WO2022111202A1 - 一种3,5-二甲基-4-砜基-1h-吡咯类化合物、制备方法和用途 - Google Patents
一种3,5-二甲基-4-砜基-1h-吡咯类化合物、制备方法和用途 Download PDFInfo
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- WO2022111202A1 WO2022111202A1 PCT/CN2021/126883 CN2021126883W WO2022111202A1 WO 2022111202 A1 WO2022111202 A1 WO 2022111202A1 CN 2021126883 W CN2021126883 W CN 2021126883W WO 2022111202 A1 WO2022111202 A1 WO 2022111202A1
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- WIPO (PCT)
- Prior art keywords
- dimethyl
- pyrrole
- chloro
- sulfonyl
- methyl
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- 238000002360 preparation method Methods 0.000 title claims abstract description 33
- -1 2,6-dimethylphenyl Chemical group 0.000 claims abstract description 46
- 150000001875 compounds Chemical class 0.000 claims abstract description 29
- 101001056180 Homo sapiens Induced myeloid leukemia cell differentiation protein Mcl-1 Proteins 0.000 claims abstract description 20
- 102100026539 Induced myeloid leukemia cell differentiation protein Mcl-1 Human genes 0.000 claims abstract description 20
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 11
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims abstract description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 7
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims abstract description 5
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims abstract description 3
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims abstract description 3
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims abstract description 3
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims abstract description 3
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims abstract description 3
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims abstract description 3
- 125000004860 4-ethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])C([H])([H])[H] 0.000 claims abstract description 3
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims abstract description 3
- 125000004861 4-isopropyl phenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims abstract description 3
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims abstract description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 3
- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims abstract description 3
- UKJLNMAFNRKWGR-UHFFFAOYSA-N cyclohexatrienamine Chemical group NC1=CC=C=C[CH]1 UKJLNMAFNRKWGR-UHFFFAOYSA-N 0.000 claims abstract description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims abstract description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims abstract description 3
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims abstract description 3
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims abstract description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 3
- 239000000126 substance Substances 0.000 claims abstract description 3
- 239000000543 intermediate Substances 0.000 claims description 18
- 239000002994 raw material Substances 0.000 claims description 10
- ZETCAKSCCOXRKK-UHFFFAOYSA-N 2,4-dimethyl-3-sulfonyl-1,2-dihydropyrrole Chemical class CC1=CNC(C1=S(=O)=O)C ZETCAKSCCOXRKK-UHFFFAOYSA-N 0.000 claims description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 239000003112 inhibitor Substances 0.000 claims description 9
- WLHCBQAPPJAULW-UHFFFAOYSA-N 4-methylbenzenethiol Chemical compound CC1=CC=C(S)C=C1 WLHCBQAPPJAULW-UHFFFAOYSA-N 0.000 claims description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 8
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 claims description 7
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 206010028980 Neoplasm Diseases 0.000 claims description 5
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 5
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 5
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 4
- HAMGRBXTJNITHG-UHFFFAOYSA-N methyl isocyanate Chemical compound CN=C=O HAMGRBXTJNITHG-UHFFFAOYSA-N 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 230000007062 hydrolysis Effects 0.000 claims description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 239000001632 sodium acetate Substances 0.000 claims description 3
- 235000017281 sodium acetate Nutrition 0.000 claims description 3
- ZXSQEZNORDWBGZ-UHFFFAOYSA-N 1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical compound C1=CN=C2NC(=O)CC2=C1 ZXSQEZNORDWBGZ-UHFFFAOYSA-N 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 2
- 239000011230 binding agent Substances 0.000 claims description 2
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 230000003647 oxidation Effects 0.000 claims description 2
- 238000007254 oxidation reaction Methods 0.000 claims description 2
- 150000002923 oximes Chemical class 0.000 claims description 2
- 229910001958 silver carbonate Inorganic materials 0.000 claims description 2
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 claims description 2
- 235000010288 sodium nitrite Nutrition 0.000 claims description 2
- 150000003568 thioethers Chemical class 0.000 claims description 2
- 230000002401 inhibitory effect Effects 0.000 abstract description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 120
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 93
- 238000005481 NMR spectroscopy Methods 0.000 description 43
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 42
- 239000000047 product Substances 0.000 description 39
- 238000004128 high performance liquid chromatography Methods 0.000 description 36
- 238000000034 method Methods 0.000 description 34
- IZSBSZYFPYIJDI-UHFFFAOYSA-N ethyl 3,5-dimethyl-1h-pyrrole-2-carboxylate Chemical compound CCOC(=O)C=1NC(C)=CC=1C IZSBSZYFPYIJDI-UHFFFAOYSA-N 0.000 description 31
- WLFFUMRAIKHQJW-UHFFFAOYSA-N 5-(3-bromopropoxy)-2-chloro-1,3-dimethylbenzene Chemical compound CC1=CC(OCCCBr)=CC(C)=C1Cl WLFFUMRAIKHQJW-UHFFFAOYSA-N 0.000 description 27
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 25
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 22
- 239000011734 sodium Substances 0.000 description 22
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
- 239000012043 crude product Substances 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 14
- 239000012131 assay buffer Substances 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 11
- 239000012074 organic phase Substances 0.000 description 10
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- 238000002474 experimental method Methods 0.000 description 9
- 101000971171 Homo sapiens Apoptosis regulator Bcl-2 Proteins 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- 229910052938 sodium sulfate Inorganic materials 0.000 description 8
- 235000011152 sodium sulphate Nutrition 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
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- 238000012360 testing method Methods 0.000 description 8
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- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
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- BAUUHRNWNWTBAY-UHFFFAOYSA-N 4-benzylsulfonyl-1-[3-(4-chloro-3,5-dimethylphenoxy)propyl]-3,5-dimethylpyrrole-2-carboxylic acid Chemical compound C(C1=CC=CC=C1)S(=O)(=O)C=1C(=C(N(C1C)CCCOC1=CC(=C(C(=C1)C)Cl)C)C(=O)O)C BAUUHRNWNWTBAY-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
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- OZKVOILNGILNPM-UHFFFAOYSA-N 1-[3-(4-chloro-3,5-dimethylphenoxy)propyl]-3,5-dimethyl-4-(4-phenoxyphenyl)sulfonylpyrrole-2-carboxylic acid Chemical compound ClC1=C(C=C(OCCCN2C(=C(C(=C2C)S(=O)(=O)C2=CC=C(C=C2)OC2=CC=CC=C2)C)C(=O)O)C=C1C)C OZKVOILNGILNPM-UHFFFAOYSA-N 0.000 description 2
- PBVUCBTVMSAJGX-UHFFFAOYSA-N 1-[3-(4-chloro-3,5-dimethylphenoxy)propyl]-3,5-dimethyl-4-(4-phenylphenyl)sulfonylpyrrole-2-carboxylic acid Chemical compound C1(=CC=C(C=C1)S(=O)(=O)C=1C(=C(N(C1C)CCCOC1=CC(=C(C(=C1)C)Cl)C)C(=O)O)C)C1=CC=CC=C1 PBVUCBTVMSAJGX-UHFFFAOYSA-N 0.000 description 2
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- DGCTVLNZTFDPDJ-UHFFFAOYSA-N heptane-3,5-dione Chemical compound CCC(=O)CC(=O)CC DGCTVLNZTFDPDJ-UHFFFAOYSA-N 0.000 description 1
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- SEXOVMIIVBKGGM-UHFFFAOYSA-N naphthalene-1-thiol Chemical compound C1=CC=C2C(S)=CC=CC2=C1 SEXOVMIIVBKGGM-UHFFFAOYSA-N 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- LFYXRHWUNNOEGI-UHFFFAOYSA-N phenyl-(4-sulfanylphenyl)methanone Chemical compound C1=CC(S)=CC=C1C(=O)C1=CC=CC=C1 LFYXRHWUNNOEGI-UHFFFAOYSA-N 0.000 description 1
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- WHMDPDGBKYUEMW-UHFFFAOYSA-N pyridine-2-thiol Chemical compound SC1=CC=CC=N1 WHMDPDGBKYUEMW-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/36—Oxygen or sulfur atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- the invention belongs to the field of medicinal chemistry, and relates to the synthesis, preparation method and application of new compounds, in particular to a 3,5-dimethyl-4-sulfonyl-1H-pyrrole compound, preparation method and application.
- Apoptosis also known as programmed cell death, plays an important role in removing harmful and potentially dangerous cells and maintaining the intracellular environment.
- Mcl-1 is usually overexpressed in tumor cells and is closely related to the occurrence of cancer and drug resistance, so it has been intensively studied as a potential target for tumor therapy.
- Small molecule BH3 mimics can mimic the binding of BH3 domain to Mcl-1 protein to inhibit the interaction between Mcl-1 and pro-apoptotic proteins. This strategy has been widely used in the design of Mcl-1 small molecule inhibitors. In recent years, more and more small-molecule inhibitors have been reported, and some Mcl-1s with high activity and good druggability are undergoing clinical research and are expected to become new cancer treatment drugs.
- the purpose of the present invention is to provide a 3,5-dimethyl-4-sulfonyl-1H-pyrrole compound, a preparation method and an application.
- R2 is any one in H, methyl, ethyl, isopropyl
- R3 is any one of benzyl, 3-thienyl, 1-naphthyl, 2-pyridyl, cyclopentyl, cyclohexyl, -Ar, wherein Ar is 4-methylphenyl, 2,6-diphenyl Methylphenyl, 3,5-dimethylphenyl, 4-ethylphenyl, 4-isopropylphenyl, 4-tert-butylphenyl, 4-biphenyl, 4-fluorophenyl, 4 -Chlorophenyl, 4-bromophenyl, 4-acetylphenyl, 3-acetylphenyl, 2-acetylphenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2- Methoxyphenyl, 4-ethoxyphenyl, 4-phenoxyphenyl, 4-benzoyl and phenyl, 4-nitrophenyl, 4-aminophenyl, 4-carboxyphenyl, Monohydroxy-substi
- R1 and R2 are methyl groups, and R3 is defined as above, and the synthetic route is as follows:
- thiol compound raw materials form active intermediates under the action of triethylaminesulfonyl chloride, and react with raw materials I-1 to generate different thioether intermediates I-2; raw materials I-3 and I-4 are in acetonitrile, Use potassium carbonate as acid binding agent to carry out nucleophilic substitution reaction to obtain intermediate I-5; use cesium carbonate as base, carry out nucleophilic substitution reaction between I-2 and I-5 to obtain intermediate I-6, I-6 is subjected to m -CPBA is oxidized to generate I-7, and I-7 is hydrolyzed under the action of NaOH to generate different target products.
