CN109593061B - Androgen receptor antagonist, preparation method and application thereof - Google Patents

Androgen receptor antagonist, preparation method and application thereof Download PDF

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CN109593061B
CN109593061B CN201811463655.7A CN201811463655A CN109593061B CN 109593061 B CN109593061 B CN 109593061B CN 201811463655 A CN201811463655 A CN 201811463655A CN 109593061 B CN109593061 B CN 109593061B
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肖绪枝
张朴永
卢法冠
王志朋
陈梦然
郭昆
周蕊
张云
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Kunming Jida Pharmaceutical Co ltd
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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 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 BDA0001889233300000011
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
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.
The present invention provides a compound represented by the following general formula (1) and a pharmaceutically acceptable salt thereof,
Figure BDA0001889233300000021
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 C6-10Aryl or heteroAnd the 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 radical, C1-8Alkoxy, halo C1-8Alkyl, halo C1-8Alkoxy, halo C1-8Alkylthio, halo C1-8Alkylsulfinyl, halogeno C1-8Alkylsulfonyl or pentafluorothio.
In another preferred embodiment, R4Is any one selected from the following groups:
Figure BDA0001889233300000022
Figure BDA0001889233300000031
wherein n represents an integer of 1 to 7.
In addition, the present invention provides a pharmaceutical composition comprising the compound of any one of claims 1 to 3, 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.
In addition, the present invention provides a method for producing a compound represented by the general formula (1), comprising the steps of:
reacting a compound (2) with oxalyl chloride or thionyl chloride in an aprotic solvent to form a compound (3);
Figure BDA0001889233300000032
step (II) of reacting the compound (3) with the compound (4) in an aprotic solvent to form a compound (5);
Figure BDA0001889233300000033
step (III) of reacting the compound (5) with piperidine in an organic solvent to form a compound (6);
Figure BDA0001889233300000041
a step (IV) of reacting the compound (6) with the compound (7) in an organic solvent to form a compound (1);
Figure BDA0001889233300000042
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.
“C1-8Alkyl "refers to a straight-or branched-chain alkyl group having 1 to 8 carbon atoms, and examples thereof include methyl, ethyl, and n-propylAnd the alkyl group includes, but is not limited to, an alkyl 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, an octyl group and the like.
“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.
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 compound of the present invention can be produced by the following method in addition to the production method described above.
Figure BDA0001889233300000061
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 1001-2053)
Figure BDA0001889233300000062
5.0g (15.4mmol,1.0eq) of Fmoc-1-aminocyclopropanecarboxylic acid was added to a 200mL three-necked flask under nitrogen protection, then 50mL of DCM, 4 drops of DMF were added in this order, 9.8g of oxalyl chloride (76.9mmol,5.0eq) were added dropwise at room temperature, the reaction was stirred at room temperature for 4 hours, two drops of the reaction mixture were taken out and treated with methanol to obtain methyl esters, completion of the reaction was detected by TLC (developer: PE: EA ═ 1:1), oxalyl chloride and DCM were removed by distillation under reduced pressure to give pale yellow solids, which were stored under nitrogen.
The pale yellow solid obtained in the previous step was taken and to this was added sequentially 90mL of dry THF, 1.9g (22.6mmol, 1.5eq) of NaHCO33.4g (18.3mmol,1.2eq) of 5-amino-3-trifluoromethyl-2-cyanopyridine was heated to 60 ℃ and reacted with stirring at the temperature maintained for 2 hours, the completion of the reaction was detected by TLC (developer: PE: EA: 1), the reaction was stopped and cooled to room temperature, 200mL of water was added to dilute the reaction system, 100mL of the product was extracted by EA 3 times, the organic phase was dried over anhydrous sodium sulfate, filtered, 40mL of piperidine was added, the reaction was stirred at room temperature for 1 hour, the completion of the reaction was detected by TLC (developer: PE: EA: 1), and the solvent was distilled off under reduced pressure in a water bath at 40 ℃ to obtain 4g of a solid. Column chromatography was performed using silica gel, eluting with petroleum ether and ethyl acetate (PE: EA ═ 5:1 to 1:1), to give 0.93g of JD1001-002-9 as a solid in 22% yield.
0.10g (0.37mmol,1.0eq) of JD1001-002-9 solid, 3.2mL of THF, 0.14g (1.11mmol,3.0eq) of DMAP and 0.22g (1.11mmol,3.0eq) of 4-fluorobenzenesulfonyl chloride were added to a 25mL round-bottomed flask under nitrogen protection, the mixture was stirred at room temperature for 3 hours, and the completion of the reaction was checked by TLC (developing agent: PE: EA ═ 1:1), and saturated NaHCO was added thereto3Quenching with water solution, extracting with ethyl acetate to obtain organic phase, washing the organic phase with 0.5N hydrochloric acid water solution for 2 times, drying with anhydrous sodium sulfate, filtering, concentrating to obtain solid, and preparing liquid phase (CH) under high pressure3CN:H2O60: 40) and the product JD1001-2053 is obtained in 19% yield by lyophilization.
1H NMR:(DMSO,ppm,400MHz)δ1.02(2H,m),1.33(2H,m),7.38(2H,m),7.85(2H,m),8.57(2H,m),9.13(1H,d),10.60(1H,s).19F NMR (DMSO, ppm,400MHz) delta-61.34, -106.22 Mass Spectrometry: 429[ M + H]+.
Example 2 (preparation of Compounds JD 1001-2054)
Figure BDA0001889233300000071
A25 mL round-bottomed flask was charged with 0.10g (0.37mmol,1.0eq) of JD1001-002-9 solid, 3.2mL of THF, 0.14g (1.11mmol,3.0eq) of DMAP, and 0.24g (1.11mmol,3.0eq) of 3, 5-difluorobenzenesulfonyl chloride under nitrogen atmosphere, stirred at room temperature for 3 hours, and checked for completion by TLC (developer: PE: EA ═ 1:1), and saturated NaHCO was added3Quenching with water solution, extracting with ethyl acetate to obtain organic phase, washing the organic phase with 0.5N hydrochloric acid water solution for 2 times, drying with anhydrous sodium sulfate, filtering, concentrating the organic phase to obtain solid, and preparing liquid phase (CH) under high pressure3CN:H2O60: 40) and the product JD1001-2054 is obtained in 16% yield by lyophilization.
1H NMR:(DMSO,ppm,400MHz)δ1.07(2H,m),1.40(2H,m),7.51(2H,m),7.57(1H,m),8.60(1H,d),8.85(1H,s),9.18(1H,d),10.64(1H,s).19F-NMR (DMSO, ppm,400MHz) delta-61.33, -106.21 Mass Spectrometry: 447[ M + H]+.
