CN114539279B - Oxidobicycloheptene sulfonamide compound containing five-membered nitrogen heterocycle and application thereof in preparation of anti-breast cancer drugs - Google Patents

Oxidobicycloheptene sulfonamide compound containing five-membered nitrogen heterocycle and application thereof in preparation of anti-breast cancer drugs Download PDF

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CN114539279B
CN114539279B CN202210134213.8A CN202210134213A CN114539279B CN 114539279 B CN114539279 B CN 114539279B CN 202210134213 A CN202210134213 A CN 202210134213A CN 114539279 B CN114539279 B CN 114539279B
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CN114539279A (en
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周海兵
董春娥
辛丽兰
李媛媛
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Wuhan University WHU
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Abstract

The invention discloses an oxido bicycloheptene sulfonamide compound containing five-membered nitrogen heterocycle and application thereof in preparing anti-breast cancer drugs, belonging to the technical field of medicines. The compound can well inhibit MCF-7 cells, has certain degradation capability on estrogen receptors, can well inhibit aromatase, and has application prospect in the treatment of breast cancer.

Description

Oxidobicycloheptene sulfonamide compound containing five-membered nitrogen heterocycle and application thereof in preparation of anti-breast cancer drugs
Technical Field
The invention belongs to the technical field of medicines, relates to a compound based on an oxido-bicyclo- [2.2.1] -heptene sulfonamide structure, and particularly relates to an oxido-bicyclo- [2.2.1] -heptene sulfonamide compound containing five-membered nitrogen heterocycle, a preparation method thereof and application thereof in preparing anti-breast cancer medicines.
Background
In recent years, breast cancer has jumped into one of the most common cancers in women. Since overexpression of Estrogen Receptor (ER) leads to the generation of breast cancer, anti-estrogen drugs are being developed and used. Research shows that long-term use of anti-estrogen drugs such as tamoxifen can cause strong side effects and cause drug-resistant breast cancer. Therefore, there is a need to develop drugs with novel mechanisms of action against this target of estrogen receptor.
Disclosure of Invention
Selective estrogen receptor down-regulators (SERDs) directed to estrogen receptors have been the focus of research because of their novel mechanism of action. The selective estrogen receptor down-regulator can degrade ER alpha and shows good treatment effect on drug-resistant breast cancer in clinical tests. The invention designs and synthesizes the dual-functional selective estrogen receptor down-regulator by using the oxygen-bridged bicyclo- [2.2.1] -heptene sulfonamide as a parent nucleus, and researches the biological activity of the dual-functional selective estrogen receptor down-regulator.
The invention designs and synthesizes a series of double-target conjugates which take oxido bridged bicyclic- [2.2.1] -heptene sulfonamide (OBHSA) as a mother nucleus and have aromatase inhibiting activity and estrogen receptor down-regulation activity. Subsequent biological activity tests show that the compounds have certain affinity and selectivity on ER alpha and have good inhibition effect on breast cancer cell proliferation, and in addition, the compounds can effectively inhibit the activity of aromatization enzyme and have certain degradation effect on ER alpha. More importantly, in the research field of the ER ligand, the bifunctional compound capable of inhibiting the activity of the aromatization enzyme and inducing the degradation of ER alpha is discovered through a molecular design concept, so that a new thought is provided for the development of the bifunctional ER ligand with structural diversity, and a new possibility is created for the development of drug-resistant breast cancer drugs.
The invention aims to provide an oxido-bicyclo- [2.2.1] -heptene sulfonamide compound containing five-membered nitrogen heterocycle, the compound is a compound with an oxido-bicyclo heptene sulfonamide structure and five-membered nitrogen heterocycle are combined to obtain an anti-tumor drug with a three-dimensional structure, and the synthesized target compound shows good anti-breast cancer cell activity in testing the biological activity of the target compound and has the capability of down-regulating the estrogen receptor level.
In addition, the invention provides application of the oxygen-bridged bicyclo- [2.2.1] -heptene sulfonamide compound containing the five-membered nitrogen heterocyclic structure in preparing anti-breast cancer drugs.
In order to achieve the purpose, the invention adopts the following technical scheme:
in a first aspect, an oxo-bridged bicyclic- [2.2.1] -heptene sulfonamide (OBHSA) compound containing a five-membered nitrogen heterocycle is provided.
The OBHSA compound containing five-membered nitrogen heterocycle has a structure shown in a general formula I, II or III:
Figure BDA0003503622770000021
in the above formula, R 1 Is selected from
Figure BDA0003503622770000022
R 2 Is selected from CH 3 、CH 2 CH 3 、CH 2 CF 3 ，R 3 Selected from H, OCH 3 。
Preferably, the five-membered nitrogen heterocycle-containing OBHSA compound is selected from the following compounds:
(1R, 4R) -6- (4- (1H-imidazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -N-methyl-N-phenyl-7-oxazolcyclo [2.2.1] hept-5-ene-2-sulfonamide (16 a),
(1R, 4R) -6- (4- (1H-imidazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -N-methyl-7-oxa [2.2.1] hept-5-ene-2-sulfonamide (16 b),
(1R, 4R) -6- (4- (1H-imidazol-1-yl) phenyl) -N-ethyl-5- (4-hydroxyphenyl) -N-phenyl-7-oxazolcyclo [2.2.1] hept-5-ene-2-sulfonamide (16 c),
(1R, 4R) -6- (4- (1H-imidazol-1-yl) phenyl) -N-ethyl-5- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -7-oxazolcyclo [2.2.1] hept-5-ene-2-sulfonamide (16 d),
(1R, 4R) -6- (4- (1H-imidazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -N-phenyl-N- (2, 2-trifluoroethyl) -7-oxacyclo [2.2.1] hept-5-ene-2-sulfonamide (16 e),
(1R, 4R) -6- (4- (1H-imidazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -N- (2, 2-trifluoroethyl) -7-oxacyclo [2.2.1] hept-5-ene-2-sulfonamide (16 f),
(1R, 4R) -6- (4- (1H-1, 2, 4-triazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -N-methyl-7-oxacyclo [2.2.1] hept-5-ene-2-sulfonamide (16 g),
(1R,4R) -5- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -N-methyl-6- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -7-oxazolcyclo [2.2.1] hept-5-ene-2-sulfonamide (16H),
(1R, 4R) -N-ethyl-5- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -6- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -7-oxazolcyclo [2.2.1] hept-5-ene-2-sulfonamide (16 j),
(1R, 4R) -5- (4-hydroxyphenyl) -6- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -N-phenyl-N- (2, 2-trifluoroethyl) -7-oxazolcyclo [2.2.1] hept-5-ene-2-sulfonamide (16 k),
(1R, 4R) -5- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -6- (4- (1-methyl-1H-pyrazolyl-4-yl) phenyl) -N- (2, 2-trifluoroethyl) -7-oxazolcyclo [2.2.1] hept-5-ene-2-sulfonamide (16 l),
(1R, 4R) -6- (4- (1H-1, 2, 4-triazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -N-methyl-7-oxacyclo [2.2.1] hept-5-ene-2-sulfonamide (16N),
(1R, 4R) -N-ethyl-6- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -5- (1-methyl-1H-pyrazol-4-yl) -7-oxazolcyclo [2.2.1] hept-5-ene-2-sulfonamide (18 a),
(1R, 4R) -N-ethyl-5- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -6- (1-methyl-1H-pyrazol-4-yl) -7-oxazolcyclo [2.2.1] hept-5-ene-2-sulfonamide (18 b),
(1R, 4R) -6- (4- (1H-1, 2, 4-triazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -N-methyl-7-oxacyclo [2.2.1] hept-5-ene-2-sulfonamide (18 c),
(1R, 4R) -N-ethyl-6- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -5- (1-methyl-1H-pyrazol-4-yl) -7-oxazolcyclo [2.2.1] hept-5-ene-2-sulfonamide (18 d).
In a second aspect, a method for preparing the above-mentioned oxido-bicyclo- [2.2.1] -heptene sulfonamide (OBHSA) compound containing a five-membered aza ring structure is provided.
