C17 polar-substituted heteroaromatic synthetic triterpenoid compounds and methods of use thereof

Abstract

Disclosed herein are compounds of the formula: wherein the variables are defined herein. Also provided are pharmaceutical compositions thereof. In some aspects, the compounds and compositions provided herein can be used as antioxidant inflammatory modulators. In some aspects, the disclosure provides methods in which the compounds and compositions described herein are used to treat diseases and disorders, including those associated with inflammation and cancer.

Description

[0001] Citation to Related Applications

[0002] This application claims the benefit of priority to U.S. Provisional Application No. 62 / 876,467, filed on July 19, 2019, and U.S. Provisional Application No. 62 / 952,048, filed on December 20, 2019, the entire contents of both of which are hereby incorporated by reference. Background of the Invention

[0003] I. Field of the Invention

[0004] The present invention relates generally to the fields of biology, chemistry and medicine. More specifically, it relates to compounds, compositions and methods for treating and preventing diseases and disorders, such as those associated with oxidative stress and inflammation.

[0005] II. Description of Related Art

[0006] The anti-inflammatory and anti-proliferative activities of the naturally occurring triterpenoid oleanolic acid have been improved by chemical modification. For example, 2-cyano-3,12-dioxooleanolic acid-1,9(11)-diene-28-oic acid (CDDO) and related compounds have been developed (Honda et al., 1997; Honda et al., 1998; Honda et al., 1999; Honda et al., 2000a; Honda et al., 2000b; Honda et al., 2002; Suh et al., 1994). 98; Suh et al., 1999; Place et al., 2003; Liby et al., 2005; and U.S. Patents 6,326,507, 6,974,801, 7,435,755, 7,795,305, 7,863,327, 7,915,402, 7,943,778, 8,034,955, 8,071,632, 8,124,656, 8,124,799, 8,129,429, 8,338,618, 8,394,967, 8,440,820, 8,440,854, 8,455,544, 8,586,775, 8,993,640, 9,090,574, 9,102,681, 9,249,089, 9,278,912, 9,278,913, 9,2 Bardoxolone methyl (CDDO-Me; RTA 402) and omaveloxolone (RTA 408) have been evaluated clinically, including, for example, for the treatment of cancer, chronic kidney disease, pulmonary hypertension, and Friedreich's ataxia (Pergola et al., 2011; Hong et al., 2012; U.S. Patent 8,993,640).

[0007] Synthetic triterpenoid analogs of oleanolic acid (OA) have also been shown 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 shown to inhibit cellular inflammatory processes, although these compounds are less extensively characterized (Honda et al., 2006). The pharmacology of these synthetic triterpenoid molecules is complex. Compounds derived from oleanolic acid have been shown to affect the function of multiple protein targets and thereby regulate the activity of several important cell signaling pathways associated with oxidative stress, cell cycle control and inflammation (e.g., Dinkova-Kostova et al., 2005; Ahmad et al., 2006; Ahmad et al., 2008; Liby et al., 2007a). While derivatives of betulinic acid have shown comparable anti-inflammatory properties, their pharmacology also appears to be significantly different compared to OA-derived compounds (Liby et al., 2007b). Given the differences in the bioactivity profiles of known triterpenoid derivatives, and given the wide variety of diseases that can be treated or prevented with compounds that have potent antioxidant and anti-inflammatory effects and the large unmet medical needs represented within these various diseases, it is desirable to synthesize novel compounds with different structures that may have improved bioactivity profiles for use in treating one or more indications. SUMMARY OF THE INVENTION

[0009] The present disclosure provides novel synthetic triterpenoid derivatives having anti-inflammatory and / or antioxidant properties, pharmaceutical compositions, methods for their preparation, and methods for their use.

[0010] In one aspect, provided is a compound of the formula:

[0011]

[0012] in:

[0013] A1 is -heteroarene diyl (C≤3) -;

[0014] R1 is a polar-substituted alkyl (C≤3) ;and

[0015] R2 and R2' are each independently hydrogen or methyl.

[0016] In some embodiments, the compound is further defined as:

[0017]

[0018] in:

[0019] A1 is -heteroarene diyl (C≤3) -;and

[0020] R1 is a polar-substituted alkyl (C≤3) ;

[0021] or a pharmaceutically acceptable salt thereof.

[0022] In some embodiments, the compound is further defined as:

[0023]

[0024] in:

[0025] A1 is -heteroarene diyl (C≤3) -;and

[0026] R1 is a polar-substituted alkyl (C≤3) ;

[0027] or a pharmaceutically acceptable salt thereof.

[0028] In some embodiments, -A1-R1 is:

[0029]

[0030] In other embodiments, -A1-R1 is:

[0031]

[0032] In other embodiments, -A1-R1 is:

[0033]

[0034] In other embodiments, -A1-R1 is:

[0035]

[0036] In some embodiments, R1 is polar-substituted ethyl. In other embodiments, R1 is polar-substituted methyl. In some embodiments, R1 is monopolar-substituted alkyl. (C≤3) In other embodiments, R1 is a monopolar-substituted ethyl. In other embodiments, R1 is a monopolar-substituted methyl. In some embodiments, R1 is a monoaminoalkyl (C≤3) , monofluoroalkyl (C≤3) or monohydroxyalkyl (C≤3) In some embodiments, R1 is monoaminoalkyl(C≤3) , such as 2-aminoethyl or aminomethyl. In other embodiments, R1 is a monofluoroalkyl (C≤3) , such as 2-fluoroethyl or fluoromethyl. In other embodiments, R1 is monohydroxyalkyl (C≤3) , such as 2-hydroxyethyl or hydroxymethyl. In other embodiments, R1 is -CH2CH2NHC(O)OCH3, -CH2CH2NHC(O)NHCH2CH3 or -CH2CH2NHC(O)CH3.

[0037] In some embodiments, -A1-R1 is R1 is aminomethyl, fluoromethyl or hydroxymethyl, R2 is hydrogen or methyl, and R2' is methyl. In some of these embodiments, -A1-R1 is R1 is fluoromethyl, R2 is hydrogen or methyl, and R2' is methyl.

[0038] It should be understood that the present invention specifically relates to each and every combination of features and embodiments described herein, including any combination of general and / or specific features / embodiments. Specifically, the present invention specifically relates to each combination of the meanings (including general and / or specific meanings) of the various groups and variables included in formula (I).

[0039] In some embodiments, the compound is further defined as:

[0040]

[0041]

[0042] or a pharmaceutically acceptable salt of any of these formulae.

[0043] In other embodiments, the compound is further defined as:

[0044]

[0045] or a pharmaceutically acceptable salt of any of these formulae.

[0046] In other embodiments, the compound is further defined as:

[0047]

[0048]

[0049] or a pharmaceutically acceptable salt of any of these formulae.

[0050] In other embodiments, the compound is further defined as:

[0051]

[0052] or a pharmaceutically acceptable salt thereof.

[0053] In other embodiments, the compound is further defined as:

[0054]

[0055] or a pharmaceutically acceptable salt thereof.

[0056] In other embodiments, the compound is further defined as:

[0057]

[0058] or a pharmaceutically acceptable salt thereof.

[0059] In other embodiments, the compound is further defined as:

[0060]

[0061] or a pharmaceutically acceptable salt thereof.

[0062] In other embodiments, the compound is further defined as:

[0063]

[0064] or a pharmaceutically acceptable salt thereof.

[0065] In other embodiments, the compound is further defined as:

[0066]

[0067] or a pharmaceutically acceptable salt thereof.

[0068] In some embodiments, the compound is further defined as:

[0069] (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-octahydrophthalene-2-carbonitrile;

[0070] (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-octahydrophthalene-2-carbonitrile;

[0071] (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-octahydrophthalimide-2-carbonitrile;

[0072] (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-octahydrophthalene-2-carbonitrile;

[0073] (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-octahydrophthalene-2-carbonitrile;

[0074] (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-octahydrophthalene-2-carbonitrile;

[0075] (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-octahydrophthalene-2-carbonitrile;

[0076] 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-hexahydrophthalimide-4a(2H)-yl)-2H-tetrazol-2-yl)ethyl acetate;

[0077] (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-octahydrophthalene-2-carbonitrile;

[0078] (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-octahydrophthalene-2-carbonitrile;

[0079] (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-octahydrophthalimide-2-carbonitrile;

[0080] 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-hexahydrophthalimide-4a(2H)-yl)-1,2,4-oxadiazol-3-yl)ethyl acetate;

[0081] (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-octahydrophthalimide-2-carbonitrile;

[0082] 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-hexahydrophthalimide-4a(2H)-yl)-1,2,4-oxadiazol-3-yl)ethyl)carbamate;

[0083] 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-hexahydrophthalimide-4a(2H)-yl)-1,2,4-oxadiazol-3-yl)ethyl)-3-ethylurea;

[0084] 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-hexahydrophthalimide-4a(2H)-yl)-1,2,4-oxadiazol-3-yl)ethyl)acetamide;

[0085] (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-octahydrophthalonitrile-2-carbonitrile;

[0086] (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-octahydrophthalonitrile-2-carbonitrile;

[0087] (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-octahydrophthalimide-2-carbonitrile;

[0088] (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-octahydrophthalene-2-carbonitrile;

[0089] (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-octahydrophthalene-2-carbonitrile;

[0090] (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-octahydrophthalene-2-carbonitrile;

[0091] (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-octahydrophthalene-2-carbonitrile; or

[0092] (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-octahydrophthalene-2-carbonitrile.

[0093] In other embodiments, the compound is further defined as:

[0094] (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-octahydrophthalene-2-carbonitrile;

[0095] (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-octahydrophthalene-2-carbonitrile;

[0096] (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-octahydrophthalimide-2-carbonitrile;

[0097] (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-octahydrophthalene-2-carbonitrile;

[0098] (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-octahydrophthalene-2-carbonitrile; or

[0099] (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-octahydrophthalene-2-carbonitrile.

[0100] In other embodiments, the compound is further defined as:

[0101] (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-octahydrophthalene-2-carbonitrile;

[0102] (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-octahydrophthalene-2-carbonitrile;

[0103] (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-octahydrophthalene-2-carbonitrile;

[0104] (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-octahydrophthalene-2-carbonitrile; or

[0105] (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-octahydrophthalene-2-carbonitrile.

[0106] In some embodiments, the compound is further defined as:

[0107] (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-octahydrophthalene-2-carbonitrile.

[0108] In other embodiments, the compound is further defined as:

[0109] (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-octahydrophthalene-2-carbonitrile.

[0110] In other embodiments, the compound is further defined as:

[0111] (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-octahydrophthalene-2-carbonitrile.

[0112] In other embodiments, the compound is further defined as:

[0113] (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-octahydrophthalene-2-carbonitrile.

[0114] In other embodiments, the compound is further defined as:

[0115] (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-octahydrophthalene-2-carbonitrile.

[0116] In other embodiments, the compound is further defined as:

[0117] (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-octahydrophthalene-2-carbonitrile.

[0118] In another aspect, the disclosure provides compounds of the formula:

[0119]

[0120]

[0121] or a pharmaceutically acceptable salt of any of these formulae.

[0122] In another aspect, the present disclosure provides:

[0123] (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-octahydrophthalene-2-carbonitrile;

[0124] (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-octahydrophthalene-2-carbonitrile;

[0125] (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-octahydrophthalene-2-carbonitrile;

[0126] (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-octahydrophthalimide-2-carbonitrile;

[0127] (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-octahydrophthalene-2-carbonitrile;

[0128] (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-octahydrophthalimide-2-carbonitrile;

[0129] (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-octahydrophthalimide-2-carbonitrile;

[0130] (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-octahydrophthalimide-2-carbonitrile;

[0131] (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-octahydrophthalimide-2-carbonitrile;

[0132] (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-octahydrophthalimide-2-carbonitrile;

[0133] (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-octahydrophthalene-2-carbonitrile;

[0134] (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-octahydrophthalimide-2-carbonitrile;

[0135] (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-octahydrophthalimide-2-carbonitrile;

[0136] (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-octahydrophthalene-2-carbonitrile;

[0137] (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-octahydrophthalene-2-carbonitrile;

[0138] (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-octahydrophthalene-2-carbonitrile;

[0139] (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-octahydrophthalimide-2-carbonitrile;

[0140] (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-octahydrophthalonitrile-2-carbonitrile;

[0141] (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-octahydrophthalonitrile-2-carbonitrile;

[0142] (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-octahydrophthalene-2-carbonitrile;

[0143] (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-octahydrophthalene-2-carbonitrile; or

[0144] (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-octahydrophthalene-2-carbonitrile.

[0145] In another aspect, the disclosure provides a pharmaceutical composition comprising a compound of the disclosure and an excipient. In some embodiments, the pharmaceutical composition is formulated for oral administration, intra-adipose, intra-arterial, intra-articular, intra-cranial, intra-dermal, intra-lesional, intra-muscular, intra-nasal, intra-ocular, intra-pericardial, intra-peritoneal, intra-pleural, intra-prostatic, intra-rectal, intra-sheath, intra-tracheal, intra-tumor, intra-umbilical, intra-vaginal, intra-venous, intra-bladder, intra-vitreal, in liposome form, locally, mucosally, parenterally, rectally, subconjunctivally, subcutaneously, sublingually, topically, buccally, transdermally, vaginally, in the form of creams, in the form of lipid compositions, via catheters, via lavage, via continuous infusion, via infusion, via inhalation, via injection, via local delivery or via local perfusion. In some embodiments, the pharmaceutical composition is formulated for oral administration. In other embodiments, the pharmaceutical composition is formulated for administration via injection. In some embodiments, the pharmaceutical composition is formulated for intra-arterial administration, intramuscular administration, intraperitoneal administration, 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 dose.

[0146] In another aspect, the present disclosure provides a method for treating or preventing a disease or condition in a patient in need thereof, comprising administering a pharmaceutically effective amount of a compound or composition of the present disclosure to the patient. In some embodiments, the patient is a mammal, such as a human. In some embodiments, the disease or condition is a condition associated with inflammation and / or oxidative stress. In some embodiments, the disease or condition is cancer. In some embodiments, the disease or condition is a cardiovascular disease, such as atherosclerosis. In some embodiments, the disease or condition is an autoimmune disease, such as Crohn's disease, rheumatoid arthritis, lupus, or psoriasis. In some embodiments, the disease or condition is a neurodegenerative disease, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, or Huntington's disease. In some embodiments, the disease or condition is chronic kidney disease, diabetes, mucositis, inflammatory bowel disease, dermatitis, sepsis, ischemia-reperfusion injury (including complications caused by 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 condition is an eye disease, such as uveitis, glaucoma, macular degeneration or retinopathy. In some embodiments, the disease or condition is a neuropsychiatric disease or condition, such as schizophrenia, depression, bipolar disorder, epilepsy, post-traumatic stress disorder, attention deficit disorder, autism or anorexia nervosa. In some embodiments, the disease or condition is associated with mitochondrial dysfunction, such as Friedreich's ataxia. In some embodiments, the disease or condition is chronic pain. In some embodiments, the disease or condition is neuropathic pain.

[0147] In another aspect, the disclosure provides methods of inhibiting nitric oxide production comprising administering to a patient in need thereof an amount of a compound or composition of the disclosure sufficient to cause inhibition of IFN-γ-induced nitric oxide production in one or more cells of the patient.

[0148] 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, while indicating specific embodiments of the present invention, are given by way of illustration only, as those skilled in the art will appreciate various changes and modifications within the spirit and scope of the present invention from the detailed description. It should be noted that just because a particular compound is attributed to a particular general formula does not mean that it may not also belong to another general formula. BRIEF DESCRIPTION OF THE DRAWINGS

[0150] The following drawings form part of this specification and are included to further demonstrate certain aspects of the present invention. The present 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.

[0151] Figure 1 CYP3A4 inhibition at 1 μM in human liver microsomes is shown, where each sample was incubated at 37°C for 10 min, each sample contained 0.1 mg / mL human liver microsomes, 5 μM midazolam as substrate and 1 μM test compound. See Example 3 for additional details.

[0152] Description of Illustrative Embodiments

[0153] Disclosed herein are novel compounds and compositions having antioxidant and / or anti-inflammatory properties, methods of making them, and methods of using them, including for treating and / or preventing disease.

[0154] I. Compounds of the Invention

[0155] Compounds of the invention (also referred to as "synthetic triterpenoid derivatives provided herein," "compounds of the disclosure," or "compounds disclosed herein") are shown, for example, above in the Summary of the Invention section, below in the Examples, Table 1, and in the claims below. They can be prepared using the synthetic methods outlined in the Examples section. These methods can be further modified and optimized using the principles and techniques of organic chemistry applied by those skilled in the art. Such principles and techniques are taught in, for example, Smith, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, (2013), which is incorporated herein by reference. In addition, synthetic methods can be further modified and optimized for preparation, pilot scale, or large-scale production, whether batch or continuous, using the principles and techniques of process chemistry applied by those skilled in the art. Such principles and techniques are taught in, for example, Anderson, Practical Process Research & Development-A Guide for Organic Chemists (2012), which is incorporated herein by reference.

[0156] Table 1: Examples of synthetic triterpenoid derivatives provided herein

[0157]

[0158]

[0159]

[0160]

[0161]

[0162]

[0163]

[0164]

[0165]

[0166]

[0167] All compounds of the present invention can be used for preventing and treating one or more diseases or conditions discussed herein or elsewhere in some embodiments. In some embodiments, one or more compounds characterized or illustrated as intermediates, metabolites and / or prodrugs herein can still be used for preventing and treating one or more diseases or conditions. Therefore, unless explicitly stated to the contrary, all compounds of the present invention are considered to be considered as "active compounds" and "therapeutic compounds" for use as active pharmaceutical ingredients (API). The combination of clinical trial protocols and prescribed procedures (such as those promulgated by the Food and Drug Administration (FDA)) is usually used to determine the actual suitability for human or veterinary applications. In the U.S., FDA is responsible for protecting public health by ensuring the safety, effectiveness, quality and reliability of human and veterinary drugs, vaccines and other biological products and medical devices.

[0168] In some embodiments, the compounds of the present invention have the advantage that they may be more effective, less toxic, longer acting, more potent, produce fewer side effects, be more readily absorbed, be more metabolically stable, more lipophilic, more hydrophilic, and / or have a better pharmacokinetic profile (e.g., higher oral bioavailability and / or lower clearance), and / or have other useful pharmacological, physical or chemical properties compared to compounds known in the prior art (whether for the indications described herein or otherwise).

[0169] The compounds of the present invention may contain one or more asymmetrically substituted carbon or nitrogen atoms and may be separated in optically active or racemic form. Thus, unless otherwise specified specific stereochemistry or isomeric forms, all chirality, diastereoisomerism, racemic form, epimeric forms and all geometric isomeric forms of chemical formulas are meant. Compounds may exist as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and each diastereomer. In some embodiments, single diastereomers are obtained. The chiral center of the compounds of the present invention may have an S or R configuration. In some embodiments, the compounds of the present invention may contain two or more atoms with a determined stereochemical orientation.

[0170] Chemical formulae used to represent compounds of the invention generally show only one of several different tautomers that may exist. For example, many types of keto groups are known to exist in equilibrium with corresponding enol groups. Similarly, many types of imine groups exist in equilibrium with enamine groups. Regardless of which tautomer is depicted for a given compound, and regardless of which is the most common, all tautomers of a given chemical formula are intended.

[0171] In addition, the atoms constituting the compounds of the present invention are intended to include all isotopic forms of such atoms. As used herein, isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and not limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include 13 C and 14 C.

[0172] In some embodiments, the compounds of the present invention function as prodrugs or can be derivatized to function as prodrugs. Since it is known that prodrugs enhance the numerous desired properties of drugs (e.g., solubility, bioavailability, manufacturing, etc.), the compounds used in some methods of the present invention can be delivered in the form of prodrugs if desired. Thus, the present invention foresees prodrugs of the compounds of the present invention and methods for delivering prodrugs. Prodrugs of the compounds used in the present invention can be prepared by modifying the functional groups present in the compounds in such a way that the modifications are cleaved into parent compounds in conventional operations or in vivo. Therefore, prodrugs include, for example, compounds described herein: wherein hydroxyl, amino or carboxyl groups are bonded to any group, and when the prodrug is administered to a patient, any group is cleaved to form hydroxyl, amino or carboxylic acid, respectively.

[0173] In some embodiments, the compounds of the present invention exist in salt 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 critical, as long as the salt as a whole is pharmacologically acceptable. Other examples of pharmaceutically acceptable salts and methods of making and using them are presented in Handbook of Pharmaceutical Salts: Properties, and Use (2002), which is incorporated herein by reference.

[0174] It should be understood that many organic compounds can form complexes with the solvents in which they react or precipitate or crystallize. These complexes are referred to as "solvates". In the case where the solvent is water, the complex is referred to as "hydrates". It should also be understood that many organic compounds can exist in more than one solid form, including crystalline forms and amorphous forms. All solid forms of the compounds provided herein, including any solvates thereof, are within the scope of the present invention.

[0175] II . Biological Activity

[0176] The results of the assay for inhibition of IFNγ-induced NO production for several compounds of the invention are shown in Tables 2 and 3 in Example 2. Table 2 presents the results compared to those of bardoxolone methyl (RTA 402, CDDO-Me). Table 3 presents the results compared to comparative compounds CC1, CC2, and CC3. Details on this assay are provided in the Examples section below.

[0177] In some embodiments, the synthetic triterpenoid derivatives provided herein that are substituted with polar substituents at the C17 heteroaryl group exhibit improved nitric oxide inhibition compared to compounds lacking such substituents (such as those disclosed in US 9,512,094, which is incorporated herein by reference). For example, the IC of fluorine-substituted T12 50 The value was 36% lower than that of the corresponding unsubstituted compound CC2 (TX63501; US ​​9,512,094) (1.27 nM vs. 1.98 nM). In another example, the IC values ​​of hydroxy-substituted T13 and acetoxy-substituted T14 were 50 The values ​​were 88% and 90% lower than the corresponding unsubstituted compound T23 (0.56 nM and 0.48 nM, respectively, compared to 4.85 nM). In another embodiment, the IC values ​​of fluoro-substituted T1, amino-substituted T2, and hydroxy-substituted T4 were 50The values ​​were 67%, 70% and 52% lower than the corresponding unsubstituted compound T20 (1.24 nM, 1.15 nM and 1.82 nM, respectively, relative to 3.79 nM). Similarly, amino-substituted T3 and hydroxy-substituted T5 were 72% and 83% lower than the corresponding unsubstituted compound T24 (2.60 nM and 1.57 nM, respectively, relative to 9.21 nM). In another embodiment, the IC values ​​of fluoro-substituted T11 were 1.24 nM, 1.15 nM and 1.82 nM, relative to 3.79 nM, respectively). Similarly, amino-substituted T3 and hydroxy-substituted T5 were 72% and 83% lower than the corresponding unsubstituted compound T24 (2.60 nM and 1.57 nM, respectively, relative to 9.21 nM). 50 The value was 52% lower than that of the corresponding unsubstituted compound CC1 (TX63384; US 9,512,094) (0.98 nM vs. 2.05 nM). In another embodiment, the IC 50 The value is 31% lower than the corresponding unsubstituted compound CC3 (TX63787; US 9,290,536) (0.93 nM relative to 1.34 nM). In some embodiments, complete replacement of all hydrogens with polar substituents results in a decrease in nitric oxide inhibitory activity. The trifluoromethyl derivative T22 (23.95 nM) was compared with the monofluoromethyl derivative T12 (1.27 nM).

