CN106810552A - Thio-hydantoin ternary and ring class androgen receptor antagonists and application thereof - Google Patents
Thio-hydantoin ternary and ring class androgen receptor antagonists and application thereof Download PDFInfo
- Publication number
- CN106810552A CN106810552A CN201710057257.4A CN201710057257A CN106810552A CN 106810552 A CN106810552 A CN 106810552A CN 201710057257 A CN201710057257 A CN 201710057257A CN 106810552 A CN106810552 A CN 106810552A
- Authority
- CN
- China
- Prior art keywords
- compound
- dmso
- nmr
- preparation
- hrms
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to medicinal chemistry art, compound (I) and (II) with anti-prostate cancer effect of the specifically related to class with thio-hydantoin diindyl quinoline as skeleton, including these compounds process for production thereof, these compounds can be with antagonism androgen receptor in molecular level, good anti-prostate cancer effect is shown in cellular level and animal level, can be used to prepare antineoplastic.
Description
Technical field
The present invention relates to medicinal chemistry art, and in particular to a class is with thio-hydantoin diindyl quinoline having as skeleton
The compound of anti-prostate cancer effect, including these compounds process for production thereof, these compounds can be male with antagonism in molecular level
Hormone receptor, good anti-prostate cancer effect is shown in cellular level and animal level, can be used to prepare antineoplastic
Thing.
Background technology
Prostate cancer is the kinds of tumor for threatening American-European middle-aging male health, in recent years, with China's living standard
Improve, life style changes therewith, and China's prostate cancer incidence is in rising trend.Huggins and Hodges is first in nineteen forty-one
The secondary prostate cancer that reports has androgen-dependent, as increasing evidence shows that prostate cancer each stage is all swashed by male
Plain signal path regulation, it is the available strategy for treating prostate cancer to block this signal path.A current clinical gamma therapy is mainly
Operation castration and androgen deprivation carry out Androgen deprivation therapy (ADT).Although most of patients with prostate cancer are in early stage to ADT's
Responsiveness is 80%-90%, and patient often occurs tolerance phenomenon after treatment a period of time is received, causes disease progression, develops into
Castration-resistant prostate cancer (CRPC).Therefore effective castration-resistant prostate cancer medicine is developed very urgent.
Find and research and develop treatment CPRC newtype drug it is critical only that elaboration of tumour mechanism is probed into from molecular level and
To the sign of target.Research shows that the main cause for causing castration to resist is the androgen signal of androgen receptor (AR) mediation
The activation of axle, the additionally regulation and control including other separate signal paths.Therefore blocking androgen synthesize and suppress AR signal shafts into
It is the first-selection strategy for the treatment of CRPC.
AR belongs to nuclear receptor superfamily, and molecular weight is about 110kDa, encodes 919 amino acid.AR is by several unique work(
Energy region composition, including the N- stub areas (NTD) with transcriptional activity, the conservative DNA calmodulin binding domain CaMs (DBD) of height, C- ends
Ligand binding region (LBD) and hinge area (H) two organic functional areas AF-1 and AF-2 are located at NTD and LBD areas respectively
Domain, can promote transcription to carry out.AR is a class ligand-dependent transcriptional factor, can be recognized and be activated by native androgens, its
Generation and development to normal prostatic growth and prostate cancer all play key effect.
Androgen receptor antagonists are divided into traditional AR antagonists and new A R antagonists, are divided into steroid and non-again by structure
Steroid.The AR antagonist Main Function targets for clinically using at present are ligand binding region (LBD), and it can be competing with androgen
Striving property combines the region, and induction H12 makes a mistake and transposition and suppresses AR and form exciting conformation.
Steroid antagonist is similar with androgen structure, including megestrol acetate and cyproterone acetate etc..It has
Bioavilability is high, the characteristics of long half time, but due to hepatotoxicity wind agitation, cardiovascular side effects, and such compound is in clinical practice side
Face is restricted.
Traditional non-steroidal AR antagonists Drogenil, Nilutamide, Bicalutamide are competitiveness AR antagonists, although its energy
With reference to LBD cause H12 cannot correctly transposition, AR can still form dimer and enter nucleus and the faint combinations of AREs, but by
Decline in binding ability, AR is suppressed with the bioconjugation of coactivator, so as to promote AR, mortifier is combined together, final shadow
Target gene transcription is rung, suppresses cell growth.Traditional non-steroidal AR antagonists avoid the side effect of steroid antagonist, but also produce
The some other problems of life.Such as the half-life short of Drogenil, patient need to 250mg tablets taken three times a day；The half of Nilutamide
Although phase of declining is improved, and can but cause the side effects such as pneumonia；Bicalutamide tolerance is good and oral availability is high, but considers
To safety issue, it is prohibitted the use of by many states.Additionally, tradition AR antagonists can induce AR in use for some time
Mutation so that antagonist produces agonism to the AR after mutation.As Bicalutamide can be with 741 bit aminos of inducing receptor LBD
Acid sports leucine (W741L) by tryptophan, and activation AR promotes target gene transcription, and then patient is produced CRPC.Therefore pass
System AR antagonists can not effectively treat CRPC, and for such case, new A R antagonists arise at the historic moment.
The content of the invention
The invention discloses a kind of with thio-hydantoin ternary and new androgen receptor antagonists of the ring as skeleton
Compound.Pharmacodynamics test proves that compound of the invention has the competitive antagonist activity of androgen receptor, is disliked with treatment
Effect of property tumour.
Compound structure of the invention is as follows：
Wherein:
X represents carbon atom or nitrogen-atoms；
R1Represent halogen or C1~4Haloalkyl；
R2Represent hydrogen, halogen, cyano group or hydroxyl；
R2Also represent C1~4Alkyl, C1~4Alkoxy, C1~4Haloalkyl, cyclopropyl, imidazole radicals, pyrazolyl, triazole
Base, tetrazole radical, morpholinyl, tetrahydrofuran base, piperidyl, piperazinyl, oxetanyl ,-C (O) Ra、-NRaRa、-COORa、-
C(O)NRaRb、-C(S)NRaRb、-NHC(O)Ra、-NHSO2RaOr-SO2NRaRb；Above-mentioned substitution base can also be optionally substituted by a hydroxyl group；Wherein
Ra、RbEach independently represent hydrogen, C1~3Alkyl, C1~3Hydroxyalkyl or Ra、RbConnection forms nafoxidine base, piperidyl, morpholine
Base, piperazinyl or N-methyl piperazinyl.
R3Represent hydrogen or halogen；
R4Represent hydrogen, halogen, cyano group, hydroxyl or C1~4Alkoxy.
Wherein R1It is preferred that representing halogen or trifluoromethyl；
R2It is preferred that representing hydrogen, halogen, cyano group, hydroxyl, cyclopropyl ,-NHC (O) Ra、-NHSO2RaOr-SO2NRaRb；Wherein Ra、
RbEach independently represent hydrogen, C1~2Alkyl, C1~2Hydroxyalkyl or Ra、RbConnection forms nafoxidine base, piperidyl, morpholine
Base, piperazinyl or N-methyl piperazinyl.
The compound of most preferably following any structure：
The preferred compound structure in part of the invention is as follows：
Compound of the invention can be prepared with following method：
The preparation of compound of Formula I：
The preparation of Compounds of formula II：
Wherein X, R1、R2、R3、R4It is as defined above.
Compound III is first and NBS reacts the bromine on benzyl position, and nucleophilic displacement of fluorine then occurs with acetamino diethyl malonate
Reaction, then intermediate compound IV, preferred 60-110 DEG C of reaction temperature, reaction time preferred 10-12h, reaction dissolvent are obtained by hydrolysis
It is preferred that chloroform, ethanol, concentrated hydrochloric acid, water etc..
Compound IV reacts cyclization and obtains tetrahydroisoquinoline ring by Pictet-Spenler, is then esterified to obtain intermediate V,
Preferred 30-80 DEG C of reaction temperature, reaction time preferred 8-18h, the preferred concentrated sulfuric acid of reaction dissolvent, acetic acid, methyl alcohol etc..
Compound V and compound VI cyclizations, obtain preferred 25-60 DEG C of series compound I. reaction temperatures, and the reaction time is preferred
1-2h, the preferred DMF of reaction dissolvent etc..Inorganic base or organic base, such as NaOH, potassium hydroxide, carbonic acid should be also added in reaction
Potassium, sodium carbonate, triethylamine etc..
Compound VII obtains intermediate VIII, preferred 30-80 DEG C of reaction temperature, reaction by itrile group sodium borohydride reduction
Time preferred 8-20h, the preferred methyl alcohol of reaction dissolvent, ethanol, tetrahydrofuran etc..
Compound VIII and compound VI cyclizations, obtain preferred 25-60 DEG C of series compound II. reaction temperatures, reaction time
It is preferred that 1-2h, the preferred DMF of reaction dissolvent etc..Should also add inorganic base or organic base in reaction, such as NaOH, potassium hydroxide,
Potassium carbonate, sodium carbonate, triethylamine etc..
Formula I, II compound can be purified using common separation method, such as recrystallization, column chromatography.
The present invention also includes hydrate, stereoisomer, solvate and the pharmaceutically acceptable salt of these compounds
Deng.They have the pharmacological activity same with formula I or II compound.
Compound of the present invention can add pharmaceutically acceptable carrier and be made common pharmaceutical formulation, such as piece
Agent, capsule, pulvis, syrup, liquor, suspending agent, injection, can add spices, sweetener, liquid or solid filler or diluent
Etc. common medicinal supplementary material.
The advantage of the invention is that:Raw materials used, reagent is simple and easy to get, and reaction scheme is simple, high income；Structure is novel；
Its anti tumor activity in vitro is better than positive control Enzalutamide or suitable with its；The compounds of this invention is for DU145 cells
Without obvious inhibiting effect (IC50>100 μM), thus can also illustrate that the cytotoxicity of the compounds of this invention is less than
Enzalutamide(IC50=46.81 μM, it is shown in Table 1), is expected to be developed into antineoplastic.
The clinical dosage used of compound of the invention is 0.01mg-1000mg/ days, also dependent on the weight or formulation of the state of an illness
Difference deviate this scope.
The following is the pharmacology test and result of part of compounds of the present invention:
(1) compound suppresses prostate gland cancer cell proliferation test:
Test objective：Inhibited proliferation of the observation test compound to prostate gland cancer cell.DU145 is an AR feminine gender
Cell, compound embodies designed compound to its inhibited proliferation to the toxic action of AR negative cells, also may be used
Whether worked by AR with from one side checking compound.LNCaP cells are the AR positive cells of mutation, compound pair
Its inhibited proliferation can embody the inhibitory action of AR positive cell of the designed compound to being mutated.
Test principle：MTT analytic approach with living cells metabolin reducing agent MTT (full name as 3- (4,5- dimethylthiazole -2) -
2,5- diphenyltetrazolium bromide bromides, trade name：Tetrazolium bromide) based on.MTT is yellow compound, is that a kind of receiving is hydrionic
Dyestuff, may act on the respiratory chain in living cells mitochondria, the tetrazole ring in the presence of succinate dehydrogenase and cromoci
Cracking, generates blue first a ceremonial jade-ladle, used in libation crystallization, and the growing amount of first a ceremonial jade-ladle, used in libation crystallization is only directly proportional (cell death then butanedioic acid to number of viable cells
Dehydrogenase disappears, it is impossible to reduce MTT).The first a ceremonial jade-ladle, used in libation crystallization for reducing generation can dissolve in DMSO, be determined using ELIASA
Optical density OD values at 492nm, to reflect number of viable cells.
Test method：1) inoculating cell：Treat that cell is long to exponential phase in the nutrient solution containing 10%FBS, use pancreatin
Individual cells suspension is digested and be made into, 96 holes are inoculated into 7 × 1000, every hole DU145 or 1 × 10000LNCaP cells respectively
Plate；2) it is administered：37 DEG C, 5%CO2After culture 24h, compound to be checked is dissolved and with nutrient solution respectively by the change after dissolving with DMSO
Compound is diluted to 0.1M/L, respectively with concentration gradient 10nM, 100nM, 1 μM, 10 μM, 100 μM of administrations, and sets blank group and solvent
Control group；3) 37 DEG C, 5%CO2Continue to cultivate 72h；4) colour generation：Add the μ l of MTT solution (5mg/ml) 20 per hole, continue incubation 4 small
When, careful suction abandons culture supernatant in hole.150 μ l DMSO are added per hole, is vibrated 10 minutes, crystal is fully melted；5) compare
Color：Selection 492nm wavelength, determines each hole absorbance value on enzyme linked immunological monitor, records result, calculates growth inhibition ratio,
Draw growth inhibition curve.
