Leukotriene synthesis inhibitors

Abstract

To provide specific leukotriene synthesis inhibitors, pharmaceutical compositions comprising the compounds, and methods of using the compounds and the pharmaceutical compositions in treating, for example, inflammatory diseases or conditions.SOLUTION: A compound of formula (1), or a pharmaceutically acceptable enantiomer, diastereomer, salt, or solvate thereof, is provided.SELECTED DRAWING: Figure 4A

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application is a continuation of U.S. Provisional Patent Application No. 62 / 791,641, filed January 11, 2019. The benefit of this application is claimed under the Patent Act, and this application is hereby incorporated by reference in its entirety for all purposes. The specification is incorporated by reference.

[0002] The present disclosure relates to certain leukotriene synthesis inhibitor compounds and pharmaceutical compositions containing the compounds. and the use of said compounds and said pharmaceutical compositions, for example in the treatment of inflammatory diseases or conditions. It covers the way something is used. [Background technology]

[0003] 5-Lipoxygenase (5-LO) is a leukotriene that mediates inflammation and disease. 5-Lipoxygenase-activating protein (FLAP) is an important enzyme in the production of riene. ), 5-LO oxidizes the substrate arachidonic acid to HPETE. E is a transient intermediate that degrades to the biologically active molecule leukotriene C4 (LTC4 ) and leukotriene A4 (L), the direct precursor of leukotriene B4 (LTB4). Leukotriene A4 is converted to LTB4 by LTA4 hydrolase. or conjugates with reduced glutathione by LTC4 synthase to form LTC4 LTC4 is converted to leukotriene D4 (LTD4) and It is converted to leukotriene E4 (LTE4) by selective amino acid hydrolysis. Leukotriene C4, leukotriene D4, and leukotriene E4 are cysteinyl leukotrienes. Leukotrienes are produced primarily by white blood cells, but LTB4 is produced, for example, by neutrophils, macrophages, and mast cells. LTC4 is expressed, for example, by macrophages, eosinophils, basophils, and mast cells. Transcellular synthesis can also occur. For example, LTA produced in neutrophils 4 was delivered to endothelial cells that lacked 5-lipoxygenase but expressed LTC4 synthase. In this case, endothelial cells may metabolize LTA4 to LTC4. The amount of LTB4 and cysteinyl leukotrienes produced by the cells was determined by the terminal enzyme L It depends on TA4 hydrolase and LTC4 synthase, respectively. Another influential factor is the subcellular localization of 5-lipoxygenase.

[0004] Leukotrienes act by specific G protein-coupled receptors present on the extracellular membrane of inflammatory cells. They act by binding to receptors, which activate signaling pathways within the cell. This leads to a range of biological responses present, for example, in inflammatory diseases and conditions. Lien is involved in the disease by, among other things, recruiting leukocytes, increasing mucus release, and increasing vascular permeability. , and play a wide range of functional roles such as increasing proliferation.

[0005] They either inhibit the synthesis of leukotrienes or block the receptors on which they function. Many strategies have been attempted to develop compounds that block LTB4 and Important drugs for disease indications involving leukotrienes and / or cysteinyl leukotrienes 5-LO inhibitors in development can be grouped according to their mechanism of inhibition: oxidation Reductive inhibitors reduce the active site iron of the enzyme to the inactive ferrous form. Generally, redox inhibitors interfere with multiple biological redox systems and cause side effects. Another group of inhibitors are the iron ligand chelators. These compounds inhibit the 5-LO enzyme. It binds to the catalytic iron in the enzyme, thereby blocking the conversion of arachidonic acid to its products. Examples of compounds in this group include hydroxamic acids and N-hydroxybenzoates. Urea derivatives are an example. Iron chelators are not considered treatment options due to potential side effects. Non-redox-competitive inhibitors are related to the class of redox and iron chelators. It specifically inhibits the 5-LO enzyme without the potential for side effects that can be associated with asthma. Zileuton, a compound used in the study, inhibits endogenous leukotriene production by an estimated 26-86%. However, liver enzyme levels must be monitored and multiple doses must be administered daily. Therefore, its clinical use is limited. FLAP was first discovered as a target of MK886. Since then, a number of compounds targeting FLAP have been developed to treat respiratory and cardiovascular diseases. Although several compounds have been introduced into clinical trials, none of them have been marketed (Non-Patent Document 1).

[0006] Furthermore, in diseases in which LTB4 is primarily involved, leukotriene A4 hydrolase (LTA Targeted inhibition of LTB4 by blocking 4H was an attractive drug target. Leukotriene A4 hydrolase (LTA4H) is important in the synthesis of leukotriene B4 This enzyme is a bifunctional enzyme that is traditionally involved in the production of LTB4 from LTA4. This enzyme is also known as carboxylase hydrolase activity during the breakdown of collagen. It has aminopeptidase activity involved in the decomposition of tripeptides formed in the nucleosomes, and acts on neutrophils. LTA4H also has chemotactic properties (Non-Patent Documents 2 and 3). Its hydrolase activity for the synthesis of oxidative LTB4 production has been recognized, but the Aminopeptidase activity may also serve as a compensatory mechanism to resolve inflammation. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] D. Petterson et al., Bioorg. Med. Chemm Lett. (2015), v25(13) pp. 2607-2612 [Non-Patent Document 2] A. Gaggar et al., J. Immunol (2008) v. 180(3) pp. 5662-5669 [Non-Patent Document 3] P. O'Reilly et al., J. Neuroimmunol (2009) v. 217(1-2) pp. 51-54; R. Snelgrove, Thorax (2011) v. 66(6) pp.550-551 Summary of the Invention [Problem to be solved by the invention]

[0008] Therefore, therapies aimed at inhibiting LTB4 production by inhibiting LTA4H are However, the aminopeptidase activity of the enzyme must also be maintained, which is essential in the treatment of inflammatory diseases. For example, leukotriene inhibition for the treatment of inflammatory diseases or conditions. The drug is still needed.

[0009] Not all subject matter described in the "Background" section is necessarily prior art. should be considered prior art solely by virtue of its inclusion in the "Background Art" section. In this regard, the disclosures in the "Background Art" section or related to such subject matter are not intended to be limiting. Recognition of a problem in relevant prior art is not considered to be prior art unless it is expressly stated to be prior art. and should not be treated as prior art. Instead, they should be included in the "Background Art" section. Any description of subject matter herein should be taken as part of the inventor's approach to a particular problem. should be treated as such and may also be inventive in their own right. [Means for solving the problem]

[0010] In one aspect, the disclosure provides a compound of formula (1). In another aspect, the disclosure provides a compound of formula ( In another aspect, the present disclosure provides a composition, e.g., a pharmaceutical composition, comprising the compound of formula 1. Methods for treating various diseases and conditions are provided, comprising administering to a patient a therapeutically effective amount of a compound of formula (1) The method includes administering a compound of formula (1) to a patient in need thereof.

[0011] Exemplary embodiments of the present disclosure include the compounds listed in Table 1, and numbered for ease of reference. The present invention includes the following embodiments: 1) A compound of formula (1) [ka] or a pharma- ceutically acceptable enantiomer, diastereomer, salt, or solvate thereof. The compound, wherein Ar is a 9- or 10-membered bicyclic aromatic ring system, Ar has 1, 2 or 3 substituents is optionally substituted with a substituent; L is selected from a direct bond and methylene; R 1 is hydrogen, halide, C1-C6 alkyl, C1-C6 haloalkyl, C1- Substituted with C6 alkoxy, C3-C6 cycloalkoxy, and C3-C6 cycloalkyl C1-C6 alkoxy; A is selected from a direct bond, -CH2-, and -CH2CH2-; E is -C(O)-R 2 , C(OR 3 )R 4 R 5 , and CH(R 6 )NR 7 R 8 from Selected; R 2 is selected from methyl, ethyl, and phenyl; R 3 is selected from H, alkyl, and substituted alkyl; R 4 is selected from hydrogen, alkyl, and phenyl; R 5 is C1-C7 alkyl, C1-C7 haloalkyl, phenyl, and substituted phenyl. Selected from the following; R 6 is selected from hydrogen, methyl, halomethyl, and ethyl; R 7 is hydrogen, R 8 is hydrogen, methyl, or ethyl; However, R 7 and R 8 and together form an optionally substituted 5- or 6-membered heterocyclic ring, A good compound. 2) The compound of embodiment 1, wherein Ar is an unsubstituted 9-membered bicyclic aromatic ring system. 3) The compound of embodiment 1, wherein Ar is a monosubstituted 9-membered bicyclic aromatic ring. 4) The compound of embodiment 1, wherein Ar is a disubstituted 9-membered bicyclic aromatic ring. 5) The compound of embodiment 1, wherein Ar is a trisubstituted 9-membered bicyclic aromatic ring. 6) The compound of embodiment 1, wherein Ar is an unsubstituted 10-membered bicyclic aromatic ring system. 7) The compound of embodiment 1, wherein Ar is a monosubstituted 10-membered bicyclic aromatic ring. 8) The compound of embodiment 1, wherein Ar is a disubstituted 10-membered bicyclic aromatic ring. 9) The compound of embodiment 1, wherein Ar is a trisubstituted 10-membered bicyclic aromatic ring. 10) Ar is 1,3-benzoxazole, 2-methylquinoline, and 1,3-benzoxazole. The compound of embodiment 1, selected from zothiazole. 11) Ar is naphthalene, 1,5-naphthyridine, 1,6-naphthyridine, 1, 7-Naphthyridine, 1,8-Naphthyridine, Isoquinoline, Phthalazine, 2,6-Naphthyridine lysine and its nitrogen-substituted analogs selected from 2,7-naphthyridine. The compound according to embodiment 1. 12) The compound of embodiment 1, wherein Ar is substituted with one -S-CH3. 13) The compound of any one of embodiments 1-12, wherein L is a direct bond. 14) The compound of any of embodiments 1-12, wherein L is methylene. 15)R 1 The compound of any one of embodiments 1-14, wherein is hydrogen. 16)R 1 The compound of any one of embodiments 1-14, wherein is halogen. 17) R 1 The compound of any one of embodiments 1-14, wherein is C1-C6 alkyl. 18)R 1 is C1-C6 haloalkyl. thing. 19) R 1 is C1-C6 alkoxy, compound. 20) The compound of any one of embodiments 1-19, wherein A is a direct bond. 21) The compound of any one of embodiments 1-19, wherein A is -CH2-. 22) The compound of any one of embodiments 1-19, wherein A is -CH2CH2-. 23) E is -C(O)-R 2 23. The compound of any one of embodiments 1-22, wherein 24)R 2 The compound of any one of embodiments 1-23, wherein is methyl. 25)R 2 The compound of any one of embodiments 1-23, wherein is ethyl. 26)R 2 The compound of any one of embodiments 1-23, wherein is phenyl. 27) E is -C(OR 3 )R 4 R 5 The compound according to any one of embodiments 1 to 26, . 28)R 3 The compound of any one of embodiments 1-27, wherein is hydrogen. 29)R 3 The compound of any one of embodiments 1-28, wherein is alkyl. 30)R 3 The compound of any one of embodiments 1-28, wherein is substituted alkyl. 31)R 4 The compound of any one of embodiments 1-30, wherein is hydrogen. 32)R 4 The compound of any one of embodiments 1-30, wherein is alkyl. 33)R 4 The compound of any one of embodiments 1-30, wherein is phenyl. 34)R 5 is C1-C7 alkyl. . 35)R 5 is C1-C7 haloalkyl, e.g., R 5 is trifluoromethyl; A compound according to any one of embodiments 1 to 34. 36)R 5 The compound of any one of embodiments 1-34, wherein is phenyl. 37)R 5 The compound of any one of embodiments 1-34, wherein is substituted phenyl. 38) E is -CH(R 6 )NR 7 R 8 The compound according to any one of embodiments 1 to 37, thing. 39)R 6 The compound of any one of embodiments 1-38, wherein is hydrogen. 40)R 6 The compound of any one of embodiments 1-38, wherein is methyl. 41)R 6 is a methyl halide. 42)R 6 The compound of any one of embodiments 1-38, wherein is ethyl. 43)R 8 The compound of any one of embodiments 1-38, wherein is hydrogen. 44)R 8 The compound of any one of embodiments 1-38, wherein is methyl. 45)R 8 The compound of any one of embodiments 1-38, wherein is ethyl. 46)R 7 and R 8 and together form a 5-membered heterocycle, Compound. 47)R 7 and R 8 and together form a substituted 5-membered heterocycle. The compound according to any one of claims 1 to 4. 48)R 7 and R 8 and together form a 6-membered heterocycle, Compound. 49)R 7 and R 8 and together form a substituted 6-membered heterocycle. The compound according to any one of claims 1 to 4. 50) 1-[4-(1,3-benzothiazol-2-yloxy)-3-methoxyphenyl 1-pentan-3-one; 1-[4-(1,3-benzoxazol-2-yloxy)-3-methoxyphenyl ]pentan-3-one; 1-[4-(1,3-benzothiazol-2-yloxy)-3-methoxyphenyl] -3-(trifluoromethyl)pentan-3-ol; 1-{3-Methoxy-4-[(4-methylsulfanyl-1,3-benzothiazole- 2-yl)oxy]phenyl}-3-(trifluoromethyl)pentan-3-ol; 1-[4-(1-methyl-1H-benzimidazol-2-yloxy)-3-methoxy [diphenyl]-3-(trifluoromethyl)pentan-3-ol; 1-{3-Methoxy-4-[(6-methylsulfonyl-1,3-benzothiazole- 2-yl)oxy]phenyl}-3-(trifluoromethyl)pentan-3-ol; 1-{4-[(4,6-difluoro-1,3-benzothiazol-2-yl)oxy] -3-Methoxyphenyl}-3-(trifluoromethyl)pentan-3-ol; 1-{4-[(6-fluoro-1,3-benzothiazol-2-yl)oxy]-3- Methoxyphenyl}-3-(trifluoromethyl)-pentan-3-ol; 1-{4-[(6-methoxy-1,3-benzothiazol-2-yl)oxy]-3- Methoxyphenyl}-3-(trifluoromethyl)pentan-3-ol; 4-[4-(1,3-Benzothiazol-2-yloxy)-3-methoxyphenyl] Butan-2-one; 4-[4-(1,3-Benzothiazol-2-yloxy)-3-methoxyphenyl] -1,1,1-trifluoro-2-methylbutan-2-ol; 1-[4-(1,3-benzothiazol-2-yloxy)-3-(isopropyloxy) (xy)-phenyl]pentan-3-one; 1-[4-(1,3-benzothiazol-2-yloxy)-3-(cyclopentyloxy) (xy)-phenyl]pentan-3-one; 1-[4-(1,3-benzothiazol-2-yloxy)-3-(cyclopropyl- (Methoxy)-phenyl]pentan-3-one; 1-[4-(1,3-benzothiazol-2-yloxy)-3-(isopropyloxy) [oxy)phenyl]-3-(trifluoromethyl)pentan-3-ol; 1-[4-(1,3-benzothiazol-2-yloxy)-3-(cyclopentyloxy) [oxy)-phenyl]-3-(trifluoromethyl)-pentan-3-ol; 1-[4-(1,3-benzothiazol-2-yloxy)-3-(cyclopropyl- methoxy)-phenyl]-3-(trifluoromethyl)-pentan-3-ol; 4-(3-Methoxy-4-{[4-(methylsulfanyl)-1,3-benzothiazole (phenyl-2-yl)oxy}phenyl)butan-2-one; 1,1,1-trifluoro-4-(3-methoxy-4-{[4-(methylsulfanyl )-1,3-Benzothiazol-2-yl]oxy}phenyl)-2-methylbutane-2 -Oar; 1-[4-(1,3-benzothiazol-2-yloxy)-3-ethoxyphenyl] -pentan-3-one; 1-[4-(1,3-benzothiazol-2-yloxy)-3-ethoxyphenyl] -3-(trifluoromethyl)pentan-3-ol; 4-[4-(1,3-Benzothiazol-2-yloxy)-3-methoxyphenyl] -butan-2-ol; 4-[4-(1,3-Benzothiazol-2-yloxy)-3-methoxyphenyl] -2-(phenyl)butan-2-ol; 4-[4-(1,3-Benzothiazol-2-yloxy)-3-methoxyphenyl] -2-Methylbutan-2-ol; 4-[4-(1,3-benzoxazol-2-yloxy)-3-methoxyphenyl ]butan-2-one; 4-[4-(1,3-benzoxazol-2-yloxy)-3-methoxyphenyl ]-2-Methylbutan-2-ol; 1-[4-(1,3-benzoxazol-2-yloxy)-3-methoxyphenyl ]-3-Methylpentan-3-ol; 4-[4-(1,3-benzoxazol-2-yloxy)-3-methoxyphenyl ]-2-phenyl-butan-2-ol; 3-[4-(1,3-benzothiazol-2-yloxy)-3-ethoxyphenyl] -1-phenylpropan-1-one; 4-[3-ethoxy-4-(1,3-benzothiazol-2-yloxy)phenyl] -1,1,1-trifluoro-2-phenylbutan-2-ol; 3-[4-(1,3-benzothiazol-2-yloxy)-3-methoxyphenyl] -1-phenylpropan-1-one; 3-[4-(1,3-benzothiazol-2-yloxy)-3-methoxyphenyl] -1-phenylpropan-1-ol; 3-[4-(1,3-benzothiazol-2-yloxy)-3-methoxyphenyl] -1-(trifluoromethyl)-1-phenylpropan-1-ol; 2-{2-Methoxyl-4-[3-phenyl-3-(pyrrolidin-1-yl)propyl ]phenoxy}-1,3-benzothiazole; 1-[4-(1,3-benzothiazol-2-yloxy)-3-methoxyphenyl] Pentan-3-amine; 4-{1-[3-methoxy-4-(1,3-benzothiazol-2-yloxy)phenyl nyl]pentan-3-yl}morpholine; 1-[4-(1,3-benzothiazol-2-yloxy)-3-methoxyphenyl] -2,2,2-trifluoroethanol; 1-[4-(1,3-benzothiazol-2-yloxy)-3-methoxyphenyl] -N-ethyl-2,2,2-trifluoroethanamine; 2,2,2-Trifluoro-1-(3-methoxy-4-{[4-(methylsulfanyl )-1,3-benzothiazol-2-yl]oxy}phenyl)ethanol; 4-[4-(1,3-benzothiazol-2-yloxy)-phenyl]-1,1,1 -Trifluoro-2-methylbutan-2-ol; 4-[4-(1,3-benzothiazol-2-yloxy)phenyl]butan-2-ol rule; 1-[4-(1,3-benzothiazol-2-yloxy)phenyl]-3,4-dimethyl Tylpentan-3-ol; 1-[4-(1,3-benzothiazol-2-yloxy)phenyl]-3-methylphenyl pentane-3-ol; 4-[4-(1,3-benzothiazol-2-yloxy)phenyl]-2-phenyl Butan-2-ol; 4-[4-(1,3-benzothiazol-2-yloxy)phenyl]-2-(4-phenyl) (fluorophenyl)butan-2-ol; 1-[4-(1,3-benzoxazol-2-yloxy)phenyl]-3-methyl Pentan-3-ol; 4-[4-(1,3-benzoxazol-2-yloxy)phenyl]-2-phenyl Louboutin-2-all; 1-[4-(1,3-benzothiazol-2-yloxy)phenyl]pentane-3- on; 1-[4-(1,3-benzothiazol-2-yloxy)-3-chlorophenyl]phenyl nthan-3-one; 1-[4-(1,3-benzothiazol-2-yloxy)phenyl]-3-(trifluoromethyl) (fluoromethyl)pentan-3-ol; 1-[4-(1,3-benzothiazol-2-yloxy)-3-chlorophenyl]- 3-(Trifluoromethyl)pentan-3-ol; 1-[4-(1,3-benzothiazol-2-yloxy)-3-fluorophenyl] -pentan-3-one; 1-[4-(1,3-benzothiazol-2-yloxy)-3-(trifluoromethyl (phenyl)pentan-3-one 1-[4-(1,3-benzothiazol-2-yloxy)-3-fluorophenyl] -3-(trifluoromethyl)pentan-3-ol; 1-[4-(1,3-benzothiazol-2-yloxy)-3-(trifluoromethyl [1-phenyl]-3-(trifluoromethyl)-pentan-3-ol; 2-{4-[3-(pyrrolidin-1-yl)butyl]phenoxy}-1,3-benzothiamine Azole; 1-{4-[4-(1,3-benzothiazol-2-yloxy)phenyl]butane- 2-yl}pyrrolidine-2-carboxylic acid; 2-{4-[3-(pyrrolidin-1-yl)pentyl]phenoxy}-1,3-benzo Thiazole; 1-[4-(1,3-benzothiazol-2-yloxy)phenyl]ethanone; 1-[4-(1,3-benzothiazol-2-yloxy)phenyl]ethanol; 2-[4-(1,3-benzothiazol-2-yloxy)phenyl]butan-2-ol rule; 2-{4-[1-(pyrrolidin-1-yl)ethyl]phenoxy}-1,3-benzothiamine Azole; 2-[4-(1,3-benzothiazol-2-yloxy)phenyl]-1,1,1- Trifluoropropan-2-ol; 2-[4-(pyrrolidin-1-ylmethyl)phenoxy]-1,3-benzothiazole ; 1-[4-(1,3-benzothiazol-2-yloxy)benzyl]pyrrolidine-2 -Carboxylic acids; 1-[4-(1,3-benzothiazol-2-yloxy)phenyl]-2,2,2- Trifluoroethanol; 1-[4-(1,3-benzothiazol-2-yloxy)-3-chlorophenyl]- 2,2,2-Trifluoroethanol; 1-[4-(1,3-benzothiazol-2-yloxy)phenyl]-N-ethyl- 2,2,2-Trifluoroethanamine; 1-{4-[(2-methyl-1,3-benzothiazol-6-yl)oxy]phenyl }Ethanone; 1,1,1-trifluoro-2-{4-[(2-methyl-1,3-benzothiazole- 6-yl)oxy]phenyl}propan-2-ol; 1-{4-[(2-methyl-1,3-benzothiazol-6-yl)oxy]phenyl }ethanol; 1-[4-(1,3-benzothiazol-2-yloxy)-3-methoxyphenyl] -Ethanone; 2-[4-(1,3-benzothiazol-2-yloxy)-3-methoxyphenyl] -1,1,1-trifluoropropan-2-ol; 4-[4-(1,3-benzothiazol-2-yloxy)-3-chlorophenyl] Tan-2-one; 4-[4-(1,3-benzothiazol-2-yloxy)-3-chlorophenyl]- 1,1,1-trifluoro-2-methylbutan-2-ol; 1-(4-{[4-(methylsulfanyl)-1,3-benzothiazol-2-yl] (oxy)phenyl)ethanol; 2-[4-(1,3-benzothiazol-2-yloxy)phenyl]propane-2- oar; 1-[4-(1,3-benzothiazol-2-yloxy)phenyl]-2,2,2- Trifluoro-N-methylethanamine; 1-{4-[(4,6-difluoro-1,3-benzothiazol-2-yl)oxy] phenyl}-2,2,2-trifluoroethanol; 1-{4-[(4,6-difluoro-1,3-benzothiazol-2-yl)oxy] phenyl}ethanol; 2-{4-[(4,6-difluoro-1,3-benzothiazol-2-yl)oxy] phenyl}-1,1,1-trifluoropropan-2-ol; 1-{4-[(1,3-benzothiazol-2-yl)oxy]-2-methoxyphenyl {2,2,2-trifluoroethane-1-ol; 1,1,1-trifluoro-2-methyl-4-[4-(quinolin-2-ylmethoxy) phenyl]butan-2-ol; 1,1,1-trifluoro-4-[3-methoxy-4-(quinolin-2-ylmethoxy) )phenyl]-2-methylbutan-2-ol; 1-[4-(quinolin-2-yl-methoxy)-phenyl]-3-(trifluoromethyl) )-pentan-3-ol; 1-[4-(1,3-benzothiazol-2-yloxy)-3-(cyclopentyloxy) (xy)-phenyl]pentan-3-ol; 1-[4-(1,3-benzothiazol-2-yloxy)-3-(cyclopropylmethyl) (tox)-phenyl)-pentan-3-ol; 1-[4-(1,3-benzothiazol-2-yloxy)-3-methoxyphenyl] -3-(4-methylpiperazinyl-1yl)pentane; 4-{4-[(quinolinyl-2-yl)methoxy]phenyl}butan-2-one; 4-{4-[(quinolinyl-2-yl)methoxy]phenyl}butane-2-pyrrolidine ; 1-(3-Methoxy-4-{[4-(methylsulfanyl)-1,3-benzothiazole (2-yl)oxy}phenyl)pentan-3-methyl-3-ol; 1-(3-Methoxy-4-{[4-(methylsulfanyl)-1,3-benzothiazole {2-yl]oxy}phenyl)pentan-3-one; 1-(3-Methoxy-4-{[4-(methylsulfanyl)-1,3-benzothiazole {2-yl]oxy}phenyl)pentan-3-ol; 1-(4-{[4-(methylsulfanyl)-1,3-benzothiazol-2-yl] oxy}phenyl)pentan-3-one; 1-(4-{[4-(methylsulfanyl)-1,3-benzothiazol-2-yl] oxy}phenyl)-3-(trifluoromethyl)pentan-3-ol; 1-[4-(1,3-benzothiazol-2-yloxy)-3-methoxyphenyl] Pentan-3-ol; 1,1,1-trifluoro-2-[4-(quinolin-2-ylmethoxy)phenyl]propane lopan-2-ol; 1,1,1-trifluoro-2-[3-methoxy-4-(quinolin-2-ylmethoxy) )phenyl]butan-3-ol; and 1,1,1-trifluoro-2-[3-methoxy-4-(quinolin-2-ylmethoxy) 2. The compound of embodiment 1, selected from: 51) The compound according to embodiment 1 as a racemic mixture of the enantiomers of the compound of formula (1) Compound. 52) The compound of any one of embodiments 1 to 51 as a non-racemic mixture of the enantiomers of the compound of formula (1) The compound according to any one of the preceding claims. 53) The compound according to any one of embodiments 1 to 51 as an isolated (S) enantiomer. Compound. 54) The compound according to any one of embodiments 1 to 51 as an isolated (R) enantiomer. Compound. 55) Ar is a 9- or 10-membered bicyclic ring system containing two aromatic rings, and Ar is unsubstituted. or halides, C1-6 alkyl; -S-C1-6 alkyl; -O-C1- 6 alkyl; and -SO2-C1-6 alkyl; ; L is selected from a direct bond and -CH2- (methylene); R 1 is hydrogen, halide, C1-C6 alkyl, C1-C6 haloalkyl, C1- Substituted with C6 alkoxy, C3-C6 cycloalkoxy, and C3-C6 cycloalkyl C1-C6 alkoxy; A is selected from a direct bond, -CH2-, and -CH2CH2-; E is -C(O)-R 2 , C(OR 3 )R 4 R 5 , and CH(R 6 )NR 7 R 8 from Selected; R 2 is selected from methyl, ethyl, and phenyl; R 3 is H; R 4 is selected from hydrogen, C1-C7 alkyl, and phenyl; R 5 is selected from C1-7 alkyl, C1-7 haloalkyl, phenyl, and halophenyl; Selected from; R 6 is selected from hydrogen, methyl, halomethyl, and ethyl; R 7 is hydrogen and R 8 is hydrogen, methyl, or ethyl; or R 7 and R 8 and optionally substituted with a substituent selected from C1-C6 alkyl and carboxylic acid. The compound of embodiment 1, wherein the compound forms a 5- or 6-membered heterocycle that is substituted. 56) The compound of embodiment 55, wherein Ar is 1,3-benzothiazole. 57) Embodiment 55, in which Ar is selected from 1,3-benzoxazole and quinoline. The compound according to claim 1, 58) The compound according to embodiment 55, wherein Ar is substituted with one substituent that is -S-CH3. compound. 59) The compound of any one of embodiments 55-58, wherein L is a direct bond. 60) The compound of any of embodiments 55-58, wherein L is methylene. 61)R 1Any of embodiments 55 to 60, wherein is hydrogen or C1-C6 alkoxy. The compound according to claim 1, 62) The compound of any of embodiments 55-61, wherein A is a direct bond. 63) The compound of any of embodiments 55-61, wherein A is -CH2CH2-. 64) E is -C(OR 3 )R 4 R 5 The compound according to any one of embodiments 55 to 63, thing. 65) Embodiments 55 to 64 as non-racemic mixtures of enantiomers of the compound of formula (1) 2. The compound according to claim 1 , 66) 1-[4-(1,3-benzothiazol-2-yloxy)-3-methoxyphenyl [l]-3-(trifluoromethyl)pentan-3-ol; 1-{3-Methoxy-4-[(4-methylsulfanyl-1,3-benzothiazole- 2-yl)oxy]phenyl}-3-(trifluoromethyl)pentan-3-ol; 1-{4-[(4,6-difluoro-1,3-benzothiazol-2-yl)oxy] -3-Methoxyphenyl}-3-(trifluoromethyl)pentan-3-ol; 1-{4-[(6-fluoro-1,3-benzothiazol-2-yl)oxy]-3- Methoxyphenyl}-3-(trifluoromethyl)-pentan-3-ol; 4-[4-(1,3-Benzothiazol-2-yloxy)-3-methoxyphenyl] -1,1,1-trifluoro-2-methylbutan-2-ol; 1,1,1-trifluoro-4-(3-methoxy-4-{[4-(methylsulfanyl )-1,3-Benzothiazol-2-yl]oxy}phenyl)-2-methylbutane-2 -Oar; 1,1,1-trifluoro-2-{4-[(2-methyl-1,3-benzothiazole- 6-yl)oxy]phenyl}propan-2-ol; 1,1,1-trifluoro-2-methyl-4-[4-(quinolin-2-ylmethoxy) phenyl]butan-2-ol; 1,1,1-trifluoro-4-[3-methoxy-4-(quinolin-2-ylmethoxy) )phenyl]-2-methylbutan-2-ol; 1-[4-(quinolin-2-yl-methoxy)-phenyl]-3-(trifluoromethyl) )-pentan-3-ol; 1-(3-Methoxy-4-{[4-(methylsulfanyl)-1,3-benzothiazole (phenyl-2-yl)oxy}phenyl)pentan-3-ol; and 1-(4-{[4-(methylsulfanyl)-1,3-benzothiazol-2-yl] oxy}phenyl)-3-(trifluoromethyl)pentan-3-ol; The compound of embodiment 55, 67) A compound according to any one of embodiments 1 to 66, or a pharma- ceutically acceptable enantiomer thereof. , salt or solvate thereof and at least one pharma- ceutically acceptable carrier, diluent, excipient and and / or an adjuvant. 68) The pharmaceutical composition according to embodiment 67, which is in the form of eye drops. 69) An effective amount of a compound according to any one of embodiments 1 to 66 or any one of embodiments 67 A method for treating an inflammatory disease or condition comprising administering the composition to a subject in need thereof. Place. 70) The method of embodiment 69 for treating an ocular inflammatory disease or condition. 71) A therapeutically effective amount of a compound according to any one of embodiments 1 to 66 or any one of embodiments 67 The present invention relates to a method for treating a respiratory disease or condition, comprising administering the composition to a subject in need thereof. How to place it. 72) A therapeutically effective amount of a compound according to any one of embodiments 1 to 66 or any one of embodiments 67 The method includes administering the composition of the present invention to a subject in need thereof, How to treat the disorder. 73) An effective amount of any of the compounds of embodiments 1 to 66 or the composition of embodiment 67, and administering to a subject in need thereof a therapeutic agent for treating asthma, chronic obstructive pulmonary disease (COPD), Respiratory diseases such as cystic fibrosis, bronchopulmonary dysplasia and idiopathic pulmonary fibrosis (IPF), lung A method for treating a pulmonary disorder or condition. 74) An effective amount of a compound according to any one of embodiments 1 to 66 or any one of embodiments 67 The method includes administering the composition to a subject in need thereof. and methods for treating autoimmune diseases or conditions, such as multiple sclerosis. 75) An effective amount of a compound according to any one of embodiments 1 to 66 or any one of embodiments 67 A method for treating an allergic disease comprising administering the composition to a subject in need thereof. 76) An effective amount of a compound according to any one of embodiments 1 to 66 or according to embodiment 67 A method of treating conjunctivitis comprising administering the composition to a subject in need thereof. 77) An effective amount of a compound according to any one of embodiments 1 to 66 or according to embodiment 67 A method for treating uveitis comprising administering the composition to a subject in need thereof. 78) An effective amount of a compound according to any one of embodiments 1 to 66 or according to embodiment 67 A method for treating dry eye comprising administering the composition to a subject in need thereof. 79) A therapeutically effective amount of a compound according to any one of embodiments 1 to 66 or embodiment 67. A method for treating diabetic retinopathy comprising administering the composition described above to a subject in need thereof. . 80) A therapeutically effective amount of a compound according to any one of embodiments 1 to 66 or any one of embodiments 67. A method for treating age-related macular degeneration comprising administering the composition described above to a subject in need thereof. . 81) A therapeutically effective amount of a compound according to any one of embodiments 1 to 66 or embodiment 67. A method for treating diabetic macular edema comprising administering the composition described above to a subject in need thereof. Law. 82) An effective amount of a compound according to any one of embodiments 1 to 66 or any one of embodiments 67 A method for treating atopic dermatitis, psoriasis, and alopecia vulgaris, comprising administering the composition to a subject in need thereof. A method for treating a skin disease or condition, such as acne. 83) An effective amount of a compound according to any one of embodiments 1 to 66 or any one of embodiments 67 A method of treating cancer comprising administering the composition to a subject in need thereof. 84) An effective amount of a compound according to any one of embodiments 1 to 66 or any one of embodiments 67 and administering the composition to a subject in need thereof. A method for treating an infectious or neurodegenerative disease. 85) An effective amount of a compound according to any one of embodiments 1 to 66 or any one of embodiments 67 administering the composition to a subject in need thereof. How to treat. 86) An effective amount of a compound according to any one of embodiments 1 to 66 or any one of embodiments 67 A method for treating cardiovascular (CV) disease comprising administering the composition to a subject in need thereof. .

[0012] The embodiments disclosed herein are illustrative of the compounds, compositions and methods of the present disclosure. Any two or more of the above may be combined.

[0013] This Summary of the Invention is set forth in a simplified form below, which is further detailed in the Detailed Description of the Invention. Unless expressly stated otherwise, This Summary is intended to identify key or essential features of the claimed subject matter. It is not intended to be limiting, nor to limit the scope of the claimed subject matter.

