CN102617502A - Benzoxazole derivatives and application of benzoxazole derivatives to medicines - Google Patents
Benzoxazole derivatives and application of benzoxazole derivatives to medicines Download PDFInfo
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- CN102617502A CN102617502A CN2012100731440A CN201210073144A CN102617502A CN 102617502 A CN102617502 A CN 102617502A CN 2012100731440 A CN2012100731440 A CN 2012100731440A CN 201210073144 A CN201210073144 A CN 201210073144A CN 102617502 A CN102617502 A CN 102617502A
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- RHJNHPNEUDZJES-UHFFFAOYSA-N NC(c1c2[o]c(S)nc2cc(F)c1)=O Chemical compound NC(c1c2[o]c(S)nc2cc(F)c1)=O RHJNHPNEUDZJES-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention provides benzoxazole derivatives with structures show as a formula (I) and application of the compounds serving as a poly (adenosine diphosphate (ADP)-ribose) polymerase active inhibitor. The invention also provides a method for preparing the compounds. The compounds have a good inhibiting effect on poly (ADP-ribose) polymerase, and can be applied to medicines for treating diseases relevant with the poly (ADP-ribose) polymerase.
Description
Technical field
The present invention relates to biomedicine field, be specifically related to one type of benzoxazole derivative with formula (I) structure, and the medicinal use of these compounds.
Background technology
PARP; Poly (ADP-ribose) polymerase; Promptly gathering (adenylic acid(AMP) di-phosphate ribose) polysaccharase, be present in all mammalian cells and the most of eukaryotic cell, is the modifying enzyme after the class protein translation; Mainly be responsible for utilizing NAD+ that ADP ribose unit is added to DNA (on the perhaps various receptor proteins), participate in gathering the ADP ribosylation process.The proliferation and differentiation of therefore, PARP and gene transcription regulation and control, proteic degraded and cell etc. are closely related.Discover; PARP is promoting DNA to repair; The control rna transcription; Regulate necrocytosis and bringing into play important effect with aspects such as controlling immunne response, these effects impel the treatment that utilizes the PARP suppressor factor might be used for some diseases, and these diseases comprise ischemic damage and reperfusion damage, septic shock, neurotoxicity, inflammatory diseases, multiple sclerosis, HIV, hepatitis B, mellitus and cancer etc.The treatment cancer is an extremely important application of PARP suppressor factor, and the PARP suppressor factor can shift and play a role through apoptosis, the restriction growth of cancers that increases cancer cells; PARP can also reach synergistic function through strengthening the result of treatment of the radiation and chemotherapy in the cancer therapy; In addition, the PARP suppressor factor has better expectation curative effect in the cancer of BRCA1 or BRCA2 defective, sudden change.
Summary of the invention
The object of the present invention is to provide the benzoxazole derivative shown in a kind of general formula (I) or its pharmacy acceptable salt:
Wherein:
X is selected from-SR
2Or-NR
3R
4
R
1Be halogen;
M is 0,1,2 or 3;
R
2Be (CH
2)
nR
5
R
3And R
4Be independently selected from hydrogen, C
1-C
6Alkyl, C
3-C
8Naphthenic base or C
6-C
10Aryl, said C
1-C
6Alkyl, C
3-C
8Naphthenic base, C
6-C
10Aryl is alternatively by one or more halogen, C of being selected from
1-C
6Alkyl, C
6-C
10Aryl or C
5-C
10The substituting group of heteroaryl replaces;
Perhaps R
3, R
4Form 5 to 8 yuan of rings with the nitrogen-atoms that they connected, said 5 to 8 yuan of rings are saturated or unsaturated, comprise and R
3, R
4The nitrogen-atoms that is connected contains one or more heteroatomss that are selected from O, S or N independently of one another interior in said 5 to 8 yuan of rings, and said 5 to 8 yuan of rings are alternatively by one or more halogen, C of being selected from
1-C
6Alkyl, C
6-C
10Aryl or C
5-C
10The substituting group of heteroaryl replaces;
N is 0,1,2,3,4,5 or 6;
R
5Be selected from hydrogen, halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, C
4-C
8Heterocyclylalkyl, C
6-C
10Aryl, C
5-C
10Heteroaryl, C
2-C
6Thiazolinyl, C
3-C
8Naphthenic base ,-C (O)-R
6Or-C (O)-O-R
7, wherein said C
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, C
4-C
8Heterocyclylalkyl, C
6-C
10Aryl, C
5-C
10Heteroaryl, C
2-C
6Thiazolinyl, C
3-C
8Naphthenic base ,-C (O)-R
6Alternatively by one or more optional halogens, C
1-C
6Alkyl ,-C (O)-R
8,-C (O)-O-R
9, nitro, cyanic acid, amino, C
1-C
6Alkoxyl group, C
6-C
10Aryl or C
6-C
10Aryloxy replaces;
R
6, R
7, R
8, R
9Be C independently
1-C
6Alkyl.
Further preferably, structure provided by the invention is suc as formula the compound shown in (I) or its pharmacy acceptable salt, wherein:
R
1Be selected from fluorine or chlorine;
M is 0 or 1;
R
2Be (CH
2)
nR
5
N is 0,1,2,3,4,5 or 6;
R
3And R
4Be independently selected from hydrogen, C
1-C
6Alkyl, C
3-C
8Naphthenic base or C
6-C
10Aryl;
Perhaps R
3, R
4Form 6 yuan of rings with the nitrogen-atoms that they connected, said 6 yuan of rings are saturated or unsaturated, comprise and R
3, R
4The nitrogen-atoms that is connected contains one or more heteroatomss that are selected from O, S or N independently of one another interior in said 6 yuan of rings; Said 6 yuan of heterocycles are alternatively by one or more optional C
1-C
6Alkyl, phenyl, phenmethyl or substituted-phenyl replace, and said substituted-phenyl is that phenyl is independently by one or more optional halogens, C
1-C
6Alkyl, nitro, cyanic acid, amino, C
1-C
6Alkoxyl group replaces;
R
5Be selected from hydrogen, halogen, C
1-C
6Alkyl, C
3-C
8Naphthenic base, C
1-C
6Alkoxyl group ,-C (O)-R
6,-C (O)-O-R
7, phenyl, phenoxy, benzoxazolyl, cyclopropyl, vinyl, morpholinyl, pyrrolidyl, piperidyl or piperazinyl, wherein said C
1-C
6Alkyl, C
3-C
8Naphthenic base, C
1-C
6Alkoxyl group ,-C (O)-R
6, phenyl, phenoxy, benzoxazolyl, morpholinyl, pyrrolidyl, piperidyl, piperazinyl be independent alternatively by one or more optional halogens, C
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-C (O)-R
8,-C (O)-O-R
9, nitro, cyanic acid, amino, phenyl or phenoxy replace;
R
6, R
7, R
8, R
9Be C independently
1-C
6Alkyl.
Further preferred, structure provided by the invention is suc as formula the compound shown in (I) or its pharmacy acceptable salt, wherein:
R
1Be fluorine;
M is 1;
R
2Be (CH
2)
nR
5
N is 0,1,2,3,4,5 or 6;
R
3And R
4Be independently selected from hydrogen, methyl, ethyl, propyl group, sec.-propyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
Perhaps R
3, R
4Form 6 yuan of saturated rings with the nitrogen-atoms that they connected, comprise and R
3, R
4The nitrogen-atoms that is connected contains one or more heteroatomss that are selected from O, S or N independently of one another interior in said 6 yuan of rings; Said 6 yuan of heterocycles are alternatively by one or more optional C
1-C
6Alkyl, phenyl or benzyl replace;
R
5Be selected from hydrogen, halogen, C
1-C
4Alkyl, C
1-C
4Alkoxyl group ,-C (O)-R
6, phenyl, phenoxy, benzoxazolyl, cyclopropyl, vinyl, morpholinyl, pyrrolidyl, piperidyl or piperazinyl, wherein said C
1-C
4Alkyl, C
1-C
4Alkoxyl group ,-C (O)-R
6, phenyl, phenoxy, benzoxazolyl, morpholinyl, pyrrolidyl, piperidyl, piperazinyl be independent alternatively by one or more optional halogens, C
1-C
4Alkyl, C
1-C
4Alkoxyl group ,-C (O)-O-R
9, nitro, cyanic acid, amino, phenyl or phenoxy replace;
R
6, R
9Be C independently
1-C
4Alkyl.
Compound preferred compound shown in the general formula of the present invention (I) includes but not limited to:
The invention still further relates to a kind of medicinal compsns, the general formula compound (I) that comprises the free form of treating significant quantity or pharmaceutical acceptable salt is as activeconstituents; One or more medicinal carrier substances and/or thinner.Also can comprise general formula compound provided by the invention (I) and pharmaceutically acceptable carrier, vehicle or thinner.
The invention still further relates to a kind of medicinal compsns of combination, comprise the free form of significant quantity or the general formula compound of pharmaceutical acceptable salt (I); One or more medicinal carrier substances and/or thinner.
Benzoxazole derivative, pharmaceutical composition shown in the general formula that the present invention relates to (I) can be applicable to treat the disease of improving because of the active inhibition of PARP, and these diseases are selected from vascular disease, septic shock, ischemic injuries, neurotoxicity, hemorrhagic shock, inflammatory diseases, multiple sclerosis.
The supplementary means that benzoxazole derivative shown in the general formula that the present invention relates to (I), pharmaceutical composition can be applicable to oncotherapy perhaps is used to strengthen radiotherapy or chemotherapy to tumor treatment.
Benzoxazole derivative, pharmaceutical composition shown in the general formula that the present invention relates to (I) can be applicable to lack the pharmaceutical use of the individuation cancer therapy that the dependent dna double splitting of chain of homologous recombination (HR) (DSB) repairs.
As preferably, said cancer contains one or more cancer cells that lowers or lose with respect to normal cell through the ability of HR DNA plerosis DSB.
As preferably, said cancer be selected from have BRCA1 or BRCA2 defective, the isophenous cancer of suddenling change.
