CN109438297A - Androgen receptor antagonists, preparation method and its application - Google Patents
Androgen receptor antagonists, preparation method and its application Download PDFInfo
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- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
- C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
- C07C311/19—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
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- C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
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Abstract
The present invention relates to androgen receptor antagonists, preparation method and its application, which is the compound that general formula (1) indicates and its pharmaceutically acceptable salt (R in general formula1、R2、R3And R4Definition as shown in specification).
Description
Technical field
The present invention relates to pharmaceutical technology fields, in particular to a kind of novel androgen receptor antagonists, its preparation side
Method and its application.
Background technique
Prostate-cancer incidence occupies second in all malignant tumours of male.Androgen receptor (Androgen
Receptor, AR) it is the important target for treating prostate cancer, the combination of androgen and AR is blocked using androgen receptor antagonists
Therapeutic purposes can be reached.Clinically used nonsteroidal androgens receptor antagonist have Bicalutamide (R-bicalutamide) and
The miscellaneous Shandong amine (Enzalutamide) of grace, structure is as follows.
These compounds are used to treatment prostate cancer, and Bicalutamide (US4636505) is Astrazeneca AB's exploitation,
Nineteen ninety-five listing, trade name Kang Shi get (Casodex).Miscellaneous Shandong amine (MDV3100, the US2007254933) trade name of grace
Xtandi is developed jointly by Medivation company and Astellas company, is supported in August, 2012 through FDA approval treatment trend
Refractory prostate cancer.Marcella Bassetto, Salvatore Ferla etc. is in " Design and synthesis of
novel bicalutamide and enzalutamide derivatives as antiproliferative agents
for the treatment of prostatecancer(European Journal of Medicinal Chemistry
118 (2016) 230-243) " in studies have shown that Bicalutamide is living in 22Rv1, DU-145, LNCaP and VCaP cell strain anticancer
Property IC50 geometric mean be 52.42 μM, the miscellaneous Shandong amine activity geometric mean of grace is then 28.10 μM, their bioactivity
It is universal not high, to reach therapeutic purposes, larger dose is needed to carry out using to increase patient's metabolic burden.In addition, than card Shandong
There are also the effects (agonist) for activating androgen receptor for amine, to stimulate cancer hyperplasia (CN104024228B).
Summary of the invention
Invent technical task to be solved
The present invention is completed in view of above-mentioned project existing in the prior art, and its purpose is to provide a kind of novel
The androgen receptor antagonists of high-efficiency low-toxicity, pharmaceutical activity is high, and dosage is low, and toxic side effect is small.
For solving the technological means of technical task
The present invention provides the compound and its pharmaceutically acceptable salt of the following general formula (1) expression,
Wherein, R1With R2It is identical or different, respectively indicate hydrogen atom or R1With R2It is formed together C3-6Naphthenic base；
R3Indicate hydrogen atom or C1-8Alkyl；
R4For substituted or unsubstituted C6-10Aryl or heteroaryl, the heteroaryl are 5- or 6-membered monocycle base, or are 5
Bicyclic group made of member or 6 unit monocycles and phenyl ring condensation.
In a preferred embodiment, R4For the C at least one substituent group6-10Aryl or heteroaryl, the substituent group are selected from
Halogen atom, cyano, nitro, C1-8Alkyl, halogenated C1-8Alkyl, halogenated C1-8Alkoxy, halogenated C1-8Alkylthio group, halogenated C1-8Alkane
Base sulfinyl, halogenated C1-8Alkyl sulphonyl or pentafluoride-sulfanyl.
In a preferred embodiment, R4For selected from any one of following radicals:
In formula, n indicates 1~7 integer.
In a preferred embodiment, the compound that above-mentioned general formula (1) indicates is selected from:
In addition, the present invention provides a kind of pharmaceutical composition, which is characterized in that containing above compound or its can pharmaceutically connect
The salt and pharmaceutically acceptable carrier received.
In addition, the invention further relates to above compound or its pharmaceutically acceptable salt preparation for prevent or treat with
Application in the drug of the relevant disease of estrogen receptor activity.Wherein, the disease packet relevant to estrogen receptor activity
It includes: hormone-sensitive prostate cancer, hormone-refractory prostate cancer, benign prostatic hyperplasis, acne, hirsutism, whelk, dark
Sore and alopecia.
In addition, the present invention provides a kind of preparation method of compound that general formula (1) indicates, which is characterized in that including as follows
Step:
Step (I) reacts compound (2) with oxalyl chloride or thionyl chloride in aprotic solvent, forms compound
(3)；
Step (II) reacts compound (3) with compound (4) in aprotic solvent, is formed compound (5)；
Step (III) in organic solvent reacts compound (5) with piperidines, is formed compound (6)；
Step (IV) in organic solvent reacts compound (6) with compound (7), is formed compound (1)；
R in the above formulas1、R2、R3And R4Definition it is same as described above.
Invention effect
(1) the compound of the present invention is the androgen antagonist of structure novel and excellent effect, can be used for treating androgen
Related disease has stronger inhibiting effect to prostate gland cancer cell, and cell activity is that clinical application Bicalutamide and grace are miscellaneous
The several times of Shandong amine.
(2) preparation method of the compound of the present invention is simple.
Specific embodiment
R used in this paper general formula1、R2、R3And R4The substituent group of the group of expression and these groups is as described below.
“C1-8Alkyl " refers to straight chain-or branched-Alkyl with 1 to 8 carbon atom, for example, methyl, second
Base, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, sec-butyl, n-pentyl, neopentyl, n-hexyl, isohesyl, 3- first
Base amyl, heptyl and octyl etc..
“C1~8Alkoxy " refers to straight chain-or branch-alkoxy (C with 1 to 8 carbon atom1-8Alkyl-O-), such as
Can enumerate methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy,
N-pentyloxy, neopentyl oxygen, positive hexyloxy, dissident's oxygroup, 3- methyl amoxy, positive oxygroup in heptan, n-octyloxy etc..
“C1~8Alkylthio group " refers to straight chain-or branch-alkylthio group (C with 1 to 8 carbon atom1-8Alkyl-S-), such as
Can enumerate methyl mercapto, ethylmercapto group, positive rosickyite base, isopropyisulfanyl, positive butylthio, isobutylthio, tertiary butylthio, secondary butylthio,
Positive penta sulfenyl, new penta sulfenyl, just own sulfenyl, isohexylthio, 3- methyl penta sulfenyl, positive sulfenyl in heptan, just pungent sulfenyl etc..
