Leukotriene synthesis inhibitors

Abstract

Provided are certain leukotriene synthesis inhibitors, pharmaceutical compositions containing the compounds, and methods of using the compounds and pharmaceutical compositions, for example, in the treatment of inflammatory diseases or conditions.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims the benefit under U.S. patent law of U.S. Provisional Patent Application No. 62 / 791,641, filed January 11, 2019, which is incorporated herein by reference in its entirety for all purposes.

[0002] The present disclosure is directed to certain leukotriene synthesis inhibitor compounds, and pharmaceutical compositions comprising the compounds, and methods of using the compounds and pharmaceutical compositions, for example, in the treatment of inflammatory diseases or conditions. [Background technology]

[0003] 5-Lipoxygenase (5-LO) is a key enzyme in the production of leukotrienes, which are proinflammatory mediators of disease. With the assistance of 5-lipoxygenase-activating protein (FLAP), 5-LO oxidizes the substrate arachidonic acid to HPETE, a transient intermediate that is degraded to the bioactive molecule leukotriene C. 4 (LTC 4 ) and leukotriene B 4 (LTB 4 ), the direct precursor of leukotriene A 4 (LTA 4 Leukotriene A 4 The LTA 4 LTB by hydrolytic enzymes 4 or converted to LTC 4 LTC is conjugated with glutathione reduced by the synthetic enzyme 4 It is possible to generate LTC 4 Leukotriene D 4 (LTD 4 ), which is converted to leukotriene E by successive amino acid hydrolysis. 4 (LTE 4 ) is converted to leukotriene C 4 , leukotriene D 4 , and leukotriene E 4are collectively known as cysteinyl leukotrienes. Leukotrienes are produced primarily, but not exclusively, by white blood cells. LTB 4 LTC is produced, for example, by neutrophils, macrophages and mast cells. 4 LTA is produced, for example, by macrophages, eosinophils, basophils, and mast cells. Transcellular synthesis may also occur. For example, LTA produced in neutrophils 4 lacks 5-lipoxygenase, but LTC 4 The synthetic enzyme may be delivered to an endothelial cell that expresses the LTA 4 LTC 4 LTB produced by various types of cells 4 The amount of cysteinyl leukotrienes and the amount of cysteinyl leukotrienes were determined by the terminal enzyme LTA 4 Hydrolases and LTCs 4 Another factor that influences leukotriene synthesis is the intracellular location of 5-lipoxygenase.

[0004] Leukotrienes act by binding to specific G protein-coupled receptors present on the extracellular membrane of inflammatory structural cells. This binding activates intracellular signaling pathways, leading to a series of biological responses present in, for example, inflammatory diseases and conditions. Leukotrienes play a wide range of functional roles in disease, including recruitment of leukocytes, increased mucus release, increased vascular permeability, and increased proliferation, among others.

[0005] Many strategies have been attempted to develop compounds that inhibit the synthesis of leukotrienes or block the receptors at which they function. 5-LO inhibits LTB 45-LO is an important drug target for disease indications involving either or both cysteinyl leukotrienes and cysteinyl leukotrienes. 5-LO inhibitors in development can be grouped according to the mechanism of inhibition. Redox inhibitors reduce the iron at the active site of the enzyme to the inactive ferrous form. However, common redox inhibitors interfere with multiple biological redox systems, resulting in side effects. Another group of inhibitors are the iron ligand chelators. These compounds bind to the catalytic iron in the 5-LO enzyme, thereby preventing the catalyst from converting arachidonic acid to its products. Examples of compounds in this group include hydroxamic acids and N-hydroxyurea derivatives. Iron chelators are not preferred treatment options due to potential side effects. Non-redox competitive inhibitors specifically inhibit the 5-LO enzyme without the potential side effects associated with the redox and iron chelator classes. Zileuton, a compound approved for the treatment of asthma, inhibits an estimated 26-86% of endogenous leukotriene production. However, its clinical use is limited because it requires monitoring of liver enzyme levels and multiple daily administrations. FLAP was first discovered as a target of MK886, and since then, many compounds targeting FLAP have been introduced into the clinic to treat respiratory and cardiovascular diseases, but none of them have been marketed (Non-Patent Document 1).

[0006] In addition, mainly LTB 4 In diseases involving leukotriene A 4 Hydrolase (LTA 4 H) by blocking LTB 4 Targeted inhibition of leukotriene A has been an attractive drug target. 4 Hydrolase (LTA 4 H) is leukotriene B 4 This enzyme is a bifunctional enzyme that is important in the synthesis of LTA. 4 From LTB 4LTA is known to have epoxide hydrolase activity involved in the generation of . This enzyme also has aminopeptidase activity involved in the degradation of tripeptides formed during collagen breakdown and is also chemotactic for neutrophils (Non-Patent Documents 2 and 3). 4 H has traditionally been associated with pro-inflammatory LTB 4 Although its hydrolase activity for the synthesis of products is recognized, the aminopeptidase activity of this enzyme 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, LTB by inhibiting LTA4H 4 Therapies aimed at inhibiting production should also maintain the aminopeptidase activity of the enzyme, which could be advantageous in the treatment of inflammatory diseases. For example, there remains a need for leukotriene inhibitors for the treatment of inflammatory diseases or conditions.

[0009] Not all of the subject matter described in the "Background Art" section is necessarily prior art, and should not be considered to be prior art merely by virtue of its description in the "Background Art" section. In this regard, recognition of problems in the prior art described in the "Background Art" section or related to such subject matter should not be treated as prior art unless expressly stated to be prior art. Instead, the description of any subject matter in the "Background Art" section should be treated as part of the inventor's approach to a particular problem, and may itself also be inventive. [Means for solving the problem]

[0010] In one aspect, the disclosure provides a compound of formula (1). In another aspect, the disclosure provides a composition, e.g., a pharmaceutical composition, comprising a compound of formula (1). In another aspect, the disclosure provides a method of treating various diseases and conditions, comprising administering a therapeutically effective amount of a compound of formula (1) or a composition comprising a compound of formula (1).

[0011] Exemplary embodiments of the present disclosure include the compounds set forth in Table 1, and the following embodiments, which are numbered for ease of reference. 1) 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 is optionally substituted with 1, 2 or 3 substituents; L is selected from a direct bond and methylene; R 1 However, hydrogen, halides, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 3 -C6 Cycloalkoxy, and C 3 -C 6 Cycloalkyl-substituted 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 Selected from; 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; 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 8 and may together form an optionally substituted 5- or 6-membered heterocycle. 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) The compound of embodiment 1, wherein Ar is selected from 1,3-benzoxazole, 2-methylquinoline, and 1,3-benzothiazole. 11) The compound of embodiment 1, wherein Ar is naphthalene or a nitrogen-substituted analog thereof selected from 1,5-naphthyridine, 1,6-naphthyridine, 1,7-naphthyridine, 1,8-naphthyridine, isoquinoline, phthalazine, 2,6-naphthyridine, and 2,7-naphthyridine. 12) -S-CH with one Ar 3 The compound of embodiment 1, wherein the compound is substituted with 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 C 1 -C 6 The compound of any one of embodiments 1-14, wherein is alkyl. 18)R 1 C 1 -C 6 The compound of any one of embodiments 1-14, wherein the compound is haloalkyl. 19) R 1 C 1 -C 6 The compound according to any one of embodiments 1-14, wherein said compound is alkoxy. 20) The compound of any one of embodiments 1-19, wherein A is a direct bond. 21) A is -CH 2 -. 22) A is -CH 2 CH 2 -. 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 of any one of embodiments 1-26, wherein 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 But, C 1 -C 7 The compound of any one of embodiments 1-33, wherein is alkyl. 35)R 5 But, C1 -C 7 Haloalkyl, e.g., R 5 The compound of any one of embodiments 1-34, wherein is trifluoromethyl. 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 of any one of embodiments 1-37, wherein 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. 47)R 7 and R 8 and together form a substituted 5-membered heterocycle. 48)R 7 and R 8 and together form a 6-membered heterocycle. 49)R 7 and R 8and together form a substituted 6-membered heterocycle. 50) 1-[4-(1,3-benzothiazol-2-yloxy)-3-methoxyphenyl]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-benzothiazol-2-yl)oxy]phenyl}-3-(trifluoromethyl)pentan-3-ol; 1-[4-(1-methyl-1H-benzimidazol-2-yloxy)-3-methoxyphenyl]-3-(trifluoromethyl)pentan-3-ol; 1-{3-methoxy-4-[(6-methylsulfonyl-1,3-benzothiazol-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-(iso-propyloxy)-phenyl]pentan-3-one; 1-[4-(1,3-benzothiazol-2-yloxy)-3-(cyclopentyloxy)-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-(iso-propyloxy)phenyl]-3-(trifluoromethyl)pentan-3-ol; 1-[4-(1,3-benzothiazol-2-yloxy)-3-(cyclopentyloxy)-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-benzothiazol-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-methylbutan-2-ol; 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]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; 1-[4-(1,3-benzothiazol-2-yloxy)phenyl]-3,4-dimethylpentan-3-ol; 1-[4-(1,3-benzothiazol-2-yloxy)phenyl]-3-methylpentan-3-ol; 4-[4-(1,3-benzothiazol-2-yloxy)phenyl]-2-phenylbutan-2-ol; 4-[4-(1,3-benzothiazol-2-yloxy)phenyl]-2-(4-fluorophenyl)butan-2-ol; 1-[4-(1,3-benzoxazol-2-yloxy)phenyl]-3-methylpentan-3-ol; 4-[4-(1,3-benzoxazol-2-yloxy)phenyl]-2-phenylbutan-2-ol; 1-[4-(1,3-benzothiazol-2-yloxy)phenyl]pentan-3-one; 1-[4-(1,3-benzothiazol-2-yloxy)-3-chlorophenyl]pentan-3-one; 1-[4-(1,3-benzothiazol-2-yloxy)phenyl]-3-(trifluoromethyl)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)-phenyl]-3-(trifluoromethyl)-pentan-3-ol; 2-{4-[3-(pyrrolidin-1-yl)butyl]phenoxy}-1,3-benzothiazole; 1-{4-[4-(1,3-benzothiazol-2-yloxy)phenyl]butan-2-yl}pyrrolidine-2-carboxylic acid; 2-{4-[3-(pyrrolidin-1-yl)pentyl]phenoxy}-1,3-benzothiazole; 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; 2-{4-[1-(pyrrolidin-1-yl)ethyl]phenoxy}-1,3-benzothiazole; 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 acid; 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-benzothiazol-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]butan-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]propan-2-ol; 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-trifluoroethan-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)-phenyl]pentan-3-ol; 1-[4-(1,3-benzothiazol-2-yloxy)-3-(cyclopropylmethoxy)-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-benzothiazol-2-yl]oxy}phenyl)pentan-3-methyl-3-ol; 1-(3-Methoxy-4-{[4-(methylsulfanyl)-1,3-benzothiazol-2-yl]oxy}phenyl)pentan-3-one; 1-(3-Methoxy-4-{[4-(methylsulfanyl)-1,3-benzothiazol-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]propan-2-ol; 1,1,1-trifluoro-2-[3-methoxy-4-(quinolin-2-ylmethoxy)phenyl]butan-3-ol; and The compound according to embodiment 1, selected from: 1,1,1-trifluoro-2-[3-methoxy-4-(quinolin-2-ylmethoxy)phenyl]propan-2-ol; 51) The compound according to embodiment 1 as a racemic mixture of enantiomers of the compound of formula (1). 52) The compound according to any one of embodiments 1 to 51 as a non-racemic mixture of enantiomers of the compound of formula (1). 53) The compound of any one of embodiments 1-51 as the isolated (S) enantiomer. 54) The compound of any of embodiments 1-51 as the isolated (R) enantiomer. 55) Ar is a 9- or 10-membered bicyclic ring system containing two aromatic rings, and Ar is unsubstituted or is a halide, C 1 - 6 Alkyl;-SC 1 - 6 Alkyl; -OC 1 - 6 Alkyl; and -SO 2 -C 1 - 6 substituted with one substituent 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, C 1 -C 6 Alkoxy, C 3 -C 6 Cycloalkoxy, and C 3 -C 6 Cycloalkyl-substituted C 1 -C 6 alkoxy; A is a direct bond, -CH 2 - and -CH 2CH 2 - Selected from; 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 H; R 4 But hydrogen, C 1 -C 7 alkyl, and phenyl; R 5 But, C 1 - 7 Alkyl, C 1 - 7 selected from haloalkyl, phenyl, and halophenyl; 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 Together, C 1 -C 6 The compound of embodiment 1, which forms a 5- or 6-membered heterocyclic ring optionally substituted with substituents selected from alkyl and carboxylic acid. 56) The compound of embodiment 55, wherein Ar is 1,3-benzothiazole. 57) The compound of embodiment 55, wherein Ar is selected from 1,3-benzoxazole and quinoline. 58) Ar is -S-CH 3 The compound of embodiment 55, wherein the compound is substituted with one substituent which is 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)R1 is hydrogen or C 1 -C 6 The compound of any one of embodiments 55-60, which is alkoxy. 62) The compound of any of embodiments 55-61, wherein A is a direct bond. 63) A is -CH 2 CH 2 -. 64) E is -C(OR 3 )R 4 R 5 The compound of any of embodiments 55-63, wherein 65) The compound according to any of embodiments 55 to 64 as a non-racemic mixture of enantiomers of the compound of formula (1). 66) 1-[4-(1,3-benzothiazol-2-yloxy)-3-methoxyphenyl]-3-(trifluoromethyl)pentan-3-ol; 1-{3-methoxy-4-[(4-methylsulfanyl-1,3-benzothiazol-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-methylbutan-2-ol; 1,1,1-trifluoro-2-{4-[(2-methyl-1,3-benzothiazol-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-benzothiazol-2-yl]oxy}phenyl)pentan-3-ol; and 56. The compound according to embodiment 55, selected from 1-(4-{[4-(methylsulfanyl)-1,3-benzothiazol-2-yl]oxy}phenyl)-3-(trifluoromethyl)pentan-3-ol. 67) A pharmaceutical composition comprising a compound according to embodiments 1 to 66, or a pharma- ceutically acceptable enantiomer, salt or solvate thereof, and at least one pharma- ceutically acceptable carrier, diluent, excipient and / or adjuvant. 68) The pharmaceutical composition according to embodiment 67, which is in the form of eye drops. 69) Treatment of an inflammatory disease or condition, comprising administering to a subject in need thereof an effective amount of a compound according to any one of embodiments 1 to 66 or a composition according to embodiment 67. 70) The method of embodiment 69 for treating an ocular inflammatory disease or condition. 71) A method for treating a respiratory disease or condition, comprising administering a therapeutically effective amount of a compound according to any one of embodiments 1 to 66 or a composition according to embodiment 67 to a subject in need thereof. 72) A method for treating a neurodegenerative disease, condition or disorder, comprising administering a therapeutically effective amount of a compound according to any one of embodiments 1 to 66 or a composition according to embodiment 67 to a subject in need thereof. 73) A method for treating a respiratory disease, pulmonary dysfunction or pulmonary condition, such as asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, bronchopulmonary dysplasia and idiopathic pulmonary fibrosis (IPF), comprising administering an effective amount of a compound of any of embodiments 1-66 or a composition of embodiment 67 to a subject in need thereof. 74) A method for treating an autoimmune disease or condition, such as Arthritis, Otis and Multiple Sclerosis, comprising administering to a subject in need thereof an effective amount of a compound according to any of embodiments 1-66 or a composition according to embodiment 67. 75) A method for treating an allergic disease, comprising administering an effective amount of a compound according to any one of embodiments 1 to 66 or a composition according to embodiment 67 to a subject in need thereof. 76) A method for treating conjunctivitis, comprising administering an effective amount of a compound according to any one of embodiments 1 to 66 or a composition according to embodiment 67 to a subject in need thereof. 77) A method for treating uveitis, comprising administering an effective amount of a compound according to any one of embodiments 1 to 66 or a composition according to embodiment 67 to a subject in need thereof. 78) A method for treating dry eye, comprising administering an effective amount of a compound according to any one of embodiments 1 to 66 or a composition according to embodiment 67 to a subject in need thereof. 79) A method for treating diabetic retinopathy, comprising administering a therapeutically effective amount of a compound according to any one of embodiments 1 to 66 or a composition according to embodiment 67 to a subject in need thereof. 80) A method for treating age-related macular degeneration, comprising administering a therapeutically effective amount of a compound according to any one of embodiments 1 to 66 or a composition according to embodiment 67 to a subject in need thereof. 81) A method for treating diabetic macular edema, comprising administering a therapeutically effective amount of a compound according to any one of embodiments 1 to 66 or a composition according to embodiment 67 to a subject in need thereof. 82) A method for treating a skin disease or condition, such as atopic dermatitis, psoriasis, acne vulgaris, etc., comprising administering to a subject in need thereof an effective amount of a compound according to any one of embodiments 1-66 or a composition according to embodiment 67. 83) A method for treating cancer, comprising administering an effective amount of a compound according to any one of embodiments 1 to 66 or a composition according to embodiment 67 to a subject in need thereof. 84) A method for treating a neuroinflammatory or neurodegenerative disease, such as Alzheimer's disease, comprising administering to a subject in need thereof an effective amount of a compound according to any one of embodiments 1 to 66 or a composition according to embodiment 67. 85) A method for treating Sjögren-Larsson syndrome, comprising administering an effective amount of a compound according to any one of embodiments 1 to 66 or a composition according to embodiment 67 to a subject in need thereof. 86) A method for treating a cardiovascular (CV) disease, comprising administering an effective amount of a compound according to any one of embodiments 1 to 66 or a composition according to embodiment 67 to a subject in need thereof.

[0012] Any two or more of the embodiments disclosed herein may be combined to describe the compounds, compositions and methods of the present disclosure.

[0013] This Summary is provided to introduce certain concepts in a simplified form that are further described below in the Detailed Description of the Invention. Unless expressly stated otherwise, this Summary is not intended to identify key or essential features of the claimed subject matter, nor is it intended to limit the scope of the claimed subject matter.

[0014] The details of one or more embodiments are set forth in the following description. Features illustrated or described in connection with an exemplary embodiment may be combined with features of other embodiments. Thus, any of the various embodiments described herein may be combined to provide yet further embodiments. Aspects of the embodiments may be modified, if necessary, to provide yet further embodiments using concepts from the various patents, applications and publications identified herein. Other features, objects and advantages will be apparent from the description, drawings, and claims. [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 may be more readily understood by reference to the following detailed description of preferred embodiments of the invention and examples contained herein. Prior to describing the invention in further detail, certain definitions used herein are set forth below, along with the following definitions, as well as certain designations used herein.

[0017] It is to be understood that the terms used herein have their usual meanings to those skilled in the art of organic chemicals.However, the following definitions apply throughout the specification and claims unless otherwise stated.These definitions apply regardless of whether the term is used alone or as part of a larger name.For example, the definition of "alkyl" applies to the term "alkyl" used by itself and to the "alkyl" portion of terms that include the alkyl concept, such as "hydroxyalkyl", "haloalkyl", "O-alkyl", etc.

[0018] Chemical names, trivial names, and chemical structures may be used interchangeably to describe the same compound. For example, a compound of formula (1) may be referred to herein by its chemical structure and / or by its chemical name. It should be understood that if both the structure and name of a compound are provided and there is a discrepancy between the name and the structure, the structural representation of the compound takes precedence.

[0019] As further explained herein, the term "substituted" means that one or more hydrogens on the designated or selected atom are replaced with a selection from the indicated group, provided that the normal valence of the designated atom under the existing circumstances is not exceeded and that the substitution results in a stable compound. Such combinations are only acceptable if they result in a stable compound. "Stable compound" or "stable structure" means that the compound can exist long enough to be isolated from a reaction mixture to a useful degree of purity and formulated into an effective therapeutic composition. It should also be noted that in the text, schemes, examples and tables of this specification, carbons and heteroatoms with unsaturated valences are assumed to have a sufficient number of hydrogen atoms to satisfy the normal valence of the atom.

[0020] "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from 1 to the specified number of carbon atoms, and attached to the remainder of the molecule by a single bond, such as methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, and the like. In one embodiment, the alkyl group has one carbon. In one embodiment, the alkyl group has two 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 four carbons. In one embodiment, the alkyl group has five carbons. In one embodiment, the alkyl group has six carbons. Two or more of these embodiments can be combined to describe the compounds of the present disclosure. "Alkoxy" refers to -O-alkyl. "Cycloalkyl" refers to cyclic aliphatic radicals containing no unsaturation, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. "Cycloalkoxy" refers to -O-cycloalkyl.

[0021] "Aryl" refers to a hydrocarbon ring system radical 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. For purposes of this disclosure, an aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, and may include fused or bridged ring systems. Aryl radicals include, but are not limited to, aryl radicals derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless otherwise stated in the specification, an aryl group may be optionally substituted by one or more substituents independently selected at each occurrence.

[0022] "Compounds of the present disclosure" (unless otherwise specified) and the equivalent term "compounds of this (or this) invention" (unless otherwise specified) refer to compounds of formula (1), including subsets thereof, as well as all pure and mixed stereoisomers (including diastereoisomers and enantiomers), tautomers and isotopically labeled compounds. Hydrates and solvates of compounds of the present invention / disclosure are also considered to be within the scope of the term compounds of the present invention / disclosure. Compounds may exist in one or more crystalline states, i.e., co-crystals or polymorphs, or may exist as amorphous solids or oils. All such forms are encompassed by the present invention and claims. "Formula (1)", "Formula 1", "Compounds of formula (1)", "Formula 1", etc. may be used interchangeably herein, and no difference or distinction is intended.

[0023] An "effective amount", "therapeutic amount", "therapeutically effective amount", or "effective dose" refers to an amount or dose of an active compound described herein sufficient to induce a desired pharmacological or therapeutic effect in a subject. In the case of a compound treating inflammation, the effective amount is an anti-inflammatory amount. In this context, an "effective amount", "therapeutic amount", "therapeutically effective amount", and "effective dose" can be easily determined by a person skilled in the art using the tools and methods generally known in the art, following the teachings of the present disclosure, often based on routine clinical or patient-specific factors. However, it is understood that the attending physician will determine the total daily dose of the compound within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient will depend on a variety of factors, including the disorder being treated and the severity of the disorder; the desired results to be obtained, the activity of the particular compound used; the given composition used; the age, weight, general health, sex, and diet of the patient; the time of administration, route of administration, and excretion rate of the particular compound used; the duration of treatment; drugs used in combination or simultaneously with the particular compound used; and similar factors known in the medical arts. However, as a general guideline, the total daily dose will typically range from about 0.0001 mg / kg / day to about 100 mg / kg / day, in single or divided doses.Typically, dosages for humans will range from about 0.1 mg to about 4000 mg per day, in single or multiple doses.

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

[0025] "Halo" refers to chloro, bromo, fluoro, and iodo. The term "halogen" refers to fluorine (which may be written as -F), chlorine (which may be written as -Cl), bromine (which may be written as -Br), or iodine (which may be written as -I). In one embodiment, the halogen is chlorine. In another embodiment, the halogen is fluorine. In another embodiment, the halogen is bromine. Thus, halophenyl refers to a phenyl group having at least one halogen substituent replacing a hydrogen normally present on the phenyl. Halogenated CH 2 What is CHF and CF? 2 CH with at least one halogen substitution, such as 2 Refers to the base.

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

[0027] "Heteroaryl" refers to "aryl" as defined herein, where the aromatic ring contains one or more heteroatoms, preferably selected from N, O and S. Thus, a heteroaryl radical refers to an aromatic ring system radical, where the ring atoms are selected from carbon, nitrogen, oxygen and sulfur, and contain at least one of nitrogen, oxygen and sulfur. For the purposes of this disclosure, a heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, and may include fused or bridged ring systems. Optionally, a heteroaryl radical is a 5-, 6- or 7-membered heteroaryl group. When multiple O and S atoms are present in a heteroaryl ring system, the O and / or S atoms are preferably not directly bonded. Exemplary heteroaryl groups include five-membered rings such as pyrrole, pyrazole, imidazole, 1,2,3-triazole, 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, 1,2,5-thiadiazole, 1,3,4-thiadiazole, and the like.The heteroaryl group may be a six-membered ring such as 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 may be an isoaryl ring such as indole, isoindole, indolizine, indazole, benzimidazole, benzotriazole, purine, naphthymidazole, phenanthrimidazole, pyridimidazole, pyrazinimidazole, quinoxalinimidazole, benzoxazole, naphthoxazole, anthroxazole, phenanthroxazole, isoxazole, benzothiazole, benzofuran, isoaryl, and fused rings containing six membered rings such as benzofuran, dibenzofuran, quinoline, isoquinoline, pteridine, benzo-5,6-quinoline, benzo-6,7-quinoline, benzo-7,8-quinoline, benzisoquinoline, acridine, phenothiazine, phenoxazine, benzopyridazine, benzopyrimidine, quinoxaline, phenazine, naphthyridine, azacarbazole, benzocarboline, phenanthridine, phenanthroline, thieno[2,3b]thiophene, thieno[3,2b]thiophene, dithienothiophene, isobenzothiophene, dibenzothiophene, and benzothiadiazothiophene. Unless stated otherwise in the specification, the ring atoms of a heteroaryl group are optionally substituted with one or more substituents independently selected at each ring atom.

[0028] "Hydroxyalkyl" refers to an alkyl group having at least one hydroxyl (-OH; also called hydroxy) substitution in place of a C-H bond. In one embodiment, there is one hydroxyl substituent on the named group (e.g., phenyl, alkyl). In embodiments, there are two hydroxyl substituents, or one to two hydroxyl substituents, or three hydroxyl substituents, or one to three hydroxyl substituents. As used herein, "C 1 -C 6 "Hydroxyalkyl" refers to a straight or branched alkyl group containing 1 to 6, e.g., 1, 2, 3, 4, 5 or 6, carbon atoms. 1 -C 6Examples of hydroxyalkyl radicals are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, where the radical may have one or more hydroxyl substituents, for example, as in one embodiment, the radical may have one hydroxyl substituent.

[0029] "Independently selected" with respect to a group of alternatives, e.g., a group of substituents, indicates that each substituent is selected without regard to the selection made for any other substituents, i.e., each substituent is independently selected. Thus, each selected substituent may be the same as or different from other substituents selected from the group of substituents. For added clarity, the disclosure that something is selected from a group is meant to mean that when selection is made multiple times, the selection is made independently at each occurrence. Unless expressly stated otherwise, and whether or not it is expressly stated that the selection is made independently, the selection of atoms and / or substituents is independently selected.

[0030] "Mammal" refers to a human or animal, including livestock and companion animals. The phrase "companion animal" or "companion animals" refers to animals kept as pets, such as cats, dogs, and horses. The term "livestock" refers to animals kept or raised in agricultural conditions to produce products, such as food or fiber, or for their labor, including, for example, cows, goats, horses, pigs, sheep, lambs, and rabbits, and birds, such as chickens, ducks, and turkeys.

