N-phenyl-1H-indole-5-amino compound as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of medicines, and relates to an N-phenyl-1H-indole-5-amino compound, a preparation method thereof and application of the N-phenyl-1H-indole-5-amino compound as a therapeutic agent, especially a TRK inhibitor. The invention relates to an N-phenyl-1H-indole-5-amino compound, the N-phenyl-1H-indole-5-amino compound is a compound as shown in a formula (I), a prodrug, a drug active metabolite and a pharmaceutically acceptable salt of the compound, and the compounds involved in the invention are not reported in literatures and have certain novelty in structure. The preparation process involved in the invention is explored and optimized for a long time, and a coupling-Boc removal reaction is carried out by using a one-pot method, so that the reaction time is shortened, and the operability of the compound preparation process is enhanced. The compound provided by the invention has a good inhibition effect on TRK kinase and can be used for treating tumors caused by NTRK gene fusion.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology and relates to a class of N-phenyl-1H-indole-5-amino compounds, their preparation methods, and their applications as therapeutic agents, especially TRK inhibitors. Background Technology

[0002] The occurrence and development of tumors are usually closely related to genetic variations, abnormal signaling pathways, and imbalances in cell cycle regulation. Among these carcinogenic factors, driver gene mutations, such as mutations in EGFR, ALK, and ROS1, have become effective targets for the treatment of certain cancers. In recent years, NTRK (neurotrophic receptor tyrosine kinase) gene fusions have been discovered in various tumors, becoming a novel oncogenic driving mechanism. The NTRK gene encodes three receptors of the TRK family: TRKA (NTRK1), TRKB (NTRK2), and TRKC (NTRK3), which play a crucial role in the development of the nervous system. However, when the NTRK gene undergoes a fusion mutation, fusion proteins are produced. These fusion proteins can autonomously activate tyrosine kinase activity, thereby driving downstream signaling pathways (such as MAPK and PI3K-AKT), leading to the proliferation and survival of cancer cells. NTRK gene fusions were initially discovered in some rare tumors, such as congenital fibrosarcoma and secretory breast cancer. However, with the application of high-throughput sequencing technology, researchers have discovered NTRK gene fusions in various solid tumors, including lung cancer, thyroid cancer, colorectal cancer, breast cancer, and neuroblastoma. These fusion mutations are often associated with high tumor dependence and treatment difficulty; therefore, small-molecule inhibitors targeting these fusion proteins have become an important advance in anti-tumor therapy. Existing TRK inhibitors, such as larotrectinib and Entrectinib, have shown good efficacy in clinical trials against various NTRK gene fusion-positive tumors. However, drug resistance remains a problem, with common resistance mechanisms including TRK kinase domain mutations leading to drug inactivation. Therefore, the search for new chemical structural frameworks and highly effective TRK inhibitors for the treatment of tumors caused by NTRK gene fusions has significant practical and economic value. Summary of the Invention

[0003] The purpose of this invention is to provide a class of N-phenyl-1H-indole-5-amino compounds, their preparation methods, and their applications as therapeutic agents, particularly TRK inhibitors.

[0004] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0005] An N-phenyl-1H-indole-5-amino compound, wherein the N-phenyl-1H-indole-5-amino compound is a compound of formula (I), its prodrug and active metabolite, and its pharmaceutically acceptable salt.

[0006]

[0007] In the formula,

[0008] R1 is selected from -CN, -CONH2, -C(O)H, -COOH, and -CONH2(CH2). n CH3, a C3-C7 ring containing at least one heteroatom;

[0009] n is 0, 1, 2, or 3;

[0010] R2 is selected from hydrogen, halogen, amino, methylamino, dimethylamino, nitro, cyano, C1-C4 alkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy.

[0011] m can be 1, 2, 3 or 4; when m is an integer from 2 to 4, R2 can be the same or different;

[0012] R3 is selected from -C(O)NH-Ar, -NHC(O)-Ar, -NHC(O)NH-Ar, and -C(O)O-Ar, where Ar is selected from unsubstituted or 1-4 identical or different Rs. a Substituted benzene rings, C1-C6 alkoxy groups; R a Selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 nitrogen-containing alkyl, and C3-C7 ring containing at least one heteroatom, and R a When it is greater than 1, two adjacent R a The carbon adjacent to Ar forms C4-C. 10 A ring containing at least one heteroatom in a C4-C ring. 10 The ring.

[0013] Preferably, the N-phenyl-1H-indole-5-amino compound is a compound of formula (I), its prodrug and active metabolite, and its pharmaceutically acceptable salt.

[0014] In the formula,

[0015] R1 is selected from -CN, -CONH2, -C(O)H, -COOH, and -CONH2(CH2). n CH3, a C3-C6 ring containing 1-2 heteroatoms;

[0016] n is 0 or 1;

[0017] R2 is selected from hydrogen, halogen, amino, methylamino, dimethylamino, nitro, cyano, C1-C4 alkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy.

[0018] m is an integer from 1 to 2; when m is 2, R² can be the same or different.

[0019] R3 is selected from -C(O)NH-Ar, -NHC(O)-Ar, -NHC(O)NH-Ar, and -C(O)O-Ar, where Ar is selected from unsubstituted or 1-4 identical or different Rs. a Substituted benzene rings, C1-C6 alkoxy groups;

[0020] R a Selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 nitrogen-containing alkyl, and C3-C6 ring containing at least one heteroatom, and R a When it is greater than 1, two adjacent R a The carbon adjacent to Ar forms C4-C. 10 A ring containing at least one heteroatom in a C4-C ring. 10 The ring.

[0021] More preferably, the N-phenyl-1H-indole-5-amino compound is a compound of formula (I), its prodrug and active metabolite, and its pharmaceutically acceptable salt.

[0022] In the formula,

[0023] R1 is selected from -CN, -CONH2, -C(O)H, -COOH, and -CONH2(CH2). n CH3, a C3-C6 ring containing 1-2 heteroatoms;

[0024] n is 0 or 1;

[0025] R2 is selected from hydrogen, halogen, amino, methylamino, dimethylamino, nitro, cyano, methyl, methoxy, and trifluoromethoxy.

[0026] m is an integer from 1 to 2; when m is 2, R² can be the same or different.

[0027] R3 is selected from -C(O)NH-Ar, -NHC(O)-Ar, -NHC(O)NH-Ar, and -C(O)O-Ar, where Ar is selected from unsubstituted or 1-4 identical or different Rs. a Substituted benzene rings, C1-C6 alkoxy groups;

[0028] R a Selected from hydrogen, halogen, amino, methylamino, dimethylamino, nitro, cyano, methyl, methoxy, trifluoromethoxy, and Ra When it is greater than 1, two adjacent R a The carbon adjacent to Ar forms a C4-C8 ring containing at least one heteroatom.

[0029] Further preferably, the N-phenyl-1H-indole-5-amino compound is a compound of formula (I), its prodrug and active metabolite, and its pharmaceutically acceptable salt.

[0030] In the formula,

[0031] R1 is selected from -CN or -CONH2;

[0032] R2 is selected from hydrogen and amino groups; m is an integer from 1 to 2; when m is 2, R2 can be the same or different.

[0033] R3 is selected from -C(O)NH-Ar or -NHC(O)NH-Ar, and Ar is selected from unsubstituted or 1-3 R groups. a Substituted benzene rings, C1-C4 alkoxy groups, R a Selected from hydrogen, halogen, methyl, methoxy, trifluoromethoxy, dimethylamino, and R a When it is greater than 1, two adjacent R a The carbon adjacent to Ar forms a C4-C8 ring containing at least one heteroatom.

[0034] The heteroatoms mentioned above can be one or more of N, S, and O.

[0035] More

[0036]

[0037]

[0038] The pharmaceutically acceptable salt of the compound is a salt formed with an acid selected from: hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, trifluoroacetic acid, or aspartic acid.

[0039] Preparation route of the compounds of this invention:

[0040]

[0041] The use of the N-phenyl-1H-indole-5-amino compound of formula (I), its prodrug and active metabolite, and its pharmaceutically acceptable salt in the preparation of TRK therapeutic agents.

[0042] The compound represented by formula (I), its prodrug and active metabolite, and its pharmaceutically acceptable salt are used in the preparation of TRK inhibitors.

[0043] Advantages of this invention:

[0044] None of the compounds involved in this invention have been reported in the literature, and their structures possess a certain degree of novelty. The preparation processes involved in this invention have undergone extensive exploration and optimization, employing a one-pot coupling-deBoc reaction, which shortens the reaction time and enhances the operability of the compound preparation process. The compounds involved in this invention exhibit good inhibitory effects on TRK kinase and can treat tumors caused by NTRK gene fusion. Detailed Implementation

[0045] The following examples depict methods for preparing some of the compounds described herein. It should be understood that the following methods, as well as other methods known to those skilled in the art, are applicable to the preparation of all the compounds described herein. The examples are intended to illustrate, but not limit, the scope of the invention.

[0046] Example 1

[0047] Synthesis of 5-nitro-1H-indole-3-carboxaldehyde (2)

[0048]

[0049] DMF (48 mL, 0.62 mol) was added to a 500 mL single-necked flask, and phosphorus oxychloride (29 mL, 0.31 mol) was added dropwise under ice bath conditions. The mixture was stirred for 0.5 h, and then 5-nitro-1H-indole (10.00 g, 61.67 mmol) was added. The mixture was reacted at room temperature for 2 h, and the reaction was monitored by TLC until it was complete. The reaction mixture was then poured into ice water, and the pH was adjusted to 8 with 6N NaOH. The mixture was filtered to obtain 10.97 g of yellow solid, with a yield of 93.5%. The crude product did not require purification and was directly used in the next step. 1 H NMR (600MHz, DMSO-d6) δ12.69(s,1H),10.03(s,1H),8.95(s,1H),8.58(s,1H),8.16(dd,J=9.0,2.4Hz,1H),7.73(d,J=9.0Hz,1H).ESI-HRMS calcd for C9H5N2O3[MH] - 189.0300, found: 189.0319.

