Fluoromethyl-substituted indeno[1,2-b]pyridine compounds having anticancer activity and methods of synthesis thereof

Abstract

The application discloses fluoromethyl-substituted indeno[1,2-b]pyridine compounds with anticancer activity and a synthesis method thereof, and belongs to the technical field of organic synthesis and drug discovery. Fluoromethyl-substituted indeno[1,2-b]pyridine compounds are prepared by mixing 5-aryl imidazole compounds 1, fluoromethyl acetylene ketone compounds 2, a rhodium catalyst, an additive and a solvent, and then performing a reaction at a high temperature, and the structural general formula of the compounds is: The one-pot cascade reaction is adopted in the application, and the process is simple and efficient. The fluoromethyl-substituted indeno[1,2-b]pyridine compounds obtained have obvious inhibitory activity on the proliferation of three kinds of cancer cells, such as Hela, A549 and HCT-116, which indicates that the compounds have anticancer activity on cervical cancer, lung cancer and colon cancer, and have potential medicinal value, and provide a new structural unit for drug screening.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of organic synthesis and drug discovery, and particularly relates to fluoromethyl-substituted indeno[1,2-b]pyridine compounds with anticancer activity and a synthetic method thereof. BACKGROUND

[0002] The indeno[1,2-b]pyridine structural unit is widely present in natural products and drug molecules. Studies have shown that many indeno[1,2-b]pyridine derivatives have biological activities such as antitumor, antimalarial, antiviral, 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 field of electronic luminescent materials. On the other hand, the introduction of the fluoromethyl structural unit often has a significant impact on the physical and chemical properties, biological activity, and metabolic stability of the parent compound, and is one of the superior structural units for new drug design.

[0003] At present, although some synthetic methods of 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 need to construct the five-membered ring in the tricyclic skeleton in steps, inevitably having problems such as multiple reaction steps, difficult-to-obtain substrates, harsh reaction conditions, and low atom economy.

[0004] Therefore, it is of important theoretical significance and practical prospect for both organic chemistry and medicinal chemistry to research and develop a green and efficient new method for synthesizing fluoromethyl-substituted indeno[1,2-b]pyridine compounds from inexpensive and readily available starting materials through simple steps. SUMMARY

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

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

[0007] The third purpose of the present application 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 application.

[0008] The fourth purpose of the present application is to provide a synthetic method of fluoromethyl-substituted indeno[1,2-b]pyridine compounds.

[0009] In order to achieve the above-mentioned purposes, the technical solutions adopted by the present application are as follows:

[0010] A fluoromethyl-substituted indeno[1,2-b]pyridine compound, having a general structure as follows:

[0011]

[0012] wherein: 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 benzene ring of the substituted phenyl being selected from C 1-4 alkyl or halogen; R 3 selected from hydrogen or C 1-4 alkyl; or R 2 and R 3 combine to form 1,3-propanediyl or 1,4-butanediyl; R 4 selected from naphthyl, thienyl, phenyl or substituted phenyl, the substituents on the benzene ring of the substituted phenyl being mono- or poly-substituted C 1-4 alkyl, C 1-4 alkoxy or halogen; R 5 selected from hydrogen, methyl, fluorine or trifluoromethyl.

[0013] Further, in the general structure above, in the most preferred case, the specific structure is selected as follows:

[0014]

[0015] The present application is designed to verify that the compound provided by the present application has the activity of inhibiting the proliferation of Hela, A549 and HCT-116 cancer cells, suggesting that the compound of the present application can be used as an active ingredient of an anticancer drug for cervical cancer, lung cancer and colon cancer. In particular, the preferred compound above can significantly inhibit the growth and proliferation of Hela, A549 and HCT-116, suggesting that such a compound as an active ingredient of an anticancer drug has the effect of preventing, treating, and inhibiting the progression of cervical cancer, lung cancer and colon cancer.

[0016] The present application also provides a synthesis method of the fluoromethyl-substituted indeno[1,2-b]pyridine compound above, and the technical solution adopted is as follows:

[0017] The synthesis method of the fluoromethyl-substituted indeno[1,2-b]pyridine compound comprises the following operations: mixing 5-aryl imidazole compound 1, fluoromethyl acetylene ketone compound 2, rhodium catalyst, additive and solvent, and reacting at elevated temperature to obtain fluoromethyl-substituted indeno[1,2-b]pyridine compound 3, and the reaction equation is as follows:

[0018]

[0019] wherein: R is selected from C 1-6 alkyl or phenyl; R 1 is selected from hydrogen, C 1-4 alkyl, C 1-4 alkoxy, phenyl or halogen; R 2 is selected from C 1-4 alkyl, C 3-5 cycloalkyl, phenyl or substituted phenyl, the substituents on the phenyl ring of the substituted phenyl being selected from C 1-4 alkyl or halogen; R 3 is selected from hydrogen or C 1-4 alkyl; or R 2 and R 3 are combined to 1,3-propanediyl or 1,4-butanediyl; R 4 is selected from naphthyl, thienyl, phenyl or substituted phenyl, the substituents on the phenyl ring of the substituted phenyl being 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] Further, in the above technical solution, the rhodium catalyst is dichloro(pentamethylcyclopentadienyl)rhodium dimer ([RhCp*Cl2]2) or bis(hexafluoroantimonate)tris(acetonitrile) (pentamethylcyclopentadienyl) rhodium ([RhCp*(MeCN)3](SbF6)2).

[0021] Further, in the above technical solution, the additive is a mixture of zinc acetate, sodium acetate, potassium acetate or cesium acetate and bis-trifluoromethanesulfonimide silver salt, silver hexafluoroantimonate, silver tetrafluoroborate, silver acetate, silver fluoride, silver trifluoromethanesulfonate or copper acetate.

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

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

[0024] Further, in the above technical solution, the temperature rising reaction is carried out under the condition of sealing the tube at 100-130℃.

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

[0026] The present application has the following beneficial effects:

[0027] (1) The fluoromethyl-substituted indeno[1,2-b]pyridine compound provided by the present application has obvious inhibitory activity on the proliferation of Hela, A549 and HCT-116 cancer cells, which indicates that the compound has anticancer activity on cervical cancer, lung cancer and colon cancer, and has potential medicinal value, thereby providing a new structural unit for drug screening;

[0028] (2) The synthesis method provided by the present application is completed through one-pot tandem reaction between 5-aryl imidazole compounds and fluoromethyl acetylene ketone compounds, and has simple and efficient process;

[0029] (3) The synthesis method provided by the present application has low-cost and easily-obtained raw materials, mild reaction conditions, simple operation, wide substrate application range and good functional group tolerance. BRIEF DESCRIPTION OF DRAWINGS

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

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

[0032] The above content of the present application will be further described through examples, but this should not be understood as the scope of the above subject matter of the present application being limited to the following examples, and any technology realized based on the above content of the present application belongs to the scope of the present application.