The preparation method of the OBHSA compound containing the five-membered nitrogen heterocycle, the structure of which is shown as the general formula I, comprises the following steps:
Figure BDA0003503622770000041
furan derivative 8a-c containing five-membered nitrogen heterocycle and R-containing compound 2 And R 3 The vinylsulfonamide derivative 24a-f of the group is prepared into the compound with the structure shown in the general formula I through Diels-Alder reaction.
The preparation method of the five-membered nitrogen heterocycle-containing OBHSA compound with the structure shown as the general formula II or III comprises the following steps:
Figure BDA0003503622770000042
bromo furan derivative 13 and compound containing R 3 The vinylsulfonamide derivative 24c-d of the group is prepared into a compound shown by 15a-d through Diels-Alder reaction, and then is coupled with (1-methyl-1H-pyrazol-4-yl) boric acid to obtain a compound shown by a general formula II and a compound shown by a general formula III.
In a third aspect, there is provided a pharmaceutically acceptable salt of the above-mentioned oxo-bridged bicyclo- [2.2.1] -heptenesulfonamide (OBHSA) compound containing a five-membered nitrogen heterocyclic structure.
In a fourth aspect, the application of the oxygen-bridged bicyclo- [2.2.1] -heptene sulfonamide (OBHSA) compound containing the five-membered nitrogen heterocyclic structure or the pharmaceutically acceptable salt thereof in preparing the medicament is provided. The medicines comprise medicines for degrading estrogen receptors, medicines for resisting breast cancer, medicines for inhibiting aromatase activity and medicines for resisting breast cancer endocrine therapy.
A drug for degrading estrogen receptors, an anti-breast cancer drug, a drug for inhibiting the activity of aromatase or a drug resistant to endocrine therapy of breast cancer comprises the five-membered nitrogen heterocycle-containing oxo-bridged bicyclo- [2.2.1] -heptene sulfonamide compound or pharmaceutically acceptable salts thereof, and further comprises one or more pharmaceutically acceptable carriers or excipients.
Compared with the prior art, the invention has the advantages and beneficial effects that: the oxygen bridge bicyclo- [2.2.1] -heptene sulfonamide compound containing the five-membered nitrogen heterocyclic structure is prepared by reacting a furan derivative containing the five-membered nitrogen heterocyclic and a vinyl sulfonamide derivative at 90 ℃ for 12 hours in one step without using a solvent or a catalyst. In vitro experiments show that most of the novel sulfonamide oxygen-bridged bicyclo- [2.2.1] -heptene compounds have stronger inhibitory activity on MCF-7 cells and certain degradation capability on estrogen receptors compared with the existing anti-breast cancer medicament tamoxifen, and in addition, have certain inhibitory effect on aromatization enzymes.
Drawings
FIG. 1 shows the results of the degradation activity of compounds 16a-r and 18a-d on ER α, where C is control (DMSO) and Ful is fulvestrant.
Detailed Description
The invention is described in further detail below with reference to examples, which are provided merely to illustrate the process of the invention and are not intended to limit the remainder of the disclosure in any way.
Furan derivatives containing five-membered nitrogen heterocycles, 3- (4-hydroxyphenyl) -4- ((1H-imidazol-1-yl) phenyl) furan 8a, 3- (4-hydroxyphenyl) -4- ((1H-1, 2, 4-triazol-1-yl) phenyl) furan 8b, 3- (4-hydroxyphenyl) -4- ((1-methyl-1H-pyrazol-4-yl) phenyl) furan 8c,4- (4-bromofuran-3-yl) phenol 13, vinylsulfonamide derivatives and target compounds were synthesized by the reactions shown below. The specific operation steps can be as follows:
1. synthesis of furan derivative 8a-c containing five-membered azacyclo
Figure BDA0003503622770000051
a Reagents and conditions:(a)NBS,p-TsOH,AlCl 3 ,CHCl 3 ,rt,12h；(b)2-(4-bromophenyl)acetic acid,Et 3 N,CH3CN,rt,12h；(c)NaH,DMSO,rt,3h；(d)BBr 3 ,CH 2 Cl 2 ,-20℃,12h；(e)DIBAL-H,THF,-78℃,8h；(f)For 8a:1H-imidazole,CuI,Cs 2 CO 3 ,DMF,120℃,24h；For 8b:1,2,4H-triazole,CuI,Cs 2 CO 3 ,DMF,120℃,24h；For 8c:1-methyl-1H-pyrazol-4-yl)boronic acid,Pd(dppf)Cl 2 ,K 3 PO 4 ,H 2 O,1,4-dioxane,80℃,16h.
a. Synthesis of p-methoxy bromoacetophenone compound 2
Weighing 1.0 eq.p-methoxyacetophenone 1, 0.2 eq.p-toluenesulfonic acid and 1.2eq.N-bromosuccinimide into a 50mL round-bottom flask, and adding 20mL of CH 3 Cl, after reacting at room temperature for 9h, TLC monitored the completion of the reaction, and the reaction mixture was desolventized under reduced pressure, dissolved in 50mL of ethyl acetate, and then dissolved in 3.0eq.2N HCl and 2X 30mL of saturated NaHCO 3 The solution was washed with 30mL of saturated NaCl and the organic layer was washed with anhydrous NaSO 4 Drying, filtering, spin-drying to obtain crude product, and purifying by column chromatography to obtain white solid compound 2.
b. Synthesis of 2- (4-methoxyphenyl) -2-oxyethyl 2- (4-bromophenyl) acetate Compound 4
Weighing 1.0eq.2 and 1.0eq.2- (4-bromophenyl) acetic acid 3 into a 50mL round-bottomed flask, adding 25mL of anhydrous acetonitrile, slowly dropwise adding 1.0 eq.anhydrous triethylamine, continuing to react for 2h at room temperature, monitoring the completion of the reaction by TLC, evaporating acetonitrile and triethylamine after the reaction is finished, adding ethyl acetate to dissolve, washing with 5.0 eq.2N diluted hydrochloric acid, 2 × 30mL of saturated sodium bicarbonate and 30mL of saturated sodium chloride, drying an organic layer with anhydrous sodium sulfate, filtering, spin-drying to obtain a crude product, and purifying by column chromatography to obtain a yellow solid compound 4.
c. Synthesis of 3- (4-bromophenyl) -4- (4-methoxyphenyl) furan-2- (5H) -one Compound 5
Baking 25mL of two-port bottle and magneton at 105 ℃ for 15min, putting the two-port bottle and magneton into a hot device, performing anhydrous and anaerobic operation, weighing 1.0eq under Ar, putting compound 4 into the device, adding 10mL of anhydrous DMSO, slowly dropwise adding 2.0eq.80% NaH, reacting for 2h at 25 ℃, monitoring the reaction by TLC, adding 5mL of 4.0eq.2N HCl to quench the reaction, extracting with 3 × 25mL of ethyl acetate, and performing organic layer anhydrous NaSO 4 Drying and desolventizing under reduced pressure gave a crude product, which was purified by silica gel column (petroleum ether/ethyl acetate = 9).
d. Synthesis of 3- (4-bromophenyl) -4- (4-hydroxyphenyl) furan-2 (5H) -one Compound 6
Baking 100mL of single-mouth bottle and magneton at 105 deg.C for 15min, loading in hot apparatus, anhydrous and oxygen-free operation, introducing Ar, and weighing 1.0 eq.5To this mixture, 25mL of DCM was added and 6.0eq.BBr was added at-20 ℃ 3 After 12h of reaction, the reaction was quenched with 10mL of water, extracted with 3X 20mL of ethyl acetate, 15mL of saturated NaHCO 3 Washing with the solution, and removing organic layer with anhydrous NaSO 4 Drying and desolventizing under reduced pressure gave the crude product, which was purified on silica gel column (petroleum ether/ethyl acetate = 7).
