CN106146525B - Three and ring class anaplastic lymphoma kinase inhibitor - Google Patents

Three and ring class anaplastic lymphoma kinase inhibitor Download PDF

Info

Publication number
CN106146525B
CN106146525B CN201510168569.3A CN201510168569A CN106146525B CN 106146525 B CN106146525 B CN 106146525B CN 201510168569 A CN201510168569 A CN 201510168569A CN 106146525 B CN106146525 B CN 106146525B
Authority
CN
China
Prior art keywords
cancer
alkyl
compound
atom
pharmaceutically acceptable
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN201510168569.3A
Other languages
Chinese (zh)
Other versions
CN106146525A (en
Inventor
吴永谦
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Xuanzhu Biopharmaceutical Co Ltd
Shandong Xuanzhu Pharma Co Ltd
Original Assignee
Shandong Xuanzhu Pharma Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shandong Xuanzhu Pharma Co Ltd filed Critical Shandong Xuanzhu Pharma Co Ltd
Priority to CN201510168569.3A priority Critical patent/CN106146525B/en
Publication of CN106146525A publication Critical patent/CN106146525A/en
Application granted granted Critical
Publication of CN106146525B publication Critical patent/CN106146525B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

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

Description

Three and ring class anaplastic lymphoma kinase inhibitor
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to three and ring class anaplastic lymphoma kinase inhibitor, its pharmacy Upper acceptable salt, ester, solvate or its stereoisomer, the preparation method of these compounds contain these compounds Pharmaceutical preparation and pharmaceutical composition and the compound, its pharmaceutically acceptable salt, ester, solvate or its alloisomerism Application of the body in preparing treatment and/or preventing the drug of the cancer-related diseases mediated by anaplastic lymphoma kinase.
Background technology
Anaplastic lymphoma kinase (Anaplastic lymphoma kinase, ALK) is receptor tyrosine kinase family Member can be raised downstream albumen by autophosphorylation, and then express specific gene, and cell metabolism and growth are adjusted.Between become Property lymphom kinase is found in primary cutaneous type (Anaplastic large cell lymphoma, ALCL) earliest In, found also there is high expression in non-small cell lung cancer (NSCLC) later.Unconventionality expressions of the ALK in certain ALCL/NSCLC From different chromosome translocations.These chromosome translocations can generate corresponding fusion protein.To these fusions point Analysis shows that they all contain the gene order in the end of ALK gene 3 ' coding intracellular kinase area, and the genetic fragment merged with ALK is equal The sequence that itself dimerization is mediated containing promoter element and coding, so as to cause the intracellular fusion egg with ALK kinase activity White high expression and excessive activation, cause the vicious transformation of cell.So the active and corresponding signal in ALK intracellular kinases area passes The approach of leading is the important molecule mechanism for causing ALCL to be formed.
Therefore, research and development can effectively reduce the ALK gene of mutation to downstream albumen for the micromolecular inhibitor of ALK Influence, and then influence the effects such as tumor cell invasion, proliferation, the final growth for influencing tumour cell is played antitumor Effect.There is gram azoles of Pfizer successfully to be listed for Buddhist nun (Crizotinib) at present, but has had an a large amount of clinical proof generation ALK inhibitor C rizotinib, easy to produce drug resistance, therefore, design and screen to the drug resistant patient of Crizotinib generations Also there are two generation ALK inhibitor of good curative effect, there is significant clinical meaning.
Therefore, new compound structure is found by compound structure modification, makes great efforts the physicochemical property for improving compound, carries High druggability such as improves the bioavilability of compound, active micromolecular inhibitor is mutated to ALK to find, for facing The treatment of the disease caused by ALK is mutated, has great importance on bed.
Invention content
The present invention has been invented and has been mediated to treating and/or preventing ALK to develop the micromolecular inhibitor for being directed to ALK as target Cancer-related diseases have good result three and ring class anaplastic lymphoma kinase inhibitor.Specific technical solution is such as Under：
General formula 1. (I) compound represented, its pharmaceutically acceptable salt, ester, solvate or its stereoisomer：
Wherein,
R1Selected from-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, nitro, amino, carboxyl, C1-6Alkoxy, C1-6Alkyl, hydroxyl C1-6Alkane Base, halogenated C1-6Alkyl, hydroxyl C1-6Alkoxy, halogenated C1-6Alkoxy, C2-8Alkenyl, C2-8Alkynyl, C1-6Alkyl amino, C1-6Alkane Base carbonyl, C1-6Alkyl carbonyl epoxide, (C1-6Alkyl)2Amino, amino C1-6Alkyl or sulfonyl C1-6Alkyl；
A rings are selected from optionally by 1~3 Q13~8 yuan of naphthenic base or 3~8 circle heterocyclic ring bases of substitution, the substituent group Q1Choosing From hydroxyl, amino, carboxyl, cyano, nitro, halogen atom, C1-6Alkyl, C1-6Alkoxy, C1-6Alkyl amino, (C1-6Alkyl)2 Amino, halogenated C1-6Alkyl, halogenated C1-6Alkoxy, C1-6Alkoxy C1-6Alkyl, C2-8Alkenyl, C2-8Alkynyl or 3~8 circle heterocyclic rings Base；
B rings are selected from optionally by 1~3 Q23~8 circle heterocyclic ring bases of substitution, or optionally by 1~3 Q25~14 yuan of substitution Heteroaryl, the substituent group Q2Selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atom, C1-6Alkyl, C1-6Alkoxy, C1-6Alkyl amino, (C1-6Alkyl)2Amino, halogenated C1-6Alkyl, halogenated C1-6Alkoxy, C1-6Alkoxy C1-6Alkyl, C1-6Alcoxyl Base C1-6Alkoxy, C2-8Alkenyl, C2-8Alkynyl or 3~8 circle heterocyclic ring bases.
2. compound as described in technical solution 1, its pharmaceutically acceptable salt, ester, solvate or its alloisomerism Body, wherein
R1Selected 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, nitro, amino, carboxyl, C1-6Alkoxy or C1-6Alkyl；
A rings are selected from optionally by 1~2 Q14~7 yuan of naphthenic base or 4~7 circle heterocyclic ring bases of substitution, the substituent group Q1Choosing From hydroxyl, amino, carboxyl, cyano, nitro, halogen atom or C1-6Alkyl；
B rings are selected from optionally by 1~2 Q25~6 circle heterocyclic ring bases of substitution, or optionally by 1~2 Q25~6 yuan of substitution are miscellaneous Aryl, the substituent group Q2Selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atom or C1-6Alkyl.
3. compound as described in technical solution 2, its pharmaceutically acceptable salt, ester, solvate or its alloisomerism Body, wherein
R1Selected from-SO2R5Or-SO2NRR5,
R、R5Independently selected from C1-6Alkyl；
R2、R3Independently selected from hydrogen atom or C1-6Alkyl；
R4Selected from halogen atom；
A rings are selected from optionally by 1~2 Q15~6 circle heterocyclic ring bases of substitution, the substituent group Q1Selected from hydroxyl, amino, carboxylic Base, cyano, nitro, halogen atom or C1-4Alkyl；
B rings are selected from optionally by 1~2 Q25~6 circle heterocyclic ring bases of substitution, the substituent group Q2Selected from hydroxyl, amino, carboxylic Base, cyano, nitro, halogen atom or C1-4Alkyl.
4. compound as described in technical solution 3, its pharmaceutically acceptable salt, ester, solvate or its alloisomerism Body, wherein
