CN105524045A - Tetracyclic anaplastic lymphoma kinase inhibitor - Google Patents

Tetracyclic anaplastic lymphoma kinase inhibitor Download PDF

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CN105524045A
CN105524045A CN201410567216.6A CN201410567216A CN105524045A CN 105524045 A CN105524045 A CN 105524045A CN 201410567216 A CN201410567216 A CN 201410567216A CN 105524045 A CN105524045 A CN 105524045A
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alkyl
amino
yuan
cancer
atom
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CN105524045B (en
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吴永谦
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Xuanzhu Biopharmaceutical Co Ltd
Shandong Xuanzhu Pharma Co Ltd
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Shandong Xuanzhu Pharma Co Ltd
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Abstract

The invention belongs to the technical field of medicine, and more specifically relates to a tetracyclic anaplastic lymphoma kinase inhibitor shown in a general formula (I), its pharmaceutically acceptable salt or its stereisomer; wherein, R<1>, R<2>, R<3>, R<4>, R<5> and ring A are defined as a specification. The invention also relates to a preparation method of the compounds, a medicinal preparation containing the compounds and a pharmaceutical composition, and an application of the compound, its pharmaceutically acceptable salt or its stereisomer on preparation of medicines for treating and/preventing diseases related to anaplastic lymphoma kinase-mediated cancer.

Description

Four lopps Nucleophosmin-anaplastic lymphoma kinase inhibitor
Technical field
The invention belongs to medical art, be specifically related to four lopps Nucleophosmin-anaplastic lymphoma kinase inhibitor, its pharmacy acceptable salt or its steric isomer, the preparation method of these compounds, pharmaceutical preparation containing these compounds and pharmaceutical composition, and this compound, its pharmacy acceptable salt or its steric isomer are preparing the application treated and/or prevented in the medicine of the cancer-related diseases mediated by Nucleophosmin-anaplastic lymphoma kinase.
Background technology
Nucleophosmin-anaplastic lymphoma kinase (Anaplasticlymphomakinase, ALK) is receptor tyrosine kinase family member, raises downstream albumen by autophosphorylation, and then expresses specific gene, regulates cellular metabolism and growth.Nucleophosmin-anaplastic lymphoma kinase is found in primary cutaneous type (Anaplasticlargecelllymphoma, ALCL) the earliest, finds also have high expression level afterwards in nonsmall-cell lung cancer (NSCLC).
The unconventionality expression of ALK in some ALCL/NSCLC derives from different chromosome translocations.These chromosome translocations all can produce corresponding fusion rotein.These analysis of fused genes are shown, they all contain the gene order that ALK gene 3 ' holds coding intracellular kinase district, and the gene fragment merged with ALK is all containing promoter element and encode and mediate the sequence of self dimerization, thus cause fusion rotein high expression level and the excessive activation in cell with ALK kinase activity, 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.
As can be seen here, research and develop the micromolecular inhibitor for ALK, the ALK gene of sudden change can be effectively reduced on the impact of downstream albumen, and then have influence on the effect such as tumor cell invasion, propagation, finally affect the growth of tumour cell, play antineoplastic action.Had gram azoles of Pfizer successfully to go on the market for Buddhist nun (Crizotinib) at present, for specific patient, ALK inhibitor illustrates good inhibit activities.But existing a large amount of clinical proof generation ALK inhibitor C rizotinib, easily produces resistance, therefore, design and screen the two generation ALK inhibitor patient of Crizotinib generation resistance also being had to good curative effect, there is significant clinical meaning.
The ALK inhibitor gone on the market comprises the Crizotinib of Pfizer's research and development, and the Alectinib of Roche research and development, structural formula is the look of Novartis research and development is auspicious for Buddhist nun (Ceritinib), and structural formula is the AZD-3463 of AstraZeneca research and development, structural formula is be in preclinical phase research at present.
Therefore, modified by compound structure and find new compound structure, make great efforts the physico-chemical property improving compound, improve druggability, as improved the bioavailability of compound, find and ALK is suddenlyd change activated micromolecular inhibitor, for clinically because ALK suddenlys change the treatment of the disease caused, have great importance.
Summary of the invention
The present invention with exploitation for the micromolecular inhibitor of ALK for target, invented the four lopps Nucleophosmin-anaplastic lymphoma kinase inhibitor cancer-related diseases treating and/or preventing ALK mediation to good result.Concrete technical scheme is as follows:
Scheme 1. leads to compound, its pharmacy acceptable salt or its steric isomer described in formula I:
Wherein,
R 1be selected from-COR 6,-CO 2r 6,-CONRR 6,-SOR 6,-SO 2r 6or-SO 2nRR 6,
R, R 6independently selected from hydrogen atom, C 1-6alkyl or 3 ~ 8 yuan of carbocyclic rings;
R 2, R 3independently selected from hydrogen atom, C 1-6alkyl or 3 ~ 8 yuan of carbocyclic rings;
R 4be selected from hydrogen atom, halogen atom, nitro, cyano group, amino, hydroxyl, carboxyl, C 1-6alkyl, hydroxyl C 1-6alkyl, carboxyl C 1-6alkyl, C 1-6alkoxy C 1-6alkyl, halo C 1-6alkyl, amino C 1-6alkyl, alkylsulfonyl C 1-6alkyl, C 1-6alkoxyl group, hydroxyl C 1-6alkoxyl group, halo C 1-6alkoxyl group, hydroxyl C 1-6alkylamino, C 2-8thiazolinyl, C 2-8alkynyl, C 1-6alkyl sulfenyl, C 1-6alkylamino, (C 1-6alkyl) 2amino, C 1-6alkyl-carbonyl, C 1-6alkyl-carbonyl oxygen base, C 1-6alkyl sulfonyl is amino, C 1-6alkyl amino sulfonyl, (C 1-6alkyl) 2amino-sulfonyl or C 1-6alkyl sulphonyl;
R 5be selected from hydrogen atom, halogen atom, cyano group, nitro, amino, carboxyl, hydroxyl, C 1-6alkoxyl group ,-OR 7, C 1-6alkyl, hydroxyl C 1-6alkyl, halo C 1-6alkyl, hydroxyl C 1-6alkoxyl group, halo C 1-6alkoxyl group, C 2-8thiazolinyl, C 2-8alkynyl, C 1-6alkylamino, C 1-6alkyl-carbonyl, C 1-6alkyl-carbonyl oxygen base, (C 1-6alkyl) 2amino or alkylsulfonyl C 1-6alkyl,
R 7be selected from 3 ~ 8 yuan of carbocyclic rings or 3 ~ 8 yuan of heterocyclic radicals;
A ring is selected from optionally by 5 ~ 6 yuan of heterocyclic radicals containing 1 ~ 3 O, S and/or atom N of 1 ~ 3 Q replacement, or optionally by 5 ~ 14 yuan of heteroaryls containing 1 ~ 3 O, S and/or atom N that 1 ~ 3 Q replaces, described substituting group Q is selected from hydroxyl, amino, carboxyl, cyano group, nitro, halogen atom, C 1-6alkyl, C 1-6alkoxyl group, C 1-6alkylamino, (C 1-6alkyl) 2amino, halo C 1-6alkyl, halo C 1-6alkoxyl group, C 1-6alkoxy C 1-6alkyl, C 2-8thiazolinyl, C 2-8alkynyl or 3 ~ 8 yuan of heterocyclic radicals.
The compound of scheme 2. as described in technical scheme 1, its pharmacy acceptable salt or its steric isomer:
Wherein,
R 1be selected from-CONRR 6,-SO 2r 6or-SO 2nRR 6,
R, R 6independently selected from C 1-6alkyl;
R 2, R 3independently selected from hydrogen atom or C 1-4alkyl;
R 4be selected from C 1-6alkoxyl group;
R 5be selected from hydrogen atom, halogen atom, cyano group, nitro, amino, carboxyl, C 1-6alkoxyl group or C 1-6alkyl;
A ring is selected from optionally by 5 ~ 6 yuan of heterocyclic radicals containing 1 ~ 2 O and/or atom N of 1 ~ 2 Q replacement, or optionally by 5 ~ 6 yuan of heteroaryls containing 1 ~ 2 O and/or atom N that 1 ~ 2 Q replaces, described substituting group Q is selected from hydroxyl, amino, carboxyl, cyano group, nitro, halogen atom or C 1-6alkyl.
The compound of scheme 3. as described in technical scheme 2, its pharmacy acceptable salt or its steric isomer:
Wherein,
R 1be selected from-SO 2r 6or-SO 2nRR 6,
R, R 6independently selected from C 1-4alkyl;
R 2, R 3independently selected from hydrogen atom;
R 4be selected from C 1-4alkoxyl group;
R 5be selected from halogen atom;
A ring is selected from optionally by 5 ~ 6 yuan of heterocyclic radicals containing 1 ~ 2 O and/or atom N that 1 ~ 2 Q replaces, and described substituting group Q is selected from hydroxyl, amino, carboxyl, cyano group, nitro, halogen atom or C 1-4alkyl.
The compound of scheme 4. as described in technical scheme 3, its pharmacy acceptable salt or its steric isomer:
Wherein,
A ring is selected from optionally by 5 ~ 6 yuan of heterocyclic radicals containing 1 atom N that 1 ~ 2 Q replaces, and described substituting group Q is selected from hydroxyl, amino, carboxyl, cyano group, nitro, halogen atom or C 1-4alkyl.
The compound of scheme 5. as described in technical scheme 3, its pharmacy acceptable salt or its steric isomer:
Wherein,
R 1be selected from-SO 2r 6or-SO 2nRR 6,
R, R 6independently selected from methyl, ethyl or sec.-propyl;
R 2, R 3independently selected from hydrogen atom;
R 4be selected from methoxyl group, oxyethyl group or isopropoxy;
R 5be selected from fluorine atom, bromine atoms or chlorine atom;
A ring is selected from optionally by piperidyl, piperazinyl, morpholinyl, pyrrolidyl, pyrrolin base, tetrahydrofuran base, the THP trtrahydropyranyl or 1 of 1 Q replacement, 4-dioxane base, described substituting group Q is selected from methyl, ethyl, n-propyl, sec.-propyl or normal-butyl.
