C17 Polar substitution heteroaromatic synthetic triterpenoids and methods of using the same

Abstract

The present disclosure provides compounds of formula (I), whose variables are defined herein. Pharmaceutical compositions thereof are also provided. In some aspects, the compounds and compositions provided herein can be used as antioxidant inflammation modulators. In some aspects, the present disclosure provides methods, in which the compounds and compositions described herein are used to treat diseases and disorders, including diseases and disorders related to inflammation and cancer. TIFF2022541545000214.tif60128

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims the benefit of priority of U.S. Provisional Application No. 62 / 876,467, filed Jul. 19, 2019, and U.S. Provisional Application No. 62 / 952,048, filed Dec. 20, 2019, the entire contents of both applications are incorporated herein by reference.

[0002] Background of the Invention I. Field of the Invention The present invention generally relates to the fields of biology, chemistry, and medicine. More particularly, it relates to compounds, compositions, and methods for the treatment and prevention of diseases and disorders such as those associated with oxidative stress and inflammation.

Background Art

[0003] II. Description of the Related Art The anti-inflammatory and anti-proliferative activities of oleanolic acid, a natural triterpenoid, have been improved by chemical modification. For example, 2-cyano-3,12-dioxoolean-1,9(11)-diene-28-oic acid (CDDO) and related compounds have been developed (Honda et al., 1997; Honda et al., 1998; Honda et al., 1999; Honda et al., 2000a; Honda et al., 2000b; Honda, et al., 2002; Suh et al. 1998; Suh et al., 1999; Place et al., 2003; Liby et al., 2005; and U.S. Patent Nos. 6,326,507, 6,974,801, 7,435,755, 7,795,305, 7,863,327, 7,915,402, 7,943,778, 8,034,955, 8,071,632, 8,124,656, 8,124,799, 8,129,429, 8,338,618, 8,394,967, 8,440,820, 8,440,854, 8,455,544, 8,586,775, 8,993,640, 9,090,574, 9,102,681, 9,249,089, 9,278,912, 9,278,913, 9,290,536, 9,593,074, 9,701,709, 9,512,094, 9,556,222, 9,670,147, 9,757,359, 9,856,286, 9,889,143, 10,093,614, 10,105,372, 10,398,711, 10,501,489, or 10,556,858). Bardoxolone methyl (CDDO-Me; RTA 402) and omaveloxolone (RTA 408) have been clinically evaluated for the treatment of, for example, cancer, chronic kidney disease, pulmonary arterial hypertension, and Friedreich's ataxia (Pergola et al., 2011; Hong et al., 2012; U.S. Patent No. 8,993,640).

[0004] Furthermore, synthetic triterpenoid analogs of oleanolic acid (OA) have been found to be inhibitors of cellular inflammatory processes such as the induction of inducible nitric oxide synthase (iNOS) and COX-2 by IFN-γ in mouse macrophages. See Honda et al. (2000a); Honda et al. (2000b); and Honda et al. (2002). Synthetic derivatives of betulinic acid, another triterpenoid, have also been found to inhibit cellular inflammatory processes, but these compounds have not been characterized as extensively (Honda et al., 2006). The pharmacological actions of these synthetic triterpenoid molecules are complex. Compounds derived from oleanolic acid have been found to affect the functions of multiple protein targets and thereby regulate the activities of several important cell signaling pathways related to oxidative stress, cell cycle regulation, and inflammation (e.g., Dinkova-Kostova et al., 2005; Ahmad et al., 2006; Ahmad et al., 2008; Liby et al., 2007a). Also, derivatives of betulinic acid have shown comparable anti-inflammatory properties but appear to have significant differences in pharmacological actions compared to OA-derived compounds (Liby et al., 2007b). Given the variability in the bioactivity profiles of known triterpenoid derivatives, and considering that there are a wide variety of diseases that can be treated or prevented with compounds having strong antioxidant and anti-inflammatory effects, and that there is a great unmet medical need represented within this wide range of diseases, it is desirable to synthesize novel compounds with diverse structures that may have improved bioactivity profiles for the treatment of one or more indications.

SUMMARY OF THE INVENTION

[0005] The present disclosure provides novel synthetic triterpenoid derivatives having anti-inflammatory and / or antioxidant properties, pharmaceutical compositions, methods for their manufacture, and methods for their use.

[0006] In one aspect, a compound of the following formula, or a pharmaceutically acceptable salt thereof, is provided: TIFF0007695229000001.tif72128In the formula, A1 is - heteroarenediyl (C≦3) -; R1 is polar substituted alkyl (C≦3) ; R2 and R2' are each independently hydrogen or methyl.

[0007] In some embodiments, the compound is further defined as a compound of the following formula, or a pharmaceutically acceptable salt thereof: TIFF0007695229000002.tif51128In the formula, A1 is - heteroarenediyl (C≦3) -; R1 is polar substituted alkyl (C≦3) ;

[0008] In some embodiments, the compound is further defined as a compound of the following formula, or a pharmaceutically acceptable salt thereof: TIFF0007695229000003.tif50128In the formula, A1 is - heteroarenediyl (C≦3) -; R1 is polar substituted alkyl (C≦3) ;

[0009] In some embodiments, -A1-R1 is of the following formula. TIFF0007695229000004.tif11128

[0010] In other embodiments, -A1-R1 is of the following formula. TIFF0007695229000005.tif11128

[0011] In still other embodiments, -A1-R1 is of the following formula. TIFF0007695229000006.tif11128

[0012] In yet other embodiments, -A1-R1 is of the following formula. TIFF0007695229000007.tif11128

[0013] In some embodiments, R1 is a polar substituted ethyl. In other embodiments, R1 is a polar substituted methyl. In some embodiments, R1 is a monopolar substituted alkyl (C≦3) . In further embodiments, R1 is a monopolar substituted ethyl. In other embodiments, R1 is a monopolar substituted methyl. In some embodiments, R1 is a monoaminoalkyl (C≦3) , a monofluoroalkyl (C≦3) , or a monohydroxyalkyl (C≦3) . In some embodiments, R1 is a monoaminoalkyl (C≦3) , such as 2-aminoethyl or aminomethyl. In other embodiments, R1 is a monofluoroalkyl (C≦3) , such as 2-fluoroethyl or fluoromethyl. In yet other embodiments, R1 is a monohydroxyalkyl (C≦3) , such as 2-hydroxyethyl or hydroxymethyl. In yet other embodiments, R1 is -CH2CH2NHC(O)OCH3, -CH2CH2NHC(O)NHCH2CH3, or -CH2CH2NHC(O)CH3.

[0014] In some embodiments, -A1-R1 is TIFF0007695229000008.tif12128, where R1 is aminomethyl, fluoromethyl, or hydroxymethyl, R2 is hydrogen or methyl, and R2' is methyl. In some of these embodiments, -A1-R1 is TIFF0007695229000009.tif12128, where R1 is fluoromethyl, R2 is hydrogen or methyl, and R2' is methyl.

[0015] It should be understood that the present invention relates specifically to any combination of the features and aspects described herein, including any combination of general and / or specific features / aspects. In particular, the present invention relates specifically to each combination of the meanings (including general and / or specific meanings) of the various groups and variable elements encompassed by formula (I).

[0016] In some embodiments, the compound is further defined as having the following formula, or a pharmaceutically acceptable salt of any of these formulas. TIFF0007695229000010.tif108132TIFF0007695229000011.tif218143TIFF0007695229000012.tif108135

[0017] In further embodiments, the compound is further defined as having the following formula, or a pharmaceutically acceptable salt of any of these formulas. TIFF0007695229000013.tif108140

[0018] In still further embodiments, the compound is further defined as having the following formula, or a pharmaceutically acceptable salt of any of these formulas. TIFF0007695229000014.tif102134

[0019] In still further embodiments, the compound is further defined as having the following formula, or a pharmaceutically acceptable salt thereof. TIFF0007695229000015.tif33128

[0020] In other embodiments, the compound is further defined as having the following formula, or a pharmaceutically acceptable salt thereof. TIFF0007695229000016.tif33128

[0021] In still further embodiments, the compound is further defined as having the following formula, or a pharmaceutically acceptable salt thereof. TIFF0007695229000017.tif33128

[0022] In yet other embodiments, the compound is further defined as the following formula, or a pharmaceutically acceptable salt thereof. TIFF0007695229000018.tif33128

[0023] In other embodiments, the compound is further defined as the following formula, or a pharmaceutically acceptable salt thereof. TIFF0007695229000019.tif33128

[0024] In yet other embodiments, the compound is further defined as the following formula, or a pharmaceutically acceptable salt thereof. TIFF0007695229000020.tif33128

[0025] In some embodiments, the compound is further defined as follows: (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(5-(fluoromethyl)-1,3,4-oxadiazol-2-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(5-(fluoromethyl)-1,2,4-oxadiazol-3-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(5-(aminomethyl)-1,2,4-oxadiazol-3-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(5-(2-aminoethyl)-1,2,4-oxadiazol-3-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(5-(hydroxymethyl)-1,2,4-oxadiazol-3-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(5-(2-hydroxyethyl)-1,2,4-oxadiazol-3-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(2-(2-hydroxyethyl)-2H-tetrazol-5-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; 2-(5-((4aS,6aR,6bS,8aR,12aS,14aR,14bS)-11-cyano-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-hexadecahydropicen-4a(2H)-yl)-2H-tetrazol-2-yl)ethyl acetate; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(2-(2-fluoroethyl)-2H-tetrazol-5-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(3-(fluoromethyl)-1,2,4-oxadiazol-5-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(3-(2-hydroxyethyl)-1,2,4-oxadiazol-5-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; 2-(5-((4aS,6aR,6bS,8aR,12aS,14aR,14bS)-11-cyano-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-hexadecahydropicen-4a(2H)-yl)-1,2,4-oxadiazol-3-yl)ethyl acetate; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(3-(2-Aminoethyl)-1,2,4-oxadiazol-5-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; Methyl (2-(5-((4aS,6aR,6bS,8aR,12aS,14aR,14bS)-11-cyano-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-hexadecahydropicene-4a(2H)-yl)-1,2,4-oxadiazol-3-yl)ethyl)carbamate; 1-(2-(5-((4aS,6aR,6bS,8aR,12aS,14aR,14bS)-11-cyano-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-hexadecahydropicene-4a(2H)-yl)-1,2,4-oxadiazol-3-yl)ethyl)-3-ethylurea; N-(2-(5-((4aS,6aR,6bS,8aR,12aS,14aR,14bS)-11-cyano-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-hexadecahydropicene-4a(2H)-yl)-1,2,4-oxadiazol-3-yl)ethyl)acetamide; (4S,4aS,6aS,6bR,8aS,12aS,12bR,14bR)-8a-(3-(fluoromethyl)-1,2,4-oxadiazol-5-yl)-4,6a,6b,11,11,14b-hexamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4S,4aS,6aS,6bR,8aS,12aS,12bR,14bR)-8a-(3-(Difluoromethyl)-1,2,4-oxadiazol-5-yl)-4,6a,6b,11,11,14b-hexamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4S,4aS,6aS,6bR,8aS,12aS,12bR,14bR)-8a-(5-(Fluoromethyl)-1,3,4-oxadiazol-2-yl)-4,6a,6b,11,11,14b-hexamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4S,4aS,6aS,6bR,8aS,12aS,12bR,14bR)-8a-(5-(Fluoromethyl)-1,2,4-oxadiazol-3-yl)-4,6a,6b,11,11,14b-hexamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(5-(Difluoromethyl)-1,2,4-oxadiazol-3-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(3-(Hydroxymethyl)-1,2,4-oxadiazol-5-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(3-(Difluoromethyl)-1,2,4-oxadiazol-5-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; or (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile.

[0026] In a further aspect, the compound is further defined as follows: (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(5-(Fluoromethyl)-1,3,4-oxadiazol-2-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(5-(Fluoromethyl)-1,2,4-oxadiazol-3-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(5-(aminomethyl)-1,2,4-oxadiazol-3-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(3-(fluoromethyl)-1,2,4-oxadiazol-5-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4S,4aS,6aS,6bR,8aS,12aS,12bR,14bR)-8a-(3-(fluoromethyl)-1,2,4-oxadiazol-5-yl)-4,6a,6b,11,11,14b-hexamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; or (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(3-(2-hydroxyethyl)-1,2,4-oxadiazol-5-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile.

[0027] In a further aspect, the compound is further defined as follows: (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(5-(fluoromethyl)-1,3,4-oxadiazol-2-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(5-(fluoromethyl)-1,2,4-oxadiazol-3-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(5-(aminomethyl)-1,2,4-oxadiazol-3-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(3-(fluoromethyl)-1,2,4-oxadiazol-5-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; or (4S,4aS,6aS,6bR,8aS,12aS,12bR,14bR)-8a-(3-(fluoromethyl)-1,2,4-oxadiazol-5-yl)-4,6a,6b,11,11,14b-hexamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile.

[0028] In some embodiments, the compound is further defined as follows: (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(5-(fluoromethyl)-1,3,4-oxadiazol-2-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile.

[0029] In other embodiments, the compound is further defined as follows: (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(5-(fluoromethyl)-1,2,4-oxadiazol-3-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile.

[0030] In still other embodiments, the compound is further defined as follows: (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(5-(aminomethyl)-1,2,4-oxadiazol-3-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile.

[0031] In yet other embodiments, the compound is further defined as follows: (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(3-(fluoromethyl)-1,2,4-oxadiazol-5-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile.

[0032] In other embodiments, the compound is further defined as follows: (4S,4aS,6aS,6bR,8aS,12aS,12bR,14bR)-8a-(3-(fluoromethyl)-1,2,4-oxadiazol-5-yl)-4,6a,6b,11,11,14b-hexamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile.

[0033] In other embodiments, the compound is further defined as follows: (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(3-(2-hydroxyethyl)-1,2,4-oxadiazol-5-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile.

[0034] In another aspect, the present disclosure provides a compound of the following formula, or a pharmaceutically acceptable salt of any of these formulas. TIFF0007695229000021.tif218137TIFF0007695229000022.tif181130

[0035] In yet another aspect, the present disclosure provides the following: (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(5-(2-methoxyethyl)-1,2,4-oxadiazol-3-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(2-(2-Methoxyethyl)-2H-tetrazol-5-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(3-(2-Methoxyethyl)-1,2,4-oxadiazol-5-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-4,4,6a,6b,11,11,14b-heptamethyl-8a-(5-methyl-1,2,4-oxadiazol-3-yl)-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-4,4,6a,6b,11,11,14b-heptamethyl-8a-(2-methyl-2H-tetrazol-5-yl)-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-8a-(3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(3-Ethyl-1,2,4-oxadiazol-5-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(5-Ethyl-1,2,4-oxadiazol-3-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-8a-(3-propyl-1,2,4-oxadiazol-5-yl)-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(3-Isopropyl-1,2,4-oxadiazol-5-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(3-(tert-Butyl)-1,2,4-oxadiazol-5-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(3-(Cyclopropylmethyl)-1,2,4-oxadiazol-5-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(3-Cyclobutyl-1,2,4-oxadiazol-5-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(3-Cyclopentyl-1,2,4-oxadiazol-5-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(3-Cyclohexyl-1,2,4-oxadiazol-5-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4S,4aS,6aS,6bR,8aS,12aS,12bR,14bR)-4,6a,6b,11,11,14b-Hexamethyl-3,13-dioxo-8a-(3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4S,4aS,6aS,6bR,8aS,12aS,12bR,14bR)-8a-(3-Ethyl-1,2,4-oxadiazol-5-yl)-4,6a,6b,11,11,14b-Hexamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-4,4,6a,6b,11,11,14b-Heptamethyl-3,13-dioxo-8a-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-4,4,6a,6b,11,11,14b-Heptamethyl-3,13-dioxo-8a-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; or (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(5-Ethyl-1,3,4-oxadiazol-2-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile.

[0036] In yet another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure and an excipient. In some embodiments, the pharmaceutical composition is formulated for administration by oral, intralipid, intraarterial, intraarticular, intracranial, intradermal, intralesional, intramuscular, intranasal, intraocular, intramembranous, intraperitoneal, intrathoracic, intraprostatic, rectal, intrathecal, intratracheal, intratumoral, intraumbilical, intravaginal, intravenous, intracystic, intravitreal, liposomal, topical, mucosal, parenteral, rectal, subconjunctival, subcutaneous, sublingual, local, buccal, transdermal, vaginal, cream, lipid composition, catheter, lavage, continuous infusion, infusion, inhalation, injection, local delivery, or regional perfusion. In some embodiments, the pharmaceutical composition is formulated for oral administration. In other embodiments, the pharmaceutical composition is formulated for administration by injection. In some embodiments, the pharmaceutical composition is formulated for intraarterial, intramuscular, intraperitoneal, or intravenous administration. In some embodiments, the pharmaceutical composition is formulated for topical administration. In some embodiments, the pharmaceutical composition is formulated for topical administration to the skin or eye. In some embodiments, the pharmaceutical composition is formulated as a unit dosage form.

[0037] In another aspect, the present disclosure provides a method of doing so in a patient in need of treating or preventing a disease or disorder, the method comprising administering to the patient a pharmaceutically effective amount of a compound or composition of the present disclosure. In some embodiments, the patient is a mammal, such as a human. In some embodiments, the disease or disorder is a condition associated with inflammation and / or oxidative stress. In some embodiments, the disease or disorder is cancer. In some embodiments, the disease or disorder is a cardiovascular disease, such as atherosclerosis. In some embodiments, the disease or disorder is an autoimmune disease, such as Crohn's disease, rheumatoid arthritis, lupus, or psoriasis. In some embodiments, the disease or disorder is a neurodegenerative disease, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, or Huntington's disease. In some embodiments, the disease or disorder is chronic kidney disease, diabetes, mucositis, inflammatory bowel disease, dermatitis, sepsis, ischemia-reperfusion injury (including complications due to sickle cell anemia), influenza, osteoarthritis, osteoporosis, pancreatitis, asthma, chronic obstructive pulmonary disease, cystic fibrosis, idiopathic pulmonary fibrosis, multiple sclerosis, muscular dystrophy, cachexia, or graft-versus-host disease. In some embodiments, the disease or disorder is an eye disease, such as uveitis, glaucoma, macular degeneration, or retinopathy. In some embodiments, the disease or disorder is a neuropsychiatric disease or disorder, such as schizophrenia, depression, bipolar disorder, epilepsy, post-traumatic stress disorder, attention deficit disorder, autism, or anorexia nervosa. In some embodiments, the disease or disorder is a disease or disorder associated with mitochondrial dysfunction, such as Friedreich's ataxia. In some embodiments, the disease or disorder is chronic pain. In some embodiments, the disease or disorder is neuropathic pain.

[0038] In yet another aspect, the present disclosure provides a method of inhibiting nitric oxide production, the method comprising administering to a patient in need thereof an amount of a compound or composition of the present disclosure sufficient to cause inhibition of IFN-γ-induced nitric oxide production in one or more cells of the patient.

[0039] [The present invention 1001] A compound of the following formula: TIFF0007695229000023.tif72128 or a pharmaceutically acceptable salt thereof, wherein A 1 is - heteroarylene diyl (C≦3) -; R 1 is polar substituted alkyl (C≦3) ; R 2 and R 2 ' are each independently hydrogen or methyl, the compound or a pharmaceutically acceptable salt thereof. [The present invention 1002] The following formula: TIFF0007695229000024.tif51128 or further defined as a pharmaceutically acceptable salt thereof, wherein A 1 is - heteroarylene diyl (C≦3) -; R 1 is polar substituted alkyl (C≦3) ; the compound of the present invention 1001. [The present invention 1003] The following formula: TIFF0007695229000025.tif51128 or further defined as a pharmaceutically acceptable salt thereof, wherein A 1 is - heteroarylene diyl (C≦3) -; R 1 is polar substituted alkyl (C≦3) ; the compound of the present invention 1001. [The present invention 1004] -A 1 -R 1 is the following formula: TIFF0007695229000026.tif11128 ; the compound of any one of the present inventions 1001 to 1003. [The present invention 1005] -A 1 -R 1 is the following formula: TIFF0007695229000027.tif11128 ; the compound of any one of the present inventions 1001 to 1003. [The present invention 1006] -A 1 -R 1 is the following formula: TIFF0007695229000028.tif11128 ; the compound of any one of the present inventions 1001 to 1003. [The present invention 1007] -A 1 -R 1 is the following formula: TIFF0007695229000029.tif11128 ; the compound of any one of the present inventions 1001 to 1003. [The present invention 1008] R 1 is polar substituted ethyl; the compound of any one of the present inventions 1001 to 1007. [The present invention 1009] R 1 is polar substituted methyl; the compound of any one of the present inventions 1001 to 1007. [The present invention 1010] R 1 is monopolar substituted alkyl (C≦3) ; the compound of any one of the present inventions 1001 to 1007. [The present invention 1011] R 1 is monopolar substituted ethyl; the compound of the present invention 1010. [The present invention 1012] R 1 is monopolar substituted methyl; the compound of the present invention 1010. [The present invention 1013] R 1 is monoaminoalkyl (C≦3) , monofluoroalkyl (C≦3) , or monohydroxyalkyl (C≦3) ; the compound of any one of the present inventions 1001 to 1007 and 1010. [The present invention 1014] R 1 is monoaminoalkyl (C≦3) ; the compound of any one of the present inventions 1001 to 1007 and 1010. [The present invention 1015] R 1 is aminoethyl; the compound of the present invention 1014. [The present invention 1016] R 1 is 2 - aminoethyl; the compound of the present invention 1015. [The present invention 1017] R 1 is aminomethyl; the compound of the present invention 1014. [The present invention 1018] R 1 is monofluoroalkyl (C≦3) ; the compound of any one of the present inventions 1001 to 1007 and 1010. [The present invention 1019] R 1 is fluoroethyl; the compound of the present invention 1018. [The present invention 1020] R 1 is 2 - fluoroethyl; the compound of the present invention 1019. [The present invention 1021] R 1 The compound of the present invention 1018, wherein it is fluoromethyl. [The present invention 1022] R 1 wherein it is monohydroxyalkyl (C≦3) and is any one of the compounds of the present invention 1001 - 1007 and 1010. [The present invention 1023] R 1 The compound of the present invention 1022, wherein it is hydroxyethyl. [The present invention 1024] R 1 The compound of the present invention 1023, wherein it is 2 - hydroxyethyl. [The present invention 1025] R 1 The compound of the present invention 1022, wherein it is hydroxymethyl. [The present invention 1026] R 1 wherein it is -CH 2 CH 2 OC(O)CH 3 and is any one of the compounds of the present invention 1001 - 1007 and 1010. [The present invention 1027] R 1 wherein it is -CH 2 CH 2 NHC(O)OCH 3 and is any one of the compounds of the present invention 1001 - 1007 and 1010. [The present invention 1028] R 1 wherein it is -CH 2 CH 2 NHC(O)NHCH 2CH 3 and is any one of the compounds of the present invention 1001 - 1007 and 1010. [The present invention 1029] R 1 wherein it is -CH 2 CH 2 NHC(O)CH 3 and is any one of the compounds of the present invention 1001 - 1007 and 1010. [The present invention 1030] The following formula: TIFF0007695229000030.tif218134TIFF0007695229000031.tif218143 or any one of the compounds of the present invention 1001 - 1029, further defined as a pharmaceutically acceptable salt of any of these formulas. [The present invention 1031] The following formula: TIFF0007695229000032.tif108133 or any one of the compounds of the present invention 1001 - 1030, further defined as a pharmaceutically acceptable salt of any of these formulas. [The present invention 1032] The following formula: TIFF0007695229000033.tif112134 or any one of the compounds of the present invention 1001 - 1031, further defined as a pharmaceutically acceptable salt of any of these formulas. [The present invention 1033] The following formula: TIFF0007695229000034.tif33128 or any one of the compounds of the present invention 1001 - 1032, further defined as its pharmaceutically acceptable salt. [The present invention 1034] The following formula: TIFF0007695229000035.tif33128 or any one of the compounds of the present invention 1001 - 1032, further defined as its pharmaceutically acceptable salt. [The present invention 1035] The following formula: TIFF0007695229000036.tif33128 or any one of the compounds of the present invention 1001 - 1032, further defined as its pharmaceutically acceptable salt. [The present invention 1036] The following formula: TIFF0007695229000037.tif33128 or any one of the compounds of the present invention 1001 - 1032, further defined as its pharmaceutically acceptable salt. [The present invention 1037] The following formula: TIFF0007695229000038.tif33128 or any one of the compounds of the present invention 1001 - 1032, further defined as its pharmaceutically acceptable salt. [The present invention 1038] The following formula: TIFF0007695229000039.tif33128 A compound of any one of 1001 to 1031 of the present invention, further defined as or a pharmaceutically acceptable salt thereof. [The present invention 1039] A compound of any one of 1001 to 1029 of the present invention, further defined as follows: (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(5-(fluoromethyl)-1,3,4-oxadiazol-2-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(5-(fluoromethyl)-1,2,4-oxadiazol-3-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(5-(aminomethyl)-1,2,4-oxadiazol-3-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(5-(2-aminoethyl)-1,2,4-oxadiazol-3-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(5-(hydroxymethyl)-1,2,4-oxadiazol-3-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(5-(2-Hydroxyethyl)-1,2,4-oxadiazol-3-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(2-(2-Hydroxyethyl)-2H-tetrazol-5-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; 2-(5-((4aS,6aR,6bS,8aR,12aS,14aR,14bS)-11-Cyano-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-hexadecahydropicene-4a(2H)-yl)-2H-tetrazol-2-yl)ethyl acetate; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(2-(2-Fluoroethyl)-2H-tetrazol-5-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(3-(Fluoromethyl)-1,2,4-oxadiazol-5-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(3-(2-Hydroxyethyl)-1,2,4-oxadiazol-5-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; 2-(5-((4aS,6aR,6bS,8aR,12aS,14aR,14bS)-11-Cyano-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-hexadecahydropicene-4a(2H)-yl)-1,2,4-oxadiazol-3-yl)ethyl acetate; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(3-(2-Aminoethyl)-1,2,4-oxadiazol-5-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; Methyl (2-(5-((4aS,6aR,6bS,8aR,12aS,14aR,14bS)-11-Cyano-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-hexadecahydropicene-4a(2H)-yl)-1,2,4-oxadiazol-3-yl)ethyl)carbamate; 1-(2-(5-((4aS,6aR,6bS,8aR,12aS,14aR,14bS)-11-Cyano-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-hexadecahydropicene-4a(2H)-yl)-1,2,4-oxadiazol-3-yl)ethyl)-3-ethylurea; N-(2-(5-((4aS,6aR,6bS,8aR,12aS,14aR,14bS)-11-cyano-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-hexadecahydropicen-4a(2H)-yl)-1,2,4-oxadiazol-3-yl)ethyl)acetamide; (4S,4aS,6aS,6bR,8aS,12aS,12bR,14bR)-8a-(3-(fluoromethyl)-1,2,4-oxadiazol-5-yl)-4,6a,6b,11,11,14b-hexamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4S,4aS,6aS,6bR,8aS,12aS,12bR,14bR)-8a-(3-(difluoromethyl)-1,2,4-oxadiazol-5-yl)-4,6a,6b,11,11,14b-hexamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4S,4aS,6aS,6bR,8aS,12aS,12bR,14bR)-8a-(5-(fluoromethyl)-1,3,4-oxadiazol-2-yl)-4,6a,6b,11,11,14b-hexamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4S,4aS,6aS,6bR,8aS,12aS,12bR,14bR)-8a-(5-(fluoromethyl)-1,2,4-oxadiazol-3-yl)-4,6a,6b,11,11,14b-hexamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(5-(Difluoromethyl)-1,2,4-oxadiazol-3-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(3-(Hydroxymethyl)-1,2,4-oxadiazol-5-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(3-(Difluoromethyl)-1,2,4-oxadiazol-5-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; or (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile. [Invention 1040] A compound of any of Inventions 1001 to 1030 and 1039, further defined as follows: (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(5-(Fluoromethyl)-1,3,4-oxadiazol-2-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(5-(fluoromethyl)-1,2,4-oxadiazol-3-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(5-(aminomethyl)-1,2,4-oxadiazol-3-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(3-(fluoromethyl)-1,2,4-oxadiazol-5-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4S,4aS,6aS,6bR,8aS,12aS,12bR,14bR)-8a-(3-(fluoromethyl)-1,2,4-oxadiazol-5-yl)-4,6a,6b,11,11,14b-hexamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; or (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(3-(2-hydroxyethyl)-1,2,4-oxadiazol-5-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile. [Invention 1041] A compound of any of Invention 1001 - 1031, 1039, and 1040, further defined as follows: (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(5-(fluoromethyl)-1,3,4-oxadiazol-2-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(5-(fluoromethyl)-1,2,4-oxadiazol-3-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(5-(aminomethyl)-1,2,4-oxadiazol-3-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(3-(fluoromethyl)-1,2,4-oxadiazol-5-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; or (4S,4aS,6aS,6bR,8aS,12aS,12bR,14bR)-8a-(3-(fluoromethyl)-1,2,4-oxadiazol-5-yl)-4,6a,6b,11,11,14b-hexamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile. [Invention 1042] A compound of any of Inventions 1001 - 1032, 1039, and 1040, further defined as follows: (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(5-(fluoromethyl)-1,3,4-oxadiazol-2-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile. [Invention 1043] A compound of any one of Inventions 1001 - 1032, 1039, and 1040, further defined as follows: (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(5-(fluoromethyl)-1,2,4-oxadiazol-3-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile. [Invention 1044] A compound of any one of Inventions 1001 - 1032, 1039, and 1040, further defined as follows: (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(5-(aminomethyl)-1,2,4-oxadiazol-3-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile. [Invention 1045] A compound of any one of Inventions 1001 - 1032, 1039, and 1040, further defined as follows: (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(3-(fluoromethyl)-1,2,4-oxadiazol-5-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile. [Invention 1046] A compound of any one of Inventions 1001 - 1032, 1039, and 1040, further defined as follows: (4S,4aS,6aS,6bR,8aS,12aS,12bR,14bR)-8a-(3-(fluoromethyl)-1,2,4-oxadiazol-5-yl)-4,6a,6b,11,11,14b-hexamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile. [Invention 1047] A compound of any one of Inventions 1001 - 1031 and 1039, further defined as follows: (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(3-(2-hydroxyethyl)-1,2,4-oxadiazol-5-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile. [Invention 1048] A compound of the following formula: TIFF0007695229000040.tif34137TIFF0007695229000041.tif218125TIFF0007695229000042.tif144131 Or a pharmaceutically acceptable salt of any of these formulas. [Invention 1049] A compound selected from the group consisting of: (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(5-(2-methoxyethyl)-1,2,4-oxadiazol-3-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(2-(2-methoxyethyl)-2H-tetrazol-5-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(3-(2-Methoxyethyl)-1,2,4-oxadiazol-5-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-4,4,6a,6b,11,11,14b-heptamethyl-8a-(5-methyl-1,2,4-oxadiazol-3-yl)-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-4,4,6a,6b,11,11,14b-heptamethyl-8a-(2-methyl-2H-tetrazol-5-yl)-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-8a-(3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(3-ethyl-1,2,4-oxadiazol-5-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(5-Ethyl-1,2,4-oxadiazol-3-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-8a-(3-propyl-1,2,4-oxadiazol-5-yl)-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(3-Isopropyl-1,2,4-oxadiazol-5-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(3-(tert-Butyl)-1,2,4-oxadiazol-5-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(3-(Cyclopropylmethyl)-1,2,4-oxadiazol-5-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(3-Cyclobutyl-1,2,4-oxadiazol-5-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(3-Cyclopentyl-1,2,4-oxadiazol-5-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(3-Cyclohexyl-1,2,4-oxadiazol-5-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4S,4aS,6aS,6bR,8aS,12aS,12bR,14bR)-4,6a,6b,11,11,14b-Hexamethyl-3,13-dioxo-8a-(3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4S,4aS,6aS,6bR,8aS,12aS,12bR,14bR)-8a-(3-Ethyl-1,2,4-oxadiazol-5-yl)-4,6a,6b,11,11,14b-hexamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-4,4,6a,6b,11,11,14b-Heptamethyl-3,13-dioxo-8a-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-4,4,6a,6b,11,11,14b-Heptamethyl-3,13-dioxo-8a-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile; and (4aR,6aS,6bR,8aS,12aS,12bR,14bS)-8a-(5-Ethyl-1,3,4-oxadiazol-2-yl)-4,4,6a,6b,11,11,14b-heptamethyl-3,13-dioxo-3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-octadecahydropicene-2-carbonitrile. [The present invention 1050] (A) A compound according to any one of the present inventions 1001 to 1049, and (B) An excipient A pharmaceutical composition comprising. [The present invention 1051] The pharmaceutical composition of the present invention 1050, which is formulated for administration by oral, intralipid, intraarterial, intraarticular, intracranial, intradermal, intralesional, intramuscular, intranasal, intraocular, intrapleural, intraperitoneal, intraprostatic, intrarectal, intrathecal, intratracheal, intratumoral, intraumbilical, intravaginal, intravenous, intracellular, intravitreal, liposome, topical, mucosal, parenteral, rectal, subconjunctival, subcutaneous, sublingual, local, buccal, transdermal, intravaginal, cream, lipid composition, catheter, washing, continuous infusion, infusion, inhalation, injection, local delivery, or regional perfusion. [The present invention 1052] The pharmaceutical composition of the present invention 1051, which is formulated for oral administration. [The present invention 1053] The pharmaceutical composition of the present invention 1051, which is formulated for administration by injection. [The present invention 1054] The pharmaceutical composition of the present invention 1053, which is formulated for intraarterial, intramuscular, intraperitoneal, or intravenous administration. [The present invention 1055] The pharmaceutical composition of the present invention 1051, which is formulated for topical administration. [The present invention 1056] The pharmaceutical composition of the present invention 1055, which is formulated for topical administration to the skin or eye. [The present invention 1057] The pharmaceutical composition of any one of the present inventions 1050 to 1056, which is formulated as a unit dosage form. [The present invention 1058] A method of performing it in a patient in need of treating or preventing a disease or disorder, the method comprising administering to the patient a pharmaceutically effective amount of any one of the compounds or compositions of the present inventions 1001 to 1057. [The present invention 1059] The method of the present invention 1058, wherein the patient is a mammal. [The present invention 1060] The method of the present invention 1059, wherein the patient is a human. [The present invention 1061] The method of the present invention 1058, wherein the disease or disorder is a condition associated with inflammation and / or oxidative stress. [The present invention 1062] The method of the present invention 1058, wherein the disease or disorder is cancer. [The present invention 1063] The method of the present invention 1058, wherein the disease or disorder is a cardiovascular disease. [The present invention 1064] The method of the present invention 1063, wherein the cardiovascular disease is atherosclerosis. [The present invention 1065] The method of the present invention 1058, wherein the disease or disorder is an autoimmune disease. [The present invention 1066] The method of the present invention 1065, wherein the autoimmune disease is Crohn's disease, rheumatoid arthritis, lupus, or psoriasis. [The present invention 1067] The method of the present invention 1058, wherein the disease or disorder is a neurodegenerative disease. [The present invention 1068] The method of the present invention 1067, wherein the neurodegenerative disease is Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, or Huntington's disease. [The present invention 1069] The method of the present invention 1058, wherein the disease or disorder is chronic kidney disease, diabetes, mucositis, inflammatory bowel disease, dermatitis, sepsis, ischemia-reperfusion injury (including complications due to sickle cell anemia), influenza, osteoarthritis, osteoporosis, pancreatitis, asthma, chronic obstructive pulmonary disease, cystic fibrosis, idiopathic pulmonary fibrosis, multiple sclerosis, muscular dystrophy, cachexia, or graft-versus-host disease. [The present invention 1070] The method of the present invention 1058, wherein the disease or disorder is an eye disease. [The present invention 1071] The method of the present invention 1070, wherein the eye disease is uveitis, glaucoma, macular degeneration, or retinopathy. [The present invention 1072] The method of the present invention 1058, wherein the disease or disorder is a neuropsychiatric disease or disorder. [The present invention 1073] The method of the present invention 1072, wherein the neuropsychiatric disease or disorder is schizophrenia, depression, bipolar disorder, epilepsy, post-traumatic stress disorder, attention deficit disorder, autism, or anorexia nervosa. [The present invention 1074] The method of the present invention 1058, wherein the disease or disorder is associated with mitochondrial dysfunction. [The present invention 1075] The method of the present invention 1074, wherein the disease or disorder associated with mitochondrial dysfunction is Friedreich's ataxia. [The present invention 1076] The method of the present invention 1058, wherein the disease or disorder is chronic pain. [The present invention 1077] The method of the present invention 1058, wherein the disease or disorder is neuropathic pain. [The present invention 1078] A method of inhibiting nitric oxide production, comprising administering to a patient in need thereof an amount of a compound or composition of the present invention 1001 - 1057 sufficient to cause inhibition of IFN-γ-induced nitric oxide production in one or more cells of the patient. Other objects, features, and advantages of the present invention will become apparent from the following detailed description. However, since various changes and modifications within the spirit and scope of the present invention will become apparent to those skilled in the art from this detailed description, the detailed description and specific examples showing specific embodiments of the present invention are to be understood as being presented for purposes of illustration only. It should be noted that just because a particular compound is assigned to one particular general formula does not mean that the compound cannot also belong to another general formula.

