Benzothia(d)azepine compounds and their use as bile acid modulators

Abstract

This invention relates to 1,5-benzothiazazacycloheptatriene and 1,2,5-benzothiazazacycloheptatriene derivatives of formula (I). These compounds are bile acid modulators having inhibitory activity against apical sodium-dependent bile acid transporters (ASBT) and / or hepatic bile acid transporters (LBAT). The invention also relates to pharmaceutical compositions comprising these compounds, and the use of these compounds in the treatment of cardiovascular diseases, fatty acid metabolism and glucose utilization disorders, gastrointestinal diseases, liver diseases, and kidney diseases. (I).

Description

[0001] Cross-reference to related applications

[0002] This application claims priority to Indian Patent Application No. 202411000913, filed on January 5, 2024, the disclosure of which is incorporated herein by reference in its entirety. Technical Field

[0003] This invention relates to 1,5-benzothiazazaheptatriene and 1,2,5-benzothiadiazaheptatriene derivatives of formula (I). These compounds are bile acid modulators with inhibitory activity against apical sodium-dependent bile acid transporters (ASBT) and / or hepatic bile acid transporters (LBAT). The invention also relates to pharmaceutical compositions comprising these compounds, and the use of these compounds in the treatment of cardiovascular diseases, fatty acid metabolism and glucose utilization disorders, gastrointestinal diseases, liver diseases, and kidney diseases. Background Technology

[0004] Bile acids are physiological cleansers, playing a crucial role in intestinal absorption and the transport of lipids, nutrients, and vitamins. They are also signaling molecules, activating nuclear receptors and regulating cellular signaling pathways that regulate lipid, glucose, and energy metabolism. Bile acids are steroid acids, synthesized from cholesterol in the liver and stored in the gallbladder as a mixture of microparticles. During digestion, the duodenum triggers the release of hormones that cause gallbladder contraction, releasing bile acids in the small intestine, enabling the absorption of fat-soluble vitamins and cholesterol. Upon reaching the ileum, bile acids are reabsorbed from the intestine and secreted into the portal vein bloodstream, returning to the liver via the portal circulation. Thus, over 90% of bile acids are recycled and return to the liver. These bile acids are then transported across the sinusoidal membrane of hepatocytes and through the tubular membrane to be secreted into the bile. In this first pass, 75-90% of bile acids are absorbed by hepatocytes, completing one cycle of enterohepatic circulation. Some bile acids that escape liver clearance enter systemic circulation. Free bile acids are filtered by the glomeruli, efficiently recycled in the proximal tubules, and expelled back into systemic circulation. Interestingly, most bile acids secreted into the bile across the tubular membrane originate from the recirculation pool, while less than 10% are newly synthesized in the liver. A small portion of bile acids that are not reabsorbed in the ileum reaches the colon. In the intestinal lumen, primary bile acids are converted into secondary bile acids by intestinal bacteria, primarily through mono- or di-dehydroxylation reactions of the steroid nucleus. Bile acids that are not absorbed by the intestines are eventually excreted in feces.

[0005] In general, an efficient transport system helps maintain a constant bile acid pool, ensuring sufficiently high levels of conjugated bile acids in the gut to promote lipid absorption and reduce small intestinal bacterial load. This system also minimizes fecal and urinary bile acid loss and protects the gut and hepatobiliary compartments by eliminating potentially cytotoxic cleansers (as reviewed by Kosters and Karpen (Xenobiotica 2008, Vol. 38, pp. 1043–1071); Chiang (J. Lipid Res. 2009, Vol. 50, pp. 1955–1966); and Dawson (Handb. Exp. Pharmacol. 2011, Vol. 201, pp. 169–203).

[0006] The regulation of bile acid pool size has been found to play a crucial role in cholesterol homeostasis via the liver's conversion of cholesterol into bile acids, representing a major pathway for the body's own cholesterol elimination. The liver plays a vital role in the body's removal of both endogenous and exogenous compounds. Normal hepatobiliary secretion and enterohepatic circulation are essential for the body's elimination of endogenous compounds such as cholesterol and bilirubin and their metabolites, thereby maintaining lipid and bile acid homeostasis (Kosters and Karpen, Xenobiotica 2008, Vol. 38, pp. 1043-1071).

[0007] The reabsorption of bile acids in the ileum can be inhibited by apical sodium-dependent bile acid transporter (ASBT) inhibitors. Inhibition of bile acid reabsorption has been reported for the treatment of several diseases, including dyslipidemia, diabetes, obesity, constipation, cholestatic liver disease, non-alcoholic steatohepatitis, and other liver diseases. A variety of ASBT inhibitor compounds have been disclosed over the past decades, see for example WO 93 / 16055, WO 94 / 18183, WO 94 / 18184, WO 96 / 05188, WO 96 / 08484, WO 96 / 16051, WO 97 / 33882, WO 98 / 03818, WO 98 / 07449, WO 98 / 40375、WO 99 / 35135、WO 99 / 64409、WO 99 / 64410、WO 00 / 47568、WO 00 / 61568、WO 00 / 38725、WO 00 / 38726、WO 00 / 38727、WO 00 / 38728、WO 00 / 38729、WO 01 / 66533、WO 01 / 68096、WO 02 / 32428、WO 02 / 50051、WO 03 / 020710、WO 03 / 022286、WO 03 / 022825、WO 03 / 022830、WO 03 / 061663、WO 03 / 091232、WO 03 / 106482、WO 2004 / 006899、WO 2004 / 076430、WO 2007 / 009655、WO 2007 / 009656、WO 2011 / 137135、WO 2019 / 234077、WO 2020 / 161216、WO 2020 / 161217、WO 2021 / 110883、WO 2021 / 110884、WO 2021 / 110885、WO 2021 / 110886、WO 2021 / 110887、WO 2022 / 029101、WO 2022117778、WO 2022 / 253997、WO 2024 / 008766, DE19825804, EP 864582, EP 489423, EP 549967, EP 573848, EP 624593, EP 624594, EP624595, EP 624596, EP 0864582, EP 1173205, EP 1535913 and EP 3210977.

[0008] Although many ASBT inhibitor compounds have been previously reported, additional bile acid modulating compounds with optimized characteristics in terms of potency, selectivity and bioavailability are still needed. Invention Details

[0010] Certain 1,5-benzothiazazazetazone hepttriene and 1,2,5-benzothiazazazetazone hepttriene derivatives have been found to be effective inhibitors of apical sodium-dependent bile acid transporters (ASBTs) and / or hepatic bile acid transporters (LBATs), and may be used to treat diseases requiring inhibition of bile acid cycling. Therefore, in a first aspect, the present invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof. (I) in M is -CH2- or -NH-; R 1 and R 2 Each independently is C 1-4 alkyl; R 3 Independently selected from hydrogen, halogen, hydroxyl, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, cyano, nitro, amino N -(C 1-4 alkyl)amino and N,N -two(C) 1-4 alkyl)amino; n is an integer, 1, 2, or 3; R 4 Selected from hydrogen, halogen, cyano, C 1-4 Alkyl, C 3-6 cycloalkyl, C 1-4 Alkoxy, C 3-6 Cycloalkoxy, C 1-4 Alkylthio, C 3-6 Cycloalkylthio, C 1-4 alkyl sulfinyl, hydroxy-C 1-4 Alkoxy, hydroxy-C 1-4 Alkylthio, amino, N -(C 1-4 alkyl)amino and N,N -two(C) 1-4 alkyl)amino; and R 5A and R 5B Each is independently selected from hydrogen and C. 1-4 Alkyl; or R 5A and R 5B Together with the carbon atoms they are attached to, they form 3- to 5-membered saturated carbon rings.

[0011] In some implementation schemes, R 1 It is n-butyl.

[0012] In some implementation schemes, R 2 It is methyl. In some embodiments, R 2 It is ethyl. In some embodiments, R 2 It is n-butyl.

[0013] In the preferred embodiment, R 1 It is n-butyl, and R 2 It can be methyl, ethyl, or n-butyl.

[0014] In some implementation schemes, R 3 It is hydrogen or halogen. In some implementations, R 3 It is hydrogen or fluorine, more preferably hydrogen or para-fluorine.

[0015] In some implementation schemes, R 4 Selected from C 1-4 Alkoxy, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkoxy and hydroxy-C 1-4 Alkylthio group. In some embodiments, R 4 Selected from methoxy, methylthio, 2-hydroxyethoxy, and 2-hydroxyethylthio. In some embodiments, R 4 Selected from C 1-4 Alkoxy and C 1-4 Alkylthio group. In some embodiments, R 4 It is methoxy or methylthio.

[0016] In some implementation schemes, R 5A and R 5B Each is hydrogen.

[0017] In some implementations, M is -CH2-. In some implementations, M is -NH-.

[0018] The preferred compounds of the present invention are compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein R 5A and R 5B Each is hydrogen, and R is hydrogen. 1 To R 4 M and n are shown in Table 1 below: Table 1

[0019]

[0020] In some embodiments, the compound of formula (I) is selected from: 2-((3-Butyl-7-methoxy-3-methyl-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; 2-((3-Butyl-7-methoxy-3-methyl-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; 2-((3-Butyl-3-methyl-7-(methylthio)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; 2-((3-Butyl-3-methyl-7-(methylthio)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; 2-((3-Butyl-7-(2-hydroxyethoxy)-3-methyl-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; 2-((3-Butyl-7-(2-hydroxyethoxy)-3-methyl-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; 2-((3-Butyl-7-((2-hydroxyethyl)thio)-3-methyl-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; 2-((3-Butyl-7-((2-hydroxyethyl)thio)-3-methyl-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; 2-((3-Butyl-5-(4-fluorophenyl)-7-methoxy-3-methyl-1,1-dioxo-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; 2-((3-Butyl-5-(4-fluorophenyl)-7-methoxy-3-methyl-1,1-dioxo-2,3,4,5-tetrahydro-1,2,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; 2-((3-Butyl-5-(4-fluorophenyl)-3-methyl-7-(methylthio)-1,1-dioxo-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; 2-((3-Butyl-5-(4-fluorophenyl)-3-methyl-7-(methylthio)-1,1-dioxo-2,3,4,5-tetrahydro-1,2,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; 2-((3-Butyl-5-(4-fluorophenyl)-7-(2-hydroxyethoxy)-3-methyl-1,1-dioxo-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; 2-((3-Butyl-5-(4-fluorophenyl)-7-(2-hydroxyethoxy)-3-methyl-1,1-dioxo-2,3,4,5-tetrahydro-1,2,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; 2-((3-Butyl-5-(4-fluorophenyl)-7-((2-hydroxyethyl)thio)-3-methyl-1,1-dioxo-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; 2-((3-Butyl-5-(4-fluorophenyl)-7-((2-hydroxyethyl)thio)-3-methyl-1,1-dioxo-2,3,4,5-tetrahydro-1,2,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; 2-((3-Butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; 2-((3-Butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; 2-((3-Butyl-3-ethyl-7-(methylthio)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; 2-((3-Butyl-3-ethyl-7-(methylthio)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; 2-((3-Butyl-3-ethyl-7-(2-hydroxyethoxy)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; 2-((3-Butyl-3-ethyl-7-(2-hydroxyethoxy)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; 2-((3-Butyl-3-ethyl-7-((2-hydroxyethyl)thio)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; 2-((3-Butyl-3-ethyl-7-((2-hydroxyethyl)thio)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; 2-((3-Butyl-3-ethyl-5-(4-fluorophenyl)-7-methoxy-1,1-dioxo-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; 2-((3-Butyl-3-ethyl-5-(4-fluorophenyl)-7-methoxy-1,1-dioxo-2,3,4,5-tetrahydro-1,2,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; 2-((3-Butyl-3-ethyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxo-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; 2-((3-Butyl-3-ethyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxo-2,3,4,5-tetrahydro-1,2,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; 2-((3-Butyl-3-ethyl-5-(4-fluorophenyl)-7-(2-hydroxyethoxy)-1,1-dioxo-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; 2-((3-Butyl-3-ethyl-5-(4-fluorophenyl)-7-(2-hydroxyethoxy)-1,1-dioxo-2,3,4,5-tetrahydro-1,2,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; 2-((3-Butyl-3-ethyl-5-(4-fluorophenyl)-7-((2-hydroxyethyl)thio)-1,1-dioxo-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; 2-((3-Butyl-3-ethyl-5-(4-fluorophenyl)-7-((2-hydroxyethyl)thio)-1,1-dioxo-2,3,4,5-tetrahydro-1,2,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; 2-((3,3-dibutyl-7-methoxy-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; 2-((3,3-dibutyl-7-methoxy-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; 2-((3,3-dibutyl-7-(methylthio)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; 2-((3,3-dibutyl-7-(methylthio)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; 2-((3,3-dibutyl-7-(2-hydroxyethoxy)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; 2-((3,3-dibutyl-7-(2-hydroxyethoxy)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; 2-((3,3-dibutyl-7-((2-hydroxyethyl)thio)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; 2-((3,3-dibutyl-7-((2-hydroxyethyl)thio)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; 2-((3,3-dibutyl-5-(4-fluorophenyl)-7-methoxy-1,1-dioxo-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; 2-((3,3-dibutyl-5-(4-fluorophenyl)-7-methoxy-1,1-dioxo-2,3,4,5-tetrahydro-1,2,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; 2-((3,3-dibutyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxo-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; 2-((3,3-dibutyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxo-2,3,4,5-tetrahydro-1,2,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; 2-((3,3-dibutyl-5-(4-fluorophenyl)-7-(2-hydroxyethoxy)-1,1-dioxo-2,3,4,5-tetrahydro-1,5-benzothiazazatrien-8-yl)methoxy)acetic acid; 2-((3,3-dibutyl-5-(4-fluorophenyl)-7-(2-hydroxyethoxy)-1,1-dioxo-2,3,4,5-tetrahydro-1,2,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; 2-((3,3-dibutyl-5-(4-fluorophenyl)-7-((2-hydroxyethyl)thio)-1,1-dioxo-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; and 2-((3,3-dibutyl-5-(4-fluorophenyl)-7-((2-hydroxyethyl)thio)-1,1-dioxo-2,3,4,5-tetrahydro-1,2,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; Or its pharmaceutically acceptable salt.

[0021] In a specific implementation scheme, the compound of formula (I) is selected from: 2-((3-Butyl-3-ethyl-5-(4-fluorophenyl)-7-methoxy-1,1-dioxo-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; (S)-2-((3-Butyl-3-ethyl-5-(4-fluorophenyl)-7-methoxy-1,1-dioxo-2,3,4,5-tetrahydro-1,5-benzothiazazatrien-8-yl)methoxy)acetic acid; (R)-2-((3-Butyl-3-ethyl-5-(4-fluorophenyl)-7-methoxy-1,1-dioxo-2,3,4,5-tetrahydro-1,5-benzothiazazatrien-8-yl)methoxy)acetic acid; 2-((3-Butyl-3-ethyl-7-(methylthio)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; (S)-2-((3-Butyl-3-ethyl-7-(methylthio)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazazazetrin-8-yl)methoxy)acetic acid; (R)-2-((3-Butyl-3-ethyl-7-(methylthio)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazazazetrin-8-yl)methoxy)acetic acid; 2-((3-Butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; (S)-2-((3-Butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; (R)-2-((3-Butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; 2-((3-Butyl-3-ethyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxo-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; (S)-2-((3-Butyl-3-ethyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxo-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; (R)-2-((3-Butyl-3-ethyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxo-2,3,4,5-tetrahydro-1,5-benzothiazazatrien-8-yl)methoxy)acetic acid; 2-((3,3-dibutyl-7-(methylthio)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; 2-((3-Butyl-3-ethyl-7-(methylthio)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; (S)-2-((3-Butyl-3-ethyl-7-(methylthio)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; (R)-2-((3-Butyl-3-ethyl-7-(methylthio)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; 2-((3-Butyl-3-methyl-7-(methylthio)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; (S)-2-((3-Butyl-3-methyl-7-(methylthio)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; (R)-2-((3-Butyl-3-methyl-7-(methylthio)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; 2-((3-Butyl-3-ethyl-7-methoxy-5-(4-methoxyphenyl)-1,1-dioxo-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; (S)-2-((3-Butyl-3-ethyl-7-methoxy-5-(4-methoxyphenyl)-1,1-dioxo-2,3,4,5-tetrahydro-1,5-benzothiazazonyl-8-yl)methoxy)acetic acid; and (R)-2-((3-Butyl-3-ethyl-7-methoxy-5-(4-methoxyphenyl)-1,1-dioxo-2,3,4,5-tetrahydro-1,5-benzothiazazatrien-8-yl)methoxy)acetic acid; Or its pharmaceutically acceptable salt.

[0022] As used in this article, the term "halogenated" refers to fluorine, chlorine, bromine, and iodine.

[0023] As used in this article, the term "C" 1-4 "Alkyl" refers to a straight-chain or branched alkyl group having 1 to 4 carbon atoms. C 1-4 Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0024] As used in this article, the term "C" 3-6 "Cycloalkyl" refers to a monocyclic saturated hydrocarbon ring with 3 to 6 carbon atoms. C 3-6 Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of 3- to 5-membered saturated carbon rings include cyclopropyl, cyclobutyl, and cyclopentyl.

[0025] As used in this article, the term "C" 1-4 "Haloalkyl" refers to the straight-chain or branched C-chain structure defined in this article. 1-4 Alkyl group, in which one or more hydrogen atoms have been replaced by halogen atoms. C 1-4 Examples of alkyl halogens include chloromethyl, fluoroethyl, and trifluoromethyl.

[0026] As used in this article, the term "C" 1-4 "alkoxy" and "C" 1-4 "Alkylthio" refers to a straight or branched carbon atom connected to the rest of the molecule via an oxygen or sulfur atom. 1-4 Alkyl group. The term "C" 3-6 "Cycloalkoxy" and "C" 3-6 The term "cycloalkylthio" should be interpreted accordingly.

[0027] As used in this article, the term "C" 1-4 "alkyl sulfinyl" refers to a straight or branched carbon chain connected to the rest of the molecule via a sulfinyl group. 1-4 Alkyl group. C 1-4 Examples of alkyl sulfinyl groups include methyl sulfinyl and ethyl sulfinyl.

[0028] As used in this article, the term "hydroxy-C" 1-4 "alkoxy" and "hydroxy-C" 1-4 "Alkylthio" refers to a straight-chain or branched C-chain group as defined herein. 1-4 Alkoxy or C 1-4 Alkylthio group, in which one or more hydrogen atoms have been replaced by a hydroxyl group. Hydroxyl-C 1-4 Examples of alkoxy groups include 2-hydroxyethoxy and 4-hydroxy-n-butoxy, and hydroxy-C 1-4 Examples of alkylthio groups include 2-hydroxyethylthio and 4-hydroxy-n-butylthio.

[0029] The term "amino" refers to the -NH2 group. As used herein, the term "amino" refers to... N -(C 1-4 "alkyl)amino" and " N,N -two(C) 1-4 "alkyl)amino" refers to a group in which one or two hydrogen atoms of an amino group are replaced by a straight-chain or branched C1-4 alkyl group. N -(C 1-4 Examples of alkyl amino groups include methylamino, ethylamino, and tert-butylamino, and N,N -two(C) 1-4 Examples of alkyl)amino groups include dimethylamino and diethylamino.

[0030] As used herein, the term “pharmaceutically acceptable” refers to compounds, substances, compositions, and / or dosage forms that are intended for human medicinal use and are generally safe, non-toxic, and neither biologically nor otherwise undesirable.

[0031] As used herein, the term "about" refers to a value or parameter, including (and description of) embodiments for that value or parameter itself. For example, a description referring to "about 20" includes the description of "20". A numerical range includes the numerical value defining that range. Generally, the term "about" refers to the specified value of a variable and all values ​​of the variable within the experimental error of the specified value (e.g., within the 95% confidence interval of the mean) or within 10% of the specified value, whichever is greater.

[0032] The 1,5-benzothiazazaheptatriene and 1,2,5-benzothiadiazaheptatriene compounds of formula (I), or pharmaceutically acceptable salts thereof, are inhibitors of apical sodium-dependent bile acid transporters (ASBT inhibitors), inhibitors of hepatic bile acid transporters (LBAT inhibitors), or inhibitors of both apical sodium-dependent bile acids and hepatic bile acid transporters (dual ASBT / LBAT inhibitors). Therefore, they are used to treat or prevent conditions, disorders, and diseases requiring inhibition of the bile acid cycle, such as cardiovascular diseases, fatty acid metabolism and glucose utilization disorders, gastrointestinal diseases, liver diseases, and kidney diseases.

[0033] Cardiovascular diseases and disorders of fatty acid metabolism and glucose utilization, including but not limited to hypercholesterolemia; fatty acid metabolism disorders; type 1 and type 2 diabetes; complications of diabetes, including cataracts, microvascular and macrovascular diseases, retinopathy, neuropathy, nephropathy and delayed wound healing, tissue ischemia, diabetic foot, arteriosclerosis, myocardial infarction, acute coronary syndrome, unstable angina, stable angina, stroke, peripheral artery occlusive disease, cardiomyopathy, heart failure, arrhythmia and restenosis; diabetes-related diseases such as insulin resistance (impaired glucose homeostasis), hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, obesity, dyslipidemia, including hyperlipidemia with hypertriglyceridemia, metabolic syndrome (Syndrome X), atherosclerosis and hypertension; and those used to increase high-density lipoprotein levels.

