Fluoromethyl-substituted pyrroloindole compounds, methods of synthesizing the same, and uses thereof in the preparation of medicaments

Abstract

The application discloses fluoromethyl-substituted pyrroloindole compounds, a synthesis method thereof and application thereof in medicine preparation, and relates to the field of organic chemistry.The fluoromethyl-substituted pyrroloindole compound has a chemical structure general formula of N-alkyloxy-1H-indole-1-carboxamide and fluoromethyl acetylenic ketone compound as starting materials, and the fluoromethyl-substituted pyrroloindole compound is obtained through one-pot cascade reaction.The compound has obvious inhibitory activity on the proliferation of Hela and A-549 cancer cells, and it is indicated that the compound has anticancer activity on cervical cancer and lung cancer, and provides a new structural unit for drug screening.

Description

Technical Field

[0001] This invention belongs to the field of chemical pharmaceuticals and organic synthesis technology, specifically relating to fluoromethyl-substituted pyrroloindole compounds, their synthesis methods, and their applications in drug preparation. Background Technology

[0002] Pyrroloindole compounds possess potent antitumor, antibacterial, anti-inflammatory, analgesic, and gastric ailment-relieving effects. On the other hand, due to the strong electron-withdrawing properties and stable carbon-fluorine bonds of trifluoromethyl groups, they can significantly modulate the acidity, lipophilicity, permeability, and metabolic stability of the parent compound. Therefore, introducing trifluoromethyl groups can enhance the bioactivity and bioavailability of lead compounds, increase target selectivity, and reduce the required drug dosage. Currently, trifluoromethyl groups have become one of the advantageous structural units in new drug design.

[0003] Given the importance of pyrroloindole and trifluoromethyl structural units, constructing trifluoromethyl-substituted pyrroloindole frameworks is essential, with the potential to discover lead compounds with enhanced biological activity. Currently, no such compounds or their synthetic methods have been reported.

[0004] Therefore, researching and developing a green and efficient new method for synthesizing fluoromethyl-substituted pyrroloindole compounds from readily available raw materials through simple steps has significant theoretical importance and practical prospects. Summary of the Invention

[0005] In order to address the problems existing in the prior art, one of the objectives of this invention is to provide fluoromethyl-substituted pyrroloindole compounds, which have anticancer activity.

[0006] The second objective of this invention is to provide the application of fluoromethyl-substituted pyrroloindole compounds in the preparation of anticancer drugs.

[0007] A third objective of this invention is to provide a pharmaceutical composition for treating cervical cancer and lung cancer, wherein the active ingredient is a fluoromethyl-substituted pyrroloindole compound provided by this invention.

[0008] The fourth objective of this invention is to provide a method for synthesizing fluoromethyl-substituted pyrroloindole compounds.

[0009] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0010] A fluoromethyl-substituted pyrroloindole compound has the following general chemical formula:

[0011]

[0012] Where R 1 For hydrogen, C1-4 Alkyl, C 1-4 Alkyl, halogen, or cyano groups; R 2 For hydrogen, C 1-4 Alkyl, C 1-4 Alkyl-substituted methyl, cyanomethyl, phenyl, or halogen; R 3 It is phenyl, substituted phenyl, naphthyl, phenanthrene, or thiophene, and the substituent on the substituted phenyl ring is a mono- or di-substituted C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl, halogen, or trifluoromethyl; R 4 It is either fluorine or trifluoromethyl.

[0013] Furthermore, in the above general formula structure, R 1 For hydrogen, R 2 For methyl, R 3 It is phenyl, substituted phenyl, naphthyl, phenanthrene, or thiophene, and the substituent on the substituted phenyl ring is a mono- or di-substituted C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl, halogen, or trifluoromethyl; R 4 It is fluorine or trifluoromethyl;

[0014] Or R 1 For hydrogen, C 1-4 Alkyl, C 1-4 Alkyl, halogen, or cyano groups; R 2 For hydrogen, C 1-4 Alkyl, C 1-4 Alkyl-substituted methyl, cyanomethyl, phenyl, or halogen; R 3 It is a phenyl group, R 4 It is either fluorine or trifluoromethyl.

[0015] Furthermore, in the above general formula structure, in the most preferred case, the following specific structure is selected:

[0016]

[0017] The experiments designed in this invention verify that the compounds provided by this invention have the activity of inhibiting the proliferation of HeLa and A-549 cancer cells, suggesting that the compounds of this invention can serve as active ingredients in drugs for treating cancers such as cervical cancer and lung cancer. In particular, the above-mentioned preferred compounds can significantly inhibit the growth and proliferation of HeLa and A-549, suggesting that such compounds, as active ingredients in anticancer drugs, have preventive, therapeutic, and inhibitory effects on the progression of cervical cancer and lung cancer.

[0018] The synthesis methods of the above compounds include preparation using N-alkoxy-1H-indole-1-carboxamide compounds and fluoromethyl acetylenes as raw materials.

[0019] Optionally, the above synthetic method specifically includes mixing N-alkoxy-1H-indole-1-carboxamide compound 1, fluoromethyl alkynone compound 2, catalyst, additive, and methanol, and reacting at room temperature or with heating to obtain fluoromethyl-substituted pyrroloindole compound 3, the reaction equation of which is:

[0020]

[0021] Where R 1 For hydrogen, C 1-4 Alkyl, C 1-4 Alkyl, halogen, or cyano groups; R 2 For hydrogen, C 1-4 Alkyl, C 1-4 Alkyl-substituted methyl, cyanomethyl, phenyl, or halogen; R 3 It is phenyl, substituted phenyl, naphthyl, phenanthrene, or thiophene, and the substituent on the substituted phenyl ring is a mono- or di-substituted C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl, halogen, or trifluoromethyl; R 4 It is fluorine or trifluoromethyl; X is C 1-4 Alkyl or benzyl.

[0022] Furthermore, in the above synthesis method, the additive is silver acetate, sodium acetate, potassium acetate, cesium acetate, or zinc acetate.

[0023] Furthermore, in the above synthesis method, the catalyst is dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer ([RhCp*Cl2]2) or di(hexafluoroantimonylic acid)triacetonitrile(pentamethylcyclopentadienyl)rhodium(III) ([RhCp*(MeCN)3](SbF6)2).

[0024] Furthermore, in the above synthesis method, the molar ratio of the N-alkoxy-1H-indole-1-carboxamide compound 1, the fluoromethyl alkynone compound 2, the catalyst, and the additive is 1-1.2:1-1.2:0.03-0.05:0.2-0.5.

[0025] Furthermore, in the above synthesis method, the reaction temperature is 20-100℃.

[0026] Furthermore, in the above synthesis method, the reaction is carried out in an air or inert gas atmosphere.

[0027] Beneficial effects of the invention:

[0028] Compared with the prior art, the present invention has the following advantages:

[0029] (1) The fluoromethyl-substituted pyrroloindole compounds provided by the present invention, through screening of compounds with various substituents and verification by anti-cancer cell activity test, show that the compounds provided by the present invention have significant inhibitory activity on the proliferation of HeLa and A-549 cancer cells, suggesting that the compounds of the present invention have anti-cancer activity against cervical cancer and lung cancer, have potential pharmaceutical value, and provide new structural units for drug screening.

[0030] (2) The synthesis method provided by the present invention uses N-alkoxy-1H-indole-1-carboxamide compounds and fluoromethyl alkynone compounds as starting materials to synthesize fluoromethyl-substituted pyrroloindole compounds through a one-pot tandem reaction. The process is simple and efficient.

[0031] (3) The synthesis method provided by the present invention uses inexpensive and readily available raw materials, mild reaction conditions, and simple operation; the substrate has a wide range of applicability and good functional group tolerance. Attached Figure Description

[0032] Figure 1 This is the X-ray single-crystal diffraction pattern of compound 3ba in Example 3. Figure 2 This is the X-ray single-crystal diffraction pattern of compound 4b in Example 5. Detailed Implementation

[0033] The following examples further illustrate the above-described content of the present invention, but it should not be construed as limiting the scope of the subject matter of the present invention to the following examples. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention.

[0034] Example 1

[0035]

[0036] Compound 1a, additive, catalyst, 2a, and methanol were added sequentially to a 15 mL reaction tube. The tube was then sealed and placed in an oil bath with stirring. After the reaction was complete, the mixture was cooled to room temperature, and the reaction was quenched with an aqueous solution of ammonium chloride. The mixture was then extracted with ethyl acetate. The organic phase was dried, concentrated under reduced pressure, and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to give a white solid product 3aa.

