Dual inhibitors for the treatment of Alzheimer's disease

Abstract

Compound (I) is provided, wherein R 1 and R 2 is H or (C1-C3)-alkyl, and X is a group of the formula -[CH2] where n=0, 1 or 2. n A is a biradical derived from a linear methylene chain or a branched saturated (C2-C4)-alkylene chain, and A is either a C-radical derived from a non-aromatic polycyclic 6- to 15-membered carbocyclic ring system or a C-radical derived from a polycyclic 6- to 15-membered heterocyclic ring system containing one or two O, S, or N atoms, and the C-radical is unsubstituted or substituted. Compound (I) is simultaneously an inhibitor of soluble epoxide hydrolase and glutaminyl cyclase. Furthermore, Compound (I) reduces the level of pro-inflammatory cytokines in LPS-stimulated BV2 cells, exhibits low cytotoxicity, and has good BBB permeability. Therefore, Compound (I) is useful as a multi-target compound for the prevention or treatment of Alzheimer's disease. TIFF2026507708000050.tif28170

Description

[Technical Field]

[0001] The present invention relates to the field of small molecule compounds for human therapy, particularly for the multi-targeted treatment of Alzheimer's disease (AD). [Background technology]

[0002] AD is a progressive neurodegenerative disease that invariably leads to the patient's death after years of declining cognitive and functional abilities, causing immeasurable suffering to patients and caregivers. AD is the most common cause of dementia and the most prevalent neurodegenerative disease. The devastating effects of AD can be attributed, at least in part, to the lack of drugs that can prevent or halt the progression of the disease. The few globally approved drugs only provide temporary symptomatic effects. Approved drugs and most drug candidates in the drug development pipeline are designed to hit a single, selected biological target, and most of the latter have failed in clinical trials.

[0003] These clinical failures may stem from a misunderstanding of AD, which is rather a complex pathological network with several interrelated targets that will continue to resist change if only one single target is modulated. In other words, AD is not a problem of just one single biological target; on the contrary, it appears to stem from a complex network in which multiple biological targets play important roles. In this scenario, novel candidates with innovative mechanisms of action that can improve cognition and halt or slow the progression of AD are desperately needed. Multitargeted drugs, i.e., single molecules that hit several targets in the complex AD network, are emerging as a realistic option for halting disease progression.

[0004] The area of ​​AD drug discovery is one in which the development of multitargeted therapies has been most vigorously pursued over the past decade. Combining two or more different pharmacological moieties into a single hybrid molecule is the most common way to construct multitargeted anti-Alzheimer's drug candidates. Using this approach, a large number of structural classes have been rationally designed, synthesized, tested in vitro against the proposed biological target, and often screened against additional proteins or pathological events of interest. However, very frequently, these are rather large molecules with high molecular weights and lipid solubility, resulting in poor physicochemical and pharmacokinetic properties. Furthermore, in many cases, these compounds were designed to hit biological targets (asynchronously) involved in different disease stages. Indeed, no rationally designed multitargeted compounds have been approved for the treatment of AD to date.

[0005] To take advantage of the beneficial effects of sEH inhibition on inflammation, one of the primary early mechanisms of AD, several types of dual inhibitors targeting soluble epoxide hydrolase (sEH, EC 3.3.2.10) have been designed (for reviews, see e.g., Non-Patent Documents 1 and 2).

[0006] Some of the present inventors discovered in 2018 that sEH inhibition is beneficial for the treatment of AD, and filed a patent application in 2019 disclosing the use of dual inhibitors of sEH and acetylcholinesterase (AChE) for the treatment of AD (see Patent Document 1). However, to date, none of these dual sEH / AChE inhibitors have been developed as drugs for the treatment of AD.

[0007] Single inhibitors of glutaminyl cyclase (QC, also known as glutaminyl-peptide cyclotransferase, QPCT, EC 2.3.2.5) are known in the art (see, for example, Non-Patent Document 3), and some of them have been proposed for the treatment of several diseases, including AD (see, for example, Non-Patent Document 4 and Non-Patent Document 5). All these QC inhibitors likely have the limitations of previously developed single-target anti-AD drug candidates. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] International Publication No. 2020 / 193448 [Non-patent literature]

[0009] [Non-Patent Document 1] K. Hiesinger et al., "Development of multitarget agents possessing soluble epoxide hydrolase inhibitory activity", Prostaglandins and Other Lipid Mediators, 2019, vol. 140, pp. 31-39 [Non-patent document 2] MR Iyer, "Soluble epoxide hydrolase inhibitors: an overview and patent review from the last decade", Expert Opinion on Therapeutic Patents, 2022, vol. 32, pp. 629-647) [Non-patent document 3] C. Xu et al., "Glutaminyl Cyclase, Diseases, and Development of Glutaminyl Cyclase Inhibitors", Journal of Medicinal Chemistry 2021, vol. 64. pp. 6549-6565 [Non-patent document 4] J. Coimbra et al., "An overview of glutaminyl cyclase inhibitors for Alzheimer's disease", Future Medicinal Chemistry 2019, vol. 11, pp. 3179-3194 [Non-Patent Document 5] DK Vijayan et al., "Human glutaminyl cyclase: Structure, function, inhibitors and involvement in Alzheimer's disease", Pharmacological Research 2019, vol. 147, 104342 Summary of the Invention [Problem to be solved by the invention]

[0010] Therefore, the discovery of new candidates with innovative mechanisms of action and the ability to halt or slow the progression of AD is both highly needed and timely. [Means for solving the problem]

[0011] The inventors have found that dual inhibition of sEH and glutaminyl cyclase (QC) has synergistic effects against simultaneous neuroinflammation and amyloid pathology, two important early mechanisms of AD. Accordingly, the inventors disclose what they believe to be the first family of small molecule compounds with dual activity against both sEH and QC and drug-like properties that retain significant potential to halt or slow the progression of AD.

[0012] One aspect of the present disclosure is a compound of Formula I, its stereoisomers and mixtures of stereoisomers, and pharmaceutically acceptable salts of any of these: TIFF2026507708000002.tif34170 formula, R 1 and R 2 are each independently one radical selected from the group consisting of H and (C1-C3)-alkyl, X is a group of the formula -[CH2] where n=0, 1 or 2. n - is a biradical selected from the group consisting of biradicals of linear methylene chains and biradicals derived from branched saturated (C2-C4)-alkylene chains, A is either a C-radical derived from a non-aromatic polycyclic 6- to 15-membered carbocyclic ring system or a C-radical derived from a non-aromatic polycyclic 6- to 15-membered heterocyclic ring system having one or two heteroatoms in the ring, the heteroatoms being independently selected from O, S and N, the C-radical being unsubstituted or one or more of whose H atoms are substituted by one or more substituents attached to any of the possible substitution positions, the substituents being independently selected from the group consisting of (C1-C4)-alkyl, O[(C1-C4)-alkyl], OH, F, Cl, Br and I, provided that radical A does not have any of the following three unsubstituted formulae or any of the possible substituted formulae derived therefrom: TIFF2026507708000003.tif28170 with the proviso that compound I does not have the following formula Ib: TIFF2026507708000004.tif35170 Provided are compounds of Formula I, stereoisomers and mixtures of stereoisomers thereof, and pharmaceutically acceptable salts of any of these:

[0013] Compound Ib has already been mentioned in the art, albeit in an unrelated context, and is hereby disclaimed. In particular, compound Ib corresponds to "compound 7" mentioned in the article "Structural Characterization and Ligand / Inhibitor Identification Provide Functional Insights into the Mycobacterium tuberculosis Cytochrome P450 CYP126A1" by JT Chenge et al., Journal of Biological Chemistry, 2017, vol. 292, pp. 1310-1329. Its formula appears on page 1315 of the article, but its preparation is neither described nor mentioned. Regarding access to "Compound 7," the paper simply states that "the novel compounds (Compounds 1-9) were either from the compound library of the Screening Facility at the Department of Medicinal Chemistry, Leibniz Institute of Molecular Pharmacology (Berlin, Germany) or supplied by ChemDiv or Vitas M" (see the Materials section at the end of page 1326). "Compound 7" was compared to several antifungal drugs (ketoconazole, clotrimazole, econazole, and miconazole) via high-throughput screening (HTS) methods, among others, and it was concluded that "Compound 7" modulates cytochrome P450 CYP126A1 via a similar but different mechanism as the antifungal drugs. Nothing is known in the art about the specific therapeutic activity of "Compound 7" (herein designated Compound Ib). However, in the present disclosure, the preparation of Compound Ib and its biological activity are fully described (see Example 2 and Table 1).

[0014] In certain embodiments of compounds of formula I, the radical A has a formula that is one of the following five unsubstituted formulas: In other certain embodiments, A has a formula that is a variation of the following five formulas, in which one or more H atoms are replaced by one or more substituents attached to any of the possible substitution positions, the substituents being (C1-C4)-alkyl, O[(C1-C4)-alkyl], OH, F, Cl, Br, or I. In other certain embodiments, the substituents are CH3, CH2CH3, OH, F, or Cl. TIFF2026507708000005.tif60170

[0015] In certain embodiments of compounds of Formula I, the biradical X is of the formula —[CH] where n=0, 1, or 2. n -, or X is -CH(CH3)-. In other particular embodiments, X is a group of formula -[CH2] where n=0, 1 or 2. n - is a linear methylene chain, and in other particular embodiments, n=0 and the biradical X is a single bond.

[0016] In certain embodiments of compounds of formula I, the radical R 1 is H or CH3. In other particular embodiments, R 1 is H.

