4 (1H-pyrazol-3-yl) piperidinyl derivative, preparation method thereof and application of 4 (1H-pyrazol-3-yl) piperidinyl derivative in preparation of MNK inhibitor

Abstract

The invention provides a 4 (1H-pyrazol-3-yl) piperidinyl derivative, the structural formula of the 4 (1H-pyrazol-3-yl) piperidinyl derivative is shown as a formula I, # imgabs0 #, R1 is an aromatic ring or a substituted aromatic ring, the substituted aromatic ring is a substituent group on the aromatic ring, and R2 is a hydrogen atom or a hydrogen atom or a substituent group on the substituted aromatic ring, so that the structural formula of the 4 (1H-pyrazol-3-yl) piperidinyl derivative is shown as a formula I; the substituent groups are selected from C1-C6 alkyl groups, C1-C6 halogenated alkyl groups, C1-C6 alkylamino groups, C1-C6 alkoxy groups, five-membered to six-membered heterocyclic groups, halogen, hydroxyl groups, cyano groups, nitryl groups, amino groups and carbonyl substituted five-membered to six-membered heterocyclic groups containing 1-2 nitrogen atoms; and R2 is H or a C1-C6 alkyl group. The 4 (1H-pyrazol-3-yl) piperidinyl derivative has MNK1 and / or MNK2 inhibitory activity, and has anti-cancer and anti-inflammatory activity; the invention also provides a preparation method of the 4 (1H-pyrazol-3-yl) piperidinyl derivative, an application of the 4 (1H-pyrazol-3-yl) piperidinyl derivative in preparation of MNK1 and / or MNK2 inhibitors, and an application of the 4 (1H-pyrazol-3-yl) piperidinyl derivative in preparation of anti-inflammatory and anti-cancer drugs.

Description

Technical Field

[0001] This invention patent relates to the technical field of pharmaceutical chemistry, and in particular to a 4(1H-pyrazol-3-yl)piperidinyl derivative, its preparation method and its application in the preparation of MNK inhibitors. Background Art

[0002] MNK (human mitogen-activated protein kinase-interacting kinase), including two subtypes MNK1 and MNK2. It has now been demonstrated that MNK is the only kinase capable of phosphorylating serine 209 of eIF4E in vivo, thereby regulating protein synthesis in organisms. Overexpression of MNKs, eIF4E, and p-eIF4E has been found in many human malignancies and is often associated with high invasiveness and poor prognosis. Therefore, these factors have been regarded as oncogenes. In addition, phosphorylated eIF4E and MNKs are also involved in physiological processes such as lipid metabolism and accumulation, and blood glucose regulation. There are also studies showing that MNK can produce inflammatory responses by regulating the expression of some pro-inflammatory factors (TNF-α, IL-6, IL-8, etc.). Therefore, inhibition of the MNK signaling pathway can not only affect tumor formation pharmacologically but also increase the survival rate of cancer patients. Summary of the Invention

[0003] To solve the deficiencies of the existing technology, the inventors designed and synthesized a series of derivatives with 4(1H-pyrazol-3-yl)piperidinyl as the core, and regulated the processes of proliferation, metastasis, etc. in tumor cells by controlling the activity of MNK protease, thereby playing a role in treating tumors.

[0004] The present invention aims to solve at least one of the technical problems existing in the prior art to some extent. Thus, in the first aspect of the present invention, the present invention provides a 4(1H-pyrazol-3-yl)piperidinyl derivative, and the structural formula of the 4(1H-pyrazol-3-yl)piperidinyl derivative is shown in Formula I,

[0005]

[0006] wherein, R 1 is an aromatic ring or a substituted aromatic ring. The aromatic ring is a monocyclic or polycyclic aryl or heterocyclic group with 6 - 12 carbon atoms. The heterocyclic group is a 5- to 6-membered heterocyclic group, which means that the heterocyclic group has ring carbon atoms and 1 - 4 ring heteroatoms. Each ring heteroatom is independently selected from nitrogen, oxygen, and sulfur; the substituted aromatic ring has substituents on the aromatic ring, and the substituents are selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkylamino, C1-C6 alkoxy, 5- to 6-membered heterocyclic ring, halogen, hydroxyl, cyano, nitro, amino, and a 5- to 6-membered heterocyclic group with 1 - 2 nitrogen atoms substituted by a carbonyl group;

[0007] R2 is H or a C1-C6 alkyl group.

[0008] The C1-C6 alkylamino group in the present invention means that one or two hydrogen atoms in the amino group (-NH 2 ) are replaced by the same or different C1-C6 alkyl groups; it can be represented as -NR 3 R 4 , R 3 , R 4 are each independently selected from H and C1-C6 alkyl groups.

[0009] The C1-C6 alkoxy group in the present invention means -OR 5 , where R 5 is selected from C1-C6 alkyl groups; the C1-C6 alkoxy group can be further preferably a C1-C3 alkoxy group, and more preferably a methoxy group, an ethoxy group, etc.

[0010] The C1-C6 alkoxycarbonyl group in the present invention means -C(O)R 6 , where R 6 is selected from C1-C6 alkoxy groups.

[0011] The 5- to 6-membered heterocyclic ring in the present invention means that the ring system has ring carbon atoms and 1-4 ring heteroatoms (preferably 1, 2, 3 ring heteroatoms), and each ring heteroatom is independently selected from nitrogen, oxygen, sulfur; in the heterocyclic group containing one or more nitrogen atoms, the connection point can be a carbon or nitrogen atom as long as the valence allows. Further preferably, a pyrrole ring, a pyrazole ring, an imidazole ring, etc.

[0012] The halogen in the present invention is fluorine, chlorine, bromine, iodine.

[0013] In one or more technical solutions of the present invention, the aromatic ring is The substituents are selected from halogen, cyano, nitro, halomethyl, C1-C3 alkyl groups, hydroxyl groups, C1-C3 alkoxy groups, amino groups, C1-C3 alkylamino groups, and R 2 is H or a C1-C3 alkyl group.

[0014] In one or more technical solutions of the present invention, R 1 is selected from at least one of them.

[0015] In the second aspect of the present invention, the present invention provides a method for preparing the 4(1H-pyrazol-3-yl)piperidinyl derivative described in the first aspect of the present invention. When R 2When it is H, the 4(1H-pyrazol-3-yl)piperidinyl derivative is prepared from the compound of formula II, and the reaction formula is as follows:

[0016]

[0017] In one or more technical solutions of the present invention, the preparation of the 4(1H-pyrazol-3-yl)piperidinyl derivative from the compound of formula II includes the following steps: refluxing the compound of formula II with an aqueous hydrazine hydrate solution for 5.5 - 6.5 h, cooling to 15 - 35 °C, and precipitating a solid, which is the 4(1H-pyrazol-3-yl)piperidinyl derivative.

[0018] In one or more technical solutions of the present invention, the mass concentration of the aqueous hydrazine hydrate solution is 19 - 25%, and the mass-volume ratio of the compound of formula II to the aqueous hydrazine hydrate solution is (190 - 210 mg): 3 mL.

[0019] In one or more technical solutions of the present invention, the compound of formula II is prepared from the compound of formula III, and the reaction formula is as follows:

[0020]

[0021] Preferably, the preparation of the compound of formula II from the compound of formula III includes the following steps: refluxing the compound of formula III or its salt with an inorganic base and R 1 CHO in ethanol to obtain the compound of formula II.

[0022] Preferably, the mass ratio of the inorganic base to the compound of formula III is 0.9 - 1.1: 4.

[0023] Preferably, the reaction time is 5 - 7 h.

[0024] Preferably, the inorganic base is NaOH.

[0025] In one or more technical solutions of the present invention, when R 2 is a C1-C6 alkyl group, the 4(1H-pyrazol-3-yl)piperidinyl derivative is prepared from the compound of formula I(A), and the reaction formula is as follows:

[0026]

[0027] Preferably, the preparation of the 4(1H-pyrazol-3-yl)piperidinyl derivative from the compound of formula I(A) includes the following steps: reacting the compound of formula I(A) with R 2 CHO under alkaline conditions to obtain the 4(1H-pyrazol-3-yl)piperidinyl derivative.

[0028] Preferably, trifluoroacetic acid is added during the reaction.

[0029] Preferably, the solvent used in the reaction is tetrahydrofuran.

[0030] In a third aspect of the present invention, the present invention provides a pharmaceutical composition comprising the 4(1H-pyrazol-3-yl)piperidinyl derivative, stereoisomer, tautomer, geometric isomer or pharmaceutically acceptable salt thereof as described in the first aspect of the present invention;

[0031] Preferably, the pharmaceutical composition is a tablet, capsule or injection.

