A 3-(2-trifluoromethyl-3-aryl-4H-chromen-4-yl)-1H-indole derivative, preparation method and application

Abstract

The application belongs to the field of pharmaceutical chemicals, and discloses a 3-(2-trifluoromethyl-3-aryl-4H-chromen-4-yl)-1H-indole derivative, a preparation method and application. The 3-(2-trifluoromethyl-3-aryl-4H-chromen-4-yl)-1H-indole derivative has a structure as shown in formula (I), wherein: R 1 is selected from aryl groups with different substituents, 2 is selected from any one or combination of -H, -F, -Cl, -CH3, -OCH3 substituted at any position, 3 is selected from any one or combination of -H, -CH3, -OCH3 substituted at any position. The compound provided by the application can be used as an anti-inflammatory drug and an analgesic drug 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 3-(2-trifluoromethyl-3-aryl-4H-chromen-4-yl)-1H-indole derivative, a preparation method and application thereof. BACKGROUND

[0002] Inflammation is one of the most important processes in the defense of the organism, however, it often develops into a disease that requires medical treatment, which is manifested as pain or chronic damage. In addition, inflammation is associated with 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 each year due to NSAIDs-related gastric diseases, in addition, there are also kidney function 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 fewer side effects.

[0003] Indole is attracting attention due to its unique chemical properties and biological activities, and its figure is also common in many marketed drugs. Indole compounds have always played an important role in the field of anti-inflammatory drugs. Among them, indomethacin and acemetacin are potent NSAIDs with therapeutic effects on various inflammatory diseases including arthritis and analgesic effects, but they are often accompanied by more serious gastrointestinal reaction side effects, such as nausea, vomiting, abdominal pain, ulceration and even bleeding, etc. Many researchers have reported that the causes of gastrointestinal side effects caused by indomethacin include direct stimulation of the naked carboxyl group in its structure, disturbance of extracellular matrix (ECM) remodeling, apoptosis, etc.

[0004] CN116375738A discloses a [1,2]thiazine[3,4-b]indole compound and a preparation method and application thereof. Indolin-2-imine is used as a raw material, and reacts with β-arylethyl vinyl sulfonyl fluoride under the action of an organic or inorganic base to obtain the target product. However, it has not been verified that the target product has an anti-inflammatory effect in vivo, and the biological safety needs to be investigated. SUMMARY

[0005] Chromene is a kind of heterocyclic compound with multiple biological activities, researchers have reported that it has anti-inflammatory and antioxidant, anticancer, antibacterial and antiviral activities. 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. In combination with 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 the phospholipids of mucosal epithelial cells, thereby increasing the permeability of the mucosa, which can ultimately cause severe gastric ulcers, and the reported structure has a carboxylic acid structure at 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 aromatic group is replaced for structural modification at the 3-position.

[0006] ECM remodeling is attributed to the activity of various matrix metalloproteinases (MMPs), and the increase in the activity of MMP-9 is often involved in the decomposition of basement membrane collagen in the process of tissue remodeling. The increase in the activity of MMP-9 is related to the gastrointestinal inflammation caused by NSAIDs, leading to damage to the integrity of the gastric ECM. However, some researchers have converted the ulcerogenicity of indomethacin to anti-ulcerogenicity by chemically modifying it. Moreover, MMP-9 inhibitors based on indole have been discovered for a long time, and some researchers have reported that melatonin, a naturally occurring indole derivative, can effectively inhibit MMP-9.

[0007] Pharmacophore assembly is one of the important strategies in drug design and development, which combines the advantages of multiple known pharmacophores, expands the chemical space of drugs, and provides a new way for the discovery of new lead compounds. At the same time, it also helps to solve the problem of drug resistance and brings hope for improving the performance of existing drugs and developing new treatment options. However, pharmacophore assembly also faces some challenges, such as the stability and toxicity of the compounds after assembly, which need to be fully evaluated and optimized. Despite this, pharmacophore assembly is still a promising method in the field of drug research, constantly pushing the progress of drug development. In summary, combining the activity of 2-trifluoromethyl chromene and indole structure, using pharmacophore assembly principle to synthesize 3-(2-trifluoromethyl-3-aryl-4H-chromen-4-yl)-1H-indole derivatives with higher activity and fewer side effects is the design idea of the present application.

[0008] On the basis of the above research, in order to solve the problems existing in the prior art, the application designs and synthesizes a 3-(2-trifluoromethyl-3-aryl-4H-chromen-4-yl)-1H-indole derivative with good anti-inflammatory activity, specifically, the trifluoromethyl imine derivative provided by the application has the structure shown in the following general formula (I),

[0009]

[0010] Among them,

[0011] R 1 is selected from any one of hydrogen, halogen, C6 and below hydrocarbon group, C3 below fluorinated alkyl, C4 and below alkoxy substituted five-membered aromatic ring or six-membered aromatic ring, preferably any one of -C6H5, -2-F-C6H4, -3-F-C6H4, -4-F-C6H4, -2-Cl-C6H4, -4-Cl-C6H4, -3-Br-C6H4, -4-Br-C6H4, -4-CF3-C6H4, -2-OCH3-C6H4, -4-OCH3-C6H4, -3-CH3-C6H4, -4-CH3-C6H4, -4-Ph-C6H4, thienyl;

[0012] R 2 is selected from any one or combination of hydrogen, halogen, C5 and below alkyl and alkoxy substituted at any position, preferably any one or combination of -H, -5-Cl, -6-F, -6-Cl, -6-CH3, -7-CH3, -6-OCH3, -7-OCH3, R 3 is selected from any one or combination of -H, -CH3, -OCH3 substituted at any position;

[0013] Preferably, the compound shown in the general formula (I) is selected from one of the following structural formulas:

[0014]

[0015] The application also provides a preparation method of any one of the above 3-(2-trifluoromethyl-3-aryl-4H-chromen-4-yl)-1H-indole derivatives (I).

[0016]

[0017] In formula (I)-(V), R 1 , R 2 , R 3 are the same as defined above;

[0018] The specific synthesis method is:

[0019] The 2-aryl-substituted carboxylic acid shown in formula (V) is used as a raw material to generate a ketone compound shown in formula (IV) through a Friedel-Crafts acylation reaction;

[0020] The ketone compound shown in formula (IV) is used as a raw material to generate a (Z)-trifluoromethyl trifluoromethyl alkenyl sulfonate shown in formula (III) through an ester / ketone exchange reaction;

[0021] The (Z)-trifluoromethyl trifluoromethyl alkenyl sulfonate shown in formula (III) is used as a raw material to generate a 3-(2-trifluoromethyl-3-aryl-4H-chromen-4-yl)-1H-indole derivative shown in formula (I) through a nucleophilic substitution reaction with R 2 substituted salicylaldehyde to generate a 2-trifluoromethyl-2-hydroxy-3-aryl-2H-chromene shown in formula (II) through a condensation cyclization reaction;

[0022] The 2-trifluoromethyl-2-hydroxy-3-aryl-2H-chromene shown in formula (II) is used as a raw material to generate a 3-(2-trifluoromethyl-3-aryl-4H-chromen-4-yl)-1H-indole derivative shown in formula (I) through a nucleophilic substitution reaction with R 3 substituted indole to generate a 3-(2-trifluoromethyl-3-aryl-4H-chromen-4-yl)-1H-indole derivative shown in formula (I).

[0023] The present application also provides the use of any of the above-mentioned 3-(2-trifluoromethyl-3-aryl-4H-chromen-4-yl)-1H-indole derivatives (I) for the preparation of an anti-inflammatory and analgesic drug.

