CN107987055A - Thiocarbamoyl imidazole diones androgen receptor antagonists and application thereof - Google Patents

Thiocarbamoyl imidazole diones androgen receptor antagonists and application thereof Download PDF

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CN107987055A
CN107987055A CN201711370349.4A CN201711370349A CN107987055A CN 107987055 A CN107987055 A CN 107987055A CN 201711370349 A CN201711370349 A CN 201711370349A CN 107987055 A CN107987055 A CN 107987055A
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compound
trifluoromethyl
bases
pyridine
dimethyl
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刘秀云
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring

Abstract

The invention discloses the thiocarbamoyl imidazole cyclohexadione compounds of such as formula (I), can be used as androgen receptor antagonists, are used to prepare treatment androgen-receptor related diseases or the medicine of disorder (such as cancer).

Description

Thiocarbamoyl imidazole diones androgen receptor antagonists and application thereof
Technical field
The present invention relates to field of medicaments, and in particular to the new thiocarbamoyl imidazole cyclohexadione compounds being substituted and its conduct are male Hormone receptor antagonists, for preventing and treating and androgen-receptor related diseases or disorder.
Background technology
Androgen receptor (AR) is the trans transcript regutation protein of the ligand dependent of 110,000 Dalton molecular weights, its One of key function is the genetic transcription of androgen activation.Androgen receptor has important in many male sex hormone relevant diseases Effect, the disease such as prostate cancer, benign prostatauxe, male hair missing, muscle reduction and hirsutism.
Prostate cancer is one of most common cancer in male, one of the main reason for being male cancer deaths.Prostate The existing standard therapeutic scheme of cancer is treated by operation or hormonotherapy.In general, hormonotherapy is also with serving as androgen receptor The drug regimen of body antagonist (such as Flutamide (flutamide) and Bicalutamide (bicalutamide)).Hormonotherapy pair In controlling cancer cell highly effective in most of patients with advanced prostate cancer.But in 2 to 5 years, cancer is almost It will be recurred in all such patients.This is because prostate gland cancer cell is finally adapted to low androgen milieu and becomes pair Hormonotherapy is resistant to.The recent reactivation for researching and proposing androgen receptor signal path is probably to produce tolerance to hormonotherapy Basic reason.The mutation of androgen receptor and overexpression are the common inherent molecular mechanisms of the tolerance observed by two.Oneself Report, which observed alpha..alpha..alpha.-Trifluoro-2-methyl-4'-nitro-m-lactotoluidide (activity form of Flutamide) and Bicalutamide, to be had the function that to activate androgen receptor, from And stimulate cancer hyperplasia.
The miscellaneous Shandong amine (enzalutamide, trade name Xtandi) of androgen receptor antagonists grace of fresh market, compared with than card Shandong amine significantly reduces to affinity height, the activity of androgen receptor, but still can induce epilepsy, and most patients finally produce drug resistance Property.
Therefore, developing new androgen receptor antagonists has significant medicine needs.
The content of the invention
The object of the present invention is to provide one kind with new compound of the androgen receptor with antagonism and its pre- Anti- and treatment and androgen-receptor related diseases or the purposes of disorder.
The present invention provides the thiocarbamoyl imidazole cyclohexadione compounds and its officinal salt of such as formula (I)：
Wherein：
X is selected from：Cyano group, halogen, C1-C4Alkyl or the optional C substituted by one or more halogens1-C4Alkyl；
R1And R2Independently selected from C1-C4Alkyl or the optional C substituted by one or more fluorine or hydroxyl1-C4Alkyl； Or R1And R2Carbon connected to them forms 3 to 6 yuan of cycloalkyl together, one or more carbon is optional by one The substitution of a or multiple fluorine or hydroxyl, and one of them or two carbon are optional is replaced by oxygen or nitrogen；
R3It is selected from：Hydrogen and halogen；
Y is selected from：Carbon and nitrogen；
Z is selected from：C(O)NR4R5、SO2R4、SO2NR4R5、C(O)NR4R5、C(O)OR4、OC(O)NR4R5, pyrazolyl, imidazoles Ji, oxazolyl, isoxazolyls, thiadiazolyl group, oxadiazolyls, triazolyl, tetrazole radical, thiazolyl, isothiazolyl；
R4And R5Independently selected from：Hydrogen, C1-C6Alkyl, C1-C6Alkenyl and C3-C6Cycloalkyl, wherein one or more carbon can Optionally substituted by one or more hydroxyls, amino, cyano group or fluorin radical；
N is selected from 1 to 4 integer.
On the further preferred solution of X, wherein X is cyano group, halogen, methyl or trifluoromethyl.
Further, wherein X is trifluoromethyl.
On R1And R2Further preferred solution, wherein R1And R2It is methyl, or R1And R2It is connected to them Carbon forms 4 to 5 yuan of cycloalkyl together, one of them or two carbon are optional is replaced with oxygen or nitrogen；
On R3Further preferred solution, wherein R3It is hydrogen or fluorine.
On the preferred solution of Z, wherein Z is pyrazolyl, imidazole radicals, oxazolyl, isoxazolyls, thiadiazolyl group, oxadiazoles Base, triazolyl, tetrazole radical, thiazolyl or isothiazolyl.
Further, wherein Z is imidazole radicals, oxazolyls, thiazolyl.
On the preferred solution of n, wherein n is 2 or 3.
Further, wherein n is 3.
Further entirety preferred solution, in formula of the invention (I) compound：X is cyano group, halogen, methyl or trifluoromethyl； R1And R2It is methyl, or R1And R2Carbon connected to them forms 4 to 5 yuan of cycloalkyl together, one of them or two carbon are appointed Selection of land is oxygen or nitrogen；R3It is hydrogen or fluorine；Y is carbon or nitrogen；Z be pyrazolyl, imidazole radicals, oxazolyl, isoxazolyls, thiadiazolyl group, Oxadiazolyl, triazolyl, tetrazole radical, thiazolyl or isothiazolyl；N is 2 or 3.
Further, in formula of the invention (I) compound：X is trifluoromethyl；R1And R2It is methyl, or R1And R2With The carbon that they are connected forms 4 to 5 yuan of cycloalkyl together, one of them or two carbon are optionally oxygen or nitrogen；R3It is hydrogen or fluorine； Y is carbon or nitrogen；Z is imidazole radicals, oxazolyls, thiazolyl；N is 3.
