Diisoprene derivative and application thereof

Abstract

The invention discloses a diisoprene derivative as shown in a structural general formula (I) and a structural general formula (II), or pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, the diisoprene derivative has the activity of regulating the expression of a low-density lipoprotein receptor (LDLR), and can inhibit tumor cell proliferation, control inflammatory factor release, inhibit tumor cell proliferation, inhibit tumor cell proliferation, inhibit tumor cell proliferation, inhibit tumor cell proliferation, inhibit tumor cell proliferation, inhibit tumor cell proliferation, inhibit tumor cell proliferation, inhibit tumor cell proliferation, inhibit tumor cell proliferation, inhibit tumor cell proliferation, inhibit tumor cell proliferation, inhibit tumor cell proliferation and inhibit tumor cell proliferation. The accumulation of retinal lipofuscin is reduced, macular degeneration is improved, and retinal injury is relieved. The diisoprene derivative can be used for treating diseases related to abnormal lipid metabolism, such as cardiovascular diseases, metabolic diseases, cancer, inflammation, retinal diseases and / or other diseases. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and specifically relates to diisoprene derivatives and their use in treating cardiovascular diseases, metabolic diseases, inflammatory diseases, cancers, retinal diseases and other diseases related to low-density lipoprotein receptor (LDLR) related to abnormal lipid metabolism. Background Art

[0002] Lipids have rich and diverse biological functions. They can serve as energy storage substances, signaling molecules, and are also key components of cell membrane structures. With the rapid development of the economy and society, modern diets are exacerbating people's tendency to consume high amounts of fat. However, lipids have inducing and promoting effects on a variety of chronic diseases, including retinal diseases (Nat. Rev. Dis. Primers 2021, 7(1), 31; JAMA. 2024, 331(2), 147-157). Excessive lipids can not only lead to metabolic-related diseases such as cardiovascular disease and obesity, but can also promote the occurrence and development of inflammation and tumors, treatment response, and recurrence and metastasis.

[0003] Statins are 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) inhibitors that primarily lower low-density lipoprotein cholesterol (LDL-C) levels in the blood by controlling cholesterol synthesis. However, the use of statins often causes serious adverse reactions, including muscle pain, fatigue, and even rhabdomyolysis (Am. Heart J. 2014, 168(1), 6-15). In addition, approximately 50% of patients have a poor response to statins, making it difficult to control LDL-C levels at an ideal level.

[0004] Low-density lipoprotein receptors (LDLRs) play a key regulatory role in lipid metabolism. LDLRs can bind to LDL-C in the blood and then transport it to liver cells for metabolism, thereby effectively lowering LDL-C levels in the blood (Curr. Med. Chem. 2020, 27(2), 317-333). Therefore, regulating LDLR levels is an effective strategy to control abnormal lipid metabolism.

[0005] Proprotein Convertase Subtilisin / Kexin Type 9 (PCSK9) is a secretory protein that binds to LDLR, promoting its degradation and thus reducing the clearance of LDL-C. Therefore, inhibiting the expression of PCSK9 or preventing the binding of PCSK9 to LDLR can effectively increase the activity of LDLR on the surface of hepatocytes, thereby enhancing the metabolic clearance efficiency of LDL-C (Atherosclerosis. 2015, 238(2), 264-270.). Currently, seven PCSK9 inhibitors such as alirocumab, evolocumab, tolcizumab, inkersiland sodium, inusumab, ongorizumab and recalcituzumab injection have been launched on the market. However, these drugs are monoclonal antibodies or siRNA drugs and are all administered by injection, with poor patient compliance and high prices. The relatively flat active pocket of PCSK9 protein makes the development of small molecule drugs targeting PCSK9 a huge challenge, and there is still no effective small molecule drug used in clinical practice. Therefore, there is an urgent clinical need to develop new small molecule drugs that can effectively regulate LDLR levels. Summary of the Invention

[0006] The object of the present invention is to provide a diisoprene derivative or a pharmaceutically acceptable salt or stereoisomer thereof, or a solvate thereof, or a prodrug thereof, wherein the diisoprene derivative can effectively regulate LDLR levels, inhibit tumor cell proliferation, inhibit the production of inflammatory factors, lower cholesterol, reduce retinal lipofuscin accumulation, and improve macular degeneration.

[0007] The structure of the diisoprene derivative is shown in the following general structural formulas (I) and (II):

[0008]

[0009] Wherein, R0 is selected from hydrogen, aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, alkyl with a functional group, cycloalkyl with a functional group, heterocycloalkyl with a functional group, alkenyl, alkenyl with a functional group; the functional group includes halogen (F, Cl, Br, I), difluoromethyl, trifluoromethyl;

[0010] R1, R2 and R3 are independently selected from hydrogen, deuterium, tritium, halogen, aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, alkyl with a functional group, cycloalkyl with a functional group, heterocycloalkyl with a functional group; the functional group includes halogen (F, Cl, Br, I), difluoromethyl, trifluoromethyl;

[0011] R4 and R5 are independently selected from hydrogen, deuterium, tritium, hydroxyl, amino, aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, acyl, alkyl with a functional group, cycloalkyl with a functional group, heterocycloalkyl with a functional group, acyl with a functional group; the functional group includes halogen (F, Cl, Br, I), difluoromethyl, trifluoromethyl;

[0012] R6 and R7 are each independently selected from hydrogen, deuterium, tritium, halogen, difluoromethyl, trifluoromethyl, alkyl, aryl, and heteroaryl.

[0013] Preferably, R0 is selected from aryl, cycloalkyl, heterocycloalkyl, and alkenyl; wherein the aryl is phenyl, or phenyl containing 1-5 substituents; the cycloalkyl is a C4-C8 membered aliphatic ring; the heterocycloalkyl refers to a 4-8 membered aliphatic ring containing nitrogen, oxygen or sulfur atoms; and the alkenyl is a C4-C6 cyclic olefin.

[0014] Preferably, R1, R2 and R3 are independently selected from hydrogen, deuterium, aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl; wherein the aryl is phenyl; the heteroaryl refers to a 5-8 membered single aromatic ring containing nitrogen, oxygen or sulfur atoms; the alkyl is a C1-C10 alkane; the cycloalkyl is a C3-C8 membered aliphatic ring; the heterocycloalkyl refers to a 4-8 membered aliphatic ring containing nitrogen, oxygen or sulfur atoms;

[0015] Preferably, R4 and R5 are independently selected from hydrogen, hydroxyl, and acyl; wherein the structure of the acyl group is as shown in formula (III):

[0016]

[0017] R is selected from C1-C5 alkyl.

[0018] Preferably, R6 and R7 are independently selected from hydrogen and deuterium.

[0019] The diisoprene derivatives described in the present invention include all possible stereoisomers, including but not limited to cis-trans isomers and enantiomers.

[0020] The diisoprene derivatives represented by structural formula (I) and formula (II) described herein can react with inorganic or organic acids or bases to produce pharmaceutically acceptable salts, including but not limited to chlorides, bromides, sulfates, phosphates, nitrates, sulfonates, formates, acetates, maleates, malates, tartrates, citrates, laurates, salicylates, succinates, sodium salts, potassium salts, and lithium salts. These salts can increase the stability of the compounds and optimize their bioavailability, thereby enhancing their therapeutic efficacy.

[0021] The solvents for forming solvates of the present invention include, but are not limited to, water, isopropanol, n-butanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. Furthermore, such compounds can also form cocrystals with appropriate cocrystal precursors to improve the solubility and stability of the drug.

[0022] The present invention also provides a medicine / pharmaceutical composition, which may comprise a therapeutically effective amount of the diisoprene derivative of the present invention, or a pharmaceutically acceptable salt or stereoisomer thereof, or a solvate thereof, or a prodrug thereof, in combination with a pharmaceutically acceptable carrier and excipients.

[0023] The medicine / pharmaceutical composition is used to treat, prevent and / or alleviate diseases or conditions caused by abnormal lipid metabolism, imbalanced cholesterol levels, and abnormal LDLR levels.

[0024] Furthermore, the drug / drug composition can be used alone and / or in combination with other drugs.

[0025] Preferably, the pharmaceutically acceptable carrier refers to a drug that does not produce adverse, allergic or other adverse reactions when properly administered to animals or humans. Pharmaceutically acceptable carriers include, but are not limited to: sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as methylcellulose, sodium methylcellulose and ethylcellulose; tragacanth powder; malt; gelatin; talc; solid lubricants such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and cocoa butter; polyols such as ethylene glycol, polyethylene glycol, propylene glycol, glycerol, sorbitol and mannitol; alginic acid; emulsifiers such as Tween-20 / 80 and HS-15; wetting agents such as sodium lauryl sulfate; colorants; flavorings; tableting agents, stabilizers; antioxidants; preservatives; isotonic saline solutions; and phosphate buffers. These materials are used as needed to aid in the stability of the formulation or to help increase the activity or its bioavailability or to produce an acceptable taste or flavor in the case of oral administration.

[0026] Specifically, the drug / drug composition may further contain physiologically compatible excipients, including buffers, diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption enhancers, surfactants, adsorption carriers, lubricants, etc.

[0027] Specifically, the drug / pharmaceutical composition can be prepared into an injection, sterile powder for injection, tablet, pill, capsule, lozenge, elixir, powder, granule, syrup, solution, tincture, aerosol, powder spray, or suppository, etc. The drugs / pharmaceutical compositions in various dosage forms can be prepared according to conventional methods in the pharmaceutical field.

[0028] Specifically, the drug / pharmaceutical composition can be introduced into the body, such as into the muscle, intradermal, subcutaneous, intravenous, or mucosal tissues, by oral administration, injection, spray, nasal instillation, eye drops, penetration, absorption, or physical or chemical methods; or can be introduced into the body after being mixed or encapsulated with other substances. Preferably, the drug / pharmaceutical composition is administered orally. The drug / pharmaceutical composition can also be used in combination with other treatment modalities, including surgery, radiotherapy, chemotherapy, and targeted therapy.

[0029] The present invention also provides the use of the diisoprene derivative, or a pharmaceutically acceptable salt or stereoisomer thereof, or a solvate thereof, or a prodrug thereof, or a drug / pharmaceutical composition thereof, in the preparation of a medicament for treating and / or preventing or alleviating diseases associated with abnormal lipid metabolism. By effectively modulating LDLR activity, the compounds of the present invention can be used to improve diseases associated with abnormal lipid metabolism and provide patients with more diverse treatment options.

[0030] The present invention also provides the use of the diisoprene derivative or its pharmaceutically acceptable salt or stereoisomer, or its solvate, or its prodrug, or the drug / drug composition in the preparation of a drug for regulating low-density lipoprotein receptor (LDLR) levels.

[0031] The present invention also provides the use of the diisoprene derivative or its pharmaceutically acceptable salt or stereoisomer, or its solvate, or its prodrug, or the drug / drug composition in the preparation of a drug for treating diseases or conditions caused by abnormal LDLR levels.

[0032] Among them, the diseases or conditions include cardiovascular diseases (such as atherosclerosis, coronary heart disease, coronary artery disease, myocardial infarction, and stroke), metabolic diseases (such as diabetes, obesity, metabolic syndrome, fatty liver, and insulin resistance diseases), endocrine disorders (such as hyperlipidemia, hypercholesterolemia), inflammatory diseases (such as acute liver injury, acute lung injury, acute kidney injury, chronic hepatitis, rheumatoid arthritis, Alzheimer's disease, and chronic tubulointerstitial inflammation), cancers (such as liver cancer, breast cancer, lung cancer, gastric cancer, colorectal cancer, hematological tumors, and gliomas), retinal diseases (such as retinal inflammation and choroiditis, optic neuritis, retinal vein occlusion, retinitis pigmentosa, retinal damage, age-related macular degeneration, and juvenile macular degeneration) and / or other conditions.