The compound of scheme 6. as described in technical scheme 5, its pharmacy acceptable salt or its steric isomer:
Wherein,
A ring forms following group together with the phenyl ring be attached thereto:
Part of compounds of the present invention
Detailed Description Of The Invention
" halogen atom " of the present invention comprises fluorine atom, chlorine atom, bromine atoms and atomic iodine etc.
" C of the present invention 1-6alkyl " represent straight or branched containing the alkyl of 1-6 carbon atom, comprise such as " C 1-4alkyl ", " C 1-3alkyl ", " C 1-2alkyl " etc.; specific examples includes but not limited to: methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, 2-methyl-propyl, 1-methyl-propyl, 1; 1-dimethyl ethyl, n-pentyl, 3-methyl butyl, 2-methyl butyl, 1-methyl butyl, 1-ethyl propyl, n-hexyl, 4-methyl amyl, 3-methyl amyl, 2-methyl amyl, 1-methyl amyl, 3; 3-dimethylbutyl, 2; 2-dimethylbutyl, 1; 1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethyl-butyl, 1,2-dimethyl propyl etc.
" C of the present invention 2-8thiazolinyl " refer to that the carbonatoms containing at least one double bond is the straight or branched of 2-8 or the thiazolinyl of ring-type, comprise such as " C 2-6thiazolinyl ", " C 2-4thiazolinyl ", " C 2-3thiazolinyl ", " C 3-6cycloalkenyl group " etc., specific examples includes but not limited to: vinyl, 1-propenyl, 2-propenyl, crotyl, 3-butenyl, 2-methyl-1-propylene base, 1-methyl-2-propenyl, 1-pentenyl, pentenyl, 3-pentenyl, 2-methyl-1-butene thiazolinyl, 3-methyl-1-butene base, 2-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1-ethyl-2-propenyl, 2-hexenyl, 3-hexenyl, 2-methyl-1-pentene thiazolinyl, 3-methyl-1-pentene thiazolinyl, 1-methyl-pentenyl, 3-methyl-pentenyl, 2-methyl-3-pentenyl, 1-methyl-4-pentenyl, 3-methyl-4-pentenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-crotyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-crotyl, 2,3-dimethyl-1-butylene base, 2-ethyl-1-butylene base, 2-ethyl-3-butenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 4-octenyl, 1,3-butadiene base, 2,4-pentadienyl, Isosorbide-5-Nitrae-hexadienyl, 2,4-hexadienyl, 1,5-heptadiene base, 2,5-heptadiene base, 2,6-octadienyl etc.
" C of the present invention 2-8alkynyl " refer to containing triple bond carbonatoms and be the alkynyl of the straight or branched of 2-8, comprising such as " C 2-6alkynyl ", " C 2-4alkynyl ", " C 2-3alkynyl " etc., specific examples includes but not limited to: ethynyl, 1-proyl, 2-butyne base, 1-methyl-2-propynyl, valerylene base, 3-pentynyl, 1-methyl-2-butyne base, 2-methyl-3-butynyl, 1, 1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 2-hexin base, 3-hexin base, 1-methyl-valerylene base, 1-methyl-3-pentynyl, 2-methyl-3-pentynyl, 1, 1-dimethyl-3-butynyl, 2-ethyl-3-butynyl, 2-heptyne base, 3-heptyne base, 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-octyne base, 3-octyne base, 4-octyne base, 4-methyl-2-heptyne base, 5-methyl-3-heptyne base, 6-methyl-3-heptyne base, 2-methyl-4-heptyne base, 2-methyl-5-heptyne base, 3-methyl-6-heptyne base etc.
" C of the present invention 1-6alkoxyl group, C 1-6alkylamino, (C 1-6alkyl) 2amino, C 1-6alkyl sulfenyl, C 1-6alkyl-carbonyl, C 1-6alkyl sulfonyl is amino, C 1-6alkyl amino sulfonyl, (C 1-6alkyl) 2amino-sulfonyl, C 1-6alkyl sulphonyl, C 1-6alkyl-carbonyl oxygen base " refer to C 1-6alkyl-O-, C 1-6alkyl-NH-, (C 1-6alkyl) 2-N-, C 1-6alkyl-S-, C 1-6alkyl-C (O)-, C 1-6alkyl-SO 2nH-, C 1-6alkyl-NHSO 2-, (C 1-6alkyl) 2-NHSO 2-, C 1-6alkyl-SO 2-, C 1-6the group that alkyl-C (O)-O-mode is formed, wherein " C 1-6alkyl " definition as mentioned before.
" C of the present invention 1-4alkoxyl group, C 1-4alkylamino, (C 1-4alkyl) 2amino, C 1-4alkyl sulfenyl, C 1-4alkyl-carbonyl, C 1-4alkyl sulfonyl is amino, C 1-4alkyl amino sulfonyl, (C 1-4alkyl) 2amino-sulfonyl, C 1-4alkyl sulphonyl, C 1-4alkyl-carbonyl oxygen base " refer to C 1-4alkyl-O-, C 1-4alkyl-NH-, (C 1-4alkyl) 2-N-, C 1-4alkyl-S-, C 1-4alkyl-C (O)-, C 1-4alkyl-SO 2nH-, C 1-4alkyl-NHSO 2-, (C 1-4alkyl) 2-NHSO 2-, C 1-4alkyl-SO 2-, C 1-4the group that alkyl-C (O)-O-mode is formed, wherein " C 1-4alkyl " definition as mentioned before.
" halo C of the present invention 1-6alkyl, hydroxyl C 1-6alkyl, amino C 1-6alkyl, alkylsulfonyl C 1-6alkyl, carboxyl C 1-6alkyl, C 1-6alkoxy C 1-6alkyl, halo C 1-6alkoxyl group, hydroxyl C 1-6alkoxyl group, hydroxyl C 1-6alkylamino " refer to one or more, such as 1 ~ 4,1 ~ 3,1 ~ 2 halogen atom, hydroxyl, amino, alkylsulfonyl, carboxyl, C 1-6alkoxyl group replaces C respectively 1-6alkyl, C 1-6alkoxyl group, C 1-6the group that hydrogen atom in alkylamino is formed.
" halo C of the present invention 1-4alkyl, hydroxyl C 1-4alkyl, amino C 1-4alkyl, alkylsulfonyl C 1-4alkyl, carboxyl C 1-4alkyl, C 1-4alkoxy C 1-4alkyl, halo C 1-4alkoxyl group, hydroxyl C 1-4alkoxyl group, hydroxyl C 1-4alkylamino " refer to one or more, such as 1 ~ 4,1 ~ 3,1 ~ 2 halogen atom, hydroxyl, amino, alkylsulfonyl, carboxyl, C 1-4alkoxyl group replaces C respectively 1-4alkyl, C 1-4alkoxyl group, C 1-4the group that hydrogen atom in alkylamino is formed.
" 3 ~ 8 yuan of cycloalkyl ", refers to that the paraffin section of 3 ~ 8 carbon atoms removes the derivative monocycle cyclic alkyl of a hydrogen atom, comprises such as " 3 ~ 6 yuan of cycloalkyl ", " 4 ~ 7 yuan of cycloalkyl ", " 4 ~ 6 yuan of cycloalkyl ", " 5 ~ 6 yuan of cycloalkyl " etc.The example includes but not limited to: cyclopropane base, tetramethylene base, pentamethylene base, cyclohexyl, suberane base, cyclooctane base etc.
" 5 ~ 14 yuan of heteroaryls " refers to containing at least one heteroatomic annular atoms number to be the heteroaryl of 5 ~ 14 yuan, comprise " 5 ~ 8 yuan of heteroaryls ", " 6 ~ 14 yuan of thick heteroaryls ", described heteroatoms has nitrogen, oxygen and sulphur etc., comprises carbon atom, nitrogen-atoms and sulphur atom by the situation of oxo simultaneously.Be specifically as follows " 5 ~ 14 yuan of heteroaryls containing 1 ~ 3 O, S and/or N ", " 5 ~ 8 yuan of heteroaryls containing 1 ~ 2 O, S and/or N ", " 5 ~ 8 yuan of heteroaryls containing 2 ~ 3 O, S and/or N ".
" 5 ~ 8 yuan of heteroaryls ", comprises such as " 5 ~ 7 yuan of heteroaryls ", " 5 ~ 6 yuan of heteroaryls " etc.Be specifically as follows " 5 ~ 6 yuan of heteroaryls containing 1 ~ 2 O and/or atom N ", " 5 ~ 6 yuan of heteroaryls containing 1 O and/or atom N ".Specific examples includes but are not limited to furyl, thienyl, pyrryl, thiazolyl, isothiazolyl, thiadiazolyl group, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, pyridyl, 2-pyridone, 4-pyridone, pyrimidyl, 1, 4-Dioxin base, 2H-1, 2-oxazinyl, 4H-1, 2-oxazinyl, 6H-1, 2-oxazinyl, 4H-1, 3-oxazinyl, 6H-1, 3-oxazinyl, 4H-1, 4-oxazinyl, pyridazinyl, pyrazinyl, 1, 2, 3-triazinyl, 1, 3, 5-triazinyl, 1, 2, 4, 5-tetrazine base, nitrogen heterocyclic heptantriene base, 1, 3-diazacyclo heptantriene base, azepine cyclooctatetraenyl etc., be preferably " 5 ~ 6 yuan of heteroaryls ".
" 6 ~ 14 yuan of thick heteroaryls ", comprises such as " 6 ~ 10 yuan of thick heteroaryls ", " 7 ~ 10 yuan of thick heteroaryls ", " 9 ~ 10 yuan of thick heteroaryls " etc.Specific examples includes but not limited to: benzofuryl, benzisoxa furyl, benzothienyl, indyl, isoindole, benzoxazolyl, benzimidazolyl-, indazolyl, benzotriazole base, quinolyl, 2-quinolinone, 4-quinolinone, 1-isoquinolines, isoquinolyl, acridyl, phenanthridinyl, benzo pyridazinyl, phthalazinyl, quinazolyl, quinoxalinyl, phenol piperazine base, pteridine radicals, purine radicals, naphthyridinyl, azophenlyene, thiodiphenylamine etc.