As preferably, said cancer is selected from cancers such as mammary cancer, ovarian cancer, carcinoma of the pancreas or prostate cancer.
In order to check the exposure level of compound provided by the invention, adopt biochemical horizontal enzymic activity to test to confirm the activity of all cpds of the present invention to the PARP enzyme for the PARP enzyme.
PARP is a kind of post transcriptional modificaiton enzyme; Dna damage can activate this enzyme; PARP catalytic process in vivo mainly is poly (ADP-ribose) process that a kind of NAD+ relies on, and its substrate mainly is some nucleoprotein that comprise PARP, and histone is a kind of for wherein; This experiment through measure PARP under the NAD+ effect to encapsulating Histonepoly in 96 orifice plates (ADP-ribose) degree; It is active to measure PARP, correspondingly measure the effect of PARP suppressor factor after PARP active, thereby estimate this compounds to the active inhibition degree of PARP.
Only if the phase counter-statement is arranged, the following term that is used in specification sheets and the claim has following implication.
Among the present invention, term " C
1-C
6Alkyl " be meant the saturated monovalence alkyl that has straight or branched part and contain 1 to 6 carbon atom.This type of examples of groups includes but not limited to methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-and the tertiary butyl." C correspondingly
1-C
4Alkyl " be meant the saturated monovalence alkyl that has straight or branched part and contain 1 to 4 carbon atom.
Term " C
3-C
8Naphthenic base " be meant to have the saturated ring structure of 3 to 8 carboatomic ring atoms altogether.This type of examples of groups includes but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
Term " C
2-C
6Thiazolinyl " be meant the unsaturated alkyl that contains at least one carbon-Tan Shuanjian that has straight or branched part and contain 2 to 6 carbon atoms.This type of examples of groups includes but not limited to vinyl (CH=CH
2), propenyl (CH=CH-CH
3), allyl group (CH2-CH=CH
2).
Term " C
6-C
10Aryl " be meant and contain the deriving of 6 to 10 carbon atoms to the group of aromatic hydrocarbons.This type of examples of groups includes but not limited to phenyl, benzyl, naphthyl.
Term " C
5-C
10Heteroaryl " be meant in its ring and contain 5 to 10 carbon atoms and contain 1 to 4 heteroatomic aromatic heterocyclic group that is selected from O, S and N independently of one another.Condition is not contain two adjacent O atoms or two adjacent S atoms on the ring of said group.This heterocyclic group comprises the fused benzo ring system.C
5-C
10The instance of heteroaryl includes but not limited to pyridyl, imidazolyl, pyrimidyl, pyrazolyl, triazolyl, pyrazinyl, tetrazyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrryl, quinolyl, isoquinolyl, indyl, benzimidazolyl-, benzofuryl, phthalazinyl, pseudoindoyl, purine radicals, benzothienyl, benzothiazolyl, benzoxazolyl
Said C
5-C
10That heteroaryl can connect for C-under possible situation or the N connection.
Term " C
4-C
8Heterocyclic radical " be meant non-aromatics, monocycle or encircle or the volution group more; this group has 4 to 8 carbon atoms and 1 to 4 heteroatoms that is selected from O, S and N independently of one another in its member ring systems, condition is that the ring of said group does not contain two adjacent O atoms or two adjacent S atoms.Work as C
4-C
8When heterocyclic radical contained sulphur atom, said sulphur atom can be by one or two Sauerstoffatom oxidation.C
4-C
8The instance of heterocyclic radical includes but not limited to that piperazinyl refers to group
Morpholinyl
Piperidyl
Pyrrolidyl
Tetrahydrofuran base, dihydrofuran-base, tetrahydro-thienyl, THP trtrahydropyranyl, dihydro pyranyl.
Term " halogen " and " halo " are meant fluorine, chlorine, bromine, iodine.
Term " C
6-C
10Aryloxy " be meant-O-C
6-C
10Aryl.
Term " C
1-C
6Alkoxyl group " be meant-O-C
1-C
6Alkyl." C correspondingly
1-C
4Alkoxyl group " be meant-O-C
1-C
4Alkyl.
" cyanic acid " expression-CN group.
" amino " expression-NH
2Group.
" nitro " expression-NO
2Group.
The meaning of so-called " randomly " is meant that the incident of subsequent descriptions or situation may also maybe not can take place, and this description comprises that things or situation may also maybe not can take place, and this description comprises that things or situation take place and two kinds of situation do not take place.
In some embodiments, " replaced " the identical or different group replacement that, two, three of being meant in specified atom or group or four Wasserstoffatomss are selected in the group of designated scope respectively by one or more groups.
" pharmacy acceptable salt " expression keeps the biological effectiveness of parent compound and those salt of character.This type salt comprises:
(1) with sour salify; Free alkali through parent compound and mineral acid or organic acid reaction get; Mineral acid comprises hydrochloric acid, Hydrogen bromide, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid and perchloric acid etc., and organic acid comprises acetate, propionic acid, vinylformic acid, oxalic acid, (D) or (L) oxysuccinic acid, fumaric acid, toxilic acid, hydroxy-benzoic acid, gamma-hydroxybutyric acid, methoxybenzoic acid, phthalic acid, methylsulfonic acid, ethyl sulfonic acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, tosic acid, Whitfield's ointment, tartrate, Hydrocerol A, lactic acid, racemic melic acid, succsinic acid or propanedioic acid etc.
(2) salt that is present in that acid proton in the parent compound is replaced by metals ion or is generated with the organic bases ligand compound; The metal example is alkalimetal ion, alkaline earth metal ion or aluminum ion for example, and organic bases is thanomin, diethylolamine, trolamine, Trometamol, N-NMG etc. for example.
" pharmaceutical composition " refers to one or more or its pharmacy acceptable salt, solvolyte, hydrate or prodrug and other chemical ingredients in the compound among the present invention, and for example pharmaceutically acceptable carrier mixes.The purpose of pharmaceutical composition is to promote administration to give the process of animal.
" pharmaceutical carrier " refers to organism do not caused tangible pungency and do not disturb the non-active ingredient in the pharmaceutical composition of biological activity and character of the compound that gives, such as but not limited to: lime carbonate, calcium phosphate, various sugar (for example lactose, N.F,USP MANNITOL etc.), starch, Schardinger dextrins, Magnesium Stearate, Mierocrystalline cellulose, magnesiumcarbonate, XPA or methacrylate polymer, gel, water, polyoxyethylene glycol, Ucar 35, terepthaloyl moietie, Viscotrol C or THIXCIN or many oxyethyl groups THIXCIN, til, Semen Maydis oil, peanut wet goods.
In the aforesaid pharmaceutical composition; Except comprising pharmaceutically acceptable carrier; Can also be included in assistant agent commonly used in medicine (agent), for example: antibacterial agent, anti-mycotic agent, biocide, preservative, toning agent, solubilizing agent, thickening material, tensio-active agent, complexing agent, protein, amino acid, fat, carbohydrate, VITAMINs, mineral substance, trace element, sweeting agent, pigment, essence or their combination etc.
" treatment significant quantity " is to realize that the treatment benefit for example stops disease or preventative prevention in suffering from the object of disease or the amount of the compound of the outbreak that wards off disease.The treatment significant quantity can be one or more symptoms of alleviating disease or illness in the object to a certain extent, it is relevant with disease or illness to make or one or more physiology of its cause of disease or biochemical parameters are partially or completely recovered the amount of the outbreak possibility of normal and/or reduction disease or illness.
Embodiment (said embodiment just is used for explaining the present invention, rather than is used for limiting the present invention)
The preparation instance of part of compounds is following:
Embodiment 1: the preparation of compound 1
2-sulfydryl-5-fluorobenzene is the [preparation of d] oxazole-7-methane amide (1) also
The preparation of 2-hydroxyl-5-fluorophenyl carbamate (intermediate B)
Take by weighing the 5-fluorosalicylic acid (A, 0.82g, 1eq) and methyl alcohol (25mL) place the 50mL three-necked bottle; Drip the vitriol oil (1.9mL) in three-necked bottle, finish, be warming up to 70 ℃ of back flow reaction 19h; Cooling is concentrated into about 5mL with reaction solution, adds frozen water (50mL); With ETHYLE ACETATE (30mL*3) extraction, the ester layer is used saturated NaHCO
3(30mL*2) wash twice, use saturated NaCl (30mL) to wash once again, last, the ester layer is used anhydrous Na SO
4Drying, concentrate solid (0.72g, 80.6%).MS(ESI)m/z：[2M+H]
+＝341.
1H-NMR(400M，CDCl
3)δ10.54(s，1H，OH)，7.54(m，1H，ArH)，7.22(m，1H，ArH)，6.96(m，1H，ArH)，3.99(s，3H，OCH
3)ppm.
The preparation of 2-hydroxyl-5-fluoro-3-nitrobenzoic acid methyl esters (midbody C)
Take by weighing 2-hydroxyl-5-fluorobenzoic acid ester (intermediate B, 0.72g, 1eq) and HOAc (4mL) place the 25mL three-necked bottle, be cooled to 5 ℃, slowly drip HNO
3(6mL) in three-necked bottle, reaction 15min removes ice bath, and room temperature reaction 1h adds ice cube (50g) in reaction solution, stir 30min, suction filtration, and drying gets solid (0.80g, 87.9%).MS(ESI)m/z：[M+H]
+＝216.1.
1H-NMR(400M，CDCl
3)δ11.74(s，1H，OH)，7.97(d，1H，ArH)，7.90(d，1H，ArH)，4.06(s，3H，OCH
3)ppm.
The preparation of 2-hydroxyl-3-amino-5-fluorophenyl carbamate (midbody D)
Take by weighing 2-hydroxyl-5-fluoro-3-nitrobenzoyl acid esters (midbody C, 0.34g, 1eq) and methyl alcohol (10mL) place the 25mL three-necked bottle, add Pd/C (0.5g), be warming up to 40 ℃ of reaction 24h, suction filtration, will filtrate concentrates, drying must solid (0.27g, 92.3%).MS(ESI)m/z：[M+H]
+＝186.1.