Example 3 (preparation of Compounds JD 1001-2055)
Figure BDA0001889233300000081
0.10g (0.37mmol,1.0eq) of JD1001-002-9 solid, 3.2mL of THF, 0.14g (1.11mmol,3.0eq) of DMAP, 0.26g (1.11mmol,3.0eq) of 3,4, 5-trifluorobenzenesulfonyl chloride, was added to a 25mL round-bottomed flask under a nitrogen blanket, the mixture was stirred at room temperature for 3 hours, and the reaction was checked by TLC for completion (developer: PE: EA ═ 1:1), saturated NaHCO was added thereto3Quenching the reaction with water solution, extracting with ethyl acetate to obtain organic phase, adding 0.5N hydrochloric acid water solutionWashing the organic phase 2 times, drying with anhydrous sodium sulfate, filtering, concentrating the organic phase to obtain solid, and preparing liquid phase (CH) under high pressure3CN:H2O60: 40) and the product JD1001-2055 is obtained in 30% yield by lyophilization, about 45 mg.
1H NMR:(DMSO,ppm,400MHz)δ1.08(2H,m),1.39(2H,m),7.73(2H,m),8.62(1H,d),8.84(1H,d),9.21(1H,d),10.63(1H,s).19F NMR (DMSO, ppm,400MHz) delta-61.40, -131.20, -131.25. Mass Spectrometry: 465[ M + H]+.
Example 4 (preparation of Compounds JD 1001-2056)
Figure BDA0001889233300000082
A25 mL round-bottomed flask was charged with 0.10g (0.37mmol,1.0eq) of JD1001-002-9 solid, 3.2mL of THF, 0.14g (1.11mmol,3.0eq) of DMAP, and 0.27g (1.11mmol,3.0eq) of 4-trifluoromethylbenzenesulfonyl chloride under nitrogen atmosphere, stirred at room temperature for 3 hours, and checked for completion by TLC (developer: PE: EA ═ 1:1), and saturated NaHCO was added3Quenching with water solution, extracting with ethyl acetate to obtain organic phase, washing the organic phase with 0.5N hydrochloric acid water solution for 2 times, drying with anhydrous sodium sulfate, filtering, concentrating the organic phase to obtain solid, and preparing liquid phase (CH) under high pressure3CN:H2O60: 40) and the product JD1001-2056 is obtained in 24% yield by lyophilization, about 27 mg.
1H NMR:(DMSO,ppm,400MHz)δ1.17(2H,m),1.39(2H,m),7.86(2H,d),8.01(2H,d),8.47(1H,d),8.75(1H,s),8.99(1H,d),10.48(1H,s).19F NMR (DMSO, ppm,400MHz) delta-61.51, -62.01. Mass Spectrometry: 479[ M + H ]]+.
Example 5 (preparation of Compounds JD 1001-2057)
Figure BDA0001889233300000091
To a 25mL round bottom flask was added 0.10g (0.37mmol,1.0eq) of JD1001-002-9 solid, 3.2mL of THF, 0.14g (1.11mmol,3.0eq), 0.27g (1.11mmol,3.0eq) of 6-trifluoromethylpyridine-3-sulfonyl chloride, the reaction was stirred at room temperature for 3 hours and checked by TLC for completion (developer: PE: EA 1:1), saturated NaHCO was added3Quenching with water solution, extracting with ethyl acetate to obtain organic phase, washing the organic phase with 0.5N hydrochloric acid water solution for 2 times, drying with anhydrous sodium sulfate, filtering, concentrating to obtain solid, and preparing liquid phase (CH) under high pressure3CN:H2O60: 40) and the product JD1001-2057 is obtained in 32% yield by lyophilization.
1H NMR:(DMSO,ppm,400MHz)δ1.20(2H,m),1.46(2H,m),8.06(1H,d),8.47(2H,m),9.05(1H,d),9.11(1H,d),10.48(1H,s).19F NMR (. delta. -61.51, DMSO, ppm,400MHz),. delta. -67.15. Mass.: 480[ M + H ]]+.
Example 6 (preparation of Compounds JD 1001-2060)
Figure BDA0001889233300000092
A25 mL round-bottomed flask was charged with 0.10g (0.37mmol,1.0eq) of JD1001-002-9 solid, 3.2mL of THF, 0.14g (1.11mmol,3.0eq) of DMAP, and 0.27g (1.11mmol,3.0eq) of 2-trifluoromethylbenzenesulfonyl chloride under nitrogen atmosphere, stirred at room temperature for 3 hours, and checked for completion by TLC (developer: PE: EA ═ 1:1), and saturated NaHCO was added3Quenching with water solution, extracting with ethyl acetate to obtain organic phase, washing the organic phase with 0.5N hydrochloric acid water solution for 2 times, drying with anhydrous sodium sulfate, filtering, concentrating the organic phase to obtain solid, and preparing liquid phase (CH) under high pressure3CN:H2O60: 40) and the product JD1001-2060 was obtained in 25% yield by lyophilization.
1H NMR:(DMSO,ppm,400MHz)δ1.03(2H,m),1.40(2H,m),7.90(3H,m),8.12(1H,d),8.57(1H,d),8.82(1H,s),9.13(1H,d),10.51(1H,s).19F NMR (DMSO, ppm,400MHz) delta-56.04, -61.28. Mass Spectrometry: 479[ M + H ]]+.
Example 7 (preparation of Compound JD 1001-2061)
Figure BDA0001889233300000101
A25 mL round-bottomed flask was charged with 0.10g (0.37mmol,1.0eq) of JD1001-002-9 solid, 3.2mL of THF, 0.14g (1.11mmol,3.0eq) of DMAP, and 0.35g (1.11mmol,3.0eq) of 3, 5-bis (trifluoromethyl) benzenesulfonyl chloride under nitrogen atmosphere, stirred at room temperature for 3 hours, and checked for completion by TLC (developing agent: PE: EA. RTM. 1:1), and saturated NaHCO was added3Quenching with water solution, extracting with ethyl acetate to obtain organic phase, washing the organic phase with 0.5N hydrochloric acid water solution for 2 times, drying with anhydrous sodium sulfate, filtering, concentrating the organic phase to obtain solid, and preparing liquid phase (CH) under high pressure3CN:H2O60: 40) and the product JD1001-2061 was obtained in about 40mg by lyophilization with a yield of 36%.