[0037] By changing the reaction conditions such as additives, catalysts, reaction temperature, and material ratio, a series of results were obtained, as shown in Table 1.

[0038] Table 1 Synthesis of 3aa under different conditions a

[0039]

[0040]

[0041] Example 2

[0042]

[0043] Add 1a (40.8 mg, 0.2 mmol), potassium acetate (3.9 mg, 0.04 mmol), [RhCp*Cl2]2 (6.2 mg, 0.01 mmol), 2a (39.6 mg, 0.2 mmol), and methanol (2 mL) sequentially to a 15 mL pressure-resistant tube. Seal the reaction tube and place it in an oil bath at 80 °C. React in air for 0.5 h. After the reaction is complete, cool the reaction system to room temperature, quench the reaction with ammonium chloride aqueous solution, extract with ethyl acetate, dry, concentrate under reduced pressure, and separate by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to give the white peptone product 3aa (42.8 mg, 65%). The characterization data of this compound are as follows: 1 H NMR (600MHz, CDCl3): δ7.49-7.48(m,2H),7.44(d,J=7.8Hz,1H),7.41(d,J=8.4Hz,1H),7.38-7. 37(m,3H),7.17(t,J=7.2Hz,1H),7.12(t,J=7.2Hz,1H),6.04(s,1H),2.93(s,1H),2.13(s,3H). 13 C{ 1 H}NMR (100MHz, CDCl3): δ144.4,138.9,134.51,134.49,132.1,129.6,128.7,128.1,125.9,124.4,123.1(q, 1 J C-F =283.9Hz), 120.3, 111.0(q, 5 J C-F =3.6Hz), 108.9, 88.7(q, 2 J C-F =34.6Hz), 9.4. 19 F NMR(565MHz,CDCl3):δ-78.77(s).HRMS(ESI)m / z:[M+H] + Calcd forC 19 H 15 F3NO 330.1100; Found 330.1108.

[0044] Example 3

[0045] According to the method and steps of Example 2 a,bBy changing reactant 1 and reactant 2, various fluoromethyl-substituted pyrroloindole compounds 3 can be synthesized, as shown in the following results:

[0046]

[0047] The representative product characterization data are as follows:

[0048] 9-Methyl-1-(p-tolyl)-3-(trifluoromethyl)-3H-pyrrolo[1,2-a]indol-3-ol(3ab)

[0049] 1 H NMR (600 MHz, CDCl3): δ7.52 (d, J = 7.8 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.46 (d, J = 7.2 Hz, 2H), 7.27-7.22 (m, 3H), 7.12 (t, J = 7.2 Hz,1H),6.09(s,1H),2.96(s,1H),2.42(s,3H),2.23(s,3H). 13 C{ 1 H}NMR (150 MHz, CDCl3): δ144.4,139.7,139.1,134.51,134.49,129.4,129.1,128.0,125.3,124.3,123.1(q, 1 J C-F =284.3 Hz), 120.3, 111.0(q, 5 J C-F =2.1 Hz), 108.8,88.7(q, 2 J C-F =33.9 Hz), 21.4, 9.5. 19 F NMR (565 MHz, CDCl3): δ-78.78 (s). HRMS (ESI) m / z: [M+H] + Calcd forC 20 H 17 F3NO 344.1257; Found 344.1254.

[0050] 1-(4-(tert-Butyl)phenyl)-9-methyl-3-(trifluoromethyl)-3H-pyrrolo[1,2-a]indol-3-ol(3ac)

[0051] 1H NMR(600 MHz,CDCl3):δ7.46-7.39(m,6H),7.17(t,J=7.8 Hz,1H),7.04(t,J=7.8 Hz,1H),6.02(s,1H),2.91(s,1H),2.18(s,3H),1.29(s,9H). 13 C{ 1 H}NMR(150 MHz,CDCl3):δ151.9,143.2,138.0,133.45,133.40,128.0,126.7,124.5,124.3,123.2,122.0(q, 1 J C-F =284.4 Hz),119.2,109.9(q, 5 J C-F =2.1 Hz),107.7,87.6(q, 2 J C-F =35.0 Hz),33.8,30.2,8.6. 19 F NMR(565 MHz,CDCl3):δ-78.79(s).HRMS(ESI)m / z:[M+H] + Calcd forC 23 H 23 F3NO 386.1726;Found 386.1743.

[0052] 1-(4-Methoxyphenyl)-9-methyl-3-(trifluoromethyl)-3H-pyrrolo[1,2-a]indol-3-ol(3ad)

[0053] 1 H NMR(600 MHz,CDCl3):δ7.53-7.47(m,4H),7.25(t,J=7.8 Hz,1H),7.12(t,J=7.2 Hz,1H),6.94(d,J=8.4 Hz,2H),6.04(s,1H),3.81(s,3H),3.12(s,1H),2.23(s,3H). 13 C{ 1 H}NMR(150 MHz,CDCl3):δ160.5,143.9,139.2,134.51,134.48,129.5,124.7,124.4,124.3,123.1(q, 1 J C-F=284.4 Hz),120.3,120.2,114.1,111.0(q, 5 J C-F =3.3 Hz),108.6,88.7(q, 2 J C-F =35.1 Hz),55.4,9.5. 19 F NMR(565 MHz,CDCl3):δ-78.78(s).HRMS(ESI)m / z:[M+Na] + Calcd for C 20 H 16 F3NNaO2382.1025;Found 382.1022.

[0054] 1-(4-Fluorophenyl)-9-methyl-3-(trifluoromethyl)-3H-pyrrolo[1,2-a]indol-3-ol(3ae)

[0055] 1 H NMR(600 MHz,CDCl3):δ7.49-7.44(m,3H),7.42(d,J=7.8 Hz,1H),7.18(t,J=7.8 Hz,1H),7.09-7.04(m,3H),6.02(s,1H),2.94(s,1H),2.13(s,3H). 13 C{ 1 H}NMR(150MHz,CDCl3):δ162.4(d, 1 J C-F =248.4 Hz),142.3,137.7,133.4,133.3,128.9(d, 3 J C-F =7.7Hz),127.1(d, 4 J C-F =3.3 Hz),124.8,123.5,121.9(q, 1 J C-F =283.4 Hz),119.32,119.26,114.7(d, 2 J C-F =21.9 Hz),109.9(q, 5 J C-F =2.1 Hz),107.8,87.7(q, 2 J C-F =33.9 Hz),8.3. 19F NMR(565 MHz,CDCl3):δ-78.79(s),-111.08–-111.13(m).HRMS(ESI)m / z:[M+H] + Calcd for C 19 H 14 F4NO 348.1006;Found348.1001.

[0056] 1-(4-Chlorophenyl)-9-methyl-3-(trifluoromethyl)-3H-pyrrolo[1,2-a]indol-3-ol(3af)

[0057] 1 H NMR(600 MHz,CDCl3):δ7.45-7.40(m,4H),7.36-7.35(m,2H),7.18(t,J=7.8Hz,1H),7.04(t,J=7.8 Hz,1H),6.03(s,1H),2.99(s,1H),2.12(s,3H). 13 C{ 1 H}NMR(150MHz,CDCl3):δ143.2,138.6,135.6,134.5,134.4,130.5,129.4,129.0,126.2,124.6,123.0(q, 1 J C-F =284.4 Hz),120.43,120.36,111.0(q, 5 J C-F =2.3 Hz),109.0,88.7(q, 2 J C-F =33.9Hz),9.4. 19 F NMR(565 MHz,CDCl3):δ-78.76(s).HRMS(ESI)m / z:[M+H] + Calcd forC 19 H 14 ClF3NO 364.0711;Found 364.0717.

[0058] Methyl 4-(3-hydroxy-9-methyl-3-(trifluoromethyl)-3H-pyrrolo[1,2-a]indol-1-yl)benzoate(3ag)

[0059] 1H NMR(600 MHz,DMSO-d6):δ8.32(s,1H),8.13(d,J=8.4 Hz,2H),7.82(d,J=7.8Hz,2H),7.60(d,J=7.8 Hz,1H),7.44(d,J=7.8 Hz,1H),7.26(t,J=7.2 Hz,1H),7.12(t,J=7.8 Hz,1H),6.61(s,1H),3.91(s,3H),2.22(s,3H). 13 C{ 1 H}NMR(100 MHz,DMSO-d6):δ166.3,141.6,138.9,136.9,134.5,134.3,130.8,130.1,129.9,128.9,124.3,124.0(q, 1 J C-F =285.3 Hz),120.7,120.3,111.1,107.2,88.9(q, 2 J C-F =33.3 Hz),52.8,9.7. 19 F NMR(565 MHz,DMSO-d6):δ-78.44(s).HRMS(ESI)m / z:[M+Na] + Calcd forC 21 H 16 F3NNaO3410.0974;Found 410.0975.

