CN109438297B - Androgen receptor antagonist, preparation method and application thereof - Google Patents

Androgen receptor antagonist, preparation method and application thereof Download PDF

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CN109438297B
CN109438297B CN201811463656.1A CN201811463656A CN109438297B CN 109438297 B CN109438297 B CN 109438297B CN 201811463656 A CN201811463656 A CN 201811463656A CN 109438297 B CN109438297 B CN 109438297B
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CN109438297A (en
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张朴永
肖绪枝
申长念
郭昆
林志刚
陈梦然
张云
王立江
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Kunming Jida Pharmaceutical Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/10—Anti-acne agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • 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
    • C07C311/20—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 a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/70—Sulfur atoms
    • C07D213/71—Sulfur atoms to which a second hetero atom is attached

Abstract

The invention relates to an androgen receptor antagonist, a preparation method and application thereof, wherein the androgen receptor antagonist is a compound represented by a general formula (1) and a pharmaceutically acceptable salt thereof (R in the general formula)1、R2、R3And R4The definition of (A) is shown in the specification).

Description

Androgen receptor antagonist, preparation method and application thereof
Technical Field
The invention relates to the technical field of medicines, in particular to a novel androgen receptor antagonist, a preparation method and application thereof.
Background
Prostate cancer incidence is second among all malignancies in men. An Androgen Receptor (AR) is an important target for treating prostate cancer, and blocking the binding of Androgen to AR using an Androgen receptor antagonist can achieve therapeutic purposes. Among the non-steroidal androgen receptor antagonists commonly used in clinical applications are bicalutamide (R-bicalutamide) and Enzalutamide (Enzalutamide), the structures of which are shown below.
Figure BDA0001889234940000011
These compounds are all used for the treatment of prostate cancer and bicalutamide (US4636505) was developed by the company astrazen and marketed in 1995 under the trade name combretan (Casodex). Enzalutamide (MDV3100, US2007254933) is under the trade name Xtandi, jointly developed by Medivation and Astellas, and FDA approved treatment trend resistant prostate cancer at 8 months of 2012. A study of Marcella Bassetto, Salvator Ferla et al in "Design and synthesis of novel bicalutamide and enzalutamide derivatives as anti-cancer agents for the treatment of cancer of the cancer patient (European Journal of Medicinal Chemistry 118(2016) 230. mu.M)" shows that the geometric mean of anti-cancer activities IC50 of bicalutamide in 22Rv1, DU-145, LNCaP and VCaP cell lines is 52.42. mu.M, and the geometric mean of enzalutamide activity is 28.10. mu.M, which are not generally high in biological activity, and need to be used in larger doses for therapeutic purposes, thereby increasing the metabolic burden of the patient. In addition, bicalutamide has the effect of activating androgen receptor (aginst), thereby stimulating cancer proliferation (CN 104024228B).
Disclosure of Invention
Technical problem to be solved by the invention
The present invention has been made in view of the above problems of the prior art, and an object of the present invention is to provide a novel androgen receptor antagonist having high potency and low toxicity, high pharmaceutical activity, low dosage and low toxic or side effects.
Means for solving the problems
The present invention provides a compound represented by the following general formula (1) and a pharmaceutically acceptable salt thereof,
Figure BDA0001889234940000021
wherein R is1And R2The same or different, each represents a hydrogen atom, or R1And R2Together form C3-6A cycloalkyl group;
R3represents a hydrogen atom or C1-8An alkyl group;
R4is substituted or unsubstituted C6-10The heteroaryl is 5-membered or 6-membered monocyclic group, or bicyclic group formed by condensing 5-membered or 6-membered monocyclic ring and benzene ring.
In a preferred embodiment, R4Is C having at least one substituent6-10Aryl or heteroaryl, the substituents being selected from halogen atoms, cyano, nitro, C1-8Alkyl, halo C1-8Alkyl, halo C1-8Alkoxy, halo C1-8Alkylthio, halo C1-8Alkylsulfinyl, halogeno C1-8Alkylsulfonyl or pentafluorothio.
In a preferred embodiment, R4Is any one selected from the following groups:
Figure BDA0001889234940000022
Figure BDA0001889234940000031
wherein n represents an integer of 1 to 7.
In a preferred embodiment, the compound represented by the above general formula (1) is selected from:
Figure BDA0001889234940000032
Figure BDA0001889234940000041
the present invention also provides a pharmaceutical composition comprising the above-mentioned compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
In addition, the invention also relates to application of the compound or the pharmaceutically acceptable salt thereof in preparing medicaments for preventing or treating diseases related to androgen receptor activity. Wherein the diseases related to the androgen receptor activity comprise: hormone sensitive prostate cancer, hormone refractory prostate cancer, benign prostatic hyperplasia, acne, hirsutism, whelk, acne and alopecia.
Further, the present invention provides a method for producing a compound represented by the general formula (1), characterized by comprising the steps of:
reacting a compound (2) with oxalyl chloride or thionyl chloride in an aprotic solvent to form a compound (3);
Figure BDA0001889234940000042
step (II) of reacting the compound (3) with the compound (4) in an aprotic solvent to form a compound (5);
Figure BDA0001889234940000043
step (III) of reacting the compound (5) with piperidine in an organic solvent to form a compound (6);
Figure BDA0001889234940000044
a step (IV) of reacting the compound (6) with the compound (7) in an organic solvent to form a compound (1);
Figure BDA0001889234940000051
in the above formulae R1、R2、R3And R4The definitions of (a) are the same as above.
Effects of the invention
(1) The compound is an androgen antagonist with novel structure and excellent effect, can be used for treating androgen-related diseases, has stronger inhibiting effect on prostate cancer cells, and has cellular activity which is several times that of clinical medicines of bicalutamide and enzalutamide.
(2) The preparation method of the compound is simple.
Detailed Description
R as used in the general formula1、R2、R3And R4The groups represented and the substituents of these groups are as follows.
