A trifluoromethyl imine derivative, preparation method and application

Abstract

The application belongs to the field of pharmaceutical chemicals, and discloses a trifluoromethyl imine derivative, a preparation method and application. 1 is selected from C35 or the following multi-methylene saturated alkyl and unsaturated hydrocarbon chain, R 2 is selected from (R 3 ) n is selected from methyl, methoxy or a combination thereof, m is 0 or 1, the wavy line is a connection position; X is selected from NH and O; 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, and some compounds show better anti-inflammatory and analgesic effects than commercially available non-steroidal anti-inflammatory drugs.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical chemicals, specifically to a trifluoromethylimine derivative, its preparation method, and its application. Background Technology

[0002] Inflammation is one of the most important processes in the body's defense system; however, it often develops into diseases requiring drug treatment, manifesting as pain or chronic damage. Furthermore, inflammation is associated with a variety of diseases, such as atherosclerosis, Alzheimer's disease, Parkinson's disease, rheumatoid arthritis, and diabetes. Worldwide, the most widely used drugs for anti-inflammation, rheumatic diseases, osteoarthritis, and pain relief are primarily nonsteroidal anti-inflammatory drugs (NSAIDs). Approximately 30 million people regularly take these medications. However, due to the predominantly exposed carboxyl groups in their structure and poor selectivity for COX-2 and COX-1, NSAIDs have significant side effects, such as approximately 107,000 people seeking medical attention annually for NSAID-related stomach problems, kidney damage, cardiotoxicity, and platelet inhibition (increasing mortality from gastrointestinal bleeding). Therefore, current NSAIDs are insufficient to meet medical needs. The safety of NSAIDs is a major concern worldwide, but it is undeniable that the overall benefits of using NSAIDs outweigh the risks (European Medicines Agency, 2006), especially in the treatment of arthritis and pain, where treatment still relies heavily on NSAIDs. Therefore, developing novel, highly selective NSAIDs with fewer side effects is of great significance. Summary of the Invention

[0003] Phospholipase A2 (PLA2) is a core enzyme in the arachidonic acid cascade reaction, and its activation has become an important promoter in the pathogenesis of many inflammatory and neurodegenerative diseases, including multiple sclerosis and Alzheimer's disease. PLA2 activation is a crucial event in the inflammatory response associated with many acute and chronic neuropathies (J. Am. Chem. Soc. 1986. 108, 3146-3147. Bioorg. Med. Chem. Lett. 1997, 7(11), 1421-1426.). Many researchers have reported that targeting PLA2 may offer an attractive approach for treating inflammatory diseases such as rheumatoid arthritis and asthma (Nat. Med. 2002, 8, 480-484.). In recent decades of research, researchers have gradually demonstrated that trifluoromethyl ketones, especially arachidonic acid trifluoromethyl ketone (AACOCF3), have excellent anti-inflammatory effects as PLA2 inhibitors. In summary, the design concept of this invention is to combine the anti-inflammatory activity of trifluoromethyl ketone and hydrazide compounds that are reported cyclooxygenase-2 (COX-2) inhibitors, and to synthesize trifluoromethylimine derivatives (trifluoromethyl hydrazone compounds and their bioisosteric trifluoromethyl oxime ester compounds) with higher activity and fewer side effects by using the splicing principle.

[0004] Based on the above research, in order to solve the problems existing in the prior art, this invention designs and synthesizes a trifluoromethylimine derivative with good anti-inflammatory activity. Specifically, the trifluoromethylimine derivative provided by this invention has the structure shown in the following general formula (I).

[0005]

[0006] in,

[0007] R 1 Selected from saturated or unsaturated hydrocarbon groups with fewer than 35 carbon atoms, preferably -C8H. 17 ,-C9H 19 ,-C 11 H 23 ,-C 13 H 27 ,-C 15 H 31 ,-C 17 H 35 ,-C 21 H 43 ,-(Z)-C7H 14 CH=CHC8H 17 ,-(Z,Z)-C7H 14 CH=CHCH2CH=CHC5H 11 ,

[0008] -(Z,Z,Z)-C7H14 CH=CHCH2CH=CHCH2CH=CHC2H5,

[0009] -(Z,Z,Z,Z)-C2H4CH=CHCH2CH=CHCH2CH=CHCH2CH=C5H 11 Any one of them;

[0010] R 2 Selected from (R 3 ) n Selected from any one or a combination of methyl, methoxy, m is 0 or 1, and the wavy line indicates the connection position; X is selected from NH, O.

[0011] Preferably, the compound represented by general formula (I) is selected from one of the following structural formulas:

[0012]

[0013]

[0014]

[0015] This invention also provides a method for preparing any of the above-mentioned trifluoromethylimine derivatives (I), wherein the synthetic route of the compound represented by formula (I) is as follows:

[0016]

[0017] In equations (I)-(VII), R 1 R 2 The definition is the same as that in claim 1;

[0018] The specific synthesis method is as follows:

[0019] Using carboxylic acids with C35 or less polymethylene saturated alkyl and unsaturated hydrocarbon chains as raw materials, Friedel-Crafts acylation reaction is carried out to generate ketone compounds as shown in formula (VI);

[0020] Using the ketone compound shown in formula (VI) as a raw material, a trifluoromethyl ketone compound shown in formula (V) is generated through an ester / ketone exchange reaction;

[0021] Using the ester compound shown in formula (IV) as a raw material, the ester undergoes ammonolysis to generate the acylhydrazine compound shown in formula (III);

[0022] Using the trifluoromethyl ketone compound shown in formula (V) and the acyl hydrazine compound shown in formula (III) as raw materials, a condensation reaction is carried out to generate the trifluoromethyl imine derivative shown in formula (I) (X = NH, such as: I-1 to I-35).

[0023] Using the trifluoromethyl ketone compound shown in formula (V) as a raw material, a condensation reaction is carried out to generate the oxime compound shown in formula (II);

[0024] Then, using the oxime compound shown in formula (II) as a raw material, a condensation reaction is carried out to generate the trifluoromethylimine derivative shown in formula (I) (X=O, such as: I-36 to I-52).

[0025] The present invention also provides the use of any of the above-mentioned trifluoromethylimine derivatives (I), specifically for the preparation of anti-inflammatory and analgesic drugs.

[0026] Preferably, the medication used in the experiment, but not limited to, the examples, is for treating acute and chronic inflammation and pain.

[0027] The trifluoromethylimine derivative (I) provided by this invention can be used as an effective ingredient in drugs for treating acute and chronic inflammation and associated hyperplasia and pain.

[0028] The advantages of this invention compared to the prior art are:

[0029] The compounds provided by the invention can be used to prepare anti-inflammatory and analgesic drugs for the treatment of acute and chronic inflammatory reactions, tissue redness, swelling, and pain. Some compounds exhibit better anti-inflammatory and analgesic effects than commercially available nonsteroidal anti-inflammatory drugs. Attached Figure Description

[0030] Figure 1 It is a cell viability assay for trifluoromethylimine derivative (I);

[0031] Figure 2 It is the inhibitory effect of trifluoromethylimine derivative (I) on NO release;

[0032] Figure 3 The therapeutic effects of compound I-26 on adjuvant-induced arthritis in rats: the effects of compound I-26 on (A) body weight, (B) left hind paw volume, (C) arthritis score and (D) 50% mechanical pain threshold (50% MWT) in AIA rats. Detailed Implementation

[0033] To enable those skilled in the art to better understand and implement the technical solutions of the present invention, the present invention will be further described below with reference to specific embodiments, but the embodiments described herein do not limit the present invention in any way.

[0034] Unless otherwise specified, the experimental methods described in the following examples are conventional methods; the reagents and materials described are commercially available unless otherwise specified.

[0035] The following lists the structures, physical properties, and... of the specific compounds I-1 to I-52 synthesized in this invention. 1 H NMR, 19 FNMR, 13 The present invention is not limited to these compounds, but includes C NMR and HRMS data.

[0036] I-1: White solid, melting point 85-87℃, yield: 75%. 1 HNMR(400MHz,CDCl3)δ10.97(s,1H,NH),8.19(d,J=8.0Hz,1H,ArH),6.94(d,J=8.0Hz,1H,ArH),6.84(s,1H,ArH),4.03(s,3H,OCH3),2.49- 2.43(m,2H,CH2),2.42(s,3H,CH3),1.70-1.59(m,2H,CH2),1.49-1.40(m,2H,CH2),1.37-1.21(m,14H,(CH2)7),0.88(t,J=6.8Hz,3H,CH3). 19 F NMR (377MHz, CDCl3) δ -69.78. 13 C NMR (101MHz, CDCl3) δ 162.0, 157.2, 145.5, 143.5 (q, J = 34.3Hz), 133.0, 122.9, 121.2 (q, J = 275.7Hz), 116.9, 112.3, 56.3, 31.9, 29.9, 29.51, 29.50, 29.4, 29.3, 29.2, 25.8, 24.8, 22.6, 21.8, 14.0. HRMS (ESI) m / z: calculated value C 22 H 33 F3N2O2Na[M+Na] + 437.2386, measured value 437.2383.

[0037] I-2: White solid, melting point 81-82℃, yield: 67%. 1HNMR(400MHz,CDCl3)δ10.96(s,1H,NH),8.22(d,J=8.0Hz,1H,ArH),6.97(d,J=8.0Hz,1H,ArH),6.84(s,1H,ArH),4.03(s,3H,OCH3),2.51- 2.38(m,2H,CH2),2.37(s,3H,CH3),1.72-1.62(m,2H,CH2),1.49-1.40(m,2H,CH2),1.38-1.20(m,18H,(CH2)9),0.88(t,J=6.8Hz,3H,CH3). 19 F NMR (377MHz, CDCl3) δ -69.81. 13 C NMR (101MHz, CDCl3) δ 162.0, 157.2, 145.4, 143.6 (q, J = 34.3Hz), 133.2, 123.0, 121.1 (q, J = 275.7Hz), 117.0, 112.3, 56.3, 31.9, 30.0, 29.62, 29.61, 29.57, 29.5, 29.4, 29.3, 29.2, 25.9, 24.9, 22.7, 21.8, 14.1. HRMS (ESI) m / z: calculated value C 24 H 37 F3N2O2Na[M+Na] + 465.2699, measured value 465.2695.