[0050] Example 2

[0051] Synthesis of 5-nitro-1H-indole-3-carboxynitrile (3)

[0052]

[0053] 5-Nitro-1H-indole-3-carboxaldehyde (2) (10.00 g, 52.59 mmol), sodium formate (5.36 g, 78.88 mmol), and 200 mL of formic acid were added to a 500 mL single-necked flask. Hydroxylamine hydrochloride (4.39 g, 63.11 mmol) was added in portions. The reaction was carried out at 80 °C for 8 h. The reaction was monitored by TLC until it was complete. The reactants were then poured into ice water, and the pH was adjusted to 8 with 6N NaOH. The product was filtered to obtain 9.13 g of a light yellow solid, with a yield of 92.8%. The crude product did not require purification and was directly used in the next step. 1 H NMR (600MHz, DMSO-d6) δ12.82(s,1H),8.55(s,1H),8.52-8.51(m,1H),8.16(dd,J=9.1,2.2Hz,1H),7.76(d,J=9.0Hz,1H).ESI-HRMS calcdfor C9H4N3O2[MH] - 186.0304, found: 186.0325.

[0054] Example 3

[0055] Synthesis of tert-butyl 3-cyano-5-nitro-1H-indole-1-carboxylic acid (4)

[0056]

[0057] 5-Nitro-1H-indole-3-carboxynitrile (3) (5.00 g, 26.72 mmol), di-tert-butyl dicarbonate (8.4 mL, 40.07 mol), and methanol (100 mL) were added to a 250 mL single-necked flask. The mixture was reacted at 45 °C for 2 h. The reaction was monitored by TLC until complete. The mixture was evaporated to dryness and recrystallized from ethyl acetate to give 5.34 g of a pale yellow solid, with a yield of 69.6%. 1 H NMR (600MHz, DMSO-d6) δ8.92(s,1H),8.48-8.47(m,1H),8.34(dd,J=9.2,2.3Hz,1H),8.31(d,J=9.1Hz,1H),1.67(s,9H).ESI-HRMS calcdfor C 14 H 13 N3O4Na[M+Na] + 310.0804, found: 310.0784.

[0058] Example 4

[0059] Synthesis of tert-butyl 3-cyano-5-amino-1H-indole-1-carboxylic acid (5)

[0060]

[0061] Add 5.00 g (17.40 mmol) of 3-cyano-5-nitro-1H-indole-1-carboxylic acid tert-butyl ester (4) and 0.25 g of palladium on carbon to a 100 mL single-necked flask, continuously purge with hydrogen gas, react at 45 °C for 6 h, monitor the reaction by TLC until complete, filter, concentrate to obtain 4.28 g of brown solid, yield 95.3%, no purification is required and proceed directly to the next step. 1 H NMR(600MHz,DMSO-d6)δ8.38(s,1H),7.78(d,J=8.7Hz,1H),6.78-6.76(m,2H),5.25(s,2H),1.62(s,9H).ESI-HRMS calcd forC 14 H 15 N3O2Na[M+Na] + 280.1062, found: 280.1042.

[0062] Example 5

[0063] Synthesis of methyl 3-[(3-cyano-1H-indole-5-yl)amino]benzoate (6)

[0064]

[0065] 3-Cyano-5-amino-1H-indole-1-carboxylic acid tert-butyl ester (5) (3.00 g, 11.66 mmol), methyl 3-iodobenzoate (3.06 g, 11.66 mmol), BrettPhos (0.63 g, 1.17 mmol), Pd2(dba)3 (1.07 g, 1.17 mmol), cesium carbonate (7.60 g, 23.32 mmol), and 1,4-dioxane (50 mL) were added to a 100 mL single-necked flask. Under argon protection, the reaction was carried out at 100 °C for 15 h. The reaction was monitored by TLC until complete. After cooling to room temperature, the mixture was filtered, concentrated, and separated by column chromatography to obtain 2.17 g of gray solid, with a yield of 63.9%. 1 HNMR(600MHz,DMSO-d6)δ12.12(s,1H),8.36(s,1H),8.19-8.18(m,1H),7.61(s,1H),7.52(d,J=8.6H z,1H),7.36-7.34(m,2H),7.31(s,1H),7.28-7.26(m,1H),7.13-7.11(m,1H),3.83(s,3H).ESI-HRMS calcd for C 17 H 12 N3O2[MH]- 290.0930, found: 290.0961.

[0066] Example 6

[0067] Synthesis of 3-[(3-cyano-1H-indole-5-yl)amino]-N-phenylbenzamide (A1)

[0068]

[0069] 0.20 g (0.69 mmol) of methyl 3-[(3-cyano-1H-indol-5-yl)amino]benzoate, 20 mL of methanol, and 3.4 mL of 1 M sodium hydroxide were added to 100 mL of water. The mixture was reacted at 60 °C for 2 h. The reaction was monitored by TLC until complete. The mixture was extracted with ethyl acetate, and the pH of the aqueous layer was adjusted to 2-3 with concentrated hydrochloric acid. The mixture was filtered to give 0.17 g of a gray solid. DMF (5 mL), EDCI (0.15 g, 0.79 mmol), HOBT (0.11 g, 0.79 mmol), aniline (61 μL, 0.67 mmol), and DIPEA (0.32 mL, 1.84 mmol) were added. The mixture was reacted at room temperature for 6 h. The reaction was monitored by TLC until complete. The mixture was separated by column chromatography to give 0.13 g of a white solid, with a yield of 60.2%. mp 194.2-195.7 °C. 1 H NMR(600MHz,DMSO-d6)δ12.08(s,1H),10.18(s,1H),8.32(s,1H),8.17(s,1H),7.77 -7.75(m,2H),7.54(s,1H),7.50(d,J=8.7Hz,1H),7.35-7.33(m,3H),7.32-7 .31(m,2H),7.22(d,J=6.9Hz,1H),7.14(d,J=8.7Hz,1H),7.10-7.08(m,1H). 13 C NMR(151MHz,DMSO-d6)δ166.32,145.53,139.61,137.90,136.19,134.38,131.27,129.55,128.95, 128.14,123.93,120.68,118.38,118.03,117.73,116.97,114.87,114.10,107.23,83.92.ESI-HRMS calcd for C 22 H 16 N4ONa[M+Na] + 375.1222, found: 375.1232.

[0070] Compounds A2 to A13 were synthesized according to the methods described in Examples 1 to 6 above;

[0071] A2 can be prepared by replacing aniline with 3-fluoroaniline.

[0072] A2: White solid, yield 60.4%, mp 107.6-108.9℃. 1 H NMR (600MHz, DMSO-d6) δ12.12(s,1H),10.38(s,1H),8.34(s,1H),8.17(s,1H),7.75(d,J=11.8Hz,1H),7.57-7.49( m,3H),7.40-7.35(m,3H)7.32-7.31(m,1H),7.23(d,J=7.6Hz,1H),7.14(dd,J=8.7,2.1Hz,1H),6.93-6.90(m,1H). 13 CNMR(151MHz,DMSO-d6)δ166.60,163.23,161.63,145.64,141.44(d,J=11.19Hz),137.83,136.24,134.79,131.33,130.59(d,J=9.24Hz) ,129.61,128.15,118.59,118.02,117.79,116.95,116.31(d,J=2.9Hz),114.81,114.12,110.41(d,J=20.9Hz),107.37,83.93.ESI-HRMS calcd for C 22 H 15 FN4ONa[M+Na] + 393.1128, found: 393.1142.

[0073] A3 can be prepared by replacing aniline with 3-chloroaniline.

[0074] A3: White solid, yield 61.6%, mp 107.3-108.9℃. 1 H NMR(600MHz,DMSO-d6)δ12.09(s,1H),10.34(s,1H),8.33(s,1H),8.17(s,1H),7.97-7.96(m,1H),7.71-7.69(m,1H), 7.54-7.53(m,1H),7.50(d,J=8.7Hz,1H),7.38-7.34(m,3H),7.32-7.31(m,1H),7.24-7.22(m,1H),7.16-7.13(m,2H). 13C NMR(151MHz,DMSO-d6)δ166.58,145.65,141.11,137.82,136.17,134.80,133.30,131.32,130.66,129.62, 128.15,123.61,120.02,118.96,118.62,118.02,117.79,116.95,114.81,114.11,107.39,83.95.ESI-HRMS calcd forC 22 H 15 ClN4ONa[M+Na] + 409.0832, found: 409.0856.

[0075] A4 can be prepared by replacing aniline with 3-bromoaniline.

[0076] A4: White solid, yield 63.9%, mp 100.3-101.4℃. 1 H NMR (600MHz, DMSO-d6) δ12.08(s,1H),10.32(s,1H),8.33(s,1H),8.17-8.16(m,1H),8.10-8.09(m,1H),7.75-7.73(m,1H),7. 54-7.53(m,1H),7.50(d,J=8.7Hz,1H),7.37-7.33(m,2H),7.32-7.27(m,3H),7.24-7.22(m,1H),7.14(dd,J=8.7,2.1Hz,1H). 13 C NMR(151MHz,DMSO-d6)δ166.54,145.65,141.25,137.82,136.14,134.80,131.32,130.97,129.62,128.15, 126.50,122.87,121.77,119.34,118.63,118.02,117.79,116.94,114.81,114.11,107.38,83.95.ESI-HRMS calcdfor C 22 H 15 BrN4ONa[M+Na] + 453.0327, found: 453.0342.

[0077] A5 can be prepared by replacing aniline with 4-fluoroaniline.

[0078] A5: White solid, yield 59.8%, mp 199.2-200.5℃.1 H NMR(600MHz,DMSO-d6)δ12.09(s,1H),10.24(s,1H),8.32(s,1H),8.17(s,1H),7.80-7.76(m,2H),7.55-7.53(m, 1H),7.50(d,J=8.7Hz,1H),7.38-7.34(m,2H),7.32-7.31(m,1H),7.23-7.16(m,3H),7.14(dd,J=8.7,2.1Hz,1H). 13 C NMR(151MHz,DMSO-d6)δ166.22,159.39,157.80,145.57,137.88,136.41,135.97(d,J=2.63Hz),134.80,131.28,129.58,128 .14,122.52(d,J=7.82Hz),118.44,117.98,117.75,116.97,115.59,115.45,114.83,114.11,107.26,83.92.ESI-HRMScalcd for C 22 H 15 FN4ONa[M+Na] + 393.1128, found: 393.1140.

[0079] A6 can be prepared by replacing aniline with 4-chloroaniline.