[0017] In certain embodiments of compounds of formula I, the radical R 2 is H or CH3. In other particular embodiments, R 2 is CH3.

[0018] In certain embodiments, the compound of Formula I has one of Formula Ia, Formula Ic, Formula Id, Formula Ie, Formula If, Formula Ig, Formula Ih, Formula Ii, Formula Ij, Formula Ik, Formula Im, Formula Io, Formula Ip, Formula Iq, Formula Ir, Formula Is, Formula It, Formula Iu, Formula Iv, Formula Iw, Formula Ix, Formula Iy, Formula Iz, Formula Iaa, Formula Iab, or Formula Iac, all of which are provided in this disclosure along with their respective preparative examples (see Examples 1 and 3-27).

[0019] Another aspect of the present disclosure provides a pharmaceutical composition comprising an effective amount of any of the compounds of formula I as defined above, together with a sufficient amount of a pharmaceutically acceptable excipient or carrier.

[0020] Another aspect of the present disclosure relates to any of the compounds of formula I defined above for use as an active pharmaceutical ingredient.

[0021] Another aspect of the present disclosure relates to any of the compounds of formula I defined above, including the compound of formula Ib, or any stereoisomer, or any mixture of stereoisomers, or any pharmaceutically acceptable salt thereof, for use in the prevention or treatment of Alzheimer's disease in an animal, including a human. This aspect also relates to the use of any of the compounds of formula I defined above, including compound Ib, in the preparation of a medicament for the prevention or treatment of AD in an animal, including a human. This aspect can relate to a method for the prevention or treatment of AD in an animal, including a human, comprising administering to the animal or human a therapeutically effective amount of any of the compounds of formula I defined above, including the compound of formula Ib, together with a sufficient amount of a pharmaceutically acceptable excipient or carrier.

[0022] As illustrated in the following preparative examples, compounds of formula I can be prepared by generally known processes from starting materials that are either known or available via analogous processes from known materials. 1 Compound I, where =H, can be prepared by a process comprising reacting the corresponding isocyanate of formula II with the corresponding amine of formula III or a salt thereof. If desired, the compound of formula I thus obtained can be converted into a pharmaceutically acceptable salt thereof by reacting it with the corresponding pharmaceutically acceptable acid. TIFF2026507708000006.tif33170

[0023] Alternative: R 1Compounds of formula I where =H can be prepared by a process comprising reacting the corresponding isocyanate of formula V with the corresponding amine of formula IV or a salt thereof. TIFF2026507708000007.tif36170

[0024] The intermediate isocyanates of Formula II and Formula V can be prepared by subjecting the corresponding primary amines of Formula IV and Formula III to a phosgenation reaction with phosgene, diphosgene, or triphosgene, respectively.

[0025] Alternative: R 1 Compounds of formula I where =H can be prepared by a process comprising reacting the corresponding amine of formula III with 1,1'-carbonyldiimidazole followed by reaction with the corresponding amine of formula IV, or by a process comprising reacting the corresponding amine of formula IV with 1,1'-carbonyldiimidazole followed by reaction with the corresponding amine of formula III.

[0026] R 1 Compounds of formula I where R =(C1-C3)-alkyl are 1 can be prepared by a process comprising reacting the corresponding amine of formula IV', where =(C1-C3)-alkyl, with the corresponding azide of formula VI, triphenylphosphine and carbon dioxide. TIFF2026507708000008.tif36170

[0027] As exemplified by the results of the in vitro assays in the following Examples, Compound I of the present invention or a pharmaceutically acceptable salt thereof simultaneously acts as an inhibitor of sEH (see Example 28) and QC (see Example 29). Furthermore, it reduces the level of pro-inflammatory cytokines in LPS-stimulated BV2 cells (see Example 30), exhibits low cytotoxicity (see Example 31), and has good blood-brain barrier (BBB) ​​permeability (see Example 32). Therefore, Compound I or a salt thereof is useful as a multi-target drug for the prevention or treatment of AD.

[0028] Throughout the specification and claims, the word "comprises" and variations of that word are not intended to exclude other technical features, additives, ingredients, or steps. Furthermore, the word "comprises" encompasses the case of "consisting only of." Additional objects, advantages, and features of the present invention will become apparent to those skilled in the art upon examination of the specification or may be learned by practice of the invention. The following examples are offered by way of illustration and are not intended to be limiting of the invention. Furthermore, the present invention includes all possible combinations of the specific and preferred embodiments described herein. DETAILED DESCRIPTION OF THE INVENTION

[0029] Melting points were measured in open capillary tubes using a Gallenkamp MFB595010M melting point apparatus. High-resolution mass spectra were performed at the Centres Cientifics i Tecnologics of the University of Barcelona using an Agilent Technologies LC / MSD TOF spectrometer. IR spectra were performed on a Perkin-Elmer Spectrum RX I spectrophotometer. Absorption values ​​are expressed in wavenumbers (cm -1 ) and the chromatographic resolution is expressed as %. Column chromatography was performed on silica gel 60 AC.C (40 mesh-60 mesh, Carlo Erba, ref. 2000027). Automated normal-phase column chromatography was performed on a CombiFlash Rf150 (Teledyne Isco) using prepacked RediSep Rf silica gel cartridges. Thin-layer chromatography was performed on silica gel 60 F254 (Merck, ref. 1.05554), and spots were visualized with 1% KMnO4 in water. Pure synthetic solvents were used for reactions, extractions, and column chromatography.

[0030] Example 1: Preparation of 1-(adamantan-1-yl)-3-[3-(5-methyl-1H-imidazol-1-yl)propyl]urea of ​​formula Ia TIFF2026507708000009.tif331701-Adamantylamine hydrochloride (282 mg, 1.50 mmol) was added to a stirred mixture of dichloromethane (6 mL) and saturated aqueous NaHCO3 (8 mL). Triphosgene (223 mg, 0.75 mmol) was then slowly added, and the reaction mixture was stirred at room temperature for 30 minutes. The two phases were then separated, and the organic layer was washed with brine, dried over anhydrous Na2SO4, and filtered. The filtrate was partially evaporated under reduced pressure below 30 °C to give a concentrated dichloromethane solution of 1-adamantyl isocyanate, which was used in the subsequent step without further purification.

[0031] To the solution of isocyanate was added a solution of 3-(5-methyl-1H-imidazol-1-yl)propan-1-amine (251 mg, 1.80 mmol) in dichloromethane (1 mL). The reaction mixture was stirred overnight at room temperature and evaporated under reduced pressure to give a beige gum (359 mg), which was purified by column chromatography (40 μm–60 μm silica gel, dichloromethane–methanol mixtures) to give the title compound (222 mg, 47% overall yield) as a yellow gummy solid.

[0032] Characterization of Ia: Melting point 80-81°C; IR(NaCl) ν: 3316 cm -1 , 2903cm -1 , 2847cm -1 , 1657cm -1 , 1565cm -1 , 1504cm -1 , 1451cm -1 , 1358cm -1 , 1293cm -1 , 1277cm -1 , 1233cm -1 , 1109cm -1 , 1093cm -1 , 928cm -1 , 822cm -1 , 753cm -1 , 666cm -1 , 630cm -1 ;[C 18 H 28 NO+H] +HRMS(ESI) calculated value for 317.2336, found value 317.2331.

[0033] Example 2: Preparation of 1-[3-(1H-imidazol-1-yl)propyl]-3-(adamantan-1-yl)urea of ​​formula Ib (prior art) This compound was prepared in a manner similar to that described for Example 1. Starting with 1-adamantylamine hydrochloride (282 mg, 1.50 mmol) and triphosgene (223 mg, 0.75 mmol), a concentrated solution of the resulting 1-adamantyl isocyanate in dichloromethane was reacted with 3-(1H-imidazol-1-yl)propan-1-amine (225 mg, 1.80 mmol) to give a yellowish solid residue (500 mg). Column chromatography purification of this residue (40 μm-60 μm silica gel, dichloromethane-methanol mixture) afforded the title compound (150 mg, 33% overall yield).

[0034] Characterization of Ib: Melting point 127°C-129°C; IR(NaCl) ν: 3354 cm -1 , 3113cm -1 , 3021cm -1 , 2907cm -1 , 2848cm -1 , 1624cm -1 , 1563cm -1 , 1504cm -1 , 1452cm -1 , 1356cm -1 , 1293cm -1 , 1280cm -1 , 1241cm -1 , 1229cm -1 , 1104cm -1 , 1090cm -1 , 1074cm -1 , 905cm -1 , 807cm -1 , 661cm -1 , 621cm -1 ;[C 17 H 26 NO+H] +HRMS(ESI) calculated for 303.2179, found 303.2177.

[0035] Example 3: Preparation of 1-[3-(5-methyl-1H-imidazol-1-yl)propyl]-3-(3-methyladamantan-1-yl)urea of ​​formula Ic This compound was prepared in a manner similar to that described for Example 1. Starting with (3-methyl-1-adamantyl)amine hydrochloride (242 mg, 1.20 mmol) and triphosgene (178 mg, 0.60 mmol), a concentrated solution of the resulting 3-methyl-1-adamantyl isocyanate in dichloromethane was reacted with 3-(5-methyl-1H-imidazol-1-yl)propan-1-amine (200 mg, 1.44 mmol) to give a yellowish residue (346 mg). Column chromatography purification of this residue (40 μm to 60 μm silica gel, dichloromethane-methanol mixture), followed by washing with pentane (3 × 2 mL) and drying at 20 Torr for 48 h, afforded the title compound (188 mg, 48% overall yield) as a white solid.

