Novel inhibitors of autotaxin

Abstract

To provide novel compounds as autotaxin (ATX) inhibitors for the treatment and prevention of conditions or disorders caused by autotaxin (ATX) activation or increased LAP concentration, and pharmaceutical compositions containing the same. [Solution] The present invention relates to compounds of general formula (I), pharmaceutically acceptable salts thereof, pharmaceutically acceptable solvates, enantiomers, diastereomers, and polymorphs, methods for preparing the compounds of the present invention, pharmaceutical compositions comprising the compounds, and their use as autotaxin inhibitors. JPEG2026143506000098.jpg41150 [In the formula, R 1 ~R 7 X, Y, Z, and W each represent specific substituents, the bond identified as "A" is either a single or double bond, and m and n are independently selected from 0, 1, or 2.

Description

[Technical Field]

[0001] This invention describes novel compounds as autotaxin (ATX) inhibitors for the treatment and prevention of conditions or disorders caused by activation of autotaxin (ATX) or increased lysophosphatidic acid (LPA) concentration. This invention also describes pharmaceutically acceptable salts, enantiomers, diastereomers, tautomers, and pharmaceutical compositions of novel autotaxin inhibitors. [Background technology]

[0002] The ATX enzyme is a bioactive signaling molecule crucial for converting lysophosphatidylcholine (LPC) to LPA. ATX, also known as ectonucleotide pyrophosphatase / phosphodiesterase 2 (ENPP-2 or NPP2), is a secreted enzyme of the ectonucleotide phosphatase family. ATX plays a vital role in the development of pathological conditions such as fibrosis, arthritis, neurodegeneration, neuropathic pain, and cancer. LPA is a bioactive lipid that influences the migration, proliferation, and survival of various cell types. LPA mediates various cellular and biological actions through LPA receptors (LPARs). LPA exhibits broad tissue expression and can bind to at least six different G proteins known as LPAR1-6, which are then supplied to multiple effector systems (Yung, Y.Cet et al., J. Lipid Res. 2014, 55, 1192 and Kihara, Y. et al., Exp. Cell Res. 2015, 333, 171). Since plasma LPA concentration is closely related to ATX activity, ATX is considered an important source of extracellular LPA.

[0003] Inhibiting ATX has been shown to reduce LPA levels in pathological settings. A reduction in LPA may offer therapeutic benefits in diseases with unmet needs, including cancer, lymphocyte homing, chronic inflammation, neuropathic pain, fibrous diseases such as idiopathic pulmonary fibrosis (IPF), thrombosis, and cholestatic pruritus, which are caused and / or spread by increased LPA levels and / or activation of ATX.

[0004] IPF is characterized by progressive scarring of lung tissue, which leads to a deterioration of lung function and ultimately death within 3 to 5 years of symptom onset. Until 2014, when the FDA approved nintedanib (Ofev) and pirfenidone (Esbriet), there were no treatment options for IPF (King, T, E. et al., Lancet 2011, 378, 1949; Richardi, L. et el., N.Engl. J.Med. 2014, 370, 2071; Roth, G. J. et al., J.Med. Chem. 2009, 52, 4466; J.Med. Chem. 2015, 58, 1053; Hilberg, F. et al., Drugs Future 2010, 35, 5; and King, T. et al., N.Engl. J.Med. 2014, 370, 2083). Despite this progress, the need for additional medications to treat IPF still remains. In patients with IPF, LPA levels are elevated in bronchoalveolar lavage fluid (BALF) and exhaled condensate. LPAR1 has been identified as the major LPA receptor (Tager, AMet al., Nat. Med. 2008, 14, 45 and Montesi, SBet al., BMC Pulm. Med. 2014). In lung fibroblasts from IPF patients, LPAR1 has been found to be responsible for enhanced fibroblast migration and vascular leakage. Therefore, LPAR1 antagonists are expected to be potential drug targets for the treatment of IPF. In recent years, several LPAR1 antagonists have been reported, and some of these compounds are currently being evaluated for the treatment of IPF (Budd, DC et al., Future Med. Chem. 2013, 5, 1935; Qian, Y. et al., J. Med. Chem. 2012, 55, 7920, and Terakado, M. et al., ACS Med. Chem. Lett. 2016, 7, 913).

[0005] Fibrosis can develop in the liver, kidneys, lungs, dermis, vascular system, intestines, and other sites. Fibrosis develops through the action of pathways involving growth factors, cytokines, integrins, and lipids. The ATX, LPA, and LPAR pathways are involved in fibrotic diseases. Elevated levels of ATX, LPA, and LPAR have been observed in various rodent models of fibrosis as well as in patient fluids and biopsy tissues. LPA can induce proliferation, survival, and chemotactic responses in cells known to be important in fibrotic diseases, including fibroblasts, smooth muscle cells, macrophages, epithelial and endothelial cells, and leukocytes. LPAR inhibitors have been shown to block or reverse fibrosis in the lungs, liver, kidneys, and skin of rodents by antagonizing receptors in this pathway. Therefore, it is desirable to reduce LPA levels in fibrotic diseases. This can be achieved by inhibiting enzymes involved in LPA biosynthesis, such as ATX.

[0006] WO2019228403, WO2019108943, WO2019029620, WO2019223721, WO2019158107, WO201815 312, WO2017152062, WO2017050791, WO2017050792, WO2017050747, WO2017050732, WO201 Various publications, including 5144605, WO2015042052, WO2015154023, WO2015175171, WO2014139882, WO2014139978, WO2014048865, WO2014202458, and WO2013186159, mention compounds that can inhibit ATX. Therefore, there is an unmet need for ATX inhibitors for use in the treatment and / or prevention of physiological and / or pathophysiological conditions such as cancer, chronic inflammation, neuropathic pain, fibrous diseases, and thrombosis, which are caused, mediated, and / or spread by increased LPA levels and / or ATX activation. [Overview of the project]

[0007] This invention describes novel compounds as autotaxin (ATX) inhibitors for the treatment and prevention of conditions or disorders caused by autotaxin (ATX) activation or increased LAP concentration, and pharmaceutical compositions containing the same.

[0008] The present invention includes specific substituted compounds described herein, salts thereof, preparations thereof, pharmaceutical compositions and formulations thereof, and methods for treating diseases with these, etc. The present invention includes novel compounds of formula (I), pharmaceutically acceptable salts thereof, tautomers, enantiomers, and diastereomers thereof. In some embodiments, the compounds of the present invention are inhibitors of ATX. Embodiments of the present invention include the compounds described herein, pharmaceutically acceptable salts thereof, any physical form thereof including solvates and hydrates, preparations of the compounds, intermediates, and pharmaceutical compositions and formulations thereof. [ka]

[0009] Embodiments of the present invention One embodiment of the present invention provides a novel compound represented by general formula (I), its tautomers, its enantiomers, its diastereomers, its stereoisomers, pharmaceutically acceptable salts thereof, and a pharmaceutical composition comprising them or mixtures thereof.

[0010] Further embodiments of the present invention provide pharmaceutical compositions comprising a novel compound of general formula (I), its tautomer, its enantiomer, its diastereomer, its stereoisomer, its pharmaceutically acceptable salt, or a mixture thereof, in combination with a suitable carrier, solvent, diluent, and other media commonly used in preparing pharmaceutical compositions.

[0011] In further embodiments, the use of the novel compounds of the present invention as ATX inhibitors is provided by administering a therapeutically effective and non-toxic amount of the novel compound of general formula (I) or a pharmaceutically acceptable composition thereof to a mammal.

[0012] In a still further embodiment, a method for preparing the novel compound of the present invention is provided. Mode for Carrying Out the Invention

[0013] Accordingly, the present invention relates to novel compounds of the following general formula (I), as well as pharmaceutically acceptable salts, enantiomers and diastereomers thereof: Chemical Formula wherein R 1 is selected from (C1-C6)alkyl, (C3-C7)cycloalkyl, heterocyclyl, heteroaryl, aryl, arylalkyl, heterocycloalkyl, heteroarylalkyl and aryloxy, and each of these groups, where applicable, is further substituted with a substituent independently selected from -H, halo, -(C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)acyloxy, -(CH2) p CF3, -CN, -O(CH2) p CF3, -OCHF2, -(CH2) p OR a , -(CR a R b ) p NR a R b , -COOR a , -C(O)NR a R b , -NR c C(O)NR a R b , -S(O)2NR a R b , -NR c S(O)2NR a R b , aryl, (C3-C7)cycloalkyl, or heterocyclyl, W is selected from -C(O)-, -C(O)-NR d -, -S(O)2-, or -S(O)2NR d -, R 2 is selected from H and (C1~C6)alkyl, R 3 and R 4 Each of these groups is independently selected from -H, (C1~C6)alkyl, (C3~C7)cycloalkyl, heterocyclyl, heteroaryl, aryl, arylalkyl, heterocycloalkyl, and heteroarylalkyl, and each of these groups, where applicable, is -H, halo, -(C1~C6)alkyl, (C1~C6)alkoxy, (C1~C6)acyloxy, (CH2) q CF3, -CN, -O(CH2) q CF3, -OCHF2, -(CH2) q Ure e ,-(CR e R f ) q NR e R f ,-COOR e -C(O)NR e R f , -NR g C(O)NR e R f -S(O)2NR e R f , -NR g S(O)2NR e R f , further substituted with substituents independently selected from aryl, (C3-C7) cycloalkyl, or heterocyclyl, R 5 H is, X is -(CR h R i ) r -,-(CR h R i ) r One or more of -C(O)-, -C(O)-, or O are independently selected. Y and Z are independently -NR i ,-(CR h R i ) s One or more of the following are selected: -, -O-, or -C(O)- R 6 and R 7are each independently selected from -H, (C1~C6)alkyl, (C3~C7)cycloalkyl, heterocyclyl, heteroaryl, aryl, arylalkyl, heterocycloalkyl, heteroarylalkyl, and each of these groups, where applicable, is further substituted with -H, halo, -(C1~C6)alkyl, (C1~C6)alkoxy, (C1~C6)acyloxy, -(CH2) t CF3, -CN, -O(CH2) t CF3, -OCHF2, -(CH2) t OR j , -(CR j R k ) t NR j R k , -COOR j , -C(O)NR j R k , -NR l C(O)NR j R k , -S(O)2NR j R k , -NR l S(O)2NR j R k , aryl, (C3~C7)cycloalkyl, or heterocyclyl, being further substituted with a substituent independently selected from the foregoing, the bond identified as "A" is a single bond or a double bond, m and n are each independently selected from 0, 1, or 2, p, q, r, s and t are each independently selected from 0, 1, 2, or 3, R a , R b , R c , R d , R e , R f , R g , R h , R i , R j , R k , and R l are each independently H, (C1~C6)alkyl, (C3~C7)cycloalkyl, -(CR j R k ) t NR j R k, -(CR j R k ) t COOR j , -(CR j R k ) t selected from (C3~C7)cycloalkylhaloalkyl, aryl, heteroaryl or arylalkyl].

[0014] In a preferred embodiment, R 1 is selected from heteroaryl and aryl further substituted with a substituent independently selected from -H, halo, (C1~C6)alkyl, (C1~C6)alkoxy, -(CH2) p CF3, -O(CH2) p CF3, p is 0, W is -C(O)-, R 2 is H, R 3 is selected from -H, (C1~C6)alkyl, (C3~C7)cycloalkyl and aryl, R 4 , R 6 , and R 7 are independently selected from -H, (C1~C6)alkyl, aryl and heteroaryl, and aryl and heteroaryl may be further substituted with a substituent independently selected from -H, halo, -(C1~C6)alkyl, (C1~C6)alkoxy, -COOR j , R j is -H, R i and R h are independently selected from -H, (C1~C6)alkyl, -(CR j R k ) t (C3~C7)cycloalkyl, -(CR j R k ) t COOR j selected from, R j and R k are -H and -(CR j R k ) t COOR j and t is selected from 0, 1 and 2.

[0015] In another preferred embodiment, the above-mentioned groups and radicals may be selected from the following:

[0016] "Alkyl," as well as other groups with the prefix "alk," such as alkoxy and alkanoyl, mean a carbon chain that may be linear or branched, and combinations thereof, unless otherwise defined. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, and hexyl. 3~10 Where a specified number of carbon atoms is permissible, the term alkyl also includes cycloalkyl groups and combinations of linear or branched alkyl chains bonded to a cycloalkyl structure.

[0017] "Cycloalkyl" is a subset of alkyl groups, meaning a saturated carbocyclic ring having a specified number of carbon atoms, preferably 3 to 6 carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Unless otherwise specified, cycloalkyl groups are generally monocyclic. Unless otherwise specified, cycloalkyl groups are saturated.