Preferably, formula of the invention (I) compound is selected from：
4- (4- (3- (6- cyano group -5- (trifluoromethyl) pyridin-3-yl) -5,5- dimethyl -4- oxo -2- thiocarbamoyl imidazoles Alkane -1- bases) -2- fluorophenyls) methyl butyrate；
4- (4- (3- (6- cyano group -5- (trifluoromethyl) pyridin-3-yl) -5,5- dimethyl -4- oxo -2- thiocarbamoyl imidazoles Alkane -1- bases) -2- fluorophenyls) butyramide；
5- (3- (the fluoro- 4- of 3- (3- (oxazole -2- bases) propyl group) phenyl) -4,4- dimethyl -5- oxo -2- thiocarbamoyl imidazoles alkane - 1- yls) -3- (trifluoromethyl) pyridine -2- formonitrile HCNs；
5- (3- (4- (3- (1H- imidazoles -2- bases) propyl group) -3- fluorophenyls) -4,4- dimethyl -5- oxo -2- thiocarbamoyl imidazoles Alkane -1- bases) -3- (trifluoromethyl) pyridine -2- formonitrile HCNs；
5- (3- (4- (3- cyanopropyls) -3- fluorophenyls) -4,4- dimethyl -5- oxo -2- thiocarbamoyl imidazole alkane -1- bases) - 3- (trifluoromethyl) pyridine -2- formonitrile HCNs；
4- (4- (3- (6- cyano group -5- (trifluoromethyl) pyridin-3-yl) -5,5- dimethyl -4- oxo -2- thiocarbamoyl imidazoles Alkane -1- bases) -2- fluorophenyls)-N- methylbutyryl amine；
5- (5- (the fluoro- 4- of 3- (3- (oxazole -2- bases) propyl group) phenyl) thio -5,7- diaza spiros [3.4] of -8- oxos -6- Octyl- 7- yls) -3- (trifluoromethyl) pyridine -2- formonitrile HCNs；
5- (1- (the fluoro- 4- of 3- (3- (oxazole -2- bases) propyl group) phenyl) thio -7- oxa-s -1,3- diazas of -4- oxos -2- Spiral shell [4.4] nonyl- 3- yls) -3- (trifluoromethyl) pyridine -2- formonitrile HCNs；
4- (5- (3- (6- cyano group -5- (trifluoromethyl) pyridin-3-yl) -5,5- dimethyl -4- oxo -2- thiocarbamoyl imidazoles Alkane -1- bases) pyridine -2- bases) methyl butyrate；
4- (5- (3- (6- cyano group -5- (trifluoromethyl) pyridin-3-yl) -5,5- dimethyl -4- oxo -2- thiocarbamoyl imidazoles Alkane -1- bases) pyridine -2- bases) butyramide；
5- (3- (6- (4- (4- hydroxy piperidine -1- bases) -4- oxos butyl) pyridin-3-yl) -4,4- dimethyl -5- oxos - 2- thiocarbamoyl imidazole alkane -1- bases) -3- (trifluoromethyl) pyridine -2- formonitrile HCNs；
5- (4,4- dimethyl -5- oxos -3- (6- (3- (thiazol-2-yl) propyl group) pyridin-3-yl) -2- thiocarbamoyl imidazoles alkane - 1- yls) -3- (trifluoromethyl) pyridine -2- formonitrile HCNs；
5- (4,4- dimethyl -3- (6- (3- (oxazole -2- bases) propyl group) pyridin-3-yl) -5- oxo -2- thiocarbamoyl imidazoles alkane - 1- yls) -3- (trifluoromethyl) pyridine -2- formonitrile HCNs；
5- (5- (6- (3- (oxazole -2- bases) propyl group) pyridin-3-yl) thio -5,7- diaza spiros [3.4] of -8- oxos -6- Octyl- 7- yls) -3- (trifluoromethyl) pyridine -2- formonitrile HCNs；
5- (1- (6- (3- (oxazole -2- bases) propyl group) pyridin-3-yl) thio -7- oxa-s -1,3- diazas of -4- oxos -2- Spiral shell [4.4] nonyl- 3- yls) -3- (trifluoromethyl) pyridine -2- formonitrile HCNs.
The above-claimed cpd of the present invention, has asymmetric center in chemical constitution, then further include its individual isomer and The mixture of various isomers.
The officinal salt of formula (I) compound of the present invention, includes but not limited to the acid that the compounds of this invention is formed with following acid Addition salts：Hydrochloric acid, hydrobromic acid, sulfuric acid, stubborn rubber acid, tartaric acid, phosphoric acid, lactic acid, acetic acid, maleic acid, fumaric acid, malic acid, apricot Benevolence acid, methanesulfonic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid, double hydroxyl bitter edible plants acid (pa is not sour), oxalic acid or butanedioic acid.
Prostate-specific antigen (prostate specific antigen, PSA) generation level can be used as androgen receptor The mark of body antagonistic activity.As seen in exemplified here, in hormone-refractory prostate cancer cell (LNCaP-AR) The suppression test that PSA is produced shows that preferred compounds of the invention shows the stronger suppression produced to PSA of the miscellaneous Shandong amine of Bean Activity.
Formula (I) compound of the present invention is the antagonist of androgen receptor, can be used as active constituents of medicine, be used alone or Used with one or more of combination with other therapeutic agents, for treating, preventing or alleviate by androgen mediated disease or disorder, Such as hormone-sensitive prostate cancer or hormone-refractory prostate cancer, benign prostatic hyperplasis, acne, hirsutism, sebum mistake Amount and alopecia etc..
Embodiment
Representative illustration hereinafter is intended to help and illustrates the present invention, and is not intended to and also should not be construed as limitation originally The scope of invention.General approach
The preparation of formula (I) compound of the present invention is shown by option A.
Option A：
In option A, formula (IV) compound is infinite to be selected from compound IV-1, can be by commercially-available.
In option A, formula (V) compound is infinite to be selected from acetone, cyclobutanone and dihydro -3 (2H)-furanone.
In certain embodiments, formula (II) compound is selected from：Y is carbon, R3It is amino meta fluorine, Z is cyano group, COOCH3、 CONH2、CONHCH3, imidazoles -2- Ji Huo oxazole -2- bases.
In certain embodiments, formula (II) compound is selected from：Y is nitrogen, R3It is hydrogen, Z is COOCH3、CONH2, oxazoles -2- Base, thiazol-2-yl or
Embodiment 1
4- (4- (3- (6- cyano group -5- (trifluoromethyl) pyridin-3-yl) -5,5- dimethyl -4- oxo -2- thiocarbamoyl imidazoles Alkane -1- bases) -2- fluorophenyls) methyl butyrate (WX-101) preparation
The preparation of compound II-1：Compound 1 (12.05g, 0.05mol), ammonium chloride (45g), iron powder are added in reaction bulb (30g), methanol (350mL) and water (250mL), stirring, be heated to flowing back and keep 1 it is small when.Cooling, filtering, is concentrated under reduced pressure and removes Methanol is removed, adds dichloromethane extraction.Organic phase is washed with salt, then is dried with anhydrous sodium sulfate.Filtering, filtrate decompression concentration To doing, the compound II-1 (9.10g, yield 86.1%) of faint yellow oily is obtained.1H-NMR (400MHz, CDC13)：δ1.83- 1.88 (m, 2H), 2.32 (t, 2H, J=7.2Hz), 2.52 (t, 2H, J=7.2Hz), 3.63 (s, 3H), 5.44 (bs, 2H), 6.31-6.37 (m, 1H), 6.90-6.98 (m, 2H).
The preparation of compound III-1：In reaction bulb add compound II-1 (1.06g, 5mmol), zinc chloride (100mg) and Acetone (10ml), stirring, adds trimethylsilyl cyanide (TMSCN) (2mL, 15mmol), is warming up to 50 DEG C, insulated and stirred 30 is divided Clock.Cooling, is concentrated under reduced pressure, sodium sulfite solution is added in residue, be extracted with ethyl acetate.Organic phase is washed with salt, then Dried with anhydrous sodium sulfate.Filtering, is concentrated under reduced pressure into dry, obtains the compound III-1 (1.32g) of pale yellowish oil, is directly used in Lower step.
