CN103374001B - Imidazo-triazine class mTOR inhibitors - Google Patents

Imidazo-triazine class mTOR inhibitors Download PDF

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CN103374001B
CN103374001B CN201210115351.8A CN201210115351A CN103374001B CN 103374001 B CN103374001 B CN 103374001B CN 201210115351 A CN201210115351 A CN 201210115351A CN 103374001 B CN103374001 B CN 103374001B
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CN103374001A (en
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王爱臣
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Shandong Xuanzhu Pharma Co Ltd
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Shandong Xuanzhu Pharma Co Ltd
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Abstract

The invention belongs to medical art, be specifically related to the imidazo-triazine class mTOR inhibitors shown in general formula (I), its pharmacy acceptable salt, its steric isomer or its deuterated thing, wherein R 1, R 2, Cy 1, Cy 2as in specification sheets define; The invention still further relates to the preparation method of these compounds, the pharmaceutical preparation containing these compounds, and these compounds treat and/or prevent the application had the suppression of mTOR activity in the medicine of the proliferative disease of response in preparation.

Description

Imidazo-triazine class mTOR inhibitors
Technical field
The invention belongs to medical art, be specifically related to imidazo-triazine class mTOR inhibitors, its pharmacy acceptable salt, its steric isomer or its deuterated thing, the preparation method of these compounds, pharmaceutical preparation containing these compounds, and these compounds treat and/or prevent the application had the suppression of mTOR activity in the medicine of the proliferative disease of response in preparation.
Background technology
Tumour be body under the effect of the various tumorigenesis factor, cause cellular genetic material to change, cause genetic expression not normal, abnormal cell proliferation and the true tumor formed.Tumour cell loses normal growth regulatory function, has autonomous or relative autonomous growth ability, still can continued growth, the in a large number nutritive substance of consumption human body after the tumorigenesis factor stops.If find and treat not in time, cancer cells also can be transferred to whole body growth and breeding everywhere, and discharges multiple toxin, causes human body sale, anaemia, the impaired extremely death of organ function.
The method of oncotherapy, mainly comprises three aspects: pharmacological agent, operative treatment and radiotherapy.Because operative treatment, radiotherapy are difficult to thorough tumor eradication, and the effect of centering patients with advanced cancer is not obvious, and therefore the status of pharmacological agent in oncotherapy is more and more obvious.Traditional anti-tumor medicine cannot distinguish tumour cell and normal tissue cell, often cause severe side effect, targeted drug is using cancer cells as specificity target spot, tumour can accurately be acted on, greatly improve treatment level, and alleviate untoward reaction rate, such as make the median survival time of advanced CRC increase by 66.7%, the treated effect of advanced breast cancer improves 71.3%.
Because each drugmaker accelerates the development of target class antitumour drug, it is sought-after to add the antitumour drug of market to this classification, and molecular targeted agents has become fastest-rising unit in global antitumor drug market.PI3K/AKT path is the place of the most often morphing in human cancer cell, can cause cell proliferation, activation, amplifying signal.
The mitogenetic activation of somatomedin to PI3K/AKT signal pathway finally produces crucial cell cycle and growth control regulatory factor mTOR, mTOR is a kind of cell signalling albumen, its regulate tumor cell is to the reaction of nutrient and somatomedin, and by the effect to vascular endothelial growth factor, control the blood supply of tumour.MTOR inhibitors can make cancer cells hungry, and by suppressing the effect of mTOR to make tumor mass reduction.
Known mTOR inhibitors rapamycin can effectively suppress Various Tissues type as the propagation of smooth muscle cell, T cell and various tumor type cell or growth, but due to mTOR Macrolide inhibitor such as rapamycins, molecular weight is large, solubleness and less stable, so need research and development solubleness and the good mTOR micromolecular inhibitor of stability, effectiveness of selection and the good compound of security, for the treatment of cancer.
Summary of the invention
The invention provides a kind of imidazo-triazine class mTOR inhibitors.
Technical scheme of the present invention is as follows:
Compound shown in general formula (I), its pharmacy acceptable salt, its steric isomer or its deuterated thing:
Wherein
R 1for-NH 2,-NR dr eor-OR d, R dfor hydrogen or C 1-6alkyl, R efor C 1-6alkyl;
Work as R 1for-NH 2time, Cy 1for not to be substituted or by the identical or different R of 1-3 3replace 6-14 unit aryl and 3-8 unit cycloalkyl;
Work as R 1for-NR dr eor-OR dtime, Cy 1for not to be substituted or by the identical or different R of 1-3 3replace 6-14 unit aryl, 3-14 unit heterocyclic radical, 3-14 unit cycloalkyl, 6-14 unit aryl and 3-8 unit heterocyclic radical, 6-14 unit aryl and 3-8 unit cycloalkyl;
R 2for hydrogen, C 1-6alkyl or-NR ar b;
Cy 2for not to be substituted or by the identical or different R of 1-3 3the 6-14 unit aryl replaced, 3-14 unit heterocyclic radical, 3-14 unit cycloalkyl;
R 3for hydrogen, halogen ,-CF 3,-OCF 3,-OR c,-NR ar b,-C (O) R a,-CO 2r a,-CONR ar b,-NO 2,-CN ,-SO 2r a,-SONR ar b,-NR ac (O) R a,-NR ac (O) OR a,-NR asO 2r a,-C (S) OR a,-C (O) SR a,-OC (O) NR ar b,-OC (O) SR a,-SC (O) NR ar b, C 1-6alkyl, C 2-6thiazolinyl, C 2-6alkynyl, C 1-6alkoxy C 1-6alkyl, C 1-6alkoxy C 2-6thiazolinyl, C 1-6alkoxy C 2-6alkynyl, C 1-6alkylthio C 1-6alkyl, C 1-6alkylthio C 2-6thiazolinyl, C 1-6alkylthio C 2-6alkynyl, 3-8 unit cycloalkyl, 3-8 unit cycloalkyl C 1-6alkyl, 3-8 unit cycloalkyl C 2-6thiazolinyl, 3-8 unit cycloalkyl C 2-6alkynyl, 3-8 unit heterocyclic radical, 3-8 unit heterocyclic radical C 1-6alkyl, 3-8 unit heterocyclic radical C 2-6thiazolinyl or 3-8 unit heterocyclic radical C 2-6alkynyl;
R a, R bindependently be hydrogen or C 1-6alkyl;
R cfor hydrogen, C 1-6alkyl, 3-8 unit cycloalkyl, 3-8 unit's heterocyclic radical or 6-8 unit aryl.