R1Selected from-SO2R5,
R5Independently selected from C1-4Alkyl；
R2、R3Independently selected from hydrogen atom or C1-4Alkyl；
R4Selected from halogen atom；
A rings are selected from optionally by 1~2 Q15~6 circle heterocyclic ring bases containing 1~2 O and/or S atom of substitution, described takes For base Q1Selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atom or C1-4Alkyl；
B rings are selected from optionally by 1~2 Q25~6 circle heterocyclic ring bases containing 1~2 N atom of substitution, the substituent group Q2 Selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atom or C1-4Alkyl.
5. compound as described in technical solution 3, its pharmaceutically acceptable salt, ester, solvate or its alloisomerism Body, wherein
R1Selected from-SO2R5,
R5Independently selected from methyl, ethyl or isopropyl；
R2、R3Independently selected from hydrogen atom or methyl；
R4Selected from chlorine atom；
A rings are selected from optionally by 1~2 Q15~6 circle heterocyclic ring bases containing 1~2 O and/or S atom of substitution, described takes For base Q1Selected from hydroxyl, amino, halogen atom or C1-4Alkyl；
B rings are selected from optionally by 1~2 Q2Substituted piperidyl, piperazinyl, morpholinyl, pyrrolidinyl, pyrrolin base, Tetrahydrofuran base, THP trtrahydropyranyl or Isosorbide-5-Nitrae-dioxane base, the substituent group Q2Selected from methyl, ethyl, n-propyl, Isopropyl or normal-butyl.
6. compound as described in technical solution 1, its pharmaceutically acceptable salt, ester, solvate or its alloisomerism Body, wherein
R1Selected 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, C1-6Alkoxy or C1-6Alkyl；
A rings are selected from optionally by 1~2 Q15~6 yuan of saturated heterocyclyls of substitution, the substituent group Q1Selected from hydroxyl, ammonia Base, carboxyl, cyano, nitro, halogen atom or C1-6Alkyl；
B rings are selected from optionally by 1~2 Q25~6 yuan of saturated heterocyclyls of substitution, the substituent group Q2Selected from hydroxyl, ammonia Base, carboxyl, cyano, nitro, halogen atom or C1-6Alkyl.
7. compound as described in technical solution 6, its pharmaceutically acceptable salt, ester, solvate or its alloisomerism Body, wherein
A rings are selected from optionally by 1~2 Q15~6 yuan of saturated heterocyclyls containing 1~2 O, S and/or N atom of substitution, institute The substituent group Q stated1Selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atom or C1-6Alkyl；
B rings are selected from optionally by 1~2 Q25~6 yuan of saturated heterocyclyls containing 1~2 O, S and/or N atom of substitution, institute The substituent group Q stated2Selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atom or C1-6Alkyl.
8. compound as described in technical solution 7, its pharmaceutically acceptable salt, ester, solvate or its alloisomerism Body, wherein
A rings are selected from optionally by 1~2 Q15~6 yuan of saturated heterocyclyls containing 1~2 O and/or S atom of substitution, it is described Substituent group Q1Selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atom or C1-6Alkyl；
B rings are selected from optionally by 1~2 Q25~6 yuan of saturated heterocyclyls containing 1~2 N atom of substitution, the substitution Base Q2Selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atom or C1-6Alkyl.
9. compound as described in technical solution 8, its pharmaceutically acceptable salt, ester, solvate or its alloisomerism Body, wherein
A rings are selected from optionally by 1~2 Q15 yuan of saturated heterocyclyls containing 1~2 O and/or S atom of substitution, it is described Substituent group Q1Selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atom or C1-6Alkyl；
B rings are selected from optionally by 1~2 Q25 yuan of saturated heterocyclyls containing 1~2 N atom of substitution, the substituent group Q2 Selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atom or C1-6Alkyl.
10. compound as described in technical solution 8, its pharmaceutically acceptable salt, ester, solvate or its alloisomerism Body, wherein
A rings are selected from optionally by 1~2 Q15~6 yuan of saturated heterocyclyls containing 1 O atom of substitution, the substituent group Q1 Selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atom or C1-6Alkyl；
B rings are selected from optionally by 1~2 Q25~6 yuan of saturated heterocyclyls containing 1 N atom of substitution, the substituent group Q2 Selected from hydroxyl, amino, carboxyl, cyano, 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 atom and iodine atom etc..
" C of the present invention1-6Alkyl " indicates the alkyl containing 1-6 carbon atom of linear chain or branched chain, including for example “C1-4Alkyl ", " C1-3Alkyl " etc., specific example include but not limited to：Methyl, ethyl, n-propyl, isopropyl, normal-butyl, 2- Methyl-propyl, 1- methyl-propyls, 1,1- dimethyl ethyls, n-pentyl, 3- methyl butyls, 2- methyl butyls, 1- methyl butyls, 1- Ethyl propyl, n-hexyl, 4- methyl amyls, 3- methyl amyls, 2- methyl amyls, 1- methyl amyls, 3,3- dimethylbutyls, 2, 2- dimethylbutyls, 1,1- dimethylbutyls, 1,2- dimethylbutyls, 1,3- dimethylbutyls, 2,3- dimethylbutyls, 2- second Base butyl, 1,2- dimethyl propyls etc..
" C of the present invention2-8Alkenyl " refers to the linear chain or branched chain that the carbon atom number containing at least one double bond is 2-8 Or cricoid alkenyl, including such as " C2-6Alkenyl ", " C2-4Alkenyl ", " C2-3Alkenyl ", " C3-6Cycloalkenyl group " etc., specific example include But it is not limited to：Vinyl, 1- acrylic, 2- acrylic, 2- cyclobutenyls, 3- cyclobutenyls, 2- methyl-1-propylenes base, 1- methyl -2- Acrylic, 1- pentenyls, 2- pentenyls, 3- pentenyls, 2-methyl-1-butene alkenyl, 3-methyl-1-butene base, 2- methyl -3- fourths Alkenyl, 1,1- dimethyl -2- acrylic, 1- ethyl -2- acrylic, 2- hexenyls, 3- hexenyls, 2- methyl-1-pentenes alkenyl, 3- Methyl-1-pentene alkenyl, 1- methyl -2- pentenyls, 3- methyl -2- pentenyls, 2- methyl-3-pentenyls, 1- methyl -4- amylenes Base, 3- methyl -4- pentenyls, 1,1- dimethyl -3- cyclobutenyls, 1,2- dimethyl -3- cyclobutenyls, 1,3- dimethyl -2- butylene Base, 2,2- dimethyl -3- cyclobutenyls, 2,3- dimethyl -2- cyclobutenyls, 2,3- dimethyl -1- cyclobutenyls, 2- ethyl -1- butylene Base, 2- ethyl -3- cyclobutenyls, 2- heptenyls, 3- heptenyls, 4- heptenyls, 1- octenyls, 3- octenyls, 4- octenyls, 1,3- Butadienyl, 2,4- pentadienyls, 1,4- hexadienyls, 2,4- hexadienyls, 1,5- heptadiene base, 2,5- heptadiene base, 2, 6- octadienyls, cyclopentenyl, 1,3- cyclopentadienyl groups, cyclohexenyl group, 1,4- cyclohexadienyls, cycloheptenyl, 1,4- cycloheptyls Dialkylene, cyclo-octene base etc..
" C of the present invention2-8Alkynyl " refers to the alkynyl for the linear chain or branched chain that the carbon atom number containing three keys is 2-8, Include such as " C2-6Alkynyl ", " C2-4Alkynyl ", " C2-3Alkynyl " etc., specific example include but not limited to：Acetenyl, 1- propine Base, 2- butynyls, 1- methyl -2-propynyl, valerylene base, 3- pentynyls, 1- methyl -2- butynyls, 2- methyl -3- butine Base, 1,1- dimethyl -2-propynyl, 1- ethyls -2-propynyl, 2- hexin bases, 3- hexin bases, 1- methyl-valerylene base, 1- first Base -3- pentynyls, 2- methyl -3- pentynyls, 1,1- dimethyl -3- butynyls, 2- ethyl -3- butynyls, 2- heptynyls, 3- heptan Alkynyl, 4- methyl -2- hexin bases, 5- methyl -2- hexin bases, 2- methyl -3- hexin bases, 5- methyl -3- hexin bases, 2- methyl - 4- hexin base 4- methyl -5- hexin bases, 2- octynyls, 3- octynyls, 4- octynyls, 4- methyl -2- heptynyls, 5- methyl -3- Heptynyl, 6- methyl -3- heptynyls, 2- methyl -4- heptynyls, 2- methyl -5- heptynyls, 3- methyl -6- heptynyls etc..