" halogen atom " indicates fluorine, chlorine, bromine and iodine.
" halogenated C1~8Alkyl " refers to above-mentioned " C1~8Hydrogen atom in alkyl " is replaced and formed by least one halogen atom
Group.Such as trihalomethyl group (such as-CF3), three halogenated ethyls are (such as-CH2CF3), five halogenated ethyls are (such as-CF2CF3) or nine halogen
For butyl (such as-CF2CF2CF2CF3) etc..
“C3~6Naphthenic base " refers to 3~6 yuan of saturation hydrocarbon rings, for example, cyclopropyl, cyclobutyl, cyclopenta, ring
Hexyl.
“C6-10Aryl " refers to the aromatic hydrocarbyl with 6~10 carbon atoms, for example, phenyl, Alpha-Naphthyl,
Betanaphthyl etc..
" heteroaryl " refers to 5- or 6-membered monocycle base, or is bicyclic made of above-mentioned 5- or 6-membered monocycle is condensed with phenyl ring
Base.5- or 6-membered monocycle base be containing selected from heteroatomic 5~6 unit's heteroaryl of at least one of N, O, S, for example,
Imidazoles, pyrazoles, pyridine, pyrazine, pyrimidine, pyridazine, thiophene, furans, pyrans, two pyrans, thiazole, isothiazole, thiadiazoles, thiazine,
Oxazole, isoxazole, pyrroles, dioxazole etc..For bicyclic group made of 5- or 6-membered monocycle and phenyl ring condensation, for example,
Benzimidazole, benzo pyridine, benzo pyrimidine, benzothiophene, benzofuran, benzothiazole, benzoxazoles, benzo isoxazole etc..
For the concrete example for the compound that general formula (1) of the invention indicates, can enumerate:
In addition, pharmaceutical composition of the invention, contains above-mentioned general formula (1) compound represented or its medicine as effective component
Acceptable salt on.The pharmaceutical compositions include compound described in any one of above embodiment and variation as work
Property ingredient, with pharmaceutically acceptable carrier, diluent or excipient composition.
Term " pharmaceutically acceptable salt " refers to the salt of the biological efficacy and property that keep the compounds of this invention, the salt one
As in terms of biology or other aspects do not have detrimental effect.In many cases, the compound of the present invention can utilize presence
Amino and/or carboxyl or similar group form hydrochlorate and/or alkali salt.
The compound of the present invention can be used in preventing or treat disease relevant to estrogen receptor activity, for example, hormone
Sensitive prostate cancer, hormone-refractory prostate cancer, benign prostatic hyperplasis, acne, hirsutism, whelk, dark sore and de-
Hair.
The compound of the present invention can be prepared via a method which.
R in formula1、R2、R3And R4Definition it is same as above.
In addition, the compound of the present invention can also be prepared by following methods.
R in formula1、R2、R3And R4Definition it is same as above, R5For tert-butyl or methyl.
Hereinafter, being illustrated by preparation method of the specific embodiment to the compound of the present invention.
Embodiment 1 (preparation of compound JD1001-1073)
By sarcosine t-butyl ester 1.82g (10mmol, 1.0eq), DCM 40ml, TEA 2.02g (20mmol, 2.0eq),
DMAP 122mg (1.0mmol, 0.1eq) is added in 100ml flask, will be to fluorophenylsulfonyl chloride under 0 DEG C of ice-water bath stirring condition
1.95g (10mmol, 1.0eq) is added dropwise in solution, reacts 2h after restoring room temperature, is determined after the reaction was completed by LCMS,
It is spin-dried for mother liquor, obtains 2.03g crude product JD1002-052-1, yield 66%.
To be added in 2.03g crude product JD1002-052-1 (10mmol, 1.0eq) DCM and TFA mixed solution (DCM:
TFA=2:1) 30ml reacts 4h after room temperature, and LCMS is determined after the reaction was completed, and 30ml H is added230ml is added in O quenching reaction
DCM extracts organic phase, dry, and revolving, column chromatographs to obtain 1.24g JD1002-052-2, yield 51%.
300mg solid JD1002-052-2 is taken, is dissolved in 3mL (3V) DCM, 3 drop DMF are added, 0 DEG C are cooled to, in low temperature
Under 3eq oxalyl chloride is added dropwise, be added dropwise and be warmed to room temperature reaction 2 hours, take it is a small amount of Derivatization of methanol is added after examined through LCMS
It surveys, end of reaction is concentrated under reduced pressure to give 350mg solid product JD1001-002-13, saves backup under nitrogen protection.
0.1g (1.0mmol, 1.0eq) JD1001-002-13,3.2mL is added under nitrogen protection into 25mL reactor
(10.0V) THF, 0.32g (3mmol, 3.1eq) NaHCO3, 0.38g (3.0mmol, 3.0eq) 4- (five fluorine are thio) aniline, heating
It is stirred to react 3 hours to 60 DEG C, TLC detects raw material end of reaction (solvent: PE/EA=1/1, UV254), stops reaction, adds
Enter water quenching reaction, organic phase is obtained by extraction with ethyl acetate, then dry, filter out organic phase, organic phase with anhydrous sodium sulfate
It is concentrated to give solid, through HPLC (CH3CN/H2O=60:40 it) isolates and purifies to obtain 52mg JD1001-1073.Yield 36%.
H-NMR-JD1001-1073:(DMSO, ppm, 400MHz) δ 2.85 (3H, s), 4.02 (2H, s), 7.48 (2H,
dd),7.73(2H,d),7.89(4H,m),10.49(1H,s).LCMS[M+H]+449
Embodiment 2 (preparation of compound JD1001-1074)
By sarcosine t-butyl ester 1.82g (10mmol, 1.0eq), DCM 40ml, TEA 2.02g (20mmol, 2.0eq),
DMAP 122mg (1.0mmol, 0.1eq) is added in 100ml flask, will be to fluorophenylsulfonyl chloride under 0 DEG C of ice-water bath stirring condition
1.95g (10mmol, 1.0eq) is added dropwise in solution, reacts 2h after restoring room temperature, LCMS is determined after the reaction was completed, is spin-dried for
Mother liquor obtains 3.03g crude product JD1002-052-1, yield 100%.