[0018] "Aryl" refers to a monocyclic or polycyclic aromatic ring system containing a carbocyclic atom. Preferred aryls are monocyclic or bicyclic 6-10 membered aromatic ring systems. Phenyl and naphthyl are preferred aryls.

[0019] Preferred groups and substituents on the group may be selected from those described in any of the Specified Terms.

[0020] As used herein, the term "substituted" means that any one or more hydrogen atoms on a designated atom are replaced with a group selected from the indicated groups, provided that the substitution does not exceed the normal valence of the designated atom and the substitution results in a stable compound.

[0021] "Pharmacologically acceptable salts" refer to derivatives of disclosed compounds modified by the parent compound to form its acid salt or base salt. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues. Such conventional non-toxic salts include 1,2-ethanedisulfonic acid, 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, glycolyarsanilic acid, hexylresorcinic acid, hydrabamic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxymaleic acid, hydro This includes, but is not limited to, derivatives derived from inorganic and organic acids selected from xinaphthoic acid, isethionic acid, lactic acid, lactobionic acid, lauryl sulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, napsylic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, subacetic acid, succinic acid, sulfamic acid, sulfanilic acid, sulfuric acid, tannic acid, tartaric acid, and toluenesulfonic acid.

[0022] The terms "by choice" or "at choice" mean that the event or situation described thereafter may or may not exist, and that description includes both cases where the event or situation exists and cases where it does not exist. For example, "optionally substituted alkyl" means either "alkyl" or "substituted alkyl". Furthermore, "optionally substituted group" means unsubstituted.

[0023] Unless otherwise specified herein, the structures shown herein also imply that they include compounds differing only by the presence of one or more isotopically enriched atoms.

[0024] In the following examples, molecules having a single chiral center exist as a racemic mixture unless otherwise specified. Those molecules having two or more chiral centers exist as a racemic mixture of diastereomers unless otherwise specified. Single enantiomers / diastereomers may be obtained by methods known to those skilled in the art.

[0025] Particularly useful compounds may be selected from, but are not limited to, the following.

[0026] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22 Table 1-23 Table 1-24 [Table 1-25] [Table 1-26] [Table 1-27] [Table 1-28] [Table 1-29] [Table 1-30] [Table 1-31] [Table 1-32] [Table 1-33]

[0027] The following is a list of abbreviations used in the description of the preparation of the compounds of the present invention. ACN: Acetonitrile BOC: tert-butyloxycarbonyl CDI: Carbonyldiimidazole DCM: Dichloromethane DIEA: Diisopropylethylamine DIPE: Diisopropyl ether DIAD: Diisopropyl azodicylate DMF: N,N-dimethylformamide DMSO: Dimethyl sulfoxide EtOH: Ethanol alkyl ethyl acetate h: time HBTU: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate HCl: Hydrochloric acid HPLC: High-performance liquid chromatography IPA: Isopropyl alcohol K2CO3: Potassium carbonate MeOH: methanol MeI: Methyl iodide NaBH4: Sodium borohydride Na2CO3: Sodium carbonate NaOH: Sodium hydroxide Na2SO4: Sodium sulfate NaHCO3: Sodium Bicarbonate / Sodium Carbonate NMP: N-methyl-2-pyrrolidone t-BuOK: Potassium tert-butoxide TEA: Triethylamine TFA: Trifluoroacetic acid THF: Tetrahydrofuran TLC: Thin-layer chromatography

[0028] Novel compounds of the present invention were prepared using the reactions and techniques described below, together with the prior art known to those skilled in the art of organic synthesis or variations thereof recognized by those skilled in the art.

[0029] The reaction can be carried out in a solvent suitable for the reagents and materials used, and is suitable for the conversion. Preferred methods include, but are not limited to, those described below, and all symbols are as previously defined unless otherwise defined below.

[0030] The compound of formula (I) can be prepared using suitable modifications / modifications that are well within the scope of the art, as described in General Scheme 1 below.

[0031] In the typical preparation of the compound of formula (I), the compounds of formulas (II) and (III) were reacted under suitable amide bonding conditions. Suitable conditions include, but are not limited to, treatment of the compounds of formulas (II) and (III) with a bonding agent such as DCC or EDC in combination with DMAP, HOBt, HOAt, etc. Furthermore, HBTU and HATU can be used in the presence of diisopropylethylamine (DIEA). Suitable solvents for use in the above process include, but are not limited to, ethers such as THF and glyme, DMF, DMSO, ACN, and halogenated solvents such as CHCl3 or DCM. Mixtures of these solvents were used as needed, but preferred solvents were DCM and DMF. The above process was carried out at a temperature of about 0°C to about 100°C. Preferably, the reaction was carried out at room temperature. The above process was preferably carried out at atmospheric pressure or about atmospheric pressure, but higher or lower pressures may be used as needed. The compounds can be prepared and the compound of formula (I) can be obtained by conventional methods reported in the literature or by conventional techniques known to those skilled in the art of organic synthesis.

[0032] [ka]

[0033] General method The melting point was recorded using a chemical melting point spectrometer and was not corrected. IR spectra were recorded using an FT-IR8300Shimadzu as neat (for oily materials) or KBr pellets (for solids), with wavenumber ν(cm²). -1 The NMR spectrum is recorded using a magnetic resonance spectrometer, Varian Unity 400 (at 400 MHz). 1 H, at 100MHz 13Measurements were taken in C). Spectra were acquired at ambient temperature in the indicated solvent. Chemical shift (δ) is expressed in parts per million (ppm), with tetramethylsilane used as the internal standard. Multiplicity is recorded as follows: s=singlet, d=doublet, t=triplet, q=quartet, br=broad. Coupling constants (J values) are expressed in Hz. Mass spectra were recorded with a Perkin-Elmer Sciex API3000. ESI-Q-TOF-MS measurements were performed with a microOTOF-QII (Bruker Daltonics) mass spectrometer. HPLC analysis was performed with an AGILENT 1100 series spectrometer using an ODSC-18 column (150 mm × 4.6 mm × 4 μm) at λmax 220 nm. The reaction was monitored using thin-layer silica gel chromatography (TLC) with a Merck 0.25 mm silica gel 60F plate. The plates were visualized by treating them with UV light, acidic p-anisaldehyde staining, and KMnO4 staining while gently heating. The products were purified by column chromatography using silica gel 100-200 mesh and the indicated solvent system.

[0034] All reactions involving compounds sensitive to air or moisture were carried out in flame-dried glassware under a nitrogen atmosphere. Tetrahydrofuran (THF) and diethyl ether (Et2O) were freshly distilled from sodium / benzophenone under a nitrogen atmosphere. Other solvents used in the reactions were purified according to standard procedures. Starting reagents were purchased from commercial suppliers and used without further purification unless otherwise specified.

[0035] Synthesis of Compound 1: 2-Fluoro-N-((2R)-3-methyl-1-(2-methyl-1,3-dioxo-4-phenyl-2,8-diazaspiro[4.5]decane-8-yl)-1-oxobutan-2-yl)-5-(trifluoromethyl)benzamide [ka] The synthesis of compound 1, 2-fluoro-N-((2R)-3-methyl-1-(2-methyl-1,3-dioxo-4-phenyl-2,8-diazaspiro[4.5]decane-8-yl))-1-oxobutan-2-yl)-5-(trifluoromethyl)benzamide, was carried out as shown in Scheme 4, and the step-by-step procedure is shown below. [ka]

[0036] Step 1: Preparation of methyl(2-fluoro-5-(trifluoromethyl)benzoyl)-D-valinate (3) To a solution of 2-fluoro-5-(trifluoromethyl)benzoic acid (5.0 g, 24.03 mmol) in DMF (20 mL), DIEA (12.59 mL, 72.1 mmol) was added at room temperature and the mixture was stirred for 15 minutes. Methyl D-valinate (1) (4.43 g, 26.4 mmol) was added to the reaction mixture and the mixture was stirred at room temperature for 16 hours. The reaction product was poured into cold water and extracted with RINKAN (2 × 50 mL). The combined organic layers were washed with water (2 × 50 mL), saturated NaHCO3 (1 × 50 mL), and brine (1 × 50 mL), dried over Na2SO4, and evaporated to dryness under reduced pressure. The residue was purified by combiflash column chromatography (hexane:EtOAC = 1:5) to obtain methyl (2-fluoro-5-(trifluoromethyl)benzoyl)-D-valinate (3) as a solid (7.3 g, yield 95.0%). 1 H NMR:(CDCl3,400MHz):δ8.42(m,1H),7.79-7.76(m,1H),7.33-7.28(m,1H),7.23-7.18(m,1H),4.83-4. 79(m,1H),3.74(s,3H),2.37-2.30(m,1H),1.50-1.47(m,1H),0.99(d,6H);ESI-MS:(m / z)322.10(M+H) + (100%).

[0037] Step 2: 2-Fluoro-5-(trifluoromethyl)benzoyl)-D-valine(4) A mixture of methylmethyl(2-fluoro-5-(trifluoromethyl)benzoyl)-D-valinate (3) (5.0 g, 15.56 mmol) in MeOH (30 mL) was mixed with LiOH (1.96 g, 46.7 mmol) in H2O (15 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated and the mixture was diluted with water. The aqueous layer was acidified with 10% HCl solution and filtered to obtain (2-fluoro-5-(trifluoromethyl)benzoyl)-D-valine (4) as a white solid (4.51 g, yield 94.4%). 1 H NMR:(DMSO-d6,400MHz):δ12.79(1H,s),8.74-8.71(d,1H,J=8.40Hz),7.97-7.93(m,1H),7.85-7.83(m,1H),7.58-7.53(t,1H,J=9.2Hz),4.36-4.32 2.20-2.15(m,1H),0.94(d,6H);ESI-MS:(m / z)308.09(M+H) + (100%).

[0038] Step 3: 2-Fluoro-N-((2R)-3-methyl-1-(2-methyl-1,3-dioxo-4-phenyl-2,8-diazaspiro[4.5]decane-8-yl)-1-oxobutan-2-yl)-5-(trifluoromethyl)benzamide (compound 1) To a solution of 2-fluoro-5-(trifluoromethyl)benzoyl)-D-valine(3) (0.34 g, 1.128 mmol) in DMF (3 mL), DIEA (0.53 mL, 3.08 mmol) was added at room temperature and the mixture was stirred for 15 minutes. 2-methyl-4-phenyl-2,8-diazaspiro[4.5]decane-1,3-dione(6-a) (0.26 g, 1.026 mmol) was added to the reaction mixture and the mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into cold water and extracted with RINKAN (2 × 25 mL). The combined organic layers were washed with water (2 × 25 mL), saturated NaHCO3 (1 × 25 mL), and saline solution (1 × 25 mL), dried over Na2SO4, and evaporated to dryness under reduced pressure. The residue was purified using preparative HPLC to obtain the title compound 2-fluoro-N-((2R)-3-methyl-1-(2-methyl-1,3-dioxo-4-phenyl-2,8-diazaspiro[4.5]decane-8-yl)-1-oxobutan-2-yl)-5-(trifluoromethyl)benzamide (compound 1) as a white solid (0.35 g, yield 64.3%). 1 H NMR:(CDCl3,400MHz):δ8.36-8.35(d,1H,J=8.56Hz),7.77-7.74(m,1H),7.47-7.34 (m,5H),7.10-7.04(m2H),5.05-4.97(m,1H),4.23-4.17(m,1H),3.92-3.82(m,2H), 3.44-3.31(m,3H),3.15(s,3H),2.12-2.07(m,2H),2.05-1.93(m,2H),1.61-1.56(m ,2H),1.30-1.27(m,1H),1.06-1.02(m,3H),0.97(d,6H);ESI-MS:(m / z)548.21(M+H) + (100%).

[0039] Synthesis of intermediate 6-a [2-methyl-4-phenyl-2,8-diazaspiro[4,5]decane-1,3-dione] [ka] The synthesis of intermediate III (2-methyl-4-phenyl-2,8-diazaspiro[4.5]decane-1,3-dione) is carried out as shown in Scheme 5, and the step-by-step procedure is shown below. [ka]

[0040] Step 1: 2-(1-benzylpiperidine-4-ylidene)-2-phenylacetonitrile (3-a) To a solution of sodium ethoxide (20 g, 88.8 mmol) in EtOH (45 mL), benzyl cyanide (5.04 g, 133.21 mmol) and N-benzylpiperidone (5.04 g, 133.21 mmol) were added at room temperature. The reaction mixture was stirred at 80-85°C for 3 hours, and then the solvent was evaporated. The residue was poured into a mixture of ice (50 g) and concentrated HCl (10 mL). Solid NaOH (2 g) was then added to adjust the pH to 9, and the mixture was extracted with ELISA (3 × 25 mL). The organic phase was separated and dried over Na₂SO₄. The solvent was evaporated, and the crude product was purified by column chromatography using a mobile phase (hexane:siRNA:TEA = 80:20:1) to obtain 2-(1-benzylpiperidine-4-ylidene)-2-phenylacetonitrile (3-a) as a yellow solid (6.40 g, yield 84.2%). 1 H NMR:(CDCl3,400MHz):δ7.43-7.41(m,3H),7.40-7.32(m,4H),7.30-7.27(m,3H),3.56(s, 2H),2.86-2.83(m,2H),2.68-2.65(m,2H),2.51-2.45(m,4H);ESI-MS:(m / z)289.16(M+H) + (100%).

