CN106188029A - Two and ring class anaplastic lymphoma kinase ALK Alk receptor tyrosine kinase inhibitor - Google Patents

Abstract

The invention belongs to pharmaceutical technology field, be specifically related to logical two shown in formula I ring class anaplastic lymphoma kinase ALK Alk receptor tyrosine kinase inhibitor, its pharmaceutically acceptable salt, ester, solvate or its stereoisomer, wherein R¹、R²、R³、R⁴、R⁵, n, X and Y be defined as in the description.The invention still further relates to the preparation method of these compounds, pharmaceutical preparation containing these compounds and pharmaceutical composition, and the application that this compound, its pharmaceutically acceptable salt, ester, solvate or its stereoisomer are in the medicine of the cancer-related diseases that preparation is treated and/or prevention is mediated by anaplastic lymphoma kinase ALK Alk receptor tyrosine kinase.

Description

Two and ring class anaplastic lymphoma kinase ALK Alk receptor tyrosine kinase inhibitor

Technical field

The invention belongs to pharmaceutical technology field, be specifically related to two and ring class anaplastic lymphoma kinase ALK Alk receptor tyrosine kinase inhibitor, it pharmaceutically can connect Salt, ester, solvate or its stereoisomer being subject to, the preparation method of these compounds, containing the medicine system of these compounds Agent and pharmaceutical composition, and this compound, its pharmaceutically acceptable salt, ester, solvate or its stereoisomer are in system Application in the medicine of the cancer-related diseases that standby treatment and/or prevention are mediated by anaplastic lymphoma kinase ALK Alk receptor tyrosine kinase.

Background technology

Anaplastic lymphoma kinase ALK Alk receptor tyrosine kinase (Anaplastic lymphoma kinase, ALK) is receptor tyrosine kinase family member, can lead to Cross autophosphorylation and raise downstream albumen, and then express specific gene, regulation cellular metabolism and growth.Anaplastic lymphoma swashs Enzyme is found in primary cutaneous type (Anaplastic large cell lymphoma, ALCL) the earliest, finds later non- Small cell lung cancer (NSCLC) also there is high expressed.ALK unconventionality expression in some ALCL/NSCLC derives from difference Chromosome translocation.These chromosome translocations all can produce corresponding fusion protein.These analysis of fused genes are shown, they All contain the gene order in ALK gene 3 ' end coding intracellular kinase district, and all first containing promoter with the genetic fragment that ALK merges Part and coding mediate the sequence of self dimerization, thus cause the intracellular fusion protein high expressed with ALK kinase activity and mistake Degree activates, and causes the vicious transformation of cell.So, activity and the corresponding signal transduction path in ALK intracellular kinase district are to cause The important molecule mechanism that ALCL is formed.

Therefore, research and develop the micromolecular inhibitor for ALK, the ALK gene of sudden change can be effectively reduced to downstream albumen Impact, and then have influence on the effect such as tumor cell invasion, propagation, finally affect the growth of tumor cell, play antineoplastic and make With.Gram azoles having had Pfizer at present successfully lists for Buddhist nun (Crizotinib), but existing a large amount of clinic proves generation ALK Inhibitor C rizotinib, easily produces drug resistance, therefore, designs and screen the activated micromolecular inhibitor that suddenlys change ALK And make great efforts to improve the physicochemical property of compound, improve druggability (as improved the bioavailability of compound), have and significantly face Bed meaning.

Summary of the invention

The present invention with exploitation for the micromolecular inhibitor of ALK as target, invented treatment and/or the cancer of prevention ALK mediation Disease relevant disease has two and ring class anaplastic lymphoma kinase ALK Alk receptor tyrosine kinase inhibitor of good result.Concrete technical scheme is as follows:

1. lead to the compound shown in formula I, its pharmaceutically acceptable salt, ester, solvate or its stereoisomer:

Wherein,

R¹Selected from hydrogen atom, hydroxyl, amino, cyano group, nitro, carboxyl, halogen atom, C_1-6Alkyl, hydroxyl C_1-6Alkyl, Halo C_1-6Alkyl, C_1-6Alkoxyl, hydroxyl C_1-6Alkoxyl, halo C_1-6Alkoxyl, C_2-8Thiazolinyl, C_2-8Alkynyl, C_1-6 Alkyl amino or (C_1-6Alkyl)₂Amino；

R²、R⁴、R⁵Separately selected from hydrogen atom, halogen atom, nitro, cyano group, amino, hydroxyl, carboxyl, C_1-6 Alkyl, hydroxyl C_1-6Alkyl, halo C_1-6Alkyl, amino C_1-6Alkyl, sulfonyl C_1-6Alkyl, C_1-6Alkoxyl, hydroxyl C_1-6Alkoxyl, halo C_1-6Alkoxyl, C_2-8Thiazolinyl, C_2-8Alkynyl, C_1-6Alkyl sulfenyl, C_1-6Alkyl-carbonyl, C_1-6Alkyl Carbonyl epoxide, C_1-6Alkyl sulfonyl amino, C_1-6Alkyl amino sulfonyl, (C_1-6Alkyl)₂Amino-sulfonyl or C_1-6Alkyl sulfonyl Base；

R³Selected from the 5～14 yuan of heteroaryls optionally replaced by W or 3～8 yuan of heterocyclic radicals；

Or R²And R³3～8 yuan of cycloalkyl, the 3～8 yuan of heterocyclic radicals or 5～14 optionally replaced by W are formed together with the carbon being attached thereto Unit's heteroaryl；

Or R⁴And R⁵6～the 8 yuan of aryl optionally replaced by W, 5～8 yuan of heteroaryls or 3～8 yuan are formed together with the carbon being attached thereto Heterocyclic radical；

X, Y are separately selected from-CO-,-CO₂-,-SO-,-SO₂-, the alkylidene optionally replaced by W or imino group；

N is selected from 0,1,2 or 3；

W is selected from hydroxyl, halogen atom, amino, nitro, cyano group, carboxyl, C_1-6Alkyl, C_1-6Alkoxyl, halo C_1-6 Alkyl, halo C_1-6Alkoxyl, C_1-6Alkyl amino, (C_1-6Alkyl)₂Amino, C_1-6Alkyl-carbonyl, C_1-6Alkyl-carbonyl epoxide, C_1-6Alkyl sulphonyl, C_1-6Alkyl sulfonyl amino, C_1-6Alkoxy C_1-6Alkyl, hydroxyl C_1-6Alkyl amino, hydroxyl C_1-6Alkane Epoxide, amino-sulfonyl, aminosulfonyl amino, amino-sulfonyl C_1-6Alkyl, aminosulfonyl amino C_1-6Alkyl, 5～6 yuan Heteroaryl, 5～6 yuan of heterocyclic radicals or 3～8 yuan of cycloalkyl.

2. compound, its pharmaceutically acceptable salt, ester, solvate or its stereoisomer as described in technical scheme 1, Wherein,

R¹Selected from hydrogen atom, halogen atom, nitro, cyano group, amino, hydroxyl, carboxyl, C_1-6Alkyl, hydroxyl C_1-6Alkyl Or halo C_1-6Alkyl；

R²、R⁴、R⁵Separately selected from hydrogen atom, halogen atom, nitro, cyano group, amino, hydroxyl, carboxyl, C_1-6 Alkyl, hydroxyl C_1-6Alkyl, halo C_1-6Alkyl, amino C_1-6Alkyl, C_1-6Alkoxyl, hydroxyl C_1-6Alkoxyl or halo C_1-6Alkoxyl；

R³Selected from the 5～8 yuan of heteroaryls optionally replaced by W or 4～6 yuan of heterocyclic radicals；

Or R²And R³5～the 8 yuan of heteroaryls or 4～6 yuan of heterocyclic radicals optionally replaced by W are formed together with the carbon being attached thereto；

Or R⁴And R⁵5～the 6 yuan of heteroaryls or 4～6 yuan of heterocyclic radicals optionally replaced by W are formed together with the carbon being attached thereto；

X, Y are separately selected from-CO-,-CO₂-,-SO-,-SO₂-, the C optionally replaced by W_1-6Alkylidene or imido Base；

N is selected from 0 or 1；

W is selected from hydroxyl, halogen atom, amino, nitro, carboxyl, cyano group, C_1-6Alkyl, C_1-6Alkoxyl, halo C_1-6 Alkyl, halo C_1-6Alkoxyl or C_1-6Alkyl amino.

3. compound, its pharmaceutically acceptable salt, ester, solvate or its stereoisomer as described in technical scheme 2, Wherein,

R¹Selected from hydrogen atom, halogen atom, nitro, cyano group, amino, hydroxyl, carboxyl or C_1-6Alkyl；

R²、R⁴、R⁵Separately selected from hydrogen atom, halogen atom, nitro, cyano group, amino, hydroxyl, carboxyl, C_1-6 Alkyl, hydroxyl C_1-6Alkyl, halo C_1-6Alkyl, amino C_1-6Alkyl, C_1-6Alkoxyl, hydroxyl C_1-6Alkoxyl or halo C_1-6Alkoxyl；

R³Selected from the 5～6 yuan of heteroaryls containing 1～2 atom N optionally replaced by W or 5～6 yuan of heterocyclic radicals；

Or R²And R³5～the 6 yuan of heterocyclic radicals containing 1～2 atom N optionally replaced by W are formed together with the carbon being attached thereto；

Or R⁴And R⁵5～6 yuan containing 1～2 O and/or S atom optionally replaced by W are formed miscellaneous together with the carbon being attached thereto Ring group；

X, Y are separately selected from-SO-,-SO₂-, the C optionally replaced by W_1-6Alkylidene or imino group；

N is selected from 0 or 1；

W is selected from hydroxyl, amino, carboxyl, cyano group, nitro, halogen atom, C_1-6Alkyl, C_1-6Alkoxyl or C_1-6Alkyl ammonia Base.

4. compound, its pharmaceutically acceptable salt, ester, solvate or its stereoisomer as described in technical scheme 3, Wherein,

X, Y are separately selected from-SO₂-or the C that optionally replaced by W_1-6Alkylidene, wherein X, Y can not be by W simultaneously Substituted C_1-6Alkylidene.

5. compound, its pharmaceutically acceptable salt, ester, solvate or its stereoisomer as described in technical scheme 3, Wherein,

R¹Selected from hydrogen atom, halogen atom, nitro, cyano group, amino, hydroxyl, carboxyl or C_1-4Alkyl；

R²、R⁴、R⁵Separately selected from hydrogen atom, halogen atom, C_1-4Alkyl, hydroxyl C_1-4Alkyl, amino C_1-4Alkane Base, halo C_1-4Alkyl, C_1-4Alkoxyl, halo C_1-4Alkoxyl or hydroxyl C_1-4Alkoxyl；

R³Selected from optionally replaced by W pyridine radicals, dihydropyridine base, tetrahydro pyridyl, pyrrole radicals, pyrrolin base, four Hydrogen pyrrole radicals, piperidyl, piperazinyl or morpholinyl；

X, Y are separately selected from-SO₂-or the C that optionally replaced by W_1-4Alkylidene；

N is selected from 0 or 1；

W is selected from hydroxyl, halogen atom, amino, nitro or C_1-4Alkyl.

6. compound, its pharmaceutically acceptable salt, ester, solvate or its stereoisomer as described in technical scheme 3, Wherein,

R¹Selected from hydrogen atom, halogen atom, nitro, cyano group, amino, hydroxyl, carboxyl or C_1-4Alkyl；

R²And R³5～the 6 yuan of heterocyclic radicals containing 1～2 atom N optionally replaced by W are formed together with the carbon being attached thereto；

R⁴、R⁵Separately selected from hydrogen atom, C_1-4Alkyl or C_1-4Alkoxyl；

X, Y are separately selected from-SO₂-or the C that optionally replaced by W_1-4Alkylidene；

N is selected from 0 or 1；

W is selected from hydroxyl, halogen atom, amino, nitro or C_1-4Alkyl.