[0032] The pharmaceutically acceptable salts of the compounds refer to the salts formed by the compounds of the present invention with acids or bases that can be used as drugs, including organic salts and inorganic salts. Exemplary acid addition salts, the acids that can form salts include but are not limited to: hydrochloric acid, sulfuric acid, hydrobromic acid, nitric acid, phosphoric acid, hydrofluoric acid, acetic acid, formic acid, propionic acid, pivalic acid, salicylic acid, lactic acid, maleic acid, methanesulfonic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, picric acid, benzenesulfonic acid, caproic acid, persulfuric acid, nicotinic acid, boric acid, ascorbic acid, amino acids (such as aspartic acid, glutamic acid, etc.), dodecyl sulfuric acid, etc.

[0033] Exemplary base addition salts, the bases that can form salts include but are not limited to salts formed based on cations of alkali metals and alkaline earth metals, such as inorganic bases like sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, sodium phosphate, etc., organic bases like ammonia water, diethylamine, triethylamine, ethanolamine, piperazine, diethanolamine, piperidine, pyridine, etc., and salts formed with amino acids (such as arginine, lysine, etc.).

[0034] In the present invention, all compounds appearing are intended to include all possible optical isomers, such as compounds with a single chirality, or mixtures of various different chiral compounds (i.e., racemates). Among all the compounds of the present invention, each chiral carbon atom can optionally be in the R configuration or S configuration, or a mixture of the two configurations.

[0035] In a fourth aspect of the present invention, the present invention provides the use of the 4(1H-pyrazol-3-yl)piperidinyl derivative, stereoisomer, tautomer, geometric isomer or pharmaceutically acceptable salt thereof as described in the first aspect of the present invention and / or the 4(1H-pyrazol-3-yl)piperidinyl derivative prepared by the preparation method of the 4(1H-pyrazol-3-yl)piperidinyl derivative as described in the second aspect of the present invention and / or the pharmaceutical composition as described in the third aspect of the present invention in the preparation of MNK1 and / or MNK2 inhibitors.

[0036] In the fifth aspect of the present invention, there is provided an application of a 4(1H-pyrazol-3-yl)piperidinyl derivative, stereoisomer, tautomer, geometric isomer or pharmaceutically acceptable salt thereof as described in the first aspect of the present invention and / or a 4(1H-pyrazol-3-yl)piperidinyl derivative prepared by the preparation method of the 4(1H-pyrazol-3-yl)piperidinyl derivative as described in the second aspect of the present invention and / or the pharmaceutical composition as described in the third aspect of the present invention in the preparation of anti-tumor drugs.

[0037] Preferably, the anti-tumor drug is a drug for preventing or treating tumors related to the activity of MNK1 and / or MNK2.

[0038] Preferably, the tumors are human non-small cell lung cancer, colon cancer, prostate cancer, acute myeloid leukemia, lymphoma and breast cancer.

[0039] In the sixth aspect of the present invention, there is provided an application of a 4(1H-pyrazol-3-yl)piperidinyl derivative, stereoisomer, tautomer, geometric isomer or pharmaceutically acceptable salt thereof as described in the first aspect of the present invention and / or a 4(1H-pyrazol-3-yl)piperidinyl derivative prepared by the preparation method of the 4(1H-pyrazol-3-yl)piperidinyl derivative as described in the second aspect of the present invention and / or the pharmaceutical composition as described in the third aspect of the present invention in the preparation of anti-inflammatory drugs.

[0040] Preferably, the anti-inflammatory drug is a drug for preventing or treating inflammation related to the activity of MNK1 and / or MNK2.

[0041] Preferably, the inflammation is acute pneumonia, acute pancreatitis or rheumatoid arthritis.

[0042] The beneficial effects of the present invention are as follows:

[0043] 1. The present invention provides a 4(1H-pyrazol-3-yl)piperidinyl derivative, which has MNK1 and / or MNK2 inhibitory activity and has anti-cancer and anti-inflammatory activities;

[0044] 2. The present invention provides a preparation method of the above 4(1H-pyrazol-3-yl)piperidinyl derivative, which is simple to prepare and has low cost;

[0045] 3. The present invention provides an application of the above 4(1H-pyrazol-3-yl)piperidinyl derivative, stereoisomer, tautomer, geometric isomer or pharmaceutically acceptable salt thereof in the preparation of MNK1 and / or MNK2 inhibitors and in the preparation of anti-inflammatory and anti-cancer drugs. Detailed embodiments

[0046] The present invention will be further described below in conjunction with specific embodiments. However, the following embodiments are only used to illustrate the present invention and should not be construed as limiting the scope of the present invention. For those conditions not specified in the following embodiments, they are carried out according to conventional conditions or the conditions recommended by the manufacturer. The methods used, unless otherwise specified, are all conventional methods well-known in the art. The consumables and reagents used, unless otherwise specified, are all commercially available. Unless otherwise stated, the professional and scientific terms used herein have the same meaning as those familiar to skilled persons in the art. In addition, any method or material similar or equivalent to the described content can also be applied to the present invention.

[0047] The present invention provides a 4(1H-pyrazol-3-yl)piperidinyl derivative, and the structural formula of the 4(1H-pyrazol-3-yl)piperidinyl derivative is shown in Formula I,

[0048]

[0049] wherein, R 1 is an aromatic ring or a substituted aromatic ring. The aromatic ring is a monocyclic or polycyclic aryl or heterocyclic group having 6 to 12 carbon atoms. The heterocyclic group is a 5- to 6-membered heterocyclic group. The 5- to 6-membered heterocyclic group means that the heterocyclic group has ring carbon atoms and 1 to 4 ring heteroatoms. Each ring heteroatom is independently selected from nitrogen, oxygen, and sulfur; the substituted aromatic ring has substituents on the aromatic ring, and the substituents are selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkylamino, C1-C6 alkoxy, 5- to 6-membered heterocyclic ring, halogen, hydroxyl, cyano, nitro, amino, and a 5- to 6-membered heterocyclic group substituted by a carbonyl group and containing 1 to 2 nitrogen atoms;

[0050] R 2 is H or C1-C6 alkyl.

[0051] Specifically, the 4(1H-pyrazol-3-yl)piperidinyl derivatives provided by the present invention are shown in Table 1 below.

[0052] Table 1

[0053]

[0054]

[0055]

[0056] The synthesis method of the general formula (I) is as follows:

[0057]

[0058] Using commercially available 3-quinuclidinone hydrochloride (Compound of Formula III) as a raw material, reacting with an inorganic base and an aromatic aldehyde under reflux in an alcohol solution to obtain a product (Compound II), then cyclizing under the condition of hydrazine hydrate to obtain the target compound I (A), and finally reacting with R 2 CHO by a substitution reaction to obtain the target compound I (B), where R 1 、R 2 Refer to the above description.

[0059] The following Examples 1-42 are respectively the preparations of the above 4(1H-pyrazol-3-yl)piperidinyl derivatives.

[0060] Example 1: 4-(3-(Piperidin-4-yl)-1H-pyrazol-5-yl)pyridine (1)

[0061] Take 200 mg of 3-quinuclidinone hydrochloride, 50 mg of NaOH, 133 mg of 4-formylpyridine and mix them evenly in 10 mL of anhydrous ethanol, and heat under reflux for 6 h. After the reaction is completed, distill off the ethanol, wash with water, extract with EA, dry over anhydrous magnesium sulfate and then evaporate the solvent to obtain 220 mg of a yellow solid (A1). React A1 (200 mg) in 3 mL of 20% hydrazine hydrate aqueous solution under reflux for 6 h, then cool to room temperature, and a solid precipitates. Filter by suction and wash with water to obtain Product 1, which is 4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)pyridine, with a yield of 49%. 1 H NMR (600 MHz, DMSO-d 6 ) δ 12.95 (s, 1H), 8.57 - 8.54 (m, 2H), 7.74 - 7.72 (m, 2H), 6.66 (s, 1H), 2.99 (dt, J = 12.3, 3.3 Hz, 2H), 2.73 (tt, J = 11.8, 3.8 Hz, 1H), 2.56 (td, J = 12.0, 2.4 Hz, 2H), 1.88 - 1.82 (m, 2H), 1.51 (qd, J = 12.2, 3.9 Hz, 2H). 13 C NMR (150 MHz, DMSO-d 6 ) δ 151.19, 150.50, 147.23, 140.97, 119.84, 100.27, 46.48, 34.35, 33.19. HRMScalculated for (M + H) + 229.1453, found 229.1485.

[0062] Example 2: 4-(5-Phenyl-1H-pyrazol-3-yl)piperidine (2)

[0063] Using 500 mg of 3-quinuclidinone hydrochloride, 120 mg of NaOH, and 328 mg of benzaldehyde as raw materials, the preparation method is the same as that of Compound 1, with a yield of 75%. 1 H NMR(500MHz,DMSO-d 6 )δ12.62(s,1H),7.74(d,J=7.5Hz,2H),7.37(t,J=7.6Hz,2H),7.26(t,J=7.3Hz,1H),6.45(s,1H),3.01-2.93(m,2H),2.68(ddd,J=11.7,8.3,3.7Hz,1H),2.55(td,J=12.0,2.2Hz,2H),2.00(dd,J=14.9,7.2Hz,1H),1.83(d,J=10.6Hz,2H),1.50(qd,J=12.2,3.8Hz,2H). 13 C NMR(125MHz,DMSO-d 6 )δ129.0,127.6,125.4,99.1,46.56,33.32.HRMS calculated for(M+H) + 228.1495,found 228.1492.