The optimal technical scheme of the compound shown in general formula (I), its pharmacy acceptable salt, its steric isomer or its deuterated thing is:
Wherein
R 1for-NH 2,-NR dr eor-OR d, R dfor hydrogen or C 1-6alkyl, R efor C 1-6alkyl;
Work as R 1for-NH 2time, Cy 1for not to be substituted or by the identical or different R of 1-3 3replace 6-8 unit aryl and 3-8 unit cycloalkyl;
Work as R 1for-NR dr eor-OR dtime, Cy 1for not to be substituted or by the identical or different R of 1-3 3replace 6-8 unit aryl, 3-8 unit heterocyclic radical, 3-8 unit cycloalkyl, 6-8 unit aryl and 3-8 unit heterocyclic radical, 6-8 unit aryl and 3-8 unit cycloalkyl;
R 2for hydrogen, C 1-6alkyl or-NR ar b;
Cy 2for not to be substituted or by the identical or different R of 1-3 3the 6-8 unit aryl replaced, 3-10 unit's heterocyclic radical or 3-10 unit cycloalkyl;
R 3for hydrogen, halogen ,-CF 3,-OCF 3,-OR c,-NR ar b,-C (O) R a,-CO 2r a,-CONR ar b,-NO 2,-CN ,-SO 2r a,-SO 2nR ar b,-NR ac (O) R a,-NR ac (O) OR a,-NR asO 2r a,-C (S) OR a,-C (O) SR a,-OC (O) NR ar b,-OC (O) SR a,-SC (O) NR ar b, C 1-6alkyl, C 2-6thiazolinyl, C 2-6alkynyl, C 1-6alkoxy C 1-6alkyl, C 1-6alkoxy C 2-6thiazolinyl, C 1-6alkoxy C 2-6alkynyl, C 1-6alkylthio C 1-6alkyl, C 1-6alkylthio C 2-6thiazolinyl, C 1-6alkylthio C 2-6alkynyl, 3-8 unit cycloalkyl, 3-8 unit cycloalkyl C 1-6alkyl, 3-8 unit cycloalkyl C 2-6thiazolinyl, 3-8 unit cycloalkyl C 2-6alkynyl, 3-8 unit heterocyclic radical, 3-8 unit heterocyclic radical C 1-6alkyl, 3-8 unit heterocyclic radical C 2-6thiazolinyl or 3-8 unit heterocyclic radical C 2-6alkynyl;
R a, R bindependently be hydrogen or C 1-6alkyl;
R cfor hydrogen, C 1-6alkyl, 3-8 unit cycloalkyl, 3-8 unit's heterocyclic radical or 6-8 unit aryl.
The optimal technical scheme of the compound shown in general formula (I), its pharmacy acceptable salt, its steric isomer or its deuterated thing is:
Wherein
R 1for-NH 2,-NR dr eor-OR d, R dfor hydrogen or C 1-6alkyl, R efor C 1-4alkyl;
Work as R 1for-NH 2time, Cy 1for not to be substituted or by the identical or different R of 1-3 3the benzo 3-8 unit cycloalkyl replaced;
Work as R 1for-NR dr eor-OR dtime, Cy 1for not to be substituted or by the identical or different R of 1-3 3replace phenyl, 3-8 unit heterocyclic radical, 3-8 unit cycloalkyl, phenyl and 3-8 unit heterocyclic radical, phenyl and 3-8 unit cycloalkyl;
R 2for hydrogen, C 1-6alkyl or-NR ar b;
R 2for hydrogen, C 1-6alkyl or-NR ar b;
Cy 2for not to be substituted or by the identical or different R of 1-3 3the phenyl replaced, 3-8 unit heterocyclic radical, 3-8 unit cycloalkyl;
R 3for hydrogen, halogen ,-CF 3,-OCF 3,-OR c,-NR ar b,-C (O) R a,-CO 2r a,-CONR ar b,-NO 2,-CN ,-SO 2r a,-SO 2nR ar b,-NR ac (O) R a,-NR ac (O) OR a,-NR asO 2r a,-C (S) OR a,-C (O) SR a,-OC (O) NR ar b,-OC (O) SR a,-SC (O) NR ar b, C 1-6alkyl, C 2-6thiazolinyl, C 2-6alkynyl, C 1-6alkoxy C 1-6alkyl, 3-8 unit saturated cyclic alkyls, 3-8 unit saturated cyclic alkyls C 1-6alkyl, 3-8 unit saturated cyclic alkyls C 2-6alkynyl, 3-8 unit's heterocyclic radical or 3-8 unit heterocyclic radical C 1-6alkyl;
R a, R bindependently be hydrogen or C 1-4alkyl;
R cfor hydrogen, C 1-6alkyl, 3-8 unit saturated cyclic alkyls, 3-8 unit's heterocyclic radical or phenyl.
The optimal technical scheme of the compound shown in general formula (I), its pharmacy acceptable salt, its steric isomer or its deuterated thing is:
Wherein
R 1for-NH 2,-NR dr eor-OR d, R dfor hydrogen or C 1-6alkyl, R efor C 1-4alkyl;
Work as R 1for-NH 2time, Cy 1for not to be substituted or by the identical or different R of 1-3 3the benzo 3-8 unit cycloalkyl replaced;
Work as R 1for-NR dr eor-OR dtime, Cy 1for not to be substituted or by the identical or different R of 1-3 3replace phenyl and 3-8 unit heterocyclic radical, phenyl and 3-8 unit cycloalkyl;
R 2for hydrogen, C 1-4alkyl or-NR ar b;
Cy 2for not to be substituted or by the identical or different R of 1-3 3the phenyl replaced, 5-6 unit heterocyclic radical, 5-6 unit cycloalkyl;
R 3for hydrogen, halogen ,-CF 3,-OCF 3,-OR c,-NR ar b,-C (O) R a,-CO 2r a,-CONR ar b,-NO 2,-CN ,-SO 2r a,-SO 2nR ar b,-NR ac (O) R a,-NR ac (O) OR a,-NR asO 2r a,-C (S) OR a,-C (O) SR a,-OC (O) NR ar b,-OC (O) SR a,-SC (O) NR ar b, C 1-4alkyl, C 1-4alkoxy C 1-4alkyl, 3-8 unit saturated cyclic alkyls, 3-8 unit saturated cyclic alkyls C 1-4alkyl, 5-6 unit's heterocyclic radical or 5-6 unit heterocyclic radical C 1-4alkyl;
R a, R bindependently be hydrogen or C 1-4alkyl;
R cfor hydrogen, C 1-6alkyl, 3-8 unit saturated cyclic alkyls, 5-6 unit's heterocyclic radical or phenyl.
