Tricyclic scaffold compound and use thereof in preparation of antitumor drugs
Patent Information
- Application Number
- AU2025240727
- Authority / Receiving Office
- AU · AU
- Patent Type
- Applications
- Current Assignee / Owner
- Priority Date
- 2024-12-13
- Filing Date
- 2025-03-21
- Publication Date
- 2026-10-29
Abstract
Description
Compound Structure Amine intermediate Acid intermediate Spectrum information 51 0 Crs HN / X| 1-4 1H NMR(400 MHz, DMSO-d6) 3 8.24 - 8.13 (m, 1H), 7.83 (dd,J = 7.6, 1.6 Hz, 1H), 7.50 (dd,J = 7.5, 1.6 Hz, 1H), 7.38 - 7.27 (m, 2H), 4.18 (s, 2H), 4.13 (d,J = 1.3 Hz, 3H), 3.28 (dt, J = 40.1, 6.7 Hz, 2H), 2.84 - 2.70 (m, 6H), 2.54 (d,J = 7.8 Hz, 1H), 2.36 - 2.28 (m, 1H), 2.20 - 2.03 (m, 2H), 1.92 - 1.81 (m, 3H), 1.78 - 1.66 (m, 6H), 1.60 - 1.35 (m, 4H).LCMS m / z [M+H]+ = 466.3 61 0 HN N^ 1-4 1H NMR(400 MHz, DMSO-d6) 8 8.22 (HCOOH, 1.45), 8.17 (t,J = 6.1 Hz, 1H), 7.83 (dd,J = 7.7, 1.6 Hz, 1H), 7.50 (dd,J = 7.4, 1.7 Hz, 1H), 7.37 - 7.27 (m, 2H), 4.18 (s, 2H), 4.13 (s, 3H), 3.23 (t,J = 6.2 Hz, 2H), 2.87 (d,J = 11.2 Hz, 2H), 2.61 (d,J = 7.6 Hz, 1H), 2.57 - 2.51 (m, 3H), 2.46 (s, 2H), 2.44 - 2.36 (m, 3H), 2.26 - 2.14 (m, 2H), 2.13 - 2.02 (m, 2H), 2.01 - 1.87 (m, 1H), 1.87 - 1.70 (m, 5H), 1.57 (dt,J = 10.9, 8.6 Hz, 2H), 1.41 (td,J = 12.7, 12.0, 9.2 Hz, 2H), 1.00 (t,J = 7.2 Hz, 3H).LCMS m / z [M+H]+ = 509.3 77 0 cP % ^N\ HN^A N^ ^N\ 1-4 1H NMR(400 MHz, DMSO-d6) 8 8.33 (t,J = 6.0 Hz, 1H), 8.17 (HCOOH, 1.9H), 7.87 - 7.79 (m, 1H), 7.50 (dd,J = 7.5, 1.6 Hz, 1H), 7.32 (dtd,J = 16.8, 7.4, 1.6 Hz, 2H), 4.18 (d,J = 3.3 Hz, 2H), 4.13 (d,J = 2.3 Hz, 3H), 3.24 (dt,J = 12.4, 6.6 Hz, 6H), 2.90 - 2.77 (m, 3H), 2.22 (ddd,J = 40.8, 21.3, 11.8 Hz, 10H), 1.98 (dq,J = 12.3, 7.1, 5.2 Hz, 2H), 1.85 - 1.71 (m, 2H), 1.59 - 1.46 (m, 1H).LCMS m / z [M+H]+ = 467.3 78 0 cP \y P^N\ HN^Y N^ ^N\ 1-4 1H NMR(400 MHz, DMSO-d6) 8 8.23 (s, 1H), 8.18 (HCOOH, 1.5H), 7.83 (d,J = 7.6 Hz, 1H), 7.50 (d,J = 7.4 Hz, 1H), 7.32 (p,J = 7.5 Hz, 2H), 4.18 (s, 2H), 4.13 (d,J = 1.9 Hz, 3H), 3.38 - 3.28 (m, 2H), 3.22 (t,J = 6.1 Hz, 2H), 2.81 (m, 2H), 2.54 (s, 1H), 2.44 (s, 3H), 2.30 (s, 4H), 2.14 (s, 4H), 2.04 (s, 2H), 1.84 (s, 1H), 1.68 (s, 4H), 1.51 (s, 1H), 1.32 (s, 2H).LCMS m / z [M+H]+=495.3 99 cP ci ^ / N\ HN"A OH -N^r° Cl LCMS m / z = 485.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) 8 8.46 - 8.30 (m, 1H), 8.13 (s, HCOOH, 0.4H), 7.75 (d, J = 9.9 Hz, 1H), 7.20 - 7.09 (m, 2H), 4.15 (s, 3H), 3.98 - 3.57 (m, 4H), 3.44 - 3.33 (m, 4H), 3.23 - 3.02 (m, 4H), 3.01 - 2.92 (m, 2H), 2.90 - 2.75 (m, 2H), 2.60 - 2.52 (m, 2H), 2.34 -1.94 (m, 4H), 1.91 - 1.66 (m, 1H). 110 CX'C.-. cP Q "......, Cl ^N\ HN^A N^ ^N\ OH ~N^d° ^rs Cl 1H NMR (400 MHz, DMSO-d6) 8 8.34 (t, J = 6.0 Hz, 1H), 8.22 (s, HCOOH, 2.1H), 7.84 (d, J = 8.5 Hz, 1H), 7.61 (s, 1H), 7.39 (d,J= 8.4 Hz, 1H), 4.23 - 4.20 (m, 2H), 4.12 (s, 3H), 3.41 - 3.31 (m, 3H), 3.30 - 3.20 (m, 3H), 3.12 - 3.02 (m, 1H), 3.00 - 2.80 (m, 4H), 2.40 - 2.30 (m, 3H), 2.27 - 2.19 (m, 3H), 2.18 - 2.15 (m, 3H), 2.03 -1.95 (m, 1H), 1.84 - 1.76 (m, 2H), 1.60 - 1.53 (m, 1H). LCMS m / z = 501.3 [M+H]+ 111 dr ^NaN^ Cl HN-n k'"' OH Cl LCMS m / z = 515.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) 8 8.40 - 8.15 (m, 1H), 8.24 (s, HCOOH, 2H), 7.84 (dd, J = 8.5, 2.2 Hz, 1H), 7.62 - 7.59 (m, 1H), 7.41 - 7.36 (m, 1H), 4.23 - 4.21 (m, 2H), 4.13 - 4.11 (m, 3H), 3.35 - 2.98 (m, 9H), 2.95 - 2.58 (m, 4H), 2.39 -2.16 (m, 7H), 2.05 - 1.90 (m, 1H), 1.82 - 1.52 (m, 2H), 1.10 - 0.82 (m, 3H). 112 cP FV°r HN-n OH ~ / yC° cP OCF3 1H NMR (400 MHz, DMSO-d6) 8 8.44 - 8.23 (m, 1H), 8.21 (s, HCOOH, 1.43H), 7.84 (d, J = 8.5 Hz, 1H), 7.13 - 6.97 (m, 2H), 5.55 - 5.39 (m, 2H), 4.16 (s, 3H), 3.36 -3.24 (m, 4H), 3.24 - 3.13 (m, 2H), 2.92 - 2.80 (m, 3H), 2.43 - 2.14 (m, 10H), 2.02 - 1.93 (m, 1H), 1.83 - 1.72 (m, 2H), 1.62 - 1.50 (m, 1H), 1.04 - 0.87 (m, 3H). LCMS m / z = 549.3 [M+H]+ 114 0 _.n%Ch Cl HN-n OH - / yc ^p Cl LCMS: m / z = 499.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 8 8.42 - 8.25 (m, 1H), 8.25 - 8.22 (m, 1H), 7.73 (dd,J= 8.2, 1.7 Hz, 1H), 7.18 - 7.10 (m, 2H), 5.49 - 5.42 (m, 2H), 4.15 - 4.13 (m, 3H), 3.45 - 3.33 (m, 2H), 3.29 - 3.07 (m, 3H), 3.01 - 2.83 (m, 3H), 2.47 -2.16 (m, 9H), 2.05 - 1.95 (m, 1H), 1.89 - 1.74 (m, 2H), 1.65 - 1.52 (m, 1H), 1.02 - 0.93 (m, 3H).
[304] Example 48
[305] In step 1: Under a nitrogen atmosphere, compound 68-1 (923 mg, 5.05 mmol, 1.0 eq) is dissolved in THF (9 mL) and cooled to -78°C. NaHMDS (2M in THF, 5.1 mL, 10.11 mmol, 2.0 eq) is added dropwise to the reaction mixture, and the mixture is stirred at -78°C for 0.5 h. Diethyl oxalate (1.48 g, 10.11 mmol, 2.0 eq) is dissolved in THF (4.5 mL) and added dropwise to the reaction mixture. The reaction mixture is stirred at -78°C for 10 min, then warmed to room temperature and stirred for 1.5 h. After reaction, the reaction is quenched with saturated NH4Cl solution and extracted with ethyl acetate (3 x 40 mL). The combined organic phases are washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain a white solid compound 68-2 (1.9 g, 100%). LCMS m / z = 283.1 [M+H]+.
[306] In step 2: Compound 68-2 (1.8 g, 6.37 mmol) is dissolved in EtOH (45 mL). Methylhydrazine (293.4 mg, 6.37 mmol) is added to the reaction mixture. The reaction mixture is stirred at room temperature for 4 h. After reaction, the reaction mixture is concentrated. The crude product is purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 10:1) to obtain white solid compound 68-3a (350 mg, 19%) and compound 68-3b (405 mg, 21.7%). 68-3a: LCMS m / z = 293.1 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 8 7.43 (d, J = 8.3 Hz, 1H), 7.04 (d, J = 2.1 Hz, 1H), 7.01 (dd,J= 8.3, 2.1 Hz, 1H), 5.49 (s, 2H), 4.42 (q,J= 7.1 Hz, 2H), 4.20 (s, 3H), 1.41 (t,J= 7.1 Hz, 3H). 68-3b: LCMS m / z = 293.1 [M+H]+; 1H NMR (400 MHz, CDCl3) 8 7.59 (d,J= 8.1 Hz, 1H), 6.94 (dd,J= 8.1, 2.0 Hz, 1H), 6.91 (d,J=2.0Hz, 1H), 5.41 (s, 2H), 4.34 (q, J = 7.1 Hz, 2H), 4.18 (s, 3H), 1.38 (t,J = 7.1 Hz, 3H).
[307] In step 3: Compound 68-3a (200 mg, 0.68 mmol, 1.0 eq) is dissolved in THF (1.5 mL). A NaOH solution (NaOH (54.7 mg, 1.37 mmol, 2.0 eq) dissolved in H2O (0.5 mL)) is slowly added. The reaction mixture is stirred at 60°C for 3 h. After reaction, the pH of the reaction mixture is adjusted to 3-4 with 2N HCl solution, and the mixture is extracted with DCM (3 x 20 mL). The combined organic phases are washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain a white solid compound 68-4a (200 mg, 100%). LCMS m / z = 265.0 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 8 7.73 (d, J = 8.2 Hz, 1H), 7.16 - 7.09 (m, 2H), 5.42 (s, 2H), 4.16 (s, 3H).
[308] In step 4: Compound 68-4a (100 mg, 0.38 mmol, 1.0 eq), HATU (186.8 mg, 0.50 mmol, 1.3 eq), and DIPEA (146.4 mg, 1.14 mmol, 3.0 eq) are dissolved in DMF (2 mL). The reaction mixture is stirred at room temperature for 0.5 h. Compound 68-5 (170.4 mg, 0.76 mmol, 2.0 eq) is dissolved in DMF (1 mL) and added dropwise to the reaction mixture. The reaction mixture is stirred at room temperature for 2.5 h. After reaction, the reaction mixture is diluted with water (40 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic phases are washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The resulting crude product is purified by preparative column chromatography to obtain a white solid compound 68 (26 mg, 28%). LCMS m / z = 487.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 6 8.72 - 8.59 (m, 1H), 7.74 (d, J = 8.3 Hz, 1H), 7.16 - 7.06 (m, 2H), 5.44 (s, 2H), 4.17 (s, 3H), 3.27 -3.23 (m, 2H), 2.96 - 2.89 (m, 2H), 2.49 - 2.41 (m, 5H), 2.39 - 2.26 (m, 5H), 2.14 (s, 3H), 2.10 - 1.94 (m, 1H), 1.90 - 1.80 (m, 2H), 1.80 - 1.70 (m, 2H), 1.69 - 1.57 (m, 2H), 1.57 - 1.43 (m, 2H).
[309] Referring to the synthesis operation of Example 68, compound 117 is synthesized by replacing compound 68-3a with compound 68-3b in step 3 1H NMR (400 MHz, DMSO-d6) 6 8.32 (t, J = 5.6 Hz, 1H), 8.18 (s, HCOOH, 1.27H), 7.60 (d, J = 8.7 Hz, 1H), 7.14 - 7.00 (m, 2H), 5.40 (s, 2H), 3.98 (s, 3H), 3.30 - 3.24 (m, 2H), 3.02(d,J= 11.4 Hz, 2H), 2.58 - 2.51 (m, 4H), 2.48 - 2.43 (m, 4H), 2.31 - 2.26 (m, 1H), 2.25 (s, 3H), 2.08 (t,J= 11.5 Hz, 2H), 1.80 - 1.68 (m, 4H), 1.49 - 1.39 (m, 2H). LCMS m / z = 487.3 [M+H]+.