[0064] Example 3: 4-(5-(3-Fluorophenyl)-1H-pyrazol-3-yl)piperidine (3)

[0065] Using 300 mg of 3-quinuclidinone hydrochloride, 74 mg of NaOH, and 330.3 mg of 3-fluorobenzaldehyde as raw materials, the preparation method is the same as that of Compound 1, with a yield of 54%. 1 H NMR(500MHz,DMSO-d 6 )δ12.73(s,1H),7.60(d,J=7.7Hz,1H),7.54(d,J=10.4Hz,1H),7.41(dd,J=14.3,7.8Hz,1H),7.08(dd,J=11.8,5.2Hz,1H),6.53(s,1H),2.99(d,J=12.1Hz,2H),2.73-2.65(m,1H),2.56(t,J=11.3Hz,2H),1.83(d,J=11.6Hz,2H),1.50(qd,J=12.3,3.6Hz,2H). 13 C NMR(125MHz,DMSO-d 6)δ163.9,162.0,131.0(d,J = 8.6Hz),121.4(d,J = 2.3Hz),114.2(d,J = 21.1Hz),111.8(d,J = 22.5Hz),99.6,46.4,34.4,33.0.HRMS calculated for(M+H) + 246.1401,found 246.1404.

[0066] Example 4: 4-(5-(4-Fluorophenyl)-1H-pyrazol-3-yl)piperidine (4)

[0067] Using 200 mg of 3-quinuclidinone hydrochloride, 50 mg of NaOH, and 154 mg of 4-fluorobenzaldehyde as starting materials, the preparation method was the same as that of Compound 1, with a yield of 65%. 1 H NMR(400MHz,DMSO-d 6 )δ12.58(s,1H),7.83 - 7.76(m,2H),7.22(t,J = 8.9Hz,2H),6.46(d,J = 4.0Hz,1H),2.99(d,J = 12.1Hz,2H),2.70(ddd,J = 11.7,8.2,3.8Hz,1H),2.61 - 2.52(m,2H),1.84(d,J = 12.5Hz,2H),1.51(qd,J = 12.3,3.8Hz,2H). 13 CNMR(100MHz,DMSO-d 6 )δ163.2,160.7,127.3(d,J = 8.0Hz),116.0,115.8,99.0,46.5,33.2,31.8.HRMS calculated for(M+H) + 246.1401,found 246.1405.

[0068] Example 5: 4-(3-(Piperidin-4-yl)-1H-pyrazol-5-yl)benzonitrile (5)

[0069] Using 300 mg of 3-quinuclidinone hydrochloride, 74.2 mg of NaOH, and 242.6 mg of 4-cyanobenzaldehyde as starting materials, the preparation method was the same as that of Compound 1, with a yield of 52%. 1 H NMR(400MHz,DMSO-d 6) δ 12.92 (s, 1H), 7.96 (d, J = 8.4 Hz, 2H), 7.84 (d, J = 8.4 Hz, 2H), 6.64 (s, 1H), 2.99 (d, J = 12.1 Hz, 2H), 2.72 (ddd, J = 15.4, 7.8, 3.7 Hz, 1H), 2.61 - 2.52 (m, 2H), 2.02 (dd, J = 53.6, 45.8 Hz, 1H), 1.84 (d, J = 10.6 Hz, 2H), 1.51 (qd, J = 12.2, 3.8 Hz, 2H). 13 C NMR (100 MHz, DMSO - d 6 ) δ 133.1, 125.9, 119.5, 109.8, 100.3, 46.5, 34.3, 33.2. HRMS calculated for (M + H) + 253.1448, found 253.1448.

[0070] Example 6: 4-(5-(4-Nitrophenyl)-1H-pyrazol-3-yl)piperidine (6)

[0071] Using 300 mg of 3 - quinuclidinone hydrochloride, 74.2 mg of NaOH, and 279.5 mg of 4 - nitrobenzaldehyde as raw materials, the preparation method is the same as that of Compound 1, with a yield of 52%. 1 H NMR (400 MHz, DMSO - d 6 ) δ 13.01 (s, 1H), 8.25 (d, J = 8.9 Hz, 2H), 8.04 (d, J = 8.9 Hz, 2H), 6.69 (s, 1H), 3.00 (d, J = 12.1 Hz, 2H), 2.73 (tt, J = 11.6, 3.5 Hz, 1H), 2.57 (td, J = 11.9, 1.9 Hz, 2H), 2.03 (dd, J = 22.9, 15.5 Hz, 1H), 1.86 (d, J = 10.7 Hz, 2H), 1.51 (qd, J = 12.3, 3.8 Hz, 2H). 13 C NMR (100 MHz, DMSO - d 6 ) δ 151.4, 147.8, 146.6, 140.6, 126.1, 124.6, 100.6, 46.5, 34.3, 33.1. HRMS calculated for (M + H) + 273.1346, found 273.1349.

[0072] Example 7: 4-(5-(4-(Trifluoromethyl)phenyl)-1H-pyrazol-3-yl)piperidine (7)

[0073] Using 400 mg of 3-quinuclidinone hydrochloride, 98.8 mg of NaOH, and 434 mg of p-trifluoromethylbenzaldehyde as raw materials, the preparation method was the same as that of Compound 1, with a yield of 86.2%. 1 H NMR (600 MHz, DMSO-d6) δ 12.82 (s, 1H), 7.99 (d, J = 7.9 Hz, 2H), 7.74 (d, J = 8.0 Hz, 2H), 6.61 (s, 1H), 3.01 (d, J = 11.9 Hz, 2H), 2.73 (d, J = 14.6 Hz, 1H), 2.58 (t, J = 11.8 Hz, 3H), 1.86 (d, J = 12.6 Hz, 2H), 1.52 (qd, J = 12.2, 3.8 Hz, 2H). 13C NMR (151 MHz, DMSO-d6) δ 156.99, 155.29, 151.08, 146.43, 146.40, 141.89, 139.34, 139.18, 128.54, 128.48, 121.53, 103.23, 103.17, 46.45, 34.18, 33.13. HRMS calculated for (M+H) + 296.1374, found 296.1420.

[0074] Example 8: 1-Methyl-4-(4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)phenyl)piperazine (8)

[0075] Using 184 mg of 3-quinuclidinone hydrochloride, 45.6 mg of NaOH, and 233 mg of 4-(N-methylpiperazine)benzaldehyde as raw materials, the preparation method was the same as that of Compound 1, with a yield of 65%. 1 H NMR (500 MHz, DMSO-d 6 ) δ 7.56 (d, J = 8.6 Hz, 2H), 6.93 (d, J = 8.5 Hz, 2H), 6.30 (s, 1H), 3.30 (s, 4H), 2.98 (d, J = 9.1 Hz, 2H), 2.65 (s, 1H), 2.55 (s, 2H), 2.46 - 2.41 (m, 4H), 2.21 (s, 3H), 1.82 (d, J = 11.9 Hz, 2H), 1.49 (qd, J = 12.3, 3.7 Hz, 2H). 13 C NMR (125 MHz, DMSO-d 6 ) δ 150.6, 126.2, 115.6, 98.2, 55.0, 48.3, 46.5, 46.2, 33.3. HRMS calculated for (M+H) +326.2339, found 326.2335. HRMS calculated for (M+H) + 326.2339, found 326.2335.

[0076] Example 9: 4-(5-(3,5-Difluorophenyl)-1H-pyrazol-3-yl)piperidine (9)

[0077] Using 200 mg of 3-quinuclidinone hydrochloride, 49.2 mg of NaOH, and 174.8 mg of 3,5-difluorobenzaldehyde as starting materials, the preparation method is the same as that of Compound 1, with a yield of 35%. 1 H NMR (600 MHz, DMSO-d 6 ) δ 12.84 (s, 1H), 7.49 - 7.44 (m, 2H), 7.11 (tt, J = 9.3, 2.5 Hz, 1H), 6.62 (s, 1H), 2.99 (d, J = 12.0 Hz, 2H), 2.71 (tt, J = 11.9, 3.8 Hz, 1H), 2.60 - 2.53 (m, 2H), 1.84 (dd, J = 12.4, 3.1 Hz, 2H), 1.50 (qd, J = 12.2, 3.9 Hz, 2H). 13 C NMR (150 MHz, DMSO-d 6 ) δ 164.10, 164.01, 162.48, 162.39, 108.28, 108.25, 108.14, 108.11, 102.87, 102.69, 102.52, 100.05, 46.41, 34.30, 33.11. HRMS calculated for (M+H) + 254.1312, found 264.1354.