The optimal technical scheme of the compound shown in general formula (I), its pharmacy acceptable salt, its steric isomer or its deuterated thing is:
Wherein
R 1for-NH 2,-NR dr eor-OR d, R dfor hydrogen or C 1-6alkyl, R efor C 1-4alkyl;
Work as R 1for-NH 2time, Cy 1for not to be substituted or by the identical or different R of 1-3 3the benzo 5-6 unit cycloalkyl replaced;
Work as R 1for-NR dr eor-OR dtime, Cy 1for not to be substituted or by the identical or different R of 1-3 3replace phenyl and 5-6 unit heterocyclic radical, phenyl and 5-6 unit cycloalkyl;
R 2for hydrogen or C 1-4alkyl;
Cy 2for not to be substituted or by the identical or different R of 1-3 3the 5-6 unit cycloalkyl replaced;
R 3for hydrogen, halogen ,-CF 3,-OCF 3,-OR c,-NR ar b,-C (O) R a,-CO 2r a,-CONR ar b,-NO 2,-CN ,-SO 2r a,-SO 2nR ar b,-NR ac (O) R a,-NR ac (O) OR a,-NR asO 2r a,-C (S) OR a,-C (O) SR a,-OC (O) NR ar b,-OC (O) SR a,-SC (O) NR ar b, C 1-4alkyl, 3-8 unit's saturated cyclic alkyls or 3-8 unit heterocyclic radical;
R a, R bindependently be hydrogen or C 1-4alkyl;
R cfor hydrogen, C 1-4alkyl, 3-8 unit's saturated cyclic alkyls or 5-6 unit heterocyclic radical.
The optimal technical scheme of the compound shown in general formula (I), its pharmacy acceptable salt, its steric isomer or its deuterated thing is:
Wherein
R 1for-NH 2,-NR dr eor-OR d, R dfor hydrogen or C 1-6alkyl, R efor C 1-4alkyl;
Work as R 1for-NH 2time, Cy 1for not to be substituted or by the identical or different R of 1-3 3the benzo 5-6 unit cycloalkyl replaced;
Work as R 1for-NR dr eor-OR dtime, Cy 1for not to be substituted or by the identical or different R of 1-3 3replace phenyl and 5-6 membered unsaturated heterocycle base, phenyl and 5-6 unit cycloalkyl;
R 2for hydrogen or C 1-4alkyl;
Cy 2for not to be substituted or by the identical or different R of 1-3 3the 5-6 unit cycloalkyl replaced;
R 3for hydrogen, halogen ,-CF 3,-OCF 3,-OR c,-NR ar b,-C (O) R a,-CO 2r a,-CONR ar b,-NO 2,-CN ,-SO 2r a,-SO 2nR ar b,-NR ac (O) R a, C 1-4alkyl, 5-6 unit's saturated cyclic alkyls or 5-6 unit heterocyclic radical;
R a, R bindependently be hydrogen or C 1-4alkyl;
R cfor hydrogen, C 1-4alkyl or 5-6 unit saturated heterocyclyl.
The optimal technical scheme of the compound shown in general formula (I), its pharmacy acceptable salt, its steric isomer or its deuterated thing is:
Wherein
R 1for-NR ar bor-OR a;
R 1for-NH 2,-NR dr eor-OR d, R dfor hydrogen or C 1-6alkyl, R efor C 1-4alkyl;
Work as R 1for-NH 2time, Cy 1for not to be substituted or by the identical or different R of 1-3 3replace
Work as R 1for-NR dr eor-OR dtime, Cy 1for not to be substituted or by the identical or different R of 1-3 3replace
R 2for hydrogen, methyl or ethyl;
Cy 2for not to be substituted or by 1 R 3the pentamethylene base replaced, cyclohexyl;
R 3for hydrogen, halogen, methyl, ethyl ,-CF 3,-OR c,-NR ar b,-CO 2h or-CONR ar b;
R a, R bindependently be hydrogen, methyl or ethyl;
R cfor hydrogen, methyl, ethyl or tetrahydrofuran base.
Part of compounds of the present invention:
" halogen " of the present invention comprises fluorine atom, chlorine atom, bromine atoms, atomic iodine.
" C of the present invention 1-6alkyl " refer to that the hydrocarbon part containing 1-6 carbon atom removes the alkyl of the straight or branched that a hydrogen atom derives, as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, isopentyl, 2-methyl butyl, neo-pentyl, 1-ethyl propyl, n-hexyl, isohexyl, 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-methyl-2-methyl-propyl etc." C of the present invention 1-4alkyl " refer in above-mentioned example containing the specific examples of 1-4 carbon atom.
" C of the present invention 2-6thiazolinyl " refer to that the carbonatoms containing double bond is the straight or branched of 2-6 or the thiazolinyl of ring-type, as vinyl, 1-propenyl, 2-propenyl, 1-methyl ethylene, 1-butylene base, crotyl, 3-butenyl, 1-methyl-1-propylene base, 2-methyl-1-propylene base, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl isophthalic acid-butenyl, 2-methyl-1-butene thiazolinyl, 3-methyl-1-butene base, 1-methyl-2-butene base, 2-methyl-2-butene base, 3-methyl-2-butene base, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentene thiazolinyl, 2-methyl-1-pentene thiazolinyl, 3-methyl-1-pentene thiazolinyl, 4-methyl-1-pentene base, 1-methyl-pentenyl, 2-methyl-pentenyl, 3-methyl-pentenyl, 4-methyl-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-crotyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-1-butylene base, 1,2-dimethyl-crotyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-1-butylene base, 1,3-dimethyl-crotyl, 1,3-dimethyl-crotyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-1-butylene base, 2,3-dimethyl-crotyl, 2,3-dimethyl-3-butenyl, 3,3-dimethyl-1-butylene base, 3,3-dimethyl-crotyl, 1-ethyl-1-butylene base, 1-ethyl-crotyl, 1-ethyl-3-butenyl, 2-ethyl-1-butylene base, 2-ethyl-crotyl, 2-ethyl-3-butenyl, 1,1,2-trimethylammonium-2-propenyl, 1-ethyl-1-methyl-2-propenyl, 1-Ethyl-2-Methyl-1-propenyl, 1-Ethyl-2-Methyl-2-propenyl, 1,3-butadiene, 1,3-pentadiene, Isosorbide-5-Nitrae-pentadiene, Isosorbide-5-Nitrae-hexadiene, cyclopentenyl, 1，3-cyclopentadiene base, cyclohexenyl, 1，4-cyclohexadiene base etc.
