N-(4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)amide derivatives and their preparation and use

Abstract

Disclosed are an N-(4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)amide derivative and its preparation and use, relating to the technical field of medicinal chemistry. The present invention designs and synthesizes a novel structure of an N-(4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)amide derivative. Screening of in vitro CDK8 kinase activity and in vitro cell activity reveals that some of the compounds exhibit strong inhibitory activity against CDK8 kinase, have good therapeutic effects on psoriasis, and have low toxicity. The compounds can be applied to the research and development of CDK8 inhibitors and psoriasis drugs.

Description

Technical field:

[0001] The present invention relates to the technical field of medicinal chemistry, and in particular to an N-(4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)amide derivative, and its preparation and use. Background technology:

[0002] Cyclin-dependent kinase 8 (CDK8) is a member of the CDK family and belongs to the serine / threonine protein kinase family. It has been demonstrated that CDK8 plays an important role in transcriptional regulation by forming kinase modules or phosphorylating transcription factors, including HIF-1α, TGF-β, β-catenin / TCF, and STAT1. In recent years, many CDK8 inhibitors have been reported as anti-tumor small molecules, such as CCT-251545, CCT-251921, BRD6989, Senexin B (BCD-115), and SEL120-34A. BCD-115 and SEL120-34A have entered clinical trials for the treatment of breast cancer and acute myeloid leukemia, respectively.

[0003] CDK8 is also considered a co-regulator of NF-κB. A key function of CDK8 in the NF-κB pathway is to regulate the phosphorylation of the C-terminal domain (CTD) of RNA Pol II to complete NF-κB-initiated transcription. It has been reported that CDK8 inhibitors can inhibit the expression of NF-κB-induced genes such as IL-8, CXCL1, and CXCL2, but generally do not affect basal expression. Different CDKs have significant differences in inhibiting NF-κB activation. The present invention aims to develop "CDK8 inhibitors" using N-(4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)amide as the core structural skeleton, in order to discover highly active CDK8 inhibitors. Summary of the invention:

[0004] The technical problem to be solved by the present invention is to design and synthesize a "CDK8 inhibitor" with N-(4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)amide as the core structural skeleton based on drug chemical structure modification with the help of computer-aided drug design technology, and to conduct research and development of a "CDK8 inhibitor" through pharmacological evaluation in order to discover highly active CDK8 inhibitors, thereby enriching the small molecule library targeting CDK8.

[0005] The technical problem to be solved by the present invention is achieved by adopting the following technical solutions:

[0006] The first object of the present invention is to provide an N-(4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)amide derivative, the structure of which is shown in Formula I:

[0007]

[0008] Among them, R 1 Any one selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, phenyl, phenoxy and the like;

[0009] R 2 Any one selected from the group consisting of alkyl, alkyl alcohol, cycloalkyl, substituted cycloalkyl, phenyl, substituted phenyl, furanyl, substituted furanyl, tetrahydrofuranyl, substituted tetrahydrofuranyl, thiazolyl, substituted thiazolyl, benzofuranyl, substituted benzofuranyl, pyridyl, substituted pyridyl, pyrimidinyl, substituted pyrimidinyl, pyridonyl, substituted pyridonyl, morpholinyl, substituted morpholinyl, tetrahydro-2H-pyranyl, substituted tetrahydro-2H-pyranyl, piperidinyl, substituted piperidinyl, piperazinyl, substituted piperazinyl and the like.

[0010] The N-(4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)amide derivatives of the present invention specifically include compounds 1-42 of the following structural formulas, as shown in Table 1.

[0011] Table 1

[0012]

[0013]

[0014]

[0015]

[0016] The second object of the present invention is to provide a method for preparing the N-(4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)amide derivative, comprising the following steps:

[0017] (1) Suzuki-Miyaura reaction with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine to give intermediate M1;

[0018] (2) Intermediate M1 and R 2 COOH or R 2 COCl undergoes amide condensation reaction to give compound 1-42.

[0019] The reaction equation is as follows:

[0020]

[0021] The third object of the present invention is to provide a pharmaceutical composition containing the N-(4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)amide derivative or a pharmaceutically acceptable salt thereof.

[0022] The fourth object of the present invention is to provide a pharmaceutical preparation comprising an active ingredient and a pharmaceutically acceptable excipient and / or carrier, wherein the active ingredient contains the N-(4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)amide derivative or a pharmaceutically acceptable salt thereof.

[0023] A fifth object of the present invention is to provide a use of the N-(4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)amide derivative or a pharmaceutically acceptable salt thereof in the preparation of a CDK8 inhibitor.

[0024] The sixth object of the present invention is to provide the use of the N-(4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)amide derivative or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating psoriasis.

[0025] The beneficial effects of the present invention are as follows: the present invention designs and synthesizes a novel structure of N-(4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)amide derivatives, and through in vitro CDK8 kinase activity and in vitro cell activity screening, it is found that some of the compounds exhibit strong inhibitory activity against CDK8 kinase, have good therapeutic effects on psoriasis, and have low toxicity, and can be applied to the research and development of CDK8 inhibitors and psoriasis drugs; and the preparation method provided by the present invention is simple and easy, with good reproducibility, and can obtain high-purity N-(4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)amide derivatives for further research. Description of the drawings:

[0026] Figure 1 Target validation for compound 36;

[0027] Figure 2 For in vitro mechanism study of compound 36;

[0028] Figure 3 This is a study on the therapeutic effect of compound 36 in a mouse psoriasis model. Specific implementation method:

[0029] In order to make the technical means, creative features, objectives and effects achieved by the present invention easier to understand, the present invention is further described below with reference to specific embodiments and illustrations.

[0030] Example 1

[0031] 1.1 Synthesis of 3-methoxy-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)aniline (Intermediate M1):

[0032]

[0033] To the reaction flask, 4-bromo-3-methoxyaniline (10 g, 49.77 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (13.4 g, 54.75 mmol), potassium carbonate (17.2 g, 124.43 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (0.73 g, 1.00 mmol), and 1,4-dioxane / water (100 mL / 35 mL) were added. The atmosphere was replaced with nitrogen, and the temperature was raised to 80°C for reaction for 14 h. After the reaction was completed, water and ethyl acetate were added with stirring, diatomaceous earth was used for filtration, and the filter cake was washed with ethyl acetate; the filtrate was allowed to stand for separation, the aqueous phase was re-extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried to obtain a black oil; column chromatography gave a yellow solid with a yield of 45.6%.

[0034] 1 H NMR (400MHz, DMSO-d6) δ11.54(s,1H),8.21(d,J=2.0Hz,1H),7.89(d,J=1.9Hz,1H),7.48-7.37(m,1H),6.99(d,J=8. 1Hz, 1H), 6.42 (dd, J=3.3, 1.8Hz, 1H), 6.35 (d, J=1.9Hz, 1H), 6.26 (dd, J=8.1, 1.9Hz, 1H), 5.23 (s, 2H), 3.69 (s, 3H). 13 C NMR (101MHz, DMSO-d6) δ157.49,149.98,147.34,143.92,131.53,128.40,127.11,126.42,119.57,116.20,106.94,100.18,98.09,55.49.

