CN106146525A - Three and ring class anaplastic lymphoma kinase inhibitor - Google Patents

Three and ring class anaplastic lymphoma kinase inhibitor Download PDF

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CN106146525A
CN106146525A CN201510168569.3A CN201510168569A CN106146525A CN 106146525 A CN106146525 A CN 106146525A CN 201510168569 A CN201510168569 A CN 201510168569A CN 106146525 A CN106146525 A CN 106146525A
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alkyl
yuan
amino
cancer
base
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CN106146525B (en
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吴永谦
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Xuanzhu Biopharmaceutical Co Ltd
Shandong Xuanzhu Pharma Co Ltd
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Shandong Xuanzhu Pharma Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring

Abstract

The invention belongs to pharmaceutical technology field, be specifically related to three shown in formula (I) ring class anaplastic lymphoma kinase inhibitor, its pharmaceutically acceptable salt, ester, solvate or its stereoisomer, wherein R1、R2、R3、R4, A ring and B ring 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 treatment and/or prevention are mediated by anaplastic lymphoma kinase.

Description

Three and ring class anaplastic lymphoma kinase inhibitor
Technical field
The invention belongs to pharmaceutical technology field, it is specifically related to three and ring class anaplastic lymphoma kinase inhibitor, its pharmaceutically acceptable salt, ester, solvate or its stereoisomer, 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 treatment and/or prevention are mediated by anaplastic lymphoma kinase.
Background technology
Anaplastic lymphoma kinase (Anaplastic lymphoma kinase, ALK) is receptor tyrosine kinase family member, can raise downstream albumen by autophosphorylation, and then express specific gene, regulation cell metabolism and growth.Anaplastic lymphoma kinase is found in primary cutaneous type (Anaplastic large cell lymphoma, ALCL) the earliest, finds also there is high expressed in non-small cell lung cancer (NSCLC) later.Unconventionality expression in some ALCL/NSCLC for the ALK derives from different chromosome translocations.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 the genetic fragment merging with ALK all mediates the sequence of self dimerization containing promoter element and coding, thus cause the intracellular fusion protein high expressed with ALK kinase activity and excessive activation, cause the vicious transformation of cell.So, the activity in ALK intracellular kinase district and corresponding signal transduction path are the important molecule mechanism causing ALCL to be formed.
Therefore, research and development are for the micromolecular inhibitor of ALK, can effectively reduce the impact on downstream albumen of the ALK gene of sudden change, and then have influence on the effect such as tumor cell invasion, propagation, finally affect the growth of tumour cell, play antineoplastic action.Gram azoles having had Pfizer at present successfully lists for Buddhist nun (Crizotinib), but existing a large amount of clinical proof generation ALK inhibitor C rizotinib, easily produce drug resistance, therefore, designing and screen the patient to Crizotinib generation resistance also has two generation ALK inhibitor of good curative effect, has significant clinical meaning.
Therefore, modified by compound structure and find new compound structure, make great efforts to improve the physicochemical property of compound, improve druggability, as improved the bioavilability of compound, find the activated micromolecular inhibitor to ALK sudden change, for the treatment of the disease causing because of ALK sudden change clinically, have great importance.
Content of the invention
The present invention, to develop micromolecular inhibitor for ALK as target, has invented the cancer-related diseases to treatment and/or prevention ALK mediation and has had three and ring class anaplastic lymphoma kinase inhibitor of good result.Concrete technical scheme is as follows:
1. the compound shown in formula (I), its pharmaceutically acceptable salt, ester, solvate or its stereoisomer:
Wherein,
R1It is selected from-COR5,-CO2R5,-CONRR5,-SOR5,-SO2R5、-S(O2)OR5Or-SO2NRR5；
R2、R3、R、R5Independently selected from hydrogen atom, C1-6Alkyl or 3～8 yuan of carbocyclic rings；
R4Selected from hydrogen atom, halogen atom, cyano group, nitro, amino, carboxyl, C1-6Alkoxyl, C1-6Alkyl, hydroxyl C1-6Alkyl, halo C1-6Alkyl, hydroxyl C1-6Alkoxyl, halo C1-6Alkoxyl, C2-8Thiazolinyl, C2-8Alkynyl, C1-6Alkyl amino, C1-6Alkyl-carbonyl, C1-6Alkyl-carbonyl epoxide, (C1-6Alkyl)2Amino, amino C1-6Alkyl or sulfonyl C1-6Alkyl；
A ring is selected from optionally by 1～3 Q1Substituted 3～8 yuan of cycloalkyl or 3～8 yuan of heterocyclic radicals, described substituent Q1Selected from hydroxyl, amino, carboxyl, cyano group, nitro, halogen atom, C1-6Alkyl, C1-6Alkoxyl, C1-6Alkyl amino, (C1-6Alkyl)2Amino, halo C1-6Alkyl, halo C1-6Alkoxyl, C1-6Alkoxy C1-6Alkyl, C2-8Thiazolinyl, C2-8Alkynyl or 3～8 yuan of heterocyclic radicals；
B ring is selected from optionally by 1～3 Q2Substituted 3～8 yuan of heterocyclic radicals, or optionally by 1～3 Q2Substituted 5～14 yuan of heteroaryls, described substituent Q2Selected from hydroxyl, amino, carboxyl, cyano group, nitro, halogen atom, C1-6Alkyl, C1-6Alkoxyl, C1-6Alkyl amino, (C1-6Alkyl)2Amino, halo C1-6Alkyl, halo C1-6Alkoxyl, C1-6Alkoxy C1-6Alkyl, C1-6Alkoxy C1-6Alkoxyl, C2-8Thiazolinyl, C2-8Alkynyl or 3～8 yuan of heterocyclic radicals.
2. the compound as described in technical scheme 1, its pharmaceutically acceptable salt, ester, solvate or its stereoisomer, wherein,
R1It is selected from-CONRR5,-SO2R5Or-SO2NRR5,
R、R5Independently selected from C1-6Alkyl；
R2、R3Independently selected from hydrogen atom or C1-6Alkyl；
R4Selected from hydrogen atom, halogen atom, cyano group, nitro, amino, carboxyl, C1-6Alkoxyl or C1-6Alkyl；
A ring is selected from optionally by 1～2 Q1Substituted 4～7 yuan of cycloalkyl or 4～7 yuan of heterocyclic radicals, described substituent Q1Selected from hydroxyl, amino, carboxyl, cyano group, nitro, halogen atom or C1-6Alkyl；
B ring is selected from optionally by 1～2 Q2Substituted 5～6 yuan of heterocyclic radicals, or optionally by 1～2 Q2Substituted 5～6 yuan of heteroaryls, described substituent Q2Selected from hydroxyl, amino, carboxyl, cyano group, nitro, halogen atom or C1-6Alkyl.