To be added in 3.03g crude product JD1002-052-1 (10mmol, 1.0eq) DCM and TFA mixed solution (DCM:
TFA=2:1) 30ml reacts 4h after room temperature, and LCMS is determined after the reaction was completed, and 30ml H is added230ml is added in O quenching reaction
DCM extracts organic phase, dry, and revolving, column chromatographs to obtain 1.17g, yield 47%.
300mg solid JD1002-052-2 is taken, is dissolved in 3mL (3V) DCM, 3 drop DMF are added, 0 DEG C are cooled to, in low temperature
Under 3eq oxalyl chloride is added dropwise, be added dropwise and be warmed to room temperature reaction 2 hours, take it is a small amount of Derivatization of methanol is added after examined through LCMS
It surveys, end of reaction is concentrated under reduced pressure to give 350mg solid product JD1001-002-13, saves backup under nitrogen protection.
0.1g (1.0mmol, 1.0eq) JD1001-002-13,3.2mL is added under nitrogen protection into 25mL reactor
(10.0V) THF, 0.32g (3mmol, 3.1eq) NaHCO3, 0.38g (3.0mmol, 3.0eq) 3- (five fluorine are thio) aniline, heating
It is stirred to react 3 hours to 60 DEG C, TLC detects raw material end of reaction (solvent: PE/EA=1/1, UV254), stops reaction, adds
Enter water quenching reaction, organic phase is obtained by extraction with ethyl acetate, then dry, filter out organic phase, organic phase with anhydrous sodium sulfate
It is concentrated to give solid, through HPLC (CH3CN/H2O=60:40 it) isolates and purifies to obtain 65mg JD1001-1074, yield 53%.
H-NMR-JD1001-1074:(DMSO, ppm, 400MHz) δ 2.87 (3H, s), 3.99 (2H, s), 7.47 (2H,
dd),7.59(2H,m),7.72(1H,d),7.89(2H,dd),8.20(1H,d),10.45(1H,s).LCMS[M+H]+449
Embodiment 3 (preparation of compound JD1001-1075)
(1) synthesis of JD1001-002-8
2.0g (15.4mmol, 1eq) Fmoc-1- aminocyclobutane carboxylic acid is added under nitrogen protection into 200mL there-necked flask,
It is added DCM 20mL (10V), 4 drop DMF is added, 4.0g oxalyl chloride (32mmol, 5eq) are added dropwise at room temperature, at room temperature
It is stirred to react 4 hours, after completion of the reaction (solvent: PE/EA=1/1, UV254) through Derivatization of methanol TLC detection, removes under reduced pressure
Oxalyl chloride and DCM, obtain faint yellow solid；It is charged with 50mL dry THF, 0.8g (22.6mmol, 1.5eq) NaHCO3,
1.4g (18.3mmol, 1.2eq) 4- (five fluorine are thio) aniline, is heated to 60 DEG C, and be stirred to react 2 hours at this temperature, TLC
It detects raw material end of reaction (solvent: PE/EA=1/1, UV254), stops reacting and dropping to room temperature, the dilution of 200mL water is added
Reaction system, with 100mL EA extraction, organic phase is dried over anhydrous sodium sulfate, filters out organic phase, be added into organic phase
Reaction 1 hour is stirred at room temperature in 40mL piperidines, end of reaction (solvent: PE/EA=1/1, UV254) is detected through TLC, 40
DEG C evaporating solvent under reduced pressure, obtains 4g solid.Solid is dissolved with methylene chloride, 16g silica gel mixed sample is added, with petroleum ether and acetic acid second
Ester separation (PE/EA=5:1~1:1) obtains 0.9g solid chemical compound JD1001-002-8, yield 38%.
LC-MS-JD1001-002-8:(ES,m/z):[M+H]+calcd for C11H13F5N2OS317,found 317
(2) preparation of compound JD1001-1075
0.3g (1.0mmol, 1.0eq) JD1001-002- as obtained above is added under nitrogen protection into 25mL reactor
8,3.2mL (10.0V) THF, 0.32g (3mmol, 3.1eq) DMAP, 0.38g (3.0mmol, 3.0eq) 4- fluorophenylsulfonyl chlorides,
It being stirred to react at room temperature 3 hours, TLC detects raw material end of reaction (solvent: PE/EA=1/1, UV254), stop reaction, with
It is saturated NaHCO3Organic phase is obtained by extraction in quenching reaction, ethyl acetate, and organic phase is with 0.5N salt acid elution 2 times, then with anhydrous sulphur
Sour sodium dries, filters out organic phase, and organic phase is concentrated to give solid, through HPLC (CH3CN/H2O=60:40 it) isolates and purifies to obtain
83mg JD1001-1075.Yield 34%.
H-NMR-JD1001-1075:(DMSO, ppm, 400MHz) δ 1.62 (1H, m), 1.75 (1H, m), 2.10 (2H, m),
2.43(2H,m),7.27(2H,m),7.75(2H,m),7.79(4H,m),8.32(1H,s),9.87(1H,s).LCMS[M+H]+
475
Embodiment 4 (preparation of compound JD1001-1076)
0.3g (1.0mmol, 1.0eq) JD1001-002-8,3.2mL is added under nitrogen protection into 25mL reactor
(10.0V) THF, 0.32g (3mmol, 3.1eq) DMAP, 0.38g (3.0mmol, 3.0eq) 3,5- difluoro chloride, in room temperature
Under be stirred to react 3 hours, TLC detect raw material end of reaction (solvent: PE/EA=1/1, UV254), stop reaction, with saturation
NaHCO3Organic phase is obtained by extraction in quenching reaction, ethyl acetate, and organic phase is with 0.5N salt acid elution 2 times, then uses anhydrous sodium sulfate
Organic phase is dried, filtered out, organic phase is concentrated to give solid, through HPLC (CH3CN/H2O=60:40 it) isolates and purifies to obtain 121mg
JD1001-1076.Yield 40%.