[0178] In some embodiments, the compounds of the present disclosure exhibit reduced inhibition of cytochrome P450 3A4 (CYP3A4) relative to known compounds. CYP3A4 is an important enzyme in the body that oxidizes small foreign organic molecules (xenobiotics), such as toxins or drugs, so that they can be removed from the body. Regulation of CYP3A4 may amplify or weaken the effects of drugs modified by CYP3A4. Inhibition of CYP3A4 may have negative side effects (e.g., reduced drug clearance, amplification of drug effects, and / or increased likelihood of drug-drug interactions) and may complicate administration. Therefore, drugs that do not inhibit CYP3A4 are often more desirable.

[0179] The results of the determination of CYP3A4 inhibition of several compounds of the present disclosure are shown in Tables 4-7 in Example 3. In some embodiments, the synthetic triterpenoid derivatives provided herein that are substituted with polar substituents at the C17 heteroaryl group exhibit reduced CYP3A4 inhibition compared to compounds lacking such substituents (such as those disclosed in US 9,512,094 and US 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; US ​​9,512,094) (29.1%, 21.4%, and 29.7% inhibition, respectively, versus 45.8% inhibition). In another embodiment, the CYP3A4 inhibition of fluoro-substituted T11 was 15% lower than that of the corresponding unsubstituted compound CC1 (TX63384; US 9,512,094) (17.7% inhibition vs. 20.7% inhibition). In another embodiment, the CYP3A4 inhibition of fluoro-substituted T34 was 22% lower than that of the corresponding unsubstituted compound CC3 (TX63787; US 9,290,536) (29.4% inhibition vs. 37.7% inhibition). In addition, each of TI, T2, T11, T12, and T34 exhibited reduced CYP3A4 inhibition ( Figure 1 ).

[0180] III. Diseases associated with inflammation and / or oxidative stress

[0181] Inflammation is a biological process that provides resistance to infectious or parasitic organisms and repair of damaged tissues. The characteristics of inflammation are usually local vasodilation, redness, swelling and pain, leukocytes are recruited to the site of infection or injury, inflammatory cytokines such as TNF-α and IL-1 are produced, and reactive oxygen or nitrogen species such as hydrogen peroxide, superoxide and peroxynitrite are produced. In the late stage 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 regulated and temporary, and once the infection or injury is properly treated, it subsides in a coordinated manner. However, if the regulatory mechanism fails, acute inflammation can become excessive and life-threatening. Alternatively, inflammation can become chronic and cause 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 diseases associated with inflammation.

[0182] Many serious and refractory human diseases involve dysregulation of inflammatory processes, including diseases such as cancer, atherosclerosis and diabetes, which are not traditionally considered as inflammatory conditions. In the case of cancer, inflammatory processes are associated with tumor formation, progression, metastasis and resistance to therapy. Atherosclerosis, which has long been considered as a lipid metabolism disorder, is now understood to be primarily an inflammatory condition, in which activated macrophages play an important role in the formation and final rupture of atherosclerotic plaques. The activation of inflammatory signaling pathways has also been shown to play a role in the development of insulin resistance and in peripheral tissue damage associated with diabetic hyperglycemia. Excessive production of reactive oxygen species and reactive nitrogen species (such as superoxide, hydrogen peroxide, nitric oxide and peroxynitrite) is a sign of inflammatory conditions. Evidence of dysregulation of peroxynitrite production has been reported in a variety of diseases (Szabo et al., 2007; Schulz et al., 2008; Forstermann, 2006; Pall, 2007). Aging-related diseases such as dementia, amyotrophy, cardiovascular disease, neurodegenerative diseases and arthritis often 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 aging-related diseases such as dementia, amyotrophy, cardiovascular disease, neurodegenerative diseases or arthritis.

[0183] Autoimmune diseases such as rheumatoid arthritis, lupus, psoriasis and multiple sclerosis are related to the inappropriate and chronic activation of inflammatory processes in the affected tissues, which is caused by the dysfunction of self relative to non-self recognition and response mechanisms in the immune system. In some embodiments, provided herein is a compound that can be used to treat and / or prevent autoimmune diseases, such as rheumatoid arthritis, lupus, psoriasis or multiple sclerosis. In neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, nerve damage is related to the activation of microglia and the elevated levels of proinflammatory proteins such as inducible nitric oxide synthase (iNOS). In some embodiments, provided herein is a compound that can be used to treat and / or prevent 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 are closely related to the presence of chronic oxidative stress and inflammation, leading to the development of fibrosis and the ultimate loss of organ function. In some embodiments, provided herein are compounds that can be used to treat and / or prevent chronic organ failure, such as renal failure, heart failure, liver failure, or chronic obstructive pulmonary disease. Oxidative stress in vascular endothelial cells lining large and small blood vessels can lead to endothelial dysfunction and is considered to be an important contributing factor in the development of systemic cardiovascular disease, diabetic complications, chronic kidney disease, and other forms of organ failure and many other aging-related diseases (including degenerative diseases of the central nervous system and retina). In some embodiments, provided herein are compounds that can be used to treat and / or prevent systemic cardiovascular disease, diabetic complications, chronic kidney disease, and other forms of organ failure and many other aging-related diseases (including degenerative diseases of the central nervous system and retina).

[0184] 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; eye diseases such as uveitis, glaucoma, macular degeneration, and various forms of retinopathy; transplant failure and rejection; ischemia-reperfusion injury; chronic pain; degenerative conditions of bones and joints, 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 to treat and / or prevent inflammatory bowel disease;Inflammatory skin diseases;Mucositis associated with radiation therapy and chemotherapy;Eye diseases such as uveitis, glaucoma, macular degeneration and various forms of retinopathy;Transplant failure and rejection;Ischemia-reperfusion injury (including complications of sickle cell anemia);Chronic pain;Degenerative conditions of bones and joints, including osteoarthritis and osteoporosis;Asthma and cystic fibrosis;Epileptic seizure disorders;And neuropsychiatric conditions, including schizophrenia, depression, bipolar disorder, post-traumatic stress disorder, attention deficit disorder, autism-spectrum disorders or eating disorders such as anorexia nervosa. The dysregulation of inflammatory signaling pathways is considered to be an important factor in 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 to treat and / or prevent muscle wasting diseases, such as muscular dystrophy and various forms of cachexia.

[0185] A variety of acute, life-threatening conditions also involve dysregulated inflammatory signaling, including acute organ failure involving the pancreas, kidneys, liver, or lungs, myocardial infarction or acute coronary syndrome, stroke, septic shock, trauma, severe burns, and anaphylaxis.

[0186] Many complications of infectious diseases are also related to the dysregulation of inflammatory response. Although inflammatory response can kill invading pathogens, excessive inflammatory response can also have considerable destructiveness, and can be a major source of damage in infected tissues in some cases. In addition, excessive inflammatory response may also cause systemic complications due to excessive production of inflammatory cytokines (such as TNF-α and IL-1). This is considered to be an important factor in the mortality rate caused by severe influenza, severe acute respiratory syndrome and sepsis caused by infection of coronavirus (including SARS-CoV-2 causing COVID-19) and other viruses causing upper respiratory diseases. In some embodiments, provided herein is a compound that can be used to treat and / or prevent influenza, severe acute respiratory syndrome or sepsis caused by infection of coronavirus (including SARS-Cov-2) or other viruses causing upper respiratory diseases.

[0187] Abnormal or overexpression of iNOS or cyclooxygenase-2 (COX-2) has been implicated in the pathogenesis of many disease processes. For example, it is clear that NO is an effective mutagen (Tamir and Tannebaum, 1996), and nitric oxide can also activate COX-2 (Salvemini et al., 1994). In addition, iNOS significantly increases in rat colon tumors induced by carcinogen azoxymethane (Takahashi et al., 1997). A series of synthetic triterpenoid analogs of oleanolic acid have been shown to be potent inhibitors of cellular inflammatory processes (such as induction of inducible nitric oxide synthase (iNOS) and COX-2 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. The elevated brain tissue levels of iNOS have also been associated with Alzheimer's disease (Sporn et al., 1996). In some embodiments, the compounds provided herein can be used to treat and / or prevent Alzheimer's disease.

[0188] In one aspect, the compounds disclosed herein are characterized in that they are capable of inhibiting nitric oxide production induced by exposure to gamma-interferon in macrophage-derived RAW264.7 cells. It is further characterized in that it is capable of inducing the expression of antioxidant proteins such as NQO1 and reducing 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 conditions involving dysregulation of oxidative stress and inflammatory processes, including cancer, complications resulting from local or systemic exposure to ionizing radiation, mucositis resulting from radiation therapy or chemotherapy, autoimmune diseases, cardiovascular disease (including atherosclerosis), ischemia-reperfusion injury (including complications of 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, diseases of the eye and retina, acute and chronic pain, degenerative bone disease (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 to treat and / or prevent cancer, complications caused by local or systemic exposure to ionizing radiation, mucositis caused by radiation therapy or chemotherapy, autoimmune diseases, cardiovascular diseases (including atherosclerosis), ischemia-reperfusion injury (including complications of 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, diseases of the eye and retina, 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.

[0189] Without being bound by theory, it is believed that activation of the antioxidant / anti-inflammatory Keap1 / Nrf2 / ARE pathway is involved in the anti-inflammatory and anti-cancer properties of the compounds disclosed herein.

[0190] In another aspect, the compounds disclosed herein can be used to treat subjects with conditions caused by increased levels of oxidative stress in one or more tissues. Oxidative stress is produced by abnormally high or prolonged levels of reactive oxygen species such as superoxide, hydrogen peroxide, nitric oxide, and peroxynitrite (formed by the reaction of nitric oxide and superoxide). Oxidative stress may be accompanied by acute or chronic inflammation. Oxidative stress may be caused by the following factors: mitochondrial dysfunction, activation of immune cells such as macrophages and neutrophils, acute exposure to external agents such as ionizing radiation or cytotoxic chemotherapeutics (e.g., doxorubicin), trauma or other acute tissue damage, ischemia / reperfusion, poor circulation or anemia, local or systemic hypoxia or hyperoxia, inflammatory cytokines and other inflammation-related proteins, and / or other abnormal physiological states such as hyperglycemia or hypoglycemia. In some embodiments, provided herein are compounds that can be used to treat and / or prevent mitochondrial dysfunction and conditions associated therewith.

[0191] In animal models of many of these conditions, 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, including models of myocardial infarction, renal failure, transplant failure and rejection, stroke, cardiovascular disease, and autoimmune disease (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 breaks down free heme into iron, carbon monoxide (CO), and biliverdin (which is subsequently converted to the potent antioxidant molecule bilirubin). Carbon monoxide has been shown to have signaling functions, and biliverdin reductase (an enzyme that catalyzes the conversion of biliverdin to bilirubin) has been shown to function as a dual-specificity kinase and to regulate HO-1 expression (Motterlini and Foresti, 2017; Florczyk et al., 2008).

[0192] In another aspect, the compounds of the present disclosure can be used to prevent or treat acute and chronic tissue damage or organ failure due to oxidative stress aggravated by inflammation. Examples of diseases falling into this category include: heart failure, liver failure, transplant failure and rejection, renal failure, pancreatitis, fibrotic lung diseases (especially cystic fibrosis, COPD and idiopathic pulmonary fibrosis), diabetes (including complications), atherosclerosis, ischemia-reperfusion injury (including complications of sickle cell anemia), glaucoma, stroke, autoimmune diseases, autism, macular degeneration and muscular dystrophy. For example, in the case of autism, studies suggest that increased oxidative stress in the central nervous system may promote the development of the disease (Chauhan and Chauhan, 2006).

[0193] Evidence also links oxidative stress and inflammation to the development and pathology of many other disorders of the central nervous system, 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, e.g., 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 severe mental illness (Dickerson et al., 2007). Microglial activation has also been associated with severe mental illness. Therefore, downregulating inflammatory cytokines and inhibiting the overactivation of microglia may be beneficial in patients with schizophrenia, major depression, bipolar disorder, autism spectrum disorder and other neuropsychiatric disorders. In some embodiments, provided herein are compounds that can be used to treat and / or prevent 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.

[0194] Thus, in pathologies involving oxidative stress alone or oxidative stress exacerbated by inflammation, treatment may include administering to the subject a therapeutically effective amount of a compound of the disclosure, such as those described above or throughout this specification. Treatment may be administered prophylactically prior to a predictable state of oxidative stress (e.g., organ transplantation or administration of radiation therapy to a cancer patient), or may be administered therapeutically in the context of established oxidative stress and inflammation.

[0195] The compounds disclosed herein may generally be useful for treating inflammatory conditions, such as sepsis, dermatitis, autoimmune diseases, and osteoarthritis. In one aspect, the compounds of the disclosure may be used to treat inflammatory pain and / or neuropathic pain, for example, by inducing Nrf2 and / or inhibiting NF-κB.

[0196] In some embodiments, the compounds disclosed herein can be used to treat and prevent diseases such as cancer, inflammation, Alzheimer's disease, Parkinson's disease, multiple sclerosis, autism, amyotrophic lateral sclerosis, Huntington's disease, autoimmune diseases such as rheumatoid arthritis, lupus, Crohn's disease and psoriasis, inflammatory bowel disease, all other diseases whose pathogenesis is thought to involve overproduction of nitric oxide or prostaglandins, and conditions involving oxidative stress alone or exacerbated by inflammation.

[0197] Another aspect of inflammation is the generation of inflammatory prostaglandins such as prostaglandin E. These molecules promote vasodilation, plasma extravasation, local pain, elevated body temperature and other inflammatory symptoms. The inducible form of enzyme COX-2 is relevant to their generation, and high levels of COX-2 are found in inflamed tissues. Therefore, the inhibition of COX-2 can alleviate many inflammatory symptoms, and a variety of important anti-inflammatory drugs (e.g., ibuprofen and celecoxib) play a role by inhibiting COX-2 activity. However, recent studies have confirmed that a class of cyclopentenone prostaglandins (cyPG) (e.g., 15-deoxyprostaglandin J2, also known as PGJ2) plays a role in the coordinated regression of stimulating inflammation (e.g., Rajakariar et al., 2007). COX-2 is also relevant to the generation of cyclopentenone prostaglandins. Therefore, the inhibition of COX-2 can interfere with the complete regression of inflammation, thereby promoting the persistence of activated immune cells in tissues and causing chronic "smoldering" inflammation potentially. This effect may contribute to the increased incidence of cardiovascular disease in patients using selective COX-2 inhibitors for long periods of time.

[0198] In one aspect, the compounds disclosed herein can be used to control the production of intracellular proinflammatory cytokines by selectively activating regulatory cysteine ​​residues (RCR) on proteins that regulate the activity of redox-sensitive transcription factors. It has been shown that cyPG activation of RCR causes such a pro-resolving program: wherein the activity of the antioxidant and cytoprotective transcription factor Nrf2 is effectively induced, and the activity of the pro-oxidative and pro-inflammatory transcription factors NF-кB and STAT is inhibited. In some embodiments, this increases the production of antioxidant and reductive molecules (NQO1, HO-1, SOD1, γ-GCS) and reduces oxidative stress and the production of pro-oxidative and pro-inflammatory molecules (iNOS, COX-2, TNF-α). In some embodiments, the compounds of the present disclosure can restore the cells that dominate inflammatory events to a non-inflammatory state by promoting the resolution of inflammation and limiting excessive tissue damage to the host.

[0199] IV. Pharmaceutical Formulations and Routes of Administration

[0200] In another aspect, in order to be administered to patients in need of such treatment, pharmaceutical preparations (also referred to as pharmaceutical products, pharmaceutical compositions, pharmaceutical products, medical products, medicines, drugs or medicaments) include a therapeutically effective amount of compounds disclosed herein, which are formulated together with one or more excipients and / or pharmaceutical carriers suitable for the indicated route of administration. In some embodiments, the compounds disclosed herein are formulated in a manner suitable for treating human and / or veterinary patients. In some embodiments, formulation includes mixing or combining one or more compounds disclosed herein with one or more of the following excipients: lactose, sucrose, starch powder, cellulose esters of alkanoic acid, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric acid and sulfuric acid, gelatin, gum arabic, sodium alginate, polyvinyl pyrrolidone and / or polyvinyl alcohol. In some embodiments, for example, for oral administration, the pharmaceutical preparation can be made into tablets or capsules. In some embodiments, the compound can be dissolved or slurried in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and / or various buffers. In some embodiments, the pharmaceutical preparation can be subjected to pharmaceutical operations, such as sterilization, and / or can contain pharmaceutical carriers and / or excipients such as preservatives, stabilizers, wetting agents, emulsifiers, encapsulating agents such as lipids, dendrimers, polymers, proteins such as albumin, nucleic acids, and buffers.

[0201] Pharmaceutical preparations can be administered by a variety of methods, such as orally or by injection (e.g., subcutaneously, intravenously, and intraperitoneally). Depending on the route of administration, the compounds disclosed herein can be encapsulated in materials to protect the compounds from the effects of acid and other natural conditions that may inactivate the compounds. In order to administer the active compound in a manner other than parenteral administration, it may be necessary to coat the compound with a substance that prevents its inactivation, or to co-administer the compound with the substance. In some embodiments, the active compound can be administered to the patient in an appropriate carrier (e.g., liposomes or diluents). Pharmaceutically acceptable diluents include saline and buffered aqueous solutions. Liposomes include water-in-oil-in-water CGF emulsions and conventional liposomes.

[0202] The compounds disclosed herein may also be administered parenterally, intraperitoneally, intraspinal or intracerebrally. Dispersions may be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof, and in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms.

[0203] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (in the case of water-soluble) or dispersions and sterile powders for the immediate preparation of sterile injectable solutions or dispersions. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyols (such as, glycerol, propylene glycol and liquid polyethylene glycol, etc.), suitable mixtures thereof and vegetable oils. Suitable fluidity may be maintained, for example, by using a coating agent such as lecithin by maintaining the desired particle size (in the case of dispersions) and by using a surfactant. The prevention of the effect of microorganisms may be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol (chlorobutanol), phenol, ascorbic acid, thimerosal, etc. In many cases, it is preferred to include an isotonic agent in the composition, for example, sugar, sodium chloride or polyols such as mannitol and sorbitol. By including an agent (for example, aluminum monostearate or gelatin) that delays absorption in the composition, the extended absorption of the injectable composition may be achieved.

[0204] The compounds disclosed herein can be administered orally, for example, with an inert diluent or an assimilable edible carrier. The compound and other ingredients can also be encapsulated in a hard or soft shell gelatin capsule, compressed into tablets, or directly incorporated into the patient's diet. For oral therapeutic administration, the compounds disclosed herein can be combined with excipients and used in the form of ingestible tablets, buccal tablets, lozenges, capsules, elixirs, suspensions, syrups, wafers, etc. The percentage of the therapeutic compound in the composition and preparation can certainly vary. The amount of the therapeutic compound in such a pharmaceutical preparation makes it possible to obtain a suitable dosage.

[0205] The therapeutic compound can also be applied topically to the skin, eyes, ears or mucous membranes. The topical application of the therapeutic compound can include compound preparations as topical solutions, lotions, creams, ointments, gels, foams, transdermal patches or tinctures. When the therapeutic compound is formulated for topical application, the compound can be combined with one or more agents that increase the permeability of the compound through the tissue to which it is applied. In other embodiments, it is expected that topical application will be applied to the eyes. Such application can be applied to the surface of the cornea, conjunctiva or sclera. Without wishing to be bound by any theory, it is believed that application to the surface of the eye allows the therapeutic compound to reach the back of the eye. Ophthalmic topical application can be formulated into solutions, suspensions, ointments, gels or emulsions. Finally, topical application can also include application to mucous membranes such as the inside of the oral cavity. Such application can be directly applied to a specific location in the mucous membrane, such as a tooth, sore or ulcer. Alternatively, if it is desired to be delivered locally to the lungs, the therapeutic compound can be applied by inhalation in the form of a dry powder or aerosol formulation.

[0206] In some embodiments, it may be advantageous to prepare a parenteral composition in a dosage unit form for ease of administration and uniform dosage. The dosage unit form used herein represents a physically discrete unit suitable as a unit dose for a patient to be treated; each unit contains a predetermined amount of a therapeutic compound calculated to produce a desired therapeutic effect in combination with a desired pharmaceutical carrier. In some embodiments, the specifications of the dosage unit form of the present invention are determined by and directly depend on: (a) the unique characteristics of the therapeutic compound and the specific therapeutic effect to be achieved, and (b) the inherent limitations in the field of preparing such a therapeutic compound for the treatment of the selected condition of the patient. In some embodiments, the active compound is administered in a therapeutically effective dose sufficient to treat a condition associated with the condition in the patient. For example, the efficacy of the compound can be evaluated in an animal model system that can predict the efficacy of treating a disease in a human or another animal.

[0207] In some embodiments, the effective dosage range of a therapeutic compound can be extrapolated from the effective dosage determined in animal studies for 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):

[0208] HED (mg / kg) = animal dose (mg / kg) × (animal K m / personK m )

[0209] K mThe use of a factor in the conversion produces HED values ​​based on body surface area (BSA) rather than just body weight. K in humans and various animals m The values ​​are well known. For example, the average 60 kg person (BSA is 1.6 m 2 ) m is 37, while a 20 kg child (BSA is 0.8 m 2 ) has a K of 25 m . K of some relevant animal models m Also well known, including: mouse K m is 3 (given a weight of 0.02 kg and a BSA of 0.007); hamster K m is 5 (given a weight of 0.08 kg and a BSA of 0.02); rat K m 6 (given a weight of 0.15 kg and a BSA of 0.025) and monkey K m is 12 (given a weight of 3 kg and a BSA of 0.24).

[0210] The exact amount of the therapeutic composition depends on the judgment of the practitioner and is specific to each individual. Nevertheless, the calculated HED dosage provides a general guide. Other factors affecting dosage include the patient's physical and clinical state, the route of administration, the intended therapeutic goal, and the efficacy, stability, and toxicity of the specific therapeutic formulation.

[0211] The amount of the actual dose of the compound of the present disclosure or the composition comprising the compound of the present disclosure administered to the patient can be determined by physical and physiological factors, such as the type of animal treated, age, sex, weight, severity of the condition, type of disease treated, previous or concurrent therapeutic interventions, idiopathic diseases of the patient, and route of administration. These factors can be determined by a technician. The practitioner responsible for administration will usually determine the concentration of the active ingredient in the composition and the appropriate dose for the individual patient. In the case of any complications, the individual physician can adjust the dosage.

[0212] In some embodiments, the therapeutically effective amount is generally between 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, about 10 mg / kg to about 150 mg / kg, administered in one or more doses per day for one or more days (depending of course on the mode of administration and the factors discussed above). Other suitable dosage ranges include 1 mg to 10,000 mg / day, 100 mg to 10,000 mg / day, 500 mg to 10,000 mg / day, and 500 mg to 1,000 mg / day. In some embodiments, the amount is less than 10,000 mg / day, ranging from 750 mg to 9,000 mg / day.

[0213] In some embodiments, the amount of active compound in the pharmaceutical formulation is from about 2 to about 75% by weight. In some of these embodiments, the amount is from about 25 to about 60% by weight.

[0214] A single dose or multiple doses of the agent are contemplated. One of ordinary skill in the art can determine the desired time interval for delivering multiple doses using no more than routine experimentation. As an example, two doses may be administered to the patient at intervals of approximately 12 hours per day. In some embodiments, the agent is administered once per day.