[0014] The details of one or more embodiments are set forth in the description below. The features illustrated or described herein may be combined with the features of other embodiments. Any of the various embodiments described herein may be combined to form further embodiments. Aspects of the embodiments may be provided as specified herein, if necessary. To use concepts from various patents, applications and publications to provide further embodiments. Other features, objects, and advantages are set forth in the description, drawings, and claims. It will be clear from the scope. [Brief description of the drawings]

[0015] [Figure 1] Effect of Compound 104 on LPS-induced neutrophil infiltration into the lungs. Animals were orally treated with 10 mg / kg Compound 104, 1 mg / kg dexamethasone, or vehicle 1 h before and 2 h after intratracheal administration of 2.5 mg / kg LPS. Six hours after LPS, animals were euthanized and BAL was collected from the lungs. Values ​​are shown as mean ± standard deviation, n = 7-10 animals per group. [Diagram 2]Figure 1 shows the effect of Compound 104 on clinical scores in an EIU rat model. Animals were treated with Compound 104 orally at 30 mg / kg or vehicle 15 min before and 5 h after subcutaneous administration of 75 μg LPS from Salmonella Typhimurium in saline at 2.5 mg / kg LPS into the plantar hind paw of each paw. The mean clinical scores were measured 24 h after LPS administration. Values ​​represent the mean ± standard deviation, n=3 per group. [Diagram 3] The superior ability of compound 104 to distribute to the posterior portion of the eye (vitreous + retina) is shown compared to the standard treatment, prednisolone. Sprague-Dawley rats were instilled with 10 μL of either compound 104 (0.4%) or commercial prednisolone acetate eye drops (1%) and 2 hours after administration, tissues were removed and compound concentrations were measured. The resulting data in Figure 3 (mean ± standard deviation, n=5 eyes for each drug) show that compound 104 was absorbed into the posterior region at approximately 50-fold the level of prednisolone 2 hours after administration. [Figure 4A] Figure 4 shows the effect of Compound 104 on clinical scores and histological evaluation in the EAU rat model. On day 0, animals were immunized with 30 μg of peptide in an emulsion containing 2 mg / mL complete Freund's adjuvant. Starting on day 6 after immunization, animals were administered 10 μL of Compound 104 at 0.5% wt / vol or vehicle topically in each eye every 3 hours for four doses, and one oral dose (30 mg / kg) immediately after the last topical dose each day. Animals were treated daily and euthanized 10 days after immunization, and tissues were harvested for histological examination. Values ​​show the mean ± standard deviation of four eyes, n=2 for each group. In this figure 4A, the mean clinical score was determined over time after immunization as shown in the figure. [Figure 4B] Data from the same experiment as described for FIG. 4A, FIG. 4B shows the histological scores obtained 10 days after immunization. [Figure 4C] Data taken from the same experiment as described for FIG. 4A, FIG. 4C shows retinal thickness measurements taken from histological slides 10 days after immunization. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] The present invention is further illustrated by the following detailed description of preferred embodiments of the invention and the examples contained herein. The present invention can be more easily understood by referring to the description. Before proceeding, certain definitions to be used herein are provided below, together with the following definitions, which are set forth in the present specification: The specific markings used in the

[0017] The terms used herein have their ordinary meaning to one skilled in the art of organic chemistry. However, unless otherwise stated, the specification and claims The following definitions apply throughout this range. These definitions apply whether a term is used in isolation or This applies whether the name is used alone or as part of a larger name. For example, the definition of "alkyl" includes the term "alkyl" used by itself and, for example, "hydrogen". Terms that contain the concept of alkyl, such as "oxyalkyl," "haloalkyl," and "O-alkyl" and the "alkyl" portion of

[0018] Chemical names, common names, and chemical structures are used interchangeably to describe the same compound. For example, the compounds of formula (1) may be identified by their chemical structure and / or by their chemical name. Both the structure and the name of the compound are provided, and the name and the structure may be In the event of any discrepancy, it is understood that the structural representation of the compound will take precedence.

[0019] As further explained herein, the term "substituted" refers to a specified or selected This means that one or more hydrogens on the indicated atom are replaced with a selection from the indicated group. However, the valence of the specified atom under the existing circumstances should not be exceeded, and the substitution should Provided that such combination results in a stable compound. A "stable compound" or "stable structure" means that the compound is It is sufficient for isolation from the reaction mixture to a useful degree of purity and formulation into an effective therapeutic composition. In addition, in the text, schemes, examples and tables of this specification, Therefore, carbon and heteroatoms with unsaturated valences must be replaced with other valences to satisfy the normal valences of the atoms. Note also that it is assumed to have a sufficient number of hydrogen atoms.

[0020] "Alkyl" means a group consisting of only carbon and hydrogen atoms, containing no unsaturation, and designated from 1. A straight or branched chain hydrocarbon having a given number of carbon atoms and attached to the rest of the molecule by a single bond. refers to free-chain radicals, e.g., methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), -propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3 -methylhexyl, 2-methylhexyl, etc. In one embodiment, the alkyl group is In one embodiment, the alkyl group has 2 carbons. In one embodiment, The alkyl group has three carbons. In one embodiment, the alkyl group has four carbons. In one embodiment, the alkyl group has 4 carbons. In one embodiment, the alkyl group has 5 carbons. In one embodiment, the alkyl group has 6 carbons. Two or more of these embodiments may be combined for purposes of description. "Alkoxy" refers to -O-alkyl. "Cycloalkyl" refers to cyclopropyl, cycloalkyl, ... Cycloaliphatic radicals containing no unsaturation, such as butyl, cyclopentyl, and cyclohexyl. "Cycloalkoxy" refers to -O-cycloalkyl.

[0021] "Aryl" means a carbon atom containing hydrogen, 6 to 18 carbon atoms and at least one aromatic ring. In one embodiment, the aryl ring system has 6 to 12 carbon atoms. In one embodiment, the aryl ring system has 6 to 10 carbon atoms. Thus, the aryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, Aryl radicals may include fused or bridged ring systems. Naphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, Luoranthene, fluorene, as-indacene, s-indacene, indane, indene, Naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene Aryl radicals include, but are not limited to, aryl radicals derived from aryl groups. Unless otherwise specified in the specification, an aryl group can be one or more independently selected groups at each occurrence. The substituents may be optionally substituted.

[0022] "Compounds of the present disclosure" (unless otherwise indicated) and equivalent terms (unless otherwise indicated) "Compound of the present (or this) invention" includes any subset thereof, and all pure and mixed compounds thereof. Stereoisomers (including diastereoisomers and enantiomers), tautomers and isomers It refers to compounds of formula (1), including topochemically labeled compounds. It also refers to hydrates of the compounds of the present invention / disclosure. and solvates are also contemplated to be within the scope of the term compounds of the invention / disclosure. The product may exist in one or more crystalline states, i.e., as cocrystals or polymorphs; and It may exist as an amorphous solid or as an oil. Such forms are encompassed within the scope of the present invention and claims. "Formula (1)", "Formula 1", "Formula (1)", "compound of formula 1", etc. may be used interchangeably herein and may refer to different or No distinction is intended.

[0023] An "effective amount," "therapeutic amount," "therapeutically effective amount," or "effective dose" refers to a therapeutically effective amount that is effective in a subject. An amount of an active compound as described herein sufficient to elicit a pharmacological or therapeutic effect. In the case of a compound that treats inflammation, an effective amount is an anti-inflammatory amount. In the present context, the terms "effective amount," "therapeutic amount," "therapeutically effective amount," and "effective dose" are often used interchangeably. Based on routine clinical or patient-specific factors, and following the teachings of this disclosure, These can be readily determined by one of ordinary skill in the art using tools and methods commonly known in the art. However, your doctor may, within the bounds of sound medical judgment, limit the total daily dose of the compound. It is understood that the particular therapeutically effective dose level for any particular patient is determined by: the disorder to be treated and the severity of the disorder; the desired result to be obtained, the activity of the particular compound to be used; the prescribed composition to be used; the age, weight, general health, sex and diet of the patient; the time, route of administration, and rate of excretion of the particular compound being used; the duration of treatment; drugs used in combination with or simultaneously with certain compounds; and similar drugs known in the medical arts. However, as a general guideline, the recommended daily intake is 100 mg / kg / day. Doses typically range from about 0.0001 mg / kg / day to about 100 mg / kg / day, in single or divided doses. Typically, human doses range from 1 mg / kg / day to 10 mg / kg / day. So, the range would be about 0.1mg to about 4000mg per day.

[0024] "Fused" refers to any of the ring structures described herein that are fused to an existing ring structure in the compounds of the present disclosure. When the fused ring system is a heterocyclyl or heteroaryl, the fused ring system is Any carbon in the existing ring structure which becomes part of the ring system may be replaced with a nitrogen.

[0025] "Halo" refers to chloro, bromo, fluoro, and iodo. The term "halogen" refers to Fluorine (may be written as -F), chlorine (may be written as -Cl), bromine (may be written as -Br , or iodine (which may be written as -I). In another embodiment, the halogen is chlorine. In another embodiment, the halogen is fluorine. In this case, the halogen is bromine. Thus, halophenyl means that the phenyl group normally present is Halogen refers to a phenyl group having at least one halogen substituent replacing a hydrogen atom. A CH2 substituted group is a CH2 group with at least one halogen substitution, such as CHF or CF2. Refers to...

[0026] "Haloalkyl" refers to an alkyl group having at least one halogen substitution in place of a C-H bond. In one embodiment, the term refers to an alkyl group having one aryl group on the named group (e.g., phenyl, alkyl). In embodiments, there are two halogen substituents, or one to two halogen substituents. or 3 halogen substituents, or 1 to 3 halogen substituents and as stated above, the halogen may be fluorine or may be selected from fluorine and chlorine. A subset of haloalkyl is "fluoroalkyl", which is a term substituted with one or more fluorine atoms, up to the total number of hydrogen atoms present on the alkyl moiety. Thus, C1-C6 fluoroalkyl refers to a fluorinated alkyl group. Groups such as trifluoromethyl or difluoroethyl (i.e., CF and CH 2CHF2). "C1-C6 fluoroalkyl" refers to 1 to 6 fluoroalkyl groups, for example, 1, 2, It denotes a straight or branched alkyl group containing 3 or 4 carbon atoms. Examples of fluoroalkyl radicals are methyl, ethyl, n-propyl, isopropyl, n- butyl, iso-butyl, sec-butyl, tert-butyl, where the radical is , 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 or more fluorine substituents, e.g. , the radical may have 1, 2 or 3 fluorine substituents.

[0027] "Heteroaryl" refers to an aromatic ring that is heteroatom-containing, preferably N, O, or S. As used herein, the term "aryl" refers to an aryl group, as defined herein, including any group selected from the group consisting of The aryl radical is an alkyl radical in which the ring atoms are selected from carbon, nitrogen, oxygen and sulfur; and sulfur. For purposes of this disclosure, The heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, and may be a fused Optionally, the heteroaryl radical may include a 5-membered, 6-membered or bridged ring system. It is a seven-membered heteroaryl group. If there are multiple O and S atoms in the heteroaryl ring system, In this case, the O and / or S atoms are preferably not directly bonded. The heteroaryl group includes pyrrole, pyrazole, imidazole, and 1,2,3-triazolate. 1,2,4-triazole, tetrazole, furan, thiophene, selenophene, Oxazole, isoxazole, 1,2-thiazole, 1,3-thiazole, 1,2, 3-Oxadiazole, 1,2,4-Oxadiazole, 1,2,5-Oxadiazole , 1,3,4-Oxadiazole, 1,2,3-Thiadiazole, 1,2,4-Thiadiazole Examples of five-membered rings include 1,2,5-thiadiazole, 1,3,4-thiadiazole, etc. The heteroaryl groups are pyridine, pyridazine, 1,3,5-triazine, 1,2 ,4-triazine, 1,2,3-tetrazine, 1,2,3,4-tetrazine, 1,2,3 ,5-tetrazine, or indole, isoindole, indole, Dolizine, indazole, benzimidazole, benzotriazole, purine, naphthimine dazole, phenanthrimidazole, pyrimidazole, pyrazinimidazole, quinoxa Linimidazole, benzoxazole, naphthoxazole, anthroxazole, Phenanthroxazole, isoxazole, benzothiazole, benzofuran, isoben Benzofuran, dibenzofuran, quinoline, isoquinoline, pteridine, benzo-5,6- Quinoline, Benzo-6,7-quinoline, Benzo-7,8-quinoline, Benzoisoquinoline , acridine, phenothiazine, phenoxazine, benzopyridazine, benzopyrimidine , quinoxaline, phenazine, naphthyridine, azacarbazole, benzocarboline, Pheno[2,3b]thiophene, phenanthroline, thieno[3,2b ]thiophene, dithienothiophene, isobenzothiophene, dibenzothiophene, and and benzothiadiazothiophene and other fused rings containing six members. Unless otherwise specified in the specification, the ring atoms of a heteroaryl group are independently selected at each ring atom. The group is optionally substituted with one or more substituents as defined above.

[0028] "Hydroxyalkyl" refers to an alkyl group having at least one hydroxyl (- In one embodiment, the nomenclature refers to an alkyl group having an OH (also called hydroxy) substitution. There is one hydroxyl substituent on the bonded group (e.g., phenyl, alkyl). In embodiments, two hydroxyl substituents, or one to two hydroxyl substituents, or There are three hydroxyl substituents, or one to three hydroxyl substituents. When used in the above, "C1-C6 hydroxyalkyl" means 1 to 6, e.g., 1, 2, It refers to a linear or branched alkyl group containing 3, 4, 5 or 6 carbon atoms. Examples of C6 hydroxyalkyl radicals are methyl, ethyl, n-propyl, iso-propyl. butyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl, where dicarbal, for example, as in one embodiment, has one or more hydroxyl substituents, The radical may have one hydroxyl substituent.

[0029] "Independently selected" with respect to a group of alternatives, e.g., a group of substituents, means that each substituent is independently selected from the others. are selected without regard to any selection made for any of the substituents, i.e., each substituent is Thus, each selected substituent is selected from a group of substituents. For clarity, the groups may be the same or different from the other substituents listed. A disclosure that something is selected from is treated as an independent entity for each occurrence if the selection is made multiple times. Unless expressly stated otherwise, and Atoms and / or the selection of substituents is independently selected.

[0030] "Mammal" refers to a human or animal, including domestic animals and companion animals. The phrase "companion animals" or "companion animals" refers to animals kept as pets. The term "livestock" refers to animals such as cats, dogs, and horses. Raised under agricultural conditions to produce products such as food or fiber, or for the labor they provide or animals that are raised, such as cattle, goats, horses, pigs, sheep, lambs, and and rabbits, as well as birds such as chickens, ducks and turkeys.

[0031] "Pharmaceutically acceptable" means suitable for use in mammals, companion animals, or livestock. Therefore, a pharma- ceutically acceptable substance or composition is a substance or composition that is used in other ways, including in pharmaceutical preparations. and / or the mammal to be treated therewith, and The materials must be biologically compatible.

[0032] A "pharmaceutical acceptable carrier, diluent or excipient" is a substance that is suitable for use in the manufacture of pharmaceuticals for humans or domestic animals. approved by the U.S. Food and Drug Administration as acceptable for use in Without limitation, any adjuvants, carriers, excipients, glidants, sweeteners, diluents, Fluxing agent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizing agent The composition may include a dispersing agent, an isotonic agent, a solvent, or an emulsifier.

[0033] A "pharmaceutically acceptable salt" may be a "pharmaceutically acceptable salt" depending on the actual structure of the compound. The compound of formula (I) is either an acid addition salt or a pharma- ceutically acceptable base addition salt. If the entity has a basic functional group, such as an amine group, a "pharmaceutically acceptable salt" is an amine salt. Such salts may refer to the acid addition salts of the compounds of the present disclosure or any of their intermediates. Illustrative inorganic acids which form suitable salts include hydrochloric acid, Hydrobromic acid, sulfuric acid, and phosphoric acid, as well as sodium monohydrogen orthophosphate and sulfuric acid Exemplary organic acids which form suitable salts include acid metal salts such as potassium hydrogen. Examples of such acids include, for example, acetic acid, glycosyl esters, and tricarboxylic acids. Acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, alcoholic acid Tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydo 2-Phenoxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, 2-phenoxybenzoic acid, p-thiamine of benzenesulfonic acid, as well as methanesulfonic acid and 2-hydroxyethanesulfonic acid Such salts may be in either hydrous or substantially anhydrous form. In general, the acid addition salts of these compounds can be formed by dissolving them in water or in various solvents. The basic nitrogen-containing group is a halogenated lower alkyl (e.g. , methyl, ethyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates ( dimethyl, diethyl, and dibutyl sulfates), long-chain halides (e.g. (e.g., decyl chloride, bromide, and iodide, lauryl, and stearyl), halogenated arylsulfates, The aryl group may be quaternized with substances such as alkyls (e.g., benzyl and phenethyl bromides). ) has an acidic functional group, e.g., a carboxylic acid group, it is considered to be "pharmacologically acceptable "Salt" may refer to a base addition salt of an acid group. Such base salts are not intended to be limiting of the compounds of the present disclosure or their The term "non-toxic organic or inorganic base addition salt" refers to any non-toxic organic or inorganic base addition salt of any of the intermediate compounds of formula (I). Basic salts include ammonium salts, sodium salts, lithium salts, and potassium salts. alkaline earth metal salts such as potassium salts, calcium and magnesium salts, dicyclohexyl salts with organic bases such as xylamine, t-butylamine, and choline (e.g., organic amines); and salts with amino acids such as arginine and lysine. The counterion of the acidic group may be a quaternized nitrogen-containing group.

[0034] A "prodrug" is a compound that is converted in vivo to produce a pharmacologic equivalent of a compound or compounds of the disclosure. Refers to compounds (e.g., drug precursors) that provide acceptable salts. Conversion can occur, for example, in blood. Prodrugs may be produced by metabolic or chemical processes, such as by hydrolysis at Prodrugs include bioreversible derivatives of the compounds of formula I of the present disclosure. These important properties can be altered by modifying the dissolution rate, lipophilicity, and in vivo distribution. By selectively modifying the This may enable the development of water-soluble IV formulations and enable targeted delivery. In addition, prodrugs have the advantages of transdermal delivery, masking taste, minimizing pain upon injection, and improving stability. This is useful in situations where the pharmacophore itself provides insufficient delivery properties. Therefore, prodrugs are one of the few drugs that can be used to salvage highly active compounds. This is one of the strategies.

[0035] All of the protons of the compounds of formula (1) can be prepared by standard methods known to those skilled in the art. Prodrugs of the compounds of formula (1) are, for example, The following references: Krise JP, Stella VJ, Advanced Drug "Prodrugs of phosphates, phosphonates es, and phosphinates", Krise JP, Stella VJ, Advanced Drug Delivery Reviews, 19 : (2) 287-310 May 22 1996; "Targeted Prodrug Design to Optimize Drug Delivery". Hyo-Kyung Han and Gordon Amidon. AAPS PharmSci 2000; 2 (1) article 6; "Prodrugs" , L. Prokai and K. Prokai-Tatrai, Chapter 12 in Injectable Drug Development: Te Chniques to Reduce Pain and Irritation, Interpharm Press, Buffalo Grove, Ind., 1 999; "Improved oral drug delivery: Solubility limitations overcome by the use of Fleisher D, Bong R, Stewart BH, Advanced Drug Delivery Reviews, 19: (2) 115-130 May 22 1996; "Permeable, water-soluble, non-irritating prodrugs of c hemotherapeutic agents with oxaalkanoic acids", PCT Int. Publication No. WO 00 / 6 7801; T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems" (1987) vol. .14 ​​of the ACS Symposium Series, and "Bioreversible Carriers in Drug Design" , (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon It can be prepared by the method disclosed in the Press.

[0036] "Solvate" refers to a physical association of a compound of the present disclosure with one or more solvent molecules. One or more of the compounds may exist in solvated and unsolvated forms, and the solvated The formulations are in association with a pharma- ceutically acceptable solvent, such as water, ethanol, etc. All such solvated and unsolvated forms are within the scope of the compounds of formula (1). The physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. Thus, the solvate can be isolated, which means that one or more solvent molecules are not present in the compound of the present disclosure. These may occur when a compound is incorporated into the crystal lattice of a crystalline solid, including a crystalline solid. The term "solvate" encompasses both solution-phase and isolatable solvates. The term encompasses hemisolvates. Non-limiting examples of solvates include methanolates, ethanolates, and the like. These include nitrates and hydrates, where the hydrates are solvates in which the associated solvent molecule is water. The compounds of the present disclosure may be prepared by methods known in the art, including any corresponding solvates. In an exemplary, non-limiting process for preparing a solvate, The compound of the present invention is dissolved in a selected amount of a desired solvent (organic solvent or is dissolved in water or a mixture thereof, and then heated at a rate slow enough so that crystals are formed. The solution can be cooled at 400° C. and the crystals isolated. tical Science (2004) v.93(3) pp. 601-611; EC Tonder et al. AAPS Pharm. Sci. T ech. (2004, Feb 23), v.5(1) p.E12; and AL Bingham et al. Chem. Commun. (200 1) pp. 603-604. Each of these documents describes the preparation of selected solvates. Provide a process for

[0037] "Subject" refers to mammals, such as humans, as well as livestock. Sometimes called the patient.

[0038] A "substituent" refers to a monovalent group that may be attached to a radical listed above. For example, "substituted "Phenyl" refers to a phenyl ring having one, two, three or four substituents attached to it. The substituents are halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 Hydroxyalkyl, -OH, -O(C1-C6 alkyl), -O(C1-C6 haloal alkyl), -O(C1-C6 hydroxyalkyl), -S(C1-C6 alkyl), -S( C1-C6 haloalkyl), -S(C1-C6 hydroxyalkyl), cyano, amino( -NH2), formyl (-CHO), carboxylic acid (-COOH), carboxylic acid ester ( -COOR, R is a C1-C6 alkyl group. The 5- or 6-membered heterocyclic ring has at least one ring atom bonded to a substituent as defined herein. It refers to a heterocyclic radical that is bonded to

[0039] A "therapeutically effective amount" is an amount that, when administered to a mammal for therapeutic purposes, is effective against a disease or condition. "Therapeutically effective amount" refers to the amount of a compound sufficient to effect such treatment. It will vary depending on the condition of the mammal being treated and its severity, its age, weight, etc.

[0040] "Treatment" or "treating" a condition includes (1) preventing the condition, i.e., may be exposed to or may be predisposed to the condition, but Clinical symptoms or signs of disease in mammals that have not yet experienced or shown symptoms / signs (2) to inhibit a condition, i.e., to prevent symptoms from developing in a subject having the condition to arrest the manifestation of the condition or its clinical symptoms / signs, including preventing the recurrence of the condition; (3) to alleviate the condition, i.e., to reduce or eliminate the condition or its "Treating" includes causing the regression of clinical symptoms / signs of Or "treatment" can mean the alleviation of symptoms associated with a disease, disorder, or condition, or the alleviation of symptoms. Depending on the patient's disease and condition, the details of this specification may be changed. The term "treatment" as used herein may include one or more of curative, palliative and prophylactic treatment. Treatment may also include administering the pharmaceutical formulations of the present disclosure in combination with other therapies. The compounds of the present disclosure may also be administered in conjunction with other drugs and / or therapies. The terminology used in the specification is for the purpose of describing particular embodiments only and is not intended to be limiting. It should be understood that this is not intended to imply that, unless specifically defined herein, Terms used in this specification are to be given their ordinary meanings as known in the relevant art. It is to be further understood that throughout this specification, the terms "in one embodiment" or "embodiment" may be used interchangeably. References to "embodiments" and variations thereof refer to the particular features, structures, or or feature is included in at least one embodiment. The phrases "in one embodiment" or "in an embodiment" in various places throughout the Moreover, references to particular features, structures, or The features may be combined in any suitable manner in one or more embodiments.

[0041] As used in this specification and the appended claims, the singular forms "a," "an," " and "the" refers to plural referents unless the content and context clearly dictate otherwise. "And" and "or" are used interchangeably in the context where appropriate. Therefore, unless expressly indicated as inclusive or exclusive, "and / or" is generally intended to include "and / or." Please also note that this is used in the broadest sense. Therefore, alternative uses (e.g. "and "or" means either one, both, or any combination of the alternatives It should also be understood that when "and / or" is used herein, it means "and The combination of "and" or "or" refers to embodiments in which all of the associated items or concepts are included; and one or more other embodiments that are not inclusive of all of the related items or concepts. It is intended to encompass all of the above.

[0042] Throughout the specification and the following claims, unless the context otherwise requires, the word "comprising" will be used interchangeably with "comprising" or "including." The term "comprises" and its synonyms and variations, such as "comprises" and "includes"; Variations thereof, such as "comprising" and "containing," are intended to mean, for example, "including, but not limited to" The term "essentially" should be interpreted in an open and inclusive way, such as "not being "Consists of" extends the scope of a patent claim to specific substances or processes, or to the basic and and are limited to those that do not substantially affect the novel features.

[0043] As described herein, for the sake of brevity, in some cases, patients, clinicians, etc. Any other person may be described in the context of the male gender. Healthcare professionals may As used herein, the terms "he," "his," "himself," etc. It is understood that the term should be interpreted broadly to include all known definitions of gender.

[0044] Any headings used in this document are for ease of reading. and should not be construed as limiting the invention or the disclosure or claims in any way. Accordingly, the headings and abstracts of the disclosure provided herein are for convenience only. These are for illustrative purposes only and do not interpret the scope or meaning of the embodiments.

[0045] In one aspect, the present disclosure provides a compound of formula (1) [ka] or a pharma- ceutically acceptable enantiomer, diastereomer, salt, or solvate thereof. wherein Ar is a 9- or 10-membered bicyclic aromatic ring system, Ar has 1, 2 or 3 substituents is optionally substituted with a substituent; L is selected from a direct bond and methylene; R 1 is hydrogen, halide, C1-C6 alkyl, C1-C6 haloalkyl, C1- Substituted with C6 alkoxy, C3-C6 cycloalkoxy, and C3-C6 cycloalkyl C1-C6 alkoxy; A is selected from a direct bond, -CH2-, and -CH2CH2-; E is -C(O)-R 2 , C(OR 3 )R 4 R 5 , and CH(R 6 )NR 7 R 8 from Selected; R 2 is selected from methyl, ethyl, and phenyl; R 3 is selected from hydrogen, alkyl, and substituted alkyl; R 4 is selected from hydrogen, alkyl, and phenyl; R 5 is C1-C7 alkyl, C1-C7 haloalkyl, phenyl, and substituted phenyl. Selected from the following; R 6 is selected from hydrogen, methyl, halogenated methyl, and ethyl; R 7 is hydrogen; R 8 is hydrogen, methyl or ethyl; However, R 7 and R 8and together form an optionally substituted 5- or 6-membered heterocyclic ring, That's fine.

[0046] For ease of explanation, formula (1) is herein written as follows: There is a match, [ka] In the above formula, Ar1 and Ar2 are used to specifically refer to one of the two aromatic rings. In addition, for each description, Ar1, which is a 9- or 10-membered bicyclic aromatic ring system, is an aromatic It is sometimes called the incense ring.

[0047] Within the scope of the compounds of formula (1) are pharma- ceutically acceptable enantiomers, diastereomeric forms thereof. When the compound of formula (1) contains a chiral center, it is It may exist in either the (R) or (S) configuration and therefore has two enantiomeric forms. In one embodiment, the present disclosure provides a method for producing two enantiomeric forms of a compound of formula (1). The compound of claim 1 is provided as a racemic mixture of isomers. The disclosure relates to a method for preparing a compound of formula (1) as a non-racemic mixture of the enantiomers of the compound of formula (1). That is, both the (R) and (S) enantiomers are present together in the mixture. However, the molar ratio of (R):(S) is not equal to 1. In one embodiment, the present disclosure provides an isolated As the (S) enantiomer, i.e. in a mixture with the corresponding (R) enantiomer The compound of formula (1) is provided in a mixture with less than 1% of the (R) enantiomer. In one embodiment, the present disclosure provides the compound as an isolated (R) enantiomer, i.e. , unmixed with the corresponding (S) enantiomer or containing less than 1% of the (S) enantiomer A compound of formula (1) is provided in admixture with an omer.

[0048] In the compounds of formula (1), Ar (Ar1) is a 9- or 10-membered bicyclic aromatic ring system. where Ar may be optionally substituted with 1, 2 or 3 substituents. A ring system refers to a moiety having two rings fused together, and a bicyclic aromatic ring is one in which at least one of the rings is fused together. A moiety having two rings fused together, one of which and optionally two (both) of which are aromatic rings. In one embodiment, only one of the two rings of the bicyclic aromatic ring system is aromatic. In one embodiment, both rings of the bicyclic aromatic ring system are aromatic rings. refers to the number of atoms that form the ring system. For example, a 6-membered ring fused to a 5-membered ring results in a 9-membered ring. A 6-membered ring is fused to a 6-membered ring to form a 10-membered ring system.

[0049] In one embodiment, Ar1 is a 9-membered bicyclic aromatic ring system in which a 5-membered ring is fused to a 6-membered ring. Examples of 9-membered Ar groups according to the present disclosure include benzofuran, 1,3-benzoxazolidine, and the like. furo[3,2-b]pyridine, furo[3,2-c]pyridine, furo[2,3-c]pyridine Lysine, furo[2,3-b]pyridine, indole, 1H-benzimidazole, 1H- Pyrrolo[3,2-b]pyridine, 1H-pyrrolo[3,2-c]pyridine, 1H-pyrrolo[ 2,3-c]pyridine, 1H-pyrrolo[2,3-b]pyridine, benzothiophene, 1, 3-Benzothiazole, thienol[3,2-b]pyridine, thieno[3,2-c]pyridine Din, thieno[2,3-c]pyridine, benzoxadiazole, benzothiadiazole , benzisoxazole, benzotriazole, and thieno[2,3-b]pyridine Each of the nine-membered ring systems listed may be an Ar group in compounds of formula (1); Each of these ring systems may be optionally substituted with one, two or three substituents.

[0050] In another embodiment, Ar is a 10-membered bicyclic aromatic ring in which the 6-membered ring is fused to another 6-membered ring. Examples of 10-membered Ar groups according to the present disclosure include naphthalene, quinoline, quinazolidinyl, and phenylalanine. quinoxaline, 1,5-naphthyridine, 1,6-naphthyridine, 1,7-naphthyridine 1,8-naphthyridine, isoquinoline, phthalazine, 2,6-naphthyridine, and Each of the ten-membered ring systems listed is a compound of formula (1). and each of these ring systems is substituted with one, two, or three substituents. It may be possible.

[0051] In one optional embodiment, the compound of formula (1) is represented by the formula A as the 1,3-benzothiazole. In another optional embodiment, the compound of formula (1) has 1,3-benzoxa and Ar is selected from zole and quinoline.

[0052] Substituents on Ar refer to monovalent groups which may be attached to any of the ring atoms of the Ar group. In the form, the substituents are halide, C1-C4 alkyl, C1-C4 haloalkyl, C 1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 thioalkyl, C1-C4 Thiohaloalkyl, C1-C4 hydroxyalkyl, -SO2(C1-C4 alkyl), The alkyl group may be selected from cyano, carboxylic acid, and C1-C4 carboxylic acid ester. In one embodiment, Ar has no substituents. In one embodiment, Ar is monosubstituted, where: Optionally, one substituent may be selected from those listed above. For example, in one embodiment In this embodiment, Ar contains one substituent that is a C1-C4 thioalkyl, e.g., -S-methyl. In another embodiment, Ar is disubstituted, where the two substituents are as listed above. In yet another embodiment, Ar is trisubstituted and wherein, optionally, the three substituents may be independently selected from those listed above. In one optional embodiment, the compound of formula (1) has one substituent on Ar, where , one of the substituents is -S-CH3.

[0053] The Ar group (sometimes referred to herein as Ar1) is a central benzoate in the compound of formula (1). It is bonded to the Zene ring (sometimes referred to as Ar2 in this specification) via a -LO group. In one embodiment, L is a directional bond and the Ar group is bonded to the In another embodiment, L is a methyl group. The Ar group is connected to the central benzene ring in the compound of formula (1) via a -CH2-O- bond. is combined with

[0054] The central benzene ring in formula (1) is R 1 is bonded to R 1 However, hydrogen, halides, C 1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C6 cyclo alkoxy, and C1-C6 alkoxy substituted with C3-C6 cycloalkyl; In one embodiment, R 1 is hydrogen, and the central benzene ring (Ar2) is unsubstituted. In another embodiment, R 1 is not hydrogen, but the central benzene ring is substituted In one embodiment, R 1 is a halide (e.g., fluoride). So, R 1 is C1-C6 alkyl, for example methyl or ethyl. , R 1 is C1-C6 haloalkyl, for example, trifluoromethyl. is R 1 is C1-C6 alkoxy, for example, methoxy or ethoxy. In this state, R 1 is C3-C6 cycloalkoxy, for example, cyclopropyloxy, cyclo butyloxy or cyclopentyloxy. In one embodiment, R 1 But C3-C6 C1-C6 alkoxy substituted with cycloalkyl, for example, -O-CH2-cycloalkyl. where -O-CH2- is a C1 alkyl group substituted with a C3 cycloalkyl group. It's Lekoxy.

[0055] In the compound of formula (1), the central aromatic ring (benzene) is preferably R 1 , and -AE. In fact, A connects the E group to the central aromatic ring. The A group is selected from a direct bond, methylene, and ethylene. The E group is -C(O)-R 2 , i.e., R 2 Carbonyl group, C(OR 3 )R 4 R 5 , i.e., OR 3 , R 4 and R 5 and CH( R 6 )NR 7 R 8 , i.e., hydrogen, R 6 and N.R. 7 R8 Select from carbons bonded to each of For example, A can be a direct bond and E can be -C(O)-R 2 , C(OR 3 ) R 4 R 5 , and CH(R 6 )NR 7 R 8 That is, in one embodiment, AE is -C(O)-R 2 and in another embodiment, AE is C(OR 3 )R 4 R 5 in and in yet another embodiment, AE is CH(R 6 )NR 7 R 8 Or, A may be methylene, and E is -C(O)-R 2 , C(OR 3 )R 4 R 5 , and C.H. (R 6 )NR 7 R 8 In one embodiment, AE is selected from the group consisting of -CH2-C (O)-R 2 and in another embodiment, AE is -CH2-C(OR 3 )R 4 R 5 Yes and in yet another embodiment, AE is -CH-CH(R 6 )NR 7 R 8 Furthermore, In another embodiment, A may be ethylene and E is -C(O)-R 2 , C(OR 3 )R 4 R 5 , and CH(R 6 )NR 7 R 8 That is, in one embodiment, , AE is CH2CH2-C(O)-R 2 and in another embodiment, AE is CH2C H2-C(OR 3 )R 4 R 5 and in yet another embodiment, AE is CH2CH2- CH(R 6 )NR 7 R 8 In one embodiment, A is a direct bond. In another embodiment, A is -CH2CH2-. In terms of form, R 5 is trifluoromethyl.

[0056] In one embodiment, E is -C(O)-R 2 where R 2 However, methyl, ethyl or is phenyl, for example, E is C(O)CH3, i.e., acetyl, C(O)CH 2CH3, or C(O)phenyl, i.e., benzoyl. Thus, in one embodiment, when A is a direct bond, -AE is -C(O)-R 2 Yes In another embodiment, when A is methylene, -AE is CH2-C(O)-R 2 Yes For example, -CH2-C(O)CH3, or -CH2C(O)CH2CH3, or In yet another embodiment, when A is ethylene, A -E is CH2CH2C(O)-R 2 For example, -CH2CH2C(O)CH3 or -CH2CH2C(O)CH2CH3 or CH2CH2C(O)phenyl.

[0057] In one embodiment, E is C(OR 3 )R 4 R 5 where R3 is hydrogen, alkyl and substituted alkyl; R 4 is selected from hydrogen, alkyl, and phenyl; And R 5 is C1-C7 alkyl, C1-C7 haloalkyl, phenyl, and substituted phenyl. In one embodiment, R 5 is trifluoromethyl, and R 3 is hydrogen It is.