The preparation of WX-101：In reaction bulb add compound IV-1 (750mg, 4.0mmol), compound III-1 (1.32g, 4.7mmol), N, N '-thiocarbonyldiimidazole (0.80g, 4.5mmol) and toluene (15mL), stirring, is heated to 100-105 DEG C, protects When temperature 20 is small.Cooling, is concentrated under reduced pressure, and n,N-dimethylacetamide (DMA) (20mL) is added in residue and enters ethanol ethanol (200mL), stirring, is heated to 70 DEG C, adds hydrochloric acid (2M, 10mL), keeps the temperature when stirring 2 is small.0 DEG C is cooled to, stirring 2 is small When.Filtering, filter cake ethanol/water (volume ratio 1：1) stir and wash, be filtered dry, be dried in vacuo, obtain the compound WX- of off-white powder 101 (1.33g, 65.4%).1H-NMR (400MHz, CDC13)：δ 1.65 (d, 6H, J=4.4Hz), 1.79-1.88 (m, 2H), 2.32 (t, 2H, J=7.2Hz), 2.56 (t, 2H, J=7.2Hz), 3.64 (s, 3H), 7.13-7.19 (m, 1H), 7.38-7.44 (m, 1H), 7.83-7.88 (m, 1H), 8.26 (d, 1H, J=2.0Hz), 8.68 (d, 1H, J=2.0Hz).MS：m/z 509.1[M +H]+。
Embodiment 2
4- (4- (3- (6- cyano group -5- (trifluoromethyl) pyridin-3-yl) -5,5- dimethyl -4- oxo -2- thiocarbamoyl imidazoles Alkane -1- bases) -2- fluorophenyls) butyramide (WX-102) preparation
The preparation of compound II-2：Compound II-1 (2.11g, 10mmol), methanol (30mL) are added in reaction bulb, is stirred Mix, add ammonium hydroxide (30mL), continue stirring 24 it is small when.It is concentrated under reduced pressure and removes methanol, residue adds water, extracted with dichloromethane. Organic phase is washed with salt, anhydrous sodium sulfate drying.Filtering, filtrate concentration, obtain white solid compound II-2 (1.54g, Yield 78.5%), it is directly used in lower step.
The preparation of compound III-2：According to the similar approach of prepare compound III-1, synthesize pale yellow by compound II-2 The compound III-2 (1.46g) of color oily, is directly used in lower step.
The preparation of compound WX-102：According to the similar approach of prepare compound WX-101, by III-2 (1.46g, 5.5mmol) and IV-1 (880mg, 4.7mmol) synthesis obtains compound WX-102 (1.33g, the yield of light yellow solid 57.1%).1H-NMR (400MHz, CDC13)：δ 1.67 (d, 6H, J=5.2Hz), 1.73-1.82 (m, 2H), 2.34 (t, 2H, J =7.2Hz), 2.53 (t, 2H, J=7.2Hz), 5.83 (bs, 2H), 7.03-7.11 (m, 1H), 7.25-7.34 (m, 1H), 7.64-7.72 (m, 1H), 8.28 (d, 1H, J=2.4Hz), 8.66 (d, 1H, J=2.4Hz).MS：m/z 494.2[M+H]+。
Embodiment 3
5- (3- (the fluoro- 4- of 3- (3- (oxazole -2- bases) propyl group) phenyl) -4,4- dimethyl -5- oxo -2- thiocarbamoyl imidazoles alkane - 1- yls) -3- (trifluoromethyl) pyridine -2- formonitrile HCNs (WX-103) preparation
The preparation of compound 2：Compound 1 (24.1g, 0.1mol), methanol (300mL) are added in reaction bulb, is stirred, is added Ammonium hydroxide (300mL), continue stirring 24 it is small when.It is concentrated under reduced pressure and removes methanol, residue adds water, extracted with dichloromethane.Organic phase Washed with salt, anhydrous sodium sulfate drying.Filtering, filtrate concentrate, and obtain compound 2 (16.7g, the yield of white solid 85.2%).1H-NMR (400MHz, CDC13)：δ 1.76-1.81 (m, 2H), 2.36 (t, 2H, J=7.6Hz), 2.57 (t, 2H, J =7.6Hz), 5.67 (bs, 2H), 7.46-7.51 (m, 1H), 7.90-7.98 (m, 2H).
The preparation of compound 3：In reaction bulb add compound 2 (11.3g, 50mmol), vinylene carbonate (5.15g, 60mmol) and polyphosphoric acids (PPA) (125g), stirring, be warming up to 160 DEG C of reactions 3 it is small when.Cooling, is added to the water, with acetic acid second Ester extracts.Organic phase is washed with salt, then is dried with anhydrous sodium sulfate.Filtering, filtrate decompression are concentrated to dryness, and residue is through silica gel Column chromatography purifies (ethyl acetate-hexane), obtains compound 3 (4.71g, yield 37.6%).1H-NMR (400MHz, CDC13)：δ 1.92-1.97 (m, 2H), 2.56-2.62 (m, 4H), 7.15 (d, 1H, J=1.6Hz), 7.44-7.48 (m, 1H), 7.61 (d, 1H, J=1.6Hz), 7.91-7.99 (m, 2H).
The preparation of compound II-3：Compound 3 (4.68g, 18.7mmol), ammonium chloride (18g), iron powder are added in reaction bulb (13g), methanol (150mL) and water (100mL), stirring, be heated to flowing back and keep 1 it is small when.Cooling, filtering, is concentrated under reduced pressure and removes Methanol is removed, adds dichloromethane extraction.Organic phase is washed with salt, then is dried with anhydrous sodium sulfate.Filtering, filtrate decompression concentration To doing, the compound II-3 (3.54g, yield 85.9%) of faint yellow oily is obtained.1H-NMR (400MHz, CDC13)：δ1.93- 1.99 (m, 2H), 2.55-2.62 (m, 4H), 6.11-6.14 (m, 1H), 6.82-6.86 (m, 1H), 6.93-6.97 (m, 1H), 7.17 (d, 1H, J=1.6Hz), 7.63 (d, 1H, J=1.6Hz).
The preparation of compound III-3：According to the similar approach of prepare compound III-1, by compound II-3 (1.10, Compound III-3 (1.13g) 5mmol) is obtained, is directly used in lower step.
The preparation of compound WX-103：According to the similar approach of prepare compound WX-101, by III-3 (1.13g, 3.9mmol) and IV-1 (620mg, 3.3mmol) synthesis obtains compound WX-103 (1.04g, the yield of faint yellow solid 60.9%).1H-NMR (400MHz, CDC13)：δ 1.68 (d, 6H, J=4.8Hz), 1.93-1.99 (m, 2H), 2.51-2.57 (m, 4H), 7.03-7.08 (m, 1H), 7.15 (d, 1H, J=7.6Hz), 7.23-7.28 (m, 1H), 7.60-7.64 (m, 2H), 8.26 (d, 1H, J=2.4Hz), 8.67 (d, 1H, J=2.4Hz).MS：m/z518.2[M+H]+。
Embodiment 4
5- (3- (4- (3- (1H- imidazoles -2- bases) propyl group) -3- fluorophenyls) -4,4- dimethyl -5- oxo -2- thiocarbamoyl imidazoles Alkane -1- bases) -3- (trifluoromethyl) pyridine -2- formonitrile HCNs (WX-104) preparation
The preparation of compound 4：Trimethyl aluminium toluene solution (32mL, 2M) is added in reaction bulb, is cooled to less than -20 DEG C, Keep temperature that ethylenediamine (6.00g, 100mmol) is slowly added dropwise.Room temperature is warming up to after adding, chemical combination is added into reaction mixture Toluene (75mL) solution of thing 1 (4.82g, 20mmol).It is heated to flowing back after adding, is kept for 30 minutes.Then 0 DEG C is cooled to, Methanol is added dropwise to be quenched, adds dichloromethane, magnesium sulfate, stirs, filtering, filtrate decompression concentration.Residue is through silica gel column chromatography (second Acetoacetic ester：Triethylamine=10：1) purify, obtain the compound 4 (2.27g, yield 51.3%) of yellow solid.1H-NMR (400MHz, CDC13)：δ 1.82-1.90 (m, 2H), 2.24 (t, 2H, J=7.2Hz), 2.65 (t, 2H, J=7.2Hz), 3.21 (bs, 1H), 3.62 (s, 4H), 7.38-7.46 (m, 1H), 7.90-7.98 (m, 2H).