[0034] Gastrointestinal disorders and disturbances include constipation (including chronic constipation, functional constipation, chronic idiopathic constipation (CIC), intermittent / occasional constipation, constipation secondary to diabetes, constipation secondary to stroke, constipation secondary to chronic kidney disease, constipation secondary to multiple sclerosis, constipation secondary to Parkinson's disease, constipation secondary to systemic sclerosis, drug-induced constipation, irritable bowel syndrome with constipation (IBS-C), mixed irritable bowel syndrome (IBS-M), functional constipation in children, and opioid-induced constipation); Crohn's disease; primary bile acid malabsorption; irritable bowel syndrome (IBS); inflammatory bowel disease (IBD); ileitis; and reflux diseases and their complications, such as Barrett's esophagus. (esophagus), bile reflux esophagitis, and bile reflux gastritis.

[0035] As defined in this article, liver disease refers to any disease of the liver and its connected organs, such as the pancreas, portal vein, liver parenchyma, intrahepatic bile tree, extrahepatic bile tree, and gallbladder. In some cases, liver disease or disorder is a bile acid-dependent liver disease or disorder, in which bile acids are involved in the occurrence or progression of the disease or disorder. Liver diseases and disorders include, but are not limited to, hereditary liver metabolic disorders; congenital errors in bile acid synthesis; congenital bile duct abnormalities; biliary atresia; post-Kasai biliary atresia; post-liver transplant biliary atresia; neonatal hepatitis; neonatal cholestasis; hereditary forms of cholestasis; cerebral tendinous xanthomatosis; secondary BA synthesis deficiency; Zellweger's syndrome; cystic fibrosis-associated liver disease; α1-antitrypsin deficiency; Alagilles syndrome (ALGS); Byler syndrome. syndrome); Primary bile acid (BA) synthesis deficiency; Progressive familial intrahepatic cholestasis (PFIC), including PFIC-1, PFIC-2, PFIC-3 and nonspecific PFIC, post-cholesterol shunt PFIC and post-liver transplant PFIC; Benign recurrent intrahepatic cholestasis (BRIC), including BRIC1, BRIC2 and nonspecific BRIC, post-cholesterol shunt BRIC and post-liver transplant BRIC; Autoimmune hepatitis; Primary biliary cirrhosis (PBC); Liver fibrosis; Nonalcoholic fatty liver disease (NAFLD); Nonalcoholic steatohepatitis (NASH); Portal hypertension; Cholestasis; Down syndrome cholestasis; Drug-induced cholestasis; Intrahepatic cholestasis of pregnancy (jaundice of pregnancy); Intrahepatic cholestasis; Extrahepatic cholestasis; Parenteral nutrition-associated cholestasis (PNAC); Hypophospholipid-associated cholestasis; Lymphedema cholestasis syndrome 1 (LCS1); Primary sclerosing cholangitis (PSC); Immunoglobulin G4-associated cholangitis; Primary biliary cholangitis; Cholelithiasis (gallstones); Bile duct stones; Common bile duct stones; Cholelithiasis pancreatitis; Caroli disease; Malignant tumors of the bile duct; Malignant tumors leading to obstruction of the bile duct tree; Biliary stricture; AIDS cholangopathy; Ischemic cholangopathy; Pruritus due to cholestasis or jaundice; Pancreatitis; Chronic autoimmune liver disease leading to progressive cholestasis; Hepatic steatosis; Alcoholic hepatitis; Acute fatty liver; Fatty liver of pregnancy; Drug-induced hepatitis; Iron overload; Congenital bile acid synthesis deficiency type 1 (BAS deficiency type 1); Drug-induced liver injury (DILI); Liver fibrosis; Congenital liver fibrosis; Cirrhosis; Langerhans cell histiocytosis (LCH);Neonatal ichthyosis-sclerosing cholangitis (NISCH); erythropoietic protoporphyria (EPP); idiopathic adult-onset bile duct absence (IAD); idiopathic neonatal hepatitis (INH); non-symptomatic interlobular bile duct absence (NS PILBD); North American Indian childhood cirrhosis (NAIC); hepatic sarcoidosis; amyloidosis; necrotizing enterocolitis; serum bile acid toxicity, including arrhythmias with abnormal serum bile acid distribution patterns (e.g., atrial fibrillation), cirrhosis-associated cardiomyopathy (“cholecardia”), and skeletal muscle atrophy associated with cholestatic liver disease; polycystic liver disease; viral hepatitis (including hepatitis A, hepatitis B, hepatitis C, hepatitis D, and hepatitis E); hepatocellular carcinoma (liver cancer); cholangiocarcinoma; bile acid-associated gastrointestinal cancers; and cholestasis caused by tumors and vegetations of the liver, bile ducts, and pancreas. Compounds of formula (I) or pharmaceutically acceptable salts thereof are also used to enhance corticosteroid therapy for liver disease.

[0036] Kidney diseases or disorders include bile acid-dependent kidney diseases or disorders, such as those that may benefit from partial or complete inhibition of renal ASBT. In some embodiments, the kidney diseases or disorders are selected from: choleretic nephropathy; chronic kidney disease; hyperbilirubinemia; renal dysfunction due to obstructive jaundice; age-related renal mitochondrial dysfunction; kidney inflammation; acute kidney injury (AKI); renal ischemia / reperfusion injury (IRI); chronic kidney disease (CKD); chronic renal insufficiency; end-stage renal disease (ESRD); proximal tubular injury of the kidney; type 1 hepatorenal syndrome; type 2 hepatorenal syndrome; chronic-on-acute liver disease; glomerular hyperfiltration; polycystic kidney disease (PKD), including autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD); and pruritus caused by renal failure. These compounds may also be used to prevent kidney injury associated with liver disease or metabolic disorders.

[0037] Other diseases that can be treated or prevented by compounds of formula (I) or their pharmaceutically acceptable salts include hyperabsorption syndromes (including abetalipoproteinemia, familial hypobetalipoproteinemia (FHBL), chylomicron retention disease (CRD), and sitosterolemia); hypervitaminosis and osteosclerosis; and hypertension.

[0038] The transport of bile acids in the human body is controlled by members of the SLC10 solute carrier protein family, especially Na+. + - Taurocholate cotransporter polypeptide (NTCP, also known as liver bile acid transporter (LBAT); gene symbol SLC10A1), which is expressed in the sinusoidal membrane of hepatocytes; and apical sodium-dependent bile acid transporter (ASBT, also known as ileal bile acid transporter (IBAT), ISBT, ABAT, or NTCP2; gene symbol SLC10A2 It is expressed in the apical membranes of ileal epithelial cells, proximal renal tubular cells, bile duct epithelial cells, gallbladder duct cells, and gallbladder epithelial cells. In the liver, bile acids are efficiently extracted from portal vein blood via hepatic bile acid transporter protein (LBAT) and transported via bile salt export pump (BSEP; gene symbol) ABCB11 The bile acids are then secreted across the tubular membrane. Reabsorption of bile acids in the ileum is handled by the apical sodium-dependent bile acid transporter (ASBT), commonly referred to as the ileal bile acid transporter (IBAT). Both IBAT and ASBT act as electrophoretic sodium-solute cotransporters, moving two or more Na+ molecules per solute molecule. + ion.

[0039] Exogenous and endogenous substances, including bile acids, are absorbed from the portal vein by the liver and secreted into bile via different transport proteins with individualized substrate specificity. Glycine-conjugated and taurine-conjugated bile acids exist in anionic form and cannot cross the membrane by diffusion; therefore, they depend entirely on membrane transport proteins for entry into or exit from hepatocytes (Kosters and Karpen, Xenobiotica 2008, Vol. 38, pp. 1043-1071). ASBT and LBAT show a preference for glycine-conjugated and taurine-conjugated bile salts over their unconjugated counterparts, and exhibit a higher affinity for dihydroxy bile salts than for trihydroxy bile salts. No non-bile acid substrates for ASBT have been identified; however, LBAT has been found to transport various steroid sulfates, hormones, and exogenous substances.

[0040] Regarding the requirements for drug inhibition, LBAT is not as thoroughly characterized as ASBT. Dong et al. have identified FDA-approved drugs that inhibit human LBAT and compared the inhibition requirements of LBAT and ASBT. Using FDA-approved drugs, a series of LBAT inhibition studies were conducted using iterative computational models. Screening studies identified 27 drugs as novel LBAT inhibitors, including irbesartan (Ki = 11.9 μM) and ezetimibe (Ki = 25.0 μM). Common pharmacophore characteristics indicate that two hydrophobic groups and one hydrogen-bonded receptor are important for LBAT inhibition. Of the 72 drugs screened in vitro, 31 inhibited LBAT, while 51 (more than half) inhibited ASBT. Therefore, despite inhibitor overlap, ASBT is surprisingly more tolerant of drug inhibition than LBAT, which may be related to the fact that LBAT has fewer pharmacophore features (Dong et al., Mol. Pharm. 2013, Vol. 10, pp. 1008-1019).

[0041] Vaz et al. described the identification of LBAT deficiency as a novel innate metabolic error with relatively mild clinical phenotypes. The identification of LBAT deficiency confirms that this transporter is the main input system for conjugated bile salts into the liver, and also indicates that helper transporters can maintain enterohepatic circulation in its absence (Vaz et al., Hepatology 2015, Vol. 61, pp. 260-267). These findings support the hypothesis that LBAT inhibition is a safe mechanism of action, as hepatocytes are still able to absorb the necessary amount of bile acids.

[0042] Liu et al. described and SLC10A1 Identification of novel hypercholesterolemia associated with homozygosity of the p.Ser267Phe mutation in (LBAT). (Gene) SLC10A1The allele frequency of this mutation varies across different populations, with the highest incidence observed in southern China (8% in Han Chinese and 12% in Dai Chinese) and Vietnam (11%). This "hidden" hypercholanemia is believed to affect 0.64% of the Han Chinese population in southern China, 1.44% of the Dai population in China, and 1.21% of the Vietnamese population. Increased serum BA levels were also observed in both conjugated and unconjugated individuals in homozygous individuals. Liu et al. suggest that this finding is most likely attributable to reduced BA transport from the portal circulation to hepatocytes. This supports the hypothesis that the physiological function of enterohepatic circulation not only recycles bile acids but also clears bile acids from the circulation to achieve homeostasis (Karpen and Dawson, Hepatology 2015, Vol. 61, pp. 24-27). Alternatively, the liver may synthesize increased bile acid levels to compensate for reduced enterohepatic recirculation in homozygous individuals. Since LBAT also transports unconjugated bile acids, the increase in unconjugated bile acids in this study was not unexpected (Liu et al., Scientific Reports 2017, 7: 9214, pp. 1-7).

[0043] LBAT has been found to be downregulated in several forms of cholestatic liver injury and cholestasis, while ASBT has been found to be downregulated in various gastrointestinal disorders, such as Crohn's disease, primary bile acid malabsorption, inflammatory bowel disease, and ileitis, but upregulated in cholestasis. LBAT also acts as a cell receptor for viral entry of hepatitis B virus (HBV) and hepatitis D virus (HDV), which are major causes of liver disease and hepatocellular carcinoma.

[0044] ASBT inhibition has been studied for its effects in lowering plasma cholesterol levels, improving insulin resistance, and reducing hepatic bile acid load in cholestatic liver disease. Furthermore, ASBT inhibition has been found to restore normal insulin and blood glucose levels, thus establishing ASBT inhibition as a promising treatment for type 2 diabetes. ASBT inhibitors are also used to treat functional constipation.

[0045] Since ASBT is primarily expressed in the ileum (where it is commonly referred to as IBAT), ASBT inhibitors do not necessarily need to be systemically available. On the other hand, ASBT is also expressed in the proximal tubular cells of the kidney. Therefore, systemically available ASBT inhibitors can also inhibit the reabsorption of bile acids in the kidney. This is believed to lead to an increase in bile acid levels in the urine and an increase in the body's removal of bile acids via urine. Therefore, systemically available ASBT inhibitors that act not only in the ileum but also in the kidney are expected to result in a greater reduction in bile acid levels than non-systemically available ASBT inhibitors that act only in the ileum.

[0046] Since ASBT is primarily expressed in the ileum (where it is commonly referred to as IBAT), ASBT inhibitors do not necessarily need to be systemically available. On the other hand, ASBT is also expressed in the proximal tubular epithelial cells of the kidney. Therefore, systemically available ASBT inhibitors can also inhibit the reabsorption of bile acids in the kidney. This is believed to lead to an increase in bile acid levels in the urine and an increase in the body's removal of bile acids via urine. Therefore, systemically available ASBT inhibitors that act not only in the ileum but also in the kidney are expected to result in a greater reduction in bile acid levels than non-systemically available ASBT inhibitors that act only in the ileum. Targeting renal ASBT may be another approach to increase bile acid excretion, thereby further reducing bile acid load in serum and the liver.

[0047] Compounds with high ASBT inhibitory potency are particularly used to treat liver diseases that cause cholestasis, such as progressive familial intrahepatic cholestasis (PFIC), Aragerry syndrome, biliary atresia, and nonalcoholic steatohepatitis (NASH).

[0048] Biliary atresia is a rare pediatric liver disease involving partial or complete obstruction (or even absence) of the bile ducts. This obstruction or absence causes bile stasis, leading to the accumulation of bile acids, which damage the liver. In some implementations, bile acid accumulation occurs in the extrahepatic bile duct tree. In other implementations, bile acid accumulation occurs in the intrahepatic bile duct tree. The current standard of care is the Kasai procedure, which involves removing the obstructed bile duct and directly connecting a portion of the small intestine to the liver. There is currently no approved drug therapy for this disorder.

[0049] This document provides a method for treating biliary atresia in individuals with this need, the method comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has undergone a Kasai procedure prior to administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is administered the compound of formula (I) or a pharmaceutically acceptable salt thereof prior to the Kasai procedure. In some embodiments, treatment of biliary atresia reduces the subject's serum bile acid levels. In some embodiments, serum bile acid levels are determined via, for example, an ELISA enzyme assay or an assay measuring total bile acids, as described in Danese et al., PLoS One. 2017, Vol. 12(6): e0179200, which is incorporated herein by reference in its entirety. In some embodiments, serum bile acid levels may be reduced by, for example, 10% to 40%, 20% to 50%, 30% to 60%, 40% to 70%, 50% to 80%, or greater than 90% of the serum bile acid levels prior to administration of the compound of formula (I) or its pharmaceutically acceptable salt. In some embodiments, treatment of biliary atresia includes treatment of pruritus.

[0050] PFIC is a rare genetic disorder that is estimated to affect one in 50,000 to 100,000 children born worldwide and causes progressive, life-threatening liver disease.

[0051] One manifestation of PFIC is pruritus, which often leads to a significant decline in quality of life. In some cases, PFIC can lead to cirrhosis and liver failure. Current treatments include partial biliary diversion (PEBD) and liver transplantation; however, these options may carry a considerable risk of postoperative complications, as well as psychological and social problems.

[0052] Three alternative gene defects have been identified, which are associated with three separate PFIC subtypes known as type 1, type 2, and type 3: PFIC type 1, sometimes called "Bayer's disease," is caused by impaired bile secretion due to a mutation in the ATP8B1 gene, which encodes a protein that helps maintain the proper balance of lipids called phospholipids in the bile duct cell membranes. Imbalances in these phospholipids are associated with cholestasis and elevated bile acid levels in the liver. Subjects affected by PFIC type 1 typically develop cholestasis in the first few months after birth and, without surgical treatment, progress to cirrhosis and end-stage liver disease before the end of their first decade of life.

[0053] PFIC type 2, sometimes called "Beyer syndrome," is caused by impaired bile salt secretion due to a mutation in the ABCB11 gene, which encodes a protein called the bile salt export pump, which removes bile acids from the liver. Individuals with PFIC type 2 typically develop liver failure within the first few years of life and have an increased risk of developing a type of liver cancer called hepatocellular carcinoma.

[0054] PFIC type 3, which usually occurs in the first few years of childhood with progressive cholestasis, is caused by a mutation in the ABCB4 gene, which encodes a transport protein that moves phospholipids across the cell membrane.

[0055] Furthermore, mutations in the TJP2, NR1H4, or Myo5b genes have been proposed as causes of PFIC. Additionally, some subjects with PFIC do not have mutations in any of the ATP8B1, ABCB11, ABCB4, TJP2, NR1H4, or Myo5b genes. In these cases, the cause of the condition is unknown.

[0056] In some implementations, the mutations in ATP8B1 are selected from L127P, G308V, T456M, D554N, F529del, I661T, E665X, R930X, R952X, R1014X, and G1040R.

[0057] In some implementations, the mutations in ABCB11 are selected from A167T, G238V, V284L, E297G, R470Q, R470X, D482G, R487H, A570T, N591S, A865V, G982R, R1153C, and R1268Q.

[0058] A method of providing a PFIC (e.g., PFIC-1 and PFIC-2) to a subject includes analyzing a sample obtained from the subject to determine whether the subject has a PFIC-related mutation (e.g., ATP8B1, ABCB11, ABCB4, TJP2, NR1H4, or Myo5b mutation), and administering (e.g., specific or selective administration) a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject determined to have a PFIC-related mutation. In some embodiments, the mutation is an ATP8B1 or ABCB11 mutation. In some embodiments, the mutation in ATP8B1 is selected from L127P, G308V, T456M, D554N, F529del, I661T, E665X, R930X, R952X, R1014X, and G1040R. In some implementations, the mutations in ABCB11 are selected from A167T, G238V, V284L, E297G, R470Q, R470X, D482G, R487H, A570T, N591S, A865V, G982R, R1153C, and R1268Q.

[0059] Methods for treating PFIC (e.g., PFIC-1 and PFIC-2) in subjects with this need are also provided, comprising: (a) detecting a PFIC-related mutation (e.g., ATP8B1, ABCB11, ABCB4, TJP2, NR1H4, or Myo5b mutation) in the subject; and (b) administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the method for treating PFIC may include administering to a subject having a PFIC-related mutation (e.g., ATP8B1, ABCB11, ABCB4, TJP2, NR1H4, or Myo5b mutation) a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the mutation is an ATP8B1 or ABCB11 mutation. In some embodiments, the mutations in ATP8B1 are selected from L127P, G308V, T456M, D554N, F529del, I661T, E665X, R930X, R952X, R1014X, and G1040R. In some embodiments, the mutations in ABCB11 are selected from A167T, G238V, V284L, E297G, R470Q, R470X, D482G, R487H, A570T, N591S, A865V, G982R, R1153C, and R1268Q.

[0060] In some embodiments, the presence of a PFIC-associated mutation in the subject or in a biopsy sample from the subject is determined using any test recognized in the art, including next-generation sequencing (NGS). In some embodiments, the presence of a PFIC-associated mutation in the subject is determined using a regulatory-approved (e.g., FDA-approved) test or analysis for identifying PFIC-associated mutations in the subject or in a biopsy sample from the subject, or by any of the non-limiting examples of performing the analysis described herein. Additional methods for diagnosing PFIC are described in Gunaydin, M. et al., Hepat Med. 2018, Vol. 10, pp. 95–104, which are incorporated herein by reference in their entirety.

[0061] In some embodiments, treatment with a PFIC (e.g., PFIC-1 or PFIC-2) reduces serum bile acid levels in the subject. In some embodiments, serum bile acid levels are determined via, for example, an ELISA enzyme assay or an assay measuring total bile acids, as described in Danese et al., PLoS One. 2017, Vol. 12(6): e0179200, which is incorporated herein by reference in its entirety. In some embodiments, serum bile acid levels may be reduced by, for example, 10% to 40%, 20% to 50%, 30% to 60%, 40% to 70%, 50% to 80%, or greater than 90% of the serum bile acid levels prior to administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, treatment with a PFIC includes treatment of pruritus.

[0062] Because LBAT is expressed on hepatocytes, LBAT and dual ASBT / LBAT inhibitors need to have at least a certain bioavailability and free fraction in the blood. Since LBAT inhibitor compounds only need to survive from the intestine to the liver, relatively low systemic exposure to such compounds is expected to be sufficient to minimize the potential risk of any side effects in the rest of the body. Inhibition of LBAT and ASBT is expected to have an additive effect, at least in reducing intrahepatic bile acid concentrations. Dual ASBT / LBAT inhibitors are also expected to reduce bile acid levels without inducing diarrhea, which has sometimes been observed with ASBT inhibitors.

[0063] Compounds with high LBAT inhibitory potency and sufficient bioavailability are expected to be particularly useful for the treatment of hepatitis. Compounds with dual ASBT / LBAT inhibitory potency and sufficient bioavailability are expected to be particularly useful for the treatment of non-alcoholic steatohepatitis (NASH).

[0064] Nonalcoholic fatty liver disease (NAFLD) is a common and serious chronic liver disease, similar to alcoholic liver disease, but occurring in people who drink little or no alcohol. In NASH patients, fat accumulation in the liver, known as NAFLD or steatosis, and other factors such as high LDL cholesterol and insulin resistance induce chronic inflammation in the liver and can lead to progressive scarring of tissues, called fibrosis and cirrhosis, ultimately resulting in liver failure and death. Total serum bile acid concentrations have been found to be significantly higher in NASH patients than in healthy subjects at both fasting (2.2 to 2.4-fold increase in NASH) and at all postprandial time points (1.7 to 2.2-fold increase in NASH). These are driven by increases in taurine-conjugated and glycine-conjugated primary and secondary bile acids. NASH patients exhibit greater variability in their fasting and postprandial bile acid profiles. These results suggest that NASH patients have higher exposure to bile acids, including more hydrophobic and cytotoxic secondary types, both fasting and postprandial. Increased bile acid exposure may be involved in liver injury and the pathogenesis of NAFLD and NASH (Ferslew et al., Dig Dis Sci. 2015, Vol. 60, pp. 3318-3328). Therefore, ASBT and / or LBAT inhibition may be beneficial for the treatment of NASH.

