4-(3-(piperidine-4-yl)-1H-pyrazol-5-yl)-1H-pyrrole [2, 3-b] pyridine derivative as well as preparation method and application thereof

Abstract

The invention provides a 4-(3-(piperidine-4-yl)-1H-pyrazole-5-yl)-1H-pyrrole [2, 3-b] pyridine derivative, and a stereoisomer, a tautomer, a geometric isomer or a pharmaceutically acceptable salt thereof, and is characterized in that the 4-(3-(piperidine-4-yl)-1H-pyrazole-5-yl)-1H-pyrrole [2, 3-b] pyridine derivative has a structural formula shown in the specification, and the structural formula is shown in the specification. The structure of the [1, 2, 3-b] pyridine derivative is shown as a formula I: # imgabs0. The invention also provides a preparation method of the compound, and the preparation method is simple in preparation process and easy to industrialize. The invention also provides application of the compound or the stereoisomer, tautomer, geometric isomer or pharmaceutically acceptable salt thereof in preparation of anti-inflammatory drugs, ROCK kinase inhibitors or drugs for reducing intraocular pressure.

Description

Technical Field

[0001] The patent of this invention relates to the field of pharmaceutical chemistry technology, and in particular to a 4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrole[2,3-b]pyridine derivative and its preparation method and application. Background Art

[0002] ROCK kinases (Rho-associated coiled-coil containing kinases) belong to the serine / threonine protein kinase family and include two subtypes, ROCK1 and ROCK2. ROCK1 and ROCK2 are widely distributed in embryonic and adult tissues, with ROCK1 being evenly distributed throughout the body, while ROCK2 is more common in the brain, heart, lungs, and muscles. In addition, ROCK is mainly present in the cytoplasm and is less common in the nucleus and cytoplasm. Activation of ROCK can regulate the reorganization of actin based on the cytoskeleton and participate in a variety of biological processes, including cell migration, adhesion, proliferation, apoptosis, and differentiation, by phosphorylating different downstream substrates; these substrates include myosin II regulatory light chains (MLCs), myosin binding subunits (MBS), also known as myosin MLC phosphatases (MLCPs), LIM kinases, ERM proteins, and Vimentin. Abnormal activation of ROCK protein kinases is associated with pathological conditions in different systems, including cancer, neurological diseases, inflammation, cardiovascular diseases, and glaucoma. ROCK inhibitors have potential applicability in the treatment of the above diseases.

[0003] Therefore, it is necessary to provide a compound having ROCK inhibitory activity. Summary of the invention

[0004] The present invention aims to solve at least one of the technical problems existing in the prior art to a certain extent. Therefore, in the first aspect of the present invention, the present invention provides a 4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridine derivative, and its stereoisomers, tautomers, geometric isomers or pharmaceutically acceptable salts. The structure of the 4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridine derivative is shown in Formula I:

[0005]

[0006] Wherein, R is selected from H, The A ring is selected from benzene, naphthalene, anthracene, pyridine, pyrimidine, pyridazine, pyrazine, and triazine; n1, n2, and n3 are independently selected from any integer from 1 to 4; R1, R2, R3, R4, and R5 are independently selected from H, C1-6 alkoxy, halogen-substituted C1-6 alkyl, C1-6 alkoxyacyl, C1-6 alkylacyl, halogen, C1-6 alkyl, phenoxy, nitro, C1-6 alkenyl, C3-8 cycloalkyl, C3-8 cycloalkyl-substituted C1-6 alkyl, and C1-6 alkyl-substituted phenyl.

[0007] In one or more embodiments of the present invention, the A ring is benzene.

[0008] In one or more embodiments of the present invention, n1, n2, and n3 are all 1.

[0009] In one or more embodiments of the present invention, R is selected from H, R2 is selected from C1-6 alkyl, halogen-substituted C1-6 alkyl, C1-6 alkoxyacyl, halogen, C1-6 alkylacyl, C1-6 alkoxy; R3 is selected from C1-6 alkenyl, halogen-substituted C1-6 alkyl, cyclopentane; R4 is selected from halogen, C1-6 straight-chain alkyl; R5 is selected from H, C1-6 alkoxy.

[0010] In one or more embodiments of the present invention, the 4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridine derivative is selected from the following compounds:

[0011]

[0012]

[0013]

[0014]

[0015] In the second aspect of the present invention, the present invention provides a method for preparing the above-mentioned 4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrole[2,3-b]pyridine derivative. When R is H, the reaction formula for preparing the 4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrole[2,3-b]pyridine derivative is as follows:

[0016]

[0017] The preparation of the 4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrole[2,3-b]pyridine derivative includes: reacting 3-quinuclidinone with 7-azaindole-4-carboxaldehyde to obtain compound D25-1, and reacting compound D25-1 with hydrazine hydrate to obtain the 4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrole[2,3-b]pyridine derivative.

[0018] In one or more embodiments of the present invention, when R is not H, the reaction formula for preparing the 4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridine derivative is as follows:

[0019]

[0020] Wherein, R is defined as in claim 1, and X is a halogen;

[0021] The preparation of the 4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrole[2,3-b]pyridine derivative comprises: reacting compound D25 with RX to obtain the 4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrole[2,3-b]pyridine derivative.

[0022] In the third aspect of the present invention, the present invention provides a pharmaceutical composition comprising the 4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridine derivative or its stereoisomers, tautomers, geometric isomers or pharmaceutically acceptable salts as described in any one of claims 1 to 4.

[0023] In one or more embodiments of the present invention, the pharmaceutical composition is eye drops, and the mass fraction of the 4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrole[2,3-b]pyridine derivative or its stereoisomer, tautomer, geometric isomer or pharmaceutically acceptable salt in the eye drops is 0.1%.

[0024] In the fourth aspect of the present invention, the present invention provides the use of the above-mentioned 4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrole[2,3-b]pyridine derivative or its stereoisomers, tautomers, geometric isomers or pharmaceutically acceptable salts and / or the above-mentioned pharmaceutical composition in the preparation of anti-inflammatory drugs.

[0025] In the fifth aspect of the present invention, the present invention provides the use of the above-mentioned 4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridine derivative or its stereoisomers, tautomers, geometric isomers or pharmaceutically acceptable salts and / or the above-mentioned pharmaceutical composition in the preparation of ROCK kinase inhibitors.

[0026] In one or more embodiments of the present invention, the ROCK kinase inhibitor includes at least one of a ROCK1 kinase inhibitor and a ROCK2 kinase inhibitor.

[0027] In the sixth aspect of the present invention, the present invention provides the use of the above-mentioned 4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrole[2,3-b]pyridine derivative or its stereoisomers, tautomers, geometric isomers or pharmaceutically acceptable salts and / or the above-mentioned pharmaceutical composition in the preparation of intraocular pressure reducing drugs.

[0028] The beneficial effects of the present invention are:

[0029] 1. The present invention provides 4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridine derivatives, which are new compounds and have ROCK kinase inhibitory activity.

[0030] 2. The present invention provides a method for preparing the above-mentioned 4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridine derivative, which has a simple preparation process and is easy to industrialize.

[0031] 3. The present invention provides the use of the above-mentioned 4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridine derivative or its stereoisomers, tautomers, geometric isomers or pharmaceutically acceptable salts in the preparation of anti-inflammatory drugs.

[0032] 4. The present invention provides the use of the above-mentioned 4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridine derivative or its stereoisomers, tautomers, geometric isomers or pharmaceutically acceptable salts in the preparation of ROCK kinase inhibitors.

[0033] 5. The present invention provides the use of the above-mentioned 4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridine derivative or its stereoisomers, tautomers, geometric isomers or pharmaceutically acceptable salts in the preparation of drugs for reducing intraocular pressure. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1This is a comparison chart of the intraocular pressure-lowering ability of 0.1% mass fraction of nesudil mesylate, R3 hydrochloride and D25 hydrochloride eye drops in normal intraocular pressure rabbits;

[0035] Figure 2 This is a comparison chart of the intraocular pressure-lowering ability of 0.1% mass fraction of nesudil mesylate, R3 hydrochloride and D25 hydrochloride eye drops in the methylcellulose-induced rabbit intraocular hypertension model. DETAILED DESCRIPTION

[0036] The present invention will be further described below in conjunction with specific examples, but the following examples are only used to illustrate the present invention and should not be considered to limit the scope of the present invention. In the following examples, if specific conditions are not specified, they are carried out according to normal conditions or conditions recommended by the manufacturer. The methods used are conventional methods known in the art unless otherwise specified, and the consumables and reagents used are commercially available unless otherwise specified. Unless otherwise specified, the professional and scientific terms used herein have the same meaning as those familiar to those skilled in the art. In addition, any method or material similar or equivalent to the recorded content may also be applied to the present invention.

[0037] The present invention provides a 4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridine derivative, and a stereoisomer, tautomer, geometric isomer or pharmaceutically acceptable salt thereof. The structure of the 4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridine derivative is shown in Formula I:

[0038]

[0039] Wherein, R is selected from H, Ring A is selected from benzene, naphthalene, anthracene, pyridine, pyrimidine, pyridazine, pyrazine, and triazine; n1, n2, n3, and n4 are independently selected from any integer from 1 to 4; R1, R2, R3, R4, R5, and R6 are independently selected from H, C1-6 alkoxy, halogen-substituted C1-6 alkyl, C1-6 alkoxyacyl, C1-6 alkylacyl, halogen, C1-6 alkyl, phenoxy, nitro, C1-6 alkenyl, C3-8 cycloalkyl, C3-8 cycloalkyl-substituted C1-6 alkyl, and C1-6 alkyl-substituted phenyl.

[0040] The following is explained in conjunction with specific examples: The structural formulas of compounds D25 and R1-R41 in the examples are shown in Table 1 below:

[0041] Table 1

[0042]

[0043]

[0044]

[0045]

[0046]

[0047] Example 1: 4-(3-(Piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridine (D25)

[0048] When R is H, the 4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridine derivative is compound D25, and the reaction formula for preparing compound D25 is as follows:

[0049]

[0050] The specific steps are as follows: 200 mg of 3-quinuclidinone hydrochloride, 49.2 mg of NaOH, and 179 mg of 7-azaindole-4-carboxaldehyde are used as raw materials, mixed evenly with an ethanol solution, and heated under reflux for 6 hours. After the reaction is completed, ethanol is evaporated, washed with water, extracted with EA, dried over anhydrous magnesium sulfate, and then the solvent is evaporated to obtain 220 mg of a yellow solid (A1). A1 (200 mg) is refluxed in 10 mL of 50% hydrazine hydrate for 6 hours, cooled at room temperature, and solids are precipitated. The product D25 is obtained by suction filtration and washed with water, with a yield of 55%. 1 H NMR (600MHz, DMSO-d6) δ12.93(s,1H),11.64(s,1H),8.21(d,J=4.9Hz,1H),7.48(d,J=3.4Hz,1H),7.41(d,J=5.0Hz,1H),6.97(d,J=3.5Hz,1H),6.7 0(s,1H),3.01(dt,J=12.2,3.3Hz,2H),2.77(tt,J=11.9,3.8Hz,1H),2.59 (td,J=12.1,2.5Hz,2H),1.91-1.87(m,2H),1.56(qd,J=12.2,3.9Hz,2H). 13 C NMR(150MHz,DMSO-d6)δ150.00,143.03,126.40,116.25,112.54,101.37,101.19,46.53,34.38,33.21.HRMS calculated for(M+H)+267.1585,found 267.1588.

