C17 polar-substituted heteroaromatic synthetic triterpenoids and methods of use thereof

Abstract

To provide novel synthetic triterpenoid derivatives having anti-inflammatory and / or antioxidant properties, pharmaceutical compositions, methods for making the same, and methods for using the same.SOLUTION: The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some aspects, the compounds and compositions may be used as antioxidant inflammation modulators.SELECTED DRAWING: None

Description

[Technical Field]

[0001] REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application No. 62 / 876,467, filed July 19, 2019, and U.S. Provisional Application No. 62 / 952,048, filed December 20, 2019, the entire contents of both applications being incorporated herein by reference.

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

[0003] II. Description of Related Art The anti-inflammatory and antiproliferative activities of the natural triterpenoid oleanolic acid have been improved by chemical modifications, e.g., 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO) and related compounds were 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, (Nos. 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] Additionally, 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 another triterpenoid, betulinic acid, have also been found to inhibit cellular inflammatory processes, although these compounds have not been characterized as extensively (Honda et al., 2006). The pharmacological effects of these synthetic triterpenoid molecules are complex. Compounds derived from oleanolic acid have been found to affect the function of multiple protein targets, thereby modulating the activity 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). Additionally, derivatives of betulinic acid have shown comparable anti-inflammatory properties but appear to have significantly different pharmacological actions compared to OA-derived compounds (Liby et al., 2007b). Given the variable bioactivity profiles of known triterpenoid derivatives, and given the wide variety of diseases that can be treated or prevented with compounds with potent antioxidant and anti-inflammatory effects, and the large unmet medical need represented within this diverse 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, and methods for their production and use.

[0006] In one aspect, there is provided a compound of the following formula, or a pharmaceutically acceptable salt thereof: TIFF2025131767000001.tif72128In formula, A1 is -heteroarenediyl (C≦3) - and; R1 is a polar substituted alkyl (C≦3) and; R2 and R2' are each independently hydrogen or methyl.

[0007] In some embodiments, the compound is further defined as the following formula, or a pharmaceutically acceptable salt thereof: TIFF2025131767000002.tif51128 formula, A1 is -heteroarenediyl (C≦3) - and; R1 is a polar substituted alkyl (C≦3) is.

[0008] In some embodiments, the compound is further defined as the following formula, or a pharmaceutically acceptable salt thereof: TIFF2025131767000003.tif50128 formula, A1 is -heteroarenediyl (C≦3) - and; R1 is a polar substituted alkyl (C≦3) is.

[0009] In some embodiments, -A1-R1 is: TIFF2025131767000004.tif11128

[0010] In another embodiment, -A1-R1 is: TIFF2025131767000005.tif11128

[0011] In yet another embodiment, -A1-R1 is: TIFF2025131767000006.tif11128

[0012] In yet another embodiment, -A1-R1 is: TIFF2025131767000007.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 monosubstituted ethyl. In other embodiments, R1 is monosubstituted methyl. In some embodiments, R1 is monoaminoalkyl. (C≦3) , monofluoroalkyl (C≦3) , or monohydroxyalkyl (C≦3) In some embodiments, R is monoaminoalkyl (C≦3) In other embodiments, R is monofluoroalkyl, for example, 2-aminoethyl or aminomethyl. (C≦3) In yet another embodiment, R is monohydroxyalkyl, for example, 2-fluoroethyl or fluoromethyl. (C≦3) , for example, 2-hydroxyethyl or hydroxymethyl. In still other embodiments, R1 is -CH2CH2NHC(O)OCH3, -CH2CH2NHC(O)NHCH2CH3, or -CH2CH2NHC(O)CH3.

[0014] In some embodiments, -A1-R1 is TIFF2025131767000008.tif12128, wherein R1 is aminomethyl, fluoromethyl, or hydroxymethyl, R2 is hydrogen or methyl, and R2' is methyl. In some of these embodiments, -A1-R1 is TIFF2025131767000009.tif12128, where R1 is fluoromethyl, R2 is hydrogen or methyl, and R2' is methyl.

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

[0016] In some embodiments, the compound is further defined as the following formula: or a pharmaceutically acceptable salt of any of these formulas: TIFF2025131767000010.tif108132TIFF2025131767000011.tif218143TIFF2025131767000012.tif108135

[0017] In a further aspect, the compound is further defined as: or a pharmaceutically acceptable salt of any of these formulas: TIFF2025131767000013.tif108140

[0018] In still a further aspect, the compound is further defined as: or a pharmaceutically acceptable salt of any of these formulas: TIFF2025131767000014.tif102134

[0019] In yet a further aspect, the compound is further defined as: or a pharmaceutically acceptable salt thereof. TIFF2025131767000015.tif33128

[0020] In another embodiment, the compound is further defined as: or a pharmaceutically acceptable salt thereof. TIFF2025131767000016.tif33128

[0021] In yet another embodiment, the compound is further defined as: or a pharmaceutically acceptable salt thereof. TIFF2025131767000017.tif33128

[0022] In yet another embodiment, the compound is further defined as: or a pharmaceutically acceptable salt thereof. TIFF2025131767000018.tif33128

[0023] In another embodiment, the compound is further defined as: or a pharmaceutically acceptable salt thereof. TIFF2025131767000019.tif33128

[0024] In yet another embodiment, the compound is further defined as: or a pharmaceutically acceptable salt thereof. TIFF2025131767000020.tif33128

[0025] In some embodiments, the compound is further defined as: (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-hexadecahydropicen-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-hexadecahydropicen-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.

[0026] In a further embodiment, the compound is further defined as: (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 still a further aspect, the compound is further defined as: (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: (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: (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 yet another embodiment, the compound is further defined as: (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 another embodiment, the compound is further defined as: (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: (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: (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 disclosure provides compounds of the following formula: or a pharmaceutically acceptable salt of any of these formulas: TIFF2025131767000021.tif218137TIFF2025131767000022.tif181130

[0035] In yet another aspect, the present disclosure provides: (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 oral, intraadipose, intra-arterial, intra-articular, intracranial, intradermal, intralesional, intramuscular, intranasal, intraocular, intrapericardial, intraperitoneal, intrapleural, intraprostatic, intrarectal, intrathecal, intratracheal, intratumoral, intraumbilical, intravaginal, intravenous, intravesicular, intravitreal, liposomal, topical, mucosal, parenteral, rectal, subconjunctival, subcutaneous, sublingual, topical, buccal, transdermal, vaginal, cream, lipid composition, catheter, irrigation, continuous infusion, infusion, inhalation, injection, local delivery, or localized perfusion administration. 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 for treating or preventing a disease or disorder in a patient in need thereof, 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, e.g., 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, e.g., atherosclerosis. In some embodiments, the disease or disorder is an autoimmune disease, e.g., Crohn's disease, rheumatoid arthritis, lupus, or psoriasis. In some embodiments, the disease or disorder is a neurodegenerative disease, e.g., 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 of 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 ophthalmic 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, comprising administering to a patient in need thereof a compound or composition of the present disclosure in an amount 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 formula: TIFF2025131767000023.tif72128 or a pharmaceutically acceptable salt thereof, wherein: A1 is -heteroarenediyl (C≦3) - and; R1 is polar-substituted alkyl (C≦3) and; R2 and R2' are each independently hydrogen or methyl; A compound or a pharmaceutically acceptable salt thereof. [The present invention 1002] The following formula: TIFF2025131767000024.tif68145, or a pharmaceutically acceptable salt thereof, wherein: A1 is -heteroarenediyl (C≦3) - and; R1 is polar-substituted alkyl (C≦3) The compound of the present invention 1001, [The present invention 1003] The following formula: TIFF2025131767000025.tif68144, or a pharmaceutically acceptable salt thereof, wherein: A1 is -heteroarenediyl (C≦3) - and; R1 is polar-substituted alkyl (C≦3) The compound of the present invention 1001, [The present invention 1004] - A1-R1 is of the formula: Any of compounds 1001 to 1003 of the present invention, which is TIFF2025131767000026.tif15130. [The present invention 1005] - A1-R1 is of the formula: Any of compounds 1001 to 1003 of the present invention, which is TIFF2025131767000027.tif14130. [The present invention 1006] - A1-R1 is of the formula: Any of compounds 1001 to 1003 of the present invention, which is TIFF2025131767000028.tif15130. [The present invention 1007] - A1-R1 is of the formula: Any of compounds 1001 to 1003 of the present invention, which is TIFF2025131767000029.tif11128. [The present invention 1008] The compound of any one of claims 1001 to 1007, wherein R1 is polar-substituted ethyl. [The present invention 1009] The compound of any one of claims 1001 to 1007, wherein R1 is polar-substituted methyl. [The present invention 1010] R1 is a mono-substituted alkyl (C≦3) The compound of any one of 1001 to 1007 of the present invention, [The present invention 1011] The compound of the present invention 1010, wherein R1 is mono-substituted ethyl. [The present invention 1012] The compound of the present invention 1010, wherein R1 is mono-substituted methyl. [The present invention 1013] R1 is monoaminoalkyl (C≦3) , monofluoroalkyl (C≦3) , or monohydroxyalkyl (C≦3) The compound of any one of 1001 to 1007 and 1010 of the present invention, [The present invention 1014] R1 is monoaminoalkyl (C≦3) The compound of any one of 1001 to 1007 and 1010 of the present invention, [The present invention 1015] 1014. The compound of the present invention, wherein R1 is aminoethyl. [The present invention 1016] 1015 compounds of the present invention, wherein R1 is 2-aminoethyl. [The present invention 1017] 1014. The compound of the present invention, wherein R1 is aminomethyl. [The present invention 1018] R1 is monofluoroalkyl (C≦3) The compound of any one of 1001 to 1007 and 1010 of the present invention, [The present invention 1019] 1018. The compound of the present invention, wherein R1 is fluoroethyl. [The present invention 1020] 1019 compounds of the present invention, wherein R1 is 2-fluoroethyl. [The present invention 1021] 1018. The compound of the present invention, wherein R1 is fluoromethyl. [The present invention 1022] R1 is monohydroxyalkyl (C≦3) The compound of any one of 1001 to 1007 and 1010 of the present invention, [The present invention 1023] The compound of the present invention 1022, wherein R1 is hydroxyethyl. [The present invention 1024] The compound of the present invention 1023, wherein R1 is 2-hydroxyethyl. [The present invention 1025] The compound of the present invention 1022, wherein R1 is hydroxymethyl. [The present invention 1026] Any of compounds 1001 to 1007 and 1010 of the present invention, wherein R1 is -CH2CH2OC(O)CH3. [The present invention 1027] The compound of any one of claims 1001 to 1007 and 1010 of the present invention, wherein R1 is -CH2CH2NHC(O)OCH3. [The present invention 1028] The compound of any one of claims 1001 to 1007 and 1010, wherein R1 is -CH2CH2NHC(O)NHCH2CH3. [The present invention 1029] Any of compounds 1001 to 1007 and 1010 of the present invention, wherein R1 is -CH2CH2NHC(O)CH3. [The present invention 1030] The following formula: TIFF2025131767000030.tif218134TIFF2025131767000031.tif218143 or a pharmaceutically acceptable salt of any of these formulas. [The present invention 1031] The following formula: TIFF2025131767000032.tif108133 or a pharmaceutically acceptable salt of any of these formulas. [The present invention 1032] The following formula: TIFF2025131767000033.tif112134 or a pharmaceutically acceptable salt of any of these formulas. [The present invention 1033] The following formula: TIFF2025131767000034.tif33128 or a pharmaceutically acceptable salt thereof. [The present invention 1034] The following formula: TIFF2025131767000035.tif33128 or a pharmaceutically acceptable salt thereof. [This invention 1035] The following formula: TIFF2025131767000036.tif33128 or a pharmaceutically acceptable salt thereof. [The present invention 1036] The following formula: TIFF2025131767000037.tif33128 or a pharmaceutically acceptable salt thereof. [This invention 1037] The following formula: TIFF2025131767000038.tif33128 or a pharmaceutically acceptable salt thereof. [The present invention 1038] The following formula: 1001-1031, a compound of any of claims 1001-1031, further defined as TIFF2025131767000039.tif33128, or a pharmaceutically acceptable salt thereof. [This invention 1039] Any of compounds 1001-1029 of the present invention further defined as: (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-hexadecahydropicen-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-hexadecahydropicen-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. [The present invention 1040] Any of compounds 1001-1030 and 1039 of the present invention further defined as: (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. [This invention 1041] Any of compounds 1001-1031, 1039, and 1040 of the present invention further defined as: (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. [The present invention 1042] Any of compounds 1001-1032, 1039, and 1040 of the present invention further defined as: (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. [This invention 1043] Any of compounds 1001-1032, 1039, and 1040 of the present invention further defined as: (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. [This invention 1044] Any of compounds 1001-1032, 1039, and 1040 of the present invention further defined as: (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. [This invention 1045] Any of compounds 1001-1032, 1039, and 1040 of the present invention further defined as: (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. [The present invention 1046] Any of compounds 1001-1032, 1039, and 1040 of the present invention further defined as: (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. [This invention 1047] Any compound of inventions 1001-1031 and 1039 further defined as: (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. [This invention 1048] A compound of the formula: TIFF2025131767000040.tif34137TIFF2025131767000041.tif218125TIFF2025131767000042.tif144131 or a pharmaceutically acceptable salt of any of these formulas. [This 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) any one of compounds 1001 to 1049 of the present invention, (B) excipients and 10. A pharmaceutical composition comprising: [This invention 1051] The pharmaceutical composition of the present invention 1050, formulated for administration by oral, intraadipose, intra-arterial, intra-articular, intracranial, intradermal, intralesional, intramuscular, intranasal, intraocular, intrapericardial, intraperitoneal, intrapleural, intraprostatic, intrarectal, intrathecal, intratracheal, intratumoral, intraumbilical, intravaginal, intravenous, intravesicular, intravitreal, liposomal, topical, mucosal, parenteral, rectal, subconjunctival, subcutaneous, sublingual, local, buccal, transdermal, vaginal, cream, lipid composition, catheter, irrigation, continuous infusion, drip, infusion, inhalation, injection, local delivery, or localized perfusion. [This invention 1052] A pharmaceutical composition of the present invention 1051 formulated for oral administration. [This invention 1053] A pharmaceutical composition of the present invention 1051 formulated for administration by injection. [This invention 1054] A pharmaceutical composition of the present invention 1053 formulated for intraarterial, intramuscular, intraperitoneal, or intravenous administration. [This invention 1055] A pharmaceutical composition of the present invention 1051 formulated for topical administration. [This invention 1056] A pharmaceutical composition of the present invention 1055 formulated for topical administration to the skin or eye. [This invention 1057] 1057. The pharmaceutical composition of any one of claims 1050 to 1056, which is formulated as a unit dosage form. [This invention 1058] A method of treating or preventing a disease or disorder in a patient in need thereof, comprising administering to said patient a pharmaceutically effective amount of any of the compounds or compositions of the present inventions 1001-1057. [This invention 1059] The method of claim 1058, wherein the patient is a mammal. [The present invention 1060] The method of claim 1059, wherein the patient is a human. [This invention 1061] The method of claim 1058, wherein the disease or disorder is a condition associated with inflammation and / or oxidative stress. [This invention 1062] The method of claim 1058, wherein the disease or disorder is cancer. [The present invention 1063] The method of claim 1058, wherein the disease or disorder is a cardiovascular disease. [This invention 1064] The method of claim 1063, wherein the cardiovascular disease is atherosclerosis. [This invention 1065] The method of claim 1058, wherein the disease or disorder is an autoimmune disease. [The present invention 1066] The method of claim 1065, wherein the autoimmune disease is Crohn's disease, rheumatoid arthritis, lupus, or psoriasis. [This invention 1067] The method of claim 1058, wherein the disease or disorder is a neurodegenerative disease. [The present invention 1068] 1068. The method of claim 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 claim 1058, wherein the disease or disorder is chronic kidney disease, diabetes, mucositis, inflammatory bowel disease, dermatitis, sepsis, ischemia-reperfusion injury (including complications from 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 claim 1058, wherein the disease or disorder is an ocular disease. [This invention 1071] The method of claim 1070, wherein the ocular disease is uveitis, glaucoma, macular degeneration, or retinopathy. [This invention 1072] The method of claim 1058, wherein the disease or disorder is a neuropsychiatric disease or disorder. [This invention 1073] 1072. The method of claim 1072, wherein the neuropsychiatric disease or disorder is schizophrenia, depression, bipolar disorder, epilepsy, post-traumatic stress disorder, attention deficit disorder, autism, or anorexia nervosa. [This invention 1074] The method of claim 1058, wherein the disease or disorder is associated with mitochondrial dysfunction. [This invention 1075] 1074. The method of claim 1074, wherein the disease or disorder associated with mitochondrial dysfunction is Friedreich's ataxia. [This invention 1076] The method of claim 1058, wherein the disease or disorder is chronic pain. [This invention 1077] The method of claim 1058, wherein the disease or disorder is neuropathic pain. [This invention 1078] A method for inhibiting nitric oxide production, comprising administering to a patient in need thereof a compound or composition of any of claims 1001 to 1057 of the present invention in an amount 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, it should be understood that the detailed description and specific examples illustrating particular embodiments of the present invention are given by way of example only, 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. It should be noted that simply because a particular compound is ascribed to one particular general formula does not mean that the compound cannot also belong to another general formula. [Brief explanation of the drawings]

[0040] The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present invention. The invention may be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein.