[0058] In one embodiment, E is CH(R 6 )NR 7 R 8 where R 6 But hydrogen, methyl , halogenated methyl, and ethyl; R 7 is hydrogen; R 8 But hydrogen, For example, in one embodiment, E is CH(R 6 )NH2, CH( R 6 )NH(CH3), and CH(R 6 )NH(CH2CH3). In the embodiment, R 7 and R 8 means, together with the nitrogen atom to which they are attached, an optionally substituted and the heterocycle may form a 5- or 6-membered heterocycle having R 7 and R 8 Both are combined and one or more, e.g., two, non-carbon atoms, e.g., oxygen or nitrogen. Therefore, optionally, R 7 and R 8 and optionally substituted 5-membered or forms a six-membered heterocyclic ring, which is 7 R 8 An example of a five-membered ring is pyrrolo. Lysine and its unsaturated analogues, such as 2,5-dihydro-1H-pyrrole. Therefore, -NR 7 R 8 may represent 2,5-dihydro-1H-pyrrole. Examples of rings are piperidine and its unsaturated analogues, such as 1,2,3,4-tetrahydropiperidine. The five-membered and six-membered heterocycles are, respectively, at least Each of the heterocyclic rings has one nitrogen atom, and optionally a second heteroatom ring atom, such as oxygen, nitrogen, and and sulfur. Five- and six-membered heterocycles are described herein. In one embodiment, the substituents are halogen, C1-C6 alkyl, C1-C6 aryl ... alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, hydroxyl(-O H), oxo(=O), -O(C1-C6 alkyl), -O(C1-C6 haloalkyl) , -O(C1-C6 hydroxyalkyl), -S(C1-C6 alkyl), -S(C1- C6 haloalkyl), S(C1-C6 hydroxyalkyl), cyano, amino(-NH2 ), formyl (-CHO), carboxylic acid (-COOH), carboxylic acid ester (-COO R, R is C1-C 10 alkyl group). Thus, in one embodiment, E is CH(R 6 )NR 7 R 8 where: (i) R 6 But hydrogen, methyl, halogen methyl, ethyl, and ethyl; and R 7 is hydrogen and R 8 But hydrogen, methyl and ethyl; or (ii) R 7 and R 8 means that the two are combined Together with the N atom, forms an optionally substituted 5- or 6-membered heterocycle, where the heterocycle is R 7 and R 8 and one or more, e.g., two non-carbon It includes atomic atoms such as oxygen or nitrogen.

[0059] In the compound of formula (1), Ar may be an unsubstituted aryl, and may be 1, 2 or In one embodiment, Ar has no substituents. In another embodiment, In yet another embodiment, Ar has one substituent. In yet another embodiment, Ar has two substituents. In yet another embodiment, Ar has three substituents. When Ar has no substituents, In this case, the present disclosure relates to a compound of formula (1) [ka] and pharma- ceutical acceptable salts thereof, wherein Ar is an unsubstituted 9- or 10-membered L is selected from a direct bond and methylene; R 1 But hydrogen, Selected from halide, C1-C6 alkyl, haloalkyl, and C1-C6 alkoxy. A is selected from a direct bond, -CH2-, and -CH2CH2-; E is - C(O)-R 2 , C(OR 3 )R 4 R 5 , and CH(R 6 )NR 7 R 8 Selected from; R 2 is selected from methyl, ethyl, and phenyl; R 3 is hydrogen, alkyl, and and substituted alkyl; R 4 is selected from hydrogen, alkyl, and phenyl; R 5is C1-C7 alkyl, C1-C7 haloalkyl (e.g., trifluoromethyl) , phenyl, and substituted phenyl; R 6 However, hydrogen, methyl, and halogenated methyl R is selected from aryl, ethyl, and 7 is hydrogen; R 8 is hydrogen, methyl or ethyl where R 7 and R 8 and each independently represent an optionally substituted 5- or 6-membered heterocycle. In one such embodiment, A is ethylene and E is -C(O)-. R 2 and R 1 is selected from halide and alkoxy to provide a compound As a result, when Ar-LO is benzoxazol-2-yloxy, Provided is a compound of the formula: [ka] For example, the following compound: [ka] In another such embodiment, A is ethylene and E is C(OR 3 )R 4 R 5 and Here, R 3 is hydrogen and R 4 is alkyl, e.g., ethyl, and R 5 C1-C7 trifluoroalkyl, for example trifluoromethyl; 1 is C1-C4 alkoxy, As a result, when Ar-LO is 1,3-benzothiazol-2-yloxy, the following formula The present invention provides a compound of the formula: [ka] For example, the following compound: [ka] [ka] [ka] and [ka] In another such embodiment, A is ethylene and E is C(OR 3 )R 4 R 5 and , where R 3 is hydrogen and R 4 is alkyl, e.g., methyl, and R 5 But, C1 -C7 haloalkyl, for example trifluoromethyl; R 1 However, C1-C4 alkoxy and thus, Ar-LO is 1,3-benzothiazol-2-yloxy. In this case, a compound of the formula: [ka] For example, the following compound: [ka] In another embodiment, A is ethylene and E is C(OR 3 )R 4 R 5 where R 3 is selected from hydrogen, alkyl, and substituted alkyl; R 4 is hydrogen and R 5 but, Selected from C1-C7 alkyl, C1-C7 haloalkyl, phenyl, and substituted phenyl. R 1is hydrogen, halide, C1-C6 alkyl, haloalkyl, and C1- C6 alkoxy, so that, for example, Ar-LO is 1,3-benzothiazo When the compound is aryl-2-yloxy, the compound is provided with the formula: [ka] For example, a compound of the formula: [ka] for example, [ka] and [ka] for example, [ka] In another embodiment, R 1 can be hydrogen, thereby providing a compound of the formula: [ka] for example, [ka] In another embodiment where Ar is unsubstituted, the disclosure provides compounds having the formula: [ka] Includes those having the formula: [ka] For example, R 1 When is alkoxy, the compound is: [ka] and [ka] In another embodiment, Ar is unsubstituted, R1 is hydrogen, A is ethylene and E is C(OR 3 )R 4 R 5 ;R 3 is selected from hydrogen, alkyl, and substituted alkyl. R 4 is selected from hydrogen, alkyl, and phenyl; R 5 But C1-C7 alkyl is selected from C1-C7 haloalkyl, phenyl, and substituted phenyl, such that For example, a compound of the formula: [ka] For example, the following compound: [ka] and [ka] In another embodiment, Ar is unsubstituted and R 1 is C2-C4 alkoxy, for example, Provided is a compound of the formula: [ka] For example, the following compound: [ka] Other compounds of the present disclosure having unsubstituted Ar groups include the following: [ka] and [ka] for example, [ka] and [ka] In another embodiment, Ar is unsubstituted and E is -C(OH)(CF3)(CH2CH3). which results in the provision of a compound of the formula: [ka] For example, the following compound: [ka] Other compounds of the present disclosure having unsubstituted Ar groups have Ar where A is ethylene and E is C(O)-phenyl, for example, a compound of the formula: [ka] For example, the following compound: [ka] In another embodiment, Ar is unsubstituted and A is a direct bond, e.g., having the formula A compound is provided. [ka] For example, the following compound: [ka] Other compounds in which A is a direct bond have R1 as a hydrogen, resulting in compounds having the formula Provide a mixture. [ka] For example, a compound having the formula: [ka] This compound has the formula: Includes things. [ka] For example, the following compound: [ka] [ka] , and [ka]

[0060] As described above, in the compound of formula (1), Ar may be unsubstituted aryl. When Ar has a substituent, the present disclosure provides a compound of the formula ( Compound 1) [ka]

[0061] and pharma- ceutically acceptable salts thereof, wherein Ar is selected from the group consisting of 1, 2 or 3 substituents. a substituted 9- or 10-membered bicyclic aromatic ring system having a substituent; L is a direct bond and methylene; R 1 is hydrogen, halide, C1-C6 alkyl, haloalkyl A is selected from a direct bond, -CH2-, and - E is selected from -C(O)-R 2 , C(OR 3 )R 4 R 5 , and CH(R 6 )NR 7 R 8 Selected from; R 2is selected from methyl, ethyl, and phenyl. Selected;R 3 is selected from hydrogen, alkyl, and substituted alkyl; R 4 But hydrogen, a R is selected from alkyl, alkyl group, and phenyl; 5 C1-C7 alkyl, C1-C7 haloa alkyl (e.g., trifluoromethyl), phenyl, and substituted phenyl; R 6 is selected from hydrogen, methyl, halogenated methyl, and ethyl; R 7 is hydrogen R 8 is hydrogen, methyl or ethyl; provided that R 7 and R 8 Both, voluntarily In one such embodiment, Ar Optionally, A is selected from CH2 and CH2CH2. For example, a compound of the formula: [ka] Compounds are provided having the formula: [ka] This includes compounds of the formula: [ka] Here, R 9 is one or two independently selected groups on Ar in each occurrence. represents a substituent, R 3 can be hydrogen, thus providing, for example, a compound of the formula . [ka] In the formula, R 4is methyl or ethyl, and the compound is of the formula: [ka] Includes compounds having the formula: [ka] For example, the following compound: [ka] Ar is one or two R 9 In one embodiment, the present disclosure provides a compound having the formula: The present invention provides a compound that [ka] R 9 is thiomethyl, and has the formula: [ka] For example, the following compound: [ka] R 1 Other compounds of the present disclosure having a methoxy group as the aryl group and substitution on Ar include Examples of the formula include: [ka] The following compounds are included: [ka] [ka] , and [ka] Further compounds of the present disclosure having substitutions on Ar include compounds having the formula: can be done. [ka] For example, the following compound: [ka] In another embodiment, Ar is substituted and R 1 is selected from halide and alkoxy; For example, the following compound is provided: [ka] [ka] [ka] [ka] [ka] [ka] and [ka]

[0062] In one embodiment, the compounds of the present disclosure contain hydroxyl and trifluoromethyl as components of the "E" group. For example, the present disclosure includes compounds of the formula [ka] and pharma- ceutically acceptable salts thereof, wherein Ar is a 9- or 10-membered bicyclic ring is an aromatic ring system of the formula, Ar is optionally substituted with 1, 2 or 3 substituents; L is , a direct bond, and methylene; R 1 However, hydrogen, halides, C1-C4 alkoxides alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy; A is directly E is selected from C(OR 3 )R 4 R 5 in where R 3 is hydrogen and R 5 is trifluoromethyl, so that E is C (OH)(CF3)R 4 ;R 4 is selected from hydrogen, methyl, and ethyl. Optionally, the compound of formula (1) comprises R 5 is C1-C7 alkyl; R 5 is methyl R 5 is ethyl; R 5 is C1-C7 haloalkyl; R 5 is phenyl A is -CH2CH2- and R 5 is C1-C7 alkyl; A is -CH2CH2 - and R 5 is methyl; A is -CH2CH2- and R 5 is ethyl; A is -CH2CH2-, and R 5 is C1-C7 haloalkyl; A is -CH2CH2 - and R 5 is phenyl; L is a direct bond and A is -CH2CH2-; R 5 is C1-C7 alkyl; L is a direct bond and A is -CH2CH2-; R 5 is methyl; L is a direct bond, A is -CH2CH2-, and R 5 Ethyl L is a direct bond, A is -CHCH-, and R 5 C1-C7 Haloal alkyl (e.g., trifluoromethyl); L is a direct bond and A is -CH2CH2 - and R 5 is phenyl;Ar is unsubstituted benzothiazol-2-yl; Ar is benzothiazol-2-yl having one substituent; Ar is benzothiazol-2-yl having two substituents and Ar is a benzothiazol-2-yl having three substituents. The present disclosure may be characterized by one or more of: The following exemplary compounds include hydroxyl and trifluoromethyl as components of the "E" group: The present invention provides a compound.

[0063] [ka] [ka]

[0064] In another embodiment, the present disclosure provides a compound of formula (1), including pharma- ceutically acceptable salts thereof. [ka] wherein Ar1 is 6-benzothiazole, where Ar1 is one or and optionally substituted with two substituents, L being a direct bond, such that formula (1) is It has the structure: [ka] In the formula, R 1 is selected from hydrogen, halide, and alkoxy; A is a direct bond, E is selected from -C(O)-R 2 , C(OR 3 )R 4 R 5, and CH(R 6 )NR 7 R 8 Selected from; R 2 However, methyl, ethyl, and phenyl; R 3 is selected from H and a hydroxyl protecting group; R 4 is selected from hydrogen, methyl, and ethyl; R 5 However, methyl, halogenated methyl (e.g. For example, trifluoromethyl, ethyl and phenyl; R 6 But hydrogen, methyl R is selected from halogen, halogenated methyl, and ethyl; 7 is hydrogen; R 8 But methyl or ethyl; 7 and R 8 and optionally substituted 5-membered or The Ar group may form a 6-membered heterocycle. Additionally, the present disclosure includes 6-benzothiazole as an Ar group. The following exemplary compounds are provided: [ka] [ka] [ka]

[0065] In another embodiment, the present disclosure provides a compound of formula (1) [ka] and pharma- ceutically acceptable salts thereof, wherein Ar1 is a naphthalene radical or or a heterocyclic analog thereof, wherein Ar1 is optionally substituted with one or two substituents. L may optionally be a methylene group (-CH-), where R 1 But hydrogen, halo A is selected from a direct bond, -CH2-, and -CH 2CH2-; E is selected from -C(O)-R 2 , C(OR 3 )R 4 R 5 , and C.H. (R 6 )NR 7 R 8 Selected from; R 2 is selected from methyl, ethyl, and phenyl; R 3 is selected from H and a hydroxyl protecting group; R 4 is hydrogen, methyl, and ethyl; R 5 However, methyl, halogenated methyl (e.g., trifluoromethyl ), ethyl and phenyl; R 6 are hydrogen, methyl, halogenated methyl, and and ethyl; R 7 is hydrogen; R 8 is methyl or ethyl; S, R 7 and R 8 and together may form an optionally substituted 5- or 6-membered heterocyclic ring. Further, the present disclosure provides the following compounds containing naphthyl or heterocyclic analogs of naphthyl as the Ar group: Exemplary compounds are provided. [ka] In the above formula, R 1 is selected from hydrogen, halide, and alkoxy; A is directly bonded to when E is selected from -CH2-, -CH2 ... 2 , C( OR 3 )R 4 R 5 , and CH(R 6 )NR 7 R 8E is selected from -C(O)-R 2 , C(OR 3 )R 4 R 5 , and CH(R 6 )NR 7 R 8 Selected from; R 2 But, Meth R is selected from aryl, ethyl, and phenyl; 3 is selected from H and a hydroxyl protecting group. Selected;R 4 is selected from hydrogen, methyl, and ethyl; R 5 But methyl, halogen R is selected from methyl (e.g., trifluoromethyl), ethyl and phenyl; 6 but , hydrogen, methyl, halogenated methyl, and ethyl; R 7 is hydrogen; R 8 is methyl or ethyl; 7 and R 8 Both of these are compounds of the formula Such optionally substituted 5- or 6-membered heterocyclic rings may be formed. [ka] In the formula, R 1 is selected from hydrogen, halide, and alkoxy; R 3 But H and hydroxyl protecting groups; R 4 is selected from hydrogen, methyl, and ethyl; R 5 However, methyl, halogenated methyl (e.g., trifluoromethyl), ethyl and phenoxy groups are nil, for example: [ka] [ka] [ka] [ka] Furthermore, the present disclosure provides the following compounds containing naphthyl or heterocyclic analogs of naphthyl as the Ar group: Exemplary compounds of the formula are provided, for example, compounds of the formula: [ka] In the above formula, R 1 is selected from hydrogen, halide, and alkoxy; A is directly bonded to when E is selected from -CH2-, -CH2 ... 2 , C( OR 3 )R 4 R 5 , and CH(R 6 )NR 7 R 8 Selected from; R 2 However, methyl, ethyl R is selected from aryl, aryl, and phenyl; 3 is selected from H and a hydroxyl protecting group; R 4 is selected from hydrogen, methyl, and ethyl; R 5 Methyl, halogenated methyl (e.g., trifluoromethyl), ethyl and phenyl; R 6 But hydrogen, methyl, halogenated methyl, and ethyl; R 7 is hydrogen; R 8 But, ethyl or ethyl; 7 and R 8 and optionally, a compound of the formula The heterocyclic ring may form an optionally substituted 5- or 6-membered heterocycle. [ka] In the formula, R 1is selected from hydrogen, halide, and alkoxy; R 2 But methyl, ethyl, and phenyl, for example a compound of the formula: [ka]

[0066] In one embodiment, the compounds of the present disclosure have a nitrogen atom as part of the E group, more specifically E is -CH(R 6 )NR 7 R 8 For example, the present disclosure provides a compound of the formula [ka] and pharma- ceutically acceptable salts thereof, wherein Ar is a 9- or 10-membered bicyclic ring is an aromatic ring system of formula: Ar may be optionally substituted with one or two substituents; L is R is selected from a direct bond and methylene; 1 are hydrogen, halide, and alkoxy. A is selected from a direct bond, -CH2-, and -CH2CH2-; E But CH(R 6 )NR 7 R 8 ;R 6 is hydrogen, methyl, methyl halide, and ethyl; R 7 is hydrogen; R 8 is methyl or ethyl; R 7 and R 8 and may together form an optionally substituted 5- or 6-membered heterocyclic ring. Optionally, the compound of formula (1) comprises R 7 and R 8 and an optionally substituted 5- or 6-membered heterocycle Form; R 1 is hydrogen; A is CH2CH2; R 7and R 8 and are optionally replaced R may form a 5- or 6-membered heterocyclic ring. 1 is hydrogen and A is CH2CH2 , for example, the following compounds are provided: [ka] [ka] [ka] Optionally, such compounds of formula (1) can be prepared, for example, to provide compounds of the formula , may be additionally characterized by specifying that A is a direct bond. [ka] [ka] and [ka] Optionally, such compounds of formula (1) can be prepared, for example, to provide compounds of the formula , R 1 is not hydrogen, but R 7 is hydrogen and R 8 Identify that is methyl or ethyl The method may be additionally characterized by: [ka]

[0067] In one embodiment, the compounds of the present disclosure have a carbonyl group (C(O)) as part of the E group. More specifically, E is -CH(R 6 )NR 7 R 8 For example, the present disclosure provides a compound having the formula ( Compound 1) [ka] and pharma- ceutically acceptable salts thereof, wherein Ar is a 9- or 10-membered diamine. A cyclic aromatic ring system, Ar is optionally substituted with 1, 2 or 3 substituents; L is selected from a direct bond and methylene; R 1 However, hydrogen, halides, C1-C6 alkyl A is selected from alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy; E is selected from -C(O)-R 2 Yes R 2 is selected from methyl, ethyl, and phenyl. For example, the present disclosure provides providing a compound of the formula [ka] In the above formula, Ar is a 9- or 10-membered bicyclic aromatic ring system, Ar is a 1-, 2- or 3-membered is optionally substituted with three substituents; L is selected from a direct bond and methylene; R 1 is selected from hydrogen, halide, C1-C6 alkyl, C1-C6 haloalkyl, and C 1-C6 alkoxy; A is -CH2CH2-; E is -C(O)-R 2 ;R 2 is phenyl, including compounds of the formula: [ka] In the above formula, Ar is a 9- or 10-membered bicyclic aromatic ring system, Ar is a 1-, 2- or 3-membered is optionally substituted with three substituents; L is selected from a direct bond and methylene; R 1is C1-C6 alkoxy, particularly methoxy; A is -CH2CH2-; E -C(O)-R 2 ;R 2 is phenyl, including compounds of the formula: [ka] In the formula, R 1 is hydrogen, halide, C1-C6 alkyl, such as the compound of the formula It is selected from C1-C6 haloalkyl, and C1-C6 alkoxy. [ka]

[0068] In one embodiment, the compounds of the present disclosure are all those having halide substitution on the central aromatic ring. That is, R 1 For example, the present disclosure relates to compounds of formula (1) in which In one aspect, the present disclosure provides a compound of formula (1): [ka] and pharma- ceutically acceptable salts thereof, wherein Ar is a 9- or 10-membered diamine. A cyclic aromatic ring system, Ar is optionally substituted with 1, 2 or 3 substituents; L is selected from a direct bond and methylene; R 1 is a halide; A is a direct bond , -CH-, and -CHCH-; E is selected from -C(O)-R 2 , C(O R 3 )R 4 R 5 , and CH(R 6 )NR 7 R 8 Selected from; R 2 However, methyl and ethyl and phenyl; R 3is selected from hydrogen, alkyl, and substituted alkyl; R 4 is selected from hydrogen, alkyl, and phenyl; R 5 But C1-C7 Al alkyl, C1-C7 haloalkyl (e.g., trifluoromethyl), phenyl, and substituted phenyl; R 6 is selected from hydrogen, methyl, halogenated methyl, and ethyl. Selected;R 7 is hydrogen; R 8 is hydrogen, methyl, or ethyl; 7 and R 8 and may together form an optionally substituted 5- or 6-membered heterocyclic ring. For example, The present disclosure provides a compound of the formula: [ka] In the formula, R 1 is a halide and R 2 is selected from methyl, ethyl, and phenyl; For example: [ka] [ka] and [ka] In the above formula, R 1 is a halide and R 3 is selected from hydrogen, alkyl, and substituted alkyl. Selected from; R 4 is selected from hydrogen, alkyl, and phenyl; R 5 But, C1-C 7 alkyl, C1-C7 haloalkyl (e.g., trifluoromethyl), phenyl, and and substituted phenyl; for example: [ka] and [ka]

[0069] Compounds of the present disclosure also include any pharma- ceutically acceptable compound of formula (1) and one or more isotopically labeled by replacing an atom of with an atom having a different atomic mass or mass number The present disclosure is intended to encompass all of the above-disclosed compounds and any subset thereof that may be incorporated into the compounds of the present disclosure. Examples of isotopes that can be determined include hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine. Examples of isotopes include: 2 H, 3 H, 11 C, 13 C. 14 C. 13 N , 15 N, 15 O. 17 O. 18 O. 31 P, 32 P, 35 S, 18 F, 36 Cl, 12 3 I, and 125 These radiolabeled compounds are, for example, Characterize the mode of action or binding affinity to pharmacologically important sites of action. It is useful to help determine or measure the effectiveness of a compound by applying Certain isotopically labeled compounds of the present disclosure, e.g., compounds incorporating a radioactive isotope, may be This is useful in drug and / or substrate tissue distribution studies. Mu, that is 3 H, and carbon 14, i.e. 14C is easily incorporated and detectable are particularly useful for this purpose because they are available in 2 Like H Substitution with heavier isotopes may result in greater metabolic stability, e.g., increased in vivo half-life. or may confer certain therapeutic advantages through reduced dosage requirements, Therefore, this may be preferable in some circumstances. 11 C. 18 F, 1 O. 13 N and other positive electrodes Substitution with neutron-emitting isotopes allows for positron emission topography to investigate substrate receptor occupancy The isotopically labeled compounds of the present disclosure may be useful in PET studies. or by processes similar to those described in the preparations and examples below. The process allows the use of suitable isotope-labeled reagents instead of the traditionally used non-labeled reagents. can be prepared.

[0070] In many cases, crystallization produces solvates of the compounds of the present disclosure. When used herein, the term "solvate" refers to a mixture of one or more molecules of a compound of the present disclosure with one or more solvent components. The solvent may be water, in which case the solvate may be a hydrate. Alternatively, the solvent may be an organic solvent. Thus, the compounds of the present disclosure may be in the form of monohydrates, dihydrates, hydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate, and the corresponding solvated forms. The compounds of the present disclosure may be true solvates, but in other cases may exist as hydrates. In some cases, the compounds of the present disclosure merely retain water adventitiously or do not retain water. and adventitious solvent.

[0071] Some of the specific compounds of the present disclosure are shown in Table 1, where the specific compounds are designated by compound number (No. .), and are identified by their compound structures and compound names, respectively.

[0072] [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]

[0073] In embodiments, the present disclosure provides a compound of Table 1 listed alone or in any combination: and pharma- ceutically acceptable enantiomers, diastereomers, salts, or solvates thereof. Provide something.

[0074] The present disclosure also relates to compounds of formula (I) as described above and in the following numbered exemplary embodiments. The present invention provides a compound of formula (I). 1) A compound of formula (1) [ka] or a pharma- ceutically acceptable enantiomer, diastereomer, salt, or solvate thereof. A solvate of the formula: Ar is a 9- or 10-membered bicyclic aromatic ring system, Ar has 1, 2 or 3 substituents is optionally substituted with a substituent; L is selected from a direct bond and methylene; R 1 is hydrogen, halide, C1-C6 alkyl, C1-C6 haloalkyl, C1- Substituted with C6 alkoxy, C3-C6 cycloalkoxy, and C3-C6 cycloalkyl C1-C6 alkoxy; A is selected from a direct bond, -CH2-, and -CH2CH2-; E is -C(O)-R 2 , C(OR 3 )R 4 R 5 , and CH(R 6 )NR 7 R 8 from Selected; R 2 is selected from methyl, ethyl, and phenyl; R 3 is selected from H, alkyl, and substituted alkyl; R 4 is selected from hydrogen, alkyl, and phenyl; R5 is C1-C7 alkyl, C1-C7 haloalkyl, phenyl, and substituted phenyl. Selected from the following; R 6 is selected from hydrogen, methyl, halogenated methyl, and ethyl; R 7 is hydrogen; R 8 is hydrogen, methyl, or ethyl; 7 and R 8 and may together form an optionally substituted 5- or 6-membered heterocycle. 2) In the above formula, Ar is a 9- or 10-membered bicyclic ring system containing two aromatic rings, and Ar is unsubstituted; , or halide, C1-6 alkyl; -S-C1-6 alkyl; -O-C1-6 a and -SO2-C1-6 alkyl; L is selected from a direct bond and -CH2- (methylene); R 1 is selected from hydrogen, halide, C1-6 alkyl, C1-6 haloalkyl, and C1 -6alkoxy; A is selected from a direct bond, -CH2-, and -CH2CH2-; E is -C(O)-R 2 , C(OR 3 )R 4 R 5 , and CH(R 6 )NR 7 R 8 from Selected; R 2 is selected from methyl, ethyl, and phenyl; R 3 is H; R 4 is selected from hydrogen, C1-C7 alkyl, and phenyl; R 5 is selected from C1-7 alkyl, C1-7 haloalkyl, phenyl, and halophenyl; Selected from; R 6 is selected from hydrogen, methyl, halogenated methyl, and ethyl; R 7 is hydrogen and R 8 is hydrogen, methyl, or ethyl; or R 7 and R 8 and optionally substituted with a substituent selected from C1-C6 alkyl and carboxylic acid. The compound of embodiment 1, or a pharmaceutical composition thereof, which forms a 5- or 6-membered heterocyclic ring having a substituent. A suitably acceptable enantiomer, diastereomer, salt, or solvate thereof. 3) The compound of embodiment 1 or 2, wherein Ar is 1,3-benzothiazole. 4) The method of embodiment 1 or 2, wherein Ar is selected from 1,3-benzoxazole and quinoline. is a compound according to 2. 5) The compound according to embodiment 1 or 2, wherein Ar is substituted with one substituent that is -S-CH3. The compounds listed above. 6) The compound of embodiment 1 or 2, wherein L is a direct bond. 7) The compound of embodiment 1 or 2, wherein L is methylene. 8) R 1 is hydrogen or C1-C6 alkoxy. thing. 9) The compound of embodiment 1 or 2, wherein A is a direct bond. 10) The compound of embodiment 1 or 2, wherein A is -CH2CH2-. 11) E is -C(OR 3 )R 4 R 5 3. The compound of embodiment 1 or 2, wherein 12) Compound of formula (1) according to embodiment 1 or 2 as a non-racemic mixture of enantiomers The compound according to claim 1, 13) 1-[4-(1,3-benzothiazol-2-yloxy)-3-methoxyphenyl [l]-3-(trifluoromethyl)pentan-3-ol; 1-{3-Methoxy-4-[(4-methylsulfanyl-1,3-benzothiazole- 2-yl)oxy]phenyl}-3-(trifluoromethyl)pentan-3-ol; 1-{4-[(4,6-difluoro-1,3-benzothiazol-2-yl)oxy] -3-Methoxyphenyl}-3-(trifluoromethyl)pentan-3-ol; 1-{4-[(6-fluoro-1,3-benzothiazol-2-yl)oxy]-3- Methoxyphenyl}-3-(trifluoromethyl)-pentan-3-ol; 4-[4-(1,3-Benzothiazol-2-yloxy)-3-methoxyphenyl] -1,1,1-trifluoro-2-methylbutan-2-ol; 1,1,1-trifluoro-4-(3-methoxy-4-{[4-(methylsulfanyl )-1,3-Benzothiazol-2-yl]oxy}phenyl)-2-methylbutane-2 -Oar; 1,1,1-trifluoro-2-{4-[(2-methyl-1,3-benzothiazole- 6-yl)oxy]phenyl}propan-2-ol; 1,1,1-trifluoro-2-methyl-4-[4-(quinolin-2-ylmethoxy) phenyl]butan-2-ol; 1,1,1-trifluoro-4-[3-methoxy-4-(quinolin-2-ylmethoxy) )phenyl]-2-methylbutan-2-ol; 1-[4-(quinolin-2-yl-methoxy)-phenyl]-3-(trifluoromethyl) )-pentan-3-ol; 1-(3-Methoxy-4-{[4-(methylsulfanyl)-1,3-benzothiazole (phenyl-2-yl)oxy}phenyl)pentan-3-ol; and 1-(4-{[4-(methylsulfanyl)-1,3-benzothiazol-2-yl] oxy}phenyl)-3-(trifluoromethyl)pentan-3-ol , the compound according to embodiment 1 or 2.

[0075] In addition to the compounds listed above, the disclosure also provides pharmaceutical compositions and methods of therapeutic use of the compounds. The following numbered exemplary embodiments are also provided: 14) A compound according to embodiment 1 or 2, or a pharma- ceutically acceptable enantiomer thereof. a compound, salt or solvate thereof, and at least one pharma- ceutically acceptable carrier, diluent or excipient. and / or an adjuvant. 15) The pharmaceutical composition according to embodiment 14, which is in the form of eye drops. 16) An effective amount of a compound according to embodiment 1 or 2 or embodiment 14 or 15 A method for treating an inflammatory disease or condition comprising administering the composition described herein to a subject in need thereof. A method for treating the condition. 17) The inflammatory disease or inflammatory condition is an ocular inflammatory disease or ocular inflammatory condition, respectively. The method of embodiment 16. 18) A therapeutically effective amount of a compound according to embodiment 1 or 2 or a combination according to embodiment 14. A method for treating a respiratory disease or condition comprising administering to a subject in need thereof a composition comprising: . 19) A therapeutically effective amount of a compound according to embodiment 1 or 2 or a combination according to embodiment 14. The method includes administering to a subject in need thereof a composition comprising: Treatment method.

[0076] As mentioned above, the compounds and compositions of the present disclosure, such as compounds of formula (1), can be used to treat The method of treatment may include administering a therapeutically effective amount of the compound / composition or a prophylactic An effective amount of any of the compounds / compositions may be provided. For example, if a patient is undergoing surgery: To minimize post-operative trauma, the compounds of the present disclosure may be administered prior to surgery. And exemplary therapeutic methods in which the compositions can be used are listed below.

[0077] In one aspect, the disclosure provides a method for treating a chronic inflammatory condition by administering a therapeutically effective amount of the compound described above to a subject in need thereof. The present invention provides a method for treating inflammation, comprising administering to said subject a therapeutically effective amount of

[0078] In another aspect, the present disclosure provides a method for treating a disease comprising administering a prophylactically effective amount of the compound described above to a subject in need thereof. The present invention provides a method for the prophylactic treatment of inflammation, such as asthma and allergies, comprising administering to the patient a therapeutically effective amount of the compound. In conditions such as these, the compounds described herein may be used to prevent the worsening or flare of the condition. It may be administered prophylactically.

[0079] In one aspect, the disclosure provides a method for treating a chronic inflammatory condition by administering a therapeutically effective amount of the compound described above to a subject in need thereof. The present invention provides a method for treating a respiratory disease or condition, comprising administering to said subject a subject a therapeutically effective amount of

[0080] In another aspect, the present disclosure provides a method for administering a therapeutically effective amount of the above-mentioned compound to a subject in need thereof. In one embodiment, the subject to be treated has mild asthma. In another embodiment, the subject to be treated has severe to moderate asthma. do.

[0081] In another aspect, the present disclosure provides a method for treating a disease comprising administering a prophylactically effective amount of the compound described above to a subject in need thereof. In one embodiment, the subject to be treated has mild asthma. In another embodiment, the subject to be treated has severe to moderate asthma. do.

[0082] In another aspect, the present disclosure provides a method for administering a therapeutically effective amount of the above-mentioned compound to a subject in need thereof. including, but not limited to, skin and eye indications. Methods for treating allergic diseases are provided.

[0083] In another aspect, the present disclosure provides a method for treating a disease comprising administering a prophylactically effective amount of the compound described above to a subject in need thereof. including, but not limited to, skin and eye indications. Methods for treating allergic diseases are provided.

[0084] In another aspect, the present disclosure provides a method for treating conjunctivitis. For example, the present disclosure provides a method for treating conjunctivitis. A method for treating allergic conjunctivitis comprising administering to a subject in need thereof an amount of the compound described above. The present invention provides a method for treating conjunctivitis caused by a virus or bacteria, as opposed to allergic conjunctivitis. Conjunctivitis may occur secondary to infections such as eye infections. This can also be caused by the use of

[0085] In another aspect, the present disclosure provides a method for treating conjunctivitis. For example, the present disclosure provides a method for treating conjunctivitis. A method for treating allergic conjunctivitis comprising administering to a subject in need thereof an amount of the compound described above. The present invention provides a method for treating conjunctivitis caused by a virus or bacteria, as opposed to allergic conjunctivitis. Conjunctivitis may occur secondary to infections such as eye infections. This can also be caused by the use of

[0086] In another aspect, the present disclosure provides a method for administering a therapeutically effective amount of the above-mentioned compound to a subject in need thereof. The present invention provides a method for treating uveitis, comprising administering to a subject, for example, an anterior, intermediate, posterior Or they may have panuveitis.

[0087] In another aspect, the present disclosure provides a method for treating a disease comprising administering a prophylactically effective amount of the compound described above to a subject in need thereof. The present invention provides a method for treating uveitis, comprising administering to a subject, for example, an anterior, intermediate, posterior Or they may have panuveitis.

[0088] In another aspect, the present disclosure provides a method for administering a therapeutically effective amount of the above-mentioned compound to a subject in need thereof. The present invention provides a method for treating atopic dermatitis, comprising:

[0089] In another aspect, the present disclosure provides a method for treating a disease comprising administering a prophylactically effective amount of the compound described above to a subject in need thereof. The present invention provides a method for treating atopic dermatitis, comprising:

[0090] In another aspect, the present disclosure provides a method for administering a therapeutically effective amount of the above-mentioned compound to a subject in need thereof. The present invention provides a method for treating psoriasis, comprising:

[0091] In another aspect, the present disclosure provides a method for treating a disease comprising administering a prophylactically effective amount of the compound described above to a subject in need thereof. The present invention provides a method for treating psoriasis, comprising:

[0092] In another aspect, the present disclosure provides a method for administering a therapeutically effective amount of the above-mentioned compound to a subject in need thereof. The present invention provides a method for treating acne vulgaris, comprising:

[0093] In another aspect, the present disclosure provides a method for treating a disease comprising administering a prophylactically effective amount of the compound described above to a subject in need thereof. The present invention provides a method for treating acne vulgaris, comprising:

[0094] In another aspect, the present disclosure provides a method for administering a therapeutically effective amount of the above-mentioned compound to a subject in need thereof. The present invention provides a method for treating tendinopathy, comprising:

[0095] In another aspect, the present disclosure provides a method for treating a disease comprising administering a prophylactically effective amount of the compound described above to a subject in need thereof. The present invention provides a method for treating tendinopathy, comprising:

[0096] In another aspect, the present disclosure provides a method for administering a therapeutically effective amount of the above-mentioned compound to a subject in need thereof. The present invention provides a method for treating bronchopulmonary dysplasia, comprising:

[0097] In another aspect, the present disclosure provides a method for treating a disease comprising administering a prophylactically effective amount of the compound described above to a subject in need thereof. The present invention provides a method for treating bronchopulmonary dysplasia, comprising:

[0098] In another aspect, the present disclosure provides a method for administering a therapeutically effective amount of the above-mentioned compound to a subject in need thereof. The present invention provides a method for treating chronic obstructive pulmonary disease (COPD), comprising administering to a subject, for example, , may have early or mild / moderate COPD.

[0099] In another aspect, the present disclosure provides a method for treating a disease comprising administering a prophylactically effective amount of the compound described above to a subject in need thereof. The present invention provides a method for treating chronic obstructive pulmonary disease (COPD), comprising administering to a subject, for example, , may have early or mild / moderate COPD.