“C1-8The alkyl group "means a straight-chain or branched-chain alkyl group having 1 to 8 carbon atoms, and examples thereof include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, a sec-butyl group, an n-pentyl group, a neopentyl group, an n-hexyl group, an isohexyl group, a 3-methylpentyl group, a heptyl group, and an octyl group.
“C1～8Alkoxy "means a straight-or branched-chain alkoxy group having 1 to 8 carbon atoms (C)1-8alkyl-O-) includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentoxy, neopentoxy, n-hexoxy, isohexoxy, 3-methylpentoxy, n-heptoxy, n-octoxy and the like.
“C1～8Alkylthio "means a straight-or branched-chain alkylthio (C) having 1 to 8 carbon atoms1-8Examples of the alkyl-S-) include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, tert-butylthio, sec-butylthio, n-pentylthio, neopentylthio, n-hexylthio, isohexylthio, 3-methylpentylthio, n-heptylthio and n-octylthio.
"halogen atom" means fluorine, chlorine, bromine and iodine.
"halo C1～8Alkyl "means" C "as defined above1～8The hydrogen atom in the alkyl group "is substituted with at least one halogen atom to form a group. For example trihalomethyl (e.g. -CF)3) Trihaloethyl (e.g. -CH)2CF3) Pentahaloethyl (e.g., -CF)2CF3) Or nonahalobutyl (e.g., -CF)2CF2CF2CF3) And the like.
“C3～6The "cycloalkyl group" refers to a 3 to 6-membered saturated hydrocarbon ring, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
“C6-10The aryl group means an aromatic hydrocarbon group having 6 to 10 carbon atoms, and examples thereof include a phenyl group, an α -naphthyl group, and a β -naphthyl group.
"heteroaryl" refers to a 5-or 6-membered monocyclic group, or a bicyclic group obtained by condensing the above 5-or 6-membered monocyclic ring with a benzene ring. The 5-or 6-membered monocyclic group is a 5-to 6-membered heteroaryl group containing at least one heteroatom selected from N, O, S, and examples thereof include imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, thiophene, furan, pyran, dipyranyl, thiazole, isothiazole, thiadiazole, thiazine, oxazole, isoxazole, pyrrole, and dioxazole. Examples of the bicyclic group formed by condensing a 5-or 6-membered monocyclic ring with a benzene ring include benzimidazole, benzopyridine, benzopyrimidine, benzothiophene, benzofuran, benzothiazole, benzoxazole and benzisoxazole.
Specific examples of the compound represented by the general formula (1) of the present invention include:
Figure BDA0001889234940000061
Figure BDA0001889234940000071
the pharmaceutical composition of the present invention contains a compound represented by the above general formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient. The pharmaceutical composition comprises a compound of any of the above embodiments and variations as an active ingredient in combination with a pharmaceutically acceptable carrier, diluent or excipient.
The term "pharmaceutically acceptable salt" refers to salts that retain the biological potency and properties of the compounds of the present invention, and which generally have no adverse biological or other effects. In many cases, the compounds of the present invention are capable of forming acid and/or base salts using the presence of amino and/or carboxyl groups or similar groups.
The compound of the present invention can be used for preventing or treating diseases associated with androgen receptor activity, for example, hormone-sensitive prostate cancer, hormone-refractory prostate cancer, benign prostatic hyperplasia, acne, hirsutism, whelk, pimples and alopecia.
The compounds of the present invention can be prepared by the following methods.
Figure BDA0001889234940000072
In the formula R1、R2、R3And R4The definitions of (a) are the same as described above.
In addition, the compounds of the present invention can also be prepared by the following methods.
Figure BDA0001889234940000081
In the formula R1、R2、R3And R4Is as defined above, R5Is tert-butyl or methyl.
Hereinafter, the method for producing the compound of the present invention will be described with reference to specific examples.
Example 1 (preparation of Compounds JD 1001-1073)
Figure BDA0001889234940000082
1.82g (10mmol, 1.0eq) of tert-butyl sarcosinate, 40ml of DCM, 2.02g (20mmol, 2.0eq) of TEA and 122mg (1.0mmol, 0.1eq) of DMAP are added into a 100ml flask, 1.95g (10mmol, 1.0eq) of p-fluorobenzenesulfonyl chloride is added dropwise into the solution under the condition of stirring in an ice-water bath at the temperature of 0 ℃, the reaction is carried out for 2h after the room temperature is recovered, and after the completion of the reaction is confirmed by LCMS, the mother liquor is dried by spinning to obtain 2.03g of a crude product JD1002-052-1 with the yield of 66%.
To 2.03g of crude JD1002-052-1(10mmol, 1.0eq) was added 30ml of a mixed solution of DCM and TFA (DCM: TFA. RTM.2: 1), reacted at room temperature for 4 hours, and after completion of the reaction by LCMS, 30ml of H was added2Quenching reaction, adding 30ml DCM to extract an organic phase, drying, rotary steaming and performing column chromatography to obtain 1.24g of JD1002-052-2 with the yield of 51%.
Dissolving 300mg of solid JD1002-052-2 in 3mL (3V) of DCM, adding 3 drops of DMF, cooling to 0 ℃, dropwise adding 3eq oxalyl chloride at low temperature, heating to room temperature after dropwise addition, reacting for 2 hours, taking a small amount of methanol for derivatization, detecting by LCMS, concentrating under reduced pressure after reaction to obtain 350mg of a solid product JD1001-002-13, and storing for later use under the protection of nitrogen.