" C of the present invention 2-6alkynyl " refer to containing triple bond carbonatoms and be the alkynyl of the straight or branched of 3-6, as ethynyl, 2-propynyl, 2-butyne base, 3-butynyl, 1-methyl-2-propynyl, valerylene base, 3-pentynyl, 4-pentynyl, 1-methyl-2-butyne base, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1, 1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 2-hexin base, 3-hexin base, 4-hexin base, 5-hexin base, 1-methyl-valerylene base, 1-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3-methyl-4-pentynyl, 4-methyl-valerylene base, 1, 1-dimethyl-2-butyne base, 1, 1-dimethyl-3-butynyl, 1, 2-dimethyl-3-butynyl, 2, 2-dimethyl-3-butynyl, 1-ethyl-2-butyne base, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl, 1-ethyl-1-methyl-2-propynyl etc.
" C of the present invention 1-6alkoxyl group " refer to " C 1-6alkyl " group that is connected with other structures by Sauerstoffatom, as methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, tert.-butoxy, sec-butoxy, pentyloxy, neopentyl oxygen, hexyloxy etc.Term " C 1-4alkoxyl group " refer in above-mentioned example containing the specific examples of 1-4 carbon atom.
" C of the present invention 1-6alkylthio " refer to " C 1-6alkyl " group that is connected with other structures by sulphur atom, as methylthio group, ethylmercapto group, rosickyite base, isopropyisulfanyl, butylthio, isobutylthio, tertiary butylthio, secondary butylthio, penta sulfenyl, new penta sulfenyl, own sulfenyl etc.Term " C 1-4alkylthio " refer in above-mentioned example containing the specific examples of 1-4 carbon atom.
" C of the present invention 1-6alkoxy C 1-6alkyl ", " C 1-6alkylthio C 1-6alkyl " refer to previously described C 1-6alkoxyl group, C 1-6alkylthio replaces previously described C 1-6the group that alkyl is formed.
" C of the present invention 1-6alkoxy C 2-6thiazolinyl ", " C 1-6alkylthio C 2-6thiazolinyl " refer to previously described C 1-6alkoxyl group, C 1-6alkylthio replaces previously described C 2-6the group that thiazolinyl is formed.
" C of the present invention 1-6alkoxy C 2-6alkynyl ", " C 1-6alkylthio C 2-6alkynyl " refer to previously described C 1-6alkoxyl group, C 1-6alkylthio replaces previously described C 2-6the group that alkynyl is formed.
" 3-14 unit cycloalkyl " of the present invention refers to that annular atoms is all carbon atom, removes the cyclic alkyl radical that a hydrogen atom is derivative, comprises 3-8 unit's cycloalkyl and 6-14 unit cycloalkyl.
3-8 unit cycloalkyl, refers to the monocyclic cycloalkyl containing 3-8 annular atoms, comprises 3-8 unit's saturated cyclic alkyls and 3-8 unit fractional saturation cycloalkyl.3-8 unit saturated cyclic alkyls, refer to that this monocycle is all saturated carbocyclic ring, the example includes but not limited to: cyclopropane base, tetramethylene base, pentamethylene base, cyclohexyl, suberane base, cyclooctane base, methyl cyclopropane base, dimethylcyclopropane base, methyl cyclobutane base, dimethylcyclobutane base, methylcyclopentane base, dimethylcyclopentane base, methyl cyclohexane alkyl, dimethyleyelohexane alkyl etc.3-8 unit fractional saturation cycloalkyl, refer to that this monocycle is the carbocyclic ring of fractional saturation, the example includes but are not limited to cyclopropenyl radical, cyclobutene base, cyclopentenyl, cyclohexenyl, 1，4-cyclohexadiene base, cycloheptenyl, 1,4-cycloheptadiene base, cyclooctene base, 1,5-cyclooctadiene base etc." 5-6 unit cycloalkyl " of the present invention refers to the monocyclic cycloalkyl containing 5-6 annular atoms, comprises 5-6 unit's saturated cyclic alkyls and 5-6 unit fractional saturation cycloalkyl.
6-14 unit cycloalkyl, refers to and shares by two or more ring texturees the condensed ring group that two adjacent carbon atoms are formed each other, comprise 6-14 unit's saturated cyclic alkyls and 6-14 unit fractional saturation cycloalkyl.6-14 unit saturated cyclic alkyls, refer to that all rings are as all saturated carbocyclic ring, the example includes but not limited to: dicyclo [3.1.0] hexyl, dicyclo [4.1.0] heptane base, dicyclo [2.2.0] hexyl, dicyclo [3.2.0] heptane base, dicyclo [4.2.0] octyl, octahydro pentalene base, octahydro-1H-indenyl, decahydronaphthalene naphthyl, ten tetrahydrochysene phenanthryl etc.6-14 unit fractional saturation cycloalkyl, refer to that at least one ring is the carbocyclic ring of fractional saturation, the example includes but not limited to: the own-2-thiazolinyl of dicyclo [3.1.0], dicyclo [4.1.0]-3-in heptan thiazolinyl, dicyclo [3.2.0]-3-in heptan thiazolinyl, pungent-3-the thiazolinyl of dicyclo [4.2.0], 1, 2, 3, 3a-tetrahydrochysene pentalene base, 2, 3, 3a, 4, 7, 7a-six hydrogen-1H-indenyl, 1, 2, 3, 4, 4a, 5, 6, the octahydro naphthyl of 8a-, 1, 2, 4a, 5, 6, 8a-hexahydro-naphthyl, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10-decahydro phenanthryl etc.
" 6-14 unit aryl " of the present invention refers to the cyclic aromatic groups containing 6-14 carbon atom, comprises 6-8 unit's aryl and 8-14 unit aryl.
6-8 unit aryl refers to the undersaturated aryl containing 6-8 carbon atom, such as phenyl, cyclooctatetraenyl etc.
8-14 unit aryl refers to and to be shared by two or more ring texturees that two adjacent carbon atoms are formed each other, have at least a ring to be the condensed ring group of whole undersaturated aromatic nucleus, comprise the whole unsaturated aryl of 8-14 unit, such as naphthalene, phenanthrene etc., also comprise 8-14 unit fractional saturation aryl, such as benzo 3-8 unit saturated cyclic alkyls, benzo 3-8 unit fractional saturation cycloalkyl, specific examples is as 2,3-dihydro-1H-indenyl, 1H-indenyl, 1,2,3,4-tetralyl, Isosorbide-5-Nitrae-dihydro naphthyl etc.
" 3-14 unit heterocyclic radical " of the present invention, refers to the cyclic group containing 3-14 annular atoms (wherein at least containing a heteroatoms), comprises 3-8 unit heterocyclic radical, 6-14 unit heterocyclic radical.