[0100] In another aspect, the present disclosure provides a method for administering a therapeutically effective amount of the above-mentioned compound to a subject in need thereof. The present invention provides a method for treating pulmonary dysfunction, comprising administering to a subject a dose of 0.1% or more of a pulmonary stimulant, such as an environmental pollutant / hazard. Patients may suffer from occupational pulmonary insufficiency associated with exposure to hazards.

[0101] In another aspect, the present disclosure provides a method for treating a disease comprising administering a prophylactically effective amount of the compound described above to a subject in need thereof. The present invention provides a method for treating pulmonary dysfunction, comprising administering to a subject a dose of 0.1% or more of a pulmonary stimulant, such as an environmental pollutant / hazard. Patients may suffer from occupational pulmonary insufficiency associated with exposure to hazards.

[0102] In another aspect, the present disclosure provides a method for administering a therapeutically effective amount of the above-mentioned compound to a subject in need thereof. The present invention provides a method for treating (e.g., neonatal) pulmonary hypertension, comprising administering to a patient a therapeutically effective amount of

[0103] In another aspect, the present disclosure provides a method for treating a disease comprising administering a prophylactically effective amount of the compound described above to a subject in need thereof. The present invention provides a method for treating (e.g., neonatal) pulmonary hypertension, comprising administering to a patient a therapeutically effective amount of

[0104] In another aspect, the present disclosure provides a method for administering a therapeutically effective amount of the above-described compound to a subject in need thereof. The present invention provides a method for treating cancer, comprising administering to the patient a therapeutically effective amount of a compound selected from the group consisting of ribozymes, cyclosporine ... The cancer may be, for example, breast cancer or ovarian cancer. The method includes determining the clinical manifestation of metastasis of an existing cancer (pr esentation) may be provided.

[0105] In another aspect, the present disclosure provides a method for administering a therapeutically effective amount of the above-mentioned compound to a subject in need thereof. The present invention provides a method for treating a neuroinflammatory disease, comprising:

[0106] In another aspect, the present disclosure provides a method for treating a disease comprising administering a prophylactically effective amount of the compound described above to a subject in need thereof. The present invention provides a method for treating a neuroinflammatory disease, comprising:

[0107] In one aspect, the disclosure provides a method for treating a chronic inflammatory condition by administering a therapeutically effective amount of the compound described above to a subject in need thereof. The present invention provides a method for treating a neurodegenerative disease, condition or disorder, comprising administering to said patient a therapeutically effective amount of ... neurodegenerative disease, condition or disorder.

[0108] In another aspect, the present disclosure provides a method for administering a therapeutically effective amount of the above-mentioned compound to a subject in need thereof. The present invention provides a method for treating multiple sclerosis, comprising administering to a patient a therapeutically effective amount of

[0109] In another aspect, the present disclosure provides a method for treating a disease comprising administering a prophylactically effective amount of the compound described above to a subject in need thereof. The present invention provides a method for treating multiple sclerosis, comprising administering to a patient a therapeutically effective amount of

[0110] In another aspect, the present disclosure provides a method for administering a therapeutically effective amount of the above-mentioned compound to a subject in need thereof. The present invention provides a method for treating cystic fibrosis, comprising administering to the patient a therapeutically effective amount of a pulmonary inflammatory agent. may be associated with (e.g., in a non-infectious stage).

[0111] In another aspect, the disclosure provides a method for treating cystic fibrosis, comprising administering a prophylactically effective amount of the above-described The method includes administering a compound to a subject in need thereof. may be associated with (e.g., in a non-infectious stage).

[0112] In another aspect, the present disclosure provides a method for administering a therapeutically effective amount of the above-mentioned compound to a subject in need thereof. The present invention provides a method for treating idiopathic pulmonary fibrosis (IPF), comprising administering to a subject a therapeutically effective amount of ... pulmonary fibrosis inhibitor.

[0113] In another aspect, the present disclosure provides a method for treating a disease comprising administering a prophylactically effective amount of the compound described above to a subject in need thereof. The present invention provides a method for treating idiopathic pulmonary fibrosis (IPF), comprising administering to a subject a therapeutically effective amount of ... pulmonary fibrosis inhibitor.

[0114] In another aspect, the present disclosure provides a method for administering a therapeutically effective amount of the above-mentioned compound to a subject in need thereof. The present invention provides a method for treating Alzheimer's disease, particularly early stage Alzheimer's disease, comprising:

[0115] In another aspect, the present disclosure provides a method for administering a therapeutically effective amount of the above-mentioned compound to a subject in need thereof. The present invention provides a method for treating Sjogren-Larsson syndrome, comprising:

[0116] In another aspect, the present disclosure provides a method for administering a therapeutically effective amount of the above-mentioned compound to a subject in need thereof. A method for treating a cardiovascular (CV) disease (e.g., ACS or plaque formation) comprising administering to said patient The population to be treated may have ischemia / reperfusion injury.

[0117] In another aspect, the present disclosure provides a method for administering a therapeutically effective amount of the above-mentioned compound to a subject in need thereof. The present invention provides a method for treating otitis, comprising administering to the ear a therapeutically effective amount of otitis media. Otitis can occur, for example, secondary to an infection. .

[0118] In another aspect, the present disclosure provides a method for administering a therapeutically effective amount of the above-mentioned compound to a subject in need thereof. The present invention provides a method for treating inflammation associated with eye surgery, comprising:

[0119] In another aspect, the disclosure provides a method for treating a disease comprising administering to a subject in need thereof a prophylactically effective amount of the compound described above. The present invention provides a method for treating inflammation associated with eye surgery, comprising administering to the patient an injection of a dermal patch or a dermal patch.

[0120] In another aspect, the present disclosure provides a method for administering a therapeutically effective amount of the above-mentioned compound to a subject in need thereof. The present invention provides a method for treating dry eye, comprising:

[0121] In another aspect, the present disclosure provides a method for administering a therapeutically effective amount of the above-mentioned compound to a subject in need thereof. The present invention provides a method for treating inflammation associated with cataract surgery, comprising:

[0122] In another aspect, the present disclosure provides a method for treating a disease comprising administering a prophylactically effective amount of the compound described above to a subject in need thereof. The present invention provides a method for treating inflammation associated with cataract surgery, comprising:

[0123] In another aspect, the present disclosure provides a method for administering a therapeutically effective amount of the above-mentioned compound to a subject in need thereof. The present invention provides a method for treating arthritis, comprising administering to the patient a therapeutically effective amount of do.

[0124] In another aspect, the present disclosure provides a method for treating a disease comprising administering a prophylactically effective amount of the compound described above to a subject in need thereof. The present invention provides a method for treating arthritis, comprising administering to the patient a therapeutically effective amount of do.

[0125] In another aspect, the present disclosure provides a method for administering a therapeutically effective amount of the above-mentioned compound to a subject in need thereof. The present invention provides a method for treating inflammation associated with laser eye surgery, comprising:

[0126] In another aspect, the present disclosure provides a method for treating a disease comprising administering a prophylactically effective amount of the compound described above to a subject in need thereof. The present invention provides a method for treating inflammation associated with laser eye surgery, comprising:

[0127] In another aspect, the present disclosure provides a method for administering a therapeutically effective amount of the above-mentioned compound to a subject in need thereof. The present invention provides a method for treating allograft rejection comprising:

[0128] In another aspect, the present disclosure provides a method for treating a disease comprising administering a prophylactically effective amount of the compound described above to a subject in need thereof. The present invention provides a method for treating allograft rejection comprising:

[0129] In another aspect, the present disclosure provides a method for administering a therapeutically effective amount of the above-mentioned compound to a subject in need thereof. The present invention provides a method for treating trauma (e.g., cerebral ischemia) comprising:

[0130] In another aspect, the present disclosure provides a method for administering a therapeutically effective amount of the above-mentioned compound to a subject in need thereof. The present invention provides a method for treating diabetic retinopathy, comprising:

[0131] In another aspect, the present disclosure provides a method for administering a therapeutically effective amount of the above-mentioned compound to a subject in need thereof. The present invention provides a method for treating age-related macular degeneration, comprising:

[0132] In another aspect, the present disclosure provides a method for administering a therapeutically effective amount of the above-mentioned compound to a subject in need thereof. The present invention provides a method for treating diabetic macular edema, comprising:

[0133] As noted elsewhere herein, the present disclosure may be used to treat the above medical conditions. These compositions contain one or more active ingredients other than the compound of formula (1). Optionally, an active agent may be included, which may, for example, supplement the activity of the compound of formula (1). , augment, or complement.

[0134] In one aspect, the disclosure provides a pharmaceutical composition comprising a compound of formula (1). The compounds of the present disclosure can be formulated into pharmaceutical compositions. and at least one pharma- ceutically acceptable carrier, excipient, or diluent. A pharmaceutical composition comprising the agent is provided.

[0135] The compounds of the present disclosure may be used in human or veterinary medicine, as well as other bioactive agents, such as anti-inflammatory agents. Such methods are well known in the art and can be formulated for administration for use in The administration of the drug may be by any route known in the art, such as subcutaneous, inhalation, oral, topical or parenteral. Similarly, the compositions may be administered in any form known to those of skill in the pharmaceutical arts. The administration of the drug may be intravenous (bolus or infusion), intraperitoneal, topical (e.g., intraocular, eye drop), subcutaneous, or intramuscular. It may be administered intramuscularly or transdermally (eg, in the form of a patch).

[0136] The composition is formulated in a form suitable for the desired route of administration. The dosage form is selected, in part, based on the desired route of administration. but includes tablets, capsules, powders, granules, sweetened tablets, creams or liquid preparations The formulation may take any form known in the art. Briefly, examples include solid (e.g., tablet) formulations. tablets, capsules, gel caps, powders, granules, sweetened tablets, delayed-release ) solid forms, slow or sustained release solid forms, capsules in a cellular solid form), or in a liquid form (e.g., liquid gel caps, suspensions, solutions, syrups, etc.) Oral administration is facilitated by the use of compositions such as capsules, elixirs, and liposomal solutions. As another example, the composition may be formulated as a liquid (e.g., , nebulizer solutions / suspensions), or solids (e.g., metered dose inhalers, dry powder inhalers As yet another example, the composition may be delivered via an implant. Examples include ocular implants (e.g., slow-release or sustained-release depot solid forms). matrix) and subcutaneous implants (e.g., sustained-release or extended-release depot pumps) In cases where a healthcare provider deems intravenous administration appropriate, the composition may be administered in a liquid form. (e.g., solution, nanosuspension, liposomal suspension, micellar suspension), or liquid form. The composition may be a solid (e.g., a lyophilized product) that can be reconstituted to provide the desired therapeutic effect. When the preferred route of administration is intramuscular administration, the composition may be administered in the form of a liquid (e.g., a solution, a nanosuspension, liposomal suspensions, micellar suspensions, oil-based formulations), or reconstituted to provide liquid forms Alternatively, the drug may be administered intramuscularly in the form of a solid (e.g., a freeze-dried product). This may be achieved by a well-placed implant. The composition may be administered subcutaneously. in which case the same formulations suitable for intramuscular administration can be used for subcutaneous administration. Intraperitoneal administration can be used to deliver the compounds or compositions of the present disclosure, In the case of, the appropriate form of intraperitoneal administration is a liquid (e.g., a solution, a nanosuspension, a liposomal suspension, , micellar suspension), or solid (lyophilized product for reconstitution). Intrathecal, where the formulation is a liquid (e.g., solution, nanosuspension, liposome, The formulation may be in the form of a liquid suspension (e.g., a micellar suspension), or a solid (e.g., a lyophilized product for reconstitution). Suitable forms include liquids (e.g., solutions, suspensions, emulsions, creams, gels, ointments, In the case of a composition comprising a carrier, the composition may be administered topically to the skin of a subject. , the appropriate form is liquid (e.g., solution, suspension, liposomal suspension, emulsion, ointment) or if solid (e.g. coated implants, implant pumps), Topical administration may be used for delivery to the eye of a subject. The compounds may be formulated into a transdermal patch, which delivers the compounds slowly or sustainably to a subject. Rectal administration may be solid / solid wax or solid oil; or semi-solid Using a suppository such as a solid / semi-solid wax oil based liquid or gel composition of The present disclosure also provides a lyophilized formulation for reconstitution with an appropriate vehicle. Freeze-drying refers to the removal of the liquid components of a formulation to produce a solid phase. The composition may be heated moderately under vacuum to remove the liquid components by techniques known in the art. This can be done by evaporating the water. Thus, the active ingredient is typically Tablets, capsules (either solid-filled, semi-solid-filled or liquid-filled), powders for constitution, Oral gels, elixirs, dispersible granules, syrups, liquids, sterile for topical administration The formulation may be selected based on the intended form of administration, such as a solution or suspension, including solutions and suspensions. In one embodiment, the composition is administered to the eye of a subject and the The composition may be in the form of a liquid composition that can be dropped onto the surface of the eye. Each composition may be prepared in accordance with conventional pharmaceutical practice.

[0137] In one embodiment, the composition is a solid form formulation. For example, for oral administration, the composition The compositions may be in the form of tablets, dispersible granules, and capsules. The active drug component may be combined with any oral, non-toxic, pharma- ceutically acceptable inert carrier. Examples include lactose, mannitol, sucrose and other sugars, starch and and cellulose; as well as calcium sulfate, magnesium stearate and dicalcium phosphate. Another example is a solid that is formulated as a suppository. In preparing suppositories, first, a mixture of fatty acid glycerides or cocoa butter is mixed. The low melting wax is melted and the active ingredient is stirred to disperse it homogeneously. The molten mixture is poured into convenient sized molds and allowed to cool and solidify.

[0138] Other ingredients that may be included in the solid dosage form include conventional binders, lubricants, disintegrants, etc. Suitable binders include starch, gelatin, natural sugars, cane, and coloring agents. Sorghum sweetener, natural and synthetic gums such as gum arabic, sodium alginate, calcium Examples of suitable adhesives include carboxymethylcellulose, polyethylene glycol, and waxes. Lubricants for use in the form include boric acid, sodium benzoate, sodium acetate, salt Disintegrants include starch, methylcellulose, guar In addition, sweeteners, flavoring agents and preservatives may also be added orally, if desired. Conventional excipients that can be included in the composition include: Examples of such antioxidants include acacia, gelatin, sorbitol, tragacanth, polysaccharides, and the like. Binders such as vinylpyrrolidone; e.g., lactose, sugar, corn starch, Fillers such as calcium phosphate, sorbitol, and glycine; magnesium stearate, tallow Tableting lubricants such as cellulose, polyethylene glycol, and silica; disintegrants; or acceptable wetting agents, such as, for example, sodium lauryl sulfate. .

[0139] The solid formulation contains about 0.5 to about 100% by weight of the active ingredient including the compound of formula (1). is fine.

[0140] The compounds of the present disclosure can be formulated into liquid pharmaceutical compositions. Examples of liquid compositions include solutions, suspensions, and emulsions. The liquid composition contains at least one substance, where water is one such material. Other liquid substances that can be administered include propylene glycol parenteral injections. Depending on the application, the liquid composition may be administered, for example, orally, topically, parenterally, intravenously, and intranasally. can.

[0141] Oral liquid formulations include, for example, aqueous or oily suspensions, solutions, emulsions, syrups or The composition may be in the form of an elixir or may be reconstituted with water or other suitable vehicle before use. Such liquid formulations may contain conventional additives. For example, sorbitol, methylcellulose, glucose syrup, gelatin, hyaluronic acid, etc. Hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate suspending agents such as oleyl ester, hydrogenated edible oils and fats; lecithin, sorbitan monooleate, acacia, etc. Any emulsifier; e.g. almond oil, glycerin, propylene glycol, ethyl alcohol non-aqueous vehicles (which may include edible oils), such as oily esters of e.g. p-hydroxybutyric acid; A preservative, such as methyl or propyl benzoate, or sorbic acid; and, if desired, Conventional flavors or colors may be included.

[0142] A liquid form of the pharmaceutical composition allows the composition to be delivered by topical administration, for example as eye drops. The eye drop formulation may be formulated with the intention of providing the eye drop with a concentration of about 0.1% to 1% (by weight) in an eye drop solution. In addition to the compound of formula (1) which may be present in the eye drops at a concentration of 0.1 to 1.0 g / l (based on the standard), cyclodextrin Optionally, the eye drop formulation may contain one or more of the following: hydrochloric acid, methylcellulose, and EDTA. Hydroxypropyl-β-cyclodextrin in the range of 1% to 40% In an exemplary embodiment, the composition may contain 0.1% to 1% of ethyl cellulose. The eye drop formulations contain 10%, 20%, or 30% by weight of hydroxypropyl-β- Cyclodextrin may be optionally included. The amount, timing and delivery of the compounds of the present disclosure may be adjusted. The dosage and mode of administration, whether prophylactic or therapeutic, will depend on the weight, age, and other factors of the individual. Factors such as the patient's gender, condition, the condition being induced or treated, and the delivery, absorption, and Based on pharmacokinetics, including half-life, and other factors known to affect efficacy In an exemplary embodiment, the ocular dose suitable for use is adjusted routinely for each individual. The range is from about 0.01 mg to 1000 mg per day, or from about 0.05 mg to Approximately 1000mg, from about 0.1mg per day to about 1000mg, from about 0.5mg per day Approximately 1000 mg, approximately 2 mg to approximately 1000 mg per day, approximately 0.05 mg to approximately 1000 mg per day 500mg, 0.10mg to 300mg per day, 0.10mg to 100mg per day g, 75mg-450mg per day, 150mg-400mg per day, About 300 mg to about 1500 mg per day, about 600 mg to about 1500 mg per day. is typically 0.5 mg to 3 mg per day, where a dose of 3 mg per day is 0.5 mg The typical oral dosage is 100 ml per day. g~3500mg twice a day.

[0143] For parenteral administration, the compound and a sterile vehicle (typically water) are used to prepare a fluid The compound of formula (1) may be administered in a unit dosage form depending on the vehicle and concentration used. The compound can be suspended or dissolved in a vehicle or other suitable solvent. When administering the compound, the compound is dissolved in water for injection, sterilized by filtration, and then dispensed into an appropriate vial or applicator. To improve stability, the composition can be filled into vials and sealed. The powder may then be packed into a container, frozen, and the water removed under vacuum. The freeze-dried powder may then be packed into a container, frozen, and the water removed under vacuum. The vial is sealed and an accompanying vial of water for injection is provided to reconstitute the liquid prior to use. Alternatively, the compound may be suspended in the vehicle instead of being dissolved, and sterilized by filtration. Parenteral suspensions are prepared in substantially the same manner, except that the compound cannot be administered intravenously. To facilitate uniform distribution, a surfactant or wetting agent is included in the composition. and suspensions may be used for topical administration.

[0144] The liquid formulation contains about 0.05 to about 95% by weight of the active ingredient including the compound of formula (1). is fine.

[0145] The pharmaceutical compositions of the present disclosure can be used to prepare liquid form formulations for either oral or parenteral administration. Such liquid preparations include solid form preparations that are intended to be converted immediately prior to use to obtain a liquid Exemplary formulations include solutions, suspensions, and emulsions.

[0146] Additionally, the compositions of the present disclosure may be formulated with any one or more of the components or The active ingredient may be formulated in sustained release form to provide a rate controlled release of the active ingredient. Suitable dosage forms include layered tablets with layers of different disintegration rates, or tablets in which the active ingredient is A controlled release polymer matrix impregnated with the compound and molded into a tablet form, or such impregnation is also Alternatively, a capsule containing an encapsulated porous polymer matrix may be mentioned.

[0147] In one embodiment, one or more compounds of formula (1) are administered orally.

[0148] In another embodiment, one or more compounds of formula (1) are administered topically.

[0149] In one embodiment, the pharmaceutical formulation comprising at least one compound of formula (1) is in unit dose form. In such form, the preparation is subdivided into unit doses containing effective amounts of the active component.

[0150] The compositions may be prepared according to conventional mixing, granulating or coating methods, respectively. and the composition, in one embodiment, comprises from about 0.5% by weight to about 95% by weight of one or more compounds represented by formula (1). In various embodiments, the composition may include a compound of the formula: In some embodiments, the composition may contain about 1% to about 70% or about 5% to about 60% of the compound of formula (1). can.

[0151] The compound of formula I may be administered in an amount of 0.001 to 150 mg / day per mammalian (e.g., human) body. The compound may be administered orally in a single or divided dose in the dose range of 100 to 2000 mg / kg. The recommended dose range is 0.01 to 100 mg / day orally in single or divided doses. Another preferred dosage range is 1 to 2 mg / kg of body weight per day orally in single or divided doses. The dosage is 0.1 to 50 mg / kg of body weight. In order to more precisely adjust the dosage, the composition contains 1.0 to 500 milligrams of active ingredient, particularly 1 , 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300 It is available in tablet or capsule form containing 100, 400, and 500 milligrams of active ingredient. The specific dose level and frequency of administration for any particular subject may vary. The activity of the particular compound used, the metabolic stability and length of action of that compound, Age, weight, general health condition, sex, diet, form and time of administration, excretion rate, drug composition The combination of these will depend on a variety of factors, including the severity of the particular condition, as well as the host receiving the treatment. Remains.

[0152] The compound of formula I may be administered as a solution of 0.1% to 2% by weight of the compound at 0.01 to 100 mg / day. Dose ranges from ~50mg, and may be administered in single or divided doses in the form of one or more eye drops. One preferred dosage range is 1 or more doses as a solution of 0.1% to 2% by weight of the compound. In the form of eye drops, the dosage is 0.1 to 10 mg per day in a single or divided dose. The preferred dosage range is 0.1% to 2% by weight of the compound in a solution, at least one point. In the form of an eye drop, the dosage is 0.3 to 3 mg per day in a single or divided dose. The dosage may be adjusted according to the symptoms of the subject to be treated, and may range from 0.01 to 3 per drop of eye drops. Milligrams of active ingredient, specifically 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, and 3 milligrams of active ingredient The specific dosage for any particular subject may be provided in the form of eye drops containing 100 mg of the active ingredient. Dosage levels and frequency may vary and may depend on the activity of the particular compound used, the nature of the compound, and the dosage form used. Stability and duration of action, age, weight, general health, sex, diet, form of administration and The dosage and time, rate of excretion, drug combination, the severity of the particular condition, and the patient receiving treatment. The results will depend on a variety of factors, including strikes.

[0153] For convenience, if necessary, the daily dose may be divided and taken in multiple portions throughout the day. In one embodiment, the daily dose is administered in one portion. In one embodiment, the total daily dose is administered in two divided doses over a 24 hour period. In an embodiment, the total daily dose is administered in three divided doses over a 24 hour period. In yet another embodiment, the total daily dose is administered in four divided doses over a 24 hour period. can be.

[0154] The amount and frequency of administration of the compound of formula (1) will depend on the age, condition and size of the subject, as well as the type of treatment. The dose is adjusted according to the judgment of the attending clinician, taking into account factors such as the severity of the condition being treated. The compositions described herein may further comprise one or more additional therapeutic agents.

[0155] The compositions containing one or more compounds of formula (1) may include additional active agents. The potent agent can, for example, increase the biological activity of the compound of formula (1) or or its activity or its biological activity. do.

[0156] Compounds of formula (1) can be prepared in a variety of ways from known or readily prepared starting materials. As shown below, the Ar group of formula (1) can be prepared by the method of Ar1, The appropriate synthesis method is easily illustrated by designating the central benzene ring as Ar2. [ka]

[0157] Some exemplary methods for preparing representative compounds of formula (1) are described in the following scheme. Additional synthetic routes and methods useful for preparing compounds of formula (1) are illustrated in the following examples. Analogous structures will be apparent to those skilled in the art of organic chemical synthesis. In some cases, the final product may be These manipulations may include, for example, manipulation of the substituents. However, the present invention does not limit the scope of the present invention, and may be implemented by any of the following methods known to those skilled in the art: reduction, oxidation, alkylation, etc. Examples of the reactions include acylating, acylating, and hydrolyzing.

[0158] One point that may be considered in preparing compounds of formula (1) is the linking of the Ar1 and Ar2 groups. This linking group is represented by -LO- in formula (1), where , O is oxygen, and L is selected from a direct bond and methylene (e.g., -CH2-). Thus, the linking group may be in the form O or CH2O.

[0159] These linking groups can be reacted with compounds containing appropriately substituted Ar1 under suitable reaction conditions. It can be formed by reacting a compound containing Ar2 with a compound containing L Compounds of formula (1) where is CH can be prepared as shown in Scheme 1. In group 1, phenol or R 1 Substituted phenols (all hydroxyl-substituted) Ar2) is converted to an X-substituted benzyl compound (having an Ar1 group) where X is a leaving group. This reaction is carried out with a suitable solvent such as potassium carbonate in combination with sodium iodide. The reaction can be carried out in the presence of a suitable base and in the presence of a suitable solvent such as acetone. [ka]

[0160] In Scheme 1, Ar1 is shown as a benzene ring, but this is for illustrative purposes only. In the compounds of the present disclosure, Ar1 is more generally represented by Ar, A 9- or 10-membered bicyclic aromatic ring system optionally substituted with 1, 2 or 3 substituents For example, Ar1 is quinoline (2(chloromethyl)quinoline as an alkylating agent). hydrochloride), naphthylene (2(chloromethyl)naphthalene as alkylating agent), ethylene) or benzothiazole (as an alkylating agent, 2(chloro) methyl) benzothiazole), as well as many other options. Also, in Scheme 1, Ar2 is shown substituted with (A / E), where are intended to collectively refer to eAE as described herein, with the Ar1 ring is a precursor which may be converted to an AE group after coupling with the Ar2 ring.

[0161] When the linking group -LO- has L as a direct bond, the linking group is oxygen (O). Such compounds can be prepared as shown in Scheme 2. [ka]

[0162] In Scheme 2, Ar1 is represented as a benzothiazole compound bearing a leaving group X at the 2-position. Although other Ar1 groups may be used in place of benzothiazole in this synthesis. Some examples are 2-chlorobenzoxazole, 2-chloroquinoline, and 3 In Scheme 2, Ar2 is substituted with (A / E). and wherein this designation refers collectively to the is intended to represent -AE, and after coupling of the Ar1 and Ar2 rings, the AE group The Ar1-containing compound and the Ar2-containing compound are precursors that may be converted to Under conditions such as in the presence of a suitable base, such as potassium carbonate, and dimethylformamide, in a suitable solvent to provide the corresponding coupled compound of formula (1). It is possible.

[0163] In Scheme 2, Ar2 contains a hydroxyl group and Ar1 contains a leaving group X. Alternatively, As shown in Scheme 3, the relative configuration of the hydroxyl group and the leaving group is Ar1 and Ar2. Compounds of the present disclosure may be prepared by the reverse process. In Scheme 3: A phenolic compound having Ar1 is reacted with a suitable amine such as potassium carbonate under suitable reaction conditions. In the presence of a suitable base and a suitable solvent such as dimethylsulfoxide, The compound of formula (1) is obtained by reacting the aryl compound with the fluoroaryl compound shown in Scheme 3. Reaction process [ka]

[0164] In Scheme 3, Ar1 is shown as a benzene ring, but this is for illustrative purposes only. In the compounds of the present disclosure, Ar1 is more generally represented by Ar, A 9- or 10-membered bicyclic aromatic ring system optionally substituted with 1, 2 or 3 substituents Also, in Scheme 3, Ar2 is shown as being substituted with (A / E), Herein, this designation is intended to refer collectively to -AE as specified herein. and is a precursor that may be converted to an AE group after coupling of the Ar1 and Ar2 rings. The reaction shown in Scheme 3 can be carried out when A / E are electron-withdrawing groups, e.g., carbonyls. In this case, (F)(R 1) The (A / E) substituent in Ar2(A / E) is -A It is the precursor of -E.

[0165] The compounds of the present disclosure may have a variety of substituents on the Ar1 and Ar2 moieties. These substituents can be prepared by standard methods known in the art. Such methods include benzylation, condensation, hydrogenolysis, O-alkylation, and Grignard reaction. , trifluoromethylation, reduction, reductive amination of aromatic / aliphatic ketones, aliphatic ketones and the reductive amination of aromatic ketones, One or more of these methods may optionally be used in the preparation of compounds of formula (1). The general formulas are given in the specific examples below, and may be modified according to the knowledge of those skilled in the art. The typical steps are described below.

[0166] Benzylation: Phenol compound (1 equivalent), benzyl bromide (1.5 equivalents) in acetone (1.5 equiv.) and K2CO3 (1.5 equiv.) under reflux and stirred for 3-18 h. The mixture is cooled to room temperature and filtered. The filter cake is washed with acetone, and the solvent is removed under reduced pressure. This material is purified by flash chromatography.

[0167] Condensation: Stir a solution of aldehyde (1 equiv.) in MeOH / HO and add ketone (4–8 equiv.) After adding 85% by weight KOH (4-6 equivalents), the mixture was incubated at room temperature for 7 days. Stir at reflux for 3 h. Quench the reaction with 1-5% dilute HCl or water and add EtOAc. The organic layer is washed with water, dried (MgSO4), filtered and concentrated under reduced pressure. The solvent is evaporated. The material is triturated with ether / hexane or flushed. The product is purified by cross-chromatography.

[0168] Hydrogenolysis: In methanol or ethyl acetate (with or without catalytic amounts of acetic acid) A mixture of the unsaturated ketone (1 equivalent) and 10% Pd / C (10% by weight) was treated with hydrogen. Stir for 1-18 hours. Filter the reaction and remove the solvent under reduced pressure. The product is purified by column chromatography. O-Alkylation: Phenol compound (1 equivalent), alkylating agent (1 to 1.5 equivalents), K 2CO3 (1-1.5 equiv.) and dimethylformamide (DMF) were mixed under argon. Heat at 90-150 °C for about 16-24 hours and cool to room temperature. Dissolve the reaction in water and ethyl acetate. The organic layer is washed with 5% aqueous sodium hydroxide and / or water, and then diluted with brine. Wash with ethyl acetate, dry (MgSO4), filter and remove the solvent under reduced pressure. Purify by rush column chromatography.

[0169] Grignard reaction: Grignard reactions were carried out using commercially available or freshly prepared This can be carried out using alkyl or aryl magnesium bromides. (1) Preparation of Grignard reagent. Freshly ground magnesium turnings (2.5 ~5.0 equivalents) in THF under argon (per mL of tetrahydrofuran (THF) 1.5 mmol of Mg) and 1,2-dibromoethane (50 μL) were added and stirred for 5 minutes. Then, ethylmagnesium bromide (50 μL, 3.0 M in ether) was added and the mixture was incubated for another 5 min. Then, add the alkyl or aryl bromide (1 eq.) and stir the reaction occasionally for 1 h. Cool in a water bath. (2) Grignard addition. Ketone (1 equivalent) as a dry THF solution. To a solution of 100% dimethylformamide (100% dimethylformamide) at 0 °C under argon, add the Grignard reagent (typically 1-2 equivalents). The reaction mixture is stirred for about 1 hour and quenched with water and / or 5% dilute HCl. The mixture was washed with brine, dried (MgSO4), filtered and the solvent was removed under reduced pressure. This material is purified by flash column chromatography.

[0170] Trifluoromethylation: A solution of ketone (1 equivalent) in dry DMF is added at room temperature or low temperature (e.g. For example, 0°C), CF3-TMS (1.5 to 2 equivalents) is added, followed by a catalytic amount of K2CO3 ( (approximately 0.1-0.3 equivalents) and stirred under argon for the desired time, typically 18-72 hours. The reaction is diluted with water and washed with brine. The organic layer is dried (MgSO4) and Filter and remove the solvent under vacuum. Add concentrated HCl to the residue in methanol to complete the reaction. The solution was stirred until 1 h (approximately 1 h). The reaction mixture was diluted with ethyl acetate and extracted with brine. Dry the organic layer (MgSO4), filter, and remove the solvent under reduced pressure. is purified by flash column chromatography.

[0171] Reduction: A solution of the ketone (1 equiv.) in methanol is treated with sodium borohydride (2 Add cerium(III) chloride heptahydrate (1 eq.) and stir for 1 hour. Optionally, add cerium(III) chloride heptahydrate (1 eq.) The reaction is diluted with water and 5% dilute HCl and extracted once with ethyl acetate. The organic layer was washed with brine, dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. This material is purified by flash column chromatography.

[0172] Reductive amination of aromatic / aliphatic ketones: TH of aromatic or aliphatic ketones (1 equivalent) The F solution was stirred at room temperature under argon, Ti(OiPr)4 (1.2 equivalents) was added, and then The amine (1.4 equiv.) was added. The reaction mixture was stirred at reflux for about 18 hours and then cooled to room temperature. Allow to cool naturally. Add NaBH4 (1.5 equiv.) and stir the reaction mixture for 1-3 h. The reaction is then quenched with water and extracted three times with ethyl acetate (EtOAc). Wash with water, dry (MgSO4), filter and remove the solvent under reduced pressure. Purify by flash chromatography.

[0173] Reductive amination of aliphatic ketones: A solution of aliphatic ketone (1 equiv.) in DCE under argon is Stir at room temperature, add amine (1.2 eq.), then add NaBH(OAc)3 (2 eq.) and and acetic acid (AcOH, 2 equivalents), and optionally 4A molecular sieves. The mixture was stirred for 18 h, quenched with water and either CH2Cl2 or EtOAc. The organic layer was dried (MgSO4), filtered, and the solvent was evaporated under reduced pressure. This material is purified by flash chromatography.

[0174] Reductive amination of aromatic aldehydes: A solution of aromatic aldehyde (1 equivalent) in DCE is added to aldehyde. The mixture was stirred at room temperature under 500 K, and the amine (1.2 equiv.) was added, followed by NaBH(OAc)3(1 The reaction mixture was stirred for 18 h, quenched with water and added CH2Cl2 The organic layer was dried (MgSO4) and extracted three times with either ethyl acetate or ethyl acetate. Filter and remove the solvent under reduced pressure. This material is purified by flash chromatography. To manufacture.

[0175] Reductive amination to generate primary and secondary alkylamines: NH4Cl(1 (equivalent) in methanol (MeOH) was stirred at room temperature under argon and (1 eq.), a ketone (1 eq.), and Ti(OiPr)4 (approx. 2 eq.) are added. The mixture was stirred for 18 h. An additional equivalent of Et3N and NH4Cl was added, and the reaction was The reaction mixture was allowed to stir for 3 h. NaBH4 (1.2 equiv.) was added and the reaction mixture was diluted with 1.5 Optionally, additional NaBH4 (0.5 equiv.) may be added and the reaction mixture is stirred for 1 h. Stir for 2 hours. Quench the reaction with water and extract with EtOAc. {Wash the organic layer with water. Dry over anhydrous MgSO4, filter, and remove the solvent under reduced pressure. Purify by chromatography.

[0176] Reductive amination trifluoromethylation: Dissolve ketone or aldehyde (1 equivalent) in THF. The solution was stirred at room temperature under argon and added with 4A molecular sieves and ethylamine (approximately 6 equivalents). The mixture is stirred under argon at room temperature for 3 hours, filtered and the solvent is evaporated under reduced pressure. To the residue, add KHF2 (approximately 0.75 equivalents), acetonitrile, and DMF and mix. Cool the mixture to 0° C. under argon. Add TFA (approximately 1.3 equiv.). Stir the mixture for 5 min. After stirring, CF3TMS (approximately 1.5 equivalents) is added. The cooling bath is removed and the reaction mixture is cooled to approximately 1 Stir for 8 hours, dilute with saturated aqueous Na2CO3, and extract with EtOAc. The residue is washed with water, dried over anhydrous MgSO4, filtered, and the solvent is removed under reduced pressure. The residue was purified by flash chromatography. 4 (0.67 equiv.) was added and the mixture was stirred under argon for 30 min. The reaction was quenched with water. The organic layer was dried over anhydrous Na2SO4, filtered, and reduced. The solvent is removed under reduced pressure and the residue is purified by flash chromatography.