7. compound, its pharmaceutically acceptable salt, ester, solvate or its stereoisomer as described in technical scheme 6, Wherein,

R²And R³The 6 yuan of heterocyclic radicals containing 1～2 atom N optionally replaced by W are formed together with the carbon being attached thereto；

W is selected from hydroxyl, halogen atom, amino, nitro or C_1-4Alkyl.

8. compound, its pharmaceutically acceptable salt, ester, solvate or its stereoisomer as described in technical scheme 6, Wherein,

R²And R³5～the 6 yuan of heterocyclic radicals containing 1 atom N optionally replaced by W are formed together with the carbon being attached thereto；

W is selected from hydroxyl, halogen atom, amino, nitro or C_1-4Alkyl.

9. compound, its pharmaceutically acceptable salt, ester, solvate or its stereoisomer as described in technical scheme 3, Wherein,

R¹Selected from hydrogen atom, halogen atom, nitro, cyano group, amino, hydroxyl, carboxyl or C_1-4Alkyl；

R²Selected from hydrogen atom, halogen atom, C_1-4Alkyl, hydroxyl C_1-4Alkyl, amino C_1-4Alkyl, C_1-4Alkoxyl or hydroxyl C_1-4Alkoxyl；

R³Selected from optionally replaced by W pyridine radicals, dihydropyridine base, tetrahydro pyridyl, pyrrole radicals, pyrrolin base, four Hydrogen pyrrole radicals, piperidyl, piperazinyl or morpholinyl；

R⁴And R⁵5～6 yuan containing 1～2 O and/or S atom optionally replaced by W are formed miscellaneous together with the carbon being attached thereto Ring group；

X, Y are separately selected from-SO₂-or the C that optionally replaced by W_1-4Alkylidene；

N is selected from 0 or 1；

W is selected from hydroxyl, halogen atom, amino, nitro or C_1-4Alkyl.

10. compound, its pharmaceutically acceptable salt, ester, solvate or its stereoisomer as described in technical scheme 9, Wherein,

R⁴And R⁵Together with the carbon being attached thereto formed optionally by W replace containing 1～2 O and/or 6 yuan of heterocyclic radicals of S atom；

W is selected from hydroxyl, halogen atom, amino, nitro or C_1-4Alkyl.

11. compound, its pharmaceutically acceptable salt, ester, solvate or its stereoisomers as described in technical scheme 10, Wherein,

R⁴And R⁵Together with the carbon being attached thereto formed optionally by W replace containing 2 O and/or 5～6 yuan of heterocyclic radicals of S atom；

W is selected from hydroxyl, halogen atom, amino, nitro or C_1-4Alkyl.

12. compound, its pharmaceutically acceptable salt, ester, solvate or its stereoisomers as described in technical scheme 2, Wherein,

R¹Selected from hydrogen atom, halogen atom, nitro, cyano group, amino, hydroxyl, carboxyl or C_1-6Alkyl；

R²、R⁴、R⁵Separately selected from hydrogen atom, C_1-6Alkyl, hydroxyl C_1-6Alkyl, halo C_1-6Alkyl, amino C_1-6 Alkyl, C_1-6Alkoxyl, hydroxyl C_1-6Alkoxyl or halo C_1-6Alkoxyl；

R³Selected from the 5～6 yuan of heterocyclic radicals optionally replaced by W；

Or R²And R³5～the 6 yuan of heterocyclic radicals optionally replaced by W are formed together with the carbon being attached thereto；

Or R⁴And R⁵Forming 5～6 yuan of heterocyclic radicals together with the carbon being attached thereto, 5～6 yuan of described heterocyclic radicals can optionally be replaced by W；

X, Y are separately selected from-SO₂-or the C that optionally replaced by W_1-6Alkylidene；

N is selected from 0 or 1；

W is selected from hydroxyl, halogen atom, amino, nitro, carboxyl, cyano group, C_1-6Alkyl or C_1-6Alkoxyl.

13. compound, its pharmaceutically acceptable salt, ester, solvate or its stereoisomers as described in technical scheme 12, Wherein,

R¹Selected from hydrogen atom, halogen atom, nitro, cyano group, amino, hydroxyl, carboxyl or C_1-6Alkyl；

R²、R⁴、R⁵Separately selected from hydrogen atom, C_1-6Alkyl, hydroxyl C_1-6Alkyl, halo C_1-6Alkyl, amino C_1-6 Alkyl, C_1-6Alkoxyl, hydroxyl C_1-6Alkoxyl or halo C_1-6Alkoxyl；

R³Selected from the 6 yuan of saturated heterocyclyls containing 1～2 atom N optionally replaced by W；

Or R²And R³The 5 yuan of saturated heterocyclyls containing 1～2 atom N optionally replaced by W are formed together with the carbon being attached thereto；

Or R⁴And R⁵6 yuan containing 1～2 O and/or S atom optionally replaced by W are formed saturated together with the carbon being attached thereto Heterocyclic radical；

W is selected from hydroxyl, halogen atom, amino, nitro, carboxyl, cyano group, C_1-6Alkyl or C_1-6Alkoxyl.

14. compound, its pharmaceutically acceptable salt, ester, solvate or its stereoisomers as described in technical scheme 12, Wherein,

R¹Selected from hydrogen atom, halogen atom, nitro, cyano group, amino, hydroxyl, carboxyl or C_1-6Alkyl；

R²、R⁴、R⁵Separately selected from hydrogen atom, C_1-6Alkyl, hydroxyl C_1-6Alkyl, halo C_1-6Alkyl, amino C_1-6 Alkyl, C_1-6Alkoxyl, hydroxyl C_1-6Alkoxyl or halo C_1-6Alkoxyl；

R³Selected from the 5～6 yuan of saturated heterocyclyls containing 1 atom N optionally replaced by W；

Or R²And R³5～the 6 yuan of saturated heterocyclyls containing 1 atom N optionally replaced by W are formed together with the carbon being attached thereto；

Or R⁴And R⁵5～6 yuan containing 2 O and/or S atom optionally replaced by W are formed saturated together with the carbon being attached thereto Heterocyclic radical；

W is selected from hydroxyl, halogen atom, amino, nitro, carboxyl, cyano group, C_1-6Alkyl or C_1-6Alkoxyl.

15. compound, its pharmaceutically acceptable salt, ester, solvate or its stereoisomers as described in technical scheme 2, Wherein,

R¹Selected from hydrogen atom, halogen atom, nitro, cyano group, amino, hydroxyl, carboxyl or C_1-6Alkyl；

R³Selected from optionally replaced by W pyridine radicals, dihydropyridine base, tetrahydro pyridyl, pyrrole radicals, pyrrolin base, four Hydrogen pyrrole radicals, piperidyl, piperazinyl or morpholinyl；

R²、R⁴、R⁵Separately selected from hydrogen atom, halogen atom, nitro, cyano group, amino, hydroxyl, carboxyl, C_1-6 Alkyl, hydroxyl C_1-6Alkyl, halo C_1-6Alkyl, amino C_1-6Alkyl, C_1-6Alkoxyl, hydroxyl C_1-6Alkoxyl or halo C_1-6Alkoxyl；

Or R²And R³Formed together with the carbon being attached thereto optionally replaced by W pyrrole radicals, pyrrolin base, nafoxidine base, Pyrazolyl, imidazole radicals, thiazolyl, oxazolyl, pyridine radicals, dihydropyridine base, tetrahydro pyridyl, pyrimidine radicals, pyrazinyl, Piperidyl, piperazinyl or morpholinyl；

Or R⁴And R⁵1,4-dioxane base, the 1,3-dioxane optionally replaced by W is formed together with the carbon being attached thereto Hexyl, 1,3-dioxolane base, 1,4-Dioxin base, tetrahydrofuran base, THP trtrahydropyranyl, 4,5- Dihydro-thiazolyl, morpholinyl, oxazolyl, 4,5-dihydro oxazolyl, 4,5-dihydro isoxazolyl, thiapyran base or thiazolyl；

X, Y are separately selected from-SO-,-SO₂-, the C optionally replaced by W_1-6Alkylidene or imino group；

N is equal to 0 or 1；

W is selected from hydroxyl, amino, carboxyl, cyano group, nitro, halogen atom, C_1-6Alkyl, C_1-6Alkoxyl or C_1-6Alkyl ammonia Base.

16. compound, its pharmaceutically acceptable salt, ester, solvate or its stereoisomers as described in technical scheme 15, Wherein,

R¹Selected from hydrogen atom, halogen atom, nitro, cyano group, amino, hydroxyl, carboxyl or C_1-6Alkyl；

R³Selected from optionally replaced by W pyridine radicals, dihydropyridine base, tetrahydro pyridyl, pyrrole radicals, pyrrolin base, four Hydrogen pyrrole radicals, piperidyl, piperazinyl or morpholinyl；

R²、R⁴、R⁵Separately selected from hydrogen atom, halogen atom, nitro, cyano group, amino, hydroxyl, carboxyl, C_1-6 Alkyl, hydroxyl C_1-6Alkyl, halo C_1-6Alkyl, amino C_1-6Alkyl, C_1-6Alkoxyl, hydroxyl C_1-6Alkoxyl or halo C_1-6Alkoxyl；

W is selected from hydroxyl, amino, carboxyl, cyano group, nitro, halogen atom, C_1-6Alkyl, C_1-6Alkoxyl or C_1-6Alkyl ammonia Base.

17. compound, its pharmaceutically acceptable salt, ester, solvate or its stereoisomers as described in technical scheme 15, Wherein,

R¹Selected from hydrogen atom, halogen atom, nitro, cyano group, amino, hydroxyl, carboxyl or C_1-6Alkyl；

R⁴、R⁵Separately selected from hydrogen atom, halogen atom, nitro, cyano group, amino, hydroxyl, carboxyl, C_1-6Alkyl, Hydroxyl C_1-6Alkyl, halo C_1-6Alkyl, amino C_1-6Alkyl, C_1-6Alkoxyl, hydroxyl C_1-6Alkoxyl or halo C_1-6Alcoxyl Base；

R²And R³Formed together with the carbon being attached thereto optionally replaced by W pyrrole radicals, pyrrolin base, nafoxidine base, pyrrole Oxazolyl, imidazole radicals, thiazolyl, oxazolyl, pyridine radicals, dihydropyridine base, tetrahydro pyridyl, pyrimidine radicals, pyrazinyl, Piperidyl, piperazinyl or morpholinyl；

W is selected from hydroxyl, amino, carboxyl, cyano group, nitro, halogen atom, C_1-6Alkyl, C_1-6Alkoxyl or C_1-6Alkyl ammonia Base.

18. compound, its pharmaceutically acceptable salt, ester, solvate or its stereoisomers as described in technical scheme 15, Wherein,

R¹Selected from hydrogen atom, halogen atom, nitro, cyano group, amino, hydroxyl, carboxyl or C_1-6Alkyl；

R³Selected from optionally replaced by W pyridine radicals, dihydropyridine base, tetrahydro pyridyl, pyrrole radicals, pyrrolin base, four Hydrogen pyrrole radicals, piperidyl, piperazinyl or morpholinyl；

R²Selected from hydrogen atom, halogen atom, nitro, cyano group, amino, hydroxyl, carboxyl, C_1-6Alkyl, hydroxyl C_1-6Alkyl, Halo C_1-6Alkyl, amino C_1-6Alkyl, C_1-6Alkoxyl, hydroxyl C_1-6Alkoxyl or halo C_1-6Alkoxyl；

R⁴And R⁵1,4-dioxane base, the 1,3-dioxa hexamethylene optionally replaced by W is formed together with the carbon being attached thereto Alkyl, 1,3-dioxolane base, 1,4-Dioxin base, tetrahydrofuran base, THP trtrahydropyranyl, 4,5-dihydro Thiazolyl, morpholinyl, oxazolyl, 4,5-dihydro oxazolyl, 4,5-dihydro isoxazolyl, thiapyran base or thiazolyl；

W is selected from hydroxyl, amino, carboxyl, cyano group, nitro, halogen atom, C_1-6Alkyl, C_1-6Alkoxyl or C_1-6Alkyl ammonia Base.