1H-NMR(400M，DMSO-d
6)δ10.42(brs，1H，OH)，6.66(m，2H，ArH)，5.37(brs，2H，NH
2)，3.90(s，3H，OCH
3)ppm.
The preparation of 2-hydroxyl-3-amino-5-fluorobenzamide (intermediate E)
Take by weighing 2-hydroxyl-3-amino-5-fluorobenzoic acid ester (midbody D, 0.22g, 1eq) and THF (4.5mL) place the 25mL three-necked bottle, add NH
3H
2O (8mL) is warming up to 50 ℃ of backflow 4h, reaction solution is concentrated column chromatography (PE/EA=8: 1), obtain solid (0.18g, 89.0%).MS(ESI)m/z：[M+H]
+＝171.0.
1H-NMR(400M，DMSO-d
6)δ13.19(brs，1H，OH)，8.26(s，1H，CONH
2)，7.90(s，1H，CONH
2)，6.86(m，1H，ArH)，6.55(m，1H，ArH)，5.16(brs，2H，NH
2)ppm.
2-sulfydryl-5-fluorobenzene is the [preparation of d] oxazole-7-methane amide (1) also
Take by weighing 2-hydroxyl-3-amino-5-fluorobenzamide (intermediate E, 0.13g, 1eq) and absolute ethyl alcohol (6mL) place the 10mL three-necked bottle, add potassium ethyl xanthonate (0.25g; 2eq) in three-necked bottle, be warming up to 78 ℃ of backflow 25h, reaction solution is concentrated into dried, add saturated NaCl; Under the ice bath, with HCI accent pH to 3～4 of 1N, suction filtration; Drying gets solid (0.31g, 91%).MS(ESI)m/z：[M+H]
+＝213.1.
1H-NMR(400M，DMSO-d
6)δ7.76(s，1H，CONH
2)，7.24(s，1H，CONH
2)，7.00(m，2H，ArH)ppm，HPLC：94.30％.
Embodiment 2: the preparation of compound 2
Also [the preparation of d] oxazole-7-methane amide (2) of 2-(2-chloroethene sulfenyl)-5-fluorobenzene
Also [(500mg 1eq) is dissolved in the acetonitrile (15mL) d] oxazole-7-methane amide (compound 1), adds 1-bromine 2-monochloroethane (677mg to take by weighing 2-sulfydryl-5-fluorobenzene; 2eq), and the dropping triethylamine (476mg, 2eq); Behind the stirring at room 50min, be warming up to 50 ℃ of backflow 2h, reaction solution is concentrated into about 5mL; Big plate purifying (DCM/MEOH=20: 1), obtain faint yellow solid (320mg, 49%).MS(ESI)m/z：[M+H]
+＝275.0.
1H-NMR(400M，DMSO-d
6)δ7.93(s，1H，CONH
2)，7.87(s，1H，CONH
2)，7.75(m，1H，ArH)，7.51(m，1H，ArH)，4.03(t，2H，CH
2)，3.74(t，2H，CH
2)ppm，HPLC：92.37％.
Embodiment 3: the preparation of compound 3
5-fluoro-2-(3-(4-morpholinyl) rosickyite base) benzo [preparation of d] oxazole-7-methane amide (3)
Take by weighing 2-sulfydryl-5-fluorobenzene also [d] oxazole-7-methane amide (compound 1) (and 85mg, 1eq) and acetonitrile (30mL) place the 50mL three-necked bottle, add 4-(3-chloropropyl) morpholine (6drops); Drip triethylamine (0.5mL); Be warming up to 50 ℃ of backflow 2h, reaction solution is concentrated into about 5mL, column chromatography (DCM/MEOH=12: 1); Get solid (41mg, 30.2%).MS(ESI)m/z：[M+H]
+＝340.1.
1H-NMR(400M，DMSO-d
6)δ7.89(s，1H，CONH
2)，7.85(s，1H，CONH
2)，7.71(dd，1H，ArH)，7.47(dd，1H，ArH)，3.57(t，4H，CH
2)，3.38(t，2H，CH
2)，2.42(t，2H，CH
2)，2.36(t，4H，CH
2)，1.98(t，2H，CH
2)ppm，HPLC：99.27％.
Embodiment 4: the preparation of compound 4
5-fluoro-2-(2-(4-morpholinyl) ethylmercapto group) benzo [preparation of d] oxazole-7-methane amide (4)
Also [(50mg 1eq) is dissolved in the acetonitrile (20mL) d] oxazole-7-methane amide (compound 1), adds 4-(2-chloroethyl) morpholine (70mg to take by weighing 2-sulfydryl-5-fluorobenzene; 2eq), and the dropping triethylamine (47mg, 2eq); Be warming up to 80 ℃ of backflow 1h, reaction solution is concentrated into about 5mL, column chromatography for separation (DCM/MEOH=16: 1); Get solid (8mg, 36%).MS(ESI)m/z：[M+H]
+＝326.1.
1H-NMR(400M，DMSO-d
6)δ7.88(s，1H，CONH
2)，7.86(s，1H，CONH
2)，7.71(m，1H，ArH)，7.47(m，1H，ArH)，3.53(t，6H，CH
2)，2.74(t，2H，CH
2)，2.45(t，4H，CH
2)ppm，HPLC：99.21％.
Embodiment 5: the preparation of compound 5
5-fluoro-2-(3-(piperidino) rosickyite base) benzo [preparation of d] oxazole-7-methane amide (5)
Also [(50mg 1eq) is dissolved in the acetonitrile (20mL) d] oxazole-7-methane amide (compound 1), adds 1-(3-bromopropyl) piperidines (76mg to take by weighing 2-sulfydryl-5-fluorobenzene; 2eq), and the dropping triethylamine (47mg, 2eq); Be warming up to 80 ℃ of backflow 1h, reaction solution is concentrated into about 5mL, column chromatography for separation (DCM/MEOH=16: 1); Get solid (56mg, 70%).MS(ESI)m/z：[M+H]
+＝338.1.
1H-NMR(400M，DMSO-d
6)δ7.95(s，1H，CONH
2)，7.87(s，1H，CONH
2)，7.71(d，1H，ArH)，7.51(d，1H，ArH)，2.83(m，6H，CH
2)，2.16(m，2H，CH
2)，1.67(m，4H，CH
2)，1.48(m，4H，CH
2)ppm，HPLC：96.52％.
Embodiment 6: the preparation of compound 6
[the preparation of d] oxazole-7-methane amide (6) of 5-fluoro-2-(2-(piperidino) ethylmercapto group) benzo
The preparation of 1-(2-chloroethyl) piperidines (midbody G)
Take by weighing piperidines (58 μ L 1eq) are dissolved in the methyl alcohol (5mL), add the 2-monochloroacetaldehyde (300mg, 1.5eq), AcOH (4d), room temperature reaction 3h is warming up to back flow reaction 30min, add NaBH (424mg, 2eq), reaction 30min is concentrated into driedly, adds entry, uses Na in batches
2CO
3The aqueous solution is regulated pH to 8-9, and with the DCM extraction, bottom filters, and filtrating is through column chromatography purification (PE/EA=1: 1), get product (31mg, 30.9%), directly be used for next step reaction.
[the preparation of d] oxazole-7-methane amide (6) of 5-fluoro-2-(2-(piperidino) ethylmercapto group) benzo
Also [(45mg 1eq) is dissolved in the acetonitrile (5mL) d] oxazole-7-methane amide (compound 1), adds TEA (59 μ L to take by weighing 2-sulfydryl-5-fluorobenzene; 2eq), and adding 1-(2-chloroethyl) piperidines (midbody G) (30mg, 1eq); Be warming up to 80 ℃ of backflow 3h, reaction solution is concentrated, add Na
2CO
3The aqueous solution, with the DCM extraction, bottom filters, and filtrating is through column chromatography (DCM/MeOH=25: 1), get solid (18mg, 26.3%).MS(ESI)m/z：[M+H]
+＝324.2.
1H-NMR(400M，DMSO-d
6)δ7.87(d，2H，CONH
2)，7.70(d，1H，ArH)，7.47(d，1H，ArH)，3.53(m，2H，CH
2)，2.73(m，2H，CH
2)，2.45(m，4H，CH
2)，1.48(m，4H，CH
2)，1.38(m，2H，CH
2)ppm，HPLC：93.67％.
Embodiment 7: the preparation of compound 7
5-fluoro-2-(2-(1-pyrrolidyl) ethylmercapto group) benzo [preparation of d] oxazole-7-methane amide (7)
The preparation of 1-(2-bromotrifluoromethane) tetramethyleneimine (intermediate compound I)
Take by weighing tetramethyleneimine (300mg 1eq) is dissolved among the THF (5mL), add NaH (243mg, 1.2eq); Be warming up to back flow reaction 2h, be cooled to room temperature add glycol dibromide (1.77mL, 5eq); Room temperature reaction 16h adds entry, and which floor filtration the EA extraction has; Filtrating is through column chromatography (EA: MeOH=25: 1), obtain colorless oil (27mg, 3.6%), directly be used for next step reaction.
5-fluoro-2-(2-(1-pyrrolidyl) ethylmercapto group) benzo [preparation of d] oxazole-7-methane amide (7)
Take by weighing 2-sulfydryl-5-fluorobenzene also [d] oxazole-7-methane amide (compound 1) (and 37mg 1eq) is dissolved in the acetonitrile (5mL), add TEA (45 μ L, 2eq); (27mg 1eq), is warming up to 80 ℃ of backflow 2h to add 1-(2-bromotrifluoromethane) tetramethyleneimine (intermediate compound I); Reaction solution is concentrated, add water, add Na
2CO
3The aqueous solution, with the DCM extraction, bottom filters, and filtrating is through column chromatography (DCM/MeOH=25: 1), get solid (38mg, 70.5%).MS(ESI)m/z：[M+H]
+＝310.1.