[0215] The medicament can be applied according to the conventional schedule. The conventional schedule used herein represents a predetermined specified time period. The conventional schedule can cover the same time period, or the time period of different lengths, as long as the schedule is predetermined. For example, the conventional schedule can include the application of the number of days or weeks of any setting 2 times a day, 1 time a day, 1 time every two days, 1 time every three days, 1 time every four days, 1 time every five days, 1 time every six days, 1 time a week, 1 time a month or therebetween. Alternatively, the predetermined conventional schedule can include the first week by applying twice a day, and then several months by applying once a day etc. In other embodiments, the invention provides that the medicament can be orally applied, and the timing of application depends on or does not depend on food intake. Therefore, for example, the medicament can be applied in the morning and / or at night every day, whether when the patient has eaten or will eat.

[0216] V. Combination Therapy

[0217] 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 enhance the function of CFTR (enhancers). For example, the combination can include the compounds of the present invention in combination with one or more correctors, one or more enhancers, a corrector and a enhancer. In other examples, the combination includes an amplifier and only one compound of the present invention or a combination of the above-mentioned combination of the compounds of the present invention and a corrector and an enhancer.

[0218] In some embodiments, a combination therapy is provided, in which the compounds disclosed herein are combined with another CF treatment, for example, a compound designed to improve the function of CFTR that has reached the cell membrane and can at least partially function. Such compounds are referred to as CFTR enhancers, and the first disease-specific therapy for CF, ivacaftor, has been clinically shown to improve CFTR function in patients with several significant mutations. Compounds that prevent the misfolding of CFTR are referred to as correctors. In some embodiments, the compounds of the present invention can be used to function as correctors. It is well understood in the art to enhance the efficacy of treating CF by combining two correctors or correctors with enhancers, and such combinations have been approved for listing or are currently being studied in clinical trials. The combination of three agents is also being studied in clinical trials. It should be recognized that multidrug therapy has or may soon become the standard of care. In some embodiments, other types 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 multidrug therapy.

[0219] Other potential combinations will be apparent to the skilled practitioner. In some embodiments, effective combination therapy is achieved using a single composition or pharmacological formulation comprising multiple agents, or with two or more different compositions or formulations administered simultaneously, wherein one composition comprises a compound of the disclosure and the other comprises an additional agent, formulated together or separately. Alternatively, in other embodiments, the therapy precedes or follows treatment with the other agent, with intervals ranging from minutes to months.

[0220] VI. Definitions

[0221] 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 taken to mean that any term not defined is undefined. Instead, all terms used are considered to describe the present disclosure in a manner that allows a person of ordinary skill to understand the scope and practice of the present disclosure.

[0222] When used in the context of chemical groups: "hydrogen" means -H; "hydroxy" means -OH; "oxo" means =O; "carbonyl" means -C(=O)-; "carboxyl" means -C(=O)OH (also written as -COOH or -CO2H); "halogen" independently means -F, -Cl, -Br or -I; "amino" means -NH2; "hydroxyamino" means -NHOH; "nitro" means -NO2; imino means =NH; "cyano" means -CN ; "isonitrile" refers to -N=C=O; "azido" refers to -N3; ​​in a monovalent context, "phosphate" refers to -OP(O)(OH)2 or a deprotonated form thereof; in a divalent context, "phosphate" refers to -OP(O)(OH)O- or a deprotonated form thereof; "thiol" refers to -SH; and "thio" refers to =S; "thiocarbonyl" refers to -C(=S)-; "sulfonyl" refers to -S(O)2-; and "sulfinyl" refers to -S(O)-.

[0223] In the context of a chemical formula, the symbol "-" refers to a single bond, "=" refers to a double bond, and "≡" refers to a triple bond. The symbol "----" represents an optional bond, which, if present, is either a single bond or a double bond. Symbols represents a single bond or a double bond. Therefore, the formula Covering, for example, And it should be understood that no such ring atom forms part of more than one double bond. In addition, it should be noted that the covalent bond symbol "-" does not indicate any preferred stereochemistry when connecting one or two stereogenic atoms. Instead, it encompasses all stereoisomers and mixtures thereof. When drawn vertically through a bond (e.g., for a methyl group, ),symbol It is intended to indicate the point of attachment of the group. It should be noted that attachment points are usually only identified in this way for larger groups to help the reader clearly identify the point of attachment. refers to a single bond where the group attached to the thick end of the wedge "comes out of the page". refers to a single bond where the group attached to the thick end of the wedge "enters the paper". Refers to a single bond, where the geometry (e.g., E or Z) around the double bond is undefined. Therefore, both options and their combinations 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 attached to that carbon is facing out of the plane of the paper. For example, the following two depictions are equivalent:

[0224]

[0225] When a variable is described as a "floating group" on a ring system, for example, the group "R" in the formula:

[0226]

[0227] The variable may replace any hydrogen atom attached to any of the ring atoms, including depicted, implied or explicitly defined hydrogens, as long as a stable structure results. When a variable is described as a "floating group" on a fused ring system, for example, the group "R" in the formula:

[0228]

[0229] Then the variable can replace any hydrogen connected to any ring atom of any one of the fused rings, unless otherwise specified.Replaceable hydrogen includes depicted hydrogen (e.g., hydrogen connected to nitrogen in the above formula), implicit hydrogen (e.g., hydrogen in the above formula not shown but understood to be present), well-defined hydrogen, and optional hydrogen (e.g., when X equals -CH-, hydrogen connected to group X) whose existence depends on the identity of the ring atom, as long as a stable structure is formed. In the example shown, R can be located on a 5- or 6-membered ring of a fused ring system. In the above formula, the subscript "y" followed by the R included in the brackets represents a numerical variable. Unless otherwise specified, this variable can be 0, 1, 2 or any integer greater than 2, limited only to the maximum number of replaceable hydrogen atoms of the ring or ring system.

[0230] For chemical groups and compound classes, the number of carbon atoms in the group or class is indicated as follows: "Cn" or "C=n" defines the exact number of carbon atoms (n) in the group / class. "C≤n" defines the maximum number of carbon atoms (n) that can be in the group / class, while the minimum number is as small as possible for the group / class in question. For example, it is understood that in the group "alkyl" (C≤8) ", "Alkanediyl (C≤8) ", "heteroaryl (C≤8) ” and “acyl (C≤8) The minimum number of carbon atoms in the group "alkenyl" is 1. (C≤8) ", "Alkynyl (C≤8) " and "heterocycloalkyl (C≤8) The minimum number of carbon atoms in a group "cycloalkyl" is 2. (C≤8) The minimum number of carbon atoms in the group "aryl" is 3. (C≤8) " and "aromatic diyl (C≤8) The minimum number of carbon atoms in a group is 6. "Cn-n'" defines the minimum number (n) and maximum number (n') of carbon atoms in a group. Thus, an "alkyl" (C2-10)" refers to those alkyl groups having 2-10 carbon atoms. These carbon number indicators may precede or follow the chemical group or class they modify, and they may or may not be included in parentheses without indicating any change in meaning. Thus, the term "C 1-4 -alkyl", "C1-4-alkyl", "alkyl (C1-4) ” and “alkyl (C≤4) " are synonymous. Except as noted below, each carbon atom is counted to determine whether the group or compound falls within the specified number of carbon atoms. For example, the group dihexylamino is dialkylamino (C12) group; however, it is not a dialkylamino (C6) Similarly, phenethyl is an aralkyl (C＝8) When any chemical group or compound class defined herein is modified by the term "substituted," any carbon atoms in the moiety replacing a hydrogen atom are not counted. Thus, a methoxyhexyl group, having a total of seven carbon atoms, is a substituted alkyl group. (C1-6) Unless otherwise indicated, any chemical group or class of compounds listed in a claim group without a carbon atom limitation has a carbon atom limitation of less than or equal to 12.

[0231] When used to modify a compound or chemical group, the term "saturated" means that the compound or chemical group has no carbon-carbon double bonds and no carbon-carbon triple bonds, unless as shown below. When the term is used to modify an atom, it means that the atom is not part of any double or triple bonds. In the case of substituted forms of saturated groups, one or more carbon-oxygen double bonds or carbon-nitrogen double bonds may be present. And when such bonds exist, carbon-carbon double bonds that may appear as part of keto-enol tautomerism or imine / enamine tautomerism are not excluded. When the term "saturated" is used to modify a solution of a substance, it means that no more of the substance can be dissolved in the solution.

[0232] The term "aliphatic" means that the compound or chemical group so modified is an acyclic or cyclic, but non-aromatic compound or group. In aliphatic compounds / groups, the carbon atoms can be linked together in straight chains, branched chains or non-aromatic rings (alicyclic). Aliphatic compounds / groups can be saturated, i.e. linked by a single carbon-carbon bond (alkanes / alkyls), or unsaturated, having one or more carbon-carbon double bonds (olefins / alkenyls) or having one or more carbon-carbon triple bonds (alkynes / alkynyls).

[0233] The term "aromatic" means that the compound or chemical group so modified has a planar unsaturated ring of atoms containing 4n+2 electrons in a completely conjugated cyclic π system. Aromatic compounds or chemical groups can be depicted as a single resonance structure; however, the depiction of one resonance structure is also used to represent any other resonance structure. For example:

[0234] Also used to indicate

[0235] Aromatic compounds can also be depicted with circles to represent the delocalized nature of the electrons in a fully conjugated cyclic π system, two non-limiting examples of which are shown below:

[0236]

[0237] The term "alkyl" means a monovalent saturated aliphatic group having a carbon atom as the point of attachment, having a straight or branched acyclic structure, and having no atoms other than carbon and hydrogen. The groups -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, tert-butyl, t-Bu or t Bu) and -CH2C(CH3)3 (neopentyl) are non-limiting examples of alkyl groups. The term "alkanediyl" means a divalent saturated aliphatic group having 1 or 2 saturated carbon atoms as points of attachment, having a straight or branched acyclic structure, no carbon-carbon double or triple bonds, and no atoms other than carbon and hydrogen. The groups -CH2-(methylene), -CH2CH2-, -CH2C(CH3)2CH2- and -CH2CH2CH2- are non-limiting examples of alkanediyl groups. The term "alkylene" means a divalent group =CRR', wherein R and R' are independently hydrogen or alkyl. Non-limiting examples of alkylene groups include: =CH2, =CH(CH2CH3) and =C(CH3)2. "Alkanes" means the class of compounds having the formula HR, wherein R is an alkyl group, as that term is defined above.

[0238] The term "cycloalkyl" means a monovalent saturated aliphatic group having a carbon atom as the point of attachment, the carbon atom forming 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, the term does not exclude the presence of one or more alkyl groups (carbon number limitations permitting) attached to carbon atoms of a non-aromatic ring structure. The term "cycloalkanediyl" means a divalent saturated aliphatic group having 2 carbon atoms as the point of attachment, no carbon-carbon double or triple bonds, and no atoms other than carbon and hydrogen. Group is a non-limiting example of a cycloalkanediyl group. "Cycloalkanes" refers to the class of compounds having the formula HR, in which R is cycloalkyl, and as that term is defined above.

[0239] The term "heterocycloalkyl" refers to a monovalent non-aromatic group with a carbon atom or a nitrogen atom as a point of attachment, wherein the carbon atom or the nitrogen atom forms a part of one or more non-aromatic ring structures, and each non-aromatic ring structure has 3-8 ring atoms, wherein at least one ring atom of the non-aromatic ring structure is nitrogen, oxygen or sulfur, and wherein the heterocycloalkyl is not composed of atoms other than carbon, hydrogen, nitrogen, oxygen and sulfur. If there is more than one ring, the ring is fused. The term used herein does not exclude the presence of one or more alkyl groups (carbon number restrictions allow) connected to one or more ring atoms. Moreover, the term does not exclude the presence of one or more double bonds in a ring or ring system, provided that the obtained group is still non-aromatic. The non-limiting examples of heterocycloalkyl include aziridine, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, pyranyl, oxacyclopropyl and oxacyclobutyl. The term "N-heterocycloalkyl" means a heterocycloalkyl group having a nitrogen atom as a point of attachment. N-pyrrolidinyl is an example of such a group. The term "heterocycloalkanediyl" means a divalent cyclic group having 2 carbon atoms, 2 nitrogen atoms or 1 carbon atom and 1 nitrogen atom as 2 points of attachment, wherein the atoms form part of one or more ring structures, wherein at least one ring atom of the non-aromatic ring structure is nitrogen, oxygen or sulfur, and wherein the divalent group is not composed of atoms other than carbon, hydrogen, nitrogen, oxygen and sulfur. If there is more than one ring, the ring is fused. The term heterocycloalkanediyl used herein does not exclude the presence of one or more alkyl groups (carbon number restrictions allow) connected to one or more ring atoms. Moreover, the term does not exclude the presence of one or more double bonds in a ring or ring system, provided that the resulting group is still non-aromatic. Non-limiting examples of heterocycloalkanediyl include:

[0240]

[0241] The term "alkenyl" refers to a monovalent unsaturated aliphatic group having a carbon atom as a point of attachment, having a straight 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=CHCH3 and -CH=CHCH=CH2. The term "alkene diyl" refers to a divalent unsaturated aliphatic group having 2 carbon atoms as points of attachment, having a straight 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. The groups -CH=CH-, -CH=C(CH3)CH2-, -CH=CHCH2- and -CH2CH=CHCH2- are non-limiting examples of alkene diyl groups. It should be noted that although the alkene diyl group is aliphatic, once attached at both ends, this does not exclude the group from forming part of an aromatic structure. The terms "olefin" and "alkene" are synonymous and refer to the class of compounds having the formula HR, wherein R is an alkenyl group, as defined above. Similarly, the terms "terminal olefin" and "alpha-olefin" are synonymous and refer to an olefin having exactly one carbon-carbon double bond, wherein the bond is part of a vinyl group at the end of the molecule.

[0242] The term "alkynyl" refers to a monovalent unsaturated aliphatic group having a carbon atom as a point of attachment, having a straight or branched acyclic structure, at least one carbon-carbon triple bond, and no atoms other than carbon and hydrogen. The term alkynyl as used herein does not exclude the presence of one or more non-aromatic carbon-carbon double bonds. The groups -C≡CH, -C≡CCH3 and -CH2C≡CCH3 are non-limiting examples of alkynyl. "Alkyne" refers to a class of compounds having the formula HR, wherein R is an alkynyl.

[0243] The term "aryl" refers to a monovalent unsaturated aromatic group with an aromatic carbon atom as a point of attachment, wherein the carbon atom forms a part of one or more aromatic ring structures, each of which has 6 ring atoms that are all carbon, and wherein the group is not composed of atoms other than carbon and hydrogen. If there is more than one ring, the ring can be fused or unfused. Unfused rings are connected by covalent bonds. The term aryl used herein does not exclude the presence of one or more alkyl groups (carbon number restrictions allow) that are connected to the first aromatic ring or any additional aromatic rings present. The non-limiting examples of aryl groups include phenyl (Ph), methylphenyl, (dimethyl) phenyl, -C6H4CH2CH3 (ethylphenyl), naphthyl and the monovalent group derived from biphenyl (for example, 4-phenylphenyl). The term "arene diradical" refers to a divalent aromatic group with 2 aromatic carbon atoms as a point of attachment, wherein the carbon atom forms a part of one or more 6-membered aromatic ring structures, each of which has 6 ring atoms that are all carbon, and wherein the divalent group is not composed of atoms other than carbon and hydrogen. The term arene diyl as used herein does not exclude the presence of one or more alkyl groups (carbon number limitation permitting) connected to the first aromatic ring or any additional aromatic rings present. If there is more than one ring, the rings may be fused or unfused. Unfused rings are connected by covalent bonds. Non-limiting examples of arene diyl groups include:

[0244]

[0245] "Aromatic hydrocarbons" refers to the class of compounds having the formula HR, wherein R is an aryl group, as that term is defined above. Benzene and toluene are non-limiting examples of aromatic hydrocarbons.

[0246] The term "aralkyl" refers to the monovalent group -alkanediyl-aryl, wherein the terms alkanediyl and aryl are each used in a manner consistent with the definitions provided above. Non-limiting examples are: phenylmethyl (benzyl, Bn) and 2-phenyl-ethyl.

[0247] The term "heteroaryl" refers to a monovalent aromatic group having an aromatic carbon atom or nitrogen atom as a point of attachment, the carbon atom or nitrogen atom forming part of one or more aromatic ring structures, each of which has 3-8 ring atoms, wherein at least one ring atom of the aromatic ring structure is nitrogen, oxygen or sulfur, and wherein the heteroaryl is not composed of atoms other than carbon, hydrogen, aromatic nitrogen, aromatic oxygen and aromatic sulfur. If more than one ring is present, the rings are fused; however, the term heteroaryl does not exclude the presence of one or more alkyl or aryl groups (carbon number limitations permitting) attached to one or more ring atoms. Non-limiting examples of heteroaryl include benzoxazolyl, benzimidazolyl, furanyl, imidazolyl (Im), indolyl, indazolyl, isoxazolyl, methylpyridyl, oxazolyl, oxadiazolyl, phenylpyridyl, pyridyl (pyridyl), pyrrolyl, pyrimidinyl, pyrazinyl, quinolyl, quinazolinyl, quinoxalinyl, triazinyl, tetrazolyl, thiazolyl, thienyl and triazolyl. The term "N-heteroaryl" means a heteroaryl having a nitrogen atom as a point of attachment. "Heteroarene" means a class of compounds having the formula HR, wherein R is a heteroaryl. Pyridine and quinoline are non-limiting examples of heteroarene. The term "heteroarene diyl" refers to a divalent aromatic group having 2 aromatic carbon atoms, 2 aromatic nitrogen atoms, or 1 aromatic carbon atom and 1 aromatic nitrogen atom as 2 points of attachment, said atoms forming part of one or more aromatic ring structures (each having 3-8 ring atoms), wherein at least one ring atom of said aromatic ring structure is nitrogen, oxygen or sulfur, and wherein said divalent group does not consist of atoms other than carbon, hydrogen, aromatic nitrogen, aromatic oxygen and aromatic sulfur. If there is more than one ring, said rings are fused; however, the term heteroarene diyl does not exclude the presence of one or more alkyl or aryl groups (carbon number limitation permitting) attached to one or more ring atoms. Non-limiting examples of heteroarene diyls include:

[0248]

[0249] The term "acyl" refers to a group-C (O) R, wherein R is hydrogen, alkyl, cycloalkyl or aryl, and those terms are as defined above. Groups-CHO,-C (O) CH (acetyl, Ac),-C (O) CH CH,-C (O) CH (CH) ,-C (O) CH (CH) ,-C (O) C H and-C (O) C H CH are non-limiting examples of acyl groups. "Thioacyl" is defined in a similar manner, but the oxygen atom of the group-C (O) R has been replaced with a sulphur atom,-C (S) R. The term "aldehyde" corresponds to an alkyl as defined above that is connected to a-CHO group.

[0250] The term "alkoxy" refers to a group -OR, wherein R is an alkyl group, as defined above. Non-limiting examples include: -OCH3 (methoxy), -OCH2CH3 (ethoxy), -OCH2CH2CH3, -OCH(CH3)2 (isopropoxy) or -OC(CH3)3 (tert-butoxy). The terms "cycloalkoxy", "alkenyloxy", "alkynyloxy", "aryloxy", "aralkyloxy", "heteroaryloxy", "heterocycloalkoxy" and "acyloxy" used without the "substituted" modifier refer to a group defined as -OR, wherein R is a cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heterocycloalkyl and acyl, respectively. The terms "alkylthio" and "acylthio" refer to a group -SR, wherein R is an alkyl and acyl, respectively. The term "alcohol" corresponds to an alkane as defined above, wherein at least one hydrogen atom has been replaced with a hydroxyl group. The term "ether" corresponds to an alkane as defined above, wherein at least one hydrogen atom has been replaced with an alkoxy group.

[0251] The term "alkylamino" refers to the group -NHR, wherein R is an alkyl group, as defined above. Non-limiting examples include: -NHCH3 and -NHCH2CH3. The term "dialkylamino" refers to the group -NRR', wherein R and R' may be the same or different alkyl groups. Non-limiting examples of dialkylamino groups include: -N(CH3)2 and -N(CH3)(CH2CH3). The terms "cycloalkylamino", "alkenylamino", "alkynylamino", "arylamino", "aralkylamino", "heteroarylamino", "heterocycloalkylamino" and "alkoxyamino" used without the "substituted" modifier refer to groups defined as -NHR, wherein R is cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heterocycloalkyl and alkoxy, respectively. A non-limiting example of an arylamino group is -NHC6H5. The term "acylamino" (acylamino) used without the "substituted" modifier refers to the group -NHR, wherein R is an acyl group, as defined above. A non-limiting example of an amido group is -NHC(O)CH3.

[0252] When a chemical group is used with the "substituted" modifier, one or more hydrogen atoms have been replaced, independently in each instance, 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: -CH2OH, -CH2Cl, -CF3, -CH2CN, -CH2C(O)OH, -CH2C(O)OCH3, -CH2C(O)NH2, -CH2C(O)CH3, -CH2OCH3, -CH2OC(O)CH3, -CH2NH2, -CH2N(CH3)2, and -CH2CH2Cl. The term "hydroxyalkyl" is a subset of substituted alkyl groups in which one or more hydrogen atoms have been replaced by a hydroxyl group (i.e., -OH) such that no atoms other than carbon, hydrogen, and oxygen are present. The groups -CH2OH, -CH2CH2OH, -CH(OH)CHOH, -CH2CH(OH)CH3, and -CH(OH)CH2OH are non-limiting examples of hydroxyalkyl groups. The term "monohydroxyalkyl" is a subset of substituted alkyl groups in which one hydrogen atom has been replaced by a hydroxyl group (i.e., -OH) such that no atoms other than carbon, hydrogen, and one oxygen are present. The groups -CH2OH, -CH2CH2OH and -CH2CH(OH)CH3 are non-limiting examples of monohydroxyalkyl. The term "fluoroalkyl" is a subset of substituted alkyl, wherein one or more hydrogen atoms have been replaced by fluorine, so that no other atoms other than carbon, hydrogen and fluorine exist. The groups -CH2F, -CHF2 and -CF3 are non-limiting examples of fluoroalkyl. The term "monofluoroalkyl" is a subset of substituted alkyl, wherein one hydrogen atom has been replaced by fluorine, so that no other atoms other than carbon, hydrogen and one fluorine exist. The groups -CH2F, -CH2CH2F and -CH2CH(F)CH3 are non-limiting examples of monofluoroalkyl. The term "aminoalkyl" is a subset of substituted alkyl, wherein one or more hydrogen atoms have been replaced by amino (i.e. -NH2), so that no other atoms other than carbon, hydrogen and nitrogen exist. The groups -CH2NH2, -CH(NH2)CH3, -CH2CH2NH2, -CH2CH(NH2)CH3 and -CH(NH2)CH2NH2 are non-limiting examples of aminoalkyl groups.The term "monoaminoalkyl" is a subset of substituted alkyl groups in which one hydrogen atom has been replaced by an amino group (i.e., -NH2) so that no atoms other than carbon, hydrogen, and one nitrogen are present. The groups -CH2NH2, -CH2CH2NH2, and -CH2CH(NH2)CH3 are non-limiting examples of monoaminoalkyl groups. Non-limiting examples of substituted aralkyl groups are: (3-chlorophenyl)-methyl and 2-chloro-2-phenyl-ethyl-1-yl. The groups -C(O)CH2CF3, -CO2H(carboxyl), -CO2CH3(methylcarboxyl), -CO2CH2CH3, -C(O)NH2(carbamoyl), and -CON(CH3)2 are non-limiting examples of substituted acyl groups. The groups -NHC(O)OCH3 and -NHC(O)NHCH3 are non-limiting examples of substituted acylamino groups.

