1,4-Diheterocyclyl-substituted aromatic or heteroaromatic ring compounds and their uses

Abstract

The present invention discloses a 1,4-diheterocyclyl-substituted aromatic or heteroaromatic compound represented by formula (I), which can effectively inhibit the formation of 20-HETE, has high activity, high selectivity and good pharmacokinetic properties, and can treat various diseases associated with 20-HETE by inhibiting the formation of 20-HETE, and has high application value. JPEG2025511097000084.jpg30170

Description

[Technical Field]

[0001] This invention claims priority to a Chinese patent application bearing application number 2022103445529 and title "1,4-diheterocyclyl-substituted aromatic or heteroaromatic ring compounds and their uses" filed with the China Patent Office on March 31, 2022, the entire contents of which are incorporated herein by reference.

[0002] The present invention relates to the technical field of chemoprevention, specifically to 1,4-diheterocyclyl-substituted aromatic or heteroaromatic ring compounds and their uses. [Background technology]

[0003] 20-Hydroxyeicosatetraenoic acid (20-HETE) is a metabolite of arachidonic acid produced by enzymes of the cytochrome P450 (CYP) 4A and 4F families. Cyp4a12 is the main enzyme producing 20-HETE in mice, while the enzymes that produce 20-HETE in rats include Cyp4a1, Cyp4a2, and Cyp4a3. The main enzymes that produce 20-HETE in humans are CYP4A11 and CYP4F2 (PNAS 2017, 114-3181-3185; Onco Targets Ther. 2013; 6: 243-255; Hypertension. 2008;51:1393-1398).

[0004] 20-HETE can promote vascular smooth muscle contraction, endothelial dysfunction, inflammation, and cell proliferation (Curr Opin Nephrol Hypertens 26: 74-82, 2017). Several studies have demonstrated that 20-HETE expression levels are significantly elevated in various diseases, including hypertension, stroke, coronary artery disease, myocardial infarction, acute renal failure, chronic kidney disease, polycystic kidney disease, tumor growth and metastasis, and end-organ damage and fibrosis (J Lipid Res 54: 786-793, 2013, Pharmacol Ther 125: 446-463, 2010).

[0005] 20-HETE also plays an important role in the development and progression of obesity, insulin resistance, and metabolic syndrome. Preclinical animal models have shown a correlation between 20-HETE levels and weight gain, as well as metabolic syndrome (hyperglycemia, diabetes, diabetes-related retinopathy, and nephropathy) [Am J Physiol Endocrinol Metab 302(5):E500-9, 2012., Am J Physiol Regul Integr Comp Physiol 315(5):R934-r44, 2018.] Clinical studies have shown that urinary and plasma 20-HETE levels are related to body mass index (BMI) and are elevated in patients with obesity, diabetes, and metabolic syndrome (Other Lipid Mediat 100-101:15-21, 2013., Prostaglandins Other Lipid Mediat 123:68-77, 2016. Free Radic Biol Med 46(2):263-70, 2009.).

[0006] In 2017, Garcia et al. discovered that GPR75 is a 20-HETE receptor and reported a proximal signaling mechanism for 20-HETE that causes hypertension and vascular dysfunction (Circ Res 2017; 120:1776-1788). Approximately 650,000 individuals were sequenced to identify individuals with rare protective mutations. Individuals with at least one inactive copy of the G protein-coupled receptor 75 (GPR75) gene had a lower body mass index (BMI), weighed approximately 12 pounds less than individuals without the mutation, had a 54% lower risk of obesity, and showed improved diabetes parameters, including lower blood glucose levels.

[0007] In a high-fat diet model, knocking out the GPR75 gene in mice conferred resistance to weight gain and improved blood glucose control. Inhibiting GPR75 may offer a therapeutic strategy for obesity (Science 373, eabf8683, 2021).

[0008] Given the important role of the 20-HETE / GPR75 pathway in the development and progression of these diseases, 20-HETE ligand generation inhibitors or GPR75 receptor antagonists may be potential treatment options for various metabolic diseases, such as obesity and diabetes. HET0016 is a highly active and selective 20-HETE inhibitor with a 20-HETE inhibitory activity of 8.9 nM, without affecting the activity of other arachidonic acid metabolic pathways, such as cyclooxygenase and epoxygenase. However, its low solubility and short half-life have prevented it from entering clinical development (Drug Metabolism & Disposition 36: 2324-2330, 2008). Recently, 20-SOLA, which has better water solubility, has been used as a 20-HETE antagonist in animal studies as a tool drug for the treatment of related diseases. 20-SOLA can normalize blood pressure in Cyp4a14- / - hypertensive mice (J Pharmacol Exp Ther 363: 412-418, 2017.), and also reduces high-fat diet-induced weight gain and improves hyperglycemia and hyperinsulinemia in Cyp4a14- / - mice (Am J Physiol Regul Integr Comp Physiol. 315: 934-944, 2018). Summary of the Invention [Problem to be solved by the invention]

[0009] Although 20-HETE is associated with the onset and progression of various diseases, there are currently no effective 20-HETE inhibitors in clinical trials. In response to this, the present invention provides 1,4-diheterocyclyl-substituted aromatic or aromatic heterocyclic compounds that can effectively inhibit the production of 20-HETE and have high activity, high selectivity, and favorable pharmacokinetic properties, and can treat various diseases associated with 20-HETE by inhibiting the production of 20-HETE. [Means for solving the problem]

[0010] The present invention includes the following technical solutions: A 1,4-diheterocyclyl-substituted aromatic or heteroaromatic compound represented by formula (I), or a pharmaceutically acceptable salt thereof or a stereoisomer thereof. JPEG0007820560000001.jpg31170 (where, X1, X2, X3, and X4 are each independently selected from N, CH, and CR1; R1 is independently selected from the group consisting of halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, halogen-substituted C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, amino-substituted C1-C6 alkyl, C1-C6 alkylamino-substituted C1-C6 alkyl, C6-C 10 selected from aryl, 5-10 membered heteroaryl, nitro, cyano, —OR, —N(R), —SR, —C(O)OR, —C(O)N(R), —C(O)R, —S(O)R, —S(O)R, —S(O)N(R), and —N(R)C(O)R; Q is -(CR2R3) p -, -C(O)-, -C(S)-, -S(O)-, -S(O)2-, -C(O)O-, -N(R4)C(O)-, -C(O)N(R4)-, -C(O)N(R4)(CR2R3)-, -N(R4)C(O)(CR2R3)-, -C(O)(CR2R3)-, -O-, -N(R4)-, and -S-, where p is selected from 0, 1 or 2; R2, R3, and R4 are each independently selected from H and C1-C6 alkyl; A is selected from substituted or unsubstituted 5- to 10-membered heterocyclyl and substituted or unsubstituted 5- to 10-membered heteroaryl; Y is C1~C 12 Alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkylmethyl, halogen-substituted C1-C 12 Alkyl, hydroxy substituted C1-C 12 Alkyl, C1-C6 alkoxy substituted C1-C 12Alkyl, amino substituted C1-C 12 Alkyl, C1-C6 alkylamino substituted C1-C 12 Alkyl, C6-C 10 Aryl-substituted C1-C 12 Alkyl, 5-10 membered heteroaryl substituted C1-C 12 Alkyl, ethynyl substituted C1-C 12 Alkyl, vinyl substituted C1-C 12 or Y is selected from alkyl, 5- to 10-membered heteroaryl, -C(O)R, and -C(O)OR; or Y is selected from a substituted or unsubstituted 4- to 12-membered monocyclic or bicyclic ring, wherein the monocyclic or bicyclic ring is a saturated, partially unsaturated, or aromatic monocyclic, fused, bridged, or spirocyclic ring, and the ring atoms of the monocyclic or bicyclic ring are one or more chemically acceptable atoms selected from C, O, N, and S; R are each independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, halogen-substituted C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, amino-substituted C1-C6 alkyl, C1-C6 alkylamino-substituted C1-C6 alkyl, and C6-C 10 aryl; Ring C is selected from substituted or unsubstituted 4- to 10-membered heterocyclyl and substituted or unsubstituted 5- to 10-membered heteroaryl.

[0011] In some embodiments, ring C is selected from a substituted or unsubstituted 4- to 10-membered heterocyclyl, wherein the heteroatoms in the heterocyclyl are 1 to 2 nitrogen atoms, and the substituents in the heterocyclyl are selected from H, halogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, cyano, and hydroxy, or two substituents together with the C atom bonded thereto form a substituted or unsubstituted 4- to 8-membered carbocyclic or 4- to 8-membered heterocyclic ring.

[0012] In some embodiments, Ring C is selected from: JPEG0007820560000002.jpg64170 (where, The dotted line in the ring containing W and V represents one single bond or none; R5 and R6 are each independently selected from H, halogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, cyano, and hydroxy; or R5 and R6 together with the C atom bonded thereto form a substituted or unsubstituted 4- to 8-membered carbocyclic or 4- to 8-membered heterocyclic ring; n is independently selected from 0, 1, and 2; V and W are each independently selected from CH and N, and V and W are not both CH.

[0013] In some embodiments, rings C and Q form the following group: JPEG0007820560000003.jpg77170

[0014] In some embodiments, the 1,4-diheterocyclyl-substituted aromatic or heteroaromatic compound has the structure of Formula (II): JPEG0007820560000004.jpg35170

[0015] In some embodiments, A is selected from the following: JPEG0007820560000005.jpg21170 (where, X5 and X6 are each independently selected from CH and N; X7 is selected from O and S; R 10 is selected from H and C1-C6 alkyl.

[0016] In some embodiments, A is selected from the following: JPEG0007820560000006.jpg34170JPEG0007820560000007.jpg18170

[0017] In some embodiments, A is selected from the following: JPEG0007820560000008.jpg15170

[0018] In some embodiments, Y is C1-C 10 alkyl, halogen-substituted C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, C1-C3 alkoxy-substituted C1-C6 alkyl, phenyl-substituted C1-C6 alkyl, ethynyl-substituted C1-C6 alkyl, vinyl-substituted C1-C6 alkyl, C3-C6 cycloalkylmethyl, and 5-6-membered heteroaryl; or Y is selected from: JPEG0007820560000009.jpg26170 (where, X8 is independently O, S, NR 10 , and CHR 14 is selected from X9, each independently, CR 18 , and N; R 18 is selected from H, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, and halogen; each m is independently selected from 1, 2, and 3; n is independently selected from 0, 1, and 2; R 10 are each independently selected from H, C1-C6 alkyl, and C1-C6 alkyl acyl; R 11 , and R 12 are each independently selected from H, C1-C6 alkyl, hydroxy, and halogen, or each pair of R 11 , and R 12 each independently optionally forms C═O together with the carbon atom to which it is bonded; R 13 , and R 14are each independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 3- to 8-membered heterocyclyl, hydroxy-substituted C1-C6 alkyl, hydroxy, halogen, amino, and C1-C6 alkanoyl, or R 13 , and R 14 form C=O together with the carbon atom to which they are bonded, or R 13 , and R 14 are one or more R together with the C atoms bonded thereto. 17 Substituted or unsubstituted C3-C8 cycloalkyl, C6-C 10 aryl, 3- to 8-membered heterocyclyl, or 5- to 6-membered heteroaryl, or R 11 , and R 13 are one or more R together with the C atoms bonded thereto. 17 forming a substituted or unsubstituted C3-C8 cycloalkyl or 3- to 8-membered heterocyclyl, R 15 , and R 16 are each independently H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkylmethyl, halogen-substituted C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, C1-C6 alkoxy-substituted C1-C6 alkyl, amino-substituted C1-C6 alkyl, C1-C6 alkylamino-substituted C1-C6 alkyl, C6-C 10 or an adjacent R selected from aryl, 5- to 10-membered heteroaryl, nitro, cyano, -OR, -N(R), -SR, -C(O)OR, -C(O)N(R), -C(O)R, -S(O)R, -S(O)R, -S(O)N(R), and -N(R)C(O)R; 15 , and R 16 are one or more R together with the C atoms bonded thereto. 17 Substituted or unsubstituted C3-C8 cycloalkyl, C6-C 10 forming an aryl, a 3- to 8-membered heterocyclyl, or a 5- to 6-membered heteroaryl; R 17are each independently selected from halogen, hydroxy, cyano, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 alkanoyl, or two R 17 form C=O together with the carbon atom to which they are attached.)

[0019] In some embodiments, Y is selected from C1-C8 alkyl, hydroxy-substituted C1-C6 alkyl, phenyl-substituted C1-C6 alkyl, ethynyl-substituted C1-C6 alkyl, vinyl-substituted C1-C6 alkyl, and C5-C6 cycloalkylmethyl; or Y is selected from: JPEG0007820560000010.jpg100170JPEG0007820560000011.jpg80170JPEG0007820560000012.jpg19170(where, R 10 are each independently selected from H, C1-C3 alkyl, and C1-C3 alkyl acyl; R 13 , and R 14 are each independently selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy, and hydroxy; R 15 is selected from H, halogen, C1-C3 alkyl, and C1-C3 alkoxy; R 18 are each independently selected from H, hydroxy, halogen, C1-C3 alkoxy, and C1-C3 alkyl.

[0020] In some embodiments, Y is selected from C4-C7 alkyl, cyclopentyl, naphthyl, hydroxy-substituted C4-C6 alkyl, phenyl-substituted C1-C6 alkyl, ethynyl-substituted C4-C6 alkyl, vinyl-substituted C4-C6 alkyl, and C5-C6 cycloalkylmethyl; alternatively, Y is selected from: JPEG0007820560000013.jpg63170 (where, R 15 is selected from H or halogen, and R 18is selected from H, hydroxy, halogen, and C1-C3 alkoxy.

[0021] In some embodiments, Q and Y are -YS(O)-, -Y-(CRR) p forming a group of -, -YC(O)-, -YN(R4)C(O)-, -YC(O)N(R4)-, -YC(O)N(R4)(CR2R3)-, or -YN(R4)C(O)(CR2R3)-, where p is selected from 0, 1 or 2, and R2, R3, and R4 are all H.

[0022] JPEG0007820560000014.jpg43170

[0023] In some embodiments, Q and Y form -YC=O, where Y is cyclopentyl, cyclohexyl, benzyl, hydroxy-substituted butyl, cyclopentylmethyl, JPEG0007820560000015.jpg58170

[0024] In some embodiments, Q and Y form YC(O)NHCH2-, where Y is selected from butyl, hexyl, pentyl, cyclopentyl, phenyl, phenyl-substituted n-pentyl, ethynyl-substituted n-pentyl, and vinyl-substituted n-pentyl.

[0025] In some embodiments, JPEG0007820560000016.jpg33170

[0026] In some embodiments, Q and Y form -Y-NHC(O)-, where Y is selected from cyclopentyl, and rings C and Q form the following group: JPEG0007820560000017.jpg16170

[0027] In some embodiments, Q and Y form -YS(O)2-, where Y is selected from cyclohexyl and 4-fluorophenyl.

[0028] In some embodiments, X1, X2, X3, and X4 are each independently selected from CH and CR1.

[0029] In some embodiments, X1 and X4 are not CR1 at the same time, and X2 and X3 are not CR1 at the same time.

[0030] In some embodiments, R1 is selected from halogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, C1-C3 alkoxy-substituted C1-C6 alkyl, amino-substituted C1-C6 alkyl, C1-C3 alkylamino-substituted C1-C6 alkyl, cyano, C1-C6 alkoxy, —N(C1-C3 alkyl)2, —C(O)OC1-C3 alkyl, —C(O)NH2, —C(O)N(C1-C3 alkyl)2, —C(O)(C1-C3 alkyl)2, and —C(O)H.

[0031] In some embodiments, R1 is selected from halogen, C1-C3 alkyl, halogen-substituted C1-C3 alkyl, cyano, formaldehyde, and hydroxy-substituted C1-C3 alkyl.

[0032] In some embodiments, R1 is selected from fluorine, chlorine, monofluoromethyl, difluoromethyl, trifluoromethyl, methyl, cyano, methoxy, formaldehyde, carbamoyl, hydroxymethyl, methoxyformyl, and dimethylamino.

[0033] In some embodiments, the 1,4-diheterocyclyl-substituted aromatic or heteroaromatic ring system is selected from the following compounds: JPEG0007820560000018.jpg185170JPEG0007820560000019.jpg230170JPEG000 7820560000020.jpg224170JPEG0007820560000021.jpg233170JPEG0007820560 000022.jpg234170JPEG0007820560000023.jpg230170JPEG0007820560000024. jpg227170JPEG0007820560000025.jpg241170JPEG0007820560000026.jpg29170

[0034] The present invention also provides the use of the above 1,4-diheterocyclyl-substituted aromatic or heteroaromatic compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, which includes the following technical solutions:

[0035] Use of the above 1,4-diheterocyclyl-substituted aromatic or heteroaromatic compound, or a pharmaceutically acceptable salt or stereoisomer thereof, in the manufacture of a 20-HETE production inhibitor.

[0036] Use of the above-mentioned 1,4-diheterocyclyl-substituted aromatic or heteroaromatic compound, or a pharmaceutically acceptable salt or stereoisomer thereof, in the prevention and / or treatment of diseases and / or symptoms associated with the 20-HETE signaling pathway.

[0037] Use of a GLP-1 receptor agonist in combination with the above-mentioned 1,4-diheterocyclyl-substituted aromatic or heteroaromatic compound, or a pharmaceutically acceptable salt or stereoisomer thereof, in the prevention and / or treatment of diseases and / or symptoms associated with the 20-HETE signaling pathway.

[0038] In some embodiments, the GLP-1 receptor agonist is semaglutide.

[0039] In some embodiments, the disease and / or condition associated with the 20-HETE signaling pathway is selected from obesity, metabolic syndrome, dyslipidemia, diabetes, diabetic retinopathy, diabetic cerebrovascular disease, diabetic neuropathy, insulin resistance, hyperglycemia, hyperlipidemia, diabetic nephropathy, hypertension, cataracts, osteoporosis, hyperuricemia, diabetes-induced infections, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, fibrosis, heart disease, stroke, cirrhosis, metabolic acidosis, ketosis, cardiovascular disease, epilepsy, atherosclerosis, Parkinson's disease, myocardial infarction, acute renal failure, chronic kidney disease, polycystic kidney disease, tumors, end-organ damage, and Alzheimer's disease.

[0040] In some embodiments, the diabetes is type 1 diabetes, type 2 diabetes, gestational diabetes, idiopathic T1D, early-onset T2DM, maturity-onset diabetes of the young, early-onset atypical diabetes, malnutrition-related diabetes, or latent autoimmune diabetes in adults. do.

[0041] The present invention also provides a pharmaceutical composition for preventing and / or treating diseases and / or symptoms associated with the 20-HETE signaling pathway, including the following technical solutions:

[0042] A pharmaceutical composition for preventing and / or treating diseases and / or conditions associated with the 20-HETE signaling pathway, comprising an active ingredient and pharmaceutically acceptable auxiliary materials and / or carriers, wherein the active ingredient comprises the above-described 1,4-diheterocyclyl-substituted aromatic or heteroaromatic ring compound, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0043] The present invention also provides a combination drug for preventing and / or treating diseases and / or conditions associated with the 20-HETE signaling pathway, including the following technical solutions:

[0044] A combination drug for preventing and / or treating a disease and / or symptom associated with the 20-HETE signaling pathway, wherein the active ingredients comprise a GLP-1 receptor agonist and the above-mentioned 1,4-diheterocyclyl-substituted aromatic or heteroaromatic ring compound, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the GLP-1 receptor agonist and the above-mentioned 1,4-diheterocyclyl-substituted aromatic or heteroaromatic ring compound, or a pharmaceutically acceptable salt or stereoisomer thereof, are each in an individual dosage unit or jointly form a combined dosage unit.

[0045] In some embodiments, the GLP-1 receptor agonist is semaglutide. [Effects of the Invention]

[0046] The present invention has the following beneficial effects.

[0047] The 1,4-diheterocyclyl-substituted aromatic or aromatic heterocyclic compounds of the present invention can effectively inhibit the production of 20-HETE and have high activity, high selectivity, and good pharmacokinetic properties. By inhibiting the production of 20-HETE, they can treat various diseases associated with 20-HETE, and have great application value. [Brief explanation of the drawings]

[0048] [Figure 1] 1 is a line graph of the mean drug blood concentration time when Compound 1, Compound 2, Compound 4, Compound 5, Compound 26, Compound 66, Compound 70, and control compound 83 are intragastrically administered to rats (20 mg / kg). [Figure 2] 1 is a line graph of the mean drug blood concentration time when Compound 71, Compound 72, Compound 91, Compound 98, Compound 113, Compound 153, Compound 163, and control compound 83 are intragastrically administered to rats (20 mg / kg). [Figure 3] 1 is a line graph of the weight gain of animals in each group in a DIO mouse model treated with Compound 1. [Figure 4]1 is a line graph showing changes in body weight of animals in each group in a DIO mouse model treated with Compound 1. [Figure 5] 1 is a line graph of OGTT of animals in each group in a DIO mouse model using Compound 1. [Figure 6] 1 is a line graph of weight gain in a DIO mouse model by Compound 2 and Compound 4. [Figure 7] 1 is a line graph showing changes in body weight in a DIO mouse model caused by Compound 2 and Compound 4. [Figure 8] 1 is a line graph of OGTT-blood glucose concentration in a DIO mouse model using Compound 2 and Compound 4. [Figure 9] 1 is a bar graph of OGTT-blood glucose AUC in a DIO mouse model using Compound 2 and Compound 4. [Figure 10] 1 is a line graph of the weight gain of animals in each group in a DIO mouse model treated with Compound 2. [Figure 11] 1 is a line graph showing changes in body weight of animals in each group in a DIO mouse model treated with Compound 2. [Figure 12] 1 is a line graph of food intake of animals in each group in a DIO mouse model with Compound 2. [Figure 13] 1 is a line graph of OGTT of animals in each group in a DIO mouse model using Compound 2. [Figure 14] 1 is a line graph of the weight gain of animals in each group in a DIO mouse model using Compound 2 and semaglutide. [Figure 15] 1 is a line graph showing the changes in body weight of animals in each group in a DIO mouse model treated with Compound 2 and semaglutide. [Figure 16] Figure 1 is a line graph of food intake of animals in each group in a DIO mouse model with Compound 2 and semaglutide. [Figure 17] FIG. 1 shows the relative 20-HETE content in each organ of a DIO mouse model treated with Compound 2. [Figure 18] FIG. 1 shows the relative 20-HETE content in each organ of a DIO rat model treated with Compound 2. DETAILED DESCRIPTION OF THE INVENTION

[0049] In the compounds described herein, when any variable (e.g., R) occurs more than once in any constituent, its definition at each occurrence is independent of its definition at every other occurrence. Similarly, combinations of substituents and variables are permissible so long as the compound is stable. Lines drawn from substituents to ring systems indicate that the indicated bond may be attached to any substitutable ring atom. If the ring system is polycyclic, it is intended that such bonds be attached only to any suitable carbon atom adjacent to the ring. It will be understood that those skilled in the art will be able to select substituents and substitution patterns for the compounds of the present invention to provide compounds that are chemically stable and can be easily synthesized from readily available starting materials using techniques in the art and the methods described below. When a substituent is itself substituted with multiple groups, it is understood that these groups may be on the same or different carbon atoms as long as the structure is stable.

[0050] As used herein, the term "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, the definition of "C1-C6" in "C1-C6 alkyl" is intended to include groups having 1, 2, 3, 4, 5, or 6 carbon atoms arranged in a straight or branched chain. For example, "C1-C6 alkyl" specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, and hexyl.

[0051] The term "cycloalkyl" refers to a monocyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms. For example, "cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and the like.

[0052] The term "alkoxy" refers to a group in which alkyl is linked directly to oxygen, i.e., a group having the structure -O-alkyl, for example, -OCH3, -OCH2CH3, -OCH2CH2CH3, -O-CH2CH(CH3)2, -OCH2CH2CH2CH3, -O-CH(CH3)2, and the like.

[0053] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent (fused, bridged, or spirocyclic) in which one or more ring atoms are heteroatoms selected from N, O, or S(O)m, where m is an integer from 0 to 2, and the remaining ring atoms are carbon, such as morpholinyl, piperidinyl, tetrahydropyrrolyl, pyrrolidinyl, dihydroimidazolyl, dihydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydroxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, tetrahydrofuranyl, tetrahydrothienyl, and the like, and N-oxides thereof, and attachment of the heterocyclic substituent can be via a carbon atom or a heteroatom.

[0054] The term "heteroaryl" refers to an aromatic ring containing one or more heteroatoms selected from O, N, or S. Heteroaryls within the scope of this invention include, but are not limited to, quinolyl, pyrazolyl, pyrrolyl, thienyl, furyl, pyridyl, pyrimidinyl, pyrazinyl, triazolyl, imidazolyl, oxazolyl, isoxazolyl, pyridazinyl, benzofuryl, benzothienyl, benzoxazolyl, indolyl, and the like. "Heteroaryl" is also understood to include any N-oxide derivative of a nitrogen-containing heteroaryl.

[0055] The term "substituted" refers to the replacement of hydrogen radicals in a particular structure with a specified substituent.

[0056] As understood by one of ordinary skill in the art, "halo" or "halogen" as used herein refers to chlorine, fluorine, bromine, and iodine.

[0057] Unless otherwise defined, alkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl substituents can be unsubstituted or substituted, for example, C1-C6 alkyl can be substituted with 1, 2, or 3 substituents selected from OH, halogen, alkoxy, dialkylamino, or heterocyclyl such as morpholinyl, piperidinyl, etc.

[0058] The present invention includes the free form of compounds of Formula (I) or Formula (II), as well as pharmaceutically acceptable salts and stereoisomers thereof. The term "free form" refers to an amine-based compound in non-salt form. The pharmaceutically acceptable salts encompassed include not only the exemplary salts of the specific compounds described herein, but also all representative pharmaceutically acceptable salts of the free form of compounds of Formula (I) or Formula (II). The free form of a specific salt of the compound can be isolated using techniques known in the art. For example, the free form can be regenerated by treating the salt with a suitable dilute aqueous alkali solution, such as dilute aqueous NaOH, potassium carbonate, ammonia, or sodium bicarbonate. While the free forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents, such acid and alkali salts are otherwise pharmaceutically equivalent to their respective free forms for purposes of the present invention.

[0059] The pharmaceutically acceptable salts of the present invention can be synthesized from the compounds of the present invention containing an alkaline or acidic moiety by conventional chemical methods. Typically, salts of alkaline compounds are prepared by ion exchange chromatography or by reacting the free alkali with a stoichiometric amount or excess of the desired salt form of an inorganic or organic acid in a suitable solvent or solvent combination. Similarly, salts of acidic compounds are formed by reaction with a suitable inorganic or organic alkali.

[0060] Thus, pharmaceutically acceptable salts of the compounds of this invention include conventional non-toxic salts of the compounds of this invention formed by reaction of an alkaline compound of this invention with an inorganic or organic acid. For example, conventional non-toxic salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like, as well as salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, 2-acetyloxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid, and the like.

[0061] When the compound of the present invention is acidic, a suitable "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic alkali, including inorganic alkali and organic alkali. Salts prepared from inorganic alkali include aluminum salts, ammonium salts, calcium salts, copper salts, iron salts, ferrous salts, lithium salts, magnesium salts, manganese salts, manganous salts, potassium salts, sodium salts, zinc salts, etc. Ammonium salts, calcium salts, magnesium salts, potassium salts, and sodium salts are particularly preferred. In salts derived from pharmaceutically acceptable organic non-toxic alkalis, the alkalis include primary amines, secondary amines, and tertiary amines, and substituted amines include naturally occurring substituted amines, cyclic amines, and alkaline ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, histidine, hydroxocobalamin, isopropylamine, lysine, methylglucosamine, morpholine, piperidine, acridine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

[0062] Berg et al., "Pharmaceutical Salts," J. Pharm. Sci. '77:66:1-19, describes in more detail the preparation of these and other exemplary pharmaceutically acceptable salts.

[0063] Under physiological conditions, deprotonated acidic moieties such as carboxy in the compounds can become anionic; this charge can be counterbalanced by protonated or alkylated alkaline moieties such as tetravalent nitrogen atoms bearing an internal cation, resulting in the compounds of the invention being potential internal salts or zwitterions.

[0064] Synthetic Methods: In addition to standard methods known in the literature or exemplified in experimental procedures, the compounds of the present invention can be prepared using the methods of the following synthetic schemes (Schemes 1-13). The following synthetic schemes, taken together, provide a better understanding of the compounds and synthetic methods described in this invention. The synthetic schemes described above describe methods that can be used to prepare the compounds of the present invention, and are merely exemplary schemes for illustrative purposes and are not intended to limit the scope of the present invention. JPEG0007820560000027.jpg241170JPEG0007820560000028.jpg213170JPEG0007820560000029.jpg212170JPEG000 7820560000030.jpg188170JPEG0007820560000031.jpg224170JPEG0007820560000032.jpg182170JPEG00078205600 00033.jpg183170JPEG0007820560000034.jpg178170JPEG0007820560000035.jpg223170JPEG0007820560000036.j pg231170JPEG0007820560000037.jpg250170JPEG0007820560000038.jpg220170JPEG0007820560000039.jpg106170

[0065] Example 1: Preparation of 1-((1-(4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (Compound 1) (prepared according to the route in Scheme 1) Step 1a: Preparation of 4-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (compound 0102-1): A mixture of 4-iodo-1H-pyrazole (15 g, 77.32 mmol, 1.0 equiv.), 3,4-dihydro-2H-pyran (7.16 g, 85.11 mmol, 1.1 equiv.), and p-toluenesulfonic acid (1.46 g, 7.73 mmol, 0.1 equiv.) in dichloromethane (100 mL) was stirred at room temperature for 3.0 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified using a silica gel column (petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to give 4-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (20.8 g, yield: 96.7%) as a colorless oil. LCMS(ESI):m / z=279[M+1] + . Step 1b: Preparation of 4-(4-bromophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (compound 0103-1): Under nitrogen protection, a mixture of (4-bromophenyl)boronic acid (0101-1) (2.4 g, 11.95 mmol, 1.0 equiv.), 4-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (0102-1) (5.0 g, 17.9 mmol, 1.5 equiv.), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (874 mg, 1.19 mmol, 0.1 equiv.), and sodium carbonate (3.8 g, 35.85 mmol, 3.0 equiv.) in dioxane / water (30 ml / 3 ml) was stirred at 90° C. for 1 hour. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried and concentrated under reduced pressure. The residue was purified using a silica gel column (petroleum ether / ethyl acetate = 10 / 1) to obtain a yellow solid product, 4-(4-bromophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (1.52 g, yield: 41.59%). LCMS (ESI): m / z = 308 [M+1] +. Step 1c: Preparation of 4-(((methanesulfonyl)oxy)methyl)piperidine-1-tert-butylcarboxylate (compound 0105-1): Under nitrogen protection, a mixture of 4-(hydroxymethyl)piperidine-1-tert-butylcarboxylate (0104-1) (10 g, 46.45 mmol, 1.0 equiv.), methanesulfonyl chloride (13.3 g, 116.13 mmol, 2.5 equiv.), and triethylamine (18.76 g, 185.78 mmol, 4.0 equiv.) in dichloromethane (120 ml) was stirred at room temperature for 4.0 hours. The reaction was quenched with sodium carbonate solution, diluted with water, and extracted with dichloromethane (50 ml x 3). The organic layer was washed with saturated brine (100 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1 to 1 / 1) to give 4-(((methanesulfonyl)oxy)methyl)piperidine-1-tert-butylcarboxylate (13.1 g, yield: 96.3%) as a yellow solid product. LCMS (ESI): m / z = 294 [M+1] + . Step 1d: Preparation of 4-((2-oxopyrrolidin-1-yl)methyl)piperidine-1-tert-butylcarboxylate (Compound 0107-1): Under nitrogen protection, sodium hydride (60%, 2.84 g, 70.97 mmol, 1.6 equiv.) was added to a mixture of 2-pyrrolidone (0106-1) (4.5 g, 53.24 mmol, 1.2 equiv.) in N,N-dimethylcarboxamide (15 mL) at 0 °C, followed by stirring at room temperature for half an hour. To the reaction mixture, a solution of 4-(((methanesulfonyl)oxy)methyl)piperidine-1-tert-butylcarboxylate (13.1 g, 44.36 mmol, 1.0 equiv.) in N,N-dimethylcarboxamide (10 mL) was added dropwise, and the mixture was reacted at 65 °C for 6 hours. The reaction mixture was diluted with water (120 ml) and extracted with ethyl acetate (25 ml x 5). The combined organic layers were washed with saturated brine (80 ml x 3), then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified using a silica gel column (petroleum ether / ethyl acetate = 5 / 1 to 1 / 2) to give 4-((2-oxopyrrolidin-1-yl)methyl)piperidine-1-tert-butylcarboxylate (7.25 g, yield: 57.9%) as a pale yellow oil. LCMS (ESI): m / z = 283 [M+1] + . Step 1e: Preparation of 1-(piperidin-4-ylmethyl)pyrrolidin-2-one (compound 0108-1): A mixture of 4-((2-oxopyrrolidin-1-yl)methyl)piperidine-1-tert-butylcarboxylate (0107-1) (7.25 g, 25.71 mmol, 1.0 equiv.) in hydrogen chloride and dioxane (4 M, 30 ml) was stirred at room temperature for 2.0 hours. The solvent was removed under reduced pressure, and the residue was diluted with water (50 ml), adjusted to pH 9 with sodium carbonate solution, and extracted with dichloromethane (10 ml × 15). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 1-(piperidin-4-ylmethyl)pyrrolidin-2-one (3.18 g, yield: 67.9%) as a yellow solid. LCMS (ESI): m / z = 183 [M+1] + . Step 1f: Preparation of 1-((1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (compound 0109-1): Under nitrogen protection, 1-(piperidin-4-ylmethyl)pyrrolidin-2-one (0108-1) (2.03 g, 11.17 mmol, 1.2 equiv.), sodium A mixture of tetramethylammonium tert-butoxide (2.24 g, 23.3 mmol, 2.5 equiv.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (539 mg, 0.932 mmol, 0.1 equiv.), and tris(dibenzylideneacetone)dipalladium(0) (427 mg, 0.466 mmol, 0.05 equiv.) in toluene (30 mL) was heated to 120 °C. A mixture of 4-(4-bromophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (0103-1) (2.86 g, 9.32 mmol, 1.0 equiv.) in toluene (15 mL) was added dropwise, and the mixture was stirred at 120 °C for 10 hours. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (30 mL x 3). The organic layer was washed with saturated brine (80 ml × 1), then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified using a silica gel column (ethyl acetate / methanol = 200 / 1 to 100 / 1) to give 1-((1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (2.09 g, yield: 54.8%) as a yellow solid. LCMS (ESI): m / z = 409 [M+1] + . Step 1g: Preparation of 1-((1-(4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (Compound 1): A mixture of 1-((1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (0109-1) (2.09 g, 5.11 mmol, 1.0 equiv) in hydrogen chloride and dioxane (4 M, 20 ml) was stirred at room temperature for 4.0 hours. The solvent was removed under reduced pressure, and the residue was diluted with water (20 ml), adjusted to pH 9 with sodium carbonate solution, and extracted with dichloromethane (8 ml × 5). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1 to 15 / 1) to give 1-((1-(4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (1.16 g, yield: 70.1%) as a white solid. LCMS (ESI): m / z = 325 [M+1] + . 1 H NMR (500 MHz, DMSO) δ 12.75 (s, 1H), 7.89 (d, J = 105.8 Hz, 2H), 7.41 (d, J = 8.6 Hz, 2H), 6.91 (d, J = 8.6 Hz, 2H), 3.66 (d, J = 12.4 Hz, 2H), 3.40 - 3.32 (m, 4H), 3.08 (d, J = 7.3 Hz, 2H), 2.63 (t, J = 11.1 Hz, 2H), 2.23 (t, J = 8.0 Hz, 2H), 2.00 - 1.89 (m, 2H), 1.74 (ddd, J = 11.1, 7.5, 3.8 Hz, 1H), 1.65 (d, J = 12.3 Hz, 2H).

[0066] Example 2: Preparation of 1-((1-(2-fluoro-4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (Compound 2) (prepared according to the route in Scheme 1) Step 2a: Preparation of 4-(4-bromo-3-fluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (compound 0103-2): Under nitrogen protection, a mixture of (4-bromo-3-fluorophenyl)boronic acid (0101-2) (500 mg, 2.28 mmol, 1.0 equiv.), 4-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (0102-1) (635 mg, 2.28 mmol, 1.0 equiv.), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (166.7 mg, 0.228 mmol, 0.1 equiv.), and potassium carbonate (787 mg, 5.70 mmol, 2.5 equiv.) in dioxane / water (15 ml / 3 ml) was stirred at 70° C. for 3 hours. After cooling to room temperature, the reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1 to 4 / 1) to give 4-(4-bromo-3-fluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (550 mg, yield: 74.22%) as a yellow oil. MS (ES) + ): m / z=327 [M+H] + . Step 2b: Preparation of 1-((1-(2-fluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (compound 0109-2): Under nitrogen protection, 1-(piperidin-4-ylmethyl)pyrrolidin-2-one (0108-1) (84 mg, 0.46 mmol, 1.0 equiv.), 4-(4-bromo-3-fluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (compound 0109-2) was added. A mixture of (triphenyl)-1H-pyrazole (0103-2) (150 mg, 0.46 mmol, 1.0 equiv.), sodium tert-butoxide (111 mg, 1.15 mmol, 2.5 equiv.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (27 mg, 0.05 mmol, 0.1 equiv.), and tris(dibenzylideneacetone)dipalladium(0) (22 mg, 0.023 mmol, 0.05 equiv.) in toluene (15 mL) was stirred at 120 °C overnight. After cooling to room temperature, the reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol = 150 / 1 to 80 / 1) to give 1-((1-(2-fluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (75 mg, yield: 38.27%) as an orange solid. MS (ES) + ): m / z = 427 [M+H] + . Step 2c: Preparation of 1-((1-(2-fluoro-4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (Compound 2): A mixture of 1-((1-(2-fluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (0109-2) (70 mg, 0.16 mmol, 1.0 equiv) in hydrogen chloride-dioxane (4 M, 5 ml) was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, and the residue was diluted with water, adjusted to pH=9 with sodium carbonate solution, and extracted with dichloromethane. The organic layer was dried and concentrated under reduced pressure. The residue was purified by preparative thick-layer chromatography (eluent: dichloromethane / methanol = 15 / 1) to give 1-((1-(2-fluoro-4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (35 mg, yield: 62.42%) as a yellow solid. MS (ES) + ): m / z = 343 [M+H] + . 1 H NMR (500 MHz, DMSO) δ 12.86 (s, 1H), 8.12 (s, 1H), 7.86 (s, 1H), 7.34 (ddd, J = 11.2, 10.1, 1.8 Hz, 2H), 6.99 (t, J = 8.9 Hz, 1H), 3.35 (dd, J = 17.9, 10.8 Hz, 4H), 3.11 (d, J = 7.1 Hz, 2H), 2.62 (t, J = 10.9 Hz, 2H), 2.23 (t, J = 8.1 Hz, 2H), 2.02 - 1.90 (m, 2H), 1.77 - 1.58 (m, 3H), 1.40 - 1.26 (m, 2H).