[0033] Example 1

[0034]

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

[0036] By changing the reaction conditions such as 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] Into a 15 mL reaction vial, 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 successively, capped with a plug, and placed in a 120 °C oil bath for stirring reaction for 4 h. After the reaction was completed, it was cooled to room temperature, suction filtered, and the filtrate was concentrated and separated by silica gel column (petroleum ether / ethyl acetate = 40 / 1) to give the product 3aa (45.3 mg, 70%) as a white solid. The characterization data of this compound are: 1 HNMR (400 MHz, CDC13): δ 8.12 (d, J = 8.0 Hz, 1H), 7.43 (t, J = 7.6 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.26 (d, J = 8.4 Hz, 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 (150 MHz, CDC13): δ 162.5, 159.6, 149.6, 139.7, 138.3, 134.9 (q, 2 J C-F = 33.8 Hz), 134.3 (q, 3 J C-F = 2.0 Hz), 130.2, 128.6, 128.0, 127.8, 127.1, 125.3, 123.0 (q, 1 J C-F = 272.9 Hz), 121.1, 117.0 (q, 3 J C-F = 4.4 Hz), 51.7, 24.6. 19 FNMR (376 MHz, CDC13): δ -62.50 (s). HRMS (ESI) m / z: [M + H] + Calcd for C 20 H 15 F3N326.1151; Found 326.1159.

[0042] Example 3

[0043] Following the method and procedure of Example 2, various fluoromethyl substituted indeno[l,2-b]pyridines 3 can be synthesized by changing the reactant 1 and reactant 2, with the specific results as follows:

[0044] Table 2. Synthesis of fluoromethyl substituted indeno[l,2-b]pyridines 3 a,b

[0045]

[0046]

[0047] Representative product characterization data are as follows:

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

[0049] 1 HNMR (400 MHz, CDC13): δ 7.99 (d, J = 8.0 Hz, 1H), 7.24-7.19 (m, 4H), 7.18 (s, 1H), 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 (150 MHz, CDC13): δ 162.7, 159.4, 149.9, 140.6, 139.9, 135.8, 134.7 (q, 2 J C-F = 34.5 Hz), 134.2 (q, 3 J C-F = 2.6 Hz), 128.9, 128.6, 128.0, 127.1, 125.8, 123.1 (q, 1 J C-F = 272.7 Hz), 120.9, 116.5 (q, 3 J C-F = 4.2 Hz), 51.6, 24.6, 21.8. 19 FNMR (376 MHz, CDC13): δ -62.47 (s). HRMS (ESI) m / z: [M + H] + Calcd for C 21 H 17 F3N340.1308; Found 340.1312.

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

[0051] 1 HNMR (600 MHz, CDC13): δ 8.01 (d, J = 8.4 Hz, 1H), 7.25 (dd, J1= 7.8 Hz, J2= 0.6 Hz, 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 = 7.8 Hz, 2H), 1.58-1.53 (m, 2H), 1.34-1.28 (m, 2H), 0.89 (t, J = 7.2 Hz, 3H). 13 C{ 1 H}NMR (150 MHz, CDC13): δ 162.7, 159.4, 149.9, 145.7, 139.9, 136.0, 134.7 (q, 2 J C-F = 34.4 Hz), 134.4 (q, 3 J C-F = 2.3 Hz), 128.6, 128.3, 128.1, 127.0, 125.1, 123.1 (q, 1 J C-F = 271.4 Hz), 120.9, 116.5 (q, 3 J C-F = 4.5 Hz), 51.6, 36.0, 33.7, 24.5, 22.4, 13.9. 19 FNMR (565 MHz, CDC13): δ -62.47 (s). HRMS (ESI) m / z: [M + H] + Calcd for C 24 H 23 F3N382.1777; Found 382.1783.

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

[0053] 1HNMR (600 MHz, CDC13): δ 8.02 (d, J = 8.4 Hz, IH), 7.24-7.20 (m, 3H), 7.13 (s, IH), 6.98-6.97 (m, 3H), 6.76 (d, J = 2.4 Hz, IH), 5.14 (s, IH), 3.77 (s, 3H), 2.72 (s, 3H). 13 C{ 1 H} NMR (150 MHz, CDC13): δ 162.5, 161.8, 159.3, 151.7, 139.8, 134.5 (q, 2 J C-F = 33.3 Hz), 133.9, 131.3, 128.6, 128.0, 127.1, 123.1 (q, 1 J C-F = 273.9 Hz), 122.2, 115.8 (q, 3 J C-F = 4.5 Hz), 114.4, 110.3, 55.5, 51.6, 24.5. 19 F NMR (565 MHz, CDC13): δ -62.48 (s). HRMS (ESI) m / z: [M + H] + Calcd for C 21 H 17 F3NO356.1257; Found 356.1246.

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

[0055] 1 HNMR (600 MHz, CDC13): δ 8.17 (d, J = 7.8 Hz, IH), 7.68 (dd, J1= 7.8 Hz, J2= 0.6 Hz, IH), 7.55 (d, J = 7.2 Hz, 2H), 7.46 (s, IH), 7.40 (t, J = 7.2 Hz, 2H), 7.32 (t, J = 7.2 Hz, IH), 7.24-7.19 (m, 4H), 7.02 (d, J = 6.6 Hz, 2H), 5.27 (s, IH), 2.76 (s, 3H). 13 C{ 1 H} NMR (100 MHz, CDC13): δ 162.3, 159.7, 150.3, 143.3, 140.8, 139.5, 137.5, 134.8 (q, 2 J C-F= 33.8 Hz), 134.6, 128.8, 128.7, 128.1, 127.7, 127.3, 127.2, 127.1, 123.9, 123.0 (q, J = 272.8 Hz), 121.4, 117.0 (q, J = 4.3 Hz), 51.8, 24.6. 1 J C-F = 272.8 Hz), 121.4, 117.0 (q, J = 4.3 Hz), 51.8, 24.6. 3 J C-F = 4.3 Hz), 51.8, 24.6. 19 FNMR (376 MHz, CDC13): δ -62.47 (s). HRMS (ESI) m / z: [M + H] + Calcd for C 26 H 19 F3N402.1464; Found 402.1459.

