2-trifluoromethyl-3-aryl-2h-chromen ether derivatives, methods of preparation and use

Abstract

The application belongs to the field of pharmaceutical chemicals, and discloses a 2-trifluoromethyl-3-aryl-2H-chromene ether derivative, a preparation method and application. The 2-trifluoromethyl-3-aryl-2H-chromene ether derivative has a structure as shown in formula (I), wherein: R 1 is selected from aryl with different substituents, 2 is selected from any one or combination of -H, -F, -Cl, -CH3, -OCH3 with arbitrary position substitution, 3 is selected from benzene, biphenyl, furan, thiophene, benzothiophene with arbitrary position substitution, and n=1 or 2. The compound provided by the application can be used as an anti-inflammatory drug and an analgesic drug, and is used for the treatment of acute and chronic inflammatory reactions, tissue swelling, hyperplasia and pain. Some of the compounds show better anti-inflammatory and analgesic effects than commercially available non-steroidal anti-inflammatory drugs.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of pharmaceutical chemicals, in particular to a 2-trifluoromethyl-3-aryl-2H-chromene ether derivative, a preparation method and application thereof. BACKGROUND

[0002] Inflammation is one of the most important processes in the defense of organisms, however, it often develops into a disease that needs drug treatment, which is manifested as pain or chronic damage. In addition, inflammation is related to various diseases, such as atherosclerosis, Alzheimer's disease, Parkinson's disease, rheumatoid arthritis and diabetes, etc. In the world, the most widely used drugs for anti-inflammatory, rheumatic diseases, osteoarthritis and pain relief are mainly non-steroidal anti-inflammatory drugs (NSAIDs). About 30 million people regularly take these drugs. Due to the exposed carboxyl group in the structure of NSAIDs and the poor selectivity of COX-2 and COX-1, NSAIDs have significant side effects, for example, about 107,000 people visit a doctor for NSAIDs-related stomach disease every year, in addition, there are also kidney damage, cardiotoxicity and platelet inhibition (increasing the mortality rate of gastrointestinal bleeding), etc., leading to the current NSAIDs cannot meet the medical needs. The safety of NSAIDs is very important all over the world, but it is undeniable that the overall benefits of NSAIDs outweigh the risks (European Medicines Agency, 2006), especially in the treatment of arthritis and pain relief, which still needs to rely on non-steroidal anti-inflammatory drugs for treatment. Therefore, it is of great significance to develop new NSAIDs with high selectivity and less side effects.

[0003] Chromene is a heterocyclic compound with multiple biological activities, researchers have reported that it has anti-inflammatory and antioxidant, anticancer, antibacterial and antiviral activities, etc. Compounds containing chromene skeleton also widely exist in natural products, its low toxicity and wide pharmacological properties inspire the inspiration of medicinal chemists to find new drugs, and the pharmaceutical industry also knows the importance of this important structure in the development of new drug candidates. Among them, many researchers have reported that 2-trifluoromethyl chromene has excellent anti-inflammatory activity as a selective COX-2 inhibitor. Patent TW091135330 new compounds of indole-3-yl-2-oxyacetamide derivatives and pharmaceutical compositions and preparation methods thereof, based on the discovery that some specific heteroatom-containing compounds have effective anticancer activity, cytotoxicity and vascular proliferation inhibition ability, and based on the discovery that some indole-3-yloxoacetamido compounds have effective anticancer activity and cytotoxicity, and the use thereof for treating various cancers. However, its preparation method is too complex and the safety is not enough. SUMMARY

[0004] In combination with the previous research work, the present application takes 2-trifluoromethyl chromene as a lead compound and modifies its structure. It has been reported that the structure of NSAIDs has a naked carboxylic acid structure that dissolves phospholipids of mucosal epithelial cells, increases the permeability of the mucosa, and ultimately causes severe gastric ulcers. Most of the reported structures have a carboxylic acid structure connected to the 3-position of the chromene ring. In order to reduce the stimulation of the digestive tract caused by naked carboxylic acid, the carboxyl structure is replaced, that is, the 3-position is modified by replacing the carboxylic acid with an aromatic group.

[0005] On the basis of the above research, in order to solve the problems existing in the prior art, the present application designs and synthesizes a 2-trifluoromethyl-3-aryl-2H-chromene ether derivative with good anti-inflammatory activity. Specifically, the 2-trifluoromethyl-3-aryl-2H-chromene ether derivative provided by the present application has the structure shown in the following general formula (I),

[0006]

[0007] Among them,

[0008] R 1 Any one selected from a five-membered ring or a six-membered ring substituted with hydrogen, halogen, C6 and lower hydrocarbyl, C4 and lower alkoxy, preferably any one of -4-F-C6H4, -2-Cl-C6H4, -4-Cl-C6H4, -3-Br-C6H4, -4-Br-C6H4, -4-OCH3-C6H4, -3-CH3-C6H4, -4-CH3-C6H4, -4-Ph-C6H4, thienyl;

[0009] R 2 Any one or combination of hydrogen, halogen, C5 and lower alkyl and alkoxy substituted at any position, preferably any one of -5-Cl, -6,8-Cl2, -6-F, -7-CH3, -6-OCH3, -5,7-(OCH3)2;

[0010] R 3 Selected from (wavy line is the connection position), C4 and lower hydrocarbyl substituted furan, thiophene, benzothiophene with substitution at any position; R 4 Selected from H, C6 and lower hydrocarbyl, C4 and lower alkoxy; preferably any one of Ph, -3-OCH3-C6H4, -4-Ph-C6H4, furan, thiophene, benzothiophene, 2-methylfuran;

[0011] n is selected from 1, 2;

[0012] Preferably, the compound represented by the general formula (I) is selected from one of the following structural formulas:

[0013]

[0014] The present application also provides a method for preparing the above-mentioned 2-trifluoromethyl-3-aryl-2H-chromen ether derivative (I).

[0015]

[0016] In the formula (I)-(V), R 1 , R 2 , R 3 and n are defined as above.

[0017] The specific synthesis method is as follows:

[0018] The 2-aryl-substituted carboxylic acid shown in the formula (V) is used as raw material to generate the ketone compound shown in the formula (IV) through a Friedel-Crafts acylation reaction.

[0019] The ketone compound shown in the formula (IV) is used as raw material to generate the (Z)-trifluoromethyl vinyl triflate compound shown in the formula (III) through an ester / ketone exchange reaction.

[0020] The (Z)-trifluoromethyl vinyl triflate compound shown in the formula (III) is used as raw material to generate the 2-trifluoromethyl-2-hydroxy-3-aryl-2H-chromene shown in the formula (II) through a condensation and cyclization reaction with the R 2 substituted salicylaldehyde.

[0021] The 2-trifluoromethyl-2-hydroxy-3-aryl-2H-chromene shown in the formula (II) is used as raw material to generate the 2-trifluoromethyl-3-aryl-2H-chromen ether derivative shown in the formula (I) through a Wittig reaction with the R 3 substituted alcohol.

[0022] The present application also provides the use of the above-mentioned 2-trifluoromethyl-3-aryl-2H-chromen ether derivative (I), which is specifically used for preparing an anti-inflammatory and analgesic drug.

[0023] Preferably, the drug is used for treating acute and chronic inflammation and pain in the test but not limited to the examples.

[0024] The 2-trifluoromethyl-3-aryl-2H-chromen ether derivative (I) provided by the present application can be used as an effective component in a drug for treating acute and chronic inflammation and accompanying hyperplasia and pain.

[0025] Compared with the prior art, the present application has the following beneficial effects:

[0026] The compounds provided by the present application can be used for preparing anti-inflammatory drugs and analgesic drugs, and are used for treating acute and chronic inflammatory reactions, tissue swelling and hyperplasia, and pain. Some of the compounds exhibit better anti-inflammatory and analgesic effects than commercially available non-steroidal anti-inflammatory drugs. BRIEF DESCRIPTION OF DRAWINGS

[0027] Figure 1 Cell viability assay of 2-trifluoromethyl-3-aryl-2H-chromen ether derivatives (I);

[0028] Figure 2 Inhibitory effect of 2-trifluoromethyl-3-aryl-2H-chromen ether derivatives (I) on NO release;

[0029] Figure 3 Inhibitory effect of compound I-25 on cotton pellet-induced granuloma in mice;

[0030] Figure 4 Inhibitory effect of compound I-25 on acetic acid-induced writhing in mice;

[0031] Figure 5 Therapeutic effect of compound I-25 on adjuvant-induced arthritis in rats: effect of compound I-25 on (A) body weight, (B) left hind paw volume, (C) arthritis score, (D) 50% mechanical withdrawal threshold (50% MWT), and (E) spleen weight of AIA rats. DETAILED DESCRIPTION

[0032] In order to enable the person skilled in the art to better understand the technical solutions of the present application and implement the same, the present application will be further described below in conjunction with specific examples, but the examples do not limit the present application in any way.

[0033] In the following examples, the test methods are conventional methods unless otherwise specified, and the reagents and materials are commercially available unless otherwise specified.

[0034] The following lists the structures, physical properties, and 1 H NMR, 19 FNMR, 13 C NMR, and HRMS data of specific compounds I-1 to I-39 synthesized by the present application, but the present application is not limited to these compounds.

[0035] I-1: pale yellow liquid, yield 85%. 1H NMR (400 MHz, CDC13) δ 7.55-7.50 (m, 2H, (ArH)2), 7.41-7.27 (m, 6H, (ArH)6), 7.19-7.13 (m, 1H, ArH), 7.10-7.04 (m, 1H, ArH), 6.96-6.86 (m, 3H, (ArH)3), 4.71 (d, J = 11.3 Hz, 1H, ½CH2), 4.65 (d, J = 11.3 Hz, 1H, ½CH2), 3.83 (s, 3H, OCH3). 19 F NMR (377 MHz, CDC13) δ -78.06. 13 C NMR (101 MHz, CDC13) (one carbon signal missing) δ 160.1, 151.4, 136.3, 131.7, 130.0, 128.6, 128.5, 128.0, 127.9, 127.7, 125.4, 123.2, 121.6 (q, J = 288.8 Hz), 117.0, 114.0, 113.7, 99.6 (q, J = 32.9 Hz), 65.8, 55.3. HRMS (ESI) m / z: calcd for C 24 H 18 ClF3KO3[M+K] + 485.0528, found: 485.0530.