[0067] Example 3: Preparation of 1-((1-(3-fluoro-4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (Compound 3) (prepared according to the route in Scheme 1) Step 3a: Preparation of 4-(4-bromo-2-fluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (compound 0103-3): Under nitrogen protection, a mixture of (4-bromo-2-fluorophenyl)boronic acid (0101-3) (500 mg, 2.28 mmol, 1.0 equiv.), 4-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (0102-1) (760 mg, 2.74 mmol, 1.2 equiv.), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (166.7 mg, 0.228 mmol, 0.1 equiv.), and sodium carbonate (725 mg, 6.84 mmol, 3.0 equiv.) in dioxane / water (10 ml / 2 ml) was stirred at 70° C. for 2.0 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried and concentrated under reduced pressure. The residue was purified using a silica gel column (petroleum ether / ethyl acetate = 10 / 1 to 4 / 1) to give 4-(4-bromo-2-fluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (420 mg, yield: 56.6%) as a yellow solid. Step 3b: Preparation of 1-((1-(3-fluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (compound 0109-3): Under nitrogen protection, 1-(piperidin-4-ylmethyl)pyrrolidin-2-one hydrochloride (0108-1) (80 mg, 0.44 mmol, 1.0 equiv.), 4-(4-bromo-2-fluorophenyl)-1-(tetrahydro-2H-pyran-2-yl) A mixture of -1H-pyrazole (0103-3) (171 mg, 0.527 mmol, 1.2 equiv.), sodium tert-butoxide (105.7 mg, 1.10 mmol, 2.5 equiv.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (25.5 mg, 0.044 mmol, 0.1 equiv.), and tris(dibenzylideneacetone)dipalladium(0) (20 mg, 0.022 mmol, 0.05 equiv.) in toluene (12 mL) was stirred overnight at 120° C. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried and concentrated under reduced pressure. The residue was purified by preparative thick-layer chromatography (ethyl acetate / methanol = 150 / 1 to 80 / 1) to give 1-((1-(3-fluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (97 mg, yield: 51.7%) as a yellow solid product. LCMS (ESI): m / z = 427 [M+1] + . Step 3c: Preparation of 1-((1-(3-fluoro-4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (Compound 3): A mixture of 1-((1-(3-fluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (97 mg, 0.227 mmol, 1.0 equiv) in hydrogen chloride and dioxane (4 M, 5 ml) was stirred at room temperature for 4.0 hours. The solvent was removed under reduced pressure, and the residue was diluted with water, adjusted to pH=9 with sodium carbonate solution, and extracted with dichloromethane. The organic layer was dried and concentrated under reduced pressure. The residue was purified by preparative thick-layer chromatography (dichloromethane / methanol=12 / 1) to give 1-((1-(3-fluoro-4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (60 mg, yield: 77.3%) as a yellow solid product. LCMS (ESI): m / z = 343 [M+1] + . 1 H NMR (500 MHz, DMSO) δ 12.88 (s, 1H), 7.97 (s, 1H), 7.80 (s, 1H), 7.49 (t, J = 9.1 Hz, 1H), 6.75 (dd, J = 7.9, 6.4 Hz, 2H), 3.72 (d, J = 12.6 Hz, 2H), 3.35 (t, J = 7.0 Hz, 2H), 3.08 (d, J = 7.3 Hz, 2H), 2.67 (dd, J = 22.9, 12.4 Hz, 2H), 2.23 (t, J = 8.0 Hz, 2H), 2.00 - 1.89 (m, 2H), 1.77 (ddd, J = 11.1, 7.4, 3.8 Hz, 1H), 1.63 (d, J = 12.0 Hz, 2H), 1.27 - 1.06 (m, 2H).

[0068] Example 4: Preparation of 1-((1-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (Compound 4) (prepared according to the route in Scheme 2) Step 4a: Preparation of 4-(4-bromo-2,3-difluorophenyl)-1H-pyrazole (Compound 0205-4): Under nitrogen protection, a mixture of 1,4-dibromo-2,3-difluorobenzene (0201-4) (800 mg, 2.94 mmol, 1.0 equiv.), (1H-pyrazol-4-yl)boronic acid (0202-4) (346 mg, 3.08 mmol, 1.05 equiv.), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (103.2 mg, 0.147 mmol, 0.05 equiv.), and sodium carbonate (623 mg, 5.88 mmol, 2.0 equiv.) in dioxane / water (5 / 1 volume ratio, 33 ml) was stirred at 80°C for 8.0 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried and concentrated under reduced pressure. The residue was purified using a silica gel column (petroleum ether / ethyl acetate = 20 / 1 to 5 / 1) to give 4-(4-bromo-2,3-difluorophenyl)-1H-pyrazole (345 mg, yield: 45.5%) as a yellow solid. MS (ES) + ): m / z=259 (M+H) + Step 4b: Preparation of 4-(4-bromo-2,3-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (compound 0103-4): To a mixture of 4-(4-bromo-2,3-difluorophenyl)-1H-pyrazole (0205-4) (305 mg, 1.18 mmol, 1.0 equiv), p-toluenesulfonic acid (33 mg, 0.177 mmol, 0.15 equiv) in dichloromethane (12 ml) was added 3,4-dihydro-2H-pyran (120 mg, 1.41 mmol, 1.2 equiv) dropwise, and the reaction was then stirred at room temperature for 8 hours. The mixture was extracted with water and dichloromethane, and the organic layer was washed with brine and concentrated under reduced pressure to give 4-(4-bromo-2,3-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (220 mg, yield: 54.4%) as a yellow solid. MS (ES) + ): m / z = 343 (M + H) + Step 4c: Preparation of 1-((1-(2,3-difluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidone (compound 0109-4): Under nitrogen protection, 1-(piperidin-4-ylmethyl)pyrrolidin-2-one (0108-1) (140 mg, 0.76 mmol, 1.3 equiv.), 4-(4-bromo-2,3-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl) A mixture of -1H-pyrazole (0103-4) (200 mg, 0.588 mmol, 1.0 equiv.), sodium tert-butoxide (157 mg, 1.764 mmol, 3.0 equiv.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (33.8 mg, 0.058 mmol, 0.1 equiv.), and tris(dibenzylideneacetone)dipalladium(0) (53.8 mg, 0.058 mmol, 0.1 equiv.) in toluene (20 mL) was stirred overnight at 120° C. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried and concentrated under reduced pressure. The residue was purified by preparative thick-layer chromatography (dichloromethane / methanol = 150 / 1 to 50 / 1) to give 1-((1-(2,3-difluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidone (90 mg, yield: 34.4%) as a yellow solid product. LCMS (ESI): m / z = 445 [M+1] + . Step 4d: Preparation of 1-((1-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (Compound 4): A mixture of 1-((1-(2,3-difluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidone (0109-4) (90 mg, 0.202 mmol, 1.0 equiv) in hydrogen chloride and dioxane (4 M, 5 ml) was stirred at room temperature for 2.0 hours. The solvent was removed under reduced pressure, and the residue was diluted with water, adjusted to pH=9 with sodium carbonate solution, and extracted with dichloromethane. The organic layer was dried and concentrated under reduced pressure. The residue was purified by preparative thick-layer chromatography (dichloromethane / methanol=10 / 1) to give 1-((1-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (46 mg, yield: 63.1%) as a yellow solid product. LCMS (ESI): m / z = 361 [M+1] + Melting point: 175~184℃. 1 H NMR (500 MHz, DMSO) δ 13.04 (s, 1H), 8.08 (s, 1H), 7.87 (s, 1H), 7.38 (td, J = 8.5, 1.8 Hz, 1H), 6.84 (t, J = 8.4 Hz, 1H), 3.42 - 3.32 (m, 4H), 3.14 - 3.05 (m, 2H), 2.68 (dt, J = 22.6, 11.3 Hz, 2H), 2.22 (q, J = 7.8 Hz, 2H), 2.01 - 1.89 (m, 2H), 1.80 - 1.62 (m, 3H), 1.34 - 1.17 (m, 2H).

[0069] Example 5: 1-((1-(2,6-difluoro-4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (Compound 5) (prepared according to the route in Scheme 2) Step 5a: Preparation of 4-(4-bromo-3,5-difluorophenyl)-1H-pyrazole (compound 0205-5): Under nitrogen protection, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-tert-butylcarboxylate (0203-5) (507 mg, 1.72 mmol, 1.1 equiv.), 2-bromo-1,3-difluorophenyl A mixture of 5-iodobenzene (0201-5) (500 mg, 1.57 mmol, 1.0 equiv.), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (115 mg, 0.157 mmol, 0.15 equiv.), and sodium carbonate (499 mg, 4.71 mmol, 3.0 equiv.) in dioxane / water (10 mL / 2 mL) was stirred at 90°C for 2.0 hours. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (8 mL x 4). The combined organic layer was washed with saturated brine (30 mL x 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified using a silica gel column (petroleum ether / ethyl acetate = 5 / 1 to 1 / 1) to give 4-(4-bromo-3,5-difluorophenyl)-1H-pyrazole (268 mg, yield: 66.1%) as a yellow solid. LCMS(ESI):m / z=259[M+1] + . Step 5b: Preparation of 4-(4-bromo-3,5-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (compound 0103-5): A mixture of 4-(4-bromo-3,5-difluorophenyl)-1H-pyrazole (0205-5) (268 mg, 1.04 mmol, 1.0 equiv.), 3,4-dihydro-2H-pyran (96.2 mg, 1.14 mmol, 1.1 equiv.), and p-toluenesulfonic acid (20 mg, 0.104 mmol, 0.1 equiv.) in dichloromethane (8 mL) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1 to 2 / 1) to give 4-(4-bromo-3,5-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (259 mg, yield: 72.6%) as a yellow solid. LCMS (ESI): m / z = 343 [M+1] + . Step 5c: Preparation of 1-((1-(2,6-difluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (compound 0109-5): Under nitrogen protection, 4-(4-bromo-3,5-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (0103-5) (209 mg, 0.609 mmol, 1.0 equiv.), 1-(piperidin-4-yl)methyl)pyrrolidin-2-one were reacted with 1-(4-bromo-3,5-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (0103-5) (209 mg, 0.609 mmol, 1.0 equiv.). A mixture of (methyl)pyrrolidin-2-one (0108-1) (122 mg, 0.67 mmol, 1.1 equiv.), sodium tert-butoxide (146 mg, 1.52 mmol, 2.5 equiv.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (35 mg, 0.0609 mmol, 0.1 equiv.), and tris(dibenzylideneacetone)dipalladium(0) (28 mg, 0.0305 mmol, 0.05 equiv.) in toluene (6 mL) was stirred at 120 °C for 10 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (8 mL × 3). The combined organic layer was washed with saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / methanol = 200 / 1 to 100 / 1) to give 1-((1-(2,6-difluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (69 mg, yield: 25.6%) as a yellow solid. LCMS (ESI): m / z = 445 [M+1] + . Step 5d: Preparation of 1-((1-(2,6-difluoro-4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (Compound 5): A mixture of 1-((1-(2,6-difluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (0109-5) (54 mg, 0.122 mmol, 1.0 equiv) in hydrogen chloride and dioxane (4 M, 2 ml) was stirred at room temperature for 1.0 hour. The solvent was removed under reduced pressure, and the residue was diluted with water (8 ml), adjusted to pH=9 with sodium carbonate solution, and extracted with dichloromethane (3 ml×5). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative thick-layer chromatography (dichloromethane / methanol=12 / 1) to give 1-((1-(2,6-difluoro-4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (37.1 mg, yield: 86.3%) as a white solid product. LCMS (ESI): m / z = 361 [M+1] + . 1 H NMR (500 MHz, DMSO) δ 12.95 (s, 1H), 8.22 (s, 1H), 7.94 (s, 1H), 7.30 (t, J = 8.0 Hz, 2H), 3.35 (t, J = 7.0 Hz, 2H), 3.19 - 3.05 (m, 4H), 2.98 (t, J = 11.3 Hz, 2H), 2.23 (t, J = 8.1 Hz, 2H), 1.94 (dd, J = 14.9, 7.4 Hz, 2H), 1.76 - 1.67 (m, 1H), 1.62 (d, J = 12.4 Hz, 2H), 1.31 - 1.23 (m, 2H).

[0070] Example 6: Preparation of 1-((1-(2,5-difluoro-4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (Compound 6) (prepared according to the route in Scheme 2) Step 6a: Preparation of 4-(4-bromo-2,5-difluorophenyl)-1H-pyrazole (compound 0205-6): Under nitrogen protection, 1,4-dibromo-2,5-difluorobenzene (0201-6) (653 mg, 2.4 mmol, 1.2 equiv.), 4-(1H-pyrazol-4-yl)boronic acid (224 mg, 2.0 mmol, 1.0 equiv.), sodium carbonate (424 mg, 4.0 mmol, 2.0 equiv.), and 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (81 mg, 0.1 mmol, 0.05 equiv.) were stirred overnight at 90° C. in a mixed solvent of 20 ml of dioxane and 2 ml of water. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, then distilled under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 200 / 1 to 30 / 1) to give 4-(4-bromo-2,5-difluorophenyl)-1H-pyrazole (119 mg, yield: 22.8%) as a yellow solid. MS (ES) + ): m / z=259 (M+H) + . Step 6b: Preparation of 4-(4-bromo-2,5-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (compound 0103-6): 4-(4-bromo-2,5-difluorophenyl)-1H-pyrazole (0205-6) (119 mg, 0.46 mmol, 1.0 equiv.) was dissolved in 20 mL of dichloromethane, and 3,4-dihydro-2H-pyran (78 mg, 0.92 mmol, 2.0 equiv.) and p-toluenesulfonic acid monohydrate (18 mg, 0.092 mmol, 0.2 equiv.) were added. The mixture was stirred at room temperature for 2 hours. The reaction was quenched with aqueous sodium carbonate. The mixture was extracted with dichloromethane and washed with water and saturated brine. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1 to 4 / 1) to give 4-(4-bromo-2,5-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (169 mg, crude product) as a yellow oil. MS (ES) + ): m / z = 343 (M + H)+ . Step 6c: Preparation of 1-((1-(2,5-difluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (compound 0109-6): Under nitrogen protection, 4-(4-bromo-2,5-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (0103-6) (134 mg, 0.39 mmol, 1.0 equiv.), 1-(piperidine-4- A mixture of (methyl)pyrrolidin-2-one ((0108-1) 86 mg, 0.47 mmol, 1.2 equiv.), sodium tert-butoxide (154 mg, 1.6 mmol, 4.0 equiv.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (47 mg, 0.08 mmol, 0.2 equiv.), and tris(dibenzylideneacetone)dipalladium(0) (37 mg, 0.04 mmol, 0.1 equiv.) in toluene (15 mL) was stirred at 120° C. overnight. After cooling to room temperature, the reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative thin-layer chromatography (developer: dichloromethane / methanol = 20 / 1) to give 1-((1-(2,5-difluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (33 mg, yield: 18.9%) as a yellow solid. MS (ES) + ): m / z=445 (M+H) + . Step 6d: Preparation of 1-((1-(2,5-difluoro-4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (Compound 6): 1-((1-(2,5-difluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (0109-6) (33 mg, 0.074 mmol, 1.0 equiv) was added to 5 mL of a 4 M solution of hydrogen chloride in methanol and the reaction was stirred at room temperature for 2 hours. The mixture was concentrated to dryness under reduced pressure. Water was added and the pH was adjusted to 10 with saturated aqueous sodium carbonate. Ethyl acetate was added for extraction, washed with water, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (eluent: dichloromethane / methanol = 12 / 1) to give 1-((1-(2,5-difluoro-4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (21 mg, yield: 78.6%) as a yellow solid. MS (ES) + ): m / z=361 (M+H) + .Melting point: turns brown at 220℃. 1 H NMR (500 MHz, DMSO) δ 13.00 (s, 1H), 8.09 (s, 1H), 7.89 (s, 1H), 7.51 (dd, J = 13.7, 7.3 Hz, 1H), 6.87 (dd, J = 12.8, 7.6 Hz, 1H), 3.44 - 3.34 (m, 4H), 3.10 (d, J = 7.2 Hz, 2H), 2.64 (t, J = 11.1 Hz, 2H), 2.23 (t, J = 8.0 Hz, 2H), 2.01 - 1.88 (m, 2H), 1.80 - 1.71 (m, 1H), 1.67 (d, J = 13.2 Hz, 2H), 1.26 (dd, J = 12.5, 5.2 Hz, 2H).

[0071] Example 7 Preparation of 1-((1-(4-(1H-pyrazol-4-yl)-2-(trifluoromethyl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (Compound 10) (Prepared according to the route in Scheme 2) Step 7a: Preparation of 4-(4-bromo-3-(trifluoromethyl)phenyl)-1H-pyrazole (compound 0205-10): To a mixture of 1-bromo-4-iodo-2-(trifluoromethyl)benzene (0201-10) (0.5 g, 1.43 mmol, 1.0 equiv), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (83 mg, 0.11 mmol, 0.08 equiv), and sodium carbonate (453 mg, 4.27 mmol, 3.0 equiv) in dioxane (10 ml) and water (1 ml) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-tert-butylcarboxylate (524 mg, 1.78 mmol, 1.25 equiv). The mixture was heated to 85°C under a nitrogen atmosphere and reacted for 5 hours. The solvent was removed under reduced pressure. The residue was separated by silica gel column chromatography (dichloromethane:methanol 30:1) to obtain 4-(4-bromo-3-(trifluoromethyl)phenyl)-1H-pyrazole (335 mg, yield: 81%) as a pale yellow oil. LCMS (ESI): m / z 291 [M+1] + TLC: Rf 0.3 (dichloromethane:methanol=30:1). Step 7b: Preparation of 4-(4-bromo-3-(trifluoromethyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (compound 0103-10): To a mixture of 4-(4-bromo-3-(trifluoromethyl)phenyl)-1H-pyrazole (0205-10) (335 mg, 1.15 mmol, 1.0 equiv.) and p-toluenesulfonic acid monohydrate (23 mg, 0.12 mmol, 0.1 equiv.) in dichloromethane (5 ml) was added 3,4-dihydro-2H-pyran (193 mg, 2.30 mmol, 2.0 equiv.). The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure. The residue was separated by column chromatography on silica gel (petroleum ether:ethyl acetate=6:1) to give 4-(4-bromo-3-(trifluoromethyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (430 mg, yield: 100%) as a pale yellow oil. LCMS (ESI): m / z 375 [M+1] + TLC: Rf 0.3 (petroleum ether:ethyl acetate=6:1). Step 7c: Preparation of 1-((1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (compound 0109-10): 4-(4-bromo-3-(trifluoromethyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (0103-10) (135 mg, 0.36 mmol, 1.0 equiv), tris(dibenzylideneacetone) To a mixture of 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (33.6 mg, 0.072 mmol, 0.2 equiv.), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (33.6 mg, 0.072 mmol, 0.2 equiv.), and sodium tert-butoxide (104 mg, 1.08 mmol, 3.0 equiv.) in dioxane (6 mL) was added 1-(piperidin-4-ylmethyl)pyrrolidin-2-one (0108-1) (79 mg, 0.43 mmol, 1.2 equiv.). The mixture was heated to 110°C under a nitrogen atmosphere and reacted for 7 hours. The mixture was diluted with water (20 mL). The aqueous layer was extracted with ethyl acetate (15 mL x 3). The combined organic layer was washed with saturated brine (20 mL x 1), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by pre-TLC (dichloromethane:methanol=25:1) to give 1-((1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (20 mg, yield: 12%) as a pale yellow solid. LCMS (ESI): m / z 477 [M+1] + TLC: Rf 0.5 (dichloromethane:methanol=25:1). Step 7d: Preparation of 1-((1-(4-(1H-pyrazol-4-yl)-2-(trifluoromethyl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (Compound 10): A mixture of 1-((1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-2-(trifluoromethyl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (0109-10) (20 mg, 0.042 mmol, 1.0 equiv) in hydrogen chloride-methanol solution (4 M, 1.5 ml) was stirred at room temperature for 2 hours. The mixture was diluted with water (15 ml). Solid sodium carbonate was added to adjust the pH to 10, and then the aqueous layer was extracted with ethyl acetate (15 ml × 3). The combined organic layer was washed with saturated brine (15 ml × 1), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by pre-TLC (ethyl acetate:methanol=10:1) to give 1-((1-(4-(1H-pyrazol-4-yl)-2-(trifluoromethyl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (13 mg, yield: 79%) as a white solid. LCMS (ESI): m / z 393 [M+1] + TLC: Rf 0.5 (dichloromethane:methanol=10:1). 1 H NMR (500 MHz, MeOD) δ 7.97 (s, 2H), 7.78 (s, 2H), 7.46 (s, 1H), 3.51 (s, 2H), 3.24 (s, 2H), 3.04 (s, 2H), 2.76 (s, 2H), 2.40 (s, 2H), 2.07 (s, 2H), 1.82 (s, 1H), 1.70 (s, 2H), 1.44 (s, 2H).

[0072] Example 8: Preparation of 1-((1-(2-chloro-4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (Compound 11) (prepared according to the route in Scheme 2) Step 8a: Preparation of 4-(4-bromo-3-chlorophenyl)-1H-pyrazole-1-tert-butylcarboxylate (compound 0204-11): Under nitrogen protection, a mixture of 1-bromo-2-chloro-4-iodobenzene (0201-11) (318 mg, 1.0 mmol, 1.0 equiv), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-tert-butylcarboxylate (353 mg, 1.2 mmol, 1.2 equiv), potassium carbonate (277 mg, 2.0 mmol, 2.0 equiv), and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (74 mg, 0.1 mmol, 0.1 equiv) in 30 ml of dioxane and 3 ml of water was stirred at 80 °C overnight. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, then distilled under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20 / 1 to 5 / 1) to give 4-(4-bromo-3-chlorophenyl)-1H-pyrazole-1-tert-butylcarboxylate (217 mg, yield: 60.6%) as a yellow solid. MS (ES) + ): m / z=357 (M+H) + . Step 8b: Preparation of 4-(4-bromo-3-chlorophenyl)-1H-pyrazole (compound 0205-11): 4-(4-bromo-3-chlorophenyl)-1H-pyrazole-1-tert-butylcarboxylate (0204-11) (200 mg, 0.56 mmol, 1.0 equiv.) was added to 5 mL of a 4 M solution of hydrogen chloride in dioxane, and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated to dryness under reduced pressure. Water was added, and the pH was adjusted to 8 with saturated aqueous sodium carbonate. Extraction was performed with ethyl acetate, followed by washing with water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 4-(4-bromo-3-chlorophenyl)-1H-pyrazole (113 mg, yield: 78.5%) as a yellow solid. MS (ES) + ): m / z=257 (M+H) + . Step 8c: Preparation of 4-(4-bromo-3-chlorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (compound 0103-11): 4-(4-bromo-3-chlorophenyl)-1H-pyrazole (0205-11) (113 mg, 0.44 mmol, 1.0 equiv.) was dissolved in 10 mL of dichloromethane, and 3,4-dihydro-2H-pyran (45 mg, 0.53 mmol, 1.2 equiv.) and p-toluenesulfonic acid monohydrate (8 mg, 0.044 mmol, 0.1 equiv.) were added. The mixture was stirred at room temperature for 2 hours. The reaction was quenched with aqueous sodium carbonate. The mixture was extracted with dichloromethane and washed with water and saturated brine. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20 / 1 to 5 / 1) to give 4-(4-bromo-3-chlorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (125 mg, yield: 83.1%) as a yellow oil. MS (ES) + ): m / z = 341 (M + H) + . Step 8d: Preparation of 1-((1-(2-chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (compound 0109-11): Under nitrogen protection, 4-(4-bromo-3-chlorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (0103-11) (108 mg, 0.32 mmol, 1.0 equiv.), 1-(piperidin-4-ylmethyl)pyrrolidin-2-one A mixture of pyrrolidin-2-one (0108-1) (64 mg, 0.35 mmol, 1.1 equiv.), sodium tert-butoxide (123 mg, 1.28 mmol, 4.0 equiv.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (37 mg, 0.064 mmol, 0.2 equiv.), and tris(dibenzylideneacetone)dipalladium(0) (29 mg, 0.032 mmol, 0.1 equiv.) in toluene (40 mL) was stirred at 120 °C overnight. After cooling to room temperature, the reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (eluent: dichloromethane / methanol = 33 / 1) to give 1-((1-(2-chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (51 mg, yield: 35.9%) as a yellow solid. MS (ES) + ): m / z=443 (M+H) + . Step 8e: Preparation of 1-((1-(2-chloro-4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (Compound 11): 1-((1-(2-chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (0109-11) (51 mg, 0.12 mmol, 1.0 equiv) was added to 2 mL of a 4 M solution of hydrogen chloride in methanol and stirred at room temperature for 2 hours. The mixture was concentrated to dryness under reduced pressure. Water was added and the pH was adjusted to 10 with saturated aqueous sodium carbonate. Ethyl acetate was added for extraction, washed with water, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (eluent: dichloromethane / methanol = 12 / 1) to give 1-((1-(2-chloro-4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (30 mg, yield: 72.0%) as a yellow solid. MS (ES) + ): m / z=359 (M+H) + ,Melting point: 188~190℃. 1 H NMR (500 MHz, DMSO) δ 12.89 (s, 1H), 8.16 (s, 1H), 7.89 (s, 1H), 7.64 (d, J = 2.0 Hz, 1H), 7.49 (dd, J = 8.3, 2.1 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 3.36 (t, J = 7.0 Hz, 2H), 3.25 (d, J = 11.7 Hz, 2H), 3.12 (d, J = 7.2 Hz, 2H), 2.60 (dd, J = 11.6, 9.9 Hz, 2H), 2.23 (t, J = 8.1Hz, 2H), 1.98 - 1.87 (m, 2H), 1.77 - 1.59 (m, 3H), 1.37 - 1.27 (m, 2H).

[0073] Example 9: Preparation of 1-((1-(2-methyl-4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (Compound 12) (prepared according to the route in Scheme 1) Step 9a: Preparation of 4-(4-bromo-3-methylphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (compound 0103-12): Under nitrogen protection, 4-bromo-3-methylphenylboronic acid (0101-12) (350 mg, 1.63 mmol, 1 equiv.), 4-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazoline A mixture of 453 mg (1.63 mmol, 1 equiv.), potassium carbonate (674 mg, 4.88 mmol, 3 equiv.), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (60 mg, 0.082 mmol, 0.05 equiv.), 1,4-dioxane (8 ml), and water (0.8 ml) was stirred at 90 °C for 30 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified using a silica gel column (petroleum ether / ethyl acetate = 10 / 1) to give 4-(4-bromo-3-methylphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (246 mg, yield: 47.16%) as a yellow oil. LCMS (ESI) [M+1] + :m / z =321. Step 9b: Preparation of 1-((1-(2-methyl-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (compound 0109-12): Under nitrogen protection, 4-(4-bromo-3-methylphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (0103-12) (128 mg, 0.40 mmol, 1 equiv.), 1-(piperidine-4 (-ylmethyl)pyrrolidin-2-one (0108-1) (80 mg, 0.44 mmol, 1.1 equiv.), sodium tert-butoxide (106 mg, 4.88 mmol, 3 equiv.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (23 mg, 0.040 mmol, 0.1 equiv.), tris(dibenzylideneacetone)dipalladium(0) (18 mg, 0.020 mmol, 0.05 equiv.), and toluene (5 mL) were mixed and stirred for 8 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column (dichloromethane / methanol=40 / 1) to give 1-((1-(2-methyl-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (60 mg, yield: 35.55%) as a yellow solid. LCMS (ESI) [M+1] + :m / z = 422. Step 9c: Preparation of 1-((1-(2-methyl-4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (Compound 12): A mixture of 1-((1-(2-methyl-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (0109-12) (60 mg, 0.14 mmol, 1.0 equiv) in hydrogen chloride-methanol (4 M, 2 ml) was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and the residue was diluted with water, adjusted to pH=9 with sodium carbonate solution, and extracted with dichloromethane. The organic layer was dried and concentrated under reduced pressure. The residue was purified by preparative thick-layer chromatography (dichloromethane / methanol=12 / 1) to give 1-((1-(2-methyl-4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (32 mg, yield: 67.62%) as a white solid product. LCMS (ESI) [M+1] + :m / z = 339. 1 H NMR (500 MHz, DMSO) δ 12.81 (s, 1H), 7.93 (d, J = 107.0 Hz, 2H), 7.51 - 7.23 (m, 2H), 6.98 (d, J = 7.5 Hz, 1H), 3.36 (s, 2H), 3.13 (d, J = 5.8 Hz, 2H), 3.04 (d, J = 9.6 Hz, 2H), 2.57 (d, J = 10.7 Hz, 2H), 2.25 (s, 5H), 1.95 (d, J = 6.0 Hz, 2H), 1.67 (d, J = 11.9 Hz, 3H), 1.30 (d, J = 10.1 Hz, 2H).

[0074] Example 10: Preparation of 2-(4-((2-oxopyrrolidin-1-yl)methyl)piperidin-1-yl)-5-(1H-pyrazol-4-yl)benzonitrile (Compound 13) (Prepared according to the route in Scheme 1) Step 10a: 2-fluoro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)benzaldehyde (compound 0103-13): Under nitrogen protection, (4-fluoro-3-formylphenyl)boronic acid (0101-13) (1 g, 5.99 mmol, 1.0 equiv.), 4-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H A mixture of 1.7 g (5.99 mmol, 1.0 equiv.), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (657 mg, 0.899 mmol, 0.15 equiv.), and potassium carbonate (2.5 g, 17.97 mmol, 3.0 equiv.) in dioxane / water (20 ml / 4 ml) was stirred at 70°C for 2.0 hours. The reaction mixture was diluted with water (50 ml) and then extracted with ethyl acetate (10 ml x 4). The organic layer was washed with saturated brine (40 ml x 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to give 2-fluoro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)benzaldehyde (884 mg, yield: 53.9%) as a yellow oil. LCMS (ESI): m / z = 275 [M+1] + . Step 10b: Preparation of 2-(4-((2-oxopyrrolidin-1-yl)methyl)piperidin-1-yl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)benzaldehyde (compound 0109-13): Under nitrogen protection, a mixture of 1-(piperidin-4-yl)pyrrolidin-2-one (0108-1) (364 mg, 2.0 mmol, 1.1 equiv), 2-fluoro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)benzaldehyde (0103-13) (500 mg, 1.82 mmol, 1.0 equiv), and potassium carbonate (753 mg, 5.46 mmol, 3.0 equiv) in N-methylpyrrolidone (8 ml) was stirred at 130° C. overnight. The reaction mixture was diluted with water (40 ml) and extracted with ethyl acetate (8 ml x 5). The organic layer was washed with saturated brine (30 ml x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified using a silica gel column (ethyl acetate / methanol = 250 / 1 to 100 / 1) to give 2-(4-((2-oxopyrrolidin-1-yl)methyl)piperidin-1-yl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)benzaldehyde (409 mg, yield: 51.6%) as a yellow solid. LCMS (ESI): m / z = 437 [M+1] + . Step 10c: Preparation of 2-(4-((2-oxopyrrolidin-1-yl)methyl)piperidin-1-yl)-5-(1H-pyrazol-4-yl)benzonitrile (Compound 13): Under nitrogen protection, a mixture of 2-(4-((2-oxopyrrolidin-1-yl)methyl)piperidin-1-yl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)benzaldehyde (0109-13) (210 mg, 0.482 mmol, 1.0 equiv), hydroxylamine hydrochloride (46.9 mg, 0.675 mmol, 1.4 equiv), and sodium ethoxide (79.1 mg, 0.964 mmol, 2.0 equiv) in acetonitrile / water (5.1 ml / 1.5 ml) was stirred at room temperature for 4.0 hours. The reaction mixture was diluted with water (20 ml) and then extracted with ethyl acetate (8 ml x 4). The combined organic layer was washed with saturated brine (30 ml x 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified using a silica gel column (dichloromethane / methanol = 60 / 1 to 40 / 1) to give (Z)-2-(4-((2-oxopyrrolidin-1-yl)methyl)piperidin-1-yl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)benzaldehyde oxime (131 mg, yield: 60.4%) as a yellow solid. LCMS (ESI): m / z 452 [M+1] + . Under nitrogen protection, a mixture of the (Z)-2-(4-((2-oxopyrrolidin-1-yl)methyl)piperidin-1-yl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)benzaldehyde oxime (131 mg, 0.288 mmol, 1.0 equivalent), potassium carbonate (79.6 mg, 0.576 mmol, 2.0 equivalent), acetic anhydride (59 mg, 0.576 mmol, 2.0 equivalent) and dimethyl sulfoxide (5 ml) was stirred at 50°C for 3.0 hours. The reaction mixture was diluted with water (20 ml) and extracted with ethyl acetate (8 ml x 4). The combined organic layer was washed with saturated brine (30 ml x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column (dichloromethane / methanol = 60 / 1 to 40 / 1) to give 2-(4-((2-oxopyrrolidin-1-yl)methyl)piperidin-1-yl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)benzonitrile (105 mg, yield: 84.7%) as a yellow oil. LCMS (ESI): m / z = 434 [M+1] + . A mixture of 2-(4-((2-oxopyrrolidin-1-yl)methyl)piperidin-1-yl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)benzonitrile (105 mg, 0.242 mmol, 1.0 equivalent) obtained above in hydrogen chloride and dioxane (4 M, 5 ml) was stirred at room temperature for 1.0 hour. The solvent was removed under reduced pressure, and the residue was diluted with water (8 ml), adjusted to pH 9 with sodium carbonate solution, and extracted with dichloromethane (4 ml × 5). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative thick-layer chromatography (dichloromethane / methanol=12 / 1) to give a pale yellow solid product, 2-(4-((2-oxopyrrolidin-1-yl)methyl)piperidin-1-yl)-5-(1H-pyrazol-4-yl)benzonitrile (72 mg, yield: 85.7%). LCMS (ESI): m / z = 350 [M+1] + . 1H NMR (500 MHz, DMSO) δ 12.92 (s, 1H), 8.21 (s, 1H), 7.94 (d, J = 2.1 Hz, 2H), 7.80 (dd, J = 8.6, 2.2 Hz, 1H), 7.13 (d, J = 8.6 Hz, 1H), 3.48 (t, J = 13.9 Hz, 2H), 3.36 (t, J = 7.0 Hz, 2H), 3.12 (d, J = 7.1 Hz, 2H), 2.76 (t, J = 11.0 Hz, 2H), 2.24 (t, J = 8.0 Hz, 2H), 1.99 - 1.87 (m, 2H), 1.75 (ddd, J = 24.9, 14.4, 8.3 Hz, 3H), 1.32 (qd, J = 12.1, 3.4 Hz, 2H).

[0075] Example 11: Preparation of 1-((1-(2-methoxy-4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (Compound 14): (Prepared according to the route in Scheme 2) Step 11a: Preparation of 4-(4-bromo-3-methoxyphenyl)-1H-pyrazole-1-tert-butylcarboxylate (compound 0204-14): Under nitrogen protection, 4-(4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde-2-yl)-1H-pyrazole-1-tert-butylcarboxylate (1.0 g, 3.4 mmol, 1.0 equiv.), 1-bromo A mixture of 4-iodo-2-methoxybenzene (0201-14) (1.6 g, 5.1 mmol, 1.5 equiv.), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (249 mg, 0.34 mmol, 0.1 equiv.), and sodium carbonate (1.08 g, 10.2 mmol, 3.0 equiv.) in dioxane / water (30 ml / 3 ml) was stirred at 85 °C for 1.5 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried and concentrated under reduced pressure. The residue was purified using a silica gel column (petroleum ether / ethyl acetate = 5 / 1) to give the product 4-(4-bromo-3-methoxyphenyl)-1H-pyrazole-1-tert-butylcarboxylate (564 mg, yield: 47.11%) as a white solid. LCMS (ESI): m / z = 353 [M+1] + . Step 11b: Preparation of 4-(4-bromo-3-methoxyphenyl)-1H-pyrazole (compound 0205-14): A mixture of 4-(4-bromo-3-methoxyphenyl)-1H-pyrazole-1-tert-butylcarboxylate (0204-14) (564 mg, 1.6 mmol, 1.0 equiv) in hydrogen chloride and dioxane (4 M, 5 ml) was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, and the residue was diluted with water, adjusted to pH = 9 with sodium carbonate solution, and extracted with dichloromethane. The organic layer was dried and concentrated under reduced pressure, and the residue was used directly in the next step without further purification. LCMS (ESI): m / z = 253 [M+1] + . Step 11c: Preparation of 4-(4-bromo-3-methoxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (compound 0103-14): A mixture of 4-(4-bromo-3-methoxyphenyl)-1H-pyrazole (0205-14) (291 mg, 1.15 mmol, 1.0 equiv.), 3,4-dihydro-2H-pyran (106.2 mg, 1.3 mmol, 1.1 equiv.), and p-toluenesulfonic acid monohydrate (21.8 mg, 0.1 mmol, 0.1 equiv.) in dichloromethane (10 ml) was stirred overnight at room temperature. The reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was dried and concentrated under reduced pressure. The residue was purified by silica gel column (petroleum ether / ethyl acetate=3 / 1) to give 4-(4-bromo-3-methoxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (200 mg, yield: 51.59%) as a white solid product. LCMS (ESI): m / z = 338 [M+1] + . Step 11d: Preparation of 1-((1-(2-methoxy-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (compound 0109-14): Under nitrogen protection, 1-(piperidin-4-ylmethyl)pyrrolidin-2-one (0108-1) (200 mg, 1.1 mmol, 1.0 equiv.), 4-(4-bromo-3-methoxyphenyl)-1-(tetrahydro-2H-pyran-2-yl) A mixture of 407 mg (1.2 mmol, 1.1 equiv.), sodium tert-butoxide (211 mg, 2.2 mmol, 2.0 equiv.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (63.19 mg, 0.11 mmol, 0.1 equiv.), and tris(dibenzylideneacetone)dipalladium(0) (50.3 mg, 0.055 mmol, 0.05 equiv.) in toluene (10 mL) was stirred overnight at 120° C. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried and concentrated under reduced pressure. The residue was purified by preparative thick-layer chromatography (dichloromethane / methanol=10 / 1) to give 1-((1-(2-methoxy-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (150 mg, yield: 31.18%) as a yellow solid product. LCMS (ESI): m / z = 439 [M+1] + . Step 11e: Preparation of 1-((1-(2-methoxy-4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (compound 14): A mixture of 1-((1-(2-methoxy-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (0109-14) (96 mg, 0.22 mmol, 1.0 equiv) in hydrogen chloride and methanol (4 M, 5 ml) was stirred at room temperature for 1.5 hours. The solvent was removed under reduced pressure, and the residue was diluted with water, adjusted to pH=9 with sodium carbonate solution, and extracted with dichloromethane. The organic layer was dried and concentrated under reduced pressure. The residue was purified by preparative thick-layer chromatography (dichloromethane / methanol=15 / 1) to give 1-((1-(2-methoxy-4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (91 mg, yield: 75.2%) as a yellow solid product. LCMS (ESI): m / z = 355 [M+1] + . 1 H NMR (500 MHz, DMSO) δ 12.80 (s, 1H), 8.08 (s, 1H), 7.84 (s, 1H), 7.14 - 7.04 (m, 2H), 6.84 (d, J = 8.1 Hz, 1H), 3.83 (s, 3H), 3.34 (dd, J = 15.8, 8.9 Hz, 4H), 3.10 (d, J = 7.1 Hz, 2H), 2.48 (d, J = 13.3 Hz, 2H), 2.23 (t, J = 8.0 Hz, 2H), 2.03 - 1.88 (m, 2H), 1.88 - 1.55 (m, 3H), 1.28 (ddd, J = 15.5, 12.4, 3.7 Hz, 2H).