3-8 unit heterocyclic radical, refers to the monocyclic heterocycles base containing 3-8 annular atoms (wherein at least containing a heteroatoms), comprises 3-8 membered unsaturated heterocycle base, 3-8 unit fractional saturation heterocyclic radical, 3-8 unit saturated heterocyclyl.3-8 membered unsaturated heterocycle base, what refer to aromaticity contains heteroatomic cyclic group, specific examples includes but are not limited to furyl, thienyl, pyrryl, thiazolyl, thiadiazolyl group, oxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, pyridyl, 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, 2, 4-triazinyl, 1, 3, 5-triazinyl, 1, 2, 4, 5-tetrazine base, oxepin base, thia cycloheptatriene base, nitrogen heterocyclic heptantriene base, 1, 3-diazacyclo heptantriene base, azepine cyclooctatetraenyl etc.3-8 unit fractional saturation heterocyclic radical, refer to containing double bond containing heteroatomic cyclic group, specific examples includes but are not limited to 2,5-dihydro-thiophene base, 4,5-pyrazoline bases, 3,4-dihydro-2H-pyranyls, 5,6-dihydro-4H-1,3-oxazinyl etc.3-8 unit saturated heterocyclyl, refer to be all saturated bond containing heteroatomic cyclic group, specific examples includes but are not limited to: ethylenimine base, azetidinyl, Thietane base, tetrahydrofuran base, Pyrrolidine base, imidazolidyl, pyrazolidyl, tetrahydrofuran base, 1,4-dioxane base, 1,3-dioxane base, 1,3-dithian base, morpholinyl, piperazinyl etc." 5-6 unit heterocyclic radical " of the present invention refers to the monocyclic heterocycles base containing 5-6 annular atoms, comprises 5-6 membered unsaturated heterocycle base, 5-6 unit fractional saturation heterocyclic radical, 5-6 unit saturated heterocyclyl.
6-14 unit heterocyclic radical, refer to that sharing two adjacent atoms containing 6-14 annular atoms (wherein at least containing a heteroatoms) each other by two or more ring texturees couples together the condensed cyclic structure formed, comprises 6-14 membered unsaturated heterocycle base, 6-14 unit fractional saturation heterocyclic radical, the first saturated heterocyclyl of 6-14.
6-14 membered unsaturated heterocycle base, refer to that whole rings is undersaturated condensed cyclic structure, as the structure that benzo 3-8 membered unsaturated heterocycle base is formed, the structure etc. that 3-8 membered unsaturated heterocycle base 3-8 membered unsaturated heterocycle base are formed, specific examples includes but not limited to: benzofuryl, benzisoxa furyl, benzothienyl, indyl, benzoxazolyl, benzimidazolyl-, indazolyl, benzotriazole base, quinolyl, isoquinolyl, acridyl, phenanthridinyl, benzo pyridazinyl, phthalazinyl, quinazolyl, quinoxalinyl, phenol piperazine base, pteridine radicals, purine radicals, naphthyridinyl etc.
6-14 unit fractional saturation heterocyclic radical, refer to the condensed cyclic structure at least containing a fractional saturation ring, as the structure that benzo 3-8 unit fractional saturation heterocyclic radical is formed, the structure etc. that 3-8 unit's fractional saturation heterocyclic radical 3-8 unit fractional saturation heterocyclic radical are formed, specific examples includes but not limited to: 1,3-dihydro benzo furyl, benzo [d] [1.3] dioxa cyclopentenyl, isoindoline base, chromanyl, 1,2,3,4-Pyrrolidine is [3,4-c] pyrryl etc. also.
6-14 unit saturated heterocyclyl, refer to that whole rings is the condensed cyclic structure of saturated rings, as 3-8 unit's saturated heterocyclyl and 3-8 unit saturated heterocyclyl the structure that formed, specific examples includes but are not limited to: tetramethylene Pyrrolidine base, pentamethylene Pyrrolidine base, azetidine imidazolidyl etc.
" 3-14 unit cycloalkyl " of the present invention, " 6-14 unit aryl ", " 3-14 unit heterocyclic radical " can also by oxo or sulfo-, described oxo is one or more atoms quilt-C (the O)-replacement on finger ring, such as 2-pyriconyl, 4-pyriconyl, 2H-pyran-2-one base etc.Described sulfo-is one or more atoms quilt-C (the S)-replacement on finger ring.
" 3-8 unit cycloalkyl C of the present invention 1-6alkyl ", " 3-8 unit cycloalkyl C 2-6thiazolinyl ", " 3-8 unit cycloalkyl C 2-6alkynyl ", refer to the previously described C of previously described 3-8 unit's cycloalkyl substituted 1-6alkyl, C 2-6thiazolinyl, C 2-6the group that alkynyl is formed.
6-14 unit aryl and 3-8 unit cycloalkyl, 6-14 unit aryl and 3-8 unit heterocyclic radical, 6-8 unit aryl and 3-8 unit cycloalkyl, 6-8 unit aryl and 3-8 unit heterocyclic radical, phenyl and 3-8 unit heterocyclic radical, phenyl and 3-8 unit cycloalkyl, phenyl and 5-6 unit heterocyclic radical, phenyl 5-6 unit cycloalkyl, phenyl and in 5-6 membered unsaturated heterocycle base " and ", refer to the condensed cyclic structure that two or more rings share two adjacent atoms and formed.
The preparation method of application claims protection (I) compound, formula (I) compound can adopt the method that describes in following flow process and/or other technology known to persons of ordinary skill in the art to synthesize, but is not limited only to following methods.
By raw material 1, raw material 2 and suitable reagent, be obtained by reacting formula (I) compound under suitable conditions.R in upper reaction equation 1, R 2, Cy 1, Cy 2as defined hereinabove, X represents chlorine, bromine, iodine etc.If desired, can protect needing the functional group of protection, after this sloughing blocking group by ordinary method; If desired, according to the character of compound, suitable replacement can be carried out to reaction solvent; If desired, according to the character of compound, increase the preparation of some compound, such as the preparation of raw material 1.
" pharmacy acceptable salt " of formula (I) compound, refer to when formula (I) compound be negatively charged ion or have can become negatively charged ion functional group (such as,-COOH), salt can be formed with suitable inorganic cation or organic cation; Be positively charged ion when formula (I) compound or have and can become cationic functional group (such as ,-NH 2), salt can be formed with suitable inorganic anion or organic cation.