[0051] Preparation of compounds R1-R41 Using D25 as raw material, the reaction formula for preparing R1-R41 is as follows:

[0052]

[0053] Wherein, R is defined as above, and R is selected from different corresponding groups according to the structures of R1-R42, and X is halogen.

[0054] The halogen is selected from F, Cl, Br, I.

[0055] The process of preparing R1-R41 is as shown in the following examples.

[0056] Example 2: 4-(3-(1-phenylpiperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridine (R1)

[0057] D25 (100 mg, 0.37 mmol) was mixed in a mixed solution of DCM / DMF 3 / 1 (12 mL), and benzyl bromide (89 μL, 0.75 mmol) and potassium carbonate (103 mg, 0.75 mmol) were added at 0°C. After stirring for 15 min, the mixture was warmed to room temperature and stirred for 3 h. TLC monitoring was performed. After the reaction was completed, the mixture was diluted with water and extracted with EA. The organic phase was collected and washed three times with a saturated NaCl solution. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and purified by column chromatography to obtain the final product, compound R1, as a yellow solid (17.2 mg, 13%). 1 H NMR (600MHz, DMSO-d6) δ12.90(s,1H),11.60(s,1H),8.20(s,1H),7.47(s,1H),7.40(d,J=4.9Hz,1H),7.34(s,4H),7.27(s,1H),6.99(s ,1H),6.73(s,1H),3.50(s,2H),2.92-2.87(m,2H),2.71(s,1H),2.08(t,J=11.5Hz,2H),1.94(d,J=12.7Hz,2H),1.73(q,J=11.9Hz,2H). 13 C NMR(150MHz,DMSO-d6)δ149.99,143.01,139.05,129.30,128.63,127.34,126 .35,116.24,112.53,101.48,62.89,53.49,32.11,29.49,22.55,14.42.HRMS calculated for (M+H)+358.2026, found 358.2029.

[0058] Example 3: 4-(3-(1-(4-methoxyphenyl)piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridine (R2)

[0059] D25 (60 mg, 0.22 mmol) was mixed in DMSO (12 mL), 4-methoxybenzyl chloride (34 mg, 0.22 mmol) and triethylamine (61 μL, 0.44 mmol) were added at 0 ° C, stirred for 15 min, warmed to room temperature, stirred for 3 h, and monitored by TLC. After the reaction was completed, it was diluted with water and extracted with EA. The organic phase was collected and washed three times with saturated NaCl solution, the organic phase was dried over anhydrous magnesium sulfate, the organic phase was filtered and concentrated under reduced pressure, and purified by column chromatography to obtain the final product compound R2 as a yellow solid (67.3 mg, 79%). 1 H NMR (600MHz, DMSO-d6) δ12.89 (s, 1H), 11.61 (s, 1H), 8.20 (d, J = 5.0Hz, 1H), 7.47 (s,1H),7.39(d,J=5.0Hz,1H),7.24-7.21(m,2H),6.97(s,1H),6.91-6.87(m,2H) ,6.73(s,1H),3.74(s,3H),3.42(s,2H),2.88(d,J=11.0Hz,2H),2.68(d,J=12.4 Hz,1H),2.03(t,J=11.4Hz,2H),1.95-1.90(m,2H),1.71(qd,J=12.1,3.6Hz,2H). 13 CNMR(150MHz,DMSO-d6)δ158.70,149.99,149.51,149.00,143.02,133.57,130.81,130.51,126.35,116 .26,113.99,112.55,101.51,101.23,62.30,55.46,53.39,40.53,32.14,22.56,14.43.HRMScalculated for(M+H)+388.2131,found 388.2136.

[0060] Example 4: 4-(3-(1-(3-methoxyphenyl)piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridine (R3)

[0061] D25 (100 mg, 0.37 mmol) was mixed in a mixed solution of DCM / DMF 3 / 1 (12 mL), 3-methoxybenzyl chloride (117 mg, 0.75 mmol) and potassium carbonate (103 mg, 0.75 mmol) were added at 0°C, stirred for 15 min, warmed to room temperature, stirred for 3 h, and monitored by TLC. After the reaction was completed, it was diluted with water and extracted with EA. The organic phase was collected and washed three times with a saturated NaCl solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and purified by column chromatography to obtain the final product, compound R3, as a white solid (3 mg, 2%). 1 H NMR (600MHz, DMSO-d6) δ12.91(s,1H),11.61(s,1H),8.20(d,J=5.0Hz,1H),7.47( s,1H),7.40(d,J=5.0Hz,1H),7.25(t,J=8.0Hz,1H),6.98(s,1H),6.90(d,J=7.8Hz ,2H),6.84-6.81(m,1H),6.74(s,1H),3.75(s,3H),3.47(s,2H),2.94-2.86(m,2H ),2.71(s,1H),2.08(d,J=13.1Hz,2H),1.94(d,J=12.7Hz,2H),1.78-1.69(m,2H). 13 C NMR(150MHz,DMSO-d6)δ159.72,150.00,149.53,148.67,143.02,140.75,133.53,129.65,126.34,121.45 ,116.26,114.70,112.70,112.54,101.53,101.24,62.81,55.42,53.52,40.53,32.13,22.56,14.42.HRMS calculated for(M+H)+388.2131,found388.2137.

[0062] Example 5: 4-(3-(1-(3-trifluoromethyl)phenyl)piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridine (R4)

[0063] D25 (60 mg, 0.22 mmol) was mixed in DMSO (12 mL), 1-chloromethyl-3-trifluoromethylbenzene (43 mg, 0.22 mmol) and triethylamine (61 μL, 0.44 mmol) were added at 0 ° C, stirred for 15 min, warmed to room temperature, stirred for 3 h, and monitored by TLC. After the reaction was completed, it was diluted with water and extracted with EA. The organic phase was collected and washed three times with a saturated NaCl solution, the organic phase was dried over anhydrous magnesium sulfate, the organic phase was filtered and concentrated under reduced pressure, and purified by column chromatography to obtain the final product, compound R4, as a light yellow solid (85 mg, 91%). 1 H NMR(600MHz,DMSO-d6)δ12.91(s,1H),11.62-11.58(m,1H),8.22-8.18(m,1H),7.67 (s,1H),7.64(dd,J=11.3,7.7Hz,2H),7.58(t,J=7.6Hz,1H),7.46(s,1H),7.40(d,J =5.0Hz,1H),6.99(s,1H),6.75-6.72(m,1H),3.60(s,2H),2.88(d,J=11.0Hz,2H),2 .72(s,1H),2.15-2.09(m,2H),1.94(d,J=12.7Hz,2H),1.74(qd,J=12.2,3.6Hz,2H). 13 CNMR(150MHz,DMSO-d6)δ150.01,149.54,148.87,143.02,140.74,133.54,133.31,129.76,129.72,129.55,129.34,129.14,126.28,125.73, 125.43,125.40,124.13,124.11,123.92,116.32,112.60,101.57,101.23,61.98,53.43,40.53,33.32,32.07,15.93,15.72.HRMScalculated for(M+H)+426.1900,found 426.1919.

[0064] Example 6: Ethyl-4-((4-(5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)benzoic acid (R5)

[0065] D25 (60 mg, 0.22 mmol) was mixed in DMSO (12 mL), ethyl 3-chloromethylbenzoate (44 mg, 0.22 mmol) and triethylamine (61 μL, 0.44 mmol) were added at 0 ° C, stirred for 15 min, warmed to room temperature, stirred for 3 h, and monitored by TLC. After the reaction was completed, it was diluted with water and extracted with EA. The organic phase was collected and washed three times with a saturated NaCl solution, the organic phase was dried over anhydrous magnesium sulfate, the organic phase was filtered and concentrated under reduced pressure, and purified by column chromatography to obtain the final product, compound R5, as a light yellow solid (50.2 mg, 55%). 1 H NMR(600MHz,DMSO-d6)δ12.91(s,1H),11.60(s,1H),8.20(d,J=4.7Hz,1H),7.93(s,1H),7.87 (dt,J=7.7,1.5Hz,1H),7.61(d,J=7.6Hz,1H),7.51-7.45(m,2H),7.40(d,J=5.0Hz,1H),6.99( s,1H),6.73(s,1H),4.32(t,J=7.1Hz,2H),3.57(s,2H),2.89(d,J=10.9Hz,2H),2.72(s,1H),2 .13-2.08(m,2H),1.94(d,J=12.6Hz,2H),1.74(qd,J=12.3,3.6Hz,2H),1.33(t,J=7.1Hz,3H). 13 C NMR (150MHz, DMSO-d6) δ166.27,150.00,149.53,148.88,143.02,139.87,134.17,133.54,130.36,129.81,129. 09,128.24,126.28,116.31,112.59,101.56,101.23,62.33,61.20,53.46,33.35,32.06,14.67.HRMScalculated for(M+H)+416.2081,found 416.2079.

[0066] Example 7: 1-4-((4-(5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl)piperidin-1-yl)methyl)ethyl-1-carbonyl (R6)

[0067] D25 (60 mg, 0.22 mmol) was mixed in DMSO (12 mL), 3-chloromethylacetophenone (37 mg, 0.22 mmol) and triethylamine (61 μL, 0.44 mmol) were added at 0°C, stirred for 15 min, warmed to room temperature, stirred for 3 h, and monitored by TLC. After the reaction was completed, it was diluted with water and extracted with EA. The organic phase was collected and washed three times with saturated NaCl solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and purified by column chromatography to obtain the final product, compound R6, as a light yellow solid (42.3 mg, 42%). 1H NMR(600MHz,DMSO-d6)δ12.91(s,1H),11.61(s,1H),8.21(d,J=5.0Hz,1H),7.91-7.8 5(m,2H),7.61(d,J=7.5Hz,1H),7.50(dd,J=17.5,9.9Hz,2H),7.40(d,J=5.0Hz,1H), 6.98(s,1H),6.74(s,1H),3.58(s,2H),2.90(d,J=11.0Hz,2H),2.72(s,1H),2.60(s, 3H),2.11(t,J=11.4Hz,2H),1.95(d,J=12.7Hz,2H),1.75(qd,J=12.4,3.6Hz,2H).13C NMR(150MHz,DMSO-d6)δ198.48,150.00,143.02,139.76,137.31,134.09,129.07,128.65, 127.57,126.33,116.27,112.55,101.54,101.25,62.44,53.49,33.39,32.12,27.28.HRMS calculated for (M+H)+400.2131, found 400.2133.

