4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrole[2,3-b]pyridine derivatives, their preparation methods and applications

Abstract

This invention provides a 4-(3-(piperidin-4-yl)-1H-pyrazole-5-yl)-1H-pyrrole[2,3-b]pyridine derivative, and its stereoisomers, tautomers, geometric isomers, or pharmaceutically acceptable salts, characterized in that the structure of the 4-(3-(piperidin-4-yl)-1H-pyrazole-5-yl)-1H-pyrrole[2,3-b]pyridine derivative is shown in Formula I. This invention also provides a method for preparing the above compound, which is simple and easily industrialized. This invention further provides the use of the above compound or its stereoisomers, tautomers, geometric isomers, or pharmaceutically acceptable salts in the preparation of anti-inflammatory drugs, ROCK kinase inhibitors, or intraocular pressure-lowering drugs.

Description

Technical Field

[0001] This invention patent 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 Technology

[0002] ROCK kinases (Rho-associated coiled-coil containing kinases) belong to the serine / threonine protein kinase family, including 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 commonly found in the brain, heart, lungs, and muscles. Furthermore, ROCK is primarily located in the cytoplasm, with fewer instances in the nucleus and cytoplasm. Activation of ROCK can regulate actin remodeling based on the cytoskeleton, participating in various biological processes through phosphorylation of different downstream substrates, including cell migration, adhesion, proliferation, apoptosis, and differentiation. These substrates include myosin II regulatory light chains (MLCs), myosin-binding subunits (MBS), also known as myosin MLC phosphatase (MLCP), LIM kinases, ERM proteins, and Vimentin. Aberrant activation of ROCK protein kinases is associated with pathological conditions in various systems, including cancer, neurological diseases, inflammation, cardiovascular diseases, and glaucoma. ROCK inhibitors have potential applicability for treating these diseases.

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

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

[0005]

[0006] Among them, 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 each independently selected from any integer in 1-4; R1, R2, R3, R4, and R5 are each independently selected from H, C1-6 alkoxy, halogen-substituted C1-6 alkyl, C1-6 alkoxy acyl, C1-6 alkyl acyl, 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 alkoxy acyl, halogen, C1-6 alkyl acyl, and C1-6 alkoxy; R3 is selected from C1-6 alkenyl, halogen-substituted C1-6 alkyl, and cyclopentane; R4 is selected from halogen and C1-6 straight-chain alkyl; R5 is selected from H and C1-6 alkoxy.

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

[0011]

[0012]

[0013]

[0014]

[0015] In a second aspect, the present invention provides a method for preparing the above-mentioned 4-(3-(piperidin-4-yl)-1H-pyrazole-5-yl)-1H-pyrrole[2,3-b]pyridine derivative, wherein when R is H, the reaction formula for preparing the 4-(3-(piperidin-4-yl)-1H-pyrazole-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 comprises: reacting 3-quinine cycloone 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-pyrrole[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 a third aspect, the present invention provides a pharmaceutical composition comprising a 4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrole[2,3-b]pyridine derivative thereof as described in any one of claims 1-4, or a stereoisomer, tautomer, geometric isomer, or pharmaceutically acceptable salt thereof.

[0023] In one or more embodiments of the present invention, the pharmaceutical composition is an eye drop, wherein 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 thereof in the eye drop is 0.1%.

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

[0025] In a fifth aspect, the present invention provides the use of the above-described 4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrole[2,3-b]pyridine derivative thereof, or its stereoisomers, tautomers, geometric isomers or pharmaceutically acceptable salts and / or the above-described pharmaceutical compositions 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 ROCK1 kinase inhibitor and ROCK2 kinase inhibitor.

[0027] In a sixth aspect of the invention, the invention provides the use of the above-described 4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrole[2,3-b]pyridine derivative thereof, or its stereoisomers, tautomers, geometric isomers, or pharmaceutically acceptable salts and / or the above-described pharmaceutical compositions in the preparation of an intraocular pressure-lowering drug.

[0028] The beneficial effects of this invention are as follows:

[0029] 1. This invention provides a 4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrole[2,3-b]pyridine derivative, which is a novel compound with 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-pyrrole[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-pyrrole[2,3-b]pyridine derivatives thereof, or their stereoisomers, tautomers, geometric isomers or pharmaceutically acceptable salts, in the preparation of anti-inflammatory drugs.