[0041] Step 2: 8-benzyl-4-phenyl-2,8-diazaspiro[4.5]decane-1,3-dione(4-a) A solution of 2-(1-benzylpiperidine-4-ylidene)-2-phenylacetonitrile (3-a) (6.35 g, 22.02 mmol) in EtOH (20 mL) was mixed with a solution of NaCN (1.08 g, 22.02 mmol) in H2O (3.8 mL). The reaction mixture was stirred at 85-90°C for 16 hours. The solvent was evaporated, and the residue was dissolved in 2N HCl (14.2 mL). Concentrated HCl (2.4 mL) was added to adjust the pH to 1-2. The reaction mixture was stirred at reflux temperature for 16 hours. After cooling to room temperature, solid Na2CO3 was added until the pH reached 8-9, and the mixture was extracted with DCM (2 × 50 mL). The organic phase was separated, dried over Na2SO4, and evaporated. The crude product was suspended in ELISA (20 mL) and left overnight at room temperature. The crystals were filtered and dried to obtain 8-benzyl-4-phenyl-2,8-diazaspiro[4.5]decane-1,3-dione(4-a) as a solid (4.8 g, yield 67%). 1 H NMR:(CDCl3,400MHz):δ7.45-7.35(m,4H),7.34-7.32(m,1H),7.28-7.23(m,2H),7.15-7.13(m,2H),4.17(s,1H),3.56(s,2H) ),2.89-2.83(m,1H),2.55-2.51(m,2H),2.17-2.12(m,2H),1.86-1.82(m,3H),1.38-1.33(m,1H);ESI-MS:(m / z)335.17(M+H) + (100%).

[0042] Step 3: 8-benzyl-2-methyl-4-phenyl-2,8-diazaspiro[4.5]decane-1,3-dione(5-a) To a solution of 8-benzyl-4-phenyl-2,8-diazaspiro[4.5]decane-1,3-dione (4-a) (1 g, 2.99 mmol) in THF (40 mL), triphenylphosphine (1.02 g, 3.89 mmol)MeOH (0.16 g, 3.89 mmol) and DIAD (0.79 g, 3.89 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The solvent was evaporated, and the crude product was purified by column chromatography using a mobile phase (DCM:MeOH = 95:5) to obtain 8-benzyl-2-methyl-4-phenyl-2,8-diazaspiro[4.5]decane-1,3-dione (5-a) (0.66 g, 70% yield). 1 H NMR:(CDCl3,400MHz):δ7.45-7.35(m,4H),7.34-7.32(m,1H),7.28-7.23(m,2H),7.15-7.13(m,1H),4.17(s,1H),3.56(s,2H),3.09 (s,3H),2.89-2.83(m,1H),2.55-2.51(m,2H),2.17-2.12(m,2H),1.86-1.82(m,3H),1.38-1.33(m,1H);ESI-MS:(m / z)349.18(M+H) + (100%).

[0043] Step 4: 2-Methyl-4-phenyl-2,8-diazaspiro[4.5]decane-1,3-dione(6-a) To a solution of 8-benzyl-2-methyl-4-phenyl-2,8-diazaspiro[4.5]decane-1,3-dione (5-a) (0.36 g, 1.033 mmol) in MeOH (10 mL), 10% Pd / C (50% w / w) (0.036 g) was added. The reaction mixture was stirred at room temperature under an H2 atmosphere for 3 hours. The reaction mixture was filtered through Celite, and the solvent was evaporated to obtain 2-methyl-4-phenyl-2,8-diazaspiro[4.5]decane-1,3-dione (6-a) (0.26 g, yield 67%). 1H NMR:(CDCl3,400MHz):δ7.39-7.28(m,5H),7.11(brs,1H),5.02-4.96(m,1H),4.17(s,1H),3.09(s,3H), 2.89-2.83(m,1H),2.55-2.51(m,2H),2.17-2.12(m,2H),1.86-1.82(m,2H);ESI-MS:(m / z)259.14(M+H) + (100%).

[0044] The following specific novel compounds of the present invention, relating to general formula (I), are prepared using the method shown in general scheme 1.

[0045] Compound 33: N-((2R)-1-(2-(2-aminoethyl)-1,3-dioxo-4-phenyl-2,8diazaspiro[4.5]decane-8-yl)-3-methyl-1-oxobutan-2-yl)-2-fluoro-5-(trifluoromethyl)benzamide [ka] 1 H NMR:(CDCl3,400MHz):δ8.37-8.34(d,1H,J=8.56Hz),7.77-7.74(m,1H),7.47-7.34 (m,5H),7.10-7.04(m2H),5.06-4.97(m,1H),4.23-4.17(m,1H),3.92-3.82(m,2H), 3.44-3.31(m,3H),3.15(s,3H),2.12-2.07(m,4H),2.05-1.93(m,4H),1.61-1.56(m ,2H),1.30-1.26(m,1H),1.06-1.02(m,3H),0.97(d,6H);ESI-MS:(m / z)577.24(M+H) + (100%).

[0046] Compound 44: 2-Fluoro-N-((2R)-3-methyl-1-(2-methyl-1-oxo-4-phenyl-2,8-diazaspiro-[4.5]decane-8-yl)-1-oxobutan-2-yl)-5-(trifluoromethyl)benzamide [ka] 1 H NMR:(DMSO-d6,400MHz):δ8.68-8.62(m,1H),7.93(s,1H),7.83-7.78(m,1H),7 .55-7.53(m,1H),7.28-7.21(m,5H),4.74-4.70(m,1H),3.72-3.69(m,2H),3.6 7-3.62(m,2H),3.51-3.48(m,2H),3.38-3.36(m,1H),2.85(s,3H),1.64-1.62( m,1H),1.53-1.46(m,4H),0.90(s,1H),0.87(d,6H);ESI-MS:(m / z)534.4(M+H) + (100%).

[0047] Compound 45: 2-Fluoro-N-((2R)-3-methyl-1-oxo-1-(1-oxo-4-phenyl-2,8-diazaspiro-[4.5]decane-8-yl)butan-2-yl)-5-(trifluoromethyl)benzamide [ka] 1 H NMR:(DMSO-d6,400MHz):δ8.67-8.62(m,1H),7.93(s,1H),7.83-7.78(m,1H ),7.55-7.53(m,1H),7.28-7.21(m,5H),4.74-4.70(m,1H),3.72-3.69(m,2H ),3.67-3.62(m,2H),3.51-3.48(m,2H),3.38-3.36(m,1H),1.64-1.62(m,1 H),1.53-1.46(m,4H),0.90(s,1H),0.87(d,6H);ESI-MS:(m / z)520.22(M+H) + (100%).

[0048] Compound 56: 2-Fluoro-N-((2R)-3-methyl-1-(2-methyl-1-oxo-4-(pyridine-3-yl)-2,8-diazaspiro[4.5]decane-8-yl)-1-oxobutan-2-yl)-5-(trifluoromethyl)benzamide [ka] 1 H NMR:(DMSO-d6,400MHz):δ8.69-8.67(m,1H),8.51-8.49(m,1H),8.46-8.42(m,1H),7.93-7.8 2(m,1H),7.66-7.62(m,1H),7.56-7.53(m,1H),7.39-7.29(m,2H),4.86-4.74(m,1H),3.85-3 .79(m,2H),3.73-3.70(m,2H),3.69-3.62(m,2H),3.55-3.52(m,1H),3.41(S,3H),2.03-1.89 (m,1H),1.76-1.72(m,1H),1.65-1.54(m,3H),0.92-0.81(m,6H);ESI-MS:(m / z)535.23(M+H) + (100%).

[0049] Compound 57: 2-Fluoro-N-((2R)-3-methyl-1-oxo-1-(1-oxo-4-(pyridine-3-yl)-2,8-diazaspiro-[4.5]decane-8-yl)butan-2-yl)-5-(trifluoromethyl)benzamide [ka] 1 H NMR:(DMSO-d6,400MHz):δ8.67-8.66(m,1H),8.53-8.50(m,1H),8.47-8.43(m,1H),7.93- 7.82(m,1H),7.66-7.62(m,1H),7.56-7.53(m,1H),7.39-7.29(m,2H),4.86-4.74(m,1H), 3.85-3.79(m,2H),3.74-3.70(m,2H),3.69-3.62(m,2H),3.55-3.52(m,1H),2.03-1.89(m ,1H),1.76-1.72(m,1H),1.65-1.54(m,3H),0.92-0.81(m,6H);ESI-MS:(m / z)521.21(M+H) + (100%).

[0050] Compound 58: N-((2R)-1-(4-(1H-indazole-5-yl)-2-methyl-1-oxo-2,8-diazaspiro[4.5]decane-8-yl)-3-methyl-1-oxobutan-2-yl)-2-fluoro-5-(trifluoromethyl)benzamide [ka] 1 H NMR:(DMSO-d6,400MHz):δ8.65-8.61(m,1H),8.51-8.49(m,1H),8.46-8.42(m,1H),7.93-7.8 2(m,2H),7.66-7.62(m,1H),7.56-7.53(m,1H),7.39-7.29(m,2H),4.86-4.74(m,1H),3.85-3 .79(m,2H),3.73-3.70(m,2H),3.69-3.62(m,2H),3.55-3.52(m,1H),3.41(S,3H),2.03-1.89 (m,1H),1.76-1.72(m,1H),1.66-1.56(m,3H),0.94-0.83(m,6H);ESI-MS:(m / z)574.40(M+H) + (100%).

[0051] Compound 62: 2-Fluoro-N-((2R)-3-methyl-1-(2-methyl-4-phenyl-2,8-diazaspiro[4.5]decane-8-yl)-1-oxobutan-2-yl)-5-(trifluoromethyl)benzamide [ka] 1H NMR:(DMSO-d6,400MHz):δ8.35-8.34(m,1H),7.76-7.73(m,1H),7.33-7.30(m,1H),7.28-7.2 5(m,2H),7.23-7.16(m,4H),5.10-5.05(m,1H),4.23-4.18(m,1H),3.89-3.85(m,1H),3.12-3 .05(m,3H),2.89-2.80(m,2H),2.58-2.52(m,2H),2.46(s,3H),1.79-1.70(m,2H),1.69-1.64 (m,1H),1.44-1.40(m,1H),0.99-0.92(m,3H),0.89-0,84(m,6H);ESI-MS:(m / z)520.26(M+H) + (100%).

[0052] Compound 64: 2-Fluoro-N-((2R)-3-methyl-1-(2-methyl-4-(pyridine-3-yl)-2,8-diazaspiro-[4.5]decane-8-yl)-1-oxobutan-2-yl)-5-(trifluoromethyl)benzamide [ka] 1 H NMR:(DMSO-d6,400MHz):δ8.66-8.64(m,1H),8.46-8.44(m,1H),8.38-833(m,1H),7.76-7.73(m,1H), 7.33-7.30(m,1H),7.28-7.25(m,1H),7.23-7.16(m,2H),5.10-5.05(m,1H),4.23-4.18(m,1H),3.89-3 .85(m,1H),3.12-3.05(m,3H),2.89-2.80(m,2H),2.58-2.52(m,2H),2.35(s,3H),1.79-1.70(m,2H),1 .69-1.64(m,1H),1.44-1.40(m,1H),0.99-0.92(m,3H),0.87-0,80(m,6H);ESI-MS:(m / z)521.25(M+H) + (100%).

[0053] Compound 65: N-((2R)-1-(4-(1H-indazole-5-yl)-2-methyl-2,8-diazaspiro[4.5]decane-8-yl)-3-methyl-1-oxobutan-2-yl)-2-fluoro-5-(trifluoromethyl)benzamide [ka] 1 H NMR:(DMSO-d6,400MHz):δ12.97(s,1H),8.17-8.16(m,1H),7.96-7.93(m,1H),7.33-7.62-7.59(m ,1H),7.51-7.47(m,2H),7.28-7.23(m,4H),4.73-4.71(m,1H),4.23-4.18(m,1H),3.89-3.85(m,1 H),3.12-3.05(m,3H),2.89-2.80(m,2H),2.58-2.52(m,2H),3.09(s,3H),1.79-1.70(m,2H),1.69 -1.64(m,1H),1.44-1.40(m,1H),0.99-0.92(m,3H),0.85-0,80(m,6H);ESI-MS:(m / z)560.53(M+H) + (100%).