The part of compounds of the present invention of table 1 is to prostate gland cancer cell (LNCaP, DU145) Proliferation Ability result of the test
| Compound number | ||
| CPU-101 | 5.32±0.60 | 143.1±0.89 |
| CPU-102 | 26.97±0.93 | >200 |
| CPU-103 | 32.60±2.22 | 67.07±2.66 |
| CPU-104 | 9.91±3.20 | >200 |
| CPU-105 | 10.44±0.61 | >200 |
| CPU-106 | 23.97±1.22 | 189.9±0.43 |
| CPU-107 | 21.71±2.19 | 78.47±1.10 |
| CPU-108 | 33.14±0.86 | >200 |
| CPU-109 | 27.77±5.63 | >200 |
| CPU-110 | 46.00±0.46 | 160.2±1.28 |
| CPU-111 | 38.40±1.67 | >200 |
| CPU-112 | 35.32±0.93 | 105.3±0.86 |
| CPU-113 | 30.87±0.57 | 113.7±1.10 |
| CPU-201 | 77.25±3.78 | 58.07±3.10 |
| CPU-202 | 29.31±0.46 | 100.6±0.37 |
| CPU-203 | 25.87±1.28 | 174.6±2.15 |
| CPU-204 | 48.47±0.49 | >200 |
| CPU-205 | 58.29±5.14 | >200 |
| CPU-206 | 54.17±2.20 | 115.4±1.25 |
| CPU-207 | 11.21±1.41 | >200 |
| CPU-208 | 67.33±0.57 | 175.2±0.22 |
| CPU-301 | 70.73±0.28 | >200 |
| CPU-302 | 44.97±0.47 | 126.3±2.06 |
| Enzalutamide | 12.51±0.36 | 46.81±0.25 |
(2) antagonism test of the compound to androgen receptor：
Test objective：Whether confirmation testing compound is to influence it with target gene androgen response element by acting on AR
Transcribed with reference to influence.Androgen can be suppressed come compound of reaction by detecting the intensity of fluorescence to be combined with androgen receptor, with
Control group is compared, if the reduction of experimental group fluorescence intensity, illustrating the compound of design can cause with androgen receptor competitive binding
AR can not Dimerized entrance nucleus and target gene response original paper combined, so as to follow-up transcription step can not be triggered.
Test principle：Luciferase gene has turned at present with one of widest reporter gene, luciferase
(luciferase) luciferin can be catalyzed and is oxidized to oxyluciferin, this reaction is ATP dependences, heterocyclic optical
Element is polyadenylation first, then by oxidative decarboxylation, produces AMP, CO2, and launched by the fluorescein intermediate product for activating
Light, then determines the bioluminescence amount discharged in luciferin oxidizing process, by data processing by fluoremetry instrument
Meter, calculates the content of luciferase in sample.
Test procedure：1) (107 is thin for pMMTV-Luc, pcDNA3.1-AR and pRL-SV40 plasmid co-transfection COS-7 cells
Born of the same parents/10cm plates), 37 DEG C, 5%CO2Continue to cultivate 24 hours；2) inoculating cell：With the tire ox processed containing 5% charcoal dextran
Serum free culture system liquid is made single cell suspension, respectively with every hole 5 × 104Individual COS-7 cells are inoculated into 96 orifice plates；3) it is administered：With
DMSO dissolves compound to be checked and by MDV3100, testing compound culture medium dissolved dilution to 0.1M/L, and with 10 μM of concentration
Administration, sets blank group and solvent control group.Each concentration sets three multiple holes；4) 37 DEG C, 5%CO2Continue to cultivate 72h；5)
Remove the culture medium in 96 orifice plates.With 1 × PBS cell, and discard PBS；6) cell lysis：1 × PLB is added to culture
Kong Zhong, per the μ L of hole 20, rocks culture plate 15min room temperature is light and slow；7) Activity determination：It is added to balancing to the LARII of room temperature
In culture hole, per the μ L of hole 100, jog is mixed and detected, is postponed within 2 seconds during measurement, 10 seconds readings；8) by balance to room temperatureReagent is added in culture hole, and per the μ L of hole 100, jog mixes detection ibid.The results are shown in Table 2.
Antagonism test result of the part of compounds of the present invention of table 2 to androgen receptor
| Compound number | Inhibiting rate % (10 μM) |
| CPU-101 | 89.4 |
| CPU-102 | 58.2 |
| CPU-103 | 29.0 |
| CPU-104 | 91.9 |
| CPU-105 | 68.3 |
| CPU-106 | 58.4 |
| CPU-107 | 21.8 |
| CPU-108 | 23.4 |
| CPU-109 | 57.1 |
| CPU-110 | 6.7 |
| CPU-111 | 13.1 |
| CPU-112 | 2.1 |
| CPU-202 | 22.9 |
| CPU-203 | 37.0 |
| CPU-204 | 39.3 |
| CPU-207 | 70.51 |
| CPU-302 | 55.1 |
| Enzalutamide | 86.5 |
(3) compound is to androgen receptor CBA：
Test objective：Whether confirmation testing compound can specifically bind with androgen receptor, and the intensity for combining.
By the ability for detecting the size of fluorescence polarization value and being combined with Selective Androgen Receptor come compound of reaction.
Test principle：Androgen receptor specific binding assays are under in vitro conditions, to detect androgen antagonist and AR
The ability of aglucon binding domain selective binding.Under in vitro conditions, fluorescent ligand specifically binds with AR aglucons binding domain, fluorescence
The part free degree is low, and fluorescence polarization value is big；When compound and fluorescent ligand competitive binding AR aglucon binding domain, fluorescent ligand
It is replaced, the fluorescent ligand free degree increases, fluorescence polarization value reduces.By detecting that fluorescence polarization is worth change come calculating
The IC of compound50Value, according to IC50Value judges the size of AR antagonists and the affinity of AR specific bindings.The results are shown in Table 3.
The part of compounds of the present invention of table 3 is to androgen receptor CBA result
| Compound number | |
| CPU-104 | 2.33±0.14 |
| CPU-105 | 2.98±3.37 |
| CPU-106 | 4.49±3.03 |
| Enzalutamide | 1.35±1.13 |
(4) internal antitumor activity
Experimental technique：Growth animated period Human Prostate Cancer Cells are collected, cell suspension is aseptically prepared into, is inoculated with
In nude mouse oxter.Nude Mice vernier caliper measurement transplantable tumor diameter, after tumour growth to will be dynamic after a certain size
Thing is grouped, every group 5.Use the method in measurement knurl footpath, the dynamic observation antineoplastic effect of tested thing.Blank such as gives at the agent
Amount HP-β-CD；Compound group：Tail vein injection, once every other day, continues 21 days.Tumor bearing nude mice is put to death after 21 days, and
Tumor mass is separated to weigh.The data obtained carries out statistical procedures (t inspections), calculates tumour inhibiting rate.Meanwhile, the final tumor mass peeled off is clapped
According to preservation picture.
The growth inhibition ratio of the LNCaP transplantable tumors of the part of compounds of the present invention of table 4
From table 4, representative compound CPU-104 of the invention has suppression well to mice-transplanted tumor LNCaP
Effect, has suitable inhibitory activity with Enzalutamide.
Specific embodiment
Embodiment 1
The synthesis (CPU102-CPU113) of compound of Formula I.
The preparation of 4- itrile groups -3- fluorine bromobenzyl (2)
3- fluorine-4-nitriles toluene 1 (10g, 74.07mmol) is dissolved in chloroform 200mL, adds BPO 1g, stirring and dissolving, in batches
NBS (19.77g, 11.11mmol) is added, flow back 12h, cooling, reaction solution saturated sodium bicarbonate aqueous solution point is washed for 3 times, in right amount
Washing 3 times, appropriate saturated common salt is washed 3 times, removes solvent under reduced pressure, and column chromatography obtains weak yellow liquid 14.00g, yield
88.79%.HRMS(ESI):m/z,calcd for C8H5BrFN 213.9678(M+H)+,found 213.9667。
The preparation of 2- (the fluoro- 4- cyanobenzyls of 3-) -2- acetamino diethyl malonates (3)
Ethanol 100mL is added in 250mL three-necked bottles, metallic sodium (0.76g, 33.16mmol) is dividedly in some parts, stirring at normal temperature is extremely
All dissolvings.Acetamino diethyl malonate (6.54g, 30.15mmol) is added, stirring and dissolving adds intermediate 2
(6.42g, 30.15mmol), is heated to backflow, reacts 18h, and reaction solution is cooled to room temperature, pours into 400mL frozen water, stands analysis
Go out white solid, suction filtration dries to obtain white solid 7.50g, yield 71.05%.HRMS (ESI):m/z,calcd for
C17H19N2O5350.1321(M+H)+,found 350.1423。
The preparation of the fluoro- 4- of 2- (2- amino -2- carboxyethyls) benzoic acid (4)
Intermediate 3 (7.50g, 21.43mmol) is dissolved in concentrated hydrochloric acid 80mL, is heated to backflow, white opacity occurs, is incubated
Stirring 15h, stops reaction.Cool, suction filtration is dried, and obtains white solid 4.21g, yield 86.53%.HRMS(ESI):m/
z,calcd for C10H10NO4 228.0603(M+H)+,found 228.0606。
The preparation of 3- (the fluoro- 4- carbomethoxvphenvls of 3-) -2- aminopropanoates (5)
Intermediate 4 (10g, 44.05mmol) is dissolved in methyl alcohol 100mL, and ice salt bath is cooled to less than 0 DEG C, is slowly added dropwise
SOCl2(10.48g, 88.10mmol), 30min is incubated after dripping, and is heated to backflow, reacts 8h, and TLC detection reactions are complete.
Cooling, separates out solid, pumping rate, dry white solid 8.50g, yield 75.66%.HRMS(ESI):m/z,calcd for
C12H14NO4 256.0917(M+H)+,found 256.0914。
The preparation of N- ethoxycarbonyls -3- (the fluoro- 4- carbomethoxvphenvls of 3-) -2- aminopropanoates (6)
Intermediate 5 (4g, 15.69mmol) is dissolved in CH2Cl2In 40mL, N is passed through2Protection, ice-water bath is cooled to 0 DEG C, adds
Pyridine (4.96g, 62.74mmol), maintains temperature at 0-5 DEG C, is slowly added dropwise ethyl chloroformate (1.70g, 15.69mmol), drips
Reaction 4.5h, TLC detection reaction is warmed to room temperature after adding complete.Remove solvent under reduced pressure, add 100mL water, 50mL ethyl acetate
Divide 3 extractions, merge organic layer, 3 washings of 50mL saturated sodium-chlorides point, organic layer anhydrous sodium sulfate drying.Filtering, filtrate
Evaporated under reduced pressure, obtains 3.08g white solids, yield 60.12%.HRMS(ESI):m/z,calcd for C15H18NO6 328.1119
(M+H)+,found 328.1123。
The preparation of N- ethoxycarbonyls -3,7- dimethoxies formoxyl -6- fluorine tetrahydroisoquinoline (7)
Intermediate 6 (3.83g, 11.71mmol) is added to CH3COOH 12mL, dense H2SO4In the nitration mixture of 4mL, stir molten
Solution.Paraformaldehyde (4.20g, 58.56mmol) is added, 5h is stirred at room temperature, TLC detection reactions are complete, stop reaction, plus 40mL water
Dilution, 3 extractions of 30mL ethyl acetate point merge organic layer, 3 washings of 30mL saturated sodium-chlorides point, anhydrous sodium sulfate drying.