[0031] "Pharmaceutically acceptable" refers to suitable for use in mammals, companion animals, or livestock. Thus, a pharmaceutically acceptable substance or composition must be chemically and / or toxicologically compatible with other ingredients comprising the formulation and / or with the mammal being treated therewith.

[0032] A "pharmaceutically acceptable carrier, diluent, or excipient" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier approved by the U.S. Food and Drug Administration as acceptable for use in humans or domestic animals.

[0033] "Pharmaceutically acceptable salt" refers to either "pharmaceutically acceptable acid addition salt" or "pharmaceutically acceptable base addition salt", depending on the actual structure of the compound. When the compound of formula (I) has a basic functional group, such as an amine group, "pharmaceutically acceptable salt" can refer to an acid addition salt of the amine group. Such salts refer to non-toxic organic or inorganic acid addition salts of the compounds of the present disclosure or any of its intermediates. Exemplary inorganic acids that form suitable salts include hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, as well as acid metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Exemplary organic acids that form suitable salts include mono-, di-, and tricarboxylic acids. Examples of such acids include, for example, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, 2-phenoxybenzoic acid, p-toluenesulfonic acid, and sulfonic acids such as methanesulfonic acid and 2-hydroxyethanesulfonic acid. Such salts can exist in either hydrous or substantially anhydrous form. In general, the acid addition salts of these compounds are soluble in water and various hydrophilic organic solvents. Basic nitrogen-containing groups may be quaternized with materials such as lower alkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, and dibutyl sulfate), long chain halides (e.g., decyl chlorides, bromides, and iodides, lauryl, and stearyl), aralkyl halides (e.g., benzyl and phenethyl bromides). When a compound of formula (I) has an acidic functional group, such as a carboxylic acid group, a "pharmaceutically acceptable salt" may refer to a base addition salt of the acid group. Such base salts refer to any non-toxic organic or inorganic base addition salt of the compounds of the present disclosure or any of its intermediates.Exemplary base salts include alkali metal salts such as ammonium, sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (e.g., organic amines) such as dicyclohexylamine, t-butylamine, choline, and salts with amino acids such as arginine, lysine, etc. The counterion of a carboxylic acid or other acidic group may be a quaternized nitrogen-containing group.

[0034] "Prodrug" refers to a compound (e.g., a drug precursor) that is converted in vivo to provide a compound of the present disclosure or a pharma- ceutically acceptable salt of the compound. The conversion may occur by metabolic or chemical processes, such as, for example, by hydrolysis in blood. Prodrugs include bioreversible derivatives of the compounds of formula I of the present disclosure. Prodrugs can alter the solubility, lipophilicity, and in vivo distribution of the drug. By deliberately altering these important properties, it may be possible to improve absorption, increase onset time, reduce first-pass metabolism, enable the development of water-soluble IV formulations, and achieve targeted delivery. Additionally, prodrugs are useful for transdermal delivery, improving masking taste, minimizing pain upon injection, improving stability, and the like. In situations where the pharmacophore itself results in poor delivery properties, prodrugs are one of the few strategies that can be used to salvage highly active compounds.

[0035] All prodrugs of compounds of formula (1), which can be prepared by standard methods known to those skilled in the art, are included within the scope of this disclosure. Prodrugs of the compound of formula (1) are described, for example, in the following literature: Krise JP, Stella VJ, Advanced Drug "Prodrugs of phosphates, phosphonates, 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: Techniques to Reduce Pain and Irritation, Interpharm Press, Buffalo Grove, Ind., 1999; "Improved oral drug delivery: Solubility limitations overcome by the use of prodrugs", Fleisher D, Bong R, Stewart BH, Advanced Drug Delivery Reviews, 19: (2) 115-130 May 22 1996; "Permeable, water-soluble, non-irritating prodrugs of chemotherapeutic agents with oxaalkanoic acids", PCT Int. Publication No. WO 00 / 67801; T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems" (1987) vol. 14 of the ACSSymposium Series, and "Bioreversible Carriers in Drug Design", (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press.

[0036] "Solvate" refers to a physical association of a compound of the present disclosure with one or more solvent molecules. One or more compounds of the present disclosure can exist in solvated and unsolvated forms, where the solvated forms are associated 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 includes varying degrees of ionic and covalent bonding, including hydrogen bonding. In some cases, the solvate can be isolated. This can occur when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid that includes a compound of the present disclosure. The term "solvate" includes both solution-phase and isolatable solvates. The term "solvate" includes hemisolvates. Non-limiting examples of solvates include methanolates, ethanolates, and hydrates, where hydrates refer to solvates where the associated solvent molecule is water. The compounds of the present disclosure may be converted to any corresponding solvate form by methods known in the art. In the exemplary non-limiting process for preparing solvate, the compound of the present invention can be dissolved in a selected amount of desired solvent (organic solvent or water or mixture thereof) at a temperature higher than room temperature, and then the solution is cooled at a rate slow enough to form crystals, and the crystals can be isolated.See, for example, M. Caira et al. J. Pharmaceutical Science (2004) v.93(3) pp. 601-611; EC Tonder et al. AAPS Pharm. Sci. Tech. (2004, Feb 23), v.5(1) p.E12; and AL Bingham et al. Chem. Commun. (2001) pp. 603-604. Each of these documents provides a process for preparing selected solvate.

[0037] "Subject" refers to mammals, such as humans, as well as livestock. A subject may also be referred to as a patient.

[0038] "Substituents" refer to monovalent groups that may be attached to the radicals listed above. For example, "substituted phenyl" refers to a phenyl ring having 1, 2, 3, or 4 substituents attached to the phenyl ring. Substituents include halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, -OH, -O(C 1 -C 6 alkyl), -O(C 1 -C 6 haloalkyl), -O(C 1 -C 6 Hydroxyalkyl), -S(C 1 -C 6 alkyl), -S(C 1 -C 6 haloalkyl), -S(C 1 -C 6 hydroxyalkyl), cyano, amino (-NH 2 ), formyl (-CHO), carboxylic acid (-COOH), carboxylic acid ester (-COOR, R is C 1 -C 6 Similarly, a substituted 5- or 6-membered heterocycle refers to a heterocycle radical in which at least one of the ring atoms is bonded to a substituent as defined herein.

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

[0040] "Treatment" or "treating" of a condition includes (1) preventing the condition, i.e., not allowing clinical symptoms or signs of the disease to develop in a mammal that may be exposed to or predisposed to the condition, but that has not yet experienced or exhibited symptoms / signs of the condition; (2) inhibiting the condition, i.e., halting or reducing the development of the condition or its clinical symptoms / signs in a subject having the condition, such as preventing the recurrence of the condition; or (3) alleviating the condition, i.e., causing the regression of the condition or its clinical symptoms / signs. Thus, "treating" or "treatment" refers to the alleviation of symptoms associated with a disease, disorder, or condition, or the halting of further progression or worsening of those symptoms. Depending on the disease and condition of the patient, 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. It is to be understood that the terms used herein are for the purpose of describing particular embodiments only and are not intended to be limiting. It is further to be understood that unless otherwise defined herein, terms used herein are to be given their conventional meanings as known in the relevant art. Throughout this specification, references to "one embodiment" or "embodiment" and variations thereof mean that a particular feature, structure, or characteristic described in connection with an embodiment is included in at least one embodiment. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification do not necessarily all refer to the same embodiment. Furthermore, particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0041] As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents, i.e., one or more, unless the content and context clearly dictate otherwise. It should also be noted that "and" and "or" are generally used in their broadest sense to include "and / or," unless the content and context clearly dictate inclusion or exclusion, as the case may be. Thus, the use of the alternative (e.g., "or") should be understood to mean either one, both, or any combination thereof of the alternatives. Also, when described herein as "and / or," the combination of "and" and "or" is intended to encompass embodiments that include all of the associated items or concepts, as well as one or more other embodiments that do not include all of the associated items or concepts.

[0042] Unless the context otherwise requires, throughout the specification and the following claims, the term "comprises" and its cognates and variations, such as "having" and "including," and variations thereof, such as "comprising" and "containing," are to be interpreted in an open and inclusive sense, for example, including, but not limited to. The term "consisting essentially of" limits the scope of a patent claim to certain materials or steps or those that do not materially affect the basic and novel characteristics of the claimed disclosure.

[0043] As described herein, for the sake of brevity, in some cases, another person, such as a patient, clinician, etc., may be described in the context of the male gender. It is understood that a healthcare professional may be of any gender, and that the terms "he," "his," "himself," etc., as used herein, should be interpreted broadly to include all known gender definitions.

[0044] Any headings used in this document are merely used for the convenience of the reader and should not be construed as limiting the invention or the disclosure or claims in any way. Thus, the headings and abstracts of the disclosure provided herein are for convenience 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 is optionally substituted with 1, 2 or 3 substituents; L is selected from a direct bond and methylene; R 1 However, hydrogen, halides, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 3 -C 6 Cycloalkoxy, and C 3 -C 6 Cycloalkyl-substituted 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 Selected from; R 2 is selected from methyl, ethyl, and phenyl; R 3is selected from hydrogen, 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; 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 8 and may together form an optionally substituted 5- or 6-membered heterocycle.

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

[0047] Included within the scope of the compound of formula (1) are its pharma- ceutically acceptable enantiomers, diastereomers, salts and solvates. When the compound of formula (1) contains a chiral center, it may exist in either the (R) or (S) configuration, thus resulting in two enantiomeric forms. In one embodiment, the present disclosure provides the compound of claim 1 as a racemic mixture of the two enantiomers of the compound of formula (1). In one embodiment, the present disclosure provides the 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 a mixture, but the molar ratio of (R):(S) is not equal to 1. In one embodiment, the present disclosure provides the compound of formula (1) as an isolated (S) enantiomer, i.e., unmixed with the corresponding (R) enantiomer or mixed with less than 1% of the (R) enantiomer. In one embodiment, the present disclosure provides a compound of formula (1) as an isolated (R) enantiomer, i.e., unmixed with the corresponding (S) enantiomer or mixed with less than 1% of the (S) enantiomer.

[0048] In the compound of formula (1), Ar (Ar1) represents a 9- or 10-membered bicyclic aromatic ring system, where Ar may be optionally substituted with one, two or three substituents. Bicyclic ring system refers to a moiety having two rings fused together, and bicyclic aromatic ring refers to a moiety having two rings fused together, where at least one, and optionally two (both) of the rings are aromatic rings. In one embodiment, only one of the two rings of the bicyclic aromatic ring system is an aromatic ring. In one embodiment, both rings of the bicyclic aromatic ring system are aromatic rings. A ring system being 9- or 10-membered 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 system, and a 6-membered ring fused to a 6-membered ring results in 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 nine-membered Ar groups according to the present disclosure include benzofuran, 1,3-benzoxazole, furo[3,2-b]pyridine, furo[3,2-c]pyridine, furo[2,3-c]pyridine, 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, 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 the compounds of formula (1), and each of these ring systems may be substituted with one, two, or three substituents.

[0050] In another embodiment, Ar is a 10-membered bicyclic aromatic ring system in which a 6-membered ring is fused to another 6-membered ring. Examples of 10-membered Ar groups according to the present disclosure include naphthalene, quinoline, quinazoline, quinoxaline, 1,5-naphthyridine, 1,6-naphthyridine, 1,7-naphthyridine, 1,8-naphthyridine, isoquinoline, phthalazine, 2,6-naphthyridine, and 2,7-naphthyridine. Each of the listed 10-membered ring systems may be the Ar group in the compound of formula (1), and each of these ring systems may be substituted with 1, 2, or 3 substituents.

[0051] In one optional embodiment, the compound of formula (1) has Ar as 1,3-benzothiazole. In another optional embodiment, the compound of formula (1) has Ar selected from 1,3-benzoxazole and quinoline.

[0052] Substituents on Ar refer to monovalent groups that may be attached to any of the ring atoms of the Ar group. In one embodiment, the substituents are halide, C 1 -C 4 Alkyl, C1 -C 4 Haloalkyl, C 1 -C 4 Alkoxy, C 1 -C 4 Haloalkoxy, C 1 -C 4 Thioalkyl, C 1 -C 4 Thiohaloalkyl, C 1 -C 4 Hydroxyalkyl, -SO 2 (C 1 -C 4 alkyl), cyano, carboxylic acid, and C 1 -C 4 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, Ar is C 1 -C 4 In another embodiment, Ar is disubstituted, where two substituents may be independently selected from those listed above. In yet another embodiment, Ar is trisubstituted, where optionally 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 the one substituent is -S-CH 3 It is.

[0053] The Ar group (sometimes referred to herein as Ar1) is attached to the central benzene ring (sometimes referred to herein as Ar2) in the compound of formula (1) through a -LO group. In one embodiment, L is a directional bond and the Ar group is attached to the central benzene ring in the compound of formula (1) through an ether (-O-) bond. In another embodiment, L is methylene and the Ar group is -CH 2 It is attached to the central benzene ring in the compound of formula (1) via an -O- bond.

[0054] The central benzene ring in formula (1) is R 1is bonded to R 1 However, hydrogen, halides, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 3 -C 6 Cycloalkoxy, and C 3 -C 6 Cycloalkyl-substituted C 1 -C 6 In one embodiment, R 1 is hydrogen and the central benzene ring (Ar2) can be said to be unsubstituted. 1 is not hydrogen and the central benzene ring is substituted. 1 is a halide (e.g., fluoride). In another embodiment, R 1 But, C 1 -C 6 alkyl, for example methyl or ethyl. In one embodiment, R 1 But, C 1 -C 6 haloalkyl, for example trifluoromethyl. In one embodiment, R 1 But, C 1 -C 6 Alkoxy, for example, methoxy or ethoxy. In one embodiment, R 1 But, C 3 -C 6 Cycloalkoxy, for example, cyclopropyloxy, cyclobutyloxy, or cyclopentyloxy. 1 But, C 3 -C 6 Cycloalkyl-substituted C 1 -C 6 Alkoxy, for example, -O-CH 2 -cyclopropyl, where -O-CH 2 - is C 3 Cycloalkyl-substituted C 1 It is an alkoxy.

[0055] In the compound of formula (1), the central aromatic ring (benzene) is preferably R 1 and -AE. In effect, A connects the E group to the central aromatic ring. The A group is selected from a direct bond, methylene, and ethylene. Independently of the selection of the A group, the E group may be substituted with -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 R 8 are each selected from a carbon bonded to the carbon atom. For example, A can be a direct bond and E is -C(O)-R 2 , C(OR 3 )R 4 R 5 , and CH(R 6 )NR 7 R 8 In one embodiment, AE is selected from -C(O)-R 2 and in another embodiment, AE is C(OR 3 )R 4 R 5 and in yet another embodiment, AE is CH(R 6 )NR 7 R 8 Alternatively, A may be methylene and E is -C(O)-R 2 , C(OR 3 )R 4 R 5 , and CH(R 6 )NR 7 R 8 In one embodiment, AE is selected from 2 -C(O)-R 2 and in another embodiment AE is -CH 2 -C(OR 3 )R4 R 5 and in yet another embodiment, AE is -CH 2 -CH(R 6 )NR 7 R 8 In yet another embodiment, A can be ethylene and E is -C(O)-R 2 , C(OR 3 )R 4 R 5 , and CH(R 6 )NR 7 R 8 In one embodiment, AE is selected from 2 CH 2 -C(O)-R 2 and in another embodiment AE is CH 2 CH 2 -C(OR 3 )R 4 R 5 and in yet another embodiment, AE is CH 2 CH 2 -CH(R 6 )NR 7 R 8 In one embodiment, A is a direct bond. In another embodiment, A is -CH 2 In another embodiment, A is -CH 2 CH 2 In another embodiment, R 5 is trifluoromethyl.

[0056] In one embodiment, E is -C(O)-R 2 where R 2 is methyl, ethyl or phenyl, for example, E is C(O)CH 3 , i.e., acetyl, C(O)CH 2 CH 3 or C(O)phenyl, i.e., benzoyl. Thus, in one embodiment, when A is a direct bond, -AE is -C(O)-R 2 In another embodiment, when A is methylene, -AE is CH 2 -C(O)-R 2For example, -CH 2 -C(O)CH 3 , or -CH 2 C(O)CH 2 CH 3 , or -CH 2 (C(O)phenyl. In yet another embodiment, when A is ethylene, AE is CH 2 CH 2 C(O)-R 2 For example, -CH 2 CH 2 C(O)CH 3 or -CH 2 CH 2 C(O)CH 2 CH 3 or CH 2 CH 2 C(O)phenyl.

[0057] In one embodiment, E is C(OR 3 )R 4 R 5 where R 3 is selected from hydrogen, 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 In one embodiment, R is selected from haloalkyl, phenyl, and substituted phenyl. 5 is trifluoromethyl, and R 3 is hydrogen.

[0058] In one embodiment, E is CH(R 6 )NR 7 R 8 where R 6 is selected from hydrogen, methyl, halogenated methyl, and ethyl; R 7 is hydrogen; R 8 is hydrogen, methyl, or ethyl. For example, in one embodiment, E is CH(R 6 )NH 2 , CH(R 6 )NH(CH3 ), and CH(R 6 )NH(CH 2 CH 3 In one embodiment, R 7 and R 8 may, together with the nitrogen atom to which they are attached, form an optionally substituted 5- or 6-membered heterocyclic ring, the heterocyclic ring being R 7 and R 8 and one or more, e.g., two, non-carbon atoms, e.g., oxygen or nitrogen. 7 and R 8 and together form an optionally substituted 5- or 6-membered heterocycle, which heterocycle is selected from the group consisting of NR 7 R 8 An example of a five-membered ring is pyrrolidine and its unsaturated analogues, such as 2,5-dihydro-1H-pyrrole. Thus, -NR 7 R 8 may represent 2,5-dihydro-1H-pyrrole. Examples of 6-membered heterocycles are piperidine and its unsaturated analogues, such as 1,2,3,4-tetrahydropyridine, and piperazine. The 5-membered and 6-membered heterocycles each have at least one nitrogen atom and may optionally have a second heteroatom ring atom, such as a heteroatom selected from oxygen, nitrogen, and sulfur. The 5-membered and 6-membered heterocycles may be substituted as described herein. In one embodiment, the substituents are halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Hydroxyalkyl, hydroxyl (-OH), oxo (=O), -O(C 1 -C 6 alkyl), -O(C 1 -C 6 haloalkyl), -O(C 1 -C 6 Hydroxyalkyl), -S(C 1 -C 6 alkyl), -S(C 1 -C 6haloalkyl), S(C 1 -C 6 hydroxyalkyl), cyano, amino (-NH 2 ), formyl (-CHO), carboxylic acid (-COOH), carboxylic acid ester (-COOR, R is C 1 -C 10 Thus, in one embodiment, E may be selected from CH(R 6 )NR 7 R 8 where: (i) R 6 is selected from hydrogen, methyl, halogenated methyl, and ethyl; and R 7 is hydrogen and R 8 is selected from hydrogen, methyl, and ethyl; or (ii) R 7 and R 8 together with the N atom to which they are attached form an optionally substituted 5- or 6-membered heterocycle, where the heterocycle is 7 and R 8 and one or more, eg, two, non-carbon atoms, eg, oxygen or nitrogen.

[0059] In the compound of formula (1), Ar may be unsubstituted aryl and may have one, two or three substituents. In one embodiment, Ar has no substituents. In 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, the present disclosure provides a compound of formula (1). [ka] and pharma- ceutically acceptable salts thereof, wherein Ar is an unsubstituted 9- or 10-membered bicyclic aromatic ring system; L is selected from a direct bond and methylene; and R 1 However, hydrogen, halides, C 1 -C 6 Alkyl, haloalkyl, and C 1 -C 6 alkoxy; A is a direct bond, -CH2 - and -CH 2 CH 2 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 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 But, C 1 -C 7 Alkyl, C 1 -C 7 haloalkyl (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 and may together form 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 compounds 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 where R 3 is hydrogen and R 4is alkyl, e.g., ethyl, and R 5 C 1 -C 7 haloalkyl, e.g. trifluoromethyl; R 1 C 1 -C 4 When Ar-LO is alkoxy, such that Ar-LO is 1,3-benzothiazol-2-yloxy, compounds 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 where R 3 is hydrogen and R 4 is alkyl, e.g., methyl, and R 5 But, C 1 -C 7 haloalkyl, for example trifluoromethyl; R 1 But, C 1 -C 4 When Ar-LO is alkoxy, such that Ar-LO is 1,3-benzothiazol-2-yloxy, compounds of the formula: [ka] For example, the following compound: [ka] In another embodiment, A is ethylene and E is C(OR3 )R 4 R 5 where R 3 is selected from hydrogen, alkyl, and substituted alkyl; R 4 is hydrogen and R 5 But, C 1 -C 7 Alkyl, C 1 -C 7 R is selected from haloalkyl, phenyl, and substituted phenyl; 1 However, hydrogen, halides, C 1 -C 6 Alkyl, haloalkyl, and C 1 -C 6 alkoxy, so that, for example, Ar-LO is 1,3-benzothiazol-2-yloxy, provides a compound of 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, R 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, C 1 -C 7 Alkyl, C 1 -C 7 haloalkyl, phenyl, and substituted phenyl, thereby providing, 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 C 2 -C 4 For example, 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)(CF 3 )(CH 2 CH 3 ) which results in providing 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, compounds of the formula: [ka] For example, the following compound: [ka] In another embodiment, compounds are provided where Ar is unsubstituted and A is a direct bond, for example having the formula: [ka] For example, the following compound: [ka] Other compounds where A is a direct bond have R1 as hydrogen, thereby providing compounds having the formula: [ka] For example, a compound having the formula: [ka] The compounds include those having the formula: using benzothiazole as an exemplary Ar group. [ka] For example, the following compound: [ka] [ka] , and [ka]

[0060] As described above, in the compound of formula (1), Ar may be an unsubstituted aryl, and may have one, two or three substituents. When Ar has a substituent, the present disclosure provides a compound of formula (1) [ka]

[0061] and pharma- ceutically acceptable salts thereof, wherein Ar is a substituted 9- or 10-membered bicyclic aromatic ring system having 1, 2, or 3 substituents; L is selected from a direct bond and methylene; and R 1 However, hydrogen, halides, C 1 -C 6 Alkyl, haloalkyl, and C 1 -C6 alkoxy; A is a direct bond, -CH 2 - and -CH 2 CH 2 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 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 But, C 1 -C 7 Alkyl, C 1 -C 7 haloalkyl (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 and may together form an optionally substituted 5- or 6-membered heterocyclic ring. In one such embodiment, Ar has one or two substituents. Optionally, A is CH 2 and C.H. 2 CH 2 For example, a compound of the formula: [ka] Compounds are provided having the formula: [ka] This includes compounds of the formula: [ka] Here, R 9represents one or two independently selected substituents on Ar at each occurrence; R 3 can be hydrogen, thus providing, for example, compounds of the formula: [ka] In the formula, R 4 is 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 substituted with a group, the disclosure provides a compound having the formula: [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 substituent on Ar include those of the formula: [ka] The following compounds are included: [ka] [ka] , and [ka] Still other compounds of the present disclosure having substitution on Ar include compounds having the formula: [ka] For example, the following compound: [ka] In another embodiment, Ar is substituted and R 1 is selected from halide and alkoxy, for example to provide the following compound: [ka] [ka] [ka] [ka] [ka] [ka] and [ka]

[0062] In one embodiment, the compounds of the present disclosure include both hydroxyl and trifluoromethyl as components of the "E" group. For example, the present disclosure provides compounds of the formula [ka] and pharma- ceutically acceptable salts thereof, wherein Ar is a 9- or 10-membered bicyclic aromatic ring system, Ar is optionally substituted with 1, 2, or 3 substituents; L is selected from a direct bond and methylene; and R 1 However, hydrogen, halides, C 1 -C 4 Alkyl, C 1 -C 4 Haloalkyl, and C 1 -C 4 alkoxy; A is a direct bond, -CH 2 - and -CH 2 CH 2 -; E is C(OR 3 )R 4 R 5 where R 3 is hydrogen and R 5 is trifluoromethyl, so that E is C(OH)(CF 3 )R 4 ;R 4 is selected from hydrogen, methyl, and ethyl. Optionally, the compound of formula (1) comprises 5 C 1 -C 7 Alkyl; R 5 is methyl; R 5 is ethyl; R 5 C 1 -C 7 Haloalkyl; R 5 is phenyl; A is -CH 2 CH 2 - and R 5 C 1 -C 7 Alkyl; A is -CH 2 CH 2 - and R 5 is methyl; A is -CH 2 CH 2 - and R 5 is ethyl; A is -CH 2 CH 2 - and R 5 C 1 -C 7 haloalkyl; A is -CH2 CH 2 - and R 5 is phenyl; L is a direct bond and A is -CH 2 CH 2 - and R 5 C 1 -C 7 alkyl; L is a direct bond and A is -CH 2 CH 2 - and R 5 is methyl; L is a direct bond and A is -CH 2 CH 2 - and R 5 is ethyl; L is a direct bond and A is -CH 2 CH 2 - and R 5 C 1 -C 7 haloalkyl (e.g., trifluoromethyl); L is a direct bond and A is -CH 2 CH 2 - and R 5 is phenyl; Ar is unsubstituted benzothiazol-2-yl; Ar is benzothiazol-2-yl with one substituent; Ar is benzothiazol-2-yl with two substituents; and Ar is benzothiazol-2-yl with three substituents. Additionally, the disclosure provides the following exemplary compounds containing hydroxyl and trifluoromethyl as components of the "E" group:

[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 optionally substituted with one or two substituents, and L is a direct bond, such that formula (1) has the following structure: [ka] In the formula, R 1 is selected from hydrogen, halide, and alkoxy; A is a direct bond, -CH 2 - and -CH 2 CH 2 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 is selected from 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 is selected from methyl, halogenated methyl (e.g., trifluoromethyl), ethyl, and phenyl; R 6 is selected from hydrogen, methyl, halogenated methyl, and ethyl; R 7 is hydrogen; R 8 is methyl or ethyl; 7 and R 8 and may together form an optionally substituted 5- or 6-membered heterocycle. Additionally, the present disclosure provides the following exemplary compounds containing 6-benzothiazole as the Ar group: [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 a heterocyclic analog thereof, Ar1 may be optionally substituted with one or two substituents, and L is optionally a methylene group (-CH 2 -), where R 1 is selected from hydrogen, halide, and alkoxy; A is a direct bond, -CH 2 - and -CH 2 CH 2 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 is selected from 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 is selected from methyl, halogenated methyl (e.g., trifluoromethyl), ethyl, and phenyl; R 6 is selected from hydrogen, methyl, halogenated methyl, and ethyl; R 7 is hydrogen; R 8 is methyl or ethyl; 7 and R 8 and may together form an optionally substituted 5- or 6-membered heterocyclic ring. Additionally, the disclosure provides the following exemplary compounds that include naphthyl or a heterocyclic analog of naphthyl as the Ar group: [ka] In the above formula, R 1 is selected from hydrogen, halide, and alkoxy; A is a direct bond, -CH 2 - and -CH 2 CH2 E is selected from -C(O)-R 2 , C(OR 3 )R 4 R 5 , and CH(R 6 )NR 7 R 8 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 is selected from 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 is selected from methyl, halogenated methyl (e.g., trifluoromethyl), ethyl, and phenyl; R 6 is selected from hydrogen, methyl, halogenated methyl, and ethyl; R 7 is hydrogen; R 8 is methyl or ethyl; 7 and R 8 and may together form an optionally substituted 5- or 6-membered heterocycle, such as the compounds of the formula: [ka] In the formula, R 1 is selected from hydrogen, halide, and alkoxy; R 3 is selected from H and a hydroxyl protecting group; R 4 is selected from hydrogen, methyl, and ethyl; R 5 is selected from methyl, halogenated methyl (eg trifluoromethyl), ethyl and phenyl, for example: [ka] [ka] [ka] [ka] Furthermore, the disclosure provides the following exemplary compounds that include naphthyl or heterocyclic analogs of naphthyl as the Ar group, for example, compounds of the formula: [ka] In the above formula, R 1 is selected from hydrogen, halide, and alkoxy; A is a direct bond, -CH 2 - and -CH 2 CH 2 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 is selected from 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 is selected from methyl, halogenated methyl (e.g., trifluoromethyl), ethyl, and phenyl; R 6 is selected from hydrogen, methyl, halogenated methyl, and ethyl; R 7 is hydrogen; R 8 is methyl or ethyl; 7 and R 8 and may together form an optionally substituted 5- or 6-membered heterocycle, such as the compounds of the formula: [ka] In the formula, R 1 is selected from hydrogen, halide, and alkoxy; R 2 is selected from 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 aromatic ring system, Ar may be optionally substituted with one or two substituents; L is selected from a direct bond and methylene; and R 1 is selected from hydrogen, halide, and alkoxy; A is a direct bond, -CH 2 - and -CH 2 CH 2 -; E is selected from CH(R 6 )NR 7 R 8 ;R 6 is selected from hydrogen, methyl, halogenated methyl, and ethyl; R 7 is hydrogen; R 8 is methyl or ethyl; 7 and R 8 and together may form an optionally substituted 5- or 6-membered heterocyclic ring. Optionally, the compound of formula (1) may further comprise R 7 and R 8 and form an optionally substituted 5- or 6-membered heterocycle; R 1 is hydrogen; A is CH 2 CH 2 R 7 and R 8 and may form an optionally substituted 5- or 6-membered heterocycle, R 1 is hydrogen and A is CH 2 CH 2 For example, the following compounds are provided: [ka] [ka] [ka] Optionally, such compounds of formula (1) may be additionally characterized by specifying that A is a direct bond, for example, to provide a compound of the formula: [ka] [ka] and [ka] Optionally, such compounds of formula (1) may be modified by adding R 1 is not hydrogen, but R 7 is hydrogen and R 8 is methyl or ethyl. [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 of formula (1) [ka] and pharma- ceutically acceptable salts thereof, wherein Ar is a 9- or 10-membered bicyclic aromatic ring system, Ar is optionally substituted with 1, 2, or 3 substituents; L is selected from a direct bond and methylene; and R 1 However, hydrogen, halides, C1 -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 -E is selected from -C(O)-R 2 ;R 2 is selected from methyl, ethyl, and phenyl. For example, the disclosure provides compounds of the formula: [ka] wherein Ar is a 9- or 10-membered bicyclic 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, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, and C 1 -C 6 alkoxy; A is selected from -CH 2 CH 2 - and E is -C(O)-R 2 ;R 2 is phenyl, including compounds of the formula: [ka] wherein Ar is a 9- or 10-membered bicyclic aromatic ring system, Ar is optionally substituted with 1, 2 or 3 substituents; L is selected from a direct bond and methylene; R 1 But, C 1 -C 6 Alkoxy, especially methoxy; A is -CH 2 CH 2 - and E is -C(O)-R 2 ;R 2 is phenyl, including compounds of the formula: [ka] In the formula, R 1 is a hydrogen, halide, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, and C 1 -C 6 alkoxy. [ka]

[0068] In one embodiment, the compounds of the present disclosure have halide substitution on the central aromatic ring, i.e., R 1 is a halide. For example, the present disclosure provides a compound of formula (1). 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 bicyclic aromatic ring system, Ar is optionally substituted with 1, 2, or 3 substituents; L is selected from a direct bond and methylene; and R 1 is a halide; A is a direct bond, -CH 2 - and -CH 2 CH 2 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 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 But, C 1 -C 7 Alkyl, C 1 -C 7haloalkyl (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; 7 and R 8 and may together form an optionally substituted 5- or 6-membered heterocycle. For example, the disclosure provides compounds 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; R 4 is selected from hydrogen, alkyl, and phenyl; R 5 But, C 1 -C 7 Alkyl, C 1 -C 7 Selected from haloalkyl (eg, trifluoromethyl), phenyl, and substituted phenyl; for example: [ka] and [ka]

[0069] The compounds of the present disclosure are also intended to include all pharma- ceutically acceptable compounds of formula (1) and subsets thereof that are isotopically labeled by replacing one or more atoms with atoms having a different atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, e.g., 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, 123 I, and 125 I, and the like. These radiolabeled compounds can be useful to aid in determining or measuring the effectiveness of compounds, for example, by characterizing the site or mode of action, or binding affinity to a pharmacologically important site of action. Certain isotopically labeled compounds of the present disclosure, for example, compounds incorporating a radioisotope, are useful in drug and / or substrate tissue distribution studies. The radioisotope tritium, i.e. 3 H, and carbon 14, i.e. 14 C is particularly useful for this purpose due to its ease of incorporation and the availability of detection means. 2 Substitution with heavier isotopes, such as H, may confer certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and therefore may be preferable in some circumstances. 11 C. 18 F, 1 O. 13Substitution with positron emitting isotopes, such as N, can be useful in Positron Emission Topography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of the present disclosure can generally be prepared by conventional techniques known to those of skill in the art, or by processes analogous to those described in the preparations and examples below, using appropriately isotopically labeled reagents in place of conventionally used non-labeled reagents.

[0070] In many cases, crystallization produces a solvate of the disclosed compound. As used herein, the term "solvate" refers to an aggregate that contains one or more molecules of the disclosed compound and one or more solvent molecules. The solvent may be water, in which case the solvate may be a hydrate. Alternatively, the solvent may be an organic solvent. Thus, the disclosed compound may exist as a hydrate, including monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate, and corresponding solvate forms. The disclosed compound may be a true solvate, but in other cases, the disclosed compound may simply retain water adventitiously or may be a mixture of water and adventitious solvent.

[0071] Some of the specific compounds of the present disclosure are shown in Table 1, where the specific compounds are identified by compound number (No.), compound structure, and compound name, 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 disclosure provides the listed compounds of Table 1, alone or in any combination, as well as pharma- ceutically acceptable enantiomers, diastereomers, salts, or solvates thereof.

[0074] The disclosure also provides compounds of formula (I) as described above and in the following numbered exemplary embodiments. 1) 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 is optionally substituted with 1, 2 or 3 substituents; L is selected from a direct bond and methylene; R 1 However, hydrogen, halides, C1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 3 -C 6 Cycloalkoxy, and C 3 -C 6 Cycloalkyl-substituted 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 Selected from; 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; 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, Ar is unsubstituted or is a halide, C1 - 6 Alkyl;-SC 1 - 6 Alkyl; -OC 1 - 6 Alkyl; and -SO 2 -C 1 - 6 substituted with one substituent selected from alkyl; L is a direct bond and -CH 2 - (methylene); R 1 However, hydrogen, halides, C 1 - 6 Alkyl, C 1 - 6 Haloalkyl, and C 1 - 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 Selected from; R 2 is selected from methyl, ethyl, and phenyl; R 3 is H; R 4 But hydrogen, C 1 -C 7 alkyl, and phenyl; R 5 But, C 1 - 7 Alkyl, C 1 - 7 selected from haloalkyl, phenyl, and halophenyl; R 6 is selected from hydrogen, methyl, halogenated methyl, and ethyl; R 7 is hydrogen and R 8is hydrogen, methyl, or ethyl; or R 7 and R 8 Together, C 1 -C 6 The compound of embodiment 1, or a pharma- ceutically acceptable enantiomer, diastereomer, salt, or solvate thereof, which forms a 5- or 6-membered heterocyclic ring, optionally substituted with substituents selected from alkyl and carboxylic acid. 3) The compound of embodiment 1 or 2, wherein Ar is 1,3-benzothiazole. 4) The compound of embodiment 1 or 2, wherein Ar is selected from 1,3-benzoxazole and quinoline. 5) Ar is -S-CH 3 The compound of embodiment 1 or 2, substituted with one substituent which is 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 C 1 -C 6 The compound of embodiment 1 or 2, wherein said compound is alkoxy. 9) The compound of embodiment 1 or 2, wherein A is a direct bond. 10) A is -CH 2 CH 2 -. 11) E is -C(OR 3 )R 4 R 5 3. The compound of embodiment 1 or 2, wherein 12) The compound according to embodiment 1 or 2 as a non-racemic mixture of enantiomers of the compound of formula (1). 13) 1-[4-(1,3-benzothiazol-2-yloxy)-3-methoxyphenyl]-3-(trifluoromethyl)pentan-3-ol; 1-{3-methoxy-4-[(4-methylsulfanyl-1,3-benzothiazol-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-methylbutan-2-ol; 1,1,1-trifluoro-2-{4-[(2-methyl-1,3-benzothiazol-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-benzothiazol-2-yl]oxy}phenyl)pentan-3-ol; and The compound according to embodiment 1 or 2, selected from 1-(4-{[4-(methylsulfanyl)-1,3-benzothiazol-2-yl]oxy}phenyl)-3-(trifluoromethyl)pentan-3-ol.

[0075] In addition to the compounds listed above, the disclosure also provides the following numbered exemplary embodiments relating to pharmaceutical compositions and methods of therapeutic use of the compounds: 14) A pharmaceutical composition comprising the compound according to Embodiment 1 or 2, or a pharmaceutically acceptable enantiomer, salt or solvate thereof, and at least one pharmaceutically acceptable carrier, diluent, excipient and / or adjuvant. 15) The pharmaceutical composition according to Embodiment 14, which is in the form of an eye drop. 16) A method for treating an inflammatory disease or inflammatory condition, comprising administering to a subject in need thereof an effective amount of the compound according to Embodiment 1 or 2 or the composition according to Embodiment 14 or 15. 17) The method according to Embodiment 16, wherein the inflammatory disease or the inflammatory condition is an eye inflammatory disease or an eye inflammatory condition, respectively. 18) A method for treating a respiratory disease or condition, comprising administering to a subject in need thereof a therapeutically effective amount of the compound according to Embodiment 1 or 2 or the composition according to Embodiment 14. 19) A method for treating a neurodegenerative disease, condition or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of the compound according to Embodiment 1 or 2 or the composition according to Embodiment 14.

[0076] As described above, the compounds and compositions of the present disclosure, for example, the compound of formula (1), may be used in a treatment method. The treatment method may provide either a therapeutically effective amount of the compound / composition or a prophylactically effective amount of the compound / composition. For example, when a patient undergoes surgery, the compound of the present disclosure may be administered before the surgery to minimize post-surgical trauma. Exemplary treatment methods in which the compounds and compositions can be used are listed below.

[0077] In one aspect, the present disclosure provides a method for treating inflammation, comprising administering to a subject in need thereof a therapeutically effective amount of the above compound.

[0078] In another aspect, the present disclosure provides a method for the prophylactic treatment of inflammation, comprising administering to a subject in need thereof a prophylactically effective amount of the above-described compound. For example, in conditions such as asthma and allergies, the compounds described herein may be administered prophylactically to prevent the condition from worsening or flaring.

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

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

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

[0082] In another aspect, the disclosure provides a method for treating allergic disorders, including but not limited to, skin and eye indications, comprising administering to a subject in need thereof a therapeutically effective amount of the compound described above.

[0083] In another aspect, the disclosure provides a method for treating allergic disorders, including but not limited to indications of the skin and eyes, comprising administering to a subject in need thereof a prophylactically effective amount of a compound as described above.

[0084] In another aspect, the present disclosure provides a method for treating conjunctivitis.For example, the present disclosure provides a method for treating allergic conjunctivitis, comprising administering a therapeutically effective amount of the above-mentioned compound to a subject in need thereof.Instead of allergic conjunctivitis, conjunctivitis may occur secondary to infection, such as viral or bacterial infection.Alternatively, conjunctivitis may occur due to the use of contact lenses.

[0085] In another aspect, the present disclosure provides a method for treating conjunctivitis.For example, the present disclosure provides a method for treating allergic conjunctivitis, comprising administering a prophylactically effective amount of the above-mentioned compound to a subject in need thereof.Instead of allergic conjunctivitis, conjunctivitis may occur secondary to infection, such as viral or bacterial infection.Alternatively, conjunctivitis may occur due to the use of contact lenses.

[0086] In another aspect, the disclosure provides a method of treating uveitis comprising administering to a subject in need thereof a therapeutically effective amount of a compound as described above. The subject may be suffering from, for example, anterior, intermediate, posterior or panuveitis.

[0087] In another aspect, the disclosure provides a method for treating uveitis comprising administering to a subject in need thereof a prophylactically effective amount of a compound as described above. The subject may be suffering from, for example, anterior, intermediate, posterior or panuveitis.

[0088] In another aspect, the disclosure provides a method of treating atopic dermatitis, comprising administering to a subject in need thereof a therapeutically effective amount of the compound described above.

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

[0090] In another aspect, the disclosure provides a method of treating psoriasis, comprising administering to a subject in need thereof a therapeutically effective amount of the compound described above.

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

[0092] In another aspect, the disclosure provides a method of treating acne vulgaris, comprising administering to a subject in need thereof a therapeutically effective amount of the compound described above.

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

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

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

[0096] In another aspect, the disclosure provides a method of treating bronchopulmonary dysplasia, comprising administering to a subject in need thereof a therapeutically effective amount of the compound described above.

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

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

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

[0100] In another aspect, the present disclosure provides a method for treating pulmonary insufficiency, comprising administering a therapeutically effective amount of the compound described above to a subject in need thereof. The subject may suffer from, for example, occupational pulmonary insufficiency associated with environmental pollutants / hazards.

[0101] In another aspect, the present disclosure provides a method for treating pulmonary insufficiency, comprising administering to a subject in need thereof a prophylactically effective amount of the compound described above. The subject may suffer from, for example, occupational pulmonary insufficiency associated with environmental pollutants / hazards.

[0102] In another aspect, the disclosure provides a method for treating pulmonary hypertension (eg, neonatal) comprising administering to a subject in need thereof a therapeutically effective amount of the compound described above.

[0103] In another aspect, the disclosure provides a method of treating pulmonary hypertension (eg, neonatal) comprising administering to a subject in need thereof a prophylactically effective amount of a compound as described above.

[0104] In another aspect, the present disclosure provides a method for treating cancer, comprising administering a therapeutically effective amount of the above-mentioned compound to a subject in need thereof.Examples of cancer include solid tumors.Cancer can be, for example, breast cancer or ovarian cancer.The method can provide a clinical presentation of metastasis of existing cancer.

[0105] In another aspect, the disclosure provides a method of treating a neuroinflammatory disease, comprising administering to a subject in need thereof a therapeutically effective amount of the compound described above.

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

[0107] In one aspect, the disclosure provides a method of treating a neurodegenerative disease, condition, or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of the compound described above.

[0108] In another aspect, the disclosure provides a method of treating multiple sclerosis, comprising administering to a subject in need thereof a therapeutically effective amount of the compound described above.

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

[0110] In another aspect, the disclosure provides a method for treating cystic fibrosis, comprising administering to a subject in need thereof a therapeutically effective amount of the compound described above. Cystic fibrosis can be associated with pulmonary inflammation (e.g., in a non-infectious stage).

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

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

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

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

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

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

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

[0118] In another aspect, the disclosure provides a method for treating inflammation associated with ocular surgery, comprising administering to a subject in need thereof a therapeutically effective amount of the compound described above.

[0119] In another aspect, the disclosure provides a method of treating inflammation associated with ocular surgery, comprising administering to a subject in need thereof a prophylactically effective amount of the compound described above.

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

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

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

[0123] In another aspect, the disclosure provides a method of treating arthritis, comprising administering to a subject in need thereof a therapeutically effective amount of a compound as described above. Arthritis can, for example, be in the early stages of development.

[0124] In another aspect, the disclosure provides a method of treating arthritis, comprising administering to a subject in need thereof a prophylactically effective amount of a compound as described above. The arthritis can be, for example, in the early stages.

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

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

[0127] In another aspect, the disclosure provides a method of treating allograft rejection, comprising administering to a subject in need thereof a therapeutically effective amount of the compound described above.

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

[0129] In another aspect, the disclosure provides a method for treating trauma (eg, cerebral ischemia), comprising administering to a subject in need thereof a therapeutically effective amount of the compound described above.

[0130] In another aspect, the disclosure provides a method of treating diabetic retinopathy, comprising administering to a subject in need thereof a therapeutically effective amount of the compound described above.

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

[0132] In another aspect, the disclosure provides a method of treating diabetic macular edema, comprising administering to a subject in need thereof a therapeutically effective amount of the compound described above.

[0133] As described elsewhere herein, the present disclosure provides compositions that can be used to treat the above medical conditions. These compositions may optionally contain one or more active agents other than the compound of formula (1), which, for example, supplement, enhance, or complement the activity of the compound of formula (1).

[0134] In one aspect, the present disclosure provides a pharmaceutical composition comprising the compound of formula (1).In other words, the compound of the present disclosure can be formulated into a pharmaceutical composition.In one aspect, the present disclosure provides a pharmaceutical composition comprising the compound of formula (1) above and at least one pharma- ceutically acceptable carrier, excipient, or diluent.

[0135] The compounds of the present disclosure can be formulated for administration for use in human or veterinary medicine, as well as other bioactive agents, such as anti-inflammatory agents. Such methods are known in the art and include administration by any route known in the art, such as subcutaneous, inhalation, oral, topical or parenteral. Similarly, the compositions can be administered in intravenous (bolus or infusion), intraperitoneal, topical (e.g., intraocular, eye drops), subcutaneous, intramuscular, or transdermal (e.g., patch) form, using any form known to those skilled in the art of pharmaceuticals.

[0136] The composition is formulated in a form suitable for the desired route of administration. In other words, the form of the composition is selected, in part, based on the desired route of administration. The composition may take any form known in the art, including, but not limited to, tablets, capsules, powders, granules, sweetened tablets, creams, or liquid formulations. Brief examples include oral administration, which is facilitated by solid (e.g., tablets, capsules, gelcaps, powders, granules, sweetened tablets, delayed-release solid forms, slow or sustained release solid forms, encapsulated solid forms) or liquid (e.g., liquid gelcaps, suspensions, solutions, syrups, elixirs, liposomal solutions) compositions. As another example, the composition may take the form of a liquid (e.g., nebulizer solution / suspension) or solid (e.g., metered dose inhaler, dry powder inhaler) for administration by inhalation. As yet another example, the composition may be delivered via an implant, including ocular implants (e.g., slow-release or sustained-release depot solid form matrices) and subcutaneous implants (e.g., slow-release or sustained-release depot pumps). If the healthcare provider deems intravenous administration appropriate, the composition may be a liquid (e.g., solution, nanosuspension, liposomal suspension, micelle suspension) or a solid (e.g., lyophilized product) that can be reconstituted to provide a liquid form. If the desired route of administration is intramuscular administration, the composition may be a liquid (e.g., solution, nanosuspension, liposomal suspension, micelle suspension, oil formulation) or a solid (e.g., lyophilized product) that can be reconstituted to provide a liquid form. Intramuscular administration may also be achieved by a suitably placed implant. The composition may be administered subcutaneously, in which case the same forms suitable for intramuscular administration may be used for subcutaneous administration. Intraperitoneal administration can be used to deliver a compound or composition of the present disclosure, where suitable forms for intraperitoneal administration are liquid (e.g., solutions, nanosuspensions, liposomal suspensions, micellar suspensions), or solids (lyophilized products for reconstitution).Another suitable route of administration is intrathecal, where the formulation may be liquid (e.g., solution, nanosuspension, liposomal suspension, micelle suspension) or solid (e.g., lyophilized product for reconstitution). The composition may be administered topically to the skin of a subject when the appropriate form is liquid (e.g., solution, suspension, emulsion, cream, gel, ointment, with carrier). Topical administration may also be used for delivery to the eye of a subject when the appropriate form is liquid (e.g., solution, suspension, liposomal suspension, emulsion, ointment) or solid (e.g., coated implant, implant pump). For transdermal delivery, the compounds of the present disclosure may be formulated into a transdermal patch, which may release the compound to the subject gradually or sustained. Rectal administration may be performed using a suppository, such as a solid / semi-solid wax oil based on a solid / solid wax or solid oil; or a semi-solid liquid or gel composition. The present disclosure also provides a lyophilized formulation for reconstitution with a suitable vehicle. Lyophilization refers to the removal of liquid components of a formulation to a solid phase. Lyophilization can be performed by techniques known in the art, such as by subjecting the composition to vacuum and moderate heating to evaporate the liquid components. Thus, the active ingredient is typically administered in admixture with carrier materials selected for the intended form of administration, such as oral tablets, capsules (either solid, semi-solid or liquid filled), powders for constitution, oral gels, elixirs, dispersible granules, syrups, liquids, solutions and suspensions, including sterile solutions or suspensions for topical administration. In one embodiment, the composition is administered to the eye of a subject, and the composition may take the form of a liquid composition that can be dropped onto the surface of the eye. Each of these compositions 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 may be in the form of tablets, dispersible granules, and capsules.In these compositions, the active drug component may be combined with any pharma-ceutically acceptable non-toxic oral inert carrier.Examples include lactose, mannitol, sucrose and other sugars, starch and cellulose; and inorganic compounds such as calcium sulfate, magnesium stearate, and dicalcium phosphate.As another example, solids may be formulated as suppositories.When preparing suppositories, first melt a low melting wax such as a mixture of fatty acid glycerides or cocoa butter, and stir the active component to disperse it homogeneously.The homogeneous molten mixture is then poured into convenient size molds and allowed to cool and solidify.

[0138] Other components that can be included in solid formulations include conventional binders, lubricants, disintegrating agents and coloring agents.Suitable binders include starch, gelatin, natural sugar, corn sweetener, natural and synthetic gums such as gum arabic, sodium alginate, carboxymethylcellulose, polyethylene glycol, and wax.Lubricants for use in dosage forms include boric acid, sodium benzoate, sodium acetate, sodium chloride, etc.Disintegrating agents include starch, methylcellulose, guar gum, etc.Sweeteners and flavoring agents and preservatives can also be included in the dosage form for oral administration as necessary. Conventional excipients that may be included in the composition include binders such as, for example, acacia, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone; fillers such as, for example, lactose, sugar, corn starch, calcium phosphate, sorbitol, glycine; tableting lubricants such as magnesium stearate, talc, polyethylene glycol, silica, disintegrating agents such as potato starch; or acceptable wetting agents such as, for example, sodium lauryl sulfate.

[0139] The solid form preparation may contain about 0.5 to about 100% by weight of the active ingredient including the compound of formula (1).

[0140] The compounds of the present disclosure can be formulated into liquid pharmaceutical compositions. Liquid form formulations include solutions, suspensions and emulsions. Liquid compositions include at least one substance that is liquid at room temperature, where water is one such material. Other liquid substances that can be included in liquid compositions include propylene glycol parenteral injection. Depending on the formulation, liquid compositions can be administered, for example, orally, topically, parenterally, intravenously and intranasally.

[0141] Oral liquid preparations can be in the form of, for example, aqueous or oily suspension, solution, emulsion, syrup or elixir, or can be provided as a dry product for reconstitution with water or other suitable vehicle before use.Such liquid preparations can contain conventional additives, for example, suspending agent such as sorbitol, methylcellulose, glucose syrup, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, hydrogenated edible oils and fats; emulsifiers such as lecithin, sorbitan monooleate, acacia; non-aqueous vehicle (can contain edible oils), for example, oily ester such as almond oil, glycerin, propylene glycol, ethyl alcohol; preservatives such as methyl or propyl p-hydroxybenzoate or sorbic acid; and if necessary, conventional flavorings or colorings.

[0142] Liquid forms of pharmaceutical compositions may be formulated with the intention that the compositions are delivered by topical administration, for example as eye drops. Eye drop formulations may optionally contain one or more of cyclodextrin, methylcellulose, and EDTA, in addition to the compound of formula (1), which may be present in the eye drop at a concentration of about 0.1% to 1% (by weight) in the eye drop solution. Eye drop formulations may optionally contain hydroxypropyl-β-cyclodextrin in the range of 1% to 40% and hydroxypropylmethylcellulose in the range of 0.1% to 1%. In exemplary embodiments, eye drop formulations may optionally contain 10%, 20%, or 30% by weight of hydroxypropyl-β-cyclodextrin. The amount, timing and mode of delivery of the compounds of the present disclosure, whether administration is prophylactic or therapeutic, are routinely adjusted for each individual based on factors such as the weight, age, sex, and condition of the individual, the condition being induced or treated, and other factors known to affect drug delivery, absorption, pharmacokinetics, including half-life, and efficacy. In exemplary embodiments, the range of ocular doses suitable for use is about 0.01 mg to 1000 mg per day, or about 0.05 mg to about 1000 mg per day, about 0.1 mg to about 1000 mg per day, about 0.5 mg to about 1000 mg per day, about 2 mg to about 1000 mg per day, about 0.05 mg to about 500 mg per day, 0.10 mg to 300 mg per day, 0.10 mg to 100 mg per day, 75 mg to 450 mg per day, 150 mg to 400 mg per day, about 300 mg to about 1500 mg per day, about 600 to about 1500 mg per day. Topical doses are typically 0.5 mg to 3 mg per day, where the 3 mg / day dose may be administered in the form of six applications of 0.5 mg each. A typical oral dosage is 100 mg to 3500 mg, taken twice per day.