[0080] A6: White solid, yield 64.6%, mp 132.3-134.1℃. 1 H NMR(600MHz,DMSO-d6)δ12.09(s,1H),10.32(s,1H),8.34(s,1H),8.17(s,1H),7.83-7.80(m,2H),7.55-7.53(m,1H),7.50 (d,J=8.7Hz,1H),7.41-7.39(m,2H),7.37-7.33(m,2H),7.32-7.31(m,1H),7.24-7.22(m,1H),7.14(dd,J=8.7,2.1Hz,1H). 13C NMR(151MHz,DMSO-d6)δ166.41,145.59,138.59,137.84,136.31,134.81,131.29,129.61,128.87, 128.14,127.52,122.16,118.51,118.02,117.76,116.97,114.82,114.11,107.30,83.93.ESI-HRMS calcd for C 22 H 15 ClN4ONa[M+Na] + 409.0832, found: 409.0849.

[0081] A7 can be prepared by replacing aniline with 4-bromoaniline.

[0082] A7: White solid, yield 60.2%, mp 136.7-138.2℃. 1 H NMR(600MHz,DMSO-d6)δ12.10(s,1H),10.31(s,1H),8.33(s,1H),8.17-8.16(m,1H),7.78-7.75(m,2H),7.55-7.51( m,3H),7.50(d,J=8.7Hz,1H),7.37-7.34(m,2H),7.32-7.31(m,1H),7.24-7.22(m,1H),7.14(dd,J=8.7,2.1Hz,1H). 13 C NMR(151MHz,DMSO-d6)δ166.42,145.61,139.02,137.85,136.31,134.79,131.77,131.31,129.60, 128.15,122.55,118.53,118.02,117.77,116.95,115.59,114.84,114.11,107.33,83.94.ESI-HRMS calcd for C 22 H 15 BrN4ONa[M+Na] + 453.0327, found: 453.0347.

[0083] A8 can be prepared by replacing aniline with 4-trifluoromethoxyaniline.

[0084] A8: White solid, yield 51.5%, mp 225.2-227.8℃. 1H NMR (600MHz, DMSO-d6) δ12.08(s,1H),10.37(s,1H),8.33(s,1H),8.17(s,1H),7.88(d,J=8.6Hz,2H),7. 54(s,1H),7.50(d,J=8.6Hz,1H),7.37-7.31(m,5H),7.23(d,J=7.4Hz,1H),7.14(dd,J=8.7,2.0Hz,1H). 13 C NMR(151MHz,DMSO-d6)δ166.47,145.62,144.17,138.84,137.85,136.25,134.80,131.31,129.61,128.15, 122.00,121.82,121.38,119.69,118.56,118.04,117.78,116.95,114.85,114.11,107.33,83.95.ESI-HRMS calcd for C 23 H 15 F3N4O2Na[M+Na] + 459.1045, found: 459.1063.

[0085] A9 can be prepared by replacing aniline with 3-chloro-4-fluoroaniline.

[0086] A9: White solid, yield 53.5%. mp 228.3-229.7℃. 1 H NMR (600MHz, DMSO-d6) δ12.09(s,1H),10.38(s,1H),8.34(s,1H),8.17(s,1H),8.07(dd,J=6.9,2.6Hz,1H),7.72-7.70(m,1H ),7.53(s,1H),7.50(d,J=8.7Hz,1H),7.43-7.36(m,2H),7.35-7.31(m,2H),7.23-7.22(m,1H),7.14(dd,J=8.7,2.1Hz,1H). 13C NMR (151MHz, DMSO-d6) δ = 166.45, 154.46, 152.85, 145.66, 137.79, 136.87 (d, J = 3.02Hz), 136.00, 134.82, 131.32, 129.66, 128.14, 122.01 ,120.95(d,J=7.13Hz),119.40(d,J=18.06Hz),118.66,117.96,117.80,117.23(t,J=21.55Hz),114.73,114.12,107.38,83.94.ESI-HRMS calcd for C 22 H 14 ClFN4ONa[M+Na] + 427.0738, found: 427.0765.

[0087] A10 can be prepared by replacing aniline with 4-methylaniline.

[0088] A10: White solid, yield 62.7%, mp 114.6-115.9℃. 1 H NMR(600MHz,DMSO-d6)δ12.08(s,1H),10.10(s,1H),8.31(s,1H),8.17(s,1H),7.64-7.63(m,2H),7.5 3(s,1H),7.50(d,J=8.7Hz,1H),7.35-7.30(m,3H),7.22-7.20(m,1H),7.14-7.12(m,3H),2.27(s,3H). 13 C NMR(151MHz,DMSO-d6)δ166.10,145.50,137.93,137.07,136.67,134.78,132.86,131.25,129.53,129 .33,128.14,120.70,118.32,117.99,117.72,116.97,114.87,114.10,107.19,83.91,20.87.ESI-HRMS calcd for C 23 H 18 N4ONa[M+Na] + 389.1378, found: 389.1392.

[0089] A11 can be prepared by replacing aniline with 3-methoxyaniline.

[0090] A11: White solid, yield 60.6%. mp 81.7-83.2℃. 1 H NMR (600MHz, DMSO-d6) δ12.08(s,1H),10.15(s,1H),8.32(s,1H),8.17(s,1H),7.53-7.52(m,1H),,7.50(d,J=8.7Hz,1H),7.46-7.45( m,1H),7.37-7.33(m,3H),7.31-7.30(m,1H),7.25-7.20(m,2H),7.14(dd,J=8.7,2.1Hz,1H),6.67(dd,J=8.0,2.5Hz,1H),3.75(s,3H). 13 C NMR (151MHz, DMSO-d6)δ=166.35,159.78,145.54,140.80,137.88,136.59,134.80,131.27,129.73,129.56,128 .14,118.42,118.00,117.75,116.97,114.81,114.11,112.87,109.44,107.27,106.32,83.92,55.37.ESI-HRMS calcd for C 23 H 18 N4O2Na[M+Na] + 405.1327, found: 405.1361.

[0091] A12 can be prepared by replacing the 6-amino-1,4-benzodioxane ring with aniline.

[0092] A12: White solid, yield 65.2%, mp 216.5-217.9℃. 1 H NMR(600MHz,DMSO-d6)δ12.08(s,1H),10.00(s,1H),8.29(s,1H),8.17-8.16(m,1H),7.52-7.48(m,2H),7.37-7.36( m,1H),7.34-7.30(m,3H),7.21-7.18(m,2H),7.13(dd,J=8.7,2.1Hz,1H),6.81(d,J=8.7Hz,1H),4.24-4.20(m,4H). 13CNMR(151MHz,DMSO-d6)δ165.90,145.52,143.19,139.94,137.94,136.64,134.76,133.25,131.26,129.51,12 8.15,118.28,117.93,117.74,116.96,114.87,114.09,113.93,109.76,107.23,83.93,64.55,64.34.ESI-HRMS calcd for C 24 H 18 N4O3Na[M+Na] + 433.1277, found: 433.1295.

[0093] A13 can be prepared by replacing aniline with 3,4-dihydro-2H-1,5-benzodioxane-7-amine.

[0094] A13: White solid, yield 55.2%, mp 134.2℃-135.7℃. 1 H NMR(600MHz,DMSO-d6)δ12.08(s,1H),10.08(s,1H),8.31(s,1H),8.17-8. 16(m,1H),7.52-7.49(m,2H),7.48-7.47(m,1H),7.36-7.33(m,1H),7.33- 7.30(m,3H),7.22-7.20(m,1H),7.14(dd,J=8.7,2.1Hz,1H),6.93(d,J=8. 6Hz, 1H), 4.12 (t, J = 5.3Hz, 2H), 4.08 (t, J = 5.4Hz, 2H), 2.11-2.07 (m, 2H). 13 C NMR(151MHz,DMSO-d6)δ166.04,151.19,147.51,145.54,137.92,136.60,135.15,134.77,131.28,129.53,128.15 ,121.64,118.33,117.95,117.74,116.96,115.68,114.86,114.09,113.95,107.24,83.94,70.96,32.21.ESI-HRMS calcd for C 25 H 20 N4O3Na[M+Na] + 447.1433, found: 447.1448.

[0095] Example 7

[0096] 5-{[3-(phenylcarbamoyl)phenyl]amino}-1H-indole-3-carboxamide (B1)

[0097]

[0098] In a 50 mL single-necked flask, 3-[(3-cyano-1H-indol-5-yl)amino]-N-phenylbenzamide (Al) (50 mg, 0.14 mmol), potassium carbonate (58 mg, 0.42 mmol), and DMSO (3 mL) were added dropwise with hydrogen peroxide (1 mL) in an ice bath. The reaction was carried out at room temperature for 1 h. The reaction was monitored by TLC until complete, and 28 mg of a white solid was obtained by column chromatography, yielding 53.2%. mp 115.7-117.1 °C. 1 H NMR (600MHz, DMSO-d6) δ11.44(s,1H),10.14(s,1H),8.13(s,1H),8.01-7.99(m,2H),7.77(d,J=8.0Hz,2H),7.46(s,1H),7.3 9(d,J=8.6Hz,1H),7.35-7.33(m,2H),7.29-7.26(m,2H),7.15-7.13(m,1H),7.10-7.08(m,1H),7.03(dd,J=8.6,2.2Hz,1H). 13 C NMR(151MHz,DMSO-d6)δ166.61,166.15,146.43,139.25,136.16,135.71,132.45,128.93,128.70,1 28.52,127.20,123.46,120.25,116.94,116.90,116.56,113.64,112.19,112.15,109.97.ESI-HRMS calcd for C 22 H 18 N4O2Na[M+Na] + 393.1327, found: 393.1361.

[0099] Compounds B2 to B11 were synthesized according to the methods described in Examples 1 to 7 above.

[0100] B2 can be prepared by replacing aniline with 3-fluoroaniline.

[0101] B2: White solid, yield 52.6%, mp 127.5-128.9℃. 1H NMR (600MHz, DMSO-d6) δ11.45(s,1H),10.32(s,1H),8.14(s,1H),7.99-7.98(m,1H),7.98-7.97(m,1H),7.75-7.72(m,1H),7.55-7.54(m,1H),7. 44-7.43(m,1H),7.38-7.35(m,2H),7.29(d,J=7.8Hz,1H),7.25-7.23(m ,1H),7.15-7.13(m,1H),7.02(dd,J=8.6,2.2Hz,1H),6.92-6.89(m,1H). 13 C NMR(151MHz,DMSO-d6)δ166.97,166.81,163.22,161.63,146.92,141.49( d,J=10.9Hz),136.19(d,J=26.7Hz),132.88,130.57(d,J=9.5Hz),129.40, 129.11,127.62,117.54,117.33,116.94,116.27(d,J=2.7Hz),113.96,112 .66(d,J=8.9Hz),110.39,110.34(d,J=21.2Hz),107.30,107.13.ESI-HRMS calcd for C 22 H 17 FN4O2Na[M+Na] + 411.1233, found: 411.1264.