1H-NMR(400M，CDCl
3)δ7.72(d，1H，ArH)，7.45(d，1H，ArH)，6.92(brs，1H，CONH
2)，6.03(brs，1H，CONH
2)，3.55(t，2H，CH
2)，2.97(t，2H，CH
2)，2.68(m，4H，CH
2)，1.79(m，2H，CH
2)，1.28(m，2H，CH
2)ppm，HPLC：97.54％.
Embodiment 8: the preparation of compound 8
5-fluoro-2-(3-(1-pyrrolidyl) rosickyite base) benzo [preparation of d] oxazole-7-methane amide (8)
Take by weighing 2-sulfydryl-5-fluorobenzene also [d] oxazole-7-methane amide (compound 1) (and 100mg, 1eq) and acetonitrile (15mL) place the 25mL three-necked bottle, add 1-(3-chloropropyl) tetramethyleneimine (1.5g; 22eq), drip triethylamine (5drops), be warming up to 80 ℃ of backflow 1.5h; Reaction solution is concentrated into about 5mL; Column chromatography for separation (DCM/MEOH=12: 1), get solid (15mg, 9.8%).MS(ESI)m/z：[M+H]
+＝324.1.
1H-NMR(400M，DMSO-d
6)δ7.94(s，1H，CONH
2)，7.87(s，1H，CONH
2)，7.72(d，1H，ArH)，7.51(d，1H，ArH)，3.53(t，2H，CH
2)，3.46(t，2H，CH
2)，3.26(t，2H，CH
2)，2.97(m，2H，CH
2)，2.23(m，2H，CH
2)，1.89(m，4H，CH
2)ppm，HPLC：97.46％.
Embodiment 9: the preparation of compound 9
[the preparation of d] oxazole-7-methane amide (9) of 5-fluoro-2-((1-cyclopropyl) methylthio group) benzo
Take by weighing 2-sulfydryl-5-fluorobenzene also [d] oxazole-7-methane amide (compound 1) (and 60mg, 1eq), (chloromethyl) Trimetylene (50mg; 2eq) be dissolved in the acetonitrile (15mL), and the dropping triethylamine (57mg, 2eq); Be warming up to 80 ℃ of backflow 18h, reaction solution is concentrated into about 5mL, column chromatography for separation (PE/EA=3: 1); Get solid (30mg, 39.8%).MS(ESI)m/z：[M+H]
+＝267.0.
1H-NMR(400M，DMSO-d
6)δ7.89(s，1H，CONH
2)，7.85(s，1H，CONH
2)，7.71(d，1H，ArH)，7.47(d，1H，ArH)，3.32(d，2H，CH
2)，1.13(m，1H，CH)，0.61(m，2H，CH
2)，0.41(m，2H，CH
2)ppm，HPLC：97.33％.
Embodiment 10: the preparation of compound 10
5-fluoro-2-((1-(4-tertbutyloxycarbonyl) piperazinyl) rosickyite base) benzo [preparation of d] oxazole-7-methane amide (10)
The preparation of tertiary butyl 4-(3-chloropropyl) piperazine-1-manthanoate (midbody K)
Take by weighing NaHCO
3(2g 1.1eq) is dissolved in the solution of THF (20mL) and water (5mL), adds tertiary butyl piperazine-1-manthanoate (3.81g; 1eq) with 1-bromo-3-chloropropane (2mL, 1eq), room temperature reaction 14h; Column chromatography for separation (DCM/MEOH=12: 1), get white oily matter (3.3g, 61.5%).Need not purifying, can directly be used for next step reaction.
5-fluoro-2-((1-(4-tertbutyloxycarbonyl) piperazinyl) rosickyite base) benzo [preparation of d] oxazole-7-methane amide (10)
(3.3g 38eq) is dissolved in the acetonitrile (25mL), adds also [d] oxazole-7-methane amide (compound 1) (70mg of 2-sulfydryl-5-fluorobenzene to take by weighing tertiary butyl 4-(3-chloropropyl) piperazine-1-manthanoate (midbody K); 1eq), and KI (0.2g, 3.6eq) and triethylamine (5d); Be warming up to 80 ℃ of backflow 4.5h, reaction solution is concentrated into about 5mL, column chromatography for separation (DCM/MeOH=12: 1); Get solid (25mg, 17.3%).MS(ESI)m/z：[M+H]
+＝439.3.
1H-NMR(400M，DMSO-d
6)δ7.89(s，1H，CONH
2)，7.86(s，1H，CONH
2)，7.71(dd，1H，ArH)，7.48(dd，1H，ArH)，3.41(m，2H，CH
2)，3.31(m，4H，CH
2)，2.43(t，2H，CH
2)，2.32(m，4H，CH
2)，2.00(m，2H，CH
2)，1.39(s，9H，C(CH
3)
3)ppm，HPLC：99.63％.
Embodiment 11: the preparation of compound 11
5-fluoro-2-(3-(1-(4-methyl) piperazinyl) rosickyite base) benzo [preparation of d] oxazole-7-methane amide (11)
(1.3g 25.5eq) is dissolved in the acetonitrile (25mL), adds also [d] oxazole-7-methane amide (compound 1) (60mg of 2-sulfydryl-5-fluorobenzene to take by weighing 1-(3-chloropropyl)-4-N-METHYL PIPERAZINE; 1eq), and KI (0.2g, 4.1eq) and triethylamine (5d); Be warming up to 80 ℃ of backflow 3.5h, reaction solution is concentrated into about 5mL, column chromatography for separation (DCM/MeOH=20: 1) purifying; Get solid (49mg, 49.2%).MS(ESI)m/z：[M+H]
+＝353.1.
1H-NMR(400M，DMSO-d
6)δ7.98(s，1H，CONH
2)，7.92(s，1H，CONH
2)，7.76(dd，1H，ArH)，7.55(dd，1H，ArH)，3.42(m，4H，CH
2)，2.57(m，6H，CH
2)，2.57(m，2H，CH
2)，2.43(s，3H，CH
2)，2.02(m，2H，CH
2)ppm，HPLC：98.78％.
Embodiment 12: the preparation of compound 12
2-ethylmercapto group-5-fluorobenzene is the [preparation of d] oxazole-7-methane amide (12) also
Take by weighing 2-sulfydryl-5-fluorobenzene also [d] oxazole-7-methane amide (compound 1) (and 150mg, 1eq) and acetonitrile (30mL) place the 50mL three-necked bottle, add iodoethane (6d); Drip triethylamine (0.5mL); Be warming up to 50 ℃ of backflow 0.5h, reaction solution is concentrated into about 5mL, column chromatography for separation (DCM/MEOH=12: 1); Get solid (96mg, 56.5%).MS(ESI)m/z：[M+H]
+＝241.1.
1H-NMR(400M，DMSO-d
6)δ7.89(s，1H，CONH
2)，7.85(s，1H，CONH
2)，7.72(dd，1H，ArH)，7.48(dd，1H，ArH)，3.45(m，2H，CH
2)，1.45(t，3H，CH
3)ppm，HPLC：97.74％.
Embodiment 13: the preparation of compound 13
2-iprotiazem base-5-fluorobenzene is the [preparation of d] oxazole-7-methane amide (13) also
Take by weighing 2-sulfydryl-5-fluorobenzene also [d] oxazole-7-methane amide (compound 1) (and 50mg, 1eq) and 2 cbloropropane isopropyl chloride (37mg 2eq) is dissolved in the acetonitrile (20mL); (4mg 0.1eq), drips triethylamine (47mg to add KI; 2eq), be warming up to 80 ℃ of reaction 19h, reaction solution is concentrated; Column chromatography purification (PE/EA=4: 1), get yellow solid (12mg, 20%).MS(ESI)m/z：[M+H]
+＝255.1.
1H-NMR(400M，DMSO-d
6)δ7.91(s，1H，CONH
2)，7.87(s，1H，CONH
2)，7.85(d，1H，ArH)，7.50(d，1H，ArH)，4.06(m，1H，CH)，1.53(d，6H，2＊CH
3)ppm，HPLC：90.27％.
Embodiment 14: the preparation of compound 14
2-(allyl group sulfenyl)-5-fluorobenzene is the preparation of [d] oxazole-7-methane amide (14) also
Take by weighing 2-sulfydryl-5-fluorobenzene also [d] oxazole-7-methane amide (compound 1) (and 80mg, 1eq) and acetonitrile (30mL) place the 50mL three-necked bottle, add allyl bromide 98 (6d); Drip triethylamine (0.5mL); Be warming up to 50 ℃ of backflow 0.5h, reaction solution is concentrated into about 5mL, column chromatography purification (DCM/MEOH=12: 1); Get solid (13mg, 13.7%).MS(ESI)m/z：[M+H]
+＝253.1.
1H-NMR(400M，DMSO-d
6)δ7.90(s，1H，CONH
2)，7.87(s，1H，CONH
2)，7.73(dd，1H，ArH)，7.49(dd，1H，ArH)，6.06(m，1H，＝CH)，5.45(m，1H，＝CH
2)，5.22(m，1H，＝CH
2)，4.06(m，2H，CH
2)ppm，HPLC：98.48％.
Embodiment 15: the preparation of compound 15
2-methoxy methylthio group-5-fluorobenzene is the [preparation of d] oxazole-7-methane amide (15) also
Take by weighing 2-sulfydryl-5-fluorobenzene also [d] oxazole-7-methane amide (compound 1) (and 50mg 1eq) is dissolved in the acetonitrile (10mL), add DIPEA (0.4mL, 10eq), the yellow clarification of solution becomes; Adding KI (3.9mg, 0.1eq), the ice bath cooling drips MOMCI (89.5 μ L; 5eq), be warming up to 50 ℃ of backflow 2.5h, reaction solution is concentrated, the DCM extraction; Drying, column chromatography purification (DCM/MEOH=100: 1), get solid (16.4mg, 26.6%).MS(ESI)m/z：[M+H]
+＝257.1.