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

[0057] 1 HNMR (400 MHz, CDC13): δ 8.07 (dd, J1= 8.4 Hz, J2= 5.2 Hz, 1H), 7.24-7.21 (m, 4H), 7.13 (td, J1= 8.8 Hz, J2= 2.0 Hz, 1H), 6.98-6.93 (m, 3H), 5.18 (s, 1H), 2.74 (s, 3H). 13 C{ 1 H}NMR (150 MHz, CDC13): δ 164.3 (d, 1 J C-F = 248.0 Hz), 161.6, 159.8, 151.8 (d, 3 J C-F = 8.4 Hz), 139.0, 134.8 (q, 2 J C-F = 33.0 Hz), 134.4 (d, 4 J C-F = 2.3 Hz), 134.1, 128.8, 127.9, 127.4, 122.9 (q, 1 J C-F = 272.7 Hz), 122.6 (d, 3 J C-F = 10.4 Hz), 116.7 (q, 3 J C-F = 4.4 Hz), 115.5 (d, 2 JC-F = 22.5 Hz), 112.5 (d, 2 J C-F = 24.2 Hz), 51.7, 24.5. 19 FNMR (376 MHz, CDC13): δ -62.53 (s), -109.95 (td, Ji = 9.4 Hz, J2= 5.3 Hz). HRMS (ESI) m / z: [M + H] + Calcd for C 20 H 14 F4N344.1057; Found 344.1063. 7-Chloro-2-methyl-5-phenyl-4-(trifluoromethyl)-5H-indeno[l,2-b]pyridine (3ga)

[0058] 1 HNMR (600 MHz, CDC13): δ 8.02 (d, J = 7.8 Hz, 1H), 7.40 (dd, Ji = 7.8 Hz, J2= 1.2 Hz, 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 (150 MHz, CDC13): δ 161.4, 159.9, 151.0, 138.8, 136.9, 136.0, 135.0 (q, 2 J C-F = 33.6 Hz), 134.1, 128.8, 128.4, 128.0, 127.5, 125.6, 122.9 (q, 1 J C-F = 273.2 Hz), 122.2, 117.3 (q, 3 J C-F = 4.2 Hz), 51.6, 24.6. 19 FNMR (565 MHz, CDC13): δ -62.52 (s). HRMS (ESI) m / z: [M + H] + Calcd for C 20 H 14 ClF3N360.0761; Found 360.0755.

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

[0060] 1 HNMR (600 MHz, CDC13): δ 7.94 (s, 1H), 7.22-7.16 (m, 5H), 7.13 (d, J = 7.8 Hz, 1H), 6.97-6.96 (m, 2H), 5.16 (s, 1H), 2.74 (s, 3H), 2.44 (s, 3H). 13 C{ 1 H} NMR (150 MHz, CDC13): δ 162.6, 159.4, 147.0, 139.9, 138.4, 137.8, 134.83 (q, 2 J C-F = 32.3 Hz), 134.79, 131.2, 128.6, 127.9, 127.0, 124.9, 123.0 (q, 1 J C-F = 273.3 Hz), 121.5, 116.9 (q, 3 J C-F = 4.4 Hz), 51.4, 24.6, 21.4. 19 F NMR (565 MHz, CDC13): δ -62.46 (s). HRMS (ESI) m / z: [M + H] + Calcd for C 21 H 17 F3N340.1308; Found 340.1305.

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

[0062] 1 HNMR (600 MHz, CDC13): δ 8.09 (d, J = 1.8 Hz, 1H), 7.30 (dd, J1= 8.4 Hz, J2= 1.8 Hz, 1H), 7.25 (s, 1H), 7.24-7.20 (m, 3H), 7.16 (d, J = 7.8 Hz, 1H), 6.96-6.94 (m, 2H), 5.17 (s, 1H), 2.74 (s, 3H). 13 C{ 1 H} NMR (150 MHz, CDC13): δ 161.2, 160.0, 147.7, 140.1, 139.0, 135.1 (q, 2 J C-F = 33.8 Hz), 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 (600 MHz, CDC13): δ 7.31 (td, J1= 7.8 Hz, J2= 4.8 Hz, 1H), 7.25 (s, 1H), 7.24-7.20 (m, 3H), 7.11 (t, J = 9.6 Hz, 1H), 7.05 (d, J = 7.8 Hz, 1H), 6.98-6.97 (m, 2H), 5.26 (s, 1H), 2.78 (s, 3H). 13 C{ 1 H}NMR (100 MHz, CDC13): δ 160.6 (d, 3 J C-F = 4.9 Hz), 160.3, 158.0 (d, 1 J C-F = 255.8 Hz), 152.0 (d, 3 J C-F = 4.3 Hz), 139.1, 134.8 (q, 2 J C-F = 33.6 Hz), 133.9 (q, 3 J C-F = 2.3 Hz), 131.4 (d, 3 J C-F = 7.7 Hz), 128.7, 127.9, 127.4, 125.6 (d, 2 J C-F = 11.8 Hz), 122.9 (q, 1 J C-F = 273.0 Hz), 121.1 (d, 4 J C-F = 4.4 Hz), 117.0 (q, 3 J C-F = 4.1 Hz), 115.1 (d, 2 J C-F = 20.1 Hz), 52.0, 24.8. 19 FNMR (376 MHz, CDC13): δ -62.53 (s), -117.47 (dd, J1= 11.3 Hz, J2= 4.5 Hz). HRMS (ESI) m / z: [M + H] + Calcd for C 20 H 14 F4N344.1057; Found 344.1069.

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

[0070] 1 HNMR (400 MHz, CDC13): δ 8.13 (d, J = 7.6 Hz, 1H), 7.43 (t, J = 7.2 Hz, 1H), 7.35 (td, J1= 7.6 Hz, J2= 1.2 Hz, 1H), 7.27-7.19 (m, 5H), 7.00-6.97 (m, 2H), 5.21 (s, 1H), 2.95 (t, J = 7.2 Hz, 2H), 1.94-1.84 (m, 2H), 1.05 (t, J = 7.6 Hz, 3H). 13 C{ 1 H}NMR (100 MHz, CDC13): δ 163.6, 162.5, 149.6, 139.8, 138.5, 134.8 (q, 2 J C-F = 33.0 Hz), 134.4 (q, 3 J C-F = 2.3 Hz), 130.1, 128.6, 128.0, 127.8, 127.1, 125.2, 123.1 (q, 1 J C-F = 273.1 Hz), 121.2, 116.4 (q, 3 J C-F = 4.3 Hz), 51.8, 40.4, 23.2, 14.0. 19 FNMR (565 MHz, CDC13): δ -62.41 (s). HRMS (ESI) m / z: [M + H] + Calcd for C 22 H 19 F3N354.1464; Found 354.1469.