[0253] When a chemical group is used with the "polar-substituted" modifier, one or more hydrogen atoms have been replaced, independently in each instance, with one of the following polar substituents: -OH, -F, -NH2, -C02H, -C02CH3, -C(O)NH2, -C(O)NHCH3, -OC(O)CH3, -NHC(O)CH3, -NHC(O)OCH3, -NHC(O)OCH2CH3, -NHC(O)NHCH3, -NHC(O)NHCH2CH3, -S(O)2OH, or -S(O)2CH3. )2 NH2, with the proviso that not every hydrogen is so replaced. Non-limiting examples of polar-substituted alkyl groups include -CH2F, -CHF2, -CH2CH2F, -CHFCH2F, -CF2CH3, -CH2OH, -CH2CH2OH, -CH2CH2CH2NH2, -CH2CH2OH, and -CH(NH2)CH2OH.

[0254] When a chemical group is used with the "monopolar-substituted" modifier, one and only one hydrogen atom has been replaced with one of the following polar substituents: -OH, -F, -NH2, -C02H, -C02CH3, -C(O)NH2, -C(O)NHCH3, -OC(O)CH3, -NHC(O)CH3, -NHC(O)OCH3, -NHC(O)OCH2CH3, -NHC(O)NHCH3, -NHC(O)NHCH2CH3, -S(O)2OH, or -S(O)2NH2. Non-limiting examples of monopolar-substituted alkyl groups include -CH2F, -CH2CH2F, -CHFCH3, -CH2OH, -CH2CH2OH, -CH(OH)CH2OH, -CH2NH2, -CH2CH2NH2, and -CH(NH2)CH3.

[0255] Some abbreviations used in this article are as follows: Ac represents acetyl (-C(O)CH3); Boc represents tert-butyloxycarbonyl; COPD represents chronic obstructive pulmonary disease; COX-2 represents cyclooxygenase-2; CYP3A4 represents cytochrome P450 3A4; cyPGs represents cyclopentenone prostaglandins; DBDMH represents 1,3-dibromo-5,5-dimethylhydantoin; DIBAL-H is diisobutylaluminum hydride; DMAP represents 4-dimethylaminopyridine; DMF is dimethylformamide; DMSO is dimethyl sulfoxide; EDC is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; Et2O, diethyl ether; HO-1 represents inducible heme oxygenase; IFNγ or IFN-γ represents interferon-γ; IL-1 represents interleukin-1 family; iNOS represents inducible nitric oxide synthase ; NCS stands for N-chlorosuccinimide; NMO stands for N-methylmorpholine N-oxide; NO stands for nitric oxide; NQO1 stands for NAD(P)H dehydrogenase (quinone 1); Nrf2 stands for nuclear factor erythroid 2-related factor 2; OA stands for oleanolic acid; Py stands for pyridine; T3P stands for propylphosphonic anhydride; TFA stands for trifluoroacetic acid; TFAA stands for trifluoroacetic anhydride; THF stands for tetrahydrofuran; TNFα or TNF-α, tumor necrosis factor-α; TPAP stands for tetrapropylammonium perruthenate; Ts stands for tosyl; TsOH or p-TsOH is p-toluenesulfonic acid; MS stands for 4 angstrom molecular sieve.

[0256] When used in conjunction with the term "comprising" in the claims and / or the specification, the use of the word "a" or "an" can mean "one", but it is also consistent with the meaning of "one or more", "at least one", and "one or more than one".

[0257] Throughout this application, the term "about" is used to indicate that a value includes the inherent variation of error for the device, method being employed to determine the value, or the variation that exists between study subjects or patients.

[0258] An "active ingredient" (AI) or active pharmaceutical ingredient (API) (also referred to as active compound, active substance, active agent, pharmaceutical agent, agent, bioactive molecule, or therapeutic compound) is the biologically active component of a drug.

[0259] The terms "comprises," "having," and "includes" 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," are 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, and also encompasses other unlisted steps.

[0260] The term "effective," as the term is used in this specification and / or claims, means sufficient to achieve a desired, expected, or intended result. When used in the context of treating a patient or subject with a compound, "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" means an amount of such a compound that, when administered to the patient or subject, is sufficient to achieve such treatment or prevention of the disease, as those terms are defined below.

[0261] "Excipient" is a pharmaceutically acceptable substance prepared with the active ingredient of a drug, pharmaceutical composition, preparation or drug delivery system. Excipients can be used, for example, to stabilize the composition, expand the composition (when used for this purpose, it is often referred to as "bulking agent", "filler" or "diluent"), or to give therapeutic enhancement to the active ingredient in the final dosage form, such as promoting drug absorption, reducing viscosity or improving solubility. Excipients include pharmaceutically acceptable forms of anti-adherents, adhesives, coatings, pigments, disintegrants, flavoring agents, glidants, lubricants, preservatives, adsorbents, sweeteners and vehicles. The main excipients that serve as a medium for transporting active ingredients are generally referred to as vehicles. Excipients can also be used in manufacturing processes, for example, to assist the processing of active substances, such as by promoting powder fluidity or non-stick properties, and to assist in vitro stability, such as preventing denaturation or aggregation within the expected shelf life. The applicability of excipients will usually change, depending on route of administration, dosage form, active ingredient and other factors.

[0262] The term "hydrate," when used as a modifier of a compound, means that the compound has less than one (e.g., hemihydrate), one (e.g., monohydrate), or more than one (e.g., dihydrate) molecule of water associated with each molecule of the compound (such as a solid form of the compound).

[0263] The term “IC 50" represents the inhibitory dose that obtains 50% of the maximal response. This quantitative measure indicates the amount of a particular drug or other substance (inhibitor) required to inhibit a given biological, biochemical, or chemical process (or component of a process, i.e., an enzyme, cell, cell receptor, or microorganism) by half. The term "relative IC 50 ” represents the fold difference in potency between two compounds. Using the following equation, the IC of the target compound in each experimental assay was calculated. 50 Divide the value by the IC of the benchmark compound 50 Value to determine it:

[0264]

[0265] "Isomers" of a first compound are individual compounds wherein each molecule contains the same constituent atoms as the first compound, but wherein the three-dimensional configuration of those atoms is different.

[0266] 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 a transgenic species thereof. In certain embodiments, the patient or subject is a primate. Non-limiting examples of human patients are adults, teenagers, infants, and fetuses.

[0267] As used generally herein, "pharmaceutically acceptable" refers to compounds, materials, 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 problems or complications, commensurate with a reasonable benefit / risk ratio.

[0268] "Pharmaceutically acceptable salts" refers to salts of compounds disclosed herein that are pharmaceutically acceptable as defined above and that possess the desired pharmacological activity. Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or organic acids such as 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 mono- and dicarboxylic acids, aliphatic sulfuric acid, aromatic sulfuric acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, carbonic acid, Pharmaceutically acceptable salts include cinnamic acid, citric acid, cyclopentanepropionic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, enanthic acid, caproic 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 acid, propionic acid, p-toluenesulfonic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, tartaric acid, tert-butylacetic acid, trimethylacetic acid, etc. Pharmaceutically acceptable salts also include base addition salts that can be formed when the acidic protons present can react with inorganic bases 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-methyl reduced glucosamine, etc. It should be recognized that the specific anion or cation forming part of any salt of the present disclosure is not critical so long as the salt as a whole is pharmacologically acceptable. Other examples of pharmaceutically acceptable salts and methods of making and using them are presented in Handbook of Pharmaceutical Salts: Properties, and Use (PH Stahl & C. G. Wermuth, ed., Verlag Helvetica Chimica Acta, 2002).

[0269] A "pharmaceutically acceptable carrier", "drug carrier" or simply "carrier" is a pharmaceutically acceptable substance formulated with an active ingredient drug that participates in the carriage, delivery and / or transport of a chemical agent. Drug carriers can be used to improve the delivery and effectiveness of drugs, including, for example, controlled release technologies to regulate drug bioavailability, reduce drug metabolism and / or reduce drug toxicity. Some drug carriers may increase the effectiveness of drug delivery to specific target sites. Examples of carriers include: liposomes, microspheres (e.g., made of poly(lactic-glycolic acid)), albumin microspheres, synthetic polymers, nanofibers, protein-DNA complexes, protein conjugates, erythrocytes, virosomes, and dendrimers.

[0270] A "pharmaceutical drug" (also referred to as a drug, drug product, pharmaceutical composition, pharmaceutical preparation, pharmaceutical product, medicinal product, drug, medicine, medicament or simply drug, medicament or preparation) is a composition used for the diagnosis, cure, treatment or prevention of disease, which comprises an active pharmaceutical ingredient (API) (as defined above) and optionally contains one or more inactive ingredients, which are also referred to as excipients (as defined above).

[0271] "Prevent" or "preventing" includes: (1) inhibiting the onset of a disease in a subject or patient who may be at risk for and / or susceptible to the disease but does not yet experience or display any or all of the symptoms or signs of the disease; and / or (2) slowing the onset of symptoms or signs of a disease in a subject or patient who may be at risk for and / or susceptible to the disease but does not yet experience or display any or all of the symptoms or signs of the disease.

[0272] "Prodrug" refers to a compound that can be converted into the active pharmaceutical ingredient of this disclosure in a metabolic manner in vivo. The prodrug itself may or may not be active in its prodrug form. For example, a compound comprising a hydroxyl group can be used as an ester that is converted into a hydroxy compound by hydrolysis in vivo. The non-limiting example of a suitable ester that can be converted into a hydroxy compound in vivo includes acetate, citrate, lactate, phosphate, tartrate, malonate, oxalate, salicylate, propionate, succinate, fumarate, maleate, methylene-di-β-hydroxynaphthoate, gentisate, isethionate, di-toluoyl tartrate, mesylate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylaminosulfonate, quinate and an amino acid ester. Similarly, a compound comprising an amine group can be used as an amide that is converted into an amine compound by hydrolysis in vivo.

[0273] "Stereoisomers" or "optical isomers" are isomers of a given compound in which the same atoms are bonded to the same other atoms, but in which the three-dimensional configurations of those atoms are different. "Enantiomers" are stereoisomers of a given compound that are mirror images of each other like the left and right hands. "Diastereomers" are stereoisomers of a given compound that are not enantiomers. Chiral molecules contain chiral centers (also called stereocenters or stereocenters), which are any points (although not necessarily atoms) in a molecule that carry multiple groups, such that the interchange of any two groups produces stereoisomers. In organic compounds, chiral centers are usually carbon, phosphorus, or sulfur atoms, although other atoms may also become stereocenters in organic and inorganic compounds. A molecule can have multiple stereocenters, thereby producing many stereoisomers of it. In compounds whose stereoisomerism can be attributed to tetrahedral stereocenters (e.g., tetrahedral carbon), it is assumed that the total number of possible stereoisomers will not exceed 2n, where n is the number of tetrahedral stereocenters. Molecules with symmetry often have a smaller number of stereoisomers than the maximum possible number. A 50:50 mixture of enantiomers is called a racemic mixture. Alternatively, a mixture of enantiomers can be enantiomerically enriched so that one enantiomer is present in an amount greater than 50%. Typically, enantiomers and / or diastereomers can be split or separated using techniques known in the art. It is expected that for any stereocenter or chiral axis whose stereochemistry has not yet been defined, the stereocenter or chiral axis can exist in its R form, S form, or as a mixture of the R form and the S form (including racemic mixtures and non-racemic mixtures). The phrase "substantially free of other stereoisomers" used herein means that the composition contains ≤15%, more preferably ≤10%, even more preferably ≤5%, or most preferably ≤1% of one or more other stereoisomers.

[0274] "Treatment" or "treating" includes (1) inhibiting the disease in a subject or patient who is experiencing or exhibiting symptoms or signs of the disease (e.g., arresting further development of the symptoms and / or symptoms), (2) ameliorating the disease in a subject or patient who is experiencing or exhibiting symptoms or signs of the disease (e.g., reversing the symptoms and / or symptoms), and / or (3) achieving any measurable reduction in the disease or its symptoms in a subject or patient who is experiencing or exhibiting symptoms or signs of the disease.

[0275] The term "unit dose" refers to a formulation of a compound or composition such that the formulation is prepared in a manner sufficient to provide a single therapeutically effective dose of the active ingredient to a patient in a single administration. Such unit dose formulations that may be used include, but are not limited to, a single tablet, capsule or other oral formulation, or a single vial with an injectable liquid or other injectable formulation.

[0276] The above definitions supersede any conflicting definitions in any references incorporated herein by reference. However, the fact that certain terms are defined should not be considered to indicate that any term not defined is indefinite. On the contrary, all terms used are considered to describe the present invention in a manner that allows those of ordinary skill in the art to understand the scope of the present invention and implement the present invention.

[0277] VII. Examples

[0278] The following examples are included to demonstrate the preferred embodiments of the present invention. It will be appreciated by those skilled in the art that the techniques disclosed in the following examples represent techniques that the inventors have found to work well in the practice of the present invention, and thus can be considered to constitute the preferred modes of its practice. However, it will be appreciated by those skilled in the art that many changes can be made in the disclosed specific embodiments and still similar or similar results can be obtained without departing from the spirit and scope of the present invention, in view of the present disclosure.

[0279] Example 1: Synthesis and characterization

[0280] A. General Information

[0281] Unless otherwise stated, commercial reagents were used as received and all reactions were performed under nitrogen. All solvents were HPLC or ACS grade. 1 Nuclear magnetic resonance (NMR) spectra were recorded at the operating frequency of H NMR. The spectra were expressed in ppm relative to the residual solvent (usually chloroform, for 1 Chemical shifts (δ) are given in Hz for H NMR (δ 7.26 ppm) and coupling constants (J) in Hz. Multiplicities are tabulated 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 may be prepared according to the methods outlined in Example 1 and methods known to the skilled artisan, including those disclosed in WO 2012 / 125488 and WO 2014 / 040056 (both of which are incorporated herein by reference).

[0282]

[0283]

[0284]

[0285]

[0286]

[0287]

[0288]

[0289]

[0290]

[0291]

[0292]

[0293]

[0294]

[0295]

[0296]

[0297]

[0298]

[0299]

[0300]

[0301]

[0302]

[0303]

[0304]

[0305]

[0306]

[0307]

[0308]

[0309] C. Characterization Data

[0310] Compound 2: Compound 1 (10.00 g, 19.71 mmol) in THF (200 mL) was cooled to 0°C under N2. DIBAL-H (1.0 M in toluene, 100 mL, 100 mmol) was added. The mixture was stirred at 0°C for 30 min, and then at room temperature for 2 h. The reactants were cooled to 0°C and carefully quenched with water (20 mL) followed by 1 N 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 Na2SO4; filtered and concentrated to give crude compound 2 (9.5 g, quantitative yield) as a white solid. m / z=482 (M+1).

[0311] Compound 3: Compound 2 (9.5 g, <19.71 mmol) was dissolved in CH2Cl2 (200 mL). MS (20g) and 4-methylmorpholine N-oxide (5.10g, 43.53mmol). The mixture was stirred at room temperature for 10min under N2. TPAP (690mg, 1.96mmol) was added. The mixture was stirred at room temperature for 1.5h, and then quenched with 10% Na2SO3 (50mL). The mixture was stirred at room temperature for 5min, and then filtered through a diatomaceous earth pad. The diatomaceous earth was eluted with CH2Cl2 (50mL). The organic phase from the filtrate was separated. The aqueous phase from the filtrate was extracted with CH2Cl2 (2×50mL) and EtOAc (2×50mL). The combined organic extracts were washed with water (100mL); dried with Na2SO4; and filtered through a silica gel pad, which was eluted with EtOAc (100mL). The filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluted with 0-35% EtOAc in hexanes) to give Compound 3 (6.39 g, 68% yield) as a white solid. m / z = 478 (M+I).

[0312] Compound 4: Compound 3 (2.72 g, 5.69 mmol), NH2OH-HCl (514 mg, 7.40 mmol) and NaOAc (841 mg, 10.2 mmol) were weighed in 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 distributed between EtOAc (50 mL) and water (30 mL). The aqueous phase was extracted with EtOAc (30 mL). The combined organic extracts were dried, filtered and concentrated with Na2SO4. The residue contained a small amount of AcOH and water. EtOH (10 mL) and toluene (10 mL) were added, and then the mixture was concentrated. The residue was ground under reflux for 10 min with CH2Cl2 (30 mL). 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 (2×5 mL); and dried under vacuum to give Compound 4 (2.15 g, 77% yield) as a white solid. m / z=493 (M+1).

[0313] Compound 5: Under N2, compound 4 (2.68 g, 5.44 mmol) was suspended in MeCN (11 mL) and cooled to -10 ° C. Aqueous HCl (12N, 91 μL, 1.09 mmol) was added, followed by N-chlorosuccinimide (726 mg, 5.44 mmol) in MeCN (11 mL). The reactants were stirred at -10 ° C for 30 min. LCMS indicated that the starting material was almost consumed. 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 (2×40 mL). The combined aqueous washings were extracted with EtOAc (30 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, 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).

[0314] Compound 6: A solution of 2-fluoroacetic acid (23 mg, 0.30 mmol) in CH2Cl2 (1 mL) was added to N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC·HCl, 57 mg, 0.30 mmol) at room temperature under N2. A catalytic amount of DMAP (1.8 mg, 0.015 mmol) was added. The mixture was stirred at room temperature for 15 min. Compound 5 (50 mg, 0.098 mmol) in CH2Cl2 (2 mL) was added. The mixture was stirred at room temperature for 1 h. The mixture was diluted with CH2Cl2 (20 mL) and washed with water (2×10 mL). The combined aqueous washings were extracted with CH2Cl2 (20 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated. The residue was combined with the crude product 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 CH2Cl2) to give compound 6 (47 mg, 69% yield) as a white solid. m / z=568 (M+1).

[0315] Compound 7: 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).

[0316] Compound 8: To a mixture of compound 7 (52 mg, 0.095 mmol) in anhydrous MeOH (1 mL) was added NaOMe (4.37 M in MeOH, 43 μL, 0.19 mmol) under N2. The mixture was heated at 55°C for 1 h and then cooled to 0°C. The mixture was diluted with 10% NaH2PO4 aqueous solution (15 mL) and extracted with EtOAc (2×15 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0-40% EtOAc in hexanes) to give compound 8 (46 mg, 88% yield) as a white solid. m / z=550 (M+1).

[0317] T1: Under N2, compound 8 (46 mg, 0.084 mmol) was dissolved in anhydrous DMF (0.4 mL) and cooled to 0°C. 1,3-dibromo-5,5-dimethylhydantoin (DBDMH, 13 mg, 0.046 mmol) was added. The mixture was stirred at 0°C for 1 h. Pyridine (30 μL, 0.38 mmol) was added. The mixture was heated at 55°C for 6 h and then cooled to room temperature. The mixture was diluted with EtOAc (25 mL); and washed with 1N HCl aqueous solution (10 mL) and water (2×15 mL) in sequence. 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 hexanes) to give compound T1 (36 mg, 79% yield) as a white solid. m / z=548 (M+1); 1 H NMR (400MHz, CDCl3) δ8.02 (s, 1H), 5.95 (s, 1H), 5.54 (d, J = 46.3Hz, 2H), 3.21 (m, 1H), 2.96 (d, J = 4.7Hz, 1H), 2.19 (td, J = 13.8, 4.2Hz, 1H) , 1.56-1.94(m, 9H), 1.44(s, 3H), 1.34-1.52(m, 3H), 1.25(s, 3H), 1.16-1.32(m, 2H), 1.15(s, 3H), 1.14(s, 3H), 1.05(s, 6H), 0.94(s, 3H).

[0318] Compound 9: A mixture of Boc-glycine (207 mg, 1.18 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (227 mg, 1.18 mmol) in CH2Cl2 (4 mL) was treated with DMAP (4.8 mg, 0.039 mmol). The mixture was stirred at room temperature for 15 min under N2. Compound 5 (200 mg, 0.39 mmol) in CH2Cl2 (4 mL) was added. The mixture was stirred at room temperature for 1 h. Water (15 mL) was added. The mixture was extracted with CH2Cl2 (3×15 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0-40% EtOAc in CH2Cl2) to obtain compound 9 (206 mg, 79% yield) as a white solid. m / z=665 (M+1).

[0319] 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. The residue was dissolved in toluene (10 mL) and concentrated again. The residue was purified by column chromatography (silica gel, eluted with 0-60% EtOAc in hexanes) to obtain compound 10 (160 mg, 80% yield) as a white solid. m / z=647 (M+1).

[0320] Compound 11: Compound 10 (159 mg, 0.25 mmol) in MeOH (2.5 mL) was treated with KCO (136 mg, 0.98 mmol) at room temperature under N. The mixture was stirred at room temperature for 14 h. LCMS indicated that the reaction was complete. 10% NaHPO aqueous solution (15 mL) was added. The mixture was extracted with 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 hexanes) to give Compound 11 (141 mg, 89% yield) as a white solid. m / z=669 (M+Na).

[0321] Compound 12: Under N2, compound 11 (140 mg, 0.22 mmol) was dissolved in anhydrous DMF (1.1 mL) and cooled to 0°C. 1,3-dibromo-5,5-dimethylhydantoin (34 mg, 0.12 mmol) was added. The mixture was stirred at 0°C for 1 h. Pyridine (70 μL, 0.87 mmol) was added. The mixture was heated at 60°C for 5 h and then cooled to room temperature. The mixture was diluted with EtOAc (25 mL); and washed with 1N HCl aqueous solution (10 mL) and water (3×15 mL) in sequence. 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 hexanes) to give compound 12 (126 mg, 90% yield) as a white solid. m / z=589 (M-C4H7).

[0322] T2: Compound 12 (113 mg, 0.18 mmol) in CH2Cl2 (1.8 mL) was treated with TFA (135 μL, 1.75 mmol) at room temperature under N2. After stirring at room temperature for 5 h, saturated NaHCO3 aqueous solution (15 mL) was added. The mixture was extracted with CH2Cl2 (3×15 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0-20% MeOH in CH2Cl2) to give Compound T2 (47 mg, 49% yield) as a yellow foam. m / z=545 (M+1); 1 H NMR (400MHz, CDCl3) δ8.02 (s, 1H), 5.95 (s, 1H), 4.08 (s, 2H), 3.21 (m, 1H), 2.99 (d, J=4.7Hz, 1H), 2.17 (td, J=13.6, 4.1Hz, 1H), 1.44 (s, 3H), 1.25 (s, 3H), 1.15 (s, 6H), 1.12-1.96 (m, 16H), 1.05 (s, 6H), 0.94 (s, 3H).

[0323] Compound 13: To a mixture of Boc-β-Ala-OH (168 mg, 0.89 mmol) and EDC·HCl (170 mg, 0.89 mmol) in CH2Cl2 (3 mL) was added DMAP (5 mg, 0.04 mmol) at room temperature under N2. The mixture was stirred at room temperature for 15 min. A solution of compound 5 (150 mg, 0.30 mmol) in CH2Cl2 (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 CH2Cl2 (3×15 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0-70% EtOAc in hexanes) to obtain compound 13 (201 mg, quantitative yield) as a white solid. m / z=679 (M+1).

[0324] Compound 14: 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 0-55% EtOAc in hexanes) to give Compound 14 (137 mg, 70% yield) as a white solid. m / z=661 (M+1).

[0325] 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% NaH2PO4 aqueous solution (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 hexanes) to give compound 15 (114 mg, 84% yield) as a white solid. m / z=683 (M+Na).