[0065] Nonalcoholic fatty liver disease (NAFL) is characterized by hepatic steatosis without secondary causes of steatosis, including excessive alcohol consumption, other known liver diseases, or long-term use of steatogenic drugs (Chalasani et al., Hepatology 2018, Vol. 67(1), pp. 328-357). NAFLD can be classified as nonalcoholic fatty liver disease (NAFL) and nonalcoholic steatohepatitis (NASH). According to Chalasani et al., NAFL is defined as the presence of ≥5% hepatic steatosis without evidence of hepatocellular damage in the form of hepatocellular swelling. NASH is defined as inflammation with ≥5% hepatic steatosis and hepatocellular damage (e.g., swelling), with or without any liver fibrosis. NASH is also commonly associated with liver inflammation and liver fibrosis, which can progress to cirrhosis, end-stage liver disease, and hepatocellular carcinoma. Although liver fibrosis is not always present in NASH, the severity of fibrosis (when present) may be related to long-term outcomes.

[0066] In some implementations, treatment of NASH may include a reduction in one or more NASH-related symptoms in a subject following administration of one or more doses of a compound of formula (I) or a pharmaceutically acceptable salt thereof; a reduction in the amount of hepatic steatosis; a reduction in hepatic inflammation; a decrease in the levels of biomarkers indicating one or more of liver injury, inflammation, liver fibrosis, and / or cirrhosis; and a reduction in fibrosis and / or cirrhosis, no further progression of fibrosis and / or cirrhosis, or a slowing of the progression of fibrosis and / or cirrhosis.

[0067] In some implementations, treatment of NASH includes a reduction in one or more NASH-related symptoms in the subject. Exemplary symptoms may include one or more of the following: enlarged liver, fatigue, right upper quadrant pain, abdominal swelling, dilated blood vessels just below the skin surface, gynecomastia, splenomegaly, palmar erythema, jaundice, and pruritus. In some implementations, the subject is asymptomatic. In some implementations, the subject's total weight does not increase. In some implementations, the subject's total weight decreases. In some implementations, the subject's body mass index (BMI) does not increase. In some implementations, the subject's body mass index (BMI) decreases. In some implementations, the subject's waist-to-hip ratio (WTH) does not increase. In some implementations, the subject's WTH ratio decreases.

[0068] In some embodiments, treatment of NASH reduces serum bile acid levels in the subject. In some embodiments, serum bile acid levels are determined by, for example, an ELISA enzyme assay or an assay measuring total bile acids, as described in Danese et al., PLoS One. 2017, Vol. 12(6): e0179200, which is incorporated herein by reference in its entirety. In some embodiments, serum bile acid levels may be reduced by, for example, 10% to 40%, 20% to 50%, 30% to 60%, 40% to 70%, 50% to 80%, or greater than 90% of the serum bile acid levels prior to administration of the compound of formula (I) or its pharmaceutically acceptable salts. In some embodiments, NASH is NASH accompanied by cholestasis. In cholestasis, the release of bile (including bile acids) from the liver is obstructed. Bile acids can cause hepatocellular damage (see, for example, Perez MJ, Briz O. World J. Gastroenterol. 2009, Vol. 15(14), pp. 1677-1689), which may lead to or increase the progression of fibrosis (e.g., cirrhosis) and increase the risk of hepatocellular carcinoma (see, for example, Sorrentino P et al., Dig. Dis. Sci. 2005, Vol. 50(6), pp. 1130-1135 and Satapathy SK and Sanyal AJ. Semin. Liver Dis 2015, Vol. 35(3), pp. 221-235 (each of which is incorporated herein by reference in its entirety). In some embodiments, treatment of NASH includes treatment of pruritus. In some embodiments, treatment of NASH with cholestasis includes treatment of pruritus. In some embodiments, a subject with NASH with cholestasis suffers from pruritus.

[0069] Some compounds of formula (I) or their pharmaceutically acceptable salts may exhibit a high free fraction in plasma. In some embodiments, the free fraction is greater than about 0.2%, such as greater than about 0.4%, such as greater than about 0.6%, such as greater than about 0.8%, such as greater than about 1.0%, such as greater than about 1.25%, such as greater than about 1.5%, such as greater than about 1.75%, such as greater than about 2.0%, such as greater than about 2.5%, such as greater than about 3%, such as greater than about 4%, such as greater than about 5%, such as greater than about 7.5%, such as greater than about 10%, or such as greater than about 20%.

[0070] Some compounds of formula (I) or pharmaceutically acceptable salts thereof may be excreted in urine. In some embodiments, the fraction of the compound excreted in urine is greater than about 0.2%, such as greater than about 0.4%, such as greater than about 0.6%, such as greater than about 0.8%, such as greater than about 1.0%, such as greater than about 2%, such as greater than about 3%, such as greater than about 5%, such as greater than about 7.5%, such as greater than about 10%, such as greater than about 15%, such as greater than about 20%, such as greater than about 30%, or such as greater than about 50%.

[0071] Following absorption by the intestine, some compounds of formula (I) or their pharmaceutically acceptable salts may circulate via enterohepatic circulation. In some embodiments, the fraction of the compound circulating via enterohepatic circulation is greater than about 0.1%, such as greater than about 0.2%, such as greater than about 0.3%, such as greater than about 0.5%, such as greater than about 1.0%, such as greater than about 1.5%, such as greater than about 2%, such as greater than about 3%, such as greater than about 5%, such as greater than about 7%, such as greater than about 10%, such as greater than about 15%, such as greater than about 20%, such as greater than about 30%, or such as greater than about 50%.

[0072] Some compounds of formula (I) or pharmaceutically acceptable salts thereof can induce the renal secretion of bile salts. In some embodiments, the fraction of circulating bile acids secreted via the renal pathway is greater than about 1%, such as greater than about 2%, such as greater than about 5%, such as greater than about 7%, such as greater than about 10%, such as greater than about 15%, such as greater than about 20%, or such as greater than about 25%.

[0073] Some compounds of formula (I) or their pharmaceutically acceptable salts may exhibit improved or optimal permeability. Permeability can be measured in Caco2 cells and the value is given as an apparent permeability (Papp) value in cm / s. In some embodiments, the permeability is greater than at least about 0.1 × 10⁻⁶. -6 cm / s, such as greater than approximately 0.2 × 10 -6 cm / s, such as greater than approximately 0.4 × 10 -6 cm / s, such as greater than approximately 0.7 × 10 cm / s -6cm / s, such as greater than approximately 1.0 × 10 cm / s -6 cm / s, such as greater than approximately 2 × 10 -6 cm / s, such as greater than approximately 3 × 10 -6 cm / s, such as greater than approximately 5 × 10 -6 cm / s, such as greater than approximately 7 × 10 -6 cm / s, such as greater than approximately 10 × 10 -6 cm / s, such as greater than approximately 15 × 10 -6 cm / second.

[0074] Some compounds of formula (I) or their pharmaceutically acceptable salts may exhibit improved or optimal bioavailability. In some embodiments, oral bioavailability is greater than about 5%, such as greater than about 7%, such as greater than about 10%, such as greater than about 15%, such as greater than about 20%, such as greater than about 30%, such as greater than about 40%, such as greater than about 50%, such as greater than about 60%, such as greater than about 70%, or such as greater than about 80%. In other embodiments, oral bioavailability is between about 10% and about 90%, such as between about 20% and about 80%, such as between about 30% and about 70%, or such as between about 40% and about 60%.

[0075] Some compounds of formula (I) or their pharmaceutically acceptable salts can serve as substrates for related transport proteins in the kidney.

[0076] Some compounds of formula (I) or their pharmaceutically acceptable salts can produce concentrations of bile acids in the intestine, liver, and serum that do not cause adverse gastrointestinal effects.

[0077] Some compounds of formula (I) or their pharmaceutically acceptable salts can reduce the concentration of bile acids in the liver without causing gastrointestinal disorders such as diarrhea.

[0078] As used herein, the term "treatment / treat / treating" refers to reversing or alleviating a disease or disorder as described herein, or one or more of its symptoms, delaying its onset, or inhibiting its progression. In some embodiments, treatment may be administered after one or more symptoms have appeared. In other embodiments, treatment may be administered even when symptoms are absent. For example, treatment may be administered to susceptible subjects before the onset of symptoms (e.g., based on a history of symptoms and / or based on genetic or other susceptibility factors). Treatment may also continue after symptoms have subsided, for example, to prevent or delay their recurrence.

[0079] Suitable pharmaceutically acceptable salts of the compounds of the present invention are, for example, base addition salts of the compounds of the present invention that have sufficient acidity, such as alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts), ammonium salts, or salts with organic bases that provide physiologically acceptable cations, such as salts with methylamine, dimethylamine, trimethylamine, piperidine, morpholine, or tri-(2-hydroxyethyl)amine.

[0080] Some compounds of formula (I) or pharmaceutically acceptable salts thereof may have chiral centers and / or geometric isomer centers (E- and Z-isomers). It should be understood that this invention covers all such optical, diastereomeric, and geometric isomers having ASBT and / or LBAT inhibitory activity. This invention also covers any and all tautomeric forms of compounds of formula (I) or pharmaceutically acceptable salts thereof having ASBT and / or LBAT inhibitory activity. Some compounds of formula (I) or pharmaceutically acceptable salts thereof may exist in both non-solvated and solvated forms, such as hydrated forms. It should be understood that this invention covers all such solvated forms having ASBT and / or LBAT inhibitory activity.

[0081] In another aspect, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. The excipients may include, for example, fillers, binders, disintegrants, flow aids, and lubricants. Generally, the pharmaceutical composition can be prepared in a conventional manner using conventional excipients.

[0082] Examples of suitable fillers include, but are not limited to, dicalcium phosphate dihydrate, calcium sulfate, lactose (such as lactose monohydrate), sucrose, mannitol, sorbitol, cellulose, microcrystalline cellulose, dry starch, hydrolyzed starch, and pregelatinized starch.

[0083] Examples of suitable adhesives include, but are not limited to, starch, pregelatinized starch, gelatin, sugars (such as sucrose, glucose, dextrose, lactose and sorbitol), polyethylene glycol, waxes, natural and synthetic gums (such as gum arabic and tragacanth), sodium alginate, cellulose derivatives (such as hydroxypropyl methylcellulose (or hydroxypropyl methylcellulose), hydroxypropyl cellulose and ethyl cellulose) and synthetic polymers (such as acrylic acid and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, aminoalkyl methacrylate copolymers, polyacrylic acid / polymethacrylic acid copolymers and polyvinylpyrrolidone (polyvinylpyrrolidone)).

[0084] Examples of suitable disintegrants include, but are not limited to, dry starch, modified starch (such as (partially) pregelatinized starch, sodium glycolate starch and sodium carboxymethyl starch), alginate, cellulose derivatives (such as sodium carboxymethyl cellulose, hydroxypropyl cellulose and low-substituted hydroxypropyl cellulose (L-HPC)) and cross-linked polymers (such as carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose, calcium carboxymethyl cellulose and cross-linked PVP (cross-linked polyvinylpyrrolidone)).

[0085] Examples of suitable gliding agents and lubricants include, but are not limited to, talc, magnesium stearate, calcium stearate, stearic acid, glyceryl behenate, colloidal silica, aqueous silica, synthetic magnesium silicate, fine silica, starch, sodium lauryl sulfate, boric acid, magnesium oxide, waxes (such as carnauba wax), hydrogenated oils, polyethylene glycol, sodium benzoate, polyethylene glycol, and mineral oils.

[0086] Pharmaceutical compositions may conventionally be coated with one or more coating layers. Enteric coatings or coating layers for delayed or targeted release (I) compounds or their pharmaceutically acceptable salts are also included. The coating layer may contain one or more coating agents and, where appropriate, plasticizers and / or pigments (or colorants).

[0087] Examples of suitable coating agents include, but are not limited to, cellulose-based polymers (such as ethyl cellulose, hydroxypropyl methyl cellulose (or hydroxypropyl methyl cellulose), hydroxypropyl cellulose, cellulose acetate phthalate, cellulose acetate succinate, hydroxypropyl methyl cellulose succinate and hydroxypropyl methyl cellulose phthalate), vinyl-based polymers (such as polyvinyl alcohol), and polymers based on acrylic acid and its derivatives (such as acrylic acid and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, aminoalkyl methacrylate copolymers, polyacrylic acid / polymethacrylic acid copolymers).

[0088] Examples of suitable plasticizers include, but are not limited to, triethyl citrate, triacetin, tributyl citrate, diethyl phthalate, acetyl tributyl citrate, dibutyl phthalate, dibutyl sebacate, and polyethylene glycol.

[0089] Examples of suitable pigments include, but are not limited to, titanium dioxide, iron oxide (such as yellow, brown, red or black iron oxide), and barium sulfate.

[0090] The pharmaceutical composition may be in a form suitable for oral administration, parenteral injection (including intravenous, subcutaneous, intramuscular, and intravascular injection), topical administration, or rectal administration. In a preferred embodiment, the pharmaceutical composition is in a form suitable for oral administration, such as tablets or capsules.

[0091] The dosage required for therapeutic or preventative treatment will depend on the route of administration, the severity of the disease, the patient's age and weight, and other factors that the attending physician typically considers when determining the appropriate regimen and dosage level for a particular patient.

[0092] The amount of the compound to be administered varies from patient to patient and can range from about 1 µg to about 50 mg per kilogram of body weight per day. Unit dosage forms such as tablets or capsules will typically contain about 1 to about 250 mg of the active ingredient, such as about 1 to about 100 mg, or such as about 1 to about 50 mg, or such as about 1 to about 20 mg, for example about 2.5 mg, or about 5 mg, or about 10 mg, or about 15 mg. The daily dose can be administered as a single dose or divided into one, two, three, or more unit doses. The daily dose of orally administered bile acid modulators is preferably from about 0.1 to about 250 mg, more preferably from about 1 to about 100 mg, such as from about 1 to about 5 mg, such as from about 1 to about 10 mg, such as from about 1 to about 15 mg, or such as from about 1 to about 20 mg.

[0093] In another aspect, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof used as a medicine. The invention also relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as a medicine.

[0094] In another aspect, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment or prevention of any of the diseases listed herein. The invention also relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prevention of any of the diseases listed herein. The invention further relates to a method of treating or preventing any of the diseases listed herein in a subject (such as a human) comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject requiring such treatment or prevention.

[0095] Combination therapy

[0096] In one aspect of the invention, a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with at least one other therapeutically active agent, such as in combination with one, two, three or more other therapeutically active agents. The compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one other therapeutically active agent may be administered simultaneously, sequentially or separately. Suitable therapeutically active agents for combination with a compound of formula (I) include, but are not limited to, known active agents for treating any of the aforementioned conditions, disorders, and diseases.

[0097] In one implementation, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with another ASBT inhibitor. Suitable ASBT inhibitors are disclosed in WO 93 / 16055, WO 94 / 18183, WO 94 / 18184, WO 96 / 05188, WO96 / 08484, WO 96 / 16051, WO 97 / 33882, WO 98 / 03818, WO 98 / 07449, WO 98 / 40375, WO 99 / 35135、WO 99 / 64409、WO 99 / 64410、WO 00 / 47568、WO 00 / 61568、WO 00 / 38725、WO 00 / 38726、WO 00 / 38727、WO 00 / 38728、WO 00 / 38729、WO 01 / 66533、WO 01 / 68096、WO 02 / 32428、WO 02 / 50051、WO 03 / 020710、WO 03 / 022286、WO 03 / 022825、WO 03 / 022830、WO 03 / 061663、WO 03 / 091232、WO 03 / 106482、WO 2004 / 006899、WO 2004 / 076430、WO 2007 / 009655、WO 2007 / 009656、WO 2011 / 137135、WO 2019 / 234077、WO 2020 / 161216、WO 2020 / 161217、WO 2021 / 110883、WO The following publications are incorporated herein by reference in their entirety: 2021 / 110884, WO 2021 / 110885, WO 2021 / 110886, WO 2021 / 110887, WO 2022 / 029101, DE 19825804, EP 864582, EP 489423, EP 549967, EP 573848, EP624593, EP 624594, EP 624595, EP 624596, EP 0864582, EP 1173205, EP 1535913, and EP3210977. Specific examples of suitable ASBT inhibitors include 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-( N -{( R )-1'-phenyl-1'-[ N' [-(carboxymethyl)carbamoyl]-methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazazepine heptadiene (eloxibat) and 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-( N-{(R)- -[ N -((S)-1-carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiazazacycloheptatriene (Ovispart).

[0098] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a bile acid conjugate (also known as a bile acid chelator or resin), such as colesevelam, cholestyramine, or cholestipol. In a preferred embodiment of such a combination, the bile acid conjugate is formulated for colonic release. Examples of such formulations are disclosed, for example, in WO 2017 / 138877, WO 2017 / 138878, WO 2019 / 032026 and WO 2019 / 032027, all of which are incorporated herein by reference in their entirety.

[0099] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a DPP-IV inhibitor, including gliptins such as sitagliptin, vildagliptin, saxagliptin, linagliptin, gemigliptin, anagliptin, teneligliptin, alogliptin, trelagliptin, omarigliptin, evogliptin, gosogliptin, and dutogliptin or a pharmaceutically acceptable salt thereof.

[0100] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with an HMG CoA reductase inhibitor, such as fluvastatin, lovastatin, pravastatin, simvastatin, atorvastatin, pitavastatin, cerivastatin, mevastatin, rosuvastatin, bevastatin, or dalvastatin or a pharmaceutically acceptable salt thereof.

[0101] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a cholesterol absorption inhibitor, such as ezetimibe or a pharmaceutically acceptable salt thereof.

[0102] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a PPARα agonist, including fibrates such as clofibrate, bezafibrate, ciprofibrate, clinofribrate, clofibride, fenofibrate, gemfibrozil, ronifibrate, and simfribrate or a pharmaceutically acceptable salt thereof.

[0103] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a PPARγ agonist, including thiazolidinediones such as pioglitazone, rosiglitazone, and lobeglitazone or a pharmaceutically acceptable salt thereof.

[0104] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a dual PPARα / γ agonist, including glitazars such as saroglitazar, alglitazar, muraglitazar, or tesaglitazar or a pharmaceutically acceptable salt thereof.

[0105] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a dual PPARα / δ agonist such as elafibranor.

[0106] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a pan-PPAR agonist (i.e., a PPAR agonist active against all of the following subtypes: α, γ, and δ), such as IVA337.

[0107] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a farnesoid X receptor (FXR) modulator, including FXR agonists such as caffeol, chenodeoxycholic acid, 6α-ethyl-chenodeoxycholic acid (obeticholic acid; INT-747), fexaramine, tropifexor, cilofexor, and MET409.

[0108] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a TGR5 receptor modulator, including a TGR5 agonist, such as 6α-ethyl-23(S)-methylcholic acid (INT-777).

[0109] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a dual FXR / TGR5 agonist such as INT-767.

[0110] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with ursodeoxycholic acid (UDCA). In yet another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with norursodeoxycholic acid (nor-UDCA).

[0111] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with an FGF19 modulator, such as NGM282.

[0112] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with an FGF21 agonist, such as BMS-986036.

[0113] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with an integrin inhibitor, such as PLN-74809 and PLN-1474.

[0114] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a CCR2 / CCR5 inhibitor, such as cenicriviroc.

[0115] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a caspase inhibitor, such as emricasan.

[0116] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a galactolectin-3 inhibitor, such as GR-MD-02.

[0117] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a stearoyl-CoA desaturase (SCD) inhibitor, such as aramchol (eicosylaminocholic acid).

[0118] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with an inhibitor of apoptosis signal-regulated kinase 1 (ASK1), such as selonsertib.

[0119] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a LOXL2 inhibitor, such as simtuzumab.

[0120] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with an ACC inhibitor, such as GS-0976.

[0121] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a thyroid hormone receptor-β agonist, such as MGL3196.

[0122] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a GLP-1 agonist such as liraglutide.

[0123] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a dual glucagon-like peptide and a glucagon receptor agonist, such as SAR425899.

[0124] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a mitochondrial pyruvate carrier inhibitor, such as MSDC-0602K.

[0125] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with an antioxidant, such as vitamin E.

[0126] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with an SGLT1 inhibitor, an SGLT2 inhibitor, or a combination of SGLT1 and SGLT2 inhibitors. Examples of such compounds are dapagliflozin, sotagliflozin, canagliflozin, empagliflozin, LIK066, and SGL5213.

[0127] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a diacylglycerol O-acyltransferase 2 (DGAT2) inhibitor, such as DGAT2RX and PF-06865571.

[0128] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a fatty acid synthase (FASN) inhibitor, such as TVB-2640.

[0129] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with an AMP-activated protein kinase (AMPK) activator, such as PXL-770.

[0130] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a glucocorticoid receptor antagonist (GR), a mineralocorticoid receptor antagonist (MR), or a dual GR / MR antagonist. Examples of such compounds are MT-3995 and CORT-118335.

[0131] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a cannabinoid receptor 1 (CB1) antagonist, such as IM102.

[0132] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with Klothoβ (KLB) and fibroblast growth factor receptor (FGFR) activators, such as MK-3655 (formerly known as NGM-313).

[0133] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a chemokine (cc motif) ligand 24 (CCL24) inhibitor, such as CM101.

[0134] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with an A3 antagonist, such as PBF-1650.