[0033] The present invention also provides a method for treating and / or preventing or alleviating diseases associated with abnormal lipid metabolism, the method comprising administering to a subject the above-described diisoprene derivative or a pharmaceutically acceptable salt or stereoisomer thereof, or a solvate thereof, or a prodrug thereof, or a drug / drug composition.

[0034] The preparation of the diisoprene derivatives involved in the present invention is based on the method disclosed in the literature (Angew. Chem. Int. Ed. 2023, 62, e2023076). Specific conditions such as reaction solvent, catalyst, temperature, etc. can be adjusted according to actual needs.

[0035] The present invention has the following beneficial effects: the compounds, drugs, or pharmaceutical compositions described herein can significantly regulate LDLR expression, lower serum and liver cholesterol levels, inhibit tumor cell proliferation, effectively control the release of the pro-inflammatory cytokine NO, significantly reduce retinal lipofuscin accumulation, improve macular degeneration, and alleviate retinal damage. This provides a new treatment option for diseases related to abnormal lipid metabolism. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1 : Quantitative analysis bar graph of the LDL-C uptake capacity of the compounds of the present invention in HepG2 cells. The results show that compared with the DMSO control group, the compounds of the present invention can significantly enhance the LDL-C uptake capacity of HepG2 cells.

[0037] Figure 2 : Effect of the compounds of the present invention on the regulation of serum and liver cholesterol in hyperlipidemia mice. Cholesterol levels in the serum and liver of mice were measured after daily intraperitoneal injection of 10 mg / kg and 30 mg / kg of the compounds of the present invention for two consecutive weeks. Serum and liver cholesterol levels were compared in the solvent control group (n=6) and mice treated with different doses of the compounds (n=6). Compared to the untreated solvent control group, the serum and liver cholesterol levels in mice treated with the compounds of the present invention were significantly reduced.

[0038] Figure 3 : The compounds of the present invention have an effect on ABCA4 - / - / RDH8 - / - Effect of retinal lipofuscin formation in a double knockout mouse model. Electron micrographs of retinal lipofuscin formation in mice after daily oral administration of 2.64 mg / kg of the compound of the present invention for 4 consecutive months. Female Abca4 control group (n=5) and female Abca4 control group (n=5) with the compound of the present invention - / - / Rdh8 - / - Retinal lipofuscin accumulation levels in double knockout mice: Compared with the untreated solvent control group, the retinal lipofuscin content levels of mice in the compound-treated group were significantly reduced. DETAILED DESCRIPTION

[0039] The present invention is further described in detail with reference to the following specific examples. Except for the contents specifically mentioned below, the processes, conditions, experimental methods, etc. for implementing the present invention are common knowledge and common common sense in the field and are not particularly limited by the present invention.

[0040] The following description of at least one exemplary embodiment is merely illustrative in nature and is in no way intended to limit the present invention, its applications, or uses. Based on the compounds of the present invention, one of ordinary skill in the art will recognize that modifying the isoprene structure in accordance with well-known principles of chemical structure connectivity to provide chemically stable compounds that can be synthesized using techniques known in the art falls within the scope of the present invention.

[0041] Example 1: Synthesis of Compound A1

[0042]

[0043] Synthesis of compound Inter-1:

[0044] Under argon atmosphere at 0 ° C, 11.2 mL of n-butyl lithium was added dropwise to a THF (30 mL) solution containing 2,2,6,6-tetramethylpiperidine (3.9339 g, 27.9 mmol). Then, a THF (55 mL) solution of bis[(pinacolato)boryl]methane (7.5035 g, 28 mmol) was added to the reaction solution. After 30 minutes, a THF (20 mL) solution containing compound 1 (2.3630 g, 20 mmol) was added. After 3 hours, saturated aqueous ammonium chloride (20 mL) and water (300 mL) were added in sequence, and the mixture was extracted three times with ethyl acetate. The organic phase was washed once with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation. Column chromatography was used for separation and purification (eluent: petroleum ether / ethyl acetate = 5 / 1) to obtain the product Inter-1 (3.5091 g, 86%): a light yellow liquid; 1 H NMR (400MHz, CDCl3): δ=6.58 (dd, J1=18.0Hz, J2=6.0Hz, 1H), 5.38 (dd, J1=18.2Hz, J2=1 .4Hz,1H),2.09-1.97(m,1H),1.79-1.68(m,4H),1.68-1.60(m,1H),1.33-1.04(m,17H); 13 C NMR (100MHz, CDCl3): δ = 159.8, 82.9, 43.2, 31.9, 26.1, 25.9, 24.7.

[0045] Synthesis of compound Inter-2:

[0046] To a dry reaction flask, Cp*Rh(OAc)2 (17.7 mg, 0.05 mmol), Cu(OAc)2·H2O (60.0 mg, 0.30 mmol), Inter-1 (236.5 mg, 1.0 mmol), THF (10 mL), S1 (105.1 mg, 1.5 mmol), and H2O (54 μL) were added. The mixture was stirred at 50°C for 23 hours. The reaction mixture was filtered through a pad of silica gel, washed with ethyl acetate (40 mL), and the solvent was removed by rotary evaporation. The product was separated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 30 / 1) to obtain the product Inter-2 (113.9 mg, 64%) as a light yellow liquid. 1 H NMR (400MHz, CDCl3): δ = 10.10 (d, J = 8.0Hz, 1H), 6.23 (dd, J1 = 15.6Hz, J2 = 6.4Hz, 1H), 6.16 (d, J=15.6Hz,1H),5.90(d,J=8.4Hz,1H),2.24(d,J=0.8Hz,3H),2.18-2.07(m,1H),1.80-1.73(m 4H),1.72-1.64(m,1H),1.38-1.07(m,5H); 13 C NMR (100MHz, CDCl3): δ=191.4,155.3,145.0,131.0,128.5,41.4,32.4,25.9,25.8,13.0.

[0047] Synthesis of compound Inter-3:

[0048] Under argon atmosphere at 0°C, 4.5 mL of n-butyllithium was added dropwise to a solution of 2,2,6,6-tetramethylpiperidine (1.9 mL, 11.36 mmol) in THF (11.36 mL). After 0.5 hour, a solution of bis[(pinacolato)boryl]methane (3.0448 g, 11.36 mmol) in THF (22.7 mL) was added to the reaction mixture. After 30 minutes, the reaction mixture was cooled to -78°C and a solution of Inter-2 (1.2647 g, 7.1 mmol) in THF (7.1 mL) was added. After 3 hours, saturated aqueous ammonium chloride (7 mL) and water (120 mL) were added sequentially, and the mixture was extracted three times with ethyl acetate. The organic phase was washed once with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation. Column chromatography was used for separation and purification (eluent: petroleum ether / ethyl acetate = 10 / 1) to obtain the product Inter-3 (1.9735 g, 92%): yellow liquid; 1H NMR (400MHz, CDCl3): δ = 7.37 (dd, J1 = 17.6Hz, J2 = 11.2Hz, 1H), 6.14-6.01 (m, 2H), 5.76 (dd, J1 = 15.6Hz, J2 = 7.2Hz, 1H), 5.53 (d ,J=17.2Hz,1H),2.11-1.99(m,1H),1.93(s,3H),1.73(d,J=10.4Hz,4H),1.69-1.61(m,1H),1.28(s,14H),1.21-1.04(m,3H); 13 C NMR (100MHz, CDCl3): δ=145.8,139.4,138.1,132.0,131.1,83.1,41.2,33.0,26.1,26.0,24.7,13.1.

[0049] Synthesis of compound A1:

[0050] To a reaction tube containing Cp*Rh(OAc)2 (26.9 mg, 0.075 mmol) and Cu(OAc)2·H2O (90.1 mg, 0.45 mmol) was added Inter-3 (3 mL, 1.5 mmol), S2 (342.9 mg, 2.25 mmol), THF (12 mL), and H2O (83.1 mg, 4.5 mmol) in the dark. After stirring at room temperature for 53 hours, the reaction mixture was filtered through a pad of silica gel, washed with ethyl acetate (40 mL), and the solvent was removed by rotary evaporation. Column chromatography (eluent: petroleum ether / ethyl acetate = 60 / 1) afforded product A1 (138.9 mg, 28%, 2E:2Z = 98:2): a yellow waxy liquid. 1 H NMR (400MHz, CDCl3): δ = 10.01 (d, J = 8.4Hz, 1H, CHO), 7.08 (dd, J1 = 15.2Hz, J2 = 11.2Hz, 1H, = C H), 6.25 (d, J = 15.2Hz, 1H, = CH), 6.13 (d, J = 14.8Hz, 2H, 2x = CH), 6.02 (d, J = 8.4Hz, 1H, = CH), 5. 83(dd,J1=15.6Hz,J2=7.2Hz,1H,=CH),2.63(d,J=6.8Hz,2H,CH2),2.13-2.03(m,1H,CH),1. 95(s,3H,CH3),1.80-1.62(m,11H),1.55-1.45(m,1H),1.36-1.04(m,9H),1.05-0.93(m,2H); 13CNMR (100MHz, CDCl3): δ=191.2,158.4,141.0,139.0,133.7,132.5,131.9 ,129.2,128.8,41.3,39.0,34.9,33.6,32.9,26.3,26.2,26.0,25.9,13.2.

[0051] The compounds described in Examples 2-22 can be prepared by referring to the methods and routes described in Example 1 above.

[0052] Example 2: Synthesis of Compound A2

[0053]

[0054] 1 H NMR (400MHz, CDCl3): δ = 10.01 (d, J = 8.4Hz, 1H, CHO), 7.08 (dd, J1 = 15.2Hz, J2 = 11.6Hz, 1H, = CH), 6. 25(d,J=15.2Hz,1H,=CH),6.19-6.09(m,2H,2x=CH),6.01(d,J=8.4Hz,1H,=CH),5.87(dd,J1=15.6 Hz,J2=8.0Hz,1H,=CH),2.63(d,J=7.2Hz,2H,CH2),2.53(sext,J=8.1Hz,1H,CH),1.96(s,3H,CH3) ,1.87-1.57(m,11H),1.53-1.44(m,1H),1.40-1.29(m,2H),1.26-1.11(m,3H),1.06-0.93(m,2H); 13 C NMR (100MHz, CDCl3): δ=191.1,158.4,140.8,138.0,133.7,132.53,132.47,129.2,128.7,43.9,39.0,34.9,33.6,33.3,26.23,26.19,25.2,13.2.

[0055] Example 3: Synthesis of Compound A3

[0056]

[0057] 11H NMR (400 MHz, CDCl3): δ = 10.01 (d, J = 8.4 Hz, 1H, CHO), 7.08 (dd, J1 = 15.2 Hz, J2 = 11.6 Hz, 1H, =CH), 6.25 (d, J = 15.2 Hz, 1H, =CH), 6.13 (d, J = 3.6 Hz, 1H, =CH), 6.10 (d, J = 8.0 Hz, 1H, =CH), 6.01 (d, J = 8.4 Hz, 1H, =CH), 5.88 (dd, J1 = 15.6 Hz, J2 = 8.0 Hz, 1H, =CH), 2.63 (d, J = 7.2 Hz, 2H, CH2), 2.32 - 2.22 (m, 1H, CH), 1.95 (s, 3H, CH3), 1.81 - 1.59 (m, 11H), 1.56 - 1.45 (m, 5H), 1.42 - 1.32 (m, 2H), 1.27 - 1.12 (m, 3H), 1.06 - 0.93 (m, 2H); 13 13C NMR (100 MHz, CDCl3): δ = 191.1, 158.4, 141.0, 139.9, 133.7, 132.5, 131.4, 129.2, 128.7, 43.3, 39.0, 34.9, 34.7, 33.6, 28.3, 26.3, 26.2, 13.2.