19. compound, its pharmaceutically acceptable salt, ester, solvate or its stereoisomers as described in technical scheme 2, Wherein,

X, Y are separately selected from-CO-,-CO₂-,-SO-,-SO₂-, the C optionally replaced by W_1-6Alkylidene or imido Representative-a CO-,-CO in base, and X, Y₂-,-SO-or-SO₂-, another represents the C optionally replaced by W_1-6Alkylene Base or imino group；

W is selected from hydroxyl, halogen atom, amino, nitro, carboxyl, cyano group, C_1-6Alkyl, C_1-6Alkoxyl, halo C_1-6 Alkyl, halo C_1-6Alkoxyl or C_1-6Alkyl 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 representing same During one compound, the name of compound is not inconsistent with chemical structural formula, is as the criterion with chemical structural formula or chemical equation.

" halogen atom " of the present invention includes fluorine atom, chlorine atom, bromine atoms and atomic iodine etc..

" C of the present invention_1-6Alkyl " represent straight or branched the alkyl containing 1-6 carbon atom, including such as " C_1-4 Alkyl ", " C_1-3Alkyl " etc., instantiation includes but not limited to: methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, 2- Methyl-propyl, 1-methyl-propyl, 1,1-dimethyl ethyl, n-pentyl, 3-methyl butyl, 2-methyl butyl, 1-methyl butyl, 1- Ethyl propyl, n-hexyl, 4-methyl amyl, 3-methyl amyl, 2-methyl amyl, 1-methyl amyl, 3,3-dimethylbutyl, 2,2- Dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethyl-butyl, 1,2-dimethyl propyl etc..

" C of the present invention_2-8Thiazolinyl " refer to the straight or branched or ring-type that the carbon number containing at least one double bond is 2-8 Thiazolinyl, including such as " C_2-6Thiazolinyl ", " C_2-4Thiazolinyl ", " C_2-3Thiazolinyl ", " C_3-6Cycloalkenyl group " etc., instantiation include but It is not limited to: vinyl, 1-acrylic, 2-acrylic, crotyl, 3-cyclobutenyl, 2-methyl-1-propylene base, 1-methyl-2- Acrylic, 1-pentenyl, pentenyl, 3-pentenyl, 2-methyl-1-butene thiazolinyl, 3-methyl-1-butene base, 2-methyl-3-butylene Base, 1,1-dimethyl-2-acrylic, 1-ethyl-2-acrylic, 2-hexenyl, 3-hexenyl, 2-methyl-1-pentene thiazolinyl, 3-methyl -1-pentenyl, 1-methyl-pentenyl, 3-methyl-pentenyl, 2-methyl-3-pentenyl, 1-methyl-4-pentenyl, 3-methyl-4- Pentenyl, 1,1-dimethyl-3-cyclobutenyl, 1,2-dimethyl-3-cyclobutenyl, 1,3-dimethyl-crotyl, 2,2-dimethyl-3-butylene Base, 2,3-dimethyl-crotyl, 2,3-dimethyl-1-butylene base, 2-ethyl-1-butylene base, 2-ethyl-3-cyclobutenyl, 2-heptene Base, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 4-octenyl, 1,3-butadienyl, 2,4-pentadienyl, 1,4- Hexadienyl, 2,4-hexadienyl, 1,5-heptadiene base, 2,5-heptadiene base, 2,6-octadienyl etc..

" C of the present invention_2-8Alkynyl " refer to the alkynyl of the straight or branched that the carbon number containing three keys is 2-8, wherein wrap Include such as " C_2-6Alkynyl ", " C_2-4Alkynyl ", " C_2-3Alkynyl " etc., instantiation includes but not limited to: acetenyl, 1-propine Base, 2-butyne base, 1-methyl-2-propynyl, valerylene base, 3-pentynyl, 1-methyl-2-butyne base, 2-methyl-3-butynyl, 1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 2-hexin base, 3-hexin base, 1-methyl-valerylene base, 1-methyl-3-penta Alkynyl, 2-methyl-3-pentynyl, 1,1-dimethyl-3-butynyl, 2-ethyl-3-butynyl, 2-heptynyl, 3-heptynyl, 4-first Base-2-hexin base, 5-methyl-2-hexin base, 2-methyl-3-hexin base, 5-methyl-3-hexin base, 2-methyl-4-hexin base 4-methyl -5-hexin base, 2-octynyl, 3-octynyl, 4-octynyl, 4-methyl-2-heptynyl, 5-methyl-3-heptynyl, 6-methyl-3- Heptynyl, 2-methyl-4-heptynyl, 2-methyl-5-heptynyl, 3-methyl-6-heptynyl etc..

" C of the present invention_1-6Alkoxyl, C_1-6Alkyl amino, (C_1-6Alkyl)₂Amino, C_1-6Alkyl sulfenyl, C_1-6Alkyl oxycarbonyl Base, C_1-6Alkyl-carbonyl epoxide, C_1-6Alkyl sulphonyl, C_1-6Alkyl sulfonyl amino, C_1-6Alkyl amino sulfonyl, (C_1-6Alkane Base)₂Amino-sulfonyl " refer to C_1-6Alkyl-O-, C_1-6Alkyl-NH-, (C_1-6Alkyl)₂-N-、C_1-6Alkyl-S-, C_1-6Alkyl -C(O)-、C_1-6Alkyl-C (O)-O-, C_1-6Alkyl-SO₂-、C_1-6Alkyl-SO₂-NH-、C_1-6Alkyl-NH-SO₂-、(C_1-6Alkane Base)₂-NH-SO₂The group that-mode is formed, wherein " C_1-6Alkyl " literary composition as defined above described in.

" C of the present invention_1-4Alkoxyl, C_1-4Alkyl amino, (C_1-4Alkyl)₂Amino, C_1-4Alkyl sulfenyl, C_1-4Alkyl oxycarbonyl Base, C_1-4Alkyl-carbonyl epoxide, C_1-4Alkyl sulphonyl, C_1-4Alkyl sulfonyl amino, C_1-4Alkyl amino sulfonyl, (C_1-4Alkane Base)₂Amino-sulfonyl " refer to C_1-4Alkyl-O-, C_1-4Alkyl-NH-, (C_1-4Alkyl)₂-N-、C_1-4Alkyl-S-, C_1-4Alkyl -C(O)-、C_1-4Alkyl-C (O)-O-, C_1-4Alkyl-SO₂-、C_1-4Alkyl-SO₂-NH-、C_1-4Alkyl-NH-SO₂-、(C_1-4Alkane Base)₂-NH-SO₂The group that-mode is formed, wherein " C_1-4Alkyl " literary composition as defined above described in.

" halo C of the present invention_1-6Alkyl, hydroxyl C_1-6Alkyl, amino C_1-6Alkyl, sulfonyl C_1-6Alkyl, amino sulphur Acyl group C_1-6Alkyl, aminosulfonyl amino C_1-6Alkyl, C_1-6Alkoxy C_1-6Alkyl, halo C_1-6Alkoxyl, hydroxyl C_1-6 Alkoxyl " refer to one or more, such as 1～4,1～3,1～2 halogen atom, hydroxyl, amino, sulfonyl, amino sulphur Acyl group, aminosulfonyl amino, C_1-6Alkoxyl replaces C respectively_1-6Alkyl, C_1-6The group that hydrogen atom in alkoxyl is formed.

" halo C of the present invention_1-4Alkyl, hydroxyl C_1-4Alkyl, amino C_1-4Alkyl, sulfonyl C_1-4Alkyl, amino sulphur Acyl group C_1-6Alkyl, aminosulfonyl amino C_1-6Alkyl, C_1-4Alkoxy C_1-4Alkyl, halo C_1-4Alkoxyl, hydroxyl C_1-4 Alkoxyl " refer to one or more, such as 1～4,1～3,1～2 halogen atom, hydroxyl, amino, sulfonyl, amino sulphur Acyl group, aminosulfonyl amino, C_1-4Alkoxyl replaces C respectively_1-4Alkyl, C_1-4The group that hydrogen atom in alkoxyl is formed.

" 3～8 yuan of cycloalkyl " of the present invention, refers to that the paraffin section of 3～8 carbon atoms removes the list that a hydrogen atom is derivative Ring cyclic alkyl, including such as " 3～6 yuan of cycloalkyl ", " 4～7 yuan of cycloalkyl ", " 4～8 yuan of cycloalkyl ", " 4～6 yuan of cycloalkyl ", " 5～6 yuan of cycloalkyl " etc..The example includes but not limited to: cyclopropane base, Tetramethylene. base, Pentamethylene. base, cyclohexyl, ring Heptane base, cyclooctane base, methyl cyclopropane base, dimethylcyclopropane base, methyl cyclobutane base, dimethylcyclobutane base, methyl Pentamethylene. 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 excellent Select N, O.

" 3～8 yuan of heterocyclic radicals " of the present invention refer to containing 3～8 annular atomses and containing at least one (such as 1,2,3, 4 or 5) monocyclic heterocyclic compound of heteroatomic saturated or fractional saturation removes the group that a hydrogen atom obtains, including example As " 3～7 yuan of heterocyclic radicals ", " 3～6 yuan of heterocyclic radicals ", " 4～7 yuan of heterocyclic radicals ", " 4～6 yuan of heterocyclic radicals ", " 5～6 yuan of heterocyclic radicals ", " 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 saturated Heterocyclic radical ", " 5～6 yuan of heterocyclic radicals containing 1～2 atom N ", " 5 yuan of heterocyclic radicals containing 1～2 atom N ", " containing 1～2 6 yuan of heterocyclic radicals of individual atom N ", " containing 1～2 O and/or 5～6 yuan of heterocyclic radicals of S atom ", " containing 1～2 O and/or S 6 yuan of heterocyclic radicals of atom ", " containing 1～2 O and/or 5 yuan of heterocyclic radicals of S atom ", " former containing 1～2 O, S and/or N 5～6 yuan of saturated heterocyclyls of son ", " containing 1～2 O and/or 5～6 yuan of saturated heterocyclyls of S atom ", " former containing 1～2 N 5～6 yuan of saturated heterocyclyls of son ", " containing 1～2 O and/or 5 yuan of saturated heterocyclyls of S atom ", " containing 1～2 O and/or 6 yuan of saturated heterocyclyls of S atom ", " 5 yuan of saturated heterocyclyls containing 1～2 atom N ", " 6 yuan containing 1～2 atom N Saturated heterocyclyl ", " containing 2 O and/or 5～6 yuan of saturated heterocyclyls of S atom ", " containing 2 O and/or the 5 of S atom～6 Unit's heterocyclic radical ", " 5～6 yuan of heterocyclic radicals containing 1 atom N ", " 5～6 yuan of saturated heterocyclyls containing 1 atom N " etc..Tool Body example includes but are not limited to: aziridine base, 2H-aziridine base, diazacyclo propyl, 3H-diaza Cyclopropanyl, azetidinyl, 1,4-dioxane base, 1,3-dioxane base, 1,3-dioxane penta Alkyl, 1,4-Dioxin base, tetrahydrofuran base, THP trtrahydropyranyl, pyrrolin base, pyrrolidinyl, imidazoles Alkyl, 4,5-glyoxalidine base, pyrazolidinyl, 4,5-pyrazoline base, 2,5-dihydro-thiophene base, tetrahydro-thienyl, 4,5- Dihydro-thiazolyl, piperidyl, piperazinyl, morpholinyl, 4,5-dihydro oxazolyl, 4,5-dihydro isoxazolyl, 2,3-dihydro Isoxazolyl, 2H-1,2-piperazine base, 6H-1,3-piperazine base, 4H-1,3-thiazinyl, 6H-1,3-thiazinyl, 2H-pyranose, 2H-pyran-2-one base, 3,4-dihydro-2H-pyranose etc..