[0032] 4. This invention provides the use of the above-mentioned 4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrole[2,3-b]pyridine derivatives thereof, or their 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-pyrrole[2,3-b]pyridine derivatives thereof, or their stereoisomers, tautomers, geometric isomers or pharmaceutically acceptable salts, in the preparation of drugs for lowering intraocular pressure. Attached Figure Description

[0034] Figure 1A comparison of the intraocular pressure-lowering abilities of 0.1% nasuddil mesylate, R3 hydrochloride, and D25 hydrochloride eye drops in rabbits with normal intraocular pressure.

[0035] Figure 2 This is a comparison of the intraocular pressure-lowering abilities of 0.1% nasudinil mesylate, R3 hydrochloride, and D25 hydrochloride eye drops in a methylcellulose-induced rabbit model of intraocular pressure elevation. Detailed Implementation

[0036] The present invention will be further described below with reference to specific embodiments. However, the following embodiments are for illustrative purposes only and should not be considered as limiting the scope of the invention. Unless otherwise specified, specific conditions in the following embodiments are performed under conventional conditions or conditions recommended by the manufacturer. Unless otherwise specified, the methods used are conventional methods known in the art, and the consumables and reagents used are commercially available. Unless otherwise stated, the technical and scientific terms used herein have the same meaning as those familiar with the art. Furthermore, any methods or materials similar to or equivalent to those described herein may also be applied to the present invention.

[0037] This invention provides a 4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrole[2,3-b]pyridine derivative, and its stereoisomers, tautomers, geometric isomers, or pharmaceutically acceptable salts, wherein the structure of the 4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrole[2,3-b]pyridine derivative is shown in Formula I:

[0038]

[0039] Among them, 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 each independently selected from any integer in 1-4; R1, R2, R3, R4, R5, and R6 are each independently selected from H, C1-6 alkoxy, halogen-substituted C1-6 alkyl, C1-6 alkoxy acyl, C1-6 alkyl acyl, 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 specific embodiments illustrate this: The structural formulas of compounds D25 and R1-R41 in the embodiments are shown in Table 1 below:

[0041] Table 1

[0042]

[0043]

[0044]

[0045]

[0046]

[0047] Example 1: 4-(3-(piperidin-4-yl)-1H-pyrazole-5-yl)-1H-pyrrole[2,3-b]pyridine (D25)

[0048] When R is H, the 4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrole[2,3-b]pyridine derivative is compound D25. The reaction formula for preparing compound D25 is shown below:

[0049]

[0050] The specific steps are as follows: Using 200 mg of 3-quinine cycloketone hydrochloride, 49.2 mg of NaOH, and 179 mg of 7-azaindole-4-carboxaldehyde as raw materials, the mixture was thoroughly mixed with an ethanol solution and heated under reflux for 6 hours. After the reaction was complete, the ethanol was evaporated, the mixture was washed with water, extracted with EA, dried over anhydrous magnesium sulfate, and the solvent was evaporated to obtain 220 mg of a yellow solid (A1). A1 (200 mg) was refluxed in 10 mL of 50% hydrazine hydrate for 6 hours, then cooled to room temperature. A solid precipitated out; this solid was filtered and washed with water to obtain product D25, 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] The reaction formula for preparing compounds R1-R41 using D25 as a starting material is shown below:

[0052]

[0053] In this context, R is defined as above. Based on the structure of R1-R42, R is taken from different corresponding groups, and X is a halogen.

[0054] Halogens are selected from F, Cl, Br, and I.

[0055] The process for preparing R1-R41 is as follows in the examples below.