[0058] Example 4: Synthesis of Compound A4

[0059]

[0060] 1 1H NMR (400 MHz, CDCl3): δ = 10.03 (d, J = 8.0 Hz, 1H, CHO), 7.45 (d, J = 7.2 Hz, 2H, Ar - H), 7.34 (t, J = 7.6 Hz, 2H, Ar - H), 7.27 - 7.23 (m, 1H, Ar - H), 7.13 (dd, J1 = 15.2 Hz, J2 = 11.6 Hz, 1H, =CH), 6.90 (d, J = 16.0 Hz, 1H, =CH), 6.72 (d, J = 16.0 Hz, 1H, =CH), 6.40 - 6.28 (m, 2H, 2x =CH), 6.05 (d, J = 8.0 Hz, 1H, =CH), 2.65 (d, J = 7.2 Hz, 2H, CH2), 2.09 (s, 3H, CH3), 1.84 - 1.64 (m, 5H), 1.57 - 1.47 (m, 1H), 1.29 - 1.14 (m, 3H), 1.08 - 0.95 (m, 2H); 13C NMR (100MHz, CDCl3): δ=191.1,158.0,140.4,137.1,135.0,132.8,132.1,131 .5,130.1,129.7,128.7,127.8,126.6,39.0,35.0,33.6,26.24,26.20,13.1.

[0061] Example 5: Synthesis of Compound A5

[0062]

[0063] 1 H NMR (400MHz, CDCl3): δ = 10.03 (d, J = 8.0Hz, 1H, CHO), 7.29-7.21 (m, 3H, Ar-H), 7.12 (dd, J1 = 15.2Hz, J2=11.6Hz,1H,=CH),7.07(d,J=6.8Hz,1H,Ar-H),6.89(d,J=16.0Hz,1H,=CH),6.69(d,J=16.0Hz,1H ,=CH),6.39-6.28(m,2H,2x=CH),6.05(d,J=8.4Hz,1H,=CH),2.65(d,J=7.2Hz,2H,CH2),2.36(s,3H, CH3),2.09(s,3H,CH3),1.80-1.64(m,5H),1.57-1.47(m,1H),1.30-1.13(m,3H),1.07-0.95(m,2H); 13 C NMR (100MHz, CDCl3): δ=191.1,158.0,140.5,138.2,137.1,134.9,132.6,132.1,131.4 ,130.3,129.7,128.7,128.6,127.3,123.8,39.0,34.9,33.6,26.25,26.21,21.4,13.1.

[0064] Example 6: Synthesis of Compound A6

[0065]

[0066] 1H NMR (400MHz, CDCl3): δ = 10.03 (d, J = 8.4Hz, 1H, CHO), 7.36-7.33 (m, 1H, Ar-H), 7.33-7.28 (m, 2H, A r-H),7.14(dd,J1=15.2Hz,J2=11.6Hz,1H,=CH),6.90(d,J=16.0Hz,1H,=CH),6.77(d,J=16.0Hz, 1H,=CH),6.39(d,J=11.2Hz,1H,=CH),6.33(d,J=15.2Hz,1H,=CH),6.05(d,J=8.4Hz,1H,=CH),2. 66(d,J=6.8Hz,2H,CH2),2.11(s,3H,CH3),1.83-1.63(m,5H),1.57-1.48(m,1H),1.35(s,18H,6x CH3),1.27-1.13(m,3H),1.08-0.95(m,2H); 13 C NMR (100MHz, CDCl3): δ=191.1,158.1,151.1,140.7,136.3,134.6,132.3,132.1,1 31.3,131.1,129.6,122.4,121.0,39.0,35.0,34.8,33.6,31.4,26.3,26.2,13.2.

[0067] Example 7: Synthesis of Compound A7

[0068]

[0069] 1 H NMR (400MHz, CDCl3): δ = 10.03 (d, J = 8.4Hz, 1H, CHO), 7.14 (dd, J1 = 15.2Hz, J2 = 11.2Hz, 1H, = CH), 6. 75(d,J=16.0Hz,1H,=CH),6.60(s,1H,Ar-H),6.35-6.18(m,3H,3x=CH),6.03(d,J=8.0Hz,1H,=CH) ,3.81(s,3H,OCH3),2.66(d,J=7.2Hz,2H,CH2),2.30(s,3H,CH3),2.24(s,3H,CH3),2.15(s,3H,CH 3),2.13(s,3H,CH3),1.81-1.64(m,5H),1.58-1.47(m,1H),1.29-1.10(m,3H),1.08-0.94(m,2H); 13C NMR (100MHz, CDCl3): δ=191.1,158.1,156.2,140.6,137.9,135.9,134.5,133.9,132.2,130.3, 129.6,129.5,129.4,122.7,109.9,55.4,39.0,34.9,33.6,26.3,26.2,21.4,17.4,13.0,11.8.

[0070] Example 8: Synthesis of Compound A8

[0071]

[0072] 1 H NMR (400MHz, CDCl3): δ = 10.03 (d, J = 8.4Hz, 1H, CHO), 7.34 (s, 1H, Ar-H), 7.25-7.17 (m, 2H, Ar-H), 7.13 (dd, J1 = 15.2Hz, J2 = 11.6Hz, 1H, = CH),6.86(d,J=16.0Hz,1H,=CH),6.72(d,J=16.0Hz,1H,=CH),6.37-6.22(m,2H,2x=CH),6.04(d,J=8.4Hz,1H,=CH),2.95-2.85(m,4H,2x CH2),2.65(d,J=7.2Hz,2H,CH2),2.14-2.03(m,5H),1.81-1.64(m,5H),1.58-1.46(m,1H),1.29-1.13(m,3H),1.07-0.94(m,2H); 13 C NMR (100MHz, CDCl3): δ=191.1,158.1,144.8,144.5,140.8,135.3,134.5,132.3,131.6,130.9 ,130.7,129.5,125.1,124.6,122.2,39.0,34.9,33.6,32.68,32.67,26.24,26.20,25.4,13.1.

[0073] Example 9: Synthesis of Compound A9

[0074]

[0075] 1H NMR (400MHz, CDCl3): δ = 10.02 (d, J = 8.4Hz, 1H, CHO), 7.10 (dd, J1 = 15.2Hz, J2 = 11.6Hz, 1H, = CH), 6.42 (d, J = 15.6Hz, 1H, = CH), 6. 32-6.18(m,3H,3x=CH),6.02(d,J=8.4Hz,1H,=CH),5.95-5.86(m,1H,=CH),2.64(d,J=7.2Hz,2H,CH2),2.19(d,J=5.2Hz,4H,2x CH2),2.00(s,3H,CH3),1.80-1.59(m,9H),1.54-1.47(m,1H),1.25-1.14(m,3H),1.07-0.95(m,2H); 13 C NMR (100MHz, CDCl3): δ=191.1,158.3,141.2,136.1,134.3,133.9,132.5,132. 3,130.1,129.3,129.1,39.0,35.0,33.6,26.27,26.25,26.2,24.5,22.4,13.1.

[0076] Example 10: Synthesis of Compound A10

[0077]

[0078] 1 H NMR (400MHz, CDCl3): δ = 10.02 (d, J = 8.4Hz, 1H, CHO), 7.12 (dd, J1 = 15.2Hz, J2 = 11.6Hz, 1H, = CH), 6.34 (d, J = 16.0Hz, 1H, = CH), 6.28 (d, J = 15.2Hz ,1H,=CH),6.19(d,J=6.8Hz,1H,=CH),6.15(d,J=11.6Hz,1H,=CH),6.02(d,J=8.4Hz,1H,=CH),2.65(d,J=6.8Hz,2H,CH2),2.09-1.99(m,5H,CH3 and CH2),1.81-1.71(m,7H),1.68-1.59(m,3H),1.54-1.45(m,3H),1.27-1.16(m,3H),1.08-0.94(m,8H); 13C NMR (100MHz, CD3CN): δ=191.2,158.3,141.0,137.6,137.1,134.0,132.4,130.4,129.7 ,129.5,129.3,39.5,39.0,35.0,34.2,33.6,33.1,28.9,26.3,26.2,21.7,19.2,13.0.

[0079] Example 11: Synthesis of Compound A11

[0080]

[0081] 1 H NMR (400MHz, CDCl3): δ = 10.06 (d, J = 8.0Hz, 1H, CHO), 7.15 (dd, J1 = 15.2Hz, J2 = 11.6Hz, 1H, =CH),6.34(d,J=16.4Hz,1H,=CH),6.28(d,J=15.2Hz,1H,=CH),6.23-6.12(m,2H,2x=CH),6 .00(d,J=8.4Hz,1H,=CH),2.78(d,J=7.6Hz,2H,CH2),2.09-1.98(m,6H),1.82-1.74(m,2H) ,1.72(s,3H,CH3),1.69-1.52(m,6H),1.50-1.45(m,2H),1.28-1.17(m,2H),1.03(s,6H,2x CH3); 13 C NMR (100MHz, CDCl3): δ=191.0,159.3,141.0,137.6,137.1,133.7,132.4,130.4,129 .6,129.5,128.9,41.4,39.5,34.2,33.1,32.74,32.67,28.9,24.6,21.7,19.1,13.0.

[0082] Example 12: Synthesis of Compound A12

[0083]

[0084] 1H NMR (400MHz, CD3CN): δ = 10.03 (d, J = 8.4 Hz, 1H, CHO), 7.25 (dd, J1 = 15.2 Hz, J2 = 11.2 Hz, 1H, = CH), 6.38 (d, J = 12.0 Hz, 1H, = CH), 6.34 (d,J=10.8Hz,1H,=CH),6.23(d,J=11.6Hz,1H,=CH),6.18(d,J=16.0Hz,1H,=CH),5.96(d,J=8.0Hz,1H,=CH),3.89-3.80(m,1H,one proton ofOCH2),3.75(dd,J1=8.4Hz,J2=6.8Hz,1H,one protonofOCH2),3.68(q,J=7.7Hz,1H,one proton of OCH2),3.40(dd,J1=8.0Hz,J2=6.4Hz,1H,one proton of OCH2),2.88(d,J=7.6Hz,2H,CH2),2.42(sept,J=7.1Hz,1H,CH),2.08-1.92(m,6H,CH3,CH2 and one proton ofCH2),1.70(s,3H,CH3),1.66-1.57(m,3H,oneproton ofCH2 and CH2),1.51-1.43(m,2H,CH2),1.03(s,6H,2x CH3); 13 C NMR (100MHz, CD3CN): δ=191.9,158.9,142.2,138.6,138.0,134.6,133.8,131.2,130.7,1 30.4,130.0,72.9,68.0,41.0,40.3,34.9,33.7,32.7,30.0,29.2,25.0,22.0,19.9,13.1.