[0036] I-2: pale yellow liquid, yield 88%. 1 H NMR (400 MHz, CDC13) δ 7.54-7.50 (m, 2H, (ArH)2), 7.39-7.35 (m, 1H, ArH), 7.24-7.20 (m, 1H, ArH), 7.18-7.13 (m, 1H, ArH), 7.10-7.05 (m, 1H, ArH), 6.93-6.82 (m, 6H, (ArH)6), 4.69 (d, J = 11.4 Hz, 1H, ½CH2), 4.63 (d, J = 11.4 Hz, 1H, ½CH2), 3.83 (s, 3H, OCH3), 3.78 (s, 3H, OCH3). 19 F NMR (377 MHz, CDC13) δ -78.00. 13C NMR (101 MHz, CDC13) δ 159.0, 158.7, 150.3, 136.8, 130.6, 129.0, 128.9, 128.4, 127.5, 126.9, 124.3, 122.1, 120.5 (q, J = 288.9 Hz), 118.8, 116.0, 113.0, 112.7, 112.6, 111.9, 98.6 (q, J = 32.7 Hz), 64.6, 54.2, 54.1. HRMS (ESI) m / z: calcd for C 25 H 20 ClF3NaO4[M + Na] + 499.0894, found: 499.0894.

[0037] I-3: White solid, m.p. 134-136 °C, yield 85%. 1 H NMR (400 MHz, CDC13) δ 7.55-7.30 (m, 12H, (ArH) 12 ), 7.17-7.11 (m, 1H, ArH), 7.09-7.02 (m, 1H, ArH), 6.94-6.85 (m, 3H, (ArH)3), 4.79 (d, J = 11.4 Hz, 1H, ½CH2), 4.72 (d, J = 11.4 Hz, 2H, ½CH2), 3.82 (s, 3H, OCH3). 19 F NMR (377 MHz, CDC13) δ -77.92. 13 C NMR (101 MHz, CDC13) δ 159.0, 150.3, 140.3, 139.7, 135.8, 130.6, 129.0, 128.9, 127.8, 127.7, 127.1 (d, J = 54.5 Hz), 126.4, 126.1, 125.7, 125.5 (d, J = 8.1 Hz), 124.3, 122.2, 120.6 (q, J = 289.0 Hz), 116.1, 113.0, 112.7, 98.6 (q, J = 32.9 Hz), 64.8, 54.2. HRMS (ESI) m / z: calcd for C 30 H 22 ClF3NaO3[M + Na] + 545.1102, found: 545.1107. I-4: Pale yellow solid, m.p. 136-137 °C, yield 82%. 1H NMR (400 MHz, CDC13) δ 7.84-7.75 (m, 1H, ArH), 7.71-7.67 (m, 1H, ArH), 7.59-7.53 (m, 2H, (ArH)2), 7.40 (s, 1H, ArH), 7.37-7.29 (m, 2H, (ArH)2), 7.17-7.06 (m, 3H, (ArH)3), 6.98-6.89 (m, 3H, (ArH)3), 4.96 (d, J = 12.0 Hz, 1H, ½CH2), 4.89 (d, J = 12.0 Hz, 1H, ½CH2), 3.84 (s, 3H, OCH3). 19 F NMR (377 MHz, CDC13) δ -77.98. 13 C NMR (101 MHz, CDC13) δ 159.1, 150.1, 146.1, 139.3, 138.4, 138.2, 130.6, 129.0, 127.3, 126.6, 124.5, 123.5, 123.3, 122.6, 122.3, 122.2, 121.3, 120.5 (q, J = 289.0 Hz), 116.0, 113.0, 112.8, 98.6 (q, J = 32.9 Hz), 60.6, 54.2. HRMS (ESI) m / z: calcd for C 26 H 18 ClF3NaO3S [M+Na] + 525.0509, found: 525.0507.

[0038] I-5: white solid, m.p. 127-128 °C, yield 89%. 1 H NMR (400 MHz, CDC13) δ 7.38-7.27 (m, 3H, (ArH)3), 7.19-7.11 (m, 2H, (ArH)2), 7.09-7.04 (m, 1H, ArH), 6.99-6.90 (m, 2H, (ArH)2), 6.88-6.80 (m, 3H, (ArH)3), 3.91-3.72 (m, 5H, OCH2+OCH3), 3.16 (t, J = 6.8 Hz, 2H, ArCH2). 19 F NMR (377 MHz, CDC13) δ -78.05. 13C NMR (101 MHz, CDC13) δ 160.0, 151.4, 139.9, 131.7, 130.01, 129.97, 128.5, 127.9, 126.9, 126.0, 125.2, 124.1, 123.2, 121.5 (q, J = 289.0 Hz), 117.1, 114.0, 113.7, 99.5 (q, J = 32.9 Hz), 64.5, 55.3, 30.1. HRMS (ESI) m / z: calcd for C 23 H 18 ClF3NaO3S [M + Na] + 489.0509, found: 489.0509.

[0039] I-6: White solid, m.p. 136-137 °C, yield 77%. 1 H NMR (400 MHz, CDC13) δ 7.54-7.50 (m, 2H, (ArH)2), 7.39-7.35 (m, 1H, ArH), 7.30-7.26 (m, 1H, ArH), 7.20-7.13 (m, 2H, (ArH)2), 7.11-7.06 (m, 1H, ArH), 7.05-7.00 (m, 1H, ArH), 6.96-6.87 (m, 3H, (ArH)3), 4.72 (d, J = 11.5 Hz, 1H, ½CH2), 4.66 (d, J = 11.5 Hz, 1H, ½CH2), 3.84 (s, 3H, OCH3). 19 F NMR (377 MHz, CDC13) δ -78.21. 13 C NMR (101 MHz, CDC13) δ 160.1, 151.4, 147.1, 137.2, 131.7, 130.1, 130.0, 128.5, 127.8, 127.1, 126.2, 125.5, 123.2, 121.5 (d, J = 288.9 Hz), 117.0, 114.0, 113.8, 99.6 (q, J = 32.8 Hz), 61.5, 55.3. HRMS (ESI) m / z: calcd for C 22 H 16 ClF3NaO3S [M + Na] + 475.0353, found: 475.0351.

[0040] I-7: Pale yellow liquid, yield 85%. 1H NMR (400 MHz, CDC13) δ 7.56 - 7.49 (m, 2H, (ArH)2), 7.41 - 7.34 (m, 3H, (ArH)3), 7.21 - 7.15 (m, 1H, ArH), 7.11 - 7.05 (m, 1H, ArH), 7.01 - 6.95 (m, 1H, ArH), 6.95 - 6.87 (m, 2H, (ArH)2), 6.41 - 6.34 (m, 1H, ArH), 4.58 (d, J = 11.4 Hz, 1H, ½CH2), 4.53 (d, J = 11.4 Hz, 1H, ½CH2), 3.84 (s, 3H, OCH3). 19 F NMR (377 MHz, CDC13) δ -78.31. 13 C NMR (101 MHz, CDC13) δ 160.1, 151.4, 143.4, 140.9, 131.7, 130.1, 130.0, 128.5, 127.7, 125.5, 123.2, 121.5 (q, J = 288.9 Hz), 120.8, 117.0, 114.0, 113.7, 110.3, 99.6 (q, J = 32.8 Hz), 57.9, 55.3. HRMS (ESI) m / z: calcd for C 22 H 16 ClF3NaO4[M+Na] + 459.0581, found: 459.0576.

[0041] I-8: white solid, m.p. 100-101 °C, yield 82%. 1 H NMR (400 MHz, CDC13) δ 7.62 - 7.57 (m, 2H, (ArH)2), 7.39 - 7.35 (m, 1H, ArH), 7.22 - 7.16 (m, 1H, ArH), 7.11 - 7.06 (m, 1H, ArH), 7.03 - 6.97 (m, 1H, ArH), 6.95 - 6.89 (m, 2H, (ArH)2), 6.17 - 6.10 (m, 1H, ArH), 5.93 - 5.86 (m, 1H, ArH), 4.58 (d, J = 11.8 Hz, 1H, ½CH2), 4.52 (d, J = 11.8 Hz, 1H, ½CH2), 3.85 (s, 3H, OCH3), 2.26 (s, 3H, CH3). 19 F NMR (377 MHz, CDC13) δ -78.21. 13C NMR (101 MHz, CDC13) δ 160.1, 153.2, 151.4, 147.6, 131.6, 130.2, 130.0, 128.5, 127.6, 125.5, 123.2, 121.8 (q, J = 288.9 Hz), 117.0, 114.1, 113.6, 111.5, 106.5, 99.5 (q, J = 32.8 Hz), 58.3, 55.3, 13.6. HRMS (ESI) m / z: calcd for C 23 H 18 ClF3NaO4[M + Na] + 473.0738, found: 473.0731.