[0024] Preferably, the drug for treating acute and chronic inflammation and pain used in the test is not limited to the drug used in the examples.

[0025] The 3-(2-trifluoromethyl-3-aryl-4H-chromen-4-yl)-1H-indole 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 proliferation and pain.

[0026] The present application has the following advantages compared with the prior art:

[0027] The compound provided by the present application can be used for preparing an anti-inflammatory drug and an analgesic drug, and is used for treating acute and chronic inflammation, tissue redness and swelling, proliferation, and pain. Some of the compounds exhibit a better anti-inflammatory and analgesic effect than commercially available non-steroidal anti-inflammatory drugs. BRIEF DESCRIPTION OF DRAWINGS

[0028] Figure 1 is a cell viability assay of 3-(2-trifluoromethyl-3-aryl-4H-chromen-4-yl)-1H-indole derivative (I);

[0029] Figure 2 is an inhibitory effect of 3-(2-trifluoromethyl-3-aryl-4H-chromen-4-yl)-1H-indole derivative (I) on NO release;

[0030] Figure 3 is the inhibitory effect of compound I-25 on cotton ball implantation-induced granuloma in mice;

[0031] Figure 4 is the inhibitory effect of compound I-25 on acetic acid-induced writhing in mice;

[0032] Figure 5 is the therapeutic effect of compound I-25 on adjuvant-induced arthritis in rats: the effects 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

[0033] In order to enable a person skilled in the art to better understand the technical solutions of the present application and implement them, 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.

[0034] In the following examples, the test methods are conventional methods unless otherwise specified; the reagents and materials are commercially available unless otherwise specified.

[0035] 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-29 synthesized in the present application, but the present application is not limited to these compounds.

[0036] I-1: pale yellow liquid, yield 67%. 1 H NMR (400 MHz, CDCl3) δ 7.95 (s, 1H, NH), 7.40-7.36 (m, 1H, ArH), 7.34-7.29 (m, 1H, ArH), 7.20-7.12 (m, 3H, (ArH)3), 7.08-6.97 (m, 3H, (ArH)3), 6.88-6.80 (m, 5H, (ArH)5), 4.93 (s, 1H, CH). 19 F NMR (377 MHz, CDCl3) δ -64.13 (3F), -114.30 (1F). 13C NMR (101 MHz, CDC13) δ 162.3 (d, J = 246.6 Hz), 149.5, 136.6, 136.0 (q, J = 34.5 Hz), 131.9 (d, J = 3.5 Hz), 130.3 (q, J = 8.3 Hz), 129.1, 128.0, 125.8, 124.6, 123.0, 122.6, 122.4, 120.1, 120.0 (q, J = 275.3 Hz), 119.8, 119.0, 117.8, 116.3, 114.8 (d, J = 21.5 Hz), 111.4, 40.2. HRMS (ESI) m / z: Calcd for C 24 H 14 F4NO[M-H] - 408.1017, Found: 408.1025.

[0037] I-2: pale yellow liquid, yield 62%. 1 H NMR (400 MHz, CDC13) δ 7.96 (s, 1H, NH), 7.42-7.37 (m, 1H, ArH), 7.33-7.26 (m, 3H, (ArH)3), 7.22-7.15 (m, 3H, (ArH)3), 7.10-6.98 (m, 3H, (ArH)3), 6.87 (s, 1H, ArH), 6.78-6.72 (m, 2H, (ArH)2), 4.94 (s, 1H, CH). 19 F NMR (377 MHz, CDC13) δ -64.13. 13 C NMR (101 MHz, CDC13) δ 149.4, 136.7, 136.0 (q, J = 34.5 Hz), 135.0, 131.0, 130.3, 129.1, 128.0, 125.7, 124.7, 122.8, 122.6, 122.4, 121.9, 120.1, 120.0 (q, J = 275.3 Hz), 119.6, 119.0, 117.6, 116.3, 111.4, 40.0. HRMS (ESI) m / z: Calcd for C 24 H 14 BrF3NO[M-H] - 468.0216, Found: 468.0212.

[0038] I-3: pale yellow liquid, yield 71%. 1H NMR (400 MHz, CDC13) δ 7.98 (s, 1H, NH), 7.44-7.33 (m, 4H, (ArH)4), 7.22-7.14 (m, 3H, (ArH)3), 7.11-6.97 (m, 5H, (ArH)5), 6.89-6.83 (m, 1H, ArH), 4.97 (s, 1H, CH). 19 F NMR (377 MHz, CDC13) δ -62.62 (3F), -64.25 (3F). 13 C NMR (101 MHz, CDC13) δ 149.4, 139.8, 136.7, 136.2 (q, J = 34.9 Hz), 129.9 (q, J = 32.4 Hz), 129.2, 129.0, 128.1, 125.7, 124.81 (q, J = 4.0 Hz), 124.76, 122.8 (q, J = 286.8 Hz), 122.7, 122.6, 122.5, 120.1, 120.0 (q, J = 275.3 Hz), 119.5 (q, J = 2.0 Hz), 118.9, 117.4, 116.4, 111.5, 40.0. HRMS (ESI) m / z: calcd for C 25 H 14 F6NO[M-H] - 458.0985, found: 458.0986.

[0039] I-4: colorless liquid, yield 52%. 1 H NMR (400 MHz, CDC13) δ 7.96 (s, 1H, NH), 7.21-7.05 (m, 5H, (ArH)5), 6.99-6.91 (m, 4H, (ArH)4), 6.71-6.63 (m, 1H, ArH), 6.62-6.53 (m, 1H, ArH), 5.03 (s, 1H, CH), 2.44 (s, 3H, CH3). 19 F NMR (377 MHz, CDC13) δ -64.28 (3F), -113.17 (1F). 13C NMR (101 MHz, CDC13) δ 162.2 (d, J = 246.2 Hz), 151.1, 137.6 (d, J = 8.1 Hz), 136.0, 135.7 (q, J = 35.1 Hz), 134.0, 129.5 (d, J = 8.4 Hz), 128.6, 125.8, 125.3, 124.7, 124.2, 122.8, 121.6, 120.6, 120.4, 120.0 (q, J = 275.3 Hz), 116.7, 115.7, 115.2, 115.0 (d, J = 21.0 Hz), 38.8, 16.5. HRMS (ESI) m / z: calcd for C 25 H 15 ClF4NO[M-H] - 456.0784, found: 456.0783.