[0085] Example 13: Synthesis of Compound A13

[0086]

[0087] 1H NMR (400MHz, CD3CN): δ = 10.03 (d, J = 8.0Hz, 1H, CHO), 7.13 (dd, J1 = 15.2Hz, J2 = 11.6Hz, 1H, =CH),6.36(d,J=16.4Hz,1H,=CH),6.30(d,J=15.2Hz,1H,=CH),6.22-6.13(m,2H,2x=CH), 6.05(d,J=8.0Hz,1H,=CH),3.97(dd,J1=11.2Hz,J2=3.6Hz,2H,OCH2),3.34(t,J=11.2Hz, 2H,OCH2),2.73(d,J=7.2Hz,2H,CH2),2.07-1.99(m,5H,CH3andCH2),1.81-1.69(m,4H,CH3 and CH),1.68-1.58(m,4H,2x CH2),1.50-1.45(m,2H,CH2),1.45-1.33(m,2H,CH2),1.04(s,6H,2x CH3); 13 C NMR (100MHz, CD3CN): δ=190.6,156.9,141.4,137.6,136.9,133.6,132.5,130.5 ,129.9,129.3,67.8,39.5,36.4,34.3,34.2,33.2,33.1,28.9,21.7,19.1,13.0.

[0088] Example 14: Synthesis of Compound A14

[0089]

[0090] 1H NMR (400MHz, acetone-d6): δ = 10.19 (d, J = 8.0Hz, 1H, CHO), 7.48 (s, 2H, furan-H), 7.41 (dd, J1= 15.2Hz,J2=11.6Hz,1H,=CH),6.46(d,J=15.2Hz,1H,=CH),6.42-6.34(m,J=12.4Hz,2H,furan-H and=CH),6.28(d,J=11.6Hz,1H,=CH),6.21(d,J=16.0Hz,1H,=CH),6.02(d,J=8.0Hz,1H,=CH),4.09(s,2H,CH2),2.05-1.99(m,5H,CH3 and CH2),1.71(s,3H,CH3),1.67-1.58(m,2H,CH2),1.51-1.45(m,2H,CH2),1.03(s,6H,2x CH3); 13 CNMR (100MHz, acetone-d6): δ = 191.5, 157.1, 144.2, 141.9, 140.8, 138.6, 138.4, 134.4, 134. 1,130.9,130.8,130.1,129.6,124.2,111.8,40.4,35.0,33.7,29.4,23.2,22.0,20.0,13.1.

[0091] Example 15: Synthesis of Compound A15

[0092]

[0093] 11H NMR (400 MHz, CDCl3): δ = 10.14 (d, J = 8.0 Hz, 1H, CHO), 7.25 (dd, J1 = 14.8 Hz, J2 = 11.2 Hz, 1H, =CH), 7.15 (d, J = 5.2 Hz, 1H, thiophene-H), 6.96 - 6.91 (m, 1H, thiophene-H), 6.87 (s, 1H, thiophene-H), 6.33 (d, J = 14.8 Hz, 2H, 2x=CH), 6.16 (d, J = 6.4 Hz, 1H, =CH), 6.13 (d, J = 11.2 Hz, 1H, =CH), 6.09 (d, J = 8.0 Hz, 1H, =CH), 4.31 (s, 2H, CH2), 2.02 (t, J = 6.0 Hz, 2H, CH2), 1.97 (s, 3H, CH3), 1.70 (s, 3H, CH3), 1.65 - 1.58 (m, 2H, CH2), 1.50 - 1.43 (m, 2H, CH2), 1.02 (s, 6H, 2x CH3); 13 13C NMR (100 MHz, CDCl3): δ = 190.7, 155.6, 141.9, 141.0, 137.6, 137.0, 133.8, 132.4, 130.6, 130.1, 129.3, 128.6, 127.1, 125.2, 124.1, 39.5, 34.2, 33.1, 28.9, 27.7, 21.7, 19.1, 13.0.

[0094] Example 16: Synthesis of Compound A16

[0095]

[0096] 1 1H NMR (400 MHz, acetone-d6): δ = 10.06 (d, J = 7.6 Hz, 1H, CHO), 7.43 (dd, J1 = 15.2 Hz, J2 = 11.6 Hz, 1H, =CH), 6.54 (d, J = 15.2 Hz, 1H, =CH), 6.42 (d, J = 16.0 Hz, 1H, =CH), 6.38 - 6.05 (m, 4H, CF2H and 3x=CH), 3.58 (td, J1 = 17.2 Hz, J2 = 4.4 Hz, 2H, CH2), 2.08 - 2.01 (m, 5H, CH3 and CH2), 1.72 (s, 3H, CH3), 1.68 - 1.58 (m, 2H, CH2), 1.52 - 1.45 (m, 2H, CH2), 1.04 (s, 6H, 2x CH3); 13C NMR (100MHz, acetone-d6): δ = 191.4, 149.3 (t, J = 5.6Hz), 142.3, 138.6, 138.3, 134.5, 134.4, 131.9, 13 0.9,130.8,130.3,116.6(t,J=239.8Hz),40.4,34.9,33.7,32.4(t,J=23.0Hz),29.3,21.9,19.9,13.0.

[0097] Example 17: Synthesis of Compound A17

[0098]

[0099] 1 H NMR (400MHz, CDCl3): δ = 10.06 (d, J = 8.4Hz, 1H, CHO), 7.17 (dd, J1 = 15.2Hz, J2 = 11.6Hz, 1H, = CH), 6.34 (d, J = 16.4Hz, 1H, = CH), 6 .26(d,J=15.2Hz,1H,=CH),6.22-6.12(m,2H,2x=CH),5.90(d,J=8.0Hz,1H,=CH),2.83-2.70(m,2H,CH2),2.06-1.97(m,5H,CH3 and CH2),1.72(s,3H,CH3),1.66-1.58(m,2H,CH2),1.53-1.43(m,4H,2x CH2),1.03(s,6H,2x CH3),1.01(s,9H,3x CH3); 13 C NMR (100MHz, CD3CN): δ=190.8,160.7,141.2,137.6,137.0,133.2,132.1,130.5,12 9.7,129.4,127.8,45.5,39.5,34.2,33.1,31.1,29.0,28.9,22.9,21.7,19.1,12.9.

[0100] Example 18: Synthesis of Compound A18

[0101]

[0102] 1H NMR (400MHz, CDCl3): δ = 10.10 (d, J = 8.0Hz, 1H, CHO), 7.14 (dd, J1 = 14.8Hz, J2 = 11.6Hz, 1H, = CH), 6.43-6.29 ( m,2H,2x=CH),6.22-6.11(m,2H,2x=CH),5.97(d,J=8.0Hz,1H,=CH),2.29(s,1H,CD2H),2.09-1.99(m,5H,CH3 and CH2),1.72(s,3H,CH3),1.66-1.58(m,2H,CH2),1.51-1.44(m,2H,CH2),1.04(s,6H,2x CH3); 13 C NMR (100MHz, CDCl3): δ=191.1,154.8,141.3,137.6,137.1,134.5,132.5,130.5,129 .7,129.4,129.0,39.6,34.2,33.1,28.9,21.7,19.2,13.0,12.4(quint,J=19.4Hz).

[0103] Example 19: Synthesis of Compound A19

[0104]

[0105] 1 H NMR (400MHz, CDCl3): δ = 10.10 (d, J = 8.0Hz, 1H, CHO), 7.14 (dd, J1 = 15.2Hz, J2 = 11.6Hz, 1H, = CH), 6. 42-6.30(m,2H,2x=CH),6.22-6.13(m,2H,2x=CH),5.97(d,J=8.4Hz,1H,=CH),2.08-2.00(m,5H,CH3 and CH2),1.72(s,3H,CH3),1.66-1.58(m,2H,CH2),1.51-1.44(m,2H,CH2),1.04(s,6H,2x CH3); 13 C NMR (100MHz, CDCl3): δ=191.1,154.7,141.2,137.6,137.0,134.5,132.5,130.5,12 9.7,129.3,129.0,39.5,34.2,33.1,28.9,21.7,19.1,12.9,12.3(hept,J=19.3Hz).

[0106] Example 20: Synthesis of Compound A20

[0107]

[0108] 1 H NMR (400MHz, CDCl3): δ = 7.14 (dd, J1 = 14.8Hz, J2 = 11.6Hz, 1H, = CH), 6.42-6.29 (m, 2H, 2x = CH),6.22-6.12(m,2H,2x=CH),5.97(s,1H,=CH),2.33(s,3H,CH3),2.08-1.98(m,5H,CH2 and CH3),1.72(s,3H,CH3),1.67-1.58(m,2H,CH2),1.51-1.43(m,2H,CH2),1.04(s,6H,2x CH3); 13 C NMR (100MHz, CDCl3): δ = 190.8 (J = 25.7Hz), 154.7, 141.3, 137.7, 137.1, 134.5, 13 2.5,130.5,129.7,129.4,128.9,39.6,34.3,33.1,29.0,21.7,19.2,13.1,13.0.

[0109] Example 21: Synthesis of Compound A21

[0110]

[0111] 1 H NMR (400MHz, CD3CN): δ = 7.23 (dd, J1 = 15.2Hz, J2 = 11.6Hz, 1H, = CH), 6.42 (d, J = 15.2Hz, 1H, = CH), 6.37 (d, J = 16.4Hz, 1H, = CH), 6.23(d,J=11.6Hz,1H,=CH),6.18(d,J=16.4Hz,1H,=CH),5.89(s,1H,=CH),2.31-2.27(m,2H,CH2D),2.07-1.98(m,5H,CH3and CH2),1.71(s,3H,CH3),1.66-1.58(m,2H,CH2),1.52-1.44(m,2H,CH2),1.03(s,6H,2xCH3); 13C NMR (100MHz, CD3CN): δ = 191.9 (t, J = 25.7Hz), 156.1, 142.0, 138.6, 138.1, 135.7, 133.6, 131.1, 130.6,130.2,129.7(t,J=3.2Hz),40.4,34.9,33.7,29.3,22.0,19.9,13.1,13.0(t,J=19.4Hz).

[0112] Example 22: Synthesis of Compound A22

[0113]

[0114] 1 H NMR (400MHz, CDCl3): δ = 7.14 (dd, J1 = 15.2Hz, J2 = 11.6Hz, 1H, = CH), 6.42-6.30 (m, 2H,2x=CH),6.22-6.13(m,2H,2x=CH),5.97(s,1H,=CH),2.08-2.00(m,5H,CH3and CH2),1.72(s,3H,CH3),1.66-1.58(m,2H,CH2),1.51-1.44(m,2H,CH2),1.04(s,6H,2xCH3); 13 C NMR (100MHz, CDCl3): δ = 190.8 (t, J = 26.1Hz), 154.8, 141.3, 137.6, 137.0, 134.5, 132.5, 13 0.5,129.7,129.4,129.0,39.6,34.2,33.1,28.9,21.7,19.2,13.0,12.4(hept,J=19.3Hz).

[0115] Example 23: Synthesis of Compound B1

[0116]

[0117] The synthetic route is:

[0118]

[0119] To a dry reaction tube, A1 (98.2 mg, 0.3 mmol, 13E:13Z = 98:2), tert-butanol (6 mL), and 2-methyl-2-butene (1.8 mL, 15 mmol) were added sequentially. An aqueous solution (3 mL) containing NaClO2 (237.9 mg) and NaH2PO4 (251.9 mg) was added dropwise to the reaction mixture. After stirring at room temperature for 13 hours, water (10 mL) was added and the mixture was extracted four times with diethyl ether, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation. The product was separated and purified by column chromatography (eluent: petroleum ether / acetone = 20 / 1) and recrystallized to obtain product B1 (42.8 mg, 42%) as a white solid. 1 H NMR (400MHz, CDCl3): δ=7.00 (dd, J1=15.2Hz, J2=11.2Hz, 1H,=CH), 6.21 (d, J=15.2Hz, 1H,=CH), 6.17-6.05 (m, 2H, 2x=C H),5.84-5.74(m,2H,2x=CH),2.80(d,J=6.8Hz,2H,CH2),2.11-2.01(m,1H,CH),1.94(s,3H,CH3),1.79-1.59(m,10H,5x CH2),1.56-1.46(m,1H,CH),1.35-0.99(m,10H,5x CH2); 13 C NMR (100MHz, CDCl3): δ=171.9,159.2,139.9,138.4,134.5,132.0,131.8, 128.9,117.4,41.3,39.0,34.9,33.5,33.0,26.4,26.4,26.1,26.0,13.1.