[0042] I-9: White solid, m.p. 71-72 °C, yield 86%. 1 H NMR (400 MHz, CDC13) δ 7.35-7.24 (m, 9H, (ArH)9), 7.19 (m, 1H, ArH), 7.11 (m, 1H, ArH), 6.89 (m, 1H, ArH), 4.81 (d, J = 11.2 Hz, 1H, ½CH2), 4.70 (d, J = 11.2 Hz, 1H, ½CH2), 2.35 (s, 3H, CH3). 19 F NMR (377 MHz, CDC13) δ -78.21. 13 C NMR (101 MHz, CDC13) δ 144.8, 138.0, 136.1, 135.5, 130.3, 130.1, 129.7, 129.3, 128.5, 128.20, 128.15, 128.1, 127.9, 127.4, 125.8, 125.3, 121.7, 121.4 (q, J = 288.9 Hz), 121.1, 100.0 (q, J = 32.8 Hz), 66.3, 21.5. HRMS (ESI) m / z: calcd for C 24 H 17 Cl2F3KO2[M + K] + 503.0189, found: 503.0188. I-10: White solid, m.p. 126-127 °C, yield 75%. 1H NMR (400 MHz, CDC13) δ 7.74-7.70 (m, 1H, ArH), 7.53-7.46 (m, 2H, (ArH)2), 7.42-7.39 (m, 1H, ArH), 7.37-7.28 (m, 5H, (ArH)5), 7.24-7.16 (m, 2H, (ArH)2), 7.13-7.08 (m, 1H, ArH), 6.96-6.91 (m, 1H, ArH), 4.72 (d, J = 11.3 Hz, 1H, ½CH2), 4.66 (d, J = 11.3 Hz, 1H, ½CH2). 19 F NMR (377 MHz, CDC13) δ -77.65. 13 C NMR (101 MHz, CDC13) δ 151.5, 138.2, 136.0, 132.1, 131.7, 131.6, 130.8, 129.8, 128.6, 128.2, 127.8, 127.4, 127.3, 127.0, 123.4, 122.4, 121.5 (q, J = 288.9 Hz), 116.6, 114.3, 99.3 (q, J = 32.8 Hz), 66.0. HRMS (ESI) m / z: Calcd for C 23 H 15 BrClF3NaO2[M+Na] + 516.9788, Found: 516.9791.

[0043] I-11: White solid, m.p. 112-113 °C, yield 88%. 1 H NMR (400 MHz, CDC13) δ 7.59-7.50 (m, 2H, (ArH)2), 7.38-7.28 (m, 5H, (ArH)5), 7.22-7.15 (m, 1H, ArH), 7.14-7.01 (m, 3H, (ArH)3), 6.97-6.90 (m, 1H, ArH), 4.72 (d, J = 11.8 Hz, 1H, ½CH2), 4.66 (d, J = 11.8 Hz, 1H, ½CH2). 19 F NMR (377 MHz, CDC13) δ -77.65 (3F), -112.72 (1F). 13C NMR (101 MHz, CDC13) δ 163.1 (d, J = 248.8 Hz), 151.4, 136.1, 132.3 (d, J = 3.6 Hz), 131.9, 130.6 (d, J = 8.3 Hz), 130.5, 128.5, 128.1, 127.7, 127.4, 126.5, 123.4, 121.5 (q, J = 288.9 Hz), 116.8, 115.4 (d, J = 21.6 Hz), 114.2, 99.3 (q, J = 32.9 Hz), 65.9. HRMS (ESI) m / z: calcd for C 23 H 15 ClF4NaO2[M + Na] + 457.0589, found: 457.0592.

[0044] I-12: White solid, m.p. 117-118 °C, yield 76%. 1 H NMR (400 MHz, CDC13) δ 7.83 - 7.75 (m, 1H, ArH), 7.74 - 7.65 (m, 1H, ArH), 7.59 - 7.44 (m, 2H, (ArH)2), 7.35 - 7.26 (m, 3H, (ArH)3), 7.24 - 7.20 (m, 1H, ArH), 7.13 (s, 1H, ArH), 7.08 - 6.90 (m, 4H, (ArH)4), 5.10 (d, J = 12.1 Hz, 1H, ½CH2), 4.92 (d, J = 12.1 Hz, 1H, ½CH2). 19 F NMR (377 MHz, CDC13) δ -76.39 (3F), -120.37 (1F). 13 C NMR (101 MHz, CDC13) δ 158.1 (d, J = 241.1 Hz), 145.7, 140.2, 139.9, 139.2, 133.9, 133.6, 132.0, 131.9, 130.2, 129.6, 126.1, 124.8, 124.5, 124.4, 123.6, 122.9, 122.4, 121.1 (q, J = 210.6 Hz), 119.3 (d, J = 8.8 Hz), 117.5 (d, J = 23.9 Hz), 117.0 (d, J = 8.3 Hz), 113.3 (d, J = 24.1 Hz), 98.3 (q, J = 32.9 Hz), 61.7. HRMS (ESI) m / z: calcd for C 25 H 15 ClF4NaO2S [M + Na] + 513.0310, found: 513.0310.

[0045] I-13: colorless liquid, yield 87%. 1 H NMR (400 MHz, CDC13) δ 7.46-7.41 (m, 1 H, ArH), 7.25-7.17 (m, 2 H, (ArH)2), 7.15-7.10 (m, 2 H, (ArH)2), 7.05-6.99 (m, 2 H, (ArH)2), 6.93-6.88 (m, 2 H, (ArH)2), 6.85 (s, 1 H, ArH), 6.82-6.78 (m, 1 H, ArH), 3.97-3.79 (m, 2 H, CH2), 3.16-3.09 (m, 2 H, CH2). 19 F NMR (377 MHz, CDC13) δ -76.74 (3F), -120.88 (1F). 13 C NMR (101 MHz, CDC13) δ 158.0 (d, J = 240.6 Hz), 145.9, 140.0, 133.9, 133.5, 131.74, 131.69, 130.1, 129.4, 126.8, 126.0, 125.8, 124.7, 124.0, 121.4 (q, J = 289.3 Hz), 119.3 (d, J = 8.8 Hz), 117.2 (d, J = 23.8 Hz), 116.8 (d, J = 8.2 Hz), 113.3 (d, J = 24.1 Hz), 98.2 (q, J = 32.5 Hz), 64.4, 30.2. HRMS (ESI) m / z: calcd for C 22 H 15 ClF4KO2S [M+K] + 493.0049, found: 493.0044.

[0046] I-14: colorless liquid, yield 78%. 1 H NMR (400 MHz, CDC13) δ 7.49-7.43 (m, 2 H, (ArH)2), 7.32-7.26 (m, 2 H, (ArH)2), 7.23-7.18 (m, 1 H, ArH), 7.15-7.11 (m, 1 H, ArH), 7.03-6.90 (m, 5 H, (ArH)5), 4.85 (d, J = 11.6 Hz, 1 H, ½CH2), 4.68 (d, J = 11.6 Hz, 1 H, ½CH2). 19 F NMR (377 MHz, CDC13) δ -76.71 (3F), -120.68 (1F). 13C NMR (101 MHz, CDC13) δ 158.0 (d, J = 241.0 Hz), 145.9, 137.5, 134.0, 133.6, 132.0, 131.7, 130.2, 129.5, 126.8, 126.1, 126.0, 124.7, 122.7, 121.5 (q, J = 289.3 Hz), 119.2 (d, J = 8.7 Hz), 117.3 (d, J = 23.8 Hz), 116.9 (d, J = 8.3 Hz), 113.4 (d, J = 24.1 Hz), 98.4 (q, J = 32.4 Hz), 61.6. HRMS (ESI) m / z: calcd for C 21 H 13 ClF4NaO2S [M + Na] + 463.0153, found: 463.0147.

[0047] I-15: pale yellow liquid, yield 82%. 1 H NMR (400 MHz, CDC13) δ 7.46-7.42 (m, 1H, ArH), 7.28-7.20 (m, 2H, (ArH)2), 7.15-7.08 (m, 2H, (ArH)2), 7.05-6.95 (m, 3H, (ArH)3), 6.93-6.87 (m, 2H, (ArH)2), 6.84 (s, 1H, ArH), 3.94-3.76 (m, 2H, CH2), 3.02-2.89 (m, 2H, CH2). 19 F NMR (377 MHz, CDC13) δ -76.90 (3F), -120.90 (1F). 13 C NMR (101 MHz, CDC13) δ 158.0 (d, J = 240.9 Hz), 146.1, 138.3, 134.0, 133.5, 131.71, 131.65, 130.1, 129.4, 128.6, 126.0, 125.4, 124.6, 121.9, 121.5 (q, J = 289.3 Hz), 119.2 (d, J = 8.8 Hz), 117.2 (d, J = 24.0 Hz), 116.7 (d, J = 8.2 Hz), 113.3 (d, J = 24.1 Hz), 98.3 (q, J = 32.5 Hz), 63.9, 30.4. HRMS (ESI) m / z: calcd for C 22 H 15 ClF4NaO2S [M + Na] + 477.0310, found: 477.0306.