[0040] I-5: pale yellow liquid, yield 59%. 1 H NMR (400 MHz, CDC13) δ 7.98 (s, 1H, NH), 7.20 - 7.07 (m, 5H, (ArH)5), 6.98 - 6.78 (m, 4H, (ArH)4), 6.70 - 6.62 (m, 1H, ArH), 6.61 - 6.54 (m, 1H, ArH), 5.00 (s, 1H, CH), 3.74 (s, 3H, OCH3). 19 F NMR (377 MHz, CDC13) δ -64.44 (3F), -113.24 (1F). 13 CNMR (101 MHz, CDC13) δ 162.2 (d, J = 246.5 Hz), 154.3, 151.0, 137.5 (d, J = 8.3 Hz), 135.6 (q, J = 35.2 Hz), 134.0, 131.4, 129.5 (d, J = 8.4 Hz), 128.6, 125.9, 124.9, 124.6, 121.3, 120.5, 120.0 (q, J = 275.3 Hz), 115.0 (d, J = 21.2 Hz), 114.9, 112.8, 112.3, 102.4 (d, J = 4.3 Hz), 99.9, 55.4, 38.6. HRMS (ESI) m / z: calcd for C 25 H 15 ClF4NO2[M-H] - 472.0733, found: 472.0735. I-6: pale yellow liquid, yield 66%. 1H NMR (400 MHz, CDC13) δ 8.05 (s, 1H, NH), 7.41-7.31 (m, 3H, (ArH)3), 7.20-7.13 (m, 3H, (ArH)3), 7.09-7.01 (m, 4H, (ArH)4), 6.96-6.91 (m, 1H, ArH), 6.76-6.67 (m, 1H, ArH), 5.02 (s, 1H, CH). 19 F NMR (377 MHz, CDC13) δ -64.38. 13 C NMR (101 MHz, CDC13) δ 151.0, 137.5, 136.4, 135.7 (q, J = 35.2 Hz), 134.0, 131.3, 131.1, 129.4, 128.6, 127.6, 125.8, 125.7, 124.4, 122.2, 121.8, 121.4, 120.5 (q, J = 2.3 Hz), 120.1, 120.0 (q, J = 275.3 Hz), 118.6, 115.13, 115.06, 111.5, 38.6. HRMS (ESI) m / z: calcd for C 24 H 13 BrClF3NO[M-H] - 501.9827, found: 501.9829.

[0041] I-7: colorless liquid, yield 52%. 1 H NMR (400 MHz, CDC13) δ 7.92 (s, 1H, NH), 7.44-7.40 (m, 1H, ArH), 7.24-7.04 (m, 5H, (ArH)5), 6.87-6.75 (m, 4H, (ArH)4), 6.36-6.30 (m, 1H, ArH), 5.10 (s, 1H, CH), 3.72 (s, 3H, OCH3). 19 F NMR (377 MHz, CDC13) δ -65.85. 13 C NMR (101 MHz, CDC13) δ 154.2, 151.1, 136.0 (q, J = 35.1 Hz), 134.2, 133.5, 132.2, 132.1, 131.3, 129.4, 129.1, 128.5, 126.3, 125.93, 125.90, 124.9, 121.1, 120.0 (q, J = 275.3 Hz), 119.4 (q, J = 2.4 Hz), 114.9, 114.8, 112.7, 112.2, 99.9, 55.4, 36.8. HRMS (ESI) m / z: calcd for C 25 H15 Cl2F3NO2[M-H] - 488.0437, found: 488.0439.

[0042] I-8: pale yellow liquid, yield 70%. 1 H NMR (400 MHz, CDC13) δ 8.00 (s, 1H, NH), 7.42-7.36 (m, 1H, ArH), 7.35-7.31 (m, 1H, ArH), 7.17-7.12 (m, 3H, (ArH)3), 7.08-7.02 (m, 2H, (ArH)2), 6.97-6.93 (m, 1H, ArH), 6.83-6.77 (m, 2H, (ArH)2), 6.73-6.68 (m, 2H, (ArH)2), 5.04 (s, 1H, CH), 3.75 (s, 3H, OCH3). 19 F NMR (377 MHz, CDC13) δ -64.20. 13 C NMR (101 MHz, CDC13) δ 159.2, 151.2, 136.3, 135.5 (q, J = 35.1 Hz), 133.9, 129.8, 128.3, 127.7, 125.8, 125.5, 124.3, 122.0, 121.94, 121.90, 120.0 (q, J = 275.3 Hz), 119.98, 119.1, 115.7, 115.1, 113.3, 111.3, 55.2, 38.9. HRMS (ESI) m / z: calcd for C 25 H 16 ClF3NO2[M-H] - 454.0827, found: 454.0824.

[0043] I-9: pale yellow liquid, yield 56%. 1 H NMR (400 MHz, CDC13) δ 8.07 (s, 1H, NH), 7.41-7.36 (m, 1H, ArH), 7.29-7.22 (m, 1H, ArH), 7.16-6.99 (m, 3H, (ArH)3), 6.85-6.70 (m, 7H, (ArH)7), 4.88 (s, 1H, CH). 19 F NMR (377 MHz, CDC13) δ -63.90 (3F), -113.89 (1F), -118.01 (1F). 13C NMR (101 MHz, CDC13) δ 162.4 (d, J = 246.9 Hz), 159.3 (d, J = 242.8 Hz), 145.6, 136.7, 136.1 (q, J = 34.4 Hz), 131.6 (d, J = 3.5 Hz), 130.4, 130.3, 125.6, 124.4 (d, J = 7.5 Hz), 122.6 (d, J = 19.7 Hz), 120.2, 120.0 (q, J = 275.3 Hz), 118.9, 117.74, 117.66, 117.1, 115.3 (d, J = 6.8 Hz), 115.08, 115.05, 115.0, 114.8, 111.6, 40.5. HRMS (ESI) m / z: calcd for C 24 H 13 F5NO[M-H] - 426.0923, found: 426.0927.

[0044] I-10: pale yellow liquid, yield 65%. 1 H NMR (400 MHz, CDC13) δ 7.89 (s, 1H, NH), 7.25-7.21 (m, 1H, ArH), 7.12-7.07 (m, 1H, ArH), 6.99-6.96 (m, 2H, (ArH)2), 6.87-6.81 (m, 7H, (ArH)7), 4.89 (s, 1H, CH), 2.43 (s, 3H, CH3). 19 F NMR (377 MHz, CDC13) δ -63.97 (3F), -113.97 (1F), -118.11 (1F). 13 C NMR (101 MHz, CDC13) δ 162.4 (d, J = 246.8 Hz), 159.3 (d, J = 242.7 Hz), 145.6, 136.3, 136.0 (q, J = 35.1 Hz), 131.6 (d, J = 3.5 Hz), 130.4 (d, J = 8.1 Hz), 125.2, 124.5 (d, J = 7.5 Hz), 123.1, 122.4, 120.7, 120.4, 120.0 (q, J = 275.3 Hz), 118.9, 117.7, 117.64, 117.55, 116.6, 115.2 (d, J = 3.7 Hz), 115.01 (d, J = 3.7 Hz), 114.95 (d, J = 21.2 Hz), 114.8, 40.6, 16.5. HRMS (ESI) m / z: calcd for C 25 H 15 F5NO[M-H] -440.1079, found: 440.1076.

[0045] I-11: pale yellow liquid, yield 53%. 1 H NMR (400 MHz, CDC13) δ 7.98 (s, 1H, NH), 7.42-7.34 (m, 1H, ArH), 7.33-7.27 (m, 2H, (ArH)2), 7.17-7.10 (m, 3H, (ArH)3), 7.04-6.98 (m, 1H, ArH), 6.92-6.87 (m, 1H, ArH), 6.82-6.73 (m, 3H, (ArH)3), 6.41-6.32 (m, 1H, ArH), 5.10 (s, 1H, CH). 19 F NMR (377 MHz, CDC13) δ -65.75 (3F), -118.19 (1F). 13 C NMR (101 MHz, CDC13) δ 159.3 (d, J = 242.7 Hz), 145.6, 136.7, 136.5 (q, J = 35.2 Hz), 133.7, 132.3, 132.0, 129.2 (d, J = 22.2 Hz), 125.9, 125.8, 124.1 (d, J = 7.5 Hz), 122.9, 122.4, 120.1, 120.0 (q, J = 275.3 Hz), 118.9, 117.7 (d, J = 8.4 Hz), 117.4, 116.9, 115.6, 115.4, 115.1, 111.5, 38.1. HRMS (ESI) m / z: calcd for C 24 H 13 ClF4NO[M-H] - 442.0627, found: 442.0630.