[0041] [Figure 1] Demonstrating CYP3A4 inhibition in human liver microsomes at 1 μM, each sample contained 0.1 mg / mL human liver microsomes, 5 μM midazolam as substrate, and 1 μM test compound, and was incubated for 10 minutes at 37° C. See Example 3 for further details. DETAILED DESCRIPTION OF THE INVENTION

[0042] DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS Disclosed herein are novel compounds and compositions having antioxidant and / or anti-inflammatory properties, methods for their preparation, and methods for their use, including the treatment and / or prevention of disease.

[0043] I. Compounds of the Invention The compounds of the present invention (also referred to as "synthetic triterpenoid derivatives provided herein," "compounds of the present disclosure," or "compounds disclosed herein") are shown, for example, in the Summary of the Invention section above, the Examples below, Table 1, and the Claims below. They can be made using the synthetic methods outlined in the Examples section. These methods can be further modified and optimized using principles and techniques of organic chemistry applied by one of ordinary skill 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. Furthermore, these synthetic methods can be further modified and optimized for preparative, pilot, or large-scale production, either batch or continuous, using principles and techniques of process chemistry applied by one of ordinary skill 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 TIFF2025131767000043.tif234108TIFF2025131767000044.tif234142TIFF2025131767000045.tif234142 TIFF2025131767000046.tif234142TIFF2025131767000047.tif233142TIFF2025131767000048.tif234142

[0045] In some embodiments, all compounds of the present 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 nevertheless be useful for the prevention and treatment of one or more diseases or disorders. Therefore, unless expressly stated to the contrary, all compounds of the present invention are considered "active compounds" and "therapeutic compounds" intended for use as active pharmaceutical ingredients (APIs). Actual suitability for human or veterinary use is typically determined using a combination of clinical trial protocols and regulatory procedures, such as those implemented by the U.S. Food and Drug Administration (FDA). In the United States, the FDA is responsible for protecting public health by ensuring the safety, effectiveness, quality, and reliability of drugs, vaccines, and other biological products for human and veterinary use, as well as medical devices.

[0046] In some embodiments, the compounds of the present invention, whether used in the indications described herein or otherwise, have the advantage that they are more effective, less toxic, longer acting, more potent, produce fewer side effects, are more readily absorbed, are more metabolically stable, are more lipophilic, are more hydrophilic, and / or exhibit favorable pharmacokinetic profiles (e.g., increased oral bioavailability and / or reduced clearance), and / or may exhibit other useful pharmacological, physical, or chemical properties than 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 or racemic forms. Thus, unless a specific stereochemical configuration or isomer is specifically indicated, all chiral, diastereomeric, racemic, epimeric, and all geometric isomers of a given chemical formula are intended. Compounds may occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers. In some embodiments, single diastereomers are obtained. The chiral centers of the compounds of the present invention may exhibit an S or R configuration. In some embodiments, the compounds may contain two or more atoms that exhibit a defined stereochemical orientation.

[0048] Typically, the chemical formulas used to represent the compounds of the invention represent only one of possibly several different tautomers. For example, many ketone groups are known to exist in equilibrium with the corresponding enol groups. Similarly, many imine groups exist in equilibrium with enamine groups. All tautomers of a given chemical formula are contemplated, regardless of which tautomer is represented for a given compound and regardless of which tautomer is most prevalent.

[0049] Furthermore, atoms constituting the compounds of the present invention are intended to include all isotopic forms of the atoms. As used herein, isotopes 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 tritium and deuterium. 13 C and 14 C is one example.

[0050] In some embodiments, the compounds of the present invention function as prodrugs or can be derivatized to function as prodrugs. Because prodrugs are known to enhance many desirable properties of pharmaceuticals (e.g., solubility, bioavailability, manufacturability, etc.), compounds used in some methods of the present invention may be delivered in prodrug form, if desired. Accordingly, the present invention contemplates prodrugs of the compounds of the present invention and methods for delivering prodrugs. Prodrugs of compounds used in the present invention can be prepared by modifying functional groups present in the compounds such that the modifications are cleaved, either by routine manipulation or in vivo, to yield the parent compound. Thus, prodrugs include, for example, compounds described herein having a hydroxy, amino, or carboxy group attached to any group that cleaves to form a hydroxy acid, amino acid, or carboxylic acid, respectively, when the prodrug is administered to a patient.

[0051] In some embodiments, the compounds of the present invention exist in salt form or non-salt form.With respect to salt form, in some embodiments, the specific anion or cation that forms part of any salt form of the compounds provided herein is not important, as long as the salt as a whole is pharmacologically acceptable.Further examples of pharmaceutically acceptable salts and their preparation and use methods are shown 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 more than one solid form, 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 Assay results for inhibition of IFNγ-induced NO production are shown for several compounds of the invention in Tables 2 and 3 of Example 2. Table 2 shows these results in comparison with those 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 provided in the Examples section below.

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

[0055] In some embodiments, compounds of the present disclosure exhibit reduced inhibition of cytochrome P450 3A4 (CYP3A4) compared to known compounds. CYP3A4 is a key enzyme in the body that oxidizes small foreign organic molecules (xenobiotics), such as toxins or drugs, allowing them to be removed from the body. The effects of drugs modified by CYP3A4 can be amplified or attenuated by modulation of CYP3A4. Inhibition of CYP3A4 can have adverse side effects (e.g., reduced drug clearance, amplified drug effects, and / or increased potential for drug-drug interactions) and can make administration difficult. Therefore, drugs that do not inhibit CYP3A4 are often desirable.

[0056] Assay results for CYP3A4 inhibition are shown in Tables 4-7 of Example 3 for several compounds of the present disclosure. In some embodiments, synthetic triterpenoid derivatives provided herein substituted with polar substituents at the C17 heteroaryl group exhibit reduced CYP3A4 inhibition compared to compounds lacking these substituents, such as those disclosed in U.S. Patent Nos. 9,512,094 and 9,290,536, both of which are incorporated herein by reference. For example, the CYP3A4 inhibition values ​​of fluoro-substituted T1, amino-substituted T2, and fluoro-substituted T12 were 36%, 53%, and 35% lower than the corresponding unsubstituted compound CC2 (TX63501; U.S. Patent No. 9,512,094) (29.1%, 21.4%, and 29.7%, 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. Pat. No. 9,512,094) (17.7% inhibition vs. 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. Pat. No. 9,290,536) (29.4% inhibition vs. 37.7% inhibition). Furthermore, T1, T2, T11, T12, and T34 each showed reduced CYP3A4 inhibition compared to historical data for RTA 402 and RTA 408 conducted under comparable conditions (Figure 1).

[0057] III. Diseases associated with inflammation and / or oxidative stress Inflammation is a biological process that provides resistance to infectious or parasitic organisms and repair of damaged tissue. Inflammation is generally characterized by localized vasodilation, redness, swelling, and pain; recruitment of leukocytes to the site of infection or injury; production of inflammatory cytokines such as TNF-α and IL-1; and production of reactive oxygen or 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 in an integrated manner once the infection or injury is properly treated. However, acute inflammation can become excessive and life-threatening if control mechanisms are disrupted. Alternatively, inflammation can become chronic, causing cumulative tissue damage or systemic complications. Based at least on the evidence presented above, the compounds of the present disclosure can be used to treat or prevent inflammation or inflammation-related diseases.

[0058] Many serious and intractable 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 cancer, inflammatory processes are associated with tumor formation, progression, metastasis, and treatment resistance. Atherosclerosis, long viewed as a disorder of lipid metabolism, is now understood to be primarily an inflammatory state, with activated macrophages playing a key role in the formation and eventual 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 and nitrogen species, such as superoxide, hydrogen peroxide, nitric oxide, and peroxynitrite, is a hallmark of inflammatory states. Evidence of dysregulated peroxynitrite production has been reported in a wide 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 disease, and arthritis involve chronic inflammation and oxidative stress as major contributing factors. In some embodiments, the compounds provided herein can be used to treat and / or prevent age-related diseases such as dementia, muscle wasting, cardiovascular disease, neurodegenerative disease, or arthritis.

[0059] Autoimmune diseases such as rheumatoid arthritis, lupus, psoriasis, and multiple sclerosis involve the inappropriate and chronic activation of inflammatory processes in affected tissues, which is caused by the dysfunction of the immune system's self-versus-nonself recognition and response mechanisms. 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, neuronal damage is correlated with the 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 related to the presence of chronic oxidative stress and inflammation, which leads to the development of fibrosis and the eventual loss of organ function. In some embodiments, provided herein are compounds that 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 the vascular endothelial cells lining large and small blood vessels can lead to endothelial dysfunction, and is believed to be an important contributing factor in the development of systemic cardiovascular disease, diabetic complications, chronic kidney disease, and other organ failure forms, as well as some other age-related diseases, including degenerative central nervous system disease and degenerative retinal disease.In some embodiments, provided herein are compounds that can be used in the treatment and / or prevention of systemic cardiovascular disease, diabetic complications, chronic kidney disease, and other organ failure forms, as well as some other age-related diseases, including degenerative central nervous system disease and degenerative retinal disease.

[0060] Many other disorders involve oxidative stress and inflammation in affected tissues, including inflammatory bowel disease; inflammatory skin diseases; mucositis associated with radiation therapy and chemotherapy; ocular 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 schizophrenia, depression, bipolar disorder, post-traumatic stress disorder, attention deficit disorder, autism spectrum disorder, and eating disorders such as anorexia nervosa. In some embodiments, provided herein are compounds that can be used in the treatment and / or prevention of inflammatory bowel disease; inflammatory skin disease; mucositis associated with radiation therapy 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 of sickle cell anemia); chronic pain; degenerative bone and joint conditions, including osteoarthritis and osteoporosis; asthma and cystic fibrosis; seizure disorders; and neuropsychiatric conditions, including schizophrenia, depression, bipolar disorder, post-traumatic stress disorder, attention deficit disorder, autism spectrum disorder, or eating disorders, such as anorexia nervosa.Dysregulation of inflammatory signaling pathways is believed to be the main cause of the pathology of muscle wasting diseases, including muscular dystrophy and various forms of cachexia.In some embodiments, provided herein are compounds that can be used in the treatment and / or prevention of muscle wasting diseases, including muscular dystrophy and various forms of cachexia.

[0061] Additionally, 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] Furthermore, many complications of infectious diseases involve dysregulated inflammatory responses. While inflammatory responses can kill invading pathogens, excessive inflammatory responses can be quite destructive and, in some cases, can be the primary source of damage in affected tissues. Furthermore, excessive inflammatory responses can lead to systemic complications due to the overproduction of inflammatory cytokines such as TNF-α and IL-1. This is thought to be an important factor in deaths resulting from severe influenza, severe acute respiratory syndrome caused by coronavirus infection, including SARS-CoV-2, which causes COVID-19, and other viruses that cause upper respiratory tract disease, as well as sepsis. In some embodiments, the compounds provided herein can be used in the treatment and / or prevention of influenza, severe acute respiratory syndrome caused by coronavirus infection, including SARS-CoV-2, or other viruses that cause upper respiratory tract disease, or sepsis.

[0063] Abnormal or overexpression of iNOS or cyclooxygenase-2 (COX-2) has been implicated in the development of many disease processes. For example, it is clear that NO is a potent mutagen (Tamir and Tannebaum, 1996) and that nitric oxide can 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), all of which are incorporated herein by reference. Additionally, elevated iNOS levels in brain tissue have 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 wide variety of diseases and disorders involving oxidative stress and dysregulation of inflammatory processes, including cancer, complications from local or systemic exposure to ionizing radiation, mucositis resulting from radiation therapy or chemotherapy, autoimmune diseases, cardiovascular diseases including atherosclerosis, ischemia-reperfusion injury (including complications from sickle cell anemia), acute and chronic organ failure including renal failure and heart failure, respiratory diseases, diabetes and diabetic complications, severe allergies, transplant rejection, graft-versus-host disease, neurodegenerative diseases, ocular and retinal diseases, acute and chronic pain, degenerative bone diseases including osteoarthritis and osteoporosis, inflammatory bowel disease, 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 from local or systemic exposure to ionizing radiation, mucositis resulting from radiation therapy or chemotherapy, autoimmune diseases, cardiovascular diseases including atherosclerosis, ischemia-reperfusion injury (including complications from sickle cell anemia), acute and chronic organ failure including renal failure and heart failure, respiratory diseases, diabetes and diabetic complications, severe allergies, transplant rejection, graft-versus-host disease, neurodegenerative diseases, eye and retinal diseases, acute and chronic pain, degenerative bone diseases including osteoarthritis and osteoporosis, inflammatory bowel disease, 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 believed 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 patients with conditions caused by elevated levels of oxidative stress in one or more tissues. 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 with superoxide). Oxidative stress can be associated with acute or chronic inflammation. Oxidative stress can be caused by mitochondrial dysfunction, activation of immune cells such as macrophages and neutrophils, acute exposure to external agents such as ionizing radiation or 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 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 bilirubin, a potent antioxidant molecule. Carbon monoxide has been shown to exhibit signaling functions, and biliverdin reductase, the enzyme that catalyzes the conversion of biliverdin to bilirubin, has been shown 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.The examples of diseases that belong to this category include heart failure, liver failure, transplant failure and transplant rejection, renal failure, pancreatitis, fibrotic lung disease (especially cystic fibrosis, COPD and idiopathic pulmonary fibrosis), diabetes (including complications), atherosclerosis, ischemia-reperfusion injury, glaucoma, stroke, autoimmune disease, autism, macular degeneration and muscular dystrophy.For example, in the case of autism, research suggests that the increase in oxidative stress in central nervous system may contribute to the occurrence of the disorder (Chauhan and Chauhan, 2006).

[0069] Evidence also links oxidative stress and inflammation to the development and pathology 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, all of which are 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. Therefore, the downregulation of inflammatory cytokines and the inhibition of microglial hyperactivation may be beneficial for patients with schizophrenia, major depression, bipolar disorder, autism spectrum disorder and other neuropsychiatric disorders.In some embodiments, provided herein is a compound that 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; or behavioral syndromes such as attention deficit disorder.

[0070] Thus, in conditions involving oxidative stress alone or oxidative stress exacerbated by inflammation, treatment can include administering to a subject a therapeutically effective amount of a compound of the present disclosure, such as a compound described above or throughout this specification. Treatment can be performed prophylactically before a foreseeable oxidative stress condition (e.g., organ transplantation or the administration of radiation therapy to a cancer patient) or therapeutically in situations involving existing oxidative stress and inflammation.

[0071] The compounds disclosed herein can be generally 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 inducing Nrf2 and / or inhibiting NF-κB.