[0068] Example 8: 4-(3-(1-(3,4-dimethoxyphenyl)piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridine (R7)

[0069] D25 (60 mg, 0.22 mmol) was mixed in DMSO (12 mL), 3,4-dimethoxybenzyl chloride (41 mg, 0.22 mmol) and triethylamine (61 μL, 0.44 mmol) were added at 0 ° C, stirred for 15 min, warmed to room temperature, stirred for 3 h, and monitored by TLC. After the reaction was completed, it was diluted with water and extracted with EA. The organic phase was collected and washed three times with a saturated NaCl solution, the organic phase was dried over anhydrous magnesium sulfate, the organic phase was filtered and concentrated under reduced pressure, and purified by column chromatography to obtain the final product, compound R7, as a light yellow solid (37.9 mg, 41%). 1 H NMR(600MHz,DMSO-d6)δ12.91(s,1H),11.60(s,1H),8.20(d,J=4.9Hz,1H),7 .46(s,1H),7.40(d,J=5.0Hz,1H),6.99(s,1H),6.90(d,J=8.9Hz,2H),6.83(d ,J=8.3Hz,1H),6.72(s,1H),3.76(s,3H),3.74(s,3H),3.43(s,2H),2.90(s,2 H), 2.71 (s, 1H), 2.04 (s, 2H), 1.94 (d, J = 12.8Hz, 2H), 1.74 (t, J = 12.5Hz, 2H). 13 C NMR(150MHz,DMSO-d6)δ150.00,149.53,149.06,148.96,148.26,143.02,133.54,131.40,126.28,121.39,1 16.31,112.95,112.60,111.98,101.57,101.18,62.65,55.96,55.92,53.40,33.46,32.09.HRMScalculated for(M+H)+418.2237,found 418.2235.

[0070] Example 9: 4-(3-(1-(3-fluorophenyl)piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridine (R8)

[0071] D25 (60 mg, 0.22 mmol) was mixed in DMSO (12 mL), and m-fluorobenzyl chloride (32 mg, 0.22 mmol) and triethylamine (61 μL, 0.44 mmol) were added at 0°C. After stirring for 15 min, the mixture was warmed to room temperature and stirred for 3 h. TLC monitoring was performed. After the reaction was completed, the mixture was diluted with water and extracted with EA. The organic phase was collected and washed three times with a saturated NaCl solution. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and purified by column chromatography to obtain the final product, compound R8, as a light yellow solid (50 mg, 60%). 1 H NMR(600MHz,DMSO-d6)δ12.91(s,1H),11.60(s,1H),8.22-8.18(m,1H),7.46( s,1H),7.41-7.35(m,2H),7.16(dd,J=13.1,8.9Hz,2H),7.08(td,J=8.5,2.7H z,1H),6.99(s,1H),6.73(s,1H),3.52(s,2H),2.89(d,J=11.0Hz,2H),2.71(s ,1H),2.13-2.06(m,2H),1.94(d,J=12.6Hz,2H),1.74(qd,J=12.4,3.5Hz,2H). 13 C NMR(150MHz,DMSO-d6)δ163.53,161.92,150.00,149.54,148.90,143.02,142.32,133.54,130.55,130.49,126.28, 125.15,116.31,115.66,115.52,114.16,114.02,112.59,101.56,101.21,62.10,53.44,40.53,33.34,32.09.HRMS calculated for (M+H)+376.1932, found 376.1931.

[0072] Example 10: 4-(3-(1-(3,4-difluorophenyl)piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridine (R9)

[0073] D25 (60 mg, 0.22 mmol) was mixed in DMSO (12 mL), and 3,4-difluorobenzyl chloride (35.7 mg, 0.22 mmol) and triethylamine (61 μL, 0.44 mmol) were added at 0°C. After stirring for 15 min, the mixture was warmed to room temperature and stirred for 3 h. TLC monitoring was performed. After the reaction was completed, the mixture was diluted with water and extracted with EA. The organic phase was collected and washed three times with a saturated NaCl solution. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and purified by column chromatography to obtain the final product, compound R9, as a light yellow solid (74.2 mg, 86%). 1 H NMR (600MHz, DMSO-d6) δ12.91(s,1H),11.60(s,1H),8.20(d,J=5.0Hz,1H),7.48-7.43(m,1H),7.38(ddd,J=20.4,10.0,6.3Hz,3H),7.19-7 .15(m,1H),6.99(s,1H),6.73(s,1H),2.89-2.84(m,2H),2.71(s,1H),2.12-2.06(m,2H),1.98-1.91(m,2H),1.74(tt,J=12.2,6.1Hz,2H). 13 C NMR (150MHz, DMSO-d6) δ150.62,150.54,150.01,149.71,149.62,149.54,149.00,148.92,148.87,148.09,148.01,143.02,137. 08,133.53,126.28,125.70,117.82,117.71,117.60,117.49,116.32,112.60,101.56,101.20,61.43,53.32,33.30,32.05.HRMS calculated for (M+H)+394.1837, found 394.1842.

[0074] Example 11: 4-(3-(1-(4-methylphenyl)piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridine (R10)

[0075] D25 (60 mg, 0.22 mmol) was mixed in DMSO (12 mL), 4-methylbenzyl chloride (31 mg, 0.22 mmol) and triethylamine (61 μL, 0.44 mmol) were added at 0 ° C, stirred for 15 min, warmed to room temperature, stirred for 3 h, and monitored by TLC. After the reaction was completed, it was diluted with water and extracted with EA. The organic phase was collected and washed three times with a saturated NaCl solution, the organic phase was dried over anhydrous magnesium sulfate, the organic phase was filtered and concentrated under reduced pressure, and purified by column chromatography to obtain the final product, compound R10, as a yellow solid (54.2 mg, 64%). 1 H NMR (600MHz, DMSO-d6) δ12.90 (s, 1H), 11.65-11.58 (m, 1H), 8.21 (d, J = 5.0Hz, 1H) ,7.47(s,1H),7.40(d,J=5.0Hz,1H),7.21(d,J=7.6Hz,2H),7.14(d,J=7.6Hz,2H), 6.98(s,1H),6.73(s,1H),2.88(d,J=11.0Hz,2H),2.69(d,J=12.4Hz,1H),2.29(s, 3H), 2.05 (t, J=10.9Hz, 2H), 1.93 (d, J=12.5Hz, 2H), 1.72 (qd, J=12.2, 3.6Hz, 2H). 13 C NMR(150MHz,DMSO-d6)δ150.00,149.55,149.00,143.02,136.33,135.92,133.54,129.29,129.2 0,126.34,116.27,112.55,101.54,101.23,62.65,53.45,33.45,32.13,21.18.HRMScalculated for(M+H)+372.2182,found 372.2186.

[0076] Example 12: 4-(3-(1-(3-methylphenyl)piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridine (R11)

[0077] D25 (60 mg, 0.22 mmol) was mixed in DMSO (12 mL), 3-methylbenzyl chloride (31 mg, 0.22 mmol) and triethylamine (61 μL, 0.44 mmol) were added at 0 ° C, stirred for 15 min, warmed to room temperature, stirred for 3 h, and monitored by TLC. After the reaction was completed, it was diluted with water and extracted with EA. The organic phase was collected and washed three times with a saturated NaCl solution, the organic phase was dried over anhydrous magnesium sulfate, the organic phase was filtered and concentrated under reduced pressure, and purified by column chromatography to obtain the final product, compound R11, as a light yellow solid (60.5 mg, 71%). 1 H NMR (600MHz, DMSO-d6) δ12.90 (s, 1H), 11.67-11.53 (m, 1H), 8.21 (d, J = 5.0Hz, 1H), 7.48 (s ,1H),7.40(d,J=5.0Hz,1H),7.22(t,J=7.6Hz,1H),7.15(s,1H),7.10(dd,J=26.6,7.3Hz, 2H),6.97(s,1H),6.74(s,1H),3.46(q,J=7.6,4.4Hz,2H),2.89(d,J=10.1Hz,2H),2.71(s ,1H),2.32(s,3H),2.07(d,J=12.3Hz,2H),1.94(d,J=12.7Hz,2H),1.73(d,J=12.5Hz,2H). 13 C NMR(150MHz,DMSO-d6)δ149.99,143.02,138.96,137.67,129.95,128.52,128 .01,126.44,116.25,112.53,101.43,62.95,53.55,33.61,32.13,21.49.HRMS calculated for (M+H)+372.2182, found 372.2187.

[0078] Example 13: 4-(3-(1-(3-anisolephenyl)piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridine (R12)

[0079] D25 (60 mg, 0.22 mmol) was mixed in DMSO (12 mL), 3-phenoxybenzyl chloride (48.1 mg, 0.22 mmol) and triethylamine (61 μL, 0.44 mmol) were added at 0 ° C, stirred for 15 min, warmed to room temperature, stirred for 3 h, and monitored by TLC. After the reaction was completed, it was diluted with water and extracted with EA. The organic phase was collected and washed three times with a saturated NaCl solution, the organic phase was dried over anhydrous magnesium sulfate, the organic phase was filtered and concentrated under reduced pressure, and purified by column chromatography to obtain the final product, compound R12, as a yellow solid (91.6 mg, 93%). 1 H NMR(600MHz,DMSO-d6)δ12.89(s,1H),11.61(s,1H),8.20(d,J=5.0Hz,1H),7.47(s,1H),7.42- 7.38(m,3H),7.35(t,J=7.8Hz,1H),7.14(tt,J=7.3,1.1Hz,1H),7.11(d,J=7.6Hz,1H),7.04-7. 00(m,2H),6.98(d,J=11.9Hz,2H),6.91-6.88(m,1H),6.73(s,1H),3.50(s,2H),2.89(d,J=11. 0Hz,2H),2.70(s,1H),2.07(t,J=11.4Hz,2H),1.96-1.89(m,2H),1.71(qd,J=12.1,3.6Hz,2H). 13 C NMR(150MHz,DMSO-d6)δ157.18,157.12,150.00,149.52,148.95,143.02,141.55,133.54,130.52,130.22,126.35,12 4.27,123.86,119.11,119.05,117.53,116.26,112.54,101.50,101.24,62.39,53.47,33.39,32.12.HRMScalculated for(M+H)+450.2288,found 450.2288.

[0080] Example 14: (4-(5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl)piperidin-1-yl)(3-methoxyphenyl)methylcarbonyl (R13)

[0081] D25 (60 mg, 0.22 mmol) was mixed in a mixed solution of DCM / DMF 3 / 1 (12 mL), and m-methoxybenzoyl chloride (37.5 mg, 0.22 mmol) and triethylamine (61 μL, 0.44 mmol) were added at 0°C. After stirring for 15 min, the mixture was warmed to room temperature and stirred for 3 h. TLC monitoring was performed. After the reaction was completed, the mixture was diluted with water and extracted with EA. The organic phase was collected and washed three times with a saturated NaCl solution. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and purified by column chromatography to obtain the final product, compound R13, as a yellow solid (46.4 mg, 51%). 1 H NMR (600MHz, DMSO-d6) δ13.00(s,1H),11.65(s,1H),8.22(d,J=5.0Hz,1H),7.49(t,J=3.0Hz,1H),7 .41(d,J=4.9Hz,1H),7.38(t,J=7.9Hz,1H),7.03(dd,J=8.2,2.6Hz,1H),6.98(d,J=7.2Hz,2H),6.96 -6.94(m,1H),6.81(s,1H),4.55(s,1H),3.80(s,3H),3.68(d,J=6.0Hz,1H),3.23-3.15(m,1H),3.04 (ddt,J=11.7,7.8,3.8Hz,1H),2.94(s,1H),2.07(s,1H),1.96-1.90(m,1H),1.68(d,J=22.6Hz,2H). 13 CNMR(150MHz,DMSO-d6)δ169.10,159.68,159.61,150.00,143.03,138.25,130.14,126.51,122.01,119.26,11 9.09,116.22,115.42,114.36,112.51,112.46,101.81,101.27,55.71,47.50,41.86,33.78,32.31,31.75.HRMS calculated for(M+H)+402.1924,found402.1922.