" C of the present invention1-6Alkoxy, C1-6Alkyl amino, (C1-6Alkyl)2Amino, C1-6Alkyl sulfenyl, C1-6Alkyl Carbonyl, C1-6Alkyl carbonyl epoxide " 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- modes are formed, wherein " C1-6Described in alkyl " text as defined above.
" C of the present invention1-4Alkoxy, C1-4Alkyl amino, (C1-4Alkyl)2Amino, C1-4Alkyl sulfenyl, C1-4Alkyl Carbonyl, C1-4Alkyl carbonyl epoxide refers to C1-4Alkyl-O-, C1-4Alkyl-NH-, (C1-4Alkyl)2-N-、C1-4Alkyl-S-, C1-4 Alkyl-C (O)-, C1-4The group that alkyl-C (O)-O- modes are formed, wherein " C1-4Described in alkyl " text as defined above.
" halogenated C of the present invention1-6Alkyl, hydroxyl C1-6Alkyl, amino C1-6Alkyl, sulfonyl C1-6Alkyl, C1-6Alkane Oxygroup C1-6Alkyl, halogenated C1-6Alkoxy, hydroxyl C1-6Alkoxy, C1-6Alkoxy C1-6Alkoxy " refers to one or more, such as 1 ~4,1~3,1~2 halogen atom, hydroxyl, amino, sulfonyl, C1-6Alkoxy replaces C respectively1-6Alkyl, C1-6Alcoxyl Hydrogen atom in base is formed by group.
" halogenated C of the present invention1-4Alkyl, hydroxyl C1-4Alkyl, amino C1-4Alkyl, sulfonyl C1-4Alkyl, C1-4Alkane Oxygroup C1-4Alkyl, halogenated C1-4Alkoxy, hydroxyl C1-4Alkoxy, C1-4Alkoxy C1-4Alkoxy " refers to one or more, such as 1~4,1~3,1~2 halogen atom, hydroxyl, amino, sulfonyl, C1-4Alkoxy replaces C respectively1-4Alkyl, C1-4Alkane Hydrogen atom in oxygroup is formed by group.
" 3~8 yuan of naphthenic base " of the present invention refers to that paraffin section one hydrogen atom of removal of 3~8 carbon atoms spreads out Raw monocycle cyclic alkyl, including for example " 3~6 yuan of naphthenic base ", " 4~7 yuan of naphthenic base ", " 4~8 yuan of naphthenic base ", " 4~6 yuan Naphthenic base ", " 5~6 yuan of naphthenic base " etc..The example includes but not limited to：Cyclopropane base, cyclobutane base, pentamethylene base, hexamethylene Base, cycloheptyl alkyl, cyclooctane base, methyl cyclopropane base, dimethylcyclopropane base, methyl cyclobutane base, dimethylcyclobutane base, Methyl cyclopentane base, dimethylcyclopentane base, methyl cyclohexane alkyl, dimethyleyelohexane alkyl etc..
" hetero atom " of the present invention refers to N, O, C (O), S, SO and/or SO2Deng, preferably N, O, S, more preferable N, O.
" 3~8 circle heterocyclic ring base " of the present invention refers to containing 3~8 annular atoms and containing at least one hetero atom The saturation of (such as 1,2,3,4 or 5 hetero atom) or the monocyclic heterocyclic compound of fractional saturation remove what a hydrogen atom obtained Group, including for example " 3~7 circle heterocyclic ring base ", " 3~6 circle heterocyclic ring base ", " 4~7 circle heterocyclic ring base ", " 4~6 circle heterocyclic ring base ", " 5~ 6 circle heterocyclic ring bases ", " 5~6 member heterocyclic ring containing nitrogen base ", " 6 member heterocyclic ring containing nitrogen base ", 5~6 circle heterocyclic ring bases of 1~2 N atom " contain ", 5 circle heterocyclic ring bases of 1~2 N atom " contain ", " 5~6 circle heterocyclic ring bases containing 1~2 O and/or S atom ", " containing 1~2 O and/ Or 5 circle heterocyclic ring bases of S atom ", 5~6 yuan of saturated heterocyclyls of 1~2 O, S and/or N atom " contain ", " containing 1~2 O and/or 5~6 yuan of saturated heterocyclyls of S atom ", " it is former to contain 1~2 O and/or S at " 5~6 yuan of saturated heterocyclyls for containing 1~2 N atom " 5 yuan of saturated heterocyclyls of son ", " contain 5~6 yuan of saturated heterocyclics of 1 O atom at " 5 yuan of saturated heterocyclyls for containing 1~2 N atom " Base ", " 5~6 yuan of saturated heterocyclyls for containing 1 N atom " etc..Specific example includes but are not limited to：Aziridine base, 2H- Aziridine base, diazacyclo propyl, 3H- diazacyclos acrylic, azetidinyl, 1,4- dioxanes Base, 1,3- dioxanes base, 1,3- dioxolane base, 1,4- Dioxins base, tetrahydrofuran base, tetrahydrochysene Pyranose, pyrrolin base, pyrrolidinyl, imidazolidinyl, 4,5- glyoxalidine base, pyrazolidinyl, 4,5- pyrazolines base, 2, 5- dihydrothiophenes, tetrahydro-thienyl, 4,5- dihydro-thiazolyls, piperidyl, piperazinyl, morpholinyl, 4,5- dihydro-oxazoles base, 4, 5- dihydro-isoxazoles base, 2,3- dihydro-isoxazoles base, 2H-1,2- oxazinyls, 6H-1,3- oxazinyls, 4H-1,3- thiazinyls, 6H- 1,3- thiazinyls, 2H- pyranoses, 2H- pyran-2-ones base, 3,4- dihydro -2H- pyranoses etc..
" 3~8 yuan of carbocyclic rings " refers to the saturation containing 3~8 carbon atoms, fractional saturation 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..Tool Body example includes but are not limited to：Cyclopropane base, cyclobutane base, pentamethylene base, cyclohexyl, cycloheptyl alkyl, cyclooctane base, ring Pentenyl, 1,3- cyclopentadienyl groups, cyclohexenyl group, 1,4- cyclohexadienyls, cycloheptenyl, 1,4- cycloheptadiene base, cyclo-octene Base, phenyl etc..It is preferred that " carbocyclic ring of 5~6 yuan of saturations or fractional saturation ".
The present invention also provides the preparation methods of above compound, but are not limited only to following methods, and reaction equation is as follows：
Reaction step：
The preparation of step 1 intermediate 1
Intermediate 1 is prepared through proper method in purchase.
The preparation of step 2 intermediate 2
Intermediate 1 is dissolved in solvent (such as methanol), addition palladium carbon, the lower 25 DEG C of reactions of hydrogen shield (such as 15-25 is small When), filtering is concentrated to give intermediate 2.
The preparation of step 3 intermediate 3
Intermediate 2 is dissolved in appropriate solvent (such as acetonitrile), is cooled to 0 DEG C, N-bromosuccinimide is added, room temperature is stirred (such as 0.5-1.5 hours) are mixed, reaction finishes, and water quenching is added to go out, organic solvent (such as ethyl acetate) extraction, and concentration is 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,N-Dimethylformamide), cuprous cyanide, 150 DEG C of reaction (examples are added Such as 1-3 hours), it is cooling, it pours into ammonium hydroxide, organic solvent (such as ethyl acetate) extraction, concentration, purified (such as silicagel column Chromatography) obtain intermediate 4.
The preparation of step 5 intermediate 5
Intermediate 4 is dissolved in appropriate solvent (such as methanol), ammonium hydroxide (10mL) and Raney's nickel, 25 DEG C of reaction (15-25 are added Hour), it filters, concentration obtains intermediate 5 through proper method.
The preparation of the logical formula (I) compound of step 6 present invention
Intermediate 5 is dissolved in appropriate solvent (such as sec-amyl alcohol), intermediate 6 and p-methyl benzenesulfonic acid is added, is stirred at 120 DEG C (such as 10-30 hours).Saturated sodium bicarbonate solution is added, organic solvent (such as ethyl acetate) extraction is dry, concentrates, warp Proper method (such as silica gel column chromatography) obtains the logical formula (I) compound of the present invention.
In reaction equation, R1、R2、R3、R4, A rings and B rings as defined hereinabove, it is former that X represents fluorine atom, chlorine atom, bromine Son and iodine atom.