[0326] 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 1N HCl aqueous solution (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 hexanes) to give compound 16 (93 mg, 82% yield) as a white solid. m / z=559 (M—C5H7O2).

[0327] T3: Compound 16 (85 mg, 0.13 mmol) in CH2Cl2 (0.65 mL) was treated with TFA (99 μL, 1.32 mmol) at room temperature. The mixture was stirred at room temperature for 5 h, and then treated with saturated NaHCO3 aqueous solution (15 mL). The mixture was extracted with CH2Cl2 (3×15 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0-20% MeOH in CH2Cl2) to give Compound T3 (56 mg, 78% yield) as a yellow solid. m / z=559 (M+1); 1H NMR (400MHz, CDCl3) δ8.02 (s, 1H), 5.94 (s, 1H), 3.21 (m, 1H), 3.16 (t, J=6.4Hz, 2H), 3.01 (m, 3H), 2.16 (td, J=13.7, 4.2H z, 1H), 1.44 (s, 3H), 1.24 (s, 3H), 1.15 (s, 3H), 1.17-1.94 (m, 16H), 1.14 (s, 3H), 1.05 (s, 3H), 1.04 (s, 3H), 0.94 (s, 3H).

[0328] Compound 17: A solution of compound 5 (100 mg, 0.20 mmol) in CH2Cl2 (1 mL) was cooled to 0°C. Et3N (55 μL, 0.39 mmol) in CH2Cl2 (0.5 mL) and acetoxyacetyl chloride (40 mg, 0.30 mmol) in CH2Cl2 (0.5 mL) were added sequentially. The mixture was stirred at 0°C for 1 h, and then treated with saturated NaHCO3 aqueous solution (5 mL). The mixture was stirred for 5 min, and then extracted with CH2Cl2 (3×10 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 hexanes) to obtain compound 17 (119 mg, quantitative yield) as a white solid. m / z=608 (M+1).

[0329] Compound 18: 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 obtain compound 18 (100 mg, 86% yield) as a white solid. m / z=590 (M+1).

[0330] Compound 19: 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% NaH2PO4 aqueous solution (10 mL) was added. The mixture was extracted with EtOAc (2×20 mL). The combined organic extracts were dried with Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0-70% EtOAc in hexanes) to obtain compound 19 (83 mg, 90% yield) as a white solid. m / z=548 (M+1).

[0331] T4: A solution of compound 19 (82 mg, 0.15 mmol) and 1,3-dibromo-5,5-dimethylhydantoin (23.5 mg, 0.082 mmol) in anhydrous DMF (1.5 mL) was cooled to 0°C under N2. 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 1N HCl aqueous solution (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 0-70% EtOAc in hexanes) to give compound T4 (67 mg, 82% yield) as a white solid. m / z=546 (M+1); 1 H NMR (400MHz, CDCl3) δ8.02 (s, 1H), 5.95 (s, 1H), 4.88 (d, J = 6.5Hz, 2H), 3.21 (dt, J = 13.7, 4.2Hz, 1H), 2.97 (d, J = 4.7Hz, 1H), 2.38 (m, 1 H), 2.18 (td, J=13.7, 4.2Hz, 1H), 1.44 (s, 3H), 1.25 (s, 3H), 1.15 (s, 3H), 1.15 (s, 3H), 1.12-1.95 (m, 14H), 1.05 (s, 6H), 0.94 (s, 3H).

[0332] Compound 20: 3-Acetoxypropionic acid (78 mg, 0.59 mmol) in CH2Cl2 (2 mL) was added to EDC·HCl (113 mg, 0.59 mmol) at room temperature. DMAP (8 mg, 0.06 mmol) was added. The mixture was stirred at room temperature for 15 min. Compound 5 (100 mg, 0.20 mmol) in CH2Cl2 (2 mL) was added. The mixture was stirred at room temperature for 1 h. Saturated NaHCO3 aqueous solution (3 mL) and water (10 mL) were added. The mixture was diluted with CH2Cl2 (20 mL) and 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 obtain compound 20 (80 mg, 66% yield) as a white solid. m / z=622 (M+1).

[0333] 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 obtain compound 21 (41 mg, 55% yield) as a white solid. m / z=604 (M+1).

[0334] Compounds 22 and 23: 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. A 10% aqueous solution of 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).

[0335] T5: A solution of compound 22 (19 mg, 0.034 mmol) in anhydrous DMF (0.3 mL) was cooled to 0°C. 1,3-dibromo-5,5-dimethylhydantoin (5.3 mg, 0.019 mmol) in DMF (55 μL) was added. The mixture was stirred at 0°C for 1 h, and then treated with pyridine (11 μL, 0.14 mmol). The mixture was heated at 60°C for 5 h, and then cooled to room temperature. The mixture was diluted with EtOAc (25 mL) and washed successively with 1N HCl aqueous solution (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 0-70% EtOAc in hexanes) to give compound T5 (16 mg, 86% yield) as a white solid. m / z=560 (M+1); 1 HNMR (400MHz, CDCl3) δ8.02 (s, 1H), 5.95 (s, 1H), 4.05 (q, J=5.8Hz, 2H), 3.19 (m, 1H), 3.11 (t, J=5.6Hz, 2H), 3.01 (d, J=4.7Hz, 1H), 2.58 (t, J= 6.5Hz, 1H), 2.17 (td, J=13.7, 4.1Hz, 1H), 1.44 (s, 3H), 1.25 (s, 3H), 1. 15(s, 3H), 1.14(s, 3H), 1.13-1.95(m, 14H), 1.04(s, 6H), 0.94(s, 3H).

[0336] T6: A solution of compound 23 (17 mg, 0.030 mmol) in anhydrous DMF (0.3 mL) was cooled to 0°C. 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 successively with 1N HCl aqueous solution (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 0-70% EtOAc in hexanes) to give compound T6 (14 mg, 83% yield) as a white solid. m / z=574 (M+1); 1HNMR (400MHz, CDCl3) δ8.02 (s, 1H), 5.94 (s, 1H), 3.79 (t, J = 6.5Hz, 2H), 3.34 (s, 3H), 3.22 (m, 1H), 3.13 (t, J = 6.5Hz, 2H), 3.00 (d, J = 4.7Hz, 1H) , 2.16(td, J=13.6, 4.2Hz, 1H), 1.44(s, 3H), 1.24(s, 3H), 1.15(s, 3H), 1 .14-1.94(m, 14H), 1.13(s, 3H), 1.05(s, 3H), 1.04(s, 3H), 0.94(s, 3H).

[0337] Compound 25: To a mixture of compound 24 (1.366 g, 3.04 mmol) in o-xylene (5 mL) was added tributyltin (IV) azido (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, eluted with 0-60% acetone in hexanes) to give partially purified compound 25, which was purified again by column chromatography (silica gel, eluted with 0-100% EtOAc in hexanes) to give compound 25 as a brown solid (710 mg, 47% yield). m / z=493 (M+1).

[0338] 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, and then an additional amount of 2-bromoethanol (40 μL, 0.56 mmol) was added. The mixture was heated at 60 ° C for another 3 h and cooled to room temperature. The mixture was diluted and filtered with EtOAc (50 mL). The filtrate was concentrated. The residue was combined with the crude product (50 mg, 0.10 mmol) obtained from compound 25, and purified by column chromatography (silica gel, eluted with 0-50% acetone in hexanes) to obtain compound 26 (222 mg, 82% yield) as a white solid. m / z=537 (M+1).

[0339] Compound 27: A mixture of compound 26 (220 mg, 0.41 mmol) in ethyl formate (1.00 mL, 12.29 mmol) was cooled to 0 ° C under N2 and treated 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 6N HCl aqueous solution (1.1 mL, 6.6 mmol) and subsequently with 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).

[0340] Compound 28: To a mixture of compound 27 (166 mg, 0.30 mmol) in anhydrous MeOH (3 mL) was added NaOMe (4.37 M in MeOH, 0.14 mL, 0.61 mmol) under N2. The mixture was heated at 55°C for 1 h and then cooled to room temperature. The mixture was diluted with 10% NaH2PO4 aqueous solution and extracted twice with EtOAc. The combined organic extracts were dried over Na2SO4, filtered and concentrated to give compound 28 (180 mg, quantitative yield) as a white solid. m / z=562 (M+1).

[0341] T7: Under N2, compound 28 (180 mg, 0.30 mmol) was dissolved in anhydrous DMF (1 mL) and cooled to 0°C. 1,3-dibromo-5,5-dimethylhydantoin (42 mg, 0.15 mmol) was added. The mixture was stirred at 0°C for 1 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 with 1N HCl aqueous solution and water (3×) in sequence. 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 hexanes) to give compound T7 (114 mg, 68% yield) as a white solid. m / z=560 (M+1); 1H NMR (400MHz, CDCl3) δ8.01 (s, 1H), 5.94 (s, 1H), 4.72 (dd, J=5.9, 4.2Hz, 2H), 4.16 (dd, J =6.1, 4.5Hz, 2H), 3.32 (dt, J = 13.7, 4.2Hz, 1H), 2.97 (d, J = 4.7Hz, 1H), 2.24 (m, 1H), 2.2 1 (t, J=6.3Hz, 1H), 2.03 (m, 1H), 1.83 (td, J=13.9, 4.5Hz, 1H), 1.42 (s, 3H), 1.24 (s, 3H) , 1.14(s, 3H), 1.12-1.78(m, 12H), 1.06(s, 3H), 1.05(s, 3H), 0.99(s, 3H), 0.95(s, 3H).

[0342] T8: A solution of compound T7 (30 mg, 0.054 mmol) in CH2Cl2 (0.5 mL) was cooled to 0°C. Pyridine (13 μL, 0.16 mmol), acetic anhydride (10 μL, 0.11 mmol) and a catalytic amount of DMAP were added 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 hexanes) to give compound T8 (23 mg, 71% yield) as a white solid. m / z=602 (M+1); 1 H NMR (400MHz, CDCl3) δ8.02 (s, 1H), 5.94 (s, 1H), 4.82 (m, 2H), 4.54 (m, 2H), 3. 31 (m, 1H), 2.95 (d, J = 4.7Hz, 1H), 2.23 (td, J = 13.7, 4.1Hz, 1H), 2.03 (m, 1H), 2 .00(s, 3H), 1.81(td, J=13.9, 4.5Hz, 1H), 1.42(s, 3H), 1.24(s, 3H), 1.14(s, 3H), 1.12-1.76 (m, 12H), 1.06 (s, 3H), 1.05 (s, 3H), 0.98 (s, 3H), 0.95 (s, 3H).

[0343] T9: A mixture of compound T7 (72 mg, 0.13 mmol), proton sponge (82 mg, 0.38 mmol) and trimethyloxonium tetrafluoroborate (56 mg, 0.38 mmol) in CH2Cl2 (1.2 mL) was stirred at room temperature for 16 h. The reaction was quenched with saturated aqueous NaHCO3; stirred for 5 min; and extracted with EtOAc. The organic extract was washed with water, 1N aqueous HCl and water in sequence; dried over Na2SO4; 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. m / z=574 (M+1); 1 HNMR (400MHz, CDCl3) δ8.02 (s, 1H), 5.94 (s, 1H), 4.74 (m, 2H), 3.89 (t, J=5.4Hz , 2H), 3.32 (m, 1H), 3.29 (s, 3H), 2.99 (d, J = 4.7Hz, 1H), 2.22 (td, J = 13.6, 4.1Hz, 1H), 2.05(m, 1H), 1.82(td, J=13.9, 4.5Hz, 1H), 1.42(s, 3H), 1.23(s, 3H), 1.14( s, 3H), 1.12-1.76 (m, 12H), 1.06 (s, 3H), 1.05 (s, 3H), 0.98 (s, 3H), 0.95 (s, 3H).

[0344] Compound 29: In a vial, a mixture of compound 25 (200 mg, 0.41 mmol) and Cs2CO3 (160 mg, 0.49 mmol) in MeCN (2 mL) was treated with 1-fluoro-2-iodoethane (100 mg, 0.58 mmol) in MeCN (2 mL). The vial was sealed and heated at 60° C. for 6 h. After cooling to room temperature, the mixture was diluted with EtOAc and filtered through a diatomaceous earth pad. The filter cake was washed with EtOAc. The combined filtrate and washings were concentrated. The residue was combined with the crude product (50 mg, 0.10 mmol) obtained from compound 25 and purified by column chromatography (silica gel, eluted with 0-50% EtOAc in hexanes) to obtain compound 29 (142 mg, 52% yield) as a light yellow solid. m / z=539 (M+1).

[0345] Compound 30: A mixture of compound 29 (142 mg, 0.26 mmol) in ethyl formate (0.64 mL, 7.86 mmol) was cooled to 0 ° C under N2 and treated 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 6N HCl aqueous solution (0.66 mL, 3.96 mmol) and subsequently with 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 hexanes) to give compound 30 (102 mg, 71% yield) as a white solid. m / z=544 (M+1).

[0346] Compound 31: Compound 30 (102 mg, 0.19 mmol) was dissolved in MeOH (1 mL) and CH2Cl2 (1 mL) and cooled to -78°C. Ozone was bubbled through the reaction mixture until the starting material was completely consumed (~10 min). Oxygen was bubbled for 5 min. NaBH4 (15 mg, 0.40 mmol) was added. The cold bath was removed. The mixture was stirred at room temperature for 3 h; diluted with EtOAc; and washed with 1N HCl aqueous solution and water. The aqueous washings were combined and extracted with EtOAc. The combined organic extracts were dried over Na2SO4; filtered; and concentrated to give Compound 31 (96 mg, 99% yield) as a white solid. m / z=518 (M+1).

[0347] Compound 32: A mixture of compound 31 (96 mg, 0.19 mmol) and Cs2CO3 (73 mg, 0.22 mmol) was treated with 1-fluoro-2-iodoethane (45 mg, 0.26 mmol) in MeCN (1.8 mL). The mixture was heated at 60°C for 6 h under N2. After cooling to room temperature, the mixture was diluted with EtOAc and washed successively with 1N HCl aqueous solution, 10% Na2SO3 aqueous solution, and 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 32 (63 mg, 60% yield) as a white solid. m / z=564 (M+1).

[0348] Compound 33: A mixture of compound 32 (61 mg, 0.11 mmol) in MeOH (1 mL) was treated with KCO (45 mg, 0.33 mmol) at room temperature. The mixture was stirred at room temperature for 16 h. 10% NaHPO aqueous solution (15 mL) was added. The mixture was extracted twice with EtOAc. The combined organic extracts were 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 33 (48 mg, 79% yield) as a white solid. m / z=564 (M+1).

[0349] T10: A solution of compound 33 (48 mg, 0.085 mmol) in anhydrous DMF (0.42 mL) was cooled to 0 °C under N2. 1,3-Dibromo-5,5-dimethylhydantoin (12 mg, 0.042 mmol) was added. The mixture was stirred at 0 °C for 1 h, and then treated with pyridine (21 μL, 0.26 mmol). The mixture was heated at 55 °C for 16 h. After cooling to room temperature, the mixture was diluted with EtOAc; and washed successively with 1N HCl aqueous solution and water (3×). 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 T10 (34 mg, 71% yield) as a white solid. m / z=562 (M+1); 1 H NMR (400MHz, CDCl3) δ8.01 (s, 1H), 5.94 (s, 1H), 4.78-5.01 (m, 4H), 3.32 (dt , J=13.6, 4.3Hz, 1H), 2.99 (d, J=4.7Hz, 1H), 2.24 (td, J=13.6, 4.1Hz, 1H), 2. 04(m, 1H), 1.82(td, J=13.9, 4.5Hz, 1H), 1.42(s, 3H), 1.23(s, 3H), 1.13(s, 3 H), 1.12-1.77 (m, 12H), 1.06 (s, 3H), 1.05 (s, 3H), 0.96 (s, 3H), 0.95 (s, 3H).

[0350] Compound 35: Compound 34 (1.00 g, 2.03 mmol) was mixed with CH2Cl2 (20 mL) and cooled to 0 ° C under N2. Oxalyl chloride (0.54 mL, 6.17 mmol) and DMF (16 μL, 0.20 mmol) were added sequentially. The cold 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.

[0351] Compound 36: Compound 35 (200 mg, 0.39 mmol) in CH2Cl2 (4 mL) was cooled to 0°C under N2. Hydrazine hydrate (50 wt%, 75 mg, 1.18 mmol) was added dropwise. The mixture was stirred at room temperature for 10 min; diluted with CH2Cl2 (10 mL); and washed with water (15 mL). The aqueous washings were extracted with CH2Cl2 (2×15 mL) and EtOAc (15 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated to give compound 36 (179 mg, 90% yield) as a glass.

[0352] Compound 37: A solution of 2-fluoroacetic acid (67 mg, 0.86 mmol) in CH2Cl2 (1 mL) was treated with EDC·HCl (164 mg, 0.85 mmol) and DMAP (3.5 mg, 0.028 mmol) at room temperature under N2. The mixture was stirred at room temperature for 15 min. Compound 36 (144 mg, 0.29 mmol) in CH2Cl2 (2 mL) was then added. The mixture was stirred at room temperature for 14 h. The reaction mixture was washed with saturated NaHCO3 aqueous solution (10 mL) and water (10 mL). The aqueous phase was extracted with CH2Cl2 (2×10 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 obtain compound 37 (96 mg, 60% yield) as a pink solid. m / z=566 (M+1).

[0353] T11: Compound 37 (115 mg, 0.20 mmol) and p-toluenesulfonic acid monohydrate (19 mg, 0.10 mmol) in toluene (10 mL) were heated at reflux for 3 h while removing water by 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 Na 2 SO 4 , filtered and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0-40% acetone in hexanes) to give Compound T11 (67 mg, 60% yield) as a white solid. m / z=548 (M+1); 1 H NMR (400MHz, CDCl3) δ8.02 (s, 1H), 5.96 (s, 1H), 5.51 (dd, J=47.0Hz, 2H), 3.18 (dt, J=13.5, 4.3Hz, 1H), 2.99 (d, J=4.7Hz, 1H), 2 .23(td, J=13.7, 4.2Hz, 1H), 1.45(s, 3H), 1.25(s, 3H), 1.20-2.02(m, 14H), 1.15(s, 6H), 1.06(s, 3H), 1.05(s, 3H), 0.96(s, 3H).

[0354] Compound 39: A solution of compound 35 [generated from compound 34 (1.52 g, 3.09 mmol)] in CH2Cl2 (25 mL) was cooled to 0°C. Et3N (1.70 mL, 12.4 mmol) and a solution of compound 38 (404 mg, 4.39 mmol) in CH2Cl2 (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 CH2Cl2 (3×30 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% acetone in hexanes) to give compound 39 (1.46 g, 84% yield) as a white solid. m / z=566 (M+1).

[0355] 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 successively with 1N aqueous HCl solution (15 mL), saturated aqueous NaHCO3 solution (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 hexanes) to give compound T12 (9 mg, 6% yield) as a white solid. m / z=548 (M+1); 1 H NMR (400MHz, CDCl3) δ8.02 (s, 1H), 5.97 (s, 1H), 5.44 (d, J = 46.5Hz, 2H), 3.26 (m, 1H), 3.03 (d, J = 4.7Hz, 1H), 2.24 (td, J = 13.8, 4.1Hz, 1 H), 1.87-2.01(m, 2H), 1.45(s, 3H), 1.25(s, 3H), 1.20-1.80(m, 12H), 1.15(s, 3H), 1.10(s, 3H), 1.06(s, 3H), 1.05(s, 3H), 0.95(s, 3H).

[0356] A stock solution of compound 35 (≤0.183 M) and trimethylamine (0.735 M) in CH2Cl2 was prepared by dissolving compound 35 (prepared from 11.11 mmol of compound 34) and triethylamine (6.20 mL, 44.5 mmol) in CH2Cl2 (52 mL). The total volume of the solution was 60.5 mL. The stock solution was used in the synthesis of compounds 40 and 41.

[0357] Compound 40: A stock solution of compound 35 and Et3N in CH2Cl2 [12.5 mL, containing compound 35 (2.29 mmol) and trimethylamine (9.19 mmol)] was treated with 3-hydroxypropionamide oxime (347 mg, 3.33 mmol). The mixture was stirred at room temperature overnight. The resulting mixture was diluted with EtOAc; washed with water, saturated aqueous NaHCO3 and brine. The organic extract was dried over Na2SO4; filtered and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0-10% MeOH in CH2Cl2) to give compound 40 as a solid (604.4 mg, 46% yield from compound 34).

[0358] T13: A mixture of compound 40 (604.4 mmol, 1.046 mmol) and tetrabutylammonium hydroxide (40% w / w in water, 2.1 mL, 3.2 mmol) in THF (8.4 mL) was stirred at room temperature overnight under N2. The resulting mixture was diluted with EtOAc; washed with water, saturated aqueous NaHCO3 and brine. The organic extract was dried over Na2SO4; filtered and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0-100% EtOAc in hexanes) to give compound T13 (265.5 mg, 45% yield) as a white solid. m / z=560.3 (M+1); 1 H NMR (400MHz, CDCl3) δ8.02 (s, 1H), 5.96 (s, 1H), 3.98 (q, J=6.0Hz, 2H), 3.24 (td, J= 4.2, 13.9Hz, 1H), 3.03 (d, J=4.7Hz, 1H), 2.99 (t, J=5.6Hz, 2H), 2.33 (t, J=6.3Hz, 1 H), 2.21 (dt, J=4.1, 13.8Hz, 1H), 1.91 (m, 2H), 1.69 (m, 7H), 1.45 (s, 3H), 1.33 (m, 5 H), 1.25(s, 3H), 1.15(s, 3H), 1.11(s, 3H), 1.05(s, 3H), 1.04(s, 3H), 0.95(s, 3H).

[0359] T14: A mixture of compound T13 (101.2 mg, 0.1808 mmol) and HCl (12M aqueous solution, 0.5 mL, 6.0 mmol) in glacial acetic acid (10 mL) was stirred at 75 ° C for 20 h under N2. The resulting mixture was azeotroped with toluene (60 mL, then 50 mL), and the residue was purified by column chromatography (silica gel, eluted with 0-100% EtOAc in hexanes) to give compound T14 as a white solid (48.0 mg, 44% yield). m / z=602.3 (M+1); 1H NMR (400MHz, CDCl3) δ8.02 (s, 1H), 5.96 (s, 1H), 4.41 (m, 2H), 3.23 (td, J=3.9, 13.3Hz, 1H), 3.05 (m, 3H), 2.20 (dt, J=4.1, 13.8Hz, 1H), 2.02 (s, 3H), 1.90 (m, 2H), 1.70 (m, 7H), 1.45 (s, 3H), 1.35 (m, 5H), 1.24 (s, 3H), 1.15(s, 3H), 1.10(s, 3H), 1.04(s, 3H), 1.04(s, 3H), 0.94(s, 3H).

[0360] Compound 41: A stock solution of compound 35 and Et3N in CH2Cl2 [12.5 mL, containing compound 35 (2.29 mmol) and trimethylamine (9.19 mmol)] was treated with 3-methoxypropionamide oxime hydrochloride (516 mg, 3.33 mmol) and additional triethylamine (0.46 mL, 3.3 mmol). The mixture was stirred at room temperature overnight. The resulting mixture was diluted with EtOAc; washed with water, saturated aqueous NaHCO3 and brine. The organic extract was dried over Na2SO4; filtered and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0-10% MeOH in CH2Cl2) to give a mixture of compound 41 and compound 34 as a solid (1.22 g, ~2.5:1-41:34), which was used without further purification.