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

[0057] D25 (100 mg, 0.37 mmol) was mixed in a DCM / DMF 3 / 1 (12 mL) mixture. 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 brought to room temperature and stirred for 3 h, monitored by TLC. After the reaction was complete, the mixture 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, filtered, concentrated under reduced pressure, and purified by column chromatography to give 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-pyrazole-5-yl)-1H-pyrrole[2,3-b]pyridine (R2)

[0059] D25 (60 mg, 0.22 mmol) was mixed in DMSO (12 mL), and 4-methoxybenzyl chloride (34 mg, 0.22 mmol) and triethylamine (61 μL, 0.44 mmol) were added at 0 °C. After stirring for 15 min, the mixture was brought to room temperature and stirred for 3 h, monitored by TLC. After the reaction was complete, the mixture 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, filtered, concentrated under reduced pressure, and purified by column chromatography to give 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-pyrazole-5-yl)-1H-pyrrole[2,3-b]pyridine (R3)

[0061] D25 (100 mg, 0.37 mmol) was mixed in a DCM / DMF 3 / 1 (12 mL) mixture. 3-Methoxybenzyl chloride (117 mg, 0.75 mmol) and potassium carbonate (103 mg, 0.75 mmol) were added at 0 °C. After stirring for 15 min, the mixture was brought to room temperature and stirred for 3 h, monitored by TLC. After the reaction was complete, the mixture 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, filtered, concentrated under reduced pressure, and purified by column chromatography to give 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-pyrazole-5-yl)-1H-pyrrole[2,3-b]pyridine (R4)

[0063] D25 (60 mg, 0.22 mmol) was mixed in DMSO (12 mL), and 1-chloromethyl-3-trifluoromethylbenzene (43 mg, 0.22 mmol) and triethylamine (61 μL, 0.44 mmol) were added at 0 °C. After stirring for 15 min, the mixture was brought to room temperature and stirred for 3 h, monitored by TLC. After the reaction was complete, the mixture 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, filtered, concentrated under reduced pressure, and purified by column chromatography to give the final product compound R4 as a pale 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), and ethyl 3-chloromethylbenzoate (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 brought to room temperature and stirred for 3 h, monitored by TLC. After the reaction was complete, the mixture 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, filtered, concentrated under reduced pressure, and purified by column chromatography to give the final product, compound R5, as a pale 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), and 3-chloromethylacetophenone (37 mg, 0.22 mmol) and triethylamine (61 μL, 0.44 mmol) were added at 0 °C. After stirring for 15 min, the mixture was brought to room temperature and stirred for 3 h, monitored by TLC. After the reaction was complete, the mixture 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, filtered, concentrated under reduced pressure, and purified by column chromatography to give the final product, compound R6, as a pale 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-pyrrole[2,3-b]pyridine (R7)

[0069] D25 (60 mg, 0.22 mmol) was mixed in DMSO (12 mL), and 3,4-dimethoxybenzyl 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 brought to room temperature and stirred for 3 h, monitored by TLC. After the reaction was complete, the mixture 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, filtered, concentrated under reduced pressure, and purified by column chromatography to give the final product, compound R7, as a pale 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-pyrrole[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 brought to room temperature and stirred for 3 h, monitored by TLC. After the reaction was complete, the mixture 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, filtered, concentrated under reduced pressure, and purified by column chromatography to give the final product, compound R8, as a pale 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-pyrrole[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 brought to room temperature and stirred for 3 h, monitored by TLC. After the reaction was complete, the mixture 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, filtered, concentrated under reduced pressure, and purified by column chromatography to give the final product, compound R9, as a pale 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-pyrrole[2,3-b]pyridine (R10)

[0075] D25 (60 mg, 0.22 mmol) was mixed in DMSO (12 mL), and 4-methylbenzyl 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 brought to room temperature and stirred for 3 h, monitored by TLC. After the reaction was complete, the mixture 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, filtered, concentrated under reduced pressure, and purified by column chromatography to give 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-pyrrole[2,3-b]pyridine (R11)

[0077] D25 (60 mg, 0.22 mmol) was mixed in DMSO (12 mL), and 3-methylbenzyl 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 brought to room temperature and stirred for 3 h, monitored by TLC. After the reaction was complete, the mixture 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, filtered, concentrated under reduced pressure, and purified by column chromatography to give the final product compound R11 as a pale 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-benzylphenyl)piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrole[2,3-b]pyridine (R12)