[0078] Example 10: 4-(5-(3,4-Difluorophenyl)-1H-pyrazol-3-yl)piperidine (10)

[0079] Using 200 mg of 3-quinuclidinone hydrochloride, 49.2 mg of NaOH, and 174.8 mg of 3,4-difluorobenzaldehyde as starting materials, the preparation method is the same as that of Compound 1, with a yield of 55%. 11H NMR (600 MHz, DMSO-d6) δ 13.01 (s, 1H), 7.80 (ddd, J = 12.1, 7.8, 2.1 Hz, 1H), 7.63 (ddd, J = 9.5, 4.7, 2.2 Hz, 1H), 7.48 (dt, J = 10.6, 8.6 Hz, 1H), 6.62 (s, 1H), 3.35 (dt, J = 12.5, 3.2 Hz, 2H), 3.08 - 2.95 (m, 3H), 2.12 (dd, J = 14.2, 3.6 Hz, 2H), 1.82 - 1.74 (m, 2H). 13 13C NMR (150 MHz, DMSO-d 6 ) δ 158.92, 158.71, 158.49, 158.27, 151.02, 150.93, 150.11, 150.03, 149.40, 149.31, 148.48, 148.40, 122.20, 122.18, 122.16, 122.14, 118.42, 118.30, 116.20, 114.38, 114.26, 100.10, 43.32, 31.43, 28.45. HRMS calculated for (M + H) + 264.1312, found 264.1354.

[0080] Example 11: 4-(5-(3,4,5-Trifluorophenyl)-1H-pyrazol-3-yl)piperidine (11)

[0081] Using 400 mg of 3-quinuclidinone hydrochloride, 108.7 mg of NaOH, and 395.2 mg of 3,4,5-trifluorobenzaldehyde as starting materials, the preparation method was the same as that of Compound 1, with a yield of 63%. 1 1H NMR (600 MHz, DMSO-d 6 ) δ 12.83 (s, 1H), 7.70 - 7.63 (m, 2H), 6.61 (s, 1H), 2.99 (dt, J = 12.3, 3.4 Hz, 2H), 2.70 (ddt, J = 11.8, 7.7, 3.8 Hz, 1H), 2.56 (td, J = 12.0, 2.5 Hz, 2H), 1.83 (dd, J = 13.4, 3.6 Hz, 2H), 1.49 (qd, J = 12.2, 3.9 Hz, 2H). 13 13C NMR (150 MHz, DMSO-d 6)δ151.90,151.85,150.26,150.19,139.11,139.00,137.46,131.21(d,J = 17.7Hz),109.65,109.62,109.53,109.51,99.89,46.43,34.25,33.15.HRMScalculated for(M+H) + 282.1218,found 282.1260.

[0082] Example 12: 4-(5-(2,4-Difluorophenyl)-1H-pyrazol-3-yl)piperidine (12)

[0083] Using 200 mg of 3-quinuclidinone hydrochloride, 49.2 mg of NaOH, and 174.8 mg of 2,4-difluorobenzaldehyde as starting materials, the preparation method was the same as that of Compound 1, with a yield of 55%. 1 H NMR(600MHz,DMSO-d 6 )δ12.83(s,1H),7.94(q,J = 8.2Hz,1H),7.30(ddd,J = 11.6,9.3,2.6Hz,1H),7.14(td,J = 8.4,2.6Hz,1H),6.37(d,J = 3.7Hz,1H),3.00(d,J = 12.0Hz,2H),2.78 - 2.70(m,1H),2.58(t,J = 12.0Hz,2H),1.85(dd,J = 12.9,3.7Hz,2H),1.52(qd,J = 12.2,4.0Hz,2H). 13 C NMR(150MHz,DMSO-d 6 )δ162.65,162.57,161.02,160.93,160.33,158.66,158.58,129.64,129.60,129.57,129.54,112.42,112.39,112.28,112.25,105.08,104.90,104.73,101.75,46.34,34.22,33.00.HRMScalculated for(M+H) + 264.1307,found 264.1308.

[0084] Example 13: 3-(3-(Piperidin-4-yl)-1H-pyrazol-5-yl)pyridine (13)

[0085] Using 200 mg of 3-quinuclidinone hydrochloride, 49.2 mg of NaOH, and 131.7 mg of 3-pyridinecarboxaldehyde as raw materials, the preparation method was the same as that of Compound 1, with a yield of 67%. 1 H NMR(600MHz,DMSO-d 6 )δ12.81(s,1H),8.99(d,J=2.2Hz,1H),8.48(dd,J=4.8,1.7Hz,1H),8.12(dt,J=7.9,2.0Hz,1H),7.41(dd,J=7.9,4.7Hz,1H),6.59(s,1H),2.99(dt,J=12.2,3.3Hz,2H),2.72(tt,J=11.8,3.8Hz,1H),2.57(td,J=12.0,2.4Hz,2H),1.87-1.81(m,2H),1.52(qd,J=12.2,3.9Hz,2H). 13 C NMR(150MHz,DMSO-d 6 )δ148.65,146.76,132.53,124.20,99.51,46.50,34.42,33.23.HRMS calculated for(M+H) + 229.1453,found229.1485.

[0086] Example 14: 5-(3-(Piperidin-4-yl)-1H-pyrazol-5-yl)pyrimidine (14)

[0087] Using 200 mg of 3-quinuclidinone hydrochloride, 49.2 mg of NaOH, and 133 mg of 5-pyrimidinecarboxaldehyde as raw materials, the preparation method was the same as that of Compound 1, with a yield of 47%. 1 H NMR(600MHz,DMSO-d 6 )δ12.98(s,1H),9.16(s,2H),9.10(s,1H),6.70(s,1H),3.00(dt,J=12.3,3.3Hz,2H),2.74(tt,J=11.8,3.8Hz,1H),2.57(td,J=12.1,2.5Hz,2H),1.88-1.82(m,2H),1.51(qd,J=12.2,3.9Hz,2H). 13 C NMR(150MHz,DMSO-d 6 )δ157.46,153.48,127.91,99.94,46.44,34.23,33.17.HRMS calculated for(M+H) +230.1405, found 230.1406.

[0088] Example 15: 2-(3-(Piperidin-4-yl)-1H-pyrazol-5-yl)pyrazine (15)

[0089] Using 400 mg of 3-quinuclidinone hydrochloride, 98.9 mg of NaOH, and 267 mg of pyrazine-2-carbaldehyde as starting materials, the preparation method is the same as that of Compound 1, with a yield of 37%. 1 H NMR(600MHz, DMSO-d 6 ) δ 13.05(s, 1H), 9.14(d, J = 1.5Hz, 1H), 8.61(t, J = 1.9Hz, 1H), 8.52(d, J = 2.6Hz, 1H), 6.67(s, 1H), 2.99(dt, J = 12.3, 3.3Hz, 2H), 2.75(tt, J = 11.9, 3.9Hz, 1H), 2.57(td, J = 12.0, 2.5Hz, 2H), 1.89 - 1.82(m, 2H), 1.52(qd, J = 12.2, 3.9Hz, 2H). 13 C NMR(150MHz, DMSO-d 6 ) δ 147.97, 144.54, 143.40, 141.57, 101.03, 46.48, 34.35, 33.17. HRMS calculated for (M + H) + 230.1405, found 230.1394.

[0090] Example 16: 4-(3-(Piperidin-4-yl)-1H-pyrazol-5-yl)pyrimidine (16)

[0091] Using 200 mg of 3-quinuclidinone hydrochloride, 49.2 mg of NaOH, and 133 mg of pyrimidine-4-carbaldehyde as starting materials, the preparation method is the same as that of Compound 1, with a yield of 32%. 1 H NMR(600MHz, DMSO-d 6 ) δ 9.17(d, J = 1.4Hz, 1H), 8.81(d, J = 5.3Hz, 1H), 7.93(dd, J = 5.3, 1.4Hz, 1H), 6.84(s, 1H), 3.36(dt, J = 12.7, 3.2Hz, 2H), 3.10 - 3.01(m, 3H), 2.15(dd, J = 14.3, 3.7Hz, 2H), 1.85 - 1.76(m, 2H). 13 C NMR(150MHz, DMSO-d 6)δ163.96,163.89,162.84,122.35,121.33,120.41,107.06,48.08,36.12,33.15.HRMScalculated for(M+H) + 230.1405,found 230.1392.

[0092] Example 17: 4-(5-(Thiophen-3-yl)-1H-pyrazol-3-yl)piperidine (17)

[0093] Using 200 mg of 3-quinuclidinone hydrochloride, 49.2 mg of NaOH, and 137 mg of 3-thiophenecarboxaldehyde as starting materials, the preparation method is the same as that of Compound 1, with a yield of 45%. 1 H NMR(600MHz,DMSO-d 6 )δ12.50(s,1H),7.70(s,1H),7.56(t,J = 3.8Hz,1H),7.45(dd,J = 5.0,1.2Hz,1H),6.35(s,1H),2.99(dt,J = 12.2,3.4Hz,2H),2.71 - 2.65(m,1H),2.56(td,J = 12.0,2.5Hz,2H),1.85 - 1.80(m,2H),1.49(qd,J = 12.2,3.9Hz,2H). 13 CNMR(150MHz,DMSO-d 6 )δ126.96,126.29,120.34,99.45,46.55,34.05,33.35.HRMScalculated for(M+H) + 234.1065,found 234.1055.

