2,7-disubstituted-5h-pyrrolo[2,3-b]pyrazine derivatives, methods of synthesis and uses thereof

Abstract

This invention discloses a 2,7-disubstituted-5H-pyrrolo[2,3-b]pyrazine derivative, its synthesis method, and its applications, as well as compounds with the structure shown in formula (I), their stereoisomers, or pharmaceutically acceptable salts thereof. These compounds can inhibit MLK3 activity and are used to prepare drugs for the prevention or treatment of diseases caused by MLK3 overexpression, including breast cancer, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, ovarian cancer, cervical cancer, prostate cancer, glioblastoma, etc. (I).

Description

Technical Field

[0001] This invention relates to the field of small molecule drugs, specifically to a 2,7-disubstituted-5H-pyrrolo[2,3-b]pyrazine derivative, its synthesis method, and its application. Background Technology

[0002] MLK3 is a 97 kDa serine / threonine protein kinase belonging to the mitogen-activated protein kinase (MAP3K) class. MLK3 phosphorylates and activates downstream kinases, leading to the activation of JNK, P38, and ERK (MAPKs) mediated signaling pathways. MLK3 controls multiple MAPK signaling pathways and regulates proliferation, apoptosis, differentiation, and migration according to the cellular environment.

[0003] K252a was the first reported MLK3 inhibitor [Roux PP, et al., J Biol Chem [2002;277(51):49473-49480.] Due to its poor selectivity for other kinases, CEP-1347 was subsequently developed [Saporito MS, et al., 2002;277(51):49473-49480.]. Prog Med Chem . 2002;40:23-62], and CEP-11004 [Falsig J, et al., J Immunol .2004;173(4):2762-2770.]. In 2008, Robert L. Hudkins et al. designed the derivative compounds DHN-14 and DHN-16 based on K252a and CEP-1347 [Hudkins RL, et al., 2004;173(4):2762-2770.]. J Med Chem . 2008;51(18):5680-5689.], Compared with compound CEP-1347, the derived compound achieved a certain selectivity between MLK1 and MLK3. In 2013, Val S. Goodfellow first identified the lead compound of the imidazopyrazinone skeleton through high-throughput screening, and then identified URMC-099 as a candidate MLK3 inhibitor through structural optimization. This compound showed good pharmacokinetic properties but only moderate selectivity in terms of kinases, and low selectivity among MLK family isotypes. Pieter H. Bos et al. obtained Prostetin / 12k[Bos PH, et al.] through further optimization of URMC-099. Cell Chem Biol [2019;26(12):1703-1715.e37.], as a MAP4K4 (HGK) kinase inhibitor, it also has good inhibitory activity against MLK3. Subsequently, CFLB-1134 [Kline EM, et al., Exp NeurolCompounds 9 and 37 have been reported as MLK3 inhibitors. [2019;318:157-164.] Currently, MLK3 has been shown to play an important role in malignant tumors such as breast cancer, cervical cancer, colorectal cancer, gastric cancer, and prostate cancer. The combination of URMC-099 and AZD6482 (a PI3Kβ inhibitor) can slow the growth of glioblastoma [Zhao HF et al., ]. Cancer Cell Int . 2021;21(1):24.];In a model of triple-negative breast cancer, URMC-099 and CEP-1347 can significantly slow tumor growth [Nair RS, et al., ... Oncogene . 2023;42(14):1132-1143.];In a mouse model of pancreatic cancer, treatment with CEP-1347 significantly prolonged the survival of mice [Viswakarma N, et al., 2023;42(14):1132-1143.]; Cancer Lett [2021;515:1-13.] This indicates that MLK3 plays an important role in various malignant tumors.

[0004] Although several MLK3 inhibitors have been shown to slow cancer progression, they have remained in preclinical studies due to issues with efficacy and selectivity. Therefore, there is an urgent need to develop a new and effective MLK3 inhibitor. Summary of the Invention

[0005] This invention provides a 2,7-disubstituted-5H-pyrrolo[2,3-b]pyrazine derivative, its synthesis method, and its application. This type of compound can inhibit MLK3 activity and can be used to treat a variety of diseases, including cancer.

[0006] The technical solution of the present invention is as follows: A compound with the structure shown in formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof: (I) in: R1 is selected from the following structure: R2 is selected from the following structures: More specifically, the compound is selected from the following structures: ; ; ; ; ; ; ; ; ; ; ; .

[0007] The method for synthesizing the 2,7-disubstituted-5H-pyrrolo[2,3-b]pyrazine derivative includes the following steps: (1) Under transition metal catalysis, the compound of formula (II) reacts with the compound of formula (III) to generate the compound of formula (IV); , , ; Formula (II) Formula (III) Formula (IV); (2) Under transition metal catalysis, the compound of formula (Ⅳ) is reacted with the compound of formula (Ⅴ) to generate the compound of formula (I); , ; Equation (Ⅳ) Equation (Ⅴ); In Equations (III), (IV) and (I), R1 has the same meaning; in Equations (V) and (I), R2 has the same meaning.

[0008] The method for synthesizing the 2,7-disubstituted-5H-pyrrolo[2,3-b]pyrazine derivative includes the following steps: (1) Under transition metal catalysis, the compound of formula (II) is reacted with the compound of formula (VI) to generate the compound of formula (VII); , , ; Formula (II) Formula (VI) Formula (VII); (2) Under transition metal catalysis, the compound of formula (VII) is reacted with the compound of formula (VIII) to generate the compound of formula (IX); , , Formula (VII) Formula (VIII) Formula (IX); Wherein, R3 is a methoxy group, a chlorine atom, or a fluorine atom, and R3 in formula (VIII) and formula (IX) has the same meaning; (3) Through reductive amination, the compound with the structure of formula (IX) is reacted with related compounds to generate the compound with the structure of formula (X); , ; Formula (IX) Formula (X); R3 in equations (X) and (IX) has the same meaning; Where R3 is a methoxy group, a chlorine atom, or a fluorine atom, and R4 is: .

[0009] The method for synthesizing the 2,7-disubstituted-5H-pyrrolo[2,3-b]pyrazine derivative includes the following steps: (1) Under transition metal catalysis, the compound of formula (II) reacts with the compound of formula (XI) to generate the compound of formula (XII); , , ; Formula (II) Formula (XI) Formula (XII); In this case, R5 is a methyl or hydrogen atom, and R5 in formulas (XI) and (XII) has the same meaning; (2) Under transition metal catalysis, the compound of formula (XII) is reacted with the compound of formula (XIII) to generate the compound of formula (XIV). , , Equation (XII) Equation (XIII) Equation (XIV); In this context, R6 is a methyl, methoxy, fluorine, or hydrogen atom, and R7 is a methyl, fluorine, or hydrogen atom. R5 in formulas (XIV) and (XII) has the same meaning, and R6 and R7 in formulas (XIV) and (XIII) have the same meaning. (3) The compound with the structure of formula (XIV) was hydrolyzed to obtain the compound with the structure of formula (XV), and then amide condensed to obtain the compound with the structure of formula (XVI); , , ; Formula (XIV) Formula (XV) Formula (XVI); R8 is: ; R5, R6, and R7 in equations (XVI), (XV), and (XIV) have the same meaning.

[0010] The MLK3 small molecule inhibitor described in this invention can be used alone, or it can be prepared as a pharmaceutically acceptable salt or used in combination with a pharmaceutically acceptable excipient or carrier.

[0011] This invention also provides a compound with the structure shown in formula (I) and its pharmaceutically acceptable salt for use as an MLK3 inhibitor. Specifically, this application is for preparing drugs to prevent or treat diseases caused by MLK3 overexpression, including breast cancer, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), ovarian cancer, cervical cancer, prostate cancer, glioblastoma, etc. Compared with the prior art, the beneficial effects of the present invention are as follows: This invention discloses novel MLK3 inhibitor structures, most of which effectively inhibit the activity of MLK3 kinase, indicating that such compounds, their stereoisomers, or pharmaceutically acceptable salts, as well as related drug combinations, have potential application value in the treatment of MLK3-related diseases. Attached Figure Description

[0012] Figure 1 For compound 19 13 C10 NMR structural characterization diagram.

[0013] Figure 2 For compound 19 1 H NMR structural characterization diagram.

[0014] Figure 3 For compound 20 13 C10 NMR structural characterization diagram.

[0015] Figure 4 For compound 20 1 H NMR structural characterization diagram.

[0016] Figure 5 For compound 21 13 C10 NMR structural characterization diagram.

[0017] Figure 6 For compound 21 1 H NMR structural characterization diagram.

[0018] Figure 7 For compound 24 13 C10 NMR structural characterization diagram.

[0019] Figure 8 For compound 24 1H NMR structural characterization diagram.

[0020] Figure 9 For compound 36 13 C10 NMR structural characterization diagram.

[0021] Figure 10 For compound 36 1 H NMR structural characterization diagram. Detailed Implementation