[0361] T15: A mixture of compound 41 (1.22 g, ~2.5:1-41:34) contaminated with compound 34 and tetrabutylammonium hydroxide (40% w / w in water, 4.2 mL, 6.4 mmol) in THF (17 mL) was stirred at room temperature overnight under N2. The resulting mixture was diluted with EtOAc; washed with water, saturated aqueous NaHCO3 and brine. The organic extract was dried over Na2SO4; filtered and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0-100% EtOAc in hexanes) to give compound T15 (494.7 mg, 37% yield from compound 34) as a white solid. m / z=574.4 (M+1); 1H NMR (400MHz, CDCl3) δ8.02 (s, 1H), 5.96 (s, 1H), 3.74 (t, J=6.6Hz, 2H), 3.33 (s, 3H ), 3.24 (td, J=4.1, 13.6Hz, 1H), 3.09 (d, J=4.7Hz, 1H), 2.99 (dt, J=2.6, 6.6Hz, 2H ), 2.20 (dt, J=4.1, 13.8Hz, 1H), 1.90 (m, 2H), 1.71 (m, 7H), 1.45 (s, 3H), 1.35 (s, 5 H), 1.25(s, 3H), 1.15(s, 3H), 1.11(s, 3H), 1.05(s, 3H), 1.04(s, 3H), 0.95(s, 3H).

[0362] Compound 42: A mixture of N-tert-butoxycarbonyl-3-aminopropionitrile (858 mg, 5.04 mmol), hydroxylamine hydrochloride (1.39 g, 20.0 mmol) and triethylamine (4.2 mL, 30 mmol) in ethanol (20 mL) was heated to 80° C. for 2 days in a sealed test tube under stirring. The resulting solution was diluted with EtOAc (300 mL) and washed with water / saturated NaHCO aqueous solution (1:1, 100 mL) and brine (25 mL). The organic extract was dried over NaSO, filtered and concentrated to give compound 42 (73:27, 773.4 mg) contaminated with N-tert-butoxycarbonyl-3-aminopropionitrile as a crystalline solid, which was used without further purification.

[0363] 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 CH2Cl2 (18 mL) was stirred at room temperature for 2 h. The resulting mixture was diluted with EtOAc (100 mL); washed with water (25 mL), saturated aqueous NaHCO3 solution (25 mL) and brine (25 mL). The organic extract was dried over Na2SO4; filtered and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0-10% MeOH in CH2Cl2) to give a mixture of compounds 43 and 34 as a solid (1.01 g, ~4:1-43:34), which was used without further purification.

[0364] Compound 44: A solution of impure compound 43 (-4:1-43:34, 904 mg, -1.07 mmol) and tetrabutylammonium hydroxide (40% w / w in water, 3.6 mL, 5.5 mmol) in THF (14 mL) was stirred at room temperature for 5 h under N2. The resulting mixture was diluted with EtOAc (200 mL); washed with water (50 mL), saturated aqueous NaHCO3 (50 mL) and brine (50 mL). The organic extract was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, 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).

[0365] 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. Additional HCl (12 M aqueous solution, 0.75 mL, 9.0 mmol) was added after 3.5 h, 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 NaHCO3 aqueous solution (25 mL). The organic extract was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0-10% MeOH in CH2Cl2) to give compound T16 (43.1 mg, 83% yield) as an off-white solid. m / z=559.3 (M+1); 1 H NMR (400MHz, CDCl3) δ8.02 (s, 1H), 5.95 (s, 1H), 3.23 (td, J=4.1, 13.9Hz, 1H), 3.06 (m, 3H), 2.84 (t, J=6.5Hz, 2H), 2.19 (dt, J =4.1, 13.8Hz, 1H), 1.76 (m, 11H), 1.43 (s, 3H), 1.23 (s, 3H), 1.20 (m, 5H), 1.13 (s, 3H), 1.10 (s, 3H), 1.03 (s, 6H), 0.93 (s, 3H).

[0366] T17: Methyl chloroformate (12 μL, 0.16 mmol) was added to a solution of compound T16 (51.7 mg, 0.0926 mmol) and triethylamine (42 μL, 0.301 mmol) in CH2Cl2 (1 mL) 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 CH2Cl2 (35 mL) and washed with HCl (1 M aqueous solution, 15 mL) and brine (15 mL). The organic extract was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0-100% EtOAc in hexanes) to give compound T17 (11.6 mg, 20% yield) as a white solid. m / z=617.4 (M+1); 1 H NMR (400MHz, CDCl3) δ8.02 (s, 1H), 5.96 (s, 1H), 5.10 (br s, 1H), 3.64 (s, 3H), 3.57 (q, J=6.2Hz, 2H), 3.23 (td, J=3.5, 13.4Hz, 1H), 3.01 (d, J=4.7Hz, 1H), 2.93 (t, J=6.4Hz, 2H), 2.20 (dt, J=4.1, 13.8 Hz, 1H), 1.90 (m, 2H), 1.69 (m, 7H), 1.44 (s, 3H), 1.30 (m, 5H), 1.24 (s, 3H), 1.15(s, 3H), 1.09(s, 3H), 1.04(s, 3H), 1.04(s, 3H), 0.94(s, 3H).

[0367] T18: Ethyl isocyanate (8 μL, 0.101 mmol) was added to a solution of compound T16 (55.8 mg, 0.0999 mmol) and triethylamine (0.14 mL, 1.0 mmol) in CH2Cl2 (1 mL) and stirred at room temperature for 1 h. The resulting mixture was diluted with CH2Cl2 (35 mL) and washed with HCl (1 M aqueous solution, 15 mL) and brine (15 mL). The organic extract was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0-100% EtOAc in hexanes) to give compound T18 (42.1 mg, 67% yield) as a white solid. m / z=630.4 (M+1); 1H NMR (400MHz, CDCl3) δ8.02 (s, 1H), 5.96 (s, 1H), 4.90 (t, J = 5.8Hz, 1H), 4.23 (t, J = 5.5Hz, 1H), 3 .56 (m, 2H), 3.24 (td, J=4.2, 14.4Hz, 1H), 3.16 (ddq, J=1.9, 5.5, 7.2Hz, 2H), 3.02 (d, J=4.7Hz, 1H), 2.92(m, 2H), 2.20(dt, J=4.1, 13.8Hz, 1H), 1.90(m, 2H), 1.70(m, 7H), 1.44(s, 3H), 1.33(m , 5H), 1.24 (s, 3H), 1.15 (s, 3H), 1.13 (t, J=7.2Hz, 3H), 1.09 (s, 3H), 1.04 (s, 6H), 0.94 (s, 3H).

[0368] T19: Acetyl chloride (0.15 mL, 2.1 mmol) was added to a solution of compound T16 (45.7 mg, 0.0818 mmol) and triethylamine (0.11 mL, 0.79 mmol) in CH2Cl2 (1 mL), 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 Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0-15% MeOH in CH2Cl2) to give compound T19 (16.3 mg, 33% yield) as a white solid. m / z=601.4 (M+1); 1 H NMR (400MHz, CDCl3) δ8.02 (s, 1H), 6.01 (br s, 1H), 5.97 (s, 1H), 3.62 (m, 2H), 3.24 (td, J=4.2, 13.6Hz, 1H), 3.01 (d, J=4.7Hz, 1H), 2.93 (t, J=6.3Hz, 2H), 2.21 (m, 1H), 1.95 (s, 3H), 1.77 (m, 9H), 1.45 (s, 3H), 1.24 (s, 3H), 1.22 (m, 5H), 1.15 (s, 3H), 1.10 (s, 3H), 1.05 (s, 3H), 1.04 (s, 3H), 0.95 (s, 3H).

[0369] Compound 45: 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 hexanes) to obtain compound 45 (40 mg, 95% yield) as a white foam. m / z=532 (M+1).

[0370] Compound 46: Compound 45 (40 mg, 0.075 mmol) was mixed with K2CO3 (44 mg, 0.32 mmol) and MeOH (2 mL). The mixture was stirred at room temperature under N2 for 14 h; treated with 10% NaH2PO4 (20 mL); and extracted with EtOAc (2×20 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The residue was combined with the crude product obtained from compound 46 (16 mg, 0.030 mmol) and purified by column chromatography (silica gel, 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).

[0371] T20: Compound 46 (43.5 mg, 0.082 mmol) and 1,3-dibromo-5,5-dimethylhydantoin (13 mg, 0.045 mmol) were mixed with anhydrous DMF (0.8 mL) at 0°C under N2. The mixture was stirred at 0°C for 1 h 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 1N HCl aqueous solution (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 hexanes) to give Compound T20 (34 mg, 78% yield) as a white solid. m / z=530 (M+1); 1 H NMR (400MHz, CDCl3) δ8.02 (s, 1H), 5.95 (s, 1H), 3.20 (m, 1H), 3.01 (d, J=4.7Hz, 1H), 2.57 (s, 3H), 2.16 (td, J=13. 5, 4.2Hz, 1H), 1.44 (s, 3H), 1.24 (s, 3H), 1.15 (s, 6H), 1.12-1.93 (m, 14H), 1.05 (s, 3H), 1.04 (s, 3H), 0.94 (s, 3H).

[0372] 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 (2M in hexanes, 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 was combined with the crude product obtained from compound 25 (50 mg, 0.10 mmol) and purified by column chromatography (silica gel, eluted with 0-35% acetone in hexanes) to give compound 47 (139 mg, 90% yield) as a white solid. m / z=507 (M+1).

[0373] 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 6N aqueous HCl (0.45 mL, 2.7 mmol), followed by EtOH (2.7 mL) and hydroxylamine hydrochloride (28 mg, 0.40 mmol). The reaction mixture was heated at 60 °C for 6 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).

[0374] Compound 49: To a mixture of compound 48 (110 mg, 0.21 mmol) in anhydrous MeOH (2 mL) was added NaOMe (4.37 M in MeOH, 95 μL, 0.42 mmol) under N2. The mixture was heated at 45°C for 1-2 h and then cooled to room temperature. The mixture was diluted with 10% NaH2PO4 aqueous solution 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 hexanes) to give compound 49 (86 mg, 77% yield) as a white solid. m / z=532 (M+1).

[0375] T21: Under N2, compound 49 (84 mg, 0.16 mmol) was dissolved in anhydrous DMF (0.4 mL) and cooled to 0°C. A solution of 1,3-dibromo-5,5-dimethylhydantoin (23 mg, 0.080 mmol) in DMF (0.4 mL) was added. The mixture was stirred at 0°C for 2 h. Pyridine (40 μL, 0.50 mmol) was added. The mixture was heated at 55°C for 6 h and then cooled to room temperature. The mixture was diluted with EtOAc and washed with 1N HCl aqueous solution and water (3×) in sequence. 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 T21 (65 mg, 78% yield) as a white solid. m / z=530 (M+1); 1 H NMR (400MHz, CDCl3) δ8.02 (s, 1H), 5.94 (s, 1H), 4.31 (s, 3H), 3.30 (m, 1H), 2.97 (d, J=4.7Hz, 1H), 2.23 (td, J=13.6, 4.2Hz, 1H), 2.02 (m, 1H), 1.83 (td, J=13.9, 4 .5Hz, 1H), 1.59-1.77(m, 7H), 1.42(s, 3H), 1.38-1.49(m, 3H), 1.24(s, 3H), 1.14 -1.30 (m, 2H), 1.14 (s, 3H), 1.06 (s, 3H), 1.05 (s, 3H), 1.00 (s, 3H), 0.95 (s, 3H).

[0376] A stock solution of compound 35 (≤0.113 M) and trimethylamine (0.453 M) in CH2Cl2 was prepared by dissolving compound 35 (prepared from 28.92 mmol of compound 34) and triethylamine (16.1 mL, 116 mmol) in CH2Cl2 (230 mL). The total volume of the solution was 256 mL. The stock solution was used to synthesize compounds 50 and 52.

[0377] Compound 50: 2,2,2-Trifluoro-N'-hydroxy-acetamidine (229.2 mg, 1.79 mmol) was added to a stock solution of compound 35 and Et3N in CH2Cl2 [26.1 mL, containing compound 35 (2.95 mmol) and Et3N (11.8 mmol)], and the mixture was stirred at room temperature overnight. The resulting mixture was diluted with EtOAc; washed with water, saturated aqueous NaHCO3 and brine. The organic extract was dried over Na2SO4; filtered and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0-10% MeOH in CH2Cl2) to give impure compound 50 (965.7 mg) as a solid, which was used without further purification. m / z=602.3 (M+1).

[0378] T22: A mixture of impure compound 50 (353 mg) and tetrabutylammonium hydroxide (40% w / w in water, 1.25 mL, 1.9 mmol) in THF (5 mL) was stirred at room temperature overnight under N2. The resulting mixture was diluted with EtOAc; washed with water, saturated aqueous NaHCO3 and brine. The organic extract was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0-100% EtOAc in hexanes) to give compound T22 (63.3 mg, 10% yield from compound 34) as a white solid. m / z=584.3 (M+1); 1 H NMR (400MHz, CDCl3) δ8.02 (s, 1H), 5.98 (s, 1H), 3.26 (td, J=4.1, 14.1Hz, 1H), 2.99 (d, J=4.7Hz, 1H), 2.27 (dt, J=4.2, 13.9Hz, 1H), 1.96 (m, 2H), 1. 74(m, 6H), 1.61(dt, J=4.4, 13.9Hz, 1H), 1.46(s, 3H), 1.36(s, 5H), 1.25( s, 3H), 1.16 (s, 3H), 1.11 (s, 3H), 1.06 (s, 3H), 1.06 (s, 3H), 0.96 (s, 3H).

[0379] Compound 51: Propionamide oxime (250 mg, 2.84 mmol) was added to a stock solution of compound 35 and Et3N in CH2Cl2 [30 mL, containing compound 35 (3.38 mmol) and Et3N (13.5 mmol)], and the mixture was stirred at room temperature overnight. The resulting mixture was diluted with EtOAc; washed with water, saturated aqueous NaHCO3 and brine. The organic extract was dried over Na2SO4; filtered and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0-10% MeOH in CH2Cl2) to give impure compound 51 (1.0959 g), which was used without further purification. m / z=562.3 (M+1).

[0380] T23: A mixture of impure compound 51 (346.2 mg) and tetrabutylammonium hydroxide (40% w / w in water, 1.25 mL, 1.9 mmol) in THF (5 mL) was stirred at room temperature overnight under N2. The resulting mixture was diluted with EtOAc; washed with water, saturated aqueous NaHCO3 and brine. The organic extract was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0-100% EtOAc in hexanes) to give compound T23 (209.9 mg, 36% yield from compound 34) as a white solid. m / z=544.3 (M+1); 1 H NMR (400MHz, CDCl3) δ8.02 (s, 1H), 5.96 (s, 1H), 3.24 (dt, J=13.1, 4.3Hz, 1H), 3.11 (d, J=4.7Hz, 1H), 2.73 (qd, J=7.6, 1.5Hz, 2H), 2.20 (td, J=13.8, 4.1Hz, 1H), 1.45 (s, 3H), 1.29 (t, J=7.6Hz, 3H), 1.24 (s, 3H), 1.18-1.97 ( m, 14H), 1.15 (s, 3H), 1.11 (s, 3H), 1.05 (s, 3H), 1.04 (s, 3H), 0.94 (s, 3H).

[0381] Compound 52a: Compound 5 (84 mg, 0.17 mmol) in CH2Cl2 (6 mL) was cooled to 0°C. Et3N (46 μL, 0.33 mmol) and propionyl chloride (23 mg, 0.25 mmol) in CH2Cl2 (1 mL) were added sequentially. After stirring at 0°C for 1 h, the mixture was treated with saturated aqueous NaHCO3 solution (5 mL); stirred for 5 min; and extracted with CH2Cl2 (3×10 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 hexanes) to give Compound 52a (83 mg, 89% yield) as a white solid. m / z=564.3 (M+1)

[0382] Compound 53a: 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).

[0383] Compound 54a: 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 (2×15 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0-45% EtOAc in hexanes) to give Compound 54a (65 mg, 97% yield) as a white solid. m / z=546.3 (M+1).

[0384] 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 N2. The mixture was stirred at 0°C for 1 h and treated with pyridine (38 μL, 0.48 mmol). The mixture was heated at 55°C for 2 h and at 60°C for 4 h; cooled to room temperature; diluted with EtOAc (25 mL); and washed with 1N HCl aqueous solution (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 0-45% EtOAc in hexanes) to give Compound T24 (49 mg, 76% yield) as a white solid. m / z=544.3 (M+1); 1 H NMR (400MHz, CDCl3) δ8.03 (s, 1H), 5.95 (s, 1H), 3.21 (dt, J=13.7, 4.3Hz, 1H), 3.03 (d, J=4.7Hz, 1H), 2.89 (q, J=7.6Hz, 2H), 2.16 (td, J=13.7, 4. 2Hz, 1H), 1.44 (s, 3H), 1.36 (t, J=7.6Hz, 3H), 1.24 (s, 3H), 1.15 (s, 3H), 1.14(s, 3H), 1.10-1.95(m, 14H), 1.05(s, 3H), 1.04(s, 3H), 0.94(s, 3H).

[0385] Compound 52b: Compound 52b (white solid, 96 mg, 82% yield) was synthesized from compound 5 (103 mg, 0.20 mmol) using the same procedure described for the synthesis of compound 52a. m / z = 576 (M+1).

[0386] Compound 53b: Compound 53b (solid, 67 mg, 72% yield) was synthesized from compound 52b (96 mg, 0.17 mmol) using the same procedure described for the synthesis of compound 53a. m / z = 558 (M+1).

[0387] Compound 54b: Compound 54b (white solid, 58 mg, 89% yield) was synthesized from compound 53b (65 mg, 0.12 mmol) using the same procedure described for the synthesis of compound 54a. m / z = 558 (M+1).

[0388] T25: Compound T25 (white solid, 44 mg, 76% yield) was synthesized from compound 54b (58 mg, 0.10 mmol) using the same procedure described for the synthesis of compound T24. m / z = 556 (M+1); 1 H NMR (400MHz, CDCl3) δ8.03 (s, 1H), 5.94 (s, 1H), 3.17 (dt, J=13.7, 4.2Hz, 1H), 3.02 (d, J=4.7Hz, 1H) , 2.15(m, 2H), 1.44(s, 3H), 1.24(s, 3H), 1.15(s, 6H), 1.11-1.92(m, 18H), 1.03(s, 6H), 0.93(s, 3H).

[0389] Compound 55a: Impure compound 55a (1.3624 g) was synthesized from compound 35 (3.67 mmol), n-butyramide oxime (234.6 mg, 2.30 mmol) and trimethylamine (14.6 mmol) using the same procedure described for the synthesis of compound 51. m / z = 576 (M+1).

[0390] 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 in water, 1.25 mL, 1.9 mmol) using the same procedure described for the synthesis of compound T23. m / z = 558 (M+1); 1 HNMR (400MHz, CDCl3) δ8.02 (s, 1H), 5.96 (s, 1H), 3.25 (m, 1H), 3.08 (d, J = 4.7Hz, 1H), 2.68 (t, J = 7.5Hz, 2H), 2.20 (td, J = 13.8, 4.1Hz, 1H), 1.90 (m, 2H), 1.45 (s, 3H), 1.24 (s, 3H), 1.17-1.81 (m, 14H), 1.15 (s, 3H), 1.1 0 (s, 3H), 1.05 (s, 3H), 1.04 (s, 3H), 0.95 (t, J=7.4Hz, 3H), 0.94 (s, 3H).

[0391] 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 described for the synthesis of compound 51. m / z = 576 (M+1).

[0392] 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 in water, 1.25 mL, 1.9 mmol) using the same procedure described for the synthesis of compound T23. m / z = 558 (M+1); 1 H NMR (400MHz, CDCl3) δ8.02 (s, 1H), 5.96 (s, 1H), 3.22 (m, 1H), 3.18 (d, J=4.8Hz, 1H ), 3.07 (hept, J=6.9Hz, 1H), 2.19 (td, J=13.8, 4.1Hz, 1H), 1.90 (td, J=13.7, 5.4Hz , 2H), 1.45 (s, 3H), 1.30 (d, J=6.9Hz, 3H), 1.30 (d, J=6.9Hz, 3H), 1.24 (s, 3H), 1.1 6-1.79 (m, 12H), 1.15 (s, 3H), 1.11 (s, 3H), 1.05 (s, 3H), 1.04 (s, 3H), 0.94 (s, 3H).

[0393] Compound 55c: Impure compound 55c (1.4948 g) was synthesized from compound 35 (3.13 mmol), N-hydroxy-2,2-dimethylpropionamidine (258.2 mg, 2.22 mmol) and trimethylamine (12.5 mmol) using the same procedure described for the synthesis of compound 51. m / z = 590 (M+1).

[0394] 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 in water, 1.25 mL, 1.9 mmol) using the same procedure described for the synthesis of compound T23. m / z = 572 (M+1); 1 H NMR (400MHz, CDCl3) 68.02 (s, 1H), 5.96 (s, 1H), 3.23 (m, 2H), 2.19 (td, J=13.7, 4.0Hz, 1H), 1.90 (m, 2H), 1.47 (m , 12H), 1.45(s, 3H), 1.33(s, 9H), 1.24(s, 3H), 1.15(s, 3H), 1.11(s, 3H), 1.04(s, 3H), 1.03(s, 3H), 0.94(s, 3H).

[0395] Compound 55d: Impure compound 55d (279.1 mg) was synthesized from compound 35 (0.64 mmol), N, hydroxycyclopropanecarboxamidine (84.3 mg, 0.842 mmol) and trimethylamine (2.6 mmol) using the same procedure described for the synthesis of compound 51. m / z = 574 (M+1).

[0396] 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 in water, 1 mL, 1.5 mmol) using the same procedure described for the synthesis of compound T23. m / z = 556 (M+1); 1 H NMR (400MHz, CDCl3) δ8.02 (s, 1H), 5.96 (s, 1H), 3.17 (m, 1H), 3.12 (d, J = 4.8Hz, 1H), 2.17 (td, J = 13.8, 4.1Hz, 1H), 2.06(m, 1H), 1.87(m, 2H), 1.46(s, 3H), 1.24(s, 3H), 1.15(s, 3H), 1.12(s, 3H), 1.02(s, 6H), 0.93(s, 3H). 0.88-1.80(m,16H).

[0397] Compound 55e: Impure compound 55e (514.3 mg) was synthesized from compound 35 (1.33 mmol), 2-cyclopropyl-N′-hydroxyacetamidine (101.3 mg, 0.887 mmol) and trimethylamine (5.31 mmol) using the same procedure described for the synthesis of compound 51. m / z=588 (M+1).

[0398] 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 in water, 1.25 mL, 1.9 mmol) using the same procedure described for the synthesis of compound T23. m / z = 570 (M+1); 1H NMR (400MHz, CDCl3) δ8.02 (s, 1H), 5.96 (s, 1H), 3.24 (m, 1H), 3.12 (d, J=4.7Hz, 1H), 2.61 (m, 2H), 2.20 (td, J=13.8, 4.1Hz, 1H), 1.91 (m, 2H) ,1.45(s,3H),1.24(s,3H),1.15(s,3H),1.12(s,3H),1.07-1.79(m,1 3H), 1.05(s, 3H), 1.04(s, 3H), 0.95(s, 3H), 0.50(m, 2H), 0.24(m, 2H).

[0399] 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 described for the synthesis of compound 51. m / z = 588 (M+1).