Brief Description of the Drawings

[0040] The following drawings form a part of this specification and are included to further illustrate specific aspects of the present invention. By referring to one or more of these drawings in combination with the detailed description of the specific embodiments presented herein, the present invention can be better understood.

[0041] [Figure 1] It shows CYP3A4 inhibition in human liver microsomes at 1 μM. Each sample containing 0.1 mg / mL human liver microsomes, 5 μM midazolam as a substrate, and 1 μM test compound was incubated at 37°C for 10 minutes. See Example 3 for further details.

Modes for Carrying Out the Invention

[0042] Description of Exemplary Embodiments Novel compounds and compositions having antioxidant and / or anti-inflammatory properties, methods for their manufacture, and methods for their use including the treatment and / or prevention of diseases are disclosed herein.

[0043] I. Compounds of the Present Invention The compounds of the present invention (also referred to as "the synthetic triterpenoid derivatives provided herein", "the compounds of the present disclosure", or "the compounds disclosed herein") are shown, for example, in the Summary of the Invention section above, the following Examples, Table 1, and the following claims. They can be prepared using the synthetic methods outlined in the Examples section. These methods can be further modified and optimized using the principles and techniques of organic chemistry that are applicable to those skilled in the art. These principles and techniques are taught, for example, in Smith, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, (2013), which is incorporated herein by reference. Further, these synthetic methods can be further modified and optimized for production on a preparative scale, either batchwise or continuous, on a pilot scale, or on a large scale using the principles and techniques of process chemistry that are applicable to those skilled in the art. These principles and techniques are taught, for example, in Anderson, Practical Process Research & Development - A Guide for Organic Chemists (2012), which is incorporated herein by reference.

[0044] (Table 1) Examples of synthetic triterpenoid derivatives provided herein TIFF0007695229000043.tif234108TIFF0007695229000044.tif234142TIFF0007695229000045.tif234142TIFF0007695229000046.tif234142TIFF0007695229000047.tif233142TIFF0007695229000048.tif234142

[0045] In some embodiments, all compounds of the invention can be used for the prevention and treatment of one or more diseases or disorders described herein or elsewhere. In some embodiments, one or more compounds characterized or exemplified herein as intermediates, metabolites, and / or prodrugs may still be useful for the prevention and treatment of one or more diseases or disorders. Thus, unless explicitly stated to the contrary, all compounds of the invention are considered “active compounds” and “therapeutic compounds” intended for use as active pharmaceutical ingredients (APIs). Typically, actual suitability for human or veterinary use is determined using a combination of clinical trial protocols and regulatory procedures such as those implemented by the US Food and Drug Administration (FDA). In the United States, the FDA is responsible for protecting public health by ensuring the safety, effectiveness, quality, and security of drugs, vaccines, and other biological products, as well as medical devices, for human and veterinary use.

[0046] In some embodiments, the compounds of the invention have the advantage that, whether used in the indications described herein or otherwise, they are more effective, less toxic, longer acting, more potent, have fewer side effects, are more readily absorbed, have high metabolic stability, are highly lipophilic, are highly hydrophilic, and / or exhibit a good pharmacokinetic profile (e.g., high oral bioavailability and / or low clearance), and / or exhibit other useful pharmacological, physical, or chemical properties compared to compounds known in the prior art.

[0047] The compounds of the present disclosure may contain one or more asymmetrically substituted carbon or nitrogen atoms and may be isolated as optically active forms or racemates. Accordingly, unless a specific stereochemical configuration or isomer is specifically indicated, all chiral forms, diastereoisomers, racemates, epimers, and all geometric isomers of a given chemical formula are intended. The compounds can occur as racemates and racemic mixtures, single enantiomers, diastereomer mixtures and individual diastereomers. In some embodiments, a single diastereomer is obtained. The chiral centers of the compounds of the present invention may exhibit the S configuration or the R configuration. In some embodiments, the compounds may contain two or more atoms exhibiting a defined stereochemical orientation.

[0048] Typically, the chemical formulas used to represent the compounds of the present invention will show only one of perhaps several different tautomers. For example, many types of ketone groups are known to exist in equilibrium with the corresponding enol groups. Similarly, many types of imine groups exist in equilibrium with enamine groups. Regardless of which tautomer is shown for a given compound and regardless of which tautomer is most dominant, all tautomers of a given chemical formula are intended.

[0049] Furthermore, the atoms making up the compounds of the present invention are intended to include all isotopic forms of the atoms. Isotopes as used herein include atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include 13 C and 14 C.

[0050] In some embodiments, the compounds of the present invention function as prodrugs or can be derivatized to function as prodrugs. Since prodrugs are known to enhance many desirable properties of pharmaceuticals, such as solubility, bioavailability, manufacturability, etc., if desired, the compounds used in some methods of the present invention may be delivered in prodrug form. Accordingly, the present invention contemplates prodrugs of the compounds of the present invention and methods of delivering prodrugs. The prodrugs of the compounds used in the present invention can be prepared by modifying the functional groups present in the compounds such that the modification is cleaved either routinely or in vivo to yield the parent compound. Thus, prodrugs include, for example, compounds described herein in which a hydroxy group, an amino group, or a carboxy group is attached to any group that cleaves upon administration of the prodrug to a patient to form a hydroxy acid, an amino acid, or a carboxylic acid, respectively.

[0051] In some embodiments, the compounds of the present invention exist in salt or non-salt form. With respect to salt forms, in some embodiments, the particular anion or cation that forms part of any salt form of the compounds provided herein is not critical so long as the salt as a whole is pharmaceutically acceptable. Further examples of pharmaceutically acceptable salts and methods of their preparation and use are set forth in Handbook of Pharmaceutical Salts: Properties, and Use (2002), which is incorporated herein by reference.

[0052] It will be appreciated that many organic compounds can form complexes with solvents in which they react or from which they precipitate or crystallize. These complexes are known as "solvates". When the solvent is water, the complex is known as a "hydrate". It will also be appreciated that many organic compounds can exist in two or more solid forms, including crystalline and amorphous forms. All solid forms of the compounds provided herein, including any solvates thereof, are within the scope of the present invention.

[0053] II. Biological Activity The assay results regarding the inhibition of IFNγ-induced NO production for several compounds of the present invention are shown in Tables 2 and 3 of Example 2. Table 2 shows these results in comparison with the results of bardoxolone methyl (RTA 402, CDDO-Me). Table 3 shows these results in comparison with comparative compounds CC1, CC2, and CC3. Details regarding this assay are shown in the Examples section below.

[0054] In some embodiments, the synthetic triterpenoid derivatives provided herein substituted with polar substituents at the C17 heteroaryl group showed improved nitric oxide inhibition in comparison with compounds lacking these substituents, e.g., the compounds disclosed in U.S. Patent No. 9,512,094, which is incorporated herein by reference. For example, the IC 50 value of fluoro-substituted T12 was 36% lower (1.27 nM vs. 1.98 nM) than that of the corresponding unsubstituted compound CC2 (TX63501; U.S. Patent No. 9,512,094). In another example, the IC 50 values of hydroxy-substituted T13 and acetoxy-substituted T14 were 88% and 90% lower, respectively, than those of the corresponding unsubstituted compound T23 (4.85 nM vs. 0.56 nM and 0.48 nM, respectively). In another example, the IC 50 values of fluoro-substituted T1, amino-substituted T2, and hydroxy-substituted T4 were 67%, 70%, and 52% lower, respectively, than those of the corresponding unsubstituted compound T20 (3.79 nM vs. 1.24 nM, 1.15 nM, and 1.82 nM, respectively). Similarly, amino-substituted T3 and hydroxy-substituted T5 were 72% and 83% lower, respectively, than the corresponding unsubstituted compound T24 (9.21 nM vs. 2.60 nM and 1.57 nM, respectively). In another example, the IC 50 value of fluoro-substituted T11 was 52% lower (0.98 nM vs. 2.05 nM) than that of the corresponding unsubstituted compound CC1 (TX63384; U.S. Patent No. 9,512,094). In yet another example, the IC 50The value is 31% lower (0.93 nM compared to 1.34 nM) than that of the corresponding unsubstituted compound CC3 (TX63787; U.S. Patent No. 9,290,536). In some embodiments, complete replacement of all hydrogens with polar substituents decreases nitric oxide inhibitory activity. Compare the trifluoromethyl derivative T22 (23.95 nM) with the monofluoromethyl derivative T12 (1.27 nM).

[0055] In some embodiments, the compounds of the present disclosure exhibit a decrease in the inhibition of cytochrome P450 3A4 (CYP3A4) in comparison to known compounds. CYP3A4 is an important enzyme in the body that enables the removal of foreign organic small molecules (xenobiotics), such as toxins or drugs, by oxidizing them so that they can be excreted from the body. The action of a drug modified by CYP3A4 can be amplified or attenuated by the regulation of CYP3A4. Inhibition of CYP3A4 can indicate adverse side effects (e.g., decreased drug clearance, amplified drug action, and / or increased likelihood of drug-drug interactions), which can make dosing difficult. Thus, in many cases, drugs that do not inhibit CYP3A4 are desirable.

[0056] The assay results regarding the inhibition of CYP3A4 for several compounds of the present disclosure are shown in Tables 4 - 7 of Example 3. In some embodiments, the synthetic triterpenoid derivatives provided herein substituted with polar substituents at the C17 heteroaryl group show a decrease in CYP3A4 inhibition compared to compounds lacking these substituents, such as the compounds disclosed in U.S. Patent No. 9,512,094 and U.S. Patent No. 9,290,536, which are hereby incorporated by reference in their entirety. For example, the CYP3A4 inhibition values of fluoro - substituted T1, amino - substituted T2, and fluoro - substituted T12 were 36%, 53%, and 35% lower, respectively, than those of the corresponding unsubstituted compound CC2 (TX63501; U.S. Patent No. 9,512,094) (29.1% inhibition, 21.4% inhibition, and 29.7% inhibition, respectively, compared to 45.8% inhibition). In another example, the CYP3A4 inhibition value of fluoro - substituted T11 was 15% lower than that of the corresponding unsubstituted compound CC1 (TX63384; U.S. Patent No. 9,512,094) (17.7% inhibition compared to 20.7% inhibition). In another example, the CYP3A4 inhibition value of fluoro - substituted T34 was 22% lower than that of the corresponding unsubstituted compound CC3 (TX63787; U.S. Patent No. 9,290,536) (29.4% inhibition compared to 37.7% inhibition). Further, T1, T2, T11, T12, and T34 each showed a decrease in CYP3A4 inhibition compared to historical data regarding RTA 402 and RTA 408 performed under equivalent conditions (Figure 1).

[0057] III. Diseases Related to Inflammation and / or Oxidative Stress Inflammation is a biological process that results in resistance to infectious or parasitic organisms and the repair of damaged tissues. Inflammation is generally characterized by localized vasodilation, erythema, swelling, and pain, the recruitment of white blood cells to the site of infection or injury, the production of inflammatory cytokines such as TNF-α and IL-1, and the production of reactive oxygen species or reactive nitrogen species such as hydrogen peroxide, superoxide, and peroxynitrite. In the later stages of inflammation, tissue remodeling, angiogenesis, and scar formation (fibrosis) can occur as part of the wound healing process. Under normal circumstances, the inflammatory response is controlled and transient, and resolves integrally if the infection or injury is appropriately addressed. However, acute inflammation can become excessive and life-threatening if the control mechanisms fail. Alternatively, inflammation can become chronic and cause cumulative tissue damage or systemic complications. Based at least on the grounds presented above, the compounds of the present disclosure can be used for the treatment or prevention of inflammation or diseases associated with inflammation.

[0058] Many severe and refractory human diseases involve dysregulation of inflammatory processes, including diseases such as cancer, atherosclerosis, and diabetes, which have not traditionally been viewed as inflammatory states. In the case of cancer, the inflammatory process is associated with tumor formation, progression, metastasis, and treatment resistance. Atherosclerosis, which has long been regarded as a lipid metabolism disorder, is primarily an inflammatory state, and it is now understood that activated macrophages play an important role in the formation and ultimate rupture of atherosclerotic plaques. Activation of inflammatory signaling pathways has also been found to play a role in the development of insulin resistance and peripheral tissue damage associated with diabetic hyperglycemia. Excessive production of reactive oxygen species and reactive nitrogen species, such as superoxide, hydrogen peroxide, nitric oxide, and peroxynitrite, is characteristic of inflammatory states. Evidence of dysregulation of peroxynitrite production has been reported in a variety of diseases (Szabo et al., 2007; Schulz et al., 2008; Forstermann, 2006; Pall, 2007). In many cases, age-related diseases such as dementia, muscle wasting, cardiovascular disease, neurodegenerative diseases, and arthritis involve chronic inflammation and oxidative stress as major contributing factors. In some aspects, the compounds provided herein can be used to treat and / or prevent age-related diseases such as dementia, muscle wasting, cardiovascular disease, neurodegenerative diseases, or arthritis.

[0059] Autoimmune diseases such as rheumatoid arthritis, lupus, psoriasis, and multiple sclerosis involve inappropriate and chronic activation of inflammatory processes in affected tissues, which results from dysfunction of the self-nonself recognition and response mechanisms in the immune system. In some embodiments, the compounds provided herein can be used in the treatment and / or prevention of autoimmune diseases such as rheumatoid arthritis, lupus, psoriasis, or multiple sclerosis. In neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, nerve damage correlates with activation of microglia and increased levels of pro-inflammatory proteins such as inducible nitric oxide synthase (iNOS). In some embodiments, the compounds provided herein can be used in the treatment and / or prevention of neurodegenerative diseases such as Alzheimer's disease or Parkinson's disease. Chronic organ failure such as renal failure, heart failure, liver failure, and chronic obstructive pulmonary disease is closely associated with the presence of chronic oxidative stress and inflammation that lead to the development of fibrosis and eventual loss of organ function. In some embodiments, the compounds provided herein can be used in the treatment and / or prevention of chronic organ failure such as renal failure, heart failure, liver failure, or chronic obstructive pulmonary disease. Oxidative stress in vascular endothelial cells lining large and small blood vessels can lead to endothelial dysfunction and is thought to be an important contributing factor in the development of several other age-related diseases, including systemic cardiovascular diseases, diabetic complications, chronic kidney diseases, and other forms of organ failure, as well as degenerative central nervous system diseases and degenerative retinal diseases. In some embodiments, the compounds provided herein can be used in the treatment and / or prevention of several other age-related diseases, including systemic cardiovascular diseases, diabetic complications, chronic kidney diseases, and other forms of organ failure, as well as degenerative central nervous system diseases and degenerative retinal diseases.

[0060] Many other disorders, including inflammatory bowel disease; inflammatory skin diseases; mucositis associated with radiotherapy and chemotherapy; eye diseases such as uveitis, glaucoma, macular degeneration, and various forms of retinopathy; transplant failure and transplant rejection; ischemia-reperfusion injury; chronic pain; degenerative bone and joint conditions including osteoarthritis and osteoporosis; asthma and cystic fibrosis; seizure disorders; and neuropsychiatric conditions including eating disorders such as schizophrenia, depression, bipolar disorder, post-traumatic stress disorder, attention deficit disorder, autism spectrum disorder, and anorexia nervosa, involve oxidative stress and inflammation in the affected tissue. In some embodiments, the compounds provided herein can be used in the treatment and / or prevention of inflammatory bowel disease; inflammatory skin diseases; mucositis associated with radiotherapy and chemotherapy; eye diseases such as uveitis, glaucoma, macular degeneration, and various forms of retinopathy; transplant failure and transplant rejection; ischemia-reperfusion injury (including complications due to sickle cell anemia); chronic pain; degenerative bone and joint conditions including osteoarthritis and osteoporosis; asthma and cystic fibrosis; seizure disorders; and neuropsychiatric conditions including eating disorders such as schizophrenia, depression, bipolar disorder, post-traumatic stress disorder, attention deficit disorder, autism spectrum disorder, or anorexia nervosa. Dysregulation of inflammatory signaling pathways is thought to be a major cause of the pathology of muscle wasting diseases including muscular dystrophy and various forms of cachexia. In some embodiments, the compounds provided herein can be used in the treatment and / or prevention of muscle wasting diseases such as muscular dystrophy and various forms of cachexia.

[0061] Furthermore, various life-threatening acute disorders involve dysregulation of inflammatory signaling, including acute organ failure involving the pancreas, kidney, liver, or lung, myocardial infarction or acute coronary syndrome, stroke, septic shock, trauma, severe burns, and anaphylaxis.

[0062] Moreover, many complications of infectious diseases involve dysregulation of the inflammatory response. The inflammatory response can kill invading pathogens, but an excessive inflammatory response can be quite destructive and, in some cases, can be the primary source of damage in the affected tissue. Furthermore, an excessive inflammatory response can lead to systemic complications due to overproduction of inflammatory cytokines such as TNF-α and IL-1. This is thought to be an important factor in deaths caused by severe influenza, infections with coronaviruses including SARS-CoV-2 which causes COVID-19, severe acute respiratory syndrome due to infections with other viruses that cause upper respiratory tract diseases, and sepsis. In some embodiments, the compounds provided herein can be used in the treatment and / or prevention of severe acute respiratory syndrome due to influenza, infections with coronaviruses including SARS-CoV-2, or infections with other viruses that cause upper respiratory tract diseases, or sepsis.

[0063] Aberrant or overexpression of iNOS or cyclooxygenase 2 (COX-2) has been implicated in the pathogenesis of many disease processes. For example, it is clear that NO is a potent mutagen (Tamir and Tannebaum, 1996), and that nitric oxide can also activate COX-2 (Salvemini et al., 1994). Furthermore, iNOS is significantly increased in rat colon tumors induced by the carcinogen azoxymethane (Takahashi et al., 1997). A series of synthetic triterpenoid analogs of oleanolic acid have been found to be potent inhibitors of cellular inflammatory processes such as the induction of inducible nitric oxide synthase (iNOS) and COX-2 by IFN-γ in mouse macrophages. See Honda et al. (2000a); Honda et al. (2000b) and Honda et al. (2002), which are hereby incorporated by reference in their entirety. Also, an increase in iNOS levels in brain tissue has been associated with Alzheimer's disease (Sporn et al., 1996). In some embodiments, the compounds provided herein can be used in the treatment and / or prevention of Alzheimer's disease.

[0064] In one aspect, the compounds disclosed herein are characterized by their ability to inhibit the production of nitric oxide in macrophage-derived RAW 264.7 cells induced by exposure to gamma interferon. They are further characterized by their ability to induce the expression of antioxidant proteins such as NQO1 and decrease the expression of pro-inflammatory proteins such as COX-2 and inducible nitric oxide synthase (iNOS). These properties are relevant to the treatment of a variety of diseases and disorders encompassing oxidative stress and dysregulation of the inflammatory process, including cancer, complications due to local or systemic exposure to ionizing radiation, mucositis resulting from radiotherapy or chemotherapy, autoimmune diseases, cardiovascular diseases including atherosclerosis, ischemia-reperfusion injury (including complications due to sickle cell anemia), acute and chronic organ failure including renal and heart failure, respiratory diseases, diabetes and diabetic complications, severe allergies, transplant rejection, graft-versus-host disease, neurodegenerative diseases, eye diseases and retinal diseases, acute and chronic pain, degenerative bone diseases including osteoarthritis and osteoporosis, inflammatory bowel diseases, dermatitis and other skin diseases, sepsis, burns, seizure disorders, and neuropsychiatric disorders. In some embodiments, the compounds provided herein can be used in the treatment and / or prevention of cancer, complications due to local or systemic exposure to ionizing radiation, mucositis resulting from radiotherapy or chemotherapy, autoimmune diseases, cardiovascular diseases including atherosclerosis, ischemia-reperfusion injury (including complications due to sickle cell anemia), acute and chronic organ failure including renal and heart failure, respiratory diseases, diabetes and diabetic complications, severe allergies, transplant rejection, graft-versus-host disease, neurodegenerative diseases, eye diseases and retinal diseases, acute and chronic pain, degenerative bone diseases including osteoarthritis and osteoporosis, inflammatory bowel diseases, dermatitis and other skin diseases, sepsis, burns, seizure disorders, or neuropsychiatric disorders.