- the methyl-substituted or unsubstituted raw material II-1 and methyl isocyanate are refluxed to obtain intermediate II-2; cesium carbonate is used as a base, and II-2 is reacted with intermediate 5 to obtain intermediate II -3, II-3 was hydrolyzed to obtain the target product.
- R1 and R2 are methyl, ethyl or isobutyl, R3 is 4-methylphenyl, and the synthetic route is as follows:
- the raw material diethyl malonate is subjected to the action of sodium nitrite and acetic acid to generate oxime intermediate III-2, III-2 and different 2,4-dicarbonyl compounds, under the conditions of zinc powder and sodium acetate, reflux to obtain pyrrole Intermediate III-3, III-3 is reacted with 4-methylthiophenol to obtain III-6, which is then subjected to nucleophilic substitution reaction, oxidation and hydrolysis to obtain the target compound.
- the 3,5-dimethyl-4-sulfonyl-1H-pyrrole compounds provided by the invention have better Mcl-1 inhibitory activity, and can inhibit other subtypes Bcl-2 and Bcl-2 of the Bcl-2 anti-apoptotic protein family.
- -xL and Bfl-1 have good selectivity.
- the compounds showed good anti-tumor cell growth ability on Mcl-1 inhibitor-sensitive tumor cell lines.
- the crude product was recrystallized with DCM to obtain 0.3 g of a white solid with a yield of 58.0%.
- This product is obtained by hydrolysis of the above 1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-4-toluenesulfonyl-1H-pyrrole-2-carboxylate methyl ester compound, The method is the same as in Example 1.
- White powder 67 mg, yield: 69%.
- This product is composed of 1-methyl-4-(prop-1-en-1-ylsulfonyl)benzene, methyl isocyanate and 5-(3-bromopropoxy)-2-chloro-1,3- Dimethylbenzene was synthesized according to Example 2, yield: 72%.
- This product consists of 3,5-diethyl-1H-pyrrole-2-carboxylic acid ethyl ester, p-methylthiophenol and 5-(3-bromopropoxy)-2-chloro-1,3-dimethyl obtained from benzene, the preparation method is the same as that of Example 1, white solid, 120 mg, yield: 24%.
- This product is composed of diethyl malonate, 6-methyl-2,4-heptanedione, p-methylthiophenol and 5-(3-bromopropoxy)-2-chloro-1,3-dione
- the crude product was prepared from methylbenzene.
- the preparation method of the crude product was the same as that of Example 4.
- This product is composed of benzyl mercaptan, 3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester, 5-(3-bromopropoxy)-2-chloro-1,3-dimethylbenzene according to Prepared by the method of Example 1, yield: 62%.
- 1 H NMR(300MHz, CDCl3) ⁇ 7.32(s,3H),7.12(d,J 6.7Hz,2H),6.65(s,2H),4.45(s,2H),4.29(s,2H), 3.93(s, 2H), 2.59(s, 3H), 2.39(s, 6H), 2.10(s, 2H), 2.02(s, 3H).
- This product is composed of 2-mercaptopyridine, 3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester, 5-(3-bromopropoxy)-2-chloro-1,3-dimethylbenzene Prepared according to the method of Example 1, yield: 57%.
- This product is composed of 2-mercaptothiophene, 3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester, 5-(3-bromopropoxy)-2-chloro-1,3-dimethylbenzene Prepared according to the method of Example 1, yield: 54%.
- This product is composed of 1-naphthalenethiol, 3,5-dimethyl-1H-pyrrole-2-carboxylate ethyl ester, 5-(3-bromopropoxy)-2-chloro-1,3-dimethyl Benzene was prepared according to the method of Example 1, yield: 63%.
- This product is composed of cyclohexanethiol, 3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester, 5-(3-bromopropoxy)-2-chloro-1,3-dimethylbenzene Prepared according to the method of Example 1, yield: 57%.
- This product is composed of cyclopentanethiol, 3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester, 5-(3-bromopropoxy)-2-chloro-1,3-dimethylbenzene
- Yield 53%.
- This product is composed of 2,6-dimethylmercaptophenol, 3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester, 5-(3-bromopropoxy)-2-chloro-1,3 -Dimethylbenzene was prepared according to the method of Example 1, yield: 55%.
- This product is composed of 3,5-dimethylmercaptophenol, 3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester, 5-(3-bromopropoxy)-2-chloro-1,3 -Dimethylbenzene was prepared according to the method of Example 1, yield: 58%.
- This product is composed of 4-ethylthiophenol, 3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester, 5-(3-bromopropoxy)-2-chloro-1,3-diethyl ester Methylbenzene was prepared according to the method of Example 1, yield: 62%.
- This product is composed of p-isopropylthiophenol, 3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester, 5-(3-bromopropoxy)-2-chloro-1,3-diethyl ester Methylbenzene was prepared according to the method of Example 1, yield: 63%.
- This product is composed of 4-tert-butylthiophenol, 3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester, 5-(3-bromopropoxy)-2-chloro-1,3- Dimethylbenzene was prepared according to the method of Example 1, yield: 61%.
- This product is composed of 4-phenylthiophenol, 3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester, 5-(3-bromopropoxy)-2-chloro-1,3-diethyl ester Methylbenzene was prepared according to the method of Example 1, yield: 65%.
- This product is composed of p-fluorothiophenol, 3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester, 5-(3-bromopropoxy)-2-chloro-1,3-dimethyl Benzene was prepared according to the method of Example 1, yield: 68%.
- This product is composed of p-chlorothiophenol, 3,5-dimethyl-1H-pyrrole-2-carboxylate ethyl ester, 5-(3-bromopropoxy)-2-chloro-1,3-dimethyl Benzene was prepared according to the method of Example 1, yield: 64%.
- This product is composed of p-bromothiophenol, 3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester, 5-(3-bromopropoxy)-2-chloro-1,3-dimethyl Benzene was prepared according to the method of Example 1, yield: 67%.
- This product is composed of 4-acetylthiophenol, 3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester, 5-(3-bromopropoxy)-2-chloro-1,3-diethyl ester Methylbenzene was prepared according to the method of Example 1, yield: 42%.
- This product is composed of 4-methoxythiophenol, 3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester, 5-(3-bromopropoxy)-2-chloro-1,3- Dimethylbenzene was prepared according to the method of Example 1, yield: 56%.
- This product is composed of 4-nitrothiophenol, 3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester, 5-(3-bromopropoxy)-2-chloro-1,3-dicarbonate Methylbenzene was prepared according to the method of Example 1, yield: 63%.
- This product consists of 4-phenoxythiophenol, 3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester, 5-(3-bromopropoxy)-2-chloro-1,3- Dimethylbenzene was prepared according to the method of Example 1, yield: 65%.
- This product is composed of 4-benzoylthiophenol, 3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester, 5-(3-bromopropoxy)-2-chloro-1,3- Dimethylbenzene was prepared according to the method of Example 1, yield: 56%.
- This product consists of 1-(3-mercaptophenyl)ethanone, 3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester, 5-(3-bromopropoxy)-2-chloro-1 , 3-dimethylbenzene was prepared according to the method of Example 1, yield: 54%.
- This product is composed of 1-(2-mercaptophenyl)ethanone, 3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester, 5-(3-bromopropoxy)-2-chloro-1 , 3-dimethylbenzene was prepared according to the method of Example 1, yield: 59%.
- This product is composed of 3-methoxythiophenol, 3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester, 5-(3-bromopropoxy)-2-chloro-1,3- Dimethylbenzene was prepared according to the method of Example 1, yield: 67%.
- This product is composed of 2-ethoxythiophenol, 3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester, 5-(3-bromopropoxy)-2-chloro-1,3- Dimethylbenzene was prepared according to the method of Example 1, yield: 34%.
- This product is composed of 4-aminothiophenol, 3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester, 5-(3-bromopropoxy)-2-chloro-1,3-dimethyl Base benzene was prepared according to the method of Example 1, yield: 47%.
- This product is composed of 4-mercaptobenzoic acid, 3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester, 5-(3-bromopropoxy)-2-chloro-1,3-dimethyl Benzene was prepared according to the method of Example 1, yield: 65%.
- This product is composed of 4-hydroxythiophenol, 3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester, 5-(3-bromopropoxy)-2-chloro-1,3-dimethyl Base benzene was prepared according to the method of Example 1, yield: 76%.
- This product is composed of 3-hydroxythiophenol, 3,5-dimethyl-1H-pyrrole-2-carboxylate ethyl ester, 5-(3-bromopropoxy)-2-chloro-1,3-dimethyl Base benzene was prepared according to the method of Example 1, yield: 37%.
- This product is composed of 2-hydroxythiophenol, 3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester, 5-(3-bromopropoxy)-2-chloro-1,3-dimethyl Base benzene was prepared according to the method of Example 1, yield: 56%.
- Mcl-1 inhibitory activity test method a 384-well black plate (model Corning #3575) was used for the test, and the final test volume was 60 ⁇ L.
- the tested compounds and fluorescent probe GR16-NH2-FITC were dissolved in DMSO (10 mmol mother solution) for use.
- Compounds were diluted with assay buffer (20mM Tris, 150mM NaCl, 3mM DTT, pH 7.5) for 12 concentration gradients, and 20 ⁇ L of diluted compounds were added to each well plate, followed by 20 ⁇ L of diluted 5nM GR16-NH2 in assay buffer.
- -FITC and 5nM protein were used for the test, and the final test volume was 60 ⁇ L.
- assay buffer 20mM Tris, 150mM NaCl, 3mM DTT, pH 7.5
- inhibition rate (%) [1-(Ptest-Pmin)/(Pmax-Pmin)] ⁇ 100%, and IC 50 was calculated by Graphpad Prism 6.0 software.
- Test method for Bcl-2 inhibitory activity a 384-well black plate (Model Corning #3575) was used for the test, and the final test volume was 60 ⁇ L.