[0400] 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 in water, 0.9 mL, 1.35 mmol) using the same procedure described for the synthesis of compound T23. m / z = 570 (M+1); 1 H NMR (400MHz, CDCl3) δ8.03 (s, 1H), 5.97 (s, 1H), 3.63 (m, 1H), 3.21 (m, 2H), 2.33 (m, 4H), 2.20 (td, J=13.9, 4.1Hz, 1H ), 1.45(s, 3H), 1.24(s, 3H), 1.17-2.14(m, 16H), 1.15(s, 3H), 1.11(s, 3H), 1.05(s, 3H), 1.04(s, 3H), 0.94(s, 3H).

[0401] Compound 55g: 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) using the same procedure described for the synthesis of compound 51. m / z = 602 (M+1).

[0402] 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 in water, 0.4 mL, 0.6 mmol) using the same procedure described for the synthesis of compound T23. m / z = 584 (M+1); 1 H NMR (400MHz, CDCl3) δ8.02 (s, 1H), 5.96 (s, 1H), 3.19 (m, 3H), 2.19 (td, J=13.8, 4.1Hz, 1H), 1.45 (s, 3H ), 1.24(s, 3H), 1.17-2.07(m, 22H), 1.15(s, 3H), 1.11(s, 3H), 1.04(s, 3H), 1.03(s, 3H), 0.94(s, 3H).

[0403] 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 described for the synthesis of compound 51. m / z=616 (M+1).

[0404] 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 in water, 1.25 mL, 1.9 mmol) using the same procedure described for the synthesis of compound T23. m / z = 598 (M+1); 1 H NMR (400MHz, CDCl3) δ8.02 (s, 1H), 5.96 (s, 1H), 3.22 (m, 1H), 3.14 (d, J=4.7Hz, 1H), 2.77 (tt, J=11.4, 3.6Hz, 1H), 2.19 (td, J =13.8, 4.1Hz, 1H), 1.58 (m, 24H), 1.45 (s, 3H), 1.24 (s, 3H), 1.15 (s, 3H), 1.10 (s, 3H), 1.05 (s, 3H), 1.03 (s, 3H), 0.94 (s, 3H).

[0405] Compound 58: Compound 56 (0.86 g, 1.9 mmol) in CH2Cl2 (19 mL) was treated 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 CH2Cl2 (25 mL) and cooled to 0°C. Et3N (1.1 mL, 7.6 mmol) was added, followed by 2-fluoro-N-hydroxyacetamidine (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 washings were extracted with EtOAc (20 mL). The combined organic extracts were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0-100% EtOAc in CH2Cl2) to give Compound 58 (0.87 g, 87% yield) as a white solid. m / z=529 (M+1).

[0406] Compound 59: Compound 58 (20 mg, 0.038 mmol) was dissolved in o-xylene (0.5 mL) and the reaction 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).

[0407] 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 (12N 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 reactants were heated at 60°C for 4 h and then cooled to room temperature. The reaction mixture was diluted with EtOAc (30 mL); washed with water (2×20 mL) and saturated NaHCO3 aqueous solution (20 mL). The aqueous washings were extracted with EtOAc (20 mL). The combined organic extracts were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0-100% EtOAc in hexanes) to give Compound 60 (265 mg, quantitative yield) as an off-white solid. m / z = 536 (M+1).

[0408] Compound 61: 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 reactant was heated at 55 ° C for 1.5 h, and then cooled to 0 ° C. 10% NaH2PO4 aqueous solution (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 hexane) to give Compound 61 (217 mg, 82% yield) as a white solid. m / z=536 (M+1).

[0409] T34: Compound 61 (217 mg, 0.41 mmol) was dissolved in DMF (1 mL) under N2 and cooled to 0°C. 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 reactants were heated at 60°C for 4 h. After cooling to room temperature, the mixture was diluted with EtOAc (20 mL) and washed with 1N HCl aqueous solution (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. m / z=534 (M+1); 1 HNMR (400MHz, CDCl3) δ8.00 (s, 1H), 6.02 (s, 1H), 5.44 (d, J=46.5Hz, 2H), 3.2 7 (dt, J=13.9, 4.6Hz, 1H), 3.05 (d, J=4.7Hz, 1H), 2.45 (dq, J=6.7, 13.4Hz, 1H ), 2.23 (td, J=13.8, 4.1Hz, 1H), 1.57 (s, 3H), 1.41 (s, 3H), 1.24 (d, J=6.7Hz, 3H), 1.21-2.00(m, 11H), 1.11(s, 3H), 1.06(s, 3H), 1.05(s, 3H), 0.95(s, 3H).

[0410] Compound 62: Compound 56 (500 mg, 1.02 mmol) in CH2Cl2 (14 mL) was treated with oxalyl chloride (275 μL, 3.14 mmol) and N,N-dimethylformamide (8 μL, 0.1 mmol) at 0°C. The reactant was stirred at room temperature for 2 h and then concentrated. The residue was dissolved in toluene (3×20 mL) and concentrated to obtain the acid chloride as a yellow solid. The acid chloride was dissolved in CH2Cl2 (14 mL) and cooled to 0°C. Triethylamine (0.58 mL, 4.16 mmol) and 2,2-difluoro-N′-hydroxyacetamidine (173 mg, 1.57 mmol) were added. The reactant was stirred at room temperature overnight. LC-MS indicated that the reaction was complete. The reactant was concentrated and the residue was distributed between ethyl acetate (20 mL) and saturated NaHCO3 aqueous solution (10 mL). The organic layer was separated and washed with saturated NaHCO3 aqueous solution (10 mL). The combined aqueous washings were extracted with ethyl acetate (20 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0-100% EtOAc in hexanes) to give compound 62 (337 mg, 57% yield). m / z=570 (M+1).

[0411] T35: Tetrabutylammonium hydroxide (40 wt % in water, 0.36 mL, 0.55 mmol) was added dropwise to a solution of compound 62 (100 mg, 0.176 mmol) in THF (4 mL) at 0°C. The reaction was stirred at room temperature overnight. LC-MS indicated that the reaction was complete. The mixture was partitioned between ethyl acetate (20 mL) and water (20 mL). The organic layer was separated and washed with water (2×10 mL). The combined aqueous washings were extracted with ethyl acetate (20 mL). The combined organic extracts were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0-100% EtOAc in hexanes) to give compound T35 (15.7 mg, 16% yield). m / z=552 (M+1); 1H NMR (400MHz, CDCl3) δ8.00 (s, 1H), 6.75 (t, J=52.5Hz, 1H), 6.02 (s, 1H), 3.26 (dd, J=13.5, 3.5Hz, 1H), 3.02 (d, J=4.7Hz, 1H), 2.45 (dt, J=13.3, 6.7 Hz, 1H), 2.25 (td, J=13.9, 4.2Hz, 1H), 2.01-1.20 (m, 14H), 1.41 (s, 3H), 1 .24(d, J=6.8Hz, 3H), 1.11(s, 3H), 1.06(s, 3H), 1.05(s, 3H), 0.96(s, 3H).

[0412] Compound 63: To a solution of compound 56 (1.21 g, 2.46 mmol) in CH2Cl2 (50 mL) was added oxalyl chloride (0.65 mL, 7.43 mmol) and N,N-dimethylformamide (20 μL, 0.26 mmol) in sequence at 0° C. The mixture was stirred at 0° C. for 20 h, and then concentrated in vacuo to give compound 63 (1.48 g, quantitative yield) as a yellow foamy solid, which was used in the next step without further purification.

[0413] Compound 64: Triethylamine (0.79 mL, 5.67 mmol) was slowly added to a solution of compound 63 (82 weight %, 860 mg, 1.42 mmol) in CH2Cl2 (15 mL) at room temperature under N2. A solution of 2,2,2-trifluoro-N′-hydroxy-acetamidine (181 mg, 1.42 mmol) in CH2Cl2 (6 mL) was then 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 NaHCO3 aqueous solution (30 mL) and brine (30 mL). The organic extract was dried with Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, eluted with a solution of 0-10% MeOH in CH2Cl2) to obtain partially purified compound 64 (615 mg) as an orange foamy solid, which was used in the next step without further purification. m / z = 588.2 (M+1).

[0414] T36: A mixture of compound 64 (615 mg, <1.04 mmol) and tetrabutylammonium hydroxide (40 wt % in water, 2.16 mL, 3.31 mmol) in THF (20 mL) was stirred at room temperature for 20 h under N2. The reaction mixture was concentrated. The residue was diluted with EtOAc (40 mL). The mixture was washed with water (20 mL). The aqueous phase was separated and extracted with EtOAc (2×20 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 0-50% EtOAc in hexanes) to give compound T36 (72.3 mg, 9% yield from compound 63) as a white solid. m / z=570.2 (M+1); 1 H NMR (400MHz, CDCl3) δ8.00 (s, 1H), 6.03 (s, 1H), 3.30-3.22 (m, 1H), 3.01 (d, J=4.7Hz, 1H), 2.46 (dt, J=13.3, 6.7Hz, 1H), 2.27 (td, J=13.9, 4.2Hz, 1H), 2.02-1.20 (m, 14H), 1.42 (s, 3H), 1.24 (d, J=6.8Hz, 3H), 1.11 (s, 3H), 1.07 (s, 3H), 1.06 (s, 3H), 0.96 (s, 3H).

[0415] Compound 65: Triethylamine (0.579 mL, 4.15 mmol) was slowly added to a solution of compound 63 (83 wt %, 620 mg, 1.04 mmol) in CH2Cl2 (10 mL) at room temperature under N2. A solution of N′-hydroxypropionamidine (92 mg, 1.04 mmol) in CH2Cl2 (6 mL) was then 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 NaHCO3 aqueous solution (30 mL) and brine (30 mL). The organic extract was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0-10% MeOH in CH2Cl2) to obtain 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).

[0416] T37: A mixture of compound 65 (520 mg, 0.95 mmol) and tetrabutylammonium hydroxide (40% w / w in water, 1.98 mL, 3.04 mmol) in THF (15 mL) was stirred at room temperature for 15 h under N2. The reaction mixture was concentrated. The residue was diluted with EtOAc (30 mL) and washed with water (20 mL). The aqueous phase was separated and extracted with EtOAc (2×20 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 0-50% EtOAc in hexanes) to give compound T37 (267 mg, 48% yield from compound 63) as a white solid. m / z=530.3 (M+1); 1 H NMR (400MHz, CDCl3) δ8.01 (s, 1H), 6.02 (s, 1H), 3.28-3.20 (m, 1H), 3.13 (d, J =4.7Hz, 1H), 2.73(qd, J=7.6, 1.6Hz, 2H), 2.45(dt, J=13.3, 6.7Hz, 1H), 2.20( td, J=13.8, 4.2Hz, 1H), 2.02-1.18 (m, 14H), 1.41 (s, 3H), 1.29 (t, J=7.6Hz, 3H ), 1.24 (d, J=6.7Hz, 3H), 1.11 (s, 3H), 1.05 (s, 3H), 1.04 (s, 3H), 0.94 (s, 3H).

[0417] Compound 66: Compound 65 (260 mg, 0.524 mmol) in CH2Cl2 (5 mL) was cooled to 0°C under N2. Hydrazine hydrate (50 wt%, 98 μL, 1.57 mmol) was added dropwise. The mixture was stirred at room temperature for 10 min; diluted with CH2Cl2 (10 mL); and washed with water (15 mL). The aqueous washings were extracted with CH2Cl2 (3×15 mL) and EtOAc (15 mL). The combined organic extracts were dried over MgSO4, filtered and concentrated to give compound 66 (220 mg, 85% yield). m / z=492 (M+1)

[0418] Compound 67: A solution of 2-fluoroacetic acid (38 μL, 0.67 mmol) in CH2Cl2 (2 mL) was treated with N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (129 mg, 0.67 mmol) and DMAP (5 mg, 0.045 mmol) at room temperature under N2. The mixture was stirred at room temperature for 15 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 CH2Cl2) to give compound 67 (72 mg, 29% yield). m / z=552 (M+1).

[0419] T38: Compound 67 (70 mg, 0.13 mmol) and p-toluenesulfonic acid monohydrate (12 mg, 0.063 mmol) were heated at reflux in toluene (7 mL) for 5 h while removing water by 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 hexanes) to give compound T38 (33 mg, 49% yield) as a white solid. m / z=534 (M+1); 1 H NMR (400MHz, CDCl3) δ8.00 (s, 1H), 6.02 (s, 1H), 5.51 (d, J=47.1, 2H), 3.19 (dt, J=13.4, 4.0Hz, 1H), 3.02 (d, J=4.7Hz, 1H), 2.46 (dq, J=13.3 , 6.7Hz, 1H), 2.23 (td, J=13.7, 4.2Hz, 1H), 2.01-1.20 (m, 14H), 1.41 (s, 3H), 1.24 (d, J=6.8Hz, 3H), 1.16 (s, 3H), 1.06 (s, 6H), 0.95 (s, 3H).

[0420] Compound 69: A mixture of compound 68 (898 mg, 1.94 mmol), NaOAc (286 mg, 3.49 mmol) and hydroxylamine hydrochloride (175 mg, 2.52 mmol) in EtOH (30 mL) and H2O (2 mL) was stirred at room temperature for 16 h. The mixture was concentrated. The residue was distributed 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 Na2SO4, filtered, and concentrated to give compound 69 (863 mg, 93% yield) as a white solid, which was used in the next step without further purification. m / z=479 (M+1).

[0421] Compound 70: Compound 69 (863 mg, 1.80 mmol) in MeCN (9 mL) was cooled to -10 ° C. A 12N HCl aqueous solution (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 allowed to run at -10 ° C for 30 min, and then ammonium hydroxide (28 wt %, aqueous solution, 3 mL, 21.5 mmol) was added. The reactants were 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 Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, 0-100% EtOAc in CH2Cl2) to obtain compound 70 (457 mg, 51% yield). m / z=494(M+1).

[0422] Compound 71: A solution of 2-fluoroacetic acid (169 mg, 2.17 mmol) in CH2Cl2 (15 mL) was added to N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC·HCl, 416 mg, 2.17 mmol) at room temperature under N2. 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 washings were extracted with ethyl acetate (20 mL). The combined organic extracts were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0-100% EtOAc in hexanes) to give Compound 71 (150 mg, 38% yield). m / z=554 (M+1).

[0423] Compound 72: Compound 71 (207 mg, 0.374 mmol) in 1,4-dioxane (3 mL) was heated at 100 °C for 5 h under N2. 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).

[0424] Compound 73: 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 reactant was heated at 55 ° C for 2.5 h, and then cooled to room temperature. A 10% NaH2PO4 aqueous solution (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 obtain compound 73 (134 mg, 85% yield). m / z=536 (M+1).

[0425] T39: Compound 73 (134 mg, 0.25 mmol) was dissolved in DMF (3 mL) under N2 and cooled to 0°C. 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 1N HCl aqueous solution (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 0-50% EtOAc in hexanes) to give Compound T39 (96 mg, 70% yield) as a white foam. m / z=534 (M+1); 1 H NMR (400MHz, CDCl3) δ8.01 (s, 1H), 6.01 (s, 1H), 5.54 (d, J=46.3, 2H), 3.22 (dt, J=13.2, 3.9Hz, 1H), 2.98 (d, J=4.7Hz, 1H), 2.45 (dq, J=13.3, 6.7H z, 1H), 2.19 (td, J=13.8, 4.2Hz, 1H), 2.01-1.20 (m, 14H), 1.41 (s, 3H), 1. 24(d, J=6.7Hz, 3H), 1.14(s, 3H), 1.06(s, 3H), 1.05(s, 3H), 0.94(s, 3H).

[0426] Compound 74: 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 reactants were stirred at room temperature for 19 h. The reaction mixture was combined with another identical reaction starting from compound 5. The mixture was diluted with EtOAc (40 mL) and washed with saturated NaHCO3 aqueous solution (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 obtain compound 74 (130 mg, 56% yield) as a white solid. m / z=586 (M+1).

[0427] Compound 75: 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 reactant was heated at 55 ° C for 2 h and then cooled to room temperature. 10% NaH2PO4 aqueous solution (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 MgSO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0-40% EtOAc in hexanes) to obtain compound 75 (85 mg, 68% yield) as a white solid. m / z=586 (M+1).

[0428] T40: Compound 75 (82 mg, 0.14 mmol) was dissolved in DMF (0.7 mL) under N2 and cooled to 0°C. 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 to dissolve the white solid precipitated during the reaction. 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 1N HCl aqueous solution (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% acetone in hexanes) to give Compound T40 (70 mg, 85% yield) as a white solid. m / z=584 (M+1); 1 HNMR (400MHz, CDCl3) δ8.02 (s, 1H), 5.97 (s, 1H), 3.26-3.19 (m, 1H), 2.95 (d, J=4.7Hz, 1H), 2.22 (td, J=13.8, 4.2Hz, 1H), 1.96 -1.83 (m, 2H), 1.80-1.20 (m, 12H), 1.45 (s, 3H), 1.25 (s, 3H), 1.16 (s, 3H), 1.14 (s, 3H), 1.06 (s, 3H), 1.05 (s, 3H), 0.95 (s, 3H).

[0429] Compound 76: To a solution of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (170 mg, 0.886 mmol) in CH2Cl2 (3 mL) was added 2,2-difluoroacetic acid (85 mg, 0.886 mmol) and DMAP (3.6 mg, 0.030 mmol) in CH2Cl2 (3 mL) at room temperature. After the reaction mixture was stirred for 15 min, a solution of compound 5 (150 mg, 0.295 mmol) in CH2Cl2 (4 mL) was added. The reactant was stirred for another 19 h at room temperature. The mixture was then diluted with CH2Cl2 (20 mL) and washed with water (15 mL). The aqueous washings were extracted with EtOAc (2×15 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0-40% EtOAc in hexanes) to give Compound 76 (106 mg, 63% yield) as a white solid. m / z = 568 (M+1).

[0430] Compound 77: 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 reactant was heated at 55 ° C for 2 h, and then cooled to room temperature. 10% NaH2PO4 aqueous solution (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).

[0431] 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 1N HCl aqueous solution (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. m / z=566 (M+1); 1H NMR (400MHz, CDCl3) δ8.02 (s, 1H), 6.79 (t, J=52.2Hz, 1H), 5.96 (s, 1H), 3.22 (dt, J=13.4, 4.4Hz, 1H), 2.92 (d, J=4.7Hz, 1H), 2.21 (td, J= 13.8, 4.2Hz, 1H), 1.96-1.83(m, 2H), 1.80-1.20(m, 12H), 1.45(s, 3H), 1.25(s, 3H), 1.15(s, 3H), 1.13(s, 3H), 1.05(s, 6H), 0.95(s, 3H).

[0432] Compound 79: Compound 35 (500 mg, 0.980 mmol) in CH2Cl2 (10 mL) was cooled to 0°C and treated with triethylamine (0.55 mL, 3.95 mmol) and compound 78 (215 mg, 1.47 mmol). The reaction mixture was stirred at ambient temperature for 2 h, and then washed with water. The aqueous layer was separated and extracted with CH2Cl2. The combined organic extracts were dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, eluted with 60% EtOAc in hexanes) to obtain compound 79 (437 mg, 72% yield) as a white solid. m / z=620 (M+1).

[0433] 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 reactant was stirred at room temperature for 11 h, and then diluted with ethyl acetate. The mixture was washed with water and brine. The organic extract was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, eluted with 30% EtOAc in hexanes) to obtain compound 80 (258 mg, 61% yield) as an off-white solid. m / z=602 (M+1).

[0434] T42: A solution of compound 80 (258 mg, 0.428 mmol) in CH2Cl2 (10 mL) was treated with trifluoroacetic acid (1 mL, 12.98 mmol) at room temperature. The reaction 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. m / z=546 (M+1); 1H NMR (400MHz, CDCl3) δ8.02 (s, 1H), 5.97 (s, 1H), 4.77 (d, J = 6.7Hz, 2H), 3.33-3.20 (m, 1H), 3.04 (d, J = 4.7Hz, 1H), 2. 27-2.16(m, 2H), 2.00-1.20(m, 14H), 1.45(s, 3H), 1.25(s, 3H), 1.15(s, 3H), 1.11(s, 3H), 1.05(s, 6H), 1.00(s, 3H).

[0435] Compound 81: A solution of triethylamine (0.266 mL, 1.90 mmol) and 2,2-difluoro-N-hydroxyacetamidine (78.6 mg, 0.71 mmol) in CH2Cl2 (3.0 mL) was added dropwise to a solution of compound 35 (243 mg, 0.476 mmol) in CH2Cl2 (4.0 mL) at 0°C under N2. The mixture was stirred at room temperature for 18 h, and then partitioned between CH2Cl2 (40 mL) and water (40 mL). The aqueous phase was separated and extracted with CH2Cl2 (2×30 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0-100% EtOAc in hexane) to obtain compound 81 (186 mg, 67% yield) as a solid. m / z=584.3 (M+1).

[0436] 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 N2. 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 Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0-50% acetone in CH2Cl2) to give T43 (73 mg, 55% yield) as a solid. m / z=566.4 (M+1); 1H NMR (400MHz, CDCl3) δ8.02 (s, 1H), 6.75 (t, J=52.5Hz, 1H), 5.97 (s, 1H), 3.29-3.23 (m, 1H), 3.00 (d, J=4.7Hz, 1H), 2.25 (td, J=13.9, 4.2Hz , 1H), 2.01-1.88(m, 2H), 1.51-1.20(m, 12H), 1.45(s, 3H), 1.25(s, 3H), 1.15(s, 3H), 1.10(s, 3H), 1.06(s, 3H), 1.05(s, 3H), 0.96(s, 3H).

[0437] Compound 82: Difluoroacetic anhydride (52 μL, 0.45 mmol) was added to a solution of compound 36 (0.19 g, 0.38 mmol) and pyridine (46 μL, 0.56 mmol) in CH2Cl2 (4 mL) at 0°C under N2. The reactant 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 1N HCl aqueous solution (20 mL), water (20 mL) and brine (10 mL). The organic extract was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0-40% EtOAc in CH2Cl2) to obtain compound 82 (95 mg, 43% yield) and a mixture of compound 82 and T44 (4 / l, 80 mg, 36% yield). Compound 82: m / z=584.3 (M+1).

[0438] T44: p-Toluenesulfonic acid monohydrate (13 mg, 0.068 mmol) was added to a mixture of compound 82 (80.0 mg, 0.14 mmol) in toluene (8 mL) at room temperature. The reaction was heated at reflux for 3 h while removing water by a Dean-Stark apparatus. After cooling to room temperature, the mixture was partitioned between EtOAc (30 mL) and water (10 mL). The organic extract was washed with water (2×10 mL) and brine (10 mL); dried over Na2SO4; filtered and concentrated. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexanes) to give compound T44 (24 mg, 31% yield) as a white solid. m / z=566.4 (M+1); 1H NMR (400MHz, CDCl3) δ8.02 (s, 1H), 6.83 (t, J=51.8Hz, 1H), 5.97 (s, 1H), 3.25-3.17 (m, 1H), 3.05 (d, J=4.7Hz, 1H), 2.25 (td, J =13.9, 4.2Hz, 1H), 2.01-1.88(m, 2H), 1.51-1.20(m, 12H), 1.45(s, 3H), 1.25(s, 3H), 1.15(s, 6H), 1.06(s, 6H), 0.96(s, 3H).

[0439] Compound 83: Trifluoroacetic anhydride (74 μL, 0.52 mmol) was added to a solution of compound 36 (0.22 g, 0.44 mmol) and pyridine (53 μL, 0.65 mmol) in CH2Cl2 (5 mL) at room temperature. 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 another 1 h. Compound 83 was completely consumed. The reaction mixture was then cooled to room temperature; diluted with EtOAc (25 mL); and washed with 1N HCl aqueous solution (20 mL), water (2×20 mL), and brine (10 mL). The organic extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0-75% EtOAc in hexanes) to give Compound 83 (0.22 g, 84% yield) as a white solid.