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

[0073] Another aspect of inflammation is the production of inflammatory prostaglandins, such as prostaglandin E. These molecules promote vasodilation, plasma extravasation, localized pain, hypertension, 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. Therefore, COX-2 inhibition 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) plays a role in stimulating the organizational resolution of inflammation (e.g., Rajakariar et al., 2007). COX-2 is also involved in the production of cyclopentenone prostaglandins. Thus, COX-2 inhibition may interfere with the complete resolution of inflammation, potentially promoting the persistence of activated immune cells in tissues and leading to chronic "smoldering" inflammation, an effect that may contribute to the increased incidence of cardiovascular disease in patients receiving long-term selective COX-2 inhibitors.

[0074] In one aspect, the compounds disclosed herein can be used to regulate the production of pro-inflammatory cytokines in cells 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 shown to initiate a pro-resolution 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 increases the production of antioxidant and reducing molecules (NQO1, HO-1, SOD1, γ-GCS) and reduces oxidative stress and the production of pro-oxidant and pro-inflammatory molecules (iNOS, COX-2, TNF-α). In some embodiments, the compounds disclosed herein can restore cells with inflammatory events to a non-inflammatory state by promoting the resolution of inflammation and limiting excessive tissue damage in the host.

[0075] IV. Pharmaceutical Formulations and Routes of Administration In another aspect, for administration to a patient in need of such treatment, a pharmaceutical formulation (also referred to as a pharmaceutical preparation, pharmaceutical composition, pharmaceutical product, medicinal product, medicament, drug, or pharmaceutical product) 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 treating a human patient and / or a veterinary patient. In some embodiments, the 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 esters, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphate and sulfate, gelatin, gum arabic, sodium alginate, polyvinylpyrrolidone, and / or polyvinyl alcohol. In some embodiments, the pharmaceutical formulation can be tableted or encapsulated, for example, for oral administration. In some embodiments, the compounds 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 formulations may be subjected to pharmaceutical operations such as sterilization and / or may include drug carriers and / or excipients, such as preservatives, stabilizers, wetting agents, emulsifiers, encapsulating agents, lipids, dendrimers, polymers, proteins such as albumin, nucleic acids, and buffers.

[0076] Pharmaceutical preparations can be administered in various ways, for example, orally or by injection (e.g., subcutaneously, intravenously, and intraperitoneally). Depending on the route of administration, the compounds disclosed herein can be coated in a material to protect them from the action of acids and other natural conditions that can inactivate the compounds. To administer an active compound other than parenterally, it may be necessary to coat the compound with a material that prevents its inactivation or to administer the compound simultaneously. In some embodiments, the active compound may be administered to a patient in a suitable carrier, such as liposomes, or a diluent. Pharmaceutically acceptable diluents include saline and aqueous buffer solutions. Liposomes include water-in-oil-in-water CGF emulsions and conventional liposomes.

[0077] The compound disclosed herein can also be administered parenterally, intraperitoneally, intraspinally or intracerebrally.Dispersion can be prepared in glycerin, liquid polyethylene glycol and its mixture, and in oil.Under normal storage and use conditions, these preparations can contain preservatives to prevent the growth of microorganisms.

[0078] Pharmaceutical compositions suitable for injection include sterile aqueous solutions (where water soluble) or dispersions, and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. The carrier can be a solvent or dispersion medium, including, for example, water, ethanol, polyols (e.g., glycerin, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. Prevention of microbial action can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it is preferable to include isotonic agents, for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, in the composition. Prolonged absorption of injectable compositions can be achieved by including in the composition an agent that delays absorption, for example, aluminum monostearate or gelatin.

[0079] The compounds disclosed herein can be orally administered, for example, 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 subject's diet.For therapeutic oral administration, the compounds disclosed herein can be incorporated with excipients and used in the form of oral ingestible tablets, buccal tablets, lozenges, capsules, elixirs, suspensions, syrups, wafers, etc.The percentage of therapeutic compounds in compositions and preparations can of course vary.The amount of therapeutic compounds in these pharmaceutical preparations is such that a suitable dosage is obtained.

[0080] The therapeutic compound can also be administered locally to the skin, eye, ear, or mucous membrane. Topical administration of a therapeutic compound can include formulating the compound as a topical solution, lotion, cream, ointment, gel, foam, transdermal patch, or tincture. When a therapeutic compound is formulated 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 as being ocular. This administration can be applied to the surface of the cornea, conjunctiva, or sclera. While not 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 segment of the eye. Ophthalmic topical administration can be formulated as a solution, suspension, ointment, gel, or emulsion. Finally, topical administration can include administration to mucous membranes, such as the inside of the mouth. This administration can be directly to a specific location within the mucous membrane, such as a tooth, sore, or ulcer. Alternatively, if local delivery to the lung is desired, the therapeutic compounds may be administered by inhalation in a dry powder or aerosol formulation.

[0081] In some embodiments, it may be advantageous to formulate parenteral compositions in unit dosage forms for ease of administration and uniformity of dosage. As used herein, unit dosage form refers to physically discrete units suitable as unit dosage forms for the patient to be treated, each unit containing a predetermined amount of therapeutic compound calculated to produce the desired therapeutic effect, in combination with the required pharmaceutical carrier. In some embodiments, the specifications of the unit dosage forms of the present invention are determined and directly depend on (a) the unique characteristics of the therapeutic compound and the specific therapeutic effect to be achieved, and (b) the limitations inherent in the field of formulating the therapeutic compound for the treatment of the selected condition in patients. In some embodiments, the active compound is administered in a therapeutically effective dose sufficient to treat the condition related to the condition in the patient. For example, the effectiveness of the compound can be evaluated in an animal model system that can predict the effectiveness of treating a disease in humans or another animal.

[0082] In some embodiments, the effective dose range of a therapeutic compound can be extrapolated from effective doses determined in animal studies involving a variety of different animals. In some embodiments, the human equivalent dose (HED) in mg / kg can be calculated according to the following formula (see, e.g., 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 ) In the transformation m The use of factors results in HED values ​​based on body surface area (BSA) rather than body weight alone. m The values ​​are well known. For example, for an average 60 kg human (BSA 1.6 m 2 (having) K m is 37, while a 20 kg child (BSA 0.8 m 2 ) is K m 25. K in several relevant animal models m is also well known, and the mouse K m 3 (body weight 0.02 kg and BSA 0.007), hamster K m 5 (body weight 0.08 kg and BSA 0.02), rat K m 6 (body weight 0.15 kg and BSA 0.025), and monkey K m 12 (assuming a body weight of 3 kg and a BSA of 0.24).

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

[0084] The actual dosage of the compound of the present disclosure or the composition containing the compound of the present disclosure administered to a patient can be determined by physical and physiological factors such as the type of animal to be treated, age, sex, weight, severity of condition, type of disease to be treated, previous or concurrent therapeutic intervention, patient's idiopathic nature, and route of administration.These factors can be determined by those skilled in the art.Usually, the practitioner responsible for administration determines the concentration of active ingredient in the composition and the dosage appropriate for each individual patient.In the event of any complications, the individual physician can adjust the dosage.

[0085] In some embodiments, a pharmaceutically effective amount typically ranges from about 0.001 mg / kg to about 1000 mg / kg, about 0.01 mg / kg to about 750 mg / kg, about 100 mg / kg to about 500 mg / kg, about 1 mg / kg to about 250 mg / kg, or about 10 mg / kg to about 150 mg / kg, administered daily, daily, or over several days, in one or more doses (depending, of course, on the mode of administration and the factors discussed above). Other suitable dose 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, in the range of 750 mg to 9,000 mg per day.

[0086] In some embodiments, the amount of 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] The agent can be administered in a single dose or multiple doses.The desired time interval for the delivery of multiple doses can be determined by those skilled in the art through routine experimentation.As an example, two doses can be administered to patients every day, with an interval of about 12 hours.In some embodiments, the agent is administered once a day.

[0088] The agent can be administered according to a daily schedule. As used herein, the term "daily schedule" refers to a predetermined, specified period. The daily schedule can include periods of the same length or different periods, as long as the schedule is predetermined. For example, the daily schedule can include twice-daily, daily, every 2 days, every 3 days, every 4 days, every 5 days, every 6 days, weekly, monthly, or any number of days or weeks set therein. Alternatively, the predetermined daily schedule can include twice-daily administration 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 can be orally ingested, and a daily schedule in which the timing is dependent or independent of food intake. Thus, for example, the agent can be taken every morning and / or every evening, regardless of whether the patient has eaten or will eat.

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

[0090] In some embodiments, combination therapy is provided that combines a compound disclosed herein with another CF treatment, such as a compound designed to improve the function of at least partially functional CFTR that has reached the cell membrane. These compounds are known as CFTR potentiators, 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 CF treatment efficacy by combining two correctors or a corrector and an potentiator is well understood in the art, and these combinations are approved for marketing or currently being tested in clinical trials. Triple-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 comprising multiple agents, or by two or more separate compositions or formulations that are co-administered, one composition comprising a compound of the present disclosure and the other composition comprising 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. Definition The following definitions supersede any conflicting definitions in any reference incorporated herein by reference. However, the fact that certain terms are defined should not be construed as indicating that any undefined term is indefinite. Rather, all terms used are believed to describe the disclosure in terms such that one skilled in the art can appreciate the scope and practice the disclosure.

[0093] When used in reference to chemical groups, "hydrogen" means -H, "hydroxy" means -OH, "oxo" means =O, "carbonyl" means -C(=O)-, "carboxy" means -C(=O)OH (also written as -COOH or -COH), "halo" independently means -F, -Cl, -Br, or -I, "amino" means -NH, "hydroxyamino" means -NHOH, "nitro" means -NO, imino means =NH, and "cyano" means -C. "N" means "isocyanyl" means -N=C=O, "azido" means -N3, in monovalent terms, "phosphate" means -OP(O)(OH)2 or its deprotonated form, and in divalent terms, "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-, and "sulfinyl" means -S(O)-.

[0094] With respect to chemical formulas, the symbol "-" denotes a single bond, "=" denotes a double bond, and "≡" denotes a triple bond. The symbol TIFF2025131767000049.tif4128 represents any bond, which, if present, may be a single or double bond. The symbol TIFF2025131767000050.tif4128 means a single or double bond. Therefore, the formula TIFF2025131767000051.tif9128, for example TIFF2025131767000052.tif11128. It is also to be understood that no ring atom forms part of more than one double bond. Furthermore, it should be noted 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 encompassed. Bond When drawn vertically across TIFF2025131767000053.tif7128 The symbol TIFF2025131767000054.tif4128 indicates the point of attachment of the radical. Note that typically only larger radicals have the point of attachment so identified to facilitate the reader in unambiguously identifying the point of attachment. The symbol TIFF2025131767000055.tif4128 represents a single bond in which the group attached to the thick end of the wedge points "outward from the page." The symbol TIFF2025131767000056.tif4128 represents a single bond in which the group attached to the thick end of the wedge points "inward toward the page." The symbol TIFF2025131767000057.tif4128 refers to a single bond with an undefined geometry (e.g., E or Z) around the double bond. Thus, both options and combinations thereof are contemplated. Any undefined valence on an atom of a structure shown in this application implicitly represents a hydrogen atom bonded to that atom. A bold dot on a carbon atom indicates that the hydrogen bonded to that carbon faces out of the plane of the paper. For example, the following two illustrations are equivalent: TIFF2025131767000058.tif21128

[0095] The variable element is a "floating group" on the ring system, such as the formula: When depicted as an "R" group in TIFF2025131767000059.tif13128, the variable can replace any hydrogen atom attached to any ring atom, including hydrogens shown, implied, or explicitly defined, so long as a stable structure is formed. When depicted as an "R" group in TIFF2025131767000060.tif17128, a variable can replace any hydrogen bonded to any ring atom of either fused ring, unless otherwise specified. Replaceable hydrogens, so long as a stable structure is formed, include depicted hydrogens (e.g., hydrogen bonded to a nitrogen in the formula above), implied hydrogens (e.g., hydrogens in the formula above that are not shown but are understood to be present), explicitly defined hydrogens, and optional hydrogens whose presence depends on the identity of the ring atom (e.g., hydrogen bonded to the X group when X is equal to -CH-). In the depicted example, R can be present in either a 5-membered or 6-membered ring of the fused ring system. The subscript "y" immediately following the parenthesized R group in the formula above represents a variable. Unless otherwise specified, this variable can be 0, 1, 2, or any integer greater than 2, limited only by the maximum number of replaceable hydrogen atoms in the ring or ring system.

[0096] With respect to chemical groups and compound classes, the number of carbon atoms in the group or class is indicated as follows: "Cn" or "C=n" specifies the exact number (n) of carbon atoms in the group / class. "C≦n" specifies the maximum number (n) of carbon atoms that can be present in the group / class, with the minimum being the smallest possible number for the group / class in question. For example, "alkyl (C≦8) ", "Alkanediyl (C≦8) ", "heteroaryl (C≦8) " and "Acyl (C≦8) The minimum number of carbon atoms in the group is one, and "alkenyl" (C≦8) ", "alkynyl (C≦8) ", and "heterocycloalkyl (C≦8) The minimum number of carbon atoms in a "cycloalkyl" group is two. (C≦8)The minimum number of carbon atoms in the group is three, and the "aryl (C≦8) " and "Arengeiil (C≦8) It will be understood that the minimum number of carbon atoms in the group is 6. "Cn-n'" defines both the minimum (n) and maximum (n') number 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 any change in meaning. Thus, "C 1~4 -alkyl", "C1-4-alkyl", "alkyl (C1~4) " and "Alkyl (C≦4) " are all synonymous. Except as otherwise noted below, all carbon atoms are counted to determine whether a group or compound is within a specified number of carbon atoms. For example, a dihexylamino group is a dialkylamino group. (C12) An example of a group is dialkylamino (C6) Similarly, phenylethyl is not an example of an aralkyl group. (C=8) is an example of a group. When any chemical group or class of compounds defined herein is modified by the term "substituted," any carbon atoms in the moiety that replace a hydrogen atom are not counted. Thus, methoxyhexyl, which has a total of 7 carbon atoms, is a substituted alkyl group. (C1~6) Unless otherwise specified, any chemical group or class of compounds recited in a claim set without a carbon atom limitation 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 or carbon-carbon triple bonds, except as noted below. When used as a modifier of an atom, the term means that the atom is not part of any double or triple bonds. In substituted versions of saturated groups, one or more carbon-oxygen or carbon-nitrogen double bonds may be present. Also, when present, this does not exclude carbon-carbon double bonds that may occur as part of keto-enol or imine / enamine tautomerism. When used as a modifier of a solution of a substance, the term "saturated" means that the substance is no longer soluble in the solution.

[0098] The term "aliphatic" means that the compound or chemical group to which it is attached is acyclic or cyclic, but non-aromatic. In an aliphatic compound / group, the carbon atoms can be joined together in a straight chain, a branched chain, or a non-aromatic ring (alicyclic). An aliphatic compound / group can be saturated, i.e., joined by carbon-carbon single bonds (alkane / alkyl), or unsaturated, having one or more carbon-carbon double bonds (alkene / alkenyl), or one or more carbon-carbon triple bonds (alkyne / alkynyl).

[0099] The term "aromatic" means that the compound or chemical group to which this modifier is attached has a planar, unsaturated ring of atoms with 4n+2 electrons in a completely conjugated cyclic π system. An aromatic compound or aromatic chemical group may be depicted as a single resonance structure, but the depiction of one resonance structure is considered to refer to any other resonance structures as well. For example, TIFF2025131767000061.tif13128 TIFF2025131767000062.tif13128. Aromatic compounds may be illustrated using circles to represent the delocalization of electrons in a completely conjugated cyclic π system, two non-limiting examples of which are shown below: TIFF2025131767000063.tif12128

[0100] The term "alkyl" means a monovalent saturated aliphatic group having a carbon atom as the point of attachment, a straight or branched acyclic structure, and containing no atoms other than carbon and hydrogen. Examples include: -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 Groups such as -Bu), and -CHC(CH) (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 points of attachment, a straight or branched acyclic structure, no carbon-carbon double or triple bonds, and no atoms other than carbon and hydrogen. Groups such as -CH- (methylene), -CHCH-, -CHC(CH)CH-, and -CHCHCH- are non-limiting examples of alkanediyl groups. The term "alkylidene" refers to the divalent group =CRR', where R and R' are independently hydrogen or alkyl. Non-limiting examples of alkylidene groups include =CH, =CH(CHCH), and =C(CH). "Alkane" refers to the class of compounds having the formula HR, where R is alkyl, as that term is defined above.