[0079] D25 (60 mg, 0.22 mmol) was mixed in DMSO (12 mL), and 3-phenoxybenzyl chloride (48.1 mg, 0.22 mmol) and triethylamine (61 μL, 0.44 mmol) were added at 0 °C. After stirring for 15 min, the mixture was brought to room temperature and stirred for 3 h, monitored by TLC. After the reaction was complete, the mixture 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, filtered, concentrated under reduced pressure, and purified by column chromatography to give 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 12 mL DCM / DMF 3 / 1 mixture. At 0 °C, m-methoxybenzoyl chloride (37.5 mg, 0.22 mmol) and triethylamine (61 μL, 0.44 mmol) were added. The mixture was stirred for 15 min, then brought to room temperature and stirred for 3 h. The reaction was monitored by TLC. After completion, the mixture 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, filtered, concentrated under reduced pressure, and purified by column chromatography to give 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 12 mL DCM / DMF 3 / 1 mixture. 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 brought to room temperature and stirred for 3 h, monitored by TLC. After the reaction was complete, the mixture 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, filtered, concentrated under reduced pressure, and purified by column chromatography to give the final product, compound R14, as a pale 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 12 mL DCM / DMF 3 / 1 mixture. 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 brought to room temperature and stirred for 3 h, monitored by TLC. After the reaction was complete, the mixture 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, filtered, concentrated under reduced pressure, and purified by column chromatography to give 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 12 mL DCM / DMF 3 / 1 mixture. 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 brought to room temperature and stirred for 3 h, monitored by TLC. After the reaction was complete, the mixture 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, filtered, concentrated under reduced pressure, and purified by column chromatography to give 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-formyl)phenyl)ethyl-1-carbonyl (R17)

[0089] D25 (60 mg, 0.22 mmol) was mixed in a 12 mL DCM / DMF 3 / 1 mixture. At 0 °C, p-acetylbenzoyl chloride (41 mg, 0.22 mmol) and triethylamine (61 μL, 0.44 mmol) were added. The mixture was stirred for 15 min, then brought to room temperature and stirred for 3 h. The reaction was monitored by TLC. After completion, the mixture 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, filtered, concentrated under reduced pressure, and purified by column chromatography to give 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 12 mL DCM / DMF 3 / 1 mixture. 4-Chlorobenzoyl chloride (28 μL, 0.22 mmol) and triethylamine (61 μL, 0.44 mmol) were added at 0 °C. After stirring for 15 min, the mixture was brought to room temperature and stirred for 3 h, monitored by TLC. After the reaction was complete, the mixture 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, filtered, concentrated under reduced pressure, and purified by column chromatography to give 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)piperidin-1-carbonyl)benzoyl (R19)