[0177] In each case, a standard reaction was monitored by thin layer chromatography (TLC). The reaction progress may be determined by increasing the conversion of starting materials to products or by To reduce product formation, the temperature and / or reaction time may be increased or decreased.

[0178] The following examples and formulations further illustrate the compounds of the disclosure and methods for preparing the compounds. The following examples and formulations are intended to be illustrative and exemplary. It should be understood that the above is not intended to be limiting in any way. The starting materials and various reactants can be obtained from commercial suppliers or may be used as described herein. They are readily prepared from commercially available organic compounds using methods known to those skilled in the art.

[0179] In the following examples, standard abbreviations are used: AcOH = acetic acid; aq. = water Solution; BnBr = benzyl bromide; CF3TMS = TMSCF3 = CF3-Si(CH3) 3; Conc. = concentrated; DCE = 1,2-dichloroethane; DMF = N,N-dimethylformamide dimethylsulfoxide; DMSO = dimethylsulfoxide; dppp = 1,3-bis(diphenylphosphine) (sphino)propane; EtOAc = ethyl acetate; Et2O = diethyl ether; h = hours ;Hex=hexane;MeCN=acetonitrile;MeOH=methanol;mL=milliliters TBS = tert-butyldimethylsilyl; TBSCl = tert-butyldimethylsilyl TFA = trifluoroacetic acid, i.e., CF3-COOH; TLC = Thin layer chromatography; wt% = weight percent, e.g., 5% EtOAc / Hex is 5 parts by weight (e.g., grams) of hexane in combination with 95 parts by weight (e.g., grams) of hexane. Refers to ethyl acetate.

[0180] In the following examples, molecules with a single chiral center are racemic unless otherwise noted. Molecules with two or more chiral centers are referred to as diastereomeric chiral compounds unless otherwise specified. It exists as a racemic mixture of 1 enantiomer and 2 diastereomers. The enantiomers can be obtained by methods known to those skilled in the art. For example, the enantiomers can be prepared by using chiral packs. (registered trademark) column (Daicel Corporation, Japan), ChiralPak AD (trademark) with a size of 4.6 x 250 mm and containing particles with an average diameter of 5 μm The mobile phase is isopropanol / hexadecyl ether. In this case, the i-PrO The H / Hexane ratio may be varied. An exemplary flow rate is 1 mL / min, and an exemplary injection volume is The volume is 50 μL and is run at a sample concentration of 5 mg / mL. Similarly, to increase the resolution The runtime may be adjusted for different purposes, with an exemplary runtime being 11 minutes.

[0181] For selected compounds prepared according to the following examples: 1 H NMR (nuclear magnetic field) Conducting resonance spectroscopy 1 H NMR spectra were obtained and are described following the examples. Characterization is provided in Table 6. EXAMPLES

[0182] [Example 1] (Preparation of Compound 101) 4-Hydroxy-3-methoxybenzaldehyde (10g, 65.8mmol) Me Stir the OH (85 mL) / HO (13 mL) solution and add 2-butanone (50 mL, 556 After addition of 1 mmol, KOH (15 g, 214 mmol) was added. The mixture was stirred at room temperature. The mixture was stirred for 7 days. Water and dilute HCl (15 mL concentrated HCl / 200 mL water) were added to the reaction mixture. The reaction was stopped and extracted with EtOAc (300 mL). The organic layer was washed with water (1 The residue was washed with 50 mL of water (twice), dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. The residue was triturated with Et2O / Hex (1:3), filtered, and reconstituted with Et2O / Hex (1:3 ) to obtain 5.2 g of 1-(4-hydroxy-3-methoxyphenyl)pent-1- En-1-en-3-one was obtained as a yellow solid.

[0183] 1-(4-hydroxy-3-methoxyphenyl)pent-1-en-3-one (5.0 g, 24 mmol) in MeOH (75 mL) was stirred and 10% Pd / C (250 mg The reaction mixture was stirred under hydrogen for 1 h, and then 10% Pd / C (250 mg) Stirring was continued under hydrogen for an additional 2 hours, after which the mixture was filtered and the solution was dissolved under reduced pressure. The solvent was evaporated and the residue was purified by flash chromatography (25% EtOAc / Hex). 2.45 g of 1-(4-hydroxy-3-methoxyphenyl)pentane-3- The compound was obtained as a colorless oil. [ka]

[0184] 1-(4-hydroxy-3-methoxyphenyl)pentan-3-one (1.5 g, 7. 20 mmol), K2CO3 (1.00 g, 7.24 mmol), and 2-chlorobenzaldehyde Zothiazole (1.00 mL, 7.68 mmol) was mixed in DMF (15 mL) and The mixture was stirred under argon at 100° C. for 18 hours.

[0185] The mixture was allowed to cool to room temperature, diluted with EtOAc (30 mL), water (30 mL), Wash with 30 mL of ethyl acetate (2 x 30 mL), dry over anhydrous MgSO4, filter, and dissolve under reduced pressure. The solvent was evaporated. The residue was purified by flash chromatography (25% EtOAc / Hex). The resulting mixture was purified by hexane distillation to give 2.10 g of compound 101 as a yellow solid.

[0186] [Example 2] [ka] 1-(4-hydroxy-3-methoxyphenyl)pentane in DMF (3 mL) 3-one (170 mg, 0.82 mmol, prepared as described in Example 1), K2CO3 (130 mg, 0.94 mmol), and 2-chlorobenzoxazole (100 μL A mixture of 1,2-dichlorophenyl ether (0.87 mmol) was stirred in a sealed tube at 83° C. for 16 hours. The mixture was allowed to cool to room temperature. Allow to cool naturally, add water (10 mL), brine (10 mL) and EtOAc (20 mL) The layers were separated, and the aqueous layer was extracted with EtOAc (10 mL). The organic layer was washed with brine (10 mL), dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The solvent was evaporated and the residue was purified by flash chromatography (30% EtOAc / Hex). Purification thus afforded 130 mg of compound 102 as an oil.

[0187] [Example 3] [ka] Compound 101 (1.50 g, 3.98 mmol) and K2CO3 (60 mg, 0.4 34 mmol) in DMF (20 mL) and stirred under argon to obtain CF3TMS ( The reaction mixture was stirred at room temperature for 18 hours. , diluted with EtOAc (40 mL) and water (10 mL) and washed with brine (40 mL). The organic layer was dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. The residue was added to MeOH (20 mL) along with concentrated HCl (2 mL) and stirred for 1 h. The solvent was evaporated under reduced pressure, and the residue was taken up in EtOAc (40 mL) and washed with water (2 x 40 mL), then The organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The solvent was removed under reduced pressure. The residue was purified by flash chromatography (25% EtOAc / Hex ) to give 1.54 g of compound 103 as a yellow oil.

[0188] [Example 4] [ka] 1-(4-hydroxy-3-methoxyphenyl)pentan-3-one (843 mg, 4 0.05 mmol, prepared as in Example 1) and KCO (56 mg, 0.405 mmol). ol) in DMF (8 mL) and stirred under argon while cooling to 0° C. in an ice bath. CF3TMS (1.50 mL, 10.2 mmol) was added dropwise. The cooling bath was removed and the reaction mixture The mixture was stirred at room temperature for 18 h. The mixture was diluted with EtOAc (40 mL) and washed with water. (2 x 25 mL). Dry the organic layer over anhydrous MgSO4, filter, and remove the solvent under reduced pressure. The residue was added to MeOH (8 mL), and concentrated HCl (0.6 mL) was added and stirred for 1 hour. The mixture was diluted with EtOAc (40 mL) and washed with water (2 x 25 mL). The organic layer was dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. The product was purified by column chromatography (30% EtOAc / Hex) to give 938 mg of 4- [3-Hydroxy-3-(trifluoromethyl)pentyl]-2-methoxyphenol Obtained as a yellow oil. [ka]

[0189] 4-[3-hydroxy-3-(trifluoromethyl)pentyl]-2-methoxyphenoxy ol (150 mg, 0.539 mmol), K2CO3 (223 mg, 1.61 mmol) ), and 2-chloro-4-(methylthio)-benzothiazole (145 mg, 0.67 2 mmol) in DMF (3 mL) and stirred in a sealed tube at 100° C. for 18 h. The mixture was allowed to cool to room temperature, diluted with EtOAc (35 mL), and washed with water (25 mL The mixture was washed with water (2x), dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. Purification by cross-linking chromatography (20% EtOAc / Hex) gave 230 mg of Compound 104 was obtained as a yellow oil that solidified at room temperature.

[0190] The two enantiomers of compound 104 were separated by HPLC using the following conditions: Column: ChiralPak AD™, particle size 5 μm, 4.6×250 mm; Mobile phase : 20% i-PrOH / Hexane; Flow rate: 1 mL / min; Injection volume: 50 μL; Sample concentration: Resolution: 5 mg / m; Run time: 11 min; Number of injections: 16. Each peak was collected manually and each The fractions containing the anantiomers were combined and the solvent was removed under reduced pressure to give two separate enantiomers. mg was obtained.

[0191] Using the same column, mobile phase, and run time as above, 1 mg / mL HPLC The purity of each combined fraction was tested by HPLC. Enantiomer 1 had a retention time of 7. The time to purification was 633 min and the purity was >99%. 1 H NMR (400M Hz, CDCl3): δ7.44-7.39(m,1H),7.26(d,1H),7. 21(d,1H),7.20(s,1H),6.89-6.82(m,2H),3.82 (s,3H),2.76(t,2H),2.55(s,3H),2.07-1.99(m ,2H), 1.90-1.80(m,2H), 1.06(t,3H). Enantiomer 2 The enantiomer 2 had a retention time of 9.368 min and a purity of >99%. 1 H NMR (400MHz, CDCl3): δ7.43-7.39(m,1H),7.26 (d,1H),7.21(d,1H),7.20(s,1H),6.89-6.82(m ,2H),3.82(s,3H),2.76(t,2H),2.55(s,3H),2. 07-1.99(m,2H),1.89-1.78(m,2H),1.06(t,3H) .

[0192] [Example 5] [ka] 2-Chloro-1-methyl instead of 2-chloro-4-(methylthio)-benzothiazole 1H-1,3-benzodiazole (112 mg, 0.672 mmol) was used. The procedure of Example 4 was followed to produce compound 104, except that the mixture was stirred at 50° C. for 64 hours. This gave 112 mg of compound 105 as a white solid.

[0193] The two enantiomers of compound 105 were separated by HPLC using the following conditions: ChiralPak AD™ column, particle size 5 μm, column size 4.6 × 250 m m; mobile phase: 90% i-PrOH / hexane; flow rate: 1 mL / min; injection volume: 50 μL; Sample concentration: 1mg / m; Run time: 17min; Number of injections: 1. Each peak was collected manually. Two fractions were obtained by eluting the eluate from each fraction. A 50 μL sample was then loaded onto the HPLC column. Enantiomer 1 had a retention time of 13.975 min and was 99% pure. Enantiomer 2 had a retention time of 15.487 min and was >99% pure. there were.

[0194] [Example 6] [ka] Instead of 2-chloro-4-(methylthio)-benzothiazole, The following reaction was performed using 167 mg (0.674 mmol) of methylsulfonylbenzothiazole. In addition, 145 mg of compound 10 was prepared according to the procedure of Example 4 to produce compound 104. 6 was obtained as a yellowish oil which solidified at room temperature.

[0195] [Example 7] [ka] 2-Chloro-4,6- instead of 2-chloro-4-(methylthio)-benzothiazole Except for the use of difluorobenzothiazole (138 mg, 0.671 mmol), Following the procedure of Example 4 to produce compound 104, 231 mg of compound 107 was dissolved in colorless Obtained as an oil.

[0196] [Example 8] [ka] 4-[3-hydroxy-3-(trifluoromethyl)phenyl]propanediol prepared in the same manner as in Example 4 1,2-Dimethoxyphenol (124 mg, 0.45 mmol), K2CO3 (100 mg, 0.71 mmol), and 2-chloro-6-fluoro-benzothiazole (16 6 mg, 0.88 mmol) in DMF (2.5 mL) and heated at 100°C for 1 The mixture was stirred for 8 h. The mixture was allowed to cool to room temperature and then diluted with EtOAc (15 mL) and H2O ( The layers were separated and the aqueous layer was extracted with EtOAc (20 mL). The organic layers were combined, washed with brine, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The solvent was removed under reduced pressure. The residue was purified by flash chromatography (20% EtOAc / Hex ) to give 83 mg of compound 108 as an oil.

[0197] [Example 9] [ka] 4-[3-hydroxy-3-(trifluoromethyl)phenyl]propanediol prepared in the same manner as in Example 4 [3,4-Dimethylphenyl]-2-methoxyphenol (124 mg, 0.45 mmol), K2CO3 (87 mg g, 0.62 mmol), and 2-chloro-6-methoxy-benzothiazole (180 mg, 0.90 mmol) in DMF (2.5 mL) and heated to 180°C in a sealed tube. The mixture was allowed to cool to room temperature and then was added with EtOAc (15 mL) and H2 The layers were separated and the aqueous layer was extracted with EtOAc (20 mL). The organic layers were combined, washed with brine, dried over anhydrous MgSO4, filtered, and The solvent was removed under reduced pressure. The residue was purified by flash chromatography (20% EtOAc / H ex) to give 118 mg of compound 109 as a colorless oil.

[0198] [Example 10] [ka] Vanillylacetone (15, 250 mg, 1.29 mmol) in DMF ( 3 mL) solution, 2-chlorobenzothiazole (168 μl, 1.29 mmol) and K2CO3 (267 mg, 1.93 mmol) was added. The reaction mixture was heated in a sealed tube at 100 °C. The mixture was stirred at rt for 18 h. The reaction mixture was diluted with water and ethyl acetate. The organic layer was then extracted with 5% The organic layer was dried (MgSO 4), filtered, and the solvent was removed under reduced pressure. Silica gel (30% EtOAc / Hex) was added. 321 mg of compound 110 was isolated by flash column chromatography using Obtained as a solid.

[0199] [Example 11] [ka] Compound 110 (150 mg, 0.458 mmol) and K2CO3 (6 mg, 0.0 43 mmol) in DMF (2 mL) and stirred at 0° C. under argon, and CF3TM S (135 μL, 0.914 mmol) was added dropwise. The cooling bath was removed and the reaction mixture was allowed to stand at room temperature. The mixture was stirred for 18 h. The mixture was diluted with EtOAc (35 mL) and washed with water (25 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and the solvent was removed under reduced pressure. It was added to MeOH (0.3 mL) along with concentrated HCl (0.3 mL) and stirred for 1 hour. The mixture was diluted with EtOAc (35 mL) and washed with water (25 mL). The organic layer was washed with anhydrous Na2 The mixture was dried over SO4, filtered, and the solvent was removed under reduced pressure. The residue was analyzed by flash chromatography. The compound 111 was purified by filtration (20% EtOAc / Hex) to give 100 mg of colorless was obtained as an oil.

[0200] [Example 12] Preparation of Compound 112 3,4-Dihydroxybenzaldehyde (0.50 g, 3.62 mmol), benzoyl bromide Diluent (0.43 mL, 3.62 mmol), K2CO3 (0.75 g, 5.43 mmol) ), NaI (0.054 g, 0.36 mmol), and acetone (10 mL) were combined. The reaction mixture was stirred at reflux for 18 hours, filtered, concentrated, and cooled to room temperature. The residue was purified by flash chromatography on silica gel (20% EtOAc / He x) and purified to give 4-(benzyloxy)-3-hydroxy-benzaldehyde 48 Obtained 3 mg as a white solid.

[0201] 4-(benzyloxy)-3-hydroxybenzaldehyde (1.50 g, 6.57 mm ol) in MeOH (14 mL) / HO (1.4 mL) was stirred to give KOH (1.73 g, 26.2 mmol) was added, followed by 2-butanone (5.3 mL, 58.80 mmol). The mixture was stirred under reflux for 2 hours. The reaction mixture was allowed to cool naturally, and then diluted with 10% The reaction was quenched with HCl (60 mL) and extracted with EtOAc (2 x 50 mL). The organic layer was washed with water (2 x 150 mL), dried over anhydrous MgSO4, filtered and The solvent was removed under reduced pressure. The residue was triturated with diethyl ether to give 0.648 g 1-[4-(benzyloxy)-3-hydroxyphenyl]pent-1-en-3-o The compound was obtained as an off-white solid.

[0202] 1-[4-(benzyloxy)-3-hydroxyphenyl]pent-1-en-3-o (0.5g, 1.77mmol), K2CO3 (0.734g, 5.31mmol), and 2-bromopropane (0.830 mL, 8.84 mmol) in DMF (5 mL). The mixture was mixed with 100 ml of ethyl acetate and stirred in a sealed tube at 90° C. for 18 hours. The mixture was allowed to cool to room temperature and was diluted with EtOAc. c (35 mL), washed with water (3 x 25 mL), dried over anhydrous MgSO4, and Filtration and removal of the solvent under reduced pressure gave 0.531 g of 1-[4-(benzyloxy)-3 -(propan-2-yloxy)phenyl]pent-1-en-3-one off-white as a solid.

[0203] 1-[4-(benzyloxy)-3-(propan-2-yloxy)phenyl]penta 1-En-3-one (0.400 g, 1.23 mmol) in EtOAc (12 mL) A solution of 10% Pd / C (0.040 g) was added to the stirred solution of 100 μL and AcOH (600 μL). The reaction mixture was stirred under hydrogen for 5 hours and then filtered. The solvent was removed under reduced pressure, and the residue was concentrated in toluene. Purification by rush chromatography (30% EtOAc / Hex) gave 0.193 g of 1-[4-(hydroxy)-3-(propan-2-yloxy)phenyl]pentane -3-on was obtained. [ka]

[0204] 1-[4-(hydroxy)-3-(propan-2-yloxy)phenyl]pentane- 3-one (236 mg, 1.00 mmol), K2CO3 (140 mg, 1.01 mmol) l), and 2-chlorobenzothiazole (0.145 mL, 1.1 mmol) in DMF (3 mL) and stirred in a sealed tube at 100 °C for 18 h. The mixture was allowed to cool to room temperature. It was warmed, diluted with EtOAc (35 mL), washed with water (2 x 25 mL) and dehydrated with anhydrous MgS Dry over O4, filter, and remove the solvent under reduced pressure. Flash chromatograph the residue. (20% EtOAc / Hex) to give 245 mg of compound 112 as a yellow solid. Obtained as an oil.

[0205] [Example 13] Preparation of Compound 113 1-[4-(benzyloxy)-3-hydroxyphenyl]pent-1-en-3-o (0.5 g, 1.77 mmol, prepared as in Example 12), K2CO3 (0.367 g, 2.66 mmol), and cyclopentyl bromide (0.290 mL, 2.70 mmol). l) was mixed in DMF (5 mL) and stirred in a sealed tube at 90° C. for 18 hours. The mixture was then cooled to room temperature. The mixture was allowed to cool naturally to 35°C, diluted with EtOAc (35 mL), washed with water (3 x 25 mL), and The water was dried over MgSO4, filtered and the solvent was removed under reduced pressure. The residue was washed with ether / Hex Triturate with 0.454 g of 1-[4-(benzyloxy)-3-(cyclopentadiene] (phenyloxy)pent-1-en-3-one was obtained as an off-white solid. .

[0206] 1-[4-(benzyloxy)-3-(cyclopentyloxy)phenyl]pent-1 -en-3-one (0.450 g, 1.28 mmol) in EtOAc (14 mL) and The AcOH (700 μL) solution was stirred and 10% Pd / C (0.045 g) was added. The mixture was stirred under hydrogen for 23 hours and then filtered. The solvent was removed under reduced pressure, and the residue was dissolved in 1,000 ml of water. Purified by cross-chromatography (30% EtOAc / Hex) to give 0.193 g 1-[4-(hydroxy)-3-(cyclopentyloxy)phenyl]pentane-3- Got on. [ka]

[0207] 1-[4-(hydroxy)-3-(cyclopentyloxy)phenyl]pentane-3- On (0.234 mg, 0.892 mmol), K2CO3 (0.124 g, 0.897 mmol), and 2-chlorobenzothiazole (0.130 mL, 0.998 mmol ) in DMF (3 mL) and stirred in a sealed tube at 100° C. for 18 h. Allow to cool to room temperature, dilute with EtOAc (35 mL), wash with water (2 x 25 mL), The mixture was dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography. The product was purified by chromatography (20% EtOAc / Hex) to give 0.245 g of compound 1. 13 was obtained as a yellow oil.

[0208] [Example 14] Preparation of Compound 114 1-[4-(benzyloxy)-3-hydroxyphenyl]pent-1-en-3-o (0.5 g, 1.77 mmol, prepared as in Example 12), K2CO3 (0.367 g, 2.66 mmol), and (bromomethyl)cyclopropane (0.260 mL, 2 0.68 mmol) in DMF (5 mL) and stirred in a sealed tube at 90° C. for 18 h. The mixture was allowed to cool to room temperature, diluted with EtOAc (35 mL), and washed with water (25 mL The mixture was washed with water (3x), dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. Triturate with Tert / Hex to obtain 0.440 g of 1-[4-(benzyloxy)-3 -(cyclopropylmethoxy)phenyl]pent-1-en-3-one was obtained as a solid. .

[0209] 1-[4-(benzyloxy)-3-(cyclopropylmethoxy)phenyl]pent- 1-En-3-one (0.440 g, 1.31 mmol) in EtOAc (14 mL) and The solution of 10% Pd / C (0.044 g) was added to the stirred solution of 10% Pd / C (700 μL). The reaction mixture was stirred under hydrogen for 18 hours and then filtered. The solvent was removed under reduced pressure, and the residue was concentrated in toluene. Purification by rush chromatography (20% EtOAc / Hex) gave 0.244 g 1-[4-(hydroxy)-3-(cyclopropylmethoxy)phenyl]pentane- 3-one was obtained. [ka]

[0210] 1-[4-(hydroxy)-3-(cyclopropylmethoxy)phenyl]pentane-3 -one (0.244 mg, 0.983 mmol), K2CO3 (0.136 g, 0.98 4 mmol), and 2-chlorobenzothiazole (0.140 mL, 1.08 mmol) ) was mixed in DMF (4 mL) and stirred in a sealed tube at 100° C. for 18 h. The mixture was then cooled to room temperature. The mixture was allowed to cool naturally to 35°C, diluted with EtOAc (35 mL), washed with water (3 x 25 mL), and The water was dried over MgSO4, filtered and the solvent was removed under reduced pressure. The residue was purified by flash chromatography. The product was purified by HPLC (20% EtOAc / Hex) to give 0.285 g of compound 11. 4 was obtained as a yellow oil.

[0211] [Example 15] [ka] Compound 112 (235 mg, 0.636 mmol) and K2CO3 (9 mg, 0.0 65 mmol) in DMF (3 mL) and stirred under argon. The reaction mixture was stirred at room temperature for 18 hours. The mixture was partitioned between EtOAc (35 mL) and water (25 mL), and the aqueous layer was diluted with EtOAc ( The combined organic layer was dried over anhydrous MgSO4, filtered, and The residue was added to MeOH (6 mL) and concentrated HCl (0.1 mg) was added, and the mixture was The mixture was stirred for 1 h. The mixture was diluted with EtOAc (35 mL) and washed with water (25 mL). The organic layer was dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by flash chromatography. The product was purified by chromatography (20% EtOAc / Hex) to give 203 mg of compound 11. 5 was obtained as a white solid.

[0212] [Example 16] [ka] Compound 113 (0.125 g, 0.316 mmol) and K2CO3 (0.004 g, 0.029 mmol) in DMF (1.5 mL) and stirred under argon. MS (0.060 mL, 0.406 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 18 h. The mixture was diluted with EtOAc (35 mL) and washed with water (2 x 25 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated. The residue was dissolved in MeOH (3 mL) Concentrated HCl (0.05 mg) was added and the mixture was stirred for 1 h. The mixture was diluted with EtOAc (35 mL) and washed with water (25 mL x 2). The organic layer was dried over anhydrous MgSO4. The residue was purified by flash chromatography (20% EtOAc / Hex) to give 0.106 g of compound 116 as a white solid.

[0213] [Example 17] [ka] Compound 114 (0.150 g, 0.393 mmol) and K2CO3 (0.006 g , 0.043 mmol) in DMF (2 mL) and stirred under argon. MS (0.080 mL, 0.572 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 18 h. The mixture was diluted with EtOAc (35 mL) and washed with water (2 x 25 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated. The residue was dissolved in MeOH (3 mL) Concentrated HCl (0.05 mg) was added and the mixture was stirred for 1 h. The mixture was diluted with EtOAc (35 mL) and washed with water (25 mL x 2). The organic layer was dried over anhydrous MgSO4. The residue was purified by flash chromatography (20% EtOAc / Hex) to give 0.121 g of compound 117 as a white solid.

[0214] [Example 18] [ka] Vanillylacetone (150 mg, 0.772 mmol), K2CO3 (160 mg, 1 .16mmol), and 2-chloro-4-(methylthio)-benzothiazole (208 A solution of 1.2 mg, 0.964 mmol) in DMF (3 mL) was stirred in a sealed tube at 100°C for 18 hours. The mixture was allowed to cool to room temperature, diluted with EtOAc (35 mL), washed with water ( The residue was washed with 25 mL of water (twice), dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (20% EtOAc / Hex) to give 21 Obtained 4 mg of compound 118 as a yellow oil.

[0215] [Example 19] [ka] Compound 118 (214 mg, 0.599 mmol) and K2CO3 (8 mg, 0.0 58 mmol) in DMF (3 mL) and stirred under argon to obtain CF3TMS (1 The reaction mixture was stirred at room temperature for 18 hours. The mixture was diluted with EtOAc (35 mL) and washed with water (2 x 25 mL). The water was dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The residue was dissolved in MeOH (3 mL ), concentrated HCl (0.3 mg) was added, and the mixture was stirred for 1 h. The mixture was diluted with EtOAc. c (35 mL) and washed with water (25 mL x 2). The organic layer was washed with anhydrous MgSO4 The mixture was dried, filtered, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography ( 20% EtOAc / Hex) to give 95 mg of compound 119 as a yellow oil. And obtained.

[0216] [Example 20] Preparation of Compound 120 3-Ethoxy-4-hydroxybenzaldehyde (2 g, 12 mmol) in MeOH( The mixture was stirred in a 2-butanone (10 mL, 111 mm H2O) / HO (2.5 mL) solution and diluted with 2-butanone (10 mL, 111 mm H2O). After adding 100 ml of 10 ... The reaction was quenched with 10% dilute HCl and extracted with EtOAc (30 mL). The organic layer was washed with brine (30 mL), dried over anhydrous MgSO4, and filtered. The solvent was removed under reduced pressure. The residue was purified by flash column chromatography (20% Et OAc / Hex) to give 2.09 g of 1-(3-ethoxy-4-hydroxyphenyl) The resulting mixture was concentrated to give 1,2-diphenylpent-1-en-3-one as a solid.

[0217] 1-(3-ethoxy-4-hydroxyphenyl)pent-1-en-3-one (1.7 A stirred solution of 3 g, 7.86 mmol) in 15 mL of EtOAc was added to 10% Pd / C (1 50 mg) was added. The reaction mixture was stirred under hydrogen for 1.5 hours and then filtered. The solvent was removed by evaporation and the residue was purified by flash chromatography (40% EtOAc / Hex). The resulting mixture was purified by the method described above, and 0.720 g of 1-(3-ethoxy-4-hydroxyphenyl)pentane was obtained. -3-on was obtained. [ka]

[0218] 1-(3-ethoxy-4-hydroxyphenyl)pentan-3-one (0.430 g, 1.94 mmol), K2CO3 (0.266 g, 1.92 mmol), and 2-chloro Mix benzothiazole (0.277 mL, 2.13 mmol) in DMF (3 mL). The mixture was then stirred at 120 °C under argon for 18 h. The mixture was allowed to cool to room temperature and EtO Dilute with Ac (20 mL), wash with water (2 x 15 mL), brine (15 mL), and The water was dried over MgSO4, filtered and the solvent was removed under reduced pressure. The residue was purified by flash chromatography. The product was purified by HPLC (20% EtOAc / Hex) to give 0.492 g of compound 12. 0 was obtained as an oil.

[0219] [Example 21] [ka] Compound 120 (0.100 g, 0.281 mmol) and K2CO3 (0.018 g ) in DMF (2 mL) and stirred under argon, and CF3TMS (0.100 mL The reaction mixture was stirred at room temperature for 18 hours, and then EtOAc was added. c (15 mL) and washed with brine (2 x 15 mL). The organic layer was diluted with anhydrous MgS The mixture was dried over O4, filtered, and the solvent was removed under reduced pressure. The residue was added to MeOH (5 mL). Concentrated HCl (0.250 mL) was added and the mixture was stirred for 1 hour. The solvent was removed under reduced pressure, and the residue was Add to EtOAc (20 mL) and wash with brine (2 x 20 mL). The mixture was dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The residue was analyzed by flash chromatography. HPLC (20% EtOAc / Hex) to give 72 mg of compound 121. Obtained as a coloured oil.

[0220] [Example 22] [ka] Following the general reduction procedure, compound 110 (0.46 mmol, prepared similarly to Example 10) was obtained. (prepared by HPLC), sodium borohydride (0.91 mmol), and methanol (3 mL) Compound 122 was prepared by flash column chromatography on silica gel. (40% EtOAc / Hex) to give 0.156 g of compound 122 as an oil. Ta.

[0221] [Example 23] [ka] Compound 110 (0.150 g, 0.46 m) was prepared according to the general Grignard addition procedure. mol, prepared as in Example 10), THF (3.0 mL), and phenylmagnesium bromide. Compound 123 was prepared from silica gel (0.30 mL, 3M / Et2O). Flash column chromatography on gel (30% EtOAc / Hex) Obtained 0.204 g of compound 123 as an oil.

[0222] [Example 24] [ka] Compound 110 (0.100 g, 0.305 g) was prepared according to the general Grignard addition procedure. (1.0 mmol, prepared as in Example 10), THF (1.0 mL), and magnesium methyl bromide. Compound 124 was prepared from silica gel (0.20 mL, 3M / Et2O). Flash column chromatography on gel (50-70% EtOAc / Hex) Subjection to afford 0.115 g of compound 124 as an oil.

[0223] [Example 25] [ka] Vanillylacetone (0.621 g, 3.20 mmol) in DMF (8 mL) was added to 2-Chlorobenzoxazole (300 μL, 2.62 mmol) and K 2CO3 (0.511 g, 3.70 mmol) was added. The reaction mixture was heated at 140 °C for 18 h. The reaction mixture was diluted with water and EtOAc. The organic layer was then washed with 5% NaOH. The organic layer was washed with aqueous solution (30 mL x 2) and brine (20 mL). The mixture was dried at 40° C., filtered, and the solvent was removed under reduced pressure. 0.483 mg of compound 125 was purified by chromatography (40% EtOAc / Hex). Obtained as a white solid.

[0224] [Example 26] [ka] Compound 125 (0.095 g, 0.305 g) was prepared according to the general Grignard addition procedure. A mixture of 1.2 mmol of 1,2-dichlorophenyl ether (1.0 mmol) in THF (3.0 mL) was placed in a flask and cooled in an ice-water bath. The mixture was stirred while stirring, and methylmagnesium bromide (0.180 mL, 3M / Et2O) was added. The ice bath was removed and the mixture was stirred at room temperature for 70 min. H2O (5 mL) was added, followed by Et OAc (10 mL) and brine (5 mL) were added. The layers were separated and the aqueous layer was diluted with EtO The mixture was extracted with Ac (10 mL x 2). The combined organic layers were washed with brine and concentrated with Mg The crude mixture was dried over SO4, filtered, and the filtrate was concentrated. Chromatography (30% EtOAc / Hex) gave 0.090 g of compound 12. 6 was obtained as a colorless oil.

[0225] [Example 27] [ka] Compound 125 (0.101 g, 0.325 g) was synthesized by the general Grignard addition procedure. A mixture of 1.2 mmol of 1,2-dichlorophenyl ether (1.0 mmol) in THF (3.0 mL) was placed in a flask and cooled in an ice-water bath. The mixture was stirred while stirring, and methylmagnesium bromide (0.180 mL, 3M / Et2O) was added. The ice bath was removed and the mixture was stirred at room temperature for 70 min. H2O (5 mL) was added, followed by Et OAc (10 mL) and brine (5 mL) were added. The layers were separated and the aqueous layer was diluted with EtO The mixture was extracted with Ac (10 mL x 2). The combined organic layers were washed with brine and concentrated with Mg The crude mixture was dried over SO4, filtered, and the filtrate was concentrated. Chromatography (40% EtOAc / Hex) gave 0.066 g of compound 12. 7 was obtained as a colorless oil.

[0226] [Example 28] [ka] Preparation of Compound 128 Compound 125 (0.097 g, 0.314 g) was prepared by the general Grignard addition procedure. A mixture of 1.2 mmol of 1,2-dichlorophenyl ether (1.0 mmol) in THF (3.0 mL) was placed in a flask and cooled in an ice-water bath. The mixture was stirred while stirring, and methylmagnesium bromide (0.180 mL, 3M / Et2O) was added. The ice bath was removed and the mixture was stirred at room temperature for 70 min. H2O (5 mL) was added, followed by Et OAc (10 mL) and brine (5 mL) were added. The layers were separated and the aqueous layer was diluted with EtO The mixture was extracted with Ac (10 mL x 2). The combined organic layers were washed with brine and concentrated with Mg The crude mixture was dried over SO4, filtered, and the filtrate was concentrated. Chromatography (40% EtOAc / Hex) gave 0.080 g of compound 12. 8 was obtained as a colorless oil.

[0227] [Example 29] Preparation of Compound 129 3-Ethoxy-4-hydroxybenzaldehyde (2.00 g, 12.0 mmol) and and 85% KOH (3.00 g, 45.4 mmol) in MeOH (17 mL) / HO ( The solution was stirred and acetophenone (4.5 mL, 38.6 mmol) was added. The mixture was stirred at room temperature while being monitored by TLC. After completion, standard workup was performed. Workup and concentration gave a residue which was used in the next step without further purification. The residue was dissolved in EtOAc (30 mL) and 10% Pd / C (320 mg) was added. The mixture was then stirred under hydrogen for 1 hour. The mixture was filtered and the filtrate was concentrated to give 1.2 g of 3 -(3-ethoxy-4-hydroxyphenyl)-1-phenylpropan-1-one yellow as a solid. [ka] 3-(3-ethoxy-4-hydroxyphenyl)-1-phenylpropan-1-one ( To a solution of 1.20 g, 4.44 mmol) in DMF (8 mL) under argon, Benzothiazole (682 μL, 5.26 mmol) and K2CO3 (0.648 g, 4.70 mmol) was added. The reaction mixture was stirred at 140° C. for 18 hours. It was diluted with water and ethyl acetate. The organic layer was then washed with brine. The organic layer was dried. (MgSO4), filtered and evaporated under reduced pressure. Flash column on silica gel Chromatography (15-20% EtOAc / Hex) gave 1.11 g of compound 1. 29 was obtained as an oil.

[0228] [Example 30] [ka] Compound 129 (0.200 g, 0.5 mmol) and K2CO3 (0.015 g, 0 0.11 mmol) in DMF (3 mL) and stirred under argon to obtain CF3TMS ( The reaction mixture was stirred at room temperature for 18 hours. The mixture was diluted with EtOAc (15 mL) and washed with brine (2 x 15 mL). The organic layer was concentrated, and the residue was taken up in MeOH (5 mL) and concentrated HCl (0.25 mL) was added. The mixture was stirred for 1 h. The mixture was diluted with EtOAc (20 mL) and washed with brine (20 The organic layer was dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (20% EtOAc / Hex) to give Obtained 178 mg of compound 130 as an oil.