1H-NMR(400M，DMSO-d
6)δ7.93(s，1H，CONH
2)，7.90(s，1H，CONH
2)，7.65(dd，1H，ArH)，7.46(dd，1H，ArH)，5.61(s，2H，OCH
2O)，3.32(s，3H，OCH
3)ppm，HPLC：97.15％.
Embodiment 16: the preparation of compound 16
Also [the preparation of d] oxazole-7-methane amide (16) of 2-(2-methoxyl group ethylmercapto group)-5-fluorobenzene
Take by weighing 2-sulfydryl-5-fluorobenzene also [d] oxazole-7-methane amide (compound 1) (and 50mg, 1eq) and acetonitrile (30mL) place the 50mL three-necked bottle, add 2-bromine methyl ethyl ether (6drops); Drip triethylamine (0.5mL); Be warming up to 50 ℃ of backflow 18h, reaction solution is concentrated into about 5mL, column chromatography purification (DCM/MEOH=12: 1); Get solid (41mg, 64.4%).MS(ESI)m/z：[M+H]
+＝271.1.
1H-NMR(400M，DMSO-d
6)δ7.96(s，1H，CONH
2)，7.92(s，1H，CONH
2)，7.78(dd，1H，ArH)，7.55(dd，1H，ArH)，3.78(m，2H，CH
2O)，3.63(m，2H，CH
2O)，3.37(s，3H，OCH
3)ppm，HPLC：92.11％.
Embodiment 17: the preparation of compound 17
Also [the preparation of d] oxazole-7-methane amide (17) of 2-(2-oxyethyl group ethylmercapto group)-5-fluorobenzene
Claim 2-sulfydryl-5-fluorobenzene also [d] oxazole-7-methane amide (compound 1) (and 60mg, 1eq) (61mg 2eq) is dissolved in the acetonitrile (15mL) with 1-chloro-2-Ethoxyethane; Drip triethylamine (57mg; 2eq), be warming up to 80 ℃ of backflow 18h, column chromatography purification (PE/EA=2: 1); Get solid (20mg, 24.9%).MS(ESI)m/z：[M+H]
+＝285.1.
1H-NMR(400M，DMSO-d
6)δ7.89(s，1H，CONH
2)，7.87(s，1H，CONH
2)，7.71(dd，1H，ArH)，7.48(dd，1H，ArH)，3.74(t，2H，CH
2O)，3.57(t，2H，CH
2O)，3.47(m，2H，CH
2O)，1.10(t，3H，CH
3)ppm，HPLC：98.95％.
Embodiment 18: the preparation of compound 18
2-ethoxycarbonyl ethanoyl methylthio group-5-fluorobenzene is the [preparation of d] oxazole-7-methane amide (18) also
Take by weighing 2-sulfydryl-5-fluorobenzene also [d] oxazole-7-methane amide (compound 1) (and 50mg 1eq) is dissolved in the acetonitrile (10mL), add TEA (67 μ L, 2eq); (38 μ L 1.2eq), are warming up to 80 ℃ of backflow 1.5h to add the 4-chloroacetyl acetacetic ester; Reaction solution is concentrated, and washing is filtered; Drying gets solid (56.7mg, 69.4%).MS(ESI)m/z：[M+H]
+＝341.1.
1H-NMR(400M，DMSO-d
6)δ7.88(s，2H，CONH
2)，7.68(dd，1H，ArH)，7.48(dd，1H，ArH)，4.59(s，2H，CH
2S)，4.12(m，2H，CH
2O)，3.96(s，2H，CH
2)，1.19(t，3H，CH
3)ppm，HPLC：94.61％.
Embodiment 19: the preparation of compound 19
2-((2-phenoxy) ethylmercapto group)-also [preparation of d] oxazole-7-methane amide (19) of 5-fluorobenzene
The preparation of (2-bromine oxethyl) benzene (midbody M)
(0.2g 1eq) in water-soluble (6mL), adds glycol dibromide (368 μ L to take by weighing methyl-phenoxide; 2eq), (84mg, aqueous solution 1eq) are warming up to 130 ℃ of reaction 22h to add NaOH; Cooling adds ethyl acetate extraction, and organic phase is filtered, and filtrating is concentrated into dried; Obtain oily matter (230mg, 54%), directly be used for next step reaction.
2-((2-phenoxy) ethylmercapto group)-also [preparation of d] oxazole-7-methane amide (19) of 5-fluorobenzene
Also [(40mg 1eq) is dissolved in the acetonitrile (5mL) d] oxazole-7-methane amide (compound 1), adds TEA (53mL) to take by weighing 2-sulfydryl-5-fluorobenzene; The solution clarification, and adding (2-bromine oxethyl) benzene (midbody M) (56mg, 1.5eq); Be warming up to 80 ℃ of backflow 3h; Column chromatography purification (DCM/MeOH=100: 1), get white solid (56mg, 89%).MS(ESI)m/z：[M+H]
+＝333.1.
1H-NMR(400M，DMSO-d
6)δ7.90(s，1H，CONH
2)，7.87(s，1H，CONH
2)，7.75(dd，1H，ArH)，7.49(dd，1H，ArH)，7.29(m，2H，ArH)，6.96(m，3H，ArH)，4.38(t，2H，CH
2S)，3.76(t，2H，CH
2O)ppm，HPLC：97.95％.
Embodiment 20: the preparation of compound 20
5-fluoro-2-(the own sulfenyl of 6-(the 4-benzene butoxy)) benzo [preparation of d] oxazole-7-methane amide (20)
Take by weighing 2-sulfydryl-5-fluorobenzene also [d] oxazole-7-methane amide (compound 1) (and 50mg 1eq) is dissolved in the acetonitrile (10mL), add TEA (67 μ L, 2eq); (88mg 1.2eq), is warming up to 80 ℃ of backflow 14h, and reaction solution is concentrated to add 6-bromine hexyl benzene butyl ether; Washing is filtered, and filtrating merges with filter cake with the DCM extraction; Column chromatography (DCM/MeOH=50: 1), get solid (68.9mg, 65%).MS(ESI)m/z：[M+H]
+＝445.1.
1H-NMR(400M，DMSO-d
6)δ7.88(s，1H，CONH
2)，7.85(s，1H，CONH
2)，7.71(dd，1H，ArH)，7.47(dd，1H，ArH)，7.25(m，2H，ArH)，7.16(m，3H，ArH)，3.35(m，4H，CH
2O?CH
2)，3.32(m，2H，CH
2S)，2.58(m，2H，CH
2Ar)，1.78-1.23(m，12H，CH
2)ppm，HPLC：92.97％.
Embodiment 21: the preparation of compound 21
2-benzylthio--5-fluorobenzene is the [preparation of d] oxazole-7-methane amide (21) also
Take by weighing also [d] oxazole-7-methane amide (compound 1) (0.4g of 2-sulfydryl-5-fluorobenzene; 1eq) and acetonitrile (30mL) place the 50mL three-necked bottle, add Benzyl Chloride (2.5mL) and triethylamine (1.5mL), be warming up to 50 ℃ of backflow 1h; Reaction solution is concentrated into dried; Column chromatography (DCM/MeOH=50: 1), get solid (0.2g, 35%).MS(ESI)m/z：[M+H]
+＝303.1.
1H-NMR(400M，DMSO-d
6)δ7.73(s，1H，CONH
2)，7.72(s，1H，CONH
2)，7.53(dd，1H，ArH)，7.50(m，2H，ArH)，7.47(dd，1H，ArH)，7.33(m，3H，ArH)，4.66(s，2H，SCH
2Ar)，ppm，HPLC：98.29％.
Embodiment 22: the preparation of compound 22
[the preparation of d] oxazole-7-methane amide (22) of 5-fluoro-2-(4-fluorine benzylthio-) benzo
Take by weighing also [d] oxazole-7-methane amide (compound 1) (60mg of 2-sulfydryl-5-fluorobenzene; 1eq) and acetonitrile (30mL) place the 50mL three-necked bottle, add 4-fluorine bromobenzyl (6d) and triethylamine (0.5mL), be warming up to 50 ℃ of backflow 1.5h; Reaction solution is concentrated into dried; Column chromatography purification (DCM/MEOH=12: 1), get solid (72mg, 79.5%).MS(ESI)m/z：[M+H]
+＝321.0.
1H-NMR(400M，DMSO-d
6)δ7.73(s，1H，CONH
2)，7.72(s，1H，CONH
2)，7.59(dd，1H，ArH)，7.50(m，2H，ArH)，7.47(dd，1H，ArH)，7.17(m，2H，ArH)，4.65(s，2H，SCH
2Ar)，ppm，HPLC：96.19％.
Embodiment 23: the preparation of compound 23
[the preparation of d] oxazole-7-methane amide (23) of 5-fluoro-2-(4-methoxy benzylthio-) benzo
Take by weighing 2-sulfydryl-5-fluorobenzene also [d] oxazole-7-methane amide (compound 1) (85mg, 1eq) and acetonitrile (30mL) place the 50mL three-necked bottle, add 4-methoxyl group benzyl chloride (6d); Triethylamine (0.5mL); Be warming up to 50 ℃ of backflow 2h, reaction solution is concentrated into about 5mL, column chromatography purification (DCM/MEOH=20: 1); Get solid (45mg, 33.8%).MS(ESI)m/z：[M+H]
+＝333.1.
1H-NMR(400M，DMSO-d
6)δ7.90(s，1H，CONH
2)，7.87(s，1H，CONH
2)，7.74(dd，1H，ArH)，7.49(dd，1H，ArH)，7.46(m，2H，ArH)，6.91(m，2H，ArH)，4.61(s，2H，SCH
2Ar)，3.73(s，3H，OCH
3)ppm，HPLC：96.19％.
Embodiment 24: the preparation of compound 24
[the preparation of d] oxazole-7-methane amide (24) of 5-fluoro-2-(4-cyanic acid benzylthio-) benzo
Also [(50mg 1eq) is dissolved in the acetonitrile (10mL) d] oxazole-7-methane amide (compound 1), adds TEA (67 μ L to take by weighing 2-sulfydryl-5-fluorobenzene; 2eq), and adding 4-(chloromethyl) benzene nitrile (42.5mg, 1.2eq); Be warming up to 80 ℃ of backflow 3h,, filter the reaction solution cooling; Drying gets solid (66.5mg, 85%).MS(ESI)m/z：[M+H]
+＝328.1.