H-NMR-JD1001-1076:(DMSO,ppm,400MHz)δ1.65(1H,m),1.78(1H,m),2.15(2H,m),
2.46(2H,m),7.36(3H,m),7.70(2H,d),7.80(2H,d),8.63(1H,bs),9.90(1H,s).LCMS[M+H]+
493
Embodiment 5 (preparation of compound JD1001-1077)
0.3g (1.0mmol, 1.0eq) above-mentioned JD1001-002-8,3.2mL is added under nitrogen protection into 25mL reactor
(10.0V) THF, 0.32g (3mmol, 3.1eq) DMAP, 0.38g (3.0mmol, 3.0eq) 3,4,5- trifluoro benzene sulfonyl chloride, in room
It is stirred to react under temperature 3 hours, TLC detects raw material end of reaction (solvent: PE/EA=1/1, UV254), stops reaction, with full
And NaHCO3Organic phase is obtained by extraction in quenching reaction, ethyl acetate, and organic phase is with 0.5N salt acid elution 2 times, then uses anhydrous slufuric acid
Sodium dries, filters out organic phase, and organic phase is concentrated to give solid, through HPLC (CH3CN/H2O=60:40 it) isolates and purifies to obtain 67mg
JD1001-1077.Yield 24%.
H-NMR-JD1001-1077:(DMSO, ppm, 400MHz) δ 1.67 (1H, m), 1.83 (1H, m), 2.22 (2H, m),
2.51(2H,m),7.52(2H,dd),7.66(2H,d),7.79(2H,m),8.65(1H,bs),9.85(1H,s).LCMS[M+H]+
511
Embodiment 6 (preparation of compound JD1001-1078)
0.3g (1.0mmol, 1.0eq) above-mentioned JD1001-002-8,3.2mL is added under nitrogen protection into 25mL reactor
(10.0V) THF, 0.32g (3mmol, 3.1eq) DMAP, 0.38g (3.0mmol, 3.0eq) 2- trifluoromethyl benzene sulfonyl chloride, in room
It is stirred to react under temperature 3 hours, TLC detects raw material end of reaction (solvent: PE/EA=1/1, UV254), stops reaction, with full
And NaHCO3Organic phase is obtained by extraction in quenching reaction, ethyl acetate, and organic phase is with 0.5N salt acid elution 2 times, then uses anhydrous slufuric acid
Sodium dries, filters out organic phase, and organic phase is concentrated to give solid, through HPLC (CH3CN/H2O=60:40 it) isolates and purifies to obtain 91mg
JD1001-1078.Yield 33%.
H-NMR-JD1001-1078:(DMSO, ppm, 400MHz) δ 1.66 (1H, m), 1.79 (1H, m), 2.23 (2H, m),
2.51(2H,m),7.60-7.90(7H,m),8.10(1H,d),8.33(1H,s),9.79(1H,s).LCMS[M+H]+525
Embodiment 7 (preparation of compound JD1001-1079)
0.3g (1.0mmol, 1.0eq) above-mentioned JD1001-002-8,3.2mL is added under nitrogen protection into 25mL reactor
(10.0V) THF, 0.32g (3mmol, 3.1eq) DMAP, 0.38g (3.0mmol, 3.0eq) 3- trifluoromethyl benzene sulfonyl chloride, in room
It is stirred to react under temperature 3 hours, TLC detects raw material end of reaction (solvent: PE/EA=1/1, UV254), stops reaction, with full
And NaHCO3Organic phase is obtained by extraction in quenching reaction, ethyl acetate, and organic phase is with 0.5N salt acid elution 2 times, then uses anhydrous slufuric acid
Sodium dries, filters out organic phase, and organic phase is concentrated to give solid, through HPLC (CH3CN/H2O=60:40 it) isolates and purifies to obtain 42mg
JD1001-1079.Yield 18%.
H-NMR-JD1001-1079:(DMSO, ppm, 400MHz) δ 1.62 (1H, m), 1.74 (1H, m), 2.12 (2H, m),
2.43(2H,m),7.63(2H,d),7.74(3H,m),7.81(1H,d),7.95(1H,s),8.01(1H,d),8.62(1H,s),
9.91(1H,s).LCMS[M+H]+525
Embodiment 8 (preparation of compound JD1001-1080)
0.3g (1.0mmol, 1.0eq) above-mentioned JD1001-002-8,3.2mL is added under nitrogen protection into 25mL reactor
(10.0V) THF, 0.32g (3mmol, 3.1eq) DMAP, 0.38g (3.0mmol, 3.0eq) 4- trifluoromethyl benzene sulfonyl chloride, in room
It is stirred to react under temperature 3 hours, TLC detects raw material end of reaction (solvent: PE/EA=1/1, UV254), stops reaction, with full
And NaHCO3Organic phase is obtained by extraction in quenching reaction, ethyl acetate, and organic phase is with 0.5N salt acid elution 2 times, then uses anhydrous slufuric acid
Sodium dries, filters out organic phase, and organic phase is concentrated to give solid, through HPLC (CH3CN/H2O=60:40 it) isolates and purifies to obtain 21mg
JD1001-1080.Yield 11%.
H-NMR-JD1001-1080:(DMSO, ppm, 400MHz) δ 1.65 (1H, m), 1.82 (1H, m), 2.22 (2H, m),
2.46(2H,m),7.57(2H,d),7.71(2H,m),7.88(2H,d),8.48(1H,s),9.75(1H,s).LCMS[M+H]+
525
Embodiment 9 (preparation of compound JD1001-1081)
0.3g (1.0mmol, 1.0eq) JD1001-002-8,3.2mL is added under nitrogen protection into 25mL reactor
(10.0V) THF, 0.32g (3mmol, 3.1eq) DMAP, 0.38g (3.0mmol, 3.0eq) 3- cyano -4- fluorophenylsulfonyl chloride,
It being stirred to react at room temperature 3 hours, TLC detects raw material end of reaction (solvent: PE/EA=1/1, UV254), stop reaction, with
It is saturated NaHCO3Organic phase is obtained by extraction in quenching reaction, ethyl acetate, and organic phase is with 0.5N salt acid elution 2 times, then with anhydrous sulphur
Sour sodium dries, filters out organic phase, and organic phase is concentrated to give solid, through HPLC (CH3CN/H2O=60:40 it) isolates and purifies to obtain
15mg JD1001-1081, yield 7%.