Filtering, filtrate decompression is evaporated, and obtains white solid product 3.66g, yield 92.16%.HRMS(ESI):m/z,calcd for
C16H18NO6 340.1118(M+H)+,found 340.1113。
The preparation of the fluoro- 3,7- dioctyl phthalate tetrahydroisoquinolines (8) of 6-
Intermediate 7 (5.00g, 14.74mmol) is dissolved in dense HCl 50mL, is heated to backflow, stirs 18h.Cool,
Separate out solid, suction filtration, dry white solid 2.65g, yield 75.23%.HRMS(ESI):m/z,calcd for
C11H10NO4240.0709(M+H)+,found 240.0706。
The preparation of 7- methoxycarbonyls base -6- fluorine tetrahydroisoquinoline -3- methyl formates (9)
Intermediate 8 (4.22g, 17.65mmol) is dissolved in methyl alcohol 50mL, and ice salt bath is cooled to less than 0 DEG C, is slowly added dropwise
SOCl2(4.20g, 35.30mmol), 30min is incubated after dripping, and is heated to backflow, reacts 8h, and TLC detection reactions are complete.Subtract
Pressure is evaporated off partial solvent, separates out solid, pumping rate, dry white solid 3.71g, yield 78.73%.HRMS(ESI):m/z,
calcd for C13H14NO4 268.0917(M+H)+,found 268.0918。
The preparation of compound CPU102
Intermediate 10 (0.23g, 1.00mmol) is dissolved in DMF 10mL, adds triethylamine (0.5g, 0.80mmol), is added
Intermediate 9 (0.27g, 1.00mmol), is stirred at room temperature 2min, and TLC detection reactions are complete, pour into 30mL frozen water, 20mL acetic acid
Points of 3 times extractions of ethyl ester, merge organic layer, are washed for 3 times with 40mL saturated common salts moisture, anhydrous sodium sulfate drying.Filtering, removes under reduced pressure
Solvent, column chromatography obtains 0.32g, 69.11%.m.p.220-225 DEG C of yield；1H-NMR (300MHz, DMSO-d6):δ8.38(d,J
=8.4Hz, 1H, Ar-H), 8.22 (s, 1H, Ar-H), 8.01 (d, J=8.4Hz, 1H, Ar-H), 7.96 (d, J=8.4Hz, 1H,
), Ar-H 7.42 (d, J=7.5Hz, 1H, Ar-H), 5.43 (s, 1H ,-CH-), 4.78 (m, 2H ,-CH2-),3.88(s,3H,-
CH3), 3.40 (d, J=4.8Hz, 1H ,-CH2-),3.34(s,1H,-CH2-)ppm；13C-NMR(75MHz,DMSO-d6):δ
172.7,171.4,165.9,158.5,142.0,139.9,134.7,132.7,130.5,129.6,119.6,118.1,
115.8,115.7,115.6,114.4,105.0,72.5,53.8,51.5,28.1ppm；HRMS(ESI):m/z,calcd for
C21H13F4N3O3S464.0616(M+H)+,found 464.0671；IR(KBr):3409,2957,1777,1628,1444,
1310,1268,1147,854,558cm-1.
Embodiment 2
The preparation of compound CPU103
CPU102 (0.20g, 0.43mmol) is dissolved in tetrahydrofuran 5mL and 1N sodium hydrate aqueous solution 5mL, normal temperature is stirred
50min is mixed, TLC detections have been reacted, and decompression evaporates organic solvent, and 1N HCl are adjusted to pH=6, separate out solid, stand crystallization, take out
Filter, column chromatography obtains 0.15g yellow solids, yield 76.53%.m.p.160-162℃；1H-NMR (300MHz, DMSO-d6):δ
13.26 (s, 1H ,-COOH), 8.13 (t, J=8.1Hz, 1H, Ar-H), 7.91 (m, 1H, Ar-H), 7.71 (d, J=8.1Hz,
1H, Ar-H), 7.56 (d, J=7.8Hz, 1H, Ar-H), 7.35 (d, J=8.1Hz, 1H, Ar-H), 5.46 (d, J=17.4Hz,
1H,-CH-),4.75-4.84(m,2H,-CH2-),3.50-3.64(m,2H,-CH2-)ppm；13C-NMR(75MHz,DMSO-d6):
δ172.7,171.1,165.1,158.9,142.9,139.9,134.7,132.7,130.9,129.6,119.6,118.1,
115.8,115.7,115.7,114.4,105.0,72.5,53.8,28.1ppm；HRMS(ESI):m/z,calcd for
C20H11F4N3O3S 450.0456(M+H)+,found 450.0530；IR(KBr):3413,2235,1718,1627,1443,
1313,1253,1140,804,558cm-1.
Embodiment 3
The preparation of compound CPU104
CPU103 (0.10g, 0.22mmol) is dissolved in dichloromethane 10mL, ice bath, addition DMTMM (0.09g,
0.33mmol), stirring 30min, addition triethylamine (0.09g, 0.88mmol), 30% methylamine alcohol solution (0.03g,
0.33mmol), 3h is stirred at room temperature, TLC detections have been reacted, and evaporated under reduced pressure solvent adds 1N HCl 20mL, 30mL ethyl acetate
Divide 3 extractions, merge organic layer, 3 washings of 30mL saturated sodium bicarbonates point, 30mL saturated common salts moisture is washed for 3 times, organic layer
With anhydrous sodium sulfate drying, suction filtration, filtrate column chromatography obtains 0.08g yellow solids, yield 80.00%.m.p.329-333℃；1H-NMR(300MHz,DMSO-d6):δ 8.38 (d, J=8.4Hz, 1H, Ar-H), 8.32 (s, 1H ,-NH-), 8.22 (s, 1H, Ar-
), H 8.02 (d, J=8.4Hz, 1H, Ar-H), 7.65 (d, J=8.4Hz, 1H, Ar-H), 7.33 (d, J=7.5Hz, 1H, Ar-
), H 5.39 (d, J=7.5Hz, 1H ,-CH-), 4.76 (m, J=7.5Hz, 2H ,-CH2-), 3.28 (t, J=7.5Hz, 2H ,-
CH2-), 1.12 (t, J=6.9Hz, 3H ,-CH3)ppm；13C-NMR(75MHz,DMSO-d6):δ172.7,171.4,167.8,
156.1,141.1,139.9,134.7,132.7,129.8,128.1,122.1,119.6,118.1,115.8,115.7,
114.6,105.0,72.5,53.4,28.1,26.7ppm；HRMS(ESI):m/z,calcd for C21H14F4N4O2S
463.0854(M+H)+,found463.0759；IR(KBr):3446,2963,1748,1649,1487,1310,1254,1140,
856,561cm-1.
Embodiment 4
The preparation of compound CPU105
Replace methylamine alcohol solution with ethamine alcoholic solution, compound is synthesized with compound CPU104 identicals method
CPU105, yield 76.41%.m.p.215-218℃；1H-NMR(300MHz,DMSO-d6):δ8.51(s,1H,Ar-H),8.41
(d, J=8.4Hz, 1H, Ar-H), 8.33 (s, 1H ,-NH-), 8.06 (d, J=8.4Hz, 1H, Ar-H), 7.95 (s, 1H, Ar-
), H 7.82 (d, J=7.5Hz, 1H, Ar-H), 5.39 (s, 1H ,-CH-), 5.32 (s, 2H ,-CH2-),3.34(s,2H,-CH2-),
3.29 (d, J=4.8Hz, 2H ,-CH2-), 1.15 (t, J=6.9Hz, 3H ,-CH3)ppm；13C-NMR(75MHz,DMSO-d6):δ
172.7,171.4,167.5,156.1,141.1,139.9,134.7,132.7,129.8,128.1,122.1,119.6,
118.1,115.8,115.7,114.6,105.0,72.5,53.4,34.6,28.1,15.0ppm；HRMS(ESI):m/z,calcd
for C22H16F4N4O2S 477.0930(M+H)+,found477.1002；IR(KBr):3403,2975,1766,1659,
1485,1312,1251,1141,849,558cm-1.
Embodiment 5
The preparation of compound CPU106
Replace methylamine alcohol solution with n-propylamine, compound CPU106 is synthesized with compound CPU104 identicals method, receive
Rate 74.77%.m.p.279-281℃；1H-NMR(300MHz,DMSO-d6):δ 8.41 (d, J=5.4Hz, 1H, Ar-H), 8.21
(s, 1H, Ar-H), 8.05 (d, J=7.8Hz, 1H, Ar-H), 7.69 (d, J=8.1Hz, 1H, Ar-H), 7.65 (d, J=
8.1Hz, 1H, Ar-H), 7.51 (d, J=7.8Hz, 1H, Ar-H), 7.09 (s, 1H ,-NH-), 5.26 (s, 2H ,-CH2-),4.04
(q, J=6.0Hz, 1H ,-CH-), 3.21 (q, 2H ,-CH2-), 1.53 (q, J=6.0Hz, 2H ,-CH2-), 1.20 (q, J=
7.2Hz,2H,-CH2-), 0.91 (t, J=7.2Hz, 3H ,-CH3)ppm；13C-NMR(75MHz,DMSO-d6):δ172.7,
171.4,167.5,156.1,141.1,139.9,134.7,132.7,129.8,128.1,122.1,119.6,118.1,
115.8,115.7,114.6,105.0,72.5,53.4,41.5,28.1,23.1,11.2ppm；HRMS(ESI):m/z,calcd
for C23H18F4N4O2S 491.1087(M+H)+,found491.1160；IR(KBr):3415,2964,1743,1617,1440,
1313,1259,1159,820,558cm-1.
Embodiment 6
The preparation of compound CPU107
Replace methylamine alcohol solution with isopropylamine, compound CPU107 is synthesized with compound CPU104 identicals method, receive
Rate 74.77%.m.p.240-243℃；1H-NMR (300MHz, DMSO-d6):δ 8.41 (d, J=5.4Hz, 1H, Ar-H), 8.21
(s, 1H ,-NH-), 8.05 (d, J=7.8Hz, 1H, Ar-H), 7.69 (d, J=8.1Hz, 1H, Ar-H), 7.51 (d, J=
7.8Hz,1H,Ar-H),7.09(s,1H,Ar-H),5.26(s,2H,-CH2-), 4.04 (q, J=6.0Hz, 1H ,-CH-), 3.21
(q,2H,-CH2-), 1.26 (d, J=6.0Hz, 3H ,-CH3), 1.20 (d, J=7.2Hz, 3H ,-CH3),0.87(m,1H,-CH-)
ppm；13C-NMR(75MHz,DMSO-d6):δ172.7,171.4,167.2,156.1,141.1,139.9,134.7,132.7,
129.8,128.1,122.1,119.6,118.1,115.8,115.7,114.6,105.0,72.5,53.4,45.2,28.1,
23.2,23.2ppm；HRMS(ESI):m/z,calcd for C23H18F4N4O2S 489.1098(M-H)-,found
489.1008；IR(KBr):3466,2971,1744,1656,1434,1314,1252,1126,897,558cm-1.
Embodiment 7
The preparation of compound CPU108
Replace methylamine alcohol solution with cyclopropylamine, compound CPU108 is synthesized with compound CPU104 identicals method, receive
Rate 74.77%.m.p.279-282℃；1H-NMR(300MHz,DMSO-d6):δ 8.51 (s, 1H, Ar-H), 8.41 (d, J=
8.4Hz, 1H, Ar-H), 8.33 (s, 1H ,-NH-), 8.06 (d, J=8.4Hz, 1H, Ar-H), 7.95 (s, 1H, Ar-H), 7.82
(d, J=7.5Hz, 1H, Ar-H), 7.64-7.72 (m, 1H, Ar-H), 7.16 (s, 1H ,-CH-), 5.32 (s, 2H ,-CH2-),
3.34(s,2H,-CH2-), 3.29 (d, J=4.8Hz, 2H ,-CH2-), 1.15 (q, J=6.9Hz, 1H ,-CH-), 1.24-1.48
(m,2H,-CH2-), 0.93 (t, J=7.2Hz, 2H ,-CH2-)ppm；13C-NMR(75MHz,DMSO-d6):δ172.7,171.4,
167.2,156.1,141.1,139.9,134.7,132.7,129.8,128.1,122.1,119.6,118.1,115.8,
115.7,114.6,105.0,72.5,53.4,28.1,26.7,6.6,6.6ppm；HRMS(ESI):m/z,calcd for
C23H16F4N4O2S 489.1254(M+H)+,found489.1076；IR(KBr):3288,3070,1744,1660,1434,
1313,1253,1127,818,558cm-1.