[0046] I-12: pale yellow liquid, yield 95%. 1 H NMR (400 MHz, CDC13) δ 7.88 (s, 1H, NH), 7.36-7.30 (m, 1H, ArH), 7.28-7.24 (m, 1H, ArH), 7.19-6.99 (m, 4H, (ArH)4), 6.91-6.82 (m, 2H, (ArH)2), 6.78-6.72 (m, 2H, (ArH)2), 6.55-6.48 (m, 1H, ArH), 6.40-6.32 (m, 1H, ArH), 5.07 (s, 1H, CH), 3.83 (s, 3H, OCH3). 19 F NMR (377 MHz, CDC13) δ -65.28 (3F), -118.81 (1F).13 C NMR (101 MHz, CDC13) δ 159.2 (d, J = 242.1 Hz), 156.1, 145.9, 136.6, 135.8 (q, J = 34.3 Hz), 131.6, 129.2, 125.9, 124.7 (d, J = 7.4 Hz), 123.8, 122.7, 122.2, 120.0 (q, J = 275.3 Hz), 119.8 (d, J = 11.9 Hz), 119.0, 117.6, 117.5, 115.5, 115.3, 115.0, 114.8, 111.4, 110.4, 55.6, 38.1. HRMS (ESI) m / z: calcd for C 25 H 16 F4NO2[M-H] - 438.1123, found: 438.1121.

[0047] I-13: pale yellow liquid, yield 80%. 1 H NMR (400 MHz, CDC13) δ 7.86 (s, 1H, NH), 7.41-7.35 (m, 1H, ArH), 7.31-7.24 (m, 1H, ArH), 7.22-6.94 (m, 5H, (ArH)5), 6.92-6.71 (m, 4H, (ArH)4), 6.67-6.58 (m, 1H, ArH), 4.91 (s, 1H, CH), 2.18 (s, 3H, CH3). 19 F NMR (377 MHz, CDC13) δ -64.00 (3F), -118.30 (1F). 13 C NMR (101 MHz, CDC13) δ 159.2 (d, J = 242.7 Hz), 145.9, 137.5, 136.7, 135.74 (q, J = 34.5 Hz), 135.69, 129.1, 128.6, 127.8, 125.79, 125.76, 124.9 (d, J = 7.5 Hz), 122.7, 122.4, 120.3, 120.1, 120.0 (q, J = 275.3 Hz), 119.0, 117.7, 117.6, 117.3, 115.1, 111.5 (d, J = 24.2 Hz), 40.6, 21.3. HRMS (ESI) m / z: calcd for C 25 H 16 F4NO[M-H] - 422.1174, found: 422.1170.

[0048] I-14: colorless liquid, yield 55%. 1H NMR (400 MHz, CDC13) δ 7.89 (s, 1H, NH), 7.28-7.23 (m, 1H, ArH), 7.13-7.07 (m, 1H, ArH), 7.03-6.99 (m, 2H, (ArH)2), 6.98-6.95 (m, 2H, (ArH)2), 6.87-6.83 (m, 2H, (ArH)2), 6.78-6.75 (m, 2H, (ArH)2), 6.67-6.59 (m, 1H, ArH), 4.90 (s, 1H, CH), 2.42 (s, 3H, CH3), 2.20 (s, 3H, CH3). 19 F NMR (377 MHz, CDC13) δ -64.13 (3F), -118.47 (1F). 13 C NMR (101 MHz, CDC13) δ 159.2 (d, J = 242.5 Hz), 145.8, 137.5, 136.3, 135.75 (q, J = 34.8 Hz), 135.69, 129.0, 128.6, 127.7, 125.8, 125.3, 123.5, 122.9, 122.3, 120.5, 120.2, 120.0 (q, J = 275.3 Hz), 118.7, 117.9, 117.6 (d, J = 8.3 Hz), 116.7, 114.9 (d, J = 25.2 Hz), 111.7, 40.6, 21.3, 16.5. HRMS (ESI) m / z: Calcd for C 26 H 18 F4NO[M-H] - 436.1330, found: 436.1331. I-15: yellowish liquid, yield 78%. 1 H NMR (400 MHz, CDC13) δ 7.94 (s, 1H, NH), 7.43-7.37 (m, 1H, ArH), 7.35-7.29 (m, 1H, ArH), 7.19-7.13 (m, 1H, ArH), 7.13-7.08 (m, 1H, ArH), 7.07-7.02 (m, 1H, ArH), 6.97-6.92 (m, 2H, (ArH)2), 6.90-6.85 (m, 2H, (ArH)2), 6.80-6.72 (m, 3H, (ArH)3), 4.91 (s, 1H, CH), 2.26 (s, 3H, CH3). 19 F NMR (377 MHz, CDC13) δ -63.94 (3F), -118.38 (1F). 13C NMR (101 MHz, CDC13) δ 159.2 (d, J = 242.5 Hz), 145.8, 135.8 (q, J = 34.5 Hz), 136.7, 135.6, 132.8, 128.9, 128.6, 128.4, 125.7, 124.8, 122.7, 122.4, 120.1, 120.0 (q, J = 275.3 Hz), 119.0, 117.7, 117.6, 117.4, 115.0 (d, J = 23.2 Hz), 111.5, 40.6, 21.2. HRMS (ESI) m / z: calcd for C 25 H 16 F4NO[M-H] - 422.1174, found: 422.1172.

[0049] I-16: pale yellow liquid, yield 58%. 1 H NMR (400 MHz, CDC13) δ 7.84 (s, 1H, NH), 7.30-7.25 (m, 1H, ArH), 7.12-7.05 (m, 1H, ArH), 7.00-6.92 (m, 4H, (ArH)4), 6.87-6.73 (m, 5H, (ArH)5), 4.89 (s, 1H, CH), 2.41 (s, 3H, CH3), 2.25 (s, 3H, CH3). 19 F NMR (377 MHz, CDC13) δ -64.00 (3F), -118.45 (1F). 13 C NMR (101 MHz, CDC13) δ 159.2 (d, J = 242.6 Hz), 145.7, 137.5, 136.3, 135.8 (q, J = 34.5 Hz), 132.8, 128.6, 128.4, 125.2, 124.9 (d, J = 7.5 Hz), 123.0, 122.3, 120.5, 120.29 (q, J = 275.3 Hz), 120.26, 120.0 (q, J = 2.4 Hz), 117.9, 117.6, 117.5, 116.7, 114.9 (d, J = 22.2 Hz), 40.6, 21.2, 16.5. HRMS (ESI) m / z: calcd for C 26 H 18 F4NO[M-H] - 436.1330, found: 436.1228.

[0050] I-17: pale yellow liquid, yield 56%. 1H NMR (400 MHz, CDC13) δ 7.96 (s, 1H, NH), 7.42-7.38 (m, 1H, ArH), 7.34-7.29 (m, 1H, ArH), 7.19-7.03 (m, 3H, (ArH)3), 6.90-6.85 (m, 2H, (ArH)2), 6.81-6.74 (m, 3H, (ArH)3), 6.70-6.66 (m, 2H, (ArH)2), 4.90 (s, 1H, CH), 3.72 (s, 3H, OCH3). 19 F NMR (377 MHz, CDC13) δ -64.03 (3F), -118.51 (1F). 13 C NMR (101 MHz, CDC13) δ 159.2 (d, J = 242.6 Hz), 159.1, 145.7, 136.7, 135.9 (q, J = 34.2 Hz), 129.7, 127.9, 125.7, 124.8 (d, J = 7.5 Hz), 122.7, 122.4, 120.3 (q, J = 275.3 Hz), 120.1, 119.7 (q, J = 2.3 Hz), 119.0, 117.7, 117.6, 117.4, 115.0 (d, J = 23.2 Hz), 113.3, 111.5, 55.1, 40.6. HRMS (ESI) m / z: calcd for C 25 H 16 F4NO2[M-H] - 438.1123, found: 438.1120.