The preparation of compound 5：Compound 4 (2.21g, 8.8mmol) and acetonitrile (200mL) are added in reaction bulb, is stirred, point Batch add potassium permanganate (2.78g, 17.6mmol) and aluminium oxide (12.2g), add continue to stir 1 it is small when.Methanol is added to be quenched, Filtering, with methylene chloride-methanol (10：1) filter wash cake.Filtrate decompression is concentrated to dryness, the compound 5 of residual yellow grease (1.67g, yield 76.1%), is directly used in lower step.
The preparation of compound 6：Compound 5 (1.67g, 6.6mmol) and dichloromethane (50mL) are added in reaction bulb, is stirred Mix, be cooled to less than 0 DEG C, add (Boc)2O (1.53g, 7.0mmol), is then added dropwise triethylamine (1.77g, 17.5mmol), adds It is complete stirring 20 it is small when.It is concentrated under reduced pressure, residue is purified through silica gel column chromatography (ethyl acetate-hexane), obtains faint yellow solid Obtain compound 6 (1.86g, yield 82.0%).1H-NMR (400MHz, CDC13)：δ 1.63 (s, 9H), 1.96-2.06 (m, 2H), 2.68 (t, 2H, J=7.2), 2.89 (t, 2H, J=7.6Hz), 6.86-6.90 (m, 1H), 7.22-7.25 (m, 1H), 7.36- 7.42 (m, 1H), 7.90-7.99 (m, 2H).
The preparation of compound II-4：In hydrogenation reactor add compound 6 (1.82g, 5.2mmol), ethanol (100mL) and 10%Pd/C (0.5g), closed reactor, nitrogen displacement three times after, hydrogen is replaced three times, finally leads to hydrogen to 0.2-0.3Mpa And keep, when reaction 3 is small, deflate, nitrogen displacement three times, with ethanol washed by filtering, filter cake.Filtrate decompression is concentrated to dryness, and is obtained yellowish The semisolid compound II-4 of color (1.51g, yield 90.4%), is directly used in lower step.
The preparation of compound III-4：According to the similar approach of prepare compound III-1, obtained by II-4 (1.51g, 4.7mmol) To the compound III-4 (1.49g, yield 82.0%) of buff oily, lower step is directly used in.
The preparation of compound WX-104：According to the similar approach of prepare compound WX-101, by III-4 (1.49g, 3.8mmol) and IV-1 (614mg, 3.28mmol) synthesis obtains compound WX-104 (1.12g, the yield of faint yellow solid 66.1%).1H-NMR (400MHz, CDC13)：δ 1.69 (d, 6H, J=4.8Hz), 1.95-2.01 (m, 2H), 2.54 (t, 2H, J =7.6Hz), 2.88 (t, 2H, J=7.6Hz), 6.99 (s, 2H), 7.01-7.04 (m, 1H), 7.23-7.27 (m, 1H), 7.62- 7.66 (m, 1H), 8.25 (d, 1H, J=2.8Hz), 8.60 (d, 1H, J=2.8Hz), 13.45 (bs, 1H).MS：m/z 517.2 [M+H]+。
Embodiment 5
5- (3- (4- (3- cyanopropyls) -3- fluorophenyls) -4,4- dimethyl -5- oxo -2- thiocarbamoyl imidazole alkane -1- bases) - The preparation of 3- (trifluoromethyl) pyridine -2- formonitrile HCNs (WX-105)
The preparation of compound 7：In reaction bulb add compound 2 (3.4g, 15mmol), triethylamine (7.6g, 75mmol) and Dichloromethane (50mL), stirring, is cooled to less than 0 DEG C, and trifluoroacetic anhydride (TFAA) (6.3g, 30mmol) is added dropwise, adds continuation Stir 1 it is small when, be then warmed to room temperature continue stirring 4 it is small when.Add frozen water to stir 10 minutes, stand liquid separation, water mutually uses dichloromethane Alkane extracts.Merge organic phase, washed with salt, then dried with anhydrous sodium sulfate.Filtering, is concentrated under reduced pressure into dry, obtains yellow oily Compound 7 (2.98g, yield 95.4%).1H-NMR (400MHz, CDC13)：δ 1.85-2.02 (m, 4H), 2.64 (t, 2H, J =7.6Hz), 7.41-7.47 (m, 1H), 7.89-7.98 (m, 2H).
It is prepared by compound II-5：According to the similar approach of prepare compound II-1, obtained by compound 7 (2.93g, 14mmol) Compound II-5 (1.94g, yield 77.7%), is directly used in lower step.
The preparation of compound III-5：According to the similar approach of prepare compound III-1, by compound II-5 (1.94g, Compound III-5 (2.03g, yield 76.6%) 10.8mmol) is obtained, is directly used in lower step.
The preparation of compound WX-105：According to the similar approach of prepare compound WX-101, by III-5 (2.03g, 8.2mmol) and IV-1 (1.30g, 6.9mmol) synthesis obtains compound WX-105 (1.85g, the yield of faint yellow solid 54.0%).1H-NMR (400MHz, CDC13)：δ 1.66 (d, 6H, J=5.6Hz), 1.88 (t, 2H, J=7.2Hz), 1.97- 2.05 (m, 2H), 2.67 (t, 2H, J=7.6Hz), 7.00-7.04 (m, 1H), 7.24-7.28 (m, 1H), 7.64-7.69 (m, 1H), 8.24 (d, 1H, J=2.4Hz), 8.65 (d, 1H, J=2.4Hz).MS：m/z 476.0[M+H]+。
Embodiment 6
4- (4- (3- (6- cyano group -5- (trifluoromethyl) pyridin-3-yl) -5,5- dimethyl -4- oxo -2- thiocarbamoyl imidazoles Alkane -1- bases) -2- fluorophenyls)-N- methylbutyryls amine (WX-106) preparation
The synthesis of compound II-6：Compound II-1 (2.11g, 10mmol), methylamine/methanol solution are added in reaction bulb (33%, 50mL), when stirring 48 is small.It is concentrated under reduced pressure and removes solvent, residue adds water, extracted with dichloromethane.Organic phase is eaten Salt is washed, anhydrous sodium sulfate drying.Filtering, filtrate are concentrated to dryness, and obtain compound II-6 (1.69g, the yield of faint yellow solid 80.4%), it is directly used in lower step.
The preparation of compound III-6：According to the similar approach of prepare compound III-1, by compound II-6 (1.69g, Compound III-6 (1.76g, yield 79.3%) 8mmol) is obtained, is directly used in lower step.
The preparation of compound WX-106：According to the similar approach of prepare compound WX-101, by III-6 (1.76g, 6.3mmol) and IV-1 (1.00g, 5.3mmol) synthesis obtains compound WX-106 (1.63g, the yield of faint yellow solid 60.6%).1H-NMR (400MHz, CDC13)：δ 1.68 (d, 6H, J=5.2Hz), 1.70-1.74 (m, 2H), 2.35 (t, 2H, J =7.2Hz), 2.56 (t, 2H, J=7.2Hz), 2.81 (d, 3H, J=4hz), 5.58 (bs, 1H), 7.02-7.07 (m, 1H), 7.23-7.29 (m, 1H), 7.64-7.70 (m, 1H), 8.26 (d, 1H, J=2.4Hz), 8.69 (d, 1H, J=2.4Hz).MS：m/ z 508.1[M+H]+。
Embodiment 7
5- (5- (the fluoro- 4- of 3- (3- (oxazole -2- bases) propyl group) phenyl) thio -5,7- diaza spiros [3.4] of -8- oxos -6- Octyl- 7- yls) -3- (trifluoromethyl) pyridine -2- formonitrile HCNs (WX-107) preparation
The synthesis of compound III-7：Compound II-3 (1.10,5mmol), zinc chloride (150mg), ring are added in reaction bulb Butanone (0.70g, 10mmol) and Isosorbide-5-Nitrae-dioxane (10ml), stirring, addition trimethylsilyl cyanide (TMSCN) (2mL, 15mmol), 50 DEG C, when insulated and stirred 1 is small are warming up to.Cooling, adds sodium sulfite solution, is extracted with ethyl acetate.Organic phase Washed with salt, then dried with anhydrous sodium sulfate.Filtering, is concentrated under reduced pressure into dry, obtains the compound III-7 of pale yellowish oil (1.41g), is directly used in lower step..