[0036] Ic characterization: Melting point 71°C-73°C; IR(ATR) ν: 3446cm -1 , 3354cm -1 , 3183cm -1 , 3113cm -1 , 2912cm -1 , 2838cm -1 , 1659cm -1 , 1563cm -1 , 1497cm -1 , 1445cm -1 , 1432cm -1 , 1355cm -1 , 1306cm -1 , 1263cm -1 , 1238cm -1 , 1206cm -1 , 1155cm -1 , 1105cm -1 , 1055cm -1 , 929cm -1 , 851cm-1 , 833cm -1 , 802cm -1 , 700cm -1 , 666cm -1 ;[C 19 H 30 NO+H] + HRMS(ESI) calculated for 331.2492, found 331.2493.

[0037] Example 4: Preparation of 1-(3-ethyladamantan-1-yl)-3-[3-(5-methyl-1H-imidazol-1-yl)propyl]urea of ​​formula Id Prepared in a manner similar to that described for the compound in Example 1. Starting with 3-ethyladamantylamine hydrochloride (324 mg, 1.50 mmol) and triphosgene (223 mg, 0.75 mmol), a concentrated solution of the resulting 3-ethyl-1-adamantyl isocyanate in dichloromethane was reacted with 3-(5-methyl-1H-imidazol-1-yl)propan-1-amine (251 mg, 1.80 mmol) to give a yellowish gum (494 mg). Column chromatography purification of this residue (40 μm-60 μm silica gel, dichloromethane-methanol mixtures) afforded the title compound (307 mg, 59% overall yield) as a yellowish gum.

[0038] Characterization of Id: IR(NaCl)ν: 3345cm -1 , 3110cm -1 , 2960cm -1 , 2908cm -1 , 2848cm -1 , 1645cm -1 , 1562cm -1 , 1505cm -1 , 1451cm -1 , 1360cm -1 , 1297cm -1 , 1246cm -1 , 1235cm -1 , 1110cm -1 , 928cm -1 , 808cm -1 ;[C20 H 32 NO+H] + HRMS(ESI) calculated for 345.2649, found 345.2651.

[0039] Example 5: Preparation of 1-(3,5-dimethyladamantan-1-yl)-3-[3-(5-methyl-1H-imidazol-1-yl)propyl]urea of ​​formula Ie This compound was prepared in a manner similar to that described for Example 1. Starting with (3,5-dimethyl-1-adamantyl)amine hydrochloride (117 mg, 0.54 mmol) and triphosgene (80 mg, 0.27 mmol), a concentrated solution of the resulting 3,5-dimethyl-1-adamantyl isocyanate in dichloromethane was reacted with 3-(5-methyl-1H-imidazol-1-yl)propan-1-amine (91 mg, 0.65 mmol) to give a yellowish residue (158 mg). After two successive column chromatographic purifications (40 μm to 60 μm silica gel, dichloromethane-methanol mixtures), followed by washing with pentane (3 × 2 mL), and drying at 20 Torr for 48 h, the title compound (65 mg, 35% overall yield) was obtained as a white solid.

[0040] Characterization of Ie: Melting point 112°C-114°C; IR(ATR) ν: 3332cm -1 , 3197cm -1 , 3099cm -1 , 3042cm -1 , 2944cm -1 , 2900cm -1 , 2839cm -1 , 1683cm -1 , 1556cm -1 , 1505cm -1 , 1453cm -1 , 1357cm -1 , 1263cm -1 , 1233cm -1 , 1206cm -1 , 1107cm -1 , 931cm -1 , 820cm -1, 693cm -1 , 666cm -1 , 626cm -1 ;[C 20 H 32 NO+H] + HRMS(ESI) calculated for 345.2649, found 345.2647.

[0041] Example 6 Preparation of 1-(3-chloroadamantan-1-yl)-3-[3-(5-methyl-1H-imidazol-1-yl)propyl]urea of ​​Formula If This compound was prepared in a manner similar to that described for Example 1. Starting with 3-chloroadamantan-1-amine hydrochloride (166 mg, 0.75 mmol) and triphosgene (133 mg, 0.45 mmol), a concentrated solution of the resulting 3-chloro-1-adamantyl isocyanate in dichloromethane was reacted with 3-(5-methyl-1H-imidazol-1-yl)propan-1-amine (149 mg, 1.07 mmol) to give a yellowish residue (231 mg). The residue was purified by column chromatography (40 μm to 60 μm silica gel, dichloromethane-methanol mixture), followed by washing with pentane (3 × 2 mL) and drying at 20 Torr for 48 h to give the title compound (55 mg, 21% overall yield) as a brown solid.

[0042] Characterization of If: Melting point 110℃~112℃; IR(ATR) ν: 3302cm -1 , 3115cm -1 , 3042cm -1 , 2913cm -1 , 2855cm -1 , 1667cm -1 , 1645cm -1 , 1638cm -1 , 1557cm -1 , 1525cm -1 , 1452cm -1 , 1390cm -1 , 1369cm -1 , 1351cm -1 , 1333cm -1 , 1291cm-1 , 1255cm -1 , 1227cm -1 , 1202cm -1 , 1184cm -1 , 1135cm -1 , 1109cm -1 , 1096cm -1 , 1043cm -1 , 977cm -1 , 962cm -1 , 939cm -1 , 833cm -1 , 802cm -1 , 756cm -1 , 725cm -1 , 695cm -1 , 657cm -1 , 634cm -1 ;[C 18 H 27 ClNO+H] + HRMS(ESI) calculated value for 351.1946, found value 351.1949.

[0043] Example 7: Preparation of 1-(3-fluoroadamantan-1-yl)-3-[3-(5-methyl-1H-imidazol-1-yl)propyl]urea of ​​Formula Ig This compound was prepared in a manner similar to that described for Example 1. Starting with 3-fluoroadamantan-1-amine (240 mg, 1.42 mmol) and triphosgene (211 mg, 0.71 mmol), a concentrated solution of the resulting 3-fluoro-1-adamantyl isocyanate in dichloromethane was reacted with 3-(5-methyl-1H-imidazol-1-yl)propan-1-amine (237 mg, 1.70 mmol) to give a yellowish residue (517 mg). The residue was purified by column chromatography (40 μm to 60 μm silica gel, dichloromethane-methanol mixture), followed by washing with pentane (3 × 2 mL) and drying at 20 Torr for 48 h to give the title compound (42 mg, 9% overall yield) as a dark yellow solid.

[0044] Characterization of Ig: Melting point 115°C-117°C; IR(ATR) ν: 3456cm-1 , 3357cm -1 , 3316cm -1 , 3123cm -1 , 2914cm -1 , 2860cm -1 , 1659cm -1 , 1562cm -1 , 1557cm -1 , 1522cm -1 , 1454cm -1 , 1442cm -1 , 1425cm -1 , 1363cm -1 , 1352cm -1 , 1330cm -1 , 1290cm -1 , 1260cm -1 , 1237cm -1 , 1202cm -1 , 1108cm -1 , 1018cm -1 , 1012cm -1 , 947cm -1 , 929cm -1 , 903cm -1 , 841cm -1 , 825cm -1 , 797cm -1 , 718cm -1 , 695cm -1 , 667cm -1 , 656cm -1 , 607cm -1 ;[C 18 H 27 FN4O+H] + HRMS(ESI) calculated for 335.2242, found 335.2245.

[0045] Example 8: Preparation of 1-(3-hydroxyadamantan-1-yl)-3-[3-(5-methyl-1H-imidazol-1-yl)propyl]urea of ​​formula Ih This compound was prepared in a manner similar to that described for Example 1. Starting with 3-amino-1-adamantanol (206 mg, 1.23 mmol) and triphosgene (183 mg, 0.62 mmol), a concentrated solution of the resulting 3-hydroxy-1-adamantyl isocyanate in dichloromethane was reacted with 3-(5-methyl-1H-imidazol-1-yl)propan-1-amine (206 mg, 1.48 mmol) to give a yellowish residue (307 mg). The residue was purified by two successive column chromatography runs (40 μm to 60 μm silica gel, dichloromethane-methanol mixtures), followed by washing with pentane (3 × 1 mL) and drying at 20 Torr for 48 h, to give the title compound (53 mg, 13% overall yield) as a beige solid.

[0046] Ih characterization: Melting point 52°C-54°C; IR(ATR) ν: 3311cm -1 , 2968cm -1 , 2909cm -1 , 2852cm -1 , 1646cm -1 , 1556cm -1 , 1503cm -1 , 1449cm -1 , 1390cm -1 , 1353cm -1 , 1332cm -1 , 1290cm -1 , 1231cm -1 , 1122cm -1 , 1107cm -1 , 1048cm -1 , 928cm -1 , 910cm -1 , 804cm -1 , 715cm -1 , 663cm -1 , 627cm -1 ;[C 18 H 28 N4O2+H] + HRMS(ESI) calculated value for 333.2285, found value 333.2281.

[0047] Example 9: Preparation of 1-(adamantan-2-yl)-3-[3-(5-methyl-1H-imidazol-1-yl)propyl]urea of ​​Formula Ii This compound was prepared in a manner similar to that described for Example 1. Starting with 2-adamantanamine hydrochloride (282 mg, 1.50 mmol) and triphosgene (223 mg, 0.75 mmol), a concentrated solution of the resulting 2-adamantyl isocyanate in dichloromethane was reacted with 3-(5-methyl-1H-imidazol-1-yl)propan-1-amine (251 mg, 1.80 mmol) to give an orange gummy residue (483 mg). The residue was purified by column chromatography (40 μm to 60 μm silica gel, dichloromethane-methanol mixtures) to give the title compound (285 mg, 60% overall yield) as a beige solid.