[310] Example 49
[311] Referring to the synthesis method of compound 68 and compound 117, the following compounds are synthesized by replacing compound 68-1 with ketone fragments and replacing compound 68-5 with amine fragments.___________________ Compound Structure Ketone fragment Amine fragment Spectrum information 69 0 v N 0 IT J 68-5 LCMS: m / z = 487.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 6 8.62 (t, J = 5.5 Hz, 1H), 8.15 (s, 1H, HCOOH), 7.71 (d, J = 7.8 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.08 (t, J = 8.0 Hz, 1H), 5.52 (s, 2H), 4.18 (s, 3H), 3.28 - 3.27 (m, 2H), 3.01 - 2.96 (m, 2H), 2.49 - 2.47 (m, 4H), 2.46 -2.31 (m, 6H), 2.20 (s, 3H), 2.14 (s, 1H), 2.02 - 1.95 (m, 2H), 1.83 - 1.76 (m, 2H), 1.71 - 1.62 (m, 2H), 1.55 - 1.46 (m, 2H). 71 0 -n-yV A° a f Cv 68-5 LCMS m / z = 471.3 [M+H]+. 1H NMR (400 MHz, Chloroform-d) 8 8.26 - 8.07 (m, 1H), 7.45 (dd, J = 8.5, 6.1 Hz, 1H), 6.82 - 6.62 (m, 2H), 5.56 (s, 2H), 4.15 (s, 3H), 3.49 (q,J= 5.8 Hz, 2H), 3.07 - 2.99 (m, 2H), 2.85 - 2.56 (m, 4H), 2.55 - 2.32 (m, 6H), 2.30 (s, 3H), 2.23 - 2.16 (m, 1H), 2.00 - 1.83 (m, 2H), 1.82 - 1.68 (m, 6H). 72 Cl \^N\ 0 ¢0 Cl 68-5 LCMS: m / z = 487.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 8 8.62 (t, J= 5.5 Hz, 1H), 8.15 (s, 1H, HCOOH), 7.71 (d, J = 7.8 Hz, 1H), 7.43 (d,J= 8.1 Hz, 1H), 7.08 (t,J= 8.0 Hz, 1H), 5.52 (s, 2H), 4.18 (s, 3H), 3.28 - 3.27 (m, 2H), 3.01 - 2.96 (m, 2H), 2.49 - 2.47 (m, 4H), 2.46 -2.31 (m, 6H), 2.20 (s, 3H), 2.14 (s, 1H), 2.02 - 1.95 (m, 2H), 1.83 - 1.76 (m, 2H), 1.71 - 1.62 (m, 2H), 1.55 -1.46 (m, 2H). 73 0 ~n;y\ ry0 f ^N\ 0 A F 68-5 LCMS m / z = 471.2 [M+H]+.1H NMR (400 MHz, CDCl3) 8 7.29 (d, J = 8.0 Hz, 1H), 7.10 - 7.02 (m, 1H), 6.98 -6.91 (m, 1H), 5.62 (s, 2H), 4.16 (s, 3H), 3.57 - 3.45 (m, 2H), 3.26 - 3.07 (m, 2H), 2.94 - 2.55 (m, 10H), 2.45 (s, 3H), 2.07 - 1.69 (m, 9H). 76 0 -nV'^ YP Yv, ^N\ 0 Fn5 68-5 LCMS m / z = 471.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 8 8.65 (t,J= 5.5 Hz, 1H), 7.57 (dd, J = 9.3, 3.0 Hz, 1H), 7.13 (td, J = 8.7, 3.0 Hz, 1H), 7.04 (dd, J= 9.0, 4.9 Hz, 1H), 5.38 (s, 2H), 4.19 (s, 3H), 3.29 - 3.26 (m, 2H), 2.93 (d, J = 11.1 Hz, 2H), 2.49 - 2.39 (m, 4H), 2.39 - 2.21 (m, 6H), 2.14 (s, 3H), 2.08 - 2.02 (m, 1H), 1.88 - 1.79 (m, 2H), 1.79 - 1.73 (m, 2H), 1.67 - 1.60 (m, 2H), 1.55 -1.45 (m, 2H) 82 -O'" tu V N ^N\ u vxb 68-5 LCMS: m / z = 478.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 8 8.67 (t, J = 5.7 Hz, 1H), 8.19 (s, HCOOH, 2H), 8.14 (s, 1H), 7.74 (d, J = 8.5 Hz, 1H), 7.16 (d, J = 8.5 Hz, 1H), 5.55 (s, 2H), 4.23 (s, 3H), 3.29 -3.27 (m, 2H), 2.97 (d, J = 11.1 Hz, 2H), 2.43 - 2.30 (m, 6H), 2.19 (s, 3H), 2.16 - 2.04 (m, 1H), 1.97 - 1.86 (m, 2H), 1.84 - 1.70 (m, 2H), 1.70 -1.61 (m, 2H), 1.58 - 1.43 (m, 2H). 84 0 Cl 0 rx^ CI^^^O h2n^^ o 0 ,> LCMS m / z = 501.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 8 8.61 (t,J= 5.5 Hz, 1H), 8.18 (s, HCOOH, 1.6H), 7.74 (d, J = 8.1 Hz, 1H), 7.21 - 7.03 (m, 2H), 5.44 (s, 2H), 4.17 (s, 3H), 3.29 - 3.26 (m, 2H), 2.97 (d,J= 11.2 Hz, 2H), 2.49 - 2.31 (m, 10H), 2.18 - 2.08 (m, 1H), 2.05 - 1.86 (m, 4H), 1.78(d,J= 11.8 Hz, 2H), 1.70 -1.62 (m, 2H), 1.57 - 1.45 (m, 2H), 1.00 (t, J = 7.2 Hz, 3H). 86 Cl k / Nx 0 h2n^^ ■-< Q LCMS m / z= 459.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) 8 8.39 (t, J = 6.0 Hz, 1H), 8.14 (s, 1H), 7.74 (d, J = 8.2 Hz, 1H), 7.17 - 7.10 (m, 2H), 5.45 (s, 2H), 4.15 (s, 3H), 3.94 - 3.87 (m, 2H), 3.62 - 3.57 (m, 2H), 3.27 -3.25 (m, 2H), 3.18 - 3.16 (m, 1H), 2.98 - 2.92 (m, 2H), 2.85 - 2.39 (m, 8H), 2.38 (s, 3H), 1.74 - 1.61 (m, 2H). 87 Cl 0 h2n^ Q / LCMS m / z = 473.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) 8 8.37 (t, J = 5.8 Hz, 1H), 8.18 (s, HCOOH, 2.46H), 7.74 (d, J = 8.1 Hz, 1H), 7.17 - 7.09 (m, 2H), 5.44 (s, 2H), 4.15 (s, 3H), 3.67 (t, J = 7.5 Hz, 2H), 3.29 -3.15 (m, 4H), 3.07 - 2.95 (m, 1H), 2.71 (t, J= 7.1 Hz, 2H), 2.50 - 2.22 (m, 10H), 1.65 - 1.51 (m, 2H), 1.01 (t, J = 7.1 Hz, 3H). 91 0 ryo xy M Mx o xy5 F3C^^^O 68-5 LCMS: m / z = 521.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 8 8.57 (t,J= 5.7 Hz, 1H), 8.15 (s, HCOOH, 2H), 7.94 (d, J = 8.1 Hz, 1H), 7.41 (d, J= 8.1 Hz, 1H), 7.33 (d,J= 1.9 Hz, 1H), 5.51 (s, 2H), 4.21 (s, 3H), 3.29 -3.26 (m, 2H), 3.12 - 3.08 (m, 2H), 2.68 - 2.54 (m, 11H), 2.33 (s, 3H), 2.26 - 2.17 (m, 2H), 1.86 - 1.80 (m, 2H), 1.77 - 1.70 (m, 2H), 1.62 - 1.55 (m, 2H). 92 0 vA ry° xy / -^N'' Br Mx O mA 68-5 LCMS: m / z=531.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 8 8.61 (t, J = 5.5 Hz, 1H), 8.17 (s, 1H), 7.67 (d, J = 8.2 Hz, 1H), 7.28 - 7.24 (m, 2H), 5.44 (s, 2H), 4.16 (s, 3H), 3.29 - 3.26 (m, 2H), 2.97 (d, J = 11.4 Hz, 2H), 2.50 - 2.48 (m, 4H), 2.47 - 2.27 (m, 6H), 2.19 (s, 3H), 2.17 - 2.07 (m, 1H), 1.98 - 1.89 (m, 2H), 1.82 - 1.73 (m, 2H), 1.72 - 1.60 (m, 2H), 1.59 -1.43 (m, 2H) 96 0 Fj S Cl Ox O jCxk 68-5 LCMS: m / z = 503.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 8 8.56 (t,J= 5.5 Hz, 1H), 8.15 (s, HCOOH, 1H), 7.85 (d, J = 8.6 Hz, 1H), 7.61 (d, J=2.2Hz, 1H), 7.39 (dd, J = 8.5, 2.2 Hz, 1H), 4.22 (s, 2H), 4.14 (s, 3H), 3.30 - 3.26 (m, 4H), 3.02 - 2.99 (m, 2H), 2.48 - 2.36 (m, 7H), 2.21 (s, 3H), 2.18 - 2.13 (m, 1H), 2.04 - 1.95 (m, 3H), 1.82 - 1.76 (m, 2H), 1.71 -1.65 (m, 2H), 1.56 - 1.48 (m, 2H). 101 0 b^v0 ^ON Cl Ox m O 68-5 1H NMR (400 MHz, DMSO-d6) 8 8.57 (t,J= 5.6 Hz, 1H), 8.15 (s, 1H), 7.97 (s, 1H), 7.33 (s, 1H), 5.46 (s, 2H), 4.19 (s, 3H), 3.29 - 3.27 (m, 2H), 3.02 - 2.98 (m, 2H), 2.57 - 2.51 (m, 4H), 2.46 - 2.40 (m, 6H), 2.23 (s, 3H), 2.18 - 2.15 (m, 1H), 2.03 - 1.98 (m, 2H), 1.81 - 1.77 (m, 2H), 1.70 -1.66 (m, 2H), 1.55 - 1.49 (m, 2H). LCMS m / z = 565.2 [M+H]+ 102 ' 2 Ov^nh NaJ O y Cl Ox m O 68-5 1H NMR (400 MHz, DMSO-d6) 8 8.36(t,J= 5.7 Hz, 1H), 8.20 (s, 1H), 7.84 (s, 1H), 7.28 (s, 1H), 5.43 (s, 2H), 3.99 (s, 3H), 3.31 - 3.22 (m, 2H), 3.03 (d,J= 11.3 Hz, 2H), 2.59 -2.50 (m, 6H), 2.54 - 2.44 (m, 4H), 2.31 - 2.25 (m, 1H), 2.25 (s, 3H), 2.12 (t,J= 11.6 Hz, 2H), 1.83 - 1.68 (m, 4H), 1.56 - 1.39 (m, 2H). LCMS: m / z= 565.1 / 567.1 [M+H]+ 105 0 -aO 0 y fY Ox F o rO f3co'x^ / ^o^ 68-5 LCMS m / z = 537.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 8 8.58 (t,J= 5.6 Hz, 1H), 8.18 (s, HCOOH, 2.85H), 7.84 (d, J = 8.6 Hz, 1H), 7.12 - 7.01 (m, 2H), 5.48 (s, 2H), 4.18 (s, 3H), 3.33 - 3.25 (m, 2H), 3.02 (d,J= 11.7 Hz, 2H), 2.63 - 2.51 (m, 5H), 2.49 - 2.40 (m, 5H), 2.24 (s, 3H), 2.21 - 2.13 (m, 1H), 2.10 - 1.97 (m, 2H), 1.85 - 1.75 (m, 2H), 1.73 - 1.63 (m, 2H), 1.61 - 1.46 (m, 2H). 106 \ 0 F^° kJ, F o fVb F3CO^^^Xy 68-5 1H NMR (400 MHz, DMSO-d6) 8 8.35 (t, J = 5.6 Hz, 1H), 8.17 (s, HCOOH, 1.13H), 7.70 (d, J = 8.3 Hz, 1H), 7.02 - 6.97 (m, 2H), 5.44 (s, 2H), 3.99 (s, 3H), 3.29 - 3.24 (m, 2H), 3.02 (d, J = 11.4 Hz, 2H), 2.56 -2.51 (m, 4H), 2.49 - 2.41 (m, 6H), 2.28 - 2.24 (m, 1H), 2.23 (s, 3H), 2.12 - 2.04 (m, 2H), 1.79 - 1.70 (m, 4H), 1.50 - 1.41 (m, 2H). LCMS m / z = 537.2 [M+H]+ 97 0 / / Vs ci 0 vA h2n^^ ■s Q LCMS: m / z = 475.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 8 8.35 (t,J= 5.8 Hz, 1H), 8.22 (s, 3H), 7.84 (d, J = 8.5 Hz, 1H), 7.63 - 7.60 (m, 1H), 7.39 (dd, J = 8.5, 2.3 Hz, 1H), 4.21 (s, 2H), 4.13 (s, 3H), 3.49 - 3.45 (m, 2H), 3.31 - 3.16 (m, 4H), 2.95 -2.82 (m, 4H), 2.39 - 2.18 (m, 7H), 2.16 (s, 3H), 1.57 - 1.48 (m, 2H). 98 0 -xVr ry° ci ^o 0 ,cO H2N—\ \ f? o o LCMS m / z = 446.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) 8 8.43 - 8.32 (m, 1H), 8.20 (s, HCOOH, 0.72H), 7.80 - 7.67 (m, 1H), 7.18 - 7.08 (m, 2H), 5.44 (s, 2H), 4.15 (s, 3H), 3.58 -3.55 (m, 4H), 3.24 - 2.95 (m, 7H), 2.68 - 2.60 (m, 2H), 2.27 - 2.20 (m, 4H), 1.59 - 1.51 (m, 2H). 