Thiazolone sulfoxide and sulfone compounds, and methods of making and using the same

Abstract

The application belongs to the field of pharmaceutical chemistry, and particularly relates to thiazolone sulfoxide and sulfone compounds, a preparation method and application thereof, and the compounds or compositions can be used for treating osteosarcoma, colorectal cancer, lung cancer and breast cancer and related diseases. The compounds prepared by the application have the potential to develop into better antitumor drugs by reducing oxidative metabolism in vivo.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry, specifically relating to thiazolidinone sulfoxides and sulfone compounds, their preparation methods, and applications. Background Technology

[0002] Osteosarcoma is the most common and serious primary malignant bone tumor originating from mesenchymal cells, with a high incidence in adolescents. It is the third most common childhood cancer, with a global incidence of 2-4 cases per million children annually. Its cancer mortality rate ranks second among children and adolescents. Before the 1970s, with advancements in medicine and pharmacology, various treatments were available, including radiotherapy, chemotherapy, gene therapy, immunotherapy, or combinations with surgery; however, these methods did not significantly improve patient prognosis and survival rates. Currently, the standard treatment for osteosarcoma includes surgical resection and combined chemotherapy, with chemotherapy primarily consisting of doxorubicin, cisplatin, methotrexate, and cyclophosphamide. Although the 5-year survival rate for osteosarcoma patients has increased to 60-70% through the application of high-dose chemotherapy drugs or combinations and sequences of chemotherapy drugs, this rate has not improved further in the past 40 years. The 5-year survival rate for patients with lung metastases is approximately 20-30%. Due to the lack of identification of key driver genes, gene therapy drugs such as olaparib, gemcitabine, and docetaxel, and immunotherapy drugs such as mirvastatin, averizumab, and pembrolizumab are not more effective than adjuvant chemotherapy. Therefore, the development of small-molecule targeted inhibitors is urgently needed.

[0003] The prior art reports four thiazolinone skeleton compounds with various pharmacological activities, such as compound 1 with antibacterial and antifungal activities, compound 2 with anti-inflammatory and anticancer activities, compound 3 with antiviral / anti-HIV activities, and compound 4 with anticancer activities.

[0004]

[0005] The applicant previously reported that the thiazolidinone scaffold exhibits good inhibitory activity against various osteosarcoma cells, but did not report the oxidation products of thiazolidinone. Sulfoxides and sulfones have similar inhibitory activities. The inventors investigated the thiazolidinone sulfoxide and sulfone products and synthesized such compounds, which may reduce oxidative metabolism in vivo, thereby developing into better osteosarcoma inhibitors. Summary of the Invention

[0006] To address the shortcomings of existing technologies, this invention provides a thiazolidinone sulfoxide and sulfone compound, its preparation method, and its application.

[0007] The technical solution of the present invention is as follows: On one hand, the present invention provides a compound as shown in Formula I or a pharmaceutically acceptable salt thereof:

[0008]

[0009] Where Y is selected from Z is selected from N or CR. 6 X is selected from CH2, O, and NH; n is an integer from 0 to 5;

[0010] R 1 Selected from 6-10 aryl, 9-10 benzo[a]heterocyclic, C3-C6 cycloalkyl, Ph(CH2). m - or 5-10 membered heteroaryl; the 6-10 membered aryl, 9-10 membered benzo[a]heterocyclic, C3-C6 cycloalkyl, Ph(CH2) m -or 5-10 heteroaryl groups optionally surrounded by one or more R 7 Replace; where m is an integer from 1 to 3;

[0011] R 2 R 6 and R 7 Independently selected from H, cyano, halogen, NO2, hydroxyl, -NR 8 R 9 C1-C6 alkyl, (C1-C6 alkyl)-O-, (C1-C6 alkyl)-S-, (C1-C6 alkyl)-C(O)-, PhC(O)-, (C1-C6 alkyl)-OC(O)-, R 8 R 9 NC(O)-, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 6-10 aryl, 3-10 heterocyclic alkyl, or 5-10 heteroaryl; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 6-10 aryl, 3-10 heterocyclic alkyl, or 5-10 heteroaryl is optionally converted by H, halogen, cyano, hydroxyl, or -NR. 8 R 9 NO2, C1-C3 alkyl, C1-C3 alkoxy or halo-C1-C3 alkyl substitution;

[0012] R 3 Selected from H, hydroxyl, 6-10 aryl, 5-10 heteroaryl, (C1-C6 alkyl)-O-, (C1-C6 alkyl)-OC(O)-, R 8 R 9 NC(O)-, PhC(O)-, Ph(CH2) q O-, where q is an integer from 1 to 3;

[0013] R 4 and R 5 Independently selected from H, C1-C6 alkyl;

[0014] R 8 and R 9 Each is independently selected from H, phenyl, or C1-C6 alkyl.

[0015] In some typical implementations, Z is selected from N or CH.

[0016] In some typical implementations, n is an integer from 0 to 2.

[0017] In some implementation schemes, R 1 The groups are selected from phenyl, naphthyl, pyridyl, benzo[d][1,3]dioxazolyl, cyclopropyl, cyclohexyl, benzyl, phenylethyl, quinolinyl, and isoxazolyl, wherein the above groups are optionally surrounded by one or more R groups. 7 replace.

[0018] In some typical implementation schemes, R 1 Selected from phenyl, naphthyl, The above groups are optionally surrounded by one or more R 7 replace.

[0019] In some implementations, the R 7 It is selected from H, C1-C6 alkyl, halogen, hydroxyl, (C1-C6 alkyl)-O- or 6-10 aryl.

[0020] In some typical implementations, the R 7 Selected from H, CH3, F, OH, CH3O-, Cl or phenyl.

[0021] In some implementation schemes, R 2 Selected from H, C2-C6 alkynyl, (C1-C6 alkyl)-OC(O)- or 6-10 aryl.

[0022] In some typical implementation schemes, R 2 Selected from H, ethynyl, CH3OC(O)- or phenyl.

[0023] In some typical implementation schemes, R 3 Selected from H, hydroxyl, phenyl, CH3O-、(CH3)3CO-、

[0024] In some typical implementation schemes, R 4 and R 5 Selected from H.

[0025] On the other hand, the present invention provides the following compounds or pharmaceutically acceptable salts thereof:

[0026]

[0027]

[0028]

[0029] On the other hand, the present invention provides a method for preparing compound I, including but not limited to the following synthetic schemes:

[0030] Synthesis Scheme 1:

[0031]

[0032] Where R 1 R 2 R 3 R 4 R 5 X, Y, Z, and n are defined as compounds of formula I.

[0033] Compound 1-1 was synthesized into methyl diformate compounds under acidic conditions, followed by single-ester hydrolysis under alkaline conditions to yield compound 1-2; compounds 1-2 and compound A condensation reaction occurs, yielding compounds 1-3; compounds 1-3 are reduced to methyl esters to give the corresponding alcohols 1-4, followed by oxidation to give aldehydes 1-5; compounds 1-5 and compound R... 1 NH2 and compounds A three-component one-pot reaction was carried out to give compounds 1-6. Compounds 1-6 were then oxidized under certain conditions in the presence of m-chloroperoxybenzoic acid to give sulfoxide and sulfone compounds 1-7.

[0034] Synthesis Scheme 2:

[0035]

[0036] Where R 1 R 2 R 3 R 4 R 5 X, Y, Z, and n are defined as compounds of formula I.

[0037] Compound 1-1 was synthesized under acidic conditions to form methyl diformate compound 2-2. Compound 2-2 underwent a single ester reduction with sodium borohydride to give alcohol compound 2-3. Compound 2-3 was oxidized by IBX to give compound 2-4. Compound 2-4 was then hydrolyzed under alkaline conditions to give compound 2-5. Compounds 2-5 and compound... A condensation reaction occurs, yielding compounds 2-6, 2-6, and R. 1 NH2 and compounds A three-component one-pot reaction was carried out to give compound 2-7. Compound 2-7 was then oxidized under certain conditions in the presence of m-chloroperoxybenzoic acid to give sulfoxide and sulfone compounds 2-8.

[0038] In some embodiments, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The pharmaceutical composition is formulated as a pill, capsule, cream, gel, excipient, injectable fluid, aerosol, syrup, or transdermal patch, etc.

[0039] The present invention also proposes the use of the compound of Formula I or a pharmaceutically acceptable salt, or a pharmaceutical composition, in the preparation of a medicament for the prevention and / or treatment of tumors.

[0040] The compound of Formula I is used to inhibit the proliferation, growth, migration, invasion, metastasis and recurrence of tumor cells, or to promote apoptosis of tumor cells.

[0041] The tumor cells include osteosarcoma cells, human colon cancer cells, lung cancer cells, and breast cancer cells. The osteosarcoma cells include SJSA-1, U2OS, HOS, MNNG / HOS, MG63, 143b, and SW1353; the lung cancer cells include A549; and the colorectal cancer cells include HCT116.

[0042] Related definitions

[0043] Unless otherwise specified, the following terms used in the specification and claims shall have the following meanings:

[0044] The "compound" of this invention may be asymmetric, for example, having one or more chiral centers. Unless otherwise stated, the "compound" of this invention refers to any one stereoisomer or a mixture of two or more stereoisomers. Stereoisomers include, but are not limited to, enantiomers and diastereomers. The compounds of this invention containing asymmetric carbon atoms can be isolated in optically active pure form or in the form of a mixture of two or more stereoisomers. The optically active pure form can be resolved from a mixture of two or more stereoisomers or synthesized using chiral starting materials or chiral reagents.

[0045] The "compound" of this invention also includes a tautomer form. The tautomer form arises from the exchange of a single bond with an adjacent double bond, accompanied by the migration of a proton.

[0046] The term “optional” or “optionally” means that the event or situation described below may or may not occur, including both the occurrence and non-occurrence of the event or situation.

[0047] The numerical ranges mentioned in this article refer to the integers within a given range. For example, "C1-C6" means that the group can have 1, 2, 3, 4, 5, or 6 carbon atoms; "C3-C6" means that the group can have 3, 4, 5, or 6 carbon atoms.

[0048] The term "membered ring" refers to the number of skeletal atoms or groups of atoms that make up the ring. For example, "5-7 members" means that the number of skeletal atoms or groups of atoms that make up the ring is 5, 6, or 7. Thus, for example, pyridine, piperidine, piperazine, and benzene are six-membered rings, while thiophene and pyrrole are five-membered rings.

[0049] The term "substituted" refers to the replacement of one or more hydrogen atoms on a specific group with a substituent, provided that the valence state of the specific group is normal and the resulting compound is stable. For example, "halogen substituted" means that one or more hydrogen atoms on a specific group are replaced by a halogen, provided that the valence state of the specific group is normal and the resulting compound is stable.

[0050] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight-chain or branched saturated hydrocarbon groups having the indicated number of carbon atoms. For example, the term "C1-C6 alkyl" includes C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, n-hexyl, 2-hexyl, 3-hexyl, etc.

[0051] The term "alkoxy" refers to a group having an alkyl-O- structure, where the alkyl group is a saturated monovalent hydrocarbon group, including straight-chain or branched groups. For example, "C1-C3 alkoxy" includes methoxy, ethoxy, n-propoxy, and isopropoxy.

[0052] The term "cycloalkyl" refers to a monocyclic saturated hydrocarbon system without heteroatoms or double bonds. Examples of the term "3-6 membered cycloalkyl" include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0053] The term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0054] The term "aryl" refers to an aromatic ring group consisting of a monocyclic or fused bicyclic ring with a conjugated π-electron system, obtained by removing a hydrogen atom from a single carbon atom of the parent aromatic ring system. This includes bicyclic groups fused with saturated, partially unsaturated, or aromatic carbon rings; examples include, but are not limited to, phenyl, naphthyl, anthracene, indene, indane, 1,2-dihydronaphthalene, and 1,2,3,4-tetrahydronaphthalene.