[0048] I-16: pale yellow liquid, yield 79%. 1 H NMR (400 MHz, CDC13) δ 7.49 - 7.43 (m, 2H, (ArH)2), 7.39 - 7.31 (m, 2H, (ArH)2), 7.31 - 7.27 (m, 1H, ArH), 7.24 - 7.19 (m, 1H, ArH), 7.08 - 7.01 (m, 2H, (ArH)2), 6.96 - 6.89 (m, 2H, (ArH)2), 6.35 - 6.27 (m, 1H, ArH), 4.71 (d, J = 11.2 Hz, 1H, ½CH2), 4.56 (d, J = 11.2 Hz, 1H, ½CH2). 19 F NMR (377 MHz, CDC13) δ -76.75 (3F), -120.65 (1F). 13 C NMR (101 MHz, CDC13) δ 158.0 (d, J = 241.0 Hz), 145.9, 143.4, 140.5, 134.0, 133.6, 132.0, 131.7, 130.2, 129.5, 126.0, 124.7, 121.5 (q, J = 289.3 Hz), 121.1, 119.3 (d, J = 8.6 Hz), 117.3 (d, J = 23.9 Hz), 116.8 (d, J = 8.2 Hz), 113.4 (d, J = 24.1 Hz), 110.0, 98.3 (q, J = 32.5 Hz), 57.9. HRMS (ESI) m / z: Calcd for C 21 H 13 ClF4NaO3[M+Na] + 447.0382, found: 447.0386. I-17: pale yellow liquid, yield 81%. 1 H NMR (400 MHz, CDC13) δ 7.42 - 7.30 (m, 4H, (ArH)4), 7.28 - 7.22 (m, 1H, ArH), 7.21 - 7.15 (m, 1H, ArH), 7.05 - 6.88 (m, 4H, (ArH)4), 6.40 - 6.33 (m, 1H, ArH), 4.61 (d, J = 11.4 Hz, 1H, ½CH2), 4.55 (d, J = 11.4 Hz, 1H, ½CH2), 2.37 (s, 3H, CH3). 19 F NMR (377 MHz, CDC13) δ -78.11 (3F), -121.14 (1F). 13C NMR (101 MHz, CDC13) δ 157.9 (d, J = 240.4 Hz), 146.5, 143.4, 140.8, 137.9, 136.0, 129.5, 129.4, 129.3, 128.6, 128.1, 125.7, 123.0, 121.5 (q, J = 289.3 Hz), 119.4 (d, J = 8.8 Hz), 117.0, 116.4 (d, J = 8.3 Hz), 113.2 (d, J = 24.1 Hz), 110.2, 99.7 (q, J = 33.0 Hz), 57.8, 21.4. HRMS (ESI) m / z: calcd for C 22 H 16 F4NaO3[M + Na] + 427.0928, found: 427.0932.

[0049] I-18: White solid, m.p. 96-97 °C, yield 86%. 1 H NMR (400 MHz, CDC13) δ 7.48-7.37 (m, 2H, (ArH)2), 7.30-7.25 (m, 1H, ArH), 7.21-7.15 (m, 1H, ArH), 7.09-6.88 (m, 4H, (ArH)4), 6.23-6.05 (m, 1H, ArH), 5.98-5.85 (m, 1H, ArH), 4.60 (d, J = 11.8 Hz, 1H, ½CH2), 4.52 (d, J = 11.8 Hz, 1H, ½CH2), 2.39 (s, 3H, CH3), 2.27 (s, 3H, CH3). 19 F NMR (377 MHz, CDC13) δ -78.14 (3F), -121.23 (1F). 13 C NMR (101 MHz, CDC13) δ 157.9 (d, J = 240.3 Hz), 153.2, 147.7, 146.6, 137.8, 136.1, 129.7, 129.43, 129.38, 128.3, 128.1, 125.9, 121.5 (q, J = 289.3 Hz), 119.3 (d, J = 8.7 Hz), 116.9 (d, J = 23.9 Hz), 116.4 (d, J = 8.1 Hz), 113.1 (d, J = 24.1 Hz), 111.5, 106.5, 99.6 (q, J = 33.0 Hz), 58.3, 21.5, 13.6. HRMS (ESI) m / z: calcd for C 23 H 18 F4NaO3[M + Na] +441.1084, found: 441.1086.

[0050] I-19: White solid, m.p. 116-117 °C, yield 77%. 1 H NMR (400 MHz, CDC13) δ 7.85-7.76 (m, 1H, ArH), 7.73-7.65 (m, 1H, ArH), 7.41-7.27 (m, 5H, (ArH)5), 7.20-7.17 (m, 1H, ArH), 7.15-7.11 (m, 1H, ArH), 7.01-6.91 (m, 4H, (ArH)4), 4.99 (d, J = 12.0 Hz, 1H, ½CH2), 4.90 (d, J = 12.0 Hz, 1H, ½CH2), 2.37 (s, 3H, CH3). 19 F NMR (377 MHz, CDC13) δ -77.70 (3F), -120.87 (1F). 13 C NMR (101 MHz, CDC13) δ 156.9 (d, J = 240.6 Hz), 145.2, 139.3, 138.5, 138.2, 136.9, 134.8, 128.6, 128.4, 128.3, 127.4, 127.1, 124.7, 123.5, 123.3, 122.6, 122.2, 121.3, 120.5 (q, J = 289.3 Hz), 118.3 (d, J = 8.7 Hz), 115.9 (d, J = 23.8 Hz), 115.5 (d, J = 8.2 Hz), 112.1 (d, J = 24.0 Hz), 98.6 (q, J = 33.0 Hz), 60.5, 20.4. HRMS (ESI) m / z: Calcd for C 26 H 18 F4NaO2[M + Na] + 493.0856, found: 493.0858.

[0051] I-20: Colorless liquid, yield 92%. 1 H NMR (400 MHz, CDC13) δ 7.23-7.11 (m, 5H, (ArH)5), 7.03-6.85 (m, 5H, (ArH)5), 6.84-6.79 (m, 1H, ArH), 3.91-3.76 (m, 2H, CH2), 3.24-3.05 (m, 2H, CH2), 2.33 (s, 3H, CH3). 19 F NMR (377 MHz, CDC13) δ -77.71 (3F), -121.16 (1F). 13C NMR (101 MHz, CDC13) δ 156.8 (d, J = 240.3 Hz), 145.4, 138.9, 136.7, 135.0, 128.24, 128.16, 128.1, 127.7, 127.0, 125.8, 124.8, 124.7, 122.9, 120.5 (q, J = 288.7 Hz), 118.3 (d, J = 8.7 Hz), 115.7 (d, J = 23.9 Hz), 115.3 (d, J = 8.2 Hz), 112.1 (d, J = 24.0 Hz), 98.4 (q, J = 32.7 Hz), 63.4, 29.1, 20.4. HRMS (ESI) m / z: calcd for C 23 H 18 F4KO2S [M + K] + 473.0595, found: 473.0594.

[0052] I-21: pale yellow solid, m.p. 102-103 °C, yield 85%. 1 H NMR (400 MHz, CDC13) δ 7.37 - 7.26 (m, 4H, (ArH)4), 7.23 - 7.15 (m, 2H, (ArH)2), 7.04 - 7.00 (m, 1H, ArH), 6.99 - 6.89 (m, 4H, (ArH)4), 4.75 (d, J = 11.5 Hz, 1H, ½CH2), 4.67 (d, J = 11.5 Hz, 1H, ½CH2), 2.35 (s, 3H, CH3). 19 F NMR (377 MHz, CDC13) δ -77.98 (3F), -121.12 (1F). 13 C NMR (101 MHz, CDC13) δ 157.9 (d, J = 240.5 Hz), 146.6, 137.9, 137.3, 136.1, 129.5, 129.4, 129.3, 128.6, 128.1, 127.1, 126.1, 125.8, 123.2, 121.5 (q, J = 288.7 Hz), 119.4 (d, J = 8.7 Hz), 116.9 (d, J = 23.9 Hz), 116.4 (d, J = 8.1 Hz), 113.2 (d, J = 24.1 Hz), 99.7 (q, J = 32.8 Hz), 61.5, 21.5. HRMS (ESI) m / z: calcd for C 22 H 16 F4KO2S [M + K] + 459.0439, found: 459.0442.

[0053] I-22: colorless liquid, yield 83%. 1 H NMR (400 MHz, CDC13) δ 7.24 - 7.12 (m, 5H, (ArH)5), 7.04 - 6.83 (m, 6H, (ArH)6), 3.89 - 3.72 (m, 2H, CH2), 3.07 - 2.94 (m, 2H, CH2), 2.34 (s, 3H, CH3). 19 F NMR (377 MHz, CDC13) δ -77.89 (3F), -121.25 (IF). 13 C NMR (101 MHz, CDC13) δ 157.8 (d, J = 240.3 Hz), 146.6, 138.3, 137.8, 136.1, 129.3, 129.2, 128.7, 128.6, 128.0, 125.7, 125.4, 120.5 (q, J = 288.7 Hz), 120.1, 119.4 (d, J = 8.5 Hz), 119.2, 116.8 (d, J = 23.9 Hz), 116.3 (d, J = 8.2 Hz), 113.1 (d, J = 24.0 Hz), 99.5 (q, J = 32.6 Hz), 64.0, 30.4, 21.5. HRMS (ESI) m / z: calcd for C 23 H 18 F4KO2S [M+K] + 473.0595, found: 473.0592.

[0054] I-23: white solid, m.p. 86-87 °C, yield 79%. 1 H NMR (400 MHz, CDC13) δ 7.52 - 7.42 (m, 2H, (ArH)2), 7.37 - 7.26 (m, 5H, (ArH)5), 6.98 - 6.83 (m, 6H, (ArH)6), 4.72 (d, J = 11.4 Hz, 1H, ½CH2), 4.66 (d, J = 11.4 Hz, 1H, ½CH2), 3.82 (s, 3H, CH3). 19 F NMR (377 MHz, CDC13) δ -77.91 (3F), -121.28 (IF). 13C NMR (101 MHz, CDC13) δ 158.9, 156.8 (d, J = 240.2 Hz), 145.4, 135.4, 128.9, 127.4, 127.1, 126.9, 126.6, 123.4, 120.5 (q, J = 288.7 Hz), 118.5 (d, J = 8.6 Hz), 118.1, 115.5 (d, J = 23.9 Hz), 115.3 (d, J = 8.2 Hz), 112.6, 112.1 (d, J = 24.1 Hz), 98.6 (q, J = 32.6 Hz), 64.7, 54.2. HRMS (ESI) m / z: calcd for C 24 H 18 F4KO3[M+K] + 469.0824, found: 469.0825.