[0082] Example 15: (4-(5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl)piperidin-1-yl)(3,4-dimethoxyphenyl)methylcarbonyl (R14)

[0083] D25 (60 mg, 0.22 mmol) was mixed in a mixed solution of DCM / DMF 3 / 1 (12 mL), and 3,4-dimethoxybenzoyl chloride (44 mg, 0.22 mmol) and triethylamine (61 μL, 0.44 mmol) were added at 0°C. After stirring for 15 min, the mixture was warmed to room temperature and stirred for 3 h. TLC monitoring was performed. After the reaction was completed, the mixture was diluted with water and extracted with EA. The organic phase was collected and washed three times with a saturated NaCl solution. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and purified by column chromatography to obtain the final product, compound R14, as a light yellow solid (57.7 mg, 61%). 1 H NMR (600MHz, DMSO-d6) δ12.96(s,1H),11.62(s,1H),8.22(d,J=4.9Hz,1H),7.49(s,1H),7.41(d,J=5.0Hz,1H),7.01(d,J=3.2Hz, 4H),6.80(s,1H),4.49(s,1H),3.92(d,J=5.1Hz,1H),3.80(s,3H),3.79(s,3H),2.01(s,2H),1.70(qd,J=14.6,13.2,4.8Hz,2H). 13 C NMR(150MHz,DMSO-d6)δ169.40,150.17,150.00,148.90,148.29,143.04,128.88,126.36,120.14 ,116.26,112.55,111.64,111.31,101.50,56.06,56.03,47.39,43.07,33.47,32.05,31.76.HRMS calculated for (M+H)+432.2030, found 432.2027.

[0084] Example 16: (4-(5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl)piperidin-1-yl)(3,4,5-trimethoxyphenyl)methylcarbonyl (R15)

[0085] D25 (60 mg, 0.22 mmol) was mixed in a mixed solution of DCM / DMF 3 / 1 (12 mL), and 3,4,5-trimethoxybenzoyl chloride (50.7 mg, 0.22 mmol) and triethylamine (61 μL, 0.44 mmol) were added at 0°C. After stirring for 15 min, the mixture was warmed to room temperature and stirred for 3 h. TLC monitoring was performed. After the reaction was completed, the mixture was diluted with water and extracted with EA. The organic phase was collected and washed three times with a saturated NaCl solution. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and purified by column chromatography to obtain the final product, compound R15, as a yellow solid (59 mg, 58%). 1 H NMR(600MHz,DMSO-d6)δ13.00(s,1H),11.65(s,1H),8.22(d,J=5.0Hz,1H),7.5 0(t,J=3.0Hz,1H),7.41(d,J=5.0Hz,1H),6.97(s,1H),6.80(s,1H),6.71(s,2H ),4.53(s,1H),3.83(s,1H),3.81(s,6H),3.70(s,3H),3.20(s,1H),3.04(tt,J =11.4,3.7Hz,1H),2.95(s,1H),2.02(d,J=47.5Hz,2H),1.71(d,J=12.6Hz,2H). 13 C NMR(150MHz,DMSO-d6)δ169.12,167.39,153.28,153.12,149.99,143.03,138.60,132.23,126.51,126.36 ,116.22,112.47,107.01,104.66,101.81,101.27,60.58,60.53,56.52,56.39,47.62,42.02,32.22.HRMS calculated for(M+H)+462.2135,found462.2137.

[0086] Example 17: (4-(5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl)piperidin-1-yl)(4-methoxyphenyl)methylcarbonyl (R16)

[0087] D25 (60 mg, 0.22 mmol) was mixed in a mixed solution of DCM / DMF 3 / 1 (12 mL), and p-methoxybenzoyl chloride (37.5 mg, 0.22 mmol) and triethylamine (61 μL, 0.44 mmol) were added at 0°C. After stirring for 15 min, the mixture was warmed to room temperature and stirred for 3 h. TLC monitoring was performed. After the reaction was completed, the mixture was diluted with water and extracted with EA. The organic phase was collected and washed three times with a saturated NaCl solution. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and purified by column chromatography to obtain the final product, compound R16, as a yellow solid (67.7 mg, 77%). 1 H NMR(600MHz,DMSO-d6)δ12.98-12.94(m,1H),11.61(s,1H),8.24-8.18(m,1H),7.48(s,1H),7.43-7.39(m,3H),7 .03-6.98(m,3H),6.79(s,1H),4.49(s,1H),3.81(s,3H),3.04(m,4H),2.00(m,2H),1.69(qd,J=11.9,3.9Hz,2H). 13 C NMR(150MHz,DMSO-d6)δ169.42,160.56,150.00,149.60,148.29,143.03,133.40,129.27,128 .73,126.33,116.31,114.12,112.56,101.48,55.71,47.69,43.65,33.41,32.10,32.09.HRMS calculated for (M+H)+402.1924, found 402.1923.

[0088] Example 18: 1-(4-(4-(5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl)piperidin-1-carbonyl)phenyl)ethyl-1-carbonyl (R17)

[0089] D25 (60 mg, 0.22 mmol) was mixed in a mixed solution of DCM / DMF 3 / 1 (12 mL), and p-acetylbenzoyl chloride (41 mg, 0.22 mmol) and triethylamine (61 μL, 0.44 mmol) were added at 0°C. After stirring for 15 min, the mixture was warmed to room temperature and stirred for 3 h. TLC monitoring was performed. After the reaction was completed, the mixture was diluted with water and extracted with EA. The organic phase was collected and washed three times with a saturated NaCl solution. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and purified by column chromatography to obtain the final product, compound R17, as a yellow solid (56.3 mg, 61%). 1H NMR(600MHz,DMSO-d6)δ12.97(s,1H),11.61(s,1H),8.21(s,1H),8.05-8.02(m,2H ),7.59-7.56(m,2H),7.48(s,1H),7.41(d,J=5.0Hz,1H),7.00(s,1H),6.80(s,1H) ,4.57(s,1H),3.58(d,J=13.4Hz,1H),3.23(t,J=12.6Hz,1H),3.02(d,J=42.9Hz,2 H),2.62(s,3H),2.14-2.07(m,1H),1.93(d,J=12.6Hz,1H),1.71(d,J=20.6Hz,2H). 13 C NMR(150MHz,DMSO-d6)δ197.99,168.53,150.00,148.19,143.04,141.19,137.63,128.8 7,127.37,126.35,116.31,112.57,101.50,47.41,41.84,40.53,27.32.HRMScalculated for(M+H)+414.1924,found 414.1923.

[0090] Example 19: (4-(5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl)piperidin-1-yl)(4-chlorophenyl)methylcarbonyl (R18)

[0091] D25 (60 mg, 0.22 mmol) was mixed in a mixed solution of DCM / DMF 3 / 1 (12 mL), 4-chlorobenzoyl chloride (28 μL, 0.22 mmol) and triethylamine (61 μL, 0.44 mmol) were added at 0°C, stirred for 15 min, warmed to room temperature, stirred for 3 h, and monitored by TLC. After the reaction was completed, it was diluted with water and extracted with EA. The organic phase was collected and washed three times with a saturated NaCl solution, the organic phase was dried over anhydrous magnesium sulfate, the organic phase was filtered and concentrated under reduced pressure, and purified by column chromatography to obtain the final product, compound R18, as a yellow solid (51.6 mg, 58%). 1H NMR (600MHz, DMSO-d6) δ12.97(s,1H),11.62(s,1H),8.24-8.19(m,1H),7.54(d,J=8.3Hz,2H),7.50-7.46(m,3H),7.41(d,J=5.1Hz,1 H),7.00(s,1H),6.79(s,1H),4.54(s,1H),3.63(s,1H),3.22(s,1H),3.00(d,J=48.2Hz,2H),2.07(s,1H),1.94(s,1H),1.71(s,2H). 13 C NMR(150MHz,DMSO-d6)δ168.38,150.00,149.60,148.22,143.04,135.59,134.51,133.47, 129.21,129.01,126.35,116.31,112.56,101.50,47.57,42.00,33.28,32.27,31.62.HRMS calculated for(M+H)+406.1429,found406.1429.

[0092] Example 20: Methyl-4-(4-(5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl)piperidine-1-carbonyl)benzoyl (R19)

[0093] D25 (60 mg, 0.22 mmol) was mixed in a mixed solution of DCM / DMF 3 / 1 (12 mL), and methyl 4-chloroformylbenzoate (43.6 mg, 0.22 mmol) and triethylamine (61 μL, 0.44 mmol) were added at 0°C. After stirring for 15 min, the mixture was warmed to room temperature and stirred for 3 h. TLC monitoring was performed. After the reaction was completed, the mixture was diluted with water and extracted with EA. The organic phase was collected and washed three times with a saturated NaCl solution. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and purified by column chromatography to obtain the final product, compound R19, as a light yellow solid (51.1 mg, 54%). 1H NMR (600MHz, DMSO-d6) δ12.97(s,1H),11.62(s,1H),8.22(s,1H),8.04(d,J=8.0Hz,2H ),7.58(d,J=7.9Hz,2H),7.48(s,1H),7.41(d,J=5.1Hz,1H),7.00(s,1H),6.80(s,1H) ,4.57(d,J=11.5Hz,1H),3.89(s,3H),3.57(d,J=12.7Hz,1H),3.24(d,J=13.2Hz,1H), 3.02(d,J=42.4Hz,2H),2.12-2.07(m,1H),1.93(d,J=12.7Hz,1H),1.78-1.66(m,2H). 13 C NMR(150MHz,DMSO-d6)δ168.42,166.19,149.99,149.60,148.18,143.02,141.36,133.47,130.67 ,129.84,127.48,126.35,116.33,112.57,101.51,52.82,47.42,41.87,33.25,32.24,31.61.HRMS calculated for (M+H)+430.1873, found 430.1873.