[0229] [Example 31] Preparation of Compound 131 Vanillin (2.00 g, 13.1 mmol), acetophenone (5.00 mL, 42. 9 mmol), and KOH (6 g, 106.5 mmol) in MeOH (20 mL) / H The mixture was stirred in 200 (58 mL) and heated to 60 °C in a sealed tube. The reaction mixture was allowed to cool to room temperature and diluted with dilute HCl (10 mL of concentrated HCl / 10 The reaction was quenched with 100 mL of water and extracted with EtOAc (100 mL). Wash with water (2 x 100 mL) and brine (20 mL) and dry over anhydrous MgSO4 The residue was purified by flash chromatography (15 % to 40% EtOAc / Hex) to give 3.8 g of 3-(4-hydroxy-3 -methoxyphenyl)-1-phenylprop-2-en-1-one was obtained. 3-(4-hydroxy-3-methoxyphenyl)-1-phenylprop-2-ene 1-one (1.27 g, 4.99 mmol) and 10% Pd / C (139 mg) were added to E The mixture was stirred in tOAc (10 mL) and Et3N (1.3 mL) under hydrogen for 2 h. After stirring, the mixture was filtered. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography ( 20% EtOAc / Hex, 30% EtOAc / Hex) to give 311 mg of 3-(4-hydroxy-3-methoxyphenyl)-1-phenylpropan-1-one was obtained. Ta. [ka]

[0230] 3-(4-hydroxy-3-methoxyphenyl)-1-phenylpropan-1-one ( 768mg, 3mmol), K2CO3(414mg, 3mmol), and 2-chloro Benzothiazole (429 μL, 3.2 mmol) was mixed in DMF (5 mL) and stirred. The reaction mixture was heated to 100° C. while stirring, and then stirred at 100° C. for 18 hours. The reaction mixture was allowed to cool to room temperature. The mixture was then diluted with EtOAc (30 mL), washed with brine (30 mL x 3), and diluted with anhydrous M Dry over gSO4, filter, and evaporate the solvent under reduced pressure to give 813 mg of compound 131. Obtained as a white solid.

[0231] [Example 32] [ka] Compound 131 (100 mg, 0.257 mmol) and NaBH4 (46 mg, 1. 22 mmol) was added to MeOH (3 mL) and stirred at room temperature under argon for 1 h. The reaction was quenched with OAc (15 mL) and 5% dilute HCl (25 mL), and the aqueous layer was diluted with Et The mixture was extracted with OAc (15 mL). The combined organic layers were washed with brine (20 mL). The mixture was washed with water (2x), dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. Purification by cross-linking chromatography (30% EtOAc / Hex) gave 114 mg of Compound 132 was obtained as a colorless oil.

[0232] [Example 33] [ka] Compound 131 (250 mg, 0.642 mmol) and K2CO3 (18 mg, 0. 130 mmol) in DMF (3 mL) and stirred under argon to obtain CF3TMS ( The reaction mixture was stirred at room temperature for 24 hours, and then The mixture was diluted with EtOAc (35 mL) and washed with brine (30 mL x 3). The water was dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The residue was dissolved in MeOH (10 ml The mixture was added to 100 mL of concentrated HCl (0.25 mL) and stirred for 2 hours. The solvent was removed under reduced pressure. The residue was added to EtOAc (30 mL) and washed with water (20 mL x 2) and brine (20 mL). L), dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. Purification by flash chromatography (20% EtOAc / Hex) gave 264m g of compound 133 was obtained as a yellowish oil.

[0233] [Example 34] [ka] A solution of compound 131 (167 mg, 0.429 mmol) in THF (8 mL) was heated under argon The mixture was stirred at room temperature under reduced pressure, and Ti(OiPr)4 (150 μL, 0.507 mmol) was added. Then, pyrrolidine (50 μL, 0.609 mmol) was added. The reaction mixture was refluxed for 16 h. After stirring for 2 h, the mixture was allowed to cool to room temperature. ) was added and the reaction mixture was stirred for 3 h, then quenched with water (25 mL) and EtO The organic layer was washed with water (35 mL) and concentrated in anhydrous MgCl. The residue was dried over gSO4, filtered, and the solvent was removed under reduced pressure. Purification by elution (EtOAc / MeOH / Et3N, 9:1:0.1) gave 108 mg of compound 134 was obtained as a yellow foam.

[0234] [Example 35] [ka] NH4Cl (313 mg, 5.85 mmol) was mixed in MeOH (6 mL) and The mixture was stirred at room temperature under high pressure, and then added Et3N (820 μL, 5.88 mmol), the compound obtained in Example 1, and Compound 101 (200mg, 0.586mmol), and Ti(OiPr)4 (350μ Et3N(82 L, 1.18 mmol) was added. The milky reaction mixture was stirred for 18 h. 0 μL) and NH4Cl (313 mg) were added and the reaction mixture was stirred for 3 h. H4 (45 mg) was added and the reaction mixture was stirred for 1.5 h. g) was added and the reaction mixture was stirred for 1 h. The reaction was quenched with water (35 mL) and EtOAc (1.5 mL). The organic layer was washed with water (2 times with 35 mL) and extracted with anhydrous Mg The mixture was dried over SO4, filtered, and the solvent was removed under reduced pressure. The residue was analyzed by flash chromatography. Fee (10% MeOH / EtOAc, then EtOAc / MeOH / Et3N, 9:1 :0.1) to give 62 mg of compound 135 as a yellowish oil.

[0235] [Example 36] [ka] AcOH (5.00 mL, 87.4 mmol) was dissolved in toluene (70 mL) at 0 °C under argon. L) and add NaBH4 (1.00 g, 26.4 mmol) in small portions over 30 min. The cooling bath was removed, the reaction mixture was stirred for 1 h, filtered, and the insoluble material was washed with ether and dried. After drying, 3.19 g of NaBH(OAc)3 was obtained.

[0236] Compound 101 (150 mg, 0.439 mmol, prepared as in Example 1) was dissolved in DCE ( The mixture was stirred at room temperature under argon and diluted with 4 Å molecular sieve powder (1 50mg), AcOH (100μL), morpholine (50μL, 0.578mmol) , and NaBH(OAc)3 (190 mg, 0.896 mmol) prepared as above. The reaction mixture was stirred for 18 h. An additional amount of morpholine (50 μL) was added. The reaction mixture was stirred for 2 hours and saturated aqueous NaHCO3 (25 mL) was added to the reaction mixture. The reaction was stopped and extraction was performed with CH2Cl2 (2 x 35 mL). The combined organic layer was washed with water. The water was dried over MgSO4, filtered and the solvent was removed under reduced pressure. The residue was purified by flash chromatography. Purification by chromatography (EtOAc / MeOH / Et3N, 9:1:0.1) gave 3 The oil was added to CH2Cl2 (3 mL) and MeOH (10 The mixture was stirred with 1.25 M HCl (0.0 μL) for 1 hour. The solvent was removed under reduced pressure. 30 mg of the hydrochloride salt of compound 136 was obtained as a white foam.

[0237] [Example 37] [ka] Vanillin (250 mg, 1.64 mmol), K2CO3 (341 mg, 2.47 mmol) ol), and 2-chlorobenzothiazole (260 μL, 2.00 mmol) in DMF (5 mL) and stirred in a sealed tube at 100° C. for 18 hours. The mixture was allowed to cool to room temperature. The mixture was then diluted with EtOAc (35 mL), washed with water (3 x 25 mL), and cooled to 30° C. with anhydrous MgSO. The mixture was dried over 4°C, filtered, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography. (20% EtOAc / Hex) to give 407 mg of 4-(1,3-benzothiazole). Azol-2-yloxy)-3-methoxybenzaldehyde was obtained as a white solid. [ka]

[0238] 4-(1,3-Benzothiazol-2-yloxy)-3-methoxybenzaldehyde (200 mg, 0.701 mmol) and K2CO3 (10 mg, 0.072 mmol) ) in DMF (3 mL) and stirred under argon, and CF3TMS (155 μL, 1 The reaction mixture was stirred at room temperature for 42 h, after which EtOAc (4.05 mmol) was added. The organic layer was diluted with 0.0 mL of water and washed with water (25 mL x 2). The organic layer was dried over anhydrous MgSO4. The residue was added to MeOH (3 mL) and concentrated HCl ( 0.15 mL) was added and stirred for 1 h. The mixture was diluted with EtOAc (40 mL) and diluted with water The organic layer was dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The solvent was removed by evaporation at 20° C. The residue was purified by flash chromatography (20% EtOAc / Hex). Purification by HPLC gave 109 mg of compound 137 as a white solid.

[0239] [Example 38] [ka] 4-(1,3-Benzothiazol-2-yloxy)-3-methoxybenzaldehyde (250 mg, 0.876 mmol, prepared as in Example 37) and anhydrous Na2SO4 A mixture of (1g) was stirred at room temperature under argon and ethylamine (2.0M in THF, The reaction mixture was stirred for 18 hours and then filtered. The solid was removed. The solvent was removed under reduced pressure to give a yellowish oil. The product and KHF2 (51 mg, 0.653 mmol) were dissolved in MeCN (3 mL) and DMF (203 μL, 2.62 mmol) and TFA (84 μL, 1. The mixture was stirred for 5 min and CF3TMS (194 μL, 1.31 The cooling bath was removed and the reaction mixture was stirred for 18 h. The mixture was diluted with saturated Na The mixture was diluted with 2CO3 aqueous solution (40 mL) and extracted with EtOAc (40 mL). The organic layer was washed with water (25 mL x 2), dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The solvent was evaporated and the residue was purified by flash chromatography (15% EtOAc / Hex). Purification thus afforded 61 mg of compound 138 as an off-white solid.

[0240] [Example 39] [ka] Vanillin (150 mg, 0.985 mmol), K2CO3 (204 mg, 1.48 mmol) mol), and 2-chloro-4-(methylthio)benzothiazole (266 mg, 1. 23 mmol) in DMF (3 mL) and stirred in a sealed tube at 100°C for 18 hours. The mixture was then cooled to room temperature, diluted with EtOAc (35 mL), and diluted with 1 M NaOH (25 mL). The organic layer was dried over anhydrous MgSO4, filtered, and cooled to room temperature. The solvent was removed under reduced pressure. The residue was purified by flash chromatography (20% EtOAc / Hex) to obtain 256 mg of 3-methoxy-4-{[4(methylsulfanilide (1,3-benzothiazol-2-yl)oxy}benzaldehyde as a white solid. And obtained. [ka]

[0241] 3-Methoxy-4-{[4-(methylsulfanyl)-1,3-benzothiazole-2 -yl]oxy}benzaldehyde (256 mg, 0.772 mmol) and KCO 3 (11 mg, 0.080 mmol) was mixed in DMF (3 mL) and stirred under argon. Then, CF3TMS (171 μL, 1.16 mmol) was added. The reaction mixture was stirred at room temperature for 42 After stirring for 1 h, it was diluted with EtOAc (35 mL) and washed with water (2 x 25 mL). The organic layer was dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. The residue was OH (3 mL), concentrated HCl (0.3 mL) was added and stirred for 1 h. The mixture was diluted with Et The organic layer was diluted with OAc (35 mL) and washed with water (2 x 25 mL). The mixture was dried over 4°C, filtered, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography. (20% EtOAc / Hex) to give 192 mg of compound 139, a yellowish white solid. This was obtained as a solid.

[0242] [Example 40] [ka] DM of 4-(4-hydroxyphenyl)-2-butanone (1.5 g, 9.1 mmol) To a solution of F (8 mL) under argon was added 2-chlorobenzothiazole (1.34 mL, 10 0.3 mmol) and K2CO3 (1.27 g, 9.2 mmol) were added to the reaction mixture. The mixture was stirred at 140° C. for 20 hours. The reaction mixture was allowed to cool to room temperature and then water (20 mL) was added. ) and extracted with EtOAc (20 mL x 3). The organic layer was washed with 5% NaOH. The organic layer was washed with aqueous solution (20 mL x 2) and brine (2 mL x 2). The mixture was cooled (MgSO4), filtered, and the solvent was removed under reduced pressure. Chromatography (30% EtOAc / Hex) gave 1.72 g of 4-[4-( 1,3-Benzothiazol-2-yloxy)phenyl]butan-2-one was obtained. [ka]

[0243] Following the general CF3TMS addition procedure disclosed herein, 4-[4-(1, 3-benzothiazol-2-yloxy)phenyl]butan-2-one (135 mg, 0 .45mmol), CF3TMS (200μL, 1.35mmol), K2CO3 (20 Compound 140 was prepared from crude 1,3-dichlorophenyl ether (1 mg, 0.14 mmol) and DMF (3 mL). The mixture was purified by flash column chromatography on silica gel (30% EtOAc / Hex ) to obtain 137 mg of compound 140 as an oil.

[0244] [Example 41] [ka] Following the general reduction procedure disclosed herein, 4-[4-(1,3-benzothiazole] Azole-2-yloxy)phenyl]butan-2-one (113 mg, 0.38 mmol) l, prepared as in Example 40), NaBH4 (25 mg, 0.59 mmol), CeCl Compound 3·7H2O (125 mg, 0.34 mmol) and MeOH (3 mL) 141 was prepared by flash column chromatography on silica gel (5 0% EtOAc / Hex) to give 100 mg of compound 141 as a colorless oil. .

[0245] [Example 42] [ka] Following the general Grignard addition procedure, 4-[4-(1,3-benzothiazole-2 128 mg, 0.43 mmol, Example 4 0), THF (2.0 mL), and isopropylmagnesium bromide (0. Compound 142 was prepared from 45 mL of 2M / THF. The crude mixture was fractionated on silica gel. The mixture was subjected to column chromatography (30% EtOAc / Hex) to obtain 52 mg of the compound. Product 142 was obtained as an oil.

[0246] [Example 43] [ka] Following the general Grignard addition procedure, 4-[4-(1,3-benzothiazole-2 4-yloxy)phenyl]butan-2-one (195 mg, 0.66 mmol, Example 4 0), THF (2.0 mL), and ethylmagnesium bromide (0.32 mL). Compound 143 was prepared from 1H 2 O (3M / Et2O). The crude mixture was flushed with silica gel. The compound was purified by column chromatography (30% EtOAc / Hex) to obtain 168 mg of the compound. I got 143.

[0247] [Example 44] [ka] Following the general Grignard addition procedure, 4-[4-(1,3-benzothiazole-2 4-yloxy)phenyl]butan-2-one (195 mg, 0.66 mmol, Example 4 0), THF (2.0 mL), and phenylmagnesium bromide (0.32 Compound 144 was prepared from 1 mL of 3M / Et2O. The crude mixture was flushed with silica gel. Column chromatography (30% EtOAc / Hex) was performed to obtain 222 g of compound 144 was obtained as an oil.

[0248] [Example 45] [ka] Following the general Grignard addition procedure, 4-[4-(1,3-benzothiazole-2 4-yloxy)phenyl]butan-2-one (220 mg, 0.74 mmol, Example 4 0), THF (9.0 mL), and 4-fluorophenylmagnesium bromide (1.0 mL). Compound 145 was prepared from 4-fluorophenylmagnesium fluoride (0.8 mmol). Magnesium bromide is a compound prepared by reacting 1-bromo-4-fluorobenzene (0.8 mmol) and magnesium. The Grignard reagent was prepared according to the general procedure for the preparation of Grignard reagents using 2.2 mmol of ammonium nitrate. The crude mixture was purified by flash column chromatography on silica gel (30% EtOAc / Hex) to give 323 mg of compound 145 as a colorless oil.

[0249] [Example 46] [ka] D of 4-(4-hydroxyphenyl)-2-butanone (518 mg, 3.2 mmol) To a solution of MF (8 mL) under argon was added 2-chlorobenzoxazole (300 μL, .6mmol) and K2CO3 (496mg, 3.6mmol) were added to the reaction mixture. The mixture was stirred at 130° C. for 15 hours. The reaction mixture was diluted with water (20 mL), brine (20 mL), and Et0Ac (30 mL). The layers were separated and the aqueous layer was diluted with EtOAc (20 mL). The combined organic layer was washed with brine (20 mL). The organic layer was dried. Dry (MgSO4), filter and remove the solvent under reduced pressure. Flash on silica gel Column chromatography (30% EtOAc / Hex) gave 605 mg of 4-[4 -(1,3-benzoxazol-2-yloxy)phenyl]butan-2-one was obtained as an oil. [ka]

[0250] Following the general Grignard addition procedure, 4-[4-(1,3-benzoxazole- 2-yloxy)phenyl]butan-2-one (101 mg, 0.36 mmol), TH F (3.0 mL), and ethylmagnesium bromide (0.150 mL, 3M / Et2O) Compound 146 was prepared from the crude mixture by flash column chromatography on silica gel. Purification with 30% EtOAc / Hex gave 80 mg of compound 146.

[0251] [Example 47] [ka] Following the general Grignard addition procedure, 4-[4-(1,3-benzoxazole- 2-yloxy)phenyl]butan-2-one (101 mg, 0.36 mmol, Example 46), THF (3.0 mL), and phenylmagnesium bromide (0.2 Compound 147 was prepared from 1 mL of 3M / Et2O. The crude mixture was flushed with silica gel. The compound was purified by column chromatography (30% EtOAc / Hex) to obtain 96 mg of the compound. I got 83.

[0252] [Example 48] Preparation of Compound 148 4-Hydroxybenzaldehyde (2.0 g, 16.4 mmol) was dissolved in MeOH (17 mL ) / H2O (2.5 mL) and 2-butanone (10 mL, 111 mmol) was added. Then, KOH (3.0 g, 45.4 mmol) was added. The mixture was stirred at room temperature for 3 days. The reaction was quenched with 10% dilute HCl (25 mL) and extracted with EtOAc (40 mL). The organic layer was washed with water (2 x 30 mL) and then with brine (1 x 30 mL). The mixture was dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. The residue was diluted with ether / H ex (40 mL, 1:1) to obtain 1.29 g of 1-(4-hydroxyphenyl) The resulting mixture was concentrated to give 1,2-diphenylpent-1-en-3-one as a solid.

[0253] 1-(4-hydroxyphenyl)pent-1-en-3-one (1.25 g, 7.17 A solution of 10 mmol of 1,2-dichlorophenyl ether (12 mL) was stirred and 10% Pd / C (125 mg) was added. The reaction mixture was stirred under hydrogen for 1 hour. The mixture was filtered and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (20%-40% EtOAc / Hex). After purification, 650 mg of 1-(4-hydroxyphenyl)pentan-3-one was obtained. [ka]

[0254] 1-(4-hydroxyphenyl)pentan-3-one (200 mg, 1.12 mmol) ), K2CO3 (154 mg, 1.11 mmol), and 2-chlorobenzothiazole (0.160 mL, 1.23 mmol) in DMF (3 mL) and mixed in a sealed tube for 120 The mixture was allowed to cool to room temperature and diluted with EtOAc (10 mL). , washed with brine (3×10 mL), dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure The solvent was evaporated and the residue was purified by flash chromatography (25% EtOAc / Hex). Purification thus afforded 303 mg of compound 148 as an oil.

[0255] [Example 49] Preparation of Compound 149 M of 3-chloro-4-hydroxybenzaldehyde (0.250 g, 1.60 mmol) A solution of eOH (2 mL) / HO (0.32 mL) was stirred and 2-butanone (0.60 mL) was added. , 6.66 mmol) was added, followed by KOH (0.422 g, 6.39 mmol). The mixture was stirred at 75°C for 2 hours. The reaction mixture was allowed to cool naturally. EtOH (35 mL) was added. ) and 10% dilute HCl (25 mL) were added. The layers were separated and the organic layer was washed with water (25 mL). The residue was washed, dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. The product was purified by column chromatography (10-20% EtOAc / Hex) to give a 0.29% yield. 0g of 1-(3-chloro-4-hydroxyphenyl)pent-1-en-3-one in yellow was obtained as an oil.

[0256] 1-(3-chloro-4-hydroxyphenyl)pent-1-en-3-one (0.69 A solution of 100 g, 1.38 mmol) in EtOAc (15 mL) was stirred and 10% Pd / C (2 9 mg) was added. The reaction mixture was stirred under hydrogen for 1 hour. The reaction mixture was filtered. The solvent was evaporated under reduced pressure and the residue was purified by flash chromatography (20% EtOAc / Hex). 0.090 g of 1-(3-chloro-4-hydroxyphenyl)pentane -3-one was obtained as a yellow oil. [ka]

[0257] 1-(3-chloro-4-hydroxyphenyl)pentan-3-one (199 mg, 0. 936 mmol), K2CO3 (194 mg, 1.40 mmol), and 2-chlorobenzaldehyde (1.2 mmol). Benzothiazole (0.150 mL, 1.15 mmol) was mixed in DMF (4 mL), The mixture was stirred in a sealed tube at 100° C. for 18 h. The mixture was allowed to cool to room temperature and was diluted with EtOAc (35 Dilute with 1 mL of water, wash with water (3 x 25 mL), dry over anhydrous MgSO4, filter, and The solvent was removed under reduced pressure. The residue was purified by flash chromatography (20% EtOAc / Hex) to give 165 mg of compound 149 as a yellow oil.

[0258] [Example 50] [ka] Compound 148 (100 mg, 0.321 mmol, prepared in the same manner as in Example 48), K2C O3 (15 mg, 0.108 mmol), and CF3TMS (0.100 ml, 0.6 (77 mmol) was added to DMF (2 ml) and mixed at room temperature under argon for 18 hours. The material was diluted with EtoAc (415 mL) and washed with brine (2 x 15 mL). The layer was concentrated under reduced pressure. The residue was taken up in MeOH (5 mL) and concentrated HCl (0.25 mL) was added. The mixture was then diluted with EtOAc (20 mL) and washed with brine. (20 mL x 2). Dry the organic layer over anhydrous MgSO4, filter, and remove the solvent under reduced pressure. The residue was purified by flash chromatography (30% EtOAc / Hex). This gave 111 mg of compound 150 as an oil.

[0259] [Example 51] [ka] Compound 149 (153 mg, 0.442 mmol; prepared as in Example 49), K2C O3 (6 mg, 0.043 mmol), and CF3TMS (0.091 ml, 0.61 A mixture of 6 mmol) in DMF (2 ml) was mixed at room temperature under argon for 18 hours. The mixture was diluted with EtOAc (35 mL) and washed with water (2 x 25 mL). The layer was dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. The residue was dissolved in MeOH( HCl (0.07 mL) was added and stirred for 1 hour. The mixture was diluted with Et The organic layer was diluted with OAc (35 mL) and washed with water (2 x 25 mL). The mixture was dried at 4°C, filtered, and the solvent was removed under reduced pressure. The residue was isolated as a colorless oil and was stirred at room temperature for 1 h. Upon standing at rt, it solidified to give 0.093 g of compound 151 as a white solid.

[0260] [Example 52] Preparation of Compound 152 3-Fluoro-4-hydroxybenzaldehyde (250 mg, 1.78 mmol), Benzyl bromide (320 μL, 2.69 mmol), and K2CO3 (372 mg, 2. 69 mmol) in acetone (5 mL), stirred under reflux for 16 hours, and then cooled to room temperature. The mixture was cooled naturally to 30° C., filtered, and washed with acetone. The filtrate was concentrated under reduced pressure, and the residue was The product was purified by column chromatography (20% EtOAc / Hex) to give 212 mg of 4 -(Benzyloxy)-3-fluorobenzaldehyde was obtained as a white solid.

[0261] 4-(benzyloxy)-3-fluorobenzaldehyde (212 mg, 0.921 m mol), 2-butanone (80 μL, 0.888 mmol), and 85% KOH (18 2 mg, 2.76 mmol) was mixed in MeOH (3 mL) and water (0.6 mL). The mixture was stirred in a sealed tube at 75°C for 1 hour. The reaction mixture was allowed to cool naturally and filtered. The solid was dissolved in water, Me OH and dried to give 146 mg of 1-[4-(benzyloxy)-3-fluorophenyl Nyl]pent-1-en-3-one was obtained as a white solid.

[0262] 1-[4-(benzyloxy)-3-fluorophenyl]pent-1-en-3-one (146 mg, 0.514 mmol) and 10% Pd / C (15 mg) were Combine in EtOAc (14 mL). Add AcOH (14 drops). Evacuate the flask. The mixture was stirred for 20 hours, filtered, and then charged with hydrogen (balloon). The filtrate was concentrated under reduced pressure to give 96 mg of 1-[4-(benzyloxy) )-3-Fluorophenyl]pentan-3-one was obtained as a white solid. [ka]

[0263] 1-[4-(benzyloxy)-3-fluorophenyl]pentan-3-one (96m g, 0.489 mmol), K2CO3 (101 mg, 0.731 mmol), and 2 -Chlorobenzothiazole (100 μL, 0.768 mmol) in DMF (2 mL) The mixture was mixed and stirred in a sealed tube at 100° C. for 16 hours. The mixture was allowed to cool to room temperature and EtO The organic layer was diluted with Ac (50 mL) and washed with water (3 x 25 mL). The mixture was dried at 40° C., filtered, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography. (20% EtOAc / Hex) to give 102 mg of compound 152 as a colorless oil. Obtained as an object.

[0264] [Example 53] Preparation of Compound 153 4-Hydroxy-3-(trifluoromethyl)benzaldehyde (250 mg, 1.3 1 mmol), benzyl bromide (230 μL, 1.94 mmol), and K2CO3 (2 72 mg, 1.97 mmol) in acetone (5 mL) and stirred under reflux for 16 hours. After that, the mixture was allowed to cool to room temperature, filtered, and washed with acetone. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (20% EtOAc / Hex) 161 mg of 4-(benzyloxy)-3-(trifluoromethyl)benzaldehyde Obtained as a white solid.

[0265] 4-(benzyloxy)-3-(trifluoromethyl)benzaldehyde (161mg , 0.574 mmol), 2-butanone (50 μL, 0.555 mmol), and 85 % KOH (114 mg, 1.73 mmol) was dissolved in MeOH (2 mL) and water (0.4 The mixture was mixed in a sealed tube and stirred at 75° C. for 1 hour. The reaction mixture was allowed to cool naturally, and then diluted with EtOAc. (35 mL) and washed with water (25 mL x 2). The organic layer was dried over anhydrous MgSO4. The mixture was dried, filtered, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography ( 0% EtOAc / Hex) to give 38 mg of 1-[4-(benzyloxy)- 3-(trifluoromethyl)phenyl]pent-1-en-3-one as a white solid Got it.

[0266] 1-[4-(benzyloxy)-3-(trifluoromethyl)phenyl]pent-1- Ene-3-one (38 mg, 0.114 mmol) and 10% Pd / C (4 mg) were Combine under argon in EtOAc (3 mL). Add AcOH (3 drops). The vessel was evacuated and filled with hydrogen (balloon). The reaction mixture was stirred for 32 hours and then filtered. The filtrate was concentrated under reduced pressure to give 22 mg of 1-[4-(benzyl Oxy)-3-(trifluoromethyl)phenyl]pentan-3-one as a colorless oil. And obtained. [ka]

[0267] 1-[4-(benzyloxy)-3-(trifluoromethyl)phenyl]pentane-3 -one (22 mg, 0.089 mmol), K2CO3 (20 mg, 0.145 mmol) ), and 2-chlorobenzothiazole (20 μL, 0.154 mmol) in DMF ( The mixture was mixed in a sealed tube at 100° C. for 16 hours and then allowed to cool to room temperature. The organic layer was diluted with EtOAc (50 mL) and washed with water (3 x 25 mL). The residue was dried over gSO4, filtered, and the solvent was removed under reduced pressure. Purified by column chromatography (20% EtOAc / Hex) to give 22 mg of compound 153, colorless. was obtained as an oil.

[0268] [Example 54] [ka] Compound 152 (94 mg, 0.285 mmol) and K2CO3 (4 mg, 0.02 9 mmol) in DMF (2 mL) and stirred under argon, and CF3TMS (60 The reaction mixture was stirred at room temperature for 18 hours, and then Et The organic layer was diluted with OAc (35 mL) and washed with water (2 x 25 mL). The mixture was dried over 4, filtered, and the solvent was removed under reduced pressure. The residue was added to MeOH (3 mL) and Concentrated HCl (0.1 mL) was added and stirred for 1 h. The mixture was concentrated under reduced pressure and the residue was diluted with The product was purified by cross-linking chromatography (20% EtOAc / Hex) to give 86 mg of the compound. Compound 154 was obtained as a colorless gum.

[0269] [Example 55] [ka] Compound 153 (22 mg, 0.058 mmol) and K2CO3 (1 mg, 0.00 7 mmol) in DMF (1 mL) and stirred under argon to give CF3TMS (12 The reaction mixture was stirred at room temperature for 18 hours, and then Et The organic layer was diluted with OAc (35 mL) and washed with water (2 x 25 mL). The mixture was dried over 4, filtered, and the solvent was removed under reduced pressure. The residue was added to MeOH (3 mL) and Concentrated HCl (0.1 mL) was added and stirred for 1 h. The mixture was concentrated under reduced pressure and the residue was diluted with The product was purified by cross-linking chromatography (20% EtOAc / Hex) to give 18 mg of the compound. Compound 155 was obtained as a colorless oil.

[0270] [Example 56] [ka] 4-[4-(1,3-benzothiazol-2-yloxy)-1,3-dihydrobenzotriazol-2-yl]-2,4-dihydrobenzotriazol-2-yl )phenyl]butan-2-one (150 mg, 0.504 mmol) in THF (3 mL) The solution was stirred at room temperature under argon and Ti(O i Pr)4 (200 μL, 0.676 mmol) l) was added, followed by pyrrolidine (100 μL, 1.22 mmol). The mixture was stirred under reflux for 18 hours and then allowed to cool to room temperature. NaBH4 (28 mg, 0. 740 mmol) was added, and the reaction mixture was stirred for 1 h, after which the reaction was quenched with water (25 mL). The mixture was cooled and extracted with EtOAc (35 mL). The organic layer was dried over anhydrous MgSO4. The residue was purified by flash chromatography (EtO Ac / MeOH / Et3N, 9:1:0.1) to obtain 60 mg of compound 156 was obtained as a yellow oil.

[0271] [Example 57] [ka] 4-[4-(1,3-benzothiazol-2-yloxy)-1,3-dihydrobenzotriazol-2-yl]-2,4-dihydrobenzotriazol-2-yl )phenyl]butan-2-one (150 mg, 0.504 mmol) in DCE (3 mL) The solution was stirred at room temperature under argon and then diluted with 4A molecular sieve powder (150 mg), L-propanediol (1.2 mL), and 10% ethanol. Lorine (75 mg, 0.651 mmol), AcOH (100 μL, 1.75 mmol) After adding NaBH(OAc)3 (214 mg, 1.01 mmol), the reaction The mixture was stirred for 18 h, then quenched with water (25 mL) and EtOAc (35 mL). The mixture was extracted with 10 mL of ethyl acetate and CH2Cl2 (2 x 35 mL). The combined organic layer was washed with anhydrous The mixture was dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The residue was analyzed by flash chromatography. The product was purified by chromatography (10% MeOH / CH2Cl2 + 1% AcOH) to give 80 mg Compound 157 was obtained as a wax.

[0272] [Example 58] [ka] DC of compound 148 (150 mg, 0.482 mmol) prepared in the same manner as in Example 48 A solution of E (3 mL) was stirred under argon and charged with 4A molecular sieve powder (150 mg), Pyrrolidine (50 μL, 0.609 mmol), AcOH (55 μL, 0.961 mmol) l) was added, followed by NaBH(OAc)3 (204 mg, 0.962 mmol). The reaction mixture was stirred for 18 h, then quenched with water (25 mL) and CH2Cl2 The combined organic layer was dried over anhydrous MgSO4 and extracted with 100 mL of ethyl acetate (35 mL x 3). After filtration, the solvent was removed under reduced pressure. The residue was purified by flash chromatography (EtOAc / MeOH / Et3N, 9:1:0.1) to obtain 160 mg of compound 158. Obtained as a colourless wax.

[0273] [Example 59] [ka] 4-Hydroxyacetophenone (109, 500 mg, 3.67 mmol), KCO 3 (435 mg, 3.15 mmol), and 2-chlorobenzothiazole (525 μL (4.04 mmol) was mixed in DMF (5 mL) and stirred at 140° C. for 18 hours. The mixture was allowed to cool to room temperature and diluted with HO (10 mL) and EtOH (30 mL). , separated, and the organic layer was washed with 5% NaOH (2 x 20 mL) and then with brine (30 mL The mixture was washed with water (3x), dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. Purification by cross-linking chromatography (30% EtOAc / Hex) gave 979 mg of Compound 159 was obtained as a yellow solid.

[0274] [Example 60] [ka] Compound 159 (100 mg, 0.371 mmol, prepared as in Example 59) in MeO The solution was stirred at room temperature under argon in H (2 mL) and added NaBH (21 mg, 0.555 mmH The reaction mixture was stirred for 2 h, then quenched with water (25 mL) and Extraction was performed with CH2Cl2 (25 mL x 3). The combined organic layer was washed with anhydrous MgSO4 The mixture was dried at 40° C., filtered, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography. (30% EtOAc / Hex) to give 40 mg of compound 160 as a white solid. And obtained.

[0275] [Example 61] [ka] Following the general Grignard addition procedure as disclosed herein, compound 159 ( 233 mg, 0.865 mmol, prepared as in Example 59), THF (4.0 mL), Compound 161 was prepared from ethylmagnesium bromide (0.57 mL, 3 M / Et2O). The crude mixture was purified by flash column chromatography on silica gel (30% EtO Ac / Hex) to give 169 mg of compound 161 as a yellow oil.

[0276] [Example 62] [ka] A solution of compound 159 (200 mg, 0.743 mmol) in THF (8 mL) was heated under argon Stir at room temperature under reduced pressure and add Ti(O i Pr)4 (265 μL, 0.895 mmol) was added. Then, pyrrolidine (85 μL, 1.04 mmol) was added. The reaction mixture was refluxed for 16 hours. After stirring for 1 h, the mixture was allowed to cool to room temperature. The reaction mixture was stirred for 1.5 h, then quenched with water (25 mL) and EtO The organic layer was washed with water (35 mL) and concentrated in anhydrous MgCl. The residue was dried over gSO4, filtered, and the solvent was removed under reduced pressure. Purification by elution (EtOAc / MeOH / Et3N, 9:1:0.1) gave 88m g of compound 162 was obtained as a yellow oil.

[0277] [Example 63] Preparation of Compound 163 [ka] Compound 159 (125 mg, 0.464 mmol, prepared as in Example 59) and K 2CO3 (6 mg, 0.043 mmol) was mixed in DMF (2 mL) and cooled under argon. The reaction mixture was stirred and CF3TMS (90 μL, 0.610 mmol) was added. After stirring for 18 h, it was diluted with EtOAc (35 mL) and washed with water (25 mL for 2 The organic layer was dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. The mixture was added to MeOH (2 mL) and concentrated HCl (0.1 mL) and stirred for 1 hour. The solvent was evaporated and the residue was purified by flash chromatography (10% EtOAc / Hex). Purification by hexanes afforded 26 mg of compound 163 as an off-white solid.

[0278] [Example 64] Preparation of Compound 164 4-Hydroxybenzaldehyde (84, 200 mg, 1.64 mmol), KCO 3 (340 mg, 2.46 mmol), and 2-chlorobenzothiazole (260 μL , 2.00 mmol) in DMF (3 mL) and stirred in a sealed tube at 100° C. for 16 hours. The mixture was allowed to cool to room temperature, diluted with EtOAc (35 mL), and washed with water (2 The residue was washed with 5 mL of water (3 times), dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. was purified by flash chromatography (20% EtOAc / Hex) to give 354 mg of 4-(1,3-benzothiazol-2-yloxy)benzaldehyde as a white solid. Got it as a body. [ka]

[0279] 4-(1,3-benzothiazol-2-yloxy)benzaldehyde (150 mg, 0.588 mmol) in DCE (3 mL) and stirred at room temperature under argon to give pyrophosphate. Lysine (60 μL, 0.730 mmol) was added, followed by NaBH(OAc)3 (190 mg, 0.896 mmol) was added. The reaction mixture was stirred for 18 h, after which water (25 ml The reaction was quenched with 10 mL of ethyl acetate and extracted with CH2Cl2 (35 mL x 3). The organic layer was dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. by chromatography (EtOAc / MeOH / Et3N, 9:1:0.1). Purification gave 153 mg of compound 164 as a colorless oil.