[0055] I-24: White solid, m.p. 107-108 °C, yield 83%. 1 H NMR (400 MHz, CDC13) δ 7.52-7.43 (m, 2H, (ArH)2), 7.31-7.26 (m, 1H, ArH), 7.19-7.13 (m, 1H, ArH), 7.06-6.99 (m, 1H, ArH), 6.99-6.86 (m, 6H, (ArH)6), 4.73 (d, J = 11.5 Hz, 1H, ½CH2), 4.67 (d, J = 11.5 Hz, 1H, ½CH2), 3.83 (s, 3H, CH3). 19 F NMR (377 MHz, CDC13) δ -78.07 (3F), -121.26 (1F). 13 C NMR (101 MHz, CDC13) δ 160.0, 157.9 (d, J = 240.3 Hz), 146.4, 137.3, 129.9, 128.5, 128.4, 128.0, 127.1, 126.1, 123.1, 121.5 (q, J = 288.7 Hz), 119.5 (d, J = 8.6 Hz), 116.6 (d, J = 23.8 Hz), 116.3 (d, J = 8.2 Hz), 113.7, 113.0 (d, J = 24.1 Hz), 99.7 (q, J = 32.9 Hz), 61.4, 55.3. HRMS (ESI) m / z: calcd for C 22 H 16 F4KO3S [M+K] + 475.0388, found: 475.0388.

[0056] I-25: white solid, m.p. 120-121 °C, yield 86%. 1 H NMR (400 MHz, CDC13) δ 7.31-7.26 (m, 2H, (ArH)2), 7.25-7.20 (m, 1H, ArH), 7.05-6.78 (m, 8H, (ArH)8), 3.84-3.76 (m, 5H, OCH3+OCH2), 3.06-2.91 (m, 2H, ArCH2). 19 F NMR (377 MHz, CDC13) δ -78.16 (3F), -121.44 (1F). 13 CNMR (101 MHz, CDC13) δ 159.9, 157.8 (d, J = 240.2 Hz), 146.5, 138.3, 129.8, 128.7, 128.4, 128.2, 128.1, 125.4, 122.0, 121.5 (q, J = 288.7 Hz), 119.5 (d, J = 8.7 Hz), 116.6 (d, J = 23.9 Hz), 116.2 (d, J = 8.2 Hz), 113.6, 112.9 (d, J = 24.1 Hz), 99.6 (q, J = 32.3 Hz), 63.9, 55.3, 30.4. HRMS (ESI) m / z: Calcd for C 23 H 18 F4KO3S [M+K] + 489.0544, Found: 489.0549.

[0057] I-26: pale yellow liquid, yield 80%. 1 H NMR (400 MHz, CDC13) δ 7.55-7.48 (m, 2H, (ArH)2), 7.32-7.27 (m, 1H, ArH), 7.05-6.85 (m, 8H, (ArH)8), 4.87 (d, J = 11.6 Hz, 1H, ½CH2), 4.82 (d, J = 11.6 Hz, 1H, ½CH2), 3.83 (s, 3H, OCH3). 19 F NMR (377 MHz, CDC13) δ -77.90 (3F), -121.13 (1F). 13C NMR (101 MHz, CDC13) δ 160.0, 157.9 (d, J = 240.4 Hz), 146.3, 138.6, 130.0, 128.5, 128.3, 128.0, 127.1, 126.7, 126.5, 121.5 (q, J = 288.7 Hz), 119.6 (d, J = 8.6 Hz), 116.7 (d, J = 23.9 Hz), 116.4 (d, J = 8.2 Hz), 113.7, 113.0 (d, J = 24.1 Hz), 99.6 (q, J = 32.9 Hz), 60.8, 55.3. HRMS (ESI) m / z: calcd for C 22 H 16 F4KO3S [M+K] + 475.0388, found: 475.0396.

[0058] I-27: white solid, m.p. 93-94 °C, yield 88%. 1 H NMR (400 MHz, CDC13) δ 7.34-7.27 (m, 2H, (ArH)2), 7.15-7.10 (m, 1H, ArH), 7.01-6.80 (m, 8H, (ArH)8), 3.86-3.78 (m, 5H, OCH2+OCH3), 3.21-3.12 (m, 2H, ArCH2). 19 F NMR (377 MHz, CDC13) δ -77.99 (3F), -121.34 (1F). 13 CNMR (101 MHz, CDC13) δ 157.9 (d, J = 240.2 Hz), 146.42, 146.40, 140.0, 129.9, 128.4, 128.2, 128.1, 126.9, 125.9, 124.0, 121.6 (q, J = 288.7 Hz), 119.5 (d, J = 8.7 Hz), 116.6 (d, J = 23.8 Hz), 116.2 (d, J = 8.3 Hz), 113.6, 113.0 (d, J = 24.0 Hz), 99.6 (q, J = 32.9 Hz), 64.4, 55.3, 30.1. HRMS (ESI) m / z: calcd for C 23 H 18 F4KO3S [M+K] + 489.0544, found: 489.0544.

[0059] I-28: white solid, m.p. 72-73 °C, yield 69%. 1H NMR (400 MHz, CDC13) δ 7.54 - 7.46 (m, 2H, (ArH)2), 7.38 - 7.25 (m, 5H, (ArH)5), 7.15 - 7.04 (m, 2H, (ArH)2), 7.00 - 6.87 (m, 4H, (ArH)4), 4.73 (d, J = 11.4 Hz, 1H, ½CH2), 4.67 (d, J = 11.4 Hz, 1H, ½CH2). 19 F NMR (377 MHz, CDC13) δ -77.53 (3F), -112.87 (1F), -120.95 (1F). 13 C NMR (101 MHz, CDC13) δ 163.0 (d, J = 248.6 Hz), 157.9 (d, J = 240.6 Hz), 146.4, 136.3, 132.2, 130.5 (d, J = 8.1 Hz), 129.5, 128.5, 128.1, 127.8, 127.6, 121.6 (q, J = 288.9 Hz), 119.2 (d, J = 8.7 Hz), 117.1 (d, J = 23.9 Hz), 116.6 (d, J = 8.3 Hz), 115.3 (d, J = 21.5 Hz), 113.2 (d, J = 24.0 Hz), 99.4 (q, J = 32.6 Hz), 65.8. HRMS (ESI) m / z: Calcd for C 23 H 15 F5NaO2[M + Na] + 441.0884, Found: 441.0888.

[0060] I-29: White solid, m.p. 119-120 °C, yield 77%. 1 H NMR (400 MHz, CDC13) δ 7.54 - 7.46 (m, 2H, (ArH)2), 7.38 - 7.25 (m, 5H, (ArH)5), 7.15 - 7.04 (m, 2H, (ArH)2), 7.00 - 6.87 (m, 4H, (ArH)4), 4.73 (d, J = 11.4 Hz, 1H, ½CH2), 4.67 (d, J = 11.4 Hz, 1H, ½CH2). 19 F NMR (377 MHz, CDC13) δ -77.56 (3F), -120.74 (1F). 13C NMR (101 MHz, CDC13) δ 157.9 (d, J = 240.9 Hz), 146.5, 138.1, 136.1, 131.6, 130.3, 129.8, 128.5, 128.1, 127.7, 127.3, 122.3, 121.5 (q, J = 288.9 Hz), 119.0 (d, J = 8.7 Hz), 117.4 (d, J = 24.0 Hz), 116.6 (d, J =, 1 / 2CH2 8.2 Hz), 113.4 (d, J = 24.1 Hz), 99.3 (q, J = 32.7 Hz), 65.9. HRMS (ESI) m / z: Calcd for C 23 H 15 BrF4NaO2[M + Na] + 501.0084, Found: 501.0098.

[0061] I-30: pale yellow liquid, yield 75%. 1 H NMR (400 MHz, CDC13) δ 7.44 - 7.39 (m, 1H, ArH), 7.36 - 7.27 (m, 6H, (ArH)6), 7.21 - 7.13 (m, 1H, ArH), 7.03 - 6.89 (m, 4H, (ArH)4), 4.84 (d, J = 11.2 Hz, 1H, 1 / 2CH2), 4.63 (d, J = 11.2 Hz, 1H, 1 / 2CH2). 19 F NMR (377 MHz, CDC13) δ -80.78 (3F), -121.23 (1F). 13 C NMR (101 MHz, CDC13) δ 157.9 (d, J = 240.5 Hz), 147.2, 137.6, 136.2, 129.4, 128.4, 128.2, 128.0, 127.9, 126.3, 122.3, 121.7 (q, J = 288.9 Hz), 119.4 (d, J = 8.7 Hz), 116.8 (d, J = 23.9 Hz), 116.6, 116.3 (d, J = 8.2 Hz), 113.2 (d, J = 24.3 Hz), 100.3 (q, J = 33.7 Hz), 66.3. HRMS (ESI) m / z: Calcd for C 21 H 14 F4NaO2S [M + Na] + 429.0543, Found: 429.0544.

[0062] I-31: colorless liquid, yield 83%. 1H NMR (400 MHz, CDC13) δ 7.84-7.78 (m, 1H, ArH), 7.71-7.65 (m, 1H, ArH), 7.55-7.49 (m, 2H, (ArH)2), 7.35-7.30 (m, 2H, (ArH)2), 7.13-7.09 (m, 2H, (ArH)2), 7.01-6.98 (m, 1H, ArH), 6.92-6.87 (m, 2H, (ArH)2), 6.86-6.81 (m, 2H, (ArH)2), 4.95 (d, J = 12.2 Hz, 1H, ½CH2), 4.89 (d, J = 12.2 Hz, 1H, ½CH2), 3.83 (s, 3H, OCH3), 2.30 (s, 3H, CH3). 19 F NMR (377 MHz, CDC13) δ -78.34. 13 C NMR (101 MHz, CDC13) δ 159.6, 150.8, 142.6, 140.8, 140.2, 139.5, 129.7, 129.2, 129.1, 126.9, 125.4, 124.21, 124.18, 123.4, 123.1, 122.4, 122.2, 121.7 (q, J = 288.9 Hz), 116.1, 115.5, 113.5, 99.5 (q, J = 32.3 Hz), 69.9, 68.1, 55.3. HRMS (ESI) m / z: Calcd for C 27 H 21 F3NaO3S [M + Na] + 505.1056, Found: 505.1052.