[0076] Example 12: Preparation of 2-(4-((2-oxopyrrolidin-1-yl)methyl)piperidin-1-yl)-5-(1H-pyrazol-4-yl)benzaldehyde (Compound 15) (prepared according to the route in Scheme 1) A mixture of 2-(4-((2-oxopyrrolidin-1-yl)methyl)piperidin-1-yl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)benzaldehyde (0109-13) (139 mg, 0.32 mmol, 1.0 equiv) in hydrogen chloride and dioxane (4 M, 5 ml) was stirred at room temperature for 1.0 hour. The solvent was removed under reduced pressure, and the residue was diluted with water (8 ml), adjusted to pH 9 with sodium carbonate solution, and extracted with dichloromethane (4 ml × 5). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative thick-layer chromatography (dichloromethane / methanol=12 / 1) to give 2-(4-((2-oxopyrrolidin-1-yl)methyl)piperidin-1-yl)-5-(1H-pyrazol-4-yl)benzaldehyde (45.8 g, yield: 40.8%) as a yellow solid. LCMS (ESI): m / z = 353 [M+1] + . 1 H NMR (500 MHz, DMSO) δ 12.91 (s, 1H), 10.20 (s, 1H), 8.18 (s, 1H), 8.03 - 7.78 (m, 3H), 7.20 (d, J = 8.5 Hz, 1H), 3.37 (t, J = 7.0 Hz, 2H), 3.22 (d, J = 12.1 Hz, 2H), 3.14 (d, J = 7.2 Hz, 2H), 2.83 (dd, J = 11.7, 10.3 Hz, 2H), 2.24 (t, J = 8.1 Hz, 2H), 2.02 - 1.88 (m, 2H), 1.88 - 1.62 (m, 3H), 1.40 (td, J = 12.0, 3.2 Hz, 2H).

[0077] Example 13: Preparation of 2-(4-((2-oxopyrrolidin-1-yl)methyl)piperidin-1-yl)-5-(1H-pyrazol-4-yl)benzamide (Compound 16) A mixture of 2-(4-((2-oxopyrrolidin-1-yl)methyl)piperidin-1-yl)-5-(1H-pyrazol-4-yl)benzonitrile (Compound 13) (30 mg, 0.086 mmol, 1.0 equivalent) and sodium hydroxide (10.3 mg, 0.258 mmol, 3.0 equivalent) in dimethyl sulfoxide / hydrogen peroxide (2 ml / 0.5 ml) was stirred at 30°C for 2.0 hours. The reaction mixture was diluted with water (10 ml) and then extracted with ethyl acetate (5 ml x 4). The combined organic layer was washed with saturated brine (20 ml x 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative thick-layer chromatography (dichloromethane / methanol=10 / 1) to give 2-(4-((2-oxopyrrolidin-1-yl)methyl)piperidin-1-yl)-5-(1H-pyrazol-4-yl)benzamide (25.5 mg, yield: 80.7%) as a white solid product. LCMS (ESI): m / z 368 [M+1] + . 1 H NMR (500 MHz, DMSO) δ 12.89 (s, 1H), 8.72 (s, 1H), 8.14 (s, 1H), 7.95 (d, J = 2.0 Hz, 1H), 7.85 (s, 1H), 7.64 (dd, J = 8.3, 2.0 Hz, 1H), 7.50 (s, 1H), 7.19 (d, J = 8.4 Hz, 1H), 3.35 (t, J = 7.0 Hz, 2H), 3.12 (d, J = 7.2 Hz, 4H), 2.68 (t, J = 11.1 Hz, 2H), 2.23 (t, J = 8.0 Hz, 2H), 1.99 - 1.87 (m, 2H), 1.78 - 1.62 (m, 3H), 1.40 - 1.27 (m, 2H).

[0078] Example 14: Preparation of 1-((1-(2-(hydroxymethyl)-4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (Compound 17) Under nitrogen protection, 2-(4-((2-oxopyrrolidin-1-yl)methyl)piperidin-1-yl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)benzaldehyde (0109-13) (120 mg, 0.275 mmol, 1.0 equivalent) and sodium borohydride (41.5 mg, 1.1 mmol, 4.0 equivalents) were stirred at room temperature for 1.5 hours. The reaction mixture was diluted with water (20 ml) and then extracted with ethyl acetate (8 ml x 5). The combined organic layer was washed with saturated brine (30 ml x 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 1-((1-(2-(hydroxymethyl)-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (118 mg, yield: 98.3%) as a white solid. LCMS (ESI): m / z 439 [M+1] + . A mixture of the above-prepared 1-((1-(2-(hydroxymethyl)-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (118 mg, 0.269 mmol, 1.0 equivalent) in hydrogen chloride and dioxane (4 M, 5 ml) was stirred at room temperature for 1.0 hour. The solvent was removed under reduced pressure, and the residue was diluted with water (8 ml), adjusted to pH 9 with sodium carbonate solution, and extracted with dichloromethane (4 ml × 5). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative thick-layer chromatography (dichloromethane / methanol=10 / 1) to give 1-((1-(2-(hydroxymethyl)-4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (72 mg, yield: 98.3%) as a white solid product. LCMS (ESI): m / z = 355 [M+1] + . 1H NMR (500 MHz, DMSO) δ 12.82 (s, 1H), 7.92 (d, J = 94.0 Hz, 2H), 7.62 (d, J = 1.9 Hz, 1H), 7.40 (dd, J = 8.2, 2.1 Hz, 1H), 7.01 (d, J = 8.3 Hz, 1H), 5.04 (t, J = 5.4 Hz, 1H), 4.54 (d, J = 5.1 Hz, 2H), 3.36 (t, J = 7.0 Hz, 2H), 3.12 (d, J = 7.2 Hz, 2H), 3.02 (d, J = 11.8 Hz, 2H), 2.58 (t, J = 10.9 Hz, 2H), 2.23 (t, J = 8.0 Hz, 2H), 1.99 - 1.86 (m, 2H), 1.69 (ddd, J = 25.8, 14.9, 8.1 Hz, 3H), 1.35 - 1.24 (m, 2H).

[0079] Example 15: Preparation of 2-(4-((2-oxopyrrolidin-1-yl)methyl)piperidin-1-yl)-5-(1H-pyrazol-4-yl)methyl benzoate (Compound 18) Under nitrogen protection, a mixture of 2-(4-((2-oxopyrrolidin-1-yl)methyl)piperidin-1-yl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)benzaldehyde (0109-13) (80 mg, 0.183 mmol, 1.0 equivalent), a methanol solution of sodium methoxide (2 ml), and aqueous hydrogen peroxide (2 ml) in methanol (2 ml) was stirred at 45° C. for 3.0 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column (petroleum ether / ethyl acetate = 3 / 1 to 1 / 1) to give 2-(4-((2-oxopyrrolidin-1-yl)methyl)piperidin-1-yl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)benzoic acid (45 mg, yield: 54.8%) as a yellow solid product. LCMS (ESI): m / z = 453 [M+1] + . A mixture of 2-(4-((2-oxopyrrolidin-1-yl)methyl)piperidin-1-yl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)benzoic acid (45 mg, 0.099 mmol, 1.0 equivalent) obtained above in hydrogen chloride and methanol (4 M, 3 ml) was stirred at room temperature for 1.0 hour. The solvent was removed under reduced pressure, and the residue was diluted with water and adjusted to pH 7 with sodium carbonate solution. Extraction was performed with dichloromethane, and the organic layer was dried and concentrated under reduced pressure to obtain 2-(4-((2-oxopyrrolidin-1-yl)methyl)piperidin-1-yl)-5-(1H-pyrazol-4-yl)benzoic acid (25 mg, yield: 69.4%) as a yellow solid product. LCMS (ESI): m / z = 369 [M+1] + . A mixture of the above-obtained 2-(4-((2-oxopyrrolidin-1-yl)methyl)piperidin-1-yl)-5-(1H-pyrazol-4-yl)benzoic acid (25 mg, 0.068 mmol, 1.0 equivalent) and thionyl chloride (12 mg, 0.101 mmol, 1.5 equivalents) in methanol (2 ml) was stirred at 65° C. for 8.0 hours. The solvent was removed under reduced pressure, and the residue was diluted with water, adjusted to pH 9 with sodium carbonate solution, and extracted with dichloromethane. The organic layer was dried and concentrated under reduced pressure. The residue was purified by preparative thick-layer chromatography (dichloromethane / methanol=10 / 1) to obtain 2-(4-((2-oxopyrrolidin-1-yl)methyl)piperidin-1-yl)-5-(1H-pyrazol-4-yl)methylbenzoate (15 mg, yield: 57.6%) as a yellow solid product. LCMS(ESI):m / z=383[M+1] + Melting point: 165-174°C. 1H NMR (500 MHz, DMSO) δ 12.86 (s, 1H), 7.98 (d, J = 100.0 Hz, 2H), 7.79 - 7.59 (m, 2H), 7.07 (d, J = 7.3 Hz, 1H), 3.81 (s, 3H), 3.35 (s, 2H), 3.19 (d, J = 9.8 Hz, 2H), 3.10 (d, J = 4.7 Hz, 2H), 2.66 (t, J = 10.7 Hz, 2H), 2.23 (s, 2H), 1.93 (s, 2H), 1.76 - 1.51 (m, 3H), 1.25 (d, J = 9.9 Hz, 2H).

[0080] Example 16: Preparation of 1-((1-(2-(difluoromethyl)-4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (Compound 19) Under nitrogen protection, (diethylamino)sulfur trifluoride (132 mg, 0.825 mmol, 3.0 equiv.) was added dropwise to a mixture of 2-(4-((2-oxopyrrolidin-1-yl)methyl)piperidin-1-yl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)benzaldehyde (0109-13) (120 mg, 0.275 mmol, 1.0 equiv.) in dichloromethane (5 mL) at 0°C. The mixture was stirred at room temperature for 5.0 hours. The reaction mixture was diluted with water (20 mL) and then extracted with dichloromethane (8 mL × 3). The organic layer was washed with saturated brine (30 mL × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative thick-layer chromatography (dichloromethane / methanol=15 / 1) to give 1-((1-(2-(difluoromethyl)-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (79 mg, yield: 62.7%) as a yellow solid. LCMS (ESI): m / z 459 [M+1] + . A mixture of 1-((1-(2-(difluoromethyl)-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (79 mg, 0.172 mmol, 1.0 equivalent) obtained above in hydrogen chloride and dioxane (4 M, 4 ml) was stirred at room temperature for 1.0 hour. The solvent was removed under reduced pressure, and the residue was diluted with water (8 ml), adjusted to pH 9 with sodium carbonate solution, and extracted with dichloromethane (4 ml × 5). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative thick-layer chromatography (dichloromethane / methanol=12 / 1) to give 1-((1-(2-(difluoromethyl)-4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (34.4 mg, yield: 53.3%) as a yellow solid product. LCMS (ESI): m / z = 375 [M+1] + . 1 H NMR (500 MHz, DMSO) δ 12.93 (s, 1H), 8.21 (s, 1H), 7.92 (s, 1H), 7.81 - 7.59 (m, 2H), 7.28 (d, J = 8.3 Hz, 1H), 7.12 (t, J = 55.4 Hz, 1H), 3.36 (t, J = 7.0 Hz, 2H), 3.12 (d, J = 7.2 Hz, 2H), 2.99 (d, J = 11.7 Hz, 2H), 2.70 (dd, J = 11.6, 9.9 Hz, 2H), 2.23 (t, J = 8.1 Hz, 2H), 2.00 - 1.88 (m, 2H), 1.80 - 1.60 (m, 3H), 1.35 (qd, J = 12.1, 3.6 Hz, 2H).

[0081] Example 17: Preparation of 1-((1-(2-(dimethylamino)-4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (Compound 20) Step 17a: To a mixture of 1-fluoro-4-iodo-2-nitrobenzene (0.13 g, 0.49 mmol, 1.0 equiv.) and potassium carbonate (0.10 g, 0.73 mmol, 1.5 equiv.) in N-methylpyrrolidone (1.5 ml) was added 1-(piperidin-4-ylmethyl)pyrrolidin-2-one (97 mg, 0.54 mmol, 1.1 equiv.). The mixture was heated to 105 °C under a nitrogen atmosphere and reacted for 6 hours. The mixture was diluted with water (20 ml) and then extracted with ethyl acetate (15 ml x 3). The combined organic layers were washed with saturated brine (20 ml x 1), dried over anhydrous sodium sulfate and concentrated to give 1-((1-(4-iodo-2-nitrophenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (0.21 g, crude product) as a brown oil. LCMS (ESI): m / z 430 [M+1] + TLC: Rf 0.5 (dichloromethane:methanol=30:1). Step 17b: To a mixture of the above-prepared 1-((1-(4-iodo-2-nitrophenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (0.21 g, 0.49 mmol, 1.0 equiv.), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (36 mg, 0.05 mmol, 0.1 equiv.), and potassium carbonate (202 mg, 1.46 mmol, 3.0 equiv.) in dioxane (5 mL) and water (1 mL) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-tert-butylcarboxylate (172 mg, 0.58 mmol, 1.2 equiv.). The mixture was heated to 90°C under a nitrogen atmosphere and reacted overnight. The solvent was removed under reduced pressure. The residue was separated by column chromatography on silica gel (dichloromethane:methanol 25:1) to give 1-((1-(2-nitro-4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (150 mg, yield: 83%) as a brown oil. LCMS (ESI): m / z 370 [M+1] + TLC: Rf 0.5 (dichloromethane:methanol=10:1). Step 17c: To a mixture of the above-prepared 1-((1-(2-nitro-4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (150 mg, 0.41 mmol, 1.0 equiv.) and ammonium chloride (219 mg, 4.1 mmol, 10.0 equiv.) in methanol (5 ml), zinc powder (264 mg, 4.1 mmol, 10.0 equiv.) was added. Under a nitrogen atmosphere, the mixture was heated to 50°C and reacted for 1.5 hours. The mixture was diluted with water (20 ml) and then extracted with ethyl acetate (15 ml x 3). The combined organic layer was washed with saturated brine (20 ml x 1), dried over anhydrous sodium sulfate and concentrated to give 1-((1-(2-amino-4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (75 mg, yield: 54%) as a pale yellow solid. LCMS (ESI): m / z 340 [M+1] + TLC: Rf 0.4 (dichloromethane:methanol=10:1). Step 17d: To a mixture of the above-obtained 1-((1-(2-amino-4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (75 mg, 0.22 mmol, 1.0 equiv.), paraformaldehyde (159 mg, 1.77 mmol, 8.0 equiv.), and acetic acid (20 mg, 0.33 mmol, 1.5 equiv.) in methanol (4 ml), sodium cyanoborohydride (84 mg, 1.33 mmol, 6.0 equiv.) was added. The mixture was stirred at room temperature overnight. The mixture was diluted with water (20 ml). Solid sodium carbonate was added to adjust the pH to 10, and then the aqueous layer was extracted with ethyl acetate (15 ml × 3). The combined organic layer was washed with saturated brine (20 ml × 1), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by pre-TLC (ethyl acetate:methanol=10:1) to give 1-((1-(2-(dimethylamino)-4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (15 mg, yield: 19%) as a white solid. LCMS (ESI): m / z 368 [M+1] + TLC: Rf 0.5 (ethyl acetate:methanol=10:1). 1H NMR (500 MHz, MeOD) δ 7.83 (s, 2H), 7.22 - 7.02 (m, 2H), 6.91 (d, J = 8.0 Hz, 1H), 3.67 - 3.57 (m, 2H), 3.50 (t, J = 7.0 Hz, 2H), 3.23 (d, J = 7.2 Hz, 2H), 2.86 (s, 6H), 2.51 (t, J = 10.9 Hz, 2H), 2.41 (t, J = 8.1 Hz, 2H), 2.10 - 1.99 (m, 2H), 1.76 (dd, J = 23.7, 8.3 Hz, 3H), 1.44 (dd, J = 11.9, 3.1 Hz, 2H).

[0082] Example 18: Preparation of 1-((1-(5-(1H-pyrazol-4-yl)pyridin-2-yl)piperidin-4-yl)methyl)pyrrolidon-2-one (Compound 21) (prepared according to the route in Scheme 1) Step 18a: Preparation of 2-bromo-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyridine (compound 0103-21): Under nitrogen protection, (6-bromopyridin-3-yl)boronic acid (0101-21) (500 mg, 2.47 mmol, 1.1 equiv.), 4-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyridine A mixture of azole (0102-1) (625 mg, 2.25 mmol, 1.0 equiv.), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (82.4 mg, 0.113 mmol, 0.05 equiv.), and potassium carbonate (931 mg, 6.75 mmol, 3.0 equiv.) in dioxane / water (20 mL / 2 mL) was stirred at 105 °C for 3.0 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried and concentrated under reduced pressure. The residue was purified using a silica gel column (petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to give the product, 2-bromo-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyridine (346 mg, yield: 50.1%) as a yellow solid. LCMS(ESI):m / z=308[M+1] + . Step 18b: Preparation of 1-((1-(5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)piperidin-4-yl)methyl)pyrrolidin-2-one (compound 0109-21): Under nitrogen protection, 1-(piperidin-4-ylmethyl)pyrrolidin-2-one (0108-1) (84 mg, 0.458 mmol, 1.0 equiv.), 2-bromo-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole- A mixture of (4-yl)pyridine (0103-21) (155 mg, 0.504 mmol, 1.1 equiv.), sodium tert-butoxide (122.5 mg, 1.377 mmol, 3.0 equiv.), di-tert-butyl N,N-diethylphosphoramidite (11.4 mg, 0.045 mmol, 0.1 equiv.), and tris(dibenzylideneacetone)dipalladium(0) (20 mg, 0.023 mmol, 0.05 equiv.) in toluene (10 mL) was stirred overnight at 120° C. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried and concentrated under reduced pressure. The residue was purified by preparative thick-layer chromatography (ethyl acetate / methanol = 100 / 1 to 50 / 1) to give the product 1-((1-(5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)piperidin-4-yl)methyl)pyrrolidin-2-one (68 mg, yield: 36.3%) as a yellow solid. LCMS (ESI): m / z = 410 [M+1] + . Step 18c: Preparation of 1-((1-(5-(1H-pyrazol-4-yl)pyridin-2-yl)piperidin-4-yl)methyl)pyrrolidin-2-one (Compound 21): A mixture of 1-((1-(5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyridin-2-yl)piperidin-4-yl)methyl)pyrrolidin-2-one (0109-21) (68 mg, 0.166 mmol, 1.0 equiv) in hydrogen chloride and dioxane (4 M, 5 ml) was stirred at room temperature for 2.0 hours. The solvent was removed under reduced pressure, and the residue was diluted with water, adjusted to pH=9 with sodium carbonate solution, and extracted with dichloromethane. The organic layer was dried and concentrated under reduced pressure. The residue was purified by preparative thick-layer chromatography (dichloromethane / methanol=10 / 1) to give 1-((1-(5-(1H-pyrazol-4-yl)pyridin-2-yl)piperidin-4-yl)methyl)pyrrolidon-2-one (35 mg, yield: 64.8%) as a yellow solid product. LCMS (ESI): m / z = 326 [M+1] + Melting point: 125-134°C. 1 H NMR (500 MHz, DMSO) δ 12.78 (s, 1H), 8.36 (s, 1H), 7.93 (s, 2H), 7.71 (d, J = 8.7 Hz, 1H), 6.83 (d, J = 8.6 Hz, 1H), 4.24 (d, J = 12.8 Hz, 2H), 3.35 (d, J = 5.8 Hz, 2H), 3.06 (d, J = 6.9 Hz, 2H), 2.78 (t, J = 12.4 Hz, 2H), 2.22 (t, J = 7.5 Hz, 2H), 1.94 (dd, J = 14.1, 6.9 Hz, 2H), 1.84 (s, 1H), 1.62 (d, J = 12.9 Hz, 2H), 1.11 (q, J = 12.2 Hz, 2H).

[0083] Example 19: Preparation of 1-((1-(6-(1H-pyrazol-4-yl)pyridin-3-yl)piperidin-4-yl)methyl)pyrrolidin-2-one (Compound 22) (prepared according to the route in Scheme 2) Step 19a: Preparation of 5-bromo-2-(1H-pyrazol-4-yl)pyridine (compound 0205-22): Under nitrogen protection, a mixture of 2,5-dibromopyridine (0201-22) (593 mg, 2.5 mmol, 1.0 equiv), 4-(1H-pyrazol-4-yl)boronic acid (280 mg, 2.5 mmol, 1.0 equiv), sodium carbonate (530 mg, 5.0 mmol, 2.0 equiv), and [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (118 mg, 0.16 mmol, 0.065 equiv) in 60 ml of dioxane and 6 ml of water was stirred at 90° C. overnight. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, then distilled under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 100 / 1 to 20 / 1) to give 5-bromo-2-(1H-pyrazol-4-yl)pyridine (190 mg, yield: 33.9%) as a yellow solid. MS (ES) + ): m / z=224 (M+H) + . Step 19b: Preparation of 5-bromo-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyridine (compound 0103-22): 5-Bromo-2-(1H-pyrazol-4-yl)pyridine (0205-22) (190 mg, 0.85 mmol, 1.0 equiv.) was dissolved in 20 mL of dichloromethane, and 3,4-dihydro-2H-pyran (143 mg, 1.70 mmol, 2.0 equiv.) and p-toluenesulfonic acid monohydrate (16 mg, 0.085 mmol, 0.1 equiv.) were added. The mixture was stirred at room temperature for 2 hours. The reaction was quenched with aqueous sodium carbonate. The mixture was extracted with dichloromethane and washed with water and saturated brine. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 10 / 1 to 4 / 1) to give 5-bromo-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyridine (181 mg, yield: 69.0%) as a yellow oil. MS (ES + ): m / z=308(M+H) + . Step 19c: Preparation of 1-((1-(6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyridin-3-yl)piperidin-4-yl)methyl)pyrrolidin-2-one (compound 0109-22): Under nitrogen protection, 5-bromo-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyridine (0103-22) (150 mg, 0.49 mmol, 1.0 equiv.), 1-(piperidin-4-ylmethyl)pyrrolidin-2-one A mixture of pyrrolidin-2-one (0108-1) (107 mg, 0.58 mmol, 1.2 equiv.), sodium tert-butoxide (187 mg, 1.95 mmol, 4.0 equiv.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (57 mg, 0.098 mmol, 0.2 equiv.), and tris(dibenzylideneacetone)dipalladium(0) (45 mg, 0.049 mmol, 0.1 equiv.) in toluene (50 mL) was stirred overnight at 120° C. After cooling to room temperature, the reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative thin-layer chromatography (eluent: dichloromethane / methanol = 30 / 1) to give 1-((1-(6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyridin-3-yl)piperidin-4-yl)methyl)pyrrolidin-2-one (23 mg, yield: 11.5%) as a brown solid. MS (ES) + ): m / z=410 (M+H) + . Step 19d: Preparation of 1-((1-(6-(1H-pyrazol-4-yl)pyridin-3-yl)piperidin-4-yl)methyl)pyrrolidin-2-one (compound 22): 1-((1-(6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyridin-3-yl)piperidin-4-yl)methyl)pyrrolidin-2-one (0109-22) (23 mg, 0.056 mmol, 1.0 equiv) was added to 2 mL of a 4 M solution of hydrogen chloride in methanol and stirred at room temperature for 2 hours. The mixture was concentrated to dryness under reduced pressure. Water was added and the pH was adjusted to 10 with saturated aqueous sodium carbonate. Ethyl acetate was added for extraction, washed with water, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (eluent: dichloromethane / methanol = 12 / 1) to give 1-((1-(6-(1H-pyrazol-4-yl)pyridin-3-yl)piperidin-4-yl)methyl)pyrrolidin-2-one (13 mg, yield: 71.4%) as a yellow solid. MS (ES) + ): m / z=326 (M+H) + Melting point: 187-189°C. 1 H NMR (500 MHz, DMSO) δ 12.84 (s, 1H), 8.21 (d, J = 2.9 Hz, 1H), 8.18 - 7.82 (m, 2H), 7.49 (d, J = 8.7 Hz, 1H), 7.31 (dd, J = 8.8, 3.0 Hz, 1H), 3.71 (d, J = 12.5 Hz, 2H), 3.36 (d, J = 7.0 Hz, 2H), 3.09 (d, J = 7.3 Hz, 2H), 2.68 (td, J = 12.2, 2.3 Hz, 2H), 2.23 (t, J = 8.1 Hz, 2H), 2.00 - 1.87 (m, 2H), 1.77 (dtd, J = 14.9, 7.4, 3.7 Hz, 1H), 1.66 (d, J = 12.7 Hz, 2H), 1.24 (dd, J = 9.2, 4.4 Hz, 2H).

[0084] Example 20: Preparation of 1-((1-(5-(1H-pyrazol-4-yl)pyrimidin-2-yl)piperidin-4-yl)methyl)pyrrolidon-2-one (Compound 23) (Prepared according to the route in Scheme 1) Step 20a: Preparation of 2-chloro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyrimidine (compound 0103-23): Under nitrogen protection, (2-chloropyrimidin-5-yl)boronic acid (0101-23) (300 mg, 1.9 mmol, 1.0 equiv.), 4-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H A mixture of 1-pyrazole (0102-1) (580 mg, 2.09 mmol, 1.1 equiv.), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (139 mg, 0.19 mmol, 0.1 equiv.), and potassium carbonate (650 mg, 4.75 mmol, 2.5 equiv.) in dioxane / water (5 mL / 1 mL) was stirred at 105 °C for 3.0 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried and concentrated under reduced pressure. The residue was purified using a silica gel column (petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to give the product, 2-chloro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyrimidine (220 mg, yield: 43.7%) as a brown solid. LCMS(ESI): m / z = 265 [M+1] + . Step 20b: Preparation of 1-((1-(5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)piperidin-4-yl)methyl)pyrrolidin-2-one (compound 0109-23): Under nitrogen protection, 1-(piperidin-4-ylmethyl)pyrrolidin-2-one (0108-1) (82.3 mg, 0.46 mm A mixture of 2-chloro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyrimidine (0103-23) (110 mg, 0.42 mmol, 1.0 equiv.), ... and potassium carbonate (116 mg, 0.84 mmol, 2.0 equiv.) in N,N-dimethylcarboxamide (5 mL) was stirred at 80° C. for 1.5 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried and concentrated under reduced pressure. The residue was purified by preparative thick-layer chromatography (ethyl acetate / methanol = 100 / 1 to 30 / 1) to give the product 1-((1-(5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)piperidin-4-yl)methyl)pyrrolidin-2-one (150 mg, yield: 87.1%) as a yellow solid. LCMS (ESI): m / z = 411 [M+1] + . Step 20c: Preparation of 1-((1-(5-(1H-pyrazol-4-yl)pyrimidin-2-yl)piperidin-4-yl)methyl)pyrrolidin-2-one (Compound 23): A mixture of 1-((1-(5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)piperidin-4-yl)methyl)pyrrolidin-2-one (0109-23) (150 mg, 0.365 mmol, 1.0 equiv) in hydrogen chloride and methanol (4 M, 5 ml) was stirred at room temperature for 2.0 hours. The solvent was removed under reduced pressure, and the residue was diluted with water, adjusted to pH=9 with sodium carbonate solution, and extracted with dichloromethane. The organic layer was dried and concentrated under reduced pressure. The residue was purified by preparative thick-layer chromatography (dichloromethane / methanol=12 / 1) to give 1-((1-(5-(1H-pyrazol-4-yl)pyrimidin-2-yl)piperidin-4-yl)methyl)pyrrolidon-2-one (50 mg, yield: 42.0%) as a yellow solid product. LCMS (ESI): m / z = 327 [M+1] + . 1 H NMR (500 MHz, DMSO) δ 12.92 (s, 1H), 8.60 (s, 2H), 8.10 (s, 1H), 7.85 (s, 1H), 4.61 (d, J = 13.2 Hz, 2H), 3.35 (t, J = 7.0 Hz, 2H), 3.06 (d, J = 7.4 Hz, 2H), 2.88 (td, J = 13.1, 2.4 Hz, 2H), 2.22 (t, J = 8.1 Hz, 2H), 2.00 - 1.82 (m, 3H), 1.68 - 1.59 (m, 2H), 1.06 (qd, J = 12.4, 4.1 Hz, 2H).

[0085] Example 21: Preparation of 1-((1-(4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperidin-2-one (Compound 25) (prepared according to the route in Scheme 1) Step 21a: Preparation of 4-(2-oxopiperidin-1-yl)methyl)piperidine-1-tert-butylcarboxylate (compound 0107-25): Under nitrogen protection and an ice bath, sodium hydride (136.5 mg, 3.4 mmol, 2.0 equiv.) was added to a mixture of piperidin-2-one (0106-25) (338 mg, 3.4 mmol, 2.0 equiv.) and N,N-dimethylcarboxamide (20 mL), and the mixture was stirred at 80° C. for 30 minutes. 4-((methanesulfonyl)oxy)methyl)piperidine-1-tert-butylcarboxylate (0105-25) (500 mg, 1.7 mmol, 1.0 equiv.) was added to the mixture, and the mixture was stirred at 85° C. overnight. After cooling to room temperature, the reaction mixture was diluted with ammonium chloride and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column (petroleum ether / ethyl acetate=5 / 1) to give 4-(2-oxopiperidin-1-yl)methyl)piperidine-1-tert-butylcarboxylate (250 mg, yield: 49.5%) as a yellow solid. LCMS (ESI): m / z = 241 [M+1] + . Step 21b: Preparation of 1-(piperidin-4-ylmethyl)piperidin-2-one hydrochloride (compound 0108-25): A mixture of 4-((2-oxopiperidin-1-yl)methyl)piperidine-1-tert-butylcarboxylate (0107-25) (250 mg, 0.84 mmol, 1.0 equiv.) in hydrogen chloride-dioxane (4 M, 5 ml) was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, and the residue was used directly in the next step without further purification. LCMS (ESI): m / z = 197 [M+1] + . Step 21c: Preparation of 1-((1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperidin-2-one (compound 0109-25): Under nitrogen protection, a mixture of 1-(piperidin-4-ylmethyl)piperidin-2-one hydrochloride (0108-25) (200 mg, 1.02 mmol, 1.0 equiv.) and sodium tert-butoxide (587.7 mg, 6.12 mmol, 6.0 equiv.) in toluene (10 ml) was added. The mixture was stirred at 120° C. for 30 minutes, after which 4-(4-bromophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (0103-1) (343.5 mg, 1.12 mmol, 1.1 equiv.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (58.7 mg, 0.10 mmol, 0.1 equiv.), and tris(dibenzylideneacetone)dipalladium(0) (46.7 mg, 0.051 mmol, 0.05 equiv.) were added to the mixture and stirred overnight at 120° C. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried and concentrated under reduced pressure. The residue was purified by preparative thick-layer chromatography (dichloromethane / methanol=20 / 1) to give 1-((1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperidin-2-one (170 mg, yield: 39.5%) as a yellow solid. LCMS (ESI): m / z = 423 [M+1] + . Step 21d: Preparation of 1-((1-(4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperidin-2-one (Compound 25): A mixture of 1-((1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperidin-2-one (0109-25) (170 mg, 0.4 mmol, 1.0 equiv) in hydrogen chloride and methanol (4 M, 5 ml) was stirred at room temperature for 1.5 hours. The solvent was removed under reduced pressure, and the residue was diluted with water, adjusted to pH=9 with sodium carbonate solution, and extracted with dichloromethane. The organic layer was dried and concentrated under reduced pressure. The residue was purified by preparative thick-layer chromatography (dichloromethane / methanol=15 / 1) to give 1-((1-(4-1-((1-(4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperidin-2-one (70 mg, yield: 52.94%) as a yellow solid product. LCMS (ESI): m / z = 339 [M+1] + . 1 H NMR (500 MHz, DMSO) δ 12.75 (s, 1H), 7.99 (s, 1H), 7.78 (s, 1H), 7.41 (d, J = 8.6 Hz, 2H), 6.90 (d, J = 8.7 Hz, 2H), 3.66 (d, J = 12.4 Hz, 2H), 3.26 (t, J = 5.5 Hz, 2H), 3.20 (d, J = 7.4 Hz, 2H), 2.62 (dd, J = 12.0, 10.2 Hz, 2H), 2.22 (t, J = 6.2 Hz, 2H), 1.87 - 1.59 (m, 7H), 1.34 - 1.20 (m, 2H).

[0086] Example 22: Preparation of 1-((1-(4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidine-2,5-dione (Compound 28) (prepared according to the route in Scheme 7) Step 22a: Preparation of methyl 1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidine-4-formate (compound 0702-28): 4-(4-bromophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (0103-1) (200 mg, 0.65 mmol, 1.0 equiv.), tris(dibenzylideneacetone)dipalladium ( To a mixture of 0701-28 (30 mg, 0.033 mmol, 0.05 equiv.), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (61 mg, 0.13 mmol, 0.2 equiv.), and cesium carbonate (530 mg, 1.63 mmol, 2.5 equiv.) in dioxane (8 mL) was added piperidine-4-methyl formate (0701-28) (117 mg, 0.81 mmol, 1.25 equiv.). The mixture was heated to 100°C under a nitrogen atmosphere and stirred for 10 hours. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=3:1) to give methyl 1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidine-4-formate (186 mg, yield: 78%) as a pale yellow solid. LCMS (ESI): m / z 370 [M+1] + TLC: Rf 0.5 (petroleum ether:ethyl acetate=1:1). Step 22b: Preparation of (1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methanol (compound 0703-28): To a mixture of 1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidine-4-formate methyl ester (0702-28) (130 mg, 0.35 mmol, 1.0 equiv) in dichloromethane (6 ml) was added diisobutylaluminum hydride (1.5 M in toluene, 0.59 ml, 0.88 mmol, 2.5 equiv) dropwise at 0° C. The mixture was stirred at 0° C. for 1 hour. The reaction was quenched by the addition of saturated ammonium chloride solution (20 ml). The aqueous layer was extracted with dichloromethane (20 ml×3). The combined organic layer was washed with saturated brine (20 ml x 1), dried over anhydrous sodium sulfate and concentrated to give (1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methanol (118 mg, yield: 99%) as a pale yellow solid. LCMS (ESI): m / z 342 [M+1] + TLC: Rf 0.3 (petroleum ether:ethyl acetate=1:1). Step 22c: Preparation of 1-((1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidine-2,5-dione (compound 0705-28): (1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methanol (0703-28 (119 mg, 0.35 mmol, 1.0 equiv), succinimide (69 mg, 0.70 mmol, 2.0 equiv), and triphenylphosphine (138 mg, 0.53 mmol, To a mixture of 1H-tetrahydro-2H-pyran-2-yl (1.5 equivalents) and tetrahydrofuran (6 ml) was added diisopropyl azodicarboxylate (107 mg, 0.53 mmol, 1.5 equivalents). The mixture was stirred overnight at 30° C. under a nitrogen atmosphere. The solvent was removed under reduced pressure. The residue was purified by column chromatography (ethyl acetate:methanol=60:1) to give 1-((1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidine-2,5-dione (66 mg, yield: 45%) as a pale yellow solid. LCMS (ESI): m / z 423 [M+1] + TLC: Rf 0.5 (dichloromethane:methanol=20:1). Step 22d: Preparation of 1-((1-(4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidine-2,5-dione (Compound 28): A mixture of 1-((1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidine-2,5-dione (0705-28) (66 mg, 0.16 mmol, 1.0 equiv) in hydrogen chloride-methanol solution (4 M, 3 ml) was stirred at room temperature for 2 hours. The mixture was diluted with water (20 ml). Solid sodium carbonate was added to adjust the pH to 10, and then the aqueous layer was extracted with ethyl acetate (20 ml × 3). The combined organic layer was washed with saturated brine (20 ml × 1), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by pre-TLC (ethyl acetate:dichloromethane:methanol=10:10:1) to give 1-((1-(4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidine-2,5-dione (25 mg, yield: 47%) as a white solid. LCMS (ESI): m / z 339 [M+1] + TLC: Rf 0.5 (dichloromethane:methanol=10:1). 1 H NMR (500 MHz, DMSO) δ 12.75 (s, 1H), 7.89 (s, 2H), 7.41 (s, 2H), 6.91 (s, 2H), 3.66 (s, 2H), 3.33 (s, 4H), 2.61 (d, J = 31.7 Hz, 4H), 1.70 (d, J = 38.6 Hz, 2H), 1.24 (s, 3H).

[0087] Example 23 Preparation of 2-((1-(4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)-2-azaspiro[4.5]decan-1-one (Compound 31) (Prepared according to the route in Scheme 7) Step 23a: Preparation of (1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl methanesulfonate (compound 0704-31): To a mixture of (1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methanol (0703-28) (294 mg, 0.86 mmol, 1.0 equiv) and N,N-diisopropylethylamine (222 mg, 1.72 mmol, 2.0 equiv) in dichloromethane (6 ml) was added methanesulfonyl chloride (148 mg, 1.29 mmol, 1.5 equiv) at 0° C. The mixture was warmed to room temperature and stirred for 0.5 hours. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:1) to give (1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl methanesulfonate (288 mg, yield: 80%) as a white solid. LCMS (ESI): m / z 420 [M+1] + TLC: Rf 0.5 (dichloromethane:methanol=20:1). Step 23b: Preparation of 2-((1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)-2-azaspiro[4.5]decan-1-one (compound 0705-31): To a mixture of sodium hydride (60% dispersion in mineral oil, 17 mg, 0.43 mmol, 2.0 equiv) in N,N-dimethylcarboxamide (3 ml) was added 2-azaspiro[4.5]decan-1-one (0704-31) (66 mg, 0.43 mmol, 2.0 equiv). The mixture was stirred at room temperature for 10 minutes, and (1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl methanesulfonate (90 mg, 0.22 mmol, 1.0 equivalent) was added. Then, under a nitrogen atmosphere, the mixture was heated to 65°C and reacted for 3 hours. The mixture was diluted with water (20 ml), and then the aqueous layer was extracted with ethyl acetate (15 ml x 3). The combined organic layer was washed with saturated brine (15 ml x 1), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by pre-TLC (ethyl acetate:dichloromethane:methanol=15:15:1) to give 2-((1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)-2-azaspiro[4.5]decan-1-one (52 mg, yield: 51%) as a pale yellow oil. LCMS (ESI): m / z 477 [M+1] + TLC: Rf 0.5 (dichloromethane:methanol=20:1). Step 23c: Preparation of 2-((1-(4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)-2-azaspiro[4.5]decan-1-one (Compound 31): A mixture of 2-((1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)-2-azaspiro[4.5]decan-1-one (0705-31) (52 mg, 0.11 mmol, 1.0 equiv) in a hydrogen chloride-methanol solution (4 M, 3 ml) was stirred at room temperature for 2 hours. The mixture was diluted with water (3 The mixture was diluted with 100 ml of ethyl acetate (15 ml x 3). Solid sodium carbonate was added to adjust the pH to 10, and then the aqueous layer was extracted with ethyl acetate (15 ml x 3). The combined organic layers were washed with saturated brine (20 ml x 1), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by pre-TLC (dichloromethane:methanol = 10:1) to give 2-((1-(4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)-2-azaspiro[4.5]decan-1-one (30 mg, yield: 70%) as a white solid. LCMS (ESI): m / z 393 [M+1] + TLC: Rf 0.5 (dichloromethane:methanol=10:1). 1 H NMR (500 MHz, MeOD) δ 7.83 (s, 2H), 7.43 (d, J = 8.6 Hz, 2H), 6.98 (d, J = 8.6 Hz, 2H), 3.66 (t, J = 10.6 Hz, 2H), 3.40 (t, J = 7.0 Hz, 2H), 3.21 (d, J = 7.3 Hz, 2H), 2.69 (t, J = 11.3 Hz, 2H), 2.01 (t, J = 6.9 Hz, 2H), 1.93 - 1.78 (m, 1H), 1.77 - 1.55 (m, 6H), 1.39 (dt, J = 19.9, 11.5 Hz, 6H), 1.29 (d, J = 3.6 Hz, 2H).