1H NMR:(DMSO,ppm,400MHz)δ1.22(2H,m),1.46(2H,m),8.32(2H,s),8.36(1H,s),8.42(1H,d),9.01(2H,m),10.47(1H,s).19F NMR (DMSO, ppm,400MHz) delta-61.61, -61.68. Mass Spectrometry: 547[ M + H]+.
Example 8 (preparation of Compounds JD 1001-2063)
Figure BDA0001889233300000111
Under the protection of nitrogen, 5.0g (14.8mmol,1.0eq) of Fmoc-1-aminocyclobutanecarboxylic acid was added to a 200mL three-necked flask, then 50mL of DCM and 4 drops of DMF were added in sequence, 9.4g (74.0mmol,5.0eq) of oxalyl chloride was added dropwise at room temperature, the mixture was stirred at room temperature for reaction for 4 hours, two drops of the reaction mixture were taken out and treated with methanol to obtain methyl esters, the completion of the reaction was detected by TLC (developer: PE: EA: 1), excess oxalyl chloride and DCM were removed by distillation under reduced pressure to obtain pale yellow solids, which were stored under nitrogen.
The pale yellow solid obtained in the previous step was taken and to this was added sequentially 90mL of dry THF, 1.9g (22.2mmol, 1.5eq) of NaHCO33.3g (17.8mmol,1.2eq) of 5-amino-3-trifluoromethyl-2-cyanopyridine were heated to 60 ℃ and stirred for 2 hours at the temperature, the reaction was checked by TLC for completion (developer: PE: EA: 1), stopped and allowed to cool to room temperatureThe reaction system was diluted with 200mL of water, EA extracted 3 times (100mL × 3 times), the organic phase was dried over anhydrous sodium sulfate, filtered, 40mL of piperidine was added, the reaction was stirred at room temperature for 1 hour, the completion of the reaction was detected by TLC (developing agent: PE: EA ═ 1:1), and the solvent was distilled off under reduced pressure in a water bath at 40 ℃ to obtain 4g of a solid. Column chromatography was performed using silica gel, eluting with petroleum ether and ethyl acetate (PE: EA ═ 5:1 to 1:1), to give 1.0g of JD1001-002-10 as a solid in 23% yield.
A25 mL round-bottomed flask was charged with 0.10g (0.35mmol,1.0eq) of JD1001-002-10 as a solid, 3.2mL of THF, 0.13g (1.05mmol,3.0eq) of DMAP, 0.20g (1.05mmol,3.0eq) of 4-fluorobenzenesulfonyl chloride under nitrogen atmosphere, stirred at room temperature for 3 hours, and checked for completion by TLC (developer: PE: EA ═ 1:1), saturated NaHCO was added3Quenching with water solution, extracting with ethyl acetate to obtain organic phase, washing the organic phase with 0.5N hydrochloric acid water solution for 2 times, drying with anhydrous sodium sulfate, filtering, concentrating the organic phase to obtain solid, and preparing liquid phase (CH) under high pressure3CN:H2O60: 40) and the product JD1001-2063 was obtained in 21% yield by lyophilization.
1H NMR:(DMSO,ppm,400MHz)δ1.60(1H,m),1.71(1H,m),2.13(2H,m),2.40(2H,m),7.31(2H,t),7.78(2H,m),8.56(2H,m),9.10(1H,d),10.60(1H,s).19F NMR (DMSO, ppm,400MHz) delta-61.40, -106.58 Mass Spectrometry: 443[ M + H ]]+.
Example 9 (preparation of Compounds JD 1001-2064)
Figure BDA0001889233300000121
A25 mL round bottom flask was charged with 0.10g (0.35mmol,1.0eq) of JD1001-002-10 as a solid, 3.2mL THF, 0.13g (1.05mmol,3.0eq) DMAP, 0.22g (1.05mmol,3.0eq)3, 5-difluorobenzenesulfonyl chloride under nitrogen blanket, stirred at room temperature for 3 hours, and checked for completion by TLC (developer: PE: EA ═ 1:1), saturated NaHCO was added3Quenching the reaction with water solution, extracting with ethyl acetate to obtain organic phase, washing the organic phase with 0.5N hydrochloric acid water solution for 2 timesDrying over anhydrous sodium sulfate, filtering, concentrating the organic phase to obtain a solid, and preparing the liquid phase (CH) under high pressure3CN:H2O60: 40) and then lyophilized to obtain 16mg of JD1001-2064 product with a yield of 9%.
1H NMR:(DMSO,ppm,400MHz)δ1.65(1H,m),1.80(1H,m),2.18(2H,m),2.45(2H,m),7.38(2H,m),7.46(1H,m),8.58(1H,d),8.98(1H,bs),9.10(1H,d),10.69(1H,s).19F NMR (DMSO, ppm,400MHz) delta-61.43, -106.77 Mass Spectrometry: 461[ M + H ]]+.
Example 10 (preparation of Compounds JD 1001-2065)
Figure BDA0001889233300000122
A25 mL round-bottomed flask was charged with 0.10g (0.35mmol,1.0eq) of JD1001-002-10 solid, 3.2mL of THF, 0.13g (1.05mmol,3.0eq) of DMAP, and 0.26g (1.05mmol,3.0eq) of 4-trifluoromethylbenzenesulfonyl chloride under nitrogen atmosphere, stirred at room temperature for 3 hours, and checked for completion by TLC (developer: PE: EA ═ 1:1), and saturated NaHCO was added3Quenching with water solution, extracting with ethyl acetate to obtain organic phase, washing the organic phase with 0.5N hydrochloric acid water solution for 2 times, drying with anhydrous sodium sulfate, filtering, concentrating to obtain solid, and preparing liquid phase (CH) under high pressure3CN:H2O60: 40) and the product JD1001-2065 was obtained in 30% yield by lyophilization.
1H NMR (. delta.1.65 (1H, m),1.81(1H, m),2.25(2H, m),2.47(2H, m),7.78(2H, d),7.90(2H, d),8.45(1H, d),8.85(1H, bs),8.98(1H, d),10.55(1H, bs). Mass Spectrometry: 493[ M + H ]]+.
Example 11 (preparation of Compounds JD 1001-2066)
Figure BDA0001889233300000131
0.10g (0.35mmol,1.0eq) of JD1001-002-10 solid, 3.2mL of THF, 0.13g (1.05mmol,3.0eq) of DMAP, 3, 5-bis (trifluoromethyl) were added to a 25mL round-bottomed flask under a nitrogen atmosphere) Benzenesulfonyl chloride 0.33g (1.05mmol,3.0eq), stirred at room temperature for 3 hours and checked by TLC for completion (developer: PE: EA 1:1), saturated NaHCO was added3Quenching with water solution, extracting with ethyl acetate to obtain organic phase, washing the organic phase with 0.5N hydrochloric acid water solution for 2 times, drying with anhydrous sodium sulfate, filtering, concentrating the organic phase to obtain solid, and preparing liquid phase (CH) under high pressure3CN:H2O60: 40) and the product JD1001-2066 was obtained in 34% yield by lyophilization.