e. Synthesis of 4- (4- (4-bromophenyl) furan-3-yl) phenol Compound 7
Baking 50mL single-mouth bottle and magneton at 105 deg.C for 15min, putting into a hot device, heating under anhydrous and oxygen-free conditions, adding Ar, weighing 1.0eq compound 6, putting into the device, adding 4.0eq diisobutylaluminum hydride (DIBAL-H) at-78 deg.C, reacting for 12H, and adding 4% H 2 SO 4 The reaction was quenched, extracted with 3X 25mL ethyl acetate, washed with 30mL saturated NaCl solution, and the organic layer was anhydrous NaSO 4 Drying and desolventizing under reduced pressure gave the crude product, which was purified on silica gel column (petroleum ether/ethyl acetate = 6) to give compound 7.
f. Synthesis of 4- (4- (4- (1H-imidazol-1-yl) phenyl) furan-3-yl) phenol and 4- (4- (4- (1H-1, 2, 4-triazol-1-yl) phenyl) furan-3-yl) phenol Compounds 8a-b
Baking 50mL of single-neck bottle and magneton at 105 deg.C for 15min, and weighing Compound 7 (1.0 equiv.), 1H-imidazole or 1,2, 4-H-triazole (1.2 equiv.), cuI (5 percent), cs, and 2 CO 3 (1.2 equiv.) by anhydrous and anaerobic procedure, dissolving with DMF, stirring at room temperature for half an hour, heating to 120 deg.C, reacting for 24h, extracting with 3X 25mL ethyl acetate, washing with 30mL saturated NaCl solution, and collecting the organic layer as anhydrous NaSO 4 Drying and desolventizing under reduced pressure gave the crude product, which was purified on silica gel column (dichloromethane/methanol =150 =1 to 50.
g. Synthesis of 4- (4- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) furan-3-yl) phenol Compound 8c
A50 mL single-necked flask was charged with compound 7 (1.0 equiv.), 4- (4- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) furan-3-yl) phenol (1.2 equiv.), pd (dppf) Cl 2 (5％mmol)、K 3 PO 4 (1.2 equiv.) with 1,4-dioxane/H 2 O = (130mL of saturated NaCl solution, and the organic layer was washed with anhydrous NaSO 4 Drying and desolventizing under reduced pressure gave a crude product which was purified on silica gel column (dichloromethane/methanol =150 =1 to 50.
2. Synthesis of 4- (4-bromofuran-3-yl) phenol 13
Figure BDA0003503622770000071
a Reagents and conditions:(a)NBS,p-TsOH,AlCl 3 ,CHCl 3 ,rt,12h；(b)2-(4-bromophenyl)acetic acid,Et 3 N,CH3CN,rt,12h；(c)NaH,DMSO,rt,3h；(d)BBr 3 ,CH 2 Cl 2 ,-20℃,12h；(e)DIBAL-H,THF,-78℃,8h.
Firstly, the compound 2 reacts with bromoacetic acid to obtain bromoacetate 9, and then the bromoacetate 9 reacts with PPh 3 And Et 3 N was refluxed at 100 ℃ to give ring-closed product 10. Adding bromine to the compound 10 under the action of NBS to obtain bromofuranone 11, and performing BBr 3 Demethylation and DIBAL-H reduction to yield bromofuran derivative 13.
3. Synthesis of ethenesulfonamide derivative 24a-f
Figure BDA0003503622770000072
a. Synthesis of N-phenylacetamide compound 20a-f
Weighing 1eq aromatic amine compounds 19a-b and 2eq acetic anhydride or trifluoroacetic anhydride in a 100mL single-neck bottle, adding 40mL dichloromethane to dissolve, slowly adding 0.1eq.4-Dimethylaminopyridine (DMAP), continuing to react for 2h at room temperature, monitoring by tlc, removing the solvent under reduced pressure to obtain a crude product, and purifying by a silica gel column (petroleum ether/ethyl acetate = 15) to obtain acetamide compounds 20a-f.
b. Synthesis of N-methyl-N-phenylacetamide Compound 21a-b
Under the protection of Ar, 1 eq.acetamide compounds 20a-b were weighed into a 150mL two-necked flask, dissolved by adding 35mL anhydrous tetrahydrofuran, slowly added with sodium hydride (2 eq.) at 0 ℃, reacted for 4h at 0 ℃, quenched with 3mL water, desolventized under reduced pressure to give crude products, which were purified by silica gel column (petroleum ether/ethyl acetate = 9) to give white N-methylacetamide compounds 21a-b.
c. Synthesis of N-methylaniline Compound 22a-b
1eq.n-methylacetamide compounds 21a-b were weighed into a 100mL single-neck flask, 20mL ethylene glycol and 10mL10% diluted hydrochloric acid were added, and after heating and refluxing for 4h, the crude product was obtained after desolvation under reduced pressure, and after purification by a silica gel column (petroleum ether/ethyl acetate = 15) white oily substances 22a-b were obtained.
d. Synthesis of N-alkylaniline compound 23c-f
Under the protection of Ar, weighing 1eq acetamide compound 20c-f in a 100mL double-mouth bottle, adding 20mL anhydrous tetrahydrofuran for dissolving, slowly dropwise adding 4eq borane-dimethyl sulfide at 0 ℃, reacting for 24h after slowly raising the temperature to 60 ℃, and adding 5mL methanol for quenching reaction; after desolventization under reduced pressure, the crude product was obtained and purified by silica gel column (petroleum ether/ethyl acetate = 12) to obtain white oils 23c-f.
e. Synthesis of sulfonamide dienophiles 24a-f
Weighing corresponding 1eq.N-methyl aromatic amide derivatives 22a-b or 23c-f, dissolving in 25mL dichloromethane, slowly adding 1.2eq.2-chloroethane sulfonyl chloride at 0 ℃, reacting for 10min, slowly dropwise adding 20% sodium hydroxide aqueous solution, reacting for 24h at room temperature, decompressing and removing the solvent to obtain a crude product, and purifying by a silica gel column (petroleum ether/ethyl acetate = 15.
4. Synthesis of target Compounds 16a-r, 18a-d
(1) Taking a 25ml double-mouth bottle, baking magnetons at 105 ℃ for 15min, putting the bottle in a hot device, performing anhydrous and oxygen-free operation, dissolving synthesized 3- (4-hydroxyphenyl) -4- ((1H-imidazol-1-yl) phenyl) furan compound 8a, 3- (4-hydroxyphenyl) -4- ((1H-1, 2, 4-triazol-1-yl) phenyl) furan compound 8b, 3- (4-hydroxyphenyl) -4- ((1-methyl-1H-pyrazol-4-yl) phenyl) furan compound 8c and ethylene sulfonamide derivative 24a-f in tetrahydrofuran under Ar, and reacting at 90 ℃ for 8 hours to prepare the oxo-bridged bicycloheptene compound 16a-r containing five-membered nitrogen heterocycle in one step, wherein the reaction formula is shown as follows:
Figure BDA0003503622770000081
(2) Taking a 25ml double-mouth bottle, baking magnetons for 15min at 105 ℃, using a hot device, performing anhydrous and anaerobic operation, dissolving synthesized 4- (4-bromofuran-3-yl) phenol 13 and vinylsulfonamide derivative 24c-d in tetrahydrofuran under the condition of introducing Ar, reacting for 8 hours at 90 ℃ to prepare an oxa-bridged bicycloheptene compound 15a-d containing five-membered nitrogen heterocycle by one step, and obtaining 18a-d through suzuki reaction, wherein the reaction formula is shown as follows:
Figure BDA0003503622770000091
example 1 preparation of 6- (4- (1H-imidazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -N-methyl-N-phenyl-7-oxacyclo [2.2.1] hept-5-ene-2-sulfonamide (16 a):
Figure BDA0003503622770000092
3- (4-hydroxyphenyl) -4- ((1H-imidazol-1-yl) phenyl) furan (8a, 1eq.) and N-methyl-N-phenylethenesulfonamide (24a, 1eq.) were dissolved in 2-3mL THF, placed in a 25mL single-neck flask and then slowly warmed to 90 ℃ for 12 hours before being spun dry and purified by direct column chromatography, with an eluent ratio of dichloromethane: methanol =60, to give a yellow solid in 61% yield. Pale yellow solid, mp 127-128 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ9.79(d,J＝15.0Hz,1H),8.33(s,1H),7.81(s,1H),7.65(dd,J＝17.9,8.4Hz,2H),7.42(d,J＝6.1Hz,2H),7.36(dd,J＝15.2,8.3Hz,5H),7.28(t,J＝6.8Hz,1H),7.18–7.13(m,2H),6.75(dd,J＝14.8,8.5Hz,2H),5.50(d,J＝9.9Hz,1H),5.44–5.38(m,1H),3.74–3.52(m,1H),3.31(d,J＝4.7Hz,3H),2.00(dd,J＝20.4,11.8Hz,1H),1.92(d,J＝5.2Hz,1H). 13 C NMR(101MHz,DMSO-d 6 )δ158.24,144.00,142.00,140.50,139.87,136.13,131.79,131.34,129.52,129.44,129.20,128.78,127.46,127.00,123.11,122.51,120.68,116.25,84.27,82.46,60.19,55.38,30.71.HRMS(ESI)calcd for C 28 H 25 N 3 O 4 S[M+H] + ,501.1639；found 501.1638.