" stereoisomer " of formula (I) compound of the present invention refers to the meeting when formula (I) compound is there are when asymmetric carbon atom Enantiomter is generated, when compound is there are when carbon-carbon double bond or cyclic structure, will produce cis-trans-isomer, when compound exists When ketone or oxime, tautomer, the enantiomter of all formula (I) compounds, diastereoisomer, racemization isomery will produce Body, cis-trans-isomer, tautomer, geometric isomer, epimer and its mixture, are included in the scope of the invention In.
If the raceme that any compound synthesis obtains shown in the logical formula (I) of the present invention, required enantiomer-pure Compound can be obtained by the method for chiral resolution：It can (image height be suppressed standby by chromatography with chiral stationary phase Liquid chromatogram, supercritical fluid chromatography).Chirality padding includes but not limited to：Chiralcel OJ-H, Chiralpak AD-H, Chiralpak IA, Chiralpak AS-H.
The present invention logical formula (I) shown in any compound pharmaceutically acceptable salt refer to by it is pharmaceutically acceptable, Salt prepared by non-toxic alkali or acid, including acylate, inorganic acid salt, organic alkali salt, inorganic base salts.
Acylate includes formic acid, acetic acid, trifluoroacetate, benzene sulfonic acid, benzoic acid, p-methyl benzenesulfonic acid, camphorsulfonic acid, lemon It is lemon acid, methanesulfonic acid, ethanesulfonic acid, propane sulfonic acid, fumaric acid, gluconic acid, glutamic acid, isethionic acid, lactic acid, maleic acid, malic acid, flat The salt of peach acid, glactaric acid, pamoic acid, pantothenic acid, succinic acid, tartaric acid etc..
Inorganic acid salt includes the salt of hydrobromic acid, hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid etc..
Organic alkali salt includes primary, secondary and tertiary amine, and substituted amine includes that naturally occurring substitution amine, cyclammonium and basic ion exchange Resin, selected from glycine betaine, caffeine, choline, N, N '-dibenzyl-ethylenediamins, diethylamine, 2- Diethylaminoethanols, 2- dimethylamine Base ethyl alcohol, ethanol amine, ethylenediamine, N- ethyl-morpholines, N-ethylpiperidine, meglumine, Glucosamine, Hai Baming, isopropyl Amine, methylglucosamine, morpholine, piperazine, piperidines, procaine, purine, theobromine, triethylamine, trimethylamine, tripropyl amine (TPA), ammonia fourth three The salt of alcohol etc..Native amino hydrochlorate for example glycine, alanine, valine, leucine, isoleucine, nor-leucine, tyrosine, Cystine, cysteine, methionine, proline, hydroxy-proline, histidine, ornithine, lysine, arginine, serine etc. Salt.
Inorganic base salts include the salt of ammonium and lithium, sodium, potassium, calcium, magnesium, zinc, barium, aluminium, iron, ketone, ferrous iron, manganese, bivalent manganese etc..
" ester " of formula (I) compound of the present invention refer to, when formula (I) compound is there are when carboxyl, can be esterified with alcohol Reaction and the ester formed can be esterified anti-with generations such as organic acid, inorganic acid, acylates when formula (I) compound is there are when hydroxyl The ester answered and formed.Under the conditions of ester is existing for acid or alkali, hydrolysis can occur and generate corresponding acid or alcohol.
Logical formula (I) compound represented, its pharmaceutically acceptable salt, ester or its stereoisomer can be solvates Form.If in the case that solvate is hydrate, aquation can be completed in preparation process or can be utilized original The hygroscopicity of no aquatic products gradually carries out.
Further requirement of the present invention protection includes any compound shown in above-mentioned formula (I), its is pharmaceutically acceptable The pharmaceutical composition of salt, ester, solvate or its stereoisomer and one or more pharmaceutical carriers and/or diluent, can be with Pharmaceutically acceptable any dosage form is made.It is applied in a manner of oral, parenteral, rectum or transpulmonary administration etc. and needs this control The patient for the treatment of.When for being administered orally, conventional solid pharmaceutical preparation, such as tablet, capsule, pill, granule can be made into；Also may be used Oral liquid, such as oral solution, oral suspensions, syrup is made.When oral preparation is made, it is suitable to be added Filler, adhesive, disintegrant, lubricant etc..When for parenteral administration, injection, including injection, injection can be made into With aseptic powdery and concentrated solution for injection.When injection is made, the conventional method production in existing pharmaceutical field can be used, prepare When injection, additives can be added without, suitable additives can also be added according to the property of drug.When for rectally, It can be made into suppository etc..When for transpulmonary administration, inhalant or spray etc. can be made into.
Further requirement of the present invention protection include any compound of formula recited above (I), its pharmaceutically acceptable salt, The pharmaceutical composition of ester, solvate or its stereoisomer and other one or more antitumor agents and immunosuppressor.Institute The antitumor agent and immunosuppressor stated are antimetabolite, including but not limited to capecitabine, gemcitabine, pemetrexed two Sodium；For growth factor receptor inhibitors, including but not limited to pazopanib, Imatinib, Erlotinib, Lapatinib, Gefitinib, Vande Thani；For antibody, including but not limited to Trastuzumab, bevacizumab；For mitotic inhibitor, it is selected from taxol, Changchun Rui Bin, docetaxel, Doxorubicin；For antitumor steroids, it is selected from Letrozole, tamoxifen, fulvestrant, Flutamide, song Puri woods；For alkylating agents, including but not limited to cyclophosphamide, mustargen, melphalan, chlorambucil, Carmustine；For metal platinum Class, including but not limited to carboplatin, cis-platinum, oxaliplatin；For immunosupress class, including but not limited to everolimus, sirolimus, Special cancer is suitable；For purine analogue, including but not limited to Ismipur, 6- thioguanines, imuran；For antibiotics, packet It includes but is not limited to rhzomorph D, daunorubicin, adriamycin, mitoxantrone, bleomycin, plicamycin；For platinum complex, including but It is not limited to cis-platinum, Kapo Platinum；For adrenal cortex inhibitor class, including but not limited to aminoglutethimide；For enzyme inhibitor, including but It is not limited to SAHA, cytarabine, methotrexate (MTX), hydroxycarbamide, Hydroxycamptothecin, Topotecan, topotecan, Irinotecan.
The present invention also provides formula (I) compound represented of the present invention, its pharmaceutically acceptable salt, ester, solvates Or its stereoisomer is in preparing treatment and/or preventing the drug of cancer-related diseases or proliferative disease that ALK is mediated Using the relevant disease of cancer includes but not limited to brain tumor, lung cancer, lung cancer in non-cellule type, squamous cell, bladder Cancer, gastric cancer, oophoroma, peritoneal cancer, cancer of pancreas, breast cancer, head and neck cancer, cervix cancer, carcinoma of endometrium, colorectal cancer, liver cancer, Kidney, adenocarcinoma of esophagus, esophageal squamous cell carcinoma, non-Hodgkin lymphoma, brain tumor, central nerve neuroma, i.e. neuroglia Tumor, 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, Small Cell Lung Cancer, Gastrointestinal Stromal Tumor, tumor of prostate, mast cell tumor, Huppert's disease, melanoma, glioma, glioblastoma, astrocyte Tumor, neuroblastoma, sarcoma；The hyperplasia of prostate of proliferative disease, including but not limited to skin or prostate.