To a 25mL reactor under nitrogen protection was added 0.1g (1.0mmol, 1.0eq) JD1001-002-13, 3.2mL (10.0V) THF, 0.32g (3mmol, 3.1eq) NaHCO30.38g (3.0mmol, 3.0eq) of 4- (pentafluorothio) aniline, heating to 60 ℃, stirring for reaction for 3 hours, detecting the reaction completion of raw materials by TLC (developing agent: PE/EA: 1/1, UV254), stopping reaction, adding water for quenching reaction, extracting with ethyl acetate to obtain an organic phase, drying with anhydrous sodium sulfate, filtering to obtain an organic phase, concentrating the organic phase to obtain a solid, and performing HPLC (CH)3CN/H2O60: 40) separationPurification yielded 52mg of JD 1001-1073. The yield thereof was found to be 36%.
H-NMR-JD1001-1073:(DMSO，ppm,400MHz)δ2.85(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
Example 2 (preparation of Compounds JD 1001-1074)
Figure BDA0001889234940000091
1.82g (10mmol, 1.0eq) of tert-butyl sarcosinate, 40ml of DCM, 2.02g (20mmol, 2.0eq) of TEA and 122mg (1.0mmol, 0.1eq) of DMAP are added into a 100ml flask, 1.95g (10mmol, 1.0eq) of p-fluorobenzenesulfonyl chloride is added into the solution dropwise under the condition of stirring in an ice-water bath at the temperature of 0 ℃, the reaction is carried out for 2h after the room temperature is recovered, and after the reaction is determined to be finished by LCMS, the mother liquor is dried by spinning to obtain 3.03g of a crude product JD1002-052-1 with the yield of 100%.
To 3.03g of crude JD1002-052-1(10mmol, 1.0eq) was added 30ml of a mixed solution of DCM and TFA (DCM: TFA. RTM.2: 1), reacted at room temperature for 4 hours, and after completion of the reaction by LCMS, 30ml of H was added2Quenching reaction, adding 30ml DCM to extract organic phase, drying, rotary steaming, and column chromatography to obtain 1.17g, yield is 47%.
Dissolving 300mg of solid JD1002-052-2 in 3mL (3V) of DCM, adding 3 drops of DMF, cooling to 0 ℃, dropwise adding 3eq oxalyl chloride at low temperature, heating to room temperature after dropwise addition, reacting for 2 hours, taking a small amount of methanol for derivatization, detecting by LCMS, concentrating under reduced pressure after reaction to obtain 350mg of a solid product JD1001-002-13, and storing for later use under the protection of nitrogen.
To a 25mL reactor under nitrogen protection was added 0.1g (1.0mmol, 1.0eq) JD1001-002-13, 3.2mL (10.0V) THF, 0.32g (3mmol, 3.1eq) NaHCO30.38g (3.0mmol, 3.0eq) of 3- (pentafluorothio) aniline, heating to 60 ℃, stirring for reaction for 3 hours, detecting the reaction completion of raw materials by TLC (developing agent: PE/EA: 1/1, UV254), stopping reaction, adding water for quenching reaction, extracting with ethyl acetate to obtain an organic phase, drying with anhydrous sodium sulfate, filtering to obtain an organic phase, concentrating the organic phase to obtain a solid, and performing HPLC (CH)3CN/H2O60: 40) is divided intoPurification gave 65mg of JD1001-1074 in 53% yield.
H-NMR-JD1001-1074:(DMSO，ppm,400MHz)δ2.87(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
Example 3 (preparation of Compounds JD 1001-1075)
(1) Synthesis of JD1001-002-8
Figure BDA0001889234940000101
Adding 2.0g (15.4mmol, 1eq) of Fmoc-1-aminocyclobutanecarboxylic acid into a 200mL three-necked flask under the protection of nitrogen, adding 20mL (10V) of DCM, adding 4 drops of DMF, dropwise adding 4.0g of oxalyl chloride (32mmol, 5eq) at room temperature, stirring and reacting for 4 hours at room temperature, detecting the reaction completion by methanol-derivatized TLC (developer: PE/EA-1/1, UV254), and evaporating off the oxalyl chloride and DCM under reduced pressure to obtain a light yellow solid; 50mL of dry THF, 0.8g (22.6mmol, 1.5eq) of NaHCO were added thereto31.4g (18.3mmol, 1.2eq) of 4- (pentafluorothio) aniline was heated to 60 ℃ and reacted at this temperature with stirring for 2 hours, the completion of the reaction of the starting materials was checked by TLC (developer: PE/EA: 1/1, UV254), the reaction was stopped and cooled to room temperature, 200mL of water was added to dilute the reaction system, 100mL of EA was used for extraction, the organic phase was dried over anhydrous sodium sulfate, the organic phase was filtered, 40mL of piperidine was added to the organic phase, the reaction was stirred at room temperature for 1 hour, the completion of the reaction was checked by TLC (developer: PE/EA: 1/1, UV254), and the solvent was distilled off under reduced pressure at 40 ℃ to obtain 4g of a solid. The solid was dissolved in dichloromethane, 16g of silica gel was added and the mixture was stirred and separated with petroleum ether and ethyl acetate (PE/EA ═ 5:1 to 1:1) to give 0.9g of JD1001-002-8 as a solid compound in 38% yield.
LC-MS-JD1001-002-8:(ES,m/z):[M+H]+calcd for C11H13F5N2OS317,found 317
(2) Preparation of Compounds JD1001-1075
Figure BDA0001889234940000111
A25 mL reactor was charged with 0.3g (1.0mmol, 1.0eq) of the previously obtained JD1001-002-8, 3.2mL (10.0V) THF, 0.32g (3mmol, 3.1eq) DMAP, 0.38g (3.0mmol, 3.0eq) 4-fluorobenzenesulfonyl chloride under nitrogen, stirred at room temperature for 3 hours, and the reaction was stopped after TLC detection of the end of the starting material reaction (developing agent: PE/EA: 1/1, UV254) and saturated NaHCO was used to stop the reaction3Quenching reaction, extracting with ethyl acetate to obtain organic phase, washing the organic phase with 0.5N hydrochloric acid for 2 times, drying with anhydrous sodium sulfate, filtering to obtain organic phase, concentrating to obtain solid, and performing HPLC (CH)3CN/H2O60: 40) to yield 83mg of JD 1001-1075. The yield thereof was found to be 34%.