" 5～14 yuan of heteroaryls " of the present invention refer to containing 5～14 annular atomses (at least one of which annular atoms is hetero atom, Such as nitrogen-atoms, oxygen atom or sulphur atom) the cyclic group with armaticity.Including such as " 5～10 yuan of heteroaryls ", " 5～8 Unit's heteroaryl ", " 5～6 yuan of heteroaryls ", " 6～12 yuan of heteroaryls " etc..Instantiation includes but are not limited to furyl, thiophene Base, pyrrole radicals, thiazolyl, isothiazolyl, thiadiazolyl group, oxazolyl, isoxazolyl, di azoly, imidazole radicals, Pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-di azoly, 1,2,4-di azoly, 1,2,5-di azoly, 1,3,4-di azoly, pyridine radicals, 2-pyriconyl, 4-pyriconyl, pyrimidine radicals, 1,4-Dioxin base, 2H-1,2- Piperazine base, 4H-1,2-piperazine base, 6H-1,2-piperazine base, 4H-1,3-piperazine base, 6H-1,3-piperazine base, 4H-1,4-piperazine Base, pyridazinyl, pyrazinyl, 1,2,3-triazine radical, cyanuro 1,3,5,1,2,4,5-tetrazine base, azacyclo-heptantriene base, 1,3-diazacyclo heptantriene base, azepine cyclooctatetraenyl etc..Described " 5～6 yuan of heteroaryls " refers in 5～14 yuan of heteroaryls Instantiation containing 5～6 annular atomses.

" 6～8 yuan of aryl " of the present invention refers to the monocyclic aryl containing 6～8 ring carbon atoms, and the example includes but do not limits In: phenyl, cyclooctatetraenyl etc..

Present invention also offers two preparation methoies of above-claimed cpd, but be not limited only to following methods, reaction equation is as follows:

Preparation method one:

Reactions steps:

The preparation of step 1 intermediate 1

Buy respectively or prepare intermediate 1.

The preparation of step 2 intermediate 2

Intermediate 1 is dissolved in appropriate solvent, and 0 DEG C adds sodium hydride, stirring, is subsequently adding raw material 1, and reactant mixture room temperature is stirred Mixing (such as 1-12h), add water cancellation, and organic solvent (such as ethyl acetate) extracts, and concentrates, purified (such as silicagel column Chromatography) obtain intermediate 2.

Step 3 present invention leads to the preparation of formula (I) compound

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 hour), filter, dilute, organic solvent (such as ethyl acetate) extracts, It is dried, concentrates, obtain the present invention through proper method (such as silica gel column chromatography) and lead to formula (I) compound.

Preparation method two:

Reactions steps:

The preparation of step 1 intermediate 1

Raw material 1 and raw material 2 are dissolved in appropriate solvent (such as DMF), under room temperature, react (such as 0.5-5 Hour), 0 DEG C of cancellation that adds water, organic solvent (such as ethyl acetate) extracts, and concentrates, 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 oxolane), is stirred at room temperature (such as 6-16 hour), 0 DEG C of cancellation that adds water, Organic solvent (such as ethyl acetate) extracts, and concentrates, and purified (such as silica gel column chromatography) obtains intermediate 2.

Step 3 present invention leads to the preparation of formula (I) compound

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 hour), filter, dilute, organic solvent (such as ethyl acetate) extracts, It is dried, concentrates, obtain the present invention through proper method (such as silica gel column chromatography) and lead to formula (I) compound.

In reaction equation, R¹、R²、R³、R⁴、R⁵, n, X and Y as defined hereinabove, it is former that M represents fluorine atom, chlorine Son, bromine atoms and atomic iodine.

" stereoisomer " of formula (I) compound of the present invention refers to when formula (I) compound exists asymmetric carbon atom, meeting Produce enantiomer, when compound exists carbon-carbon double bond or circulus, cis-trans-isomer can be produced, work as compound When there is ketone or oxime, tautomer can be produced, the enantiomer of all formulas (I) compound, diastereomer, Racemization isomer, cis-trans-isomer, tautomer, geometric isomer, epimer and mixture thereof, all include In the scope of the invention.

If the raceme that the arbitrary compou nd synthesis shown in the logical formula (I) of the present invention obtains, required enantiomer-pure Compound can be obtained by the method for chiral separation: can by have chiral stationary phase chromatography (image height compacting standby Liquid chromatograph, supercritical fluid chromatography).Chirality padding includes but not limited to: Chiralcel OJ-H, Chiralpak AD-H, Chiralpak IA, Chiralpak AS-H.

Arbitrary compound pharmaceutically acceptable salt shown in the logical formula (I) of the present invention refers to by pharmaceutically acceptable, non- Toxic bases or the standby salt of processed with acid, including acylate, inorganic acid salt, organic alkali salt, inorganic base salts.

Acylate include formic acid, acetic acid, trifluoroacetate, benzenesulfonic acid, benzoic acid, p-methyl benzenesulfonic acid, camphorsulfonic acid, Citric acid, methanesulfonic acid, ethyl sulfonic acid, propane sulfonic acid, fumaric acid, gluconic acid, glutamic acid, isethionic acid, lactic acid, Malaysia The salt of acid, malic acid, mandelic 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, sulphuric acid, phosphoric acid etc..

Organic alkali salt includes primary, secondary and tertiary amine, is replaced amine and includes naturally occurring replacement amine, cyclammonium and basic ion exchange Resin, selected from glycine betaine, caffeine, choline, N, N '-dibenzyl-ethylenediamin, diethylamine, 2-Diethylaminoethanol, 2-dimethylamino-ethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, meglumine, glucosamine, Hai Baming, isopropylamine, methylglucosamine, morpholine, piperazine, piperidines, procaine, purine, theobromine, three second The salt of amine, trimethylamine, tripropyl amine (TPA), trometamol etc..Native amino hydrochlorate such as glycine, alanine, valine, bright Propylhomoserin, isoleucine, nor-leucine, tyrosine, cystine, cysteine, methionine, proline, hydroxyl dried meat ammonia The salt of acid, histidine, ornithine, lysine, arginine, serine etc..

Inorganic base salts includes ammonium and lithium, sodium, potassium, calcium, magnesium, zinc, barium, aluminum, ferrum, ketone, ferrous iron, manganese, bivalence The salt of manganese etc..

" ester " of formula (I) compound of the present invention refers to, when formula (I) compound exists carboxyl, can occur with alcohol Esterification and the ester that formed, when there is hydroxyl in formula (I) compound, can be with organic acid, mineral acid, acylate etc. There is esterification and the ester that formed.Ester, under conditions of acid or alkali exist, can occur hydrolysis to generate corresponding Acid or alcohol.

Logical compound shown in formula (I), its pharmaceutically acceptable salt, ester or its stereoisomer can be solvate shapes Formula.If in the case of solvate is hydrate, hydration can complete in preparation process or can utilize original The hygroscopicity of anhydrous product is gradually carried out.

Further requirement of the present invention protection include the above-mentioned arbitrary compound shown in formula (I), its pharmaceutically acceptable salt, Ester, solvate or its stereoisomer and one or more pharmaceutical carriers and/or the pharmaceutical composition of diluent, can make Pharmaceutically acceptable arbitrary dosage form.It is applied to need this controlling in modes such as oral, parenteral, rectum or transpulmonary administration The patient treated.When oral administration, can be made into the solid preparation of routine, such as tablet, capsule, pill, granule Deng；May be made as oral liquid, such as oral solution, oral suspensions, syrup etc..When making oral formulations, Suitable filler, binding agent, disintegrating agent, lubricant etc. can be added.When parenteral, can be made into injection Agent, including injection, injectable sterile powder and concentrated solution for injection.When making injection, existing pharmacy can be used to lead Conventional method in territory produces, and during preparation injection, can be added without additives, it is possible to it is suitable to add according to the character of medicine Additives.When rectally, can be made into suppository etc..When transpulmonary administration, can be made into inhalant or spray etc..

Further requirement of the present invention protection include formula recited above (I) arbitrary compound, its pharmaceutically acceptable salt, ester, Solvate or its stereoisomer and other one or more antitumor agents and the pharmaceutical composition of immunosuppressant.Described is anti- Tumor agent and immunosuppressant are antimetabolite, include but not limited to capecitabine, gemcitabine, pemetrexed disodium；Make a living Long factor inhibitors, includes but not limited to pazopanib, imatinib, erlotinib, Lapatinib, gefitinib, all morals He is Buddhist nun；For antibody, include but not limited to Trastuzumab, bevacizumab；For mitotic inhibitor, auspicious selected from paclitaxel, Changchun Shore, docetaxel, doxorubicin；For antitumor hormones, include but not limited to letrozole, tamoxifen, fulvestrant, Flutamide, triptorelin；For alkylating agent class, include but not limited to cyclophosphamide, chlormethine, L-Sarcolysinum, Chlorambucil, Ka Mosi Spit of fland；For metal platinum class, include but not limited to carboplatin, cisplatin, oxaliplatin；For immunosuppressant class, include but not limited to according to dimension Mo Si, sirolimus, special cancer are fitted；For purine analogue, include but not limited to that Ismipur, 6-thioguanine, sulfur azoles are fast Purine；For antibiotics, include but not limited to that rhzomorph D, daunorubicin, amycin, mitoxantrone, bleomycin A5, general card are mould Element；For platinum complex, include but not limited to cisplatin, NSC-241240；For adrenal cortex inhibitor class, include but not limited to ammonia Shandong Meter Te；For enzyme inhibitor, include but not limited to SAHA, cytosine arabinoside, methotrexate, hydroxyurea, hydroxycamptothecin, topology Te Ken, topotecan, Irinotecan.

Present invention also offers the compound shown in formula (I) of the present invention, its pharmaceutically acceptable salt, ester, solvate or its Stereoisomer application in the medicine of preparation treatment and/or the cancer-related diseases of prevention ALK mediation or non-cancerous disease, The disease that described cancer is relevant includes but not limited to the brain cancer, pulmonary carcinoma, lung cancer in non-cellule type, squamous cell cancer, bladder cancer, Gastric cancer, ovarian cancer, peritoneal cancer, cancer of pancreas, breast carcinoma, head and neck cancer, cervical cancer, carcinoma of endometrium, colorectal cancer, liver Cancer, renal carcinoma, the esophageal carcinoma, adenocarcinoma of esophagus, esophageal squamous cell carcinoma, non-Hodgkin lymphoma, cerebroma, central nervous system swells Tumor, glioma, glioblastoma multiforme, glioma sarcomatosum, carcinoma of prostate, thyroid carcinoma, female reproductive tract cancer, Cancer in situ, lymphoma, histocytic lymphoma, neurofibroma, osteocarcinoma, skin carcinoma, colon cancer, carcinoma of testis, minicell Pulmonary carcinoma, gastrointestinal stromal tumor, tumor of prostate, mast cell tumor, multiple myeloma, melanoma, glioma, glue Matter blastoma, astrocytoma, neuroblastoma, sarcoma；Proliferative disease, includes but not limited to skin or prostate Hyperplasia of prostate.

The compounds of this invention has the advantage that

(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 show Going out good biological stability, act on more longlasting, bioavailability is high；

(3) the compounds of this invention preparation technology is simple, and medicine purity is high, steady quality, it is easy to carry out large-scale industrial production.

The compounds of this invention beneficial effect is expanded on further below by way of the experiment of external zymetology inhibitory activity, but this should be interpreted as The compounds of this invention only has following beneficial effect.