The compounds of this invention has the following advantages：
(1) formula (I) compound of the present invention, its pharmaceutically acceptable salt, ester, solvate or its stereoisomer have Excellent ALK inhibitory activity；
(2) formula (I) compound of the present invention, its pharmaceutically acceptable salt, ester, solvate or its stereoisomer are shown Go out good biological stability, effect is more longlasting, and bioavilability is high；
(3) the compounds of this invention preparation process is simple, and drug purity is high, stable quality, is easy to carry out large-scale industry life Production.
Below by way of external zymetology and cytology inhibitory activity experiment the present invention is further explained compound advantageous effect, but This should not be interpreted as to the compounds of this invention only has following advantageous effect.
Experimental example 1 The external zymetology activity experiment of the compounds of this invention
Test sample：The compounds of this invention 1, chemical name and preparation method are shown in the preparation embodiment of compound 1.
Comparison medicine ceritinib, self-control (prepared by the preparation method of referenced patent WO2008/073687A2 compounds 66).
Meaning representated by the abbreviation of following middle experiments is as follows：
DMSO：Dimethyl sulfoxide (DMSO)
DTT：Dithiothreitol (DTT)
ALK：Anaplastic lymphoma kinase
HEPES：4- hydroxyethyl piperazineethanesulfonic acids
Brij-35：Brij-35
EDTA：Ethylenediamine tetra-acetic acid
Experimental method：The inhibitory activity that ALK kinases is carried out using Caliper Mobility Shift methods is measured
1.1 times of kinase buffer liquids are prepared：
The HEPES of pH7.5, a concentration of 30% Brij-35, the MgCl that mother liquid concentration is 1M are taken respectively2Solution, mother liquor are dense Degree is the DTT of 1M, and ultra-pure water mixing is added, makes 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 terminate liquid
It is 4% coating buffer Coating Reagent#3 (12- used in Caliper instruments to take mother liquid concentration respectively In sipper chip carry coating buffer), the EDTA that mother liquid concentration is the HEPES of 1000mM pH7.5, mother liquid concentration is 0.5M, The Brij-35 that mother liquid concentration is 30% is added ultra-pure water mixing, makes Coating Reagent#3 final concentration of 0.2%, HEPES final concentration of 100mM, EDTA final concentration of 50mM, Brij-35 final concentration of 0.015%.
3.5 times of test solutions are prepared：
The DMSO storing solutions of test sample are prepared：Weigh Compound is appropriate (specific sample weighting amount is see following table) respectively, is added suitable DMSO dissolvings are measured, mixing is spare.
A concentration of 50 μM of solution is made with DMSO dilutions, as mother liquor in the DMSO storing solutions for taking test sample.It will with DMSO Above-mentioned mother liquor four dilutes step by step again, and then each concentration dilutes 10 times with 1 times of kinase buffer liquid respectively, and it is molten that 5 times of test samples are made Liquid.
4. the preparation of various other reagents
Required 2.5 times of ALK kinase solutions, 2.5 times of polypeptide solutions are prepared respectively with 1 times of kinase buffer liquid, it is spare.
5. zymetology is reacted：
1) it is prepared that the prepared 5 times of test solutions of 5 μ L, 10 μ L are separately added into 384 orifice plates in corresponding hole 2.5 times of kinase solutions are incubated at room temperature 10 minutes.
2) corresponding Kong Zhongzai is separately added into the prepared 2.5 times of polypeptide solutions of 10 μ L, keeps tester final concentration of 1000nM,250nM,63nM,16nM,4nM,1nM,0.2nM,0.1nM,0.02nM,0.004nM.Start enzyme reaction, 28 DEG C of incubations 1 hour.
6. zymetology detects：
25 μ L terminate liquids are separately added into each corresponding hole, terminate reaction.Caliper instruments read data, and lead to It crosses data and calculates inhibiting rate,
Inhibiting rate (%)=(maximum value-sample value)/(maximum value-minimum value) × 100, using XLFIT software marches Line is fitted, and obtains IC50Value.
Maximum value：It is not added with the positive control of tester, minimum value：Not enzyme negative control.
Experimental result and conclusion：
The external zymetology inhibitory activity of 1 the compounds of this invention of table
By table 1 as it can be seen that the compounds of this invention has good inhibitory activity to ALK kinases, can be used for treating and kinases phase The disease of pass, especially ALK kinase mediated illness or the patient's condition have significant clinical meaning.
Experimental example 2 The cell in vitro activity experiment of the compounds of this invention
Test sample：The compounds of this invention 1, chemical name and preparation method are shown in the preparation embodiment of compound 1.
Comparison medicine Ceritinib makes by oneself (preparation of 66 preparation method of referenced patent WO2008/073687A2 compounds).
Meaning representated by the abbreviation of following middle experiments is as follows：
rpm：Rpm
DMSO：Dimethyl sulfoxide (DMSO)
MTS：Thiazole bromide blue tetrazolium
RPMI1640：1640 culture medium (RPMI:Roswell Park Memorial Institute)
500 ×, 1000 ×, 10 × "×" therein：Times
Experimental method：
NCI-H3122 cells：
(1) culture medium is prepared：
The RPMI1640 culture mediums containing 2.5% fetal calf serum are prepared, it is spare.
(2) cell culture：
In 5%CO2, 37 DEG C of conditions incubator in, NCI-H3122 cells are set in T25 culture bottles and are prepared in " (1) " Good medium culture cell is to 80% fusion.
(3) inoculating cell：
With trypsin digestion cell, 1000rpm centrifuges 4min, removes supernatant, is suspended again with culture medium, and adjustment cell is close Degree, takes 90 μ L of the cell suspension to be inoculated into 96 orifice plates, obtains final cell density and is：3000 cells/wells；Then exist 5%CO2, cultivate for 24 hours in 37 DEG C of incubators.
(4) test sample is added：
(4.1) test solution is prepared
Compare drug solns：Comparison medicine 2.17mg is weighed, appropriate DMSO is added and dissolves and is made respectively of DMSO gradient dilutions A series of mother liquor (1000 × control drug solns) of concentration, then dilute the mother liquor 100 with culture medium respectively and obtain 10 × control again Drug solns take 10 μ L of the solution, are added in the corresponding hole of 96 orifice plates respectively, obtain control drug solns ultimate density and are：10μM, 2.5μM、625nM、156nM、39nM、9.8nM、2.5nM、0.625nM。
1 solution of compound：Weigh Compound 8mg is added appropriate DMSO and dissolves and be made one with DMSO gradient dilutions respectively The mother liquor (1000 × compound, 1 solution) of series concentration, then dilute the mother liquor 100 with culture medium respectively and obtain 10 × compound again 1 solution takes 10 μ L of the solution, is added in the corresponding hole of 96 orifice plates respectively, obtains 1 solution ultimate density of compound and is： 10μ M、2.5μM、625nM、156nM、39nM、9.8nM、2.5nM、0.625nM。