" 3 ~ 8 yuan of heterocyclic radicals " refers to containing 3 ~ 8 annular atomses and contains at least one heteroatomic cyclic group, comprise 3 ~ 8 yuan of saturated heterocyclyls, 3 ~ 8 yuan of fractional saturation heterocyclic radicals, be specifically as follows " 3 ~ 7 yuan of heterocyclic radicals ", " 3 ~ 6 yuan of heterocyclic radicals ", " 3 ~ 5 yuan of heterocyclic radicals ", " 4 ~ 7 yuan of heterocyclic radicals ", " 4 ~ 6 yuan of heterocyclic radicals ", " 5 ~ 6 yuan of heterocyclic radicals ", 6 ~ 7 yuan of heterocyclic radicals ", " 6 ~ 8 yuan of heterocyclic radicals " etc.Can also be specifically: " containing 1 ~ 3 O, 5 ~ 6 yuan of heterocyclic radicals of S and/or atom N ", " containing 1 ~ 2 O, 5 ~ 6 yuan of heterocyclic radicals of S and/or atom N ", " 5 ~ 6 yuan of heterocyclic radicals containing 1 ~ 2 O and/or atom N ", " 6 yuan of heterocyclic radicals containing 1 ~ 2 O and/or atom N ", " 5 yuan of heterocyclic radicals containing 1 ~ 2 O and/or atom N ", " 5 ~ 6 yuan of heterocyclic radicals containing 1 O or atom N ", " 6 yuan of heterocyclic radicals containing 1 O or atom N ", " 5 yuan of heterocyclic radicals containing 1 O or atom N ", " 5 ~ 6 yuan of heterocyclic radicals containing 1 atom N ", " 5 ~ 6 yuan of heterocyclic radicals containing 1 O atom ".Specific examples includes but are not limited to: ethylenimine base, 2H-ethylenimine base, diazacyclo propyl, 3H-diazacyclo propenyl, azetidinyl, Isosorbide-5-Nitrae-dioxane base, 1,3-dioxane base, 1,3-dioxolane base, Isosorbide-5-Nitrae-Dioxin base, tetrahydrofuran base, THP trtrahydropyranyl, pyrrolin base, pyrrolidyl, imidazolidyl, 4,5-glyoxalidine base, pyrazolidyl, 4,5-pyrazoline base, 2,5-dihydro-thiophene base, tetrahydro-thienyl, 4,5-dihydro-thiazolyl, piperidyl, piperazinyl, morpholinyl, 4,5-dihydro-oxazole base, 4,5-dihydro-isoxazole base, 2,3-dihydro-isoxazole base, 2H-1,2-oxazinyl, 6H-1,3-oxazinyl, 4H-1,3-thiazinyl, 6H-1,3-thiazinyl, 2H-pyranyl, 2H-pyran-2-one base, 3,4-dihydro-2H-pyranyl, 2,5-dihydro-thiophene base, 3,4-dihydro-2H-pyranyl, 5,6-dihydro-4H-1,3-oxazinyl, 1,2,3,6-tetrahydro pyridyl, 1,2,3,4-tetrahydro pyridyl, 2,3,4,5-tetrahydro pyridyls etc., are preferably " 5 ~ 6 yuan of heterocyclic radicals ".
" heteroatoms " of the present invention refers to N, O, C (O), S, SO and/or SO 2deng, preferred N, O, S, more preferably N, O.
" 3 ~ 8 yuan of carbocyclic rings " refers to saturated, fractional saturation containing 3 ~ 8 carbon atoms or undersaturated monocyclic compound, such as, can be 3 ~ 8 yuan of cycloalkyl, 3 ~ 8 member cycloalkenyl, 6 ~ 8 yuan of aryl etc.Comprise 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.Specific examples includes but are not limited to: cyclopropane base, tetramethylene base, pentamethylene base, cyclohexyl, suberane base, cyclooctane base, cyclopentenyl, 1,3-cyclopentadienyl, cyclohexenyl, 1,4-cyclohexadienyl, cycloheptenyl, Isosorbide-5-Nitrae-cycloheptadiene base, cyclooctene base, phenyl etc.Preferably " carbocyclic rings of 5 ~ 6 yuan of saturated or fractional saturations ".
" steric isomer " of formula (I) compound refers to when formula (I) compound exists unsymmetrical carbon, enantiomer can be produced, when there is carbon-carbon double bond or ring texture in compound, cis-trans-isomer can be produced, when there is ketone or oxime in compound, tautomer can be produced, the enantiomer, diastereomer, racemization isomer, cis-trans-isomer, tautomer, geometrical isomer, epimer and composition thereof of all formulas (I) compound, include in the scope of the invention.
General formula of the present invention (I) if shown in the raceme that obtains of arbitrary compou nd synthesis, the compound of required enantiomer-pure can be obtained by the method for chiral separation: can by having the chromatography (image height pressure preparative liquid chromatography, supercritical fluid chromatography) of chiral stationary phase.Chirality padding includes but not limited to: ChiralcelOJ-H, ChiralpakAD-H, ChiralpakIA, ChiralpakAS-H.
Arbitrary compound pharmacy acceptable salt shown in general formula of the present invention (I) refers to the salt by pharmaceutically acceptable, non-toxic alkali or acid preparation, comprises organic acid salt, inorganic acid salt, organic alkali salt, inorganic base salts.
Organic acid salt comprises the salt of formic acid, acetic acid, trifluoroacetate, Phenylsulfonic acid, phenylformic acid, tosic acid, camphorsulfonic acid, citric acid, methylsulfonic acid, ethyl sulfonic acid, propanesulfonic acid, fumaric acid, glyconic acid, L-glutamic acid, isethionic acid, lactic acid, toxilic acid, oxysuccinic acid, amygdalic acid, glactaric acid, pamoic acid, pantothenic acid, succsinic acid, tartrate etc.
Inorganic acid salt comprises the salt of Hydrogen bromide, spirit of salt, nitric acid, sulfuric acid, phosphoric acid etc.
Organic alkali salt comprises primary, secondary and tertiary amine, be substituted amine and comprise naturally occurring replacement amine, cyclammonium and basic ion-exchange resins, be selected from trimethyl-glycine, caffeine, choline, N, N ' salt of-dibenzyl-ethylenediamin, diethylamine, 2-Diethylaminoethanol, 2-dimethylamino-ethanol, thanomin, quadrol, N-ethyl-morpholine, N-ethylpiperidine, meglumine, glucosamine, Hai Baming, isopropylamine, methylglucosamine, morpholine, piperazine, piperidines, PROCAINE HCL, PHARMA GRADE, purine, Theobromine, triethylamine, Trimethylamine 99, tripropyl amine, Trometamol etc.Native amino hydrochlorate is as the salt of glycine, L-Ala, α-amino-isovaleric acid, leucine, Isoleucine, nor-leucine, tyrosine, Gelucystine, halfcystine, methionine(Met), proline(Pro), oxyproline, Histidine, ornithine, Methionin, arginine, Serine etc.
Inorganic base salts comprises the salt of ammonium and lithium, sodium, potassium, calcium, magnesium, zinc, barium, aluminium, iron, ketone, ferrous iron, manganese, bivalent manganese etc.
The present invention is the claimed pharmaceutical preparation comprising the above-mentioned arbitrary compound shown in formula (I), its pharmacy acceptable salt or its steric isomer and one or more pharmaceutical carriers and/or thinner further, can make pharmaceutically acceptable arbitrary formulation.With oral, parenteral, rectum or be applied to through modes such as lung administrations the patient needing this treatment.During for oral administration, can be made into conventional solid preparation, as tablet, capsule, pill, granule etc.; Also can be made into oral liquid, as oral solution, oral suspensions, syrup etc.When making oral preparations, suitable weighting agent, tackiness agent, disintegrating agent, lubricant etc. can be added.During for administered parenterally, can be made into injection, comprise injection liquid, injectable sterile powder and concentrated solution for injection.When making injection, the ordinary method in existing pharmacy field can be adopted to produce, during preparation injection, can not additives be added, also can add suitable additives according to the character of medicine.During for rectal administration, can be made into suppository etc.For through lung administration time, can be made into inhalation or sprays etc.
The present invention is the claimed pharmaceutical composition comprising formula recited above (I) arbitrary compound, its pharmacy acceptable salt or its steric isomer and other one or more antineoplastic agents and/or immunosuppressor further.Described antineoplastic agent and/or immunosuppressor are metabolic antagonist, are selected from capecitabine, gemcitabine, pemetrexed disodium; For growth factor receptor inhibitors, be selected from pazopanib, imatinib, erlotinib, lapatinibditosylate, Gefitinib, ZD6474; For antibody, be selected from Trastuzumab, rhuMAb-VEGF; For mitotic inhibitor, be selected from taxol, vinorelbine, docetaxel, Dx; For antitumor hormones, be selected from letrozole, tamoxifen, fulvestrant, flutamide, triptorelin; For alkylating agent class, be selected from endoxan, mustargen, melphalan, Chlorambucil, carmustine; For metal platinum class, be selected from carboplatin, cis-platinum, oxaliplatin; For immunosuppression class, be selected from everolimus, sirolimus, special cancer fit; For purine analogue, be selected from Ismipur, 6-Tioguanine, azathioprine; For antibiotics, be selected from rhzomorph D, daunorubicin, Zorubicin, mitoxantrone, bleomycin, Plicamycin; For platinum complex, be selected from cis-platinum, NSC-241240; For adrenal cortex inhibitor class, be selected from aminoglutethimide; For enzyme inhibitors, be selected from Vorinostat, cytosine arabinoside, methotrexate, hydroxyurea, Hydroxycamptothecin, camptothecine, Topotecan, topotecan, Rinotecan.