[0088] Example 24 Preparation of 2-((1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)-2-azabicyclo[2.2.1]heptan-3-one (Compound 33) (Prepared according to the route in Scheme 7) Step 24a: Preparation of 2-((1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)-2-azabicyclo[2.2.1]heptan-3-one (compound 0705-33): To a mixture of sodium hydride (60% dispersion in mineral oil, 15 mg, 0.38 mmol, 2.0 equiv.) in N,N-dimethylcarboxamide (2.5 ml) was added 2-azabicyclo[2.2.1]heptan-3-one (0704-31) (42 mg, 0.38 mmol, 2.0 equiv.). The mixture was stirred at room temperature for 10 minutes. (1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl methanesulfonate (80 mg, 0.19 mmol, 1.0 equivalent) was added, and then the mixture was heated to 65°C under a nitrogen atmosphere and reacted for 3 hours. The mixture was diluted with water (20 ml), and then the aqueous layer was extracted with ethyl acetate (15 ml x 3). The combined organic layer was washed with saturated brine (20 ml x 1), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by pre-TLC (ethyl acetate:dichloromethane:methanol=15:15:1) to give 2-((1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)-2-azabicyclo[2.2.1]heptan-3-one (40 mg, yield: 48%) as a pale yellow oil. LCMS (ESI): m / z 435 [M+1] + TLC: Rf 0.5 (dichloromethane:methanol=20:1). Step 24b: Preparation of 2-((1-(4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)-2-azabicyclo[2.2.1]heptan-3-one (Compound 33): A mixture of 2-((1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)-2-azabicyclo[2.2.1]heptan-3-one (0705-33) (40 mg, 0.092 mmol, 1.0 equiv) in hydrogen chloride-methanol solution (4 M, 2.5 ml) was stirred at room temperature for 2 hours. The mixture was diluted with water (15 ml). Solid sodium carbonate was added to adjust the pH to 10, and then the aqueous layer was extracted with ethyl acetate (15 ml x 3). The combined organic layer was washed with saturated brine (20 ml × 1), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by pre-TLC (dichloromethane:methanol:ammonia water = 10:1:0.1) to give 2-((1-(4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)-2-azabicyclo[2.2.1]heptan-3-one (17 mg, yield: 53%) as a white solid. LCMS (ESI): m / z 351 [M+1] + TLC: Rf 0.5 (dichloromethane:methanol=10:1). 1 H NMR (500 MHz, MeOD) δ 7.83 (s, 2H), 7.44 (d, J = 8.5 Hz, 2H), 6.99 (d, J = 8.6 Hz, 2H), 3.95 (s, 1H), 3.68 (d, J = 11.6 Hz, 2H), 3.28 (d, J = 7.6 Hz, 1H), 2.92 - 2.64 (m, 4H), 2.00 - 1.64 (m, 7H), 1.44 (ddd, J = 28.4, 23.3, 13.1 Hz, 4H).

[0089] Example 25: Preparation of 1-((1-(4-(isoxazol-5-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (Compound 34) 1-(piperidin-4-ylmethyl)pyrrolidin-2-one (120 mg, 0.66 mmol, 1.0 equiv.) was added to a mixture of 4-iodoacetophenone (162 mg, 0.66 mmol, 1.0 equiv.), palladium acetate (14.8 mg, 0.066 mmol, 0.1 equiv.), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (62 mg, 0.132 mmol, 0.2 equiv.), and cesium carbonate (430 mg, 1.32 mmol, 2.0 equiv.) in toluene (15 mL). The mixture was heated to 100 °C under a nitrogen atmosphere and reacted for 5 hours. The solvent was removed under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol=30:1) to give 1-((1-(4-acetylphenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (68 mg, yield: 34%) as a pale yellow solid. LCMS (ESI): m / z 301 [M+1] + TLC: Rf 0.5 (dichloromethane:methanol=10:1). To a mixture of the 1-((1-(4-acetylphenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (68 mg, 0.23 mmol, 1.0 equivalent) obtained above and N,N-dimethylcarboxamide (1 ml) was added 1,1-dimethoxy-N,N-dimethylmethylamine (0.5 ml). The mixture was heated to 125°C under a nitrogen atmosphere and reacted overnight. The solvent was removed under reduced pressure, and the residue was then dried in vacuo to obtain (E)-1-((1-(4-(3-(dimethylamino)acryloyl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (85 mg, crude product) as a pale yellow solid. LCMS (ESI): m / z 356 [M+1] + TLC: Rf 0.3 (dichloromethane:methanol=20:1). To a mixture of the (E)-1-((1-(4-(3-(dimethylamino)acryloyl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (81 mg, 0.23 mmol, 1.0 equivalent) obtained above in ethanol (3 ml) was added hydroxylamine hydrochloride (20.5 mg, 0.30 mmol, 1.3 equivalent). Under a nitrogen atmosphere, the mixture was heated to 90°C and reacted for 1.5 hours. The mixture was diluted with water (15 ml). Solid sodium carbonate was added to adjust the pH to 10, and then the aqueous layer was extracted with ethyl acetate (15 ml x 3). The combined organic layer was washed with saturated brine (20 ml x 1), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by pre-TLC (ethyl acetate:dichloromethane:methanol=15:15:2) to give (1-((1-(4-(isoxazol-5-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (28 mg, yield: 38%) as a pale yellow solid. LCMS (ESI): m / z 326 [M+1] + TLC: Rf 0.5 (dichloromethane:methanol=15:1). 1 H NMR (500 MHz, MeOD) δ 8.33 (d, J = 1.9 Hz, 1H), 7.67 (t, J = 5.8 Hz, 2H), 7.02 (d, J = 8.9 Hz, 2H), 6.54 (d, J = 1.9 Hz, 1H), 3.86 (d, J = 12.8 Hz, 2H), 3.50 (t, J = 7.1 Hz, 2H), 3.20 (d, J = 7.4 Hz, 2H), 2.81 (td, J = 12.5, 2.5 Hz, 2H), 2.40 (t, J = 8.1 Hz, 2H), 2.15 - 1.97 (m, 2H), 1.88 (ddd, J = 11.3, 7.5, 3.8 Hz, 1H), 1.75 (d, J = 12.5 Hz, 2H), 1.36 (ddd, J = 17.9, 12.1, 6.2 Hz, 2H).

[0090] Example 26: Preparation of 1-(4-(1H-pyrazol-4-yl)phenyl)-4-(pyrrolidin-1-ylmethyl)piperidine (Compound 40) (prepared according to the route in Scheme 3) Step 26a: Preparation of 4-(pyrrolidine-1-carbonyl)piperidine-1-tert-butylcarboxylate (compound 0302-40): To a mixture of 1-(tert-butoxycarbonyl)piperidine-4-formic acid (0301-40) (350 mg, 1.53 mmol, 1.0 equiv.), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (380 mg, 1.98 mmol, 1.3 equiv.), 1-hydroxybenzotriazole (267 mg, 1.98 mmol, 1.3 equiv.), and N,N-diisopropylethylamine (592 mg, 4.59 mmol, 3.0 equiv.) in dichloromethane (10 mL) was added tetrahydropyrrole (141 mg, 1.98 mmol, 1.3 equiv.). The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure. The residue was separated by column chromatography on silica gel (dichloromethane:methanol 150:1) to give 4-(pyrrolidine-1-carbonyl)piperidine-1-tert-butylcarboxylate (420 mg, yield: 97%) as a pale yellow oil. LCMS (ESI): m / z 283 [M+1] + TLC: Rf 0.5 (dichloromethane:methanol=60:1). Step 26b: Preparation of piperidin-4-yl(pyrrolidin-1-yl)methanone (compound 0303-40): A mixture of 4-(pyrrolidine-1-carbonyl)piperidine-1-tert-butylcarboxylate (0302-40) (300 mg, 1.06 mmol, 1.0 equiv) in hydrogen chloride dioxane (4 M, 3 ml) was stirred at room temperature for 1.5 hours. The mixture was diluted with water (20 ml). Solid sodium carbonate was added to adjust the pH to 10, and then the aqueous layer was extracted with dichloromethane (10 ml x 8). The combined organic layer was washed with saturated brine (20 ml x 1), dried over anhydrous sodium sulfate, and concentrated to give piperidin-4-yl(pyrrolidin-1-yl)methanone (120 mg, yield: 62%) as a pale yellow oil. LCMS (ESI): m / z 183 [M+1] +TLC: Rf 0.3 (dichloromethane:methanol=5:1). Step 26c: Preparation of pyrrolidin-1-yl(1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methanone (compound 0304-40): 4-(4-bromophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (0103-1) (50 mg, 0.16 mmol, 1.0 equiv.), tris(dibenzylideneacetone)dipalladium ( To a mixture of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (7.5 mg, 0.008 mmol, 0.05 equiv.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (9.3 mg, 0.016 mmol, 0.1 equiv.), and sodium tert-butoxide (39 mg, 0.41 mmol, 2.5 equiv.) in toluene (5 mL) was added piperidin-4-yl(pyrrolidin-1-yl)methanone (0303-40) (36 mg, 0.20 mmol, 1.2 equiv.). The mixture was heated to 120° C. under a nitrogen atmosphere and reacted overnight. The solvent was removed under reduced pressure. The residue was purified by pre-TLC (ethyl acetate:methanol=30:1) to give pyrrolidin-1-yl(1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methanone (25 mg, yield: 38%) as a colorless oil. LCMS (ESI): m / z 409 [M+1] + TLC: Rf 0.5 (ethyl acetate:methanol=30:1). Step 26d: Preparation of 4-(pyrrolidin-1-ylmethyl)-1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidine (compound 0305-40): Under nitrogen protection, to a solution of pyrrolidin-1-yl(1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methanone (0304-40) (120 mg, 0.294 mmol, 1.0 equivalent) in tetrahydrofuran (12 ml), lithium aluminum hydride (0.88 ml, 1 mol / L tetrahydrofuran solution, 3.0 equivalents) was added at 0° C., and the mixture was stirred at 0° C. for 40 minutes. The reaction mixture was quenched with water, then 15% sodium hydroxide solution was added, and the mixture was filtered. The filtrate was extracted with ethyl acetate. The organic layer was dried and concentrated under reduced pressure. The residue was purified by preparative thick-layer chromatography (dichloromethane / methanol=12 / 1) to give 4-(pyrrolidin-1-ylmethyl)-1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidine (84 mg, yield: 73.0%) as a white solid product. LCMS (ESI): m / z = 395 [M+1] + . Step 26e: Preparation of 1-(4-(1H-pyrazol-4-yl)phenyl)-4-(pyrrolidin-1-ylmethyl)piperidine (Compound 40): A mixture of 4-(pyrrolidin-1-ylmethyl)-1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidine (0305-40) (50 mg, 0.118 mmol, 1.0 equiv) in hydrogen chloride in dioxane (4 M, 5 ml) was stirred at room temperature for 1.5 hours. The solvent was removed under reduced pressure, and the residue was diluted with water, adjusted to pH 9 with sodium carbonate solution, extracted with dichloromethane, and the organic layer was dried and concentrated under reduced pressure. The residue was purified by preparative thick-layer chromatography (dichloromethane / methanol=12 / 1) to give 1-(4-(1H-pyrazol-4-yl)phenyl)-4-(pyrrolidin-1-ylmethyl)piperidine (40 mg, yield: 60.6%) as a white solid product. LCMS (ESI): m / z = 311 [M+1] + .1 H NMR (500 MHz, DMSO) δ 12.76 (s, 1H), 7.99 (s, 1H), 7.78 (s, 1H), 7.41 (d, J = 8.7 Hz, 2H), 6.91 (d, J = 8.8 Hz, 2H), 3.60 (t, J = 38.4 Hz, 2H), 2.63 (dd, J = 12.0, 10.1 Hz, 3H), 2.43 (d, J = 65.9 Hz, 5H), 1.75 (dd, J = 70.4, 29.6 Hz, 7H), 1.26 - 1.17 (m, 2H).

[0091] Example 27: Preparation of 1-(4-(1H-pyrazol-4-yl)phenyl)-4-(4-chlorobenzyl)piperidine (Compound 41) (prepared according to the route in Scheme 4) Step 27a: Preparation of 4-(4-chlorobenzyl)piperidine (compound 0401-41): JPEG0007820560000042.jpg39170Under nitrogen protection, n-butyllithium (dissolved in 2.5 mmol / L tetrahydrofuran) (6.8 ml, 17.01 mmol, 1.3 equivalents) was added dropwise to a solution of 4-bromochlorobenzene (2.5 g, 13.09 mmol, 1 equivalent) in tetrahydrofuran (25 ml) at -70°C. The mixture was stirred for 30 minutes. 4-Formylpiperidine-1-tert-butylcarboxylate was slowly added dropwise to the mixture, and the reaction was stirred for 6 hours. The reaction solution was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column (petroleum ether / ethyl acetate=6 / 1) to give 4-((4-chlorophenyl)(hydroxy)methyl)piperidine-1-tert-butyl carbonate (2.01 g, yield: 47.21%) as a yellow oil. LCMS (ESI) [M+1] + :m / z =326. The 4-((4-chlorophenyl)(hydroxy)methyl)piperidine-1-tert-butyl carbonate (2.03 g, 6.25 mmol, 1 equivalent) obtained above, p-toluenesulfonic acid monohydrate (2.38 g, 12.50 mmol, 2 equivalents), and toluene (65 ml) were mixed at 120°C and stirred for 24 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified using alkaline alumina (dichloromethane / methanol = 20 / 1) to give 4-(4-chlorobenzylidene)piperidine (810 mg, yield: 62.61%) as a yellow oil. LCMS (ESI) [M+1] + :m / z = 208. Under a hydrogen atmosphere, the above-obtained 4-(4-chlorobenzylidene)piperidine (443 mg, 2.14 mmol, 1.0 equivalent), platinum dioxide (48 mg, 0.21 mmol, 0.1 equivalent), ethanol (2 ml), and acetic acid (2 ml) were stirred at room temperature for 2 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was adjusted to pH 9 with sodium carbonate solution and extracted with dichloromethane. The organic layer was dried and concentrated under reduced pressure to obtain 4-(4-chlorobenzyl)piperidine (423 mg, yield: 94.58%) as a pale yellow solid crude product. LCMS (ESI) [M+1] + :m / z = 210. Step 27b: Preparation of 4-(4-chlorobenzyl)-1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidine (compound 0402-41): Under nitrogen protection, 4-(4-chlorobenzyl)piperidine (0401-41) (100 mg, 0.48 mmol, 1 equiv.), 4-(4-bromophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolomethane were reacted at 120° C. A mixture of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (28 mg, 0.048 mmol, 0.1 equiv.), tris(dibenzylideneacetone)dipalladium(0) (22 mg, 0.024 mmol, 0.05 equiv.), and toluene (4 mL) was stirred overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified on a thick preparative silica gel plate (dichloromethane / methanol = 30 / 1) to give 4-(4-chlorobenzyl)-1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidine (47 mg, yield: 22.56%) as a white solid. LCMS (ESI) [M+1] + :m / z = 436. Step 27c: Preparation of 1-(4-(1H-pyrazol-4-yl)phenyl)-4-(4-chlorobenzyl)piperidine (compound 41): A mixture of 4-(4-chlorobenzyl)-1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidine (0402-41) (47 mg, 0.11 mmol, 1.0 equiv) and hydrogen chloride in methanol (4 M, 2 ml) was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and the residue was diluted with water, adjusted to pH 9 with sodium carbonate solution, and extracted with dichloromethane. The organic layer was dried and concentrated under reduced pressure. The residue was purified by preparative thick-layer chromatography (dichloromethane / methanol=10 / 1) to give 1-(4-(1H-pyrazol-4-yl)phenyl)-4-(4-chlorobenzyl)piperidine (34 mg, yield: 90.26%) as a white solid. LCMS (ESI) [M+1] + :m / z = 352. 1 H NMR (500 MHz, DMSO) δ 12.74 (s, 1H), 7.88 (d, J = 87.4 Hz, 2H), 7.37 (dd, J = 31.1, 8.2 Hz, 4H), 7.22 (d, J = 8.0 Hz, 2H), 6.92 (t, J = 27.0 Hz, 2H), 3.64 (d, J = 12.2 Hz, 2H), 2.57 (dd, J = 24.9, 9.1 Hz, 4H), 1.63 (d, J = 11.5 Hz, 3H), 1.31 (dd, J = 20.8, 10.7 Hz, 2H).

[0092] Example 28: Preparation of 2-((1-(4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one (Compound 42) (prepared according to the route in Scheme 4) Step 28a: Preparation of 2-(piperidin-4-ylmethyl)-3,4-dihydroisoquinolin-1(2H)-one hydrochloride (Compound 0403-42): Under nitrogen protection and an ice bath, sodium hydride (262.1 mg, 5.46 mmol, 2.0 equiv.) was added to a mixture of 3,4-dihydroisoquinolin-1(2H)-one (803.6 mg, 5.46 mmol, 2.0 equiv.) in N,N-dimethylcarboxamide (20 mL), and the mixture was stirred at 65° C. for 30 minutes. 4-((methanesulfonyl)oxy)methyl)piperidine-1-tert-butylcarboxylate (800 mg, 2.73 mmol, 1.0 equiv.) was added to the mixture, and the mixture was stirred at 65° C. overnight. After cooling to room temperature, the reaction mixture was diluted with ammonium chloride and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column (petroleum ether / ethyl acetate=5 / 1) to give 4-(1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidine-1-tert-butylcarboxylate (784 mg, yield: 83.4%) as a yellow solid product. LCMS (ESI): m / z = 289 [M+1] + . A mixture of the above-obtained 4-(1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidine-1-tert-butylcarboxylate (784 mg, 2.72 mmol, 1.0 equivalent) in hydrogen chloride-dioxane (4 M, 5 ml) was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, and the residue was used directly in the next step without further purification. LCMS (ESI): m / z = 233 [M+1] + . Step 28b: Preparation of 2-((1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one (compound 0404-42): Under nitrogen protection, 2-(piperidin-4-ylmethyl)-3,4-dihydroisoquinolin-1(2H)-one hydrochloride (0403-42) (200 mg, 0.5 mmol, 1.0 equiv.) and sodium tert-butoxide (334.8 mg, 3.49 mmol, 6.0 equiv.) were dissolved in toluene. The mixture was stirred at 120° C. for 30 minutes, and then 4-(4-bromophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (0103-1) (195.7 mg, 0.64 mmol, 1.1 equiv.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (33.4 mg, 0.058 mmol, 0.1 equiv.), and tris(dibenzylideneacetone)dipalladium(0) (26.6 mg, 0.029 mmol, 0.05 equiv.) were added to the mixture, and the mixture was stirred overnight at 120° C. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried and concentrated under reduced pressure. The residue was purified by preparative thick-layer chromatography (dichloromethane / methanol=20 / 1) to give 2-((1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one (70.3 mg, yield: 25.75%) as a yellow solid product. LCMS (ESI): m / z = 471 [M+1] + . Step 28c: Preparation of 2-((1-(4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one (compound 42): A mixture of 2-((1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one (0404-42) (70.3 mg, 0.15 mmol, 1.0 equiv) in hydrogen chloride and methanol (4 M, 5 ml) was stirred at room temperature for 1.5 hours. The solvent was removed under reduced pressure, and the residue was diluted with water, adjusted to pH=9 with sodium carbonate solution, and extracted with dichloromethane. The organic layer was dried and concentrated under reduced pressure. The residue was purified by preparative thick-layer chromatography (dichloromethane / methanol=12 / 1) to give 2-((1-(4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one (35 mg, yield: 60.64%) as a yellow solid product. LCMS (ESI): m / z = 387 [M+1] + . 1 H NMR (500 MHz, DMSO) δ 12.75 (s, 1H), 7.99 (s, 1H), 7.87 (d, J = 7.6 Hz, 1H), 7.78 (s, 1H), 7.49 - 7.37 (m, 3H), 7.39 - 7.22 (m, 2H), 6.91 (d, J = 8.4 Hz, 2H), 3.68 (d, J = 12.1 Hz, 2H), 3.57 (t, J = 6.3 Hz, 2H), 3.41 (d, J = 7.1 Hz, 2H), 2.98 (t, J = 6.0 Hz, 2H), 2.64 (t, J = 11.4 Hz, 2H), 1.87 (s, 1H), 1.71 (d, J = 12.1 Hz, 2H), 1.33 (dd, J = 20.8, 11.3 Hz, 2H).

[0093] Example 29: Preparation of N-((1-(4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)acetamide (Compound 43) (prepared according to the route in Scheme 5) Step 29a: Preparation of 4-(acetamidomethyl)piperidine-1-tert-butylcarboxylate (compound 0504-43): Acetyl chloride (322 mg, 5.13 mmol, 1.1 equiv.) was added to a mixture of 4-(aminomethyl)piperidine-1-tert-butylcarboxylate (0501-43) (800 mg, 4.67 mmol, 1.0 equiv.) and diisopropylethylamine (1.4 g, 14.0 mmol, 3.0 equiv.) in tetrahydrofuran under ice cooling. The reaction was then stirred at room temperature for 3 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried and concentrated under reduced pressure. The residue was purified using a silica gel column (dichloromethane / methanol = 10 / 1) to give 4-(acetamidomethyl)piperidine-1-tert-butylcarboxylate (554.6 mg, yield: 58.03%) as a yellow solid product. CMS (ESI): m / z = 308 [M+1] + Step 29b: Preparation of N-(piperidin-4-ylmethyl)acetamide (compound 0505-43): A mixture of 4-(acetamidomethyl)piperidine-1-tert-butylcarboxylate (0504-43) (554.6 mg, 1.8 mmol, 1.0 equiv) in hydrogen chloride-dioxane (4 M, 5 ml) was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, the pH was adjusted to alkaline with a small amount of saturated sodium bicarbonate solution, extracted with dichloromethane, and concentrated under reduced pressure. The residue was used directly in the next step without further purification. LCMS (ESI): m / z = 157 [M+1] + . Step 29c: Preparation of N-((1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)acetamide (compound 0506-43): Under nitrogen protection, N-(piperidin-4-ylmethyl)acetamide (0505-43) (200 mg, 0.78 mmol, 1.0 equiv.), 4-(4-bromophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)acetamide (compound 0506-43) was added. A mixture of 0103-1 (263 mg, 0.86 mmol, 1.1 equiv.), sodium tert-butoxide (450 mg, 4.68 mmol, 6.0 equiv.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (45 mg, 0.039 mmol, 0.1 equiv.), and tris(dibenzylideneacetone)dipalladium(0) (35 mg, 0.039 mmol, 0.05 equiv.) in toluene (10 mL) was stirred overnight at 120 °C. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried and concentrated under reduced pressure. The residue was purified by preparative thick-layer chromatography (dichloromethane / methanol=20 / 1) to give N-((1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)acetamide (91 mg, yield: 36.46%) as a yellow solid product. LCMS (ESI): m / z = 383 [M+1] + . Step 29d: Preparation of N-((1-(4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)acetamide (Compound 43): A mixture of N-((1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)acetamide (0506-43) (91 mg, 0.238 mmol, 1.0 equiv) in hydrogen chloride and methanol (4 M, 5 ml) was stirred at room temperature for 1.5 hours. The solvent was removed under reduced pressure, and the residue was diluted with water, adjusted to pH=9 with sodium carbonate solution, and extracted with dichloromethane. The organic layer was dried and concentrated under reduced pressure. The residue was purified by preparative thick-layer chromatography (dichloromethane / methanol=12 / 1) to give N-((1-(4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)acetamide (36.52 mg, yield: 51.49%) as a yellow solid product. LCMS (ESI): m / z = 299 [M+1] + . 1 H NMR (500 MHz, DMSO) δ 12.74 (s, 1H), 7.87 (dd, J = 44.2, 38.6 Hz, 3H), 7.41 (d, J = 8.6 Hz, 2H), 6.91 (d, J = 8.7 Hz, 2H), 3.66 (d, J = 12.3 Hz, 2H), 2.97 (t, J = 6.3 Hz, 2H), 2.74 - 2.52 (m, 3H), 1.81 (s, 3H), 1.71 (d, J = 11.7 Hz, 2H), 1.53 (ddt, J = 14.5, 7.4, 3.7 Hz, 1H), 1.27 - 1.23 (m, 2H).

[0094] Example 30: Preparation of N-((1-(4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)-6-hydroxyhexamide (Compound 45) (prepared according to the route in Scheme 5) Step 30a: Preparation of ((1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)benzylcarbamate (compound 0508-45)): Under nitrogen protection, (piperidin-4-ylmethyl)benzylcarbamate (0507-45) (400 mg, 1.61 mmol, 1.0 equiv.), 4-(4-bromophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (0 A mixture of 103-1 (737 mg, 2.41 mmol, 1.5 equiv.), sodium tert-butoxide (459 mg, 4.83 mmol, 3.0 equiv.), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (37.5 mg, 0.08 mmol, 0.05 equiv.), and tris(dibenzylideneacetone)dipalladium(0) (73.7 mg, 0.08 mmol, 0.05 equiv.) in toluene (15 mL) was stirred overnight at 120°C. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried and concentrated under reduced pressure. The residue was purified by preparative thick-layer chromatography (dichloromethane / methanol = 150 / 1 to 50 / 1) to give the product (1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)benzylcarbamate (55 mg, yield: 7.2%) as a yellow solid. LCMS (ESI): m / z = 475 [M+1] + . Step 30b: Preparation of (1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methylamine (compound 0509-45): Under nitrogen protection, a mixture of ((1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)benzylcarbamate (0508-45) (55 mg, 0.116 mmol, 1.0 equivalent) and wet palladium carbon (6 mg, 10% mass ratio) in methanol (20 ml) was stirred at room temperature for 5.0 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give (1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methylamine (32 mg, yield: 82.2%) as a yellow oil. MS (ES + ): m / z=341 (M+H) + Step 30c: Preparation of 6-hydroxy-N-((1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)hexamide (compound 0506-45): (1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methylamine (05 A mixture of 09-45 (32 mg, 0.094 mmol, 1.0 equiv.), 6-hydroxycaproic acid (0503-45) (18.6 mg, 0.14 mmol, 1.5 equiv.), triethylamine (18.9 mg, 0.188 mmol, 2.0 equiv.), and HATU (46.4 mg, 0.122 mmol, 1.3 equiv.) in N,N-dimethylcarboxamide (5 mL) was stirred at room temperature for 6.0 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 1 to 3 / 1) to give 6-hydroxy-N-((1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)hexamide (15 mg, yield: 35.2%) as a yellow oil. MS (ES)+ ): m / z=455 (M+H) + Step 30d: Preparation of N-((1-(4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)-6-hydroxyhexamide (Compound 45): A mixture of 6-hydroxy-N-((1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)hexamide (0506-45) (15 mg, 0.032 mmol, 1.0 equiv) in hydrogen chloride and methanol (4 M, 3 ml) was stirred at room temperature for 2.0 hours. The solvent was removed under reduced pressure, and the residue was diluted with water, adjusted to pH=9 with sodium carbonate solution, and extracted with dichloromethane. The organic layer was dried and concentrated under reduced pressure. The residue was purified by preparative thick-layer chromatography (dichloromethane / methanol=10 / 1) to give N-((1-(4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)-6-hydroxyhexamide (7 mg, yield: 58.3%) as a yellow solid product. LCMS (ESI): m / z = 371 [M+1] + Melting point: 103~114℃. 1 H NMR (500 MHz, DMSO) δ 12.74 (s, 1H), 7.99 (s, 1H), 7.77 (s, 2H), 7.41 (d, J = 8.5 Hz, 2H), 6.91 (d, J = 8.6 Hz, 2H), 4.30 (t, J = 4.8 Hz, 1H), 3.66 (d, J = 12.3 Hz, 2H), 3.37 (dd, J = 11.7, 6.3 Hz, 2H), 2.97 (t, J = 6.1 Hz, 2H), 2.60 (t, J = 11.6 Hz, 2H), 2.07 (t, J = 7.4 Hz, 2H), 1.71 (d, J = 11.8 Hz, 2H), 1.48 (dt, J = 28.4, 10.4 Hz, 3H), 1.44 - 1.34 (m, 2H), 1.26 (dd, J = 15.6, 8.7 Hz, 4H).

[0095] Example 31: Preparation of N-((1-(4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)cyclopentanecarboxamide (Compound 46) (prepared according to the route in Scheme 5) Step 31a: Preparation of 4-(cyclopentanecarboxamidomethyl)piperidine-1-tert-butylcarboxylate (compound 0504-46): To a mixture of cyclopentacarboxylic acid (0503-46) (548 mg, 4.8 mmol, 1.2 equiv.), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.98 g, 5.2 mmol, 1.3 equiv.), and triethylamine (1.01 g, 10.0 mmol, 2.5 equiv.) in N,N-dimethylcarboxamide (10 mL) was added 4-(aminomethyl)piperidine-1-tert-butylcarboxylate (0501-43) (856 mg, 4.0 mmol, 1.0 equiv.). The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with water and saturated brine. The organic layer was then distilled under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 200 / 1 to 30 / 1) to give 4-(cyclopentanecarboxamidomethyl)piperidine-1-tert-butylcarboxylate (1.63 g, crude product) as a yellow oil. MS (ES) + ): m / z=311 (M+H) + . Step 31b: Preparation of N-(piperidin-4-ylmethyl)cyclopentanecarboxamide hydrochloride (compound 0505-46): 4-(cyclopentanecarboxamidomethyl)piperidine-1-tert-butylcarboxylate (0504-46) (500 mg, 1.61 mmol, 1.0 equiv) was added to 5 mL of a 4 M solution of hydrogen chloride in methanol. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated to dryness under reduced pressure, and the residue was used directly in the next step without further purification (300 mg, crude product). MS (ES) + ): m / z=211 (M+H) + . Step 31c: Preparation of N-((1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)cyclopentanecarboxamide (compound 0506-46): Under nitrogen protection, 4-(4-bromophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (0103-1) (150 mg, 0.49 mmol, 1.0 equiv.), N-(piperidin-4-ylmethyl)cyclopentane A mixture of benzophenone carboxamide hydrochloride (0505-46) (242 mg, 0.98 mmol, 2.0 equiv.), sodium tert-butoxide (283 mg, 2.94 mmol, 6.0 equiv.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (58 mg, 0.1 mmol, 0.2 equiv.), and tris(dibenzylideneacetone)dipalladium(0) (46 mg, 0.05 mmol, 0.1 equiv.) in toluene (40 mL) was stirred overnight at 120° C. After cooling to room temperature, the reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative thin-layer chromatography (eluent: dichloromethane / methanol = 15 / 1) to give N-((1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)cyclopentanecarboxamide (51 mg, yield: 23.8%) as a yellow solid. MS (ES) + ): m / z=437 (M+H) + . Step 31d: Preparation of N-((1-(4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)cyclopentanecarboxamide (Compound 46): N-((1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)cyclopentanecarboxamide (0506-46) (51 mg, 0.117 mmol, 1.0 equiv) was added to 10 mL of a 4 M solution of hydrogen chloride in methanol and stirred at room temperature for 2 hours. The mixture was concentrated to dryness under reduced pressure. Water was added and the pH was adjusted to 10 with saturated aqueous sodium carbonate. The mixture was extracted with ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (eluent: dichloromethane / methanol = 12 / 1) to give N-((1-(4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)cyclopentanecarboxamide (23 mg, yield: 54.7%) as a yellow solid. MS (ES) + ): m / z=353 (M+H) + .Melting point: 215~217℃. 1 H NMR (500 MHz, DMSO) δ 12.73 (s, 1H), 7.86 (d, J = 7.5 Hz, 2H), 7.74 (t, J = 5.5 Hz, 1H), 7.41 (d, J = 8.4 Hz, 2H), 6.91 (d, J = 8.3 Hz, 2H), 3.66 (d, J = 12.2 Hz, 2H), 2.98 (t, J = 6.2 Hz, 2H), 2.68 - 2.52 (m, 3H), 1.71 (dd, J = 16.3, 6.9 Hz, 4H), 1.65 - 1.41 (m, 8H), 1.25 (s, 1H).

[0096] Example 32: Preparation of N-((1-(4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)benzamide (Compound 47) (prepared according to the route in Scheme 5) Step 32a: Preparation of 4-(benzamidomethyl)piperidine-1-tert-butylcarboxylate (compound 0504-47): Under nitrogen protection, a mixture of benzoic acid (300 mg, 2.46 mmol, 1.0 equiv.), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0501-43) (707 mg, 3.69 mmol, 1.5 equiv.), 1-hydroxybenzotriazole (498 mg, 3.69 mmol, 1.5 equiv.), and N,N-diisopropylethylamine (952 mg, 7.38 mmol, 3.0 equiv.) in N,N-dimethylcarboxamide (8 ml) was stirred at room temperature for 15 minutes. Then, a solution of 4-(aminomethyl)piperidine-1-tert-butylcarboxylate (631 mg, 2.95 mmol, 1.2 equivalents) in N,N-dimethylcarboxamide (8 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 3.0 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried and concentrated under reduced pressure. The residue was purified using a silica gel column (ethyl acetate) to obtain 4-(benzamidomethyl)piperidine-1-tert-butylcarboxylate (690 mg, yield: 81.4%) as a yellow solid product. Step 32b: Preparation of N-(piperidin-4-ylmethyl)benzamide (compound 0505-47): A mixture of 4-(benzamidomethyl)piperidine-1-tert-butylcarboxylate (0504-47) (510 mg, 0.675 mmol, 1.0 equiv) in hydrogen chloride-dioxane (4 M, 6 ml) was stirred at room temperature for 1.0 h. The solvent was removed under reduced pressure, and the residue was diluted with water, adjusted to pH=9 with sodium carbonate solution, and extracted with dichloromethane. The organic layer was dried and concentrated under reduced pressure. The residue was used directly in the next step without further purification. LCMS (ESI): m / z = 219 [M+1] + . Step 32c: Preparation of N-((1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)benzamide (compound 0506-47): Under nitrogen protection, N-(piperidin-4-ylmethyl)benzamide (0505-47) (250 mg, 1.15 mmol, 1.0 equiv.), 4-(4-bromophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole A mixture of (0103-1) (352 mg, 1.15 mmol, 1.0 equiv.), sodium tert-butoxide (275 mg, 2.86 mmol, 2.5 equiv.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (66.5 mg, 0.115 mmol, 0.1 equiv.), and tris(dibenzylideneacetone)dipalladium(0) (52 mg, 0.057 mmol, 0.05 equiv.) in toluene (15 mL) was stirred overnight at 120° C. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried and concentrated under reduced pressure. The residue was purified by preparative thick-layer chromatography (petroleum ether / ethyl acetate = 4 / 1 to 1 / 2) to give N-((1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)benzamide (120 mg, yield: 23.57%) as a yellow solid product. LCMS (ESI): m / z = 445 [M+1] + . Step 32d: Preparation of N-((1-(4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)benzamide (Compound 47): A mixture of N-((1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)benzamide (0506-47) (120 mg, 0.270 mmol, 1.0 equiv) in hydrogen chloride in dioxane (4 M, 5 ml) was stirred at room temperature for 1.5 hours. The solvent was removed under reduced pressure, and the residue was diluted with water, adjusted to pH=9 with sodium carbonate solution, extracted with dichloromethane, and the organic layer was dried and concentrated under reduced pressure. The residue was purified by preparative thick-layer chromatography (dichloromethane / methanol=12 / 1) to give a pink solid product, N-((1-(4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)benzamide (40 mg, yield: 33.61%). LCMS (ESI): m / z = 361 [M+1] + .

[0097] Example 33: Preparation of 1-(2-(1-(4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)ethyl)pyrrolidin-2-one (Compound 48) (prepared according to the route in Scheme 1) Step 33a: Preparation of 4-(2-((methanesulfonyl)oxy)ethyl)piperidine-1-tert-butylcarboxylate (compound 0105-48): Under nitrogen protection, a solution of methanesulfonyl chloride (275 mg, 3.27 mmol, 2.5 equiv) in dichloromethane (2 ml) was added to a mixture of 4-(2-hydroxyethyl)piperidine-1-tert-butylcarboxylate (0104-48) (300 mg, 1.31 mmol, 1.0 equiv), triethylamine (595 mg, 5.89 mmol, 4.5 equiv) in dichloromethane (8 ml) at 0° C. The mixture was stirred at room temperature for 3.0 hours. The reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was washed with brine and concentrated under reduced pressure. The residue was purified by silica gel column (petroleum ether / ethyl acetate=1 / 1) to give 4-(2-((methanesulfonyl)oxy)ethyl)piperidine-1-tert-butylcarboxylate (400 mg, yield: 99.26%) as a white solid product. LCMS (ESI): m / z = 308 [M+1] + . Step 33b: Preparation of 4-(2-(2-oxopyrrolidin-1-yl)ethyl)piperidine-1-tert-butylcarboxylate (Compound 0107-48): Under nitrogen protection, sodium hydride (77 mg, 1.92 mmol, 1.6 equiv.) was added to a mixture of pyrrolidone (0106-1) (123 mg, 1.44 mmol, 1.2 equiv.) in N,N-dimethylcarboxamide (8 mL) at 0° C. The mixture was stirred at room temperature for 30 minutes. Then, a solution of 4-(2-((methanesulfonyl)oxy)ethyl)piperidine-1-tert-butylcarboxylate (0105-48) (370 mg, 1.20 mmol, 1.0 equiv.) in N,N-dimethylcarboxamide (2 mL) was added to the mixture. The mixture was stirred at 65° C. for 3 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine and concentrated under reduced pressure. The residue was purified by silica gel column (dichloromethane / methanol=10 / 1) to give 4-(2-(2-oxopyrrolidin-1-yl)ethyl)piperidine-1-tert-butylcarboxylate (320 mg, yield: 90.14%) as a white oil. LCMS (ESI): m / z = 297 [M+1] +. Step 33c: Preparation of 1-(2-(piperidin-4-yl)ethyl)pyrrolidin-2-one hydrochloride (compound 0108-48): A mixture of 4-(2-(2-oxopyrrolidin-1-yl)ethyl)piperidine-1-tert-butylcarboxylate (0107-48) (320 mg, 1.08 mmol, 1.0 equiv) in hydrogen chloride-methanol (4 M, 4 ml) was stirred at room temperature for 2.0 hours. The solvent was removed under reduced pressure to give 1-(2-(piperidin-4-yl)ethyl)pyrrolidin-2-one hydrochloride (270 mg, crude product) as a white solid product. LCMS (ESI): m / z = 197 [M+1] + . Step 33d: Preparation of 1-(2-(1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)ethyl)pyrrolidin-2-one (compound 0109-48): Under nitrogen protection, 1-(2-(piperidin-4-yl)ethyl)pyrrolidin-2-one hydrochloride (0108-48) (100 mg, 0.43 mmol, 1.0 equiv.), 4-(4-bromophenyl)-1-(tetrahydro-2H-pyran- A mixture of (2-yl)-1H-pyrazole (133 mg, 0.43 mmol, 1.0 equiv.), sodium tert-butoxide (166 mg, 1.72 mmol, 4.0 equiv.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (25 mg, 0.043 mmol, 0.1 equiv.), and tris(dibenzylideneacetone)dipalladium(0) (20 mg, 0.022 mmol, 0.05 equiv.) in toluene (8 mL) was stirred overnight at 120° C. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried and concentrated under reduced pressure. The residue was purified by preparative thick-layer chromatography (dichloromethane / methanol=10 / 1) to give 1-(2-(1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)ethyl)pyrrolidin-2-one (45 mg, yield: 24.86%) as a yellow solid product. LCMS (ESI): m / z = 423 [M+1] + . Step 33e: Preparation of 1-(2-(1-(4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)ethyl)pyrrolidin-2-one (Compound 48): A mixture of 1-(2-(1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)ethyl)pyrrolidin-2-one (0109-48) (45 mg, 0.107 mmol, 1.0 equiv) in hydrogen chloride-methanol (4 M, 2 ml) was stirred at room temperature for 3.0 hours. The solvent was removed under reduced pressure, and the residue was diluted with water, adjusted to pH=9 with sodium carbonate solution, and extracted with dichloromethane. The organic layer was dried and concentrated under reduced pressure. The residue was purified by preparative thick-layer chromatography (dichloromethane / methanol=12 / 1) to give 1-(2-(1-(4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)ethyl)pyrrolidin-2-one (25 mg, yield: 69.44%) as a yellow solid product. LCMS (ESI): m / z = 339 [M+1] + . 1 H NMR (500 MHz, DMSO) δ 12.75 (s, 1H), 7.89 (d, J = 94.1 Hz, 2H), 7.41 (d, J = 8.7 Hz, 2H), 6.90 (d, J = 8.8 Hz, 2H), 3.64 (d, J = 12.4 Hz, 2H), 3.32 (t, J = 7.0 Hz, 2H), 3.23 (t, J = 7.2 Hz, 2H), 2.66 - 2.53 (m, 2H), 2.20 (t, J = 8.1 Hz, 2H), 1.97 - 1.82 (m, 2H), 1.77 (d, J = 11.2 Hz, 2H), 1.48 - 1.37 (m, 2H), 1.37 - 1.29 (m, 1H), 1.29 - 1.23 (m, 2H).