H-NMR-JD1001-1075:(DMSO，ppm,400MHz)δ1.62(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
Example 4 (preparation of Compounds JD 1001-1076)
Figure BDA0001889234940000121
A25 mL reactor was charged with 0.3g (1.0mmol, 1.0eq) of JD1001-002-8, 3.2mL (10.0V) of THF, 0.32g (3mmol, 3.1eq) of DMAP, 0.38g (3.0mmol, 3.0eq) of 3, 5-difluorobenzenesulfonyl chloride under nitrogen, stirred at room temperature for 3 hours, TLC detected that the starting material had reacted (developer: PE/EA: 1/1, UV254), the reaction was stopped, and saturated NaHCO was added3Quenching reaction, extracting with ethyl acetate to obtain organic phase, washing the organic phase with 0.5N hydrochloric acid for 2 times, drying with anhydrous sodium sulfate, filtering to obtain organic phase, concentrating to obtain solid, and performing HPLC (CH)3CN/H2O60: 40) to yield 121mg of JD 1001-1076. The yield thereof was found to be 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
Example 5 (preparation of Compounds JD 1001-1077)
Figure BDA0001889234940000122
To a 25mL reactor under nitrogen protection was added 0.3g (1.0mmol, 1.0eq) of JD1001-002-8, 3.2mL (10.0V) of THF, 0.32g (3mmol, 3.1eq) of DMAP, 0.38g (3.0mmol, 3.0eq) of 3,4, 5-trifluorobenzenesulfonyl chloride, the reaction was stirred at room temperature for 3 hours, and the reaction was stopped by TLC after the reaction of the starting materials was completed (developer: PE/EA: 1/1, UV254), and saturated NaHCO was added3Quenching reaction, extracting with ethyl acetate to obtain organic phase, washing the organic phase with 0.5N hydrochloric acid for 2 times, drying with anhydrous sodium sulfate, filtering to obtain organic phase, concentrating to obtain solid, and performing HPLC (CH)3CN/H2O60: 40) to yield 67mg of JD 1001-1077. The yield thereof was found to be 24%.
H-NMR-JD1001-1077:(DMSO，ppm,400MHz)δ1.67(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
Example 6 (preparation of Compounds JD 1001-1078)
Figure BDA0001889234940000131
To a 25mL reactor under nitrogen protection was added 0.3g (1.0mmol, 1.0eq) of JD1001-002-8, 3.2mL (10.0V) of THF, 0.32g (3mmol, 3.1eq) of DMAP, 0.38g (3.0mmol, 3.0eq) of 2-trifluoromethylbenzenesulfonyl chloride, the reaction was stirred at room temperature for 3 hours, TLC detected that the reaction of the starting material was completed (developer: PE/EA: 1/1, UV254), the reaction was stopped, and saturated NaHCO was used as a trigger3Quenching reaction, extracting with ethyl acetate to obtain organic phase, washing the organic phase with 0.5N hydrochloric acid for 2 times, drying with anhydrous sodium sulfate, filtering to obtain organic phase, concentrating to obtain solid, and performing HPLC (CH)3CN/H2O60: 40) to yield 91mg of JD 1001-1078. The yield thereof was found to be 33%.
H-NMR-JD1001-1078:(DMSO，ppm,400MHz)δ1.66(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
Example 7 (preparation of Compounds JD 1001-1079)
Figure BDA0001889234940000132
To a 25mL reactor under nitrogen protection was added 0.3g (1.0mmol, 1.0eq) of JD1001-002-8, 3.2mL (10.0V) of THF, 0.32g (3mmol, 3.1eq) of DMAP, 0.38g (3.0mmol, 3.0eq) of 3-trifluoromethylbenzenesulfonyl chloride, the reaction was stirred at room temperature for 3 hours, TLC detected that the reaction of the starting material was completed (developer: PE/EA: 1/1, UV254), the reaction was stopped, and saturated NaHCO was used as a trigger3Quenching reaction, extracting with ethyl acetate to obtain organic phase, washing the organic phase with 0.5N hydrochloric acid for 2 times, drying with anhydrous sodium sulfate, filtering to obtain organic phase, concentrating to obtain solid, and performing HPLC (CH)3CN/H2O60: 40) to yield 42mg JD 1001-1079. The yield thereof was found to be 18%.
H-NMR-JD1001-1079:(DMSO，ppm,400MHz)δ1.62(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
Example 8 (preparation of Compound JD 1001-1080)
Figure BDA0001889234940000141
To a 25mL reactor under nitrogen protection was added 0.3g (1.0mmol, 1.0eq) of JD1001-002-8, 3.2mL (10.0V) of THF, 0.32g (3mmol, 3.1eq) of DMAP, 0.38g (3.0mmol, 3.0eq) of 4-trifluoromethylbenzenesulfonyl chloride, the reaction was stirred at room temperature for 3 hours, TLC detected that the starting material had reacted (developer: PE/EA: 1/1, UV254), the reaction was stopped, and saturated NaHCO was added3Quenching reaction, extracting with ethyl acetate to obtain organic phase, washing the organic phase with 0.5N hydrochloric acid for 2 times, drying with anhydrous sodium sulfate, filtering to obtain organic phase, concentrating to obtain solid, and performing HPLC (CH)3CN/H2O60: 40) to yield 21mg JD 1001-1080. The yield thereof was found to be 11%.