[0065] Without being bound by theory, activation of the antioxidant / anti-inflammatory Keap1 / Nrf2 / ARE pathway is thought to be associated with both the anti-inflammatory and anti-tumorigenic properties of the compounds disclosed herein.

[0066] In another aspect, the compounds disclosed herein can be used to treat a patient having an elevated level of oxidative stress in one or more tissues that causes a state. Oxidative stress is caused by abnormally high or persistent levels of reactive oxygen species such as superoxide, hydrogen peroxide, nitric oxide, and peroxynitrite (formed by the reaction of nitric oxide and superoxide). Oxidative stress may be accompanied by acute or chronic inflammation. Oxidative stress can be caused by mitochondrial dysfunction, activation of immune cells such as macrophages and neutrophils, external agents such as ionizing radiation, or acute exposure to cytotoxic chemotherapeutic agents (e.g., doxorubicin), trauma or other acute tissue injury, ischemia-reperfusion, poor circulation or anemia, localized or systemic hypoxia or hyperoxia, elevated levels of inflammatory cytokines and other inflammation-related proteins, and / or other abnormal physiological conditions such as hyperglycemia or hypoglycemia. In some embodiments, the compounds provided herein can be used in the treatment and / or prevention of mitochondrial dysfunction and disorders associated therewith.

[0067] In animal models of many of these conditions, including models of myocardial infarction, renal failure, transplant failure and rejection, stroke, cardiovascular disease, and autoimmune disease, stimulation of the expression of inducible heme oxygenase (HO-1), a target gene of the Nrf2 pathway, has been shown to have significant therapeutic effects (e.g., Sacerdoti et al., 2005; Abraham & Kappas, 2005; Bach, 2006; Araujo et al., 2003; Liu et al., 2006; Ishikawa et al., 2001; Kruger et al., 2006; Satoh et al., 2006; Zhou et al., 2005; Morse and Choi, 2005; Morse and Choi, 2002). This enzyme degrades free heme into iron, carbon monoxide (CO), and biliverdin (which is subsequently converted to the powerful antioxidant molecule bilirubin). Carbon monoxide has been shown to have signaling functions, and biliverdin reductase, an enzyme that catalyzes the conversion of biliverdin to bilirubin, has been found to function as a dual-specificity kinase and regulate HO-1 expression (Motterlini & Foresti, 2017; Florczyk et al., 2008).

[0068] In another aspect, the compounds of the present disclosure can be used in the prevention or treatment of acute and chronic tissue damage or organ failure caused by oxidative stress exacerbated by inflammation. Examples of diseases belonging to this classification include heart failure, liver failure, transplant failure and rejection, renal failure, pancreatitis, fibrotic lung diseases (particularly cystic fibrosis, COPD, and idiopathic pulmonary fibrosis), diabetes (including complications), atherosclerosis, ischemia-reperfusion injury, glaucoma, stroke, autoimmune diseases, autism, macular degeneration, and muscular dystrophy. For example, in the case of autism, studies have suggested that increased oxidative stress in the central nervous system may contribute to the development of the disorder (Chauhan and Chauhan, 2006).

[0069] Moreover, evidence indicates an association between oxidative stress and inflammation and the development and pathogenesis of many other central nervous system disorders, including psychiatric disorders such as psychosis, major depression, post-traumatic stress disorder (PTSD), and bipolar disorder; seizure disorders such as epilepsy; pain and sensory syndromes such as migraine, neuropathic pain, or tinnitus; and behavioral syndromes such as attention deficit disorder. See, for example, Dickerson et al., 2007; Hanson et al., 2005; Kendall-Tackett, 2007; Lencz et al., 2007; Dudhgaonkar et al., 2006; Lee et al., 2007; Morris et al., 2002; Ruster et al., 2005; McIver et al., 2005; Sarchielli et al., 2006; Kawakami et al., 2006; Ross et al., 2003, each of which is incorporated herein by reference. For example, elevated levels of inflammatory cytokines, including TNF, interferon γ, and IL-6, are associated with major psychiatric disorders (Dickerson et al., 2007). Microglial activation is also associated with major psychiatric disorders. Thus, downregulation of inflammatory cytokines and inhibition of microglial overactivation may be beneficial in patients with schizophrenia, major depression, bipolar disorder, autism spectrum disorder, and other neuropsychiatric disorders. In some embodiments, the compounds provided herein can be used in the treatment and / or prevention of central nervous system disorders, including psychiatric disorders such as psychosis, major depression, post-traumatic stress disorder (PTSD), and bipolar disorder; seizure disorders such as epilepsy; pain and sensory syndromes such as migraine, neuropathic pain, or tinnitus; and behavioral syndromes such as attention deficit disorder.

[0070] Thus, in conditions that are exacerbated by oxidative stress, including oxidative stress exacerbated by a single oxidative stress or inflammation, treatment can include administering to a subject a therapeutically effective amount of a compound of the present disclosure, such as the compounds described above or the compounds described throughout this specification. Treatment may be carried out prophylactically before a predictable oxidative stress state (such as an organ transplant or the administration of radiotherapy to a cancer patient), or may be carried out therapeutically in a situation that already includes oxidative stress and inflammation.

[0071] The compounds disclosed herein can generally be applied to the treatment of inflammatory conditions such as sepsis, dermatitis, autoimmune diseases, and osteoarthritis. In one aspect, the compounds of the present disclosure can be used to treat inflammatory pain and / or neuropathic pain, for example, by induction of Nrf2 and / or inhibition of NF-κB.

[0072] In some embodiments, the compounds disclosed herein can be used in the treatment and prevention of diseases such as cancer, inflammation, Alzheimer's disease, Parkinson's disease, multiple sclerosis, autism, amyotrophic lateral sclerosis, Huntington's disease, rheumatoid arthritis, lupus, Crohn's disease, and psoriasis, autoimmune diseases, inflammatory bowel diseases, all other diseases whose onset is thought to involve overproduction of nitric oxide or prostaglandins, and conditions that include oxidative stress exacerbated by a single oxidative stress or inflammation.

[0073] Another aspect of inflammation is the production of inflammatory prostaglandins such as prostaglandin E. These molecules promote vasodilation, extravasation of plasma, localized pain, hyperthermia, and other symptoms of inflammation. The inducible form of the enzyme COX-2 is associated with their production, and high levels of COX-2 are found in inflamed tissues. Thus, inhibition of COX-2 can alleviate many symptoms of inflammation, and several important anti-inflammatory drugs (e.g., ibuprofen and celecoxib) act by inhibiting COX-2 activity. However, recent studies have shown that a class of cyclopentenone prostaglandins (cyPGs) (e.g., 15-deoxyprostaglandin J2, also known as PGJ2) play a role in stimulating the tissue resolution of inflammation (e.g., Rajakariar et al., 2007). COX-2 is also associated with the production of cyclopentenone prostaglandins. Thus, inhibition of COX-2 may potentially promote the persistence of activated immune cells in tissues and lead to chronic "smoldering" inflammation by interfering with the complete resolution of inflammation. This effect may contribute to the increased incidence of cardiovascular disease in patients using selective COX-2 inhibitors for extended periods.

[0074] In one aspect, the compounds disclosed herein can be used to modulate the production of pro-inflammatory cytokines within a cell by selectively activating regulatory cysteine residues (RCRs) on proteins that control the activity of redox-sensitive transcription factors. Activation of RCRs by cyPGs has been found to initiate a resolution-promoting program that potently induces the activity of the antioxidant and cytoprotective transcription factor Nrf2 and suppresses the activity of the pro-oxidant and pro-inflammatory transcription factors NF-κB and STAT. In some embodiments, this results in increased production of antioxidant and reducing molecules (NQO1, HO-1, SOD1, γ-GCS) and decreased production of pro-oxidant and pro-inflammatory molecules (iNOS, COX-2, TNF-α). In some embodiments, the compounds of the present disclosure can return cells having an inflammatory event to a non-inflammatory state by promoting the resolution of inflammation and limiting excessive tissue damage to the host.

[0075] IV. Pharmaceutical Formulations and Routes of Administration In another aspect, with respect to administration to a patient in need of the above treatment, a pharmaceutical formulation (also referred to as a pharmaceutical preparation, pharmaceutical composition, pharmaceutical product, medicinal product, medicine, drug, or pharmaceutical) comprises a therapeutically effective amount of a compound disclosed herein formulated with one or more excipients and / or drug carriers suitable for the indicated route of administration. In some embodiments, the compounds disclosed herein are formulated in a manner suitable for the treatment of human and / or veterinary patients. In some embodiments, formulation comprises mixing or combining one or more compounds disclosed herein with one or more of the following excipients: lactose, sucrose, starch powder, cellulose alkanoate, cellulose alkyl ester, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, gum arabic, sodium alginate, polyvinylpyrrolidone, and / or polyvinyl alcohol. In some embodiments, for example with respect to oral administration, the pharmaceutical formulation can be tableted or encapsulated. In some embodiments, the compound can be dissolved or slurried in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and / or various buffers. In some embodiments, the pharmaceutical formulation may be subjected to pharmaceutical operations such as sterilization, and / or the pharmaceutical formulation may contain drug carriers and / or excipients such as preservatives, stabilizers, wetting agents, emulsifying agents, encapsulating agents such as lipids, dendrimers, polymers, proteins such as albumin, nucleic acids, and buffers.

[0076] The pharmaceutical formulations can be administered in various ways, for example, orally or by injection (e.g., subcutaneous, intravenous, and intraperitoneal). Depending on the route of administration, the compounds disclosed herein can be coated in a material to protect the compounds from the action of acids that can inactivate the compounds and other natural conditions. To administer the active compounds other than parenterally, it may be necessary to coat the compounds with a material that prevents their inactivation or co-administer the compounds with it. In some embodiments, the active compounds may be administered to a patient in a suitable carrier, such as liposomes, or a diluent. Pharmaceutically acceptable diluents include saline and buffered aqueous solutions. Liposomes include water-in-oil-in-water type CGF emulsions and normal liposomes.

[0077] Also, the compounds disclosed herein can be administered parenterally, intraperitoneally, intraspinally, or intracerebrally. Dispersion agents can be prepared in glycerin, liquid polyethylene glycol, and mixtures thereof, as well as in oils. Under ordinary storage and use conditions, these preparations may contain preservatives to prevent the growth of microorganisms.

[0078] Suitable pharmaceutical compositions for injection include sterile aqueous solutions (in the case of water-soluble substances) or aqueous dispersion solutions, and sterile powders for the immediate preparation of sterile injection solutions or dispersion solutions. The carrier can be a solvent or dispersion medium, for example, including water, ethanol, polyols (such as glycerin, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils. Appropriate fluidity can be maintained, for example, by the use of coatings such as lecithin, maintaining the required particle size in the case of dispersion solutions, and the use of surfactants. Prevention of the action of microorganisms can be achieved with various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc. In many cases, it is preferable to include in the composition an isotonic agent, such as sugar, sodium chloride, or polyhydric alcohols such as mannitol and sorbitol. Prolonged absorption of the injection composition can be brought about by including in the composition an agent that delays absorption, such as aluminum monostearate or gelatin.

[0079] The compounds disclosed herein can be administered orally, for example, together with an inert diluent or an assimilable edible carrier. The compounds and other ingredients can also be enclosed in hard or soft shell gelatin capsules, compressed into tablets, or directly incorporated into the diet of the subject. For therapeutic oral administration, the compounds disclosed herein can be incorporated with excipients and used in the form of tablets for oral ingestion, buccal tablets, troches, capsules, elixirs, suspensions, syrups, oblatum, etc. The proportion of the therapeutic compound in the composition and preparation can naturally vary. The amount of the therapeutic compound in these pharmaceutical formulations is an amount that gives a suitable dosage.

[0080] In addition, the therapeutic compound can be topically administered to the skin, eye, ear, or mucosa. Topical administration of the therapeutic compound can include formulation of the compound as a topical solution, lotion, cream, ointment, gel, foam, transdermal patch, or tincture. When formulating the therapeutic compound for topical administration, the compound can be combined with one or more agents that increase the permeability of the compound through the tissue to which it is administered. In other embodiments, topical administration is envisioned to be to the eye. This administration can be applied to the surface of the cornea, conjunctiva, or sclera. Without wishing to be bound by theory, it is believed that administration to the surface of the eye can allow the therapeutic compound to reach the posterior portion of the eye. Ophthalmic topical administration can be formulated as a solution, suspension, ointment, gel, or emulsion. Finally, topical administration can include administration to mucosa such as the inside of the mouth. This administration can be performed directly to a specific location within the mucosa such as a tooth, erosion, or ulcer. Alternatively, if local delivery to the lungs is desired, the therapeutic compound can be administered by inhalation in a dry powder or aerosol formulation.

[0081] In some embodiments, it may be advantageous to formulate the parenteral composition in unit dosage form to facilitate administration and to achieve uniform dosage. As used herein, unit dosage form means a physically discrete unit suitable as a unit dosage for the patient to be treated, each unit containing a predetermined quantity of the therapeutic compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. In some embodiments, the specifications for the unit dosage forms of the invention are determined by and directly dependent on (a) the unique properties of the therapeutic compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding the therapeutic compound for the treatment of the selected condition in a patient. In some embodiments, the active compound is administered in a therapeutically effective dosage sufficient to treat the condition-related condition in a patient. For example, the efficacy of the compound can be evaluated in an animal model system capable of predicting efficacy in treating a disease in a human or other animal.

[0082] In some embodiments, the effective amount range of a therapeutic compound can be extrapolated from the effective amounts determined in animal tests on various different animals. In some embodiments, the human equivalent dose (HED) in mg / kg can be calculated according to the following formula (see, for example, Reagan-Shaw et al., FASEB J., 22(3):659-661, 2008, which is incorporated herein by reference). HED (mg / kg) = animal dose (mg / kg) x (animal K m / human K m ) Using the K m factor in the conversion results in an HED value based on body surface area (BSA) rather than just body weight. The K m values for humans and various animals are well known. For example, the K 2 of an average 60 kg human (having a BSA of 1.6 m m ) is 37, while that of a 20 kg child (BSA 0.8 m 2 ) would have a K m of 25. The K m values for several relevant animal models are also well known, including K m of 3 for a mouse (assuming a body weight of 0.02 kg and a BSA of 0.007), K m of 5 for a hamster (assuming a body weight of 0.08 kg and a BSA of 0.02), K m of 6 for a rat (assuming a body weight of 0.15 kg and a BSA of 0.025), and K m of 12 for a monkey (assuming a body weight of 3 kg and a BSA of 0.24).

[0083] The exact amount of the therapeutic composition depends on the judgment of the practicing physician and is specific to each individual. Nevertheless, the calculated HED dose provides a general guideline. Other factors that can affect the dose include the patient's physical and clinical condition, the route of administration, the intended treatment goal, and the potency, stability, and toxicity of the particular therapeutic formulation.

[0084] The actual dosage of the compounds of the present disclosure or the compositions containing the compounds of the present disclosure administered to a patient can be determined by physical and physiological factors such as the type of animal being treated, age, sex, body weight, severity of the condition, type of disease being treated, previous or concurrent therapeutic interventions, the idiosyncrasy of the patient, and the route of administration. These factors can be determined by those skilled in the art. Usually, the practicing physician responsible for administration determines the concentration of the active ingredient in the composition and the dosage suitable for an individual patient. In the event of any complications, the individual physician can adjust the dosage.

[0085] In some embodiments, typically, the pharmaceutically effective amount varies from about 0.001 mg / kg to about 1000 mg / kg, from about 0.01 mg / kg to about 750 mg / kg, from about 100 mg / kg to about 500 mg / kg, from about 1 mg / kg to about 250 mg / kg, from about 10 mg / kg to about 150 mg / kg in single or multiple dose administrations per day, over one day, or over several days (of course, depending on the mode of administration and the factors described above). Other suitable dosage ranges include 1 mg to 10,000 mg per day, 100 mg to 10,000 mg per day, 500 mg to 10,000 mg per day, and 500 mg to 1,000 mg per day. In some embodiments, the amount is less than 10,000 mg per day and in the range of 750 mg to 9,000 mg per day.

[0086] In some embodiments, the amount of the active compound in the pharmaceutical formulation is from about 2 to about 75 weight percent. In some of these embodiments, the amount is from about 25 to about 60 weight percent.

[0087] Single or multiple dose formulations are contemplated. Desirable time intervals for multiple dose delivery can be determined by those skilled in the art using routine experimental methods. As an example, two doses can be administered to a patient daily at approximately 12 - hour intervals. In some embodiments, the formulation is administered once a day.

[0088] The agent can be administered on a daily schedule. As used herein, a daily schedule means a predetermined specified period. The daily schedule can include periods of the same length or different lengths as long as the schedule is predetermined. For example, the daily schedule can include administration twice a day, daily, every two days, every three days, every four days, every five days, every six days, weekly, monthly, or any number of days or weeks set therein. Alternatively, a given daily schedule can include twice a day for the first week, daily administration for the next several months, etc. In other embodiments, the present invention provides a daily schedule in which the agent is orally ingestible, and a daily schedule whose timing is dependent or independent of food intake. Thus, for example, the agent can be ingested every morning and / or every night, regardless of whether the patient has eaten or is about to eat.

[0089] V. Combination Therapy In addition to use as monotherapy, the compounds of the present disclosure may be used in combination therapy. In some embodiments, the compounds of the present disclosure may be combined with one or more agents (correctors) that promote proper folding or assembly of CFTR, or one or more agents (enhancers) that enhance the function of CFTR. For example, the combination can include the compound of the present invention in combination with one or more correctors, with one or more enhancers, or with a combination of correctors and enhancers. In other examples, the combination includes an amplifier in combination with only one compound of the present invention, or in combination with the compound of the present invention and the above combination of correctors and enhancers.

[0090] In some embodiments, combination therapy is provided that combines the compounds disclosed herein with another CF treatment, such as a compound designed to improve the function of CFTR that has reached the cell membrane and is capable of at least partial function. These compounds are known as CFTR enhancers, and ivacaftor, the first disease-specific treatment for CF, has been clinically demonstrated to improve CFTR function in patients with several significant mutations. Compounds that prevent CFTR misfolding are known as correctors. In some embodiments, the compounds of the present invention can be used to function as correctors. The enhancement of efficacy of CF treatment by combining two correctors, or a corrector and an enhancer, is well understood in the art, and these combinations are approved for marketing or are currently being tested in clinical trials. Three-drug combinations are also being tested in clinical trials. It will be recognized that multi-drug therapy is or may soon become the standard of care. In some embodiments, other classes of CFTR modulators, such as "amplifiers" that increase the steady-state level of CFTR, may become available and may also be used as part of multi-drug therapy.

[0091] Other potential combinations will be apparent to the skilled practitioner. In some embodiments, effective combination therapy is achieved by a single composition or pharmacological formulation containing multiple agents, or by two or more separate compositions or formulations that are co-administered, one composition containing a compound of the present disclosure and the other composition containing an additional agent, formulated together or separately. Alternatively, in other embodiments, treatment precedes or follows treatment with the other agent by intervals ranging from minutes to months.

[0092] VI. Definitions The following definitions supersede any conflicting definitions in any reference incorporated herein by reference. However, the fact that a particular term is defined should not be construed as indicating that any undefined term is indefinite. Rather, all terms used are considered to be descriptive of the disclosure such that one of ordinary skill in the art can appreciate the scope of the disclosure and practice the disclosure.

[0093] When used with respect to chemical groups, "hydrogen" means -H, "hydroxy" means -OH, "oxo" means =O, "carbonyl" means -C(=O)-, "carboxy" means -C(=O)OH (also denoted as -COOH or -CO2H), "halo" independently means -F, -Cl, -Br, or -I, "amino" means -NH2, "hydroxyamino" means -NHOH, "nitro" means -NO2, imino means =NH, "cyano" means -CN, "isocyananyl" means -N=C=O, "azido" means -N3, with respect to monovalency, "phosphate" means -OP(O)(OH)2 or its deprotonated form, with respect to divalency, "phosphate" means -OP(O)(OH)O- or its deprotonated form, "mercapto" means -SH, "thio" means =S, "thiocarbonyl" means -C(=S)-, "sulfonyl" means -S(O)2-, "sulfinyl" means -S(O)-.

[0094] With respect to chemical formulas, the symbol "-" means a single bond, "=" means a double bond, and "≡" means a triple bond. The symbol TIFF0007695229000049.tif4128, when present, represents any bond that is either a single bond or a double bond. The symbol TIFF0007695229000050.tif4128 means a single bond or a double bond. Thus, the formula TIFF0007695229000051.tif9128, for example Cover TIFF0007695229000052.tif11128. It should also be understood that no single ring atom forms part of more than one double bond. Further, note that the symbol "-" for a covalent bond when connecting one or two asymmetric atoms does not indicate any preferred stereochemical configuration. Instead, all stereoisomers and mixtures thereof are covered. Bond When drawn perpendicular across TIFF0007695229000053.tif7128 The symbol TIFF0007695229000054.tif4128 indicates the point of attachment of the group. Note that in order to prompt the reader to clearly identify the point of attachment, this is usually only done for relatively large groups. The symbol TIFF0007695229000055.tif4128 means that the group attached to the thick end of the wedge represents a single bond "going out of the page". The symbol TIFF0007695229000056.tif4128 means that the group attached to the thick end of the wedge represents a single bond "going into the page". The symbol TIFF0007695229000057.tif4128 means a single bond where the geometric configuration (e.g., E or Z) around the double bond is undetermined. Thus, both options and combinations thereof are intended. Any undefined valency on an atom in the structures shown in this application implicitly represents a hydrogen atom bonded to that atom. The bold dot on a carbon atom indicates that the hydrogen bonded to that carbon points out of the plane of the paper. For example, the following two illustrations are equivalent. TIFF0007695229000058.tif21128

[0095] The variable element is a "floating group" on the ring system, e.g., the following formula: When illustrated as the "R" group in TIFF0007695229000059.tif13128, the variable element can replace any hydrogen atom bonded to any ring atom, including hydrogen that is illustrated, implied, or explicitly defined, as long as a stable structure is formed. When the variable element is a "floating group" on a fused ring system, e.g., the following formula: When illustrated as the "R" group in TIFF0007695229000060.tif17128, the variable element can replace any hydrogen bonded to any ring atom of any fused ring, unless otherwise specified. As replaceable hydrogen as long as a stable structure is formed, there are illustrated hydrogen (e.g., hydrogen bonded to nitrogen in the above formula), implied hydrogen (e.g., hydrogen of the above formula that is not illustrated but is understood to be present), explicitly defined hydrogen, and any arbitrary hydrogen whose existence depends on the uniqueness of the ring atom (e.g., hydrogen bonded to the X group when X is equal to -CH-). In the illustrated example, R can be present in the 5-membered or 6-membered ring of the fused ring system. The subscript "y" immediately following the R group enclosed in parentheses in the above formula represents a variable. Unless otherwise specified, this variable can be 0, 1, 2, or any integer greater than 2, and is limited only by the maximum number of replaceable hydrogen atoms of the ring or ring system.

[0096] Regarding chemical groups and compound classes, the number of carbon atoms in a group or class is as indicated below. "Cn" or "C=n" defines the exact number (n) of carbon atoms in the group / class. "C≦n" defines the maximum number (n) of carbon atoms that can be present in the group / class, and the minimum number is as small as possible for the group / class in question. For example, the minimum number of carbon atoms in the "alkyl" (C≦8) ", "alkanediyl" (C≦8) ", "heteroaryl" (C≦8) ", and "acyl" (C≦8) " groups is 1, and the minimum number of carbon atoms in the "alkenyl" (C≦8) ", "alkynyl" (C≦8) ", and "heterocycloalkyl" (C≦8) " groups is 2, and the minimum number of carbon atoms in the "cycloalkyl" (C≦8)The minimum number of carbon atoms in the "]] group is 3, and for the "aryl (C≦8) " and "arenediyl (C≦8) " groups, it will be understood that the minimum number of carbon atoms is 6. "Cn~n'" defines both the minimum number (n) and the maximum number (n') of carbon atoms in the group. Thus, "alkyl (C2~10) " means an alkyl group having 2 to 10 carbon atoms. These carbon number indicators may precede or follow the chemical group or class they modify, and may or may not be enclosed in parentheses, without indicating a change in meaning. Thus, the terms "C 1~4 -alkyl", "C1~4-alkyl", "alkyl (C1~4) ", and "alkyl (C≦4) " are all synonymous. Except as specifically noted below, all carbon atoms are counted to determine whether a group or compound is within the specified number of carbon atoms. For example, the dihexylamino group is an example of a dialkylamino (C12) group, but not an example of a dialkylamino (C6) group. Similarly, phenylethyl is an example of an aralkyl (C=8) group. When any chemical group or compound class defined herein is modified by the term "substituted", any carbon atom in the moiety replacing the hydrogen atom is not counted. Thus, methoxyhexyl having a total of 7 carbon atoms is an example of a substituted alkyl (C1~6) . Unless otherwise specified, any chemical group or compound class listed in a set of claims without limitation on carbon atoms shall have a carbon atom limitation of 12 or less.

[0097] The term "saturated", when used to modify a compound or chemical group, means that the compound or chemical group has no carbon-carbon double bonds and no carbon-carbon triple bonds, except as described below. When this term is used as a modifier of an atom, it means that the atom is not part of any double bond or triple bond. In the case of substituted versions of saturated groups, one or more carbon-oxygen double bonds, or carbon-nitrogen double bonds, may be present. Also, when such bonds are present, carbon-carbon double bonds that can occur as part of keto-enol tautomerism or imine / enamine tautomerism are not excluded. The term "saturated", when used as a modifier regarding a solution of a substance, means that the substance is no longer soluble in that solution.

[0098] The term "aliphatic" means that a compound or chemical group so modified is a compound or group that is acyclic or cyclic but non-aromatic. In an aliphatic compound / group, carbon atoms can be joined together in straight chains, branched chains, or non-aromatic rings (alicyclic). Aliphatic compounds / groups may be saturated, i.e., joined by carbon-carbon single bonds (alkanes / alkyls), unsaturated, having one or more carbon-carbon double bonds (alkenes / alkenyls), or having one or more carbon-carbon triple bonds (alkynes / alkynyls).

[0099] The term "aromatic" means that a compound or chemical group so modified has a planar unsaturated ring of atoms with 4n + 2 electrons in a fully conjugated cyclic π-system. An aromatic compound or aromatic chemical group can be depicted as a single resonance structure, and the depiction of one resonance structure is considered to refer to any other resonance structure as well. For example, TIFF0007695229000061.tif13128 is also considered to refer to TIFF0007695229000062.tif13128. Aromatic compounds may be depicted using a circle to represent the delocalization of electrons in the fully conjugated cyclic π-system, and two non-limiting examples of this are shown below. TIFF0007695229000063.tif12128

[0100] The term "alkyl" means a monovalent saturated aliphatic group having a carbon atom as the point of attachment, having a straight-chain or branched acyclic structure, and having no atoms other than carbon and hydrogen. Groups such as -CH3 (Me), -CH2CH3 (Et), -CH2CH2CH3 (n-Pr or propyl), -CH(CH3)2 (i-Pr, i Pr, or isopropyl), -CH2CH2CH2CH3 (n-Bu), -CH(CH3)CH2CH3 (sec-butyl), -CH2CH(CH3)2 (isobutyl), -C(CH3)3 (tert-butyl, t-butyl, t-Bu, or t Bu), and -CH2C(CH3)3 (neopentyl) are non-limiting examples of alkyl groups. The term "alkanediyl" means a divalent saturated aliphatic group having one or two saturated carbon atoms as the points of attachment, having a straight-chain or branched acyclic structure, having no carbon-carbon double or triple bonds, and having no atoms other than carbon and hydrogen. Groups such as -CH2- (methylene), -CH2CH2-, -CH2C(CH3)2CH2-, and -CH2CH2CH2- are non-limiting examples of alkanediyl groups. The term "alkylidene" means a divalent group =CRR' where R and R' are independently hydrogen or alkyl. Non-limiting examples of alkylidene groups include =CH2, =CH(CH2CH3), and =C(CH3)2. "Alkane" means a class of compounds having the formula H-R where R is alkyl and the term is as defined above.