[0054] Compound 102: 2-Fluoro-N-((2R)-1-(4-(4-fluorophenyl)-1-oxo-2,8-diazaspiro[4.5]decane-8-yl)-3-methyl-1-oxobutan-2-yl)-5-(trifluoromethyl)benzamide [ka] 1H NMR:(DMSO-d6,400MHz):δ8.35-8.33(m,1H),7.76-7.73(m,1H),7.30-7.25(m,1H), 7.24-20(m,1H),7.19-7.14(m,2H),7.06-7.00(m,2H),5.86-5.84(m,1H),5.10-5.05 (m,1H),4.12-4.09(m,1H),3.83-3.75(m,3H),3.64-3.55(m,2H),2.02-1.94(m,2H), 1.71-1.67(m,3H),1.04-0.99(m,3H),0.97-0.89(d,6H);ESI-MS:(m / z)538.30(M+H) + (100%).

[0055] Compound 103: 2-Fluoro-N-((2R)-1-(4-(4-fluorophenyl)-2-methyl-1-oxo-2,8-diazaspiro-[4.5]decane-8-yl)-3-methyl-1-oxobutan-2-yl)-5-(trifluoromethyl)benzamide [ka] 1 H NMR:(DMSO-d6,400MHz):δ8.35-8.33(m,1H),7.76-7.73(m,1H),7.53-7.51(m, 1H),7.28-7.25(m,1H),7.10-6.97(m,4H),5.05-5.00(m,1H),4.12-3.96(m,1H) ),3.76-3.71(m,3H),3.66-3.558(m,2H),3.24-3.21(m,2H),2.99(s,3H),2.09 -1.95(m,2H),1.67-1.63(m,2H),1.04-0.89(m,6H);ESI-MS:(m / z)552.32(M+H) + (100%).

[0056] Compound 104: N-((2R)-1-(2-ethyl-4-(4-fluorophenyl)-1-oxo-2,8-diazaspiro[4.5]decane-8-yl)-3-methyl-1-oxobutan-2-yl)-2-fluoro-5-(trifluoromethyl)benzamide [ka] 1 H NMR:(DMSO-d6,400MHz):δ8.35-8.33(m,1H),7.76-7.73(m,1H),7.53-7.51(m,1H),7 .28-7.25(m,1H),7.10-6.97(m,4H),5.05-5.00(m,1H),4.12-3.96(m,1H),3.76-3.71 (m,3H),3.66-3.558(m,2H),3.46-3.42(m,2H),3.24-3.21(m,2H),2.09-1.95(m,2H) ,1.67-1.63(m,2H),1.24-1.14(m,3H),1.04-0.89(m,6H);ESI-MS:(m / z)566.30(M+H) + (100%).

[0057] Compound 105: 2-Fluoro-5-methoxy-N-((2R)-3-methyl-1-(2-methyl-1-oxo-4-phenyl-2,8-diazaspiro[4.5]decane-8-yl)-1-oxobutan-2-yl)benzamide [ka] 1 H NMR:(DMSO-d6,400MHz):δ8.32-8.29(m,1H),7.76-7.73(m,1H),7.51-7.49(m,1H),7.40-7.24 (m,6H),5.32(s,1H),5.02-5.00(m,2H),4.32-4.29(m,2H),3.84-3.81(m,2H),3.77(s,3H),3.5 0-3.44(m,1H),3.39-3.37(m,1H),2.98(s,3H),2.96-2.94(m,1H),1.96-1.91(m,1H),1.68-1. 62(m,2H),1.40-1.379m,2H),1.02-0.97(m,3H),0.91-0.85(m,4H);ESI-MS:(m / z)496.30(M+H) + (100%).

[0058] Compound 106: (R)-2-fluoro-N-(3-methyl-1-(2-methyl-1-oxo-4-phenyl-2,8-diazaspiro-[4.5]des-3-en-8-yl)-1-oxobutan-2-yl)-5-(trifluoromethyl)benzamide [ka] 1 H NMR:(DMSO-d6,400MHz):δ8.38-8.36(m,1H),7.79-7.76(m,1H),7.58-7.54(m,1H),7. 36-7.32(m,2H),7.28-7.23(m,3H),6.60(s,1H),5.15-5.11(m,1H),4.53-4.50(m,1H), 4.21-4.17(m,1H),3.93-3.90(m,1H),3.71-3.68(m,1H),3.15(s,3H),2.16-2.11(m,2H ),1.69-1.62(m,2H),0.99-0.90(m,3H),0.89-0.84(m,3H);ESI-MS:(m / z)532.21(M+H) + (100%).

[0059] Compound 107: 2-Fluoro-N-((2R)-3-methyl-1-(2-methyl-1-oxo-4-phenyl-2,8-diazaspiro-[4.5]decane-8-yl)-1-oxobutan-2-yl)benzamide [ka] 1 H NMR:(DMSO-d6,400MHz):δ8.67-8.62(m,1H),7.94(s,1H),7.82-7.78(m,2H),7 .55-7.53(m,1H),7.28-7.21(m,5H),4.74-4.70(m,1H),3.72-3.69(m,2H),3.6 7-3.62(m,2H),3.51-3.48(m,2H),3.38-3.36(m,1H),2.85(s,3H),1.64-1.62( m,1H),1.54-1.47(m,4H),0.92(s,1H),0.87(d,6H);ESI-MS:(m / z)466.32(M+H) +(100%).

[0060] Compound 108: N-((2R)-3-methyl-1-(2-methyl-1-oxo-4-phenyl-2,8-diazaspiro[4.5]decane-8-yl)-1-oxobutan-2-yl)-3-(trifluoromethyl)benzamide [ka] 1 H NMR:(DMSO-d6,400MHz):δ8.86-8.84(m,1H),8.22-8.16(m,2H),7.82-7.78(m,2 H),7.55-7.53(m,1H),7.28-7.21(m,4H),4.74-4.70(m,1H),3.72-3.69(m,2H),3 .67-3.62(m,2H),3.51-3.48(m,2H),3.38-3.36(m,1H),2.84(s,3H),1.64-1.62 (m,1H),1.54-1.47(m,4H),0.92(s,1H),0.87(d,6H);ESI-MS:(m / z)516.05(M+H) + (100%).

[0061] Compound 109: 2-Fluoro-5-methyl-N-((2R)-3-methyl-1-(2-methyl-1-oxo-4-phenyl-2,8-diazaspiro[4.5]decane-8-yl)-1-oxobutan-2-yl)benzamide [ka] 1 H NMR:(DMSO-d6,400MHz):δ7.55-7.53(m,1H),7.37-7.21(m,6H),7.13-7.10 (m,1H),4.95-4.91(m,1H),4.88-4.84(m,1H),3.87-3.81(m,2H),3.69-3.6 2(m,3H),3.33-3.31(m,1H),2.39-2.34(m,3H),1.81-1.79(m,2H),1.76-1. 72(m,2H),1.01-0.98(m,3H),0.95-0.89(m,5H);ESI-MS:(m / z)479.59(M+H)+ (100%).

[0062] Compound 110: 2-Fluoro-N-((2R)-3-methyl-1-(2-methyl-1-oxo-4-phenyl-2,8-diazaspiro-[4.5]decane-8-yl)-1-oxobutan-2-yl)-5-(trifluoromethoxy)benzamide [ka] 1 H NMR:(DMSO-d6,400MHz):δ7.91-7.89(m,1H),7.55-7.53(m,1H),7.36-7.30 (m,3H),7.20-7.15(m,3H),4.74-4.70(m,1H),3.72-3.69(m,2H),3.67-3.62 (m,2H),3.51-3.48(m,2H),3.38-3.36(m,1H),2.85(s,3H),1.64-1.62(m,1 H),1.53-1.46(m,4H),0.90(s,1H),0.87(d,6H);ESI-MS:(m / z)550.23(M+H) + (100%).

[0063] Compound 111: 2-Fluoro-N-((2R)-1-(4-(4-fluorophenyl)-2-isopropyl-1-oxo-2,8-diazaspiro-[4.5]decane-8-yl)-3-methyl-1-oxobutan-2-yl)-5-(trifluoromethyl)benzamide [ka] 1H NMR:(DMSO-d6,400MHz):δ8.35-8.33(m,1H),7.76-7.73(m,1H),7.53-7.51(m,1 H),7.28-7.25(m,1H),7.10-6.97(m,4H),5.05-5.00(m,1H),4.12-3.96(m,1H),3 .76-3.71(m,3H),3.66-3.558(m,2H),3.24-3.21(m,3H),2.09-1.95(m,2H),1.6 7-1.63(m,2H),1.04-0.89(m,6H);0.86-0.82(m,6H);ESI-MS:(m / z)580.26(M+H) + (100%).

[0064] Compound 112: N-((2R)-1-(2-(cyclopropylmethyl)-4-(4-fluorophenyl)-1-oxo-2,8-diasaspiro-[4.5]decane-8-yl)-3-methyl-1-oxobutan-2-yl)-2-fluoro-5-(trifluoromethyl)benzamide [ka] 1 H NMR:(DMSO-d6,400MHz):δ8.36-8.34(m,1H),7.75-7.74(m,1H),7.51-7.41(m,1H),7.28- 7.25(m,1H),7.19-7.12(m,2H),7.06-0.99(m,2H),5.05-5.00(m,1H),3.97-3.78(m,5H), 3.31-3.27(m,2H),3.26-3.21(m,3H),2.12-2.05(m,2H),1.67-1.65(m,1H),1.05-0.98(m ,4H),0.95-0.87(m,4H),0.61-0.58(m,2H),0.31-0.28(m,2H);ESI-MS:(m / z)592.26(M+H) + (100%).

[0065] Compound 113: N-((2R)-1-(2-(cyclopropylmethyl)-1-oxo-4-(pyridine-3-yl)-2,8-diazaspiro-[4.5]decane-8-yl)-3-methyl-1-oxobutan-2-yl)-2-fluoro-5-(trifluoromethyl)benzamide [ka] 1 H NMR:(DMSO-d6,400MHz):δ8.36-8.34(m,1H),7.68-7.60(m,1H),7.51-7.41(m,1H),7.25- 7.22(m,1H),7.16-7.12(m,1H),7.06-0.99(m,2H),5.05-5.00(m,1H),3.97-3.78(m,5H), 3.31-3.27(m,2H),3.26-3.21(m,3H),2.12-2.05(m,2H),1.67-1.65(m,1H),1.05-0.98(m ,4H),0.95-0.87(m,4H),0.61-0.58(m,2H),0.31-0.28(m,2H);ESI-MS:(m / z)575.26(M+H) + (100%).

[0066] Compound 114: 2-Fluoro-N-((2R)-1-(4-(4-methoxyphenyl)-2-methyl-1-oxo-2,8-diazaspiro-[4.5]decane-8-yl)-3-methyl-1-oxobutan-2-yl)-5-(trifluoromethyl)benzamide [ka] 1H NMR:(DMSO-d6,400MHz):δ8.35-8.33(m,1H),7.76-7.73(m,1H),7.53-7.51(m,1H) ,7.28-7.25(m,1H),7.10-6.97(m,4H),5.05-5.00(m,1H),4.12-3.96(m,1H),3.76 -3.71(m,3H),3.66-3.558(m,2H),3.24-3.21(m,2H),3.21(s,3H),2.99(s,3H),2. 09-1.95(m,2H),1.67-1.63(m,2H),1.04-0.89(m,6H);ESI-MS:(m / z)564.25(M+H) + (100%).

[0067] Compound 115: 2-Fluoro-N-((2R)-3-methyl-1-oxo-1-(2-oxo-4-phenyl-1-oxa-3,8-diazaspiro-[4.5]decane-8-yl)butan-2-yl)-5-(trifluoromethyl)benzamide [ka] 1 H NMR:(DMSO-d6,400MHz):δ8.68-8.62(m,1H),7.93(s,1H),7.83-7.78(m,1H ),7.55-7.53(m,1H),7.28-7.21(m,5H),4.74-4.70(m,1H),3.72-3.69(m,2H ),3.67-3.62(m,2H),3.51-3.48(m,2H),3.38-3.36(m,1H),1.64-1.62(m,1 H),1.53-1.46(m,2H),0.90(s,1H),0.87(d,6H);ESI-MS:(m / z)522.23(M+H) + (100%).