- inhibition rate (%) [1-(Ptest-Pmin)/(Pmax-Pmin)] ⁇ 100%.
- Test method for Bfl-1 inhibitory activity a 384-well black plate (model Corning #3575) was used for the test, and the final test volume was 60 ⁇ L.
- inhibition rate (%) [1-(Ptest-Pmin)/(Pmax-Pmin)] ⁇ 100%.
- the antiproliferative activity of the compounds of the present invention against human multiple myeloma cell line H929 was tested.
- the experimental method is as follows: select H929 tumor cells, inoculate the cells in a 96-well plate (about 4000 cells per well), incubate at 37°C under 5% CO 2 for 24 hours, and add compounds of different concentrations to the cells. After culturing for another 72 hours, 20 ⁇ l of MTT in PBS (concentration of 5 mg/ml) was added to each well, incubated at 37°C for 4 hours, MTT and medium were removed, and 150 ⁇ L of DMSO was added to each well, respectively. Detected at 490 nm (using a Thermo Multiskan Spectrum plate reader), the results were analyzed by Graphpad Prism6.
- the 3,5-dimethyl-4-sulfonyl-1H-pyrrole compounds provided by the invention have better Mcl-1 inhibitory activity, and can inhibit other subtypes Bcl-2 and Bcl-2 of the Bcl-2 anti-apoptotic protein family.
- -xL and Bfl-1 have good selectivity.
- these compounds showed good anti-tumor cell growth ability against Mcl-1 inhibitor-sensitive tumor cell line H929.
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Abstract
本发明公开了一种3,5-二甲基-4-砜基-1H-吡咯类化合物、制备方法和用途，化学结构为I。R1、R2为H、甲基、乙基或异丙基；R3为苄基、3-噻吩基、1-萘基、2-吡啶基、环戊基、环己基或-Ar，Ar为4-甲基苯基、2,6-二甲基苯基、3,5-二甲基苯基、4-乙基苯基、4-异丙基苯基、4-叔丁基苯基、4-联苯、4-氟苯基、4-氯苯基、4-溴苯基、4-乙酰基苯基、3-乙酰基苯基、2-乙酰基苯基、4-甲氧基苯基、3-甲氧基苯基、2-甲氧基苯基、4-乙氧基苯基、4-苯氧基苯基、4-苯甲酰及苯基、4-硝基苯基、4-氨基苯基、4-羧基苯基、不同位置单羟基取代的苯基。该化合物对Mcl-1抑制活性较好。
Description
本发明属于药物化学领域，涉及新化合物的合成、制备方法和用途，具体涉及一种3,5-二甲基-4-砜基-1H-吡咯类化合物、制备方法和用途。
细胞凋亡又称细胞程序性死亡，其对于清除有害细胞和潜在的危险细胞以及维持细胞内环境有重要作用。Mcl-1作为抗凋亡蛋白通常在肿瘤细胞中过表达，并且与癌症的发生和耐药性的产生密切相关，因而作为肿瘤治疗的潜在靶点被深入研究。
内源性凋亡通路中的一个重要过程是促凋亡蛋白Bax/Bak互相结合形成二聚体使线粒体外膜去极化，使得细胞色素c等凋亡因子外流，诱导下游凋亡信号通路转导。Mcl-1则能够通过其疏水沟槽与Bax/Bak结合抑制其二聚体的形成从而抑制细胞凋亡。
小分子的BH3模拟物能够模拟BH3结构域与Mcl-1蛋白的结合从而抑制Mcl-1与促凋亡蛋白的相互作用，这一策略被广泛地应用于Mcl-1小分子抑制剂的设计。近年来，越来越多小分子抑制剂被报道，一些具有高活性及良好成药性Mcl-1正在进行临床研究，有望成为新的癌症治疗药物。
发明内容
本发明的目的在于提供一种3,5-二甲基-4-砜基-1H-吡咯类化合物、制备方法和用途。
本发明上述目的通过如下技术方案实现：
一种3,5-二甲基-4-砜基-1H-吡咯类化合物，具有如下的化学结构：
其中，R1为H、甲基、乙基、异丙基中的任一种；
R2为H、甲基、乙基、异丙基中的任一种；
R3为苄基、3-噻吩基、1-萘基、2-吡啶基、环戊基、环己基、-Ar中的任一种，其中Ar为4-甲基苯基、2,6-二甲基苯基、3,5-二甲基苯基、4-乙基苯基、4-异丙基苯基、4-叔丁基苯基、4-联苯、4-氟苯基、4-氯苯基、4-溴苯基、4-乙酰基苯基、3-乙酰基苯基、2-乙酰基苯基、4-甲氧基苯基、3-甲氧基苯基、2-甲氧基苯基、4-乙氧基苯基、4-苯氧基苯基、4-苯甲酰及苯基、4-硝基苯基、4-氨基苯基、4-羧基苯基、不同位置单羟基取代的苯基。
上述3,5-二甲基-4-砜基-1H-吡咯类化合物的制备方法，R1和R2为甲基，R3的定义同上，合成路线如下：
不同种类的巯基化合物原料，在三乙胺磺酰氯的作用下形成活性中间体，与原料I-1反应生成不同的硫醚中间体I-2；原料I-3和I-4在乙腈中，以碳酸钾为缚酸剂，进行亲核取代反应得到中间体I-5；以碳酸铯为碱，I-2和I-5进行亲核取代反应得到中间体I-6，I-6经m-CPBA氧化生成I-7，I-7在NaOH作用下水解生成不同的目标产物。
上述3,5-二甲基-4-砜基-1H-吡咯类化合物的制备方法，R1为H，R2为H或者甲基，R3为4-甲基苯基，合成路线如下：
甲基取代或无取代的原料II-1与异腈酸甲酯在碳酸银的催化作用下，回流得到中间体II-2；碳酸铯作为碱，II-2与中间体5反应得到中间体II-3，II-3水解得到目标产物。
上述3,5-二甲基-4-砜基-1H-吡咯类化合物的制备方法，R1和R2为甲基、乙基或异丁基，R3为4-甲基苯基，合成路线如下：
原料丙二酸二乙酯在亚硝酸钠、醋酸作用下生成肟中间体III-2，III-2与不同的2,4-二羰基化合物，在锌粉、醋酸钠的条件下，回流得到吡咯中间体III-3，III-3与4-甲基苯硫酚反应得到III-6，再经亲核取代反应，氧化，水解得到目标物。
上述3,5-二甲基-4-砜基-1H-吡咯类化合物用于制备Mcl-1抑制剂的用途。
上述3,5-二甲基-4-砜基-1H-吡咯类化合物在制备治疗对Mcl-1抑制剂敏感的肿瘤的药物方面的应用。
本发明提供的3,5-二甲基-4-砜基-1H-吡咯类化合物具有较好的Mcl-1抑制活性，对Bcl-2抗凋亡蛋白家族的其他亚型Bcl-2、Bcl-xL和Bfl-1具有良好的选择性。此外，该类化合物对Mcl-1抑制剂敏感性肿瘤细胞株表现出了良好的抗肿瘤细胞生长的能力。
下面结合实施例具体介绍本发明实质性内容，但并不以此限定本发明的保护范围。
一、化合物制备
实施例1
1-(3-(4-氯-3,5-二甲基苯氧基)丙基)-3,5-二甲基-4-甲苯磺酰基-1H-吡咯-2-羧酸(DDO-1)的制备
(1)3,5-二甲基-4-(对甲苯硫基)-1H-吡咯-2-羧酸乙酯的制备
将4-甲基苯硫酚(2.5g，20mmol，2eq)、三乙胺(cat.)溶于30ml DCM，冰浴条件下缓慢滴加SO2Cl2(2eq)，撤去冰浴，室温条件下搅拌1h后将上述溶液加入到3,5-二甲基-1H-吡咯-2-羧酸乙酯(1eq)的DCM(30ml)溶液中，室温反应0.5h。反应完全后，缓慢加入饱和碳酸氢钠溶液至气泡完全消失，用DCM萃取(3次)，合并有机相，饱和食盐水洗、硫酸钠干燥、悬干溶剂，粗品用DCM重结晶，得到白色固体1.5g，产率51.9％。
(2)5-(3-溴丙氧基)-2-氯-1,3-二甲基苯的制备
将4-氯-3,5-二甲基苯酚(25.6mmol，4g，1eq)溶于40ml乙腈中，加入碳酸钾(3eq)、1,3-二溴丙烷(3eq)，回流3h。反应完全后冷却至室温，加入150ml水，EA萃取3次，合并有机相，饱和食盐水洗、硫酸钠干燥，悬干有机相，制砂，柱层析(PE)，得无色液体6g，产率85.2％。
(3)标题化合物的制备
将上述3,5-二甲基-4-(对甲苯硫基)-1H-吡咯-2-羧酸乙酯(1mmol，0.289g，1eq)溶于20ml DMF中，加入碳酸铯(2eq)，50℃搅拌5min后加入上述5-(3-溴丙氧基)-2-氯-1,3-二甲基苯(2eq)，反应完全后冷却至室温，加入60ml水，EA萃取3次，合并有机相，饱和食盐水洗、硫酸钠干燥，悬干有机相，制砂，柱层析(EA：PE＝20:1)得到无色液体0.35g，产率76.4％。上述无色液体(0.35g，0.76mmol)溶于DCM 20ml中，冰浴条件下加入m-CPBA(2eq)，室温搅拌0.5h，反应完全后，缓慢加入饱和碳酸氢钠溶20ml，用DCM萃取(3次)，合并有机相、饱和食盐水洗、硫酸钠干燥、悬干溶剂，粗品用DCM重结晶，得到白色固体0.3g，产率58.0％。将上述白色固体(0.3g，0.58mmol，1eq)溶于乙醇/四氢呋喃混合溶液(7ml/7ml)，加入NaOH(2M，10eq)，50℃加热搅拌过夜，反应完全后冷却至室温，加1M HCl至pH＝1，过滤、水洗滤饼、干燥得淡黄色固体0.252g，产率95％。
1H NMR(300MHz,CDCl
3)δ7.40(d,J＝8.1Hz,2H),7.29(d,J＝6.1Hz,2H),6.63(s,2H),4.49(t,J＝6.7Hz,2H),3.88(t,J＝5.3Hz,2H),2.42(s,3H),2.38(s,3H),2.36(s,9H),2.18(m,J＝12.3,6.4Hz,2H).HRMS(ESI):calcd for C
25H
28ClNO
3S[M-H]
-457.1398,found 456.1399.HPLC(80:20 methanol:water with 1‰TFA):t
R＝8.251min,96.115％.