Embodiment 8
The preparation of compound CPU109
Replace methylamine alcohol solution with n-butylamine, compound CPU109 is synthesized with compound CPU104 identicals method, receive
Rate 74.77%.m.p.178-183℃；1H-NMR(300MHz,DMSO-d6):δ 8.51 (s, 1H, Ar-H), 8.41 (d, J=
8.4Hz, 1H, Ar-H), 8.33 (s, 1H ,-NH-), 8.06 (d, J=8.4Hz, 1H, Ar-H), 7.95 (s, 1H, Ar-H), 7.82
(d, J=7.5Hz, 1H, Ar-H), 7.64-7.72 (m, 1H, Ar-H), 7.16 (s, 1H ,-CH-), 5.32 (s, 2H ,-CH2-),
3.34(s,2H,-CH2-), 3.29 (d, J=4.8Hz, 2H ,-CH2-), 1.15 (q, J=6.9Hz, 2H ,-CH2-),1.24-1.48
(m,2H,-CH2-), 0.93 (t, J=7.2Hz, 3H ,-CH3)ppm；13C-NMR(75MHz,DMSO-d6):δ172.7,171.4,
167.5,156.1,141.1,139.9,134.7,132.7,129.8,128.1,122.1,119.6,118.1,115.8,
115.7,114.6,105.0,72.5,53.4,39.4,32.2,28.1,19.8,13.8ppm；HRMS(ESI):m/z,calcd
for C24H20F4N4O2S 505.1254(M+H)+,found 505.1320；IR(KBr):3415,2361,1711,1654,
1444,1311,1269,1148,1053,617cm-1.
Embodiment 9
The preparation of compound CPU110
Replace methylamine alcohol solution with isobutyl amine, compound CPU110 is synthesized with compound CPU104 identicals method, receive
Rate 74.77%.m.p.136-140℃；1H-NMR(300MHz,DMSO-d6):δ 8.41 (d, J=8.4Hz, 1H, Ar-H), 8.33
(s, 1H ,-NH-), 8.12 (d, J=8.4Hz, 1H, Ar-H), 7.95 (s, 1H, Ar-H), 7.64 (d, J=7.5Hz, 1H, Ar-
H),7.25(m,1H,Ar-H),5.53(s,1H,-CH-),4.77(s,1H,-CH2-),3.53(s,1H,-CH2-),3.09(d,J
=4.8Hz, 2H ,-CH2-), 2.25 (q, J=6.9Hz, 2H ,-CH2-), 1.01 (m, 1H ,-CH-), 0.90 (t, J=7.2Hz,
3H,-CH3), 0.76 (t, J=7.2Hz, 3H ,-CH3)ppm；13C-NMR(75MHz,DMSO-d6):δ172.7,171.4,167.5,
156.1,141.1,139.9,134.7,132.7,129.8,128.1,122.1,119.6,118.1,115.8,115.7,
114.6,105.0,72.5,53.4,47.5,28.6,28.1,20.3,20.3ppm；HRMS(ESI):m/z,calcd for
C24H20F4N4O2S 503.1118(M-H)-,found 503.1158；IR(KBr):3376,2961,1751,1659,1453,
1314,1272,1137,679,558cm-1.
Embodiment 10
The preparation of compound CPU111
Replace methylamine alcohol solution with cyclohexylamine, compound CPU111 is synthesized with compound CPU104 identicals method, receive
Rate 74.77%.m.p.230-236℃；1H-NMR(300MHz,DMSO-d6):δ 8.51 (s, 1H, Ar-H), 8.41 (d, J=
8.4Hz, 1H, Ar-H), 8.33 (s, 1H ,-NH-), 8.06 (d, J=8.4Hz, 1H, Ar-H), 7.95 (s, 1H, Ar-H), 7.82
(d, J=7.5Hz, 1H, Ar-H), 7.64-7.72 (m, 1H, Ar-H), 7.16 (s, 1H ,-CH-), 5.32 (s, 2H ,-CH2-),
3.34(s,2H,-CH2-), 3.29 (d, J=4.8Hz, 2H ,-CH2-), 1.15 (q, J=6.9Hz, 1H ,-CH-), 1.24-1.48
(m,2H,-CH2-), 0.93 (t, J=7.2Hz, 2H ,-CH2-)ppm；13C-NMR(75MHz,DMSO-d6):δ172.7,171.4,
167.2,156.1,141.1,139.9,134.7,132.7,129.8,128.1,122.1,119.6,118.1,115.8,
115.7,114.6,105.0,72.5,53.4,51.6,32.3,32.3,28.1,25.7,24.8,24.8ppm；HRMS(ESI):
m/z,calcd for C26H22F4N4O2S 531.1432(M+H)+,found 531.1457；IR(KBr):3414,2930,
1750,1633,1426,1316,1258,1129,802,558cm-1.
Embodiment 11
The preparation of compound CPU112
Replace methylamine alcohol solution with monoethanolamine, compound CPU112 is synthesized with compound CPU104 identicals method, receive
Rate 74.77%.m.p.225-230℃；1H-NMR (300MHz, DMSO-d6):δ 8.51 (s, 1H, Ar-H), 8.41 (d, J=
8.4Hz, 1H, Ar-H), 8.33 (s, 1H ,-NH-), 8.06 (d, J=8.4Hz, 1H, Ar-H), 7.95 (s, 1H, Ar-H), 7.82
(d, J=7.5Hz, 1H, Ar-H), 7.64-7.72 (m, 1H, Ar-H), 5.38 (s, 1H ,-CH-), 4.75 (s, 2H ,-CH2-),
3.51(m,2H,-CH2-), 3.39 (d, J=4.8Hz, 2H ,-CH2-),3.32(m,2H,-CH2-),1.99(s,1H,-OH)ppm
；13C-NMR(75MHz,DMSO-d6):δ172.7,171.4,167.5,156.1,141.1,139.9,134.7,132.7,
129.8,128.1,122.1,119.6,118.1,115.8,115.7,114.6,105.0,72.5,61.0,53.4,42.1,
28.1ppm；HRMS(ESI):m/z,calcd for C22H16F4N4O3S 493.0954(M+H)+,found 493.0957；IR
(KBr):3481,2386,1769,1670,1492,1310,1261,1149,646,559cm-1.
Embodiment 12
The preparation of compound CPU113
Replace methylamine alcohol solution with isopropanolamine, compound CPU113 synthesized with compound CPU104 identicals method,
Yield 74.77%.m.p.264-268℃；1H-NMR (300MHz, DMSO-d6):δ 8.39 (d, J=8.4Hz, 1H, Ar-H),
8.21 (d, J=8.4Hz, 2H, Ar-H), 8.02 (s, 1H ,-NH-), 7.69 (d, J=8.4Hz, 1H, Ar-H), 7.33 (s, 1H,
Ar-H),5.39(s,1H,-CH-),4.78(s,2H,-CH2-),4.68(s,1H,-CH2-), 3.80 (d, J=4.8Hz, 1H ,-
CH2-),3.38(s,1H,-CH-),3.29(s,1H,-OH),3.21(t,2H,-CH2-), 1.09 (d, 3H, J=8.4Hz ,-CH3)
ppm；13C-NMR(75MHz,DMSO-d6):δ172.7,171.4,167.5,156.1,141.1,139.9,134.7,132.7,
129.8,128.1,122.1,119.6,118.1,115.8,115.7,114.6,105.0,72.5,68.2,53.4,51.2,
28.1,21.1ppm；HRMS(ESI):m/z,calcd for C23H18F4N4O3S 507.1134(M+H)+,found
507.1106；IR(KBr):3445,2964,1747,1661,1487,1312,1259,1138,802,559cm-1.
Embodiment 13
The preparation of compound CPU301
The preparation of tetrahydroisoquinoline -3- carboxylic acid hydrochlorides (12)
Phenylalanine (16.50g, 0.1mol) is dissolved in concentrated hydrochloric acid 150mL, 40% formalin of addition (70mL,
1mol), it is heated to reflux to solid being completely dissolved, flow back 6h, filtering, washing and drying obtains white solid 8.53g, yield 48.19%.
m.p.247℃；1H-NMR(300MHz,DMSO-d6):δ10.07(s,1H,-COOH),7.27(s,4H,Ar-H),4.43-4.40
(m,2H,-CH2-),3.81(s,1H,-CH-),3.45-3.10(m,2H,-CH2-)；HRMS(ESI):m/z,calcd for
C10H11NO2178.1276(M+H)+,found 178.1230.
The preparation of compound (CPU301)
Intermediate 13 (0.18g, 1.00mmol) is dissolved in DMF 10mL, triethylamine (0.5g, 0.80mmol) is added, in
Mesosome 12 (0.18g, 1.00mmol), is stirred at room temperature 2min, and TLC detection reactions are complete, pour into 30mL frozen water, 20mL acetic acid second
Points of 3 times extractions of ester, merge organic layer, are washed for 3 times with 40mL saturated common salts moisture, anhydrous sodium sulfate drying.Filtering, removes under reduced pressure molten
Agent, column chromatography obtains 0.19g, yield 56.38%.m.p.210-214℃；1H-NMR(300MHz,DMSO-d6):δ8.38(s,1H,
), Ar-H 8.15 (d, J=8.04Hz, 1H, Ar-H), 8.12 (d, J=3.6Hz, 1H, Ar-H), 7.74 (m, 1H, Ar-H), 7.65
(d, J=8.46Hz, 1H, Ar-H), 7.55 (m, 1H, Ar-H), 5.49 (t, J=18.66Hz, 1H ,-CH2-), 4.83 (dd, J=
5.43Hz,1H,-CH2-), 3.47 (t, J=2.97Hz, 1H ,-CH-) ppm；13C-NMR(75MHz,DMSO-d6):δ172.7,
171.4,160.8,141.2,134.0,130.4,128.6,127.5,126.9,126.3,125.7,121.3,110.8,
108.1,108.0,72.5,53.8,28.1ppm；HRMS(ESI):m/z,calcd for C18H12FN3OS 338.0097(M+H
)+,found338.0085；IR(KBr):3125,2231,1752,1617,1525,1400,1347,1069,860,515cm-1.
Embodiment 14
The preparation of compound CPU302
The preparation of 7- nitros tetrahydroisoquinoline -3- carboxylic acid hydrochlorides (14)
Concentrated sulfuric acid 12.5mL is poured into 100mL three-necked bottles, -10 DEG C are cooled to, tetrahydroisoquinoline -3- carboxylic acids 12 are dividedly in some parts
(2.5g, 14.11mmol), maintains the temperature at less than -10 DEG C, while potassium nitrate (1.48g, 14.74mmol) is dissolved in into the concentrated sulfuric acid
It is stored refrigerated in 5mL.After 12 concentrated sulfuric acid solution stirs, the concentrated sulfuric acid solution of potassium nitrate, duration requirement are slowly instilled
In more than 1.5h, reaction temperature is kept for less than -10 DEG C.After after completion of dropping, be warmed to room temperature stirring 1h, then by reaction solution incline to
In 100mL frozen water, ammoniacal liquor adjusts pH to neutrality, and suction filtration washes filter cake, obtains yellow solid 1.41g, yield 45.13%；1H-
NMR(300MHz,D2O):δ 8.35 (d, 1H, Ar-H), 8.17 (dd, 1H, Ar-H), 7.63 (d, 1H, Ar-H), 4.61-4.32
(m,3H),3.62–3.21(m,2H)ppm；HRMS(ESI):m/z,calcd for C10H10N2O4 223.0698(M+H)+,
found 223.0667.