[0120] The compounds described in Examples 24-47 can be prepared by referring to the methods and routes described in Example 23 above.

[0121] Example 24: Synthesis of Compound B2

[0122]

[0123] Yellow solid; 1H NMR (400MHz, CDCl3): δ=7.00 (dd, J1=14.8Hz, J2=11.2Hz, 1H,=CH), 6.21 (d, J=15.2Hz, 1H,=CH), 6.15 (d, J=15.6Hz, 1H,=CH), 6.10 (d, J=11.2Hz, 1H,=C H),5.89-5.76(m,2H,2x=CH),2.80(d,J=6.8Hz,2H,CH2),2.53(sext,J=8.0Hz,1H,CH),1.95(s,3H,CH3),1.88-1.78(m,2H,CH2),1.75-1.64(m,6H,3x CH2),1.64-1.47(m,4H,2x CH2),1.39-1.28(m,2H,CH2),1.23-1.11(m,3H,CH2 and CH),1.10-0.98(m,2H,CH2); 13 CNMR (100MHz, CDCl3): δ=171.8,159.2,139.7,137.3,134.5,132.6,131.8,128.8,117.4,43.9,39.0,33.5,33.4,26.5,26.4,25.2,13.2.

[0124] Example 25: Synthesis of Compound B3

[0125]

[0126] Yellow solid; 1 H NMR (400MHz, CDCl3): δ=7.00 (dd, J1=14.8Hz, J2=11.2Hz, 1H,=CH), 6.21 (d, J=15.2Hz, 1H,=CH), 6.14-6.06 (m, 2H, 2x=CH) ,5.89-5.78(m,2H,2x=CH),2.80(d,J=7.2Hz,2H,CH2),2.32-2.21(m,1H,CH),1.94(s,3H,CH3),1.81-1.58(m,11H,5xCH2 and one proton ofCH2),1.56-1.43(m,5H,2x CH2 and one proton ofCH2),1.41-1.32(m,2H,CH2),1.25-1.11(m,3H,CH2 and CH),1.10-0.97(m,2H,CH2); 13C NMR (100MHz, CDCl3): δ=172.1,159.2,140.0,139.2,134.4,131.8,131.5, 128.8,117.4,43.3,39.0,34.9,34.8,33.5,28.4,26.5,26.4,26.2,13.2.

[0127] Example 26: Synthesis of Compound B4

[0128]

[0129] Yellow solid; 1 H NMR (400MHz, CDCl3): δ = 7.45 (d, J = 7.6Hz, 2H, Ar-H), 7.33 (t, J = 7.6Hz, 2H, Ar-H), 7.24 (t,J=7.2Hz,1H,Ar-H),7.06(dd,J1=15.2Hz,J2=11.6Hz,1H,=CH),6.90(d,J=16.0Hz,1 H,=CH),6.69(d,J=16.0Hz,1H,=CH),6.38-6.26(m,2H,2x=CH),5.85(s,1H,=CH),2.83( d,J=7.2Hz,2H,CH2),2.08(s,3H,CH3),1.78-1.67(m,4H,2xCH2),1.66-1.60(m,1H,one proton ofCH2),1.58-1.48(m,1H,one proton of CH2),1.27-1.13(m,3H,CH2 and CH),1.12-0.99(m,2H,CH2); 13 C NMR (100MHz, CDCl3): δ=172.2,159.0,139.5,137.4,135.8,133.0,131.8,13 1.5,129.6,128.7,127.7,126.6,118.2,39.0,35.0,33.5,26.5,26.4,13.2.

[0130] Example 27: Synthesis of Compound B5

[0131]

[0132] Yellow solid; 1H NMR (400MHz, CDCl3): δ=7.30-7.20(m,3H,Ar-H),7.12-7.00(m,2H,Ar-H and=CH),6.89(d,J=16.0Hz,1H,=CH),6.66(d,J=16.0Hz,1H,=CH),6.38-6.23(m,2H,2x=CH),5.8 5(s,1H,=CH),2.83(d,J=7.2Hz,2H,CH2),2.36(s,3H,CH3),2.07(s,3H,CH3),1.78-1.67(m,4H,2x CH2),1.66-1.60(m,1H,one proton ofCH2),1.59-1.48(m,1H,one proton ofCH2),1.27-1.13(m,3H,CH2 and CH),1.12-1.00(m,2H,CH2); 13 C NMR (100MHz, CDCl3): δ=172.1,159.0,139.5,138.2,137.2,135.6,132.8,131.5,131. 5,129.7,128.6,128.5,127.3,123.8,118.1,39.0,34.9,33.5,26.4,26.4,21.4,13.1.

[0133] Example 28: Synthesis of Compound B6

[0134]

[0135] Yellow solid; 1H NMR (400MHz, CDCl3): δ = 7.34 (s, 1H, Ar-H), 7.30 (s, 2H, Ar-H), 7.07 (dd, J1 = 14.8Hz, J2 = 11.2Hz, 1H, = CH), 6.90 (d, J = 16.0Hz, 1H, = CH), 6.73 (d, J = 16.0Hz ,1H,=CH),6.36(d,J=11.6Hz,1H,=CH),6.30(d,J=15.2Hz,1H,=CH),5.85(s ,1H,=CH),2.83(d,J=6.8Hz,2H,CH2),2.10(s,3H,CH3),1.79-1.68(m,4H,2x CH2),1.67-1.60(m,1H,one proton ofCH2),1.60-1.51(m,1H,one proton ofCH2),1.35(s,18H,6x CH3),1.26-1.14(m,3H,CH2 and CH),1.12-1.01(m,2H,CH2); 13 C NMR (100MHz, CDCl3): δ=172.2,159.0,151.1,139.7,136.5,135.4,132.3,131.6,1 31.3,130.7,122.3,120.9,118.0,39.0,34.9,34.8,33.5,31.4,26.5,26.4,13.2.

[0136] Example 29: Synthesis of Compound B7

[0137]

[0138] Yellow liquid; 1H NMR (400MHz, CDCl3): δ = 7.07 (dd, J1 = 14.8Hz, J2 = 11.2Hz, 1H, = CH), 6.71 (d, J = 16.4Hz, 1H ,=CH),6.60(s,1H,Ar-H),6.28(d,J=4.8Hz,1H,=CH),6.24(d,J=6.0Hz,1H,=CH),6.20(d ,J=11.2Hz,1H,=CH),5.83(s,1H,=CH),3.82(s,3H,OCH3),2.83(d,J=6.8Hz,2H,CH2),2. 30(s,3H,CH3),2.24(s,3H,CH3),2.15(s,3H,CH3),2.11(s,3H,CH3),1.78-1.67(m,4H,2x CH2),1.66-1.60(m,1H,one proton ofCH2),1.59-1.49(m,1H,one proton of CH2),1.27-1.13(m,3H,CH2 and CH),1.12-1.00(m,2H,CH2); 13 C NMR (100MHz, CDCl3): δ=172.2,159.0,156.2,139.6,138.1,135.9,135.3,133.9,131.5,130.4, 129.8,128.8,122.7,117.9,109.9,55.5,39.0,34.9,33.5,26.5,26.4,21.4,17.4,13.0,11.8.

[0139] Example 30: Synthesis of Compound B8

[0140]

[0141] Yellow solid; 1H NMR (400MHz, CDCl3): δ = 7.34 (s, 1H, Ar-H), 7.20 (dd, J1 = 15.6Hz, J2 = 8.0Hz, 2H, Ar-H), 7.06 (dd, J1 = 15.2Hz, J2 = 11.6Hz, 1H, = C H),6.86(d,J=16.0Hz,1H,=CH),6.69(d,J=16.0Hz,1H,=CH),6.35-6.24(m,2H,2x=CH),5.85(s,1H,=CH),2.95-2.87(m,4H,2x CH2),2.82(d,J=6.8Hz,2H,CH2),2.13-2.04(m,5H,CH3 and CH2),1.78-1.67(m,4H,2x CH2),1.66-1.60(m,1H,one proton of CH2),1.58-1.49(m,1H,one proton ofCH2),1.27-1.13(m,3H,CH2 and CH),1.12-1.00(m,2H,CH2); 13 C NMR (100MHz, CDCl3): δ=170.8,159.0,144.9,144.3,139.8,135.5,135.3,131.9,131.6,1 31.1,130.1,125.1,124.6,122.2,117.5,39.0,34.9,33.5,32.7,26.5,26.4,25.5,13.1.

[0142] Example 31: Synthesis of Compound B9

[0143]

[0144] Yellow solid; 1H NMR (400MHz, CDCl3): δ = 7.04 (dd, J1 = 14.8Hz, J2 = 11.6Hz, 1H, = CH), 6.35-6.21 (m, 2H, 2x = CH), 6.20-6.10(m,2H,2x=CH),5.82(s,1H,=CH),2.81(d,J=7.2Hz,2H,CH2),2.09-1.97(m,5H,CH3 and CH2),1.76-1.66(m,7H,CH3 and 2x CH2),1.65-1.58(m,3H,one proton ofCH2 and CH2),1.53-1.43(m,3H,one proton ofCH2 and CH2),1.21-1.14(m,3H,CH2 and CH),1.10-0.99(m,8H,2x CH3 and CH2); 13 C NMR (100MHz, CDCl3): δ=171.7,159.2,140.0,137.7,137.2,134.7,131.7,130.1,129.6 ,129.0,117.4,39.6,39.0,34.9,34.2,33.5,33.1,28.9,26.5,26.4,21.7,19.2,13.0.

[0145] Example 32: Synthesis of Compound B10

[0146]

[0147] Yellow solid; 1 H NMR (400MHz, CDCl3): δ = 7.07 (dd, J1 = 14.8Hz, J2 = 11.2Hz, 1H, = CH), 6.34-6.21 (m, 2H, 2x = CH), 6. 20-6.10(m,2H,2x=CH),5.79(s,1H,=CH),2.95(d,J=7.6Hz,2H,CH2),2.10-1.96(m,6H,CH3,CH2 and one proton ofCH2),1.75-1.59(m,9H,CH3and3x CH2),1.53-1.44(m,4H,2x CH2),1.30-1.22(m,2H,one proton ofCH2 and CH),1.03(s,6H,2x CH3); 13C NMR (100MHz, CDCl3): δ=172.1,160.0,140.0,137.7,137.2,134.4,131.7,130.1,12 9.6,129.0,117.1,41.0,39.6,34.2,33.1,32.6,32.5,28.9,24.7,21.7,19.2,13.0.