[0038] I-3: White solid, melting point 86-87℃, yield: 62%. 1 HNMR (400MHz, CDCl3) δ10.96(s,1H,NH),8.22(d,J=8.0Hz,1H,ArH),6.97(d,J=8.0Hz,1H,ArH),6.84(s,1H,ArH),4.03(s,3 H,OCH3),2.50-2.44(m,2H,CH2),2.43(s,3H,CH3),1.72-1.62(m,2H,CH2),1.49-1.39(m,2H,CH2),1.37-1.21(m,22H,(CH2) 11 ),0.88(t,J=6.8Hz,3H,CH3). 19 F NMR (377MHz, CDCl3) δ -69.81. 13C NMR (101MHz, CDCl3) (missing one carbon signal) δ 161.9, 157.2, 145.4, 143.6 (q, J = 34.3Hz), 133.2, 123.0, 121.2 (q, J = 275.7Hz), 117.0, 112.3, 56.3, 31.9, 30.0, 29.67, 29.65, 29.63, 29.58, 29.5, 29.4, 29.3, 29.2, 25.9, 24.9, 22.7, 21.8, 14.1. HRMS (ESI) m / z: calculated C 26 H 41 F3N2O2Na[M+Na] + 493.3012, measured value 493.3009.

[0039] I-4: White solid, melting point 85-86℃, yield: 69%. 1 HNMR (400MHz, CDCl3) δ10.97(s,1H,NH),8.21(d,J=8.0Hz,1H,ArH),6.96(d,J=8.0Hz,1H,ArH),6.84(s,1H,ArH),4.03(s,3 H,OCH3),2.50-2.43(m,2H,CH2),2.42(s,3H,CH3),1.71-1.60(m,2H,CH2),1.49-1.40(m,2H,CH2),1.36-1.22(m,26H,(CH2) 13 ),0.88(t,J=6.8Hz,3H,CH3). 19 F NMR (377MHz, CDCl3) δ -69.80. 13 C NMR (101MHz, CDCl3) (missing two carbon signals) δ 162.0, 157.2, 145.4, 143.5 (q, J = 34.3Hz), 133.1, 122.9, 121.2 (q, J = 275.7Hz), 116.9, 112.3, 56.3, 31.9, 29.9, 29.68, 29.66, 29.64, 29.62, 29.58, 29.5, 29.4, 29.3, 29.2, 25.8, 24.8, 22.7, 21.8, 14.1. HRMS (ESI) m / z: calculated C 28 H 45 F3N2O2Na[M+Na] + 521.3325, measured value 521.3322.

[0040] I-5: White solid, melting point 91-92℃, yield: 50%. 1HNMR (400MHz, CDCl3) δ10.97(s,1H,NH),8.22(d,J=8.0Hz,1H,ArH),6.97(d,J=8.0Hz,1H,ArH),6.84(s,1H,ArH),4.03(s,3 H,OCH3),2.51-2.44(m,2H,CH2),2.43(s,3H,CH3),1.71-1.62(m,2H,CH2),1.49-1.40(m,2H,CH2),1.38-1.23(m,30H,(CH2) 15 ),0.88(t,J=6.7Hz,3H,CH3). 19 F NMR (377MHz, CDCl3) δ -69.82. 13 C NMR (101MHz, CDCl3) (missing four carbon signals) δ 162.0, 157.2, 145.4, 143.6 (q, J = 34.3Hz), 133.2, 123.0, 121.1 (q, J = 275.7Hz), 117.0, 112.2, 56.3, 31.9, 30.0, 29.7, 29.69, 29.67, 29.66, 29.61, 29.55, 29.43, 29.37, 29.2, 25.9, 24.9, 22.7, 21.9, 14.1. HRMS (ESI) m / z: calculated C 30 H 49 F3N2NaO2[M+Na] + 549.3638, measured value 549.3640.

[0041] I-6: White solid, melting point 80-81℃, yield: 65%. 1 HNMR (400MHz, CDCl3) δ10.97(s,1H,NH),8.22(d,J=8.0Hz,1H,ArH),6.97(d,J=8.1Hz,1H,ArH),6.84(s,1H,ArH),4.03(s,3 H,OCH3),2.50-2.44(m,2H,CH2),2.43(s,3H,CH3),1.70-1.64(m,2H,CH2),1.47-1.39(m,2H,CH2),1.36-1.22(m,34H,(CH2) 17 ),0.88(t,J=6.8Hz,3H,CH3). 19 F NMR (377MHz, CDCl3) δ -69.81. 13C NMR (101MHz, CDCl3) (missing eight carbon signals) δ 162.0, 157.2, 145.4, 143.6 (q, J = 34.3Hz), 133.2, 123.0, 121.2 (q, J = 275.7Hz), 117.0, 112.3, 56.3, 31.9, 30.0, 29.69, 29.65, 29.6, 29.5, 29.41, 29.35, 29.2, 25.9, 24.9, 22.7, 21.8, 14.1. HRMS (ESI) m / z: calculated C 32 H 53 F3N2O2Na[M+Na] + 577.3951, measured value 577.3945.

[0042] I-7: Colorless liquid, yield: 67%. 1 H NMR (400MHz, CDCl3) δ10.97(s,1H,NH),8.22(d,J=8.0Hz,1H,ArH),6.97(d,J=8.0Hz,1H,A rH),6.84(s,1H,ArH),5.45-5.25(m,4H,(CH=CH)2),4.03(s,3H,OCH3),2.76(t,J=6.1Hz,2 H,CH2),2.50-2.43(m,2H,CH2),2.43(s,3H,CH3),2.09-1.97(m,4H,(CH2)2),1.69-1.61(m ,2H,CH2),1.50-1.42(m,2H,CH2),1.46-1.22(m,12H,(CH2)6),0.88(t,J=7.5Hz,3H,CH3). 19 F NMR (377MHz, CDCl3) δ -69.80. 13 C NMR (101MHz, CDCl3) δ 162.0, 157.2, 145.5, 143.5 (q, J = 34.3Hz), 133.2, 130.3, 129.8, 128.2, 127.8, 123.0, 121.2 (q, J = 275.7Hz), 116.9, 112.3, 56.3, 31.5, 30.0, 29.5, 29.3, 29.2, 29.0, 27.2, 27.1, 25.9, 25.6, 24.8, 22.6, 21.9, 14.1. HRMS (ESI) m / z: calculated value C 28 H 41 F3N2O2Na[M+Na] + 517.3012, measured value 517.3008.

[0043] I-8: Colorless liquid, yield: 51%. 1 H NMR (400MHz, CDCl3) δ10.97 (s, 1H, NH), 8.22 (d, J = 8.0Hz, 1H, ArH), 6.97 (d, J = 8.0Hz ,1H,ArH),6.84(s,1H,ArH),5.46-5.25(m,6H,(CH=CH)3),4.03(s,3H,OCH3),2.81-2 .78(m,2H,CH2),2.49-2.43(m,2H,CH2),2.43(s,3H,CH3),2.10-2.02(m,4H,(CH2)2 ),1.68-1.60(m,4H,(CH2)2),1.41-1.30(m,8H,(CH2)4),0.97(t,J=7.5Hz,3H,CH3). 19 F NMR (377MHz, CDCl3) δ -69.80. 13 C NMR (101MHz, CDCl3) δ 162.0, 157.2, 145.5, 143.5 (q, J = 34.3Hz), 133.2, 132.0, 130.0, 128.4, 128.2, 127.9, 127.1, 123.0, 121.1 (q, J = 275.7Hz), 116.9, 112.3, 56.3, 30.0, 29.5, 29.2, 29.1, 27.1, 25.9, 25.6, 25.5, 24.8, 21.9, 20.5, 14.3. HRMS (ESI) m / z: calculated value C 28 H 39 F3N2O2Na[M+Na] + 515.2856, measured value 515.2856.

[0044] I-9: Pale yellow liquid, yield: 60%. 1HNMR (400MHz, CDCl3) δ10.95 (s, 1H, NH), 8.21 (d, J = 8.0Hz, 1H, ArH), 6.97 (d, J = 8.0Hz, 1H, ArH),6.83(s,1H,ArH),5.50-5.29(m,8H,(CH=CH)4),4.02(s,3H,OCH3),2.84-2.80(m,4H ,(CH2)2),2.50-2.44(m,2H,CH2),2.43(s,3H,CH3),2.28-2.20(m,2H,CH2),2.08-2.00(m ,2H,CH2),1.78-1.71(m,2H,CH2),1.38-1.25(m,8H,(CH2)4),0.88(t,J=7.5Hz,3H,CH3). 19 F NMR (377MHz, CDCl3) δ -69.75. 13 C NMR (101MHz, CDCl3) δ 162.0, 157.2, 145.5, 143.2 (q, J = 34.3Hz), 133.3, 130.6, 130.0, 128.8, 128.7, 127.8, 127.63, 127.59, 127.4, 123.1, 121.1 (q, J = 275.7Hz), 117.0, 112.3, 65.6, 56.4, 31.5, 29.3, 27.2, 25.7, 25.3, 24.6, 22.6, 21.9, 19.2, 14.1, 13.7. HRMS (ESI) m / z: Calculated value C 30 H 41 F3N2O2Na[M+Na] + 541.3012, measured value 541.3012.

[0045] I-10: White solid, melting point 110-112℃, yield: 81%. 1 HNMR(400MHz,CDCl3)δ9.48(s,1H,NH),9.65-9.31(m,2H,(ArH)2),7.25-7.20(m,1H,ArH),3.89(s,3H,OCH3),2.55-2.51(m,2H,C H2),2.29(s,3H,Ar-CH3),1.70-1.60(m,2H,CH2),1.49-1.39(m,2H,CH2),1.38-1.23(m,10H,(CH2)5),0.90(t,J=6.8Hz,3H,CH3). 19 F NMR (377MHz, CDCl3) δ -69.84. 13C NMR (101MHz, CDCl3) δ 157.4, 132.1, 132.0, 130.6, 130.6, 130.5, 130.1, 121.1 (q, J = 275.7Hz), 111.4, 55.3, 31.8, 29.7, 29.4, 29.23, 29.21, 25.4, 24.8, 22.6, 16.4, 14.1. HRMS (ESI) m / z: calculated value C 20 H 29 F3N2O2Na[M+Na] + 409.2073, measured value 409.2073.