The preparation of 7- nitros tetrahydroisoquinoline -3- carboxylate methyl ester hydrochlorides (15)
Intermediate 14 (1.00g, 4.48mmol) is dissolved in methyl alcohol 30mL, ice salt bath is cooled to less than -10 DEG C, chlorine is added dropwise
Change sulfoxide (1.07g, 8.96mmol), equality of temperature stirring 30min, then intensification makes reaction solution back flow reaction 14h, lowers the temperature, and decompression is steamed
Except partial solvent, solid is separated out, suction filtration is dried to obtain yellow solid 0.52g, yield 48.72%.(product directly carries out lower step
Reaction) HRMS (ESI):m/z,calcd for C11H12N2O4 237.0819(M+H)+,found 237.0821。
The preparation of compound CPU302
Intermediate 13 (0.18g, 1.00mmol) is dissolved in DMF 10mL, adds triethylamine (0.5g, 0.80mmol), middle
Body 15 (0.24g, 1.00mmol), is stirred at room temperature 2min, and TLC detection reactions are complete, pour into 30mL frozen water, 20mL ethyl acetate
Points of 3 times extractions, merge organic layer, are washed for 3 times with 40mL saturated common salts moisture, anhydrous sodium sulfate drying.Filtering, removes under reduced pressure molten
Agent, column chromatography obtains 0.27g, yield 70.68%.m.p.212-214℃；1H-NMR(300MHz,DMSO-d6):δ 8.15 (d, J=
8.04Hz, 1H, Ar-H), 8.12 (d, J=3.6Hz, 1H, Ar-H), 7.74 (m, 1H, Ar-H), 7.65 (d, J=8.46Hz, 1H,
), Ar-H 7.55 (m, 1H, Ar-H), 5.38 (d, J=18.66Hz, 1H ,-CH-), 4.75 (m, 2H ,-CH2-), 3.30 (t, J=
2.97Hz,2H,-CH2-)ppm；13C-NMR(75MHz,DMSO-d6):δ172.7,171.4,160.8,150.4,141.2,
136.5,135.0,134.0,129.8,122.1,121.7,121.3,110.8,108.1,108.0,72.5,52.8,
28.1ppm；HRMS(ESI):m/z,calcd for C18H11FN4O3S 383.0678(M+H)+,found 383.0545；IR
(KBr):3123,1750,1615,1434,1400,1310,1280,1158,765cm-1.
Embodiment 15
The preparation of compound CPU303
Intermediate 13 (0.18g, 1.00mmol) is dissolved in DMF 10mL, adds triethylamine (0.5g, 0.80mmol), intermediate 9
(0.28g, 1.00mmol), is stirred at room temperature 2min, and TLC detection reactions are complete, pour into 30mL frozen water, 20mL ethyl acetate point 3
Secondary extraction, merges organic layer, is washed for 3 times with 40mL saturated common salts moisture, anhydrous sodium sulfate drying.Filtering, removes solvent, post under reduced pressure
Chromatograph to obtain 0.29g, yield 70.22%.m.p.228-230℃；1H-NMR(300MHz,DMSO-d6):δ 8.14 (t, J=5.4Hz,
1H, Ar-H), 7.95 (d, J=5.4Hz, 1H, Ar-H), 7.71 (d, J=7.8Hz, 1H, Ar-H), 7.56 (d, J=8.1Hz,
1H, Ar-H), 7.41 (d, J=8.1Hz, 1H, Ar-H), 5.41 (m, 1H ,-CH-), 4.78 (m, 2H ,-CH2-),3.87(s,
3H,-CH3), 3.37 (q, J=6.0Hz, 2H ,-CH2-)ppm；13C-NMR(75MHz,DMSO-d6):δ172.7,171.4,
165.9,160.8,158.5,142.0,141.2,134.0,30.5,129.6,121.3,115.6,114.4,110.8,108.1,
108.0,72.5,53.8,51.5,28.1ppm；HRMS(ESI):m/z,calcd for C20H13F2N3O3S 414.0747(M+
H)+,found414.0713；IR(KBr):3482,2236,1662,1444,1367,1200,1140,890,558cm-1.
Embodiment 16
The preparation of compound CPU304
CPU303 (0.20g, 0.48mmol) is dissolved in tetrahydrofuran 5mL and 1N sodium hydrate aqueous solution 5mL, room temperature is stirred
50min is mixed, TLC detections have been reacted, and decompression evaporates organic solvent, and 1N HCl are adjusted to pH=6, separate out solid, stand crystallization, take out
Filter, column chromatography obtains 0.15g yellow solids, yield 77.72%.m.p.246-248℃；1H-NMR(300MHz,DMSO-d6):δ
13.26 (s, 1H ,-COOH), 8.13 (t, J=8.1Hz, 1H, Ar-H), 7.91 (m, 1H, Ar-H), 7.71 (d, J=8.1Hz,
1H, Ar-H), 7.56 (d, J=7.8Hz, 1H, Ar-H), 7.35 (d, J=8.1Hz, 1H, Ar-H), 5.46 (d, J=17.4Hz,
1H,-CH-),4.84-4.75(m,2H,-CH2-),3.64-3.50(m,2H,-CH2-)ppm；13C-NMR(75MHz,DMSO-d6):
δ172.7,171.4,165.1,160.8,158.9,142.9,141.2,134.0,130.9,129.6,121.3,115.7,
114.4,110.8,108.1,108.0,72.5,53.8,28.1ppm；HRMS(ESI):m/z,calcd for
C19H11F2N3O3S400.5090(M+H)+,found 400.0489；IR(KBr):3531,2234,1760,1628,1449,
1376,1251,1139,896,558cm-1.
Embodiment 17
The preparation of compound CPU305
CPU304 (0.10g, 0.25mmol) is dissolved in dichloromethane 15mL, ice bath, addition DMTMM (0.04g,
0.37mmol), 30min is stirred, triethylamine (0.13g, 1.25mmol), methylamine alcohol solution (0.05g, 0.49mmol), room is added
Temperature stirring 3h, TLC detection has been reacted, and evaporated under reduced pressure solvent adds 3 extractions of 1N HCl 20mL, 30mL ethyl acetate point, closes
And organic layer, 3 washings of 30mL saturated sodium bicarbonates point, 3 washings of 30mL saturated common salts moisture, organic layer anhydrous sodium sulfate
Dry, suction filtration, filtrate column chromatography obtains 0.08g yellow solids, yield 78.77%.m.p.306-309℃；1H-NMR(300MHz,
DMSO-d6):δ 8.25 (s, 1H ,-NH-), 8.13 (t, J=8.4Hz, 1H, Ar-H), 7.69 (m, 2H, Ar-H), 7.55 (d, J=
8.4Hz, 1H, Ar-H), 7.32 (d, J=8.4Hz, 1H, Ar-H), 5.33 (d, 1H ,-CH-), 4.75 (m, 2H ,-CH2-),3.33
(s,2H,-CH2-), 2.77 (d, J=8.4Hz, 3H ,-CH3)ppm；13C-NMR(75MHz,DMSO-d6):δ172.7,171.4,
167.8,160.8,156.1,141.2,141.1,134.0,129.8,128.1,122.1,121.3,114.6,110.8,
108.1,108.0,72.5,53.4,28.1,26.7ppm；HRMS(ESI):m/z,calcd for
C20H14F2N4O2S413.0811(M+H)+,found 413.0884；IR(KBr):3424,2244,1748,1620,1450,
1380,1247,1168,819,512cm-1.
Embodiment 18
The preparation of compound CPU306
Replace methylamine alcohol solution with ethamine alcoholic solution, compound is synthesized with compound CPU305 identicals method
CPU306, yield 79.73%.m.p.274-276℃；1H-NMR (300MHz, DMSO-d6):δ8.51(s,1H,Ar-H),8.41
(d, J=8.4Hz, 1H, Ar-H), 8.33 (s, 1H ,-NH-), 8.06 (d, J=8.4Hz, 1H, Ar-H), 7.95 (s, 1H, Ar-
H), 7.82 (d, J=7.5Hz, 1H, Ar-H), 7.64-7.72 (m, 1H, Ar-H), 5.38 (d, 1H ,-CH-), 4.75 (s, 2H ,-
CH2-),3.99(m,1H,-CH2-),3.27(m,2H,-CH2-),1.24(m,1H,-CH2-), 1.13 (d, 3H, J=8.4Hz ,-
CH3)ppm；13C-NMR(75MHz,DMSO-d6):δ172.7,171.4,167.5,160.8,156.1,141.2,141.1,
134.0,129.8,128.1,122.1,121.3,114.6,110.8,108.1,108.0,72.5,53.4,28.1,34.6,
15.0ppm；HRMS(ESI):m/z,calcd for C21H16F2N4O2 427.0966(M+H)+,found 427.1038；IR
(KBr):3412,2244,1751,1617,1448,1377,1308,1253,826,612cm-1.
Embodiment 19
The preparation of compound CPU307
Replace methylamine alcohol solution with monoethanolamine, compound CPU307 is synthesized with compound CPU305 identicals method, receive
Rate 74.97%.m.p.208-210℃；1H-NMR(300MHz,DMSO-d6):δ 8.23 (s, 1H ,-NH-), 8.12 (t, J=
8.4Hz, 1H, Ar-H), 7.73 (m, 2H, Ar-H), 7.55 (t, J=8.4Hz, 1H, Ar-H), 7.32 (s, 1H, Ar-H), 5.37
(d, J=4.8Hz, 1H ,-CH-), 4.77 (t, J=4.8Hz, 2H ,-CH2-), 4.66 (s, 1H ,-OH), 3.50 (t, J=
4.8Hz,2H,-CH2-),3.36(m,4H,-CH2-)ppm；13C-NMR(75MHz,DMSO-d6):δ172.7,171.4,167.5,
160.8,156.1,141.2,141.1,134.0,129.8,128.1,122.1,121.3,114.6,110.8,108.1,
108.0,72.5,61.0,53.4,42.1,28.1ppm；HRMS(ESI):m/z,calcd for C21H16F2N4O3S
443.0911(M+H)+,found 443.0984；IR(KBr):3408,2243,1751,1617,1448,1377,1254,
1164,825,611cm-1.
Embodiment 20
The preparation of compound CPU308
Replace methylamine alcohol solution with isopropanolamine, compound CPU308 synthesized with compound CPU305 identicals method,
Yield 75.89%.m.p.230-234℃；1H-NMR(300MHz,DMSO-d6):δ 8.51 (s, 1H, Ar-H), 8.41 (d, J=
8.4Hz, 1H, Ar-H), 8.33 (s, 1H ,-NH-), 8.06 (d, J=8.4Hz, 1H, Ar-H), 7.95 (s, 1H, Ar-H), 7.82
(d, J=7.5Hz, 1H, Ar-H), 7.64-7.72 (m, 1H, Ar-H), 5.38 (s, 1H ,-CH-), 4.75 (s, 2H ,-CH2-),
4.66(s,1H,-OH),3.78(m,2H,-CH2-), 3.36 (d, J=4.8Hz, 1H ,-CH-), 3.31 (m, 2H ,-CH2-),1.08
(d, 3H, J=8.4Hz ,-CH3)ppm；13C-NMR(75MHz,DMSO-d6):δ172.7,171.4,167.5,160.8,156.1,
141.2,141.1,134.0,129.8,128.1,122.1,121.3,114.6,110.8,108.1,108.0,72.5,68.2,
53.4,51.2,28.1,21.1ppm；HRMS(ESI):m/z,calcd for C22H18F2N4O3S 457.1067(M+H)+,
found 457.1140；IR(KBr):3448,2236,1769,1615,1445,1311,1249,1164,1089,805,
512cm-1.
Embodiment 21
The synthesis (CPU401-CPU409) of formula Ia compounds
The preparation of 7- amino -1,2,3,4- tetrahydroisoquinolines -3- methyl formates hydrochloride (17)
7- nitros -1,2,3,4- tetrahydroisoquinolines -3- methyl formates hydrochloride (0.10g, 0.37mmol) is dissolved in 10mL
In methyl alcohol, Pd/C, room temperature reaction 10min, suction filtration is added to remove palladium carbon, filtrate rotation obtains sepia solid 0.07g, produces except solvent
Rate 80.0%.m.p.236℃；HRMS(ESI):m/z,calcd for C11H14N2O2 207.1128(M+H)+,found
207.1129。1H-NMR(300MHz,DMSO-d6):δ3.52-3.01(m,2H),3.80(s,3H,-OCH3),4.51-4.22(m,
3H),7.43-7.10(m,3H)。
The preparation of N- tertbutyloxycarbonyls -7- nitros tetrahydroisoquinoline -3- carboxylate methyl ester hydrochlorides (18)
7- nitros tetrahydroisoquinoline -3- carboxylate methyl ester hydrochlorides (7.01g, 0.03mol) is dissolved in 100mL dichloromethane,
Ice bath adds (3.00g, 0.03mol) triethylamine to 0 DEG C, is added dropwise (13.08g, 0.06mmol) (Boc)2O, emits a large amount of bubbles,
TLC detections have been reacted after 3h is reacted under normal temperature, and evaporated under reduced pressure, column chromatography obtains 5.60g yellow oils, and yield is 55.6%.