[0102] B3 can be prepared by replacing aniline with 3-chloroaniline.

[0103] B3: White solid, yield 51.9%, mp 175.2-176.9℃. 1 H NMR(600MHz,DMSO-d6)δ11.44(s,1H),10.26(s,1H),8.13(s,1H),7.99-7.97(m,2H),7.82-7.77(m,2H),7.44-7.3 3(m,1H),7.40-7.36(m,3H),7.30-7.27(m,1H),7.25-7.23(m,1H),7.14-7.12(m,1H),7.01(dd,J=8.6,2.2Hz,1H). 13CNMR(151MHz,DMSO-d6)δ166.97,166.63,146.88,138.65,136.26,136.04,132.86,129.38, 129.10,128.84,127.61,127.44,122.13,117.47,117.31,116.95,113.98,112.60,110.38.C 22 H 17 ClN4O2Na[M+Na] + 427.0938, found: 427.0967.

[0104] B4 can be prepared by replacing aniline with 3-bromoaniline.

[0105] B4: White solid, yield 53.2%, mp 134.5-135.7℃. 1 H NMR(600MHz,DMSO-d6)δ11.45(s,1H),10.28(s,1H),8.14(s,1H),8.10-8.09(m,1H),7.99-7.97(m,2H),7.75-7.73(m,1H),7.45-7 .44(m,1H),7.38(d,J=8.6Hz,1H),7.32-7.27(m,3H),7.25-7.23(m,1H),7.14(dd,J=8.0,1.4Hz,1H),7.02(dd,J=8.6,2.2Hz,1H). 13 C NMR(151MHz,DMSO-d6)δ166.98,166.76,146.92,141.30,136.08,136.02,132.88,130.95,129.41,129.11,1 27.62,126.44,122.83,121.76,119.31,117.59,117.32,116.95,113.97,112.64,112.60,110.39.ESI-HRMS calcd for C 22 H 17 BrN4O2Na[M+Na] + 471.0433, found: 471.0433.

[0106] B5 can be prepared by replacing aniline with 4-fluoroaniline.

[0107] B5: White solid, yield 54.5%, mp 139.3-140.4℃. 1H NMR(600MHz,DMSO-d6)δ11.45(s,1H),10.19(s,1H),8.12(s,1H),7.80-7.99(m,1H),7.98-7.97(m,1H),7.79-7.75(m,2H),7.45-7.44(m,1H) ),7.37(d,J=8.5Hz,1H),7.30-7.27(m,J=7.8Hz,1H),7.25-7.23(m,1H),7.19-7.15(m,2H),7.14-7.12(m,1H),7.01(dd,J=8.6,2.2Hz,1H). 13 C NMR(151MHz,DMSO-d6)δ166.98,166.45,159.35,157.76,146.86,136.37,136.07,136.04(d,J=2.6Hz),132.85,12 9.35,129.10,127.61,122.46,122.41,117.38,117.30,116.90,115.56,115.41,114.00,112.59,110.38.ESI-HRMS calcd for C 22 H 17 FN4O2Na[M+Na] + 411.1233, found: 411.1260.

[0108] B6 can be prepared by replacing aniline with 4-chloroaniline.

[0109] B6: White solid, yield 51.4%, mp 204.3-205.9℃. 1 H NMR (600MHz, DMSO-d6) δ11.45(s,1H),10.30(s,1H),8.14(s,1H),7.99-7.97(m,2H),7.96-7.95(m,1H),7.69(dd,J=8.3,2.0Hz, 1H),7.45-7.44(m,1H),7.38-7.35(m,2H),7.30-7.28(m,1H),7.25-7.23(m,1H),7.15-7.12(m,2H),7.02(dd,J=8.6,2.2Hz,1H). 13C NMR(151MHz,DMSO-d6)δ166.98,166.76,146.92,141.30,136.08,136.02,132.88,130.95,129.41,129.11,1 27.62,126.44,122.83,121.76,119.31,117.59,117.32,116.95,113.97,112.64,112.60,110.39.ESI-HRMS calcd for C 22 H 17 ClN4O2Na[M+Na] + 427.0938, found: 427.0976.

[0110] B7 can be prepared by replacing aniline with 4-bromoaniline.

[0111] B7: White solid, yield 49.4%, mp 170.1-171.5℃. 1 H NMR (600MHz, DMSO-d6) δ11.45(s,1H),10.26(s,1H),8.13(s,1H),7.98(dd,J=10.4,2.6Hz,2H),7.77-7.73(m,2H),7.53-7.50(m,2H), 7.44(s,1H),7.37(d,J=8.6Hz,1H),7.30-7.27(m,1H),7.24(d,J=7.5Hz,1H),7.14(dd,J=8.0,2.4Hz,1H),7.01(dd,J=8.6,2.2Hz,1H). 13 C NMR (151MHz, DMSO-d6) δ166.97,166.64,146.88,139.08,136.25,136.04,132.86,131.75,129. 38,129.10,127.61,122.50,117.48,117.30,116.95,115.50,113.98,112.60,110.38.ESI-HRMS calcd forC 22 H 17 BrN4O2Na[M+Na] + 471.0433, found: 471.0469.

[0112] B8 can be prepared by replacing aniline with 4-trifluoromethoxyaniline.

[0113] B8: White solid, yield 55.9%, mp 148.9-151.2℃.1 H NMR (600MHz, DMSO-d6) δ11.45(s,1H),10.32(s,1H),8.13(s,1H),7.99-7.98(m,2H),7.90-7.86(m,2H),7.46-7.45(m,1H),7. 37(d,J=8.4Hz,1H),7.35-7.33(m,2H),7.30-7.27(m,1H),7.26-7.25(m,1H),7.16-7.14(m,1H),7.02(dd,J=8.6,2.2Hz,1H). 13 C NMR(151MHz,DMSO-d6)δ166.97,166.69,146.90,144.11,138.90,136.20,136.04,132.87,129.39,1 29.10,127.61,121.95,121.80,117.51,117.31,116.97,114.00,112.61,112.59,110.39.ESI-HRMS calcd forC 23 H 17 F3N4O3Na[M+Na] + 477.1150, found: 477.1179.

[0114] B9 can be prepared by replacing aniline with 4-methylaniline.

[0115] B9: White solid, yield 48.4%, mp 227.2-228.9℃. 1 H NMR(600MHz,DMSO-d6)δ11.43(s,1H),10.04(s,1H),8.10(s,1H),7.98-7.96(m,2H),7.64-7.62(m,2H),7.44-7.43(m,1H) ,7.36(d,J=8.6Hz,1H),7.28-7.26(m,1H),7.24-7.22(m,1H),7.14-7.11(m,3H),7.01(dd,J=8.6,2.2Hz,1H),2.27(s,3H). 13C NMR (151MHz, DMSO-d6) δ166.97,166.32,146.80,137.14,136.63,136.12,132.83,132.76,129.30,129. 08,127.60,120.66,120.63,117.27,117.23,116.90,114.04,112.57,112.53,110.37,20.86.ESI-HRMS calcd for C 23 H 20 N4O2Na[M+Na] + 407.1484, found: 407.1488.

[0116] B10 can be prepared by replacing the 6-amino-1,4-benzodioxane ring with aniline.

[0117] B10: White solid, yield 54.4%, mp 121.3-122.4℃. 1 H NMR(600MHz,DMSO-d6)δ11.43(s,1H),9.96(s,1H),8.10(s,1H),7.99-7.9 8(m,1H),7.97-7.96(m,1H),7.42-7.41(m,1H),7.37-7.36(m,2H),7.29-7 .26(m,1H),7.22-7.20(m,1H),7.18(dd,J=8.8,2.5Hz,1H),7.13-7.11(m, 1H),7.01(dd,J=8.6,2.2Hz,1H),6.80(d,J=8.7Hz,1H),4.24-4.20(m,4H). 13 CNMR(151MHz,DMSO-d6)δ166.98,166.13,146.82,143.17,139.88,136.61,136.13,133.33,132.84,129.28,129 .08,127.62,117.29,117.19,116.94,116.85,114.04,113.89,112.57,110.39,109.71,64.55,64.33.ESI-HRMS calcd for C 24 H 20 N4O4Na[M+Na] + 451.1382, found: 451.1390.

[0118] B11 can be prepared by replacing aniline with 3,4-dihydro-2H-1,5-benzodioxane-7-amine.

[0119] B11: White solid, yield 55.6%, mp 124.7-126.1℃. 1 H NMR(600MHz,DMSO-d6)δ11.44(s,1H),10.03(s,1H),8.11(s,1H),7.99-7.98(m,1H),7.98- 7.97(m,1H),7.47-7.46(m,1H),7.43-7.42(m,1H),7.37(d,J=8.6Hz,1H),7.31(dd,J=8.7,2 .6Hz,1H),7.30-7.26(m,1H),7.22-7.20(m,1H),7.13-7.11(m,1H),7.01(dd,J=8.6,2.2Hz, 1H), 6.92 (d, J = 8.7Hz, 1H), 4.11 (t, J = 5.4Hz, 2H), 4.07 (t, J = 5.4Hz, 2H), 2.09-2.06 (m, 2H). 13 C NMR(151MHz,DMSO-d6)δ166.98,166.27,151.18,147.45,146.83,136.56,136.11,135.22,132.84,129.31,129.09, 127.62,121.62,117.29,117.27,116.88,115.64,114.02,113.90,112.58,112.55,110.39,70.95,32.22.ESI-HRMS calcd for C 25 H 22 N4O4Na[M+Na] + 465.1539, found: 465.1551.