The preparation of compound WX-107：According to the similar approach of prepare compound WX-101, by III-7 (1.41g, 4.7mmol) and IV-1 (750mg, 4mmol) synthesis obtains compound WX-107 (1.36g, the yield of faint yellow solid 64.2%).1H-NMR (400MHz, CDC13)：δ 1.67-1.72 (m, 1H), 1.96-2.05 (m, 3H), 2.21-2.29 (m, 2H), 2.48-2.56 (m, 2H), 2.61-2.70 (m, 4H), 7.04-7.09 (m, 1H), 7.16 (d, 1H, J=7.6Hz), 7.25-7.32 (m, 1H), 7.62-7.66 (m, 2H), 8.26 (d, 1H, J=2.8Hz), 8.68 (d, 1H, J=2.8Hz).MS：m/z 530.1[M +H]+。
Embodiment 8
5- (1- (the fluoro- 4- of 3- (3- (oxazole -2- bases) propyl group) phenyl) thio -7- oxa-s -1,3- diazas of -4- oxos -2- Spiral shell [4.4] nonyl- 3- yls) -3- (trifluoromethyl) pyridine -2- formonitrile HCNs (WX-108) preparation
The synthesis of compound III-8：Compound II-3 (1.10,5mmol), zinc chloride (150mg), two are added in reaction bulb Hydrogen -3 (2H)-furanone (0.86g, 10mmol) and Isosorbide-5-Nitrae-dioxane (10ml), stirring, adds trimethylsilyl cyanide (TMSCN) (2mL, 15mmol), is warming up to 50 DEG C, when insulated and stirred 2 is small.Cooling, adds sodium sulfite solution, uses ethyl acetate Extraction.Organic phase is washed with salt, then is dried with anhydrous sodium sulfate.Filtering, is concentrated under reduced pressure into dry, obtains the chemical combination of pale yellowish oil Thing III-8 (1.36g), is directly used in lower step..
The preparation of compound WX-108：According to the similar approach of prepare compound WX-101, by III-8 (1.36g, 4.3mmol) and IV-1 (700mg, 3.7mmol) synthesis obtains compound WX-108 (1.13g, the yield of faint yellow solid 55.4%).1H-NMR (400MHz, CDC13)：δ 1.96-2.05 (m, 2H), 2.15-2.22 (m, 1H), 2.39-2.44 (m, 1H), 2.62-2.69 (m, 4H), 3.70-3.82 (m, 2H), 4.05 (d, 1H, J=4.8Hz), 4.31 (d, 1H, J=4.8Hz), 7.02- 7.06 (m, 1H), 7.15 (d, 1H, J=7.2Hz), 7.23-7.29 (m, 1H), 7.60-7.65 (m, 2H), 8.25 (d, 1H, J= 2.4Hz), 8.67 (d, 1H, J=2.4Hz).MS：m/z 546.2[M+H]+。
Embodiment 9
4- (5- (3- (6- cyano group -5- (trifluoromethyl) pyridin-3-yl) -5,5- dimethyl -4- oxo -2- thiocarbamoyl imidazoles Alkane -1- bases) pyridine -2- bases) methyl butyrate (WX-109) preparation
The preparation of compound 9：Compound 8 (21g, 0.1mol) and methanol (210mL) are added in reaction bulb, is stirred, is added Sulfuric acid (0.2g, 2mmol), be heated to reflux 2 it is small when.Cooling, is concentrated under reduced pressure and removes solvent, and residue adds saturated sodium bicarbonate water Solution, is extracted with dichloromethane.Organic phase is washed with salt, then is dried with anhydrous sodium sulfate.Filtering, filtrate are concentrated to dryness, obtain The compound 9 (21.2g, yield 94.5%) of yellow oily.1H-NMR (400MHz, CDC13)：δ 1.92-1.98 (m, 2H), 2.36 (t, 2H, J=7.6Hz), 2.86 (t, 2H, J=7.2Hz), 3.66 (s, 3H), 7.29 (d, 1H, J=7.2Hz), 8.46 (dd, 1H, J=7.2,2.0Hz), 9.34 (d, 1H, J=2.0Hz).
The preparation of compound II-9：According to the similar approach of prepare compound II-1, closed by compound 9 (6.7g, 30mmol) Into the compound II-9 (4.95g, yield 84.9%) for obtaining buff oily.1H-NMR (400MHz, CDC13)：δ1.91-1.97 (m, 2H), 2.35 (t, 2H, J=7.6Hz), 2.82 (t, 2H, J=7.2Hz), 3.65 (s, 3H), 7.02-7.08 (m, 2H), 7.89 (d, 1H, J=2.0Hz).
The preparation of compound III-9：According to the similar approach of prepare compound III-1, by compound II-9 (1.94g, The compound III-9 (2.07g, yield 79.2%) of brown oil 10mmol) is obtained, is directly used in lower step.
The preparation of compound WX-109：According to the similar approach of prepare compound WX-101, by III-9 (2.07g, 7.9mmol) and IV-1 (1.25g, 6.7mmol) synthesis obtains compound WX-109 (1.83g, the yield of faint yellow solid 55.6%).1H-NMR (400MHz, CDC13)：δ 1.64 (d, 6H, J=4.4Hz), 1.94-2.01 (m, 2H), 2.36 (t, 2H, J =7.2Hz), 2.88 (t, 2H, J=7.6Hz), 3.65 (s, 3H), 7.08-7.15 (m, 2H), 7.79 (d, 1H, J=1.6Hz), 8.24 (d, 1H, J=2.0Hz), 8.67 (d, 1H, J=2.0Hz).MS：m/z492.1[M+H]+。
Embodiment 10
4- (5- (3- (6- cyano group -5- (trifluoromethyl) pyridin-3-yl) -5,5- dimethyl -4- oxo -2- thiocarbamoyl imidazoles Alkane -1- bases) pyridine -2- bases) butyramide (WX-110) preparation
The preparation of compound 10：According to the similar approach of prepare compound II-2, by compound II-9 (1.94g, 10mmol) Synthesize dark yellow solid compound II-10 (1.47g, yield 82.0%), be directly used in lower step.
The preparation of compound III-10：According to the similar approach of prepare compound III-1, by compound II-10 (1.47, 8.2mmol) synthesize dark-brown oily compound III-10 (1.52g), be directly used in lower step.