[0093] D25 (60 mg, 0.22 mmol) was mixed in a 12 mL DCM / DMF 3 / 1 mixture. 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 brought to room temperature and stirred for 3 h, monitored by TLC. After the reaction was complete, the mixture 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, filtered, concentrated under reduced pressure, and purified by column chromatography to give the final product, compound R19, as a pale 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 12 mL DCM / DMF 3 / 1 mixture. 4-Trifluoromethylbenzoyl chloride (45.8 mg, 0.22 mmol) and triethylamine (61 μL, 0.44 mmol) were added at 0 °C. After stirring for 15 min, the mixture was brought to room temperature and stirred for 3 h, monitored by TLC. After the reaction was complete, the mixture 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, filtered, concentrated under reduced pressure, and purified by column chromatography to give 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 12 mL DCM / DMF 3 / 1 mixture. At 0 °C, m-fluorobenzoyl chloride (34.8 mg, 0.22 mmol) and triethylamine (61 μL, 0.44 mmol) were added. The mixture was stirred for 15 min, then brought to room temperature and stirred for 3 h. The reaction was monitored by TLC. After completion, the mixture 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, filtered, concentrated under reduced pressure, and purified by column chromatography to give 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 12 mL DCM / DMF 3 / 1 mixture. 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 brought to room temperature and stirred for 3 h, monitored by TLC. After the reaction was complete, the mixture 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, filtered, concentrated under reduced pressure, and purified by column chromatography to give 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 12 mL DCM / DMF 3 / 1 mixture. 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 brought to room temperature and stirred for 3 h, monitored by TLC. After the reaction was complete, the mixture 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, filtered, concentrated under reduced pressure, and purified by column chromatography to give 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 12 mL DCM / DMF 3 / 1 mixture. 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 brought to room temperature and stirred for 3 h, monitored by TLC. After the reaction was complete, the mixture 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, filtered, concentrated under reduced pressure, and purified by column chromatography to give 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 12 mL DCM / DMF 3 / 1 mixture. p-Toluyl 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 brought to room temperature and stirred for 3 h, monitored by TLC. After the reaction was complete, the mixture 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, filtered, concentrated under reduced pressure, and purified by column chromatography to give 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 12 mL DCM / DMF 3 / 1 mixture. 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 brought to room temperature and stirred for 3 h, monitored by TLC. After the reaction was complete, the mixture 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, filtered, concentrated under reduced pressure, and purified by column chromatography to give the final product, compound R26, as a pale 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 12 mL DCM / DMF 3 / 1 mixture. 3-Methoxyphenylacetyl 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 brought to room temperature and stirred for 3 h, monitored by TLC. After the reaction was complete, the mixture 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, filtered, concentrated under reduced pressure, and purified by column chromatography to give the final product, compound R27, as a pale 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 brought to room temperature and stirred for 3 h, monitored by TLC. After the reaction was complete, the mixture 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, filtered, concentrated under reduced pressure, and purified by column chromatography to give the final product, compound R28, as a pale 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 12 mL DCM / DMF 3 / 1 mixture. Acryloyl chloride (20 mg, 0.22 mmol) and triethylamine (61 μL, 0.44 mmol) were added at 0 °C. The mixture was stirred for 15 min, then brought to room temperature and stirred for 3 h. The reaction was monitored by TLC. After the reaction was complete, the mixture 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, filtered, concentrated under reduced pressure, and purified by column chromatography to give 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 12 mL DCM / DMF 3 / 1 mixture. 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 brought to room temperature and stirred for 3 h, monitored by TLC. After the reaction was complete, the mixture 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, filtered, concentrated under reduced pressure, and purified by column chromatography to give 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 12 mL DCM / DMF 3 / 1 mixture. Chloroacetonitrile (16.6 mg, 0.22 mmol) and triethylamine (61 μL, 0.44 mmol) were added at 0 °C. The mixture was stirred for 15 min, then brought to room temperature and stirred for 3 h. The reaction was monitored by TLC. After completion, the mixture 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, filtered, concentrated under reduced pressure, and purified by column chromatography to give the final product, compound R31, as 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 12 mL DCM / DMF 3 / 1 mixture. Acetyl chloride (17.3 mg, 0.22 mmol) and triethylamine (61 μL, 0.44 mmol) were added at 0 °C. After stirring for 15 min, the mixture was brought to room temperature and stirred for 3 h, monitored by TLC. After the reaction was complete, the mixture 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, filtered, concentrated under reduced pressure, and purified by column chromatography to give the final product, compound R32, as 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 12 mL DCM / DMF 3 / 1 mixture. Cyclopropylformyl 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 brought to room temperature and stirred for 3 h, monitored by TLC. After the reaction was complete, the mixture 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, filtered, concentrated under reduced pressure, and purified by column chromatography to give the final product, compound R33, as 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 12 mL DCM / DMF 3 / 1 mixture. Cyclobutylformyl chloride (26 mg, 0.22 mmol) and triethylamine (61 μL, 0.44 mmol) were added at 0 °C. The mixture was stirred for 15 min, then brought to room temperature and stirred for 3 h. The reaction was monitored by TLC. After completion, the mixture 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, filtered, concentrated under reduced pressure, and purified by column chromatography to give 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 12 mL DCM / DMF 3 / 1 mixture. Cyclopentylformyl 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 brought to room temperature and stirred for 3 h, monitored by TLC. After the reaction was complete, the mixture 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, filtered, concentrated under reduced pressure, and purified by column chromatography to give 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 12 mL DCM / DMF 3 / 1 mixture. Cyclohexylformyl 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 brought to room temperature and stirred for 3 h, monitored by TLC. After the reaction was complete, the mixture 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, filtered, concentrated under reduced pressure, and purified by column chromatography to give the final product, compound R36, as 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 12 mL DCM / DMF 3 / 1 mixture. Cyclopropane acetyl 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 brought to room temperature and stirred for 3 h, monitored by TLC. After the reaction was complete, the mixture 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, filtered, concentrated under reduced pressure, and purified by column chromatography to give 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, and 1-(fluorosulfonyl)-2,3-dimethyl-1H-imidazolium-3-onium trifluoromethanesulfonate (79 mg, 0.24 mmol) was added at 0 °C. After stirring for 15 min, the mixture was brought to room temperature and stirred for 3 h, monitored by TLC. After the reaction was complete, the solution 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, filtered, concentrated under reduced pressure, and purified by column chromatography to give the final product compound R38 as 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-pyrazole-5-yl)-1H-pyrrole[2,3-b]pyridine (R39)