[0101] The term "cycloalkyl" refers to a monovalent saturated aliphatic group having a carbon atom as the point of attachment that forms part of one or more non-aromatic ring structures, no carbon-carbon double or triple bonds, and no atoms other than carbon and hydrogen. Non-limiting examples include -CH(CH2)2 (cyclopropyl), cyclobutyl, cyclopentyl, or cyclohexyl (Cy). As used herein, this term does not preclude the presence of one or more alkyl groups (with possible carbon number limitations) attached to a carbon atom of a non-aromatic ring structure. The term "cycloalkanediyl" refers to a divalent saturated aliphatic group having two carbon atoms as the point of attachment, no carbon-carbon double or triple bonds, and no atoms other than carbon and hydrogen. A group such as TIFF2025131767000064.tif8128 is a non-limiting example of a cycloalkanediyl group. "Cycloalkane" refers to the class of compounds having the formula HR, where R is cycloalkyl, as that term is defined above.

[0102] The term "heterocycloalkyl" refers to a monovalent, non-aromatic group having a carbon or nitrogen atom as the point of attachment that forms part of one or more non-aromatic ring structures, each having 3 to 8 ring atoms, where at least one ring atom of the non-aromatic ring structure is nitrogen, oxygen, or sulfur, and the heterocycloalkyl group does not consist solely of atoms other than carbon, hydrogen, nitrogen, oxygen, and sulfur. When more than one ring is present, the rings are fused. As used herein, the term does not preclude the presence of one or more alkyl groups (with possible carbon number limitations) attached to one or more ring atoms. The term also does not preclude the presence of one or more double bonds in the ring or ring system, provided 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" refers to a heterocycloalkyl group having a nitrogen atom as the point of attachment. N-pyrrolidinyl is an example of this group. The term "heterocycloalkanediyl" refers to a divalent cyclic group having two carbon atoms, two nitrogen atoms, or one carbon atom and one nitrogen atom as two points of attachment forming part of one or more ring structures, where at least one ring atom of the non-aromatic ring structure is nitrogen, oxygen, or sulfur, and the divalent group consists of atoms other than carbon, hydrogen, nitrogen, oxygen, and sulfur. When more than one ring is present, the rings are fused. As used herein, the term heterocycloalkanediyl does not exclude the presence of one or more alkyl groups (with possible carbon number limitations) attached to one or more ring atoms. The term also 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: TIFF2025131767000065.tif15128

[0103] The term "alkenyl" refers to a monovalent unsaturated aliphatic group having a carbon atom as the point of attachment, a linear or branched acyclic structure, at least one non-aromatic carbon-carbon double bond, no carbon-carbon triple bonds, and no atoms other than carbon and hydrogen. Non-limiting examples include -CH=CH2 (vinyl), -CH=CHCH3, -CH=CHCH2CH3, -CH2CH=CH2 (allyl), -CH2CH=CHCHCH3, and -CH=CHCH=CH2. The term "alkenediyl" refers to a divalent unsaturated aliphatic group having two carbon atoms as points of attachment, a linear or branched acyclic structure, at least one non-aromatic carbon-carbon double bond, no carbon-carbon triple bonds, and 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 alkenediyl groups are aliphatic, this does not preclude the group from forming part of an aromatic structure when attached at both ends. The terms "alkene" and "olefin" are synonymous and refer to the class of compounds having the formula HR, where R is alkenyl, as defined above. Similarly, the terms "terminal alkene" and "α-olefin" are synonymous and refer to an alkene that has only one carbon-carbon double bond, which is part of a vinyl group at one end of the molecule.

[0104] The term "alkynyl" refers to a monovalent unsaturated aliphatic group having a carbon atom as the point of attachment, a linear or branched acyclic structure, at least one carbon-carbon triple bond, and no atoms other than carbon and hydrogen. As used herein, the term alkynyl 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" refers to the class of compounds having the formula HR where R is alkynyl.

[0105] The term "aryl" refers to a monovalent unsaturated aromatic group having an aromatic carbon atom as a point of attachment that forms part of one or more aromatic ring structures, each having six all-carbon ring atoms, and consisting of atoms other than carbon and hydrogen. When more than one ring is present, the rings may be fused or unfused. Non-fused rings are connected by covalent bonds. As used herein, the term aryl does not exclude the presence of one or more alkyl groups (possibly limited in number of carbon atoms) attached to the first aromatic ring or any additional aromatic rings present. Non-limiting examples of aryl groups include monovalent groups derived from phenyl (Ph), methylphenyl, (dimethyl)phenyl, -CHCHCH(ethylphenyl), naphthyl, and biphenyl (e.g., 4-phenylphenyl). The term "arenediyl" refers to a divalent aromatic group having two aromatic carbon atoms as points of attachment that form part of one or more six-membered aromatic ring structures, each having six all-carbon ring atoms, and 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 may be limited) attached to the first aromatic ring or any additional aromatic rings present. When two or more rings are present, the rings may be fused or unfused. Non-fused rings are connected by a covalent bond. Non-limiting examples of arenediyl groups include: TIFF2025131767000066.tif16156 "Arene" means the class of compounds having the formula H-R, where R is aryl, as that term is defined above. Benzene and toluene are non-limiting examples of arenes.

[0106] The term "aralkyl" refers to the monovalent group -alkanediyl-aryl, where the terms alkanediyl and aryl are each used as defined above. Non-limiting examples include phenylmethyl (benzyl, Bn) and 2-phenyl-ethyl.

[0107] The term "heteroaryl" refers to a monovalent aromatic group having an aromatic carbon or nitrogen atom as the point of attachment that forms part of one or more aromatic ring structures, each having from 3 to 8 ring atoms, in which at least one ring atom is nitrogen, oxygen, or sulfur, and in which the heteroaryl group consists solely of atoms of carbon, hydrogen, aromatic nitrogen, aromatic oxygen, and aromatic sulfur. When more than one ring is present, the rings are fused, but the term heteroaryl does not preclude the presence of one or more alkyl or aryl groups (which may be limited in number of carbon atoms) attached 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, quinazolyl, quinoxalinyl, triazinyl, tetrazolyl, thiazolyl, thienyl, and triazolyl. The term "N-heteroaryl" refers to a heteroaryl group having a nitrogen atom as the attachment point. "Heteroarene" refers to the class of compounds having the formula HR where R is heteroaryl. Pyridine and quinoline are non-limiting examples of heteroarenes. The term "heteroarenediyl" refers to 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 points of attachment forming part of one or more aromatic ring structures, each having 3 to 8 ring atoms, wherein at least one ring atom of the aromatic ring structure is nitrogen, oxygen, or sulfur, and the divalent group consists of atoms other than carbon, hydrogen, aromatic nitrogen, aromatic oxygen, and aromatic sulfur. When more than one ring is present, the rings are fused, but the term heteroarenediyl does not preclude the presence of one or more alkyl or aryl groups (which may have limited carbon atoms) attached to one or more ring atoms. Non-limiting examples of heteroarenediyl groups include: TIFF2025131767000067.tif15128

[0108] The term "acyl" refers to a -C(O)R group, where R is hydrogen, alkyl, cycloalkyl, or aryl, 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)CH6H5, and -C(O)CH4CH3 are non-limiting examples of acyl groups. "Thioacyl" is similarly defined except that the oxygen atom in the -C(O)R group is replaced with a sulfur atom, resulting in -C(S)R. The term "aldehyde" corresponds to an alkyl group, as defined above, attached to a -CHO group.

[0109] The term "alkoxy" refers to the group -OR, where R is alkyl, as that term is defined above. Non-limiting examples include -OCH (methoxy), -OCHCH (ethoxy), -OCHCHCH, -OCH(CH) (isopropoxy), or -OC(CH) (tert-butoxy). The terms "cycloalkoxy," "alkenyloxy," "alkynyloxy," "aryloxy," "aralkoxy," "heteroaryloxy," "heterocycloalkoxy," and "acyloxy," when used without the "substituted" modifier, refer to the group defined as -OR, where R is cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heterocycloalkyl, and acyl, respectively. The terms "alkylthio" and "acylthio" refer to the group -SR, where R is alkyl and acyl, respectively. The term "alcohol" corresponds to an alkane, as defined above, in which at least one hydrogen atom has been replaced with a hydroxy group. The term "ether" corresponds to an alkane, as defined above, in which at least one hydrogen atom has been replaced with an alkoxy group.

[0110] The term "alkylamino" refers to the group -NHR, where R is alkyl, as that term is defined above. Non-limiting examples include -NHCH and -NHCHCH. The term "dialkylamino" refers to the group -NRR, where R and R can be the same or different alkyl groups. Non-limiting examples of dialkylamino groups include -N(CH) and -N(CH)(CHCH). The terms "cycloalkylamino," "alkenylamino," "alkynylamino," "arylamino," "aralkylamino," "heteroarylamino," "heterocycloalkylamino," and "alkoxyamino," when used without the "substituted" modifier, refer to a group 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 -NHCH. The term "amido" (acylamino) when used without the "substituted" modifier refers to the group -NHR, where R is acyl, as that term is defined above. A non-limiting example of an amido group is -NHC(O)CH.

[0111] When a chemical group is used with the "substituted" modifier, one or more hydrogen atoms are each independently replaced with -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: -CHOH, -CHCl, -CF, -CHCN, -CHC(O)OH, -CHC(O)OCH, -CHC(O)NH, -CHC(O)CH, -CHOCH, -CHOC(O)CH, -CHNH, -CHN(CH), and -CHCHCl. ​​The term "hydroxyalkyl" is a subset of substituted alkyl in which one or more hydrogen atoms have been replaced with a hydroxy (i.e., -OH) group, and thus no atoms other than carbon, hydrogen, and oxygen are present. Groups such as -CHOH, -CHCHOH, -CH(OH)CHOH, -CHCH(OH)CH, and -CH(OH)CHOH are non-limiting examples of hydroxyalkyl groups. The term "monohydroxyalkyl" is a subset of substituted alkyl, where one hydrogen atom is replaced with a hydroxy (i.e., -OH) group, such that there are no atoms other than carbon, hydrogen, and one oxygen. Groups such as -CHOH, -CHCHOH, and -CHCH(OH)CH are non-limiting examples of monohydroxyalkyl groups. The term "fluoroalkyl" is a subset of substituted alkyl, where one or more hydrogen atoms are replaced with fluoro, such that there are no atoms other than carbon, hydrogen, and fluorine. Groups such as -CHF, -CHF, and -CF are non-limiting examples of fluoroalkyl groups. The term "monofluoroalkyl" is a subset of substituted alkyl, where one hydrogen atom is replaced with fluoro, such that there are no atoms other than carbon, hydrogen, and one fluorine.Groups such as -CHF, -CHCHF, and -CHCH(F)CH are non-limiting examples of monofluoroalkyl groups. The term "aminoalkyl" is a subset of substituted alkyl, where one or more hydrogen atoms are replaced with an amino (i.e., -NH) group, and thus no atoms other than carbon, hydrogen, and nitrogen are present. Groups such as -CHNH, -CH(NH)CH, -CHCHNH, -CHCH(NH)CH, and -CH(NH)CHNH are non-limiting examples of aminoalkyl groups. The term "monoaminoalkyl" is a subset of substituted alkyl, where one hydrogen atom is replaced with an amino (i.e., -NH) group, and thus no atoms other than carbon, hydrogen, and one nitrogen are present. Groups such as -CHNH, -CHCHNH, and -CHCH(NH)CH are non-limiting examples of monofluoroalkyl groups. Non-limiting examples of substituted aralkyls include (3-chlorophenyl)-methyl and 2-chloro-2-phenyl-eth-1-yl. Groups such as -C(O)CHCF, -COH(carboxyl), -COCH(methylcarboxyl), -COCHCH, -C(O)NH(carbamoyl), and -CON(CH) are non-limiting examples of substituted acyl groups. Groups such as -NHC(O)OCH and -NHC(O)NHCH are non-limiting examples of substituted amido groups.

[0112] When a chemical group is used with the "polar substituted" modifier, one or more hydrogen atoms are each independently replaced with one of the following polar substituents, but not all hydrogens are so replaced: -OH, -F, -NH, -COH, -COCH, -C(O)NH, -C(O)NHCH, -OC(O)CH, -NHC(O)CH, -NHC(O)OCH, -NHC(O)OCHCH, -NHC(O)NHCH, -NHC(O)NHCHCH, -S(O)OH, or -S(O)NH. Non-limiting examples of polar substituted alkyl groups include -CHF, -CHF, -CHCHF, -CHFCHF, -CFCH, -CHOH, -CHCHOH, -CHCHCHCHNH, -CHCHOH, and -CH(NH)CHOH.

[0113] When a chemical group is used with the "monopolar substituted" modifier, only one hydrogen atom has been replaced with one of the following polar substituents: -OH, -F, -NH, -COH, -COCH, -C(O)NH, -C(O)NHCH, -OC(O)CH, -NHC(O)CH, -NHC(O)OCH, -NHC(O)OCHCH, -NHC(O)NHCH, -NHC(O)NHCHCH, -S(O)OH, or -S(O)NH. Non-limiting examples of monopolar substituted alkyl groups include -CHF, -CHCHF, -CHFCH, -CHOH, -CHCHOH, -CH(OH)CHOH, -CHNH, -CHCHNH, and -CH(NH)CH.

[0114] Some abbreviations used herein 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 gamma, 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 erythroid transcription factor 2-related transcription factor 2, OA refers to oleanolic acid, Py refers to pyridine, T3P refers to propylphosphonic anhydride, TFA is trifluoroacetic acid, TFAA refers to trifluoroacetic anhydride, THF is tetrahydrofuran, TNFα or TNF-α is tumor necrosis factor alpha, TPAP is tetrapropylammonium perruthenate, Ts refers to tosyl, TsOH or p-TsOH is p-toluenesulfonic acid, and 4Å MS refers to 4 Å molecular sieves.

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

[0116] Throughout this specification, the term "about" is used to indicate that a value includes the inherent variation of error for the device or the method being employed to determine the value, or the variation that exists among test subjects or patients.

[0117] An "active ingredient" (AI) or active pharmaceutical ingredient (API) (also known as an active compound, active substance, active agent, pharmaceutical drug, agent, bioactive molecule, or therapeutic compound) is the component in a pharmaceutical drug that is biologically active.

[0118] The terms "comprise," "have," and "include" are open-ended linking verbs. Any form or tense of one or more of these verbs, such as "comprises," "comprising," "has," "having," "includes," and "including," is also open-ended. 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 covers other unlisted steps.

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

[0120] An "excipient" is a pharmaceutically acceptable substance formulated with the active ingredient of a drug, pharmaceutical composition, formulation, or drug delivery system. Excipients can be used, for example, to stabilize the composition, bulk the composition (and thus are often called "bulking agents," "fillers," or "diluents" when used for this purpose), or to provide therapeutic enhancements of the active ingredient in the final dosage form, such as facilitating drug absorption, reducing viscosity, or improving solubility. Excipients include anti-adherents, binders, coating agents, colorants, disintegrants, flavorings, glidants, lubricants, preservatives, absorbents, sweeteners, and pharmaceutically acceptable versions of vehicles. The primary excipient that serves as a vehicle for delivering the active ingredient is typically referred to as the vehicle. Excipients may be used in the manufacturing process to facilitate handling of the active ingredient, for example, by promoting powder flowability or non-stickiness, in addition to promoting in vitro stability, e.g., preventing denaturation or aggregation over the expected shelf life. Generally, the suitability of an excipient will vary depending on the route of administration, dosage form, active ingredient, and other factors.