[0098] Example 34: Preparation of (1-(4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)(pyrrolidin-1-yl)methanone (Compound 49) A mixture of pyrrolidin-1-yl(1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methanone (0304-40) (25 mg, 0.061 mmol, 1.0 equiv.) in hydrogen chloride-methanol solution (4 M, 2 ml) was stirred at room temperature for 1.5 hours. The mixture was diluted with water (20 ml). Solid sodium carbonate was added to adjust the pH to 10, and then the aqueous layer was extracted with ethyl acetate (15 ml × 3). The combined organic layer was washed with saturated brine (20 ml × 1), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by pre-TLC (ethyl acetate:dichloromethane:methanol=10:10:2) to give (1-(4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)(pyrrolidin-1-yl)methanone (15 mg, yield: 76%) as a white solid. LCMS (ESI): m / z 325 [M+1] + TLC: Rf 0.5 (dichloromethane:methanol=10:1). 1 H NMR (500 MHz, MeOD) δ 7.83 (s, 2H), 7.44 (d, J = 8.7 Hz, 2H), 6.99 (d, J = 8.7 Hz, 2H), 3.74 (d, J = 12.4 Hz, 2H), 3.60 (t, J = 6.8 Hz, 2H), 3.42 (t, J = 6.9 Hz, 2H), 2.76 (td, J = 12.1, 3.2 Hz, 2H), 2.70 - 2.61 (m, 1H), 2.00 (p, J = 6.7 Hz, 2H), 1.94 - 1.78 (m, 6H).

[0099] Example 35: Preparation of (1-(4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)(morpholinyl)methanone (Compound 50) (prepared according to the route in Scheme 3) Step 35a: Preparation of 4-(morpholine-4-carbonyl)piperidine-1-tert-butylcarboxylate (compound 0302-50): A mixture of morpholine (228 mg, 2.62 mmol, 1.2 equiv), 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (0301-40) (500 mg, 2.18 mmol, 1.0 equiv), triethylamine (550 mg, 5.45 mmol, 2.5 equiv), 1-hydroxybenzotriazole (412 mg, 3.05 mmol, 1.4 equiv), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (586 mg, 3.05 mmol, 1.4 equiv) in N,N-dimethylcarboxamide (15 ml) was stirred at room temperature for 5 hours. The mixture was extracted with water and ethyl acetate, and the organic layer was washed with brine and concentrated under reduced pressure to give 4-(morpholine-4-carbonyl)piperidine-1-tert-butylcarboxylate (620 mg, yield: 95.3%) as a clear oil. MS (ES + ): m / z=299 (M+H) + Step 35b: Preparation of morpholine(piperidin-4-yl)methanone (compound 0303-50): A mixture of 4-(morpholine-4-carbonyl)piperidine-1-tert-butylcarboxylate (600 mg, 2.01 mmol, 1.0 equiv.) in hydrogen chloride and methanol (4 M, 10 ml) was stirred at room temperature for 3.0 hours. The solvent was removed under reduced pressure, and the residue was diluted with water, adjusted to pH 9 with sodium carbonate solution, extracted with dichloromethane, and the organic layer was dried and concentrated under reduced pressure. The residue was purified by preparative thick-layer chromatography (dichloromethane / methanol = 40 / 1) to give the product morpholine(piperidin-4-yl)methanone (395 mg, yield: 99.2%) as a yellow solid. LCMS (ESI): m / z = 199 [M+1] + . Step 35c: Preparation of morpholine(1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methanone (compound 0304-50): Under nitrogen protection, morpholine(piperidin-4-yl)methanone (0303-50) (200 mg, 1.01 mmol, 1.0 equiv.), 4-(4-bromophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole ( A mixture of 0103-1 (401 mg, 1.31 mmol, 1.3 equiv.), sodium tert-butoxide (270 mg, 3.03 mmol, 3.0 equiv.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (58.1 mg, 0.1 mmol, 0.1 equiv.), and tris(dibenzylideneacetone)dipalladium(0) (91.6 mg, 0.1 mmol, 0.1 equiv.) in toluene (15 mL) was stirred overnight at 120° C. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried and concentrated under reduced pressure. The residue was purified by preparative thick-layer chromatography (dichloromethane / methanol = 120 / 1 to 40 / 1) to give morpholine (1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methanone (65 mg, yield: 15.1%) as a yellow solid product. LCMS (ESI): m / z = 425 [M+1] + . Step 35d: Preparation of (1-(4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)(morpholinyl)methanone (Compound 50): A mixture of morpholine (1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methanone (50 mg, 0.117 mmol, 1.0 equiv) in hydrogen chloride and dioxane (4 M, 5 ml) was stirred at room temperature for 2.0 hours. The solvent was removed under reduced pressure, and the residue was diluted with water, adjusted to pH=9 with sodium carbonate solution, and extracted with dichloromethane. The organic layer was dried and concentrated under reduced pressure. The residue was purified by preparative thick-layer chromatography (dichloromethane / methanol=10 / 1) to give (1-(4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)(morpholinyl)methanone (15 mg, yield: 37.5%) as a yellow solid product. LCMS (ESI): m / z = 341 [M+1] + Melting point: 185-192°C. 1 H NMR (500 MHz, DMSO) δ 12.74 (s, 1H), 7.89 (d, J = 105.6 Hz, 2H), 7.55 - 7.28 (m, 2H), 7.03 - 6.78 (m, 2H), 3.82 - 3.42 (m, 10H), 2.83 - 2.64 (m, 3H), 1.78 - 1.58 (m, 4H).

[0100] Example 36: Preparation of (1-(4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)(piperazin-1-yl)methanone (Compound 51) (prepared according to the route in Scheme 3) Step 36a: Preparation of 4-(1-(tert-butoxycarbonyl)piperidine-4-carbonyl)piperazine-1-benzyl formate (compound 0302-51): To a mixture of 1-(tert-butoxycarbonyl)piperidine-4-formic acid (0301-40) (350 mg, 1.53 mmol, 1.0 equiv), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (380 mg, 1.98 mmol, 1.3 equiv), 1-hydroxybenzotriazole (267 mg, 1.98 mmol, 1.3 equiv), and N,N-diisopropylethylamine (592 mg, 4.59 mmol, 3.0 equiv) in dichloromethane (10 ml) was added benzyl piperazine-1-formate (403 mg, 1.83 mmol, 1.2 equiv). The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate 8:1) to give benzyl 4-(1-(tert-butoxycarbonyl)piperidine-4-carbonyl)piperazine-1-formate (615 mg, yield: 93%) as a pale yellow oil. LCMS (ESI): m / z 432 [M+1] + TLC: Rf 0.5 (petroleum ether:ethyl acetate=5:1). Step 36b: Preparation of 4-(piperidine-4-carbonyl)piperazine-1-benzyl formate (compound 0303-51): A mixture of 4-(1-(tert-butoxycarbonyl)piperidine-4-carbonyl)piperazine-1-benzyl formate (0302-51) (615 mg, 1.43 mmol, 1.0 equiv) in hydrogen chloride-dioxane solution (4 M, 5 ml) was stirred at room temperature for 1.5 hours. The mixture was diluted with water (20 ml). Solid sodium carbonate was added to adjust the pH to 10, and then the aqueous layer was extracted with dichloromethane (20 ml × 6). The combined organic layer was washed with saturated brine (20 ml × 1), dried over anhydrous sodium sulfate, and concentrated to give 4-(piperidine-4-carbonyl)piperazine-1-benzyl formate (0.47 g, yield: 100%) as a white solid. LCMS(ESI):m / z 332[M+1] + TLC: Rf 0.3 (dichloromethane:methanol=10:1). Step 36c: Preparation of 4-(1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidine-4-carbonyl)piperazine-1-benzyl formate (compound 0304-51): 4-(4-bromophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (0103-1) (100 mg, 0.33 mmol, 1.0 equiv.), tris(dibenzylideneacetone)dipalladium To a mixture of ammonium(0) (14.7 mg, 0.016 mmol, 0.05 equiv.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (18.8 mg, 0.033 mmol, 0.1 equiv.), and cesium carbonate (266 mg, 0.82 mmol, 2.5 equiv.) in toluene (8 mL) was added benzyl 4-(piperidine-4-carbonyl)piperazine-1-formate (0303-51) (129 mg, 0.39 mmol, 1.2 equiv.). The mixture was heated to 120°C under a nitrogen atmosphere and reacted for 9 hours. The solvent was removed under reduced pressure. The residue was purified by pre-TLC (ethyl acetate:methanol=60:1) to give benzyl 4-(1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidine-4-carbonyl)piperazine-1-formate (58 mg, yield: 32%) as a pale yellow solid. LCMS (ESI): m / z 558 [M+1] + TLC: Rf 0.5 (ethyl acetate:methanol=60:1). Step 36d: Preparation of (1-(4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)(piperazin-1-yl)methanone (Compound 51): A mixture of 4-(1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidine-4-carbonyl)piperazine-1-formate benzyl (0304-51) (56 mg, 0.10 mmol, 1.0 equiv) in hydrogen bromide in acetic acid (33% solution, 2 ml) was stirred at room temperature for 1 hour. The mixture was diluted with water (15 ml) and adjusted to pH 10 by adding solid sodium carbonate. The aqueous layer was then extracted with dichloromethane (15 ml × 4). The combined organic layer was washed with saturated brine (20 ml × 1), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by pre-TLC (dichloromethane:methanol:ammonia water=60:10:1) to give (1-(4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)(piperazin-1-yl)methanone (18 mg, yield: 53%) as a white solid. LCMS (ESI): m / z 340 [M+1] + TLC: Rf 0.3 (dichloromethane:methanol=10:1). 1 H NMR (500 MHz, MeOD) δ 7.84 (s, 2H), 7.45 (d, J = 8.6 Hz, 2H), 7.01 (d, J = 8.6 Hz, 2H), 3.88 (d, J = 23.5 Hz, 4H), 3.73 (d, J = 12.4 Hz, 2H), 3.29 - 3.18 (m, 4H), 2.82 (ddd, J = 23.5, 11.1, 3.7 Hz, 3H), 1.94 - 1.78 (m, 4H).

[0101] Example 37: Preparation of (1-(4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)(piperidin-1-yl)methanone (Compound 54) (prepared according to the route in Scheme 3) Step 37a: Preparation of 4-(piperidine-1-carbonyl)piperidine-1-tert-butylcarboxylate (compound 0302-54): Under nitrogen protection, a mixture of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (0301-40) (200 mg, 0.87 mmol, 1.0 equiv.), piperidine hydrochloride (127 mg, 1.05 mmol, 1.2 equiv.), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (250 mg, 1.30 mmol, 1.5 equiv.), 1-hydroxybenzotriazole (176 mg, 1.30 mmol, 1.5 equiv.), and N,N-diisopropylethylamine (562 mg, 4.36 mmol, 5.0 equiv.) in N,N-dimethylcarboxamide (10 ml) was stirred at room temperature for 4.0 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried and concentrated under reduced pressure. The residue was purified using a silica gel column (ethyl acetate) to give 4-(piperidine-1-carbonyl)piperidine-1-tert-butylcarboxylate (210 mg, yield: 81.4%) as a white solid product. Step 37b: Preparation of piperidin-1-yl(piperidin-4-yl)methanone hydrochloride (compound 0303-54): A mixture of 4-(piperidine-1-carbonyl)piperidine-1-tert-butylcarboxylate (0302-54) (200 mg, 0.228 mmol, 1.0 equiv) in hydrogen chloride-dioxane (4 M, 8 ml) was stirred at room temperature for 1.0 hour. The solvent was removed under reduced pressure, and the residue was used directly in the next step without further purification. LCMS (ESI): m / z = 197 [M+1] + . Step 37c: Preparation of piperidin-1-yl(1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methanone (compound 0304-54): Under nitrogen protection, piperidin-1-yl(piperidin-4-yl)methanone hydrochloride (0303-54) (150 mg, 0.44 mmol, 1.0 equiv.), 4-(4-bromophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1 A mixture of H-pyrazole (178 mg, 0.580 mmol, 0.9 equiv.), sodium tert-butoxide (248 mg, 2.58 mmol, 4.0 equiv.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (37 mg, 0.064 mmol, 0.1 equiv.), and tris(dibenzylideneacetone)dipalladium(0) (29.5 mg, 0.032 mmol, 0.05 equiv.) in toluene (12 mL) was stirred overnight at 120° C. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried and concentrated under reduced pressure. The residue was purified by preparative thick-layer chromatography (petroleum ether / ethyl acetate = 4 / 1 to 1 / 2) to give the product piperidin-1-yl(1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methanone (70 mg, yield: 25.73%) as a yellow solid. LCMS (ESI): m / z = 423 [M+1] + . Step 37d: Preparation of (1-(4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)(piperidin-1-yl)methanone (compound 54): A mixture of piperidin-1-yl(1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methanone (0304-54) (50 mg, 0.118 mmol, 1.0 equiv) in hydrogen chloride in dioxane (4 M, 5 ml) was stirred at room temperature for 1.5 hours. The solvent was removed under reduced pressure, and the residue was diluted with water, adjusted to pH=9 with sodium carbonate solution, and extracted with dichloromethane. The organic layer was dried and concentrated under reduced pressure. The residue was purified by preparative thick-layer chromatography (dichloromethane / methanol=12 / 1) to give a yellow solid product (1-(4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)(piperidin-1-yl)methanone (30 mg, yield: 75.22%). LCMS (ESI): m / z = 339 [M+1] + . 1 H NMR (500 MHz, DMSO) δ 12.75 (s, 1H), 7.89 (d, J = 109.1 Hz, 2H), 7.42 (d, J = 8.7 Hz, 2H), 6.91 (d, J = 8.8 Hz, 2H), 3.69 (d, J = 12.3 Hz, 2H), 3.47 (t, J = 20.6 Hz, 4H), 2.75 (ddt, J = 15.1, 12.3, 7.7 Hz, 3H), 1.72 - 1.63 (m, 4H), 1.59 (dt, J = 11.2, 5.6 Hz, 2H), 1.51 (s, 2H), 1.42 (s, 2H).

[0102] Example 38: Preparation of 1-(4-(1H-pyrazol-4-yl)phenyl)-N-cyclopentylpiperidine-4-carboxamide (Compound 55) (prepared according to the route in Scheme 8) Step 38a: Preparation of 1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidine-4-formic acid (compound 0801-55): To a mixture of methyl 1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidine-4-formate (0702-28) (100 mg, 0.27 mmol, 1.0 equiv) in tetrahydrofuran (5 ml) and water (2 ml) was added sodium hydroxide (33 mg, 0.81 mmol, 3.0 equiv). The mixture was stirred at room temperature for 3 hours. The mixture was diluted with water (15 ml). 1N hydrochloric acid was added to adjust the pH to 4, and then the aqueous layer was extracted with dichloromethane (15 ml x 4). The combined organic layer was washed with saturated brine (15 ml x 1), dried over anhydrous sodium sulfate and concentrated to give 1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidine-4-formic acid (90 mg, yield: 94%) as a white solid. LCMS (ESI): m / z 356 [M+1] + TLC: Rf 0.4 (dichloromethane:ethyl formate=10:1). Step 38b: Preparation of N-cyclopentyl-1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidine-4-carboxamide (compound 0802-55): 1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidine-4-formic acid (0801-55) (45 mg, 0.13 mmol, 1.0 equiv.) To a mixture of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (32 mg, 0.17 mmol, 1.3 equiv.), 1-hydroxybenzotriazole (22 mg, 0.17 mmol, 1.3 equiv.), and N,N-diisopropylethylamine (33 mg, 0.25 mmol, 2.0 equiv.) in dichloromethane (5 mL) was added cyclopentylamine (14 mg, 0.17 mmol, 1.3 equiv.). The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure. The residue was purified by pre-TLC (ethyl acetate:dichloromethane:methanol=15:15:1) to give N-cyclopentyl-1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidine-4-carboxamide (37 mg, yield: 69%) as a white solid. LCMS(ESI):m / z 423[M+1] + TLC: Rf 0.5 (dichloromethane:methanol=20:1). Step 38c: Preparation of 1-(4-(1H-pyrazol-4-yl)phenyl)-N-cyclopentylpiperidine-4-carboxamide (Compound 55): A mixture of N-cyclopentyl-1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidine-4-carboxamide (0802-55) (37 mg, 0.088 mmol, 1.0 equiv) in hydrogen chloride-methanol (4 M, 3 ml) was stirred at room temperature for 2 hours. The mixture was diluted with water (20 ml) and adjusted to pH=10 by the addition of solid sodium carbonate. The mixture was filtered. The solid was washed with water and then dried in vacuo to give 1-(4-(1H-pyrazol-4-yl)phenyl)-N-cyclopentylpiperidine-4-carboxamide (20 mg, 67% yield) as a white solid. LCMS(ESI):m / z 339[M+1]+ TLC: Rf 0.5 (dichloromethane:methanol=10:1). 1 H NMR (500 MHz, DMSO) δ 12.72 (s, 1H), 7.89 (s, 2H), 7.70 (d, J = 5.9 Hz, 1H), 7.41 (d, J = 7.8 Hz, 2H), 6.91 (d, J = 7.7 Hz, 2H), 3.98 (d, J = 6.4 Hz, 1H), 3.69 (d, J = 11.2 Hz, 2H), 2.63 (t, J = 10.9 Hz, 2H), 2.23 (s, 1H), 1.70 (dd, J = 40.1, 24.5 Hz, 8H), 1.49 (s, 2H), 1.35 (d, J = 6.1 Hz, 2H).

[0103] Example 39: Preparation of 1-(4-(1H-pyrazol-4-yl)phenyl)-N-phenylpiperidine-4-carboxamide (Compound 58) (prepared according to the route in Scheme 3) Step 39a: Preparation of 4-(phenylcarbamoyl)piperidine-1-tert-butylcarboxylate (compound 0306-58): Under nitrogen protection, a mixture of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (0301-40) (500 mg, 2.18 mmol, 1.0 equiv.), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (628 mg, 3.28 mmol, 1.5 equiv.), 1-hydroxybenzotriazole (442 mg, 3.28 mmol, 1.5 equiv.), and N,N-diisopropylethylamine (845 mg, 6.55 mmol, 3.0 equiv.) in N,N-dimethylcarboxamide (15 mL) was stirred at room temperature for 15 minutes. Aniline (203 mg, 2.18 mmol, 1.0 equiv.) was then added to the mixture. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine and concentrated under reduced pressure. The residue was purified using a silica gel column (petroleum ether / ethyl acetate = 1 / 1) to give 4-(phenylcarbamoyl)piperidine-1-tert-butylcarboxylate (395 mg, yield: 59.31%) as a yellow solid product. LCMS (ESI): m / z = 305 [M+1] + . Step 39b: Preparation of N-phenylpiperidine-4-carboxamide hydrochloride (compound 0307-58): A mixture of 4-(phenylcarbamoyl)piperidine-1-tert-butylcarboxylate (0306-58) (370 mg, 1.21 mmol, 1.0 equiv) in hydrogen chloride-methanol (4 M, 8 ml) was stirred at room temperature for 1.0 h. The solvent was removed under reduced pressure, and the residue was used directly in the next step without further purification. LCMS (ESI): m / z = 205 [M+1] + . Step 39c: Preparation of N-phenyl-1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidine-4-carboxamide (compound 0307-58): Under nitrogen protection, N-phenylpiperidine-4-carboxamide hydrochloride (0306-58) (200 mg, 0.98 mmol, 1.0 equiv.), 4-(4-bromophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole A mixture of (0103-1) (300 mg, 0.98 mmol, 1.0 equiv.), sodium tert-butoxide (282 mg, 2.93 mmol, 3.0 equiv.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (57 mg, 0.098 mmol, 0.1 equiv.), and tris(dibenzylideneacetone)dipalladium(0) (45 mg, 0.049 mmol, 0.05 equiv.) in toluene (10 mL) was stirred overnight at 120° C. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1 to 1 / 1) to give N-phenyl-1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidine-4-carboxamide (45 mg, yield: 11.46%) as a yellow solid product. LCMS (ESI): m / z = 431 [M+1] + . Step 39d: Preparation of 1-(4-(1H-pyrazol-4-yl)phenyl)-N-phenylpiperidine-4-carboxamide (Compound 58): A mixture of N-phenyl-1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidine-4-carboxamide (0308-58) (45 mg, 0.102 mmol, 1.0 equiv) in hydrogen chloride in dioxane (4 M, 5 ml) was stirred at room temperature for 1.5 hours. The solvent was removed under reduced pressure and the residue was diluted with water. The pH was adjusted to 9 with sodium carbonate solution and the mixture was extracted with dichloromethane. The organic layer was dried and concentrated under reduced pressure. The residue was purified by preparative thick-layer chromatography (dichloromethane / methanol=12 / 1) to give 1-(4-(1H-pyrazol-4-yl)phenyl)-N-phenylpiperidine-4-carboxamide (20 mg, yield: 55.56%) as a yellow solid product. LCMS (ESI): m / z = 347 [M+1] + . 1 H NMR (500 MHz, DMSO) δ 12.77 (s, 1H), 9.92 (s, 1H), 7.90 (s, 2H), 7.62 (d, J = 8.2 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 7.28 (t, J = 7.7 Hz, 2H), 7.02 (t, J = 7.3 Hz, 1H), 6.95 (d, J = 8.5 Hz, 2H), 3.76 (d, J = 12.3 Hz, 2H), 2.71 (t, J = 11.3 Hz, 2H), 2.52 (d, J = 15.0 Hz, 1H), 1.88 (d, J = 11.5 Hz, 2H), 1.82 - 1.71 (m, 2H).

[0104] Example 40 Preparation of (1-(4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)(2-azabicyclo[2.2.1]heptan-2-yl)methanone (Compound 65) (Prepared according to the route in Scheme 8) Step 40a: Preparation of (2-azabicyclo[2.2.1]heptan-2-yl)(1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methanone (compound 0803-65): 1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin To a mixture of benzo-4-formic acid (0801-55) (58 mg, 0.16 mmol, 1.0 equiv.), HATU (92 mg, 0.25 mmol, 1.5 equiv.), and N,N-diisopropylethylamine (42 mg, 0.32 mmol, 2.0 equiv.) in dichloromethane (5 mL) was added 2-azabicyclo[2.2.1]heptane (20 mg, 0.21 mmol, 1.3 equiv.). The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure. The residue was purified by pre-TLC (dichloromethane:methanol=20:1) to give (2-azabicyclo[2.2.1]heptan-2-yl)(1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methanone (50 mg, yield: 70%) as a pale yellow oil. LCMS (ESI): m / z = 435 [M+1] + TLC: Rf 0.5 (dichloromethane:methanol=20:1). Step 40b: Preparation of (1-(4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)(2-azabicyclo[2.2.1]heptan-2-yl)methanone (Compound 65): A mixture of (2-azabicyclo[2.2.1]heptan-2-yl)(1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methanone (15 mg, 0.035 mmol, 1.0 equiv) in hydrogen chloride-methanol solution (4 M, 2 ml) was stirred at room temperature for 2 hours. The mixture was diluted with water (15 ml). Solid sodium carbonate was added to adjust the pH to 10, and then the aqueous layer was extracted with ethyl acetate (10 ml × 3). The combined organic layer was washed with saturated brine (15 ml × 1), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by pre-TLC (ethyl acetate:methanol=10:1) to give (1-(4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)(2-azabicyclo[2.2.1]heptan-2-yl)methanone (10 mg, yield: 83%) as a white solid. LCMS (ESI): m / z 351 [M+1] + TLC: Rf 0.5 (ethyl acetate:methanol=10:1). 1 H NMR (500 MHz, DMSO) δ 12.74 (s, 1H), 8.12 - 7.67 (m, 2H), 7.42 (d, J = 8.2 Hz, 2H), 7.01 - 6.78 (m, 2H), 4.39 (s, 1H), 3.68 (t, J = 21.0 Hz, 2H), 3.43 (d, J = 8.7 Hz, 1H), 3.16 (d, J = 8.4 Hz, 1H), 2.75 - 2.55 (m, 3H), 1.79 - 1.27 (m, 11H).

[0105] Example 41: Preparation of (1-(4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)(isoindolin-2-yl)methanone (Compound 66) (prepared according to the route in Scheme 3) Step 41a: Preparation of 4-(isoindoline-2-carbonyl)piperidine-1-tert-butylcarboxylate (Compound 0302-66): Under nitrogen protection, isoindoline hydrochloride (220 mg, 1.40 mmol, 1.0 equiv.), 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (356 mg, 1.55 mmol, 1.1 equiv.), N,N-diisopropylethylamine (547 mg, 4.24 mmol, 3.0 equiv.), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (591 mg, 1.55 mmol, 1.1 equiv.) were stirred in N,N-dimethylcarboxamide (10 mL) for 3 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column (eluent: ethyl acetate) to give 4-(isoindoline-2-carbonyl)piperidine-1-tert-butylcarboxylate (408 mg, yield: 88.04%) as a yellow solid product. LCMS (ESI): m / z = 331 [M+H] + . Step 41b: Preparation of isoindolin-2-yl(piperidin-4-yl)methanone (compound 0303-66): A mixture of 4-(isoindoline-2-carbonyl)piperidine-1-carboxylate (0302-66) (408 mg, 1.24 mmol, 1.0 equiv) in hydrogen chloride and dioxane (4 M, 6 ml) was stirred at room temperature for 1.0 hour. The solvent was removed under reduced pressure, and the residue was then diluted with water, adjusted to pH=9 with sodium carbonate solution, and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was used directly in the next step without further purification. LCMS (ESI): m / z = 231 [M+H] + . Step 41c: Preparation of isoindolin-2-yl(1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methanone (compound 0304-66): Under nitrogen protection, isoindolin-2-yl(piperidin-4-yl)methanone (0303-66) (260 mg, 0.98 mmol, 1.0 equiv.), 4-(4-bromophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H- A mixture of pyrazole (0103-1) (360 mg, 1.18 mmol, 1.2 equiv.), sodium tert-butoxide (282 mg, 2.94 mmol, 2.5 equiv.), 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (45 mg, 0.10 mmol, 0.1 equiv.), and tris(dibenzylideneacetone)dipalladium(0) (46 mg, 0.05 mmol, 0.05 equiv.) in toluene (15 mL) was stirred at 120 °C overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column (dichloromethane / methanol = 50 / 1 to 20 / 1) to give isoindolin-2-yl(1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methanone (290 mg, yield: 64.89%) as a pink solid product. LCMS (ESI): m / z = 457 [M+H] + . Step 41d: Preparation of (1-(4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)(isoindolin-2-yl)methanone (Compound 66): A mixture of isoindolin-2-yl(1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methanone (0304-66) (60 mg, 0.132 mmol, 1.0 equiv) in hydrogen chloride and dioxane (4 M, 5 ml) was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure. The residue was diluted with water, adjusted to pH=9 with sodium carbonate solution, and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative thick-layer chromatography (dichloromethane / methanol=15 / 1) to give a yellow solid product (1-(4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)(isoindolin-2-yl)methanone (37 mg, yield: 75.43%). LCMS (ESI): m / z = 373 [M+H] + . 1 H NMR (500 MHz, DMSO) δ 12.76 (s, 1H), 8.01 (s, 1H), 7.79 (s, 1H), 7.43 (d, J = 8.6 Hz, 2H), 7.33 (dd, J = 21.8, 8.1 Hz, 4H), 6.95 (d, J = 8.6 Hz, 2H), 4.96 (s, 2H), 4.65 (s, 2H), 3.76 (d, J = 12.2 Hz, 2H), 2.74 (dd, J = 26.1, 13.9 Hz, 3H), 1.84 (d, J = 12.1 Hz, 2H), 1.81 - 1.66 (m, 2H).

[0106] Example 42: Preparation of (1-(4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)(2-azaspiro[3.3]heptan-2-yl)methanone (Compound 67) (prepared according to the route in Scheme 3) Step 42a: Preparation of 4-(2-azaspiro[3.3]heptane-2-carbonyl)piperidine-1-tert-butylcarboxylate (Compound 0302-67): 2-Azaspiro[3.3]heptane hydrochloride (100 mg, 0.75 mmol, 1.0 equiv.), 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (0301-40) (188.7 mg, 0.8232 mmol, 1.1 equiv.), N,N-diisopropylethylamine (289.6 g, 2.2 mmol, 3.0 equiv.), and HATU (312.8 mg, 0.8232 mmol, 1.1 equiv.) were dissolved in 10 mL of N,N-dimethylcarboxamide. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with water and saturated brine. The organic layer was then purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1 to 1 / 2) to give 4-(2-azaspiro[3.3]heptane-2-carbonyl)piperidine-1-tert-butylcarboxylate (295.4 mg, crude product) as a yellow oil. MS (ES) + ): m / z = 309 (M + H) + . Step 42b: Preparation of piperidin-4-yl(2-azaspiro[3.3]heptan-2-yl)methanone hydrochloride (compound 0303-67): 4-(2-azaspiro[3.3]heptane-2-carbonyl)piperidine-1-tert-butylcarboxylate (0302-67) (295.4 mg, 0.95 mmol, 1.0 equiv) was added to 5 mL of 4 M hydrogen chloride in dioxane. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated to dryness under reduced pressure, and the residue was used directly in the next step without further purification (289.5 mg, crude product). MS (ES) + ): m / z=244 (M+H) + . Step 42c: Preparation of (2-azaspiro[3.3]heptan-2-yl)(1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methanone (compound 0304-67): Under nitrogen protection, piperidin-4-yl(2-azaspiro[3.3]heptan-2-yl)methanone hydrochloride (0303-67) (236.4 mg, 0.96 mmol, 2.0 equiv.), 4-(4-bromophenyl)-1-(tetrahydro-2H-pyran A mixture of (2-yl)-1H-pyrazole (0103-1) (147.3 mg, 0.48 mmol, 1.0 equiv.), sodium tert-butoxide (556 mg, 5.76 mmol, 12.0 equiv.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (55.8 mg, 0.096 mmol, 0.2 equiv.), and tris(dibenzylideneacetone)dipalladium(0) (44 mg, 0.048 mmol, 0.1 equiv.) in toluene (16 mL) was stirred overnight at 120° C. After cooling to room temperature, the reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative thin-layer chromatography (eluent: dichloromethane / methanol = 10 / 1) to give (2-azaspiro[3.3]heptan-2-yl)(1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methanone (47.9 mg, yield: 23.0%) as a yellow solid. MS (ES) + ): m / z = 435 (M + H) + . Step 42d: Preparation of (1-(4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)(2-azaspiro[3.3]heptan-2-yl)methanone (Compound 67): (2-Azaspiro[3.3]heptan-2-yl)(1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methanone (0304-67) (47.9 mg, 0.110 mmol, 1.0 equiv) was added to 10 mL of a 4 M solution of hydrogen chloride in methanol and stirred at room temperature for 2 hours. The mixture was concentrated to dryness under reduced pressure. Water was added and the pH was adjusted to 10 with saturated aqueous sodium carbonate. The mixture was extracted with ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (eluent: dichloromethane / methanol = 20 / 1) to give (1-(4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)(2-azaspiro[3.3]heptan-2-yl)methanone (10.5 mg, yield: 27.0%) as a white solid. MS (ES) + ): m / z = 351 (M + H) + .Melting point: 229~231℃. 1 H NMR (500 MHz, DMSO) δ 12.76 (s, 1H), 7.89 (d, J = 103.5 Hz, 2H), 7.41 (d, J = 8.6 Hz, 2H), 6.91 (d, J = 8.7 Hz, 2H), 4.14 (s, 2H), 3.80 (s, 2H), 3.68 (d, J = 12.4 Hz, 2H), 2.68 (dd, J = 11.9, 10.0 Hz, 2H), 2.39 - 2.27 (m, 1H), 2.19 - 2.05 (m, 4H), 1.77 (p, J = 7.2 Hz, 2H), 1.71 - 1.54 (m, 4H).

[0107] Example 43: Preparation of 1-(1-(4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)pyrrolidin-2-one (Compound 73) (prepared according to the route in Scheme 6) Step 43a: Preparation of 4-(2-oxopyrrolidin-1-yl)piperidine-1-tert-butylcarboxylate (compound 0603-73): Under nitrogen protection, a mixture of 4-aminopiperidine-1-tert-butylcarboxylate (0601-73) (2 g, 9.99 mmol, 1.0 equiv.), 4-chlorobutyryl chloride (1.55 g, 10.99 mmol, 1.1 equiv.), and N,N-diisopropylethylamine (1.94 g, 14.99 mmol, 1.5 equiv.) in dichloromethane (20 ml) was stirred at room temperature for 2.0 hours. The reaction was quenched by the addition of sodium carbonate solution. The reaction mixture was diluted with water and extracted with dichloromethane (10 ml × 4). The combined organic layer was washed with saturated brine (40 ml × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 ml) and cooled to 0 °C. Under nitrogen protection, NaH (60%, 799 mg, 19.98 mmol, 2.0 equiv.) was added and the reaction was stirred at room temperature for 0.5 h. The mixture was then stirred at 85 °C for 6 h. Saturated ammonium chloride solution (10 ml) was added to quench the reaction. The mixture was diluted with water (50 ml) and extracted with ethyl acetate (20 ml × 3). The combined organic layers were washed with brine (50 ml × 1), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified using a silica gel column (eluent: petroleum ether / ethyl acetate = 3 / 1 to 1 / 4) to give 4-(2-oxopyrrolidin-1-yl)piperidine-1-tert-butylcarboxylate (1.46 g, yield: 54.2%) as a white solid. Step 43b: Preparation of 1-(piperidin-4-yl)pyrrolidin-2-one (compound 0603-73): A mixture of 4-(2-oxopyrrolidin-1-yl)piperidine-1-tert-butylcarboxylate (0602-73) (1.46 g, 5.45 mmol, 1.0 equiv.) in hydrogen chloride and dioxane (4 M, 15 ml) was stirred at room temperature for 1.5 hours. The solvent was removed under reduced pressure, and the residue was diluted with water (15 ml), adjusted to pH 9 with sodium carbonate solution, and extracted with dichloromethane (10 ml x 15). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 1-(piperidin-4-yl)pyrrolidin-2-one (830 mg, yield: 90.7%) as a yellow solid product. LCMS (ESI): m / z = 169 [M+1] + . Step 43c: Preparation of 1-(1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)pyrrolidin-2-one (compound 0604-73): Under nitrogen protection, 1-(piperidin-4-yl)pyrrolidin-2-one (0603-73) (98.6 mg, 0.587 mmol, 1.2 equiv.), 4-(4-bromophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (01 A mixture of 03-1 (150 g, 0.489 mmol, 1.0 equiv.), sodium tert-butoxide (117.5 mg, 1.22 mmol, 2.5 equiv.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (28.3 mg, 0.0489 mmol, 0.1 equiv.), and tris(dibenzylideneacetone)dipalladium(0) (22.4 mg, 0.025 mmol, 0.05 equiv.) in toluene (5 mL) was stirred at 120 °C for 10.0 hours. The reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (10 mL x 3). The organic layer was washed with saturated brine (30 mL x 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 60 / 1 to 30 / 1) to give 1-(1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)pyrrolidin-2-one (138 mg, yield: 71.8%) as a yellow solid. LCMS (ESI): m / z = 395 [M+1] + . Step 43d: Preparation of 1-(1-(4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)pyrrolidin-2-one (Compound 73): A mixture of 1-(1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)pyrrolidin-2-one (0604-73) (138 mg, 0.35 mmol, 1.0 equiv) in hydrogen chloride and dioxane (4 M, 5 ml) was stirred at room temperature for 1.0 hour. The solvent was removed under reduced pressure, and the residue was diluted with water (8 ml), adjusted to pH 9 with sodium carbonate solution, extracted with dichloromethane (4 ml × 5), and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative thick-layer chromatography (dichloromethane / methanol=12 / 1) to give 1-(1-(4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)pyrrolidin-2-one (45.8 g, yield: 42.4%) as a white solid product. LCMS (ESI): m / z = 311 [M+1] + . 1 H NMR (500 MHz, DMSO) δ 12.76 (s, 1H), 8.00 (s, 1H), 7.79 (s, 1H), 7.42 (d, J = 8.7 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 3.90 (tt, J = 12.0, 4.0 Hz, 1H), 3.75 (d, J = 12.6 Hz, 2H), 3.32 (d, J = 6.9 Hz, 2H), 2.82 - 2.63 (m, 2H), 2.23 (dd, J = 10.4, 5.8 Hz, 2H), 1.91 (dd, J = 15.0, 7.4 Hz, 2H), 1.89 - 1.72 (m, 2H), 1.62 (d, J = 9.9 Hz, 2H).