实施例2
1-(3-(4-氯-3,5-二甲基苯氧基)丙基)-4-甲苯磺酰基-1H-吡咯-2-羧酸(DDO-2)的制备
(1)4-甲苯磺酰基-1H-吡咯-2-羧酸甲酯的制备
在1-(乙炔基磺酰基)-4-甲基苯(500mg,3mmol)，Ag
2CO
3(0.1eq)和1,4-二氧六环(20ml)的混合物中加入异腈酸甲酯(1eq)，80℃加热1h。反应完全后冷却至室温后加入60ml水EA萃取3次，合并有机相、饱和食盐水洗、硫酸钠干燥、悬干溶剂得粗品。粗品柱层析(PE：EA＝8：1)得黄色油状物150mg，产率:18％。
(2)1-(3-(4-氯-3,5-二甲基苯氧基)丙基)-4-甲苯磺酰基-1H-吡咯-2-羧酸甲酯的制备
在4-甲苯磺酰基-1H-吡咯-2-羧酸甲酯(150mg,0.5mmol)的DMF溶液中，加入Cs
2CO
3(2eq)，50℃搅拌5min后，加入实施例1中制得的5-(3-溴丙氧基)-2-氯-1,3-二甲基苯。反应完全后冷却至室温，加入60ml水，EA萃取3次，合并有机相，饱和食盐水洗、硫酸钠干燥，悬干有机相，制砂，柱层析(EA：PE＝20:1)得到黄色油状物100mg，产率:42％。
(3)标题化合物的制备
本品用上述1-(3-(4-氯-3,5-二甲基苯氧基)丙基)-4-甲苯磺酰基-1H-吡咯-2-羧酸甲酯化合物经水解得到，方法同实施例1。白色粉末67mg，产率:69％。
1H NMR(300MHz,DMSO)δ12.89(s,1H),7.81(s,1H),7.72(d,J＝6.8Hz,2H),7.34(d,J＝7.9Hz,2H),7.05(s,1H),6.71(s,2H),4.46(t,J＝5.1Hz,2H),3.83(t,J＝6.2Hz,2H),2.35(s,3H),2.28(s,6H),2.17–2.08(m,2H).HRMS(ESI):calcd for C
23H
24ClNO
5S[M+NH4]
+479.1402,found 479.1402.HPLC(80:20 methanol:water with 1‰TFA):t
R＝8.076min,96.038％.
实施例3
1-(3-(4-氯-3,5-二甲基苯氧基)丙基)-3-甲基-4-甲苯磺酰基-1H-吡咯-2-羧酸(DDO-3)的制备
本品由1-甲基-4-(丙-1-烯-1-基磺酰基)苯、异腈酸甲酯和5-(3-溴丙氧基)-2-氯-1,3-二甲基苯按照实施例2合成，产率:72％。
1H NMR(300MHz,CDCl
3)δ7.71(d,J＝8.2Hz,2H),7.54(s,1H),7.26(d,J＝8.2Hz,2H),6.64(s,2H),4.54(t,J＝6.5Hz,2H),3.83(t,J＝5.5Hz,2H),2.48(s,3H),2.44(s,3H),2.38(s,6H),2.25(dt,J＝11.6,5.8Hz,2H).HRMS(ESI):calcd for C
24H
26ClNO
5S[M+Na]
+498.1112,found 498.1116.HPLC(80:20 methanol:water with 1‰TFA):t
R＝9.083min,98.189％.
实施例4
1-(3-(4-氯-3,5-二甲基苯氧基)丙基)-3,5-二乙基-4-甲苯磺酰基-1H-吡咯-2-羧酸(DDO-4)的制备
(1)3,5-二乙基-1H-吡咯-2-羧酸乙酯的制备
0℃条件下，在丙二酸二乙酯(3.2g,20mmol，1eq)中加入NaNO
2溶液(6M,3eq)。室温搅拌24h，反应液用二氯甲烷萃取3次，合并有机相、饱和食盐水洗、硫酸钠干燥。悬干溶剂得粗品无色液体2g。
在上述无色液体中加入冰醋酸(100mL)、3,5-庚二酮(1eq)、锌粉(3eq)和乙酸钠(3eq)，混合物搅拌加热回流2h。反应完全后，反应液冷却至室温，过滤，滤液加入300ml水，用EA萃取3次，合并有机相、饱和食盐水洗、硫酸钠干燥，悬干得粗品，粗品柱层析(PE：EA＝15:1)纯化得到白色固体500mg，产率:12％。
(2)标题化合物的制备
本品由3,5-二乙基-1H-吡咯-2-羧酸乙酯、对甲基苯硫酚和5-(3-溴丙氧基)-2-氯-1,3-二甲基苯制得，制备方法同实施例1，白色固体，120mg，产率:24％。
1H NMR(300MHz,CDCl3)δ7.76(d,J＝8.2Hz,2H),7.28(s,2H),6.64(s,2H),4.53(t,J＝7.1Hz,2H),3.93(t,J＝5.4Hz,2H),3.15(q,J＝7.4Hz,2H),3.06(q,J＝7.3Hz,2H),2.45(s,3H),2.37(s,6H),2.26–2.15(m,2H),1.27(t,J＝7.4Hz,3H),1.09(t,J＝7.3Hz,3H).HRMS(ESI):calcd for C
27H
32ClNO
5S[M+Na]
+540.1582,found 540.1582.HPLC(80:20 methanol:water with 1‰TFA):t
R＝16.018min,96.009％.
实施例5
1-(3-(4-氯-3,5-二甲基苯氧基)丙基)-3-乙基-5-甲基-4-甲苯磺酰基-1H-吡咯-2-羧酸(DDO-5)的制备
本品由丙二酸二乙酯、2,4-己二酮、对甲基苯硫酚和5-(3-溴丙氧基)-2-氯-1,3-二甲基苯制得，粗品的制备方法同实施例4，粗品经柱层析(DCM；MeOH＝20:1)得到白色固体46mg，产率56％。
1H NMR(300MHz,DMSO)δ12.84(s,1H),7.66(d,J＝8.1Hz,2H),7.36(d,J＝7.9Hz,2H),6.73(s,2H),4.42(t,J＝6.2,2H),3.88(t,J＝5.0Hz,2H),2.87(q,J＝7.3Hz,2H),2.54(s,3H),2.35(s,3H),2.28(s,6H),2.04(dt,J＝10.9,5.4Hz,2H),0.94(t,J＝6.8Hz,3H).HRMS(ESI):calcd for C
26H
30ClNO
5S[M+Na]
+526.1425,found 526.1426.HPLC(80:20 methanol:water with 1‰TFA):t
R＝12.782min,98.091％.
实施例6
1-(3-(4-氯-3,5-二甲基苯氧基)丙基)-3-乙基-5-甲基-4-甲苯磺酰基-1H-吡咯-2-羧酸(DDO-6)的制备
本品由丙二酸二乙酯、2,4-己二酮、对甲基苯硫酚和5-(3-溴丙氧基)-2-氯-1,3-二甲基苯 制得，粗品的制备方法同实施例4，粗品经柱层析(DCM；MeOH＝20:1)得到白色固体55mg，产率62％。
1H NMR(300MHz,DMSO)δ7.64(d,J＝8.9Hz,2H),6.98(d,J＝8.9Hz,2H),6.63(s,2H),4.29(t,J＝6.7Hz,2H),4.09(q,J＝7.1Hz,2H),3.79(t,J＝5.6Hz,2H),2.46(s,3H),2.26(s,3H),2.18(s,6H),1.93(s,2H),1.14(t,J＝7.1Hz,3H).HRMS(ESI):calcd for C
26H
30ClNO
5S[M+Na]
+526.1425,found 526.1425.HPLC(80:20 methanol:water with 1‰TFA):t
R＝14.702min,97.737％.
实施例7
1-(3-(4-氯-3,5-二甲基苯氧基)丙基)-5-异丁基-3-甲基-4-甲苯基-1H-吡咯-2-羧酸(DDO-7)的制备
本品由丙二酸二乙酯、6-甲基-2,4-庚二酮、对甲基苯硫酚和5-(3-溴丙氧基)-2-氯-1,3-二甲基苯制得，粗品的制备方法同实施例4，粗品经柱层析(DCM；MeOH＝20:1)得到白色固体63mg，产率71％。
1H NMR(300MHz,DMSO)δ12.89(s,1H),7.59(d,J＝7.8Hz,2H),7.31(d,J＝7.7Hz,2H),6.70(s,2H),4.51–4.33(m,2H),3.81(t,J＝5.1Hz,2H),2.82(d,J＝6.9Hz,2H),2.46(s,3H),2.32(s,3H),2.25(s,6H),2.00(s,2H),1.77(s,1H),0.76(d,J＝6.3Hz,6H).HRMS(ESI):calcd for C
28H
34ClNO
5S[M+NH4]
+549.2184,found 549.2180.HPLC(80:20 methanol:water with 1‰TFA):t
R＝16.854min,97.336％.
实施例8
1-(3-(4-氯-3,5-二甲基苯氧基)丙基)-3-异丁基-5-甲基-4-甲苯基-1H-吡咯-2-羧酸(DDO-8)的制备
本品由丙二酸二乙酯、6-甲基-2,4-庚二酮、对甲基苯硫酚和5-(3-溴丙氧基)-2-氯-1,3-二甲基苯制得，粗品的制备方法同实施例4，粗品经柱层析(DCM；MeOH＝20:1)得到白色固体75mg，产率86％。
1H NMR(300MHz,DMSO)δ12.94(s,1H),7.55(d,J＝8.0Hz,2H),7.31(d,J＝8.0Hz,2H),6.71(s,2H),4.42(t J＝6.7Hz,2H),3.79(t,J＝5.6Hz,2H),2.88(d,J＝7.3Hz,2H),2.33(s,3H),2.26(s,6H),2.24(s,3H),2.00–1.88(m,3H),0.87(d,J＝6.4Hz,6H).HRMS(ESI):calcd for C
28H
34ClNO
5S[M+NH4]
+549.2184,found 549.2185.HPLC(80:20 methanol:water with 1‰TFA):t
R＝22.916min,96.785％.