[0143] For parenteral administration, a fluid unit dose form is prepared using the compound and a sterile vehicle (typically water). Depending on the vehicle and concentration used, the compound of formula (1) can be suspended or dissolved in the vehicle or other suitable solvent. In preparing a solution, the compound can be dissolved in water for injection, sterilized by filtration, and then filled into a suitable vial or ampoule and sealed. To improve stability, the composition may be frozen after filling into a vial and the water removed under vacuum. The lyophilized powder may then be sealed in a vial and an accompanying vial of water for injection may be provided to reconstitute the liquid before use. Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilization cannot be achieved by filtration. A surfactant or wetting agent is included in the composition to distribute the compound uniformly. Parenteral solutions and suspensions may be used for topical administration.

[0144] Liquid form preparations may contain about 0.05 to about 95% by weight of the active ingredient, including the compound of formula (1).

[0145] The pharmaceutical compositions of the present disclosure include solid form preparations that are intended to be converted immediately before use to produce liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions, and emulsions.

[0146] Furthermore, the composition of the present disclosure may be formulated into sustained release form, so that any one or more components or active ingredients are released at a controlled rate to optimize therapeutic effect.Suitable dosage forms for sustained release include layered tablets with multiple layers with different disintegration rates, or controlled release polymer matrices impregnated with active ingredients and formed into tablet form, or capsules containing such impregnated or encapsulated porous polymer matrices.

[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 preparation containing 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 ingredient.

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

[0151] The compound of formula I can be administered orally in a dosage range of 0.001 to 150 mg / kg of mammalian (e.g., human) body weight per day, in single or divided doses. One preferred dosage range is 0.01 to 100 mg / kg of body weight per day, orally, in single or divided doses. Another preferred dosage range is 0.1 to 50 mg / kg of body weight per day, orally, in single or divided doses. For oral administration, the composition may be provided in the form of a tablet or capsule containing 1.0 to 500 milligrams of active ingredient, in particular 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, and 500 milligrams of active ingredient, in order to adjust the dosage according to the condition of the subject to be treated. The specific dose level and frequency of administration for any particular subject may vary and will depend on a variety of factors, including the activity of the particular compound employed, the metabolic stability and length of action of that compound, age, body weight, general health, sex, diet, form and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host being treated.

[0152] The compound of formula I may be administered in a dosage range of 0.01 to 50 mg per day in one or more eye drops as a 0.1% to 2% by weight solution of the compound, either in a single dose or in divided doses. One preferred dosage range is 0.1 to 10 mg per day in one or more eye drops as a 0.1% to 2% by weight solution of the compound, either in a single dose or in divided doses. Another preferred dosage range is 0.3 to 3 mg per day in one or more eye drops as a 0.1% to 2% by weight solution of the compound, either in a single dose or in divided doses. The composition may be provided in the form of eye drops containing 0.01 to 3 milligrams of active ingredient per drop, particularly 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, and 3 milligrams of active ingredient, to adjust the dosage according to the condition of the subject being treated. The specific dose level and frequency of administration for any particular subject may vary and will depend on a variety of factors, including the activity of the particular compound employed, the metabolic stability and length of action of that compound, age, body weight, general health, sex, diet, form and time of administration, rate of excretion, drug combination, severity of the particular condition, and the host being treated.

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

[0154] The amount and frequency of administration of the compound of formula (1) will be regulated according to the judgment of the attending clinician, taking into consideration factors such as the age, condition and size of the subject, and the severity of the condition being treated. The compositions of the present disclosure may further comprise one or more additional therapeutic agents.

[0155] Compositions including one or more compounds of formula (1) may include additional active agents that, for example, can enhance, complement, or supplement the biological activity of the compounds of formula (1).

[0156] Compounds of formula (1) may be prepared in a variety of ways from known or readily prepared starting materials. Suitable synthetic methods are easily illustrated by designating the Ar group in formula (1) as Ar1 and the central benzene ring in formula (1) as Ar2, as shown below. [ka]

[0157] Some exemplary methods for preparing representative compounds of formula (1) are illustrated in the following schemes and examples. Alternative synthetic routes and similar structures useful for preparing compounds of formula (1) will be apparent to those skilled in the art of organic chemical synthesis. In some cases, the final product may be further manipulated, for example, by manipulation of substituents. These manipulations may include, but are not limited to, reduction, oxidation, alkylation, acylation, and hydrolysis reactions known to those skilled in the art, as further described herein below.

[0158] One consideration in preparing compounds of formula (1) is the identity of the group linking the Ar1 and Ar2 groups. This linking group is represented in formula (1) by -LO-, where O is oxygen and L is any combination of a direct bond and a methylene (e.g., -CH 2 -) is selected from the group O or CH 2 It may take the shape of O.

[0159] These linking groups can be formed by reacting a compound containing an appropriately substituted Ar1 with a compound containing Ar2 under suitable reaction conditions. For example, L is CH 2 Compounds of formula (1), wherein R1 A substituted phenol (both represented by hydroxyl group substituted Ar2) is reacted with an X-substituted benzyl compound (having an Ar1 group) where X is a leaving group. This reaction can be carried out in the presence of a suitable base, such as potassium carbonate in combination with sodium iodide, 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 more generally represents a 9- or 10-membered bicyclic aromatic ring system, represented by Ar, which may be optionally substituted with 1, 2 or 3 substituents. For example, Ar1 may be quinoline (introduced using 2(chloromethyl)quinoline hydrochloride as an alkylating agent), naphthylene (introduced using 2(chloromethyl)naphthylene as an alkylating agent), or benzothiazole (introduced using 2(chloromethyl)benzothiazole as an alkylating agent), as well as many other options. Also in scheme 1, Ar2 is shown substituted with (A / E), where this designation is intended to collectively represent eAE as described herein, which is a precursor that may be converted to an AE group after coupling of the Ar1 and Ar2 rings.

[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 shown as a benzothiazole compound with a leaving group X at the 2-position, although other Ar1 groups may be used in place of benzothiazole in this synthesis. Some examples include 2-chlorobenzoxazole, 2-chloroquinoline, and 3-chloroisoquinoline. Also in Scheme 2, Ar2 is shown as being substituted with (A / E), where this designation is intended to collectively represent -AE as specified herein, which is a precursor that may be converted to an AE group after coupling of the Ar1 and Ar2 rings. The Ar1 and Ar2 containing compounds can be combined under suitable reaction conditions, for example, in the presence of a suitable base such as potassium carbonate and in a suitable solvent such as dimethylformamide, to provide the corresponding coupled compound of formula (1).

[0163] In scheme 2, Ar2 contains a hydroxyl group and Ar1 contains a leaving group X. Alternatively, compounds of the present disclosure may be prepared by a process in which the relative configuration of the hydroxyl group and the leaving group is reversed between Ar1 and Ar2, as shown in scheme 3. In scheme 3, a phenolic compound having Ar1 is reacted with a fluoroaryl compound having Ar2 under suitable reaction conditions, for example, in the presence of a suitable base such as potassium carbonate, and in the presence of a suitable solvent such as dimethylsulfoxide, to obtain a compound of formula (1). The reaction process shown in scheme 3 [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 more generally represents a 9- or 10-membered bicyclic aromatic ring system, designated Ar, which may be optionally substituted with one, two or three substituents. Also in Scheme 3, Ar2 is shown as substituted with (A / E), where this designation is intended to collectively represent -AE as specified herein, which 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 is favored when A / E is an electron-withdrawing group, such as a carbonyl, in which case (F)(R 1 The (A / E) substituent in Ar2(A / E) is a precursor of -AE.

[0165] The compounds of the present disclosure may have various 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, Grignard reaction, trifluoromethylation, reduction, reductive amination of aromatic / aliphatic ketones, reductive amination of aliphatic ketones, and reductive amination of aromatic ketones, any one or more of which may be optionally used in the preparation of compounds of formula (1). These methods may also be modified according to the knowledge of those skilled in the art. The following describes general procedures exemplified in certain specific examples below.

[0166] Benzylation: phenolic compound (1 equiv.), benzyl bromide (1.5 equiv.), and K in acetone. 2 CO 3 (1.5 equiv.) is stirred at reflux for 3-18 h. The reaction mixture is allowed to cool to room temperature and filtered. The filter cake is washed with acetone and the solvent is removed under reduced pressure. The material is purified by flash chromatography.

[0167] Condensation: aldehyde (1 equiv.) in MeOH / H 2The 20O solution is stirred and a ketone (4-8 equiv.) is added followed by 85% by weight KOH (4-6 equiv.). The mixture is stirred at room temperature for 7 days or at reflux for 3 hours. The reaction is quenched with 1-5% dilute HCl or water and extracted with EtOAc. The organic layer is washed with water and dried (MgSO 4 ), filter and remove the solvent under reduced pressure. This material is triturated with ether / hexanes or purified by flash chromatography.

[0168] Hydrogenolysis: A mixture of unsaturated ketone (1 equivalent) and 10% Pd / C (10% by weight) in methanol or ethyl acetate (with or without catalytic amounts of acetic acid) is stirred under hydrogen for 1-18 hours. The reaction is filtered and the solvent is removed under reduced pressure. The material is purified by flash chromatography. O-Alkylation: Phenol compound (1 equivalent), alkylating agent (1 to 1.5 equivalents), K 2 CO 3 (1-1.5 equiv.), and dimethylformamide (DMF) are heated under argon at 90-150 °C for approximately 16-24 h and allowed to cool to room temperature. The reaction is diluted with water and ethyl acetate. The organic layer is washed with 5% aqueous sodium hydroxide and / or water, washed with brine, dried (MgSO 4 ), filter and remove the solvent under reduced pressure. This material is purified by flash column chromatography.

[0169] Grignard Reaction: Grignard reactions can be carried out using alkyl or aryl magnesium bromides, either commercially available or freshly prepared as follows: (1) Preparation of Grignard Reagent. Freshly ground magnesium turnings (2.5-5.0 equiv.) are placed in THF under argon (1.5 mmol Mg per mL of tetrahydrofuran (THF)), 1,2 dibromoethane (50 μL) is added, stirred for 5 min, followed by ethylmagnesium bromide (50 μL, 3.0 M in ether) and stirring for an additional 5 min. The alkyl or aryl bromide (1 equiv.) is then added and the reaction is cooled for 1 h by occasional immersion in a water bath. (2) Grignard Addition. To a 0°C solution of the ketone (1 equiv.) in dry THF, the Grignard reagent (typically 1-2 equiv.) is added under argon. The reaction is stirred for approximately 1 h and quenched with water and / or 5% dilute HCl. Extract with water, wash with brine and dry (MgSO 4 ), filter and remove the solvent under reduced pressure. This material is purified by flash column chromatography.

[0170] Trifluoromethylation: A solution of ketone (1 equiv.) in dry DMF is added with CF 3 -TMS (1.5 to 2 equivalents) was added, followed by a catalytic amount of K 2 CO 3 (approximately 0.1-0.3 equiv.) and stir under argon for the desired time, typically 18-72 h. Dilute the reaction with water and wash with brine. Dry the organic layer (MgSO 4 ), filter and remove the solvent under vacuum. Add concentrated HCl to the residue in methanol and stir the solution until the reaction is complete (approximately 1 h). Dilute the reaction with ethyl acetate and extract with brine. Dry the organic layer (MgSO 4 ), filter and remove the solvent under reduced pressure. This material is purified by flash column chromatography.

[0171] Reduction: A solution of the ketone (1 eq.) in methanol under argon is treated with sodium borohydride (2 eq.) and stirred for 1 h. Optionally, cerium(III) chloride heptahydrate (1 eq.) can be added. The reaction is diluted with water and 5% dilute HCl and extracted once with ethyl acetate. The organic layer is washed with brine, dried (MgSO 4 ), filter and remove the solvent under reduced pressure. This material is purified by flash column chromatography.

[0172] Reductive amination of aromatic / aliphatic ketones: A solution of aromatic or aliphatic ketone (1 equiv.) in THF was stirred at room temperature under argon and treated with Ti(OiPr). 4 (1.2 equiv.) is added followed by the amine (1.4 equiv.). The reaction mixture is stirred at reflux for approximately 18 hours and then allowed to cool to room temperature. NaBH 4 (1.5 equiv.) is added and the reaction mixture is stirred for 1-3 h. The reaction is then quenched with water and extracted three times with ethyl acetate (EtOAc). The organic layer is washed with water and dried (MgSO 4 ), filter and remove the solvent under reduced pressure. This material is purified by flash chromatography.

[0173] Reductive amination of aliphatic ketones: A solution of aliphatic ketone (1 equiv.) in DCE was stirred at room temperature under argon, and the amine (1.2 equiv.) was added, followed by NaBH(OAc). 3 (2 equiv.) and acetic acid (AcOH, 2 equiv.), and optionally 4A molecular sieves are added. The reaction mixture is stirred for 18 h, quenched with water, and diluted with CH 2 Cl 2 The organic layer was dried (MgSO 4 ), filter and remove the solvent under reduced pressure. This material is purified by flash chromatography.

[0174] Reductive amination of aromatic aldehydes: A solution of aromatic aldehyde (1 equiv.) in DCE was stirred at room temperature under argon, and the amine (1.2 equiv.) was added, followed by NaBH(OAc) 3(1.5 equiv.) was added. The reaction mixture was stirred for 18 h, quenched with water and CH 2 Cl 2 The organic layer was dried (MgSO 4 ), filter and remove the solvent under reduced pressure. This material is purified by flash chromatography.

[0175] Reductive amination to generate primary and secondary alkylamines: NH 4 A mixture of Cl (1 eq.) in methanol (MeOH) was stirred at room temperature under argon and then diluted with Et 3 N (1 equiv.), ketone (1 equiv.), and Ti(OiPr) 4 (approximately 2 equiv.) is added. The reaction mixture is stirred for 18 h. An additional 1 equiv. of Et 3 N and NH 4 After addition of Cl, the reaction mixture can be stirred for 3 hours. 4 (1.2 eq.) is added and the reaction mixture is stirred for 1.5 h. 4 (0.5 equiv.) may be optionally added and the reaction mixture is stirred for 1 h. The reaction is quenched with water and extracted with EtOAc. {The organic layer is washed with water and treated with anhydrous MgSO 4 Dry at 40° C., filter and evaporate the solvent under reduced pressure. The residue is purified by flash chromatography.

[0176] Reductive amination trifluoromethylation: A solution of ketone or aldehyde (1 eq.) in THF is stirred at room temperature under argon, and 4A molecular sieves and ethylamine (approximately 6 eq.) are added. The mixture is stirred at room temperature under argon for 3 hours, filtered, and the solvent is removed under reduced pressure. The residue is diluted with KHF. 2 (about 0.75 equiv.), acetonitrile, and DMF are added and the mixture is cooled to 0° C. under argon. TFA (about 1.3 equiv.) is added. The mixture is stirred for 5 min, then CF 3 Add TMS (approximately 1.5 equiv.). Remove the cooling bath and stir the reaction mixture for approximately 18 h. Add saturated Na 2 CO 3The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water and then with anhydrous MgSO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography. MeOH was added to the residue, followed by NaBH 4 (0.67 equiv.) is added and the mixture is stirred under argon for 30 min. The reaction is quenched with water and extracted with EtOAc. The organic layer is washed with anhydrous Na 2 SO 4 Dry at 40° C., filter and evaporate the solvent under reduced pressure. The residue is purified by flash chromatography.

[0177] In each case, standard reactions may be monitored by thin layer chromatography (TLC) to determine the progress of the reaction. The temperature and / or reaction time may be increased or decreased to increase the conversion of starting materials to products or to decrease the formation of by-products.

[0178] The following examples and formulations further illustrate and exemplify the compounds of the present disclosure and the methods for preparing said compounds. It should be understood that the scope of the following examples and formulations does not limit the scope of the present invention in any way. The starting materials and various reactants utilized or referenced in the examples can be obtained from commercial suppliers or can be easily 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. = aqueous solution; BnBr = benzyl bromide; CF 3 TMS=TMSCF 3 =CF 3 -Si(CH 3 )3;Conc.=concentrated;DCE=1,2-dichloroethane;DMF=N,N-dimethylformamide;DMSO=dimethylsulfoxide;dppp=1,3-bis(diphenylphosphino)propane;EtOAc=ethyl acetate;Et 2O = diethyl ether; h = hours; Hex = hexane; MeCN = acetonitrile; MeOH = methanol; mL = milliliters; TBS = tert-butyldimethylsilyl; TBSCl = tert-butyldimethylsilyl chloride; TFA = trifluoroacetic acid, i.e., CF 3 -COOH; TLC = thin layer chromatography; wt% = weight percent, for example, 5% EtOAc / Hex refers to 5 parts by weight (eg, grams) of ethyl acetate combined with 95 parts by weight (eg, grams) of hexane.

[0180] In the following examples, molecules with a single chiral center are present as a racemic mixture unless otherwise stated. Molecules with two or more chiral centers are present as a racemic mixture of diastereomers unless otherwise stated. A single enantiomer / diastereomer can be obtained by methods known to those skilled in the art. For example, enantiomers can be separated by HPLC using a chiral column such as a ChiralPak® column (Daicel Corporation, Japan), for example, a ChiralPak AD™ column with a size of 4.6×250 mm and particles with an average diameter of 5 μm. The mobile phase can be a mixture of isopropanol / hexane, where the i-PrOH / hexane ratio can be changed to change the degree of separation of the enantiomers. An exemplary flow rate is 1 mL / min, an exemplary injection volume is 50 μL, and run at a sample concentration of 5 mg / mL. Similarly, the run time can be adjusted to increase the degree of resolution, an exemplary run time is 11 minutes.

[0181] For selected compounds prepared according to the following examples: 1 H NMR (nuclear magnetic resonance spectroscopy) was performed 1 1 H NMR spectra were obtained and are characterized as provided in Table 6 following the examples. EXAMPLES

[0182] [Example 1] (Preparation of Compound 101) 4-Hydroxy-3-methoxybenzaldehyde (10 g, 65.8 mmol) in MeOH (85 mL) / H 2 A stirred solution of 2-butanone (50 mL, 556 mmol) was added followed by KOH (15 g, 214 mmol). The mixture was stirred at room temperature for 7 days. The reaction was quenched with water and dilute HCl (15 mL concentrated HCl / 200 mL water) and extracted with EtOAc (300 mL). The organic layer was washed with water (2 x 150 mL) and diluted with anhydrous MgSO. 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and the solvent was removed under reduced pressure. 2 Triturate with 1:3 O / Hex, filter, and 2 Washing with O / Hex (1:3) gave 5.2 g of 1-(4-hydroxy-3-methoxyphenyl)pent-1-en-1-en-3-one as a yellow solid.

[0183] A solution of 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) was added. The reaction mixture was stirred under hydrogen for 1 h, after which an additional 10% Pd / C (250 mg) was added. Stirring under hydrogen was continued for an additional 2 h, after which the mixture was filtered. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (25% EtOAc / Hex) to give 2.45 g of 1-(4-hydroxy-3-methoxyphenyl)pentan-3-one as a colorless oil. [ka]

[0184] 1-(4-hydroxy-3-methoxyphenyl)pentan-3-one (1.5 g, 7.20 mmol), K 2 CO 3 (1.00 g, 7.24 mmol), and 2-chlorobenzothiazole (1.00 mL, 7.68 mmol) were mixed in DMF (15 mL) and stirred at 100° C. under argon for 18 h.

[0185] The mixture was allowed to cool to room temperature, diluted with EtOAc (30 mL), washed with water (30 mL), brine (2 x 30 mL), and anhydrous MgSO 4 The mixture was dried at 40° C., filtered and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (25% EtOAc / Hex) to give 2.10 g of compound 101 as a yellow solid.

[0186] [Example 2] [ka] 1-(4-hydroxy-3-methoxyphenyl)pentan-3-one (170 mg, 0.82 mmol, prepared as described in Example 1) in DMF (3 mL), K 2 CO 3 A mixture of 2-chlorobenzoxazole (100 μL, 0.87 mmol) and 2-chlorobenzoxazole (130 mg, 0.94 mmol) was stirred at 83 °C for 16 h in a sealed tube. The mixture was allowed to cool to room temperature and water (10 mL), brine (10 mL) and EtOAc (20 mL) were added. The layers were separated and the aqueous layer was extracted with EtOAc (10 mL) and the combined organic layers were washed with brine (10 mL) and anhydrous MgSO 4 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 130 mg of compound 102 as an oil.

[0187] [Example 3] [ka] Compound 101 (1.50 g, 3.98 mmol) and K 2 CO 3 (60 mg, 0.434 mmol) in DMF (20 mL) was stirred under argon and CF 3 TMS (1.30 mL, 8.80 mmol) was added. The reaction mixture was stirred at room temperature for 18 h, then diluted with EtOAc (40 mL) and water (10 mL) and washed with brine (3 x 40 mL). The organic layer was washed with anhydrous MgSO 4The mixture was dried over 1000 ml, 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 removed under reduced pressure and the residue was added to EtOAc (40 mL) and washed with water (2 x 40 mL) and then with brine (40 mL). The organic layer was washed with anhydrous MgSO 4 The mixture was dried at 40° C., filtered and 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, 4.05 mmol, prepared as in Example 1) and K 2 CO 3 (56 mg, 0.405 mmol) in DMF (8 mL) was stirred under argon while cooling to 0° C. in an ice bath, and CF 3 TMS (1.50 mL, 10.2 mmol) was added dropwise. The cooling bath was removed and the reaction 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). The organic layer was washed with anhydrous MgSO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and the solvent was removed under reduced pressure. The residue was added to MeOH (8 mL), and concentrated HCl (0.6 mL) was added and stirred for 1 h. The mixture was diluted with EtOAc (40 mL) and washed with water (2 x 25 mL). The organic layer was washed with anhydrous MgSO 4 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 938 mg of 4-[3-hydroxy-3-(trifluoromethyl)pentyl]-2-methoxyphenol as a yellow oil. [ka]

[0189] 4-[3-hydroxy-3-(trifluoromethyl)pentyl]-2-methoxyphenol (150 mg, 0.539 mmol), K 2 CO 3 (223 mg, 1.61 mmol), and 2-chloro-4-(methylthio)-benzothiazole (145 mg, 0.672 mmol) in DMF (3 mL) were 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), washed with water (2 x 25 mL), and diluted with anhydrous MgSO 4 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 230 mg of compound 104 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™, 5 μm particle size, 4.6×250 mm; Mobile phase: 20% i-PrOH / Hexane; Flow rate: 1 mL / min; Injection volume: 50 μL; Sample concentration: 5 mg / m; Run time: 11 min; Number of injections: 16. Each peak was manually collected, and the fractions containing each enantiomer were combined and the solvent was removed under reduced pressure to give 2 mg of each enantiomer.

[0191] The purity of each combined fraction was tested by HPLC at 1 mg / mL using the same column, mobile phase, and run time as above. Enantiomer 1 had a retention time of 7.633 minutes and was greater than 99% pure. 1 H NMR (400 MHz, CDCl 3 ): δ 7.44-7.39 (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 had a retention time of 9.368 min and was >99% pure. 1 H NMR (400 MHz, 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] The procedure of Example 4 for producing compound 104 was followed, except that 2-chloro-1-methyl-1H-1,3-benzodiazole (112 mg, 0.672 mmol) was used instead of 2-chloro-4-(methylthio)-benzothiazole and the mixture was stirred at 150° C. for 64 hours to give 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, 5 μm particle size, 4.6×250 mm column size; mobile phase: 90% i-PrOH / Hexane; flow rate: 1 mL / min; injection volume: 50 μL; sample concentration: 1 mg / m; run time: 17 min; number of injections: 1. Each peak was manually collected to obtain two fractions. 50 μL samples from each fraction were re-injected separately 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.

[0194] [Example 6] [ka] Following the procedure of Example 4 to produce compound 104, except using 2-chloro-6-(methylsulfonyl)benzothiazole (167 mg, 0.674 mmol) instead of 2-chloro-4-(methylthio)-benzothiazole, 145 mg of compound 106 was obtained as a yellowish oil that solidified at room temperature.

[0195] [Example 7] [ka] The procedure of Example 4 for producing compound 104 was followed, except that 2-chloro-4,6-difluorobenzothiazole (138 mg, 0.671 mmol) was used instead of 2-chloro-4-(methylthio)-benzothiazole to give 231 mg of compound 107 as a colorless oil.

[0196] [Example 8] [ka] 4-[3-hydroxy-3-(trifluoromethyl)pentyl]-2-methoxyphenol (124 mg, 0.45 mmol), prepared as in Example 4, 2 CO 3 (100 mg, 0.71 mmol), and 2-chloro-6-fluoro-benzothiazole (166 mg, 0.88 mmol) were mixed in DMF (2.5 mL) and stirred at 100° C. for 18 h in a sealed tube. The mixture was allowed to cool to room temperature and was diluted with EtOAc (15 mL) and H 2 The mixture was diluted with 200 mL of EtOAc (15 mL). The layers were separated and the aqueous layer was extracted with EtOAc (20 mL). The organic layers were combined, washed with brine and diluted with anhydrous MgSO. 4 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 83 mg of compound 108 as an oil.

[0197] [Example 9] [ka] 4-[3-hydroxy-3-(trifluoromethyl)pentyl]-2-methoxyphenol (124 mg, 0.45 mmol), prepared as in Example 4, 2 CO 3(87 mg, 0.62 mmol) and 2-chloro-6-methoxy-benzothiazole (180 mg, 0.90 mmol) were mixed in DMF (2.5 mL) and stirred at 100 °C for 18 h in a sealed tube. The mixture was allowed to cool to room temperature and then diluted with EtOAc (15 mL) and H 2 The mixture was diluted with 200 mL of EtOAc (15 mL). The layers were separated and the aqueous layer was extracted with EtOAc (20 mL). The organic layers were combined, washed with brine and diluted with anhydrous MgSO. 4 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 118 mg of compound 109 as a colorless oil.

[0198] [Example 10] [ka] Under argon, a solution of vanillylacetone (15, 250 mg, 1.29 mmol) in DMF (3 mL) was treated with 2-chlorobenzothiazole (168 μl, 1.29 mmol) and K 2 CO 3 (267 mg, 1.93 mmol) was added. The reaction mixture was stirred in a sealed tube at 100 °C for 18 h. The reaction mixture was diluted with water and ethyl acetate. The organic layer was then washed with 5% aqueous sodium hydroxide, water, and brine. The organic layer was dried (MgSO 4 ), filtered, and the solvent was removed under reduced pressure. Flash column chromatography on silica gel (30% EtOAc / Hex) afforded 321 mg of compound 110 as a white solid.

[0199] [Example 11] [ka] Compound 110 (150 mg, 0.458 mmol) and K 2 CO 3 (6 mg, 0.043 mmol) in DMF (2 mL) was stirred at 0° C. under argon and CF 3TMS (135 μL, 0.914 mmol) was added dropwise. The cooling bath was removed and the reaction mixture was stirred at room temperature for 18 h. The mixture was diluted with EtOAc (35 mL) and washed with water (25 mL). The organic layer was washed with anhydrous Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and the solvent was removed under reduced pressure. The residue was added to MeOH (0.3 mL) along with concentrated HCl (0.3 mL) and stirred for 1 h. The mixture was diluted with EtOAc (35 mL) and washed with water (25 mL). The organic layer was washed with anhydrous Na 2 SO 4 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 100 mg of compound 111 as a colorless oil.