3. the compound as described in technical scheme 2, its pharmaceutically acceptable salt, ester, solvate or its stereoisomer, wherein,
R1It is selected from-SO2R5Or-SO2NRR5,
R、R5Independently selected from C1-6Alkyl；
R2、R3Independently selected from hydrogen atom or C1-6Alkyl；
R4Selected from halogen atom；
A ring is selected from optionally by 1～2 Q1Substituted 5～6 yuan of heterocyclic radicals, described substituent Q1Selected from hydroxyl, amino, carboxyl, cyano group, nitro, halogen atom or C1-4Alkyl；
B ring is selected from optionally by 1～2 Q2Substituted 5～6 yuan of heterocyclic radicals, described substituent Q2Selected from hydroxyl, amino, carboxyl, cyano group, nitro, halogen atom or C1-4Alkyl.
4. the compound as described in technical scheme 3, its pharmaceutically acceptable salt, ester, solvate or its stereoisomer, wherein,
R1It is selected from-SO2R5,
R5Independently selected from C1-4Alkyl；
R2、R3Independently selected from hydrogen atom or C1-4Alkyl；
R4Selected from halogen atom；
A ring is selected from optionally by 1～2 Q1Substituted 5～6 yuan of heterocyclic radicals containing 1～2 O and/or S atom, described substituent Q1Selected from hydroxyl, amino, carboxyl, cyano group, nitro, halogen atom or C1-4Alkyl；
B ring is selected from optionally by 1～2 Q2Substituted 5～6 yuan of heterocyclic radicals containing 1～2 N atom, described substituent Q2Selected from hydroxyl, amino, carboxyl, cyano group, nitro, halogen atom or C1-4Alkyl.
5. the compound as described in technical scheme 3, its pharmaceutically acceptable salt, ester, solvate or its stereoisomer, wherein,
R1It is selected from-SO2R5,
R5Independently selected from methyl, ethyl or isopropyl；
R2、R3Independently selected from hydrogen atom or methyl；
R4Selected from chlorine atom；
A ring is selected from optionally by 1～2 Q1Substituted 5～6 yuan of heterocyclic radicals containing 1～2 O and/or S atom, described substituent Q1Selected from hydroxyl, amino, halogen atom or C1-4Alkyl；
B ring is selected from optionally by 1～2 Q2Substituted piperidyl, piperazinyl, morpholinyl, pyrrolidinyl, pyrrolin base, tetrahydrofuran base, THP trtrahydropyranyl or Isosorbide-5-Nitrae-dioxane base, described substituent Q2Selected from methyl, ethyl, n-propyl, isopropyl or normal-butyl.
6. the compound as described in technical scheme 1, its pharmaceutically acceptable salt, ester, solvate or its stereoisomer, wherein,
R1It is selected from-SO2R5Or-SO2NRR5,
R、R5Independently selected from C1-6Alkyl；
R2、R3Independently selected from hydrogen atom or C1-6Alkyl；
R4Selected from hydrogen atom, halogen atom, amino, C1-6Alkoxyl or C1-6Alkyl；
A ring is selected from optionally by 1～2 Q1Substituted 5～6 yuan of saturated heterocyclyls, described substituent Q1Selected from hydroxyl, amino, carboxyl, cyano group, nitro, halogen atom or C1-6Alkyl；
B ring is selected from optionally by 1～2 Q2Substituted 5～6 yuan of saturated heterocyclyls, described substituent Q2Selected from hydroxyl, amino, carboxyl, cyano group, nitro, halogen atom or C1-6Alkyl.
7. the compound as described in technical scheme 6, its pharmaceutically acceptable salt, ester, solvate or its stereoisomer, wherein,
A ring is selected from optionally by 1～2 Q1Substituted 5～6 yuan of saturated heterocyclyls containing 1～2 O, S and/or N atom, described substituent Q1Selected from hydroxyl, amino, carboxyl, cyano group, nitro, halogen atom or C1-6Alkyl；
B ring is selected from optionally by 1～2 Q2Substituted 5～6 yuan of saturated heterocyclyls containing 1～2 O, S and/or N atom, described substituent Q2Selected from hydroxyl, amino, carboxyl, cyano group, nitro, halogen atom or C1-6Alkyl.
8. the compound as described in technical scheme 7, its pharmaceutically acceptable salt, ester, solvate or its stereoisomer, wherein,
A ring is selected from optionally by 1～2 Q1Substituted 5～6 yuan of saturated heterocyclyls containing 1～2 O and/or S atom, described substituent Q1Selected from hydroxyl, amino, carboxyl, cyano group, nitro, halogen atom or C1-6Alkyl；
B ring is selected from optionally by 1～2 Q2Substituted 5～6 yuan of saturated heterocyclyls containing 1～2 N atom, described substituent Q2Selected from hydroxyl, amino, carboxyl, cyano group, nitro, halogen atom or C1-6Alkyl.
9. the compound as described in technical scheme 8, its pharmaceutically acceptable salt, ester, solvate or its stereoisomer, wherein,
A ring is selected from optionally by 1～2 Q1The substituted 5 yuan of saturated heterocyclyls containing 1～2 O and/or S atom, described substituent Q1Selected from hydroxyl, amino, carboxyl, cyano group, nitro, halogen atom or C1-6Alkyl；
B ring is selected from optionally by 1～2 Q2The substituted 5 yuan of saturated heterocyclyls containing 1～2 N atom, described substituent Q2Selected from hydroxyl, amino, carboxyl, cyano group, nitro, halogen atom or C1-6Alkyl.
10. the compound as described in technical scheme 8, its pharmaceutically acceptable salt, ester, solvate or its stereoisomer, wherein,
A ring is selected from optionally by 1～2 Q1Substituted 5～6 yuan of saturated heterocyclyls containing 1 O atom, described substituent Q1Selected from hydroxyl, amino, carboxyl, cyano group, nitro, halogen atom or C1-6Alkyl；
B ring is selected from optionally by 1～2 Q2Substituted 5～6 yuan of saturated heterocyclyls containing 1 N atom, described substituent Q2Selected from hydroxyl, amino, carboxyl, cyano group, nitro, halogen atom or C1-6Alkyl.
The part of compounds of the present invention
Detailed Description Of The Invention
" halogen atom " of the present invention includes fluorine atom, chlorine atom, bromine atoms and atomic iodine etc..