[0133] D25 (60 mg, 0.22 mmol) was mixed in a 12 mL DCM / DMF 3 / 1 mixture. Ethylsulfonyl chloride (28 mg, 0.22 mmol) and triethylamine (61 μL, 0.44 mmol) were added at 0 °C. The mixture was stirred for 15 min, then brought to room temperature and stirred for 3 h. The reaction was monitored by TLC. After completion, the mixture 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, filtered, concentrated under reduced pressure, and purified by column chromatography to give the final product, compound R39, as 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-pyrazole-5-yl)-1H-pyrrole[2,3-b]pyridine (R40)

[0135] D25 (60 mg, 0.22 mmol) was mixed in a 12 mL DCM / DMF 3 / 1 mixture. Cyclopropanesulfonyl chloride (31 mg, 0.22 mmol) and triethylamine (61 μL, 0.44 mmol) were added at 0 °C. The mixture was stirred for 15 min, then brought to room temperature and stirred for 3 h. The reaction was monitored by TLC. After completion, the mixture 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, filtered, concentrated under reduced pressure, and purified by column chromatography to give 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-pyrazole-5-yl)-1H-pyrrole[2,3-b]pyridine (R41)

[0137] D25 (60 mg, 0.22 mmol) was mixed in a 12 mL DCM / DMF 3 / 1 mixture. 4-Toluenesulfonyl chloride (42 mg, 0.22 mmol) and triethylamine (61 μL, 0.44 mmol) were added at 0 °C. After stirring for 15 min, the mixture was brought to room temperature and stirred for 3 h, monitored by TLC. After the reaction was complete, the mixture 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, filtered, concentrated under reduced pressure, and purified by column chromatography to give 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 compounds D25 and R1-R41 were tested, as detailed below:

[0139] 1) The ROCK1 / 2 protease inhibitory activity of compounds D25 and R1-R41 obtained in this invention was tested.

[0140] The inhibitory activity of the compounds against ROCK1 / 2 kinases was assessed using a commercially available ADP-Glo ​​kit. Following the kit instructions, KD025 and nesuddil were used as positive controls. Protein (1 nM), substrate (10 μM), and ATP (5 μM) were diluted to the appropriate concentrations using enzyme buffer (40 mM Tris pH 7.5, 20 mM MgCl2, 0.1 mg / mL BSA, 50 μM DTT). In 384-well plates, 4 μL of enzyme buffer or 4 μL of the corresponding concentration of compound solution (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. The plates were incubated at room temperature for 40 min. Then, 10 μL of ADP-Glo ​​reagent was added to each well, and the mixture was incubated at room temperature for another 40 min. Finally, 20 μL of enzyme assay reagent was added to each well, and the plates were incubated at room temperature for 30 min. Record the corresponding fluorescence values ​​using a microplate reader; the fluorescence value of the compound well is denoted as Lum. compound The fluorescence value of the negative control group is denoted as Lum. vehicle The fluorescence value of the blank well is denoted as Lum.blank The inhibition rate is calculated using this formula: (Lum vehicle -Lum compound ) / (Lum vehicle -Lum blank )×100%. IC 50 The 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 the compound in RAW264.7 cells

[0145] The anti-inflammatory activity of the compounds was determined by testing the NO production level in RAW264.7 cells. RAW264.7 cells in logarithmic growth phase were seeded at 100 μL per well in 96-well plates. When the cell concentration reached approximately 90%, the cells were pretreated with the corresponding compound (20 μM) and dexamethasone (20 μM) for 1 h. Subsequently, LPS was added to each well to a final concentration of 0.1 μg / mL. After culturing for 24 hours, 70 μL of the supernatant from each well was mixed with 70 μL of Griess reagent and incubated for 15 minutes. The OD value of each well was measured at 546 nm using a microplate reader, and the corresponding inhibition rate was calculated. The results are shown in Table 3.