[0200] [Example 12] Preparation of Compound 112 3,4-Dihydroxybenzaldehyde (0.50 g, 3.62 mmol), benzyl bromide (0.43 mL, 3.62 mmol), K 2 CO 3 (0.75 g, 5.43 mmol), NaI (0.054 g, 0.36 mmol), and acetone (10 mL) were combined and stirred under argon at reflux. The reaction mixture was stirred at reflux for 18 h, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (20% EtOAc / Hex) to give 483 mg of 4-(benzyloxy)-3-hydroxy-benzaldehyde as a white solid.

[0201] 4-(Benzyloxy)-3-hydroxybenzaldehyde (1.50 g, 6.57 mmol) in MeOH (14 mL) / H 2 The solution was stirred in 1.4 mL of HO and 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 h. The reaction mixture was allowed to cool naturally, then quenched with 10% dilute HCl (60 mL) and extracted with EtOAc (2 x 50 mL). The organic layer was washed with water (2 x 150 mL) and diluted with anhydrous MgSO. 4The mixture was dried at 40° C., filtered and the solvent was removed under reduced pressure. The residue was triturated with diethyl ether to give 0.648 g of 1-[4-(benzyloxy)-3-hydroxyphenyl]pent-1-en-3-one as an off-white solid.

[0202] 1-[4-(benzyloxy)-3-hydroxyphenyl]pent-1-en-3-one (0.5 g, 1.77 mmol), K 2 CO 3 (0.734 g, 5.31 mmol), and 2-bromopropane (0.830 mL, 8.84 mmol) were mixed 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), washed with water (3 x 25 mL), and diluted with anhydrous MgSO 4 Drying at 40° C., 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 as an off-white solid.

[0203] A stirred solution of 1-[4-(benzyloxy)-3-(propan-2-yloxy)phenyl]pent-1-en-3-one (0.400 g, 1.23 mmol) in EtOAc (12 mL) and AcOH (600 μL) was added with 10% Pd / C (0.040 g). The reaction mixture was stirred under hydrogen for 5 h and then filtered. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (30% EtOAc / Hex) to give 0.193 g of 1-[4-(hydroxy)-3-(propan-2-yloxy)phenyl]pentan-3-one. [ka]

[0204] 1-[4-(hydroxy)-3-(propan-2-yloxy)phenyl]pentan-3-one (236 mg, 1.00 mmol), K 2 CO 3(140 mg, 1.01 mmol), and 2-chlorobenzothiazole (0.145 mL, 1.1 mmol) were mixed 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), washed with water (2 x 25 mL), and diluted with anhydrous MgSO 4 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 245 mg of compound 112 as a yellow oil.

[0205] [Example 13] Preparation of Compound 113 1-[4-(benzyloxy)-3-hydroxyphenyl]pent-1-en-3-one (0.5 g, 1.77 mmol, prepared as in Example 12), K 2 CO 3 (0.367 g, 2.66 mmol), and cyclopentyl bromide (0.290 mL, 2.70 mmol) were mixed 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), washed with water (3 x 25 mL), and diluted with anhydrous MgSO 4 The mixture was dried at 40° C., filtered and the solvent was removed under reduced pressure. The residue was triturated with ether / Hex to give 0.454 g of 1-[4-(benzyloxy)-3-(cyclopentyloxy)phenyl]pent-1-en-3-one as an off-white solid.

[0206] A solution of 1-[4-(benzyloxy)-3-(cyclopentyloxy)phenyl]pent-1-en-3-one (0.450 g, 1.28 mmol) in EtOAc (14 mL) and AcOH (700 μL) was stirred and 10% Pd / C (0.045 g) was added. The reaction mixture was stirred under hydrogen for 23 h and then filtered. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (30% EtOAc / Hex) to give 0.193 g of 1-[4-(hydroxy)-3-(cyclopentyloxy)phenyl]pentan-3-one. [ka]

[0207] 1-[4-(hydroxy)-3-(cyclopentyloxy)phenyl]pentan-3-one (0.234 mg, 0.892 mmol), K 2 CO 3 (0.124 g, 0.897 mmol), and 2-chlorobenzothiazole (0.130 mL, 0.998 mmol) were mixed 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), washed with water (2 x 25 mL), and diluted with anhydrous MgSO 4 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 0.245 g of compound 113 as a yellow oil.

[0208] [Example 14] Preparation of Compound 114 1-[4-(benzyloxy)-3-hydroxyphenyl]pent-1-en-3-one (0.5 g, 1.77 mmol, prepared as in Example 12), K 2 CO 3 (0.367 g, 2.66 mmol), and (bromomethyl)cyclopropane (0.260 mL, 2.68 mmol) were mixed 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), washed with water (3 x 25 mL), and diluted with anhydrous MgSO 4 The mixture was dried at 40° C., filtered and the solvent was removed under reduced pressure. The residue was triturated with ether / Hex to give 0.440 g of 1-[4-(benzyloxy)-3-(cyclopropylmethoxy)phenyl]pent-1-en-3-one as a solid.

[0209] A solution of 1-[4-(benzyloxy)-3-(cyclopropylmethoxy)phenyl]pent-1-en-3-one (0.440 g, 1.31 mmol) in EtOAc (14 mL) and AcOH (700 μL) was stirred and 10% Pd / C (0.044 g) was added. The reaction mixture was stirred under hydrogen for 18 h and then filtered. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (20% EtOAc / Hex) to give 0.244 g of 1-[4-(hydroxy)-3-(cyclopropylmethoxy)phenyl]pentan-3-one. [ka]

[0210] 1-[4-(hydroxy)-3-(cyclopropylmethoxy)phenyl]pentan-3-one (0.244 mg, 0.983 mmol), K 2 CO 3 (0.136 g, 0.984 mmol), and 2-chlorobenzothiazole (0.140 mL, 1.08 mmol) were mixed in DMF (4 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), washed with water (3 x 25 mL), and diluted with anhydrous MgSO 4 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 0.285 g of compound 114 as a yellow oil.

[0211] [Example 15] [ka] Compound 112 (235 mg, 0.636 mmol) and K 2 CO 3 (9 mg, 0.065 mmol) in DMF (3 mL) was stirred under argon and CF 3TMS (0.120 mL, 0.813 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 18 h. The mixture was partitioned between EtOAc (35 mL) and water (25 mL), and the aqueous layer was extracted with EtOAc (35 mL). The combined organic layer was washed with anhydrous MgSO 4 The organic layer was dried over 1000 ml of ethyl acetate, filtered and concentrated. The residue was added to MeOH (6 mL), concentrated HCl (0.1 mg) was added and the mixture was stirred for 1 h. The mixture was diluted with EtOAc (35 mL) and washed with water (2 x 25 mL). The organic layer was washed with anhydrous MgSO 4 The residue was purified by flash chromatography (20% EtOAc / Hex) to give 203 mg of compound 115 as a white solid.

[0212] [Example 16] [ka] Compound 113 (0.125 g, 0.316 mmol) and K 2 CO 3 (0.004 g, 0.029 mmol) in DMF (1.5 mL) was stirred under argon and CF 3 TMS (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 washed with anhydrous MgSO 4 The mixture was dried over 1000 ml, filtered and concentrated. The residue was added to 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 (2 x 25 mL). The organic layer was washed with anhydrous MgSO 4 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 K2 CO 3 (0.006 g, 0.043 mmol) in DMF (2 mL) was stirred under argon and CF 3 TMS (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 washed with anhydrous MgSO 4 The mixture was dried over 1000 ml, filtered and concentrated. The residue was added to 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 (2 x 25 mL). The organic layer was washed with anhydrous MgSO 4 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), K 2 CO 3 A solution of 2-chloro-4-(methylthio)-benzothiazole (160 mg, 1.16 mmol) (160 mg, 1.16 mmol) and 2-chloro-4-(methylthio)-benzothiazole (208 mg, 0.964 mmol) in DMF (3 mL) was 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), washed with water (2 x 25 mL), and diluted with anhydrous MgSO 4 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 214 mg of compound 118 as a yellow oil.

[0215] [Example 19] [ka] Compound 118 (214 mg, 0.599 mmol) and K 2 CO 3(8 mg, 0.058 mmol) in DMF (3 mL) was stirred under argon and CF 3 TMS (133 μL, 0.901 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 washed with anhydrous MgSO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and the solvent was removed under reduced pressure. The residue was added to MeOH (3 mL), concentrated HCl (0.3 mg) was added, and the mixture was stirred for 1 h. The mixture was diluted with EtOAc (35 mL) and washed with water (2 x 25 mL). The organic layer was washed with anhydrous MgSO 4 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 95 mg of compound 119 as a yellow oil.

[0216] [Example 20] Preparation of Compound 120 3-Ethoxy-4-hydroxybenzaldehyde (2 g, 12 mmol) in MeOH (17 mL) / H 2 To a stirred solution of 2H2O (2.5 mL) was added 2-butanone (10 mL, 111 mmol) followed by KOH (3 g, 45 mmol). The mixture was stirred at room temperature for 18 h. The reaction was quenched with 10% dilute HCl and extracted with EtOAc (3 x 30 mL). The organic layer was washed with brine (30 mL) and diluted with anhydrous MgSO 4 The mixture was dried at 40° C., filtered and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography (20% EtOAc / Hex) to give 2.09 g of 1-(3-ethoxy-4-hydroxyphenyl)pent-1-en-3-one as a solid.

[0217] A solution of 1-(3-ethoxy-4-hydroxyphenyl)pent-1-en-3-one (1.73 g, 7.86 mmol) in EtOAc (15 mL) was stirred and 10% Pd / C (150 mg) was added. The reaction mixture was stirred under hydrogen for 1.5 h and then filtered. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (40% EtOAc / Hex) to give 0.720 g of 1-(3-ethoxy-4-hydroxyphenyl)pentan-3-one. [ka]

[0218] 1-(3-ethoxy-4-hydroxyphenyl)pentan-3-one (0.430 g, 1.94 mmol), K 2 CO 3 (0.266 g, 1.92 mmol), and 2-chlorobenzothiazole (0.277 mL, 2.13 mmol) were mixed in DMF (3 mL) and stirred under argon at 120 °C for 18 h. The mixture was allowed to cool to room temperature, diluted with EtOAc (20 mL), washed with water (2 x 15 mL), brine (15 mL), and anhydrous MgSO 4 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 0.492 g of compound 120 as an oil.

[0219] [Example 21] [ka] Compound 120 (0.100 g, 0.281 mmol) and K 2 CO 3 (0.018 g) in DMF (2 mL) was stirred under argon and CF 3 TMS (0.100 mL, 0.678 mmol) was added. The reaction mixture was stirred at room temperature for 18 h, then diluted with EtOAc (15 mL) and washed with brine (2 x 15 mL). The organic layer was washed with anhydrous MgSO 4The mixture was dried over 1000 ml, filtered, and the solvent was removed under reduced pressure. The residue was added to MeOH (5 mL), and concentrated HCl (0.250 mL) was added and stirred for 1 h. The solvent was removed under reduced pressure, and the residue was added to EtOAc (20 mL) and washed with brine (2 x 20 mL). The organic layer was washed with anhydrous MgSO 4 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 72 mg of compound 121 as a colorless oil.

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

[0221] [Example 23] [ka] Following the general Grignard addition procedure, compound 110 (0.150 g, 0.46 mmol, prepared as in Example 10), THF (3.0 mL), and phenylmagnesium bromide (0.30 mL, 3M / Et 2 Compound 123 was prepared from 1H) by flash column chromatography on silica gel (30% EtOAc / Hex) to give 0.204 g of compound 123 as an oil.

[0222] [Example 24] [ka] Following the general Grignard addition procedure, compound 110 (0.100 g, 0.305 mmol, prepared as in Example 10), THF (1.0 mL), and methylmagnesium bromide (0.20 mL, 3M / Et 2 Compound 124 was prepared from 1H) by flash column chromatography on silica gel (50-70% EtOAc / Hex) to give 0.115 g of compound 124 as an oil.

[0223] [Example 25] [ka] A solution of vanillylacetone (0.621 g, 3.20 mmol) in DMF (8 mL) was treated under argon with 2-chlorobenzoxazole (300 μL, 2.62 mmol) and K 2 CO 3 (0.511 g, 3.70 mmol) was added. The reaction mixture was stirred at 140 °C for 18 h. The reaction mixture was diluted with water and EtOAc. The organic layer was then washed with 5% aqueous NaOH (2 x 30 mL) and brine (20 mL). The organic layer was diluted with MgSO 4 The mixture was dried at 40° C., filtered and the solvent was removed under reduced pressure. Flash column chromatography on silica gel (40% EtOAc / Hex) afforded 0.483 mg of compound 125 as a white solid.

[0224] [Example 26] [ka] Following the general Grignard addition procedure, a mixture of compound 125 (0.095 g, 0.305 mmol) in THF (3.0 mL) was placed in a flask, stirred and cooled in an ice-water bath, and methylmagnesium bromide (0.180 mL, 3M / Et 2 O) was added. The ice bath was removed and the mixture was stirred at room temperature for 70 min. 2O (5 mL) was added, followed by EtOAc (10 mL) and brine (5 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine and washed with MgSO. 4 The crude mixture was dried at 40° C., filtered, and the filtrate was concentrated. Flash column chromatography on silica gel (30% EtOAc / Hex) afforded 0.090 g of compound 126 as a colorless oil.

[0225] [Example 27] [ka] Following the general Grignard addition procedure, a mixture of compound 125 (0.101 g, 0.325 mmol) in THF (3.0 mL) was placed in a flask, stirred and cooled in an ice-water bath, and methylmagnesium bromide (0.180 mL, 3M / Et 2 O) was added. The ice bath was removed and the mixture was stirred at room temperature for 70 min. 2 O (5 mL) was added, followed by EtOAc (10 mL) and brine (5 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine and washed with MgSO. 4 The crude mixture was dried at 40° C., filtered, and the filtrate was concentrated. Flash column chromatography on silica gel (40% EtOAc / Hex) afforded 0.066 g of compound 127 as a colorless oil.

[0226] [Example 28] [ka] Preparation of Compound 128 Following the general Grignard addition procedure, a mixture of compound 125 (0.097 g, 0.314 mmol) in THF (3.0 mL) was placed in a flask, stirred and cooled in an ice-water bath, and methylmagnesium bromide (0.180 mL, 3M / Et 2 O) was added. The ice bath was removed and the mixture was stirred at room temperature for 70 min. 2O (5 mL) was added, followed by EtOAc (10 mL) and brine (5 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine and washed with MgSO. 4 The crude mixture was dried at 40° C., filtered, and the filtrate was concentrated. Flash column chromatography on silica gel (40% EtOAc / Hex) afforded 0.080 g of compound 128 as a colorless oil.

[0227] [Example 29] Preparation of Compound 129 Dissolve 3-ethoxy-4-hydroxybenzaldehyde (2.00 g, 12.0 mmol) and 85% KOH (3.00 g, 45.4 mmol) in MeOH (17 mL) / H 2 A solution of 2H2O (2.5 mL) was stirred and acetophenone (4.5 mL, 38.6 mmol) was added. The mixture was stirred at room temperature with monitoring by TLC. After completion, standard workup and concentration gave a residue which was used in the next step without further purification. The residue was dissolved in EtOAc (30 mL), 10% Pd / C (320 mg) was added and the mixture was stirred under hydrogen for 1 h. The mixture was filtered and the filtrate was concentrated to give 1.2 g of 3-(3-ethoxy-4-hydroxyphenyl)-1-phenylpropan-1-one as a yellow solid. [ka] A solution of 3-(3-ethoxy-4-hydroxyphenyl)-1-phenylpropan-1-one (1.20 g, 4.44 mmol) in DMF (8 mL) was treated under argon with 2-chlorobenzothiazole (682 μL, 5.26 mmol) and K 2 CO 3 (0.648 g, 4.70 mmol) was added. The reaction mixture was stirred at 140° C. for 18 h. The reaction mixture was diluted with water and ethyl acetate. The organic layer was then washed with brine. The organic layer was dried (MgSO 4), filtered, and evaporated under reduced pressure, followed by flash column chromatography on silica gel (15-20% EtOAc / Hex) afforded 1.11 g of compound 129 as an oil.

[0228] [Example 30] [ka] Compound 129 (0.200 g, 0.5 mmol) and K 2 CO 3 (0.015 g, 0.11 mmol) in DMF (3 mL) was stirred under argon and CF 3 TMS (0.172 mL, 1.16 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 18 h. 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 and stirred for 1 h. The mixture was diluted with EtOAc (20 mL) and washed with brine (2 x 20 mL). The organic layer was washed with anhydrous MgSO 4 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 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) were dissolved in MeOH (20 mL) / H 2 The mixture in 200 (58 mL) was heated to 60 °C in a sealed tube with stirring and stirred at 60 °C for 4 h. The reaction mixture was allowed to cool to room temperature, quenched with dilute HCl (10 mL concentrated HCl / 100 mL water), and extracted with EtOAc (100 mL). The organic layer was washed with water (2 x 100 mL) and brine (20 mL), and then diluted with anhydrous MgSO. 4The mixture was dried at 40° C., filtered, and the solvent was removed under reduced pressure. 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. 3-(4-Hydroxy-3-methoxyphenyl)-1-phenylprop-2-en-1-one (1.27 g, 4.99 mmol) and 10% Pd / C (139 mg) were dissolved in EtOAc (10 mL) and Et 3 The mixture in N (1.3 mL) was stirred under hydrogen for 2 h, then 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. [ka]

[0230] 3-(4-hydroxy-3-methoxyphenyl)-1-phenylpropan-1-one (768 mg, 3 mmol), K 2 CO 3 (414 mg, 3 mmol), and 2-chlorobenzothiazole (429 μL, 3.2 mmol) were mixed in DMF (5 mL) and heated with stirring to 100 °C and stirred at 100 °C for 18 h. The reaction mixture was allowed to cool to room temperature, diluted with EtOAc (30 mL), washed with brine (3 x 30 mL), and diluted with anhydrous MgSO 4 The mixture was dried at rt, filtered, and the solvent was removed under reduced pressure to give 813 mg of compound 131 as a white solid.

[0231] [Example 32] [ka] Compound 131 (100 mg, 0.257 mmol) and NaBH 4(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 EtOAc (15 mL) and 5% dilute HCl (25 mL) and the aqueous layer was extracted with EtOAc (15 mL). The combined organic layers were washed with brine (2 x 20 mL) and diluted with anhydrous MgSO 4 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 114 mg of compound 132 as a colorless oil.

[0232] [Example 33] [ka] Compound 131 (250 mg, 0.642 mmol) and K 2 CO 3 (18 mg, 0.130 mmol) in DMF (3 mL) was stirred under argon and CF 3 TMS (200 μL, 1.35 mmol) was added. The reaction mixture was stirred at room temperature for 24 h, then diluted with EtOAc (35 mL) and washed with brine (30 mL x 3). The organic layer was washed with anhydrous MgSO 4 The mixture was dried over 500 ml, filtered and the solvent was removed under reduced pressure. The residue was added to MeOH (10 mL) and stirred with concentrated HCl (0.25 mL) for 2 h. The solvent was removed under reduced pressure and the residue was added to EtOAc (30 mL) and washed with water (20 mL x 2) and brine (20 mL) and diluted with anhydrous MgSO 4 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 264 mg of compound 133 as a yellowish oil.

[0233] [Example 34] [ka] A solution of compound 131 (167 mg, 0.429 mmol) in THF (8 mL) was stirred at room temperature under argon and Ti(OiPr) 4(150 μL, 0.507 mmol) was added, followed by pyrrolidine (50 μL, 0.609 mmol). The reaction mixture was stirred under reflux for 16 h and then allowed to cool to room temperature. NaBH 4 (24 mg, 0.634 mmol) was added and the reaction mixture was stirred for 3 h, then quenched with water (25 mL) and extracted with EtOAc (2 x 35 mL). The organic layer was washed with water (35 mL) and concentrated with anhydrous MgSO 4 The residue was purified by flash chromatography (EtOAc / MeOH / Et 3 N, 9:1:0.1) to give 108 mg of compound 134 as a yellow foam.

[0234] [Example 35] [ka] NH 4 Cl (313 mg, 5.85 mmol) was mixed in MeOH (6 mL) and stirred at room temperature under argon, and then diluted with Et 3 N (820 μL, 5.88 mmol), compound 101 obtained in Example 1 (200 mg, 0.586 mmol), and Ti(OiPr) 4 (350 μL, 1.18 mmol) was added. The milky reaction mixture was stirred for 18 h. Et 3 N (820 μL) and NH 4 Cl (313 mg) was added and the reaction mixture was stirred for 3 h. 4 (45 mg) was added and the reaction mixture was stirred for 1.5 h. 4 (23 mg) was added and the reaction mixture was stirred for 1 h. The reaction was quenched with water (35 mL) and extracted with EtOAc (40 mL). The organic layer was washed with water (2 x 35 mL) and diluted with anhydrous MgSO 4 The residue was purified by flash chromatography (10% MeOH / EtOAc, then EtOAc / MeOH / Et 3 N, 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 added to toluene (70 mL) at 0 °C under argon and NaBH 4 (1.00 g, 26.4 mmol) was added portionwise over 30 min. The cooling bath was removed and the reaction mixture was stirred for 1 h, filtered, and the insoluble material was washed with ether and dried to give 3.19 g of NaBH(OAc). 3 obtained.

[0236] A mixture of compound 101 (150 mg, 0.439 mmol, prepared as in Example 1) in DCE (3 mL) was stirred at room temperature under argon and then diluted with 4 Å molecular sieve powder (150 mg), AcOH (100 μL), morpholine (50 μL, 0.578 mmol), and NaBH(OAc) prepared as above. 3 (190 mg, 0.896 mmol) was added. The reaction mixture was stirred for 18 h. An additional amount of morpholine (50 μL) was added and stirring was continued for 2 h. The reaction mixture was diluted with saturated NaHCO 3 The reaction was quenched by adding aqueous solution (25 mL) and CH 2 Cl 2 The combined organic layer was extracted with anhydrous MgSO 4 The residue was purified by flash chromatography (EtOAc / MeOH / Et 3 N, 9:1:0.1) to give 30 mg of a colorless oil. 2 Cl 2 (3 mL) and stirred with 1.25 M HCl in MeOH (100 μL) for 1 h. The solvent was removed under reduced pressure to give 30 mg of the hydrochloride salt of compound 136 as a white foam.

[0237] [Example 37] [ka] Vanillin (250 mg, 1.64 mmol), K 2 CO 3 (341 mg, 2.47 mmol), and 2-chlorobenzothiazole (260 μL, 2.00 mmol) were mixed in DMF (5 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), washed with water (3 x 25 mL), and diluted with anhydrous MgSO 4 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 407 mg of 4-(1,3-benzothiazol-2-yloxy)-3-methoxybenzaldehyde as a white solid. [ka]

[0238] 4-(1,3-benzothiazol-2-yloxy)-3-methoxybenzaldehyde (200 mg, 0.701 mmol) and K 2 CO 3 (10 mg, 0.072 mmol) in DMF (3 mL) was stirred under argon and CF 3 TMS (155 μL, 1.05 mmol) was added. The reaction mixture was stirred at room temperature for 42 h, then diluted with EtOAc (40 mL) and washed with water (2 x 25 mL). The organic layer was washed with anhydrous MgSO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and the solvent was removed under reduced pressure. 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 washed with water (2 x 25 mL). The organic layer was washed with anhydrous MgSO 4 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 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 Na 2 SO 4 A mixture of (1g) was stirred at room temperature under argon and ethylamine (2.0M / THF solution, 2.0mL, 4.0mmol) was added. The reaction mixture was stirred for 18 hours and then filtered to remove solids. The solvent was removed under reduced pressure to give a yellowish oil. The oil and KHF 2 (51 mg, 0.653 mmol) was added to MeCN (3 mL) and DMF (203 μL, 2.62 mmol) under argon at 0° C. and TFA (84 μL, 1.10 mmol) was added. The mixture was stirred for 5 min and CF 3 TMS (194 μL, 1.31 mmol) was added. The cooling bath was removed and the reaction mixture was stirred for 18 h. The mixture was diluted with saturated Na 2 CO 3 The mixture was diluted with aqueous solution (40 mL) and extracted with EtOAc (40 mL). The organic layer was washed with water (2 x 25 mL) and washed with anhydrous MgSO. 4 The mixture was dried at 40° C., filtered and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (15% EtOAc / Hex) to give 61 mg of compound 138 as an off-white solid.

[0240] [Example 39] [ka] Vanillin (150 mg, 0.985 mmol), K 2 CO 3 (204 mg, 1.48 mmol) and 2-chloro-4-(methylthio)benzothiazole (266 mg, 1.23 mmol) were mixed in DMF (3 mL) and stirred in a sealed tube at 100 °C for 18 h, then allowed to cool to room temperature, diluted with EtOAc (35 mL), and washed with 1 M NaOH (25 mL x 2) and water (25 mL). The organic layer was washed with anhydrous MgSO 4The 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 256 mg of 3-methoxy-4-{[4(methylsulfanyl)-1,3-benzothiazol-2-yl]oxy}benzaldehyde as a white solid. [ka]

[0241] 3-Methoxy-4-{[4-(methylsulfanyl)-1,3-benzothiazol-2-yl]oxy}benzaldehyde (256 mg, 0.772 mmol) and K 2 CO 3 (11 mg, 0.080 mmol) in DMF (3 mL) was stirred under argon and CF 3 TMS (171 μL, 1.16 mmol) was added. The reaction mixture was stirred at room temperature for 42 h, then diluted with EtOAc (35 mL) and washed with water (2 x 25 mL). The organic layer was washed with anhydrous MgSO 4 The mixture was dried over 1000 ml of ethyl acetate, 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 h. The mixture was diluted with EtOAc (35 mL) and washed with water (2 x 25 mL). The organic layer was washed with anhydrous MgSO 4 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 192 mg of compound 139 as a yellowish solid.