H-NMR-JD1001-1081:(DMSO, ppm, 400MHz) δ 1.65 (1H, m), 1.82 (1H, m), 2.02 (2H, m),
2.23(2H,m),7.52(1H,dd),7.64(2H,m),7.76(2H,m),8.01(1H,m),8.07(1H,d),8.90(1H,
bs),9.95(1H,s).LCMS[M+H]+499
Embodiment 10 (preparation of compound JD1001-1082)
0.3g (1.0mmol, 1.0eq) above-mentioned JD1001-002-8,3.2mL is added under nitrogen protection into 25mL reactor
The fluoro- 3- trifluoromethyl benzene sulfonyl of (10.0V) THF, 0.32g (3mmol, 3.1eq) DMAP, 0.38g (3.0mmol, 3.0eq) 4-
Reaction 3 hours is stirred at room temperature in chlorine, and TLC detects raw material end of reaction (solvent: PE/EA=1/1, UV254), stops anti-
It answers, to be saturated NaHCO3Organic phase is obtained by extraction in quenching reaction, ethyl acetate, and organic phase is with 0.5N salt acid elution 2 times, then uses nothing
Aqueous sodium persulfate dries, filters out organic phase, and organic phase is concentrated to give solid, through HPLC (CH3CN/H2O=60:40 it) isolates and purifies
To 52mg JD1001-1082, yield 24%.
H-NMR-JD1001-1082:(DMSO, ppm, 400MHz) δ 1.65 (1H, m), 1.82 (1H, m), 2.21 (2H, m),
2.46(2H,m),7.50-7.65(3H,m),7.74(2H,d),7.93(1H,t),8.03(1H,m),8.74(1H,bs),9.91
(1H,s).LCMS[M+H]+543
Embodiment 11 (preparation of compound JD1001-1083)
0.3g (1.0mmol, 1.0eq) JD1001-002-8,3.2mL is added under nitrogen protection into 25mL reactor
(10.0V) THF, 0.32g (3mmol, 3.1eq) DMAP, 0.38g (3.0mmol, 3.0eq) 6- trifluoromethyl pyridine -3- sulphonyl
Reaction 3 hours is stirred at room temperature in chlorine, and TLC detects raw material end of reaction (solvent: PE/EA=1/1, UV254), stops anti-
It answers, to be saturated NaHCO3Organic phase is obtained by extraction in quenching reaction, ethyl acetate, and organic phase is with 0.5N salt acid elution 2 times, then uses nothing
Aqueous sodium persulfate dries, filters out organic phase, and organic phase is concentrated to give solid, through HPLC (CH3CN/H2O=60:40 it) isolates and purifies
To 65mg JD1001-1083, yield 27%.
H-NMR-JD1001-1083:(DMSO, ppm, 400MHz) δ 1.67 (1H, m), 1.85 (1H, m), 2.27 (2H, m),
2.50(2H,m),7.55(2H,d),7.72(1H,d),7.86(1H,d),8.28(1H,dd),8.96(1H,d),9.86(1H,
s).LCMS[M+H]+526
Embodiment 12 (preparation of compound JD1001-1089)
0.3g (1.0mmol, 1.0eq) above-mentioned JD1001-002-8,3.2mL is added under nitrogen protection into 25mL reactor
Bis- (trifluoromethyl) benzene sulfonyl of (10.0V) THF, 0.32g (3mmol, 3.1eq) DMAP, 0.38g (3.0mmol, 3.0eq) 3,5-
Reaction 3 hours is stirred at room temperature in chlorine, and TLC detects raw material end of reaction (solvent: PE/EA=1/1, UV254), stops anti-
It answers, to be saturated NaHCO3Organic phase is obtained by extraction in quenching reaction, ethyl acetate, and organic phase is with 0.5N salt acid elution 2 times, then uses nothing
Aqueous sodium persulfate dries, filters out organic phase, and organic phase is concentrated to give solid, through HPLC (CH3CN/H2O=60:40 it) isolates and purifies
To 131mg JD1001-1089.Yield 46%.
H-NMR-JD1001-1089:(DMSO, ppm, 400MHz) δ 1.66 (1H, m), 1.84 (1H, m), 2.23 (2H, m),
2.51(2H,m),7.53(2H,d),7.69(2H,d),8.10(1H,s),8.16(2H,s),8.88(1H,s),9.83(1H,s)
.LCMS[M+H]+593
Embodiment 13 (preparation of compound JD1001-1090)
5.0g (15.4mmol, 1eq) Fmoc-1- aminocyclobutane carboxylic acid is added under nitrogen protection into 200mL there-necked flask,
It is added DCM 50mL (10V), 4 drop DMF is added, 9.8g oxalyl chloride (76.9mmol, 5eq) are added dropwise at room temperature, in room temperature
Under be stirred to react 4 hours, through Derivatization of methanol TLC detection after completion of the reaction (solvent: PE/EA=1/1, UV254), decompression steam
Except oxalyl chloride and DCM, faint yellow solid is obtained；It is charged with 90mL dry THF, 1.9g (22.6mmol, 1.5eq)
NaHCO3, 3.4g (18.3mmol, 1.2eq) 3- (five fluorine are thio) aniline is heated to 60 DEG C, and be stirred to react 2 at this temperature
Hour, TLC detects raw material end of reaction (solvent: PE/EA=1/1, UV254), stops reacting and drops to room temperature, is added
200mL water diluting reaction system, with 200mL EA extraction, organic phase is dried over anhydrous sodium sulfate, and filters out organic phase, past organic
In phase be added 40mL piperidines, be stirred at room temperature reaction 1 hour, through TLC detection end of reaction (solvent: PE/EA=1/1,
UV254), in 40 DEG C of evaporating solvent under reduced pressure, 8g solid is obtained.Solid is dissolved with methylene chloride, 16g silica gel mixed sample is added, with stone
Oily ether and ethyl acetate separation (PE/EA=5:1~1:1) obtain 1.6g solid chemical compound JD1001-002-14, yield 37%.
0.1g (1.0mmol, 1.0eq) JD1001-002-14,3.2mL is added under nitrogen protection into 25mL reactor
Bis- (trifluoromethyl) benzene sulfonyl of (10.0V) THF, 0.32g (3mmol, 3.1eq) DMAP, 0.38g (3.0mmol, 3.0eq) 3,5-
Reaction 3 hours is stirred at room temperature in chlorine, and TLC detects raw material end of reaction (solvent: PE/EA=1/1, UV254), stops anti-
It answers, to be saturated NaHCO3Organic phase is obtained by extraction in quenching reaction, ethyl acetate, and organic phase is with 0.5N salt acid elution 2 times, then uses nothing
Aqueous sodium persulfate dries, filters out organic phase, and organic phase is concentrated to give solid, through HPLC (CH3CN/H2O=60:40 it) isolates and purifies
To 53mg JD1001-1090, yield 35%.