[0022] Example 1: 7-(1H-indol-5-yl)-2-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-5H-pyrrolo[2,3-b]pyrazine (Compound 1) Step 1: 2-Bromo-7-(1H-indol-5-yl)-5H-pyrrolo[2,3-b]pyrazole (Compound 1-1) 2-Bromo-7-iodo-5H-pyrrolo[2,3-b]pyrazin-5-carboxylic acid tert-butyl ester (500 mg, 1.0 eq) and 5-indoleboronic acid pinacol ester (286.6 mg, 1.0 eq) were dissolved in a mixture of 1,4-dioxane (50 mL) and water (10 mL), followed by the addition of K₂CO₃ (488.2 mg, 3.0 eq) and Pd(dppf)Cl₂ (43.1 mg, 0.05 eq). The reaction mixture was protected under nitrogen and stirred at 110 °C for 10 hours. After the reaction was complete, the mixture was cooled to room temperature and concentrated under reduced pressure, followed by purification by silica gel column chromatography to give compound 1-1 (80 mg, 21.6%). 13 C NMR (101 MHz, DMSO- D 6) δ 141.15, 138.05,137.35, 135.38, 132.49, 129.19, 128.43, 126.27, 124.15, 120.37, 117.94,115.22, 112.10, 101.84. 1 H NMR (400 MHz, DMSO- D 6) δ 12.41 (d, J = 2.9 Hz, 1H),11.07 (s, 1H), 8.36 (d, J = 5.7 Hz, 2H), 8.29 (d, J = 1.5 Hz, 1H), 7.78 (dd, J= 8.5, 1.7 Hz, 1H), 7.43 (d, J = 8.5 Hz, 1H), 7.32 (t, J = 2.8 Hz, 1H), 6.46 (t, J = 2.7 Hz, 1H). Step 2: 7-(1H-indol-5-yl)-2-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-5H-pyrrolo[2,3-b]pyrazine (Compound 1) Compound 1-1 (80 mg, 1.0 eq) and pinacol 4-(4-methyl-1-piperazinmethyl)phenylboronic acid (80.8 mg, 1.0 eq) were dissolved in a mixture of 1,4-dioxane (25 mL) and water (5 mL), followed by the addition of K₂CO₃ (105.8 mg, 3.0 eq) and Pd(dppf)Cl₂ (9.3 mg, 0.05 eq). The reaction mixture was protected under nitrogen and stirred at 110 °C for 10 hours. After the reaction was complete, the mixture was cooled to room temperature and concentrated under reduced pressure, followed by purification by silica gel column chromatography to give compound 1 (89 mg, 82.4%). LC-MS (M+H) + =423.93, 13 C NMR (101 MHz, DMSO- D 6) δ 145.68, 141.75,139.08, 137.34, 136.67, 135.24, 135.02, 129.95, 128.48, 127.91, 126.89,126.04, 125.13, 120.50, 117.98, 115.49, 112.02, 101.85, 62.22, 55.06, 52.81,45.95. 1 H NMR (400 MHz, DMSO- D 6) δ 12.17 (d, J = 2.7 Hz, 1H), 11.11 (d, J = 2.3Hz, 1H), 8.83 (s, 1H), 8.50 (d, J = 1.5 Hz, 1H), 8.28 (d, J = 2.4 Hz, 1H),8.17 – 8.10 (m, 2H), 7.97 (dd, J = 8.5, 1.7 Hz, 1H), 7.43 (t, J= 8.2 Hz, 3H), 7.30 (t, J = 2.7 Hz, 1H), 6.46 (t, J = 2.5 Hz, 1H), 3.49 (s, 2H), 2.46 –2.30 (m, 8H), 2.16 (s, 3H). Example 2: 2-Methoxy-5-(2-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)benzonitrile (Compound 2) Step 1: 5-(2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2-methoxybenzonitrile (compound 2-1) The procedure is the same as step 1 in Example 1, where tert-butyl 2-bromo-7-iodo-5H-pyrrolo[2,3-b]pyrazine-5-carboxylate (300 mg, 1.0 eq) and 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)benzonitrile (183.3 mg, 1.0 eq) are reacted to generate compound 2-1 (233 mg, 91%). 13 C NMR (101 MHz, DMSO- D 6) δ159.61, 141.08, 138.68, 136.81, 132.85, 132.47, 130.43, 130.35, 126.71,117.15, 113.22, 111.17, 101.04, 56.90. 1 H NMR (400 MHz, DMSO- D 6) δ 8.50 (s,1H), 8.42 – 8.37 (m, 2H), 8.35 (d, J = 2.2 Hz, 1H), 7.32 (d, J = 8.9 Hz, 1H), 3.91 (s, 3H). The procedure was the same as step 2 in Example 1, reacting compound 2-1 (100 mg, 1.0 eq) with pinacol 4-(4-methyl-1-piperazinmethyl)phenylboronic acid (96 mg, 1.0 eq) to generate compound 2 (74 mg, 55.5%). LC-MS (M+H) + =439.87, 1H NMR (400 MHz, DMSO) δ 12.42 (s, 1H), 8.90 (s, 1H), 8.71 (dd, J = 8.9, 2.3 Hz, 1H), 8.61 (d, J = 2.3 Hz, 1H), 8.51 (s, 1H), 8.14 (d, J = 8.0 Hz, 2H), 7.47(d, J = 8.0 Hz, 2H), 7.39 (d, J = 9.0 Hz, 1H), 3.97 (s, 3H), 3.39 (d, J = 7.3Hz, 2H), 2.56 – 2.46 (m, 8H), 2.30 (s, 3H). 13 C NMR (101 MHz, DMSO) δ 159.29, 146.02, 141.62, 136.98, 136.06, 135.53, 132.48, 130.43, 129.89, 129.16, 127.66, 126.85, 117.20, 113.12,111.39, 100.95, 61.89, 56.81, 54.66, 52.53, 52.21, 45.33. Example 3: N-(4-(2-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)phenyl)acetamide (compound 3) Step 1: N-(4-(2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)phenyl)acetamide (compound 3-1) The procedure is the same as step 1 in Example 1, where tert-butyl 2-bromo-7-iodo-5H-pyrrolo[2,3-b]pyrazine-5-carboxylate (300 mg, 1.0 eq) and pinacol 4-acetamidophenylboronic acid (184.8 mg, 1.0 eq) are reacted to generate compound 3-1 (160 mg, 68%). 13 C NMR (101 MHz, DMSO- D6) δ 168.75, 141.12, 138.36, 138.18,137.11, 132.70, 129.78, 128.16, 126.46, 119.73, 113.32, 24.55. 1 H NMR (400MHz, DMSO- D 6) δ 9.96 (s, 1H), 8.38 (d, J = 5.5 Hz, 2H), 8.00 (d, J = 8.7 Hz, 2H), 7.61 (d, J = 8.7 Hz, 2H), 2.02 (s, 3H). The procedure was the same as step 2 in Example 1, reacting compound 3-1 (160 mg, 1.0 eq) with pinacol 4-(4-methyl-1-piperazinmethyl)phenylboronic acid (152 mg, 1.0 eq) to generate compound 3 (168 mg, 78.9%). LC-MS (M+H) + =441.89, 1 H NMR (400 MHz, DMSO) δ 12.27 (s, 1H), 10.00 (s, 1H), 8.88 (s, 1H), 8.37 (s, 1H), 8.21 (dd, J = 39.1, 8.2 Hz, 4H), 7.70 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 7.9Hz, 2H), 3.53 (s, 2H), 2.51 – 2.27 (m, 8H), 2.19 (s, 3H), 2.09 (s, 3H). 13 C NMR(101 MHz, DMSO) δ 168.62, 145.88, 141.65, 139.17, 137.78, 137.05, 136.38,135.20, 129.87, 129.10, 128.45, 126.83, 126.42, 119.66, 113.58, 62.20, 55.10,52.88, 46.02, 24.50. Example 4: 7-(1H-indol-5-yl)-2-(4-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-5H-pyrrolo[2,3-b]pyrazine (compound 4) The procedure was the same as step 2 in Example 1, reacting compound 1-1 (200 mg, 1.0 eq) with 4-(4-methylpiperazine-1-ylsulfonyl)phenylboronic acid pinacol ester (234 mg, 1.0 eq) to generate compound 4 (198 mg, 65.6%). LC-MS (M+H) + =427.83, 1 H NMR (400 MHz, DMSO) δ 12.31 (d, J = 2.7 Hz, 1H), 11.09 (s, 1H), 9.03 (s, 1H), 8.60 – 8.47 (m, 3H), 8.40 (d, J = 2.7 Hz, 1H), 8.03 (dd, J =8.4, 1.7 Hz, 1H), 7.89 (d, J = 8.2 Hz, 2H), 7.51 (d, J = 8.5 Hz, 1H), 7.37(t, J = 2.7 Hz, 1H), 6.54 (t, J = 2.5 Hz, 1H), 2.96 (t, J = 5.0 Hz, 4H), 2.38(t, J = 5.0 Hz, 4H), 2.14 (s, 3H). 13 C NMR (101 MHz, DMSO) δ 143.69, 142.86,142.16, 136.90, 135.65, 135.27, 134.86, 128.72, 128.65, 128.46, 127.55,126.02, 124.78, 120.51, 118.06, 115.75, 111.98, 101.89, 53.99, 46.24, 45.73. Example 5: (4-(7-(1H-indol-5-yl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)phenyl)(4-methylpiperazin-1-yl)methyl ketone (compound 5) The procedure was the same as step 2 in Example 1, reacting compound 1-1 (200 mg, 1.0 eq) with pinacol 4-(4-methylpiperazine-1-carbonyl)phenylboronic acid (211 mg, 1.0 eq) to generate compound 5 (189 mg, 67.7%). LC-MS (M+H) + =437.86,1 H NMR (400 MHz, DMSO) δ 12.22 (d, J = 2.8 Hz, 1H), 11.08 (s, 1H), 8.95 (s, 1H), 8.55 (d, J = 1.6 Hz, 1H), 8.39 – 8.25 (m, 3H), 8.03 (dd, J = 8.5, 1.7 Hz, 1H), 7.58 (d, J = 8.0 Hz, 2H), 7.50 (d, J = 8.5 Hz, 1H), 7.36 (t, J = 2.7 Hz, 1H), 6.52 (t, J = 2.5 Hz, 1H), 3.80 – 3.45 (m, 4H), 2.43 – 2.29 (m, 4H), 2.22(s, 3H). 13 C NMR (101 MHz, DMSO) δ 169.24, 144.84, 141.91, 139.52, 136.74,136.20, 135.22, 128.44, 128.18, 128.11, 126.90, 126.00, 124.95, 120.50,117.98, 115.60, 111.95, 101.84, 46.04. Example 6: 2-methoxy-5-(2-(4-(4-methylpiperazin-1-formyl)phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)benzonitrile (Compound 6) The procedure was the same as step 2 in Example 1, reacting compound 2-1 (57 mg, 1.0 eq) with pinacol 4-(4-methylpiperazine-1-carbonyl)phenylboronic acid (57.2 mg, 1.0 eq) to generate compound 6 (39 mg, 49.7%). LC-MS (M+H) + =453.86, 1 H NMR (400 MHz, DMSO-) D 6) δ 12.50 (d, J = 2.8 Hz, 1H), 8.92 (s, 1H), 8.69 (dd, J =8.9, 2.3 Hz, 1H), 8.51 (dd, J= 10.5, 2.4 Hz, 2H), 8.22 (d, J = 8.3 Hz, 2H), 7.52 (d, J = 8.3 Hz, 2H), 7.35 (d, J = 9.0 Hz, 1H), 3.92 (s, 3H), 3.51 – 3.38 (m, 4H), 2.40 – 2.28 (m, 4H), 2.19 (s, 3H). 13 C NMR (101 MHz, DMSO- D 6) δ169.23, 159.41, 145.29, 141.89, 139.22, 136.47, 136.23, 135.88, 132.65,130.50, 129.67, 128.17, 127.61, 127.01, 117.27, 113.21, 111.55, 101.03,56.89, 46.00, 29.54. Example 7: 2-methoxy-5-(2-(4-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)benzonitrile (Compound 7) The procedure was the same as step 2 in Example 1, reacting compound 2-1 (57 mg, 1.0 eq) with 4-(4-methylpiperazine-1-ylsulfonyl)phenylboronic acid pinacol ester (63.4 mg, 1.0 eq) to generate compound 7 (50 mg, 59%). LC-MS (M+H) + =489.85, 13 C NMR (101 MHz, DMSO-D6) δ 159.44, 144.19, 142.63, 142.11, 136.36, 136.28,135.04, 132.72, 130.54, 130.11, 128.88, 128.75, 128.68, 127.74, 127.42,117.22, 113.15, 111.70, 101.05, 56.86, 54.01, 46.28, 45.76. 1 H NMR (400 MHz, DMSO- D 6) δ 12.57 (s, 1H), 8.98 (s, 1H), 8.67 (dd, J = 8.9, 2.3 Hz, 1H), 8.51(dd,J = 8.5, 2.0 Hz, 2H), 8.41 (d, J = 8.6 Hz, 2H), 7.86 – 7.81 (m, 2H), 7.32 (d, J = 9.0 Hz, 1H), 3.92 (s, 3H), 2.94 – 2.87 (m, 4H), 2.38 – 2.32 (m,4H), 2.10 (s, 3H). Example 8: 7-(3-fluoro-4-methoxyphenyl)-2-(4-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-5H-pyrrolo[2,3-b]pyrazine (compound 8) Step 1: 2-Bromo-7-(3-fluoro-4-methoxyphenyl)-5H-pyrrole[2,3-b]pyrazine (compound 4-1) The procedure was the same as step 1 in Example 1, where tert-butyl 2-bromo-7-iodo-5H-pyrrolo[2,3-b]pyrazine-5-carboxylate (656 mg, 1.0 eq) and pinacol 3-fluoro-4-methoxyphenylboronic acid (262.9 mg, 1.0 eq) were reacted to generate compound 4-1 (330 mg, 66.2%). 13 C NMR (101 MHz, DMSO- D 6) δ 150.93, 145.98, 141.12, 138.50,136.95, 132.74, 130.09, 122.34, 114.70, 113.57, 113.38, 112.15, 56.55. 1 H NMR (400 MHz, DMSO-) D 6) δ 8.44 (d, J = 2.3 Hz, 1H), 8.38 (s, 1H), 7.96 – 7.84 (m,2H), 7.23 (d, J = 8.8 Hz, 1H), 3.83 (s, 3H). The procedure was the same as step 2 in Example 1, reacting compound 4-1 (100 mg, 1.0 eq) with 4-(4-methylpiperazine-1-ylsulfonyl)phenylboronic acid pinacol ester (113.7 mg, 1.0 eq) to generate compound 8 (84 mg, 56.2%). LC-MS (M+H) + =482.85, 1H NMR (400 MHz, DMSO) δ 12.47 (s, 1H), 9.03 (s, 1H), 8.55 – 8.42 (m,3H), 8.22 – 8.11 (m, 2H), 7.90 (d, J = 8.2 Hz, 2H), 7.28 (t, J = 9.0 Hz, 1H),3.90 (s, 3H), 2.97 (t, J = 5.0 Hz, 4H), 2.39 (t, J = 4.9 Hz, 4H), 2.15 (s, 3H). 13 C NMR (101 MHz, DMSO) δ 153.33, 150.92, 145.87, 145.76, 144.04, 142.62,142.11, 136.46, 136.05, 135.03, 129.67, 128.70, 127.61, 127.27, 127.20,122.40, 114.62, 113.63, 113.44, 112.68, 112.66, 56.49, 53.99, 46.25, 45.73. Example 9: (4-(7-(3-fluoro-4-methoxyphenyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)phenyl)(4-methylpiperazin-1-yl)methyl ketone (compound 9) The procedure was the same as step 2 in Example 1, reacting compound 4-1 (100 mg, 1.0 eq) with pinacol 4-(4-methylpiperazine-1-carbonyl)phenylboronic acid (102.5 mg, 1.0 eq) to generate compound 9 (76 mg, 56.7%). LC-MS (M+H) + =446.87, 1 HNMR (400 MHz, DMSO) δ 12.39 (s, 1H), 8.96 (s, 1H), 8.46 (s, 1H), 8.27 (d, J =7.9 Hz, 2H), 8.21 – 8.12 (m, 2H), 7.57 (d, J = 7.9 Hz, 2H), 7.28 (t, J = 8.9Hz, 1H), 3.90 (s, 3H), 3.65 (t, 4H), 2.35 (t, 4H), 2.22 (s, 3H).13 C NMR (101MHz, DMSO) δ 169.16, 145.80, 145.69, 145.12, 141.88, 139.21, 136.40, 136.31,135.62, 129.21, 128.10, 127.46, 126.89, 122.32, 114.64, 113.57, 113.38,112.52, 56.50, 46.07. Example 10: 7-(3-fluoro-4-methoxyphenyl)-2-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-5H-pyrrolo[2,3-b]pyrazine (Compound 10) The procedure was the same as step 2 in Example 1, reacting compound 4-1 (100 mg, 1.0 eq) with pinacol 4-(4-methyl-1-piperazinmethyl)phenylboronic acid (98.1 mg, 1.0 eq) to generate compound 10 (74 mg, 60%). LC-MS (M+H) + =432.88, 1 H NMR (400 MHz, DMSO) δ 12.33 (s, 1H), 8.89 (s, 1H), 8.43 (s, 1H), 8.21 – 8.11 (m,4H), 7.46 (d, J = 8.0 Hz, 2H), 7.28 (t, J = 8.8 Hz, 1H), 3.89 (s, 3H), 3.52(s, 2H), 2.49 – 2.25 (m, 8H), 2.16 (s, 3H). 