Present invention also offers the compound shown in formula (I), its pharmacy acceptable salt or the application of its steric isomer in the medicine for the preparation of the proliferative disease or cancer-related diseases that treat and/or prevent ALK mediation, the disease that described cancer is relevant is selected from lung cancer, brain tumor, squamous cell, bladder cancer, cancer of the stomach, ovarian cancer, peritoneal cancer, carcinoma of the pancreas, mammary cancer, head and neck cancer, cervical cancer, carcinoma of endometrium, colorectal cancer, liver cancer, kidney, adenocarcinoma of esophagus, esophageal squamous cell carcinoma, non-Hodgkin lymphoma, central nerve neuroma, prostate cancer, thyroid carcinoma, female reproductive tract cancer, carcinoma in situ, lymphoma, histocytic lymphoma, neurofibromatosis, osteocarcinoma, skin carcinoma, colorectal carcinoma, small cell lung cancer, lung cancer in non-cellule type, carcinoma of testis, gastrointestinal stromal tumor, mast cell tumor, multiple myeloma, melanoma, glioma, astrocytoma, neuroblastoma, sarcoma, proliferative disease, is selected from skin or prostatic hyperplasia of prostate.
Present invention also offers the preparation method of above-claimed cpd, but be not limited only to following methods, reaction equation is as follows:
In reaction equation, R 1, R 2, R 3, R 4, R 5with A ring as defined hereinabove, X represents fluorine atom, chlorine atom, bromine atoms and atomic iodine.
Reactions steps
Method one: intermediate 1 and intermediate 2 are dissolved in solvent (such as dioxane); add metal palladium catalyst; add appropriate (such as 1 ~ 5 equivalent) mineral alkali (such as cesium carbonate); (such as 70 ~ 90 DEG C) reaction (such as 12 ~ 24h) is heated under nitrogen protection; filter; filtrate concentrates, and obtains general formula of the present invention (I) compound through proper method (such as preparing high performance liquid phase purifying).
Method two: intermediate 1 and intermediate 2 are dissolved in organic solvent (such as sec.-amyl alcohol and tosic acid), heating (such as 100 DEG C ~ 150 DEG C) reaction (such as 10 ~ 30h).Except desolventizing, add water, with organic solvent (such as ethyl acetate) extraction, concentrated, obtain general formula of the present invention (I) compound through proper method (such as silica gel column chromatography) purifying.
In reaction equation, the group not participating in reacting can exist with the form of protecting group, then adopts suitable method removing protecting group.
The compounds of this invention has the following advantages:
(1) formula (I) compound, its pharmacy acceptable salt or its steric isomer have excellent ALK inhibit activities;
(2) formula (I) compound, its pharmacy acceptable salt or its steric isomer demonstrate good biologically stable, and effect is more lasting, and bioavailability is high;
(3) the compounds of this invention preparation technology is simple, and medicine purity is high, steady quality, is easy to carry out large-scale commercial production.
Set forth the beneficial effect of the compounds of this invention below by way of external zymetology and the experiment of cytology inhibit activities further, but this should be interpreted as the compounds of this invention only has following beneficial effect.
The implication representated by abbreviation of following middle experiment is as follows:
DMSO: dimethyl sulfoxide (DMSO) (Dimethylsulfoxide)
DTT: dithiothreitol (DTT) (DL-Dithiothreitol)
SEB: enzyme catalyst buffered soln (SupplementEnzymaticbuffer)
ATP: adenosine triphyosphate (AdenosineTriphosphate)
ALK: Nucleophosmin-anaplastic lymphoma kinase (AnaplasticLymphomaKinase)
SA-XL665: the donor (Streptavidin-XL665) of marked by streptavidin
HEPES:4-hydroxyethyl piperazine ethanesulfonic acid
Brij-35: Brij-35
EDTA: ethylenediamine tetraacetic acid (EDTA)
2.5 ×, 5 ×, 10 × "×" wherein: doubly
the external zymetology activity experiment of experimental example 1 the compounds of this invention
Tester: the compounds of this invention 3, its chemical name and preparation method ask for an interview the preparation embodiment of this compound.
Experimental technique:
ALK kinase buffer liquid is prepared:
Get the MgCl that appropriate mother liquid concentration is 1000mM respectively 2, 2500nM DTT, 5 × enzyme buffer liquid of SEB, 100mM, join in ultrapure water, ultimate density be respectively: 5mM, 25nM, 1mM, 1 × enzyme buffer liquid, mixing, stand-by.
2.5 × tester solution preparation:
The 1mM storing solution preparation of compound: Weigh Compound 1.1mg, adds appropriate DMSO and dissolve, mixing, for subsequent use.
Get 1mM storing solution respectively, make the solution that concentration is 200 μMs, as mother liquor with DMSO dilution.With DMSO, above-mentioned mother liquor three times of stepwise dilutions are made the solution of a series of concentration, then each concentration dilutes 80 times with ALK kinase buffer liquid respectively, make each 2.5 × tester solution, concentration is respectively: 2500nM, 833.33nM, 277.78nM, 92.59nM, 30.86nM, 10.29nM, 3.43nM, 1.14nM, 0.38nM, 0.13nM, 0.04nM.
Other preparation of reagents various:
Required 5 × ALK kinase solution, 5 × substrate solution, 5 × ATP solution is prepared respectively with ALK kinase buffer liquid, for subsequent use.
ALK zymetology is reacted:
1) add 2.5 × tester solution that 4 μ L prepare in corresponding in 384 orifice plates hole respectively, 5 × ALK kinase solution that 2 μ L prepare, hatch 10 minutes for 25 DEG C.
2) corresponding Kong Zhongzai adds 5 × substrate solution that 2 μ L prepare and 5 × ATP solution that 2 μ L prepare respectively, starts enzyme reaction, hatches 30 minutes for 25 DEG C.
Zymetology detects:
Prepare the SA-XL665 of desired concn with detection damping fluid (detectionbuffer), then with isopyknic tyrosine-kinase enzyme antibody mixing, add this antibody-solutions that 10 μ L prepare in corresponding hole respectively, termination reaction.Hatch 1h for 25 DEG C.
Microplate reader 665nm/615nm reads plate.
IC 50: calculate inhibiting rate (%)=(maximum value-sample value)/(maximum value-minimum value) × 100, adopt Graphprisim software to carry out curve fitting, draw IC 50value.
Maximum value: the positive control not adding compound, minimum value: not enzyme-added negative control.
Experimental result and conclusion:
The external zymetology inhibit activities of table 1 the compounds of this invention
From table 1, the compounds of this invention has good inhibit activities to ALK kinases, can be used for treating the kinase mediated illness of the disease, particularly ALK relevant to kinases or the patient's condition, has significant clinical meaning.
the external zymetology activity experiment of experimental example 2 the compounds of this invention
Tester: the compounds of this invention 1,2, its chemical name and preparation method ask for an interview the preparation embodiment of each compound.
Contrast medicine Ceritinib, self-control (referenced patent WO2008/073687A2 preparation method preparation).
Experimental technique: adopt CaliperMobilityShift method to carry out the kinase whose inhibit activities of ALK and measure
1.1 times of kinase buffer liquid preparations
Get the HEPES of pH7.5 respectively, concentration be 30% Brij-35, mother liquid concentration be the MgCl of 1M 2solution, mother liquid concentration are the DTT of 1M, add ultrapure water mixing, and making the final concentration of HEPES be the final concentration of 50mM, Brij-35 is 0.0015%, MgCl 2final concentration be the final concentration of 10mM, DTT be 2mM.
2. the preparation of stop buffer
Get coating buffer CoatingReagent#3 (carrying coating buffer in the 12-sipperchip that Caliper instrument uses) that mother liquid concentration is 4% respectively, EDTA that HEPES that mother liquid concentration is 1000mMpH7.5, mother liquid concentration are 0.5M, mother liquid concentration be the Brij-35 of 30%, add ultrapure water mixing, CoatingReagent#3 final concentration is made to be 0.2%, HEPES final concentration is 100mM, EDTA final concentration is 50mM, Brij-35 final concentration is 0.015%.
3.5 times of tester solution preparations
The DMSO storing solution preparation of tester: Weigh Compound appropriate (concrete sample weighting amount please see the following form) respectively, adds appropriate DMSO and dissolve, mixing, for subsequent use.
Get the DMSO storing solution of tester, make the solution that concentration is 50 μMs, as mother liquor with DMSO dilution.With DMSO by above-mentioned mother liquor four times of stepwise dilutions, then each concentration dilutes 10 times with 1 times of kinase buffer liquid respectively, makes 5 times of tester solution.
4. the preparation of other reagent various
2.5 times of required ALK kinase solution, 2.5 times of polypeptide solutions are prepared respectively with 1 times of kinase buffer liquid, for subsequent use.
5. zymetology reaction
1) add 5 times of tester solution that 5 μ L prepare in corresponding in 384 orifice plates hole respectively, 2.5 times of kinase solution that 10 μ L prepare, incubated at room 10 minutes.
2) corresponding Kong Zhongzai adds 2.5 times of polypeptide solutions that 10 μ L prepare respectively, makes tester final concentration be 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 detects
25 μ L stop buffers are added respectively, termination reaction in each corresponding hole.Caliper instrument reading of data, and calculate inhibiting rate by data,
Inhibiting rate (%)=(maximum value-sample value)/(maximum value-minimum value) × 100, adopt XLFIT software to carry out curve fitting, draw IC 50value.
Maximum value: the positive control not adding tester, minimum value: not enzyme-added negative control.
Experimental result and conclusion:
The external zymetology inhibit activities of table 2 the compounds of this invention
From table 2, the compounds of this invention has good inhibit activities to ALK kinases, can be used for treating the kinase mediated illness of the disease, particularly ALK relevant to kinases or the patient's condition, has significant clinical meaning.
the cell in vitro activity experiment of experimental example 3 the compounds of this invention
Tester: the compounds of this invention 1,2, its chemical name and preparation method are shown in the preparation embodiment of each compound.