H-NMR-JD1001-1080:(DMSO，ppm,400MHz)δ1.65(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
Example 9 (preparation of Compound JD 1001-1081)
Figure BDA0001889234940000151
0.3g (1.0mmol, 1.0eq) of JD1001-002-8, 3.2mL (10.0V) of THF, 0.32g (3mmol, 3.1eq) of DMAP, 0.38g (3.0mmol, 3.0eq) of 3-cyano-4-fluorobenzenesulfonyl chloride are added to a 25mL reactor under the protection of nitrogen, the mixture is stirred at room temperature for 3 hours, TLC detects that the raw materials are reacted completely (developing agent: PE/EA: 1/1, UV254), the reaction is stopped, and saturated NaHCO is used for reaction3Quenching reaction, extracting with ethyl acetate to obtain organic phase, washing the organic phase with 0.5N hydrochloric acid for 2 times, drying with anhydrous sodium sulfate, filtering to obtain organic phase, concentrating to obtain solid, and performing HPLC (CH)3CN/H2O60: 40) to yield 15mg of JD1001-1081 in 7% yield.
H-NMR-JD1001-1081:(DMSO，ppm,400MHz)δ1.65(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
Example 10 (preparation of Compound JD 1001-1082)
Figure BDA0001889234940000152
To a 25mL reactor under nitrogen protection was added 0.3g (1.0mmol, 1.0eq) of JD1001-002-8, 3.2mL (10.0V) of THF, 0.32g (3mmol, 3.1eq) of DMAP, 0.38g (3.0mmol, 3.0eq) of 4-fluoro-3-trifluoromethylbenzenesulfonyl chloride, the reaction was stirred at room temperature for 3 hours, the reaction was stopped after TLC detection of the completion of the reaction of the starting material (developer: PE/EA: 1/1, UV254), and the reaction was stopped with saturated NaHCO3Quenching reaction, extracting with ethyl acetate to obtain organic phase, washing the organic phase with 0.5N hydrochloric acid for 2 times, drying with anhydrous sodium sulfate, filtering to obtain organic phase, concentrating to obtain solid, and performing HPLC (CH)3CN/H2O＝60:40) to obtain 52mg of JD1001-1082 with the yield of 24%.
H-NMR-JD1001-1082:(DMSO，ppm,400MHz)δ1.65(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
Example 11 (preparation of Compound JD 1001-1083)
Figure BDA0001889234940000161
0.3g (1.0mmol, 1.0eq) of JD1001-002-8, 3.2mL (10.0V) of THF, 0.32g (3mmol, 3.1eq) of DMAP, 0.38g (3.0mmol, 3.0eq) of 6-trifluoromethylpyridine-3-sulfonyl chloride were added to a 25mL reactor under nitrogen protection, the mixture was stirred at room temperature for 3 hours, the reaction was stopped after the reaction of the starting materials was completed by TLC detection (developing agent: PE/EA: 1/1, UV254), and saturated NaHCO was used to stop the reaction3Quenching reaction, extracting with ethyl acetate to obtain organic phase, washing the organic phase with 0.5N hydrochloric acid for 2 times, drying with anhydrous sodium sulfate, filtering to obtain organic phase, concentrating to obtain solid, and performing HPLC (CH)3CN/H2O60: 40) to yield 65mg of JD1001-1083 in 27% yield.
H-NMR-JD1001-1083:(DMSO，ppm,400MHz)δ1.67(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
Example 12 (preparation of Compound JD 1001-1089)
Figure BDA0001889234940000162
Under nitrogen protection, 0.3g (1.0mmol, 1.0eq) of JD1001-002-8, 3.2mL (10.0V) of THF, 0.32g (3mmol, 3.1eq) of DMAP, 0.38g (3.0mmol, 3.0eq) of 3, 5-bis (trifluoromethyl) benzenesulfonyl chloride were added to a 25mL reactor, the mixture was stirred at room temperature for 3 hours, and the reaction was stopped by TLC after the reaction of the starting materials was completed (developer: PE/EA: 1/1, UV254), and NaHCO was saturated3Quenching reaction, extracting with ethyl acetate to obtain organic phaseWashing the organic phase with 0.5N hydrochloric acid for 2 times, drying with anhydrous sodium sulfate, filtering to obtain organic phase, concentrating the organic phase to obtain solid, and performing HPLC (CH)3CN/H2O60: 40) to yield 131mg of JD 1001-1089. The yield thereof was found to be 46%.
H-NMR-JD1001-1089:(DMSO，ppm,400MHz)δ1.66(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
Example 13 (preparation of Compound JD 1001-1090)
Figure BDA0001889234940000171
Adding 5.0g (15.4mmol, 1eq) of Fmoc-1-aminocyclobutanecarboxylic acid into a 200mL three-necked flask under the protection of nitrogen, adding 50mL (10V) of DCM, adding 4 drops of DMF, dropwise adding 9.8g of oxalyl chloride (76.9mmol, 5eq) at room temperature, stirring at room temperature for reaction for 4 hours, detecting the reaction completion by methanol derivatization TLC (developer: PE/EA-1/1, UV254), and evaporating off oxalyl chloride and DCM under reduced pressure to obtain a light yellow solid; to this was added 90mL of dry THF, 1.9g (22.6mmol, 1.5eq) of NaHCO33.4g (18.3mmol, 1.2eq) of 3- (pentafluorothio) aniline was heated to 60 ℃ and reacted at this temperature with stirring for 2 hours, the completion of the reaction of the starting materials was detected by TLC (developer: PE/EA: 1/1, UV254), the reaction was stopped and cooled to room temperature, 200mL of water was added to dilute the reaction system, extraction was performed with 200mL of EA, the organic phase was dried over anhydrous sodium sulfate, the organic phase was filtered, 40mL of piperidine was added to the organic phase, reaction was performed at room temperature with stirring for 1 hour, the completion of the reaction was detected by TLC (developer: PE/EA: 1/1, UV254), and the solvent was distilled off under reduced pressure at 40 ℃ to obtain 8g of a solid. The solid was dissolved in dichloromethane, 16g of silica gel was added and the mixture was stirred and separated with petroleum ether and ethyl acetate (PE/EA ═ 5:1 to 1:1) to give 1.6g of JD1001-002-14 as a solid in 37% yield.