[0101] The term "cycloalkyl" means a monovalent saturated aliphatic group having carbon atoms as the bonding points that form part of one or more non-aromatic ring structures, having no carbon-carbon double or triple bonds, and having no atoms other than carbon and hydrogen. Non-limiting examples include -CH(CH2)2 (cyclopropyl), cyclobutyl, cyclopentyl, or cyclohexyl (Cy). This term as used herein does not exclude the presence of one or more alkyl groups (which may be limited in the number of carbon atoms) bonded to the carbon atoms of the non-aromatic ring structure. The term "cycloalkanediyl" means a divalent saturated aliphatic group having two carbon atoms as the bonding points, having no carbon-carbon double or triple bonds, and having no atoms other than carbon and hydrogen. Groups such as TIFF0007695229000064.tif8128 are non-limiting examples of cycloalkanediyl groups. "Cycloalkane" means a class of compounds having the formula H-R where R is cycloalkyl and the term is as defined above.

[0102] The term "heterocycloalkyl" means a monovalent non-aromatic group having a carbon atom or a nitrogen atom as a bonding point that forms part of one or more non-aromatic ring structures, each having 3 to 8 ring atoms, with at least one ring atom of the non-aromatic ring structure being nitrogen, oxygen, or sulfur, and the heterocycloalkyl group not consisting of atoms other than carbon, hydrogen, nitrogen, oxygen, and sulfur. When two or more rings are present, the rings are fused. This term as used herein does not exclude the presence of one or more alkyl groups (with possible carbon number limitations) bonded to one or more ring atoms. Also, this term does not exclude the presence of one or more double bonds in the ring or ring system, provided that the resulting group remains non-aromatic. Non-limiting examples of heterocycloalkyl groups include aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothiofuranyl, tetrahydropyranyl, pyranyl, oxiranyl, and oxetanyl. The term "N-heterocycloalkyl" means a heterocycloalkyl group having a nitrogen atom as a bonding point. N-pyrrolidinyl is an example of this group. The term "heterocycloalkanediyl" means a divalent cyclic group having two carbon atoms, two nitrogen atoms, or one carbon atom and one nitrogen atom as two bonding points that form part of one or more ring structures, with at least one ring atom of the non-aromatic ring structure being nitrogen, oxygen, or sulfur, and the divalent group not consisting of atoms other than carbon, hydrogen, nitrogen, oxygen, and sulfur. When two or more rings are present, the rings are fused. The term heterocycloalkanediyl as used herein does not exclude the presence of one or more alkyl groups (with possible carbon number limitations) bonded to one or more ring atoms. Also, this term does not exclude the presence of one or more double bonds in the ring or ring system, provided that the resulting group remains non-aromatic. Non-limiting examples of heterocycloalkanediyl groups include the following. TIFF0007695229000065.tif15128

[0103] The term "alkenyl" means a monovalent unsaturated aliphatic group having a carbon atom as a point of attachment, having a straight-chain or branched acyclic structure, having at least one non-aromatic carbon-carbon double bond, having no carbon-carbon triple bond, and having no atoms other than carbon and hydrogen. Non-limiting examples include -CH=CH2 (vinyl), -CH=CHCH3, -CH=CHCH2CH3, -CH2CH=CH2 (allyl), -CH2CH=CHCH3, and -CH=CHCH=CH2. The term "alkenediyl" means a divalent unsaturated aliphatic group having two carbon atoms as points of attachment, having a straight-chain or branched acyclic structure, having at least one non-aromatic carbon-carbon double bond, having no carbon-carbon triple bond, and having no atoms other than carbon and hydrogen. Groups such as -CH=CH-, -CH=C(CH3)CH2-, -CH=CHCH2-, and -CH2CH=CHCH2- are non-limiting examples of alkenediyl groups. It should be noted that although the alkenediyl group is aliphatic, when connected at both ends, it is not precluded that this group forms part of an aromatic structure. The terms "alkene" and "olefin" are synonymous and mean a class of compounds having the formula H-R where R is alkenyl as defined above. Similarly, the terms "terminal alkene" and "α-olefin" are synonymous and mean an alkene having only one carbon-carbon double bond and the bond being part of a vinyl group at one end of the molecule.

[0104] The term "alkynyl" means a monovalent unsaturated aliphatic group having a carbon atom as a point of attachment, having a straight-chain or branched acyclic structure, having at least one carbon-carbon triple bond, and having no atoms other than carbon and hydrogen. The term alkynyl as used herein does not preclude the presence of one or more non-aromatic carbon-carbon double bonds. Groups such as -C≡CH, -C≡CCH3, and -CH2C≡CCH3 are non-limiting examples of alkynyl groups. "Alkyne" means a class of compounds having the formula H-R where R is alkynyl.

[0105] The term "aryl" means a monovalent unsaturated aromatic group having aromatic carbon atoms as bonding points that form part of one or more aromatic ring structures, each having 6 ring atoms all of which are carbon, and not consisting of atoms other than carbon and hydrogen. When two or more rings are present, the rings may or may not be fused. Non-fused rings are connected by covalent bonds. The term "aryl" as used herein does not exclude the presence of one or more alkyl groups (the number of carbon atoms can be limited) bonded to the first aromatic ring or any additional aromatic ring present. Non-limiting examples of aryl groups include phenyl (Ph), methylphenyl, (dimethyl)phenyl, -C6H4CH2CH3 (ethylphenyl), naphthyl, and monovalent groups derived from biphenyl (e.g., 4-phenylphenyl). The term "arenediyl" means a divalent aromatic group having two aromatic carbon atoms as bonding points that form part of one or more 6-membered aromatic ring structures, each having 6 ring atoms all of which are carbon, and not consisting of atoms other than carbon and hydrogen. The term "arenediyl" as used herein does not exclude the presence of one or more alkyl groups (the number of carbon atoms can be limited) bonded to the first aromatic ring or any additional aromatic ring present. When two or more rings are present, the rings may or may not be fused. Non-fused rings are connected by covalent bonds. Non-limiting examples of arenediyl groups include the following. TIFF0007695229000066.tif16156 "Arene" means a class of compounds having the formula H-R, where R is aryl and the term is as defined above. Benzene and toluene are non-limiting examples of arenes.

[0106] The term "aralkyl" means a monovalent group -alkanediyl-aryl, where the terms "alkanediyl" and "aryl" are used in the same manner as the definitions shown above, respectively. Non-limiting examples include phenylmethyl (benzyl, Bn) and 2-phenyl-ethyl.

[0107] The term "heteroaryl" means a monovalent aromatic group having an aromatic carbon atom or a nitrogen atom as a bonding point that forms part of one or more aromatic ring structures each having 3 to 8 ring atoms, at least one ring atom of the aromatic ring structure being nitrogen, oxygen, or sulfur, and the heteroaryl group not consisting of atoms other than carbon, hydrogen, aromatic nitrogen, aromatic oxygen, and aromatic sulfur. When two or more rings are present, the rings are fused, but the term "heteroaryl" does not exclude the presence of one or more alkyl groups or aryl groups (with possible carbon number limitations) bonded to one or more ring atoms. Non-limiting examples of heteroaryl groups include benzoxazolyl, benzimidazolyl, furanyl, imidazolyl (Im), indolyl, indazolyl, isoxazolyl, methylpyridinyl, oxazolyl, oxadiazolyl, phenylpyridinyl, pyridinyl (pyridyl), pyrrolyl, pyrimidinyl, pyrazinyl, quinolyl, quinazolinyl, quinoxalinyl, triazinyl, tetrazolyl, thiazolyl, thienyl, and triazolyl. The term "N-heteroaryl" means a heteroaryl group having a nitrogen atom as a bonding point. The term "heteroarene" means a class of compounds having the formula H-R where R is heteroaryl. Pyridine and quinoline are non-limiting examples of heteroarenes. The term "heteroarenediyl" means a divalent aromatic group having two aromatic carbon atoms, two aromatic nitrogen atoms, or one aromatic carbon atom and one aromatic nitrogen atom as two bonding points that form part of one or more aromatic ring structures each having 3 to 8 ring atoms, at least one ring atom of the aromatic ring structure being nitrogen, oxygen, or sulfur, and the divalent group not consisting of atoms other than carbon, hydrogen, aromatic nitrogen, aromatic oxygen, and aromatic sulfur. When two or more rings are present, the rings are fused, but the term "heteroarenediyl" does not exclude the presence of one or more alkyl groups or aryl groups (with possible carbon number limitations) bonded to one or more ring atoms. Non-limiting examples of heteroarenediyl groups include the following. TIFF0007695229000067.tif15128

[0108] The term "acyl" means a -C(O)R group where R is hydrogen, alkyl, cycloalkyl, or aryl, and those terms are as defined above. Groups such as -CHO, -C(O)CH3 (acetyl, Ac), -C(O)CH2CH3, -C(O)CH(CH3)2, -C(O)CH(CH2)2, -C(O)C6H5, and -C(O)C6H4CH3 are non-limiting examples of acyl groups. "Thioacyl" is similarly defined except that the oxygen atom of the -C(O)R group is replaced by a sulfur atom to give -C(S)R. The term "aldehyde" corresponds to the alkyl group as defined above bonded to a -CHO group.

[0109] The term "alkoxy" means an -OR group where R is alkyl and the term is as defined above. Non-limiting examples include -OCH3 (methoxy), -OCH2CH3 (ethoxy), -OCH2CH2CH3, -OCH(CH3)2 (isopropoxy), or -OC(CH3)3 (tert-butoxy). The terms "cycloalkoxy", "alkenyloxy", "alkynyloxy", "aryloxy", "aralkoxy", "heteroaryloxy", "heterocycloalkoxy", and "acyloxy" when used without the modifier "substituted" mean groups defined as -OR where R is cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heterocycloalkyl, and acyl, respectively. The terms "alkylthio" and "acylthio" mean -SR groups where R is alkyl and acyl, respectively. The term "alcohol" corresponds to an alkane as defined above where at least one hydrogen atom is replaced by a hydroxy group. The term "ether" corresponds to an alkane as defined above where at least one hydrogen atom is replaced by an alkoxy group.

[0110] The term "alkylamino" means an -NHR group where R is alkyl and the term is as defined above. Non-limiting examples include -NHCH3 and -NHCH2CH3. The term "dialkylamino" means an -NRR' group where R and R' may be the same or different alkyl groups. Non-limiting examples of dialkylamino groups include -N(CH3)2 and -N(CH3)(CH2CH3). The terms "cycloalkylamino", "alkenylamino", "alkynylamino", "arylamino", "aralkylamino", "heteroarylamino", "heterocycloalkylamino", and "alkoxyamino", when used without the modifier "substituted", mean groups defined as -NHR where R is cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heterocycloalkyl, and alkoxy, respectively. A non-limiting example of an arylamino group is -NHC6H5. The term "amide" (acylamino), when used without the modifier "substituted", means an -NHR group where R is acyl and the term is as defined above. A non-limiting example of an amide group is -NHC(O)CH3.

[0111] When a chemical group is used with the modifier "substituted", one or more hydrogen atoms are each independently replaced by -OH, -F, -Cl, -Br, -I, -NH2, -NO2, -CO2H, -CO2CH3, -CO2CH2CH3, -CN, -SH, -OCH3, -OCH2CH3, -C(O)CH3, -NHCH3, -NHCH2CH3, -N(CH3)2, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -OC(O)CH3, -NHC(O)CH3, -S(O)2OH, or -S(O)2NH2. For example, the following groups are non-limiting examples of substituted alkyl groups: -CH2OH, -CH2Cl, -CF3, -CH2CN, -CH2C(O)OH, -CH2C(O)OCH3, -CH2C(O)NH2, -CH2C(O)CH3, -CH2OCH3, -CH2OC(O)CH3, -CH2NH2, -CH2N(CH3)2, and -CH2CH2Cl. The term "hydroxyalkyl" is a subset of substituted alkyl where one or more hydrogen atoms are replaced by hydroxy (i.e., -OH) groups, and thus no atoms other than carbon, hydrogen, and oxygen are present. Groups such as -CH2OH, -CH2CH2OH, -CH(OH)CHOH, -CH2CH(OH)CH3, and -CH(OH)CH2OH are non-limiting examples of hydroxyalkyl groups. The term "monohydroxyalkyl" is a subset of substituted alkyl where one hydrogen atom is replaced by hydroxy (i.e., -OH) groups, and thus no atoms other than carbon, hydrogen, and one oxygen are present. Groups such as -CH2OH, -CH2CH2OH, and -CH2CH(OH)CH3 are non-limiting examples of monohydroxyalkyl groups. The term "fluoroalkyl" is a subset of substituted alkyl where one or more hydrogen atoms are replaced by fluoro, and thus no atoms other than carbon, hydrogen, and fluorine are present. Groups such as -CH2F, -CHF2, and -CF3 are non-limiting examples of fluoroalkyl groups. The term "monofluoroalkyl" is a subset of substituted alkyl where one hydrogen atom is replaced by fluoro, and thus no atoms other than carbon, hydrogen, and one fluorine are present.Groups such as -CH2F, -CH2CH2F, and -CH2CH(F)CH3 are non-limiting examples of monofluoroalkyl groups. The term "aminoalkyl" is a subset of substituted alkyl where one or more hydrogen atoms are replaced by amino (i.e., -NH2) groups, and thus no atoms other than carbon, hydrogen, and nitrogen are present. Groups such as -CH2NH2, -CH(NH2)CH3, -CH2CH2NH2, -CH2CH(NH2)CH3, and -CH(NH2)CH2NH2 are non-limiting examples of aminoalkyl groups. The term "monoaminoalkyl" is a subset of substituted alkyl where one hydrogen atom is replaced by an amino (i.e., -NH2) group, and thus no atoms other than carbon, hydrogen, and one nitrogen are present. Groups such as -CH2NH2, -CH2CH2NH2, and -CH2CH(NH2)CH3 are non-limiting examples of monoaminoalkyl groups. Non-limiting examples of substituted aralkyl include (3-chlorophenyl)-methyl and 2-chloro-2-phenyl-ethan-1-yl. Groups such as -C(O)CH2CF3, -CO2H (carboxyl), -CO2CH3 (methyl carboxyl), -CO2CH2CH3, -C(O)NH2 (carbamoyl), and -CON(CH3)2 are non-limiting examples of substituted acyl groups. Groups such as -NHC(O)OCH3 and -NHC(O)NHCH3 are non-limiting examples of substituted amide groups.

[0112] When a chemical group is used with the modifier "polar substitution", one or more hydrogen atoms are each independently replaced by one of the following polar substituents, provided that not all hydrogens are so replaced: -OH, -F, -NH2, -CO2H, -CO2CH3, -C(O)NH2, -C(O)NHCH3, -OC(O)CH3, -NHC(O)CH3, -NHC(O)OCH3, -NHC(O)OCH2CH3, -NHC(O)NHCH3, -NHC(O)NHCH2CH3, -S(O)2OH, or -S(O)2NH2. Non-limiting examples of polar substitution alkyl groups include -CH2F, -CHF2, -CH2CH2F, -CHFCH2F, -CF2CH3, -CH2OH, -CH2CH2OH, -CH2CH2CH2NH2, -CH2CH2OH, and -CH(NH2)CH2OH.

[0113] When a chemical group is used with the modifier "monopolar substitution", only one hydrogen atom is replaced by one of the following polar substituents: -OH, -F, -NH2, -CO2H, -CO2CH3, -C(O)NH2, -C(O)NHCH3, -OC(O)CH3, -NHC(O)CH3, -NHC(O)OCH3, -NHC(O)OCH2CH3, -NHC(O)NHCH3, -NHC(O)NHCH2CH3, -S(O)2OH, or -S(O)2NH2. Non-limiting examples of monopolar substitution alkyl groups include -CH2F, -CH2CH2F, -CHFCH3, -CH2OH, -CH2CH2OH, -CH(OH)CH2OH, -CH2NH2, -CH2CH2NH2, and -CH(NH2)CH3.

[0114] Some of the abbreviations used in this specification are as follows. Ac refers to an acetyl group (-C(O)CH3), Boc refers to tert-butyloxycarbonyl, COPD refers to chronic obstructive pulmonary disease, COX-2 refers to cyclooxygenase-2, CYP3A4 refers to cytochrome P450 3A4, cyPG refers to cyclopentenone prostaglandin, DBDMH refers to 1,3-dibromo-5,5-dimethylhydantoin, DIBAL-H is diisobutylaluminum hydride, DMAP refers to 4-dimethylaminopyridine, DMF is dimethylformamide, DMSO is dimethyl sulfoxide, EDC is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, Et2O is diethyl ether, HO-1 refers to inducible heme oxygenase, IFNγ or IFN-γ refers to interferon γ, IL-1 refers to the interleukin 1 family, iNOS refers to inducible nitric oxide synthase, NCS refers to N-chlorosuccinimide, NMO refers to N-methylmorpholine N-oxide, NO refers to nitric oxide, NQO1 refers to NAD(P)H dehydrogenase (quinone 1), Nrf2 refers to nuclear factor erythroid 2-related factor 2, OA refers to oleanolic acid, Py refers to pyridine, T3P refers to propylphosphonic anhydride, TFA is trifluoroacetic acid, TFAA is trifluoroacetic anhydride, THF is tetrahydrofuran, TNFα or TNF-α is tumor necrosis factor α, TPAP is tetrapropylammonium perruthenate, Ts refers to tosyl, TsOH or p-TsOH is p-toluenesulfonic acid, and 4Å MS refers to 4 angstrom molecular sieves.

[0115] The use of the word "a" or "an" in combination with the term "comprising" in the claims and / or the specification can mean "one", but is also consistent with the meanings of "one or more", "at least one", and "one or two or more".

[0116] Throughout this specification, the term "about" is used to indicate that a value includes the variability of error inherent in the device or method used to determine that value, or the variability that exists between test subjects or test patients.

[0117] "Active ingredient" (AI) or pharmaceutically active ingredient (API) (also referred to as an active compound, active substance, active agent, pharmaceutical agent, agent, bioactive molecule, or therapeutic compound) refers to the ingredient in a biologically active pharmaceutical.

[0118] The terms "comprise", "have", and "include" are non-limiting conjunctive verbs. Any form or tense of one or more of these verbs, such as "comprises", "comprising", "has", "having", "includes", and "including", is also non-limiting. For example, any method that "comprises", "has", or "includes" one or more steps is not limited to having only those one or more steps, but also encompasses other unlisted steps.

[0119] As used in the specification and / or claims, the term "effective" means sufficient to achieve a desired, expected, or intended result. When used in connection with treating a patient or subject with a compound, an "effective amount", "therapeutically effective amount", or "pharmaceutically effective amount" of the compound means an amount of the compound sufficient to effect the treatment or prevention of a disease as defined by the terms below when administered to the subject or patient.

[0120] "Excipient" refers to a pharmaceutically acceptable substance that is formulated together with the active ingredient of a drug, pharmaceutical composition, formulation, or drug delivery system. Excipients can be used, for example, to stabilize a composition, to bulk up a composition (and thus are often referred to as "bulking agents", "fillers", or "diluents" when used for this purpose), or to achieve improvements in the therapeutic aspects of the active ingredient in the final dosage form, such as promoting drug absorption, reducing viscosity, or improving solubility. Excipients include antiadhesion agents, binders, coating agents, coloring agents, disintegrants, flavors, lubricants, glidants, preservatives, absorbents, sweeteners, and pharmaceutically acceptable versions of the vehicle. The main excipient that usually serves as the vehicle for delivering the active ingredient is called the vehicle. Excipients can be used in the manufacturing process to facilitate the handling of the active substance, for example, by promoting in vitro stability such as preventing degradation or aggregation over the expected shelf life, and by promoting, for example, the flowability or non-stickiness of powders. Usually, the compatibility of excipients varies depending on the route of administration, dosage form, active ingredient, and other factors.

[0121] The term "hydrate" when used as a modifier for a compound means that the compound has less than one water molecule bound to each compound molecule (e.g., hemihydrate), one water molecule (e.g., monohydrate), or two or more water molecules (e.g., dihydrate), for example, in the solid form of the compound.

[0122] As used herein, "IC 50 " means the inhibitory dose that is 50% of the maximum response obtained. This quantitative measure indicates how much of a particular drug or other substance (inhibitor) is required to half-inhibit a given biological, biochemical, or chemical process (or a component of the process, i.e., an enzyme, cell, cell receptor, or microorganism). "Relative IC 50 " means the fold difference in potency between two compounds. Relative IC 50 is calculated within each experimental assay using the following formula to determine the IC 50 value of the compound of interest relative to the IC50 It is determined by dividing by the value. TIFF0007695229000068.tif10128

[0123] The "isomer" of the first compound refers to another compound in which each molecule contains the same constituent atoms as the first compound, but the three-dimensional configuration of the atoms is different.

[0124] As used herein, the terms "patient" or "subject" mean living mammalian organisms such as humans, monkeys, female cows, sheep, goats, dogs, cats, mice, rats, guinea pigs, or transgenic species thereof. In certain embodiments, the patient or subject is a primate. Non-limiting examples of human patients include adults, juveniles, infants, and fetuses.

[0125] As generally used herein, "pharmaceutically acceptable" means suitable for use in contact with human and animal tissues, organs, and / or body fluids within the scope of sound medical judgment, without undue toxicity, irritation, allergic response, or other problems or complications, and commensurate with a reasonable benefit / risk ratio, for compounds, raw materials, compositions, and / or dosage forms.

[0126] "Pharmaceutically acceptable salts" means salts of the compounds disclosed herein that are pharmaceutically acceptable as defined above and have the desired pharmacological activity. These salts include salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; or 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, 2-naphthalenesulfonic acid, 3-phenylpropionic acid, 4,4'-methylenebis(3-hydroxy-2-ene-1-carboxylic acid), 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, acetic acid, aliphatic monocarboxylic and dicarboxylic acids, aliphatic sulfuric acids, aromatic sulfuric acids, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, carbonic acid, cinnamic acid, citric acid, cyclopentanepropionic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, heptanoic acid, hexanoic acid, hydroxynaphthoic acid, lactic acid, lauryl sulfuric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, muconic acid, o-(4-hydroxybenzoyl)benzoic acid, oxalic acid, p-chlorobenzenesulfonic acid, phenyl-substituted alkanoic acids, propionic acid, p-toluenesulfonic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, tartaric acid, tert-butylacetic acid, trimethylacetic acid, and other organic acids. Pharmaceutically acceptable salts also include base addition salts that can be formed when the acidic protons present are capable of reacting with an inorganic base or an organic base. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide, and calcium hydroxide. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. It should be recognized that the specific anions or cations that form part of any salt of the present disclosure are not critical as long as the salt as a whole is pharmacologically acceptable. Further examples of pharmaceutically acceptable salts and their preparation and use methods are presented in Handbook of Pharmaceutical Salts: Properties, and Use (P. H. Stahl & C. G. Wermuth eds., Verlag Helvetica Chimica Acta, 2002).

[0127] "Pharmaceutically acceptable carrier", "drug carrier", or simply "carrier" refers to a pharmaceutically acceptable substance that is formulated with an active ingredient drug involved in transporting, delivering, and / or transporting a chemical agent. A drug carrier can be used to improve the delivery and effectiveness of a drug, for example, including controlled release techniques that regulate the bioavailability of the drug, to reduce the metabolism of the drug, and / or to reduce the toxicity of the drug. Some drug carriers can increase the effectiveness of drug delivery to a specific target site. Examples of carriers include liposomes, microspheres (e.g., made of poly(lactic-co-glycolic acid)), albumin microspheres, synthetic polymers, nanofibers, protein-DNA complexes, protein conjugates, red blood cells, virosomes, and dendrimers.

[0128] "Pharmaceutical" (also referred to as pharmaceutical product, pharmaceutical preparation, pharmaceutical composition, pharmaceutical formulation, pharmaceutical product, pharmaceutical, medicine, drug, pharmaceutical, or simply drug, agent, or preparation) refers to a composition used for diagnosing, curing, treating, or preventing a disease, which contains a pharmaceutically active ingredient (API) (as defined above) and, optionally, one or more inactive ingredients, also referred to as excipients (as defined above).

[0129] "Prevent" or "preventing" includes (1) inhibiting the onset of a disease in a subject or patient who has a risk and / or predisposition for the disease but has not yet experienced or exhibited any or all of the disease state or overall symptoms, and / or (2) delaying the onset of the disease state or overall symptoms of a disease in a subject or patient who has a risk and / or predisposition for the disease but has not yet experienced or exhibited any or all of the disease state or overall symptoms.

[0130] "Prodrug" means a compound that can be metabolically converted in vivo to a pharmaceutically active ingredient of the present disclosure. The prodrug itself may or may not have activity in the prodrug form. For example, a compound containing a hydroxy group can be administered as an ester that is converted to a hydroxy compound by hydrolysis in vivo. Non-limiting examples of suitable esters that can be converted to a hydroxy compound in vivo include acetate esters, citrate esters, lactate esters, phosphate esters, tartrate esters, malonate esters, oxalate esters, salicylate esters, propionate esters, succinate esters, fumarate esters, maleate esters, methylene-bis-β-hydroxynaphthoate esters, gentisate esters, isethionate esters, di-p-toluoyl tartrate esters, methanesulfonate esters, ethanesulfonate esters, benzenesulfonate esters, p-toluenesulfonate esters, cyclohexylsulfamate esters, quinate esters, and amino acid esters. Similarly, a compound containing an amine group can be administered as an amide that is converted to an amine compound by hydrolysis in vivo.

[0131] "Stereoisomer" or "optical isomer" refers to an isomer of a given compound in which the same atoms are bonded to other same atoms, but the three-dimensional configuration of the atoms is different. "Enantiomer" refers to a stereoisomer of a given compound that is a mirror image of each other like the left and right hands. "Diastereomer" refers to a stereoisomer of a given compound that is not an enantiomer. A chiral molecule contains a chiral center, also called a stereocenter or an asymmetric center, which is any point in a molecule having a group such that the exchange of any two groups results in a stereoisomer, but is not necessarily an atom. Usually, in organic compounds, the chiral center is a carbon atom, a phosphorus atom, or a sulfur atom, but other atoms can also be stereocenters in organic and inorganic compounds. A molecule can have many stereoisomers by having multiple stereocenters. In a compound whose stereoisomerism is derived from a tetrahedral asymmetric center (e.g., tetrahedral carbon), the total number of hypothetically possible stereoisomers is 2 nnot exceeding, where n is the number of tetrahedral stereocenters. Often, molecules with symmetry have fewer stereoisomers than the maximum possible number. A 50:50 mixture of enantiomers is called a racemic mixture. Alternatively, a mixture of enantiomers may be enantiomerically enriched such that one enantiomer is present in an amount exceeding 50%. Usually, enantiomers and / or diastereomers are separable or resolvable using techniques known in the art. For any stereocenter or chirality axis for which the stereochemical configuration is not specified, the stereocenter or chirality axis is assumed to be present as the R form, the S form, or a mixture of the R and S forms including racemic and non-racemic mixtures. As used herein, the phrase "substantially free of other stereoisomers" means that the composition contains 15% or less, more preferably 10% or less, still more preferably 5% or less, and most preferably 1% or less of another stereoisomer.

[0132] "Treatment" or "treating" includes (1) inhibiting a disease in a subject or patient experiencing or displaying the pathology or general symptoms of the disease (e.g., stopping further development of the pathology and / or general symptoms), (2) alleviating a disease in a subject or patient experiencing or displaying the pathology or general symptoms of the disease (e.g., reversing the pathology and / or general symptoms), and / or (3) effecting any measurable decrease in the disease or its symptoms in a subject or patient experiencing or displaying the pathology or general symptoms of the disease.

[0133] The term "unit dosage form" means a formulation of a compound or composition prepared in a manner sufficient to administer a therapeutically effective single dose of the active ingredient in a single administration to a patient. These unit dosage form formulations that can be used include, but are not limited to, one tablet, capsule, or other oral formulation, or one vial with a syringe-injectable liquid formulation or other injectable formulation.

[0134] The above definition prevails over any conflicting definition in any reference incorporated herein by reference. However, the fact that a particular term is defined should not be construed as indicating that any undefined term is uncertain. Rather, all terms used are considered to be terms by which one of ordinary skill in the art can recognize the scope of the invention and can practice the invention, and to describe the invention.