[0048] Characterization of II: Melting point 76°C-77°C; IR (ATR) ν: 3320 cm -1 , 2904cm -1 , 2850cm -1 , 1674cm -1 , 1563cm -1 , 1557cm -1 , 1511cm -1 , 1465cm -1 , 1449cm -1 , 1366cm -1 , 1274cm -1 , 1246cm -1 , 1233cm -1 , 1209cm -1 , 1106cm -1 , 1063cm -1 , 931cm -1 , 814cm -1 , 803cm -1 ;[C 18 H 28 NO+H] + HRMS(ESI) calculated value for 317.2336, found value 317.2335.

[0049] Example 10: Preparation of 1-[3-(1H-imidazol-1-yl)propyl]-3-(adamantan-2-yl)urea of ​​formula Ij This compound was prepared in a manner similar to that described for Example 1. Starting with 2-adamantanamine hydrochloride (1.04 g, 5.52 mmol) and triphosgene (820 mg, 2.76 mmol), a concentrated solution of the resulting 2-adamantyl isocyanate in dichloromethane was reacted with 3-(1H-imidazol-1-yl)propan-1-amine (0.75 mL, 6.39 mmol) to give an orange gummy residue (3.11 g). The residue was purified by column chromatography (40 μm–60 μm silica gel, dichloromethane–methanol mixtures), followed by washing with pentane (3 × 3 mL) and drying at 20 Torr for 48 h to give the title compound (1.08 g, 67% overall yield) as a white solid.

[0050] Ij characterization: Melting point 144°C-146°C; IR(ATR) ν: 3395cm -1 , 3264cm -1 , 3101cm -1 , 2903cm -1 , 2885cm -1 , 2850cm -1 , 1662cm -1 , 1554cm -1 , 1517cm -1 , 1500cm -1 , 1470cm -1 , 1450cm -1 , 1440cm -1 , 1390cm -1 , 1361cm -1 , 1346cm -1 , 1321cm -1 , 1295cm -1 , 1278cm -1 , 1256cm -1 , 1235cm -1 , 1106cm -1 , 1096cm -1 , 1078cm -1 , 1064cm -1 , 1042cm -1, 1029cm -1 , 1000cm -1 , 971cm -1 , 963cm -1 , 915cm -1 , 872cm -1 , 839cm -1 , 814cm -1 , 741cm -1 , 670cm -1 , 641cm -1 , 627cm -1 ;[C 17 H 26 NO+H] + HRMS(ESI) calculated for 303.2179, found 303.2179.

[0051] Example 11: Preparation of 1-[(adamantan-1-yl)methyl]-3-[3-(5-methyl-1H-imidazol-1-yl)propyl]urea of ​​formula Ik This compound was prepared in a manner similar to that described for Example 1. Starting with (adamantan-1-yl)methanamine (190 mg, 1.15 mmol) and triphosgene (171 mg, 0.57 mmol), a concentrated solution of the resulting (adamantan-1-yl)methyl isocyanate in dichloromethane was reacted with 3-(5-methyl-1H-imidazol-1-yl)propan-1-amine (192 mg, 1.38 mmol) to give a yellowish residue (387 mg). The residue was purified by column chromatography (40 μm to 60 μm silica gel, dichloromethane-methanol mixture), followed by washing with pentane (3 × 3 mL) and drying at 20 Torr for 48 h to give the title compound (148 mg, 39% overall yield) as a brown viscous oil.

[0052] Characterization of Ik: IR (ATR) ν: 3323 cm -1 , 3113cm -1 , 3043cm -1 , 2898cm -1 , 2845cm -1 , 1639cm -1 , 1563cm -1 , 1503cm-1 , 1448cm -1 , 1394cm -1 , 1364cm -1 , 1346cm -1 , 1310cm -1 , 1281cm -1 , 1264cm -1 , 1233cm -1 , 1187cm -1 , 1152cm -1 , 1107cm -1 , 1065cm -1 , 983cm -1 , 965cm -1 , 925cm -1 , 806cm -1 , 732cm -1 , 664cm -1 ;[C 19 H 30 NO+H] + HRMS(ESI) calculated for 331.2492, found 331.2496.

[0053] Example 12: Preparation of 1-[3-(1H-imidazol-1-yl)propyl]-3-[(adamantan-1-yl)methyl]urea of ​​formula Im This compound was prepared in a manner similar to that described for Example 1. Starting with (adamantan-1-yl)methanamine (178 mg, 1.08 mmol) and triphosgene (160 mg, 0.54 mmol), a concentrated solution of the resulting (adamantan-1-yl)methyl isocyanate in dichloromethane was reacted with 3-(1H-imidazol-1-yl)propan-1-amine (0.15 mL, 1.29 mmol) to give a yellowish solid residue (526 mg). The residue was purified by column chromatography (40 μm to 60 μm silica gel, dichloromethane-methanol mixture), followed by washing with pentane (3 × 3 mL) and drying at 20 Torr for 48 h to give the title compound (110 mg, 32% overall yield) as a pale yellow viscous oil.

[0054] Im characterization: IR (ATR) ν: 3322 cm -1, 3110cm -1 , 2898cm -1 , 2845cm -1 , 1634cm -1 , 1563cm -1 , 1507cm -1 , 1449cm -1 , 1399cm -1 , 1363cm -1 , 1346cm -1 , 1310cm -1 , 1285cm -1 , 1230cm -1 , 1188cm -1 , 1107cm -1 , 1079cm -1 , 1032cm -1 , 988cm -1 , 975cm -1 , 915cm -1 , 812cm -1 , 728cm -1 , 662cm -1 , 622cm -1 ;[C 18 H 28 NO+H] + HRMS(ESI) calculated value for 317.2336, found value 317.2337.

[0055] Example 13: Preparation of 1-[2-(adamantan-1-yl)ethyl]-3-[3-(5-methyl-1H-imidazol-1-yl)propyl]urea of ​​formula Io TIFF2026507708000021.tif33170 Prepared in a manner similar to that described for the compound of Example 1. Starting from 2-(adamantan-1-yl)ethan-1-amine (250 mg, 1.39 mmol) and triphosgene (207 mg, 0.70 mmol), a concentrated solution of the resulting 2-(adamantan-1-yl)ethyl isocyanate in dichloromethane was reacted with 3-(5-methyl-1H-imidazol-1-yl)propan-1-amine (233 mg, 1.67 mmol) to give a yellowish residue (443 mg). The residue was subjected to two successive column chromatographic purifications (40 μm–60 μm silica gel, dichloromethane–methanol mixtures), followed by washing with pentane (3 × 2 mL) and drying at 20 Torr for 48 h to afford the title compound (95 mg, 20% overall yield) as a colorless oil.

[0056] Io characterization: IR (ATR) ν: 3308 cm -1 , 3114cm -1 , 2898cm -1 , 2845cm -1 , 1639cm -1 , 1563cm -1 , 1503cm -1 , 1448cm -1 , 1387cm -1 , 1364cm -1 , 1355cm -1 , 1312cm -1 , 1265cm -1 , 1237cm -1 , 1215cm -1 , 1194cm -1 , 1167cm -1 , 1108cm -1 , 1071cm -1 , 989cm -1 , 967cm -1 , 956cm -1 , 925cm -1 , 809cm -1 , 733cm -1 , 693cm -1 , 664cm -1 ;[C 20 H 32 NO+H]+ HRMS(ESI) calculated for 345.2649, found 345.2649.

[0057] Example 14: Preparation of 1-[2-(adamantan-2-yl)ethyl]-3-[3-(5-methyl-1H-imidazol-1-yl)propyl]urea of ​​formula Ip TIFF2026507708000022.tif50170 Prepared in a manner similar to that described for the compound of Example 1. Starting from 2-(adamantan-2-yl)ethan-1-amine hydrochloride (192 mg, 0.89 mmol) and triphosgene (132 mg, 0.44 mmol), a concentrated solution of the resulting 2-(adamantan-2-yl)ethyl isocyanate in dichloromethane was reacted with 3-(5-methyl-1H-imidazol-1-yl)propan-1-amine (149 mg, 1.07 mmol) to give a brown viscous residue (323 mg). The residue was purified by column chromatography (40 μm–60 μm silica gel, dichloromethane–methanol mixtures), followed by washing with pentane (3 × 3 mL) and drying at 20 Torr for 48 h to afford the title compound (135 mg, 44% overall yield) as a yellowish viscous semisolid.

[0058] Ip characterization: IR (ATR) ν: 3301 cm -1 , 3102cm -1 , 2900cm -1 , 2848cm -1 , 2676cm -1 , 1638cm -1 , 1557cm -1 , 1499cm -1 , 1447cm -1 , 1388cm -1 , 1365cm -1 , 1353cm -1 , 1245cm -1 , 1232cm -1 , 1207cm -1 , 1176cm -1 , 1107cm -1 , 1072cm -1 , 921cm -1 , 806cm -1, 771cm -1 , 731cm -1 , 664cm -1 , 625cm -1 ;[C 20 H 32 NO+H] + HRMS(ESI) calculated for 345.2649, found 345.2652.

[0059] Example 15: Preparation of 1-(2-oxadamantan-1-yl)-3-[3-(5-methyl-1H-imidazol-1-yl)propyl]urea of ​​formula Iq Prepared in a manner similar to that described for the compound in Example 1. Starting with 2-oxadamantan-1-amine hydrochloride (284 mg, 1.50 mmol) and triphosgene (223 mg, 0.75 mmol), a concentrated solution of the resulting 2-oxadamantan-1-yl isocyanate in dichloromethane was reacted with 3-(5-methyl-1H-imidazol-1-yl)propan-1-amine (251 mg, 1.80 mmol) to give a yellowish gummy residue (359 mg). The residue was purified by column chromatography (40 μm to 60 μm silica gel, dichloromethane-methanol mixtures) to give the title compound (167 mg, 35% overall yield) as a beige gum.