[0120] Example 8

[0121] Synthesis of methyl 3-[(3-cyano-1H-indol-5-yl)amino]-5-nitrobenzoate (7)

[0122]

[0123] 3-Cyano-5-amino-1H-indole-1-carboxylic acid tert-butyl ester (5) (3.00 g, 11.66 mmol), methyl 3-bromo-5-nitrobenzene (3.03 g, 11.66 mmol), BrettPhos (0.63 g, 1.17 mmol), Pd2(dba)3 (1.07 g, 1.17 mmol), cesium carbonate (7.60 g, 23.32 mmol), and 1,4-dioxane (50 mL) were added to a 100 mL single-necked flask. Under argon protection, the reaction was carried out at 100 °C for 15 h. The reaction was monitored by TLC until complete. After cooling to room temperature, the mixture was filtered, concentrated, and separated by column chromatography to give 2.37 g of a yellow solid, with a yield of 60.4%. 1 H NMR(400MHz,DMSO-d6)δ12.25(s,1H),8.95(s,1H),8.26(s,1H),7.94-7.93(m,1H),7.89-7.88(m,1H),7.85 -7.84(m,1H),7.60(d,J=8.7Hz,1H),7.40-7.39(m,1H),7.19(dd,J=8.7,2.1Hz,1H),3.89(s,3H).ESI-HRMS calcd for C 17 H 11 N4O4[MH] - 335.0780, found: 335.0796.

[0124] Example 9

[0125] Synthesis of 3-[(3-cyano-1H-indol-5-yl)amino]-5-nitrobenzoic acid (8)

[0126]

[0127] Methyl 3-[(3-cyano-1H-indol-5-yl)amino]-5-nitrobenzene (7) (2.00 g, 5.95 mmol), methanol (10 mL), and 4M sodium hydroxide (7.4 mL) were added to 100 mL. The mixture was reacted at 60 °C for 2 h. The reaction was monitored by TLC until complete. The mixture was extracted with ethyl acetate, and the pH of the aqueous layer was adjusted to 2-3 with concentrated hydrochloric acid. The mixture was then filtered to give 1.57 g of a yellow solid, with a yield of 81.9%. (ESI-HRMS calcd for C) 16 H9N4O4[MH] - 321.0624, found: 321.0633.

[0128] Example 10

[0129] Synthesis of 3-amino-5-[(3-cyano-1H-indole-5-yl)amino]-N-(3-methoxyphenyl)benzamide (C1)

[0130]

[0131] 3-[(3-cyano-1H-indol-5-yl)amino]-5-nitrobenzoic acid (8) (0.10 g, 0.31 mmol), EDCI (77 mg, 0.40 mmol), HOBT (55 mg, 0.40 mmol), m-aminoanisole (39 μL, 0.34 mmol), DIPEA (0.16 mL, 0.93 mmol), and DMF (5 mL) were added to 100 mL of water. The mixture was reacted at room temperature for 6 h. The reaction was monitored by TLC until complete. Ethyl acetate was added, and the mixture was washed with water and saturated brine. The solution was dried over anhydrous sodium sulfate. The filtrate was concentrated to give a yellow solid, which was used directly in the next reaction without purification. Methanol (10 mL) and palladium on carbon (10 mg) were added, and hydrogen gas was continuously bubbled through the mixture. The reaction was carried out at 45 °C for 6 h. The reaction was monitored by TLC until complete. The solid was separated by column chromatography to give 52 mg of a pale yellow solid, with a yield of 42.2%. 1 H NMR(400MHz,DMSO-d6)δ12.02(s,1H),10.01(s,1H),8.13(s,1H),7.96(s, 1H),7.47-7.43(m,2H),7.35-7.33(m,1H),7.26-7.25(m,1H),7.22-7.18( m,1H),7.09(dd,J=8.7,2.1Hz,1H),6.69-6.68(m,1H),6.65-6.62(m,1H), 6.52-6.51(m,1H),6.47-6.46(m,1H),5.19(s,2H),3.73(s,3H).ESI-HRMS calcd forC 23 H 19 N5O2Na[M+Na] + 420.1436, found: 420.1424.

[0132] Compounds C2 to C13 were synthesized according to the methods described in Examples 1 to 4 and Examples 8 to 10 above.

[0133] C2 can be prepared by replacing aniline with 2-methoxyethylamine.

[0134] C2: Pale yellow solid, yield 56.3%, mp 89.3-91.6℃. 1H NMR(600MHz,DMSO-d6)δ12.01(s,1H),8.12(d,J=3.0Hz,1H),8.09(t,J=5.6Hz ,1H),7.87(s,1H),7.44(d,J=8.7Hz,1H),7.22(d,J=2.0Hz,1H),7.06(dd,J=8 .7,2.1Hz,1H),6.64(t,J=1.8Hz,1H),6.46(t,J=1.8Hz,1H),6.42(t,J=2.0Hz ,1H),5.11(s,2H),3.41(t,J=5.9Hz,2H),3.35(t,J=5.8Hz,2H),3.25(s,3H). 13 C NMR(151MHz,DMSO)δ=167.92,149.65,145.77,138.80,136.91,134.49,130.85,128.10,117 .71,117.10,113.82,106.70,105.02,104.05,103.85,83.80,70.84,60.14,58.27.ESI-HRMS calcd for C 19 H 19 N5O2Na[M+Na] + 372.1436, found: 372.1480.

[0135] C3 can be prepared by replacing aniline with 3-methoxypropylamine.

[0136] C3: Pale yellow solid, yield 57.8%, mp 77.2-78.6℃. 1 H NMR (600MHz, DMSO-d6) δ12.00(s,1H),8.12(d,J=2.9Hz,1H),8.09(t,J=5.7Hz,1H ),7.86(s,1H),7.43(d,J=8.7Hz,1H),7.22(d,J=2.1Hz,1H),7.06(dd,J=8.7,2.1 Hz,1H),6.63(t,J=1.8Hz,1H),6.44(t,J=1.7Hz,1H),6.41(t,J=2.0Hz,1H),5.08 (s,2H),3.35(t,J=6.4Hz,2H),3.32(s,3H),3.22-3.19(m,2H),1.72-1.69(m,2H). 13C NMR (151MHz, DMSO) δ = 167.85, 149.70, 145.72, 138.84, 137.19, 134.47, 130.82, 128.11, 117.67 ,117.09,113.79,106.62,105.01,103.99,103.75,83.80,70.27,58.29,36.81,29.63.ESI-HRMS calcd for C 20 H 22 N5O2[M+H] + 364.1773, found: 364.1776.

[0137] C4 can be prepared by replacing aniline with 4-fluoro-3-methoxyaniline.

[0138] C4: Pale yellow solid, yield 48.8%. mp 124.6-125.8℃. 1 H NMR(600MHz,DMSO-d6)δ12.02(s,1H),10.06(s,1H),8.13(d,J=2.9Hz,1H),7.96 (s,1H),7.65(dd,J=8.1,2.5Hz,1H),7.45(d,J=8.7Hz,1H),7.34(ddd,J=8.9,3. 9,2.4Hz,1H),7.26(s,1H),7.14(dd,J=11.4,8.8Hz,1H),7.09(dd,J=8.7,2.1Hz ,1H),6.70(s,1H),6.53(s,1H),6.48(t,J=2.1Hz,1H),5.19(s,2H),3.81(s,3H). 13 C NMR (151MHz, DMSO) δ = 167.24, 149.87, 148.70, 147.11 (t, J = 7.2Hz), 145.97, 138.62, 137.35, 136.68, 134.57, 130.95, 128.12, 117 .81,117.08,115.84(d,J=18.3Hz),113.86,112.22(d,J=6.4Hz),106.99,106.46,105.12,104.02,103.88,83.83,56.15.ESI-HRMS calcd for C 23 H 19 FN5O2[M+H] + 416.1523, found: 416.1522.

[0139] C5 can be prepared by replacing aniline with 4-dimethylaminoaniline.

[0140] C5: Pale yellow solid, yield 52.5%, mp 114.5-115.8℃. 1 H NMR (600MHz, DMSO-d6) δ12.01(s,1H),9.74(s,1H),8.13(d,J=3.1Hz,1H),7.92(s,1H),7.55-7.53(m,2H),7.44(d,J=8.7Hz,1H),7.25( d,J=2.1Hz,1H),7.09(dd,J=8.7,2.1Hz,1H),6.71-6.69(m,3H),6.52(t,J=1.8Hz,1H),6.45(t,J=2.1Hz,1H),5.15(s,2H),2.85(s,6H). 13 C NMR (151MHz, DMSO) δ = 166.56, 149.74, 147.46, 145.81, 138.76, 137.85, 134.52, 130.88, 129.72, 128. 13,121.86,117.71,117.09,113.82,112.90,106.80,105.21,104.20,103.65,83.81,40.91.ESI-HRMS calcd for C 24 H 22 N6ONa[M+Na] + 433.1753, found: 433.1777.

[0141] C6 can be prepared by replacing aniline with 2-methoxyaniline.

[0142] C6: Pale yellow solid, yield 52.4%. mp 152.3-153.4℃. 1 H NMR (600MHz, DMSO-d6) δ12.01(s,1H),9.90(s,1H),8.13(d,J=3.0Hz,1H),7.94(s,1H),7.66-7.63(m,2H),7.45(d,J=8.7Hz,1H),7.26(d,J=2.0Hz, 1H),7.09(dd,J=8.7,2.1Hz,1H),6.90-6.88(m,2H),6.70(t,J=1.8Hz,1H ),6.53(t,J=1.8Hz,1H),6.47(t,J=2.1Hz,1H),5.17(s,2H),3.73(s,3H). 13C NMR (151MHz, DMSO) δ = 166.89, 155.63, 149.81, 145.89, 138.70, 137.64, 134.53, 133.00, 130.91, 128. 13,121.99,117.76,117.09,114.04,113.84,106.89,105.19,104.15,103.72,83.83,55.53.ESI-HRMS calcd for C 23 H 19 N5O2Na[M+Na] + 420.1436, found: 420.1448.

[0143] C7 can be prepared by replacing aniline with 4-methoxyaniline.