[0035] 1.2 Synthesis of N-(3-methoxy-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acetamide (Compound 1):

[0036]

[0037] To the reaction flask, add intermediate M1 (240 mg, 1 mmol), N,N-diethylisopropylamine (194 mg, 1.5 mmol), acetyl chloride (85 mg, 1.1 mmol), and dichloromethane (10 mL). The temperature was raised to 30°C and the reaction was allowed to react for 2 h. After the reaction was completed, the product was concentrated, stirred with water and ethyl acetate, and allowed to stand for separation. The aqueous phase was re-extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain a white solid in a yield of 52.5%.

[0038] 1 H NMR (400MHz, DMSO-d6) δ11.64(s,1H),10.06(s,1H),8.28(d,J=1.9Hz,1H),7.98(d,J=1.6Hz,1 H),7.48(d,J=3.4Hz,2H),7.27(s,2H),6.46(dd,J=3.1,1.7Hz,1H),3.75(s,3H),2.08(s,3H). 13 C NMR(101MHz,DMSO-d6)δ168.85,156.75,147.76,143.81,140.28,131.15,128 .80,126.79,126.03,123.36,119.57,111.75,103.10,100.36,55.81,24.59.

[0039] Example 2

[0040] Synthesis of 2-hydroxy-N-(3-methoxy-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acetamide (Compound 2):

[0041]

[0042] To a reaction flask, intermediate M1 (240 mg, 1 mmol), N,N-diethylisopropylamine (194 mg, 1.5 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 420 mg, 1.1 mmol), glycolic acid (73 mg, 1.1 mmol), and dichloromethane (10 mL) were added and the temperature was raised to 50°C for 10 h. After the reaction was completed, the mixture was concentrated, stirred with water and ethyl acetate, and allowed to stand for separation. The aqueous phase was extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain a white solid in a yield of 38.55%.

[0043] 1H NMR (400MHz, DMSO-d6) δ11.64(s,1H),9.76(s,1H),8.28(d,J=2.0Hz,1H),7.99(d,J=1.9Hz,1H),7.59(d,J=1.8Hz,1H),7.55 -7.39(m,2H),7.29(d,J=8.2Hz,1H),6.46(dd,J=3.4,1.8Hz,1H),5.76(t,J=6.0Hz,1H),4.03(d,J=5.9Hz,2H),3.75(s,3H). 13 CNMR(101MHz,DMSO-d6)δ171.44,156.73,147.77,143.81,139.45,131.09,12 8.83,126.80,125.99,123.75,119.57,112.28,103.82,100.38,62.40,55.89.

[0044] Example 3

[0045] Synthesis of N-(3-methoxy-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)propionamide (Compound 3):

[0046]

[0047] Referring to Example 1, acetyl chloride was replaced by propionyl chloride.

[0048] 1 H NMR (500MHz, DMSO-d6) δ11.61(s,1H),9.95(s,1H),8.28(d,J=2.1Hz,1H),7.98(d,J=1.9Hz,1H),7.52(s,1H),7.49-7.4 4(m,1H),7.27(d,J=0.6Hz,2H),6.46(dd,J=3.4,1.9Hz,1H),3.75(s,3H),2.36(q,J=7.5Hz,2H),1.12(t,J=7.6Hz,3H). 13 C NMR(126MHz,DMSO-d6)δ172.55,156.79,147.78,143.82,140.36,131.11,128.79 ,126.76,126.07,123.30,119.58,111.79,103.22,100.37,55.83,30.08,10.11.

[0049] Example 4

[0050] Synthesis of N-(3-methoxy-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)butanamide (Compound 4):

[0051]

[0052] Referring to Example 1, acetyl chloride was replaced by butyryl chloride.

[0053] 1 H NMR (500MHz, DMSO-d6) δ11.54(s,1H),9.89(s,1H),8.20(d,J=2.0Hz,1H),7.90(d,J=1.8Hz,1H),7.45(s,1H),7.41-7.36(m,1 H),7.20(s,2H),6.38(dd,J=3.3,1.8Hz,1H),3.68(s,3H),2.25(t,J=7.3Hz,2H),1.57(h,J=7.4Hz,2H),0.87(t,J=7.4Hz,3H). 13 CNMR(126MHz,DMSO-d6)δ171.72,156.79,147.78,143.83,140.32,131.11,128.79,1 26.76,126.08,123.36,119.59,111.82,103.23,100.37,55.83,38.91,19.03,14.11.

[0054] Example 5

[0055] Synthesis of N-(3-methoxy-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)isobutylamine (Compound 5):

[0056]

[0057] Referring to Example 1, acetyl chloride was replaced by isobutyryl chloride.

[0058] 1 H NMR (500MHz, DMSO-d6) δ11.53(s,1H),9.84(s,1H),8.20(d,J=2.0Hz,1H),7.91(d,J=1.9Hz,1H),7.48(d,J=1.1Hz,1H),7 .42-7.37(m,1H),7.23-7.18(m,2H),6.39(dd,J=3.3,1.8Hz,1H),3.68(s,3H),2.61-2.50(m,1H),1.06(d,J=6.8Hz,6H). 13C NMR(126MHz,DMSO-d6)δ175.81,156.78,147.78,143.82,140.45,131.08,128.79,1 26.76,126.08,123.33,119.58,111.87,103.30,100.37,55.83,35.51,19.98(2C).

[0059] Example 6

[0060] Synthesis of N-(3-methoxy-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)pivalamide (Compound 6):

[0061]

[0062] Referring to Example 1, acetyl chloride was replaced with tert-butyl chloride.

[0063] 1 H NMR (500MHz, DMSO-d6) δ11.53(s,1H),9.19(s,1H),8.21(d,J=1.9Hz,1H),7.91(d,J=1.8Hz,1H),7.49(d,J= 1.7Hz,1H),7.42-7.30(m,2H),7.19(d,J=8.2Hz,1H),6.39(dd,J=3.2,1.8Hz,1H),3.69(s,3H),1.19(s,9H). 13 C NMR(126MHz,DMSO-d6)δ177.03,156.63,147.78,143.82,140.44,130.85,128.79,1 26.75,126.10,123.45,119.59,112.75,104.22,100.37,55.88,39.75,27.68(3C).

[0064] Example 7

[0065] Synthesis of N-(3-methoxy-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)cyclopropanecarboxamide (Compound 7):

[0066]

[0067] Referring to Example 1, acetyl chloride was replaced by cyclopropylcarbonyl chloride.

[0068] 1H NMR (400MHz, DMSO-d6) δ11.64(s,1H),10.32(s,1H),8.27(d,J=2.0Hz,1H),7.98(d,J=1.8Hz,1H),7.54(d,J=1.3Hz,1H),7.4 9-7.44(m,1H),7.32-7.20(m,2H),6.46(dd,J=3.4,1.8Hz,1H),3.75(s,3H),1.81(dq,J=7.5,4.9Hz,1H),0.89-0.71(m,4H). 13 CNMR(101MHz,DMSO-d6)δ172.19,156.77,147.75,143.81,140.33,131.15,128.80, 126.78,126.04,123.25,119.56,111.66,103.08,100.36,55.79,15.11,7.70(2C).

[0069] Example 8

[0070] Synthesis of N-(3-methoxy-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-1-methylcyclopropane-1-carboxamide (Compound 8):

[0071]

[0072] Referring to Example 1, acetyl chloride was replaced by 1-methylcyclopropylcarbonyl chloride.