[0060] Characterization of Iq: IR(NaCl)ν: 3329cm -1 , 2926cm -1 , 2852cm -1 , 1659cm -1 , 1561cm -1 , 1504cm -1 , 1447cm -1 , 1377cm -1 , 1324cm -1 , 1275cm -1 , 1262cm -1 , 1195cm -1 , 1118cm -1 , 1093cm -1 , 994cm -1 , 965cm -1 , 765cm-1 , 750cm -1 ;[C 17 H 26 N4O2+H] + HRMS(ESI) calculated value for 319.2120, found value 319.2132.

[0061] Example 16: Preparation of 1-[3-(5-methyl-1H-imidazol-1-yl)propyl]-3-(3-methyl-2-oxadamantan-1-yl)urea of ​​formula Ir Prepared in a manner similar to that described for the compound in Example 1. Starting with 3-methyl-2-oxadamantan-1-amine hydrochloride (203 mg, 1.00 mmol) and triphosgene (148 mg, 0.50 mmol), a concentrated solution of the resulting 3-methyl-2-oxadamantan-1-yl isocyanate in dichloromethane was reacted with 3-(5-methyl-1H-imidazol-1-yl)propan-1-amine (139 mg, 1.00 mmol) to give an orange gummy residue (282 mg). The residue was purified by column chromatography (40 μm to 60 μm silica gel, dichloromethane-methanol mixtures) to give the title compound (70 mg, 21% overall yield) as a beige gum.

[0062] Characterization of Ir: IR(NaCl)ν: 3311cm -1 , 3111cm -1 , 3059cm -1 , 2967cm -1 , 2924cm -1 , 2851cm -1 , 1680cm -1 , 1557cm -1 , 1449cm -1 , 1376cm -1 , 1340cm -1 , 1324cm -1 , 1302cm -1 , 1259cm -1 , 1218cm -1 , 1192cm -1 , 1143cm -1 , 1072cm -1, 1035cm -1 , 994cm -1 , 949cm -1 , 920cm -1 , 895cm -1 ;[C 18 H 28 N4O2+H] + HRMS(ESI) calculated value for 333.2285, found value 333.2295.

[0063] Example 17: Preparation of 1-(3-ethyl-2-oxadamantan-1-yl)-3-[3-(5-methyl-1H-imidazol-1-yl)propyl]urea of ​​formula Is This compound was prepared in a manner similar to that described for Example 1. Starting with 3-ethyl-2-oxadamantan-1-amine hydrochloride (79 mg, 0.36 mmol) and triphosgene (54 mg, 0.18 mmol), a concentrated solution of the resulting 3-ethyl-2-oxadamantan-1-yl isocyanate in dichloromethane was reacted with 3-(5-methyl-1H-imidazol-1-yl)propan-1-amine (50 mg, 0.36 mmol) to give an orange gummy residue (124 mg). The residue was purified by column chromatography (40 μm to 60 μm silica gel, dichloromethane-methanol mixtures) to give the title compound (70 mg, 56% overall yield) as a yellowish gum.

[0064] Characterization of Is: IR(NaCl)ν: 3358cm -1 , 3100cm -1 , 2926cm -1 , 2853cm -1 , 1673cm -1 , 1551cm -1 , 1501cm -1 , 1447cm -1 , 1375cm -1 , 1298cm -1 , 1259cm -1 , 1208cm -1 , 1109cm -1 , 1074cm -1 , 1005cm-1 , 969cm -1 , 940cm -1 , 897cm -1 , 805cm -1 ;[C 19 H 30 N4O2+H] + HRMS(ESI) calculated for 347.2442, found 347.2447.

[0065] Example 18: Preparation of 1-(noradamantan-3-yl)-3-[3-(5-methyl-1H-imidazol-1-yl)propyl]urea of ​​formula It This compound was prepared in a manner similar to that described for Example 1. Starting with 3-noradamantanamine hydrochloride (200 mg, 1.15 mmol) and triphosgene (171 mg, 0.58 mmol), a concentrated solution of the resulting 3-noradamantyl isocyanate in dichloromethane was reacted with 3-(5-methyl-1H-imidazol-1-yl)propan-1-amine (192 mg, 1.38 mmol) to give a yellowish residue (303 mg). The residue was purified by column chromatography (40 μm to 60 μm silica gel, dichloromethane-methanol mixture), followed by washing with pentane (3 × 3 mL) and drying at 20 Torr for 48 h to give the title compound (156 mg, 45% overall yield) as a white solid.

[0066] Its characteristics: Melting point 126℃~128℃; IR(ATR) ν: 3368cm -1 , 3314cm -1 , 2955cm -1 , 2931cm -1 , 2906cm -1 , 2865cm -1 , 2839cm -1 , 1629cm -1 , 1562cm -1 , 1529cm -1 , 1500cm -1 , 1445cm -1 , 1365cm -1 , 1348cm -1 , 1329cm-1 , 1308cm -1 , 1295cm -1 , 1282cm -1 , 1262cm -1 , 1245cm -1 , 1226cm -1 , 1205cm -1 , 1191cm -1 , 1143cm -1 , 1136cm -1 , 1118cm -1 , 1106cm -1 , 1092cm -1 , 1056cm -1 , 1000cm -1 , 918cm -1 , 860cm -1 , 844cm -1 , 826cm -1 , 806cm -1 , 795cm -1 , 778cm -1 , 724cm -1 , 697cm -1 , 688cm -1 , 662cm -1 , 647cm -1 ;[C 17 H 26 NO+H] + HRMS(ESI) calculated for 303.2179, found 303.2187.

[0067] Example 19: Preparation of 1-[(noradamantan-3-yl)methyl]-3-[3-(5-methyl-1H-imidazol-1-yl)propyl]urea of ​​formula Iu Prepared in a manner similar to that described for the compound in Example 1. Starting with (noradamantan-3-yl)methanamine hydrochloride (220 mg, 1.17 mmol) and triphosgene (174 mg, 0.59 mmol), a concentrated solution of the resulting (noradamantan-3-yl)methyl isocyanate in dichloromethane was reacted with 3-(5-methyl-1H-imidazol-1-yl)propan-1-amine (196 mg, 1.41 mmol) to give a yellow residue (318 mg). Column chromatography purification of this residue (40 μm to 60 μm silica gel, dichloromethane-methanol mixture), followed by washing with pentane (3 × 3 mL) and drying at 20 Torr for 48 h, afforded the title compound (206 mg, 56% overall yield) as a yellow viscous gum.

[0068] Iu characterization: IR (ATR) ν: 3313 cm -1 , 3109cm -1 , 2918cm -1 , 2860cm -1 , 1635cm -1 , 1557cm -1 , 1500cm -1 , 1445cm -1 , 1388cm -1 , 1364cm -1 , 1331cm -1 , 1309cm -1 , 1232cm -1 , 1124cm -1 , 1108cm -1 , 1077cm -1 , 995cm -1 , 921cm -1 , 863cm -1 , 806cm -1 , 773cm -1 , 730cm -1 , 664cm -1 ;[C 18 H 28 NO+H] + HRMS(ESI) calculated for 317.2336, found 317.2339.

[0069] Example 20: 1-[3-(5-methyl-1H-imidazol-1-yl)propyl]-3-(3,4,8,9-tetramethyltetracyclo[4.4.0.0] of Formula Iv 3,9 .0 4,8 Preparation of ]decan-1-yl)urea TIFF2026507708000028.tif39170 Prepared in a manner similar to that described for the compound of Example 1. 3,4,8,9-Tetramethyltetracyclo[4.4.0.0 3,9 .0 4,8 ] Starting from decan-1-amine hydrochloride (119 mg, 0.58 mmol) and triphosgene (86 mg, 0.29 mmol), 3,4,8,9-tetramethyltetracyclo[4.4.0.0 3,9 .0 4,8 A concentrated solution of decan-1-yl isocyanate in dichloromethane was reacted with 3-(5-methyl-1H-imidazol-1-yl)propan-1-amine (97 mg, 0.70 mmol) to give a yellowish residue (167 mg). The residue was purified by column chromatography (40 μm–60 μm silica gel, dichloromethane–methanol mixture), followed by washing with pentane (3 × 1 mL) and drying at 20 Torr for 48 h to give the title compound (87 mg, 41% overall yield) as a white solid.

[0070] Iu characterization: Melting point 130°C-133°C; IR(ATR) ν: 3279cm -1 , 3121cm -1 , 2972cm -1 , 2944cm -1 , 2908cm -1 , 2864cm -1 , 1675cm -1 , 1556cm -1 , 1505cm -1 , 1478cm -1 , 1454cm -1 , 1439cm -1 , 1384cm -1 , 1368cm -1 , 1335cm -1 , 1315cm -1 , 1290cm -1, 1262cm -1 , 1243cm -1 , 1234cm -1 , 1208cm -1 , 1108cm -1 , 1062cm -1 , 1033cm -1 , 933cm -1 , 847cm -1 , 803cm -1 , 793cm -1 , 766cm -1 , 728cm -1 , 697cm -1 , 666cm -1 , 631cm -1 ;[C 22 H 34 NO+H] + HRMS(ESI) calculated value for 371.2805, found value 371.2815.

