carboxyl, C1-6Alkyl, hydroxyl C1-6Alkyl is halogenated C1-6Alkyl；
    R2、R4、R5Separately it is selected from hydrogen atom, halogen atom, nitro, cyano, amino, hydroxyl, carboxyl, C1-6Alkyl, hydroxyl Base C1-6Alkyl, halogenated C1-6Alkyl, amino C1-6Alkyl, C1-6Alkoxy, hydroxyl C1-6Alkoxy or halogenated C1-6Alkoxy；
    R3Selected from optionally by W 5~8 unit's heteroaryls replaced or 4~6 circle heterocyclic ring bases；
    Or R2And R3It is formed optionally by W 5~8 unit's heteroaryls replaced or 4~6 circle heterocyclic ring bases together with the carbon being attached thereto；
    Or R4And R5It is formed optionally by W 5~6 unit's heteroaryls replaced or 4~6 circle heterocyclic ring bases together with the carbon being attached thereto；
    X, Y is separately selected from-SO2, or the C that is optionally replaced by W1-4Alkylidene；
    N is selected from 0 or 1；
    W is selected from hydroxyl, halogen atom, amino, nitro, carboxyl, cyano, C1-6Alkyl, C1-6Alkoxy, halogenated C1-6It is alkyl, halogenated C1-6Alkoxy or C1-6Alkyl amino.
  3. 3. compound, its pharmaceutically acceptable salt or its stereoisomer as claimed in claim 2：
    Wherein,
    R1Selected from hydrogen atom, halogen atom, nitro, cyano, amino, hydroxyl, carboxyl or C1-6Alkyl；
    R2、R4、R5Separately it is selected from hydrogen atom, halogen atom, nitro, cyano, amino, hydroxyl, carboxyl, C1-6Alkyl, hydroxyl Base C1-6Alkyl, halogenated C1-6Alkyl, amino C1-6Alkyl, C1-6Alkoxy, hydroxyl C1-6Alkoxy or halogenated C1-6Alkoxy；
    R3Selected from 5~6 unit's heteroaryls or 5~6 circle heterocyclic ring bases containing 1~2 N atom optionally replaced by W；
    Or R2And R35~6 circle heterocyclic ring bases containing 1~2 N atom optionally replaced by W are formed together with the carbon being attached thereto；
    Or R4And R55~6 circle heterocyclic rings containing 1~2 O and/or S atom optionally replaced by W are formed together with the carbon being attached thereto Base；
    X, Y is separately selected from-SO2, or the C that is optionally replaced by W1-4Alkylidene；
    N is selected from 0 or 1；
    W is selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atom, C1-6Alkyl, C1-6Alkoxy or C1-6Alkyl amino.
  4. 4. compound as claimed in claim 3, its pharmaceutically acceptable salt or its stereoisomer：
    Wherein,
    R1Selected from hydrogen atom, halogen atom, nitro, cyano, amino, hydroxyl, carboxyl or C1-4Alkyl；
    R2、R4、R5Separately it is selected from hydrogen atom, halogen atom, C1-4Alkyl, hydroxyl C1-4Alkyl, amino C1-4It is alkyl, halogenated C1-4Alkyl, C1-4Alkoxy, halogenated C1-4Alkoxy or hydroxyl C1-4Alkoxy；
    R3Selected from pyridyl group, dihydropyridine base, tetrahydro pyridyl, pyrrole radicals, pyrrolin base, the nafoxidine optionally replaced by W Base, piperidyl, piperazinyl or morpholinyl；
    X, Y is separately selected from-SO2Or the C optionally replaced by W1-4Alkylidene；
    N is selected from 0 or 1；
    W is selected from hydroxyl, halogen atom, amino, nitro or C1-4Alkyl.
  5. 5. compound as claimed in claim 3, its pharmaceutically acceptable salt or its stereoisomer：
    Wherein,
    R1Selected from hydrogen atom, halogen atom, nitro, cyano, amino, hydroxyl, carboxyl or C1-4Alkyl；
    R2And R35~6 circle heterocyclic ring bases containing 1~2 N atom optionally replaced by W are formed together with the carbon being attached thereto；
    R4、R5Separately it is selected from hydrogen atom, C1-4Alkyl or C1-4Alkoxy；
    X, Y is separately selected from-SO2Or the C optionally replaced by W1-4Alkylidene；
    N is selected from 0 or 1；
    W is selected from hydroxyl, halogen atom, amino, nitro or C1-4Alkyl.