[0073] 1 H NMR(400MHz,DMSO-d6)δ11.64(s,1H),9.26(s,1H),8.29(s,1H),7.99(s,1H),7.55(s,1H),7.47(s,1H),7.34 (dd,J=58.1,8.2Hz,2H),6.46(s,1H),3.75(s,3H),1.44(s,3H),1.13(d,J=1.6Hz,2H),0.66(d,J=1.9Hz,2H).

[0074] Example 9

[0075] Synthesis of 2-cyclopropyl-N-(3-methoxy-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)acetamide (Compound 9):

[0076]

[0077] Referring to Example 1, acetyl chloride was replaced by 2-cyclopropylacetyl chloride.

[0078] 1 H NMR (500MHz, DMSO-d6) δ11.60(s,1H),9.89(s,1H),8.27(d,J=2.0Hz,1H),7.97(d,J=1.9Hz,1H),7.53(s,1H),7.49-7.43(m,1H),7. 27(s,2H),6.45(dd,J=3.3,1.8Hz,1H),3.75(s,3H),2.23(d,J=7.0Hz,2H),1.13-1.02(m,1H),0.54-0.46(m,2H),0.26-0.16(m,2H). 13 C NMR (126MHz, DMSO-d6) δ171.35,156.80,147.78,143.82,140.32,131.12,128.79,126.7 6,126.07,123.40,119.59,111.82,103.23,100.38,55.84,42.00,8.23(2C),4.59(2C).

[0079] Example 10

[0080] Synthesis of N-(3-methoxy-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)cyclobutaneamide (Compound 10):

[0081]

[0082] Referring to Example 1, acetyl chloride was replaced by cyclobutylcarbonyl chloride.

[0083] 1 H NMR (500MHz, DMSO-d6) δ11.53(s,1H),9.74(s,1H),8.20(d,J=2.0Hz,1H),7.90(d,J=1.9Hz,1H),7.47(d,J=1.2Hz,1H) ,7.42-7.36(m,1H),7.21(dt,J=13.7,4.8Hz,2H),6.38(dd,J=3.3,1.8Hz,1H),3.68(s,3H),3.18(p,J=8.3Hz,1H),2.26 -2.12(m,2H),2.06(tdd,J=11.8,8.8,3.4Hz,2H),1.93-1.81(m,1H),1.81-1.68(m,1H). 13C NMR(126MHz,DMSO-d6)δ173.49,156.78,147.78,143.83,140.36,131.09,128.79,1 26.75,126.08,123.33,119.58,111.89,103.31,100.37,55.83,25.09(2C),18.21.

[0084] Example 11

[0085] Synthesis of N-(3-methoxy-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)cyclopentaneamide (Compound 11):

[0086]

[0087] Referring to Example 1, acetyl chloride was replaced by cyclopentylcarbonyl chloride.

[0088] 1 H NMR(500MHz,DMSO-d6)δ11.53(s,1H),9.88(s,1H),8.20(d,J=2.0Hz,1H), 7.90(d,J=1.9Hz,1H),7.48(s,1H),7.42-7.36(m,1H),7.19(s,2H),6.39( dd,J=3.4,1.8Hz,1H),3.68(s,3H),2.73(dd,J=15.9,7.9Hz,1H),1.79(dd d,J=6.7,5.5,2.8Hz,2H),1.73-1.58(m,4H),1.50(dt,J=7.9,3.2Hz,2H). 13 C NMR(126MHz,DMSO-d6)δ174.98,156.78,147.77,143.82,140.47,131.08,128.78,126.76 ,126.09,123.28,119.58,111.84,103.26,100.37,55.83,45.84,30.57(2C),26.18(2C).

[0089] Example 12

[0090] Synthesis of N-(3-methoxy-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)cyclohexaneamide (Compound 12):

[0091]

[0092] Referring to Example 1, acetyl chloride was replaced by cyclohexylcarbonyl chloride.

[0093] 1 H NMR (500MHz, DMSO-d6) δ11.53(s,1H),9.81(s,1H),8.19(d,J=2.0Hz,1H),7.90(d,J=1.8 Hz,1H),7.48(s,1H),7.42-7.36(m,1H),7.19(d,J=2.7Hz,2H),6.38(dd,J=3.3,1.8Hz,1 H),3.67(s,3H),2.28(tt,J=11.5,3.3Hz,1H),1.73(dd,J=26.9,12.3Hz,4H),1.59(d,J= 12.1Hz,1H),1.37(ddd,J=25.1,12.7,2.9Hz,2H),1.29-1.17(m,2H),1.17-1.10(m,1H). 13 C NMR (126MHz, DMSO-d6) δ174.88,156.76,147.77,143.81,140.50,131.06,128.77,126.76 ,126.09,123.25,119.57,111.81,103.23,100.36,55.82,45.46,29.64(2C),25.72(2C).

[0094] Example 13

[0095] Synthesis of N-(3-methoxy-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)benzamide (Compound 13):

[0096]

[0097] Referring to Example 1, acetyl chloride was replaced by benzoyl chloride.

[0098] 1 H NMR (500MHz, DMSO-d6) δ11.56(s,1H),10.26(s,1H),8.24(d,J=2.0Hz,1H),7.97-7.93(m,2H),7.92(d,J=1.5Hz,1H),7.63(d,J=1.8Hz,1 H),7.59-7.51(m,1H),7.48(dd,J=10.3,4.6Hz,3H),7.43-7.38(m,1H),7.27(d,J=8.2Hz,1H),6.40(dd,J=3.4,1.8Hz,1H),3.72(s,3H). 13C NMR (126MHz, DMSO-d6) δ166.04,156.75,147.84,143.85,140.17,135.42,132.09,131.07,128. 89(2C),128.85,128.12(2C),126.81,126.04,124.06,119.60,113.04,104.47,100.41,55.93.

[0099] Example 14

[0100] Synthesis of N-(3-methoxy-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)tetrahydrofuran-2-carboxamide (Compound 14):

[0101]

[0102] Referring to Example 2, glycolic acid was replaced by tetrahydrofuran-2-carboxylic acid.

[0103] 1 H NMR (400MHz, DMSO-d6) δ11.64(s,1H),9.77(s,1H),8.27(d,J=1.6Hz,1H),7.99(s ,1H),7.59(s,1H),7.46(d,J=7.6Hz,2H),7.28(d,J=8.2Hz,1H),6.46(s,1H),4.42 (dd,J=8.0,5.7Hz,1H),4.06-3.97(m,1H),3.86(dd,J=14.4,6.9Hz,1H),3.75(s,3 H), 2.20 (dd, J=13.6, 6.2Hz, 1H), 2.01 (td, J=12.6, 6.7Hz, 1H), 1.96-1.82 (m, 2H). 13 C NMR(101MHz,DMSO-d6)δ172.05,156.70,147.78,143.80,139.40,131.02,128.81,126.8 1,125.98,123.92,119.57,112.52,104.07,100.37,78.44,69.33,55.91,30.46,25.56.

[0104] Example 15

[0105] Synthesis of N-(3-methoxy-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)furan-2-carboxamide (Compound 15):

[0106]

[0107] Referring to Example 2, glycolic acid was replaced by furan-2-carboxylic acid.