实施例9
4-(苄基磺酰基)-1-(3-(4-氯-3,5-二甲基苯氧基)丙基)-3,5-二甲基-1H-吡咯-2-羧酸(DDO-9)
本品由苄硫醇、3,5-二甲基-1H-吡咯-2-羧酸乙酯、5-(3-溴丙氧基)-2-氯-1,3-二甲基苯按照实施例1的方法制备，产率:62％。
1H NMR(300MHz,CDCl3)δ7.32(s,3H),7.12(d,J＝6.7Hz,2H),6.65(s,2H),4.45(s,2H),4.29(s,2H),3.93(s,2H),2.59(s,3H),2.39(s,6H),2.10(s,2H),2.02(s,3H).HRMS(ESI):calcd for C
25H
28ClNO
5S[M+Na]
+512.1275,found 512.1266.HPLC(80:20 methanol:water with 1‰TFA):t
R＝9.794min,97.934％.
实施例10
1-(3-(4-氯-3,5-二甲基苯氧基)丙基)-3,5-二甲基-4-(吡啶-2-基磺酰基)-1H-吡咯-2-羧酸(DDO-10)
本品由2-巯基吡啶、3,5-二甲基-1H-吡咯-2-羧酸乙酯、5-(3-溴丙氧基)-2-氯-1,3-二甲基苯按照实施例1的方法制备，产率:57％。
1H NMR(300MHz,DMSO-d
6)δ12.74(s,1H),8.64(d,J＝3.7Hz,1H),8.08(s,2H),7.63(s,1H),6.73(s,2H),4.42(s,2H),3.87(s,2H),2.53(s,3H),2.39(s,3H),2.28(s,6H),2.03(s,2H).HRMS(ESI):calcd for C
25H
28ClNO
3S[M+H]
+477.1253,found 477.1242.HPLC(80:20 methanol:water with 1‰TFA):t
R＝6.488min,98.051％.
实施例11
1-(3-(4-氯-3,5-二甲基苯氧基)丙基)-3,5-二甲基-4-(噻吩-2-基磺酰基)-1H-吡咯-2-羧酸(DDO-11)
本品由2-巯基噻吩、3,5-二甲基-1H-吡咯-2-羧酸乙酯、5-(3-溴丙氧基)-2-氯-1,3-二甲基 苯按照实施例1的方法制备，产率:54％。
1H NMR(300MHz,DMSO-d
6)δ12.91(s,1H),7.95(s,1H),7.65(s,1H),7.15(s,1H),6.73(s,2H),4.42(s,2H),3.87(s,2H),2.54(s,3H),2.44(s,3H),2.28(s,6H),2.03(s,2H).HRMS(ESI):calcd for C
22H
24ClNO
5S
2[M+Na]
+504.0682,found 504.0686.HPLC(80:20 methanol:water with 1‰TFA):t
R＝8.641min,98.534％.
实施例12
1-(3-(4-氯-3,5-二甲基苯氧基)丙基)-3,5-二甲基-4-(萘-1-基磺酰基)-1H-吡咯-2-羧酸(DDO-12)
本品由1-萘硫酚、3,5-二甲基-1H-吡咯-2-羧酸乙酯、5-(3-溴丙氧基)-2-氯-1,3-二甲基苯按照实施例1的方法制备，产率:63％。
1H NMR(300MHz,DMSO-d
6)δ12.88(s,1H),8.43–8.33(m,1H),8.24(d,J＝8.2Hz,1H),8.16(d,J＝7.2Hz,1H),8.11–8.01(m,1H),7.68(t,J＝7.8Hz,1H),7.60(dd,J＝6.3,3.3Hz,2H),6.70(s,2H),4.44(t,J＝6.7Hz,2H),3.84(t,J＝5.5Hz,2H),2.61(s,3H),2.27(s,6H),2.24(s,3H),2.10–1.99(m,2H).HRMS(ESI):calcd for C
28H
28ClNO
5S[M+Na]
+548.1275,found 548.1266.HPLC(80:20 methanol:water with 1‰TFA):t
R＝13.955min,95.107％.
实施例13
1-(3-(4-氯-3,5-二甲基苯氧基)丙基)-4-(环己基磺酰基)-3,5-二甲基-1H-吡咯-2-羧酸(DDO-13)
本品由环己硫醇、3,5-二甲基-1H-吡咯-2-羧酸乙酯、5-(3-溴丙氧基)-2-氯-1,3-二甲基苯按照实施例1的方法制备，产率:57％。
1H NMR(300MHz,CDCl3)δ6.61(s,2H),4.53(s,2H),3.87(s,2H),3.40(s,1H),2.61(d,J＝13.0Hz,6H),2.34(s,6H),2.18(s,2H),2.07–1.52(m,10H).HRMS(ESI):calcd for C
24H
32ClNO
5S[M+Na]
+504.1587,found 504.1580.HPLC(80:20 methanol:water with 1‰TFA):t
R＝9.162min,96.493％.
实施例14
1-(3-(4-氯-3,5-二甲基苯氧基)丙基)-4-(环戊基磺酰基)-3,5-二甲基-1H-吡咯-2-羧酸(DDO-14)
本品由环戊硫醇、3,5-二甲基-1H-吡咯-2-羧酸乙酯、5-(3-溴丙氧基)-2-氯-1,3-二甲基苯按照实施例1的方法制备，产率:53％。
1H NMR(300MHz,CDCl3)δ6.61(s,2H),4.53(s,2H),3.87(s,2H),3.40(s,1H),2.61(d,J＝13.0Hz,6H),2.34(s,6H),2.18(s,2H),2.01–1.60(m,8H).HRMS(ESI):calcd for C
23H
30ClNO
5S[M+NH4]
+485.1877,found 485.1877.
实施例15
1-(3-(4-氯-3,5-二甲基苯氧基)丙基)-4-((2,6-二甲基苯基)磺酰基)-3,5-二甲基-1H-吡咯-2-羧酸(DDO-15)
本品由2,6-二甲基巯基苯酚、3,5-二甲基-1H-吡咯-2-羧酸乙酯、5-(3-溴丙氧基)-2-氯-1,3-二甲基苯按照实施例1的方法制备，产率:55％。
1H NMR(300MHz,CDCl3)δ7.32(t,J＝8.5Hz,1H),7.12(d,J＝7.6Hz,2H),6.61(s,2H),4.54(t,J＝6.9Hz,2H),3.89(t,J＝5.4Hz,2H),2.60(s,6H),2.57(s,3H),2.36(s,6H),2.30(s,3H),2.23–2.14(m,2H).HRMS(ESI):calcd for C
26H
30ClNO
5S[M+Na]
+526.1425,found 526.1423.HPLC(80:20 methanol:water with 1‰TFA):t
R＝15.329min,97.155％.
实施例16
1-(3-(4-氯-3,5-二甲基苯氧基)丙基)-4-((3,5-二甲基苯基)磺酰基)-3,5-二甲基-1H-吡咯-2-羧酸(DDO-16)
本品由3,5-二甲基巯基苯酚、3,5-二甲基-1H-吡咯-2-羧酸乙酯、5-(3-溴丙氧基)-2-氯-1,3-二甲基苯按照实施例1的方法制备，产率:58％。
1H NMR(300MHz,CDCl3)δ7.49(s,2H),7.20(s,1H),6.63(s,2H),4.53(t,J＝7.0Hz,2H),3.91(t,J＝5.5Hz,2H),2.68(s,3H),2.61(s,3H), 2.39(s,6H),2.36(s,6H),2.23–2.13(m,2H).HRMS(ESI):calcd for C
26H
30ClNO
5S[M+Na]
+526.1425,found 526.1425.HPLC(80:20 methanol:water with 1‰TFA):t
R＝15.590min,96.092％.
实施例17
1-(3-(4-氯-3,5-二甲基苯氧基)丙基)-4-((4-乙基苯基)磺酰基)-3,5-二甲基-1H-吡咯-2-羧酸(DDO-17)
本品由4-乙基苯硫酚、3,5-二甲基-1H-吡咯-2-羧酸乙酯、5-(3-溴丙氧基)-2-氯-1,3-二甲基苯按照实施例1的方法制备，产率:62％。
1H NMR(300MHz,CDCl3)δ7.79(d,J＝8.3Hz,2H),7.33(d,J＝8.3Hz,2H),6.63(s,2H),4.52(t,J＝7.0Hz,2H),3.96–3.84(m,2H),2.81–2.70(m,2H),2.69(d,J＝4.3Hz,3H),2.59(s,3H),2.37(d,J＝7.5Hz,6H),2.17(t,J＝6.3Hz,2H),1.28(t,J＝7.6Hz,3H).HRMS(ESI):calcd for C
26H
30ClNO
5S[M+Na]
+526.1431,found 526.1424.HPLC(80:20 methanol:water with 1‰TFA):t
R＝15.275min,98.986％.
实施例18
1-(3-(4-氯-3,5-二甲基苯氧基)丙基)-4-((4-异丙基苯基)磺酰基)-3,5-二甲基-1H-吡咯-2-羧酸(DDO-18)
本品由对异丙基苯硫酚、3,5-二甲基-1H-吡咯-2-羧酸乙酯、5-(3-溴丙氧基)-2-氯-1,3-二甲基苯按照实施例1的方法制备，产率:63％。
1H NMR(300MHz,DMSO)δ12.88(s,1H),7.69(d,J＝8.2Hz,2H),7.40(d,J＝8.3Hz,2H),6.72(s,2H),4.39(t,J＝6.8Hz,2H),3.85(d,J＝5.2Hz,2H),2.92(dt,J＝13.5,6.8Hz,1H),2.54(s,3H),2.35(s,3H),2.26(s,6H),2.01(s,2H),1.16(d,J＝6.9Hz,6H).HRMS(ESI):calcd for C
27H
32ClNO
5S[M+Na]
+540.1587,found 540.1577.HPLC(80:20 methanol:water with 1‰TFA):t
R＝20.331min,97.317％.