1H-NMR(400M，DMSO-d
6)δ7.89(s，1H，CONH
2)，7.84(s，1H，CONH
2)，7.79(m，2H，ArH)，7.72(m，2H，ArH)，7.72(dd，1H，ArH)，7.49(dd，1H，ArH)，4.73(s，2H，SCH
2Ar)ppm，HPLC：96.19％.
Embodiment 25: the preparation of compound 25
2-(2, the 6-benzyl dichloride sulfenyl)-also [preparation of d] oxazole-7-methane amide (25) of 5-fluorobenzene
Take by weighing 2-sulfydryl-5-fluorobenzene also [d] oxazole-7-methane amide (compound 1) (and 50mg 1eq) is dissolved in the acetonitrile (10mL), add TEA (67 μ L, 2eq); Add 1, (55.3mg 1.2eq), is warming up to 80 ℃ of backflow 14h to 3-two chloro-2-(chloromethyl) benzene; With the reaction solution cooling, filter, filter cake is washed with minor amounts of acetonitrile; Drying gets solid (69.7mg, 78.2%).MS(ESI)m/z：[M+H]
+＝371.8.
1H-NMR(400M，DMSO-d
6)δ7.91(s，1H，CONH
2)，7.87(s，1H，CONH
2)，7.80(dd，1H，ArH)，7.57(m，2H，ArH)，7.46(m，1H，ArH)，7.42(dd，1H，ArH)，4.95(s，2H，SCH
2Ar)ppm，HPLC：96.20％.
Embodiment 26: the preparation of compound 26
Also [the preparation of d] oxazole-7-methane amide (26) of 2-(4-nitrobenzyl sulfenyl)-5-fluorobenzene
Take by weighing 2-sulfydryl-5-fluorobenzene also [d] oxazole-7-methane amide (compound 1) (and 500mg 1eq) is dissolved in the acetonitrile (30mL), add 1-(chloromethyl)-4-oil of mirbane (485mg, 1.2eq); Adding TEA (660 μ L, 2eq), reaction solution is clarified rapidly, is safran; Be warming up to 80 ℃ of backflow 1h, reaction solution be concentrated into dried, add water, filter; Filter cake is used water washing, and drying gets solid (806mg, 98%).MS(ESI)m/z：[M+H]
+＝348.0.
1H-NMR(400M，DMSO-d
6)δ8.22(d，2H，ArH)，7.89(s，2H，CONH
2)，7.82(d，2H，ArH)，7.73(dd，1H，ArH)，7.48(dd，1H，ArH)，4.78(s，2H，SCH
2Ar)ppm，HPLC：96.87％.
Embodiment 27: the preparation of compound 27
Also [the preparation of d] oxazole-7-methane amide (27) of 2-(4-tertiary butyl benzylthio-)-5-fluorobenzene
Also [(50mg 1eq) is dissolved in the acetonitrile (10mL) d] oxazole-7-methane amide (compound 1), adds TEA (67 μ L to take by weighing 2-sulfydryl-5-fluorobenzene; 2eq), and the adding 1-tertiary butyl-4-(chloromethyl) benzene (52mg, 1.2eq); Be warming up to 80 ℃ of backflow 4h, reaction solution is concentrated, washing; Drying gets solid (62.3mg, 72%).MS(ESI)m/z：[M+H]
+＝359.1.
1H-NMR(400M，DMSO-d
6)δ7.89(s，2H，CONH
2)，7.74(m，1H，ArH)，7.46(m，3H，ArH)，7.38(m，2H，ArH)，4.64(s，2H，SCH
2Ar)，1.27(s，9H，C(CH
3)
3)ppm，HPLC：96.73％.
Embodiment 28: the preparation of compound 28
2-((the 2-benzo [d] oxazole) methylthio group)-also [preparation of d] oxazole-7-methane amide (28) of 5-fluorobenzene
Take by weighing 2-sulfydryl-5-fluorobenzene also [d] oxazole-7-methane amide (compound 1) (and 93mg 1eq) is dissolved in the acetonitrile (30mL), add TEA (120 μ L, 2eq); Add 2-chloromethyl benzo [d] oxazole (1.2eq), be warming up to 80 ℃ of backflow 30min, add entry; With the EA extraction, which floor has filter, filtrating concentrates; Column chromatography purification (PE/EA=1: 1), get white solid (90mg, 60%).MS(ESI)m/z：[M+H]
+＝344.1.
1H-NMR(400M，DMSO-d
6)δ7.75(s，1H，CONH
2)，7.73(s，1H，CONH
2)，7.52(m，3H，ArH)，7.41(m，1H，ArH)，7.38(m，2H，ArH)，5.04(s，2H，SCH
2Ar)ppm，HPLC：99.64％.
Embodiment 29: the preparation of compound 29
[the preparation of d] oxazole-7-methane amide (29) of 5-fluoro-2-(3-phenylpropyl alcohol sulfenyl) benzo
Take by weighing 2-sulfydryl-5-fluorobenzene also [d] oxazole-7-methane amide (compound 1) (and 120mg 1eq) is dissolved in the acetonitrile (10mL), drip triethylamine (115mg, 2eq); The reaction solution flavescence, after the clarification, adding 3-bromopropyl benzene (227mg, 2eq); Rise to 80 ℃ of backflow 8h, cooling, suction filtration; Drying gets white solid (24mg, 13%).MS(ESI)m/z：[M+H]
+＝331.1.
1H-NMR(400M，DMSO-d
6)δ7.72(s，1H，CONH
2)，7.70(s，1H，CONH
2)，7.69(dd，1H，ArH)，7.45(dd，1H，ArH)，7.31-7.17(m，5H，ArH)，3.38(t，2H，SCH
2)，2.76(t，2H，CH
2Ar)，2.11(m，2H，CH
2)ppm，HPLC：99.67％.
Embodiment 30: the preparation of compound 30
[the preparation of d] oxazole-7-methane amide (30) of 5-fluoro-2-((4-oil of mirbane) ethylmercapto group) benzo
Take by weighing 2-sulfydryl-5-fluorobenzene also [d] oxazole-7-methane amide (compound 1) (and 212mg 1eq) is dissolved in the acetonitrile (10mL), drip triethylamine (152mg, 1.5eq); The reaction solution flavescence, (345mg 1.5eq), rises to 80 ℃ of backflow 4.5h to add 1-(2-bromotrifluoromethane)-4-oil of mirbane; Reaction solution is concentrated, add entry, ice bath held 2h, suction filtration; Drying gets yellow solid (250mg, 69%).MS(ESI)m/z：[M+H]
+＝362.1.
1H-NMR(400M，DMSO-d
6)δ7.90(d，2H，ArH)，7.75(s，1H，CONH
2)，7.72(s，1H，CONH
2)，7.63(dd，1H，ArH)，7.49(d，2H，ArH)，7.47(dd，1H，ArH)，3.68(t，2H，SCH
2)，3.32(t，2H，CH
2Ar)ppm，HPLC：94.69％.
Embodiment 31: the preparation of compound 31
[the preparation of d] oxazole-7-methane amide (31) of 5-fluoro-2-((4-amino-benzene) ethylmercapto group) benzo
Take by weighing 5-fluoro-2-((4-oil of mirbane) ethylmercapto group) benzo [d] oxazole-7-methane amide (30) (and 200mg 1eq) is dissolved among the THF (25mL), add iron powder (155mg, 5eq); Add entry (10mL), add the HCl (4drops) of 1N, be warming up to 60 ℃ of reactions, be warming up to 67 ℃ of reactions; The reaction solution flavescence, behind the reaction 4h, reaction solution black in color, muddiness are cooled to room temperature; Suction filtration is gone out iron powder, and filtrating is concentrated into dried, adds dissolve with methanol; Through column chromatography for separation (DCM/MeOH=12: 1), obtain yellow solid (109mg, 59.6%).MS(ESI)m/z：[M+H]
+＝332.1.
1H-NMR(400M，DMSO-d
6)δ7.88(s，1H，CONH
2)，7.87(s，1H，CONH
2)，7.72(dd，1H，ArH)，7.47(dd，1H，ArH)，6.96(d，2H，ArH)，6.50(d，2H，ArH)，4.92(brs，2H，NH
2)，3.51(t，2H，SCH
2)，2.92(t，2H，CH
2Ar)ppm，HPLC：96.33％.
Embodiment 32: the preparation of compound 32
[the preparation of d] oxazole-7-methane amide (32) of 5-fluoro-2-(piperidines-1-yl) benzo
Take by weighing 2-ethylmercapto group-5-fluorobenzene also [d] oxazole-7-methane amide (12) (and 42mg 1eq) is dissolved in the acetonitrile (15mL), add piperidines (39.5mg, 3eq); Rise to 85 ℃ of backflow 17h, cooling is concentrated into reaction solution dried; Column chromatography purification (DCM/MeOH=15: 1), get solid (35mg, 71.4%).MS(ESI)m/z：[M+H]
+＝264.2.
1H-NMR(400M，DMSO-d
6)δ7.77(s，1H，CONH
2)，7.68(s，1H，CONH
2)，7.25(dd，1H，ArH)，7.10(dd，1H，ArH)，3.64(m，4H，N(CH
2)
2)，2.50(m，6H，CH
2)ppm，HPLC：99.17％
Embodiment 33: the preparation of compound 33
[the preparation of d] oxazole-7-methane amide (33) of 5-fluoro-2-(4-N-METHYL PIPERAZINE-1-yl) benzo
Also [(30mg 1eq) is dissolved in the 1-N-METHYL PIPERAZINE (0.5mL) d] oxazole-7-methane amide (12), 130 ℃ of reactions of microwave 40min to take by weighing 2-ethylmercapto group-5-fluorobenzene; The cooling, reaction solution is concentrated into dried, column chromatography purification (DCM/MeOH=12: 1); Get faint yellow solid (30mg, 85.7%).MS(ESI)m/z：[M+H]
+＝279.2.