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

[0072] 1 HNMR (600 MHz, CDC13): δ 8.05 (d, J = 7.8 Hz, 1H), 7.39 (t, J = 7.8 Hz, 1H), 7.32 (td, J1= 7.2 Hz, J2= 0.6 Hz, 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 (100 MHz, CDC13): δ 164.2, 162.4, 149.6, 139.9, 138.6, 134.5 (q, 2 J C-F = 33.8 Hz), 133.7 (q, 3 J C-F = 2.7 Hz), 130.0, 128.6, 128.0, 127.7, 127.0, 125.2, 123.1 (q, 1 J C-F = 272.9 Hz), 121.1, 115.1 (q, 3 J C-F = 5.0 Hz), 51.7, 17.5, 10.6, 10.5. 19 F NMR (565 MHz, CDC13): δ -62.46 (s). HRMS (ESI) m / z: [M + H] + Calcd for C 22 H 17 F3N352.1308; Found 352.1315.

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

[0074] 1 H NMR (400 MHz, CDC13): δ 8.22 (d, J = 7.6 Hz, 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= 7.6 Hz, J2= 1.2 Hz, 1H), 7.28 (d, J = 7.6 Hz, 1H), 7.26-7.21 (m, 3H), 7.03-7.01 (m, 2H), 5.28 (s, 1H). 13 C{ 1 H} NMR (150 MHz, CDC13): δ 163.0, 158.3, 149.7, 139.6, 138.4, 135.6, 135.4 (q, 2 J C-F = 34.4 Hz), 130.4, 129.7, 129.0, 128.7, 128.1, 128.0, 127.2, 125.3, 123.1 (q, 1 J C-F = 272.4 Hz), 121.5, 114.3 (q, 3J C-F = 5.4 Hz), 51.9. 19 FNMR (376 MHz, CDC13): δ -62.42 (s). HRMS (ESI) m / z: [M + H]+calcd for C + Calcd for C 25 H 17 F3N388.1308; Found 388.1300.

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

[0076] 1 HNMR (600 MHz, CDC13): δ 8.14 (d, J = 7.2 Hz, 1H), 8.00 (d, J = 8.4 Hz, 2H), 7.68 (s, 1H), 7.38 (t, J = 7.2 Hz, 1H), 7.29 (t, J = 7.2 Hz, 1H), 7.26 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 7.8 Hz, 1H), 7.17-7.13 (m, 3H), 6.94 (d, J = 6.6 Hz, 2H), 5.19 (s, 1H), 2.36 (s, 3H). 13 C{ 1 H}NMR (150 MHz, CDC13): δ 162.9, 158.3, 149.7, 139.8, 139.7, 138.5, 135.7, 135.3 (q, 2 J C-F = 33.8 Hz), 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 = 272.7 Hz), 121.4, 114.0 (q, 3 J C-F = 4.2 Hz), 51.9, 21.4. 19 FNMR (565 MHz, CDC13): δ -62.43 (s). HRMS (ESI) m / z: [M + H]+calcd for C + Calcd for C 26 H 19 F3N402.1464; Found 402.1461.

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

[0078] 1 HNMR (400 MHz, CDC13): δ 8.21-8.15 (m, 3H), 7.72 (s, 1H), 7.46 (t, J = 7.2 Hz, 1H), 7.38 (td, Ji = 7.2 Hz, J2= 0.8 Hz, 1H), 7.28 (d, J = 7.6 Hz, 1H), 7.25-7.19 (m, 5H), 7.02-7.00 (m, 2H), 5.26 (s, 1H). 13 C{ 1 H}NMR (150 MHz, CDC13): δ 164.0 (d, 1 J C-F = 248.4 Hz), 163.0, 157.2, 149.7, 139.5, 138.3, 135.5 (q, 3 J C-F = 2.6 Hz), 135.5 (q, 2 J C-F = 34.1 Hz), 134.6 (d, 4 J C-F = 2.4 Hz), 130.5, 129.1 (d, 3 J C-F = 8.4 Hz), 128.7, 128.0, 127.9, 127.2, 125.3, 123.0 (q, 1 J C-F = 274.2 Hz), 121.4, 115.9 (d, 2 J C-F = 20.9 Hz), 113.9 (q, 3 J C-F = 4.4 Hz), 51.9. 19 FNMR (376 MHz, CDC13): δ -62.45 (s), -111.81 - -111.88 (m). HRMS (ESI) m / z: [M + H] + Calcd for C 25 H 16 F4N406.1213; Found 406.1217.

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

[0080] 1 HNMR (400 MHz, CDC13): δ 8.08 (d, J = 7.6 Hz, 1H), 7.38 (t, J = 7.2 Hz, 1H), 7.30 (t, J = 7.6 Hz, 1H), 7.26-7.17 (m, 4H), 6.96-6.94 (m, 2H), 5.27 (d, J = 1.2 Hz, 1H), 3.03 (q, J = 7.6 Hz, 2H), 2.44 (q, J = 2.0 Hz, 3H), 1.42 (t, J = 7.6 Hz, 3H). 13 C{ 1 H}NMR (150 MHz, CDC13): δ 163.7, 159.5, 149.0, 141.1, 138.4, 134.9 (q, 3 J C-F = 1.8 Hz), 133.8 (q, 2 J C-F = 30.8 Hz), 129.5, 128.6, 127.6, 127.3, 126.8, 126.5, 124.9, 124.1 (q, 1 J C-F = 276.0 Hz), 120.8, 52.8 (q, 4 J C-F = 1.8 Hz), 29.4, 15.0 (q, 4 J C-F = 1.2 Hz), 12.9. 19 FNMR (376 MHz, CDC13): δ -57.26 (s). HRMS (ESI) m / z: [M + H] + Calcd for C 22 H 19 F3N354.1464; Found 354.1472.

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

[0082] 1HNMR (400 MHz, CDC13): δ 8.08 (d, J = 7.6 Hz, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7.31 (td, J1= 7.2 Hz, J2= 0.8 Hz, 1H), 7.25-7.16 (m, 4H), 6.98-6.96 (m, 2H), 5.22 (s, 1H), 3.19 (t, J = 7.6 Hz, 2H), 3.16-3.07 (m, 2H), 2.30-2.16 (m, 2H). 13 C{ 1 H}NMR (100 MHz, CDC13): δ 168.0, 161.4, 149.4, 140.4, 138.2, 135.0 (q, 3 J C-F = 2.4 Hz), 132.6 (q, 3 J C-F = 1.8 Hz), 131.2 (q, 2 J C-F = 33.7 Hz), 129.6, 128.6, 127.73, 127.68, 126.9, 125.1, 123.6 (q, 1 J C-F = 273.6 Hz), 120.7, 51.9, 34.1, 30.2 (q, 4 J C-F = 1.8 Hz), 23.2. 19 FNMR (376 MHz, CDC13): δ -59.95 (s). HRMS (ESI) m / z: [M + H] + Calcd for C 22 H 17 F3N352.1308; Found 352.1304.