[0068] Compound 118: (R)-2-fluoro-N-(1-(1-(4-fluorophenyl)-3-methyl-4-oxo-2,3,8-triazaspiro-[4.5]des-1-en-8-yl)-3-methyl-1-oxobutan-2-yl)-5-(trifluoromethyl)benzamide [ka] 1 H NMR:(DMSO-d6,400MHz):δ9.04-9.02(m,1H),7.96-7.94(m,1H),7.88-7.87(m,1H) ,7.77-7.71(m,2H),7.57-7.53(m,1H),7.47-7.46(m,1H),7.36-7.32(m,2H),4.82- 4.77(m,1H),4.40-4.38(m,1H),4.18-4.14(m,1H),2.68(s,3H),2.19-2.10(m,3H), 2.08-2.04(m,3H),1.01-0.94(m,6H)1.04-0.89(m,6H);ESI-MS:(m / z)533.22(M+H) + (100%).

[0069] Compound 119: 2-Fluoro-N-((2R)-1-(4-(4-fluorophenyl)-2-methyl-2,8-diazaspiro[4.5]decane-8-yl)-3-methyl-1-oxobutan-2-yl)-5-(trifluoromethyl)benzamide [ka] 1 H NMR:(DMSO-d6,400MHz):δ8.56-8.54(m,1H),7.94-7.92(m,1H),7.82-7.80(m,1H), 7.52-7.50(m,1H),7.29-7.26(m,1H),7.20-7.18(m,1H),7.05-7.01(m,2H),4.72-4 .70(m,1H),4.68-4.65(m,2H),3.09-2.94(m,4H),2.72-2.65(m,4H),2.51(s,3H),2 .03-1.96(m,2H),1.26-1.20(m,2H),1.10-0.89(m,6H);ESI-MS:(m / z)538.32(M+H) + (100%).

[0070] Compound 120: 2-Fluoro-N-((2R)-1-(4-(4-fluorophenyl)-2-isopropyl-2,8-diazaspiro[4.5]-decane-8-yl)-3-methyl-1-oxobutan-2-yl)-5-(trifluoromethyl)benzamide [ka] 1 H NMR:(DMSO-d6,400MHz):δ8.52-8.50(m,1H),7.94-7.92(m,1H),7.82-7.80(m,1 H),7.52-7.50(m,1H),7.29-7.26(m,1H),7.20-7.18(m,1H),7.05-7.01(m,2H),4 .72-4.70(m,1H),4.68-4.65(m,2H),3.09-2.94(m,4H),2.72-2.65(m,4H),2.03 -1.96(m,2H),1.26-1.20(m,2H),1.10-0.89(m,12H);ESI-MS:(m / z)566.28(M+H) + (100%).

[0071] Compound 121: N-((2R)-1-(2-(cyclopropylmethyl)-4-(4-fluorophenyl)-2,8-diazaspiro[4.5]-decane-8-yl)-3-methyl-1-oxobutan-2-yl)-2-fluoro-5-(trifluoromethyl)benzamide [ka] 1H NMR:(DMSO-d6,400MHz):δ8.36-8.34(m,1H),7.75-7.74(m,1H),7.51-7.41(m,1H),7.28- 7.25(m,1H),7.19-7.12(m,2H),7.06-0.99(m,2H),5.05-5.00(m,1H),3.97-3.78(m,5H), 3.31-3.27(m,2H),3.26-3.21(m,3H),2.12-2.05(m,4H),1.67-1.65(m,1H),1.05-0.98(m ,4H),0.95-0.87(m,4H),0.61-0.58(m,2H),0.31-0.28(m,2H);ESI-MS:(m / z)578.28(M+H) + (100%).

[0072] Compound 122: 2-Fluoro-N-((2R)-1-(4-(4-methoxyphenyl)-2-methyl-2,8-diazaspiro[4.5]-decane-8-yl)-3-methyl-1-oxobutan-2-yl)-5-(trifluoromethyl)benzamide [ka] 1 H NMR:(DMSO-d6,400MHz):δ8.35-8.33(m,1H),7.76-7.73(m,1H),7.53-7.51(m,1H) ,7.28-7.25(m,1H),7.10-6.97(m,4H),5.05-5.00(m,1H),4.12-3.96(m,1H),3.76 -3.71(m,3H),3.66-3.558(m,2H),3.24-3.21(m,2H),3.21(s,3H),2.99(s,3H),2. 09-1.95(m,4H),1.67-1.63(m,2H),1.04-0.89(m,6H);ESI-MS:(m / z)560.27(M+H) + (100%).

[0073] Compound 123: 2-Fluoro-N-((2R)-1-(4-(4-methoxyphenyl)-2-methyl-2,8-diazaspiro-[4.5]decane-8-yl)-3-methyl-1-oxobutan-2-yl)-5-methylbenzamide [ka] 1 H NMR:(DMSO-d6,400MHz):δ8.19-8.16(m,1H),7.76-7.73(m,1H),7.48-7.46(m,1H),7 .28-7.25(m,1H),7.10-6.97(m,4H),5.05-5.00(m,1H),4.12-3.96(m,1H),3.76-3.71 (m,3H),3.66-3.558(m,2H),3.24-3.21(m,2H),3.21(s,3H),2.56(s,3H),2.33(s,3H) ,2.09-1.95(m,4H),1.67-1.63(m,2H),0.86-0.70(m,6H);ESI-MS:(m / z)496.29(M+H) + (100%).

[0074] Compound 129: N-((2R)-1-(4-(4-fluorophenyl)-2-methyl-2,8-diazaspiro-[4.5]decane-8-yl)-3-methyl-1-oxobutan-2-yl)-4-methylpicolinamide [ka] 1 H NMR:(DMSO-d6,400MHz):δ8.68-8.64(m,1H),8.43-8.40(m,1H),7.99-7.96(m,1H),7.23- 7.18(m,2H),7.07-7.04(m,1H),6.93-6.91(m,1H),4.96-4.93(m,1H),4.32-4.28(m,2H), 3.06-3.01(m,2H),2.89-2.82(m,2H),2.78-2.76(m,1H),2.63-2.60(m,2H),2.45-2.42(m ,4H),2.09-2.07(m,1H),1.74-1.67(m,6H),0.96-0.85(m,6H);ESI-MS:(m / z)467.28(M+H) + (100%).

[0075] Compound 130: Methyl-8-((2-fluoro-5-(trifluoromethyl)benzoyl)-D-valyl)-4-(4-fluorophenyl)-2,8-diazaspiro[4.5]decane-2-carboxylate [ka] 1 H NMR:(DMSO-d6,400MHz):δ8.67-8.65(m,1H),7.94-7.92(m,1H),7.82-7.80(m,1H), 7.52-7.50(m,1H),7.29-7.26(m,1H),7.20-7.18(m,1H),7.05-7.01(m,2H),4.72-4 .70(m,1H),4.68-4.65(m,2H),3.09-2.94(m,4H),2.72-2.65(m,4H),2.51(s,3H),2 .03-1.96(m,2H),0.96-0.89(m,2H),0.79-0.66(m,6H);ESI-MS:(m / z)582.24(M+H) + (100%).

[0076] Compound 131: Ethyl 8-((2-fluoro-5-(trifluoromethyl)benzoyl)-D-valyl)-4-(4-fluorophenyl)-2,8-diazaspiro[4.5]decane-2-carboxylate [ka] 1 H NMR:(DMSO-d6,400MHz):δ8.67-8.65(m,1H),7.94-7.92(m,1H),7.82-7.80(m,1H), 7.52-7.50(m,1H),7.29-7.26(m,1H),7.20-7.18(m,1H),7.05-7.01(m,2H),4.72-4 .70(m,1H),4.68-4.65(m,4H),3.09-2.94(m,4H),2.72-2.65(m,4H),2.51(s,3H),2 .03-1.96(m,2H),0.96-0.89(m,5H),0.79-0.66(m,6H);ESI-MS:(m / z)596.25(M+H) + (100%).

[0077] Compound 132: 4-(8-((2-fluoro-5-(trifluoromethyl)benzoyl)-D-valyl)-2-methyl-2,8-diazaspiro[4.5]decane-4-yl)benzoic acid [ka] 1 H NMR:(DMSO-d6,400MHz):δ12.005(brs,1H),8.56-8.54(m,1H),7.94-7.92(m,1H),7.82 -7.80(m,1H),7.52-7.50(m,1H),7.29-7.26(m,1H),7.20-7.18(m,1H),7.05-7.01(m,1H ),4.72-4.70(m,1H),4.68-4.65(m,2H),3.09-2.94(m,4H),2.72-2.65(m,4H),2.51(s,3 H),2.03-1.96(m,2H),1.26-1.20(m,2H),1.10-0.89(m,6H);ESI-MS:(m / z)564.23(M+H) + (100%).

[0078] Compound 133: 2-Fluoro-N-((R)-1-((R)-4-(4-fluorophenyl)-2-methyl-2,8-diazaspiro[4.5]-decane-8-yl)-3-methyl-1-oxobutan-2-yl)-5-(trifluoromethyl)benzamide [ka] 1H NMR:(DMSO-d6,400MHz):δ8.56-8.54(m,1H),7.94-7.92(m,1H),7.82-7.80(m,1H), 7.52-7.50(m,1H),7.29-7.26(m,1H),7.20-7.18(m,1H),7.05-7.01(m,2H),4.72-4 .70(m,1H),4.68-4.65(m,2H),3.09-2.94(m,4H),2.72-2.65(m,4H),2.51(s,3H),2 .03-1.96(m,2H),1.26-1.20(m,2H),1.10-0.89(m,6H);ESI-MS:(m / z)538.25(M+H) + (100%).

[0079] Compound 134: 2-Fluoro-N-((R)-1-((S)-4-(4-fluorophenyl)-2-methyl-2,8-diazaspiro[4.5]-decane-8-yl)-3-methyl-1-oxobutan-2-yl)-5-(trifluoromethyl)benzamide [ka] 1 H NMR:(DMSO-d6,400MHz):δ8.56-8.54(m,1H),7.94-7.92(m,1H),7.82-7.80(m,1H), 7.52-7.50(m,1H),7.29-7.26(m,1H),7.20-7.18(m,1H),7.05-7.01(m,2H),4.72-4 .70(m,1H),4.68-4.65(m,2H),3.09-2.94(m,4H),2.72-2.65(m,4H),2.51(s,3H),2 .03-1.96(m,2H),1.26-1.20(m,2H),1.10-0.89(m,6H);ESI-MS:(m / z)538.25(M+H) + (100%).

[0080] Compound 136: 2-Fluoro-N-((2R)-3-methyl-1-(2-methyl-4-(p-tolyl)-2,8-diazaspiro[4.5]decane-8-yl)-1-oxobutan-2-yl)-5-(trifluoromethyl)benzamide

Chem.

[0081] Compound 138: N-((2R)-1-(4-(3,5-dimethylphenyl)-2-methyl-2,8-diazaspiro[4.5]decan-8-yl)-3-methyl-1-oxobutan-2-yl)-2-fluoro-5-(trifluoromethyl)benzamide

Chem.

[0082] Compound 140: 2-Fluoro-N-((1R)-2-(4-(4-fluorophenyl)-2-methyl-2,8-diazaspiro[4.5]decane-8-yl)-2-oxo-1-phenylethyl)-5-(trifluoromethyl)benzamide [ka] 1 H NMR:(DMSO-d6,400MHz):δ8.51-8.49(m,1H),8.33-8.31(m,1H),7.71-7.6 9(m,1H),7.45-7.01(m,8H),6.99-6.95(m,2H),5.88-5.86(m,1H),4.23-4 .21(m,1H),3.53-3.50(m,1H),3.10-3.05(m,1H),2.77-2.70(m,4H),2.49 (s,3H),1.78-1.71(m,3H),1.27-1.25(m,2H);ESI-MS:(m / z)572.23(M+H) + (100%).

[0083] Compound 142: N-((1R)-1-cyclohexyl-2-(4-(4-fluorophenyl)-2-methyl-2,8-diazaspiro[4.5]-decane-8-yl)-2-oxoethyl)-2-fluoro-5-(trifluoromethyl)benzamide [ka] 1 H NMR:(DMSO-d6,400MHz):δ8.60-8.58(m,1H),7.94-7.92(m,1H),7.82-7.80(m,1H), 7.52-7.50(m,1H),7.29-7.26(m,1H),7.20-7.18(m,1H),7.05-7.01(m,2H),4.72-4 .70(m,1H),4.68-4.65(m,2H),3.09-2.94(m,4H),2.72-2.65(m,4H),2.51(s,3H),2 .03-1.96(m,4H),1.26-1.20(m,4H),1.10-0.89(m,4H);ESI-MS:(m / z)578.28(M+H) + (100%).