  6. 6. compound as claimed in claim 3, its pharmaceutically acceptable salt or its stereoisomer：
    Wherein,
    R1Selected from hydrogen atom, halogen atom, nitro, cyano, amino, hydroxyl, carboxyl or C1-4Alkyl；
    R2Selected from hydrogen atom, halogen atom, C1-4Alkyl, hydroxyl C1-4Alkyl, amino C1-4Alkyl, C1-4Alkoxy or hydroxyl C1-4Alkane Oxygroup；
    R3Selected from pyridyl group, dihydropyridine base, tetrahydro pyridyl, pyrrole radicals, pyrrolin base, the nafoxidine optionally replaced by W Base, piperidyl, piperazinyl or morpholinyl；
    R4And R55~6 circle heterocyclic rings containing 1~2 O and/or S atom optionally replaced by W are formed together with the carbon being attached thereto Base；
    X, Y is separately selected from-SO2Or the C optionally replaced by W1-4Alkylidene；
    N is selected from 0 or 1；
    W is selected from hydroxyl, halogen atom, amino, nitro or C1-4Alkyl.
  7. 7. compound as described in claim 1, its pharmaceutically acceptable salt or its stereoisomer, wherein the compound It is selected from：
  8. 8. the compound, its pharmaceutically acceptable salt as described in claim 1~7 any claim or its stereoisomer It is pharmaceutically acceptable any dosage form with preparation made of one or more pharmaceutical carriers.
  9. 9. it is different to contain the compound as described in claim 1~7 any claim, its pharmaceutically acceptable salt or its solid The pharmaceutical composition of structure body also contains one or more active constituents of medicine.
  10. 10. composition as claimed in claim 9, which is characterized in that one or more active constituents of medicine are anti-swollen Tumor agent and/or immunosuppressor, the antitumor agent and/or immunosuppressor are antimetabolite, selected from capecitabine, Ji Xi His shore, pemetrexed disodium；For growth factor receptor inhibitors, it is selected from pazopanib, Imatinib, Erlotinib, Lapatinib, Ji It is non-to replace Buddhist nun, Vande Thani；For antibody, it is selected from Trastuzumab, bevacizumab；It is auspicious selected from taxol, Changchun for mitotic inhibitor Shore, docetaxel, Doxorubicin；For antitumor steroids, it is selected from Letrozole, tamoxifen, fulvestrant, Flutamide, Qu Pu Rayleigh；For alkylating agents, it is selected from cyclophosphamide, mustargen, melphalan, chlorambucil, Carmustine；For metal platinum class, selected from carboplatin, Cis-platinum, oxaliplatin；It is suitable selected from everolimus, sirolimus, special cancer for immunosupress class；For purine analogue, it is selected from 6- mercaptos Base purine, 6- thioguanines, imuran；For antibiotics, selected from rhzomorph D, daunorubicin, adriamycin, mitoxantrone, win honour for Mycin, plicamycin；For platinum complex, it is selected from cis-platinum, Kapo Platinum；For adrenal cortex inhibitor class, it is selected from aminoglutethimide；For Enzyme inhibitor selected from SAHA, cytarabine, methotrexate (MTX), hydroxycarbamide, Hydroxycamptothecin, Topotecan, topotecan, is replaced according to vertical Health.
  11. 11. the compound, its pharmaceutically acceptable salt as described in claim 1~7 any claim or its alloisomerism Application of the body in the drug for preparing the cancer-related diseases or non-cancerous disease for treating and/or preventing ALK mediations, it is described The relevant disease of cancer be selected from the cancer of the brain, lung cancer, dermoid cancer, carcinoma of urinary bladder, gastric cancer, oophoroma, peritoneal cancer, cancer of pancreas, Breast cancer, head and neck cancer, cervix cancer, carcinoma of endometrium, colorectal cancer, liver cancer, kidney, the cancer of the esophagus, adenocarcinoma of esophagus, esophagus squameous Cell cancer, non-Hodgkin lymphoma, brain tumor, central nerve neuroma, glioma, glioblastoma multiforme, glue Matter sarcoma, prostate cancer, thyroid cancer, female reproductive tract cancer, carcinoma in situ, lymthoma, histocytic lymphoma, nerve fibre Tumor, osteocarcinoma, cutaneum carcinoma, colon cancer, carcinoma of testis, gastrointestinal stromal tumor, mast cell tumor, Huppert's disease, melanoma, Glioma, glioblastoma, astrocytoma, neuroblastoma, sarcoma；Non-cancerous disease is selected from skin or prostate Hyperplasia of prostate.
  12. 12. application as claimed in claim 11, the lung cancer are selected from non-small cell lung cancer and Small Cell Lung Cancer.
CN201510224442.9A 2015-05-05 2015-05-05 Two and ring class anaplastic lymphoma kinase inhibitor Active CN106188029B (en)

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