[0063] I-32: colorless liquid, yield 88%. 1 H NMR (400 MHz, CDC13) δ 7.32-7.27 (m, 2H, (ArH)2), 7.15-7.11 (m, 1H, ArH), 7.06-7.03 (m, 1H, ArH), 6.94-6.91 (m, 1H, ArH), 6.90-6.86 (m, 2H, (ArH)2), 6.84-6.79 (m, 4H, (ArH)4), 3.84-3.77 (m, 5H, OCH2+OCH3), 3.20-3.13 (m, 2H, ArCH2), 2.35 (s, 3H, CH3). 19 F NMR (377 MHz, CDC13) δ -78.45. 13C NMR (101 MHz, CDC13) δ 159.5, 150.6, 140.9, 140.2, 129.8, 129.3, 129.1, 127.0, 126.9, 125.9, 125.1, 123.9, 123.3, 121.7 (q, J = 288.9 Hz), 116.0, 115.6, 113.5, 99.6 (q, J = 32.8 Hz), 64.2, 55.2, 30.1, 21.6. HRMS (ESI) m / z: calcd for C 24 H 21 F3NaO3S [M + Na] + 469.1056, found: 469.1058.

[0064] I-33: colorless liquid, yield 90%. 1 H NMR (400 MHz, CDC13) δ 7.50-7.45 (m, 2H, (ArH)2), 7.29-7.26 (m, 1H, ArH), 7.20-7.17 (m, 1H, ArH), 7.10-7.06 (m, 1H, ArH), 7.06-7.01 (m, 1H, ArH), 6.98-6.95 (m, 1H, ArH), 6.90-6.83 (m, 4H, (ArH)4), 4.71 (d, J = 11.5 Hz, 1H, ½CH2), 4.66 (d, J = 11.5 Hz, 1H, ½CH2), 3.83 (s, 3H, OCH3), 2.35 (s, 3H, CH3). 19 F NMR (377 MHz, CDC13) δ -78.55. 13 C NMR (101 MHz, CDC13) δ 159.7, 150.6, 141.0, 137.5, 129.8, 129.6, 129.1, 127.2, 127.0, 126.0, 125.1, 123.3, 123.0, 121.7 (q, J = 288.9 Hz), 116.1, 115.6, 113.6, 99.7 (q, J = 32.6 Hz), 61.2, 55.3, 21.6. HRMS (ESI) m / z: calcd for C 23 H 19 F3NaO3S [M + Na] + 455.0899, found: 455.0898.

[0065] I-34: white solid, m.p. 108-109 °C, yield 91%. 1H NMR (400 MHz, CDC13) δ 7.31 - 7.26 (m, 2H, (ArH)2), 7.25 - 7.21 (m, 1H, ArH), 7.09 - 6.99 (m, 2H, (ArH)2), 6.95 - 6.91 (m, 1H, ArH), 6.90 - 6.84 (m, 2H, (ArH)2), 6.83 - 6.76 (m, 3H, (ArH)3), 3.83 - 3.75 (m, 5H, OCH2 + OCH3), 3.05 - 2.93 (m, 2H, ArCH2), 2.35 (s, 3H, CH3). 19 F NMR (377 MHz, CDC13) δ -78.58. 13 C NMR (101 MHz, CDC13) δ 159.5, 150.6, 140.9, 138.5, 129.7, 129.2, 129.1, 128.8, 126.9, 125.3, 125.2, 123.2, 121.9, 121.7 (q, J = 288.9 Hz), 116.0, 115.5, 113.5, 99.6 (q, J = 32.6 Hz), 63.7, 55.2, 30.4, 21.6. HRMS (ESI) m / z: calcd for C 24 H 21 F3NaO3S [M + Na] + 469.1056, found: 469.1054.

[0066] I-35: colorless liquid, yield 57%. 1 H NMR (400 MHz, CDC13) δ 7.29 - 7.25 (m, 2H, (ArH)2), 7.24 - 7.14 (m, 5H, (ArH)5), 7.08 - 7.00 (m, 3H, (ArH)3), 6.92 - 6.78 (m, 3H, (ArH)3), 3.79 (t, J = 7.1 Hz, 2H, OCH2), 3.04 - 2.88 (m, 2H, PhCH2), 2.34 (s, 6H, (CH3)2). 19 F NMR (377 MHz, CDC13) δ -78.56. 13C NMR (101 MHz, CDC13) δ 149.6, 139.9, 137.1, 136.8, 132.8, 128.8, 128.2, 127.7, 127.34, 127.30, 126.0, 125.4, 124.4, 122.1, 120.6 (q, J = 288.9 Hz), 114.9, 114.5, 98.5 (q, J = 32.6 Hz), 63.4, 35.0, 20.6, 20.1. HRMS (ESI) m / z: Calcd for C 26 H 23 F3NaO2[M + Na] + 447.1542, Found: 447.1536.

[0067] I-36: White solid, m.p. 171-172 °C, yield 78%. 1 H NMR (400 MHz, CDC13) δ 7.66-7.56 (m, 6H, (ArH)6), 7.47-7.42 (m, 2H, (ArH)2), 7.38-7.27 (m, 6H, (ArH)6), 7.15-7.08 (m, 2H, (ArH)2), 6.90-6.81 (m, 2H, (ArH)2), 4.74 (d, J = 11.4 Hz, 1H, ½CH2), 4.69 (d, J = 11.4 Hz, 1H, ½CH2), 2.36 (s, 3H, CH3). 19 F NMR (377 MHz, CDC13) δ -78.43. 13 C NMR (101 MHz, CDC13) δ 150.8, 141.4, 140.9, 140.5, 136.6, 135.6, 130.6, 128.9, 128.8, 128.4, 127.9, 127.7, 127.5, 127.2, 127.0, 126.8, 125.1, 123.4, 121.7 (q, J = 288.9 Hz), 115.9, 115.7, 99.7 (q, J = 32.6 Hz), 65.6, 21.6. HRMS (ESI) m / z: Calcd for C 30 H 23 F3NaO2[M + Na] + 495.1542, Found: 495.1541.

[0068] I-37: Pale yellow liquid, yield 85%. 1H NMR (400 MHz, CDC13) δ 7.49 - 7.44 (m, 2H, (ArH)2), 7.37 - 7.28 (m, 7H, (ArH)7), 7.16 - 7.11 (m, 1H, ArH), 7.00 - 6.97 (m, 1H, ArH), 6.63 - 6.58 (m, 1H, ArH), 6.57 - 6.53 (m, 1H, ArH), 4.70 (d, J = 11.4 Hz, 1H, ½CH2), 4.65 (d, J = 11.4 Hz, 1H, ½CH2), 3.81 (s, 3H, OCH3). 19 F NMR (377 MHz, CDC13) δ -78.30. 13 C NMR (101 MHz, CDC13) δ 162.0, 152.1, 136.4, 135.3, 134.1, 130.7, 129.8, 128.5, 128.40, 128.36, 128.0, 127.6, 122.4, 121.5 (q, J = 288.9 Hz), 111.6, 109.5, 100.4, 99.7 (q, J = 32.6 Hz), 65.6, 55.6. HRMS (ESI) m / z: calcd for C 24 H 18 ClF3KO3[M+K] + 485.0528, found: 485.0530.

[0069] I-38: colorless liquid, yield 87%. 1 H NMR (400 MHz, CDC13) δ 7.49 - 7.44 (m, 2H, (ArH)2), 7.37 - 7.28 (m, 7H, (ArH)7), 7.16 - 7.11 (m, 1H, ArH), 7.00 - 6.97 (m, 1H, ArH), 6.63 - 6.58 (m, 1H, ArH), 6.57 - 6.53 (m, 1H, ArH), 4.70 (d, J = 11.4 Hz, 1H, ½CH2), 4.65 (d, J = 11.4 Hz, 1H, ½CH2), 3.81 (s, 3H, OCH3). 19 F NMR (377 MHz, CDC13) δ -78.60. 13C NMR (101 MHz, CDC13) δ 162.6, 156.8, 152.8, 139.2, 136.4, 131.4, 130.7, 129.6, 128.4, 127.9, 127.7, 127.1, 126.3, 122.2, 121.6 (q, J = 288.9 Hz), 119.8, 101.8, 99.8 (q, J = 32.6 Hz), 93.0, 92.3, 65.6, 55.7, 55.6. HRMS (ESI) m / z: Calcd for C 25 H 20 BrF3KO4[M+K] + 559.0129, Found: 559.0130.

[0070] I-39: White solid, m.p. 159-160 °C, yield 90%. 1 H NMR (400 MHz, CDC13) δ 7.47 - 7.39 (m, 4H, (ArH)4), 7.37 - 7.27 (m, 6H, (ArH)6), 6.24 - 6.16 (m, 1H, ArH), 6.15 - 6.07 (m, 1H, ArH), 4.67 (d, J = 11.4 Hz, 1H, ½CH2), 4.63 (d, J = 11.4 Hz, 1H, ½CH2), 3.84 (s, 3H, OCH3), 3.80 (s, 3H, OCH3). 19 F NMR (377 MHz, CDC13) δ -78.53. 13 C NMR (101 MHz, CDC13) δ 162.5, 156.7, 152.7, 136.5, 136.1, 131.3, 130.1, 128.4, 127.9, 127.7, 125.7, 121.5 (q, J = 288.9 Hz), 122.0, 120.1, 101.8, 99.8 (q, J = 32.6 Hz), 93.0, 92.3, 65.5, 55.7, 55.6. HRMS (ESI) m / z: Calcd for C 25 H 20 BrF3NaO4[M+Na] + 543.0389, Found: 543.0395.

[0071] The above target compounds can be obtained in moderate to high yield, meeting the needs of new drug development.