103 0 -VV fy° V Cl 0 ,cO H2N^ s Q r LCMS: m / z = 487.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 8 8.38 (t,J= 5.9 Hz, 1H), 8.15 (s, HCOOH, 0.77H), 7.74 (d, J = 8.2 Hz, 1H), 7.21 - 7.09 (m, 2H), 5.44 (s, 2H), 4.15 (s, 3H), 3.85 (t, J = 8.3 Hz, 2H), 3.55 -3.45 (m,2H), 3.25 (q,J=6.4Hz,2H), 3.20 - 3.10 (m, 2H), 3.01 - 2.92 (m, 1H), 2.93 - 2.84 (m, 2H), 2.79 - 2.70 (m, 4H), 2.52 - 2.41 (m, 2H), 1.66 (p, J = 6.9 Hz, 2H), 1.39-1.31 (m, 1H), 1.09 (d, J= 6.5 Hz, 6H). 104 0 / / V° ci Ly OH 0 oxX h2n^ "7 HO LCMS: m / z = 446.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 8 8.38 (t,J=5.9Hz, 1H), 8.15 (s, HCOOH, 0.5H), 7.74 (d,J= 8.2 Hz, 1H), 7.17 - 7.11 (m, 2H), 5.45 (s, 2H), 4.24 -4.20 (m, 1H), 4.15 (s, 3H), 3.84 (t, J = 8.3 Hz, 2H), 3.59 - 3.54 (m, 2H), 3.36 - 3.32 (m, 2H), 3.26 - 3.23 (m, 2H), 2.90 (t, J = 7.3 Hz, 2H), 2.78 -2.73 (m, 1H), 2.66 - 2.60 (m, 1H), 2.55 - 2.52 (m, 1H), 2.40 - 2.34 (m, 1H), 2.00 - 1.95 (m, 1H), 1.67 - 1.56 (m, 3H). 107 0 F fV° ^N\ F o / VS FaCO'^^O^ 4 0 LCMS m / z = 509.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 8 8.37 (t,J=5.8Hz, 1H), 8.20 (s, 1H), 7.84 (d, J= 8.5 Hz, 1H), 7.11 - 7.05 (m, 1H), 7.05 - 7.02 (m, 1H), 5.48 (s, 2H), 4.17 (s, 3H), 3.51 - 3.47 (m, 2H), 3.25 - 3.20 (m, 2H), 2.94 - 2.86 (m, 3H), 2.57 - 2.51 (m, 2H), 2.44 -2.19 (m, 8H), 2.17 (s, 3H), 1.58 -1.48 (m, 2H). 108 \ ° fV° \ F O yyb Faco^'^ry h2n^^ o LCMS m / z = 509.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) 8 8.49 - 8.39 (m, 1H), 7.76 - 7.62 (m, 1H), 7.06 -6.91 (m, 2H), 5.47 (s, 2H), 4.00 (s, 3H), 3.86 - 3.72 (m, 2H), 3.51 - 3.39 (m, 2H), 3.32 - 3.23 (m, 2H), 3.16 -3.07 (m, 2H), 2.95 - 2.82 (m, 3H), 2.61 - 2.53 (m, 2H), 2.43 - 2.29 (m, 7H), 1.74 - 1.62 (m, 2H). 109 0 -as y V Cl 0 oxX H2N^ Q / LCMS m / z = 489.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 8 8.37 (t,J=5.9Hz, 1H), 8.18 (s, 1H), 7.84 (d,J=8.5Hz, 1H), 7.61 (s, 1H), 7.39 (d,J=8.4Hz, 1H), 4.21 (s, 2H), 4.13 (s, 3H), 3.60 - 3.59 (m, 4H), 3.27 -3.22 (m, 2H), 3.12 - 3.06 (m, 2H), 3.01 - 2.95 (m, 1H), 2.65 (t, J = 7.0 Hz, 2H), 2.46 - 2.25 (m, 8H), 1.62 -1.54 (m, 2H), 0.99 (t, J = 7.1 Hz, 3H). 118 Cl k / N\ 0 oxX h2n^ 0 1H NMR (400 MHz, DMSO-d6) 8 8.33 (t, J = 5.6 Hz, 1H), 8.24 (s, HCOOH, 1H), 7.65 - 7.57 (m, 1H), 7.10 - 7.02 (m, 2H), 5.41 (s, 2H), 3.98 (s, 3H), 3.62 - 3.50 (m, 2H), 3.27 - 3.22 (m, 2H), 3.07 - 3.61 (m, 6H), 2.50 - 1.96 (m, 10H), 1.58 -1.54 (m, 2H). LCMS m / z = 459.2 [M+H]+
[312] Example 50 (200 mg, 0.59 mmol, 1.0 eq) and
[313] In step 1: Br 1-Methylpyrazole-4-boronic acid pinacol ester (370 mg, 1.78 mmol, 3.0 eq) are mixed in Dioxane (4 mL) and water (1 mL). Pd(dppf)2Cl2 (45 mg, 0.059 mmol, 0.1 eq) and potassium carbonate (244.6 mg, 1.78 mmol, 3.0 eq) are added. The reaction mixture is purged with nitrogen three times and stirred at 90°C under a nitrogen atmosphere for 2 h. After reaction, the reaction mixture is diluted with water (50 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic phases are washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The resulting crude product is purified by silica gel column chromatography to obtain compound 95-1 (190 mg, 94.6%) as a yellow solid. LCMS m / z = 339.1 [M+H]+
[314] In step 2: Referring to the synthesis method of Example 68, compound 95 is synthesized by replacing compound 68-3a with compound 95-1.LCMS m / z = 533.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 5 8.45 (t, J = 5.8 Hz, 1H), 8.20 (s, 1H), 8.15 (s, HCOOH, 3.5H), 7.92 (s, 1H), 7.69 (d, J = 8.1 Hz, 1H), 7.28 (dd, J = 8.0, 1.8 Hz, 1H), 7.24 (d, J = 1.8 Hz, 1H), 5.41 (s, 2H), 4.16 (s, 3H), 3.86 (s, 3H), 3.30-3.26 (m, 2H), 3.18 -3.15 (m, 2H), 2.73-2.60 (m, 10H), 2.40 (s, 3H), 2.38-2.31 (m, 3H), 1.89 - 1.76 (m, 4H), 1.66 - 1.54 (m, 2H).
[315] Example 51
[316] Referring to the synthesis method of Example 95, the following compounds \ n—. are synthesized by replacing °"S with boronic acids or borates, replacing fragments. with bromo fragments, and replacing compound 68-5 with amine Compound Structure Boronic acid or borate Bromo fragment Amine fragment Spectrum information 93 Fj 0 4 ^N\ OH b' OH k Br 68-5 LCMS m / z = 493.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 8.60-8.46 (m, 1H), 8.20 (s, HCOOH, 3.23H), 7.59-7.56 (m, 1H), 6.81-6.70 (m, 2H), 5.35 (s, 3H), 4.13 (s, 2H), 3.29 - 3.25 (m, 4H), 3.01 -2.96 (m, 4H), 2.47 - 2.39 (m, 4H), 2.22 - 2.21 (m, 4H), 1.99 - 1.97 (m, 2H), 1.93 - 1.87 (m, 1H), 1.81 - 1.76 (m, 4H), 1.68 -1.66 (m, 2H), 1.57 - 1.47 (m, 2H), 0.97 - 0.95 (m, 2H), 0.70 - 0.68 (m, 2H). 116 Fj 0 k / X OH —BZ OH ■ Br 68-5 1H NMR (400 MHz, DMSO-d6) 5 8.30 (t, J = 5.6 Hz, 1H), 8.17 (s, 1H), 7.48 (d, J = 7.7 Hz, 1H), 6.82 (dd,J= 7.8, 1.6 Hz, 1H), 6.78 (d, J = 1.5 Hz, 1H), 5.32 (s, 2H), 3.96 (s, 3H), 3.29-3.23 (m, 2H), 3.09(d,J= 11.5 Hz, 2H), 2.64 - 2.52 (m, 10H), 2.37 - 2.19 (m, 6H), 1.83 - 1.72 (m, 4H), 1.55 -1.46 (m, 2H). LCMS m / z = 467.3 [M+H]+ 115 k / Y OH —BZ OH ■ Br H2N^^ t( Q 1H NMR (400 MHz, DMSO-d6) 8 8.33 (t, J = 5.5 Hz, 1H), 8.23 (s, HCOOH, 1H), 7.48 (d, J =7.7 Hz, 1H), 6.82 (d,J = 7.8 Hz, 1H), 6.78 (s, 1H), 5.33 (s, 2H), 3.97 (s, 3H), 3.63 (t, J = 7.4 Hz, 2H), 3.27 - 3.13 (m, 4H), 3.06 - 2.90 (m, 2H), 2.70 (t, J = 7.1 Hz, 2H), 2.46 - 2.28 (m, 7H), 2.26 (s, 3H), 2.22 (s, 3H), 1.68 -1.52 (m, 2H). LCMS m / z = 439.2 [M+H]+ 120 kjk° C^k pH —B OH # Br 68-5 LCMS: m / z = 467.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 8 8.52 (t, J = 5.7 Hz, 1H), 8.19 (s, HCOOH, 2.75H), 7.61 (d,J=7.9 Hz, 1H), 6.91 - 6.80 (m, 2H), 5.36 (s, 2H), 4.14 (s, 3H), 3.32 -3.25 (m, 3H), 3.04 - 2.96 (m, 3H), 2.59 - 2.52 (m, 2H), 2.48 - 2.41 (m, 5H), 2.29 (s, 3H), 2.23 (s, 3H), 2.20-2.14 (m, 1H), 2.06 - 1.95 (m, 3H), 1.82 -1.76 (m, 2H), 1.73 - 1.65 (m, 2H), 1.61 - 1.50 (m, 2H). 121 OH —BZ OH -n^Y^oe* > Br H2N^^ t( Q LCMS: m / z= 439.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6)8 8.31 (t,J=5.8Hz, 1H), 8.20 (s, HCOOH, 3H), 7.60 (d,J=7.9Hz, 1H), 6.94 - 6.81 (m, 2H), 5.36 (s, 2H), 4.13 (s, 3H), 3.57 -3.52 (m, 2H), 3.28 - 3.18 (m, 2H), 3.00 - 2.90 (m, 3H), 2.57 (t,J=7.0Hz, 2H), 2.43 - 2.31 (m, 4H), 2.29 - 2.19 (m, 5H), 2.18 (s, 3H), 2.04 - 1.94 (m, 1H), 1.62 - 1.48 (m, 2H). 123 \ U n nT t Fy0 ''^ rS F^F. hn.^ / " ' HN—, NU< ,0 / ? yc °~A ■ Br 68-5 1H NMR (400 MHz, DMSO-d6) 8 9.72 (s, 1H), 8.39 (t, J = 5.8 Hz, 1H), 8.10 - 8.01 (m, 2H), 7.57 (d, J = 7.9 Hz, 1H), 7.28 (d, J = 7.9 Hz, 1H), 7.22 (s, 1H), 5.38 (s, 2H), 3.99 (s, 3H), 3.33 - 3.29 (m, 4H), 3.12 - 2.86 (m, 10H), 2.77 (s, 3H), 2.70 -2.51 (m, 3H), 2.02 - 1.62 (m, 6H). LCMS m / z = 519.4 [M+H]+ 127 fyV A0 XT 0^ ™-N HN—, NU< ,0 / ? yc °~A -n^Y^oei > Br 68-5 LCMS m / z = 519.4 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 8 8.52 - 8.42 (m, 1H), 8.25 (s, HCOOH, 2.94H), 8.12 (s, 2H), 7.67 (d, J = 8.0 Hz, 1H), 7.36-7.27 (m, 2H), 5.40 (s, 2H), 4.16 (s, 3H), 3.27 (q, J = 6.2 Hz, 2H), 3.11 (d,J= 11.2 Hz, 2H), 2.70 - 2.51 (m, 10H), 2.35 (s, 3H), 2.31 - 2.20 (m, 3H), 1.85 - 1.70 (m, 4H), 1.63 - 1.51 (m, 2H). 133 0 Q zN~N < 1 ,o / 6- / - / y^OEt y Br H2N^ \ 0 Q ) LCMS m / z = 547.4 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 8 8.55 - 8.45 (m, 1H), 8.20 (s, 1H), 8.15 (s, HCOOH, 2.02H), 7.91 (s, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.27 (d, J = 8.1 Hz, 1H), 7.24 (s, 1H), 5.40 (s, 2H), 4.17 (s, 3H), 3.86 (s, 3H), 3.29 - 3.27 (m, 2H), 3.08 -3.04 (m, 2H), 2.65 - 2.52 (m, 10H), 2.49 - 2.45 (m, 2H), 2.29 - 2.22 (m, 1H), 2.18 - 2.06 (m, 2H), 1.86 - 1.79 (m, 2H), 1.75 -1.67 (m, 2H), 1.61 - 1.50 (m, 2H), 1.04 (t, J = 7.2 Hz, 3H).