[0094] Example 21: (4-(5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl)piperidin-1-yl)(4-trifluoromethylphenyl)methylcarbonyl (R20)

[0095] D25 (60 mg, 0.22 mmol) was mixed in a mixed solution of DCM / DMF 3 / 1 (12 mL), 4-trifluoromethylbenzoyl chloride (45.8 mg, 0.22 mmol) and triethylamine (61 μL, 0.44 mmol) were added at 0°C, stirred for 15 min, warmed to room temperature, stirred for 3 h, and monitored by TLC. After the reaction was completed, it was diluted with water and extracted with EA. The organic phase was collected and washed three times with a saturated NaCl solution, the organic phase was dried over anhydrous magnesium sulfate, the organic phase was filtered and concentrated under reduced pressure, and purified by column chromatography to obtain the final product, compound R20, as a yellow solid (45.8 mg, 47% yield). 1H NMR (600MHz, DMSO-d6) δ12.97 (s, 1H), 11.63 (s, 1H), 8.22 (d, J = 5.0Hz, 1H), 7.84 (d, J=8.0Hz,2H),7.66(d,J=7.9Hz,2H),7.49(s,1H),7.41(d,J=5.0Hz,1H),6.98(s,1H ),6.80(s,1H),4.57(d,J=12.7Hz,1H),3.56(d,J=13.5Hz,1H),3.24(t,J=12.9Hz,1 H),3.09-2.96(m,2H),2.10(d,J=13.0Hz,1H),1.96-1.90(m,1H),1.79-1.66(m,2H). 13 C NMR(150MHz,DMSO-d6)δ168.04,149.98,143.03,140.97,130.10,129.89,127.97,127.14,126.39,126.04 ,126.01,125.99,125.96,125.34,123.54,112.51,101.50,47.47,41.90,33.23,32.27,31.61,29.48.HRMS calculated for (M+H)+440.1692, found 440.1696.

[0096] Example 22: (4-(5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl)piperidin-1-yl)(3-fluorophenyl)methylcarbonyl (R21)

[0097] D25 (60 mg, 0.22 mmol) was mixed in a mixed solution of DCM / DMF 3 / 1 (12 mL), and m-fluorobenzoyl chloride (34.8 mg, 0.22 mmol) and triethylamine (61 μL, 0.44 mmol) were added at 0°C. After stirring for 15 min, the mixture was warmed to room temperature and stirred for 3 h. TLC monitoring was performed. After the reaction was completed, the mixture was diluted with water and extracted with EA. The organic phase was collected and washed three times with a saturated NaCl solution. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and purified by column chromatography to obtain the final product, compound R21, as a yellow solid (46 mg, 54% yield). 1H NMR(600MHz,DMSO-d6)δ12.96(s,1H),11.61(s,1H),8.21(s,1H),7.52(q, J=7.5Hz,1H),7.48(s,1H),7.41(d,J=5.0Hz,1H),7.30(dt,J=19.0,7.7Hz, 3H),7.00(s,1H),6.80(s,1H),4.54(s,1H),3.66-3.57(m,1H),3.23(s,1H) ,3.01(d,J=47.3Hz,2H),2.08(s,1H),1.93(s,1H),1.71(d,J=12.8Hz,2H). 13 CNMR(150MHz,DMSO-d6)δ167.93,167.91,163.16,161.53,150.00,149.60,148.21,143.03,139.17,133.45,131.25,131.19 ,126.36,123.22,123.20,116.78,116.64,116.31,114.24,114.09,112.56,101.51,47.48,41.93,33.27,32.12,31.28.HRMS calculated for(M+H)+390.1724,found390.1721.

[0098] Example 23: (4-(5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl)piperidin-1-yl)(4-fluorophenyl)methylcarbonyl (R22)

[0099] D25 (60 mg, 0.22 mmol) was mixed in a mixed solution of DCM / DMF 3 / 1 (12 mL), and p-fluorobenzoyl chloride (34.8 mg, 0.22 mmol) and triethylamine (61 μL, 0.44 mmol) were added at 0°C. After stirring for 15 min, the mixture was warmed to room temperature and stirred for 3 h. TLC monitoring was performed. After the reaction was completed, the mixture was diluted with water and extracted with EA. The organic phase was collected and washed three times with a saturated NaCl solution. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and purified by column chromatography to obtain the final product, compound R22, as a yellow solid (56.4 mg, 66%). 1H NMR (600MHz, DMSO-d6) δ12.96(s,1H),11.62(s,1H),8.22(s,1H),7.53-7.50(m,2H),7.48(s,1H),7.41(d,J=5.0Hz,1H),7.32-7.28( m,2H),7.00(s,1H),6.80(s,1H),4.54(s,1H),3.22(s,1H),3.04(s,1H),2.97(s,1H),2.01(d,J=67.4Hz,2H),1.70(d,J=12.7Hz,2H). 13 C NMR(150MHz,DMSO-d6)δ168.56,163.74,162.11,150.00,149.60,148.24,143.04,133.46,133.21,133.20, 129.80,129.75,126.35,116.31,115.94,115.80,112.56,101.49,47.63,42.08,33.31,32.24,31.76.HRMS calculated for (M+H)+390.1724,found 390.1723.

[0100] Example 24: (4-(5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl)piperidin-1-yl)(3,4-difluorophenyl)methylcarbonyl (R23)

[0101] D25 (60 mg, 0.22 mmol) was mixed in a mixed solution of DCM / DMF 3 / 1 (12 mL), and 3,4-difluorobenzoyl chloride (38.8 mg, 0.22 mmol) and triethylamine (61 μL, 0.44 mmol) were added at 0°C. After stirring for 15 min, the mixture was warmed to room temperature and stirred for 3 h. TLC monitoring was performed. After the reaction was completed, the mixture was diluted with water and extracted with EA. The organic phase was collected and washed three times with a saturated NaCl solution. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and purified by column chromatography to obtain the final product, compound R23, as a yellow solid (54.6 mg, 61%). 1H NMR (600MHz, DMSO-d6) δ12.96 (s, 1H), 11.63 (s, 1H), 8.22 (d, J = 4.9Hz, 1H), 7.5 8-7.51(m,2H),7.49(s,1H),7.41(d,J=5.0Hz,1H),7.31(ddt,J=8.1,4.4,1.6H z,1H),6.98(s,1H),6.80(s,1H),4.52(s,1H),3.63(s,1H),3.04(t,J=11.8Hz, 1H),2.96(s,1H),2.11-2.02(m,1H),1.94(s,1H),1.71(qd,J=12.3,4.1Hz,2H). 13 CNMR(150MHz,DMSO-d6)δ167.22,151.26,151.18,150.56,150.48,150.00,149.62,149.54,148.92,148.84,143.04,134.24,126.40,124. 55,124.53,124.51,124.49,118.34,118.22,116.97,116.85,116.27,112.51,101.48,47.55,42.08,33.25,32.12,31.62.HRMScalculated for(M+H)+408.1630,found 408.1635.

[0102] Example 25: (4-(5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl)piperidin-1-yl)(4-nitrophenyl)methylcarbonyl (R24)

[0103] D25 (60 mg, 0.22 mmol) was mixed in a mixed solution of DCM / DMF 3 / 1 (12 mL), and p-nitrobenzoyl chloride (41 mg, 0.22 mmol) and triethylamine (61 μL, 0.44 mmol) were added at 0°C. After stirring for 15 min, the mixture was warmed to room temperature and stirred for 3 h. TLC monitoring was performed. After the reaction was completed, the mixture was diluted with water and extracted with EA. The organic phase was collected and washed three times with a saturated NaCl solution. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and purified by column chromatography to obtain the final product, compound R24, as a yellow solid (32.9 mg, 36%). 1H NMR(600MHz,DMSO-d6)δ12.96(s,1H),11.65(s,1H),8.33-8.29(m,2H),8.22(d,J= 5.0Hz,1H),7.74-7.70(m,2H),7.50(s,1H),7.41(d,J=5.0Hz,1H),6.97(s,1H),6.8 1(s,1H),4.57(d,J=12.9Hz,1H),3.53(d,J=13.5Hz,1H),3.25(t,J=12.7Hz,1H),3. 10-2.98(m,2H),2.11(d,J=13.1Hz,1H),1.93(d,J=12.9Hz,1H),1.79-1.66(m,2H). 13 C NMR(150MHz,DMSO-d6)δ167.49,150.00,148.20,144.57,143.18,143.04,128.49, 125.92,124.30,116.23,112.20,101.46,47.40,41.90,32.22,31.55,29.48.HRMS calculated for (M+H)+417.1669, found 417.1675.

[0104] Example 26: (4-(5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl)piperidin-1-yl)(p-tolyl)methylcarbonyl (R25)

[0105] D25 (64 mg, 0.24 mmol) was mixed in a mixed solution of DCM / DMF 3 / 1 (12 mL), p-methylbenzoyl chloride (37.1 mg, 0.24 mmol) and triethylamine (66 μL, 0.48 mmol) were added at 0°C, stirred for 15 min, warmed to room temperature, stirred for 3 h, and monitored by TLC. After the reaction was completed, it was diluted with water and extracted with EA. The organic phase was collected and washed three times with a saturated NaCl solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and purified by column chromatography to obtain the final product, compound R25, as a yellow solid (78 mg, 99% yield). 1H NMR (600MHz, DMSO-d6) δ12.97(s,1H),11.64(s,1H),8.22(d,J=5.0Hz,1H),7.49(s,1H),7.41(d,J=5.0Hz,1H),7.33(d,J=8.0Hz,2H),7.27(d,J= 7.8Hz,2H),6.98(s,1H),6.80(s,1H),4.55(s,1H),3.70(s,1H),3.23-2 .92(m,3H),2.35(s,3H),1.99(d,J=67.1Hz,2H),1.69(d,J=12.4Hz,2H). 13 C NMR(150MHz,DMSO-d6)δ169.57,150.00,143.03,139.47,133.90,129.78,129.52, 129.36,127.30,126.47,116.23,112.49,101.50,47.61,41.98,40.53,21.37.HRMS calculated for(M+H)+386.1975,found386.1977.

[0106] Example 27: 1-(4-(5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl)piperidin-1-yl)-2-phenylethyl-1-carbonyl (R26)

[0107] D25 (64 mg, 0.24 mmol) was mixed in a mixed solution of DCM / DMF 3 / 1 (12 mL), and phenylacetyl chloride (37.1 mg, 0.24 mmol) and triethylamine (66 μL, 0.48 mmol) were added at 0°C. After stirring for 15 min, the mixture was warmed to room temperature and stirred for 3 h. TLC monitoring was performed. After the reaction was completed, the mixture was diluted with water and extracted with EA. The organic phase was collected and washed three times with a saturated NaCl solution. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and purified by column chromatography to obtain the final product, compound R26, as a light yellow solid (18.7 mg, 20%). 1H NMR (600MHz, DMSO-d6) δ12.93(s,1H),11.64(s,1H),8.21(d,J=5.0Hz,1H),7.49(s,1H),7.39(d,J=5. 0Hz,1H),7.32(t,J=7.6Hz,2H),7.28-7.25(m,2H),7.23(t,J=7.3Hz,1H),6.99-6.92(m,1H),6.71(s,1 H),4.48(dd,J=11.2,6.1Hz,1H),4.05-4.01(m,1H),3.76(d,J=5.0Hz,2H),3.15(td,J=13.8,12.9,2.7 Hz,1H),2.98-2.93(m,1H),2.77-2.71(m,1H),2.01-1.91(m,2H),1.48(dqd,J=49.6,12.4,4.1Hz,2H). 13 C NMR(151MHz,DMSO-d6)δ169.12,149.95,143.01,136.49,129.38,128.80,126.79 ,116.23,112.48,101.80,45.93,41.67,32.42,31.55,29.47,22.56,14.42.HRMS calculated for (M+H)+386.1975, found 386.1978.