[0108] 1 H NMR (500MHz, DMSO-d6) δ11.57(s,1H),10.61(s,1H),9.32(s,1H),9.24(s,2H),8.25(d,J=2.0Hz,1H),7.96(d,J=1. 9Hz,1H),7.57(d,J=1.7Hz,1H),7.45-7.40(m,2H),7.31(d,J=8.2Hz,1H),6.40(dd,J=3.3,1.8Hz,1H),3.73(s,3H). 13 C NMR(126MHz,DMSO-d6)δ162.66,160.63,156.81,156.70(2C),147.87,143.82,139.46,1 31.24,129.05,128.88,126.86,125.87,124.71,119.60,113.05,104.42,100.43,55.97.

[0109] Example 16

[0110] Synthesis of N-(3-methoxy-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)furan-3-carboxamide (Compound 16):

[0111]

[0112] Referring to Example 2, glycolic acid was replaced by furan-3-carboxylic acid.

[0113] 1 H NMR (500MHz, DMSO-d6) δ11.55(s,1H),9.94(s,1H),8.35(s,1H),8.24(d,J=1.9Hz,1H),7.94(d,J=1.7Hz,1H),7.74(d,J=1.5Hz,1H),7. 53(d,J=1.6Hz,1H),7.40(dd,J=5.9,2.4Hz,2H),7.26(d,J=8.2Hz,1H),6.97(d,J=1.0Hz,1H),6.40(dd,J=3.2,1.7Hz,1H),3.72(s,3H). 13C NMR (126MHz, DMSO-d6) δ160.92,156.76,147.83,146.35,144.72,143.84,139.84,131.11, 128.84,126.80,126.01,124.00,123.54,119.60,112.89,109.72,104.29,100.40,55.92.

[0114] Example 17

[0115] Synthesis of N-(3-methoxy-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)5-methylfuran-3-carboxamide (Compound 17):

[0116]

[0117] Referring to Example 2, glycolic acid was replaced by 5-methyl-furan-3-carboxylic acid.

[0118] 1 H NMR (500MHz, DMSO-d6) δ11.62(s,1H),10.09(s,1H),8.31(d,J=2.1Hz,1H),8.01(d,J=1.9Hz,1H),7.61(d,J=1.9Hz,1H),7.55(dd,J=8.3,1.9Hz,1H) ,7.50-7.45(m,1H),7.32(d,J=8.2Hz,1H),7.26(d,J=3.3Hz,1H),6.47(dd ,J=3.4,1.8Hz,1H),6.35(dd,J=3.3,0.9Hz,1H),3.79(s,3H),2.41(s,3H). 13 C NMR(126MHz,DMSO-d6)δ156.72,156.70,155.68,147.82,146.50,143.84,139.66,131.07,128 .83,126.80,126.01,123.96,119.60,116.49,112.96,109.09,104.42,100.40,55.93,14.06.

[0119] Example 18

[0120] Synthesis of N-(3-methoxy-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)thiazole-4-carboxamide (Compound 18):

[0121]

[0122] Referring to Example 2, glycolic acid was replaced by thiazole-4-carboxylic acid.

[0123] 1 H NMR (500MHz, DMSO-d6) δ11.55(s,1H),10.33(s,1H),9.22(d,J=2.0Hz,1H),8.46(d,J=2.0Hz,1H),8.24(d,J=2.0Hz,1H),7.95(d,J=1.8H z,1H),7.69(d,J=1.9Hz,1H),7.58(dd,J=8.3,1.9Hz,1H),7.40(m,1H),7.26(d,J=8.2Hz,1H),6.40(dd,J=3.4,1.8Hz,1H),3.72(s,3H). 13 C NMR(126MHz,DMSO-d6)δ159.61,156.76,155.56,151.18,147.84,143.85,139.45,131 .07,128.86,126.81,126.07,126.00,124.26,119.60,113.04,104.68,100.41,55.98.

[0124] Example 19

[0125] Synthesis of N-(3-methoxy-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)benzofuran-2-carboxamide (Compound 19):

[0126]

[0127] Referring to Example 1, acetyl chloride was replaced with benzofuran-2-carbonyl chloride.

[0128] 1 H NMR (500MHz, DMSO-d6) δ11.57(s,1H),10.54(s,1H),8.25(d,J=2.0Hz,1H),7.96(d,J=1.8Hz,1H),7.81-7.71(m,2H),7.65(dd,J=19.8,5.0Hz ,2H),7.55(dd,J=8.3,1.9Hz,1H),7.44(ddd,J=16.4,7.0,2.0Hz,2H),7.31(dd,J=14.3,7.9Hz,2H),6.41(dd,J=3.3,1.8Hz,1H),3.74(s,3H). 13C NMR(126MHz,DMSO-d6)δ157.13,156.77,154.96,149.28,147.86,143.84,139.31,131.16,128.87,127.69, 127.65,126.84,125.94,124.51,124.36,123.43,119.61,113.21,112.41,111.24,104.68,100.42,55.97.

[0129] Example 20

[0130] Synthesis of N-(3-methoxy-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)picolinamide (Compound 20):

[0131]

[0132] Referring to Example 2, glycolic acid was replaced by 2-pyridinecarboxylic acid.

[0133] 1 H NMR (500MHz, DMSO-d6) δ11.63(s,1H),10.74(d,J=19.3Hz,1H),8.76(dd,J=10.4 ,4.6Hz,1H),8.32(d,J=2.0Hz,1H),8.25-8.17(m,1H),8.09(td,J=7.7,1.6Hz,1 H),8.03(d,J=1.9Hz,1H),7.82(d,J=1.9Hz,1H),7.74-7.67(m,2H),7.48(dd,J= 8.5,5.7Hz,1H),7.36(d,J=8.2Hz,1H),6.48(dd,J=3.3,1.8Hz,1H),3.81(s,3H). 13 C NMR (126MHz, DMSO-d6) δ162.94,156.84,150.31,148.90,147.84,143.85,139.27,138.66,131 .13,128.87,127.45,126.81,125.99,124.35,122.84,119.61,112.88,104.56,100.42,56.02.

[0134] Example 21

[0135] Synthesis of N-(3-methoxy-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)nicotinamide (Compound 21):

[0136]

[0137] Referring to Example 2, glycolic acid was replaced by 3-pyridinecarboxylic acid.

[0138] 1 H NMR (500MHz, DMSO-d6) δ11.56(s,1H),10.46(s,1H),9.09(d,J=1.9Hz,1H),8.71(dd,J=4.8,1.6Hz,1H),8.30-8.22(m,2H),7.95(d,J=1.9Hz ,1H),7.60(d,J=1.8Hz,1H),7.52(dd,J=7.9,4.9Hz,1H),7.49-7.38(m,2H),7.29(d,J=8.2Hz,1H),6.41(dd,J=3.4,1.8Hz,1H),3.73(s,3H). 13 C NMR (126MHz, DMSO-d6) δ164.54,156.77,152.63,149.15,147.85,143.83,139.79,135.92,131 .15,131.04,128.87,126.84,125.95,124.40,123.99,119.60,113.07,104.48,100.42,55.95.

[0139] Example 22

[0140] Synthesis of N-(3-methoxy-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)isonicotinamide (Compound 22):

[0141]

[0142] Referring to Example 2, glycolic acid was replaced by 4-pyridinecarboxylic acid.