1H NMR (. delta.1.69 (1H, m),1.87(1H, m),2.27(2H, m),2.54(2H, m),8.19(2H, s),8.29(1H, s),8.39(1H, d),8.95(1H, d),9.09(1H, s),10.53(1H, s). Mass Spectrometry: 561[ M + H ]]+.
Example 12 (preparation of Compound JD 1001-2137)
Figure BDA0001889233300000141
Adding 3.9g (20.0mmol, 1.0eq) of 1-aminocyclohexanecarboxylic acid methyl ester hydrochloride and 30mL of THF (tetrahydrofuran) into a 100mL round-bottom flask under the protection of nitrogen gas, adding 3.0g (3.0mmol, 1.5eq) of triethylamine, 244mg (2mmol, 0.1eq) of DMAP and 6.88g (22.2mmol, 1.1eq) of 3, 5-bis (trifluoromethyl) benzenesulfonyl chloride dropwise under the stirring condition at room temperature, continuing to stir for reaction at room temperature for 3h, detecting the completion of the reaction by TLC (developer: PE: EA ═ 1:1), and adding saturated NaHCO3The reaction was quenched with aqueous solution, EA extracted the product 50ml x 3 times, the organic phase was washed 2 times with 0.5N hydrochloric acid, dried over anhydrous sodium sulfate, filtered and concentrated to a solid.
Dissolving the solid obtained in the previous step in 100mL of ethanol, adding 30mL of water, then adding 4g (5.0eq) of sodium hydroxide solid, heating and stirring the mixture in an oil bath at 60 ℃ for reaction for 2 hours, detecting the completion of the reaction by LCMS, and distilling the mixture under reduced pressure to remove the solvent. DCM and H were added2Stirring 50ml of O respectively for 0.5h, keeping the water phase after liquid separation, adding 1N hydrochloric acid under the condition of stirring at room temperature to adjust the pH value to 5, separating out a large amount of solids, filtering and drying to obtain 3.8 g of light yellow solids. 335mg (0.8mmol, 1.0eq) of a pale yellow solid was added to a 25mL round bottom flask, followed by 3mL of DCM, 3 drops of DMF, 0 deg.CAdding 300mg (2.4mmol, 3.0eq) of oxalyl chloride dropwise under the condition of stirring in an ice water bath, then heating to room temperature for reaction for 2 hours, taking out two drops of reaction liquid, adding methanol to treat the reaction liquid into methyl ester, detecting the reaction completion by LCMS, concentrating under reduced pressure to obtain 350mg of a solid product JD1001-002-20, and storing for later use under the condition of nitrogen protection.
To a 25mL round bottom flask was added 109mg (0.25mmol, 1.0eq) of JD1001-002-20 solid, 3.2mL of THF, NaHCO under nitrogen blanket363mg (0.75mmol, 3.0eq), 140mg (0.75mmol, 3.0eq) of 5-amino-3-trifluoromethyl-2-cyanopyridine was reacted at 60 ℃ with stirring for 3 hours, and the reaction was detected by TLC (developer: PE: EA: 1), followed by addition of 5ml of water to quench the reaction, extraction of EA to give an organic phase, concentration, and HPLC (CH)3CN/H2O60: 40) and freeze-dried to yield the product JD1001-2137 in 15% yield.
1H NMR (. delta.1.1-1.3 (6H, m),1.35-1.60(2H, m),1.8-2.0(2H, m),8.24(2H, s),8.38(1H, s),8.44(1H, s),8.99(1H, s),10.25(1H, s),11.85(1H, s). Mass Spectrometry: 589[ M + H]+.
Example 13 (preparation of Compound JD 1001-2139)
Figure BDA0001889233300000151
3.1g (20.0mmol, 1.0eq) of methyl aminoisobutyrate hydrochloride and 30mL of THF are added to a 100mL round-bottomed flask under nitrogen protection, 3.0g (30.0mmol, 1.5eq) of triethylamine, 244mg (2mmol, 0.1eq) of DMAP, 6.88g (22.2mmol, 1.1eq) of 3, 5-bis (trifluoromethyl) benzenesulfonyl chloride are added dropwise under stirring at room temperature, the reaction is continued for 3h under stirring at room temperature, the reaction is completed by TLC detection (developer: PE: EA ═ 1:1), and saturated NaHCO is added3The reaction was quenched with aqueous solution, EA extracted the product 3 times (50ml x 3 times), the organic phase was washed 2 times with 0.5N hydrochloric acid, dried over anhydrous sodium sulfate, filtered, and concentrated to a solid.
Dissolving the solid in 100mL of ethanol, adding 30mL of water, adding 4g (5.0eq) of sodium hydroxide solid, heating in an oil bath at 60 ℃, stirring, reacting for 2h, detecting the completion of the reaction by LCMS, and distilling under reduced pressure to removeThe solvent was removed. DCM and H were added2Stirring 50ml of O respectively for 0.5h, keeping a water phase after liquid separation, adding 1N hydrochloric acid to adjust the pH value to 5 under the condition of stirring at room temperature, separating out a large amount of solid, and filtering and drying to obtain 1.8 g of light yellow solid. Adding 300mg (0.8mmol, 1.0eq) of light yellow solid into a 25mL round-bottom flask, sequentially adding 3mL of DCM and 3 drops of DMF, dropwise adding 300mg (2.4mmol, 3.0eq) of oxalyl chloride under the condition of stirring in an ice-water bath at 0 ℃, then heating to room temperature for reaction for 2 hours, taking out two drops of reaction liquid, adding methanol to treat the reaction liquid into the reaction liquid to obtain methyl ester, detecting the reaction completion through LCMS, concentrating under reduced pressure to obtain 320mg of a solid product JD1001-002-22, and storing for later use under the condition of nitrogen protection.
99mg (0.25mmol, 1.0eq) of JD1001-002-22 solid, 3.2mL of THF, 63mg (0.75mmol, 3.0eq) of NaHCO were added to a 25mL round bottom flask under nitrogen blanket3140mg (0.75mmol, 3.0eq) of 5-amino-3-trifluoromethyl-2-cyanopyridine are heated and stirred at 60 ℃ for reaction for 3 hours, TLC detects the completion of the reaction (developer: PE: EA 1:1), 5ml of water is added to quench the reaction, EA is extracted to obtain an organic phase, the organic phase is concentrated to obtain a solid, and HPLC (CH)3CN/H2O60: 40) and freeze-dried to yield the product JD1001-2139 in 13% yield.