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

[0084] 1 HNMR (400 MHz, CDC13): δ 8.06 (d, J = 7.6 Hz, 1H), 7.38 (t, J = 7.2 Hz, 1H), 7.31 (td, J1= 8.0 Hz, J2= 1.2 Hz, 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 (150 MHz, CDC13): δ 159.7, 159.2, 149.2, 141.1, 138.0, 135.2, 133.4 (q, 2 J C-F = 31.8 Hz), 129.8, 128.6, 128.1, 127.7, 127.3, 126.8, 125.0, 124.0 (q, 1 J C-F = 275.0 Hz), 120.8, 52.7, 33.6, 26.0 (q, 4 J C-F = 3.5 Hz), 22.5, 22.4. 19 F NMR (376 MHz, CDC13): δ -57.95 (s). HRMS (ESI) m / z: [M + H] + Calcd for C 23 H 19 F3N366.1464; Found 366.1466.

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

[0086] 1 H NMR (400 MHz, CDC13): δ 8.10 (d, J = 7.6 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H), 7.34 (td, Ji = 7.6 Hz, J2= 1.2 Hz, 1H), 7.25 (d, J = 7.6 Hz, 1H), 7.21 (s, 1H), 7.02 (d, J = 8.0 Hz, 2H), 6.86 (d, J = 7.6 Hz, 2H), 5.18 (s, 1H), 2.74 (s, 3H), 2.28 (s, 3H). 13 C{ 1 H} NMR (150 MHz, CDC13): δ 162.6, 159.5, 149.8, 138.3, 136.7, 136.6, 134.8 (q, 2 J C-F = 33.3 Hz), 134.5, 130.2, 129.3, 127.8, 127.7, 125.2, 123.1 (q, 1 J C-F = 273.0 Hz), 121.1, 117.0 (q, 3 J C-F= 4.2 Hz), 51.4, 24.6, 21.1. 19 FNMR (565 MHz, CDC13): δ -62.41 (s). HRMS (ESI) m / z: [M+H] + Calcd for C 21 H 17 F3N340.1308; Found 340.1315.

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

[0088] 1 HNMR (400 MHz, CDC13): δ 8.10 (d, J = 7.6 Hz, 1H), 7.42 (t, J = 7.2 Hz, 1H), 7.35 (td, J1= 7.6 Hz, J2= 1.2 Hz, 1H), 7.25 (d, J = 7.6 Hz, 1H), 7.21 (s, 1H), 6.89 (d, J = 8.8 Hz, 2H), 6.75 (d, J = 8.8 Hz, 2H), 5.16 (s, 1H), 3.74 (s, 3H), 2.73 (s, 3H). 13 C{ 1 H}NMR (150 MHz, CDC13): δ 162.4, 159.5, 158.7, 149.9, 138.3, 134.8 (q, 2 J C-F = 34.1 Hz), 134.6 (q, 3 J C-F = 2.3 Hz), 131.5, 130.2, 129.0, 127.8, 125.2, 123.1 (q, 1 J C-F = 272.3 Hz), 121.1, 117.0 (q, 3 J C-F = 4.5 Hz), 114.0, 55.2, 51.0, 24.5. 19 FNMR (565 MHz, CDC13): δ -62.41 (s). HRMS (ESI) m / z: [M+H] + Calcd for C 21 H 17 F3NO356.1257; Found 356.1264.

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

[0090] 1 HNMR (400 MHz, CDC13): δ 8.11 (d, J = 7.6 Hz, 1H), 7.44 (t, J = 7.2 Hz, 1H), 7.36 (td, Ji = 7.6 Hz, J2= 1.2 Hz, 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 (150 MHz, CDC13): δ 162.4, 162.0 (d, 1 J C-F = 243.8 Hz), 159.8, 149.3, 138.3, 135.4 (d, 4 J C-F = 1.8 Hz), 134.8 (q, 2 J C-F = 34.5 Hz), 134.1, 130.2, 129.5 (d, 3 J C-F = 8.4 Hz), 128.0, 125.2, 123.0 (q, 1 J C-F = 274.1 Hz), 121.2, 117.0 (q, 3 J C-F = 4.5 Hz), 115.5 (d, 2 J C-F = 21.6 Hz), 50.9, 24.6. 19 FNMR (376 MHz, CDC13): δ -62.46 (s), -115.44 - -115.52 (m). HRMS (ESI) m / z: [M + H] + Calcd for C 20 H 14 F4N344.1057; Found 344.1062.

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

[0092] 1HNMR (400 MHz, CDC13): δ 8.11 (d, J = 7.2 Hz, 1H), 7.44 (t, J = 7.6 Hz, 1H), 7.36 (td, J1= 7.6 Hz, J2= 1.2 Hz, 1H), 7.24-7.22 (m, 2H), 7.19 (d, J = 8.8 Hz, 2H), 6.91 (d, J = 8.8 Hz, 2H), 5.17 (s, 1H), 2.74 (s, 3H). 13 C{ 1 H}NMR (150 MHz, CDC13): δ 162.5, 159.9, 149.0, 138.4, 138.3, 134.9 (q, 2 J C-F = 33.5 Hz), 133.8, 132.9, 130.3, 129.3, 128.8, 128.1, 125.2, 123.0 (q, 1 J C-F = 272.6 Hz), 121.3, 117.1 (q, 3 J C-F = 4.1 Hz), 51.0, 24.6. 19 FNMR (565 MHz, CDC13): δ -62.39 (s). HRMS (ESI) m / z: [M + H] + Calcd for C 20 H 14 ClF3N360.0761; Found 360.0759.

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

[0094] 1 HNMR (600 MHz, CDC13): δ 8.12 (d, J = 7.8 Hz, 1H), 7.45 (t, J = 7.2 Hz, 1H), 7.38-7.34 (m, 3H), 7.26-7.23 (m, 2H), 6.86 (d, J = 7.8 Hz, 2H), 5.17 (s, 1H), 2.75 (s, 3H). 13 C{ 1 H}NMR (150 MHz, CDC13): δ 162.5, 159.9, 149.0, 138.8, 138.4, 134.9 (q, 2 J C-F = 34.1 Hz), 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. 19F NMR (565 MHz, CDC13): δ -62.46 (s). HRMS (ESI) m / z: [M+H] + Calcd for C 21 H 17 F3N340.1308; Found 340.1317.