HRMS(ESI):m/z,calcd for C16H20N2O6 337.1394(M+H)+,found 337.1396。
The preparation of N- tertbutyloxycarbonyls -7- amino tetrahydroisoquinoline -3- carboxylate methyl ester hydrochlorides (19)
N- tertbutyloxycarbonyls 7- nitros tetrahydroisoquinoline -3- carboxylate methyl ester hydrochlorides (5.60g, 16.67mmol) is dissolved in
In 56mL methyl alcohol, add 0.56g Pd/C, normal temperature and pressure to be passed through hydrogen, react 6h, TLC detection reactions are complete, and suction filtration, filtrate subtracts
Pressure is evaporated, and obtains 4.51g off-white powders, yield 88.4%.HRMS(ESI):m/z,calcd for C16H22N2O4 307.1652
(M+H)+,found 307.1653。
The preparation of N- tertbutyloxycarbonyls -7- acetamidos tetrahydroisoquinoline -3- carboxylate methyl esters (20a)
N- tertbutyloxycarbonyls 7- amino tetrahydroisoquinoline -3- carboxylate methyl ester hydrochlorides (0.61g, 1.99mmol) is dissolved in 10mL
In dichloromethane, ice bath is added dropwise (0.80g, 7.96mmol) triethylamine, and (0.31g, 3.96mmol) chloroacetic chloride is dissolved in into 2mL bis-
In chloromethanes, it is slowly dropped in reaction solution, room temperature reaction 3h, TLC detection reaction is complete, adds 30mL water, 20mL dichloromethanes
Alkane is extracted three times, merges organic layer, and 30mL saturated sodium bicarbonates are washed three times, 30mL saturated common salts water washing three times, organic layer
With anhydrous sodium sulfate drying, suction filtration, filtrate decompression is evaporated, and obtains 0.62g yellow solids, yield 89.9%.HRMS(ESI):m/z,
calcd for C18H24N2O5 349.1758(M+H)+,found 349.1760。
The preparation of 7- acetamidos tetrahydroisoquinoline -3- carboxylate methyl esters (21a)
N- tertbutyloxycarbonyls 7- acetamidos tetrahydroisoquinoline -3- carboxylate methyl esters (0.62g, 1.78mmol) is dissolved in 12mL bis-
In chloromethanes, trifluoracetic acid 1.24mL is added dropwise under ice bath, is stirred overnight, remove solvent, plus 10mL water, saturated sodium bicarbonate under reduced pressure
PH=7 is adjusted to, 30mL ethyl acetate is extracted three times, merges organic layer, and 50mL saturated aqueous common salts are washed twice, and anhydrous sodium sulfate is done
Dry, suction filtration, filtrate decompression is evaporated to obtain brown solid 0.29g, and yield is 65.9%.HRMS(ESI):m/z,calcd
forC13H16N2O3 249.1234(M+H)+,found 249.1236。
The preparation of compound CPU401
Intermediate 15 (0.27g, 1.00mmol) is dissolved in 10mL dry DMFs, adds triethylamine (0.10g, 1.00mmol)
Clarify solution, at 28 DEG C to added in reaction solution 5- isothiocyanates -3- trifluoromethyl -2- itrile groups pyridine 16 (0.23g,
1.00mmol), temperature slightly rises.2min is stirred at room temperature, TLC detection reactions are complete, pour into 20mL frozen water, 20mL dichloromethane
Extraction 3 times, merges organic layer, is washed 3 times with 40mL saturated common salts, anhydrous sodium sulfate drying.Filtering, removes solvent, post under reduced pressure
Chromatograph to obtain 0.15g bright yellow solids, yield 38.6%.m.p.134-136℃；1H-NMR(300MHz,DMSO-d6):δ9.18(d,
J=1.6Hz, 1H, Ar-H), 8.72 (d, J=1.6Hz, 1H, Ar-H), 8.38 (d, J=1.5Hz, 1H, Ar-H), 8.16-8.13
(m, 1H, Ar-H), 7.66 (d, J=8.6Hz, 1H, Ar-H), 5.55 (d, J=18.2Hz, 1H ,-CH2-),4.94-4.90(m,
1H ,-CH-), 4.87 (d, J=18.2Hz, 1H ,-CH2-),3.56-3.43(m,2H,-CH2-)ppm；13C NMR(75MHz,
DMSO-d6):δ177.5,172.0,153.5,147.6,135.5,135.4,133.2,130.7,129.6,123.3,119.7,
117.3,114.3,113.6,110.7,58.3,45.6,28.5ppm；HRMS(ESI):m/z,calcd for C18H10F3N5O3S
433.0456(M-H)-,found 433.0455；IR(KBr):3448,1762,1499,1491,1348,1309,1257,
1172,1146,1058,743,641cm-1.
Embodiment 22
The preparation of compound CPU402
Replace intermediate 15 with intermediate 17, compound CPU402 is synthesized with compound CPU401 identicals method, receive
Rate 27.9%.m.p.206-208℃；1H-NMR(300MHz,DMSO-d6):δ9.16(s,1H,Ar-H),8.72(s,1H,Ar-
), H 6.97-7.02 (m, 1H, Ar-H), 6.48 (s, 2H, Ar-H), 5.22 (d, J=17.1Hz, 1H ,-CH2-),5.11(s,
2H,-NH2),4.80-4.60(m,2H,-CH2-), 4.54 (d, J=17.1Hz, 1H ,-CH2-),3.11(s,2H,-CH2-)ppm
；13C-NMR(75MHz,DMSO-d6):δ177.5,172.0,153.5,147.6,135.5,135.4,133.2,130.7,
129.6,123.3,119.7,117.3,114.3,113.6,110.7,58.3,45.7,28.5ppm；HRMS(ESI):m/z,
calcd for C18H12F3N5OS 403.0715(M-H)-,found 403.0710；IR(KBr):3448,1763,1624,
1508,1483,1376,1271,1175,1140,1058cm-1.
Embodiment 23
The preparation of compound CPU403
Replace intermediate 15 with intermediate 21a, compound CPU403 is synthesized with compound CPU401 identicals method, receive
Rate 22.9%.m.p.230-232℃；1H-NMR(300MHz,DMSO-d6):δ10.01(s,1H,-NH-),9.18(s,1H,Ar-
), H 8.73 (s, 1H, Ar-H), 7.60 (s, 1H, Ar-H), 7.42 (s, 1H, Ar-H), 7.27 (s, 1H, Ar-H), 5.37 (d, J=
15.7Hz,1H,-CH2-), 4.84-4.82 (m, 1H ,-CH-), 4.70 (d, J=15.7Hz, 1H ,-CH2-),3.26-3.24(m,
2H,-CH2-),2.04(s,3H,-CH3)ppm；13C-NMR(75MHz,DMSO-d6):δ177.7,171.9,168.3,153.5,
138.2,135.5,135.4,133.2,130.8,129.4,128.8,125.2,123.3,118.1,116.5,114.2,57.8,
45.7,28.7,23.9ppm；HRMS(ESI):m/z,calcd for C20H14F3N5O2S 445.0820(M-H)-,found
445.0817；IR(KBr):3422,3373,2926,1769,1459,1289,1172,1142cm-1.
Embodiment 24
The preparation of compound CPU404
Replace chloroacetic chloride with propionyl chloride, first synthetic intermediate 20b and 21b, then with compound CPU401 identical sides
Method synthesizes compound CPU404, yield 26.7%.m.p.152-154℃；1H-NMR(300MHz,DMSO-d6):δ9.94(s,
1H ,-NH-), 9.18 (d, J=1.5Hz, 1H, Ar-H), 8.73 (d, J=1.5Hz, 1H, Ar-H), 7.63 (s, 1H, Ar-H),
7.45 (d, J=8.0Hz, 1H, Ar-H), 7.27 (d, J=8.0Hz, 1H, Ar-H), 5.35 (d, J=17.4Hz, 1H ,-CH2-),
4.87-4.81 (m, 1H ,-CH-), 4.71 (d, J=17.4Hz, 1H ,-CH2-),3.27-3.24(m,2H,-CH2-),2.33(q,
2H, J=7.4Hz ,-CH2-), 1.09 (t, J=7.4Hz, 3H ,-CH3)ppm；13C-NMR(75MHz,DMSO-d6):δ177.7,
172.0,171.9,153.5,138.2,135.5,135.4,133.2,130.7,129.4,128.9,125.1,123.3,
118.2,116.6,114.2,57.8,45.7,29.4,28.7,9.6ppm；HRMS(ESI):m/z,calcd for
C21H16F3N5O2S 459.0977(M-H)-,found459.0972；IR(KBr):3432,1745,1507,1498,1491,
1459,1313,1285,1173,1145,1059cm-1.
Embodiment 25
The preparation of compound CPU405
Replace chloroacetic chloride with butyl chloride, first synthetic intermediate 20c and 20c, then with compound CPU401 identical sides
Method synthesizes compound CPU405, yield 45.8%.m.p.120-128℃；1H-NMR(300MHz,DMSO-d6):δ9.94(s,
1H,-NH-),9.19(s,1H,Ar-H),8.73(s,1H,Ar-H),7.64(s,1H,Ar-H),7.44(m,1H,Ar-H),7.28
(s, 1H, Ar-H), 5.34 (d, J=17.2Hz, 1H ,-CH2-), 4.83-4.70 (m, 1H ,-CH-), 4.70 (d, J=17.2Hz,
1H,-CH2-),3.26-3.24(m,2H,-CH2-),2.28(s,2H,-CH2-),1.62-1.60(m,2H,-CH2-),0.92(s,
3H,-CH3)ppm；13C-NMR(75MHz,DMSO-d6):δ177.7,171.9,171.1,153.5,139.4,138.2,136.9,
135.4,133.2,130.8,129.4,128.7,125.2,118.1,116.6,114.2,57.8,45.7,38.2,28.7,
18.5,13.6ppm；HRMS(ESI):m/z,calcd for C22H18F3N5O2S 473.1133(M-H)-,found
473.1126；IR(KBr):3426,2382,1745,1668,1598,1509,1464,1282,1173,1146,1060,
808cm-1.
Embodiment 26
The preparation of compound CPU407
Replace chloroacetic chloride, first synthetic intermediate 20d and 21d, then with identical with compound CPU401 with ethyl chloroformate
Method synthesis compound CPU407, yield 24.0%.m.p.193-195℃；1H-NMR (300MHz, DMSO-d6):δ9.73
(s, 1H ,-NH-), 9.19 (s, 1H ,-ArH), 8.74 (s, 1H, Ar-H), 8.02 (d, J=8.4Hz, 1H, Ar-H), 7.46-
7.24 (m, 3H, Ar-H), 5.34 (d, J=17.4Hz, 1H ,-CH-), 4.86-4.81 (m, 1H ,-CH-), 4.69 (d, J=
17.4Hz,1H,-CH-),4.15-4.12(m,2H,-O-CH2-),3.26-3.23(m,2H,-CH2-),1.25-1.09(m,3H,-
CH3)ppm；13C-NMR(75MHz,DMSO-d6):δ177.7,171.9,153.5,138.1,135.5,135.4,133.2,
130.8,129.5,128.5,125.2,124.5,119.7,117.3,115.6,114.2,60.2,57.8,45.7,28.6,
14.5ppm；HRMS(ESI):m/z,calcd for C21H16F3N5O3S 475.0926(M-H)-,found 475.0916；IR
(KBr):3450,2361,1757,1724,1498,1464,1312,1286,1238,1171,1143,1060cm-1；HPLC:
94.53%.
Embodiment 27
The preparation of compound CPU408
Replace chloroacetic chloride with mesyl chloride, first synthetic intermediate 20e and 21e, then with compound CPU401 identicals
Method synthesizes compound CPU408, yield 27.8%.m.p.220-222℃；1H-NMR(300MHz,DMSO-d6):δ9.84(s,
1H ,-NH-), 9.19 (d, J=1.6Hz, 1H, Ar-H), 8.74 (d, J=1.6Hz, 1H, Ar-H), 7.32 (d, J=8.3Hz,
1H, Ar-H), 7.20 (s, 1H, Ar-H), 7.3-7.09 (m, 1H, Ar-H), 5.39 (d, J=17.8Hz, 1H ,-CH2-),4.86-
4.82 (m, H ,-CH-), 4.73 (d, J=17.8Hz, 1H ,-CH2-),3.28-3.25(m,2H,-CH2-),3.03(s,3H,-
CH3)ppm；13C-NMR(75MHz,DMSO-d6):δ177.7,171.9,171.8,153.5,137.2,135.4,135.3,
133.1,132.3,131.6,130.1,126.2,118.9,117.4,114.2,57.7,57.5,45.6,28.6ppm；HRMS
(ESI):m/z,calcd for C19H14F3N5O3S2 481.0490(M-H)-,found 481.0482；IR(KBr):3267,
1753,1618,1488,1461,1380,1314,1268,1149,1059,977,512cm-1；HPLC:91.94%.