The external zymetology activity experiment of experimental example 1 the compounds of this invention

Test sample: the trifluoroacetate of the compounds of this invention 2, compound 3 and compound 4, according to the trifluoro second of compound 2 Prepared by the preparation embodiment of hydrochlorate, compound 3 and compound 4.

The implication representated by abbreviation of following middle experiment is as follows:

DMSO: dimethyl sulfoxide

DTT: dithiothreitol, DTT

SEB: enzyme catalyst buffer solution

ATP: adenosine triphyosphate

ALK: anaplastic lymphoma kinase ALK Alk receptor tyrosine kinase

The donor of SA-XL665: marked by streptavidin

2.5 ×, 5 ×, 10 × "×" therein: times

Experimental technique:

ALK kinase buffer liquid is prepared:

Take the MgCl that appropriate mother liquid concentration is 1000mM respectively₂, the DTT of SEB, 100mM of 2500nM, 5 × Enzyme buffer liquid, joins in ultra-pure water so that ultimate density is respectively as follows: 5mM, 25nM, 1mM, 1 × enzyme buffer liquid, Mixing, stand-by.

2.5 × need testing solution is prepared:

The 1mM storing solution preparation of comparison medicine: weigh comparison medicine (1.48mg), adds appropriate DMSO and dissolves, and mixing is standby With.

The 1mM storing solution preparation of compound: Weigh Compound is appropriate (concrete sample weighting amount please see table) respectively, adds appropriate DMSO dissolves, mixing, standby.

Take 1mM storing solution respectively, make the solution that concentration is 200 μMs, as mother solution with DMSO dilution.Use DMSO Three times of stepwise dilutions of above-mentioned mother solution are made the solution of a series of concentration, and the most each concentration is respectively with ALK kinase buffer liquid Dilute 80 times, make each 2.5 × need testing solution, concentration be respectively as follows: 2500nM, 833.33nM, 277.78nM, 92.59 nM、30.86nM、10.29nM、3.43nM、1.14nM、0.38nM、0.13nM、0.04nM。

Other preparation of reagents various:

Required 5 × ALK kinase solution, 5 × substrate solution, 5 × ATP solution is prepared respectively with ALK kinase buffer liquid, Standby.

ALK zymetology is reacted:

1) be separately added into 2.5 × need testing solution that 4 μ L prepare in hole corresponding in 384 orifice plates, 2 μ L prepare 5 × ALK kinase solution, hatches 10 minutes for 25 DEG C.

2) corresponding Kong Zhongzai is separately added into 5 × substrate solution that 2 μ L prepare and 5 × ATP that 2 μ L prepare is molten Liquid, starts enzyme reaction, hatches 30 minutes for 25 DEG C.

Zymetology detects:

With the SA-XL665 of detection buffer (detection buffer) preparation desired concn, then with isopyknic tyrosine-kinase Enzyme antibody mixes, and is separately added into this antibody-solutions that 10 μ L prepare in corresponding hole, terminates reaction.Hatch for 25 DEG C 1h。

Microplate reader 665nm/615nm reads plate.

IC₅₀: calculate suppression ratio (%)=(maximum-sample value)/(maximum-minima) × 100, use Graph prism soft Part carries out curve fitting, and draws IC₅₀Value.

Maximum: be not added with the positive control of compound；Minima: the most enzyme-added negative control.

Experimental result and conclusion:

The external zymetology inhibitory activity of table 1. the compounds of this invention

From table 1, the compounds of this invention has good inhibitory activity to ALK kinases, can be used for treating and kinases phase The disease closed, disease that particularly ALK is kinase mediated or the patient's condition, have significant clinical meaning.

Detailed description of the invention

The detailed description of the invention of form by the following examples, is described in further detail the foregoing of the present invention.But no This should being interpreted as, the scope of the above-mentioned theme of the present invention is only limitted to following example.All skills realized based on foregoing of the present invention Art belongs to the scope of the present invention.

Embodiment 1 4-(the chloro-2-of 5-((2-isopropoxy-5-methyl-4-(piperidin-4-yl) phenyl) amino) pyrimidine-4-yl)-3,4-dihydro The preparation of-2H-benzo [b] [1,4] thiazine 1,1-dioxide (compound 1) trifluoroacetate

(1) preparation of 2-((2-chloroethyl) sulfur generation) aniline

In the there-necked flask of a 250mL, add 2-aminothiophenol (10g, 79.88mmol), 1,2-dichloroethanes (78g, 788.3mmol).The lower reactant mixture of nitrogen protection is heated to backflow, then drips the methanol solution of Feldalat NM (15g), drips Finish, be heated to reflux 3 hours.Question response is complete, and reactant liquor cooling is poured in frozen water, then extracts with dichloromethane (3 × 100mL) Take, merge organic layer, wash with saturated sodium bicarbonate, separate organic layer anhydrous sodium sulfate and be dried, be concentrated to give product (8g, Productivity 53%).

(2) preparation of N-(2-((2-chloroethyl) sulfur generation) phenyl) acetamide

In the single port bottle of a 100mL, addition 2-((2-chloroethyl) sulfur generation) aniline (7.5g, 40.0mmol), acetic anhydride (7.5g, 73mmol).Reactant mixture is heated to reflux 2 hours, and reactant liquor cooling is poured in frozen water, extracts by ethyl acetate (80mL × 3), Merging organic facies, saturated aqueous common salt washed once, and organic layer anhydrous sodium sulfate is dried.Concentrating under reduced pressure, residue is through column chromatography (second Acetoacetic ester: petroleum ether=1:5) obtain product (5.7g, productivity is 62%).

(3) preparation of 1-(2,3-dihydro-4H-benzo [b] [1,4] thiazine-4-base) ethyl ketone

N-(2-((2-chloroethyl) sulfur generation) phenyl) acetamide (5.4g, 23.5mmol) is added in the there-necked flask of a 250mL, T-BuOH (50mL), is heated to 45 DEG C, then drips t-BuOH (50mL) solution of t-BuOK (2.7g, 24.1mmol). Reactant mixture 45 DEG C reacts 1 hour.Reactant liquor cooling is poured in frozen water, regulates pH=4～5 with hydrochloric acid (1M), uses dichloromethane Alkane (50mL × 3) extracts, and merges organic facies, and saturated aqueous common salt washs, and anhydrous sodium sulfate is dried, and is concentrated under reduced pressure to give crude product (3.8g).

(4) preparation of 1-(1,1-dioxo-2,3-dihydro-4H-benzo [b] [1,4] thiazine-4-base) ethyl ketone

In the there-necked flask of a 250mL add 1-(2,3-dihydro-4H-benzo [b] [1,4] thiazine-4-base) ethyl ketone (3.8g, 19.66 And methanol (50mL) mmol).Add (NH₄)₂MoO₄The aqueous solution (20mL) of (2.7g, 13.78mmol).It is subsequently adding H₂O₂ (10mL, 30%).Reactant mixture stirred overnight at room temperature, decompression removes methanol, and residual solution ethyl acetate (50mL × 3) extracts, Merging organic facies, concentrate, residue obtains product (2g, two step productivity are 38%) through column chromatography (ethyl acetate: petroleum ether=1:5).

(5) preparation of 3,4-dihydro-2H-benzo [b] [1,4] thiazine 1,1-dioxide

1-(1,1-dioxo-2,3-dihydro-4H-benzo [b] [1,4] thiazine-4-base) ethyl ketone (2 is added in the single port bottle of a 100mL G, 8.88mmol), methanol (20mL), concentrated hydrochloric acid (5mL).Reactant mixture stirred overnight at room temperature, with saturated sodium bicarbonate Regulation pH value, to 8～9, is extracted with ethyl acetate, and merges organic facies, is concentrated to give product (800mg, productivity is 49%).

(6) preparation of 4-(2,5-dichloro pyrimidine-4-base)-3,4-dihydro-2H-benzo [b] [1,4] thiazine 1,1-dioxide

In the single port bottle of a 100mL add 3,4-dihydro-2H-benzo [b] [1,4] thiazine 1,1-dioxide (500mg, 2.73 mmol)、DMSO(10mL).Then 0 DEG C adds sodium hydride (60%, 126mg, 3.15mmol).Stir 10 minutes.Then Add 2,4,5-trichloropyrimidine (500mg, 2.73mmol).Reactant mixture stirred overnight at room temperature.It is subsequently adding water (2mL) cancellation, And add water (50mL) dilution.Extract by ethyl acetate (100mL × 2), merge organic facies, with saturated aqueous common salt (100mL × 3) Washing.Separating organic layer, be dried with anhydrous sodium sulfate, concentrating under reduced pressure, residue is through column purification (ethyl acetate: petroleum ether=1:15～1:3) Obtain product (200mg, productivity 22%).

(7) tert-butyl group 4-(4-((the chloro-4-of 5-(1,1-dioxide-2,3-dihydro-4H-benzo [b] [1,4] thiazine-4-base) pyrimidine-2-base) ammonia Base)-5-isopropoxy-2-aminomethyl phenyl) preparation of piperidines-1-formic acid esters

4-(2,5-dichloro pyrimidine-4-base)-3,4-dihydro-2H-benzo [b] [1,4] thiazine 1,1-is added in the single port bottle of a 100mL Dioxide (200mg, 0.61mmol), tert-butyl group 4-(4-amino-5-isopropoxy-2-aminomethyl phenyl) piperidines-1-formic acid esters (180 Mg, 0.52mmol), 1,4-dioxane (20mL), cesium carbonate (400mg, 1.23mmol) and Pd (dppf) Cl₂(50mg).? Under nitrogen protection, reactant mixture is heated to 80 DEG C of reactions overnight, filters, and filter cake ethyl acetate (50mL) is washed, filtrate Adding water (100mL) dilution, extract by ethyl acetate (50mL × 3), merge organic facies, anhydrous sodium sulfate is dried.Concentrating under reduced pressure, Residue is through Prep-HPLC purification (Column:Water Sunfire C18,19x150mm, Phase A:H₂O (0.05%TFA), B:CH₃CN.25mL/min), collect component, be concentrated to give product (70mg, productivity 21%).

(8) 4-(the chloro-2-of 5-((2-isopropoxy-5-methyl-4-(piperidin-4-yl) phenyl) amino) pyrimidine-4-yl)-3,4-dihydro-2H-benzo The preparation of [b] [1,4] thiazine 1,1-dioxide trifluoroacetate

Tert-butyl group 4-(4-((the chloro-4-of 5-(1,1-dioxide-2,3-dihydro-4H-benzo is added in the single port bottle of a 100mL [b] [1,4] thiazine-4-base) pyrimidine-2-base) amino)-5-isopropoxy-2-tolyl) piperidines-1-formic acid esters (70mg, 0.11mmol) and Dichloromethane (5mL).Room temperature adds trifluoroacetic acid (0.5mL).Reactant mixture stirred overnight at room temperature.Reactant liquor concentrating under reduced pressure, Residue divides water to be dried to obtain end-product (61.5mg, productivity 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=8.1 Hz),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).

Embodiment 2 3-(the chloro-2-of 5-((2-isopropoxy-5-methyl-4-(piperidin-4-yl) phenyl) amino) pyrimidine-4-yl)-2,3-dihydrobenzene And the preparation of [d] thiazole 1,1-dioxide (compound 2) trifluoroacetate

(1) preparation of 2-((2,5-dichloro pyrimidine-4-base) amino) benzenethiol

2-aminobenzene-1-mercaptan (6g, 47.93mmol), N,N-dimethylformamide is added in the there-necked flask of a 250mL (100mL), sodium tert-butoxide (5.53g), then drip 2,4,5-trichloropyrimidines (8.78g, 47.87mmol), drip complete, room temperature Stir 1 hour.0 DEG C adds shrend in ice-water bath and goes out reaction, and regulating pH value with hydrochloric acid (1M) is 7, then uses ethyl acetate (100mL × 3) extract, and merge organic layer and wash with saturated aqueous common salt, separating organic layer anhydrous sodium sulfate and be dried.Decompression removes Removing solvent, residue obtains product (6.5g, productivity 50%) through column chromatography purification (petroleum ether: ethyl acetate=1:1).