[0148] Example 33: Synthesis of Compound B11

[0149]

[0150] Yellow liquid; 1 H NMR (400MHz, CDCl3): δ=7.08 (dd, J1=15.2Hz, J2=11.6Hz, 1H,=CH), 6.31 (d, J=16.4Hz, 1H,=CH) ,6.26(d,J=15.2Hz,1H,=CH),6.20-6.10(m,2H,2x=CH),5.83(s,1H,=CH),3.97-3.90(m,1H,one proton ofOCH2),3.86(t,J=7.6Hz,1H,oneproton ofOCH2),3.77(q,J=7.6Hz,1H,one proton ofOCH2),3.52(t,J=7.6Hz,1H,oneproton of OCH2),3.08(dd,J1=12.8Hz,J2=8.0Hz,1H,one proton ofCH2),2.93(dd,J1=12.4Hz,J2=7.2Hz,1H,one proton ofCH2),2.49(sept,J=7.2Hz,1H,CH),2.05-1.95(m,6H,CH3,CH2and one proton ofCH2),1.75-1.67(m,4H,CH3 and one proton ofCH2),1.65-1.59(m,2H,CH2),1.50-1.44(m,2H,CH2),1.03(s,6H,2x CH3); 13 C NMR (100MHz, CDCl3): δ=171.5,158.1,140.6,137.7,137.1,133.9,131.9,130.2,129.3,1 29.3,117.7,72.8,67.8,39.8,39.6,34.2,33.1,31.9,29.8,28.9,24.8,21.7,19.2,13.0.

[0151] Example 34: Synthesis of Compound B12

[0152]

[0153] Yellow liquid; 1 H NMR (400MHz, CDCl3): δ = 7.06 (dd, J1 = 15.2Hz, J2 = 11.6Hz, 1H, = CH), 6.39-6.23 (m, 2H, 2x = CH), 6.22-6.09 (m, 2H, 2x = CH), 5.84 (s, 1 H,=CH),3.96(dd,J1=10.8Hz,J2=2.8Hz,2H,OCH2),3.35(t,J=11.0Hz,2H,OCH2),2.87(d,J=7.2Hz,2H,CH2),2.10-1.95(m,5H,CH3 and CH2),1.85-1.77(m,1H,CH),1.72(s,3H,CH3),1.66-1.57(m,4H,2x CH2),1.51-1.42(m,4H,2x CH2),1.03(s,6H,2x CH3); 13 C NMR (100MHz, CDCl3): δ=171.7,158.0,140.4,137.7,137.1,134.4,131.9,130.2, 129.4,129.3,117.9,68.1,39.5,36.1,34.2,33.2,33.1,28.9,21.7,19.2,13.0.

[0154] Example 35: Synthesis of Compound B13

[0155]

[0156] Yellow solid; 1 H NMR (400MHz, CDCl3): δ = 7.30 (d, J = 14.8Hz, 2H, oxole-H), 7.14 (dd, J1 = 15.2Hz, J2 = 11.6Hz, 1H, = CH), 6.35-6.23 (m, 3H, oxole-H and 2x=CH),6.18-6.09(m,2H,2x=CH),5.87(s,1H,=CH),4.06(s,2H,CH2),2.02(t,J=5.8Hz,2H,CH2), 1.97(s,3H,CH3),1.71(s,3H,CH3),1.65-1.57(m,2H,CH2),1.49-1.43(m,2H,CH2),1.02(s,6H,2x CH3);13 C NMR (100MHz, CDCl3): δ=172.0,157.0,142.6,140.7,139.7,137.7,137.1,133.1,132. 8,130.2,129.3,122.4,117.4,111.1,39.6,34.2,33.1,28.9,23.2,21.7,19.2,12.9.

[0157] Example 36: Synthesis of Compound B14

[0158]

[0159] Yellow solid; 1 H NMR (400MHz, CDCl3): δ=7.22 (dd, J1=4.8Hz, J2=3.2Hz, 1H, thiophene-H), 7.11 (dd, J1=14. 8Hz, J2=11.6Hz,1H,=CH),7.05-6.92(m,2H,thiophene-H),6.34-6.20(m,2H,2x=CH),6.12( d,J=15.2Hz,1H,=CH),5.90(s,1H,=CH),4.28(s,2H,CH2),2.02(t,J=5.8Hz,2H,CH2),1.93( s,3H,CH3),1.70(s,3H,CH3),1.65-1.56(m,2H,CH2),1.50-1.42(m,2H,CH2),1.01(s,6H,2x CH3); 13 C NMR (100MHz, CDCl3): δ=171.5,156.9,140.7,139.1,137.7,137.1,133.3,133.0,130.2,1 29.4,129.3,128.2,125.2,121.1,117.4,39.6,34.2,33.1,28.9,28.4,21.7,19.2,12.9.

[0160] Example 37: Synthesis of Compound B15

[0161]

[0162] Yellow solid; 1H NMR (400MHz, CDCl3): δ = 7.19 (dd, J1 = 15.2Hz, J2 = 11.6Hz, 1H, = CH), 7.12-7.06 (m, 1H, thiophene-H), 6.89 (d, J = 3.6Hz, 2H, 2x thiophene-H),6.34-6.21(m,2H,2x=CH),6.19-6.08(m,2H,2x=CH),5.89(s,1H,=CH),4.46(s,2H,CH2),2.02(t,J= 6.2Hz,2H,CH2),1.97(s,3H,CH3),1.70(s,3H,CH3),1.65-1.57(m,2H,CH2),1.49-1.43(m,2H,CH2),1.02(s,6H,2x CH3); 13 C NMR (100MHz, CDCl3): δ=171.6,156.1,141.6,140.8,137.7,137.1,133.1,132.8,130. 2,129.3,126.7,125.2,123.5,117.8,39.6,34.2,33.1,28.9,27.7,21.7,19.2,12.9.

[0163] Example 38: Synthesis of Compound B16

[0164]

[0165] Orange liquid; 1 H NMR (400MHz, CDCl3): δ = 7.14 (dd, J1 = 15.2Hz, J2 = 11.6Hz, 1H, = CH), 6.39-6.28 (m, 2H, 2x = CH), 6.20-5.82 (m, 4H, CF2H and 3x=CH),3.46(td,J1=16.1Hz,J2=4.5Hz,2H,CH2),2.06-2.00(m,5H,CH3 and CH2),1.72(s,3H,CH3),1.66-1.58(m,2H,CH2),1.50-1.44(m,2H,CH2),1.03(s,6H,2x CH3); 13C NMR (100MHz, CDCl3): δ = 171.2, 150.2 (t, J = 6.1Hz), 141.8, 137.6, 137.0, 133.6, 133.0, 130.5, 129.9 ,129.2,119.2,116.1(t,J=241.0Hz),39.6,34.3,33.1,33.0(t,J=23.5Hz),28.9,21.7,19.2,13.0; 19 F NMR (376MHz, CDCl3): δ = -113.4.

[0166] Example 39: Synthesis of Compound B17

[0167]

[0168] Orange liquid; 1 H NMR (400MHz, CDCl3): δ = 7.08 (dd, J1 = 14.8Hz, J2 = 11.2Hz, 1H, = CH), 6.41-6.29 (m, 2H, 2x = CH), 6.24-6.11(m,2H,2x=CH),6.04(s,1H,=CH),3.90(q,J=10.4Hz,2H,CH2),2.09-1.98(m,5H,CH3 and CH2),1.72(s,3H,CH3),1.66-1.59(m,2H,CH2),1.51-1.44(m,2H,CH2),1.03(s,6H,2x CH3); 13 C NMR (100MHz, CDCl3): δ = 170.8, 146.6 (q, J = 2.6Hz), 141.7, 137.6, 137.0, 133.3, 132.2, 130.5, 130.0 ,129.1,125.2(q,J=276.5Hz),120.9,39.6,34.3,33.1,31.3(q,J=30.3Hz),28.9,21.7,19.2,13.0; 19 FNMR (376MHz, CDCl3): δ = -63.3.

[0169] Example 40: Synthesis of Compound B18

[0170]

[0171] Yellow solid; 1H NMR (400MHz, CDCl3): δ=7.06 (dd, J1=14.8Hz, J2=11.2Hz, 1H,=CH), 6.26 (d, J=12.4Hz, 1H,=CH), 6.19 (d, J=13 .2Hz,1H,=CH),6.20-6.10(m,2H,2x=CH),5.76(s,1H,=CH),2.92-2.82(m,2H,CH2),2.07-1.98(m,5H,CH3and CH2),1.72(s,3H,CH3),1.65-1.59(m,2H,CH2),1.53-1.41(m,6H,3x CH2),1.03(s,6H,2x CH3),0.95(t,J=7.2Hz,3H,CH3); 13 C NMR (100MHz, CDCl3): δ=171.9,160.5,140.1,137.7,137.2,134.0,131.5,130.1,129.6 ,129.0,116.8,39.6,34.2,33.1,32.0,29.0,28.9,27.5,23.0,21.7,19.2,13.9,12.9.

[0172] Example 41: Synthesis of Compound B19

[0173]

[0174] Yellow solid; 1 H NMR (400MHz, CDCl3): δ=7.06 (dd, J1=14.8Hz, J2=11.2Hz, 1H,=CH), 6.30 (d, J=16.0Hz, 1H,=CH), 6.22 (d, J=15 .2Hz,1H,=CH),6.19-6.10(m,2H,2x=CH),5.75(s,1H,=CH),2.92-2.79(m,2H,CH2),2.07-1.99(m,5H,CH3and CH2),1.72(s,3H,CH3),1.66-1.58(m,2H,CH2),1.54-1.45(m,4H,2x CH2),1.45-1.38(m,2H,CH2),1.36-1.29(m,4H,2x CH2),1.03(s,6H,2x CH3),0.93-0.87(m,3H,CH3); 13C NMR (100MHz, CDCl3): δ=172.2,160.5,140.1,137.7,137.2,134.0,131.5,130.1,129.6,1 29.0,117.0,39.6,34.2,33.1,31.5,29.8,29.5,29.0,27.8,22.5,21.7,19.2,14.1,12.9.

[0175] Example 42: Synthesis of Compound B20

[0176]

[0177] Yellow solid; 1 H NMR (400MHz, CDCl3): δ=7.06 (dd, J1=15.2Hz, J2=11.6Hz, 1H,=CH), 6.30 (d, J=16.0Hz, 1H,=CH), 6.22 (d, J=15. 2Hz,1H,=CH),6.19-6.10(m,2H,2x=CH),5.74(s,1H,=CH),2.88(q,J=7.5Hz,2H,CH2),2.06-1.97(m,5H,CH3and CH2),1.72(s,3H,CH3),1.65-1.59(m,2H,CH2),1.50-1.45(m,2H,CH2),1.15(t,J=7.6Hz,3H,CH3),1.03(s,6H,2x CH3); 13 C NMR (100MHz, CDCl3): δ=171.0,161.7,140.1,137.7,137.3,133.6,131.5,130 .2,129.6,129.0,116.4,39.6,34.3,33.1,29.0,21.8,21.1,19.2,14.3,13.0.

[0178] Example 43: Synthesis of Compound B21

[0179]

[0180] Yellow solid; 1H NMR (400MHz, CDCl3): δ=7.07 (dd, J1=14.8Hz, J2=11.6Hz, 1H,=CH), 6.30 (d, J=16.0Hz, 1H,=CH), 6.22 (d, J=15 .2Hz,1H,=CH),6.19-6.10(m,2H,2x=CH),5.74(s,1H,=CH),2.93-2.76(m,2H,CH2),2.07-1.95(m,5H,CH3and CH2),1.71(s,3H,CH3),1.66-1.58(m,2H,CH2),1.51-1.45(m,2H,CH2),1.42-1.35(m,2H,CH2),1.03(s,6H,2xCH3),0.99(s,9H,3x CH3); 13 C NMR (100MHz, CDCl3): δ=171.5,161.0,140.2,137.7,137.2,133.8,131.5,130.1,12 9.5,129.0,116.7,43.7,39.6,34.2,33.1,30.9,29.1,28.9,23.6,21.7,19.2,12.8.