0.1g (1.0mmol, 1.0eq) of JD1001-002-14, 3.2mL (10.0V) of THF, 0.32g (3mmol, 3.1eq) of DMAP, 0.38g (3.0mmol, 3.0eq) of 3, 5-bis (trifluoromethyl) benzenesulfonyl chloride were added to a 25mL reactor under nitrogen protection, the mixture was stirred at room temperature for 3 hours, and the original sample was detected by TLCAfter the reaction (developing agent: PE/EA: 1/1, UV254), the reaction was stopped and saturated NaHCO was added3Quenching reaction, extracting with ethyl acetate to obtain organic phase, washing the organic phase with 0.5N hydrochloric acid for 2 times, drying with anhydrous sodium sulfate, filtering to obtain organic phase, concentrating to obtain solid, and performing HPLC (CH)3CN/H2O60: 40) to yield 53mg of JD1001-1090 in 35% yield.
H-NMR-JD1001-1090:(DMSO，ppm,400MHz)δ1.68(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
Example 14 (preparation of Compound JD 1001-1091)
Figure BDA0001889234940000181
To a 25mL reactor was added 3.0g (2.0mmol, 1.0eq) of methyl 1-aminocyclopropanecarboxylate hydrochloride under nitrogen, 30mL (10.0V) of THF was added to the system, 3.0g (3.0mmol, 1.5eq) of triethylamine was added dropwise at room temperature, followed by 0.3g (0.2mmol, 0.1eq) of DMAP, followed by 4.2g (2.2mmol, 1.1eq) of 3, 5-bis (trifluoromethyl) benzenesulfonyl chloride was added dropwise, the reaction was stirred at room temperature for 3 hours, TLC detection of completion of the reaction of the starting material (developer: PE/EA ═ 1/1, UV254) stopped, and saturated NaHCO was used to stop the reaction3The reaction was quenched, extracted with ethyl acetate to give an organic phase, which was washed 2 times with 0.5N hydrochloric acid, dried over anhydrous sodium sulfate, filtered to give an organic phase, which was concentrated to give 6.8g of a solid. Dissolving the solid in ethanol (100mL,15V), adding 30mL (5V) of water, then adding 4g (5.0eq) of NaOH, heating to 60 ℃, stirring and reacting for 2 hours, monitoring the reaction by LCMS, stopping the reaction after the reaction is finished, decompressing and concentrating to remove the ethanol, adding DCM for extraction, detecting that the organic phase does not contain the product, adding hydrochloric acid into the aqueous phase to adjust the pH value to 5, separating out the solid, and filtering to obtain 3.5g of light yellow solid. Dissolving 300mg of solid in 3mL (3V) of DCM, adding 3 drops of DMF, cooling to 0 ℃, dropwise adding 3eq of oxalyl chloride at low temperature, heating to room temperature after dropwise adding, reacting for 2 hours, adding a small amount of methanol for derivatization, detecting by LCMS (liquid crystal display system), and concentrating under reduced pressure after the reaction is finished350mg of solid product JD1001-002-12 is obtained and stored for later use under the protection of nitrogen.
LC-MS-JD1001-002-12 (methyl ester) (ES, M/z): M + H]+calcd for C13H11F6NO4S 392,found 392
To a 25mL reactor under nitrogen protection was added 0.1g (1.0mmol, 1.0eq) JD1001-002-12, 3.2mL (10.0V) THF, 0.32g (3mmol, 3.1eq) NaHCO30.38g (3.0mmol, 3.0eq) of 2- (Pentafluorothio) aniline is heated to 60 ℃ and stirred for reaction for 3 hours, TLC detects that the raw material reaction is finished (developing agent: PE/EA: 1/1, UV254), the reaction is stopped, water is added for quenching reaction, ethyl acetate is used for extraction to obtain an organic phase, the organic phase is dried by anhydrous sodium sulfate, filtration is carried out, the organic phase is concentrated to obtain a solid, and HPLC (CH)3CN/H2O60: 40) to yield 76mg of JD 1001-1091. The yield thereof was found to be 41%.
LC-MS-JD1001-1091:(ES,m/z):[M+H]+calcd for C18H13F11N2O3S2 579,found 579
H-NMR-JD1001-1091:(DMSO，ppm,400MHz)δ1.03(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 JD1001-1183 Compound)
(1) Synthesis of JD1001-002-22
Figure BDA0001889234940000201
To a 25mL reactor was added 3.0g (2.0mmol, 1.0eq) of methyl 1-aminocyclobutanecarboxylate hydrochloride under nitrogen, 30mL (10.0V) of THF was added to the system, 3.0g (3.0mmol, 1.5eq) of triethylamine was added dropwise at room temperature, followed by 0.3g (0.2mmol, 0.1eq) of DMAP, followed by 4.2g (2.2mmol, 1.1eq) of 3, 5-bis (trifluoromethyl) benzenesulfonyl chloride was added dropwise, the reaction was stirred at room temperature for 3 hours, TLC detected that the starting material had reacted (developer: PE/EA-1/1, UV254), the reaction was stopped, and saturated NaHCO was used3Quenching reaction, extracting with ethyl acetate to obtain organic phase, washing the organic phase with 0.5N hydrochloric acid for 2 times, and adding anhydrous sulfuric acidSodium was dried, the organic phase filtered off and concentrated to give 6.8g of a solid. Dissolving the solid in ethanol (100mL,15V), adding 30mL (5V) of water, then adding 4g (5.0eq) of NaOH, heating to 60 ℃, stirring and reacting for 2 hours, monitoring the reaction by LCMS, stopping the reaction after the reaction is finished, decompressing and concentrating to remove the ethanol, adding DCM for extraction, detecting that the organic phase does not contain the product, adding hydrochloric acid into the aqueous phase to adjust the pH value to 5, separating out the solid, and filtering to obtain 3.5g of light yellow solid. Dissolving 300mg of solid in 3mL (3V) of DCM, adding 3 drops of DMF, cooling to 0 ℃, dropwise adding 3eq of oxalyl chloride at low temperature, heating to room temperature after dropwise adding, reacting for 2 hours, adding a small amount of methanol for derivatization, detecting by LCMS, concentrating under reduced pressure after the reaction is finished to obtain 350mg of solid product JD1001-002-22, and storing for later use under the protection of nitrogen.