[0144] C7: Pale yellow solid, yield 51.8%, mp 92.3-94.6℃. 1 H NMR (600MHz, DMSO-d6) δ12.03(s,1H),8.85(s,1H),8.14(d,J=3.0Hz,1H),8.01(dd,J=7.9,1.6Hz,1H),7.99(s,1H),7.47(d,J=8.7Hz,1H),7.27(d, J=2.0Hz,1H),7.12-7.08(m,3H),6.97-6.94(m,1H),6.70(t,J=1.8Hz,1H ),6.55(t,J=1.8Hz,1H),6.48(t,J=2.0Hz,1H),5.24(s,2H),3.85(s,3H). 13 C NMR (151MHz, DMSO) δ = 166.04, 150.22, 150.20, 146.34, 138.43, 136.74, 134.61, 131.05, 128.10, 127.71, 124. 98,122.12,120.76,118.03,117.04,113.86,111.50,107.28,104.43,103.76,103.37,83.88,56.26.ESI-HRMS calcd for C 23 H 19 N5O2Na[M+Na] + 420.1436, found: 420.1456.

[0145] C8 can be prepared by replacing aniline with 2,3-dimethoxyaniline.

[0146] C8: Pale yellow solid, yield 47.6%, mp 106.9-108.2℃. 1 H NMR(600MHz,DMSO-d6)δ12.03(s,1H),8.97(s,1H),8.14(d,J=3.0Hz,1H),8.00(s,1H), 7.63(dd,J=8.2,1.4Hz,1H),7.46(d,J=9.1Hz,1H),7.27(d,J=2.0Hz,1H),7.11(dd,J=8 .7,2.1Hz,1H),7.05(t,J=8.3Hz,1H),6.85(dd,J=8.4,1.4Hz,1H),6.71(t,J=1.8Hz,1H ),6.55(t,J=1.8Hz,1H),6.48(t,J=2.0Hz,1H),5.26(s,2H),3.83(s,3H),3.78(s,3H). 13 C NMR (151MHz, DMSO) δ = 166.25, 152.59, 150.21, 146.35, 139.86, 138.41, 136.67, 134.62, 132.43, 131.06, 128.10, 123.98,118.06,117.03,114.83,113.87,109.12,107.34,104.54,103.80,103.32,83.87,60.68,56.20.ESI-HRMS calcd for C 24 H 21 N5O3Na[M+Na] + 450.1542, found: 450.1553.

[0147] C9 can be prepared by replacing aniline with 2,4-dimethoxyaniline.

[0148] C9: Pale yellow solid, yield 48.7%. mp 103.1-104.4℃. 1H NMR (600MHz, DMSO-d6) δ12.02 (s, 1H), 8.80 (s, 1H), 8.14 (d, J = 3.0Hz, 1H), 7.95 (s, 1H) ),7.72(d,J=8.7Hz,1H),7.46(d,J=8.7Hz,1H),7.26(d,J=2.1Hz,1H),7.09(dd,J=8.7 ,2.1Hz,1H),6.70(t,J=1.8Hz,1H),6.65(d,J=2.7Hz,1H),6.54(t,J=1.8Hz,1H),6.52 (dd,J=8.7,2.7Hz,1H),6.46(t,J=2.0Hz,1H),5.20(s,2H),3.82(s,3H),3.76(s,3H). 13 C NMR(151MHz, DMSO)δ=166.10,157.45,152.28,150.04,146.16,138.56,136.91,134.57,130.98,128.11,124.25, 120.84,117.93,117.06,113.84,107.08,104.67,104.54,103.75,103.61,99.25,83.85,56.25,55.72.ESI-HRMS calcd for C 24 H 21 N5O3Na[M+Na] + 450.1542, found: 450.1555.

[0149] C10 can be prepared by replacing aniline with 2,6-dimethoxyaniline.

[0150] C10: Pale yellow solid, yield 49.3%. mp 186.3-187.7℃. 1 H NMR (600MHz, DMSO-d6) δ12.00(s,1H),8.91(s,1H),8.12(d,J=3.0Hz,1H),7.88(s,1H),7.44(d,J=8.7Hz,1H),7.25(d,J=2.1Hz,1H),7 .21(t,J=8.4Hz,2H),7.08(dd,J=8.7,2.1Hz,1H),6.77(s,1H),6.69(d,J=8.4Hz,2H),6.45(d,J=2.1Hz,1H),5.10(s,2H),3.72(s,6H). 13C NMR (151MHz, DMSO) δ = 156.66, 149.67, 145.66, 138.90, 136.97, 134.46, 130.80, 128.11, 127.84, 1 17.69,117.11,115.81,113.80,106.52,105.70,104.82,104.61,104.02,83.80,56.10.ESI-HRMS calcd for C 24 H 21 N5O3Na[M+Na] + 450.1542, found: 450.1555.

[0151] C11 can be prepared by replacing aniline with 3,4-dimethoxyaniline.

[0152] C11: Pale yellow solid, yield 50.4%, mp 132.6-133.9℃. 1 H NMR (600MHz, DMSO-d6) δ12.02(s,1H),9.88(s,1H),8.13(d,J=3.1Hz,1H),7.94(s,1H),7.46-7.44(m,2H),7.31(dd,J=8.7,2.4Hz,1H),7.26(d,J=2 .0Hz,1H),7.09(dd,J=8.7,2.1Hz,1H),6.89(d,J=8.7Hz,1H),6.70(s,1H ),6.53(s,1H),6.46(t,J=2.0Hz,1H),5.17(s,2H),3.73(d,J=3.6Hz,6H). 13 C NMR (151MHz, DMSO) δ = 166.89, 149.81, 148.79, 145.89, 145.23, 138.69, 137.64, 134.55, 133.51, 130.91, 128. 12,117.76,117.09,113.85,112.32,106.89,105.64,105.15,104.08,103.78,83.82,56.12,55.74.ESI-HRMS calcd for C 24 H 21 N5O3Na[M+Na] + 450.1542, found: 450.1549.

[0153] C12 can be prepared by replacing aniline with 3,5-dimethoxyaniline.

[0154] C12: Pale yellow solid, yield 49.3%. mp 79.1-80.2℃. 1 H NMR(600MHz,DMSO-d6)δ12.02(s,1H),9.96(s,1H),8.13(d,J=3.0Hz,1H),7 .95(s,1H),7.45(d,J=8.7Hz,1H),7.26(d,J=2.1Hz,1H),7.09(dd,J=8.7,2 .1Hz,1H),7.06(d,J=2.3Hz,2H),6.68(t,J=1.8Hz,1H),6.51(t,J=1.8Hz,1 H), 6.47 (t, J = 2.0Hz, 1H), 6.22 (t, J = 2.3Hz, 1H), 5.19 (s, 2H), 3.72 (s, 6H). 13 C NMR (151MHz, DMSO) δ = 167.39, 160.71, 149.84, 145.94, 141.55, 138.62, 137.51, 134.56, 130.94, 128 .12,117.80,117.07,113.85,106.98,105.15,104.08,103.81,98.64,95.71,83.84,55.44.ESI-HRMS calcd for C 24 H 21 N5O3Na[M+Na] + 450.1542, found: 450.1588.

[0155] C13 can be prepared by replacing aniline with 3,4,5-trimethoxyaniline.

[0156] C13: Pale yellow solid, yield 54.5%. mp 132.7-134.9℃. 1 H NMR (600MHz, DMSO-d6) δ12.02(s,1H),9.92(s,1H),8.13(d,J=2.9Hz,1H),7.95(s,1H),7.45(d,J=8.7Hz,1H),7.27(s,1H),7.22(s,2H), 7.09(dd,J=8.8,2.1Hz,1H),6.70(t,J=1.8Hz,1H),6.52(t,J=1.7Hz,1H),6.47(t,J=2.0Hz,1H),5.19(s,2H),3.75(s,6H),3.63(s,3H). 13C NMR(151MHz,DMSO)δ=167.12,152.93,149.83,145.93,138.65,137.52,136.03,134.56,133.80,130.93,128 .12,117.79,117.08,113.86,106.95,105.10,103.99,103.89,98.13,83.83,60.48,60.13,56.07.ESI-HRMS calcd for C 25 H 23 N5O4Na[M+Na] + 480.1648, found: 480.1678.

[0157] Example 11

[0158] Synthesis of 5-[(3-nitrophenyl)amino]-1H-indole-3-carboxynitrile (9)

[0159]

[0160] 3-Cyano-5-amino-1H-indole-1-carboxylic acid tert-butyl ester (5) (3.00 g, 11.66 mmol), 1-iodo-3-nitrobenzene (2.90 g, 11.66 mmol), BrettPhos (0.63 g, 1.17 mmol), Pd2(dba)3 (1.07 g, 1.17 mmol), cesium carbonate (7.60 g, 23.32 mmol), and 1,4-dioxane (50 mL) were added to a 100 mL single-necked flask. Under argon protection, the reaction was carried out at 100 °C for 15 h. The reaction was monitored by TLC until complete. After cooling to room temperature, the mixture was filtered, concentrated, and separated by column chromatography to give 2.35 g of yellow solid, with a yield of 72.4%. 1 H NMR(400MHz,DMSO-d6)δ12.18(s,1H),8.68(s,1H),8.23(s,1H),7.74-7.72(m,1H),7.58- 7.53(m,2H),7.48-7.44(m,1H),7.40-7.36(m,2H),7.17(dd,J=8.7,2.1Hz,1H).ESI-HRMS calcd for C 15 H9N4O2[MH] - 277.0726, found: 277.0757.

[0161] Example 12

[0162] 5-[(3-aminophenyl)amino]-1H-indole-3-carboxynitrile (10)

[0163]

[0164] 5-[(3-nitrophenyl)amino]-1H-indole-3-carboxynitrile (2.00 g, 7.19 mmol) and palladium on carbon (0.15 g) were added to a 100 mL single-necked flask. Hydrogen gas was continuously bubbled through the flask, and the reaction was carried out at 45 °C for 6 h. The reaction was monitored by TLC until it was complete. The mixture was filtered and concentrated to give 1.63 g of a brown solid, with a yield of 91.3%. No further purification was required, and the reaction proceeded directly to the next step. 1 HNMR (400MHz, DMSO-d6) δ11.99(s,1H),8.11(s,1H),7.75(s,1H),7.44(d,J=8.8Hz,1H),7.26(s,1H),7.07(dd,J=8.8,2.1Hz ,1H),6.90-6.86(m,1H),6.35-6.34(m,1H),6.27(dd,J=7.7,2.1Hz,1H),6.08(dd,J=7.6,2.0Hz,1H),4.94(s,2H).ESI-HRMS calcd for C 15 H 12 N4Na[M+Na] + 271.0960, found: 271.0945.