13 C NMR (101 MHz, DMSO) δ 150.93,145.96, 145.73, 145.62, 141.66, 139.33, 136.97, 136.21, 135.35, 129.82,128.83, 127.60, 127.53, 126.80, 122.27, 114.63, 113.55, 113.36, 112.40,62.21, 56.49, 55.20, 53.01, 46.16. Example 11: (4-(7-(1-methyl-1H-indol-5-yl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)phenyl)(4-methylpiperazin-1-yl)methyl ketone (Compound 11) Step 1: 2-Bromo-7-(1-Methyl-1H-indol-5-yl)-5H-pyrrole[2,3-b]pyrazine (Compound 5-1) The procedure is the same as step 1 in Example 1, where tert-butyl 2-bromo-7-iodo-5H-pyrrolo[2,3-b]pyrazine-5-carboxylate (500 mg, 1.0 eq) and pinacol 1-methylindole-5-boronic acid (303 mg, 1.0 eq) are reacted to generate compound 5-1 (100 mg, 25.9%). 13 C NMR (101 MHz, DMSO- D 6) δ 141.17, 138.08, 137.33, 135.90, 132.50,130.56, 129.31, 128.78, 124.29, 120.32, 118.15, 114.98, 110.40, 101.08,33.06. 1 H NMR (400 MHz, DMSO- D 6) δ 8.39 (d, J = 2.9 Hz, 1H), 8.37 (s, 1H), 8.32– 8.30 (m, 1H), 7.84 (dd, J = 8.5, 1.7 Hz, 1H), 7.46 (dd, J = 8.6, 0.8 Hz, 1H), 7.29 (d, J = 3.1 Hz, 1H), 6.45 (dd, J = 3.1, 0.8 Hz, 1H), 3.77 (s, 3H). The procedure was the same as step 2 in Example 1, reacting compound 5-1 (100 mg, 1.0 eq) with pinacol 4-(4-methylpiperazine-1-carbonyl)phenylboronic acid (100.1 mg, 1.0 eq) to generate compound 11 (110 mg, 75.5%). LC-MS (M+H) + =451.85, 1 HNMR (400 MHz, DMSO- D 6) δ 8.91 (s, 1H), 8.51 (d, J = 1.5 Hz, 1H), 8.34 (d, J =2.6 Hz, 1H), 8.26 (d, J = 8.4 Hz, 2H), 8.06 (dd,J = 8.6, 1.6 Hz, 1H), 7.53(d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.6 Hz, 1H), 7.28 (d, J = 3.0 Hz, 1H), 6.46(dd, J = 3.0, 0.8 Hz, 1H), 3.77 (s, 3H), 3.61 (s, 2H), 2.47 – 2.23 (m, 6H), 2.16 (s, 3H). 13 C NMR (101 MHz, DMSO- D 6) δ 169.31, 144.88, 141.99, 139.56,136.79, 136.26, 135.81, 135.32, 130.39, 128.85, 128.40, 128.20, 126.95,125.19, 120.53, 118.21, 115.38, 110.32, 101.12, 46.10, 33.04. Example 12: (4-(7-(benzo[b]thiophene-5-yl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)phenyl)(4-methylpiperazin-1-yl)methyl ketone (compound 12) Step 1: 7-(benzo[b]thiophen-5-yl)-2-bromo-5H-pyrrole[2,3-b]pyrazole (compound 6-1) The procedure was the same as step 1 in Example 1, where tert-butyl 2-bromo-7-iodo-5H-pyrrolo[2,3-b]pyrazine-5-carboxylate (500 mg, 1.0 eq) and 2-(1-benzothiophene-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxoborane (306.8 mg, 1.0 eq) were reacted to generate compound 6-1 (150 mg, 38.5%). 13 C NMR (101 MHz, DMSO- D 6) δ 141.26,140.44, 138.52, 137.57, 137.26, 132.82, 130.47, 129.74, 128.42, 124.69,123.31, 123.10, 120.86, 113.50. 1 H NMR (400 MHz, DMSO-D 6) δ 8.61 (d, J = 1.6Hz, 1H), 8.54 (s, 1H), 8.41 (s, 1H), 8.11 – 8.00 (m, 2H), 7.74 (d, J = 5.4Hz, 1H), 7.49 (dd, J = 5.4, 0.7 Hz, 1H). The procedure was the same as step 2 in Example 1, reacting compound 6-1 (150 mg, 1.0 eq) with pinacol 4-(4-methylpiperazine-1-carbonyl)phenylboronic acid (150 mg, 1.0 eq) to generate compound 12 (146 mg, 70%). LC-MS (M+H) + =454.87, 1 H NMR (400 MHz, DMSO-) D 6) δ 12.45 (s, 1H), 8.94 (s, 1H), 8.85 (d, J = 1.6 Hz, 1H),8.50 (s, 1H), 8.32 – 8.22 (m, 3H), 8.04 (d, J = 8.5 Hz, 1H), 7.74 (d, J = 5.4Hz, 1H), 7.55 – 7.50 (m, 3H), 3.72 – 3.38 (m, 4H), 2.42 – 2.22 (m, 4H), 2.16(s, 3H). 13 C NMR (101 MHz, DMSO- D 6) δ 169.28, 145.21, 142.05, 140.51, 139.35,137.25, 136.69, 136.38, 135.68, 130.58, 129.65, 128.21, 127.06, 124.83,123.24, 123.20, 121.03, 113.87, 46.12. Example 13: 7-(benzo[b]thiophene-5-yl)-2-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-5H-pyrrolo[2,3-b]pyrazine (Compound 13) The procedure was the same as step 2 in Example 1, reacting compound 6-1 (164 mg, 1.0 eq) with pinacol 4-(4-methyl-1-piperazinmethyl)phenylboronic acid (157 mg, 1.0 eq) to generate compound 13 (160 mg, 74%). LC-MS (M+H) + =440.88, 1 H NMR (400 MHz, DMSO) δ 12.38 (s, 1H), 8.96 – 8.89 (m, 2H), 8.52 (s, 1H), 8.32 (dd, J = 8.5, 1.7 Hz, 1H), 8.24 – 8.16 (m, 2H), 8.09 (d, J = 8.5 Hz, 1H), 7.79 (d, J = 5.4 Hz, 1H), 7.56 (d, J = 5.4 Hz, 1H), 7.48 (d, J = 8.0 Hz, 2H), 3.53 (s,2H), 2.52 – 2.29 (m, 8H), 2.19 (s, 3H). 13 C NMR (101 MHz, DMSO) δ 146.00,141.79, 140.43, 139.21, 137.12, 137.04, 136.52, 135.34, 130.63, 129.87,129.15, 128.04, 126.89, 124.74, 123.18, 123.07, 120.95, 113.75, 62.18, 55.09,52.86, 45.99. Example 14: 2-(3-fluoro-4-((4-methylpiperazin-1-yl)methyl)phenyl)-7-(1H-indol-5-yl)-5H-pyrrolo[2,3-b]pyrazine (Compound 14) Step 1: 4-(7-(1H-indol-5-yl)-5H-carbazolo[2,3-b]pyrazin-2-yl)-2-fluorobenzaldehyde (compound 7-1) The procedure was the same as step 2 in Example 1, where compound 1-1 (250 mg, 1.0 eq) and pinacol 3-fluoro-4-aldehyde phenylboronic acid (134.1 mg, 1.0 eq) were reacted to generate compound 7-1 (152 mg, 53.4%). 13C NMR (101 MHz, DMSO- D 6) δ188.09, 146.70, 142.78, 142.36, 136.97, 136.06, 135.34, 130.60, 129.01,128.51, 126.16, 124.72, 123.17, 120.60, 118.12, 115.89, 114.51, 114.29,112.09, 101.92. 1 H NMR (400 MHz, DMSO- D 6) δ 12.31 (d, J = 2.8 Hz, 1H), 11.06(s, 1H), 10.25 (s, 1H), 9.04 (s, 1H), 8.46 (d, J = 1.6 Hz, 1H), 8.36 (d, J =2.8 Hz, 1H), 8.27 (dd, J = 8.1, 1.5 Hz, 1H), 8.21 (dd, J = 12.3, 1.6 Hz, 1H),8.00 – 7.94 (m, 2H), 7.46 (d, J = 8.5 Hz, 1H), 7.32 (t, J = 2.7 Hz, 1H), 6.47(ddd, J = 2.9, 1.9, 0.9 Hz, 1H). Step 2: 2-(3-fluoro-4-((4-methylpiperazin-1-yl)methyl)phenyl)-7-(1H-indol-5-yl)-5H-pyrrolo[2,3-b]pyrazine (compound 14) Compound 7-1 (200 mg, 1.0 eq) and N-methylpiperazine (122.3 mg, 2 eq) were dissolved in a mixture of DCM (20 mL) and methanol (4 mL), followed by the addition of NaBH3CN (52.9 mg, 1.5 eq) and AcOH (212 mg, 6.3 eq). The mixture was refluxed and stirred at 50 °C for 8 hours. After the reaction was complete, the mixture was cooled to room temperature and concentrated under reduced pressure, followed by purification by silica gel column chromatography to give compound 14 (47 mg, 19%). LC-MS (M+H) + =441.89, 13 C NMR (101 MHz, DMSO- D6) δ 144.25,141.99, 139.78, 136.66, 135.27, 135.20, 128.49, 128.29, 126.10, 125.30,125.15, 124.98, 122.56, 120.56, 118.02, 115.61, 112.04, 101.88, 55.20, 54.96,52.92, 46.22. 1 H NMR (400 MHz, DMSO- D 6) δ 12.18 (s, 1H), 11.05 (s, 1H), 8.89 (s, 1H), 8.47 (d, J = 1.5 Hz, 1H), 8.30 (s, 1H), 8.01 (dd, J = 7.9, 1.7 Hz,1H), 7.98 – 7.93 (m, 2H), 7.51 (t, J = 7.9 Hz, 1H), 7.45 (d, J = 8.5 Hz, 1H), 7.31 (t, J = 2.7 Hz, 1H), 6.46 (t, J = 1.1 Hz, 1H), 3.53 (s, 2H), 2.43 – 2.24(m, 8H), 2.11 (s, 3H). Example 15: 7-(1-methyl-1H-indol-5-yl)-2-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-5H-pyrrole[2,3-b]pyrazine (compound 15) The procedure was the same as step 2 in Example 1, reacting compound 5-1 (74 mg, 1.0 eq) with pinacol 4-(4-methyl-1-piperazinmethyl)phenylboronic acid (71.5 mg, 1.0 eq) to generate compound 15 (72 mg, 73%). LC-MS (M+H) + =437.92, 1 H NMR (400 MHz, DMSO) δ 12.18 (d, J = 2.7 Hz, 1H), 8.88 (s, 1H), 8.56 (d, J = 1.6Hz, 1H), 8.35 (d, J = 2.6 Hz, 1H), 8.17 (d, J= 8.1 Hz, 2H), 8.10 (dd, J =8.6, 1.7 Hz, 1H), 7.50 (dd, J = 20.4, 8.3 Hz, 3H), 7.32 (d, J = 3.1 Hz, 1H), 6.50 (d, J = 3.0 Hz, 1H), 3.82 (s, 3H), 3.54 (s, 2H), 2.51 – 2.30 (m, 8H), 2.20 (s, 3H). 13 C NMR (101 MHz, DMSO) δ 145.66, 141.72, 139.06, 137.26, 136.60,135.72, 134.99, 130.27, 129.86, 128.79, 127.92, 126.81, 125.23, 120.47,118.14, 115.24, 110.20, 101.05, 62.16, 55.06, 52.80, 45.94, 32.97. Example 16: 4-(4-(7-(1H-indol-5-yl)-5H-pyrrolo[2,3-b]pyrimidin-2-yl)-2-fluorobenzyl)morpholine (compound 16) The procedure was the same as step 2 in Example 1, reacting compound 1-1 (150 mg, 1.0 eq) with pinacol ester of 3-fluoro-4-(4-morpholinomethyl)phenylboronic acid (153.8 mg, 1.0 eq) to generate compound 16 (32 mg, 15.6%). LC-MS (M+H) + =428.91, 1 H NMR (400 MHz, DMSO- D 6) δ 12.25 (s, 1H), 11.13 (s, 1H), 8.90 (s, 1H), 8.47(s, 1H), 8.30 (d, J = 2.8 Hz, 1H), 8.11 – 7.82 (m, 3H), 7.54 (s, 1H), 7.45(d, J = 8.5 Hz, 1H), 7.31 (t, J = 2.7 Hz, 1H), 6.46 (s, 1H), 3.63 – 3.49 (m, 6H), 2.45 – 2.14 (m, 4H).13 C NMR (101 MHz, DMSO- D 6) δ 160.65, 144.15, 142.00,136.67, 135.27, 135.21, 128.48, 128.34, 126.10, 124.97, 122.58, 120.53,118.00, 115.58, 113.51, 113.27, 112.06, 101.84, 66.66, 53.48, 29.56. Example 17: 7-(3-fluorophenyl)-2-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-5H-pyrrolo[2,3-b]pyrazine (compound 17) Step 1: 2-Bromo-7-(3-fluorophenyl)-5H-pyrrolo[2,3-b]pyrazine (Compound 8-1) The procedure is the same as step 1 in Example 1, where tert-butyl 2-bromo-7-iodo-5H-pyrrolo[2,3-b]pyrazine-5-carboxylate (500 mg, 1.0 eq) and pinacol 3-fluorophenylboronic acid (165 mg, 1.0 eq) are reacted to generate compound 8-1 (150 mg, 43.7%). 13 C NMR (101 MHz, DMSO- D 6) δ 161.88, 141.25, 138.74, 137.06, 132.99,131.22, 122.01 (d, J = 2.7 Hz), 113.40, 113.19, 112.52, 112.30. 1 H NMR (400MHz, DMSO- D 6) δ 8.57 (s, 1H), 8.40 (s, 1H), 7.99 – 7.87 (m, 2H), 7.44 (td, J = 8.0, 6.4 Hz, 1H), 7.06 – 6.99 (m, 1H). The procedure was the same as step 2 in Example 1, reacting compound 8-1 (150 mg, 1.0 eq) with pinacol 4-(4-methyl-1-piperazinmethyl)phenylboronic acid (162.6 mg, 1.0 eq) to generate compound 17 (80 mg, 38.8%). LC-MS (M+H) + =402.94, 13C NMR (101 MHz, DMSO- D 6) δ 164.33, 161.92, 146.25, 141.82, 139.39, 136.98,136.37, 135.64, 130.19, 129.97, 126.94, 122.04, 112.95, 112.74, 112.56,112.34, 62.18, 55.08, 52.83, 45.98. 1 H NMR (400 MHz, DMSO- D 6) δ 12.48 (s, 1H), 8.86 (s, 1H), 8.52 (s, 1H), 8.19 – 8.14 (m, 2H), 8.10 (d, J = 8.3 Hz, 2H),7.49 – 7.40 (m, 3H), 7.11 – 6.87 (m, 1H), 3.49 (s, 2H), 2.46 – 2.26 (m, 8H),2.15 (s, 3H). Example 18: 4-(2-fluoro-4-(7-(3-fluorophenyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)benzyl)morpholine (compound 18) The procedure was the same as step 2 in Example 1, reacting compound 8-1 (150 mg, 1.0 eq) with pinacol ester of 3-fluoro-4-(4-morpholinomethyl)phenylboronic acid (165 mg, 1.0 eq) to generate compound 18 (50 mg, 24%). LC-MS (M+H) + =407.86, 13 CNMR (101 MHz, DMSO- D 6) δ 161.91, 160.61, 142.06, 136.36, 135.78, 130.99,130.58, 122.61, 122.08, 113.58, 113.35, 113.03, 112.82, 112.41, 112.37,66.71, 55.34, 53.53. 1 H NMR (400 MHz, DMSO- D 6) δ 12.55 (s, 1H), 8.92 (s, 1H), 8.54 (s, 1H), 8.18 – 8.09 (m, 2H), 7.98 (dd, J= 7.9, 1.7 Hz, 1H), 7.93 (dd, J = 11.5, 1.7 Hz, 1H), 7.52 (t, J = 7.8 Hz, 1H), 7.48 – 7.40 (m, 1H), 7.08 – 6.97 (m, 1H), 3.56 – 3.52 (m, 6H), 2.41 – 2.33 (m, 4H). Example 19: (4-(7-(1H-indol-5-yl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-2-methoxyphenyl)(4-methylpiperazin-1-yl)methyl ketone (compound 19) Step 1: Methyl 4-(7-(1H-indol-5-yl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-2-methoxybenzoate (Compound 9-1) The procedure was the same as step 2 in Example 1, where compound 1-1 (100 mg, 1.0 eq) and pinacol 3-methoxy-4-methoxycarbonylphenylboronic acid (93.2 mg, 1.0 eq) were reacted to generate compound 9-1 (100 mg, 78%). 13 C NMR (101 MHz, DMSO- D 6) δ 166.52, 159.35, 144.13, 143.54, 142.18, 136.80, 135.65, 135.25, 132.15,128.52, 128.43, 126.14, 124.92, 120.43, 119.96, 118.51, 118.17, 115.58,112.04, 110.58, 101.87, 56.31, 52.47. 1 H NMR (400 MHz, DMSO- D 6) δ 12.22 (s,1H), 11.04 (s, 1H), 9.01 (s, 1H), 8.72 – 8.41 (m, 1H), 8.34 (d, J = 2.7 Hz,1H), 8.01 – 7.93 (m, 2H), 7.87 (dd, J = 8.1, 1.5 Hz, 1H), 7.81 (d, J = 8.1Hz, 1H), 7.45 (dt, J= 8.6, 0.9 Hz, 1H), 7.32 (t, J = 2.7 Hz, 1H), 6.45 (ddd, J = 2.9, 1.9, 0.9 Hz, 1H), 3.99 (s, 3H), 3.80 (s, 3H). Step 2: 4-(7-(1H-indol-5-yl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-2-methoxybenzoic acid (compound 10-1) Compound 9-1 (225 mg, 1 eq) was dissolved in THF (10 mL) and H2O (10 mL). LiOH (238 mg, 10 eq) was added with stirring at 0 °C, and the reaction was then refluxed and stirred at 50 °C for 10 hours. After the reaction was complete, the mixture was cooled to room temperature and concentrated under reduced pressure to remove THF. The solution was then extracted twice with EA, and the aqueous layer was collected. Citric acid was added to the aqueous layer, and the precipitated solid was filtered and then purified by silica gel column chromatography to obtain compound 10-1 (197 mg, 90%).