" steric isomer " of formula (I) compound, refer to when formula (I) compound exists other unsymmetrical carbons, during carbon-carbon double bond etc., its all enantiomers, diastereomer, racemization isomer, cis-trans-isomer, tautomer, geometrical isomer, epimer and composition thereof of producing, include in the present invention.
" the deuterated thing " of application claims protection (I) compound, when the hydrogen atom in compound is by its isotropic substance deuterium (symbol is D) some or all of replacement, the material produced also belongs to category of the present invention.
Formula (I) compound, its pharmacy acceptable salt, its steric isomer or its deuterated thing, pharmaceutically acceptable pharmaceutical preparation can be made with one or more pharmaceutical carriers, be applied in modes such as oral, parenterals the patient needing this treatment.During oral administration, conventional solid preparation can be made, as tablet, capsule, pill, granule etc. with the weighting agent of routine, tackiness agent, disintegrating agent, lubricant, thinner etc.; 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.
Present invention also offers formula (I) compound, its pharmacy acceptable salt, its steric isomer or its deuterated thing and treat and/or prevent the application had the suppression of mTOR activity in the medicine of the proliferative disease of response in preparation.
Described proliferative disease is such as:
(1) cancer, comprises bladder cancer, the cancer of the brain, mammary cancer, colon and rectum carcinoma, kidney, liver cancer, lung cancer, ovarian cancer, carcinoma of the pancreas, adrenal carcinoma, prostate cancer, cancer of the stomach, carcinoma of vagina, cervical cancer, carcinoma of endometrium, thyroid carcinoma and skin carcinoma etc.;
(2) lymphohematological knurl, comprises acute lymphoblastic leukemia, B cell lymphoma and Burketts lymphoma etc.;
(3) marrow hemopoietic system knurl, comprises acute and chronic myelocytic leukemia and promyelocytic leukemia;
(4) knurl of mesenchymal derivation, comprises fibrosarcoma and rhabdosarcoma;
(5) other tumours, comprise melanoma, spermocytoma, teratoma, neuroblastoma and neurospongioma.
the cell in vitro inhibit activities of experimental example 1 the compounds of this invention
Trial-product contrast medicine OSI-027, with reference to WO2007061737 preparation;
The compounds of this invention, self-control, its chemical name and structural formula are shown in the preparation embodiment of each compound;
Experimental technique
1. reagent and compound preparation configuration PBS, XTT testing liquid, taxol liquid storage and gradient dilution solution, test compounds liquid storage and gradient dilution solution;
2. Cell Culture Cells recovery, goes down to posterity, frozen;
3. plating cells prepares cell suspension, cell suspension is added 96 orifice plate every hole 100 μ l, 37 DEG C, 5%CO 2overnight incubation in cell culture incubator;
4. medicine adds in Tissue Culture Plate by drug treating, puts into CO 2cultivate 72 hours in cell culture incubator;
5.XTT method detects cell viability and adds XTT working fluid, at CO 2place 2 hours in cell culture incubator, put into microplate reader and read 450nm extinction;
6. data processing
1) % suppression=(reading Vehicle-reading compound)/(reading Vehicle-reading Positive control) × 100%;
2) input GraphPad Prism5.0 mapping, obtain curve and IC 50;
Experimental result
Table 1. the compounds of this invention cell in vitro determination of activity (IC 50)
Trial-product U87MG cell (nM) A549 cell (nM)
OSI-027 ++ ++
Compound 1 ++ +++
Compound 2 +++ +++
Compound 5 +++ +++
+++ represent IC 50for 0-300nM, ++ represent IC 50for 0.3-3 μM ,+represent IC 50for > 3 μMs; In the present invention, to the inhibit activities of U87MG and A549 cancer cells at IC 50for≤3000nm is the compound that the present invention is good, and≤300nm's is better compound.
Experiment conclusion
The compounds of this invention 1 is for the inhibit activities of U87MG cell with to contrast medicine suitable, and the inhibit activities for A549 cell is better than contrast medicine; The inhibit activities of compound 2 and compound 5 pairs of U87MG and A549 cells is all better than contrast medicine, illustrates that the present invention has significant progress.
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.
Embodiment 1 3-(1,3-dioxoisoindolin-2-base)-2 hydroxy propanoic acid methyl esters (M2)
By M1-1 (39.3g, 0.267mol) with M1-2 (5.44g, 0.029mol) be dissolved in DMF (200mL), under room temperature, DMF (100mL) solution of M1 (30g, 0.29mol) be added dropwise in above-mentioned reaction solution.Drip to finish and be warming up to 900 DEG C of stirring reactions and spend the night.Reaction solution is poured into water with dichloromethane extraction, and organic phase semi-saturation brine It four times, to obtain M2 (35g) crude product with concentrated after anhydrous sodium sulfate drying.
Embodiment 2 3-(1,3-dioxoisoindolin-2-base)-Acetylformic acid methyl esters (M3)
At ice bath 0 DEG C, M2 (35g, 0.14mol) is dissolved in dry methylene dichloride (300mL).Dess-Martin reagent (711g, 0.168mol) is added above-mentioned reaction solution in batches.After adding, reaction solution rises to room temperature and continues stirring reaction 2 hours.Add 500mL ethyl acetate and form suspension liquid, continue stirring and filter after 10 minutes, after filtering, concentrated filtrate obtains crude product, obtains M3 (25g, 72%) after recrystallizing methanol.
Embodiment 3 2-((5-oxo-3-sulfo--2,3,4,5-tetrahydrochysene-1,2,4-triazine-6-base) methyl) isoindoline-1,3-diketone (M4)
At ice bath 0 DEG C, M3-1 (10.1g, 0.11mol) is joined in acetic acid (100mL) solution of M3 (25g, 0.10mol).At being warming up to 120 DEG C after adding, reaction is spent the night.Reacting liquid filtering, filter cake acetic acid washs, and vacuum-drying obtains M4 (15g, 51.5%).
Embodiment 4 2-((5-oxo-4,5-dihydro-1,2,4-triazine-6-base) methyl) isoindoline-1,3-diketone (M5)
M4 (15g, 52mmol) is dissolved in ethanol (300mL), adds under Raney's nickel (3g) nitrogen protection back flow reaction 4 hours.Filter gained suspension liquid after being chilled to room temperature, filter cake refluxes after adding ethanol, and filter, after merging filtrate, concentrating under reduced pressure obtains M5 (10g, 75.1%).
Embodiment 5 6-(aminomethyl)-1,2,4-triazine-5 (4H)-one (M6)
M5 (10g, 39mmol) is dissolved in the mixed solution of 100mL methylene dichloride and 100mL ethanol, adds hydrazine hydrate (5.58g, 117mmol), add rear reaction solution stirred overnight at room temperature.Pressurization steaming desolventizes resistates and obtain M6 (3.2g, 65%) after methanol crystallization.