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

[0122] As used herein, "IC 50 The term "relative IC" refers to an inhibitory dose that is 50% of the maximal response obtained. This quantitative measure indicates how much of a particular drug or other substance (inhibitor) is required to inhibit half of a given biological, biochemical, or chemical process (or component of the process, i.e., enzyme, cell, cell receptor, or microorganism). 50 The term "relative IC" refers to the fold difference in potency between two compounds. 50 Determine the IC of the compound of interest within each experimental assay using the formula below: 50 Benchmark compound IC values50 It is determined by dividing by the value. TIFF2025131767000068.tif10128

[0123] An "isomer" of a first compound is another compound whose each molecule contains the same constituent atoms as the first compound, but whose atoms are arranged differently in three dimensions.

[0124] As used herein, the term "patient" or "subject" refers to a living mammalian organism, such as a human, monkey, cow, sheep, goat, dog, cat, mouse, rat, guinea pig, 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 compounds, ingredients, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues, organs, and / or body fluids of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0126] "Pharmaceutically acceptable salts" refers to salts of the compounds disclosed herein that are pharmaceutically acceptable as defined above and have the desired pharmacological activity. These salts include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or salts with 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, glucoheptone, etc. Pharmaceutically acceptable salts include acid addition salts formed with organic acids such as 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, and trimethylacetic acid. Pharmaceutically acceptable salts also include base addition salts that can be formed when acidic protons present are capable of reacting with inorganic or organic bases. 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 particular anion or cation forming a part of any salt of the present disclosure is not critical, so long as the salt, as a whole, is pharmacologically acceptable. Further examples of pharmaceutically acceptable salts and their methods of preparation and use are provided in Handbook of Pharmaceutical Salts: Properties, and Use (PH Stahl & CG Wermuth eds., Verlag Helvetica Chimica Acta, 2002).

[0127] A "pharmaceutically acceptable carrier," "drug carrier," or simply "carrier" refers to a pharmaceutically acceptable substance formulated with an active drug that is involved in carrying, delivering, and / or transporting a chemical agent. Drug carriers can be used to improve drug delivery and efficacy, including, for example, controlled-release technologies that regulate drug bioavailability, reduce drug metabolism, and / or reduce drug toxicity. Some drug carriers can increase the effectiveness of drug delivery to specific target sites. 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] A "pharmaceutical product" (also known as a pharmaceutical product, pharmaceutical preparation, pharmaceutical composition, pharmaceutical formulation, pharmaceutical product, medicinal product, medicament, drug, pharmaceutical product, or simply drug, agent, or preparation) is a composition used to diagnose, cure, treat, or prevent disease that contains an active pharmaceutical ingredient (API) (as defined above) and, optionally, one or more non-active ingredients, also called excipients (as defined above).

[0129] "Prevention" or "preventing" includes (1) inhibiting the onset of a disease in a subject or patient who may be at risk and / or predisposed to the disease, but who has not yet experienced or displayed any or all of the disease's symptoms or symptomology, and / or (2) delaying the onset of a disease's symptoms or symptomology in a subject or patient who may be at risk and / or predisposed to the disease, but who has not yet experienced or displayed any or all of the disease's symptoms or symptomology.

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

[0131] "Stereoisomers" or "optical isomers" are isomers of a given compound in which the same atoms are bonded to other identical atoms but differ in the arrangement of those atoms in three dimensions. "Enantiomers" are stereoisomers of a given compound that are mirror images of each other, like left and right hands. "Diastereomers" are stereoisomers of a given compound that are not enantiomers. Chiral molecules contain a chiral center, also called a stereogenic center or asymmetric center; a chiral center is any point, but not necessarily an atom, in a molecule bearing groups where the interchange of any two groups gives rise to a stereoisomer. Typically, in organic compounds, the chiral center is a carbon, phosphorus, or sulfur atom, although other atoms can be stereogenic centers in organic and inorganic compounds. A molecule can have multiple stereogenic centers, resulting in many stereoisomers. For compounds whose stereoisomerism derives from a tetrahedral asymmetric center (e.g., a tetrahedral carbon), the total number of hypothetical possible stereoisomers is 2. nwhere n is the number of tetrahedral stereocenters. Often, molecules with symmetry have fewer than the maximum possible number of stereoisomers. 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 greater than 50%. Typically, enantiomers and / or diastereomers can be resolved or separated using techniques known in the art. For any stereocenter or chirality axis with undefined stereochemical configuration, it is assumed that the stereocenter or chirality axis may exist 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 of another stereoisomer, more preferably 10% or less, even more preferably 5% or less, and most preferably 1% or less.

[0132] "Treatment" or "treating" includes (1) inhibiting a disease (e.g., halting further development of the pathology and / or symptomology) in a subject or patient experiencing or exhibiting the pathology or symptomology of the disease, (2) ameliorating a disease (e.g., reversing the pathology and / or symptomology) in a subject or patient experiencing or exhibiting the pathology or symptomology of the disease, and / or (3) effecting any measurable diminution of the disease or its symptoms in a subject or patient experiencing or exhibiting the pathology or symptomology of the disease.

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

[0134] The above definitions supersede any conflicting definitions in any reference incorporated herein by reference. However, the fact that certain terms are defined should not be construed as indicating that any undefined term is indefinite. Rather, all terms used are intended to describe the invention in terms that will enable one of ordinary skill in the art to appreciate the scope and practice the invention. [Example]

[0135] VII. Working Examples The following examples are included to demonstrate preferred embodiments of the invention. Those of skill in the art should appreciate that the techniques disclosed in the examples which follow represent techniques discovered by the inventors to function well in the practice of the invention, and as such can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.

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

[0137] B. Synthetic Routes to Compounds of the Present Disclosure Scheme 1 TIFF2025131767000069.tif22992Reagents and conditions: a) DIBAL-H, toluene, THF, 0°C to room temperature; b) NMO, TPAP, 4Å 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 TIFF2025131767000070.tif23889Reagents 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 TIFF2025131767000071.tif23578Reagents 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 TIFF2025131767000072.tif24078 Reagents 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 TIFF2025131767000073.tif23484 Reagents 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 TIFF2025131767000074.tif24084 Reagents and conditions: a) 3-acetoxypropanoic acid, EDC·HCl, DMAP, CH2Cl2, room temperature, 66%; b) AcOH, 100°C, 55%; c) NaOMe, MeOH, 55°C, 51% 22, 45% 23; d) DBDMH, DMF, 0°C; Py, 60°C, 86% T5; 83% T6.

[0143] Scheme 7 TIFF2025131767000075.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, 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, CHCl2, 0°C, 71%.

[0144] Scheme 8 TIFF2025131767000076.tif158128Reagents and conditions: a) Trimethyloxonium tetrafluoroborate, proton sponge, CH2Cl2, room temperature, 43%.

[0145] Scheme 9 TIFF2025131767000077.tif23776 Reagents and Conditions: a) 1-fluoro-2-iodoethane, Cs2CO3, MeCN, 60°C, 52%; b) HCO2Et, NaOMe, MeOH, 0°C to room temperature; 6N aqueous HCl, NH2OH·HCl, EtOH, 55°C, 71%; c) O3 / O2, MeOH, CHCl2, -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 TIFF2025131767000078.tif21394 Reagents and conditions: a) (COCl)2, DMF, CH2Cl2, 0°C–RT; b) hydrazine hydrate, CH2Cl2, 0°C–RT, 90%; c) 2-fluoroacetic acid, EDC·HCl, DMAP, CH2Cl2, RT, 60%; d) TsOH·H2O, toluene, reflux, 60%.

[0147] Scheme 11 TIFF2025131767000079.tif24037Reagents and conditions: a) Et3N, CH2Cl2, 0°C to room temperature, 84%; b) T3P, Et3N, EtOAc, 125°C, microwave, 6%.

[0148] Scheme 12 TIFF2025131767000080.tif23442Reagents and conditions: a) 3-hydroxypropionamidoxime, Et3N, CH2Cl2, room temperature, 34 to 46%; b) Bu4NOH, water, THF, room temperature, 45%; c) 12N aqueous HCl, AcOH, 75°C, 44%.

[0149] Scheme 13 TIFF2025131767000081.tif23941Reagents and conditions: a) 3-methoxypropionamidoxime hydrochloride, Et3N, CH2Cl2, room temperature; b) Bu4NOH, water, THF, room temperature, 37% from 34.

[0150] Scheme 14 TIFF2025131767000082.tif22089Reagents and conditions: a) NH2OH·HCl, Et3N, EtOH, 80°C; b) 35, Et3N, CH2Cl2, room temperature; c) Bu4NOH, water, THF, room temperature, 45% of 34; d) 12M aqueous HCl, MeOH, room temperature, 83%.

[0151] Scheme 15 TIFF2025131767000083.tif19245Reagents and conditions: a) methyl chloroformate, Et3N, CH2Cl2, room temperature, 20% T17; b) ethyl isocyanate, Et3N, CH2Cl2, room temperature, 67% T18; c) acetyl chloride, Et3N, CH2Cl2, room temperature, 33% T19.

[0152] Scheme 16 TIFF2025131767000084.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 TIFF2025131767000085.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 TIFF2025131767000086.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 TIFF2025131767000087.tif23943Reagents and conditions: a) propionamidoxime, Et3N, CH2Cl2, room temperature; b) Bu4NOH, water, THF, room temperature, 34 to 36%.

[0156] Scheme 20 TIFF2025131767000088.tif237103 Reagents and conditions: a) propionyl chloride, Et3N, CH2Cl2, 0°C, 89% 52a; 82% 52b; b) AcOH, 100°C, 77% 53a; 72% 53b; c) NaOMe, MeOH, 55°C, 97% 54a; 89% 54b; d) DBDMH, DMF, 0°C; Py, 55-60°C, 76% T24; 76% T25.

[0157] Scheme 21 TIFF2025131767000089.tif237101 Reagents and conditions: a) RC(NH)NHOH, E3N, CH2Cl2, room temperature; b) Bu4NOH, water, THF, yields from 35: T26 47%; T27 57%; T28 52%; T29 36%; T30 52%; T31 36%; T32 16%; T33 56%.

[0158] Scheme 22 TIFF2025131767000090.tif24176 Reagents and conditions: a) oxalyl chloride, DMF, CHCl, room temperature; b) 2-fluoro-N-hydroxyethanimidamide, EtN, room temperature, 56-87%; c) o-xylene, 180°C, 49%; d) HC0Et, NaOMe, MeOH, 0°C-room temperature; 12M aqueous HCl, NHOH·HCl, EtOH, H0, 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 TIFF2025131767000091.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 TIFF2025131767000092.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 TIFF2025131767000093.tif22039Reagents and conditions: a) N'-hydroxypropanimidamide, Et3N, CH2Cl2, room temperature; b) tetrabutylammonium hydroxide, H2O, THF, room temperature, 48% from 63.

[0162] Scheme 26 TIFF2025131767000094.tif24032Reagents and conditions: a) hydrazine hydrate, CH2Cl2, 0°C–RT, 85%; b) 2-fluoroacetic acid, EDC·HCl, DMAP, CH2Cl2, RT, 29%; c) TsOH·H2O, toluene, reflux, 48%.

[0163] Scheme 27 TIFF2025131767000095.tif23873 Reagents and conditions: a) NH2OH-HCl, NaOAc, EtOH, H2O, room temperature, 93%; b) aqueous HCl, NCS, MeCN, -10°C; aqueous NH3, room temperature, 51%; c) 2-fluoroacetic acid, EDC·HCl, DMAP, CHCl, room temperature, 38%; d) 1,4-dioxane, 100°C, 79%; e) NaOMe, MeOH, 55°C, 85%; f) DBDMH, DMF, 0°C; Py, 60°C, 70%.

[0164] Scheme 28 TIFF2025131767000096.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 TIFF2025131767000097.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 TIFF2025131767000098.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 TIFF2025131767000099.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 TIFF2025131767000100.tif23739Reagents and conditions: a) difluoroacetic anhydride, pyridine, CH2Cl2, 0°C to room temperature, 79%; b) TsOH·H2O, toluene, reflux temperature, 31%.

[0169] Scheme 33 TIFF2025131767000101.tif23540Reagents and conditions: a) (CF3CO)2O, pyridine, CH2Cl2, 40°C, 84%; b) Burgess reagent, THF, reflux temperature, 54%.

[0170] Scheme 34 TIFF2025131767000102.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) TIFF2025131767000103.tif24177 Reagents and conditions: a) oxalyl chloride, DMF, CHCl, 0°C to room temperature; b) 2-fluoro-N-hydroxyethanimidamide, EtN, room temperature, 85-89%; (c) Tp, EtN, o-xylene, 36%; d) HC0Et, NaOMe, MeOH, 0°C to room temperature; 6M aqueous HCl, NHOH·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 Data compound 2 A solution of compound 1 (10.00 g, 19.71 mmol) in THF (200 mL) was cooled to 0 °C under N. DIBAL-H (1.0 M in toluene, 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 was cooled to 0 °C and carefully quenched with water (20 mL), followed by the addition of 1N aqueous HCl (300 mL). The mixture was extracted with EtOAc (4 × 150 mL). The combined organic extracts were washed with water (100 mL) and brine (100 mL), dried over NaSO, 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, <19.71 mmol) was dissolved in CHCl (200 mL). 4Å MS (20 g) and 4-methylmorpholine N-oxide (5.10 g, 43.53 mmol) were added. The mixture was stirred at room temperature for 10 minutes under N. TPAP (690 mg, 1.96 mmol) was added. The mixture was stirred at room temperature for 1.5 hours and then quenched with 10% NaSO (50 mL). The mixture was stirred at room temperature for 5 minutes and then filtered through a pad of Celite. The Celite was eluted with CHCl (50 mL). The organic phase from the filtrate was separated. The aqueous phase from the filtrate was extracted with CHCl (2 x 50 mL) and EtOAc (2 x 50 mL). The combined organic extracts were washed with water (100 mL), dried over NaSO, filtered through a pad of silica gel, and eluted with EtOAc (100 mL). The filtrate was concentrated, and the residue was purified by column chromatography (silica gel, eluted 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), NHOH-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. The mixture was stirred at room temperature for 14 h and then 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 NaSO, filtered, and concentrated. The residue contained a small amount of AcOH and water. EtOH (10 mL) and toluene (10 mL) were added, and the mixture was concentrated. The residue was triturated with CHCl (30 mL) at reflux for 10 min. After cooling to room temperature, the mixture was kept at room temperature for 30 min. The precipitated solid was collected by filtration, washed with CH2Cl2 (2 x 5 mL), and dried under vacuum to give compound 4 (2.15 g, 77% yield) as a white solid, m / z = 493 (M+1).

[0175] compound 5 Compound 4 (2.68 g, 5.44 mmol) was suspended in MeCN (11 mL) under N2 and cooled to -10 °C. Aqueous HCl (12 N, 91 μL, 1.09 mmol) was added, followed by a solution of N-chlorosuccinimide (726 mg, 5.44 mmol) in MeCN (11 mL). The reaction was stirred at -10 °C for 30 min. LCMS showed that the starting material was nearly all consumed. Aqueous ammonia (28%, 3.7 mL, 54.4 mmol) was added. The mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with EtOAc (100 mL) and washed with water (2 x 40 mL). The combined aqueous washes 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, eluted 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 N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC·HCl, 57 mg, 0.30 mmol) was added to a solution of 2-fluoroacetic acid (23 mg, 0.30 mmol) in CHCl (1 mL) at room temperature under N. A catalytic amount of DMAP (1.8 mg, 0.015 mmol) was added. The mixture was stirred at room temperature for 15 min. A solution of compound 5 (50 mg, 0.098 mmol) in CHCl (2 mL) was added. The mixture was stirred at room temperature for 1 h. The mixture was diluted with CHCl (20 mL) and washed with water (2 × 10 mL). The combined aqueous washes were extracted with CHCl (20 mL). The combined organic extracts were dried over NaSO, 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, eluted with 0–50% EtOAc in CHCl) 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, eluted with 0-30% EtOAc in hexanes) 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) under N was added NaOMe (4.37 M in MeOH, 43 μL, 0.19 mmol). The mixture was heated at 55 °C for 1 h and then cooled to 0 °C. The mixture was diluted with 10% aqueous NaHPO (15 mL) and extracted with EtOAc (2 × 15 mL). The combined organic extracts were dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted 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 Compound 8 (46 mg, 0.084 mmol) was dissolved in anhydrous DMF (0.4 mL) under N2 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 sequentially with 1 N aqueous HCl (10 mL) and water (2 × 15 mL). The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0–35% EtOAc in hexane) to give compound T1 (36 mg, 79% yield) as a white solid. TIFF2025131767000104.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 CHCl (4 mL) was treated with DMAP (4.8 mg, 0.039 mmol). The mixture was stirred at room temperature under N for 15 min. A solution of compound 5 (200 mg, 0.39 mmol) in CHCl (4 mL) was added. The mixture was stirred at room temperature for 1 h. Water (15 mL) was added. The mixture was extracted with CHCl (3 × 15 mL). The combined organic extracts were dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0–40% EtOAc in CHCl) 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) was heated at 160 °C for 100 min in a pressure vessel. 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 hexanes) 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 at room temperature for 14 h. LCMS showed 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, eluted 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 Compound 11 (140 mg, 0.22 mmol) was dissolved in anhydrous DMF (1.1 mL) under N2 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 sequentially with 1 N aqueous HCl (10 mL) and water (3 × 15 mL). The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0–60% EtOAc in hexane) to give compound 12 (126 mg, 90% yield) as a white solid. m / z = 589 (M-C4H7).