[0051] I-18: pale yellow liquid, yield 50%. 1 H NMR (400 MHz, CDC13) δ 8.00 (s, 1H, NH), 7.39-7.31 (m, 1H, ArH), 7.23-7.18 (m, 1H, ArH), 7.17-7.04 (m, 2H, (ArH)2), 7.03-6.95 (m, 1H, ArH), 6.93-6.86 (m, 1H, ArH), 6.86-6.79 (m, 2H, (ArH)2), 6.79-6.70 (m, 3H, (ArH)3), 4.85 (s, 1H, CH), 3.74 (s, 3H, OCH3). 19 F NMR (377 MHz, CDC13) δ -64.31 (3F), -117.92 (1F). 13C NMR (101 MHz, CDC13) δ 159.3 (d, J = 243.0 Hz), 154.2, 145.6, 137.7, 136.0 (q, J = 34.8 Hz), 131.7, 131.3, 131.0, 129.4, 127.6, 125.9, 124.2 (d, J = 7.4 Hz), 123.3, 121.8, 120.0 (q, J = 274.5 Hz), 118.3, 117.5 (d, J = 8.4 Hz), 116.5, 115.3 (d, J = 24.2 Hz), 112.7 (d, J = 60.6 Hz), 100.0, 55.5, 40.4. HRMS (ESI) m / z: calcd for C 25 H 15 BrF4NO2[M-H] - 516.0226, found: 516.0228. I-19: yellowish liquid, yield 50%. 1 H NMR (400 MHz, CDC13) δ 8.08 (s, 1H, NH), 7.48-7.43 (m, 1H, ArH), 7.36-7.31 (m, 1H, ArH), 7.21-7.16 (m, 2H, (ArH)2), 7.13-6.99 (m, 3H, (ArH)3), 6.92-6.78 (m, 3H, (ArH)3), 6.70-6.67 (m, 1H, ArH), 4.96 (s, 1H, CH). 19 F NMR (377 MHz, CDC13) δ -63.84 (3F), -117.74 (1F). 13 C NMR (101 MHz, CDC13) δ 159.4 (d, J = 243.0 Hz), 145.2, 137.3 (q, J = 34.6 Hz), 136.7, 135.7, 128.2, 126.4 (d, J = 20.2 Hz), 125.8, 124.6 (d, J = 7.6 Hz), 123.2, 122.5, 120.3 (q, J = 274.5 Hz), 120.2, 118.8, 117.9, 117.8, 117.6, 115.3 (d, J = 12.4 Hz), 114.9 (d, J = 12.0 Hz), 113.4, 111.6, 40.5. HRMS (ESI) m / z: calcd for C 22 H 12 F4NOS[M-H] - 414.0581, found: 414.0579.

[0052] I-20: colorless liquid, yield 77%. 1H NMR (400 MHz, CDC13) δ 7.95 (s, 1H, NH), 7.41-7.35 (m, 1H, ArH), 7.33-7.27 (m, 1H, ArH), 7.26-7.08 (m, 8H, (ArH)8), 7.00-6.82 (m, 3H, (ArH)3), 4.91 (s, 1H, CH). 19 F NMR (377 MHz, CDC13) δ -64.13. 13 C NMR (101 MHz, CDC13) δ 148.2, 136.7, 135.7 (q, J = 34.7 Hz), 135.6, 129.3, 128.9, 128.5, 128.2, 127.93, 127.89, 125.7, 124.8, 122.8, 122.5, 120.7 (q, J = 2.3 Hz), 120.2 (q, J = 274.5 Hz), 120.1, 119.0, 117.8, 117.2, 111.5, 40.2. HRMS (ESI) m / z: calcd for C 24 H 14 ClF3NO [M-H] - 424.0721, found: 424.0724.

[0053] I-21: pale yellow liquid, yield 53%. 1 H NMR (400 MHz, CDC13) δ 7.79 (s, 1H, NH), 7.53-7.46 (m, 2H, (ArH)2), 7.45-7.41 (m, 1H, ArH), 7.40-7.33 (m, 4H, (ArH)4), 7.29-7.22 (m, 2H, (ArH)2), 7.14-7.09 (m, 1H, ArH), 7.04-6.92 (m, 5H, (ArH)5), 6.80-6.75 (m, 2H, (ArH)2), 4.93 (s, 1H, CH), 2.27 (s, 3H, CH3). 19 F NMR (377 MHz, CDC13) δ -63.85. 13C NMR (101 MHz, CDC13) δ 149.5, 140.6, 140.3, 138.1, 136.7, 135.9 (q, J = 34.2 Hz), 135.3, 129.0, 128.8, 127.4, 127.0, 126.5, 126.2, 125.9, 125.5, 122.6, 122.3, 120.8, 120.4 (q, J = 274.5 Hz), 120.3, 119.9, 119.2, 118.2, 116.6, 111.4, 40.0, 21.1. HRMS (ESI) m / z: calcd for C 31 H 21 F3NO[M-H] - 480.1581, found: 480.1580.

[0054] I-22: pale yellow liquid, yield 54%. 1 H NMR (400 MHz, CDC13) δ 7.93 (s, 1H, NH), 7.40-7.35 (m, 1H, ArH), 7.33-7.29 (m, 1H, ArH), 7.17-7.08 (m, 2H, (ArH)2), 7.04-6.78 (m, 6H, (ArH)6), 6.70-6.62 (m, 1H, ArH), 6.62-6.54 (m, 1H, ArH), 4.91 (s, 1H, CH), 2.30 (s, 3H, CH3). 19 F NMR (377 MHz, CDC13) δ -64.31 (3F), -113.60 (IF). 13 C NMR (101 MHz, CDC13) δ 162.1 (d, J = 246.0 Hz), 149.3, 138.3, 138.2, 136.7, 136.1 (q, J = 34.8 Hz), 129.3 (d, J = 8.4 Hz), 128.8, 125.8, 125.6, 124.5, 122.4, 122.3, 120.1 (q, J = 274.5 Hz), 120.0, 119.9, 119.6, 119.0, 117.9, 116.6, 115.7 (d, J = 22.1 Hz), 114.6 (d, J = 21.0 Hz), 111.3, 39.8, 21.0. HRMS (ESI) m / z: calcd for C 25 H 16 F4NO[M-H] - 422.1174, found: 422.1174.

[0055] I-23: pale yellow liquid, yield 81%. 1H NMR (400 MHz, CDC13) δ 7.89 (s, 1H, NH), 7.40-7.35 (m, 1H, ArH), 7.31-7.27 (m, 1H, ArH), 7.17-7.08 (m, 3H, (ArH)3), 7.04-6.92 (m, 3H, (ArH)3), 6.84-6.76 (m, 4H, (ArH)4), 4.88 (s, 1H, CH), 2.29 (s, 3H, CH3). 19 F NMR (377 MHz, CDC13) δ -64.00. 13 C NMR (101 MHz, CDC13) δ 149.2, 138.2, 136.7, 136.0 (q, J = 34.4 Hz), 134.6, 133.6, 130.0, 128.8, 128.1, 125.7, 125.6, 122.5, 122.3, 120.2 (q, J = 274.5 Hz), 120.0, 119.8, 119.6 (q, J = 2.7 Hz), 119.1, 117.8, 116.6, 111.4, 39.9, 21.0. HRMS (ESI) m / z: calcd for C 25 H 16 ClF3NO[M-H] - 438.0878, found: 438.0883.