Example 2 preparation of (1R, 4R) -6- (4- (1H-imidazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -N-methyl-7-oxacyclo [2.2.1] hept-5-ene-2-sulfonamide (16 b):
Figure BDA0003503622770000101
3- (4-hydroxyphenyl) -4- ((1H-imidazol-1-yl) phenyl) furan (8a, 1eq.) and N- (4-methoxyphenyl) -N-methylchlorosulfamide (24b, 1eq.) were dissolved in 2-3mL THF, placed in a 25mL single vial flask and then slowly warmed to 90 ℃ for 12 hours before being spun dry and purified by direct column chromatography, eluent ratio dichloromethane: methanol =60, product was a pale yellow solid in 75% yield. 1 H NMR(400MHz,DMSO-d 6 )δ9.75(s,1H),7.80(s,1H),7.68(d,J＝8.7Hz,2H),7.40(d,J＝8.6Hz,2H),7.31(d,J＝9.0Hz,2H),7.17(d,J＝8.6Hz,2H),7.12(s,1H),6.88(d,J＝9.0Hz,2H),6.73(d,J＝8.6Hz,2H),5.51(s,1H),5.40(s,1H),3.73(s,3H),3.63(dd,J＝12.0,5.7Hz,2H),3.17(d,J＝5.2Hz,3H),2.00(s,4H). 13 C NMR(101MHz,DMSO)δ158.54,158.17,144.63,140.66,140.07,136.54,136.17,135.89,134.57,131.85,131.40,130.44,129.61,129.18,128.70,123.59,122.08,120.85,120.67,118.23,116.27,116.08,115.04,114.55,84.17,82.30,59.97,59.63,55.71,49.08.HRMS(ESI)calcd for C 29 H 27 N 3 O 5 S[M+H] + ,529.1671；found.
Example 3 preparation of (1R, 4R) -6- (4- (1H-imidazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -N-methyl-N-phenyl-7-oxazolcyclo [2.2.1] hept-5-ene-2-sulfonamide (16 c):
Figure BDA0003503622770000102
3- (4-hydroxyphenyl) -4- ((1H-imidazol-1-yl) phenyl) furan (8a, 1eq.) and N-ethyl-N-phenylvinylsulfonamide (24c, 1eq.) were dissolved in 2-3mL of THF, placed in a 25mL single-necked round-bottomed flask, then slowly warmed to 90 ℃ for reaction for 12 hours, spun dry, and subjected to direct column chromatography for purification, wherein the eluent ratio is dichloromethane: methanol = 60. 1 H NMR(400MHz,DMSO-d 6 )δ9.75(s,1H),8.33(s,1H),7.84(s,1H),7.66(t,J＝11.2Hz,2H),7.53(s,1H),7.40(d,J＝6.3Hz,2H),7.33(d,J＝14.2Hz,5H),7.17(d,J＝3.4Hz,2H),6.73(d,J＝7.2Hz,2H),5.53(s,1H),5.41(s,1H),3.76(d,J＝6.7Hz,2H),3.60(s,1H),1.99(s,2H),0.96(s,3H). 13 C NMR(101MHz,DMSO-d 6 )δ158.14,143.96,139.17,136.20,131.32,129.56,129.49,129.20,129.15,128.15,123.17,120.88,116.06,84.16,82.67,61.22,46.13,30.40,14.72.HRMS(ESI)calcd for C 29 H 27 N 3 O 4 S[M+H] + ,514.1795；found514.1798.
Example 4 preparation of (1R, 4R) -6- (4- (1H-imidazol-1-yl) phenyl) -N-ethyl-5- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -7-oxazolcyclo [2.2.1] hept-5-ene-2-sulfonamide (16 d):
Figure BDA0003503622770000111
3- (4-hydroxyphenyl) -4- ((1H-imidazol-1-yl) phenyl) furan (8a, 1eq.) and N-ethyl-N- (4-methoxyphenyl) vinylamide (24d, 1eq.) were dissolved in 2-3mL of THF, placed in a 25mL single-neck flask, slowly warmed to 90 ℃ for reaction for 12 hours, spun dry, and directly purified by column chromatography, eluting with dichloromethane: methanol =60, the product was a yellow solid in 68% yield, m.p.137-138 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ9.80(s,1H),8.31(s,1H),7.80(s,1H),7.67(dd,J＝14.1,8.6Hz,2H),7.44(dd,J＝16.4,8.2Hz,4H),7.34(dd,J＝15.0,7.3Hz,2H),7.28(d,J＝7.7Hz,1H),7.22(dd,J＝12.9,8.6Hz,2H),7.13(s,1H),6.77(dd,J＝10.7,8.7Hz,2H),5.79(d,J＝14.2Hz,1H),5.54(d,J＝12.2Hz,1H),3.92(ddd,J＝19.5,10.6,5.6Hz,1H),2.27(dd,J＝12.0,4.6Hz,1H),2.19(dd,J＝12.1,8.3Hz,1H). 13 C NMR(101MHz,DMSO-d 6 )δ158.27,149.33,144.33,140.18,136.63,135.83,131.66,131.00,130.57,129.88,129.20,128.77,122.75,120.79,116.25,84.00,82.69,60.78,30.54.HRMS(ESI)calcd for C 27 H 22 N 2 O 5 S[M+H] + ,487.1322；found 487.1323.
EXAMPLE 5 preparation of (1R, 4R) -6- (4- (1H-imidazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -N-phenyl-N- (2, 2-trifluoroethyl) -7-oxacyclo [2.2.1] hept-5-ene-2-sulfonamide (16 e):
Figure BDA0003503622770000112
weighing 3- (4-hydroxyphenyl) -4- ((1H-imidazol-1-yl) phenyl) furan (8a, 1eq.) and N-phenyl-N- (2, 2-trifluoroethyl) vinylamide (24e, 1eq.) and dissolving with 2-3mL THF, placing in a 25mL single-mouth round-bottom bottle, slowly heating to 90 ℃, reacting for 12 hours, spin-drying, directly separating and purifying by column chromatography, wherein the eluent ratio is dichloromethane: methanol =60, the product is yellow solid, the yield is 78%, 1 H NMR(400MHz,Acetone-d 6 )δ8.13(s,5H),7.86(d,J＝1.8Hz,4H),7.72(d,J＝1.7Hz,4H),7.64–7.56(m,13H),7.42(d,J＝8.6Hz,6H),7.15–7.11(m,12H),6.84(d,J＝8.5Hz,7H),5.64(d,J＝4.3Hz,1H),5.47–5.38(m,1H),4.61(qd,J＝8.7,8.2,4.1Hz,2H),3.76(dd,J＝8.3,4.4Hz,1H),3.63(dd,J＝8.0,4.8Hz,1H),2.21(q,J＝4.5Hz,1H),2.19–2.08(m,2H). 13 C NMR(101MHz,Acetone)δ159.15,156.95,141.17,140.69,136.26,135.34,131.26,130.08,129.79,129.61,129.33,129.07,128.87,128.45,128.32,125.64,124.81,122.82,120.81,120.65,120.60,117.75,117.62,115.87,115.66,115.41,82.84,81.42,71.39,71.06,42.95,23.43.