[0143] 1 H NMR (500MHz, DMSO-d6) δ11.57(s,1H),10.51(s,1H),8.75(d,J=5.8Hz,2H),8.25(d,J=2.0Hz,1H),7.96(d,J=1.9Hz,1H),7.87–7.79(m,2H ),7.60(d,J=1.7Hz,1H),7.47(dd,J=8.3,1.8Hz,1H),7.44–7.39(m,1H),7.30(d,J=8.2Hz,1H),6.41(dd,J=3.3,1.8Hz,1H),3.73(s,3H). 13C NMR(126MHz,DMSO-d6)δ164.46,156.78,150.77(2C),147.87,143.83,142.37,139.55,131 .17,128.88,126.85,125.91,124.64,122.04(2C),119.61,113.19,104.59,100.42,55.96.

[0144] Example 23

[0145] Synthesis of N-(3-methoxy-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)pyrimidine-5-carboxamide (Compound 23):

[0146]

[0147] Referring to Example 2, glycolic acid was replaced by pyrimidine-5-carboxylic acid.

[0148] 1 H NMR (500MHz, DMSO-d6) δ11.56(s,1H),10.44(s,1H),8.61(s,1H),8.24(d,J=2.1Hz,1H),7.95(d,J=3.5Hz,2H ),7.52(d,J=1.9Hz,1H),7.47-7.38(m,2H),7.28(d,J=8.2Hz,1H),6.40(dd,J=3.4,1.8Hz,1H),3.72(s,3H). 13 C NMR(126MHz,DMSO-d6)δ156.78,155.42,154.33,147.86,145.70,143.82,139.03,131 .20,130.61,128.87,126.84,125.87,124.63,119.60,113.19,104.60,100.42,55.96.

[0149] Example 24

[0150] Synthesis of N-(3-methoxy-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-methylnicotinamide (Compound 24):

[0151]

[0152] Referring to Example 2, glycolic acid was replaced by 2-methylnicotinic acid.

[0153] 1H NMR (500MHz, DMSO-d6) δ11.56(s,1H),10.47(s,1H),8.51(dd,J=4.9,1.7Hz,1H),8.23(d,J=2.0Hz,1H),7.94(d,J=1.9Hz,1H),7.83(dd ,J=7.7,1.6Hz,1H),7.57(d,J=1.4Hz,1H),7.43–7.33(m,2H),7.32–7.24(m,2H),6.40(dd,J=3.4,1.8Hz,1H),3.71(s,3H),2.54(s,3H). 13 C NMR (126MHz, DMSO-d6) δ167.15,156.85,155.55,150.27,147.85,143.83,139.98,135.64,132.7 3,131.24,128.85,126.84,125.98,124.28,121.41,119.60,112.45,103.83,100.41,55.92,23.1

[0154] Example 25

[0155] Synthesis of N-(3-methoxy-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (Compound 25):

[0156]

[0157] Referring to Example 2, glycolic acid was replaced by 1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid.

[0158] 1 H NMR (500MHz, DMSO-d6) δ12.23(s,1H),11.55(s,1H),8.41(dd,J=7.3,2.2Hz,1H),8.23(d,J=2.1Hz,1H),8.10(dd,J=6.5,2.1Hz,1H),7.94(d,J=1.9Hz, 1H),7.50(d,J=1.8Hz,1H),7.43-7.38(m,1H),7.30(dt,J=20.1,5.0Hz,2H) ,6.59-6.52(m,1H),6.40(dd,J=3.4,1.9Hz,1H),3.74(s,3H),3.59(s,3H). 13C NMR (126MHz, DMSO-d6) δ162.56,162.03,157.06,147.83,145.01,144.06,143.82,139.31,131.46 ,128.85,126.82,125.93,124.29,119.78,119.59,112.47,107.09,103.80,100.41,56.01,38.41.

[0159] Example 26

[0160] Synthesis of N-(3-methoxy-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-(pyridin-2-yl)acetamide (Compound 26):

[0161]

[0162] Referring to Example 2, glycolic acid was replaced by 2-(pyridin-2-yl)acetic acid.

[0163] 1 H NMR (500MHz, DMSO-d6) δ11.61(s,1H),10.34(s,1H),8.57(s,1H),8.49(s,1H),8.27(d,J=1.5Hz,1H),7.98(d,J=1.9Hz,1H),7.77(d,J=7 .8Hz,1H),7.51(d,J=1.0Hz,1H),7.50–7.44(m,1H),7.39(d,J=4.7Hz,1H),7.31–7.23(m,2H),6.46(dd,J=3.3,1.8Hz,1H),3.75(s,5H). 13 C NMR (126MHz, DMSO-d6) δ169.10,156.83,150.68,148.29,147.80,143.80,140.02,137.26,132.09 ,131.20,128.80,126.79,125.98,123.91,123.76,119.58,111.91,103.33,100.38,55.85,40.74.

[0164] Example 27

[0165] Synthesis of N-(3-methoxy-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-(pyridin-3-yl)acetamide (Compound 27):

[0166]

[0167] Referring to Example 2, glycolic acid was replaced by 2-(pyridin-3-yl)acetic acid.

[0168] 11 H NMR (500MHz, DMSO-d6) δ11.61(s,1H),10.35(s,1H),8.55-8.50(m,1H),8.28(d,J=2.0Hz,1H),7.98(d,J=1.9Hz,1H),7.77(td ,J=7.7,1.8Hz,1H),7.55(s,1H),7.49-7.40(m,2H),7.33-7.25(m,3H),6.46(dd,J=3.4,1.9Hz,1H),3.89(s,2H),3.75(s,3H). 13 CNMR(126MHz,DMSO-d6)δ168.76,156.82,156.47,149.47,147.80,143.82,140.14,137.03,131.18 ,128.81,126.78,126.01,124.49,123.65,122.40,119.58,111.86,103.28,100.38,55.85,46.45.

[0169] Example 28

[0170] Synthesis of N-(3-methoxy-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-(pyridin-4-yl)acetamide Compound 28:

[0171]

[0172] Referring to Example 2, glycolic acid was replaced by 2-(pyridin-4-yl)acetic acid.

[0173] 1 H NMR (500MHz, DMSO-d6) δ11.60(s,1H),10.35(s,1H),8.55-8.50(m,1H),8.28(d,J=2.0Hz,1H),7.98(d,J=1.9Hz,1H),7.77(td, J=7.6,2.0Hz,1H),7.53(s,1H),7.48-7.43(m,2H),7.36-7.30(m,3H),6.46(dd,J=3.24,2.0Hz,1H),3.89(s,2H),3.75(s,3H). 13CNMR(126MHz,DMSO-d6)δ168.76,156.82,156.47,149.47,147.80,143.82 ,140.14,137.03,131.18,128.81,126.78,126.01,124.51,123.65,122.44 119.58,111.84,103.28,100.37,55.85,46.44.

[0174] Example 29

[0175] Synthesis of N-(3-methoxy-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-(pyridin-4-yl)acrylamide (Compound 29):

[0176]

[0177] Referring to Example 2, glycolic acid was replaced by 3-(pyridin-4-yl)acrylic acid.