[317] Example 52
[318] In step 1: Under a nitrogen atmosphere, (300 mg, 0.89 mmol, 1.0 eq) is dissolved in DMF (10 mL). Zn(CN)2 (209 mg, 1.78 mmol, 2.0 eq) and tetrakis(triphenylphosphine) palladium(0) (Pd(PPh3)4, 205.6 mg, 0.178 mmol, 0.2 eq) are added to the reaction mixture. The reaction mixture is purged with nitrogen three times and stirred at 130°C under a nitrogen atmosphere for 2 h. After reaction, the reaction mixture is filtered. The filtrate is diluted with water (100 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The crude product is purified by silica gel column chromatography (eluent: ethyl acetate: petroleum ether = 1:1) to obtain a yellow solid compound 94-1 (140 mg, 55%). LCMS: m / z = 284.1 [M+H]+
[319] In step 2: Referring to the synthesis method of Example 68, compound 94 is synthesized by replacing compound 68-3a with compound 94-1. LCMS: m / z = 478.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 8 8.69 (t, J = 5.4 Hz, 1H), 8.20 (s, 2H), 7.90 (d, J = 8.1 Hz, 1H), 7.57 - 7.46 (m, 2H), 5.50 (s, 2H), 4.21 (s, 3H), 3.28 (q, J = 6.2 Hz, 2H), 2.96 (d, J = 11.2 Hz, 2H), 2.50 - 2.46 (m, 4H), 2.43 - 2.30 (m, 6H), 2.17 (s, 3H), 2.14 - 2.07 (m, 1H), 1.94 - 1.85 (m, 2H), 1.80 - 1.74 (m, 2H), 1.69 - 1.61 (m, 2H), 1.55 - 1.45 (m, 2H).
[320] Example 53
[321] Referring to the synthesis method of Example 30, compound 75 is synthesized by replacing compound 1-4 with compound 7-2. LCMS m / z = 501.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 8 8.75 - 8.63 (s, 1H), 8.04(t,J=7.8Hz, 2H), 7.90(t,J=7.8Hz, 1H), 7.73 (t,J=7.7Hz, 1H), 4.92 (s, 2H), 4.29 (s, 3H), 3.24 - 3.18 (m, 2H), 3.15 - 3.07 (m, 2H), 3.06 - 2.82 (m, 2H), 2.77 - 2.51 (m, 10H), 2.32 (s, 3H), 2.04 - 1.94 (m, 1H), 1.90 - 1.80 (m, 2H), 1.79 - 1.67 (m, 2H), 1.62 - 1.46 (m, 2H).
[322] Example 54
[323] Compound 41 (0.13 g, 0.25 mmol), 3-bromopropionitrile (0.12 g, 0.88 mmol), and potassium carbonate (0.17 g, 1.25 mmol) are added to acetonitrile (2 mL). The reaction mixture is stirred at room temperature overnight. LCMS shows that the reaction is complete. The mixture is extracted, concentrated, and purified by preparative TLC to obtain compound 79 (0.03 g, yield: 23.98%). 1H NMR(400 MHz, DMSO-d6) 5 8.55 (t,J = 5.6 Hz, 1H), 7.84 (dd,J = 7.6, 1.6 Hz, 1H), 7.50 (dd,J = 7.5, 1.6 Hz, 1H), 7.32 (dtd,J = 17.0, 7.5, 1.5 Hz, 2H), 4.18 (s, 2H), 4.15 (s, 3H), 3.26 (m, 6H), 2.97 (m, 2H), 2.64 (t,J = 6.7 Hz, 2H), 2.52 (m, 3H), 2.39 (m, 4H), 2.14 (dd,J = 13.3, 5.6 Hz, 1H), 2.05 - 1.87 (m, 2H), 1.79 (d,J = 11.3 Hz, 2H), 1.72 - 1.63 (m, 2H), 1.59 - 1.44 (m, 2H), 1.27 (d,J = 16.0 Hz, 1H). LCMS m / z [M+H]+= 508.3.
[324] Example 55
[325] Referring to the synthesis method of Example 94, the following compounds o -O'” O'0 are synthesized by replacing Br with bromo fragments and replacing o j? hnO^0E‘ oh J? J) DJr° compound 68-5 with amine fragments. Fragments ci and F f are prepared by referring to the synthetic method of intermediate 83-2. Compound Structure Bromo fragment Amine fragment Spectrum information 113 Cl Ox x-O Cl 68-5 LCMS m / z = 512.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) 5 8.68 (t,J=5.5 Hz, 1H), 8.23 (s, 1H), 8.17 (s, 1H), 7.41 (s, 1H), 5.60 (s, 2H), 4.22 (s, 3H), 3.29 -3.26 (m, 2H), 3.01 - 2.97 (m, 2H), 2.59 - 2.49 (m, 4H), 2.47 -2.38 (m, 6H), 2.21 (s, 3H), 2.18 - 2.10 (m, 1H), 1.99 - 1.93 (m, 2H), 1.82 - 1.77 (m, 2H), 1.69 -1.64 (m, 2H), 1.57 - 1.48 (m, 2H). 119 fYo Cl k / k 0 ^k^00 BrX° Cl H2N^ t( Q 1H NMR (400 MHz, DMSO-d6) 8 8.42 (t, J = 5.8 Hz, 1H), 8.22 (s, 1H), 8.17 (s, HCOOH, 2.18H), 7.42 (s, 1H), 5.60 (s, 2H), 4.20 (s, 3H), 3.27 - 3.19 (m, 2H), 3.02 - 2.90 (m, 3H), 2.59 (t, J = 7.0 Hz, 2H), 2.42 -2.14 (m, 11H), 2.02 - 1.95 (m, 2H), 1.57 - 1.51 (m, 2H). LCMS m / z = 484.2 [M+H]+ 122 \ J jkro n^ I 1 / N Cl ^k \ 5 N0fOEt DXr° Cl 68-5 1H NMR (400 MHz, DMSO-d6) 8 8.44 (t, J = 5.7 Hz, 1H), 8.18 (s, HCOOH, 1.57H), 8.04 (s, 1H), 7.37 (s, 1H), 5.59 (s, 2H), 4.00 (s, 3H), 3.30 - 3.25 (m, 2H), 3.12 (d, J = 11.6 Hz, 2H), 2.63 - 2.58 (m, 9H), 2.38 - 2.28 (m, 7H), 1.84 - 1.77 (m, 4H), 1.59 - 1.52 (m, 2H). LCMS: m / z = 512.2 [M+H]+ 128 0 ^kV / kX0 N^\k I i Cl kA HN^k'OEl .k Cl 68-5 LCMS m / z = 498.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 8 8.48 (t,J=5.8 Hz, 1H), 8.15 (s, HCOOH, 1.26H), 8.10 (s, 1H), 7.36 (s, 1H), 5.69 (s, 2H), 3.29 -3.24 (m, 2H), 3.11 (d, J = 11.6 Hz, 2H), 2.68 - 2.55 (m, 10H), 2.38 - 2.22 (m, 6H), 1.84 - 1.72 (m, 4H), 1.58 - 1.49 (m, 2H). 129 0 ^kr j / V0 I 1 / x Cl kL o nN^k00 ry° Br'\k Cl H2N^ \ 0 o ) LCMS m / z = 512.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 8 8.57 - 8.51 (m, 1H), 8.13 (s, overlapped with HCOOH, 1H), 7.36 (s, 1H), 5.69 (s, 2H), 3.29 -3.24 (m, 2H), 2.97 - 2.55 (m, 15H), 1.89 - 1.78 (m, 4H), 1.70 - 1.60 (m, 2H), 1.55 - 1.38 (m, 2H), 1.12(d,J=7.1 Hz, 3H). 130 o J / V0 N^\==X [ 1 / N > o hiAA® fV0 Br'X^ / F F F 68-5 LCMS: m / z = 532.25 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 8 8.48 (t, J = 5.8 Hz, 1H), 8.25 (s, 1H), 8.19 (s, HCOOH, 3.19H), 7.50 (s, 1H), 5.75 (s, 2H), 3.28 - 3.25 (m, 2H), 2.97 (d, J =11.3 Hz, 2H), 2.45 - 2.33 (m, 7H), 2.26 - 2.14 (m, 5H), 2.05 - 1.92 (m, 4H), 1.76 - 1.66 (m, 4H), 1.48 - 1.40 (m, 2H) 131 o “Cx^r J / V ° F"A k / N. F F O nKX / 1'00 -Jr0 Br'X^ / F F F H2N^ Q LCMS m / z = 504.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 8 8.51 - 8.45 (m, 1H), 8.24 (s, 1H), 8.20 (s, HCOOH, 1.57H), 7.50 (s, 1H), 5.75 (s, 2H), 3.54 -3.45 (m, 2H), 3.32 - 3.19 (m, 2H), 2.98 - 2.88 (m, 4H), 2.60 -2.53 (m, 2H), 2.36 - 2.21 (m, 7H), 2.17 (s, 3H), 1.62 - 1.51 (m, 2H). 132 O hn:v\ £V° I 1 / x A N | VF O nKX / 1'00 -Jr0 Br'X^ / F F F h2n^^ o n ^N ) LCMS m / z = 546.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 8 8.52 (t,J=5.6 Hz, 1H), 8.29 (s, 1H), 8.19 (s, HCOOH, 1.29H), 7.49 (s, 1H), 5.75 (s, 2H), 3.30 -3.24 (m, 2H), 3.03 (d, J = 11.2 Hz, 2H), 2.65 - 2.53 (m, 7H), 2.49 - 2.44 (m, 5H), 2.34 - 2.25 (m, 1H), 2.10 (t, J = 11.6 Hz, 2H), 1.82 - 1.75 (m, 2H), 1.75 -1.67 (m, 2H), 1.56 - 1.43 (m, 2H), 1.03 (t,J=7.2Hz,3H).
[326] Example 56
[327] In step 1: Compound 1-2 (6.0 g, 22.7 mmol, 1.0 eq) is dissolved in EtOH (60 mL). Hydrazine hydrate (1.42 g, 22.7 mmol, 1.0 eq) is added to the solution. The reaction mixture is stirred at room temperature overnight. After reaction, the reaction mixture is concentrated. The crude product is purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 8:1) to obtain compound 83-1 (4.45 g, 75.39%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) S 14.06 (s, 1H), 7.87 - 7.71 (m, 1H), 7.43 - 7.32 (m, 1H), 7.28 - 7.21 (m, 2H), 4.38 - 4.27 (m, 2H), 4.27-4.21 (m, 2H), 1.36- 1.29 (m, 3H). LCMS m / z = 261.1 [M+H]+.
[328] In step 2: Referring to the synthesis method of Example 14, compound 83 is synthesized by replacing compound 14-1 with compound 83-1 and replacing compound 7-3 with compound 68-5.1H NMR (400 MHz, DMSO-d6) S 8.41 - 8.37 (m, 1H), 7.73 - 7.69 (m, 1H), 7.37 - 7.35 (m, 1H), 7.25 - 7.23 (m, 2H), 4.24 (s, 2H), 3.25 - 3.21 (m, 2H), 2.78 - 2.66 (m, 10H), 2.64 - 2.62 (m, 2H), 2.46 - 2.43 (m, 1H), 2.40 (s, 3H), 1.97 - 1.93 (m, 2H), 1.85 - 1.79 (m, 4H), 1.62 - 1.52 (m, 2H). LCMS m / z =455.2 [M+H]+.
[329] Example 57
[330] In step 1: Compound 83-1 (2.0 g, 7.69 mmol) is dissolved in DMF (30 mL). Cesium carbonate (3.76 g, 11.53 mmol) and 3-iodooxetane (1.7 g, 9.23 mmol) are added to the reaction mixture. The reaction mixture is stirred at 110°C for 1 h. After reaction, the reaction mixture is diluted with water (200 mL) and extracted with ethyl acetate (3 x 80 mL). The combined organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The resulting crude product is purified by silica gel column chromatography (petroleum ether: ethyl acetate = 8:1) to obtain a yellow solid compound 88-1a (170 mg, 2.88 %) and a yellow solid compound 88-1b (1.3 g, 53.43%). 1H NMR (400 MHz, DMSO-d6) S 7.55 - 7.52 (m, 1H), 7.50 - 7.47 (m, 1H), 7.36 - 7.32 (m, 2H), 6.01 - 5.92 (m, 1H), 5.03 - 4.97 (m, 4H), 4.35 (q,J=7.1 Hz, 2H), 4.14 (s, 2H), 1.33 (d,J=7.1 Hz, 3H). LCMS m / z = 317.1 [M+H]+.