Example

[0135] VII. Example The following examples are included to illustrate preferred embodiments of the invention. One of ordinary skill in the art should recognize that the techniques disclosed in the following examples represent techniques discovered by the inventors to function well in the practice of the invention, and thus constitute preferred modes of practice thereof. However, one of ordinary skill in the art should also recognize that, in light of the present disclosure, many modifications can be made to the specific embodiments disclosed and still obtain similar or analogous results without departing from the spirit and scope of the invention.

[0136] Example 1 Synthesis and Characterization A. General Information Unless otherwise noted, commercially available reagents were used as received and all reactions were carried out under a nitrogen atmosphere. All solvents were of HPLC or ACS grade. Nuclear magnetic resonance (NMR) spectra were recorded on a Varian Inova-400 spectrometer operating at a frequency of 400 MHz ( 1 1H NMR). Chemical shifts (δ) were referenced to the residual solvent (usually 11H NMR is reported in ppm relative to chloroform (δ 7.26 ppm), and coupling constants (J) are reported in Hz. For multiplicity, singlet is denoted as s, doublet as d, triplet as t, quartet as q, and multiplet as m. Mass spectra were recorded on an Agilent 6120 mass spectrometer. The compounds of the present disclosure can be prepared according to the methods outlined in Example 1 and methods known to those skilled in the art, including the methods disclosed in WO 2012 / 125488 and WO 2014 / 040056, both of which are incorporated herein by reference.

[0137] B. Synthetic Routes to the Compounds of the Present Disclosure Scheme 1 TIFF0007695229000069.tif22992 Reagents and conditions: a) DIBAL-H, toluene, THF, 0 °C to room temperature; b) NMO, TPAP, 4 Å MS, CH2Cl2, room temperature, 68% from 1; c) NH2OH-HCl, NaOAc, EtOH, H2O, room temperature, 77%; d) aqueous HCl, NCS, MeCN, -10 °C; aqueous NH3, room temperature, 68%.

[0138] Scheme 2 TIFF0007695229000070.tif23889 Reagents and conditions: a) 2-fluoroacetic acid, EDC·HCl, DMAP, CH2Cl2, room temperature, 69%; b) AcOH, 100 °C, 84%; c) NaOMe, MeOH, 55 °C, 88%; d) DBDMH, DMF, 0 °C; Py, 55 °C, 79%.

[0139] Scheme 3 TIFF0007695229000071.tif23578 Reagents and conditions: a) Boc-glycine, EDC·HCl, DMAP, CH2Cl2, room temperature, 79%; b) 1,4-dioxane, 160 °C, 80%; c) K2CO3, MeOH, room temperature, 89%; d) DBDMH, DMF, 0 °C; Py, 60 °C, 90%; e) TFA, CH2Cl2, room temperature, 49%.

[0140] Scheme 4 TIFF0007695229000072.tif24078Reagents and conditions: a) Boc-β-Ala-OH, EDC·HCl, DMAP, CH2Cl2, room temperature, quantitative yield; b) 1,4-dioxane, 160 °C, 70%; c) K2CO3, MeOH, room temperature, 84%; d) DBDMH, DMF, 0 °C; Py, 60 °C, 82%; e) TFA, CH2Cl2, room temperature, 78%.

[0141] Scheme 5 TIFF0007695229000073.tif23484Reagents and conditions: a) acetoxyacetyl chloride, Et3N, CH2Cl2, 0 °C, quantitative yield; b) AcOH, 100 °C, 86%; c) NaOMe, MeOH, 55 °C, 90%; d) DBDMH, DMF, 0 °C; Py, 60 °C, 82%.

[0142] Scheme 6 TIFF0007695229000074.tif24084Reagents and conditions: a) 3-acetoxypropanoic acid, EDC·HCl, DMAP, CH2Cl2, room temperature, 66%; b) AcOH, 100 °C, 55%; c) NaOMe, MeOH, 55 °C, 22 is 51%, 23 is 45%; d) DBDMH, DMF, 0 °C; Py, 60 °C, T5 is 86%; T6 is 83%.

[0143] Scheme 7 TIFF0007695229000075.tif23895Reagents and conditions: a) n-Bu3SnN3, o-xylene, 150 °C, 47%; b) 2-bromoethanol, Cs2CO3, MeCN, 60 °C, 82%; c) HCO2Et, NaOMe, MeOH, 0 °C to room temperature; 6N aqueous HCl solution, NH2OH·HCl, EtOH, 55 °C, 72%; d) NaOMe, MeOH, 55 °C, quantitative yield; e) DBDMH, DMF, 0 °C; pyridine, 55 °C, 68%; f) Ac2O, pyridine, DMAP, CH2Cl2, 0 °C, 71%.

[0144] Scheme 8 TIFF0007695229000076.tif158128Reagents and conditions: a) Trimethyloxonium tetrafluoroborate, proton sponge, CH2Cl2, room temperature, 43%.

[0145] Scheme 9 TIFF0007695229000077.tif23776Reagents and conditions: a) 1-Fluoro-2-iodoethane, Cs2CO3, MeCN, 60 °C, 52%; b) HCO2Et, NaOMe, MeOH, 0 °C to room temperature; 6N aqueous HCl solution, NH2OH·HCl, EtOH, 55 °C, 71%; c) O3 / O2, MeOH, CH2Cl2, -78 °C; NaBH4, room temperature, 99%; d) 1-Fluoro-2-iodoethane, Cs2CO3, MeCN, 60 °C, 60%; e) K2CO3, MeOH, room temperature, 79%; f) DBDMH, DMF, 0 °C; pyridine, 55 °C, 71%.

[0146] Scheme 10 TIFF0007695229000078.tif21394Reagents and conditions: a) (COCl)2, DMF, CH2Cl2, 0 °C to room temperature; b) hydrazine hydrate, CH2Cl2, 0 °C to room temperature, 90%; c) 2-Fluoroacetic acid, EDC·HCl, DMAP, CH2Cl2, room temperature, 60%; d) TsOH·H2O, toluene, reflux temperature, 60%.

[0147] Scheme 11 TIFF0007695229000079.tif24037Reagents and conditions: a) Et3N, CH2Cl2, 0 °C to room temperature, 84%; b) T3P, Et3N, EtOAc, 125 °C, microwave, 6%.

[0148] Scheme 12 TIFF0007695229000080.tif23442Reagents and conditions: a) 3-Hydroxypropionamide oxime, Et3N, CH2Cl2, room temperature, from 34 to 46%, b) Bu4NOH, water, THF, room temperature, 45%; c) 12N aqueous HCl solution, AcOH, 75 °C, 44%.

[0149] Scheme 13 TIFF0007695229000081.tif23941Reagents and conditions: a) 3-methoxypropionamide oxime hydrochloride, Et3N, CH2Cl2, room temperature; b) Bu4NOH, water, THF, room temperature, 34 to 37%.

[0150] Scheme 14 TIFF0007695229000082.tif22089Reagents and conditions: a) NH2OH·HCl, Et3N, EtOH, 80 °C; b) 35, Et3N, CH2Cl2, room temperature; c) Bu4NOH, water, THF, room temperature, 34 to 45%; d) 12M aqueous HCl, MeOH, room temperature, 83%.

[0151] Scheme 15 TIFF0007695229000083.tif19245Reagents and conditions: a) methyl chloroformate, Et3N, CH2Cl2, room temperature, T17 is 20%; b) ethyl isocyanate, Et3N, CH2Cl2, room temperature, T18 is 67%; c) acetyl chloride, Et3N, CH2Cl2, room temperature, T19 is 33%.

[0152] Scheme 16 TIFF0007695229000084.tif24433Reagents and conditions: a) Ac2O, AcOH, room temperature to 100 °C, 95%; b) K2CO3, MeOH, room temperature, 78%; c) DBDMH, DMF, 0 °C; Py, 55 °C, 78%.

[0153] Scheme 17 TIFF0007695229000085.tif21680Reagents and conditions: a) (trimethylsilyl)diazomethane, THF, MeOH, hexane, 0 °C, 90%; b) HCO2Et, NaOMe, MeOH, 0 °C; 6N aqueous HCl, NH2OH·HCl, EtOH, 60 °C, 78%; c) NaOMe, MeOH, 45 °C, 77%; d) DBDMH, DMF, 0 °C; pyridine, 55 °C, 78%.

[0154] Scheme 18 TIFF0007695229000086.tif24042Reagents and conditions: a) 2,2,2-trifluoro-N'-hydroxy-ethanimidamide, Et3N, CH2Cl2, room temperature; b) Bu4NOH, water, THF, room temperature, 10% from 34.

[0155] Scheme 19 TIFF0007695229000087.tif23943Reagents and conditions: a) propionamide oxime, Et3N, CH2Cl2, room temperature; b) Bu4NOH, water, THF, room temperature, 36% from 34.

[0156] Scheme 20 TIFF0007695229000088.tif237103Reagents and conditions: a) propionyl chloride, Et3N, CH2Cl2, 0 °C, 89% for 52a; 82% for 52b; b) AcOH, 100 °C, 77% for 53a; 72% for 53b; c) NaOMe, MeOH, 55 °C, 97% for 54a; 89% for 54b; d) DBDMH, DMF, 0 °C; Py, 55 - 60 °C, 76% for T24; 76% for T25.

[0157] Scheme 21 TIFF0007695229000089.tif237101Reagents and conditions: a) RC(NH)NHOH, E3N, CH2Cl2, room temperature; b) Bu4NOH, water, THF, yields from 35: 47% for T26; 57% for T27; 52% for T28; 36% for T29; 52% for T30; 36% for T31; 16% for T32; 56% for T33.

[0158] Scheme 22 TIFF0007695229000090.tif24176Reagents and conditions: a) Oxalyl chloride, DMF, CH2Cl2, room temperature; b) 2-Fluoro-N-hydroxyethanimidamide, Et3N, room temperature, 87% from 56%; c) o-Xylene, 180 °C, 49%; d) HCO2Et, NaOMe, MeOH, 0 °C to room temperature; 12 M aqueous HCl, NH2OH·HCl, EtOH, H2O, 60 °C, quantitative yield; e) NaOMe, MeOH, 55 °C, 82%; f) 1,3-Dibromo-5,5-dimethylhydantoin, DMF, 0 °C; pyridine, 60 °C, 78%.

[0159] Scheme 23 TIFF0007695229000091.tif22839Reagents and conditions: a) 1) (COCl)2, DMF, CH2Cl2, 0 °C to room temperature; 2) 2,2-Difluoro-N'-hydroxyethanimidamide, Et3N, 0 °C to room temperature, 57%; b) Tetrabutylammonium hydroxide, H2O, THF, 0 °C to room temperature, 16%.

[0160] Scheme 24 TIFF0007695229000092.tif23932Reagents and conditions: a) Oxalyl chloride, DMF, CH2Cl2, 0 °C, quantitative yield; b) 2,2,2-Trifluoro-N'-hydroxy-ethanimidamide, Et3N, CH2Cl2, room temperature; c) Tetrabutylammonium hydroxide, H2O, THF, room temperature, 9% from 63%.

[0161] Compound 25 TIFF0007695229000093.tif22039Reagents and conditions: a) N'-Hydroxypropanimidamide, Et3N, CH2Cl2, room temperature; b) Tetrabutylammonium hydroxide, H2O, THF, room temperature, 48% from 63%.

[0162] Scheme 26 TIFF0007695229000094.tif24032Reagents and conditions: a) Hydrazine hydrate, CH2Cl2, 0 °C to room temperature, 85%; b) 2-Fluoroacetic acid, EDC·HCl, DMAP, CH2Cl2, room temperature, 29%; c) TsOH·H2O, toluene, reflux temperature, 48%.

[0163] Scheme 27 TIFF0007695229000095.tif23873Reagents and conditions: a) NH2OH-HCl, NaOAc, EtOH, H2O, room temperature, 93%; b) Aqueous HCl solution, NCS, MeCN, -10 °C; Aqueous NH3 solution, room temperature, 51%; c) 2-Fluoroacetic acid, EDC·HCl, DMAP, CH2Cl2, room temperature, 38%; d) 1,4-Dioxane, 100 °C, 79%; e) NaOMe, MeOH, 55 °C, 85%; f) DBDMH, DMF, 0 °C; Pyridine, 60 °C, 70%.

[0164] Scheme 28 TIFF0007695229000096.tif24133Reagents and conditions: a) TFAA, Et3N, 1,4-Dioxane, 0 °C to room temperature, 56%; b) NaOMe, MeOH, 55 °C, 68%; c) 1,3-Dibromo-5,5-dimethylhydantoin, DMF, 0 °C; Pyridine, 55 °C, 85%.

[0165] Scheme 29 TIFF0007695229000097.tif24433Reagents and conditions: a) 2,2-Difluoroacetic acid, EDC·HCl, DMAP, CH2Cl2, room temperature, 63%; b) NaOMe, MeOH, 55 °C, 85%; c) 1,3-Dibromo-5,5-dimethylhydantoin, DMF, 0 °C; Pyridine, 55 °C, 87%.

[0166] Scheme 30 TIFF0007695229000098.tif182128Reagents and conditions: a) Et3N, CH2Cl2, room temperature, 72%; b) tetrabutylammonium hydroxide, MeOH, room temperature, 61%; c) CF3CO2H, CH2Cl2, room temperature, 76%.

[0167] Scheme 31 TIFF0007695229000099.tif22939Reagents and conditions: a) 2,2-difluoro-N-hydroxyethanimidamide, Et3N, CH2Cl2, 0 °C to room temperature, 67%; b) TBAF, THF, reflux temperature, 55%.

[0168] Scheme 32 TIFF0007695229000100.tif23739Reagents and conditions: a) difluoroacetic anhydride, pyridine, CH2Cl2, 0 °C to room temperature, 79%; b) TsOH·H2O, toluene, reflux temperature, 31%.

[0169] Scheme 33 TIFF0007695229000101.tif23540Reagents and conditions: a) (CF3CO)2O, pyridine, CH2Cl2, 40 °C, 84%; b) Burgess reagent, THF, reflux temperature, 54%.

[0170] Scheme 34 TIFF0007695229000102.tif24039Reagents and conditions: a) propionic anhydride, pyridine, CH2Cl2, 40 °C, 76%; b) Burgess reagent, THF, reflux temperature, 74%.

[0171] Scheme 35 (Alternative route to T12) TIFF0007695229000103.tif24177Reagents and conditions: a) Oxalyl chloride, DMF, CH2Cl2, 0 °C to room temperature; b) 2-Fluoro-N-hydroxyethanimidamide, Et3N, room temperature, 89% from 85%; (c) T3P, Et3N, o-xylene, 36%; d) HCO2Et, NaOMe, MeOH, 0 °C to room temperature; 6M aqueous HCl solution, NH2OH·HCl, EtOH, 60 °C, 92%; e) NaOMe, MeOH, 55 °C, 92%; f) 1,3-Dibromo-5,5-dimethylhydantoin, DMF, 0 °C; pyridine, 60 °C, 96%.

[0172] C. Characterization evaluation data Compound 2 A solution of compound 1 (10.00 g, 19.71 mmol) in THF (200 mL) was cooled to 0 °C under N2. DIBAL-H (1.0 M toluene solution, 100 mL, 100 mmol) was added. The mixture was stirred at 0 °C for 30 minutes and then at room temperature for 2 hours. The reaction solution was cooled to 0 °C, carefully quenched with water (20 mL), and then 1N aqueous HCl solution (300 mL) was added. The mixture was extracted with EtOAc (4 x 150 mL). The combined organic extracts were washed with water (100 mL) and brine (100 mL), dried over Na2SO4, filtered, and concentrated to give crude compound 2 (9.5 g, quantitative yield) as a white solid. m / z = 482 (M+1).

[0173] Compound 3 Compound 2 (9.5 g, less than 19.71 mmol) was dissolved in CH2Cl2 (200 mL). 4 Å MS (20 g) and 4-methylmorpholine N-oxide (5.10 g, 43.53 mmol) were added. The mixture was stirred for 10 minutes at room temperature under N2. TPAP (690 mg, 1.96 mmol) was added. After the mixture was stirred for 1.5 hours at room temperature, the reaction was quenched with 10% Na2SO3 (50 mL). The mixture was stirred for 5 minutes at room temperature and then filtered through a pad of celite. The celite was eluted with CH2Cl2 (50 mL). The organic phase was separated from the filtrate. The aqueous phase from the filtrate was extracted with CH2Cl2 (2 x 50 mL) and EtOAc (2 x 50 mL). The combined organic extracts were washed with water (100 mL), dried over Na2SO4, filtered through a pad of silica gel, and eluted with EtOAc (100 mL). The filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 35% EtOAc in hexane) to give Compound 3 (6.39 g, 68% yield) as a white solid. m / z = 478 (M+1).

[0174] Compound 4 Compound 3 (2.72 g, 5.69 mmol), NH2OH-HCl (514 mg, 7.40 mmol), and NaOAc (841 mg, 10.2 mmol) were weighed into a flask. EtOH (120 mL) and water (8 mL) were added. After the mixture was stirred for 14 hours at room temperature, it was concentrated. The residue was partitioned between EtOAc (50 mL) and water (30 mL). The aqueous phase was extracted with EtOAc (30 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The residue contained a small amount of AcOH and water. After adding EtOH (10 mL) and toluene (10 mL), the mixture was concentrated. The residue was triturated with CH2Cl2 (30 mL) at reflux temperature for 10 minutes. After cooling to room temperature, the mixture was held at room temperature for 30 minutes. The precipitated solid was collected by filtration, washed with CH2Cl2 (2 x 5 mL), and dried under reduced pressure to give Compound 4 (2.15 g, 77% yield) as a white solid. m / z = 493 (M+1).

[0175] Compound 5 Under N2, compound 4 (2.68 g, 5.44 mmol) was suspended in MeCN (11 mL) and cooled to -10 °C. After adding aqueous HCl solution (12 N, 91 μL, 1.09 mmol), a solution of N-chlorosuccinimide (726 mg, 5.44 mmol) in MeCN (11 mL) was added. The reaction mixture was stirred at -10 °C for 30 minutes. LCMS indicated that almost all of the starting material had been consumed. Aqueous ammonia (28%, 3.7 mL, 54.4 mmol) was added. The mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with EtOAc (100 mL) and washed with water (2 x 40 mL). The combined aqueous washings were extracted with EtOAc (30 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 60% EtOAc in CH2Cl2) to give compound 5 (1.87 g, 68% yield) as a white solid. m / z = 508 (M+1).

[0176] Compound 6 A solution of 2-fluoroacetic acid (23 mg, 0.30 mmol) in CH2Cl2 (1 mL) was added to N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC·HCl, 57 mg, 0.30 mmol) under N2 at room temperature. A catalytic amount of DMAP (1.8 mg, 0.015 mmol) was added. The mixture was stirred at room temperature for 15 minutes. A solution of compound 5 (50 mg, 0.098 mmol) in CH2Cl2 (2 mL) was added. The mixture was stirred at room temperature for 1 hour. The mixture was diluted with CH2Cl2 (20 mL) and washed with water (2 x 10 mL). The combined aqueous washings were extracted with CH2Cl2 (20 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The residue was combined with the crude product obtained from compound 5 (11 mg, 0.022 mmol) using the same procedure and purified by column chromatography (silica gel, eluting with 0 - 50% EtOAc in CH2Cl2) to give compound 6 (47 mg, 69% yield) as a white solid. m / z = 568 (M+1).

[0177] Compound 7 A solution of compound 6 (47 mg, 0.083 mmol) in AcOH (1 mL) was heated at 100 °C for 40 min under N2. The mixture was cooled to room temperature, diluted with toluene (15 mL), and concentrated. The residue was diluted again with toluene (15 mL) and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 30% EtOAc in hexane) to give compound 7 (38 mg, 84% yield) as a white solid. m / z = 550 (M+1).

[0178] Compound 8 To a mixture of compound 7 (52 mg, 0.095 mmol) in anhydrous MeOH (1 mL) was added NaOMe (4.37 M MeOH solution, 43 μL, 0.19 mmol) under N2. The mixture was heated at 55 °C for 1 h and then cooled to 0 °C. The mixture was diluted with 10% aqueous NaH2PO4 (15 mL) and extracted with EtOAc (2 x 15 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 40% EtOAc in hexane) to give compound 8 (46 mg, 88% yield) as a white solid. m / z = 550 (M+1).

[0179] T1 Under N2, compound 8 (46 mg, 0.084 mmol) was dissolved in anhydrous DMF (0.4 mL) and cooled to 0 °C. 1,3 - Dibromo - 5,5 - dimethylhydantoin (DBDMH, 13 mg, 0.046 mmol) was added. The mixture was stirred at 0 °C for 1 h. Pyridine (30 μL, 0.38 mmol) was added. The mixture was heated at 55 °C for 6 h and then cooled to room temperature. The mixture was diluted with EtOAc (25 mL) and washed successively with 1 N aqueous HCl (10 mL) and water (2 x 15 mL). The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 35% EtOAc in hexane) to give compound T1 (36 mg, 79% yield) as a white solid. TIFF0007695229000104.tif26155

[0180] Compound 9 A mixture of Boc-glycine (207 mg, 1.18 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (227 mg, 1.18 mmol) in CH2Cl2 (4 mL) was treated with DMAP (4.8 mg, 0.039 mmol). The mixture was stirred for 15 minutes at room temperature under N2. A solution of compound 5 (200 mg, 0.39 mmol) in CH2Cl2 (4 mL) was added. The mixture was stirred for 1 hour at room temperature. Water (15 mL) was added. The mixture was extracted with CH2Cl2 (3 x 15 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 40% EtOAc in CH2Cl2) to give compound 9 (206 mg, 79% yield) as a white solid. m / z = 665 (M+1).

[0181] Compound 10 A mixture of compound 9 (206 mg, 0.31 mmol) in 1,4-dioxane (4 mL) in a pressure vessel was heated at 160 °C for 100 minutes. After cooling to room temperature, the reaction mixture was concentrated on a rotary evaporator (rotvap). The residue was dissolved in toluene (10 mL) and concentrated again. The residue was purified by column chromatography (silica gel, eluting with 0 - 60% EtOAc in hexane) to give compound 10 (160 mg, 80% yield) as a white solid. m / z = 647 (M+1).

[0182] Compound 11 A solution of compound 10 (159 mg, 0.25 mmol) in MeOH (2.5 mL) was treated with K2CO3 (136 mg, 0.98 mmol) at room temperature under N2. The mixture was stirred for 14 hours at room temperature. LCMS indicated that the reaction was complete. 10% Aqueous NaH2PO4 (15 mL) was added. The mixture was extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 70% EtOAc in hexane) to give compound 11 (141 mg, 89% yield) as a white solid. m / z = 669 (M+Na).

[0183] Compound 12 Under N2, Compound 11 (140 mg, 0.22 mmol) was dissolved in anhydrous DMF (1.1 mL) and cooled to 0 °C. 1,3-Dibromo-5,5-dimethylhydantoin (34 mg, 0.12 mmol) was added. The mixture was stirred at 0 °C for 1 h. Pyridine (70 μL, 0.87 mmol) was added. The mixture was heated at 60 °C for 5 h and then cooled to room temperature. The mixture was diluted with EtOAc (25 mL) and washed successively with 1 N aqueous HCl solution (10 mL) and water (3 x 15 mL). The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 60% EtOAc in hexane) to give Compound 12 (126 mg, yield 90%) as a white solid. m / z = 589 (M - C4H7).

[0184] T2 A solution of Compound 12 (113 mg, 0.18 mmol) in CH2Cl2 (1.8 mL) was treated with TFA (135 μL, 1.75 mmol) under N2 at room temperature. After stirring at room temperature for 5 h, saturated aqueous NaHCO3 solution (15 mL) was added. The mixture was extracted with CH2Cl2 (3 x 15 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 20% MeOH in CH2Cl2) to give Compound T2 (47 mg, yield 49%) as a yellow foam. TIFF0007695229000105.tif18155

[0185] Compound 13 To a mixture of Boc-β-Ala-OH (168 mg, 0.89 mmol) and EDC·HCl (170 mg, 0.89 mmol) in CH2Cl2 (3 mL) under N2 at room temperature, DMAP (5 mg, 0.04 mmol) was added. The mixture was stirred at room temperature for 15 minutes. A solution of compound 5 (150 mg, 0.30 mmol) in CH2Cl2 (3 mL) was added. After the mixture was stirred at room temperature for 1 hour, it was treated with water (15 mL). The mixture was extracted with CH2Cl2 (3 x 15 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 70% EtOAc in hexane) to give compound 13 (201 mg, quantitative yield) as a white solid. m / z = 679 (M+1).

[0186] Compound 14 A solution of compound 13 (200 mg, 0.30 mmol) in 1,4-dioxane (5 mL) was heated at 160 °C for 1 hour. The mixture was cooled to room temperature and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 55% EtOAc in hexane) to give compound 14 (137 mg, 70% yield) as a white solid. m / z = 661 (M+1).

[0187] Compound 15 A mixture of compound 14 (135 mg, 0.20 mmol) in MeOH (2 mL) was treated with K2CO3 (113 mg, 0.82 mmol) at room temperature. The mixture was stirred at room temperature for 14 hours. 10% Aqueous NaH2PO4 (15 mL) was added. The mixture was extracted with EtOAc (30 mL). The organic extract was washed with water (10 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 70% EtOAc in hexane) to give compound 15 (114 mg, 84% yield) as a white solid. m / z = 683 (M+Na).

[0188] Compound 16 A solution of compound 15 (114 mg, 0.17 mmol) and 1,3-dibromo-5,5-dimethylhydantoin (27 mg, 0.095 mmol) in anhydrous DMF (1.7 mL) was stirred at 0 °C for 1 h under N2. The mixture was treated with pyridine (56 μL, 0.69 mmol) and then heated at 60 °C for 5 h. After cooling to room temperature, the mixture was diluted with EtOAc (25 mL) and washed with 1 N aqueous HCl solution (10 mL) and water (3 x 15 mL). The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 60% EtOAc in hexane) to give compound 16 (93 mg, 82% yield) as a white solid. m / z = 559 (M - C5H7O2).

[0189] T3 A solution of compound 16 (85 mg, 0.13 mmol) in CH2Cl2 (0.65 mL) was treated with TFA (99 μL, 1.32 mmol) at room temperature. The mixture was stirred at room temperature for 5 h and then treated with saturated aqueous NaHCO3 solution (15 mL). The mixture was extracted with CH2Cl2 (3 x 15 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 20% MeOH in CH2Cl2) to give compound T3 (56 mg, 78% yield) as a yellow solid. TIFF0007695229000106.tif26156

[0190] Compound 17 A solution of compound 5 (100 mg, 0.20 mmol) in CH2Cl2 (1 mL) was cooled to 0 °C. A solution of Et3N (55 μL, 0.39 mmol) in CH2Cl2 (0.5 mL) and a solution of acetoxyacetyl chloride (40 mg, 0.30 mmol) in CH2Cl2 (0.5 mL) were added sequentially. After stirring the mixture at 0 °C for 1 h, it was treated with saturated aqueous NaHCO3 (5 mL). After stirring the mixture for 5 min, it was extracted with CH2Cl2 (3 x 10 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 60% EtOAc in hexane) to give compound 17 (119 mg, quantitative yield) as a white solid. m / z = 608 (M+1).

[0191] Compound 18 A solution of compound 17 (119 mg, 0.20 mmol) in AcOH (1 mL) was heated at 100 °C for 1 h and then cooled to room temperature. The mixture was diluted with toluene (15 mL) and then concentrated. The residue was diluted with toluene (10 mL) and concentrated again. The residue was purified by column chromatography (silica gel, eluting with 0 - 50% EtOAc in hexane) to give compound 18 (100 mg, 86% yield) as a white solid. m / z = 590 (M+1).

[0192] Compound 19 A solution of compound 18 (99 mg, 0.17 mmol) in MeOH (1.7 mL) was treated with NaOMe (4.37 M MeOH solution, 0.12 mL, 0.50 mmol) at room temperature. The mixture was heated at 55 °C for 1 h and then cooled to room temperature. 10% Aqueous NaH2PO4 (10 mL) was added. The mixture was extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 70% EtOAc in hexane) to give compound 19 (83 mg, 90% yield) as a white solid. m / z = 548 (M+1).