example 6 preparation of (1R, 4R) -6- (4- (1H-imidazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -N- (2, 2-trifluoroethyl) -7-oxacyclo [2.2.1] hept-5-ene-2-sulfonamide (16 f):
Figure BDA0003503622770000121
3- (4-hydroxyphenyl) -4- ((1H-imidazol-1-yl) phenyl) furan (8a, 1eq.) and N- (4-methoxyphenyl) -N- (2, 2-trifluoroethyl) vinylamide (24f, 1eq.) were weighed, dissolved in 2-3mL THF, placed in a 25mL single-neck flask and then slowly warmed to 90 ℃ for 12 hours, spun dry, and directly purified by column chromatography, eluting with dichloromethane: methanol =60, the product was a yellow solid in 54% yield, mp 129-131 ℃. 1 H NMR(400MHz,Acetone-d 6 )δ8.94(s,1H),8.22(s,1H),7.73(s,1H),7.65(d,J＝8.5Hz,2H),7.49(d,J＝8.5Hz,2H),7.41(d,J＝8.9Hz,2H),7.23(d,J＝8.6Hz,3H),6.90(d,J＝9.0Hz,2H),6.83(d,J＝8.6Hz,2H),5.64(s,1H),5.43(d,J＝4.2Hz,1H),4.54(q,J＝8.6Hz,2H),3.79(d,J＝7.1Hz,3H),3.73(dd,J＝8.2,4.4Hz,1H),2.21(dt,J＝12.0,4.4Hz,1H),2.12(d,J＝9.2Hz,1H). 13 C NMR(101MHz,Acetone-d 6 )δ159.49,144.31,136.19,131.90,131.46,130.34,129.64,129.14,128.84,128.19,125.80,123.45,120.81,115.59,114.32,113.08,84.24,82.85,61.89,59.67,54.89,54.08,19.94.HRMS(ESI)calcd for C 30 H 26 F 3 N 3 O 5 S[M+H] + ,598.1618；found 598.1615.
Example 7 preparation of (1R, 4R) -5- (4-hydroxyphenyl) -N-methyl-6- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -N-phenyl-7-oxazolcyclo [2.2.1] hept-5-ene-2-sulfonamide (16 g):
Figure BDA0003503622770000131
weighing 3- (4-hydroxyphenyl) -4- ((1H-1, 2, 4-triazol-1-yl) phenyl) furan (8b, 1eq.) and N-methyl-N-phenylethenesulfonamide (24a, 1eq.) and dissolving with 2-3mL THF, placing in a 25mL single-neck round-bottom bottle, slowly heating to 90 ℃, reacting for 12 hours, drying by spinning, separating and purifying by direct column chromatography, wherein the eluent ratio is dichloromethane: methanol =60, the product is pale yellow solid, the yield is 59%, 13 C NMR(101MHz,Acetone-d 6 )δ157.62,142.80,142.26,140.81,139.31,137.22,136.02,132.73,130.31,129.19,128.92,127.79,127.55,127.30,126.45,125.29,125.15,123.96,123.35,122.18,115.55,84.27,82.83,60.82,38.27,30.46.
example 8 preparation of (1R, 4R) -5- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -N-methyl-6- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -7-oxazolcyclo [2.2.1] hept-5-ene-2-sulfonamide (16H):
Figure BDA0003503622770000132
weighing 3- (4-hydroxyphenyl) -4- ((1H-1, 2, 4-triazol-1-yl) phenyl) furan (8b, 1eq.) and N- (4-methoxyphenyl) -N-methylchlorosulfamide (24b, 1eq.) dissolved in 2-3mL THF, placing in a 25mL single-neck round-bottom bottle, slowly heating to 90 ℃, reacting for 12 hours, spin-drying, direct column chromatography for separation and purification, wherein the eluent ratio is dichloromethane: methanol =60, the product is yellow solid, the yield is 70%, 1 H NMR(400MHz,Methanol-d 4 )δ7.92(d,J＝12.6Hz,1H),7.81(d,J＝11.7Hz,1H),7.50–7.39(m,1H),7.37–7.21(m,3H),7.15(dd,J＝8.6,6.8Hz,2H),6.85(dd,J＝31.3,9.0Hz,2H),6.74(dd,J＝17.1,8.6Hz,2H),5.47(d,J＝8.1Hz,1H),5.32(t,J＝4.8Hz,1H),3.91(d,J＝5.0Hz,3H),3.75(d,J＝12.3Hz,2H),3.54(d,J＝4.0Hz,0H),3.33(d,J＝3.3Hz,2H),2.46–2.15(m,0H),1.99(d,J＝8.4Hz,0H).
example 9 preparation of (1R, 4R) -N-ethyl-5- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -6- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -7-oxazolcyclo [2.2.1] hept-5-ene-2-sulfonamide (16 j):
Figure BDA0003503622770000141
3- (4-hydroxyphenyl) -4- ((1H-1, 2, 4-triazol-1-yl) phenyl) furan (8b, 1eq.) and N-ethyl-N- (4-methoxyphenyl) vinylamide (24d, 1eq.) are weighed, dissolved in 2-3mL THF, placed in a 25mL single-neck round-bottom bottle, slowly heated to 90 ℃, reacted for 12 hours, then dried in a spinning mode, and directly subjected to column chromatography to separate pure substancesEluent ratio dichloromethane to methanol =60, product is yellow solid, yield 78%, 1 H NMR(400MHz,Methanol-d 4 )δ7.88(d,J＝49.7Hz,1H),7.46(s,1H),7.37–7.13(m,4H),6.88(d,J＝52.9Hz,4H),5.50(d,J＝9.4Hz,1H),5.35(s,1H),3.92(d,J＝7.1Hz,2H),3.78(s,2H),2.74–2.18(m,1H),2.04(s,1H),1.34–1.21(m,8H).
example 10 preparation of (1R, 4R) -5- (4-hydroxyphenyl) -6- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -N-phenyl-N- (2, 2-trifluoroethyl) -7-oxazolcyclo [2.2.1] hept-5-ene-2-sulfonamide (16 k):
Figure BDA0003503622770000142
3- (4-hydroxyphenyl) -4- ((1H-1, 2, 4-triazol-1-yl) phenyl) furan (8b, 1eq.) and N-phenyl-N- (2, 2-trifluoroethyl) vinylamide (24e, 1eq.) were weighed, dissolved in 2-3mL THF, placed in a 25mL single vial flask and then slowly warmed to 90 ℃ for 12 hours before spin-drying for direct column chromatography purification, with an eluent ratio dichloromethane: methanol =60, to give 125mg of a yellow solid in 76% yield, m.p.145-146 ℃. 1 H NMR(400MHz,Methanol-d 4 )δ7.94(d,J＝13.8Hz,1H),7.82(d,J＝12.4Hz,1H),7.47(dd,J＝16.0,8.1Hz,2H),7.32(d,J＝5.8Hz,2H),7.29–7.24(m,1H),7.17(d,J＝8.6Hz,1H),6.78(d,J＝8.6Hz,1H),6.73(d,J＝8.8Hz,1H),5.49(d,J＝4.9Hz,1H),5.34(t,J＝4.2Hz,1H),3.92(d,J＝5.0Hz,3H),3.86–3.78(m,1H),3.49(ddd,J＝34.1,8.3,4.4Hz,1H),2.22(ddd,J＝18.6,8.2,4.3Hz,0H),2.04(dd,J＝37.5,8.4Hz,0H),1.09–1.03(m,2H).HRMS(ESI)calcd for C 28 H 24 N 2 O 5 S[M+H] + ,；found.