[0242] [Example 40] [ka] A solution of 4-(4-hydroxyphenyl)-2-butanone (1.5 g, 9.1 mmol) in DMF (8 mL) was treated with 2-chlorobenzothiazole (1.34 mL, 10.3 mmol) and K 2 CO 3(1.27 g, 9.2 mmol) was added. The reaction mixture was stirred at 140 °C for 20 h. After the reaction mixture was allowed to cool naturally to room temperature, it was diluted with water (20 mL) and extracted with EtOAc (3 times with 20 mL). The organic layer was washed with 5% aqueous NaOH solution (2 times with 20 mL) and brine (2 times with 2 mL). The organic layer was dried (MgSO 4 ), filtered, and the solvent was distilled off under reduced pressure. Flash column chromatography on silica gel (30% EtOAc / Hex) gave 1.72 g of 4-[4-(1,3-benzothiazol-2-yloxy)phenyl]butan-2-one. [Chemical formula]

[0243] Following the general procedure for CF 3 TMS addition, compound 140 was prepared from 4-[4-(1,3-benzothiazol-2-yloxy)phenyl]butan-2-one (135 mg, 0.45 mmol), CF 3 TMS (200 μL, 1.35 mmol), K 2 CO 3 (20 mg, 0.14 mmol), and DMF (3 mL). The crude mixture was subjected to flash column chromatography on silica gel (30% EtOAc / Hex) to give 137 mg of compound 140 as an oil.

[0244] [Example 41] [Chemical formula] Following the general procedure for reduction disclosed herein, 4-[4-(1,3-benzothiazol-2-yloxy)phenyl]butan-2-one (113 mg, 0.38 mmol, prepared as in Example 40), NaBH 4 (25 mg, 0.59 mmol), CeCl 3 ·7H 2Compound 141 was prepared from 2H2O (125 mg, 0.34 mmol), and MeOH (3 mL). The crude mixture was subjected to flash column chromatography on silica gel (50% EtOAc / Hex) to give 100 mg of compound 141 as a colorless oil.

[0245] [Example 42] [ka] Following the general Grignard addition procedure, compound 142 was prepared from 4-[4-(1,3-benzothiazol-2-yloxy)phenyl]butan-2-one (128 mg, 0.43 mmol, prepared similarly to Example 40), THF (2.0 mL), and isopropylmagnesium bromide (0.45 mL, 2M / THF). The crude mixture was subjected to flash column chromatography on silica gel (30% EtOAc / Hex) to give 52 mg of compound 142 as an oil.

[0246] [Example 43] [ka] Following the general Grignard addition procedure, 4-[4-(1,3-benzothiazol-2-yloxy)phenyl]butan-2-one (195 mg, 0.66 mmol, prepared as in Example 40), THF (2.0 mL), and ethylmagnesium bromide (0.32 mL, 3M / Et 2 Compound 143 was prepared from 1H) by flash column chromatography on silica gel (30% EtOAc / Hex) to give 168 mg of compound 143.

[0247] [Example 44] [ka] Following the general Grignard addition procedure, 4-[4-(1,3-benzothiazol-2-yloxy)phenyl]butan-2-one (195 mg, 0.66 mmol, prepared as in Example 40), THF (2.0 mL), and phenylmagnesium bromide (0.32 mL, 3M in Et 2 Compound 144 was prepared from 1H) by flash column chromatography on silica gel (30% EtOAc / Hex) to give 222 g of compound 144 as an oil.

[0248] [Example 45] [ka] Following the general Grignard addition procedure, compound 145 was prepared from 4-[4-(1,3-benzothiazol-2-yloxy)phenyl]butan-2-one (220 mg, 0.74 mmol, prepared as in Example 40), THF (9.0 mL), and 4-fluorophenylmagnesium bromide (0.8 mmol). 4-Fluorophenylmagnesium bromide was prepared following the general Grignard reagent preparation procedure using 1-bromo-4-fluorobenzene (0.8 mmol) and magnesium (2.2 mmol). The crude mixture was subjected to flash column chromatography on silica gel (30% EtOAc / Hex) to give 323 mg of compound 145 as a colorless oil.

[0249] [Example 46] [ka] A solution of 4-(4-hydroxyphenyl)-2-butanone (518 mg, 3.2 mmol) in DMF (8 mL) was treated under argon with 2-chlorobenzoxazole (300 μL, 2.6 mmol) and K 2 CO 3(496 mg, 3.6 mmol) was added. The reaction mixture was stirred at 130 °C for 15 h. The reaction mixture was diluted with water (20 mL), brine (20 mL), and EtoAc (30 mL). The layers were separated and the aqueous layer was extracted with EtOAc (20 mL) and the combined organic layers were washed with brine (20 mL). The organic layer was dried (MgSO 4 ), filtered and evaporated under reduced pressure. Flash column chromatography on silica gel (30% EtOAc / Hex) afforded 605 mg of 4-[4-(1,3-benzoxazol-2-yloxy)phenyl]butan-2-one as a colorless oil. [ka]

[0250] Following the general Grignard addition procedure, 4-[4-(1,3-benzoxazol-2-yloxy)phenyl]butan-2-one (101 mg, 0.36 mmol), THF (3.0 mL), and ethylmagnesium bromide (0.150 mL, 3M / Et 2 Compound 146 was prepared from 1H) by flash column chromatography on silica gel (30% EtOAc / Hex) to give 80 mg of compound 146.

[0251] [Example 47] [ka] Following the general Grignard addition procedure, 4-[4-(1,3-benzoxazol-2-yloxy)phenyl]butan-2-one (101 mg, 0.36 mmol, prepared as in Example 46), THF (3.0 mL), and phenylmagnesium bromide (0.2 mL, 3M in Et 2 Compound 147 was prepared from 1H) by flash column chromatography on silica gel (30% EtOAc / Hex) to give 96 mg of compound 83.

[0252] [Example 48] Preparation of Compound 148 4-Hydroxybenzaldehyde (2.0 g, 16.4 mmol) was dissolved in MeOH (17 mL) / H 2 The mixture was mixed in 2.5 mL of HO and 2-butanone (10 mL, 111 mmol) was added followed by KOH (3.0 g, 45.4 mmol). 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), then with brine (1 x 30 mL) and diluted with anhydrous MgSO. 4 The mixture was dried at 40° C., filtered and the solvent was removed under reduced pressure. The residue was triturated with ether / Hex (40 mL, 1:1) to give 1.29 g of 1-(4-hydroxyphenyl)pent-1-en-3-one as a solid.

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

[0254] 1-(4-hydroxyphenyl)pentan-3-one (200 mg, 1.12 mmol), K 2 CO 3 (154 mg, 1.11 mmol), and 2-chlorobenzothiazole (0.160 mL, 1.23 mmol) were mixed in DMF (3 mL) and stirred in a sealed tube at 120 °C for 18 h. The mixture was allowed to cool to room temperature, diluted with EtOAc (10 mL), washed with brine (3 x 10 mL), and diluted with anhydrous MgSO 4The mixture was dried at 40° C., filtered and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (25% EtOAc / Hex) to give 303 mg of compound 148 as an oil.

[0255] [Example 49] Preparation of Compound 149 3-Chloro-4-hydroxybenzaldehyde (0.250 g, 1.60 mmol) in MeOH (2 mL) / H 2 To a stirred solution of 2-butanone (0.60 mL, 6.66 mmol) in 1H2O (0.32 mL) was added followed by KOH (0.422 g, 6.39 mmol). The mixture was stirred at 75 °C for 2 h. The reaction was allowed to cool. EtOH (35 mL) and 10% dilute HCl (25 mL) were added. The layers were separated and the organic layer was washed with water (25 mL) and anhydrous MgSO 4 The mixture was dried at 40° C., filtered and the solvent was removed under reduced pressure, and the residue was purified by flash chromatography (10-20% EtOAc / Hex) to give 0.290 g of 1-(3-chloro-4-hydroxyphenyl)pent-1-en-3-one as a yellow oil.

[0256] A solution of 1-(3-chloro-4-hydroxyphenyl)pent-1-en-3-one (0.690 g, 1.38 mmol) in EtOAc (15 mL) was stirred and 10% Pd / C (29 mg) was added. The reaction mixture was stirred under hydrogen for 1 h. The reaction mixture was filtered. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (20% EtOAc / Hex) to give 0.090 g of 1-(3-chloro-4-hydroxyphenyl)pentan-3-one as a yellow oil. [ka]

[0257] 1-(3-chloro-4-hydroxyphenyl)pentan-3-one (199 mg, 0.936 mmol), K 2 CO 3(194 mg, 1.40 mmol), and 2-chlorobenzothiazole (0.150 mL, 1.15 mmol) were mixed in DMF (4 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), washed with water (3 x 25 mL), and diluted with anhydrous MgSO 4 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 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), K 2 CO 3 (15 mg, 0.108 mmol), and CF 3 TMS (0.100 ml, 0.677 mmol) was added to DMF (2 ml) and mixed at room temperature under argon for 18 h. The mixture was diluted with EtoAc (415 mL) and washed with brine (2 x 15 mL). The organic layer was concentrated under reduced pressure. The residue was added to MeOH (5 mL) and concentrated HCl (0.25 mL) was added and stirred for 1 h. The mixture was diluted with EtOAc (20 mL) and washed with brine (2 x 20 mL). The organic layer was washed with anhydrous MgSO 4 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 111 mg of compound 150 as an oil.

[0259] [Example 51] [ka] Compound 149 (153 mg, 0.442 mmol; prepared as in Example 49), K 2 CO 3 (6 mg, 0.043 mmol), and CF 3A mixture of TMS (0.091 ml, 0.616 mmol) in DMF (2 ml) was mixed at room temperature under argon for 18 h. The mixture was diluted with EtOAc (35 mL) and washed with water (2 x 25 mL). The organic layer was washed with anhydrous MgSO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and the solvent was removed under reduced pressure. The residue was added to MeOH (4.5 mL), and concentrated HCl (0.07 mL) was added and stirred for 1 h. The mixture was diluted with EtOAc (35 mL) and washed with water (2 x 25 mL). The organic layer was washed with anhydrous MgSO 4 The mixture was dried at 40° C., filtered, and the solvent was removed under reduced pressure. The residue was isolated as a colorless oil that solidified upon standing at room temperature 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 K 2 CO 3 (372 mg, 2.69 mmol) was mixed in acetone (5 mL) and stirred under reflux for 16 h, then allowed to cool to room temperature, filtered, and washed with acetone. The filtrate was concentrated under reduced pressure, and the residue was purified by flash chromatography (20% EtOAc / Hex) to give 212 mg of 4-(benzyloxy)-3-fluorobenzaldehyde as a white solid.

[0261] 4-(Benzyloxy)-3-fluorobenzaldehyde (212 mg, 0.921 mmol), 2-butanone (80 μL, 0.888 mmol), and 85% KOH (182 mg, 2.76 mmol) were mixed in MeOH (3 mL) and water (0.6 mL) and stirred at 75° C. for 1 h in a sealed tube. The reaction was allowed to cool and filtered. The solid was washed with water, MeOH, and dried to give 146 mg of 1-[4-(benzyloxy)-3-fluorophenyl]pent-1-en-3-one 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 combined in EtOAc (14 mL) under argon. AcOH (14 drops) was added. The flask was evacuated and filled with hydrogen (balloon). The reaction mixture was stirred for 20 h, then filtered and washed with EtOAc. The filtrate was concentrated under reduced pressure to give 96 mg of 1-[4-(benzyloxy)-3-fluorophenyl]pentan-3-one as a white solid. [ka]

[0263] 1-[4-(benzyloxy)-3-fluorophenyl]pentan-3-one (96 mg, 0.489 mmol), K 2 CO 3 (101 mg, 0.731 mmol), and 2-chlorobenzothiazole (100 μL, 0.768 mmol) were mixed in DMF (2 mL) and stirred at 100 °C for 16 h in a sealed tube. The mixture was allowed to cool to room temperature, diluted with EtOAc (50 mL), and washed with water (3 x 25 mL). The organic layer was washed with anhydrous MgSO 4 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.

[0264] [Example 53] Preparation of Compound 153 4-Hydroxy-3-(trifluoromethyl)benzaldehyde (250 mg, 1.31 mmol), benzyl bromide (230 μL, 1.94 mmol), and K 2 CO 3(272 mg, 1.97 mmol) was mixed in acetone (5 mL) and stirred under reflux for 16 h, then allowed to cool to room temperature, filtered, and washed with acetone. The filtrate was concentrated under reduced pressure, and the residue was purified by flash chromatography (20% EtOAc / Hex) to give 161 mg of 4-(benzyloxy)-3-(trifluoromethyl)benzaldehyde as a white solid.

[0265] 4-(Benzyloxy)-3-(trifluoromethyl)benzaldehyde (161 mg, 0.574 mmol), 2-butanone (50 μL, 0.555 mmol), and 85% KOH (114 mg, 1.73 mmol) were mixed in MeOH (2 mL) and water (0.4 mL) and stirred at 75 °C for 1 h in a sealed tube. The reaction was allowed to cool, diluted with EtOAc (35 mL), and washed with water (2 x 25 mL). The organic layer was removed using anhydrous MgSO 4 The mixture was dried at 40° C., filtered and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (10% EtOAc / Hex) to give 38 mg of 1-[4-(benzyloxy)-3-(trifluoromethyl)phenyl]pent-1-en-3-one as a white solid.

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

[0267] 1-[4-(benzyloxy)-3-(trifluoromethyl)phenyl]pentan-3-one (22 mg, 0.089 mmol), K2 CO 3 (20 mg, 0.145 mmol), and 2-chlorobenzothiazole (20 μL, 0.154 mmol) were mixed in DMF (1 mL) and stirred at 100 °C in a sealed tube for 16 h. The mixture was allowed to cool to room temperature, diluted with EtOAc (50 mL), and washed with water (3 x 25 mL). The organic layer was washed with anhydrous MgSO 4 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 22 mg of compound 153 as a colorless oil.

[0268] [Example 54] [ka] Compound 152 (94 mg, 0.285 mmol) and K 2 CO 3 (4 mg, 0.029 mmol) in DMF (2 mL) was stirred under argon and CF 3 TMS (60 μL, 0.406 mmol) was added. The reaction mixture was stirred at room temperature for 18 h, then diluted with EtOAc (35 mL) and washed with water (2 x 25 mL). The organic layer was washed with anhydrous MgSO 4 The mixture was dried at 40° C., filtered and the solvent was removed under reduced pressure. The residue was taken up in MeOH (3 mL) and stirred with concentrated HCl (0.1 mL) for 1 h. The mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (20% EtOAc / Hex) to give 86 mg of compound 154 as a colorless gum.

[0269] [Example 55] [ka] Compound 153 (22 mg, 0.058 mmol) and K 2 CO 3 (1 mg, 0.007 mmol) in DMF (1 mL) was stirred under argon and CF 3TMS (12 μL, 0.081 mmol) was added. The reaction mixture was stirred at room temperature for 18 h, then diluted with EtOAc (35 mL) and washed with water (2 x 25 mL). The organic layer was washed with anhydrous MgSO 4 The mixture was dried at 40° C., filtered and the solvent was removed under reduced pressure. The residue was added to MeOH (3 mL) and stirred with concentrated HCl (0.1 mL) for 1 h. The mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (20% EtOAc / Hex) to give 18 mg of compound 155 as a colorless oil.

[0270] [Example 56] [ka] A solution of 4-[4-(1,3-benzothiazol-2-yloxy)phenyl]butan-2-one (150 mg, 0.504 mmol), prepared as in Example 40, in THF (3 mL) was stirred at room temperature under argon and the Ti(O i P) 4 (200 μL, 0.676 mmol) was added, followed by pyrrolidine (100 μL, 1.22 mmol). The reaction mixture was stirred under reflux for 18 hours and then allowed to cool to room temperature. NaBH 4 (28 mg, 0.740 mmol) was added, and the reaction mixture was stirred for 1 h. The reaction was then quenched with water (25 mL) and extracted with EtOAc (35 mL). The organic layer was washed with anhydrous MgSO 4 The residue was purified by flash chromatography (EtOAc / MeOH / Et 3 N, 9:1:0.1) to give 60 mg of compound 156 as a yellow oil.

[0271] [Example 57] [ka] A solution of 4-[4-(1,3-benzothiazol-2-yloxy)phenyl]butan-2-one (150 mg, 0.504 mmol) prepared in the same manner as in Example 40 in DCE (3 mL) was stirred at room temperature under argon, and 4A molecular sieve powder (150 mg), L-proline (75 mg, 0.651 mmol), and AcOH (100 μL, 1.75 mmol) were added, followed by NaBH(OAc) 3 (214 mg, 1.01 mmol) was added. The reaction mixture was stirred for 18 h, then quenched with water (25 mL) and diluted with EtOAc (35 mL) and CH 2 Cl 2 The combined organic layer was extracted with anhydrous MgSO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (10% MeOH / CH 2 Cl 2 +1% AcOH) to give 80 mg of compound 157 as a wax.

[0272] [Example 58] [ka] A solution of compound 148 (150 mg, 0.482 mmol) prepared as in Example 48 in DCE (3 mL) was stirred under argon, and 4A molecular sieve powder (150 mg), pyrrolidine (50 μL, 0.609 mmol), AcOH (55 μL, 0.961 mmol) were added, followed by NaBH(OAc) 3 (204 mg, 0.962 mmol) was added. The reaction mixture was stirred for 18 h, then quenched with water (25 mL) and CH 2 Cl 2 The combined organic layer was extracted with anhydrous MgSO 4 The residue was purified by flash chromatography (EtOAc / MeOH / Et 3 N, 9:1:0.1) to give 160 mg of compound 158 as a colorless wax.

[0273] [Example 59] [ka] 4-Hydroxyacetophenone (109, 500 mg, 3.67 mmol), K 2 CO 3 (435 mg, 3.15 mmol), and 2-chlorobenzothiazole (525 μL, 4.04 mmol) were mixed in DMF (5 mL) and stirred at 140° C. for 18 h. The mixture was allowed to cool to room temperature and then heated to 100° C. for 18 h. 2 Dilute with HO (10 mL) and Et0Ac (30 mL), separate, and wash the organic layer with 5% NaOH (2 x 20 mL), then with brine (3 x 30 mL) and anhydrous MgSO 4 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 979 mg of compound 159 as a yellow solid.

[0274] [Example 60] [ka] A solution of compound 159 (100 mg, 0.371 mmol, prepared as in Example 59) in MeOH (2 mL) was stirred at room temperature under argon and treated with NaBH 4 (21 mg, 0.555 mmol) was added. The reaction mixture was stirred for 2 h, then quenched with water (25 mL) and CH 2 Cl 2 The combined organic layer was extracted with anhydrous MgSO 4 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.

[0275] [Example 61] [ka] Following the general Grignard addition procedure as disclosed herein, compound 159 (233 mg, 0.865 mmol, prepared similarly to Example 59), THF (4.0 mL), and ethylmagnesium bromide (0.57 mL, 3M / Et 2 Compound 161 was prepared from 1H) by flash column chromatography on silica gel (30% EtOAc / 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 stirred at room temperature under argon and Ti(O i Pr) 4 (265 μL, 0.895 mmol) was added, followed by pyrrolidine (85 μL, 1.04 mmol). The reaction mixture was stirred under reflux for 16 h and then allowed to cool to room temperature. NaBH 4 (42 mg, 1.11 mmol) was added and the reaction mixture was stirred for 1.5 h, then quenched with water (25 mL) and extracted with EtOAc (2 x 35 mL). The organic layer was washed with water (35 mL) and diluted with anhydrous MgSO 4 The residue was purified by flash chromatography (EtOAc / MeOH / Et 3 N, 9:1:0.1) to give 88 mg of compound 162 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 2 CO 3 (6 mg, 0.043 mmol) in DMF (2 mL) was stirred under argon and CF 3TMS (90 μL, 0.610 mmol) was added. The reaction mixture was stirred at room temperature for 18 h, then diluted with EtOAc (35 mL) and washed with water (2 x 25 mL). The organic layer was washed with anhydrous MgSO 4 The mixture was dried at 40° C., filtered and evaporated under reduced pressure. The residue was added to MeOH (2 mL) and stirred with concentrated HCl (0.1 mL) for 1 h. The solvent was evaporated under reduced pressure and the residue was purified by flash chromatography (10% EtOAc / Hex) to give 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), K 2 CO 3 (340 mg, 2.46 mmol), and 2-chlorobenzothiazole (260 μL, 2.00 mmol) were mixed in DMF (3 mL) and stirred at 100 °C in a sealed tube for 16 h. The mixture was allowed to cool to room temperature, diluted with EtOAc (35 mL), washed with water (3 x 25 mL), and diluted with anhydrous MgSO 4 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 354 mg of 4-(1,3-benzothiazol-2-yloxy)benzaldehyde as a white solid. [ka]

[0279] 4-(1,3-Benzothiazol-2-yloxy)benzaldehyde (150 mg, 0.588 mmol) was mixed in DCE (3 mL) and stirred at room temperature under argon. Pyrrolidine (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, then quenched with water (25 mL) and CH 2 Cl 2 The combined organic layer was extracted with anhydrous MgSO4 The residue was purified by flash chromatography (EtOAc / MeOH / Et 3 N, 9:1:0.1) to give 153 mg of compound 164 as a colorless oil.

[0280] [Example 65] [ka] Following the procedure previously described to produce compound 157, L-proline (81 mg, 0.704 mmol), 4-(1,3-benzothiazol-2-yloxy)benzaldehyde (150 mg, 0.588 mmol), and NaBH(OAc) were added. 3 A non-clinical modification was performed using 190 mg (0.896 mmol) in DCE (3 mL) at room temperature under argon and 10% MeOH / CH 2 Cl 2 Purification using +1.5% in AcOH as eluent 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 K 2 CO 3 (7 mg, 0.051 mmol) in DMF (2 mL) was stirred under argon and CF 3 TMS (94 μL, 0.655 mmol) was added. The reaction mixture was stirred at room temperature for 18 h, then diluted with EtOAc (35 mL) and washed with water (2 x 25 mL). The organic layer was washed with anhydrous MgSO 4 The mixture was dried at 40° C., filtered, and evaporated under reduced pressure. The residue was added to MeOH (2 mL) and stirred with concentrated HCl (0.1 mL) for 1 h. The solvent was evaporated under reduced pressure and the residue was purified by flash chromatography (20% EtOAc / Hex) to give 94 mg of compound 166 as a white solid.

[0282] [Example 67] Preparation of Compound 167 3-Chloro-4-hydroxybenzothiazole (250 mg, 1.60 mmol), K 2 CO 3 (332 mg, 2.40 mmol), and 2-chlorobenzothiazole (260 μL, 2.00 mmol) were mixed 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), washed with water (3 x 25 mL), and diluted with anhydrous MgSO 4 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 187 mg of 4-(1,3-benzothiazol-2-yloxy)-3-chlorobenzaldehyde as a white solid. [ka]

[0283] 4-(1,3-benzothiazol-2-yloxy)-3-chlorobenzaldehyde (187 mg, 0.645 mmol) and K 2 CO 3 (9 mg, 0.065 mmol) in DMF (2 mL) was stirred under argon and CF 3 TMS (143 μL, 0.968 mmol) was added. The reaction mixture was stirred at room temperature for 4 days, then diluted with EtOAc (40 mL) and washed with water (2 x 25 mL). The organic layer was washed with anhydrous MgSO 4 The mixture was dried over 500 ml of ethyl acetate, filtered, and the solvent was removed under reduced pressure. 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 (2 x 25 mL). The organic layer was washed with anhydrous MgSO 4 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 90 mg of compound 167 as a white solid.

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

[0285] 1-[4-(1,3-benzothiazol-2-yloxy)phenyl]-N-ethylmethanimine (1.18 mmol) and KHF 2 (69 mg, 0.883 mmol) was added to MeCN (4 mL) and DMF (274 μL) under argon at 0° C. and TFA (113 μL, 1.48 mmol) was added. The mixture was stirred for 5 min and then CF 3 TMS (261 μL, 1.78 mmol) was added. The cooling bath was removed and the reaction mixture was stirred for 18 h. Saturated Na 2 CO 3 The mixture was diluted with aqueous solution (40 mL) and extracted with EtOAc (40 mL). The organic layer was washed with water (25 mL) and dried over anhydrous MgSO. 4 The mixture was dried at 40° C., filtered and the solvent was removed under reduced pressure The residue was purified by flash chromatography (5% EtOAc / Hex) to give 294 mg of a yellow oil.

[0286] To further purify the desired compound, the oil was dissolved in MeOH (2 mL) and concentrated to NaBH 4 (30 mg) was added and the mixture was stirred under argon for 30 min. The reaction was quenched with water (25 mL) and extracted with EtOAc (35 mL). The organic layer was washed with anhydrous Na 2 SO 4The mixture was dried at 40° 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.

[0287] [Example 69] [ka] 4'-Fluoroacetophenone (177, 150 μL, 1.24 mmol), 2-methyl-5-benzothiazolol (205 mg, 1.24 mmol), and K 2 CO 3 (514 mg, 3.72 mmol) in DMSO (3 mL) was mixed and stirred in a sealed tube at 100 °C for 18 h, then allowed to cool to room temperature, diluted with EtOAc (35 mL), and washed with 1 M NaOH (25 mL x 2) and water (25 mL). The organic layer was washed with anhydrous Na 2 SO 4 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 as an off-white solid.

[0288] [Example 70] Preparation of compound 170 [ka] Compound 169 (150 mg, 0.529 mmol, prepared as in Example 69) and K 2 CO 3 (7 mg, 0.051 mmol) in DMF (3 mL) was stirred under argon and CF 3 TMS (195 μL, 1.32 mmol) was added. The reaction mixture was stirred at room temperature for 5 days, then diluted with EtOAc (35 mL) and washed with water (2×25 mL). The organic layer was washed with anhydrous Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, 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 h. The mixture was diluted with EtOAc (35 mL) and washed with saturated Na2 CO 3 The organic layer was washed with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and the solvent was removed under reduced pressure.

[0289] To further purify the desired compound, the residue was taken up in MeOH (3 mL) and 20 mg of NaBH 4 The reaction mixture was stirred for 1 hour, then quenched with water (25 mL) and extracted with EtOAc (35 mL). The organic layer was washed with water (25 mL) and extracted with anhydrous Na 2 SO 4 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 52 mg of compound 170 as an off-white solid.

[0290] [Example 71] [ka] A suspension of compound 169 (75 mg, 0.265 mmol), prepared as in Example 69, in MeOH (2 mL) was added with NaBH 4 (15 mg, 0.396 mmol) was added. The mixture was stirred under argon for 1 h, and then 10 mg of NaBH 4 The mixture was stirred for 30 min, after which the solution became clear. The reaction was quenched with water (25 mL) and extracted with EtOAc (35 mL). The organic layer was washed with water (25 mL) and diluted with anhydrous Na 2 SO 4 Drying at 400 C, filtration and evaporation of the solvent under reduced pressure gave 40 mg of compound 171 as a yellowish oil.