" C of the present invention1-6Alkyl " represents the alkyl containing 1-6 carbon atom of straight or branched, including such as " C1-4Alkyl ", " C1-3Alkyl " etc.; instantiation includes but is not limited to: methyl, ethyl, n-propyl, 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 invention2-8Thiazolinyl " refers to straight or branched that the carbon number containing at least one double bond is 2-8 or ring-type thiazolinyl, including such as " C2-6Thiazolinyl ", " C2-4Thiazolinyl ", " C2-3Thiazolinyl ", " C3-6nullCycloalkenyl group " etc.，Instantiation includes but is not limited to: vinyl、1-acrylic、2-acrylic、2-cyclobutenyl、3-cyclobutenyl、2-methyl-1-propylene base、1-methyl-2-acrylic、1-pentenyl、2-pentenyl、3-pentenyl、2-methyl-1-butene thiazolinyl、3-methyl-1-butene base、2-methyl-3-cyclobutenyl、1,1-dimethyl-2-acrylic、1-ethyl-2-acrylic、2-hexenyl、3-hexenyl、2-methyl-1-pentene thiazolinyl、3-methyl-1-pentene thiazolinyl、1-methyl-2-pentenyl、3-methyl-2-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-2-cyclobutenyl、2,2-dimethyl-3-cyclobutenyl、2,3-dimethyl-2-cyclobutenyl、2,3-dimethyl-1-cyclobutenyl、2-ethyl-1-cyclobutenyl、2-ethyl-3-cyclobutenyl、2-heptenyl、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、Cyclopentenyl、1,3-cyclopentadienyl group、Cyclohexenyl group、1,4-cyclohexadienyl、Cycloheptenyl、1,4-cycloheptadiene base、Cyclo-octene base etc..
" C of the present invention2-8Alkynyl " refers to the alkynyl of the straight or branched that the carbon number containing three keys is 2-8, including such as " C2-6Alkynyl ", " C2-4Alkynyl ", " C2-3nullAlkynyl " etc.，Instantiation includes but is not limited to: acetenyl、1-propinyl、2-butynyl、1-methyl-2-propynyl、Valerylene base、3-pentynyl、1-methyl-2-butynyl、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-pentynyl、2-methyl-3-pentynyl、1,1-dimethyl-3-butynyl、2-ethyl-3-butynyl、2-heptynyl、3-heptynyl、4-methyl-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 invention1-6Alkoxyl, C1-6Alkyl amino, (C1-6Alkyl)2Amino, C1-6Alkyl sulfenyl, C1-6Alkyl-carbonyl, C1-6Alkyl-carbonyl epoxide " refers to C1-6Alkyl-O-, C1-6Alkyl-NH-, (C1-6Alkyl)2-N-、C1-6Alkyl-S-, C1-6Alkyl-C (O)-, C1-6The group that alkyl-C (O)-O-mode is formed, wherein " C1-6Described in the literary composition as defined above of alkyl ".
" C of the present invention1-4Alkoxyl, C1-4Alkyl amino, (C1-4Alkyl)2Amino, C1-4Alkyl sulfenyl, C1-4Alkyl-carbonyl, C1-4Alkyl-carbonyl epoxide refers to C1-4Alkyl-O-, C1-4Alkyl-NH-, (C1-4Alkyl)2-N-、C1-4Alkyl-S-, C1-4Alkyl-C (O)-, C1-4The group that alkyl-C (O)-O-mode is formed, wherein " C1-4Described in the literary composition as defined above of alkyl ".
" halo C of the present invention1-6Alkyl, hydroxyl C1-6Alkyl, amino C1-6Alkyl, sulfonyl C1-6Alkyl, C1-6Alkoxy C1-6Alkyl, halo C1-6Alkoxyl, hydroxyl C1-6Alkoxyl, C1-6Alkoxy C1-6Alkoxyl " refers to one or more, such as 1～4,1～3,1～2 halogen atom, hydroxyl, amino, sulfonyl, C1-6Alkoxyl replaces C respectively1-6Alkyl, C1-6The group that hydrogen atom in alkoxyl is formed.
" halo C of the present invention1-4Alkyl, hydroxyl C1-4Alkyl, amino C1-4Alkyl, sulfonyl C1-4Alkyl, C1-4Alkoxy C1-4Alkyl, halo C1-4Alkoxyl, hydroxyl C1-4Alkoxyl, C1-4Alkoxy C1-4Alkoxyl " refers to one or more, such as 1～4,1～3,1～2 halogen atom, hydroxyl, amino, sulfonyl, C1-4Alkoxyl replaces C respectively1-4Alkyl, C1-4The group that hydrogen atom in alkoxyl is formed.
" 3～8 yuan of cycloalkyl " of the present invention, refer to that the paraffin section of 3～8 carbon atoms removes the derivative monocyclic cyclic alkyl of a hydrogen atom, 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 is not limited to: cyclopropane base, cyclobutane base, pentamethylene base, cyclohexyl, 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 preferably N, O.
null" 3～8 yuan of heterocyclic radicals " of the present invention refers to containing 3～8 annular atomses、And contain at least one hetero atom (such as 1、2、3、4 or 5 hetero atoms) the monocyclic heterocyclic compound of saturated or fractional saturation remove the group that a hydrogen atom obtains，Including such 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 "、" 6 member heterocyclic ring containing nitrogen base "、" 5～6 yuan of heterocyclic radicals containing 1～2 N atom "、" 5 yuan of heterocyclic radicals containing 1～2 N atom "、" contain 5～6 yuan of heterocyclic radicals of 1～2 O and/or S atom "、" contain 5 yuan of heterocyclic radicals of 1～2 O and/or S atom "、" contain 1～2 O、5～6 yuan of saturated heterocyclyls of S and/or N atom "、" contain 5～6 yuan of saturated heterocyclyls of 1～2 O and/or S atom "、" 5～6 yuan of saturated heterocyclyls containing 1～2 N atom "、" contain 5 yuan of saturated heterocyclyls of 1～2 O and/or S atom "、" 5 yuan of saturated heterocyclyls containing 1～2 N atom "、" 5～6 yuan of saturated heterocyclyls containing 1 O atom "、" 5～6 yuan of saturated heterocyclyls containing 1 N atom " etc..nullInstantiation includes but are not limited to: aziridine base、2H-aziridine base、Diazacyclo propyl、3H-diazacyclo acrylic、Azetidinyl、1,4-dioxane base、1,3-dioxane base、1,3-dioxolane base、1,4-Dioxin base、Tetrahydrofuran base、THP trtrahydropyranyl、Pyrrolin base、Pyrrolidinyl、Imidazolidinyl、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..