[0181] Example 44: Synthesis of Compound B22

[0182]

[0183] Yellow solid; 1 H NMR (400MHz, CDCl3): δ=7.28-7.22(m,4H,Ar-H),7.20-7.14(m,1H,Ar-H),7.04(dd,J 1=15.2Hz, J2=11.2Hz, 1H,=CH), 6.25(d, J=15.2Hz, 2H, 2x=CH), 6.12-6.04(m, 2H, 2x=C H),5.97(s,1H,=CH),4.32(s,2H,CH2),2.00(t,J=6.0Hz,2H,CH2),1.87(s,3H,CH3), 1.68(s,3H,CH3),1.64-1.55(m,2H,CH2),1.48-1.42(m,2H,CH2),1.00(s,6H,2xCH3); 13C NMR (100MHz, CDCl3): δ=171.7,156.8,140.5,139.1,137.7,137.1,133.4,133.3,130.1,1 29.4,129.2,128.5,128.2,126.0,118.2,39.6,34.2,33.4,33.1,28.9,21.7,19.2,12.8.

[0184] Example 45: Synthesis of Compound B23

[0185]

[0186] White solid; 1 H NMR (400MHz, CDCl3): δ = 6.99 (dd, J1 = 15.2Hz, J2 = 11.6Hz, 1H, = CH), 6.23 (d, J = 15.2Hz, 1H ,=CH),6.19-6.09(m,2H,2x=CH),5.82(s,1H,=CH),5.76(dd,J1=15.6Hz,J2=6.8Hz,1H,=C H),3.99(dd,J1=11.6Hz,J2=2.4Hz,2H,OCH2),3.44(td,J1=12.0Hz,J2=2.0Hz,2H,OCH2) ,2.80(d,J=6.8Hz,2H,CH2),2.39-2.27(m,1H,CH),1.95(s,3H,CH3),1.75-1.59(m,8H,4x CH2),1.58-1.44(m,4H,2x CH2),1.23-1.11(m,3H,CH2 andCH),1.10-0.97(m,2H,CH2); 13 C NMR (100MHz, CDCl3): δ=170.7,159.0,139.3,135.8,135.0,132.9,131.5,129.6,117.4,67.7,38.9,38.5,34.9,33.5,32.7,26.5,26.4,13.1.

[0187] Example 46: Synthesis of Compound B24

[0188]

[0189] Yellow solid; 1H NMR (400MHz, CDCl3): δ = 7.45 (s, 1H, Ar-H), 7.32-7.27 (m, 3H, Ar-H), 7.06 (dd, J1 = 15.2Hz, J2 = 11.6Hz, 1H, = CH), 6.90 (d, J = 16.0Hz, 1H, = CH), 6.71 (d, J = 16. 0Hz,1H,=CH),6.35(d,J=11.6Hz,1H,=CH),6.30(d,J=15.2Hz,1H,=CH),5.85( s,1H,=CH),2.83(d,J=6.8Hz,2H,CH2),2.09(s,3H,CH3),1.78-1.67(m,4H,2x CH2),1.66-1.61(m,1H,one proton ofCH2),1.58-1.51(m,1H,one proton ofCH2),1.35(s,9H,3xCH3),1.24-1.14(m,3H,CH2 and CH),1.12-1.01(m,2H,CH2); 13 C NMR (100MHz, CDCl3): δ=171.7,159.0,151.5,139.6,137.0,135.6,132.7,131.5,131.5,1 30.1,128.4,125.0,124.0,123.5,117.9,39.0,34.9,34.7,33.5,31.3,26.5,26.4,13.1.

[0190] Example 47: Synthesis of Compound B25

[0191]

[0192] Yellow solid; 1 H NMR (400MHz, CDCl3): δ = 11.76 (br, 1H, COOH), 7.04 (dd, J1 = 15.0Hz, J2 = 11.4Hz, 1H, = CH), 6 .37-6.25(m,2H,2x=CH),6.20-6.10(m,2H,2x=CH),5.80(s,1H,=CH),2.06-1.98(m,5H,CH2 and CH3),1.72(s,3H,CH3),1.66-1.58(m,2H,CH2),1.51-1.44(m,2H,CH2),1.03(s,6H,2x CH3); 13C NMR (100MHz, CDCl3): δ=172.6,155.2,140.2,137.7,137.2,134.9,131.8,130.2,12 9.4,129.0,117.8,39.6,34.2,33.1,28.9,21.7,19.2,13.3(sept,J=19.2Hz),12.9.

[0193] The compounds described in Examples 48-51 can be synthesized using the aldehydes described in the above examples as substrates using techniques / methods known in the art.

[0194] Example 48: Synthesis of Compound B26

[0195]

[0196] 1 H NMR (400MHz, C6D6): δ = 6.65 (dd, J1 = 14.8Hz, J2 = 11.2Hz, 1H, = CH), 6.35-6.13 (m, 4H, 4x = CH), 5.62 (s, 1H, = CH), 1.97 (t, J = 6.0Hz, 2 H,CH2),1.86(s,3H,CH3),1.78(s,3H,CH3),1.69(s,3H,CH3),1.63-1.56(m,2H,CH2),1.52-1.44(m,2H,CH2),1.12(s,6H,2xCH3); 13 C NMR (100MHz, C6D6): δ=170.1,139.1,138.5,138.3,136.7,136.4,131.0,129.4,127.1,126.0,125. 6,60.5(quint,J=22.1Hz),39.9,34.6,33.3,29.2,22.0,20.5,19.7,12.8,11.9(sept,J=19.2Hz).

[0197] Example 49: Synthesis of Compound B27

[0198]

[0199] 1H NMR (400MHz, C6D6): δ = 6.65 (dd, J1 = 15.2Hz, J2 = 11.2Hz, 1H, = CH), 6.35-6.13 (m, 4H, 4x = CH), 5.63 (d, J = 7.2Hz, 1H, = CH), 4.64 (d, J = 7.2Hz, 1H, OCDH ),1.96(t,J=6.0Hz,2H,CH2),1.86(s,3H,CH3),1.78(s,3H,CH3),1.69(s,3H,CH3),1.63-1.55(m,2H,CH2),1.52-1.44(m,2H,CH2),1.12(s,6H,2x CH3); 13 C NMR (100MHz, C6D6): δ=170.1,139.0,138.5,138.3,136.7,136.4,131.0,129.4,127.1,126.0,12 5.7,60.8(t,J=22.1Hz),39.9,34.6,33.3,29.2,22.0,20.5,19.7,12.8,11.9(sept,J=19.3Hz).

[0200] Example 50: Synthesis of Compound B28

[0201]

[0202] 1 H NMR (400MHz, C6D6): δ = 6.66 (dd, J1 = 15.0Hz, J2 = 11.4Hz, 1H, = CH), 6.35-6.14 (m, 4H, 4x = CH), 5.62 (s, 1H, = CH), 1.97 (t, J = 6.0Hz, 2H, CH2 ),1.86(s,3H,CH3),1.78(s,3H,CH3),1.69(s,3H,CH3),1.67(s,3H,CH3),1.63-1.56(m,2H,CH2),1.52-1.45(m,2H,CH2),1.13(s,6H,2x CH3); 13 C NMR (100MHz, C6D6): δ=170.1,139.1,138.5,138.3,136.7,136.4,131.0,129.4,127.1,12 6.0,125.6,60.5(quint,J=21.9Hz),39.9,34.6,33.3,29.2,22.0,20.5,19.7,12.8,12.6.

[0203] Example 51: Synthesis of Compound B29

[0204]

[0205] 1 H NMR (400MHz, C6D6): δ = 6.65 (dd, J1 = 15.2Hz, J2 = 11.2Hz, 1H, = CH), 6.35-6.13 (m, 4H, 4x = CH), 5.63 (t, J = 7.4Hz, 1H, = CH), 4.66 (d, J = 6.8Hz, 2H, OCH2 ),1.97(t,J=6.2Hz,2H,CH2),1.86(s,3H,CH3),1.78(s,3H,CH3),1.70(s,3H,CH3),1.63-1.55(m,2H,CH2),1.52-1.44(m,2H,CH2),1.12(s,6H,2x CH3); 13 C NMR (100MHz, C6D6): δ=170.0,138.9,138.5,138.2,136.6,136.3,131.0,129.3,127.0,12 5.9,125.7,61.1,39.9,34.5,33.3,29.1,21.9,20.5,19.7,12.7,11.8(sept,J=19.2Hz).

[0206] Example 52: Synthesis of Compound B30

[0207]

[0208] 1 H NMR (400MHz, CDCl3) δ6.61 (dd, J1=15.1, J2=11.2Hz, 1H), 6.29 (d, J=15.2Hz, 1H), 6.22-6.04 (m, 3H), 5.69 ( s,1H),2.02(t,J=6.2Hz,2H),1.96(s,3H),1.71(s,3H),1.66-1.55(m,3H),1.50-1.44(m,2H),1.02(s,6H).

[0209] Example 53: Synthesis of Compound B31

[0210]

[0211] 1H NMR (400MHz, CDCl3) δ6.61 (dd, J1=15.1, J2=11.2Hz, 1H), 6.29 (d, J=15.2Hz, 1H), 6.22-6.05 (m, 3H), 5.69 (d, J=7.0Hz, 1H), 4.29 (s, 1H), 2.02 (t, J = 6.2Hz, 2H), 1.96 (s, 3H), 1.71 (s, 3H), 1.66-1.55 (m, 3H), 1.49-1.43 (m, 2H), 1.02 (s, 6H).

[0212] Example 54: Western blot detection of the effects of the compounds of the present invention on LDLR protein expression

[0213] Experimental methods:

[0214] HepG2 cells were seeded in 12-well plates at 100,000 per well. After culturing for 24 hours, the cells were washed twice with PBS the next day and replaced with serum-free RPMI 1640 medium containing 0.3% BSA overnight. The compound of the present invention (25 μM) and DMSO control were then added. After 24 hours, 100 μL of SDS lysis buffer (62.5 mM Tris pH 6.8, 1% SDS) was added to each well for cell lysis. Protein concentration was determined using a NanoDrop spectrophotometer. Equal amounts of protein were loaded onto SDS-PAGE gels and subsequently transferred to nitrocellulose membranes. After the membranes were blocked in 5% skim milk powder, the primary antibody was added and incubated at 4°C overnight. The membranes were washed and incubated with HRP-labeled secondary antibodies for 1 hour at room temperature. Enhanced chemiluminescence (ECL) kits were used for development, and images were captured using the ChemiDoc Touch imaging system. The acquired images were analyzed using Image J software. The relative level of LDLR protein was calculated as the ratio of the LDLR protein expression in the compound-treated group to the LDLR protein expression in the DMSO control group, where the LDLR protein expression in the control group was set to 1.0.

[0215] Experimental results: Table 1 below shows the results of the compounds of the present invention regulating LDLR expression levels.

[0216] Table 1

[0217]

[0218] The compounds listed in Table 1 can all increase the expression level of LDLR protein in HepG2 cells. Therefore, the compounds of the present invention can be used to treat diseases caused by cell functions related to abnormal LDLR levels, especially diseases caused by lipid metabolism disorders.