[0108] Example 28: 1-(4-(5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl)piperidin-1-yl)-2-(3-methoxyphenyl)-ethyl-1-carbonyl (R27)

[0109] D25 (60 mg, 0.22 mmol) was mixed in a mixed solution of DCM / DMF 3 / 1 (12 mL), 3-methoxyphenylacetyl chloride (41 mg, 0.22 mmol) and triethylamine (61 μL, 0.44 mmol) were added at 0°C, stirred for 15 min, warmed to room temperature, stirred for 3 h, and monitored by TLC. After the reaction was completed, it was diluted with water and extracted with EA. The organic phase was collected and washed three times with a saturated NaCl solution, the organic phase was dried over anhydrous magnesium sulfate, the organic phase was filtered and concentrated under reduced pressure, and purified by column chromatography to obtain the final product, compound R27, as a light yellow solid (26.1 mg, 28%). 1H NMR(600MHz,DMSO-d6)δ12.94(s,1H),11.62(s,1H),8.21(d,J=4.9Hz,1H),7.49(s,1H), 7.39(d,J=5.0Hz,1H),7.23(t,J=8.0Hz,1H),6.96(s,1H),6.85-6.79(m,3H),6.70(s,1H) ,4.47(d,J=12.9Hz,1H),4.03(d,J=13.5Hz,1H),3.73(d,J=8.3Hz,5H),3.18-3.11(m,1H ),2.96(s,1H),2.74(td,J=12.5,12.0,2.8Hz,1H),2.01-1.90(m,2H),1.57-1.41(m,2H). 13 C NMR(150MHz,DMSO-d6)δ168.99,159.72,149.96,143.02,137.93,129.82,121.55,115.05,112.22,55.43,45.95,41.66,32.41.HRMScalculated for(M+H)+416.2081,found 416.2080.

[0110] Example 29: 1-(4-(5-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl)piperidin-1-yl)-2-(4-methoxyphenyl)ethyl-1-carbonyl (R28)

[0111] D25 (60 mg, 0.22 mmol) was mixed in DMSO (12 mL), and p-methoxybenzoyl chloride (40.6 mg, 0.22 mmol) and triethylamine (61 μL, 0.44 mmol) were added at 0 ° C. After stirring for 15 min, the mixture was warmed to room temperature and stirred for 3 h. TLC monitoring was performed. After the reaction was completed, the mixture was diluted with water and extracted with EA. The organic phase was collected and washed three times with a saturated NaCl solution. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and purified by column chromatography to obtain the final product, compound R28, as a light yellow solid (20 mg, 22%). 1H NMR (600MHz, DMSO-d6) δ12.92(s,1H),11.66(s,1H),8.21(d,J=5.0Hz,1H),7.49(t,J=2.9Hz,1H),7 .40(d,J=5.0Hz,1H),7.19-7.16(m,2H),6.95(s,1H),6.89-6.87(m,2H),6.71(s,1H),4.49-4.45(m, 1H),4.05-4.00(m,1H),3.72(s,3H),3.67(d,J=3.7Hz,2H),3.13(td,J=13.5,12.9,2.6Hz,1H),2.9 6(ddt,J=11.6,7.8,3.8Hz,1H),2.72(td,J=12.7,2.8Hz,1H),1.99-1.91(m,2H),1.55-1.41(m,2H). 13 CNMR(150MHz,DMSO-d6)δ169.42,158.27,149.99,143.03,130.82,130.33,128.27,126.51,116.21,114. 23,114.12,112.48,101.58,101.57,101.23,55.46,45.90,41.65,33.62,32.42,31.58.HRMScalculated for(M+H)+416.2081,found 416.2084.

[0112] Example 30: 1-(4-(5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl)piperidin-1-yl)propyl-2-vinyl-1-carbonyl (R29)

[0113] D25 (60 mg, 0.22 mmol) was mixed in a mixed solution of DCM / DMF 3 / 1 (12 mL), and acryloyl chloride (20 mg, 0.22 mmol) and triethylamine (61 μL, 0.44 mmol) were added at 0°C. After stirring for 15 min, the mixture was warmed to room temperature and stirred for 3 h. TLC monitoring was performed. After the reaction was completed, the mixture was diluted with water and extracted with EA. The organic phase was collected and washed three times with a saturated NaCl solution. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and purified by column chromatography to obtain the final product, compound R29, as a yellow solid (40 mg, 57% yield). 1H NMR (600MHz, DMSO-d6) δ12.95(s,1H),11.61(s,1H),8.21(d,J=5.0Hz,1H),7.48(s,1H),7.40(d ,J=5.0Hz,1H),6.99(s,1H),6.85(dd,J=16.7,10.5Hz,1H),6.77(s,1H),6.12(dd,J=16.7,2.5Hz ,1H),5.68(dd,J=10.5,2.5Hz,1H),4.51(d,J=13.0Hz,1H),4.15(d,J=13.5Hz,1H),3.21(t,J=12 .8Hz,1H),3.01(d,J=11.8Hz,1H),2.81(t,J=12.5Hz,1H),2.05-1.97(m,2H),1.67-1.53(m,2H). 13 CNMR(150MHz,DMSO-d6)δ164.72,149.86,142.90,128.90,127.41,126.51,116.29,112.50,101.52,45.37,41.87,32.62,31.65.HRMS calculated for(M+H)+322.1662, found 322.1662.

[0114] Example 31: 1-(4-(5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl)piperidin-1-yl)-2-chloroethyl-1-carbonyl (R30)

[0115] D25 (60 mg, 0.22 mmol) was mixed in a mixed solution of DCM / DMF 3 / 1 (12 mL), and chloroacetyl chloride (25 mg, 0.22 mmol) and triethylamine (61 μL, 0.44 mmol) were added at 0°C. After stirring for 15 min, the mixture was warmed to room temperature and stirred for 3 h. TLC monitoring was performed. After the reaction was completed, the mixture was diluted with water and extracted with EA. The organic phase was collected and washed three times with a saturated NaCl solution. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and purified by column chromatography to obtain the final product, compound R30, as a yellow solid (47 mg, 62% yield). 1H NMR (600MHz, DMSO-d6) δ12.95(s,1H),11.90(s,1H),8.27(d,J=5.2Hz,1H),7.55(t,J=2.9Hz, 1H),7.51(d,J=5.2Hz,1H),7.04(d,J=4.6Hz,1H),6.84(s,1H),4.45-4.38(m,3H),3.93(d,J= 13.6Hz,1H),3.23(dd,J=26.0,2.7Hz,1H),3.03(ddt,J=11.6,7.7,3.9Hz,1H),2.82(td,J=12 .7,2.8Hz,1H),2.06-1.99(m,2H),1.71(qd,J=12.4,4.0Hz,1H),1.58(qd,J=12.4,4.2Hz,1H). 13 C HRMS calculated for(M+H)+344.1273, found 344.1282.

[0116] Example 32: 2-(4-(5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl)piperidin-1-yl)acetonitrile (R31)

[0117] D25 (60 mg, 0.22 mmol) was mixed in a mixed solution of DCM / DMF 3 / 1 (12 mL), and chloroacetonitrile (16.6 mg, 0.22 mmol) and triethylamine (61 μL, 0.44 mmol) were added at 0°C. After stirring for 15 min, the mixture was warmed to room temperature and stirred for 3 h. TLC monitoring was performed. After the reaction was completed, the mixture was diluted with water and extracted with EA. The organic phase was collected and washed three times with a saturated NaCl solution. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and purified by column chromatography to obtain the final product, compound R31, a yellow solid (36 mg, 54%). 1H NMR (600MHz, DMSO-d6) δ12.93(s,1H),11.69-11.56(m,1H),8.23-8.19(m,1H),7.47(s,1H),7.40(d,J=5.0Hz,1H),7.02-6.96(m,1H),6.74(s ,1H),3.76(s,2H),2.89(dt,J=11.5,3.4Hz,2H),2.71(s,1H),2.31(td,J=11.6,2.5Hz,2H),2.03-1.98(m,2H),1.74(qd,J=12.1,3.8Hz,2H). 13 C NMR(150MHz,DMSO-d6)δ150.00,149.57,148.48,143.03,133.48,126.31,116 .40,116.32,112.62,101.57,101.28,51.99,49.07,45.98,32.50,31.59.HRMS calculated for (M+H)+307.1666,found 307.1664.

[0118] Example 33: 1-(4-(5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl)piperidin-1-yl)ethyl-1-carbonyl (R32)

[0119] D25 (60 mg, 0.22 mmol) was mixed in a mixed solution of DCM / DMF 3 / 1 (12 mL), acetyl chloride (17.3 mg, 0.22 mmol) and triethylamine (61 μL, 0.44 mmol) were added at 0°C, stirred for 15 min, warmed to room temperature, stirred for 3 h, and monitored by TLC. After the reaction was completed, it was diluted with water and extracted with EA. The organic phase was collected and washed three times with a saturated NaCl solution, the organic phase was dried over anhydrous magnesium sulfate, the organic phase was filtered and concentrated under reduced pressure, and purified by column chromatography to obtain the final product, compound R32, a yellow solid (18 mg, 26% yield). 1H NMR (600MHz, DMSO-d6) δ12.96 (s, 1H), 11.66 (s, 1H), 8.22 (d, J = 5.0Hz, 1H), 7.49 (s ,1H),7.41(d,J=4.9Hz,1H),6.98(s,1H),6.77(s,1H),4.44(dd,J=13.3,4.5Hz,1H) ,3.92-3.87(m,1H),3.20-3.14(m,1H),3.02-2.94(m,1H),2.69(td,J=12.8,2.8Hz ,1H),2.03(s,5H),1.65(qd,J=12.3,4.0Hz,1H),1.52(qd,J=12.4,4.2Hz,1H).HRMS calculated for (M+H)+310.1662, found 310.1667.

[0120] Example 34: (4-(5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl)piperidin-1-yl)(cyclopropane)methylcarbonyl (R33)

[0121] D25 (60 mg, 0.22 mmol) was mixed in a mixed solution of DCM / DMF 3 / 1 (12 mL), and cyclopropylcarbonyl chloride (23 mg, 0.22 mmol) and triethylamine (61 μL, 0.44 mmol) were added at 0°C. After stirring for 15 min, the mixture was warmed to room temperature and stirred for 3 h. TLC monitoring was performed. After the reaction was completed, the mixture was diluted with water and extracted with EA. The organic phase was collected and washed three times with a saturated NaCl solution. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and purified by column chromatography to obtain the final product, compound R33, a green solid (40 mg, 55%). 1 H NMR (600MHz, DMSO-d6) δ13.01-12.87(m,1H),11.69-11.59(m,1H),8.21(d,J=5.0Hz,1H),7.49( s,1H),7.41(d,J=5.0Hz,1H),6.98(s,1H),6.78(s,1H),4.45(d,J=13.1Hz,1H),4.34(d,J=13.6 Hz,1H),3.24(t,J=12.2Hz,1H),3.01(tt,J=12.0,3.7Hz,1H),2.77-2.70(m,1H),2.08-1.93(m, 4H),1.70-1.61(m,1H),1.53(d,J=12.3Hz,1H),0.78-0.72(m,2H),0.71(dd,J=8.0,3.2Hz,2H). 13C NMR (150MHz, DMSO-d6) δ171.25,149.86,142.90,126.51,116.29,112.50,101.52,45.37,42.10,32.76,31.74,10.81,7.31.HRMS calculated for(M+H)+336.1819, found 336.1818.