[0055] The term "heteroaryl" refers to a monovalent aryl group that contains at least one heteroatom independently selected from nitrogen, oxygen, and sulfur. Examples of "5-7 membered heteroaryl" include, but are not limited to, pyridyl, thiophene, imidazolyl, pyrimidinyl, furanyl, pyrazinyl, and thiazolyl.

[0056] The term "9-10 membered benzo[a]heterocyclic group" refers to a ring system with 9-10 ring atoms or ring groups formed by the fusion of a benzene ring and a heterocycle. The benzene ring and the heterocycle share a pair of adjacent ring atoms, and the connection site with the parent nucleus is located in the benzene ring portion. The heterocycle portion is a 5-6 membered saturated, partially unsaturated, or fully unsaturated ring system with a cyclic carbon atom and 1 to 4 cyclic heteroatoms or heterogroups. The heteroatoms or heterogroups are independently selected from nitrogen, sulfur, oxygen, sulfoxide, sulfone, etc.

[0057] The term "halogenated C1-C3 alkyl" refers to a group formed by replacing any number of hydrogen atoms on a C1-C3 alkyl group with fluorine, chlorine, bromine, and iodine.

[0058] In It refers to the junction of chemical bonds.

[0059] This refers to the hydrogen atoms on the ring being arbitrarily separated by one or more R atoms. 2 replace.

[0060] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological potency of a particular compound as a free acid or base without any adverse biological effects. Examples include acid (including organic and inorganic acids) addition salts or base addition salts (including organic and inorganic bases).

[0061] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture thereof.

[0062] The term "effective dose" or "therapeutic effective dose" refers to a sufficient amount of a drug or agent that is non-toxic but achieves the desired effect.

[0063] The term "pharmaceutically acceptable carrier" refers to carriers that do not cause significant irritation to the body and do not impair the biological activity and properties of the active compound. This includes, but is not limited to, any diluents, disintegrants, binders, glidants, and wetting agents approved by the State Food and Drug Administration for use in humans or animals.

[0064] The beneficial effects of the present invention are as follows: The present invention discloses sulfoxide and sulfone compounds or pharmaceutically acceptable salts of thiazolidinone and their preparation methods. These compounds or compositions can be used to treat osteosarcoma, human colon cancer, breast cancer and lung cancer and other related diseases, which is of great significance in the research of tumor diseases. Detailed Implementation

[0065] The following embodiments are intended to enable those skilled in the art to more fully understand the present invention, but are not intended to limit the invention to the scope of the embodiments described.

[0066] Long-chain amine compounds The synthesis methods are not limited to the following preparation methods.

[0067] Method 1:

[0068]

[0069] In reaction (I), R 3 The definition is the same as that of formula (I).

[0070] Compound A and sodium hydride were added to a dry three-necked flask under nitrogen protection. Dry DMSO or DMF was then added, and the mixture was stirred at 110°C for 10 min. N-(4-bromobutyl)phthalimide and a catalytic amount of KI, dissolved in dry DMSO or DMF, were then added to the reaction mixture. Stirring continued at 110°C, and the reaction was monitored by thin-layer chromatography. After the reaction was complete, saturated sodium chloride was added, and the mixture was extracted three times with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 9:1).

[0071] Ethanol, water and hydrazine were added to the product obtained by the above separation and purification, and the reaction was carried out at 65°C for 15 h. The reaction was monitored by thin-layer chromatography. After the reaction was complete, 1M sodium hydroxide solution was added, and the product was extracted three times with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, concentrated and used directly in the reaction without further purification.

[0072] Method 2:

[0073]

[0074] The specific operational steps for reaction (2) are as follows:

[0075] In a dry three-necked flask, tetrahydrofuran was used as a solvent. Compound 1 and triethylamine were added, and di-tert-butyl dicarbonate was added dropwise at 0°C. The reaction was allowed to proceed overnight. After post-treatment, the mixture was quenched with water, extracted with ethyl acetate, and the organic phase was collected. The organic phase was washed with 1M hydrochloric acid (3 times), dried with anhydrous sodium sulfate, and evaporated to dryness to obtain compound 2. Subsequently, compound 2, 4-n-butylammonium bromide and sodium hydroxide (50% w) were added to toluene. The mixture was moved to 0°C and reacted for 30 minutes. Iodomethane was added, and the reaction was allowed to proceed overnight. After post-treatment, the mixture was extracted with diethyl ether, evaporated to dryness, and wet-processed. Column chromatography was used to separate compound 3. Finally, the Boc protecting group was removed by reaction in 4M hydrochloric acid and ethyl acetate to obtain compound 4, which is a long-chain amino group.

[0076] Method 3:

[0077]

[0078] The specific operation of reaction (3) is as follows:

[0079] Compound 1 was protected with a Boc group to obtain compound 2. Then, compound 2 was reacted with a phenyl Grignard reagent (PhMgBr), and post-treatment was performed to obtain ring-opening compound 3. Compound 3 was reduced under sodium borohydride conditions to obtain compound 4. Finally, the Boc protecting group was removed under trifluoroacetic acid conditions to obtain the final long-chain alkylamine compound 5.

[0080] Method 4:

[0081]

[0082] The route for synthesizing long-chain alkylamines using reaction formula (4):

[0083] Compound 1 can be esterified under acidic conditions to give long-chain alkyl ester compound 2. Alternatively, compound 1 can be protected with an amino protecting group (Boc) under basic conditions to give compound 3, which is then condensed with an amino compound to give amide compound 4. Finally, it can be hydrolyzed under acidic conditions to give long-chain alkyl compound 5.

[0084] Example 1

[0085]

[0086] Taking compound 1 as an example, the specific operation steps are as follows:

[0087]

[0088] Step ab: Concentrated sulfuric acid (0.5 mL) was added to a stirred solution of pyridine-2,6-dicarboxylic acid (10 g) in methanol (100 mL). The reaction mixture was refluxed at 80 °C for 16 hours. After the reaction was complete, the solvent was removed by vacuum evaporation, water was added, the solid was filtered and dried to obtain dimethyl pyridine-2,6-dicarboxylic acid. Then, dimethyl pyridine-2,6-dicarboxylic acid (2 g) was dissolved in methanol (20 mL), KOH (1.2 eq.) was added, and the reaction was carried out overnight at room temperature. Post-treatment: methanol was removed by vacuum distillation, water and ethyl acetate were added for extraction, the aqueous layer was collected, and the pH was adjusted to 7 by adding 1 M hydrochloric acid. Then, it was extracted with ethyl acetate again, the organic phase was collected, dried, and concentrated to obtain a white solid 6-(methoxycarbonyl)pyridinecarboxylic acid (1.2 g).

[0089] Step c: Add 6-(methoxycarbonyl)pyridinecarboxylic acid (1 eq.), HOBt (2 eq.), and DIPEA (4 eq.) to a 50 mL round-bottom flask. Then, react under nitrogen at 0 °C for 10 minutes, add EDCI (2 eq.), continue stirring for 10 minutes, add 4-phenylbutylamine (1.1 eq.), then move the reaction to room temperature and react for 16 hours. Detect the reaction by TLC. New spots were formed, quenched with water, extracted with dichloromethane, collected the organic phase, dried, concentrated, loaded with wet chromatography, and purified by column chromatography to obtain the amide condensation product 3a.

[0090] Step d: Compound 3a (1 eq.) was dissolved in methanol, followed by the addition of sodium methoxide (cat.) and sodium borohydride (2 eq.). The reaction was carried out at room temperature for 16 hours. TLC analysis showed that the starting material had completely reacted and a new spot had formed. The spot was quenched with water, and methanol was removed by vacuum distillation. The residue was then extracted with ethyl acetate, the organic phase was collected, dried, concentrated, and purified by column chromatography to obtain the ester-reduced product 4a.

[0091] Step e: Dissolve compound 4a (1 eq.) in ethyl acetate, add IBX (1.1 eq.), then raise the temperature to 85°C and react overnight. TLC detection showed that the starting material reacted completely, a new spot was formed, and a white solid was present in the reaction. The filtrate was filtered, the solvent was removed by vacuum distillation, and then purified by column chromatography to obtain compound 5a, which has hydroxyl groups oxidized to aldehydes.

[0092] Step f: Aldehyde compound 5a (1 eq.) and 4-methylpyridin-2-amine (1 eq.) were added to toluene and stirred at 140 °C for 30 minutes. After cooling, mercaptoacetic acid (3 eq.) was added, and the reaction was carried out overnight at 140 °C. TLC and LCMS showed that the starting material had completely reacted and a new spot had formed. The dissolved substance was removed under reduced pressure, followed by wet loading and column chromatography to obtain thiazolidinone compound 6a.

[0093] Step g: Thiazolone compound 6a (1 eq.) and anhydrous dichloromethane were added to a 50 mL round-bottom flask. The mixture was then transferred to 0 °C, and m-chloroperoxybenzoic acid (3 eq.) was added. The mixture was then moved to room temperature and reacted overnight. LCMS analysis showed that the starting material had completely reacted and the target molecular weight was generated. For post-treatment, saturated sodium thiosulfate was added to the reaction mixture, followed by extraction with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, evaporated to dryness, and purified by column chromatography to obtain the final thiazolidinone sulfone target compound 1. 1 H NMR (400MHz, CDCl3) δ8.21(d,J=7.8Hz,1H),8.17(s,1H),8.01–7.96(m,2H),7.69(d,J=7.8Hz,1H),7.51(t,J=6.0Hz,1H),7.28(t,J=7.2Hz,2H),7.1 8(d,J=7.6Hz,3H),6.88(d,J=5.2Hz,1H),6.81(s,1H),4.19–4.03(m,2H), 3.50-3.37(m,2H),2.65(t,J=7.2Hz,2H),2.34(s,3H),1.69-1.60(m,4H); 13 C NMR (100MHz, CDCl3) δ163.33,163.25,150.2,150.1,149.9,149.6,147.3,142.1,139.3,12 8.52,128.46,126.7,125.9,123.3,122.6,117.0,80.3,53.1,39.4,35.6,29.1,28.8,21.5.

[0094] Example 2

[0095]

[0096] 1 H NMR (400MHz, CDCl3) δ8.23(d,J=7.8Hz,1H),8.11(d,J=4.4Hz,1H),7.95(t,J=7.8Hz,1H),7.76(s,1H),7.60(d,J=7.8Hz,1H),7.37(t,J=8.8H z,1H),7.30-7.18(m,2H),7.20(t,J=8.2Hz,4H),6.56(s,1H),4.13-4. 04(m,2H),3.55-3.39(m,2H),2.67(t,J=6.6Hz,2H),1.70–1.65(m,4H); 13C NMR (100MHz, CDCl3) δ163.2,161.1,153.6(J=270Hz),150.7,148.0,144.3(J=5Hz),142.3,139.3,137.6(J=1 3Hz),128.6,128.5,126.2,126.0,125.7(J=18Hz),125.0(J=4Hz),123.6,81.8,51.8,39.6,35.7,29.2,28.9; 19 F NMR (375MHz, CDCl3) δ -118.97.

[0097] Example 3

[0098]

[0099] 1 H NMR (400MHz, CDCl3) δ8.35 (dd, J=9.2, 4.0Hz, 1H), 8.22 (dd, J=7.8, 1.0Hz, 1H), 8.01–7.97(m,2H),7.70(dd,J=7.6Hz,0.4Hz,1H),7.45(t,J=6.0Hz,1H),7.39-7 .34(m,1H),7.29(t,J=7.2Hz,2H),7.22-7.18(m,3H),6.73(d,J=0.8Hz,1H),4.1 8–4.03(m,2H),3.42(q,J=6.2Hz,2H),2.65(t,J=7.2Hz,2H),1.66–1.61(m,4H); 13 C NMR (100MHz, CDCl3) δ 163.3, 163.1, 158.4-155.8 (J = 253.5Hz), 150.3, 149.4, 145.5 (J = 2.4Hz), 142.1, 139.5, 135.5-135.3 (J = 25. 8Hz),128.54,128.49,126.7,126.0,125.8-125.6(J=16.9Hz),123.4,117.7-117.6(J=4.6Hz),80.3,52.8,39.5,35.6,29.1,28.8; 19 F NMR (376MHz, CDCl3) δ-129.4.