" 3～8 yuan of carbocyclic rings " refers to saturated, the fractional saturation containing 3～8 carbon atoms or undersaturated monocyclic compound.Including such as " 3～7 yuan of carbocyclic rings ", " 3～6 yuan of carbocyclic rings ", " 4～7 yuan of carbocyclic rings ", " 4～6 yuan of carbocyclic rings ", " 5～6 yuan of carbocyclic rings " etc..Instantiation includes but are not limited to: cyclopropane base, cyclobutane base, pentamethylene base, cyclohexyl, cycloheptyl alkyl, cyclooctane base, cyclopentenyl, 1,3-cyclopentadienyl group, cyclohexenyl group, 1,4-cyclohexadienyl, cycloheptenyl, 1,4-cycloheptadiene base, cyclo-octene base, phenyl etc..Preferably " 5～6 yuan saturated or the carbocyclic ring of fractional saturation ".
Present invention also offers the preparation method of above-claimed cpd, but be not limited only to following methods, reaction equation is as follows:
Reactions steps:
The preparation of step 1 intermediate 1
Buy or prepare intermediate 1 through proper method.
The preparation of step 2 intermediate 2
Intermediate 1 is dissolved in solvent (such as methyl alcohol), adds palladium carbon, the lower 25 DEG C of reactions of hydrogen shield (such as 15-25 hour), filters, be concentrated to give intermediate 2.
The preparation of step 3 intermediate 3
Intermediate 2 is dissolved in appropriate solvent (such as acetonitrile), it is cooled to 0 DEG C, add N-bromosuccinimide, (such as 0.5-1.5 hour) is stirred at room temperature, reaction finishes, and add water cancellation, and organic solvent (such as ethyl acetate) extracts, concentrating, purified (such as silica gel column chromatography) obtains intermediate 3.
The preparation of step 4 intermediate 4
Intermediate 3 is dissolved in appropriate solvent (such as N, dinethylformamide), add cuprous cyanide, 150 DEG C of reactions (such as 1-3 hour), cooling, pours in ammoniacal liquor, and organic solvent (such as ethyl acetate) extracts, concentrating, purified (such as silica gel column chromatography) obtains intermediate 4.
The preparation of step 5 intermediate 5
Intermediate 4 is dissolved in appropriate solvent (such as methyl alcohol), adds ammoniacal liquor (10mL) and Raney's nickel, 25 DEG C of reactions (15-25 hour), filter, concentrate, obtain intermediate 5 through proper method.
Step 6 present invention leads to the preparation of formula (I) compound
Intermediate 5 is dissolved in appropriate solvent (such as sec-amyl alcohol), adds intermediate 6 and p-methyl benzenesulfonic acid, at 120 DEG C, stir (such as 10-30 hour).Adding saturated sodium bicarbonate solution, organic solvent (such as ethyl acetate) extracts, and is dried, and concentrates, obtains 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, A ring and B ring as defined hereinabove, X represents fluorine atom, chlorine atom, bromine atoms and atomic iodine.
" stereoisomer " of formula (I) compound of the present invention refers to when formula (I) compound exists asymmetric carbon atom, enantiomter can be produced, when there is carbon-carbon double bond or circulus in compound, cis-trans-isomer can be produced, when there is ketone or oxime in compound, dynamic isomer can be produced, the enantiomter of all formulas (I) compound, diastereoisomer, racemization isomers, cis-trans-isomer, dynamic isomer, geometric isomer, epimer and mixture thereof, be included 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, the compound of required enantiomer-pure can be obtained by the method for chiral resolution: can be by having the chromatography (image height pressure preparative liquid chromatography, supercritical fluid chromatography) of chiral stationary phase.Chirality padding includes but is 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 the salt of pharmaceutically acceptable, non-toxic alkali or acid preparation, including acylate, inorganic acid salt, organic alkali salt, inorganic base salts.
Acylate includes the salt of formic acid, acetic acid, trifluoroacetate, benzene sulfonic 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, maleic acid, malic acid, mandelic acid, glactaric acid, pamoic acid, pantothenic acid, butanedioic acid, tartaric acid etc..
Inorganic acid salt includes the salt of hydrobromic acid, hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid etc..
Organic alkali salt includes primary, secondary and tertiary amine, substituted amine includes naturally occurring replacement amine, cyclammonium and basic ion-exchange resins, selected from glycine betaine, caffeine, choline, N, the salt of N '-dibenzyl-ethylenediamin, diethylamine, 2-Diethylaminoethanol, 2-dimethylamino-ethanol, monoethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, meglumine, Glucosamine, Hai Baming, isopropylamine, methylglucosamine, morpholine, piperazine, piperidines, procaine, purine, theobromine, triethylamine, trimethylamine, tripropyl amine (TPA), tromethamine etc..The salt of native amino hydrochlorate such as glycine, alanine, valine, leucine, isoleucine, nor-leucine, tyrosine, cystine, cysteine, methionine, proline, hydroxy-proline, histidine, ornithine, lysine, arginine, serine etc..
Inorganic base salts includes 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 refers to, when there is carboxyl in formula (I) compound, the ester that can be formed with alcohol generation esterification, when formula (I) compound exists hydroxyl, with organic acid, inorganic acid, acylate etc. esterification can occur and the ester that be 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 forms.If solvate is hydrate in the case that, aquation can complete in preparation process or the hygroscopicity of original anhydrous product can be utilized gradually to carry out.
Further requirement of the present invention protection includes the pharmaceutical composition of 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 diluent, can make pharmaceutically acceptable arbitrary formulation.It is applied to need the patient of this treatment in modes such as oral, parenteral, rectum or transpulmonary administration.During for oral administration, can be made into the solid pharmaceutical preparation of routine, such as tablet, capsule, pill, granule etc.；May be made as oral liquid, such as oral solution, oral suspensions, syrup etc..When making oral formulations, suitable filler, adhesive, disintegrant, lubricant etc. can be added.During for parenteral, can be made into injection, including parenteral solution, injection sterile powder and concentrated solution for injection.When making injection, the conventional method in existing pharmaceutical field can be used to produce, during preparation injection, additives can be added without, it is possible to the character according to medicine adds suitable additives.During for rectally, can be made into suppository etc..During for transpulmonary administration, can be made into inhalant or spray etc..