[0060] 9-Methyl-1-(m-tolyl)-3-(trifluoromethyl)-3H-pyrrolo[1,2-a]indol-3-ol(3ah)

[0061] 1 H NMR(600 MHz,CDCl3):δ7.45(d,J=7.8 Hz,1H),7.42(d,J=8.4 Hz,1H),7.32-7.25(m,3H),7.19-7.16(m,2H),7.04(t,J=7.2 Hz,1H),6.03(s,1H),2.92(s,1H),2.34(s,3H),2.15(s,3H). 13 C{ 1H}NMR(150 MHz,CDCl3):δ143.4,137.9,137.4,133.43,133.41,130.9,129.2,127.7,127.5,124.6,124.1,123.3,122.0(q, 1 J C-F =284.4 Hz),119.2,109.9(q, 5 J C-F =3.3 Hz),107.7,87.7(q, 2 J C-F =35.0 Hz),20.3,8.4. 19 F NMR(565 MHz,CDCl3):δ-78.78(s).HRMS(ESI)m / z:[M+H] + Calcd forC 20 H 17 F3NO 344.1257;Found 344.1254.

[0062] 1-(3-Methoxyphenyl)-9-methyl-3-(trifluoromethyl)-3H-pyrrolo[1,2-a]indol-3-ol(3ai)

[0063] 1 H NMR(600 MHz,CDCl3):δ7.44-7.41(m,2H),7.26(t,J=7.8 Hz,1H),7.18-7.16(m,1H),7.06-7.02(m,2H),6.99(t,J=1.8 Hz,1H),6.87(dd,J1=8.4 Hz,J2=1.8 Hz,1H),6.03(s,1H),3.72(s,3H),3.11(s,1H)2.14(s,3H). 13 C{ 1 H}NMR(150 MHz,CDCl3):δ159.6,144.2,138.8,134.51,134.47,133.4,129.8,126.0,124.4,123.1(q, 1 J C-F =284.4 Hz),120.6,120.3,115.2,113.6,111.0(q, 5 J C-F =2.3 Hz),108.9,88.7(q, 2 J C-F=33.9 Hz),55.4,9.5. 19 F NMR(565 MHz,CDCl3):δ-78.77(s).HRMS(ESI)m / z:[M+H] + Calcd forC 20 H 17 F3NO2360.1206;Found 360.1211.

[0064] 1-(3-Fluorophenyl)-9-methyl-3-(trifluoromethyl)-3H-pyrrolo[1,2-a]indol-3-ol(3aj)

[0065] 1 H NMR(400 MHz,CDCl3):δ7.54(d,J=8.0 Hz,1H),7.50(d,J=8.4 Hz,1H),7.47-7.41(m,1H),7.38-7.35(m,1H),7.30-7.25(m,2H),7.18-7.11(m,2H),6.15(s,1H),3.09(s,1H),2.23(s,3H). 13 C{ 1 H}NMR(100 MHz,CDCl3):δ162.8(d, 1 J C-F =245.6 Hz),143.2,138.4,134.5,134.4,134.2(d, 3 J C-F =8.0 Hz),130.4(d, 3 J C-F =8.6Hz),126.6,124.6,123.9(d, 4 J C-F =2.9 Hz),123.0(q, 1 J C-F =284.6 Hz),120.43,120.38,116.5(d, 2 J C-F =21.0 Hz),115.2(d, 2 J C-F =22.4 Hz),111.0(q, 5 J C-F =2.9 Hz),109.1,88.7(q, 2 J C-F =34.6 Hz),9.4. 19F NMR(376 MHz,CDCl3):δ-78.78(s),-112.10(td,J1=8.3 Hz,J2=5.6 Hz).HRMS(ESI)m / z:[M+H] + Calcd forC 19 H 14 F4NO 348.1006;Found 348.1011.

[0066] 1-(3-Chlorophenyl)-9-methyl-3-(trifluoromethyl)-3H-pyrrolo[1,2-a]indol-3-ol(3ak)

[0067] 1 H NMR(600 MHz,CDCl3):δ7.49(s,1H),7.45(d,J=7.8 Hz,1H),7.41(d,J=8.4Hz,1H),7.39-7.31(m,3H),7.19(t,J=7.8 Hz,1H),7.05(t,J=7.8 Hz,1H),6.07(s,1H),2.95(s,1H),2.14(s,3H). 13 C{ 1 H}NMR(150 MHz,CDCl3):δ142.0,137.3,133.7,133.5,133.3,132.7,128.9,128.5,127.1,125.5,125.2,123.5,121.9(q, 1 J C-F =284.4 Hz),119.4,119.3,109.9(q, 5 J C-F =3.3 Hz),108.0,87.7(q, 2 J C-F =35.1 Hz),8.3. 19 F NMR(565MHz,CDCl3):δ-78.75(s).HRMS(ESI)m / z:[M+H] + Calcd forC 19 H 14 ClF3NO 364.0711;Found364.0712.

[0068] 1-(3-Bromophenyl)-9-methyl-3-(trifluoromethyl)-3H-pyrrolo[1,2-a]indol-3-ol(3al)

[0069] 1 H NMR(600 MHz,CDCl3):δ7.74(t,J=1.8 Hz,1H),7.60-7.58(m,1H),7.53(d,J=7.8 Hz,1H),7.52-7.49(m,2H),7.34(t,J=7.8 Hz,1H),7.28-7.25(m,1H),7.14-7.12(m,1H),6.15(s,1H),3.19(s,1H),2.22(s,3H). 13 C{ 1 H}NMR(100 MHz,CDCl3):δ142.9,138.4,134.5,134.4,134.1,132.5,131.1,130.2,126.7,124.6,123.0(q, 1 J C-F =284.6 Hz),122.8,120.43,120.38,111.0(q, 5 J C-F =2.9 Hz),109.0,88.7(q, 2 J C-F =34.7 Hz),9.4. 19 FNMR(565 MHz,CDCl3):δ-78.77(s).HRMS(ESI)m / z:[M+H] + Calcd for C 19 H 14 BrF3NO408.0205;Found 408.0209.

[0070] 9-Methyl-3-(trifluoromethyl)-1-(3-(trifluoromethyl)phenyl)-3H-pyrrolo[1,2-a]indol-3-ol(3am)

[0071] 1 H NMR(600 MHz,CDCl3):δ7.78(s,1H),7.69(d,J=7.8 Hz,1H),7.65(d,J=7.8Hz,1H),7.53(t,J=7.2 Hz,1H),7.46(d,J=7.8 Hz,1H),7.43(d,J=8.4 Hz,1H),7.20(t,J=7.8 Hz,1H),7.06(t,J=7.8 Hz,1H),6.13(s,1H),2.98(s,1H),2.13(s,3H).13 C{ 1 H}NMR(150 MHz,CDCl3):δ141.9,137.2,133.5,133.3,131.8,130.232(q, 2 J C-F =32.9 Hz),130.231,128.3,125.8,125.2(q, 3 J C-F =4.4 Hz),124.0(q, 3 J C-F =4.4 Hz),123.6,122.8(q, 1 J C-F =270.2 Hz),121.9(q, 1 J C-F =284.4 Hz),119.5,119.4,109.9(q, 5 J C-F =3.3 Hz),108.1,87.7(q, 2 J C-F =35.0 Hz),8.3. 19 F NMR(565MHz,CDCl3):δ-62.78(s),-78.75(s).HRMS(ESI)m / z:[M+H] + Calcd forC 20 H 14 F6NO 398.0974;Found 398.0969.

[0072] 1-(3,4-Dimethoxyphenyl)-9-methyl-3-(trifluoromethyl)-3H-pyrrolo[1,2-a]indol-3-ol(3an)

[0073] 1 H NMR(600 MHz,CDCl3):δ7.53-7.50(m,2H),7.27-7.24(m,1H),7.14-7.11(m,2H),7.05(d,J=1.8 Hz,1H),6.90(d,J=8.4 Hz,1H),6.07(s,1H),3.870(s,3H),3.866(s,3H),3.44(s,1H),2.27(s,3H). 13 C{ 1H}NMR(150 MHz,CDCl3):δ150.1,148.8,143.8,139.1,134.5,134.4,124.9,124.7,124.3,123.1(q, 1 J C-F =284.3 Hz),120.9,120.24,120.17,111.2,111.1,110.0(q, 5 J C-F =2.3 Hz),108.4,88.7(q, 2 J C-F =33.9 Hz),55.98,55.96,9.8. 19 F NMR(565 MHz,CDCl3):δ-78.79(s).HRMS(ESI)m / z:[M+Na] + Calcd forC 21 H 18 F3NNaO3412.1131;Found 412.1129.