[0072] Example 1

[0073]

[0074] Under ice water bath condition, different 4-methoxyphenylacetic acid (V-1, 1.0 eq, 0.050 mol), anisole (1.0 eq, 0.05 mol) and phosphoric acid (1.1 eq, 0.055 mol) were added into a round bottom flask, which was cooled to 0 °C under magnetic stirring, then trifluoroacetic anhydride (4.0 eq, 0.200 mol) was added dropwise, after the dropwise addition was completed, the reaction solution was poured into excess pre-cooled sodium hydroxide solution, and magnetic stirring was carried out, and white solid was precipitated within a few minutes, then the solid was filtered, washed with water and dried to obtain intermediate 1,2-bis(4-methoxyphenyl)ethan-1-one (IV-1).

[0075] Under argon atmosphere, sodium hydride (2.0 eq, 12 mmol), ethyl trifluoroacetate (4.0 eq, 24 mmol), intermediate 1,2-bis(4-methoxyphenyl)ethan-1-one (compound VI-1, 1.0 eq, 6 mmol) were added into a Schlenk flask, then tetrahydrofuran (25 mL) was added, and then the reaction system was heated to reflux for 12 h. Then, the reaction flask was placed in an ice water bath under argon protection, and after the liquid in the reaction system was completely cooled, triflic anhydride (2.0 eq, 12 mmol) was slowly added dropwise, and the reaction was carried out for 10 min. Then, the reaction was quenched by adding water, and the reaction solution was extracted with ethyl acetate, and the organic layer was collected and the solvent was concentrated under vacuum, and the pure product intermediate (E)-3,3,3-trifluoro-1-(4-methoxyphenyl)prop-1-en-2-yl trifluoromethanesulfonate (III-1) was obtained by silica gel column separation and purification.

[0076] Then, under argon atmosphere, (E)-3,3,3-trifluoro-1-(4-methoxyphenyl)prop-1-en-2-yl trifluoromethanesulfonate (intermediate III-1, 2.0 eq, 6.0 mmol), 2-chloro-6-hydroxybenzaldehyde (1.0 eq, 3.0 mmol), tetrahydropyrrole (2.0 eq, 6.0 mmol) and solvent ethanol (6 mL) were added into a Schlenk flask, which was heated to 65 °C under magnetic stirring and reacted for 8 h. After the reaction was completed by TLC monitoring, the reaction solution was extracted with ethyl acetate and concentrated under reduced pressure to remove the solvent, and then the intermediate 5-chloro-2-hydroxy-3-(4-methoxyphenyl)-2-trifluoromethyl-2H-chromene (II-1) was obtained by silica gel column chromatography.

[0077] Finally, under argon protection, into a Schlenk reactor, at 0°C, were sequentially added intermediate 5-chloro-2-hydroxy-3-(4-methoxyphenyl)-2-trifluoromethyl-2H-chromene (II-1, 1.0 eq, 1.0 mmol), benzyl alcohol (1.2 eq, 1.2 mmol), triphenylphosphine (1.2 eq, 1.2 mmol), diethyl azodicarboxylate (1.2 eq, 1.2 mmol) and solvent tetrahydrofuran (10 mL), and the reaction was stirred magnetically in a low temperature reactor for 12 h. After the reaction was completed by TLC monitoring, the reaction mixture was extracted with ethyl acetate and concentrated under reduced pressure, and the target compound I-1 was obtained by silica gel column chromatography.

[0078] The target compounds I-2 to I-39 were prepared by referring to the preparation of the target compound I-1, changing the substituents in the corresponding raw materials.

[0079] Example 2

[0080] Cytotoxicity assay of 2-trifluoromethyl-3-aryl-2H-chromene ether derivatives (I)

[0081] The cell viability was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide cell viability assay (MTT method), and the test concentration of the compound (I) and the positive drug indomethacin was 30 μM. RAW 264.7 cells were selected for the determination, 1 x 10 5 cells were inoculated in each well of a 96-well plate, and the culture conditions were as follows: DMEM complete medium with the addition of 10% fetal bovine serum and 1% penicillin and streptomycin, and incubation in a 37°C constant temperature incubator containing 5% CO2. After 24 h of inoculation, the compound (I) or the positive drug (both dissolved in DMSO, with a final concentration of 0.5%) was added, 1 h later, lipopolysaccharide (LPS) was added to make the final concentration 1 μg / mL, and after 24 h of culture, MTT was added to the culture solution to make the final concentration 0.5 mg / mL, and the culture was continued for 4 h, after which the culture medium was removed, 150 μL of DMSO was added to each well, the plate was shaken for 10 min, and the absorbance at 570 nm was determined by an enzyme-labeled instrument. The test results are shown in Table 1, and all the compounds had no cytotoxicity at the test concentration. Figure 1

[0082] Example 3

[0083] Determination of the inhibitory effect of 2-trifluoromethyl-3-aryl-2H-chromene ether derivatives (I) on NO release

[0084] ​The inflammatory effects are associated with a number of inflammatory mediators, including cytokines, NO and enzymes, which are released when macrophages produce different phenotypes in response to stimuli. NO is catalyzed by iNOS and is considered to be an important mediator in the inflammatory process, and is reported to affect the products of the cyclooxygenase metabolic pathway, producing two cyclooxygenase subtypes, COX-1 and COX-2. The inflammatory factor NO can be detected by the Griess reagent. The RAW 264.7 cell line was used for the assay, with 1 x 10 5 cells per well in a 96-well plate, and the culture conditions were DMEM complete medium with 10% fetal bovine serum and 1% penicillin and streptomycin, in a 37°C incubator with 5% CO2. After 24 h of incubation, 10 μM of compound (I) or a positive drug (both dissolved in DMSO, with a final DMSO concentration of 0.5%) was added, and after 1 h, lipopolysaccharide (LPS) was added to a final concentration of 1 μg / mL. After 24 h of incubation, 100 μL of supernatant per well was taken to a 96-well plate, 50 μL of Griess reagent A was added, and the plate was incubated in a 37°C incubator for 10 min. Then, 50 μL of Griess reagent B was added, and the plate was incubated in a 37°C incubator for 10 min. Subsequently, the absorbance at 550 nm was measured using a microplate reader.

[0085] The results are shown in Table 1. Figure 2 Most of the target compounds had a certain inhibitory effect on the LPS-induced overproduction of NO in RAW264.7 cells, and the effects of I-24, I-25 and I-27 were better than that of the positive drug indomethacin. Therefore, the IC 50 values of the three compounds for inhibiting the release of NO were further measured by a concentration gradient test (Table 1). Among them, the IC 50 of I-25 was the lowest (IC 50 = 5.03 ± 0.30 μM), which was even lower than that of the positive drug indomethacin (IC 50 = 4.93 ± 0.56 μM). The structure-activity relationship (SAR) that can be summarized from the results of the in vitro test in this part is that the activity is generally higher when the 6-position of the chromene ring is substituted with a fluorine atom. By comparing I-14, I-21 and I-24, and I-15, I-22 and I-25, it can be found that the methoxy group at the 4-position of the benzene ring connected to the 3-position of the chromene ring has a greater impact on the activity. By comparing I-23 to I-27, it can be found that the structure in which one or two methylenes are connected to the 3-position of the thiophene through an ether bond at the 2-position of the chromene ring has higher activity, and it is observed that two methylenes are better than one methylene, which is probably because two methylenes have higher flexibility and are more easily combined with the active site. Therefore, I-25 was selected as the target molecule for further study.

[0086] Table 1 Inhibitory effect of some target compounds on NO

[0087]

[0088] RAW264.7 cells were pre-treated with different concentrations (20, 10, 5, 2.5 and 1.25 μM) of the compound for 1 h, followed by the addition of LPS (1 μg / mL) for co-culture for 24 h; the concentration of NO in the medium supernatant was determined by Griess reagent.

[0089] Example 4

[0090] Inhibitory effect of compound I-25 on carrageenan-induced rat paw edema

[0091] The carrageenan-induced rat paw edema model can be used to detect the local acute inflammatory response mediated by PGE2 production and to screen effective anti-inflammatory drugs. Male Wistar rats (n = 6, body weight 180-200 g) were administered by gavage with the target compound I-25 or the positive drug indomethacin (suspended in 0.5% CMC-Na) at a dose of 20 mg / kg, and 1 h later, 0.1 mL of a sterile physiological saline solution containing 1% carrageenan (Sigma, USA) was injected subcutaneously into the plantar of the right hind paw of the rats. The control group was tested under the same conditions, but only gavaged with the vehicle. The paw volume was measured using a plethysmograph (Ugo Basile, Italy) before the injection of carrageenan and at 1, 3 and 5 h after the injection, respectively. The results, as shown in Table 2, showed that I-25 had an inhibition rate of 40.74% at 5 h after the injection of carrageenan, which was significantly better than that of the positive drug indomethacin (inhibition rate of 27.78%) at the same dose. This result demonstrated that I-25 had an excellent effect on anti-acute inflammation in rats.

[0092] Table 2 Inhibitory effect of I-25 on carrageenan-induced rat paw edema

[0093]

[0094] Ctrl (vehicle; 0.5% CMC-Na), indomethacin, and I-25 suspended in 0.5% CMC-Na. n = 6.