[0184] T2 A solution of compound 12 (113 mg, 0.18 mmol) in CHCl (1.8 mL) was treated with TFA (135 μL, 1.75 mmol) at room temperature under N. After stirring at room temperature for 5 h, saturated aqueous NaHCO (15 mL) was added. The mixture was extracted with CHCl (3 × 15 mL). The combined organic extracts were dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0–20% MeOH in CHCl) to give compound T2 (47 mg, 49% yield) as a yellow foam. TIFF2025131767000105.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 CHCl (3 mL) was added DMAP (5 mg, 0.04 mmol) at room temperature under N. The mixture was stirred at room temperature for 15 min. A solution of compound 5 (150 mg, 0.30 mmol) in CHCl (3 mL) was added. The mixture was stirred at room temperature for 1 h and then treated with water (15 mL). The mixture was extracted with CHCl (3 × 15 mL). The combined organic extracts were dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted 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 h. The mixture was cooled to room temperature and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0 to 55% EtOAc in hexanes) 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 h. 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, eluted 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 (10 mL) and water (3 × 15 mL). The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted 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 CHCl (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 NaHCO (15 mL). The mixture was extracted with CHCl (3 × 15 mL). The combined organic extracts were dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0–20% MeOH in CHCl) to give compound T3 (56 mg, 78% yield) as a yellow solid. TIFF2025131767000106.tif26156

[0190] compound 17 A solution of compound 5 (100 mg, 0.20 mmol) in CHCl (1 mL) was cooled to 0 °C. A solution of EtN (55 μL, 0.39 mmol) in CHCl (0.5 mL) and a solution of acetoxyacetyl chloride (40 mg, 0.30 mmol) in CHCl (0.5 mL) were added sequentially. The mixture was stirred at 0 °C for 1 h and then treated with saturated aqueous NaHCO (5 mL). The mixture was stirred for 5 min and then extracted with CHCl (3 × 10 mL). The combined organic extracts were dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0–60% EtOAc in hexanes) 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, eluted with 0-50% EtOAc in hexanes) 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 in MeOH, 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, eluted with 0-70% EtOAc in hexanes) 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 N. The mixture was stirred at 0 °C for 2 h and then 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 (10 mL) and water (2 × 15 mL). The organic extract was dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0–70% EtOAc in hexane) to give compound T4 (67 mg, 82% yield) as a white solid. TIFF2025131767000107.tif25155

[0194] compound 20 A solution of 3-acetoxypropanoic acid (78 mg, 0.59 mmol) in CHCl (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 CHCl (2 mL) was added. The mixture was stirred at room temperature for 1 h. Saturated aqueous NaHCO (3 mL) and water (10 mL) were added. The mixture was diluted with CHCl (20 mL) and EtOAc (2 × 20 mL). The combined organic extracts were dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted 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, eluted with 0-50% EtOAc in hexanes) 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 with NaOMe (4.37 M in MeOH, 45 μL, 0.20 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 × 20 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0–70% EtOAc in hexanes) 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 sequentially with 1 N aqueous HCl (10 mL) and water (2 × 15 mL). The organic extract was dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0–70% EtOAc in hexane) to give compound T5 (16 mg, 86% yield) as a white solid. TIFF2025131767000108.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 h and then treated with pyridine (9.5 μL, 0.12 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 sequentially with 1 N aqueous HCl (10 mL) and water (2 × 15 mL). The organic extract was dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0–70% EtOAc in hexane) to give compound T6 (14 mg, 83% yield) as a white solid. TIFF2025131767000109.tif26156

[0199] compound 25 To a mixture of compound 24 (1.366 g, 3.04 mmol) in o-xylene (5 mL) was added azidotributyltin(IV) (1.00 mL, 3.65 mmol). The mixture was heated at 150 °C for 48 h. The crude reaction mixture was purified by column chromatography (silica gel, eluting with 0-60% acetone in hexanes) to give partially purified compound 25, which was purified again by column chromatography (silica gel, eluting with 0-100% EtOAc in hexanes) 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, after which 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 and the crude product obtained from compound 25 (50 mg, 0.10 mmol) were combined and purified by column chromatography (silica gel, eluting with 0–50% acetone in hexanes) 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) under N2 was cooled to 0 °C and treated dropwise with 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 6 N 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, eluted with 0–100% EtOAc in hexanes) 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) under N was added NaOMe (4.37 M in MeOH, 0.14 mL, 0.61 mmol). The mixture was heated at 55 °C for 1 h and then cooled to room temperature. The mixture was diluted with 10% aqueous NaHPO and extracted twice with EtOAc. The combined organic extracts were dried over NaSO, filtered, and concentrated to give compound 28 (180 mg, quantitative yield) as a white solid. m / z = 562 (M+1).

[0203] T7 Compound 28 (180 mg, 0.30 mmol) was dissolved in anhydrous DMF (1 mL) under N2 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 h. Pyridine (72 μL, 0.89 mmol) was added. The mixture was heated at 55 °C for 16 h and then cooled to room temperature. The mixture was diluted with EtOAc and washed sequentially 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, eluted with 0–70% EtOAc in hexane) to give compound T7 (114 mg, 68% yield) as a white solid. TIFF2025131767000110.tif32156

[0204] T8 A solution of compound T7 (30 mg, 0.054 mmol) in CHCl (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 sequentially. The mixture was stirred at 0 °C for 2.5 h and diluted with toluene (5 mL). The mixture was concentrated. The residue was purified by column chromatography (silica gel, eluted with 0–45% EtOAc in hexane) to give compound T8 (23 mg, 71% yield) as a white solid. TIFF2025131767000111.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 CHCl (1.2 mL) was stirred at room temperature for 16 h. The reaction was quenched with saturated aqueous NaHCO, stirred for 5 min, and extracted with EtOAc. The organic extract was washed sequentially with water, 1N aqueous HCl, and water, dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0–80% EtOAc in hexanes) to give compound T9 (32 mg, 43% yield) as a white solid. TIFF2025131767000112.tif25155

[0206] compound 29 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) in a vial. 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 Celite pad. The filter cake was washed with EtOAc. The combined filtrate and washings were concentrated. The residue and the crude product obtained from compound 25 (50 mg, 0.10 mmol) were combined and purified by column chromatography (silica gel, eluting with 0–50% EtOAc in hexanes) to give compound 29 (142 mg, 52% yield) as a light 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) under N2 was cooled to 0 °C and treated dropwise with 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, eluted 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 CHCl (1 mL) and cooled to −78 °C. Ozone was bubbled through the reaction mixture until the starting material was completely consumed (approximately 10 min). Oxygen was bubbled through for 5 min. NaBH (15 mg, 0.40 mmol) was added. The cooling bath was removed. The mixture was stirred at room temperature for 3 h, diluted with EtOAc, and washed with 1N aqueous HCl and water. The aqueous washes were combined and extracted with EtOAc. The combined organic extracts were dried over NaSO, 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 CsCO (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 under N for 6 h. After cooling to room temperature, the mixture was diluted with EtOAc and washed sequentially with 1 N aqueous HCl, 10% aqueous NaSO, and water. The organic extract was dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted 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, eluted 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 sequentially 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, eluted with 0–50% EtOAc in hexane) to give compound T10 (34 mg, 71% yield) as a white solid. TIFF2025131767000113.tif25156

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

[0213] compound 36 A solution of compound 35 (200 mg, 0.39 mmol) in CHCl (4 mL) was cooled to 0 °C under N. Hydrazine hydrate (50 wt%, 75 mg, 1.18 mmol) was added dropwise. The mixture was stirred at room temperature for 10 min, diluted with CHCl (10 mL), and washed with water (15 mL). The aqueous washes were extracted with CHCl (2 × 15 mL) and EtOAc (15 mL). The combined organic extracts were dried over NaSO, filtered, and concentrated to give compound 36 (179 mg, 90% yield) as a glass.

[0214] compound 37 A solution of 2-fluoroacetic acid (67 mg, 0.86 mmol) in CHCl (1 mL) was treated with EDC·HCl (164 mg, 0.85 mmol) and DMAP (3.5 mg, 0.028 mmol) at room temperature under N. The mixture was stirred at room temperature for 15 min. Then, a solution of compound 36 (144 mg, 0.29 mmol) in CHCl (2 mL) was added. The mixture was stirred at room temperature for 14 h. The reaction mixture was washed with saturated aqueous NaHCO (10 mL) and water (10 mL). The aqueous phase was extracted with CHCl (2 × 10 mL). The combined organic extracts were dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0–60% EtOAc in CHCl) to give compound 37 (96 mg, 60% yield) as a pink solid. m / z = 566 (M+1).

[0215] T11 A solution of compound 37 (115 mg, 0.20 mmol) and p-toluenesulfonic acid monohydrate (19 mg, 0.10 mmol) in toluene (10 mL) was heated at reflux for 3 h 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 Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0-40% acetone in hexane) to give compound T11 (67 mg, 60% yield) as a white solid. TIFF2025131767000114.tif26156

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

[0217] T12 A mixture of compound 39 (148 mg, 0.26 mmol), T3P (50 wt% in EtOAc, 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 h in a Biotage microwave synthesizer. After cooling to room temperature, the mixture was diluted with EtOAc (20 mL) and washed sequentially with 1 N 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, eluted with 0–80% EtOAc in hexane) to give compound T12 (9 mg, 6% yield) as a white solid. TIFF2025131767000115.tif26156

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

[0219] compound 40 A stock solution of compound 35 and EtN in CHCl [12.5 mL, containing compound 35 (2.29 mmol) and trimethylamine (9.19 mmol)] was treated with 3-hydroxypropionamidoxime (347 mg, 3.33 mmol). The mixture was stirred at room temperature overnight. The resulting mixture was diluted with EtOAc and washed with water, saturated aqueous NaHCO, and brine. The organic extract was dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0–10% MeOH in CHCl) 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 N. The resulting mixture was diluted with EtOAc and washed with water, saturated aqueous NaHCO, and brine. The organic extract was dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0–100% EtOAc in hexanes) to give compound T13 (265.5 mg, 45% yield) as a white solid. TIFF2025131767000116.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 under N at 75 °C for 20 h. 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 hexanes) to give compound T14 (48.0 mg, 44% yield) as a white solid. TIFF2025131767000117.tif25155

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

[0223] T15 A mixture of compound 41 and compound 34 (1.22 g, ca. 2.5:1 to 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 N. The resulting mixture was diluted with EtOAc and washed with water, saturated aqueous NaHCO, and brine. The organic extract was dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0–100% EtOAc in hexanes) to give compound T15 (494.7 mg, 37% yield from compound 34) as a white solid. TIFF2025131767000118.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 with stirring in a sealed tube for 2 days. The resulting solution was diluted with EtOAc (300 mL) and washed with water / saturated aqueous NaHCO (1:1, 100 mL) and brine (25 mL). The organic extract was dried over NaSO, filtered, and concentrated to give 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 A mixture of compound 35 [synthesized from compound 34 (1.08 g, 2.20 mmol)], impure compound 42 (73:27 - Int4:N-tert-butoxycarbonyl-3-aminopropionitrile, 773.4 mg), and triethylamine (1.23 mL, 8.83 mmol) in CHCl (18 mL) was stirred at room temperature for 2 h. The resulting mixture was diluted with EtOAc (100 mL) and washed with water (25 mL), saturated aqueous NaHCO (25 mL), and brine (25 mL). The organic extract was dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0–10% MeOH in CHCl) to give a mixture of compounds 43 and 34 (1.01 g, ca. 4:1–43:34) as a solid, which was used without further purification.

[0226] compound 44 A solution of impure compound 43 (ca. 4:1 to 43:34, 904 mg, ca. 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 under N for 5 h. The resulting mixture was diluted with EtOAc (200 mL) and washed with water (50 mL), saturated aqueous NaHCO (50 mL), and brine (50 mL). The organic extract was dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0–100% EtOAc in hexanes) 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 NaHCO (25 mL). The organic extract was dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0–10% MeOH in CHCl) to give compound T16 (43.1 mg, 83% yield) as an off-white solid. TIFF2025131767000119.tif25156

[0228] T17 To a solution of compound T16 (51.7 mg, 0.0926 mmol) and triethylamine (42 μL, 0.301 mmol) in CHCl (1 mL) was added methyl chloroformate (12 μL, 0.16 mmol) and stirred at room temperature for 2 h. Additional methyl chloroformate (30 μL, 0.39 mmol) was added and stirring continued overnight. The mixture was diluted with CHCl (35 mL) and washed with HCl (1 M aqueous solution, 15 mL) and brine (15 mL). The organic extract was dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0–100% EtOAc in hexanes) to give compound T17 (11.6 mg, 20% yield) as a white solid. TIFF2025131767000120.tif25166

[0229] T18 To a solution of compound T16 (55.8 mg, 0.0999 mmol) and triethylamine (0.14 mL, 1.0 mmol) in CHCl (1 mL), ethyl isocyanate (8 μL, 0.101 mmol) was added and stirred at room temperature for 1 h. The resulting mixture was diluted with CHCl (35 mL) and washed with HCl (1 M aqueous solution, 15 mL) and brine (15 mL). The organic extract was dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0–100% EtOAc in hexane) to give compound T18 (42.1 mg, 67% yield) as a white solid. TIFF2025131767000121.tif32165

[0230] T19 To a solution of compound T16 (45.7 mg, 0.0818 mmol) and triethylamine (0.11 mL, 0.79 mmol) in CHCl (1 mL) was added acetyl chloride (0.15 mL, 2.1 mmol), and the mixture was stirred at room temperature for 15 min. 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 NaSO, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0–15% MeOH in CHCl) to give compound T19 (16.3 mg, 33% yield) as a white solid. TIFF2025131767000122.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 min and then heated at 100°C for 2 h. The mixture was cooled to room temperature, diluted with toluene (10 mL), and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0-40% EtOAc in hexane) to give compound 45 (40 mg, 95% yield) 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 under N2 at room temperature for 14 h, 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 and the crude product obtained from compound 46 (16 mg, 0.030 mmol) were combined and purified by column chromatography (silica gel, eluted with 0-40% EtOAc in hexanes) 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 N. The mixture was stirred at 0 °C for 1 h and treated with pyridine (20 μL, 0.25 mmol). The mixture was 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 × 15 mL). The organic extract was dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0–35% EtOAc in hexane) to give compound T20 (34 mg, 78% yield) as a white solid. TIFF2025131767000123.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 in hexane, 183 μL, 0.366 mmol) was added. The mixture was stirred at 0 °C for 20 min, quenched with acetic acid, diluted with toluene, and concentrated. The residue and the crude product obtained from compound 25 (50 mg, 0.10 mmol) were combined 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 dropwise with sodium methoxide solution (4.37 M in methanol, 0.62 mL, 2.71 mmol). The reaction mixture was stirred at 0 °C for 1 h and then treated with 6 N 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 h, 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, eluted with 0–50% EtOAc in hexanes) 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 in MeOH, 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, eluted 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 Compound 49 (84 mg, 0.16 mmol) was dissolved in anhydrous DMF (0.4 mL) under N2 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 sequentially 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, eluted with 0–50% EtOAc in hexane) to give compound T21 (65 mg, 78% yield) as a white solid. TIFF2025131767000124.tif32156