Contrast medicine Ceritinib, self-control (referenced patent WO2008/073687A2 preparation method preparation).
The implication representated by abbreviation of following middle experiment is as follows:
Rpm: rpm
DMSO: dimethyl sulfoxide (DMSO)
MTS: thiazole bromide blue tetrazolium
RPMI1640:1640 substratum (RPMI:RoswellParkMemorialInstitute)
500 ×, 1000 ×, 10 × "×" wherein: doubly
Experimental technique:
(1) NCI-H3122 cell:
(1) cell preparation:
With the RPMI-1640 substratum containing 10% foetal calf serum, 100U/ml penicillin, 100mg/ml Streptomycin sulphate, at 5%CO 2, 37 DEG C of conditions incubator in, culturing cell to 80% merges, for subsequent use.
(2) inoculating cell:
With trypsin digestion cell, the centrifugal 4min of 1000rpm, removes supernatant liquor, with the RPMI-1640 substratum suspendible again containing 2.5% foetal calf serum, adjustment cell density, gets this cell suspension 90 μ L and is inoculated in 96 orifice plates, and obtaining final cell density is 3000/hole; Then at 5%CO 2, cultivate 24h in 37 DEG C of incubators.
(3) tester is added:
(3.1) tester solution preparation
Tester solution preparation: take tester appropriate (concrete sample weighting amount please see the following form) respectively, add appropriate DMSO to dissolve and the mother liquor (1000 × tester solution) making a series of concentration respectively with DMSO gradient dilution, dilute this mother liquor 100 with substratum respectively again and doubly obtain 10 × tester solution, get this solution 10 μ L respectively, join in the 96 corresponding holes of orifice plate, obtaining each tester solution ultimate density is: 10 μMs, 2.5 μMs, 625nM, 156nM, 39nM, 9.8nM, 2.5nM.
(3.2) control wells is arranged:
Vehicle controls: 0.1%DMSO.
Cell controls a: inoculating cell, does not add compound.
Blank: substratum, instrument returns to zero.
(3.3) 96 orifice plates are put 37 DEG C, 5%CO 272h is cultivated in incubator.
(4) detect:
MTS detection method:
1. by CellTiter reagent room temperature in single solution 96 porocyte propagation detection kit places 90min.
2. in each test holes of 96 orifice plates, CellTiter is added aQueous mono-solution reagent 20 μ L.
3. 96 orifice plates are put 5%CO 2, cultivate 40min in 37 DEG C of incubators.
4. microplate reader determined wavelength 490nm is set, reads result.
(5) result treatment:
IC 50calculate: cell survival rate (%)=(OD sample value-OD blank value)/(OD maximum value-OD blank value) × 100, adopt Graphprisim software to carry out curve fitting, draw IC 50value.
OD maximum value: do not add the cell controls that compound only adds solvent, OD blank value: blank value.
(2) NCI-H2228 cell:
(1) cell preparation:
With the RPMI-1640 substratum containing 10% foetal calf serum, at 5%CO 2, 37 DEG C of conditions incubator in, culturing cell to 80% merges, for subsequent use.
(2) inoculating cell:
With trypsin digestion cell, the centrifugal 4min of 1000rpm, removes supernatant liquor, with the RPMI-1640 substratum suspendible again containing 2.5% foetal calf serum, and adjustment cell density 2 × 10 4individual/mL, gets this cell suspension 100 μ L and is inoculated in 96 orifice plates, obtains final cell density to be: 2000 cells/well.
(3) tester is added:
(3.1) tester solution preparation: take tester appropriate (concrete sample weighting amount please see the following form) respectively, add appropriate DMSO, dissolve, mixing, uses DMSO gradient dilution, obtain the solution of each a series of concentration by solution, for subsequent use.
Getting 99 μ L substratum joins in each hole of 96 orifice plates respectively, then the solution 1 μ L getting the above-mentioned different concns prepared joins in corresponding hole, makes the ultimate density of compound and contrast medicine Ceritinib to be: 10000nM, 2500nM, 625nM, 156.25nM, 39.06nM, 9.77nM, 2.44nM, 0.61nM.
(3.2) control wells is arranged:
Vehicle controls: 0.5%DMSO.
Cell controls a: inoculating cell, does not add compound.
Blank: substratum, instrument returns to zero.
(3.3) this 96 orifice plate is put 5%CO 2, 37 DEG C of conditions incubator in cultivate 96h.
(4) detect:
CTG detection method:
1. substratum in the 96 every holes of orifice plate is removed 80 μ L, equilibrium at room temperature 30min.
2. in each test holes of 96 orifice plates, CellTiter-is added reagent 60 μ L.
3. 96 orifice plates microwell plate vibrator lucifuge vibration mixing 2min, makes lysis.
4. by 96 orifice plate lucifuge incubated at room 10min, the optical signal value of generation is stablized.
5. microplate reader reads result under luminescence pattern.
(5) result treatment:
IC 50calculate: cell inhibitory rate (%)=(OD maximum value-OD compound)/(OD maximum value-OD blank) × 100, adopt Graphprisim software to carry out curve fitting, draw IC 50value.
OD maximum value: do not add compound only add solvent cell controls, OD blank: substratum blank
Experimental result:
The cell inhibitory activity of table 3 the compounds of this invention
From table 3, the compounds of this invention all has good inhibit activities to cell NCI-H3122 and NCI-H2228, can be used for treating the kinase mediated illness of ALK or the patient's condition, has significant clinical meaning.
Embodiment
The embodiment of form by the following examples, is described in further detail 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 examples.All technology realized based on foregoing of the present invention all belong to scope of the present invention.
Be defined as follows representated by following abbreviation:
DMF:N, dinethylformamide
Boc: tert-butoxycarbonyl
TFA: trifluoroacetic acid
DMSO: dimethyl sulfoxide (DMSO)
EA: ethyl acetate
TEA: trifluoroacetic acid
THF: tetrahydrofuran (THF)
DIEA:N, N-diisopropylethylamine
the chloro-N of embodiment 15- 2 -(6-isopropoxy isoindoline-5-base)-N 4 -(2-(isopropelsulfonyl) phenyl) pyrimidine-2,4- the preparation of diamines
(1) preparation of 4-hydroxyl phthalic dimethyl ester
4-hydroxyl phthalic (50g, 274.5mmol) is dissolved in methyl alcohol (800mL), is cooled to 10 DEG C, under stirring, slowly drip sulfuric acid (134g, 1.37mol), be warming up to 70 DEG C of reactions after dropwising and spend the night.Be cooled to room temperature, vacuum concentration, add ethyl acetate (700mL), washing (500mL × 3), organic phase anhydrous sodium sulfate drying, vacuum concentration obtains product (32g, productive rate 55%).
(2) preparation of 4-hydroxyl-5-nitrophthalic acid dimethyl ester
At 0 DEG C, by 4-hydroxyl phthalic dimethyl ester (24g, 114.2mmol) batch dissolution in the vitriol oil (240mL).Be cooled to-10 DEG C, drip concentrated nitric acid (massfraction 65%, 13.2mL, 190.7mmol), react 30 minutes at 0 DEG C, pour cancellation in frozen water (300mL) into, ethyl acetate (300mL × 3) extracts, organic phase merges, and washes with water (200mL × 3), anhydrous sodium sulfate drying, filter, concentrated, crude product obtains product (16g, productive rate 55%) through silica gel column chromatography (ethyl acetate: sherwood oil=1:20 ~ 1:5) purifying.
(3) preparation of 4-isopropoxy-5-nitrophthalic acid dimethyl ester
By 4-hydroxyl-5-nitrophthalic acid dimethyl ester (16g, 62.70mmol) be dissolved in N, in dinethylformamide (200mL), add cesium carbonate (61g, 187.2mmol) with 2-iodopropane (53g, 311.8mmol), be warming up to 80 DEG C of reactions to spend the night, be cooled to room temperature, filter, filter cake ethyl acetate washing (200mL × 3), filtrate merges, add water (300mL), separatory, aqueous phase ethyl acetate (300mL × 3) extracts, organic phase merges, washing (300mL × 3), anhydrous sodium sulfate drying, concentrated, crude product obtains product (10g through silica gel column chromatography (ethyl acetate: sherwood oil=1:20 ~ 1:10) purifying, productive rate 54%).
(4) preparation of (4-isopropoxy-5-nitro-1,2-phenylene) dimethanol
By Lithium Aluminium Hydride (3.0g, 79.1mmol) be suspended in tetrahydrofuran (THF) (100mL), 4-isopropoxy-5-nitrophthalic acid dimethyl ester (10g is slowly dripped at 0 DEG C, tetrahydrofuran (THF) (30mL) solution 33.64mmol), 0 DEG C of reaction 30 minutes after dropwising, water (3mL) is dripped successively in reaction solution, sodium hydroxide solution (massfraction 15%, 9mL) with water (3mL) cancellation, filter, filter cake tetrahydrofuran (THF) (100mL × 3) is washed, filtrate merges, anhydrous sodium sulfate drying, vacuum concentration, crude product obtains product (4g through silica gel column chromatography (ethyl acetate: sherwood oil=1:10 ~ 1:5) purifying, productive rate 49%).
The preparation of two (the chloromethyl)-4-isopropoxy-5-oil of mirbane of (5) 1,2-
By (4-isopropoxy-5-nitro-1, 2-phenylene) dimethanol (4g, 16.58mmol) be dissolved in toluene (50mL), add sulfur oxychloride (9.8g, 82.4mmol) and N, dinethylformamide (2.4g, 32.8mmol), be heated to 60 DEG C of reactions 2 hours, be cooled to room temperature, add ethyl acetate (50mL) dilution, gained solution with water is washed (50mL × 3), anhydrous sodium sulfate drying, vacuum concentration, crude product obtains product (3.2g through silica gel column chromatography (ethyl acetate: sherwood oil=1:20 ~ 1:10) purifying, productive rate 69%).