[0046] I-11: White solid, melting point 111-112℃, yield: 84%. 1 HNMR (400MHz, CDCl3) δ7.66-7.27(m,2H,(ArH)2),7.19-7.14(m,1H,ArH),3.84(s,3H,OCH3),2.66-2.53(m,2H,CH2),2. 26(s,3H,CH3),1.68-1.58(m,2H,CH2),1.47-1.37(m,2H,CH2),1.33-1.17(m,14H,(CH2)7),0.88(t,J=6.9Hz,3H,CH3). 19 F NMR (377MHz, CDCl3) δ -69.78. 13 C NMR (101MHz, CDCl3) (missing three carbon signals) δ 157.4, 131.9, 130.7, 130.1, 121.1 (q, J = 275.7Hz), 111.6, 55.2, 31.9, 29.7, 29.59, 29.57, 29.4, 29.31, 29.27, 25.4, 24.9, 22.7, 16.3, 14.0. HRMS (ESI) m / z: calculated C 22 H 33 F3N2O2Na[M+Na] + 437.2386, measured value 437.2386.

[0047] I-12: White solid, melting point 106-107℃, yield: 88%. 1HNMR (400MHz, CDCl3) δ7.66-7.28(m,2H,(ArH)2),7.18-7.10(m,1H,ArH),3.83(s,3H,OCH3),2.69-2.53(m,2H,CH2),2. 25(s,3H,CH3),1.70-1.57(m,2H,CH2),1.47-1.36(m,2H,CH2),1.33-1.16(m,18H,(CH2)9),0.88(t,J=6.7Hz,3H,CH3). 19 F NMR (377MHz, CDCl3) δ -69.75. 13 C NMR (101MHz, CDCl3) (missing three carbon signals) δ 170.8, 157.2, 131.8, 130.7, 130.0, 121.2 (q, J = 275.7Hz), 111.9, 55.2, 31.9, 29.69, 29.67, 29.66, 29.6, 29.5, 29.4, 29.3, 25.5, 24.9, 22.7, 16.3, 14.0. HRMS (ESI) m / z: calculated C 24 H 37 F3N2O2Na[M+Na] + 465.2699, measured value 465.2702.

[0048] I-13: White solid, melting point 109-110℃, yield: 67%. 1 HNMR (400MHz, CDCl3) δ7.62-7.28 (m, 2H, (ArH)2), 7.18 (d, J = 7.7Hz, 1H, ArH), 3.85 (s, 3H, OCH3), 2.52-2. 52(m,2H,CH2),2.26(s,3H,CH3),1.64-1.57(m,2H,CH2),1.48-1.37(m,2H,CH2),1.34-1.19(m,22H,(CH2) 11 ),0.87(t,J=6.8Hz,3H,CH3). 19 F NMR (377MHz, CDCl3) δ -69.81. 13 C NMR (101MHz, CDCl3) (missing seven carbon signals) δ 157.4, 130.6, 130.1, 121.1 (q, J = 275.7Hz), 111.7, 55.3, 31.9, 29.70, 29.67, 29.64, 29.58, 29.43, 29.37, 29.3, 25.4, 24.9, 22.7, 16.4, 14.1. HRMS (ESI) m / z: calculated C26 H 41 F3N2O2Na[M+Na] + 493.3012, measured value 493.3007.

[0049] I-14: White solid, melting point 112-113℃, yield: 83%. 1 HNMR(400MHz, CDCl3)δ7.59-7.29(m,2H,(ArH)2),7.20-7.15(m,1H,ArH),3.86(s,3H,OCH3),2.63-2.48 (m,2H,CH2),2.26(s,3H,CH3),1.70-1.57(m,2H,CH2),1.47-1.37(m,2H,CH2),1.34-1.18(m,26H,(CH2) 13 ),0.88(t,J=6.7Hz,3H,CH3). 19 F NMR (377MHz, CDCl3) δ -69.81. 13 C NMR (101MHz, CDCl3) (missing eight carbon signals) δ 157.4, 132.1, 130.6, 130.1, 121.2 (q, J = 275.7Hz), 111.5, 55.3, 31.9, 29.7, 29.66, 29.63, 29.57, 29.42, 29.36, 29.2, 25.4, 24.8, 22.7, 16.4, 14.1. HRMS (ESI) m / z: calculated value C 28 H 45 F3N2O2Na[M+Na] + 521.3325, measured value 521.3322.

[0050] I-15: White solid, melting point 115-117℃, yield: 58%. 1 HNMR(400MHz, CDCl3)δ9.22(s,1H,NH),7.58-7.30(m,2H,(ArH)2),7.20(s,1H,ArH),3.88(s,3H,OCH3),2.52 -2.44(m,2H,CH2),2.27(s,3H,CH3),1.66-1.60(m,2H,CH2),1.47-1.37(m,2H,CH2),1.33-1.22(m,30H,(CH2) 15 ),0.88(t,J=6.7Hz,3H,CH3). 19 F NMR (377MHz, CDCl3) δ -69.95. 13C NMR (101MHz, CDCl3) (missing six carbon signals) δ 162.0, 157.5, 145.4, 143.6 (q, J = 34.3Hz), 137.1, 132.2, 130.2, 121.0 (q, J = 275.7Hz), 111.2, 55.4, 31.9, 29.74, 29.70, 29.65, 29.61, 29.55, 29.39, 29.36, 29.2, 25.3, 24.8, 22.7, 16.4, 14.1. HRMS (ESI) m / z: calculated C 30 H 49 F3N2O2Na[M+Na] + 549.3638, measured value 549.3640.

[0051] I-16: Pale yellow liquid, yield: 72%. 1 HNMR(500MHz,CDCl3)δ7.59-7.28(m,2H,(ArH)2),7.21-7.14(m,1H,ArH),5.57 -5.20(m,8H,(CH=CH)4),3.86(s,3H,OCH3),2.82-2.77(m,4H,(CH2)2),2.62-2. 47(m,2H,CH2),2.26(s,3H,CH3),2.25-2.18(m,2H,CH2),2.07-2.03(m,2H,CH2) ,1.78-1.67(m,2H,CH2),1.37-1.23(m,8H,(CH2)4),0.88(t,J=6.8Hz,3H,CH3). 19 F NMR (470MHz, CDCl3) δ -69.81. 13 CNMR (126MHz, CDCl3) (missing seven carbon signals) δ 132.1, 130.6, 130.2, 128.7, 128.6, 128.0, 127.7, 127.5, 121.1 (q, J = 275.1Hz), 112.7, 55.4, 31.5, 29.3, 27.2, 26.8, 25.70, 25.65, 25.6, 25.1, 24.1, 22.6, 16.5, 14.1. HRMS (ESI) m / z: calculated value C 30 H 41 F3N2NaO2[M+Na] + 541.3012, measured value 541.3016.

[0052] I-17: Colorless liquid, yield: 81%. 1H NMR(400MHz,CDCl3)δ9.46(s,1H,NH),7.24-7.17(m,1H,ArH),6.95-6.86(m,2H,(ArH)2),6.83-6.76(m,1H,ArH),3.97(s,2H,CO CH2),3.78(s,3H,OCH3),2.45-2.34(m,2H,CH2),1.57-1.46(m,2H,CH2),1.38-1.20(m,10H,(CH2)5),0.88(t,J=6.6Hz,3H,CH3). 19 F NMR (377MHz, CDCl3) δ -69.94. 13 C NMR (101MHz, CDCl3) δ 175.6, 159.7, 141.6 (q, J = 34.3Hz), 135.7, 129.4, 121.9, 121.1 (q, J = 275.7Hz), 115.1, 112.8, 55.0, 39.6, 31.8, 29.4, 29.2, 29.1, 25.4, 25.1, 22.6, 14.0. HRMS (ESI) m / z: Calculated C 19 H 27 F3N2O2Na[M+Na] + 395.1917, measured value 395.1917.

[0053] I-18: Pale yellow liquid, yield: 63%. 1 HNMR(400MHz,CDCl3)δ10.00(s,1H,NH),7.23-7.18(m,1H,ArH),6.93-6.84(m,2H,(ArH)2),6.79(m,1H,ArH),3.96(s,2H,COCH 2),3.77(s,3H,OCH3),2.46-2.36(m,2H,CH2),1.54-1.45(m,2H,CH2),1.35-1.22(m,12H,(CH2)6),0.88(t,J=6.8Hz,3H,CH3). 19 F NMR (377MHz, CDCl3) δ -69.89. 13C NMR (101MHz, CDCl3) δ 175.1, 159.7, 141.3 (q, J = 33.3Hz), 135.6, 129.4, 121.9, 121.0 (q, J = 275.7Hz), 115.0, 112.8, 55.1, 39.6, 31.8, 29.5, 29.4, 29.3, 29.2, 25.3, 25.0, 22.7, 14.1. HRMS (ESI) m / z: calculated value C 20 H 29 F3N2O2Na[M+Na] + 409.2073, measured value 409.2072.

[0054] I-19: White solid, melting point 56-57℃, yield: 78%. 1 HNMR(400MHz,CDCl3)δ9.43(s,1H,NH),7.24-7.18(m,1H,ArH),6.93-6.86(m,2H,(ArH)2),6.82-6.76(m,1H,ArH),3.97(s,2H,CO CH2),3.78(s,3H,OCH3),2.43-2.34(m,2H,CH2),1.55-1.44(m,2H,CH2),1.36-1.22(m,16H,(CH2)8),0.88(t,J=6.7Hz,3H,CH3). 19 F NMR (377MHz, CDCl3) δ -69.94. 13 C NMR (101MHz, CDCl3) δ 175.5, 159.7, 141.6 (q, J = 34.3Hz), 135.7, 129.4, 121.9, 121.1 (q, J = 275.7Hz), 115.1, 112.8, 55.0, 39.6, 31.9, 29.7, 29.6, 29.42, 29.38, 29.34, 29.25, 25.4, 25.1, 22.7, 14.1. HRMS (ESI) m / z: calculated value C 22 H 33 F3N2O2Na[M+Na] + 437.2386, measured value 437.2385.