[0280] [Example 65] [ka] Following the procedure described above to produce compound 157, L-proline (81 mg, 0.70 4mmol), 4-(1,3-benzothiazol-2-yloxy)benzaldehyde ( 150 mg, 0.588 mmol), and NaBH(OAc)3 (190 mg, 0.8 A non-clinical variant was performed using 96 mmol) in DCE (3 mL) at room temperature under argon. and purified using 10% MeOH / CH2Cl2 + 1.5% AcOH as eluent. This gave 132 mg of compound 165 as a white solid.

[0281] [Example 66] [ka] 4-(1,3-benzothiazol-2-yloxy)benzaldehyde (125 mg, 0.490 mmol) and K2CO3 (7 mg, 0.051 mmol) in DMF (2 ml Mix in 1000 mL of CF3TMS (94 μL, 0.655 mmol) and stir under argon. The reaction mixture was stirred at room temperature for 18 h and then diluted with EtOAc (35 mL). The organic layer was dried over anhydrous MgSO4, filtered, and concentrated. The solvent was removed under reduced pressure. The residue was added to MeOH (2 mL) and concentrated HCl (0.1 mL) was added. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography ( 0% EtOAc / Hex) to give 94 mg of compound 166 as a white solid. Got it.

[0282] [Example 67] Preparation of Compound 167 3-Chloro-4-hydroxybenzothiazole (250 mg, 1.60 mmol), K 2CO3 (332 mg, 2.40 mmol), and 2-chlorobenzothiazole (26 0 μL, 2.00 mmol) in DMF (3 mL) and incubated at 100°C for 18 hours in a sealed tube. The mixture was allowed to cool to room temperature, diluted with EtOAc (35 mL) and washed with water. (25 mL x 3), dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (20% EtOAc / Hex) to give 187mg of 4-(1,3-benzothiazol-2-yloxy)-3-chlorobenzaldehyde The aldehyde was obtained as a white solid. [ka]

[0283] 4-(1,3-Benzothiazol-2-yloxy)-3-chlorobenzaldehyde ( (187 mg, 0.645 mmol) and K2CO3 (9 mg, 0.065 mmol) Mix in DMF (2 mL), stir under argon, and CF3TMS (143 μL, 0.9 The reaction mixture was stirred at room temperature for 4 days, after which EtOAc (40 ml) was added. The organic layer was diluted with 10 mL of water and washed with water (25 mL x 2). The organic layer was dried over anhydrous MgSO4 and The solvent was removed under reduced pressure after filtration. The residue was added to MeOH (3 mL) and concentrated HCl (0. 2 mL) was added and stirred for 1 h. The mixture was diluted with EtOAc (40 mL) and washed with water. The organic layer was dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (20% EtOAc / Hex). The resulting mixture was purified by hexane distillation to give 90 mg of compound 167 as a white solid.

[0284] [Example 68] Preparation of Compound 168 4-(1,3-benzothiazol-2-yloxy)benzaldehyde (300 mg, 1.18 mmol, prepared as in Example 64), 4A molecular sieves (600 mg) , and a mixture of ethylamine (2.0 M in THF, 3.0 mL, 6.0 mmol) The mixture was stirred at room temperature under argon for 3 hours. The reaction mixture was filtered and the solvent was removed under reduced pressure. , crude 1-[4-(1,3-benzothiazol-2-yloxy)phenyl]-N- Ethylmethanimine was obtained. [ka]

[0285] 1-[4-(1,3-benzothiazol-2-yloxy)phenyl]-N-ethyl methyl Tanimine (1.18 mmol) and KHF2 (69 mg, 0.883 mmol) were added to M In addition to eCN (4 mL) and DMF (274 μL), TFA (11 The mixture was stirred for 5 min, and then CF3TMS(2 61 μL, 1.78 mmol) was added. The cooling bath was removed and the reaction mixture was stirred for 18 h. Dilute with saturated aqueous Na2CO3 (40 mL) and extract with EtOAc (40 mL). The organic layer was washed with water (25 mL), dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The solvent was removed under reduced pressure. The residue was purified by flash chromatography (5% EtOAc / Hex). Purification by HPLC gave 294 mg of a yellow oil.

[0286] To further purify the desired compound, the oil was dissolved in MeOH (2 mL) and added with Na BH4 (30 mg) was added and the mixture was stirred under argon for 30 min. The reaction was stopped and extracted with EtOAc (35 mL). The organic layer was washed with anhydrous Na2SO The mixture was dried over 4°C, filtered, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography. - (10% EtOAc / Hex) to give 133 mg of compound 168 as a colorless oil. It was obtained as a solid.

[0287] [Example 69] [ka] 4'-Fluoroacetophenone (177, 150 μL, 1.24 mmol), 2-methyl 1,2-dichloro-5-benzothiazolol (205 mg, 1.24 mmol), and K2CO3 (5 14 mg, 3.72 mmol) in DMSO (3 mL) and heated at 100°C for 1 After stirring for 8 hours, the mixture was allowed to cool to room temperature, diluted with EtOAc (35 mL), and diluted with 1M N The organic layer was washed with aOH (25 mL x 2) and water (25 mL). The mixture was dried at 40° C., filtered, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography. (20% EtOAc / Hex) to give 306 mg of compound 169 off-white. This was obtained as a solid.

[0288] [Example 70] Preparation of compound 170 [ka] Compound 169 (150 mg, 0.529 mmol, prepared as in Example 69) and K 2CO3 (7 mg, 0.051 mmol) was mixed in DMF (3 mL) and cooled under argon. The reaction mixture was stirred and CF3TMS (195 μL, 1.32 mmol) was added. After stirring for 5 days, the mixture was diluted with EtOAc (35 mL) and washed with water (2 x 25 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and the solvent was removed under reduced pressure. The mixture was added to MeOH (3 mL) and stirred with concentrated HCl (0.3 mL) for 1 hour. The solution was diluted with EtOAc (35 mL) and washed with saturated aqueous Na2CO3 (2 x 25 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and the solvent was removed under reduced pressure.

[0289] To further purify the desired compound, the residue was added to MeOH (3 mL) and 20 mg of NaBH4 was added. The reaction was stirred for 1 h, then quenched with water (25 mL). The organic layer was extracted with EtOAc (35 mL), washed with water (25 mL), and concentrated in anhydrous N The mixture was dried over a2SO4, filtered, and the solvent was removed under reduced pressure. The residue was analyzed by flash chromatography. HPLC (30% EtOAc / Hex) to give 52 mg of compound 170. Obtained as a white solid.

[0290] [Example 71] [ka] Compound 169 (75 mg, 0.2 mL), prepared as in Example 69, was dissolved in MeOH (2 mL). 65mmol) was suspended in water, and NaBH4 (15mg, 0.396mmol) was added. The mixture was stirred under argon for 1 h, after which 10 mg of NaBH4 was added. The mixture was stirred for 30 min, after which the solution became clear. The reaction was quenched with water (25 mL) and The organic layer was extracted with tOAc (35 mL). Dry over 2SO4, filter, and remove the solvent under reduced pressure to obtain 40 mg of compound 171 in yellow. Obtained as a tasty oil.

[0291] [Example 72] [ka] A solution of acetovanillone (250 mg, 1.50 mmol) in DMF (5 mL) was added to argon. 2-Chlorobenzothiazole (235 μL, 1.80 mmol) and KCO 3 (311 mg, 2.25 mmol) was added, and the reaction mixture was heated in a sealed tube at 100 °C for 18 h. The reaction mixture was diluted with ethyl acetate (35 mL). The organic layer was then washed with 1M N The organic layer was washed with aqueous aOH (25 mL x 2) and water (25 mL). The mixture was dried over 4°C, filtered, and the solvent was removed under reduced pressure. 437 mg of compound 172 was isolated by chromatography (20% EtOAc / Hex). Obtained as a colored solid.

[0292] [Example 73] [ka] Compound 172 (150 mg, 0.501 mmol) and K2CO3 (7 mg, 0.0 51 mmol) in DMF (3 mL) and stirred under argon, and CF3TMS (1 The reaction mixture was stirred at room temperature for 44 hours, and then CF3TMS (222 μL, 1.54 mmol) was added and stirring was continued for 3 days. The mixture was diluted with EtOAc (35 mL) and washed with water (25 mL). The organic layer was washed with anhydrous N The mixture was dried over a2SO4, filtered, and the solvent was removed under reduced pressure. The residue was dissolved in MeOH (3 mL). HCl (0.3 mL) was added and stirred for 1 h. The mixture was diluted with EtOAc (35 ml The organic layer was dried over anhydrous Na2SO4 and filtered. Then, the solvent was distilled off under reduced pressure.

[0293] To separate the product from the by-product, the residue was added to MeOH (3 mL) and (22 mg) was added and the mixture was stirred for 30 min. The mixture was diluted with EtOAc (35 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The solvent was removed under reduced pressure. The residue was purified by flash chromatography (20% EtOAc / He x) to give 56 mg of compound 173 as a white solid.

[0294] [Example 74] Preparation of Compound 174 3-Chloro-4-hydroxybenzaldehyde (900 mg, 5.75 mmol) A solution of acetone (10 mL) / HO (10 mL) was stirred and treated with NaOH (1 g, 25 mmol). The mixture was stirred at room temperature for 18 hours. 5% dilute HCl (10 mL) was added to the reaction mixture. The reaction was stopped and extracted with EtOAc (15 mL). The organic layer was washed with water (10 mL twice). ), washed with brine (10 mL), dried over anhydrous MgSO4, filtered and dissolved in vacuum. The solvent was removed by distillation to give 1.1 g of 4-(3-chloro-4-hydroxyphenyl)but-3-ene. The 2-one was obtained as a yellow oil.

[0295] 4-(3-chloro-4-hydroxyphenyl)but-3-en-2-one (626mg A solution of 10% Pd / C (100 The reaction mixture was stirred under hydrogen for 1.5 hours. The mixture was filtered and The solvent was removed under reduced pressure and the residue was purified by flash chromatography (25% EtOAc / Hex ) and 333 mg of 4-(3-chloro-4-hydroxyphenyl)butane- The 2-one was obtained as an oil. [ka]

[0296] 4-(3-chloro-4-hydroxyphenyl)butan-2-one (333 mg, 1.6 A solution of 2-chlorobenzothiazole ( (239 μL, 1.84 mmol) and K2CO3 (231 mg, 1.67 mmol) The reaction mixture was stirred at 140° C. for 18 hours. The reaction mixture was allowed to cool to room temperature. The mixture was then diluted with water (30 mL) and extracted with EtOAc (40 mL). The organic layer was dried (MgSO4), filtered and washed with brine (3 x 40 mL). The solvent was removed under reduced pressure. Flash column chromatography on silica gel (25% EtOAc / Hex) to give 429 mg of compound 174 as a yellow oil.

[0297] [Example 75] [ka] Following the general CF3TMS addition procedure as disclosed herein, compound 174 (1 05mg, 0.36mmol), CF3TMS (97μL, 0.65mmol), K2C O3 (15 mg, 0.11 mmol), and DMF (2 mL), then MeOH (5 mL Compound 175 was prepared from 1,2-dichlorophenyl ether (1H) and HCl (250 μL). The crude mixture was washed with silica gel. was subjected to flash column chromatography (20% EtOAc / Hex) to obtain 109m g of compound 175 was obtained as an oil.

[0298] [Example 76] Preparation of Compound 176 4-Hydroxyacetophenone (150 mg, 1.10 mmol), K2CO3 (22 8 mg, 1.65 mmol), and 2-chloro-4-(methylthio)-benzothiazo The mixture was heated at 100°C in a sealed tube. The mixture was allowed to cool to room temperature and was then added HO (10 mL) and EtOH (1 mL). c (30 mL), separated, and the organic layer was washed with 5% NaOH (2 x 20 mL), then with Brassica naphtha (10 mL). Wash with ethyl acetate (30 mL x 3), dry over anhydrous MgSO4, filter, and remove the solvent under reduced pressure. The residue was purified by flash chromatography (20% EtOAc / Hex). 338 mg of 1-(4-{[4-(methylsulfanyl)-1,3-benzothiamine Azol-2-yl]oxy}phenyl)ethan-1-one was obtained as a white solid. [ka]

[0299] 1-(4-{[4-(methylsulfanyl)-1,3-benzothiazol-2-yl] (oxy}phenyl)ethan-1-one (150 mg, 0.476 mmol) in MeOH( The solution was stirred at room temperature under argon and added NaBH4 (27 mg, 0.714 mmol). The reaction mixture was stirred for 1 h, then quenched with water (25 mL) and E Extraction was performed with tAOc (35 mL). The organic layer was dried over anhydrous MgSO4 and filtered. The solvent was removed under reduced pressure. The residue was purified by flash chromatography (20% EtOAc / Hex) to give 134 mg of compound 176 as a colorless oil.

[0300] [Example 77] Preparation of Compound 177 [ka] Compound 159 (150 mg, 0.557 mmol) in diethyl ether (9 mL) was stirred at 0° C. under argon and added to ether (0.3 mL, 0.9 mmol) M MeMgBr was added. The reaction mixture was stirred at 0° C. for 10 min. The cooling bath was removed and the reaction The mixture was stirred for 1 h, then quenched with water (10 mL) and 5% HCl (10 mL). The mixture was diluted with EtOAc (35 mL) and extracted with EtOAc (35 mL). The organic layer was washed with water (20 mL). The mixture was washed, dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. The compound was purified by column chromatography (20% EtOAc / Hex) to give 93 mg of compound A. 177 was obtained as a colorless oil.

[0301] [Example 78] Preparation of Compound 178 4-(1,3-benzothiazol-2-yloxy)benzaldehyde (300 mg, 1.18 mmol, prepared as in Example 64), 4A molecular sieves (600 mg) , methylamine (2.0 M in THF, 3.0 mL, 6.0 mmol), and anhydrous D The mixture was stirred at room temperature under argon for 18 hours. The solvent was removed under reduced pressure to give crude 1-[4-(1,3-benzothiazole-2- As a result, 4-(1-phenyl)-N-methylmethanimine was obtained. [ka] 1-[4-(1,3-benzothiazol-2-yloxy)phenyl]-N-methylmethyl Tanimine (1.18 mmol) and KHF2 (69 mg, 0.883 mmol) were added to M In addition to eCN (4 mL) and DMF (274 μL), TFA (11 The mixture was stirred for 5 min, and then CF3TMS(2 The cooling bath was removed and the reaction mixture was stirred for 20 hours. Dilute with saturated aqueous Na2CO3 (40 mL) and extract with EtOAc (40 mL). The organic layer was washed with water (25 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The solvent was removed under reduced pressure.

[0302] The residue was taken up in MeOH (2 mL), NaBH4 (45 mg) was added and the mixture was blanketed in argon The reaction was stirred under reduced pressure for 30 min. The reaction was quenched with water (25 mL) and extracted with EtOAc (35 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (20% EtOAc / Hex). This gave 109 mg of compound 178 as a colorless oil.

[0303] [Example 79] Preparation of Compound 179 4-Hydroxybenzaldehyde (100 mg, 0.819 mmol), K2CO3( 170 mg, 1.23 mmol), and 2-chloro-4,6-difluoro-benzothiazol- 168 mg (0.817 mmol) of 1-phenylpropanediol (168 mg, 0.817 mmol) was mixed in DMF (3 mL) and The mixture was stirred at 00° C. for 18 h. The mixture was allowed to cool to room temperature and diluted with EtOAc (35 mL). The solution was diluted with water, washed with 1M NaOH (25 mL x 2) and water (25 mL), and then diluted with anhydrous NaSO. Dry over O4, filter, and remove the solvent under reduced pressure to give 216 mg of 4-(4,6-difluorophenyl) (1,3-benzothiazol-2-yloxy)benzaldehyde was obtained as a white solid. I got it. [ka]

[0304] 4-(4,6-difluoro-1,3-benzothiazol-2-yloxy)benzal aldehyde (216 mg, 0.742 mmol) and KCO (10 mg, 0.072 mmol). mol) in DMF (2 mL) and stirred under argon, and CF3TMS (220 μL) was added. The reaction mixture was stirred at room temperature for 20 hours, and then EtOAc was added. The mixture was diluted with c (35 mL) and washed with water (25 mL). The organic layer was dried over anhydrous Na2SO4. The residue was added to MeOH (3 mL) and concentrated HCl (0.3 mL) was added and stirred for 1 h. EtoAc (35 mL) was added and the mixture was diluted with water ( The organic layer was dried over anhydrous Na2SO4 and filtered. The residue was purified by flash chromatography (20% EtOAc / Hex). Purification gave 116 mg of compound 179 as a white solid.

[0305] [Example 80] Preparation of Compound 180 4-Hydroxyacetophenone (150 mg, 1.10 mmol), K2CO3 (22 8 mg, 1.65 mmol), and 2-chloro-4,6-difluoro-benzothiazo The mixture was heated at 100°C in a sealed tube. The mixture was allowed to cool to room temperature and diluted with EtOAc (35 mL). The organic layer was separated and washed with 1M NaOH (2 x 25 mL), then with water (25 mL), and washed with water. Dry with water Na2SO4, filter, and remove the solvent under reduced pressure to obtain 335 mg of 1-[4- (4,6-Difluoro-1,3-benzothiazol-2-yloxy)phenyl]ethane -1-one was obtained as a light brown solid. [ka]

[0306] 1-[4-(4,6-difluoro-1,3-benzothiazol-2-yloxy)phenyl A solution of [nyl]ethan-1-one (100 mg, 0.328 mmol) in MeOH (2 mL) was stirred at room temperature under argon and NaBH4 (18 mg, 0.476 mmol) was added. The reaction mixture was stirred for 1 h, then quenched with water (25 mL) and EtOAc (35 The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The solvent was evaporated and the residue was purified by flash chromatography (30% EtOAc / Hex). Purification thus afforded 80 mg of compound 180 as a colorless oil.

[0307] [Example 81] [ka] 1-[4-(4,6-difluoro-1,3-benzothiazol-2-yloxy)phenyl nyl]ethan-1-one (150 mg, 0.491 mmol) and K2CO3 (7 mg A solution of CF3TMS ( The reaction mixture was stirred at room temperature for 4 days, and then The organic layer was diluted with EtOAc (35 mL) and washed with water (25 mL). The mixture was dried over 4, filtered, and the solvent was removed under reduced pressure. The residue was added to MeOH (3 mL) and Concentrated HCl (0.3 mL) was added and stirred for 1 hour. EtoAc (35 mL) was added and mixed. The residue was taken up in MeOH (3 mL) and diluted with NaBH4 (27 mL). g) was added and the mixture was stirred for 1 h. EtoAc (35 mL) was added and the mixture was diluted with water (2 The organic layer was dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure. The residue was purified by flash chromatography (20% EtOAc / Hex). This gave 27 mg of compound 181 as a white solid.

[0308] [Example 82] Preparation of Compound 182 4-Hydroxy-2-methoxybenzaldehyde (250 mg, 1.64 mmol), K2CO3 (340 mg, 2.46 mmol), and 2-chlorobenzothiazole (2 15 μL, 1.65 mmol) in DMF (5 mL) and heated at 100°C for 18 h in a sealed tube. The mixture was allowed to cool to room temperature, diluted with EtOAc (35 mL), and diluted with 1 M Washed with NaOH (25 mL x 2) and water (25 mL) and dried over anhydrous Na2SO4. The mixture was filtered, the solvent was removed under reduced pressure, and the residue was purified by flash chromatography ( 20% EtOAc) to give 457 mg of 4-(1,3-benzothiazole-2 -yloxy)-2-methoxybenzaldehyde as a white solid. [ka]

[0309] 4-(1,3-Benzothiazol-2-yloxy)-2-methoxybenzaldehyde (200 mg, 0.701 mmol) and K2CO3 (10 mg, 0.072 mmol) ) in DMF (3 mL) and stirred under argon, and CF3TMS (207 μL, 1 The reaction mixture was stirred at room temperature for 20 hours, then EtOAc ( The organic layer was dried over anhydrous Na2SO4 and washed with water (25 mL). The residue was added to MeOH (3 mL) and concentrated HCl (0 EtoAc (35 mL) was added and the mixture was diluted with water (25.3 mL). The organic layer was dried over anhydrous Na2SO4 and filtered. The solvent was distilled off under reduced pressure. The residue was purified by flash chromatography (20% EtOAc / Hex). This gave 172 mg of compound 182 as a white solid.

[0310] [Example 83] [ka] 4-(4-hydroxyphenyl)-2-butanone (150 mg, 0.914 mmol) and K2CO3 (13 mg, 0.094 mmol) in DMF (2 mL) were mixed and The mixture was stirred under argon at 0° C., and CF3TMS (340 μL, 2.30 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 42 h. The mixture was diluted with EtOAc (20 mL) and washed with water. Wash (20 mL x 2), dry over anhydrous Na2SO4, filter, and remove the solvent under reduced pressure. The residue was added with MeOH (3 mL) and 6N dilute HCl (0.3 mL), and the reaction mixture was The mixture was stirred for 1 h. The reaction was diluted with EtOAc (20 mL) and saturated aqueous NaHCO (20 mL x 2), washed with water (20 mL), dried over anhydrous Na2SO4, filtered, and The solvent was removed under reduced pressure. The residue was purified by flash chromatography (20% EtOAc / hexane) to obtain 145 mg of 4-(4,4,4-trifluoro-3-hydroxyphenyl) The resulting mixture was concentrated to give 3-methyl-1-methoxy-3-methylbutylphenol as a white solid.

[0311] 4-(4,4,4-trifluoroacetamide) in DMF (2 mL) was prepared in the same manner as in Example 97. 145 mg, 0.619 mmol ), 2-(chloromethyl)quinoline hydrochloride (146 mg, 0.682 mmol), and From K2CO3 (342 mg, 2.47 mmol), 173 mg of compound 183 was Prepared as a solid.

[0312] [Example 84] Preparation of Compound 184 Vanillylacetone (250 mg, 1.52 mmol), K2CO3 (377 mg, 2. 73 mmol), and 2-(chloromethyl)quinoline hydrochloride (343 mg, 1.60 m mol) in DMF (6 mL) and stirred in a sealed tube at 130° C. for 22 h. The mixture was allowed to cool to room temperature. Water (20 mL) was added, and the mixture was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The solvent was removed under reduced pressure. The residue was purified by flash chromatography (25% EtOAc / Hex ) and 344 mg of 4-{3-methoxy-4-[(quinolin-2-yl)methyl]phenyl Toxo[phenyl]butan-2-one was obtained as a yellow oil. [ka] 4-{3-Methoxy-4-[(quinolin-2-yl)methoxy]phenyl}butane-2 -one (120 mg, 0.36 mmol) and K2CO3 (33 mg, 0.24 mmol) l) in DMF (3 mL) and stirred under argon, and CF3TMS (175 μL, The reaction mixture was stirred at room temperature for 21 h, then EtOAc ( The organic layer was diluted with water (25 mL) and washed with brine (25 mL). The organic layer was dried over anhydrous Na2SO4. The residue was taken up in MeOH (5 mL) and concentrated with HCl (1 mL). The mixture was stirred with 0.2 mL of ethyl acetate for 75 min. The solvent was removed under reduced pressure, and EtOAc (25 ml) was added. L) was added and the mixture was washed with water (25 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (25% EtOAc / Hex). Preparation gave 100 mg of compound 184 as an off-white solid.

[0313] [Example 85] Preparation of Compound 185 1-(4-hydroxyphenyl)pentan-3-one (175 mg, 0.98 mmol) (prepared as in Example 48), KCO (150 mg, 1.09 mmol), and 2 -(Chloromethyl)quinoline hydrochloride (150 mg, 0.70 mmol) was dissolved in DMF (3 mL The mixture was mixed in a sealed tube at 140°C for 20 hours and then stirred at 140°C for 20 hours. The mixture was allowed to cool to room temperature and then cooled with water. (25 mL) was added and the mixture was extracted with EtOAc (3 x 25 mL). The combined organic layers were washed with brine (25 mL), dried over Na2SO4, filtered and The solvent was removed under reduced pressure. The residue was purified by flash chromatography (25% EtOAc / H ex) and 254 mg of 1-{4-[(quinolin-2-yl)methoxy]fluorenone was obtained. {phenyl}pentan-3-one was obtained as a yellow oil. [ka]

[0314] 1-{4-[(quinolin-2-yl)methoxy]phenyl}pentan-3-one (13 (5 mg, 0.42 mmol) and K2CO3 (40 mg, 0.29 mmol) in DMF (3 mL) and stirred under argon, and CF3TMS (200 μL, 1.35 mm The reaction mixture was stirred at room temperature for 20 h and then diluted with EtOAc (35 mL). The organic layer was diluted and washed with water (2 x 50 mL) and brine (15 mL). The mixture was dried over a2SO4, filtered, and the solvent was removed under reduced pressure. The residue was diluted with MeOH (5 mL). HCl (0.2 mL) was added and stirred for 1 hour. The solvent was removed under reduced pressure, and Et OAc (25 mL) was added and the mixture was washed with water (25 mL) and dried over Na2SO4. The residue was purified by flash chromatography (25% EtOAc / He x) to give 83 mg of compound 185.

[0315] [Example 86] Preparation of Compound 186 [ka] Following the general reduction procedure, compound 113 (105 mg, 0.265 mmol, Example 1) was obtained. 13), sodium borohydride (20 mg, 0.529 mmol), and Compound 186 was prepared from 1,2-dichlorophenyl ether (1 mL) and methanol (2 mL). The crude mixture was flushed with silica gel. The product was subjected to column chromatography (20% EtOAc / Hex) to obtain 0.083 g of the compound. Compound 186 was obtained as a colorless glass.

[0316] [Example 87] [ka] Following the general reduction procedure, compound 114 (115 mg, 0.301 mmol, Example 1) was obtained. 14), sodium borohydride (23 mg, 0.608 mmol), and Compound 187 was prepared from 1,2-dichlorophenyl ether (1 mL) and methanol (2 mL). The crude mixture was flushed with silica gel. The product was subjected to column chromatography (20% EtOAc / Hex) to obtain 0.080 g of the compound. Compound 187 was obtained as a colorless glass.

[0317] [Example 88] [ka] DCE of compound 101 (150 mg, 0.439 mmol) prepared as in Example 1 The (3 mL) solution was stirred at room temperature under argon and diluted with 4A molecular sieve powder (156 mg ), 1-methylpiperazine (70 μL, 0.631 mmol), AcOH (100 μL, 1.75mmol) was added, followed by NaBH(OAc)3 (190mg, 0.896mmol). The reaction mixture was stirred for 18 h and then washed with saturated NaHCO3 (25 mL). The reaction was quenched and extracted with CH2Cl2 (2 x 35 mL). The mixture was dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. Purified by chromatography (EtOAc / MeOH / Et3N, 9:1:0.1). Compound 188 was then dissolved in CH2Cl2 to give 24 mg of compound 188 as a colorless oil. Add 2 (2 mL) and 1.25 M HCl / MeOH (0.15 mL) and stir for 1 hour. The mixture was evaporated under reduced pressure to give the hydrochloride salt of compound 188 as a colorless foam. (27 mg).

[0318] [Example 89] [ka] 4-(4-hydroxyphenyl)-2-butanone (500 mg, 3.04 mmol), K2CO3 (443 mg, 3.21 mmol), and 2-(chloromethyl)quinoline salt The acid salt (400 mg, 1.866 mmol) was mixed in DMF (6 mL) and the mixture was stirred for 15 min in a sealed tube. The mixture was stirred at 0° C. for 20 hours. The mixture was allowed to cool to room temperature. Water (20 mL) was added and mixed. The product was extracted with EtOAc (20 mL x 3). The combined organic layer was washed with MgSO The mixture was dried over 4°C, filtered, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography. - (20% EtOAc / Hex) to give 603 mg of compound 189 as a yellow oil. It was obtained as a solid.

[0319] [Example 90] [ka] DCE of compound 189 (115 mg, 0.378 mmol, prepared as in Example 89) (3 mL) solution was stirred at room temperature under argon and added glacial acetic acid (0.050 mL), NaBH( OAc), and pyrrolidine (40 μL, 1.04 mmol) were added. The reaction mixture was The mixture was stirred at room temperature for 20 hours. The reaction was quenched with water (20 mL) and extracted with CH2Cl2. The organic layer was washed with brine (20 mL) and diluted with anhydrous MgSO4. The mixture was dried, filtered, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography ( Compound 190 was purified by EtOAc / MeOH / Et3N, 9:1:0.1) to give compound 190 in yellow. Obtained as a coloured oil.

[0320] [Example 91] [ka] A solution of compound 118 (154 mg, 0.431 mmol) in anhydrous THF was stirred under argon for 0 The mixture was stirred at 37 °C and 3.0 M EtMgBr in ether (180 μL, 0.540 mmol) was added. The reaction mixture was stirred at 0° C. for 10 min, then the cooling bath was removed and the mixture was stirred at room temperature. The reaction was continued for 1 h. The reaction was quenched with saturated aqueous NH4Cl (10 mL) and EtOAc ( The organic layer was washed with water (10 mL) and dried over anhydrous Na2SO4. The mixture was dried, filtered, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography ( 0% EtOAc / Hexanes) to give 114 mg of compound 191 as a yellow oil. Obtained as.

[0321] The two enantiomers of compound 191 were separated by HPLC using the following conditions: ChiralPak AD™ column, particle size 5 μm, column size 4.6 × 250 m m; mobile phase: 90% i-PrOH / hexane; flow rate: 1 mL / min; injection volume: 50 μL; Sample concentration: 1mg / m; Run time: 22min; Number of injections: 1. Each peak was collected manually. The same migration phase and run times as above were used to generate two pools of fractions. 50 μL samples from each pool were injected separately onto the HPLC column. Enantiomer 1 was The retention time was 17.014 min and the purity was >99%. The retention time was 18.709 minutes and the purity was greater than 99%.

[0322] [Example 92] [ka] 1-(4-hydroxy-3-methoxyphenyl)pentan-3-one (343 mg, 1 .65 mmol), K2CO3 (342 mg, 2.47 mmol), and 2-chloro- 4-(Methylthio)benzothiazole (392 mg, 1.82 mmol) was dissolved in DMF (4 mL) L) and stirred in a sealed tube under argon at 100° C. for 20 hours. The mixture was allowed to cool to room temperature. Allow to cool, dilute with EtOAc (25 mL), wash with brine (2 x 25 mL), and The residue was purified by flash chromatography. The product was purified by chromatography (20% EtOAc / Hex) to give 400 mg of compound 19. 2 was obtained as a white solid.

[0323] [Example 93] [ka] Compound 192 (150 mg, 0.39 mmol) was suspended in MeOH (5 mL). The turbid solution was stirred under argon and NaBH4 (22 mg, 0.58 mmol) was added. The mixture was stirred for 30 min, after which an additional 22 mg of NaBH4 was added. After stirring for 30 min, it was diluted with EtOAc (30 mL) and washed with water (2 x 20 mL). ), dried over anhydrous Na2SO4, filtered, and the solvent was removed under reduced pressure. Trituration with c / hexane gave 70 mg of compound 193 as a white solid.

[0324] [Example 94] [ka] 1-(4-hydroxyphenyl)-2-(2-(4-phenyl)phenyl)-2-(2-(4-hydroxyphenyl)-1-(2-(4-phenyl)phenyl)-1 ... ) pentan-3-one (390 mg, 2.19 mmol), 2-chloro-4-(methylthio) Benzothiazole (520 mg, 2.41 mmol) and K2CO3 (454 m g, 3.28 mmol) gave 613 mg of compound 194 as an off-white solid. Made.

[0325] [Example 95] [ka] Compound 194 (150 mg, 0.458 mmol) and K2CO3 (6 mg, 0.0 43 mmol) in DMF (3 mL) and stirred at 0° C. under argon, and CF3TM S (160 μL, 1.08 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 42 hours. The mixture was diluted with EtOAc (25 mL), washed with water (2 x 25 mL), and washed with anhydrous Na The mixture was dried over 2SO4, filtered, and the solvent was removed under reduced pressure. and 6N dilute HCl (0.2 mL) were added and the reaction was stirred for 1 h. The reaction was diluted with EtOAc. c (25 mL), washed with water (2 x 25 mL), dried over anhydrous Na2SO4 The residue was dissolved in MeOH (2 mL) and NaBH4 (1 0 mg) was added and the reaction was stirred for 45 min. The solvent was removed under reduced pressure and the residue was flash-dried. Purify by chromatography (20% EtOAc / hexane) to obtain 95 mg of compound 195 was obtained as a colorless oil.

[0326] [Example 96] [ka] 1-(4-hydroxy-3-methoxyphenyl)pentan-3-one (1.72 g, 8 0.26 mmol) in MeOH (20 mL) and incubated at 0 °C under argon with NaBH4 (46 9 mg, 12.4 mmol) was added in portions over 15 min. The reaction mixture was incubated at room temperature for 1 h. After stirring, the reaction was quenched with water (35 mL) and extracted with EtOAc (50 mL). The organic layer was washed with water (35 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The solvent was removed under reduced pressure to give 1.17 g of 4-(3-hydroxypentyl)-2-methoxyphenyl The phenol was obtained as a pale yellow oil.

[0327] 4-(3-hydroxypentyl) )-2-Methoxyphenol (100 mg, 0.48 mmol), 2-chlorobenzothiazide sol (70 μL, 0.54 mmol), and K2CO3 (199 mg, 1.44 mmol). ol) to prepare 113 mg of compound 196 as a colorless wax.

[0328] [Example 97] [ka] 4'-Hydroxyacetophenone (150 mg, 1.10 mmol) and K2CO3 (15 mg, 0.11 mmol) in DMF (2 mL) and stirred at 0°C under argon. The mixture was stirred and CF3TMS (410 μL, 2.78 mmol) was added dropwise. The reaction mixture was allowed to stand at room temperature. The mixture was stirred for 90 h. The mixture was diluted with EtOAc (20 mL) and washed with water (20 mL). The residue was washed with MeOH (2x), dried over anhydrous Na2SO4, filtered, and the solvent was removed under reduced pressure. OH (3 mL) and dilute 6N HCl (0.3 mL) were added and the reaction was stirred for 1 h. The reaction was diluted with EtOAc (20 mL) and saturated aqueous NaHCO3 (2 x 20 mL). , washed with water (20 mL), dried over anhydrous Na2SO4, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography (30% EtOAc / hexanes). Purify and obtain 135 mg of 4-(1,1,1-trifluoro-2-hydroxypropane-2- The yl)phenol was obtained as a white solid.

[0329] 4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenol ( 135mg, 0.655mmol), K2CO3(362mg, 2.62mmol), and 2-(chloromethyl)quinoline hydrochloride (154 mg, 0.719 mmol) in DMF (2 mL) and stirred in a sealed tube at 80° C. for 18 hours. The mixture was allowed to cool to room temperature. The mixture was diluted with EtOAc (20 mL), washed with water (2 x 20 mL), and then washed with anhydrous Na2S Dry over O4, filter, and remove the solvent under reduced pressure. Flash chromatograph the residue. Compound 197 was purified by elution with 20% EtOAc / Hex to give 156 mg of yellowish white solid. This was obtained as a clear solid.

[0330] [Example 98] [ka] 4-[3-hydroxy-3-(trifluoromethyl)pentyl]-2-methoxyphenoxy ol (189 mg, 0.679 mmol), K2CO3 (375 mg, 2.71 mmol) ), and 2-(chloromethyl)quinoline hydrochloride (160 mg, 0.747 mmol) The mixture was mixed in anhydrous acetone (4 mL) and stirred in a sealed tube at 60° C. for 18 hours. The mixture was cooled naturally to 200° C., filtered, washed with acetone, and the solvent was removed under reduced pressure. Two flash columns (20% EtOAc / Hex, then 10% EtOAc / CH2 Purification by HCl) gave 75 mg of compound 198 as a colorless glass.