[0440] T45: Burgess reagent (0.42 g, 1.76 mmol) was added to a solution of compound 83 (0.21 g, 0.35 mmol) in THF (4 mL) at room temperature. The reaction 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 Na2SO4; filtered and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0-40% EtOAc in hexanes) to give compound T45 (0.11 g, 54% yield) as a white solid. m / z = 584.3 (M+1); 1H NMR (400MHz, CDCl3) δ8.02 (s, 1H), 5.98 (s, 1H), 3.24-3.16 (m, 1H), 3.05 (d, J=4.7Hz, 1H), 2.26 (td, J=14.0, 4.2Hz, 1H) , 2.01-1.88(m, 2H), 1.80-1.20(m, 12H), 1.46(s, 3H), 1.25(s, 3H), 1.16(s, 6H), 1.06(s, 3H), 1.05(s, 3H), 0.96(s, 3H).

[0441] Compound 84: Propionic anhydride (0.076 mL, 0.59 mmol) was added to a solution of compound 36 (0.25 g, 0.49 mmol) and pyridine (60 μL, 0.74 mmol) in CH2Cl2 (5 mL). The reactant 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 Na2SO4, 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).

[0442] T46: Burgess reagent (0.21 g, 0.88 mmol) was added to a mixture of compound 84 (99 mg, 0.18 mmol) in THF (2 mL) 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 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 Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, eluted with 0-80% EtOAc in hexanes) to give compound T46 (71 mg, 74% yield) as a white solid. m / z 544.3 (M+1); 1H NMR (400MHz, CDCl3) δ8.02 (s, 1H), 5.95 (s, 1H), 3.13 (dt, J=13.4, 4.1Hz, 1H), 2.96 (d, J=4.7Hz, 1H), 2.85 (q, J=7.6Hz, 2H), 2.21-2.13 (m, 1 H), 2.01-1.20 (m, 14H), 1.44 (s, 3H), 1.35 (t, J=7.5Hz, 3H), 1.24 (s, 3H), 1.17 (s, 3H), 1.15 (s, 3H), 1.05 (s, 3H), 1.04 (s, 3H), 0.94 (s, 3H).

[0443] Compound 87: Oxalyl chloride (3.69 mL, 42.1 mmol) and DMF (0.11 mL, 1.40 mmol) were added to a solution of compound 85 (6.58 g, 14.0 mmol) in CHCl (66 mL) at 0°C under N2. 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.

[0444] Compound 86 is dissolved in CH2Cl2 (100mL) and cooled to 0°C. Triethylamine (7.83mL, 56.2mmol) and 2-fluoro-N-hydroxyacetamidine (1.94g, 21.1mmol) are added successively. The mixture is stirred at room temperature for 4h, and then washed with water (20mL). The aqueous phase is separated and extracted with CH2Cl2 (20mL). The combined organic extracts are dried with Na2SO4, filtered and concentrated. The residue is purified by column chromatography (silica gel, eluted with 0-100% EtOAc solution in hexanes) to obtain compound 87 (6.81g, 89% yield) as a yellow solid. m / z=543.3 (M+1).

[0445] 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 % in EtOAc, 17.3 mL, 29.1 mmol) were added in sequence. The mixture was heated at reflux for 7 h and then cooled to 0°C. Saturated aqueous NaHCO3 solution (100 mL) was slowly added. After the addition was complete, the mixture was extracted with CH2Cl2 (100 mL). The organic extract was washed with saturated aqueous NaHCO3 solution (100 mL) and water (100 mL). The combined aqueous washings were extracted with EtOAc (2×150 mL). The organic extract was dried over Na2SO4; filtered through a silica gel pad (25 g); and eluted with EtOAc (100 mL). The filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluting with 0-100% EtOAc in hexanes) to give the compound as an off-white solid (1.65 g, 36% yield). m / z = 525.3 (M+1).

[0446] 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 (6M 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 washings 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).

[0447] Compound 90: 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 N2. The mixture was heated at 55°C for 1.5 h; cooled to 0°C; and treated with 10% aqueous NaH2PO4 solution (30 mL). The mixture was partitioned between EtOAc (50 mL) and brine (30 mL). The aqueous phase was separated and extracted with EtOAc (50 mL). The combined organic extracts were dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography (silica gel, 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).

[0448] T12: Compound 90 (2.570 g, 4.675 mmol) was dissolved in DMF (12 mL) under N2 and cooled to 0°C. 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 1N HCl aqueous solution (30 mL), water (2×30 mL) and brine (20 mL). The aqueous washings 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, eluted with 0-30% acetone in hexanes) to give compound T12 (2.456 g, 96% yield) as a light yellow solid. m / z=548.3 (M+1); 1 H NMR (400MHz, CDCl3) δ8.02 (s, 1H), 5.97 (s, 1H), 5.44 (d, J = 46.5Hz, 2H), 3.26 (m, 1H), 3.03 (d, J = 4.7Hz, 1H), 2.24 (td, J = 13.8, 4.1Hz, 1 H), 1.87-2.01(m, 2H), 1.45(s, 3H), 1.25(s, 3H), 1.20-1.80(m, 12H), 1.15(s, 3H), 1.10(s, 3H), 1.06(s, 3H), 1.05(s, 3H), 0.95(s, 3H).

[0449] Example 2: Nitric Oxide Inhibition Data

[0450] Tissue Culture. RAW 264.7, a mouse 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, 1% penicillin / streptomycin. All cell culture supplies were obtained from Life Technologies (Grand Island, NY) and VWR (Radnor, PA).

[0451] Nitric oxide inhibition assay. RAW 264.7 cells were plated at 30,000 cells per well in Falcon-96-well clear bottom plates (Corning, NY) one day before experimental treatment using RPMI1640 supplemented with 0.5% fetal bovine serum and 1% penicillin-streptomycin in a total volume of 200 μL per well. The next day, cells were pretreated with compounds serially diluted from 1000× stock solutions. All compounds were dissolved in dimethyl sulfoxide (DMSO) at 10 mM stock solutions. The compounds were then diluted in DMSO and RPMI 1640. Each well received a final concentration of 0.1% DMSO. The cells were pretreated for 2 hours and incubated at 37°C, followed by treatment with 20 ng / mL interferon gamma (R&D Systems, Minneapolis, MN) per well for 24 hours. The next day, nitrite standards were serially diluted from 100 μM to 1.6 μM in RPMI 1640. Afterwards, 50 μL of cell culture supernatant was transferred from each well to a new Falcon-96 well clear bottom plate. Nitrite was measured as a surrogate for nitric oxide using Promega's Griess Detection Kit #G2930 (Madison, WI), which involves adding 50 μL of the sulfonamide solution provided 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 N-1-naphthylethylenediamine dihydrochloride (NED) solution provided was added to the sulfonamide reaction and incubated in the dark at room temperature for 10 minutes. Afterwards, ethanol vapor was used to remove bubbles, and the absorbance was measured using a Spectramax M2e plate reader set to 525 nm in wavelength. Viability was assessed using the WST-1 cell proliferation reagent from Roche (Base1, Switzerland). After removing the culture medium for nitric oxide inhibition assay, 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 for 30 minutes at 37° C. The absorbance was measured using a Spectramax M2e plate reader with wavelengths set to 440 nm and 700 nm.

[0452] With respect to the ability of compounds to inhibit the increase in nitric oxide release caused by interferon gamma, the absolute amount of nitrite produced in each well was extrapolated from the nitrite standard using a linear regression fit. All values ​​were then normalized to DMSO-interferon gamma treated wells and plotted as percentage of nitric oxide. IC was calculated based on the dependence on WST1 activity using Excel and / or GraphPad Prism (San Diego, CA). 50 The data are shown in Table 2.

[0453] Table 2: Nitric oxide inhibition (NO IC50 ) and NO IC relative to RTA 402 50 .

[0454]

[0455]

[0456]

[0457]

[0458]

[0459]

[0460]

[0461]

[0462]

[0463]

[0464]

[0465] a The average of the ratios from replicate experiments.

[0466] Table 3: NO IC relative to comparative compounds 50 .

[0467]

[0468]

[0469]

[0470] b Average of ratios from experiments with direct contrasts.

[0471] Example 3: CYP3A4 Inhibition

[0472] Methods. Several compounds were evaluated for CYP3A4 (midazolam) inhibition at 1 μM 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, which is incorporated herein by reference). Each sample contained 0.1 mg / mL human liver microsomes, 5 μM midazolam as a substrate, and 1 μM test compound, and each sample was incubated at 37°C for 10 minutes. After incubation, the metabolite 1-hydroxymidazolam was measured using HPLC-MS / MS. The peak area corresponding to the substrate metabolite was recorded. The control activity percentage was then calculated by comparing the peak area obtained in the presence of the test compound with the peak area obtained in the absence of the test compound. Subsequently, the inhibition percentage was calculated for each compound by subtracting the control activity percentage from 100. The results of the CYP3A4 assay are shown in Tables 4-7 below.

[0473] Table 4: CYP3A4 (midazolam) inhibition.

[0474]

[0475]

[0476]

[0477] Comparative compounds CC1 and T11 (both containing a 1,3,4-oxadiazole-2,5-diyl moiety) were also tested for CYP3A4 inhibition. The results of the CYP3A4 assay are shown in Table 5 below.

[0478] Table 5: CYP3A4 (midazolam) inhibition of T11 compared to CC1.

[0479]

[0480] Comparative compounds CC2 and T12 (both containing a 1,2,4-oxadiazole-3,5-diyl moiety) were also tested for CYP3A4 inhibition. The results of the CYP3A4 assay are shown in Table 6 below.

[0481] Table 6: CYP3A4 (midazolam) inhibition of T12 compared to CC2.

[0482]

[0483] Comparative compounds CC3 and T34 (both containing a 1,2,4-oxadiazole-3,5-diyl moiety and a monomethyl substitution at C4) were also tested for CYP3A4 inhibition. The results are shown in Table 7 below.

[0484] Table 7: CYP3A4 (midazolam) inhibition of T34 compared to CC3.

[0485]

[0486] Example 4: Glutathione determination

[0487] The effect of compound treatment on total glutathione levels was evaluated in the mouse AML-12 hepatocyte cell line. Glutathione (a tripeptide composed of cysteine, glutamate, and glycine) is the main thiol-containing protein in cells and regulates the redox balance of cells. 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 two subunits of glutamate cysteine ​​ligase (GCL), which catalyzes the rate-limiting step of glutathione biosynthesis (Thimmulappa et al., 2002).

[0488] AML-12 cells were plated in white transparent bottom 96-well plates in 200 μL of DMEM / F12 culture medium supplemented with 10% FBS and 1% penicillin / streptomycin at a density of 8,000 cells / well. The next day, cells were treated with vehicle (DMSO) or test compound (0.03nM to 1000nM). Each well received a final concentration of 0.1% DMSO. Cells were incubated at 37°C, 5% CO2 for 24 hours. According to the manufacturer's instructions, total glutathione concentration was measured using GSH-Glo glutathione assay kit (Promega). In short, a standard curve was prepared by serial dilution of the glutathione solution provided. The 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 culture medium from the sample wells, 100 μL of the glutathione reaction mixture consisting of GSH-Glo reaction buffer, glutathione S-transferase, luciferin-NT and TCEP was added to each sample well and all standard curve wells. After incubation at room temperature for 30 minutes, 100 μL of luciferin detection reagent was added to all sample wells and standard wells and incubated for 15 minutes. Luminescence was measured using a PHERAstar plate reader. EC was determined using Excel and GraphPad Prism software. 50 The basal concentration of glutathione was set as 0%, and the highest concentration of glutathione produced after treatment with the test compound was set as 100%, and a dose-response curve was generated. The dose-response curve was fitted using nonlinear regression analysis and used to extrapolate the EC 50 Value. 50The value is defined as the concentration of test compound required to increase glutathione concentration to 50% of the maximum concentration. The data are shown in Tables 8 and 9.

[0489] Table 8: Glutathione (GSH) EC50 and EC50 relative to RTA 402.

[0490]

[0491]

[0492]

[0493]

[0494]

[0495]

[0496]

[0497] c The average of the ratios from replicate experiments.

[0498] Table 9: Glutathione (GSH) EC50 relative to control compounds.

[0499]

[0500]

[0501]

[0502] d Average of ratios from experiments with direct contrasts.

[0503] Example 5: Effect on luciferase reporter gene activation

[0504] 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). The cell line was stably transfected with a luciferase reporter gene under the transcriptional control of eight copies of the rat GSTA2 ARE sequence.

[0505] The effects of several compounds disclosed herein on luciferase reporter gene activation were evaluated in the AREc32 reporter cell line (see Tables 10 and 11). The cell line is derived from human breast cancer MCF-7 cells and is stably transfected with a luciferase reporter gene under the transcriptional control of eight copies of an antioxidant response element from the rat Gsta2 gene (a Nrf2 target gene) (Frilling et al., 1990). AREc32 cells were plated in black 96-well plates at 20,000 cells / well in 200 μL of culture medium. 24 hours after plating, cells were treated with vehicle (DMSO) or test compounds at concentrations ranging from 0.03-1000 nM for 19 hours. The culture medium was removed and 100 μL of a 1:1 mixture of One-Glo luciferase assay reagent and culture medium was added to each well. After incubation at room temperature for 5 minutes, the luminescent signal was measured on a PHERAstar plate reader. EC was determined using Excel and GraphPad Prism software 2X The fold increase in luminescence signal of cells treated with each concentration of compound relative to cells treated with vehicle was determined, and dose-response curves were generated. Dose-response curves were fitted using nonlinear regression analysis and used to extrapolate EC 2X Value. 2X The value is defined as the concentration of test compound required to increase the luminescent signal more than 2-fold to the level in vehicle-treated samples.

[0506] Table 10: AREc32 EC 2X and EC relative to RTA 402 2X .

[0507]

[0508]

[0509]

[0510]

[0511]

[0512]

[0513]

[0514]

[0515] e The average of the ratios from replicate experiments.

[0516] fThe repeat number in this case refers only to AREc32 EC 2X This compound was not run side-by-side against RTA402 in the same experiment.

[0517] Table 11: AREc32 EC relative to comparative compounds 2X .

[0518]

[0519]

[0520]

[0521]

[0522] g Average of ratios from experiments with direct contrasts.

[0523] ****************

[0524] In view of the present disclosure, all compounds, preparations and methods disclosed and claimed herein can be prepared and implemented without too much experimentation. Although the compounds, preparations and methods of the present disclosure have been described in the form of preferred embodiments, it is obvious to those skilled in the art that changes can be applied to the steps or the order of steps of the methods described herein, without departing from the concept, spirit and scope of the present invention. More specifically, it is obvious that certain medicaments related both chemically and physiologically can be used to replace the medicaments described herein, while achieving the same or similar results. All such similar substitutions and modifications apparent to those skilled in the art are considered to fall within the spirit, scope and concept of the present invention as defined by the appended claims.

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Claims

1. A compound of the following formula or a pharmaceutically acceptable salt thereof: in: A1 is selected from -heteroarene diyl- with C≤3; R1 is a monopolar, substituted alkyl group having C≤3, wherein the monopolar substituent is selected from the group consisting of -OH, -F, -OC(O)CH3, and -NHC(O)OCH3; and R2 and R2′ are each independently hydrogen or methyl; Therein the term "monopolar-substituted" means that one and only one hydrogen atom of the group so modified has been replaced by one of the monopolar substituents.

2. The compound of claim 1, wherein the compound is further defined as: in: A1 is selected from -heteroarene diyl- with C≤3; and R1 is a monopolar substituted alkyl group with C≤3; or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1, wherein the compound is further defined as: in: A1 is selected from -heteroarene diyl- with C≤3; and R1 is a monopolar substituted alkyl group with C≤3; or a pharmaceutically acceptable salt thereof.

4. The compound according to any one of claims 1 to 3, wherein R1 is a monopolar-substituted ethyl group.

5. The compound according to any one of claims 1 to 3, wherein R1 is a monopolar-substituted methyl group.

6. The compound according to any one of claims 1 to 3, wherein R1 is a monofluoroalkyl group having C≤3 or a monohydroxyalkyl group having C≤3. The compound according to claim 6 , wherein R 1 is a monofluoroalkyl group with C ≤ 3.

8. The compound of claim 7, wherein R1 is fluoroethyl.

9. The compound of claim 8, wherein R1 is 2-fluoroethyl.

10. The compound of claim 7, wherein R1 is fluoromethyl. The compound according to claim 6 , wherein R 1 is a monohydroxyalkyl group with C ≤ 3.

12. The compound of claim 11, wherein R1 is hydroxyethyl.

13. The compound of claim 12, wherein R1 is 2-hydroxyethyl.

14. The compound of claim 11, wherein R1 is hydroxymethyl.

15. The compound according to any one of claims 1 to 3, wherein R1 is -CH2CH2OC(O)CH3.

16. The compound of any one of claims 1-3, wherein R1 is -CH2CH2NHC(O)OCH3.

17. The compound of claim 1, further defined as: or a pharmaceutically acceptable salt of any of these formulae.

18. The compound according to claim 17, further defined as: or a pharmaceutically acceptable salt of any of these formulae.

19. The compound according to claim 18, further defined as: or a pharmaceutically acceptable salt of any of these formulae.

20. The compound of claim 19, further defined as: or a pharmaceutically acceptable salt thereof.

21. The compound of claim 19, further defined as: or a pharmaceutically acceptable salt thereof.

22. The compound of claim 19, further defined as: or a pharmaceutically acceptable salt thereof.

23. The compound of claim 19, further defined as: or a pharmaceutically acceptable salt thereof.

24. The compound of claim 18, further defined as: or a pharmaceutically acceptable salt thereof.

25. The compound of claim 1, 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-octahydropyridine-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-octahydrophthalene-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-octahydrophthalene-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-octahydropyridine-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-octahydropyridine-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-octahydropyridine-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-hexahydrophthalimide-4a(2H)-yl)-1,2,4-oxadiazol-3-yl)ethyl acetate; 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-hexahydrophthalimide-4a(2H)-yl)-1,2,4-oxadiazol-3-yl)ethyl)carbamate; (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-octahydrophthalonitrile-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-octahydrophthalonitrile-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-octahydrophthalene-2-carbonitrile; or (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-octahydrophthalene-2-carbonitrile.

26. The compound of claim 25, 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-octahydropyridine-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-octahydrophthalene-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-octahydropyridine-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-octahydrophthalene-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-octahydrophthalene-2-carbonitrile.

27. The compound of claim 26, 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-octahydropyridine-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-octahydrophthalene-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-octahydrophthalene-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-octahydrophthalonitrile-2-carbonitrile.

28. The compound of claim 27, 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-octahydrophthalene-2-carbonitrile.

29. The compound of claim 27, 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-octahydrophthalene-2-carbonitrile.

30. The compound of claim 27, 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-octahydrophthalene-2-carbonitrile.

31. The compound of claim 27, 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-octahydrophthalonitrile-2-carbonitrile.

32. The compound of claim 26, 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-octahydrophthalene-2-carbonitrile.

33. Compounds of the formula: or a pharmaceutically acceptable salt of any of these formulae.

34. A compound selected from the group consisting of: (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-octahydrophthalene-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-octahydrophthalene-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-hexahydrophthalimide-4a(2H)-yl)-2H-tetrazol-2-yl)ethyl acetate; or (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-octahydrophthalene-2-carbonitrile.

35. A pharmaceutical composition comprising: (A) a compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt thereof; and (B) Excipients.

36. The pharmaceutical composition of claim 35, wherein the pharmaceutical composition is formulated for oral administration.

37. The pharmaceutical composition of claim 35, wherein the pharmaceutical composition is formulated for administration via injection.

38. The pharmaceutical composition of claim 37, wherein the pharmaceutical composition is formulated for intra-arterial administration, intramuscular administration, intraperitoneal administration, or intravenous administration.

39. The pharmaceutical composition of claim 35, wherein the pharmaceutical composition is formulated for topically administration.

40. The pharmaceutical composition of claim 39, wherein the pharmaceutical composition is formulated for topical administration to the skin or the eye.

41. The pharmaceutical composition according to any one of claims 35-40, wherein the pharmaceutical composition is formulated as a unit dose.

42. Use of a compound or pharmaceutically acceptable salt thereof as described in any one of claims 1 to 34 or a pharmaceutical composition as described in any one of claims 35 to 41 for the preparation of a medicament for treating or preventing a disease or condition in a patient in need thereof, wherein the disease or condition is selected from cancer, cardiovascular disease, autoimmune disease, neurodegenerative disease, chronic kidney disease, diabetes, mucositis, inflammatory bowel disease, dermatitis, sepsis, ischemia-reperfusion injury, influenza, osteoarthritis, osteoporosis, pancreatitis, asthma, chronic obstructive pulmonary disease, cystic fibrosis, idiopathic pulmonary fibrosis, multiple sclerosis, muscular dystrophy, cachexia, graft-versus-host disease, eye disease, neuropsychiatric disease or condition, disease or condition associated with mitochondrial dysfunction, chronic pain or neuropathic pain.

43. The use of claim 42, wherein the patient is a mammal.

44. The use of claim 43, wherein the patient is a human.

45. The use of claim 42, wherein the disease or disorder is a condition associated with inflammation and / or oxidative stress.

46. ​​The use of claim 42, wherein the disease or condition is cancer.

47. The use of claim 42, wherein the disease or disorder is cardiovascular disease.

48. The use of claim 47, wherein the cardiovascular disease is atherosclerosis.

49. The use of claim 42, wherein the disease or disorder is an autoimmune disease.

50. The use of claim 49, wherein the autoimmune disease is Crohn's disease, rheumatoid arthritis, lupus or psoriasis.

51. The use of claim 42, wherein the disease or disorder is a neurodegenerative disease.

52. The use of claim 51, wherein the neurodegenerative disease is Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis or Huntington's disease.

53. The use of claim 42, wherein the disease or condition is chronic kidney disease, diabetes, mucositis, inflammatory bowel disease, dermatitis, sepsis, ischemia-reperfusion injury, influenza, osteoarthritis, osteoporosis, pancreatitis, asthma, chronic obstructive pulmonary disease, cystic fibrosis, idiopathic pulmonary fibrosis, multiple sclerosis, muscular dystrophy, cachexia, or graft-versus-host disease.

54. The use of claim 53, wherein the ischemia-reperfusion injury is a complication caused by sickle cell anemia.

55. The use of claim 42, wherein the disease or disorder is an eye disease.

56. The use of claim 55, wherein the eye disease is uveitis, glaucoma, macular degeneration or retinopathy.

57. The use of claim 42, wherein the disease or disorder is a neuropsychiatric disease or disorder.

58. The use of claim 57, wherein the neuropsychiatric disease or condition is schizophrenia, depression, bipolar disorder, epilepsy, post-traumatic stress disorder, attention deficit disorder, autism, or anorexia nervosa.

59. The use of claim 42, wherein the disease or disorder is associated with mitochondrial dysfunction.

60. The use of claim 59, wherein the disease or disorder associated with mitochondrial dysfunction is Friedreich's ataxia.

61. The use of claim 42, wherein the disease or condition is chronic pain.

62. The use of claim 42, wherein the disease or condition is neuropathic pain.

63. Use of a compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 34 or a pharmaceutical composition as described in any one of claims 35 to 41 for the preparation of a medicament for inhibiting IFN-γ-induced nitric oxide production in one or more cells of a patient.

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