[0023] Step 3: (4-(7-(1H-indol-5-yl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-2-methoxyphenyl)(4-methylpiperazin-1-yl)methyl ketone (compound 19) Compound 10-1 (195 mg, 1 eq), DIPEA (196.8 mg, 3 eq), and HATU (289.5 mg, 1.5 eq) were sequentially added to DMF (10 mL). After stirring at 50 °C for 30 minutes, N-methylpiperazine (203.4 mg, 4 eq) was added, and the reaction was allowed to proceed for 8 hours. After the reaction was complete, the mixture was cooled to room temperature and concentrated under reduced pressure, followed by purification by silica gel column chromatography to obtain compound 19 (116 mg, 35.6%). LC-MS (M+H) + =467.2, 13 C NMR (101 MHz, DMSO- D 6) δ 166.77, 155.97, 144.84,142.01, 140.66, 136.68, 135.37, 135.22, 128.86, 128.49, 126.17, 126.10,125.01, 120.40, 119.34, 118.08, 115.48, 112.03, 109.67, 101.83, 56.05, 55.28,54.82, 46.74, 46.16, 41.43. 1H NMR (400 MHz, DMSO- D 6) δ 12.22 (d, J = 2.8 Hz, 1H), 11.10 (d, J = 2.2 Hz, 1H), 8.95 (s, 1H), 8.58 (d, J = 1.6 Hz, 1H), 8.31(d, J = 2.7 Hz, 1H), 7.95 (dd, J = 8.5, 1.7 Hz, 1H), 7.90 (d, J = 1.5 Hz, 1H), 7.83 (dd, J = 7.8, 1.5 Hz, 1H), 7.44 (d, J = 8.5 Hz, 1H), 7.35 – 7.27(m, 2H), 6.44 (ddd, J = 2.9, 1.9, 0.8 Hz, 1H), 3.95 (s, 3H), 3.61 (d, J =21.9 Hz, 2H), 3.21 – 3.14 (m, 2H), 2.40 – 2.19 (m, 4H), 2.16 (s, 3H). Example 20: 4-(2-fluoro-4-(7-(1-methyl-1H-indol-5-yl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)benzyl)morpholine (compound 20) The procedure was the same as step 2 in Example 1, where compound 5-1 (100 mg, 1.0 eq) and 3-fluoro-4-(4-morpholinomethyl)phenylboronic acid pinacol ester (117.8 mg, 1.2 eq) were reacted to generate compound 20 (35 mg, 26%). 13 C NMR (101 MHz, DMSO- D 6) δ 142.01, 136.65, 135.81, 135.23, 130.42, 128.84, 128.45, 125.15,122.57, 120.54, 118.18, 115.33, 113.49, 110.34, 101.10, 66.71, 55.36, 53.54,33.05. 1 H NMR (400 MHz, DMSO- D 6) δ 12.26 (d,J = 2.8 Hz, 1H), 8.90 (s, 1H), 8.47 (d, J = 1.5 Hz, 1H), 8.33 (d, J = 2.8 Hz, 1H), 8.07 – 7.95 (m, 3H), 7.54– 7.47 (m, 2H), 7.29 (d, J = 3.0 Hz, 1H), 6.45 (dd, J = 3.0, 0.8 Hz, 1H), 3.78 (s, 3H), 3.57 – 3.52 (m, 6H), 2.43 – 2.35 (m, 4H). Example 21: (2-methoxy-4-(7-(1-methyl-1H-indol-5-yl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)phenyl)(4-methylpiperazin-1-yl)methyl ketone (Compound 21) Step 1: Methyl 2-methoxy-4-(7-(1-methyl-1H-indol-5-yl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)benzoate (Compound 11-1) The procedure was the same as step 2 in Example 1, where compound 5-1 (130 mg, 1.0 eq) and pinacol 3-methoxy-4-methoxycarbonylphenylboronic acid (127.7 mg, 1.1 eq) were reacted to generate compound 11-1 (75 mg, 45.8%).