Embodiment 6 7-methoxyl group-2-(4,4,5,5 ,-tetramethyl--1,3,2-dioxaborolan-2-base)-1H-indoles (M8)
By M7 (20g; 0.136mol); M7-1 (20.14g; 81.6mmol); methoxyl group (cyclooctadiene) closes iridium dimer (0.45g) and 4,4-di-t-butyl dipyridyl (0.36g) and adds the backflow of 200mL normal hexane stirred under nitrogen atmosphere and spend the night.Filter, after filtrate is concentrated, obtain thick product, after preparation liquid phase purifying, obtain M8 (21g, 56.7%).
Embodiment 7 (1r, 4r)-hexanaphthene-Isosorbide-5-Nitrae-dicarboxylic acid methylester (M10)
At 0 DEG C, thionyl chloride (60mL) is slowly added drop-wise to (1L) in methyl alcohol, drips to finish and react 1 hour in stirred at ambient temperature, added by M9 (50g, 0.29mol) in above-mentioned reaction solution, stirred at ambient temperature reaction is spent the night.Remove solvent under reduced pressure, residue from dichloromethane dissolves rear saturated sodium bicarbonate aqueous solution and salt solution washs successively.Concentrate to obtain crude product after organic phase anhydrous sodium sulfate drying, after normal hexane crystallization, obtain M10 (55g, 94.1%).
Embodiment 8 (1r, 4r)-4-(methoxycarbonyl) hexahydrobenzoic acid (M11)
By M10 (25g, 0.125mol) be dissolved in tetrahydrofuran (THF) (200mL), by sodium methylate (6.95g, 0.128mol) water-soluble (2.25g, 0.125mol) He in methyl alcohol (17.8g, 0.556mol) instill in above-mentioned reaction solution at ice bath 0 DEG C.Stirring continues reaction 3 hours after rising to room temperature.Add normal hexane (500mL) and form suspension liquid, stir at 0 DEG C after 30 minutes and filter, gained solid n-hexane, adds concentrated hydrochloric acid (15mL) at ice bath 0 DEG C, water (150mL) and methylene dichloride (250mL) stir separatory after 10 minutes.Revolve steaming after the drying of organic phase anhydrous slufuric acid ammonium, products therefrom obtains M11 (10g, 43%) after normal hexane crystallization.
Embodiment 9 (1r, 4r)-1-(2,5-dioxo pyrroles-1-base) oxygen carbonyl-cyclohexane-4-carboxylate methyl ester (M12)
M11 (29g, 0.155mol) with M11-1 (17.9g, 0.156mmol) be dissolved in tetrahydrofuran (THF), 0 DEG C by DCC (32.81g, tetrahydrofuran (THF) (300mL) solution 0.159mol) instills in above-mentioned reaction solution, continues to react after stirring rises to room temperature to spend the night.Be warming up to 45 DEG C of reactions 3 hours, filtered while hot, filtrate reduced in volume.Resistates obtains M12 (19g, 42.7%) with after Virahol crystallization.
Embodiment 10 (1r, 4r)-4-((5-oxo-4,5-dihydro-1,2,4-triazine-6-base) methylcarbamoyl) hexahydrobenzoic acid methyl esters (M13)
By M6 (3.83g, 30.38mmol) (30mL) soluble in water, add sodium bicarbonate (5.10g, 60.77mmol), by M12 (17.2g, mixed solution 60.77mmol) being dissolved in tetrahydrofuran (THF) and acetonitrile (1: 1,60mL) instills above-mentioned reaction solution.Stirred overnight at room temperature.Steaming desolventizes rear resistates and blends in methyl alcohol (300mL), filters, and filtrate concentrates to obtain crude product M13 (8g, 44.7%).
Embodiment 11 (1r, 4r)-4-(4-oxo-3,4-glyoxalidine is [1,5-f] [1,2,4] triazine-7-base also) hexahydrobenzoic acid methyl esters (M14)
Phosphorus oxychloride (72.8g, 480.8mmol) be added dropwise in ethylene dichloride (100mL) solution of M13 (8g, 27.2mmol), stirring and refluxing reaction is spent the night.Steaming desolventizes, and adds ethyl acetate (500mL) and forms suspension liquid, and filter, filter cake ethyl acetate is washed, and resistates is extracted with ethyl acetate three times after being dissolved in saturated sodium bicarbonate solution, merges organic layer and drying after brine It, concentrated.Resistates obtains M14 (5g, 66.5%) after column chromatography purification.
Embodiment 12 (1r, 4r)-4-(5-iodo-4-oxo-3,4-glyoxalidine is [1,5-f] [1,2,4] triazine-7-base also) hexahydrobenzoic acid methyl esters (M15)
Added in DMF (100mL) solution of M14 (4g, 14.49mmol) by NIS (34.66g, 144.9mmol) (N-N-iodosuccinimide), stirring at room temperature reacts 2 days.Methylene dichloride (500mL) is added after having reacted, add the washing of saturated sodium sulfite solution, organic phase half saturated salt solution (800mL) washs three times, dry and concentratedly to obtain thick product, M15 (4.5g, 77.3%) is obtained after recrystallizing methanol.
Embodiment 13 (1r, 4r)-4-(4-amino-5-iodine imidazo [1,5-f] [1,2,4] triazine-7-base) hexahydrobenzoic acid methyl esters (M16)
By phosphorus oxychloride (2.83g, 18.63mol) instill M15-1 1H-1,2,4-triazole (3.86g, in pyridine (50mL) solution 55.97mmol), stirring at room temperature adds M15 (2.5g, 6.21mmol) after reacting 3 hours, reaction solution stirred overnight at room temperature.React with excessive 2N ammonia aqueous isopropanol cancellation, reaction solution stirring at room temperature 2 hours, remove solvent under reduced pressure, resistates is dissolved in saturated sodium bicarbonate solution (500mL), extract three times by ethyl acetate (200mL), after merging organic phase, use saturated common salt water washing, after dry, concentrate to obtain crude product, M16 (2g, 80.3%) is obtained after refined methanol recrystallization.