[0193] T4 A solution of compound 19 (82 mg, 0.15 mmol) and 1,3-dibromo-5,5-dimethylhydantoin (23.5 mg, 0.082 mmol) in anhydrous DMF (1.5 mL) was cooled to 0 °C under N2. After the mixture was stirred at 0 °C for 2 h, it was treated with pyridine (48 μL, 0.60 mmol). The mixture was heated at 60 °C for 6 h and then cooled to room temperature. The mixture was diluted with EtOAc (25 mL) and washed with 1 N aqueous HCl solution (10 mL) and water (2 x 15 mL). The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 70% EtOAc in hexane) to give compound T4 (67 mg, 82% yield) as a white solid. TIFF0007695229000107.tif25155

[0194] Compound 20 A solution of 3-acetoxypropanoic acid (78 mg, 0.59 mmol) in CH2Cl2 (2 mL) was added to EDC·HCl (113 mg, 0.59 mmol) at room temperature. DMAP (8 mg, 0.06 mmol) was added. The mixture was stirred at room temperature for 15 min. A solution of compound 5 (100 mg, 0.20 mmol) in CH2Cl2 (2 mL) was added. The mixture was stirred at room temperature for 1 h. Saturated aqueous NaHCO3 solution (3 mL) and water (10 mL) were added. The mixture was diluted with CH2Cl2 (20 mL) and EtOAc (2 x 20 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 70% EtOAc in hexane) to give compound 20 (80 mg, 66% yield) as a white solid. m / z = 622 (M+1).

[0195] Compound 21 Compound 20 (77 mg, 0.12 mmol) was dissolved in AcOH (1 mL) and heated at 100 °C for 2 h. After cooling to room temperature, the mixture was diluted with toluene (10 mL) and concentrated. The residue was diluted with toluene (10 mL) and concentrated again. The residue was purified by column chromatography (silica gel, eluting with 0 - 50% EtOAc in hexane) to give Compound 21 (41 mg, 55% yield) as a white solid. m / z = 604 (M+1).

[0196] Compounds 22 and 23 A solution of Compound 21 (40 mg, 0.066 mmol) in MeOH (1.2 mL) was treated at room temperature with NaOMe (4.37 M MeOH solution, 45 μL, 0.20 mmol). The mixture was heated at 55 °C for 1 h and then cooled to room temperature. 10% Aqueous NaH2PO4 solution (10 mL) was added. The mixture was extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 70% EtOAc in hexane) to give Compound 22 (19 mg, 51% yield) and Compound 23 (17 mg, 45% yield) as white solids. Compound 22: m / z = 562 (M+1); Compound 23: m / z = 576 (M+1).

[0197] T5 A solution of Compound 22 (19 mg, 0.034 mmol) in anhydrous DMF (0.3 mL) was cooled to 0 °C. A solution of 1,3 - dibromo - 5,5 - dimethylhydantoin (5.3 mg, 0.019 mmol) in DMF (55 μL) was added. The mixture was stirred at 0 °C for 1 h and then treated with pyridine (11 μL, 0.14 mmol). The mixture was heated at 60 °C for 5 h and then cooled to room temperature. The mixture was diluted with EtOAc (25 mL) and washed successively with 1 N aqueous HCl solution (10 mL) and water (2 x 15 mL). The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 70% EtOAc in hexane) to give Compound T5 (16 mg, 86% yield) as a white solid. TIFF0007695229000108.tif26156

[0198] T6 A solution of compound 23 (17 mg, 0.030 mmol) in anhydrous DMF (0.3 mL) was cooled to 0 °C. A solution of 1,3-dibromo-5,5-dimethylhydantoin (4.6 mg, 0.016 mmol) in DMF (46 μL) was added. The mixture was stirred at 0 °C for 1 hour and then treated with pyridine (9.5 μL, 0.12 mmol). The mixture was heated at 60 °C for 5 hours and then cooled to room temperature. The mixture was diluted with EtOAc (25 mL) and washed successively with 1N aqueous HCl solution (10 mL) and water (2 x 15 mL). The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 70% EtOAc in hexane) to give compound T6 (14 mg, 83% yield) as a white solid. TIFF0007695229000109.tif26156

[0199] Compound 25 To a mixture of compound 24 (1.366 g, 3.04 mmol) in o-xylene (5 mL) was added azidotributylstannane(IV) (1.00 mL, 3.65 mmol). The mixture was heated at 150 °C for 48 hours. The crude reaction mixture was purified by column chromatography (silica gel, eluting with 0 - 60% acetone in hexane) to give a partially purified compound 25, which was purified again by column chromatography (silica gel, eluting with 0 - 100% EtOAc in hexane) to give compound 25 (710 mg, 47% yield) as a brown solid. m / z = 493 (M+1).

[0200] Compound 26 A mixture of compound 25 (200 mg, 0.41 mmol) and Cs2CO3 (160 mg, 0.49 mmol) in MeCN (4 mL) was treated with 2-bromoethanol (40 μL, 0.56 mmol) at room temperature. The mixture was heated at 60 °C for 3 h, then an additional amount of 2-bromoethanol (40 μL, 0.56 mmol) was added. The mixture was heated at 60 °C for an additional 3 h and cooled to room temperature. The mixture was diluted with EtOAc (50 mL) and filtered. The filtrate was concentrated. The residue was combined with the crude product obtained from compound 25 (50 mg, 0.10 mmol) and purified by column chromatography (silica gel, eluting with 0 - 50% acetone in hexane) to give compound 26 (222 mg, 82% yield) as a white solid. m / z = 537 (M+1).

[0201] Compound 27 A mixture of compound 26 (220 mg, 0.41 mmol) in ethyl formate (1.00 mL, 12.29 mmol) was cooled to 0 °C under N2 and treated by dropwise addition of sodium methoxide solution (4.37 M in methanol, 1.40 mL, 6.12 mmol). The reaction mixture was stirred at room temperature for 1.5 h and then cooled to 0 °C. The mixture was treated with 6N aqueous HCl (1.1 mL, 6.6 mmol), followed by EtOH (8 mL) and hydroxylamine hydrochloride (43 mg, 0.62 mmol). The reaction mixture was heated at 55 °C for 5 h, cooled to room temperature, and concentrated. The residue was diluted with EtOAc and washed with water. The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 100% EtOAc in hexane) to give compound 27 (166 mg, 72% yield) as a white solid. m / z = 562 (M + 1).

[0202] Compound 28 To a mixture of compound 27 (166 mg, 0.30 mmol) in anhydrous MeOH (3 mL) was added NaOMe (4.37 M MeOH solution, 0.14 mL, 0.61 mmol) under N2. The mixture was heated at 55 °C for 1 hour and then cooled to room temperature. The mixture was diluted with 10% aqueous NaH2PO4 and extracted twice with EtOAc. The combined organic extracts were dried over Na2SO4, filtered, and concentrated to give compound 28 (180 mg, quantitative yield) as a white solid. m / z = 562 (M+1).

[0203] T7 Under N2, compound 28 (180 mg, 0.30 mmol) was dissolved in anhydrous DMF (1 mL) and cooled to 0 °C. 1,3-Dibromo-5,5-dimethylhydantoin (42 mg, 0.15 mmol) was added. The mixture was stirred at 0 °C for 1 hour. Pyridine (72 μL, 0.89 mmol) was added. The mixture was heated at 55 °C for 16 hours and then cooled to room temperature. The mixture was diluted with EtOAc and washed successively with 1 N aqueous HCl and water (3x). The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 70% EtOAc in hexane) to give compound T7 (114 mg, 68% yield) as a white solid. TIFF0007695229000110.tif32156

[0204] T8 A solution of compound T7 (30 mg, 0.054 mmol) in CH2Cl2 (0.5 mL) was cooled to 0 °C. Pyridine (13 μL, 0.16 mmol), acetic anhydride (10 μL, 0.11 mmol), and a catalytic amount of DMAP were added successively. The mixture was stirred at 0 °C for 2.5 hours and diluted with toluene (5 mL). The mixture was concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 45% EtOAc in hexane) to give compound T8 (23 mg, 71% yield) as a white solid. TIFF0007695229000111.tif25156

[0205] T9 A mixture of compound T7 (72 mg, 0.13 mmol), proton sponge (82 mg, 0.38 mmol), and trimethyloxonium tetrafluoroborate (56 mg, 0.38 mmol) in CH2Cl2 (1.2 mL) was stirred at room temperature for 16 h. The reaction mixture was quenched with saturated aqueous NaHCO3, stirred for 5 min, and extracted with EtOAc. The organic extract was washed sequentially with water, 1N aqueous HCl, and water, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 80% EtOAc in hexane) to afford compound T9 (32 mg, 43% yield) as a white solid. TIFF0007695229000112.tif25155

[0206] Compound 29 In a vial, a mixture of compound 25 (200 mg, 0.41 mmol) and Cs2CO3 (160 mg, 0.49 mmol) in MeCN (2 mL) was treated with a solution of 1 - fluoro - 2 - iodoethane (100 mg, 0.58 mmol) in MeCN (2 mL). The vial was sealed and heated at 60 °C for 6 h. After cooling to room temperature, the mixture was diluted with EtOAc and filtered through a pad of celite. The filter cake was washed with EtOAc. The combined filtrate and washings were concentrated. The residue was combined with the crude product obtained from compound 25 (50 mg, 0.10 mmol) and purified by column chromatography (silica gel, eluting with 0 - 50% EtOAc in hexane) to afford compound 29 (142 mg, 52% yield) as a bright yellow solid. m / z = 539 (M+1).

[0207] Compound 30 A mixture of compound 29 (142 mg, 0.26 mmol) in ethyl formate (0.64 mL, 7.86 mmol) was cooled to 0 °C under N2 and treated with a dropwise addition of sodium methoxide solution (4.37 M in methanol, 0.90 mL, 3.93 mmol). The reaction mixture was stirred at room temperature for 1.5 h and then cooled to 0 °C. The mixture was treated with 6 N aqueous HCl (0.66 mL, 3.96 mmol), followed by EtOH (5.2 mL) and hydroxylamine hydrochloride (28 mg, 0.40 mmol). The reaction mixture was heated at 55 °C for 5 h, cooled to room temperature, and concentrated. The residue was diluted with EtOAc and washed with water. The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 50% EtOAc in hexane) to give compound 30 (102 mg, 71% yield) as a white solid. m / z = 544 (M+1).

[0208] Compound 31 Compound 30 (102 mg, 0.19 mmol) was dissolved in MeOH (1 mL) and CH2Cl2 (1 mL) and cooled to -78 °C. Ozone was bubbled through the reaction mixture until the starting material was completely consumed (about 10 min). Oxygen was bubbled through for 5 min. NaBH4 (15 mg, 0.40 mmol) was added. The cold bath was removed. The mixture was stirred at room temperature for 3 h, diluted with EtOAc, and washed with 1 N aqueous HCl and water. The aqueous washings were combined and extracted with EtOAc. The combined organic extracts were dried over Na2SO4, filtered, and concentrated to give compound 31 (96 mg, 99% yield) as a white solid. m / z = 518 (M+1).

[0209] Compound 32 A mixture of Compound 31 (96 mg, 0.19 mmol) and Cs2CO3 (73 mg, 0.22 mmol) was treated with a solution of 1-fluoro-2-iodoethane (45 mg, 0.26 mmol) in MeCN (1.8 mL). The mixture was heated at 60 °C for 6 h under N2. After cooling to room temperature, the mixture was diluted with EtOAc and washed successively with 1N aqueous HCl, 10% aqueous Na2SO3, and water. The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 50% EtOAc in hexane) to give Compound 32 (63 mg, 60% yield) as a white solid. m / z = 564 (M+1).

[0210] Compound 33 A mixture of Compound 32 (61 mg, 0.11 mmol) in MeOH (1 mL) was treated with K2CO3 (45 mg, 0.33 mmol) at room temperature. The mixture was stirred at room temperature for 16 h. 10% aqueous NaH2PO4 (15 mL) was added. The mixture was extracted twice with EtOAc. The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 50% EtOAc in hexane) to give Compound 33 (48 mg, 79% yield) as a white solid. m / z = 564 (M+1).

[0211] T10 A solution of Compound 33 (48 mg, 0.085 mmol) in anhydrous DMF (0.42 mL) was cooled to 0 °C under N2. 1,3-Dibromo-5,5-dimethylhydantoin (12 mg, 0.042 mmol) was added. The mixture was stirred at 0 °C for 1 h and then treated with pyridine (21 μL, 0.26 mmol). The mixture was heated at 55 °C for 16 h. After cooling to room temperature, the mixture was diluted with EtOAc and washed successively with 1N aqueous HCl and water (3x). The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 50% EtOAc in hexane) to give Compound T10 (34 mg, 71% yield) as a white solid. TIFF0007695229000113.tif25156

[0212] Compound 35 Compound 34 (1.00 g, 2.03 mmol) was mixed with CH2Cl2 (20 mL) and cooled to 0 °C under N2. Oxalyl chloride (0.54 mL, 6.17 mmol) and DMF (16 μL, 0.20 mmol) were sequentially added. The cold bath was removed. The mixture was stirred at room temperature for 2 hours and then concentrated. The residue was dissolved in toluene (3 x 10 mL) and concentrated to remove residual oxalyl chloride. Crude Compound 35 (1 g) was obtained as a pale yellow solid and used in the next step without further purification.

[0213] Compound 36 A solution of Compound 35 (200 mg, 0.39 mmol) in CH2Cl2 (4 mL) was cooled to 0 °C under N2. Hydrazine hydrate (50 wt%, 75 mg, 1.18 mmol) was added dropwise. The mixture was stirred at room temperature for 10 minutes, diluted with CH2Cl2 (10 mL), and washed with water (15 mL). The aqueous washings were extracted with CH2Cl2 (2 x 15 mL) and EtOAc (15 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated to give Compound 36 (179 mg, 90% yield) as a glassy solid.

[0214] Compound 37 A solution of 2-fluoroacetic acid (67 mg, 0.86 mmol) in CH2Cl2 (1 mL) was treated with EDC·HCl (164 mg, 0.85 mmol) and DMAP (3.5 mg, 0.028 mmol) at room temperature under N2. The mixture was stirred at room temperature for 15 minutes. Next, a solution of Compound 36 (144 mg, 0.29 mmol) in CH2Cl2 (2 mL) was added. The mixture was stirred at room temperature for 14 hours. The reaction mixture was washed with saturated aqueous NaHCO3 (10 mL) and water (10 mL). The aqueous phase was extracted with CH2Cl2 (2 x 10 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 60% EtOAc in CH2Cl2) to give Compound 37 (96 mg, 60% yield) as a peach-colored solid. m / z = 566 (M+1).

[0215] T11 While removing water with a Dean-Stark apparatus, a toluene (10 mL) solution of compound 37 (115 mg, 0.20 mmol) and p-toluenesulfonic acid monohydrate (19 mg, 0.10 mmol) was heated at reflux temperature for 3 hours. The mixture was cooled to room temperature, diluted with EtOAc (10 mL), and washed with water (2 x 15 mL). The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 40% acetone in hexane) to give compound T11 (67 mg, 60% yield) as a white solid. TIFF0007695229000114.tif26156

[0216] Compound 39 A CH2Cl2 (25 mL) solution of compound 35 [produced from compound 34 (1.52 g, 3.09 mmol)] was cooled to 0 °C. Solutions of Et3N (1.70 mL, 12.4 mmol) and compound 38 (404 mg, 4.39 mmol) in CH2Cl2 (5 mL) were added sequentially. After stirring at room temperature for 4 hours, the mixture was treated with water (30 mL). The organic phase was separated. The aqueous phase was extracted with CH2Cl2 (3 x 30 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 60% acetone in hexane) to give compound 39 (1.46 g, 84% yield) as a white solid. m / z = 566 (M+1).

[0217] T12 In a Biotage microwave synthesizer, a mixture of compound 39 (148 mg, 0.26 mmol), T3P (50 wt% EtOAc solution, 0.40 g, 0.63 mmol), and Et3N (0.18 mL, 1.31 mmol) in EtOAc (1 mL) was heated at 125 °C for 1 hour. After cooling to room temperature, the mixture was diluted with EtOAc (20 mL) and washed successively with 1N aqueous HCl (15 mL), saturated aqueous NaHCO3 (15 mL), and water (15 mL). The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 80% EtOAc in hexane) to give compound T12 (9 mg, 6% yield) as a white solid. TIFF0007695229000115.tif26156

[0218] A stock solution of compound 35 (prepared from 11.11 mmol of compound 34) and triethylamine (6.20 mL, 44.5 mmol) in CH2Cl2 (52 mL) was prepared to obtain a stock solution of compound 35 (≤0.183 M) and trimethylamine (0.735 M) in CH2Cl2. The total volume of the solution was 60.5 mL. The stock solution was used in the synthesis of compounds 40 and 41.

[0219] Compound 40 A stock solution of compound 35 and Et3N in CH2Cl2 [12.5 mL, containing compound 35 (2.29 mmol) and trimethylamine (9.19 mmol)] was treated with 3 - hydroxypropionamide oxime (347 mg, 3.33 mmol). The mixture was stirred overnight at room temperature. The resulting mixture was diluted with EtOAc and washed with water, saturated aqueous NaHCO3, and brine. The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 10% MeOH in CH2Cl2) to give compound 40 (604.4 mg, 46% yield from compound 34) as a solid.

[0220] T13 A mixture of compound 40 (604.4 mmol, 1.046 mmol) and tetrabutylammonium hydroxide (40% w / w aqueous solution, 2.1 mL, 3.2 mmol) in THF (8.4 mL) was stirred overnight at room temperature under N2. The resulting mixture was diluted with EtOAc and washed with water, saturated aqueous NaHCO3, and brine. The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 100% EtOAc in hexane) to give compound T13 (265.5 mg, 45% yield) as a white solid. TIFF0007695229000116.tif33156

[0221] T14 A mixture of compound T13 (101.2 mg, 0.1808 mmol) and HCl (12 M aqueous solution, 0.5 mL, 6.0 mmol) in glacial acetic acid (10 mL) was stirred at 75 °C for 20 h under N2. The resulting mixture was azeotroped with toluene (60 mL, then 50 mL), and the residue was purified by column chromatography (silica gel, eluting with 0 - 100% EtOAc in hexane) to give compound T14 (48.0 mg, 44% yield) as a white solid. TIFF0007695229000117.tif25155

[0222] Compound 41 A stock solution of compound 35 and Et3N in CH2Cl2 [12.5 mL, containing compound 35 (2.29 mmol) and trimethylamine (9.19 mmol)] was treated with 3 - methoxypropionamide oxime hydrochloride (516 mg, 3.33 mmol) and additional triethylamine (0.46 mL, 3.3 mmol). The mixture was stirred overnight at room temperature. The resulting mixture was diluted with EtOAc and washed with water, saturated aqueous NaHCO3, and brine. The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 10% MeOH in CH2Cl2) to give a mixture of compound 41 and compound 34 (1.22 g, approximately 2.5:1 - 41:34) as a solid, which was used without further purification.

[0223] T15 A mixture of Compound 41 and Compound 34 (1.22 g, approximately 2.5:1 - 41:34) and tetrabutylammonium hydroxide (40% w / w aqueous solution, 4.2 mL, 6.4 mmol) in THF (17 mL) was stirred overnight at room temperature under N₂. The resulting mixture was diluted with EtOAc and washed with water, saturated aqueous NaHCO₃, and brine. The organic extract was dried over Na₂SO₄, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 100% EtOAc in hexane) to obtain Compound T15 (494.7 mg, 37% yield from Compound 34) as a white solid. TIFF0007695229000118.tif25156

[0224] Compound 42 A mixture of N-tert-butoxycarbonyl-3-aminopropionitrile (858 mg, 5.04 mmol), hydroxylamine hydrochloride (1.39 g, 20.0 mmol), and triethylamine (4.2 mL, 30 mmol) in ethanol (20 mL) was heated to 80 °C for 2 days with stirring in a sealed tube. The resulting solution was diluted with EtOAc (300 mL) and washed with water / saturated aqueous NaHCO₃ (1:1, 100 mL) and brine (25 mL). The organic extract was dried over Na₂SO₄, filtered, and concentrated to obtain a mixture of Compound 42 and N-tert-butoxycarbonyl-3-aminopropionitrile (73:27, 773.4 mg) as a crystalline solid, which was used without further purification.

[0225] Compound 43 Compound 35 [synthesized from Compound 34 (1.08 g, 2.20 mmol)], an impure mixture of Compound 42 (73:27 - Int4:N-tert-butoxycarbonyl-3-aminopropionitrile, 773.4 mg), and triethylamine (1.23 mL, 8.83 mmol) in CH2Cl2 (18 mL) was stirred at room temperature for 2 hours. The resulting mixture was diluted with EtOAc (100 mL) and washed with water (25 mL), saturated aqueous NaHCO3 (25 mL), and brine (25 mL). The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 10% MeOH in CH2Cl2) to give a mixture of Compound 43 and 34 (1.01 g, approximately 4:1 - 43:34) as a solid, which was used without further purification.

[0226] Compound 44 A solution of impure Compound 43 (approximately 4:1 - 43:34, 904 mg, approximately 1.07 mmol) and tetrabutylammonium hydroxide (40% w / w aqueous solution, 3.6 mL, 5.5 mmol) in THF (14 mL) was stirred at room temperature for 5 hours under N2. The resulting mixture was diluted with EtOAc (200 mL) and washed with water (50 mL), saturated aqueous NaHCO3 (50 mL), and brine (50 mL). The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 100% EtOAc in hexane) to give Compound 44 (578.2 mg, 45% yield from Compound 34) as a solid. m / z = 559.4 (M - Boc + 2).

[0227] T16 A mixture of Compound 44 (61 mg, 0.093 mmol) and HCl (12 M aqueous solution, 0.25 mL, 3.0 mmol) in MeOH (2.5 mL) was stirred at room temperature. After 3.5 h, additional HCl (12 M aqueous solution, 0.75 mL, 9.0 mmol) was added and stirring was continued at room temperature for a total of 24 h. The resulting mixture was diluted with EtOAc (50 mL) and washed with saturated aqueous NaHCO3 (25 mL). The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 10% MeOH in CH2Cl2) to give Compound T16 (43.1 mg, 83% yield) as a pale yellowish-white solid. TIFF0007695229000119.tif25156

[0228] T17 To a solution of Compound T16 (51.7 mg, 0.0926 mmol) and triethylamine (42 μL, 0.301 mmol) in CH2Cl2 (1 mL) was added methyl chloroformate (12 μL, 0.16 mmol), and the mixture was stirred at room temperature for 2 h. Additional methyl chloroformate (30 μL, 0.39 mmol) was added and stirring was continued overnight. The mixture was diluted with CH2Cl2 (35 mL) and washed with HCl (1 M aqueous solution, 15 mL) and brine (15 mL). The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 100% EtOAc in hexane) to give Compound T17 (11.6 mg, 20% yield) as a white solid. TIFF0007695229000120.tif25166

[0229] T18 To a solution of compound T16 (55.8 mg, 0.0999 mmol) and triethylamine (0.14 mL, 1.0 mmol) in CH2Cl2 (1 mL) was added ethyl isocyanate (8 μL, 0.101 mmol), and the mixture was stirred at room temperature for 1 hour. The resulting mixture was diluted with CH2Cl2 (35 mL) and washed with HCl (1 M aqueous solution, 15 mL) and brine (15 mL). The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 100% EtOAc in hexane) to obtain compound T18 (42.1 mg, yield 67%) as a white solid. TIFF0007695229000121.tif32165

[0230] T19 To a solution of compound T16 (45.7 mg, 0.0818 mmol) and triethylamine (0.11 mL, 0.79 mmol) in CH2Cl2 (1 mL) was added acetyl chloride (0.15 mL, 2.1 mmol), and the mixture was stirred at room temperature for 15 minutes. The resulting heterogeneous mixture was diluted with HCl (1 M aqueous solution, 15 mL) and extracted with EtOAc (50 mL). The organic fraction was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 15% MeOH in CH2Cl2) to obtain compound T19 (16.3 mg, yield 33%) as a white solid. TIFF0007695229000122.tif25155

[0231] Compound 45 A solution of compound 5 (40 mg, 0.079 mmol) in AcOH (1 mL) was treated with acetic anhydride (11 μL, 0.12 mmol) at room temperature. The mixture was stirred at room temperature for 30 minutes and then heated at 100 °C for 2 hours. The mixture was cooled to room temperature, diluted with toluene (10 mL), and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 40% EtOAc in hexane) to obtain compound 45 (40 mg, yield 95%) as a white foam. m / z = 532 (M+1).

[0232] Compound 46 Compound 45 (40 mg, 0.075 mmol) was mixed with K2CO3 (44 mg, 0.32 mmol) and MeOH (2 mL). The mixture was stirred at room temperature for 14 h under N2, treated with 10% NaH2PO4 (20 mL), and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The residue was combined with the crude product obtained from Compound 46 (16 mg, 0.030 mmol) and purified by column chromatography (silica gel, eluting with 0 - 40% EtOAc in hexane) to give Compound 46 (43.5 mg, 78% yield) as a white solid. m / z = 532 (M+1).

[0233] T20 Compound 46 (43.5 mg, 0.082 mmol) and 1,3 - dibromo - 5,5 - dimethylhydantoin (13 mg, 0.045 mmol) were mixed with anhydrous DMF (0.8 mL) at 0 °C under N2. The mixture was stirred at 0 °C for 1 h, treated with pyridine (20 μL, 0.25 mmol), heated at 55 °C for 6 h, cooled to room temperature, diluted with EtOAc (25 mL), and washed with 1 N aqueous HCl (10 mL) and water (2 x 15 mL). The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 35% EtOAc in hexane) to give Compound T20 (34 mg, 78% yield) as a white solid. TIFF0007695229000123.tif25156

[0234] Compound 47 A solution of compound 25 (150 mg, 0.30 mmol) in THF (2.4 mL) and MeOH (0.6 mL) was cooled to 0 °C. (Trimethylsilyl)diazomethane (2 M hexane solution, 183 μL, 0.366 mmol) was added. The mixture was stirred at 0 °C for 20 minutes, quenched with acetic acid, diluted with toluene, and concentrated. The residue was combined with the crude product obtained from compound 25 (50 mg, 0.10 mmol) and purified by column chromatography (silica gel, eluting with 0 - 35% acetone in hexane) to give compound 47 (139 mg, 90% yield) as a white solid. m / z = 507 (M+1).

[0235] Compound 48 A mixture of compound 47 (137 mg, 0.27 mmol) in ethyl formate (0.65 mL, 8.08 mmol) was cooled to 0 °C under N2 and treated by dropwise addition of sodium methoxide solution (4.37 M in methanol, 0.62 mL, 2.71 mmol). After the reaction mixture was stirred at 0 °C for 1 hour, it was treated with 6N aqueous HCl (0.45 mL, 2.7 mmol), followed by EtOH (2.7 mL) and hydroxylamine hydrochloride (28 mg, 0.40 mmol). The reaction mixture was heated at 60 °C for 6 hours, cooled to room temperature, diluted with EtOAc, and washed with water. The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 50% EtOAc in hexane) to give compound 48 (112 mg, 78% yield) as a white solid. m / z = 532 (M + 1).

[0236] Compound 49 To a mixture of compound 48 (110 mg, 0.21 mmol) in anhydrous MeOH (2 mL) under N2, NaOMe (4.37 M MeOH solution, 95 μL, 0.42 mmol) was added. The mixture was heated at 45 °C for 1 - 2 h and then cooled to room temperature. The mixture was diluted with 10% aqueous NaH2PO4 and extracted twice with EtOAc. The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 50% EtOAc in hexane) to give compound 49 (86 mg, 77% yield) as a white solid. m / z = 532 (M+1).

[0237] T21 Under N2, compound 49 (84 mg, 0.16 mmol) was dissolved in anhydrous DMF (0.4 mL) and cooled to 0 °C. A solution of 1,3 - dibromo - 5,5 - dimethylhydantoin (23 mg, 0.080 mmol) in DMF (0.4 mL) was added. The mixture was stirred at 0 °C for 2 h. Pyridine (40 μL, 0.50 mmol) was added. The mixture was heated at 55 °C for 6 h and then cooled to room temperature. The mixture was diluted with EtOAc and washed successively with 1N aqueous HCl and water (3x). The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 50% EtOAc in hexane) to give compound T21 (65 mg, 78% yield) as a white solid. TIFF0007695229000124.tif32156

[0238] A stock solution of compound 35 (≤0.113 M) and trimethylamine (0.453 M) in CH2Cl2 was prepared by dissolving compound 35 (prepared from 28.92 mmol of compound 34) and triethylamine (16.1 mL, 116 mmol) in CH2Cl2 (230 mL). The total volume of the solution was 256 mL. The stock solution was used for the synthesis of compounds 50 and 52.