[0165] Example 13

[0166] Synthesis of phenylphenylcarbamate (12a)

[0167]

[0168] Aniline (3.00 g, 32.21 mmol) and N,N-diisopropylethylamine (8.4 mL, 48.32 mmol) were added to a 100 mL single-necked flask. Phenyl chloroformate (4.4 mL, 35.43 mmol) was added dropwise under ice bath conditions. The reaction was carried out at room temperature for 4 h. The mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated to give 6.37 g of a white solid, with a yield of 92.7%. It could be used directly in the next reaction without further purification.

[0169] Example 14

[0170] Synthesis of 1-{3-[(3-cyano-1H-indol-5-yl)amino]phenyl}-3-phenylurea (D1)

[0171]

[0172] 5-[(3-aminophenyl)amino]-1H-indole-3-carboxynitrile (0.20 g, 0.81 mmol), phenylphenylcarbamate (12a) (0.21 g, 0.96 mmol), and KOH (0.14 g, 2.42 mmol) were added to a 100 mL single-necked flask. The reaction was carried out at room temperature for 4 h. The reaction was monitored by TLC until complete. Column chromatography was used to separate 0.17 g of a white solid, yielding 57.4%. mp 76.9-78.3 °C. 1 HNMR(600MHz,DMSO-d6)δ12.04(s,1H),8.62(s,1H),8.60(s,1H),8.14-8.13(m,1H),8.07(s,1H),7.47-7.42(m ,3H),7.29-7.24(m,4H),7.12-7.08(m,2H),6.96-6.94(m,1H),6.85-6.83(m,1H),6.65(dd,J=8.0,2.2Hz,1H). 13 C NMR(151MHz,DMSO-d6)δ152.91,145.73,141.06,140.24,138.59,134.66,131.01,129.85,129.24, 128.21,122.16,118.54,117.69,117.15,114.00,109.92,109.54,106.63,105.84,83.92.ESI-HRMS calcd for C 22 H 16 N5O[MH] - 366.1355, found: 366.1373.

[0173] Compounds D2 to D8 were synthesized according to the methods described in Examples 1 to 4 and Examples 11 to 14 above.

[0174] D2 can be prepared by replacing aniline with 4-fluoroaniline.

[0175] D2: White solid, yield 56.8%, mp 96.1-97.6℃. 1H NMR(600MHz,DMSO-d6)δ12.03(s,1H),8.65(s,1H),8.58(s,1H),8.14-8.13(m,1H),8.07(s,1H),7.46-7.45(m,1H),7.44-7.43(m,2H),7 .28-7.27(m,1H),7.25-7.24(m,1H),7.12-7.11(m,1H),7.10-7.09(m,2H),7.09(s,1H),6.85-6.82(m,1H),6.65(dd,J=8.1,2.2Hz,1H). 13 C NMR(151MHz,DMSO-d6)δ156.93,153.00,145.72,141.03,138.58,136.59,134.66,131.01,129.85,128.21, 120.30,120.25,117.69,117.14,115.79,115.64,114.00,109.97,109.58,106.63,105.87,83.92.ESI-HRMS calcd for C 22 H 15 FN5O[MH] - 384.1261, found: 384.1278.

[0176] D3 can be prepared by replacing aniline with 4-trifluoromethylaniline.

[0177] D3: White solid, yield 50.2%, mp 84.6-86.2℃. 1 H NMR(600MHz,DMSO-d6)δ12.04(s,1H),9.02(s,1H),8.71(s,1H),8.15-8.14(m,1H),8.10(s,1H),7.66-7.64(m,2H),7.62-7.61(m,2 H),7.46(d,J=8.7Hz,1H),7.30-7.29(m,1H),7.27-7.26(m,1H),7.14-7.09(m,2H),6.86-6.84(m,1H),6.68(dd,J=8.1,2.2Hz,1H). 13C NMR(151MHz,DMSO-d6)δ152.64,145.79,144.00,140.64,138.49,134.69,131.05,129.91,128.21,126.54,126.51, 125.94,124.15,122.19,121.98,118.21,117.75,117.13,114.02,110.28,109.71,106.74,105.98,83.95.ESI-HRMS calcd for C 23 H 15 F3N5O[MH] - 434.1229, found: 434.1246.

[0178] D4 can be prepared by replacing aniline with 4-trifluoromethoxyaniline.

[0179] D4: White solid, yield 54.3%, mp 148.7-150.4℃. 1 H NMR (600MHz, DMSO-d6) δ12.04(s,1H),8.87(s,1H),8.68(s,1H),8.15-8.14(m,1H),8.09(s,1H),7.56-7.53(m,2H),7.46(d,J= 8.7Hz,1H),7.29-7.28(m,1H),7.28-7.25(m,3H),7.12-7.09(m,2H),6.85(dd,J=7.9,2.0Hz,1H),6.67(dd,J=8.1,2.2Hz,1H). 13 C NMR (151MHz, DMSO-d6) δ152.86,145.75,142.93,140.87,139.58,138.55,134.66,131.02,129.87,128. 21,122.17,121.51,119.69,117.71,117.14,114.00,110.08,109.63,106.67,105.92,83.93.ESI-HRMS calcd forC 23 H 16 F3N5O2Na[M+Na] + 474.1154, found: 474.1155.

[0180] D5 can be prepared by replacing aniline with 3-chloro-4-fluoroaniline.

[0181] D5: White solid, yield mp 80.3-82.1℃. 1 H NMR (600MHz, DMSO-d6) δ12.04(s,1H),8.86(s,1H),8.71(s,1H),8.14-8.13(m,1H),8.08(s,1H),7.79(dd,J=6.8,2.5Hz,1H),7.46(d,J=8.7H z,1H),7.33-7.32(m,1H),7.30-7.28(m,2H),7.25-7.24(m,1H),7.12-7.08(m,2H),6.84(dd,J=8.0,2.0Hz,1H),6.67(dd,J=8.2,2.4Hz,1H). 13 C NMR (151MHz, DMSO-d6) δ153.52,152.86,151.92,145.74,140.76,138.53,137.58,137.56,134.67,131.03,129.87,128.21,119. 81,119.53(d,J=18.2Hz),118.85(d,J=6.6Hz),117.70,117.24(t,J=21.6Hz),114.01,110.18,109.71,106.65,105.99.ESI-HRMS calcd for C 22 H 14 ClFN5O[MH] - 418.0871, found: 418.0897.

[0182] D6 can be prepared by replacing aniline with 3-chloroaniline.

[0183] D6: White solid, yield 51.8%, mp 98.6-100.3℃. 1 H NMR (600MHz, DMSO-d6) δ12.04(s,1H),8.86(s,1H),8.70(s,1H),8.14-8.13(m,1H),8.08(s,1H),7.70-7.69(m,1H),7.46(d,J=8.7Hz,1H ),7.30-7.27(m,2H),7.26-7.24(m,2H),7.12-7.09(m,2H),7.01-6.99(m,1H),6.85(dd,J=7.9,2.0Hz,1H),6.67(dd,J=8.1,2.2Hz,1H). 13C NMR(151MHz,DMSO-d6)δ152.75,145.76,141.82,140.77,138.53,134.67,133.65,131.03,130.84,129.88, 128.21,121.77,117.88,117.71,117.13,116.98,114.02,110.15,109.67,106.67,105.96,83.93.ESI-HRMS calcd for C 22 H 15 ClN5O[MH] - 400.0965, found: 400.0992.

[0184] D7 can be prepared by replacing aniline with 3-bromoaniline.

[0185] D7: White solid, yield 54.1%, mp 94.2-95.8℃. 1 H NMR(600MHz,DMSO-d6)δ12.03(s,1H),8.80(s,1H),8.66(s,1H),8.14-8.13(m,1H),8.08(s,1H),7.84-7.83(m,1H),7.46 (d,J=8.7Hz,1H),7.29-7.28(m,2H),7.25-7.20(m,2H),7.14-7.08(m,3H),6.84(d,J=8.0Hz,1H),6.67(d,J=8.0Hz,1H). 13 C NMR(151MHz,DMSO-d6)δ152.72,145.76,141.95,140.75,138.53,134.68,131.15,131.04,129.89,128.21, 124.69,122.19,120.75,117.71,117.40,117.13,114.02,110.16,109.69,106.68,105.97,83.93.ESI-HRMS calcd for C 22 H 15 BrN5O[MH] - 444.0460, found: 444.0481.

[0186] D8 can be prepared by replacing aniline with 3-methylaniline.

[0187] D8: White solid, yield 43.6%, mp 76.2-78.3℃. 1H NMR(400MHz,DMSO-d6)δ12.02(s,1H),8.54(s,1H),8.50(s,1H),8.14-8.1 3(m,1H),8.06(s,1H),7.46(d,J=8.7Hz,1H),7.29-7.28(m,2H),7.27-7.25 (m,1H),7.22-7.19(m,1H),7.16-7.12(m,1H),7.09(dd,J=8.3,2.7Hz,2H) ,6.85-6.81(m,1H),6.77(d,J=7.3Hz,1H),6.67-6.63(m,1H),2.27(s,3H). 13 C NMR(101MHz,DMSO-d6)δ152.88,145.74,141.08,140.15,138.61,138.39,134.64,131.02,129.84,129.07,128 .22,122.93,119.09,117.71,117.12,115.75,114.00,109.94,109.53,106.64,105.84,83.95,21.69.ESI-HRMS calcd for C 23 H 19 N5ONa[M+Na] + 404.1487, found: 404.1487.

[0188] Example 15

[0189] 5-{[3-(3-phenylureo)phenyl]amino}-1H-indole-3-carboxamide (E1)

[0190]

[0191] 1-{3-[(3-cyano-1H-indol-5-yl)amino]phenyl}-3-phenylurea (D1) (50 mg, 0.14 mmol), potassium carbonate (56 mg, 0.42 mmol), and DMSO (3 mL) were added to a 50 mL single-necked flask. Hydrogen peroxide (1 mL) was added dropwise under ice bath conditions. The reaction was carried out at room temperature for 1 h. The reaction was monitored by TLC until complete. Column chromatography yielded 26 mg of a white solid, with a yield of 49.6%. mp 132.1-134.9 °C. 1HNMR(600MHz,DMSO-d6)δ11.40(s,1H),8.63(s,1H),8.55(s,1H),7.97-7.96(m, 1H),7.94-7.93(m,1H),7.87(s,1H),7.43-7.40(m,2H),7.33(d,J=8.6Hz,1H),7 .27-7.24(m,2H),7.07-7.06(m,1H),7.04-7.02(m,1H),6.98(dd,J=8.6,2.2Hz, 1H), 6.96-6.93 (m, 1H), 6.82 (dd, J=8.1, 2.0Hz, 1H), 6.58 (dd, J=8.3, 2.2Hz, 1H). 13 C NMR(151MHz,DMSO-d6)δ167.11,152.89,147.12,140.92,140.30,136.70,132.66,129.67,129.23,1 29.06,127.62,122.09,118.46,117.32,112.49,112.23,110.43,108.95,108.51,104.80.ESI-HRMS calcd forC 22 H 19 N5O2Na[M+Na] + 408.1436, found: 408.1424.