(4.2) control wells are arranged：
Vehicle controls：0.1%DMSO.
Blank control：Culture medium, instrument zeroing.
(4.3) 96 orifice plates are put into 37 DEG C, 5%CO272h is cultivated in incubator.
(5) it detects：
10 μ L of CCK-8 reagents are added into each test hole of 96 orifice plates, put back to 5%CO2, cultivate in 37 DEG C of incubators 1h.Microplate reader Detection wavelength 450nm is set, result is read.
(6)IC50It calculates：Cell survival rate (%)=(sample value-blank value)/(maximum value-blank value) × 100, is adopted It is carried out curve fitting with Graph prism softwares, obtains IC50Value.
Maximum value：It is not added with the cell controls i.e. Vehicle controls of compound solubilization matchmaker, blank value：Culture medium blank pair According to.
Experimental result and conclusion：
The cell inhibitory activity of 2 the compounds of this invention of table
As can be seen from Table 2, compared with comparison medicine, the compounds of this invention has better inhibitory activity to cell NCI-H3122, It can be used for treating ALK kinase mediated illness or the patient's condition, there is significant clinical meaning.
Specific implementation mode
The specific implementation mode of form by the following examples makees further specifically the above of the present invention It is bright.But the range that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to following embodiment.It is all to be based on the above of the present invention The technology realized all belongs to the scope of the present invention.
Embodiment 1 The chloro- N of 5-4(2- isopropelsulfonyls) phenyl)-N2(2,3,7,8- tetrahydrochysene -1H- furans simultaneously [3,2- E] iso-indoles -5- bases) pyrimidine -2,4- diamines preparation
(1) preparation of 2,3- Dihydrobenzofuranes -5- carboxylate methyl esters
2,3- Dihydrobenzofuranes -5- carboxylic acids (15g, 0.091mol) are dissolved in methanol (800mL), the concentrated sulfuric acid is added (2mL), 65 DEG C are reacted 20 hours, cooling, and sodium bicarbonate is added, and concentration adds water (200mL) to dilute, ethyl acetate (150mL × 3) it extracts, anhydrous sodium sulfate drying, filtering is concentrated to give product (15.8g, yield 97.5%).
(2) preparation of 7- nitros -2,3- Dihydrobenzofuranes -5- carboxylate methyl esters
2,3- Dihydrobenzofuranes -5- carboxylate methyl esters (14g, 78.6mmol) are dissolved in acetic anhydride (200mL), are cooled to 0 DEG C, concentrated nitric acid (mass fraction 65%, 7mL, 102.2mmol) is added dropwise, stirring 1 hour is warmed to room temperature after being added dropwise, has been reacted It pours into water (200mL), ethyl acetate (150mL × 3) extraction, anhydrous sodium sulfate drying is filtered, and concentration, crude product is through silicagel column Chromatograph (petroleum ether:Ethyl acetate=5:1) product (13g, yield 74.3%) is purified to obtain.
(3) preparation of 7- amino -2,3- Dihydrobenzofuranes -5- carboxylate methyl esters
7- nitro -2,3- Dihydrobenzofuranes -5- carboxylate methyl esters (10g, 44.8mmol) are dissolved in methanol (300mL), Palladium carbon (1g) is added, lower 25 DEG C of atmosphere of hydrogen is reacted 20 hours, and filtering, filtrate is concentrated to give product (6g, yield 69.4%).
(4) preparation of the bromo- 2,3- Dihydrobenzofuranes -5- carboxylate methyl esters of 7- amino -4-
7- amino -2,3- Dihydrobenzofuranes -5- carboxylate methyl esters (5.4g, 28mmol) are dissolved in acetonitrile (100mL), it is cold But to 0 DEG C, N-bromosuccinimide (5.98g, 33.6mmol) is added portionwise, finishes to be warmed to room temperature to stir 1 hour and react Entirely, it pours into water (100mL), ethyl acetate (150mL × 3) extraction, anhydrous sodium sulfate drying is filtered, and concentration, crude product is through silica gel Column chromatography (petroleum ether:Ethyl acetate=3:1) product (5g, yield 65.6%) is purified to obtain.
(5) preparation of 7- amino -4- cyano -2,3- Dihydrobenzofuranes -5- carboxylate methyl esters
The bromo- 2,3- Dihydrobenzofuranes -5- carboxylate methyl esters (4g, 14.7mmol) of 7- amino -4- are dissolved in N, N- dimethyl In formamide (50mL), cuprous cyanide (1.57g, 17.6mmol) is added, 150 DEG C are reacted 2 hours, cooling, pour into ammonium hydroxide In (80mL), ethyl acetate (150mL × 3) extraction, anhydrous sodium sulfate drying is filtered, and concentration, crude product is through silica gel column chromatography (two Chloromethanes:Methanol=30:1) product (1.4g, yield 43.7%) is purified to obtain.
(6) preparation of 5- amino -1,2,7,8- tetrahydrochysene -3H- furans simultaneously [3,2-e] iso-indoles -3- ketone
7- amino -4- cyano -2,3- Dihydrobenzofuranes -5- carboxylate methyl esters (0.4g, 1.83mmol) are dissolved in methanol Ammonium hydroxide (10mL) and Raney's nickel (0.1g) is added in (100mL), and 25 DEG C are reacted 20 hours.Filtering, filtrate are concentrated to give product (0.28g, yield 80%).
(7) preparation of tertiary butyl 5- amino -1,3,7,8- tetrahydrochysene -2H- furans simultaneously [3,2-e] iso-indoles -2- carboxylates
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 In tetrahydrofuran (20mL), borane methyl sulfide ethereal solution (2mol/L, 2.57mL, 5.14mmol) is added dropwise at 0 DEG C, 65 after adding DEG C reaction 24 hours.It is cooled to 0 DEG C, methanol (5mL) is added dropwise, reaction is quenched, adds 4mol/L hydrochloric acid (5mL), 65 DEG C of stirrings 4 Hour.Rotary evaporation removes solvent after cooling, is diluted with water, and sodium hydroxide solution is added and is adjusted to pH=10, two carbonic acid two are added The tert-butyl ester (416mg, 1.91mmol) is stirred at room temperature 1 hour, ethyl acetate (10mL × 3) extraction, anhydrous sodium sulfate drying, mistake Filter, concentration, crude product is through silica gel column chromatography (petroleum ether:Ethyl acetate=2:1) product (75mg, yield 18.5%) is purified to obtain.
(8) preparation of bis- chloro- N- of 2,5- (2- (isopropelsulfonyl) phenyl) pyrimidine -4- amine
2- (isopropelsulfonyl) aniline (1g, 5mmol) and 2,4,5- trichloropyrimidines (1.1g, 6mmol) are dissolved in N, N- In dimethylformamide (30mL), sodium hydride (content 60%, 0.4g, 10mmol) is added, is reacted 12 hours at 25 DEG C.Add water, Ethyl acetate extracts (30mL × 3), and organic phase merges, saturated common salt water washing, and anhydrous sodium sulfate drying is concentrated in vacuo, crude product Through silica gel column chromatography (petroleum ether:Ethyl acetate=25:1) product (0.8g, yield 46%) is obtained.
(9) the chloro- N of 5-4(2- isopropelsulfonyls) phenyl)-N2(2,3,7,8- tetrahydrochysene -1H- furans simultaneously [3,2-e] different Yin Diindyl -5- bases) pyrimidine -2,4- diamines preparation
By tertiary butyl 5- amino -1,3,7,8- tetrahydrochysene -2H- furans simultaneously [3,2-e] iso-indoles -2- carboxylates (70mg, It 0.25mmol) is dissolved in sec-amyl alcohol (8mL), 2,5- bis- chloro- N- (2- (isopropelsulfonyl) phenyl) pyrimidine -4- amine is added (104mg, 0.3mmol) and p-methyl benzenesulfonic acid (86mg, 0.5mmol) stirs 20 hours at 120 DEG C.Rotary evaporation removes solvent, Saturated sodium bicarbonate solution, ethyl acetate (10mL × 3) extraction, anhydrous sodium sulfate drying is added to be concentrated in vacuo, crude product is through silicagel column Chromatograph (dichloromethane:Methanol:Ammonium hydroxide=10:1:0.1) final product (10mg, yield 8.2%) is obtained.
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 (9)