Embodiment 28
The preparation of compound CPU409
Replace chloroacetic chloride with fourth sulfonic acid chloride, first synthetic intermediate 20f and 21f, then with compound CPU401 identicals
Method synthesizes compound CPU409, yield 29.5%.m.p.245-247℃；1H-NMR(300MHz,DMSO-d6):δ9.76(s,
1H ,-NH-), 8.37 (d, J=8.5Hz, 1H ,-ArH), 8.22 (s, 1H ,-ArH), 8.09-8.01 (m, 1H ,-ArH), 7.28
(d, J=7.8Hz, 1H ,-ArH), 7.17-7.12 (m, 1H ,-ArH), 7.02 (d, J=7.8Hz, 1H ,-ArH), 5.34 (d, J=
17.7Hz,1H,-CH-),4.87-4.84(m,2H,-CH2-), 4.50 (dd, J=16.02,16.08Hz, 2H ,-CH2-),3.29-
3.18(m,2H,-CH2-), 1.62 (t, J=6.9Hz, 2H ,-CH2-),1.39-1.33(m,2H,-CH2-),0.88-0.80(m,
3H,-CH3)ppm；13C-NMR(75MHz,DMSO-d6):δ178.2,172.0,171.0,137.9,136.7,133.7,132.9,
131.7,130.0,126.1,118.3,117.0,116.7,115.0,108.3,57.5,53.5,52.3,50.3,45.5,
43.9,28.6,25.0,20.6,13.7ppm；HRMS(ESI):m/z,calcd for C22H20F3N5O3S2 523.0960(M-
H)-,found 523.0961；IR(KBr):3433,2360,2342,1752,1618,1491,1459,1312,1147,405cm-1；HPLC:93.01%.
Embodiment 29
The preparation (CPU601-CPU611) of Compounds of formula II
The preparation of 2- quinolinecarboxylic acids methyl esters (23)
2- quinolinecarboxylic acids 22 (0.50g, 2.91mmol) are dissolved in 30mL methyl alcohol, in being slowly added dropwise at 0 DEG C (0.69g,
5.82mmol) thionyl chloride, drop finishes, equality of temperature stirring 30min, back flow reaction 8h, TLC detection is warming up to afterwards and reacts complete, subtracts
Pressure concentrated solvent, suction filtration, ethyl acetate filter wash cake obtains off-white powder 0.49g, yield 92.3%.Product directly carries out lower step
Reaction.HRMS(ESI):m/z,calcd for C11H9NO2 188.0706(M+H)+,found 188.0711。
The preparation of 1,2,3,4- tetrahydroquinoline -2- methyl formates (24)
Intermediate 23 (0.49g, 2.62mmol) is dissolved in 10mL methyl alcohol and 20mL tetrahydrofuran mixed solutions, adds cyano group
Sodium borohydride 0.50g (7.86mmol), after pH to 3-4 is adjusted with 1M aqueous hydrochloric acid solutions after sodium cyanoborohydride dissolving, maintaining should
PH value of solution, normal-temperature reaction 3h, TLC detection reaction is complete, and be concentrated under reduced pressure solvent, plus 100mL water, with ethyl acetate (30mL × 3)
Extraction.Merge organic layer, saturated common salt washing, anhydrous sodium sulfate drying.Filtering, removes solvent under reduced pressure, obtains yellow oil
0.41g, yield 81.9%.Product directly carries out the next step.HRMS(ESI):m/z,calcd for C11H13NO2
192.1019(M+H)+,found 192.1021。
The preparation of compound (CPU601)
Intermediate 10 (0.23g, 1.01mmol) is dissolved in 10mL DMF, under normal temperature add intermediate 24 (0.19g,
1.01mmol), equality of temperature stirring 5min, TLC detection reactions are complete, in addition 30mL frozen water, ethyl acetate (30mL × 3) extraction,
Merge organic layer, saturated common salt washing, anhydrous sodium sulfate drying.Filtering, removes solvent under reduced pressure, and column chromatography obtains white solid
0.20g, yield 51.7%.m.p.218-220℃；1H-NMR(300MHz,DMSO-d6):δ 8.43 (d, J=7.3Hz, 1H, Ar-
), H 8.39 (d, J=8.0Hz, 1H, Ar-H), 8.26 (s, 1H, Ar-H), 8.04 (d, J=7.1Hz, 1H, Ar-H), 7.22-
7.31(m,3H,Ar-H),4.81-4.84(m,1H,-CH-),3.05-3.16(m,2H,-CH2-),2.39-2.50(m,2H,-
CH2-)ppm；13C-NMR(75MHz,DMSO-d6):δ176.8,171.0,139.1,136.3,134.4,132.4,130.6,
128.4,128.3,123.2,122.5,119.6,118.2,115.0,108.7,60.5,25.6,23.8ppm；HRMS(ESI):
m/z,calcd for C19H12F3N3OS 386.0580(M-H)-,found 386.0587；IR(KBr):3420,3124,
1758,1491,1417,1410,1313,1260,1132,1056,804,758cm-1.
Embodiment 30
The preparation of compound (CPU602)
N- acetyl group -1, the preparation of 2,3,4- tetrahydroquinoline -2- methyl formates (25)
Intermediate 24 (0.38g, 2.10mmol) is dissolved in 20mL dichloromethane, and (2.56g, 2.52mmol) is added at 0 DEG C
Triethylamine, chloroacetic chloride (0.24g, 3.16mmol) is added after equality of temperature stirring 5min, is warming up to 30 DEG C of reaction 1h, TLC detection reactions
Completely, reaction solution adds 100mL water, and dichloromethane (30mL × 3) extraction merges organic layer, saturated common salt washing, anhydrous slufuric acid
Sodium is dried.Filtering, removes solvent under reduced pressure, and column chromatography obtains 0.38g faint yellow solids, yield 77.7%.Product directly carries out lower step
Reaction.HRMS(ESI):m/z,calcd for C13H15NO3 234.1125(M+H)+,found 234.1132.
The preparation of tetrahydroquinoline -2- methyl formates (26) of N- acetyl group -6- bromo- 1,2,3,4-
Intermediate 25 (0.38g, 1.63mmol) is dissolved in 10mL dry DMFs, be slowly added dropwise at 0 DEG C (0.26g,
1.63mmol) bromine, equality of temperature stirring 40min, TLC detection reaction is complete, and reaction solution is passed through nitrogen discharge excess liquid bromine, plus
100mL water, ethyl acetate (30mL × 3) extraction merges organic layer, saturated common salt washing, anhydrous sodium sulfate drying.Filtering, subtracts
Pressure is evaporated off solvent, and column chromatography obtains 0.35g orange solids, yield 68.8%.Product directly carries out the next step.HRMS(ESI):m/
z,calcd for C13H14BrNO3 312.0230(M+H)+,found 312.0235.
The preparation of tetrahydroquinoline -2- formic acid (27) of 6- bromo- 1,2,3,4-
0.32g (1.12mmol) intermediate 26 is dissolved in 20ml concentrated hydrochloric acids, is warming up to backflow, reacts 2h, TLC detection reactions
Completely, remove solvent under reduced pressure, obtain brown solid 0.27g, yield 94.5%.Product directly carries out the next step.HRMS(ESI):
m/z,calcd for C10H10BrNO2 255.9968(M+H)+,found 255.9981.
The preparation of tetrahydroquinoline -2- methyl formates (28) of 6- bromo- 1,2,3,4-
Intermediate 27 (0.27g, 1.05mmol) is dissolved in 30mL methyl alcohol, in being slowly added dropwise at 0 DEG C (0.25g,
2.10mmol) thionyl chloride, drop finishes, equality of temperature stirring 30min, back flow reaction 6h, TLC detection is warming up to afterwards and reacts complete, subtracts
Pressure concentrated solvent, suction filtration obtains orange solids 0.27g, yield 96.2%.Product directly carries out the next step.HRMS(ESI):m/
z,calcd for C11H12NO2 270.0124(M+H)+,found 270.0151.
The preparation of compound (CPU602)
Intermediate 10 (0.23g, 1.01mmol) is dissolved in 10mL DMF, is added in the middle of (0.27g, 1.01mmol) under normal temperature
Body 28, equality of temperature stirring 5min, TLC detection reaction is complete, adds in 30mL frozen water, and ethyl acetate (30mL × 3) extraction is associated with
Machine layer, saturated common salt washing, anhydrous sodium sulfate drying.Filtering, removes solvent under reduced pressure, and column chromatography obtains white solid 0.22g, yield
47.2%.m.p.219-222℃；1H-NMR(300MHz,DMSO-d6):δ 8.84 (d, J=8.9Hz, 1H, Ar-H), 8.40 (d, J
=8.2Hz, 1H, Ar-H), 8.26 (s, 1H, Ar-H), 8.04 (d, J=7.4Hz, 1H, Ar-H), 7.57-7.49 (m, 2H, Ar-
), H 4.83 (dd, J=11.5Hz, 3.6Hz, 1H ,-CH-), 3.16-3.11 (m, 2H ,-CH2-),2.33-2.28(m,2H,-
CH2-)ppm；13C-NMR(75MHz,DMSO-d6):δ176.9,170.8,138.1,136.3,134.4,131.9,131.4,
130.9,128.3,128.2,127.5,123.2,120.3,117.8,115.0,108.7,60.4,25.3,23.4ppm；HRMS
(ESI):m/z,calcd for C19H12BrF3N3OS 463.9686(M-H)-,found 463.9676；IR(KBr):3447,
3133,1754,1440,1401,1317,1258,1144,1084,749,544cm-1.
Embodiment 31
The preparation of compound (CPU603)
The preparation of N- oxidations -6- oxyquinolines (30)
Intermediate 29 (2.00g, 13.79mmol) is dissolved in 50mL ethyl acetate, added in three times at 0 DEG C (5.95g,
34.48mmol) metachloroperbenzoic acid, N2Protection, equality of temperature reaction 2h.It is to slowly warm up to normal temperature to continue to react 6h, TLC detections are anti-
Should be complete, suction filtration obtains brown solid 1.86g, yield 83.8%.Product directly carries out the next step.1H-NMR(300MHz,
DMSO-d6):δ 10.67 (s, 1H ,-OH), 8.42 (d, J=8.8Hz, 1H, Ar-H), 8.01 (d, J=9.2Hz, 1H, Ar-H),
(s, 1H, the Ar-H) ppm. of 7.90 (d, J=8.4Hz, 1H, Ar-H), 7.50 (dd, J=9.0Hz, 2.6Hz, 1H, Ar-H), 10.67
The preparation of the itrile group quinoline (31) of 6- oxyquinolines -2
Intermediate 30 (1.86g, 11.55mmol) is dissolved in 50mL acetonitriles, adds triethylamine (5.36g, 53.13mmol), three
Methyl silicon cyanogen (4.92g, 49.66mmol), normal-temperature reaction 10h.TLC detection reactions are complete, remove solvent under reduced pressure, obtain brown oil
Thing 1.87g.Yield 95.1%.Product directly carries out the next step.HRMS(ESI):m/z,calcd for C10H6N2O
171.0553(M+H)+,found 171.0568.
The preparation of 6- oxyquinoline -2- formic acid (32)
Intermediate 31 (1.87g, 10.99mmol) is dissolved in 30mL concentrated hydrochloric acids, is warming up to back flow reaction 7h.TLC detection reactions
Completely, remove solvent under reduced pressure, obtain brown solid 1.73g.Yield 83.3%.Product directly carries out the next step.HRMS(ESI):
m/z,calcd for C10H6N2O 190.0499(M+H)+,found 190.0518.