[0146] Table 3

[0147]

[0148]

[0149] 3) The intraocular pressure reduction of compounds D25 and R3 in a hypertensive model: a. The intraocular pressure-reducing ability of compounds R3 and D25 in normal rabbits.

[0150] This experiment prepared eye drops containing the same excipients as commercially available Netarsudil mesylate (0.1% by mass), R3 hydrochloride (0.1% by mass), and D25 hydrochloride (0.1% by mass). A blank control was also included. The intraocular pressure-lowering ability of these three eye drops in normal rabbits was tested, ΔIOP = IOP. instillation -IOP control Among them, IOP instillation Intraocular pressure (IOP) in the treatment group controlThe intraocular pressure was used as a blank control group, and the results were as follows: Figure 1 As shown.

[0151] b. The intraocular pressure-lowering ability of compounds R3 and D25 in a methylcellulose-induced rabbit model of intraocular pressure hypertension.

[0152] This experiment prepared eye drops identical to those for commercially available Netarsudil mesylate (0.1% by mass), R3 hydrochloride (0.1% by mass), and D25 hydrochloride (0.1% by mass), using the same excipients. A blank control was also included. A methylcellulose-induced rabbit model of intraocular pressure (IOP) was constructed, and the IOP-lowering ability of these three eye drops in this model was tested. ΔIOP = IOP instillation -IOP control Among them, IOP instillation Intraocular pressure (IOP) in the treatment group control The intraocular pressure was used as a blank control group, and the results were as follows: Figure 2 As shown.

[0153] Figure 1 , Figure 2 In this context, 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 at a mass fraction of 0.1% can significantly reduce intraocular pressure, with effects comparable to positive control drugs. When using high concentrations of (S)-Netarsudil (0.1%), very significant ocular irritation was observed, including severe conjunctival hyperemia, eyelid swelling, and increased discharge. However, no significant ocular irritation was observed with R3 and D25 at the same mass fraction, possibly indicating that both have weaker irritant properties.

[0155] Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those skilled in the art can make changes, modifications, substitutions and variations to the above embodiments within the scope of the present invention, all of which should be included within the protection scope of the present invention.

Claims

1. A 4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrole[2,3-b]pyridine derivative or a pharmaceutically acceptable salt, characterized in that, The 4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrole[2,3-b]pyridine derivatives are selected from the following compounds: 。 2. A method for preparing the 4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrole[2,3-b]pyridine derivative according to claim 1, characterized in that, The reaction formula for preparing the 4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrole[2,3-b]pyridine derivative is shown below: 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.

3. A pharmaceutical composition, characterized in that, Includes the 4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrole[2,3-b]pyridine derivative of claim 1 or a pharmaceutically acceptable salt.

4. The use of a 4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrole[2,3-b]pyridine derivative or pharmaceutically acceptable salt of claim 1 or the pharmaceutical composition of claim 3 in the preparation of an anti-inflammatory drug.

5. The use of a 4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrole[2,3-b]pyridine derivative or pharmaceutically acceptable salt of claim 1 or the pharmaceutical composition of claim 3 in the preparation of a ROCK kinase inhibitor.

6. The use of a 4-(3-(piperidin-4-yl)-1H-pyrazole-5-yl)-1H-pyrrole[2,3-b]pyridine derivative or a pharmaceutically acceptable salt in the preparation of an intraocular pressure-lowering drug; wherein the 4-(3-(piperidin-4-yl)-1H-pyrazole-5-yl)-1H-pyrrole[2,3-b]pyridine derivative is selected from the following structures: 、 。

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