[0291] [Example 72] [ka] A solution of acetovanillone (250 mg, 1.50 mmol) in DMF (5 mL) was treated under argon with 2-chlorobenzothiazole (235 μL, 1.80 mmol) and K2 CO 3 (311 mg, 2.25 mmol) was added. The reaction mixture was stirred 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 1 M aqueous NaOH (2×25 mL) and water (25 mL). The organic layer was washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and the solvent was removed under reduced pressure. Flash column chromatography on silica gel (20% EtOAc / Hex) afforded 437 mg of compound 172 as a white solid.

[0292] [Example 73] [ka] Compound 172 (150 mg, 0.501 mmol) and K 2 CO 3 (7 mg, 0.051 mmol) in DMF (3 mL) was stirred under argon and CF 3 TMS (111 μL, 0.752 mmol) was added. The reaction mixture was stirred at room temperature for 44 h, then CF 3 An additional 222 μL (1.54 mmol) of TMS was added and stirring was continued for 3 days. The mixture was then diluted with EtOAc (35 mL) and washed with water (25 mL). The organic layer was washed with anhydrous Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, 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 h. The mixture was diluted with EtOAc (35 mL) and washed with water (25 mL). The organic layer was washed with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and the solvent was removed under reduced pressure.

[0293] To separate the product from the by-product, the residue was added to MeOH (3 mL) and concentrated with NaBH 4 (22 mg) was added and the mixture was stirred for 30 min. The mixture was diluted with EtOAc (35 mL) and washed with water (25 mL). The organic layer was washed with anhydrous Na 2 SO 4The 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 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) in acetone (10 mL) / H 2 The solution was stirred in 200 (10 mL) and NaOH (1 g, 25 mmol) was added. The mixture was stirred at room temperature for 18 h. The reaction was quenched with 5% dilute HCl (10 mL) and extracted with EtOAc (15 mL). The organic layer was washed with water (2 x 10 mL), brine (10 mL) and anhydrous MgSO 4 Drying at 40° C., filtration and removal of the solvent under reduced pressure gave 1.1 g of 4-(3-chloro-4-hydroxyphenyl)but-3-en-2-one as a yellow oil.

[0295] A solution of 4-(3-chloro-4-hydroxyphenyl)but-3-en-2-one (626 mg, 3.18 mmol) in EtOAc (12 mL) was stirred and 10% Pd / C (100 mg) was added. The reaction mixture was stirred under hydrogen for 1.5 h. The mixture was filtered, the solvent was evaporated under reduced pressure and the residue was purified by flash chromatography (25% EtOAc / Hex) to give 333 mg of 4-(3-chloro-4-hydroxyphenyl)butan-2-one as an oil. [ka]

[0296] A solution of 4-(3-chloro-4-hydroxyphenyl)butan-2-one (333 mg, 1.67 mmol) in DMF (5 mL) was treated with 2-chlorobenzothiazole (239 μL, 1.84 mmol) and K under argon. 2 CO 3(231 mg, 1.67 mmol) was added. The reaction mixture was stirred at 140 °C for 18 h. The reaction mixture was allowed to cool to room temperature, diluted with water (30 mL), and extracted with EtOAc (40 mL). The organic layer was washed with brine (3 x 40 mL). The organic layer was dried (MgSO 4 ), filtered and evaporated under reduced pressure. Flash column chromatography on silica gel (25% EtOAc / Hex) afforded 429 mg of compound 174 as a yellow oil.

[0297] [Example 75] [ka] As disclosed herein, 3 Following the TMS addition procedure, compound 174 (105 mg, 0.36 mmol), CF 3 TMS (97 μL, 0.65 mmol), K 2 CO 3 Compound 175 was prepared from (15 mg, 0.11 mmol) and DMF (2 mL), followed by MeOH (5 mL) and HCl (250 μL). The crude mixture was subjected to flash column chromatography on silica gel (20% EtOAc / Hex) to give 109 mg of compound 175 as an oil.

[0298] [Example 76] Preparation of Compound 176 4-Hydroxyacetophenone (150 mg, 1.10 mmol), K 2 CO 3 (228 mg, 1.65 mmol), and 2-chloro-4-(methylthio)-benzothiazole (297 mg, 1.38 mmol) were mixed in DMF (3 mL) and stirred at 100 °C for 18 h in a sealed tube. The mixture was allowed to cool to room temperature and then heated with H 2 Dilute with HO (10 mL) and Et0Ac (30 mL), separate, and wash the organic layer with 5% NaOH (2 x 20 mL), then with brine (3 x 30 mL) and anhydrous MgSO 4The 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 338 mg of 1-(4-{[4-(methylsulfanyl)-1,3-benzothiazol-2-yl]oxy}phenyl)ethan-1-one as a white solid. [ka]

[0299] A solution of 1-(4-{[4-(methylsulfanyl)-1,3-benzothiazol-2-yl]oxy}phenyl)ethan-1-one (150 mg, 0.476 mmol) in MeOH (10 mL) was stirred at room temperature under argon and added with NaBH 4 (27 mg, 0.714 mmol) was added. The reaction mixture was stirred for 1 h, quenched with water (25 mL), and extracted with EtAOc (35 mL). The organic layer was washed with anhydrous MgSO 4 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 134 mg of compound 176 as a colorless oil.

[0300] [Example 77] Preparation of Compound 177 [ka] A solution of compound 159 (150 mg, 0.557 mmol) in diethyl ether (9 mL) was stirred under argon at 0 °C and 3.0 M MeMgBr in ether (0.3 mL, 0.9 mmol) was added. The reaction mixture was stirred at 0 °C for 10 min. The cooling bath was removed and the reaction mixture was stirred for 1 h, after which it was quenched with water (10 mL), diluted with 5% HCl (10 mL) and extracted with EtOAc (35 mL). The organic layer was washed with water (20 mL) and anhydrous MgSO 4 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 93 mg of compound 177 as a colorless oil.

[0301] [Example 78] Preparation of Compound 178 A mixture of 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 DCE (3.0 mL) was stirred at room temperature under argon for 18 hours. The reaction mixture was filtered and the solvent was removed under reduced pressure to give crude 1-[4-(1,3-benzothiazol-2-yloxy)phenyl]-N-methylmethanimine. [ka] 1-[4-(1,3-benzothiazol-2-yloxy)phenyl]-N-methylmethanimine (1.18 mmol) and KHF 2 (69 mg, 0.883 mmol) was added to MeCN (4 mL) and DMF (274 μL) under argon at 0° C. and TFA (113 μL, 1.48 mmol) was added. The mixture was stirred for 5 min and then CF 3 TMS (261 μL, 1.78 mmol) was added. The cooling bath was removed and the reaction mixture was stirred for 20 h. Saturated Na 2 CO 3 The mixture was diluted with aqueous solution (40 mL) and extracted with EtOAc (40 mL). The organic layer was washed with water (25 mL) and diluted with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and the solvent was removed under reduced pressure.

[0302] The residue was added to MeOH (2 mL) and dissolved in NaBH 4 (45 mg) was added and the mixture was stirred under argon for 30 min. The reaction was quenched with water (25 mL) and extracted with EtOAc (35 mL). The organic layer was washed with anhydrous Na 2 SO 4 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 109 mg of compound 178 as a colorless oil.

[0303] [Example 79] Preparation of Compound 179 4-Hydroxybenzaldehyde (100 mg, 0.819 mmol), K 2 CO 3 (170 mg, 1.23 mmol), and 2-chloro-4,6-difluoro-benzothiazole (168 mg, 0.817 mmol) were mixed 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), washed with 1 M NaOH (2 x 25 mL) and water (25 mL), and then washed with anhydrous Na 2 SO 4 The extract was dried at 40° C., filtered, and the solvent was removed under reduced pressure to give 216 mg of 4-(4,6-difluoro-1,3-benzothiazol-2-yloxy)benzaldehyde as a white solid. [ka]

[0304] 4-(4,6-difluoro-1,3-benzothiazol-2-yloxy)benzaldehyde (216 mg, 0.742 mmol) and K 2 CO 3 (10 mg, 0.072 mmol) in DMF (2 mL) was stirred under argon and CF 3 TMS (220 μL, 1.49 mmol) was added. The reaction mixture was stirred at room temperature for 20 h, then diluted with EtOAc (35 mL) and washed with water (25 mL). The organic layer was washed with anhydrous Na 2 SO 4 The mixture was dried over 1000 ml of water, 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 the mixture was washed with water (25 mL). The organic layer was washed with anhydrous Na 2 SO 4 The mixture was dried at 40° C. and filtered. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (20% EtOAc / Hex) to give 116 mg of compound 179 as a white solid.

[0305] [Example 80] Preparation of Compound 180 4-Hydroxyacetophenone (150 mg, 1.10 mmol), K 2 CO 3 (228 mg, 1.65 mmol), and 2-chloro-4,6-difluoro-benzothiazole (226 mg, 1.10 mmol) were mixed 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), separated, and the organic layer was washed with 1 M NaOH (2 x 25 mL), then water (25 mL), and washed with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered, and the solvent was removed under reduced pressure to give 335 mg of 1-[4-(4,6-difluoro-1,3-benzothiazol-2-yloxy)phenyl]ethan-1-one as a light brown solid. [ka]

[0306] A solution of 1-[4-(4,6-difluoro-1,3-benzothiazol-2-yloxy)phenyl]ethan-1-one (100 mg, 0.328 mmol) in MeOH (2 mL) was stirred at room temperature under argon and added with NaBH 4 (18 mg, 0.476 mmol) was added. The reaction mixture was stirred for 1 h, quenched with water (25 mL), and extracted with EtOAc (35 mL). The organic layer was washed with anhydrous Na 2 SO 4 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 80 mg of compound 180 as a colorless oil.

[0307] [Example 81] [ka] 1-[4-(4,6-difluoro-1,3-benzothiazol-2-yloxy)phenyl]ethan-1-one (150 mg, 0.491 mmol) and K2 CO 3 A solution of (7 mg, 0.051 mmol) in DMF (3 mL) was stirred under argon and CF 3 TMS (145 μL, 0.982 mmol) was added. The reaction mixture was stirred at room temperature for 4 days, then diluted with EtOAc (35 mL) and washed with water (25 mL). The organic layer was washed with anhydrous Na 2 SO 4 The mixture was dried over 1000 ml of water, filtered, and the solvent was removed under reduced pressure. The residue was added to MeOH (3 mL) and stirred with concentrated HCl (0.3 mL) for 1 h. EtoAc (35 mL) was added and the mixture was washed with water (25 mL). The residue was added to MeOH (3 mL) and stirred with NaBH 4 (27 mg) was added and the mixture was stirred for 1 h. Et0Ac (35 mL) was added and the mixture was washed with water (25 mL). The organic layer was extracted with anhydrous Na 2 SO 4 The mixture was dried at 40° C. and filtered. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (20% EtOAc / Hex) to give 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), K 2 CO 3 (340 mg, 2.46 mmol), and 2-chlorobenzothiazole (215 μL, 1.65 mmol) were mixed in DMF (5 mL) and stirred at 100 °C in a sealed tube for 18 h. The mixture was allowed to cool to room temperature, diluted with EtOAc (35 mL), washed with 1 M NaOH (2 x 25 mL) and water (25 mL), and then washed with anhydrous Na 2 SO 4 Drying at 40° C., filtration, evaporation of the solvent under reduced pressure and purification of the residue by flash chromatography (20% EtOAc in the mixture) gave 457 mg of 4-(1,3-benzothiazol-2-yloxy)-2-methoxybenzaldehyde as a white solid. [ka]

[0309] 4-(1,3-benzothiazol-2-yloxy)-2-methoxybenzaldehyde (200 mg, 0.701 mmol) and K 2 CO 3 (10 mg, 0.072 mmol) in DMF (3 mL) was stirred under argon and CF 3 TMS (207 μL, 1.402 mmol) was added. The reaction mixture was stirred at room temperature for 20 h, then diluted with EtOAc (35 mL) and washed with water (25 mL). The organic layer was washed with anhydrous Na 2 SO 4 The mixture was dried over 1000 ml of water, 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 the mixture was washed with water (25 mL). The organic layer was washed with anhydrous Na 2 SO 4 The mixture was dried at 40° C. and filtered. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (20% EtOAc / Hex) to give 172 mg of compound 182 as a white solid.

[0310] [Example 83] [ka] 4-(4-hydroxyphenyl)-2-butanone (150 mg, 0.914 mmol) and K 2 CO 3 (13 mg, 0.094 mmol) in DMF (2 mL) was stirred at 0° C. under argon and CF 3 TMS (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), washed with water (2×20 mL), and washed with anhydrous Na 2 SO 4 The reaction was dried over 1000 ml of EtOAc (20 mL), filtered, and the solvent was removed under reduced pressure. MeOH (3 mL) and dilute 6N HCl (0.3 mL) were added to the residue, and the reaction was stirred for 1 h. The reaction was diluted with EtOAc (20 mL) and saturated NaHCO 3 Wash with aqueous solution (20 mL x 2) and water (20 mL), and then with anhydrous Na2 SO 4 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 / hexanes) to give 145 mg of 4-(4,4,4-trifluoro-3-hydroxy-3-methylbutyl)phenol as a white solid.

[0311] A mixture of 4-(4,4,4-trifluoro-3-hydroxy-3-methylbutyl)phenol (145 mg, 0.619 mmol), 2-(chloromethyl)quinoline hydrochloride (146 mg, 0.682 mmol), and K in DMF (2 mL) was prepared in the same manner as in Example 97. 2 CO 3 (342 mg, 2.47 mmol) to prepare 173 mg of compound 183 as a white solid.

[0312] [Example 84] Preparation of Compound 184 Vanillylacetone (250 mg, 1.52 mmol), K 2 CO 3 (377 mg, 2.73 mmol) and 2-(chloromethyl)quinoline hydrochloride (343 mg, 1.60 mmol) were mixed 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 (3×20 mL). The combined organic layers were washed with Na 2 SO 4 The mixture was dried at 40° C., filtered, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (25% EtOAc / Hex) to give 344 mg of 4-{3-methoxy-4-[(quinolin-2-yl)methoxy]phenyl}butan-2-one as a yellow oil. [ka] 4-{3-methoxy-4-[(quinolin-2-yl)methoxy]phenyl}butan-2-one (120 mg, 0.36 mmol) and K 2 CO 3(33 mg, 0.24 mmol) in DMF (3 mL) was stirred under argon and CF 3 TMS (175 μL, 1.18 mmol) was added. The reaction mixture was stirred at room temperature for 21 h, then diluted with EtOAc (25 mL) and washed with brine (25 mL). The organic layer was washed with anhydrous Na 2 SO 4 The mixture was dried over 500 ml, filtered and the solvent was removed under reduced pressure. The residue was added to MeOH (5 mL) and stirred with concentrated HCl (0.2 mL) for 75 min. The solvent was removed under reduced pressure, EtOAc (25 mL) was added and the mixture was washed with water (25 mL) and sodium hydroxide. 2 SO 4 The residue was purified by flash chromatography (25% EtOAc / Hex) to give 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), K 2 CO 3 (150 mg, 1.09 mmol) and 2-(chloromethyl)quinoline hydrochloride (150 mg, 0.70 mmol) were mixed in DMF (3 mL) and stirred in a sealed tube at 140° C. for 20 h. The mixture was allowed to cool to room temperature, water (25 mL) was added, and the mixture was extracted with EtOAc (3×25 mL). The combined organic layer was washed with brine (25 mL) and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (25% EtOAc / Hex) to give 254 mg of 1-{4-[(quinolin-2-yl)methoxy]phenyl}pentan-3-one as a yellow oil. [ka]

[0314] 1-{4-[(quinolin-2-yl)methoxy]phenyl}pentan-3-one (135 mg, 0.42 mmol) and K 2 CO 3 (40 mg, 0.29 mmol) in DMF (3 mL) was stirred under argon and CF 3 TMS (200 μL, 1.35 mmol) was added. The reaction mixture was stirred at room temperature for 20 h, then diluted with EtOAc (35 mL) and washed with water (2×50 mL) and brine (15 mL). The organic layer was washed with anhydrous Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and the solvent was removed under reduced pressure. The residue was added to MeOH (5 mL), and concentrated HCl (0.2 mL) was added and stirred for 1 hour. The solvent was removed under reduced pressure, EtOAc (25 mL) was added, and the mixture was washed with water (25 mL), and Na 2 SO 4 The residue was purified by flash chromatography (25% EtOAc / Hex) to give 83 mg of compound 185.

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

[0316] [Example 87] [ka] Following the general reduction procedure, compound 187 was prepared from compound 114 (115 mg, 0.301 mmol, prepared similarly to Example 14), sodium borohydride (23 mg, 0.608 mmol), and methanol (2 mL). The crude mixture was subjected to flash column chromatography on silica gel (20% EtOAc / Hex) to give 0.080 g of compound 187 as a colorless glass.

[0317] [Example 88] [ka] A solution of compound 101 (150 mg, 0.439 mmol) prepared in the same manner as in Example 1 in DCE (3 mL) was stirred at room temperature under argon, and 4A molecular sieve powder (156 mg), 1-methylpiperazine (70 μL, 0.631 mmol), and AcOH (100 μL, 1.75 mmol) were added, followed by NaBH(OAc) 3 (190 mg, 0.896 mmol) was added. The reaction mixture was stirred for 18 h, then saturated NaHCO 3 (25 mL) and CH 2 Cl 2 The combined organic layer was extracted with anhydrous MgSO 4 The residue was purified by flash chromatography (EtOAc / MeOH / Et 3 N, 9:1:0.1) to give 24 mg of compound 188 as a colorless oil. Compound 188 was then purified by CH 2 Cl 2 (2 mL) and 1.25 M HCl / MeOH (0.15 mL) was added and stirred for 1 h. 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), K2 CO 3 (443 mg, 3.21 mmol) and 2-(chloromethyl)quinoline hydrochloride (400 mg, 1.866 mmol) were mixed in DMF (6 mL) and stirred in a sealed tube at 150 °C for 20 h. The mixture was allowed to cool to room temperature. Water (20 mL) was added and the mixture was extracted with EtOAc (3 x 20 mL). The combined organic layer was washed with MgSO 4 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 603 mg of compound 189 as a yellow oil.

[0319] [Example 90] [ka] A solution of compound 189 (115 mg, 0.378 mmol, prepared as in Example 89) in DCE (3 mL) was stirred at room temperature under argon and added glacial acetic acid (0.050 mL), NaBH(OAc) 3 , and pyrrolidine (40 μL, 1.04 mmol) were added. The reaction mixture was stirred at room temperature for 20 h. The reaction was quenched with water (20 mL) and diluted with CH 2 Cl 2 The organic layer was washed with brine (20 mL) and anhydrous MgSO 4 The residue was purified by flash chromatography (EtOAc / MeOH / Et 3 N, 9:1:0.1) to give compound 190 as a yellow oil.

[0320] [Example 91] [ka] A solution of compound 118 (154 mg, 0.431 mmol) in anhydrous THF was stirred under argon at 0° C. and a 3.0 M solution of EtMgBr in ether (180 μL, 0.540 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 10 min, after which the cooling bath was removed and stirring continued at room temperature for 1 h. Saturated NH 4The reaction was quenched with aqueous Cl (10 mL) and extracted with EtOAc (15 mL). The organic layer was washed with water (10 mL) and diluted with anhydrous Na 2 SO 4 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 / Hexanes) to give 114 mg of compound 191 as a yellow oil.

[0321] The two enantiomers of compound 191 were separated by HPLC using the following conditions: ChiralPak AD™ column, 5 μm particle size, 4.6×250 mm column size; mobile phase: 90% i-PrOH / Hexane; flow rate: 1 mL / min; injection volume: 50 μL; sample concentration: 1 mg / m; run time: 22 min; number of injections: 1. Each peak was collected manually and two pools of fractions were made. 50 μL samples from each pool were injected separately onto the HPLC column using the same mobile phase and run time as above. Enantiomer 1 had a retention time of 17.014 min and was >99% pure. Enantiomer 2 had a retention time of 18.709 min and was >99% pure.

[0322] [Example 92] [ka] 1-(4-hydroxy-3-methoxyphenyl)pentan-3-one (343 mg, 1.65 mmol), K 2 CO 3 (342 mg, 2.47 mmol), and 2-chloro-4-(methylthio)benzothiazole (392 mg, 1.82 mmol) were mixed in DMF (4 mL) and stirred at 100 °C for 20 h in a sealed tube under argon. The mixture was allowed to cool to room temperature, diluted with EtOAc (25 mL), washed with brine (2 x 25 mL), and washed with anhydrous Na 2 SO 4 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 400 mg of compound 192 as a white solid.

[0323] [Example 93] [ka] A suspension of compound 192 (150 mg, 0.39 mmol) in MeOH (5 mL) was stirred under argon and treated with NaBH 4 (22 mg, 0.58 mmol) was added. The reaction mixture was stirred for 30 min, after which an additional 22 mg of NaBH 4 The reaction mixture was stirred for 30 min, then diluted with EtOAc (30 mL), washed with water (2 x 20 mL), and washed with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and the solvent was removed under reduced pressure. The residue was triturated with EtOAc / hexane to give 70 mg of compound 193 as a white solid.

[0324] [Example 94] [ka] A mixture of 1-(4-hydroxyphenyl)pentan-3-one (390 mg, 2.19 mmol), 2-chloro-4-(methylthio)benzothiazole (520 mg, 2.41 mmol), and K in DMF (5 mL) was prepared in the same manner as in Example 92. 2 CO 3 (454 mg, 3.28 mmol) to prepare 613 mg of compound 194 as an off-white solid.

[0325] [Example 95] [ka] Compound 194 (150 mg, 0.458 mmol) and K 2 CO 3 (6 mg, 0.043 mmol) in DMF (3 mL) was stirred at 0° C. under argon and CF 3 TMS (160 μL, 1.08 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 42 h. The mixture was diluted with EtOAc (25 mL), washed with water (2×25 mL), and washed with anhydrous Na 2 SO4 The mixture was dried over 1000 ml of ethyl acetate, filtered, and the solvent was removed under reduced pressure. MeOH (2 mL) and 6N dilute HCl (0.2 mL) were added to the residue, and the reaction was stirred for 1 h. The reaction was diluted with EtOAc (25 mL), washed with water (2 x 25 mL), and washed with anhydrous Na 2 SO 4 The residue was dried over 1000 ml of MeOH (2 mL) and NaBH 4 (10 mg) was added and the reaction was stirred for 45 min. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (20% EtOAc / Hexanes) to give 95 mg of compound 195 as a colorless oil.

[0326] [Example 96] [ka] 1-(4-Hydroxy-3-methoxyphenyl)pentan-3-one (1.72 g, 8.26 mmol) was added to MeOH (20 mL) and incubated with NaBH at 0 °C under argon. 4 (469 mg, 12.4 mmol) was added portionwise over 15 min. The reaction mixture was stirred at room temperature for 1 h, quenched with water (35 mL) and extracted with EtOAc (50 mL). The organic layer was washed with water (35 mL) and diluted with anhydrous Na 2 SO 4 Drying at 40° C., filtration, and removal of the solvent under reduced pressure gave 1.17 g of 4-(3-hydroxypentyl)-2-methoxyphenol as a pale yellow oil.

[0327] Similar to the procedure in Example 92, 4-(3-hydroxypentyl)-2-methoxyphenol (100 mg, 0.48 mmol), 2-chlorobenzothiazole (70 μL, 0.54 mmol), and K in DMF (2 mL) were 2 CO 3 (199 mg, 1.44 mmol) to prepare 113 mg of compound 196 as a colorless wax.

[0328] [Example 97] [ka] 4'-Hydroxyacetophenone (150 mg, 1.10 mmol) and K 2 CO 3 (15 mg, 0.11 mmol) in DMF (2 mL) was stirred at 0° C. under argon and CF 3 TMS (410 μL, 2.78 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 90 h. The mixture was diluted with EtOAc (20 mL), washed with water (2×20 mL), and washed with anhydrous Na 2 SO 4 The reaction was dried over 1000 ml of EtOAc (20 mL), filtered, and the solvent was removed under reduced pressure. MeOH (3 mL) and dilute 6N HCl (0.3 mL) were added to the residue, and the reaction was stirred for 1 h. The reaction was diluted with EtOAc (20 mL) and saturated NaHCO 3 Wash with aqueous solution (20 mL x 2) and water (20 mL), and then with anhydrous Na 2 SO 4 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 / Hexanes) to give 135 mg of 4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenol as a white solid.

[0329] 4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenol (135 mg, 0.655 mmol), K 2 CO 3 (362 mg, 2.62 mmol), and 2-(chloromethyl)quinoline hydrochloride (154 mg, 0.719 mmol) were mixed in DMF (2 mL) and stirred in a sealed tube at 80 °C for 18 h. The mixture was allowed to cool to room temperature, diluted with EtOAc (20 mL), washed with water (2 x 20 mL), and washed with anhydrous Na 2 SO 4 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 156 mg of compound 197 as a yellowish solid.

[0330] [Example 98] [ka] 4-[3-hydroxy-3-(trifluoromethyl)pentyl]-2-methoxyphenol (189 mg, 0.679 mmol), K 2 CO 3 (375 mg, 2.71 mmol), and 2-(chloromethyl)quinoline hydrochloride (160 mg, 0.747 mmol) were mixed in anhydrous acetone (4 mL) and stirred at 60 °C in a sealed tube for 18 h. The mixture was allowed to cool to room temperature, filtered, washed with acetone, and the solvent was removed under reduced pressure. The residue was sequentially purified by two flash columns (20% EtOAc / Hex, followed by 10% EtOAc / CH 2 Cl 2 ) to give 75 mg of compound 198 as a colorless glass.

[0331] [Example 99] [ka] 4'-Hydroxy-3'-methoxyacetophenone (150 mg, 0.903 mmol) in DMF (2 mL), CF 3 TMS (340 μL, 2.30 mmol), and K 2 CO 3 (12 mg, 0.087 mmol) was used to prepare 132 mg of 2-methoxy-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenol. Following the procedure of Example 97, 2-methoxy-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenol (132 mg, 0.560 mmol), 2-(chloromethyl)quinoline hydrochloride (132 mg, 0.620 mmol), and K in DMF (2 mL) were mixed. 2 CO 3 (310 mg, 2.24 mmol) to prepare 161 mg of compound 199 as a white solid.

[0332] [Example 100] (MC / 9 HPLC Assay) Cultured MC / 9 cells (cell number 3 × 10 6 ) in 1 mL HBSS and preincubated with compounds dissolved in DMSO at varying concentrations for 30 min. Leukotriene production was stimulated by adding 1 μM calcium ionophore (A23187), diluted from a 4 mM DMSO stock / HBSS and incubated at room temperature for 20 min. The reaction was stopped by adding 500 μL of methanol containing 20 ng / mL prostaglandin B2 as an internal standard. Samples were taken and stored at -20°C for at least 2 h or overnight, then centrifuged at 13,000 rpm for 15 min and loaded onto a C18 SEP-PAK column (Canadian Lifesciences, IS12000) for solid phase extraction. Leukotrienes were analyzed by HPLC using an ACE C18 column (4.5 mm × 150 mm, 5 μm) (H 3 PO 4 Elution with a mixture of acetonitrile / methanol / water containing LTB, pH 3.5 (37:26:37), flow rate 1.8 mL / min. 4 (Cayman Chemical, 20110) and LTC 4 (Cayman Chemical, 20210) was calculated based on the reference standard, and the amount of LTB induced by the test compound was 4 The level of inhibition was calculated relative to the control sample. The results are shown in Table 2, where Compound No. refers to the compound identified in Table 1.