(2) preparation of 3-(2,5-dichloro pyrimidine-4-base)-2,3-dihydrobenzo [d] thiazole

In the there-necked flask of a 250mL add 2-((2,5-dichloro pyrimidine-4-base) amino) benzenethiol (3.5g, 12.86mmol), Oxolane (50mL), LiHMDS (1M, in THF) (25.8mL), CH₂I₂(3.45g, 12.88mmol), reactant mixture Stirred overnight at room temperature.0 DEG C adds shrend in ice-water bath and goes out reaction, then with ethyl acetate (50mL × 3) extraction, merges organic Layer also washs with saturated aqueous common salt, separates organic layer anhydrous sodium sulfate and is dried.Removal of solvent under reduced pressure, residue is pure through column chromatography Change (petroleum ether: ethyl acetate=5:1) and obtain product (550mg, productivity 15%).

(3) preparation of 3-(2,5-dichloro pyrimidine-4-base)-2,3-dihydrobenzo [d] thiazole 1,1-dioxide

In the there-necked flask of a 50mL add 3-(2,5-dichloro pyrimidine-4-base)-2,3-dihydrobenzo [d] thiazole (540mg, 1.90 Mmol), dichloromethane (10mL), m-CPBA (723mg, 4.19mmol).Reactant mixture stirred overnight at room temperature, then Add Na₂S₂O₃(10%) aqueous solution cancellation reaction, extracts with dichloromethane (20mL × 3), merges organic layer and use saturated food Saline washs, and separates organic layer anhydrous sodium sulfate and is dried.Removal of solvent under reduced pressure, residue is through column chromatography purification (petroleum ether: acetic acid Ethyl ester=3:1) obtain product (480mg, productivity 80%).

(4) tert-butyl group 4-(4-((the chloro-4-of 5-(1,1-dioxo benzo [d] thiazole-3 (2H)-yl) pyrimidine-2-base) amino)-5-isopropyl-2- Aminomethyl phenyl) preparation of piperidines-1-formic acid esters

3-(2,5-dichloro pyrimidine-4-base)-2,3-dihydrobenzo [d] thiazole 1,1-titanium dioxide is added in the there-necked flask of a 100mL Thing (480mg, 1.52mmol), tert-butyl group 4-(4-amino-5-isopropoxy-2-aminomethyl phenyl) piperidines-1-formic acid esters (529mg, 1.52 Mmol), 1,4-dioxane (15mL), cesium carbonate (1.47g, 4.51mmol), Pd (dppf) Cl₂.CH₂Cl₂(125mg,0.15 Mmol), it is warming up to 80 DEG C of reactions under nitrogen protection overnight, is cooled to room temperature, is filtered to remove insoluble solid.With acetonitrile washing filter Cake, filtrate concentrates.Residue Prep-HPLC purifies (Column:Water Sunfire C18,19x150mm, 5um, Phase A:H₂O (0.05%TFA), B:CH₃CN.B:45-90%, 7min, 25mL/min.), collect component and be concentrated under reduced pressure to give product (200mg, productivity 21%).

(5) 3-(the chloro-2-of 5-((2-isopropoxy-5-methyl-4-(piperidin-4-yl) phenyl) amino) pyrimidine-4-yl)-2,3-dihydrobenzo [d] thiophene The preparation of azoles 1,1-dioxide trifluoroacetate

Tert-butyl group 4-(4-((the chloro-4-of 5-(1,1-dioxo benzo [d] thiazole-3 (2H)-yl) is added in the there-necked flask of a 100mL Pyrimidine-2-base) amino)-5-isopropoxy-2-aminomethyl phenyl) piperidines-1-formic acid esters (200mg, 0.32mmol), dichloromethane (10 ML), trifluoroacetic acid (1mL).Reactant mixture stirred overnight at room temperature, through being concentrated under reduced pressure to give end-product (182mg, productivity 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).

Embodiment 3 3-(the chloro-2-of 5-((7-methyl-8-(piperidin-4-yl)-2,3-dihydrobenzo [b] [1,4] two English-5-base) amino) piperidines-4 Base) preparation of-2,3-dihydrobenzo [d] thiazole 1,1-dioxide (compound 3)

(1) preparation of 2-methoxyl group-4-methyl-6-nitrophenol

2-methoxyl group-4-methylphenol (50.0g, 0.362mol) is dissolved in chloroform (1L), is cooled to 0 DEG C, by fuming nitric aicd (22.8g, 0.362mol) is dissolved in acetic acid (120mL), slowly drops in solution, and internal temperature control, below 0 DEG C, rises Reaction 0.5 hour is continued to room temperature.Completely, rotary evaporation removes solvent in reaction, and residue adds methanol (200mL), filters, It is vacuum dried to obtain product (30g, productivity 45.4%).

(2) preparation of 5-methyl-3-nitro benzene-1,2-glycol

2-methoxyl group-4-methyl-6-nitrophenol (30.0g, 0.164mol) is joined in hydrobromic acid (200mL, 80%), add 20g tetrabutyl ammonium fluoride, is heated to 110 DEG C, and reaction is overnight.Reaction completes, and adds water (1000mL), by ethyl acetate (5 × 500 ML) extraction, organic facies merges, and saturated aqueous common salt (250mL) washs, and anhydrous sodium sulfate is dried.Filtering, rotary evaporation removes molten Agent, residue is directly used in next step.

(3) preparation of 7-methyl-5-nitro-2,3-dihydrobenzo [b] [1,4] two English

By 5-methyl-3-nitro benzene-1,2-glycol (20g, 0.118mol) is dissolved in DMF (100mL), adds Glycol dibromide (44.4g, 0.236mol) and potassium carbonate (49.2g, 0.356mol).Being heated to 60 DEG C, reaction is overnight.React Becoming, add water (300mL), extract by ethyl acetate (3 × 200mL), merge organic facies, rotary evaporation removes solvent, residue Thing obtains product (19g, productivity 82.6%) through silica gel column chromatography (petroleum ether: ethyl acetate=5:1).

(4) preparation of 6-bromine-7-methyl-5-nitro-2,3-dihydrobenzo [b] [1,4] two English

7-methyl-5-nitro-2,3-dihydrobenzo [b] [1,4] two English (19g, 0.097mol) is dissolved in N, N-dimethyl formyl In amine (200mL), it is dividedly in some parts N-bromosuccinimide (34.5g, 0.194mol).Being heated to 60 DEG C, reaction is overnight.Instead Should complete, add water (300mL), extract by ethyl acetate (3 × 200mL), merge organic facies, rotary evaporation removes solvent, Residue obtains product (18g, productivity 67.7%) through silica gel column chromatography (petroleum ether: ethyl acetate=5:1).

(5) preparation of 6-bromine-7-methyl-2,3-dihydrobenzo [b] [1,4] two English-5-amine

6-bromine-7-methyl-5-nitro-2,3-dihydrobenzo [b] [1,4] two English (18g, 65.7mmol) is dissolved in ethanol (200mL) In, add acetic acid (20mL), be heated to 70 DEG C, iron powder (36.8g, 657.1mmol) is dividedly in some parts.It is warming up to 80 DEG C, instead Answer 3 hours, after having reacted, be cooled to room temperature, filter, filtrate adds water (300mL), with ethyl acetate (3 × 300mL) Extraction, merges organic facies, and rotary evaporation removes solvent, and residue is produced through silica gel column chromatography (petroleum ether: ethyl acetate=2:1) Thing (12g, productivity 75%).

(6) preparation of the bromo-8-of 6-iodo-7-methyl-2,3-dihydrobenzo [b] [1,4] two English-5-amine

6-bromine-7-methyl-2,3-dihydrobenzo [b] [1,4] two English-5-amine (12g, 49.16mmol) is dissolved in toluene (100mL) In, add acetic acid (5mL) and N-iodosuccinimide (16.6g, 73.78mmol), react 3 hours under room temperature.Reaction completes, Add water (100mL), extract by ethyl acetate (3 × 200mL), merge organic facies, wash with sodium sulfite solution (200mL), Rotary evaporation removes organic facies, and residue obtains product (7g, productivity through silica gel column chromatography (petroleum ether: ethyl acetate=2:1) 38.5%).

(7) tert-butyl group 4-(8-amino-7-bromo-6-methyl-2,3-dihydrobenzo [b] [1,4] two English-5-base)-3,6-dihydropyridine-1 (2H)- The preparation of formic acid esters

By bromo-for 6-8-iodo-7-methyl-2,3-dihydrobenzo [b] [1,4] two English-5-amine (7.0g, 18.92mmol) and the tert-butyl group 4-(4,4,5,5-tetramethyl-1,3,2-dioxy boron pentane-2-base)-3,6-dihydropyridine-1 (2H)-formic acid esters (5.8g, 18.76mmol) is molten In Isosorbide-5-Nitrae-dioxane (100mL), add water (15mL) and [1,1'-pair (diphenylphosphine) ferrocene] palladium chloride (1.4g, 1.91 Mmol), potassium carbonate (7.83g, 56.7mmol), it is heated to 80 DEG C, reacts 3 hours.Reaction completes, and adds water (100mL), Extracting with dichloromethane (3 × 200mL), merge organic facies, wash with saturated aqueous common salt (100mL), rotary evaporation removes organic Phase, residue obtains product (5g, productivity 62.7%) through silica gel column chromatography (petroleum ether: ethyl acetate=5:1).

(8) preparation of tert-butyl group 4-(8-amino-6-methyl-2,3-dihydrobenzo [b] [1,4] two English-5-base) piperidines-1-formic acid esters

By tert-butyl group 4-(8-amino-7-bromo-6-methyl-2,3-dihydrobenzo [b] [1,4] two English-5-base)-3,6-dihydropyridine -1 (2H)-formic acid esters (5g, 11.76mmol) is dissolved in methanol (150mL), adds 4g palladium charcoal, is passed through hydrogen, anti-under room temperature Should be overnight.Reaction completes, and filters, and rotary evaporation removes solvent, obtains product (2.5g, productivity 61.1%).

(9) preparation of 2-((2,5-dichloro pyrimidine-4-base) amino) phenylmercaptan.

By 2,4,5-trichloropyrimidines (15.0g, 81.8mmol) are dissolved in DMF (50mL), add 2-aminobenzene Thiophenol (10.24g, 81.8mmol) and potassium carbonate (2.26g, 16.4mmol), react 3 hours under room temperature.Reaction completely, adds water (300mL), extracting by ethyl acetate (3 × 200mL), merge organic facies, rotary evaporation removes solvent, and residue is through silicagel column Chromatography (petroleum ether: ethyl acetate=2:1) obtains product (12g, productivity 53.8%).

(10) preparation of 3-(2,5-dichloro pyrimidine-4-base)-2,3-dihydrobenzo [d] thiazole

2-((2,5-dichloro pyrimidine-4-base) amino) phenylmercaptan. (12.0g, 44.1mmol) is dissolved in oxolane (50mL), 1N bis-(trimethyl is silica-based) Lithamide. (88.2mL, 88.2mmol) is joined in solution by 0 DEG C, stirs 0.5 hour.By two Iodomethane (11.82g, 44.1mmol) drops in reactant liquor, is stirred overnight under room temperature.Reaction completes, and adds water (50mL) Cancellation is reacted, and extracts by ethyl acetate (3 × 50mL), merges organic facies, and rotary evaporation removes solvent, and residue is through silica gel column layer Analysis (petroleum ether: ethyl acetate=2:1) obtains product (2.0g, productivity 16%).