[0122] Example 35: (4-(5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl)piperidin-1-yl)(cyclobutane)methylcarbonyl (R34)

[0123] D25 (60 mg, 0.22 mmol) was mixed in a mixed solution of DCM / DMF 3 / 1 (12 mL), and cyclobutylcarbonyl chloride (26 mg, 0.22 mmol) and triethylamine (61 μL, 0.44 mmol) were added at 0°C. After stirring for 15 min, the mixture was warmed to room temperature and stirred for 3 h. TLC monitoring was performed. After the reaction was completed, the mixture was diluted with water and extracted with EA. The organic phase was collected and washed three times with a saturated NaCl solution. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and purified by column chromatography to obtain the final product, compound R34, as a white solid (39 mg, 51%). 1 H NMR (600MHz, DMSO-d6) δ12.96(s,1H),11.68(s,1H),8.22(d,J=5.0Hz,1H),7.49(t,J=3.0Hz,1H),7.42(d,J=5 .0Hz,1H),6.98(s,1H),6.77(s,1H),4.47-4.41(m,1H),3.79-3.75(m,1H),3.08(td,J=13.7,12.9,2.7Hz,1H) ,2.97(tt,J=11.9,4.0Hz,1H),2.70(td,J=12.7,2.8Hz,1H),2.24-2.14(m,2H),2.14-2.07(m,2H),1.97(ddd, J=15.4,8.8,3.5Hz,2H),1.94-1.87(m,1H),1.75(dddt,J=12.0,10.4,6.7,2.2Hz,1H),1.60-1.44(m,3H).HRMS calculated for (M+H)+350.1975, found 350.1985.

[0124] Example 36: (4-(5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl)piperidin-1-yl)(cyclopentyl)methylcarbonyl (R35)

[0125] D25 (60 mg, 0.22 mmol) was mixed in a mixed solution of DCM / DMF 3 / 1 (12 mL), and cyclopentylcarbonyl chloride (29 mg, 0.22 mmol) and triethylamine (61 μL, 0.44 mmol) were added at 0°C. After stirring for 15 min, the mixture was warmed to room temperature and stirred for 3 h. TLC monitoring was performed. After the reaction was completed, the mixture was diluted with water and extracted with EA. The organic phase was collected and washed three times with a saturated NaCl solution. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and purified by column chromatography to obtain the final product, compound R35, as a green solid (43 mg, 55%). 1 H NMR (600MHz, DMSO-d6) δ12.90(s,1H),11.67(s,1H),8.22(d,J=5.0Hz,1H),7.49(t,J=2.9Hz,1H),7.42 (d,J=5.0Hz,1H),6.98(s,1H),6.77(s,1H),4.49(dd,J=11.1,6.3Hz,1H),4.06(d,J=13.6Hz,1H),3.14 (d,J=11.7Hz,1H),3.04-2.95(m,2H),2.70(td,J=12.8,2.8Hz,1H),2.04-1.94(m,2H),1.77(tq,J=12. 8,8.0,6.2Hz,2H),1.69(ddd,J=16.0,12.4,7.1Hz,2H),1.64-1.57(m,3H),1.53(td,J=9.2,4.8Hz,3H). 13 CNMR(150MHz,DMSO-d6)δ173.63,172.47,149.66,142.73,126.59,116.36,112.49,1 01.74,101.39,45.33,41.73,32.79,31.82,30.17,30.08,26.16,26.13,21.52.HRMS calculatedfor(M+H)+364.2132,found 364.2134.

[0126] Example 37: (4-(5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl)piperidin-1-yl)(cyclohexyl)methylcarbonyl (R36)

[0127] D25 (60 mg, 0.22 mmol) was mixed in a mixed solution of DCM / DMF 3 / 1 (12 mL), and cyclohexylcarbonyl chloride (32 mg, 0.22 mmol) and triethylamine (61 μL, 0.44 mmol) were added at 0°C. After stirring for 15 min, the mixture was warmed to room temperature and stirred for 3 h. TLC monitoring was performed. After the reaction was completed, the mixture was diluted with water and extracted with EA. The organic phase was collected and washed three times with a saturated NaCl solution. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and purified by column chromatography to obtain the final product, compound R36, a green solid (25 mg, 30%). 1 H NMR (600MHz, DMSO-d6) δ12.84(s,1H),11.64(s,1H),8.21(d,J=5.0Hz,1H),7.48(t,J=2.9Hz,1H),7 .40(d,J=5.0Hz,1H),6.97(s,1H),6.77(s,1H),4.48(d,J=13.1Hz,1H),4.03(d,J=13.4Hz,1H),3.1 6(t,J=12.6Hz,1H),2.98(tt,J=11.7,3.8Hz,1H),2.69-2.58(m,2H),2.07-1.94(m,2H),1.74-1.58 (m,6H),1.56-1.45(m,1H),1.32(t,J=11.8Hz,4H),1.16(ddtd,J=16.7,10.0,7.5,6.2,3.8Hz,1H). 13 CNMR(150MHz,DMSO-d6)δ173.70,172.47,162.77,149.92,142.96,126.50,116.25,112. 49,101.69,101.30,45.23,41.47,32.91,31.88,29.80,29.63,26.10,25.68,21.52.HRMS calculatedfor(M+H)+378.2288,found 378.2287.

[0128] Example 38: 1-(4-(5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl)piperidin-1-yl)-2-cyclopropylethyl-1-carbonyl (R37)

[0129] D25 (60 mg, 0.22 mmol) was mixed in a mixed solution of DCM / DMF 3 / 1 (12 mL), and cyclopropaneacetyl chloride (26 mg, 0.22 mmol) and triethylamine (61 μL, 0.44 mmol) were added at 0°C. After stirring for 15 min, the mixture was warmed to room temperature and stirred for 3 h. TLC monitoring was performed. After the reaction was completed, the mixture was diluted with water and extracted with EA. The organic phase was collected and washed three times with a saturated NaCl solution. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and purified by column chromatography to obtain the final product, compound R37, as a white solid (23 mg, 30%). 1 H NMR (600MHz, DMSO-d6) δ12.95(s,1H),11.62(s,1H),8.21(d,J=5.0Hz,1H),7.48(s,1H),7.40(d,J=5.0Hz,1 H),6.98(s,1H),6.76(s,1H),4.48(d,J=13.0Hz,1H),3.93(d,J=13.6Hz,1H),3.18-3.12(m,1H),2.97(d,J= 12.2Hz,1H),2.73-2.67(m,1H),2.29(dd,J=6.8,2.5Hz,2H),1.99(t,J=14.1Hz,2H),1.57(dqd,J=50.1,12. 2,4.1Hz,2H),0.98(dddd,J=13.3,9.9,5.8,1.6Hz,1H),0.46(dt,J=8.6,2.7Hz,2H),0.13(h,J=3.4Hz,2H). 13 C NMR(151MHz,DMSO-d6)δ170.52,162.77,149.99,149.26,148.62,143.03,133.75,126.39, 116.23,112.54,101.45,45.57,41.41,38.01,33.42,32.66,31.70,7.82,4.79,4.77.HRMS calculated for (M+H)+350.1975, found 450.1982.

[0130] Example 39: 4-(5-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl)piperidine-1-sulfonyl fluoride (R38)

[0131] D25 (60 mg, 0.22 mmol) was mixed in 10 mL of acetonitrile solution, 1-(fluorosulfonyl)-2,3-dimethyl-1H-imidazol-3-ium trifluoromethanesulfonate (79 mg, 0.24 mmol) was added at 0°C, stirred for 15 min, warmed to room temperature, stirred for 3 h, and monitored by TLC. After the reaction was completed, it was diluted with water and extracted with EA. The organic phase was collected and washed three times with a saturated NaCl solution, the organic phase was dried over anhydrous magnesium sulfate, the organic phase was filtered and concentrated under reduced pressure, and purified by column chromatography to obtain the final product, compound R38, a yellow solid (70 mg, 91%). 1 H NMR (600MHz, DMSO-d6) δ13.02(s,1H),11.65(s,1H),8.22(d,J=4.7Hz,1H),7.50(s,1H),7.41(d,J=5.0Hz,1H),6.98(s,1H),6.82(s,1H) ,3.89(dt,J=12.6,3.9Hz,2H),3.35(d,J=3.0Hz,1H),3.31(d,J=3.0Hz,1H),3.01(d,J=6.0Hz,1H),2.16-2.11(m,2H),1.87-1.79(m,3H). 13 C NMR(150MHz,DMSO-d6)δ162.77,149.98,143.04,126.39,116.25,112.54,101.37,101.19,47.32,36.25,31.24,30.57.HRMS calculatedfor(M+H)+350.1082,found 350.1082.

[0132] Example 40: 4-(3-(1-(ethylsulfonyl)piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridine (R39)

[0133] D25 (60 mg, 0.22 mmol) was mixed in a mixed solution of DCM / DMF 3 / 1 (12 mL), ethylsulfonyl chloride (28 mg, 0.22 mmol) and triethylamine (61 μL, 0.44 mmol) were added at 0°C, stirred for 15 min, warmed to room temperature, stirred for 3 h, and monitored by TLC. After the reaction was completed, it was diluted with water and extracted with EA. The organic phase was collected and washed three times with a saturated NaCl solution, the organic phase was dried over anhydrous magnesium sulfate, the organic phase was filtered and concentrated under reduced pressure, and purified by column chromatography to obtain the final product, compound R39, a green solid (18 mg, 23%). 1H NMR(600MHz,DMSO-d6)δ12.98(s,1H),11.64-11.58(m,1H),8.26-8.18(m,1H),7. 50-7.45(m,1H),7.41(d,J=5.0Hz,1H),7.00(s,1H),6.78(s,1H),3.69(dt,J=12. 7,3.7Hz,2H),3.08(q,J=7.4Hz,2H),2.96(td,J=12.1,2.5Hz,2H),2.89(s,1H),2 .06(dd,J=13.5,3.8Hz,2H),1.72(qd,J=12.2,4.0Hz,2H),1.24(t,J=7.4Hz,3H). 13 CNMR(150MHz,DMSO-d6)δ162.77,149.95,148.07,142.99,126.40,116.31,112.58,101.53,45.68,43.17,36.25,31.72,8.05.HRMS calculated for(M+H)+360.1489,found360.1497.