(6) preparation of 2-(2,4-dimethoxy-benzyl)-5-isopropoxy-6-nitro isoindoline
By 1, two (the chloromethyl)-4-isopropoxy-5-oil of mirbane (3g of 2-, 10.79mmol) and 2,4-dimethoxybenzylamine (5.4g, 32.3mmol) be dissolved in tetrahydrofuran (THF) (30mL), at 0 DEG C, drip DIPEA (6.9g, 53.4mmol), dropwise rear room temperature reaction to spend the night.Add ethyl acetate (50mL) dilution, gained reaction solution washes with water (50mL × 3), anhydrous sodium sulfate drying, vacuum concentration, crude product obtains product (3.1g, productive rate 77%) through silica gel column chromatography (ethyl acetate: sherwood oil=1:10 ~ 1:5) purifying.
(7) preparation of 5-isopropoxy-6-nitro isoindoline
By 2-(2,4-dimethoxy-benzyl)-5-isopropoxy-6-nitro isoindoline (2.6g, 6.98mmol) be dissolved in methylene dichloride (30mL), be cooled to 0 DEG C, drip 1-chloroethylchloroformate ester (3g, 20.98mmol), 40 DEG C of reactions 1 hour is risen to after dropwising, rotary evaporation, except desolventizing, adds methyl alcohol (30mL), and 70 DEG C are reacted 1 hour.Be cooled to room temperature, concentrated, add water (50mL), by sodium hydrogen carbonate solution adjust ph to 7 ~ 8, ethyl acetate (50mL × 3) extracts, and organic phase merges, washing (30mL × 3), anhydrous sodium sulfate drying, concentrates and obtains product (1.4g, productive rate 90%).
(8) preparation of tertiary butyl 5-isopropoxy-6-nitro isoindoline-2-manthanoate
5-isopropoxy-6-nitro isoindoline (1.4g, 6.3mmol) is dissolved in methyl alcohol (30mL), adds triethylamine (3.18g, 31.43mmol) and tert-Butyl dicarbonate (4.12g, 18.88mmol).Reaction solution at room temperature stirs 3 hours, concentrated, add ethyl acetate (50mL) dilution, washing (30mL × 3), anhydrous sodium sulfate drying, vacuum concentration, crude product obtains product (1.7g, productive rate 84%) through silica gel column chromatography (ethyl acetate: sherwood oil=1:10 ~ 1:3) purifying.
(9) preparation of tertiary butyl 5-amino-6-isopropoxy isoindoline-2-manthanoate
By tertiary butyl 5-isopropoxy-6-nitro isoindoline-2-manthanoate (1.7g, 5.27mmol) add in reaction flask with palladium carbon (0.3g), add ethyl acetate (20mL), system vacuumizes replacing hydrogen, at room temperature reacts 2 hours.Filter, filter cake ethyl acetate (20mL × 3) washing, filtrate merges, and vacuum concentration obtains product (1.5g, productive rate 97%).
The preparation of the chloro-N-of (10) 2,5-bis-(2-(isopropelsulfonyl) phenyl) pyrimidine-4-amine
By 2-(isopropelsulfonyl) aniline (1g; 5.02mmol) He 2; 4; 5-trichloropyrimidine (1.1g, 6mmol) is dissolved in DMF (30mL); add sodium hydride (massfraction 60%; 0.4g, 10mmol), react 12 hours at 25 DEG C.Add water (20mL), extraction into ethyl acetate (30mL × 3), organic phase merges, saturated sodium-chloride water solution washs, anhydrous sodium sulfate drying, vacuum concentration, crude product obtains product (0.8g, productive rate 46%) through silica gel column chromatography (sherwood oil: ethyl acetate=25:1) purifying.
(11) the chloro-N of 5- 2-(6-isopropoxy isoindoline-5-base)-N 4the preparation of-(2-(isopropelsulfonyl) phenyl) pyrimidine-2,4-diamines
By tertiary butyl 5-amino-6-isopropoxy isoindoline-2-manthanoate (100mg; 0.34mmol) be dissolved in sec.-amyl alcohol (8mL); add 2; the chloro-N-of 5-bis-(2-(isopropelsulfonyl) phenyl) pyrimidine-4-amine (141mg; 0.408mmol) with tosic acid (117mg; 0.68mmol), 120 DEG C are reacted 20 hours.Rotary evaporation is except desolventizing, add water (10mL), ethyl acetate (10mL × 3) extracts, anhydrous sodium sulfate drying, vacuum concentration, crude product obtains end product (76mg, productive rate 44%) through silica gel column chromatography (methylene dichloride: methyl alcohol: ammoniacal liquor=10:1:0.1) purifying.
Molecular formula: C 24h 28clN 5o 3s molecular weight: 502.03LC-MS (m/z): 502 [M] +
1H-NMR(400MHz,MeOD)δ:8.38(d,J＝8.0,1H),8.16(s,1H),7.99(s,1H),7.93(dd,J 1＝8.0,J 2＝1.2,1H),7.73-7.75(m,1H),7.39-7.43(m,1H),6.98(s,1H),4.61-4.67(m,1H),4.24(s,2H),4.11(s,2H),3.31-3.32(m,1H),2.68(s,2H),1.35(d,J＝6.0,6H),1.24(d,J＝6.8,6H).
embodiment 22-((the chloro-2-of 5-((6-isopropoxy isoindoline-5-base) is amino) pyrimidine-4-yl) is amino)-N, N-dimethyl the preparation of benzsulfamide
(1) preparation of N, N-dimethyl-2-nitrobenzene sulfonamide
Be dissolved in by 2-nitrobenzene sulfonyl chloride (4.43g, 20mmol) in methylene dichloride (50mL), add triethylamine (8.08g, 80mmol), dimethylamine hydrochloride (1.63g, 20mmol), 25 DEG C are reacted 12 hours.Add water (35mL), extraction into ethyl acetate (50mL × 3), organic phase merges, saturated sodium-chloride water solution washs, anhydrous sodium sulfate drying, vacuum concentration, crude product obtains product (2.3g, productive rate 50%) through silica gel column chromatography (sherwood oil: ethyl acetate=3:1) purifying.
(2) preparation of 2-amino-N, N-dimethyl benzene sulfonamide
By N, N-dimethyl-2-nitrobenzene sulfonamide (2g, 8.7mmol), be dissolved in methyl alcohol (100mL), add palladium carbon (200mg), 25 DEG C are reacted 12 hours, filter, filtrate rotary evaporation removes desolventizing and obtains product (1.5g, productive rate 86%).
(3) preparation of 2-((2,5-dichloro pyrimidine-4-base) is amino)-N, N-dimethyl benzene sulfonamide
By 2-amino-N, N-dimethyl benzene sulfonamide (1g, 5mmol) be dissolved in DMF (20mL), add sodium hydride (massfraction 60%, 400mg, 10mmol) with 2,4,5-trichloropyrimidine (1.1g, 6mmol), 25 DEG C are reacted 12 hours.Add water (15mL), extraction into ethyl acetate (20mL × 3), organic phase merges, saturated sodium-chloride water solution washs, anhydrous sodium sulfate drying, vacuum concentration, crude product obtains product (270mg, productive rate 15.6%) through silica gel column chromatography (sherwood oil: ethyl acetate=3:1) purifying.
(4) preparation of 2-((the chloro-2-of 5-((6-isopropoxy isoindoline-5-base) is amino) pyrimidine-4-yl) is amino)-N, N-dimethyl benzene sulfonamide
By tertiary butyl 5-amino-6-isopropoxy isoindoline-2-manthanoate, (preparation method is shown in embodiment 1,100mg, 0.34mmol) be dissolved in sec.-amyl alcohol (8mL), add 2-((2,5-dichloro pyrimidine-4-base) amino)-N, N-dimethyl benzene sulfonamide (142mg, 0.409mmol) and tosic acid (117mg, 0.68mmol), 120 DEG C are reacted 20 hours.Rotary evaporation is except desolventizing, add water (10mL), ethyl acetate (10mL × 3) extracts, anhydrous sodium sulfate drying, vacuum concentration, crude product obtains end product (75mg, productive rate 44%) through silica gel column chromatography (methylene dichloride: methyl alcohol: ammoniacal liquor=10:1:0.1) purifying.
Molecular formula: C 23h 27clN 6o 3s molecular weight: 503.02LC-MS (m/z): 503 [M] +
1H-NMR(400MHz,DMSO)δ:8.34(d,J＝8.0,1H),8.24(s,1H),8.00(s,1H),7.81(d,J＝7.2,1H),7.69(s,1H),7.61-7.65(m,1H),7.35-7.39(m,1H),6.97(s,1H),4.51-4.57(m,1H),4.04(s,2H),3.93(s,2H),2.61(s,6H),1.23(d,J＝6.0,6H).
the chloro-N of embodiment 35- 2 -(7-isopropoxy-1,2,3,4-tetrahydroisoquinoline-6-base)-N 4 -(2-(isopropylsulfonyl) phenyl) pyrimidine the preparation of-2,4-diamines 2,2,2-trifluoroacetates
(1) preparation of bromo-3,4-dihydro-isoquinoline-2 (the 1H)-carboxylicesterss of tertiary butyl 7-
In the three-necked bottle of 100mL, add bromo-1,2,3, the 4-tetrahydroisoquinoline (1g, 4.72mmol) of 7-, methylene dichloride (30mL), triethylamine (712mg, 7.04mmol), stir 10 minutes, then add Boc 2o (1.02g, 4.67mmol).Reaction mixture stirring at room temperature 24 hours, concentrating under reduced pressure, residuum obtains product (1.1g, productive rate 75%) through silica gel column chromatography (sherwood oil: ethyl acetate=20:1).