[0094] Example 18: 5-(3-(Piperidin-4-yl)-1H-pyrazol-5-yl)thiazole (18)

[0095] Using 200 mg of 3-quinuclidinone hydrochloride, 49.2 mg of NaOH, and 138.1 mg of 5-thiophenecarboxaldehyde as starting materials, the preparation method is the same as that of Compound 1, with a yield of 72%. 1 H NMR(600MHz,DMSO-d 6) δ 12.82 (s, 1H), 8.98 (s, 1H), 8.17 (s, 1H), 6.48 (s, 1H), 3.09 (dt, J = 12.5, 3.4 Hz, 2H), 2.80 (tt, J = 11.7, 3.8 Hz, 1H), 2.70 (td, J = 12.2, 2.6 Hz, 2H), 1.95 - 1.89 (m, 2H), 1.57 (qd, J = 12.3, 3.9 Hz, 2H). 13 C NMR (150 MHz, DMSO - d 6 ) δ 158.39, 153.00, 150.17, 139.67, 132.54, 99.85, 45.48, 33.18, 31.69. HRMS calculated for (M + H) + 235.1018, found 235.1019.

[0096] Example 19: 2 - Methyl - 4-(3-(piperidin - 4 - yl)-1H - pyrazol - 5 - yl)pyridine (19)

[0097] Using 400 mg of 3 - quinuclidinone hydrochloride, 108.7 mg of NaOH, and 300 mg of 3 - methyl - 4 - pyridinecarboxaldehyde as starting materials, the preparation method was the same as that of Compound 1, with a yield of 76%. 1 H NMR (600 MHz, DMSO - d 6 ) δ 12.91 (s, 1H), 8.42 (d, J = 5.2 Hz, 1H), 7.61 (d, J = 1.6 Hz, 1H), 7.52 (dd, J = 5.2, 1.6 Hz, 1H), 6.63 (s, 1H), 2.99 (dt, J = 12.3, 3.3 Hz, 2H), 2.72 (tt, J = 11.8, 3.9 Hz, 1H), 2.56 (td, J = 12.0, 2.4 Hz, 2H), 2.49 (s, 3H), 1.87 - 1.81 (m, 2H), 1.50 (qd, J = 12.2, 3.9 Hz, 2H). 13 C NMR (150 MHz, DMSO - d 6 ) δ 158.70, 149.78, 119.02, 117.11, 100.20, 46.48, 34.36, 33.19, 24.58. HRMS calculated for (M + H) + 243.1609, found 243.1598.

[0098] Example 20: 2,6 - Dimethyl - 4-(3-(piperidin - 4 - yl)-1H - pyrazol - 5 - yl)pyridine (20)

[0099] Using 200 mg of 3-quinuclidinone hydrochloride, 49.2 mg of NaOH, and 166.2 mg of 2,6-dimethyl-4-pyridinecarboxaldehyde as raw materials, the preparation method was the same as that of Compound 1, with a yield of 64%. 1 H NMR(600MHz,DMSO-d 6 )δ12.87(s,1H),7.40(s,2H),6.59(s,1H),2.99(dt,J=12.2,3.3Hz,2H),2.71(tt,J=11.8,3.8Hz,1H),2.56(td,J=12.0,2.4Hz,2H),2.44(s,6H),1.87-1.82(m,2H),1.54-1.46(m,2H). 13 C NMR(150MHz,DMSO-d 6 )δ162.67,156.28,152.49,146.27,121.00,104.90,51.23,39.13,37.95,29.26.HRMS calculated for(M+H) + 257.1766,found 257.1751.

[0100] Example 21: 3-Fluoro-4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)pyridine (21)

[0101] Using 200 mg of 3-quinuclidinone hydrochloride, 49.2 mg of NaOH, and 153.7 mg of 3-fluoropyridine-4-carboxaldehyde as raw materials, the preparation method was the same as that of Compound 1, with a yield of 37%. 1 H NMR(600MHz,DMSO-d 6 )δ13.16(s,1H),8.60(d,J=2.8Hz,1H),8.42(dd,J=5.1,1.1Hz,1H),7.92(dd,J=6.7,5.0Hz,1H),6.55(d,J=3.7Hz,1H),2.99(dt,J=12.2,3.3Hz,2H),2.76(tt,J=11.8,3.8Hz,1H),2.56(td,J=12.1,2.5Hz,2H),1.88-1.82(m,2H),1.51(qd,J=12.2,3.9Hz,2H). 13 C NMR(150MHz,DMSO-d 6)δ157.00,155.30,151.10,146.43,146.40,141.91,139.34,139.18,128.54,128.48,121.53,103.23,103.17,46.45,34.18,33.13.HRMS calculated for(M+H) + 247.1359,found 247.1346

[0102] Example 22: 2-Fluoro-4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)pyridine (22)

[0103] Using 200 mg of 3-quinuclidinone hydrochloride, 49.2 mg of NaOH, and 153.7 mg of 2-fluoropyridine-4-carbaldehyde as starting materials, the preparation method was the same as that of Compound 1, with a yield of 41%. 1 H NMR(600MHz,DMSO-d 6 )δ13.41(s,1H),8.24(d,J = 5.3Hz,1H),7.75(d,J = 5.1Hz,1H),7.52(s,1H),6.83(s,1H),3.29 - 3.25(m,3H),3.04 - 2.94(m,3H),2.12(dd,J = 14.1,3.7Hz,2H),1.86(qd,J = 12.3,3.9Hz,2H). 13 C NMR(150MHz,DMSO-d 6 )δ156.99,155.29,151.08,146.43,146.40,141.89,139.34,139.18,128.54,128.48,121.53,103.23,103.17,46.45,34.18,33.13.HRMS calculated for(M+H) + 247.1359,found247.1344

[0104] Example 23: 2-Chloro-4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)pyridine (23)

[0105] Using 200 mg of 3-quinuclidinone hydrochloride, 49.2 mg of NaOH, and 172.8 mg of 2-chloropyridine-4-carbaldehyde as starting materials, the preparation method was the same as that of Compound 1, with a yield of 84%. 1 H NMR(600MHz,DMSO-d 6) δ 13.23 (s, 1H), 8.41 (d, J = 5.2 Hz, 1H), 7.86 (s, 1H), 7.79 (d, J = 5.2 Hz, 1H), 6.87 (s, 1H), 3.05 (td, J = 12.6, 6.5 Hz, 3H), 2.14 (dd, J = 14.5, 3.8 Hz, 2H), 1.84 - 1.74 (m, 2H). 13 C NMR (150 MHz, DMSO - d 6 ) δ 151.52, 150.74, 150.30, 146.28, 144.80, 119.70, 119.19, 100.97, 46.39, 34.19, 33.07. HRMS calculated for (M + H) + 263.1063, found 263.1087.

[0106] Example 24: 3 - Chloro - 4-(3-(piperidin - 4 - yl)-1H - pyrazol - 5 - yl)pyridine (24)

[0107] Using 200 mg of 3 - quinuclidinone hydrochloride, 49.2 mg of NaOH, and 172.8 mg of 3 - chloro - 4 - pyridinecarboxaldehyde as starting materials, the preparation method was the same as that of Compound 1, with a yield of 84%. 1 H NMR (600 MHz, DMSO - d 6 ) δ 13.16 (s, 1H), 8.66 (s, 1H), 8.50 (d, J = 5.1 Hz, 1H), 7.86 (d, J = 5.1 Hz, 1H), 6.73 (s, 1H), 2.99 (dt, J = 12.4, 3.3 Hz, 2H), 2.77 (tt, J = 11.8, 3.8 Hz, 1H), 2.57 (td, J = 12.1, 2.4 Hz, 2H), 1.87 - 1.83 (m, 2H), 1.49 (qd, J = 12.2, 3.9 Hz, 2H). 13 C NMR (150 MHz, DMSO - d 6 ) δ 150.74, 150.46, 148.36, 144.84, 139.37, 128.30, 123.60, 103.35, 46.45, 34.18, 33.14. HRMS calculated for (M + H) + 263.1063, found 263.1089.

[0108] Example 25: 2,6 - Dichloro - 4-(3-(piperidin - 4 - yl)-1H - pyrazol - 5 - yl)pyridine (25)

[0109] Using 200 mg of 3-quinuclidinone hydrochloride, 49.2 mg of NaOH, and 216.5 mg of 2,6-dichloro-4-pyridinecarboxaldehyde as raw materials, the preparation method was the same as that of Compound 1, with a yield of 44%. 1 H NMR(600MHz,DMSO-d 6 )δ13.18(s,1H),7.88(d,J=1.6Hz,2H),6.87(s,1H),3.00(dt,J=12.4,3.4Hz,2H),2.77-2.70(m,1H),2.57(td,J=12.0,2.4Hz,2H),1.87-1.81(m,2H),1.49(qd,J=12.1,3.9Hz,2H). 13 C NMR(150MHz,DMSO-d 6 )δ151.38,150.31,147.67,145.48,118.99,101.66,46.30,34.05,32.95.HRMScalculated for(M+H) + 297.0674,found 267.0707.