1H-NMR(400M，DMSO-d
6)δ7.83(s，1H，CONH
2)，7.72(s，1H，CONH
2)，7.33(dd，1H，ArH)，7.18(dd，1H，ArH)，3.77(m，4H，N(CH
2)
2)，2.77(m，4H，CH
2)，2.46(s，3H，CH
3)ppm，HPLC：98.51％.
Embodiment 34: the preparation of compound 34
[the preparation of d] oxazole-7-methane amide (34) of 5-fluoro-2-(piperazine-1-yl) benzo
Take by weighing 2-ethylmercapto group-5-fluorobenzene also [d] oxazole-7-methane amide (12) (and 40mg, 1eq) and piperazine (44mg 3eq) places microwave tube; 130 ℃ of reaction 40min, cooling is after the reaction solution dilution; Column chromatography purification (DCM/MeOH=12: 1), get white solid (25mg, 56.8%).MS(ESI)m/z：[M+H]
+＝265.1.
1H-NMR(400M，DMSO-d
6)δ7.80(s，1H，CONH
2)，7.69(s，1H，CONH
2)，7.28(d，1H，ArH)，7.15(d，1H，ArH)，3.67(m，4H，N(CH
2)
2)，2.92(m，4H，N(CH
2)
2)ppm，HPLC：94.38％.
Embodiment 35: the preparation of compound 35
Also [the preparation of d] oxazole-7-methane amide (35) of 2-(4-benzyl diethylenediamine-1-yl)-5-fluorobenzene
Take by weighing 2-ethylmercapto group-5-fluorobenzene also [d] oxazole-7-methane amide (12) (and 40mg, 1eq) and benzyl diethylenediamine (104mg 3eq) places microwave tube; 130 ℃ of reaction 40min, cooling is after the reaction solution dilution; Column chromatography purification (DCM/MeOH=12: 1), get white solid (40mg, 44%).MS(ESI)m/z：[M+H]
+＝355.2.
1H-NMR(400M，DMSO-d
6)δ7.80(s，1H，CONH
2)，7.69(s，1H，CONH
2)，7.35(m，4H，ArH)，7.28(m，2H，ArH)，7.13(dd，1H，ArH)，3.68(m，4H，N(CH
2)
2)，3.55(s，2H，NCH
2Ar)，2.55(m，4H，N(CH
2)
2)ppm，HPLC：98.31％.
Embodiment 36: the preparation of compound 36
[the preparation of d] oxazole-7-methane amide (36) of 5-fluoro-2-(4-phenylpiperazine-1-yl) benzo
Also [(40mg 1eq) is dissolved in the 1-phenylpiperazine (0.5mL) d] oxazole-7-methane amide (12), 150 ℃ of reactions of microwave 1h to take by weighing 2-ethylmercapto group-5-fluorobenzene; Add entry, the DCM extraction, bottom filters; Filtrating is through column chromatography purification (PE/EA=1: 1), get solid (77mg, 95%).MS(ESI)m/z：[M+H]
+＝341.2.
1H-NMR(400M，DMSO-d
6)δ7.81(s，1H，CONH
2)，7.73(s，1H，CONH
2)，7.32(m，1H，ArH)，7.26(m，2H，ArH)，7.15(m，1H，ArH)，7.05(m，2H，ArH)，6.84(m，1H，ArH)，3.82(m，4H，N(CH
2)
2)，3.30(m，4H，N(CH
2)
2)ppm，HPLC：99.44％.
Embodiment 37: the preparation of compound 37
[the preparation of d] oxazole-7-methane amide (37) of 5-fluoro-2-methylamino-benzo
Take by weighing 2-ethylmercapto group-5-fluorobenzene also [d] oxazole-7-methane amide (12) (and 300mg, 1eq) and methylamine (490mg 5eq) places the 10mL eggplant-shape bottle; Be warming up to 90 ℃ of backflow 2.5h; The cooling, reaction solution is concentrated into dried, column chromatography for separation (DCM/MeOH=20: 1) purifying; Get solid (147mg, 56.3%).MS(ESI)m/z：[M+H]
+＝210.1.
1H-NMR(400M，DMSO-d
6)δ8.17(d，1H，NH)，7.76(s，1H，CONH
2)，7.64(s，1H，CONH
2)，7.24(dd，1H，ArH)，7.08(dd，1H，ArH)，2.92(d，3H，NCH
3)ppm，HPLC：96.89％.
Embodiment 38: the preparation of compound 38
5-fluoro-2-encircles the preparation of penta amino benzo [d] oxazole-7-methane amide (38)
Take by weighing 2-ethylmercapto group-5-fluorobenzene also [d] oxazole-7-methane amide (12) (and 30mg, 1eq) and NSC 32389 (54mg 5eq) places the 10mL eggplant-shape bottle; Be warming up to 130 ℃ of backflow 3.5h; The cooling, reaction solution is concentrated into dried, column chromatography for separation (DCM/MeOH=20: 1) purifying; Get solid (15mg, 45.6%).MS(ESI)m/z：[M+H]
+＝264.0.
1H-NMR(400M，DMSO-d
6)δ8.40(d，1H，NH)，7.83(s，1H，CONH
2)，7.69(s，1H，CONH
2)，7.31(dd，1H，ArH)，7.12(dd，1H，ArH)，4.14(m，1H，NCH)，2.01(m，2H，CH
2)，1.76(m，2H，CH
2)，1.67(m，4H，CH
2)ppm，HPLC：94.78％.
Embodiment 39: the preparation of compound 39
The preparation of amino benzo [d] oxazole of 5-fluoro-2-hexamethylene-7-methane amide (39)
Take by weighing 2-ethylmercapto group-5-fluorobenzene also [d] oxazole-7-methane amide (12) (and 30mg, 1eq) and hexahydroaniline (62mg 5eq) places microwave tube, be warming up to 130 ℃ the reaction 30min; Cooling is concentrated into reaction solution dried, obtains faint yellow solid, adds toluene; Ice bath grinds down, obtains white solid, filters; Drying obtains white solid solid (26mg, 74%).MS(ESI)m/z：[M+H]
+＝278.1.
1H-NMR(400M，DMSO-d
6)δ8.36(d，1H，NH)，7.83(s，1H，CONH
2)，7.69(s，1H，CONH
2)，7.29(dd，1H，ArH)，7.13(dd，1H，ArH)，3.63(m，1H，NCH)，2.03(m，2H，CH
2)，1.82(m，2H，CH
2)，1.37(m，4H，CH
2)，1.21(m，4H，CH
2)ppm，HPLC：99.22％.
Embodiment 40: the horizontal PARP activity experiment of the external biochemistry of compound
Experimental principle:
PARP is a kind of post transcriptional modificaiton enzyme, can rely on NAD catalysis self and other comprise histone nucleoprotein poly (ADP-ribose), and present method is measured the PARP restraining effect of compound through measuring the catalysis degree of PARP to substrate histone.
Material is prepared:
PBST (0.1%tween-20/PBS); 1%DMSO/H2O; Dd H2O; The 50-200ul volley of rifle fire and rifle head; 96 hole dispensing plates; Loading slot; Each range single track rifle and rifle head; EP manages (1.5-15ml); TREVIGEN KIT (4677-096-K).Experimental procedure: aquation (buffer) 50ul/well, 30min; Add testing compound, 10ul/well; Positive and negative hole add 10ul/well buffer; Add PARP (0.5unit/15ul), RT 10min; Add cocktail&DNA (25ul/well), RT 60min; Add strep-HRP 50ul/well, RT60min; PPST washing 3 times, PBS washing 3 times; Measure the OD value in the 450nM place.
Result and calculating:
The calculating of medicine inhibiting rate: inhibiting rate=(control group OD-administration group OD)/(control group OD-blank control group OD) * 100%
Compound concentrations and suppressor factor are through Prism5.0 (software of GraphPad) statistical study, based on the IC of this computerized compound
50Value (reaching the required compound concentrations of inhibiting rate peaked 50%).
Wherein among the embodiment, compound 3,4,5,9,11,12,13,16,17,18,31,32,34,35,36,37 IC
50Value is not more than 1 μ M (table 1).
Table 1 compound is to the inhibiting rate of PARP enzymic activity 1 μ M
Claims (10)
1. the compound shown in the formula (I) or its pharmacy acceptable salt:
Wherein:
X is selected from-SR
2Or-NR
3R
4
R
1Be halogen;
M is 0,1,2 or 3;
R
2Be (CH
2)
nR
5
R
3And R
4Be independently selected from hydrogen, C
1-C
6Alkyl, C
3-C
8Naphthenic base or C
6-C
10Aryl, said C
1-C
6Alkyl, C
3-C
8Naphthenic base, C
6-C
10Aryl is alternatively by one or more halogen, C of being selected from
1-C
6Alkyl, C
6-C
10Aryl or C
5-C
10The substituting group of heteroaryl replaces;
Perhaps R
3, R
4Form 5 to 8 yuan of rings with the nitrogen-atoms that they connected, said 5 to 8 yuan of rings are saturated or unsaturated, comprise and R
3, R
4The nitrogen-atoms that is connected contains one or more heteroatomss that are selected from O, S or N independently of one another interior in said 5 to 8 yuan of rings, and said 5 to 8 yuan of rings are alternatively by one or more halogen, C of being selected from
1-C
6Alkyl, C
6-C
10Aryl or C
5-C
10The substituting group of heteroaryl replaces;
N is 0,1,2,3,4,5 or 6;
R
5Be selected from hydrogen, halogen, C
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, C
4-C
8Heterocyclylalkyl, C
6-C
10Aryl, C
5-C
10Heteroaryl, C
2-C
6Thiazolinyl, C
3-C
8Naphthenic base ,-C (O)-R
6Or-C (O)-O-R
7, wherein said C
1-C
6Alkyl, C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, C
4-C
8Heterocyclylalkyl, C
6-C
10Aryl, C
5-C
10Heteroaryl, C
2-C
6Thiazolinyl, C
3-C
8Naphthenic base ,-C (O)-R
6Alternatively by one or more optional halogens, C
1-C
6Alkyl ,-C (O)-R
8,-C (O)-O-R
9, nitro, cyanic acid, amino, C
1-C
6Alkoxyl group, C
6-C
10Aryl or C
6-C
10Aryloxy replaces;
R
6, R
7, R
8, R
9Be C independently
1-C
6Alkyl.