1H NMR (. delta.1.47 (6H, s),8.31(2H, s),8.38(1H, s),8.49(1H, d),8.68(1H, s),9.12(1H, d),10.48(1H, s). Mass Spectrometry: [ M + H ]]+549.
Example 14 (preparation of Compounds JD 1001-2156)
Figure BDA0001889233300000161
To a 100mL reactor was added 3.0g (18mmol, 1.0eq) of methyl 1-aminocyclobutanecarboxylate hydrochloride under nitrogen, 30mL (10.0V) of THF was added to the system, 3.0g (30.0mmol, 1.6eq) of triethylamine was added dropwise at room temperature, followed by 0.3 g (2.3mmol, 0.13eq) of DMAP, 5.05g (19.8mmol, 1.1eq) of 4-bromobenzenesulfonyl chloride was added dropwise, the reaction was stirred at room temperature for 3 hours, TLC was used to detect completion of the reaction of the starting material (developer: PE/EA. RTM. 1/1, UV254), the reaction was stopped, and saturated NaHCO was used3The reaction is quenched,the organic phase is extracted with ethyl acetate and washed 2 times with 0.5N hydrochloric acid, dried over anhydrous sodium sulfate, filtered off and concentrated to give 6.3 g of a solid.
Dissolving the solid in 5mL of THF, adding 15mL of water, then adding 1.2g of LiOH (51.3mmol, 3.0eq), stirring at normal temperature for reacting overnight, monitoring the reaction by LCMS, stopping the reaction after the reaction is finished, decompressing and concentrating to remove THF, adding dilute hydrochloric acid (1N) into the system to adjust the pH value to 4, precipitating a large amount of solid, filtering to obtain 2.1 g of white solid, and drying. Dissolving 1g of solid in 3mL (3V) of DCM, adding 3 drops of DMF, cooling to 0 ℃, dropwise adding 0.5mL of oxalyl chloride at low temperature, heating to room temperature after dropwise adding, reacting for 0.5 hour, taking a small amount of reaction liquid, adding methanol for derivatization, detecting by LCMS, concentrating under reduced pressure after reaction is finished to obtain 1.5g of a solid product JD1001-002-23, and storing for later use under the protection of nitrogen.
200mg (0.57mmol, 1.0eq) of JD1001-002-23, 3mL of THF, 144mg (1.71mmol, 3eq) of NaHCO were added to a 25mL reactor in sequence under nitrogen protection385.73mg (0.456mmol, 0.8eq) of 2, 3-difluoro-5-aminopyridine was heated to 60 ℃ and stirred for reaction for 3 hours, TLC detected the completion of the reaction of the raw materials (developing solvent: PE/EA ═ 1/1, UV254), the reaction was stopped, water was added to quench the reaction, ethyl acetate was used for extraction to obtain an organic phase, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated to obtain 200mg of a solid, and purified by HPLC to obtain 26mg of a white solid. The yield is 15.4%
1H NMR: (DMSO, ppm,400MHz) delta 10.49(s,1H),9.03(s,1H),8.54-8.53(s,2H),7.63-7.61(m, 4H),2.50(m,2H),2.46-2.43(m,2H),1.78-1.75(m,1H), 1.66-1.63(m, 1H) Mass Spectrometry: 504[ M + H]+
Comparative example 1 (preparation of Compound JD 1001-2103)
Figure BDA0001889233300000171
To a 100mL reactor under nitrogen atmosphere was added 3.0g (20.0mmol, 1.0eq) of methyl 1-aminocyclobutanecarboxylate hydrochloride, 30mL (10.0V) of THF was added to the system, and 3.0g (30.0mmol, 1.5eq) was added dropwise at room temperatureTriethylamine was added thereto, 0.3 g (2mmol, 0.1eq) of DMAP was added thereto, 4.2g (22.2mmol, 1.1eq) of 4- (Pentafluosulfur) benzanesulfonyl chloride was added dropwise thereto, the reaction was stirred at room temperature for 3 hours, TLC was performed to detect that the reaction of the starting material was completed (developer: PE/EA: 1/1, UV254), the reaction was stopped, and saturated NaHCO was used3The 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 3.4g of a solid.
Dissolving the solid in ethanol (100mL,15V), adding 30mL (5V) of water, then adding 4g of NaOH (5.0eq), 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 ethanol, adding DCM for extraction, detecting that an organic phase does not contain the product, adding hydrochloric acid into an aqueous phase to adjust the pH value to 5, separating out a large amount of solid, and filtering to obtain 1.6 g 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 JD1001-002-16, and storing for later use under the protection of nitrogen.
0.1g (0.25mmol, 1.0eq) of JD1001-002-16, 3.2mL (10.0V) of THF, 0.32g (0.75mmol, 3.1eq) of NaHCO were added to a 25mL reactor in sequence under nitrogen protection30.38g (0.75.0mmol, 3.0eq) of 3-amino-2-trifluoromethylpyridine 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 38mg of JD1001-2103 in 25% yield.
1H NMR: (DMSO, ppm,400MHz) δ 1.66(1H, m),1.81(1H, m),2.22(2H, m),7.94(4H, m),8.27(1H, dd),8.62(1H, d),8.69(1H, d),8.81(1H, d),9.97(1H, s). mass spectrum: 526[ M + H ]]+
Comparative example 2 (preparation of Compound JD 1001-2124)
Figure BDA0001889233300000181
To a 100mL reactor was added 3.0g (20.0mmol, 1.0eq) of methyl 1-aminocyclopropanecarboxylate hydrochloride under nitrogen, 30mL (10.0V) of THF was added to the system, 3.0g (30.0mmol, 1.5eq) of triethylamine was added dropwise at room temperature, followed by 0.3 g (2mmol, 0.1eq) of DMAP, followed by 4.2g (22.2mmol, 1.1eq) of 3, 5-bis (trifluoromethyl) benzenesulfonyl chloride was added dropwise, the reaction was stirred at room temperature for 3 hours, and the starting material was detected by TLC to be over (developer: PE/EA: 1/1, UV254), the reaction was stopped, and saturated NaHCO was used3The 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 3.4g 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 ethanol, adding DCM for extraction, detecting that an organic phase does not contain the product, adding hydrochloric acid into an aqueous phase to adjust the pH value to 5, separating out solids, and filtering to obtain 1.6 g 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 JD1001-002-12, and storing for later use under the protection of nitrogen.