[0110] Example 26: 3,5-Dichloro-4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)pyridine (26)

[0111] Using 200 mg of 3-quinuclidinone hydrochloride, 49.2 mg of NaOH, and 216.5 mg of 3,5-dichloro-4-pyridinecarboxaldehyde as raw materials, the preparation method was the same as that of Compound 1, with a yield of 23%. 1 H NMR(600MHz,DMSO-d 6 )δ13.03(s,1H),8.71(s,2H),6.25(s,1H),2.99(dt,J=12.4,3.4Hz,2H),2.77(tt,J=12.1,3.8Hz,1H),2.60-2.53(m,2H),1.87(dd,J=13.1,3.6Hz,2H),1.51(qd,J=12.2,3.9Hz,2H). 13 C NMR(150MHz,DMSO-d 6 )δ148.28,140.59,132.18,103.29,46.44,34.17,33.15.HRMS calculated for(M+H) + 297.0674,found 267.0705.

[0112] Example 27: 2-Bromo-4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)pyridine (27)

[0113] Using 200 mg of 3-quinuclidinone hydrochloride, 49.2 mg of NaOH, and 216.5 mg of 3-bromo-4-pyridinecarboxaldehyde as starting materials, the preparation method is the same as that of Compound 1, with a yield of 87%. 1 H NMR (600 MHz, DMSO-d 6 ) δ 13.07 (s, 1H), 8.36 (d, J = 5.1 Hz, 1H), 7.96 (d, J = 1.4 Hz, 1H), 7.79 (dd, J = 5.2, 1.4 Hz, 1H), 6.76 (s, 1H), 2.99 (dt, J = 12.3, 3.4 Hz, 2H), 2.73 (tt, J = 11.8, 3.8 Hz, 1H), 2.56 (td, J = 12.1, 2.4 Hz, 2H), 1.87 - 1.81 (m, 2H), 1.50 (qd, J = 12.1, 3.9 Hz, 2H). 13 C NMR (150 MHz, DMSO-d 6 ) δ 151.39, 151.21, 146.10, 144.50, 142.65, 123.40, 119.49, 100.97, 46.41, 34.21, 33.10. HRMS calculated for (M+H) + 307.0558, found 307.0592.

[0114] Example 28: 4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)pyridin-2-ol (28)

[0115] Using 200 mg of 3-quinuclidinone hydrochloride, 49.2 mg of NaOH, and 227 mg of 3-hydroxy-4-pyridinecarboxaldehyde as starting materials, the preparation method is the same as that of Compound 1, with a yield of 33%. 1 H NMR (600 MHz, DMSO-d 6 ) δ 13.03 (s, 2H), 7.36 (d, J = 6.8 Hz, 1H), 6.66 (s, 1H), 6.63 (d, J = 6.7 Hz, 1H), 6.58 (s, 1H), 2.99 (dt, J = 12.3, 3.5 Hz, 2H), 2.71 (tt, J = 11.8, 3.8 Hz, 1H), 2.57 (td, J = 12.2, 2.4 Hz, 2H), 1.84 - 1.80 (m, 2H), 1.50 (qd, J = 12.2, 4.0 Hz, 2H). 13 C NMR (150 MHz, DMSO-d 6)δ164.79,147.67,113.98,105.81,100.46,46.36,34.30,33.04.HRMS calculated for(M+H) + 245.1402,found 245.1426.

[0116] Example 29: 2-Methoxy-4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)pyridine (29)

[0117] Using 200 mg of 3-quinuclidinone hydrochloride, 49.2 mg of NaOH, and 168 mg of 3-methoxy-4-pyridinecarboxaldehyde as starting materials, the preparation method was the same as that of Compound 1, with a yield of 86%. 1 H NMR(600MHz,DMSO-d 6 )δ12.92(s,1H),8.15(d,J=5.3Hz,1H),7.36(dd,J=5.4,1.4Hz,1H),7.13(d,J=1.4Hz,1H),6.65(s,1H),3.87(s,3H),3.00(d,J=12.0Hz,2H),2.73(td,J=11.5,5.7Hz,1H),2.57(t,J=11.9Hz,2H),1.87-1.80(m,2H),1.51(qd,J=12.2,3.9Hz,2H). 13 C NMR(150MHz,DMSO-d 6 )δ164.79,147.67,113.98,105.81,100.46,53.58,46.36,34.30,33.04.HRMS calculated for(M+H) + 259.1559,found259.1583.

[0118] Example 30: 4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)-2-(trifluoromethyl)pyridine (30)

[0119] Using 200 mg of 3-quinuclidinone hydrochloride, 49.2 mg of NaOH, and 215 mg of 3-(trifluoromethyl)-4-pyridinecarboxaldehyde as starting materials, the preparation method was the same as that of Compound 1, with a yield of 90%. 1 H NMR(600MHz,DMSO-d 6)δ13.13(s,1H),8.74(d,J=5.1Hz,1H),8.19 - 8.18(m,1H),8.05(dd,J=5.1,1.6Hz,1H),6.87(s,1H),3.00(dt,J=12.2,3.3Hz,2H),2.75(tt,J=11.8,3.8Hz,1H),2.57(td,J=12.1,2.5Hz,2H),1.88 - 1.81(m,2H),1.52(qd,J=12.2,3.9Hz,2H). 13 C NMR(150MHz,DMSO - d 6 )δ151.47,151.19,147.78,147.56,146.45,143.37,123.14,122.83,121.32,116.36,116.34,116.32,116.30,101.07,46.40,34.18,33.10.HRMS calculated for(M + H) + 297.1327,found 297.1325.

[0120] Example 31: 4-(3-(Piperidin - 4 - yl)-1H - pyrazol - 5 - yl)pyridin - 2 - amine(31)

[0121] Using 200 mg of 3 - quinuclidinone hydrochloride, 49.2 mg of NaOH, and 150 mg of 3 - amino - 4 - pyridinecarboxaldehyde as starting materials, the preparation method is the same as that of Compound 1, with a yield of 21%. 1 H NMR(600MHz,DMSO - d 6 )δ13.48(s,1H),8.17(s,2H),7.98(d,J=6.7Hz,1H),7.35(s,1H),7.25(dd,J=6.7,1.6Hz,1H),6.78(s,1H),3.36(dt,J=13.1,3.7Hz,2H),3.05(dq,J=11.8,4.0Hz,3H),2.17 - 2.10(m,2H),1.83 - 1.74(m,2H). 13 C NMR(150MHz,DMSO - d 6 )δ159.44,159.23,159.02,158.81,155.07,136.97,120.49,118.51,116.53,114.56,109.54,106.99,101.93,43.18,30.86,28.27.HRMS calculated for(M + H) +244.1562, found 244.1585.

[0122] Example 32: 4-(3-(Piperidin-4-yl)-1H-pyrazol-5-yl)pyridin-3-amine (32)

[0123] Using 200 mg of 3-quinuclidinone hydrochloride, 49.2 mg of NaOH, and 150 mg of 2-amino-4-pyridinecarboxaldehyde as starting materials, the preparation method is the same as that of Compound 1, with a yield of 36%. 1 H NMR(600MHz, DMSO-d 6 ) δ 13.48(s, 1H), 8.17(s, 2H), 7.98(d, J = 6.7Hz, 1H), 7.35(s, 1H), 7.25(dd, J = 6.7, 1.6Hz, 1H), 6.78(s, 1H), 3.36(dt, J = 13.1, 3.7Hz, 2H), 3.05(dq, J = 11.8, 4.0Hz, 3H), 2.17 - 2.10(m, 2H), 1.83 - 1.74(m, 2H). 13 C NMR(150MHz, DMSO-d 6 ) δ 159.44, 159.23, 159.02, 158.81, 155.07, 136.97, 120.49, 118.51, 116.53, 114.56, 109.54, 106.99, 101.93, 43.18, 30.86, 28.27. HRMS calculated for (M + H) + 244.1562, found 244.1585.

[0124] Example 33: 5-(3-(Piperidin-4-yl)-1H-pyrazol-5-yl)pyridin-2-amine (33)

[0125] Using 200 mg of 3-quinuclidinone hydrochloride, 49.2 mg of NaOH, and 150 mg of 2-amino-5-pyridinecarboxaldehyde as starting materials, the preparation method is the same as that of Compound 1, with a yield of 51%. 1 H NMR(600MHz, DMSO-d 6) δ 12.42 (s, 1H), 8.30 (d, J = 2.4 Hz, 1H), 7.74 - 7.68 (m, 1H), 6.46 (d, J = 8.6 Hz, 1H), 6.29 (s, 1H), 5.98 (s, 2H), 2.98 (dt, J = 12.4, 3.4 Hz, 2H), 2.70 - 2.62 (m, 1H), 2.55 (td, J = 12.1, 2.5 Hz, 2H), 1.81 (dd, J = 13.3, 3.6 Hz, 2H), 1.49 (qd, J = 12.2, 3.9 Hz, 2H). 13 C NMR (150 MHz, DMSO - d 6 ) δ 159.48, 145.12, 134.47, 108.17, 97.74, 46.58, 34.25, 33.36. HRMS calculated for (M + H) + 244.1562, found 244.1586.