[0108] Example 44: Preparation of 1-((1-(4-(1H-pyrazol-4-yl)phenyl)pyrrolidin-3-yl)methyl)pyrrolidin-2-one (Compound 74) (prepared according to the route in Scheme 1) Step 44a: Preparation of 3-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-tert-butylcarboxylate (compound 0105-74): Under nitrogen protection, to a mixture of 3-(hydroxymethyl)pyrrolidine-1-tert-butylcarboxylate (0105-74) (1.0 g, 4.97 mmol, 1.0 equiv.) and triethylamine (1.0 g, 9.94 mmol, 2.0 equiv.) in dichloromethane (20 ml) was added methylsulfonyl chloride (740 mg, 6.46 mmol, 1.3 equiv.) dropwise at 0° C. The mixture was stirred at room temperature for 4.0 hours. The reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 1 to 10 / 1) to give 3-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-tert-butylcarboxylate (1.32 g, yield: 95.2%) as a yellow oil. MS (ES) + ): m / z=280 (M+H) + Step 44b: Preparation of 3-((2-oxopyrrolidin-1-yl)methyl)pyrrolidine-1-tert-butylcarboxylate (compound 0107-74): Under nitrogen protection, to a mixture of 2-pyrrolidone (0106-1) (201 mg, 2.36 mmol, 1.1 equiv) in N,N-dimethylcarboxamide (15 ml) was added sodium hydride (130 mg, 3.23 mmol, 1.5 equiv). The mixture was stirred at 0° C. for 1 hour. Then, 3-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-tert-butylcarboxylate (0105-74) (600 mg, 2.15 mmol, 1.0 equiv) was added dropwise at 0° C., and the reaction was then stirred at 65° C. for 8 hours. The mixture was extracted with water and ethyl acetate, and the organic layer was washed with brine and concentrated under reduced pressure to give 3-((2-oxopyrrolidin-1-yl)methyl)pyrrolidine-1-tert-butylcarboxylate (395 mg, yield: 68.5%) as a yellow oil. MS (ES + ): m / z=269(M+H) + 。 Step 44c: Preparation of 1-(pyrrolidin-3-ylmethyl)pyrrolidin-2-one (compound 0108-74): A mixture of 3-((2-oxopyrrolidin-1-yl)methyl)pyrrolidine-1-tert-butylcarboxylate (0107-74) (390 mg, 1.45 mmol, 1.0 equiv) in hydrogen chloride and methanol (4 M, 8 ml) was stirred at room temperature for 2.0 hours. The solvent was removed under reduced pressure, and the residue was diluted with water, adjusted to pH 9 with sodium carbonate solution, and extracted with dichloromethane. The organic layer was dried and concentrated under reduced pressure to give 1-(pyrrolidin-3-ylmethyl)pyrrolidin-2-one (240 mg, yield: 98.3%) as a yellow oil. LCMS (ESI): m / z = 169 [M+1] + . Step 44d: Preparation of 1-((1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)pyrrolidin-3-yl)methyl)pyrrolidin-2-one (compound 0109-74): Under nitrogen protection, 1-(pyrrolidin-3-ylmethyl)pyrrolidin-2-one (0108-74) (174 mg, 0.849 mmol, 1.3 equiv.), 4-(4-bromophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (0 A mixture of 103-1) (200 mg, 0.653 mmol, 1.0 equiv.), sodium tert-butoxide (186 mg, 1.959 mmol, 3.0 equiv.), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (14.9 mg, 0.032 mmol, 0.05 equiv.), and tris(dibenzylideneacetone)dipalladium(0) (29.3 mg, 0.032 mmol, 0.05 equiv.) in toluene (10 mL) was stirred overnight at 120°C. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried and concentrated under reduced pressure. The residue was purified by silica gel column (dichloromethane / methanol = 150 / 1 to 50 / 1) to give the yellow solid product 1-((1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)pyrrolidin-3-yl)methyl)pyrrolidin-2-one (105 mg, yield: 40.8%). LCMS (ESI): m / z = 395 [M+1] + . Step 44e: Preparation of 1-((1-(4-(1H-pyrazol-4-yl)phenyl)pyrrolidin-3-yl)methyl)pyrrolidin-2-one (Compound 74): A mixture of 1-((1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)pyrrolidin-3-yl)methyl)pyrrolidin-2-one (0109-74) (105 mg, 0.266 mmol, 1.0 equiv) in hydrogen chloride and methanol (4 M, 5 ml) was stirred at room temperature for 2.0 hours. The solvent was removed under reduced pressure, and the residue was diluted with water, adjusted to pH=9 with sodium carbonate solution, and extracted with dichloromethane. The organic layer was dried and concentrated under reduced pressure. The residue was purified by preparative thick-layer chromatography (dichloromethane / methanol=10 / 1) to give 1-((1-(4-(1H-pyrazol-4-yl)phenyl)pyrrolidin-3-yl)methyl)pyrrolidin-2-one (36 mg, yield: 43.9%) as a yellow solid product. LCMS (ESI): m / z = 311 [M+1] + Melting point: 95~104℃. 1 H NMR (500 MHz, DMSO) δ 12.70 (s, 1H), 7.84 (d, J = 82.1 Hz, 2H), 7.38 (d, J = 8.5 Hz, 2H), 6.51 (d, J = 8.5 Hz, 2H), 3.40 (t, J = 6.9 Hz, 2H), 3.35 (d, J = 9.1 Hz, 1H), 3.28 - 3.16 (m, 4H), 2.94 (dd, J = 9.1, 6.6 Hz, 1H), 2.59 (dt, J = 14.2, 7.1 Hz, 1H), 2.24 (t, J = 8.0 Hz, 2H), 2.04 (td, J = 12.3, 7.2 Hz, 1H), 2.00 - 1.85 (m, 2H), 1.76 - 1.61 (m, 1H).

[0109] Example 45: Preparation of 1-((1-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperidin-2-one (Compound 26) (prepared according to the route in Scheme 1) Step 45a: Preparation of 1-(1-(2,3-difluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperidin-2-one (Compound 0109-26): Under nitrogen protection, 4-(4-bromo-2,3-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (0103-4) (170 mg, 0.50 mmol, 1.0 equiv.), 1-(piperidin-4-yl) A mixture of (methyl)piperidin-2-one (0108-26) (147 mg, 0.75 mmol, 1.5 equiv.), sodium tert-butoxide (209 mg, 2.25 mmol, 4.5 equiv.), 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (24 mg, 0.05 mmol, 0.1 equiv.), and tris(dibenzylideneacetone)dipalladium (23 mg, 0.025 mmol, 0.05 equiv.) in toluene (10 mL) was stirred at 120 °C overnight. After cooling to room temperature, the reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 50 / 1 to 20 / 1) to give 1-((1-(2,3-difluoro-4-(1-(tetrahydro-2H-pyran))-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperidin-2-one (198 mg, yield: 86.46%) as a yellow solid. MS (ES+): m / z = 459 [M+H] + . Step 45b: Preparation of 1-((1-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperidin-2-one (Compound 26): A mixture of 1-((1-(2,3-difluoro-4-(1-(tetrahydro-2H-pyran))-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperidin-2-one (0109-26) (50 mg, 0.11 mmol, 1.0 equiv) in hydrogen chloride-methanol (4 M, 3 ml) was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and the pH of the residue was adjusted to 9 with sodium carbonate solution and extracted with dichloromethane. The organic layer was dried and concentrated under reduced pressure. The residue was purified by preparative thick-layer chromatography (eluent: dichloromethane / methanol=15 / 1) to give 1-((1-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperidin-2-one (27 mg, yield: 65.55%) as a yellow solid. MS(ES+):m / z =375[M+H]+. 1H NMR (500 MHz, DMSO) δ 13.04 (s, 1H), 8.08 (s, 1H), 7.86 (s, 1H), 7.38 (t, J = 7.8 Hz, 1H), 6.84 (t, J = 8.2 Hz, 1H), 3.39 (s, 2H), 3.28 - 3.25 (m, 2H), 3.22 (d, J = 7.4 Hz, 2H), 2.67 (t, J = 11.4 Hz, 2H), 2.22 (t, J = 6.0 Hz, 2H), 1.81 (s, 1H), 1.69 (dd, J = 21.3, 9.0 Hz, 6H), 1.32 (dd, J = 21.1, 11.4 Hz, 2H).

[0110] Example 46: Preparation of 1-((1-(2,6-difluoro-4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperidin-2-one (Compound 27) (prepared according to the route in Scheme 1) Step 46a: Preparation of 1-((1-(2,6-difluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperidin-2-one (Compound 0109-27): Under nitrogen protection, 4-(4-bromo-3,5-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (0103-5) (173 mg, 0.88 mmol, 1.0 equiv.), 1-(piperidin-4-yl) A mixture of (trimethyl)piperidin-2-one (0108-26) (173 mg, 0.88 mmol, 1.5 equiv.), sodium tert-butoxide (198 mg, 2.07 mmol, 3.5 equiv.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (35 mg, 0.06 mmol, 0.1 equiv.), and tris(dibenzylideneacetone)dipalladium(0) (27 mg, 0.03 mmol, 0.05 equiv.) in toluene (10 mL) was stirred at 120 °C overnight. After cooling to room temperature, the reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 50 / 1 to 20 / 1) to give 1-((1-(2,6-difluoro-4-(1-(tetrahydro-2H-pyran))-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperidin-2-one (35 mg, yield: 12.92%) as a yellow solid. MS (ES) + ): m / z = 459 [M+H] + . Step 46b: Preparation of 1-((1-(2,6-difluoro-4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperidin-2-one (Compound 27): A mixture of 1-((1-(2,6-difluoro-4-(1-(tetrahydro-2H-pyran))-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperidin-2-one (0109-27) (35 mg, 0.076 mmol, 1.0 equiv) in hydrogen chloride-methanol (4 M, 3 ml) was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and the pH of the residue was adjusted to 9 with sodium carbonate solution and extracted with dichloromethane. The organic layer was dried and concentrated under reduced pressure. The residue was purified by preparative thick-layer chromatography (eluent: dichloromethane / methanol = 15 / 1) to give 1-((1-(2,6-difluoro-4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)piperidin-2-one (22 mg, yield: 77.40%) as a yellow solid. MS (ES) + ): m / z = 375 [M+H] + . 1 H NMR (500 MHz, DMSO) δ 12.95 (s, 1H), 8.21 (s, 1H), 7.94 (s, 1H), 7.29 (d, J = 10.4 Hz, 2H), 3.28 - 3.25 (m, 2H), 3.21 (d, J = 7.4 Hz, 2H), 3.14 (d, J = 11.6 Hz, 2H), 2.97 (t, J = 11.3 Hz, 2H), 2.22 (t, J = 6.0 Hz, 2H), 1.74 (dd, J = 30.6, 7.6 Hz, 5H), 1.61 (d, J = 11.9 Hz, 2H), 1.27 - 1.17 (m, 2H).

[0111] Example 47: Preparation of 1-((1-(2,3-difluoro-4-(isoxazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (Compound 37) JPEG0007820560000043.jpg28170 Step 47a: Preparation of 1-((1-(4-bromo-2,3-difluorophenyl)piperidin-4-yl)methyl)pyrrolidin-2-one: Under nitrogen protection, 1-(piperidin-4-ylmethyl)pyrrolidin-2-one (0108-1) (500 mg, 2.75 mmol, 1 equiv.), 1,4-dibromo-2,3-difluorobenzene (0201-4) (8 A mixture of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (162 mg, 0.28 mmol, 0.1 equiv.), tris(dibenzylideneacetone)dipalladium (44 mg, 0.12 mmol, 0.05 equiv.), sodium tert-butoxide (660 mg, 6.87 mmol, 2.5 equiv.), and toluene (20 ml) was stirred at 120° C. for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified using a silica gel column (dichloromethane / methanol = 30 / 1) to give 1-((1-(4-bromo-2,3-difluorophenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (689 mg, yield: 67.4%) as a yellow solid. LCMS (ESI) [M+1] + :m / z =373. Step 47b: Preparation of 1-((1-(2,3-difluoro-4-(isoxazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (Compound 37): Under nitrogen protection, 1-((1-(4-bromo-2,3-difluorophenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (120 mg, 0.32 mmol, 1 equiv.), 4-isoxazoleboronic acid pinacol ester (125 mg, 0.64 mmol, 2 equiv.), sodium carbonate (68 mg, 0.64 mmol, 2 equiv.), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (24 mg, 0.032 mmol, 0.1 equiv.), 1,4-dioxane (5 ml), and water (0.5 ml) were mixed and stirred at 90° C. for 6.5 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified using a preparative plate (dichloromethane / methanol = 30 / 1) to obtain crude 1-((1-(2,3-difluoro-4-(isoxazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (38 mg, purity: 88%) as a yellow solid. The crude product was purified by HPLC to obtain 1-((1-(2,3-difluoro-4-(isoxazol-4-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (22.2 mg, yield: 19.3%) as a white solid. LCMS (ESI) [M+1] + :m / z =362. 1H NMR (500 MHz, DMSO) δ 9.31 (s, 1H), 9.10 (s, 1H), 7.47 (t, J = 7.9 Hz, 1H), 6.92 (t, J = 8.1 Hz, 1H), 3.44 (d, J = 11.9 Hz, 2H), 3.36 (t, J = 6.9 Hz, 2H), 3.11 (d, J = 7.2 Hz, 2H), 2.73 (t, J = 11.5 Hz, 2H), 2.23 (t, J = 8.0 Hz, 2H), 2.05 - 1.87 (m, 2H), 1.85 - 1.70 (m, 1H), 1.68 (d, J = 12.4 Hz, 2H), 1.37 - 1.27 (m, 2H).

[0112] Example 48: Preparation of N-((1-(4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)heptamide (Compound 44) ​​(prepared according to the route in Scheme 5) Step 48a: Preparation of N-((1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)heptamide (compound 0506-44): Under nitrogen protection, (1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methylamine A mixture of (0509-45) (60 mg, 0.176 mmol, 1.0 equiv.), enanthic acid (25 mg, 0.194 mmol, 1.1 equiv.), HATU (100 mg, 0.264 mmol, 1.5 equiv.), and N,N-diisopropylethylamine (68 mg, 0.528 mmol, 3.0 equiv.) in N,N-dimethylcarboxamide (3.5 mL) was stirred at room temperature for 2.0 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried and concentrated under reduced pressure. The residue was purified by preparative thick-layer chromatography (developing agent: dichloromethane / methanol = 14 / 1) to give N-((1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)heptamide (56 mg, yield: 70.4%) as a yellow solid product. Step 48b: Preparation of N-((1-(4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)heptamide (Compound 44): A mixture of N-((1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)heptamide (0506-44) (56 mg, 0.124 mmol, 1.0 equiv) in hydrogen chloride-dioxane (4 M, 5 ml) was stirred at room temperature for 1.0 hour. The solvent was removed under reduced pressure, and the residue was diluted with water. The pH of the solution was adjusted to 9 with sodium carbonate solution, and the solution was extracted with dichloromethane. The organic layer was dried and concentrated under reduced pressure. The residue was purified by preparative thick-layer chromatography (eluent: dichloromethane / methanol = 12 / 1) to give N-((1-(4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)heptamide (37 mg, yield: 81.1%) as a white solid product. LCMS (ESI): m / z = 369 [M+1] + . 1 H NMR (500 MHz, DMSO) δ 12.75 (s, 1H), 7.88 (d, J = 106.5 Hz, 3H), 7.41 (d, J = 8.5 Hz, 2H), 6.91 (d, J = 8.6 Hz, 2H), 3.66 (d, J = 12.0 Hz, 2H), 2.97 (t, J = 6.1 Hz, 2H), 2.60 (t, J = 11.4 Hz, 2H), 2.07 (t, J = 7.4 Hz, 2H), 1.70 (d, J = 11.8 Hz, 2H), 1.49 (s, 3H), 1.24 (s, 8H), 0.86 (t, J = 6.6 Hz, 3H).

[0113] Example 49: Preparation of 1-(4-(1H-pyrazol-4-yl)phenyl)-N-cyclohexylpiperidine-4-carboxamide (Compound 57) (prepared according to the route in Scheme 8) Step 49a: Preparation of N-cyclohexyl-1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidine-4-carboxamide (compound 0802-57): To a mixture of 1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidine-4-formic acid (0801-55) (45 mg, 0.13 mmol, 1.0 equiv), HATU (63 mg, 0.17 mmol, 1.3 equiv), N,N-diisopropylethylamine (33 mg, 0.25 mmol, 2.0 equiv), and dichloromethane (5 ml) was added cyclohexylamine (16 mg, 0.17 mmol, 1.3 equiv). The mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure. The residue was purified by pre-TLC (ethyl acetate:dichloromethane:methanol=15::15:1) to give N-cyclohexyl-1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidine-4-carboxamide (36 mg, yield: 65%) as a white solid. LCMS (ESI): m / z = 437 [M+1] + TLC: Rf 0.5 (dichloromethane:methanol=20:1). Step 49b: Preparation of 1-(4-(1H-pyrazol-4-yl)phenyl)-N-cyclohexylpiperidine-4-carboxamide (Compound 57): A mixture of N-cyclohexyl-1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidine-4-carboxamide (0802-57) (36 mg, 0.083 mmol, 1.0 equiv) and hydrogen chloride in methanol (4 M, 3 ml) was stirred at room temperature for 1.5 hours. The mixture was diluted with water (20 ml). Solid sodium carbonate was added to adjust the pH to 10. The mixture was filtered. The solid was washed with water and then dried in vacuo to give 1-(4-(1H-pyrazol-4-yl)phenyl)-N-cyclohexylpiperidine-4-carboxamide (21 mg, yield: 72%) as a white solid. LCMS (ESI): m / z = 353 [M+1] + TLC: Rf 0.5 (dichloromethane:methanol=10:1). 1H NMR (500 MHz, DMSO) δ 12.75 (s, 1H), 7.89 (s, 2H), 7.60 (s, 1H), 7.42 (s, 2H), 6.92 (s, 2H), 3.69 (s, 2H), 3.51 (s, 1H), 2.64 (s, 2H), 2.23 (s, 1H), 1.62 (d, J = 74.0 Hz, 10H), 1.13 (s, 4H).

[0114] Example 50: Preparation of 1-(4-(1H-pyrazol-4-yl)phenyl)-N-(4-fluorophenyl)piperidine-4-carboxamide (Compound 61) (prepared according to the route in Scheme 8) Step 50a: Preparation of N-(4-fluorophenyl)-1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidine-4-carboxamide (compound 0802-61): Under nitrogen protection, a mixture of 1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidine-4-carboxylic acid (0801-55) (60 mg, 0.17 mmol, 1.0 equiv), 4-fluoroaniline (23 mg, 0.20 mmol, 1.2 equiv), HATU (97 mg, 0.25 mmol, 1.5 equiv), N,N-diisopropylethylamine (66 mg, 0.51 mmol, 3.0 equiv), and N,N-dimethylcarboxamide (3 ml) was stirred at room temperature for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried and concentrated under reduced pressure. The residue was purified using a silica gel column (dichloromethane / methanol = 10 / 1) to obtain N-(4-fluorophenyl)-1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidine-4-carboxamide (45 mg, yield: 59.30%) as a yellow solid product. LCMS (ESI): m / z = 449 [M+1] + . Step 50b: Preparation of 1-(4-(1H-pyrazol-4-yl)phenyl)-N-(4-fluorophenyl)piperidine-4-carboxamide (Compound 61): A mixture of (4-fluorophenyl)-1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidine-4-carboxamide (0802-61) (45 mg, 0.10 mmol, 1.0 equiv) and hydrogen chloride in methanol (4 M, 2 ml) was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and the residue was diluted with water, adjusted to pH=8 with sodium carbonate solution, and extracted with dichloromethane. The organic layer was dried and concentrated under reduced pressure. The residue was purified by preparative thick-layer chromatography (eluent: dichloromethane / methanol = 12 / 1) to give 1-(4-(1H-pyrazol-4-yl)phenyl)-N-(4-fluorophenyl)piperidine-4-carboxamide (25 mg, yield: 69.44%) as a yellow solid product. LCMS (ESI): m / z = 365 [M+1] + . 1 H NMR (500 MHz, DMSO) δ 12.77 (s, 1H), 9.95 (s, 1H), 8.02 (s, 1H), 7.79 (s, 1H), 7.63 (dd, J = 8.8, 5.1 Hz, 2H), 7.43 (d, J = 8.6 Hz, 2H), 7.12 (t, J = 8.8 Hz, 2H), 6.95 (d, J = 8.6 Hz, 2H), 3.76 (d, J = 12.3 Hz, 2H), 2.71 (t, J = 11.5 Hz, 2H), 2.46 (s, 1H), 1.84 (dd, J = 38.3, 7.4 Hz, 2H), 1.76 (dd, J = 12.0, 2.8 Hz, 2H).

[0115] Example 51: Preparation of 1-(4-(1H-pyrazol-4-yl)phenyl)-N-(benzofuran-5-yl)piperidine-4-carboxamide (Compound 62) (prepared according to the route in Scheme 8) Step 51a: Preparation of N-(benzofuran-5-yl)-1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidine-4-carboxamide (compound 0802-62): To a mixture of 1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidine-4-formic acid (0801-55) (55 mg, 0.16 mmol, 1.0 equiv), HATU (77 mg, 0.20 mmol, 1.3 equiv), N,N-diisopropylethylamine (60 mg, 0.47 mmol, 3.0 equiv), and dichloromethane (3 ml) was added benzofuran-5-amine (25 mg, 0.19 mmol, 1.2 equiv). The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure. The residue was purified by pre-TLC (dichloromethane:ethyl acetate=4:1) to give N-(benzofuran-5-yl)-1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidine-4-carboxamide (41 mg, yield: 56%) as a white solid. LCMS (ESI): m / z = 471 [M+1] + TLC: Rf 0.5 (dichloromethane:methanol=30:1). Step 51b: Preparation of 1-(4-(1H-pyrazol-4-yl)phenyl)-N-(benzofuran-5-yl)piperidine-4-carboxamide (Compound 62): A mixture of N-(benzofuran-5-yl)-1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidine-4-carboxamide (41 mg, 0.087 mmol, 1.0 equiv) and hydrogen chloride in methanol (4 M, 2.5 ml) was stirred at room temperature for 2 hours. The mixture was diluted with water (20 ml). Solid sodium carbonate was added to adjust the pH to 10. The mixture was filtered. The solid was washed with water and then dried in vacuo to give 1-(4-(1H-pyrazol-4-yl)phenyl)-N-(benzofuran-5-yl)piperidine-4-carboxamide (27 mg, yield: 80%) as a white solid. LCMS (ESI): m / z = 387 [M+1] + TLC: Rf 0.5 (dichloromethane:methanol=10:1).1 H NMR (500 MHz, DMSO) δ 12.77 (s, 1H), 9.92 (s, 1H), 8.03 (s, 2H), 7.93 (s, 1H), 7.79 (s, 1H), 7.47 (dd, J = 33.0, 7.8 Hz, 4H), 7.09 - 6.81 (m, 3H), 3.77 (d, J = 11.7 Hz, 2H), 2.72 (t, J = 11.6 Hz, 2H), 2.53 (s, 1H), 1.97 - 1.74 (m, 4H).

[0116] Example 52: Preparation of 1-(4-(1H-pyrazol-4-yl)phenyl)-N-(naphthalen-2-yl)piperidine-4-carboxamide (Compound 64) (prepared according to the route in Scheme 8) Step 52a: Preparation of N-(naphthalen-2-yl)-1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidine-4-carboxamide (compound 0802-64): To a mixture of 1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidine-4-formic acid (0801-55) (55 mg, 0.16 mmol, 1.0 equiv), HATU (77 mg, 0.20 mmol, 1.3 equiv), N,N-diisopropylethylamine (60 mg, 0.47 mmol, 3.0 equiv), and dichloromethane (3 ml) was added naphthalen-2-amine (27 mg, 0.19 mmol, 1.2 equiv). The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure. The residue was purified by pre-TLC (dichloromethane:ethyl acetate=4:1) to give N-(naphthalen-2-yl)-1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidine-4-carboxamide (41 mg, yield: 55%) as a white solid. LCMS (ESI): m / z = 481 [M+1] + TLC: Rf 0.5 (dichloromethane:methanol=30:1). Step 52b: Preparation of 1-(4-(1H-pyrazol-4-yl)phenyl)-N-(naphthalen-2-yl)piperidine-4-carboxamide (Compound 64): A mixture of N-(naphthalen-2-yl)-1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidine-4-carboxamide (41 mg, 0.085 mmol, 1.0 equiv) and hydrogen chloride in methanol (4 M, 2.5 ml) was stirred at room temperature for 2 hours. The mixture was diluted with water (20 ml). Solid sodium carbonate was added to adjust the pH to 10. The mixture was filtered. The solid was washed with water and then dried in vacuo to give 1-(4-(1H-pyrazol-4-yl)phenyl)-N-(naphthalen-2-yl)piperidine-4-carboxamide (26 mg, yield: 77%) as a white solid. LCMS (ESI): m / z = 397 [M+1] + TLC: Rf 0.5 (dichloromethane:methanol=10:1). 1 H NMR (500 MHz, DMSO) δ 12.77 (s, 1H), 10.12 (s, 1H), 8.33 (s, 1H), 8.12 - 7.70 (m, 5H), 7.61 (d, J = 8.7 Hz, 1H), 7.54 - 7.31 (m, 4H), 6.97 (d, J = 8.5 Hz, 2H), 3.78 (d, J = 12.3 Hz, 2H), 2.73 (t, J = 11.6 Hz, 2H), 2.58 (t, J = 11.5 Hz, 1H), 1.99 - 1.74 (m, 4H).

[0117] Example 53: Preparation of N-(1-(4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)cyclopentylcarboxamide (Compound 69) (prepared according to the route in Scheme 5) Step 53a: Preparation of 4-(cyclopentylcarboxamido)piperidine-1-tert-butylcarboxylate (compound 0504-69): To a mixture of cyclopentanecarboxylic acid (188 mg, 1.6 mmol, 1.1 equiv.), 4-aminopiperidine-1-tert-butylcarboxylate (0601-73) (300 mg, 1.5 mmol, 1.0 equiv.), N,N-diisopropylethylamine (579.7 mg, 4.49 mmol, 3.0 equiv.), and N,N-dimethylcarboxamide (10 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (626 mg, 1.6 mmol, 1.1 equiv.). The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with water and saturated brine. The organic layer was then distilled under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1 to 1 / 3) to give 4-(cyclopentylcarboxamido)piperidine-1-tert-butylcarboxylate (420 mg, yield: 94.6%) as a white solid. LCMS (ESI): m / z = 297 (M+H). + . Step 53b: Preparation of N-(piperidin-4-yl)cyclopentylcarboxamide hydrochloride (compound 0505-69): 4-(cyclopentylcarboxamido)piperidine-1-tert-butylcarboxylate (0504-69) (420 mg, 1.4 mmol, 1.0 equiv) was added to 5 ml of a 4 M solution of hydrogen chloride in dioxane. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated to dryness under reduced pressure, and the residue was used directly in the next step without further purification. LCMS (ESI): m / z = 197 (M+H). + . Step 53c: Preparation of N-(1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)cyclopentylcarboxamide (compound 0506-69): Under nitrogen protection, a mixture of N-(piperidin-4-yl)cyclopentylcarboxamide hydrochloride (0505-69) (200 mg, 0.67 mmol, 1.0 equiv.) and sodium tert-butoxide (389.2 mg, 4.05 mmol, 6.0 equiv.) in toluene (10 ml) was The mixture was stirred at 120° C. for 30 minutes, and then 4-(4-bromophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (0103-1) (227.4 mg, 0.74 mmol, 1.1 equiv.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (38.8 mg, 0.068 mmol, 0.1 equiv.), and tris(dibenzylideneacetone)dipalladium (30.9 mg, 0.034 mmol, 0.05 equiv.) were added to the mixture, followed by stirring overnight at 120° C. After cooling to room temperature, the reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative thin-layer chromatography (developer: dichloromethane / methanol=15 / 1) to give N-((1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)cyclopentylcarboxamide (78.9 mg, yield: 27.7%) as a yellow solid. LCMS (ESI): m / z = 423 (M+H) + . Step 53d: Preparation of N-(1-(4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)cyclopentylcarboxamide (Compound 69): N-((1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)cyclopentanecarboxamide (0506-69) (78.9 mg, 0.19 mmol, 1.0 equiv) was added to 10 mL of a 4 M solution of hydrogen chloride in methanol and stirred at room temperature for 2 hours. The mixture was concentrated to dryness under reduced pressure. Water was added and the pH was adjusted to 10 with saturated aqueous sodium carbonate. The mixture was extracted with ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (eluent: dichloromethane / methanol = 10 / 1) to give N-(1-(4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)cyclopentylcarboxamide (25 mg, yield: 39.8%) as a yellow solid. LCMS (ESI): m / z = 339 (M+H) + . 1 H NMR (500 MHz, DMSO) δ 12.75 (s, 1H), 7.89 (s, 2H), 7.67 (d, J = 7.6 Hz, 1H), 7.41 (d, J = 8.6 Hz, 2H), 6.92 (d, J = 8.7 Hz, 2H), 3.72 - 3.69 (m, 1H), 3.62 (d, J = 12.6 Hz, 2H), 3.51 (s, 1H), 2.76 (t, J = 11.3 Hz, 2H), 1.79 (d, J = 10.9 Hz, 2H), 1.73 - 1.66 (m, 2H), 1.60 (d, J = 11.6 Hz, 4H), 1.48 (q, J = 11.8 Hz, 4H).

[0118] Example 54: Preparation of (4-(4-(1H-pyrazol-4-yl)phenyl)piperidin-1-yl)(cyclopentyl)methanone (Compound 70) (prepared according to the route in Scheme 9) Step 54a: Preparation of 4-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)-3,6-dihydropyridine-1(2H)-tert-butylcarboxylate (compound 0902-70): Under nitrogen protection, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-tert-butylcarboxylate (0901-70) (500 mg, 1.62 mmol, (1.0 equiv.), 4-(4-bromophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (0103-1) (544.3 mg, 1.78 mmol, 1.1 equiv.), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (118.3 mg, 0.16 mmol, 0.1 equiv.), and sodium carbonate (514 mg, 4.85 mmol, 3.0 equiv.) were added to a dioxane / water (30 / 3) mixture and stirred at 85 °C overnight. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to give the product 4-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)-3,6-dihydropyridine-1(2H)-tert-butylcarboxylate (416.8 mg, yield: 62.9%) as a white solid. LCMS (ESI): m / z = 410 [M+1] + . Step 54b: Preparation of 4-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidine-1-tert-butylcarboxylate (compound 0903-70): Under a hydrogen atmosphere, a solution of 4-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)-3,6-dihydropyridine-1(2H)-tert-butylcarboxylate (0902-70) (416.8 mg, 1.0 mmol, 1.0 equivalent) and palladium / carbon (64.2 mg, 15% by mass) in methanol (5 ml) was stirred overnight at room temperature. The reaction mixture was filtered and concentrated to dryness under reduced pressure. The residue was purified using a silica gel column (petroleum ether / ethyl acetate=10 / 1) to give 4-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidine-1-tert-butylcarboxylate (284.9 mg, yield: 66.3%) as a white solid. LCMS (ESI): m / z = 412 (M+H)+. Step 54c: Preparation of 4-(4-(1H-pyrazol-4-yl)phenyl)piperidine hydrochloride (compound 0904-70): A mixture of 4-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidine-1-tert-butylcarboxylate (284 mg, 0.69 mmol, 1.0 equiv.) and hydrogen chloride-dioxane (4 M, 5 ml) was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, and the residue was diluted with water, adjusted to pH=9 with sodium carbonate solution, extracted with dichloromethane, the organic layer was dried and concentrated under reduced pressure, and the residue was used directly in the next step without further purification. LCMS (ESI): m / z = 228 [M+1] + . Step 54d: Preparation of (4-(4-(1H-pyrazol-4-yl)phenyl)piperidin-1-yl)(cyclopentyl)methanone (Compound 70): To a mixture of cyclopentanecarboxylic acid (25 mg, 0.2 mmol, 1.1 equiv.), 4-(4-(1H-pyrazol-4-yl)phenyl)piperidine hydrochloride (0904-70) (62 mg, 0.2 mmol, 1.0 equiv.), N,N-diisopropylethylamine (77.04 mg, 0.60 mmol, 3.0 equiv.), and 10 mL of N,N-dimethylcarboxamide was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (83.2 mg, 0.22 mmol, 1.1 equiv.). The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with water and saturated brine. The organic layer was then distilled under reduced pressure, and the residue was purified by preparative thin-layer chromatography (eluent: petroleum ether / ethyl acetate = 1 / 3) to give (4-(4-(1H-pyrazol-4-yl)phenyl)piperidin-1-yl)(cyclopentyl)methanone (28 mg, yield: 31.9%) as a white solid. LCMS (ESI): m / z = 324 (M+H). + . 1 H NMR (500 MHz, DMSO) δ 12.86 (s, 1H), 8.11 (s, 1H), 7.87 (s, 1H), 7.51 (d, J = 8.1 Hz, 2H), 7.21 (d, J = 8.1 Hz, 2H), 4.56 (d, J = 12.0 Hz, 1H), 4.09 (d, J = 13.2 Hz, 1H), 3.09 (t, J = 12.5 Hz, 1H), 3.01 (p, J = 7.9 Hz, 1H), 2.75 (t, J = 12.0 Hz, 1H), 2.59 (t, J = 12.3 Hz, 1H), 1.83 - 1.43 (m, 12H).

[0119] Example 55 Preparation of (4-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)piperidin-1-yl)(pyrrolidin-1-yl)methanone (Compound 71) (prepared according to the route in Scheme 9) Step 55a: Preparation of 4-(4-bromo-2,3-difluorophenyl)-3,6-dihydropyridine-1(2H)-tert-butylcarboxylate (compound 0905-71): Under nitrogen protection, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-tert-butylcarboxylate (0901-70) (378 mg, 1.22 A mixture of 4-(4-bromo-2,3-difluorophenyl)-3,6-dihydropyridine-1(2H)-tert-butylcarboxylate (240 mg, 5.2 mmol, 1 equiv.), 1,4-dibromo-2,3-difluorobenzene (400 mg, 1.44 mmol, 1.2 equiv.), sodium carbonate (256 mg, 2.4 mmol, 2 equiv.), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (44 mg, 0.12 mmol, 0.05 equiv.), 1,4-dioxane (8 ml), and water (0.8 ml) was mixed and stirred at 90°C for 5 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified using a silica gel column (petroleum ether / ethyl acetate = 3 / 1) to give 4-(4-bromo-2,3-difluorophenyl)-3,6-dihydropyridine-1(2H)-tert-butylcarboxylate (240 mg, yield: 52.7%) as a yellow solid. LCMS (ESI) [M+1] + :m / z =374. Step 55b: Preparation of 4-(4-bromo-2,3-difluorophenyl)piperidine-1-tert-butylcarboxylate (compound 0906-71): Under a hydrogen atmosphere, 4-(4-bromo-2,3-difluorophenyl)-3,6-dihydropyridine-1(2H)-tert-butylcarboxylate (0905-71) (212 mg, 0.57 mmol, 1.0 equiv), platinum dioxide (13 mg, 0.057 mmol, 0.1 equiv), ethanol (2 ml), and acetic acid (2 ml) were stirred at room temperature for 1 hour. The mixture was filtered, the filtrate was removed under reduced pressure, the residue was adjusted to pH=9 with sodium carbonate solution, extracted with dichloromethane, the organic layer was dried and concentrated under reduced pressure to give crude 4-(4-bromo-2,3-difluorophenyl)piperidine-1-tert-butylcarboxylate (212 mg, yield: 99.1%) as a pale yellow solid. LCMS (ESI): m / z = 376 [M+1] + . Step 55c: Preparation of 4-(4-bromo-2,3-difluorophenyl)piperidine (compound 0907-71): A mixture of 4-(4-bromo-2,3-difluorophenyl)piperidine-1-tert-butylcarboxylate (0906-71) (212 mg, 0.57 mmol, 1.0 equiv.) and hydrogen chloride in methanol (4 M, 4 ml) was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and the residue was diluted with water and adjusted to pH 9 with sodium carbonate solution. Extraction with dichloromethane was performed. The organic layer was dried and concentrated under reduced pressure to give crude 4-(4-bromo-2,3-difluorophenyl)piperidine (150 mg, 95.7% yield) as a yellow solid. LCMS (ESI): m / z = 276 [M+1] + . Step 55d: Preparation of (4-(4-bromo-2,3-difluorophenyl)piperidin-1-yl)(pyrrolidin-1-yl)methanone (compound 0908-71): 1-Pyrrolidinecarbonyl chloride (88 mg, 0.65 mmol, 1.5 equiv.) was added dropwise to a mixture of 4-(4-bromo-2,3-difluorophenyl)piperidine (0907-71) (120 mg, 0.44 mmol, 1 equiv.), triethylamine (178 mg, 1.76 mmol, 4 equiv.), and dichloromethane (2 ml) at room temperature, and the mixture was stirred for 1 hour. The reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column (dichloromethane / methanol=60 / 1) to give (4-(4-bromo-2,3-difluorophenyl)piperidin-1-yl)(pyrrolidin-1-yl)methanone (137 mg, yield: 83.7%) as a colorless oil. LCMS (ESI): m / z = 373 [M+1] + . Step 55e: Preparation of (4-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)piperidin-1-yl)(pyrrolidin-1-yl)methanone (Compound 71): Under nitrogen protection, (4-(4-bromo-2,3-difluorophenyl)piperidin-1-yl)(pyrrolidin-1-yl)methanone (0908-71) (137 mg, 0.37 mmol, 1 equiv.), 1-methyl A mixture of pyrazole-4-boronic acid pinacol ester (162 mg, 0.55 mmol, 1.5 equiv.), sodium carbonate (78 mg, 0.74 mmol, 2 equiv.), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (26 mg, 0.037 mmol, 0.1 equiv.), acetonitrile (4 ml), and water (0.8 ml) was stirred at 90°C for 6 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified using a thick preparative plate (dichloromethane / methanol = 30 / 1) to give (4-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)piperidin-1-yl)(pyrrolidin-1-yl)methanone (69 mg, yield: 52.2%) as a yellow solid. LCMS(ESI):m / z=361[M+1] + . 1 H NMR (500 MHz, DMSO) δ 13.13 (s, 1H), 8.17 (s, 1H), 7.94 (s, 1H), 7.48 (t, J = 7.1 Hz, 1H), 7.13 (t, J = 6.9 Hz, 1H), 3.78 (d, J = 12.6 Hz, 2H), 3.29 - 3.22 (m, 4H), 3.00 (t, J = 11.6 Hz, 1H), 2.80 (t, J = 12.2 Hz, 2H), 1.89 - 1.57 (m, 8H).