(11) preparation of 3-(2,5-dichloro pyrimidine-4-base)-2,3-dihydrobenzo [d] thiazole 1,1-dioxide

By 3-(2,5-dichloro pyrimidine-4-base)-2,3-dihydrobenzo [d] thiazole (2.0g, 7.04mmol) is dissolved in dichloromethane (50mL), It is dividedly in some parts metachloroperbenzoic acid (3.63g, 21.03mmol), reacts overnight under room temperature.Reaction completes, and adds sulfur for sulfur Acid sodium solution (30mL), separatory, aqueous phase with dichloromethane (3 × 20mL) extract, merge organic facies, with saturated sodium bicarbonate, Sodium chloride solution washs, and rotary evaporation removes solvent, and residue obtains product through silica gel column chromatography (petroleum ether: ethyl acetate=2:1) (1.5g, productivity 67.4%).

(12) tert-butyl group 4-(8-((the chloro-4-of 5-(1,1-dioxo benzo [d] thiazole-3 (2H)-yl) pyrimidine-2-base) amino)-6-methyl-2,3- Dihydrobenzo [b] [1,4] two English-5-base) preparation of piperidines-1-carboxylate

By 3-(2,5-dichloro pyrimidine-4-base)-2,3-dihydrobenzo [d] thiazole 1,1-dioxide (181mg, 0.572mmol) and uncle Butyl 4-(8-amino-6-methyl-2,3-dihydrobenzo [b] [1,4] two English-5-base) piperidines-1-formic acid esters (200mg, 0.574mmol) is molten In Isosorbide-5-Nitrae-dioxane (15mL), add [1,1'-double (diphenylphosphine) ferrocene] palladium chloride (42mg, 0.057mmol), carbon Acid caesium (560mg, 1.72mmol), is heated to 110 DEG C, overnight.Reaction completes, and filters, and rotary evaporation removes solvent, residue Thing obtains product (80mg, productivity 22.3%) through silica gel column chromatography (dichloromethane: methanol=20:1).

(13) 3-(the chloro-2-of 5-((7-methyl-8-(piperidin-4-yl)-2,3-dihydrobenzo [b] [1,4] two English-5-base) amino) piperidines-4 Base) preparation of-2,3-dihydrobenzo [d] thiazole 1,1-dioxide

By tert-butyl group 4-(8-((the chloro-4-of 5-(1,1-dioxo benzo [d] thiazole-3 (2H)-yl) pyrimidine-2-base) amino)-6-methyl-2,3-two Hydrogen benzo [b] [Isosorbide-5-Nitrae] two English-5-base) piperidines-1-carboxylate (80mg, 0.127mmol) is dissolved in dichloromethane (10mL), adds Enter trifluoroacetic acid (2mL), stir 3 hours under room temperature.Reaction completes, and rotary evaporation removes solvent, adds ethyl acetate (50 ML), saturated sodium bicarbonate solution washs, and rotary evaporation removes organic facies, and residue is through silica gel column chromatography (dichloromethane: methanol =15:1) obtain end-product (40mg, productivity 59.7%).

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).

Embodiment 4 3-(the chloro-2-of 5-((6-isopropoxy isoindoline-5-base) amino) pyrimidine-4-yl)-2,3-dihydrobenzo [d] thiazole The preparation of 1,1-dioxide (compound 4)

(1) preparation of 2-bromo-5-methoxyl methyl benzoate

3-methoxyl methyl benzoate (16.6g, 0.10mol) is dissolved in dichloromethane (150mL), under ice bath, is slowly added to bromine (16.0g, 0.10mol), after dropping, room temperature reaction 2 hours.Add saturated sodium thiosulfate solution (20mL) cancellation reaction, Extracting with dichloromethane (200mL), organic phase washed with water three times, be dried, rotary evaporation removes solvent, and residue is through post color Spectrum separates (petroleum ether: ethyl acetate=20:1) and obtains product (15.9g, productivity 64.9%).

(2) preparation of 2-cyano group-5-methoxyl methyl benzoate

Bromo-for 2-5-methoxyl methyl benzoate (15.9g, 64.9mmol), Cupricin. (6.39g, 71.4mmol) are joined N, N- In dimethylformamide (150mL).It is heated to 140 DEG C and reacts half an hour.Add ethyl acetate (500mL), use saturated aqueous common salt Washing, organic facies is dried, rotary evaporation remove solvent, residue through column chromatography (petroleum ether: ethyl acetate=20:1) product (6.7g, Productivity 54.0%).

(3) preparation of 6-methoxyl group isoindoline-1-ketone

2-cyano group-5-methoxyl methyl benzoate (6.7g, 35.1mmol) is dissolved in methanol (50mL), adds Raney Ni (335 Mg), replacing hydrogen, it is stirred at room temperature 2 hours, sucking filtration, filter cake washs with a small amount of methanol, merging filtrate, and rotary evaporation removes molten Agent, residue obtains product (4.7g, productivity 82%) through pillar layer separation (DCM:MeOH=10:1).

(4) preparation of 6-hydroxyl 1-isoindolinone

Being joined by 6-methoxyl group isoindoline-1-ketone (4.7g, 28.8mmol) in dry aluminum chloride (30g), stirring is to filling Dividing mix homogeneously, nitrogen is protected, and is heated to 120 DEG C and reacts 2 hours, is cooled to room temperature, adds ethyl acetate (150mL) stirring Uniformly, gained suspension sucking filtration, organic facies saturated aqueous common salt washs 3 times, and anhydrous sodium sulfate is dried, through pillar layer separation (DCM:MeOH=20:1) product (1.19g, productivity 27.7%) is obtained.

(5) preparation of 6-isopropoxy 1-isoindolinone

6-hydroxyl 1-isoindolinone (1.0g, 6.71mmol) is dissolved in acetonitrile (25mL), and addition potassium carbonate (926mg, 6.71 Mmol), 3-Iso-Propyl iodide (1.14g, 6.71mmol), be heated to 70 DEG C react 2 hours, rotary evaporation remove solvent, add Entering saturated solution of sodium bicarbonate (10mL), extract with dichloromethane, organic facies anhydrous sodium sulfate is dried, and rotary evaporation removes molten Agent, obtains product (803mg, productivity 62.6%) through pillar layer separation (petroleum ether: ethyl acetate=3:1).

(6) preparation of 6-isopropoxy-5-nitro iso-indoles-1-ketone

6-isopropoxy 1-isoindolinone (803mg, 4.20mmol) is dissolved in the mixed of trifluoroacetic anhydride and acetonitrile (10mL, 1:1) Close in solution, under ice bath, be slowly added to potassium nitrate (424mg, 4.20mmol), be warmed to room temperature reaction 2 hours, add 50mL Saturated solution of sodium bicarbonate cancellation, extracts with dichloromethane, and organic facies anhydrous sodium sulfate is dried, and rotary evaporation removes solvent, Residue obtains product (612mg, productivity 61.7%) through pillar layer separation (petroleum ether: ethyl acetate=5:1).

(7) preparation of 5-amino-6-isopropoxy 1-isoindolinone

6-isopropoxy-5-nitro 1-isoindolinone (612mg, 2.59mmol) is dissolved in methanol (15mL), adds palladium carbon (31 Mg), replacing hydrogen, it is stirred at room temperature 30 minutes.Reactant liquor sucking filtration, rotary evaporation removes solvent and obtains crude product (530mg).

(8) preparation of 6-isopropoxy isoindoline-5-amine

5-amino-6-isopropoxy 1-isoindolinone (530mg, 2.57mmol) is dissolved in methanol (10mL), protects at nitrogen The tetrahydrofuran solution (2.57mL, 5.14mmol) of the borane dimethylsulf iotade of lower addition 2.0mol/L, is heated to back flow reaction 8 little Time, it 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 revolve Turning evaporation of solvent, residue obtains product (80mg, productivity 16.2%) through pillar layer separation (DCM:MeOH=10:1).

(9) preparation of tert-butyl group 5-amino-6-isopropoxy isoindoline-2-formic acid esters

6-isopropoxy isoindoline-5-amine (80mg, 0.417mmol) is dissolved in the dichloromethane of 5mL, adds triethylamine (42mg, 0.416mmol), Bis(tert-butoxycarbonyl)oxide (91mg, 0.417mmol), be stirred at room temperature 2 hours, and rotary evaporation removes Solvent, pillar layer separation (DCM:MeOH=10:1) obtains product (95mg, productivity 78%).

(10) preparation of 3-(2,5-dichloro pyrimidine-4-base)-2,3-dihydrobenzo [d] thiazole 1,1-dioxide

By 2,3-dihydrobenzo [d] thiazole-1,1-dioxide (507mg, 3.0mmol) is dissolved in 10mL oxolane, under ice bath Add sodium hydride (86.4mg, 3.6mmol), be slow added into 2 after stirring 10 minutes, 4,5-trichloropyrimidine (549mg, 3.0m Mol), being warmed to room temperature stirring 2 hours, add 20mL sodium chloride saturated solution, extract with dichloromethane, organic facies is with anhydrous Sodium sulfate is dried, rotary evaporation remove solvent, residue through pillar layer separation (petroleum ether: ethyl acetate=10:1) product (376mg, Productivity 39.7%).

(11) tert-butyl group 5-((the chloro-4-of 5-(1,1-dioxy benzo [d] thiazole-3 (2H)-yl) pyrimidine-2-base) amino)-6-isopropoxy different two The preparation of hydrogen indole-2-carboxylic acid ester

By 3-(2,5-dichloro pyrimidine-4-base)-2,3-dihydrobenzo [d] thiazole 1,1-dioxide (103mg, 0.326mmol), tertiary fourth Base 5-amino-6-isopropoxy isoindoline-2-formic acid esters (95mg, 0.325mmol), Pd₂(dba)₃(10mg), X-Phos (20 Mg), cesium carbonate (106mg, 0.326mmol), join in the Isosorbide-5-Nitrae-dioxane of 10mL, nitrogen protect, 110 DEG C of heating 6 hours.Rotary evaporation removes solvent, adds 10mL sodium chloride saturated solution, extracts with dichloromethane, and organic facies is with anhydrous Sodium sulfate is dried, and rotary evaporation removes solvent, and residue obtains product through pillar layer separation (DCM:MeOH=10:1), and (82mg produces Rate 44.0%).