[0178] 1 H NMR (500MHz, DMSO-d6) δ11.63(s,1H),10.47(s,1H),8.67(d,J=5.8Hz,2H),8.30(d,J=2.0Hz,1H),8.01(d,J=1.9Hz,1H),7.64-7.57(m,4H ),7.50-7.45(m,1H),7.41(dd,J=8.2,1.7Hz,1H),7.34(d,J=8.2Hz,1H),7.08(d,J=15.8Hz,1H),6.47(dd,J=3.3,1.8Hz,1H),3.79(s,3H). 13 C NMR(126MHz,DMSO-d6)δ163.33,156.88,150.93(2C),147.84,143.82,142.39,139.90,138.16,131 .33,128.84,127.22,126.83,125.95,124.18,122.24(2C),119.59,112.23,103.53,100.41,55.91.

[0179] Example 30

[0180] Synthesis of N-(3-methoxy-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-(pyridin-4-yl)propionamide (Compound 30):

[0181]

[0182] Referring to Example 2, glycolic acid was replaced by 3-(pyridin-4-yl)propionic acid.

[0183] 1 H NMR (500MHz, DMSO-d6) δ11.62(s,1H),10.06(s,1H),8.48(dd,J=4.5,1.5Hz,2H),8.27(d,J=2.0Hz,1H),7.98(d,J=1.9Hz,1H),7 .47(t,J=2.7Hz,2H),7.33-7.23(m,4H),6.46(dd,J=3.4,1.8Hz,1H),3.75(s,3H),2.96(t,J=7.5Hz,2H),2.72(t,J=7.6Hz,2H). 13 C NMR(126MHz,DMSO-d6)δ169.45,155.74,149.50(2C),148.91,146.72,142.74,139.01,130.11,12 7.72,125.72,124.95,123.22(2C),122.48,118.51,110.80,102.18,99.31,54.78,35.88,29.25.

[0184] Example 31

[0185] Synthesis of N-(3-methoxy-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-(pyridin-2-yl)benzamide (Compound 31):

[0186]

[0187] Referring to Example 2, glycolic acid was replaced by 4-(pyridin-2-yl)benzoic acid.

[0188] 1 H NMR(500MHz,DMSO-d6)δ11.56(s,1H),10.35(s,1H),8.69-8.64(m,1H),8.23(d d,J=23.1,5.3Hz,3H),8.05(dd,J=23.0,8.2Hz,3H),7.96(d,J=1.9Hz,1H),7.87 (td,J=7.7,1.8Hz,1H),7.65(d,J=1.8Hz,1H),7.52(dd,J=8.3,1.9Hz,1H),7.4 4-7.32(m,2H),7.29(d,J=8.2Hz,1H),6.41(dd,J=3.3,1.9Hz,1H),3.74(s,3H).13 C NMR(126MHz,DMSO-d6)δ165.59,156.75,155.44,150.22,147.84,143.85,141.97,140.13,137.89,135.56,131.09, 128.87,128.67(2C),126.91(2C),126.82,126.03,124.13,123.73,121.29,119.61,113.10,104.52,100.42,55.95.

[0189] Example 32

[0190] Synthesis of N-(3-methoxy-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-(pyridin-3-yl)benzamide (Compound 32):

[0191]

[0192] Referring to Example 2, glycolic acid was replaced by 4-(pyridin-3-yl)benzoic acid.

[0193] 1 H NMR(500MHz,DMSO-d6)δ11.66(s,1H),10.48(s,1H),9.01(d,J=2.1Hz,1H),8.64(d d,J=4.7,1.4Hz,1H),8.32(d,J=2.0Hz,1H),8.24-8.13(m,3H),8.03(d,J=2.0Hz,1 H),7.94(d,J=8.3Hz,2H),7.75(d,J=1.5Hz,1H),7.57(ddd,J=12.7,8.1,3.3Hz,2H ),7.48(d,J=3.2Hz,1H),7.35(d,J=8.2Hz,1H),6.48(d,J=3.3Hz,1H),3.81(s,3H). 13 C NMR (126MHz, DMSO-d6) δ165.49,156.74,149.60,148.33,147.83,143.84,140.55,140.16,135.06,134.86,134.76, 131.06,129.01(2C),128.84,127.31(2C),126.83,126.02,124.44,124.11,119.60,113.10,104.53,100.39,55.96.

[0194] Example 33

[0195] Synthesis of N-(3-methoxy-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-(pyridin-4-yl)benzamide (Compound 33):

[0196]

[0197] Referring to Example 2, glycolic acid was replaced by 4-(pyridin-4-yl)benzoic acid.

[0198] 1 H NMR (500MHz, DMSO-d6) δ11.62(s,1H),10.54(s,1H),8.67-8.60(m,2H),8.25(d,J=2.0Hz,1H),8.15(d,J=8.3Hz,2H),7.94(dd,J=16.7,5.1 Hz,3H),7.79-7.69(m,3H),7.57(dd,J=8.3,1.1Hz,1H),7.45-7.39(m,1H),7.28(d,J=8.2Hz,1H),6.41(dd,J=3.3,1.8Hz,1H),3.74(s,3H). 13 C NMR(126MHz,DMSO-d6)δ165.38,156.71,150.84(2C),147.81,146.45,143.83,140.51,140.15,135.71,131.02, 129.14(2C),128.84,127.29(2C),126.84,126.02,124.12,121.86(2C),119.61,113.19,104.66,100.38,55.97.

[0199] Example 34

[0200] Synthesis of N-(3-methoxy-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-morpholinobenzamide (Compound 34):

[0201]

[0202] Referring to Example 2, glycolic acid was replaced by 4-morpholinobenzoic acid.

[0203] 1H NMR(500MHz,DMSO-d6)δ11.69(s,1H),11.62(s,1H),10.04(s,1H),8.54(d,J=2.1Hz,1H) ,8.31(d,J=2.0Hz,1H),8.23(d,J=2.0Hz,1H),8.01(d,J=1.8Hz,1H),7.94(d,J=8.9Hz,2 H),7.70(d,J=1.8Hz,1H),7.57-7.45(m,3H),7.31(d,J=8.2Hz,1H),7.05(d,J=8.9Hz,2H ),6.49(ddd,J=20.2,3.3,1.8Hz,2H),3.79(s,3H),3.78-3.71(m,4H),3.29-3.23(m,4H). 13 C NMR (126MHz, DMSO-d6) δ164.40,155.62,152.63,147.22,146.72,142.78,141.11,129.90,128.46,127.74,126 .48,126.24,125.70,125.05,122.48,119.16,112.74,111.82,103.24,99.43,65.32(2C).,54.83,46.66,46.59

[0204] Example 35

[0205] Synthesis of N-(3-methoxy-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-4-(morpholinomethyl)benzamide (Compound 35):

[0206]

[0207] Referring to Example 2, glycolic acid was replaced by 4-(morpholinomethyl)benzoic acid.

[0208] 1 H NMR (500MHz, DMSO-d6) δ10.29(s,1H),8.31(d,J=1.9Hz,1H),8.02(d,J=1.8Hz,1H),7.96(d,J=8.2Hz,2H),7.69(d,J=1.8Hz,1H) ,7.48(t,J=5.8Hz,3H),7.34(d,J=8.2Hz,1H),6.47(d,J=1.5Hz,1H),3.79(s,3H),3.66-3.57(m,4H),3.56(s,2H),2.39(s,4H). 13C NMR(126MHz,DMSO-d6)δ165.87,156.73,147.83,143.84,142.25,140.20,134.17,131.06,129.28(2C),128.83 ,128.11(2C),126.80,126.04,124.00,119.60,112.99,104.41,100.40,66.65(2C),62.42,55.92,53.64(2C).