[0120] Example 56: Preparation of (4-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)piperazin-1-yl)(pyrrolidin-1-yl)methanone (Compound 72) (prepared according to the route in Scheme 10) Step 56a: Preparation of 4-(pyrrolidine-1-carbonyl)piperazine-1-tert-butylcarboxylate (compound 1002-72): Under nitrogen protection, piperazine-1-tert-butylcarboxylate (500 mg, 2.7 mmol, 1 equiv.), N,N-carbonyldiimidazole (650 mg, 4.0 mmol, 1.5 equiv.), pyridine (2.1 mL, 22.7 mmol, 10 equiv.), and tetrahydrofuran (8 mL) were mixed and stirred at 0 °C for 30 minutes. Next, pyrrolidine (960 mg, 13.5 mmol, 5 equiv.) was added, and the reaction mixture was warmed to room temperature and mixed and stirred for 2 hours. The reaction mixture was quenched with water, washed with aqueous hydrochloric acid to remove pyridine, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column (petroleum ether / ethyl acetate=3 / 1) to give 4-(pyrrolidine-1-carbonyl)piperazine-1-tert-butylcarboxylate (167 mg, yield: 21.9%) as a white solid. LCMS (ESI) [M+1] + :m / z =284. Step 56b: Preparation of piperazin-1-yl(pyrrolidin-1-yl)methanone (compound 1003-72): A mixture of 4-(pyrrolidine-1-carbonyl)piperazine-1-tert-butylcarboxylate (1002-72) (167 mg, 0.59 mmol, 1 equiv.) and hydrogen chloride in methanol (4 M, 4 ml) was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and the residue was diluted with water and adjusted to pH 9 with sodium carbonate solution. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give (89 mg, yield: 82.4%) as a yellow solid. LCMS (ESI): m / z = 184 [M+1] + . Step 56c: Preparation of (4-(2,3-difluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)(pyrrolidin-1-yl)methanone (compound 1004-72): Under nitrogen protection, piperazin-1-yl(pyrrolidin-1-yl)methanone (1003-72) (69 mg, 0.31 mmol, 1 equiv.), 4-(4-bromo-2,3-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)(pyrrolidin-1-yl)methanone A mixture of (ran-2-yl)-1H-pyrazole (0103-4) (161 mg, 0.47 mmol, 1.5 equiv.), sodium tert-butoxide (119 mg, 1.24 mmol, 4 equiv.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (36 mg, 0.062 mmol, 0.2 equiv.), tris(dibenzylideneacetone)dipalladium (28 mg, 0.031 mmol, 0.1 equiv.), and toluene (4 ml) was stirred overnight at 120° C. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified on a thick preparative silica gel plate (dichloromethane / methanol = 30 / 1) to give (4-(2,3-difluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)(pyrrolidin-1-yl)methanone (77 mg, yield: 55.8%) as a yellow solid. LCMS (ESI): m / z = 446 [M+1] + . Step 56d: Preparation of (4-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)piperazin-1-yl)(pyrrolidin-1-yl)methanone (Compound 72): A mixture of (4-(2,3-difluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)(pyrrolidin-1-yl)methanone (1004-72) (77 mg, 0.17 mmol, 1.0 equiv) and hydrogen chloride in methanol (4 M, 2 ml) was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and the residue was diluted with water, adjusted to pH 9 with sodium carbonate solution, extracted with dichloromethane, and the organic layer was dried and concentrated under reduced pressure. The residue was purified by preparative thick-layer chromatography (dichloromethane / methanol = 10 / 1) to give (4-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)piperazin-1-yl)(pyrrolidin-1-yl)methanone (45 mg, yield: 73.3%) as a white solid product. LCMS (ESI): m / z = 362 [M+1] + . 1 H NMR (500 MHz, DMSO) δ 13.06 (s, 1H), 8.10 (s, 1H), 7.89 (s, 1H), 7.41 (t, J = 7.8 Hz, 1H), 6.87 (t, J = 8.1 Hz, 1H), 3.32 (d, J = 4.7 Hz, 6H), 3.04 (s, 4H), 2.50 (s, 2H), 1.76 (s, 4H).

[0121] Example 57: Preparation of 1-((1-(2-fluoro-4-(1H-pyrazol-3-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (Compound 76) (prepared according to the route in Scheme 1) Step 57a: Preparation of 3-(4-bromo-3-fluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (compound 0111-76): To a mixture of 3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (318 mg, 1.14 mmol, 1.0 equiv.), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (65 mg, 0.08 mmol, 0.07 equiv.), sodium carbonate (363 mg, 3.42 mmol, 3.0 equiv.), dioxane (5 mL), and water (1 mL) was added (4-bromo-3-fluorophenyl)boronic acid (250 mg, 1.14 mmol, 1.0 equiv.). The mixture was heated to 85°C under a nitrogen atmosphere and reacted for 3 hours. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate 10:1 to 8:1) to give 3-(4-bromo-3-fluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (340 mg, yield: 92%) as a pale yellow oil. LCMS (ESI): m / z = 325 [M+1] + TLC: Rf 0.5 (petroleum ether:ethyl acetate=5:1). Step 57b: Preparation of 1-((1-(2-fluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (compound 0112-76): 3-(4-bromo-3-fluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (0111-76) (150 mg, 0.46 mmol, 1.0 equiv), tris(dibenzylidene nitrile) To a mixture of 4,5-diphenylacetone)dipalladium (21 mg, 0.023 mmol, 0.05 equiv.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (26.6 mg, 0.046 mmol, 0.12 equiv.), sodium tert-butoxide (111 mg, 1.15 mmol, 2.5 equiv.), and toluene (6 mL) was added 1-(piperidin-4-ylmethyl)pyrrolidin-2-one (101 mg, 0.55 mmol, 1.2 equiv.). The mixture was heated to 120°C under a nitrogen atmosphere and reacted overnight. The mixture was diluted with water (20 mL). The aqueous layer was extracted with ethyl acetate (15 mL × 3). The combined organic layer was washed with saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by pre-TLC (dichloromethane:methanol=15:1) to give 1-((1-(2-fluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (30 mg, yield: 15%) as a pale yellow solid. LCMS (ESI): m / z = 427 [M+1] + TLC: Rf 0.5 (dichloromethane:methanol=15:1). Step 57c: Preparation of 1-((1-(2-fluoro-4-(1H-pyrazol-3-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (Compound 76): A mixture of 1-((1-(2-fluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (0112-76) (30 mg, 0.07 mmol, 1.0 equiv) and hydrogen chloride in methanol (4 M, 2.5 ml) was stirred at room temperature for 1.5 hours. The mixture was diluted with water (15 ml). Solid sodium carbonate was added to adjust the pH to 10, and then the aqueous layer was extracted with dichloromethane (15 ml × 3). The combined organic layer was washed with saturated brine (15 ml × 1), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by pre-TLC (dichloromethane:methanol=10:1) to give 1-((1-(2-fluoro-4-(1H-pyrazol-3-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (17 mg, yield: 71%) as a white solid. LCMS (ESI): m / z = 343 [M+1] + TLC: Rf 0.5 (dichloromethane:methanol=10:1). 1 H NMR (500 MHz, MeOD) δ 7.61 (s, 1H), 7.43 (d, J = 15.2 Hz, 2H), 7.05 (t, J = 8.6 Hz, 1H), 6.58 (s, 1H), 3.48 (dd, J = 18.1, 10.9 Hz, 4H), 3.22 (t, J = 8.9 Hz, 2H), 2.69 (t, J = 11.3 Hz, 2H), 2.39 (t, J = 8.1 Hz, 2H), 2.13 - 1.95 (m, 2H), 1.79 (ddd, J = 31.7, 17.6, 8.5 Hz, 3H), 1.50 - 1.36 (m, 2H).

[0122] Example 58: Preparation of 1-((1-(2,3-difluoro-4-(1H-pyrazol-3-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (Compound 77) Under nitrogen protection, 1-((1-(4-bromo-2,3-difluorophenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (100 mg, 0.27 mmol, 1.0 equiv.), (1H-pyrazol-3-yl)boronic acid (61 mg, 0.54 mmol, 2.0 equiv.), sodium carbonate (86 mg, 0.81 mmol, 2.0 equiv.), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (14 mg, 0.016 mmol, 0.06 equiv.), 1,4-dioxane (5 ml), and water (1 ml) were mixed and stirred at 90 °C overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried and concentrated under reduced pressure. The residue was purified by thick preparative plate (dichloromethane / methanol=15 / 1) to give 1-((1-(2,3-difluoro-4-(1H-pyrazol-3-yl)phenyl)piperidin-4-yl)methyl)pyrrolidin-2-one (26 mg, yield: 26.8%) as a white solid. LCMS (ESI) [M+1] + :m / z =361. 1 H NMR (500 MHz, DMSO) δ 13.01 (s, 1H), 7.81 (s, 1H), 7.60 (s, 1H), 6.89 (s, 1H), 6.57 (s, 1H), 3.43 (d, J = 10.7 Hz, 2H), 3.36 (t, J = 6.9 Hz, 2H), 3.11 (d, J = 7.2 Hz, 2H), 2.72 (t, J = 11.2 Hz, 2H), 2.23 (t, J = 8.0 Hz, 2H), 2.02 - 1.89 (m, 2H), 1.82 - 1.62 (m, 3H), 1.39 - 1.27 (m, 2H).

[0123] Example 59 Preparation of (4-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)piperazin-1-yl)(piperidin-1-yl)methanone (Compound 88) (Prepared according to the route in Scheme 10) Step 59a: Preparation of 4-(piperidine-1-carbonyl)piperazine-1-tert-butylcarboxylate (compound 1002-88): Under nitrogen protection, a mixture of piperazine-1-tert-butylcarboxylate (200 mg, 1.36 mmol, 1.0 equiv.), piperidine-1-carbonyl chloride (278 mg, 1.49 mmol, 1.1 equiv.), triethylamine (206 mg, 2.03 mmol, 1.5 equiv.), and dichloromethane (5 mL) was stirred at room temperature for 1 hour. The reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was dried and concentrated under reduced pressure to give 4-(piperidine-1-carbonyl)piperazine-1-tert-butylcarboxylate (380 mg, crude product) as a white solid. LCMS (ESI): m / z = 298 [M+1] + . Step 59b: Preparation of piperazin-1-yl(piperidin-1-yl)methanone (compound 1003-88): A mixture of 4-(piperidine-1-carbonyl)piperazine-1-tert-butylcarboxylate (1002-88) (380 mg, 1.28 mmol, 1.0 equiv.) and hydrogen chloride in methanol (4 M, 5 ml) was stirred at room temperature for 1.0 h. The solvent was removed under reduced pressure, and the residue was diluted with water and adjusted to pH = 8 with sodium carbonate solution. The mixture was extracted with dichloromethane. The organic layer was dried and concentrated under reduced pressure to give the product piperazin-1-yl(piperidin-1-yl)methanone (173 mg, crude) as a yellow solid. LCMS (ESI): m / z = 198 [M+1] + . Step 59c: Preparation of (4-(2,3-difluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)(piperidin-1-yl)methanone (compound 1004-88): Under nitrogen protection, piperazin-1-yl(piperidin-1-yl)methanone (1003-88) (80 mg, 0.404 mmol, 1.0 equiv.), 4-(4-bromo-2,3-difluorophenyl)-1-(tetrahydro-2H-pyrazol-4-yl)phenyl)piperazin-1-yl)(piperidin-1-yl)methanone A mixture of (2-phenyl-2-yl)-1H-pyrazole (0103-4) (139 mg, 0.404 mmol, 1.0 equiv.), sodium tert-butoxide (117 mg, 1.21 mmol, 3.0 equiv.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (24 mg, 0.04 mmol, 0.1 equiv.), tris(dibenzylideneacetone)dipalladium (19 mg, 0.02 mmol, 0.05 equiv.), and toluene (5 mL) was stirred overnight at 120° C. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried and concentrated under reduced pressure. The residue was purified by silica gel column (petroleum ether / ethyl acetate=1 / 1) to give a yellow solid product (4-(2,3-difluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)(piperidin-1-yl)methanone (70 mg, yield: 37.63%). LCMS (ESI): m / z = 460 [M+1] + . Step 59d: Preparation of (4-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)piperazin-1-yl)(piperidin-1-yl)methanone (compound 88): A mixture of (4-(2,3-difluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperazin-1-yl)(piperidin-1-yl)methanone (1004-88) (70 mg, 0.15 mmol, 1.0 equiv) and hydrogen chloride in methanol (4 M, 3 ml) was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, and the residue was diluted with water, adjusted to pH 9 with sodium carbonate solution, and extracted with dichloromethane. The organic layer was dried and concentrated under reduced pressure. The residue was purified by preparative thick-layer chromatography (dichloromethane / methanol=15 / 1) to give the product (4-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)piperazin-1-yl)(piperidin-1-yl)methanone (30 mg, yield: 52.63%) as a yellow solid. LCMS (ESI): m / z = 376 [M+1] + . 1 H NMR (500 MHz, DMSO) δ 13.06 (s, 1H), 8.11 (s, 1H), 7.88 (s, 1H), 7.41 (t, J = 7.8 Hz, 1H), 6.87 (t, J = 8.2 Hz, 1H), 3.27 (s, 4H), 3.15 (d, J = 5.0 Hz, 4H), 3.04 (d, J = 4.3 Hz, 4H), 1.51 (dd, J = 25.7, 3.8 Hz, 6H).

[0124] Example 60: Preparation of N-cyclopentyl-4-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)piperazine-1-carboxamide (Compound 89) A mixture of 4-(2,3-difluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperazine-1-tert-butylcarboxylate (156 mg, 0.35 mmol, 1.0 equivalent) and hydrogen chloride in dioxane (4 M, 5 ml) was stirred at room temperature for 1.0 hour. The mixture was concentrated to give the concentrate, which was ready for use. To a mixture of cyclopentylamine (30 mg, 0.35 mmol, 1.0 equiv.) and N,N-diisopropylethylamine (225 mg, 1.75 mmol, 5.0 equiv.) in tetrahydrofuran, N,N-carbonyldiimidazole (68 mg, 0.42 mmol, 1.2 equiv.) was added and stirred at room temperature for 1 hour. The concentrate was then added and stirred at room temperature for 1 hour. Water was added to quench the reaction. The resulting reaction mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was concentrated, and the residue was purified on a thick, preparative thin-layer silica gel plate (eluent: dichloromethane / methanol = 15 / 1) to give N-cyclopentyl-4-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)piperazine-1-carboxamide (35 mg, yield: 26.51%) as a white solid. LCMS(ESI):m / z=376[M+1] + . 1 H NMR (500 MHz, DMSO) δ 13.06 (s, 1H), 8.10 (s, 1H), 7.88 (s, 1H), 7.41 (t, J = 8.0 Hz, 1H), 6.87 (t, J = 8.2 Hz, 1H), 6.30 (d, J = 6.7 Hz, 1H), 3.92 (dd, J = 14.1, 7.1 Hz, 1H), 3.44 (d, J = 4.5 Hz, 4H), 2.99 (s, 4H), 1.84 - 1.76 (m, 2H), 1.63 (s, 2H), 1.51 - 1.33 (m, 4H).

[0125] Example 61: Preparation of (4-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)(pyrrolidin-1-yl)methanone (Compound 91) (prepared according to the route in Scheme 9) Step 61a: Preparation of 4-(2,3-difluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)-3,6-dihydropyridine-1(2H)-tert-butylcarboxylate (compound 0902-91): Under a nitrogen atmosphere, 4-(4-bromo-2,3-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (0103-4) (340 mg, 1 mmol, 1.0 equiv.), 4-(4,4,5,5- Tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-tert-butylcarboxylate (340 mg, 1.1 mmol, 1.1 equiv.), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (73 mg, 0.1 mmol, 0.1 equiv.), and sodium carbonate (318 mg, 3 mmol, 3.0 equiv.) were added to a 10:1 dioxane / water (11 ml) mixture, and the mixture was stirred at 90°C for 3 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1 to 2 / 1) to give 4-(2,3-difluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)-3,6-dihydropyridine-1(2H)-tert-butylcarboxylate (350 mg, yield: 79.18%) as a yellow oil. LCMS (ESI): m / z = 446 [M+1] + . Step 61b: Preparation of (4-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)(pyrrolidin-1-yl)methanone (Compound 91): A mixture of 4-(2,3-difluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)-3,6-dihydropyridine-1(2H)-tert-butylcarboxylate (0902-91) (88 mg, 0.2 mmol, 1.0 equivalent) and hydrogen chloride-dioxane (4 M, 5 ml) was stirred at room temperature for 1.0 hour. The mixture was concentrated and then dissolved in tetrahydrofuran. To the solution were added pyrrolidine-1-carbonyl chloride (20 mg, 0.15 mmol, 0.8 equiv.) and N,N-diisopropylethylamine (98 mg, 0.76 mmol, 4.0 equiv.). The mixture was stirred at room temperature for 1 hour. Water was added to quench the reaction. The mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was concentrated, and the residue was purified on a thick preparative thin-layer silica gel plate (eluent: dichloromethane / methanol = 15 / 1) to give the product (4-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)-3,6-dihydropyridin-1(2H)-yl)(pyrrolidin-1-yl)methanone (30 mg, yield: 42.25%) as a white solid. LCMS (ESI): m / z = 359 [M+1] + . 1 H NMR (500 MHz, DMSO) δ 13.16 (s, 1H), 8.21 (s, 1H), 7.97 (s, 1H), 7.52 (t, J = 7.6 Hz, 1H), 7.17 (t, J = 7.7 Hz, 1H), 6.10 (s, 1H), 3.90 (s, 2H), 3.39 (t, J = 5.3 Hz, 2H), 3.30 (s, 4H), 2.49 - 2.46 (m, 2H), 1.77 (s, 4H).

[0126] Example 62: Preparation of N-(cyclopentylmethyl)-4-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)piperazine-1-carboxamide (Compound 92) A mixture of cyclopentylmethylamine (36.8 mg, 0.273 mmol, 1.2 equiv.), 1-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)piperazine (60 mg, 0.227 mmol, 1.0 equiv.), N,N-diisopropylethylamine (146 mg, 1.135 mmol, 5.0 equiv.), and N,N'-carbonyldiimidazole (44 mg, 0.272 mmol, 1.2 equiv.) in N,N-dimethylcarboxamide (6 mL) was stirred at room temperature for 6.0 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column (eluent: dichloromethane / methanol = 50 / 1 to 10 / 1) to give N-(cyclopentylmethyl)-4-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)piperazine-1-carboxamide (11 mg, yield: 12.5%) as a white solid product. LCMS (ESI): m / z = 390 (M+H). + Melting point: 155~162℃. 1 H NMR (500 MHz, DMSO) δ 13.06 (s, 1H), 8.10 (s, 1H), 7.88 (s, 1H), 7.41 (t, J = 7.9 Hz, 1H), 6.87 (t, J = 8.2 Hz, 1H), 6.55 (s, 1H), 3.45 (s, 4H), 2.97 (dd, J = 14.4, 5.7 Hz, 6H), 2.02 (dd, J = 14.7, 7.4 Hz, 1H), 1.70 - 1.38 (m, 6H), 1.19 (dd, J = 12.1, 6.6 Hz, 2H).

[0127] Example 63 Preparation of 2-cyclopentyl-1-(4-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)piperidin-1-yl)ethan-1-one (Compound 93) (prepared according to the route in Scheme 9) A mixture of 2-cyclopentylacetic acid (16.1 mg, 0.13 mmol, 1.05 equiv.), 4-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)piperidine hydrochloride (40 mg, 0.12 mmol, 1.0 equiv.), N,N-diisopropylethylamine (93 mg, 0.72 mmol, 6.0 equiv.), and HATU (51 mg, 0.13 mmol, 1.1 equiv.) in N,N-dimethylcarboxamide (3 mL) was stirred at room temperature for 1 hour. The reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative thick-layer chromatography (eluent: dichloromethane / methanol=15 / 1) to give 2-cyclopentyl-1-(4-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)piperidin-1-yl)ethan-1-one (31 mg, yield: 69.17%) as a white solid product. LCMS (ESI): m / z = 374 [M+H] + . 1 H NMR (500 MHz, DMSO) δ 13.13 (s, 1H), 8.17 (s, 1H), 7.93 (s, 1H), 7.48 (t, J = 7.3 Hz, 1H), 7.12 (t, J = 7.3 Hz, 1H), 4.57 (d, J = 12.3 Hz, 1H), 4.01 (d, J = 12.9 Hz, 1H), 3.19 - 3.01 (m, 2H), 2.61 (t, J = 12.3 Hz, 1H), 2.36 (d, J = 7.1 Hz, 2H), 2.20 - 2.06 (m, 1H), 1.77 (d, J = 11.1 Hz, 4H), 1.59 (s, 3H), 1.54 - 1.42 (m, 3H), 1.14 (s, 2H).

[0128] Example 64: Preparation of N-benzyl-4-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)piperazine-1-carboxamide (Compound 94) (prepared according to the route in Scheme 10) Step 64a: Preparation of 4-(benzylcarbamoyl)piperazine-1-tert-butylcarboxylate (compound 1002-94): To a mixture of benzylamine (300 mg, 2.80 mmol, 1.0 equiv.) and N,N-dimethylcarboxamide (3 mL) was added carbonyldiimidazole (499 mg, 3.08 mmol, 1.1 equiv.). The mixture was stirred at room temperature for 1.5 hours, and then piperazine-1-tert-butylcarboxylate (626 mg, 3.36 mmol, 1.2 equiv.) was added and the mixture was stirred at room temperature overnight. The mixture was diluted with water (30 mL). The aqueous layer was extracted with ethyl acetate (15 mL × 4). The combined organic layer was washed with saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, and concentrated. The residue was separated by column chromatography on silica gel (dichloromethane:methanol 50:1) to give 4-(benzylcarbamoyl)piperazine-1-tert-butylcarboxylate (701 mg, yield: 78%) as a white solid. LCMS (ESI): m / z = 320 [M+1] + TLC: Rf 0.5 (dichloromethane:methanol=30:1). Step 64b: Preparation of N-benzylpiperazine-1-carboxamide (compound 1003-94): A mixture of 4-(benzylcarbamoyl)piperazine-1-tert-butylcarboxylate (1002-94) (701 mg, 2.19 mmol, 1.0 equiv.) and hydrogen chloride in methanol (4 M, 5 ml) was stirred at room temperature for 2 hours. The mixture was diluted with water (25 ml). Solid sodium carbonate was added to adjust the pH to 10, and the aqueous layer was then extracted with dichloromethane (10 ml × 6). The combined organic layer was washed with saturated brine (20 ml × 1), dried over anhydrous sodium sulfate, and concentrated to give N-benzylpiperazine-1-carboxamide (392 mg, 82% yield) as a white solid. LCMS (ESI): m / z = 220 [M+1] + TLC: Rf 0.3 (dichloromethane:methanol=10:1). Step 64c: Preparation of N-benzyl-4-(2,3-difluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperazine-1-carboxamide (compound 1004-94): 4-(4-bromo-2,3-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (0103-4) (150 mg, 0.44 mmol, 1.0 equiv), tris(dibenzylidene N-Benzylpiperazine-1-carboxamide (1003-94) (15 mg, 0.53 mmol, 1.2 equiv.) was added to a mixture of (acetone)dipalladium (20 mg, 0.022 mmol, 0.05 equiv.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (25 mg, 0.044 mmol, 0.1 equiv.), sodium tert-butoxide (105 mg, 1.09 mmol, 2.5 equiv.), and toluene (6 mL). The mixture was heated to 120°C under a nitrogen atmosphere and reacted overnight. The mixture was diluted with water (30 mL). The aqueous layer was extracted with ethyl acetate (15 mL × 3). The combined organic layer was washed with saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by pre-TLC (dichloromethane:methanol=20:1) to give N-benzyl-4-(2,3-difluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperazine-1-carboxamide (41 mg, yield: 20%) as a pale yellow oil. LCMS (ESI): m / z = 482 [M+1] + TLC: Rf 0.5 (dichloromethane:methanol=20:1). Step 64d: Preparation of N-benzyl-4-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)piperazine-1-carboxamide (Compound 94): A mixture of N-benzyl-4-(2,3-difluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperazine-1-carboxamide (1004-94) (41 mg, 0.085 mmol, 1.0 equiv) and hydrogen chloride in methanol (4 M, 2.5 ml) was stirred at room temperature for 2 hours. The mixture was diluted with water (20 ml). Solid sodium carbonate was added to adjust the pH to 10, and then the aqueous layer was extracted with ethyl acetate (20 ml × 3). The combined organic layer was washed with saturated brine (20 ml × 1), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by pre-TLC (dichloromethane:methanol=10:1) to give N-benzyl-4-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)piperazine-1-carboxamide (23 mg, yield: 68%) as a white solid. LCMS (ESI): m / z = 398 [M+1] + TLC: Rf 0.5 (dichloromethane:methanol=10:1). 1 H NMR (500 MHz, DMSO) δ 13.07 (s, 1H), 8.11 (s, 1H), 7.88 (s, 1H), 7.41 (t, J = 7.8 Hz, 1H), 7.30 (dd, J = 15.1, 7.9 Hz, 4H), 7.19 (dt, J = 11.1, 6.3 Hz, 2H), 6.88 (t, J = 8.1 Hz, 1H), 4.27 (d, J = 5.6 Hz, 2H), 3.51 (s, 4H), 3.02 (d, J = 4.2 Hz, 4H).

[0129] Example 65: Preparation of N-benzyl-1-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)piperidine-4-carboxamide (Compound 95) (prepared according to the route in Scheme 3) Step 65a: Preparation of 4-(benzylcarbamoyl)piperidine-1-tert-butylcarboxylate (compound 0302-95): A mixture of benzylamine (225 mg, 2.09 mmol, 1.2 equiv.), 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (0301) (400 mg, 1.74 mmol, 1.0 equiv.), triethylamine (440 mg, 4.35 mmol, 2.5 equiv.), and HATU (860 mg, 2.27 mmol, 1.3 equiv.) in N,N-dimethylcarboxamide (15 mL) was stirred at room temperature for 4.0 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 1 to 10 / 1) to give 4-(benzylcarbamoyl)piperidine-1-tert-butylcarboxylate (450 mg, yield: 81.3%) as a yellow oil. LCMS (ESI): m / z = 319 (M+H)+ Step 65b: Preparation of N-benzylpiperidine-4-carboxamide (compound 0303-95): A mixture of 4-(benzylcarbamoyl)piperidine-1-tert-butylcarboxylate (0302-95) (450 mg, 1.41 mmol, 1.0 equiv.) and hydrogen chloride in methanol (4 M, 4 ml) was stirred at room temperature for 2.0 hours. The solvent was removed under reduced pressure. The residue was diluted with water, adjusted to pH 9 with sodium carbonate solution, extracted with dichloromethane, and the organic layer was dried and concentrated under reduced pressure to give N-benzylpiperidine-4-carboxamide (256 mg, yield: 83.1%) as a yellow oil. LCMS (ESI): m / z = 219 [M+1]+. Step 65c: Preparation of N-benzyl-1-(2,3-difluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidine-4-carboxamide (compound 0304-95): Under nitrogen protection, N-benzylpiperidine-4-carboxamide (0303-95) (123 mg, 0.564 mmol, 1.6 equiv.), 4-(4-bromo-2,3-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidine-4-carboxamide (0303-95) (123 mg, 0.564 mmol, 1.6 equiv.) A mixture of H-pyrazole (0103-4) (120 mg, 0.353 mmol, 1.0 equiv.), sodium tert-butoxide (101 mg, 1.059 mmol, 3.0 equiv.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (20.4 mg, 0.035 mmol, 0.1 equiv.), and tris(dibenzylideneacetone)dipalladium (16.2 mg, 0.018 mmol, 0.05 equiv.) in toluene (8 mL) was stirred overnight at 120° C. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 150 / 1 to 50 / 1) to give N-benzyl-1-(2,3-difluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidine-4-carboxamide (120 mg, yield: 70.8%) as a yellow solid. LCMS (ESI): m / z = 481 [M+1] + . Step 65d: Preparation of N-benzyl-1-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)piperidine-4-carboxamide (Compound 95): A mixture of N-benzyl-1-(2,3-difluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidine-4-carboxamide (0304-95) (120 mg, 0.25 mmol, 1.0 equiv) and hydrogen chloride in methanol (4 M, 5 ml) was stirred at room temperature for 2.0 hours. The solvent was removed under reduced pressure. The residue was diluted with water, adjusted to pH 9 with sodium carbonate solution, and extracted with dichloromethane. The organic layer was dried and concentrated under reduced pressure. The residue was purified by preparative thick-layer chromatography (dichloromethane / methanol=10 / 1) to give N-benzyl-1-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)piperidine-4-carboxamide (49 mg, yield: 49.5%) as a yellow solid product. LCMS (ESI): m / z = 397 [M+1] + Melting point: 165-173°C. 1 H NMR (500 MHz, DMSO) δ 13.05 (s, 1H), 8.34 (s, 1H), 7.98 (s, 2H), 7.43 - 7.28 (m, 3H), 7.24 (d, J = 7.5 Hz, 3H), 6.87 (t, J = 8.2 Hz, 1H), 4.29 (d, J = 5.5 Hz, 2H), 3.43 (d, J = 11.5 Hz, 2H), 2.74 (t, J = 11.1 Hz, 2H), 2.36 (s, 1H), 1.91 - 1.68 (m, 4H).

[0130] Example 66: Preparation of cyclohexyl(4-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)piperidin-1-yl)methanone (Compound 97) (prepared according to the route in Scheme 9) Step 66a: Preparation of 4-(2,3-difluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidine-1-tert-butylcarboxylate (Compound 0903-97): Under nitrogen protection, zinc powder (0.63 g, 9.65 mmol, 3.0 equiv.) was baked at high temperature (500 °C) for 15 minutes and allowed to cool. N,N-dimethylacetamide (8 ml) and 1,2-dibromoethane (60 mg, 0.32 mmol, 0.1 equiv.) were added to the cooled zinc powder, and the reaction was then initiated at 50 °C. When the reaction temperature was changed to 35 °C, trimethylchlorosilane (35 mg, 0.32 mmol, 0.1 equiv.) was added to the mixture. The mixture was reacted at 35 °C for 5 minutes. Then, 4-iodopiperidine-1-tert-butylcarboxylate (1.0 g, 3.22 mmol, 1.0 equiv.) was slowly added to the mixture, and the temperature was maintained at 40 °C. The mixture was reacted at 40 °C for 30 minutes. The mixture was filtered, and the filtrate was immediately used in the next step. Under nitrogen protection, a mixture of 4-(4-bromo-2,3-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (0103-4) (200 mg, 0.588 mmol, 1.0 equiv.), the filtrate from the previous step, cuprous iodide (23 mg, 0.118 mmol, 1.0 equiv.), and 1,1-bis(diphenylphosphino)ferrocene palladium dichloromethane complex (48 mg, 0.059 mmol, 0.1 equiv.) was stirred at 85 °C overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried and concentrated under reduced pressure. The residue was purified using a silica gel column (petroleum ether / ethyl acetate=4 / 1) to obtain a yellow solid product, 4-(2,3-difluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidine-1-tert-butylcarboxylate (130 mg, yield: 49.43%). LCMS (ESI): m / z = 448 [M+1] + . Step 66b: Preparation of 4-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)piperidine hydrochloride (compound 0904-97): A mixture of 4-(2,3-difluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidine-1-tert-butylcarboxylate (0903-97) (130 mg, 0.29 mmol, 1.0 equiv) and hydrogen chloride in methanol (4 M, 4 ml) was stirred at room temperature for 2.0 hours. The solvent was removed under reduced pressure. The residue was used directly in the next step without further purification. LCMS (ESI): m / z = 264 [M+1] + . Step 66c: Preparation of cyclohexyl(4-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)piperidin-1-yl)methanone (Compound 97): Under nitrogen protection, a mixture of 4-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)piperidine hydrochloride (0904-97) (40 mg, 0.134 mmol, 1.0 equiv.), cyclohexanecarboxylic acid (20.6 mg, 0.161 mmol, 1.2 equiv.), HATU (76.4 mg, 0.201 mmol, 1.5 equiv.), N,N-diisopropylethylamine (51.8 mg, 0.402 mmol, 3.0 equiv.), and N,N-dimethylcarboxamide (3 mL) was stirred at room temperature for 2.0 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried and concentrated under reduced pressure. The residue was purified by preparative thick-layer chromatography (developing agent: ethyl acetate) to obtain cyclohexyl(4-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)piperidin-1-yl)methanone (11 mg, yield: 22.1%) as a yellow solid product. 1H NMR (500 MHz, DMSO) δ 13.13 (s, 1H), 8.17 (s, 1H), 7.94 (s, 1H), 7.47 (t, J = 7.3 Hz, 1H), 7.13 (t, J = 7.4 Hz, 1H), 4.57 (d, J = 11.5 Hz, 1H), 4.06 (d, J = 12.1 Hz, 1H), 3.11 (dt, J = 24.3, 12.2 Hz, 2H), 2.61 (d, J = 8.2 Hz, 2H), 1.87 - 1.75 (m, 2H), 1.58 (dd, J = 91.4, 16.8Hz, 8H), 1.39 - 1.28 (m, 4H).

[0131] Example 67: Preparation of cyclopentyl(4-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)piperidin-1-yl)methanone (Compound 98) (prepared according to the route in Scheme 9) Under nitrogen protection, a mixture of 4-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)piperidine hydrochloride (0904-97) (40 mg, 0.119 mmol, 1.0 equiv.), cyclopentanecarboxylic acid (17 mg, 0.143 mmol, 1.2 equiv.), HATU (69 mg, 0.179 mmol, 1.5 equiv.), N,N-diisopropylethylamine (47 mg, 0.358 mmol, 3.0 equiv.), and N,N-dimethylcarboxamide (5 ml) was stirred at room temperature for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried and concentrated under reduced pressure. The residue was purified by preparative thick-layer chromatography (dichloromethane / methanol = 20 / 1) to give cyclopentyl(4-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)piperidin-1-yl)methanone (38 mg, yield: 88.37%) as a white solid product. LCMS (ESI): m / z = 360 [M+1] + . 1H NMR (500 MHz, DMSO) δ 13.13 (s, 1H), 8.17 (s, 1H), 7.93 (s, 1H), 7.47 (t, J = 7.3 Hz, 1H), 7.13 (t, J = 7.3 Hz, 1H), 4.57 (d, J = 11.9 Hz, 1H), 4.11 (d, J = 12.4 Hz, 1H), 3.07 (ddd, J = 39.6, 20.1, 10.5 Hz, 3H), 2.63 (t, J = 12.2 Hz, 1H), 1.69 (ddd, J = 76.8, 51.7, 34.0 Hz, 12H).

[0132] Example 68: Preparation of cyclopentyl(4-(2,6-difluoro-4-(1H-pyrazol-4-yl)phenyl)piperidin-1-yl)methanone (Compound 99) (prepared according to the route in Scheme 9) Step 68a: Preparation of 4-(2,6-difluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)-3,6-dihydropyridine-1(2H)-tert-butylcarboxylate (Compound 0902-99): 4-(4-bromo-3,5-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (0103-5) (0.2 g, 0.58 mmol, 1.0 equiv.), [1,1′-bis( To a mixture of [(diphenylphosphino)ferrocene]palladium(II) dichloride (33 mg, 0.041 mmol, 0.07 equiv.) and sodium carbonate (185 mg, 1.75 mmol, 3.0 equiv.) in dioxane (5 mL) and water (1 mL) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-tert-butylcarboxylate (216 mg, 0.70 mmol, 1.25 equiv.) under a nitrogen atmosphere, the mixture was heated to 100°C overnight. The solvent was removed under reduced pressure. The residue was separated by column chromatography on silica gel (petroleum ether:ethyl acetate=3:1) to give 4-(2,6-difluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)-3,6-dihydropyridine-1(2H)-tert-butylcarboxylate (259 mg, yield: 100%) as a pale yellow oil. LCMS (ESI): m / z = 446 [M+1] + TLC: Rf 0.5 (petroleum ether:ethyl acetate=1:1). Step 68b: Preparation of 4-(2,6-difluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidine-1-tert-butylcarboxylate (compound 0903-99): To a mixture of 4-(2,6-difluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)-3,6-dihydropyridine-1(2H)-tert-butylcarboxylate (0902-99) (230 mg, 0.52 mmol, 1.0 equiv.) and ethanol (8 ml), palladium hydroxide on carbon (60 mg) was added. The mixture was heated to 65° C. under hydrogen balloon pressure and reacted overnight. The mixture was filtered. The filtrate was concentrated under reduced pressure to give 4-(2,6-difluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidine-1-tert-butylcarboxylate (220 mg, yield: 95%) as a colorless oil. LCMS (ESI): m / z = 448 [M+1] + TLC: Rf 0.5 (petroleum ether:ethyl acetate=1:1). Step 68c: Preparation of 4-(2,6-difluoro-4-(1H-pyrazol-4-yl)phenyl)piperidine hydrochloride (compound 0904-99): A mixture of 4-(2,6-difluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidine-1-tert-butylcarboxylate (0903-99) (220 mg, 0.49 mmol, 1.0 equiv.) and hydrogen chloride in methanol (4 M, 3 ml) was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure. The residue was dried in vacuo to give 4-(2,6-difluoro-4-(1H-pyrazol-4-yl)phenyl)piperidine hydrochloride (161 mg, crude product) as a white solid. LCMS (ESI): m / z = 264 [M+1] + TLC: Rf 0.2 (dichloromethane:methanol=10:1). Step 68d: Preparation of cyclopentyl(4-(2,6-difluoro-4-(1H-pyrazol-4-yl)phenyl)piperidin-1-yl)methanone (Compound 99): To a mixture of 4-(2,6-difluoro-4-(1H-pyrazol-4-yl)phenyl)piperidine hydrochloride (0904-99) (61 mg, 0.20 mmol, 1.0 equiv.), cyclopentylcarboxylic acid (28 mg, 0.24 mmol, 1.2 equiv.), and N,N-diisopropylethylamine (79 mg, 0.60 mmol, 3.0 equiv.) in dichloromethane (5 mL) was added HATU (100 mg, 0.26 mmol, 1.3 equiv.). The mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure. The residue was purified by pre-TLC (dichloromethane:ethyl acetate=1:1) to give cyclopentyl(4-(2,6-difluoro-4-(1H-pyrazol-4-yl)phenyl)piperidin-1-yl)methanone (36 mg, yield: 49%) as a white solid. LCMS (ESI): m / z = 360 [M+1] + TLC: Rf 0.5 (dichloromethane:ethyl acetate=1:1). 1 H NMR (500 MHz, MeOD) δ 7.98 (d, J = 56.7 Hz, 2H), 7.17 (d, J = 10.0 Hz, 2H), 4.70 (d, J = 13.2 Hz, 1H), 4.23 (d, J = 13.2 Hz, 1H), 3.20 (t, J = 13.1 Hz, 1H), 3.15 - 3.02 (m, 1H), 2.70 (t, J = 12.6 Hz, 1H), 1.85 (dddd, J = 74.2, 68.0, 42.5, 7.0 Hz, 13H).

[0133] Example 69: Preparation of (4-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)piperidin-1-yl)(4,4-difluorocyclohexyl)methanone (Compound 101) (prepared according to the route in Scheme 9) A mixture of 4,4-difluorocyclohexane-1-carboxylic acid (21 mg, 0.13 mmol, 1.3 equiv.), 4-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)piperidine hydrochloride (0904-97) (34 mg, 0.10 mmol, 1.0 equiv.), N,N-diisopropylethylamine (75 mg, 0.604 mmol, 6.0 equiv.), and HATU (42 mg, 0.11 mmol, 1.1 equiv.) in N,N-dimethylcarboxamide (3 mL) was stirred at room temperature for 2 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative thick-layer chromatography (eluent: dichloromethane / methanol = 15 / 1) to give the product (4-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)piperidin-1-yl)(4,4-difluorocyclohexyl)methanone (35 mg, yield: 85.48%) as a yellow solid. LCMS (ESI): m / z = 410 [M+H] + . 1 H NMR (500 MHz, DMSO) δ 13.13 (s, 1H), 8.18 (s, 1H), 7.93 (s, 1H), 7.48 (t, J = 7.5 Hz, 1H), 7.14 (t, J = 7.5 Hz, 1H), 4.57 (d, J = 12.3 Hz, 1H), 4.12 (d, J = 12.8 Hz, 1H), 3.14 (dt, J = 24.3, 12.4 Hz, 2H), 2.84 (t, J = 11.1 Hz, 1H), 2.63 (t, J = 12.3 Hz, 1H), 2.14 - 1.51 (m, 12H).