(12) 3-(the chloro-2-of 5-((6-isopropoxy isoindoline-5-base) amino) pyrimidine-4-yl)-2,3-dihydrobenzo [d] thiazole 1,1-bis- The preparation of oxide

By tert-butyl group 5-((the chloro-4-of 5-(1,1-dioxy benzo [d] thiazole-3 (2H)-yl) pyrimidine-2-base) amino)-6-isopropoxy different dihydro Yin Diindyl-2-formic acid esters (82mg, 0.143mmol) is dissolved in the dichloromethane of 5mL and trifluoroacetic acid mixed solution (1:1), is stirred at room temperature 2 hours, rotary evaporation removed solvent, and residue obtains end-product through pillar layer separation (DCM:MeOH=10:1), and (46mg produces Rate 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=7.2 Hz), 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 (11)

1. lead to the compound shown in formula I, its pharmaceutically acceptable salt, ester, solvate or its stereoisomer:

Wherein,

R¹Selected from hydrogen atom, hydroxyl, amino, cyano group, nitro, carboxyl, halogen atom, C_1-6Alkyl, hydroxyl C_1-6Alkyl, Halo C_1-6Alkyl, C_1-6Alkoxyl, hydroxyl C_1-6Alkoxyl, halo C_1-6Alkoxyl, C_2-8Thiazolinyl, C_2-8Alkynyl, C_1-6 Alkyl amino or (C_1-6Alkyl)₂Amino；

R²、R⁴、R⁵Separately selected from hydrogen atom, halogen atom, nitro, cyano group, amino, hydroxyl, carboxyl, C_1-6 Alkyl, hydroxyl C_1-6Alkyl, halo C_1-6Alkyl, amino C_1-6Alkyl, sulfonyl C_1-6Alkyl, C_1-6Alkoxyl, hydroxyl C_1-6Alkoxyl, halo C_1-6Alkoxyl, C_2-8Thiazolinyl, C_2-8Alkynyl, C_1-6Alkyl sulfenyl, C_1-6Alkyl-carbonyl, C_1-6Alkyl Carbonyl epoxide, C_1-6Alkyl sulfonyl amino, C_1-6Alkyl amino sulfonyl, (C_1-6Alkyl)₂Amino-sulfonyl or C_1-6Alkyl sulfonyl Base；

R³Selected from the 5～14 yuan of heteroaryls optionally replaced by W or 3～8 yuan of heterocyclic radicals；

Or R²And R³3～8 yuan of cycloalkyl, the 3～8 yuan of heterocyclic radicals or 5～14 optionally replaced by W are formed together with the carbon being attached thereto Unit's heteroaryl；

Or R⁴And R⁵6～the 8 yuan of aryl optionally replaced by W, 5～8 yuan of heteroaryls or 3～8 yuan are formed together with the carbon being attached thereto Heterocyclic radical；

X, Y are separately selected from-CO-,-CO₂-,-SO-,-SO₂-, the alkylidene optionally replaced by W or imino group；

N is selected from 0,1,2 or 3；

W is selected from hydroxyl, halogen atom, amino, nitro, cyano group, carboxyl, C_1-6Alkyl, C_1-6Alkoxyl, halo C_1-6 Alkyl, halo C_1-6Alkoxyl, C_1-6Alkyl amino, (C_1-6Alkyl)₂Amino, C_1-6Alkyl-carbonyl, C_1-6Alkyl-carbonyl epoxide, C_1-6Alkyl sulphonyl, C_1-6Alkyl sulfonyl amino, C_1-6Alkoxy C_1-6Alkyl, hydroxyl C_1-6Alkyl amino, hydroxyl C_1-6Alkane Epoxide, amino-sulfonyl, aminosulfonyl amino, amino-sulfonyl C_1-6Alkyl, aminosulfonyl amino C_1-6Alkyl, 5～6 yuan Heteroaryl, 5～6 yuan of heterocyclic radicals or 3～8 yuan of cycloalkyl.

2. compound as claimed in claim 1, its pharmaceutically acceptable salt, ester, solvate or its stereoisomer:

Wherein,

R¹Selected from hydrogen atom, halogen atom, nitro, cyano group, amino, hydroxyl, carboxyl, C_1-6Alkyl, hydroxyl C_1-6Alkyl Or halo C_1-6Alkyl；

R²、R⁴、R⁵Separately selected from hydrogen atom, halogen atom, nitro, cyano group, amino, hydroxyl, carboxyl, C_1-6 Alkyl, hydroxyl C_1-6Alkyl, halo C_1-6Alkyl, amino C_1-6Alkyl, C_1-6Alkoxyl, hydroxyl C_1-6Alkoxyl or halo C_1-6Alkoxyl；

R³Selected from the 5～8 yuan of heteroaryls optionally replaced by W or 4～6 yuan of heterocyclic radicals；

Or R²And R³5～the 8 yuan of heteroaryls or 4～6 yuan of heterocyclic radicals optionally replaced by W are formed together with the carbon being attached thereto；

Or R⁴And R⁵5～the 6 yuan of heteroaryls or 4～6 yuan of heterocyclic radicals optionally replaced by W are formed together with the carbon being attached thereto；

X, Y are separately selected from-CO-,-CO₂-,-SO-,-SO₂-, the C optionally replaced by W_1-6Alkylidene or imido Base；

N is selected from 0 or 1；

W is selected from hydroxyl, halogen atom, amino, nitro, carboxyl, cyano group, C_1-6Alkyl, C_1-6Alkoxyl, halo C_1-6 Alkyl, halo C_1-6Alkoxyl or C_1-6Alkyl amino.

3. compound as claimed in claim 2, its pharmaceutically acceptable salt, ester, solvate or its stereoisomer:

Wherein,

R¹Selected from hydrogen atom, halogen atom, nitro, cyano group, amino, hydroxyl, carboxyl or C_1-6Alkyl；

R²、R⁴、R⁵Separately selected from hydrogen atom, halogen atom, nitro, cyano group, amino, hydroxyl, carboxyl, C_1-6 Alkyl, hydroxyl C_1-6Alkyl, halo C_1-6Alkyl, amino C_1-6Alkyl, C_1-6Alkoxyl, hydroxyl C_1-6Alkoxyl or halo C_1-6Alkoxyl；

R³Selected from the 5～6 yuan of heteroaryls containing 1～2 atom N optionally replaced by W or 5～6 yuan of heterocyclic radicals；

Or R²And R³5～the 6 yuan of heterocyclic radicals containing 1～2 atom N optionally replaced by W are formed together with the carbon being attached thereto；

Or R⁴And R⁵5～6 yuan containing 1～2 O and/or S atom optionally replaced by W are formed miscellaneous together with the carbon being attached thereto Ring group；

X, Y are separately selected from-SO-,-SO₂-, the C optionally replaced by W_1-6Alkylidene or imino group；

N is selected from 0 or 1；

W is selected from hydroxyl, amino, carboxyl, cyano group, nitro, halogen atom, C_1-6Alkyl, C_1-6Alkoxyl or C_1-6Alkyl ammonia Base.

4. compound as claimed in claim 3, its pharmaceutically acceptable salt, ester, solvate or its stereoisomer:

Wherein,

R¹Selected from hydrogen atom, halogen atom, nitro, cyano group, amino, hydroxyl, carboxyl or C_1-4Alkyl；

R²、R⁴、R⁵Separately selected from hydrogen atom, halogen atom, C_1-4Alkyl, hydroxyl C_1-4Alkyl, amino C_1-4Alkane Base, halo C_1-4Alkyl, C_1-4Alkoxyl, halo C_1-4Alkoxyl or hydroxyl C_1-4Alkoxyl；

R³Selected from optionally replaced by W pyridine radicals, dihydropyridine base, tetrahydro pyridyl, pyrrole radicals, pyrrolin base, four Hydrogen pyrrole radicals, piperidyl, piperazinyl or morpholinyl；

X, Y are separately selected from-SO₂-or the C that optionally replaced by W_1-4Alkylidene；

N is selected from 0 or 1；

W is selected from hydroxyl, halogen atom, amino, nitro or C_1-4Alkyl.

5. compound as claimed in claim 3, its pharmaceutically acceptable salt, ester, solvate or its stereoisomer:

Wherein,

R¹Selected from hydrogen atom, halogen atom, nitro, cyano group, amino, hydroxyl, carboxyl or C_1-4Alkyl；

R²And R³5～the 6 yuan of heterocyclic radicals containing 1～2 atom N optionally replaced by W are formed together with the carbon being attached thereto；

R⁴、R⁵Separately selected from hydrogen atom, C_1-4Alkyl or C_1-4Alkoxyl；

X, Y are separately selected from-SO₂-or the C that optionally replaced by W_1-4Alkylidene；

N is selected from 0 or 1；

W is selected from hydroxyl, halogen atom, amino, nitro or C_1-4Alkyl.

6. compound as claimed in claim 3, its pharmaceutically acceptable salt, ester, solvate or its stereoisomer:

Wherein,

R¹Selected from hydrogen atom, halogen atom, nitro, cyano group, amino, hydroxyl, carboxyl or C_1-4Alkyl；

R²Selected from hydrogen atom, halogen atom, C_1-4Alkyl, hydroxyl C_1-4Alkyl, amino C_1-4Alkyl, C_1-4Alkoxyl or hydroxyl C_1-4Alkoxyl；

R³Selected from optionally replaced by W pyridine radicals, dihydropyridine base, tetrahydro pyridyl, pyrrole radicals, pyrrolin base, four Hydrogen pyrrole radicals, piperidyl, piperazinyl or morpholinyl；

R⁴And R⁵5～6 yuan containing 1～2 O and/or S atom optionally replaced by W are formed miscellaneous together with the carbon being attached thereto Ring group；

X, Y are separately selected from-SO₂-or the C that optionally replaced by W_1-4Alkylidene；

N is selected from 0 or 1；

W is selected from hydroxyl, halogen atom, amino, nitro or C_1-4Alkyl.

7. compound as claimed in claim 1, its pharmaceutically acceptable salt, ester, solvate or its stereoisomer, Wherein said compound is selected from:

8. compound as described in claim 1～7 any claim, its pharmaceutically acceptable salt, ester, solvate Or the preparation that its stereoisomer is made with one or more pharmaceutical carriers, for pharmaceutically acceptable arbitrary dosage form.

9. contain the compound as described in claim 1～7 any claim, its pharmaceutically acceptable salt, ester, solvent Compound or the pharmaceutical composition of its stereoisomer, possibly together with one or more active constituents of medicine.

10. compositions as claimed in claim 9, it is characterised in that one or more described active constituents of medicine are for anti-swollen Tumor agent and/or immunosuppressant, described antitumor agent and/or immunosuppressant are antimetabolite, selected from capecitabine, Ji Xi His shore, pemetrexed disodium；For growth factor receptor inhibitors, selected from pazopanib, imatinib, erlotinib, Lapatinib, Gefitinib, ZD6474；For antibody, selected from Trastuzumab, bevacizumab；For mitotic inhibitor, selected from paclitaxel, Vinorelbine, docetaxel, doxorubicin；For antitumor hormones, selected from letrozole, tamoxifen, fulvestrant, fluorine His amine, triptorelin；For alkylating agent class, selected from cyclophosphamide, chlormethine, L-Sarcolysinum, Chlorambucil, carmustine；For metal Platinum class, selected from carboplatin, cisplatin, oxaliplatin；For immunosuppressant class, fit selected from everolimus, sirolimus, special cancer；For Purine analogue, selected from Ismipur, 6-thioguanine, azathioprine；For antibiotics, selected from rhzomorph D, soft red mould Element, amycin, mitoxantrone, bleomycin A5, plicamycin；For platinum complex, selected from cisplatin, NSC-241240；For adrenal gland Cortex inhibitor class, selected from aminoglutethimide；For enzyme inhibitor, selected from SAHA, cytosine arabinoside, methotrexate, hydroxyurea, Hydroxycamptothecin, Topotecan, topotecan, Irinotecan.

11. compounds as described in claim 1～7 any claim, its pharmaceutically acceptable salt, ester, solvate Or its stereoisomer is in the medicine of the cancer-related diseases prepared for treating and/or prevent ALK to mediate or non-cancerous disease Application, the relevant disease of described cancer selected from the brain cancer, pulmonary carcinoma, lung cancer in non-cellule type, squamous cell cancer, bladder cancer, Gastric cancer, ovarian cancer, peritoneal cancer, cancer of pancreas, breast carcinoma, head and neck cancer, cervical cancer, carcinoma of endometrium, colorectal cancer, liver Cancer, renal carcinoma, the esophageal carcinoma, adenocarcinoma of esophagus, esophageal squamous cell carcinoma, non-Hodgkin lymphoma, cerebroma, central nervous system swells Tumor, glioma, glioblastoma multiforme, glioma sarcomatosum, carcinoma of prostate, thyroid carcinoma, female reproductive tract cancer, Cancer in situ, lymphoma, histocytic lymphoma, neurofibroma, osteocarcinoma, skin carcinoma, colon cancer, carcinoma of testis, minicell Pulmonary carcinoma, gastrointestinal stromal tumor, mast cell tumor, multiple myeloma, melanoma, glioma, glioblastoma multiforme, Astrocytoma, neuroblastoma, sarcoma；Non-cancerous disease, selected from skin or prostatic hyperplasia of prostate.