Embodiment 14 (1r, 4r)-4-(5-(7-methoxyl group-1H-indoles-2-base)-4-(methyl amido) imidazo [1,5-f] [1,2,4] triazine-7-base) hexahydrobenzoic acid (compound 1)
(1) (1r, 4r)-4-(the iodo-4-of 5-(methyl amido) imidazo [1,5-f] [1,2,4] triazine-7-base) hexahydrobenzoic acid methyl esters (M18)
By phosphorus oxychloride (0.57g, 3.72mol) instill in pyridine (50mL) solution of M15-1 (0.77g, 11.19mmol), stirring at room temperature adds M15 (0.5g after reacting 3 hours, 1.24mmol), reaction solution stirred overnight at room temperature.React with excessive 2N methylamine aqueous isopropanol cancellation, reaction solution stirring at room temperature 2 hours, remove solvent under reduced pressure, resistates is dissolved in saturated sodium bicarbonate solution (100mL), extract three times by ethyl acetate (100mL), after merging organic phase, use saturated common salt water washing, after dry, concentrate to obtain crude product, M18 (0.35g, 67.8%) is obtained after refined methanol recrystallization.
(2) (1r, 4r)-4-(5-(7-methoxyl group-1H-indoles-2-base)-4-(methyl amido) imidazo [1,5-f] [1,2,4] triazine-7-base) hexahydrobenzoic acid methyl esters (M19)
M18 (350mg; 0.85mmol); M8 (279mg; 1.02mmol); sodium carbonate (270mg; 2.55mmol) He four-triphenyl phosphorus palladium (97mg, 0.085mmol) is dissolved in the mixed solution of dioxane (50mL) and water (20mL), is warming up to 80 DEG C of reactions 3 hours under nitrogen protection; after being chilled to room temperature; reaction solution ethyl acetate (200mL) extraction, separates organic phase, uses saturated common salt water washing; anhydrous sodium sulfate drying; obtain crude product after concentrating under reduced pressure, after column chromatography purification, obtain M19 (300mg, 81.9%).
(3) preparation of compound 1
Water (2mL) solution of sodium hydroxide (138mg, 3.45mmol) is added drop-wise in methyl alcohol (5mL) solution of M19 (300mg, 0.69mmol), reaction solution stirred overnight at room temperature.Reaction solution adjusts pH=3, is extracted with ethyl acetate, and organic phase drying concentrates to obtain compound 1 (200mg, 68.9%) afterwards.
Molecular formula: C 22h 24n 6o 3molecular weight: 420.46
1H NMR(400MHz DMSO)δ7.96(s，1H)，7.18(d，1H)，6.96(t，1H)，6.70(d，2H)，3.94(s，3H)，3.20-3.17(m，1H)，3.02(s，3H)，2.28(t，1H)，2.05(d，4H)，1.77-1.68(m，2H)，1.54-1.48(m，2H)
Embodiment 15 (1r, 4r)-4-(4-hydroxyl-5-(7-methoxyl group-1H-indoles-2-base) imidazo [1,5-f] [1,2,4] triazine-7-base) hexahydrobenzoic acid (compound 2)
M15 (300mg, 0.74mmol), compound 8 (244mg, 0.89mmol), sodium carbonate (235mg, 2.22mmol) He four-triphenyl phosphorus palladium (84mg, 0.074mmol) be dissolved in the mixed solution of dioxane (5mL) and water (2mL), 80 DEG C of reactions 5 hours are warming up under nitrogen protection, after being chilled to room temperature, reaction solution adds the hydrochloric acid (5mL) of ethyl acetate (20mL) and 0.1N, separate organic phase, use saturated common salt water washing, anhydrous sodium sulfate drying, crude product (120mg) is obtained after concentrating under reduced pressure, compound 2 (70mg is obtained after preparation liquid phase purifying, 23.1%).
Molecular formula: C 21h 21n 5o 4molecular weight: 407.42
1H NMR(400MHz DMSO)δ12.10(s，2H)，11.78(s，1H)，7.97(s，1H)，7.17(d，1H)，7.04(s，1H)，6.96(t，1H)，6.71(d，1H)，3.95(s，3H)，3.19-3.12(m，1H)，2.38-2.33(m，1H)，2.05-2.03(m，4H)，1.78-1.70(m，2H)，1.54-1.45(m，2H)
Embodiment 16 (1r, 4r)-4-(4-amino-5-(2,3-dihydro-1H-indenes-5-base) imidazo [1,5-f] [1,2,4] triazine-7-base) hexahydrobenzoic acid (compound 5)
M16 (300mg, 0.75mmol), M21 (219mg, 0.9mmol), sodium carbonate (238mg, 2.25mmol) He four-triphenyl phosphorus palladium (85mg, 0.75mmol) be dissolved in the mixed solution of dioxane (5mL) and water (2mL), 80 DEG C of reactions 5 hours are warming up under nitrogen protection, after being chilled to room temperature, reaction solution adds ethyl acetate (20mL), separate organic phase, wash successively with water and saturated aqueous common salt, anhydrous sodium sulfate drying, crude product is obtained after concentrating under reduced pressure, compound 5 (110mg is obtained after preparation liquid phase purifying, 39%).
Molecular formula: C 21h 23n 5o 2molecular weight: 377.44
1H NMR(400MHz DMSO)δ7.96(s，1H)，7.48(s，1H)，7.37(s，2H)，3.24-3.18(m，1H)， 2.96-2.91(m，4H)，2.33-2.28(m，1H)，2.09-2.03(m，6H)，1.76-1.66(m，2H)，1.53-1.47(m，2H) 。

Claims (4)

1. logical compound shown in formula I, its pharmacy acceptable salt, its steric isomer or its deuterated thing:
Wherein
R 1for-NH 2,-NR dr eor-OR d, R dfor hydrogen or C 1-2alkyl, R efor C 1-2alkyl;
Work as R 1for-NH 2time, Cy 1for not to be substituted or by 1 R 3replace
Work as R 1for-NR dr eor-OR dtime, Cy 1for not to be substituted or by 1 R 3replace
R 2for hydrogen;
Cy 2for not to be substituted or by 1 R 3the pentamethylene base replaced, cyclohexyl;
R 3for hydrogen ,-OR c,-CO 2h;
R cfor hydrogen, methyl, ethyl.
2. compound, its pharmacy acceptable salt, its steric isomer or its deuterated thing as claimed in claim 1:
3. comprise the pharmaceutical composition of the compound described in any one of claim 1 ~ 2, its pharmacy acceptable salt, its steric isomer or its deuterated thing and one or more pharmaceutical carriers, it is characterized in that described pharmaceutical composition is for clinically or pharmaceutically acceptable arbitrary formulation.
4. the compound described in any one of claim 1 ~ 2, its pharmacy acceptable salt, its steric isomer or its deuterated thing treat and/or prevent the application had the suppression of mTOR activity in the medicine of the proliferative disease of response in preparation.
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Inventor after: Wang Aichen

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