[0134] Example 70: Preparation of (S)-(4-(2,3-difluoro-4-pyrazol-4-yl)phenyl)-3-methylpiperazin-1-yl)(pyrrolidin-1-yl)methanone (Compound 102) (prepared according to the route in Scheme 10) Step 70a: Preparation of (S)-4-(4-bromo-2,3-difluorophenyl)-3-methylpiperazine-1-tert-butylcarboxylate (Compound 1002-102): Under nitrogen protection, 1,4-dibromo-2,3-difluorobenzene (600 mg, 2.21 mmol, 1.0 equiv.), (S)-3-methylpiperazine-1-tert-butylcarboxylate (530 mg, 2 A mixture of (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (138 mg, 0.221 mmol, 0.1 equiv.), sodium tert-butoxide (531 mg, 5.53 mmol, 2.5 equiv.), (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (138 mg, 0.221 mmol, 0.1 equiv.), palladium acetate (50 mg, 0.221 mmol, 0.1 equiv.), and toluene (25 ml) was stirred at 120°C for 1.5 hours. The reaction mixture was diluted with water (30 ml) and extracted with ethyl acetate (12 ml x 4). The combined organic layer was washed with saturated brine (40 ml x 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20 / 1 to 15 / 1) to give (S)-4-(4-bromo-2,3-difluorophenyl)-3-methylpiperazine-1-tert-butylcarboxylate (93 mg, yield: 10.7%) as a yellow oil. LCMS (ESI): m / z = 391 [M+1] + . Step 70b: Preparation of (S)-1-(4-bromo-2,3-difluorophenyl)-2-methylpiperazine hydrochloride (compound 1003-102): (S)-4-(4-bromo-2,3-difluorophenyl)-3-methylpiperazine-1-tert-butylcarboxylate (1002-102) (93 mg, 0.238 mmol, 1.0 equiv) in hydrogen chloride-methanol (4 M, 5 ml) was stirred at room temperature for 1.5 hours. The solvent was removed under reduced pressure to give (S)-1-(4-bromo-2,3-difluorophenyl)-2-methylpiperazine hydrochloride (73 mg, yield: 94.2%) as a yellow solid. LCMS (ESI): m / z = 291 [M+1] + . Step 70c: Preparation of (S)-(4-(4-bromo-2,3-difluorophenyl)-3-methylpiperazin-1-yl)(pyrrolidin-1-yl)methanone: Under nitrogen protection, a mixture of (S)-1-(4-bromo-2,3-difluorophenyl)-2-methylpiperazine hydrochloride (1003-102) (73 mg, 0.223 mmol, 1.0 equiv), 1-pyrrolidinecarbonyl chloride (32.7 mg, 0.245 mmol, 1.1 equiv), and triethylamine (56 mg, 0.558 mmol, 2.5 equiv) in dichloromethane (2 mL) was stirred at room temperature for 1.5 hours. The reaction was quenched with sodium carbonate solution, diluted with water (10 mL), and extracted with dichloromethane (6 mL × 4). The combined organic layer was washed with saturated brine (20 ml × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative thick-layer chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1) to give (S)-(4-(4-bromo-2,3-difluorophenyl)-3-methylpiperazin-1-yl)(pyrrolidin-1-yl)methanone (77 mg, yield: 89.5%) as a yellow oil. LCMS (ESI): m / z = 388 [M+1] + . Step 70d: (S)-(4-(2,3-Difluoro-4-pyrazol-4-yl)phenyl)-3-methylpiperazin-1-yl)(pyrrolidin-1-yl)methanone (Compound 102): Under nitrogen protection, (S)-(4-(4-bromo-2,3-difluorophenyl)-3-methylpiperazin-1-yl)(pyrrolidin-1-yl)methanone (77 mg, 0.199 mmol, 1.0 equiv.), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborola (Benzen-2-yl)-1H-pyrazole-1-tert-butylcarboxylate (70 mg, 0.239 mmol, 1.2 equiv.), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (16 mg, 0.0199 mmol, 0.1 equiv.), and sodium carbonate (63 mg, 0.597 mmol, 3.0 equiv.) were dissolved in a 5:1 mixture of dioxane and water (3 ml / 0.6 ml), and the mixture was stirred at 90°C overnight. The reaction mixture was diluted with water (10 ml) and then extracted with ethyl acetate (6 ml × 4). The combined organic layer was washed with saturated brine (20 ml × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative thick-layer chromatography (dichloromethane / methanol = 12 / 1) to give (S)-(4-(2,3-difluoro-4-pyrazol-4-yl)phenyl)-3-methylpiperazin-1-yl)(pyrrolidin-1-yl)methanone (12 mg, yield: 16.2%) as a white solid product. LCMS (ESI): m / z = 376 [M+1] + . 1 H NMR (500 MHz, DMSO) δ 13.08 (s, 1H), 8.12 (s, 1H), 7.90 (s, 1H), 7.43 (t, J = 7.9 Hz, 1H), 6.94 (t, J = 8.1 Hz, 1H), 3.51 (s, 1H), 3.37 (dd, J = 12.7, 2.8 Hz, 2H), 3.31 (s, 4H), 3.25 - 3.07 (m, 3H), 2.89 (dd, J = 9.9, 5.3 Hz, 1H), 1.76 (s, 4H), 0.94 (d, J = 6.3 Hz, 3H).

[0135] Example 71: Preparation of (R)-(4-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)-2-methylpiperazin-1-yl)(pyrrolidin-1-yl)methanone (Compound 103) (prepared according to the route in Scheme 10) Step 71a: Preparation of (R)-(2-methylpiperazin-1-yl)(pyrrolidin-1-yl)methanone (Compound 1002-103): Under a nitrogen atmosphere, (S)-3-methylpiperazine-1-tert-butylcarboxylate (500 mg, 2.5 mmol, 1.0 equiv.) was dissolved in 10 mL of tetrahydrofuran, and triethylamine (505 mg, 5.0 mmol, 2.0 equiv.) was added. The reaction mixture was cooled in an ice-water bath. Pyrrolidine-1-carbonyl chloride (350 mg, 2.625 mmol, 1.05 equiv.) was dissolved in 1 mL of tetrahydrofuran and added dropwise to the above mixture. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water, extracted with ethyl acetate, and the organic layer was dried and concentrated under reduced pressure. The residue was mixed with hydrogen chloride in dioxane (4 M, 6 mL) and stirred at room temperature for 1 hour. The mixture was concentrated and the pH of the residue was adjusted to 9 with sodium carbonate solution. The mixture was extracted with ethyl acetate and the organic layer was dried and concentrated under reduced pressure. The residue was used directly in the next step without further purification. LCMS (ESI): m / z = 198 [M+1] + . Step 71b: Preparation of (R)-(4-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)-2-methylpiperazin-1-yl)(pyrrolidin-1-yl)methanone (Compound 103): Under a nitrogen atmosphere, 4-(4-bromo-2,3-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (0103-4) (100 mg, 0.294 mmol, 1.0 equiv.), (R)-(2-methylpiperazin-1-yl)(pyrrolidin-1) A mixture of (-yl)methanone (1002-103) (103 mg, 0.441 mmol, 1.5 equiv.), tris(dibenzylideneacetone)dipalladium (26 mg, 0.029 mmol, 0.1 equiv.), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (27 mg, 0.058 mmol, 0.2 equiv.), and sodium tert-butoxide (226 mg, 0.235 mmol, 4.0 equiv.) in toluene (6 mL) was stirred at 125 °C overnight. The reaction mixture was cooled to room temperature and quenched with water. The mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative thick-layer chromatography (dichloromethane / methanol = 10 / 1) to give a yellow solid. The yellow solid was dissolved in hydrogen chloride-dioxane (4M, 6 ml). The mixture was stirred at room temperature for 1.0 hour. The mixture was concentrated, and the pH of the residue was adjusted to 9 with sodium carbonate solution. The mixture was extracted with ethyl acetate, and the organic layer was dried and concentrated under reduced pressure. The residue was purified by preparative thick-layer chromatography (dichloromethane / methanol=10 / 1) to give (R)-(4-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)-2-methylpiperazin-1-yl)(pyrrolidin-1-yl)methanone as a yellow solid (32 mg, yield: 29.09%). LCMS (ESI): m / z = 376 [M+1] + . 1H NMR (500 MHz, DMSO) δ 13.06 (s, 1H), 8.10 (s, 1H), 7.88 (s, 1H), 7.41 (t, J = 7.9 Hz, 1H), 6.84 (t, J = 8.2 Hz, 1H), 4.05 - 3.84 (m, 1H), 3.56 - 3.40 (m, 1H), 3.29 - 3.08 (m, 7H), 2.94 - 2.71 (m, 2H), 1.76 (s, 4H), 1.35 - 1.23 (m, 3H).

[0136] Example 72: Preparation of (R)-(4-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)-3-methylpiperazin-1-yl)(pyrrolidin-1-yl)methanone (Compound 104) (prepared according to the route in Scheme 10) Step 72a: Preparation of (R)-4-(4-bromo-2,3-difluorophenyl)-3-methylpiperazine-1-tert-butylcarboxylate (compound 1002-104): To a mixture of 1,4-dibromo-2,3-difluorobenzene (500 mg, 1.84 mmol, 1.0 equiv), palladium acetate (41 mg, 0.18 mmol, 0.1 equiv), (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (115 mg, 0.18 mmol, 0.1 equiv), sodium tert-butoxide (442 mg, 4.60 mmol, 2.5 equiv), and toluene (25 mL) was added (R)-3-methylpiperazine-1-tert-butylcarboxylate (368 mg, 1.84 mmol, 1.0 equiv). The mixture was heated to 120°C under a nitrogen atmosphere and reacted for 1.5 hours. The solvent was removed under reduced pressure. The residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate 30:1) to obtain (R)-4-(4-bromo-2,3-difluorophenyl)-3-methylpiperazine-1-tert-butylcarboxylate (75 mg, yield: 10%) as a pale yellow oil. LCMS (ESI): m / z = 391 [M+1] + TLC: Rf 0.5 (petroleum ether:ethyl acetate=10:1). Step 72b: Preparation of (R)-(4-(4-bromo-2,3-difluorophenyl)-3-methylpiperazin-1-yl)(pyrrolidin-1-yl)methanone: A mixture of (R)-4-(4-bromo-2,3-difluorophenyl)-3-methylpiperazine-1-tert-butylcarboxylate (1002-104) (75 mg, 0.19 mmol, 1.0 equiv) and hydrogen chloride in methanol (4 M, 2.5 ml) was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (5 ml), and N,N-diisopropylethylamine (124 mg, 0.96 mmol, 5.0 equiv) and pyrrolidine-1-carbonyl chloride (28 mg, 0.21 mmol, 1.1 equiv) were added. The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure. The residue was separated by column chromatography on silica gel (petroleum ether:ethyl acetate 1:2) to give (R)-(4-(4-bromo-2,3-difluorophenyl)-3-methylpiperazin-1-yl)(pyrrolidin-1-yl)methanone (60 mg, yield: 81%) as a pale yellow oil. LCMS (ESI): m / z = 388 [M+1] + TLC: Rf 0.3 (petroleum ether:ethyl acetate=1:1). Step 72c: Preparation of (R)-(4-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)-3-methylpiperazin-1-yl)(pyrrolidin-1-yl)methanone (Compound 104): (R)-(4-(4-bromo-2,3-difluorophenyl)-3-methylpiperazin-1-yl)(pyrrolidin-1-yl)methanone (60 mg, 0.16 mmol, 1.0 equiv.), [1,1′-bis(diphenylphosphine)] To a mixture of [(phino)ferrocene]palladium(II) dichloride (13 mg, 0.016 mmol, 0.1 equiv.), sodium carbonate (49 mg, 0.48 mmol, 3.0 equiv.), dioxane (5 mL), and water (1 mL) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-tert-butylcarboxylate (55 mg, 0.19 mmol, 1.2 equiv.). The mixture was heated to 102°C under a nitrogen atmosphere and reacted overnight. The mixture was diluted with water (20 mL). The aqueous layer was extracted with ethyl acetate (15 mL × 3). The combined organic layer was washed with saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by pre-TLC (dichloromethane:methanol=10:1) to give (R)-(4-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)-3-methylpiperazin-1-yl)(pyrrolidin-1-yl)methanone (15 mg, yield: 26%) as a white solid. LCMS (ESI): m / z = 376 [M+1] + TLC: Rf 0.5 (dichloromethane:methanol=10:1). 1 H NMR (500 MHz, DMSO) δ 13.09 (s, 1H), 8.13 (s, 1H), 7.90 (s, 1H), 7.43 (s, 1H), 6.94 (s, 1H), 3.51 (s, 4H), 2.90 (s, 7H), 1.76 (s, 4H), 0.94 (d, J = 4.8 Hz, 3H).

[0137] Example 73: Preparation of (S)-(4-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)-2-methylpiperazin-1-yl)(pyrrolidin-1-yl)methanone (Compound 105) (prepared according to the route in Scheme 10) Step 73a: Preparation of (S)-3-methyl-4-(pyrrolidine-1-carbonyl)piperazine-1-tert-butylcarboxylate (Compound 1002-105): Under nitrogen protection, pyrrolidine-1-carbonyl chloride (400 mg, 3.00 mmol, 1.2 equiv.) was added to a mixture of (S)-3-methylpiperazine-1-tert-butylcarboxylate (500 mg, 2.50 mmol, 1.0 equiv.), triethylamine (506 mg, 5.00 mmol, 2.0 equiv.), and dichloromethane. The mixture was stirred at room temperature for 2 hours. The reaction was quenched with water and extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 4 / 1 to 1 / 1) to give (S)-3-methyl-4-(pyrrolidine-1-carbonyl)piperazine-1-tert-butylcarboxylate (402 mg, yield: 54.14%) as a white solid product. MS (ES) + ): m / z = 298 [M+H] + . Step 73b: Preparation of (S)-(2-methylpiperazin-1-yl)(pyrrolidin-1-yl)methanone (compound 1003-105): (S)-3-Methyl-4-(pyrrolidine-1-carbonyl)piperazine-1-tert-butylcarboxylate (1002-105) (402 mg, 1.35 mmol, 1.0 equiv) in a trifluoroacetic acid / dichloromethane (1 / 2) mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and the pH of the residue was adjusted to 9 with 2 mol / L sodium hydroxide solution and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was used directly in the next step without further purification. MS (ES) + ): m / z = 198 [M+H] + . Step 73c: Preparation of ((2S)-4-(2,3-difluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)-2-methylpiperazin-1-yl)(pyrrolidin-1-yl)methanone (compound 1004-105): Under nitrogen protection, (S)-(2-methylpiperazin-1-yl)(pyrrolidin-1-yl)methanone (1003-105) (75 mg, 0.38 mmol, 1.3 equiv.), 4-(4-bromo-2,3-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)-2-methylpiperazin-1-yl)(pyrrolidin-1-yl)methanone A mixture of (H-pyran-2-yl)-1H-pyrazole (0103-4) (100 mg, 0.29 mmol, 1.0 equiv.), sodium tert-butoxide (78 mg, 0.81 mmol, 2.5 equiv.), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (13.5 mg, 0.03 mmol, 0.1 equiv.), tris(dibenzylideneacetone)dipalladium(0) (14 mg, 0.015 mmol, 0.05 equiv.), and toluene (6 mL) was stirred at 120 °C overnight. After cooling to room temperature, the reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative thick-layer chromatography (eluent: dichloromethane / methanol = 30 / 1) to give ((2S)-4-(2,3-difluoro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)-2-methylpiperazin-1-yl)(pyrrolidin-1-yl)methanone (70 mg, yield: 52.58%) as a yellow oil. MS (ES) + ): m / z = 460 [M+H] + . Step 73d: Preparation of (S)-(4-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)-2-methylpiperazin-1-yl)(pyrrolidin-1-yl)methanone (compound 105): A mixture of ((2S)-4-(2,3-difluoro-4-(1-(tetrahydro2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)-2-methylpiperazin-1-yl)(pyrrolidin-1-yl)methanone (1004-105) (70 mg, 0.15 mmol, 1.0 equiv) and hydrogen chloride in methanol (4 M, 3 ml) was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and the pH of the residue was adjusted to 9 with sodium carbonate solution and extracted with dichloromethane. The organic layer was dried and concentrated under reduced pressure. The residue was purified by preparative thick-layer chromatography (eluent: dichloromethane / methanol = 15 / 1) to give (S)-(4-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)-2-methylpiperazin-1-yl)(pyrrolidin-1-yl)methanone (43 mg, yield: 76.36%) as a white solid product. MS (ES) + ): m / z = 376 [M+H] + . 1 H NMR (500 MHz, DMSO) δ 13.06 (s, 1H), 8.10 (s, 1H), 7.88 (s, 1H), 7.41 (t, J = 7.9 Hz, 1H), 6.84 (t, J = 8.2 Hz, 1H), 3.97 (d, J = 6.1 Hz, 1H), 3.49 (d, J = 13.1 Hz, 1H), 3.30 (s, 2H), 3.28 - 3.26 (m, 2H), 3.26 - 3.06 (m, 3H), 2.92 - 2.72 (m, 2H), 1.76 (s, 4H), 1.31 (t, J = 11.0 Hz, 3H).

[0138] Example 74: Preparation of (4-(2-fluoro-4-(1H-pyrazol-4-yl)phenyl)piperidin-1-yl)(hexahydrocyclopentane[c]pyrrol-2(1H)-yl)methanone (Compound 106) (Prepared according to the route in Scheme 9) Under a nitrogen atmosphere and an ice bath, BTC (16 mg, 0.053 mmol, 0.5 equiv.) was added to a mixture of octahydrocyclopentane[c]pyrrole hydrochloride (16 mg, 0.106 mmol, 1.0 equiv.) and pyridine (17 mg, 0.212 mmol, 2.0 equiv.) in dichloromethane. The mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with 2N hydrochloric acid and extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran. The tetrahydrofuran solution of the residue was added to a mixture of 4-(2-fluoro-4-(1H-pyrazol-4-yl)phenyl)piperidine hydrochloride (30 mg, 0.106 mmol, 1.0 equiv.) and N,N-diisopropylethylamine (41 mg, 0.318 mmol, 3.0 equiv.) in tetrahydrofuran. The mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was concentrated, and the residue was purified on a thick preparative thin-layer silica gel plate (eluent: dichloromethane / methanol = 10 / 1) to give the product (4-(2-fluoro-4-(1H-pyrazol-4-yl)phenyl)piperidin-1-yl)(hexahydrocyclopentane[c]pyrrol-2(1H)-yl)methanone (14 mg, yield: 32.78%) as a yellow solid. LCMS (ESI): m / z = 383 [M+1] + . 1 H NMR (500 MHz, DMSO) δ 12.93 (s, 1H), 8.20 (s, 1H), 7.93 (s, 1H), 7.39 (t, J = 8.5 Hz, 2H), 7.28 (t, J = 8.2 Hz, 1H), 3.77 (d, J = 12.9 Hz, 2H), 3.55 - 3.41 (m, 2H), 3.03 (dd, J = 10.9, 3.6 Hz, 2H), 2.94 (t, J = 11.9 Hz, 1H), 2.80 (t, J = 12.1 Hz, 2H), 2.55 (d, J = 3.0 Hz, 2H), 1.77 - 1.56 (m, 7H), 1.51 (dt, J = 12.7, 6.4 Hz, 1H), 1.42 - 1.30 (m, 2H).

[0139] Example 75: Preparation of 4-(4-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)piperidine-1-carbonyl)cyclohexan-1-one (Compound 107) (prepared according to the route in Scheme 9) A mixture of 4-oxocyclohexane-1-carboxylic acid (19 mg, 0.13 mmol, 1.3 equiv.), 4-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)piperidine hydrochloride (0904-97) (34 mg, 0.10 mmol, 1.0 equiv.), N,N-diisopropylethylamine (75 mg, 0.604 mmol, 6.0 equiv.), and HATU (42 mg, 0.11 mmol, 1.1 equiv.) in N,N-dimethylcarboxamide (3 mL) was stirred at room temperature for 2 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative thick-layer chromatography (eluent: dichloromethane / methanol=15 / 1) to give the product 4-(4-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)piperidine-1-carbonyl)cyclohexan-1-one (30 mg, yield: 77.43%) as a white solid. LCMS (ESI): m / z = 379 [M+H] + . 1 H NMR (500 MHz, DMSO) δ 13.14 (s, 1H), 8.18 (s, 1H), 7.94 (s, 1H), 7.48 (t, J = 7.3 Hz, 1H), 7.15 (t, J = 7.4 Hz, 1H), 4.59 (d, J = 11.5 Hz, 1H), 4.20 (d, J = 12.4 Hz, 1H), 3.25 - 3.05 (m, 3H), 2.64 (d, J = 11.0 Hz, 1H), 2.49 - 2.42 (m, 2H), 2.27 (s, 2H), 1.98 (s, 2H), 1.88 - 1.51 (m, 6H).

[0140] Example 76: Preparation of 2-(4-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)piperidine-1-carbonyl)cyclohexan-1-one (Compound 109) (prepared according to the route in Scheme 9) A mixture of ethyl 2-oxocyclohexane-1-carboxylate (170 mg, 1 mmol, 1.0 equiv.), sodium hydroxide (80 mg, 2 mmol, 2.0 equiv.), and water (5 mL) was stirred at room temperature for 1.0 hour. The pH of the mixture was adjusted to 3 with concentrated hydrochloric acid. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and concentrated. The residue was dissolved in N,N-dimethylcarboxamide. To the solution were added 4-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)piperidine (0904-97) (30 mg, 0.09 mmol, 1.0 equiv.), HATU (37 mg, 0.1 mmol, 1.1 equiv.), and triethylamine (45 mg, 0.45 mmol, 5.0 equiv.). The mixture was stirred at room temperature for 1.0 hour. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative thick-layer chromatography (dichloromethane / methanol = 20 / 1) to give 2-(4-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)piperidine-1-carbonyl)cyclohexan-1-one (16 mg, yield: 45.71%) as a yellow solid product. LCMS (ESI): m / z = 389 [M+1] + . 1 H NMR (500 MHz, DMSO) δ 13.13 (s, 1H), 8.17 (s, 1H), 7.93 (s, 1H), 7.49 (dd, J = 16.6, 8.3 Hz, 1H), 7.09 (dt, J = 30.5, 7.3 Hz, 1H), 4.73 - 4.43 (m, 1H), 4.05 - 3.86 (m, 1H), 3.80 (s, 1H), 3.15 - 2.91 (m, 2H), 2.75 - 2.52 (m, 2H), 2.28 (t, J = 14.3 Hz, 1H), 2.05 - 1.88 (m, 3H), 1.86 - 1.55 (m, 7H).

[0141] Example 77: Preparation of (4-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)piperidin-1-yl)(1-hydroxycyclohexyl)methanone (Compound 110) (prepared according to the route in Scheme 9) A mixture of 1-hydroxycyclohexane-1-carboxylic acid (14 mg, 0.13 mmol, 1.05 equiv.), 4-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)piperidine hydrochloride (0904-97) (40 mg, 0.12 mmol, 1.0 equiv.), N,N-diisopropylethylamine (93 mg, 0.72 mmol, 6.0 equiv.), and HATU (51 mg, 0.13 mmol, 1.1 equiv.) in N,N-dimethylcarboxamide (3 mL) was stirred at room temperature for 1 hour. The reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative thick-layer chromatography (eluent: dichloromethane / methanol = 10 / 1) to give the product (4-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)piperidin-1-yl)(1-hydroxycyclohexyl)methanone (23 mg, yield: 49.21%) as a white solid. LCMS (ESI): m / z = 390 [M+H] + . 1 H NMR (500 MHz, DMSO) δ 13.13 (s, 1H), 8.17 (s, 1H), 7.93 (s, 1H), 7.48 (t, J = 7.4 Hz, 1H), 7.10 (t, J = 7.4 Hz, 1H), 5.19 (s, 1H), 4.82 (s, 2H), 3.11 (t, J = 12.0 Hz, 1H), 2.79 (d, J = 30.0 Hz, 2H), 1.86 - 1.39 (m, 14H).

[0142] Example 78: Preparation of 1-(4-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)piperidin-1-yl)-2-phenylethan-1-one (Compound 111) (prepared according to the route in Scheme 9) Step 78a: Preparation of 2-phenylacetic acid: A mixture of methyl 2-phenylacetate (500 mg, 3.3 mmol, 1.0 equiv.), sodium hydroxide (340 mg, 8.3 mmol, 2.5 equiv.), and tetrahydrofuran (15 ml) was stirred at room temperature for 2.0 hours. The solvent was removed under reduced pressure. The residue was diluted with water, the pH was adjusted to 4 with hydrochloric acid solution, and extracted with dichloromethane. The organic layer was dried and concentrated under reduced pressure. The residue was purified by preparative thick-layer chromatography (dichloromethane / methanol = 80 / 1) to give 2-phenylacetic acid (420 mg, yield: 92.9%) as a yellow solid product. LCMS (ESI): m / z = 137 [M+1]+. Step 78b: Preparation of 1-(4-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)piperidin-1-yl)-2-phenylethan-1-one (Compound 111): A mixture of 4-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)piperidine (0904-97) (32 mg, 0.1 mmol, 1.0 equiv), 2-phenylacetic acid (18 mg, 0.12 mmol, 1.2 equiv), triethylamine (30.3 mg, 0.3 mmol, 3.0 equiv), HATU (49.4 mg, 0.12 mmol, 1.2 equiv), and N,N-dimethylcarboxamide (4 ml) was stirred at room temperature for 4.0 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column (petroleum ether / ethyl acetate = 50 / 1 to 1 / 2) to give 1-(4-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)piperidin-1-yl)-2-phenylethan-1-one (15 mg, yield: 39.2%) as a yellow oil. LCMS (ESI): m / z = 382 (M+H) + Melting point: 141~152℃. 1H NMR (500 MHz, DMSO) δ 13.07 (s, 1H), 8.05 (s, 2H), 7.47 (t, J = 7.4 Hz, 1H), 7.32 - 7.11 (m, 5H), 7.03 (t, J = 7.3 Hz, 1H), 4.57 (d, J = 12.7 Hz, 1H), 4.07 (d, J = 13.0 Hz, 1H), 3.75 (s, 2H), 3.09 (dt, J = 24.1, 12.1 Hz, 2H), 2.66 (t, J = 12.2 Hz, 1H), 1.73 (dd, J = 30.3, 12.4Hz, 2H), 1.55 - 1.39 (m, 2H).

[0143] Example 79 Preparation of (4-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)piperidin-1-yl)((1s,4r)-4-pentylcyclohexyl)methanone (Compound 112) (Prepared according to the route in Scheme 9) Under nitrogen protection, a mixture of 4-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)piperidine hydrochloride (0904-97) (33 mg, 0.099 mmol, 1.0 equiv.), (1s,4r)-4-pentylcyclohexane-1-carboxylic acid (24 mg, 0.119 mmol, 1.2 equiv.), HATU (57 mg, 0.148 mmol, 1.5 equiv.), N,N-diisopropylethylamine (39 mg, 0.296 mmol, 3.0 equiv.), and N,N-dimethylcarboxamide (3 mL) was stirred at room temperature for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried and concentrated under reduced pressure. The residue was purified by preparative thick-layer chromatography (dichloromethane / methanol = 20 / 1) to give the product (4-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)piperidin-1-yl)((1s,4r)-4-pentylcyclohexyl)methanone (20 mg, yield: 46.51%) as a yellow solid. LCMS (ESI): m / z = 444 [M+1] + . 1H NMR (500 MHz, DMSO) δ 13.13 (s, 1H), 8.17 (s, 1H), 7.93 (s, 1H), 7.47 (t, J = 7.2 Hz, 1H), 7.13 (t, J = 7.1 Hz, 1H), 4.57 (d, J = 11.2 Hz, 1H), 4.06 (d, J = 11.3 Hz, 1H), 3.10 (dd, J = 24.4, 12.3 Hz, 2H), 2.77 - 2.53 (m, 2H), 1.84 - 1.12 (m, 21H), 0.86 (t, J = 6.8 Hz, 3H).

[0144] Example 80: Preparation of N-((1-(4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)-6-phenylhexamide (Compound 113) (prepared according to the route in Scheme 5) Step 80a: Preparation of 6-phenyl-N-((1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)hexamide (compound 0506-113): 6-phenylcaproic acid (38 mg, 0.19 mmol, 1.1 equiv.), (1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)hexamide A mixture of (4-(isothiazol-4-yl)phenyl)piperidin-4-yl)methylamine (0509-45) (60 mg, 0.18 mmol, 1.0 equiv.), N,N-diisopropylethylamine (70 mg, 0.54 mmol, 3.0 equiv.), HATU (74 mg, 0.19 mmol, 1.1 equiv.), and N,N-dimethylcarboxamide (3 ml) was stirred at room temperature for 2 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative thick-layer chromatography (eluent: dichloromethane / methanol=30 / 1) to give 6-phenyl-N-((1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H)-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)hexamide (68 mg, yield: 73.35%) as a yellow solid. LCMS (ESI): m / z = 515 [M+H]+ . Step 80b: Preparation of N-((1-(4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)-6-phenylhexamide (Compound 113): To a mixture of 6-phenyl-N-((1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H)-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)hexamide (0506-113) (68 mg, 0.132 mmol, 1.0 equiv.) and dichloromethane (5 ml), trifluoroacetic acid (2 ml) was added. The mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and the pH of the residue was adjusted to 9 with sodium carbonate solution and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative thick-layer chromatography (eluent: dichloromethane / methanol=15 / 1) to give N-((1-(4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)-6-phenylhexamide (53 mg, yield: 93.25%) as a white solid. LCMS (ESI): m / z = 431 [M+H] + . 1 H NMR (500 MHz, DMSO) δ 12.75 (s, 1H), 7.87 (d, J = 99.8 Hz, 3H), 7.41 (d, J = 8.5 Hz, 2H), 7.26 (t, J = 7.5 Hz, 2H), 7.16 (dd, J = 14.9, 7.3 Hz, 3H), 6.91 (d, J = 8.5 Hz, 2H), 3.65 (d, J = 12.2 Hz, 2H), 2.96 (t, J = 6.2 Hz, 2H), 2.58 (dd, J = 21.2, 9.7 Hz, 4H), 2.07 (t, J = 7.3 Hz, 2H), 1.69 (d, J = 12.2 Hz, 2H), 1.55 (dt, J = 15.8, 7.6 Hz, 5H), 1.26 (dd, J = 17.4, 10.1 Hz, 4H).

[0145] Example 81: Preparation of N-((1-(4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)oct-7-ynamide (Compound 114) (prepared according to the route in Scheme 5) Step 81a: Preparation of N-((1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)oct-7-ynamide (compound 0506-114): A mixture of (1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methylamine (0509-45) (50 mg, 0.14 mmol, 1.0 equiv), 7-octynoic acid (25 mg, 0.17 mmol, 1.2 equiv), HATU (73 mg, 0.19 mmol, 1.3 equiv), and triethylamine (30 mg, 0.29 mmol, 2.0 equiv) in N,N-dimethylcarboxamide (5 ml) was stirred at room temperature for 1.0 hour. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative thick-layer chromatography (dichloromethane / methanol=20 / 1) to obtain N-((1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)oct-7-ynamide (58 mg, yield: 85.42%) as a yellow solid product. LCMS (ESI): m / z = 463 [M+1] + . Step 81b: Preparation of N-((1-(4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)oct-7-ynamide (Compound 114): A mixture of N-((1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)oct-7-ynamide (0506-114) (58 mg, 0.125 mmol, 1.0 equiv) and hydrogen chloride-dioxane (4 M, 3 ml) was stirred at room temperature for 1.0 hour. The mixture was concentrated, and the pH of the residue was adjusted to 9 with sodium carbonate solution. The mixture was filtered and slurried with methanol. The mixture was filtered and dried to give the product N-((1-(4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)oct-7-ynamide (21 mg, yield: 44.21%) as a white solid. LCMS (ESI): m / z = 380 [M+1] + . 1 H NMR (500 MHz, DMSO) δ 12.75 (s, 1H), 7.99 (s, 1H), 7.78 (t, J = 5.2 Hz, 2H), 7.41 (d, J = 8.6 Hz, 2H), 6.91 (d, J = 8.7 Hz, 2H), 3.66 (d, J = 12.3 Hz, 2H), 2.97 (t, J = 6.2 Hz, 2H), 2.72 (s, 1H), 2.60 (t, J = 11.4 Hz, 2H), 2.14 (td, J = 7.0, 2.5 Hz, 2H), 2.07 (t, J = 7.4 Hz, 2H), 1.71 (d, J = 12.3 Hz, 2H), 1.57 - 1.38 (m, 6H), 1.35 - 1.28 (m, 2H), 1.24 (t, J = 10.5 Hz, 2H).

[0146] Example 82: Preparation of N-((1-(4-(1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)oct-7-enamide (Compound 115) (prepared according to the route in Scheme 5) Step 82a: Preparation of N-((1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)piperidin-4-yl)methyl)oct-7-enamide (compound 0506-115): Under nitrogen protection, a mixture of (1-(4-(1-(tetrahyd...

Claims

1. A 1,4-diheterocyclyl-substituted aromatic or heteroaromatic compound represented by formula (I), or a pharmaceutically acceptable salt thereof or a stereoisomer thereof. (where, X １ , X ２ , X ３ , and X ４ are each independently N, CH, and CR １ is selected from R １ are each independently a halogen, C １ ~C ６ Alkyl, halogen-substituted C １ ~C ６ Alkyl, hydroxy-substituted C １ ~C ６ Alkyl, C １ ~C ３ Alkoxy-substituted C １ ~C ６ Alkyl, amino-substituted C １ ~C ６ Alkyl, C １ ~C ３ Alkylamino-substituted C １ ~C ６ Alkyl, cyano, C １ ~C ６ Alkoxy, —N(C １ ~C ３ alkyl) ２ , -C(O)OC １ ~C ３ Alkyl, —C(O)NH ２ , -C(O)N(C １ ~C ３ alkyl) ２ , -C(O)(C １ ~C ３ alkyl) ２ and —C(O)H; Q is -(CR ２ R ３ ) ｐ -, -C(O)-, -S(O) ２ -, -N(R ４ )C(O)-, -C(O)N(R ４ )-, -C(O)N(R ４ ) (CR ２ R ３ ) -, -N(R ４ ) C(O)(CR ２ R ３ )-, where p is selected from 0, 1 or 2; R ２ , R ３ , and R ４ are each independently H and C １ ~C ６ alkyl, Y is a hydroxy-substituted C ４ ~C ６ Alkyl, ethynyl substituted C １ ~C ６ Alkyl, vinyl substituted C １ ~C ６ Alkyl, C ５ ~C ６ cycloalkylmethyl; or Y is selected from: Here, each R in Y １０ are each independently H, C １ ~C ３ Alkyl, C １ ~C ３ alkyl acyls, R １３ and R １４ are each independently H, halogen, or C １ ~C ６ Alkyl, C １ ~C ６ alkoxy, hydroxy; R １８ are each independently H, hydroxy, halogen, C １ ~C ３ Alkoxy, C １ ~C ３ alkyl, Rings C and Q form the following group:

2. 2. The 1,4-diheterocyclyl-substituted aromatic or heteroaromatic ring compound according to claim 1, wherein A is selected from the following:

3. Y is a hydroxy-substituted C ４ ~C ６ Alkyl, ethynyl substituted C ４ ~C ６ Alkyl, vinyl substituted C ４ ~C ６ Alkyl, and C ５ ~C ６ cycloalkylmethyl; or Y is selected from the following: (where, R １８ is H, hydroxy, halogen, and C １ ~C ３ alkoxy.)

4. X １ , X ２ , X ３ , and X ４ are each independently CH and CR １ The 1,4-diheterocyclyl-substituted aromatic or heteroaromatic compound, or a pharmaceutically acceptable salt or stereoisomer thereof, according to any one of claims 1 to 3, wherein the compound is selected from the group consisting of:

5. X １ and X ４ At the same time, CR １ Not X ２ and X ３ At the same time, CR １ The 1,4-diheterocyclyl-substituted aromatic or heteroaromatic compound, or a pharmaceutically acceptable salt or stereoisomer thereof according to claim 4, which is not:

6. R １ is a halogen, C １ ~C ３ Alkyl, halogen-substituted C １ ~C ３ Alkyl, cyano, formaldehyde, and hydroxy substituted C １ ~C ３ The 1,4-diheterocyclyl-substituted aromatic or heteroaromatic ring compound, or a pharmaceutically acceptable salt or stereoisomer thereof, according to any one of claims 1 to 3, wherein the 1,4-diheterocyclyl-substituted aromatic or heteroaromatic ring compound is selected from the group consisting of aryl, arylsulfonyl ...

7. R １ is selected from fluorine, chlorine, monofluoromethyl, difluoromethyl, trifluoromethyl, methyl, cyano, methoxy, formaldehyde, carbamoyl, hydroxymethyl, methoxyformyl, and dimethylamino.

8. 2. The 1,4-diheterocyclyl-substituted aromatic or heteroaromatic compound according to claim 1, or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, which is selected from the following compounds:

9. Use of the 1,4-diheterocyclyl-substituted aromatic or heteroaromatic compound, or a pharmaceutically acceptable salt or stereoisomer thereof according to any one of claims 1 to 3 and 8 in the manufacture of a 20-HETE production inhibitor.

10. Use of the 1,4-diheterocyclyl-substituted aromatic or heteroaromatic compound, or a pharmaceutically acceptable salt or stereoisomer thereof, according to any one of claims 1 to 3 and 8 in the manufacture of a medicament for the prevention and / or treatment of a disease and / or symptom associated with the 20-HETE signaling pathway.

11. 10. Use of a GLP-1 receptor agonist in combination with a 1,4-diheterocyclyl-substituted aromatic or heteroaromatic compound according to any one of claims 1 to 3 and 8, or a pharmaceutically acceptable salt or stereoisomer thereof, in the manufacture of a medicament for the prevention and / or treatment of a disease and / or symptom associated with the 20-HETE signaling pathway.

12. The use according to claim 11, wherein the GLP-1 receptor agonist is semaglutide.

13. 11. The use according to claim 10, wherein the disease and / or condition associated with the 20-HETE signaling pathway is selected from obesity, metabolic syndrome, dyslipidemia, diabetes, diabetic retinopathy, diabetic cerebrovascular disease, diabetic neuropathy, insulin resistance, hyperglycemia, hyperlipidemia, diabetic nephropathy, hypertension, cataracts, osteoporosis, hyperuricemia, diabetes-induced infections, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, fibrosis, heart disease, stroke, liver cirrhosis, metabolic acidosis, ketosis, cardiovascular disease, epilepsy, atherosclerosis, Parkinson's disease, myocardial infarction, acute renal failure, chronic kidney disease, polycystic kidney disease, tumors, end-organ damage, and Alzheimer's disease.

14. 14. The use according to claim 13, wherein the diabetes is type 1 diabetes, type 2 diabetes, gestational diabetes, idiopathic T1D, early onset T2DM, maturity onset diabetes of the young, atypical diabetes of the young, malnutrition-related diabetes, or potential autoimmune diabetes in adults.

15. A pharmaceutical composition for preventing and / or treating a disease and / or condition associated with the 20-HETE signaling pathway, comprising an active ingredient and pharmaceutically acceptable auxiliary materials and / or carriers, wherein the active ingredient comprises a 1,4-diheterocyclyl-substituted aromatic or heteroaromatic compound according to any one of claims 1 to 3 and 8, or a pharmaceutically acceptable salt or stereoisomer thereof.

16. 1. A pharmaceutical combination for preventing and / or treating a disease and / or condition associated with the 20-HETE signaling pathway, comprising: A combination drug characterized in that the active ingredients comprise a GLP-1 receptor agonist and a 1,4-diheterocyclyl-substituted aromatic ring or aromatic heterocyclic compound according to any one of claims 1 to 3 and 8, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein the GLP-1 receptor agonist and the 1,4-diheterocyclyl-substituted aromatic ring or aromatic heterocyclic compound according to any one of claims 1 to 3 and 8, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, are each in the form of an individual dosage unit, or together form a combined dosage unit.

17. 17. The combination drug of claim 16, wherein the GLP-1 receptor agonist is semaglutide.

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