[0135] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a P2x7 receptor antagonist, such as SGM 1019.

[0136] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a P2Y13 receptor agonist, such as CER-209.

[0137] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a sulfated oxysterol, such as Dur-928.

[0138] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a leukotriene D4 (LTD4) receptor antagonist, such as MN-001.

[0139] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a type 1 natural killer T cell (NKT1) inhibitor, such as GRI-0621.

[0140] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with an anti-lipopolysaccharide (LPS) compound, such as IMM-124E.

[0141] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a VAP1 inhibitor, such as BI1467335.

[0142] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with an A3 adenosine receptor agonist, such as CF-102.

[0143] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a SIRT-1 activator, such as NS-20.

[0144] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a nicotinic acid receptor 1 agonist, such as ARI-3037MO.

[0145] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a TLR4 antagonist, such as JKB-121.

[0146] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a hexylose kinase inhibitor, such as PF-06835919.

[0147] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with an adiponectin receptor agonist, such as ADP-335.

[0148] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with an inhibitor of autocrine motor factors, such as PAT-505 and PF8380.

[0149] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a chemokine (cc motif) receptor 3 (CCR3) antagonist, such as bertilimumab.

[0150] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a chloride channel stimulant, such as cobiprostone and lubiprostone.

[0151] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a heat shock protein 47 (HSP47) inhibitor, such as ND-L02-s0201.

[0152] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a sterol regulatory element binding protein (SREBP) transcription factor inhibitor, such as CAT-2003 and MDV-4463.

[0153] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with biguanides, such as metformin.

[0154] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with insulin.

[0155] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a glycogen phosphorylase inhibitor and / or a glucose-6-phosphatase inhibitor.

[0156] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with sulfonylureas, such as glipizide, glibenklamid, and glimepirid.

[0157] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with meglitinide, such as repaglinide, nateglinide and ormiglitinide.

[0158] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a glucosidase inhibitor, such as acarbose or miglitol.

[0159] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a squalene synthase inhibitor, such as TAK-475.

[0160] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a PTPB1 inhibitor, such as trodusquemine, ertiprotafib, JTT-551, and claramine.

[0161] Preparation of compounds

[0162] The compounds of the present invention can be prepared as free acids or pharmaceutically acceptable salts thereof by the methods described below. Throughout the following description of such methods, it should be understood that, where appropriate, suitable protecting groups will be added to and subsequently removed from the various reactants and intermediates in a manner readily understood by those skilled in the art of organic synthesis. Conventional procedures using such protecting groups and examples of suitable protecting groups are described, for example, in PGM Wutz and TW Greene's work. Greene's Protective Groups in Organic Synthesis , 4th edition, John Wiley & Sons, Hoboken, 2006.

[0163] General methods

[0164] All solvents used were analytical grade. Commercially available anhydrous solvents were routinely used for the reactions. Starting materials were available from commercial sources or prepared according to literature procedures. 7-Bromo-3-butyl-3-ethyl-5-(4-fluorophenyl)-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazazonylheptanetriene 1,1-dioxide and 3-butyl-3-ethyl-5-(4-fluorophenyl)-8-hydroxy-7-(methylthio)-2,3,4,5-tetrahydro-1,5-benzothiazazonylheptanetriene 1,1-dioxide were prepared according to WO 2020 / 161216 (intermediates 43 and 70, respectively). 7-Bromo-3-butyl-3-ethyl-8-methoxy-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazazonylheptanetriene 1,1-dioxide can be prepared according to WO 2019 / 234077 (Intermediate 22). 3,3-Dibutyl-8-hydroxy-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazazonylheptanetriene 1,1-dioxide can be prepared according to WO 02 / 50051 (Method 26). 3-Butyl-3-ethyl-8-hydroxy-2-(4-methoxybenzyl)-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiazazacycloheptatriene 1,1-dioxide can be prepared according to WO 2019 / 234077 (Intermediate 128). Room temperature refers to 20-25°C. The composition of the solvent mixture is given as a volume percentage or volume ratio.

[0165] LCMS: Instrument Name: Agilent 1290 Infinity II. Method A: Mobile phase: A: 0.1% HCOOH aqueous solution: ACN (95:5), B: ACN; Flow rate: 1.5 mL / min; Column: ZORBAX XDB C-18 (50 x 4.6 mm) 3.5 μM.

[0166] Method B: Mobile phase: A: 10 mM aqueous solution of NH4HCO3, B: ACN; Flow rate: 1.2 mL / min; Column: XBridge C8 (50 x 4.6 mm), 3.5 μM.

[0167] Method C: Mobile phase: A: 0.1% aqueous solution of HCOOH: ACN (95:5), B: ACN; Flow rate: 1.5 mL / min; Column: ATLANTIS dC18 (50 x 4.6 mm), 5 μM.

[0168] Method D: Mobile phase: A: 10 mM aqueous solution of NH4OAc, B: ACN; Flow rate: 1.2 mL / min; Column: ZorbaxExtend C18 (50 x 4.6 mm) 5 μM.

[0169] Method E: Mobile phase: A: 0.1% TFA aqueous solution: ACN (95:5), B: 0.1% TFA in ACN solution; Flow rate: 1.5 mL / min; Column: XBridge C8 (50 x 4.6 mm), 3.5 μM.

[0170] Method F: Mobile phase: A: 0.1% aqueous solution of TFA, B: 0.1% ACN solution of TFA; Flow rate: 0.8 mL / min; Column: ZORBAX ECLIPSE PLUS C18 (50 x 2.1 mm), 1.8 μM.

[0171] Method G: Mobile phase: A: 0.1% aqueous solution of TFA, B: 0.1% ACN solution of TFA; Flow rate: 0.8 mL / min; Column: Acquity UPLC BEH C18 (2.1 x 50 mm), 1.7 μM.

[0172] Method H: Mobile phase: A: 10 mM NH4OAc, B: 100% ACN; Flow rate: 0.8 mL / min; Column: AcquityUPLC BEH C18 (2.1 x 50) mm; 1.7 μM.

[0173] Method I: Mobile phase: A: 0.1% aqueous solution of HCOOH: ACN (95:5), B: ACN; Flow rate: 0.8 mL / min; Column: ZORBAX ECLIPSE PLUS C18 (2.1 x 50) mm, 1.8 μM.

[0174] Method J: Mobile phase: A: 0.1% aqueous solution of TFA, B: 0.1% ACN solution of TFA; Flow rate: 1.5 mL / min; Column: XBridge C8 (50 x 4.6 mm), 3.5 μM.

[0175] Method K: Mobile phase: A: 0.1% aqueous solution of HCOOH, B: 0.05% HCOOH in ACN solution; Flow rate: 0.8 mL / min; Column: Acquity UPLC BEH C18 (2.1 x 50) mm; 1.7 μM.

[0176] Method L: Mobile phase: A: 5 mM aqueous solution of NH4HCO3, B: ACN; Flow rate: 2.2 mL / min; Column: XBridgeBEH C18 (4.6 x 50) mm; 2.5 μM.

[0177] Method M: Mobile phase: A: 10 mM aqueous solution of NH4HCO3, B: ACN; Flow rate: 1.2 mL / min; Column: XBridge C18 (50 x 4.6 mm), 3.5 μM.

[0178] Method N: Mobile phase: A: 0.1% aqueous solution of TFA, B: 0.05% ACN solution of TFA; Flow rate: 2.0 mL / min; Column: XBridge BEH C18 (4.6 x 50) mm; 2.5 μM.

[0179] Method O: Mobile phase: A: 0.1% aqueous solution of TFA, B: ACN; Flow rate: 2.0 mL / min; Column: XBridge C8 (4.6 x 50) mm; 3.5 μM.

[0180] Method P: Mobile phase: A: 5 mM aqueous solution of NH4HCO3, B: ACN; Flow rate: 2.2 mL / min; Column: XBridge C8 (4.6 x 50) mm; 3.5 μM.

[0181] Instrument Name: Waters Acquity UPLC Class I / SQ Detector 2

[0182] Method K: Mobile phase: A: 0.1% aqueous solution of HCOOH: ACN (95:5), B: ACN; Flow rate: 0.8 mL / min; Column: BEH C18 (50 x 2.1 mm), 1.7 µm.

[0183] UPLC: Instrument Name: Waters Acquity I Class Method A: Mobile phase: A: 0.1% aqueous solution of HCOOH, B: 0.1% ACN solution of HCOOH; Flow rate: 0.8 mL / min; Column: Acquity UPLC HSS T3 (2.1 x 50) mm; 1.8 μM.

[0184] Method B: Mobile phase: A: 0.1% aqueous solution of TFA, B: 0.05% ACN solution of TFA; Flow rate: 1.0 mL / min; Column: Acquity BEH C18 (30 x 2.1) mm; 1.7 μM.

[0185] Method C: Mobile phase: A: 5 mM aqueous solution of NH4HCO3, B: ACN; Flow rate: 1.0 mL / min; Column: AcquityBEH (30 x 2.1) mm; 1.7 μM.

[0186] HPLC: Instrument name: Agilent 1260 Infinity II series instrument, using % and UV detection (maxplot) as shown below.

[0187] Method A: Mobile phase: A: 10 mM aqueous solution of NH4HCO3, B: ACN; Flow rate: 1.0 mL / min; Column: XBridge C8 (50 x 4.6 mm, 3.5 µm).

[0188] Method B: Mobile phase: A: 0.1% aqueous solution of TFA, B: 0.1% ACN solution of TFA; Flow rate: 2.0 mL / min; Column: XBridge C8 (50 x 4.6 mm, 3.5 µm).

[0189] Method C: Mobile phase: A: 10 mM NH4OAc in a milli-q aqueous solution, B: ACN; Flow rate: 1.0 ml / min; Column: Phenomenex Gemini C18 (150 x 4.6 mm, 3.0 µm).

[0190] Method D: Mobile phase: A: 0.1% aqueous solution of TFA, B: ACN; Flow rate: 1.0 mL / min; Column: ATLANTIS dC18 (250 x 4.6 mm, 5.0 µm).

[0191] Method E: Mobile phase: A: 0.1% aqueous solution of TFA, B: ACN, Flow rate: 2.0 mL / min; Column: X-Bridge C8 (50 X 4.6 mm, 3.5 µm).

[0192] Chiral SFC: Instrument Name: PIC SFC 10 (Analytical) The ratio of CO2 to cosolvent is between 60:40 and 80:20. Method A: Mobile phase: 0.5% isopropylamine in IPA solution; Flow rate: 3 mL / min; Column: YMC amylose-SA (250 x 4.6 mm, 5 µm).

[0193] Method B: Mobile phase: 0.5% isopropylamine in IPA solution; Flow rate: 3 mL / min; Column: Chiralpak AD-H (250 x 4.6 mm, 5 µm).

[0194] Method C: Mobile phase: 20 mM ammonia in methanol; Flow rate: 3 mL / min; Column: YMC cellulose-SC (250 x 4.6 mm, 5 µm).

[0195] Method D: Mobile phase: methanol; Flow rate: 3 mL / min; Column: Lux A1 (250 x 4.6 mm, 5 µm).

[0196] Method E: Mobile phase: 0.5% isopropylamine in methanol; Flow rate: 5 mL / min; Column: Lux C4.

[0197] Method F: Mobile phase: 0.5% isopropylamine in methanol; Flow rate: 3 mL / min; Column: YMC cellulose-SC.

[0198] Method G: Mobile phase: 0.5% isopropylamine in methanol; Flow rate: 3 mL / min; Column: Lux Al.

[0199] Method H: Mobile phase: 0.5% isopropylamine in IPA solution; Flow rate: 3 mL / min; Column: Lux A1 (250 x 4.6 mm, 5 µm).

[0200] Method I: Mobile phase: 0.5% isopropylamine in methanol; Flow rate: 3 mL / min; Column: chiral CCS (250 x 4.6 mm, 5 µm).

[0201] Method J: Mobile phase: 0.5% isopropylamine in IPA solution; Flow rate: 5 mL / min; Column: YMC cellulose-SC AD-H (250 x 4.6 mm, 5 µm).

[0202] Method K: Mobile phase: 0.5% isopropylamine in methanol; Flow rate: 4 mL / min; Column: (R,R)-Whelk-01 (250 x 4.6 mm, 5 µm).

[0203] Method L: Mobile phase: 0.5% isopropylamine in IPA solution; Flow rate: 3 mL / min; Column: Chiralcel OX-H (250 x 4.6 mm, 5 µm).

[0204] Method M: Mobile phase: 0.5% isopropylamine in IPA solution; Flow rate: 5 mL / min; Column: YMC cellulose-SC (250 x 4.6 mm, 5 µm).

[0205] Method N: Mobile phase: methanol, flow rate: 5 mL / min; column: Chiralcel OX-H (250 x 4.6 mm, 5 µm).

[0206] Method O: Mobile phase: 0.1% isopropylamine in IPA:methanol (1:1) solution, flow rate: 3 mL / min; column: Chiralpak AS-H (250 x 4.6 mm, 5 µm).

[0207] Method P: Mobile phase: 0.5% isopropylamine in methanol solution; Flow rate: 3 mL / min; Column: Chiralpak AS-H (250 x 4.6 mm, 5 µm).

[0208] Method Q: Mobile phase: IPA, flow rate: 3 mL / min; column: Lux A1 (250 x 4.6 mm, 5 µm).

[0209] Method R: Mobile phase: 0.1% isopropylamine in IPA:methanol (1:1) solution, flow rate: 3 mL / min; column: Lux A1 (250 x 4.6 mm, 5 µm).

[0210] Method S: Mobile phase: 0.5% isopropylamine in IPA solution (1:1), flow rate: 3 mL / min; column: Chiralpak AS-H (250 x 4.6 mm, 5 µm).

[0211] Method T: Mobile phase: 0.5% isopropylamine in IPA solution (1:1), flow rate: 4 mL / min; Column: ChiralpakOX-H (250 x 4.6 mm, 5 µm).

[0212] Method U: Mobile phase: IPA, Flow rate: 3 mL / min; Column: Chiralpak AS-H (250 x 4.6 mm, 5 µm).

[0213] Method V: Mobile phase: 0.5% isopropylamine in methanol solution; Flow rate: 3 mL / min; Column: Chiralpak OX-H (250 x 4.6 mm, 5 µm).

[0214] Method W: Mobile phase: 0.5% isopropylamine in IPA solution, flow rate: 5 mL / min; Column: Chiralpak IG (250 x 4.6 mm, 5 µm).

[0215] Method X: Mobile phase: 0.1% diethanolamine in methanol solution; Flow rate: 3 mL / min; Column: Chiralpak AS-H (250 x 4.6 mm, 5 µm).

[0216] Preparative HPLC : Instrument Name: Agilent 1290 Infinity II Method A: Mobile phase: A: 0.1% aqueous solution of TFA; B: 0.1% TFA in ACN solution; Flow rate: 2.0 mL / min; Column: X-Bridge C8 (50 X 4.6 mm, 3.5 µm).

[0217] Method B: Mobile phase: A: 10 mM NH4OAc aqueous solution; B: ACN; Flow rate: 35 mL / min; Column: X select C18 (30 x 150 mm, 5 µm).

[0218] Method C: Mobile phase: A: 10 mM aqueous solution of NH4HCO3; B: ACN; Flow rate: 1.0 mL / min; Column: XBridge C8 (50 x 4.6 mm, 3.5 µm).

[0219] Method D: Mobile phase: A: 0.1% aqueous solution of HCOOH; B: ACN; Flow rate: 1.0 mL / min; Column: X-select C18 (30 x 150 mm, 5 µm).

[0220] Method E: Mobile phase: A: 0.1% TFA aqueous solution, B: ACN; Flow rate: 15 mL / min; Column: Sunfire C18 (19 x 150 mm, 5 µm).

[0221] Chiral preparative SFC: Instrument names: PIC SFC 100 and PSC SFC 400 The ratio of CO2 to cosolvent is between 60:40 and 80:20. Method A: Mobile phase: 0.5% isopropylamine in IPA solution; Flow rate: 3 mL / min; Column: YMC amylose-SA (250 x 30 mm, 5 µm).

[0222] Method B: Mobile phase: 0.5% isopropylamine in IPA solution; Flow rate: 3 mL / min; Column: Chiralpak AD-H (250 x 30 mm, 5 µm).

[0223] Method C: Mobile phase: 20 mM ammonia in methanol; Flow rate: 3 mL / min; Column: YMC cellulose-SC (250 x 30 mm, 5 µm).

[0224] Method D: Mobile phase: methanol; Flow rate: 3 mL / min; Column: chiral CCS (250 x 30 mm, 5 µm).

[0225] Method E: Mobile phase: methanol; Flow rate: 3 mL / min; Column: Lux A1 (250 x 30 mm, 5 µm).

[0226] Method F: Mobile phase: 0.5% isopropylamine in IPA solution; Flow rate: 3 mL / min; Column: Lux A1 (250 x 30 mm, 5 µm).

[0227] Method G: Mobile phase: 0.5% isopropylamine in methanol; Flow rate: 3 mL / min; Column: chiral CCS (250 x 30 mm, 5 µm).

[0228] Method H: Mobile phase: 0.5% isopropylamine in methanol; Flow rate: 4 mL / min; Column: (R,R)-Whelk-01 (250 x 30 mm, 5 µm).

[0229] Method I: Mobile phase: 0.5% isopropylamine in IPA solution; Flow rate: 5 mL / min; Column: YMC cellulose-SC (250 x 30 mm, 5 µm).

[0230] Method J: Mobile phase: 0.5% isopropylamine in IPA solution; Flow rate: 3 mL / min; Column: Chiralcel OX-H (250 x 30 mm, 5 µm).

[0231] Method K: Mobile phase: 0.5% isopropylamine in methanol; Flow rate: 5 mL / min; Column: YMC cellulose-SC (250 x 30 mm, 5 µm).

[0232] Method L: Mobile phase: methanol; Flow rate: 5 mL / min; Column: Chiralcel OX-H (250 x 30 mm, 5 µm).

[0233] Method M: Mobile phase: 0.5% isopropylamine in methanol solution, flow rate: 3 mL / min; Column: Chiralpak AS-H (250 x 4.6 mm, 5 µm).

[0234] Method N: Mobile phase: 0.1% isopropylamine in IPA:MeOH (1:1) solution; Flow rate: 3 mL / min; Column: Chiralpak AS-H (250 x 4.6 mm, 5 µm).

[0235] Method O: Mobile phase: 0.5% isopropylamine in IPA solution; Flow rate: 5 mL / min; Column: Chiralpak IG (250 x 4.6 mm, 5 µm).

[0236] Method P: Mobile phase: 0.1% diethanolamine in methanol solution; Flow rate: 3 mL / min; Column: Chiralpak AS-H (250 x 4.6 mm, 5 µm).

[0237] Method Q: Mobile phase: 0.5% isopropylamine in IPA solution; Flow rate: 4 mL / min; Column: Chiralpak AS-H (250 x 4.6 mm, 5 µm).

[0238] abbreviation

[0239] ACN Acetonitrile

[0240] DCM dichloromethane

[0241] DMF (dimethylformamide)

[0242] dppf 1,1′-bis(diphenylphosphine)ferrocene

[0243] HPLC (High Performance Liquid Chromatography)

[0244] IPA isopropanol

[0245] LCMS (Liquid Chromatography-Mass Spectrometry)

[0246] PE petroleum ether

[0247] Pd2(dba)3 tris(dibenzylacetone)dipalladium(0)

[0248] PMB p-methoxybenzyl

[0249] RT room temperature

[0250] SFC Supercritical Fluid Chromatography

[0251] TFA (trifluoroacetic acid)

[0252] THF Tetrahydrofuran

[0253] TLC (Thin Layer Chromatography)

[0254] UPLC (Ultra-High Performance Liquid Chromatography)

[0255] The present invention will now be described by way of the following embodiments, which do not limit the invention in any way. All listed documents and references are incorporated herein by reference.

[0256] Example

[0257] Intermediate 1

[0258] 7-Bromo-3-butyl-3-ethyl-5-(4-fluorophenyl)-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazazepine-heptane-1,1-dioxide

[0259] At -15°C, BBr3 (6.19 mL, 6.19 mmol) was added to a stirred solution of 7-bromo-3-butyl-3-ethyl-5-(4-fluorophenyl)-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazazepine heptatriene 1,1-dioxide (2.0 g, 4.13 mmol) in DCM (10 mL), and the reaction mixture was stirred at -15°C for 45 min. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with MeOH (5 mL) and then concentrated. The residue was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with water (5 mL) and brine (5 mL) and dried over anhydrous Na2SO4. The organic fraction was filtered, concentrated under vacuum, and the crude product was purified by Isolera column chromatography (eluent: 0-30% EtOAc / PE; silica gel: 230-400 mesh) to obtain the title compound. Yield: 33% (1 g, brown solid).

[0260] LCMS: (Method N) 470.0 (M + +H), Rt. 2.60 min, 64.16% (maximum).

[0261] Intermediate 2

[0262] 3-Butyl-3-ethyl-5-(4-fluorophenyl)-8-hydroxy-7-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazazepine-heptanetriene 1,1-dioxide

[0263] At 0°C, sodium methoxide (25% methanol solution, 12.9 mL, 14.88 mmol) and cuprous bromide (I) (0.43 g, 2.98 mmol) were added to a MeOH solution of 1,1-dioxide (intermediate 1; 1.4 g, 2.98 mmol) in 10 mL of MeOH under stirring. The reaction mixture was stirred at 75°C for 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with water (10 mL), and the aqueous layer was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with water (10 mL) and brine (10 mL) and dried over anhydrous Na₂SO₄. The organic extract was filtered, concentrated under vacuum, and the crude substance was purified by Isolera column chromatography (eluent: 0-25% EtOAc / PE; silica gel: 230-400 mesh) to obtain the title compound. Yield: 78% (1 g, off-white solid).