[0074] 9-Methyl-1-(o-tolyl)-3-(trifluoromethyl)-3H-pyrrolo[1,2-a]indol-3-ol(3ao)

[0075] 1 H NMR(600 MHz,CDCl3):δ7.43-7.40(m,2H),7.28-7.25(m,1H),7.23-7.17(m,4H),7.03(t,J=7.8 Hz,1H),5.96(s,1H),2.90(s,1H),2.26(s,3H),1.85(s,3H). 13 C{ 1 H}NMR(150 MHz,CDCl3):δ143.7,140.0,136.2,134.4,134.3,131.9,130.4,129.1,128.7,127.0,126.0,124.3,123.1(q, 1 J C-F =284.4 Hz),120.27,120.25,110.9(q, 5 J C-F =3.2 Hz),108.7,89.0(q, 2 J C-F =35.1 Hz),19.6,8.0. 19F NMR(565 MHz,CDCl3):δ-79.01(s).HRMS(ESI)m / z:[M+H] + Calcd for C 20 H 17 F3NO 344.1257;Found 344.1251.

[0076] 1-(2-Fluorophenyl)-9-methyl-3-(trifluoromethyl)-3H-pyrrolo[1,2-a]indol-3-ol(3ap)

[0077] 1 H NMR(600 MHz,CDCl3):δ7.44-7.41(m,3H),7.37-7.33(m,1H),7.18-7.14(m,2H),7.13-7.09(m,1H),7.05-7.02(m,1H),6.14(s,1H),3.04(s,1H),2.05(s,3H). 13 C{ 1 H}NMR(150 MHz,CDCl3):δ158.9(d, 1 J C-F =248.3 Hz),138.0,136.6,133.4(d, 3 J C-F =11.0Hz),130.1(d, 3 J C-F =7.7 Hz),129.60,129.58,127.31,127.29,123.3,123.2(d, 4 J C-F =3.3Hz),121.9(q, 1 J C-F =284.4 Hz),119.2,119.0(d, 2 J C-F =14.3 Hz),115.1(d, 2 J C-F =20.7Hz),109.9(q, 5 J C-F =3.3 Hz),108.0,87.8(q, 2 J C-F =35.0 Hz),7.7(d, 6 J C-F =2.3 Hz). 19FNMR(565 MHz,CDCl3):δ-78.82(s),-113.09–-113.13(m).HRMS(ESI)m / z:[M+H] + Calcd forC 19 H 14 F4NO 348.1006;Found 348.0998.

[0078] 9-Methyl-1-(naphthalen-2-yl)-3-(trifluoromethyl)-3H-pyrrolo[1,2-a]indol-3-ol(3aq)

[0079] 1 H NMR(600 MHz,CDCl3):δ7.98(s,1H),7.83(d,J=8.4 Hz,1H),7.80-7.79(m,2H),7.55(dd,J1=8.4 Hz,J2=1.8 Hz,1H),7.46-7.44(m,4H),7.19(t,J=7.8 Hz,1H),7.05(t,J=7.8 Hz,1H),6.14(s,1H),3.01(s,1H),2.16(s,3H). 13 C{ 1 H}NMR(150 MHz,CDCl3):δ143.3,138.0,133.5,133.4,132.6,132.0,128.4,127.4,127.2,126.8,126.5,125.9,125.8,125.0,124.5,123.4,122.0(q, 1 J C-F =284.4 Hz),119.3,119.2,109.9(q, 5 J C-F =2.3 Hz),107.9,87.7(q, 2 J C-F =35.1 Hz),8.5. 19 F NMR(565MHz,CDCl3):δ-78.68(s).HRMS(ESI)m / z:[M+Na] + Calcd for C 23 H 16 F3NNaO402.1076;Found 402.1064.

[0080] 9-Methyl-1-(phenanthren-9-yl)-3-(trifluoromethyl)-3H-pyrrolo[1,2-a]indol-3-ol(3ar)

[0081] 1 H NMR(600 MHz,CDCl3):δ7.70(d,J=8.4 Hz,1H),7.66(d,J=8.4 Hz,1H),8.00(d,J=8.4 Hz,1H),7.84(d,J=8.4 Hz,1H),7.78(s,1H),7.66-7.62(m,2H),7.57(t,J=7.2 Hz,1H),7.52(d,J=8.4 Hz,1H),7.49(t,J=7.2 Hz,1H),7.38(d,J=7.8 Hz,1H),7.20(t,J=7.8 Hz,1H),7.03(t,J=7.8 Hz,1H),6.27(s,1H),4.91(br s,1H),1.59(s,3H). 13 C{ 1 H}NMR(150 MHz,CDCl3):δ141.3,139.9,133.5,133.1,130.1,129.7,129.4,129.2,128.1,128.0,127.9,126.4,126.08,126.07,125.3,123.1,122.3(q, 1 J C-F =284.4Hz),122.0,121.7,119.1,119.0,110.0(q, 5 J C-F =2.3 Hz),107.2,88.1(q, 2 J C-F =33.9 Hz),7.4. 19 F NMR(565 MHz,CDCl3):δ-78.98(s).HRMS(ESI)m / z:[M+Na] + Calcd for C 27 H 18 F3NNaO452.1233;Found 452.1242.

[0082] 9-Methyl-1-(thiophen-3-yl)-3-(trifluoromethyl)-3H-pyrrolo[1,2-a]indol-3-ol(3as)

[0083] 1 H NMR(600 MHz,CDCl3):δ7.54(dd,J1=3.0 Hz,J2=1.2 Hz,1H),7.48(d,J=7.8Hz,1H),7.43(d,J=7.8 Hz,1H),7.36(dd,J1=4.8 Hz,J2=3.0 Hz,1H),7.24(dd,J1=4.8Hz,J2=1.2 Hz,1H),7.21-7.19(m,1H),7.08-7.05(m,1H),6.09(s,1H),2.90(s,1H),2.26(s,3H). 13 C{ 1 H}NMR(150 MHz,CDCl3):δ137.8,137.7,133.4,131.6,126.5,125.4,124.2,124.1,123.4,122.0(q, 1 J C-F =284.4 Hz),119.3,119.2,109.9(q, 5 J C-F =3.3 Hz),107.6,87.6(q, 2 J C-F =35.1 Hz),8.6. 19 F NMR(565 MHz,CDCl3):δ-78.75(s).HRMS(ESI)m / z:[M+Na] + Calcd for C 17 H 12 F3NNaOS 358.0484;Found358.0489.

[0084] 9-Methyl-3-(perfluoroethyl)-1-phenyl-3H-pyrrolo[1,2-a]indol-3-ol(3at)

[0085] 1 H NMR(600 MHz,CDCl3):δ7.48-7.43(m,4H),7.39-7.37(m,3H),7.17(t,J=7.8Hz,1H),7.04(t,J=7.2 Hz,1H),6.04(s,1H),2.92(s,1H),2.13(s,3H). 13 C{ 1H}NMR(150MHz,CDCl3):δ143.9,138.7,135.0,134.6,132.1,129.6,128.7,128.1,126.1,124.4,120.4,120.3,118.8(qt, 1 J C-F =285.5 Hz, 2 J C-F =35.0 Hz),113.0(tq, 1 J C-F =260.3 Hz, 2 J C-F =36.2 Hz),111.4-111.3(m),109.2,89.6-89.2(m),9.4. 19 FNMR(565 MHz,CDCl3):δ-80.06(s),-121.47–-123.20(m).HRMS(ESI)m / z:[M+Na] + Calcd for C 20 H 14 F5NNaO402.0888;Found 402.0892.

[0086] 1-Phenyl-3-(trifluoromethyl)-3H-pyrrolo[1,2-a]indol-3-ol(3ba)

[0087] 1 H NMR(600 MHz,CDCl3):δ7.75-7.74(m,2H),7.61(d,J=7.8 Hz,1H),7.55(d,J=8.4 Hz,1H),7.49-7.46(m,3H),7.27-7.25(m,1H),7.13(t,J=7.8 Hz,1H),6.65(s,1H),6.40(s,1H),3.11(s,1H). 13 C{ 1 H}NMR(150 MHz,CDCl3):δ142.6,141.9,134.5,133.2,131.2,130.1,129.1,127.1,124.6,124.2,123.0(q, 1 J C-F =284.4 Hz),122.3,120.9,111.1(q, 5 J C-F =3.3 Hz),99.3,89.3(q, 2 J C-F=35.1 Hz). 19 F NMR(565MHz,CDCl3):δ-78.59(s).HRMS(ESI)m / z:[M+H] + Calcd for C 18 H 13 F3NO 316.0944;Found 316.0946.