H-NMR-JD1001-1090:(DMSO, ppm, 400MHz) δ 1.68 (1H, m), 1.86 (1H, m), 2.26 (2H, m),
2.51(2H,m),7.43(1H,m),7.51(1H,m),7.63(1H,dd),7.90(1H,dd),8.17(1H,d),8.88(1H,
s),9.79(1H,s).LCMS[M+H]+593
Embodiment 14 (preparation of compound JD1001-1091)
3.0g (2.0mmol, 1.0eq) 1- amino-cyclopropane methyl formate salt is added under nitrogen protection into 25mL reactor
30mL (10.0V) THF is added into system, 3.0g (3.0mmol, 1.5eq) triethylamine is added dropwise at room temperature, then for hydrochlorate
0.3 gram of (0.2mmol, 0.1eq) DMAP is added, bis- (trifluoromethyl) benzene sulphur of 4.2g (2.2mmol, 1.1eq) 3,5- is then added dropwise
Reaction 3 hours is stirred at room temperature in acyl chlorides, and TLC detects raw material end of reaction (solvent: PE/EA=1/1, UV254), stops
Reaction, to be saturated NaHCO3Organic phase is obtained by extraction in quenching reaction, ethyl acetate, and organic phase is with 0.5N salt acid elution 2 times, then uses
Anhydrous sodium sulfate dries, filters out organic phase, and organic phase is concentrated to give 6.8 grams of solids.Solid is dissolved in ethyl alcohol (100mL, 15V),
30mL (5V) water is added, 4 grams of NaOH (5.0eq) is then added, is heated to 60 DEG C and is stirred to react 2 hours, reaction is supervised through LCMS
Control stops reaction after the reaction was completed, is concentrated under reduced pressure ethyl alcohol, and DCM extraction is added, and organic phase is free of product through detection, and water phase adds
Enter salt acid for adjusting pH value to 5, there is solid precipitation, 3.5 grams of faint yellow solids are obtained by filtration.300mg solid is taken, 3mL (3V) is dissolved in
In DCM, 3 drop DMF are added, is cooled to 0 DEG C, 3eq oxalyl chloride is added dropwise at low temperature, is added dropwise that be warmed to room temperature reaction 2 small
When, it is detected after taking a small amount of addition Derivatization of methanol through LCMS, end of reaction is concentrated under reduced pressure to give 350mg solid product JD1001-
002-12 is saved backup under nitrogen protection.
LC-MS-JD1001-002-12 (methyl esters): (ES, m/z): [M+H]+calcd for C13H11F6NO4S 392,
found 392
0.1g (1.0mmol, 1.0eq) JD1001-002-12,3.2mL is added under nitrogen protection into 25mL reactor
(10.0V) THF, 0.32g (3mmol, 3.1eq) NaHCO3, 0.38g (3.0mmol, 3.0eq) 2- (Pentafluorothio)
Aniline is heated to 60 DEG C and is stirred to react 3 hours, and TLC detects raw material end of reaction (solvent: PE/EA=1/1, UV254),
Stop reaction, water quenching reaction is added, organic phase is obtained by extraction with ethyl acetate, then dried, filtered with anhydrous sodium sulfate, it is organic
It is mutually concentrated to give solid, through HPLC (CH3CN/H2O=60:40 it) isolates and purifies to obtain 76mg JD1001-1091.Yield 41%.
LC-MS-JD1001-1091:(ES,m/z):[M+H]+calcd for C18H13F11N2O3S2 579,found 579
H-NMR-JD1001-1091:(DMSO, ppm, 400MHz) δ 1.03 (2H, m), 1.38 (2H, m), 7.50 (2H, m),
7.65(1H,m),7.96(1H,dd),8.38(2H,s),8.52(1H,s),9.24(1H,s),9.50(1H,s).
Comparative example 1 (synthesis of compound JD1001-1183)
(1) synthesis of JD1001-002-22
3.0g (2.0mmol, 1.0eq) 1- amino cyclobutane formate methyl esters salt is added under nitrogen protection into 25mL reactor
30mL (10.0V) THF is added into system, 3.0g (3.0mmol, 1.5eq) triethylamine is added dropwise at room temperature, then for hydrochlorate
0.3g (0.2mmol, 0.1eq) DMAP is added, bis- (trifluoromethyl) benzene sulfonyl of 4.2g (2.2mmol, 1.1eq) 3,5- is then added dropwise
Reaction 3 hours is stirred at room temperature in chlorine, and TLC detects raw material end of reaction (solvent: PE/EA=1/1, UV254), stops anti-
It answers, to be saturated NaHCO3Organic phase is obtained by extraction in quenching reaction, ethyl acetate, and organic phase is with 0.5N salt acid elution 2 times, then uses nothing
Aqueous sodium persulfate dries, filters out organic phase, and organic phase is concentrated to give 6.8g solid.Solid is dissolved in ethyl alcohol (100mL, 15V), is added
Then 30mL (5V) water is added NaOH 4g (5.0eq), is heated to 60 DEG C and is stirred to react 2 hours, reaction is monitored through LCMS, reacts
Stop reaction after the completion, be concentrated under reduced pressure ethyl alcohol, DCM extraction is added, organic phase is free of product through detection, and hydrochloric acid tune is added in water phase
PH value is saved to 5, has solid precipitation, 3.5g faint yellow solid is obtained by filtration.300mg solid is taken, is dissolved in 3mL (3V) DCM, is added
3 drop DMF, are cooled to 0 DEG C, 3eq oxalyl chloride are added dropwise at low temperature, be added dropwise and be warmed to room temperature reaction 2 hours, take a small amount of add
It is detected after entering Derivatization of methanol through LCMS, end of reaction is concentrated under reduced pressure to give 350mg solid product JD1001-002-22, nitrogen
It is saved backup under protection.