[0055] I-20: White solid, melting point 61-62℃, yield: 67%. 1HNMR(400MHz, CDCl3)δ8.97(s,1H,NH),7.22(m,1H,ArH),6.95-6.87(m,2H,(ArH)2),6.84-6.78(m,1H,ArH),3 .97(s,2H,COCH2),3.79(s,3H,OCH3),2.39-2.30(m,2H,CH2),1.56-1.47(m,2H,CH2),1.35-1.21(m,24H,(CH2) 12 ),0.88(t,J=6.7Hz,3H,CH3). 19 F NMR (377MHz, CDCl3) δ -69.99. 13 C NMR (101MHz, CDCl3) δ 174.9, 159.7, 141.1 (q, J = 34.3Hz), 135.6, 129.4, 121.9, 121.0 (q, J = 275.7Hz), 115.0, 112.9, 55.1, 39.6, 31.9, 29.7, 29.69, 29.67, 29.66, 29.63, 29.61, 29.5, 29.4, 29.36, 29.2, 25.3, 25.0, 22.7, 14.1. HRMS (ESI) m / z: calculated value C 26 H 41 F3N2O2Na[M+Na] + 493.3012, measured value 493.3011.

[0056] I-21: White solid, melting point 66-67℃, yield: 71%. 1 HNMR(400MHz, CDCl3)δ8.99(s,1H,NH),7.24-7.18(m,1H,ArH),6.94-6.87(m,2H,(ArH)2),6.83-6.77(m,1H,ArH) ,3.95(s,2H,COCH2),3.78(s,3H,OCH3),2.41-2.31(m,2H,CH2),1.56-1.46(m,2H,CH2),1.33-1.21(m,28H,(CH2) 14 ),0.87(t,J=6.7Hz,3H,CH3). 19 F NMR (377MHz, CDCl3) δ -69.98. 13C NMR (101MHz, CDCl3) (five carbon signals missing) δ 175.4, 159.7, 141.5 (q, J = 34.3Hz), 135.7, 129.4, 122.4, 121.0 (q, J = 275.7Hz), 115.1, 112.8, 55.0, 39.6, 32.0, 29.73, 29.69, 29.67, 29.44, 29.42, 29.39, 29.3, 25.4, 25.1, 22.7, 14.1. HRMS (ESI) m / z: calculated C 28 H 45 F3N2NaO2[M+Na] + 521.3325, measured value 521.3321.

[0057] I-22: White solid, melting point 72-73℃, yield: 45%. 1 HNMR(400MHz, CDCl3)δ8.99(s,1H,NH),7.25-7.19(m,1H,ArH),6.94-6.87(m,2H,(ArH)2),6.80(m,1H,ArH),3 .97(s,2H,COCH2),3.78(s,3H,OCH3),2.44-2.28(m,2H,CH2),1.56-1.46(m,2H,CH2),1.29-1.22(m,32H,(CH2) 16 ),0.88(t,J=6.7Hz,3H,CH3). 19 F NMR (377MHz, CDCl3) δ -69.98. 13 C NMR (101MHz, CDCl3) (five carbon signals missing) δ 175.0, 159.7, 141.2 (q, J = 34.3Hz), 135.6, 129.4, 121.9, 121.0 (q, J = 275.7Hz), 115.0, 112.9, 55.1, 39.6, 32.0, 29.72, 29.70, 29.68, 29.65, 29.64, 29.5, 29.42, 29.38, 29.2, 25.3, 25.0, 22.7, 14.1. HRMS (ESI) m / z: calculated C 30 H 49 F3N2O2Na[M+Na] + 549.3638, measured value 549.3639.

[0058] I-23: White solid, melting point 72-73℃, yield: 65%. 1HNMR(400MHz, CDCl3)δ9.09(s,1H,NH),7.25-7.18(m,1H,ArH),6.94-6.86(m,2H,(ArH)2),6.83-6.77(m,1H,ArH) ,3.97(s,2H,COCH2),3.78(s,3H,OCH3),2.39-2.32(m,2H,CH2),1.57-1.46(m,2H,CH2),1.34-1.21(m,36H,(CH2) 18 ),0.88(t,J=6.7Hz,3H,CH3). 19 F NMR (377MHz, CDCl3) δ -69.97. 13 C NMR (101MHz, CDCl3) (missing eight carbon signals) δ 175.1, 159.7, 141.3 (q, J = 34.3Hz), 135.6, 129.4, 121.9, 121.0 (q, J = 275.7Hz), 115.0, 112.8, 55.1, 39.6, 32.0, 29.72, 29.71, 29.65, 29.63, 29.5, 29.43, 29.38, 29.2, 25.3, 25.0, 22.7, 14.1. HRMS (ESI) m / z: calculated C 32 H 53 F3N2O2Na[M+Na] + 577.3951, measured value 577.3949.

[0059] I-24: Colorless liquid, yield: 59%. 1 H NMR(400MHz, CDCl3)δ9.33(s,1H,NH),7.24-7.18(m,1H,ArH),6.93-6.86(m,2H,(Ar H)2),6.82-6.78(m,1H,ArH),5.43-5.26(m,4H,(CH=CH)2),3.97(s,2H,COCH2),3.78 (s,3H,OCH3),2.80-2.73(m,2H,CH2),2.41-2.31(m,2H,CH2),2.09-1.97(m,4H,(CH2 )2),1.56-1.46(m,2H,CH2),1.36-1.26(m,14H,(CH2)7),0.89(t,J=6.8Hz,3H,CH3). 19 F NMR (377MHz, CDCl3) δ -69.94. 13C NMR (101MHz, CDCl3) δ 175.1, 159.7, 141.2 (q, J = 34.3Hz), 135.6, 130.3, 129.9, 129.4, 128.2, 127.9, 122.3, 121.9, 121.0 (q, J = 275.7Hz), 115.0, 112.8, 55.1, 39.6, 31.5, 29.6, 29.42, 29.36, 29.1, 29.0, 27.22, 27.17, 25.6, 25.3, 25.0, 22.6, 14.1. HRMS (ESI) m / z: calculated value C 28 H 41 F3N2O2Na[M+Na] + 517.3012, measured value 517.3013.

[0060] I-25: Colorless liquid, yield: 57%. 1 H NMR(400MHz, CDCl3)δ9.18(s,1H,NH),7.25-7.18(m,1H,ArH),6.95-6.86(m,2H,(Ar H)2),6.83-6.77(m,1H,ArH),5.45-5.27(m,6H,(CH=CH)3),3.97(s,2H,COCH2),3.78 (s,3H,OCH3),2.84-2.77(m,2H,CH2),2.40-2.31(m,2H,CH2),2.10-2.00(m,4H,(CH2 )2),1.55-1.46(m,2H,CH2),1.38-1.24(m,10H,(CH2)5),0.97(t,J=7.5Hz,3H,CH3). 19 F NMR (377MHz, CDCl3) δ -69.96. 13 C NMR (101MHz, CDCl3) δ 175.08, 159.67, 141.2 (q, J = 34.3Hz), 135.57, 131.98, 130.16, 129.41, 128.33, 128.22, 127.84, 127.11, 121.94, 121.0 (q, J = 275.7Hz), 115.05, 112.84, 55.1, 39.6, 29.6, 29.4, 29.1, 29.0, 27.2, 25.6, 25.5, 25.3, 25.0, 20.6, 14.3. HRMS (ESI) m / z: Calculated value C 28 H 39 F3N2O2Na[M+Na] + 515.2856, measured value 515.2855.

[0061] I-26: Pale yellow liquid, yield: 67%. 1 HNMR(400MHz, CDCl3)δ8.91(s,1H,NH),7.24-7.18(m,1H,ArH),6.93-6.87(m,2H,(ArH)2) ,6.82-6.78(m,1H,ArH),5.50-5.27(m,8H,(CH=CH)4),3.97(s,2H,COCH2),3.78(s,3H,OCH 3),2.86-2.75(m,6H,(CH2)3),2.40-2.31(m,2H,CH2),2.17-2.09(m,2H,CH2),2.08-2.00( m,2H,CH2),1.65-1.58(m,2H,CH2),1.41-1.23(m,6H,(CH2)3),0.88(t,J=6.8Hz,3H,CH3). 19 F NMR (377MHz, CDCl3) δ -69.92. 13 C NMR (101MHz, CDCl3) δ 175.1, 159.7, 140.9 (q, J = 34.3Hz), 135.5, 130.5, 129.6, 129.4, 128.7, 128.4, 128.2, 127.9, 127.8, 127.5, 121.9, 121.0 (q, J = 275.7Hz), 115.0, 112.9, 55.1, 39.6, 31.5, 29.3, 27.2, 26.8, 25.7, 25.64, 25.63, 25.1, 24.4, 22.6, 14.1. HRMS (ESI) m / z: calculated value C 30 H 41 F3N2O2Na[M+Na] + 541.3012, measured value 541.3016.

[0062] I-27: White solid, melting point 80-81℃, yield: 80%. 1 HNMR(400MHz, CDCl3)δ8.99(s,1H,NH),7.25-7.20(m,2H,(ArH)2),7.18-7.11(m,2H,(ArH)2),3.98(s,2H,COCH2),2.4 1-2.36(m,2H,CH2),2.35(s,3H,CH3),1.58-1.47(m,2H,CH2),1.38-1.23(m,12H,(CH2)6),0.90(t,J=6.7Hz,3H,CH3). 19F NMR (377MHz, CDCl3) δ -70.00. 13 C NMR (101MHz, CDCl3) δ 176.0, 141.5 (q, J = 34.3Hz), 136.5, 131.3, 129.5, 129.2, 121.1 (q, J = 275.7Hz), 39.1, 31.9, 29.4, 29.39, 29.36, 29.3, 25.4, 25.1, 22.7, 21.0, 14.1. HRMS (ESI) m / z: calculated value C 20 H 29 F3N2ONa[M+Na] + 393.2124, measured value 393.2126.

[0063] I-28: White solid, melting point 81-82℃, yield: 89%. 1 HNMR(400MHz, CDCl3)δ9.38(s,1H,NH),7.22-7.17(m,2H,(ArH)2),7.14-7.08(m,2H,(ArH)2),3.95(s,2H,COCH2),2.4 0-2.33(m,2H,CH2),2.32(s,3H,CH3),1.54-1.44(m,2H,CH2),1.35-1.21(m,16H,(CH2)8),0.88(t,J=6.7Hz,3H,CH3). 19 F NMR (377MHz, CDCl3) δ -69.95. 13 C NMR (101MHz, CDCl3) (missing one carbon signal) δ 175.6, 141.2 (q, J = 34.3Hz), 136.5, 131.2, 129.5, 129.2, 121.1 (q, J = 275.7Hz), 39.1, 31.9, 29.7, 29.6, 29.4, 29.35, 29.27, 25.3, 25.0, 22.7, 21.1, 14.1. HRMS (ESI) m / z: calculated C 22 H 33 F3N2ONa[M+Na] + 421.2437, measured value 421.2432.