The preparation of compound WX-110：According to the similar approach of prepare compound WX-101, by III-10 (1.52g, 7.5mmol) and IV-1 (1.20g, 6.4mmol) synthesis obtains compound WX-110 (1.51g, the yield of faint yellow solid 49.5%).1H-NMR (400MHz, CDC13)：δ 1.65 (d, 6H, J=4.8Hz), 1.74-1.79 (m, 2H), 2.39 (t, 2H, J =7.6Hz), 2.85 (t, 2H, J=7.6Hz), 4.43 (bs, 2H), 7.07-7.13 (m, 2H), 7.77 (d, 1H, J=1.6Hz), 8.22 (d, 1H, J=2.0Hz), 8.64 (d, 1H, J=2.0Hz).MS：m/z477.2[M+H]+。
Embodiment 11
5- (3- (6- (4- (4- hydroxy piperidine -1- bases) -4- oxos butyl) pyridin-3-yl) -4,4- dimethyl -5- oxos - 2- thiocarbamoyl imidazole alkane -1- bases) -3- (trifluoromethyl) pyridine -2- formonitrile HCNs (WX-111) preparation
The preparation of compound 10：Compound 8 (2.1g, 10mmol) and dichloromethane (150mL) are added in reaction bulb, is stirred Mix, successively add n,N-diisopropylethylamine (3.3g, 25mmol) and HATU (5.7g, 15mmol), add stir 1 it is small when, add Enter 4- hydroxy piperidines (1.5g, 15mmol), continue stirring 10 it is small when.Water is added, stirring, stands liquid separation.Water mutually uses dichloromethane Extraction.Merge organic phase, washed with salt, anhydrous sodium sulfate drying.Filtering, evaporated under reduced pressure, residue is through silica gel column chromatography (second Acetoacetic ester-n-hexane) purify, obtain the compound 10 (2.75g, yield 93.8%) of white solid.1H-NMR (400MHz, CDC13)：δ 1.67-1.72 (m, 2H), 1.91-1.98 (m, 2H), 2.02-2.07 (m, 2H), 2.34 (t, 2H, J=7.2Hz), 2.83 (t, 2H, J=7.2Hz), 3.51-3.55 (m, 2H), 3.72-3.76 (m, 2H), 7.28 (d, 1H, J=7.2Hz), 8.47 (dd, 1H, J=7.2,2.0Hz), 9.32 (d, 1H, J=2.0Hz).
The preparation of compound 11：Compound 10 (2.70g, 9.2mmol) and dichloromethane (75mL) are added in reaction bulb, is stirred Mix, be cooled to less than 0 DEG C, add imidazoles (1.26g, 18.4mmol), add tert-butyl chloro-silicane (2.08g, 13.8mmol), continue stirring 16 it is small when.Add frozen water, stirring, liquid separation.Organic phase is washed with salt, then is concentrated under reduced pressure into dry The compound 11 (3.16g, yield 84.2%) of faint yellow oily, is directly used in lower step.
The preparation of compound II-11：According to the similar approach of prepare compound II-1, by compound 11 (3.16g, 7.75mmol) synthesize yellow oily compound II-11 (2.73g, yield 93.3%).
The preparation of compound III-11：According to the similar approach of prepare compound III-1, by compound II-11 (2.73g, The compound III-11 (2.81g, yield 87.8%) of buff oily 7.2mmol) is obtained, is directly used in lower step.
The preparation of compound WX-111：According to the similar approach of prepare compound WX-101, by III-11 (2.81g, 6.3mmol) and IV-1 (1.00g, 5.4mmol) synthesis obtains compound WX-111 (1.92g, the yield of faint yellow solid 63.4%).1H-NMR (400MHz, CDC13)：δ 1.51-1.54 (m, 2H), 1.66 (d, 6H, J=4.4Hz), 1.78-1.82 (m, 2H), 1.94-2.01 (m, 2H), 2.34 (t, 2H, J=7.2Hz), 2.87 (t, 2H, J=7.2Hz), 3.29-3.33 (m, 2H), 3.79-3.84 (m, 2H), 7.07-7.15 (m, 2H), 7.78 (d, 1H, J=1.6Hz), 8.24 (d, 1H, J=2.0Hz), 8.68 (d, 1H, J=2.0Hz).MS：m/z561.3[M+H]+。
Embodiment 12
5- (4,4- dimethyl -5- oxos -3- (6- (3- (thiazol-2-yl) propyl group) pyridin-3-yl) -2- thiocarbamoyl imidazoles alkane - 1- yls) -3- (trifluoromethyl) pyridine -2- formonitrile HCNs (WX-112) preparation
The preparation of compound 12：According to the similar approach of prepare compound II-2, synthesized by compound 9 (13.5g, 60mmol) Obtain the compound 12 (10.7g, yield 85.2%) of yellow solid.1H-NMR (400MHz, CDC13)：δ 1.77-1.82 (m, 2H), 2.41 (t, 2H, J=7.6Hz), 2.86 (t, 2H, J=7.2Hz), 4.66 (bs, 2H), 7.27 (d, 1H, J=7.6Hz), 8.48 (dd, 1H, J=7.6,2.0Hz), 9.31 (d, 1H, J=2.0Hz).
The preparation of compound 13：Compound 12 (1.05g, 5mmol) and tetrahydrofuran (10mL) are added in reaction bulb, is stirred Mix, be heated to 30 DEG C, lawesson reagent (1.37g, 3.4mmol) is added, when continuation insulated and stirred 2 is small.Vacuum distillation removes solvent, Residue adds saturated sodium bicarbonate solution, is extracted with ethyl acetate.Organic phase is washed with saturated sodium bicarbonate solution, then with anhydrous Sodium sulphate is dried.Filtering, filtrate are concentrated to dryness, and residue purifies (ethyl acetate-hexane) with silica gel column chromatography must be faint yellow The compound 13 (880mg, yield 78.1%) of solid.δ 2.02-2.14 (m, 2H), 2.68 (t, 2H, J=7.2Hz), 2.91 (t, 2H, J=7.2Hz), 7.28 (d, 1H, J=7.6Hz), 7.76 (bs, 2H), 8.48 (dd, 1H, J=7.6,2.0Hz), 9.32 (d, 1H, J=2.0Hz).
The synthesis of compound 14：Compound 13 (865mg, 3.8mmol), bromo- 1, the 1- dimethoxys of 2- are added in reaction bulb Ethane (2.57g, 15.2mmol) and diethoxymethane (40mL), stirring, is added dropwise concentrated hydrochloric acid (0.2mL), it is small to be heated to reflux 6 When.Room temperature is down to, adds saturated sodium bicarbonate solution, is stirred 10 minutes, stands liquid separation.Water is mutually extracted with diethoxymethane. Merge organic phase, washed with salt, then dried with anhydrous sodium sulfate.Filtering, is concentrated under reduced pressure.Residue is purified with silica gel column chromatography (ethyl acetate-hexane) obtains the compound 14 (753mg, yield 79.5%) of off-white powder.δ 2.19-2.26 (m, 2H), 2.78 (t, 2H, J=7.2Hz), 2.98 (t, 2H, J=7.6Hz), 7.20 (d, 1H, 7.2Hz), 7.29 (d, 1H, J=7.6Hz), 7.67 (d, 1H, J=7.2Hz), 8.48 (dd, 1H, J=7.6,1.6Hz), 9.30 (d, 1H, J=1.6Hz).
The preparation of compound II-12：According to the similar approach of prepare compound II-1, by compound 14 (745mg, 3mmol) Synthesize pale yellowish oil compound II-12 (542mg, yield 82.3%), be directly used in lower step.
The preparation of compound III-12：According to the similar approach of prepare compound III-1, by compound II-12 (542mg, 2.47mmol) synthesize yellow oily compound III-12 (577mg), be directly used in lower step.