[0071] Example 21: 1-[3-(5-methyl-1H-imidazol-1-yl)propyl]-3-[(3,4,8,9-tetramethyltetracyclo[4.4.0.0] of formula Iw 3,9 .0 4,8 Preparation of ]decan-1-yl)methyl]urea TIFF2026507708000029.tif33170 Prepared in a manner similar to that described for the compound of Example 1. (3,4,8,9-tetramethyltetracyclo[4.4.0.0 3,9 .0 4,8 Starting from ]decan-1-yl)methanamine hydrochloride (42 mg, 0.16 mmol) and triphosgene (24 mg, 0.08 mmol), the obtained (3,4,8,9-tetramethyltetracyclo[4.4.0.0 3,9 .0 4,8A concentrated solution of 5-(decane-1-yl)methyl isocyanate in dichloromethane was reacted with 3-(5-methyl-1H-imidazol-1-yl)propan-1-amine (27 mg, 0.20 mmol) to give a pale orange residue (79 mg). The residue was purified by column chromatography (40 μm–60 μm silica gel, dichloromethane–methanol mixture), followed by washing with pentane (3 × 0.5 mL) and drying at 20 Torr for 48 h to give the title compound (10 mg, 16% overall yield) as a yellowish semisolid.

[0072] Characterization of Iw: IR(NaCl)ν: 3302cm -1 , 3111cm -1 , 3045cm -1 , 2944cm -1 , 2863cm -1 , 1723cm -1 , 1647cm -1 , 1567cm -1 , 1503cm -1 , 1453cm -1 , 1385cm -1 , 1371cm -1 , 1340cm -1 , 1262cm -1 , 1109cm -1 , 1076cm -1 , 1038cm -1 , 927cm -1 , 807cm -1 , 775cm -1 , 732cm -1 , 700cm -1 , 665cm -1 , 637cm -1 ;[C 23 H 36 NO+H] + HRMS(ESI) calculated for 385.2962, found 385.2962.

[0073] Example 22: Preparation of 1-[1-(adamantan-1-yl)ethyl]-3-[3-(5-methyl-1H-imidazol-1-yl)propyl]urea of ​​Formula Ix Prepared in a manner similar to that described for the compound in Example 1. Starting with 1-(adamantan-1-yl)ethan-1-amine hydrochloride (247 mg, 1.14 mmol) and triphosgene (170 mg, 0.57 mmol), a concentrated solution of the resulting 1-(adamantan-1-yl)ethyl isocyanate in dichloromethane was reacted with 3-(5-methyl-1H-imidazol-1-yl)propan-1-amine (191 mg, 1.37 mmol) to give a yellow residue (356 mg). Column chromatography purification of this residue (40 μm to 60 μm silica gel, dichloromethane-methanol mixture), followed by washing with pentane (3 × 1 mL) and drying at 20 Torr for 48 h, afforded the title compound (93 mg, 24% overall yield) as a yellow semisolid.

[0074] Characterization of Ix: IR(ATR)ν: 3321cm -1 , 3109cm -1 , 2971cm -1 , 2899cm -1 , 2846cm -1 , 2690cm -1 , 1632cm -1 , 1556cm -1 , 1501cm -1 , 1446cm -1 , 1378cm -1 , 1362cm -1 , 1350cm -1 , 1319cm -1 , 1291cm -1 , 1259cm -1 , 1233cm -1 , 1194cm -1 , 1153cm -1 , 1108cm -1 , 1091cm -1 , 1079cm -1 , 1052cm -1 , 1023cm -1 , 969cm -1 , 923cm -1 , 875cm -1 , 806cm -1 , 771cm -1, 755cm -1 , 664cm -1 , 620cm -1 ;[C 20 H 32 NO+H] + HRMS(ESI) calculated for 345.2649, found 345.2654.

[0075] Example 23: Preparation of 1-(adamantan-2-yl)-1-methyl-3-[3-(5-methyl-1H-imidazol-1-yl)propyl]urea of ​​formula Iy To a stirred solution of N-methyladamantan-2-amine (102 mg, 0.62 mmol) and 1-(3-azidopropyl)-5-methyl-1H-imidazole (112 mg, 0.68 mmol) in toluene (10 mL) was added triphenylphosphine (194 mg, 0.74 mmol). The solution was degassed and a stream of carbon dioxide obtained from dry ice at room temperature was bubbled through it, first at room temperature and then at 80° C. for 5.5 hours. The resulting mixture was evaporated under reduced pressure to give the crude product (395 mg) as a pale orange semisolid. Column chromatography purification of this crude product (40 μm-60 μm silica gel, dichloromethane-methanol mixture), followed by washing with pentane (3×2 mL) and drying at 20 Torr for 48 h, afforded the title compound (112 mg, 55% yield) as a white solid.

[0076] Characterization of Iy: Melting point 103°C to 105°C; IR (ATR) ν: 3302 cm -1 , 3109cm -1 , 3048cm -1 , 2904cm -1 , 2850cm -1 , 2675cm -1 , 1621cm -1 , 1526cm -1 , 1501cm -1 , 1470cm -1 , 1449cm -1 , 1360cm -1 , 1350cm -1 , 1334cm -1, 1305cm -1 , 1287cm -1 , 1266cm -1 , 1232cm -1 , 1198cm -1 , 1169cm -1 , 1108cm -1 , 1098cm -1 , 1060cm -1 , 1047cm -1 , 999cm -1 , 967cm -1 , 947cm -1 , 923cm -1 , 881cm -1 , 807cm -1 , 774cm -1 , 731cm -1 , 700cm -1 , 665cm -1 , 628cm -1 ;[C 19 H 30 NO+H] + HRMS(ESI) calculated for 331.2492, found 331.2496.

[0077] Example 24: Preparation of (±)-1-(1-chloroadamantan-2-yl)-3-[3-(5-methyl-1H-imidazol-1-yl)propyl]urea of ​​Formula Iz This compound was prepared in a manner similar to that described for Example 1. Starting with 1-chloroadamantan-2-amine (133 mg, 0.72 mmol) and triphosgene (106 mg, 0.36 mmol), a concentrated dichloromethane solution of the resulting 1-chloroadamantan-2-yl isocyanate was reacted with 3-(5-methyl-1H-imidazol-1-yl)propan-1-amine (120 mg, 0.86 mmol) to give a dark yellow residue (183 mg). Column chromatography purification of this residue (40 μm to 60 μm silica gel, dichloromethane-methanol mixture), followed by washing with pentane (3 × 1 mL) and drying at 20 Torr for 48 h, afforded the title compound (59 mg, 24% overall yield) as a pale yellow viscous oil.

[0078] Characterization of Iz: IR (ATR) ν: 3301 cm -1 , 3116cm -1 , 3053cm -1 , 2912cm -1 , 2856cm -1 , 1642cm -1 , 1557cm -1 , 1504cm -1 , 1474cm -1 , 1451cm -1 , 1390cm -1 , 1361cm -1 , 1338cm -1 , 1313cm -1 , 1291cm -1 , 1257cm -1 , 1243cm -1 , 1215cm -1 , 1161cm -1 , 1106cm -1 , 1077cm -1 , 1066cm -1 , 1028cm -1 , 980cm -1 , 948cm -1 , 930cm -1 , 843cm -1 , 827cm -1 , 813cm -1 , 774cm -1 , 726cm -1 , 664cm -1 , 631cm -1 ;[C 18 H 27 ClNO+H] + HRMS(ESI) calculated for 351.1946, found 351.1929.

[0079] Example 25: Preparation of (±)-1-(1-fluoroadamantan-2-yl)-3-[3-(5-methyl-1H-imidazol-1-yl)propyl]urea of ​​Formula Iaa This compound was prepared in a manner similar to that described for Example 1. Starting with 1-fluoroadamantan-2-amine (197 mg, 1.16 mmol) and triphosgene (173 mg, 0.58 mmol), a concentrated solution of the resulting 1-fluoroadamantan-2-yl isocyanate in dichloromethane was reacted with 3-(5-methyl-1H-imidazol-1-yl)propan-1-amine (194 mg, 1.40 mmol) to give a yellow residue (332 mg). Column chromatography purification of this residue (40 μm to 60 μm silica gel, dichloromethane-methanol mixture), followed by washing with pentane (3 × 3 mL) and drying at 20 Torr for 48 hours, gave the title compound (120 mg, 31% overall yield) as a yellow viscous oil.

[0080] Characterization of Iaa: IR (ATR) ν: 3321 cm -1 , 3114cm -1 , 2914cm -1 , 2861cm -1 , 1640cm -1 , 1556cm -1 , 1503cm -1 , 1476cm -1 , 1451cm -1 , 1391cm -1 , 1366cm -1 , 1343cm -1 , 1317cm -1 , 1297cm -1 , 1261cm -1 , 1239cm -1 , 1225cm -1 , 1148cm -1 , 1107cm -1 , 1077cm -1 , 1060cm -1 , 982cm -1 , 960cm -1 , 931cm -1 , 912cm -1 , 883cm -1 , 829cm -1 , 814cm -1 , 781cm -1 , 732cm-1 , 699cm -1 , 664cm -1 , 630cm -1 ;[C 18 H 27 FN4O+H] + HRMS(ESI) calculated for 335.2242, found 335.2235.