Further requirement of the present invention protection includes the pharmaceutical composition of the arbitrary compound of formula recited above (I), its pharmaceutically acceptable salt, ester, solvate or its stereoisomer and other one or more antitumor agents and immunodepressant.Described antitumor agent and immunodepressant are antimetabolite, including but not limited to capecitabine, gemcitabine, pemetrexed disodium；For growth factor receptor inhibitors, including but not limited to pazopanib, Imatinib, Erlotinib, Lapatinib, Gefitinib, ZD6474；For antibody, including but not limited to Trastuzumab, bevacizumab；It for mitotic inhibitor, is selected from taxol, vinorelbine, docetaxel, Doxorubicin；It for antitumor steroids, is selected from Letrozole, tamoxifen, fulvestrant, Flutamide, Triptorelin；For alkylating agent class, including but not limited to endoxan, mustargen, melphalan, chlorambucil, BCNU；For metal platinum class, including but not limited to carboplatin, cis-platinum, oxaliplatin；For immunosupress class, including but not limited to everolimus, sirolimus, special cancer is fitted；For purine analogue, including but not limited to Ismipur, 6-thioguanine, imuran；For antibiotics, including but not limited to rhzomorph D, daunorubicin, adriamycin, mitoxantrone, bleomycin, plicamycin；For platinum complex, including but not limited to cis-platinum, NSC-241240；For adrenal cortex inhibitor class, including but not limited to aminoglutethimide；For enzyme inhibitor, including but not limited to SAHA, cytarabine, methotrexate (MTX), hydroxycarbamide, Hydroxycamptothecin, Topotecan, TPT, Irinotecan.
nullPresent invention also offers the compound shown in formula (I) of the present invention、Its pharmaceutically acceptable salt、Ester、Solvate or application in the cancer-related diseases of preparation treatment and/or prevention ALK mediation or the medicine of proliferative disease for its stereoisomer，The related disease of described cancer includes but is not limited to brain tumor，Lung cancer，Lung cancer in non-cellule type，Squamous cell，Carcinoma of urinary bladder，Cancer of the stomach，Oophoroma，Peritoneal cancer，Cancer of pancreas，Breast cancer，Head and neck cancer，Cervix cancer，Carcinoma of endometrium，Colorectal cancer，Liver cancer，Kidney，Adenocarcinoma of esophagus，Esophageal squamous cell carcinoma，NHL，Brain tumor，Central nerve neuroma，I.e. glioma，Glioblastoma multiforme，Glioma sarcomatosum，Prostate cancer，Thyroid cancer，Female reproductive tract cancer，Carcinoma in situ，Lymthoma，Histocytic lymphoma，Neurofibromatosis，Osteocarcinoma，Cutaneum carcinoma，Colon cancer，Carcinoma of testis，ED-SCLC，Gastrointestinal stromal tumor，Tumor of prostate，Mast cell tumor，Huppert's disease，Melanoma，Glioma，Glioblastoma，Astrocytoma，Neuroblastoma，Sarcoma；Proliferative disease, including but not limited to skin or prostatic 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 demonstrate good biological stability, act on more longlasting, and bioavilability 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.
Test below by way of external zymetology and cytology inhibitory activity and the compounds of this invention beneficial effect is expanded on further, but this should be interpreted as the compounds of this invention only has following beneficial effect.
Experimental example 1 The external zymetology activity experiment of the compounds of this invention
Test sample: the compounds of this invention 1, its chemical name and preparation method are shown in the preparation embodiment of compound 1.
Comparison medicine ceritinib, makes by oneself (prepared by the preparation method of referenced patent WO2008/073687A2 compound 66).
The implication that the abbreviation of following middle experiment is representative is as follows:
DMSO: dimethyl sulfoxide (DMSO)
DTT: dithiothreitol (DTT)
ALK: anaplastic lymphoma kinase
HEPES:4-HEPES
Brij-35: Brij-35
EDTA: ethylenediamine tetra-acetic acid
Experimental technique: the inhibitory activity using Caliper Mobility Shift method to carry out ALK kinases measures
1.1 times of kinase buffer liquid preparations:
Take the HEPES of pH7.5 respectively, MgCl that Brij-35 that concentration is 30%, mother liquid concentration are 1M2Solution, mother liquid concentration are the DTT of 1M, add ultra-pure water to mix, make the final concentration of 50mM of HEPES, final concentration of the 0.0015% of Brij-35, MgCl2Final concentration of 10mM, the final concentration of 2mM of DTT.
2. the preparation of stop buffer
Take that mother liquid concentration is 4% respectively be coated liquid Coating Reagent#3 (carry in the 12-sipper chip that Caliper instrument is used and be coated liquid), mother liquid concentration is the HEPES of 1000mM pH7.5, mother liquid concentration is the EDTA of 0.5M, mother liquid concentration is 30% Brij-35, ultra-pure water is added to mix, make Coating Reagent#3 final concentration of 0.2%, the final concentration of 100mM of HEPES, the final concentration of 50mM of EDTA, Brij-35 final concentration of 0.015%.
3.5 times of need testing solution preparations:
The DMSO storing solution preparation of test sample: Weigh Compound is appropriate (concrete sample weighting amount please see table) respectively, adds appropriate DMSO to dissolve, and mixes, standby.
Take the DMSO storing solution of test sample, make, with DMSO dilution, the solution that concentration is 50 μM, as mother liquor.With DMSO by four times of stepwise dilutions of above-mentioned mother liquor, then each concentration dilutes 10 times with 1 times of kinase buffer liquid respectively, makes 5 times of need testing solutions.
4. the preparation of other reagent various
2.5 times of ALK kinase solution required for being prepared respectively by 1 times of kinase buffer liquid, 2.5 times of polypeptide solutions, standby.
5. zymetology reaction:
1) corresponding in 384 orifice plates hole is separately added into 2.5 times of kinase solution that the 5 times of need testing solutions, 10 μ L that 5 μ L prepare prepare, incubated at room 10 minutes.
2) corresponding Kong Zhongzai is separately added into 2.5 times of polypeptide solutions that 10 μ L prepare, and makes tester final concentration of 1000nM, 250nM, 63nM, 16nM, 4nM, 1nM, 0.2nM, 0.1nM, 0.02nM, 0.004nM.Start enzyme reaction, hatch 1 hour for 28 DEG C.
6. zymetology detection:
Each corresponding hole is separately added into 25 μ L stop buffers, terminates reaction.Caliper instrument reads data, and calculates inhibiting rate by data,
Inhibiting rate (%)=(maximum-sample value)/(maximum-minimum of a value) × 100, use XLFIT software to carry out curve fitting, draw IC50Value.
Maximum: be not added with the positive control of tester, minimum of a value: not 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 the treatment disease related to kinases, the kinase mediated illness of particularly ALK or the patient's condition, has significant clinical meaning.
Experimental example 2 The cell in vitro activity experiment of the compounds of this invention
Test sample: the compounds of this invention 1, its chemical name and preparation method are shown in the preparation embodiment of compound 1.
Comparison medicine Ceritinib, makes by oneself (prepared by referenced patent WO2008/073687A2 compound 66 preparation method).
The implication that the abbreviation of following middle experiment is representative is as follows:
Rpm: rpm
DMSO: dimethyl sulfoxide (DMSO)
MTS: thiazole bromide blue tetrazolium
RPMI1640:1640 culture medium (RPMI:Roswell Park Memorial Institute)
500 ×, 1000 ×, 10 × "×" therein: times
Experimental technique:
NCI-H3122 cell:
(1) culture medium preparation:
The RPMI1640 culture medium containing the hyclone of 2.5% for the preparation, standby.