[0100] Example 4

[0101]

[0102] 1H NMR(400MHz, CDCl3)δ8.20(d,J=7.6Hz,1H),7.99–7.88(m,4H),7.62(d,J=7.6Hz,1H),7.31-7.27(m,3H),7.22–7.17(m,3H) ,7.13(dd,J=8.0,4.6Hz,1H),7.04(s,1H),4.23–4.11(m,2H),3.55–3.36(m,2H),2.67(t,J=6.4Hz,2H),1.72–1.66(m,4H); 13 CNMR (100MHz, CDCl3) δ164.8,163.3,150.7,147.3,146.1,142.4,140.8,139.4,139.2 ,130.0,128.6,128.5,126.6,126.0,125.0,123.7,82.4,53.1,39.6,35.7,29.1,29.0.

[0103] Example 5

[0104]

[0105] 1 H NMR (400MHz, CDCl3) δ8.18(d,J=7.8Hz,1H),8.05–7.80(m,3H),7.64(d,J=7.8Hz,1H),7.30-7.25(m,4H),7.18(t,J=7 .2Hz,4H),6.49(s,1H),4.12–4.02(m,2H),3.90(s,3H),3.51-3.40(m,2H),2.66(t,J=7.2Hz,2H),1.73-1.63(m,4H); 13 C NMR (100MHz, CDCl3) δ163.5,161.3,150.6,150.5,148.4,142.2,140.4,138.9,138.8,12 8.6,128.5,125.9,125.7,124.8,123.2,121.2,82.5,56.5,51.8,39.6,35.6,29.4,28.9.

[0106] Example 6

[0107]

[0108] 1H NMR (400MHz, CDCl3) δ8.24(d,J=7.8Hz,1H),7.91(t,J=7.8Hz,1H),7.81(t,J =6.2Hz,1H),7.53(d,J=7.8Hz,1H),7.28(t,J=7.2Hz,3H),7.20–7.14(m,4H) ,6.94(d,J=8.4Hz,1H),6.84(t,J=7.8Hz,1H),6.17(s,1H),4.10–3.98(m,2H ),3.85(s,3H),3.53–3.48(m,2H),2.68(t,J=7.0Hz,2H),1.75–1.67(m,4H); 13 C NMR (100MHz, CDCl3) δ163.3,163.2,154.6,150.7,148.5,142.2,139.1,130.6,129.4,128.6, 128.5,126.6,126.0,123.62,123.55,121.1,112.6,82.9,56.1,50.8,39.6,35.6,29.4,28.9.

[0109] Example 7

[0110]

[0111] Taking compound 7 as an example, the specific operation steps are as follows:

[0112]

[0113] Step a: Add concentrated sulfuric acid (0.5 mL) to a stirred solution of resorcinol (10 g) in methanol (100 mL). Reflux the reaction mixture at 80 °C for 16 hours. After the reaction is complete, remove the solvent by vacuum evaporation, add water, filter the resulting solid, and dry to obtain dimethyl resorcinol (2b, 9 g).

[0114] Step b: Compound 2b (1 eq.) was dissolved in tetrahydrofuran, followed by the addition of sodium borohydride (1.2 eq.). Methanol was added dropwise at 50 °C, and the reaction was carried out for 5 hours. TLC was used to detect the reaction of the starting material and the formation of a new spot, which was quenched with water. Methanol and tetrahydrofuran were removed by vacuum distillation. The residue was then extracted with ethyl acetate, the organic phase was collected, dried, concentrated, and purified by column chromatography to obtain the ester-reduced product 3b.

[0115] Step c: Dissolve compound 3b (1 eq.) in ethyl acetate, add IBX (1.1 eq.), then raise the temperature to 85°C and react overnight. TLC detection showed that the starting material reacted completely, a new spot was formed, and a white solid was present in the reaction. The filtrate was filtered, the solvent was removed by vacuum distillation, and then purified by column chromatography to obtain compound 4b, which has hydroxyl groups oxidized to aldehydes.

[0116] Step d: Ester compound 4b (1 eq.) was dissolved in methanol, and potassium hydroxide (2 eq.) was added. The reaction proceeded overnight, and TLC analysis showed that the starting material had completely reacted. Subsequently, water was added for dilution, methanol was removed by vacuum distillation, and the mixture was extracted with ethyl acetate. The pH of the aqueous phase was adjusted to 6 with 1M hydrochloric acid. A white solid precipitated, and the mixture was filtered to obtain a white solid 5b.

[0117] Step e: Add 3-formylbenzoic acid (5b, 1 eq.), HOBt (2 eq.), and DIPEA (4 eq.) to a 50 mL round-bottom flask. Then, react under nitrogen at 0 °C for 10 minutes, add EDCI (2 eq.), continue stirring for 10 minutes, add 4-phenylbutanylamine (1.1 eq.), and then move the reaction to room temperature. After reacting for 16 hours, the reaction is detected by TLC. A new spot is formed, quenched with water, extracted with dichloromethane, the organic phase is collected, dried, concentrated, wet-processed, and purified by column chromatography to obtain the amide condensation product 6b.

[0118] Step f: Aldehyde compound 6b (1 eq.) and 3-methoxypyridine-2-amine (1 eq.) were added to toluene and stirred at 140 °C for 30 minutes. After cooling, mercaptoacetic acid (3 eq.) was added, and the reaction was carried out overnight at 140 °C. TLC and LCMS showed that the starting material had completely reacted and a new spot had formed. The dissolved substance was removed under reduced pressure, followed by wet loading and column chromatography to obtain thiazolidinone compound 7b.

[0119] Step g: Thiazolone compound 7b (1 eq.) and anhydrous dichloromethane were added to a 50 mL round-bottom flask. The mixture was then transferred to 0 °C, and m-chloroperoxybenzoic acid (3 eq.) was added. The mixture was then moved to room temperature and reacted overnight. LCMS analysis showed that the starting material had completely reacted and the target molecular weight was generated. For post-treatment, saturated sodium thiosulfate was added to the reaction mixture, followed by extraction with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, evaporated to dryness, and purified by column chromatography to obtain the final thiazolidinone sulfone target compound 7. 1H NMR (400MHz, CDCl3) δ7.94(d,J=4.4Hz,1H),7.83(s,1H),7.74(d,J=7.8Hz,1H),7.57 (d,J=7.8Hz,1H),7.40(t,J=7.8Hz,1H),7.30–7.26(m,2H),7.25(d,J=7.8Hz,1H),7.2 1(d,J=5.6Hz,1H),7.17(t,J=6.6Hz,3H),6.50(s,1H),6.15(t,J=5.8Hz,1H),4.17–4 .06(m,2H),3.91(s,3H),3.49–3.38(m,2H),2.66(t,J=7.2Hz,2H),1.74–1.58(m,4H); 13 C NMR (100MHz, CDCl3) δ166.6,161.2,151.3,142.1,140.5,138.3,135.7,131.8,129.3,129.2 ,128.5,128.5,128.1,127.2,126.0,125.2,120.9,82.2,56.4,51.7,40.1,35.6,29.3,28.8.

[0120] Example 8

[0121]

[0122] 1 H NMR (400MHz, CDCl3) δ7.79(d,J=9.8Hz,2H),7.57(s,1H),7.32(t,J=7.8Hz,2H),7.28–7.22(m,5H),7.18(t,J=7.4Hz,3H), 6.15(s,1H),5.99(s,1H),4.12–4.03(m,2H),3.42(q,J=6.6Hz,2H),3.18(s,1H),2.65(t,J=7.2Hz,2H),1.73–1.57(m,4H); 13 C NMR (100MHz, CDCl3) δ165.5,162.1,142.1,136.5,135.7,133.7,132.2,130.3,129.8,128.56 ,128.55,128.4,127.5,126.1,125.2,124.2,83.2,81.5,80.2,50.9,40.3,35.6,29.2,28.8.

[0123] Example 9

[0124]

[0125] 1 H NMR (400MHz, CDCl3) δ8.21(d,J=7.6Hz,1H),7.98–7.94(m,3H),7.70(d,J=7.6Hz,1H),7.52(t,J=5.8Hz,1H),7.29–7.25(m,2H),7.19–7.17(m ,3H),6.85(s,1H),6.60(dd,J=5.8,2.4Hz,1H),4.21–4.03(m,2H),3.82(s,3H),3.49–3.36(m,2H),2.65(t,J=7.2Hz,2H),1.71–1.58(m,4H); 13 C NMR (100MHz, CDCl3) δ167.4,163.4,163.2,151.0,150.2,149.8,148.4,142.1,139.3,12 8.5,128.4,126.7,125.9,123.2,108.7,101.8,80.2,55.6,53.1,39.4,35.5,29.1,28.7.

[0126] Example 10

[0127]

[0128] 1 H NMR (400MHz, CDCl3) δ8.21(d,J=8.0Hz,2H),7.98(t,J=8.0Hz,2H),7.69(d,J=7.8Hz,1H),7.51–7.45(m,2H),7.28(t,J=7.4Hz,2H) ,7.19(t,J=6.8Hz,3H),6.80(s,1H),4.17–4.02(m,2H),3.46–3.39(m,2H),2.65(t,J=7.2Hz,2H),2.23(s,3H),1.68–1.59(m,4H); 13 C NMR (100MHz, CDCl3) δ163.22,163.17,150.2,149.8,147.7,147.4,142.2,139.3,139.1,1 31.1,128.6,128.5,126.7,126.0,123.3,116.0,80.3,53.0,39.5,35.6,29.2,28.8,17.9.

[0129] Example 11

[0130]

[0131] 1 1H NMR (400 MHz, CDCl3) δ 8.33 (d, J=8.4 Hz, 1H), 8.21 (d, J=7.8 Hz, 1H), 8.14 (d, J=4.0 Hz, 1H), 7.98 (t, J=7.8 Hz, 1H), 7.71 (d, J=7.6 Hz, 1H), 7.65 (td, J=8.8, 1.8 Hz, 1H), 7.50 (t, J=6.0 Hz, 1H), 7.29 (t, J=8.0 Hz, 2H), 7.19 (t, J=6.8 Hz, 3H), 7.06–7.03 (m, 1H), 6.83 (s, 1H), 4.20–4.04 (m, 2H), 3.42 (q, J=6.4 Hz, 2H), 2.65 (t, J=7.2 Hz, 2H), 1.68–1.58 (m, 4H); 13 13C NMR (100 MHz, CDCl3) δ 163.4, 163.1, 150.1, 149.6, 149.4, 147.7, 142.1, 139.3, 138.4, 128.5, 128.4, 126.7, 125.9, 123.2, 121.3, 116.5, 80.1, 52.9, 39.4, 35.5, 29.0, 28.7.

[0132] Example 12

[0133]

[0134] 1 1H NMR (400 MHz, CDCl3) δ 8.22 (d, J=7.8 Hz, 1H), 8.10 (dd, J=4.6, 1.6 Hz, 1H), 7.93 (t, J=7.8 Hz, 1H), 7.65 (t, J=6.0 Hz, 1H), 7.57–7.54 (m, 2H), 7.28 (t, J=8.0 Hz, 2H), 7.18 (t, J=7.4 Hz, 3H), 7.12 (dd, J=7.6, 4.6 Hz, 1H), 6.45 (s, 1H), 4.17–4.04 (m, 2H), 3.45 (q, J=6.4 Hz, 2H), 2.65 (t, J=7.2 Hz, 2H), 2.35 (s, 3H), 1.71–1.60 (m, 4H); 13C NMR (100MHz, CDCl3) δ163.3,162.1,150.7,148.6,148.1,146.5,142.2,140.4,139.1,13 0.5,128.6,128.5,126.2,126.0,123.7,123.4,82.6,52.1,39.5,35.6,29.3,28.9,18.3

[0135] Example 13

[0136]

[0137] 1 H NMR (400MHz, CDCl3) δ8.37(d,J=8.4Hz,1H),8.21(d,J=7.8Hz,1H),8.16(d,J=4.8Hz,1H),7.99(t,J=7.6Hz,1H),7.77–7.70(m,2H),7.46(t,J=6. 0Hz,1H),7.08(t,J=6.0Hz,1H),6.83(s,1H),4.24–4.09(m,2H),3.41–3 .36(m,2H),1.57–1.50(m,2H),1.38–1.29(m,2H),0.93(t,J=7.4Hz,3H); 13 C NMR (100MHz, CDCl3) δ163.4,163.1,150.3,149.7,149.6,147.8,139.4,138.5,126.7,123.3,121.4,116.6,80.2,53.1,39.3,31.5,20.2,13.8.