[0024] Step 2: 2-Methoxy-4-(7-(1-methyl-1H-indol-5-yl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)benzoic acid (compound 12-1) The procedure is the same as step 2 in Example 19, where compound 11-1 (75 mg, 1.0 eq) is hydrolyzed to generate compound 12-1 (55 mg, 76%).

[0025] The procedure was the same as step 3 of Example 19, reacting compound 12-1 (55 mg, 1.0 eq) with N-methylpiperazine (55 mg, 4 eq) to generate compound 21 (20 mg, 30%). LC-MS (M+H) + =481.25, 13 C NMR (101 MHz, DMSO- D6) δ156.07, 144.70, 142.06, 136.70, 135.77, 135.45, 130.44, 128.85, 128.39,125.15, 124.78, 120.40, 119.40, 118.27, 115.25, 110.32, 101.05, 45.90, 42.59,38.50, 33.07, 29.56, 8.98. 1 H NMR (400 MHz, DMSO- D 6) δ 8.97 (s, 1H), 8.59 (d, J = 1.6 Hz, 1H), 8.35 (d, J = 2.8 Hz, 1H), 8.03 (dd, J = 8.6, 1.6 Hz, 1H), 7.96– 7.82 (m, 2H), 7.48 (d, J = 8.6 Hz, 1H), 7.40 (s, 1H), 7.29 (d, J = 3.0 Hz, 1H), 6.42 (d, J = 3.0 Hz, 1H), 3.98 (s, 3H), 3.78 (s, 3H), 3.02 (qd, J = 7.3, 4.8 Hz, 11H). Example 22: (4-(7-(1H-indol-5-yl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-3-methylphenyl)(4-methylpiperazin-1-yl) methyl ketone (compound 22) Step 1: Methyl 4-(7-(1H-indol-5-yl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-3-methylbenzoate (Compound 13-1) The procedure was the same as step 2 in Example 1, where compound 1-1 (100 mg, 1.0 eq) and 4-(methoxycarbonyl)-2-methylphenylboronic acid pinacol ester (97 mg, 1.1 eq) were reacted to generate compound 13-1 (90 mg, 73.8%). 13 C NMR (101 MHz, DMSO- D6) δ 166.70, 147.21, 143.57, 141.33, 137.48, 137.36, 136.28, 135.24, 132.04,131.13, 129.58, 128.44, 128.15, 127.38, 126.09, 124.91, 120.45, 117.95,115.59, 111.98, 101.79, 52.75, 21.01. 1 H NMR (400 MHz, DMSO- D 6) δ 12.22 (d, J =2.9 Hz, 1H), 11.02 (d, J = 2.7 Hz, 1H), 8.49 – 8.40 (m, 2H), 8.33 (d, J = 2.8Hz, 1H), 7.96 (d, J = 1.8 Hz, 1H), 7.89 (ddd, J = 8.6, 6.9, 1.7 Hz, 2H), 7.67(d, J = 8.0 Hz, 1H), 7.40 (d, J = 8.5 Hz, 1H), 7.28 (t, J = 2.7 Hz, 1H), 6.40(t, J = 2.6 Hz, 1H), 3.87 (s, 3H), 2.51 (s, 3H). Step 2: 4-(7-(1H-indol-5-yl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-3-methylbenzoic acid (compound 14-1) The procedure was the same as step 2 in Example 19, where compound 13-1 (140 mg, 1.0 eq) was hydrolyzed to generate compound 14-1 (36 mg, 26.7%). 13 C NMR (101 MHz, DMSO- D6) δ 167.79, 147.42, 143.17, 141.31, 137.49,137.11, 136.27, 135.23, 132.24, 130.97, 130.75, 128.44, 128.08, 127.54,126.09, 124.93, 120.45, 117.94, 115.57, 111.99, 101.80, 21.03. 1 H NMR (400MHz, DMSO- D 6) δ 12.21 (d, J = 2.9 Hz, 1H), 11.02 (s, 1H), 8.45 (s, 1H), 8.43(d, J = 0.9 Hz, 1H), 8.33 (d, J = 2.8 Hz, 1H), 7.94 (s, 1H), 7.89 (d, J = 8.5Hz, 2H), 7.64 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 8.5 Hz, 1H), 7.28 (t, J = 2.7Hz, 1H), 6.41 (d, J = 1.0 Hz, 1H), 2.50 (s, 3H). The procedure was the same as step 3 of Example 19, reacting compound 14-1 (70 mg, 1.0 eq) with N-methylpiperazine (76.2 mg, 4.0 eq) to generate compound 22 (22 mg, 25.6%). LC-MS (M+H) + =451.25.