[0209] Example 36

[0210] Synthesis of N-(3-methoxy-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)morpholine-4-carboxamide (Compound 36):

[0211]

[0212] Referring to Example 1, acetyl chloride was replaced by morpholinecarbonyl chloride.

[0213] 1 H NMR (400MHz, DMSO-d6) δ11.62(s,1H),8.65(s,1H),8.27(d,J=2.0Hz,1H),7.97(d,J=1.8Hz,1H),7.53-7.43(m,1H),7.37 (d,J=0.9Hz,1H),7.22(t,J=5.3Hz,2H),6.45(dd,J=3.3,1.8Hz,1H),3.74(s,3H),3.68-3.60(m,4H),3.55-3.41(m,4H). 13 C NMR(101MHz,DMSO-d6)δ156.61,155.54,147.69,143.83,141.45,130.82,128.74,126 .72,126.23,122.11,119.57,112.14,103.63,100.33,66.47(2C),55.78,44.64(2C).

[0214] Example 37

[0215] Synthesis of N-(3-methoxy-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-morpholinoacetamide (Compound 37):

[0216]

[0217] Referring to Example 2, glycolic acid was replaced by 2-morpholinoacetic acid.

[0218] 1 H NMR (500MHz, DMSO-d6) δ11.54(s,1H),9.74(s,1H),8.20(d,J=2.0Hz,1H),7.91(d,J=1.8Hz,1H),7.45(d,J=1.7Hz,1H),7.42-7.37(m,1H),7. 28(dd,J=8.2,1.8Hz,1H),7.21(d,J=8.2Hz,1H),6.39(dd,J=3.3,1.8Hz,1H),3.69(s,3H),3.62-3.56(m,4H),3.09(s,2H),2.49-2.44(m,4H). 13 C NMR (126MHz, DMSO-d6) δ168.65,156.81,147.80,143.81,139.56,131.12,128.80,126.79 ,126.01,123.84,119.58,112.23,103.68,100.38,66.56(2C),62.64,55.94,53.66(2C).

[0219] Example 38

[0220] Synthesis of N-(3-methoxy-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-3-morpholinopropionamide (Compound 38):

[0221]

[0222] Referring to Example 2, glycolic acid was replaced by 3-morpholinepropionic acid.

[0223] 1 H NMR (500MHz, DMSO-d6) δ11.59(s,1H),10.17(s,1H),8.20(d,J=1.9Hz,1H),7.91(d,J=2.0Hz,1H),7.44(s,1H),7.40(s,1H),7 .20(s,2H),6.39(d,J=3.0Hz,1H),3.68(s,3H),3.56-3.51(m,4H),2.58(t,J=7.0Hz,2H),2.46(d,J=8.0Hz,2H),2.36(s,4H). 13CNMR(126MHz,DMSO-d6)δ170.72,156.79,147.77,143.79,140.25,131.14,128.78,126.80,1 26.04,123.43,119.58,111.83,103.23,100.35,66.68(2C),55.85,54.67,53.53(2C),34.47.

[0224] Example 39

[0225] Synthesis of N-(3-methoxy-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)tetrahydro-2H-pyran-4-carboxamide (Compound 39):

[0226]

[0227] Referring to Example 2, glycolic acid was replaced by tetrahydro-2H-pyran-4-carboxylic acid.

[0228] 1 H NMR (400MHz, DMSO-d6) δ11.63(s,1H),10.00(s,1H),8.27(d,J=2.0Hz,1H),7.98(d,J=1.8Hz,1H),7.49(dd,J=20.3,17.2Hz,2H),7.27(d,J=0.7Hz,2 H),6.46(dd,J=3.4,1.8Hz,1H),3.93(dd,J=8.0,2.9Hz,2H),3.75(s,3H), 3.44-3.32(m,2H),2.62(ddd,J=15.4,10.3,5.3Hz,1H),1.89-1.61(m,4H). 13 C NMR(101MHz,DMSO-d6)δ173.57,156.77,147.77,143.81,140.32,131.11,128.79,126.79 ,126.04,123.40,119.57,111.83,103.23,100.37,66.87(2C),55.82,42.35,29.35(2C).

[0229] Example 40

[0230] Synthesis of N-(3-methoxy-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-(tetrahydro-2H-pyran-4-yl)acetamide (Compound 40):

[0231]

[0232] Referring to Example 2, glycolic acid was replaced with 2-(tetrahydro-2H-pyran-4-yl)acetic acid.

[0233] 1 H NMR (500MHz, DMSO-d6) δ11.54(s,1H),9.93(s,1H),8.20(d,J=2.0Hz,1H),7.90(d,J =1.9Hz,1H),7.47-7.36(m,2H),7.23-7.18(m,2H),6.38(dd,J=3.4,1.8Hz,1H),3.77 (dd,J=11.4,2.6Hz,2H),3.68(s,3H),3.24(td,J=11.7,1.8Hz,2H),2.21(d,J=7.1Hz ,2H),2.07-1.91(m,1H),1.54(dd,J=12.8,1.7Hz,2H),1.20(qd,J=12.0,4.4Hz,2H). 13 CNMR(126MHz,DMSO-d6)δ170.59,156.79,147.78,143.82,140.18,131.13,128.79,126.77,1 26.06,123.47,119.58,111.84,103.23,100.37,67.36(2C),55.84,44.21,32.89(2C),32.61.

[0234] Example 41

[0235] Synthesis of N-(3-methoxy-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)-2-(piperidin-1-yl)acetamide (Compound 41):

[0236]

[0237] Referring to Example 2, glycolic acid was replaced by 2-(piperidin-1-yl)acetic acid.

[0238] 1H NMR (500MHz, DMSO-d6) δ11.62(s,2H),9.73(s,2H),8.28(d,J=2.0Hz,2H),7. 98(d,J=1.8Hz,2H),7.53(d,J=1.7Hz,2H),7.50-7.44(m,2H),7.36(dd,J=8. 2,1.7Hz,2H),7.28(d,J=8.2Hz,2H),6.47(dd,J=3.3,1.8Hz,2H),3.77(s,6H ),3.10(s,4H),2.52-2.50(m,3H),1.67-1.54(m,8H),1.42(d,J=4.8Hz,4H). 13 C NMR (126MHz, DMSO-d6) δ169.18,156.84,147.80,143.81,139.56,131.13,128.80,126.7 9,126.02,123.79,119.58,112.12,103.59,100.38,63.26,55.96,54.56,25.91,24.03.

[0239] Example 42

[0240] Synthesis of tert-butyl-4-(2-((3-methoxy-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)amino)-2-oxoethyl)piperazine-1-carboxylate (Compound 42):

[0241]

[0242] Referring to Example 2, glycolic acid was replaced by 4-tert-butoxycarbonyl-1-piperazineacetic acid.