[0056] I-24: pale yellow liquid, yield 70%. 1 H NMR (400 MHz, CDC13) δ 7.89 (s, 1H, NH), 7.46-7.38 (m, 1H, ArH), 7.30-7.25 (m, 1H, ArH), 7.16-7.10 (m, 1H, ArH), 7.05-7.00 (m, 1H, ArH), 7.00-6.88 (m, 4H, (ArH)4), 6.86-6.81 (m, 1H, ArH), 6.81-6.72 (m, 3H, (ArH)3), 4.90 (s, 1H, CH), 2.29 (s, 3H, CH3), 2.26 (s, 3H, CH3). 19 F NMR (377 MHz, CDC13) δ -64.05. 13C NMR (101 MHz, CDC13) δ 149.5, 138.0, 137.4, 136.7, 135.8 (q, J = 34.1 Hz), 133.3, 128.8, 128.6, 128.5, 125.9, 125.5, 122.5, 122.2, 121.2, 120.5, 120.4 (q, J = 274.5 Hz), 119.9, 119.2, 118.2, 116.6, 111.4, 40.1, 21.2, 21.1. HRMS (ESI) m / z: calcd for C 26 H 19 F3NO[M-H] - 418.1424, found: 418.1426.

[0057] I-25: pale yellow liquid, yield 58%. 1 H NMR (400 MHz, CDC13) δ 7.95 (s, 1H, NH), 7.41-7.37 (m, 1H, ArH), 7.34-7.29 (m, 1H, ArH), 7.19-7.02 (m, 5H, (ArH)5), 6.87-6.83 (m, 1H, ArH), 6.81-6.73 (m, 3H, (ArH)3), 6.57-6.53 (m, 1H, ArH), 4.88 (s, 1H, CH), 3.64 (s, 3H, OCH3). 19 F NMR (377 MHz, CDC13) δ -64.07. 13 C NMR (101 MHz, CDC13) δ 156.3, 143.6, 136.7, 136.2 (q, J = 34.5 Hz), 134.6, 133.6, 130.0, 128.1, 125.7, 123.6, 122.6, 122.4, 120.4 (q, J = 274.5 Hz), 120.0, 119.0, 118.5 (q, J = 2.6 Hz), 117.4, 117.2, 114.1, 113.2, 111.4, 55.5, 40.5. HRMS (ESI) m / z: calcd for C 25 H 16 ClF3NO2[M-H] - 454.0827, found: 454.0825.

[0058] I-26: pale yellow liquid, yield 51%. 1H NMR (400 MHz, CDC13) δ 7.91 (s, 1H, NH), 7.19 - 7.07 (m, 4H, (ArH)4), 6.83 - 6.73 (m, 6H, (ArH)6), 6.60 - 6.53 (m, 1H, ArH), 4.82 (s, 1H, CH), 3.73 (s, 3H, OCH3), 3.64 (s, 3H, OCH3). 19 F NMR (377 MHz, CDC13) δ -64.12. 13 C NMR (101 MHz, CDC13) δ 156.4, 154.1, 143.7, 136.0 (q, J = 34.6 Hz), 134.6, 133.7, 131.7, 130.1, 128.1, 126.1, 123.4, 123.1, 120.2 (q, J = 274.5 Hz), 118.4 (q, J = 2.2 Hz), 117.1, 117.0, 114.2, 113.2, 112.9, 112.2, 100.2, 55.5, 55.4, 40.7. HRMS (ESI) m / z: calcd for C 26 H 18 ClF3NO3[M-H] - 484.0933, found: 484.0932. I-27: yellowish liquid, yield 53%. 1 H NMR (400 MHz, CDC13) δ 7.95 (s, 1H, NH), 7.46 - 7.40 (m, 1H, ArH), 7.34 - 7.28 (m, 1H, ArH), 7.18 - 7.12 (m, 1H, ArH), 7.10 - 7.00 (m, 2H, (ArH)2), 6.89 - 6.85 (m, 1H, ArH), 6.89 - 6.85 (m, 2H, (ArH)2), 6.75 - 6.71 (m, 1H, ArH), 6.69 - 6.65 (m, 2H, (ArH)2), 6.59 - 6.55 (m, 1H, ArH), 4.89 (s, 1H, CH), 3.73 (s, 3H, OCH3), 3.64 (s, 3H, OCH3). 19 F NMR (377 MHz, CDC13) δ -63.93. 13C NMR (101 MHz, CDC13) δ 159.0, 156.2, 143.8, 136.7, 136.0 (q, J = 34.6 Hz), 129.8, 128.4, 125.9, 124.1, 122.5, 122.2, 120.1 (q, J = 274.5 Hz), 119.9, 119.7, 119.2, 118.0, 117.1, 113.9, 113.2, 113.1, 111.3, 55.5, 55.1, 40.8. HRMS (ESI) m / z: calcd for C 26 H 19 F3NO3[M-H] - 450.1323, found: 450.1322.

[0059] I-28: pale yellow liquid, yield 83%. 1 H NMR (400 MHz, CDC13) δ 7.92 (s, 1H, NH), 7.39 - 7.30 (m, 2H, (ArH)2), 7.17 - 7.07 (m, 2H, (ArH)2), 7.05 - 6.99 (m, 1H, ArH), 6.97 - 6.88 (m, 2H, (ArH)2), 6.85 - 6.81 (m, 1H, ArH), 6.71 - 6.63 (m, 2H, (ArH)2), 6.60 - 6.54 (m, 2H, (ArH)2), 4.90 (s, 1H, CH), 3.78 (s, 3H, OCH3). 19 F NMR (377 MHz, CDC13) δ -64.00 (3F), -118.30 (IF). 13 C NMR (101 MHz, CDC13) δ 159.2 (d, J = 242.7 Hz), 145.9, 137.5, 136.7, 135.74 (q, J = 34.7 Hz), 135.69, 129.1, 128.6, 127.8, 125.79, 125.76, 124.9 (d, J = 7.5 Hz), 122.7, 122.4, 120.3, 120.2 (q, J = 274.5 Hz), 120.1, 119.0, 117.7, 117.6, 117.3, 115.1 (d, J = 24.2 Hz), 111.5, 40.6, 21.3. HRMS (ESI) m / z: calcd for C 25 H 16 F4NO2[M-H] - 438.1123, found: 438.1120.

[0060] I-29: pale yellow liquid, yield 75%. 1H NMR (400 MHz, CDC13) δ 7.92 (s, 1H, NH), 7.37-7.30 (m, 2H, (ArH)2), 7.18-7.09 (m, 3H, (ArH)3), 7.04-6.99 (m, 1H, ArH), 6.97-6.91 (m, 1H, ArH), 6.83-6.75 (m, 3H, (ArH)3), 6.70-6.67 (m, 1H, ArH), 6.58-6.53 (m, 1H, ArH), 4.87 (s, 1H, CH), 3.78 (s, 3H, OCH3). 19 F NMR (377 MHz, CDC13) δ -64.09. 13 C NMR (101 MHz, CDC13) δ 158.3, 148.9, 135.6, 134.8 (q, J = 34.9 Hz), 133.5, 132.6, 128.9, 128.7, 127.0, 124.7, 121.5, 121.3, 119.1 (q, J = 274.5 Hz), 118.9, 118.8 (q, J = 2.3 Hz), 118.0, 116.7, 113.7, 110.9, 110.3, 99.7, 54.5, 38.6. HRMS (ESI) m / z: calcd for C 25 H 16 ClF3NO2[M-H] - 454.0827, found: 454.0827.