To a 25mL reactor under nitrogen protection was added 0.1g (0.25mmol, 1.0eq) JD1001-002-12, 3.2mL (10.0V) THF, 0.32g (0.75mmol, 3.1eq) NaHCO30.38g (0.75mmol, 3.0eq) of 2-fluoro-5-aminopyridine, 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 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 41mg of JD 1001-2124. The yield thereof was found to be 35%.
1H NMR (. delta.1.15 (2H, m),1.38(2H, m),7.09(1H, dd),7.88(1H, m),8.14(1H, d),8.32(2H, s),8.38(1H, s),8.96(1H, s),9.74(1H, s). Mass Spectrometry: 472[ M + H]+
Comparative example 3 (preparation of Compound JD 1001-2125)
Figure BDA0001889233300000191
To a 25mL reactor was added 3.0g (20.0mmol, 1.0eq) of methyl 1-aminocyclobutanecarboxylate hydrochloride under nitrogen, to which was added 30mL (10.0V) of THF, 3.0g (30.0mmol, 1.5eq) of triethylamine, followed by 0.3 g (2mmol, 0.1eq) of DMAP, followed by 6.88g (22.2mmol, 1.1eq) of 3, 5-bis (trifluoromethyl) benzenesulfonyl chloride, dropwise added at room temperature, the reaction was stirred at room temperature for 3 hours, and the reaction was stopped with saturated NaHCO (developer: PE/EA: 1/1, UV254), after the reaction was completed, which was detected by TLC3The 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 2.8 g 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 ethanol, adding DCM for extraction, detecting that an organic phase does not contain the product, adding hydrochloric acid into an aqueous phase to adjust the pH value to 5, precipitating a large amount of solid, and filtering to obtain 1.3 g 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, taking a small amount of reaction liquid, adding methanol for derivatization, detecting by LCMS, concentrating under reduced pressure after the reaction is finished to obtain 350mg of a solid product JD1001-002-16, and storing for later use under the protection of nitrogen.
To a 25mL reactor under nitrogen protection was added 0.1g (0.25mmol, 1.0eq) JD1001-002-12, 3.2mL (10.0V) THF, 0.32g (0.75mmol, 3.1eq) NaHCO30.38g (0.75mmol, 3.0eq) of 2-amino-5-fluoropyridine was heated to 60 ℃ and stirred for reaction for 3 hours, and TLC detection showed that the reaction of the starting material was completed (developer): PE/EA 1/1, UV254), stop the reaction, quench the reaction with water, extract with ethyl acetate to give an organic phase, dry over anhydrous sodium sulfate, filter the organic phase, concentrate to give a solid, and isolate and purify by HPLC (CH3CN/H2O 60:40) to give 27mg JD 1001-2125. The yield thereof was found to be 18%.
1H NMR (. delta.1.23 (2H, m),1.39(2H, m),7.65(2H, m),8.20(1H, m),8.26(3H, s),9.02(1H, s),9.78(1H, s). Mass Spectrometry: 472[ M + H]+
Comparative example 4 (preparation of Compound JD 1001-2126)
Figure BDA0001889233300000201
To a 100mL reactor was added 3.0g (20.0mmol, 1.0eq) of methyl 1-aminocyclopropanecarboxylate hydrochloride under nitrogen, to which was added 30mL (10.0V) of THF, 3.0g (30.0mmol, 1.5eq) of triethylamine, followed by 0.3 g (2mmol, 0.1eq) of DMAP, followed by 4.2g (22.2mmol, 1.1eq) of 3, 5-bis (trifluoromethyl) benzenesulfonyl chloride, dropwise added at room temperature, the reaction was stirred at room temperature for 3 hours, and the starting material was detected by TLC to be over (developer: PE/EA: 1/1, UV254), stopped, and saturated NaHCO was added3The 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 3.4g 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 3.5 g 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 JD1001-002-12, and storing for later use under the protection of nitrogen.
0.1g (0.25mmol, 1.0eq) of JD1001-002-12, 3.2mL (10.0V) of THF, 0.32g (0.75mmol, 3.1eq) of NaHCO were added to a 25mL reactor in sequence under nitrogen protection30.38g (0.75mmol, 3.0eq) of 2-amino-5-trifluoromethylpyridine is heated to 60 ℃ and stirred for reaction for 3 hours, TLC detects that the raw material reaction is finished (developing solvent: 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 and filtered, the organic phase is concentrated to obtain a solid, and the solid is separated and purified by HPLC (CH3 CN/H2O: 60:40) to obtain 38mg of JD 1001-2126. The yield thereof was found to be 26%.
1H NMR (. delta.1.27 (2H, m),1.43(2H, m),7.78(1H, d),8.10(1H, dd),8.20(1H, s),8.26(2H, s),8.59(1H, dd),9.03(1H, s),10.18(1H, s). Mass Spectrometry: 522[ M + H]+
Comparative example 5 (preparation of Compound JD 1001-2131)
Figure BDA0001889233300000221
To a 100mL reactor was added 3.0g (20.0mmol, 1.0eq) of methyl 1-aminocyclopropanecarboxylate hydrochloride under nitrogen, to which was added 30mL (10.0V) of THF, 3.0g (30.0mmol, 1.5eq) of triethylamine, followed by 0.3 g (2mmol, 0.1eq) of DMAP, followed by 4.2g (22.2mmol, 1.1eq) of 3, 5-bis (trifluoromethyl) benzenesulfonyl chloride, dropwise added at room temperature, the reaction was stirred at room temperature for 3 hours, and the starting material was detected by TLC to be over (developer: PE/EA: 1/1, UV254), stopped, and saturated NaHCO was added3The 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 6.8 g 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 3.5 g 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 JD1001-002-12, and storing for later use under the protection of nitrogen.
To a 25mL reactor under nitrogen protection was added 0.1g (0.25mmol, 1.0eq) JD1001-002-12, 3.2mL (10.0V) THF, 0.32g (0.75mmol, 3.1eq) NaHCO30.38g (0.75mmol, 3.0eq) of 2-amino-5-trifluoromethylpyridine 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 and filtered, the organic phase is concentrated to obtain a solid, and HPLC (CH)3CN/H2O60: 40) to yield 15mg of JD 1001-2131. The yield thereof was found to be 11%.