[0088] 8-Methyl-1-phenyl-3-(trifluoromethyl)-3H-pyrrolo[1,2-a]indol-3-ol(3ca)

[0089] 1 H NMR(600 MHz,CDCl3):δ7.76(dd,J1=7.8 Hz,J2=1.8 Hz,2H),7.50-7.46(m,3H),7.39(d,J=8.4 Hz,1H),7.17(t,J=7.2 Hz,1H),6.94(d,J=7.2 Hz,1H),6.66(s,1H),6.38(s,1H),3.10(s,1H),2.53(s,3H). 13 C{ 1 H}NMR(150 MHz,CDCl3):δ142.1,141.9,134.3,132.9,131.9,131.3,130.1,129.1,127.2,124.4,124.3,123.0(q, 1 J C-F =283.2Hz),121.2,108.7(q, 5 J C-F =3.3 Hz),97.7,89.3(q, 2 J C-F =33.9Hz),18.7. 19 F NMR(565MHz,CDCl3):δ-78.53(s).HRMS(ESI)m / z:[M+H] + Calcd for C 19 H 15 F3NO 330.1100;Found330.1084.

[0090] 8-Methoxy-1-phenyl-3-(trifluoromethyl)-3H-pyrrolo[1,2-a]indol-3-ol(3da)

[0091] 1H NMR(600 MHz,CDCl3):δ7.73-7.72(m,2H),7.46-7.45(m,3H),7.16(d,J=8.4Hz,1H),7.11(t,J=8.4 Hz,1H),6.70(s,1H),6.51(d,J=7.8 Hz,1H),6.36(s,1H),3.92(s,3H),3.52(s,1H). 13 C{ 1 H}NMR(150 MHz,CDCl3):δ153.9,141.7,141.1,135.7,131.1,130.0,128.9,127.1,125.1,123.9,123.3,123.0(q, 1 J C-F =282.2Hz),104.7(q, 5 J C-F =3.3Hz),101.2,96.3,89.3(q, 2 J C-F =35.1 Hz),55.5. 19 F NMR(565 MHz,CDCl3):δ-78.50(s).HRMS(ESI)m / z:[M+H] + Calcd for C 19 H 15 F3NO2346.1049;Found 346.1050.

[0092] 8-Fluoro-1-phenyl-3-(trifluoromethyl)-3H-pyrrolo[1,2-a]indol-3-ol(3ea)

[0093] 1 H NMR(600 MHz,CDCl3):δ7.67-7.66(m,2H),7.42-7.39(m,3H),7.25(d,J=8.4Hz,1H),7.10(td,J1=8.4 Hz,J2=5.4 Hz,1H),6.74(dd,J1=10.2 Hz,J2=7.8Hz,1H),6.67(s,1H),6.36(s,1H),3.26(s,1H). 13 C{ 1 H}NMR(150 MHz,CDCl3):δ157.0(d, 1 J C-F =247.2Hz),142.6,141.8,136.5(d, 3 JC-F =11.0 Hz),130.8,130.3,129.1,127.1,124.9,124.8(d, 3 J C-F =7.7 Hz),122.9(q, 1 J C-F =284.4 Hz),121.9(d, 2 J C-F =21.9 Hz),107.31-107.26(m),106.0(d, 2 J C-F =18.6 Hz),94.9,89.4(q, 2 J C-F =34.1 Hz). 19 F NMR(565 MHz,CDCl3):δ-78.60(s),-120.90(dd,J1=10.2 Hz,J2=4.0 Hz).HRMS(ESI)m / z:[M+H] + Calcd forC 18 H 12 F4NO 334.0850;Found334.0849.

[0094] 8-Bromo-1-phenyl-3-(trifluoromethyl)-3H-pyrrolo[1,2-a]indol-3-ol(3fa)

[0095] 1 H NMR(600 MHz,CDCl3):δ7.76-7.42(m,2H),7.51-7.47(m,4H),7.30(d,J=7.2Hz,1H),7.11(t,J=8.4 Hz,1H),6.73(s,1H),6.44(s,1H),3.23(s,1H). 13 C{ 1 H}NMR(150MHz,CDCl3):δ143.0,142.0,134.8,133.6,130.7,130.3,129.1,127.2,125.1,124.9,123.9,122.8(q, 1 J C-F =283.2 Hz),115.8,110.2(q, 5 J C-F =2.3 Hz),99.3,89.6(q, 2 J C-F =33.9 Hz).19 F NMR(565 MHz,CDCl3):δ-78.63(s).HRMS(ESI)m / z:[M+H] + Calcd forC 18 H 12 BrF3NO 394.0049;Found 394.0055.

[0096] 7-Methoxy-1-phenyl-3-(trifluoromethyl)-3H-pyrrolo[1,2-a]indol-3-ol(3ga)

[0097] 1 H NMR(600 MHz,CDCl3):δ7.73-7.72(m,2H),7.49-7.46(m,3H),7.38(d,J=9.0Hz,1H),6.99(d,J=2.4 Hz,1H),6.84(dd,J1=8.4 Hz,J2=2.4 Hz,1H),6.53(s,1H),6.40(s,1H),3.77(s,3H),3.64(s,1H). 13 C{ 1 H}NMR(150 MHz,CDCl3):δ154.3,143.3,141.8,133.7,131.2,130.0,129.8,129.0,127.1,124.7,123.0(q, 1 J C-F =284.4 Hz),113.5,111.7(q, 5 J C-F =3.3 Hz),104.8,98.9,89.2(q, 2 J C-F =35.0 Hz),56.0. 19 F NMR(565 MHz,CDCl3):δ-78.84(s).HRMS(ESI)m / z:[M+H] + Calcd forC 19 H 15 F3NO2346.1049;Found 346.1048.

[0098] 7-Fluoro-1-phenyl-3-(trifluoromethyl)-3H-pyrrolo[1,2-a]indol-3-ol(3ha)

[0099] 1H NMR(600 MHz,CDCl3):δ7.74-7.72(m,2H),7.50-7.45(m,4H),7.26(dd,J1=9.0Hz,J2=2.4 Hz,1H),7.00(td,J1=9.0 Hz,J2=2.4 Hz,1H),6.62(s,1H),6.43(s,1H),3.32(s,1H). 13 C{ 1 H}NMR(150 MHz,CDCl3):δ158.3(d, 1 J C-F =234.2 Hz),144.2,142.0,133.7(d, 3 J C-F =9.9 Hz),131.0,130.9,130.2,129.1,127.1,125.0,122.9(q, 1 J C-F =284.4 Hz),112.2(d, 2 J C-F =25.2 Hz),111.7(dq, 3 J C-F =8.7 Hz, 5 J C-F =3.3Hz),107.4(d, 2 J C-F =24.2Hz),99.1(d, 4 J C-F =4.4 Hz),89.3(q, 2 J C-F =35.0 Hz). 19 FNMR(565 MHz,CDCl3):δ-78.78(s),-123.18(td,J1=8.5 Hz,J2=4.0 Hz).HRMS(ESI)m / z:[M+H] + Calcd for C 18 H 12 F4NO334.0850;Found 334.0856.

[0100] 7-Chloro-1-phenyl-3-(trifluoromethyl)-3H-pyrrolo[1,2-a]indol-3-ol(3ia)

[0101] 1H NMR(600 MHz,CDCl3):δ7.73-7.71(m,2H),7.57(d,J=1.8 Hz,1H),7.49-7.48(m,3H),7.45(d,J=9.0 Hz,1H),7.21(dd,J1=8.4 Hz,J2=1.8 Hz,1H),6.59(s,1H),6.44(s,1H),3.35(s,1H). 13 C{ 1 H}NMR(150 MHz,CDCl3):δ143.9,141.9,134.2,132.8,130.8,130.3,129.1,127.1,126.5,125.0,124.4,122.8(q, 1 J C-F =283.4 Hz),121.7,112.0(q, 5 J C-F =3.3 Hz),98.6(s),89.3(q, 2 J C-F =35.0 Hz). 19 FNMR(565 MHz,CDCl3):δ-78.77(s).HRMS(ESI)m / z:[M+H] + Calcd forC 18 H 12 ClF3NO 350.0554;Found 350.0549.