[0192] Compounds E2 and E3 were synthesized according to the methods described in Examples 1-4 and Examples 11-15 above.

[0193] E2 can be prepared by replacing aniline with 4-fluoroaniline.

[0194] E2: White solid, yield 59.3%, mp 136.9-139.2℃. 1 H NMR(600MHz,DMSO-d6)δ11.39(s,1H),8.60(s,1H),8.49(s,1H),7.97-7.96 (m,1H),7.93-7.92(m,1H),7.86(s,1H),7.45-7.40(m,2H),7.33(d,J=8.6H z,1H),7.12-7.07(m,2H),7.06-7.05(m,1H),7.04-7.02(m,1H),6.98(dd,J =8.6, 2.2Hz, 1H), 6.81 (dd, J = 7.8, 2.4Hz, 1H), 6.58 (dd, J = 8.1, 2.5Hz, 1H). 13C NMR(151MHz,DMSO-d6)δ167.10,158.48,156.90,152.96,147.12,140.86,136.68,132.67,129.67,129.05,1 27.61,120.25,120.20,117.34,115.78,115.63,112.50,112.25,110.43,109.03,108.57,104.82.ESI-HRMS calcd for C 22 H 18 FN5O2Na[M+Na] + 426.1342, found: 426.1334.

[0195] E3 can be prepared by replacing aniline with 3-chloro-4-fluoroaniline.

[0196] E3: White solid, yield 55.1%, mp 145.2-147.5℃. 1 H NMR (600MHz, DMSO-d6) δ11.40(s,1H),8.82(s,1H),8.62(s,1H),7.97-7.96(m,1H),7.94-7.93(m,1H),7.87(s,1H),7.77(dd,J=6.8,2.6Hz,1H) ,7.35-7.30(m,2H),7.30-7.24(m,2H),7.06-7.02(m,2H),6.98(dd,J=8.6,2.2Hz,1H),6.82(dd,J=7.3,1.6Hz,1H),6.59(dd,J=7.9,2.0Hz,1H). 13 C NMR(151MHz,DMSO-d6)δ167.10,152.82,147.15,140.60,137.60(d,J=2.8Hz),136.64,132.69,129.96,129.70,129.06,127.63,119.75 ,119.57(d,J=18.1Hz),118.78(d,J=6.7Hz),117.34,117.31(d,J=21.8Hz),112.50,112.28,110.43,109.22,108.69,104.96.ESI-HRMS calcd for C 22 H 17 ClFN5O2Na[M+Na] + 460.0953, found: 460.0948.

[0197] Example 16

[0198] In vitro kinase inhibitory activity study of the target compound

[0199] (1) Experimental materials

[0200]

[0201] (2) Experimental steps

[0202] Add 25 nL of each of the above compounds to a 384-well plate and centrifuge at 1000 rpm for 1 minute. Next, add 2.5 μL of TRKAWT enzyme solution to each well, centrifuge again at 1000 rpm for 1 minute, and incubate at room temperature for 30 minutes. Then, add 2.5 μL of a TK substrate mixture (TK substrate-biotin and ATP) to the plate, centrifuge at 1000 rpm for 1 minute, and incubate at room temperature for 90 minutes. Finally, add 5 μL of the detection solution to each well and centrifuge at 1000 rpm for 30 seconds. The F500 records the ratio of HTRF signals at 665nm and 615nm, and calculates the IC based on the suppression curve. 50 value.

[0203] (3) IC of compounds in some examples 50 value

[0204] Example <![CDATA[IC 50 (μM)]]> Example <![CDATA[IC 50 (μM)]]> A1 1.15 C1 0.0076 A2 1.02 C2 0.055 A3 1.04 C3 0.063 A4 0.40 C4 0.026 A5 0.94 C5 0.014 A6 0.85 C6 0.0046 A7 0.79 C7 0.0058 A8 0.69 C8 0.014 A9 0.39 C9 0.0092 A10 0.68 C10 0.017 A11 0.19 C11 0.0018 A12 0.42 C12 0.013 A13 1.04 C13 0.0087 B1 7.98 D1 0.0036 B2 >10 D2 0.0011 B3 2.29 D3 0.0037 B4 3.87 D4 0.0024 B5 >10 D5 0.0031 B6 1.43 D6 0.0035 B7 1.52 D7 0.0022 B8 5.01 D8 0.0068 B9 8.96 E1 0.0091 B10 >10 E2 0.011 B11 5.02 E3 0.0085

[0205] 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. An N-phenyl-1H-indole-5-amino compound, characterized in that: N-phenyl-1H-indole-5-amino compounds are those represented by formula (I), their prodrugs and active metabolites, and their pharmaceutically acceptable salts. In the formula, R1 is selected from -CN, -CONH2, -C(O)H, -COOH, and -CONH2(CH2). n CH3, a C3-C7 ring containing at least one heteroatom; n is 0, 1, 2, or 3; R2 is selected from hydrogen, halogen, amino, methylamino, dimethylamino, nitro, cyano, C1-C4 alkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy. m can be 1, 2, 3 or 4; when m is an integer from 2 to 4, R2 can be the same or different; R3 is selected from -C(O)NH-Ar, -NHC(O)-Ar, -NHC(O)NH-Ar, and -C(O)O-Ar, where Ar is selected from unsubstituted or 1-4 identical or different Rs. a Substituted benzene rings, C1-C6 alkoxy groups; R a Selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 nitrogen-containing alkyl, and C3-C7 ring containing at least one heteroatom, and R a When it is greater than 1, both R a The carbon adjacent to Ar forms C4-C. 10 A ring containing at least one heteroatom in a C4-C ring. 10 The ring.

2. The N-phenyl-1H-indole-5-amino compound according to claim 1, characterized in that: The N-phenyl-1H-indole-5-amino compounds are compounds of formula (I), their prodrugs and active metabolites, and their pharmaceutically acceptable salts. In the formula, R1 is selected from -CN, -CONH2, -C(O)H, -COOH, and -CONH2(CH2). n CH3, a C3-C6 ring containing 1-2 heteroatoms; n is 0 or 1; R2 is selected from hydrogen, halogen, amino, methylamino, dimethylamino, nitro, cyano, C1-C4 alkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy. m is an integer from 1 to 2; when m is 2, R² can be the same or different. R3 is selected from -C(O)NH-Ar, -NHC(O)-Ar, -NHC(O)NH-Ar, and -C(O)O-Ar, where Ar is selected from unsubstituted or 1-4 identical or different Rs. a Substituted benzene rings, C1-C6 alkoxy groups; R a Selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 nitrogen-containing alkyl, and C3-C6 ring containing at least one heteroatom, and R a When it is greater than 1, two adjacent R a The carbon adjacent to Ar forms C4-C. 10 A ring containing at least one heteroatom in a C4-C ring. 10 The ring.

3. The N-phenyl-1H-indole-5-amino compound according to claim 2, characterized in that: The N-phenyl-1H-indole-5-amino compounds are compounds of formula (I), their prodrugs and active metabolites, and their pharmaceutically acceptable salts. In the formula, R1 is selected from -CN, -CONH2, -C(O)H, -COOH, and -CONH2(CH2). n CH3, a C3-C6 ring containing 1-2 heteroatoms; n is 0 or 1; R2 is selected from hydrogen, halogen, amino, methylamino, dimethylamino, nitro, cyano, methyl, methoxy, and trifluoromethoxy. m is an integer from 1 to 2; when m is 2, R² can be the same or different. R3 is selected from -C(O)NH-Ar, -NHC(O)-Ar, -NHC(O)NH-Ar, and -C(O)O-Ar, where Ar is selected from unsubstituted or 1-4 identical or different Rs. a Substituted benzene rings, C1-C6 alkoxy groups; R a Selected from hydrogen, halogen, amino, methylamino, dimethylamino, nitro, cyano, methyl, methoxy, trifluoromethoxy; and R a When it is greater than 1, two adjacent R a The carbon adjacent to Ar forms a C4-C8 ring, a C4-C8 ring containing at least one heteroatom.

4. The N-phenyl-1H-indole-5-amino compound according to claim 3, characterized in that: The N-phenyl-1H-indole-5-amino compounds are compounds of formula (I), their prodrugs and active metabolites, and their pharmaceutically acceptable salts. In the formula, R1 is selected from -CN or -CONH2; R2 is selected from hydrogen and amino groups; m is an integer from 1 to 2; when m is 2, R2 can be the same or different. R3 is selected from -C(O)NH-Ar or -NHC(O)NH-Ar, and Ar is selected from unsubstituted or 1-3 R groups. a Substituted benzene rings, C1-C4 alkoxy groups, R a Selected from hydrogen, halogen, methyl, methoxy, trifluoromethoxy, dimethylamino, and R a When it is greater than 1, two adjacent R a The carbon adjacent to Ar forms a C4-C8 ring containing at least one heteroatom.

5. The N-phenyl-1H-indole-5-amino compound according to any one of claims 1-4, characterized in that: The pharmaceutically acceptable salt of the compound is a salt formed with an acid selected from: hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, trifluoroacetic acid, or aspartic acid.

6. The application of the N-phenyl-1H-indole-5-amino compound according to claim 1, characterized in that: The use of the compound represented by formula (I), its prodrug and active metabolite, and its pharmaceutically acceptable salt in the preparation of TRK therapeutic agents.

7. The application of the N-phenyl-1H-indole-5-amino compound according to claim 6, characterized in that: The compound represented by formula (I), its prodrug and active metabolite, and its pharmaceutically acceptable salt are used in the preparation of TRK inhibitors.

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