[0138] Example 14

[0139]

[0140] 1 H NMR (400MHz, CDCl3) δ8.33(d,J=8.4Hz,1H),8.20(d,J=7.8Hz,1H),8.15(d,J=4.8Hz,1H),7.99(t,J=7.8Hz,1H),7.71(d,J=7.8Hz,2H),7.53–7.49 (m,2H),7.39(s,1H),7.07(t,J=6.2Hz,1H),6.81(s,1H),6.23(s,1H),4. 31–4.08(m,4H),3.42–3.30(m,2H),1.93–1.86(m,2H),1.59–1.52(m,2H);13 C NMR (100MHz, CDCl3) δ163.5,163.3,150.1,149.8,149.51,147.8,139.41,139.37,1 38.6,129.2,126.8,123.3,121.4,116.6,105.5,80.2,53.1,51.6,38.9,27.7,26.7.

[0141] Example 15

[0142]

[0143] 1 H NMR (400MHz, CDCl3) δ8.33(d,J=8.6Hz,1H),8.20(d,J=7.8Hz,1H),8.15(d,J=5.0Hz,1H),7.9 7(t,J=7.8Hz,1H),7.90(t,J=5.8Hz,1H),7.72(d,J=7.8Hz,1H),7.49(td,J1=8.0Hz,J2=2.0H z,1H),7.35–7.28(m,5H),7.04(t,J=6.2Hz,1H),6.79(s,1H),4.61–4.54(m,2H),4.18(d,J=1 6.6Hz,1H),3.75(d,J=16.6Hz,1H),3.71–3.67(m,1H),3.65–3.61(m,2H),3.59–3.52(m,1H); 13 C NMR (100MHz, CDCl3) δ163.2,163.0,150.23,150.18,149.6,147.6,139.2,138.5,13 8.0,128.6,128.0,127.9,127.2,123.3,121.3,116.7,80.1,73.3,68.6,53.0,39.4.

[0144] Example 16

[0145]

[0146] 1H NMR(400MHz, CDCl3)δ8.34(d,J=8.4Hz,1H),8.15–8.10(m,3H),7.91(t,J=7.8Hz,1 H),7.71–7.65(m,2H),7.00(dd,J=7.2,4.8Hz,1H),6.78(s,1H),5.31(d,J=16.8Hz, 1H),4.07(d,J=16.8Hz,1H),3.61–3.52(m,1H),3.37–3.27(m,4H),3.13–3.07(m,1 H),2.31(t,J=6.4Hz,2H),2.09–2.01(m,1H),1.89–1.79(m,3H),1.77–1.62(m,2H); 13 CNMR (100MHz, CDCl3) δ171.2,163.6,163.4,150.5,150.3,149.6,147.4,138.7,138. 3,127.3,123.1,121.1,116.6,80.3,53.4,46.7,45.8,39.9,32.7,26.0,24.3,23.6.

[0147] Example 17

[0148]

[0149] 1 H NMR (400MHz, CDCl3) δ8.35(d,J=8.4Hz,1H),8.20(d,J=7.6Hz,1H),8.15(d,J=4.8Hz,1H),7.97(t,J=7.8Hz,1H),7.75–7.69(m,2H),7.56(t,J=5. 4Hz,1H),7.06(t,J=6.2Hz,1H),6.82(s,1H),4.29(d,J=16.4Hz,1H),4. 10(d,J=16.8Hz,1H),3.45–3.38(m,4H),3.32(s,3H),1.64–1.58(m,4H); 13 C NMR (100MHz, CDCl3) δ163.4,163.3,150.3,149.8,149.5,147.7,139.3,13 8.5,126.8,123.3,121.4,116.7,80.2,72.3,58.7,53.1,39.2,26.8,26.4.

[0150] Example 18

[0151]

[0152] 1 H NMR (400 MHz, CDCl3 ) δ 8.18 (d, J=7.8 Hz, 1H), 8.01 (t, J=5.6 Hz, 1H), 7.95 (d, J=4.6 Hz, 1H), 7.90 (t, J=7.8 Hz, 1H), 7.64 (d, J=7.8 Hz, 1H), 7.32 (d, J=8.4 Hz, 1H), 7.22 (dd, J=8.4, 4.6 Hz, 1H), 6.48 (s, 1H), 4.18–4.05 (m, 2H), 3.95 (s, 3H), 3.56–3.47 (m, 1H), 3.45–3.40 (m, 3H), 3.33 (s, 3H), 1.71–1.62 (m, 4H); 13 C NMR (100 MHz, CDCl3) δ 163.5, 161.3, 150.7, 150.6, 148.4, 140.4, 138.9, 138.8, 125.7, 124.9, 123.3, 121.2, 82.6, 72.3, 58.7, 56.5, 51.8, 39.5, 27.1, 26.6.

[0153] Example 19

[0154]

[0155] 1 H NMR (400 MHz, CDCl3) δ 8.35 (d, J=8.4 Hz, 1H), 8.18 (d, J=7.8 Hz, 1H), 8.13 (d, J=4.4 Hz, 1H), 7.96 (t, J=7.8 Hz, 1H), 7.71 (d, J=7.6 Hz, 2H), 7.65 (d, J=6.4 Hz, 1H), 7.05 (t, J=6.0 Hz, 1H), 6.82 (s, 1H), 4.52 (dd, J=16.6, 2.0 Hz, 1H), 4.12 (d, J=16.6 Hz, 1H), 3.57 (s, 3H), 3.53–3.46 (m, 1H), 3.41–3.33 (m, 1H), 2.35 (t, J=7.2 Hz, 2H), 1.95–1.85 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 173.9, 163.44, 163.38, 150.1, 150.0, 149.5, 147.7, 139.2, 138.5, 127.1, 123.3, 121.3, 116.6, 80.3, 53.2, 51.8, 39.0, 31.6, 24.5.

[0156] Example 20

[0157]

[0158] 1 H NMR (400MHz, CDCl3) δ8.07(s,1H),8.02(d,J=4.8Hz,1H),7.81(d,J=10.0Hz,2H),7.49(s,1H),7.43(d,J=6.4Hz,2H),7.38(s,1H),7.10(s,1H ),6.88(d,J=5.2Hz,1H),6.87(s,1H),6.24(s,1H),4.20–4.00(m,4H), 3.41–3.37(m,2H),2.36(s,3H),1.96–1.89(m,2H),1.60–1.53(m,2H); 13 C NMR (100MHz, CDCl3) δ166.7,162.1,150.0,149.2,147.4,139.2,135.7,131.2,129.9,12 9.4,129.3,128.6,125.9,122.9,118.3,105.6,80.7,52.1,51.2,39.6,28.0,25.9,21.4.

[0159] Example 21

[0160]

[0161] 1 H NMR (400MHz, CDCl3) δ8.30 (s, 1H), 8.02 (d, J = 5.0Hz, 1H), 7.79 (s, 1H), 7.69 (d, J = 7. 2Hz,1H),7.44–7.38(m,2H),7.26(t,J=7.4Hz,2H),7.16(t,J=8.6Hz,3H),6.88(d,J =5.8Hz,2H),6.42(t,J=5.8Hz,1H),3.91(d,J=17.2Hz,1H),3.59(dd,J=17.0,1.6Hz ,1H),3.41(q,J=6.4Hz,2H),2.63(t,J=7.2Hz,2H),2.38(s,3H),1.71–1.57(m,4H); 13C NMR (100MHz, CDCl3) δ168.3,166.5,151.0,149.9,147.4,142.1,136.2,132.2,129.8,128.8, 128.49,128.46,127.8,126.0,125.2,122.4,115.8,83.6,53.6,40.2,35.5,29.2,28.7,21.5.

[0162] Example 22

[0163]

[0164] 1 H NMR (400MHz, CDCl3) δ8.30(s,1H),8.03(s,1H),7.84(s,1H),7.77(d,J=6.8H z,1H),7.49(s,1H),7.47–7.39(m,3H),6.99(s,1H),6.88(s,2H),6.25(s,1H ),4.19(t,J=7.0Hz,2H),3.95(d,J=17.2Hz,1H),3.62(d,J=16.8Hz,1H),3.4 4–3.40(m,2H),2.39(d,J=3.0Hz,3H),1.98–1.92(m,2H),1.63–1.57(m,2H); 13 C NMR (100MHz, CDCl3) δ168.3,166.7,151.1,149.9,147.5,139.3,136.1,132.2,129.8,12 9.5,128.9,128.0,125.3,122.4,115.9,105.8,83.7,53.6,51.3,39.8,28.2,26.0,21.6.

[0165] Example 23

[0166]

[0167] 1 H NMR(400MHz, CDCl3)δ7.80(s,1H),7.74(s,1H),7.48(s,2H),7.32–7.23(m,7H),7.19(t,J=7.2Hz,3H),6.13 (s,1H),6.03(s,1H),4.07(t,,J=18.8Hz,2H),3.50–3.39(m,2H),2.66(t,J=7.0Hz,2H),1.75–1.63(m,4H); 13C NMR (100MHz, CDCl3) δ166.4,162.2,142.1,136.3,135.9,130.7,129.8,129.7,129.6, 128.8,128.6,128.5,128.2,127.3,126.0,125.2,83.5,50.9,40.2,35.6,29.3,28.8.

[0168] Example 24

[0169]

[0170] 1 H NMR (400MHz, CDCl3) δ7.69(s,1H),7.50(d,J=8.4Hz,1H),7.37(d,J=8.0Hz,1H),7.34–7.24(m,8H),7.18(t,J=6.6Hz,3H) ,7.08(d,J=7.6Hz,1H),5.91(s,1H),4.08–3.98(m,2H),2.65(t,J=7.0Hz,2H),2.32(t,J=6.8Hz,2H),1.78–1.67(m,4H); 13 C NMR (100MHz, CDCl3) δ171.5,162.4,142.1,139.3,136.2,130.23,130.15,129.6,12 8.6,128.5,128.1,126.0,125.2,123.2,118.9,83.9,50.7,37.7,35.8,31.1,25.1.

[0171] Example 25

[0172]

[0173] 1 H NMR (400MHz, CDCl3) δ7.80 (s, 1H), 7.75 (t, J = 3.4Hz 1H),7.48(d,J=4.4Hz,2H),7.28(d,J=7.4Hz,2H),7.20–7.16(m,4H),7.12(s,1H),7.05–7.00(m,2H),6.20(t,J=5. 8Hz,1H),6.01(s,1H),4.10–4.00(m,2H),3.45–3.40(m,2H),2.65(t,J=7.2Hz,2H),2.28(s,3H),1.74–1.58(m,4H); 13C NMR (100MHz, CDCl3) δ166.4,162.3,142.1,139.8,136.2,135.7,130.7,129.7,129.6,129.4,129.2,1 28.9,128.6,128.55,128.52,127.3,126.02,125.97,122.4,83.7,50.9,40.2,35.6,29.2,28.8,21.5.