(2) cell is cultivated:
At 5%CO2, 37 DEG C of conditions incubator in, NCI-H3122 cell is put in T25 blake bottle and merges with the medium culture cell preparing in " (1) " to 80%.
(3) inoculating cell:
With trypsin digestion cell, 1000rpm centrifuges 4min, removes supernatant, again suspended with culture medium, adjusts cell density, takes this cell suspension 90 μ L and be inoculated in 96 orifice plates, it is thus achieved that final cell density is: 3000 cells/well；Then at 5%CO2, 24h cultivated by 37 DEG C of incubators.
(4) test sample is added:
(4.1) need testing solution preparation
Comparison drug solns: weigh comparison medicine 2.17mg, add appropriate DMSO to dissolve and make the mother liquor (1000 × comparison drug solns) of a series of concentration respectively with DMSO gradient dilution, dilute this mother liquor 100 with culture medium respectively again and obtain 10 × comparison drug solns again, take this solution 10 μ L respectively, joining in the 96 corresponding holes of orifice plate, obtaining comparison drug solns ultimate density is: 10 μM, 2.5 μM, 625nM, 156nM, 39nM, 9.8nM, 2.5nM, 0.625nM.
Compound 1 solution: Weigh Compound 8mg, add appropriate DMSO to dissolve and make the mother liquor (1000 × compound 1 solution) of a series of concentration respectively with DMSO gradient dilution, dilute this mother liquor 100 with culture medium respectively again and obtain 10 × compound 1 solution again, take this solution 10 μ L respectively, joining in the 96 corresponding holes of orifice plate, obtaining compound 1 solution ultimate density is: 10 μM, 2.5 μM, 625nM, 156nM, 39nM, 9.8nM, 2.5nM, 0.625nM.
(4.2) control wells is arranged:
Vehicle controls: 0.1%DMSO.
Blank: culture medium, instrument returns to zero.
(4.3) 96 orifice plates are put 37 DEG C, 5%CO2Incubator is cultivated 72h.
(5) detect:
Add CCK-8 reagent 10 μ L in each test hole of 96 orifice plates, put back to 5%CO2, 1h cultivated by 37 DEG C of incubators.ELIASA detection wavelength 450nm is set, reads result.
(6)IC50Calculate: cell survival rate (%)=(sample value-blank value)/(maximum-blank value) × 100, use Graph prism software to carry out curve fitting, draw IC50Value.
Maximum: be not added with compound solubilization matchmaker cell controls i.e. Vehicle controls, blank value: culture medium blank.
Experimental result and conclusion:
The cell inhibitory activity of table 2 the compounds of this invention
From table 2, compared with comparison medicine, the compounds of this invention has more preferable inhibitory activity to cell NCI-H3122, can be used for treating the kinase mediated illness of ALK or the patient's condition, has 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 to the foregoing of the present invention.But this should be interpreted as that the scope of the above-mentioned theme of the present invention is only limitted to following example.All technology being realized based on foregoing of the present invention belong to the scope of the present invention.
Embodiment 1 5- Chlorine -N 4 -(2-isopropelsulfonyl ) Phenyl )-N 2 -(2,3,7,8-tetrahydrochysene -1H- Furans is simultaneously [3,2-e] Iso-indoles -5- Base ) Pyrimidine -2,4- The preparation of diamines
(1) preparation of 2,3-Dihydrobenzofuranes-5-carboxylate methyl ester
By 2,3-Dihydrobenzofuranes-5-carboxylic acid (15g, 0.091mol) is dissolved in methyl alcohol (800mL), adding the concentrated sulfuric acid (2mL), 65 DEG C are reacted 20 hours, cooling, add sodium acid carbonate, concentrating, add water (200mL) dilution, and ethyl acetate (150mL × 3) extracts, anhydrous sodium sulfate is dried, filter, be concentrated to give product (15.8g, productivity 97.5%).
(2) preparation of 7-nitro-2,3-Dihydrobenzofuranes-5-carboxylate methyl ester
By 2,3-Dihydrobenzofuranes-5-carboxylate methyl ester (14g, it 78.6mmol) is dissolved in acetic anhydride (200mL), it is cooled to 0 DEG C, dropping red fuming nitric acid (RFNA) (mass fraction 65%, 7mL, 102.2mmol), dropping is warmed to room temperature stirring 1 hour after finishing, reacted and poured in water (200mL), ethyl acetate (150mL × 3) extracts, anhydrous sodium sulfate is dried, and filters, and concentrates, crude product purifies to obtain product (13g, productivity 74.3%) through silica gel column chromatography (petroleum ether: ethyl acetate=5:1).
(3) preparation of 7-amino-2,3-Dihydrobenzofuranes-5-carboxylate methyl ester
By 7-nitro-2,3-Dihydrobenzofuranes-5-carboxylate methyl ester (10g, 44.8mmol) is dissolved in methyl alcohol (300mL), adding palladium carbon (1g), lower 25 DEG C of atmosphere of hydrogen is reacted 20 hours, filters, filtrate is concentrated to give product (6g, productivity 69.4%).
(4) preparation of 7-amino-4-bromo-2,3-Dihydrobenzofuranes-5-carboxylate methyl ester
By 7-amino-2,3-Dihydrobenzofuranes-5-carboxylate methyl ester (5.4g, it 28mmol) is dissolved in acetonitrile (100mL), it is cooled to 0 DEG C, it is dividedly in some parts N-bromosuccinimide (5.98g, 33.6mmol), finish and be warmed to room temperature stirring reaction in 1 hour completely, pouring in water (100mL), ethyl acetate (150mL × 3) extracts, and anhydrous sodium sulfate is dried, filter, concentrating, crude product purifies to obtain product (5g, productivity 65.6%) through silica gel column chromatography (petroleum ether: ethyl acetate=3:1).
(5) preparation of 7-amino-4-cyano group-2,3-Dihydrobenzofuranes-5-carboxylate methyl ester
By 7-amino-4-bromo-2,3-Dihydrobenzofuranes-5-carboxylate methyl ester (4g, it 14.7mmol) is dissolved in N, in dinethylformamide (50mL), add cuprous cyanide (1.57g, 17.6mmol), 150 DEG C are reacted 2 hours, and cooling is poured in ammoniacal liquor (80mL), ethyl acetate (150mL × 3) extracts, anhydrous sodium sulfate is dried, and filters, and concentrates, crude product purifies to obtain product (1.4g, productivity 43.7%) through silica gel column chromatography (dichloromethane: methyl alcohol=30:1).