[0243] 1 H NMR (400MHz, DMSO-d6) δ11.64(s,1H),9.84(s,1H),8.27(d,J=2.0Hz,1H),7.98(d,J=1.9Hz,1H),7.52(d,J=1.8Hz,1H),7.50-7.45(m,1H),7.3 6(dd,J=8.3,1.8Hz,1H),7.29(d,J=8.2Hz,1H),6.46(dd,J=3.4,1.8Hz,1H),3.76(s,3H),3.41(s,4H),3.37(s,4H),3.19(s,2H),1.41(s,9H). 13C NMR (101MHz, DMSO-d6) δ166.67,156.78,154.33,147.78,143.79,139.55,131.13,128.81,126. 82,125.98,123.79,119.57,112.16,103.57,100.37,79.29,55.92(2C),52.88(2C),28.52(3C).

[0244] Example 43

[0245] In vitro CDK8 kinase inhibitory activity and in vitro cell activity evaluation:

[0246] The inhibitory activity of compounds 1-42 of the present invention against CDK8 kinase was tested using the ADP-Glo ​​Kinase Assay (Promega) in a 384-well plate. Active CDK8 kinase was diluted in a mixture (5 ng CDK8 kinase, 0.5 μg substrate, 50 μM DTT, 1 μL buffer, and dd H2O was added to each well to make 3 μL). Then, 1 μL of a 1 μM compound solution was added to each well (the final compound concentration was 200 nM), followed by 1 μL of ATP (adenosine triphosphate) to a final concentration of 50 μM. After incubation at room temperature for 1 hour, the ADP-Glo ​​solution and kinase detection reagent were added, and the data were collected by a microplate reader. CCT251545 was selected as the positive control, and the results are shown in Table 2.

[0247] Table 2 CDK8 inhibitory activity of compounds 1-42 at a concentration of 200 nM

[0248]

[0249]

[0250] The compounds with high inhibition rates were screened from Table 2 and their CDK8 IC values ​​were further determined. 50 , IL-8 inhibition rate and NF-KB inhibition rate, the results are shown in Table 3.

[0251] Table 3 Activity data of some highly active compounds

[0252]

[0253] As can be seen from Table 3, compound 36 exhibits good CDK8 inhibitory activity, and also has good inhibitory activity against IL-8 and NF-κB.

[0254] Example 44

[0255] Target validation of compound 36:

[0256] The pull-down assay was used to verify the targeting of compound 36. HCT-116 cells were seeded into 60 mm culture dishes at 1×10 6 cells; pretreated with compound 36 (or co-treated with compound 36 and CCT-251545) for 12 h, then lysed with NP-40 containing PMSF and centrifuged at 14,000 rpm for 30 min at 4°C, and the supernatant was collected; 40 μL of the supernatant was then aspirated and 10 μL of 5×SDS loading buffer was added as the input group, and the remaining supernatant was mixed with streptavidin agarose; after incubation at 4°C for 6 h, the beads were washed three times with lysis buffer and resuspended in 2×SDS loading buffer.

[0257] HEK293T cells were seeded into 60 mm culture dishes and cultured overnight. 10 μg of CDK8 plasmid was then transfected into the HEK293T cells using Lipofectamine 2000 in serum-free medium. Six hours later, the serum-free medium was replaced with complete DMEM. Subsequent processing was the same as above.

[0258] See the results Figure 1 .from Figure 1 It can be seen that compound 36 can bind to CDK8 protein in a concentration-dependent manner and compete with CCT-251545 for binding to CDK8.

[0259] Example 45

[0260] In vitro mechanism study of compound 36:

[0261] HEK293 cells were plated at 3 × 10 4 Cells were seeded at a density of 100 cells / well in a 96-well plate. Twelve hours later, pNF-κB-TA-Gluc plasmid (100 ng per well) was transfected into the cells using Lipofectamine 2000. Six hours later, different concentrations of compound 36 were added, and the cells were subsequently treated with 10 ng / mL recombinant human TNF-α for 3 hours. The collected cell supernatants were analyzed using a human IL-8 ELISA kit, and NF-κB transcriptional activity was detected using a dual-luciferase assay kit.

[0262] HEK-293 cells were seeded into 60 mm culture dishes and incubated for 24 hours. The cells were then treated with 0.1% DMSO, compound 36, or 50 μM PTCK for 2 hours, followed by 20 ng / mL TNF-α for 30 minutes. Nuclear proteins were extracted using a nuclear extract kit, and the expression of P65 and P50 in the nucleus was analyzed by Western blotting.

[0263] See the results Figure 2 .from Figure 2It can be seen that compound 36 can significantly inhibit the expression of IL-8 and the activity of NF-κB induced by TNF-α, but has no effect on the nuclear translocation of P65 and P50, indicating that the effect of compound 36 on NF-κB acts in the nucleus, which is consistent with the specificity of CDK8 inhibitors for NF-κB.

[0264] Example 46

[0265] Study on the therapeutic effect of compound 36 in a mouse psoriasis model:

[0266] Male Balb / C mice were randomly divided into five groups, and a 2 cm × 3 cm area of ​​the back skin of the mice was shaved. The next day, the control group mice were given petrolatum cream, the model group mice were treated with 5% imiquimod cream, and the compound group mice (5, 10, 20 mg / kg) were given 5% imiquimod cream and different doses of compound 36. The mice were scored daily, ranging from 0 to 4 points to describe the severity of psoriasis. 0: None; 1: Mild; 2: Moderate; 3: Marked; 4: Very obvious. Photographs were taken every day to observe changes in the skin. At the end of the experiment, all mice were killed by cervical dislocation. Blood and skin samples were collected. Some dorsal lesion skin samples were collected in 10% formalin for hematoxylin and eosin staining, and the remaining skin samples were analyzed by western blot. Blood samples were analyzed using IL-6 and TNF-α ELISA kits.

[0267] See the results Figure 3 .from Figure 3 It can be seen that compound 36 has a significant alleviating effect on the mouse psoriasis model.

[0268] The basic principles, main features, and advantages of the present invention are shown and described above. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The above embodiments and descriptions are merely illustrative of the principles of the present invention. Various changes and modifications may be made to the present invention without departing from the spirit and scope of the present invention. Such changes and modifications are intended to fall within the scope of the present invention. The scope of protection claimed in the present invention is defined by the appended claims and their equivalents.

Claims

1. An N-(4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)amide derivative, characterized in that: The structure is as follows:

2. The method for preparing the N-(4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)amide derivative according to claim 1, characterized in that: The following steps are involved: (1) Suzuki-Miyaura reaction with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine to give intermediate M1; (2) Intermediate M1 and R 2 COOH or R 2 COCl undergoes amide condensation reaction to give compounds 1, 2, 3, 5, 8, 11, 36, 37, 38, and 39; The reaction equation is as follows:

3. A pharmaceutical composition comprising the N-(4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)amide derivative according to claim 1 or a pharmaceutically acceptable salt thereof.

4. A pharmaceutical preparation comprising an active ingredient and a pharmaceutically acceptable excipient and / or carrier, wherein the active ingredient contains the N-(4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)amide derivative according to claim 1 or a pharmaceutically acceptable salt thereof.

5. Use of the N-(4-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)amide derivative or a pharmaceutically acceptable salt thereof according to claim 1 in the preparation of a CDK8 inhibitor.

6. Use of compound 36 or a pharmaceutically acceptable salt thereof as claimed in claim 1 in the preparation of a medicament for treating psoriasis.

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