1H NMR (. delta.1.17 (2H, d),1.42(2H, d),7.79(1H, d),8.04(1H, dd),8.32(2H, s),8.34(1H, s)8.66(1H, d),8.96(1H, s),10.04(1H, s). Mass Spectrometry: 522[ M + H]+
Comparative example 6 (preparation of JD1001-2111 Compound)
Figure BDA0001889233300000231
To a 100mL reactor was added 3.0g (20.0mmol, 1.0eq) of methyl 1-aminocyclopropanecarboxylate hydrochloride under nitrogen, to which was added 30mL (10.0V) of THF, 3.0g (30.0mmol, 1.5eq) of triethylamine, followed by 0.3 g (2mmol, 0.1eq) of DMAP, followed by 4.2g (22.2mmol, 1.1eq) of 3, 5-bis (trifluoromethyl) benzenesulfonyl chloride, dropwise added at room temperature, the reaction was stirred at room temperature for 3 hours, and the starting material was detected by TLC to be over (developer: PE/EA: 1/1, UV254), stopped, and saturated NaHCO was added3The 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, and the organic phase was concentrated to give 3.4g of a solid. The solid was dissolved in ethanol (100mL,15V), 30mL (5V) water was added, followed by 4g (5.0eq) NaOH, heated to 60 deg.C and stirredThe reaction was monitored by LCMS for 2 hours, after completion, the reaction was stopped, ethanol was concentrated under reduced pressure, DCM was added and extracted, the organic phase was checked to be free of product, hydrochloric acid was added to the aqueous phase to adjust the pH to 5, a large amount of solid was precipitated and filtered to give 1.6 g of a pale 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 JD1001-002-12, and storing for later use under the protection of nitrogen.
0.1g (0.25mmol, 1.0eq) of JD1001-002-12, 3.2mL (10.0V) of THF, 0.32g (0.75mmol, 3.1eq) of NaHCO were added to a 25mL reactor in sequence under nitrogen protection30.38g (0.75mmol, 3.0eq) of 2-amino-5-trifluoromethylpyridine 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 and filtered, the organic phase is concentrated to obtain a solid, and HPLC (CH)3CN/H2O60: 40) to yield 39mg of JD 1001-2111. The yield thereof was found to be 31%.
1H NMR:(DMSO，ppm,400MHz)δ1.23(2H,dd),1.44(2H,dd),8.09(1H,dd),8.29(1H,s),8.32(2H,s),8.63(1H,d),8.78(1H,d),8.99(1H,s),9.98(1H,s).19F NMR (DMSO, ppm,400MHz) delta-61.47, -61.77 Mass Spectrometry: 522[ M + H]+
Comparative example 7 (preparation of Compound JD 1001-2132)
Figure BDA0001889233300000241
To a 100mL reactor was added 3.0g (20.0mmol, 1.0eq) of methyl 1-aminocyclopropanecarboxylate hydrochloride under nitrogen, 30mL (10.0V) of THF was added to the system, 3.0g (30.0mmol, 1.5eq) of triethylamine was added dropwise at room temperature, followed by 0.3 g (2mmol, 0.1eq) of DMAP, followed by 4.2g (22.2mmol, 1.1eq) of 3, 5-bis (trifluoromethyl) benzenesulfonyl chloride and the reaction was stirred at room temperature for 3 hours, TLC, detecting that the raw materials are completely reacted (developing agent: PE/EA: 1/1, UV254), stopping the reaction, and saturating NaHCO3The 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, and the organic phase was concentrated to give 3.4g 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 ethanol, adding DCM for extraction, detecting that an organic phase does not contain the product, adding hydrochloric acid into an aqueous phase to adjust the pH value to 5, precipitating a large amount of solid, and filtering to obtain 1.6 g 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, taking a small amount of reaction liquid, adding methanol for derivatization, detecting by LCMS, concentrating under reduced pressure after the reaction is finished to obtain 350mg of solid product JD1001-002-12, and storing for later use under the protection of nitrogen.
0.1g (0.25mmol, 1.0eq) of JD1001-002-12, 3.2mL (10.0V) of THF, 0.32g (0.75mmol, 3.1eq) of NaHCO were added to a 25mL reactor in sequence under nitrogen protection30.38g (0.75mmol, 3.0eq) of 2-amino-5-trifluoromethylpyridine 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 and filtered, the organic phase is concentrated to obtain a solid, and HPLC (CH)3CN/H2O60: 40) to yield 24mg of JD1001-2132 in 19% yield.
1H NMR (. delta.1.17 (2H, d),1.39(2H, d),7.27(1H, dd),7.93(1H, d),8.00(1H, m),8.32(1H, s),8.38(1H, s),9.21(1H, s),9.31(1H, s). Mass Spectrometry: 472[ M + H]+
Comparative example 8 (preparation of Compound JD 1001-2147)
Figure BDA0001889233300000251
Nitrogen protection downward 100Into a mL reactor was added 3.0g (20.0mmol, 1.0eq) of methyl 1-aminocyclobutanecarboxylate hydrochloride, 30mL (10.0V) of THF was added thereto, 3.0g (30.0mmol, 1.5eq) of triethylamine was added dropwise at room temperature, followed by 0.3 g (2mmol, 0.1eq) of DMAP, 4.2g (22.2mmol, 1.1eq) of 3, 5-bis (trifluoromethyl) benzenesulfonyl chloride was added dropwise, the reaction was stirred at room temperature for 3 hours, the reaction was stopped by TLC, and the starting material was reacted completely (developer: PE/EA. RTM. 1/1, UV254), and the reaction was stopped by saturated NaHCO3The 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 3.4g 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 ethanol, adding DCM for extraction, detecting that an organic phase does not contain the product, adding hydrochloric acid into an aqueous phase to adjust the pH value to 5, precipitating a large amount of solid, and filtering to obtain 1.6 g 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, taking a small amount of reaction liquid, adding methanol for derivatization, detecting by LCMS, concentrating under reduced pressure after the reaction is finished to obtain 350mg of solid product JD1001-002-12, and storing for later use under the protection of nitrogen.
0.1g (0.25mmol, 1.0eq) of JD1001-002-12, 3.2mL (10.0V) of THF, 0.32g (0.75mmol, 3.1eq) of NaHCO were added to a 25mL reactor in sequence under nitrogen protection30.38g (0.75mmol, 3.0eq) of 2-chloro-3-amino-5-methylpyridine, heating to 60 ℃, stirring for reaction for 3 hours, detecting the completion of the reaction of the raw materials by TLC (developing agent: PE/EA: 1/1, UV254), stopping the reaction, adding water to quench the reaction, extracting with ethyl acetate to obtain an organic phase, drying with anhydrous sodium sulfate, filtering, concentrating the organic phase to obtain a solid, and performing HPLC (CH) chromatography (HPLC)3CN/H2O60: 40) to yield 38mg JD 1001-2147. The yield thereof was found to be 20%.