[0064] I-29: White solid, melting point 70-71℃, yield: 79%. 1HNMR(400MHz, CDCl3)δ9.62(s,1H,NH),7.22-7.17(m,2H,(ArH)2),7.13-7.08(m,2H,(ArH)2),3.94(s, 2H,COCH2),2.41-2.34(m,2H,CH2),2.31(s,3H,CH3),1.55-1.44(m,2H,CH2),1.34-1.22(m,20H,(CH2) 10 ),0.88(t,J=6.8Hz,3H,CH3). 19 F NMR (377MHz, CDCl3) δ -69.92. 13 C NMR (101MHz, CDCl3) (missing two carbon signals) δ 175.7, 141.4 (q, J = 34.3Hz), 136.5, 131.2, 129.5, 129.2, 121.1 (q, J = 275.7Hz), 39.1, 31.9, 29.70, 29.67, 29.5, 29.42, 29.37, 29.3, 25.4, 25.1, 22.7, 21.0, 14.1. HRMS (ESI) m / z: calculated C 24 H 37 F3N2ONa[M+Na] + 449.2750, measured value 449.2744.

[0065] I-30: White solid, melting point 72-73℃, yield: 87%. 1 HNMR(400MHz, CDCl3)δ9.74(s,1H,NH),7.25-7.20(m,2H,(ArH)2),7.17-7.10(m,2H,(ArH)2),3.97(s, 2H,COCH2),2.44-2.38(m,2H,CH2),2.35(s,3H,CH3),1.57-1.46(m,2H,CH2),1.36-1.24(m,24H,(CH2) 12 ),0.91(t,J=6.7Hz,3H,CH3). 19 F NMR (377MHz, CDCl3) δ -69.92. 13C NMR (101MHz, CDCl3) δ 175.4, 141.1 (q, J = 34.3Hz), 136.6, 131.1, 129.5, 129.2, 121.0 (q, J = 275.7Hz), 39.1, 31.9, 29.72, 29.71, 29.70, 29.68, 29.66, 29.64, 29.5, 29.44, 29.38, 29.3, 25.3, 25.0, 22.7, 21.1, 14.1. HRMS (ESI) m / z: calculated value C 26 H 41 F3N2ONa[M+Na] + 477.3063, measured value 477.3064.

[0066] I-31: White solid, melting point 72-73℃, yield: 91%. 1 HNMR(400MHz, CDCl3)δ9.07(s,1H,NH),7.24-7.17(m,2H,(ArH)2),7.14-7.09(m,2H,(ArH)2),3.95(s, 2H,COCH2),2.40-2.35(m,2H,CH2),2.34(s,3H,CH3),1.55-1.45(m,2H,CH2),1.32-1.22(m,28H,(CH2) 14 ),0.88(t,J=6.7Hz,3H,CH3). 19 F NMR (377MHz, CDCl3) δ -69.98. 13 C NMR (101MHz, CDCl3) (seven carbon signals missing) δ 175.8, 141.4 (q, J = 34.3Hz), 136.5, 131.2, 129.5, 129.2, 121.1 (q, J = 275.7Hz), 39.1, 32.0, 29.8, 29.7, 29.5, 29.4, 29.3, 25.4, 25.1, 22.7, 21.1, 14.1. HRMS (ESI) m / z: calculated C 28 H 45 F3N2ONa[M+Na] + 505.3376, measured value 505.3369.

[0067] I-32: White solid, melting point 77-78℃, yield: 65%. 1HNMR(400MHz, CDCl3)δ8.95(s,1H,NH),7.21(d,J=7.9Hz,2H,(ArH)2),7.12(d,J=7.9Hz,2H,(ArH)2),3 .96(s,2H,COCH2),2.41-2.34(m,2H,CH2),2.32(s,3H,CH3),1.55-1.45(m,2H,CH2),1.25(s,32H,(CH2) 16 ),0.88(t,J=6.7Hz,3H,CH3). 19 F NMR (377MHz, CDCl3) δ -69.99. 13 C NMR (101MHz, CDCl3) (missing six carbon signals) δ 175.4, 141.1 (q, J = 34.3Hz), 136.6, 131.1, 129.5, 129.2, 121.0 (q, J = 275.7Hz), 39.1, 32.0, 29.74, 29.70, 29.68, 29.66, 29.48, 29.45, 29.4, 29.3, 25.3, 25.0, 22.7, 21.1, 14.1. HRMS (ESI) m / z: calculated C 30 H 49 F3N2ONa[M+Na] + 533.3689, measured value 533.3691.

[0068] I-33: White solid, melting point 76-77℃, yield: 85%. 1 HNMR(400MHz, CDCl3)δ9.02(s,1H,NH),7.23-7.18(m,2H,(ArH)2),7.14-7.08(m,2H,(ArH)2),3.96 (s,2H,COCH2),2.40-2.33(m,2H,CH2),2.32(s,3H,CH3),1.55-1.46(m,2H,CH2),1.25(m,36H,(CH2) 18 ),0.88(t,J=6.7Hz,3H,CH3). 19 F NMR (377MHz, CDCl3) δ -69.96. 13C NMR (101MHz, CDCl3) (missing ten carbon signals) δ 175.70, 141.4 (q, J = 34.3Hz), 136.5, 131.2, 129.5, 129.15, 121.1 (q, J = 275.7Hz), 39.1, 32.0, 29.73, 29.69, 29.5, 29.43, 29.39, 29.3, 25.4, 25.0, 22.7, 21.0, 14.1. HRMS (ESI) m / z: calculated C 32 H 53 F3N2ONa[M+Na] + 561.4002, measured value 561.4004.

[0069] I-34: Colorless liquid, yield: 67%. 1 H NMR(400MHz, CDCl3)δ9.73(s,1H,NH),7.21-7.17(m,2H,(ArH)2),7.13-7.07( m,2H,(ArH)2),5.42-5.29(m,4H,(CH=CH)2),3.94(s,2H,COCH2),2.82-2.73( m,2H,CH2),2.41-2.35(m,2H,CH2),2.31(s,3H,CH3),2.08-2.00(m,4H,(CH2) 2),1.49(m,2H,CH2),1.39-1.23(m,14H,(CH2)7),0.88(t,J=6.7Hz,3H,CH3). 19 F NMR (377MHz, CDCl3) δ -69.97. 13 C NMR (101MHz, CDCl3) δ 175.1, 140.9 (q, J = 34.3Hz), 136.6, 131.1, 130.3, 129.9, 129.5, 129.2, 128.2, 127.9, 121.0 (q, J = 275.7Hz), 39.1, 31.5, 29.6, 29.5, 29.4, 29.1, 29.0, 27.22, 27.16, 25.7, 25.3, 24.9, 22.6, 21.1, 14.1. HRMS (ESI) m / z: calculated value C 28 H 41 F3N2ONa[M+Na] + 501.3063, measured value 501.3061.

[0070] I-35: Pale yellow liquid, yield: 46%. 1H NMR(500MHz,CDCl3)δ10.15(s,1H,NH),7.20-7.16(m,2H,(ArH)2),7.11-7.05(m,2H,(ArH)2),5.45-5.30(m,8H,(CH=CH)4),3.94(s,2H,COCH2),2.88- 2.74(m,6H,(CH2)3),2.45-2.38(m,2H,CH2),2.11-2.00(m,4H,(CH2)2),1. 61-1.50(m,2H,CH2),1.34-1.24(m,6H,(CH2)3),0.88(t,J=6.7Hz,3H,CH3). 19 F NMR (470MHz, CDCl3) δ -69.84. 13 C NMR (126MHz, CDCl3) δ 175.6, 140.8 (q, J = 34.3Hz), 136.6, 131.1, 130.5, 129.49, 129.46, 129.2, 128.7, 128.41, 128.35, 127.9, 127.8, 127.5, 121.0 (q, J = 274.9Hz), 39.1, 31.5, 29.3, 27.2, 26.8, 25.7, 25.6, 25.6, 25.1, 24.5, 22.6, 21.1, 14.1. HRMS (ESI) m / z: calculated value C 30 H 41 F3N2NaO[M+Na] + 525.3063, measured value 525.3060.

[0071] I-36: Colorless liquid, yield: 74%. 1 H NMR(400MHz, CDCl3)δ7.79(d,J=7.9Hz,1H,ArH),6.90-6.80(m,2H,(ArH)2),3.92(s,3H,OCH3),2.69-2.61(m,2H,CH2), 2.44(s,3H,CH3),1.75-1.64(m,2H,CH2),1.41-1.38(m,2H,CH2),1.35-1.21(m,8H,(CH2)4),0.88(t,J=6.7Hz,3H,CH3). 19 F NMR (377MHz, CDCl3) δ -69.25. 13CNMR (101MHz, CDCl3) δ 162.8, 159.6, 157.5 (q, J = 32.3Hz), 146.1, 132.4, 121.3, 120.6 (q, J = 277.8Hz), 114.4, 112.8, 55.8, 31.7, 29.6, 29.04, 29.03, 26.3, 25.8, 22.6, 22.0, 14.0. HRMS (ESI) m / z: Calculated value C 19 H 26 F3NO3Na[M+Na] + 396.1757, measured value 396.1761.

[0072] I-37: White solid, yield: 88%, mp 55-56℃. 1 HNMR(400MHz, CDCl3)δ7.77(d,J=7.9Hz,1H,ArH),6.87-6.80(m,2H,(ArH)2),3.90(s,3H,OCH3),2.66-2.60( m,2H,CH2),2.42(s,3H,CH3),1.72-1.62(m,2H,CH2),1.43-1.21(m,16H,(CH2)8),0.88(t,J=6.7Hz,3H,CH3). 19 F NMR (377MHz, CDCl3) δ -69.25. 13 C NMR (101MHz, CDCl3) (missing one carbon signal) δ 162.7, 159.5, 157.4 (q, J = 32.3Hz), 146.0, 132.4, 121.3, 120.6 (q, J = 277.8Hz), 114.6, 112.8, 55.8, 31.9, 29.6, 29.56, 29.4, 29.3, 29.1, 26.4, 25.8, 22.7, 22.0, 14.1. HRMS (ESI) m / z: calculated C 22 H 32 F3NO3Na[M+Na] + 438.2226, measured value 438.2222.

[0073] I-38: White solid, yield: 79%, mp 61-62℃. 1HNMR (400MHz, CDCl3) δ7.77 (d, J = 7.9Hz, 1H, ArH), 6.87-6.79 (m, 2H, (ArH) 2), 3.90 (s, 3H, OCH3), 2.67-2. 59(m,2H,CH2),2.42(s,3H,CH3),1.72-1.63(m,2H,CH2),1.42-1.36(m,2H,CH2),1.31-1.20(m,26H,(CH2) 13 ),0.88(t,J=6.7Hz,3H,CH3). 19 F NMR (377MHz, CDCl3) δ -69.25. 13 C NMR (101MHz, CDCl3) (five carbon signals missing) δ 162.7, 159.5, 157.4 (q, J = 32.3Hz), 146.0, 132.4, 121.3, 120.6 (q, J = 277.8Hz), 114.6, 112.8, 55.8, 31.9, 29.7, 29.66, 29.61, 29.56, 29.4, 29.36, 29.1, 26.4, 25.8, 22.7, 22.0, 14.1. HRMS (ESI) m / z: calculated C 28 H 44 F3NO3Na[M+Na] + 522.3165, measured value 522.3166.

[0074] I-39: Colorless liquid, yield: 60%. 1 H NMR(400MHz, CDCl3)δ7.79(d,J=7.9Hz,1H,ArH),6.90-6.82(m,2H,(ArH)2),5.49-5.26(m,4H,(CH=CH)2),3.92(s,3H,OCH3),2.82-2.76(m,2H,CH2), 2.71-2.61(m,2H,CH2),2.44(s,3H,CH3),2.10-1.99(m,4H,(CH2)2),1.75 -1.66(m,2H,CH2),1.47-1.23(m,14H,(CH2)7),0.90(t,J=6.7Hz,3H,CH3). 19 F NMR (377MHz, CDCl3) δ -69.24. 13C NMR (101MHz, CDCl3) δ 162.7, 159.5, 157.4 (q, J = 32.3Hz), 146.0, 132.4, 130.3, 129.9, 128.2, 127.8, 121.3, 120.6 (q, J = 277.8Hz), 114.5, 112.8, 55.8, 31.5, 29.6, 29.56, 29.3, 29.05, 29.02, 27.2, 27.1, 26.4, 25.8, 25.6, 22.57, 22.1, 14.1. HRMS (ESI) m / z: calculated value C 28 H 40 F3NO3Na[M+Na] + 518.2852, measured value 518.2850.

[0075] I-40: Colorless liquid, yield: 70%. 1 H NMR(400MHz, CDCl3)δ7.79(d,J=7.9Hz,1H,ArH),6.89-6.80(m,2H,(ArH)2),5.47-5.29(m,6H,(CH=CH)3),3.91(s,3H,OCH3),2.83(m,4H,(CH 2)2),2.64(m,2H,CH2),2.43(s,3H,CH3),2.16-2.01(m,4H,(CH2)2),1.70(m,2H,CH2),1.47-1.24(m,8H,(CH2)4),0.99(t,J=6.7Hz,3H,CH3). 19 F NMR (377MHz, CDCl3) δ -69.23. 13 CNMR (101MHz, CDCl3) δ 162.7, 159.5, 157.4 (q, J = 32.3Hz), 146.0, 132.4, 132.0, 130.1, 128.3, 128.2, 127.8, 127.1, 121.3, 120.6 (q, J = 277.8Hz), 114.6, 112.8, 55.8, 29.6, 29.5, 29.05, 29.03, 27.2, 26.4, 25.8, 25.6, 25.5, 22.1, 20.5, 14.3. HRMS (ESI) m / z: Calculated value C 28 H 38 F3NO3Na[M+Na] + 516.2696, measured value 516.2696.

[0076] I-41: Pale yellow liquid, yield: 72%. 7.79(d, J=7.9Hz, 1H, ArH), 6.89-6.81(m, 2H, (ArH)2), 5.52-5.30(m, 8H, (CH=CH)4), 3.91(s, 3H, OCH3), 2.89-2.79(m, 6H, (CH2)3), 2.70-2.62(m, 2H, CH2), 2.46-2.41(m, 3H, CH3), 2.21(m, 2H, CH2), 2.10-2.03(m, 2H, CH2), 1.85-1.74(m, 2H, CH2), 1.41-1.24(m, 6H, (CH2)3), 0.91(t, J=6.9Hz, 3H, CH3). 19 F NMR (377MHz, CDCl3) δ -69.33. 13 C NMR (101MHz, CDCl3) (missing one carbon signal) δ 162.6, 159.5, 157.1 (q, J = 32.3Hz), 146.1, 132.4, 130.5, 129.5, 128.7, 128.4, 128.2, 127.8, 127.7, 127.5, 121.3, 120.5 (q, J = 277.8Hz), 114.5, 112.8, 55.8, 31.5, 29.3, 27.2, 27.1, 26.0, 25.7, 25.64, 25.62, 22.6, 22.1, 14.1. HRMS (ESI) m / z: calculated value C 30 H 40 F3NO3Na[M+Na] + 542.2852, measured value 542.2853.

[0077] I-42: Colorless liquid, yield: 80%. 1 H NMR (400MHz, CDCl3) δ7.28-7.25(m,1H,ArH),6.95-6.82(m,3H,(ArH)3),3.87-3.79(m,5H,COCH2+OCH3) ,2.48-2.41(m,2H,CH2),1.54-1.43(m,2H,CH2),1.32-1.25(m,10H,(CH2)5),0.92(t,J=6.9Hz,3H,CH3). 19 F NMR (377MHz, CDCl3) δ -69.58. 13C NMR (101MHz, CDCl3) δ 166.4, 158.9, 156.7 (q, J = 32.3Hz), 132.8, 128.8, 120.6, 119.3 (q, J = 277.8Hz), 114.0, 112.0, 54.2, 39.0, 30.8, 28.5, 28.0, 25.1, 24.7, 23.1, 21.6, 13.0. HRMS (ESI) m / z: calculated value C 19 H 26 F3NO3Na[M+Na] + 396.1757, measured value 396.1761.

[0078] I-43: Colorless liquid, yield: 89%. 1 H NMR (400MHz, CDCl3) δ7.28-7.25(m,1H,ArH),6.93-6.83(m,3H,(ArH)3),3.87-3.80(m,5H,COCH2+OCH3) ,2.49-2.41(m,2H,CH2),1.54-1.42(m,2H,CH2),1.32-1.25(m,16H,(CH2)8),0.91(t,J=6.9Hz,3H,CH3). 19 F NMR (377MHz, CDCl3) δ -69.56. 13 C NMR (101MHz, CDCl3) δ 167.3, 159.9, 157.5 (q, J = 32.3Hz), 133.9, 129.8, 121.6, 120.3 (q, J = 277.8Hz), 115.0, 113.0, 55.2, 40.0, 31.9, 29.60, 29.57, 29.4, 29.3, 29.1, 26.1, 25.8, 24.1, 22.7, 14.1. HRMS (ESI) m / z: calculated value C 22 H 32 F3NO3Na[M+Na] + 438.2226, measured value 438.2224.

[0079] I-44: Colorless liquid, yield: 85%. 1 H NMR (400MHz, CDCl3) δ7.28-7.22(m,1H,ArH),6.91-6.81(m,3H,(ArH)3),3.84-3.75(m ,5H,COCH2+OCH3),2.47-2.37(m,2H,CH2),1.50-1.42(m,2H,CH2),1.25(m,28H,(CH2) 14),0.88(t,J=6.9Hz,3H,CH3). 19 F NMR (377MHz, CDCl3) δ -69.56. 13 C NMR (101MHz, CDCl3) (missing three carbon signals) δ 167.3, 159.9, 157.7 (q, J = 32.3Hz), 133.9, 129.8, 121.6, 120.3 (q, J = 277.8Hz), 115.0, 113.0, 55.2, 40.0, 31.9, 29.7, 29.68, 29.66, 29.64, 29.59, 29.57, 29.4, 29.36, 29.1, 26.1, 25.8, 22.7, 14.1. HRMS (ESI) m / z: calculated C 28 H 44 F3NO3Na[M+Na] + 522.3165, measured value 522.3162.

[0080] I-45: Pale yellow liquid, yield: 67%. 1 H NMR (400MHz, CDCl3) δ7.26-7.23(m,1H,ArH),6.90-6.80(m,3H,(ArH)3),5.53-5.27(m,8H,(CH=CH)4),3.80(s,2H,COCH2),3.79(s,3H,OCH3),2.82 (m,6H,(CH2)3),2.47-2.37(m,2H,CH2),2.11-1.99(m,4H,(CH2)2),1.56-1.50(m,2H,CH2),1.38-1.22(m,6H,(CH2)3),0.89(t,J=6.9Hz,3H,CH3). 19 F NMR (377MHz, CDCl3) δ -69.60. 13 C NMR (101MHz, CDCl3) δ 167.2, 159.9, 157.4 (q, J = 32.3Hz), 133.8, 130.6, 129.8, 129.6, 128.7, 128.5, 128.0, 127.8, 127.7, 127.5, 121.6, 120.3 (q, J = 277.8Hz), 115.0, 113.0, 65.6, 55.2, 40.0, 31.5, 30.6, 29.3, 27.2, 27.0, 25.7, 25.6, 25.5, 22.6, 14.0. HRMS (ESI) m / z: calculated value C 30 H 41 F3N2O2Na[M+Na] +542.2852, measured value 542.2847.

[0081] I-46: Colorless liquid, yield: 83%. 1 H NMR (400MHz, CDCl3) δ7.22-7.11(m,4H,(ArH)4),3.79(s,2H,COCH2),2.48-2.38(m,2H,CH2),2. 34(s,3H,CH3),1.50-1.39(m,2H,CH2),1.32-1.21(m,10H,(CH2)5),0.90(t,J=6.6Hz,3H,CH3). 19 F NMR (377MHz, CDCl3) δ -69.58. 13 C NMR (101MHz, CDCl3) δ 166.5, 156.6 (q, J = 32.3Hz), 136.2, 128.5, 128.4, 128.1, 119.3 (q, J = 277.8Hz), 38.6, 30.8, 28.6, 28.1, 28.0, 25.0, 24.7, 21.6, 20.0, 13.0. HRMS (ESI) m / z: calculated value C 19 H 26 F3NO2Na[M+Na] + 380.1808, measured value 380.1807.

[0082] I-47: Colorless liquid, yield: 87%. 1 H NMR (400MHz, CDCl3) δ7.21-7.12(m,4H,(ArH)4),3.79(s,2H,COCH2),2.45-2.38(m,2H,CH2),2. 34(s,3H,CH3),1.50-1.40(m,2H,CH2),1.36-1.20(m,12H,(CH2)6),0.89(t,J=6.6Hz,3H,CH3). 19 F NMR (377MHz, CDCl3) δ -69.58. 13 C NMR (101MHz, CDCl3) (missing one carbon signal) δ 167.6, 157.6 (q, J = 32.3Hz), 137.2, 129.5, 129.1, 120.4 (q, J = 277.8Hz), 39.7, 31.9, 29.6, 29.4, 29.3, 29.1, 26.0, 25.8, 22.7, 21.0, 14.1. HRMS (ESI) m / z: calculated value C 20 H 28 F3NO2Na[M+Na]+ 394.1964, measured value 394.1968.

[0083] I-48: Colorless liquid, yield: 83%. 1 H NMR(400MHz, CDCl3)δ7.24-7.15(m,4H,(ArH)4),3.86-3.78(s,2H,COCH2),2.49-2.41(m,2H,CH2) ,2.36(s,3H,CH3),1.53-1.42(m,2H,CH2),1.33-1.24(m,16H,(CH2)8),0.91(t,J=6.6Hz,3H,CH3). 19 FNMR (377MHz, CDCl3) δ -69.58. 13 CNMR (101MHz, CDCl3) δ 166.6, 156.6 (q, J = 32.3Hz), 136.2, 128.5, 128.4, 128.1, 119.3 (q, J = 277.8Hz), 38.6, 30.9, 28.6, 28.58, 28.4, 28.3, 28.1, 28.07, 25.1, 24.7, 21.67, 20.0, 13.1. HRMS (ESI) m / z: Calculated value C 22 H 32 F3NO2Na[M+Na] + 422.2277, measured value 422.2280.

[0084] I-49: Pale yellow liquid, yield: 90%. 1 H NMR (400MHz, CDCl3) δ7.22-7.12(m,4H,(ArH)4),3.79(s,2H,COCH2),2.45-2.38(m,2H,CH2),2.34(s,3H,CH3),1.50-1.39(m,2H,CH2),1.26(m,24H,(CH2) 12 ),0.87(t,J=6.6Hz,3H,CH3). 19 F NMR (377MHz, CDCl3) δ -69.59. 13C NMR (101MHz, CDCl3) δ 166.6, 156.6 (q, J = 32.3Hz), 136.2, 128.5, 128.4, 128.1, 119.3 (q, J = 277.8Hz), 38.6, 30.9, 28.7, 28.69, 28.67, 28.62, 28.59, 28.43, 28.38, 28.1, 25.1, 24.7, 24.4, 23.1, 21.7, 20.0, 13.1. HRMS (ESI) m / z: calculated value C 26 H 40 F3NO2Na[M+Na] + 478.2903, measured value 478.2898.

[0085] I-50: Colorless liquid, yield: 88%. 1 H NMR(400MHz, CDCl3)δ7.20-7.12(m,4H,(ArH)4),3.79(s,2H,COCH2),2.44-2.38 (m,2H,CH2),2.34(s,3H,CH3),1.50-1.40(m,2H,CH2),1.28-1.24(m,28H,(CH2) 14 ),0.88(t,J=6.6Hz,3H,CH3). 19 F NMR (377MHz, CDCl3) δ -69.59. 13 C NMR (101MHz, CDCl3) (missing one carbon signal) δ 167.6, 157.6 (q, J = 32.3Hz), 137.2, 129.5, 129.4, 129.1, 120.3 (q, J = 277.8Hz), 39.6, 31.95, 29.72, 29.70, 29.68, 29.63, 29.61, 29.44, 29.39, 29.2, 29.1, 26.1, 25.8, 25.4, 24.1, 22.7, 21.1, 14.1. HRMS (ESI) m / z: calculated value C 28 H 44 F3NO2Na[M+Na] + 506.3216, measured value 506.3212.

[0086] I-51: Pale yellow liquid, yield: 78%. 1H NMR (400MHz, CDCl3) δ7.22-7.12(m,4H,(ArH)4),5.43-5.29(m,2H,CH=CH),3.79(s,2H,COCH2),2.45-2.38 (m,2H,CH2),2.34(s,3H,CH3),2.09-1.94(m,4H,(CH2)2),1.50-1.41(m,2H,CH2),1.36-1.21(m,20H,(CH2) 10 ),0.88(t,J=6.6Hz,3H,CH3). 19 F NMR (377MHz, CDCl3) δ -69.58. 13 C NMR (101MHz, CDCl3) δ 167.6, 157.6 (q, J = 32.3Hz), 137.2, 130.2, 129.6, 129.5, 129.4, 129.2, 120.3 (q, J = 277.8Hz), 39.6, 31.9, 29.8, 29.7, 29.6, 29.57, 29.5, 29.3, 29.1, 29.0, 27.3, 27.2, 26.1, 25.7, 22.7, 21.1, 14.1. HRMS (ESI) m / z: calculated value C 28 H 42 F3NO2Na[M+Na] + 504.3060, measured value 504.3058.

[0087] I-52: Pale yellow liquid, yield: 62%. 1 HNMR(400MHz, CDCl3)δ7.21-7.12(m,4H,(ArH)4),5.44-5.33(m,8H,(CH=CH)4),3.79(s,2H,COCH2),2.86-2.77(m,6H,(CH2)3 ),2.48-2.40(m,2H,CH2),2.33(s,3H,CH3),2.09-2.02(m,4H,(CH2)2),1.37-1.26(m,8H,(CH2)4),0.89(t,J=6.8Hz,3H,CH3). 19 F NMR (377MHz, CDCl3) δ -69.60. 13C NMR (101MHz, CDCl3) δ 167.5, 157.1 (q, J = 32.3Hz), 137.3, 130.6, 129.5, 129.5, 129.4, 129.1, 128.7, 128.5, 128.0, 127.8, 127.7, 127.5, 120.3 (q, J = 277.8Hz), 39.5, 31.5, 29.3, 27.2, 27.0, 25.7, 25.6, 25.5, 25.3, 23.7, 22.6, 21.1, 14.0. HRMS (ESI) m / z: calculated value C 30 H 40 F3NNaO2[M+Na] + 526.2903, measured value 526.2900.

[0088] Example 1

[0089]

[0090] Preparation of 1-substituted-1-(2,4-dimethoxyphenyl)ones (Compound VI)

[0091] Under ice-water bath conditions, carboxylic acids VII (1.0 eq, 0.05 mol), 1,3-dimethoxyphenyl (1.0 eq, 0.05 mol), and phosphoric acid (1.1 eq, 0.055 mol) with different structures were added to a round-bottom flask. The mixture was cooled to 0°C with magnetic stirring, and then trifluoroacetic anhydride (4.0 eq, 0.2 mol) was slowly added dropwise. After the addition was complete, the reaction solution was poured into an excess of pre-cooled sodium hydroxide solution and magnetically stirred. Within a few minutes, a white solid precipitated, which was directly filtered to obtain the product; or a yellow oily substance floated on the aqueous solution, which was extracted with ethyl acetate, concentrated under reduced pressure, and separated by silica gel column chromatography to obtain the intermediate 1-substituted-1-(2,4-dimethoxyphenyl)one (VI).

[0092] Example 2

[0093]

[0094] Preparation of 1-substituted trifluoromethyl ketone (V) compounds

[0095] Under argon atmosphere, sodium hydride (2.0 eq, 12 mmol), ethyl trifluoromethyl (4.0 eq, 24 mmol), and intermediate ketone (compound VI, 1.0 eq, 6 mmol) were added to a Schlenk flask, along with 25 mL of tetrahydrofuran solvent. The reaction mixture was then heated to reflux and reacted for 12 h. Subsequently, the reaction flask was placed in an ice-water bath under argon protection. After the reaction mixture had completely cooled, excess deionized water was slowly added to quench the reaction. The reaction mixture was extracted with ethyl acetate, the organic layer was collected, and the solvent was concentrated under vacuum. After purification and enrichment by silica gel column chromatography, pure 1-substituted trifluoromethyl ketone (V) compound was obtained.

[0096] Example 3

[0097]

[0098] Preparation of 1-substituted acylhydrazide(III) compounds

[0099] An ester with different substituents (compound IV, 1 eq, 5 mmol) was dissolved in methanol (20 mL), and 85% hydrazine monohydrate (2 mL) was added. The mixture was heated to reflux for 8 h until no ester (IV) starting material remained as monitored by TLC. Subsequently, the solvent was removed under reduced pressure to obtain a white solid. To remove excess hydrazine monohydrate from the solid, it was washed with a small amount of deionized water and dried to obtain the intermediate 1-substituted hydrazide (III) compound.

[0100] Example 4

[0101]

[0102] Preparation of trifluoromethylimine derivatives I-1 to I-35

[0103] 1-Substituted trifluoromethyl ketone (compound VI, 1 eq, 1 mmol), intermediate 1-substituted acylhydrazine (compound IV, 2 eq, 2 mmol), and acetic acid (1.5 eq, 1.5 mmol) were dissolved in ethanol (20 mL), and the mixture was heated to reflux under stirring and reacted for 12 h. The solvent was removed under reduced pressure, and the mixture was purified by silica gel column chromatography using petroleum ether / ethyl acetate as the mobile phase to obtain the target compounds, trifluoromethylimine derivatives I-1 to I-35.