[0134] Example 41: 4-(3-(1-(cyclopropanesulfonyl)piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridine (R40)

[0135] D25 (60 mg, 0.22 mmol) was mixed in a mixed solution of DCM / DMF 3 / 1 (12 mL), and cyclopropanesulfonyl chloride (31 mg, 0.22 mmol) and triethylamine (61 μL, 0.44 mmol) were added at 0°C. After stirring for 15 min, the mixture was warmed to room temperature and stirred for 3 h. TLC monitoring was performed. After the reaction was completed, the mixture was diluted with water and extracted with EA. The organic phase was collected and washed three times with a saturated NaCl solution. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and purified by column chromatography to obtain the final product, compound R40, as a white solid (40 mg, 49%). 1H NMR (600MHz, DMSO-d6) δ13.04(s,1H),11.73(s,1H),8.23(d,J=5.1Hz,1H),7.51(t,J =2.9Hz,1H),7.44(d,J=5.1Hz,1H),7.00(s,1H),6.81(s,1H),3.72-3.67(m,2H),2.99 (td,J=12.2,2.5Hz,2H),2.90(d,J=5.1Hz,1H),2.62(tt,J=7.9,4.8Hz,1H),2.10-2.0 5(m,2H),1.79-1.72(m,2H),1.00(dt,J=8.5,3.0Hz,2H),0.95(qd,J=4.8,1.7Hz,2H). 13 C NMR(150MHz,DMSO-d6)δ162.77,149.24,142.36,126.74,116.50,112.49,101.59,46.23,36.25,31.47,25.70,4.71,4.39.HRMS calculated for(M+H)+372.1489, found 372.1492.

[0136] Example 42: 4-(3-(1-p-Toluenesulfonylpiperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridine (R41)

[0137] D25 (60 mg, 0.22 mmol) was mixed in a mixed solution of DCM / DMF 3 / 1 (12 mL), 4-toluenesulfonyl chloride (42 mg, 0.22 mmol) and triethylamine (61 μL, 0.44 mmol) were added at 0°C, stirred for 15 min, warmed to room temperature, stirred for 3 h, and monitored by TLC. After the reaction was completed, it was diluted with water and extracted with EA. The organic phase was collected and washed three times with a saturated NaCl solution, the organic phase was dried over anhydrous magnesium sulfate, the organic phase was filtered and concentrated under reduced pressure, and purified by column chromatography to obtain the final product, compound R41, as a yellow solid (32 mg, 35%). 1H NMR(600MHz,DMSO-d6)δ12.89(s,1H),11.66(s,1H),8.21(d,J=5.0Hz,1H),7.67 (d,J=8.2Hz,2H),7.48(t,J=7.2Hz,3H),7.38(d,J=5.0Hz,1H),6.94(s,1H),6.7 2(s,1H),3.70(dt,J=12.2,3.7Hz,2H),2.71(td,J=8.2,4.5Hz,1H),2.42(s,3H) ,2.38(td,J=12.1,2.6Hz,2H),2.06-2.01(m,2H),1.74(qd,J=12.2,4.0Hz,2H). 13 C NMR(151MHz,DMSO-d6)δ174.96,149.83,143.98,142.90,133.09,130.33,127.99,116.26,112.46,101.27,46.30,31.08,29.47,21.49.HRMS calculated for(M+H)+422.1645,found422.1645.

[0138] The effects of compound D25 and compounds R1-R41 were tested as follows:

[0139] 1) Testing the ROCK1 / 2 protease inhibitory activity of the compound D25 and compounds R1-R41 obtained in the present invention

[0140] The inhibitory activity of the compound on ROCK1 / 2 kinase was determined using a commercial ADP-Glo ​​kit. The kit instructions were followed, and KD025 and nasudilide were used as positive control compounds. Protein (1 nM), substrate (10 μM), and ATP (5 μM) were diluted to the corresponding concentrations using enzyme buffer (40 mM Tris pH = 7.5, 20 mM MgCl2, 0.1 mg / mL BSA, 50 μM DTT). In a 384-well plate, 4 μL of enzyme buffer or 4 μL of compound solution of corresponding concentration (10 μM, 1 μM, 0.1 μM, 0.01 μM, 0.001 μM, 0.0001 μM), 2 μL of protease, and 2 μL of substrate / ATP mixture were added to each well, incubated at room temperature for 40 minutes, and 10 μL of ADP-Glo ​​reagent was added to each well, mixed and incubated at room temperature for 40 minutes. Finally, 20 μL of enzyme detection reagent was added to each well, mixed and incubated at room temperature for 30 minutes. The corresponding fluorescence value was recorded by microplate reader, and the fluorescence value of compound well was recorded as Lum compound The fluorescence value of the negative control group is recorded as Lum vehicle The fluorescence value of the blank well is recorded as Lumblank The inhibition rate is calculated using this formula: (Lum vehicle -Lum compound ) / (Lum vehicle -Lum blank )×100%.IC 50 Calculations were performed using GraphPad Prism 6. The results are shown in Table 2.

[0141] Table 2

[0142]

[0143]

[0144] 2) Anti-inflammatory activity test of compounds in RAW264.7 cells

[0145] The anti-inflammatory activity of the compound was determined by testing the NO production level in RAW264.7 cells. RAW264.7 cells in the logarithmic growth phase were inoculated in a 96-well plate at a volume of 100 μL per well. When the cell concentration was about 90, the cells were pretreated with the corresponding compound (20 μM) and dexamethasone (20 μM) for 1 h. LPS was then added to each well, and the final concentration of LPS was 0.1 μg / mL. After continuing to culture for 24, 70 μL of the supernatant and 70 μL of Griess reagent were taken from each well and mixed evenly. After incubation for 15 minutes, the OD value of each well at a wavelength of 546 nm was measured by an enzyme reader, and the corresponding inhibition rate was calculated. The results are shown in Table 3.

[0146] Table 3

[0147]

[0148]

[0149] 3) Compound D25 and Compound R3 reduce intraocular pressure in the model of high intraocular pressure a. The ability of Compound R3 and Compound D25 to reduce intraocular pressure in normal rabbits

[0150] In this experiment, Netarsudil mesylate (netarsudil mesylate with a mass fraction of 0.1%), R3 hydrochloride (R3 hydrochloride with a mass fraction of 0.1%) and D25 hydrochloride (D25 hydrochloride with a mass fraction of 0.1%) eye drops were prepared with the same excipients. A blank control was also set up. The three eye drops were tested for their ability to lower intraocular pressure in normal rabbits, ΔIOP = IOP instillation -IOP control , among which, IOP instillation is the intraocular pressure of the drug-treated group, IOP controlis the intraocular pressure of the blank control group. Figure 1 shown.

[0151] b. IOP-lowering ability of compound R3 and compound D25 in methylcellulose-induced rabbit ocular hypertension model

[0152] In this experiment, Netarsudil mesylate (0.1% Netarsudil mesylate by mass), R3 hydrochloride (0.1% R3 hydrochloride by mass) and D25 hydrochloride (0.1% D25 hydrochloride by mass) eye drops were prepared with the same excipients. A blank control was also set up. A methylcellulose-induced rabbit model of intraocular hypertension was constructed to test the intraocular pressure-lowering ability of the three eye drops in the methylcellulose-induced rabbit model of intraocular hypertension, ΔIOP = IOP instillation -IOP control , among which, IOP instillation is the intraocular pressure of the drug-treated group, IOP control is the intraocular pressure of the blank control group. Figure 2 shown.

[0153] Figure 1 , Figure 2 Here, 0.1% R3 represents R3 hydrochloride eye drops with a mass fraction of 0.1%, 0.1% D25 represents D25 hydrochloride eye drops with a mass fraction of 0.1%, and 0.1% (S)-Netarsudil represents netarsudil mesylate eye drops with a mass fraction of 0.1%.

[0154] The results show that D25 and R3 can significantly reduce intraocular pressure at a mass fraction of 0.1%, and the effect is equivalent to that of positive drugs. When using high concentration (S)-Netarsudil (0.1%), very obvious eye irritation can be observed, including severe conjunctival congestion, eyelid redness and swelling, increased secretions and other adverse reactions, but no obvious eye irritation was observed with the same mass fraction of R3 and D25, which may indicate that the irritation of the two is weak.

[0155] Although the embodiments of the present invention have been shown and described above, it is to be understood that the above embodiments are illustrative and are not to be construed as limitations on the present invention. A person skilled in the art may make changes, modifications, substitutions and variations to the above embodiments within the scope of the present invention, which shall all be included in the scope of protection of the present invention.

Claims

1. A 4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridine derivative, and a stereoisomer, tautomer, geometric isomer or pharmaceutically acceptable salt thereof, characterized in that: The structure of the 4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridine derivative is shown in Formula I: Wherein, R is selected from H, The A ring is selected from benzene, naphthalene, anthracene, pyridine, pyrimidine, pyridazine, pyrazine, and triazine; n1, n2, and n3 are independently selected from any integer from 1 to 4; R1, R2, R3, R4, and R5 are independently selected from H, C1-6 alkoxy, halogen-substituted C1-6 alkyl, C1-6 alkoxyacyl, C1-6 alkylacyl, halogen, C1-6 alkyl, phenoxy, nitro, C1-6 alkenyl, C3-8 cycloalkyl, C3-8 cycloalkyl-substituted C1-6 alkyl, and C1-6 alkyl-substituted phenyl.

2. The 4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridine derivative according to claim 1, characterized in that The A ring is benzene, and n1, n2, and n3 are all 1.

3. The 4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridine derivative according to claim 1, characterized in that R is selected from H, R2 is selected from C1-6 alkyl, halogen-substituted C1-6 alkyl, C1-6 alkoxyacyl, halogen, C1-6 alkylacyl, C1-6 alkoxy; R3 is selected from C1-6 alkenyl, halogen-substituted C1-6 alkyl, cyclopentane; R4 is selected from halogen, C1-6 straight-chain alkyl; R5 is selected from H, C1-6 alkoxy.

4. The 4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridine derivative according to claim 1, characterized in that The 4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridine derivative is selected from the following compounds:

5. A method for preparing the 4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridine derivative according to any one of claims 1 to 4, characterized in that: When R is H, the reaction formula for preparing the 4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridine derivative is as follows: The preparation of the 4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrole[2,3-b]pyridine derivative includes: reacting 3-quinuclidinone with 7-azaindole-4-carboxaldehyde to obtain compound D25-1, and reacting compound D25-1 with hydrazine hydrate to obtain the 4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrole[2,3-b]pyridine derivative.

6. A method for preparing the 4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridine derivative according to any one of claims 1 to 4, characterized in that: When R is not H, the reaction formula for preparing the 4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridine derivative is as follows: Wherein, R is defined as in claim 1, and X is a halogen; The preparation of the 4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrole[2,3-b]pyridine derivative comprises: reacting compound D25 with RX to obtain the 4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrole[2,3-b]pyridine derivative.

7. A pharmaceutical composition, characterized in that The invention comprises the 4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridine derivative or its stereoisomer, tautomer, geometric isomer or pharmaceutically acceptable salt as described in any one of claims 1 to 4.

8. Use of a 4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridine derivative according to any one of claims 1 to 4 or its stereoisomers, tautomers, geometric isomers or pharmaceutically acceptable salts and / or a pharmaceutical composition according to claim 7 or 8 in the preparation of an anti-inflammatory drug.

9. Use of a 4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridine derivative according to any one of claims 1 to 4 or a stereoisomer, tautomer, geometric isomer or pharmaceutically acceptable salt thereof and / or a pharmaceutical composition according to claim 7 or 8 in the preparation of a ROCK kinase inhibitor.

10. Use of the 4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridine derivative according to any one of claims 1 to 4 or its stereoisomers, tautomers, geometric isomers or pharmaceutically acceptable salts and / or the pharmaceutical composition according to claim 7 or 8 in the preparation of a drug for reducing intraocular pressure.

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