[0081] Example 26: Preparation of trans-1-(5-chloroadamantan-2-yl)-3-[3-(5-methyl-1H-imidazol-1-yl)propyl]urea of ​​Formula Iab This compound was prepared in a manner similar to that described for Example 1. Starting with 5-chloroadamantan-2-amine (189 mg, 1.02 mmol) and triphosgene (151 mg, 0.51 mmol), a concentrated solution of the resulting trans-5-chloroadamantan-2-yl isocyanate in dichloromethane was reacted with 3-(5-methyl-1H-imidazol-1-yl)propan-1-amine (170 mg, 1.22 mmol) to give a yellow residue (278 mg). Column chromatography purification of this residue (40 μm to 60 μm silica gel, dichloromethane-methanol mixture), followed by washing with pentane (3 × 3 mL) and drying at 20 Torr for 48 hours, gave the title compound (100 mg, 28% overall yield) as a pale yellow solid.

[0082] Characterization of Iab: Melting point 120°C-122°C; IR(ATR) ν: 3289cm -1 , 3104cm -1 , 2915cm -1 , 2865cm -1 , 1655cm -1 , 1567cm -1 , 1527cm -1 , 1502cm -1 , 1475cm -1 , 1458cm -1 , 1443cm -1 , 1428cm -1 , 1366cm -1 , 1345cm -1, 1331cm -1 , 1317cm -1 , 1291cm -1 , 1268cm -1 , 1246cm -1 , 1206cm -1 , 1197cm -1 , 1145cm -1 , 1107cm -1 , 1092cm -1 , 1069cm -1 , 1057cm -1 , 1039cm -1 , 1023cm -1 , 988cm -1 , 961cm -1 , 946cm -1 , 920cm -1 , 886cm -1 , 872cm -1 , 822cm -1 , 800cm -1 , 686cm -1 , 666cm -1 ;[C 18 H 27 ClNO+H] + HRMS(ESI) calculated for 351.1946, found 351.1942.

[0083] Example 27 Preparation of trans-1-(5-fluoroadamantan-2-yl)-3-[3-(5-methyl-1H-imidazol-1-yl)propyl]urea of ​​Formula Iac This compound was prepared in a manner similar to that described for Example 1. Starting with 5-fluoroadamantan-2-amine (137 mg, 0.81 mmol) and triphosgene (120 mg, 0.41 mmol), a concentrated solution of the resulting trans-5-fluoroadamantan-2-yl isocyanate in dichloromethane was reacted with 3-(5-methyl-1H-imidazol-1-yl)propan-1-amine (135 mg, 0.97 mmol) to give a dark yellow residue (206 mg). Column chromatography purification of this residue (40 μm to 60 μm silica gel, dichloromethane-methanol mixture), followed by washing with pentane (3 × 1 mL) and drying at 20 Torr for 48 h, afforded the title compound (20 mg, 7% overall yield) as a white solid.

[0084] Iac characterization: Melting point 198°C-200°C; IR(ATR) ν: 3322cm -1 , 3303cm -1 , 3114cm -1 , 3053cm -1 , 3028cm -1 , 2966cm -1 , 2916cm -1 , 2861cm -1 , 2813cm -1 , 2716cm -1 , 2670cm -1 , 2600cm -1 , 1830cm -1 , 1769cm -1 , 1658cm -1 , 1618cm -1 , 1554cm -1 , 1482cm -1 , 1460cm -1 , 1446cm -1 , 1432cm -1 , 1400cm -1 , 1378cm -1 , 1350cm -1 , 1334cm -1 , 1314cm -1 , 1295cm -1 , 1267cm -1 , 1245cm-1 , 1193cm -1 , 1184cm -1 , 1132cm -1 , 1110cm -1 , 1074cm -1 , 1039cm -1 , 1011cm -1 , 990cm -1 , 969cm -1 , 951cm -1 , 930cm -1 , 910cm -1 , 857cm -1 , 829cm -1 , 786cm -1 , 732cm -1 , 647cm -1 , 632cm -1 , 623cm -1 ;[C 18 H 27 FN4O+H] + HRMS(ESI) calculated for 335.2242, found 335.2253.

[0085] Example 28: In vitro measurement of sEH inhibitory activity The following fluorescent assay was performed to measure sEH inhibitory activity (IC) using the substrate and control compound (TPPU) shown below. 50 ) was used for the measurement.

[0086] Substrate: cyano(6-methoxynaphthalen-2-yl)methyl 2-(3-phenyloxiran-2-yl)acetate (PHOME; Cayman Chemical Company, product number 10009134; CAS1028430-42-3); see NM Wolf et al., Analitical Biochemistry 2006, vol. 355, pp. 71-80.

[0087] Control compound (TPPU): N-[1-(1-oxopropyl)-4-piperidinyl]-N'-[4-(trifluoromethoxy)phenyl]urea.

[0088] solution: Assay buffer: 25 mM Bis / Tris HCl, pH 7.0, containing 0.1 mg / mL bovine serum albumin (BSA). 200 μM PHOME in DMSO. A solution of recombinant human sEH (hsEH) (Cayman Chemical Co., product number 10011669) diluted in assay buffer. Inhibitors dissolved in DMSO at appropriate concentrations.

[0089] Protocol: In a black 96-well plate (Greiner Bio-One, product number 655900), background wells were filled with 90 μL of assay buffer, and positive control and inhibitor wells with 85 μL of assay buffer. 5 μL of DMSO was added to the background and positive control wells, followed by 5 μL of inhibitor solution in the inhibitor wells. 5 μL of hsEH solution was added to the positive control and inhibitor wells, and the mixture was vortexed. A 1 / 21 dilution of PHOME solution was prepared in assay buffer according to the required final volume, followed by 105 μL of each well. The plate was carefully shaken for 10 seconds and incubated at room temperature for 5 minutes. Fluorescence appearance was measured (FLUOStar OPTIMA microplate reader, BMG) at an excitation wavelength of 337 nm and an emission wavelength of 460 nm. Fluorescence intensity was used to calculate the IC. 50 The values ​​were analyzed and calculated. Results were obtained by regression analysis from at least three data points within the linear region of the curve. IC 50 Values ​​are the average of at least three independent replicates. Table 1 shows the human hsEH inhibitory activity (IC) of several compounds of Formula I and the control compound TPPU. 50 (expressed as

[0090] [Table 1]

[0091] Example 29: In vitro measurement of human QC inhibitory activity Compounds were evaluated for their ability to inhibit human recombinant glutaminyl cyclase (hQC) using the SensoLyte™ Green Glutaminyl Cyclase Activity Assay Kit Fluorimetric (Eurogentec, AS-72230) according to the manufacturer's instructions. Compounds were tested at seven concentrations, with each condition evaluated in triplicate.

[0092] Inhibitors to be tested were dissolved in DMSO as 250 mM stock solutions and stored at -20 °C until further use. For the assay, compounds were diluted to the desired concentrations, ranging from 100 μM to 0.1 nM, in the provided assay buffer, such that the final DMSO concentration in all wells was 0.6%. The enzyme solution was prepared immediately before use by diluting 10 μL of recombinant enzyme (component C) into 3.99 mL of assay buffer (component E) and stored on ice. The substrate solution was prepared by diluting 50 μL of glutaminyl cyclase substrate (0.5 mM, component A) into 4.95 mL of assay buffer (component E). The developer solution was prepared by diluting 50 μL of glutaminyl cyclase developer (component D) and 50 μL of 1-benzylimidazole (component F) into 4.9 mL of assay buffer (component E) and kept on ice until use.

[0093] Briefly, 10 μL of inhibitor solution was placed in a well of a black 96-well plate and combined with 40 μL of diluted enzyme solution. 50 μL of glutaminyl cyclase substrate solution was added to initiate the reaction. After 30 minutes of incubation at 37°C, 50 μL of developer solution was added and mixed. After a further 30 minutes of incubation at 37°C, the signal in EX485 / EM535 was measured using a Cytation 5 multimode reader. A solvent control (0.6% DMSO without inhibitor), a substrate control (assay buffer only, no enzyme solution), and an inhibitor control (1 mM 1-benzylimidazole) were included on each plate. The % activity of the solvent controls was calculated and the IC value was calculated using GraphPad Prism 9. 50 was used to evaluate (log(inhibitor) vs. response - variable slope (4 parameters)).

[0094] Basic statistical analysis was performed. Table 2 shows the hQC inhibitory activity of several compounds of formula I and the control compound 1-[3-(1H-imidazol-1-yl)propyl]-3-(3,4-dimethoxyphenyl)thiourea (PBD-150).

[0095] [Table 2]

[0096] Example 30: Effect of compounds of formula I on cytokine release in LPS-stimulated BV2 cells Compounds of formula I were diluted from a 250 mM DMSO stock solution to a 10 mM stock in DMSO. Compounds were then diluted to 10 μM and 1 μM in culture medium so that the final DMSO concentration in the wells was 0.1% for all conditions. Stock solutions were stored at -20°C until further use.

[0097] BV-2 Cell Culture and Treatment: The mouse microglial cell line BV-2 was cultured in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal calf serum (FCS), 1% penicillin / streptomycin, and 2 mM L-glutamine (culture medium). For lipopolysaccharide (LPS) stimulation assays, 20,000 BV-2 cells were plated per well (uncoated 96-well plates). After 48 hours, the medium was changed to treatment medium (DMEM, 5% FCS, 2 mM L-glutamine), and cells were maintained in treatment medium for the remainder of the culture period. After cells were changed to treatment medium, compounds were administered 1 hour before LPS stimulation (Sigma-Aldrich; L6529; 1 mg / mL stock in ddH2O, final concentration in well: 100 ng / mL (diluted in medium)). Vehicle- and LPS-only-treated cells served as controls. All wells were treated in the same manner. 24 hours after stimulation, cell supernatants were collected for cytokine measurements. Experiments were performed with n=6 technical replicates for all groups.