[331] In step 2: Compound 88-1a (63 mg, 0.199 mmol, 1.0 eq) is dissolved in a mixture of MeOH (1 mL) and THF (1 mL). A NaOH solution (NaOH (25.32 mg, 0.633 mmol, 2.0 eq) dissolved in H2O (1 mL)) is slowly added. The reaction mixture is stirred at 60°C for 2 h. After reaction, the pH of the reaction mixture is adjusted to 3-4 with 2N HCl solution, and the mixture is extracted with DCM (3 x 20 mL). The combined organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain a yellow solid compound 88-2a (57 mg, 100%). LCMS m / z = 289.0 [M+H]+.
[332] In step 3: Compound 88-2a (57 mg, 0.198 mmol), HATU (112.93 mg, 0.297 mmol), and DIPEA (76.77 mg, 0.594 mmol) are dissolved in DMF (2 mL). The reaction mixture is stirred at room temperature for 0.5 h. Compound 68-5 (118.82 mg, 0.494 mmol) is added to the reaction mixture. The reaction mixture is stirred at room temperature overnight. After reaction, the reaction mixture is diluted with water (40 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic phases are dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The resulting crude product is purified by preparative column chromatography to obtain compound 88 (20.6 mg, 20.4%). 1H NMR (400 MHz, DMSO-d6) 5 8.46 (t, J = 6.1 Hz, 1H), 8.17 (s, 1H), 7.53 - 7.44 (m, 2H), 7.35 - 7.30 (m, 2H), 5.99 - 5.88 (m, 1H), 5.12 - 5.01 (m, 4H), 4.17 (s, 2H), 3.33 - 3.31 (m, 2H), 3.23 - 3.19 (m, 2H), 2.75 - 2.63 (m, 10H), 2.47 - 2.32 (m, 7H), 2.11 - 1.94 (m, 1H), 1.92 - 1.84 (m, 4H), 1.72 - 1.64 (m, 2H). LCMS m / z = 511.2 [M+H]+.
[333] Referring to the synthesis method of Example 88, compound 89 is synthesized by replacing compound 88-1a with compound 88-1b. 1H NMR (400 MHz, DMSO-d6) 5 8.51 - 8.41 (m, 1H), 8.22 (s, HCOOH, 1H), 7.98 - 7.83 (m, 1H), 7.43 - 7.19 (m, 3H), 5.88 - 5.73 (m, 1H), 5.05 - 4.83 (m, 4H), 4.09 (s, 2H), 3.32 -3.10 (m, 2H), 3.04 - 2.90 (m, 2H), 2.72 - 2.58 (m, 1H), 2.41 - 2.28 (m, 10H), 2.17 (s, 3H), 2.04 - 1.89 (m, 2H), 1.80 - 1.66 (m, 4H), 1.48 - 1.33 (m, 2H). LCMS m / z = 511.2 [M+H]+.
[334] Example 58
[335] Referring to the synthesis method of Example 88, compound 90 is synthesized by replacing 3-iodooxetane with 1-chloro-2-methyl-2-propanol. 1H NMR (400 MHz, DMSO-d6) 5 8.33 (t, J = 6.2 Hz, 1H), 8.23 (dd, J = 7.6, 1.6 Hz, 1H), 7.51 (dd, J = 7.4, 1.6 Hz, 1H), 7.35 - 7.26 (m, 2H), 4.92 (s, 1H), 4.30 (s, 2H), 4.16 (s, 2H), 3.33 -3.28 (m, 2H), 3.17-2.54 (m, 16H), 1.90 - 1.72 (m , 6H), 1.19 (s, 6H). LCMS: m / z= 527.3 [M+H] +.
[336] Example 59
[337] Referring to the synthesis method of Example 83, the following compounds are synthesized by replacing compound 1-2 with ci o o and replacing compound 68-5 with appropriate amine fragments. Compound Structure Amine fragment Spectrum information 125 hn-W ci o. 68-5 LCMS: m / z = 473.3 [M+H] +; 1H NMR (400 MHz, DMSO-d6) 5 8.46 (t,J= 5.8 Hz, 1H), 8.19 (s, HCOOH, 1.34H), 7.64 (d, J= 8.2 Hz, 1H), 7.16 - 6.99 (m, 2H), 5.52 (s, 2H), 3.27 (q,J=6.5 Hz, 2H), 3.13 (d,J= 11.6 Hz, 2H), 2.67 - 2.57 (m, 10H), 2.41 - 2.24 (m, 6H), 1.91 - 1.70 (m, 4H), 1.65 - 1.52 (m, 2H). 126 Cl H2N^ q LCMS m / z = 445.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 5 8.46 (t,J= 5.9 Hz, 1H), 8.20 (s, HCOOH, 2.08H), 7.66 (d,J= 8.2 Hz, 1H), 7.12 (dd, J= 8.2, 2.1 Hz, 1H), 7.07 (d,J= 2.0 Hz, 1H), 5.55 (s, 2H), 3.76 -3.73 (m, 2H), 3.34 - 3.22 (m, 5H), 3.09 - 3.05 (m, 1H), 2.80 (t, J = 7.3 Hz, 2H), 2.51 - 2.30 (m, 7H), 2.28 (s, 3H), 1.68 - 1.60 (m, 2H).
[338] Example 60 z-VA 0Et fl
[339] In step 1: (300 mg, 0.89 mmol, 1.0 eq), 1,2,3-triazole (74 mg, 1.07 mmol, 1.2 eq), and K3PO4 (380 mg, 1.78 mmol, 2.0 eq) are mixed in toluene (5 mL). 4MetBuXPhos (85 mg, 0.18 mmol, 0.2 eq) and Pd2(dba)3 (80 mg, 0.09 mmol, 0.1 eq) are added to the mixture. The reaction mixture is purged with nitrogen three times and stirred at 120°C under a nitrogen atmosphere for 5 h. After reaction, the reaction mixture is quenched with water (50 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic phases are washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The crude product is purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 5:1) to obtain a white solid compound 124-1 (100 mg, 34.6 %). LCMS m / z = 326.1 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 5 8.13 (s, 2H), 7.77 (d, J =8.3 Hz, 1H), 7.68 (dd, J =8.4, 2.1Hz, 1H), 7.55-7.50 (m, 1H), 5.51 (s, 2H), 4.31 (q,J=7.1 Hz, 2H), 4.14 (s, 3H), 1.33 (t,J=7.0Hz, 3H).
[340] In step 2: Referring to the synthesis method of Example 95, compound 124 is synthesized by replacing compound 95-1 with compound 124-1.LCMS m / z = 520.4 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 5 8.34 (t,J= 5.6 Hz, 1H), 8.13 (s, 2H), 7.78 (d,J= 8.3 Hz, 1H), 7.69 (dd,J= 8.3, 2.1 Hz, 1H), 7.56 (d,J=2.0Hz, 1H), 5.46 (s, 2H), 4.00 (s, 3H), 3.30 - 3.36 (m, 2H), 3.00 (d, J = 11.2 Hz, 2H), 2.55 - 2.51 (m, 4H), 2.48 - 2.32 (m, 6H), 2.28 - 2.22 (m, 1H), 2.20 (s, 3H), 2.06 - 1.97 (m, 2H), 1.78 -1.68 (m, 4H), 1.48 - 1.39 (m, 2H).
[341] Effect Example
[342] Cell IC50 Assay
[343] (1) Cell Preparation: Hepatoma cells (PLC / PRF / 5, sourced from the Chinese Academy of Sciences; MHCC97H, sourced from this research institute) in good growth condition are prepared. The cells are trypsinized, diluted, and seeded into 96-well cell culture plates. 1,000-3,000 cells are added per well. The plates are then placed in a cell culture incubator at 37°C with 5% CO2. Drugs are added after the cells have adhered for 24 h.
[344] (2) Drug Addition: The drugs are subjected to gradient dilution, typically setting 9 concentrations. Control groups containing no drug medium and medium containing only the drug solvent are also set up. The diluted drugs are added to the cell culture plates seeded the previous day. The plates are incubated for 72 h.
[345] (3) CCK8 Assay for Cell Viability: CCK8 is mixed with culture medium at a 1:10 ratio. 100 pL of this mixture is added to each well of the cell culture plate. After incubating for 2-4 h, the OD values are measured using a microplate reader.
[346] (4) Data Analysis: Based on the corresponding OD values, the data are compiled, IC50 curves are plotted, and the IC50 values are obtained.
[347] (5) IC50 Verification: The theoretical IC50 value is identified from the IC50 curve. Drug concentrations at 1 / 2 times, 1 time, and 2 times this theoretical value are used for verification. Compound Structure IC50 value of cell viability (^M) PLC / PRF / 5 KSR2 OE (PLC cells overexpressing KSR2) MHCC97H KSR2 OE (97H cells overexpressing KSR2) 1 0 F 45 41 17 9 0 Z— / o= / 9b 21 57 2 0)^ / \ 9=0 ^-2 __ / I 0 0 84 >100 16 99 O \ ^= O ^2 J I >—2 Z 0 26 46 6 99 / =° ^2 __ / I 0 42 70 4 99 \ / =° ^-2 __ / I r—2 — / 22 15 3 / =o / —z __ / z 0 d 32 56 10 0 d? V Jd 16 38 13 OO 0=0 P 1 o 2 2 11 v^O ° zz > 0 35 62 14 0 y—Z z^7 Z^^ O==d 39 14 15 <\ 0 V / Y^nh fys ^N0 10 39 5 00 ~~~~\ / =° / —z __ / z / —z z-^ V 25 44 7 0 'N0r Ov^o 00 ° ' ^ 'Q 85 88 12 \ / = o z __ / \ 0 0 56 86 18 90 \ )=° / —z __ / z 0 8 0 42 40 19 90 tn^y \ / =O / —z __ / z 0 0 40 40 8 \ n N0\ 0 0 / S 0 / N'^\] 61 62 22 00’ )=° ^z __ / z _0 {jT- 15 30 21 0 '"0^0 00s Tl^i 7 6 20 0 o\ fys N 29 32 23 / / < / > \ / =o 8 8 25 0 20 37 26 0 ^N P) A 14 >100 27 Qp X A^0 P^ — o 31 13 24 0 ~n?C^ fys kzN^.CI u 18 39 28 QP / =° / —■Z. __ / X 0 / 0 11 31 29 0 -N^Z1^ 0pS 0-N\z^, UL ^N 41 2 30 Qy p=o ^-2 __ / X p 0 / 9 6 31 0 -Op Py s Pp 21 19 32 Op ^o ^2 __ / X ^-2 op— / X / 17 16 33 0 -Op Jo rF P a^ k / N\ 19 18 34 Qp / ^° / —2 / X p’’ 0 12 14 35 0 .0 / 2-^ o=( VP 28 22 36 o 0e I / ’Z.—' y 62 71 37 0 OS T ry® n \ F F 19 28 38 04 ^^y \ ^o / —z ___ / ZE p 3 4 39 0 _n-n*Onh Op rys ' -VJ / / 40 p Jj X / z—J 0=0 \ / co PO 21 >100 41 0 / Tys Onh 8 7 42 04 A—Z ___ / IE p 0 43 39 43 04 ^^y \ )=° p 1 o^Zz^ 41 43 44 0 2 0.2 45 0 1 5 6 46 0 -n^r / ^VS nQ^ OH 2 6 47 04 cn^ / \ / ° 0 1 ^Z 2 4 48 0 'O\ ^^OH 5 5 49 0 -00^0^ dP Q 0 7 7 50 0 ~Or d? ^Nx 7 6 51 0 yd fVs 1 1 52 0 59 50 53 0 S \^ '— / N— / 92 63 54 \ z— d X / Z—1 o=( W) 6 5 55 cxi Z d I / -Z.—' ^=( Vb 4 5 56 0 Frs diN^ 50 62 57 0 '"dr >• 2 21 58 0 ^JV^NH d\ kNA ' u0^ 2 2 59 0 rys 0 11 31 60 0 tys AN^ 2 4 61 0 -n'NAnh ’Ey Ps Ay 0.2 1 62 0 m-nY^nh y \ yys ty AN^ . to / / 63 0 . / S^NH S\ ^s ^■V 12 10 64 0 m-nY^nh aA PtS ^nA A An^ 5 6 65 9A \ / ^° <—z __ / t p —z / =\ vvJ> 8 14 66 0 xNAA jy A U, AN^ 19 21 67 0 a An AN^OH 20 24 68 0 -oA Ay° Ay Cl Aa 0.7 2 69 0 .aAnh A\ A ^N\ 0.6 5 70 0 _n<nY^nh A \ A tu Oa 39 9 71 0 'nAn< (A0 / AAn^\ F Aa 8 5 72 0 ~naC^ Ay ° Ay ci ANv 2 2 73 0 A 12 3 74 0 AV 10 8 75 0 - / ky fY^O \A 0 fl ^Nx 18 105 76 0 _AAh K\ Ar ^Nx 18 22 77 0 ~"Vr F?s ^N3< VA ^Nx 21 27 78 0 _n-nvAh aSi 6s k / N\ 12 6 79 0 Vy^nh a\ 6s Lo^ ^N 57 40 80 0 -nNAnh K k / N^ 28 8 81 0 fys b 26 11 82 0 b -A k / N\ 8 8 83 ™Ab fjrs bN\ 18 10 84 0 -bb (b Cl Ab 2 1 85 0 ~Nb\ fys b ^N\ 25 19 86 0 € / 0 Cl ^Nx 6 6 87 0 ~Yt y Cl k^NxX 6 3 88 0 b^r <r ^N\ 22 41 89 A f^rs ^N\ 15 32 90 HO / 0 vaAh A ^N\ 21 34 91 0 Fy-o ^Ay FA Ox 2 4 92 0 tA Fyo Ay F x-a^x Br A 4 4 93 0 -AjA Fy° Ay y n^ A k / N\ 3 4 94 0 -aO Av° / A^n^A / / / k / Nx N \x \ 7 10 95 0 xnY^nh Fn ry° j ^NO A ON\ / N'N 2 2 96 0 -aO rVs / Cl 4 1 97 0 ~aO Cl ^Nx 7 5 98 0 -yyO fy° C! L^o 18 29 99 0 fyo Nn Cl ^N\ 9 17 100 0 Gj s ^NCV\ y-7 61 71 101 0 -Nyv FV0 Br^yy L A / Cl Mx 1 1 102 ' u NaJ / y° Br r' MN^ Cl G 1 1 103 0 yys A° ci 5 5 104 0 / Gr0 ^Ny ci Ly bn 30 41 105 0 -n,NY^nh y \ ry° E / 'X / X^| fV° ^Nx F 4 3 106 ' E Nyr fy° x^ fV° F 4 2 107 0 -nNA p y F^° ^Nx F 2 5 108 ' u U k F. V F^° A / N\ F 5 8 109 0 / kys y Cl 7 10 110 0 ~Nkkr / Tys Cl ^N\ 4 9 111 0 -t / r fys ^na yp Cl 6 9 112 0 - / Y^nh Ovo N^ yo F 3 4 113 0 ~N?Ck l A z\ Cl Ox 1 0.8 114 iOsa / Ty-o na Cl k / N^ 4 2 115 \ 2 Npor fy° ^na 43 18 116 \ ° Npk^Nk Or0 ^N\ 18 7 117 \ s Np\ s kjr0 Cl Ox 6 0.7 118 Cl 0¼ 10 5 119 0 / / V° N0 N^V7 Cl 5 7 120 O —N NV^NH Z \ Fy° kN^ 8 10 121 ppp ^r ^^N^p ^-N\ 18 20 122 \ g Npp r FV0 N^ I 1 _ / N °' 4 5 123 \ g ppp (Or0 ^N^| pp HN^P 114 85 124 \ ? Npjp FjT° NPN 2 5 125 0 npT^T fV0 Cl 1 1 126 0 Fp^0 ^Np Cl k / N\ 9 7 127 0 0 z-^ o^ \_Z^o -2¼ 8 4 128 0 HNyXV / / V° Cl 4 6 129 z \\\ o 0=^ \ ^o y—z 0 1 0 ( 5 4 130 z -n A X-JJ \ )=o 0 1 0 / 10 4 131 0 HNy^0 07^° N-' f4f 14 9 132 z -n ^0¾ o^z \ 0 1 / —-Z. 4 1 133 0 ~nVy Fjt0 r\ ^Nx / zn7 2 1
[348] "\" represents undetected.