[0095] Example 5

[0096] Inhibitory effect of compound I-25 on cotton pellet-induced granuloma in mice

[0097] Chronic inflammation has a clear granuloma feature and multinucleated giant cells. A cotton pellet-induced granuloma is a model of chronic inflammation that can be used to evaluate the inhibitory effect of a compound on the proliferation of tissues in the later stage of inflammation. Male C57B1 / 6 mice weighing 26-28 g were randomly divided into groups of 6. After anesthesia with sodium pentobarbital (30 mg / kg, intraperitoneal injection), the back was prepared for skin and sterilized under aseptic conditions, and then two sterile cotton pellets (10 mg) were implanted subcutaneously on both sides of the scapula of the mouse by aseptic surgery. From the day of the operation, the target compound I-25 (20 mg / kg), the positive drug indomethacin (20 mg / kg), or the vehicle (0.5% CMC-Na) was administered by gavage to the mice every 24 h for 7 consecutive days. After the mice were sacrificed with CO2 on the 8th day of the experiment, the cotton pellets with the surrounding proliferating granuloma tissue were carefully dissected, and then the cotton pellets were dried at 60°C to a constant weight. The results were recorded as the difference between the final dried weight of the cotton pellets and the initial weight of the cotton pellets (10 mg), and the inhibition rate was calculated. At both test concentrations of 10 and 20 mg / kg, I-25 significantly inhibited the weight of the granuloma, with inhibition rates of 27.0% and 47.7%, respectively. At the same test concentration (20 mg / kg), I-25 showed a better inhibitory effect on the cotton pellet-induced granuloma than the positive drug indomethacin (inhibition rate of 32.0%). This experiment demonstrated that I-25 has a certain therapeutic effect on the granuloma and tissue proliferation in chronic inflammatory reactions, and has a good anti-inflammatory therapeutic effect on chronic inflammation with proliferation.

[0098] Example 6

[0099] Inhibition of acetic acid-induced writhing in mice by compound I-25

[0100] The acetic acid-induced writhing model in mice can be used to evaluate the analgesic effect of a compound in animals. Male C57B1 / 6 mice weighing 26-28 g were randomly divided into 4 groups of 6. The target compound I-25 (10 or 20 mg / kg), the positive drug indomethacin (20 mg / kg), or the vehicle (0.5% CMC-Na) was administered by gavage, and 30 min later, 0.6% acetic acid (v / v; 0.1 mL / 10 g body weight) was injected intraperitoneally to induce writhing in mice. The number of writhing (i.e., abdominal contraction, back bending and stretching) of the mouse body within 20 min after the start of injection was counted. The results were expressed as the number of writhing within 20 min. The results of the experiment are shown in Table 1. Figure 4As shown, I-25 significantly reduced the number of writhing movements induced by acetic acid in mice in a dose-dependent manner. I-25 at a dose of 10 mg / kg was comparable to the therapeutic level of the positive control drug indomethacin at a dose of 20 mg / kg, and I-25 was significantly superior to indomethacin at the same dose of 20 mg / kg. These results indicate that I-25 has a good analgesic effect in vivo in this study, and is significantly superior to the control drug indomethacin.

[0101] Example 7

[0102] Determination of the anti-inflammatory and analgesic effects of compound I-25 in an adjuvant-induced rat model of arthritis

[0103] Adjuvant-induced arthritis (AIA) serves as an animal model of inflammatory and reactive rheumatoid arthritis and is an industry-standard model for predicting the clinical efficacy of novel nonsteroidal anti-inflammatory drugs (NSAIDs). Furthermore, due to the similarity between the pathological changes in animals after adjuvant injection and clinical rheumatoid arthritis, the AIA model is considered most suitable for comparison with human rheumatoid arthritis. Arthritis was induced by subcutaneous injection of 0.1 mL of sterile mineral oil containing 10 mg / mL heat-inactivated Mycobacterium tuberculosis into the right posterior paw of each Lewis rat (male, 150–170 g). Rats injected with the same volume of saline at the same site served as a blank control group. After 7 days of immunization, the immunized rats were randomly divided into four groups of six. From day 8 to day 28 after immunization, rats were treated daily by gavage with I-25 (10 and 20 mg / kg) and indomethacin (20 mg / kg) suspended in 0.5% sodium carboxymethyl cellulose. The blank control group and the model group were administered the same amount of 0.5% sodium carboxymethyl cellulose daily by gavage. Rats were weighed and had their left hind paw volume measured every two days. Standardized clinical scores were applied to the three untreated paws (each paw was scored from mild to severe, with a maximum score of 12 per rat). On day 28 after immunization, rats were placed in a test cage with a wire mesh bottom for 30 minutes to acclimatize. Then, mechanical stimulation of the center of the left hind paw was performed using von Frey fibers (North Coast, USA) and the "up and down" method provided by the device manufacturer. The force causing paw withdrawal or vocalization was measured. Specific procedures and data analysis followed the manufacturer's instructions. Results are as follows: Figure 5 As shown, compound I-25 significantly improved adjuvant-induced weight loss in rats in a dose-dependent manner. Figure 5 A) Swelling of the feet ( Figure 5 B) and clinical symptoms such as redness, swelling, and deformity of the feet and claws. Figure 5 C). Furthermore, the 50% mechanical pain threshold (50% MWT) in rats treated with compound I-25 was significantly higher than that in the model group, indicating good analgesic activity. Figure 5D), which also suggests that compound I-25 can relieve the symptoms of pain in rheumatoid arthritis in clinical practice. In addition, it was observed that I-25 has an inhibitory effect on the phenomenon of splenomegaly caused by adjuvant injection Figure 5 E), indicating that it can have certain immunomodulatory effects. These results suggest that I-25 can have a positive impact on reducing the symptoms and pain of patients with rheumatoid arthritis and improving the quality of life.

[0104] Example 8

[0105] Determination of the level of acute gastric ulceration in rats caused by compound I-25

[0106] One of the aspects of NSAIDs that is controversial in clinical use is their serious side effects, of which the highest incidence is gastrointestinal side effects (2-4% of patients who use them develop serious complications every year), which also leads to the fact that current NSAIDs do not fully meet the medical needs. Therefore, improving the safety of the digestive tract of NSAIDs is of great importance for patients who can be used more widely and for a longer period of time. Therefore, we studied the effect of the potential ulcerogenic effect of compound I-25 administered orally to rats.

[0107] Male Wistar rats (180-200 g, n=5) were administered orally with vehicle (0.5% CMC-Na) or the target compound I-25 (50 or 100 mg / kg) or indomethacin (50 mg / kg). Six hours after administration, the rats were sacrificed, the stomach was surgically removed and cut along the greater curvature. The ulcer lesion index of the rats was calculated according to the following scoring scheme:

[0108] 1. The diameter of the ulcer lesion was measured with a vernier caliper;

[0109] 2. Ulcers were defined as grade I, ulcer area less than 1 mm in diameter; grade II, ulcer area between 1 and 3 mm in diameter; and grade III, ulcer area greater than 3 mm in diameter.

[0110] 3. The sum of the ulcer readings for each group of 5 test animals is reported as the ulcer index (UI), calculated as follows: 1 x number of grade I ulcers + 2 x number of grade II ulcers + 3 x number of grade III ulcers.

[0111] The results are shown in Table 3, where indomethacin administered orally at a dose of 50 mg / kg caused a total of 32 gastric ulcer lesions in 5 rats, with an ulcer index (UI) of 48, while I-25 did not cause acute ulcer symptoms at the same dose. Subsequently, rats were administered orally with a high concentration of I-25 at 100 mg / kg, which showed a slight ulcerogenic effect in these rats, causing a total of 9 ulcer lesions, with an ulcer index of 11, much lower than the ulcer damage caused by indomethacin at a concentration of 50 mg / kg.

[0112] Table 3I-25 was compared with indomethacin-induced acute gastric ulcer in rats

[0113]

[0114] * Ctrl (vehicle; 0.5% CMC-Na), Indomethacin and I-25 suspended in 0.5% CMC-Na. n = 5.

[0115] The above-described examples are only preferred embodiments for fully illustrating the present application, and the scope of protection is not limited thereto. Any equivalent replacement or transformation made by those skilled in the art on the basis of the present application is within the scope of protection of the present application, and the scope of protection of the present application is subject to the claims.

Claims

1. A 2-trifluoromethyl-3-aryl-2 H - Chromene ether derivatives, characterized in that It has any of the following structural formulas: 。 2. An anti-inflammatory drug, characterized in that, The ingredient comprises the 2-trifluoromethyl-3-aryl-2-propanediol of claim 1. H - Any one of the chromene ether derivatives.

3. A method for preparing the 2-trifluoromethyl-3-aryl-2-propane as described in claim 1 H The method for chromene ether derivatives, characterized in that... The synthetic route is as follows: In equations (I)-(V), R 1 R 2 R 3 The definitions of n and n are the same as in claim 1.

4. The 2-trifluoromethyl-3-aryl-2-propane as described in claim 3 H The method for preparing chromene ether derivatives is characterized by, The specific synthesis method is as follows: Using 2-aryl-substituted carboxylic acids of formula (V) as starting materials, Friedel-Crafts acylation reaction is carried out to generate ketone compounds of formula (IV); Using the ketone compound shown in formula (IV) as a starting material, an ester / ketone exchange reaction is performed to produce the compound shown in formula (III). Z )-Trifluoromethyl alkenyl trifluoromethanesulfonate compound; As shown in equation (III) Z Using trifluoromethyl alkenyl trifluoromethanesulfonate as a raw material, and R 2 The condensation cyclization of substituted salicylaldehyde produces 2-trifluoromethyl-2-hydroxy-3-aryl-2 as shown in formula (II). H -chromene; Then, using formula (II) 2-trifluoromethyl-2-hydroxy-3-aryl-2 H -Phenylene as a raw material, and R 3 The substituted alcohol undergoes a nucleophilic substitution reaction to produce 2-trifluoromethyl-3-aryl-2- as shown in formula (I). H - Chromene ether derivatives.

5. A 2-trifluoromethyl-3-aryl-2-property as described in claim 1 H The application of chromene ether derivatives is characterized by... Used in the preparation of anti-inflammatory and analgesic drugs.

6. The 2-trifluoromethyl-3-aryl-2-propane as described in claim 5 H - Chromene ether derivatives are used to prepare drugs for treating acute and chronic inflammation.

7. The 2-trifluoromethyl-3-aryl-2-propanediol of claim 5 H The application of chromene ether derivatives is characterized by... Used to prepare drugs for the treatment of rheumatoid arthritis.

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