(2) preparation of tertiary butyl 7-(4,4,5,5-tetramethyl--1,3,2-dioxy borine-2-base)-3,4-dihydro-isoquinoline-2-(1H)-carboxylicesterss
Tertiary butyl 7-bromo-3 is added in the three-necked bottle of 250mL, 4-dihydro-isoquinoline-2 (1H)-carboxylicesters (1.1g, 3.52mmol), connection boric acid pinacol ester (1.07g, 4.21mmol), Isosorbide-5-Nitrae-dioxane (50mL), Potassium ethanoate (1.03g, 10.50mmol), tricyclohexyl phosphine (196mg, 0.70mmol), Pd 2(dba) 3.CHCl 3(181mg, 0.17mmol).The lower 80 DEG C of reactions of nitrogen protection 24 hours.Mixture is poured into water, then ethyl acetate (3 × 50mL) extraction, merge organic phase, wash with saturated sodium-chloride water solution, organic phase anhydrous sodium sulfate drying, concentrated, residue by silicagel column chromatography (sherwood oil: ethyl acetate=15:1) obtains product (500mg, productive rate 39%).
(3) preparation of tertiary butyl 7-hydroxyl-3,4-dihydro-isoquinoline-2 (1H)-carboxylicesters
Tertiary butyl 7-(4 is added in the single port bottle of 100mL, 4,5,5-tetramethyl--1,3,2-dioxy borine-2-base)-3,4-dihydro-isoquinoline-2-(1H)-carboxylicesters (500mg, 1.39mmol), tetrahydrofuran (THF) (20mL), the hydrogen peroxide (10mL) of 30%.Stirring at room temperature 1h, ethyl acetate (3 × 20mL) extraction of mixture, merge organic phase, wash with saturated sodium-chloride water solution, anhydrous sodium sulphate is dry, and concentrated, residuum is through column chromatography (sherwood oil: ethyl acetate=5:1), obtain product (100mg, productive rate is 29%).
(4) 6-nitro-1,2, the preparation of 3,4-tetrahydroisoquinoline-7-alcohol
Tertiary butyl 7-hydroxyl-3,4-dihydro-isoquinoline-2 (1H)-carboxylicesters (600mg, 2.41mmol) is added, CF in the single port bottle of 100mL 3cOOH (15mL).Under agitation condition, divide and add NaNO 5 times 2(166mg, 2.41mmol).Stirring at room temperature 1h, mixture concentrating under reduced pressure, residuum preparative HPLC is separated (chromatographic column: WaterSunfireC 18, 19 × 150mm, 5 μm, PhaseA: water (20mMNH 4hCO 3), B:CH 3cN, 5-10%B, 25mL/min) obtain product (90mg, productive rate 19%).
(5) preparation of tertiary butyl 7-hydroxyl-6-nitro-3,4-dihydro-isoquinoline-2 (1H)-carboxylicesters
In the single port bottle of 100mL, add 6-nitro-1,2,3,4-tetrahydroisoquinoline-7-alcohol (90mg, 0.46mmol), methylene dichloride (15mL), triethylamine (70mg, 0.69mmol), stirring at room temperature 10 minutes, drip Boc 2o (100mg, 0.46mmol), stirring at room temperature 24h, mixture concentrating under reduced pressure, residuum preparative HPLC is separated (chromatographic column: WaterSunfireC 18, 19 × 150mm, 5 μm, PhaseA:H 2o (20mMNH 4hCO 3), B:CH 3cN, 5-10%B, 25mL/min) obtain product (55mg, productive rate is 40%).
(6) preparation of tertiary butyl 7-isopropoxy-6-nitro-3,4-dihydro-isoquinoline-2 (1H)-carboxylicesters
Tertiary butyl 7-hydroxyl-6-nitro-3 is added in the tube sealing of 40mL, 4-dihydro-isoquinoline-2 (1H)-carboxylicesters (55mg, 0.19mmol), N, dinethylformamide (5mL), cesium carbonate (187mg, 0.57mmol), 2-iodopropane (323mg, 1.90mmol).Reaction mixture 80 DEG C stirs 24h.After reaction mixture cooling, be poured into water, then use ethyl acetate (3 × 15mL) to extract, merge organic phase, with saturated aqueous NaCl wash, anhydrous sodium sulphate is dry, concentrated, obtains product (50mg, productive rate is 80%).
(7) preparation of tertiary butyl 6-amino-7-isopropoxy-3,4-dihydro-isoquinoline-2 (1H)-carboxylicesters
Ethyl acetate (20mL) is added in 100mL round-bottomed flask, the Pd-C (10mg) of 10%, tertiary butyl 7-isopropoxy-6-nitro-3,4-dihydro-isoquinoline-2 (1H)-carboxylicesters (50mg, 0.15mmol), after substituting nitrogen, under 4 atmospheric hydrogen, carry out hydrogenation, room temperature hydrogenation 24 hours.Filter, filter cake ethyl acetate is washed, and filtrate concentrates, and obtains product (33mg, productive rate is 72%).
The preparation of the chloro-N-of (8) 2,5-bis-(2-(isopropylsulfonyl) phenyl) pyrimidine-4-amine
Plus hydrogenated sodium (390mg in the there-necked flask of 250mL; 9.75mmol; 60%); DMSO/DMF (1mL/10mL); system is cooled to 0 DEG C; then DMSO/DMF (1mL/10mL) solution of 2-(isopropelsulfonyl) aniline (1.5g, 7.53mmol) is dripped.Reaction solution 0 DEG C reaction 30 minutes.Keep 0 DEG C, the DMSO/DMF (1mL/10mL) of 2,4,5-trichloropyrimidine (2.06g, 11.23mmol) is added drop-wise to reaction system, dropwises, rise to room temperature and continue reaction 24 hours.Reactant adds shrend in 0 DEG C and goes out, and be 7 with the salt acid for adjusting pH value of 1M, mixture is extracted with ethyl acetate, and merges organic phase, uses anhydrous sodium sulfate drying.Concentrated, residuum obtains product (700mg, productive rate is 27%) through column chromatography (ethyl acetate: sherwood oil=1:1) purifying.
(9) preparation of tertiary butyl 6-((the chloro-4-of 5-((2-(isopropylsulfonyl) phenyl) is amino) pyrimidine-2-base) is amino)-7-isopropoxy-3,4-dihydro-isoquinoline-2 (1H)-carboxylicesters
2 are added in the round-bottomed bottle of 50mL; the chloro-N-of 5-bis-(2-(isopropylsulfonyl) phenyl) pyrimidine-4-amine (37mg; 0.11mmol), tertiary butyl 6-amino-7-isopropoxy-3,4-dihydro-isoquinoline-2 (1H)-carboxylicesters (33mg; 0.11mmol); Isosorbide-5-Nitrae-dioxane (15mL), cesium carbonate (108mg; 0.33mmol), Pd (dppf) Cl 2.CH 2cl 2(9mg, 0.01mmol), the lower 80 DEG C of reaction 24h of nitrogen protection condition.Reactant is chilled to room temperature, filters, and filtrate concentrates, and residuum purifies (chromatographic column WaterPhenylC with preparing high performance liquid phase 18, 19 × 150mm, 5 μm, PhaseA:H 2o (0.05%TFA), B:CH 3cN, 70-92%B, 9min, 20mL/min).Collection component concentrates, and obtains product (10mg, productive rate is 15%).
(10) the chloro-N of 5- 2-(7-isopropoxy-1,2,3,4-tetrahydroisoquinoline-6-base)-N 4the preparation of-(2-(isopropylsulfonyl) phenyl) pyrimidine-2,4-diamines 2,2,2-trifluoroacetate
Tertiary butyl 6-((the chloro-4-of 5-((2-(isopropylsulfonyl) phenyl) is amino) pyrimidine-2-base) is amino)-7-isopropoxy-3 is added in the round-bottomed bottle of 50mL; 4-dihydro-isoquinoline-2 (1H)-carboxylicesters (10mg; 0.02mmol), methylene dichloride (5mL).Then drip trifluoroacetic acid (0.3mL), reaction system stirring at room temperature 24h, concentrated, residuum dehydration obtains end product (3mg, productive rate is 29%).
Molecular formula: C 27h 31clF 3n 5o 5s molecular weight: 630.08LC-MS (m/z): 516 [M+H] +
1H-NMR(300MHz,d 6-DMSO)δ:9.47(1H,s),8.90(2H,brs),8.43-8.40(1H,d,J＝8.4Hz),8.29(1H,s),8.11(1H,s),7.89-7.86(1H,d,J＝7.8Hz),7.76-7.71(1H,t,J＝8.4Hz),7.64(1H,s),7.57-7.52(1H,br),7.43-7.38(1H,t,J＝7.5Hz),6.93(1H,s),4.58-4.54(1H,m),4.21(2H,m),3.37(1H,m),2.74-2.72(2H,m),1.27-1.25(6H,d,J＝6.0Hz),1.17-1.15(6H,d,J＝6.9Hz).