[0126] Example 34: 5-(3-(Piperidin - 4 - yl)-1H - pyrazol - 5 - yl)pyrimidin - 2 - amine (34)

[0127] Using 200 mg of 3 - quinuclidinone hydrochloride, 49.2 mg of NaOH, and 151 mg of 2 - amino - 5 - pyrimidinecarbaldehyde as starting materials, the preparation method is the same as that of Compound 1, with a yield of 49%. 1 H NMR (600 MHz, DMSO - d 6 ) δ 12.57 (s, 1H), 8.59 (s, 2H), 6.70 (s, 2H), 6.39 (s, 1H), 2.98 (dt, J = 12.6, 3.4 Hz, 2H), 2.68 (ddt, J = 11.9, 8.2, 3.6 Hz, 1H), 2.55 (td, J = 12.0, 2.4 Hz, 2H), 1.84 - 1.79 (m, 2H), 1.49 (qd, J = 12.2, 3.9 Hz, 2H). 13 C NMR (150 MHz, DMSO - d 6 ) δ 163.25, 155.18, 97.98, 46.52, 34.51, 33.28. HRMS calculated for (M + H) + 245.1514, found 245.1538.

[0128] Example 35: 3-(3-(Piperidin - 4 - yl)-1H - pyrazol - 5 - yl)pyridin - 2 - amine (35)

[0129] Using 200 mg of 3-quinuclidinone hydrochloride, 49.2 mg of NaOH, and 150 mg of 2-amino-3-pyridinecarboxaldehyde as starting materials, the preparation method was the same as that of Compound 1, with a yield of 32%. 1 H NMR(600MHz,DMSO-d 6 )δ12.52(s,1H),7.70(d,J=3.0Hz,1H),7.56(t,J=3.9Hz,1H),7.46(d,J=5.0Hz,1H),6.35(s,1H),2.98(dt,J=12.2,3.4Hz,2H),2.68(tt,J=12.0,3.8Hz,1H),2.56(td,J=12.0,2.5Hz,2H),1.82(dd,J=13.1,3.5Hz,2H),1.49(qd,J=12.2,3.9Hz,2H). 13 C NMR(150MHz,DMSO-d 6 )δ126.95,126.29,120.33,99.45,46.55,34.61,33.36.HRMS calculated for(M+H) + 244.1562,found244.1586.

[0130] Example 36: 4-(3-(Piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridine (36)

[0131] Using 200 mg of 3-quinuclidinone hydrochloride, 49.2 mg of NaOH, and 179 mg of 7-azaindole-4-carboxaldehyde as starting materials, the preparation method was the same as that of Compound 1, with a yield of 55%. 1 H NMR(600MHz,DMSO-d 6 )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),6.70(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-d 6)δ150.00,143.03,126.40,116.25,112.54,101.37,101.19,46.53,34.38,33.21.HRMScalculated for(M+H) + 267.1585,found 267.1588.

[0132] Example 37: 1-Methyl-4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)-1H-pyrrolo[2,3-b]pyridine (37)

[0133] Using 200 mg of 3-quinuclidinone hydrochloride, 49.2 mg of NaOH, and 197 mg of 1-methyl-1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde as starting materials, the preparation method is the same as that of Compound 1, with a yield of 62%. 1 H NMR(600MHz,DMSO-d 6 )δ12.95(s,1H),8.26(d,J = 5.0Hz,1H),7.53(d,J = 3.4Hz,1H),7.44(d,J = 5.0Hz,1H),6.98(d,J = 3.5Hz,1H),6.71(s,1H),3.84(s,3H),3.02(dt,J = 12.5,3.4Hz,2H),2.77(tt,J = 11.8,3.9Hz,1H),2.59(td,J = 12.1,2.5Hz,2H),1.92 - 1.86(m,2H),1.57(qd,J = 12.2,3.9Hz,2H). 13 C NMR(150MHz,DMSO-d 6 )δ148.92,142.89,130.36,116.51,112.60,101.27,100.40,46.42,34.27,33.06,31.43.HRMS calculated for(M+H) + 282.1713,found 282.1716.

[0134] Example 38: N,N-Dimethyl-4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)pyridin-2-amine (38)

[0135] Using 200 mg of 3-quinuclidinone hydrochloride, 49.2 mg of NaOH, and 185 mg of 2-(dimethylamino)-4-pyridinecarbaldehyde as starting materials, the preparation method is the same as that of Compound 1, with a yield of 62%. 1 H NMR(600MHz,DMSO-d 6)δ12.80(s,1H),8.06(d,J=5.2Hz,1H),6.96(s,1H),6.94(s,1H),6.61(s,1H),3.06(s,6H),2.99(dt,J=12.2,3.3Hz,2H),2.71(tt,J=11.9,3.8Hz,1H),2.56(td,J=12.1,2.5Hz,2H),1.86-1.81(m,2H),1.51(qd,J=12.1,3.9Hz,2H). 13 C NMR(150MHz,DMSO-d 6 )δ158.39,153.00,139.67,132.54,99.85,45.48,40.51,33.18,31.69.HRMS calculated for(M+H) + 272.1876,found272.1878.

[0136] Example 39: N-Methyl-4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)pyridin-2-amine (39)

[0137] Using 200 mg of 3-quinuclidinone hydrochloride, 49.2 mg of NaOH, and 167 mg of 2-methylaminopyridine-4-carbaldehyde as starting materials, the preparation method was the same as that of Compound 1, with a yield of 62%. 1 H NMR(600MHz,DMSO-d 6 )δ12.91-12.64(m,1H),7.96(d,J=5.3Hz,1H),6.85(dd,J=5.3,1.4Hz,1H),6.79(s,1H),6.46(s,1H),6.40(q,J=4.7Hz,1H),2.99(dt,J=12.3,3.4Hz,2H),2.79(d,J=4.8Hz,3H),2.70(tq,J=13.1,5.3,4.5Hz,1H),2.56(td,J=12.0,2.5Hz,2H),1.86-1.79(m,2H),1.50(qd,J=12.2,3.9Hz,2H). 13 C NMR(150MHz,DMSO-d 6 )δ160.51,148.46,108.84,103.03,99.66,46.49,33.19,28.60.HRMS calculated for(M+H) + 258.1718,found 258.1712.

[0138] Example 40: N-Ethyl-4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)pyridin-2-amine (40)

[0139] Using 200 mg of 3-quinuclidinone hydrochloride, 49.2 mg of NaOH, and 185 mg of 2-ethylaminopyridine-4-carbaldehyde as starting materials, the preparation method was the same as that of Compound 1, with a yield of 62%. 1 H NMR(600MHz,DMSO-d 6 )δ13.44(s,1H),9.00 - 8.93(m,1H),8.76 - 8.66(m,1H),7.96(d,J = 6.6Hz,1H),7.33(s,1H),7.22(d,J = 6.6Hz,1H),6.82(s,1H),3.37(t,J = 11.2Hz,4H),3.09 - 3.00(m,3H),2.15(dd,J = 14.2,3.7Hz,2H),1.80(qd,J = 12.6,3.9Hz,2H),1.23(t,J = 7.2Hz,3H). 13 C NMR(150MHz,DMSO-d 6 )δ159.20,158.99,158.78,158.57,153.57,120.50,118.52,116.54,114.55,109.19,102.02,43.19,37.06,28.30,14.11.HRMS calculated for(M + H) + 272.1870,found 272.1872.

[0140] Example 41: 3-Bromo-4-(3-(piperidin-4-yl)-1H-pyrazol-5-yl)pyridine (41)

[0141] Using 200 mg of 3-quinuclidinone hydrochloride, 49.2 mg of NaOH, and 216.5 mg of 2-bromopyridine-4-carbaldehyde as starting materials, the preparation method was the same as that of Compound 1, with a yield of 88%. 1 H NMR(600MHz,DMSO-d 6 )δ13.13(s,1H),8.78(s,1H),8.53(d,J = 5.0Hz,1H),7.78(d,J = 5.0Hz,1H),6.73(s,1H),2.99(dt,J = 12.3,3.3Hz,2H),2.77(tt,J = 11.8,3.8Hz,1H),2.57(td,J = 12.0,2.4Hz,2H),1.88 - 1.82(m,2H),1.52(qd,J = 12.2,3.9Hz,2H).13 C NMR (150 MHz, DMSO-d 6 ) δ 153.21, 150.21, 148.75, 146.18, 141.53, 124.66, 118.82, 103.00, 46.44, 34.18, 33.16. HRMS calculated for (M+H) + 307.0558, found 307.0592.