  1. General formula 1. (I) compound represented, its pharmaceutically acceptable salt or its stereoisomer：
    Wherein,
    R1Selected from-SO2R5,
    R5Independently selected from C1-4Alkyl；
    R2、R3Independently selected from hydrogen atom or C1-4Alkyl；
    R4Selected from halogen atom；
    A rings are selected from optionally by 1~2 Q15~6 circle heterocyclic ring bases containing 1~2 O and/or S atom of substitution, the substituent group Q1Selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen atom or C1-4Alkyl；
    B rings are selected from optionally by 1~2 Q25~6 circle heterocyclic ring bases containing 1~2 N atom of substitution, the substituent group Q2It is selected from Hydroxyl, amino, carboxyl, cyano, nitro, halogen atom or C1-4Alkyl.
  2. 2. compound as described in claim 1, its pharmaceutically acceptable salt or its stereoisomer：
    Wherein,
    R1Selected from-SO2R5,
    R5Independently selected from methyl, ethyl or isopropyl；
    R2、R3Independently selected from hydrogen atom or methyl；
    R4Selected from chlorine atom；
    A rings are selected from optionally by 1~2 Q15~6 circle heterocyclic ring bases containing 1~2 O and/or S atom of substitution, the substituent group Q1Selected from hydroxyl, amino, halogen atom or C1-4Alkyl；
    B rings are selected from optionally by 1~2 Q2Substituted piperidyl, piperazinyl, pyrrolidinyl, pyrrolin base, the substituent group Q2Selected from methyl, ethyl, n-propyl, isopropyl or normal-butyl.
  3. 3. compound as described in claim 1, its pharmaceutically acceptable salt or its stereoisomer, wherein the compound It is selected from：
  4. 4. the compound, its pharmaceutically acceptable salt as described in claims 1 to 3 any claim or its stereoisomer It is pharmaceutically acceptable any dosage form with pharmaceutical preparation made of one or more pharmaceutical carriers.
  5. 5. it is different to contain the compound as described in claims 1 to 3 any claim, its pharmaceutically acceptable salt or its solid The pharmaceutical composition of structure body also contains one or more active constituents of medicine.
  6. 6. pharmaceutical composition as claimed in claim 5, which is characterized in that one or more active constituents of medicine are anti- Tumour agent and/or immunosuppressor, the antitumor agent and/or immunosuppressor are antimetabolite, selected from capecitabine, Ji His shore, pemetrexed disodium of west；For growth factor receptor inhibitors, selected from pazopanib, Imatinib, Erlotinib, Lapatinib, Gefitinib, Vande Thani；For antibody, it is selected from Trastuzumab, bevacizumab；For mitotic inhibitor, it is selected from taxol, Changchun Rui Bin, docetaxel, Doxorubicin；For antitumor steroids, it is selected from Letrozole, tamoxifen, fulvestrant, Flutamide, song Puri woods；For alkylating agents, it is selected from cyclophosphamide, mustargen, melphalan, chlorambucil, Carmustine；For metal platinum class, it is selected from card Platinum, cis-platinum, oxaliplatin；It is suitable selected from everolimus, sirolimus, special cancer for immunosupress class；For purine analogue, it is selected from Ismipur, 6- thioguanines, imuran；For antibiotics, selected from rhzomorph D, daunorubicin, adriamycin, mitoxantrone, Bleomycin, plicamycin；For adrenal cortex inhibitor class, it is selected from aminoglutethimide；For enzyme inhibitor, it is selected from SAHA, arabinose Cytidine, methotrexate (MTX), hydroxycarbamide, Hydroxycamptothecin, Topotecan, topotecan, Irinotecan.
  7. 7. the compound or its pharmaceutically acceptable salt as described in claims 1 to 3 any claim are being prepared for controlling Treat and/or prevent the application in the cancer-related diseases of ALK mediations or the drug of proliferative disease, the relevant disease of cancer Selected from brain tumor, lung cancer, squamous cell, carcinoma of urinary bladder, gastric cancer, peritoneal cancer, cancer of pancreas, breast cancer, head and neck cancer, colorectal cancer, Liver cancer, kidney, adenocarcinoma of esophagus, esophageal squamous cell carcinoma, solid tumor, non-Hodgkin lymphoma, central nerve neuroma are that is, refreshing Through glioma, glioblastoma multiforme, glioma sarcomatosum, prostate cancer, thyroid cancer, female reproductive tract cancer, carcinoma in situ, leaching Bar tumor, histocytic lymphoma, neurofibromatosis, osteocarcinoma, cutaneum carcinoma, colon cancer, carcinoma of testis, gastrointestinal stromal tumor, forefront Adenoncus tumor, mast cell tumor, Huppert's disease, melanoma, glioma, glioblastoma, astrocytoma, nerve Blastoma, sarcoma；Proliferative disease, the hyperplasia of prostate selected from skin or prostate.
  8. 8. the use as claimed in claim 7, the lung cancer is selected from lung cancer in non-cellule type.
  9. 9. the use as claimed in claim 7, the female reproductive tract cancer is selected from cervix cancer, carcinoma of endometrium, oophoroma.
CN201510168569.3A 2015-04-10 2015-04-10 Three and ring class anaplastic lymphoma kinase inhibitor Active CN106146525B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201510168569.3A CN106146525B (en) 2015-04-10 2015-04-10 Three and ring class anaplastic lymphoma kinase inhibitor