[0174] Example 26

[0175]

[0176] 1 H NMR (400MHz, CDCl3) δ7.79(s,1H),7.75(d,J=6.2Hz,1H),7.47(s,2H),7.29(t,J=7.2Hz,2H),7.18(d,J=7.4Hz,3H),6.77(s,1H),6 .66(q,J=8.4Hz,2H),6.27(s,1H),5.93(s,3H),4.09–3.99(m,2H),3.42(q,J=6.4Hz,2H),2.65(t,J=7.4Hz,2H),1.75–1.60(m,4H); 13 C NMR (100MHz, CDCl3) δ166.4,162.5,148.4,147.6,142.1,136.2,130.9,129.7,129.3,129.2,128. 9,128.55,128.51,127.5,126.0,119.4,108.6,107.2,102.1,84.0,50.9,40.2,35.6,29.2,28.8.

[0177] Example 27

[0178]

[0179] 11H NMR (400 MHz, CDCl3) δ 7.80 (s, 1H), 7.76–7.73 (m, 1H), 7.49-7.47 (m, 2H), 7.28 (t, J=7.8 Hz, 2H), 7.22-7.17 (m, 4H), 6.87 (t, J=2.2 Hz, 1H), 6.81-6.75 (m, 2H), 6.17 (t, J=5.4 Hz, 1H), 6.01 (s, 1H), 4.10-4.01 (m, 2H), 3.72 (s, 3H), 3.43 (q, J=6.8 Hz, 2H), 2.66 (t, J=7.2 Hz, 2H), 1.74–1.59 (m, 4H); 13 13C NMR (100 MHz, CDCl3) δ 166.4, 162.2, 160.3, 142.1, 136.8, 136.2, 130.7, 130.3, 129.7, 129.5, 128.9, 128.6, 128.5, 127.2, 126.0, 117.3, 113.6, 111.6, 83.5, 55.6, 51.0, 40.2, 35.6, 29.2, 28.8.

[0180] Example 28

[0181]

[0182] 1 1H NMR (400 MHz, CDCl3) δ 7.82 (s, 1H), 7.75 (d, J=7.0 Hz, 1H), 7.50–7.44 (m, 2H), 7.30–7.22 (m, 3H), 7.18 (t, J=8.0 Hz, 3H), 7.10 (d, J=9.6 Hz, 1H), 7.02 (d, J=8.0 Hz, 1H), 6.93 (t, J=8.2 Hz, 1H), 6.30 (t, J=5.8 Hz, 1H), 6.04 (s, 1H), 4.11–4.02 (m, 2H), 3.42–3.39 (m, 2H), 2.65 (t, J=7.2 Hz, 2H), 1.73–1.58 (m, 4H); 13C NMR (100MHz, CDCl3) δ166.3,162.7(J=247.1Hz),162.2,142.1,137.2(J=9.8Hz),136.3,130.8(J=8.9Hz),130.6,129.8,129.1,1 29.0,128.54,128.51,127.3,126.0,120.4(J=3.3Hz),115.1(J=20.9Hz),112.7(J=24.7Hz),80.3,52.9,40.2,35.6,29.2,28.8; 19 F NMR (376MHz, CDCl3) δ-109.7.

[0183] Example 29

[0184]

[0185] 1 H NMR (400MHz, CDCl3) δ7.81 (s, 1H), 7.75 (d, J = 7.6Hz, 1H), 7.53–7.45 (m, 2H), 7.36 (s, 1H), 7.28 (t, J = 7.2Hz, 2H), 7.22–7. 12(m,6H),6.15(s,1H),6.01(s,1H),4.07(t,J=17.8Hz,2H),3.47–3.43(m,2H),2.66(t,J=7.0Hz,2H),1.72–1.61(m,4H); 13 C NMR (100MHz, CDCl3) δ166.3,162.2,142.1,136.9,136.3,135.2,130.6,129.9,129.2,129 .0,128.6,128.5,128.4,127.3,126.0,125.4,123.1,83.2,50.8,40.3,35.6,29.2,28.8.

[0186] Example 30

[0187]

[0188] 1H NMR (400MHz, CDCl3) δ7.78(s,1H),7.69(d,J=7.6Hz,1H),7.52(d,J=7.6Hz,1H),7.43(t,J=7.8Hz,1H),7.28(t,J=7.8Hz,3H),7.23–7.17(m,4H) ,6.89–6.84(m,2H),6.22(s,1H),6.03(s,1H),4.09(t,J=17.4Hz,2H),3 .84(s,3H),3.46–3.42(m,2H),2.67(t,J=7.2Hz,2H),1.75–1.61(m,4H); 13 C NMR (100MHz, CDCl3) δ166.6,162.6,154.5,142.1,135.7,132.0,130.5,129.8,129.2,128.8,12 8.6,128.5,128.3,128.1,126.0,123.3,121.1,112.5,82.6,56.0,51.2,40.2,35.6,29.3,28.8.

[0189] Example 31

[0190]

[0191] 1 H NMR(400MHz, CDCl3)δ7.86(s,1H),7.76–7.74(m,1H),7.53–7.47(m,6H),7.41(t,J=7.4Hz,2H),7.39–7.32(m,3H),7.29–7.26(m,2H) ),7.18(t,J=6.8Hz,3H),6.22(s,1H),6.08(s,1H),4.14–4.05(m,2H),3.47–3.41(m,2H),2.65(t,J=7.2Hz,2H),1.74–1.59(m,4H); 13 C NMR (100MHz, CDCl3) δ166.4,162.3,142.1,141.1,139.7,136.3,134.9,130.7,129.8,129.5,129.0,1 28.9,128.55,128.52,128.2,128.0,127.3,127.2,126.0,125.4,83.5,51.0,40.2,35.6,29.2,28.8.

[0192] Example 32

[0193]

[0194] 1 H NMR (400 MHz, CDCl3) δ 9.81 (s, 1H), 8.16 (d, J=8.0 Hz, 1H), 8.05 (d, J=8.0 Hz, 1H), 8.02 (s, 1H), 7.86 (d, J=7.6 Hz, 2H), 7.77 (d, J=8.8 Hz, 1H), 7.65–7.58 (m, 2H), 7.50 (t, J=7.8 Hz, 1H), 7.40 (d, J=8.8 Hz, 1H), 7.19 (t, J=7.4 Hz, 2H), 7.10 (t, J=7.0 Hz, 3H), 6.67 (s, 1H), 6.05 (s, 1H), 4.03–3.89 (m, 2H), 3.44–3.30 (m, 2H), 2.57 (t, J=7.0 Hz, 2H), 1.66–1.55 (m, 4H); 13 C NMR (100 MHz, CDCl3) δ 167.0, 163.1, 142.2, 136.0, 134.1, 133.7, 132.5, 130.2, 129.4, 129.1, 128.74, 128.71, 128.6, 128.5, 128.4, 128.3, 128.2, 125.9, 125.4, 125.2, 122.7, 69.3, 58.9, 40.1, 35.5, 29.2, 28.8.

[0195] Example 33

[0196]

[0197] 1 H NMR (400 MHz, CDCl3) δ 7.80 (d, J=7.8 Hz, 1H), 7.75 (s, 1H), 7.56 (t, J=7.8 Hz, 1H), 7.43 (d, J=7.8 Hz, 1H), 7.31–7.26 (m, 2H), 7.20–7.17 (m, 3H), 6.23 (s, 1H), 5.46 (s, 1H), 3.85 (s, 2H), 3.49–3.44 (m, 2H), 2.69–2.60 (m, 3H), 1.75–1.63 (m, 4H), 1.04–0.94 (m, 2H), 0.69–0.59 (m, 2H); 13C NMR (100MHz, CDCl3) δ166.5,163.7,142.1,136.5,130.6,130.1,129.9,128.8, 128.6,128.5,126.8,126.0,82.9,51.2,40.3,35.6,29.3,28.8,26.7,8.4,6.3.

[0198] Example 34

[0199] 1 H NMR (400MHz, CDCl3) δ7.77(d,J=7.6Hz,2H),7.53(t,J=7.6Hz,1H),7.43(d,J=7.6Hz,1 H),7.28(t,J=7.4Hz,2H),7.18(d,J=7.2Hz,3H),6.23(s,1H),5.55(s,1H),4.32(t,J=1 1.8Hz,1H),3.87–3.74(m,2H),3.50–3.45(m,2H),2.67(t,J=7.0Hz,2H),1.90–1.81(m ,2H),1.73–1.54(m,6H),1.51(t,J=12.0Hz,1H),1.41–1.22(m,3H),1.03–0.87(m,2H); 13 CNMR (100MHz, CDCl3) δ166.5,162.8,142.1,136.3,133.0,129.7,129.6,128.6,128.5 ,126.4,126.0,79.6,54.5,50.2,40.3,35.6,31.8,29.9,29.3,28.8,25.7,25.4,25.1.

[0200] Example 35

[0201]

[0202] 1H NMR(400MHz, CDCl3)δ7.81(d,J=7.6Hz,1H),7.62(s,1H),7.46(t,J=7.6Hz ,1H),7.30–7.23(m,6H),7.14(d,J=6.8Hz,3H),7.04(s,2H),6.51(t,J=5.2 Hz,1H),5.38(d,J=14.8Hz,1H),5.34(s,1H),3.90–3.80(m,2H),3.69(d,J =14.8Hz,1H),3.40–3.35(m,2H),2.61(t,J=6.8Hz,2H),1.67–1.56(m,4H); 13 C NMR (100MHz, CDCl3) δ166.4,162.7,142.1,136.2,133.6,131.1,129.7,129.3,129.2,12 8.7,128.6,128.5,128.4,126.9,125.9,80.7,50.3,45.8,40.1,35.5,29.1,28.7,14.2.

[0203] Example 36

[0204]

[0205] 1 H NMR(400MHz, CDCl3)δ7.81(d,J=7.6Hz,1H),7.54(s,1H),7.51(t,J=7.8Hz,1H) ,7.32–7.24(m,6H),7.21–7.18(m,3H),7.10(d,J=7.2Hz,2H),6.19(t,J=5.2Hz, 1H),5.15(s,1H),4.33–4.28(m,1H),3.84(t,J=17.2Hz,2H),3.48–3.43(m,2H), 2.97–2.89(m,2H),2.86–2.79(m,1H),2.67(t,J=7.2Hz,2H),1.76–1.61(m,4H); 13 C NMR (100MHz, CDCl3) δ166.4,162.6,142.1,137.6,136.3,131.1,129.8,129.2,129.1,12 8.8,128.6,128.5,127.5,127.3,126.0,82.2,50.5,44.4,40.2,35.6,33.6,29.3,28.8.

[0206] Example 37

[0207]

[0208] 1 H NMR (400MHz, CDCl3) δ7.74(d,J=12.0Hz,2H),7.51(t,J=7.6Hz,1H),7.45(d,J=7.8Hz,1H),7.28(t,J=7.8Hz,2H),7.18(t,J=6.6Hz,3H ),6.83(s,1H),6.31(s,1H),6.15(s,1H),4.06–3.95(m,2H),3.47–3.42(m,2H),2.66(t,J=7.2Hz,2H),2.39(s,3H),1.75–1.63(m,4H); 13 C NMR (100MHz, CDCl3) δ171.5,166.4,160.8,156.4,142.1,136.2,130.4,130.0,12 9.8,128.6,128.5,126.0,125.5,97.2,80.9,50.0,40.2,35.6,29.3,28.8,12.8.

[0209] Example 38

[0210]

[0211] 1 H NMR (400MHz, CDCl3) δ8.29(d,J=8.4Hz,1H),8.19(d,J=4.4Hz,1H),7.77–7.71(m,3H),7.46(d,J=4.0Hz,2H),7.28(t,J=7.8Hz,2H),7.18(d,J=7. 2Hz,3H),7.10–7.07(t,J=6.2Hz,1H),6.88(s,1H),6.15(s,1H),4.17–4 .04(m,2H),3.46–3.41(m,2H),2.65(t,J=7.2Hz,2H),1.74–1.59(m,4H); 13 C NMR (100MHz, CDCl3) δ166.7,162.2,149.2,148.0,142.1,138.6,136.0,131.4,129.9,129. 5,128.6,128.5,128.3,126.03,126.00,121.8,117.9,80.7,52.2,40.2,35.6,29.3,28.8.