[0239] Compound 50 To a stock solution of Compound 35 and Et3N in CH2Cl2 [26.1 mL, containing Compound 35 (2.95 mmol) and Et3N (11.8 mmol)] was added 2,2,2-trifluoro-N'-hydroxy-ethanimidamide (229.2 mg, 1.79 mmol), and the mixture was stirred overnight at room temperature. The resulting mixture was diluted with EtOAc and washed with water, saturated aqueous NaHCO3, and brine. The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 10% MeOH in CH2Cl2) to give impure Compound 50 (965.7 mg) as a solid, which was used without further purification. m / z = 602.3 (M+1).

[0240] T22 A mixture of impure Compound 50 (353 mg) and tetrabutylammonium hydroxide (40% w / w aqueous solution, 1.25 mL, 1.9 mmol) in THF (5 mL) was stirred overnight at room temperature under N2. The resulting mixture was diluted with EtOAc and washed with water, saturated aqueous NaHCO3, and brine. The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 100% EtOAc in hexane) to give Compound T22 (63.3 mg, 10% yield from Compound 34) as a white solid. TIFF0007695229000125.tif33156

[0241] Compound 51 To a stock solution of compound 35 and Et3N in CH2Cl2 [30 mL, containing compound 35 (3.38 mmol) and Et3N (13.5 mmol)] was added propionamide oxime (250 mg, 2.84 mmol), and the mixture was stirred at room temperature overnight. The resulting mixture was diluted with EtOAc and washed with water, saturated aqueous NaHCO3, and brine. The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 10% MeOH in CH2Cl2) to give impure compound 51 (1.0959 g), which was used without further purification. m / z = 562.3 (M+1).

[0242] T23 A mixture of impure compound 51 (346.2 mg) and tetrabutylammonium hydroxide (40% w / w aqueous solution, 1.25 mL, 1.9 mmol) in THF (5 mL) was stirred at room temperature overnight under N2. The resulting mixture was diluted with EtOAc and washed with water, saturated aqueous NaHCO3, and brine. The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 100% EtOAc in hexane) to give compound T23 (209.9 mg, 36% yield from compound 34) as a white solid. TIFF0007695229000126.tif32156

[0243] Compound 52a A solution of compound 5 (84 mg, 0.17 mmol) in CH2Cl2 (6 mL) was cooled to 0 °C. Solutions of Et3N (46 μL, 0.33 mmol) and propionyl chloride (23 mg, 0.25 mmol) in CH2Cl2 (1 mL) were added sequentially. After stirring at 0 °C for 1 h, the mixture was treated with saturated aqueous NaHCO3 (5 mL). After stirring for 5 min, it was extracted with CH2Cl2 (3 x 10 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 60% EtOAc in hexane) to give compound 52a (83 mg, 89% yield) as a white solid. m / z = 564.3 (M+1)

[0244] Compound 53a A solution of compound 52a (83 mg, 0.15 mmol) in AcOH (1 mL) was heated at 100 °C for 1 h. The mixture was cooled to room temperature, diluted with toluene (15 mL), and concentrated. The residue was diluted with toluene (10 mL) and concentrated again. The residue was purified by column chromatography (silica gel, eluting with 0 - 40% EtOAc in hexane) to give compound 53a (67 mg, 77% yield) as a white solid. m / z = 546.3 (M+1).

[0245] Compound 54a A solution of compound 53a (67 mg, 0.12 mmol) in MeOH (1.2 mL) was treated with sodium methoxide (25 wt% MeOH solution, 66 mg, 0.31 mmol) at room temperature. The mixture was stirred at 55 °C for 1 h. After cooling to room temperature, the mixture was treated with 10% NaH2PO4 (5 mL) and extracted with EtOAc (2 x 15 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 45% EtOAc in hexane) to give compound 54a (65 mg, 97% yield) as a white solid. m / z = 546.3 (M+1).

[0246] T24 Compound 54a (65 mg, 0.12 mmol) and 1,3 - dibromo - 5,5 - dimethylhydantoin (18.7 mg, 0.066 mmol) were mixed with anhydrous DMF (0.6 mL) under N2 at 0 °C. The mixture was stirred at 0 °C for 1 h and treated with pyridine (38 μL, 0.48 mmol). The mixture was heated at 55 °C for 2 h and at 60 °C for 4 h, cooled to room temperature, diluted with EtOAc (25 mL), and washed with 1N aqueous HCl solution (10 mL) and water (2 x 15 mL). The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 45% EtOAc in hexane) to give compound T24 (49 mg, 76% yield) as a white solid. TIFF0007695229000127.tif25155

[0247] Compound 52b Using the same procedure as described for the synthesis of compound 52a, compound 52b (white solid, 96 mg, 82% yield) was synthesized from compound 5 (103 mg, 0.20 mmol). m / z = 576 (M+1).

[0248] Compound 53b Using the same procedure as described for the synthesis of compound 53a, compound 53b (solid, 67 mg, 72% yield) was synthesized from compound 52b (96 mg, 0.17 mmol). m / z = 558 (M+1).

[0249] Compound 54b Using the same procedure as described for the synthesis of compound 54a, compound 54b (white solid, 58 mg, 89% yield) was synthesized from compound 53b (65 mg, 0.12 mmol). m / z = 558 (M+1).

[0250] T25 Using the same procedure as described for the synthesis of compound T24, compound T25 (white solid, 44 mg, 76% yield) was synthesized from compound 54b (58 mg, 0.10 mmol). TIFF0007695229000128.tif18155

[0251] Compound 55a Using the same procedure as described for the synthesis of compound 51, impure compound 55a (1.3624 g) was synthesized from compound 35 (3.67 mmol), n-butylamidoxime (234.6 mg, 2.30 mmol), and trimethylamine (14.6 mmol). m / z = 576 (M+1).

[0252] T26 Using the same procedure as described for the synthesis of compound T23, compound T26 (white solid, 159.3 mg, 47% yield from 35) was synthesized from compound 55a (361.1 mg) and tetrabutylammonium hydroxide (40% w / w aqueous solution, 1.25 mL, 1.9 mmol). TIFF0007695229000129.tif25165

[0253] Compound 55b Using the same procedure as described for the synthesis of compound 51, impure compound 55b (1.1737 g) was synthesized from compound 35 (3.67 mmol), isobutylamidoxime (255.1 mg, 2.50 mmol), and trimethylamine (14.6 mmol). m / z = 576 (M+1).

[0254] T27 Using the same procedure as described for the synthesis of compound T23, compound T27 (white solid, 240.3 mg, 57% yield from 35) was synthesized from compound 55b (354.1 mg) and tetrabutylammonium hydroxide (40% w / w aqueous solution, 1.25 mL, 1.9 mmol). TIFF0007695229000130.tif25165

[0255] Compound 55c Using the same procedure as described for the synthesis of compound 51, impure compound 55c (1.4948 g) was synthesized from compound 35 (3.13 mmol), N-hydroxy-2,2-dimethylpropanimidamide (258.2 mg, 2.22 mmol), and trimethylamine (12.5 mmol). m / z = 590 (M+1).

[0256] T28 Using the same procedure as described for the synthesis of compound T23, compound T28 (white solid, 157.2 mg, 52% yield from 35) was synthesized from compound 55c (357.7 mg) and tetrabutylammonium hydroxide (40% w / w aqueous solution, 1.25 mL, 1.9 mmol). TIFF0007695229000131.tif18165

[0257] Compound 55d Using the same procedure as described for the synthesis of Compound 51, impure Compound 55d (279.1 mg) was synthesized from Compound 35 (0.64 mmol), N'-hydroxycyclopropanecarboximidamide (84.3 mg, 0.842 mmol), and trimethylamine (2.6 mmol). m / z = 574 (M+1).

[0258] T29 Using the same procedure as described for the synthesis of Compound T23, Compound T29 (white solid, 129.3 mg, 36% yield from 35) was synthesized from Compound 55d (279.1 mg) and tetrabutylammonium hydroxide (40% w / w aqueous solution, 1 mL, 1.5 mmol). TIFF0007695229000132.tif26156

[0259] Compound 55e Using the same procedure as described for the synthesis of Compound 51, impure Compound 55e (514.3 mg) was synthesized from Compound 35 (1.33 mmol), 2-cyclopropyl-N'-hydroxyethanimidamide (101.3 mg, 0.887 mmol), and trimethylamine (5.31 mmol). m / z = 588 (M+1).

[0260] T30 Using the same procedure as described for the synthesis of Compound T23, Compound T30 (white solid, 176.0 mg, 52% yield from 35) was synthesized from Compound 55e (344.0 mg) and tetrabutylammonium hydroxide (40% w / w aqueous solution, 1.25 mL, 1.9 mmol). TIFF0007695229000133.tif25166

[0261] Compound 55f Using the same procedure as described for the synthesis of compound 51, impure compound 55f (239.0 mg) was synthesized from compound 35 (0.64 mmol), N'-hydroxycyclobutanecarboximidamide (89.8 mg, 0.787 mmol), and trimethylamine (2.6 mmol). m / z = 588 (M+1).

[0262] T31 Using the same procedure as described for the synthesis of compound T23, compound T31 (white solid, 129.9 mg, 36% yield from 35) was synthesized from compound 55f (239.0 mg) and tetrabutylammonium hydroxide (40% w / w aqueous solution, 0.9 mL, 1.35 mmol). TIFF0007695229000134.tif18165

[0263] Compound 55g Using the same procedure as described for the synthesis of compound 51, compound 55g (115.6 mg) was synthesized from compound 35 (0.64 mmol), N-hydroxycyclopentanecarboximidamide (97.7 mg, 0.762 mmol), and trimethylamine (2.6 mmol). m / z = 602 (M+1).

[0264] T32 Using the same procedure as described for the synthesis of compound T23, compound T32 (white solid, 60.9 mg, 16% yield from 35) was synthesized from compound 55g (115.6 mg, 0.192 mmol) and tetrabutylammonium hydroxide (40% w / w aqueous solution, 0.4 mL, 0.6 mmol). TIFF0007695229000135.tif18155

[0265] Compound 55h Using the same procedure as described for the synthesis of compound 51, impure compound 55h (544.9 mg) was synthesized from compound 35 (1.06 mmol), N'-hydroxycyclohexanecarboximidamide (99.5 mg, 0.700 mmol), and trimethylamine (4.2 mmol). m / z = 616 (M+1).

[0266] T33 Using the same procedure as described for the synthesis of compound T23, compound T33 (white solid, 149.8 mg, 56% yield from 35) was synthesized from compound 55h (346.1 mg) and tetrabutylammonium hydroxide (40% w / w aqueous solution, 1.25 mL, 1.9 mmol). TIFF0007695229000136.tif18165

[0267] Compound 58 A solution of compound 56 (0.86 g, 1.9 mmol) in CH2Cl2 (19 mL) was sequentially treated with oxalyl chloride (0.5 mL, 5.7 mmol) and DMF (15 μL, 0.19 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 hours and then concentrated. The residue was dissolved in toluene (3 x 20 mL) and concentrated to give compound 57 as a yellow solid. Compound 57 was dissolved in CH2Cl2 (25 mL) and cooled to 0 °C. After adding Et3N (1.1 mL, 7.6 mmol), 2-fluoro-N-hydroxyethanimidamide (0.26 g, 2.8 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. Next, the reaction mixture was concentrated and partitioned between EtOAc (30 mL) and water (20 mL). The layers were separated and the organic layer was washed with water (2 x 20 mL). The aqueous washings were extracted with EtOAc (20 mL). The combined organic extracts were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 100% EtOAc in CH2Cl2) to give compound 58 (0.87 g, 87% yield) as a white solid. m / z = 529 (M+1).

[0268] Compound 59 Compound 58 (20 mg, 0.038 mmol) was dissolved in o-xylene (0.5 mL), and the reaction solution was heated in a sealed tube at 180 °C for 14 h. The reaction mixture was concentrated, and the residue was purified by column chromatography (silica gel, eluted with 0 - 100% EtOAc in hexane) to give Compound 59 (9 mg, 49% yield) as a white solid. m / z = 511 (M+1).

[0269] Compound 60 Compound 59 (233 mg, 0.46 mmol) was dissolved in ethyl formate (3.3 mL, 41 mmol) and cooled to 0 °C. Sodium methoxide solution (25 wt% in MeOH, 1 mL, 4.56 mmol) was added under N2. After stirring at room temperature for 1.5 h, the reaction mixture was cooled to 0 °C. HCl (12 N aqueous solution, 0.8 mL, 4.56 mmol) was added, followed by EtOH (5 mL) and hydroxylamine hydrochloride (47.6 mg, 0.68 mmol). The reaction solution was heated at 60 °C for 4 h and then cooled to room temperature. The reaction mixture was diluted with EtOAc (30 mL) and washed with water (2 x 20 mL) and saturated aqueous NaHCO3 (20 mL). The aqueous washings were extracted with EtOAc (20 mL). The combined organic extracts were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0 - 100% EtOAc in hexane) to give Compound 60 (265 mg, quantitative yield) as a pale yellowish-white solid. m / z = 536 (M+1).

[0270] Compound 61 A solution of compound 60 (265 mg, 0.49 mmol) in MeOH (5 mL) was treated with sodium methoxide (25 wt% MeOH solution, 226 μL, 0.99 mmol) at room temperature. The reaction mixture was heated at 55 °C for 1.5 h and then cooled to 0 °C. 10% Aqueous NaH2PO4 solution (10 mL) was added and the mixture was extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 100% EtOAc in hexane) to give compound 61 (217 mg, 82% yield) as a white solid. m / z = 536 (M+1).

[0271] T34 Compound 61 (217 mg, 0.41 mmol) was dissolved in DMF (1 mL) and cooled to 0 °C under N2. A solution of 1,3 - dibromo - 5,5 - dimethylhydantoin (58 mg, 0.20 mmol) in DMF (1 mL) was added dropwise. The mixture was stirred at 0 °C for 2 h. Then pyridine (98 μL, 1.21 mmol) was added. The reaction mixture was heated at 60 °C for 4 h. After cooling to room temperature, the mixture was diluted with EtOAc (20 mL) and washed with 1N aqueous HCl solution (10 mL), water (2 x 15 mL), and brine (10 mL). The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 100% EtOAc in hexane) to give compound T34 (168 mg, 78% yield) as a white solid. TIFF0007695229000137.tif32155

[0272] Compound 62 A solution of compound 56 (500 mg, 1.02 mmol) in CH2Cl2 (14 mL) was sequentially treated with oxalyl chloride (275 μL, 3.14 mmol) and N,N-dimethylformamide (8 μL, 0.1 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 h and then concentrated. The residue was dissolved in toluene (3 x 20 mL) and concentrated to give the acid chloride as a yellow solid. The acid chloride was dissolved in CH2Cl2 (14 mL) and cooled to 0 °C. Triethylamine (0.58 mL, 4.16 mmol) and 2,2-difluoro-N'-hydroxyethanimidamide (173 mg, 1.57 mmol) were added. The reaction mixture was stirred at room temperature overnight. LC-MS indicated that the reaction was complete. The reaction mixture was concentrated, and the residue was partitioned between ethyl acetate (20 mL) and saturated aqueous NaHCO3 (10 mL). The organic layer was separated and washed with saturated aqueous NaHCO3 (10 mL). The combined aqueous washings were extracted with ethyl acetate (20 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 100% EtOAc in hexane) to give compound 62 (337 mg, 57% yield). m / z = 570 (M+1).

[0273] T35 To a solution of compound 62 (100 mg, 0.176 mmol) in THF (4 mL) was added tetrabutylammonium hydroxide (40 wt% aqueous solution, 0.36 mL, 0.55 mmol) dropwise at 0 °C. The reaction mixture was stirred at room temperature overnight. LC-MS indicated that the reaction was complete. The mixture was partitioned between ethyl acetate (20 mL) and water (20 mL). The organic layer was separated and washed with water (2 x 10 mL). The combined aqueous washings were extracted with ethyl acetate (20 mL). The combined organic extracts were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 100% EtOAc in hexane) to give compound T35 (15.7 mg, 16% yield). TIFF0007695229000138.tif25156

[0274] Compound 63 To a solution of Compound 56 (1.21 g, 2.46 mmol) in CH₂Cl₂ (50 mL) at 0 °C, oxalyl chloride (0.65 mL, 7.43 mmol) and N,N-dimethylformamide (20 μL, 0.26 mmol) were sequentially added. The mixture was stirred at 0 °C for 20 hours and then concentrated under reduced pressure to obtain Compound 63 (1.48 g, quantitative yield) as a yellow foamy solid, which was used in the next step without further purification.

[0275] Compound 64 To a solution of Compound 63 (82 wt%, 860 mg, 1.42 mmol) in CH₂Cl₂ (15 mL) under N₂ at room temperature, triethylamine (0.79 mL, 5.67 mmol) was slowly added. Next, a solution of 2,2,2-trifluoro-N'-hydroxy-ethanimidamide (181 mg, 1.42 mmol) in CH₂Cl₂ (6 mL) was added dropwise. The reaction mixture was stirred at room temperature for 16 hours and then concentrated. The residue was diluted with EtOAc (100 mL). The mixture was washed with saturated aqueous NaHCO₃ (30 mL) and brine (30 mL). The organic extract was dried over Na₂SO₄, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 10% MeOH in CH₂Cl₂) to obtain partially purified Compound 64 (615 mg) as an orange foamy solid, which was used in the next step without further purification. m / z = 588.2 (M+1).

[0276] T36 A mixture of Compound 64 (615 mg, <1.04 mmol) and tetrabutylammonium hydroxide (40 wt% aqueous solution, 2.16 mL, 3.31 mmol) in THF (20 mL) was stirred at room temperature for 20 hours under N₂. The reaction mixture was concentrated. The residue was diluted with EtOAc (40 mL). The mixture was washed with water (20 mL). The aqueous phase was separated and extracted with EtOAc (2x20 mL). The combined organic extracts were washed with brine (20 mL), dried over Na₂SO₄, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 50% EtOAc in hexane) to obtain Compound T36 (72.3 mg, 9% yield from Compound 63) as a white solid. TIFF0007695229000139.tif26156

[0277] Compound 65 To a solution of compound 63 (83 wt%, 620 mg, 1.04 mmol) in CH2Cl2 (10 mL) was slowly added triethylamine (0.579 mL, 4.15 mmol) at room temperature under N2. Next, a solution of N'-hydroxypropanimidamide (92 mg, 1.04 mmol) in CH2Cl2 (6 mL) was added dropwise. The mixture was stirred at room temperature for 16 h and then concentrated. The residue was diluted with EtOAc (100 mL). The resulting mixture was washed with saturated aqueous NaHCO3 (30 mL) and brine (30 mL). The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 10% MeOH in CH2Cl2) to give partially purified compound 65 (520 mg) as a yellow solid, which was used in the next step without further purification. m / z = 548.3 (M+1).

[0278] T37 A mixture of compound 65 (520 mg, 0.95 mmol) and tetrabutylammonium hydroxide (40% w / w aqueous solution, 1.98 mL, 3.04 mmol) in THF (15 mL) was stirred at room temperature for 15 h under N2. The reaction mixture was concentrated. The residue was diluted with EtOAc (30 mL) and washed with water (20 mL). The aqueous phase was separated and extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 50% EtOAc in hexane) to give compound T37 (267 mg, 48% yield from compound 63) as a white solid. TIFF0007695229000140.tif25156

[0279] Compound 66 A solution of compound 65 (260 mg, 0.524 mmol) in CH2Cl2 (5 mL) was cooled to 0 °C under N2. Hydrazine hydrate (50 wt%, 98 μL, 1.57 mmol) was added dropwise. The mixture was stirred at room temperature for 10 minutes, diluted with CH2Cl2 (10 mL), and washed with water (15 mL). The aqueous washings were extracted with CH2Cl2 (3 x 15 mL) and EtOAc (15 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated to give compound 66 (220 mg, 85% yield). m / z = 492 (M+1).

[0280] Compound 67 A solution of 2-fluoroacetic acid (38 μL, 0.67 mmol) in CH2Cl2 (2 mL) was treated with N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (129 mg, 0.67 mmol) and DMAP (5 mg, 0.045 mmol) at room temperature under N2. The mixture was stirred at room temperature for 15 minutes. Then compound 66 (220 mg, 0.45 mmol) was added and the mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated and the residue was purified by column chromatography (silica gel, eluting with 0 - 60% EtOAc in CH2Cl2) to give compound 67 (72 mg, 29% yield). m / z = 552 (M+1).

[0281] T38 A solution of compound 67 (70 mg, 0.13 mmol) and p-toluenesulfonic acid monohydrate (12 mg, 0.063 mmol) in toluene (7 mL) was heated at reflux temperature for 5 hours while removing water with a Dean - Stark apparatus. The mixture was cooled to room temperature, diluted with EtOAc (10 mL), and washed with water (2 x 15 mL). The organic extract was dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with acetone in hexane) to give compound T38 (33 mg, 49% yield) as a white solid. TIFF0007695229000141.tif26156

[0282] Compound 69 A mixture of compound 68 (898 mg, 1.94 mmol), NaOAc (286 mg, 3.49 mmol), and hydroxylamine hydrochloride (175 mg, 2.52 mmol) in EtOH (30 mL) and H2O (2 mL) was stirred at room temperature for 16 h. The mixture was concentrated. The residue was partitioned between ethyl acetate (20 mL) and water (10 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 x 20 mL). The combined organic extracts were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated to give compound 69 (863 mg, 93% yield) as a white solid, which was carried on to the next step without further purification. m / z = 479 (M+1).

[0283] Compound 70 A solution of compound 69 (863 mg, 1.80 mmol) in MeCN (9 mL) was cooled to -10 °C. Solutions of 12N aqueous HCl (30 μL, 0.36 mmol) and N-chlorosuccinimide (241 mg, 1.80 mmol) in MeCN (9 mL) were added sequentially. After the reaction was carried out at -10 °C for 30 min, ammonium hydroxide (28 wt% aqueous solution, 3 mL, 21.5 mmol) was added. The reaction mixture was stirred at room temperature overnight. Ethyl acetate (30 mL) and water (20 mL) were added. The layers were separated. The aqueous layer was extracted with ethyl acetate (4 x 20 mL). The combined organic extracts were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, 0 - 100% EtOAc in CH2Cl2) to give compound 70 (457 mg, 51% yield). m / z = 494 (M+1).

[0284] Compound 71 To N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC·HCl, 416 mg, 2.17 mmol) under N2 at room temperature was added a solution of 2-fluoroacetic acid (169 mg, 2.17 mmol) in CH2Cl2 (15 mL). A catalytic amount of DMAP (8 mg, 0.072 mmol) was added. The mixture was stirred at room temperature for 15 minutes. Next, compound 70 (357 mg, 0.72 mmol) was added. The mixture was stirred at room temperature for 2 hours and then concentrated. The residue was diluted with ethyl acetate (30 mL) and washed with water (2 x 20 mL). The combined aqueous washes were extracted with ethyl acetate (20 mL). The combined organic extracts were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 100% EtOAc in hexane) to give compound 71 (150 mg, 38% yield). m / z = 554 (M+1).

[0285] Compound 72 A solution of compound 71 (207 mg, 0.374 mmol) in 1,4-dioxane (3 mL) was heated at 100 °C for 5 hours under N2. The mixture was cooled to room temperature and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 30% EtOAc in hexane) to give compound 72 (158 mg, 79% yield). m / z = 536 (M+1).

[0286] Compound 73 A solution of compound 72 (158 mg, 0.295 mmol) in MeOH (4 mL) was treated at room temperature with NaOMe (25 wt% MeOH solution, 135 μL, 0.59 mmol). The reaction mixture was heated at 55 °C for 2.5 hours and then cooled to room temperature. 10% Aqueous NaH2PO4 solution (20 mL) was added. The mixture was extracted with ethyl acetate (2 x 30 mL). The combined organic extracts were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 40% EtOAc in hexane) to give compound 73 (134 mg, 85% yield). m / z = 536 (M+1).

[0287] T39 Compound 73 (134 mg, 0.25 mmol) was dissolved in DMF (3 mL) and cooled to 0 °C under N2. A solution of 1,3-dibromo-5,5-dimethylhydantoin (38 mg, 0.13 mmol) in DMF (1 mL) was added dropwise. The mixture was stirred at 0 °C for 2 hours. Next, pyridine (61 μL, 0.75 mmol) was added and the reaction mixture was heated at 60 °C for 4 hours. After cooling to room temperature, the mixture was diluted with EtOAc (20 mL) and washed with 1N aqueous HCl solution (10 mL), water (2 x 10 mL), and brine (10 mL). The organic extract was dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 50% EtOAc in hexane) to give Compound T39 (96 mg, 70% yield) as a white foam. TIFF0007695229000142.tif33156

[0288] Compound 74 A solution of Compound 5 (150 mg, 0.295 mmol) in 1,4-dioxane (3 mL) was cooled to 0 °C. Triethylamine (124 μL, 0.886 mmol) and trifluoroacetic anhydride (45 μL, 0.325 mmol) were added sequentially. The reaction mixture was stirred at room temperature for 19 hours. Another reaction mixture starting from Compound 5 was combined with this one. The mixture was diluted with EtOAc (40 mL) and washed with saturated aqueous NaHCO3 solution (2 x 20 mL) and brine (10 mL). The organic extract was dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 100% EtOAc in hexane) to give Compound 74 (130 mg, 56% yield) as a white solid. m / z = 586 (M+1).

[0289] Compound 75 A solution of compound 74 (125 mg, 0.213 mmol) in MeOH (2 mL) was treated with sodium methoxide (25 wt% MeOH solution, 100 μL, 0.44 mmol) at room temperature. The reaction mixture was heated at 55 °C for 2 h and then cooled to room temperature. 10% Aqueous NaH2PO4 (20 mL) was added and the mixture was extracted with EtOAc (2 x 30 mL). The combined organic extracts were washed with brine (20 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 40% EtOAc in hexane) to give compound 75 (85 mg, 68% yield) as a white solid. m / z = 586 (M+1).

[0290] T40 Compound 75 (82 mg, 0.14 mmol) was dissolved in DMF (0.7 mL) and cooled to 0 °C under N2. A solution of 1,3 - dibromo - 5,5 - dimethylhydantoin (20 mg, 0.070 mmol) in DMF (0.2 mL) was added dropwise. The mixture was stirred at 0 °C for 1 h. DMF (0.5 mL) was added during the reaction to dissolve the precipitated white solid. The reaction mixture was stirred at room temperature for 10 min. Then pyridine (45 μL, 0.56 mmol) was added and the reaction mixture was heated at 55 °C for 5 h. The mixture was cooled to room temperature, diluted with EtOAc (20 mL), and washed with 1N aqueous HCl (10 mL), water (2 x 10 mL), and brine (10 mL). The organic extract was dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 40% acetone in hexane) to give compound T40 (70 mg, 85% yield) as a white solid. TIFF0007695229000143.tif25156

[0291] Compound 76 A solution of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (170 mg, 0.886 mmol) in CH2Cl2 (3 mL) was sequentially added with a solution of 2,2-difluoroacetic acid (85 mg, 0.886 mmol) in CH2Cl2 (3 mL) and DMAP (3.6 mg, 0.030 mmol) at room temperature. After the reaction mixture was stirred for 15 minutes, a solution of compound 5 (150 mg, 0.295 mmol) in CH2Cl2 (4 mL) was added. The reaction solution was stirred at room temperature for an additional 19 hours. Next, the mixture was diluted with CH2Cl2 (20 mL) and washed with water (15 mL). The aqueous washings were extracted with EtOAc (2 x 15 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 40% EtOAc in hexane) to give compound 76 (106 mg, 63% yield) as a white solid. m / z = 568 (M+1).

[0292] Compound 77 A solution of compound 76 (106 mg, 0.187 mmol) in MeOH (1.8 mL) was treated with sodium methoxide (25 wt% MeOH solution, 85.5 μL, 0.373 mmol) at room temperature. The reaction solution was heated at 55 °C for 2 hours and then cooled to room temperature. 10% Aqueous NaH2PO4 solution (20 mL) was added. The mixture was extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 40% EtOAc in hexane) to give compound 77 (90 mg, 85% yield) as a white solid. m / z = 568 (M+1).