[0264] LCMS: (Method K) 422.0 (M + +H), Rt. 2.38 min, 33.04% (maximum).

[0265] Intermediate 3

[0266] 3-Butyl-3-ethyl-5-(4-fluorophenyl)-7-methoxy-1,1-dioxo-2,3,4,5-tetrahydro-1,5-benzothiazazonyl-8-yl ester of trifluoromethanesulfonate

[0267] At 0°C, pyridine (0.8 mL, 9.49 mmol) and trifluoromethanesulfonic anhydride (1.2 mL, 7.12 mmol) were added to a DCM (15 mL) solution of 3-butyl-3-ethyl-5-(4-fluorophenyl)-8-hydroxy-7-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatriene 1,1-dioxide (intermediate 2; 2.0 g, 4.74 mmol) under stirring. The reaction mixture was stirred at room temperature for 30 min. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with water (10 mL), and the aqueous layer was extracted with DCM (3 x 20 mL). The combined organic layers were washed with water (10 mL) and brine (10 mL) and then dried over anhydrous Na₂SO₄. The organic fraction was filtered, concentrated under vacuum, and the crude product was purified by Isolera column chromatography (eluent: 0-30% EtOAc / PE; silica gel: 230-400 mesh) to obtain the title compound. Yield: 31.3% (1.4 g, off-white solid).

[0268] LCMS: (Method N) 554.1 (M + +H), Rt. 2.77 min, 58.73% (maximum).

[0269] Intermediate 4

[0270] 1,1-dioxide of methyl 8-(3-butyl-3-ethyl-5-(4-fluorophenyl)-7-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-carboxylate

[0271] At room temperature, triethylamine (0.35 mL, 2.53 mmol), Pd2(dba)3 (0.12 g, 0.13 mmol), and dppf (0.17 g, 0.30 mmol) were added to a solution of 3-butyl-3-ethyl-5-(4-fluorophenyl)-7-methoxy-1,1-dioxo-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-yl ester (intermediate 3; 1.4 g, 2.53 mmol) in DMF (10 mL) and MeOH (15 mL). The resulting reaction mixture was stirred at 75°C for 16 hours under a carbon monoxide gas pressure of 5 kg in a small pressure reactor. After the reaction was complete (monitored by TLC), the reaction mixture was concentrated under vacuum and quenched with water (20 mL). The aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na₂SO₄. The organic fraction was filtered, concentrated under vacuum, and the resulting crude product was used directly in the next step without any further purification. Yield: 1.3 g (crude product, brown liquid).

[0272] LCMS: (Method B) 464.3 (M + +H), Rt. 2.31 min, 31.16% (maximum).

[0273] Intermediate 5

[0274] 3-Butyl-3-ethyl-5-(4-fluorophenyl)-8-(hydroxymethyl)-7-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazazepine-heptane-1,1-dioxide

[0275] At 0°C, LiAlH4 (1.54 mL, 3.08 mmol) was added dropwise to a THF (15 mL) solution of methyl 3-butyl-3-ethyl-5-(4-fluorophenyl)-7-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-carboxylate 1,1-dioxide (intermediate 4; 1.3 g, 2.80 mmol) under stirring. The resulting reaction mixture was stirred at room temperature for 30 min. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with a saturated ammonium chloride solution (15 mL), and the aqueous layer was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na2SO4. The organic fraction was filtered, concentrated under vacuum, and the crude product was used directly for the next step without any further purification. Yield: 1.1 g (crude product, pale brown solid).

[0276] LCMS: (Method K) 436.2 (M + +H), Rt. 2.26 min, 51.11% (maximum).

[0277] Intermediate 6

[0278] 2-((3-Butyl-3-ethyl-5-(4-fluorophenyl)-7-methoxy-1,1-dioxo-2,3,4,5-tetrahydro-1,5-benzothiazazatrien-8-yl)methoxy)tert-butyl acetate

[0279] Sodium hydride (60%, 0.18 g, 4.59 mmol) was added to a DMF (8 mL) solution of 3-butyl-3-ethyl-5-(4-fluorophenyl)-8-(hydroxymethyl)-7-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatriene 1,1-dioxide (intermediate 5; 1 g, 2.3 mmol) under stirring at 0°C, and the reaction mixture was stirred at room temperature for 10 min. Then, tert-butyl 2-bromoacetate (0.67 mL, 4.59 mmol) was added to the reaction mixture at 0°C, and stirring was continued at room temperature for 1 h. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with water (10 mL), and the aqueous layer was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na₂SO₄. The organic fraction was filtered, concentrated under vacuum, and the crude product was purified by Isolera column chromatography (eluent: 0-30% EtOAc / PE; silica gel: 230-400 mesh) to obtain the title compound. Yield: 71.3% (1.2 g, off-white solid).

[0280] LCMS: (Method K) 531.2 (M + -18), Rt. 1.54 min, 75.15% (maximum).

[0281] Intermediate 7

[0282] 3-Butyl-3-ethyl-8-hydroxy-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatriene 1,1-dioxide

[0283] Sodium methanethiol (2.63 g, 37.5 mmol) was added to a DMF (30 mL) solution of 7-bromo-3-butyl-3-ethyl-8-methoxy-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatriene 1,1-dioxide (3.5 g, 7.50 mmol) under stirring at room temperature, and the reaction mixture was stirred at 90°C for 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with water (20 mL), and the aqueous layer was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (30 mL) and dried over anhydrous Na2SO4. The organic fraction was filtered, concentrated under vacuum, and the crude product was purified by Isolera column chromatography (eluent: 0-25% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 44% (3.2 g, grayish-white solid).

[0284] LCMS: (Method E) 420.2 (M + +H), Rt. 2.32 min, 43.26% (maximum).

[0285] Intermediate 8

[0286] 3-Butyl-3-ethyl-7-(methylthio)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazazonyl-8-yl ester of trifluoromethanesulfonate

[0287] At 0°C, pyridine (0.9 mL, 10.96 mmol) and trifluoromethanesulfonic anhydride (1.39 mL, 8.22 mmol) were added to a DCM (30 mL) solution of 3-butyl-3-ethyl-8-hydroxy-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatriene 1,1-dioxide (intermediate 7; 2.3 g, 5.48 mmol) under stirring. The reaction mixture was stirred at room temperature for 30 min. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with water (20 mL), and the aqueous layer was extracted with DCM (3 x 20 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na₂SO₄. The organic fraction was filtered, concentrated under vacuum, and the crude product was purified by Isolera column chromatography (eluent: 0-30% EtOAc / PE; silica gel: 230-400 mesh) to obtain the title compound. Yield: 56.6% (2 g, off-white solid).

[0288] LCMS: (Method L) 552.0 (M) + +H), Rt. 2.57 min, 85.50% (maximum).

[0289] Intermediate 9

[0290] 1,1-dioxide of methyl 3-butyl-3-ethyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-carboxylate

[0291] At room temperature, triethylamine (0.51 mL, 3.63 mmol), Pd2(dba)3 (0.16 g, 0.18 mmol), and dppf (0.24 g, 0.44 mmol) were added to a solution of 3-butyl-3-ethyl-7-(methylthio)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-yl ester (intermediate 8; 2.0 g, 3.63 mmol) in DMF (10 mL) and MeOH (15 mL). The resulting reaction mixture was stirred at 75°C for 12 hours under a pressure of 5 kg carbon monoxide gas in a small pressure reactor. After the reaction was complete (monitored by TLC), the reaction mixture was concentrated under vacuum, and the crude product was purified by Isolera column chromatography (eluent: 0-30% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 58.2% (1.5 g, yellow solid).

[0292] LCMS: (Method K) 462.1 (M + +H), Rt. 2.52 min, 64.99% (maximum).

[0293] Intermediate 10

[0294] 3-Butyl-3-ethyl-8-(hydroxymethyl)-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatriene 1,1-dioxide

[0295] At 0°C, LiAlH4 (2M THF solution, 1.63 mL, 3.25 mmol) was added dropwise to a THF (10 mL) solution of methyl 3-butyl-3-ethyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-carboxylate 1,1-dioxide (intermediate 9; 1.5 g, 3.25 mmol) under stirring. The reaction mixture was stirred at room temperature for 30 min. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with a saturated ammonium chloride solution (15 mL), and the aqueous layer was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na2SO4. The organic fraction was filtered, concentrated under vacuum, and the crude product was used directly in the next step without any further purification. Yield: 66.2% (1.4 g, yellow solid).

[0296] LCMS: (Method K) 436.1 (M + -17), Rt. 2.34 min, 66.62% (maximum).

[0297] Intermediate 11

[0298] 2-((3-Butyl-3-ethyl-7-(methylthio)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazazazetrin-8-yl)methoxy)tert-butyl acetate

[0299] At 0°C, NaH (0.09 g, 2.31 mmol) was added to a THF (10 mL) solution of 3-butyl-3-ethyl-8-(hydroxymethyl)-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatriene 1,1-dioxide (intermediate 10; 0.5 g, 1.15 mmol) under stirring, and the reaction mixture was stirred for 30 min. Then, tert-butyl 2-bromoacetate (0.17 mL, 1.15 mmol) was added, and the reaction mixture was stirred at room temperature for 3 h. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with water (10 mL), and the aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na₂SO₄. The organic fraction was filtered, concentrated under vacuum, and the crude product was purified by Isolera column chromatography (eluent: 0-30% EtOAc / PE; silica gel: 230-400 mesh) to obtain the title compound. Yield: 39.3% (450 mg, off-white solid).

[0300] Intermediate 12

[0301] 7-Bromo-3-butyl-3-ethyl-8-hydroxy-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazazonium heptatriene 1,1-dioxide

[0302] At -15°C, BBr3 (1M DCM solution, 12.86 mL, 12.86 mmol) was added dropwise to a stirred solution of 7-bromo-3-butyl-3-ethyl-8-methoxy-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatriene 1,1-dioxide (3 g, 6.43 mmol) in 10 mL of DCM, and the reaction mixture was stirred for 10 min. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with methanol (10 mL) at 0°C and concentrated under vacuum. The crude product was purified by Isolera column chromatography (eluent: 0-30% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 48% (2.9 g, brown solid).

[0303] Intermediate 13

[0304] 3-Butyl-3-ethyl-8-hydroxy-7-methoxy-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazazonylheptatriene 1,1-dioxide

[0305] At room temperature, cuprous bromide (I) (0.63 g, 4.42 mmol) was added to a solution of 7-bromo-3-butyl-3-ethyl-8-hydroxy-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatriene 1,1-dioxide (intermediate 12; 2.0 g, 4.42 mmol) in sodium methoxide (28% MeOH solution, 1.9 mL, 8.84 mmol). The reaction mixture was stirred at 85°C for 6 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with water (20 mL), and the aqueous layer was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na₂SO₄. The organic fraction was filtered, concentrated under vacuum, and the crude product was purified by Isolera column chromatography (eluent: 0-30% EtOAc / PE; silica gel: 230-400 mesh) to obtain the title compound. Yield: 98.87% (1.76 g, brown solid).

[0306] LCMS: (Method A) 404.1 (M + +H), Rt. 2.94 min, 98.03% (maximum).

[0307] Intermediate 14

[0308] 3-Butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazazonyl-8-yl ester of trifluoromethanesulfonate

[0309] At 0°C, pyridine (0.36 mL, 4.46 mmol) and trifluoromethanesulfonic anhydride (0.37 mL, 2.23 mmol) were added dropwise to a stirred solution of 1,1-dioxide of 3-butyl-3-ethyl-8-hydroxy-7-methoxy-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatriene 1,1-dioxide (intermediate 13; 900 mg, 2.23 mmol) in DCM (10 mL). The resulting reaction mixture was stirred at room temperature for 30 min. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with water (80 mL), and the aqueous layer was extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na₂SO₄. The organic fraction was filtered, concentrated under vacuum, and the crude product was purified by Isolera column chromatography (eluent: 0-30% ethyl acetate / PE; silica gel: 230-400 mesh) to obtain the title compound. Yield: 88% (1.1 g, off-white solid).

[0310] LCMS: (Method L) 536.0 (M + +H), Rt. 2.51 min, 96.18% (maximum).

[0311] Intermediate 15

[0312] 1,1-dioxide of 3-butyl-3-ethyl-7-methoxy-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-carboxylic acid

[0313] At room temperature, triethylamine (0.57 mL, 4.11 mmol), Pd(OAc)₂ (0.46 g, 2.05 mmol), and dppf (1.14 g, 2.05 mmol) were added to a solution of 3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-yl ester (intermediate 14; 1.1 g, 2.05 mmol) in a mixture of DMSO (10 mL) and ethanol (5 mL). The resulting reaction mixture was stirred at 75°C for 12 hours under a carbon monoxide gas pressure of 5 kg. After the reaction was complete (monitored by TLC), the reaction mixture was concentrated under vacuum, and the resulting residue was partitioned between water (20 mL) and EtOAc (20 mL). The aqueous layer was extracted with EtOAc (2 x 50 mL), and the combined organic layers were washed with brine (10 mL) and dried over anhydrous Na₂SO₄. The organic fraction was filtered, concentrated under vacuum, and the crude product was used directly in the next step without any further purification. Yield: 66.1% (1.2 g, brown solid).

[0314] LCMS: (Method J) 460.1 (M + +H), Rt. 2.39 min, 52.04% (maximum).

[0315] Intermediate 16

[0316] 3-Butyl-3-ethyl-8-(hydroxymethyl)-7-methoxy-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatriene 1,1-dioxide

[0317] At 0°C, a solution of LiAlH4 (2 M THF solution, 2 mL, 4.00 mmol) was added dropwise to a THF solution of ethyl 3-butyl-3-ethyl-7-methoxy-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-carboxylate 1,1-dioxide (intermediate 15; 1.2 g, 2.61 mmol) under stirring. The resulting reaction mixture was stirred at room temperature for 30 min. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with a saturated aqueous solution of ammonium chloride (10 mL), and the aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na2SO4. The organic fraction was filtered, concentrated under vacuum, and the crude product was purified by Isolera column chromatography (eluent: 0-30% ethyl acetate / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 58.4% (650 mg, off-white solid).

[0318] 1 H-NMR (400 MHz, DMSO- d 6 ): δ 7.90 (s, 1H), 7.30-7.26 (m, 2H), 7.13-7.11(m, 2H), 6.97-6.94 (m, 1H), 6.38 (s, 1H), 5.24-5.22 (m, 1H), 4.46-4.45 (m,2H), 3.75 (s, 2H), 3.57 (s, 3H), 3.25 (s, 2H), 1.52-1.46 (m, 1H), 1.36-1.31(m, 3H), 1.20-1.18 (m, 4H), 0.77-0.72 (m, 6H). LCMS: (Method E) 400.2 (M + -17), Rt. 2.19 min, 98.10% (maximum).

[0319] Intermediate 17

[0320] 2-((3-Butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-yl)methoxy)tert-butyl acetate

[0321] At 0°C, NaH (192 mg, 4.79 mmol) was added to a THF (10 mL) solution of 3-butyl-3-ethyl-8-(hydroxymethyl)-7-methoxy-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazazepine heptatriene 1,1-dioxide (intermediate 16; 400 mg, 0.96 mmol) under stirring, followed by the addition of tert-butyl 2-bromoacetate (374 mg, 1.92 mmol). The resulting reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete (monitored by LCMS), the reaction mixture was quenched with water (10 mL), and the aqueous layer was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na₂SO₄. The organic fraction was filtered, concentrated under vacuum, and the resulting crude product was used directly in the next step without any further purification. Yield: 58.9% (400 mg, off-white solid).

[0322] LCMS: (Method B) 549.2 (M + + NH4 + Rt. 2.80 min, 75.09% (maximum).

[0323] Intermediate 18

[0324] 3-Butyl-3-ethyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxo-2,3,4,5-tetrahydro-1,5-benzothiazazonyl-8-yl ester of trifluoromethanesulfonate

[0325] At 0°C, pyridine (0.37 mL, 4.57 mmol) and trifluoromethanesulfonic anhydride (0.77 mL, 4.57 mmol) were added to a DCM (20 mL) solution of 2.0 g (4.57 mmol) of 3-butyl-3-ethyl-5-(4-fluorophenyl)-8-hydroxy-7-(methylthio)-2,3,4,5-tetrahydro-1,5-benzothiazazazepine 1,1-dioxide at room temperature. The reaction mixture was stirred for 30 min at room temperature. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with water (15 mL), and the aqueous layer was extracted with DCM (3 x 20 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na₂SO₄. The organic fraction was filtered, concentrated under vacuum, and the crude product was purified by Isolera column chromatography (eluent: 0-25% EtOAc / PE; silica gel: 230-400 mesh) to obtain the title compound. Yield: 95% (2.5 g, off-white solid).

[0326] LCMS: (Method O) 570.1 (M + +H), Rt. 2.61 min, 98.76% (maximum).

[0327] Intermediate 19

[0328] 1,1-dioxide of methyl 8-(butyl-3-ethyl-5-(4-fluorophenyl)-7-(methylthio)-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-carboxylate

[0329] At room temperature, triethylamine (0.6 mL, 4.39 mmol), Pd₂(dba)₃ (0.20 g, 0.22 mmol), and dppf (0.29 g, 0.53 mmol) were added to a solution of 3-butyl-3-ethyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxo-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-yl ester (intermediate 18; 2.5 g, 4.39 mmol) in a mixture of DMF (10 mL) and MeOH (15 mL). The resulting reaction mixture was stirred at 75°C for 12 hours under a pressure of 5 kg of carbon monoxide gas in a small pressure reactor. After the reaction was complete (monitored by TLC), the reaction mixture was concentrated under vacuum, and the crude product was purified by Isolera column chromatography (eluent: 0-30% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 53.2% (2 g, yellow solid).

[0330] LCMS: (Method L) 480.1 (M + +H), Rt. 2.40 min, 54.98% (maximum).

[0331] Intermediate 20

[0332] 3-Butyl-3-ethyl-5-(4-fluorophenyl)-8-(hydroxymethyl)-7-(methylthio)-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatriene 1,1-dioxide

[0333] At 0°C, LiAlH4 (2.09 mL, 4.17 mmol) was added dropwise to a THF (10 mL) solution of methyl 3-butyl-3-ethyl-5-(4-fluorophenyl)-7-(methylthio)-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-carboxylate 1,1-dioxide (intermediate 19; 2.0 g, 4.17 mmol) under stirring. The reaction mixture was stirred at room temperature for 30 min. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with a saturated ammonium chloride solution (10 mL), and the aqueous layer was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na2SO4. The organic fraction was filtered, concentrated under vacuum, and the crude product was used directly in the next step without any further purification. Yield: 1.5 g (crude product, grayish-white solid).

[0334] LCMS: (Method B) 434.1 (M + -17), Rt. 2.51 min, 77.23% (maximum).

[0335] Intermediate 21

[0336] 2-((3-Butyl-3-ethyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxo-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-yl)methoxy)tert-butyl acetate

[0337] Sodium hydride (0.09 g, 2.21 mmol) was added to a THF (10 mL) solution of 3-butyl-3-ethyl-5-(4-fluorophenyl)-8-(hydroxymethyl)-7-(methylthio)-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatriene 1,1-dioxide (intermediate 20; 0.5 g, 1.11 mmol) under stirring at 0°C, and the reaction mixture was stirred for 30 min. Then, tert-butyl 2-bromoacetate (0.2 mL, 1.33 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 3 h. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with water (15 mL), and the aqueous layer was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na₂SO₄. The organic fraction was filtered, concentrated under vacuum, and the crude product was purified by Isolera column chromatography (eluent: 0-30% EtOAc / PE; silica gel: 230-400 mesh) to obtain the title compound. Yield: 53.9% (400 mg, off-white solid).

[0338] LCMS: (Method L) 583.3 (M + +NH4), Rt. 2.56 min, 84.36% (maximum).

[0339] Intermediate 22

[0340] 3,3-Dibutyl-7-(methylthio)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazazonyl-8-yl ester of trifluoromethanesulfonic acid

[0341] At 0°C, pyridine (0.35 mL, 4.46 mmol) was added dropwise to a solution of 1,1-dioxide (1.0 g, 2.23 mmol) of 3,3-dibutyl-8-hydroxy-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatriene (1,1-dioxide) in dry DCM (10 mL), followed by the addition of trifluoromethanesulfonic anhydride (0.56 mL, 3.35 mmol). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with ice-cold water (20 mL), and the aqueous layer was extracted with DCM (2 x 50 mL). The combined organic layers were washed with water (10 mL) and brine (10 mL), and then dried over anhydrous Na₂SO₄. The organic fraction was filtered, concentrated under vacuum, and the crude product was purified by Isolera column chromatography (eluent: 20% EtOAc / PE; silica gel: 230-400 mesh). The resulting solid was ground with petroleum ether (2 x 10 mL) and dried under vacuum to give the title compound. Yield: 85% (1.1 g, off-white solid).

[0342] 1 H NMR (400 MHz, DMSO- d 6 ): δ 7.70 (s, 1H), 7.43-7.30 (m, 4H), 7.18 (t, J = 6.8 Hz, 1H), 6.53 (s, 1H), 3.90-3.88 (m, 2H), 3.54 (s, 2H), 2.18 (s, 3H), 1.65-1.20 (m, 4H), 1.20-0.90 (m, 8H), 0.80-0.62 (m, 6H). LCMS: (Method E) 579.9 (M + +H), Rt. 3.52 min, 96.63% (maximum).