[0212] Example 39

[0213]

[0214] 1 H NMR(400MHz,CDCl3)δ8.11(s,1H),8.04(d,J=4.4Hz,1H),7.75(s,1H),7.71(s,1H),7.46(d,J=4.0Hz,2H),7.28(t,J=8.2Hz,2H),7.19(t,J=6.8Hz,3H),6.90(d,J=4.8Hz,1H),6.88(s,1H),6.09(s,1H),4.15–4.03(m,2H),3.47–3.43(m,2H),2.66(t,J=7.0Hz,2H),2.39(s,3H),1.75–1.62(m,4H); 13 C NMR(100MHz,CDCl3)δ166.7,162.1,150.2,149.3,147.6,142.1,136.0,131.5,129.9,129.5,128.6,128.5,128.2,126.04,126.00,123.1,118.4,80.8,52.2,40.2,35.6,29.3,28.8,21.5.

[0215] Example 40

[0216]

[0217] 1 H NMR(400MHz,CDCl3)δ8.92(d,J=3.2Hz,1H),8.10(d,J=8.4Hz,1H),7.78(s,1H),7.73(t,J=7.2Hz,2H),7.64(d,J=7.2Hz,1H),7.55(d,J=8.0Hz,1H),7.45–7.40(m,2H),7.34–7.28(m,3H),7.18(t,J=9.4Hz,3H),7.06(s,1H),6.13(s,1H),4.35–4.22(m,2H),3.39–3.31(m,2H),2.63(t,J=7.0Hz,2H),1.70–1.56(m,4H); 13C NMR (100MHz, CDCl3) δ166.6,163.8,150.8,143.5,142.1,136.7,135.5,132.6,132.0,131.0,129 .5,129.1,128.6,128.5,128.4,127.4,126.2,126.0,122.2,83.1,51.6,40.1,35.6,29.2,28.8.

[0218] Example 41

[0219]

[0220] 1 H NMR (400MHz, CDCl3) δ8.30(s,1H),8.12(s,1H),8.08(s,1H),7.31–7.15(m,10H),6.37(s,1H),6.11(s ,1H),4.18–4.06(m,2H),3.91(s,3H),3.41(q,J=6.4Hz,2H),2.64(t,J=7.2Hz,2H),1.72–1.57(m,4H); 13 C NMR (100MHz, CDCl3) δ165.4,165.2,162.2,142.1,136.4,135.5,132.0,131.7,131.6,130.3, 129.7,129.3,128.54,128.51,128.4,126.0,125.4,83.2,52.9,51.0,40.3,35.5,29.1,28.8.

[0221] Example 42

[0222]

[0223] 1 H NMR (400MHz, CDCl3) δ8.29 (d, J=8.4Hz, 1H), 8.18 (dd, J=5.2, 1.8Hz, 1H), 7.79 –7.72(m,3H),7.53(s,1H),7.28(t,J=7.2Hz,3H),7.18(t,J=8.2Hz,3H),7.09 (dd,J=7.4,4.8Hz,1H),6.83(s,1H),6.27(t,J=5.8Hz,1H),4.18–4.04(m,2H) ,3.41(q,J=6.6Hz,2H),3.15(s,1H),2.64(t,J=7.2Hz,2H),1.72–1.57(m,4H); 13C NMR (100MHz, CDCl3) δ165.7,162.0,149.0,148.0,142.1,138.6,136.2,132.8,132.1,131.7,128 .54,128.51,126.5,126.0,123.8,121.9,117.7,81.8,80.3,79.8,52.2,40.3,35.5,29.2,28.8.

[0224] Example 43

[0225]

[0226] 1 H NMR (400MHz, CDCl3) δ7.95(d,J=1.2Hz,1H),7.75(s,1H),7.64(s,1H),7.51–7.40(m,5H),7.34–7.23(m,7H),7.18(t,J =6.4Hz,3H),6.31(s,1H),6.10(s,1H),4.12–4.01(m,2H),3.46–3.40(m,2H),2.65(t,J=7.2Hz,2H),1.73–1.58(m,4H); 13 C NMR (101MHz, CDCl3) δ 166.4, 162.3 (J = 8.2Hz) 143.1 (J = 2.7Hz), 142.1, 139.0, 136.8, 135.8, 129.9 (J = 3.5Hz), 129.7, 129.4 ,129.2,128.60,128.55,128.51,128.2,127.9(J=2.2Hz),127.4,126.0,125.7,125.3,83.5,51.0,40.3,35.6,29.2,28.8.

[0227] Example 44

[0228]

[0229] 1 H NMR (400MHz, CDCl3) δ8.31(d,J=7.6Hz,1H),7.99(t,J=7.8Hz,1H),7.66(s,1H),7.55(d,J=7.6Hz,1H),7.34–7 .16(m,10H),5.97(s,1H),4.03(t,J=18.6Hz,2H),3.52–3.46(m,2H),2.66(t,J=6.2Hz,2H),1.70–1.66(m,4H);13 C NMR (100MHz, CDCl3) δ163.2,163.0,151.0,148.7,142.2,139.7,136.2,129.8,128 .6,128.5,128.4,126.4,126.0,125.0,124.0,83.7,51.1,39.6,35.6,29.3,28.9.

[0230] Example 45

[0231]

[0232] 1 H NMR (400MHz, CDCl3) δ8.24(s,1H),8.13(d,J=7.6Hz,1H),8.00(d,J=5.2Hz,1H),7.91(t,J=7. 8Hz,1H),7.68(t,J=5.8Hz,1H),7.61(d,J=7.6Hz,1H),7.48(s,1H),7.39(d,J=2.0Hz,1H),6. 87(d,J=5.2Hz,1H),6.82(s,1H),6.22(s,1H),4.16(t,J=7.0Hz,2H),4.10(d,J=17.2Hz,1H), 3.72(d,J=17.2Hz,1H),3.48–3.32(m,2H),2.37(s,3H),1.94–1.87(m,2H),1.61–1.54(m,2H); 13 C NMR (100MHz, CDCl3) δ168.4,163.4,151.0,150.6,150.2,149.8,147.2,139.3,139.2 ,129.2,125.0,122.7,122.2,115.5,105.4,83.9,54.6,51.5,38.8,27.7,26.6,21.4.

[0233] Example 46

[0234]

[0235] 1H NMR (400 MHz, CDCl3) δ 8.32 (d, J=7.8 Hz, 1H), 8.02 (t, J=7.8 Hz, 1H), 7.58 (d, J=7.8 Hz, 2H), 7.26 (s, 3H), 7.17 (d, J=7.6 Hz, 3H), 7.07 (d, J=9.6 Hz, 1H), 6.97 (d, J=5.6 Hz, 2H), 5.97 (s, 1H), 4.02 (s, 2H), 3.47 (p, J=7.8 Hz, 2H), 2.66 (t, J=7.0 Hz, 2H), 1.76–1.62 (m, 4H); 13 C NMR (100 MHz, CDCl3) δ 163.1, 162.9, 162.8 (J=247.3 Hz), 151.1, 148.3, 142.1, 139.9, 137.6 (J=9.9 Hz), 130.9 (J=9.1 Hz), 128.6, 128.5, 126.4, 126.0, 124.1, 119.9 (J=3.3 Hz), 115.2 (J=20.9 Hz), 112.4 (J=24.7 Hz), 83.2, 51.1, 39.6, 35.6, 29.2, 28.9; 19 F NMR (375 MHz, CDCl3) δ -109.5.

[0236] Example 47

[0237]

[0238] 1 H NMR (400 MHz, CDCl3) δ 8.31 (d, J=7.8 Hz, 1H), 8.01 (t, J=7.8 Hz, 1H), 7.63–7.58 (m, 2H), 7.32 (s, 1H), 7.29–7.22 (m, 4H), 7.20–7.17 (m, 3H), 7.09–7.06 (m, 1H), 6.00–5.98 (m, 1H), 4.07–3.98 (m, 2H), 3.50–3.46 (m, 2H), 2.66 (t, J=7.0 Hz, 2H), 1.72–1.64 (m, 4H); 13 C NMR (100 MHz, CDCl3) δ 163.2, 162.9, 151.0, 148.2, 142.1, 139.8, 137.2, 135.3, 130.7, 128.55, 128.48, 128.4, 126.5, 126.0, 125.2, 124.1, 122.7, 83.1, 51.0, 39.6, 35.6, 29.2, 28.9.

[0239] Example 48

[0240]

[0241] 1 H NMR (400MHz, CDCl3) δ8.20(d,J=7.6Hz,1H),8.12(d,J=8.2Hz,1H),7.98(t,J =7.8Hz,1H),7.71(d,J=7.6Hz,1H),7.55–7.47(m,2H),7.28(t,J=8.2Hz,2H), 7.19(t,J=6.2Hz,3H),6.88(d,J=7.6Hz,1H),6.87(s,1H),4.21-4.04(m,2H), 3.42(q,J=6.0Hz,2H),2.65(t,J=7.2Hz,2H),2.26(s,3H),1.68-1.59(m,4H); 13 C NMR (100MHz, CDCl3) δ162.9,156.6,149.9,149.8,148.3,141.8,138.9,138.4,128.2 ,128.1,126.4,125.6,122.9,120.4,113.0,79.9,52.9,39.1,35.3,28.8,28.5,23.7.

[0242] Example 49

[0243]

[0244] 1 H NMR (400MHz, CDCl3) δ8.47(d,J=1.6Hz,1H),8.23(d,J=7.8Hz,1H),8.06(d,J=5. 2Hz,1H),8.00(t,J=7.8Hz,1H),7.71(d,J=7.8Hz,1H),7.43(t,J=5.8Hz,1H),7. 28(t,J=7.6Hz,2H),7.20–7.17(m,3H),7.09(dd,J=5.4,1.8Hz,1H),6.77(s,1H) ,4.19–4.04(m,2H),3.49–3.36(m,2H),2.66(t,J=7.2Hz,2H),1.70–1.58(m,4H); 13C NMR (100MHz, CDCl3) δ163.6,163.1,150.32,150.31,149.4,148.3,146.2,142.1,139.5 ,128.6,128.5,126.8,126.0,123.5,121.9,116.7,80.1,52.9,39.5,35.6,29.1,28.8.

[0245] Example 50

[0246]

[0247] 1 H NMR (400MHz, CDCl3) δ8.35(d,J=8.4Hz,1H),8.14(t,J=5.6Hz,2H),7.96–7.89(m,3H),7.74-764(m,3H),7.53(t,J=7.2Hz,1H),7.41(t,J=7.6Hz, 2H),7.02(t,J=6.0Hz,1H),6.83(s,1H),4.60(d,J=16.6Hz,1H),4.13(d, J=16.6Hz,1H),3.59–3.43(m,2H),3.11–2.97(m,2H),2.12–1.97(m,2H); 13 C NMR (100MHz, CDCl3) δ200.0,163.5,163.4,150.1,150.0,149.5,147.6,139.1,138.5,136.7,133.3,128.7,128.2 127.0,123.3,121.3,116.7,80.2,53.2,39.3,36.1,23.8.

[0248] Example 51

[0249]

[0250] 1H NMR (400 MHz, CDCl3) δ 8.50 (s, 1H), 8.35 (d, J=8.4 Hz, 1H), 8.17 (t, J=5.8 Hz, 2H), 7.97 (t, J=7.8 Hz, 1H), 7.75–7.71 (m, 2H), 7.56 (d, J=8.0 Hz, 2H), 7.29 (t, J=7.8 Hz, 2H), 7.10–7.06 (m, 2H), 6.81 (s, 1H), 4.45 (d, J=16.6 Hz, 1H), 4.11 (d, J=16.6 Hz, 1H), 3.62-3.44 (m, 2H), 2.44–2.31 (m, 2H), 2.03-1.95 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 170.8, 164.2, 163.9, 149.91, 149.87, 149.4, 147.9, 139.4, 138.6, 138.3, 129.1, 127.1, 124.2, 123.4, 121.6, 119.8, 116.7, 80.2, 53.2, 38.7, 35.0, 26.1.