The preparation of 6- oxyquinoline -2- methyl formates (33)
Intermediate 32 (1.73g, 9.10mmol) is dissolved in 30mL methyl alcohol, in being slowly added dropwise at 0 DEG C (2.17g,
18.21mmol) thionyl chloride, drop finishes, equality of temperature stirring 30min, back flow reaction 12h, TLC detection is warming up to afterwards and reacts complete,
Remove solvent under reduced pressure, obtain brown oil 1.68g, yield 91.9%.Product directly carries out the next step.HRMS(ESI):m/z,
calcd for C11H9NO3 204.0655(M+H)+,found 204.0651.
6- hydroxyl -1, the preparation of 2,3,4- tetrahydroquinoline -2- methyl formates (34)
Intermediate 33 (1.68g, 8.27mmol) is dissolved in 15mL methyl alcohol and 30mL tetrahydrofuran mixed solutions, adds cyano group
Sodium borohydride (1.56g, 24.83mmol), after pH to 3-4 is adjusted with 1M aqueous hydrochloric acid solutions after sodium cyanoborohydride dissolving, maintains
The pH value of solution, normal-temperature reaction 24h, TLC detection reaction is complete, and be concentrated under reduced pressure solvent, plus 100mL water, with ethyl acetate (30mL ×
3) extract.Merge organic layer, saturated common salt washing, anhydrous sodium sulfate drying.Filtering, removes solvent under reduced pressure, and column chromatography obtains yellow
Grease 0.76g, yield 37.4%.HRMS(ESI):m/z,calcd for C11H13NO3 208.0968(M+H)+,found
208.0962.
The preparation of compound (CPU603)
Intermediate 10 (0.23g, 1.01mmol) is dissolved in 10mL DMF, is added in the middle of (0.21g, 1.01mmol) under normal temperature
Body 34, equality of temperature stirring 5min, TLC detection reaction is complete, adds in 30mL frozen water, and ethyl acetate (30mL × 3) extraction is associated with
Machine layer, saturated common salt washing, anhydrous sodium sulfate drying.Filtering, removes solvent under reduced pressure, and column chromatography obtains white solid 0.10g, yield
24.8%.m.p.221-223℃；1H-NMR(300MHz,DMSO-d6):δ 9.60 (s, 1H ,-OH), 8.63 (d, J=9.6Hz,
1H, Ar-H), 8.39 (d, J=8.2Hz, 1H, Ar-H), 8.25 (s, 1H, Ar-H), 8.03 (d, J=8.2Hz, 1H, Ar-H),
6.70-6.68 (m, 2H, Ar-H), 4.75 (dd, J=11.4Hz, 4.0Hz, 1H ,-CH-), 3.08-2.95 (m, 2H ,-CH2-),
2.39-2.26(m,2H,-CH2-)ppm；13C-NMR(75MHz,DMSO-d6):δ176.9,171.0,155.5,139.1,
136.3,134.4,132.6,130.6,128.4,128.3,123.2,122.5,119.6,118.2,115.0,108.7,60.5,
25.6,23.9ppm；HRMS(ESI):m/z,calcd for C19H12F3N3O2S 402.0530(M-H)-,found
402.0660；IR(KBr):3373,3128,1773,1473,1409,1354,1270,1168,1132,1099,512cm-1.
Claims (7)
1. the compound of formula I or II or its pharmaceutically acceptable salt：
Wherein:
X represents carbon atom or nitrogen-atoms；
R1Represent halogen or C1~4Haloalkyl；
R2Represent hydrogen, halogen, cyano group or hydroxyl；
R2Also represent C1~4Alkyl, C1~4Alkoxy, C1~4Haloalkyl, cyclopropyl, imidazole radicals, pyrazolyl, triazolyl, tetrazolium
Base, morpholinyl, tetrahydrofuran base, piperidyl, piperazinyl, oxetanyl ,-C (O) Ra、-NRaRa、-COORa、-C(O)
NRaRb、-C(S)NRaRb、-NHC(O)Ra、-NHSO2RaOr-SO2NRaRb；Above-mentioned substitution base can also be optionally substituted by a hydroxyl group；Wherein Ra、Rb
Each independently represent hydrogen, C1~3Alkyl, C1~3Hydroxyalkyl or Ra、RbConnection formed nafoxidine base, piperidyl, morpholine base,
Piperazinyl or N-methyl piperazinyl.
R3Represent hydrogen or halogen；
R4Represent hydrogen, halogen, cyano group, hydroxyl or C1~4Alkoxy.
2. the compound of claim 1 or its pharmaceutically acceptable salt, wherein R1Represent halogen or trifluoromethyl.
3. the compound of claim 1 or its pharmaceutically acceptable salt, wherein R2Represent hydrogen, halogen, cyano group, hydroxyl, ring third
Base ,-NHC (O) Ra、-NHSO2RaOr-SO2NRaRb；Wherein Ra、RbEach independently represent hydrogen, C1~2Alkyl, C1~2Hydroxyalkyl or
Ra、RbConnection forms nafoxidine base, piperidyl, morpholine base, piperazinyl or N-methyl piperazinyl.
4. the compound of claim 1 or its pharmaceutically acceptable salt, are the compound of following any structure：
5. a kind of pharmaceutical composition, wherein containing the compound of any one of Claims 1-4 or its pharmaceutically acceptable salt
And pharmaceutically acceptable carrier.
6. the compound of any one of Claims 1-4 or its pharmaceutically acceptable salt are used as the competitiveness of androgen receptor
The purposes of antagonist.
7. the compound of any one of Claims 1-4 or its pharmaceutically acceptable salt are used to prepare treatment malignant tumour
The purposes of medicine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710057257.4A CN106810552B (en) | 2017-01-20 | 2017-01-20 | Thio-hydantoin ternary and ring class androgen receptor antagonists and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710057257.4A CN106810552B (en) | 2017-01-20 | 2017-01-20 | Thio-hydantoin ternary and ring class androgen receptor antagonists and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106810552A true CN106810552A (en) | 2017-06-09 |
| CN106810552B CN106810552B (en) | 2019-05-07 |
Family
ID=59112563
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710057257.4A Active CN106810552B (en) | 2017-01-20 | 2017-01-20 | Thio-hydantoin ternary and ring class androgen receptor antagonists and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106810552B (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108864086A (en) * | 2018-07-20 | 2018-11-23 | 新乡学院 | A kind of tetrahydroisoquinoline and imidazole skeleton compound and preparation method thereof |
| CN110028475A (en) * | 2019-05-13 | 2019-07-19 | 中国药科大学 | Novel C DK9 inhibitor, preparation method and application based on benzofuran structure |
| CN110256342A (en) * | 2019-07-16 | 2019-09-20 | 河南省科学院化学研究所有限公司 | A kind of synthetic method of 2- cyano-quinoline derivatives |
| CN110950797A (en) * | 2019-12-06 | 2020-04-03 | 丽水绿氟科技有限公司 | Preparation method of 2-trifluoromethyl-3-fluoro-4-picolinic acid and derivatives thereof |
| CN111518102A (en) * | 2019-05-14 | 2020-08-11 | 南京工业大学 | Cycloformyl and cyclic ketone compound, preparation method and pharmaceutical application thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101460467A (en) * | 2006-03-29 | 2009-06-17 | 加利福尼亚大学董事会 | Diarylthiohydantoin compounds |
-
2017
- 2017-01-20 CN CN201710057257.4A patent/CN106810552B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101460467A (en) * | 2006-03-29 | 2009-06-17 | 加利福尼亚大学董事会 | Diarylthiohydantoin compounds |
Non-Patent Citations (1)
| Title |
|---|
| PETR JANSA ET AL.: "HYDANTOINS AND THIOHYDANTOINS DERIVED FROM", 《HETEROCYCLES》 * |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108864086A (en) * | 2018-07-20 | 2018-11-23 | 新乡学院 | A kind of tetrahydroisoquinoline and imidazole skeleton compound and preparation method thereof |
| CN110028475A (en) * | 2019-05-13 | 2019-07-19 | 中国药科大学 | Novel C DK9 inhibitor, preparation method and application based on benzofuran structure |
| CN110028475B (en) * | 2019-05-13 | 2022-07-01 | 中国药科大学 | Novel CDK9 inhibitor based on benzopyran structure, preparation method and application thereof |
| CN111518102A (en) * | 2019-05-14 | 2020-08-11 | 南京工业大学 | Cycloformyl and cyclic ketone compound, preparation method and pharmaceutical application thereof |
| WO2020228783A1 (en) * | 2019-05-14 | 2020-11-19 | 南京工业大学 | Cyclic formyl and cyclic ketone compounds, preparation method therefor, and pharmaceutical use |
| CN111518102B (en) * | 2019-05-14 | 2023-09-05 | 南京工业大学 | Cycloformyl and cyclic ketone compounds, and preparation method and pharmaceutical application thereof |
| CN110256342A (en) * | 2019-07-16 | 2019-09-20 | 河南省科学院化学研究所有限公司 | A kind of synthetic method of 2- cyano-quinoline derivatives |
| CN110256342B (en) * | 2019-07-16 | 2022-06-07 | 河南省科学院化学研究所有限公司 | Synthetic method of 2-cyano quinoline derivative |
| CN110950797A (en) * | 2019-12-06 | 2020-04-03 | 丽水绿氟科技有限公司 | Preparation method of 2-trifluoromethyl-3-fluoro-4-picolinic acid and derivatives thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106810552B (en) | 2019-05-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106810552B (en) | Thio-hydantoin ternary and ring class androgen receptor antagonists and application thereof | |
| KR20220151616A (en) | Methods of treating estrogen receptor-related diseases | |
| CN106420745A (en) | Application of nuclear receptor binding agents in preparation of drugs for treating obesity, fibrosis, and cardiovascular diseases | |
| TW200302726A (en) | Nitrogen-containing bicyclic compound and medicament containing same as active ingredient | |
| KR20140101399A (en) | Fluorinated estrogen receptor modulators and uses thereof | |
| WO2010003313A1 (en) | Icotinib hydrochloride, synthesis, crystallographic form, medical combination, and uses thereof | |
| CN104367575B (en) | A kind of Bouchardatine and Bouchardatine derivatives and its preparation method and application | |
| CA2635318A1 (en) | Triterpenequinone and triterpenephenol derivatives and their application for the treatment of tumors and parasitic diseases | |
| JP6779318B2 (en) | Anti-metastatic 2H-selenopheno [3,2-h] chromen, their synthesis, and how to use the drug | |
| Guo et al. | Design, synthesis and biological evaluation of potential anti-AD hybrids with monoamine oxidase B inhibitory and iron-chelating effects | |
| Lu et al. | Design, synthesis and biological evaluation of fluorinated selective estrogen receptor degraders (FSERDs)---A promising strategy for advanced ER positive breast cancer | |
| CN106565674A (en) | Octahydrocyclopentano[c]pyrrole derivatives, and preparation methods and medicinal application thereof | |
| WO2021104072A1 (en) | Hydrogen peroxide-responsive keap1-nrf2 ppi inhibitor prodrug, preparation method therefor, and pharmaceutical use thereof | |
| CN102066362A (en) | Dihydroindolinone derivatives | |
| Tan et al. | Design, synthesis and biological evaluation of novel dihydroquinolin-4 (1H)-one derivatives as novel tubulin polymerization inhibitors | |
| CN107406425A (en) | As adenosine A2bReceptor antagonist and melatonin MT3The derivative of 2 aminopyridines of the part of acceptor | |
| CN111454229B (en) | Dihydronaphthoisoxazole derivative and application thereof in antitumor drugs | |
| Gao et al. | The discovery of a novel series of potential ERRα inverse agonists based on p-nitrobenzenesulfonamide template for triple-negative breast cancer in vivo | |
| CN105017145B (en) | 7-chloro-4-oxo-quinoline derivative with antitumor activity | |
| US20190071410A1 (en) | 3-Phenyl-7-Hydroxy-Isocoumarins as Macrophage Migration Inhibitory Factor (MIF) Inhibitors | |
| JP6021148B2 (en) | Compound transported by LST-1 and / or LST-2 | |
| WO2021104507A1 (en) | Substituted phenoxyamide derivative, use thereof and drugs for treating parkinson's disease | |
| US9381260B2 (en) | Hypoxia inducible factor-1 pathway inhibitors and uses as anticancer and imaging agents | |
| JP2022517396A (en) | EGFR inhibitor salt, crystalline form and method for producing it | |
| Hu et al. | Synthesis, biological evaluation and preliminary mechanisms of 6-amino substituted harmine derivatives as potential antitumor agents |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |