Fluoromethyl substituted indeno [1, 2-b] pyridine compound with anti-cancer activity and synthesis method of fluoromethyl substituted indeno [1, 2-b] pyridine compound

Abstract

The invention discloses a fluoromethyl substituted indeno [1, 2-b] pyridine compound with anticancer activity and a synthesis method thereof, and belongs to the technical field of organic synthesis and drug discovery. A 5-arylimidazole compound 1, a fluoromethyl acetylenic ketone compound 2, a rhodium catalyst, an additive and a solvent are mixed, a temperature rise reaction is performed to prepare the fluoromethyl substituted indeno [1, 2-b] pyridine compound, and the structural general formula of the compound is # imgabs0 #. The preparation method is completed by adopting a one-pot cascade reaction, and the process is simple and efficient; the obtained fluoromethyl substituted indeno [1, 2-b] pyridine compound has the activity of obviously inhibiting proliferation of three kinds of cancer cells such as Hela, A549 and HCT-116, so that the compound disclosed by the invention has the anti-cancer activity on cervical cancer, lung cancer and colon cancer, has potential medicinal value, and provides a new structural unit for drug screening.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis and drug discovery, and specifically relates to fluoromethyl-substituted indeno[1,2-b]pyridine compounds with anticancer activity and a synthesis method thereof. Background Art

[0002] Indeno[1,2-b]pyridine structural units are widely present in natural products and drug molecules. Studies have shown that many indeno[1,2-b]pyridine derivatives have biological activities such as anti-tumor, anti-malarial, anti-viral, anti-allergic, anti-inflammatory and bactericidal. In addition, indeno[1,2-b]pyridine compounds also have unique optical properties and can be used as luminescent ligands in the fields of electronic luminescent materials. On the other hand, the introduction of fluoromethyl structural units usually has a significant effect on the physicochemical properties, biological activity and metabolic stability of the parent compound, and is one of the advantageous structural units for new drug design.

[0003] At present, although some synthetic methods for indeno[1,2-b]pyridine compounds have been developed, most of these methods are based on the cyclization reaction of 2-arylpyridine or aryl(pyridin-3-yl)methanone derivatives, which require the step-by-step construction of the five-membered ring in the tricyclic skeleton. There are inevitably problems such as many reaction steps, difficult to obtain substrates, harsh reaction conditions and low atom economy.

[0004] Therefore, researching and developing a green and efficient new method for synthesizing fluoromethyl-substituted indeno[1,2-b]pyridine compounds from cheap and readily available raw materials through simple steps has important theoretical significance and practical prospects both for organic chemistry and medicinal chemistry. Summary of the invention

[0005] In order to solve the problems existing in the prior art, one of the objectives of the present invention is to provide fluoromethyl-substituted indeno[1,2-b]pyridine compounds, which have anticancer activity.

[0006] The second object of the present invention is to provide the use of fluoromethyl substituted indeno[1,2-b]pyridine compounds in the preparation of anticancer drugs.

[0007] The third object of the present invention is to provide a pharmaceutical composition for treating cervical cancer, lung cancer and colon cancer, wherein the active ingredient is the fluoromethyl-substituted indeno[1,2-b]pyridine compound provided by the present invention.

[0008] A fourth object of the present invention is to provide a method for synthesizing fluoromethyl-substituted indeno[1,2-b]pyridine compounds.

[0009] In order to achieve the above object, the technical solution adopted by the present invention is as follows:

[0010] Fluoromethyl substituted indeno[1,2-b]pyridine compounds, the general structural formula of which is:

[0011]

[0012] Where: R 1 Selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, phenyl or halogen; R 2 Selected from C 1-4 Alkyl, C 3-5 Cycloalkyl, phenyl or substituted phenyl, the substituents on the substituted phenyl ring are selected from C 1-4 Alkyl or halogen; R 3 Selected from hydrogen or C 1-4 Alkyl; or R 2 and R 3 The combination is 1,3-propanediyl or 1,4-butanediyl; R 4 is selected from naphthyl, thienyl, phenyl or substituted phenyl, wherein the substituent on the phenyl ring of the substituted phenyl is a mono- or poly-substituted C 1-4 Alkyl, C 1-4 Alkoxy or halogen; R 5 is selected from hydrogen, methyl, fluorine or trifluoromethyl.

[0013] Furthermore, in the above general structure, in the most preferred case, the following specific structures are selected:

[0014]

[0015] The present invention designs experiments to verify that the compounds provided by the present invention have the activity of inhibiting the proliferation of three cancer cells, Hela, A549 and HCT-116, indicating that the compounds of the present invention can be used as active ingredients of drugs for treating cancers such as cervical cancer, lung cancer and colon cancer. In particular, the above-mentioned preferred compounds can significantly inhibit the growth and proliferation of Hela, A549 and HCT-116, indicating that such compounds as active ingredients of anticancer drugs have the effects of preventing, treating and inhibiting the progression of cervical cancer, lung cancer and colon cancer.

[0016] The present invention also provides a method for synthesizing the above-mentioned fluoromethyl-substituted indeno[1,2-b]pyridine compounds, and the technical scheme adopted is:

[0017] The synthesis method of fluoromethyl substituted indeno[1,2-b]pyridine compounds comprises the following steps: mixing a 5-aryl imidazole compound 1, a fluoromethyl alkynyl ketone compound 2, a rhodium catalyst, an additive and a solvent, and heating the mixture to obtain a fluoromethyl substituted indeno[1,2-b]pyridine compound 3, wherein the reaction formula is:

[0018]

[0019] Where: R is selected from C 1-6 Alkyl or phenyl; R 1 Selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, phenyl or halogen; R 2 Selected from C 1-4 Alkyl, C 3-5 Cycloalkyl, phenyl or substituted phenyl, the substituents on the substituted phenyl ring are selected from C 1-4 Alkyl or halogen; R 3 Selected from hydrogen or C 1-4 Alkyl; or R 2 and R 3 The combination is 1,3-propanediyl or 1,4-butanediyl; R 4 is selected from naphthyl, thienyl, phenyl or substituted phenyl, wherein the substituent on the phenyl ring of the substituted phenyl is a mono- or poly-substituted C 1-4 Alkyl, C 1-4 Alkoxy or halogen; R 5 is selected from hydrogen, methyl, fluorine or trifluoromethyl.

[0020] Furthermore, in the above technical scheme, the rhodium catalyst is dichloro(pentamethylcyclopentadienyl)rhodium dimer ([RhCp*Cl2]2) or di(hexafluoroantimonate)triacetonitrile(pentamethylcyclopentadienyl)rhodium ([RhCp*(MeCN)3](SbF6)2).

[0021] Furthermore, in the above technical solution, the additive is a mixture of zinc acetate, sodium acetate, potassium acetate or cesium acetate and silver bis(trifluoromethanesulfonyl)imide, silver hexafluoroantimonate, silver tetrafluoroborate, silver acetate, silver fluoride, silver trifluoromethanesulfonate or copper acetate.

[0022] Furthermore, in the above technical solution, the molar ratio of the 5-aryl imidazole compound 1, the fluoromethyl alkynyl ketone compound 2, the catalyst, and the additive is 1:1-1.5:0.03-0.06:1-2.

[0023] Furthermore, in the above technical solution, the solvent is hexafluoroisopropanol, trifluoroethanol or methanol.

[0024] Furthermore, in the above technical solution, the temperature-raising reaction is carried out under the condition of sealing the tube at 100-130°C.

[0025] Furthermore, in the above technical solution, the gas atmosphere is an air atmosphere.

[0026] Beneficial effects of the invention:

[0027] (1) The fluoromethyl-substituted indeno[1,2-b]pyridine compounds provided by the present invention are screened for compounds having various substituents and verified by anticancer cell activity tests. The compounds provided by the present invention have the activity of significantly inhibiting the proliferation of three cancer cells, namely Hela, A549 and HCT-116, indicating that the compounds of the present invention have anticancer activity against cervical cancer, lung cancer and colon cancer, have potential medicinal value, and provide new structural units for drug screening;

[0028] (2) The synthesis method provided by the present invention is completed by a one-pot series reaction between a 5-aryl imidazole compound and a fluoromethyl alkynyl ketone compound, and the process is simple and efficient;

[0029] (3) The synthetic method provided by the present invention has cheap and readily available raw materials, mild reaction conditions, simple operation, a wide range of substrate applications, and good functional group tolerance. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 This is the X-ray single crystal diffraction pattern of compound 3ab in Example 3.

[0031] Figure 2 This is the X-ray single crystal diffraction pattern of compound 5 in Example 4. DETAILED DESCRIPTION

[0032] The above contents of the present invention are further described in detail below through examples, but this should not be understood as the scope of the above subject matter of the present invention being limited to the following examples, and all technologies implemented based on the above contents of the present invention belong to the scope of the present invention.

[0033] Example 1

[0034]

[0035] Compound 1a, rhodium catalyst, additive 1 and additive 2, solvent and compound 2a were added to a 15 mL reaction tube in sequence, the reaction tube was sealed, and placed in an oil bath for stirring and heating for 4 h. After the reaction was completed, it was cooled to room temperature, filtered, concentrated, and separated by a silica gel column (petroleum ether / ethyl acetate = 40 / 1) to obtain a white solid product 3aa.

[0036] By changing the reaction conditions such as the material ratio, additive 1, additive 2, rhodium catalyst, solvent and reaction temperature, a series of results were obtained, as shown in Table 1.

[0037] Table 1 Synthesis of 3aa under various conditions a

[0038]

[0039] Example 2

[0040]

[0041] 1a (37.3 mg, 0.2 mmol), [RhCp*Cl2]2 (6.2 mg, 0.01 mmol), zinc acetate (55.0 mg, 0.3 mmol), silver acetate (6.7 mg, 0.04 mmol), 2a (47.6 mg, 0.24 mmol) and hexafluoroisopropanol (2 mL) were added to a 15 mL reaction bottle in sequence, and the bottle was sealed with a stopper, and the bottle was placed in a 120°C oil bath and stirred for 4 h. After the reaction was completed, the bottle was cooled to room temperature, filtered, and the filtrate was concentrated and separated by a silica gel column (petroleum ether / ethyl acetate = 40 / 1) to obtain a white solid product 3aa (45.3 mg, 70%). The characterization data of the compound are: 1 HNMR (400MHz, CDCl3): δ8.12(d,J=8.0Hz,1H),7.43(t,J=7.6Hz,1H),7.36(t,J=7.6Hz,1H ),7.26(d,J=8.4Hz,1H),7.22-7.21(m,4H),6.99-6.97(m,2H),5.21(s,1H),2.75(s,3H). 13 C{ 1 H}NMR (150MHz, CDCl3): δ162.5,159.6,149.6,139.7,138.3,134.9(q, 2 J C-F =33.8Hz),134.3(q, 3 J C-F =2.0Hz),130.2,128.6,128.0,127.8,127.1,125.3,123.0(q, 1 J C-F =272.9Hz),121.1,117.0(q, 3 J C-F =4.4Hz),51.7,24.6. 19 FNMR(376MHz,CDCl3):δ-62.50(s).HRMS(ESI)m / z:[M+H] + CalcdforC 20 H 15 F3N326.1151; Found326.1159.

[0042] Example 3

[0043] According to the method and steps of Example 2, by changing reactant 1 and reactant 2, various fluoromethyl-substituted indeno[1,2-b]pyridine compounds 3 can be synthesized. The specific results are as follows:

[0044] Table 2 Synthesis of fluoromethyl substituted indeno[1,2-b]pyridine compound 3 a,b

[0045]

[0046]

[0047] Representative product characterization data are as follows:

[0048] 2,7-Dimethyl-5-phenyl-4-(trifluoromethyl)-5H-indeno[1,2-b]pyridine(3ba)

[0049] 1 HNMR (400MHz, CDCl3): δ7.99 (d, J = 8.0Hz, 1H), 7.24-7.19 (m, 4H), 7.18 (s, 1 H),7.06(s,1H),6.98-6.96(m,2H),5.15(s,1H),2.73(s,3H),2.34(s,3H). 13 C{ 1 H}NMR (150MHz, CDCl3): δ162.7,159.4,149.9,140.6,139.9,135.8,134.7(q, 2 J C-F =34.5Hz),134.2(q, 3 J C-F =2.6Hz),128.9,128.6,128.0,127.1,125.8,123.1(q, 1 J C-F =272.7Hz),120.9,116.5(q, 3 J C-F =4.2Hz),51.6,24.6,21.8. 19 FNMR(376MHz,CDCl3):δ-62.47(s).HRMS(ESI)m / z:[M+H] + CalcdforC 21 H 17 F3N340.1308;Found340.1312.

[0050] 7-Butyl-2-methyl-5-phenyl-4-(trifluoromethyl)-5H-indeno[1,2-b]pyridine(3ca)

[0051] 1 HNMR(600MHz,CDCl3):δ8.01(d,J=8.4Hz,1H),7.25(dd,J1=7.8Hz,J2=0.6Hz,1H),7.24-7.18(m,3H),7.17(s,1H),7.06(s,1H),6.99-6.97(m,2H),5.16(s,1H),2.72(s,3H),2.59(t,J=7.8Hz,2H),1.58-1.53(m,2H),1.34-1.28(m,2H),0.89(t,J=7.2Hz,3H). 13 C{ 1 H}NMR(150MHz,CDCl3):δ162.7,159.4,149.9,145.7,139.9,136.0,134.7(q, 2 J C-F =34.4Hz),134.4(q, 3 J C-F =2.3Hz),128.6,128.3,128.1,127.0,125.1,123.1(q, 1 J C-F =271.4Hz),120.9,116.5(q, 3 J C-F =4.5Hz),51.6,36.0,33.7,24.5,22.4,13.9. 19 FNMR(565MHz,CDCl3):δ-62.47(s).HRMS(ESI)m / z:[M+H] + CalcdforC 24 H 23 F3N382.1777;Found382.1783.

[0052] 7-Methoxy-2-methyl-5-phenyl-4-(trifluoromethyl)-5H-indeno[1,2-b]pyridine(3da)

[0053] 1HNMR(600MHz,CDCl3):δ8.02(d,J=8.4Hz,1H),7.24-7.20(m,3H),7.13(s,1H),6.98-6.97(m,3H),6.76(d,J=2.4Hz,1H),5.14(s,1H),3.77(s,3H),2.72(s,3H). 13 C{ 1 H}NMR(150MHz,CDCl3):δ162.5,161.8,159.3,151.7,139.8,134.5(q, 2 J C-F =33.3Hz),133.9,131.3,128.6,128.0,127.1,123.1(q, 1 J C-F =273.9Hz),122.2,115.8(q, 3 J C-F =4.5Hz),114.4,110.3,55.5,51.6,24.5. 19 FNMR(565MHz,CDCl3):δ-62.48(s).HRMS(ESI)m / z:[M+H] + CalcdforC 21 H 17 F3NO356.1257;Found356.1246.

[0054] 2-Methyl-5,7-diphenyl-4-(trifluoromethyl)-5H-indeno[1,2-b]pyridine(3ea)

[0055] 1 HNMR(600MHz,CDCl3):δ8.17(d,J=7.8Hz,1H),7.68(dd,J1=7.8Hz,J2=0.6Hz,1H),7.55(d,J=7.2Hz,2H),7.46(s,1H),7.40(t,J=7.2Hz,2H),7.32(t,J=7.2Hz,1H),7.24-7.19(m,4H),7.02(d,J=6.6Hz,2H),5.27(s,1H),2.76(s,3H). 13 C{ 1 H}NMR(100MHz,CDCl3):δ162.3,159.7,150.3,143.3,140.8,139.5,137.5,134.8(q, 2 J C-F=33.8Hz),134.6,128.8,128.7,128.1,127.7,127.3,127.2,127.1,123.9,123.0(q, 1 J C-F =272.8Hz),121.4,117.0(q, 3 J C-F =4.3Hz),51.8,24.6. 19 FNMR(376MHz,CDCl3):δ-62.47(s).HRMS(ESI)m / z:[M+H] + CalcdforC 26 H 19 F3N402.1464;Found402.1459.

[0056] 7-Fluoro-2-methyl-5-phenyl-4-(trifluoromethyl)-5H-indeno[1,2-b]pyridine(3fa)

[0057] 1 HNMR(400MHz,CDCl3):δ8.07(dd,J1=8.4Hz,J2=5.2Hz,1H),7.24-7.21(m,4H),7.13(td,J1=8.8Hz,J2=2.0Hz,1H),6.98-6.93(m,3H),5.18(s,1H),2.74(s,3H). 13 C{ 1 H}NMR(150MHz,CDCl3):δ164.3(d, 1 J C-F =248.0Hz),161.6,159.8,151.8(d, 3 J C-F =8.4Hz),139.0,134.8(q, 2 J C-F =33.0Hz),134.4(d, 4 J C-F =2.3Hz),134.1,128.8,127.9,127.4,122.9(q, 1 J C-F =272.7Hz),122.6(d, 3 J C-F =10.4Hz),116.7(q, 3 J C-F =4.4Hz),115.5(d, 2 JC-F =22.5Hz),112.5(d, 2 J C-F =24.2Hz),51.7,24.5. 19 FNMR(376MHz,CDCl3):δ-62.53(s),-109.95(td,J1=9.4Hz,J2=5.3Hz).HRMS(ESI)m / z:[M+H] + CalcdforC 20 H 14 F4N344.1057;Found344.1063.7-Chloro-2-methyl-5-phenyl-4-(trifluoromethyl)-5H-indeno[1,2-b]pyridine(3ga)

[0058] 1 HNMR(600MHz,CDCl3):δ8.02(d,J=7.8Hz,1H),7.40(dd,J1=7.8Hz,J2=1.2Hz,1H),7.26-7.23(m,5H),6.97-6.95(m,2H),5.17(s,1H),2.74(s,3H). 13 C{ 1 H}NMR(150MHz,CDCl3):δ161.4,159.9,151.0,138.8,136.9,136.0,135.0(q, 2 J C-F =33.6Hz),134.1,128.8,128.4,128.0,127.5,125.6,122.9(q, 1 J C-F =273.2Hz),122.2,117.3(q, 3 J C-F =4.2Hz),51.6,24.6. 19 FNMR(565MHz,CDCl3):δ-62.52(s).HRMS(ESI)m / z:[M+H] + CalcdforC 20 H 14 ClF3N360.0761;Found360.0755.

[0059] 2,8-Dimethyl-5-phenyl-4-(trifluoromethyl)-5H-indeno[1,2-b]pyridine(3ha)

[0060] 1 HNMR(600MHz,CDCl3):δ7.94(s,1H),7.22-7.16(m,5H),7.13(d,J=7.8Hz,1H),6.97-6.96(m,2H),5.16(s,1H),2.74(s,3H),2.44(s,3H). 13 C{ 1 H}NMR(150MHz,CDCl3):δ162.6,159.4,147.0,139.9,138.4,137.8,134.83(q, 2 J C-F =32.3Hz),134.79,131.2,128.6,127.9,127.0,124.9,123.0(q, 1 J C-F =273.3Hz),121.5,116.9(q, 3 J C-F =4.4Hz),51.4,24.6,21.4. 19 FNMR(565MHz,CDCl3):δ-62.46(s).HRMS(ESI)m / z:[M+H] + CalcdforC 21 H 17 F3N340.1308;Found340.1305.

[0061] 8-Chloro-2-methyl-5-phenyl-4-(trifluoromethyl)-5H-indeno[1,2-b]pyridine(3ia)

[0062] 1 HNMR(600MHz,CDCl3):δ8.09(d,J=1.8Hz,1H),7.30(dd,J1=8.4Hz,J2=1.8Hz,1H),7.25(s,1H),7.24-7.20(m,3H),7.16(d,J=7.8Hz,1H),6.96-6.94(m,2H),5.17(s,1H),2.74(s,3H). 13 C{ 1 H}NMR(150MHz,CDCl3):δ161.2,160.0,147.7,140.1,139.0,135.1(q, 2 J C-F =33.8Hz),134.8(q, 3 J C-F=2.3Hz),134.2,130.1,128.7,127.9,127.4,126.4,122.9(q, 1 J C-F =274.2Hz),121.3,117.7(q, 3 J C-F =4.5Hz),51.4,24.5. 19 FNMR(565MHz,CDCl3):δ-62.51(s).HRMS(ESI)m / z:[M+H] + CalcdforC 20 H 14 ClF3N360.0761;Found360.0764.

[0063] 8-Methoxy-2-methyl-5-phenyl-4-(trifluoromethyl)-5H-indeno[1,2-b]pyridine(3ja)

[0064] 1 HNMR(600MHz,CDCl3):δ7.61(d,J=2.4Hz,1H),7.22-7.18(m,4H),7.13(d,J=8.4Hz,1H),6.97-6.95(m,2H),6.92(dd,J1=8.4Hz,J2=2.4Hz,1H),5.13(s,1H),3.90(s,3H),2.74(s,3H). 13 C{ 1 H}NMR(100MHz,CDCl3):δ162.5,159.9,159.4,142.1,139.9,139.6,135.4(q, 3 J C-F =1.4Hz),134.8(q, 2 J C-F =34.2Hz),128.6,127.9,127.0,126.0,123.0(q, 1 J C-F =272.9Hz),118.4,117.0(q, 3 J C-F =4.5Hz),104.2,55.7,51.0,24.6. 19 FNMR(565MHz,CDCl3):δ-62.41(s).HRMS(ESI)m / z:[M+H] + CalcdforC 21 H 17F3NO356.1257;Found356.1254.

[0065] 6-Methoxy-2-methyl-5-phenyl-4-(trifluoromethyl)-5H-indeno[1,2-b]pyridine(3ja')

[0066] 1 HNMR(600MHz,CDCl3):δ7.74(d,J=7.2Hz,1H),7.42(t,J=8.4Hz,1H),7.19(s,1H),7.17-7.13(m,3H),6.99-6.98(m,2H),6.85(d,J=7.8Hz,1H),5.32(s,1H),3.66(s,3H),2.73(s,3H). 13 C{ 1 H}NMR(150MHz,CDCl3):δ162.4,159.3,156.3,140.2,138.6,136.9,135.3,134.5(q, 2 J C-F =34.7Hz),129.8,128.5,127.9,126.6,123.0(q, 1 J C-F =272.1Hz),117.0(q, 3 J C-F =4.5Hz),113.6,112.4,55.5,49.6,24.5. 19 FNMR(565MHz,CDCl3):δ-62.61(s).HRMS(ESI)m / z:[M+H] + CalcdforC 21 H 17 F3NO356.1257;Found356.1251.

[0067] 9-Fluoro-2-methyl-5-phenyl-4-(trifluoromethyl)-5H-indeno[1,2-b]pyridine(3ka)

[0068] 1HNMR(600MHz,CDCl3):δ7.31(td,J1=7.8Hz,J2=4.8Hz,1H),7.25(s,1H),7.24-7.20(m,3H),7.11(t,J=9.6Hz,1H),7.05(d,J=7.8Hz,1H),6.98-6.97(m,2H),5.26(s,1H),2.78(s,3H). 13 C{ 1 H}NMR(100MHz,CDCl3):δ160.6(d, 3 J C-F =4.9Hz),160.3,158.0(d, 1 J C-F =255.8Hz),152.0(d, 3 J C-F =4.3Hz),139.1,134.8(q, 2 J C-F =33.6Hz),133.9(q, 3 J C-F =2.3Hz),131.4(d, 3 J C-F =7.7Hz),128.7,127.9,127.4,125.6(d, 2 J C-F =11.8Hz),122.9(q, 1 J C-F =273.0Hz),121.1(d, 4 J C-F =4.4Hz),117.0(q, 3 J C-F =4.1Hz),115.1(d, 2 J C-F =20.1Hz),52.0,24.8. 19 FNMR(376MHz,CDCl3):δ-62.53(s),-117.47(dd,J1=11.3Hz,J2=4.5Hz).HRMS(ESI)m / z:[M+H] + CalcdforC 20 H 14 F4N344.1057;Found344.1069.

[0069] 5-Phenyl-2-propyl-4-(trifluoromethyl)-5H-indeno[1,2-b]pyridine(3la)

[0070] 1 HNMR(400MHz,CDCl3):δ8.13(d,J=7.6Hz,1H),7.43(t,J=7.2Hz,1H),7.35(td,J1=7.6Hz,J2=1.2Hz,1H),7.27-7.19(m,5H),7.00-6.97(m,2H),5.21(s,1H),2.95(t,J=7.2Hz,2H),1.94-1.84(m,2H),1.05(t,J=7.6Hz,3H). 13 C{ 1 H}NMR(100MHz,CDCl3):δ163.6,162.5,149.6,139.8,138.5,134.8(q, 2 J C-F =33.0Hz),134.4(q, 3 J C-F =2.3Hz),130.1,128.6,128.0,127.8,127.1,125.2,123.1(q, 1 J C-F =273.1Hz),121.2,116.4(q, 3 J C-F =4.3Hz),51.8,40.4,23.2,14.0. 19 FNMR(565MHz,CDCl3):δ-62.41(s).HRMS(ESI)m / z:[M+H] + CalcdforC 22 H 19 F3N354.1464;Found354.1469.

[0071] 2-Cyclopropyl-5-phenyl-4-(trifluoromethyl)-5H-indeno[1,2-b]pyridine(3ma)

[0072] 1 HNMR(600MHz,CDCl3):δ8.05(d,J=7.8Hz,1H),7.39(t,J=7.8Hz,1H),7.32(td,J1=7.2Hz,J2=0.6Hz,1H),7.24-7.17(m,5H),6.98-6.96(m,2H),5.17(s,1H),2.21-2.16(m,1H),1.27-1.22(m,2H),1.10-1.08(m,2H). 13 C{1 H}NMR(100MHz,CDCl3):δ164.2,162.4,149.6,139.9,138.6,134.5(q, 2 J C-F =33.8Hz),133.7(q, 3 J C-F =2.7Hz),130.0,128.6,128.0,127.7,127.0,125.2,123.1(q, 1 J C-F =272.9Hz),121.1,115.1(q, 3 J C-F =5.0Hz),51.7,17.5,10.6,10.5. 19 FNMR(565MHz,CDCl3):δ-62.46(s).HRMS(ESI)m / z:[M+H] + CalcdforC 22 H 17 F3N352.1308;Found352.1315.

[0073] 2,5-Diphenyl-4-(trifluoromethyl)-5H-indeno[1,2-b]pyridine(3na)

[0074] 1 HNMR(400MHz,CDCl3):δ8.22(d,J=7.6Hz,1H),8.20-8.17(m,2H),7.79(s,1H),7.56-7.52(m,2H),7.50-7.45(m,2H),7.38(td,J1=7.6Hz,J2=1.2Hz,1H),7.28(d,J=7.6Hz,1H),7.26-7.21(m,3H),7.03-7.01(m,2H),5.28(s,1H). 13 C{ 1 H}NMR(150MHz,CDCl3):δ163.0,158.3,149.7,139.6,138.4,135.6,135.4(q, 2 J C-F =34.4Hz),130.4,129.7,129.0,128.7,128.1,128.0,127.2,125.3,123.1(q, 1 J C-F =272.4Hz),121.5,114.3(q, 3J C-F =5.4Hz),51.9. 19 FNMR(376MHz,CDCl3):δ-62.42(s).HRMS(ESI)m / z:[M+H] + CalcdforC 25 H 17 F3N388.1308;Found388.1300.

[0075] 5-Phenyl-2-(p-tolyl)-4-(trifluoromethyl)-5H-indeno[1,2-b]pyridine(3oa)

[0076] 1 HNMR(600MHz,CDCl3):δ8.14(d,J=7.2Hz,1H),8.00(d,J=8.4Hz,2H),7.68(s,1H),7.38(t,J=7.2Hz,1H),7.29(t,J=7.2Hz,1H),7.26(d,J=8.4Hz,2H),7.20(d,J=7.8Hz,1H),7.17-7.13(m,3H),6.94(d,J=6.6Hz,2H),5.19(s,1H),2.36(s,3H). 13 C{ 1 H}NMR(150MHz,CDCl3):δ162.9,158.3,149.7,139.8,139.7,138.5,135.7,135.3(q, 2 J C-F =33.8Hz),135.2,130.3,129.7,128.7,128.1,127.9,127.2,127.1,125.2,123.1(q, 1 J C-F =272.7Hz),121.4,114.0(q, 3 J C-F =4.2Hz),51.9,21.4. 19 FNMR(565MHz,CDCl3):δ-62.43(s).HRMS(ESI)m / z:[M+H] + CalcdforC 26 H 19 F3N402.1464;Found402.1461.

[0077] 2-(4-Fluorophenyl)-5-phenyl-4-(trifluoromethyl)-5H-indeno[1,2-b]pyridine(3pa)

[0078] 1 HNMR(400MHz,CDCl3):δ8.21-8.15(m,3H),7.72(s,1H),7.46(t,J=7.2Hz,1H),7.38(td,J1=7.2Hz,J2=0.8Hz,1H),7.28(d,J=7.6Hz,1H),7.25-7.19(m,5H),7.02-7.00(m,2H),5.26(s,1H). 13 C{ 1 H}NMR(150MHz,CDCl3):δ164.0(d, 1 J C-F =248.4Hz),163.0,157.2,149.7,139.5,138.3,135.5(q, 3 J C-F =2.6Hz),135.5(q, 2 J C-F =34.1Hz),134.6(d, 4 J C-F =2.4Hz),130.5,129.1(d, 3 J C-F =8.4Hz),128.7,128.0,127.9,127.2,125.3,123.0(q, 1 J C-F =274.2Hz),121.4,115.9(d, 2 J C-F =20.9Hz),113.9(q, 3 J C-F =4.4Hz),51.9. 19 FNMR(376MHz,CDCl3):δ-62.45(s),-111.81–-111.88(m).HRMS(ESI)m / z:[M+H] + CalcdforC 25 H 16 F4N406.1213;Found406.1217.

[0079] 2-Ethyl-3-methyl-5-phenyl-4-(trifluoromethyl)-5H-indeno[1,2-b]pyridine(3qa)

[0080] 1 HNMR(400MHz,CDCl3):δ8.08(d,J=7.6Hz,1H),7.38(t,J=7.2Hz,1H),7.30(t,J=7.6Hz,1H),7.26-7.17(m,4H),6.96-6.94(m,2H),5.27(d,J=1.2Hz,1H),3.03(q,J=7.6Hz,2H),2.44(q,J=2.0Hz,3H),1.42(t,J=7.6Hz,3H). 13 C{ 1 H}NMR(150MHz,CDCl3):δ163.7,159.5,149.0,141.1,138.4,134.9(q, 3 J C-F =1.8Hz),133.8(q, 2 J C-F =30.8Hz),129.5,128.6,127.6,127.3,126.8,126.5,124.9,124.1(q, 1 J C-F =276.0Hz),120.8,52.8(q, 4 J C-F =1.8Hz),29.4,15.0(q, 4 J C-F =1.2Hz),12.9. 19 FNMR(376MHz,CDCl3):δ-57.26(s).HRMS(ESI)m / z:[M+H] + CalcdforC 22 H 19 F3N354.1464;Found354.1472.

[0081] 9-Phenyl-10-(trifluoromethyl)-1,2,3,9-tetrahydrocyclopenta[b]indeno[2,1-e]pyridine(3ra)

[0082] 1HNMR(400MHz,CDCl3):δ8.08(d,J=7.6Hz,1H),7.40(t,J=7.6Hz,1H),7.31(td,J1=7.2Hz,J2=0.8Hz,1H),7.25-7.16(m,4H),6.98-6.96(m,2H),5.22(s,1H),3.19(t,J=7.6Hz,2H),3.16-3.07(m,2H),2.30-2.16(m,2H). 13 C{ 1 H}NMR(100MHz,CDCl3):δ168.0,161.4,149.4,140.4,138.2,135.0(q, 3 J C-F =2.4Hz),132.6(q, 3 J C-F =1.8Hz),131.2(q, 2 J C-F =33.7Hz),129.6,128.6,127.73,127.68,126.9,125.1,123.6(q, 1 J C-F =273.6Hz),120.7,51.9,34.1,30.2(q, 4 J C-F =1.8Hz),23.2. 19 FNMR(376MHz,CDCl3):δ-59.95(s).HRMS(ESI)m / z:[M+H] + CalcdforC 22 H 17 F3N352.1308;Found352.1304.

[0083] 11-Phenyl-10-(trifluoromethyl)-7,8,9,11-tetrahydro-6H-indeno[1,2-b]quinoline(3sa)

[0084] 1 HNMR(400MHz,CDCl3):δ8.06(d,J=7.6Hz,1H),7.38(t,J=7.2Hz,1H),7.31(td,J1=8.0Hz,J2=1.2Hz,1H),7.26-7.15(m,4H),6.97-6.95(m,2H),5.27(s,1H),3.24-3.08(m,2H),2.93-2.92(m,2H),2.06-1.73(m,4H).13 C{ 1 H}NMR(150MHz,CDCl3):δ159.7,159.2,149.2,141.1,138.0,135.2,133.4(q, 2 J C-F =31.8Hz),129.8,128.6,128.1,127.7,127.3,126.8,125.0,124.0(q, 1 J C-F =275.0Hz),120.8,52.7,33.6,26.0(q, 4 J C-F =3.5Hz),22.5,22.4. 19 FNMR(376MHz,CDCl3):δ-57.95(s).HRMS(ESI)m / z:[M+H] + CalcdforC 23 H 19 F3N366.1464;Found366.1466.

[0085] 2-Methyl-5-(p-tolyl)-4-(trifluoromethyl)-5H-indeno[1,2-b]pyridine(3ab)

[0086] 1 HNMR(400MHz,CDCl3):δ8.10(d,J=7.6Hz,1H),7.42(t,J=7.6Hz,1H),7.34(td,J1=7.6Hz,J2=1.2Hz,1H),7.25(d,J=7.6Hz,1H),7.21(s,1H),7.02(d,J=8.0Hz,2H),6.86(d,J=7.6Hz,2H),5.18(s,1H),2.74(s,3H),2.28(s,3H). 13 C{ 1 H}NMR(150MHz,CDCl3):δ162.6,159.5,149.8,138.3,136.7,136.6,134.8(q, 2 J C-F =33.3Hz),134.5,130.2,129.3,127.8,127.7,125.2,123.1(q, 1 J C-F =273.0Hz),121.1,117.0(q, 3 J C-F=4.2Hz),51.4,24.6,21.1. 19 FNMR(565MHz,CDCl3):δ-62.41(s).HRMS(ESI)m / z:[M+H] + CalcdforC 21 H 17 F3N340.1308;Found340.1315.

[0087] 5-(4-Methoxyphenyl)-2-methyl-4-(trifluoromethyl)-5H-indeno[1,2-b]pyridine(3ac)

[0088] 1 HNMR(400MHz,CDCl3):δ8.10(d,J=7.6Hz,1H),7.42(t,J=7.2Hz,1H),7.35(td,J1=7.6Hz,J2=1.2Hz,1H),7.25(d,J=7.6Hz,1H),7.21(s,1H),6.89(d,J=8.8Hz,2H),6.75(d,J=8.8Hz,2H),5.16(s,1H),3.74(s,3H),2.73(s,3H). 13 C{ 1 H}NMR(150MHz,CDCl3):δ162.4,159.5,158.7,149.9,138.3,134.8(q, 2 J C-F =34.1Hz),134.6(q, 3 J C-F =2.3Hz),131.5,130.2,129.0,127.8,125.2,123.1(q, 1 J C-F =272.3Hz),121.1,117.0(q, 3 J C-F =4.5Hz),114.0,55.2,51.0,24.5. 19 FNMR(565MHz,CDCl3):δ-62.42(s).HRMS(ESI)m / z:[M+H] + CalcdforC 21 H 17 F3NO356.1257;Found356.1264.

[0089] 5-(4-Fluorophenyl)-2-methyl-4-(trifluoromethyl)-5H-indeno[1,2-b]pyridine(3ad)

[0090] 1 HNMR(400MHz,CDCl3):δ8.11(d,J=7.6Hz,1H),7.44(t,J=7.2Hz,1H),7.36(td,J1=7.6Hz,J2=1.2Hz,1H),7.24-7.22(m,2H),6.96-6.88(m,4H),5.19(s,1H),2.74(s,3H). 13 C{ 1 H}NMR(150MHz,CDCl3):δ162.4,162.0(d, 1 J C-F =243.8Hz),159.8,149.3,138.3,135.4(d, 4 J C-F =1.8Hz),134.8(q, 2 J C-F =34.5Hz),134.1,130.2,129.5(d, 3 J C-F =8.4Hz),128.0,125.2,123.0(q, 1 J C-F =274.1Hz),121.2,117.0(q, 3 J C-F =4.5Hz),115.5(d, 2 J C-F =21.6Hz),50.9,24.6. 19 FNMR(376MHz,CDCl3):δ-62.46(s),-115.44–-115.52(m).HRMS(ESI)m / z:[M+H] + CalcdforC 20 H 14 F4N344.1057;Found344.1062.

[0091] 5-(4-Chlorophenyl)-2-methyl-4-(trifluoromethyl)-5H-indeno[1,2-b]pyridine(3ae)

[0092] 1HNMR(400MHz,CDCl3):δ8.11(d,J=7.2Hz,1H),7.44(t,J=7.6Hz,1H),7.36(td,J1=7.6Hz,J2=1.2Hz,1H),7.24-7.22(m,2H),7.19(d,J=8.8Hz,2H),6.91(d,J=8.8Hz,2H),5.17(s,1H),2.74(s,3H). 13 C{ 1 H}NMR(150MHz,CDCl3):δ162.5,159.9,149.0,138.4,138.3,134.9(q, 2 J C-F =33.5Hz),133.8,132.9,130.3,129.3,128.8,128.1,125.2,123.0(q, 1 J C-F =272.6Hz),121.3,117.1(q, 3 J C-F =4.1Hz),51.0,24.6. 19 FNMR(565MHz,CDCl3):δ-62.39(s).HRMS(ESI)m / z:[M+H] + CalcdforC 20 H 14 ClF3N360.0761;Found360.0759.

[0093] 5-(4-Bromophenyl)-2-methyl-4-(trifluoromethyl)-5H-indeno[1,2-b]pyridine(3af)

[0094] 1 HNMR(600MHz,CDCl3):δ8.12(d,J=7.8Hz,1H),7.45(t,J=7.2Hz,1H),7.38-7.34(m,3H),7.26-7.23(m,2H),6.86(d,J=7.8Hz,2H),5.17(s,1H),2.75(s,3H). 13 C{ 1 H}NMR(150MHz,CDCl3):δ162.5,159.9,149.0,138.8,138.4,134.9(q, 2 J C-F =34.1Hz),133.7(q, 3 J C-F=2.1Hz),131.8,130.3,129.7,128.1,125.2,123.0(q, 1 J C-F =273.6Hz),121.3,121.0,117.1(q, 3 J C-F =4.2Hz),51.1,24.6. 19 FNMR(565MHz,CDCl3):δ-62.39(s).HRMS(ESI)m / z:[M+H] + CalcdforC 20 H 14 BrF3N404.0256;Found404.0263.

[0095] 2-Methyl-5-(m-tolyl)-4-(trifluoromethyl)-5H-indeno[1,2-b]pyridine(3ag)

[0096] 1 HNMR(400MHz,CDCl3):δ8.11(d,J=7.6Hz,1H),7.42(t,J=7.2Hz,1H),7.35(td,J1=7.6Hz,J2=1.2Hz,1H),7.27(d,J=7.6Hz,1H),7.22(s,1H),7.11(t,J=7.6Hz,1H),7.00(d,J=7.6Hz,1H),6.80(d,J=7.6Hz,1H),6.74(s,1H),5.17(s,1H),2.75(s,3H),2.23(s,3H). 13 C{ 1 H}NMR(150MHz,CDCl3):δ162.6,159.5,149.7,139.5,138.3,138.2,134.9(q, 2 J C-F =34.2Hz),134.4(q, 3 J C-F =2.3Hz),130.2,128.5,128.4,127.9,127.8,125.2,125.1,123.0(q, 1 J C-F =273.9Hz),121.1,117.0(q, 3 J C-F =4.5Hz),51.7,24.6,21.4. 19FNMR(565MHz,CDCl3):δ-62.46(s).HRMS(ESI)m / z:[M+H] + CalcdforC 21 H 17 F3N340.1308;Found340.1317.

[0097] 5-(3-Methoxyphenyl)-2-methyl-4-(trifluoromethyl)-5H-indeno[1,2-b]pyridine(3ah)

[0098] 1 HNMR(600MHz,CDCl3):δ8.11(d,J=7.2Hz,1H),7.43(t,J=7.2Hz,1H),7.36(td,J1=7.2Hz,J2=0.6Hz,1H),7.29(d,J=7.8Hz,1H),7.23(s,1H),7.15(t,J=7.8Hz,1H),6.74(dd,J1=7.8Hz,J2=1.8Hz,1H),6.59(d,J=7.8Hz,1H),6.51(s,1H),5.19(s,1H),3.70(s,3H),2.75(s,3H). 13 C{ 1 H}NMR(150MHz,CDCl3):δ162.5,159.65,159.60,149.3,141.2,138.3,134.9(q, 2 J C-F =34.2Hz),134.1,130.2,129.6,127.9,125.2,123.0(q, 1 J C-F =272.1Hz),121.2,120.4,117.1(q, 3 J C-F =4.1Hz),114.0,112.1,55.2,51.7,24.6. 19 FNMR(565MHz,CDCl3):δ-62.48(s).HRMS(ESI)m / z:[M+H] + CalcdforC 21 H 17 F3NO356.1257;Found356.1262.

[0099] 5-(3-Fluorophenyl)-2-methyl-4-(trifluoromethyl)-5H-indeno[1,2-b]pyridine(3ai)

[0100] 1 HNMR(400MHz,CDCl3):δ8.12(d,J=7.6Hz,1H),7.45(t,J=7.2Hz,1H),7.37(td,J1=7.6Hz,J2=1.2Hz,1H),7.26(d,J=7.2Hz,1H),7.24(s,1H),7.20(td,J1=8.4Hz,J2=6.4Hz,1H),6.92-6.87(m,1H),6.82(d,J=7.6Hz,1H),6.66-6.63(m,1H),5.20(s,1H),2.75(s,3H). 13 C{ 1 H}NMR(150MHz,CDCl3):δ162.8(d, 1 J C-F =244.5Hz),162.5,160.0,148.8,142.2(d, 3 J C-F =7.1Hz),138.4,134.9(q, 2 J C-F =34.4Hz),133.6(q, 3 J C-F =2.1Hz),130.3,130.1(d, 3 J C-F =6.8Hz),128.1,125.2,123.8(d, 4 J C-F =3.0Hz),123.0(q, 1 J C-F =272.6Hz),121.3,117.1(q, 3 J C-F =4.5Hz),114.8(d, 2 J C-F =21.6Hz),114.2(d, 2 J C-F =21.6Hz),51.3,24.6. 19 FNMR(565MHz,CDCl3):δ-62.52(s),-112.82–-112.85(m).HRMS(ESI)m / z:[M+H] + CalcdforC 20 H14 F4N344.1057;Found344.1064.

[0101] 5-(3-Chlorophenyl)-2-methyl-4-(trifluoromethyl)-5H-indeno[1,2-b]pyridine(3aj)

[0102] 1 HNMR(600MHz,CDCl3):δ8.12(d,J=7.2Hz,1H),7.45(t,J=7.2Hz,1H),7.37(t,J=7.8Hz,1H),7.26(d,J=7.2Hz,1H),7.24(s,1H),7.19-7.15(m,2H),6.94(s,1H),6.89(d,J=6.6Hz,1H),5.17(s,1H),2.75(s,3H). 13 C{ 1 H}NMR(150MHz,CDCl3):δ162.5,160.0,148.8,141.8,138.4,134.9(q, 2 J C-F =33.5Hz),134.3,133.5,130.3,129.9,128.1,128.0,127.4,126.3,125.2,123.0(q, 1 J C-F =273.9Hz),121.3,117.1(q, 3 J C-F =4.7Hz),51.2,24.6. 19 FNMR(565MHz,CDCl3):δ-62.45(s).HRMS(ESI)m / z:[M+H] + CalcdforC 20 H 14 ClF3N360.0761;Found360.0764.

[0103] 5-(3-Bromophenyl)-2-methyl-4-(trifluoromethyl)-5H-indeno[1,2-b]pyridine(3ak)

[0104] 1HNMR(400MHz,CDCl3):δ8.12(d,J=8.0Hz,1H),7.45(t,J=7.6Hz,1H),7.39-7.33(m,2H),7.26(d,J=7.6Hz,1H),7.24(s,1H),7.12-7.08(m,2H),6.93(d,J=7.6Hz,1H),5.16(s,1H),2.75(s,3H). 13 C{ 1 H}NMR(150MHz,CDCl3):δ162.5,160.0,148.7,142.0,138.4,134.9(q, 2 J C-F =34.2Hz),133.5(q, 3 J C-F =2.6Hz),130.8,130.4,130.3,130.2,128.1,126.8,125.2,123.0(q, 1 J C-F =272.7Hz),122.5,121.3,117.1(q, 3 J C-F =4.4Hz),51.2,24.6. 19 FNMR(376MHz,CDCl3):δ-62.44(s).HRMS(ESI)m / z:[M+H] + CalcdforC 20 H 14 BrF3N404.0256;Found404.0260.

[0105] 5-(3,4-Dimethoxyphenyl)-2-methyl-4-(trifluoromethyl)-5H-indeno[1,2-b]pyridine(3al)

[0106] 1 HNMR(400MHz,CDCl3):δ8.11(d,J=7.6Hz,1H),7.44(t,J=7.2Hz,1H),7.37(td,J1=7.2Hz,J2=0.8Hz,1H),7.28(d,J=7.6Hz,1H),7.23(s,1H),6.75(d,J=8.4Hz,1H),6.64(dd,J1=8.0Hz,J2=2.0Hz,1H),6.36(d,J=1.6Hz,1H),5.16(s,1H),3.83(s,3H),3.69(s,3H),2.75(s,3H).13 C{ 1 H}NMR(150MHz,CDCl3):δ162.4,159.6,149.6,149.0,148.2,138.2,134.9(q, 2 J C-F =34.1Hz),134.4,131.9,130.2,127.8,125.1,123.0(q, 1 J C-F =272.6Hz),121.1,120.5,117.0(q, 3 J C-F =4.4Hz),111.1,110.8,55.9,55.8,51.4,24.6. 19 FNMR(376MHz,CDCl3):δ-62.42(s).HRMS(ESI)m / z:[M+H] + CalcdforC 22 H 19 F3NO2386.1362;Found386.1365.

[0107] 5-(3,5-Dichlorophenyl)-2-methyl-4-(trifluoromethyl)-5H-indeno[1,2-b]pyridine(3am)

[0108] 1 HNMR(400MHz,CDCl3):δ8.13(d,J=7.6Hz,1H),7.47(t,J=7.6Hz,1H),7.40(td,J1=7.6Hz,J2=0.8Hz,1H),7.27-7.25(m,2H),7.21(t,J=1.6Hz,1H),6.87(d,J=1.6Hz,2H),5.13(s,1H),2.76(s,3H). 13 C{ 1 H}NMR(100MHz,CDCl3):δ162.4,160.4,148.0,143.2,138.4,135.0,134.9(q, 2 J C-F =33.8Hz),132.8(q, 3 J C-F =1.2Hz),130.4,128.4,127.6,126.4,125.1,122.9(q, 1 J C-F =273.0Hz),121.5,117.2(q,3 J C-F =4.4Hz),50.8,24.6. 19 FNMR(376MHz,CDCl3):δ-62.43(s).HRMS(ESI)m / z:[M+H] + CalcdforC 20 H 13 Cl2F3N394.0372;Found394.0368.

[0109] 2-Methyl-5-(naphthalen-2-yl)-4-(trifluoromethyl)-5H-indeno[1,2-b]pyridine(3an)

[0110] 1 HNMR(400MHz,CDCl3):δ8.15(d,J=7.6Hz,1H),7.79(d,J=8.0Hz,1H),7.76-7.74(m,2H),7.61(d,J=8.4Hz,1H),7.48-7.40(m,3H),7.33(t,J=7.6Hz,1H),7.27(d,J=7.6Hz,1H),7.24(s,1H),6.76(dd,J1=8.4Hz,J2=0.8Hz,1H),5.38(s,1H),2.77(s,3H). 13 C{ 1 H}NMR(150MHz,CDCl3):δ162.7,159.8,149.4,138.5,137.1,135.1(q, 2 J C-F =33.3Hz),134.2,133.6,132.6,130.2,128.5,128.0,127.71,127.69,127.4,126.2,125.8,125.44,125.36,123.0(q, 1 J C-F =273.2Hz),121.2,117.1(q, 3 J C-F =4.4Hz),51.8,24.6. 19 FNMR(376MHz,CDCl3):δ-62.40(s).HRMS(ESI)m / z:[M+H] + CalcdforC 24 H 17 F3N376.1308;Found376.1309.

[0111] 2-Methyl-5-(thiophen-2-yl)-4-(trifluoromethyl)-5H-indeno[1,2-b]pyridine(3ao)

[0112] 1 HNMR(600MHz,CDCl3):δ8.10(d,J=7.8Hz,1H),7.47-7.44(m,1H),7.41-7.38(m,2H),7.24(s,1H),7.12(dd,J1=4.8Hz,J2=0.6Hz,1H),6.94(d,J=3.0Hz,1H),6.90(dd,J1=4.8Hz,J2=3.0Hz,1H),5.56(s,1H),2.75(s,3H). 13 C{ 1 H}NMR(100MHz,CDCl3):δ161.9,160.0,148.6,141.9,137.9,134.9(q, 2 J C-F =34.1Hz),133.6(q, 3 J C-F =2.7Hz),130.3,128.2,126.6,125.8,125.1,124.6,123.0(q, 1 J C-F =272.9Hz),121.2,117.2(q, 3 J C-F =4.3Hz),46.6,24.6. 19 FNMR(565MHz,CDCl3):δ-62.41(s).HRMS(ESI)m / z:[M+H] + CalcdforC 18 H 13 F3NS332.0715;Found332.0723.

[0113] 2-Methyl-5-(thiophen-3-yl)-4-(trifluoromethyl)-5H-indeno[1,2-b]pyridine(3ap)

[0114] 1HNMR(600MHz,CDCl3):δ8.11(d,J=7.2Hz,1H),7.45(t,J=7.2Hz,1H),7.39(td,J1=7.8Hz,J2=1.2Hz,1H),7.32(dd,J1=7.2Hz,J2=0.6Hz,1H),7.23(s,1H),7.19(dd,J1=3.0Hz,J2=1.2Hz,1H),7.13(dd,J1=5.4Hz,J2=3.0Hz,1H),6.41(dd,J1=4.8Hz,J2=1.2Hz,1H),5.40(s,1H),2.74(s,3H). 13 C{ 1 H}NMR(150MHz,CDCl3):δ162.1,159.6,148.5,138.9,138.3,134.9(q, 2 J C-F =34.4Hz),133.8,130.2,127.9,126.2,125.9,125.2,123.0(q, 1 J C-F =273.3Hz),122.4,121.2,117.0(q, 3 J C-F =4.5Hz),46.9,24.6. 19 FNMR(565MHz,CDCl3):δ-62.54(s).HRMS(ESI)m / z:[M+H] + CalcdforC 18 H 13 F3NS332.0715;Found332.0724.

[0115] 4-(Difluoromethyl)-2-methyl-5-phenyl-5H-indeno[1,2-b]pyridine(3aq)

[0116] 1 HNMR(400MHz,CDCl3):δ8.13(d,J=7.6Hz,1H),7.44(t,J=7.2Hz,1H),7.35(td,J1=7.6Hz,J2=1.2Hz,1H),7.29-7.24(m,4H),7.19(d,J=1.2Hz,1H),7.05-7.03(m,2H),6.20(t,J=55.2Hz,1H),5.12(s,1H),2.73(s,3H). 13 C{ 1H}NMR(150MHz,CDCl3):δ161.3,159.4,149.2,139.1,138.9,138.7(dd, 2 J C-F =24.3,21.9Hz),135.5(dd, 3 J C-F =7.1,2.6Hz),129.8,129.1,128.2,127.9,127.5,125.2,121.1,116.5(dd, 3 J C-F =8.4,4.1Hz),111.6(dd, 1 J C-F =240.6,237.5Hz),51.0,24.7. 19 FNMR(376MHz,CDCl3):δ-111.90(dd,J1=299.7Hz,J2=54.9Hz,1F),-125.38(dd,J1=301.9Hz,J2=55.6Hz,1F).HRMS(ESI)m / z:[M+H] + CalcdforC 20 H 16 F2N308.1245;Found308.1243.

[0117] 4-(1,1-Difluoroethyl)-2-methyl-5-phenyl-5H-indeno[1,2-b]pyridine(3ar)

[0118] 1 HNMR(600MHz,CDCl3):δ8.12(d,J=8.4Hz,1H),7.42(t,J=7.8Hz,1H),7.33(td,J1=7.2Hz,J2=0.6Hz,1H),7.24-7.17(m,4H),7.05(s,1H),6.98(d,J=7.2Hz,2H),5.24(s,1H),2.71(s,3H),1.14(dd,J1=19.2Hz,J2=18.6Hz,3H). 13 C{ 1 H}NMR(150MHz,CDCl3):δ161.8,158.9,149.9,143.1(t, 2 J C-F =28.5Hz),140.4,139.0,134.1(d, 3 J C-F=5.3Hz),129.7,128.61,128.56,127.6,127.1,125.2,121.8(dd, 1 J C-F =240.9,238.7Hz),121.0,117.4(t, 3 J C-F =6.3Hz),51.8(d, 4 J C-F =3.2Hz),24.8(t, 2 J C-F =29.0Hz),24.5. 19 FNMR(565MHz,CDCl3):δ-85.95(dq,J1=247.5Hz,J2=20.3Hz,1F),-90.73(dq,J1=245.8Hz,J2=17.5Hz,1F).HRMS(ESI)m / z:[M+H] + CalcdforC 21 H 18 F2N322.1402;Found322.1409.

[0119] 2-Methyl-4-(perfluoroethyl)-5-phenyl-5H-indeno[1,2-b]pyridine(3as)

[0120] 1 HNMR(600MHz,CDCl3):δ8.12(d,J=7.2Hz,1H),7.42(t,J=7.2Hz,1H),7.34(td,J1=7.2Hz,J2=1.2Hz,1H),7.23(dd,J1=7.8Hz,J2=0.6Hz,1H),7.21-7.16(m,3H),7.15(s,1H),6.94-6.93(m,2H),5.23(s,1H),2.75(s,3H). 13 C{ 1 H}NMR(150MHz,CDCl3):δ162.9,159.4,149.8,140.6,138.0,135.6,133.6(t, 2 J C-F =25.2Hz),130.3,128.6,127.8,127.7,126.8,125.2,121.2,118.8(qt, 1 J C-F =285.5Hz, 2 J C-F=38.1Hz),118.5(t, 3 J C-F =6.3Hz),113.4(tq, 1 J C-F =254.6Hz, 2 J C-F =37.5Hz),52.2,24.5. 19 FNMR (565MHz, CDCl3): δ-83.98 (s, 3F), -109.92 (d, J=273.5Hz, 1F), -114.89 (d, J=274.0Hz, 1F). HRMS (ESI) m / z: [M+H] + Calcdfor C 21 H 15 F5N376.1119;Found376.1124.

[0121] Example 4

[0122] The fluoromethyl-substituted indeno[1,2-b]pyridine compound 3aa synthesized by the present invention can be subjected to a series of reactions to synthesize further derivatives.

[0123]

[0124] 3aa (65.1 mg, 0.2 mmol), selenium dioxide (39.9 mg, 0.36 mmol), dioxane (3.2 mL) and H2O (0.2 mL) were added to a 25 mL round-bottom flask in sequence. The mixture was then stirred under reflux (oil bath) for 5 hours. After the reaction was completed, the residue was dissolved in dichloromethane (10 mL) and filtered through a diatomaceous earth pad. The mixture was then extracted with dichloromethane (10 mL × 3), the organic phases were combined, washed with water, dried, filtered, concentrated, and separated by a silica gel column (petroleum ether / ethyl acetate = 10 / 1) to obtain a white solid product 4 (29.0 mg, 42%). The characterization data of the compound are as follows: 1 HNMR (400MHz, DMSO-d6): δ7.90(d,J=6.8Hz,1H),7.45-7.41(m,2H),7.38(td,J1=7.6Hz,J2=1.2Hz,1H),7.24-7.14(m,6H),6.60(brs,1H),2.68(s,3H). 13 C{ 1 H}NMR (100MHz, DMSO-d6): δ161.5,161.2,154.0,143.6,138.3(q, 3 J C-F=1.1Hz),137.0,134.0(q, 2 J C-F =33.5Hz),131.4,129.4,128.5,127.1,124.9,123.2(q, 1 J C-F =273.4Hz),121.0,118.4(q, 3 J C-F =3.9Hz),81.9,24.4. 19 FNMR(376MHz,DMSO-d6):δ-59.53(s).HRMS(ESI)m / z:[M+H] + CalcdforC 20 H 15 F3NO 342.1100; Found342.1110.