[0026] Example 23: (4-(7-(1H-indol-5-yl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-2-fluorophenyl)(4-methylpiperazin-1-yl) methyl ketone (compound 23) Step 1: Methyl 4-(7-(1H-indol-5-yl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-2-fluorobenzoate (Compound 15-1) The procedure was the same as step 2 in Example 1, where compound 1-1 (100 mg, 1.0 eq) and 3-fluoro-4-(methoxycarbonyl)phenylboronic acid pinacol ester (63.2 mg, 1.0 eq) were reacted to generate compound 15-1 (86 mg, 70%). 13 C NMR (101 MHz, DMSO- D 6)δ 164.42, 145.32, 142.82, 142.32, 136.89, 135.83, 135.33, 133.03, 128.89,128.50, 126.15, 124.77, 122.69, 120.59, 118.12, 117.81, 115.83, 114.96,114.72, 112.07, 101.91, 52.94. 1 H NMR (400 MHz, DMSO- D 6) δ 12.28 (d, J = 2.8Hz, 1H), 11.06 (s, 1H), 9.01 (s, 1H), 8.47 – 8.45 (m, 1H), 8.35 (d, J = 2.9Hz, 1H), 8.21 – 8.13 (m, 2H), 8.03 (t, J = 8.0 Hz, 1H), 7.95 (dd, J = 8.5, 1.7 Hz, 1H), 7.46 (d, J = 8.5 Hz, 1H), 7.32 (t, J = 2.7 Hz, 1H), 6.47 (t, J =2.8 Hz, 1H), 3.86 (s, 3H). Step 2: 4-(7-(1H-indol-5-yl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-2-fluorobenzoic acid (compound 16-1) The procedure was the same as step 2 in Example 19, where compound 15-1 (155 mg, 1.0 eq) was hydrolyzed to generate compound 16-1 (34 mg, 24.5%). 13 C NMR (101 MHz, DMSO- D6) δ 165.44, 160.99, 144.78, 143.04, 142.28,136.87, 135.77, 135.32, 133.20, 128.81, 128.50, 126.15, 124.80, 122.54,120.60, 118.10, 115.81, 114.90, 114.66, 112.08, 101.92. 1 H NMR (400 MHz, DMSO- D 6) δ 12.27 (d, J = 2.8 Hz, 1H), 11.06 (s, 1H), 9.00 (s, 1H), 8.56 – 8.41 (m,1H), 8.34 (d, J = 2.8 Hz, 1H), 8.17 (dd, J = 8.2, 1.7 Hz, 1H), 8.12 (dd, J =12.4, 1.7 Hz, 1H), 8.02 (t, J = 8.0 Hz, 1H), 7.96 (dd, J = 8.5, 1.7 Hz, 1H), 7.46 (dd, J = 8.4, 0.9 Hz, 1H), 7.32 (t, J = 2.7 Hz, 1H), 6.47 (ddd, J = 3.0, 1.9, 0.9 Hz, 1H). The procedure was the same as step 3 in Example 19, reacting compound 16-1 (110 mg, 1.0 eq) with N-methylpiperazine (118.4 mg, 4 eq) to generate compound 23 (57 mg, 42.5%). LC-MS (M+H) + =455.17, 13 C NMR (101 MHz, DMSO- D 6) δ 164.37, 143.50, 142.17, 136.76, 135.47, 135.30, 130.05, 128.64, 128.48,126.13, 124.86, 123.27, 120.55, 118.03, 115.69, 112.08, 101.85, 54.87, 54.35,46.57, 45.81. 1H NMR (400 MHz, DMSO- D 6) δ 12.29 (d, J = 2.8 Hz, 1H), 11.12 (d, J = 2.3 Hz, 1H), 8.96 (s, 1H), 8.46 (d, J = 1.5 Hz, 1H), 8.33 (d, J = 2.7 Hz,1H), 8.18 – 8.05 (m, 2H), 7.96 (dd, J = 8.5, 1.7 Hz, 1H), 7.54 (t, J = 7.6Hz, 1H), 7.45 (d, J = 8.5 Hz, 1H), 7.31 (t, J = 2.7 Hz, 1H), 6.46 (t, J = 2.6Hz, 1H), 3.69 (t, 2H), 2.99 (q, J = 7.3 Hz, 2H), 2.46 – 2.37 (m, 4H), 2.26(s, 3H). Example 24: (4-(7-(1H-indol-5-yl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-2-methylphenyl)(4-methylpiperazin-1-yl) methyl ketone (compound 24) Step 1: Methyl 4-(7-(1H-indol-5-yl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-2-methylbenzoate (Compound 17-1) The procedure is the same as step 2 in Example 1, where compound 1-1 (150 mg, 1.0 eq) and methyl 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)benzoate (145.6 mg, 1.1 eq) are reacted to generate compound 17-1 (150 mg, 82%). 13 C NMR (101 MHz, DMSO- D6) δ 167.66, 144.31, 142.06, 141.84,140.48, 136.86, 135.59, 135.28, 131.47, 129.91, 129.37, 128.50, 128.41,126.11, 124.94, 124.42, 120.57, 118.12, 115.70, 112.04, 101.90, 52.48,22.07. 1 H NMR (400 MHz, DMSO- D 6) δ 12.20 (d, J = 2.8 Hz, 1H), 11.05 (s, 1H), 8.94 (s, 1H), 8.52 – 8.48 (m, 1H), 8.31 (d, J = 2.8 Hz, 1H), 8.19 – 8.12 (m,2H), 8.01 – 7.92 (m, 2H), 7.48 – 7.43 (m, 1H), 7.32 (t, J = 2.7 Hz, 1H), 6.47(ddd, J = 3.0, 1.8, 0.8 Hz, 1H), 3.83 (s, 3H), 2.63 (s, 3H). Step 2: 4-(7-(1H-indol-5-yl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-2-methylbenzoic acid (compound 18-1) The procedure was the same as step 2 in Example 19, where compound 17-1 (150 mg, 1.0 eq) was hydrolyzed to generate compound 18-1 (26 mg, 18%). 1 H NMR (400 MHz, DMSO- D 6) δ 12.19 (d, J = 2.9 Hz, 1H), 11.05 (d, J = 2.3Hz, 1H), 8.93 (s, 1H), 8.50 (d, J = 1.5 Hz, 1H), 8.31 (d, J = 2.8 Hz, 1H), 8.12 (d, J = 7.8 Hz, 2H), 8.02 – 7.85 (m, 2H), 7.45 (d, J= 8.4 Hz, 1H), 7.31(t, J = 2.7 Hz, 1H), 6.47 (t, J = 2.5 Hz, 1H), 2.64 (s, 3H). 13 C NMR (101 MHz, DMSO- D 6) δ 169.04, 144.53, 142.02, 141.46, 140.38, 136.83, 135.55, 135.27,131.64, 130.53, 129.87, 128.49, 128.34, 126.11, 124.96, 124.33, 120.57,118.10, 115.68, 112.04, 101.90, 22.24. The procedure was the same as step 3 in Example 19, reacting compound 18-1 (100 mg, 1.0 eq) with N-methylpiperazine (108.7 mg, 4 eq) to generate compound 24 (22 mg, 18%). LC-MS (M+H) + =451.20, 13 C NMR (101 MHz, DMSO- D 6)δ 168.91, 145.10, 141.89, 138.77, 136.85, 136.72, 135.25, 134.92, 128.74,128.48, 128.13, 126.95, 126.08, 125.04, 124.55, 120.54, 118.04, 115.58,112.04, 101.86, 55.33, 54.81, 46.72, 46.05, 19.47. 1 H NMR (400 MHz, DMSO- D 6) δ12.19 (d, J = 2.8 Hz, 1H), 11.09 (d, J = 2.3 Hz, 1H), 8.87 (s, 1H), 8.50 (s,1H), 8.29 (d, J = 2.8 Hz, 1H), 8.11 – 8.03 (m, 2H), 7.96 (dd, J = 8.5, 1.7Hz, 1H), 7.45 (d, J= 8.5 Hz, 1H), 7.32 – 7.27 (m, 2H), 6.46 (ddd, J = 3.0,1.9, 0.8 Hz, 1H), 3.66 (t, 2H), 3.18 (t, J = 5.1 Hz, 2H), 2.37 (t, 2H), 2.32(s, 3H), 2.23 (t, J = 15.8 Hz, 2H), 2.17 (s, 3H). Example 25: (4-(7-(1H-indol-5-yl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-3-fluorophenyl)(4-methylpiperazin-1-yl) methyl ketone (Compound 25) Step 1: Methyl 4-(7-(1H-indol-5-yl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-3-fluorobenzoate (Compound 19-1) The procedure was the same as step 2 in Example 1, where compound 1-1 (100 mg, 1.0 eq) and 2-fluoro-4-(methoxycarbonyl)phenylboronic acid pinacol ester (98.4 mg, 1.1 eq) were reacted to generate compound 19-1 (94 mg, 76.4%). 13 C NMR (101 MHz, DMSO- D 6) δ 165.58, 158.65, 141.70, 141.07, 137.82, 137.28, 135.32, 132.17,131.80, 131.12, 128.75, 128.46, 126.12, 124.73, 120.56, 118.14, 117.60,117.35, 115.81, 112.03, 101.89, 53.12. 1 H NMR (400 MHz, DMSO- D 6) δ 12.31 (d, J = 2.8 Hz, 1H), 11.04 (s, 1H), 8.72 (d, J = 2.5 Hz, 1H), 8.45 (d, J = 1.5 Hz, 1H), 8.37 (d, J = 2.8 Hz, 1H), 8.21 (t, J= 7.9 Hz, 1H), 7.94 (ddd, J = 19.3,8.3, 1.7 Hz, 2H), 7.85 (dd, J = 11.5, 1.6 Hz, 1H), 7.43 (d, J = 8.5 Hz, 1H), 7.31 (t, J = 2.7 Hz, 1H), 6.44 (ddd, J = 3.0, 1.8, 0.8 Hz, 1H), 3.88 (s, 3H). Step 2: 4-(7-(1H-indol-5-yl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-3-fluorobenzoic acid (compound 20-1) The procedure is the same as step 2 in Example 19, where compound 19-1 (80 mg, 1.0 eq) is hydrolyzed to generate compound 20-1 (19 mg, 25%). 13 C NMR (101 MHz, DMSO- D 6) δ 166.69, 161.12, 158.65, 141.66, 137.85 (d, J = 9.7 Hz), 137.25, 135.31, 131.98, 128.56 (d, J = 18.7 Hz), 126.31, 126.11,124.76, 120.57, 118.12, 117.62, 117.38, 115.79, 112.04, 101.89. 1 H NMR (400MHz, DMSO- D 6) δ 12.30 (d, J = 2.8 Hz, 1H), 11.04 (t, J = 2.3 Hz, 1H), 8.71(d, J = 2.6 Hz, 1H), 8.45 (d, J = 1.6 Hz, 1H), 8.36 (d, J = 2.8 Hz, 1H), 8.17(t, J = 7.9 Hz, 1H), 7.94 (ddd, J = 9.8, 8.2, 1.6 Hz, 2H), 7.82 (dd,J =11.5, 1.6 Hz, 1H), 7.43 (d, J = 8.5 Hz, 1H), 7.30 (t, J = 2.7 Hz, 1H), 6.44(t, J = 2.4 Hz, 1H). The procedure was the same as step 3 of Example 19, reacting compound 20-1 (60 mg, 1.0 eq) with N-methylpiperazine (64.6 mg, 4.0 eq) to generate compound 25 (40 mg, 54%). LC-MS (M+H) + =455.17, 13 C NMR (101 MHz, DMSO- D 6) δ 167.77, 161.05, 141.56, 137.15, 135.29, 131.91, 128.44, 126.11, 124.82,124.09, 120.53, 118.05, 115.68, 112.05, 101.83, 47.52, 46.06, 41.99. 1 H NMR (400 MHz, DMSO-) D 6) δ 12.33 (d, J = 2.8 Hz, 1H), 11.12 (s, 1H), 8.67 (d, J =2.5 Hz, 1H), 8.44 (s, 1H), 8.34 (d, J = 2.6 Hz, 1H), 8.09 (t, J = 8.0 Hz, 1H), 7.92 (dd, J = 8.5, 1.6 Hz, 1H), 7.45 – 7.38 (m, 3H), 7.30 (t, J = 2.7Hz, 1H), 6.43 (t, J = 2.6 Hz, 1H), 3.73 – 3.41 (m, 4H), 2.39 – 2.24 (m, 4H), 2.18 (s, 3H). Example 26: (4-(7-(1H-indol-5-yl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-2-methoxyphenyl)(3,4-dimethylpiperazin-1-yl)methyl ketone (compound 26) The procedure was the same as step 3 of Example 19, reacting compound 10-1 (150 mg, 1.0 eq) with 1,2-dimethylpiperazine (178.4 mg, 4.0 eq) to generate compound 26 (40 mg, 21%). LC-MS (M+H) + =481.19, 1 H NMR (400MHz, DMSO- D 6) δ 12.18 (d, J = 2.8 Hz, 1H), 11.05 (d, J = 2.2 Hz, 1H), 8.95(d, J = 4.8 Hz, 1H), 8.58 (d, J = 1.6 Hz, 1H), 8.31 (d, J = 2.6 Hz, 1H), 7.95 (dd, J = 8.5, 1.7 Hz, 1H), 7.90 (dd, J = 5.6, 1.5 Hz, 1H), 7.83 (t, J = 7.0Hz, 1H), 7.44 (d, J = 8.5 Hz, 1H), 7.31 (t, J = 2.7 Hz, 2H), 6.44 (d, J = 2.5Hz, 1H), 3.95 (s, 3H), 3.35 – 3.07 (m, 5H), 2.75 (d, J = 5.5 Hz, 1H), 2.64(s, 1H), 2.14 (s, 3H), 1.02 (d, 3H). 13 C NMR (101 MHz, DMSO- D 6) δ 155.97,144.86, 142.02, 140.62, 136.68, 135.38, 135.22, 128.84, 128.50, 128.16,126.11, 125.01, 120.43, 119.31, 118.10, 115.50, 112.02, 109.67, 101.86,57.91, 56.09, 55.99, 54.89, 47.71, 42.63, 16.57. Example 27: (4-(7-(1H-indol-5-yl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-2-methoxyphenyl)(4-(2-hydroxyethyl)piperazin-1-yl)methyl ketone (Compound 27) The procedure was the same as step 3 in Example 19, reacting compound 10-1 (150 mg, 1.0 eq) with N-hydroxyethylpiperazine (203.4 mg, 4.0 eq) to generate compound 27 (45 mg, 23%). LC-MS (M+H) + =497.26, 13 C NMR (101 MHz, DMSO- D 6) δ 166.71, 155.98, 144.87, 142.01, 140.64, 135.38, 135.22, 128.89, 128.50,126.19, 126.11, 125.01, 120.43, 119.34, 118.09, 115.49, 112.02, 109.68,101.86, 60.62, 58.95, 56.04, 53.90, 53.44, 46.90. 1 H NMR (400 MHz, DMSO- D 6) δ12.18 (d, J = 2.9 Hz, 1H), 11.04 (d, J = 2.3 Hz, 1H), 8.95 (s, 1H), 8.58 (d, J = 1.5 Hz, 1H), 8.31 (d, J = 2.8 Hz, 1H), 7.95 (dd, J = 8.5, 1.7 Hz, 1H), 7.89 (d, J = 1.5 Hz, 1H), 7.83 (dd, J = 7.8, 1.5 Hz, 1H), 7.44 (d, J = 8.5Hz, 1H), 7.34 – 7.28 (m, 2H), 6.44 (d, J = 1.0 Hz, 1H), 4.43 (t, J = 5.4 Hz,1H), 3.95 (s, 3H), 3.64 – 3.44 (m, 4H), 3.17 (q, J= 4.9 Hz, 2H), 2.49 – 2.47(m, 6H). Example 28: (4-(7-(1H-indol-5-yl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-2-methoxyphenyl)(4-(2-methoxyethyl)piperazin-1-yl)methyl ketone (Compound 28) The procedure was the same as step 3 in Example 19, reacting compound 10-1 (150 mg, 1.0 eq) with 1-(2-methoxyethyl)piperazine (225 mg, 4.0 eq) to generate compound 28 (39 mg, 19.5%). LC-MS (M+H) + =511.25, 13 C NMR (101MHz, DMSO- D 6) δ 166.70, 155.98, 144.86, 142.01, 140.65, 136.68, 135.22,128.89, 128.50, 126.17, 125.01, 120.42, 119.34, 118.08, 115.48, 112.02,109.67, 101.85, 70.36, 58.53, 57.45, 56.04, 53.86, 53.39, 46.92. 1 H NMR (400MHz, DMSO- D 6) δ 12.19 (s, 1H), 11.06 (d, J = 2.2 Hz, 1H), 8.95 (s, 1H), 8.58(d, J = 1.5 Hz, 1H), 8.31 (s, 1H), 7.95 (dd, J = 8.5, 1.7 Hz, 1H), 7.89 (d, J = 1.5 Hz, 1H), 7.83 (dd, J = 7.8, 1.4 Hz, 1H), 7.44 (d, J = 8.5 Hz, 1H), 7.34– 7.27 (m, 2H), 6.44 (t, J = 2.6 Hz, 1H), 3.95 (s, 3H), 3.39 (t, J = 5.7 Hz, 6H), 3.19 (s, 3H), 2.52 – 2.47 (m, 6H). Example 29: 7-(1H-indol-5-yl)-2-(3-methoxy-4-((4-methylpiperazin-1-yl)methyl)phenyl)-5H-pyrrolo[2,3-b]pyrazine (compound 29) Step 1: 4-(7-(1H-indol-5-yl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-2-methoxybenzaldehyde (Compound 21-1) The procedure is the same as step 2 in Example 1, where compound 1-1 (300 mg, 1.0 eq) and 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)benzaldehyde (276.3, 1.1 eq) react to generate compound 21-1 (120 mg, 34%). 13 C NMR (101 MHz, DMSO- D 6) δ 143.97, 142.01, 139.22, 136.70, 135.76,135.26, 135.19, 134.62, 132.02, 128.47, 127.42, 126.15, 125.48, 124.96,120.54, 118.06, 115.61, 112.04, 101.82, 58.54, 54.23, 51.55. 1 H NMR (400 MHz, DMSO- D 6) δ 12.20 (d, J = 3.0 Hz, 1H), 11.07 (s, 1H), 8.90 (d, J = 2.4 Hz,1H), 8.47 (s, 1H), 8.30 (d, J = 2.3 Hz, 1H), 8.23 ​​(d, J = 1.9 Hz, 1H), 8.15(dd, J = 8.1, 2.0 Hz, 1H), 7.93 (dd, J = 8.6, 1.5 Hz, 1H), 7.61 (dd, J = 8.1, 3.7 Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.32 (t, J = 2.8 Hz, 1H), 6.44 (t, J=2.5 Hz, 1H), 3.64 (d, J = 3.9 Hz, 3H). The procedure was the same as step 2 in Example 14, reacting compound 21-1 (100 mg, 1.0 eq) with N-methylpiperazine (54.4 mg, 2.0 eq) to generate compound 29 (37 mg, 30%). LC-MS (M+H) + =453.21, 13 C NMR (101 MHz, DMSO- D 6) δ 158.46, 145.37, 141.86, 139.06, 136.61, 135.18, 131.43, 128.48, 127.95,126.12, 125.08, 120.39, 118.85, 118.09, 115.39, 112.02, 109.28, 101.83,55.96, 55.08, 53.73, 50.80, 43.75. 1 H NMR (400 MHz, DMSO- D 6) δ 8.91 (s, 1H), 8.59 (d, J = 1.6 Hz, 1H), 8.29 (d, J = 2.4 Hz, 1H), 7.94 (dd, J = 8.5, 1.7Hz, 1H), 7.84 (d, J = 1.6 Hz, 1H), 7.77 (dd, J = 7.9, 1.6 Hz, 1H), 7.43 (d, J = 8.2 Hz, 2H), 7.31 (t, J = 2.6 Hz, 1H), 6.43 (t, J = 2.6 Hz, 1H), 3.94 (s,3H), 3.62 (s, 2H), 3.12 – 2.83 (m, 5H), 2.70 – 2.58 (m, 3H), 2.56 (s, 3H). Example 30: 2-(3-chloro-4-((4-methylpiperazin-1-yl)methyl)phenyl)-7-(1H-indol-5-yl)-5H-pyrrolo[2,3-b]pyrazine (compound 30) Step 1: 4-(7-(1H-indol-5-yl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-2-chlorobenzaldehyde (Compound 22-1) The procedure is the same as step 2 in Example 1, where compound 1-1 (300 mg, 1.0 eq) and 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)benzaldehyde (281.1 mg, 1.1 eq) react to generate compound 22-1 (90 mg, 25%).