[0098] Cytokine measurement: Samples were diluted 1:2 and analyzed for four cytokines (IL-1β, IL-2, IL-6, and TNF-α) using a commercially available immunosorbent assay kit (U-plex, K15069L, Mesoscale Discovery) according to the manufacturer's instructions. Briefly, 25 μL of diluent 41 and 25 μL of sample or respective standard were added to wells of a precoated U-plex plate and incubated for 1 h at room temperature on an orbital shaker. The plate was washed three times with phosphate-buffered saline containing 0.05% Tween 20 (PBST), after which 50 μL of detection antibody was added. The plate was again incubated for 1 h at room temperature on an orbital shaker. After three additional washing steps with PBST, 150 μL of Mesoscale Discovery (MSD) GOLD Read Buffer was added, and the plate was read on a Sector imager. Data were evaluated by comparing with the calibration curve provided with the kit.

[0099] Statistics: Basic statistical analysis was performed. Group differences were assessed, when appropriate, by, for example, one-way analysis of variance followed by post-hoc tests.

[0100] Table 3 shows the effect of compounds of formula I at concentrations of 1 μM and 10 μM on the levels of pro-inflammatory cytokines (TNF-α, IL-6, IL-2 and IL-1β) in LPS-stimulated BV2 cells, expressed as a percentage of the solvent control, using TPPU and dexamethasone as controls.

[0101] [Table 3]

[0102] Example 31: Effect of compounds of formula I on the viability of mouse primary neurons Compounds were diluted from 250 mM DMSO stocks to 100 mM stocks in DMSO. Compounds were then diluted in culture medium to 100 μM, 20 μM, 5 μM, 1 μM, 0.2 μM, 0.05 μM, 0.01 μM, and 0.001 μM dilutions, such that the final DMSO concentration in the wells was 0.1% for all conditions. Stock solutions were stored at -20°C until further use.

[0103] Isolation and processing of primary mouse cortical neurons: Primary cortical neurons were prepared from wild-type C57BL / 6JRccHsd mice between days 16.5 and 18 of gestation. Animals were euthanized with carbon dioxide, and embryos were dissected in calcium- and magnesium-free Hank's balanced salt solution (CMF-HBSS) containing 15 mM HEPES and 10 mM NaHCO3 at pH 7.2. Embryos were decapitated, the skin and skull were gently removed, and the cortical hemispheres were isolated. After removing the meninges and brainstem, the cortices were isolated and minced with a sterile razor blade in Chop solution (calcium-free Hibernate-E containing 2% B-27) and digested in 2 mg / mL papain (Worthington) dissolved in calcium-free Hibernate-E for 30 min at 30°C. Cortices were triturated 10 to 15 times with a flame-polished, silanized Pasteur pipette in calcium-free Hibernate-E containing 2% B-27, 0.01% DNase I, 1 mg / mL BSA, and 1 mg / mL ovomucoid inhibitor. Undispersed fragments were allowed to settle by gravity for 1 minute, and the supernatant was centrifuged at 228 g for 3 minutes. The pellet was resuspended in Hibernate-E containing 2% B-27, 0.01% DNase I, 1 mg / mL BSA, and 1 mg / mL ovomucoid inhibitor, and then diluted with Hibernate-E containing 2% B-27. After a second centrifugation step (228 g for 3 minutes), the pellet was resuspended in glutamate-free nutrient medium (Neurobasal, 2% B-27, 0.5 mM glutamine, 1% penicillin-streptomycin). Cells were counted using a hemocytometer and plated in nutrient medium on poly-D-lysine pre-coated plates. Cells were cultured at 37°C, 95% humidity, and 5% CO2. All wells were treated in the same manner. On DIV8, cells were treated with compounds for evaluation of neurotoxic effects. On DIV9, MTT and LDH assays were performed as described below. Experiments were performed with six technical replicates for every group per experiment.

[0104] MTT viability assay: The viability of the cultures was measured by MTT assay using a plate reader (570 nm) on DIV9. MTT solution was added to each well at a final concentration of 0.5 mg / mL. After 2 hours, the MTT-containing medium was aspirated. Cells were dissolved in 3% SDS, and formazan crystals were dissolved in isopropanol / HCl. Optical density was measured at a wavelength of 570 nm on a plate reader. Cell viability was expressed as optical density (OD). Values ​​were calculated as a percentage of the control value (solvent control).

[0105] LDH toxicity assay: Cell supernatants were subjected to lactate dehydrogenase (LDH) toxicity assays using a Cytotoxicity Detection Kit (Roche Diagnostics, catalog number: 11644793001). 70 μL of cell culture supernatant was transferred to a clear 96-well plate. 70 μL of freshly prepared reaction mixture was added to each well, and the mixture was incubated at room temperature for 20–30 minutes protected from light. Absorbance was measured at reference wavelengths of 492 nm and 620 nm. Cell death was expressed as optical density (OD). Values ​​were calculated as a percentage of the control value (solvent control).

[0106] Table 4 shows the survival of primary cortical neurons after treatment with different concentrations of compounds of formula I, expressed as % of the solvent control, as assessed by both the MTT and LDH assays.

[0107] [Table 4]

[0108] Example 32: Parallel artificial membrane permeability assay - blood-brain barrier The brain permeability of the compound of formula I was evaluated using a parallel artificial membrane permeability assay for the blood-brain barrier (PAMPA-BBB) according to the method described by L. Di et al., "High throughput artificial membrane permeability assay for blood-brain barrier," European Journal of Medicinal Chemistry, 2003, vol. 38, pp. 223-232. The in vitro permeability (Pe) of the test compound through a lipid extract of porcine brain membrane was measured. The assay compounds were tested using a mixture of PBS:EtOH (70:30). Validation of the assay was performed by comparing the experimental and reported permeability values ​​of a set of 14 commercially available drugs, and a linear correlation was obtained between the experimental and reported permeability values ​​of the 14 commercially available drugs (y=1.678x-1.447; R 2 = 0.9313). From this equation, and taking into account the limits established by Di et al. for BBB permeability, the permeability range was established as follows: High BBB permeability compounds (CNS+): Pe(10 -6 cm s -1 )>5.26; Compound with low BBB permeability (CNS-): Pe(10 -6 cm s -1 )<1.91; Compounds of uncertain BBB permeability (CNS+ / -): 5.26>Pe(10 -6 cm s -1 ) > 1.91. Permeability results are the average of three replicates from three different experiments and also show the predicted permeability in the CNS (Table 5).

[0109] [Table 5]

Claims

1. A compound of formula I, a stereoisomer thereof or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt of any of these, During the ceremony, R １ and R ２ are each independently one radical selected from the group consisting of H and (C1-C3)-alkyl, X is a group of the formula -[CH ２ ] ｎ - is a biradical selected from the group consisting of biradicals of linear methylene chains and biradicals derived from branched saturated (C2-C4)-alkylene chains, A is either a C-radical derived from a non-aromatic polycyclic 6- to 15-membered carbocyclic ring system or a C-radical derived from a non-aromatic polycyclic 6- to 15-membered heterocyclic ring system having one or two heteroatoms in the ring, the heteroatoms being independently selected from O, S and N, the C-radical being unsubstituted or the C-radical having one or more H atoms substituted by one or more substituents attached to any of the possible substitution positions, the substituents being independently selected from the group consisting of (C1-C4)-alkyl, O[(C1-C4)-alkyl], OH, F, Cl, Br and I, provided that radical A does not have any of the following three unsubstituted formulae or any of the possible substituted formulae derived therefrom: provided that compound I does not have the following formula Ib: A compound of Formula I, a stereoisomer thereof or a mixture of stereoisomers thereof, or a pharmaceutically acceptable salt of any of these.

2. 10. The compound of claim 1, wherein A has a formula that is one of the following unsubstituted formulas, or a variation of the following formula, wherein A is attached to any of the possible substitution positions and one or more of the H atoms is replaced by one or more substituents independently selected from the group consisting of (C1-C4)-alkyl, O[(C1-C4)-alkyl], OH, F, Cl, Br, and I.

3. A has one of the above unsubstituted formulas, or A is attached to any of the possible substitution positions and is CH ３ , C.H. ２ CH ３ 3. The compound of claim 2, having a formula that is a variation of the above formula, wherein one or more of the H atoms are replaced by one or more substituents independently selected from the group consisting of: OH, F, and Cl.

4. The biradical X is a group of the formula -[CH ２ ] ｎ -, a straight methylene chain biradical, and the biradical -CH(CH ３ 4. The compound according to claim 1, wherein the compound is selected from the group consisting of:

5. The biradical X is a group of the formula -[CH ２ ] ｎ 5. The compound of claim 4, wherein the biradical is a straight methylene chain biradical of the formula:

6. 6. The compound of claim 5, wherein n=0 and the biradical X is a single bond.

7. R １ is H or CH ３ The compound according to any one of claims 1 to 6,

8. R １ The compound of claim 7 , wherein is H.

9. R ２ is H or CH ３ The compound according to any one of claims 1 to 8, wherein

10. R ２ is CH ３ 10. The compound of claim 9, wherein:

11. 2. The compound of claim 1 having a formula independently selected from the group consisting of: Ia, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Im, Io, Ip, Iq, Ir, Is, It, Iu, Iv, Iw, Ix, Iy, Iz, Iaa, Iab, and Iac.

12. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 11 together with a sufficient amount of a pharmaceutically acceptable excipient or carrier.

13. A compound according to any one of claims 1 to 11 for use as an active pharmaceutical ingredient.

14. A compound according to any one of claims 1 to 11, or defined by formula Ib below, for use in the prevention or treatment of Alzheimer's disease in animals, including humans. 【Transformation 6】

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