Claims (11)

1. logical compound shown in formula I, its pharmacy acceptable salt or its steric isomer:
Wherein,
R 1be selected from-COR 6,-CO 2r 6,-CONRR 6,-SOR 6,-SO 2r 6or-SO 2nRR 6,
R, R 6independently selected from hydrogen atom, C 1-6alkyl or 3 ~ 8 yuan of carbocyclic rings;
R 2, R 3independently selected from hydrogen atom, C 1-6alkyl or 3 ~ 8 yuan of carbocyclic rings;
R 4be selected from hydrogen atom, halogen atom, nitro, cyano group, amino, hydroxyl, carboxyl, C 1-6alkyl, hydroxyl C 1-6alkyl, carboxyl C 1-6alkyl, C 1-6alkoxy C 1-6alkyl, halo C 1-6alkyl, amino C 1-6alkyl, alkylsulfonyl C 1-6alkyl, C 1-6alkoxyl group, hydroxyl C 1-6alkoxyl group, halo C 1-6alkoxyl group, hydroxyl C 1-6alkylamino, C 2-8thiazolinyl, C 2-8alkynyl, C 1-6alkyl sulfenyl, C 1-6alkylamino, (C 1-6alkyl) 2amino, C 1-6alkyl-carbonyl, C 1-6alkyl-carbonyl oxygen base, C 1-6alkyl sulfonyl is amino, C 1-6alkyl amino sulfonyl, (C 1-6alkyl) 2amino-sulfonyl or C 1-6alkyl sulphonyl;
R 5be selected from hydrogen atom, halogen atom, cyano group, nitro, amino, carboxyl, hydroxyl, C 1-6alkoxyl group ,-OR 7, C 1-6alkyl, hydroxyl C 1-6alkyl, halo C 1-6alkyl, hydroxyl C 1-6alkoxyl group, halo C 1-6alkoxyl group, C 2-8thiazolinyl, C 2-8alkynyl, C 1-6alkylamino, C 1-6alkyl-carbonyl, C 1-6alkyl-carbonyl oxygen base, (C 1-6alkyl) 2amino or alkylsulfonyl C 1-6alkyl,
R 7be selected from 3 ~ 8 yuan of carbocyclic rings or 3 ~ 8 yuan of heterocyclic radicals;
A ring is selected from optionally by 5 ~ 6 yuan of heterocyclic radicals containing 1 ~ 3 O, S and/or atom N of 1 ~ 3 Q replacement, or optionally by 5 ~ 14 yuan of heteroaryls containing 1 ~ 3 O, S and/or atom N that 1 ~ 3 Q replaces, described substituting group Q is selected from hydroxyl, amino, carboxyl, cyano group, nitro, halogen atom, C 1-6alkyl, C 1-6alkoxyl group, C 1-6alkylamino, (C 1-6alkyl) 2amino, halo C 1-6alkyl, halo C 1-6alkoxyl group, C 1-6alkoxy C 1-6alkyl, C 2-8thiazolinyl, C 2-8alkynyl or 3 ~ 8 yuan of heterocyclic radicals.
2. compound, its pharmacy acceptable salt or its steric isomer as claimed in claim 1:
Wherein,
R 1be selected from-CONRR 6,-SO 2r 6or-SO 2nRR 6,
R, R 6independently selected from C 1-6alkyl;
R 2, R 3independently selected from hydrogen atom or C 1-4alkyl;
R 4be selected from C 1-6alkoxyl group;
R 5be selected from hydrogen atom, halogen atom, cyano group, nitro, amino, carboxyl, C 1-6alkoxyl group or C 1-6alkyl;
A ring is selected from optionally by 5 ~ 6 yuan of heterocyclic radicals containing 1 ~ 2 O and/or atom N of 1 ~ 2 Q replacement, or optionally by 5 ~ 6 yuan of heteroaryls containing 1 ~ 2 O and/or atom N that 1 ~ 2 Q replaces, described substituting group Q is selected from hydroxyl, amino, carboxyl, cyano group, nitro, halogen atom or C 1-6alkyl.
3. compound, its pharmacy acceptable salt or its steric isomer as claimed in claim 2:
Wherein,
R 1be selected from-SO 2r 6or-SO 2nRR 6,
R, R 6independently selected from C 1-4alkyl;
R 2, R 3independently selected from hydrogen atom;
R 4be selected from C 1-4alkoxyl group;
R 5be selected from halogen atom;
A ring is selected from optionally by 5 ~ 6 yuan of heterocyclic radicals containing 1 ~ 2 O and/or atom N that 1 ~ 2 Q replaces, and described substituting group Q is selected from hydroxyl, amino, carboxyl, cyano group, nitro, halogen atom or C 1-4alkyl.
4. compound, its pharmacy acceptable salt or its steric isomer as claimed in claim 3:
Wherein,
A ring is selected from optionally by 5 ~ 6 yuan of heterocyclic radicals containing 1 atom N that 1 ~ 2 Q replaces, and described substituting group Q is selected from hydroxyl, amino, carboxyl, cyano group, nitro, halogen atom or C 1-4alkyl.
5. compound, its pharmacy acceptable salt or its steric isomer as claimed in claim 3:
Wherein,
R 1be selected from-SO 2r 6or-SO 2nRR 6,
R, R 6independently selected from methyl, ethyl or sec.-propyl;
R 2, R 3independently selected from hydrogen atom;
R 4be selected from methoxyl group, oxyethyl group or isopropoxy;
R 5be selected from fluorine atom, bromine atoms or chlorine atom;
A ring is selected from optionally by piperidyl, piperazinyl, morpholinyl, pyrrolidyl, pyrrolin base, tetrahydrofuran base, the THP trtrahydropyranyl or 1 of 1 Q replacement, 4-dioxane base, described substituting group Q is selected from methyl, ethyl, n-propyl, sec.-propyl or normal-butyl.
6. compound, its pharmacy acceptable salt or its steric isomer as claimed in claim 5:
Wherein,
A ring forms following group together with the phenyl ring be attached thereto:
7. compound, its pharmacy acceptable salt or its steric isomer as claimed in claim 1, wherein said compound is selected from:
8. the pharmaceutical preparation that the compound described in the arbitrary claim of claim 1 ~ 7, its pharmacy acceptable salt or its steric isomer and one or more pharmaceutical carriers and/or thinner are made is pharmaceutically acceptable arbitrary formulation.
9. the pharmaceutical composition containing compound, its pharmacy acceptable salt or its steric isomer described in the arbitrary claim of claim 1 ~ 7, also containing one or more antineoplastic agents and/or immunosuppressor.
10. pharmaceutical composition as claimed in claim 9, described antineoplastic agent and/or immunosuppressor are metabolic antagonist, are selected from capecitabine, gemcitabine, pemetrexed disodium; For growth factor receptor inhibitors, be selected from pazopanib, imatinib, erlotinib, lapatinibditosylate, Gefitinib, ZD6474; For antibody, be selected from Trastuzumab, rhuMAb-VEGF; For mitotic inhibitor, be selected from taxol, vinorelbine, docetaxel, Dx; For antitumor hormones, be selected from letrozole, tamoxifen, fulvestrant, flutamide, triptorelin; For alkylating agent class, be selected from endoxan, mustargen, melphalan, Chlorambucil, carmustine; For metal platinum class, be selected from carboplatin, cis-platinum, oxaliplatin; For immunosuppression class, be selected from everolimus, sirolimus, special cancer fit; For purine analogue, be selected from Ismipur, 6-Tioguanine, azathioprine; For antibiotics, be selected from rhzomorph D, daunorubicin, Zorubicin, mitoxantrone, bleomycin, Plicamycin; For platinum complex, be selected from cis-platinum, NSC-241240; For adrenal cortex inhibitor class, be selected from aminoglutethimide; For enzyme inhibitors, be selected from Vorinostat, cytosine arabinoside, methotrexate, hydroxyurea, Hydroxycamptothecin, camptothecine, Topotecan, topotecan, Rinotecan.
Compound as described in 11. claims as arbitrary in claim 1 ~ 7, its pharmacy acceptable salt or the application of its steric isomer in the medicine for the preparation of the proliferative disease or cancer-related diseases that treat and/or prevent ALK mediation, the disease that described cancer is relevant is selected from lung cancer, brain tumor, squamous cell, bladder cancer, cancer of the stomach, ovarian cancer, peritoneal cancer, carcinoma of the pancreas, mammary cancer, head and neck cancer, cervical cancer, carcinoma of endometrium, colorectal cancer, liver cancer, kidney, adenocarcinoma of esophagus, esophageal squamous cell carcinoma, non-Hodgkin lymphoma, central nerve neuroma, prostate cancer, thyroid carcinoma, female reproductive tract cancer, carcinoma in situ, lymphoma, histocytic lymphoma, neurofibromatosis, osteocarcinoma, skin carcinoma, colorectal carcinoma, small cell lung cancer, lung cancer in non-cellule type, carcinoma of testis, gastrointestinal stromal tumor, mast cell tumor, multiple myeloma, melanoma, glioma, astrocytoma, neuroblastoma, sarcoma, proliferative disease, is selected from skin or prostatic hyperplasia of prostate.
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WO2019029295A1 (en) * 2017-08-10 2019-02-14 山东大学 Pazopanib-based hdac and vegfr double-target inhibitor, preparation method therefor and application thereof
CN111484484A (en) * 2020-04-13 2020-08-04 沈阳药科大学 2, 4-diaryl aminopyrimidine derivative containing aromatic heterocycle and preparation and application thereof
WO2023134582A1 (en) * 2022-01-14 2023-07-20 上海立森印迹医药技术有限公司 Pyrimidine-2,4-diamine derivatives as well as preparation method therefor and use thereof
EP4079726A4 (en) * 2019-12-16 2024-01-24 Korea Res Inst Chemical Tech Novel pyrimidin derivative and use thereof
EP4103182A4 (en) * 2020-02-14 2024-02-21 Salk Inst For Biological Studi Inhibitors of ulk1/2 and methods of using same

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106366089A (en) * 2016-08-19 2017-02-01 爱斯特（成都）生物制药股份有限公司 Preparation method of dihydroisoindolyl derivative and analogue thereof
CN106366089B (en) * 2016-08-19 2019-06-11 爱斯特（成都）生物制药股份有限公司 The preparation method of dihydroisoindole derivatives and the like
WO2019029295A1 (en) * 2017-08-10 2019-02-14 山东大学 Pazopanib-based hdac and vegfr double-target inhibitor, preparation method therefor and application thereof
EP4079726A4 (en) * 2019-12-16 2024-01-24 Korea Res Inst Chemical Tech Novel pyrimidin derivative and use thereof
EP4103182A4 (en) * 2020-02-14 2024-02-21 Salk Inst For Biological Studi Inhibitors of ulk1/2 and methods of using same
CN111484484A (en) * 2020-04-13 2020-08-04 沈阳药科大学 2, 4-diaryl aminopyrimidine derivative containing aromatic heterocycle and preparation and application thereof
CN111484484B (en) * 2020-04-13 2021-11-23 沈阳药科大学 2, 4-diaryl aminopyrimidine derivative containing aromatic heterocycle and preparation and application thereof
WO2023134582A1 (en) * 2022-01-14 2023-07-20 上海立森印迹医药技术有限公司 Pyrimidine-2,4-diamine derivatives as well as preparation method therefor and use thereof

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