EXAMPLE 11 preparation of (1R, 4R) -5- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -6- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -N- (2, 2-trifluoroethyl) -7-oxazolcyclo [2.2.1] hept-5-ene-2-sulfonamide (16 l):
Figure BDA0003503622770000151
3- (4-hydroxyphenyl) -4- ((1H-1, 2, 4-triazol-1-yl) phenyl) furan (8b, 1eq.) and N- (4-methoxyphenyl) -N- (2, 2-trifluoroethyl) vinylamide (24f, 1eq.) were weighed, dissolved in 2-3mL THF, placed in a 25mL single vial flask and then slowly warmed to 90 ℃ for 12 hours, spun dry, purified by direct column chromatography, with the eluent ratio dichloromethane: methanol =60, the product was a yellow solid, 42 yield, 136-137 ℃ yield. 1 H NMR(400MHz,DMSO-d 6 )δ9.74(s,1H),8.16(s,1H),7.87(s,1H),7.50(d,J＝8.2Hz,2H),7.26(dd,J＝11.4,8.7Hz,4H),7.18(d,J＝8.4Hz,2H),6.85(d,J＝8.8Hz,2H),6.77(d,J＝8.5Hz,2H),5.56(d,J＝8.9Hz,1H),5.41(s,1H),4.58–4.46(m,2H),3.85(s,3H),3.78–3.69(m,3H),3.51(t,J＝6.1Hz,1H),2.00(d,J＝6.2Hz,2H). 13 C NMR(101MHz,DMSO-d 6 )δ159.22,158.18,140.77,139.27,136.56,132.55,131.84,130.65,129.81,128.38,127.68,125.41,122.69,121.88,116.16,114.77,84.16,82.40,61.17,55.74,52.17,30.79,26.81.HRMS(ESI)calcd for C 31 H 28 F 3 N 3 O 5 S[M+Na] + ,634.1594；found 634.1588.
EXAMPLE 12 preparation of (1R, 4R) -6- (4- (1H-1, 2, 4-triazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -N-methyl-7-oxacyclo [2.2.1] hept-5-ene-2-sulfonamide (16N):
Figure BDA0003503622770000152
3- (4-hydroxyphenyl) -4- ((1-methyl-1H-pyrazol-4-yl) phenyl) furan (8c, 1eq.) and N- (4-methoxyphenyl) -N-methyl chlorosulfonamide (24b, 1eq.) are weighed, dissolved in 2-3mL of THF, placed in a 25mL single-neck round bottom bottle, slowly heated to 90 ℃ for 12 hours, and then dried by spinning, separated and purified by direct column chromatography, wherein the eluent ratio is dichloromethane: methanol =60, the product is yellow solid, and the yield is 65%, 1 H NMR(400MHz,Acetone-d 6 )δ9.07(d,J＝9.5Hz,2H),8.81(d,J＝19.8Hz,2H),8.12(d,J＝5.4Hz,3H),7.85(d,J＝8.9Hz,1H),7.47(dd,J＝16.8,8.7Hz,7H),7.35(q,J＝6.6Hz,6H),7.28(d,J＝8.2Hz,4H),7.21(d,J＝11.8Hz,2H),6.87–6.79(m,5H),5.54(s,2H),5.41–5.37(m,4H),3.67(ddd,J＝49.1,8.4,5.1Hz,3H),3.41(s,5H),2.96(s,22H),2.23–2.14(m,2H),2.13–1.98(m,3H).
EXAMPLE 13 preparation of (1R, 4R) -N-ethyl-6- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -5- (1-methyl-1H-pyrazol-4-yl) -7-oxazolo [2.2.1] hept-5-ene-2-sulfonamide (18 a):
Figure BDA0003503622770000161
(1S, 4R) -6-bromo-N-ethyl-5- (4-hydroxyphenyl) -N-phenyl-7-oxazolylcyclo [2.2.1]Hept-5-ene-2-sulfonamide (15a, 1.0eq.), (1-methyl-1H-pyrazol-4-yl) boronic acid (1.0 eq.), 1' -bisdiphenylphosphinoferrocene palladium dichloride (0.5% mmol), and barium hydroxide (1.0 eq.), using 1,4-dioxane/H 2 Dissolving O (10. 1 H NMR(400MHz,Acetone-d 6 )δ8.76(s,1H),7.74(s,1H),7.49(s,1H),7.44(d,J＝7.5Hz,2H),7.39(t,J＝7.5Hz,2H),7.33(d,J＝7.1Hz,1H),7.29(d,J＝8.6Hz,2H),6.82(dd,J＝25.4,8.6Hz,2H),5.49(s,1H),5.24(d,J＝4.0Hz,1H),3.89(s,3H),3.88–3.81(m,2H),3.38(dd,J＝8.2,4.5Hz,1H),2.25–2.17(m,1H),2.12(dd,J＝23.9,6.9Hz,1H),1.02(dt,J＝25.5,7.0Hz,4H). 13 C NMR(101MHz,Acetone-d 6 )δ157.25,139.86,139.47,137.35,129.77,129.17,128.98,128.72,128.06,127.49,124.93,115.50,113.06,84.01,82.57,61.68,46.13,38.23,31.11,13.99.HRMS(ESI)calcd for C 24 H 25 N 3 O 4 S[M+H] + ,452.1639；found 452.1638.
EXAMPLE 14 preparation of (1R, 4R) -N-ethyl-5- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -6- (1-methyl-1H-pyrazol-4-yl) -7-oxazolo [2.2.1] hept-5-ene-2-sulfonamide (18 b):
Figure BDA0003503622770000162
(1S, 4R) -6-bromo-N-ethyl-5- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -7-oxazolylcyclo [2.2.1]Hept-5-ene-2-sulfonamide (15b, 1.0eq.), (1-methyl-1H-pyrazol-4-yl) boronic acid (1.0 eq.), 1' -bisdiphenylphosphinoferrocene palladium dichloride (0.5% mmol), and barium hydroxide (1.0 eq.), using 1,4-dioxane/H 2 Dissolving O (10. 1 H NMR(400MHz,Acetone-d 6 )δ8.73(s,1H),7.76(s,1H),7.50(s,1H),7.31(dd,J＝14.4,8.7Hz,4H),6.92(d,J＝8.9Hz,2H),6.86(d,J＝8.5Hz,2H),5.48(s,1H),5.24(d,J＝4.2Hz,1H),3.89(s,3H),3.84–3.73(m,5H),3.35(d,J＝12.7Hz,1H),2.21(d,J＝12.0Hz,1H),2.11(s,1H),1.04(t,J＝7.1Hz,3H). 13 C NMR(101MHz,Acetone-d 6 )δ160.79,158.96,141.54,139.16,133.57,132.39,131.66,130.47,129.83,126.82,117.26,115.82,114.85,85.80,84.35,63.21,56.63,48.13,40.01,32.93,15.78.HRMS(ESI)calcd for C 25 H 27 N 3 O 5 S[M+H] + ,482.1744；found 482.1743.
Example 15 preparation of (1R, 4R) -6- (4- (1H-1, 2, 4-triazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -N-methyl-7-oxocyclo [2.2.1] hept-5-ene-2-sulfonamide (18 c):
Figure BDA0003503622770000171
(1R, 4S) -6-bromo-N-ethyl-5- (4-hydroxyphenyl) -N-phenyl-7-oxazolylcyclo [2.2.1]Hept-5-ene-2-sulfonamide (15c, 1.0eq.), (1-methyl-1H-pyrazol-4-yl) boronic acid (1.0 eq.), 1' -bisdiphenylphosphinoferrocene palladium dichloride (0.5% mmol), and barium hydroxide (1.0 eq.), using 1,4-dioxane/H 2 Dissolving O (10And (3) direct column chromatography separation and purification, wherein the eluent ratio is dichloromethane to methanol =60, the product is light yellow solid, the yield is 35%, and the temperature is mp 116-117 ℃. 1 H NMR(400MHz,Acetone-d 6 )δ8.82(s,1H),7.79(s,1H),7.53(s,1H),7.44–7.31(m,5H),7.28(d,J＝8.6Hz,2H),6.89(d,J＝8.6Hz,2H),5.38(d,J＝12.8Hz,1H),5.35(d,J＝4.3Hz,1H),3.90–3.82(m,5H),3.52(dd,J＝8.3,4.4Hz,1H),2.15–2.09(m,1H),1.90(dd,J＝11.9,8.4Hz,1H),1.05(t,J＝7.1Hz,3H). 13 C NMR(101MHz,DMSO-d 6 )δ157.64,139.20,137.48,135.70,133.08,129.52,129.49,129.42,128.69,128.08,123.76,116.11,113.62,84.06,82.21,61.73,55.40,46.00,30.57,14.71.HRMS(ESI)calcd for C 24 H 25 N 3 O 4 S[M+H] + ,452.1639；found 452.1634.