2. compound according to claim 1 or its pharmacy acceptable salt, wherein:
R
1Be selected from fluorine or chlorine;
M is 0 or 1;
R
2Be (CH
2)
nR
5
N is 0,1,2,3,4,5 or 6;
R
3And R
4Be independently selected from hydrogen, C
1-C
6Alkyl, C
3-C
8Naphthenic base or C
6-C
10Aryl;
Perhaps R
3, R
4Form 6 yuan of rings with the nitrogen-atoms that they connected, said 6 yuan of rings are saturated or unsaturated, comprise and R
3, R
4The nitrogen-atoms that is connected contains one or more heteroatomss that are selected from O, S or N independently of one another interior in said 6 yuan of rings; Said 6 yuan of heterocycles are alternatively by one or more optional C
1-C
6Alkyl, phenyl, phenmethyl or substituted-phenyl replace, and said substituted-phenyl is that phenyl is independently by one or more optional halogens, C
1-C
6Alkyl, nitro, cyanic acid, amino, C
1-C
6Alkoxyl group replaces;
R
5Be selected from hydrogen, halogen, C
1-C
6Alkyl, C
3-C
8Naphthenic base, C
1-C
6Alkoxyl group ,-C (O)-R
6,-C (O)-O-R
7, phenyl, phenoxy, benzoxazolyl vinyl, morpholinyl, pyrrolidyl, piperidyl or piperazinyl, wherein said C
1-C
6Alkyl, C
3-C
8Naphthenic base, C
1-C
6Alkoxyl group ,-C (O)-R
6, phenyl, phenoxy, benzoxazolyl, morpholinyl, pyrrolidyl, piperidyl, piperazinyl be independent alternatively by one or more optional halogens, C
1-C
6Alkyl, C
1-C
6Alkoxyl group ,-C (O)-R
8,-C (O)-O-R
9, nitro, cyanic acid, amino, phenyl or phenoxy replace;
R
6, R
7, R
8, R
9Be C independently
1-C
6Alkyl.
3. compound according to claim 1 or its pharmacy acceptable salt, wherein:
R
1Be fluorine;
M is 1;
R
2Be (CH
2)
nR
5
N is 0,1,2,3,4,5 or 6;
R
3And R
4Be independently selected from hydrogen, methyl, ethyl, propyl group, sec.-propyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
Perhaps R
3, R
4Form 6 yuan of saturated rings with the nitrogen-atoms that they connected, comprise and R
3, R
4The nitrogen-atoms that is connected contains one or more heteroatomss that are selected from O, S or N independently of one another interior in said 6 yuan of rings; Said 6 yuan of heterocycles are alternatively by one or more optional C
1-C
6Alkyl, phenyl or benzyl replace;
R
5Be selected from hydrogen, halogen, C
1-C
4Alkyl, C
1-C
4Alkoxyl group ,-C (O)-R
6, phenyl, phenoxy, benzoxazolyl, cyclopropyl, vinyl, morpholinyl, pyrrolidyl, piperidyl or piperazinyl, wherein said C
1-C
4Alkyl, C
1-C
4Alkoxyl group ,-C (O)-R
6, phenyl, phenoxy, benzoxazolyl, morpholinyl, pyrrolidyl, piperidyl, piperazinyl be independent alternatively by one or more optional halogens, C
1-C
4Alkyl, C
1-C
4Alkoxyl group ,-C (O)-O-R
9, nitro, cyanic acid, amino, phenyl or phenoxy replace;
R
6, R
9Be C independently
1-C
4Alkyl.
4. compound or its pharmacy acceptable salt, wherein said compound is selected from:
5. pharmaceutical composition, said compsn comprise among the claim 1-4 each compound or its pharmacy acceptable salt and pharmaceutically acceptable carrier.
6. the application that is used for suppressing the active medicine of PARP in preparation according to each compound or its pharmacy acceptable salt in the claim 1 to 4.
7. according to each compound or its pharmacy acceptable salt application in the preparation medicine in the claim 1 to 4, said medicine is used to treat and suppresses the disease improved because of PARP is active; Said disease is selected from vascular disease, septic shock, ischemic injuries, neurotoxicity, hemorrhagic shock, inflammatory diseases or multiple sclerosis.
8. according to each compound or its pharmacy acceptable salt application in the preparation medicine in the claim 1 to 4, said medicine as the supplementary means of oncotherapy or be used to strengthen radiotherapy and/or chemotherapy to tumor treatment.
9. according to each compound or its pharmacy acceptable salt application in the preparation medicine in the claim 1 to 4, said medicine is used to treat cancer, and wherein said treatment cancer is meant the cancer to BRCA1 or BRCA2 defective, mutant phenotype.
10. according to the purposes of claim 9, wherein said cancer is mammary cancer, ovarian cancer, carcinoma of the pancreas or prostate cancer etc.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103819343A (en) * | 2014-02-17 | 2014-05-28 | 青岛农业大学 | Preparation method of compound 2-allyl-4-fluoro-6-nitrophenol and agricultural bio-activity thereof |
| JP2017534686A (en) * | 2014-11-03 | 2017-11-24 | オロン ソシエタ ペル アチオニＯｌｏｎ Ｓｐａ | Preparation of 1- (2-halogen-ethyl) -4-piperidinecarboxylic acid ethyl ester |
| WO2019100743A1 (en) * | 2017-11-21 | 2019-05-31 | 中国药科大学 | Parp-1 and pi3k dual target inhibitor comprising benzofuran |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1332731A (en) * | 1998-11-27 | 2002-01-23 | 巴斯福股份公司 | Substituted benzimidazoles and their prep. and use |
| WO2003106430A1 (en) * | 2002-06-14 | 2003-12-24 | Pfizer Inc. | Benzimidazole inhibitors of poly(adp-ribosyl) polymerase |
| KR20100022619A (en) * | 2008-08-20 | 2010-03-03 | 한국화학연구원 | 2-benzylsulfanyl-benzimidazole-4-carboxamide derivatives or pharmaceutically acceptable salts thereof, preparation method thereof and pharmaceutical composition containing the same as an active ingredient for the prevention and treatment of the diseases induced by the overactivation of poly(adp-ribose)polymerase-1 |
| KR20100022620A (en) * | 2008-08-20 | 2010-03-03 | 한국화학연구원 | 2-(2-oxo-2-phenylethylsulfanyl)-benzimidazole-4-carboxamide derivatives or pharmaceutically acceptable salts thereof, preparation method thereof and pharmaceutical composition containing the same as an active ingredient for the prevention and treatment of the diseases induced by the overactivation of poly(adp-ribose)polymerase-1 |
| KR20100022618A (en) * | 2008-08-20 | 2010-03-03 | 한국화학연구원 | 2-sulfanyl-benzimidazole-4-carboxamide derivatives or pharmaceutically acceptable salts thereof, preparation method thereof and pharmaceutical composition containing the same as an active ingredient for the prevention and treatment of the diseases induced by the overactivation of poly(adp-ribose)polymerase-1 |
-
2012
- 2012-03-19 CN CN2012100731440A patent/CN102617502A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1332731A (en) * | 1998-11-27 | 2002-01-23 | 巴斯福股份公司 | Substituted benzimidazoles and their prep. and use |
| WO2003106430A1 (en) * | 2002-06-14 | 2003-12-24 | Pfizer Inc. | Benzimidazole inhibitors of poly(adp-ribosyl) polymerase |
| KR20100022619A (en) * | 2008-08-20 | 2010-03-03 | 한국화학연구원 | 2-benzylsulfanyl-benzimidazole-4-carboxamide derivatives or pharmaceutically acceptable salts thereof, preparation method thereof and pharmaceutical composition containing the same as an active ingredient for the prevention and treatment of the diseases induced by the overactivation of poly(adp-ribose)polymerase-1 |
| KR20100022620A (en) * | 2008-08-20 | 2010-03-03 | 한국화학연구원 | 2-(2-oxo-2-phenylethylsulfanyl)-benzimidazole-4-carboxamide derivatives or pharmaceutically acceptable salts thereof, preparation method thereof and pharmaceutical composition containing the same as an active ingredient for the prevention and treatment of the diseases induced by the overactivation of poly(adp-ribose)polymerase-1 |
| KR20100022618A (en) * | 2008-08-20 | 2010-03-03 | 한국화학연구원 | 2-sulfanyl-benzimidazole-4-carboxamide derivatives or pharmaceutically acceptable salts thereof, preparation method thereof and pharmaceutical composition containing the same as an active ingredient for the prevention and treatment of the diseases induced by the overactivation of poly(adp-ribose)polymerase-1 |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103819343A (en) * | 2014-02-17 | 2014-05-28 | 青岛农业大学 | Preparation method of compound 2-allyl-4-fluoro-6-nitrophenol and agricultural bio-activity thereof |
| CN103819343B (en) * | 2014-02-17 | 2016-03-23 | 青岛农业大学 | The preparation method of the fluoro-6-nitrophenols of compound 2-allyl group-4-and agricultural biological activity |
| JP2017534686A (en) * | 2014-11-03 | 2017-11-24 | オロン ソシエタ ペル アチオニＯｌｏｎ Ｓｐａ | Preparation of 1- (2-halogen-ethyl) -4-piperidinecarboxylic acid ethyl ester |
| WO2019100743A1 (en) * | 2017-11-21 | 2019-05-31 | 中国药科大学 | Parp-1 and pi3k dual target inhibitor comprising benzofuran |
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