The preparation of compound WX-112：According to the similar approach of prepare compound WX-101, by III-12 (577mg, 2.0mmol) and IV-1 (320mg, 1.7mmol) synthesis obtains compound WX-112 (486mg, the yield of faint yellow solid 55.3%).1H-NMR (400MHz, CDC13)：δ 1.66 (d, 6H, J=4.4Hz), 2.18-2.26 (m, 2H), 2.38 (t, 2H, J =7.6Hz), 2.86 (t, 2H, J=7.6Hz), 7.05-7.12 (m, 2H), 7.21 (d, 1H, 7.2Hz), 7.68 (d, 1H, J= 7.2Hz), 7.75 (d, 1H, J=1.6Hz), 8.23 (d, 1H, J=2.0Hz), 8.67 (d, 1H, J=2.0Hz).MS：m/z 517.2[M+H]+。
Embodiment 13
5- (4,4- dimethyl -3- (6- (3- (oxazole -2- bases) propyl group) pyridin-3-yl) -5- oxo -2- thiocarbamoyl imidazoles alkane - 1- yls) -3- (trifluoromethyl) pyridine -2- formonitrile HCNs (WX-113) preparation
The preparation of compound 15：According to the similar approach of prepare compound 3, reacted by compound 12 (9.62g, 46mmol) Compound 15 (5.42g, yield 50.5%).1H-NMR (400MHz, CDC13)：δ 2.02-2.08 (m, 2H), 2.54 (t, 2H, J= 7.2Hz), 2.77 (t, 2H, J=7.2Hz), 7.15 (d, 1H, J=7.2Hz), 7.28 (d, 1H, J=7.6Hz), 7.60 (d, 1H, J=7.2Hz), 8.49 (dd, 1H, J=7.6,2.0Hz), 9.32 (d, 1H, J=2.0Hz)
The preparation of compound II-13：According to the similar approach of prepare compound II-1, by compound 15 (5.41g, 23mmol) Synthesize pale yellowish oil compound II-13 (4.06g, yield 86.8%), be directly used in lower step.
The preparation of compound III-13：According to the similar approach of prepare compound III-1, by compound II-13 (1.35g, 6.6mmol) synthesize yellow oily compound III-13 (1.44g), be directly used in lower step.
The preparation of compound WX-113：According to the similar approach of prepare compound WX-101, by III-13 (1.44g, 5.3mmol) and IV-1 (840mg, 4.5mmol) synthesis obtains compound WX-113 (1.38g, the yield of faint yellow solid 61.2%).1H-NMR (400MHz, CDC13)：δ 1.64 (d, 6H, J=4.8Hz), 2.01-2.06 (m, 2H), 2.57 (t, 2H, J =7.2Hz), 2.87 (t, 2H, J=7.2Hz), 7.04-7.11 (m, 2H), 7.26 (d, 1H, J=7.2Hz), 7.61 (d, 1H, J =7.2Hz), 7.68 (d, 1H, J=1.6Hz), 8.24 (d, 1H, J=2.0Hz), 8.66 (d, 1H, J=2.0Hz).MS：m/z 501.2[M+H]+。
Embodiment 14
5- (5- (6- (3- (oxazole -2- bases) propyl group) pyridin-3-yl) thio -5,7- diaza spiros [3.4] of -8- oxos -6- Octyl- 7- yls) -3- (trifluoromethyl) pyridine -2- formonitrile HCNs (WX-114) preparation
The preparation of compound III-14：According to the similar approach of prepare compound III-7, by compound II-13 (1.35g, 6.6mmol) synthesize yellow oily compound III-14 (1.61g), be directly used in lower step.
The preparation of compound WX-114：According to the similar approach of prepare compound WX-101, by III-14 (1.61g, 5.7mmol) and IV-1 (900mg, 4.8mmol) synthesis obtains compound WX-114 (1.42g, the yield of faint yellow solid 67.7%).1H-NMR (400MHz, CDC13)：δ 1.65-1.70 (m, 1H), 1.99-2.05 (m, 3H), 2.23-2.30 (m, 2H), 2.47-2.54 (m, 2H), 2.59 (t, 2H, J=7.2Hz), 2.85 (t, 2H, J=7.2Hz), 7.03-7.09 (m, 2H), 7.24 (d, 1H, J=7.6Hz), 7.60 (d, 1H, J=7.6Hz), 7.67 (d, 1H, J=2.0Hz), 8.25 (d, 1H, J=2.4Hz), 8.67 (d, 1H, J=2.4Hz).MS：m/z 513.2[M+H]+。
Embodiment 15
5- (1- (6- (3- (oxazole -2- bases) propyl group) pyridin-3-yl) thio -7- oxa-s -1,3- diazas of -4- oxos -2- Spiral shell [4.4] nonyl- 3- yls) -3- (trifluoromethyl) pyridine -2- formonitrile HCNs (WX-115) preparation
The preparation of compound III-15：According to the similar approach of prepare compound III-8, by compound II-13 (1.36g, 6.7mmol) synthesize yellow oily compound III-15 (1.82g), be directly used in lower step.
The preparation of compound WX-115：According to the similar approach of prepare compound WX-101, by III-12 (1.82g, 6.1mmol) and IV-1 (970mg, 5.2mmol) synthesis obtains compound WX-115 (1.53g, the yield of faint yellow solid 55.6%).1H-NMR (400MHz, CDC13)：δ 1.94-2.03 (m, 2H), 2.13-2.2.19 (m, 1H), 2.38-2.42 (m, 1H), 2.57 (t, 2H, J=7.2Hz), 2.86 (t, 2H, J=7.2Hz), 3.72-3.83 (m, 2H), 4.03 (d, 1H, J= 4.8Hz), 4.30 (d, 1H, J=4.8Hz), 7.03-7.10 (m, 2H), 7.24 (d, 1H, J=7.2Hz), 7.59 (d, 1H, J= 7.2Hz), 7.68 (d, 1H, J=2.0Hz), 8.25 (d, 1H, J=2.0Hz), 8.65 (d, 1H, J=2.0Hz).MS：m/ z529.2[M+H]+。
Test example biological activity test
Test the suppression that PSA is produced in compound on prostate cancer (LNCaP-AR) cell
(LNCaP-AR) cell culture of androgen-dependent prostate cancer is passed through at glucose activity charcoal containing 10% The RPMI1640 nutrient solutions of the hyclone of reason, cultivate to cell and are in exponential phase, with trypsin digestion cell and use platform Expect that blue dye method carries out plating cells after counting, add 100 μ L cell suspensions per hole, include 5000 cells.When plating cells 24 are small Afterwards, add R1881 (AR activators) (final concentration of 1ng/mL), test-compound or the miscellaneous Shandong amine of grace (final concentration of 0.005, 0.025,0.05,0.250,0.5,2.5,5 μM).Three days after addition, the PSA in the supernatant of culture solution is measured by ELISA Concentration.At room temperature, by culture medium and standard items (200 μ L/ holes) in the coated plate of antibody in plate oscillator with 500rpm extremely When 600rpm incubations 2 are small.Then, hole is washed 5 times.HRP conjugates are diluted to 1 with measure buffer:20, into all holes Add 100 μ L.At room temperature, plate is incubated on the oscillator 30 minutes, and is washed as previously described, add the TMB of 100 μ L (0.4g/L).Plate is incubated on the oscillator 10 minutes, is terminated and reacted with 100 μ L terminate liquids.Using plate reader at 450nm (there is 650nm with reference to wave filter) read plate.After a variety of processing, make the horizontal growth differences for being directed to LNCaP-AR cells of PSA To normalize, determined as measured by MTS.Measure (concentration of test-compound) based on seven points calculates PSA's IC50, the results are shown in table 1.
The suppression that 1 compound of table produces PSA in LNCaP-AR cells
1 compound pair of tableLNCaPThe suppression that PSA is produced in-AR cells
Compound IC50(μM)
The miscellaneous Shandong amine of grace 2.1
WX-101 1.3
WX-102 0.38
WX-103 0.064
WX-104 0.82
WX-105 0.21
WX-106 0.27
WX-107 0.096
WX-108 0.12
WX-109 0.85
WX-110 1.4
WX-111 0.78
WX-112 0.13
WX-113 0.043
WX-114 0.086
WX-115 0.11
Such as clearly visible from table 1, compared with the miscellaneous Shandong amine of grace, preferred compounds of the invention is shown in prostate gland cancer cell Go out the stronger suppression effect produced to PSA.