[0125]

[0126] 3aa (65.1 mg, 0.2 mmol) and 1 mL of HOAc were added to a 15 mL pressure tube, and the mixture was evacuated and filled with oxygen (3 times), and then placed in a module at 120°C for 48 h. After the reaction was completed, the mixture was cooled to room temperature, and then 5 mL of saturated sodium bicarbonate solution was added to neutralize the reaction, and the mixture was extracted with ethyl acetate three times, and then washed with water, washed with salt, dried over anhydrous sodium sulfate, concentrated, and separated by a silica gel column (petroleum ether / ethyl acetate = 10 / 1) to obtain a white solid product 5 (33.3 mg, 47%). The characterization data of the compound are as follows: 1 HNMR (400MHz, DMSO-d6): δ8.30(d,J=7.2Hz,1H),8.24(s,1H),7.56(t,J=7.2Hz ,1H),7.52-7.51(m,3H),7.48-7.39(m,4H),7.00(d,J=7.6Hz,1H),2.59(s,3H). 13 C{ 1 H}NMR (150MHz, DMSO-d6): δ151.6,143.0,142.4,141.3,136.9,130.6,129.6,129.1,128.6,128.5,127.2,126.8,125.3(q, 2 J C-F =31.2Hz),123.2,123.0(q, 1 J C-F =271.8Hz),119.9(q, 3 J C-F=3.0Hz),101.2,23.9. 19 FNMR(565MHz,DMSO-d6):δ-61.91(s).HRMS(ESI)m / z:[M+H] + CalcdforC 20 H 15 F3NO2358.1049; Found358.1052.

[0127] Example 6

[0128] The anticancer activity of the compounds provided by the present invention is evaluated by studying the antiproliferative activity on cancer cells using the CCK-8 method.

[0129] The specific method is that, first, the cells are inoculated into a 96-well plate with 100 μL of culture medium per well at a density of 5000 cells per well, and incubated overnight at 37 ° C and 5% CO2. On the second day, 100 μL of the test compound diluted with culture medium (concentration of 0.03nM-30 μM) is added to each well, and then the cells are incubated for 72 hours at 37 ° C and 5% CO2. Then, 10 μL of CCK8 is added to each well, and the 96-well plate is placed at 37 ° C and incubated for 2 hours. The absorbance is measured at 450 nm using EnVision multilatelbelReader (Perkinermer) (using 630 nm as the reference wavelength), and the IC50 value is calculated using GraphPad Prism6.0 software. All experiments were applied with two parallel samples and repeated twice. Three cancer cells, Hela, A-549 and HCT-116, were selected as research subjects, and 5-fluorouracil (5-FU) was used as a positive control of the drug.

[0130] The anticancer activity results of some compounds are as follows:

[0131]

[0132] The activity results show that the fluoromethyl-substituted indeno[1,2-b]pyridine compound 3 provided by the present invention can inhibit the proliferation activity of three cancer cells, Hela, A549 and HCT-116, among which 3ac, 3ah, 3al and 3ap have significant anti-Hela cancer cell proliferation activity; compounds 3ac and 3al have significant inhibitory effects on the proliferation of A-549 and HCT-116 cancer cells, indicating that this type of compound has medicinal value for preventing / treating / inhibiting the progression of cancer, especially cervical cancer, lung cancer and colon cancer.

[0133] The above embodiments describe the basic principles, main features and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited by the above embodiments, and the above embodiments and descriptions are only for explaining the principles of the present invention. Without departing from the scope of the principles of the present invention, the present invention may have various changes and improvements, and these changes and improvements all fall within the scope of protection of the present invention.

Claims

1. Fluoromethyl substituted indeno[1,2-b]pyridine compounds, the general structural formula of which is: in: R 1 Selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, phenyl or halogen; R 2 Selected from C 1-4 Alkyl, C 3-5 Cycloalkyl, phenyl or substituted phenyl, the substituents on the substituted phenyl ring are selected from C 1-4 Alkyl or halogen; R 3 Selected from hydrogen or C 1-4 Alkyl; or R 2 and R 3 The combination is 1,3-propanediyl or 1,4-butanediyl; R 4 is selected from naphthyl, thienyl, phenyl or substituted phenyl, wherein the substituent on the phenyl ring of the substituted phenyl is a mono- or poly-substituted C 1-4 Alkyl, C 1-4 Alkoxy or halogen; R 5 is selected from hydrogen, methyl, fluorine or trifluoromethyl.

2. The fluoromethyl-substituted indeno[1,2-b]pyridine compound according to claim 1, characterized in that: The structure of the compound is 3. Use of the fluoromethyl-substituted indeno[1,2-b]pyridine compound as claimed in claim 1 or 2 in the preparation of anticancer active drugs.

4. The use of the fluoromethyl-substituted indeno[1,2-b]pyridine compound according to claim 1 or 2 in the preparation of an anticancer active drug, characterized in that: Anticancer activity is against cervical cancer, lung cancer and colon cancer.

5. The use of the fluoromethyl-substituted indeno[1,2-b]pyridine compound according to claim 4 in the preparation of an anticancer active drug, characterized in that: The anti-cervical cancer, lung cancer and colon cancer correspond to the anti-Hela, A549 and HCT-116 cancer cells, respectively.

6. A pharmaceutical composition for treating cervical cancer, lung cancer and colon cancer, wherein the active ingredient comprises the fluoromethyl-substituted indeno[1,2-b]pyridine compound according to claim 1 or 2.

7. A method for synthesizing a fluoromethyl-substituted indeno[1,2-b]pyridine compound, characterized in that: The method comprises the following steps: mixing a 5-aryl imidazole compound 1, a fluoromethyl alkynyl ketone compound 2, a rhodium catalyst, an additive and a solvent, and heating the mixture to react to obtain a fluoromethyl substituted indeno[1,2-b]pyridine compound 3. The reaction equation is: Where: R is selected from C 1-6 Alkyl or phenyl; R 1 Selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, phenyl or halogen; R 2 Selected from C 1-4 Alkyl, C 3-5 Cycloalkyl, phenyl or substituted phenyl, the substituents on the substituted phenyl ring are selected from C 1-4 Alkyl or halogen; R 3 Selected from hydrogen or C 1-4 Alkyl; or R 2 and R 3 The combination is 1,3-propanediyl or 1,4-butanediyl; R 4 is selected from naphthyl, thienyl, phenyl or substituted phenyl, wherein the substituent on the phenyl ring of the substituted phenyl is a mono- or poly-substituted C 1-4 Alkyl, C 1-4 Alkoxy or halogen; R 5 is selected from hydrogen, methyl, fluorine or trifluoromethyl.

8. The method for synthesizing fluoromethyl-substituted indeno[1,2-b]pyridine compounds according to claim 7, characterized in that: The rhodium catalyst is selected from dichloro(pentamethylcyclopentadienyl)rhodium dimer or di(hexafluoroantimonate)triacetonitrile(pentamethylcyclopentadienyl)rhodium; the additive is selected from a mixture of zinc acetate, sodium acetate, potassium acetate or cesium acetate and bis(trifluoromethanesulfonyl)silver salt, silver hexafluoroantimonate, silver tetrafluoroborate, silver acetate, silver fluoride, silver trifluoromethanesulfonate or copper acetate.

9. The method for synthesizing fluoromethyl-substituted indeno[1,2-b]pyridine compounds according to claim 7, characterized in that: The molar ratio of the 5-aryl imidazole compound 1, the fluoromethyl alkynyl ketone compound 2, the rhodium catalyst and the additive is 1:1-1.5:0.03-0.06:1-2.

10. The method for synthesizing fluoromethyl-substituted indeno[1,2-b]pyridine compounds according to claim 7, characterized in that: The solvent is hexafluoroisopropanol, trifluoroethanol or methanol; the temperature reaction is carried out under the condition of sealing the tube at 100-130°C.

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