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

[0098] 1 HNMR (600 MHz, CDC13): δ 8.11 (d, J = 7.2 Hz, 1H), 7.43 (t, J = 7.2 Hz, 1H), 7.36 (td, J1= 7.2 Hz, J2= 0.6 Hz, 1H), 7.29 (d, J = 7.8 Hz, 1H), 7.23 (s, 1H), 7.15 (t, J = 7.8 Hz, 1H), 6.74 (dd, J1= 7.8 Hz, J2= 1.8 Hz, 1H), 6.59 (d, J = 7.8 Hz, 1H), 6.51 (s, 1H), 5.19 (s, 1H), 3.70 (s, 3H), 2.75 (s, 3H). 13 C{ 1 H}NMR (150 MHz, CDC13): δ 162.5, 159.65, 159.60, 149.3, 141.2, 138.3, 134.9 (q, 2 J C-F = 34.2 Hz), 134.1, 130.2, 129.6, 127.9, 125.2, 123.0 (q, 1 J C-F = 272.1 Hz), 121.2, 120.4, 117.1 (q, 3 J C-F = 4.1 Hz), 114.0, 112.1, 55.2, 51.7, 24.6. 19 F NMR (565 MHz, CDC13): δ -62.46 (s). HRMS (ESI) m / z: [M+H] + Calcd for C 21 H 17 F3NO356.1257; Found 356.1262.

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

[0100] 1 HNMR (400 MHz, CDC13): δ 8.12 (d, J = 7.6 Hz, 1H), 7.45 (t, J = 7.2 Hz, 1H), 7.37 (td, Ji = 7.6 Hz, J2= 1.2 Hz, 1H), 7.26 (d, J = 7.2 Hz, 1H), 7.24 (s, 1H), 7.20 (td, Ji = 8.4 Hz, J2= 6.4 Hz, 1H), 6.92-6.87 (m, 1H), 6.82 (d, J = 7.6 Hz, 1H), 6.66-6.63 (m, 1H), 5.20 (s, 1H), 2.75 (s, 3H). 13 C{ 1 H}NMR (150 MHz, CDC13): δ 162.8 (d, 1 J C-F = 244.5 Hz), 162.5, 160.0, 148.8, 142.2 (d, 3 J C-F = 7.1 Hz), 138.4, 134.9 (q, 2 J C-F = 34.4 Hz), 133.6 (q, 3 J C-F = 2.1 Hz), 130.3, 130.1 (d, 3 J C-F = 6.8 Hz), 128.1, 125.2, 123.8 (d, 4 J C-F = 3.0 Hz), 123.0 (q, 1 J C-F = 272.6 Hz), 121.3, 117.1 (q, 3 J C-F = 4.5 Hz), 114.8 (d, 2 J C-F = 21.6 Hz), 114.2 (d, 2 J C-F = 21.6 Hz), 51.3, 24.6. 19 FNMR (565 MHz, CDC13): δ -62.52 (s), -112.82 - -112.85 (m). HRMS (ESI) m / z: [M + H] + Calcd for C 20 H14 F4 N 344.1057; Found 344.1064.

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

[0102] 1 HNMR (600 MHz, CDC13): δ 8.12 (d, J = 7.2 Hz, 1H), 7.45 (t, J = 7.2 Hz, 1H), 7.37 (t, J = 7.8 Hz, 1H), 7.26 (d, J = 7.2 Hz, 1H), 7.24 (s, 1H), 7.19-7.15 (m, 2H), 6.94 (s, 1H), 6.89 (d, J = 6.6 Hz, 1H), 5.17 (s, 1H), 2.75 (s, 3H). 13 C{ 1 H}NMR (150 MHz, CDC13): δ 162.5, 160.0, 148.8, 141.8, 138.4, 134.9 (q, 2 J C-F = 33.5 Hz), 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 = 273.9 Hz), 121.3, 117.1 (q, 3 J C-F = 4.7 Hz), 51.2, 24.6. 19 FNMR (565 MHz, CDC13): δ -62.45 (s). HRMS (ESI) m / z: [M + H] + Calcd for C 20 H 14 ClF3N360.0761; Found 360.0764.

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

[0104] 1HNMR (400 MHz, CDC13): δ 8.12 (d, J = 8.0 Hz, 1H), 7.45 (t, J = 7.6 Hz, 1H), 7.39-7.33 (m, 2H), 7.26 (d, J = 7.6 Hz, 1H), 7.24 (s, 1H), 7.12-7.08 (m, 2H), 6.93 (d, J = 7.6 Hz, 1H), 5.16 (s, 1H), 2.75 (s, 3H). 13 C{ 1 H}NMR (150 MHz, CDC13): δ 162.5, 160.0, 148.7, 142.0, 138.4, 134.9 (q, 2 J C-F = 34.2 Hz), 133.5 (q, 3 J C-F = 2.6 Hz), 130.8, 130.4, 130.3, 130.2, 128.1, 126.8, 125.2, 123.0 (q, 1 J C-F = 272.7 Hz), 122.5, 121.3, 117.1 (q, 3 J C-F = 4.4 Hz), 51.2, 24.6. 19 FNMR (376 MHz, CDC13): δ -62.44 (s). HRMS (ESI) m / z: [M + H] + Calcd for C 20 H 14 BrF3N404.0256; Found 404.0260.

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

[0106] 1 HNMR (400 MHz, CDC13): δ 8.11 (d, J = 7.6 Hz, 1H), 7.44 (t, J = 7.2 Hz, 1H), 7.37 (td, J1= 7.2 Hz, J2= 0.8 Hz, 1H), 7.28 (d, J = 7.6 Hz, 1H), 7.23 (s, 1H), 6.75 (d, J = 8.4 Hz, 1H), 6.64 (dd, J1= 8.0 Hz, J2= 2.0 Hz, 1H), 6.36 (d, J = 1.6 Hz, 1H), 5.16 (s, 1H), 3.83 (s, 3H), 3.69 (s, 3H), 2.75 (s, 3H).13 C{ 1 H}NMR (150 MHz, CDC13): δ 162.4, 159.6, 149.6, 149.0, 148.2, 138.2, 134.9 (q, 2 J C-F = 34.1 Hz), 134.4, 131.9, 130.2, 127.8, 125.1, 123.0 (q, 1 J C-F = 272.6 Hz), 121.1, 120.5, 117.0 (q, 3 J C-F = 4.4 Hz), 111.1, 110.8, 55.9, 55.8, 51.4, 24.6. 19 F NMR (376 MHz, CDC13): δ -62.42 (s). HRMS (ESI) m / z: [M + H] + Calcd for C 22 H 19 F3NO2386.1362; Found 386.1365.