Example 16 preparation of (1R, 4R) -N-ethyl-6- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -5- (1-methyl-1H-pyrazol-4-yl) -7-oxazolcyclo [2.2.1] hept-5-ene-2-sulfonamide (18 d):
Figure BDA0003503622770000172
(1R, 4S) -6-bromo-N-ethyl-5- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -7-oxazolylcyclo [2.2.1]Hept-5-ene-2-sulfonamide (15d, 1.0eq.), (1-methyl-1H-pyrazol-4-yl) boronic acid (1.0 eq.), 1' -bisdiphenylphosphinoferrocene palladium dichloride (0.5% mmol), and barium hydroxide (1.0 eq.), using 1,4-dioxane/H 2 Dissolving O (10. 1 H NMR(400MHz,Acetone-d 6 )δ8.75(s,1H),7.79(s,1H),7.53(s,1H),7.29(d,J＝8.7Hz,4H),6.89(d,J＝8.1Hz,4H),5.39(s,1H),5.35(d,J＝4.3Hz,1H),3.87(s,3H),3.81(s,3H),3.80–3.75(m,2H),3.49(dd,J＝8.3,4.4Hz,1H),2.13(d,J＝11.8Hz,1H),1.91(dd,J＝11.8,8.4Hz,1H),1.04(t,J＝7.1Hz,3H). 13 C NMR(101MHz,Acetone-d 6 )δ158.99,157.31,137.16,136.02,133.25,131.78,130.56,128.54,124.38,115.66,114.04,113.82,84.22,82.28,61.92,54.84,46.31,38.16,30.23,13.99.HRMS(ESI)calcd for C 25 H 27 N 3 O 5 S[M+H] + ,482.1744；found 482.1744.
[ example 17 ] anti-tumor Activity test of Oxybicyclo- [2.2.1] -heptene sulfonamides having different five-membered aza-ring structures
MCF-7 human breast cancer cell line and MCF-10A normal breast cells were obtained from ATCC. The cells were cultured in phenol red-containing DMEM with 10% FBS and 1% double antibody. Test compounds were dissolved in DMSO at a drug concentration of 100mol/L. Cells were seeded in 96-well plates (Nest Biotech Co, china) and incubated in an incubator for 24h. Different concentrations of test compound were added to 96-well plates, 3 wells in parallel per concentration, and vehicle DMSO was used as a negative control, 4-hydroxy tamoxifen as a positive control. After 72H, 10. Mu.L of a solution of 2- (2-methoxy-4-nitrophenyl) -3- (4-nitrophenyl) -5- (2, 4-disulfonated benzene) -2H-tetrazole monosodium salt (CCK-8) was added to each well and incubated for an additional 2H. Absorbance (OD) was read at 490nm on a WellscanMK-2 microplate reader. IC determination by the Logit method 50 (concentration to induce apoptosis of 50%). All compounds were tested in at least 3 replicates and the results are shown in table 1.
TABLE 1 test of MCF-7 inhibitory Activity of OBHSA Compounds of different five-membered Nitrogen heterocyclic structures (IC) 50 ,μM)
Figure BDA0003503622770000181
Figure BDA0003503622770000191
a IC 50 Is the mean ± standard deviation of at least three independent experiments.
This example tested the inhibitory activity of these 23 compounds against MCF-7 and the inhibitory activity of LCC2 in drug-resistant breast cancer cells, and the results are listed in table 1. As can be seen from the above table, most of the compounds have certain inhibitory activity on MCF-7 cells and have no substantial toxicity on MCF-10A. Wherein the inhibition activity of the compounds 16f, 16h and 16q on MCF-7 is better than that of 4-hydroxy tamoxifen, and the inhibition activity of the compound 16a on MCF-7 is equivalent to that of 4-hydroxy tamoxifen. The inhibitory activity of the compound on LCC 2-resistant strain cells is tested next, and the inhibitory activity of 16b, 16e on the LCC 2-resistant strain cells is better than that of 4-hydroxy tamoxifen, and the inhibitory activity of 16b and 16r on the LCC 2-resistant strain cells is equivalent to that of 4-hydroxy tamoxifen.
[ example 18 ] assay of aromatization enzyme inhibitory Activity of Compounds
Aromatase (CYP 19A) inhibitor screening kit (fluorescence) kit selected from Biovision, inc. recombinant human aromatase stock (2X) was prepared by reconstitution with 1mL of aromatase assay buffer. The contents were mixed thoroughly by vortexing to obtain a homogeneous solution (the solution would have a slightly opaque milky appearance) and the solution was transferred to a 15mL conical tube. The volume was increased to 2450. Mu.L using an Aromatase Assay Buffer, and 50. Mu.L of NADPH generating system (10X) was added to give a final total volume of 2.5mL.
Solutions containing test compound and corresponding no-inhibitor control, background control solution (without fluorescent aromatase substrate) and 5 μ M letrozole solution (5 × positive inhibition control solution, 1 μ M final concentration) were prepared. An aliquot of aromatase assay buffer was prepared containing an organic solvent to dissolve the test compound at a final concentration of 5 ×.
TABLE 2 solution formulation for each test well in aromatization enzyme test
No inhibitor (mu L) Test Compound (μ L) Negative control (. Mu.L) Positive control (μ L)
Aromatization enzyme stock solution (2X) 50 50 50 50
Test Compound solution (5X) -- 20 -- --
5 μ M letrozole solution (5X) -- -- -- 20
Aromatization enzyme buffer (5X) 20 -- 50 --
The Corning 384-well plate was incubated at 37 ℃ for at least 10 minutes to allow the test ligand to interact with the aromatase enzyme. Depending on the mechanism of action, the pre-incubation time can be optimized for other test ligands.
During incubation, aromatase substrate/NADP was prepared by adding 6. Mu.L of reconstituted 1mM aromatase + Mixture (3X) substrate stock solution and 50. Mu.L of reconstituted 10mM β -NADP + Store (100X) to 1444. Mu.L of aromatase assay buffer in a total volume of 1.5mL.
Add 30. Mu.l aromatase substrate/NADP to each well by using multichannel pipette + (3X) the mixture (except for background control) was started to react, resulting in a final reaction volume of 100. Mu.L/well.
Fluorescence was measured immediately (over 1 min) at Ex/Em =488/527nm in kinetic mode for 60 min. Δ F = (RFU) 2 –RFU 1 )，ΔT＝(T 2 –T 1 )。R＝(ΔF-ΔF BC )/ΔT。％Relative Inhibition＝(R SC –R TC )/R SC ×100％。
TABLE 3 OBHSA family of compounds with different five-membered nitrogen heterocyclic structures tested for their aromatase inhibiting activity (IC) 50 ,nM)
Figure BDA0003503622770000201
Figure BDA0003503622770000211
The 23 compounds tested in this example have certain inhibitory activity on aromatization enzymes, and it can be seen from the table that the compounds with imidazole substituent all have certain inhibitory activity on aromatization enzymes, and the compounds with N-methylpyrazole substituent have no inhibitory activity on aromatization enzymes.
[ example 19 ] determination of degradation Activity of Compounds 16a-r and 18a-d on ER α
Cells were incubated with DMSO or compound (5 μ M) for 24 hours. Whole proteins were extracted and analyzed for ER α protein levels by western blot. Proteins from cell lysates were separated using 8-% SDS-PAGE gel electrophoresis. The gel was then electroblotted onto polyvinylidene fluoride (PVDF) membranes, blocked with 5% skim milk, incubated with rabbit anti-era antibody (1. The membrane was washed 3 times 5 minutes with TBS containing 0.1% Tween-20. The membrane was then incubated with goat anti-rabbit secondary antibody for 1 hour at room temperature, and the membrane was washed with 0.1% tween-20 in TBS for 3 times 10 minutes. Taking the film to a dark room and developing the film by an X-ray film. The developed film is shot by a camera, and the film is put into Quantity One software for analysis and quantification.