[0102] 6-Methyl-1-phenyl-3-(trifluoromethyl)-3H-pyrrolo[1,2-a]indol-3-ol(3ja)

[0103] 1 H NMR(600 MHz,CDCl3):δ7.74-7.73(m,2H),7.49-7.45(m,4H),7.35(s,1H),6.96(d,J=7.8 Hz,1H),6.60(s,1H),6.36(s,1H),3.08(s,1H),2.47(s,3H). 13 C{ 1 H}NMR(150MHz,CDCl3):δ142.1,141.9,134.9,134.4,131.3,130.9,130.0,129.0,127.1,124.1,123.0(q, 1 J C-F=284.4 Hz),122.5,121.9,111.2(q, 5 J C-F =3.3 Hz),99.2,89.2(q, 2 J C-F =33.9Hz),22.0. 19 F NMR(565 MHz,CDCl3):δ-78.47(s).HRMS(ESI)m / z:[M+H] + Calcd forC 19 H 15 F3NO 330.1100;Found 330.1092.

[0104] 6-Methoxy-1-phenyl-3-(trifluoromethyl)-3H-pyrrolo[1,2-a]indol-3-ol(3ka)

[0105] 1 H NMR(400 MHz,CDCl3):δ7.65-7.63(m,2H),7.39-7.37(m,4H),6.96(s,1H),6.67(dd,J1=8.8 Hz,J2=2.0 Hz,1H),6.50(s,1H),6.25(s,1H),3.74(s,3H),3.22(s,1H). 13 C{ 1 H}NMR(100 MHz,CDCl3):δ157.8,141.9,141.5,135.6,131.3,130.0,129.0,127.1,123.5,123.1(d, 1 J C-F =284.5 Hz),122.8,110.5,99.2,95.1(q, 5 J C-F =2.9Hz),89.2(q, 2 J C-F =34.7Hz),55.7. 19 F NMR(376 MHz,CDCl3):δ-78.31(s).HRMS(ESI)m / z:[M+H] + Calcd forC 19 H 15 F3NO2346.1049;Found 346.1055.

[0106] 6-Chloro-1-phenyl-3-(trifluoromethyl)-3H-pyrrolo[1,2-a]indol-3-ol(3la)

[0107] 1 H NMR(400 MHz,CDCl3):δ7.74-7.72(m,2H),7.55(s,1H),7.52-7.47(m,4H),7.11(dd,J1=8.4 Hz,J2=1.6 Hz,1H),6.64(s,1H),6.43(s,1H),3.22(s,1H). 13 C{ 1 H}NMR(150MHz,CDCl3):δ143.2,142.0,134.7,131.7,130.9,130.23,130.20,129.1,127.1,124.6,123.0,122.8(q, 1 J C-F =284.4 Hz),121.6,111.3(q, 5 J C-F =3.3 Hz),99.2,89.3(q, 2 J C-F =35.1 Hz). 19 F NMR(376 MHz,CDCl3):δ-78.67(s).HRMS(ESI)m / z:[M+H] + Calcd forC 18 H 12 ClF3NO 350.0554;Found 350.0556.

[0108] 3-Hydroxy-1-phenyl-3-(trifluoromethyl)-3H-pyrrolo[1,2-a]indole-6-carbonitrile(3ma)

[0109] 1 H NMR(600 MHz,DMSO-d6):δ8.76(s,1H),7.97(d,J=6.6 Hz,2H),7.87(d,J=7.8Hz,1H),7.81(s,1H),7.58-7.54(m,3H),7.52(dd,J1=8.4 Hz,J2=1.2 Hz,1H),7.16(s,1H),7.12(s,1H). 13 C{ 1H}NMR(150 MHz,DMSO-d6):δ146.6,139.5,136.9,132.9,130.7,130.6,129.7,129.4,127.5,123.9,123.7(q, 1 J C-F =284.4 Hz),120.4,114.9,105.4,99.1,89.9(q, 2 J C-F =33.9 Hz). 19 F NMR(565 MHz,DMSO-d6):δ-78.62(s).HRMS(ESI)m / z:[M+Na] + Calcd for C 19 H 11 F3N2NaO 363.0716;Found363.0713.

[0110] 9-Isopropyl-1-phenyl-3-(trifluoromethyl)-3H-pyrrolo[1,2-a]indol-3-ol(3na)

[0111] 1 H NMR(600 MHz,CDCl3):δ7.67(d,J=7.8 Hz,1H),7.46-7.42(m,3H),7.38-7.36(m,3H),7.17-7.15(m,1H),7.02-6.99(m,1H),6.01(s,1H),3.07-3.02(m,1H),2.97(s,1H),1.28(d,J=7.2 Hz,3H),1.24(d,J=6.6 Hz,3H). 13 C{ 1 H}NMR(150 MHz,CDCl3):δ144.7,137.5,135.3,132.7,131.9,129.4,128.6,127.9,126.9,124.0,123.1(q, 1 J C-F =284.4Hz),122.7,120.1,119.9,111.4(q, 5 J C-F =2.1 Hz),88.7(q, 2 J C-F =33.9 Hz),25.3,22.7,22.6. 19F NMR(565 MHz,CDCl3):δ-78.63(s).HRMS(ESI)m / z:[M+Na] + Calcd forC 21 H 18 F3NNaO 380.1233;Found 380.1237.

[0112] Ethyl 2-(3-hydroxy-1-phenyl-3-(trifluoromethyl)-3H-pyrrolo[1,2-a]indol-9-yl)acetate(3oa)

[0113] 1 H NMR(600 MHz,CDCl3):δ7.54-7.49(m,4H),7.44-7.39(m,3H),7.25-7.23(m,1H),7.10-7.08(m,1H),6.10(s,1H),4.17(s,1H),3.98-3.89(m,2H),3.58(s,2H),1.11(t,J=7.2 Hz,3H). 13 C{ 1 H}NMR(150 MHz,CDCl3):δ171.7,143.5,140.7,134.6,133.4,132.0,129.5,128.8,127.9,127.7,124.4,123.0(q, 1 J C-F =283.4 Hz),120.7,120.2,111.4(q, 5 J C-F =3.2 Hz),104.9,89.0(q, 2 J C-F =33.9 Hz),61.2,30.1,14.0. 19 F NMR(565 MHz,CDCl3):δ-78.74(s).HRMS(ESI)m / z:[M+Na] + Calcdfor C 22 H 18 F3NNaO3424.1131;Found 424.1115.

[0114] 2-(3-Hydroxy-1-phenyl-3-(trifluoromethyl)-3H-pyrrolo[1,2-a]indol-9-yl)acetonitrile(3pa)

[0115] 1 H NMR(600 MHz,DMSO-d6):δ8.52(s,1H),7.77(d,J=8.4 Hz,1H),7.67-7.65(m,2H),7.60-7.55(m,3H),7.50(d,J=7.8 Hz,1H),7.35-7.32(m,1H),7.22-7.19(m,1H),6.64(s,1H),3.98(d,J=18.6 Hz,1H),3.94(d,J=18.0 Hz,1H). 13 C{ 1 H}NMR(150 MHz,DMSO-d6):δ141.7,140.5,134.2,132.2,131.8,130.7,130.3,129.6,128.0,124.9,123.8(q, 1 J C-F =285.3 Hz),121.1,120.5,118.6,111.5,100.1,89.4(q, 2 J C-F =33.3 Hz),13.0. 19 F NMR(565 MHz,DMSO-d6):δ-78.40(s).HRMS(ESI)m / z:[M+Na] + Calcd for C 20 H 13 F3N2NaO377.0872;Found 377.0878.

[0116] 1,9-Diphenyl-3-(trifluoromethyl)-3H-pyrrolo[1,2-a]indol-3-ol(3qa)

[0117] 1 H NMR(600 MHz,CDCl3):δ7.55(d,J=8.4 Hz,1H),7.51(d,J=8.4 Hz,1H),7.23-7.20(m,1H),7.17-7.11(m,3H),7.10-7.09(m,3H),7.08-7.04(m,3H),7.02-7.00(m,2H),6.17(s,1H),3.07(s,1H). 13 C{ 1H}NMR(150 MHz,CDCl3):δ143.2,137.1,133.2,131.7,131.6,130.0,129.5,128.1,127.04,127.00,126.96,126.0,125.8,123.6,122.0(q, 1 J C-F =284.4 Hz),120.2,119.9,114.1,110.0(q, 5 J C-F =3.2 Hz),87.9(q, 2 J C-F =35.1 Hz). 19 FNMR(565 MHz,CDCl3):δ-78.40(s).HRMS(ESI)m / z:[M+H] + Calcd for C 24 H 17 F3NO 392.1257;Found 392.1254.