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

[0108] 1 H NMR (400 MHz, CDC13): δ 8.13 (d, J = 7.6 Hz, 1H), 7.47 (t, J = 7.6 Hz, 1H), 7.40 (td, Ji = 7.6 Hz, J2= 0.8 Hz, 1H), 7.27-7.25 (m, 2H), 7.21 (t, J = 1.6 Hz, 1H), 6.87 (d, J = 1.6 Hz, 2H), 5.13 (s, 1H), 2.76 (s, 3H). 13 C{ 1 H}NMR (100 MHz, CDC13): δ 162.4, 160.4, 148.0, 143.2, 138.4, 135.0, 134.9 (q, 2 J C-F = 33.8 Hz), 132.8 (q, 3 J C-F = 1.2 Hz), 130.4, 128.4, 127.6, 126.4, 125.1, 122.9 (q, 1 J C-F = 273.0 Hz), 121.5, 117.2 (q,3 J C-F = 33.3 Hz), 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, J = 272.8 Hz), 121.2, 117.1 (q, J = 21.6 Hz), 114.9, 109.6, 50.8, 24.6. 19 FNMR (376 MHz, CDC13): δ -62.43 (s). HRMS (ESI) m / z: [M+H] Calcd for C + H 20 H 13 Cl2F3N394.0372; Found 394.0368.

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

[0110] 1 HNMR (400 MHz, CDC13): δ 8.15 (d, J = 7.6 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.76-7.74 (m, 2H), 7.61 (d, J = 8.4 Hz, 1H), 7.48-7.40 (m, 3H), 7.33 (t, J = 7.6 Hz, 1H), 7.27 (d, J = 7.6 Hz, 1H), 7.24 (s, 1H), 6.76 (dd, J1= 8.4 Hz, J2= 0.8 Hz, 1H), 5.38 (s, 1H), 2.77 (s, 3H). 13 C{ 1 H}NMR (150 MHz, CDC13): δ 162.7, 159.8, 149.4, 138.5, 137.1, 135.1 (q, 2 J C-F = 33.3 Hz), 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, J = 272.8 Hz), 121.2, 117.1 (q, J = 21.6 Hz), 114.9, 109.6, 50.8, 24.6. 1 J C-F = 33.3 Hz), 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, J = 272.8 Hz), 121.2, 117.1 (q, J = 21.6 Hz), 114.9, 109.6, 50.8, 24.6. 3 J C-F = 33.3 Hz), 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, J = 272.8 Hz), 121.2, 117.1 (q, J = 21.6 Hz), 114.9, 109.6, 50.8, 24.6. 19 FNMR (376 MHz, CDC13): δ -62.43 (s). HRMS (ESI) m / z: [M+H] + H 24 H 17 F3N376.1308; Found 376.1309.

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

[0112] 1 HNMR (600 MHz, CDC13): δ 8.10 (d, J = 7.8 Hz, 1H), 7.47-7.44 (m, 1H), 7.41-7.38 (m, 2H), 7.24 (s, 1H), 7.12 (dd, J1= 4.8 Hz, J2= 0.6 Hz, 1H), 6.94 (d, J = 3.0 Hz, 1H), 6.90 (dd, J1= 4.8 Hz, J2= 3.0 Hz, 1H), 5.56 (s, 1H), 2.75 (s, 3H). 13 C{ 1 H}NMR (100 MHz, CDC13): δ 161.9, 160.0, 148.6, 141.9, 137.9, 134.9 (q, 2 J C-F = 34.1 Hz), 133.6 (q, 3 J C-F = 2.7 Hz), 130.3, 128.2, 126.6, 125.8, 125.1, 124.6, 123.0 (q, 1 J C-F = 272.9 Hz), 121.2, 117.2 (q, 3 J C-F = 4.3 Hz), 46.6, 24.6. 19 FNMR (565 MHz, CDC13): δ -62.41 (s). HRMS (ESI) m / z: [M + H] + Calcd for C 18 H 13 F3NS332.0715; Found 332.0723.

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

[0114] 1HNMR (600 MHz, CDC13): δ 8.11 (d, J = 7.2 Hz, 1H), 7.45 (t, J = 7.2 Hz, 1H), 7.39 (td, J1= 7.8 Hz, J2= 1.2 Hz, 1H), 7.32 (dd, J1= 7.2 Hz, J2= 0.6 Hz, 1H), 7.23 (s, 1H), 7.19 (dd, J1= 3.0 Hz, J2= 1.2 Hz, 1H), 7.13 (dd, J1= 5.4 Hz, J2= 3.0 Hz, 1H), 6.41 (dd, J1= 4.8 Hz, J2= 1.2 Hz, 1H), 5.40 (s, 1H), 2.74 (s, 3H). 13 C{ 1 H}NMR (150 MHz, CDC13): δ 162.1, 159.6, 148.5, 138.9, 138.3, 134.9 (q, 2 J C-F = 34.4 Hz), 133.8, 130.2, 127.9, 126.2, 125.9, 125.2, 123.0 (q, 1 J C-F = 273.3 Hz), 122.4, 121.2, 117.0 (q, 3 J C-F = 4.5 Hz), 46.9, 24.6. 19 FNMR (565 MHz, CDC13): δ -62.54 (s). HRMS (ESI) m / z: [M + H] + Calcd for C 18 H 13 F3NS332.0715; Found 332.0724.

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

[0116] 1 HNMR (400 MHz, CDC13): δ 8.13 (d, J = 7.6 Hz, 1H), 7.44 (t, J = 7.2 Hz, 1H), 7.35 (td, J1= 7.6 Hz, J2= 1.2 Hz, 1H), 7.29-7.24 (m, 4H), 7.19 (d, J = 1.2 Hz, 1H), 7.05-7.03 (m, 2H), 6.20 (t, J = 55.2 Hz, 1H), 5.12 (s, 1H), 2.73 (s, 3H). 13 C{ 1H} NMR (150 MHz, CDC13): δ 161.3, 159.4, 149.2, 139.1, 138.9, 138.7 (dd, 2 J C-F = 24.3, 21.9 Hz), 135.5 (dd, 3 J C-F = 7.1, 2.6 Hz), 129.8, 129.1, 128.2, 127.9, 127.5, 125.2, 121.1, 116.5 (dd, 3 J C-F = 8.4, 4.1 Hz), 111.6 (dd, 1 J C-F = 240.6, 237.5 Hz), 51.0, 24.7. 19 F NMR (376 MHz, CDC13): δ -111.90 (dd, Ji = 299.7 Hz, J2= 54.9 Hz, IF), -125.38 (dd, Ji = 301.9 Hz, J2= 55.6 Hz, IF). HRMS (ESI) m / z: [M + H] + Calcd for C 20 H 16 F2N308.1245; Found 308.1243.