[0219] Example 55: Effects of the compounds of the present invention on cancer cell viability

[0220] HGC27 cells were seeded in a 96-well plate at a density of 5000 cells per well. After overnight culture, the compounds of the present invention (100, 30, 10, 3, 1, 0.3 μM) and DMSO control were added. After 48 hours of action, 100 μL of 20% cold trichloroacetic acid (TCA) was added and fixed at 4°C for 30-60 minutes. The plate was discarded and washed 5-8 times, inverted, and dried. 100 μL of SRB (0.4% SRB, 1% acetic acid) was added and placed at room temperature for 30 minutes. The SRB was aspirated, washed 5 times with 1% acetic acid, dried, and dissolved with 100 μL of 10 mM Tris solution for 10 minutes. The absorbance (OD) was measured by a microplate reader. The cell proliferation inhibition activity was calculated, and a concentration-inhibition rate curve was plotted using GraphPad, and the half-inhibitory concentration (IC50) was fitted. 50 )

[0221] Cell survival rate (%) = 100 × (absorbance value of the treatment group / absorbance value of the DMSO control group)

[0222] The results are shown in Table 2. All compounds of the present invention can inhibit the proliferation of gastric cancer HGC27 cells. The IC values of some compounds on HGC27 are 50 Less than 10μM.

[0223] Table 2 Half inhibitory concentration of the compounds of the present invention for inhibiting the proliferation of gastric cancer HGC27 cells

[0224] Compound <![CDATA[IC 50 (μM)]]> Compound <![CDATA[IC 50 (μM)]]> Compound <![CDATA[IC 50 (μM)]]> control group ＞100 A18 26.88 B14 23.37 A1 35.33 A19 19.68 B15 34.99 A2 30.26 A20 20.20 B16 7.52 A3 26.57 A21 19.64 B17 28.74 A4 15.12 A22 11.80 B18 9.20 A5 26.63 B1 9.53 B19 11.98 A6 32.45 B2 28.96 B20 18.02 A7 16.58 B3 16.52 B21 8.40 A8 9.36 B4 7.54 B22 28.75 A9 36.98 B5 8.16 B23 41.23 A10 21.30 B6 11.62 B24 14.16 A11 41.69 B7 16.79 B25 24.61 A12 33.63 B8 14.23 B26 30.25 A13 25.68 B9 30.17 B27 13.69 A14 19.67 B10 24.15 B28 16.72 A15 10.81 B11 30.36 B29 17.83 A16 29.66 B12 25.63 B30 6.51 A17 31.38 B13 29.30 B31 8.76

[0225] Example 56: Inhibitory activity of the compounds of the present invention on the release of cellular inflammatory factor NO

[0226] RAW264.7 cells were seeded at a density of 20,000 cells / well in 96-well plates. After overnight culture, the cells were incubated with a 10 μM concentration of a compound of the invention for 1 hour, followed by treatment with 10 ng / mL LPS for 24 hours. After 24 hours, NO levels in the culture medium were quantified using the Griess reaction. Absorbance was measured over 30 minutes using a 540 nm filter, and NO inhibition was calculated using a standard curve.

[0227] Experimental results: The compounds of the present invention have inhibitory activity on the release of inflammatory factor NO, and the NO inhibition rate reaches or exceeds 50% (Table 3).

[0228] Table 3 Inhibition rate of the compounds of the present invention on the release of inflammatory factor NO

[0229]

[0230]

[0231] Example 57: Regulatory effect of the compounds of the present invention on LDL-C uptake in HepG2 cells

[0232] Experimental procedure: HepG2 cells were cultured at 2×10 5 The cells were seeded in a black 96-well plate at a density of 100 cells and cultured overnight. The culture medium was then removed and replaced with serum-free RPMI 1640 medium containing 0.3% bovine serum albumin (BSA), and the culture was continued for 24 hours. The cells were then treated with the compound of the present invention for 24 hours, after which the cell culture medium was replaced with serum-free RPMI 1640 medium containing 0.3% BSA and 20 μg / mL DiI-LDL, and incubated with DiI-LDL for 4 hours. After the incubation, the HepG2 cells were washed three times with PBS containing 0.4% BSA and then washed twice with PBS. For quantitative fluorescence detection, 500 μL of isopropanol was added to each well, incubated in the dark at room temperature for 20 minutes and continuously shaken. The fluorescence intensity was measured using a microplate reader with an excitation wavelength of 514 nm and an emission wavelength of 565 nm.

[0233] Experimental results: The results are as follows Figure 1 As shown, compounds B9 and B10 of the present invention have the effect of significantly enhancing LDL-C uptake in HepG2 cells. This indicates that the compounds of the present invention have the ability to regulate cellular LDL-C uptake and can be used to improve hypercholesterolemia caused by elevated LDL-C.

[0234] Example 58: Effect of the Compounds of the Invention on Cholesterol Regulation in Vivo

[0235] Mice modeled with hyperlipidemia induced by a high-fat diet were randomly divided into three groups, A, B, and C, with six mice in each group. Groups A and B were intraperitoneally injected daily with 10 mg / kg and 30 mg / kg of the compound B9 of the present invention, respectively. Group C was administered the same volume of solvent as a control. After two weeks of treatment, serum and liver tissue samples were collected to measure cholesterol levels.

[0236] Experimental results: Compared with the untreated solvent control group, the cholesterol levels in the serum and liver of mice treated with compound B9 of the present invention were significantly reduced (see Appendix Figure 2 ).

[0237] Example 59: Effects of the compounds of the present invention on retinal lipofuscin formation in vivo

[0238] Two-month-old ABCA4 - / - / RDH8 - / -Double-knockout female mice were randomly divided into three groups (A, B, and C), with five mice in each group. Groups A and B were orally administered daily with 2.64 mg / kg of compounds B26 and B27 of the present invention, respectively. Group C was administered the same volume of solvent as a control. After four months of treatment, the mouse retinas were harvested and imaged by TEM to investigate lipofuscin formation.

[0239] Experimental results: Compared with the untreated solvent control group, the retinal lipofuscin content of mice treated with compounds B26 and B27 of the present invention was significantly reduced (see Appendix Figure 3 ).

[0240] Unless otherwise defined, all technical and scientific terms used in the present invention have the same meaning as those commonly understood by those skilled in the art of the present invention. The terms used in the specification of the present invention are only for the purpose of describing specific embodiments and are not intended to limit the present invention.

[0241] As used herein, the terms “include” and “comprising” are open-ended expressions, that is, including the contents specified in the present invention but not excluding other aspects.

[0242] As used herein, the term "and / or" includes any and all combinations of one or more of the associated listed items.

[0243] As used herein, "treating" means preventing, slowing, stopping, or reversing the progression of a disease. Treating may also mean ameliorating one or more symptoms of a disease.

[0244] The compounds of the present invention can be administered in a variety of forms, including but not limited to those described herein. Treatment with the compounds of the present invention can be part of a combination therapy or adjuvant therapy, i.e., combining one or more compounds of the present invention to treat a subject in need of the drug, or administering another drug for the disease. Depending on the dosage form employed, they can be administered independently by the same or two or more different routes of administration.

[0245] The protection content of the present invention is not limited to the above embodiments. Without departing from the spirit and scope of the present invention, changes and advantages that can be thought of by ordinary technicians in this field are included in the present invention and are protected by the appended claims.

Claims

1. A diisoprene derivative or a pharmaceutically acceptable salt or stereoisomer thereof, or a solvate thereof, or a prodrug thereof, characterized in that: The structures of the diisoprene derivatives are shown in formula (I) and formula (II): Wherein, R0 is selected from hydrogen, aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, alkyl with a functional group, cycloalkyl with a functional group, heterocycloalkyl with a functional group, alkenyl, alkenyl with a functional group; R1, R2 and R3 are independently selected from hydrogen, deuterium, tritium, halogen, aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, alkyl with a functional group, cycloalkyl with a functional group, heterocycloalkyl with a functional group; R4 and R5 are independently selected from hydrogen, deuterium, tritium, hydroxyl, amino, aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, acyl, alkyl with a functional group, cycloalkyl with a functional group, heterocycloalkyl with a functional group, and acyl with a functional group; R6 and R7 are each independently selected from hydrogen, deuterium, tritium, halogen, difluoromethyl, trifluoromethyl, alkyl, aryl, and heteroaryl.

2. The diisoprene derivative or pharmaceutically acceptable salt or stereoisomer thereof, or solvate thereof, or prodrug thereof according to claim 1, wherein: R0 is selected from aryl, cycloalkyl, heterocycloalkyl, and alkenyl; wherein the aryl is phenyl or phenyl containing 1-5 substituents; the cycloalkyl is a C4-C8 membered aliphatic ring; the heterocycloalkyl refers to a 4-8 membered aliphatic ring containing nitrogen, oxygen or sulfur atoms; the alkenyl is a C4-C6 cyclic olefin; R1, R2 and R3 are each independently selected from hydrogen, deuterium, aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl; R4 and R5 are independently selected from hydrogen, hydroxyl, and acyl; the aryl group is phenyl, and the heteroaryl group refers to a 5-8 membered single aromatic ring containing nitrogen, oxygen or sulfur atoms; the alkyl group is a C1-C10 alkane; the cycloalkyl group is a C3-C8 membered aliphatic ring; the heterocycloalkyl group refers to a 4-8 membered aliphatic ring containing nitrogen, oxygen or sulfur atoms; the acyl group has a structure as shown in formula (III): wherein R is selected from a C1-C5 alkyl group; R6 and R7 are independently selected from hydrogen, deuterium; And / or, the functional group includes halogen, difluoromethyl, trifluoromethyl.

3. A drug / drug composition, characterized in that: The invention comprises a therapeutically effective amount of one or more diisoprene derivatives according to claim 1 or pharmaceutically acceptable salts or stereoisomers thereof, or solvates thereof, or prodrugs thereof as active ingredients and pharmaceutically acceptable excipients.

4. Use of the diisoprene derivative according to claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, or a solvate thereof, or a prodrug thereof, or the drug / pharmaceutical composition according to claim 3 in the preparation of a medicament for treating and / or preventing or alleviating diseases associated with abnormal lipid metabolism.

5. Use of the diisoprene derivative according to claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, or a solvate thereof, or a prodrug thereof, or the drug / pharmaceutical composition according to claim 3 in the preparation of a medicament for regulating the level of low-density lipoprotein receptor (LDLR).

6. Use of the diisoprene derivative according to claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, or a solvate thereof, or a prodrug thereof, or the drug / drug composition according to claim 3 in the preparation of a medicament for treating a disease or condition associated with an abnormal LDLR level.

7. The use according to claim 6, characterized in that The diseases or conditions include diseases associated with abnormal lipid metabolism, abnormal cholesterol levels and dyslipidemia.

8. The use according to claim 7, characterized in that The diseases associated with abnormal lipid metabolism include cardiovascular diseases, metabolic diseases, endocrine disorders, inflammatory diseases, cancer, and retinal diseases; and / or, the abnormal cholesterol level includes fatty liver.

9. The use according to claim 8, characterized in that The cardiovascular diseases include atherosclerosis, coronary heart disease, coronary artery disease, myocardial infarction, and stroke; and / or the metabolic diseases include diabetes, obesity, metabolic syndrome, and insulin resistance diseases; and / or the endocrine disorders include hyperlipidemia and hypercholesterolemia; the inflammatory diseases include acute / chronic liver injury, acute / chronic lung injury, acute kidney injury, chronic hepatitis, rheumatoid arthritis, Alzheimer's disease, and chronic tubulointerstitial inflammation; and / or the cancers include liver cancer, breast cancer, lung cancer, gastric cancer, colorectal cancer, hematologic malignancies, and gliomas.

10. The use according to claim 8, characterized in that The retinal diseases include retinal inflammation and choroiditis, optic neuritis, retinal vein occlusion, retinitis pigmentosa, retinal damage, age-related macular degeneration, and juvenile macular degeneration.

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