[0118] 9-Chloro-1-phenyl-3-(trifluoromethyl)-3H-pyrrolo[1,2-a]indol-3-ol(3ra)

[0119] 1 H NMR(600 MHz,CDCl3):δ7.65-7.63(m,2H),7.55(d,J=7.8 Hz,1H),7.45(d,J=8.4 Hz,1H),7.40-7.38(m,3H),7.26-7.23(m,1H),7.14-7.11(m,1H),6.18(s,1H),3.14(s,1H). 13 C{ 1 H}NMR(150 MHz,CDCl3):δ143.3,137.0,133.6,131.2,130.4,130.0,128.6,128.4,126.8,125.5,122.7(q, 1 J C-F =284.4 Hz),121.4,120.0,111.4(q, 5 J C-F =2.1 Hz),102.8,89.3(q, 2 J C-F =35.0 Hz). 19F NMR(565 MHz,CDCl3):δ-78.67(s).HRMS(ESI)m / z:[M+H] + Calcd for C 18 H 12 ClF3NO 350.0554;Found 350.0561.

[0120] 7,9-Dimethyl-1-phenyl-3-(trifluoromethyl)-3H-pyrrolo[1,2-a]indol-3-ol(3sa)

[0121] 1 H NMR(600 MHz,CDCl3):δ7.57-7.56(m,2H),7.46-7.44(m,3H),7.38(d,J=8.4Hz,1H),7.31(s,1H),7.08(d,J=8.4 Hz,1H),6.10(s,1H),3.02(s,1H),2.43(s,3H),2.19(s,3H). 13 C{ 1 H}NMR(150 MHz,CDCl3):δ144.4,139.1,134.7,132.8,132.2,129.7,129.5,128.7,128.1,125.8,125.7,123.1(q, 1 J C-F =283.2 Hz),120.1,110.6(q, 5 J C-F =2.3 Hz),108.5,88.6(q, 2 J C-F =35.0 Hz),21.4,9.4. 19 F NMR(565MHz,CDCl3):δ-78.84(s).HRMS(ESI)m / z:[M+Na] + Calcd for C 20 H 16 F3NNaO366.1076;Found 366.1079.

[0122] 7-Fluoro-9-methyl-1-phenyl-3-(trifluoromethyl)-3H-pyrrolo[1,2-a]indol-3-ol(3ta)

[0123] 1H NMR(600 MHz,CDCl3):δ7.49-7.47(m,2H),7.40-7.38(m,3H),7.33(dd,J1=8.4Hz,J2=4.2 Hz,1H),7.09(dd,J1=9.0 Hz,J2=2.4 Hz,1H),6.91(td,J1=9.0Hz,J2=2.4Hz,1H),6.08(s,1H),3.15(s,1H),2.09(s,3H). 13 C{ 1 H}NMR(150MHz,CDCl3):δ158.2(d, 1 J C-F =235.2 Hz),144.4,140.5,135.1(d, 3 J C-F =8.7 Hz),131.8,131.0,129.7,128.7,128.0,126.3,122.9(q, 1 J C-F =284.4 Hz),112.3(d, 2 J C-F =25.2 Hz),111.6(dq, 3 J C-F =8.7 Hz, 5 J C-F =3.3 Hz),108.7(d, 4 J C-F =4.4 Hz),105.6(d, 2 J C-F =23.1 Hz),88.8(q, 2 J C-F =35.0Hz),9.4. 19 F NMR(565 MHz,CDCl3):δ-78.99(s),-123.42(td,J1=8.5 Hz,J2=4.0 Hz).HRMS(ESI)m / z:[M+H] + Calcd forC 19 H 14 F4NO 348.1006;Found 348.1019.

[0124] Ethyl 2-(3-hydroxy-1-(p-tolyl)-3-(trifluoromethyl)-3H-pyrrolo[1,2-a]ind-ol-9-yl)acetate(3ob)

[0125] 1 H NMR(400 MHz,CDCl3):δ7.50-7.47(m,2H),7.41(d,J=8.0 Hz,2H),7.24-7.18(m,3H),7.07(t,J=7.2 Hz,1H),6.04(s,1H),4.15(s,1H),3.97-3.88(m,2H),3.57(s,2H),2.38(s,3H),1.10(t,J=7.2 Hz,3H). 13 C{ 1 H}NMR(100 MHz,CDCl3):δ171.7,143.4,140.9,139.6,134.6,133.4,129.4,129.1,127.8,127.1,124.3,123.0(q, 1 J C-F =283.8 Hz),120.6,120.2,111.4(q, 5 J C-F =2.2 Hz),104.8,89.0(q, 2 J C-F =34.0 Hz),61.1,30.2,21.4,14.0. 19 F NMR(376 MHz,CDCl3):δ-78.74(s).HRMS(ESI)m / z:[M+Na] + Calcd forC 23 H 20 F3NNaO3438.1287;Found 438.1268.

[0126] Ethyl 2-(3-hydroxy-1-(3-methoxyphenyl)-3-(trifluoromethyl)-3H-pyrrolo[1,2-a]indol-9-yl)acetate(3oi)

[0127] 1 H NMR(600 MHz,CDCl3):δ7.51-7.48(m,2H),7.31(t,J=7.8 Hz,1H),7.25-7.23(m,1H),7.11-7.06(m,3H),6.96-6.94(m,1H),6.10(s,1H),4.05(s,1H),3.99-3.93(m,2H),3.79(s,3H),3.61(s,2H),1.13(t,J=7.2 Hz,3H). 13 C{ 1H}NMR(150 MHz,CDCl3):δ171.6,159.8,143.4,140.6,134.6,133.4,133.3,129.9,127.7,124.4,123.0(q, 1 J C-F =283.4Hz),120.7,120.3,120.2,115.3,113.3,111.3(q, 5 J C-F =2.1 Hz),105.0,89.0(q, 2 J C-F =35.0 Hz),61.2,55.4,30.2,14.0. 19 F NMR(565 MHz,CDCl3):δ-78.71(s).HRMS(ESI)m / z:[M+Na] + Calcd for C 23 H 20 F3NNaO4454.1237;Found 454.1234.

[0128] Ethyl 2-(3-hydroxy-1-(o-tolyl)-3-(trifluoromethyl)-3H-pyrrolo[1,2-a]indol-9-yl)acetate(3oo)

[0129] 1 H NMR(400 MHz,CDCl3):δ7.52(d,J=8.4 Hz,1H),7.47(d,J=8.0 Hz,1H),7.35-7.20(m,5H),7.11-7.08(m,1H),6.04(s,1H),3.98(s,1H),3.95-3.87(m,2H),3.34(d,J=16.4 Hz,1H),3.23(d,J=16.4 Hz,1H),2.29(s,3H),1.09(t,J=7.2 Hz,3H). 13 C{ 1 H}NMR(100 MHz,CDCl3):δ171.3,142.5,141.6,136.2,134.5,133.2,131.3,130.5,129.1,128.8,128.7,125.9,124.3,123.0(q, 1 J C-F =284.6 Hz),120.6,120.3,111.3(q, 5 J C-F=2.9 Hz), 104.8,89.3(q, 2 J C-F =34.7 Hz),61.0,29.3,19.6,14.0. 19 F NMR (376 MHz, CDCl3): δ-79.01 (s). HRMS (ESI) m / z: [M+Na] + Calcd for C 23 H 20 F3NNaO4438.1287;Found 438.1297.

[0130] Example 4

[0131] The fluoromethyl-substituted pyrroloindole compound 3 synthesized in this invention can undergo a series of reactions to synthesize further derivatives, thus demonstrating its important application value in organic synthesis. For example, fluoromethyl-substituted pyrroloindole compound 3 can undergo Friedel-Crafts acylation, protonation, and β-H elimination in the presence of polyphosphoric acid to obtain product 4.