[349] Although specific implementations of the present disclosure are described above, those skilled in the art should understand that these are merely examples, and various changes or modifications can be made to these implementations without departing from the principle and essence of the present disclosure. Therefore, the claimed scope of the present disclosure shall be defined by the appended claims.
Claims
1. A compound of Formula (IA) or a pharmaceutically acceptable salt thereof,(IA)wherein ring C is selected from the group consisting of a benzene ring and "a 5-to 6-membered heteroaromatic ring having 1, 2, or 3 heteroatoms being 1, 2, or 3 selected from a group consisting of N, O, and S";R1 is selected from a group consisting of halogen, cyano, C1-6 alkyl, C3-10 cycloalkyl, C1-6 alkoxy, C1-6 alkyl substituted with one or more halogens, C1-6 alkoxy substituted with one or more halogens, "5- to 10-membered heteroaryl having 1, 2, or 3 heteroatoms being 1, 2, or 3 selected from the group consisting of N, O, and S", and "5- to 10-membered heteroaryl having 1, 2, or 3 heteroatoms being 1, 2, or 3 selected from the group consisting of N, O, and S" substituted with one or more R1-1;R1-1 is C1-6 alkyl;m and k are independently 0, 1, or 2;X1 is selected from a group consisting of -CH2-, -O-, -S-, -NH-, and -S(=O)2-;X2 is selected from a group consisting of -C(RaRb)- and -O-;Ra and Rb are independently selected from a group consisting of hydrogen, deuterium, and C1-6 alkyl; alternatively, Ra, Rb, and a shared carbon atom thereof are joined together to form a 3- to 10-membered saturated carbocyclic ring;n is 0 or 1;"—" represents a single bond or a double bond;X3 and X4 are independently selected from a group consisting of C and N;ring A is a pyrazole ring;R2 is selected from a group consisting of H, halogen, C1-6 alkyl, C3-10 cycloalkyl, "3- to 10-membered heterocycloalkyl having 1, 2, or 3 heteroatoms being 1, 2, or 3 selected from the group consisting of N, O, and S", C6-10 aryl, C1-6 alkyl substituted with one or more R2-1, and "5- to 10-membered heteroaryl having 1, 2, or 3 heteroatoms being 1, 2, or 3 selected from the group consisting of N, O, and S"substituted with one or more R2-2;R2-1 and R2-2 are independently selected from a group consisting of halogen, hydroxy, C1-6 alkyl, -N(R2aR2b), C3-10 cycloalkyl, C1-6 alkoxy, "3- to 10-membered heterocycloalkyl having 1, 2, or 3 heteroatoms being 1, 2, or 3 selected from the group consisting of N, O, and S", C6-10 aryl, and "5- to 10-membered heteroaryl having 1, 2, or 3 heteroatoms being 1, 2, or 3 selected from the group consisting of N, O, and S";R2a and R2b are independently selected from a group consisting of H and C1-6 alkyl;N—iE is selected from a group consisting of -N(R3)- and ; n1 is 1, 2, or 3;# represents an end linked to -C(O)- in Formula (IA);R3 is selected from a group consisting of hydrogen, C1-6 alkyl, and C3-10 cycloalkyl;L is selected from a group consisting of C1-6 alkylene, C1-6 alkylene substituted with one or more RL, "-(C1-6 alkylene) -LA-*", and -LA-;RL is selected from a group consisting of deuterium, C1-6 alkoxy, C3-10 cycloalkyl, hydroxy, halogen, and oxo (=O); alternatively, when two RL substituents are on a shared carbon atom, the two RL substituents and the shared carbon atom are joined together to form a 3- to 10-membered saturated carbocyclic ring or "a 3- to 10-membered saturated heterocyclic ring having 1, 2, or 3 heteroatoms being 1, 2, or 3 selected from the group consisting of N, O, and S";LA is selected from a group consisting of -C(O)NH-, -O-, -N(RLA)-, vinylene, ethynylene, a 3- to 10-membered saturated carbocyclic ring, and "a 3- to 10-membered saturated heterocyclic ring having 1, 2, or 3 heteroatoms being 1, 2, or 3 selected from the group consisting ofN, O, and S";RLA is selected from a group consisting of H, C1-6 alkyl, C3-10 cycloalkyl, and "3-to 10-membered heterocycloalkyl having 1, 2, or 3 heteroatoms being 1, 2, or 3 selected from the group consisting ofN, O, and S";ring B is selected from a group consisting of a 3- to 10-membered saturated or unsaturated carbocyclic ring, a 3- to 10-membered saturated or unsaturated carbocyclic ring substituted with one or more RB-1, "a 3- to 10-membered saturated or unsaturated heterocyclic ring having 1, 2, or 3 heteroatoms being 1, 2, or 3 selected from the group consisting of N, O, and S", and "a 3- to 10-membered saturated or unsaturated heterocyclic ring having 1, 2, or 3 heteroatoms being 1, 2, or 3 selectedfrom the group consisting of N, O, and S" substituted with one or more RB-2;RB-1 and RB-2 are independently selected from a group consisting of hydroxy,halogen, oxo (=O), C1-6 alkyl, C1-6 alkoxy, and C1-6 alkyl substituted with one or morehydroxy groups;when U is absent, the ring B isU is absent or selected from a group consisting of -N(R')(R"), C3-6 alkyl, C1-6 alkyl substituted with one or more RU-1, C3-10 cycloalkyl, C3-10 cycloalkyl substituted with one or more RU-2, "3- to 10-membered heterocycloalkyl having 1, 2, or 3 heteroatoms being 1, 2, or 3 selected from the group consisting of N, O, and S", "3- to 10-membered heterocycloalkyl having 1, 2, or 3 heteroatoms being 1, 2, or 3 selected from the group consisting of N, O, and S" substituted with one or more RU-3, C6-10 aryl, C6-10 aryl substituted with one or more RU-4, "5- to 10-membered heteroaryl having 1, 2, or 3 heteroatoms being 1, 2, or 3 selected from the group consisting of N, O, and S", "5- to 10-membered heteroaryl having 1, 2, or 3 heteroatoms being 1, 2, or 3 selected from the group consisting of N, O, and S" substituted with one or more RU-5, and-X-RU-6;X is selected from a group consisting of -C(O)-, -SO2-, and -O-;R' and R" are independently selected from a group consisting of hydrogen, C1-6 alkyl, -C(O)-C3-10 cycloalkyl, and C1-6 alkyl substituted with one or more R'''; R''' is C6-10 aryl;RU-1 is selected from a group consisting of -N(R')(R"), halogen, C3-10 cycloalkyl, C6-10 aryl, "5- to 10-membered heteroaryl having 1, 2, or 3 heteroatoms being 1, 2, or 3 selected from the group consisting of N, O, and S", or "5- to 10-membered heteroaryl having 1, 2, or 3 heteroatoms being 1, 2, or 3 selected from the group consisting of N, O, and S" substituted with one or more RU-1-1;RU-1-1 is C1-6 alkyl;RU-2, RU-3, RU-4, and RU-5 are independently selected from a group consisting of halogen, cyano, hydroxy, -SO2-C1-6 alkyl, -C(O)-C1-6 alkyl, -C(O)O-C1-6 alkyl, -C(O)NH-C1-6 alkyl, C1-6 alkyl, C1-6 alkyl substituted with one or more RU-3-1, C1-6 alkoxy, C1-6 alkoxy substituted with one or more RU-3-2, C3-10 cycloalkyl, "3- to 10-membered heterocycloalkyl having 1, 2, or 3 heteroatoms being 1, 2, or 3 selected from the group consisting of N, O, and S", and -O-"3- to 10-membered heterocycloalkyl having 1, 2, or 3 heteroatoms being 1, 2, or 3 selected from the groupconsisting of N, O, and S";RU-3-1 and RU-3-2 are independently selected from a group consisting of halogen, C3-10 cycloalkyl, C6-10 aryl, C1-6 alkoxy, hydroxy, cyano, and "3- to 10-membered heterocycloalkyl having 1, 2, or 3 heteroatoms being 1, 2, or 3 selected from the group consisting of N, O, and S";RU-6 is selected from a group consisting of C6-10 aryl and "5- to 10-membered heteroaryl having 1, 2, or 3 heteroatoms being 1, 2, or 3 selected from the group consisting of N, O, and S"; andthe compound of Formula (IA) is not any one selected from a group consisting offollowing compounds:, and2. The compound of Formula (IA) or the pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of Formula (IA) is a compound of Formula (IIA):R1 is selected from the group consisting of halogen, cyano, C1-6 alkyl, C3-10 cycloalkyl, C1-6 alkoxy, C1-6 alkyl substituted with one or more halogens, C1-6 alkoxy substituted with one or more halogens, "5- to 10-membered heteroaryl having 1, 2, or 3 heteroatoms being 1, 2, or 3 selected from the group consisting of N, O, and S", and "5- to 10-membered heteroaryl having 1, 2, or 3 heteroatoms being 1, 2, or 3 selected from the group consisting of N, O, and S" substituted with one or more R1-1;R1-1 is C1-6 alkyl;m and k are independently 0, 1, or 2;X1 is selected from a group consisting of -CH2-, -O-, -S-, and -S(=O)2-;R2 is selected from a group consisting of H, C1-6 alkyl, C1-6 alkyl substituted with one or more R2-1, and "3- to 10-membered heterocycloalkyl having 1, 2, or 3 heteroatoms being 1, 2, or 3 selected from the group consisting of N, O, and S";R2-1 is selected from a group consisting of hydroxy and C3-10 cycloalkyl;"—" represents a single bond or a double bond;N—।E is selected from the group consisting of -N(R3)- and ; n1 is 1, 2, or3; # represents an end linked to -C(O)- in Formula (IA);R3 is selected from a group consisting of hydrogen and C1-6 alkyl;L is selected from a group consisting of C1-6 alkylene, C1-6 alkylene substituted with one or more RL, and "-(C1-6 alkylene) -LA-*";RL is selected from a group consisting of hydroxy and halogen; alternatively, when two RL substituents are on a shared carbon atom, the two RL substituents and theshared carbon atom are joined together to form a 3- to 10-membered saturatedcarbocyclic ring;LA is selected from a group consisting of -NH-, -N(C1-6 alkyl)-, and a 3- to 10-membered saturated carbocyclic ring;the ring B is selected from a group consisting of "a 3- to 10-membered saturatedor unsaturated heterocyclic ring having 1, 2, or 3 heteroatoms being 1, 2, or 3 selected from the group consisting of N, O, and S" and "a 3- to 10-membered saturated orunsaturated heterocyclic ring having 1, 2, or 3 heteroatoms being 1, 2, or 3 selectedfrom the group consisting of N, O, and S" substituted with one or more RB-2;RB-2 is selected from a group consisting of hydroxy, halogen, C1-6 alkyl, C1-6alkoxy, and Ci-6 alkyl substituted with one or more hydroxy groups;when U is absent, the ring B isU is absent or selected from a group consisting of -N(R')(R"), C3-6 alkyl, C1-6 alkyl substituted with one or more RU-1, C3-10 cycloalkyl, C3-10 cycloalkyl substituted with one or more RU-2, "3- to 10-membered heterocycloalkyl having 1, 2, or 3 heteroatoms being 1, 2, or 3 selected from the group consisting of N, O, and S", "3- to 10-membered heterocycloalkyl having 1, 2, or 3 heteroatoms being 1, 2, or 3 selected from the group consisting of N, O, and S" substituted with one or more RU-3, C6-10 aryl, C6-10 aryl substituted with one or more RU-4, "5- to 10-membered heteroaryl having 1, 2, or 3 heteroatoms being 1, 2, or 3 selected from the group consisting of N, O, and S", and "5- to 10-membered heteroaryl having 1, 2, or 3 heteroatoms being 1, 2, or 3 selected from the group consisting of N, O, and S" substituted with one or more RU-5;R' and R" are independently selected from a group consisting of hydrogen, C1-6 alkyl, -C(O)-C3-10 cycloalkyl, and C1-6 alkyl substituted with one or more R'''; R''' is C6-10 aryl;RU-1 is selected from a group consisting of -N(R')(R"), C3-10 cycloalkyl, and C6-10 aryl;RU-2, RU-3, RU-4, and RU-5 are independently selected from a group consisting of halogen, -SO2-C1-6 alkyl, -C(O)-C1-6 alkyl, C3-10 cycloalkyl, "3- to 10-memberedheterocycloalkyl having 1, 2, or 3 heteroatoms being 1, 2, or 3 selected from the group consisting of N, O, and S", cyano, hydroxy, C1-6 alkyl, C1-6 alkyl substituted with one or more RU-3-1, C1-6 alkoxy, and C1-6 alkoxy substituted with one or more RU-3-2; andRU-3-1 and RU-3-2 are independently selected from a group consisting of halogen, C3-10 cycloalkyl, C6-10 aryl, C1-6 alkoxy, hydroxy, cyano, and "3- to 10-membered heterocycloalkyl having 1, 2, or 3 heteroatoms being 1, 2, or 3 selected from the group consisting of N, O, and S".