[0251] Example 52

[0252]

[0253] 1 H NMR (400 MHz, CDCl3) δ 8.37 (d, J=8.4 Hz, 1H), 8.17–8.12 (m, 2H), 8.06 (t, J=5.8 Hz, 1H), 7.93 (t, J=7.6 Hz, 1H), 7.72–7.68 (m, 2H), 7.03 (t, J=6.2 Hz, 1H), 6.79 (s, 1H), 5.10 (d, J=16.8 Hz, 1H), 4.07 (d, J=16.8 Hz, 1H), 3.57–3.49 (m, 1H), 3.41–3.34 (m, 1H), 3.29–3.15 (m, 4H), 2.38 (t, J=6.6 Hz, 2H), 2.07–2.02 (m, 1H), 1.91–1.81 (m, 1H), 1.11 (t, J=7.0 Hz, 3H), 0.97 (t, J=7.0 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 171.6, 163.6, 163.5, 150.6, 150.3, 149.7, 147.5, 138.9, 138.4, 127.2, 123.3, 121.2, 116.7, 80.3, 53.4, 42.1, 40.4, 39.9, 31.1, 24.2, 14.3, 13.0.

[0254] Example 53

[0255]

[0256] 1 H NMR (400MHz, CDCl3) δ8.36(d,J=8.4Hz,1H),8.21(d,J=8.0Hz,1H),8.16(d,J=4.8Hz,1H),7.99(t,J=7.6Hz,1H),7.77–7.71(m,2H),7. 56(t,J=6.0Hz,1H),7.08(dd,J1=7.2Hz,J2=5.2Hz,1H),6.82(s,1H),4.32(d,J=16.4Hz,1H),4.11(d,J=16.8Hz,1H),3.67(s,3H),3.48 -3.32(m,2H),2.36(t,J=7.0Hz,2H),1.70–1.58(m,4H); 13 C NMR (100MHz, CDCl3) δ174.0,163.5,163.3,150.3,149.8,149.6,147.8,139.3 ,138.6,126.9,123.4,121.4,116.6,80.2,53.2,51.8,39.0,33.5,29.0,22.0;

[0257] Example 54

[0258]

[0259] 1 H NMR(400MHz, CDCl3)8.40(d,J=8.4Hz,1H),8.21–8.16(m,3H),7.97(t,J=7.6Hz,1H),7.73(t,J=8.0Hz,2H),7.06(t,J=6.0Hz ,1H),6.81(s,1H),4.59(d,J=16.4Hz,1H),4.12(d,J=16.4Hz,1H),3.80–3.70(m,4H),3.65–3.54(m,1H),2.67–2.54(m,2H); 13 C NMR (100MHz, CDCl3) δ173.1,163.2,163.0,150.4,150.3,149.7,147.6,139.1,138.5,127.6,123.3,121.3,116.8,80.3,53.5,52.1,34.8,33.6.

[0260] Example 55

[0261]

[0262] 1 H NMR (400MHz, CDCl3) δ8.34(d,J=8.4Hz,1H),8.22(d,J=7.6Hz,1H),8.16(d,J=4.4Hz,1H),7.99(t,J=7.6Hz,1H),7.77–7.71(m,3H),7.09(t,J=6. 2Hz,1H),6.81(s,1H),4.34(d,J=16.4Hz,1H),4.11(d,J=16.4Hz,1H),3 .69(t,J=5.8Hz,2H),3.53–3.38(m,2H),1.87(s,1H),1.87–1.57(m,4H); 13 C NMR (100MHz, CDCl3) δ163.9,163.3,150.5,149.8,149.5,147.8,139.3,138.6,127.0,123.5,121.5,116.6,80.3,62.5,53.3,39.2,29.9,26.2.

[0263] Example 56

[0264]

[0265] 1 H NMR (400MHz, CDCl3) δ8.38(d,J=8.4Hz,1H),8.22(d,J=7.6Hz,1H),8.17(d,J=4.0Hz,1H),7.99(t,J=7.8Hz,1H),7.76(t,J=7.8Hz,1H),7.71( d,J=7.6Hz,1H),7.51(t,J=5.2Hz,1H),7.10–7.07(m,1H),6.84(s,1H) ,4.28–4.09(m,2H),3.44–3.36(m,4H),1.66–1.53(m,4H),1.19(s,9H); 13 C NMR (100MHz, CDCl3) δ163.2,163.1,150.3,149.6,149.5,147.7,139.2,138.5 ,126.6,123.2,121.3,116.6,80.1,72.6,60.9,53.0,39.3,27.8,27.6,26.5.

[0266] Example 57

[0267]

[0268] 1 1H NMR (400 MHz, CDCl3) δ 8.22 (dd, J=13.6, 8.2 Hz, 2H), 7.97 (t, J=7.6 Hz, 2H), 7.69 (d, J=7.6 Hz, 1H), 7.58–7.53 (m, 2H), 6.81 (s, 1H), 4.26 (d, J=16.4 Hz, 1H), 4.09 (d, J=16.4 Hz, 1H), 3.45–3.39 (m, 4H), 3.33 (s, 3H), 2.25 (s, 3H), 1.65–1.59 (m, 4H); 13 13C NMR (100 MHz, CDCl3) δ 163.3, 163.1, 150.3, 149.9, 147.7, 147.4, 139.2, 139.1, 131.1, 126.8, 123.3, 116.1, 80.4, 72.3, 58.7, 53.1, 39.2, 26.9, 26.4, 17.9.

[0269] Example 58

[0270]

[0271] 1 1H NMR (400 MHz, CDCl3) δ 8.23 (d, J=7.8 Hz, 1H), 8.13 (d, J=4.4 Hz, 1H), 7.93 (t, J=7.8 Hz, 1H), 7.74 (t, J=5.2 Hz, 1H), 7.59 (d, J=7.6 Hz, 1H), 7.55 (d, J=7.8 Hz, 1H), 7.15 (dd, J=7.6, 4.8 Hz, 1H), 6.46 (s, 1H), 4.25 (d, J=16.4 Hz, 1H), 4.09 (d, J=16.4 Hz, 1H), 3.52–3.40 (m, 4H), 3.33 (s, 3H), 2.36 (s, 3H), 1.69–1.63 (m, 4H); 13 13C NMR (100 MHz, CDCl3) δ 163.4, 162.0, 150.8, 148.8, 140.5, 139.1, 130.6, 126.3, 123.8, 123.5, 82.8, 72.4, 58.7, 52.1, 39.3, 26.9, 26.6, 18.2.

[0272] Example 59

[0273]

[0274] 1 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J=4.4 Hz, 1H), 7.86 (s, 1H), 7.74 (d, J=7.6 Hz, 1H), 7.55 (d, J=7.8 Hz, 1H), 7.37 (t, J=7.6 Hz, 1H), 7.25 (t, J=8.4 Hz, 1H), 7.17 (dd, J1=8.4 Hz, J2=4.8 Hz, 1H), 6.75 (t, J=4.8 Hz, 1H), 6.50 (s, 1H), 4.18–4.06 (m, 2H), 3.93 (s, 3H), 3.41–3.37 (m, 4H), 3.32 (s, 3H), 1.68–1.61 (m, 4H); 13 13C NMR (100 MHz, CDCl3) δ 166.6, 161.3, 151.2, 140.4, 138.3, 135.7, 131.6, 129.1, 128.1, 127.4, 125.2, 120.8, 82.2, 72.5, 58.7, 56.3, 51.6, 40.0, 27.2, 26.4.

[0275] Example 60

[0276]

[0277] 1 1H NMR (400 MHz, CDCl3) δ 7.85 (s, 1H), 7.73 (d, J=7.2 Hz, 1H), 7.55-7.48 (m, 2H), 7.41-7.33 (m, 4H), 7.30-7.23 (m, 4H), 7.19 (t, J=7.4 Hz, 2H), 6.12 (s, 1H), 5.96 (s, 1H), 3.92 (d, J=17.0 Hz, 1H), 3.61 (d, J=17.0 Hz, 1H), 3.47 (q, J=6.4 Hz, 2H), 2.67 (t, J=7.2 Hz, 2H), 1.76-1.63 (m, 4H); 13 13C NMR (100 MHz, CDCl3) δ 168.3, 166.2, 142.1, 137.9, 136.76, 131.9, 130.3, 129.6, 128.9, 128.6, 128.2, 127.4, 126.1, 125.5, 123.8, 86.6, 52.5, 40.3, 35.6, 29.3, 28.8.

[0278] Example 61

[0279]

[0280] 1 ¹H NMR (400 MHz, CDCl₃) δ 7.87(s,1H),7.76(d,J=7.6Hz,1H),7.55–7.48(m,2H),7.28(t,J=7.0Hz,4H),7.23–7.16(m,4H),7.11(t,J=7.0Hz,1H),7.06(d,J=7.6Hz,1H),6.26(s,1H),5.95(s,1H),3.91(d,J=16.8Hz,1H),3.57(d,J=17.2Hz,1H),3.49–3.43(m,2H),2.66(t,J=7.2Hz,2H),2.31(s,3H),1.73–1.62(m,4H); 13 ¹³C NMR (100 MHz, CDCl₃) δ 168.4,166.2,142.1,139.8,137.7,136.6,131.8,130.3,129.4,128.9,128.54,128.52,128.4,128.3,126.0,125.5,124.7,121.0,86.7,52.4,40.3,35.6,29.3,28.8,21.6.

[0281] Example 62

[0282]

[0283] 1 ¹H NMR (400 MHz, CDCl₃) δ 7.89(s,1H),7.78(d,J=7.6Hz,1H),7.52(t,J=7.6Hz,1H),7.46(d,J=7.6Hz,1H),7.26(t,J=7.0Hz,3H),7.18–7.10(m,4H),6.92(t,J=8.0Hz,1H),6.51(s,1H),5.98(s,1H),3.90(d,J=17.2Hz,1H),3.55(d,J=16.8Hz,1H),3.46–3.41(m,2H),2.64(t,J=6.8Hz,2H),1.70–1.60(m,4H); 13C NMR (100MHz, CDCl3) δ168.4, 166.1, 162.8 (J = 245.8Hz), 142.1, 139.3 (J = 10.0Hz), 136.7, 131.2, 130.7 (J = 9.1Hz), 130.33, 128 .8,128.50,128.46,126.0,125.4,118.4(J=3.1Hz),114.0(J=21.0Hz),110.7(J=25.4Hz),86.0,52.3,40.2,35.5,29.2,28.8; 19 F NMR (375MHz, CDCl3) δ-109.9.

[0284] Example 63

[0285]

[0286] 1 H NMR(400MHz, CDCl3)δ7.74(d,J=7.6Hz,1H),7.56(s,1H),7.49(t,J=7.6Hz, 1H),7.31–7.26(m,7H),7.22–7.17(m,4H),6.19(s,1H),5.37(s,1H),5.30( d,J=15.2Hz,1H),3.97(d,J=14.8Hz,2H),3.82(d,J=17.2Hz,1H),3.52(d,J =17.2Hz,1H),3.45–3.43(m,2H),2.67(t,J=7.2Hz,2H),1.75–1.61(m,4H); 13 C NMR (100MHz, CDCl3) δ168.8,166.2,142.0,136.5,134.1,131.0,130.1,129.2,129.1,128. 44,128.42,128.35,128.26,128.2,125.9,125.1,83.8,52.2,47.0,40.1,35.5,29.2,28.7.