[0142] Example 42: 4-(3-(1-Methylpiperidin-4-yl)-1H-pyrrol-5-yl)pyridine (42)

[0143] Using compound 1 as the raw material (200 mg), it was mixed evenly with sodium borohydride (304 mg) under nitrogen protection. Then, 10 mL of anhydrous tetrahydrofuran and 324 μL of formaldehyde were added successively. After reacting for one hour, 4 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 10 h. After quenching the reaction with 10% aqueous sodium hydroxide solution, column chromatography was performed to obtain 20 mg of white solid, and the yield was 9%. 1 H NMR (600 MHz, DMSO-d 6 ) δ 12.99 (s, 1H), 8.57 (d, J = 4.8 Hz, 2H), 7.75 - 7.70 (m, 2H), 6.75 - 6.67 (m, 1H), 3.42 - 3.33 (m, 2H), 3.10 - 2.99 (m, 2H), 2.78 - 2.70 (m, 1H), 2.44 - 2.37 (m, 3H), 2.04 - 1.97 (m, 2H), 1.82 - 1.71 (m, 2H). 13 C NMR (150 MHz, DMSO-d 6 ) δ 150.55, 141.45, 119.85, 100.43, 54.68, 45.33, 31.98, 30.77. HRMS calculated for (M+H) + 243.1610, found 243.1614.

[0144] Example 43: Test on the inhibitory activity of the compounds of the present invention against MNKs protease

[0145] The enzyme activities of MNK1 and MNK2 were tested using the LANCE Ultra enzyme activity assay method from PerkinElmer. Blank control and positive control were set, and cercosporamide was used as the positive control compound. 1 ng of MNK1 or 0.05 ng of MNK2 was incubated with 5 μM of the compound in the reaction buffer at 25 °C for 1 h. Subsequently, 5 μL of EDTA / Detection buffer and 5 μL of Eu-CREB / Detection buffer were added and incubated for another 1 h. The HTRF signals at 615 and 665 nm were detected using a microplate reader, and the inhibition rate of the protease was calculated using the ratio. For the MNK1 protease, the reaction system contained 12.5 nM CREB, 450 μM ATP, 2 mM DTT, and 1x buffer; for the MNK2 protease, the reaction system contained 12.5 nM CREB, 100 μM ATP, 2 mM DTT, and 1x buffer. (Inhibition rate 80%-100%: +++ ; 50%-80%: ++ ; <50%: +). The inhibition rate results of compounds 1-42 against MNK1 and MNK2 enzymes are shown in Table 2 below.

[0146] Table 2

[0147]

[0148]

[0149] Example 44: Test its cytotoxicity in tumor cells

[0150] Human acute leukemia MV-4-11 cells in the logarithmic phase were taken and added to a 96-well plate at a density of 3000 cells per well, and the compound was added simultaneously and incubated for 48 h. The CCK-8 method was used to detect the cytotoxic activity; human non-small cell lung cancer A549 cells in the logarithmic phase were taken and added to a 96-well plate at a density of 5000 cells per well. After the cells adhered, the compound was added and incubated for 48 h. The MTT method was used to detect the cytotoxic activity. The compound concentration was 20 μM. The results are shown in Table 2. Compound 36 showed excellent cytotoxic activity in MV-4-11 cells. The detection results of compounds 1-42 are shown in Table 3 below.

[0151] Table 3

[0152]

[0153]

[0154] Although the embodiments of the present invention have been shown and described above, it can be understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those of ordinary skill in the art can make changes, modifications, substitutions, and variations to the above embodiments within the scope of the present invention, and all such changes, modifications, substitutions, and variations should be included within the protection scope of the present invention.

Claims

1. A 4-(1H-pyrazol-3-yl)piperidinyl derivative, characterized in that, the structural formula of the 4-(1H-pyrazol-3-yl)piperidinyl derivative is shown in Formula I, Wherein, R 1 is an aromatic ring or a substituted aromatic ring, the aromatic ring is a monocyclic or polycyclic aryl or heterocyclic group having 6 to 12 carbon atoms, the heterocyclic group is a 5- to 6-membered heterocyclic group, and the 5- to 6-membered heterocyclic group means that the heterocyclic group has ring carbon atoms and 1 to 4 ring heteroatoms, wherein each ring heteroatom is independently selected from nitrogen, oxygen, and sulfur; the substituted aromatic ring has substituents on the aromatic ring, and the substituents are selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkylamino, C1-C6 alkoxy, 5- to 6-membered heterocyclic group, halogen, hydroxyl, cyano, nitro, amino, carbonyl-substituted 5- to 6-membered heterocyclic group containing 1-2 nitrogen atoms; R 2 is H or a C1-C6 alkyl group.

2. The 4-(1H-pyrazol-3-yl)piperidinyl derivative according to claim 1, characterized in that, The aromatic ring is The substituents are selected from halogen, cyano, nitro, halomethyl, C1-C3 alkyl, hydroxy, C1-C3 alkoxy, amino, C1-C3 alkylamino, and R 2 is H or C1-C3 alkyl.

3. The 4-(1H-pyrazol-3-yl)piperidinyl derivative according to claim 1, characterized in that, R 1 selected from at least one of 4. A method for preparing the 4-(1H-pyrazol-3-yl)piperidinyl derivative according to any one of claims 1-3, characterized in that, When R 2 is H, the 4-(1H-pyrazol-3-yl)piperidinyl derivative is prepared from the compound of formula II, and the reaction formula is as follows: Preferably, the preparation of the 4-(1H-pyrazol-3-yl)piperidinyl derivative from the compound of Formula II includes the following steps: refluxing the compound of Formula II with an aqueous hydrazine solution for 5.5-6.5 h, cooling to 15-35 °C, and precipitating a solid, which is the 4-(1H-pyrazol-3-yl)piperidinyl derivative; Preferably, the mass concentration of the aqueous hydrazine solution is 19-25%, and the mass-to-volume ratio of the compound of Formula II to the aqueous hydrazine solution is (190-210 mg): 3 mL.

5. The method for preparing the 4-(1H-pyrazol-3-yl)piperidinyl derivative according to claim 4, characterized in that, the compound of Formula II is prepared from the compound of Formula III, and the reaction formula is as follows: Preferably, the preparation of the compound of formula II from the compound of formula III comprises the following steps: reacting the compound of formula III or its salt with an inorganic base and R 1 CHO by refluxing in ethanol to obtain the compound of formula II; Preferably, the mass ratio of the inorganic base to the compound of Formula III is 0.9-1.1: 4; Preferably, the reaction time is 5-7 h; Preferably, the inorganic base is NaOH.

6. A method for preparing the 4-(1H-pyrazol-3-yl)piperidinyl derivative according to any one of claims 1-3, characterized in that, When R 2 is a C1-C6 alkyl group, the 4(1H-pyrazol-3-yl)piperidinyl derivative is prepared from the compound of formula I(A), and the reaction formula is as follows: Preferably, the preparation of the 4-(1H-pyrazol-3-yl)piperidinyl derivative from the compound of formula I(A) comprises the following steps: reacting the compound of formula I(A) with R 2 CHO under basic conditions to obtain the 4-(1H-pyrazol-3-yl)piperidinyl derivative; Preferably, trifluoroacetic acid is added during the reaction; Preferably, the solvent used in the reaction is tetrahydrofuran.

7. A pharmaceutical composition, characterized in that, it comprises the 4-(1H-pyrazol-3-yl)piperidinyl derivative according to any one of claims 1-3, stereoisomers, tautomers, geometric isomers or pharmaceutically acceptable salts thereof; Preferably, the pharmaceutical composition is a tablet, capsule or injection.

8. Use of the 4-(1H-pyrazol-3-yl)piperidinyl derivative according to any one of claims 1-3, stereoisomers, tautomers, geometric isomers or pharmaceutically acceptable salts thereof and / or the 4-(1H-pyrazol-3-yl)piperidinyl derivative prepared by the method for preparing the 4-(1H-pyrazol-3-yl)piperidinyl derivative according to any one of claims 4-6 and / or the pharmaceutical composition according to claim 7 in the preparation of MNK1 and / or MNK2 inhibitors.

9. Use of the 4-(1H-pyrazol-3-yl)piperidinyl derivative, stereoisomer, tautomer, geometric isomer or pharmaceutically acceptable salt thereof according to any one of claims 1-3, and / or the 4-(1H-pyrazol-3-yl)piperidinyl derivative prepared by the preparation method of the 4-(1H-pyrazol-3-yl)piperidinyl derivative according to any one of claims 4-6, and / or the pharmaceutical composition according to claim 7 in the preparation of an anti-tumor drug.

10. Use of the 4-(1H-pyrazol-3-yl)piperidinyl derivative, stereoisomer, tautomer, geometric isomer or pharmaceutically acceptable salt thereof according to any one of claims 1-3, and / or the 4-(1H-pyrazol-3-yl)piperidinyl derivative prepared by the preparation method of the 4-(1H-pyrazol-3-yl)piperidinyl derivative according to any one of claims 4-6, and / or the pharmaceutical composition according to claim 7 in the preparation of an anti-inflammatory drug.

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