实施例19
4-((4-(叔丁基)苯基)磺酰基)-1-(3-(4-氯-3,5-二甲基苯氧基)丙基)-3,5-二甲基-1H-吡咯-2-羧酸(DDO-19)
本品由4-叔丁基苯硫酚、3,5-二甲基-1H-吡咯-2-羧酸乙酯、5-(3-溴丙氧基)-2-氯-1,3-二甲基苯按照实施例1的方法制备，产率:61％。
1H NMR(300MHz,DMSO)δ12.79(s,1H),7.62(d,J＝8.2Hz,2H),7.48(d,J＝8.3Hz,2H),6.65(s,2H),4.31(s,2H),3.79(s,2H),2.47(s,3H),2.28(s,3H),2.18(s,6H),1.94(s,2H),1.17(s,9H).HRMS(ESI):calcd for C
28H
34ClNO
5S[M+Na]
+554.1744,found 554.1736.HPLC(80:20 methanol:water with 1‰TFA):t
R＝25.537min,95.823％.
实施例20
4-([1,1'-联苯]-4-基磺酰基)-1-(3-(4-氯-3,5-二甲基苯氧基)丙基)-3,5-二甲基-1H-吡咯-2-羧酸(DDO-20)
本品由4-苯基苯硫酚、3,5-二甲基-1H-吡咯-2-羧酸乙酯、5-(3-溴丙氧基)-2-氯-1,3-二甲基苯按照实施例1的方法制备，产率:65％。
1H NMR(300MHz,DMSO-d
6)δ12.93(s,1H),7.93–7.37(m,9H),6.74(s,2H),4.42(s,2H),3.88(s,2H),2.59(s,3H),2.41(s,3H),2.26(s,6H),2.05(s,2H).
13C NMR(75MHz,CDCl3)δ166.34(s),156.23(s),145.58(s),142.30(s),140.64(s),139.26(s),137.22(s),132.89(s),129.06(s),128.50(s),127.56(d,J＝18.9Hz),127.30(s),126.85(s),126.58(s),120.29(s),119.15(s),114.31(s),64.51(s),43.00(s),30.45(s),20.95(s),12.18(s),11.26(s).HRMS(ESI):calcd for C
30H
30ClNO
5S[M+H]
+552.1611,found 552.1603.HPLC(80:20 methanol:water with 1‰TFA):t
R＝2.076min,98.474％.
实施例21
1-(3-(4-氯-3,5-二甲基苯氧基)丙基)-4-((4-氟苯基)磺酰基)-3,5-二甲基-1H-吡咯-2-羧酸(DDO-21)
本品由对氟苯硫酚、3,5-二甲基-1H-吡咯-2-羧酸乙酯、5-(3-溴丙氧基)-2-氯-1,3-二甲基苯按照实施例1的方法制备，产率:68％。
1H NMR(300MHz,DMSO)δ12.83(s,1H),7.76(d,J＝5.3Hz,1H),7.65(dd,J＝16.2,8.5Hz,2H),7.29(t,J＝8.8Hz,1H),6.63(s,2H),4.32(t,J＝6.9Hz,2H),3.77(t,J＝4.9Hz,2H),2.44(s,3H),2.27(s,3H),2.18(s,6H),1.94(s,2H).HRMS(ESI):calcd for C
24H
25ClFNO
5S[M+Na]
+516.1024,found 516.1021.HPLC(80:20 methanol:water with 1‰TFA):t
R＝10.369min,95.484％.
实施例22
1-(3-(4-氯-3,5-二甲基苯氧基)丙基)-4-((4-氯苯基)磺酰基)-3,5-二甲基-1H-吡咯-2-羧酸(DDO-22)
本品由对氯苯硫酚、3,5-二甲基-1H-吡咯-2-羧酸乙酯、5-(3-溴丙氧基)-2-氯-1,3-二甲基苯按照实施例1的方法制备，产率:64％。
1H NMR(300MHz,DMSO)δ12.93(s,1H),7.80(d,J＝8.5Hz,2H),7.62(d,J＝8.7Hz,2H),6.73(s,2H),4.42(t,J＝8.1Hz,2H),3.87(t,J＝4.7Hz,2H),2.54(s,3H),2.36(s,3H),2.28(s,6H),2.04(s,2H).HRMS(ESI):calcd for C
24H
25Cl
2NO
5S[M+Na]
+532.0728,found 532.0726.HPLC(80:20 methanol:water with 1‰TFA):t
R＝15.248min,95.159％.
实施例23
4-((4-溴苯基)磺酰基)-1-(3-(4-氯-3,5-二甲基苯氧基)丙基)-3,5-二甲基-1H-吡咯-2-羧酸(DDO-23)
本品由对溴苯硫酚、3,5-二甲基-1H-吡咯-2-羧酸乙酯、5-(3-溴丙氧基)-2-氯-1,3-二甲基苯按照实施例1的方法制备，产率:67％。
1H NMR(300MHz,DMSO)δ12.83(s,1H),7.65(dd,J＝16.7,8.6Hz,4H),6.63(s,2H),4.32(t,J＝5.6Hz,2H),3.78(t,J＝5.0Hz,2H),2.43(d,J＝6.2Hz,3H),2.27(s,3H),2.18(s,6H),1.94(s,2H).
13C NMR(75MHz,DMSO)δ162.52(s),156.71(s),143.29(s),139.57(s),136.97(s),132.96(s),128.30(s),127.98(s),127.18(s),125.57(s),121.34(s),118.10(s),115.05(s),65.20(s),60.21(s),42.94(s),30.18(s),20.90(s),11.94(s),11.09(s).HRMS(ESI):calcd for C
24H
25BrClNO
5S[M+Na]
+578.0203,found 578.0198.HPLC(80:20 methanol:water with 1‰TFA):t
R＝16.322min,97.869％.
实施例24
4-((4-乙酰苯基)磺酰基)-1-(3-(4-氯-3,5-二甲基苯氧基)丙基)-3,5-二甲基-1H-吡 咯-2-羧酸(DDO-24)
本品由4-乙酰基苯硫酚、3,5-二甲基-1H-吡咯-2-羧酸乙酯、5-(3-溴丙氧基)-2-氯-1,3-二甲基苯按照实施例1的方法制备，产率:42％。
1H NMR(300MHz,DMSO)δ12.93(s,1H),8.07(d,J＝8.3Hz,2H),7.90(d,J＝8.3Hz,2H),6.71(s,2H),4.40(t,J＝6.7Hz,2H),3.85(t,J＝5.9Hz,2H),2.59(s,3H),2.54(s,3H),2.35(s,3H),2.25(s,6H),2.01(s,2H).
13C NMR(75MHz,DMSO)δ197.73(s),162.57(s),156.74(s),139.28(s),137.99(s),137.00(s),129.13(s),125.34(d,J＝37.2Hz),121.06(s),115.06(s),65.13(s),42.77(s),30.37(s),27.29(s),20.89(s),11.57(s),10.56(s).HRMS(ESI):calcd for C
26H
28ClNO
6S[M+Na]
+540.1218,found 540.1217.HPLC(80:20 methanol:water with 1‰TFA):t
R＝7.502min,97.428％.
实施例25
1-(3-(4-氯-3,5-二甲基苯氧基)丙基)-4-((4-甲氧基苯基)磺酰基)-3,5-二甲基-1H-吡咯-2-羧酸(DDO-25)
本品由4-甲氧基苯硫酚、3,5-二甲基-1H-吡咯-2-羧酸乙酯、5-(3-溴丙氧基)-2-氯-1,3-二甲基苯按照实施例1的方法制备，产率:56％。
1H NMR(300MHz,DMSO)δ12.79(s,1H),7.72(d,J＝8.6Hz,2H),7.06(d,J＝8.6Hz,2H),6.73(s,2H),4.40(t,J＝6.1Hz,2H),3.87(t,J＝4.3Hz,2H),2.53(s,3H),2.36(s,3H),2.28(s,6H),2.02(s,2H).
13C NMR(75MHz,DMSO)δ162.72(d,J＝19.1Hz),156.72(s),138.83(s),136.97(s),135.89(s),128.49(s),127.77(s),125.56(s),120.99(s),119.55(s),115.01(d,J＝7.5Hz),65.20(s),56.11(s),42.82(s),30.26(s),20.88(s),11.95(s),11.03(s).HRMS(ESI):calcd for C
25H
28ClNO
6S[M+Na]
+528.1218,found 528.1221.HPLC(80:20 methanol:water with 1‰TFA):t
R＝9.522min,95.393％.
实施例26
1-(3-(4-氯-3,5-二甲基苯氧基)丙基)-3,5-二甲基-4-((4-硝基苯基)磺酰基)-1H-吡咯-2-羧酸(DDO-26)
本品由4-硝基苯硫酚、3,5-二甲基-1H-吡咯-2-羧酸乙酯、5-(3-溴丙氧基)-2-氯-1,3-二甲基苯按照实施例1的方法制备，产率:63％。
1H NMR(300MHz,DMSO)δ12.89(s,1H),8.25(d,J＝8.7Hz,2H),7.96(d,J＝8.7Hz,2H),6.63(s,2H),4.33(t,J＝6.8Hz,2H),3.78(t,J＝5.2Hz,2H),2.47(s,3H),2.29(s,3H),2.18(s,6H),1.95(s,2H).HRMS(ESI):calcd for C
24H
25ClN
2O
7S[M-H]
+519.0998,found 519.0990.HPLC(80:20 methanol:water with 1‰TFA):t
R＝10.447min,95.757％.
实施例27
1-(3-(4-氯-3,5-二甲基苯氧基)丙基)-4-((4-乙氧基苯基)磺酰基)-3,5-二甲基-1H-吡咯-2-羧酸(DDO-27)
本品由4-乙氧基苯硫酚、3,5-二甲基-1H-吡咯-2-羧酸乙酯、5-(3-溴丙氧基)-2-氯-1,3-二甲基苯按照实施例1的方法制备，产率:58％。
1H NMR(300MHz,DMSO)δ12.87(s,1H),7.71(d,J＝8.8Hz,2H),7.05(d,J＝8.8Hz,2H),6.73(s,2H),4.40(t,J＝6.3Hz,2H),4.08(dd,J＝13.6,6.7Hz,2H),3.87(t,J＝5.6Hz,2H).HRMS(ESI):calcd for C
26H
30ClNO
6S[M+Na]
+542.1380,found 542.1373.