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

[0239] compound 50 To a stock solution of compound 35 and EtN in CHCl [26.1 mL, containing compound 35 (2.95 mmol) and EtN (11.8 mmol)], 2,2,2-trifluoro-N'-hydroxy-ethanimidamide (229.2 mg, 1.79 mmol) was added, and the mixture was stirred at room temperature overnight. The resulting mixture was diluted with EtOAc and washed with water, saturated aqueous NaHCO, and brine. The organic extract was dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0–10% MeOH in CHCl) 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 N. The resulting mixture was diluted with EtOAc and washed with water, saturated aqueous NaHCO, and brine. The organic extract was dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0–100% EtOAc in hexanes) to give compound T22 (63.3 mg, 10% yield from compound 34) as a white solid. TIFF2025131767000125.tif33156

[0241] compound 51 To a stock solution of compound 35 and EtN in CHCl [30 mL, containing compound 35 (3.38 mmol) and EtN (13.5 mmol)], propionamide oxime (250 mg, 2.84 mmol) was added, and the mixture was stirred at room temperature overnight. The resulting mixture was diluted with EtOAc and washed with water, saturated aqueous NaHCO, and brine. The organic extract was dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0–10% MeOH in CHCl) 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 overnight at room temperature under N. The resulting mixture was diluted with EtOAc and washed with water, saturated aqueous NaHCO, and brine. The organic extract was dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0–100% EtOAc in hexanes) to give compound T23 (209.9 mg, 36% yield from compound 34) as a white solid. TIFF2025131767000126.tif32156

[0243] Compound 52a A solution of compound 5 (84 mg, 0.17 mmol) in CHCl (6 mL) was cooled to 0 °C. EtN (46 μL, 0.33 mmol) and a solution of propionyl chloride (23 mg, 0.25 mmol) in CHCl (1 mL) were added sequentially. After stirring at 0 °C for 1 h, the mixture was treated with saturated aqueous NaHCO (5 mL). After stirring for 5 min, the mixture was extracted with CHCl (3 × 10 mL). The combined organic extracts were dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0–60% EtOAc in hexanes) 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, eluted with 0-40% EtOAc in hexanes) 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% in MeOH, 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, eluted with 0 to 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) at 0 °C under N. 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 1 N aqueous HCl (10 mL) and water (2 × 15 mL). The organic extract was dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0–45% EtOAc in hexane) to give compound T24 (49 mg, 76% yield) as a white solid. TIFF2025131767000127.tif25155

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

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

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

[0250] T25 Compound T25 (white solid, 44 mg, 76% yield) was synthesized from compound 54b (58 mg, 0.10 mmol) using the same procedure as described for the synthesis of compound T24. TIFF2025131767000128.tif18155

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

[0252] T26 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) using the same procedure as described for the synthesis of compound T23. TIFF2025131767000129.tif25165

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

[0254] T27 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) using the same procedure as described for the synthesis of compound T23. TIFF2025131767000130.tif25165

[0255] compound 55c 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) using the same procedure as described for the synthesis of compound 51. m / z = 590 (M+1).

[0256] T28 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) using the same procedure as described for the synthesis of compound T23. TIFF2025131767000131.tif18165

[0257] compound 55d 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) using the same procedure as described for the synthesis of compound 51. m / z = 574 (M+1).

[0258] T29 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) using the same procedure as described for the synthesis of compound T23. TIFF2025131767000132.tif26156

[0259] compound 55e 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) using the same procedure as described for the synthesis of compound 51. m / z = 588 (M+1).

[0260] T30 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) using the same procedure as described for the synthesis of compound T23. TIFF2025131767000133.tif25166

[0261] compound 55f 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) using the same procedure as described for the synthesis of compound 51. m / z = 588 (M+1).

[0262] T31 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) using the same procedure as described for the synthesis of compound T23. TIFF2025131767000134.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 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) using the same procedure as described for the synthesis of compound T23. TIFF2025131767000135.tif18155

[0265] compound 55h 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) using the same procedure as described for the synthesis of compound 51. m / z = 616 (M+1).

[0266] T33 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) using the same procedure as described for the synthesis of compound T23. TIFF2025131767000136.tif18165

[0267] compound 58 A solution of compound 56 (0.86 g, 1.9 mmol) in CHCl (19 mL) was treated sequentially with oxalyl chloride (0.5 mL, 5.7 mmol) and DMF (15 μL, 0.19 mmol) at 0 °C. The reaction was stirred at room temperature for 2 h and then concentrated. The residue was dissolved in toluene (3 × 20 mL) and concentrated to give compound 57 as a yellow solid. Compound 57 was dissolved in CHCl (25 mL) and cooled to 0 °C. EtN (1.1 mL, 7.6 mmol) was added, followed by 2-fluoro-N-hydroxyethanimidamide (0.26 g, 2.8 mmol). The reaction was stirred at room temperature for 2 h. The reaction mixture was then concentrated and partitioned between EtOAc (30 mL) and water (20 mL). The layers were separated, and the organic layer was washed with water (2 × 20 mL). The aqueous washes were extracted with EtOAc (20 mL). The combined organic extracts were washed with brine (20 mL), dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0-100% EtOAc in CHCl) 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 mixture 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 hexanes) 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 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 × 20 mL) and saturated aqueous NaHCO3 (20 mL). The aqueous washes 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 hexanes) to give compound 60 (265 mg, quantitative yield) as an off-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% in MeOH, 226 μL, 0.99 mmol) at room temperature. The reaction was heated at 55 °C for 1.5 h and then cooled to 0 °C. 10% aqueous NaH2PO4 (10 mL) was added, and the mixture was extracted with EtOAc (2 × 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, eluted with 0–100% EtOAc in hexanes) 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. Pyridine (98 μL, 1.21 mmol) was then added. The reaction was heated at 60 °C for 4 h. After cooling to room temperature, the mixture was diluted with EtOAc (20 mL) and washed with 1 N aqueous HCl (10 mL), water (2 × 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, eluted with 0–100% EtOAc in hexanes) to give compound T34 (168 mg, 78% yield) as a white solid. TIFF2025131767000137.tif32155

[0272] compound 62 A solution of compound 56 (500 mg, 1.02 mmol) in CHCl (14 mL) was treated sequentially with oxalyl chloride (275 μL, 3.14 mmol) and N,N-dimethylformamide (8 μL, 0.1 mmol) at 0 °C. The reaction was stirred at room temperature for 2 hours and then concentrated. The residue was dissolved in toluene (3 × 20 mL) and concentrated to give the acid chloride as a yellow solid. The acid chloride was dissolved in CHCl (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 was stirred at room temperature overnight. LC-MS indicated the reaction was complete. The reaction was concentrated, and the residue was partitioned between ethyl acetate (20 mL) and saturated aqueous NaHCO (10 mL). The organic layer was separated and washed with saturated aqueous NaHCO3 (10 mL). The combined aqueous washes 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, eluted with 0-100% EtOAc in hexanes) 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 was stirred at room temperature overnight. LC-MS showed 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 × 10 mL). The combined aqueous washes were extracted with ethyl acetate (20 mL). The combined organic extracts were washed with brine (20 mL), dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0–100% EtOAc in hexanes) to give compound T35 (15.7 mg, 16% yield). TIFF2025131767000138.tif25156

[0274] compound 63 To a solution of compound 56 (1.21 g, 2.46 mmol) in CHCl (50 mL) was added oxalyl chloride (0.65 mL, 7.43 mmol) and N,N-dimethylformamide (20 μL, 0.26 mmol) sequentially at 0° C. The mixture was stirred at 0° C. for 20 h and then concentrated under reduced pressure to give 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 CHCl (15 mL) was added triethylamine (0.79 mL, 5.67 mmol) slowly at room temperature under N. Then, a solution of 2,2,2-trifluoro-N'-hydroxy-ethanimidamide (181 mg, 1.42 mmol) in CHCl (6 mL) was added dropwise. The reaction mixture was stirred at room temperature for 16 h and then concentrated. The residue was diluted with EtOAc (100 mL). The mixture was washed with saturated aqueous NaHCO (30 mL) and brine (30 mL). The organic extract was dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0–10% MeOH in CHCl) to give 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 under N at room temperature for 20 h. 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 (2 x 20 mL). The combined organic extracts were washed with brine (20 mL), dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0-50% EtOAc in hexanes) to give compound T36 (72.3 mg, 9% yield from compound 63) as a white solid. TIFF2025131767000139.tif26156

[0277] compound 65 To a solution of compound 63 (83% wt, 620 mg, 1.04 mmol) in CHCl (10 mL) was added triethylamine (0.579 mL, 4.15 mmol) slowly at room temperature under N. Next, a solution of N'-hydroxypropanimidamide (92 mg, 1.04 mmol) in CHCl (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 NaHCO (30 mL) and brine (30 mL). The organic extract was dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0–10% MeOH in CHCl) 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 under N at room temperature for 15 h. 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 × 20 mL). The combined organic extracts were washed with brine (20 mL), dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0–50% EtOAc in hexanes) to give compound T37 (267 mg, 48% yield from compound 63) as a white solid. TIFF2025131767000140.tif25156

[0279] compound 66 A solution of compound 65 (260 mg, 0.524 mmol) in CHCl (5 mL) was cooled to 0 °C under N. Hydrazine hydrate (50 wt%, 98 μL, 1.57 mmol) was added dropwise. The mixture was stirred at room temperature for 10 min, diluted with CHCl (10 mL), and washed with water (15 mL). The aqueous washes were extracted with CHCl (3 × 15 mL) and EtOAc (15 mL). The combined organic extracts were dried over MgSO, 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 CHCl (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 N. The mixture was stirred at room temperature for 15 min. Compound 66 (220 mg, 0.45 mmol) was then added, and the mixture was stirred at room temperature for 24 h. The reaction mixture was concentrated, and the residue was purified by column chromatography (silica gel, eluted with 0–60% EtOAc in CHCl) 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 for 5 h 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 × 15 mL). The organic extract was dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with acetone in hexane) to give compound T38 (33 mg, 49% yield) as a white solid. TIFF2025131767000141.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 HO (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 × 20 mL). The combined organic extracts were washed with brine (20 mL), dried over NaSO, 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. 12 N aqueous HCl (30 μL, 0.36 mmol) and a solution of N-chlorosuccinimide (241 mg, 1.80 mmol) in MeCN (9 mL) were added sequentially. The reaction was carried out at -10 °C for 30 min, after which ammonium hydroxide (28 wt% aqueous solution, 3 mL, 21.5 mmol) was added. The reaction 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 × 20 mL). The combined organic extracts were washed with brine (20 mL), dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (silica gel, 0–100% EtOAc in CHCl) to give compound 70 (457 mg, 51% yield). m / z = 494 (M+1).

[0284] compound 71 N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC·HCl, 416 mg, 2.17 mmol) was added to a solution of 2-fluoroacetic acid (169 mg, 2.17 mmol) in CHCl (15 mL) at room temperature under N. A catalytic amount of DMAP (8 mg, 0.072 mmol) was added. The mixture was stirred at room temperature for 15 min. Compound 70 (357 mg, 0.72 mmol) was then added. The mixture was stirred at room temperature for 2 h and then concentrated. The residue was diluted with ethyl acetate (30 mL) and washed with water (2 × 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 NaSO, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0–100% EtOAc in hexanes) 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 under N for 5 h. The mixture was cooled to room temperature and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0-30% EtOAc in hexanes) 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 with NaOMe (25 wt% in MeOH, 135 μL, 0.59 mmol) at room temperature. The reaction was heated at 55 °C for 2.5 h and then cooled to room temperature. 10% aqueous NaH2PO4 (20 mL) was added. The mixture was extracted with ethyl acetate (2 × 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, eluted with 0–40% EtOAc in hexanes) 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 N. 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 h. Pyridine (61 μL, 0.75 mmol) was then added, and the reaction was heated at 60 °C for 4 h. After cooling to room temperature, the mixture was diluted with EtOAc (20 mL) and washed with 1 N aqueous HCl (10 mL), water (2 × 10 mL), and brine (10 mL). The organic extract was dried over MgSO, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0–50% EtOAc in hexanes) to give compound T39 (96 mg, 70% yield) as a white foam. TIFF2025131767000142.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 was stirred at room temperature for 19 h. This reaction mixture was combined with another identical reaction starting with compound 5. The mixture was diluted with EtOAc (40 mL) and washed with saturated aqueous NaHCO3 (2 × 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, eluted with 0–100% EtOAc in hexanes) 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% in MeOH, 100 μL, 0.44 mmol) at room temperature. The reaction was heated at 55 °C for 2 h and then cooled to room temperature. 10% aqueous NaHPO (20 mL) was added, and the mixture was extracted with EtOAc (2 × 30 mL). The combined organic extracts were washed with brine (20 mL), dried over MgSO, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0–40% EtOAc in hexanes) 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 N. 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 was stirred at room temperature for 10 min. Pyridine (45 μL, 0.56 mmol) was then added, and the reaction was heated at 55 °C for 5 h. The mixture was cooled to room temperature, diluted with EtOAc (20 mL), and washed with 1 N aqueous HCl (10 mL), water (2 × 10 mL), and brine (10 mL). The organic extract was dried over MgSO, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0-40% acetone in hexane) to give compound T40 (70 mg, 85% yield) as a white solid. TIFF2025131767000143.tif25156

[0291] compound 76 To a solution of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (170 mg, 0.886 mmol) in CHCl (3 mL) at room temperature, a solution of 2,2-difluoroacetic acid (85 mg, 0.886 mmol) in CHCl (3 mL) and DMAP (3.6 mg, 0.030 mmol) were added sequentially. After stirring the reaction mixture for 15 min, a solution of compound 5 (150 mg, 0.295 mmol) in CHCl (4 mL) was added. The reaction mixture was stirred at room temperature for an additional 19 h. The mixture was then diluted with CHCl (20 mL) and washed with water (15 mL). The aqueous washes were extracted with EtOAc (2 x 15 mL). The combined organic extracts were dried over NaSO, 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% in MeOH, 85.5 μL, 0.373 mmol) at room temperature. The reaction was heated at 55 °C for 2 h and then cooled to room temperature. 10% aqueous NaH2PO4 (20 mL) was added. The mixture was extracted with EtOAc (2 × 20 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0–40% EtOAc in hexanes) 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 h. Pyridine (38 μL, 0.47 mmol) was then added, and the reaction was heated at 55 °C for 5 h. After cooling to room temperature, the mixture was diluted with EtOAc (20 mL) and washed with 1 N aqueous HCl (10 mL), water (2 × 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, eluted with 0–40% EtOAc in hexanes) to give compound T41 (57 mg, 87% yield) as a white solid. TIFF2025131767000144.tif26156

[0294] compound 79 A solution of compound 35 (500 mg, 0.980 mmol) in CHCl (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 h and then washed with water. The aqueous layer was separated and extracted with CHCl. ​​The combined organic extracts were dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted 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 was stirred at room temperature for 11 hours and 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, eluted with 30% EtOAc in hexane) to give compound 80 (258 mg, 61% yield) as an off-white solid. m / z = 602 (M+1).