[0084] Compound 147: 2-Fluoro-N-((2R)-1-(4-(4-fluorophenyl)-2-methyl-2,8-diazaspiro[4.5]decane-8-yl)-4-methyl-1-oxopentan-2-yl)-5-(trifluoromethyl)benzamide [ka] 1 H NMR:(DMSO-d6,400MHz):δ8.48-8.46(m,1H),7.94-7.92(m,1H),7.82-7.80(m,1H), 7.52-7.50(m,1H),7.29-7.26(m,1H),7.20-7.18(m,1H),7.05-7.01(m,2H),4.72-4 .70(m,1H),4.68-4.65(m,2H),3.09-2.94(m,4H),2.72-2.65(m,4H),2.53(s,3H),2 .03-1.96(m,4H),1.26-1.20(m,2H),1.10-0.92(m,6H);ESI-MS:(m / z)552.26(M+H) + (100%).

[0085] Compound 149: 2,5-Difluoro-N-((2R)-1-(4-(4-fluorophenyl)-2-methyl-2,8-diazaspiro[4.5]-decane-8-yl)-3-methyl-1-oxobutan-2-yl)benzamide [ka] 1H NMR:(DMSO-d6,400MHz):δ8.56-8.54(m,1H),7.94-7.92(m,1H),7.82-7.80(m,1H), 7.52-7.50(m,1H),7.29-7.26(m,1H),7.20-7.18(m,1H),7.05-7.01(m,2H),4.72-4 .70(m,1H),4.68-4.65(m,2H),3.09-2.94(m,4H),2.72-2.65(m,4H),2.51(s,3H),2 .03-1.96(m,2H),1.26-1.20(m,2H),1.10-0.89(m,6H);ESI-MS:(m / z)488.20(M+H) + (100%).

[0086] Compound 151: 2,5-Dichloro-N-((2R)-1-(4-(4-fluorophenyl)-2-methyl-2,8-diazaspiro[4.5]-decane-8-yl)-3-methyl-1-oxobutan-2-yl)benzamide [ka] 1 H NMR:(DMSO-d6,400MHz):δ8.53-8.51(m,1H),7.94-7.92(m,1H),7.82-7.80(m,1H), 7.52-7.50(m,1H),7.29-7.26(m,1H),7.20-7.18(m,1H),7.05-7.01(m,2H),4.72-4 .70(m,1H),4.68-4.65(m,2H),3.09-2.94(m,4H),2.72-2.65(m,4H),2.54(s,3H),2 .03-1.96(m,2H),1.26-1.20(m,2H),1.10-0.89(m,6H);ESI-MS:(m / z)520.19(M+H) + (100%).

[0087] Compound 153: N-((2R)-1-(4-(4-fluorophenyl)-2-methyl-2,8-diazaspiro[4.5]decane-8-yl)-3-methyl-1-oxobutan-2-yl)-1-methyl-1H-indazole-3-carboxamide [Chemical formula] 1 ¹H NMR: (DMSO-d₆, 400 MHz): δ 8.26-8.24 (m, 1H), 7.84-7.82 (m, 1H), 7.76-7.74 (m, 1H), 7.52-7.50 (m, 2H), 7.29-7.26 (m, 1H), 7.20-7.18 (m, 1H), 7.05-7.01 (m, 2H), 4.72-4.70 (m, 1H), 4.68-4.65 (m, 2H), 4.14 (s, 3H), 3.09-2.94 (m, 4H), 2.72-2.65 (m, 4H), 2.51 (s, 3H), 2.03-1.96 (m, 2H), 1.26-1.20 (m, 2H), 1.10-0.89 (m, 6H); ESI-MS: (m / z) 506.04 (M+H) + (100%).

[0088] Compound 158: N-((2R)-1-(4-(4-fluorophenyl)-2-methyl-2,8-diazaspiro[4.5]decan-8-yl)-3-methyl-1-oxobutan-2-yl)-4,6-dimethylpicolinamide [Chemical formula] 1 ¹H NMR: (DMSO-d₆, 400 MHz): δ 8.68-8.64 (m, 1H), 8.43-8.40 (m, 1H), 7.99-7.96 (m, 1H), 7.23-7.18 (m, 2H), 7.07-7.04 (m, 1H), 6.93-6.91 (m, 1H), 4.96-4.93 (m, 1H), 4.32-4.28 (m, 2H), 3.06-3.01 (m, 2H), 2.89-2.82 (m, 2H), 2.78-2.76 (m, 1H), 2.63-2.60 (m, 2H), 2.56 (s, 3H), 2.45 (s, 3H), 2.42 (s, 3H), 2.09-2.07 (m, 2H), 1.74-1.67 (m, 6H), 0.96-0.85 (m, 6H); ESI-MS: (m / z) 491.12 (M+H) + (100%).

[0089] Compound 162: 4-methyl-N-((2R)-3-methyl-1-(2-methyl-4-(pyridine-3-yl)-2,8-diazaspiro-[4.5]decane-8-yl)-1-oxobutan-2-yl)picolinamide [ka] 1 H NMR:(DMSO-d6,400MHz):δ8.64-8.62(m,1H),8.43-8.40(m,1H),7.99-7.96(m,1H),7.23-7 .18(m,1H),7.07-7.04(m,2H),6.93-6.91(m,1H),4.96-4.93(m,1H),4.32-4.28(m,2H),3.0 6-3.01(m,2H),2.89-2.82(m,2H),2.78-2.76(m,1H),2.63-2.60(m,2H),2.56(s,3H),2.45( s,3H),2.09-2.07(m,2H),1.74-1.67(m,6H),0.96-0.85(m,6H);ESI-MS:(m / z)450.26(M+H) + (100%).

[0090] Compound 163: 2-Fluoro-N-((2R)-3-methyl-1-oxo-1-(10-oxo-7-phenyl-3,9-diazaspiro[5.5]-undecane-3-yl)butan-2-yl)-5-(trifluoromethyl)benzamide [ka] 1H NMR:(DMSO-d6,400MHz):δ8.66-8.64(m,1H),7.94-7.92(m,1H),7.83-7.81(m,1 H),7.55-7.50(m,2H),7.27-7.17(m,4H),4.74-4.70(m,2H),4.14-4.10(m,2H), 3.52-3.50(m,2H),3.35-3.33(m,2H),3.03-2.96(m,2H),2.24-2.20(m,2H),1.4 6-1.41(m,2H),1.34-1.30(m,2H),0.88-0.73(m,6H);ESI-MS:(m / z)534.23(M+H) + (100%).

[0091] Compound 164: 2-Fluoro-N-((2R)-1-(7-(4-fluorophenyl)-10-oxo-3,9-diazaspiro[5.5]-undecane-3-yl)-3-methyl-1-oxobutan-2-yl)-5-(trifluoromethyl)benzamide [ka] 1 H NMR:(DMSO-d6,400MHz):δ8.67-8.64(m,1H),7.94-7.92(m,1H),7.83-7.81(m,1 H),7.55-7.50(m,1H),7.27-7.17(m,4H),4.74-4.70(m,2H),4.14-4.10(m,2H), 3.52-3.50(m,2H),3.35-3.33(m,2H),3.03-2.96(m,2H),2.24-2.20(m,2H),1.4 6-1.41(m,2H),1.34-1.30(m,2H),0.88-0.73(m,6H);ESI-MS:(m / z)552.22(M+H) + (100%).

[0092] Compound 174: 2-Fluoro-N-((2R)-3-methyl-1-(9-methyl-10-oxo-7-phenyl-3,9-diazaspiro-[5,5]undecane-3-yl)-1-oxobutan-2-yl)-5-(trifluoromethyl)benzamide [ka] 1 H NMR:(DMSO-d6,400MHz):δ8.64-8.62(m,1H),7.93-7.91(m,1H),7.83-7.81(m,1H),7.55-7.53(m,1H),7.33 -7.14(m,5H),4.71-4.70(m,1H),4.12-4.08(m,1H),3.85-3.83(m,1H),3.65-3.63(m,1H),3.46-3.44(m,1H) ),3.33-3.25(m,1H),3.08-3.06(m,1H),2.89(s,3H),2.85-2.83(m,1H),2.27-2.25(m,1H),1.91-1.88(m,1 H),1.44-1.40(m,2H),1.33-1.30(m,2H),1.25-1.23(m,1H),0.88-0.82(m,6H);ESI-MS:(m / z)548.25(M+H) + (100%).

[0093] Compound 176: 2-Fluoro-N-((2R)-1-(7-(4-fluorophenyl)-9-methyl-10-oxo-3,9-diazaspiro-[5.5]undecane-3-yl)-3-methyl-1-oxobutan-2-yl)-5-(trifluoromethyl)benzamide [ka] 1H NMR:(DMSO-d6,400MHz):δ8.67-8.65(m,1H),7.93-7.92(m,1H),7.83-7.81(m,1H),7.55-7.53(m,1H),7.33 -7.14(m,4H),4.71-4.70(m,1H),4.12-4.08(m,1H),3.85-3.83(m,1H),3.65-3.63(m,1H),3.46-3.44(m,1H) ),3.33-3.25(m,1H),3.08-3.06(m,1H),2.88(s,3H),2.85-2.83(m,1H),2.27-2.25(m,1H),1.91-1.88(m,1 H),1.44-1.40(m,2H),1.33-1.30(m,2H),1.25-1.23(m,1H),0.88-0.82(m,6H);ESI-MS:(m / z)566.24(M+H) + (100%).

[0094] Compound 177: N-((2R)-1-(9-ethyl-7-(4-fluorophenyl)-10-oxo-3,9-diazaspiro[5.5]undecane-3-yl)-3-methyl-1-oxobutan-2-yl)-2-fluoro-5-(trifluoromethyl)benzamide [ka] 1 H NMR:(DMSO-d6,400MHz):δ8.67-8.65(m,1H),7.93-7.92(m,1H),7.83-7.81(m,1H),7.55-7.53(m,1H),7.33- 7.14(m,4H),4.71-4.70(m,1H),4.12-4.08(m,1H),3.85-3.83(m,3H),3.65-3.63(m,1H),3.46-3.44(m,1H), 3.33-3.25(m,1H),3.08-3.06(m,1H),2.85-2.83(m,1H),2.27-2.25(m,1H),1.91-1.88(m,1H),1.44-1.40(m ,2H),1.33-1.30(m,2H),1.25-1.23(m,1H),1.09-1.05(m,3H),0.88-0.82(m,6H);ESI-MS:(m / z)580.26(M+H) +(100%).

[0095] Compound 185: 2-Fluoro-N-((2S)-3-methyl-1-(9-methyl-10-oxo-7-phenyl-3,9-diazaspiro-[5.5]undecane-3-yl)-1-oxobutan-2-yl)-5-(trifluoromethyl)benzamide [ka] 1 H NMR:(DMSO-d6,400MHz):δ8.64-8.62(m,1H),7.93-7.91(m,1H),7.83-7.81(m,1H),7.55-7.53(m,1H),7.33 -7.14(m,5H),4.71-4.70(m,1H),4.12-4.08(m,1H),3.85-3.83(m,1H),3.65-3.63(m,1H),3.46-3.44(m,1H) ),3.33-3.25(m,1H),3.08-3.06(m,1H),2.89(s,3H),2.85-2.83(m,1H),2.27-2.25(m,1H),1.91-1.88(m,1 H),1.44-1.40(m,2H),1.33-1.30(m,2H),1.25-1.23(m,1H),0.88-0.82(m,6H);ESI-MS:(m / z)548.25(M+H) + (100%).

[0096] Compound 194: N-((2R)-3-methyl-1-(9-methyl-10-oxo-7-phenyl-3,9-diazaspiro[5.5]-undecane-3-yl)-1-oxobutan-2-yl)-4-(trifluoromethyl)picolinamide [ka] 1H NMR:(DMSO-d6,400MHz):δ8.51-8.49(m,1H),7.90-7.87(m,1H),7.85-7.83(m,1H),7.46-7.44(m,1H),7.33-7. 14(m,5H),4.71-4.70(m,1H),4.12-4.08(m,1H),3.85-3.83(m,1H),3.65-3.63(m,1H),3.46-3.44(m,1H),3.33 -3.25(m,1H),3.08-3.06(m,1H),2.89(s,3H),2.85-2.83(m,1H),2.50(s,3H),2.27-2.25(m,1H),1.91-1.88(m ,1H),1.44-1.40(m,2H),1.33-1.30(m,2H),1.25-1.23(m,1H),0.88-0.82(m,6H);ESI-MS:(+mode)477.28(M+H) + (100%).