(6) preparation of 5-amino-1,2,7,8-tetrahydrochysene-3H-furans simultaneously [3,2-e] iso-indoles-3-ketone
By 7-amino-4-cyano group-2,3-Dihydrobenzofuranes-5-carboxylate methyl ester (0.4g, 1.83mmol) is dissolved in methyl alcohol (100mL), adds ammoniacal liquor (10mL) and Raney's nickel (0.1g), and 25 DEG C are reacted 20 hours.Filtering, filtrate is concentrated to give product (0.28g, productivity 80%).
(7) preparation of tert-butyl group 5-amino-1,3,7,8-tetrahydrochysene-2H-furans simultaneously [3,2-e] iso-indoles-2-carboxylate
By 5-amino-1,2,7,8-tetrahydrochysene-3H-furans simultaneously [3,2-e] iso-indoles-3-ketone (0.28g, 1.47mmol) is dissolved in oxolane (20mL), borane methyl sulfide ethereal solution (2mol/L is dripped at 0 DEG C, 2.57mL, 5.14mmol), add latter 65 DEG C and react 24 hours.It is cooled to 0 DEG C, dropping methyl alcohol (5mL) cancellation reaction, add 4mol/L hydrochloric acid (5mL), 65 DEG C are stirred 4 hours.After cooling, rotary evaporation removes solvent, it is diluted with water, add sodium hydroxide solution to be adjusted to pH=10, add di-tert-butyl dicarbonate (416mg, 1.91mmol), being stirred at room temperature 1 hour, ethyl acetate (10mL × 3) extracts, and anhydrous sodium sulfate is dried, filter, concentrating, crude product purifies to obtain product (75mg, productivity 18.5%) through silica gel column chromatography (petroleum ether: ethyl acetate=2:1).
(8) preparation of the chloro-N-of 2,5-bis-(2-(isopropelsulfonyl) phenyl) pyrimidine-4-amine
By 2-(isopropelsulfonyl) aniline (1g; 5mmol) He 2; 4; 5-trichloropyrimidine (1.1g, 6mmol) is dissolved in DMF (30mL); add sodium hydride (content 60%; 0.4g, 10mmol), react 12 hours at 25 DEG C.Adding water, ethyl acetate extracts (30mL × 3), and organic phase merges, saturated aqueous common salt washs, and anhydrous sodium sulfate is dried, and is concentrated in vacuo, crude product obtains product (0.8g, productivity 46%) through silica gel column chromatography (petroleum ether: ethyl acetate=25:1).
(9) the chloro-N of 5-4-(2-isopropelsulfonyl) phenyl)-N2The preparation of-(2,3,7,8-tetrahydrochysene-1H-furans simultaneously [3,2-e] iso-indoles-5-base) pyrimidine-2,4-diamines
By tert-butyl group 5-amino-1; 3; 7,8-tetrahydrochysene-2H-furans simultaneously [3,2-e] iso-indoles-2-carboxylate (70mg; it 0.25mmol) is dissolved in sec-amyl alcohol (8mL); add 2, the chloro-N-of 5-bis-(2-(isopropelsulfonyl) phenyl) pyrimidine-4-amine (104mg, 0.3mmol) and p-methyl benzenesulfonic acid (86mg; 0.5mmol), stirring 20 hours at 120 DEG C.Rotary evaporation removes solvent, adds saturated sodium bicarbonate solution, and ethyl acetate (10mL × 3) extracts, anhydrous sodium sulfate is dried, being concentrated in vacuo, crude product obtains end-product (10mg, productivity 8.2%) through silica gel column chromatography (dichloromethane: methyl alcohol: ammoniacal liquor=10:1:0.1).
Molecular formula: C23H24ClN5O3S molecular weight: 485.99LC-MS (m/z): 486 [M]+
1H-NMR(400MHz,MeOD-d4) δ: 8.49 (d, J=8.0Hz, 1H), 8.14 (s, 1H), 7.90 (d, J=8.0Hz, 1H), 7.72 (s, 1H), 7.70-7.67 (m, 1H), 7.39-7.35 (m, 1H), 4.65 (t, J=8.6Hz, 2H), 4.53 (s, 2H), 4.45 (s, 2H), 3.26 (t, J=8.8Hz, 2H), 1.19 (d, J=6.8Hz, 6H).

Claims (10)

1. the compound shown in formula (I), its pharmaceutically acceptable salt, ester, solvate or its stereoisomer:
Wherein,
R1It is selected from-COR5,-CO2R5,-CONRR5,-SOR5,-SO2R5、-S(O2)OR5Or-SO2NRR5；
R2、R3、R、R5Independently selected from hydrogen atom, C1-6Alkyl or 3～8 yuan of carbocyclic rings；
R4Selected from hydrogen atom, halogen atom, cyano group, nitro, amino, carboxyl, C1-6Alkoxyl, C1-6Alkyl, hydroxyl C1-6 Alkyl, halo C1-6Alkyl, hydroxyl C1-6Alkoxyl, halo C1-6Alkoxyl, C2-8Thiazolinyl, C2-8Alkynyl, C1-6Alkyl ammonia Base, C1-6Alkyl-carbonyl, C1-6Alkyl-carbonyl epoxide, (C1-6Alkyl)2Amino or sulfonyl C1-6Alkyl；
A ring is selected from optionally by 1～3 Q1Substituted 3～8 yuan of cycloalkyl or 3～8 yuan of heterocyclic radicals, described substituent Q1It is selected from Hydroxyl, amino, carboxyl, cyano group, nitro, halogen atom, C1-6Alkyl, C1-6Alkoxyl, C1-6Alkyl amino, (C1-6Alkane Base)2Amino, halo C1-6Alkyl, halo C1-6Alkoxyl, C1-6Alkoxy C1-6Alkyl, C2-8Thiazolinyl, C2-8Alkynyl or 3～8 Unit's heterocyclic radical；
B ring is selected from optionally by 1～3 Q2Substituted 3～8 yuan of heterocyclic radicals, or optionally by 1～3 Q2Substituted 5～14 yuan of heteroaryls Base, described substituent Q2Selected from hydroxyl, amino, carboxyl, cyano group, nitro, halogen atom, C1-6Alkyl, C1-6Alcoxyl Base, C1-6Alkyl amino, (C1-6Alkyl)2Amino, halo C1-6Alkyl, halo C1-6Alkoxyl, C1-6Alkoxy C1-6Alkyl, C2-8Thiazolinyl, C2-8Alkynyl or 3～8 yuan of heterocyclic radicals.