实施例28
1-(3-(4-氯-3,5-二甲基苯氧基)丙基)-3,5-二甲基-4-((4-苯氧基苯基)磺酰基)-1H-吡咯-2-羧酸(DDO-28)
本品由4-苯氧基硫代苯酚、3,5-二甲基-1H-吡咯-2-羧酸乙酯、5-(3-溴丙氧基)-2-氯-1,3-二甲基苯按照实施例1的方法制备，产率:65％。
1H NMR(300MHz,CDCl3)δ7.82(d,J＝8.6 Hz,2H),7.44(t,J＝7.8Hz,2H),7.26(t,J＝7.3Hz,1H),7.06(dd,J＝15.6,8.3Hz,4H),6.63(s,2H),4.53(t,J＝6.6Hz,2H),3.91(t,J＝5.0Hz,2H),2.68(s,3H),2.59(s,3H),2.36(s,6H),2.24–2.12(m,2H).HRMS(ESI):calcd for C
30H
30ClNO
6S[M+NH4]
+585.1821,found 585.1819.HPLC(80:20 methanol:water with 1‰TFA):t
R＝22.460min,96.239％.
实施例29
4-((4-苯甲酰基苯基)磺酰基)-1-(3-(4-氯-3,5-二甲基苯氧基)丙基)-3,5-二甲基-1H-吡咯-2-羧酸(DDO-29)
本品由4-苯甲酰基苯硫酚、3,5-二甲基-1H-吡咯-2-羧酸乙酯、5-(3-溴丙氧基)-2-氯-1,3-二甲基苯按照实施例1的方法制备，产率:56％。
1H NMR(300MHz,CDCl3)δ7.99(d,J＝8.4Hz,2H),7.90(d,J＝8.4Hz,2H),7.85–7.79(m,2H),7.68(t,J＝7.4Hz,1H),7.54(t,J＝7.6Hz,2H),6.63(s,2H),4.55(t,J＝6.9Hz,2H),3.91(t,J＝5.4Hz,2H),2.71(s,3H),2.61(s,3H),2.35(s,6H),2.19(s,2H).HRMS(ESI):calcd for C
31H
30ClNO
6S[M+NH4]
+597.1821,found 597.1815.HPLC(80:20 methanol:water with 1‰TFA):t
R＝15.325min,95.339％.
实施例30
4-((3-乙酰基苯基)磺酰基)-1-(3-(4-氯-3,5-二甲基苯氧基)丙基)-3,5-二甲基-1H-吡咯-2-羧酸(DDO-30)
本品由1-(3-巯基苯基)乙酮、3,5-二甲基-1H-吡咯-2-羧酸乙酯、5-(3-溴丙氧基)-2-氯-1,3-二甲基苯按照实施例1的方法制备，产率:54％。
1H NMR(300MHz,DMSO)δ12.98(s,1H),8.25(d,J＝12.4Hz,2H),8.05(d,J＝7.8Hz,1H),7.76(t,J＝7.7Hz,1H),6.75(s,2H),4.45(t,J＝6.2Hz,2H),3.90(t,J＝4.5Hz,2H),2.65(s,3H),2.59(s,3H),2.42(s,3H),2.30(s,6H),2.07(s,2H).HRMS(ESI):calcd for C
26H
28ClNO
6S[M+NH4]
+535.1664,found 535.1660.HPLC(80:20 methanol:water with 1‰TFA):t
R＝7.762min,95.784％.
实施例31
4-((2-乙酰基苯基)磺酰基)-1-(3-(4-氯-3,5-二甲基苯氧基)丙基)-3,5-二甲基-1H-吡咯-2-羧酸(DDO-31)
本品由1-(2-巯基苯基)乙酮、3,5-二甲基-1H-吡咯-2-羧酸乙酯、5-(3-溴丙氧基)-2-氯-1,3-二甲基苯按照实施例1的方法制备，产率:59％。
1H NMR(300MHz,DMSO)δ12.95(s,1H),7.67(dd,J＝47.1,19.2Hz,4H),6.77(s,2H),4.44(s,2H),3.92(s,2H),2.45(s,6H),2.25(d,J＝15.6Hz,9H),2.06(s,2H).HRMS(ESI):calcd for C
26H
28ClNO
6S[M+NH4]
+535.1664,found 535.1661.HPLC(80:20 methanol:water with 1‰TFA):t
R＝23.096min,97.237％.
实施例32
1-(3-(4-氯-3,5-二甲基苯氧基)丙基)-4-((3-甲氧基苯基)磺酰基)-3,5-二甲基-1H-吡咯-2-羧酸(DDO-32)
本品由3-甲氧基苯硫酚、3,5-二甲基-1H-吡咯-2-羧酸乙酯、5-(3-溴丙氧基)-2-氯-1,3-二甲基苯按照实施例1的方法制备，产率:67％。
1H NMR(300MHz,DMSO)δ12.91(s,1H),7.55–7.45(m,1H),7.34(d,J＝8.2Hz,1H),7.31–7.16(m,2H),6.77(s,2H),4.42(s,2H),3.90(d,J＝11.5Hz,2H),3.80(s,3H),2.55(s,3H),2.39(s,3H),2.28(s,6H),2.04(s,2H).HRMS(ESI):calcd for C
25H
28ClNO
6S[M+NH4]
+523.1664,found 523.1663.HPLC(80:20 methanol:water with 1‰TFA):t
R＝35.646min,97.083％.
实施例33
1-(3-(4-氯-3,5-二甲基苯氧基)丙基)-4-((2-甲氧基苯基)磺酰基)-3,5-二甲基-1H-吡咯-2-羧酸(DDO-33)
本品由2-乙氧基苯硫酚、3,5-二甲基-1H-吡咯-2-羧酸乙酯、5-(3-溴丙氧基)-2-氯-1,3- 二甲基苯按照实施例1的方法制备，产率:34％。
1H NMR(300MHz,DMSO)δ12.76(s,1H),7.95(d,J＝7.4Hz,1H),7.67–7.55(m,1H),7.13(d,J＝5.1Hz,2H),6.73(s,2H),4.44(s,2H),3.90(s,2H),3.72(s,3H),2.52(s,3H),2.26(d,J＝8.3Hz,9H),2.04(s,2H).HRMS(ESI):calcd for C
25H
28ClNO
6S[M+NH4]
+523.1664,found 523.1667.HPLC(80:20 methanol:water with 1‰TFA):t
R＝7.366min,95.109％.
实施例34
4-((4-氨基苯基)磺酰基)-1-(3-(4-氯-3,5-二甲基苯氧基)丙基)-3,5-二甲基-1H-吡咯-2-羧酸(DDO-34)
本品由4-氨基苯硫酚、3,5-二甲基-1H-吡咯-2-羧酸乙酯、5-(3-溴丙氧基)-2-氯-1,3-二甲基苯按照实施例1的方法制备，产率:47％。
1H NMR(300MHz,DMSO)δ12.77(s,1H),7.42(d,J＝8.7Hz,2H),6.75(d,J＝5.1Hz,2H),6.58(d,J＝8.7Hz,2H),6.03(s,2H),4.39(t,J＝6.9Hz,2H),3.87(t,J＝5.7Hz,2H),2.51(s,3H),2.35(s,3H),2.28(s,6H),2.01(dd,J＝8.6,5.5Hz,2H).HRMS(ESI):calcd for C
24H
27ClN
2O
5S[M+Na]
+513.1221,found 513.1225.HPLC(80:20 methanol:water with 1‰TFA):t
R＝5.130min,95.033％.
实施例35
4-((4-羧基苯基)磺酰基)-1-(3-(4-氯-3,5-二甲基苯氧基)丙基)-3,5-二甲基-1H-吡咯-2-羧酸(DDO-35)
本品由4-巯基苯甲酸、3,5-二甲基-1H-吡咯-2-羧酸乙酯、5-(3-溴丙氧基)-2-氯-1,3-二甲基苯按照实施例1的方法制备，产率:65％。
1H NMR(300MHz,DMSO)δ13.34(s,1H),8.11(d,J＝8.4Hz,2H),7.93(d,J＝8.3Hz,2H),6.76(s,2H),4.45(s,2H),3.89(s,2H),2.58(s,3H),2.40(s,3H),2.30(s,6H),2.07(s,2H).HRMS(ESI):calcd for C
25H
26ClNO
7S[M+NH4]
+537.1457,found 537.1461.HPLC(80:20 methanol:water with 1‰TFA):t
R＝6.632min,97.747％.
实施例36
1-(3-(4-氯-3,5-二甲基苯氧基)丙基)-4-((4-羟基苯基)磺酰基)-3,5-二甲基-1H-吡咯-2-羧酸(DDO-36)
本品由4-羟基苯硫酚、3,5-二甲基-1H-吡咯-2-羧酸乙酯、5-(3-溴丙氧基)-2-氯-1,3-二甲基苯按照实施例1的方法制备，产率:76％。
1H NMR(300MHz,DMSO)δ12.85(s,1H),10.51(s,1H),7.65(d,J＝8.7Hz,2H),6.91(d,J＝8.7Hz,2H),6.77(s,2H),4.43(t,J＝6.7Hz,2H),3.89(t,J＝5.5Hz,2H),2.55(s,3H),2.39(s,3H),2.31(s,6H),2.05(dt,J＝13.0,6.6Hz,2H).
13C NMR(75MHz,DMSO)δ162.64(s),161.74(s),156.74(s),138.59(s),136.98(s),134.22(s),128.69(s),127.70(s),125.56(s),120.94(s),119.94(s),116.16(s),115.07(s),65.23(s),42.76(s),30.29(s),20.89(s),11.96(s),11.02(s).HRMS(ESI):calcd for C
24H
26ClNO
6S[M+NH4]+509.1508,found 509.1507.HPLC(80:20 methanol:water with 1‰TFA):t
R＝14.949min,95.270％.