[0061] The above target compounds can be obtained in moderate to high yield to meet the needs of new drug development.

[0062] Example 1

[0063]

[0064] First, under the condition of ice water bath, different 4-fluorobenzoic 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, and the reaction liquid was poured into an excess of pre-cooled sodium hydroxide solution under magnetic stirring, and white solid was precipitated within a few minutes. After filtration, water washing and drying, the intermediate 2-(4-fluorophenyl)-1-(4-methoxyphenyl)ethan-1-one (IV-1) was obtained.

[0065] Sodium hydride (2.0 eq, 12 mmol), ethyl trifluoroacetate (4.0 eq, 24 mmol), intermediate 2-(4-fluorophenyl)-l-(4-methoxyphenyl)ethan-l-one (compound VI-1, 1.0 eq, 6 mmol) were added into a Schlenk flask under argon atmosphere, followed by adding solvent tetrahydrofuran (25 mL), and then the reaction system was heated to reflux for 12 h. Subsequently, the reaction flask was placed in an ice-water bath under argon atmosphere, and after the liquid in the reaction system was completely cooled, triflic anhydride (2.0 eq, 12 mmol) was slowly added dropwise into the system and reacted for 10 min. Subsequently, the reaction was quenched by adding water, and the reaction liquid was extracted with ethyl acetate, the organic layer was collected and the solvent was concentrated under vacuum, and the pure product (E)-3,3,3-trifluoro-l-(4-fluorophenyl)prop-l-en-2-yl trifluoromethanesulfonate (III-1) was obtained by silica gel column separation and purification.

[0066] Subsequently, (E)-3,3,3-trifluoro-l-(4-fluorophenyl)prop-l-en-2-yl trifluoromethanesulfonate (intermediate III-1, 2.0 eq, 6.0 mmol), salicylaldehyde (1.0 eq, 3.0 mmol), tetrahydro-pyrrole (2.0 eq, 6.0 mmol) and solvent ethanol (6 mL) were added into a Schlenk flask under argon atmosphere, and heated to 65°C under magnetic stirring for 8 h. After the reaction was completed by TLC monitoring, the reaction was extracted with ethyl acetate and the solvent was removed by concentration under reduced pressure, and then the intermediate 2-trifluoromethyl-2-hydroxy-3-(4-fluorophenyl)-2H-chromene (II-1) was obtained by silica gel column chromatography.

[0067] Finally, 2-trifluoromethyl-2-hydroxy-3-(4-fluorophenyl)-2H-chromene (II-1, 1.0 eq, 1.0 mmol), indole (1.2 eq, 1.2 mmol), p-toluenesulfonic acid (0.5 eq, 0.5 mmol) and solvent acetonitrile (5 mL) were sequentially added into a reaction flask, and stirred at 40°C for 12 h. After the reaction was completed, the target compound I-1 was obtained by extraction with ethyl acetate, concentration, and separation by silica gel column chromatography.

[0068] The preparation of target compounds I-2 to I-29 can be carried out by referring to the preparation of target compound I-1, and changing the corresponding different substituents of the raw materials.

[0069] Example 2

[0070] Cytotoxicity assay of 3-(2-trifluoromethyl-3-aryl-4H-chromen-4-yl)-lH-indole derivatives (I)

[0071] Cell viability was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The test concentration of compound (I) and 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 96-well plate, and the culture condition was DMEM complete medium with 10% fetal bovine serum and 1% penicillin and streptomycin, and the plate was placed in a 37°C incubator with 5% CO2. After 24 h of inoculation, compound (I) or positive drug (both dissolved in DMSO, and the final concentration of DMSO was 0.5%) was added, and 1 h later, lipopolysaccharide (LPS) was added to make the final concentration 1 μg / mL. 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. Then 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 a microplate reader. The test results are shown in Table 1. Figure 1 All the compounds had no cytotoxicity at the test concentration.

[0072] Example 3

[0073] Determination of the inhibitory effect of 3-(2-trifluoromethyl-3-aryl-4H-chromen-4-yl)-1H-indole derivatives (I) on NO release

[0074] The inflammatory effect is related to many inflammatory mediators, including cytokines, NO and enzymes, which are released when macrophages produce different phenotypes in response to stimulation. NO is catalyzed by iNOS and is considered an important mediator in the inflammatory process, which can 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 Griess reagent. RAW 264.7 cell line was selected for the determination. 1 x 10 5 cells were inoculated in each well of 96-well plate, and the culture condition was DMEM complete medium with 10% fetal bovine serum and 1% penicillin and streptomycin, and the plate was placed in a 37°C incubator with 5% CO2. After 24 h of inoculation, compound (I) or positive drug (both dissolved in DMSO, and the final concentration of DMSO was 0.5%) was added, and 1 h later, lipopolysaccharide (LPS) was added to make the final concentration 1 μg / mL. 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. Then 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 a microplate reader. The test results are shown in Table 1.

[0075] The results are shown in Table 2. Figure 2Most of the compounds were able to inhibit NO release to some extent, i.e. they had anti-inflammatory activity in vitro. The structure-activity relationship (SAR) derived from the preliminary results of this Example indicated that the anti-inflammatory effect was better when there was a methoxy group at the 6- or 7-position of the chromene ring, as shown by comparing I-23, I-25 and I-29; and the effect was better when there was a chloro atom at the para position of the phenyl ring at the 3-position of the chromene, as shown by comparing I-25 and I-27. Since compounds I-25, I-26 and I-29 showed stronger inhibitory effects on NO release than the positive drug indomethacin, the IC50values of these three compounds were further determined by concentration gradient tests (Table 1). The IC50value of I-25 was the lowest (IC50= 4.82 ± 0.34 μM) among the four compounds tested, and was comparable to that of the positive drug indomethacin (IC50= 4.93 ± 0.56 μM). Therefore, I-25 was determined to be an active compound for further determination of anti-inflammatory activity in vivo. 50 50 50 50

[0076] Table 1 Inhibitory effects of some target compounds on NO release

[0077]

[0078] *RAW264.7 cells were pre-treated with different concentrations (20, 10, 5, 2.5 and 1.25 μM) of the compounds for 1 h, and then LPS (1 μg / mL) was added for co-culture for 24 h; the NO concentration in the culture supernatant was determined by Griess reagent.

[0079] Example 4

[0080] Inhibitory effect of compound I-25 on carrageenan-induced rat paw edema

[0081] ​​​​The rat paw edema model induced by carrageenan 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 given target compound I-25 or positive drug indomethacin (suspended in 0.5% CMC-Na) by gavage at a dose of 20 mg / kg. After 1 h, 0.1 mL of 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 given the vehicle by gavage. The paw volume was measured using a plethysmograph (Ugo Basile, Italy) before carrageenan injection and at 1, 3 and 5 h after injection, respectively. The results are shown in Table 2. After 5 h of injection, the inhibition rates of I-25 and the positive drug indomethacin on rat paw edema were almost the same, 29.63% and 27.78%, respectively, indicating that I-25 has a certain inhibitory effect on acute inflammation in rats.

[0082] Table 2 Inhibition of rat paw edema induced by carrageenan by I-25

[0083]

[0084] * Ctrl (vehicle; 0.5% CMC-Na), Indomethacin, and I-25 suspended in 0.5% CMC-Na. n=6.