Since sulfonamide compounds were found to have the effect of degrading ER α, this example was conducted to measure the ER α degrading activity of the sulfonamide compounds 16a-r and 18a-d, and the results are shown in FIG. 1. Protein immunoblot Western blot experiments were performed with 5 μ M selected for the drug concentration of all compounds including the control drug fulvestrant, taking into account the cell antiproliferative activity of the compounds. The results show that the compounds 16m, 16q, 16l and 16r have obvious protein degradation effect, the degradation effect of the compounds 16a-c has certain degradation effect, and other compounds have no degradation activity.

Claims (10)

1. An oxygen bridge bicyclo- [2.2.1] -heptene sulfonamide compound containing five-membered nitrogen heterocycle, which is characterized in that: has a structure represented by general formula I, II or III:
Figure FDA0004012253620000011
in the above formula, R 1 Is selected from
Figure FDA0004012253620000012
R 2 Is selected from CH 3 、CH 2 CH 3 、CH 2 CF 3 ，R 3 Selected from H, OCH 3 。
2. The five-membered nitrogen heterocycle-containing oxo-bridged bicyclo- [2.2.1] -heptene sulfonamide compound as claimed in claim 1, wherein: a compound selected from the group consisting of:
(1R, 4R) -6- (4- (1H-imidazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -N-methyl-N-phenyl-7-oxazolcyclo [2.2.1] hept-5-ene-2-sulfonamide,
(1R, 4R) -6- (4- (1H-imidazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -N-methyl-7-oxacyclo [2.2.1] hept-5-ene-2-sulfonamide,
(1R, 4R) -6- (4- (1H-imidazol-1-yl) phenyl) -N-ethyl-5- (4-hydroxyphenyl) -N-phenyl-7-oxazolcyclo [2.2.1] hept-5-ene-2-sulfonamide,
(1R,4R) -6- (4- (1H-imidazol-1-yl) phenyl) -N-ethyl-5- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -7-oxazolcyclo [2.2.1] hept-5-ene-2-sulfonamide,
(1R, 4R) -6- (4- (1H-imidazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -N-phenyl-N- (2, 2-trifluoroethyl) -7-oxacyclo [2.2.1] hept-5-ene-2-sulfonamide,
(1R, 4R) -6- (4- (1H-imidazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -N- (2, 2-trifluoroethyl) -7-oxacyclo [2.2.1] hept-5-ene-2-sulfonamide,
(1R, 4R) -6- (4- (1H-1, 2, 4-triazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -N-methyl-7-oxacyclo [2.2.1] hept-5-ene-2-sulfonamide,
(1R, 4R) -5- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -N-methyl-6- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -7-oxazolcyclo [2.2.1] hept-5-ene-2-sulfonamide,
(1R, 4R) -N-ethyl-5- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -6- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -7-oxazolcyclo [2.2.1] hept-5-ene-2-sulfonamide,
(1R,4R) -5- (4-hydroxyphenyl) -6- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -N-phenyl-N- (2, 2-trifluoroethyl) -7-oxazolcyclo [2.2.1] hept-5-ene-2-sulfonamide,
(1R,4R) -5- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -6- (4- (1-methyl-1H-pyrazolyl-4-yl) phenyl) -N- (2, 2-trifluoroethyl) -7-oxazolcyclo [2.2.1] hept-5-ene-2-sulfonamide,
(1R, 4R) -6- (4- (1H-1, 2, 4-triazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -N-methyl-7-oxacyclo [2.2.1] hept-5-ene-2-sulfonamide,
(1R, 4R) -N-ethyl-6- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -5- (1-methyl-1H-pyrazol-4-yl) -7-oxazol-cyclo [2.2.1] hept-5-ene-2-sulfonamide,
(1R, 4R) -N-ethyl-5- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -6- (1-methyl-1H-pyrazol-4-yl) -7-oxazol-cyclo [2.2.1] hept-5-ene-2-sulfonamide,
(1R, 4R) -6- (4- (1H-1, 2, 4-triazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -N-methyl-7-oxacyclo [2.2.1] hept-5-ene-2-sulfonamide,
(1R, 4R) -N-ethyl-6- (4-hydroxyphenyl) -N- (4-methoxyphenyl) -5- (1-methyl-1H-pyrazol-4-yl) -7-oxazolcyclo [2.2.1] hept-5-ene-2-sulfonamide.
3. The process for preparing oxygen-bridged bicyclo- [2.2.1] -heptene sulfonamide compound containing five-membered nitrogen heterocycle as claimed in claim 1, wherein:
the preparation method of the OBHSA compound containing the five-membered nitrogen heterocycle as shown in the general formula I comprises the following steps: furan derivatives containing five-membered nitrogen heterocycles and compounds containing R 2 And R 3 Preparing a compound with a structure shown in a general formula I by using a vinylsulfonamide derivative of a group through a Diels-Alder reaction;
the preparation method of the five-membered nitrogen heterocycle-containing OBHSA compound with the structure shown as the general formula II or III comprises the following steps: bromo-furan derivatives and compounds containing R 3 Preparing an intermediate product from a vinylsulfonamide derivative of the group through a Diels-Alder reaction, and coupling the intermediate product with (1-methyl-1H-pyrazol-4-yl) boric acid to obtain compounds shown in a general formula II and a general formula III;
the structural formula of the furan derivative containing five-membered nitrogen heterocycle is
Figure FDA0004012253620000031
The structural formula of the vinylsulfonamide derivative containing R2 and R3 groups is shown in the specification
Figure FDA0004012253620000032
The structural formula of the bromofuran derivative is shown in the specification
Figure FDA0004012253620000033
R3 group-containing ethenesulfonamide derivative
Figure FDA0004012253620000034
In each structural formula, R 1 Is selected from
Figure FDA0004012253620000035
R 2 Is selected from CH 3 、CH 2 CH 3 、CH 2 CF 3 ，R 3 Selected from H, OCH 3 。
4. The five-membered nitrogen heterocycle-containing oxo-bridged bicyclo- [2.2.1] -heptene sulfonamide compound as claimed in claim 1 or 2, which is a pharmaceutically acceptable salt.
5. The use of the oxo-bridged bicyclo- [2.2.1] -heptene sulfonamide compound containing five-membered nitrogen heterocycle or the pharmaceutically acceptable salt thereof as claimed in claim 1 or 2 for the preparation of a medicament, wherein: the drug is selected from the following classes of drugs: drugs for degrading estrogen receptors, anti-breast cancer drugs, drugs for inhibiting aromatase activity, and drugs for resisting endocrine therapy of breast cancer.
6. A drug for degrading an estrogen receptor, comprising: a bridged bicyclic- [2.2.1] -heptene sulfonamide compound containing a five-membered nitrogen heterocycle, or a pharmaceutically acceptable salt thereof, as claimed in claim 1 or 2.
7. An anti-breast cancer drug, which is characterized in that: a bridged bicyclic- [2.2.1] -heptene sulfonamide compound containing a five-membered nitrogen heterocycle, or a pharmaceutically acceptable salt thereof, as claimed in claim 1 or 2.
8. A medicament for inhibiting aromatase activity, characterized by: an oxido-bicyclo- [2.2.1] -heptene sulfonamide compound containing a five-membered nitrogen heterocycle, or a pharmaceutically acceptable salt thereof, as claimed in claim 1 or 2.
9. A drug resistant to endocrine therapy of breast cancer, which is characterized in that: a bridged bicyclic- [2.2.1] -heptene sulfonamide compound containing a five-membered nitrogen heterocycle, or a pharmaceutically acceptable salt thereof, as claimed in claim 1 or 2.
10. The medicament according to any one of claims 6 to 9, characterized in that: comprising one or more pharmaceutically acceptable carriers or excipients.
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