[0296] T42 A solution of compound 80 (258 mg, 0.428 mmol) in CHCl (10 mL) was treated with trifluoroacetic acid (1 mL, 12.98 mmol) at room temperature. The reaction was stirred for 22 h and then concentrated. The residue was dissolved in toluene and concentrated. The residue was purified by column chromatography (silica gel, eluted with 30–100% EtOAc in hexanes) to give compound T42 (178 mg, 76% yield) as a white solid. TIFF2025131767000145.tif26156

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

[0298] T43 To a solution of compound 81 (136.0 mg, 0.23 mmol) in anhydrous THF (10 mL) was added tetrabutylammonium fluoride (1.0 M in THF, 0.70 mL, 0.70 mmol) at room temperature under N. The mixture was stirred at reflux 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 × 30 mL). The combined organic extracts were washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0–50% acetone in CHCl) to give T43 (73 mg, 55% yield) as a solid. TIFF2025131767000146.tif25156

[0299] compound 82 To a solution of compound 36 (0.19 g, 0.38 mmol) and pyridine (46 μL, 0.56 mmol) in CHCl (4 mL) was added difluoroacetic anhydride (52 μL, 0.45 mmol) under N at 0 °C. The reaction 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 NaSO, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0–40% EtOAc in CHCl) to give compound 82 (95 mg, 43% yield) and 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 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 × 10 mL) and brine (10 mL), dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give compound T44 (24 mg, 31% yield) as a white solid. TIFF2025131767000147.tif26156

[0301] compound 83 To a solution of compound 36 (0.22 g, 0.44 mmol) and pyridine (53 μL, 0.65 mmol) in CHCl (5 mL) at room temperature, trifluoroacetic anhydride (74 μL, 0.52 mmol) was added. The mixture was stirred at 40 °C for 75 min. An additional amount of trifluoroacetic anhydride (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 × 20 mL), and brine (10 mL). The organic extract was dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted 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 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 Burgess reagent (210 mg, 0.88 mmol) was added, and the resulting mixture was stirred at 70 °C overnight. Compound 83 was completely consumed. The reaction mixture was cooled to room temperature and then 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 × 10 mL) and brine (10 mL), dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0–40% EtOAc in hexane) to give compound T45 (0.11 g, 54% yield) as a white solid. TIFF2025131767000148.tif25155

[0303] compound 84 To a solution of compound 36 (0.25 g, 0.49 mmol) and pyridine (60 μL, 0.74 mmol) in CHCl (5 mL) was added propionic anhydride (0.076 mL, 0.59 mmol). The reaction was stirred at 40 °C for 2 h. The mixture was diluted with EtOAc (25 mL) and washed with 1N aqueous solution (1N, 20 mL), water (2 × 20 mL), and brine (10 mL). The organic extract was dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0–100% EtOAc in hexanes) to give 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) was added Burgess reagent (0.21 g, 0.88 mmol) at room temperature. The reaction 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 × 10 mL) and brine (10 mL), dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0–80% EtOAc in hexane) to give compound T46 (71 mg, 74% yield) as a white solid. TIFF2025131767000149.tif25156

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

[0306] Compound 86 was dissolved in CHCl (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 added sequentially. The mixture was stirred at room temperature for 4 h and then washed with water (20 mL). The aqueous phase was separated and extracted with CHCl (20 mL). The combined organic extracts were dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0–100% EtOAc in hexanes) 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 propylphosphonic anhydride (50 wt% solution in EtOAc, 17.3 mL, 29.1 mmol) were added sequentially. The mixture was heated at reflux for 7 h and then cooled to 0 °C. Saturated aqueous NaHCO (100 mL) was added slowly. After the addition was complete, the mixture was extracted with CHCl (100 mL). The organic extract was washed with saturated aqueous NaHCO (100 mL) and water (100 mL). The combined aqueous washes were extracted with EtOAc (2 × 150 mL). The organic extract was dried over NaSO and filtered through a pad of silica gel (25 g), eluting with EtOAc (100 mL). The filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluting with 0-100% EtOAc in hexanes) to give the compound (1.65 g, 36% yield) as an off-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% in MeOH, 12.3 mL, 53.8 mmol) was added. The mixture was stirred at room temperature for 1.5 h 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 h, cooled to room temperature, and concentrated. The residue was dissolved in EtOAc (60 mL) and washed with water (2 × 30 mL). The combined aqueous washes were extracted with EtOAc (2 × 20 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0-50% EtOAc in hexanes) to give compound 89 (2.754 g, 92% yield) 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% in MeOH, 2.29 mL, 10.0 mmol) at room temperature under N. The mixture was heated at 55 °C for 1.5 h, cooled to 0 °C, treated with 10% aqueous NaHPO (30 mL), and 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 MgSO, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0–30% acetone in hexanes) 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. 1,3-Dibromo-5,5-dimethylhydantoin (735 mg, 2.57 mmol) was added, followed by an additional amount of DMF (11 mL). 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 sequentially with 1 N aqueous HCl (30 mL), water (2 × 30 mL), and brine (20 mL). The aqueous washes were combined and extracted with EtOAc (2 × 30 mL). The combined organic extracts were washed with water (2 × 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 light yellow solid. TIFF2025131767000150.tif27156

[0311] Example 2 Nitric oxide inhibition data tissue culture RAW 264.7, a murine macrophage cell line, 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 subcultured 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 experimental treatment, RAW 264.7 cells were plated onto Falcon-96-well clear-bottom plates (Corning, NY) at a concentration of 30,000 cells per well in RPMI 1640 supplemented with 0.5% fetal bovine serum and 1% penicillin-streptomycin in a total volume of 200 μL per well. The following day, cells were pretreated with compounds serially diluted from a 1000x stock. All compounds were dissolved in dimethyl sulfoxide (DMSO) to a 10 mM stock solution. Compounds were subsequently diluted in DMSO and RPMI 1640. Each well received a final concentration of 0.1% DMSO. Cells were pretreated for 2 hours, incubated at 37°C, and then treated with 20 ng / mL interferon-γ (R&D Systems, Minneapolis, MN) per well for 24 hours. The next day, the nitrite standard was serially diluted from 100 μM to 1.6 μM in RPMI 1640. Then, 50 μL of cell culture supernatant was transferred from each well to a new Falcon 96-well clear-bottom plate. Nitrite, a surrogate for nitric oxide, was measured 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 mixture and incubated at room temperature for 10 minutes in the dark. Afterwards, air bubbles were removed using ethanol vapor, and absorbance was measured using a Spectramax M2e plate reader with the wavelength set at 525 nm. Viability was assessed using WST-1 cell proliferation reagent (Roche, Basel, Switzerland). For the nitric oxide inhibition assay, the medium was removed and 15 μL of WST-1 reagent was added to each cell well. The plate was mixed briefly on an orbital shaker, and the cells were incubated at 37°C for 30 minutes. Absorbance was measured using a Spectramax M2e plate reader at wavelengths set at 440 nm and 700 nm.

[0313] Regarding the ability of compounds to inhibit the increase in nitric oxide release caused by interferon-γ, the absolute amount of nitrite produced in each well was extrapolated from the nitrite standards using a linear regression fit. All values ​​were then normalized to DMSO-interferon-γ treated wells and plotted as percent nitric oxide. IC 50 Values ​​were calculated based on WST1 survival using Excel and / or GraphPad Prism (San Diego, CA). Data are shown in Table 2.

[0314] (Table 2) Nitric oxide inhibition (NO IC 50 ), and NO IC compared to RTA 402 50 TIFF2025131767000151.tif242120TIFF2025131767000152.tif242120TIFF2025131767000153.tif242120TIFF2025131767000154.tif242121TIFF202 5131767000155.tif242121TIFF2025131767000156.tif242120TIFF2025131767000157.tif242121TIFF2025131767000158.tif242121TIFF2025131767 000159.tif242120TIFF2025131767000160.tif242120TIFF2025131767000161.tif242120TIFF2025131767000162.tif242120TIFF2025131767000163. tif242120TIFF2025131767000164.tif242120TIFF2025131767000165.tif242120TIFF2025131767000166.tif242120TIFF2025131767000167.tif24287 a Average ratios from replicate experiments.

[0315] (Table 3) NO IC compared to comparative compounds 50 TIFF2025131767000168.tif242116TIFF2025131767000169.tif242150TIFF2025131767000170.tif242116TIFF2025131767000171.tif24348 b Average ratios from experiments with 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 an in vitro assay generally described in 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 areas corresponding to the metabolites of the substrate were recorded. Percent control activity was then calculated by comparing the peak areas obtained in the presence of the test compound with those obtained in the absence of the test compound. Percent inhibition was then calculated for each compound by subtracting the percent control activity from 100. The results of the CYP3A4 assay are shown below in Tables 4-7.

[0317] (Table 4) CYP3A4 (midazolam) inhibition TIFF2025131767000172.tif241156

[0318] Comparison compounds CC1 and T11, both of which contain 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 TIFF2025131767000173.tif73156

[0320] Comparison compounds CC2 and T12, both of which contain 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 TIFF2025131767000174.tif73156

[0322] Comparison 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, and the results are shown in Table 7 below.

[0323] Table 7. CYP3A4 (midazolam) inhibition of T34 compared to CC3 TIFF2025131767000175.tif73156

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

[0325] AML-12 cells were plated at a density of 8,000 cells / well in 200 μL of DMEM / F12 medium supplemented with 10% FBS and 1% penicillin / streptomycin in white, clear-bottom 96-well plates. The following day, cells were treated with vehicle (DMSO) or test compounds (0.03 nM–1000 nM). Each well received a final concentration of 0.1% DMSO. Cells were incubated at 37°C and 5% CO2 for 24 hours. Total glutathione concentrations were measured using the GSH-Glo Glutathione Assay Kit (Promega) according to the manufacturer's instructions. Briefly, a standard curve was generated by serially diluting the provided glutathione solution. Final concentrations of 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 glutathione reaction mixture consisting of GSH-Glo reaction buffer, glutathione S-transferase, luciferin-NT, and TCEP was added to each sample well and all standard curve wells. After a 30-minute incubation at room temperature, 100 μL of luciferin detection reagent was added to all sample 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% and the maximum concentration of glutathione produced after treatment with the test compound was set to 100% to generate a dose-response curve. The dose-response curve was fitted using nonlinear regression analysis to obtain the EC 50 was used to extrapolate the values. 50 Values ​​are defined as the concentration of test compound required to increase glutathione levels by 50% of the maximum concentration. The data are shown in Tables 8 and 9.

[0326] Table 8. EC50 of glutathione (GSH) and EC50 compared to RTA 402 TIFF2025131767000176.tif242120TIFF2025131767000177.tif242120TIFF2025131767000178.t if242120TIFF2025131767000179.tif242121TIFF2025131767000180.tif242121TIFF2025131767 000181.tif242121TIFF2025131767000182.tif242121TIFF2025131767000183.tif242120TIFF20 25131767000184.tif242120TIFF2025131767000185.tif242120TIFF2025131767000186.tif24253 c Average ratios from replicate experiments.

[0327] Table 9. Glutathione (GSH) EC50 compared to comparative compounds TIFF2025131767000187.tif24248TIFF2025131767000188.tif242150TIFF2025131767000189.tif242150TIFF2025131767000190.tif24382 d Average ratios from experiments with 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 was stably transfected with a luciferase reporter gene under the transcriptional control of eight copies of the rat GSTA2 ARE sequence.

[0329] The effects of several 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 stably transfected with eight copies of a luciferase reporter gene under the transcriptional control of the antioxidant response element derived from the rat Gsta2 gene, an Nrf2 target gene (Frilling et al., 1990). AREc32 cells were plated in black 96-well plates at 20,000 cells per well in 200 μL of medium. 24 hours after plating, cells were treated with vehicle (DMSO) or test compounds at concentrations ranging from 0.03 to 1000 nM for 19 hours. 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 a 5-minute incubation at room temperature, luminescence signals were 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 each concentration of compound relative to vehicle-treated cells was determined, and a dose-response curve was generated. The dose-response curve was fitted using nonlinear regression analysis to obtain the EC 2X was used to extrapolate the values. 2X Values ​​are 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 of AREc32 2X , and EC in comparison with RTA 402 2X TIFF2025131767000191.tif242120TIFF2025131767000192.tif242120TIFF2025131767000193.tif242120TIFF202 5131767000194.tif242121TIFF2025131767000195.tif242121TIFF2025131767000196.tif242121TIFF2025131767 000197.tif242121TIFF2025131767000198.tif242121TIFF2025131767000199.tif242120TIFF2025131767000200. tif242120TIFF2025131767000201.tif242120TIFF2025131767000202.tif242120TIFF2025131767000203.tif24253 e Average ratios from replicate experiments. f In this case, the number of iterations is AREc32 EC 2X Refers to measurements only. This compound was not run in parallel to RTA 402 in the same experiment.

[0331] Table 11. AREc32 EC compared to comparator compounds 2X TIFF2025131767000204.tif24248TIFF2025131767000205.tif242150TIFF20251317670 00206.tif242150TIFF2025131767000207.tif243150TIFF2025131767000208.tif24349 g Average ratios from experiments with direct comparison.

[0332] All compounds, formulations, and methods disclosed and claimed herein can be made and executed without undue experimentation in light of this disclosure. Although the compounds, formulations, and methods of the present disclosure have been described in terms of preferred embodiments, it will be apparent to those skilled in the art that modifications can be made to the compounds, formulations, and methods, and to the steps or order of steps of the methods described herein, without departing from the concept, spirit, and scope of the present invention. More specifically, it will be apparent that certain 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 apparent to those skilled in the art are deemed to be within the spirit, scope, and concept of the present invention, as defined by the appended claims.

[0333] References The following references, to the extent that they provide exemplary procedural or other details supplementary to those disclosed herein, are specifically incorporated herein by reference. TIFF2025131767000209.tif20322TIFF2025131767000210.tif231144TIFF2025131767000211.tif231121TIFF2025131767000212.tif121144

Claims

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

2. The following formula: or a pharmaceutically acceptable salt thereof, wherein: A 1 is of the following formula: -heteroarenediyl selected from (C≦3) - and R 1 is a mono-substituted alkyl (C≦3) wherein the term "monopolar substituted" means that only one hydrogen atom of the group so modified is replaced with a monopolar substituent, and the monopolar substituent is -OH, -F, -OC(O)CH 3 and -NHC(O)OCH 3 2. The compound of claim 1, selected from the group consisting of:

3. The following formula: or a pharmaceutically acceptable salt thereof, wherein: A 1 is of the following formula: -heteroarenediyl selected from (C≦3) - and R 1 is a mono-substituted alkyl (C≦3) wherein the term "monopolar substituted" means that only one hydrogen atom of the group so modified is replaced with a monopolar substituent, and the monopolar substituent is -OH, -F, -OC(O)CH 3 and -NHC(O)OCH 3 2. The compound of claim 1, selected from the group consisting of:

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

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

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

7. R 1 7. The compound of any one of claims 1 to 6, wherein is a monopolar substituted ethyl.

8. R 1 7. The compound of any one of claims 1 to 6, wherein is a monopolar substituted methyl.

9. R 1 is monofluoroalkyl (C≦3) , or monohydroxyalkyl (C≦3) 7. The compound of any one of claims 1 to 6, wherein

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

11. R 1 11. The compound of claim 10, wherein is fluoroethyl.

12. R 1 12. The compound of claim 11, wherein is 2-fluoroethyl.

13. R 1 11. The compound of claim 10, wherein is fluoromethyl.

14. R 1 is monohydroxyalkyl (C≦3) 10. The compound of any one of claims 1 to 6 and 9, wherein

15. R 1 15. The compound of claim 14, wherein is hydroxyethyl.

16. R 1 16. The compound of claim 15, wherein is 2-hydroxyethyl.

17. R 1 15. The compound of claim 14, wherein is hydroxymethyl.

18. R 1 Ga-CH 2 CH 2 OC(O)CH 3 7. The compound of any one of claims 1 to 6, wherein

19. R 1 Ga-CH 2 CH 2 NHC(O)OCH 3 7. The compound of any one of claims 1 to 6, wherein

20. The following formula:

20. The compound of any one of claims 1-19, further defined as:

21. A compound of the formula:

21. The compound of claim 20, further defined as: or a pharmaceutically acceptable salt thereof.

22. A compound of the formula:

21. The compound of claim 20, further defined as: or a pharmaceutically acceptable salt thereof.

23. A compound of the 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) excipients and 10. A pharmaceutical composition comprising:

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

26. 24. A composition comprising a compound of any one of claims 1 to 23 for use in a method for 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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