[0027] The procedure was the same as step 2 in Example 14, reacting compound 22-1 (90 mg, 1.0 eq) with N-methylpiperazine (78 mg, 2.0 eq) to generate compound 30 (60 mg, 54.5%). LC-MS (M+H) + =457.12, 13 C NMR (101 MHz, DMSO- D 6) δ143.94, 142.00, 139.28, 136.69, 135.56, 135.26, 135.20, 134.66, 132.09,128.46, 127.43, 126.16, 125.49, 124.94, 120.53, 118.06, 115.59, 112.07,101.81, 58.33, 53.71, 50.78, 45.92. 1 H NMR (400 MHz, DMSO- D 6) δ 8.90 (s, 1H), 8.47 (d, J = 1.6 Hz, 1H), 8.30 (d, J = 2.2 Hz, 1H), 8.23 ​​(d, J = 1.8 Hz, 1H), 8.15 (dd, J = 8.0, 1.8 Hz, 1H), 7.93 (dd, J = 8.5, 1.7 Hz, 1H), 7.61 (d, J =8.1 Hz, 1H), 7.45 (d, J = 8.5 Hz, 1H), 7.31 (t, J = 2.7 Hz, 1H), 6.44 (dd, J= 2.7, 1.5 Hz, 1H), 3.65 (s, 2H), 3.04 – 2.97 (m, 4H), 2.74 – 2.58 (m, 4H), 2.53 (s, 3H). Example 31: 2-(4-(4-(7-(1H-indol-5-yl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-2-methoxybenzyl)piperazin-1-yl)ethane-1-ol (Compound 31) The procedure was the same as step 2 in Example 14, reacting compound 21-1 (70 mg, 1.0 eq) with N-hydroxyethylpiperazine (49.4 mg, 2.0 eq) to generate compound 31 (33 mg, 36%). LC-MS (M+H) + =483.27, 13 C NMR (101 MHz, DMSO- D 6) δ 158.47, 145.36, 141.88, 136.62, 135.19, 128.49, 127.95, 126.11, 125.09,120.39, 118.84, 118.09, 115.40, 112.01, 109.28, 101.82, 55.96, 55.15, 52.41,50.91, 46.25. 1 H NMR (400 MHz, DMSO- D 6) δ 12.13 (d, J = 2.8 Hz, 1H), 11.03 (d, J =2.3 Hz, 1H), 8.91 (s, 1H), 8.59 (d, J = 1.6 Hz, 1H), 8.29 (d, J = 2.7 Hz, 1H), 7.94 (dd, J = 8.5, 1.7 Hz, 1H), 7.85 (d, J = 1.7 Hz, 1H), 7.78 (dd, J =7.8, 1.6 Hz, 1H), 7.44 (dd, J = 8.2, 4.5 Hz, 2H), 7.31 (t, J = 2.7 Hz, 1H), 6.43 (t, J= 2.4 Hz, 1H), 5.03 – 4.77 (m, 1H), 3.94 (s, 3H), 3.64 (s, 2H), 3.52 (s, 2H), 3.03 (t, J = 7.3 Hz, 2H), 2.98 – 2.69 (m, 8H). Example 32: 7-(1H-indol-5-yl)-2-(3-methoxy-4-((4-(2-methoxyethyl)piperazin-1-yl)methyl)phenyl)-5H-pyrrolo[2,3-b]pyrazine (compound 32) The procedure was the same as step 2 in Example 14, reacting compound 21-1 (100 mg, 1.0 eq) with 1-(2-methoxyethyl)piperazine (78.3 mg, 2.0 eq) to generate compound 32 (62 mg, 46%). LC-MS (M+H) + =497.26, 13 C NMR (101 MHz, DMSO- D 6) δ 158.46, 145.38, 141.87, 136.62, 135.18, 131.40, 128.49, 127.93,126.10, 125.09, 120.39, 118.84, 118.09, 115.40, 112.00, 109.26, 101.83,58.60, 56.68, 55.95, 55.29, 52.72, 51.82. 1 H NMR (400 MHz, DMSO- D 6) δ 12.12 (d, J = 2.9 Hz, 1H), 11.03 (d, J = 2.3 Hz, 1H), 8.91 (s, 1H), 8.60 (s, 1H), 8.29(d, J = 2.8 Hz, 1H), 7.94 (dd, J = 8.5, 1.7 Hz, 1H), 7.84 (d, J = 1.7 Hz, 1H), 7.77 (dd, J = 7.9, 1.6 Hz, 1H), 7.44 (dd, J = 8.2, 2.9 Hz, 2H), 7.31 (t, J= 2.7 Hz, 1H), 6.44 (d, J = 2.5 Hz, 1H), 3.94 (s, 3H), 3.63 (s, 2H), 3.45(t, 2H), 3.21 (s, 3H), 2.78 – 2.52 (m, 10H). Example 33: 4-(4-(7-(1H-indol-5-yl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-2-methoxybenzyl)morpholine (compound 33) The procedure was the same as step 2 in Example 14, reacting compound 21-1 (150 mg, 1.0 eq) with morpholine (71 mg, 2 eq) to generate compound 33 (52 mg, 29%). LC-MS (M+H) + =440.11, 13 C NMR (101 MHz, DMSO- D 6) δ 158.39,145.51, 141.85, 136.60, 135.19, 135.14, 128.50, 127.87, 126.09, 125.13,120.41, 118.80, 118.08, 115.38, 111.99, 109.21, 101.84, 66.80, 56.23, 55.90,53.89. 1 H NMR (400 MHz, DMSO- D 6) δ 12.12 (d, J = 2.9 Hz, 1H), 11.04 (s, 1H), 8.90 (s, 1H), 8.60 (d, J = 1.6 Hz, 1H), 8.29 (d, J = 2.7 Hz, 1H), 7.96 (dd, J = 8.4, 1.6 Hz, 1H), 7.83 (d, J = 1.6 Hz, 1H), 7.79 – 7.73 (m, 1H), 7.44 (dd, J = 8.3, 2.1 Hz, 2H), 7.31 (t, J = 2.6 Hz, 1H), 6.44 (t, J= 2.5 Hz, 1H), 3.93 (s, 3H), 3.62 – 3.55 (m, 4H), 3.51 (s, 2H), 2.44 – 2.29 (m, 4H). Example 34: 2-(4-(7-(1H-indol-5-yl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-2-methoxybenzyl)-8-methyloctahydro-2H-pyrazinolo[1,2-a]pyrazine (Compound 34) 2-Methyloctahydro-1H-pyrazolo[1,2-A]pyrazine trihydrochloride (100 mg, 1.0 eq) was dissolved in a mixture of DCM (15 mL) and MeOH (3 mL). DIPEA was added dropwise to adjust the pH of the mixture to 7-8. Then, compound 21-1 (208 mg, 1.5 eq), NaBH3CN (71.2 mg, 3 eq), and AcOH (42.8 mg, 6.3 eq) were added, and the mixture was refluxed and stirred at 50 °C for 8 hours. After the reaction was complete, the mixture was cooled to room temperature and concentrated under reduced pressure, followed by purification by silica gel column chromatography to give compound 34 (36 mg, 18.8%). LC-MS (M+H) + =508.28, 13 C NMR (101 MHz, DMSO- D 6) δ 141.87, 136.62, 135.19,128.47, 128.00, 126.11, 125.04, 120.36, 118.88, 118.06, 115.38, 112.05,109.35, 101.78, 56.03, 45.82, 8.93. 1 H NMR (400 MHz, DMSO- D 6) δ 8.92 (s, 1H),8.59 (s, 1H), 8.29 (d, J = 2.7 Hz, 1H), 7.94 (d, J = 6.9 Hz, 1H), 7.86 (s,1H), 7.79 (d, J = 7.9 Hz, 1H), 7.44 (d, J = 8.5 Hz, 2H), 7.30 (t, J= 2.6 Hz,1H), 6.43 (s, 1H), 3.95 (s, 3H), 3.76 (s, 2H), 2.96 – 2.74 (m, 8H), 2.65 –2.57 (m, 5H), 2.43 (s, 3H). Example 35: 7-(1H-indol-5-yl)-2-(3-methoxy-4-((3-(4-methylpiperazin-1-yl)azacyclobutane-1-yl)methyl)phenyl)-5H-pyrrolo[2,3-b]pyrazine (compound 35) The procedure was the same as in Example 34, reacting compound 21-1 (209 mg, 1.5 eq) with 1-(azacyclobutane-3-yl)-4-methylpiperazine trihydrochloride (100 mg, 1.0 eq) to generate compound 35 (40 mg, 20.9%). LC-MS (M+H) + =508.28, 13 CNMR (101 MHz, DMSO- D 6) δ 172.87, 157.88, 145.50, 138.39, 136.57, 135.18,135.08, 130.00, 128.48, 127.09, 126.10, 125.10, 120.37, 118.80, 118.07,115.34, 112.02, 108.88, 101.81, 58.95, 55.77, 55.61, 54.74, 46.16, 45.92. 1 HNMR (400 MHz, DMSO- D 6) δ 8.89 (d, J = 7.7 Hz, 1H), 8.59 (dd, J = 3.3, 1.6 Hz, 1H), 8.28 (d, J = 2.4 Hz, 1H), 7.93 (ddd, J = 8.5, 3.4, 1.7 Hz, 1H), 7.86 –7.67 (m, 2H), 7.46 – 7.28 (m, 3H), 6.43 (q, J = 2.3 Hz, 1H), 3.93 (d, J=10.2 Hz, 3H), 3.58 (s, 2H), 2.93 – 2.81 (m, 4H), 2.66 – 2.60 (m, 1H), 2.46 –2.45 (m, 8H), 2.10 (s, 3H). Example 36: 2-(4-((3,4-dimethylpiperazin-1-yl)methyl)-3-methoxyphenyl)-7-(1H-indol-5-yl)-5H-pyrrolo[2,3-b]pyrazine (compound 36) The procedure was the same as step 2 in Example 14, reacting compound 21-1 (150 mg, 1.0 eq) with 1,2-dimethylpiperazine (93 mg, 2.0 eq) to generate compound 36 (64 mg, 33.7%). LC-MS (M+H) + =467.26, 13 C NMR (101 MHz, DMSO- D 6) δ 172.67, 158.37, 145.47, 141.83, 138.64, 136.60, 135.19, 135.12,130.99, 128.49, 126.10, 120.40, 118.84, 118.08, 115.39, 112.01, 109.22,101.84, 59.54, 58.17, 55.91, 55.42, 52.39, 41.80, 21.63. 1 H NMR (400 MHz, DMSO- D 6) δ 12.13 (d, J = 2.8 Hz, 1H), 11.05 (d, J = 2.3 Hz, 1H), 8.90 (s,1H), 8.59 (d, J = 1.6 Hz, 1H), 8.28 (d, J = 2.2 Hz, 1H), 7.94 (dd, J = 8.5, 1.6 Hz, 1H), 7.83 (d, J = 1.6 Hz, 1H), 7.76 (dd, J = 7.8, 1.6 Hz, 1H), 7.43(dd, J = 8.2, 4.7 Hz, 2H), 7.31 (t, J= 2.6 Hz, 1H), 6.43 (d, J = 2.9 Hz,1H), 3.93 (s, 3H), 3.51 (s, 2H), 2.41 – 2.18 (m, 7H), 1.87 (s, 3H), 0.99 (d, J = 6.3 Hz, 3H). In vitro kinase inhibition assay (refer to CN 113968860 A) 1. Compound preparation Weigh 1 mg of the above compound and dissolve it in 100% DMSO-d6 to prepare a 10 mM stock solution, which is then stored in a nitrogen cabinet away from light.

[0028] 2. Kinase reaction process (1) Prepare 1×Kinase buffer. (2) Preparation of compound concentration gradients: The initial test concentration of the test compound was 2400 nM, with 7 concentrations and replicate detection. The compound was diluted 100 times to a final concentration of 100% DMSO-d in a 384 source plate. 250 nL of the 100-fold final concentration of the compound was transferred to the target 3575 plate using an Echo 550 dispenser.

[0029] (3) Prepare a kinase solution with a final concentration of 2.5 times using 1×Kinase buffer.

[0030] (4) Add 10 μL of kinase solution at a final concentration of 2.5 times to the compound wells and the positive control wells, respectively; add 10 μL of kinase solution at a final concentration of 2.5 times to the negative control wells. Add 10 μl of 1×Kinase buffer to the well. (5) Centrifuge at 1000 rpm for 30 seconds, shake the reaction plate to mix, and incubate at room temperature for 10 minutes.

[0031] (6) Prepare a mixed solution of ATP and Kinase substrate 2 at a final concentration of 5 / 3 times using 1×Kinase buffer.

[0032] (7) Add 15 μl of a mixture of ATP and substrate at 5 / 3 times the final concentration to initiate the reaction.

[0033] (8) Centrifuge the 384-well plate at 1000 rpm for 30 seconds, shake to mix, and incubate at room temperature for 30 minutes.

[0034] (9) Add 30 μL of the stop detection solution to stop the kinase reaction, centrifuge at 1000 rpm for 30 seconds, and shake to mix.

[0035] (10) Read the conversion rate using Caliper EZ Reader.

[0036] The results are shown in Table 1. Table 1. MLK3 inhibition results of compounds 1-36 Note: A≤100nM, 100

Claims

1. A 2,7-disubstituted-5H-pyrrolo[2,3-b]pyrazine derivative, characterized in that, Compounds with the structure shown in formula (I), their stereoisomers, or pharmaceutically acceptable salts thereof: （I） in: R1 is selected from the following structure: R2 is selected from the following structures: 。 2. The 2,7-disubstituted-5H-pyrrolo[2,3-b]pyrazine derivative according to claim 1, characterized in that, Compounds with the following structures: ； ； ； ； ； ； ； ； ； ； ； 。 3. The method for synthesizing the 2,7-disubstituted-5H-pyrrolo[2,3-b]pyrazine derivative according to claim 1, characterized in that, Includes the following steps: (1) Under transition metal catalysis, the compound of formula (II) reacts with the compound of formula (III) to generate the compound of formula (IV); 、 、 ； Formula (II) Formula (III) Formula (IV); (2) Under transition metal catalysis, the compound of formula (Ⅳ) is reacted with the compound of formula (Ⅴ) to generate the compound of formula (I); 、 ； Equation (Ⅳ) Equation (Ⅴ); In Equations (III), (IV) and (I), R1 has the same meaning; in Equations (V) and (I), R2 has the same meaning.

4. The method for synthesizing the 2,7-disubstituted-5H-pyrrolo[2,3-b]pyrazine derivative according to claim 2, characterized in that, Includes the following steps: (1) Under transition metal catalysis, the compound of formula (II) is reacted with the compound of formula (VI) to generate the compound of formula (VII); 、 、 ； Formula (II) Formula (VI) Formula (VII); (2) Under transition metal catalysis, the compound of formula (VII) is reacted with the compound of formula (VIII) to generate the compound of formula (IX); 、 、 Formula (VII) Formula (VIII) Formula (IX); Wherein, R3 is a methoxy group, a chlorine atom, or a fluorine atom, and R3 in formula (VIII) and formula (IX) has the same meaning; (3) Through reductive amination, the compound with the structure of formula (IX) is reacted with related compounds to generate the compound with the structure of formula (X); 、 ； Formula (IX) Formula (X); R3 in equations (X) and (IX) has the same meaning; Where R3 is a methoxy group, a chlorine atom, or a fluorine atom, and R4 is: 。 5. The method for synthesizing the 2,7-disubstituted-5H-pyrrolo[2,3-b]pyrazine derivative according to claim 2, characterized in that, Includes the following steps: (1) Under transition metal catalysis, the compound of formula (II) reacts with the compound of formula (XI) to generate the compound of formula (XII); 、 、 ； Formula (II) Formula (XI) Formula (XII); In this case, R5 is a methyl or hydrogen atom, and R5 in formulas (XI) and (XII) has the same meaning; (2) Under transition metal catalysis, the compound of formula (XII) is reacted with the compound of formula (XIII) to generate the compound of formula (XIV). 、 、 Equation (XII) Equation (XIII) Equation (XIV); In this context, R6 is a methyl, methoxy, fluorine, or hydrogen atom, and R7 is a methyl, fluorine, or hydrogen atom. R5 in formulas (XIV) and (XII) has the same meaning, and R6 and R7 in formulas (XIV) and (XIII) have the same meaning. (3) The compound with the structure of formula (XIV) was hydrolyzed to obtain the compound with the structure of formula (XV), and then amide condensed to obtain the compound with the structure of formula (XVI); 、 、 ； Formula (XIV) Formula (XV) Formula (XVI); R8 is: ； R5, R6, and R7 in equations (XVI), (XV), and (XIV) have the same meaning.

6. The use of the 2,7-disubstituted-5H-pyrrolo[2,3-b]pyrazine derivative according to claim 1 or 2 in the preparation of a medicament for the prevention or treatment of diseases caused by MLK3 overexpression.

7. The application according to claim 6, characterized in that, In the drug, the 2,7-disubstituted-5H-pyrrolo[2,3-b]pyrazine derivative is used alone, or prepared as a pharmaceutically acceptable salt, or in combination with a pharmaceutically acceptable excipient or carrier.

8. The application according to claim 6, characterized in that, The diseases mentioned are breast cancer, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, ovarian cancer, cervical cancer, prostate cancer, or glioblastoma.

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