[0097] Compound 220: 2-Fluoro-N-((2R)-3-methyl-1-(9-methyl-7-phenyl-3,9-diazaspiro[5.5]-undecane-3-yl)-1-oxobutan-2-yl)-5-(trifluoromethyl)benzamide [ka] 1 H NMR:(DMSO-d6,400MHz):δ8.63-8.61(m,1H),7.92-7.90(m,1H),7.81-7.80(m,1H),7.75- 7.74(m,1H),7.29-7.13(m,5H),4.67-4.60(m,1H),4.08-4.04(m,1H),3.83-3.81(m,1H),3 .24-3.21(m,1H),2.77-2.65(m,3H),2.27-2.16(m,5H),1.86-1.84(m,1H),1.76-1.72(m, 2H),1.38-1.24(m,3H),0.85-0.83(m,3H),0.58-0.53(m,3H);ESI-MS:(+mode)534.27(M+H) + (100%).

[0098] Compound 221: 2-Fluoro-N-((2R)-1-(7-(4-fluorophenyl)-9-methyl-3,9-diazaspiro[5.5]-undecane-3-yl)-3-methyl-1-oxobutan-2-yl)-5-(trifluoromethyl)benzamide [ka] 1 H NMR:(DMSO-d6,400MHz):δ8.62-8.60(m,1H),7.93-7.92(m,1H),7.81-7.80(m,1H),7.75- 7.74(m,1H),7.29-7.13(m,4H),4.67-4.60(m,1H),4.08-4.04(m,1H),3.83-3.81(m,1H),3 .24-3.21(m,1H),2.77-2.65(m,3H),2.27-2.16(m,5H),1.86-1.84(m,1H),1.76-1.72(m, 2H),1.38-1.24(m,3H),0.85-0.83(m,3H),0.58-0.55(m,3H);ESI-MS:(+mode)552.26(M+H) + (100%).

[0099] In some embodiments, the present invention includes a pharmaceutical composition comprising any one of the novel compounds of formula (I) or a salt thereof, formulated with or without one or more pharmaceutical carriers.

[0100] In some embodiments, the present invention includes a method for treating at least one of cancer, chronic inflammation, neuropathic pain, and fibrous disease, which is partially mediated by ATX, comprising administering a therapeutically effective amount of a novel compound or salt of formula (I) to a subject in need thereof.

[0101] Biological research: ATX inhibitory activity (IC 50 measurement): ATX inhibitory activity was measured by biochemical or whole blood assays, as previously described (Bretschneider, T. et al., SLAS Discov 2017, 22, 425). The biochemical reaction consisted of 5 nM recombinant rat ATX, 5 μM 18:1 LPC, and 50 mM Tris (pH 8.0), 3 mM KCl, 1 mM CaCl2, 1 mM MgCl2, 0.14 mM NaCl, and 0.1% bovine serum albumin, supplemented with 5 nM recombinant rat ATX, 5 μM 18:1 LPC, and the test compound (0.1–10 μM). The reaction was stopped at 2 hours by adding butanol, and analysis was performed based on RapidFire-MS.

[0102] The whole blood assay consisted of 45 μL of heparinized mouse / rat whole blood and the test compound (0.12–100 μM). After 1 hour at 37°C, the reaction was stopped by adding 100 μL of 40 mM disodium hydrogen phosphate buffer containing 30 mM citrate (pH 4) and 1 μM 17:0 LPA (internal standard). The samples were then processed as described above and analyzed by LC-MS / MS. Data were analyzed using a graphpad prism (v7.03) to determine the 50% inhibitory concentration (IC) of the test compound. 50 ) was obtained.

[0103] Representative compounds' inhibitory activity of mouse serum ATX (IC) 50 The following are listed in Table 2:

[0104] [Table 2-1] [Table 2-2]

[0105] In one embodiment, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) and one or more pharmaceutically acceptable excipients of choice. The novel compounds of the present invention can be formulated into suitable pharmaceutically acceptable compositions by combining them with suitable excipients, depending on known techniques and processes and concentrations.

[0106] Compounds of formula (I) or pharmaceutical compositions containing the same are useful as pharmaceuticals for inhibiting ATX activity, are suitable for humans and other warm-blooded animals, and may be administered orally, topically, or parenterally.

[0107] The amount of the active ingredient in the pharmaceutical composition and its unit dosage form, i.e., the novel compound of formula (I) according to the present invention, may vary or be adjusted widely depending on several factors, such as the specific method of application, the potency of the specific compound, and the desired concentration.

[0108] The novel compounds of the present invention can be formulated into suitable pharmaceutically acceptable compositions by combining them with suitable excipients, depending on known techniques, processes, and concentrations. The pharmaceutical compositions further contain an effective amount of an ATX inhibitor. The dosage of the ATX inhibitor may vary within a broad range and needs to be adjusted to suit the individual condition in each specific case.

[0109] In one embodiment, the compound of formula (I) may be used alone or in combination with one or more therapeutic agents, such as anti-inflammatory agents, antitumor agents, antifibrotic agents, autotaxin inhibitors, immunomodulators, and cardiovascular agents, as well as other therapeutic agents known to skilled healthcare professionals. The choice of such therapeutic agents may depend on the type and severity of the disease, the condition of the patient being treated, and other medications the patient may be taking.

[0110] In some embodiments, the present invention includes a pharmaceutical composition comprising any one of the novel compounds of formula (I) or a salt thereof, formulated with or without one or more pharmaceutical carriers.

[0111] In some embodiments, the present invention includes a method for treating at least one of cancer, chronic inflammation, neuropathic pain, and fibrous disease, which is partially mediated by ATX, comprising administering a therapeutically effective amount of a novel compound or salt of formula (I) to a subject in need thereof.

Claims

1. Compounds of formula (I), pharmaceutically acceptable salts thereof, enantiomers, and diastereomers thereof: 【Chemistry 1】 [In the formula, R １ is (C １ -C ６ )alkyl, (C ３ -C ７ )cycloalkyl, heterocyclyl, heteroaryl, aryl, arylalkyl, heterocycloalkyl, heteroarylalkyl, aryloxy; each of these groups, where applicable, is further substituted with one or more substituents independently selected from -H, halo, -(C １ -C ６ )alkyl, (C １ -C ６ )alkoxy, (C １ -C ６ )acyloxy, -(CH ２ ) ｐ CF ３ , -CN, -O(CH ２ ) ｐ CF ３ , -OCHF ２ , -(CH ２ ) ｐ OR ａ , -(CR ａ R ｂ ) ｐ NR ａ R ｂ , -COOR ａ , -C(O)NR ａ R ｂ , -NR ｃ C(O)NR ａ R ｂ , -S(O) ２ NR ａ R ｂ , -NR ｃ S(O) ２ NR ａ R ｂ , aryl, (C ３ -C ７ )cycloalkyl, or heterocyclyl W is -C(O)-, -C(O)-NR ｄ -, -S(O) ２ -, or -S(O) ２ NR ｄ - Selected from, R ２ H, (C １ ~C ６ ) Selected from alkyl groups, R ３ and R ４ are each independently selected from -H, (C １ -C ６ )alkyl, (C ３ -C ７ )cycloalkyl, heterocyclyl, heteroaryl, aryl, arylalkyl, heterocycloalkyl, heteroarylalkyl, and each of these groups is, where applicable, further substituted with a substituent independently selected from -H, halo, -(C １ -C ６ )alkyl, (C １ -C ６ )alkoxy, (C １ -C ６ )acyloxy, (CH ２ ) ｑ CF ３ , -CN, -O(CH ２ ) ｑ CF ３ , -OCHF ２ , -(CH ２ ) ｑ OR ｅ , -(CR ｅ R ｆ ) ｑ NR ｅ R ｆ , -COOR ｅ , -C(O)NR ｅ R ｆ , -NR ｇ C(O)NR ｅ R ｆ , -S(O) ２ NR ｅ R ｆ , -NR ｇ S(O) ２ NR ｅ R ｆ , aryl, (C ３ -C ７ )cycloalkyl, or heterocyclyl, R ５ H is, X is -(CR ｈ R ｉ ) ｒ -, -(CR ｈ R ｉ ) ｒ -C(O)-, -C(O)- or O, and is independently selected from one or more of the foregoing, Y and Z are each independent of -NR ｉ ,-(CR ｈ R ｉ ) ｓ One or more of the following are selected: -, -O-, or -C(O)- R ６ and R ７ These are, independently, -H, (C １ ~C ６ ) alkyl, (C ３ ~C ７ ) Selected from cycloalkyl, heterocyclyl, heteroaryl, aryl, arylalkyl, heterocycloalkyl, heteroarylalkyl, and each of these groups, where applicable, -H, halo, -(C １ ~C ６ ) alkyl, (C １ ~C ６ ) Alkoxy, (C １ ~C ６ ) Acyloxy, -(CH ２ ) ｔ CF ３ , -CN, -O(CH ２ ) ｔ CF ３ , -OCHF ２ ,-(CH ２ ) ｔ OR ｊ ,-(CR ｊ R ｋ ) ｔ NR ｊ R ｋ , -COOR ｊ , -C(O)NR ｊ R ｋ , -NR ｌ C(O)NR ｊ R ｋ , -S(O) ２ NR ｊ R ｋ , -NR ｌ S(O) ２ NR ｊ R ｋ ,Ayl, (C ３ ~C ７ ) Further substituted with substituents independently selected from cycloalkyl or heterocyclyl, The bond identified as "A" is either a single bond or a double bond. m and n are independently selected from 0, 1, or 2. p, q, r, s, and t are independently selected from 0, 1, 2, or 3. R ａ , R ｂ , R ｃ , R ｄ , R ｅ , R ｆ , R ｇ , R ｈ , R ｉ , R ｊ , R ｋ , and R ｌ H, (C １ ~C ６ ) alkyl, (C ３ ~C ７ ) Cycloalkyl, -(CR ｊ R ｋ ) ｔ NR ｊ R ｋ ,-(CR ｊ R ｋ ) ｔ COOR ｊ ,-(CR ｊ R ｋ ) ｔ (C ３ ~C ７ [Selected from cycloalkylhaloalkyl, aryl, heteroaryl, or arylalkyl].

2. R １ However, they are selected from heteroaryl and aryl, and both are independently -H, halo, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) Alkoxy, -(CH ２ ) ｐ CF ３ , -O(CH ２ ) ｐ CF ３ The compound according to formula (I) of claim 1, wherein p is optionally substituted and p is 0.

3. The compound according to formula (I) of claim 1, wherein W is -C(O).

4. R ２ and R ４ However, independently, it is -H, and R ３ However, -H, (C １ ~C ６ ) alkyl, (C ３ ~C ７ ) Selected from cycloalkyl and aryl, R ６ and R ７ However, they are independently selected from -H, aryl, and heteroaryl, where aryl and heteroaryl are -H, halo, and -(C １ ~C ６ ) alkyl, (C １ ~C ６ ) Alkyl, -COOR ｊ A compound of formula (I) according to claim 1, further substituted with substituents independently selected from the above.

5. R ｉ , R ｈ However, independently, -H, (C １ ~C ６ ) alkyl, -(CR ｊ R ｋ ) ｔ (C ３ ~C ７ ) Cycloalkyl, -(CR ｊ R ｋ ) ｔ COOR ｊ Selected from, R ｊ and R ｋ The compound according to formula (I) of claim 1, wherein the compound is -H and t is selected from 1 and 2.