[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 (150 MHz, CDC13): δ 161.3, 159.4, 149.2, 139.1, 138.9, 138.7 (dd, 2 J C-F = 28.5 Hz), 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 indono[1,2-b]pyridine compound 3aa synthesized in this invention can undergo a series of reactions to synthesize further derivatives. For example...

[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 sequentially to a 25 mL round-bottom flask. The mixture was then stirred under reflux (oil bath) for 5 hours. After the reaction was complete, the residue was dissolved in dichloromethane (10 mL) and filtered through a diatomaceous earth mat. The mixture was then extracted with dichloromethane (10 mL × 3), the organic phases were combined, washed with water, dried, filtered, concentrated, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give a white solid product 4 (29.0 mg, 42%). The characterization data of this 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-resistant tube, and the tube was evacuated and purged with oxygen (three times). The tube was then placed in a module at 120 °C and reacted for 48 h. After the reaction was complete, the mixture was cooled to room temperature, and then 5 mL of saturated sodium bicarbonate solution was added to neutralize the reaction. The mixture was extracted three times with ethyl acetate, washed with water and salt, dried over anhydrous sodium sulfate, concentrated, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give a white solid product 5 (33.3 mg, 47%). The characterization data of this 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= 3.0 Hz), 101.2, 23.9. 19 FNMR (565 MHz, DMSO-d6): δ -61.91 (s). HRMS (ESI) m / z: [M+H] + Calcd for C 20 H 15 F3NO2358.1049; Found 358.1052.

[0127] Example 6

[0128] The anti-cancer activity of the compounds is evaluated by the CCK-8 method through the anti-proliferative activity study on cancer cells.

[0129] Specifically, first, cells are seeded into a 96-well plate at a density of 5000 cells per well in 100 μL of medium per well and incubated at 37°C in a 5% CO2 environment overnight. The next day, 100 μL of the test compound diluted with medium (at a concentration of 0.03 nM-30 μM) is added to each well, and then the cells are incubated at 37°C in a 5% CO2 environment for 72 hours. Then, 10 μL of CCK8 is added to each well, and the 96-well plate is incubated at 37°C for 2 hours. The absorbance is measured at 450 nm using an EnVision multilabel Reader (Perkinermer) with 630 nm as the reference wavelength, and the IC50 value is calculated using GraphPad Prism 6.0 software. All experiments are performed in duplicate and repeated twice. Hela, A-549, and HCT-116 cancer cells are selected as the research object, and 5-fluorouracil (5-FU) is used as a positive control for the drug.

[0130] The anti-cancer activity results of some of the 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 application can inhibit the proliferation activity of Hela, A549, and HCT-116 cancer cells, wherein 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, suggesting that such compounds have medicinal value for preventing / treating / inhibiting the progression of cancer, particularly cervical cancer, lung cancer, and colon cancer.

[0133] The above examples describe the basic principles, main features and advantages of the present application. Those skilled in the art should understand that the present application is not limited to the above examples, and the above examples and descriptions in the specification are only to illustrate the principles of the present application. Without departing from the principles of the present application, various changes and improvements can be made to the present application, and these changes and improvements all fall within the scope of the present application.

Claims

1. Fluoromethyl-substituted indeno[1,2-b]pyridine compounds characterized in that: The structure of the compound is: 。 2. Use of the fluoromethyl-substituted indeno[l,2-b]pyridine compounds according to claim 1 for the preparation of medicaments for the treatment of cancer, wherein: 3ac has anti-cervical cancer activity, anti-lung cancer activity and anti-colon cancer activity, 3ah has anti-cervical cancer activity, 3al has anti-cervical cancer activity, anti-lung cancer activity and anti-colon cancer activity, and 3ap has anti-cervical cancer activity.

3. Use of the fluoromethyl-substituted indeno[1,2-b]pyridine compounds according to claim 2 for the preparation of medicaments with anticancer activity, characterized by the fact that: Anti-cervical cancer, lung cancer and colon cancer correspond to anti-Hela, A549 and HCT-116 cancer cells respectively.

4. A pharmaceutical composition for treating cervical cancer, lung cancer, and colon cancer, wherein the active ingredient comprises the fluoromethyl-substituted indono[1,2-b]pyridine compound of claim 1, wherein: 3ac has anti-cervical cancer activity, anti-lung cancer activity and anti-colon cancer activity, 3ah has anti-cervical cancer activity, 3al has anti-cervical cancer activity, anti-lung cancer activity and anti-colon cancer activity, and 3ap has anti-cervical cancer activity.

5. The method for synthesizing fluoromethyl-substituted indono[1,2-b]pyridine compounds as described in claim 1, characterized in that, The method comprises the following steps: mixing 5-aryl imidazole compound 1, fluoromethyl acetylene ketone compound 2, a rhodium catalyst, an additive and a solvent, and performing a warming reaction to obtain a fluoromethyl-substituted indeno[1,2-b]pyridine compound 3, and the reaction equation is as follows: wherein: R is selected from C 1-6 alkyl, R 1 -R 5 in accordance with the substituents of the corresponding compound in claim 1 ; the rhodium catalyst is selected from dichloro(pentamethylcyclopentadienyl)rhodium dimer or bis(hexafluoroantimonate)triethylacetonitrile(pentamethylcyclopentadienyl)rhodium; the additive is selected from zinc acetate, sodium acetate, potassium acetate or cesium acetate in mixture with bis-trifluoromethanesulfonimide silver salt, silver hexafluoroantimonate, silver tetrafluoroborate, silver acetate, silver fluoride, silver trifluoromethanesulfonate or copper acetate; the solvent is selected from hexafluoroisopropanol, trifluoroethanol or methanol.

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

7. The method for synthesizing fluoromethyl-substituted indono[1,2-b]pyridine compounds according to claim 5, characterized in that: The warming reaction is performed under a sealed tube condition at 100-130 DEG C.

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