LC-MS-JD1001-002-22 (methyl ester) (ES, M/z): M + H]+406
(2) Synthesis of JD1001-1183
Figure BDA0001889234940000202
To a 25mL reactor under nitrogen protection was added 0.1g (1.0mmol, 1.0eq) of the JD1001-002-22, 3.2mL (10.0V) of THF, 0.32g (3mmol, 3.1eq) of NaHCO3Heating 0.38g (3.0mmol, 3.0eq) o-aminobenzotrifluoride to 60 deg.C, stirring and reacting for 3 hr, detecting by TLC that the raw material reaction is finished (developing agent: PE/EA: 1/1, UV254), stopping reaction, adding water to quench reaction, extracting with ethyl acetate to obtain organic phase, drying with anhydrous sodium sulfate, filtering to obtain organic phase, concentrating the organic phase to obtain solid, and performing HPLC (CH)3CN/H2O60: 40) to yield 21mg of JD 1001-1183. The yield thereof was found to be 23%.
LC-MS-JD1001-1183:(ES,m/z):[M+H]+535
H-NMR-JD1001-1183:(DMSO，ppm,400MHz)δ1.70(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 JD1001-1184 Compound)
Figure BDA0001889234940000211
To a 25mL reactor under nitrogen protection was added 0.1g (1.0mmol, 1.0eq) JD1001-002-22, 3.2mL (10.0V) THF, 0.32g (3mmol, 3.1eq) NaHCO3Heating 0.38g (3.0mmol, 3.0eq) of m-amino benzotrifluoride to 60 ℃, stirring and reacting for 3 hours, detecting the reaction completion of raw materials by TLC (developing agent: PE/EA: 1/1, UV254), stopping reaction, adding water to quench reaction, extracting with ethyl acetate to obtain an organic phase, drying with anhydrous sodium sulfate, filtering out the organic phase, concentrating the organic phase to obtain a solid, and performing HPLC (CH)3CN/H2O60: 40) to yield 18mg of JD 1001-1184. The yield thereof was found to be 21%.
LC-MS-JD1001-1184:(ES,m/z):[M+H]+535
H-NMR-JD1001-1184:(DMSO，ppm,400MHz)δ1.69(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 JD1001-1185 Compound)
Figure BDA0001889234940000221
To a 25mL reactor under nitrogen protection was added 0.1g (1.0mmol, 1.0eq) of the JD1001-002-22, 3.2mL (10.0V) of THF, 0.32g (3mmol, 3.1eq) of NaHCO30.38g (3.0mmol, 3.0eq) of p-aminotrifluorotoluene is heated to 60 ℃ and stirred for reaction for 3 hours, TLC detects that the raw material reaction is finished (developing agent: PE/EA: 1/1, UV254), the reaction is stopped, water is added for quenching reaction, ethyl acetate is used for extraction to obtain an organic phase, anhydrous sodium sulfate is used for drying, the organic phase is filtered, the organic phase is concentrated to obtain a solid, and HPLC (CH)3CN/H2O60: 40) to yield 31mg of JD 1001-1185. The yield thereof was found to be 29%.
LC-MS-JD1001-1185:(ES,m/z):[M+H]+535
H-NMR-JD1001-1185:(DMSO，ppm,400MHz)δ1.66(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 JD1001-1186 Compound)
Figure BDA0001889234940000222
To a 25mL reactor under nitrogen protection was added 0.1g (1.0mmol, 1.0eq) of the JD1001-002-22, 3.2mL (10.0V) of THF, 0.32g (3mmol, 3.1eq) of NaHCO3Heating 0.38g (3.0mmol, 3.0eq) of p-aminobenzonitrile to 60 ℃, stirring and reacting for 3 hours, detecting the reaction completion of raw materials by TLC (developing agent: PE/EA: 1/1, UV254), stopping reaction, adding water to quench and react, extracting by ethyl acetate to obtain an organic phase, drying by anhydrous sodium sulfate, filtering out the organic phase, concentrating the organic phase to obtain a solid, and performing HPLC (CH)3CN/H2O60: 40) to yield 41mg of JD 1001-1186. The yield thereof was found to be 38%.
LC-MS-JD1001-1186:(ES,m/z):[M+H]+492
H-NMR-JD1001-1186:(DMSO，ppm,400MHz)δ1.72(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 JD1001-1187 Compound)
Figure BDA0001889234940000231
To a 25mL reactor under nitrogen protection was added 0.1g (1.0mmol, 1.0eq) of the JD1001-002-22, 3.2mL (10.0V) of THF, 0.32g (3mmol, 3.1eq) of NaHCO3Heating 0.38g (3.0mmol, 3.0eq) of p-aminobenzonitrile to 60 ℃, stirring and reacting for 3 hours, detecting the reaction completion of raw materials by TLC (developing agent: PE/EA: 1/1, UV254), stopping reaction, adding water to quench and react, extracting by ethyl acetate to obtain an organic phase, drying by anhydrous sodium sulfate, filtering out the organic phase, concentrating the organic phase to obtain a solid, and performing HPLC (CH)3CN/H2O60: 40) to yield 16mg of JD 1001-1187. The yield thereof was found to be 12%.