6. below: 2-Fluoro-N-((2R)-3-methyl-1-(2-methyl-1,3-dioxo-4-phenyl-2,8-diazaspiro[4.5]decane-8-yl)-1-oxobutan-2-yl)-5-(trifluoromethyl)benzamide; N-((2R)-1-(2-(2-aminoethyl)-1,3-dioxo-4-phenyl-2,8-diazaspiro[4.5]decane-8-yl)-3-methyl-1-oxobutan-2-yl)-2-fluoro-5-(trifluoromethyl)benzamide; 2-Fluoro-N-((2R)-3-methyl-1-(2-methyl-1-oxo-4-phenyl-2,8-diazaspiro[4.5]decane-8-yl)-1-oxobutan-2-yl)-5-(trifluoromethyl)benzamide; 2-Fluoro-N-((2R)-3-methyl-1-oxo-1-(1-oxo-4-phenyl-2,8-diazaspiro[4.5]decane-8-yl)butan-2-yl)-5-(trifluoromethyl)benzamide; 2-Fluoro-N-((2R)-3-methyl-1-(2-methyl-1-oxo-4-(pyridine-3-yl)-2,8-diazaspiro[4.5]decane-8-yl)-1-oxobutan-2-yl)-5-(trifluoromethyl)benzamide; 2-Fluoro-N-((2R)-3-methyl-1-oxo-1-(1-oxo-4-(pyridine-3-yl)-2,8-diazaspiro[4.5]decane-8-yl)butan-2-yl)-5-(trifluoromethyl)benzamide; N-((2R)-1-(4-(1H-indazole-5-yl)-2-methyl-1-oxo-2,8-diazaspiro[4.5]decane-8-yl)-3-methyl-1-oxobutan-2-yl)-2-fluoro-5-(trifluoromethyl)benzamide; 2-Fluoro-N-((2R)-3-methyl-1-(2-methyl-4-phenyl-2,8-diazaspiro[4.5]decane-8-yl)-1-oxobutan-2-yl)-5-(trifluoromethyl)benzamide; 2-Fluoro-N-((2R)-3-methyl-1-(2-methyl-4-(pyridine-3-yl)-2,8-diazaspiro[4.5]decane-8-yl)-1-oxobutan-2-yl)-5-(trifluoromethyl)benzamide; N-((2R)-1-(4-(1H-indazole-5-yl)-2-methyl-2,8-diazaspiro[4.5]decane-8-yl)-3-methyl-1-oxobutan-2-yl)-2-fluoro-5-(trifluoromethyl)benzamide; 2-Fluoro-N-((2R)-1-(4-(4-fluorophenyl)-1-oxo-2,8-diazaspiro[4.5]decane-8-yl)-3-methyl-1-oxobutan-2-yl)-5-(trifluoromethyl)benzamide; 2-Fluoro-N-((2R)-1-(4-(4-fluorophenyl)-2-methyl-1-oxo-2,8-diazaspiro[4.5]decane-8-yl)-3-methyl-1-oxobutan-2-yl)-5-(trifluoromethyl)benzamide; N-((2R)-1-(2-ethyl-4-(4-fluorophenyl)-1-oxo-2,8-diazaspiro[4.5]decane-8-yl)-3-methyl-1-oxobutan-2-yl)-2-fluoro-5-(trifluoromethyl)benzamide; 2-Fluoro-5-methoxy-N-((2R)-3-methyl-1-(2-methyl-1-oxo-4-phenyl-2,8-diazaspiro[4.5]decane-8-yl)-1-oxobutan-2-yl)benzamide; (R)-2-fluoro-N-(3-methyl-1-(2-methyl-1-oxo-4-phenyl-2,8-diazaspiro[4.5]des-3-en-8-yl)-1-oxobutan-2-yl)-5-(trifluoromethyl)benzamide; 2-Fluoro-N-((2R)-3-methyl-1-(2-methyl-1-oxo-4-phenyl-2,8-diazaspiro[4.5]decane-8-yl)-1-oxobutan-2-yl)benzamide; N-((2R)-3-methyl-1-(2-methyl-1-oxo-4-phenyl-2,8-diazaspiro[4.5]decane-8-yl)-1-oxobutan-2-yl)-3-(trifluoromethyl)benzamide; 2-Fluoro-5-methyl-N-((2R)-3-methyl-1-(2-methyl-1-oxo-4-phenyl-2,8-diazaspiro[4.5]decane-8-yl)-1-oxobutan-2-yl)benzamide; 2-Fluoro-N-((2R)-3-methyl-1-(2-methyl-1-oxo-4-phenyl-2,8-diazaspiro[4.5]decane-8-yl)-1-oxobutan-2-yl)-5-(trifluoromethoxy)benzamide; 2-Fluoro-N-((2R)-1-(4-(4-fluorophenyl)-2-isopropyl-1-oxo-2,8-diazaspiro[4.5]decane-8-yl)-3-methyl-1-oxobutan-2-yl)-5-(trifluoromethyl)benzamide; N-((2R)-1-(2-(cyclopropylmethyl)-4-(4-fluorophenyl)-1-oxo-2,8-diazaspiro[4.5]decane-8-yl)-3-methyl-1-oxobutan-2-yl)-2-fluoro-5-(trifluoromethyl)benzamide; N-((2R)-1-(2-(cyclopropylmethyl)-1-oxo-4-(pyridine-3-yl)-2,8-diazaspiro[4.5]decane-8-yl)-3-methyl-1-oxobutan-2-yl)-2-fluoro-5-(trifluoromethyl)benzamide; 2-Fluoro-N-((2R)-1-(4-(4-methoxyphenyl)-2-methyl-1-oxo-2,8-diazaspiro[4.5]decane-8-yl)-3-methyl-1-oxobutan-2-yl)-5-(trifluoromethyl)benzamide; 2-Fluoro-N-((2R)-3-methyl-1-oxo-1-(2-oxo-4-phenyl-1-oxa-3,8-diazaspiro[4.5]decane-8-yl)butan-2-yl)-5-(trifluoromethyl)benzamide; (R)-2-fluoro-N-(1-(1-(4-fluorophenyl)-3-methyl-4-oxo-2,3,8-triazaspiro[4.5]des-1-en-8-yl)-3-methyl-1-oxobutan-2-yl)-5-(trifluoromethyl)benzamide; 2-Fluoro-N-((2R)-1-(4-(4-fluorophenyl)-2-methyl-2,8-diazaspiro[4.5]decane-8-yl)-3-methyl-1-oxobutan-2-yl)-5-(trifluoromethyl)benzamide; 2-Fluoro-N-((2R)-1-(4-(4-fluorophenyl)-2-isopropyl-2,8-diazaspiro[4.5]decane-8-yl)-3-methyl-1-oxobutan-2-yl)-5-(trifluoromethyl)benzamide; N-((2R)-1-(2-(cyclopropylmethyl)-4-(4-fluorophenyl)-2,8-diazaspiro[4.5]decane-8-yl)-3-methyl-1-oxobutan-2-yl)-2-fluoro-5-(trifluoromethyl)benzamide; 2-Fluoro-N-((2R)-1-(4-(4-methoxyphenyl)-2-methyl-2,8-diazaspiro[4.5]decane-8-yl)-3-methyl-1-oxobutan-2-yl)-5-(trifluoromethyl)benzamide; 2-Fluoro-N-((2R)-1-(4-(4-methoxyphenyl)-2-methyl-2,8-diazaspiro[4.5]decane-8-yl)-3-methyl-1-oxobutan-2-yl)-5-methylbenzamide; N-((2R)-1-(4-(4-fluorophenyl)-2-methyl-2,8-diazaspiro-[4.5]decane-8-yl)-3-methyl-1-oxobutan-2-yl)-4-methylpicolinamide; Methyl 8-((2-fluoro-5-(trifluoromethyl)benzoyl)-D-valyl)-4-(4-fluorophenyl)-2,8-diazaspiro[4.5]decane-2-carboxylate; Ethyl 8-((2-fluoro-5-(trifluoromethyl)benzoyl)-D-valyl)-4-(4-fluorophenyl)-2,8-diazaspiro[4.5]decane-2-carboxylate; 4-(8-((2-fluoro-5-(trifluoromethyl)benzoyl)-D-valyl)-2-methyl-2,8-diazaspiro[4.5]decane-4-yl)benzoic acid; 2-Fluoro-N-((R)-1-((R)-4-(4-fluorophenyl)-2-methyl-2,8-diazaspiro[4.5]decane-8-yl)-3-methyl-1-oxobutan-2-yl)-5-(trifluoromethyl)benzamide; 2-Fluoro-N-((R)-1-((S)-4-(4-fluorophenyl)-2-methyl-2,8-diazaspiro[4.5]decane-8-yl)-3-methyl-1-oxobutan-2-yl)-5-(trifluoromethyl)benzamide; 2-Fluoro-N-((2R)-3-methyl-1-(2-methyl-4-(p-tolyl)-2,8-diazaspiro[4.5]decane-8-yl)-1-oxobutan-2-yl)-5-(trifluoromethyl)benzamide; N-((2R)-1-(4-(3,5-dimethylphenyl)-2-methyl-2,8-diazaspiro[4.5]decane-8-yl)-3-methyl-1-oxobutan-2-yl)-2-fluoro-5-(trifluoromethyl)benzamide; 2-Fluoro-N-((1R)-2-(4-(4-fluorophenyl)-2-methyl-2,8-diazaspiro[4.5]decane-8-yl)-2-oxo-1-phenylethyl)-5-(trifluoromethyl)benzamide; N-((1R)-1-cyclohexyl-2-(4-(4-fluorophenyl)-2-methyl-2,8-diazaspiro[4.5]decane-8-yl)-2-oxoethyl)-2-fluoro-5-(trifluoromethyl)benzamide 2-Fluoro-N-((2R)-1-(4-(4-fluorophenyl)-2-methyl-2,8-diazaspiro[4.5]decane-8-yl)-4-methyl-1-oxopentan-2-yl)-5-(trifluoromethyl)benzamide; 2,5-Difluoro-N-((2R)-1-(4-(4-fluorophenyl)-2-methyl-2,8-diazaspiro[4.5]decane-8-yl)-3-methyl-1-oxobutan-2-yl)benzamide; 2,5-Dichloro-N-((2R)-1-(4-(4-fluorophenyl)-2-methyl-2,8-diazaspiro[4.5]decane-8-yl)-3-methyl-1-oxobutan-2-yl)benzamide; N-((2R)-1-(4-(4-fluorophenyl)-2-methyl-2,8-diazaspiro[4.5]decane-8-yl)-3-methyl-1-oxobutan-2-yl)-1-methyl-1H-indazole-3-carboxamide; N-((2R)-1-(4-(4-fluorophenyl)-2-methyl-2,8-diazaspiro[4.5]decane-8-yl)-3-methyl-1-oxobutan-2-yl)-4,6-dimethylpicolinamide; 4-methyl-N-((2R)-3-methyl-1-(2-methyl-4-(pyridine-3-yl)-2,8-diazaspiro[4.5]decane-8-yl)-1-oxobutan-2-yl)picolinamide; 2-Fluoro-N-((2R)-3-methyl-1-oxo-1-(10-oxo-7-phenyl-3,9-diazaspiro[5.5]undecane-3-yl)butan-2-yl)-5-(trifluoromethyl)benzamide; 2-Fluoro-N-((2R)-1-(7-(4-fluorophenyl)-10-oxo-3,9-diazaspiro[5.5]undecane-3-yl)-3-methyl-1-oxobutan-2-yl)-5-(trifluoromethyl)benzamide; 2-Fluoro-N-((2R)-3-methyl-1-(9-methyl-10-oxo-7-phenyl-3,9-diazaspiro[5.5]undecane-3-yl)-1-oxobutan-2-yl)-5-(trifluoromethyl)benzamide; 2-Fluoro-N-((2R)-1-(7-(4-fluorophenyl)-9-methyl-10-oxo-3,9-diazaspiro[5.5]undecane-3-yl)-3-methyl-1-oxobutan-2-yl)-5-(trifluoromethyl)benzamide; N-((2R)-1-(9-ethyl-7-(4-fluorophenyl)-10-oxo-3,9-diazaspiro[5.5]undecane-3-yl)-3-methyl-1-oxobutan-2-yl)-2-fluoro-5-(trifluoromethyl)benzamide; 2-Fluoro-N-((2S)-3-methyl-1-(9-methyl-10-oxo-7-phenyl-3,9-diazaspiro[5.5]undecane-3-yl)-1-oxobutan-2-yl)-5-(trifluoromethyl)benzamide; N-((2R)-3-methyl-1-(9-methyl-10-oxo-7-phenyl-3,9-diazaspiro[5.5]undecane-3-yl)-1-oxobutan-2-yl)-4-(trifluoromethyl)picolinamide; 2-Fluoro-N-((2R)-3-methyl-1-(9-methyl-7-phenyl-3,9-diazaspiro[5.5]undecane-3-yl)-1-oxobutan-2-yl)-5-(trifluoromethyl)benzamide; 2-Fluoro-N-((2R)-1-(7-(4-fluorophenyl)-9-methyl-3,9-diazaspiro[5.5]undecane-3-yl)-3-methyl-1-oxobutan-2-yl)-5-(trifluoromethyl)benzamide A compound according to formula (I) of claim 1, selected from the above.

7. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) according to any one of claims 1 to 6, and one or more pharmaceutically acceptable excipients of any choice.

8. The pharmaceutical composition according to claim 8, in combination with other suitable therapeutic agents such as anti-inflammatory agents, antitumor agents, antifibrotic agents, autotaxin inhibitors, immunomodulators, and cardiovascular agents.

9. The compound or pharmaceutical composition thereof according to claim 1, which is useful for the prevention or treatment of at least one of cancer, lymphocyte homing, chronic inflammation, neuropathic pain, fibrous disease, thrombosis, and cholestatic pruritus.

10. A method for treating diseases such as fibrosis, inflammation, cancer, or neovascular diseases, preferably cancer, lymphocyte homing, chronic inflammation, neuropathic pain, fibrotic diseases, thrombosis, and cholestatic pruritus, comprising administering an effective amount of the compound of formula (I) described in claim 1 to a patient in need thereof.

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