[0287] Example 64

[0288]

[0289] 1H NMR (400MHz, CDCl3) δ7.72(s,1H),7.68(d,J=7.6Hz,1H),7.49(t,J=7.6Hz,1 H),7.41(d,J=8.0Hz,1H),7.28(t,J=8.4Hz,2H),7.19(t,J=7.2Hz,3H),6.96( s,1H),6.32(s,1H),6.11(s,1H),3.86(d,J=17.2Hz,1H),3.59(d,J=17.2Hz,1 H),3.48–3.43(m,2H),2.67(t,J=7.2Hz,2H),2.41(s,3H),1.74–1.62(m,4H); 13 C NMR (100MHz, CDCl3) δ171.2,167.9,166.5,157.8,142.1,136.5,130.6,130.1,128.8, 128.54,128.51,128.1,126.0,125.0,95.7,83.1,52.1,40.2,35.6,29.2,28.8,12.8.

[0290] Example 65

[0291]

[0292] 1 H NMR (400MHz, CDCl3) δ8.25(d,J=7.6Hz,1H),7.98(t,J=7.8Hz,1H),7.68(s,1H),7.55(d,J=7.8Hz,1H),7.37–7.26(m,8H),7.18(d,J= 6.4Hz,3H),6.01(s,1H),3.95(d,J=16.8Hz,1H),3.66(d,J=17.2Hz,1H),3.52–3.46(m,2H),2.67(t,J=6.4Hz,2H),1.71–1.67(m,4H); 13 C NMR (100MHz, CDCl3) δ168.5,163.0,151.3,149.8,142.2,139.9,137.7,129.7,128 .6,128.5,127.7,126.0,124.5,124.3,123.4,86.8,53.2,39.6,35.6,29.3,28.9.

[0293] Example 66

[0294]

[0295] 1 H NMR (400MHz, CDCl3) δ8.14(d,J=7.6Hz,1H),8.01–7.98(m,2H),7.89(t,J=7.8Hz,1H),7.70(d,J=7.6Hz,1H),7.33(d,J=8.0Hz,1H),7.25- 7.22(m,1H),6.36(s,1H),3.99(d,J=16.8Hz,1H),3.93(s,3H),3.66(d,J=16.8Hz,1H),3.55–3.40(m,4H),3.33(s,3H),1.72–1.62(m,4H); 13 C NMR (100MHz, CDCl3) δ167.5,163.4,150.8,150.7,150.6,140.5,139.9,139.2 ,124.6,124.3,122.7,121.2,85.2,72.3,58.7,56.5,53.3,39.4,27.1,26.6.

[0296] Test Example 1: Antitumor Activity Test Experiment

[0297] The CCK-8 assay was used to determine the inhibitory effects of the compounds prepared in this invention on the proliferation of six osteosarcoma cell lines (SJSA-1, U2OS, HOS, MNNG / HOS, MG63, 143b and SW1353), one pancreatic cancer cell line (PANC-1), one lung cancer cell line (A549) and one colon cancer cell line (HCT116).

[0298] 1. Cell seeding:

[0299] 1) Prepare a single-cell suspension using 1640 culture medium containing 10% fetal bovine serum, 1% penicillin and streptomycin, and seed 2500 SJSA-1 osteosarcoma cells per well into a 96-well cell culture plate, with a volume of 100 μl per well.

[0300] 2) Prepare a single-cell suspension using DMEM culture medium containing 10% fetal bovine serum, 1% penicillin and streptomycin, and seed 2500 MNNG / HOS osteosarcoma cells per well into a 96-well cell culture plate, with a volume of 100 μl per well.

[0301] 3) Prepare a single-cell suspension using McCoy'5A culture medium containing 10% fetal bovine serum, 1% penicillin and streptomycin, and seed 2500 U-2-OS osteosarcoma cells per well into a 96-well cell culture plate, with a volume of 100 μl per well.

[0302] 4) Prepare a single-cell suspension using DMEM culture medium containing 10% fetal bovine serum, 1% penicillin and streptomycin, and seed 2500 MG63 osteosarcoma cells per well into a 96-well cell culture plate, with a volume of 100 μl per well.

[0303] 5) Prepare a single-cell suspension using 1640 culture medium containing 10% fetal bovine serum, 1% penicillin and streptomycin, and seed 2500 HOS osteosarcoma cells per well into a 96-well cell culture plate, with a volume of 100 μl per well.

[0304] 6) Prepare a single-cell suspension using 1640 culture medium containing 10% fetal bovine serum, 1% penicillin and streptomycin, and seed 2500 143B osteosarcoma cells per well into a 96-well cell culture plate, with a volume of 100 μl per well.

[0305] 7) Prepare a single-cell suspension using 1640 culture medium containing 10% fetal bovine serum, 1% penicillin and streptomycin, and seed 2500 A549 lung cancer cells per well into a 96-well cell culture plate, with a volume of 100 μl per well.

[0306] 8) Prepare a single-cell suspension using 1640 culture medium containing 10% fetal bovine serum, 1% penicillin and streptomycin, and seed 2500 HCT116 colorectal cancer cells per well into a 96-well cell culture plate, with a volume of 100 μl per well.

[0307] 9) Prepare a single-cell suspension using 1640 culture medium containing 10% fetal bovine serum, 1% penicillin and streptomycin, and seed 2500 SW1353 osteosarcoma cells per well into a 96-well cell culture plate, with a volume of 100 μl per well.

[0308] 2. Then, the 21 compounds prepared in this invention were dissolved in DMSO and prepared into drug solutions with a final concentration of 1 μM using the corresponding cell culture medium. These solutions were then added to ten different cell types (100 μL / well), while the control group was treated with 1‰ DMSO. The cells were cultured in a CO2 incubator for 72 hours.

[0309] 3. After culturing for 72 hours, the culture medium was discarded, and 100 μL of 1:10 diluted CCK-8 solution was added. After incubation at 37°C for 2 hours, the absorbance A at 450 nm was measured using a LabServK3 microplate reader. The reference wavelength was 620 nm. The cell viability was calculated (see Table 1).

[0310] 4. Cell proliferation activity (%) = [A(drug-treated) - A(blank)] / [A(0-drug-treated) - A(blank)] × 100.

[0311] Table 1

[0312]

[0313]

[0314] Table 1 shows the activity data of some of the compounds of the present invention. As shown in Table 1, the survival rate of osteosarcoma SJSA-1 cells was less than 10% under the action of 14 compounds (compounds 2-7, 11, 13, 15, 17-21), indicating that these 14 compounds had a very good inhibitory effect on osteosarcoma SJSA-1 cells; 13 compounds (compounds 2-7, etc.) had a certain inhibitory effect on osteosarcoma U2OS cells; the survival rate of osteosarcoma HOS cells was less than 10% under the action of 7 compounds (compounds 4-6, etc.), indicating that these 7 compounds had a good inhibitory effect on HOS cells; 14 compounds (compound 2, etc.) had a good inhibitory effect on MNNG / HOS cells; 14 compounds (compound 1, etc.) had a good inhibitory effect on MG63 cells; compounds 5 and 6 had a good inhibitory effect on 143b cells; compounds 11 and 2 compounds had a good inhibitory effect on human colon cancer cells HCT116; compounds 4 and 3 compounds had a good inhibitory effect on lung cancer cells A549; and compounds 2 and 14 compounds had a certain inhibitory effect on osteosarcoma SW1353 cells. The unshown compounds also exhibited some inhibitory activity against the proliferation of the aforementioned cells.

[0315] Test Example 2: Metabolic Stability

[0316] Of the compounds mentioned above, compounds 17 and 18 were selected for liver microparticle testing based on their structure and activity. Compared to compound R-8i previously studied by the inventors, compounds 17 and 18 showed an inhibitory activity of 200 nM in MNNG-HOS cells. However, in in vitro liver microparticle metabolism experiments in humans and mice, the half-lives of both compounds were improved, with the best reaching 156 minutes, a 75-fold increase. Metabolic bioavailability improved from poor to moderately good.

[0317] Table 2. Liver microsomal stability of the compounds a

[0318]

[0319] a The stability of the microspheres was determined by the Shanghai Institute of Materia Medica, Chinese Academy of Sciences.

[0320] b Inherent clearance rate of liver microsomes (mL / min / g protein).

[0321] c Metabolic stability standards: Metabolic stability > 70, good stability; 70 > metabolic stability > 30, moderate stability; metabolic stability < 30, poor stability.

[0322] R-8i:

Claims

1. The compound represented by Formula I or a pharmaceutically acceptable salt thereof: Where Y is selected from Z is selected from N; X is selected from NH; n is an integer from 0 to 5; R 1 It is a pyridyl group, which is optionally substituted with an R7 selected from CH3O-; R 2 It is hydrogen; R 3 Selected from methoxy groups; R 4 and R 5 Independently selected from H, C1-C6 alkyl groups.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, n is an integer between 0 and 2.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, R 4 and R 5 Selected from H.

4. The following compounds or their pharmaceutically acceptable salts, 。 5. A pharmaceutical composition comprising a therapeutically effective amount of the compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein, The pharmaceutical composition is formulated into pills, capsules, creams, gels, injectable fluids, aerosols, syrups, or transdermal patches.

6. The use of the following compounds or pharmaceutically acceptable salts or the pharmaceutical composition of claim 5 in the preparation of a medicament for the prevention and / or treatment of tumors, wherein, The compound is used to inhibit the proliferation, growth, migration, invasion, metastasis, and recurrence of tumor cells, or to promote apoptosis of tumor cells; the tumor cells are selected from osteosarcoma cells, lung cancer cells, and colorectal cancer cells, the osteosarcoma cells are selected from SJSA-1, U2OS, HOS, MNNG / HOS, MG63, 143b, and SW1353; the lung cancer cells are selected from A549; the colorectal cancer cells are selected from HCT116; The specific structure of the compound is as follows: 。 7. The use of the following compounds or pharmaceutically acceptable salts or the pharmaceutical composition of claim 5 in the preparation of a medicament for the prevention and / or treatment of tumors, wherein, The compound is used to inhibit the proliferation, growth, migration, invasion, metastasis, and recurrence of tumor cells, or to promote apoptosis of tumor cells; the tumor cells are selected from osteosarcoma cells, lung cancer cells, and colorectal cancer cells, the osteosarcoma cells are selected from SJSA-1, U2OS, HOS, MNNG / HOS, 143b, and SW1353; the lung cancer cells are selected from A549; the colorectal cancer cells are selected from HCT116; The specific structure of the compound is as follows: 。 8. A method for preparing the compound of formula I according to claim 1, comprising synthetic scheme 1 or 2: Synthesis Scheme 1: Where R 1 R 2 R 3 R 4 R 5 X, Y, Z, and n are as defined in claim 1; Compound 1-1 was synthesized into methyl diformate compounds under acidic conditions, followed by single-ester hydrolysis under alkaline conditions to yield compound 1-2; compounds 1-2 and compound A condensation reaction occurs, yielding compounds 1-3; Compounds 1-3 were reduced to methyl esters to give the corresponding alcohols 1-4, which were then oxidized to give aldehydes 1-5; compounds 1-5, compounds and compounds A three-component one-pot reaction was carried out to give compounds 1-6. Compounds 1-6 were oxidized under certain conditions in the presence of m-chloroperoxybenzoic acid to give sulfone compound I. Synthesis Scheme 2: Where R 1 R 2 R 3 R 4 R 5 X, Y, Z, and n are as defined in claim 1; Compound 1-1 was synthesized into methyl diformate compound 2-2 under acidic conditions. Compound 2-2 underwent a single ester reduction with sodium borohydride to give alcohol compound 2-3. Compound 2-3 was oxidized by IBX to give compound 2-4, and compound 2-4 was hydrolyzed under alkaline conditions to give compound 2-5. Compound 2-5 and compound A condensation reaction occurs, yielding compound 2-6, compound 2-6, and compound and compounds A three-component one-pot reaction was carried out to give compound 2-7. Compound 2-7 was then oxidized under certain conditions in the presence of m-chloroperoxybenzoic acid to give sulfone compound I.

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