LC-MS-JD1001-1187:(ES,m/z):[M+H]+492
H-NMR-JD1001-1187:(DMSO，ppm,400MHz)δ1.67(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 JD1001-1188 Compound)
Figure BDA0001889234940000232
To a 25mL reactor under nitrogen protection was added 0.1g (1.0mmol, 1.0eq) of the JD1001-002-22, 3.2mL (10.0V) of THF, 0.32g (3mmol, 3.1eq) of NaHCO3Heating 0.38g (3.0mmol, 3.0eq) of p-aminobenzonitrile to 60 ℃, stirring and reacting for 3 hours, detecting the reaction completion of raw materials by TLC (developing agent: PE/EA: 1/1, UV254), stopping reaction, adding water to quench and react, extracting by ethyl acetate to obtain an organic phase, drying by anhydrous sodium sulfate, filtering out the organic phase, concentrating the organic phase to obtain a solid, and performing HPLC (CH)3CN/H2O60: 40) to yield 18mg of JD 1001-1188. The yield thereof was found to be 13%.
LC-MS-JD1001-1188:(ES,m/z):[M+H]+492
H-NMR-JD1001-1188:(DMSO，ppm,400MHz)δ1.65(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 examples
The activity test was carried out on the compounds of the above examples and comparative examples according to the following method:
(1) the resulting compound was dissolved in DMSO to prepare a 10mM solution, which was stored at-20 ℃.
(2) Cells in logarithmic growth phase were collected, counted, resuspended in complete medium, adjusted to the appropriate concentration (the number of cells inoculated per well was optimized according to the number of cells and the results of the preliminary experiments were as follows: Du-145 (human prostate cancer cell line, androgen-independent, AR-/PSA-, purchased from Saiki bioengineering Co., Ltd.), 4000/well, 22RV-1 (human prostate cancer cell line, androgen-dependent, AR +/PSA +, purchased from Saiki bioengineering Co., Ltd.), andfrom jenie european biotechnology limited): 5000 per well), 96-well plates were seeded, and 100. mu.l of cell suspension was added per well. Cells were incubated at 37 ℃ and 100% relative humidity, 5% CO2Incubate in incubator for 24 hours.
(3) The test compound was diluted with the medium to the set corresponding effect concentration and the cells were added at 25. mu.l/well. The final concentration of compound effect was started at 40. mu.M, diluted in a 2-fold gradient, and tested in 6 concentration points (40. mu.M, 20. mu.M, 10. mu.M, 5. mu.M, 2.5. mu.M, 1.25. mu.M) with 3 duplicate wells per concentration point.
(4) The cells were incubated at 37 ℃ and 100% relative humidity with 5% CO2Incubate in incubator for 72 hours.
(5) Adding 10 mul of CCK-8 detection reagent into each well of a 96-well plate, uniformly mixing, standing for 1-2 hours at room temperature, measuring a light absorption signal (OD value) on a microplate Reader FLUOstar Omega Multilabel Reader, and calculating the inhibition rate.
Specific activity results are shown in the following table
Figure BDA0001889234940000251
Figure BDA0001889234940000261
Figure BDA0001889234940000271
As can be seen from the comparison of the activity data, in examples 1 to 14, the left benzene ring in the compounds of the present invention is replaced with SF5(Sulfur pentafluoride) group substitution is a highly active anti-prostate cancer compound, and compared with the compounds shown in comparative examples 1-6, the IC of DU-145 and 22RV-150The value is obviously reduced, in addition, the activity of the compound also has outstanding effect compared with the drugs such as bicalutamide, enzalutamide and the like clinically used at present, and the activity is obviously higher than that of other compounds (JD1001-1183\1184\1185\1186\1187\ 1188) with electron-withdrawing substituents (cyano, trifluoromethyl and the like))。
The above data indicate that the benzene ring is SF5The substituted compound of the present invention has an excellent effect in the treatment of prostate cancer and the like.

Claims (7)

1. A compound represented by the general formula (1) and a pharmaceutically acceptable salt thereof,
Figure FDA0002929822270000011
wherein R is1And R2Each represents a hydrogen atom, or R1And R2Together form C3-6A cycloalkyl group;
R3represents a hydrogen atom or C1-8An alkyl group;
R4is C having at least one substituent6-10The heteroaryl is 5-membered or 6-membered monocyclic group or bicyclic group formed by condensing 5-membered or 6-membered monocyclic ring and benzene ring, and the substituent is selected from halogen atom, cyano, nitro and C1-8Alkyl radical, C1-8Alkoxy, halo C1-8Alkyl, halo C1-8Alkoxy, halo C1-8Alkylthio, halo C1-8Alkylsulfinyl, halogeno C1-8Alkylsulfonyl or pentafluorothio.
2. The compound of claim 1, wherein R is selected from the group consisting of4Comprises the following steps:
Figure FDA0002929822270000012
Figure FDA0002929822270000021
wherein n represents an integer of 1 to 7.
3. The compound of claim 1, wherein the compound is selected from the group consisting of:
Figure FDA0002929822270000022
Figure FDA0002929822270000031
4. a pharmaceutical composition comprising a compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
5. The use of a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the prevention or treatment of a condition associated with androgen receptor activity.
6. The use of claim 5, wherein the disorder associated with androgen receptor activity comprises: hormone sensitive prostate cancer, hormone refractory prostate cancer, benign prostatic hyperplasia, acne, hirsutism and alopecia.
7. The process for producing a compound represented by the general formula (1) according to claim 1, which comprises the steps of:
reacting a compound (2) with oxalyl chloride or thionyl chloride in an aprotic solvent to form a compound (3);
Figure FDA0002929822270000032
step (II) of reacting the compound (3) with the compound (4) in an aprotic solvent to form a compound (5);
Figure FDA0002929822270000033
step (III) of reacting the compound (5) with piperidine in an organic solvent to form a compound (6);
Figure FDA0002929822270000034
a step (IV) of reacting the compound (6) with the compound (7) in an organic solvent to form a compound (1);
Figure FDA0002929822270000041
in the above formulae R1、R2、R3And R4Is as defined in claim 1.
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