Claims (10)

  1. Formula 1. (I) compound or pharmaceutically acceptable salt thereof：
    Wherein：
    X is selected from：Cyano group, halogen, C1-C4Alkyl or the C optionally substituted by one or more halogens1-C4Alkyl；
    R1And R2Independently selected from C1-C4Alkyl or the C optionally substituted by one or more fluorine or hydroxyl1-C4Alkyl；Or R1 And R2Carbon connected to them forms 3 to 6 yuan of cycloalkyl together, one or more carbon is optional by one or more The substitution of a fluorine or hydroxyl, and one of them or two carbon are optional is replaced with oxygen or nitrogen；
    R3It is selected from：Hydrogen and halogen；
    Y is selected from：Carbon and nitrogen；
    Z is selected from：C(O)NR4R5、SO2R4、SO2NR4R5、C(O)NR4R5、C(O)OR4、OC(O)NR4R5, pyrazolyl, imidazole radicals, Evil Oxazolyl, isoxazolyls, thiadiazolyl group, oxadiazolyls, triazolyl, tetrazole radical, thiazolyl, isothiazolyl；
    R4And R5Independently selected from：Hydrogen, C1-C6Alkyl, C1-C6Alkenyl and C3-C6Cycloalkyl, wherein one or more carbon can be optional Ground is substituted by one or more hydroxyls, amino, cyano group or fluorin radical；
    N is selected from 1 to 4 integer.
  2. 2. compound according to claim 1, wherein X are cyano group, halogen, methyl or trifluoromethyl.
  3. 3. compound according to claim 1, wherein R1And R2It is methyl, or R1And R2Carbon connected to them is together Form 4 to 5 yuan of cycloalkyl, one of them or two carbon are optional is replaced with oxygen or nitrogen.
  4. 4. compound according to claim 1, wherein R3It is hydrogen or fluorine.
  5. 5. compound according to claim 1, wherein Z are pyrazolyl, imidazole radicals, oxazolyl, isoxazolyls, thiadiazoles Ji, oxadiazolyls, triazolyl, tetrazole radical, thiazolyl or isothiazolyl.
  6. 6. compound according to claim 1, wherein n are 2 or 3.
  7. 7. compound according to claim 1, it is selected from：
    4- (4- (3- (6- cyano group -5- (trifluoromethyl) pyridin-3-yl) -5,5- dimethyl -4- oxo -2- thiocarbamoyl imidazole alkane -1- Base) -2- fluorophenyls) methyl butyrate；
    4- (4- (3- (6- cyano group -5- (trifluoromethyl) pyridin-3-yl) -5,5- dimethyl -4- oxo -2- thiocarbamoyl imidazole alkane -1- Base) -2- fluorophenyls) butyramide；
    5- (3- (the fluoro- 4- of 3- (3- (oxazole -2- bases) propyl group) phenyl) -4,4- dimethyl -5- oxo -2- thiocarbamoyl imidazole alkane -1- Base) -3- (trifluoromethyl) pyridine -2- formonitrile HCNs；
    5- (3- (4- (3- (1H- imidazoles -2- bases) propyl group) -3- fluorophenyls) -4,4- dimethyl -5- oxo -2- thiocarbamoyl imidazoles alkane - 1- yls) -3- (trifluoromethyl) pyridine -2- formonitrile HCNs；
    5- (3- (4- (3- cyanopropyls) -3- fluorophenyls) -4,4- dimethyl -5- oxo -2- thiocarbamoyl imidazole alkane -1- bases) -3- (three Methyl fluoride) pyridine -2- formonitrile HCNs；
    4- (4- (3- (6- cyano group -5- (trifluoromethyl) pyridin-3-yl) -5,5- dimethyl -4- oxo -2- thiocarbamoyl imidazole alkane -1- Base) -2- fluorophenyls)-N- methylbutyryl amine；
    5- (5- (the fluoro- 4- of 3- (3- (oxazole -2- bases) propyl group) phenyl) thio -5,7- diaza spiros [3.4] octyl-s of -8- oxos -6- 7- yls) -3- (trifluoromethyl) pyridine -2- formonitrile HCNs；
    5- (1- (the fluoro- 4- of 3- (3- (oxazole -2- bases) propyl group) phenyl) thio -7- oxa-s -1,3- diaza spiros of -4- oxos -2- [4.4] nonyl- 3- yls) -3- (trifluoromethyl) pyridine -2- formonitrile HCNs；
    4- (5- (3- (6- cyano group -5- (trifluoromethyl) pyridin-3-yl) -5,5- dimethyl -4- oxo -2- thiocarbamoyl imidazole alkane -1- Base) pyridine -2- bases) methyl butyrate；
    4- (5- (3- (6- cyano group -5- (trifluoromethyl) pyridin-3-yl) -5,5- dimethyl -4- oxo -2- thiocarbamoyl imidazole alkane -1- Base) pyridine -2- bases) butyramide；
    5- (3- (6- (4- (4- hydroxy piperidine -1- bases) -4- oxos butyl) pyridin-3-yl) -4,4- dimethyl -5- oxo -2- sulphur For imidazolidine -1- bases) -3- (trifluoromethyl) pyridine -2- formonitrile HCNs；
    5- (4,4- dimethyl -5- oxos -3- (6- (3- (thiazol-2-yl) propyl group) pyridin-3-yl) -2- thiocarbamoyl imidazole alkane -1- Base) -3- (trifluoromethyl) pyridine -2- formonitrile HCNs；
    5- (4,4- dimethyl -3- (6- (3- (oxazole -2- bases) propyl group) pyridin-3-yl) -5- oxo -2- thiocarbamoyl imidazole alkane -1- Base) -3- (trifluoromethyl) pyridine -2- formonitrile HCNs；
    5- (5- (6- (3- (oxazole -2- bases) propyl group) pyridin-3-yl) thio -5,7- diaza spiros [3.4] octyl-s of -8- oxos -6- 7- yls) -3- (trifluoromethyl) pyridine -2- formonitrile HCNs；
    5- (1- (6- (3- (oxazole -2- bases) propyl group) pyridin-3-yl) thio -7- oxa-s -1,3- diaza spiros of -4- oxos -2- [4.4] nonyl- 3- yls) -3- (trifluoromethyl) pyridine -2- formonitrile HCNs.
  8. 8. the compound or pharmaceutically acceptable salt thereof any one of claim 1 to 7 is in androgen receptor antagonists are prepared Purposes；And preparing for preventing and treating disease relevant with estrogen receptor activity or disorder, slowing down the disease or disorderly Process, the treatment disease or the disorder of unrest make the disease or the purposes of the disorderly medicine to disappear.
  9. 9. purposes according to claim 8, wherein the disease or disorder are selected from：Hormone-sensitive prostate cancer or hormone Refractory prostate cancer, benign prostatic hyperplasis, acne, hirsutism, sebum excess and alopecia.
  10. 10. compound any one of claim 1 to 7 prepare be used as in prostate cancer antitumor agent or moderator, Purposes in the medicine of adjuvant or new adjuvant adjuvant hormonal；And preparing the incidence for being used to reduce prostate cancer, stopping forefront Gland cancer or make prostate cancer disappear medicine in purposes.
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CN114014850A (en) * 2021-12-17 2022-02-08 山东汇海医药化工有限公司 Prudelamine intermediate, synthesis method thereof and method for synthesizing prasulamine from intermediate
CN114181138A (en) * 2021-12-23 2022-03-15 大连万福制药有限公司 Method for preparing prochloraz intermediate from derivative of nitropyridine butanamide
CN114181138B (en) * 2021-12-23 2023-09-05 大连万福制药有限公司 Method for preparing pramipexole amine intermediate from nitropyridine butyramide derivative

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