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201510168569.3A CN106146525B (en) 2015-04-10 2015-04-10 Three and ring class anaplastic lymphoma kinase inhibitor

Publications (2)

Publication Number Publication Date
CN106146525A CN106146525A (en) 2016-11-23
CN106146525B true CN106146525B (en) 2018-11-02

Family

ID=57337023

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201510168569.3A Active CN106146525B (en) 2015-04-10 2015-04-10 Three and ring class anaplastic lymphoma kinase inhibitor

Country Status (1)

Country Link
CN (1) CN106146525B (en)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112384508B (en) * 2018-09-30 2022-08-02 山东轩竹医药科技有限公司 Tricyclic ASK1 inhibitor and application thereof
CA3161667A1 (en) * 2019-12-16 2021-06-24 Pil Ho Kim Novel pyrimidine derivative and use thereof

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0319227D0 (en) * 2003-08-15 2003-09-17 Novartis Ag Organic compounds
GB0321710D0 (en) * 2003-09-16 2003-10-15 Novartis Ag Organic compounds
US20070105839A1 (en) * 2003-09-18 2007-05-10 Patricia Imbach 2, 4-Di (phenylamino) pyrimidines useful in the treatment of proliferative disorders
GB0419161D0 (en) * 2004-08-27 2004-09-29 Novartis Ag Organic compounds
AU2012212142B2 (en) * 2011-02-02 2015-09-24 Novartis Ag Methods of using ALK inhibitors
US9206166B2 (en) * 2012-11-06 2015-12-08 SHANGHAI iNSTITUTE OF MATERIA MEDICA ACADEMY OF SCIENCES Certain protein kinase inhibitors
RU2656591C2 (en) * 2013-07-11 2018-06-06 Бетта Фармасьютикалз Ко., Лтд Protein tyrosine kinase modulators and methods of use
WO2015038868A1 (en) * 2013-09-13 2015-03-19 Cephalon, Inc. Fused bicyclic 2,4-diaminopyrimidine derivatives

Also Published As

Publication number Publication date
CN106146525A (en) 2016-11-23

Similar Documents

Publication Publication Date Title
CN105263934B (en) It is used as the ketone derivatives of pyrazoles pyrrolizine 4 and its purposes in treatment disease of BET inhibitor
CN106188138B (en) A kind of diaminopyrimidine compounds and the composition comprising the compound
WO2017198149A1 (en) Fgfr4 inhibitor, preparation method therefor, and applications thereof
US11267815B2 (en) Class of amino-substituted nitrogen-containing fused ring compounds, preparation method therefor, and use thereof
CN109721600B (en) Nitrogen-containing fused ring compounds and preparation method and application thereof
CN105712998B (en) Azaindole derivatives, preparation method and medical application thereof
WO2018028664A1 (en) Fgfr4 inhibitor and preparation method and use thereof
CN110964012B (en) Fused heterocyclic biaryl benzyl alcohol compound, preparation method and application
WO2022135432A1 (en) Macrocyclic heterocyclic compounds as egfr inhibitors, and use thereof
FR2941948A1 (en) AZAINDOLE DERIVATIVES AS INHIBITOR OF ABL KINASE PROTEINS AND SRC
CN113527299B (en) Nitrogen-containing condensed ring compound, preparation method and application
CN107531683A (en) USP7 inhibitor compounds and application method
CN105732615A (en) CDK kinase inhibitor
CN105884695B (en) Heterocyclic derivatives species tyrosine kinase inhibitor
CN106928200A (en) For the pyrrolotriazine derivatives for the treatment of cancer
CN105524045A (en) Tetracyclic anaplastic lymphoma kinase inhibitor
CN106146525B (en) Three and ring class anaplastic lymphoma kinase inhibitor
CN107383019B (en) Pyrazolo [4,3-h] quinazoline compounds and application thereof
TW201028420A (en) 6-cycloamino-2,3-dipyridylimidazo[1,2-b]-pyridazine derivatives, preparation and therapeutic use thereof
WO2020098716A1 (en) Inhibitor of bruton tyrosine kinase
CN104876914B (en) Pyrimidine derivative type anaplastic lymphoma kinase inhibitor
WO2020187123A1 (en) Pyrrole amidopyridone compound, preparation method therefor and use thereof
CN104804016B (en) Four and ring class anaplastic lymphoma kinase inhibitor
CN106188029B (en) Two and ring class anaplastic lymphoma kinase inhibitor
CN103965170A (en) Benzene sulfonamide pyrazole kinase inhibitor

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant
TR01 Transfer of patent right
TR01 Transfer of patent right

Effective date of registration: 20190114

Address after: 570105 Tianyi International Building, 85 Binhai Avenue, Longhua District, Haikou City, Hainan Province, 27th Floor

Patentee after: Hainan Xuanzhu Pharma Co.,Ltd.

Address before: 250101 2518 Tianchen Road, hi tech Development Zone, Ji'nan, Shandong

Patentee before: XUANZHU PHARMA Co.,Ltd.

CP01 Change in the name or title of a patent holder
CP01 Change in the name or title of a patent holder

Address after: 570105 Tianyi International Building, 85 Binhai Avenue, Longhua District, Haikou City, Hainan Province, 27th Floor

Patentee after: Xuanzhu (Hainan) Pharmaceutical Technology Co.,Ltd.

Address before: 570105 Tianyi International Building, 85 Binhai Avenue, Longhua District, Haikou City, Hainan Province, 27th Floor

Patentee before: Hainan Xuanzhu Pharma Co.,Ltd.

TR01 Transfer of patent right
TR01 Transfer of patent right

Effective date of registration: 20200103

Address after: High tech Zone Tianchen road Ji'nan City, Shandong province 250101 No. 2518

Co-patentee after: Xuanzhu (Hainan) Pharmaceutical Technology Co.,Ltd.

Patentee after: XUANZHU PHARMA Co.,Ltd.

Address before: 570105 Tianyi International Building, 85 Binhai Avenue, Longhua District, Haikou City, Hainan Province, 27th Floor

Patentee before: Xuanzhu (Hainan) Pharmaceutical Technology Co.,Ltd.

CP01 Change in the name or title of a patent holder
CP01 Change in the name or title of a patent holder

Address after: High tech Zone Tianchen road Ji'nan City, Shandong province 250101 No. 2518

Patentee after: XUANZHU PHARMA Co.,Ltd.

Patentee after: Xuanzhu Biotechnology Co.,Ltd.

Address before: High tech Zone Tianchen road Ji'nan City, Shandong province 250101 No. 2518

Patentee before: XUANZHU PHARMA Co.,Ltd.

Patentee before: Xuanzhu (Shijiazhuang) Biotechnology Co.,Ltd.

Address after: High tech Zone Tianchen road Ji'nan City, Shandong province 250101 No. 2518

Patentee after: XUANZHU PHARMA Co.,Ltd.

Patentee after: Xuanzhu (Shijiazhuang) Biotechnology Co.,Ltd.

Address before: High tech Zone Tianchen road Ji'nan City, Shandong province 250101 No. 2518

Patentee before: XUANZHU PHARMA Co.,Ltd.

Patentee before: Xuanzhu (Hainan) Pharmaceutical Technology Co.,Ltd.

CP01 Change in the name or title of a patent holder
CP01 Change in the name or title of a patent holder

Address after: No. 2518, Tianchen Road, Ji'nan high tech Zone, Shandong, Shandong

Patentee after: XUANZHU PHARMA Co.,Ltd.

Patentee after: Xuanzhu Biotechnology Co.,Ltd.

Address before: No. 2518, Tianchen Road, Ji'nan high tech Zone, Shandong, Shandong

Patentee before: XUANZHU PHARMA Co.,Ltd.

Patentee before: Xuanzhu Biotechnology Co.,Ltd.