[0085] Example 5

[0086] Inhibition of cotton pellet-induced granuloma in mice by compound I-25

[0087] Chronic inflammation has obvious granuloma characteristics and multinucleated giant cells. Cotton pellet-induced granuloma is a chronic inflammation model that can be used to evaluate the inhibitory effect of a compound on tissue hyperplasia in the later stage of inflammation. Male C57Bl / 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 and disinfected under sterile conditions, and then two sterile cotton pellets (10 mg) were implanted subcutaneously on both sides of the scapula of the mice by aseptic surgery. Starting from the day of the operation, the mice were given target compound I-25 (20 mg / kg), positive drug indomethacin (20 mg / kg) or vehicle (0.5% CMC-Na) by gavage every 24 h for 7 consecutive days. On the 8th day of the experiment, after the mice were sacrificed with CO2, the cotton pellets surrounded by hyperplastic tissue were carefully peeled off, 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. The results are shown in Table 3. After 8 days of operation, the inhibition rates of I-25 and the positive drug indomethacin on cotton pellet-induced granuloma in mice were 23.33% and 22.22%, respectively, indicating that I-25 has a certain inhibitory effect on the hyperplasia of granuloma tissue in mice. Figure 3As shown, I-25 at both test concentrations significantly inhibited the granulation tissue proliferation caused by the cotton pellet implantation subcutaneously, and showed a dose-dependent manner. In addition, there was no significant difference in the inhibition rate between the I-25 group at 10 mg / kg and the indomethacin group at 20 mg / kg; while at the same test concentration (20 mg / kg), the granulation weight in the I-25 group (average weight of granulation 20.4 mg, inhibition rate 43.2%) was significantly lower than that in the positive drug indomethacin group (average weight of granulation 35.9 mg, inhibition rate 32.0%). The results of this test proved that the compound I-25 has good anti-inflammatory ability in vivo, and has a certain therapeutic effect on the symptoms such as tissue proliferation in chronic inflammatory response.

[0088] Example 6

[0089] Inhibition of acetic acid-induced writhing in mice by compound I-25

[0090] The acetic acid-induced writhing model in mice can be used to evaluate the analgesic effect of a compound in animals. Male C57Bl / 6 mice weighing 26-28 g were randomly divided into 4 groups, 6 mice in each group. 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 response 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 test results are shown in Table 2. Figure 4 As shown, I-25 at both test concentrations significantly inhibited the granulation tissue proliferation caused by the cotton pellet implantation subcutaneously, and showed a dose-dependent manner. In addition, there was no significant difference in the inhibition rate between the I-25 group at 10 mg / kg and the indomethacin group at 20 mg / kg; while at the same test concentration (20 mg / kg), the granulation weight in the I-25 group (average weight of granulation 20.4 mg, inhibition rate 43.2%) was significantly lower than that in the positive drug indomethacin group (average weight of granulation 35.9 mg, inhibition rate 32.0%). The results of this test proved that the compound I-25 has good anti-inflammatory ability in vivo, and has a certain therapeutic effect on the symptoms such as tissue proliferation in chronic inflammatory response.

[0091] Example 7

[0092] Anti-inflammatory and analgesic effects of compound I-25 in adjuvant-induced arthritis model in rats

[0093] 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 5 (D) This also suggests that compound I-25 can clinically alleviate tenderness symptoms in rheumatoid arthritis. Furthermore, compound I-25 can improve splenomegaly induced by adjuvant injection, indicating that it may have some immunomodulatory effects. In summary, I-25 has positive significance for treating symptoms and pain in patients with rheumatoid arthritis and improving their quality of life.

[0094] Example 8

[0095] Determination of Compound I-25-induced acute gastric ulcer levels in rats

[0096] One of the controversial aspects of the clinical use of NSAIDs is their serious side effects, the most frequent of which are gastrointestinal side effects (2-4% of patients who take them annually develop serious complications), which also leads to the fact that current NSAIDs do not fully meet the medical needs. Therefore, improving the safety of NSAIDs in the digestive tract is of great importance for their use in a wider range of patients and for long-term use. Thus, we studied the potential ulcerogenic effect of compound I-25 administered orally to rats.

[0097] 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:

[0098] 1. The diameter of the ulcer lesion was measured with a vernier caliper.

[0099] 2. Ulcers were defined as grade I, ulcerated areas less than 1 mm in diameter; grade II, ulcerated areas between 1 and 3 mm in diameter; and grade III, ulcerated areas greater than 3 mm in diameter.

[0100] 3. The sum of the ulcer readings for each group of 5 test animals was 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.

[0101] 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, a total of 12 grade I and II ulcer lesions, without grade III ulcers, with an Ulcer Index of 15, much lower than the ulcer damage caused by indomethacin at a concentration of 50 mg / kg.

[0102] Table 3 Comparison of the acute gastric ulcerogenic effect of I-25 and indomethacin in rats

[0103]

[0104] * Ctrl (vehicle; 0.5% CMC-Na), Indomethacin and I-25 suspended in 0.5% CMC-Na. n=5.

[0105] The above embodiments are only the preferred embodiments of the present application, and the protection scope of the present application is not limited thereto. Any equivalent substitutions or changes made by those skilled in the art based on the present application shall fall within the protection scope of the present application, and the protection scope of the present application is subject to the claims.

Claims

1. A 3-(2-trifluoromethyl-3-aryl-4 H - chromen-4-yl) - 1 H - indole derivative, characterized in that, Any one of the following structures: 。 2. An anti-inflammatory medicament, characterized by, The composition comprises 3-(2-trifluoromethyl-3-aryl-4 H - chromen-4-yl)-1 H - indole derivatives.

3. A process for the preparation of 3-(2-trifluoromethyl-3-aryl-4 H - chromen-4-yl) - 1 H - indole derivatives as claimed in claim 1, characterized in that, In the formulae (I) - (V), R 1 , R 2 , R 3 are as defined in claim 1, and the synthetic route is:

4. The 3-(2-trifluoromethyl-3-aryl-4 H - chromen-4-yl) -1 H - indole derivatives, characterized by, The specific synthesis method is: 2-aryl-substituted carboxylic acid shown in formula (V) as raw material, by Fu-Cl acylation reaction to generate ketone compound shown in formula (IV); The ketone compound represented by formula (IV) is used as a raw material to generate the compound represented by formula (III) through an ester / ketone exchange reaction Z -trifluoromethyl alkyl ene triflate compound; starting from a compound of formula (III) Z - trifluoromethyl alkyl sulfonate compound as a raw material, and R 2 substituted salicylaldehyde condensation cyclization reaction to generate 2-trifluoromethyl-2-hydroxy-3-aryl-2 H - chromene; Again, 2-trifluoromethyl-2-hydroxy-3-aryl-2 H - chromene as a starting material, and R 3 substituted indole undergoes nucleophilic substitution reaction to generate 3-(2- trifluoromethyl-3-aryl-4 H - chromen-4-yl) -1 H - indole derivatives.

5. Use of a 3-(2-trifluoromethyl-3-aryl-4H-chromen-4-yl)-1 H-indole derivative according to claim 1, characterized in that, For preparing anti-inflammatory and analgesic drugs.

6. Use of a 3-(2-trifluoromethyl-3-aryl-4H-chromen-4-yl)-1 H-indole derivative according to claim 5, characterized in that, For preparing drugs for treating acute and chronic inflammation.

7. Use of a 3-(2-trifluoromethyl-3-aryl-4H-chromen-4-yl)-1 H-indole derivative according to claim 6, characterized in that, Acute and chronic inflammation is rheumatoid arthritis.

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