2. compound as claimed in claim 1, its pharmaceutically acceptable salt, ester, solvate or its stereoisomer:
Wherein,
R1It is selected from-CONRR5,-SO2R5Or-SO2NRR5,
R、R5Independently selected from C1-6Alkyl；
R2、R3Independently selected from hydrogen atom or C1-6Alkyl；
R4Selected from hydrogen atom, halogen atom, cyano group, nitro, amino, carboxyl, C1-6Alkoxyl or C1-6Alkyl；
A ring is selected from optionally by 1～2 Q1Substituted 4～7 yuan of cycloalkyl or 4～7 yuan of heterocyclic radicals, described substituent Q1It is selected from Hydroxyl, amino, carboxyl, cyano group, nitro, halogen atom or C1-6Alkyl；
B ring is selected from optionally by 1～2 Q2Substituted 5～6 yuan of heterocyclic radicals, or optionally by 1～2 Q2Substituted 5～6 yuan of heteroaryls Base, described substituent Q2Selected from hydroxyl, amino, carboxyl, cyano group, nitro, halogen atom or C1-6Alkyl.
3. compound as claimed in claim 2, its pharmaceutically acceptable salt, ester, solvate or its stereoisomer:
Wherein,
R1It is selected from-SO2R5Or-SO2NRR5,
R、R5Independently selected from C1-6Alkyl；
R2、R3Independently selected from hydrogen atom or C1-6Alkyl；
R4Selected from halogen atom；
A ring is selected from optionally by 1～2 Q1Substituted 5～6 yuan of heterocyclic radicals, described substituent Q1Selected from hydroxyl, amino, carboxylic Base, cyano group, nitro, halogen atom or C1-4Alkyl；
B ring is selected from optionally by 1～2 Q2Substituted 5～6 yuan of heterocyclic radicals, described substituent Q2Selected from hydroxyl, amino, carboxylic Base, cyano group, nitro, halogen atom or C1-4Alkyl.
4. compound as claimed in claim 3, its pharmaceutically acceptable salt, ester, solvate or its stereoisomer:
Wherein,
R1It is selected from-SO2R5,
R5Independently selected from C1-4Alkyl；
R2、R3Independently selected from hydrogen atom or C1-4Alkyl；
R4Selected from halogen atom；
A ring is selected from optionally by 1～2 Q1Substituted 5～6 yuan of heterocyclic radicals containing 1～2 O and/or S atom, described replacement Base Q1Selected from hydroxyl, amino, carboxyl, cyano group, nitro, halogen atom or C1-4Alkyl；
B ring is selected from optionally by 1～2 Q2Substituted 5～6 yuan of heterocyclic radicals containing 1～2 N atom, described substituent Q2Choosing From hydroxyl, amino, carboxyl, cyano group, nitro, halogen atom or C1-4Alkyl.
5. compound as claimed in claim 3, its pharmaceutically acceptable salt, ester, solvate or its stereoisomer:
Wherein,
R1It is selected from-SO2R5,
R5Independently selected from methyl, ethyl or isopropyl；
R2、R3Independently selected from hydrogen atom or methyl；
R4Selected from chlorine atom；
A ring is selected from optionally by 1～2 Q1Substituted 5～6 yuan of heterocyclic radicals containing 1～2 O and/or S atom, described replacement Base Q1Selected from hydroxyl, amino, halogen atom or C1-4Alkyl；
B ring is selected from optionally by 1～2 Q2Substituted piperidyl, piperazinyl, morpholinyl, pyrrolidinyl, pyrrolin base, Tetrahydrofuran base, THP trtrahydropyranyl or Isosorbide-5-Nitrae-dioxane base, described substituent Q2Selected from methyl, ethyl, positive third Base, isopropyl or normal-butyl.
6. compound as claimed in claim 1, its pharmaceutically acceptable salt, ester, solvate or its stereoisomer, Wherein said compound is selected from:
7. the compound as described in claim 1～6 any claim, its pharmaceutically acceptable salt, ester, solvate Or the pharmaceutical preparation that its stereoisomer is made with one or more pharmaceutical carriers, it is pharmaceutically acceptable arbitrary formulation.
8. contain the compound as described in claim 1～6 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.
9. pharmaceutical composition as claimed in claim 8, it is characterised in that one or more described active constituents of medicine are anti- Tumour agent and/or immunodepressant, described antitumor agent and/or immunodepressant are antimetabolite, are selected from capecitabine, Ji His shore, pemetrexed disodium of west；For growth factor receptor inhibitors, selected from pazopanib, Imatinib, Erlotinib, handkerchief is drawn to replace Buddhist nun, Gefitinib, ZD6474；It for antibody, is selected from Trastuzumab, bevacizumab；It for mitotic inhibitor, is selected from Japanese yew Alcohol, vinorelbine, docetaxel, Doxorubicin；For antitumor steroids, selected from Letrozole, tamoxifen, fulvestrant, Flutamide, Triptorelin；It for alkylating agent class, is selected from endoxan, mustargen, melphalan, chlorambucil, BCNU；For gold Belong to platinum class, be selected from carboplatin, cis-platinum, oxaliplatin；For immunosupress class, fit selected from everolimus, sirolimus, special cancer； It for purine analogue, is selected from Ismipur, 6-thioguanine, imuran；For antibiotics, selected from rhzomorph D, soft red Mycin, adriamycin, mitoxantrone, bleomycin, plicamycin；It for platinum complex, is selected from cis-platinum, NSC-241240；For on kidney Gland cortex inhibitor class, is selected from aminoglutethimide；For enzyme inhibitor, selected from SAHA, cytarabine, methotrexate (MTX), hydroxycarbamide, Hydroxycamptothecin, Topotecan, TPT, Irinotecan.
10. the compound as described in claim 1～6 any claim or its pharmaceutically acceptable salt are used for treating in preparation And/or the application in the cancer-related diseases of prevention ALK mediation or the medicine of proliferative disease, the related disease choosing of described cancer From brain tumor, lung cancer, lung cancer in non-cellule type, squamous cell, carcinoma of urinary bladder, cancer of the stomach, oophoroma, peritoneal cancer, cancer of pancreas, Breast cancer, head and neck cancer, cervix cancer, carcinoma of endometrium, colorectal cancer, liver cancer, kidney, adenocarcinoma of esophagus, esophagus squameous is thin Born of the same parents' cancer, solid tumor, NHL, central nerve neuroma, i.e. glioma, glioblastoma multiforme, Glioma sarcomatosum, prostate cancer, thyroid cancer, female reproductive tract cancer, carcinoma in situ, lymthoma, histocytic lymphoma, neural Fibromatosis, thyroid cancer, osteocarcinoma, cutaneum carcinoma, the cancer of the brain, colon cancer, carcinoma of testis, ED-SCLC, gastrointestinal stromal tumor, Tumor of prostate, mast cell tumor, Huppert's disease, melanoma, glioma, glioblastoma, astrocyte Knurl, neuroblastoma, sarcoma；Proliferative disease, is selected from skin or prostatic hyperplasia of prostate.
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