LC-MS-JD1001-002-22 (methyl esters): (ES, m/z): [M+H]+406
(2) synthesis of JD1001-1183
0.1g (1.0mmol, 1.0eq) above-mentioned JD1001-002-22 is added under nitrogen protection into 25mL reactor,
3.2mL (10.0V) THF, 0.32g (3mmol, 3.1eq) NaHCO3, 0.38g (3.0mmol, 3.0eq) neighbour's 5 amido benzotrifluoride,
It is heated to 60 DEG C to be stirred to react 3 hours, TLC detects raw material end of reaction (solvent: PE/EA=1/1, UV254), stops anti-
It answers, water quenching reaction is added, organic phase is obtained by extraction with ethyl acetate, then dry, filter out organic phase with anhydrous sodium sulfate, had
Machine is mutually concentrated to give solid, through HPLC (CH3CN/H2O=60:40 it) isolates and purifies to obtain 21mg JD1001-1183.Yield 23%.
LC-MS-JD1001-1183:(ES,m/z):[M+H]+535
H-NMR-JD1001-1183:(DMSO, ppm, 400MHz) δ 1.70 (2H, m), 2.08 (2H, m), 2.41 (2H, m),
7.40(1H,d),7.45(1H,dd),7.66(1H,dd),7.74(1H,d),8.38(2H,s),8.50(1H,s),9.06(1H,
s),9.24(1H,s).
Comparative example 2 (synthesis of compound JD1001-1184)
0.1g (1.0mmol, 1.0eq) JD1001-002-22,3.2mL is added under nitrogen protection into 25mL reactor
(10.0V) THF, 0.32g (3mmol, 3.1eq) NaHCO3, 0.38g (3.0mmol, 3.0eq) mamino-trifluoromethyl benzene is heated to
60 DEG C are stirred to react 3 hours, and TLC detects raw material end of reaction (solvent: PE/EA=1/1, UV254), stop reaction, are added
Water quenching reaction is obtained by extraction organic phase with ethyl acetate, then dries, filters out organic phase with anhydrous sodium sulfate, and organic phase is dense
Contract to obtain solid, through HPLC (CH3CN/H2O=60:40 it) isolates and purifies to obtain 18mg JD1001-1184.Yield 21%.
LC-MS-JD1001-1184:(ES,m/z):[M+H]+535
H-NMR-JD1001-1184:(DMSO, ppm, 400MHz) δ 1.69 (1H, m), 1.87 (1H, m), 2.28 (2H, m),
2.53(2H,m),7.32(1H,d),7.40(1H,d),7.59(1H,d),7.67(1H,s),8.09(1H,s),8.17(2H,s),
8.81(1H,s),9.65(1H,s).
Comparative example 3 (synthesis of compound JD1001-1185)
0.1g (1.0mmol, 1.0eq) above-mentioned JD1001-002-22 is added under nitrogen protection into 25mL reactor,
3.2mL (10.0V) THF, 0.32g (3mmol, 3.1eq) NaHCO3, 0.38g (3.0mmol, 3.0eq) to 5 amido benzotrifluoride,
It is heated to 60 DEG C to be stirred to react 3 hours, TLC detects raw material end of reaction (solvent: PE/EA=1/1, UV254), stops anti-
It answers, water quenching reaction is added, organic phase is obtained by extraction with ethyl acetate, then dry, filter out organic phase with anhydrous sodium sulfate, had
Machine is mutually concentrated to give solid, through HPLC (CH3CN/H2O=60:40 it) isolates and purifies to obtain 31mg JD1001-1185.Yield 29%.
LC-MS-JD1001-1185:(ES,m/z):[M+H]+535
H-NMR-JD1001-1185:(DMSO, ppm, 400MHz) δ 1.66 (1H, m), 1.84 (1H, m), 2.24 (2H, m),
2.52(2H,m),7.53(4H,m),8.13(1H,s),8.17(2H,s),8.78(1H,bs),9.74(1H,s).
Comparative example 4 (synthesis of compound JD1001-1186)
0.1g (1.0mmol, 1.0eq) above-mentioned JD1001-002-22 is added under nitrogen protection into 25mL reactor,
(3.2mL 10.0V) THF, 0.32g (3mmol, 3.1eq) NaHCO3, 0.38g (3.0mmol, 3.0eq) p-aminophenyl first cyanogen adds
Heat is stirred to react 3 hours to 60 DEG C, and TLC detects raw material end of reaction (solvent: PE/EA=1/1, UV254), stops reaction,
Water quenching reaction is added, organic phase is obtained by extraction with ethyl acetate, then dry, filter out organic phase with anhydrous sodium sulfate, it is organic
It is mutually concentrated to give solid, through HPLC (CH3CN/H2O=60:40 it) isolates and purifies to obtain 41mg JD1001-1186.Yield 38%.
LC-MS-JD1001-1186:(ES,m/z):[M+H]+492
H-NMR-JD1001-1186:(DMSO, ppm, 400MHz) δ 1.72 (2H, m), 2.13 (2H, m), 2.47 (2H, m),
7.32(1H,d),7.36(1H,m),7.64(1H,m),7.80(1H,dd),8.33(2H,s),8.45(1H,s),8.99(1H,
s),9.78(1H,s).
Comparative example 5 (synthesis of compound JD1001-1187)
0.1g (1.0mmol, 1.0eq) above-mentioned JD1001-002-22 is added under nitrogen protection into 25mL reactor,
3.2mL (10.0V) THF, 0.32g (3mmol, 3.1eq) NaHCO3, 0.38g (3.0mmol, 3.0eq) p-aminophenyl first cyanogen adds
Heat is stirred to react 3 hours to 60 DEG C, and TLC detects raw material end of reaction (solvent: PE/EA=1/1, UV254), stops reaction,
Water quenching reaction is added, organic phase is obtained by extraction with ethyl acetate, then dry, filter out organic phase with anhydrous sodium sulfate, it is organic
It is mutually concentrated to give solid, through HPLC (CH3CN/H2O=60:40 it) isolates and purifies to obtain 16mg JD1001-1187.Yield 12%.
LC-MS-JD1001-1187:(ES,m/z):[M+H]+492
H-NMR-JD1001-1187:(DMSO, ppm, 400MHz) δ 1.67 (1H, m), 1.85 (1H, m), 2.27 (2H, m),
2.54(2H,m),7.39(1H,dd),7.45(1H,d),7.59(1H,d),7.74(1H,s),8.15(1H,s),8.18(2H,
s),8.82(1H,s),9.69(1H,s).