[0293] T41 Compound 77 (66 mg, 0.12 mmol) and 1,3-dibromo-5,5-dimethylhydantoin (17 mg, 0.058 mmol) were weighed into a round-bottom flask and cooled to 0 °C. DMF (1.2 mL) was added under N2. The mixture was stirred at 0 °C for 1 hour. Next, pyridine (38 μL, 0.47 mmol) was added and the reaction solution was heated at 55 °C for 5 hours. After cooling to room temperature, the mixture was diluted with EtOAc (20 mL) and washed with 1N aqueous HCl (10 mL), water (2 x 10 mL), and brine (10 mL). The organic extract was dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 40% EtOAc in hexane) to give Compound T41 (57 mg, 87% yield) as a white solid. TIFF0007695229000144.tif26156

[0294] Compound 79 A solution of Compound 35 (500 mg, 0.980 mmol) in CH2Cl2 (10 mL) was cooled to 0 °C and treated with triethylamine (0.55 mL, 3.95 mmol) and Compound 78 (215 mg, 1.47 mmol). The reaction mixture was stirred at ambient temperature for 2 hours and then washed with water. The aqueous layer was separated and extracted with CH2Cl2. The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 60% EtOAc in hexane) to give Compound 79 (437 mg, 72% yield) as a white solid. m / z = 620 (M+1).

[0295] Compound 80 A solution of compound 79 (437 mg, 0.705 mmol) in THF (15 mL) was treated with tetrabutylammonium hydroxide (1.0 M solution in methanol, 1.41 mL, 1.41 mmol) at room temperature. The reaction mixture was stirred at room temperature for 11 h, then diluted with ethyl acetate. The mixture was washed with water and brine, and the organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 30% EtOAc in hexane) to give compound 80 (258 mg, 61% yield) as a pale yellowish-white solid. m / z = 602 (M+1).

[0296] T42 A solution of compound 80 (258 mg, 0.428 mmol) in CH2Cl2 (10 mL) was treated with trifluoroacetic acid (1 mL, 12.98 mmol) at room temperature. The reaction mixture was stirred for 22 h, then concentrated. The residue was dissolved in toluene and concentrated. The residue was purified by column chromatography (silica gel, eluting with 30 - 100% EtOAc in hexane) to give compound T42 (178 mg, 76% yield) as a white solid. TIFF0007695229000145.tif26156

[0297] Compound 81 To a solution of compound 35 (243 mg, 0.476 mmol) in CH2Cl2 (4.0 mL) was added dropwise a solution of triethylamine (0.266 mL, 1.90 mmol) and 2,2-difluoro-N-hydroxyethanimidamide (78.6 mg, 0.71 mmol) in CH2Cl2 (3.0 mL) at 0 °C under N2. The mixture was stirred at room temperature for 18 h, then partitioned between CH2Cl2 (40 mL) and water (40 mL). The aqueous phase was separated and extracted with CH2Cl2 (2 x 30 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 100% EtOAc in hexane) to give compound 81 (186 mg, 67% yield) as a solid. m / z = 584.3 (M+1).

[0298] T43 A solution of compound 81 (136.0 mg, 0.23 mmol) in anhydrous THF (10 mL) was added with tetrabutylammonium fluoride (1.0 M THF solution, 0.70 mL, 0.70 mmol) at room temperature under N₂. The mixture was stirred at reflux temperature for 5.5 h and then concentrated. The residue was partitioned between EtOAc (40 mL) and water (40 mL). The aqueous layer was separated and extracted with EtOAc (3 x 30 mL). The combined organic extracts were washed with brine, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 50% acetone in CH₂Cl₂) to give T43 (73 mg, 55% yield) as a solid. TIFF0007695229000146.tif25156

[0299] Compound 82 To a solution of compound 36 (0.19 g, 0.38 mmol) and pyridine (46 μL, 0.56 mmol) in CH₂Cl₂ (4 mL) was added anhydrous difluoroacetic acid (52 μL, 0.45 mmol) at 0 °C under N₂. The reaction solution was stirred at 0 °C for 30 min and then at room temperature for 75 min. The reaction mixture was diluted with EtOAc (25 mL) and washed with 1 N aqueous HCl (20 mL), water (20 mL), and brine (10 mL). The organic extract was dried over Na₂SO₄, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 40% EtOAc in CH₂Cl₂) to give compound 82 (95 mg, 43% yield), as well as a mixture of compound 82 and T44 (4 / 1, 80 mg, 36% yield). Compound 82: m / z = 584.3 (M+1).

[0300] T44 To a mixture of compound 82 (80.0 mg, 0.14 mmol) in toluene (8 mL) was added p-toluenesulfonic acid monohydrate (13 mg, 0.068 mmol) at room temperature. The reaction mixture was heated at reflux temperature for 3 h while removing water with a Dean-Stark apparatus. After cooling to room temperature, the mixture was partitioned between EtOAc (30 mL) and brine (10 mL). The organic extract was washed with water (2 x 10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with EtOAc in hexane) to give compound T44 (24 mg, 31% yield) as a white solid. TIFF0007695229000147.tif26156

[0301] Compound 83 To a solution of compound 36 (0.22 g, 0.44 mmol) and pyridine (53 μL, 0.65 mmol) in CH2Cl2 (5 mL) was added anhydrous trifluoroacetic acid (74 μL, 0.52 mmol) at room temperature. The mixture was stirred at 40 °C for 75 min. An additional amount of anhydrous trifluoroacetic acid (20 μL, 0.14 mmol) was added and the resulting mixture was stirred for an additional 1 h. Compound 83 was completely consumed. The reaction mixture was then cooled to room temperature, diluted with EtOAc (25 mL), and washed with 1 N aqueous HCl (20 mL), water (2 x 20 mL), and brine (10 mL). The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 75% EtOAc in hexane) to give compound 83 (0.22 g, 84% yield) as a white solid.

[0302] T45 To a solution of compound 83 (0.21 g, 0.35 mmol) in THF (4 mL) was added the Burgess reagent (0.42 g, 1.76 mmol) at room temperature. The reaction mixture was stirred at 70 °C for 7 h. An additional amount of the Burgess reagent (210 mg, 0.88 mmol) was added and the resulting mixture was stirred at 70 °C overnight. Compound 83 was completely consumed. After cooling the reaction mixture to room temperature, it was partitioned between EtOAc (25 mL) and water (10 mL). The aqueous phase was separated and extracted with EtOAc (20 mL). The combined organic extracts were washed with water (2 x 10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 40% EtOAc in hexanes) to afford compound T45 (0.11 g, 54% yield) as a white solid. TIFF0007695229000148.tif25155

[0303] Compound 84 To a solution of compound 36 (0.25 g, 0.49 mmol) and pyridine (60 μL, 0.74 mmol) in CH2Cl2 (5 mL) was added propionic anhydride (0.076 mL, 0.59 mmol). The reaction mixture was stirred at 40 °C for 2 h. The mixture was diluted with EtOAc (25 mL) and washed with 1 N aqueous solution (1 N, 20 mL), water (2 x 20 mL), and brine (10 mL). The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 100% EtOAc in hexanes) to afford compound 84 (0.21 g, 76% yield) as a white solid. m / z = 562.3 (M+1).

[0304] T46 To a mixture of compound 84 (99 mg, 0.18 mmol) in THF (2 mL) at room temperature was added Burgess reagent (0.21 g, 0.88 mmol). The reaction mixture was stirred at 70 °C overnight and then cooled to room temperature. The mixture was partitioned between EtOAc (25 mL) and brine (10 mL). The aqueous phase was separated and extracted with EtOAc (20 mL). The combined organic extracts were washed with water (2 x 10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 80% EtOAc in hexane) to give compound T46 (71 mg, 74% yield) as a white solid. TIFF0007695229000149.tif25156

[0305] Compound 87 To a solution of compound 85 (6.58 g, 14.0 mmol) in CH2Cl2 (66 mL) under N2 at 0 °C were sequentially added oxalyl chloride (3.69 mL, 42.1 mmol) and DMF (0.11 mL, 1.40 mmol). The mixture was stirred at room temperature for 2 hours and then concentrated. The residue was dissolved in toluene (3 x 60 mL) and concentrated to remove residual oxalyl chloride. Compound 86 was obtained as a yellow solid and used in the next step without further purification.

[0306] Compound 86 was dissolved in CH2Cl2 (100 mL) and cooled to 0 °C. Triethylamine (7.83 mL, 56.2 mmol) and 2 - fluoro - N - hydroxyacetimidamide (1.94 g, 21.1 mmol) were sequentially added. The mixture was stirred at room temperature for 4 hours and then washed with water (20 mL). The aqueous phase was separated and extracted with CH2Cl2 (20 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 100% EtOAc in hexane) to give compound 87 (6.81 g, 89% yield) as a yellow solid. m / z = 543.3 (M+1).

[0307] Compound 88 Compound 87 (4.782 g, 8.811 mmol) was dissolved in anhydrous o-xylene (48 mL). Triethylamine (6.75 mL, 48.5 mmol) and anhydrous propylphosphonic acid (50 wt% solution in EtOAc, 17.3 mL, 29.1 mmol) were added sequentially. The mixture was heated at reflux temperature for 7 hours and then cooled to 0 °C. Saturated aqueous NaHCO3 solution (100 mL) was added slowly. After the addition was complete, the mixture was extracted with CH2Cl2 (100 mL). The organic extract was washed with saturated aqueous NaHCO3 solution (100 mL) and water (100 mL). The combined aqueous washings were extracted with EtOAc (2 x 150 mL). The organic extracts were dried over Na2SO4, filtered through a silica gel pad (25 g), and eluted with EtOAc (100 mL). The filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 100% EtOAc in hexane) to give the compound (1.65 g, yield 36%) as a pale yellowish-white solid. m / z = 525.3 (M+1).

[0308] Compound 89 A mixture of compound 88 (2.865 g, 5.460 mmol) in ethyl formate (13.2 mL, 164 mmol) was cooled to 0 °C under N2. Sodium methoxide (25 wt% MeOH solution, 12.3 mL, 53.8 mmol) was added. The mixture was stirred at room temperature for 1.5 hours and then cooled to 0 °C. HCl (6 M aqueous solution, 9.10 mL, 54.6 mmol), EtOH (55 mL), and hydroxylamine hydrochloride (569 mg, 8.19 mmol) were added sequentially. The mixture was heated at 60 °C for 3 hours, cooled to room temperature, and concentrated. The residue was dissolved in EtOAc (60 mL) and washed with water (2 x 30 mL). The combined aqueous washings were extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 50% EtOAc in hexane) to give compound 89 (2.754 g, yield 92%) as a white solid. m / z = 550.3 (M+1).

[0309] Compound 90 A solution of compound 89 (2.754 g, 5.010 mmol) in MeOH (50 mL) was treated with sodium methoxide (25 wt% MeOH solution, 2.29 mL, 10.0 mmol) at room temperature under N2. The mixture was heated at 55 °C for 1.5 h, cooled to 0 °C, treated with 10% aqueous NaH2PO4 (30 mL), and the mixture was partitioned between EtOAc (50 mL) and brine (30 mL). The aqueous phase was separated and extracted with EtOAc (50 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 30% acetone in hexane) to give compound 90 (2.52 g, 92% yield) as a white solid. m / z = 550.3 (M+1).

[0310] T12 Compound 90 (2.570 g, 4.675 mmol) was dissolved in DMF (12 mL) and cooled to 0 °C under N2. After addition of 1,3 - dibromo - 5,5 - dimethylhydantoin (735 mg, 2.57 mmol), an additional amount of DMF (11 mL) was added. The mixture was stirred at 0 °C for 2 h. Pyridine (1.51 mL, 18.7 mmol) was added. The mixture was heated at 60 °C for 4 h and then cooled to room temperature. The mixture was diluted with EtOAc (50 mL) and washed successively with 1N aqueous HCl (30 mL), water (2 x 30 mL), and brine (20 mL). The aqueous washings were combined and extracted with EtOAc (2 x 30 mL). The combined organic extracts were washed with water (2 x 30 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0 - 30% acetone in hexane) to give compound T12 (2.456 g, 96% yield) as a bright yellow solid. TIFF0007695229000150.tif27156

[0311] Example 2 Nitric oxide inhibition data Tissue culture The mouse macrophage cell line RAW 264.7 was obtained from the American Type Culture Collection (Manassas, VA) and maintained in logarithmic growth phase in Roswell Park Memorial Institute medium 1640 (RPMI 1640) supplemented with 10% heat-inactivated fetal bovine serum (FBS) and 1% penicillin-streptomycin. Cells were cultured and maintained in a humidified incubator at 37 °C under 5% CO2. Cells were passaged every 3 days. Alpha mouse liver (AML-12) cells were purchased from ATCC and cultured in DMEM / F12 medium supplemented with 10% FBS and 1% penicillin / streptomycin. All cell culture supplies were obtained from Life Technologies (Grand Island, NY) and VWR (Radnor, PA).

[0312] Nitric oxide inhibition assay One day before the experiment, RAW 264.7 cells were plated at a density of 30,000 cells per well in a total volume of 200 μL per well on a Falcon-96 well clear-bottom plate (Corning, NY) using RPMI 1640 supplemented with 0.5% fetal bovine serum and 1% penicillin-streptomycin. The next day, the cells were pretreated with compounds serially diluted from a 1000-fold stock. All compounds were dissolved in dimethyl sulfoxide (DMSO) to make 10 mM stock solutions. Subsequently, the compounds were diluted in DMSO and RPMI 1640. Each well received a final concentration of 0.1% DMSO. The cells were pretreated for 2 hours and incubated at 37 °C, and then treated with 20 ng / mL of interferon γ (R&D Systems, Minneapolis, MN) per well for 24 hours. The next day, nitrite standard solutions were serially diluted from 100 μM to 1.6 μM in RPMI 1640. Then, 50 μL of the cell culture supernatant was transferred from each well to a new Falcon-96 well clear-bottom plate. Nitrite was measured as a surrogate for nitric oxide using Promega's Griess detection kit #G2930 (Madison, WI). This kit involves adding 50 μL of the provided sulfanilamide solution to each well of the transferred cell culture supernatant and standard, followed by incubation at room temperature for 10 minutes. Next, 50 μL of the provided N-1-naphthylethylenediamine dihydrochloride (NED) solution was added to the sulfanilamide reaction solution, and the mixture was incubated at room temperature for 10 minutes in the dark. Then, air bubbles were removed using ethanol vapor, and the absorbance was measured at a wavelength set to 525 nm using a Spectramax M2e plate reader. Cell viability was evaluated using Roche's (Basel, Switzerland) WST-1 cell proliferation reagent. After removing the medium for the nitric oxide inhibition assay, 15 μL of the WST-1 reagent was added to each cell well. The plate was briefly mixed on an orbital shaker, and the cells were incubated at 37 °C for 30 minutes. The absorbance was measured at wavelengths set to 440 nm and 700 nm using a Spectramax M2e plate reader.

[0313] Regarding the ability of a compound to suppress the increase in nitric oxide release induced by interferon γ, the absolute amount of nitrous acid produced in each well was extrapolated from a nitrous acid standard solution using linear regression fitting. Next, all values were normalized against DMSO-interferon γ-treated wells and plotted as percent nitric oxide. IC 50 Values were calculated using Excel and / or GraphPad Prism (San Diego, CA) based on WST1 viability. The data are shown in Table 2.

[0314] (Table 2) Nitric oxide inhibition (NO IC 50 ), and NO IC 50 TIFF0007695229000151.tif242120TIFF0007695229000152.tif242120TIFF0007695229000153.tif242120TIFF0007695229000154.tif242121TIFF0007695229000155.tif242121TIFF0007695229000156.tif242120TIFF0007695229000157.tif242121TIFF0007695229000158.tif242121TIFF0007695229000159.tif242120TIFF0007695229000160.tif242120TIFF0007695229000161.tif242120TIFF0007695229000162.tif242120TIFF0007695229000163.tif242120TIFF0007695229000164.tif242120TIFF0007695229000165.tif242120TIFF0007695229000166.tif242120TIFF0007695229000167.tif24287 a Mean value of ratios from replicate experiments.

[0315] (Table 3) NO IC 50 TIFF0007695229000168.tif242116TIFF0007695229000169.tif242150TIFF0007695229000170.tif242116TIFF0007695229000171.tif24348 b Average value of the ratio from experiments by direct comparison.

[0316] Example 3 CYP3A4 inhibition Method Several compounds were evaluated at 1 μM for CYP3A4 (midazolam) inhibition in human liver microsomes. CYP3A4 inhibition was tested using the in vitro assay generally described by Dierks et al. (Drug Metabolism Deposition, 29:23-29, 2001, incorporated herein by reference). Each sample containing 0.1 mg / mL human liver microsomes, 5 μM midazolam as substrate, and 1 μM test compound was incubated at 37 °C for 10 minutes. After incubation, the metabolite 1-hydroxymidazolam was measured using HPLC-MS / MS. The peak area corresponding to the metabolite of the substrate was recorded. Next, the percent control activity was calculated by comparing the peak area obtained in the presence of the test compound with the peak area obtained in the absence of the test compound. Subsequently, the percent inhibition was calculated by subtracting the percent control activity from 100 for each compound. The results of the CYP3A4 assay are shown in Tables 4-7 below.

[0317] (Table 4) CYP3A4 (midazolam) inhibition TIFF0007695229000172.tif241156

[0318] The comparative compounds CC1 and T11, both containing a 1,3,4-oxadiazole-2,5-diyl moiety, were also tested for CYP3A4 inhibition. The results of the CYP3A4 assay are shown in Table 5 below.

[0319] (Table 5) CYP3A4 (midazolam) inhibition of T11 compared to CC1 TIFF0007695229000173.tif73156

[0320] The comparative compounds CC2 and T12, both containing a 1,2,4-oxadiazole-3,5-diyl moiety, were also tested for CYP3A4 inhibition. The results of the CYP3A4 assay are shown in Table 6 below.

[0321] (Table 6) CYP3A4 (midazolam) inhibition of T12 compared to CC2 TIFF0007695229000174.tif73156

[0322] The comparative compounds CC3 and T34, both containing a 1,2,4-oxadiazole-3,5-diyl moiety and a monomethyl substitution at the C4 position, were also tested for CYP3A4 inhibition. The results are shown in Table 7 below.

[0323] (Table 7) CYP3A4 (midazolam) inhibition of T34 compared to CC3 TIFF0007695229000175.tif73156

[0324] Example 4 Glutathione assay The effect of compound treatment on total glutathione levels was evaluated in mouse AML-12 hepatocyte cell line. Glutathione, a tripeptide consisting of cysteine, glutamic acid, and glycine, is the major intracellular thiol-containing protein and controls the cellular redox balance. Glutathione also plays an important role in detoxification, protein glutathionylation, and iron-sulfur cluster biosynthesis (Bachhawat and Yadav, 2018). Nrf2 controls the expression of many genes involved in glutathione synthesis and metabolism, including both subunits of glutamate cysteine ligase (GCL), an enzyme that catalyzes the rate-limiting step of glutathione biosynthesis (Thimmulappa et al., 2002).

[0325] AML-12 cells were plated in a white transparent bottom 96-well plate at a density of 8,000 cells / well in 200 μL of DMEM / F12 medium supplemented with 10% FBS and 1% penicillin / streptomycin. The next day, the cells were treated with vehicle (DMSO) or test compounds (0.03 nM - 1000 nM). Each well received a final concentration of 0.1% DMSO. The cells were incubated at 37 °C, 5% CO2 for 24 hours. The total glutathione concentration was measured using the GSH-Glo Glutathione Assay Kit (Promega) according to the manufacturer's instructions. Briefly, a calibration curve was created by serially diluting the provided glutathione solution. The final concentrations of the total glutathione standards were 5, 2.5, 1.25, 0.625, 0.313, 0.156, 0.078, 0.039, and 0.0195 μM. After removing the medium from the sample wells, 100 μL of the glutathione reaction mixture consisting of GSH-Glo reaction buffer, glutathione S-transferase, luciferin-NT, and TCEP was added to each sample well and all calibration curve wells. After incubating at room temperature for 30 minutes, 100 μL of the luciferin detection reagent was added to all sample wells and standard wells and incubated for 15 minutes. Luminescence was measured using a PHERAstar plate reader. EC 50 values were determined using Excel and GraphPad Prism software. The basal concentration of glutathione was set to 0%, the maximum concentration of glutathione generated after treatment with the test compound was set to 100%, and a dose-response curve was created. The dose-response curve was fitted using non-linear regression analysis and used to extrapolate the EC 50 values. The EC 50 value is defined as the concentration of the test compound required to increase the glutathione concentration to 50% of the maximum concentration. The data are shown in Tables 8 and 9.

[0326] (Table 8) EC50 of glutathione (GSH) and EC50 in comparison with RTA 402 TIFF0007695229000176.tif242120TIFF0007695229000177.tif242120TIFF0007695229000178.tif242120TIFF0007695229000179.tif242121TIFF0007695229000180.tif242121TIFF0007695229000181.tif242121TIFF0007695229000182.tif242121TIFF0007695229000183.tif242120TIFF0007695229000184.tif242120TIFF0007695229000185.tif242120TIFF0007695229000186.tif24253 c The average value of the ratio from repeated experiments.

[0327] (Table 9) Glutathione (GSH) EC50 in comparison with the comparative compounds TIFF0007695229000187.tif24248TIFF0007695229000188.tif242150TIFF0007695229000189.tif242150TIFF0007695229000190.tif24382 d The average value of the ratio from experiments by direct comparison.

[0328] Example 5 Effect on luciferase reporter activation The AREc32 reporter cell line (derived from human breast cancer MCF7 cells) was obtained from CXR Bioscience Limited (Dundee, UK) and cultured in DMEM (low glucose) supplemented with 10% FBS, 1% penicillin / streptomycin, and 0.8 mg / ml Geneticin (G418). This cell line has the luciferase reporter gene stably transfected under the transcriptional regulation of 8 copies of the rat GSTA2 ARE sequence.

[0329] The effects of some of the compounds disclosed herein on luciferase reporter activation were evaluated in the AREc32 reporter cell line (see Tables 10 and 11). This cell line is derived from human breast cancer MCF-7 cells and has the luciferase reporter gene stably transfected under the transcriptional control of an antioxidant response element derived from the rat Gsta2 gene, which is an Nrf2 target gene, in 8 copies (Frilling et al., 1990). AREc32 cells were plated in black 96-well plates at 20,000 cells per well in 200 μL of medium. Twenty-four hours after plating, the cells were treated for 19 hours with vehicle (DMSO) or test compounds at concentrations ranging from 0.03 to 1000 nM. The medium was removed and 100 μL of a 1:1 mixture of One-Glo luciferase assay reagent and medium was added to each well. After incubation for 5 minutes at room temperature, the luminescence signal was measured on a PHERAstar plate reader. EC 2X values were determined using Excel and GraphPad Prism software. The fold increase in luminescence signal of cells treated with the compound at each concentration relative to vehicle-treated cells was determined and a dose-response curve was generated. The dose-response curve was fitted using non-linear regression analysis and used to extrapolate the EC 2X values. The EC 2X value is defined as the concentration of test compound required to increase the luminescence signal to twice the level in vehicle-treated samples.

[0330] (Table 10) EC 2X of AREc32 and EC 2X TIFF0007695229000191.tif242120TIFF0007695229000192.tif242120TIFF0007695229000193.tif242120TIFF0007695229000194.tif242121TIFF0007695229000195.tif242121TIFF0007695229000196.tif242121TIFF0007695229000197.tif242121TIFF0007695229000198.tif242121TIFF0007695229000199.tif242120TIFF0007695229000200.tif242120TIFF0007695229000201.tif242120TIFF0007695229000202.tif242120TIFF0007695229000203.tif24253 e Average value of the ratio from repeated experiments. f The number of repetitions in this case is AREc32 EC 2X Refers only to the measurement. This compound was not run in parallel with RTA 402 in the same experiment.

[0331] (Table 11) AREc32 EC in comparison with the comparative compound 2X TIFF0007695229000204.tif24248TIFF0007695229000205.tif242150TIFF0007695229000206.tif242150TIFF0007695229000207.tif243150TIFF0007695229000208.tif24349 g Average value of the ratio from the experiment by direct comparison.

[0332] All of the compounds, formulations, and methods disclosed and claimed in this specification can be made and executed without undue experimentation in light of the present disclosure. Although the compounds, formulations, and methods of the present disclosure have been described in preferred embodiments, it will be apparent to those skilled in the art that variations can be applied to the compounds, formulations, and methods, and to the steps or the order of steps of the methods described herein without departing from the concept, spirit, and scope of the invention. More specifically, it will be apparent that specific chemically and physiologically related agents can be substituted for the agents described herein while achieving the same or similar results. All such similar substitutes and modifications that are apparent to those skilled in the art are considered to be within the spirit, scope, and concept of the invention as defined by the appended claims.

[0333] References The following references are specifically incorporated herein by reference to the extent that they show details of exemplary procedures or other details that supplement the details disclosed herein. TIFF0007695229000209.tif20322TIFF0007695229000210.tif231144TIFF0007695229000211.tif231121TIFF0007695229000212.tif121144

Claims

1. A compound of the following formula: or a pharmaceutically acceptable salt thereof; wherein, A 1 is a - heteroarylene selected from the following formula: - and is; (C≦3) -; R 1 is monopolar substituted alkyl (C≦3) where the term "monopolar substitution" means that only one hydrogen atom of the group so modified is replaced by a monopolar substituent, and the monopolar substituent is selected from the group consisting of -OH, -F, -OC(O)CH 3 and -NHC(O)OCH 3; and R 2 and R 2 ' are each independently hydrogen or methyl.

2. Further defined as a compound of the following formula: or a pharmaceutically acceptable salt thereof, wherein, A 1 is a - heteroarylene selected from the following formula: - and is; and (C≦3) -; R 1 is monopolar substituted alkyl (C≦3) where the term "monopolar substitution" means that only one hydrogen atom of the group so modified is replaced by a monopolar substituent, and the monopolar substituent is selected from the group consisting of -OH, -F, -OC(O)CH 3 and -NHC(O)OCH 3, the compound according to Claim 1.

3. Further defined as a compound of the following formula: or a pharmaceutically acceptable salt thereof, wherein, A 1 is a - heteroarylene selected from the following formula: - and is; and (C≦3) -; R 1 is monopolar substituted alkyl (C≦3)and wherein the term "monopolar substitution" means that only one hydrogen atom of the group so modified is replaced by a monopolar substituent, and the monopolar substituent is selected from the group consisting of -OH, -F, -OC(O)CH3 and -NHC(O)OCH3, the compound according to claim 1.

4. -A 1 -R 1 is of the following formula: the compound according to any one of claims 1 to 3.

5. -A 1 -R 1 is of the following formula: the compound according to any one of claims 1 to 3.

6. -A 1 -R 1 is of the following formula: the compound according to any one of claims 1 to 3.

7. R 1 is monopolar substituted ethyl, the compound according to any one of claims 1 to 6.

8. R 1 is monopolar substituted methyl, the compound according to any one of claims 1 to 6.

9. R 1 is monofluoroalkyl (C≦3) , or monohydroxyalkyl (C≦3) the compound according to any one of claims 1 to 6.

10. R 1 is monofluoroalkyl (C≦3) the compound according to any one of claims 1 to 6 and 9.

11. The compound according to claim 10, wherein R1 is fluoroethyl.

12. R 1 is 2-fluoroethyl, the compound according to claim 11.

13. R 1 The compound according to claim 10, wherein is fluoromethyl.

14. R 1 is monohydroxyalkyl (C≦3) The compound according to any one of claims 1 to 6 and 9.

15. The compound according to claim 14, wherein R1 is hydroxyethyl.

16. R 1 is 2-hydroxyethyl, the compound according to claim 15.

17. R 1 is hydroxymethyl, the compound according to claim 14.

18. R 1 is -CH 2 CH 2 OC(O)CH 3 The compound according to any one of claims 1 to 6.

19. R 1 is -CH 2 CH 2 NHC(O)OCH 3 The compound according to any one of claims 1 to 6.

20. The following formula: Or the compound according to any one of claims 1 to 19, further defined as a pharmaceutically acceptable salt of any of these formulas.

21. The compound of the following formula: Or the compound according to claim 20, further defined as a pharmaceutically acceptable salt thereof.

22. The compound of the following formula: Or the compound according to claim 20, further defined as a pharmaceutically acceptable salt thereof.

23. The compound of the following formula: Or a pharmaceutically acceptable salt of any of these formulas.

24. (A) A compound according to any one of claims 1 to 23, and (B) an excipient A pharmaceutical composition comprising the same.

25. A composition comprising a compound according to any one of claims 1 to 23 for use in a method of doing so in a patient in need of treating or preventing a disease or disorder, the method comprising administering to the patient a pharmaceutically effective amount of the compound.

26. A composition comprising a compound according to any one of claims 1 to 23 for use in a method of inhibiting nitric oxide production, the method comprising administering to a patient in need thereof an amount of the compound sufficient to cause inhibition of IFN-γ-induced nitric oxide production in one or more cells of the patient.

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