1H NMR (. delta.1.72 (1H, m),1.80(1H, m),2.20(2H, m),2.24(3H, s),2.46(2H, m),7.68(1H, d),8.02(1H, d),8.31(2H, s),8.44(1H, s),8.96(1H, s),9.11(1H, s). Mass spectrometry：516[M+H]+
Comparative example 9 (preparation of Compound JD 1001-2155)
Figure BDA0001889233300000261
To a 100mL reactor was added 3.0g (20.0mmol, 1.0eq) of methyl 1-aminocyclobutanecarboxylate hydrochloride under nitrogen, to which was added 30mL (10.0V) of THF, 3.0g (30.0mmol, 1.5eq) of triethylamine, followed by 0.3 g (2mmol, 0.1eq) of DMAP, followed by 4.2g (22.2mmol, 1.1eq) of 3, 5-bis (trifluoromethyl) benzenesulfonyl chloride, dropwise at room temperature, and the reaction was stirred at room temperature for 3 hours, after which the starting material was reacted by TLC (developer: PE/EA: 1/1, UV254), the reaction was stopped, and saturated NaHCO was added3The 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, and the organic phase was concentrated to give 3.4g of a solid.
Dissolving the solid in 100mL (15V) of ethanol, 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 water phase to adjust the pH value to 5, separating out a large amount of solid, and filtering to obtain 1.6 g 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, taking a small amount of reaction liquid, adding methanol for derivatization, detecting by LCMS, concentrating under reduced pressure after the reaction is finished to obtain 350mg of solid product JD1001-002-12, and storing for later use under the protection of nitrogen.
0.1g (0.25mmol, 1.0eq) of JD1001-002-12, 3.2mL (10.0V) of THF, 0.32g (0.75mmol, 3.1eq) of NaHCO were added to a 25mL reactor in sequence under nitrogen protection30.38g (0.75mmol, 3.0eq) of 5, 6-difluoropyridin-3-amine 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 and filtered, and the organic phase is extracted by anhydrous sodium sulfate and filteredConcentrating to obtain solid, and performing HPLC (CH)3CN/H2O60: 40) to yield 26mg of JD 1001-2155. The yield thereof was found to be 17%.
1H NMR:(DMSO，ppm,400MHz)δ9.95(s,1H),8.93(s,1H),8.30(s,1H),8.19(s,2H),7.96-7.95(m,2H),2.50(m,2H),2.26(m，2H),1.86-1.83(m,1H)，1.70-1.62(m,1H).19F NMR (DMSO, ppm,400MHz) delta-61.70, -73.57, -94.30, -139.80. Mass Spectrometry: 504[ M + H]+
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 the 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 cell count as described below: Du-145 (human prostate cancer cell line, androgen-independent, AR-/PSA-, from Saiki bioengineering Co., Ltd.), 4000/well; LNcap (human prostate cancer cell line, androgen-dependent, AR +/PSA +, from cell bank of the culture Collection of the type of Chinese academy of sciences): 5000/well), 96-well plates were inoculated, 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) Cells were incubated at 37 ℃ and 100% relative humidity, 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 BDA0001889233300000281
Figure BDA0001889233300000291
Figure BDA0001889233300000301
As can be seen from the comparison of the activity data, the compounds of the general formula of the invention are anti-prostate cancer compounds with extremely high activity (see examples 1-14), and compared with the compounds shown in comparative examples 1-9, the IC of DU-145 and LNcap is higher50The values are significantly reduced and in addition, the anti-prostate cancer activity is also more significant compared to the bicalutamide and enzalutamide currently used clinically. The above data indicate that the compound of the present invention, in which both trifluoromethyl and cyano groups are substituted on the pyridine ring, has an excellent therapeutic effect on diseases such as prostate cancer.

Claims (6)

1. A compound represented by the general formula (1) and a pharmaceutically acceptable salt thereof,
Figure FDA0003152163460000011
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 FDA0003152163460000012
Figure FDA0003152163460000021
wherein n represents an integer of 1 to 7.
3. A pharmaceutical composition comprising a compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
4. The use of a compound according to claim 1 or 2, 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.
5. The use of claim 4, wherein the disorder associated with androgen receptor activity comprises: hormone sensitive prostate cancer, hormone refractory prostate cancer, benign prostatic hyperplasia, acne, hirsutism and alopecia.
6. 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 FDA0003152163460000022
step (II) of reacting the compound (3) with the compound (4) in an aprotic solvent to form a compound (5);
Figure FDA0003152163460000031
step (III) of reacting the compound (5) with piperidine in an organic solvent to form a compound (6);
Figure FDA0003152163460000032
a step (IV) of reacting the compound (6) with the compound (7) in an organic solvent to form a compound (1);
Figure FDA0003152163460000033
in the above formulae R1、R2、R3And R4Is as defined in claim 1.
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998022432A1 (en) * 1996-11-18 1998-05-28 Yamanouchi Pharmaceutical Co., Ltd. Novel acylamino-substituted acylanilide derivatives or pharmaceutical composition comprising the same
CN104903290A (en) * 2012-06-20 2015-09-09 安国乐品株式会社 Novel compound having ability to inhibit 11beta-HSD1 enzyme or pharmaceutically acceptable salt thereof, method for producing same, and pharmaceutical composition containing same as active ingredient
WO2016079522A1 (en) * 2014-11-20 2016-05-26 University College Cardiff Consultants Limited Androgen receptor modulators and their use as anti-cancer agents
CN108558760A (en) * 2018-05-29 2018-09-21 杨国宏 A kind of aromatic amides and its preparation method and application

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998022432A1 (en) * 1996-11-18 1998-05-28 Yamanouchi Pharmaceutical Co., Ltd. Novel acylamino-substituted acylanilide derivatives or pharmaceutical composition comprising the same
CN104903290A (en) * 2012-06-20 2015-09-09 安国乐品株式会社 Novel compound having ability to inhibit 11beta-HSD1 enzyme or pharmaceutically acceptable salt thereof, method for producing same, and pharmaceutical composition containing same as active ingredient
WO2016079522A1 (en) * 2014-11-20 2016-05-26 University College Cardiff Consultants Limited Androgen receptor modulators and their use as anti-cancer agents
CN108558760A (en) * 2018-05-29 2018-09-21 杨国宏 A kind of aromatic amides and its preparation method and application

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