[0104] Example 5

[0105]

[0106] Preparation of 1-substituted trifluoromethyl oxime(II)

[0107] First, hydroxylamine hydrochloride (1.5 eq, 4.5 mmol) and pyridine (2.5 eq, 7.5 mmol) were dissolved in ethanol (30 mL), and the reaction mixture was heated to 75 °C to homogenize the system. Then, 1-substituted trifluoromethyl ketone (compound V, 1 eq, 3 mmol) was added dropwise to the reaction system, and the reaction was continued for 2.5 h. After the reaction was complete, the solvent was removed under reduced pressure to obtain a concentrate. The concentrate was redissolved in ethyl acetate and washed with saturated NH4Cl solution. The organic layer was separated and washed twice with water and once with saturated brine, then dried over anhydrous sodium sulfate. After removing the solvent under reduced pressure, the crude product was obtained. The intermediate 1-substituted trifluoromethyl oxime (II) was purified by silica gel column chromatography using petroleum ether / ethyl acetate as the mobile phase.

[0108] Example 6

[0109]

[0110] Preparation of trifluoromethylimine derivatives I-36 to I-52

[0111] 1-substituted trifluoromethyl oxime (compound II, 1 eq, 1 mmol), various substituted carboxylic acids, 4-dimethylaminopyridine (DMAP, 0.1 eq, 0.1 mmol), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 2.5 eq, 2.5 mmol) were dissolved in dichloromethane (20 mL) and reacted at room temperature for 12 h. After the reaction was complete, the solvent was removed under reduced pressure, and the target compounds, trifluoromethylimide derivatives I-36 to I-52, were purified by silica gel column chromatography using petroleum ether / ethyl acetate as the mobile phase.

[0112] Example 7

[0113] Cytotoxicity assay of trifluoromethylimine derivative (I)

[0114] Cell viability was determined using the MTT assay (3-(4,5-dimethylthiazol-2)-2,5-diphenyltetrazolium bromide), with compound (I) and the positive control drugs indomethacin and arachidonic acid trifluoromethyl ketone (AACOCF3) at a concentration of 30 μM. RAW 264.7 cells were selected for the assay, and 1 × 10⁶ cells were seeded per well in a 96-well plate. 5Cells were cultured in DMEM complete medium supplemented with 10% fetal bovine serum and 1% penicillin and streptomycin, and placed in a 37°C incubator containing 5% CO2. 24 h after inoculation, compound (I) or a positive control drug (both dissolved in DMSO, final concentration 0.5%) was added. One h later, lipopolysaccharide (LPS) was added to a final concentration of 1 μg / mL. After 24 h of culture, MTT was added to the culture medium to a final concentration of 0.5 mg / mL, and cultured for another 4 h. The medium was then removed, and 150 μL of DMSO was added to each well. The plates were shaken for 10 min, and the absorbance at 570 nm was measured using a microplate reader. The results are as follows: Figure 1 Except for compounds I-10, I-14 and I-15, the other compounds showed no cytotoxicity at the tested concentrations.

[0115] Example 8

[0116] Determination of the inhibitory effect of trifluoromethylimine derivative (I) on NO release

[0117] Inflammatory effects are associated with many inflammatory mediators, including cytokines, NO, and enzymes, which are released when macrophages produce different phenotypes in response to stimuli. NO, catalyzed by iNOS, is considered an important mediator in the inflammatory process and has been reported to affect the products of the cyclooxygenase metabolic pathway, producing two cyclooxygenase isoforms, COX-1 and COX-2.

[0118] The inflammatory factor NO was detected using Griess reagent. RAW 264.7 cell line was used for the assay, with 1 × 10⁶ cells seeded per well in a 96-well plate. 5 Cells were cultured in DMEM complete medium supplemented with 10% fetal bovine serum and 1% penicillin and streptomycin at 37°C in a 5% CO2 incubator. 24 h after seeding, 10 μM compound (I) or a positive control drug (both dissolved in DMSO, final DMSO concentration 0.5%) was added. One h later, lipopolysaccharide (LPS) was added to a final concentration of 1 μg / mL. After 24 h of culture, 100 μL of supernatant was transferred from each well to a 96-well plate, followed by 50 μL of Griess reagent A and incubation at 37°C for 10 min. Then, 50 μL of Griess reagent B was added, and the plates were incubated at 37°C for another 10 min. The absorbance at 550 nm was then measured using a microplate reader.

[0119] The results are as follows Figure 2Most of the compounds inhibited NO release to varying degrees, exhibiting in vitro anti-inflammatory activity. Structure-activity relationship (SAR) analysis based on preliminary results from this embodiment indicated that in the trifluoromethyl ketone side, unsaturated long carbon chains, particularly arachidonic acid groups (e.g., I-9, I-16, I-26, I-35, I-41, and I-45) and linolenic acid groups (e.g., I-8, I-26, and I-40), were more effective than saturated carbon chains. Compounds I-8, I-25, and I-26, and their bioisostere I-45, showed stronger NO release inhibition than the positive control drug indomethacin. Therefore, a series of concentrations (20, 10, 5, 2.5, and 1.25 μM) were set to further determine the IC50 values ​​of these four compounds. 50 The results are shown in Table 1. Compound I-26 among the four compounds had a lower IC50 than the positive control drug indomethacin. 50 This means that I-26 has stronger anti-inflammatory activity. Therefore, I-26 was identified as the active compound for further in vivo anti-inflammatory activity assays.

[0120] Table 1 shows the inhibitory effects of some compounds on NO.

[0121]

[0122] *RAW264.7 cells were pretreated with different concentrations (20, 10, 5, 2.5 and 1.25 μM) of the compound for 1 h, followed by co-culture with LPS (1 μg / mL) for 24 h; the NO concentration in the culture supernatant was determined by Griess reagent.

[0123] Example 9

[0124] Determination of the anti-inflammatory and analgesic effects of compound I-26 in an adjuvant-induced rat model of arthritis

[0125] Adjuvant-induced arthritis (AIA), as an animal model of inflammatory and reactive rheumatoid arthritis, is the industry-standard model for predicting the clinical efficacy of novel nonsteroidal anti-inflammatory drugs (NSAIDs). Furthermore, because the changes in pathological state in animals after adjuvant injection are similar to those in clinical rheumatoid arthritis, the AIA model is also considered most suitable for comparison with human rheumatoid arthritis.

[0126] 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 hind paw of each male Lewis rat (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 4 groups of 6 rats each. From day 8 to day 28 after immunization, the rats were treated daily by gavage with I-26 (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. The rats' body weight and left hind paw volume were measured every 2 days, and standardized clinical scores were performed on the three untreated paws (symptom severity was scored from mild to severe on a scale of 0-4, 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 was performed on the center of the left hind paw using von Frey fiber (North Coast, USA) and the "up and down" method provided by the instrument manufacturer. The force that caused the rat to withdraw its paw or make a sound was measured. The specific operation method and data statistics were performed according to the specific instructions provided by the instrument manufacturer.

[0127] The results are as follows Figure 3 As shown, compound I-26 significantly improved adjuvant-induced weight loss in rats in a dose-dependent manner. Figure 3 A) Swelling of the feet ( Figure 3 B) and clinical symptoms such as redness, swelling, and deformity of the feet and claws. Figure 3 C). Furthermore, the 50% mechanical pain threshold (50% MWT) in rats treated with compound I-26 was significantly higher than that in the model group, indicating good analgesic activity. Figure 3 (D) This also suggests that compound I-26 may clinically alleviate tenderness symptoms in rheumatoid arthritis. These results indicate that I-26 may have a positive impact on reducing symptoms and pain and improving the quality of life in patients with rheumatoid arthritis.

[0128] The embodiments described above are merely preferred embodiments for fully illustrating the present invention, and their protection scope is not limited thereto. Equivalent substitutions or modifications made by those skilled in the art based on the present invention are all within the protection scope of the present invention, which is defined by the claims.

Claims

1. A trifluoromethylimine derivative, characterized in that, It has the structure shown in the following general formula (I): （I） in, R 1 Selected from -C8H 17 , -C9H 19 , -C 11 H 23 , -C 13 H 27 , -C 15 H 31 , -C 17 H 35 , -C 21 H 43 , -( Z )-C7H 14 CH=CHC8H 17 ,-( Z,Z )-C7H 14 CH=CHCH2CH=CHC5H 11 , -( Z,Z,Z )-C7H 14 CH=CHCH2CH=CHCH2CH=CHC2H5, -( Z,Z,Z,Z )-C2H4CH=CHCH2CH=CHCH2CH=CHCH2CH=C5H 11 Any one of them; R 2 Selected from , (R 3 ) n Selected from any one or combination of methyl, methoxy, m is 0 or 1, and the wavy line indicates the connection position; X is selected from NH and O.

2. A method for preparing a trifluoromethylimine derivative, characterized in that, The synthetic route for the compound represented by formula (I) according to claim 1 is as follows: In equations (I)-(VII), R 1 R 2 The definition is the same as in claim 1.

3. The method for preparing a trifluoromethylimine derivative as described in claim 2, characterized in that, The specific synthesis method is as follows: R as shown in equation (VII) 1 Using substituted carboxylic acids as starting materials, Friedel-Crafts acylation reaction is carried out to generate ketone compounds as shown in formula (VI); Using the ketone compound shown in formula (VI) as a raw material, a trifluoromethyl ketone compound shown in formula (V) is generated through an ester / ketone exchange reaction; Using the ester compound shown in formula (IV) as a raw material, the ester undergoes ammonolysis to generate the acylhydrazine compound shown in formula (III); Using the trifluoromethyl ketone compound shown in formula (V) and the acyl hydrazine compound shown in formula (III) as raw materials, a trifluoromethyl imine derivative shown in formula (I) is generated through a condensation reaction, where X = NH; Using the trifluoromethyl ketone compound shown in formula (V) as a raw material, a condensation reaction is carried out to generate the oxime compound shown in formula (II); Using the oxime compound shown in formula (II) as a raw material, a condensation reaction is carried out to generate the trifluoromethylimine derivative shown in formula (I), X=O.

4. The use of the trifluoromethylimine derivative as described in any one of claims 1-3, characterized in that, Used in the preparation of anti-inflammatory and analgesic drugs.

5. The use of the trifluoromethylimine derivative according to claim 4, for the preparation of a medicament for treating acute and chronic inflammation, including rheumatoid arthritis.

6. An anti-inflammatory drug, characterized in that, The main component is the trifluoromethylimine derivative as described in any one of claims 1-3.

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