[0343] Intermediate 23

[0344] 3,3-Dibutyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatriene-8-carboxynitrile-1,1-dioxide

[0345] At room temperature, zinc powder (0.02 g, 0.26 mmol) and Zn(CN)₂ (0.68 g, 6.47 mmol) were added to a solution of 3,3-dibutyl-7-(methylthio)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-yl ester (intermediate 22; 2.5 g, 4.31 mmol) in degassed DMF (25 mL). The reaction mixture was then purged with N₂ for 10 min. Then, under nitrogen atmosphere, dppf (0.29 g, 0.52 mmol) and Pd₂(dba)₃ (0.24 g, 0.26 mmol) were added at room temperature. The resulting reaction mixture was stirred at 65°C for 12 h. After the reaction was complete (monitored by TLC), the reaction mixture was passed through a diatomaceous earth bed, which was then washed with EtOAc (100 mL). The organic layer was washed with water (20 mL) and brine (20 mL), and then dried over anhydrous Na2SO4. The organic fraction was filtered, concentrated under vacuum, and the crude product was purified by Isolera column chromatography (eluent: 0-20% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield 67% (3.3 g, grayish-white solid).

[0346] 1 H NMR (400 MHz, DMSO- d 6 ): δ 8.12 (s, 1H), 7.53-7.46 (m, 4H), 7.30 (t, J = 7.0 Hz, 1H), 6.27 (s, 1H), 3.99 (s, 2H), 3.59 (s, 2H), 2.13 (s, 3H), 1.46-1.43 (m, 2H), 1.29-1.26 (m, 2H), 1.09-1.06 (m, 4H), 0.97-0.91 (m, 4H),0.72 (t, J = 6.48 Hz, 6H). LCMS: (Method A) 457.2 (M + +H), Rt. 3.23 min, 81.85% (maximum).

[0347] Intermediate 24

[0348] 3,3-Dibutyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatriene-8-carboxaldehyde 1,1-dioxide

[0349] At -78°C, diisobutylaluminum hydride (1.3 mL, 1 M toluene solution, 0.86 mmol) was added dropwise to a dry DCM (5 mL) solution of 3,3-dibutyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatriene-8-carboxynitrile 1,1-dioxide (intermediate 23; 500 mg, 1.09 mmol) under stirring. The reaction mixture was stirred at room temperature for 6 hours. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with dilute HCl (1.5 N, 5 mL), and the aqueous layer was extracted with DCM (2 x 15 mL). The combined organic layers were washed with water (10 mL) and brine (10 mL) and then dried over anhydrous Na₂SO₄. The organic fraction was filtered, concentrated under vacuum, and the crude product was used directly for the next step without any further purification. Yield: 300 mg (crude product, white solid).

[0350] LCMS: (Method C) 460.1 (M + +H), Rt. 3.27 min, 93.45% (maximum).

[0351] Intermediate 25

[0352] 3,3-Dibutyl-8-(hydroxymethyl)-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatriene 1,1-dioxide

[0353] At 0°C, NaBH4 (160 mg, 4.25 mmol) was added to a stirred solution of 3,3-dibutyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-carboxaldehyde 1,1-dioxide (intermediate 24; 1.3 g, 2.83 mmol) in a mixture of MeOH and THF (1:1, 20 mL), and the reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with water (50 mL), and the aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL) and then dried over anhydrous Na2SO4. The organic fraction was filtered, concentrated under vacuum, and the crude product was purified by Isolera column chromatography (eluent: 0-25% EtOAc / PE; silica gel: 230-400 mesh) to obtain the title compound. Yield: 74% (965 mg, off-white solid).

[0354] 1 H NMR (400 MHz, DMSO- d 6 ): δ 7.91 (s, 1H), 7.31 (t, J = 8.0 Hz, 2H), 7.18 (d, J = 6.9 Hz, 2H), 7.01 (t, J = 7.3 Hz, 1H), 6.59 (s, 1H), 5.48 (t, J = 5.5 Hz, 1H), 4.44 (d, J = 5.4 Hz, 2H), 3.77-3.72 (m, 2H), 3.32 (s, 2H), 2.16 (s, 3H), 1.43-1.29 (m, 4H), 1.20-0.98 (m, 8H), 0.75 (t, J = 6.56 Hz, 6H). LCMS: (Method A) 462.1 (M + +H) & 444.2 (M + -18), Rt. 3.08 min, 98.51% (maximum).

[0355] Intermediate 26

[0356] 2-((3,3-dibutyl-7-(methylthio)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-yl)methoxy)ethyl acetate

[0357] At 0°C, NaH (9 mg, 0.22 mmol) was added to a THF (5 mL) solution of 3,3-dibutyl-8-(hydroxymethyl)-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatriene 1,1-dioxide (intermediate 25; 50 mg, 0.11 mmol) under stirring. The reaction mixture was stirred at room temperature for 10 min. Then, ethyl 2-bromoacetate (0.015 mL, 0.13 mmol) was added at 0°C, and the reaction mixture was stirred at room temperature for 12 h. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with dilute HCl (1.5 N, 5 mL), and the aqueous layer was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with water (10 mL) and brine (10 mL) and then dried over anhydrous Na₂SO₄. The organic fraction was filtered and concentrated under vacuum to obtain a crude compound, which was used directly in the next step without any further purification. Yield: 60 mg (crude product, grayish-white solid).

[0358] LCMS: (Method C) 565.1 (M + +18) Rt. 3.33 min, 75.72% (maximum).

[0359] Intermediate 27

[0360] 3-Butyl-3-ethyl-2-(4-methoxybenzyl)-7-(methylthio)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiazazacycloheptatrien-8-yl ester

[0361] At 0°C, pyridine (0.7 mL, 8.51 mmol) and trifluoromethanesulfonic anhydride (1.07 mL, 6.38 mmol) were added dropwise to a DCM solution (15 mL) of 2.3 g (4.25 mmol) of 3-butyl-3-ethyl-8-hydroxy-2-(4-methoxybenzyl)-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiazazacycloheptatriene 1,1-dioxide (1.3 g, 4.25 mmol) under stirring. The reaction mixture was stirred at room temperature for 30 min. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with water (20 mL), and the aqueous layer was extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na₂SO₄. The organic fraction was filtered, concentrated under vacuum, and the crude product was purified by Isolera column chromatography (eluent: 0-30% EtOAc / PE; silica gel: 230-400 mesh) to obtain the title compound. Yield: 53.5% (2 g, white solid).

[0362] Intermediate 28

[0363] 3-Butyl-3-ethyl-2-(4-methoxybenzyl)-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiazazacycloheptatrien-8-carboxylic acid methyl ester 1,1-dioxide

[0364] Triethylamine (0.41 mL, 2.97 mmol), Pd₂(dba)₃ (0.14 g, 0.15 mmol), and dppf (0.19 g, 0.36 mmol) were added to a solution of 3-butyl-3-ethyl-2-(4-methoxybenzyl)-7-(methylthio)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiazazacycloheptatrien-8-yl ester (intermediate 27; 2.0 g, 2.97 mmol) in DMF (10 mL) and MeOH (15 mL). The resulting reaction mixture was stirred at 75°C for 12 hours under a carbon monoxide gas pressure of 5 kg in a small pressure reactor. After the reaction was complete (monitored by TLC), the reaction mixture was concentrated under vacuum. The residue was quenched with water (50 mL) and extracted with EtOAc (3 x 25 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na2SO4. The organic fraction was filtered, concentrated under vacuum, and the crude product was purified by Isolera column chromatography (eluent: 0-30% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 84% (1.8 g, brown solid).

[0365] LCMS: (Method B) 583.2 (M + +H), Rt. 2.85 min, 81.31% (maximum).

[0366] Intermediate 29

[0367] 1,1-dioxide of methyl 3-butyl-3-ethyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiazazacycloheptatrien-8-carboxylate

[0368] At 0°C, triphenylamine (0.17 g, 0.69 mmol) and 2,2,2-trifluoroacetic acid (0.05 mL, 0.69 mmol) were added to a toluene (10 mL) solution of methyl 3-butyl-3-ethyl-2-(4-methoxybenzyl)-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiazazazaheptatrien-8-carboxylate 1,1-dioxide (intermediate 28; 0.2 g, 0.34 mmol) under stirring. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete (monitored by UPLC), the reaction mixture was concentrated under vacuum, and the resulting residue was quenched with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na₂SO₄. The organic fraction was filtered, concentrated under vacuum, and the crude product was purified by Isolera column chromatography (eluent: 0-30% EtOAc / PE; silica gel: 230-400 mesh) to obtain the title compound. Yield: 78% (140 mg, brown solid).

[0369] LCMS: (Method O) 463.3 (M + +H), Rt. 2.43 min, 88.39% (maximum).

[0370] Intermediate 30

[0371] 3-Butyl-3-ethyl-8-(hydroxymethyl)-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiazazacycloheptatriene 1,1-dioxide

[0372] At 0°C, LAH (2M THF solution, 0.15 mL, 0.30 mmol) was added dropwise to a THF (10 mL) solution of methyl 3-butyl-3-ethyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiazazacycloheptatrien-8-carboxylate 1,1-dioxide (intermediate 29; 0.14 g, 0.30 mmol) under stirring. The reaction mixture was stirred at room temperature for 30 min. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with a saturated ammonium chloride solution (10 mL), and the aqueous layer was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na₂SO₄. The organic fraction was filtered, concentrated under vacuum, and the crude product was used directly for the next step without any further purification. Yield: 100 mg (crude product, off-white solid).

[0373] LCMS: (Method Q) 417.2 (M + -18), Rt. 2.21 min, 81.45% (maximum).

[0374] Intermediate 31

[0375] 2-((3-Butyl-3-ethyl-7-(methylthio)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiazazacycloheptatrien-8-yl)methoxy)tert-butyl acetate

[0376] Sodium hydride (0.02 g, 0.46 mmol) was added to a THF (5 mL) solution of 3-butyl-3-ethyl-8-(hydroxymethyl)-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiazazacycloheptatriene 1,1-dioxide (intermediate 30; 0.1 g, 0.23 mmol) under stirring at 0°C, and the reaction mixture was stirred at room temperature for 10 min. Then, tert-butyl 2-bromoacetate (0.05 mL, 0.35 mmol) was added, and the reaction mixture was stirred at room temperature for 1 h. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with water (10 mL), and the aqueous layer was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na₂SO₄. The organic fraction was filtered, concentrated under vacuum, and the crude product was purified by Isolera column chromatography (eluent: 0-30% EtOAc / PE; silica gel: 230-400 mesh) to obtain the title compound. Yield: 8.47% (90 mg, off-white solid).

[0377] LCMS: (Method L) 547.3 (M + -H), Rt. 2.94 min, 11.88% (maximum).

[0378] Intermediate 32

[0379] 2-Aminohexanoate ethyl hydrochloride

[0380] At 0°C, thionyl chloride (33 mL, 457 mmol) was added to a stirred ethanol (130 mL) solution of 12 g, 91 mmol, and the reaction mixture was heated at 80°C for 16 hours. The reaction mixture was then concentrated under vacuum to give the crude title compound, which was used directly in the next step without any further purification. Yield: 94% (18 g, white solid).

[0381] LCMS: (Method B) 160.3 (M + +H), Rt. 1.72 min, 93.76% (maximum).

[0382] Intermediate 33

[0383] Ethyl (E)-2-(benzylideneamino)hexanoate

[0384] Triethylamine (25.6 mL, 184 mmol) was added over 30 minutes to a DCM (170 mL) solution of ethyl 2-aminohexanoate hydrochloride (intermediate 32; 18 g, 92 mmol) under stirring at 0°C. Magnesium sulfate (11.07 g, 92 mmol) was then added in portions over 0°C. Benzaldehyde (9.37 mL, 92 mmol) was added to the reaction mixture over 20 minutes over 0°C, and the mixture was stirred at room temperature for 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under vacuum. The crude product was dissolved in petroleum ether (1000 mL), filtered again through diatomaceous earth, and the filtrate was concentrated under vacuum to give the title compound. This crude product was used directly in the next step without any further purification. Yield: 73.5% (22 g, pale brown liquid).

[0385] LCMS: (Method B) 248.2 (M + +H), Rt. 2.48 min, 93.76% (maximum).

[0386] Intermediate 34

[0387] Ethyl (E)-2-(benzylideneamino)-2-methylhexanoate

[0388] At 0°C, a solution of (E)-2-(benzylamino)hexanoate (intermediate 33; 20 g, 81 mmol) in DMF (150 mL) was slowly added over 30 minutes to a stirred solution of NaH (60%, 3.23 g, 81 mmol) in 50 mL of DMF. The reaction mixture was stirred at room temperature for 1.5 hours. Iodomethane (5 mL, 81 mmol) was then added at 0°C, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was then quenched with 2-propanol (10 mL) at 0°C and diluted with water (500 mL). The aqueous layer was extracted with petroleum ether (2 x 500 mL). The organic layer was washed with brine (200 mL) and dried over anhydrous Na₂SO₄. The organic fraction was concentrated under vacuum, and the crude product was used directly for the next step without any further purification. Yield: 65.6% (21 g, yellow liquid).

[0389] LCMS: (Method B) 262.2 (M + +H), Rt. 2.64 min, 66.47% (maximum).

[0390] Intermediate 35

[0391] Ethyl 2-amino-2-methylhexanoate

[0392] At 0°C, dilute HCl (150 mL, 1.5 N) was added to a petroleum ether (100 mL) solution of ethyl (E)-2-(benzylamino)-2-methylhexanoate (intermediate 34; 30 g, 115 mmol) under stirring. The reaction mixture was vigorously stirred at room temperature for 16 hours. The organic layer was separated, and the aqueous layer was washed with EtOAc (2 x 100 mL). The aqueous layer was then alkalized with solid sodium bicarbonate (5 g) (pH ~8.5) and extracted with EtOAc (2 x 100 mL). The organic layer was then washed with water (2 x 25 mL). The combined organic fractions were dried over anhydrous Na2SO4 and concentrated under vacuum to give the title compound. The crude material was used directly for the next step without any further purification. Yield: 39.8% (8 g, pale yellow liquid).

[0393] LCMS: (Method C) 174.3 (M + +1), Rt. 1.1 min, 99.74% (maximum).

[0394] Intermediate 36

[0395] 2-Amino-2-methyl-N-phenylhexanamide

[0396] At -78°C, aniline (8.96 mL, 98 mmol) was added dropwise over 30 minutes to a stirred THF (80 mL) solution. n -BuLi (2.5 M hexane solution) (41.6 mL, 104 mmol) was added, and the reaction mixture was stirred at -25°C to -30°C for 45 min. Then, a THF (80 mL) solution of ethyl 2-amino-2-methylhexanoate (intermediate 35; 10 g, 57.7 mmol) was added at -78°C, and the reaction mixture was stirred at -78°C for 2 h. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with water (200 mL) at -78°C, and the reaction mixture was extracted with EtOAc (2 x 250 mL). The organic layer was washed with water (2 x 25 mL), dried over anhydrous Na2SO4, and concentrated under vacuum to give the title compound in crude form. The crude product was dissolved in petroleum ether (1000 mL), washed with an aqueous solution of 30% methanol (2 x 250 mL), and dried over anhydrous Na2SO4. The organic fraction was concentrated under vacuum, and the resulting crude product was used directly in the next step without any further purification. Yield: 72% (15 g, yellow liquid).

[0397] LCMS: (Method E) 221.3 (M + +1), Rt. 1.15 min, 61.25% (maximum).

[0398] Intermediate 37

[0399] 2-Methyl-N1-phenylhexane-1,2-diamine

[0400] At 0°C, a borane dimethyl sulfide complex (2M THF solution, 61.3 mL, 123 mmol) was added to a THF solution of 2-amino-2-methyl-N-phenylhexanoamide (intermediate 36; 27 g, 123 mmol) under stirring. The reaction mixture was heated at 70°C for 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with methanol (65 mL) at 0°C and heated at 70°C for 2 hours. The reaction mixture was then concentrated under vacuum, and the resulting residue was dissolved in EtOAc (250 mL). The organic layer was washed with water (2 x 50 mL), dried over anhydrous Na2SO4, and concentrated under vacuum. The crude product was purified by Isolera column chromatography (eluent: 40% EtOAc in hexane solution; silica gel: 230-400 mesh) to give the title compound. Yield: 31.3% (8 g, yellow liquid).

[0401] 1 H NMR (400 MHz, DMSO- d 6 ): δ 7.07-7.03 (m, 2H), 6.62 (dd, J = 1.2, 8.6Hz, 2H), 6.52-6.52 (m, 1H), 5.30 (t, J = 5.6 Hz, 1H), 2.85 (d, J = 6.0 Hz,2H), 2.26 (bs, 2H), 1.36-1.32 (m, 3H), 1.30-1.24 (m, 3H), 1.02 (s, 3H), 0.88(t, J = 6.8 Hz, 3H). LCMS: (Method C) 207.3 (M + +H), Rt. 1.44 min, 99.59% (maximum).

[0402] Intermediate 38

[0403] 1,2-bis(2,4-dibromo-5-methoxyphenyl)dithion

[0404] At 0°C, bromine (73 mL, 1.4 mol) was added dropwise to a stirred methanol (1000 mL) solution of 100 g, 0.7 mol, and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was evaporated under vacuum, and the crude product was diluted with EtOAc (2000 mL) and washed with water (2 x 500 mL). The organic layer was dried over anhydrous Na₂SO₄ and concentrated under vacuum. The resulting crude product was dissolved in glacial acetic acid (600 mL), and bromine (20 mL) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The resulting solid was filtered off, ground with DCM, and dried under vacuum to give the pure title compound. Yield: 37% (78 g, white solid).

[0405] 1 H NMR (400 MHz, DMSO- d 6 ): δ 7.69 (s, 2H), 7.17 (s, 2H), 3.84 (s, 6H).

[0406] Intermediate 39

[0407] 2,4-Dibromo-5-methoxybenzenesulfonyl chloride

[0408] At 0°C, thioyl chloride (13.6 mL, 168.35 mmol) was added dropwise to a suspension of 1,2-bis(2,4-dibromo-5-methoxyphenyl)dithione (intermediate 38; 20.0 g, 33.67 mmol) and potassium nitrate (17.02 g, 168.35 mmol) in acetonitrile (200 mL). The reaction mixture was stirred at room temperature for 24 hours. After the reaction was complete (monitored by TLC), the reaction mixture was poured onto crushed ice, and the resulting solid was filtered off. The solid was washed with water and dried under vacuum to give the pure title compound. Yield: 91% (22.5 g, white solid).

[0409] 1 H NMR (400 MHz, DMSO- d 6 ): δ 8.05 (s, 1H), 7.66 (s, 1H), 4.01 (s, 3H).

[0410] Intermediate 40

[0411] 2,4-Dibromo-5-methoxy-N-(2-methyl-1-(phenylamino)hex-2-yl)benzenesulfonamide

[0412] At 0°C, 2,4-dibromo-5-methoxybenzenesulfonyl chloride (intermediate 39; 21.2 g, 58.2 mmol) and triethylamine (20.3 mL, 145 mmol) were added to a THF (100 mL) solution of 2-methyl-N1-phenylhexane-1,2-diamine (intermediate 37; 10 g, 48.5 mmol) under stirring. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with EtOAc (250 mL). The organic layer was washed with water (2 x 50 mL) and dried over anhydrous Na2SO4. The organic fraction was concentrated under vacuum, and the crude product was purified by Isolera column chromatography (eluent: 10% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 60.4% (23 g, white solid).

[0413] LCMS: (Method C) 533.1 (M + +H), Rt. 2.71 min, 79.63% (maximum).

[0414] Intermediate 41

[0415] 7-Bromo-3-butyl-8-methoxy-3-methyl-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiazazacycloheptatriene 1,1-dioxide

[0416] Potassium carbonate (11.6 g, 84.3 mmol) and copper powder (885 mg, 14.05 mmol) were added to a DMF (100 mL) solution of 2,4-dibromo-5-methoxy-N-(2-methyl-1-(phenylamino)hex-2-yl)benzenesulfonamide (intermediate 40; 15 g, 28.1 mmol) under stirring. The reaction mixture was heated at 150°C for 24 hours. The reaction mixture was then filtered through diatomaceous earth and washed with EtOAc (250 mL). The filtrate was partially concentrated under vacuum, and the crude product was purified by Isolera column chromatography (eluent: 20% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 66.5% (9 g, white solid).

[0417] 1 H NMR (400 MHz, DMSO- d 6): δ 7.40-7.36 (m, 2H), 7.27 (t, J = 8.0 Hz,2H), 7.16 (bs, 1H), 7.10-7.05 (m, 2H), 6.94-6.92 (m, 1H), 3.90 (s, 3H), 3.31(s, 2H), 1.71-1.61 (m, 1H), 1.35-1.30 (m, 2H), 1.18-1.10 (m, 6H), 0.78 (t, J = 6.8 Hz, 3H). LCMS: (Method E) 455.1 (M + +2), Rt. 2.54 min, 94.22% (maximum).

[0418] Intermediate 42

[0419] 7-Bromo-3-Butyl-8-methoxy-2-(4-methoxybenzyl)-3-methyl-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiazazacycloheptatriene 1,1-dioxide

[0420] At 0°C, Cs₂CO₃ (3.59 g, 11.03 mmol) was added to a DMF (25 mL) solution of 7-bromo-3-butyl-8-methoxy-3-methyl-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiazazacycloheptatriene 1,1-dioxide (intermediate 41; 2.5 g, 5.51 mmol) under stirring. Then, 1-(chloromethyl)-4-methoxybenzene (1.30 g, 8.27 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with water (50 mL), and the aqueous layer was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by Isolera column chromatography (eluent: 20% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 70% (2.25 g, brown solid).