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

[0334] LTC4 and L.T.B. 4 The enantiomers of compound 104 differed in their potency in inhibiting LTC. Notably, enantiomer 1 inhibited LTC (0.3 μM-10%) at a significantly lower level than enantiomer 2 (0.3 μM-10%). 4 Also of note, enantiomer 1 increased the % inhibition of LTB (0.3 μM-74%) compared to enantiomer 2 (0.3 μM-24%). 4 showed increased inhibition of β-lactamase (0.3 μM-83%).

[0335] Notably, compound 104 showed significantly higher LTC activity compared to compound 103 (50-70%). 4 Also noteworthy, compound 104 inhibited LTB (90%) more effectively than compound 103 (50-70%). 4 (1 μM) (90%). Structurally, compounds 103 and 104 have an -S-alkyl substituent on the Ar ring in compound 104, more specifically -S-CH 3 The only difference is the presence of the group.

[0336] Thus, in one embodiment, the present disclosure provides a compound of formula (1) having an -S-alkyl substituent on Ar, more specifically a compound of formula (1) [ka] and pharma- ceutically acceptable salts thereof, wherein Ar is a 9- or 10-membered bicyclic aromatic ring system and Ar is at least one -S-alkyl, where -S-alkyl is -SC 1 -C 6 L is selected from a direct bond and methylene; R 1 However, hydrogen, halides, C 1 - 6 Alkyl, C 1 - 6 Haloalkyl, and C 1 - 6alkoxy; A is a direct bond, -CH 2 - and -CH 2 CH 2 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 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 R is selected from haloalkyl, phenyl, and substituted phenyl; 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 heterocyclic ring. With respect to the Ar group, optionally Ar is a monosubstituted 9-membered bicyclic aromatic ring; or optionally Ar is a disubstituted 9-membered bicyclic aromatic ring; or optionally Ar is a trisubstituted 9-membered bicyclic aromatic ring; or 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 selected from 1,3-benzoxazole and 1,3-benzothiazole; or optionally Ar is naphthalene or a nitrogen-substituted analog thereof selected from 1,5-naphthyridine, 1,6-naphthyridine, 1,7-naphthyridine, 1,8-naphthyridine, isoquinoline, phthalazine, 2,6-naphthyridine, and 2,7-naphthyridine. Other substituents may be one or more of the following to further describe the compounds of this embodiment: L is a direct bond; L is methylene; R 1is hydrogen; R 1 is a halogen; R 1 C 1 -C 6 Alkyl; R 1 C 1 -C 6 Haloalkyl; R 1 C 1 -C 6 Alkoxy; A is a direct bond; A is -CH 2 -; A is -CH 2 CH 2 -; E is -C(O)-R 2 R 2 is methyl; R 2 is ethyl; 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; R 5 C 1 -C 7 Alkyl; R 5 C 1 -C 7 Haloalkyl, e.g., R 5 is trifluoromethyl; R 5 is phenyl; R 5 is a substituted phenyl; E is -CH(R 6 )NR 7 R 8 R 6 is hydrogen; R 6 is 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 together form a five-membered heterocyclic ring; R 7 and R8 and together form a substituted 5-membered heterocyclic ring; R 7 and R 8 and together form a 6-membered heterocyclic ring; and / or R 7 and R 8 and together form a substituted 6-membered heterocycle.

[0337] Notably, when comparing the performance of compound 103 with compound 150, compound 103 outperformed LTC 4 The inhibition percentage (1μM) of LTB was 50-70%. 4 The % inhibition (1 μM) of LTC was 50-70%. That is, there was no detectable difference in performance. However, compound 150 inhibited LTC 4 The inhibition percentage (1μM) of LTB is 10-30%. 4 The inhibition percentage (1 μM) of 103 was 50-70%. That is, there was a detectable difference in performance. Structurally, compound 103 and compound 150 have the same structure as compound 103, but the same structure as compound 150, except that compound 103 has an R 1 The substituents include -O-alkyl substituents, more specifically -O-CH 3 The only difference is the presence of the group.

[0338] Thus, in one embodiment, the present disclosure provides a method for the preparation of a compound comprising: 1 is O-alkyl, more specifically compounds of formula (1) [ka] and pharma- ceutically acceptable salts thereof, wherein Ar is a 9- or 10-membered bicyclic aromatic ring system, Ar is optionally substituted with 1, 2, or 3 substituents; L is selected from a direct bond and methylene; and R 1 But, C 1 -C 6 alkoxy; A is a direct bond, -CH 2 - and -CH 2 CH 2 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 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 R is selected from haloalkyl, phenyl, and substituted phenyl; 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 together may form an optionally substituted 5- or 6-membered heterocyclic ring. With respect to the group Ar, optionally Ar is an unsubstituted 9-membered bicyclic aromatic ring; or optionally Ar is a monosubstituted 9-membered bicyclic aromatic ring; 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 10-membered bicyclic aromatic ring; or optionally Ar is a disubstituted 10-membered bicyclic aromatic ring; or optionally Ar is a is a trisubstituted 10-membered bicyclic aromatic ring; or optionally Ar is selected from 1,3-benzoxazole and 1,3-benzothiazole; or optionally Ar is naphthalene or a nitrogen-substituted analogue thereof selected from 1,5-naphthyridine, 1,6-naphthyridine, 1,7-naphthyridine, 1,8-naphthyridine, isoquinoline, phthalazine, 2,6-naphthyridine, and 2,7-naphthyridine. As other substituents, one or more of the following may be used to further describe the compounds of this embodiment: L is a direct bond; L is methylene; A is a direct bond; A is -CH 2 A is -CH 2 CH 2 -; E is -C(O)-R 2 R 2 is methyl; R 2 is ethyl; R2 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; R 5 C 1 -C 7 Alkyl; R 5 C 1 -C 7 Haloalkyl, e.g., R 5 is trifluoromethyl; R 5 is phenyl; R 5 is a substituted phenyl; E is -CH(R 6 )NR 7 R 8 R 6 is hydrogen; R 6 is 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 together form a five-membered heterocyclic ring; R 7 and R 8 and together form a substituted 5-membered heterocyclic ring; R 7 and R 8 and together form a 6-membered heterocyclic ring; and / or R 7 and R 8 and together form a substituted 6-membered heterocycle.

[0339] [Example 101] (Whole Blood HPLC Assay) Porcine or human whole blood (1 mL) was pre-incubated for 30 min with compounds dissolved in DMSO at varying concentrations. Leukotriene production was stimulated by adding 20 μM calcium ionophore (A23187), diluted from a 4 mM DMSO stock in HBSS and incubated at room temperature for 20 min. Pig blood was spiked with 20 μM arachidonic acid along with calcium ionophore. Blood was centrifuged at 2000 rpm for 15 min and the plasma fraction was removed for further processing. Plasma samples were diluted with 500 μL acidified water (HCl pH 3.0) and loaded onto a C18 SEP-PAK column (Canadian Lifesciences, IS12000) for solid phase extraction. Leukotrienes were analyzed by HPLC using an ACE C18 column (4.5 mm × 150 mm, 5 μm) (H 3 PO 4 Elution with a mixture of acetonitrile / methanol / water containing LTB, pH 3.5 (37:26:37), flow rate 1.8 mL / min. 4 (Cayman Chemical, 20110) was calculated based on the reference standard, and the amount of LTB induced by the test compound was calculated. 4 The level of inhibition was calculated relative to the control sample. The results shown in Table 3 are calculated based on a five-point curve with 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 preincubated with 0.5 μg of human recombinant leukotriene A4 hydrolase (Cayman Chemical 10007817) in 50 μL assay buffer (50 mM Tris-HCl, 100 mM KCl) in the absence of light. The reaction was stimulated by adding 50 μL of 6 mM alanine-4-nitroanilide (Sigma Aldrich, A9325) to the assay buffer. The amount of aminopeptidase activity was measured by determining the change in absorbance at 405 nm due to 4-nitroanaline production and comparing the percentage change with a reference standard (Sigma Aldrich, 185310). The aminopeptidase activity was compared to the control sample and the inhibition level was calculated. Compounds that increase peptidase activity are represented by negative values. The results are shown in Table 4, where Compound No. refers to the compounds listed in Table 1.

[0342] [Example 103] (Aminopeptidase Assay-PGP) Varying concentrations of compounds were assayed with 50 ng of human recombinant leukotriene A in 50 μL assay buffer (50 mM Tris-HCl, 100 mM KCl). 4 The peptides were preincubated with hydrolase (Cayman Chemical, 10007817). The reaction was stimulated by adding 50 μL of 1 mM proline-glycine-proline (Bachem, H-7284) 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 peptides was detected by reaction with ninhydrin. 150 μL of 25 mg / mL ninhydrin (BDH, B10132) in 60:40 acetic acid / water was added to each sample and boiled at 100°C for 30 min. The samples were allowed to cool to room temperature, after which 350 μL of toluene was added to extract the ninhydrin reaction products. The amount of free proline was determined by comparing the absorbance at 520 nm with that of L-proline (Sigma Aldrich, 81709) reference standard. Inhibition of free proline production was calculated based on the control samples. The results are shown in Table 4, where Compound No. refers to the compounds listed in Table 1.

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

[0344] [Example 104] (Arachidonic acid (AA)-induced mouse ear edema model) The mouse arachidonic acid-induced ear edema model is a model of acute skin inflammation that responds to skin irritation with redness and swelling. One group serves as a control and receives 20 μL of vehicle (10 μL applied to the inside of the pinna and 10 μL applied to the outside) into the pinna of each ear. One or more other groups serve as test groups. A volume of 20 μL of test compound (10 μL applied to the inside of the pinna and 10 μL applied to the outside) was applied to the pinna of one ear of the mice. Test compound or control vehicle (acetone / 1% DMSO) was applied topically to the right ear 4 hours and 1 hour before 2 mg of AA was applied to each ear as irritation to both the inside and outside surfaces of CD-1 mice. Vehicle (acetone / 1% DMSO) alone was applied to the left ear.

[0345] The animals were lightly anesthetized again with isofluorane to allow the application of the stimuli. For the control group, arachidonic acid (2 mg per ear) in a total volume of 20 μL acetone (10 μL applied inside the pinna and 10 μL applied outside) was applied to the pinna of only one ear as a stimulus. 20 μL acetone was applied to the other ear. This allowed the increase in ear weight due to arachidonic acid in the absence of test compound to be determined. For the test group, arachidonic acid (2 mg per ear) in a total volume of 20 μL acetone (10 μL applied inside the pinna and 10 μL applied outside the pinna) was applied to the pinna of each ear as a stimulus. In each case, the animals were allowed to recover after application of the stimuli. After 60 min, the animals were euthanized and samples for standard biopsies were taken from each ear using a 6 mm skin biopsy punch (Acuderm). Ear edema was defined as an increase in tissue weight due to fluid accumulation as a result of plasma extravasation. The ears were weighed separately using a balance suitable for weighing 0.1 mg. For the control group, the weight of the stimulated ear was subtracted from the weight of the unstimulated ear to obtain the ear weight difference, which was a measure of the increase in ear weight due to edema. The percentage increase in ear weight was obtained 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 ear weight difference was obtained by subtracting the weight of the untreated ear from the weight of the test compound treated ear. The percent inhibition of the increase in ear weight for the test compound treated ear was estimated by first subtracting the average ear weight of the untreated control from each tissue to obtain the increase in tissue weight due to application of arachidonic acid. Percent inhibition = 1 - (test drug stimulated ear (mg) / control stimulated ear (mg)) x 100

[0346] Table 5 shows data for inhibition of AA-induced ear edema by topical application of compounds in mice. Compounds (0.3 or 1 mg / ear) were applied to the ear 4 and 1 hour prior to topical application of arachidonic acid (AA; 2 mg per ear). Representative data from 4-6 mice in each treatment group are shown below, where Compound No. refers to the compound 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 lung tissue, which can be measured by the time course of BAL fluid during lung lavage after LPS challenge. Neutrophilia is characterized by a significant increase in cells in the BAL after 6 hours, with a maximal response by 24 hours.

[0349] CD-1 mice were administered a volume of 50 μL of phosphate-buffered saline (PBS) or 2.5 mg / kg lipopolysaccharide (LPS) in PBS into the lungs by intraoral instillation. Animals were lightly anesthetized using isofluorane to allow for application of LPS. Upon anesthesia, animals were positioned on a board at a 45° angle. The tongue was rolled to one side and a volume of 50 μL of LPS was administered directly into the trachea. The animals were held in that position for 1–2 min to allow retention of LPS in the lungs. Once the LPS challenge time had elapsed, the animals were again euthanized with an overdose of isofluorane. The trachea was exposed and the lungs were intubated using a 21 G catheter tube. The lungs were lavaged twice at room temperature with 1 mL of PBS. The collected bronchoalveolar lavage fluid (BAL) was placed on ice and centrifuged at 2500 rpm (tabletop centrifuge) for 5 min to pellet the collected cells. The BAL supernatant was removed and the cell pellet was resuspended in 150 μL of PBS. Differential cell counts were determined using an automated cell counter (Abraxia) set to measure mouse cells. The cell concentration of the resuspended samples was expressed as the total number of cells harvested in the total volume of BAL collected.

[0350] Animals are orally dosed with a test drug or vehicle (polyethylene glycol 200 (PEG200) containing 1% DMSO) at a dose of 10-30 mg / kg several times before and after the instillation of LPS. For example, test drugs may be administered 30 min before LPS and then again 2 h after LPS, or may be administered simultaneously with LPS and then again 2 and 4 h after LPS.

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

[0352] [Example 106] (Rat endotoxin-induced uveitis (EIU) model) In the endotoxin-induced uveitis (EIU) model, rats are injected with LPS into the hind foodpad and ocular inflammation is assessed 24 hours later. EIU can be induced by systemic injection of lipopolysaccharide (LPS), which produces an inflammatory response primarily in the anterior uvea and a milder response in the posterior region of the eye, mimicking the pathological condition in human acute anterior uveitis.

[0353] Generally, cellular inflammation in EIU begins 4 hours after injection of LPS, with maximal penetration 18-24 hours later. Ocular inflammation is determined by assessment of clinical scores and determination of cell counts and protein content in the aqueous and vitreous humor of each eye. Aqueous and vitreous humor from normal control animals have few detectable cells, low levels of protein, and organized tissue layers under histological examination. In contrast, after LPS, the aqueous humor has increased cell counts and protein content and extravasation into the anterior cavity, as indicated by the ability to remove more fluid for evaluation. Similar effects are seen in the vitreous humor, with larger volumes of vitreous humor being readily harvested for evaluation. Histologically, the intratissue architecture shows a poor degree of organization, evidence of inflammatory cell infiltration, a large amount of protein matrix in the aqueous humor, and associated collapse and inflammatory cell infiltration of the iris and ciliary body.

[0354] To induce disease, rats were injected into the plantar hind paw with 75 μg LPS in 100 μL saline. The level of ocular inflammation was assessed by clinical scores assessing iris hyperemia, pupil dilation, exudate, and hypopyon, and by histological examination of tissue sections to measure cell counts and protein content in the aqueous and vitreous humor of each eye.

[0355] Animals were orally dosed with test drug or vehicle (PEG200 with 1% DMSO) at a dose of 30 mg / kg several times before and after injection of LPS. Animals may also receive topical doses of test drug, where a 10 μL drop of test drug is administered directly to the eye at various times before and after LPS administration using an application solution containing up to 1% test drug in a formulation consisting of 20% hydroxypropyl beta-cyclodextrin, 0.5% hydroxypropyl methylcellulose, and 1.6 mM EDTA in PBS.

[0356] The results of oral administration of test drugs are shown in Figure 2. Figure 2 shows the effect of Compound 104 on clinical scores in the EIU rat model. Animals were treated with Compound 104 at 30 mg / kg or vehicle (PEG200 with 1% DMSO) orally 15 min before and 5 h after subcutaneous administration of 75 μg LPS from Salmonella Typhimurium in 100 μL saline solution into the hind plantar region of each paw. The mean clinical scores were measured 24 h after LPS administration. Values ​​shown in Figure 2 represent the mean ± standard deviation, n=3 for each group.

[0357] [Example 107] (Rat ocular distribution model) Eye drops were prepared by adding compound at a theoretical concentration of 10 mg / mL to a 2 mL microcentrifuge tube, followed by a stir bar and the selected formulation consisting of hydroxypropyl beta-cyclodextrin (Trappsol) (20%), hydroxylpropyl methylcellulose (0.5%), and EDTA (1.6 mM) / phosphate buffered saline (w / v). The tube containing the compound in the eye drop formulation was heated to 60-65°C and stirred for at least 4 hours to overnight. The tube was removed from the hot bath and centrifuged at 10,000 rcf for 5 minutes to clarify the solution and ensure that there was no residual drug in solution. The supernatant was removed from the tube and one 10 μL sample was taken for HPLC analysis, dissolved, and analyzed by HPLC using an ACE C18 column (4.5 mm × 150 mm, 5 μm) (H 3 PO 4 Elution was performed with a mixture of acetonitrile / methanol / water containing 0.01% EDTA, pH 3.5 (50:30:20) at a flow rate of 2.5 mL / min. The solubilized concentration of each compound was calculated by interpolation from a standard curve based on reference standards dissolved in methanol during assay validation.

[0358] A drop of 10 μL of compound was applied to the rat and aqueous humor, and the eyes were washed to remove residual formulation, after which the posterior ocular regions (vitreous and retina) were harvested from each eye at the designated time points. Tissues were collected into pre-weighed collection tubes, and tissue weights were determined for each sample. An internal standard (IS) mixture containing reference compounds was added to the samples at 1 μL per 4 mg of tissue, mixed, and then diluted 4.25-fold with acetonitrile:MeOH (9:1). Aqueous humor samples were vortex mixed for 10 seconds. Vitreous and retina were vortex mixed twice for 10 seconds each, and further mixed on a benchtop shaker at 750 rpm for 6 minutes, followed by a final vortex mix (10 seconds). All samples were centrifuged to pellet particulate matter, and the supernatant was transferred to an LC vial. 10 μL samples were then applied to the HPLC during LC / MS / MS analysis. A calibration curve of the compound (0.588-176.471 ng / mL) in rat plasma was constructed and the concentration of the compound in each matrix analyzed was estimated using the area under the curve (AUC) normalized to the AUC of the internal standard to measure the response. It was assumed that 1 mg of tissue corresponds to 1 μL of plasma. The measured concentration in each tissue was then normalized to the amount of drug applied to account for differences in the soluble drug in each formulation. Mean concentrations and standard deviations were calculated based on "n" = number of eyes evaluated, rather than the number of animals.

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

[0360] [Table 6]

[0361] In another study, Sprague-Dawley rats were instilled with a 10 μL drop of either Compound 104 (0.4%) or commercial ophthalmic prednisolone acetate (1%), and 2 hours after administration, tissues were removed and compound concentrations were measured by LC / MS / MS. The resulting data in Figure 3 (mean ± SD, 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.

[0362] [Example 108] (Experimental autoimmune uveitis (EAU) model in rats) Experimental autoimmune uveitis is an organ-specific T cell-mediated autoimmune disease targeting the retinal nerve and associated tissues induced by immunization with retinal antigens. Histologically, it involves inflammatory cell infiltration of the retina, causing photoreceptor damage extending to the inner nuclear layer, resulting in edema and, at peak severity, retinal detachment. In addition to posterior segment changes, the anterior region of the eye is marked by inflammatory cell infiltration, with vascular congestion, loss of the red reflex, and anterior chamber opacification.

[0363] Experimental models of autoimmune uveitis (EAU) are initiated by injecting heat-killed cells of a laboratory strain of Mycobacterium tuberculosis and complete Freund's adjuvant (CFA) containing peptides directed against inflammatory retinal proteins into the eyes of susceptible animals, such as Lewis rats. Clinical signs of ocular inflammation appear approximately 6-7 days after injection of CFA and retinal proteins, peak at approximately 10-14 days, and largely resolve within 21 days.

[0364] Lewis rats were injected subcutaneously with 100 μL of an emulsion of retinal peptide (<100 μg) in complete Freund's adjuvant (2–3 mg / ml) at the base of the tail and 50 μL in each thigh. The procedure was performed in a biological safety cabinet and the animals remained in their containment chambers for the duration of the study. To allow for application of the stimuli, the animals were lightly anesthetized with isofluorane. Six to eight days after immunization, rats were lightly anesthetized using isofluorane to allow for the direct instillation of a 10 μL dose of test drug into the eye using an application solution containing up to 1% test drug in a formulation consisting of 20% hydroxypropyl beta-cyclodextrin, 0.5% hydroxypropyl methylcellulose, and 1.6 mM EDTA in PBS, and treatment was continued throughout the development of disease over several days. Symptoms of the disease were scored to assess vasodilation, vascular congestion, changes in the red reflex, and anterior chamber opacification and exophthalmos (scored 0–4) (Agarwal et al Autoimmunity: Methods and Protocols, Methods in Molecular Biology, vol. 900, Ch 22). Animals were treated with isoflurane and CO 2 Mice were euthanized by vitrification, and eyes were excised and evaluated histologically for intraocular structural changes and inflammatory cell infiltration, with a score based on pathological changes (Gadjanski et al. / Experimental Eye Research 93 (2011) 82e90). Retinal thickness from the retinal pigment epithelium layer to the inner border layer was measured in histological sections using an Aperio ImageScope (Leica Biosystems).

[0365] The results of this example are shown in Figures 4A, 4B, and 4C. These figures show 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 of complete Freund's adjuvant. Starting on day 6 after immunization, animals were administered 10 μL of 0.5% wt / vol compound 104 or vehicle (a liquid formulation containing 20% ​​hydroxypropyl beta-cyclodextrin, 0.5% hydroxypropyl methylcellulose, and 1.6 mM EDTA / PBS) topically to each eye every day for four doses every 3 hours, 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 collected for histological examination. Values ​​represent the mean ± standard deviation of four eyes, n=2 for each group. Figure 4A shows the mean clinical scores over time after immunization. Figure 4B shows the histological scores obtained 10 days after immunization. Figure 4C shows the retinal thickness measurements obtained from histological slides 10 days after immunization.

[0366] For selected compounds prepared according to the preceding examples, 1 H nuclear magnetic resonance spectroscopy was performed to 1 H NMR spectra were obtained and are characterized as described and shown in Table 7.

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

[0368] Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, described herein are a limited number of exemplary methods and materials. In general, unless otherwise indicated, materials for producing the present invention and / or components thereof may be selected from suitable starting materials.

[0369] Where a range of values ​​is described herein, it is understood that each of the intervening values ​​is encompassed within the disclosure, unless the context clearly dictates otherwise, between the upper and lower limits of that range, as well as any other stated value or values ​​within the stated range, to the tenth of the unit of the lower limit. The upper and lower limits of such subranges may be independently encompassed within these subranges, subject to any specifically excluded boundaries in the stated range. Where a stated range includes one or both of the boundaries, ranges excluding either or both of such included boundaries are also included in the disclosure.

[0370] For example, any concentration range, percentage range, ratio range, or integer value range described herein should be understood to include any integer value within the recited range, and, where appropriate, to include fractions thereof (such as tenths and hundredths of integers), unless otherwise indicated. Also, any numerical range recited herein in relation to any physical characteristic, such as polymer subunits, size, or thickness, should be understood to include any integer within the recited range, unless otherwise indicated. As used herein, the term "about" means ±20% of the indicated range, value, or structure, unless otherwise indicated.

[0371] All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent publications cited herein and / or listed in the Application Data Sheet are incorporated herein by reference. Such documents may be incorporated by reference, for example, for the purpose of describing and disclosing the materials and methods described in the publications, which may be used in connection with the inventions of this disclosure. The publications described above and herein are provided solely for their disclosure prior to the filing date of this application. Nothing herein should be construed as an admission by the inventors that the present invention is not entitled by virtue of prior invention to any cited publication.

[0372] In general, in the following claims, the terms used should not be construed to limit the claims to the specific embodiments disclosed in the specification and the claims, but should be construed to include all possible embodiments, along with the full scope of equivalents to which such claims are entitled. Thus, the claims are not limited by the disclosure.

Claims

1. 1-[4-(1,3-benzothiazol-2-yloxy)-3-methoxyphenyl]-3-(trifluoromethyl)pentan-3-ol; 1-{3-methoxy-4-[(4-methylsulfanyl-1,3-benzothiazol-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-methylbutan-2-ol; 1-(3-methoxy-4-{[4-(methylsulfanyl)-1,3-benzothiazol-2-yl]oxy}phenyl)pentan-3-ol; and A compound selected from 1-(4-{[4-(methylsulfanyl)-1,3-benzothiazol-2-yl]oxy}phenyl)-3-(trifluoromethyl)pentan-3-ol.

2. 10. A pharmaceutical composition comprising a compound according to claim 1, or a pharma- ceutically acceptable enantiomer, salt or solvate thereof, and at least one pharma- ceutically acceptable carrier, diluent, excipient and / or adjuvant.

3. The pharmaceutical composition of claim 2 in an oral or topical dosage form.

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

5. 5. The use according to claim 4, wherein the inflammatory disease or condition is an ocular inflammatory disease or condition.

6. 5. The use according to claim 4, wherein the disease is a respiratory disease or condition.

7. The use according to claim 4, wherein the disease is a neurodegenerative disease, condition or disorder.

8. The compound of claim 1 which is 1-{3-methoxy-4-[(4-methylsulfanyl-1,3-benzothiazol-2-yl)oxy]phenyl}-3-(trifluoromethyl)pentan-3-ol.

9. 9. A pharmaceutical composition comprising a compound according to claim 8, or a pharma- ceutically acceptable enantiomer, salt or solvate thereof, and at least one pharma- ceutically acceptable carrier, diluent, excipient and / or adjuvant.

10. 10. The pharmaceutical composition of claim 9, in an oral or topical administration form.

11. 10. Use of a compound according to claim 8 for the manufacture of a medicament for the treatment of an inflammatory disease or condition, an autoimmune disease or condition, a respiratory disease, or a neurodegenerative disease, condition or disorder.

12. 12. Use of a compound according to claim 11 for the manufacture of a medicament for the treatment of an inflammatory disease or condition, wherein said inflammatory disease or condition is an ocular inflammatory disease or condition.

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