[0132] The process of synthesizing compound 4a from compound 3oa is as follows:

[0133]

[0134] Add 3oa (70.9 mg, 0.2 mmol) and polyphosphoric acid (PPA, 20.2 mg) to a reaction tube, then seal the tube and place it in an oil bath at 120 °C for 1 hour in air. After the reaction, cool the resulting mixture to room temperature, neutralize with saturated sodium bicarbonate aqueous solution, and extract with ethyl acetate. Combine the organic phases, dry, concentrate under reduced pressure, and separate by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to give a yellow solid product 4a (30.3 mg, 45%). The characterization data of this compound are as follows: 1 H NMR (600MHz, CDCl3): δ8.59(d,J=7.8Hz,1H),7.95(d,J=7.8Hz,1H),7.75(d,J=7.2Hz,1H),7. 63(t,J=7.2Hz,1H),7.49(t,J=7.8Hz,1H),7.47-7.43(m,2H),7.34(s,1H),7.26-7.22(m,2H). 13 C{ 1H}NMR (150MHz, CDCl3): δ186.8,138.8,136.4,134.2,132.3,131.9,131.2, 130.9,130.1,129.1,127.7,125.2,124.1,123.3,122.7,121.3,119.60(q, 2 J C-F =40.5Hz), 119.58(q, 1 J C-F =265.8Hz), 111.8. 19 F NMR(565MHz,CDCl3):δ-59.44(s).HRMS(ESI)m / z:[M+Na] + Calcd for C 20 H 10 F3NNaO 360.0607; Found 360.0599.

[0135] Example 5

[0136] According to the method and steps of Example 4 a,b By modifying compound 3, various products 4 can be synthesized, as shown in the following results:

[0137]

[0138]

[0139] The representative product characterization data are as follows:

[0140] 2-Methyl-6-(trifluoromethyl)-13H-benzo[b]benzo[6,7]cyclohepta[1,2,3-gh]pyrr olizin-13-one(4b)

[0141] 1 H NMR (600MHz, CDCl3): δ8.51(s,1H),7.95(d,J=8.4Hz,1H),7.84(d,J=7.8Hz,1H),7.55-7.51(m,3H),7.44(s,1H),7.33-7.30(m,2H),2.51(s,3H). 13 C{ 1H}NMR(150MHz,CDCl3):δ187.7,139.8,139.0,137.2,134.9,133.4,133.2,132.8,131.8,130.2,128.7,126.3,125.0,124.1,123.6,122.4,120.64(q, 1 J C-F =265.8Hz),120.57(q, 2 J C-F =40.5Hz),112.73-112.69(m),21.5. 19 F NMR(565MHz,CDCl3):δ-59.41(s).HRMS(ESI)m / z:[M+H] + Calcd for C 21 H 13 F3NO 352.0944;Found352.0935.

[0142] 3-Methoxy-6-(trifluoromethyl)-13H-benzo[b]benzo[6,7]cyclohepta[1,2,3-gh]py rrolizin-13-one(4c)

[0143] 1 H NMR(600MHz,CDCl3):δ8.69(d,J=9.0Hz,1H),7.84(d,J=7.8Hz,1H),7.56-7.51(m,2H),7.43(s,1H),7.40(d,J=3.0Hz,1H),7.34-7.31(m,2H),7.14(dd,J1=9.0Hz,J2=2.4Hz,1H),3.98(s,3H). 13 C{ 1 H}NMR(150MHz,CDCl3):δ186.8,162.5,139.7,135.6,133.2,132.8,131.7,131.4,130.2,125.1,125.0,123.7,122.0,120.6(q, 1 J C-F =266.9Hz),120.4(q, 2 J C-F =40.5Hz),115.9,112.83-112.78(m),109.1,55.6. 19F NMR(565MHz,CDCl3):δ-59.41(s).HRMS(ESI)m / z:[M+H] + Calcd for C 21 H 13 F3NO2368.0893;Found 368.0891.

[0144] 4-Methyl-6-(trifluoromethyl)-13H-benzo[b]benzo[6,7]cyclohepta[1,2,3-gh]pyrr olizin-13-one(4d)

[0145] 1 H NMR (600MHz, CDCl3): δ8.36 (d, J = 8.4Hz, 1H), 7.84 (d, J = 7.2Hz, 1H), 7.58-7.53 (m,4H),7.46(t,J=7.2Hz,1H),7.39(s,1H),7.32(t,J=7.2Hz,1H),2.86(s,3H). 13 C{ 1 H}NMR (100MHz, CDCl3): δ190.1,140.6,139.2,135.9,135.8,133.3,131.7,131.4,130.7,130.1,127.9,125.1,124.0,123.5,121.6,120.8(q, 1 J C-F =265.8Hz), 118.9(q, 2 J C-F =40.4Hz), 117.4(q, 3 J C-F =4.3Hz), 112.7(q, 5 J C-F =3.6Hz), 26.2. 19 F NMR(565MHz,CDCl3):δ-59.05(s).HRMS(ESI)m / z:[M+H] + Calcd for C 21 H 13 F3NO 352.0944; Found 352.0935.

[0146] Example 6

[0147] The anticancer activity of the compounds provided in this invention was evaluated using CCK8 analysis and through cell antiproliferative activity studies.

[0148] The specific method is as follows: First, cells were seeded at a density of 5000 cells per well into 96-well plates containing 100 μL of culture medium per well, and incubated overnight at 37°C and 5% CO2. The next day, 100 μL of the test compound diluted with culture medium (concentration 0.03 nM–30 μM) was added to each well, and the cells were then incubated at 37°C and 5% CO2 for 72 hours. Then, 10 μL of CCK8 was added to each well, and the 96-well plate was incubated at 37°C for 2 hours. The absorbance was measured at 450 nm using an EnVision multilatelbel Reader (PerkinErmer) (with 630 nm as the reference wavelength), and the IC50 was calculated using GraphPad Prism 6.0 software. 50 Values. All experiments were performed with three parallel samples and repeated three times. Hela and A-549 cancer cells were selected as the research subjects, and 5-fluorouracil (5-FU) was used as a positive control.

[0149] The results of the anticancer activity of some compounds are as follows:

[0150]

[0151] The activity results indicate that the fluoromethyl-substituted pyrroloindole compound 3 provided by this invention can inhibit the proliferation of HeLa and A-549 cancer cells. Among them, compounds 3ae, 3am, 3ba, and 3ta have significant anti-proliferative activity against HeLa cancer cells; compounds 3aa, 3ae, 3am, 3ba, and 3ta have significant inhibitory effects on the proliferation of A-549 cancer cells, suggesting that this type of compound has medicinal value in preventing / treating / inhibiting the progression of cancer, especially cervical cancer and lung cancer.

[0152] 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 to the above embodiments. The embodiments and descriptions in the specification are merely illustrative of the principles of the present invention. Various changes and modifications can be made to the present invention without departing from its principles, and all such changes and modifications fall within the scope of protection of the present invention.

Claims

1. A fluoro-methyl substituted pyrrolo-indole compound, having a chemical structure of a general formula: ###0001### 3aa, 3ae, 3am, 3as, 3ba, 3ta. 。 2. The use of the fluoromethyl-substituted pyrroloindole compound as described in claim 1 in the preparation of an active drug for cervical or lung cancer, wherein: 3aa, 3ae, 3am, 3as, 3ba, 3ta have anti-lung cancer activity, 3ae, 3am, 3ba, 3ta have anti-cervical cancer activity.

3. Use of the fluoromethyl-substituted pyrroloindole compounds according to claim 2 for the preparation of a medicament for the treatment of cervical cancer or lung cancer. The anti-cervical cancer is against Hela, and the anti-lung cancer is against A-549.

4. A pharmaceutical composition, wherein an active ingredient comprises the compound of claim 1.

5. The method for preparing fluoromethyl-substituted pyrroloindole compounds as described in claim 1, characterized in that, comprising the steps of: N -alkoxy-1 H The fluoromethyl-substituted pyrroloindole compound 3 is prepared by mixing the indole-1-carboxamide compound 1, the fluoromethyl alkynone compound 2, a catalyst, an additive and methanol, and reacting at room temperature or at an elevated temperature, as shown in the following reaction equation: wherein: the fluoromethyl substituted pyrroloindole compound 3 is 3aa, 3ae, 3am, 3as, 3ba, 3ta according to claim 1, X is C 1-4 alkyl; the catalyst is selected from [RhCp*Cl2]2 or [RhCp*(MeCN)3](SbF6)2; the additive is selected from silver acetate, sodium acetate, potassium acetate, cesium acetate or zinc acetate.

6. The method for preparing the fluoromethyl-substituted pyrroloindole compound according to claim 5, characterized in that: The reaction temperature is 20-100 ℃.

7. The method for preparing fluoromethyl-substituted pyrroloindole compounds according to claim 5, characterized in that: The N -alkoxy-1 H -Indole-1-carboxamide compounds 1, fluoromethyl ketone compounds 2, catalyst and additive molar ratio is 1-1.2 : 1-1.2 : 0.03-0.05 : 0.2-0.5.

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