实施例37
1-(3-(4-氯-3,5-二甲基苯氧基)丙基)-4-((3-羟苯基)磺酰基)-3,5-二甲基-1H-吡咯-2-羧酸(DDO-37)
本品由3-羟基苯硫酚、3,5-二甲基-1H-吡咯-2-羧酸乙酯、5-(3-溴丙氧基)-2-氯-1,3-二甲基苯按照实施例1的方法制备，产率:37％。
1H NMR(300MHz,DMSO)δ12.91(s,1H),10.18(s,1H),7.39(t,J＝7.8Hz,1H),7.22(d,J＝9.9Hz,2H),7.02(d,J＝8.0Hz,1H),6.76(s,2H),4.44(s,2H),3.91(s,2H),2.56(s,3H),2.41(s,3H),2.31(s,6H),2.05(dd,J＝12.3,6.3Hz,2H).HRMS(ESI):calcd for C
24H
26ClNO
6S[M+NH4]
+509.1508,found 509.1507.HPLC(80:20 methanol:water with 1‰TFA):t
R＝6.465min,97.143％.
实施例38
1-(3-(4-氯-3,5-二甲基苯氧基)丙基)-4-((2-羟基苯基)磺酰基)-3,5-二甲基-1H-吡咯-2-羧酸(DDO-38)
本品由2-羟基苯硫酚、3,5-二甲基-1H-吡咯-2-羧酸乙酯、5-(3-溴丙氧基)-2-氯-1,3-二甲基苯按照实施例1的方法制备，产率:56％。
1H NMR(300MHz,CDCl3)δ9.44(s,1H),7.44(d,J＝7.7Hz,2H),7.03(d,J＝8.2Hz,1H),6.94(t,J＝7.6Hz,1H),6.63(s,2H),4.55(t,J＝7.0Hz,2H),3.90(t,J＝5.4Hz,2H),2.68(s,3H),2.57(s,3H),2.37(s,6H),2.20(dt,J＝12.1,5.9Hz,2H).13C NMR(75MHz,DMSO)δ162.73(s),158.73(s),156.73(s),156.22(s),140.24(s),139.05(s),136.98(s),135.05(s),129.23(s),128.71(d,J＝20.7Hz),125.55(s),120.18(s),118.89(s),117.80(s),115.12(s),112.59(s),65.17(s),42.58(s),21.50(s),20.91(s),11.91(s),11.26(s).HRMS(ESI):calcd for C
24H
26ClNO
6S[M+NH4]
+509.1508,found 509.1505.HPLC(80:20 methanol:water with 1‰TFA):t
R＝6.325min,99.161％.
二、药理实验
2.1采用荧光偏正的方法(FP实验)测试化合物对Mcl-1、Bcl-2、Bfl-1的抑制活性
Mcl-1抑制活性测试方法：测试使用384孔黑板(型号为Corning#3575)，测试终体积选择60μL，所测试化合物和荧光探针GR16-NH2-FITC溶于DMSO(10mmol母液)中备用。将化合物用assay buffer(20mM Tris,150mM NaCl,3mM DTT,pH 7.5)倍比稀释12个浓度梯度，每个孔板加入20μL稀释好的化合物，再依次加入20μL assay buffer稀释好的5nM GR16-NH2-FITC和5nM蛋白。每个化合物浓度设定两个附孔，每次实验设置空白对照(20μL GR16-NH2-FITC+40μL assay buffer，记为Pmin)和阴性对照(20μL GR16-NH2-FITC+20μL蛋白+20μL assay buffer，记为Pmax)。之后在4℃摇床上震摇孵育30min，用Synergy读板器扫板，激发波长设置为485nm，发射波长设置为535nm，测试孔读数记为Ptest。
抑制率计算公式为：抑制率(％)＝[1-(Ptest-Pmin)/(Pmax-Pmin)]×100％，采用Graphpad Prism 6.0软件计算IC
50。
Bcl-2抑制活性的测试方法：测试使用384孔黑板(型号为Corning#3575)，测试终体积选择60μL，所测试化合物和荧光探针FAM-Bid溶于DMSO(10mmol母液)中备用。将化合物用assay buffer(55mM Hepes,274mM NaCl,1.48mM Na
2HPO
4,pH＝7)稀释为20μM，每个孔板加入20μL稀释好的化合物，再依次加入20μL assay buffer稀释好的2nM/L FAM-Bid和60nM/L蛋白。每个化合物浓度设定两个附孔，每次实验设置空白对照(20μL FAM-Bid+40μL assay buffer，记为Pmin)和阴性对照(20μL FAM-Bid+20μL蛋白+20μL assay buffer，记为Pmax)。之后在4℃摇床上震摇孵育30min，用Synergy读板器扫板，激发波长设置为485nm，发射波长设置为535nm，测试孔读数记为Ptest。
抑制率计算公式为：抑制率(％)＝[1-(Ptest-Pmin)/(Pmax-Pmin)]×100％。
Bfl-1抑制活性的测试方法：测试使用384孔黑板(型号为Corning#3575)，测试终体积选择60μL，所测试化合物和荧光探针FITC-Bid溶于DMSO(10mmol母液)中备用。将化合物用assay buffer(55mM Hepes,274mM NaCl,1.48mM Na
2HPO
4,pH＝7)稀释为20μM，每个孔板加入20μL稀释好的化合物，再依次加入20μL assay buffer稀释好的1nM/L FITC-Bid和40nM/L蛋白。每个化合物浓度设定两个附孔，每次实验设置空白对照(20μL FITC-Bid+40μL assay buffer，记为Pmin)和阴性对照(20μL FITC-Bid+20μL蛋白+20μL assay buffer，记为Pmax)。之后在4℃摇床上震摇孵育30min，用Synergy读板器扫板，激发波长设置为485nm，发射波长设置为535nm，测试孔读数记为Ptest。
抑制率计算公式为：抑制率(％)＝[1-(Ptest-Pmin)/(Pmax-Pmin)]×100％。
2.2对肿瘤细胞的抗增殖实验(MTT实验)
测试本发明所述化合物对人类多发性骨髓瘤细胞株H929的抗增殖活性。实验方法为：选用H929肿瘤细胞，将细胞接种于96孔平板中(每孔约有4000个细胞)，于37℃，5％CO
2条件下孵育24小时后，将不同浓度的化合物加入至细胞中，再培养72小时后，各小孔中分别加入20μl MTT的PBS溶液(浓度为5mg/ml)，于37℃孵育4小时，除去MTT和培养基，每个小孔中分别加入150μL DMSO，于490nm下检测(采用Thermo Multiskan Spectrum读板器)，测试结果Graphpad Prism6分析。
三、实验结果
3.1 FP实验
FP实验结果表明所有化合物均具有Mcl-1抑制活性，其中部分化合物具有低微摩尔级抑制活性，结果见表1。
表1化合物的Mcl-1抑制活性结果
3.2 MTT实验
在体外的细胞毒活性评价中，部分化合物对Mcl-1抑制剂敏感性肿瘤细胞株H929表现 出了良好的抗肿瘤细胞生长的能力，对Mcl-1抑制剂不敏感的细胞株K562活性较差。实验结果见表2。
表2 DDO-11、DDO-17、DDO-23、DDO-24、DDO-25、DDO-38的抗细胞增殖活性
本发明提供的3,5-二甲基-4-砜基-1H-吡咯类化合物具有较好的Mcl-1抑制活性，对Bcl-2抗凋亡蛋白家族的其他亚型Bcl-2、Bcl-xL和Bfl-1具有良好的选择性。此外，该类化合物对Mcl-1抑制剂敏感性肿瘤细胞株H929表现出了良好的抗肿瘤细胞生长的能力。
上述实施例的作用在于具体介绍本发明的实质性内容，但本领域技术人员应当知道，不应将本发明的保护范围局限于该具体实施例。
Claims (6)
- 一种3,5-二甲基-4-砜基-1H-吡咯类化合物，其特征在于，具有如下的化学结构：
其中，R1为H、甲基、乙基、异丙基中的任一种；R2为H、甲基、乙基、异丙基中的任一种；R3为苄基、3-噻吩基、1-萘基、2-吡啶基、环戊基、环己基、-Ar中的任一种，其中Ar为4-甲基苯基、2,6-二甲基苯基、3,5-二甲基苯基、4-乙基苯基、4-异丙基苯基、4-叔丁基苯基、4-联苯、4-氟苯基、4-氯苯基、4-溴苯基、4-乙酰基苯基、3-乙酰基苯基、2-乙酰基苯基、4-甲氧基苯基、3-甲氧基苯基、2-甲氧基苯基、4-乙氧基苯基、4-苯氧基苯基、4-苯甲酰及苯基、4-硝基苯基、4-氨基苯基、4-羧基苯基、不同位置单羟基取代的苯基。 - 权利要求1所述3,5-二甲基-4-砜基-1H-吡咯类化合物的制备方法，R1和R2为甲基，R3的定义同权利要求1，合成路线如下：
不同种类的巯基化合物原料，在三乙胺磺酰氯的作用下形成活性中间体，与原料I-1反应生成不同的硫醚中间体I-2；原料I-3和I-4在乙腈中，以碳酸钾为缚酸剂，进行亲核取代反应得到中间体I-5；以碳酸铯为碱，I-2和I-5进行亲核取代反应得到中间体I-6，I-6经m-CPBA氧化生成I-7，I-7在NaOH作用下水解生成不同的目标产物。 - 权利要求1所述3,5-二甲基-4-砜基-1H-吡咯类化合物的制备方法，R1为H，R2为H或者甲基，R3为4-甲基苯基，合成路线如下：
甲基取代或无取代的原料II-1与异腈酸甲酯在碳酸银的催化作用下，回流得到中间体II-2；碳酸铯作为碱，II-2与中间体5反应得到中间体II-3，II-3水解得到目标产物。 - 权利要求1所述3,5-二甲基-4-砜基-1H-吡咯类化合物的制备方法，R1和R2为甲基、乙基或异丁基，R3为4-甲基苯基，合成路线如下：
原料丙二酸二乙酯在亚硝酸钠、醋酸作用下生成肟中间体III-2，III-2与不同的2,4-二羰基化合物，在锌粉、醋酸钠的条件下，回流得到吡咯中间体III-3，III-3与4-甲基苯硫酚反应得到III-6，再经亲核取代反应，氧化，水解得到目标物。 - 权利要求1所述3,5-二甲基-4-砜基-1H-吡咯类化合物用于制备Mcl-1抑制剂的用途。
- 权利要求1所述3,5-二甲基-4-砜基-1H-吡咯类化合物在制备治疗对Mcl-1抑制剂敏感的肿瘤的药物方面的应用。
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