3. The compound of Formula (IA) or the pharmaceutically acceptable salt thereofaccording to claim 1, wherein the compound of Formula (IA) is selected from a groupconsisting of a compound of Formula (IIIA) and a compound of Formula (IIIB):andR1 is selected from the group consisting of halogen, cyano, C1-6 alkyl, C3-10 cycloalkyl, C1-6 alkoxy, C1-6 alkyl substituted with one or more halogens, C1-6 alkoxy substituted with one or more halogens, "5- to 10-membered heteroaryl having 1, 2, or 3 heteroatoms being 1, 2, or 3 selected from the group consisting of N, O, and S", and "5- to 10-membered heteroaryl having 1, 2, or 3 heteroatoms being 1, 2, or 3 selected from the group consisting of N, O, and S" substituted with one or more R1-1;R1-1 is C1-6 alkyl;m is 0, 1, or 2;X1 is selected from a group consisting of -CH2-, -O-, -S-, and -S(=O)2-;R2 is selected from a group consisting of H, C1-6 alkyl, C1-6 alkyl substituted with one or more R2-1, and "3- to 10-membered heterocycloalkyl having 1, 2, or 3 heteroatoms being 1, 2, or 3 selected from the group consisting of N, O, and S";R2-1 is selected from a group consisting of hydroxy and C3-10 cycloalkyl;N—IE is selected from the group consisting of -N(Rs)- and < ; n1 is 1, 2, or 3; # represents an end linked to -C(O)- in Formula (IA);R3 is selected from a group consisting of hydrogen and C1-6 alkyl;L is selected from a group consisting of C1-6 alkylene, C1-6 alkylene substituted with one or more RL, and "-(C1-6 alkylene) -LA-*";RL is selected from a group consisting of hydroxy and halogen; alternatively, when two RL substituents are on a shared carbon atom, the two RL substituents and theshared carbon atom are joined together to form a 3- to 10-membered saturatedcarbocyclic ring;LA is a 3- to 10-membered saturated carbocyclic ring;the ring B is selected from a group consisting of "a 3- to 10-membered saturatedor unsaturated heterocyclic ring having 1, 2, or 3 heteroatoms being 1, 2, or 3 selectedfrom the group consisting of N, O, and S" and "a 3- to 10-membered saturated or unsaturated heterocyclic ring having 1, 2, or 3 heteroatoms being 1, 2, or 3 selectedfrom the group consisting of N, O, and S" substituted with one or more RB-2;Rb-2 is selected from a group consisting of halogen and C1-6 alkyl;when U is absent, the ring B isU is absent or selected from a group consisting of -N(R')(R"), C1-6 alkyl substituted with one or more RU-1, C3-10 cycloalkyl, C3-10 cycloalkyl substituted with one or more RU-2, "3- to 10-membered heterocycloalkyl having 1, 2, or 3 heteroatoms being 1, 2, or 3 selected from the group consisting of N, O, and S", "3- to 10-membered heterocycloalkyl having 1, 2, or 3 heteroatoms being 1, 2, or 3 selected from the group consisting ofN, O, and S" substituted with one or more RU-3, C6-10 aryl, C6-10 aryl substituted with one or more RU-4, and "5- to 10-membered heteroaryl having 1, 2, or 3 heteroatoms being 1, 2, or 3 selected from the group consisting of N, O, and S";R' and R" are independently selected from the group consisting of hydrogen, C1-6 alkyl, -C(O)-C3-10 cycloalkyl, and C1-6 alkyl substituted with one or more R'''; R''' is C6-10 aryl;RU-1 is selected from a group consisting of C3-10 cycloalkyl and C6-10 aryl;RU-2, RU-3, and RU-4 are independently selected from a group consisting of halogen, hydroxy, -SO2-C1-6 alkyl, -C(O)-C1-6 alkyl, C1-6 alkyl, C3-10 cycloalkyl, "3- to 10-membered heterocycloalkyl having 1, 2, or 3 heteroatoms being 1, 2, or 3 selected from the group consisting ofN, O, and S", C1-6 alkoxy, and C1-6 alkyl substituted with one or more RU-3-1; andRU-3-1 is selected from a group consisting of halogen, C3-10 cycloalkyl, C6-10 aryl,C1-6 alkoxy, hydroxy, cyano, and "3- to 10-membered heterocycloalkyl having 1, 2, or 3 heteroatoms being 1, 2, or 3 selected from the group consisting of N, O, and S".
4. The compound of Formula (IA) or the pharmaceutically acceptable salt thereof according to claim 1, wherein one or more of following conditions are satisfied:(1) R1 is selected from a group consisting of halogen, cyano, C1-6 alkyl, C3-10 cycloalkyl, C1-6 alkyl substituted with one or more halogens, C1-6 alkoxy substituted with one or more halogens, "5- to 10-membered heteroaryl having 1, 2, or 3 heteroatoms being 1, 2, or 3 selected from the group consisting of N, O, and S", and "5- to 10-membered heteroaryl having 1, 2, or 3 heteroatoms being 1, 2, or 3 selected from the group consisting of N, O, and S" substituted with one or more R1-1;R1-1 is C1-6 alkyl;(2) R2 is selected from the group consisting of H, C1-6 alkyl, C1-6 alkyl substituted with one or more R2-1, and "3- to 10-membered heterocycloalkyl having 1, 2, or 3 heteroatoms being 1, 2, or 3 selected from the group consisting of N, O, and S";R2-1 is selected from a group consisting of hydroxy and C3-10 cycloalkyl;(3) E is -N(R3)-;(4) L is selected from a group consisting of C1-6 alkylene, C1-6 alkylene substituted with one or more RL, and "-(C1-6 alkylene) -LA-*";RL is selected from a group consisting of hydroxy and halogen; alternatively, when two RL substituents are on a shared carbon atom, the two RL substituents and the shared carbon atom are joined together to form a 3- to 10-membered saturated carbocyclic ring;LA is selected from a group consisting of -NH-, -N(C1-6 alkyl)-, and a 3- to 10-membered saturated carbocyclic ring, preferably the 3- to 10-membered saturated carbocyclic ring;(5) the ring B is selected from a group consisting of "a 3- to 10-membered saturated or unsaturated heterocyclic ring having 1, 2, or 3 heteroatoms being 1, 2, or 3 selected from the group consisting of N, O, and S" and "a 3- to 10-membered saturated or unsaturated heterocyclic ring having 1, 2, or 3 heteroatoms being 1, 2, or 3 selected from the group consisting of N, O, and S" substituted with one or more RB-2;RB-2 is selected from a group consisting of hydroxy, halogen, C1-6 alkyl, C1-6 alkoxy, and C1-6 alkyl substituted with one or more hydroxy groups, preferably thehalogen or the C1-6 alkyl;(6) U is absent or selected from a group consisting of -N(R')(R"), C3-6 alkyl, C1-6 alkyl substituted with one or more RU-1, C3-10 cycloalkyl, C3-10 cycloalkyl substituted with one or more RU-2, "3- to 10-membered heterocycloalkyl having 1, 2, or 3 heteroatoms being 1, 2, or 3 selected from the group consisting of N, O, and S", "3- to 10-membered heterocycloalkyl having 1, 2, or 3 heteroatoms being 1, 2, or 3 selected from the group consisting of N, O, and S" substituted with one or more RU-3, C6-10 aryl, C6-10 aryl substituted with one or more RU-4, "5- to 10-membered heteroaryl having 1, 2, or 3 heteroatoms being 1, 2, or 3 selected from the group consisting of N, O, and S", and "5- to 10-membered heteroaryl having 1, 2, or 3 heteroatoms being 1, 2, or 3 selected from the group consisting of N, O, and S" substituted with one or more RU-5;R' and R" are independently selected from the group consisting of hydrogen, C1-6 alkyl, -C(O)-C3-10 cycloalkyl, and C1-6 alkyl substituted with one or more R'''; R''' is C6-10 aryl;RU-1 is selected from a group consisting of -N(R')(R"), C3-10 cycloalkyl, and C6-10 aryl;RU-2, RU-3, RU-4, and RU-5 are independently selected from a group consisting of halogen, -SO2-C1-6 alkyl, -C(O)-C1-6 alkyl, C3-10 cycloalkyl, "3- to 10-membered heterocycloalkyl having 1, 2, or 3 heteroatoms being 1, 2, or 3 selected from the group consisting of N, O, and S", cyano, hydroxy, C1-6 alkyl, C1-6 alkyl substituted with one or more RU-3-1, C1-6 alkoxy, and C1-6 alkoxy substituted with one or more RU-3-2; andRU-3-1 and RU-3-2 are independently selected from a group consisting of halogen, C3-10 cycloalkyl, C6-10 aryl, C1-6 alkoxy, hydroxy, cyano, and "3- to 10-membered heterocycloalkyl having 1, 2, or 3 heteroatoms being 1, 2, or 3 selected from the group consisting of N, O, and S";preferably, U is absent or selected from a group consisting of -N(R')(R"), C1-6 alkyl substituted with one or more RU-1, C3-10 cycloalkyl, C3-10 cycloalkyl substituted with one or more RU-2, "3- to 10-membered heterocycloalkyl having 1, 2, or 3 heteroatoms being 1, 2, or 3 selected from the group consisting of N, O, and S", "3- to 10-membered heterocycloalkyl having 1, 2, or 3 heteroatoms being 1, 2, or 3 selected from the group consisting of N, O, and S" substituted with one or more RU-3, C6-10 aryl, C6-10 aryl substituted with one or more RU-4, and "5- to 10-membered heteroaryl having 1, 2, or 3 heteroatoms being 1, 2, or 3 selected from the group consisting of N, O, and S";RU-1 is selected from a group consisting of C3-10 cycloalkyl and C6-10 aryl;RU-2, RU-3, and RU-4 are independently selected from a group consisting of halogen, hydroxy, -SO2-C1-6 alkyl, -C(O)-C1-6 alkyl, C1-6 alkyl, C3-10 cycloalkyl, "3- to 10-membered heterocycloalkyl having 1, 2, or 3 heteroatoms being 1, 2, or 3 selected from the group consisting of N, O, and S", C1-6 alkoxy, and C1-6 alkyl substituted with one or more RU-3-1; andRU-3-1 is selected from a group consisting of halogen, C3-10 cycloalkyl, C6-10 aryl, C1-6 alkoxy, hydroxy, cyano, and "3- to 10-membered heterocycloalkyl having 1, 2, or 3 heteroatoms being 1, 2, or 3 selected from the group consisting of N, O, and S".