Comparative example 6 (synthesis of compound JD1001-1188)
0.1g (1.0mmol, 1.0eq) above-mentioned JD1001-002-22 is added under nitrogen protection into 25mL reactor,
3.2mL (10.0V) THF, 0.32g (3mmol, 3.1eq) NaHCO3, 0.38g (3.0mmol, 3.0eq) p-aminophenyl first cyanogen adds
Heat is stirred to react 3 hours to 60 DEG C, and TLC detects raw material end of reaction (solvent: PE/EA=1/1, UV254), stops reaction,
Water quenching reaction is added, organic phase is obtained by extraction with ethyl acetate, then dry, filter out organic phase with anhydrous sodium sulfate, it is organic
It is mutually concentrated to give solid, through HPLC (CH3CN/H2O=60:40 it) isolates and purifies to obtain 18mg JD1001-1188.Yield 13%.
LC-MS-JD1001-1188:(ES,m/z):[M+H]+492
H-NMR-JD1001-1188:(DMSO, ppm, 400MHz) δ 1.65 (1H, m), 1.82 (1H, m), 2.20 (2H, m),
2.48(2H,m),7.54(2H,dd),7.64(2H,dd),8.18(2H,s),8.25(1H,s),8.34(1H,s),9.82(1H,
s).
Test example
In accordance with the following methods, activity test is carried out for the compound of above-described embodiment and comparative example:
(1) gained compound is dissolved in DMSO, is configured to the solution of 10mM, saved in -20 DEG C.
(2) logarithmic growth phase cell is collected, is counted, with complete medium again suspension cell, adjusts cell concentration to conjunction
Suitable concentration (it is as follows that every hole inoculating cell number according to cell number optimizes preliminary result: Du-145 (human prostate cancer cell line,
Androgen independence, AR-/PSA-, purchased from neat (Shanghai) the bioengineering Co., Ltd of match), 4000/hole；22RV-1 is (before people
Column adenocarcinoma cell strain, androgen-dependent, AR+/PSA+ are purchased from Ji Niou Biotechnology Co., Ltd): 5000/hole), connect
96 orifice plates of kind, every hole adds 100 μ l cell suspensions.Cell is at 37 DEG C, 100% relative humidity, 5%CO2It is small that 24 are incubated in incubator
When.
(3) untested compound is diluted to set respective action concentration with culture medium, cell is added by 25 holes μ l/.
Compound effects final concentration is since 40 μM, 2 times of gradient dilutions, totally 6 concentration points (40 μM, 20 μM, 10 μM, 5 μM, 2.5 μM,
1.25 μM), each 3 multiple holes of concentration point test.
(4) cell is placed in 37 DEG C, 100% relative humidity, 5%CO2It is incubated for 72 hours in incubator.
(5) the every hole of 96 orifice plates is added to the CCK-8 detection reagent of 10 μ l, is mixed, in micropore after standing 1-2 hours at room temperature
Light absorption signal (OD value) is measured on plate readout instrument FLUOstar Omega Multilabel Reader, and calculates inhibiting rate.
Specific Activity Results see the table below
By the comparison of above-mentioned activity data it is found that left side benzene in embodiment 1~14, in general formula compound of the present invention
Ring is by SF5(sulfur pentafluoride) group replaces, and is the high anti-prostate cancer compound of a kind of activity, and shown in comparative example 1~6
Compound is compared, the IC of DU-145 and 22RV-150Value significantly reduces, in addition, the Bicalutamide of its activity and current clinical use
Comparing with drugs such as the miscellaneous Shandong amine of grace also has effect outstanding, and activity is apparently higher than other electron-withdrawing substituent (cyano and trifluoros
Methyl etc.) compound (JD1001-1183 1184 1185 1186 1187 1188).
It is above-mentioned statistics indicate that, by SF on phenyl ring5Substituted the compounds of this invention has in the treatment of the diseases such as prostate cancer
There is excellent effect.
Claims (8)
1. compound and its pharmaceutically acceptable salt that general formula (1) indicates,
Wherein, R1With R2It is identical or different, respectively indicate hydrogen atom or R1With R2It is formed together C3-6Naphthenic base；
R3Indicate hydrogen atom or C1-8Alkyl；
R4For substituted or unsubstituted C6-10Aryl or heteroaryl, the heteroaryl are 5- or 6-membered monocycle base or are 5 yuan
Or 6 unit monocycle and phenyl ring condensation made of bicyclic group.
2. compound as described in claim 1 and its pharmaceutically acceptable salt, wherein
R4For the C at least one substituent group6-10Aryl or heteroaryl,
The substituent group is selected from halogen atom, cyano, nitro, C1-8Alkyl, C1-8Alkoxy, halogenated C1-8Alkyl, halogenated C1-8Alkane
Oxygroup, halogenated C1-8Alkylthio group, halogenated C1-8Alkyl sulphinyl, halogenated C1-8Alkyl sulphonyl or pentafluoride-sulfanyl.
3. compound as described in claim 1 and its pharmaceutically acceptable salt, wherein R4Are as follows:
In formula, n indicates 1~7 integer.
4. compound as described in claim 1 and its pharmaceutically acceptable salt, wherein the compound is selected from:
5. a kind of pharmaceutical composition, which is characterized in that containing compound of any of claims 1-4 or its pharmaceutically
Acceptable salt and pharmaceutically acceptable carrier.
6. compound according to any one of claims 1 to 4 or its pharmaceutically acceptable salt are in preparation for preventing or controlling
Treat the application in the drug of disease relevant to estrogen receptor activity.
7. application as claimed in claim 6, wherein the disease relevant to estrogen receptor activity includes: hormone-sensitive
Property prostate cancer, hormone-refractory prostate cancer, benign prostatic hyperplasis, acne, hirsutism, whelk, dark sore and alopecia.
8. the preparation method for the compound that general formula (1) described in claim 1 indicates, which comprises the steps of:
Step (I) reacts compound (2) with oxalyl chloride or thionyl chloride in aprotic solvent, is formed compound (3)；
Step (II) reacts compound (3) with compound (4) in aprotic solvent, is formed compound (5)；
Step (III) in organic solvent reacts compound (5) with piperidines, is formed compound (6)；
Step (IV) in organic solvent reacts compound (6) with compound (7), is formed compound (1)；
R in the above formulas1、R2、R3And R4Definition with claim 1.
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| Publication number | Priority date | Publication date | Assignee | Title |
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