[0421] LCMS: (Method C) 575.3 (M + +2), Rt.2.59 min, 98.8% (maximum).

[0422] Intermediate 43

[0423] 3-Butyl-8-hydroxy-2-(4-methoxybenzyl)-3-methyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiazazacycloheptatriene 1,1-dioxide

[0424] Sodium methanethiol (1.29 g, 18.49 mmol) was added to a DMF (20 mL) solution of 7-bromo-3-butyl-8-methoxy-2-(4-methoxybenzyl)-3-methyl-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiazazacycloheptatriene 1,1-dioxide (intermediate 42; 2 g, 3.70 mmol) under stirring. The reaction mixture was stirred at 90°C for 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with water (100 mL), and the aqueous layer was extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by Isolera column chromatography (eluent: 0-20% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 46% (1.5 g, white solid).

[0425] LCMS: (Method C) 527.3 (M + +1), Rt.2.38 min, 60.06% (maximum).

[0426] Intermediate 44

[0427] 3-Butyl-2-(4-methoxybenzyl)-3-methyl-7-(methylthio)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiazazacycloheptatrien-8-yl ester of trifluoromethanesulfonate

[0428] At 0°C, pyridine (0.6 mL, 7.60 mmol) and trifluoromethanesulfonic anhydride (0.96 mL, 5.70 mmol) were added dropwise to a DCM (15 mL) solution of 3-butyl-8-hydroxy-2-(4-methoxybenzyl)-3-methyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiazazacycloheptatriene 1,1-dioxide (intermediate 43; 2 g, 3.80 mmol) under stirring. The reaction mixture was stirred at room temperature for 30 min. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with water (20 mL), and the aqueous layer was extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na₂SO₄. The organic fraction was filtered, concentrated under vacuum, and the crude product was purified by Isolera column chromatography (eluent: 0-30% EtOAc / PE; silica gel: 230-400 mesh) to obtain the title compound. Yield: 84% (2.1 g, white solid).

[0429] Intermediate 45

[0430] 3-Butyl-2-(4-methoxybenzyl)-3-methyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiazazacycloheptatrien-8-carboxylic acid ethyl ester 1,1-dioxide

[0431] Triethylamine (0.85 mL, 6.07 mmol), Pd₂(dba)₃ (0.69 g, 0.76 mmol), and dppf (0.42 g, 0.76 mmol) were added to a solution of 3-butyl-2-(4-methoxybenzyl)-3-methyl-7-(methylthio)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiazazacycloheptatrien-8-yl ester (intermediate 44; 2.0 g, 3.04 mmol) in DMSO (20 mL) and EtOH (6 mL). The resulting reaction mixture was stirred at 75°C for 12 hours under a pressure of 5 kg of carbon monoxide gas in a small pressure reactor. After the reaction was complete (monitored by TLC), the reaction mixture was concentrated under vacuum, and the resulting residue was quenched with water (50 mL). The aqueous layer was extracted with EtOAc (3 x 25 mL), and the combined organic layers were washed with brine (20 mL) and dried over anhydrous Na₂SO₄. The organic fraction was filtered, concentrated under vacuum, and the crude product was purified by Isolera column chromatography (eluent: 0-30% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 40% (850 mg, brown solid).

[0432] LCMS: (Method L) 583.7 (M + +H), Rt. 3.06 min, 82.82% (maximum).

[0433] Intermediate 46

[0434] 1,1-dioxide of ethyl 3-butyl-3-methyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiazazacycloheptatrien-8-carboxylate

[0435] At 0°C, triphenylamine (0.42 g, 1.71 mmol) and 2,2,2-trifluoroacetic acid (1.31 mL, 17.16 mmol) were added to a toluene (10 mL) solution of ethyl 3-butyl-2-(4-methoxybenzyl)-3-methyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiazazacycloheptatrien-8-carboxylate 1,1-dioxide (intermediate 45; 0.5 g, 0.86 mmol) under stirring. The reaction mixture was stirred at room temperature for 16 hours. After completion (monitored by UPLC), the reaction mixture was concentrated under vacuum, and the resulting solids were quenched with water (10 mL). The aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na₂SO₄. The organic fraction was filtered, concentrated under vacuum, and the crude product was purified by Isolera column chromatography (eluent: 0-30% EtOAc / PE; silica gel: 230-400 mesh) to obtain the title compound. Yield: 43.8% (450 mg, brown solid).

[0436] LCMS: (Method O) 463.2 (M + +H), Rt. 2.40 min, 38.61% (maximum).

[0437] Intermediate 47

[0438] 3-Butyl-8-(hydroxymethyl)-3-methyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiazazacycloheptatriene 1,1-dioxide

[0439] At 0°C, LiAlH4 (2M THF solution, 0.5 mL, 0.97 mmol) was added dropwise to a THF solution of ethyl 3-butyl-3-methyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiazazacycloheptatrien-8-carboxylate 1,1-dioxide (intermediate 46; 0.45 g, 0.97 mmol) under stirring. The reaction mixture was stirred at room temperature for 30 min. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with a saturated ammonium chloride solution (10 mL), and the aqueous layer was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na2SO4. The organic fraction was filtered, concentrated under vacuum, and the crude product was used directly for the next step without any further purification. Yield: 370 mg (grayish-white solid, crude product).

[0440] LCMS: (Method O) 403.2 (M + -17), Rt. 2.15 min, 38.87% (maximum).

[0441] Intermediate 48

[0442] 2-((3-Butyl-3-methyl-7-(methylthio)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiazazacycloheptatrien-8-yl)methoxy)tert-butyl acetate

[0443] Sodium hydride (0.07 g, 0.18 mmol) was added to a THF (10 mL) solution of 3-butyl-8-(hydroxymethyl)-3-methyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiazazacycloheptatriene 1,1-dioxide (intermediate 47; 0.37 g, 0.88 mmol) under stirring at 0°C, and the reaction mixture was stirred at room temperature for 10 min. Then, tert-butyl 2-bromoacetate (0.2 mL, 1.32 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 1 h. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with water (10 mL), and the aqueous layer was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na₂SO₄. The organic fraction was filtered, concentrated under vacuum, and the crude product was purified by Isolera column chromatography (eluent: 0-30% EtOAc / PE; silica gel: 230-400 mesh) to obtain the title compound. Yield: 30.8% (300 mg, off-white solid).

[0444] LCMS: (Method B) 533.2 (M + -H), Rt. 2.98 min, 48.32% (maximum).

[0445] Intermediate 49

[0446] 3-Butyl-3-ethyl-8-hydroxy-7-methoxy-5-(4-methoxyphenyl)-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatriene 1,1-dioxide

[0447] At 0°C, sodium methoxide (2.54 g, 11.76 mmol) and cuprous bromide (0.675 g, 4.71 mmol) were added to a MeOH solution of 1,1-dioxide (1.25 g, 2.35 mmol) in 7-bromo-5-(4-bromophenyl)-3-butyl-3-ethyl-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatriene 1,1-dioxide under stirring. The reaction mixture was stirred at 75°C for 48 hours. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with water (20 mL), and the aqueous layer was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (30 mL) and dried over anhydrous Na₂SO₄. The organic fraction was filtered, concentrated under vacuum, and the crude product was purified by Isolera column chromatography (eluent: 0-25% EtOAc / PE; silica gel: 230-400 mesh) to obtain the title compound. Yield: 66.7% (0.8 g, off-white solid).

[0448] LCMS: (Method O) 434.0 (M + +H), Rt. 1.25 min, 85.15% (maximum).

[0449] Intermediate 50

[0450] 3-Butyl-3-ethyl-7-methoxy-5-(4-methoxyphenyl)-1,1-dioxo-2,3,4,5-tetrahydro-1,5-benzothiazazonyl-8-yl ester of trifluoromethanesulfonate

[0451] At 0°C, pyridine (0.3 mL, 3.69 mmol) and trifluoromethanesulfonic anhydride (1.31 mL, 1.84 mmol) were added to a DCM (10 mL) solution of 3-butyl-3-ethyl-8-hydroxy-7-methoxy-5-(4-methoxyphenyl)-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatriene 1,1-dioxide (intermediate 49; 0.8 g, 1.84 mmol) under stirring. The reaction mixture was stirred at room temperature for 30 min. After the reaction was complete (monitored by TLC), the reaction mixture was diluted with water (20 mL), and the aqueous layer was extracted with DCM (3 x 20 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na₂SO₄. The organic fraction was filtered, concentrated under vacuum, and the crude product was purified by Isolera column chromatography (eluent: 0-30% EtOAc / PE; silica gel: 230-400 mesh) to obtain the title compound. Yield: 60.2% (0.7 g, off-white solid).

[0452] LCMS: (Method O) 566.2 (M + +H), Rt. 1.48 min, 89.78% (maximum).

[0453] Intermediate 51

[0454] 1,1-dioxide of methyl 8-butyl-3-butyl-3-ethyl-7-methoxy-5-(4-methoxyphenyl)-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-carboxylate

[0455] At room temperature, triethylamine (0.38 mL, 2.69 mmol), Pd₂(dba)₃ (0.12 g, 0.13 mmol), and dppf (0.18 g, 0.32 mmol) were added to a solution of 3-butyl-3-ethyl-7-methoxy-5-(4-methoxyphenyl)-1,1-dioxo-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-yl ester (intermediate 50; 1.52 g, 3.63 mmol) in a mixture of DMF (10 mL) and MeOH (15 mL). The resulting reaction mixture was stirred at 75°C for 12 hours under a pressure of 5 kg of carbon monoxide gas in a small pressure reactor. After the reaction was complete (monitored by TLC), the reaction mixture was concentrated under vacuum, and the crude product was purified by Isolera column chromatography (eluent: 0-30% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 67.6% (1.0 g, yellow solid).

[0456] LCMS: (Method O) 476.2 (M + +H), Rt. 1.32 min, 86.39% (maximum).

[0457] Intermediate 52

[0458] 3-Butyl-3-ethyl-8-(hydroxymethyl)-7-methoxy-5-(4-methoxyphenyl)-2,3,4,5-tetrahydro-1,5-benzothiazazepine-heptane-1,1-dioxide

[0459] At 0°C, LiAlH4 (1.53 mL, 1.05 mmol) was added dropwise to a THF (10 mL) solution of methyl 3-butyl-3-ethyl-7-methoxy-5-(4-methoxyphenyl)-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-carboxylate 1,1-dioxide (intermediate 51; 0.5 g, 1.05 mmol) under stirring. The reaction mixture was stirred at room temperature for 30 min. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with a saturated ammonium chloride solution (15 mL), and the aqueous layer was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na2SO4. The organic fraction was filtered, concentrated under vacuum, and the crude product was used directly for the next step without any further purification. Yield: 77% (0.4 g, yellow solid).

[0460] LCMS: (Method O) 430.1 (M + -17), Rt. 1.21 min, 90.08% (maximum).

[0461] Intermediate 53

[0462] 2-((3-Butyl-3-ethyl-7-methoxy-5-(4-methoxyphenyl)-1,1-dioxo-2,3,4,5-tetrahydro-1,5-benzothiazazatrien-8-yl)methoxy)tert-butyl acetate

[0463] At 0°C, NaH (0.07 g, 1.78 mmol) was added to a THF (10 mL) solution of 3-butyl-3-ethyl-8-(hydroxymethyl)-7-methoxy-5-(4-methoxyphenyl)-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatriene 1,1-dioxide (intermediate 52; 0.4 g, 0.89 mmol) under stirring, and the reaction mixture was stirred for 30 min. Then, tert-butyl 2-bromoacetate (0.2 mL, 1.34 mmol) was added, and the reaction mixture was stirred at room temperature for 3 h. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with water (10 mL), and the aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na₂SO₄. The organic fraction was filtered, concentrated under vacuum, and the crude material was purified by Isolera column chromatography (eluent: 0-30% EtOAc / PE; silica gel: 230-400 mesh) to obtain the title compound.

[0464] Yield: 29.6% (200 mg, grayish-white solid).

[0465] Example 1

[0466] 2-((3-Butyl-3-ethyl-5-(4-fluorophenyl)-7-methoxy-1,1-dioxo-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid

[0467] At 0°C, a solution of tert-butyl acetate (intermediate 6; 1 g, 1.8 mmol) in a mixture of THF (9 mL) and MeOH (3 mL) was added to a solution of 10% NaOH in H₂O (2.18 mL, 5.46 mmol). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete (monitored by TLC), the reaction mixture was acidified with dilute HCl (1.5 N, 10 mL), and the aqueous layer was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL) and dried over anhydrous Na₂SO₄. The organic layers were filtered and concentrated under vacuum. The crude product was purified by preparative HPLC (Method C) to obtain the title compound. Yield: 58.6% (71 mg, off-white solid).

[0468] 1 H-NMR (400 MHz, DMSO- d 6 ): δ 12.72 (s, 1H), 7.83 (s, 1H), 7.25 (d, J =4.4 Hz, 2H), 7.16 (t, J = 8.4 Hz, 2H), 6.27 (s, 1H), 4.50 (s, 2H), 4.11 (s, 2H), 3.77 (s, 2H), 3.56 (s, 3H), 3.31 (s, 2H), 1.55-1.30 (m, 4H), 1.14-0.99 (m, 4H), 0.76-0.73 (m, 6H). LCMS: (Method L) 492.1 (M + -H), Rt. 1.06 min, 98.69% (maximum). HPLC: (Method E) Rt. 5.54 min, 98.97% (maximum).

[0469] Example 2

[0470] (S)-2-((3-Butyl-3-ethyl-5-(4-fluorophenyl)-7-methoxy-1,1-dioxo-2,3,4,5-tetrahydro-1,5-benzothiazazonyl-8-yl)methoxy)acetic acid and (R)-2-((3-Butyl-3-ethyl-5-(4-fluorophenyl)-7-methoxy-1,1-dioxo-2,3,4,5-tetrahydro-1,5-benzothiazazonyl-8-yl)methoxy)acetic acid

[0471] Two enantiomers of racemic 2-((3-butyl-3-ethyl-5-(4-fluorophenyl)-7-methoxy-1,1-dioxo-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid (Example 1; 200 mg, 0.405 mmol) were separated by chiral SFC (Method Z). The substance was concentrated under vacuum at 40°C. The first elution fraction corresponds to enantiomer 1 and the second elution fraction corresponds to enantiomer 2. The absolute configurations of these two enantiomers are unknown.

[0472] Enantiomer 1: Yield: 8.90% (18 mg, off-white solid). 1 H-NMR (400 MHz, DMSO- d 6 ): δ 12.69 (bs, 1H), 7.83 (s, 1H), 7.25 (d, J = 4.4 Hz, 2H), 7.16 (t, J = 8.8Hz, 2H), 6.27 (s, 1H), 4.50 (s, 2H), 4.12 (s, 2H), 3.77-3.72 (m, 2H), 3.56 (s, 3H), 3.30 (m, 2H), 1.51-1.31 (m, 4H), 1.12-0.99 (m, 4H), 0.76-0.69 (m, 6H). LCMS: (Method O) 492.1 (M + -H), Rt. 1.29 min, 99.62% (maximum). HPLC: (Method A) Rt. 5.05 min, 98.94% (maximum). Chiral SFC: (Method Z) Rt. 3.0 min, 100% (maximum).

[0473] Enantiomer 2: Yield: 9.31% (19 mg, off-white solid). 1 H-NMR (400 MHz, DMSO-d 6 ): δ 12.74 (s, 1H), 7.83 (s, 1H), 7.27 (d, J = 7.6 Hz, 2H), 7.16 (t, J = 8.4 Hz, 2H), 6.27 (s, 1H), 4.49 (s, 2H), 4.09 (s, 2H), 3.77-3.71 (m, 2H), 3.56 (s, 3H), 3.32 (m, 2H), 1.52-1.49 (m, 4H), 1.12-0.99 (m, 4H), 0.76-0.69 (m, 6H). LCMS: (Method O) 492.3 (M + -H), Rt. 1.24 min, 98.27% (maximum). HPLC: (Method A) Rt. 5.05 min, 98.02% (maximum). Chiral SFC: (Method Z) Rt. 4.19 min, 100% (maximum).

[0474] Example 3

[0475] 2-((3-Butyl-3-ethyl-7-(methylthio)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid

[0476] At 0°C, 0.33 g, 0.82 mmol of NaOH was added to a solution of 2-((3-butyl-3-ethyl-7-(methylthio)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-yl)methoxy)tert-butyl acetate (intermediate 11; 0.45 g, 0.82 mmol) in MeOH (5 mL) and THF (5 mL) under stirring. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete (monitored by TLC), the reaction mixture was acidified with dilute HCl (1.5 N, 10 mL), and the aqueous layer was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with water (10 mL) and brine (10 mL) and dried over anhydrous Na₂SO₄. The organic layers were filtered, concentrated under vacuum, and the crude product was purified by preparative HPLC (method C) to give the title compound. Yield: 24% (100 mg, off-white solid).

[0477] 1H-NMR (400 MHz, DMSO- d 6 ): δ 7.86 (s, 1H), 7.31 (t, J = 7.60 Hz, 2H),7.21-7.19 (m, 2H), 7.02 (t, J = 7.20 Hz, 1H), 6.60 (s, 1H), 4.53 (s, 2H), 4.00 (s, 2H), 3.79 (bs, 2H), 3.21 (s, 2H), 2.15 (s, 3H), 1.52-1.67 (m, 1H), 1.40-1.36 (m, 3H), 1.31-1.10 (m, 4H), 0.78-0.70 (m, 6H). LCMS: (Method L) 490.1 (M + -H), Rt. 1.55 min, 98.74% (maximum). HPLC: (Method A) Rt. 9.25 min, 97.14% (maximum). Chiral SFC: (Method P) Rt. 4.36 min, 100% (maximum).

[0478] Example 4

[0479] (S)-2-((3-Butyl-3-ethyl-7-(methylthio)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazazonyl-8-yl)methoxy)acetic acid and (R)-2-((3-Butyl-3-ethyl-7-(methylthio)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazazonyl-8-yl)methoxy)acetic acid

[0480] Two enantiomers of racemic 2-((3-butyl-3-ethyl-7-(methylthio)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid (Example 3; 80 mg, 0.16 mmol) were separated by chiral SFC (Method M). The substance was concentrated under vacuum at 40°C. The first elution fraction corresponded to enantiomer 1 and the second elution fraction corresponded to enantiomer 2. The residue was purified by preparative HPLC (Method C). The absolute configurations of the two enantiomers are unknown.

[0481] Enantiomer 1: Yield: 6.23% (5 mg, off-white solid). 1H-NMR (400 MHz, DMSO- d 6 ): δ12.55 (bs, 1H), δ 7.85 (s, 1H), 7.32 (t, J = 8.4 Hz, 2H), 7.20 (d, J = 7.6Hz, 2H), 7.02 (t, J = 7.20 Hz, 1H), 6.60 (s, 1H), 4.52 (s, 2H), 4.05 (s, 2H), 3.79 (bs, 2H), 3.25-3.19 (m, 2H), 2.16 (s, 3H), 1.58-1.52 (m, 1H), 1.43-1.29(m, 3H), 1.15-0.96 (m, 4H), 0.74 (t, J = 6.40 Hz, 6H). LCMS: (Method L) 490.2 (M + -H), Rt. 1.65 min, 99.68% (maximum). HPLC: (Method B) Rt. 5.61 min, 99.71% (maximum). Chiral SFC: (Method P) Rt. 4.36 min, 100% (maximum).

[0482] Enantiomer 2: Yield: 6.22% (5 mg, off-white solid). 1 H-NMR (400 MHz, DMSO- d 6 ): δ12.73 (bs, 1H), δ 7.85 (s, 1H), 7.32 (t, J = 8.4 Hz, 2H), 7.21 (d, J = 8.0Hz, 2H), 7.03 (t, J = 7.20 Hz, 1H), 6.60 (s, 1H), 4.53 (s, 2H), 4.12 (s, 2H), 3.79 (bs, 2H), 3.23-3.18 (m, 2H), 2.15 (s, 3H), 1.58-1.52 (m, 1H), 1.43-1.29 (m, 3H), 1.15-0.96 (m, 4H), 0.76-0.71 (m, 6H). LCMS: (Method L) 490.2 (M +-H), Rt. 1.64 min, 98.24% (maximum). HPLC: (Method B) Rt. 5.62 min, 99.58% (maximum). Chiral SFC: (Method P) Rt. 5.61 min, 100% (maximum).

[0483] Example 5

[0484] 2-((3-Butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid

[0485] At 0°C, tert-butyl acetate (intermediate 17; 400 mg, 0.75 mmol) of 2-((3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetate (intermediate 17; 400 mg, 0.75 mmol) in a mixture of THF (3 mL) and MeOH (1 mL) was added to a 10% aqueous solution of NaOH (5 mL, 0.75 mmol). The resulting reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete (monitored by TLC), the reaction mixture was concentrated under vacuum, and the resulting residue was acidified with dilute HCl (1.5 N, 10 mL). The aqueous layer was extracted with EtOAc (3 x 25 mL), and the combined organic layers were washed with brine (10 mL) and dried over anhydrous Na₂SO₄. The organic layer was filtered, concentrated under vacuum, and the resulting crude product was purified by preparative HPLC (Method B) to give the title compound. Yield: 82% (300 mg, grayish-white solid).