5. The compound of Formula (IA) or the pharmaceutically acceptable salt thereof according to claim 1, wherein one or more of following conditions are satisfied:(1) R1 is halogen;(2) m and k are independently 0 or 1;(3) R2 is selected from a group consisting of C1-6 alkyl and C1-6 alkyl substituted with one or more R2-1;R2-1 is C3-10 cycloalkyl;(4) R3 is selected from a group consisting of hydrogen and C1-6 alkyl;(5) L is selected from a group consisting of C1-6 alkylene, C1-6 alkylene substituted with one or more RL, and "-(C1-6 alkylene) -LA-*";RL is selected from a group consisting of hydroxy and halogen; alternatively, when two RL substituents are on a shared carbon atom, the two RL substituents and the shared carbon atom are joined together to form a 3- to 10-membered saturated carbocyclic ring;LA is selected from a group consisting of -NH- and -N(C1-6 alkyl)-, preferably the -NH-;(6) the ring B is selected from a group consisting of "a 3- to 10-membered saturated or unsaturated heterocyclic ring having 1, 2, or 3 heteroatoms being 1, 2, or 3 selected from the group consisting of N, O, and S" and "a 3- to 10-membered saturated or unsaturated heterocyclic ring having 1, 2, or 3 heteroatoms being 1, 2, or 3 selected from the group consisting of N, O, and S" substituted with one or more RB-2;RB-2 is selected from a group consisting of hydroxy, halogen, C1-6 alkoxy, andC1-6 alkyl substituted with one or more hydroxy groups, preferably the halogen; and(7) U is selected from a group consisting of C3-6 alkyl, C1-6 alkyl substituted with one or more RU-1, C3-10 cycloalkyl, C3-10 cycloalkyl substituted with one or more RU-2, "3- to 10-membered heterocycloalkyl having 1, 2, or 3 heteroatoms being 1, 2, or 3 selected from the group consisting of N, O, and S", "3- to 10-membered heterocycloalkyl having 1, 2, or 3 heteroatoms being 1, 2, or 3 selected from the group consisting of N, O, and S" substituted with one or more RU-3, C6-10 aryl, C6-10 aryl substituted with one or more RU-4, "5- to 10-membered heteroaryl having 1, 2, or 3 heteroatoms being 1, 2, or 3 selected from the group consisting of N, O, and S", and "5- to 10-membered heteroaryl having 1, 2, or 3 heteroatoms being 1, 2, or 3 selected from the group consisting of N, O, and S" substituted with one or more RU-5;RU-1 is selected from a group consisting of C3-10 cycloalkyl and C6-10 aryl;RU-2, RU-3, RU-4, and RU-5 are independently selected from a group consisting of halogen, C3-10 cycloalkyl, "3- to 10-membered heterocycloalkyl having 1, 2, or 3 heteroatoms being 1, 2, or 3 selected from the group consisting of N, O, and S", cyano, hydroxy, C1-6 alkyl, C1-6 alkyl substituted with one or more RU-3-1, C1-6 alkoxy, and C1-6 alkoxy substituted with one or more RU-3-2; andRU-3-1 and RU-3-2 are independently selected from a group consisting of halogen and C3-10 cycloalkyl.
6. The compound of Formula (IA) or the pharmaceutically acceptable salt thereof according to claim 1, wherein one or more of following conditions are satisfied:(1) R3 is hydrogen;(2) L is selected from a group consisting of C1-6 alkylene and C1-6 alkylene substituted with one or more RL;RL is selected from a group consisting of hydroxy and halogen, preferably the hydroxy;(3) the ring B is "a 3- to 10-membered saturated or unsaturated heterocyclic ring having 1, 2, or 3 heteroatoms being 1, 2, or 3 selected from the group consisting of N, O, and S"; and(4) U is selected from a group consisting of C1-6 alkyl substituted with one or more RU-1, C3-10 cycloalkyl, C3-10 cycloalkyl substituted with one or more RU-2, "3- to 10-membered heterocycloalkyl having 1, 2, or 3 heteroatoms being 1, 2, or 3 selected from the group consisting of N, O, and S", C6-10 aryl, C6-10 aryl substituted with one ormore RU-4, and "5- to 10-membered heteroaryl having 1, 2, or 3 heteroatoms being 1, 2, or 3 selected from the group consisting of N, O, and S";RU-1 is selected from a group consisting of C3-10 cycloalkyl and C6-10 aryl;RU-2 and RU-4 are independently selected from a group consisting of halogen, C1-6 alkoxy, and C1-6 alkyl substituted with one or more RU-3-1; andRU-3-1 is halogen.
7. The compound of Formula (IA) or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein one or more of following conditions are satisfied:(1) in the ring C, the "5- to 6-membered heteroaromatic ring having 1, 2, or 3 heteroatoms being 1, 2, or 3 selected from the group consisting of N, O, and S" is "a 5- to 6-membered heteroaromatic ring having 1 or 2 heteroatoms being N";(2) the "C1-6 alkyl" is selected from a group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, and sec-butyl;(3) the "C1-6 alkoxy" is selected from a group consisting of methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, isobutoxy, and sec-butoxy;(4) the "halogen" is selected from a group consisting of fluorine, chlorine, bromine, and iodine;(5) when Ra, Rb, and the shared carbon atom thereof are joined together to form a 3- to 10-membered saturated carbocyclic ring, the "3- to 10-membered saturated carbocyclic ring" is a 3-membered saturated carbocyclic ring;(6) the "C3-10 cycloalkyl" is selected from a group consisting of C3-6 monocyclic cycloalkyl and C5-10 polycyclic cycloalkyl (comprising spiro cycloalkyl, fused cycloalkyl, or bridged cycloalkyl);(7) the "3- to 10-membered heterocycloalkyl having 1, 2, or 3 heteroatoms being 1, 2, or 3 selected from the group consisting of N, O, and S" is selected from a group consisting of 4- to 6-membered monocyclic heterocycloalkyl and 5- to 10-membered polycyclic heterocycloalkyl (comprising spiro heterocycloalkyl, fused heterocycloalkyl, or bridged heterocycloalkyl);(8) the "C6-10 aryl" is selected from a group consisting of phenyl and naphthyl;(9) the "5- to 10-membered heteroaryl having 1, 2, or 3 heteroatoms being 1, 2, or 3 selected from the group consisting of N, O, and S" is 5- to 6-membered monocyclic heteroaryl, preferably 5- to 6-membered monocyclic heteroaryl having 1,2, or 3 heteroatoms being N;(10) the "C1-6 alkylene" is C1-4 alkylene;(11) when two RL substituents are on a shared carbon atom, the "3- to 10-membered saturated carbocyclic ring" formed by the two RL substituents and the shared carbon atom being joined together is a 3-membered saturated carbocyclic ring;(12) when LA is a 3- to 10-membered saturated carbocyclic ring, the "3- to 10-membered saturated carbocyclic ring" is a 4- to 6-membered saturated carbocyclic ring, comprising ; and(13) the "3- to 10-membered saturated or unsaturated heterocyclic ring having 1, 2, or 3 heteroatoms being 1, 2, or 3 selected from the group consisting of N, O, and S" is "a 4- to 8-membered saturated or unsaturated heterocyclic ring having 1 or 2 heteroatoms being 1 or 2 selected from a group consisting of N and O", preferably "a 5- to 6-membered saturated or unsaturated heterocyclic ring having 1 or 2 heteroatoms being N".
8. The compound of Formula (IA) or the pharmaceutically acceptable salt thereof according to claim 7, wherein one or more of following conditions are satisfied:(1) in the ring C, the "5- to 6-membered heteroaromatic ring having 1, 2, or 3 heteroatoms being 1, 2, or 3 selected from the group consisting of N, O, and S" is selected from a group consisting of a pyridine ring and a pyrimidine ring;(2) the "C1-6 alkyl" is selected from a group consisting of methyl and ethyl;(3) the "C1-6 alkoxy" is methoxy;(4) the "halogen" is selected from a group consisting of fluorine, chlorine, and bromine, preferably the fluorine or the chlorine, more preferably the fluorine;(5) when Ra, Rb, and the shared carbon atom thereof are joined together to form a 3- to 10-membered saturated carbocyclic ring, the "3- to 10-membered saturatedX Icarbocyclic ring" is ;(6) the "C3-6 monocyclic cycloalkyl" is selected from a group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl;(7) the "C5-10 polycyclic cycloalkyl" is C5-10 spiro cycloalkyl, preferably ;(8) the "4- to 6-membered monocyclic heterocycloalkyl" is selected from a group consisting of "4- to 6-membered monocyclic heterocycloalkyl having 1 or 2heteroatoms being 1 or 2 selected from a group consisting of N and O" (preferably, or) and "6-membered heterocycloalkyl having 1 or 2heteroatoms being 1 or 2 selected from a group consisting of N and O" (preferablyNH |—N / \), or \— / );(9) the "5- to 10-membered polycyclic heterocycloalkyl" is selected from a group consisting of 5- to 10-membered spiro heterocycloalkyl and bridged heterocycloalkyl,preferablyor 6-membered spiro 3-membered heterocycloalkyl, morepreferably(10) the "C6-10 aryl" is phenyl;(11) the "5- to 10-membered heteroaryl having 1, 2, or 3 heteroatoms being 1, 2, or 3 selected from the group consisting of N, O, and S" is 5- to 6-membered monocyclic heteroaryl, the 5- to 6-membered monocyclic heteroaryl is "5- to 6-membered monocyclic heteroaryl having 1 or 2 heteroatoms being N, preferably, or; alternatively, the 5- to6-membered monocyclic heteroaryl is 5- to 6-membered monocyclic heteroarylhaving 3 heteroatoms being N, preferably(12) the "C1-6 alkylene" is selected, and;from a group consisting of methylene,(13) when two RL substituents are;on a shared carbon atom, the "3- to10-membered saturated carbocyclic ring" formed by the two Rl substituents and theX Ishared carbon atom being joined together is ; and(14) the "3- to 10-membered saturated or unsaturated heterocyclic ring having 1,2, or 3 heteroatoms being 1, 2, or 3 selected from the group consisting of N, O, and S"is selected from a group consisting of, and9. The compound of Formula (IA) or the pharmaceutically acceptable salt thereof according to claim 1, wherein one or more of following conditions are satisfied:(1) the ring C is a benzene ring;(2) Ri is selected from a group consisting of fluorine, chlorine, bromine, cyano,trifluoromethyl, cyclopropyl, trifluoromethoxy, methyl,and; m is 0, 1, or 2;(3) X1 is selected from a group consisting of -CH2-, -O-, -S-, and -S(=O)2-; X2 is -CH2-; n is 0; X3 and X4 are C;(4) R2 is selected from a group consisting of hydrogen, methyl, ethyl, HO, and; k is 0 or 1;(5) a structural moietyis selected froma group consistingofand(6) R3 is selected from a group consisting of hydrogen and methyl;(7) L is selected from a group consisting of methylene,(8) the ring B is selected from a group consisting of,and, -NH2,,,,, and; and(10) E is selected from a group consisting of -NH-, -N(CH3)-, and10. The compound of Formula (IA) or the pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of Formula (IA) is any one selected from a group consisting of following compounds:
11. A pharmaceutical composition, comprising: a substance A and a pharmaceutically acceptable excipient, wherein the substance A is selected from a group consisting of a compound of Formula (X-A) and a pharmaceutically acceptable salt thereof;(X-A) ,wherein ring A, ring B, ring C, X1, X2, X3, X4, R1, R2, E, m, n, k, L, B, and U are as defined according to claim 1; andpreferably, the pharmaceutical composition is used for treating and / or preventing a Kinase Suppressor of Ras 2-Adenosine 5'-Monophosphate-activated Protein Kinase (KSR2-AMPK)-related disease or disorder comprising cancer, wherein the cancer comprises liver cancer.
12. Use of the substance A or the pharmaceutical composition according to claim 11 in preparation of a KSR2-AMPK inhibitor, wherein the KSR2-AMPK inhibitor is used in vivo in a mammalian organism; the KSR2-AMPK inhibitor is also used in vitro primarily for an experimental purpose; for example, the KSR2-AMPK inhibitor is provided as a standard or a control for comparison, or made into a kit according to conventional methods in the prior art to provide rapid detection of an effect of inhibiting KSR2-AMPK.
13. Use of the substance A or the pharmaceutical composition according to claim 11 in preparation of a drug, wherein the drug is for treating and / or preventing a KSR2-AMPK-related disease or disorder; the substance A is in a therapeutically effective amount; and the KSR2-AMPK-related disease or disorder is preferably a cancer, comprising liver cancer.
14. Use of the substance A or the pharmaceutical composition according to claim 11 in preparation of a drug, wherein the drug is for treating and / or preventing a cancer, comprising liver cancer; and the substance A is in a therapeutically effective amount.