[0331] [Example 99] [ka] 4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenol Similar to the procedure, 4'-hydroxy-3'-methoxyacetophenone was dissolved in DMF (2 mL). Non (150 mg, 0.903 mmol), CF3TMS (340 μL, 2.30 mmol), l) and K2CO3 (12 mg, 0.087 mmol) to produce 132 mg of 2-methionine. Oxy-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenol A solution was prepared. 2-Methoxy-4-(1,1,1)-2-(4-(2-methoxy-1,1,1)-propanediol in DMF (2 mL) according to the procedure of Example 97 -Trifluoro-2-hydroxypropan-2-yl)phenol (132 mg, 0.5 60mmol), 2-(chloromethyl)quinoline hydrochloride (132mg, 0.620mmol l), and K2CO3 (310 mg, 2.24 mmol) to give 161 mg of compound 1 99 was prepared as a white solid.

[0332] [Example 100] (MC / 9 HPLC Assay) Cultured MC / 9 cells (cell number 3 × 10 6 ) into 1 mL of HBSS and change the concentration. The cells were preincubated with compounds dissolved in DMSO for 30 minutes. Onophore (A23187) was added to stimulate leukotriene production, and 4 mM DMS The internal standard was diluted from the O stock / HBSS and incubated at room temperature for 20 min. Add 500 μL of methanol containing 20 ng / mL prostaglandin B2. The reaction was stopped. Samples were taken and stored at -20°C for at least 2 hours or overnight. After that, the mixture was centrifuged at 13,000 rpm for 15 minutes and then loaded onto a C18 SEP-PAK column (Can The solid phase extraction was performed by loading the sample onto a microcentrifuge tube (Divisional Lifesciences, IS12000). Leukotrienes were analyzed using an ACE C18 column (4.5 mm × 150 mm, 5 μm). was analyzed by HPLC (a mixture of acetonitrile / methanol / water containing H3PO4, p H3.5 (37:26:37, eluted at a flow rate of 1.8 mL / min). Chemical, 20110) and LTC4 (Cayman Chemical, 20210) was calculated based on the reference standard, and the amount of LT induced by the test compound was The level of inhibition of B4 production was calculated relative to the control sample. The results are shown in Table 2. Compound No. refers to the compound specified in Table 1.

[0333] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4]

[0334] The enantiomers of compound 104 have different potencies in inhibiting LTC4 and LTB4. Of note, enantiomer 1 was significantly more potent than enantiomer 2 (0.3 μM 0%), increased the inhibition of LTC4 (0.3 μM-74%). Notably, enantiomer 1 was significantly more potent than enantiomer 2 (0.3 μM-24%). showed increased inhibition of LTB4 (0.3 μM-83%).

[0335] Notably, compound 104 showed significantly higher LT activity compared to compound 103 (50-70%). It is also noteworthy that compound 10 increased the inhibition rate of C4 (1 μM) by 90%. Compound 4 increased the % inhibition of LTB4 (1 μM) compared to compound 103 (50-70%). Structurally, compounds 103 and 104 are different in that compound 104 has Ar They differ only in the presence of an -S-alkyl substituent on the ring, more specifically, an -S-CH3 group. .

[0336] Thus, in one embodiment, the present disclosure provides a compound of the formula ( 1), more specifically, a compound of formula (1) [ka] and pharma- ceutically acceptable salts thereof, wherein Ar is a 9- or 10-membered bicyclic ring Formula aromatic ring system, Ar is at least one -S-alkyl (-S-alkyl is -S -C1-C6 alkyl, for example, -S-methyl) L is selected from a direct bond and methylene; R 1 is selected from hydrogen, halide, C1-6 alkyl, C1-6 haloalkyl, and C1-6 a A is selected from a direct bond, -CH2-, and -CH2CH2-. E is -C(O)-R 2 , C(OR 3 )R 4 R 5 , and CH(R 6 )NR 7 R 8 Selected from; R 2 is selected from methyl, ethyl, and phenyl; R 3 But, H, A alkyl, and substituted alkyl; R 4 is hydrogen, alkyl, and phenyl. Selected from; R 5 is C1-C7 alkyl, C1-C7 haloalkyl, phenyl, and substituted phenyl; R 6 hydrogen, methyl, halogenated methyl, and ethyl Selected from; R 7 is hydrogen; R 8 is hydrogen, methyl, or ethyl; R 7 and R 8and may together form an optionally substituted 5- or 6-membered heterocyclic ring. With respect to the r group, optionally Ar is a monosubstituted 9-membered bicyclic aromatic ring; or optionally Ar is a disubstituted or optionally Ar is a trisubstituted 9-membered bicyclic aromatic ring; or optionally Ar is a trisubstituted 9-membered bicyclic aromatic ring; Optionally, Ar is a monosubstituted 10-membered bicyclic aromatic ring; or optionally, Ar is a disubstituted 10-membered bicyclic aromatic ring. or optionally Ar is a trisubstituted 10-membered bicyclic aromatic ring; or optionally Ar is , 1,3-benzoxazole and 1,3-benzothiazole; or Optionally, Ar is naphthalene, or 1,5-naphthyridine, 1,6-naphthyridine, 1, 7-Naphthyridine, 1,8-Naphthyridine, Isoquinoline, Phthalazine, 2,6-Naphthyridine Lysine and its nitrogen-substituted analogs selected from 2,7-naphthyridine. Substituents may be used, one or more of the following, to further describe the compounds of this embodiment: L is a direct bond; L is methylene; R 1 is hydrogen; R 1 is halogen Yes;R 1 is C1-C6 alkyl; R 1 is C1-C6 haloalkyl; R 1 but C1-C6 alkoxy; A is a direct bond; A is -CH2-; A is -CH 2CH2-; E is -C(O)-R 2 R 2 is methyl; R 2 is ethyl Yes;R 2 is phenyl; E is -C(OR 3 )R 4 R 5 R 3 is hydrogen; R 3 is alkyl; R 3 is a substituted alkyl; R4 is hydrogen; R 4 Is alkyl R 4 is phenyl; R 5 is C1-C7 alkyl; R 5 C1-C7 arylalkyl, e.g., R 5 is trifluoromethyl; R 5 is phenyl; R 5 but E is -CH(R 6 )NR 7 R 8 R 6 is hydrogen; R 6 but Methyl; R 6 is a methyl halide; R 6 is ethyl; R 8 is hydrogen ;R 8 is methyl; R 8 is ethyl; R 7 and R 8 and form a 5-membered heterocycle together. R 7 and R 8 and together form a substituted 5-membered heterocyclic ring; R 7 and R 8 Together, 6 members forming a heterocyclic ring; and / or R 7 and R 8 and together form a substituted six-membered heterocycle do.

[0337] Notably, when comparing the performance of compound 103 with compound 150, compound 103 The inhibition percentage of LTC4 (1 μM) was 50-70%, and the inhibition percentage of LTB4 (1 μM) was 50. ∼70%. That is, there was no detectable difference in performance. However, compound 1 50 is the inhibition percentage of LTC4 (1 μM) of 10 to 30%, and the inhibition percentage of LTB4 (1 μM ) was 50-70%. That is, there was a detectable difference in performance. Compound 103 and compound 150 have R on the benzene ring of compound 103. 1 -O-a as a substituent They differ only in the presence of an alkyl substituent, more specifically, an -O-CH3 group.

[0338] Thus, in one embodiment, the present disclosure provides a method for the preparation of a compound comprising: 1 Compounds of formula (1) in which , more specifically a compound of formula (1) [ka] and pharma- ceutically acceptable salts thereof, wherein Ar is a 9- or 10-membered bicyclic ring is an aromatic ring system of the formula, Ar is optionally substituted with 1, 2 or 3 substituents; L is , a direct bond, and methylene; R 1 is C1-C6 alkoxy; A is E is selected from a direct bond, -CH-, and -CHCH-; 2 , C(OR 3 )R 4 R 5 , and CH(R 6 )NR 7 R 8 Selected from; R 2 But, Meth R is selected from aryl, ethyl, and phenyl; 3 H, alkyl, and substituted alkyl Selected from; R 4 is selected from hydrogen, alkyl, and phenyl; R 5 But C1- selected from C7 alkyl, C1-C7 haloalkyl, phenyl, and substituted phenyl; R 6 is selected from hydrogen, methyl, halogenated methyl, and ethyl; R 7 is hydrogen R 8 is hydrogen, methyl, or ethyl; 7 and R8 Both are optional. With respect to the Ar group, optionally Ar may form a 5- or 6-membered heterocyclic ring substituted with or optionally Ar is a monosubstituted 9-membered bicyclic aromatic ring; or or optionally Ar is a disubstituted 9-membered bicyclic aromatic ring; or optionally Ar is a trisubstituted 9-membered bicyclic aromatic ring; optionally Ar is an unsubstituted 10-membered bicyclic aromatic ring; or optionally Ar is a monosubstituted or optionally Ar is a disubstituted 10-membered bicyclic aromatic ring; or or optionally Ar is a trisubstituted 10-membered bicyclic aromatic ring; or optionally Ar is a 1,3-benzo oxazole and 1,3-benzothiazole; or optionally Ar is selected from Na Phthalene, or 1,5-naphthyridine, 1,6-naphthyridine, 1,7-naphthyridine , 1,8-naphthyridine, isoquinoline, phthalazine, 2,6-naphthyridine, and 2 ,7-naphthyridine and its nitrogen-substituted analogs. Other substituents include To further describe the compounds of the embodiments, one or more of the following may be used: L is methylene; A is a direct bond; A is -CH2; A is -CH 2CH2-; E is -C(O)-R 2 R 2 is methyl; R 2 is ethyl Yes;R 2 is phenyl; E is -C(OR 3 )R 4 R 5 R 3 is hydrogen; R 3 is alkyl; R 3 is a substituted alkyl; R 4 is hydrogen; R 4 Is alkyl R 4 is phenyl; R5 is C1-C7 alkyl; R 5 C1-C7 arylalkyl, e.g., R 5 is trifluoromethyl; R 5 is phenyl; R 5 but E is -CH(R 6 )NR 7 R 8 R 6 is hydrogen; R 6 but Methyl; R 6 is a methyl halide; R 6 is ethyl; R 8 is hydrogen ;R 8 is methyl; R 8 is ethyl; R 7 and R 8 and form a 5-membered heterocycle together. R 7 and R 8 and together form a substituted 5-membered heterocyclic ring; R 7 and R 8 Together, 6 members forming a heterocyclic ring; and / or R 7 and R 8 and together form a substituted six-membered heterocycle do.

[0339] [Example 101] (Whole Blood HPLC Assay) Porcine or human whole blood (1 mL) was mixed with various concentrations of compounds dissolved in DMSO for 30 min. The plate was preincubated for 1 min. 20 μM calcium ionophore (A23187) was added. was added to stimulate leukotriene production and diluted from a 4 mM DMSO stock in HBSS. The pig blood was incubated at room temperature for 20 minutes with calcium ionophore. 20 μM arachidonic acid was added. Blood was centrifuged at 2000 rpm for 15 min and further The plasma fraction was removed for processing. Plasma samples were diluted with 500 μL of acidified water (HCl pH 3.0) and column C18SEP-PAK (Canadian Lifesciences) The solid phase extraction was performed by loading the sample onto an ACE C18 column (4 Leukotrienes were analyzed by HPLC using a .5mm x 150mm, 5μm (H3P Acetonitrile / methanol / water mixture containing O4, pH 3.5 (37:26:37) eluted at a flow rate of 1.8 mL / min). LTB4 (Cayman Chemical, 2011 The amount of LTB4 production inhibition induced by the test compound was calculated based on the reference standard. The level of inhibition was calculated relative to the control sample. The results shown in Table 3 are based on a five-point curve. Calculated IC 50 In the table, Compound No. refers to the compound specified in Table 1.

[0340] [Table 3]

[0341] [Example 102] (Aminopeptidase Assay-Alanine-4-nitroanalide) Varying concentrations of compounds were added to 50 μL assay buffer (50 mM Tris-HCl, 100 mM 0.5 μg of recombinant human leukotriene A4 hydrolase (Cay) in 10 mL of KCl Preincubate in the absence of light with 100 mL of 100 mL of 100% ethanol (Man Chemical 10007817). The assay buffer contained 50 μL of 6 mM alanine-4-nitroanilide (Sigma-Aldrich). The reaction was stimulated by the addition of 4-nitro The change in absorbance at 405 nm due to analine production was measured, and the rate of change was compared with the reference standard (Sigma a Aldrich, 185310) to confirm the activity of aminopeptidases. The amount of aminopeptidase activity was measured and compared with the control sample to calculate the inhibition level. Compounds that increase peptidase activity are expressed as negative values. The results are shown in Table 4. , Compound No. refers to the compounds listed in Table 1.

[0342] [Example 103] (Aminopeptidase Assay-PGP) Varying concentrations of compounds were added to 50 μL assay buffer (50 mM Tris-HCl, 100 mM 50 ng of recombinant human leukotriene A4 hydrolase (Cayman The samples were preincubated with 50 μL of 1 mM Propionibacterium phosphate phosphate phosphate (Proc. No. 10007817). The reaction was performed by adding lysine-glycine-proline (Bachem, H-7284). The reaction was stimulated and incubated at 37°C for 30 min. The reaction was stopped by adding 150 μL of glacial acetic acid. The amount of free proline released from the peptide was determined by reaction with ninhydrin. 25 mg / mL ninhydrin (BDH, B101) in 60:40 acetic acid / water was detected. 32) 150 μL was added to each sample, boiled at 100 °C for 30 min, and the samples were then stored at room temperature. After allowing the mixture to cool naturally, 350 μL of toluene was added to extract the ninhydrin reaction product. The absorbance at 520 nm was measured using L-proline (Sigma Aldrich, 81709). The amount of free proline was determined by comparison with a reference standard. The control was calculated based on the control sample. The results are shown in Table 4, where Compound No. is the compound number in Table 1. This refers to the compounds listed in.

[0343] [Table 4-1] [Table 4-2]

[0344] [Example 104] (Arachidonic acid (AA)-induced mouse ear edema model) The arachidonic acid-induced ear edema model in mice induces redness and swelling in response to skin stimulation. This is a model of acute skin inflammation. Group 1 was the control and 20 μL of vehicle ( Apply 10 μL to the inside of the ear and 10 μL to the outside of the ear. The mice were assigned to the experimental group. A 20 μL volume of the test compound was placed in the pinna of one ear (10 μL was placed on the inside of the pinna). 10 μL was applied to the outside of the skin of a CD-1 mouse. As a stimulation, 2 mg of AA was applied to each ear 4 hours and 1 hour before the test compound or control. Vehicle (acetone / 1% DMSO) was applied topically to the right ear. Only acetone / 1% DMSO) was applied.

[0345] The animals were lightly anesthetized again with isofluorane to allow for application of the stimuli. A total of 20 μL of acetone was applied (10 μL on the inside of the ear and 10 μL on the outside). Arachidonic acid (2 mg per ear) added to the stimuli was applied to the pinna of one ear only. One ear received 20 μL of acetone, which allowed the determination of arabinoid activity in the absence of test compound. The increase in ear weight due to quidonic acid was measured. Arachidonic acid in seton (10 μL applied to the inside of the pinna and 10 μL to the outside of the pinna) (2 mg per ear) was applied to the pinna of each ear as a stimulus. After application of the sarcolemma, the animals were allowed to recover. After 60 min, the animals were euthanized and a 6 mm skin biopsy pan was inserted. Standard biopsy samples were taken from each ear using Acuderm. As a result, ear edema was defined as an increase in tissue weight due to accumulation of body fluid. For the control group, the weight of the stimulated ear was subtracted from the weight of the unstimulated ear. The difference in ear weight was calculated by subtracting the amount of edema from the weight of the unstimulated ear. The percent increase in ear weight was calculated by dividing the increase in the weight of the stimulated ear by the weight of the unstimulated ear and multiplying by 100. For the test group, the weight of the test compound-treated ear was subtracted from the weight of the untreated ear. The ear weight differences were calculated by first subtracting the mean ear weight of the untreated control from each tissue. The amount of arachidonic acid administered was subtracted from the total amount of arachidonic acid administered to obtain the increase in tissue weight. The percent inhibition of ear weight gain in compound-treated ears was estimated. Percent inhibition = 1 - (test drug stimulated ear (mg) / control stimulated ear (mg)) x 10 0

[0346] Table 5 shows data on inhibition of AA-induced ear edema by topical application of compounds in mice. Compound (0.01 mg / kg) was administered 4 hours and 1 hour before topical application of rachidonic acid (AA; 2 mg / kg / each ear). A dose of 0.3 or 1 mg / ear was applied to the ear. Representative data from 4–6 mice in each treatment group. are shown below, in which compound No. refers to the compounds listed in Table 1.

[0347] [Table 5]

[0348] [Example 105] (Lipopolysaccharide (LPS) mouse lung inflammation model) In this model, LPS was instilled into the lungs of mice to induce neutrophilia in the lung tissue. Neutrophil counts can be measured by time course of BAL fluid following lung lavage after LPS challenge. Addition of 100 mg / kg of DMSO resulted in a significant increase in cells in the BAL after 6 hours, with the response reaching a maximum by 24 hours.

[0349] CD-1 mice were treated with 50 μL of phosphate-buffered saline (PBS) or PBS plus The resulting lipopolysaccharide (LPS) was administered at 2.5 mg / kg via oral instillation into the lungs. The mice were lightly anesthetized using isofluorane to allow for the application of LPS. The animal was placed on the board at a 45° angle, with the tongue curled to one side, and a volume of 50 μL of LPS was applied. The animals were held in that position for 1-2 minutes to allow LPS to be retained in the lungs. After the LPS challenge period, the animals were again given an overdose of isofluorane to ensure their comfort. The trachea was exposed and the lungs were intubated using a 21G catheter tube. The lungs were washed twice with PBS at room temperature. The collected bronchoalveolar lavage fluid (BAL) was stored on ice. Place the plate on a plate and centrifuge at 2500 rpm (tabletop centrifuge) for 5 minutes to pellet the collected cells. The BAL supernatant was removed and the cell pellet was resuspended in 150 μL of PBS. Cells were counted using an automated cell counter (Abraxia) set to measure spheroid cells. The cell concentration of the resuspended samples was calculated based on the total volume of BAL collected. The results were expressed as total cell numbers detected.

[0350] Several times before and after the instillation of LPS, the animals were treated with either the test drug or a dose of 10 to 30 mg / kg. or vehicle (1% DMSO in polyethylene glycol 200 (PEG200)). For example, the test drug is administered 30 minutes before LPS and then 2 hours after LPS. Whether administered once or simultaneously with LPS and then again 2 and 4 hours after LPS, good.

[0351] The data obtained are shown in Figure 1, which shows the effect of LPS on neutrophil infiltration into the lungs. The effect of compound 104 on the pulmonary circulation is shown. Animals are intratracheally administered 2.5 mg / kg LPS. Compound 104, 10 mg / kg, orally, 1 mg / kg, 1 hour before and 2 hours after of dexamethasone or administered vehicle (PEG200 containing 1% DMSO) Six hours after LPS, the animals were euthanized and BAL was collected from the lungs. The results showing the inhibitory effect are shown in FIG. 1, which shows the mean ± standard deviation and the number of animals in each group. n=7-10.

[0352] [Example 106] (Rat endotoxin-induced uveitis (EIU) model) In the endotoxin-induced uveitis (EIU) model, the hind paw of rats was ad) and evaluate ocular inflammation 24 hours later. EIU is lipopolysaccharide (LP) It can be induced by systemic injection of S, which produces an inflammatory response mainly in the anterior uvea and posterior uvea of ​​the eye. It produces a mild reaction in the anterior uveitis area, mimicking the pathological condition in human acute anterior uveitis. That is why.

[0353] In general, cellular inflammation in EIU begins 4 hours after LPS injection and progresses 18–24 hours later. Ocular inflammation was assessed by clinical score and aqueous and nitric oxide in each eye. The results are determined by determining the cell count and protein content in the hemolymph of normal control animals. The aqueous and vitreous humor from the spleen showed few detectable cells and low protein levels. The aqueous humor is low in sera and has well-organized tissue layers under histological examination. In contrast, after LPS, The cell number and protein content were increased, with extravasation into the anterior lumen, which was evaluated. This is indicated by the fact that more fluid can be removed. Similar effects were observed and large amounts of vitreous humor could be easily collected for evaluation. Histologically, the tissue structure was poorly organized, with inflammatory cell infiltration and a large amount of protein matrix in the aqueous humor. There is evidence of vitreous keratoconjunctivitis, iris- and ciliary body-associated collapse and inflammatory cell infiltration.

[0354] To induce disease, rats were inoculated with 100 μL of saline solution into the plantar hind paw. The level of inflammation in the eye was measured as iris congestion, pupil dilation, exudate and The clinical score for evaluating hypopyon and histological examination of tissue sections were used. The results were assessed by measuring cell counts and protein content in the aqueous and vitreous humor of the eyes. .

[0355] Animals were treated with test drugs or vehicle (P containing 1% DMSO) several times before and after injection of LPS. EG200) was orally administered at a dose of 30 mg / kg. The animals were also administered the test drug topically. In this case, 20% hydroxypropyl beta-cyclodextrin in PBS may be used. phosphate, 0.5% hydroxypropyl methylcellulose, and 1.6 mM EDTA. The application solution contained up to 1% of the test drug in a formulation consisting of Test medication may be administered directly to the eye in one 10 μL drop at various times.

[0356] The results of oral administration of the test drugs are shown in Figure 2. Figure 2 shows the clinical profile of the EIU rat model. The effect of Compound 104 on the core is shown. 75 μg of LPS in 100 μL saline solution was administered subcutaneously into the plantar hind paw of each paw. 15 minutes before and 5 hours after, subjects were treated with 30 mg / kg of Compound 104 orally or with Vehicle (PEG200 containing 1% DMSO) was administered. The average clinical score was measured. The values ​​shown in Figure 2 are the mean ± standard deviation, and n = 3 for each group. Ta.

[0357] [Example 107] (Rat ocular distribution model) Compounds with theoretical concentration of 10 mg / mL were added to a 2 mL microcentrifuge tube and then mixed. bar and hydroxypropyl beta-cyclodextrin (Trappsol) (20% ), hydroxypropyl methylcellulose (0.5%) and EDTA (1.6 mM) / Phosphate buffered saline (w / v) and the selected formulation are added to prepare eye drops. The tubes containing the compounds in the eye drop formulation were heated to 60-65°C and incubated for at least 4 hours. The tubes were removed from the water bath and centrifuged at 10,000 rcf for 5 minutes. The solution was clear and free of residual drug. The supernatant was removed and one 10 μL sample was taken for HPLC analysis, dissolved, and purified to obtain ACE The samples were analyzed by HPLC using a C18 column (4.5 mm × 150 mm, 5 μm) (H3 A mixture of acetonitrile / methanol / water containing PO4, pH 3.5 (50:30:20 ), elution at a flow rate of 2.5 mL / min. The solubilized concentration of each compound was determined using metabolites during assay validation. The concentrations were calculated by interpolation from a standard curve based on reference standards dissolved in ethanol.

[0358] A drop of 10 μL of compound was applied to the rat and aqueous humor, and the eye was then rinsed with water to remove any residual formulation. After washing the eyes, the posterior regions of the eye (vitreous and retina) were harvested from each eye at the designated time points. The tissue was collected into pre-weighed collection tubes and the tissue weight was recorded for each sample. The internal standard (IS) mixture containing the reference compounds was added at a dose of 1 μL per 4 mg of tissue. The solution was added to the sample at 1:1 ratio and mixed, then diluted with acetonitrile:MeOH (9:1) to obtain a 4.25 The aqueous humor samples were vortex mixed for 10 seconds. The vitreous and retina were then separated. Each was vortex mixed twice for 10 seconds and then mixed on a tabletop shaker at 750 rpm for 6 minutes. A final vortex mix was then performed (10 seconds). All samples were centrifuged. The particulate matter was pelleted and the supernatant was transferred to an LC vial. During S analysis, 10 μL of the sample was applied to the HPLC. To create a calibration curve (range 8 to 176.471 ng / mL) and measure the response, the internal standard The area under the curve (AUC) normalized to AUC was used to determine the concentration of compounds in each matrix analyzed. The concentration was estimated by assuming that 1 mg of tissue corresponds to 1 μL of plasma. To account for differences in drug solubility, the measured concentrations in each tissue were multiplied by the amount of drug applied. Average concentrations and concentrations were normalized based on "n" = number of eyes evaluated, not number of animals. and standard deviation were calculated.

[0359] In Table 6, data from distribution studies performed in Lewis rats are shown for each topical formulation. The concentration of each compound present in the retina 0.5 hours after administration of one drop (10 μL) of the compound is shown. The individual formulations were mixed in pairs in ratios to produce a mixture containing approximately 2.5 mg / mL of each compound. Representative data from two eyes are shown, and in the table, Compound No. refers to the compound identified in Table 1. Refers to...

[0360] [Table 6]

[0361] In another study, Sprague-Dawley rats were given either Compound 104 (0.4%) or a commercial ophthalmic solution. 10μL of either prednisolone acetate (1%) was instilled into the tissue 2 hours after administration. The concentration of the compounds was measured by LC / MS / MS after removing the ions. Data are ± standard deviation, n=5 eyes for each drug) for Compound 104 at 2 hours after administration. This shows that it was absorbed into the posterior region at a level approximately 50 times that of prednisolone.

[0362] [Example 108] (Experimental autoimmune uveitis (EAU) model in rats) Experimental autoimmune uveitis is a neuroretinopathy induced by immunization with a retinal antigen. It is an organ-specific T cell-mediated autoimmune disease that targets relevant tissues. Inflammatory cell infiltration of the membrane is involved, causing damage to the photoreceptors extending to the inner nuclear layer, resulting in edema. At the peak of severity, this can lead to retinal detachment. In addition to the posterior segment changes, the anterior region of the eye There is prominent inflammatory cell infiltration, accompanied by vascular congestion, loss of red reflex, and opacification of the anterior chamber.

[0363] The experimental autoimmune uveitis (EAU) model was developed using heat-killed Mycobacterium tuberculosis strains. , which directs peptides toward retinal proteins that cause inflammation in the eyes of susceptible animals such as Lewis rats. The first step is to inject the mouse with complete Freund's adjuvant (CFA) containing the peptide. Approximately 6-7 days after injection of A and retinal proteins, clinical signs of ocular inflammation appeared, and approximately 10 It peaks at ~14 days and mostly resolves within 21 days.

[0364] Retinal peptide (<100 μg) and complete Freund's adjuvant (2–3 mg / ml) The emulsion was injected into the base of the tail of Lewis rats at 100 μL, into each thigh at 50 μL, and The procedure was performed in a biological safety cabinet and the animals were kept in a ventilated place for the duration of the study. The objects remained in the containment chamber. To allow for the application of stimuli, the animals were Six to eight days after immunization, rats were lightly anesthetized using isofluorane. , 20% hydroxypropyl beta-cyclodextrin in PBS, 0.5% hyaluronan In a formulation consisting of hydroxypropyl methylcellulose and 1.6 mM EDTA, Using an application solution containing 1% test drug at 25°C, a 10 μL drop of test drug was applied directly to the eye. The infusion was allowed and treatment continued for several days as the disease progressed. Core formation, vasodilation, vascular congestion, changes in the red reflex, and opacification of the anterior chamber and exophthalmos The autoimmunity assessment was performed using a scale of 0 to 4 (Agarwal et al. Autoimmunity: Methods and Protocols, Methods in Molecular Biology, vol. 900, Ch 22). The animals were treated with isoflurane and CO2 The animals were euthanized by IV injection, and the eyes were excised and evaluated histologically for intraocular structural changes and inflammatory cell infiltration. The results were evaluated and scored based on pathological changes (Gadjanski et al. / Experimental Eye Review search 93 (2011) 82e90). Aperio ImageScope(Leica Bio Using the retinal thickness measuring system, the thickness of the retina from the retinal pigment epithelium to the inner boundary layer was measured in tissue sections. Measured.

[0365] The results of this example are shown in Figures 4A, 4B and 4C. The effect of Compound 104 on clinical scores and histological evaluation in a rat model is shown. On day 0, 3% guinea pigs were injected with 2 mg / mL of Freund's complete adjuvant in emulsion. Animals were immunized with 0.0 μg of peptide. Starting on day 6 post-immunization, animals were administered 0.5% wt / v ol of compound 104 or vehicle (20% hydroxypropyl beta-cyclodexamyl thorin, 0.5% hydroxypropyl methylcellulose, and 1.6 mM EDTA 10 μL of each of the liquid preparations (containing 10 μL / PBS) was administered every 3 hours for four doses each day. The subjects were administered topically to the eye of 100 mg / kg ... Animals were treated daily and euthanized 10 days after immunization, and tissues were harvested for histological examination. Values ​​are the mean ± standard deviation of four eyes, n = 2 for each group. Figure 4A shows the mean ± standard deviation of four eyes after immunization. Figure 4B shows the histological scores obtained 10 days after immunization. FIG. 4C shows the results of retinal thickness measurements taken from histological slides 10 days after immunization. vinegar.

[0366] For selected compounds prepared according to the preceding examples, 1 H nuclear magnetic resonance spectroscopy was performed. By implementing 1H NMR spectra were obtained and were characterized as described and shown in Table 7. The device is then subjected to characterization.

[0367] [Table 7-1] [Table 7-2] [Table 7-3] [Table 7-4] [Table 7-5] [Table 7-6] [Table 7-7]

[0368] Any methods and materials similar or equivalent to those described herein also can be used in the practice or manufacture of the present invention. can be used in the study, but only a limited number of exemplary methods are described herein. In general, unless otherwise indicated, the invention and / or its components are manufactured The materials for fabrication may be selected from suitable starting materials.

[0369] When a range of values ​​is given herein, each of the intervening values ​​is understood to be within the scope of the present invention as defined by the context. Unless expressly indicated otherwise, the upper and lower limits of the range, as well as any other A stated value or a value falling within a stated range is disclosed to the tenth of the lowest unit. It is understood that the upper and lower limits of such subranges are independently within the ranges set forth herein. These subsections are subject to any specifically excluded boundaries in the scope set forth herein. When the stated range includes one or both of the limits, such inclusion is Ranges excluding either or both of the included limits are also included in the disclosure.

[0370] For example, any of the concentration ranges, percentage ranges, ratio ranges, or Integer value ranges include any integer value within the recited range unless otherwise indicated, and may be expanded as appropriate. In some cases, this should be understood to include decimal values ​​thereof (such as tenths and hundredths of integers). Also, the present invention relates to any physical characteristics of the polymer subunits, such as size or thickness. Any numerical range recited herein may, unless otherwise indicated, be any integer within the recited range. As used herein, the term "about" means any number of units, unless otherwise indicated. In all cases, this means ±20% of the indicated range, value, or structure.

[0371] All U.S. patents cited herein and / or listed in the Application Data Sheet , U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent publications. Such documents include, for example, the materials described in the publications. and methods, which may be incorporated by reference herein for purposes of describing and disclosing the present disclosure. The publications cited above and described herein are incorporated by reference as of the filing date of this application. Nothing herein is intended to be construed as a substitute for any of the foregoing disclosures. that the invention is not entitled to novelty over any cited publication; Nothing herein should be construed as an admission by the inventors.

[0372] Generally, in the following claims, the terms used refer to the claims as follows: It should not be construed as being limited to the specific embodiments disclosed in the specification and claims. rather, all possible claims are to be treated as equivalents to the full scope of equivalents to which such claims are entitled. Therefore, the claims should be construed to include any embodiment that may be possible without the need to limit the scope of the invention as set forth herein. There is no limitation.

Claims

1. Compound of formula (1) 【Chemical 1】 or a pharmaceutically acceptable enantiomer, diastereomer, salt, or solvate thereof, wherein: Ar is a 9- or 10-membered bicyclic ring system containing one benzene ring and one nitrogen atom-containing aromatic ring, and Ar is unsubstituted or is selected from the group consisting of halide, C １ - ６ Alkyl; -S-C １ - ６ Alkyl; —O—C １ - ６ alkyl; and —SO ２ -C １ - ６ substituted with one or two substituents selected from alkyl; L is a direct bond and —CH ２ -(methylene); R １ However, hydrogen, halides, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, and C １ -C ６ alkoxy; A is a direct bond, —CH ２ - and -CH ２ CH ２ - selected from; E is -C(O)-R ２ , C(OR ３ ) R ４ R ５ , and CH(R ６ ) NR ７ R ８ with the proviso that when E is CH(R 6 )NR 7 R 8 , R 1 is not hydrogen or halide; R ２ is selected from methyl, ethyl, and phenyl; R ３ is selected from H, alkyl, and substituted alkyl; R ４ is selected from hydrogen, alkyl, and phenyl; R ５ But C １ -C ７ Alkyl, C １ -C ７ selected from haloalkyl, phenyl, and substituted phenyl; however, 2-[4-(1-hydroxyhexyl)phenoxymethyl]quinoline; A compound of formula (1) wherein Ar is benzothiazole, L is a direct bond, R 1 is hydrogen, A is a direct bond, E is C(O)R 2 and R 2 is methyl; A compound of formula (1) wherein Ar is benzothiazole, L is a direct bond, R 1 is methoxy, A is a direct bond, E is C(O)R 2 and R 2 is methyl; A compound of formula (1) wherein Ar is benzothiazole, L is a direct bond, R 1 is hydrogen, A is ethylene, E is C(O)R 2 , and R 2 is methyl; Excluding compounds.

2. Ar is 1,3-benzothiazole optionally substituted with one substituent selected from halide, C 1-6 alkyl, —S—C 1-6 alkyl, —O—C 1-6 alkyl, and —SO 2 —C 1-6 alkyl; R 3 is H; R 4 is selected from hydrogen, C 1 -C 7 alkyl, and phenyl; 2. The compound of claim 1, wherein R 5 is selected from C 1 -C 7 alkyl, C 1 -C 7 haloalkyl, phenyl, and halophenyl.

3. The compound of claim 1, wherein Ar is substituted with one substituent that is —S—CH 3 .

4. The compound according to claim 1, wherein L is a direct bond.

5. The compound according to claim 1, wherein R 1 is hydrogen or C 1 -C 6 alkoxy.

6. The compound of claim 1, wherein A is —CH 2 CH 2 —.

7. The compound of claim 1, wherein R 8 is hydrogen, methyl, or ethyl.

8. The compound of claim 1, wherein E is —C(OR 3 )R 4 R 5 .

9. The compound of claim 8, wherein R 3 is H.

10. The compound according to claim 8 or 9, wherein R 4 is hydrogen or C 1 -C 7 alkyl.

11. The compound according to any one of claims 8 to 10, wherein R 5 is trifluoromethyl.

12. The compound of claim 1 as a pharmaceutically acceptable enantiomer of formula (1).

13. A pharmaceutical composition comprising a compound according to claim 1, or a pharmaceutically acceptable enantiomer, salt or solvate thereof, and at least one pharmaceutically acceptable carrier, diluent, excipient and / or adjuvant.

14. The pharmaceutical composition of claim 13, which is in the form of oral or topical administration.

15. Use of a compound according to claim 1 for the manufacture of a pharmaceutical for the treatment of an inflammatory disease or condition, an autoimmune disease or condition, a respiratory disease, or a neurodegenerative disease, condition or disorder.

16. The use described in claim 15, wherein the inflammatory disease or inflammatory condition is an ocular inflammatory disease or condition.

17. The method of claim 15, wherein the disease is a respiratory disease or condition.

18. The method of claim 15, wherein the disease is a neurodegenerative disease, condition or disorder.

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