[0486] 1 H-NMR (400 MHz, DMSO- d 6 ): δ 7.85 (s, 1H), 7.31-7.27 (m, 2H), 7.17-7.15(m, 2H), 7.00-6.97 (m, 1H), 6.38 (s, 1H), 4.50 (s, 2H), 4.03 (s, 2H), 3.75-3.73 (m, 2H), 3.57 (s, 3H), 3.33-3.28 (m, 3H), 1.55-1.53 ​​(m, 1H), 1.41-1.30 (m, 3H), 1.24-0.97 (m, 4H), 0.76-0.71 (m, 6H). LCMS: (Method L) 474.2 (M+ -H), Rt. 1.48 min, 98.57% (maximum). HPLC: (Method E) Rt. 5.50 min, 97.79% (maximum).

[0487] Example 6

[0488] (S)-2-((3-Butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazazonyl-8-yl)methoxy)acetic acid and (R)-2-((3-Butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazazonyl-8-yl)methoxy)acetic acid

[0489] Two enantiomers of racemic 2-((3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid (Example 5; 140 mg, 0.29 mmol) were separated by chiral SFC (Method Q). The substance was concentrated under vacuum at 40°C. The first elution fraction corresponded to enantiomer 1 and the second elution fraction corresponded to enantiomer 2. The residue was further purified by preparative HPLC (Method C). The absolute configurations of the two enantiomers are unknown.

[0490] Enantiomer 1: Yield: 29.4% (42 mg, off-white solid). 1 H-NMR (400 MHz, DMSO- d 6 ):δ 7.86 (s, 1H), 7.29 (t, J = 7.20 Hz, 2H), 7.16 (d, J = 7.60 Hz, 2H), 6.98(t, J = 7.60 Hz, 1H), 6.38 (s, 1H), 4.50 (s, 2H), 4.04-4.01 (m, 2H), 3.76-3.75 (m, 2H), 3.56 (s, 3H), 3.33-3.28 (m, 2H), 1.55-1.51 (m, 1H), 1.37-1.30 (m, 3H), 1.18-1.06 (m, 4H), 1.00-0.97 (m, 6H) LCMS: (Method L) 474.2 (M +-H), Rt. 1.49 min, 98.80% (maximum). HPLC: (Method E) Rt. 5.38 min, 98.98% (maximum). Chiral SFC: (Method S) Rt. 3.28 min, 100% (maximum).

[0491] Enantiomer 2: Yield: 25.2% (36 mg, off-white solid). 1 H-NMR (400 MHz, DMSO- d 6 ):δ 7.86 (s, 1H), 7.29 (t, J = 7.60 Hz, 2H), 7.16 (d, J = 7.60 Hz, 2H), 6.98(t, J = 7.20 Hz, 1H), 6.38 (s, 1H), 4.50 (s, 2H), 3.99-3.93 (m, 2H), 3.75-3.74 (m, 2H), 3.56 (s, 3H), 3.33-3.28 (m, 2H), 1.55-1.34 (m, 4H), 1.24-1.10 (m, 4H), 0.98-0.96 (m, 6H) LCMS: (Method L) 474.2 (M + -H), Rt. 1.48 min, 98.35% (maximum). HPLC: (Method E) Rt. 5.38 min, 98.83% (maximum). Chiral SFC: (Method S) Rt. 4.61 min, 100% (maximum).

[0492] Example 7

[0493] 2-((3-Butyl-3-ethyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxo-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid

[0494] At 0°C, tert-butyl methoxy)acetate (intermediate 21; 0.2 g, 0.35 mmol) of 2-((3-butyl-3-ethyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxo-2,3,4,5-tetrahydro-1,5-benzothiazazatrien-8-yl)methoxy)acetate (intermediate 21; 0.2 g, 0.35 mmol) in a mixture of MeOH (2 mL) and THF (3 mL) was added to NaOH (10% aqueous solution, 0.14 g, 0.35 mmol), and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete (monitored by UPLC), the reaction mixture was acidified with dilute HCl (1.5 N, 15 mL). The resulting solid was filtered off and dried under vacuum to give the title compound. Yield: 87% (165 mg, white solid).

[0495] 1 H-NMR (400 MHz, DMSO- d 6 ): δ 12.74 (s, 1H), 7.83 (s, 1H), 7.30-7.29 (m, 2H), 7.20-7.16 (m, 2H), 6.50 (s, 1H), 4.52 (s, 2H), 4.15-4.13 (m, 2H), 3.79-3.74 (m, 2H), 3.38-3.33 (m, 2H), 2.20-2.16 (m, 3H), 1.53-1.48 (m, 1H), 1.38-1.31 (m, 3H), 1.11-1.09 (m, 2H), 0.99-0.97 (m, 2H), 0.76-0.69 (m, 6H). LCMS: (Method L) 508.1 (M + -H), Rt. 1.56 min, 95.17% (maximum). HPLC: (Method E) Rt. 5.63 min, 99.93% (maximum).

[0496] Example 8

[0497] (S)-2-((3-Butyl-3-ethyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxo-2,3,4,5-tetrahydro-1,5-benzothiazazonyl-8-yl)methoxy)acetic acid and (R)-2-((3-Butyl-3-ethyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxo-2,3,4,5-tetrahydro-1,5-benzothiazazonyl-8-yl)methoxy)acetic acid

[0498] Two enantiomers of racemic 2-((3-butyl-3-ethyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxo-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid (Example 7; 140 mg, 0.27 mmol) were separated by chiral SFC (Method Q). The substance was concentrated under vacuum at 40°C. The first elution fraction corresponded to enantiomer 1 and the second elution fraction corresponded to enantiomer 2. The residue was further purified by preparative HPLC (Method C). The absolute configurations of the two enantiomers are unknown.

[0499] Enantiomer 1: Yield: 17.84% (25 mg, off-white solid). 1 H-NMR (400 MHz, DMSO- d 6 ): δ 7.84 (s, 1H), 7.29-7.28 (m, 2H), 7.17 (t, J = 9.20 Hz, 2H), 6.50 (s, 1H), 4.51 (s, 2H), 4.00 (s, 2H), 3.78-3.73 (m, 2H), 3.37-3.33 (m, 2H), 2.16 (s, 3H), 1.54-1.50 (m, 1H), 1.38-1.31 (m, 3H), 1.12-0.98 (m, 4H), 0.76-0.73 (m, 6H). LCMS: (Method L) 508.1 (M + -H), Rt. 1.58 min, 99.43% (maximum). HPLC: (Method E) Rt. 5.63 min, 99.93% (maximum). Chiral SFC: (Method S) Rt. 2.44 min, 100% (maximum).

[0500] Enantiomer 2: Yield: 17.73% (25 mg, off-white solid). 1 H-NMR (400 MHz, DMSO- d 6 ): δ 7.84 (s, 1H), 7.30-7.27 (m, 2H), 7.17 (t, J= 9.20 Hz, 2H), 6.50 (s, 1H), 4.51 (s, 2H), 3.98 (s, 2H), 3.78-3.73 (m, 2H), 3.36-3.33 (m, 2H), 2.16 (s, 3H), 1.54-1.50 (m, 1H), 1.38-1.31 (m, 3H), 1.15-0.99 (m, 4H), 0.76-0.74 (m, 6H). LCMS: (Method L) 508.1 (M + -H), Rt. 1.56 min, 99.84% (maximum). HPLC: (Method E) Rt. 5.63 min, 99.26% (maximum). Chiral SFC: (Method S) Rt. 3.27 min, 99.08% (maximum).

[0501] Example 9

[0502] 2-((3,3-Dibutyl-7-(methylthio)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid

[0503] LiOH·H₂O (14 mg, 0.33 mmol) was added to a solution of ethyl 2-((3,3-dibutyl-7-(methylthio)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-yl)methoxy)methoxy)acetate (intermediate 26; 60 mg, 0.11 mmol) in 1,4-dioxane (5 mL) and water (1 mL) under stirring. The reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete (monitored by TLC), the reaction mixture was quenched with dilute HCl (1.5 N, 10 mL), and the aqueous layer was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na₂SO₄. The organic fraction was filtered, concentrated under vacuum, and the crude product was purified by preparative HPLC (Method D) to give the title compound. Yield: 20% (11 mg, off-white solid).

[0504] 1 H-NMR (400 MHz, DMSO- d 6 ): δ 7.85 (s, 1H), 7.30 (t, J = 8.0 Hz, 2H), 7.19 (d,J = 7.2 Hz, 2H), 7.00 (t, J = 7.2 Hz, 1H), 6.59 (s, 1H), 4.48 (s,2H), 4.15 (bs, 1H), 3.76 (bs, 1H), 3.61 (s, 2H), 3.17 (s, 2H), 2.15 (s, 3H),1.56-1.24 (m, 4H), 1.18-0.98 (m, 8H), 0.75 (t, J = 6.40 Hz, 6H). LCMS: (Method A) 518.2 (M + -H), Rt. 1.01 min, 98.96% (maximum). HPLC: (Method B) Rt. 6.33 min, 97.83% (maximum).

[0505] Example 10

[0506] 2-((3-Butyl-3-ethyl-7-(methylthio)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid

[0507] At 0°C, a solution of 10% NaOH in H₂O (0.07 mL, 0.18 mmol) was added to a THF (2 mL) solution of 2-((3-butyl-3-ethyl-7-(methylthio)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiazazacycloheptatrien-8-yl)methoxy)tert-butyl acetate (intermediate 31; 0.1 g, 0.18 mmol) under stirring. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete (monitored by TLC), the reaction mixture was acidified with dilute HCl (1.5 N, 10 mL), and the aqueous layer was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with water (10 mL) and brine (10 mL) and then dried over anhydrous Na₂SO₄. The organic layers were filtered, concentrated under vacuum, and the crude product was purified by preparative HPLC (method C) to give the title compound. Yield: 10.67% (10 mg, grayish-white solid).

[0508] 1 H-NMR (400 MHz, DMSO- d 6): δ 12.75 (s, 1H), 7.68 (s, 1H), 7.47 (bs, 1H), 7.38 (t, J = 7.60 Hz, 2H), 7.29 (d, J = 7.60 Hz, 2H), 7.12 (t, J = 7.20Hz, 1H), 6.45 (s, 1H), 4.49 (s, 2H), 4.09 (s, 2H), 4.01(bs, 2H), 2.08 (s,3H), 1.63-1.62 (m, 2H), 1.50-1.36 (m, 2H), 1.24-1.15 (m, 2H), 0.90-0.88 (m,2H), 0.74-0.62 (m, 6H). LCMS: (Method L) 491.1 (M + -H), Rt. 1.92 min, 95.79% (maximum). HPLC: (Method E) Rt. 5.48 min, 92.77% (maximum).

[0509] Example 11

[0510] (S)-2-((3-Butyl-3-ethyl-7-(methylthio)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiazazazepine-8-yl)methoxy)acetic acid and (R)-2-((3-Butyl-3-ethyl-7-(methylthio)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiazazepine-8-yl)methoxy)acetic acid

[0511] Two enantiomers of racemic 2-((3-butyl-3-ethyl-7-(methylthio)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid (Example 10; 120 mg, 0.244 mmol) were separated by chiral SFC (Method P). The substance was concentrated under vacuum at 40°C. The first elution fraction corresponds to enantiomer 1 and the second elution fraction corresponds to enantiomer 2. The absolute configurations of these two enantiomers are unknown.

[0512] Enantiomer 1: Yield: 33% (40 mg, off-white solid). 1 H-NMR (400 MHz, DMSO- d 6): δ12.74 (bs, 1H), 7.68 (s, 1H), 7.47 (bs, 1H), 7.38 (t, J = 8.0 Hz, 2H), 7.29(d, J = 7.6 Hz, 2H), 7.12 (t, J = 7.2 Hz, 1H), 6.45 (s, 1H), 4.49 (s, 2H), 4.09 (s, 2H), 3.99 (bs, 2H), 2.08 (s, 3H), 1.63-1.36 (m, 4H), 1.24-0.86 (m, 4H), 0.72-0.67 (m, 6H). LCMS: (Method L) 490.8 (M + -2), Rt. 1.91 min, 98.65% (maximum). HPLC: (Method E) Rt. 5.48 min, 98.63% (maximum). Chiral SFC: (Method P) Rt. 3.24 min, 100% (maximum).

[0513] Enantiomer 2: Yield: 31% (38 mg, off-white solid). 1 H-NMR (400 MHz, DMSO- d 6 ): δ12.71 (bs, 1H), 7.68 (s, 1H), 7.47 (bs, 1H), 7.38 (t, J = 8.0 Hz, 2H), 7.29(d, J = 6.8 Hz, 2H), 7.12 (t, J = 7.2 Hz, 1H), 6.45 (s, 1H), 4.49 (s, 2H), 4.09 (s, 2H), 3.99 (bs, 2H), 2.08 (s, 3H), 1.62-1.36 (m, 4H), 1.24-0.86 (m, 4H), 0.72-0.69 (m, 6H), .LCMS:(Method L) 490.8 (M + -2), Rt. 1.92 min, 97.79% (maximum). HPLC: (Method E) Rt. 5.48 min, 98.04% (maximum). Chiral SFC: (Method P) Rt. 4.38 min, 98.85% (maximum).

[0514] Example 12

[0515] 2-((3-Butyl-3-methyl-7-(methylthio)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid

[0516] At 0°C, tert-butyl methoxy)acetate (intermediate 48; 0.3 g, 0.56 mmol) was added dropwise to a solution of 2-((3-butyl-3-methyl-7-(methylthio)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetate (intermediate 48; 0.3 g, 0.56 mmol) in THF (6 mL) and MeOH (2 mL). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete (monitored by TLC), the reaction mixture was acidified with dilute HCl (1.5 N, 15 mL), and the aqueous layer was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with water (10 mL) and brine (10 mL) and dried over anhydrous Na2SO4. The organic layer was filtered, concentrated under vacuum, and the crude product was purified by preparative HPLC (Method C) to obtain the title compound. Yield: 55.3% (15 mg, off-white solid).

[0517] 1 H-NMR (400 MHz, DMSO- d 6 ): δ 12.75 (bs, 1H), 7.73 (s, 1H), 7.50 (bs, 1H), 7.33 (t, J = 7.6 Hz, 2H), 7.25-7.18 (m, 2H), 7.05-7.04 (m, 1H), 6.59 (s,1H), 4.51 (s, 2H), 4.09 (s, 2H), 3.94 (bs, 2H), 2.14 (s, 3H), 1.63-1.51 (m,1H), 1.40-1.36 (m, 2H), 1.24-1.10 (m, 6H), 0.77 (t, J = 6.80 Hz, 3H). LCMS: (Method B) 477.1 (M + -H), Rt. 1.81 min, 97.48% (maximum). HPLC: (Method E) Rt. 5.34 min, 98.93% (maximum).

[0518] Example 13

[0519] (S)-2-((3-Butyl-3-methyl-7-(methylthio)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiazazazepine-8-yl)methoxy)acetic acid and (R)-2-((3-Butyl-3-methyl-7-(methylthio)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiazazepine-8-yl)methoxy)acetic acid

[0520] Two enantiomers of racemic 2-((3-butyl-3-methyl-7-(methylthio)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid (Example 12; 60 mg, 0.125 mmol) were separated by SFC (Method R). The substance was concentrated under vacuum at 40°C. The first elution fraction corresponds to enantiomer 1 and the second elution fraction corresponds to enantiomer 2. The absolute configurations of these two enantiomers are unknown.

[0521] Enantiomer 1: Yield: 23.37% (12 mg, off-white solid). 1 H-NMR (400 MHz, DMSO- d 6 ): δ 12.78 (bs, 1H), 7.73 (s, 1H), 7.50 (s, 1H), 7.33 (t, J = 7.6 Hz, 2H), 7.22-7.21 (m, 2H), 7.10-7.04 (m, 1H), 6.59 (s, 1H), 4.51 (s, 2H), 4.10 (s, 2H), 3.99 (bs, 2H), 2.14 (s, 3H), 1.63-1.36 (m, 3H), 1.15-1.10 (m, 6H), 0.78-0.75 (m, 3H). LCMS: (Method L) 477.1 (M + -H), Rt. 1.03 min, 99.43% (maximum). HPLC: (Method E) Rt. 5.37 min, 99.90% (maximum). Chiral SFC: (Method Y) Rt. 8.42 min, 100% (maximum).

[0522] Enantiomer 2: Yield: 25.2% (36 mg, off-white solid).1 H-NMR (400 MHz, DMSO- d 6 ): δ 12.71 (bs, 1H), 7.68 (s, 1H), 7.47 (s, 1H), 7.38 (t, J = 8.0 Hz, 2H), 7.29(d, J = 6.8 Hz, 2H), 7.12 (t, J = 7.2 Hz, 1H), 6.45 (s, 1H), 4.49 (s, 2H), 4.09 (s, 2H), 3.99 (bs, 2H), 2.08 (s, 3H), 1.62-1.36 (m, 3H), 1.15-0.90 (m, 6H), 0.72-0.69 (m, 3H). LCMS: (Method L) 477.1 (M + -H), Rt. 1.03 min, 99.50% (maximum). HPLC: (Method E) Rt. 5.37 min, 99.93% (maximum). Chiral SFC: (Method Y) Rt. 10.50 min, 98.89% (maximum).

[0523] Example 14

[0524] 2-((3-Butyl-3-ethyl-7-methoxy-5-(4-methoxyphenyl)-1,1-dioxo-2,3,4,5-tetrahydro-1,5-benzothiazazepine-8-yl)methoxy)acetic acid

[0525] At 0°C, a solution of tert-butyl acetate (intermediate 53; 0.05 g, 0.089 mmol) in water (2 mL) and NaOH (0.036 g, 0.089 mmol) was added to a solution of 2-((3-butyl-3-ethyl-7-methoxy-5-(4-methoxyphenyl)-1,1-dioxo-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetate (intermediate 53; 0.05 g, 0.089 mmol) in a mixture of MeOH (2 mL) and THF (3 mL) under stirring. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete (monitored by TLC), the reaction mixture was acidified with dilute HCl (1.5 N, 10 mL), and the aqueous layer was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with water (10 mL) and brine (10 mL) and dried over anhydrous Na₂SO₄. The organic layer was filtered, concentrated under vacuum, and the resulting crude product was purified by preparative HPLC (Method C) to obtain the title compound. Yield: 10.66% (5 mg, off-white solid).

[0526] 1 H-NMR (400 MHz, DMSO- d 6 ): δ 12.87 (s, 1H), 7.78 (s, 1H), 7.25 (d, J =8.8 Hz, 2H), 6.94 (d, J = 8.8 Hz, 2H), 6.10 (s, 1H), 4.46 (s, 2H), 4.07 (s, 2H), 3.72-3.56 (m, 6H), 3.50-3.49 (s, 4H), 1.53-1.52 (m, 1H), 1.38-1.36 (m, 3H), 1.12-0.97 (m, 4H), 0.75-0.66 (m, 6H). LCMS: (Method B) 504.1 (M + -H), Rt. 2.49 min, 98.95% (maximum). HPLC: (Method C) Rt. 9.48 min, 95.93% (maximum).

[0527] Example 15

[0528] (S)-2-((3-Butyl-3-ethyl-7-methoxy-5-(4-methoxyphenyl)-1,1-dioxo-2,3,4,5-tetrahydro-1,5-benzothiazazonyl-8-yl)methoxy)acetic acid and (R)-2-((3-Butyl-3-ethyl-7-methoxy-5-(4-methoxyphenyl)-1,1-dioxo-2,3,4,5-tetrahydro-1,5-benzothiazazonyl-8-yl)methoxy)acetic acid

[0529] Two enantiomers of racemic 2-((3-butyl-3-ethyl-7-methoxy-5-(4-methoxyphenyl)-1,1-dioxo-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid (Example 14; 100 mg, 0.198 mmol) were separated by chiral SFC (Method P). The substance was concentrated under vacuum at 40°C. The first elution fraction corresponds to enantiomer 1 and the second elution fraction corresponds to enantiomer 2. The absolute configurations of these two enantiomers are unknown.

[0530] Enantiomer 1: Yield: 14.94% (15 mg, off-white solid). 1 H-NMR (400 MHz, DMSO- d 6 ): δ 12.71 (s, 1H), 7.78 (s, 1H), 7.26-7.24 (m, 2H), 6.95-6.93 (m, 2H), 6.11 (s, 1H), 4.46 (s, 2H), 4.04 (s, 2H), 3.76 (s, 2H), 3.75 (s, 3H), 3.50 (s,3H), 3.33 (s, 2H), 1.39-1.24 (m, 4H), 1.10-0.97 (m, 4H), 0.75-0.66 (m, 6H).LCMS: (Method O) 504.1 (M + -H), Rt. 5.74 min, 99.56% (maximum). HPLC: (Method F) Rt. 6.58 min, 99.62% (maximum). Chiral SFC: (Method P) Rt. 3.27 min, 100% (maximum).

[0531] Enantiomer 2: Yield: 14.98% (15 mg, off-white solid). 1 H-NMR (400 MHz, DMSO- d 6): δ 12.67 (bs, 1H), 7.78 (s, 1H), 7.27-7.20 (m, 2H), 6.95-6.91 (m, 2H), 6.10 (s, 1H), 4.46 (s, 2H), 4.09 (s, 2H), 3.76 (s, 2H), 3.75 (s, 3H), 3.50(s, 3H), 3.33 (s, 2H), 1.52-1.24 (m, 4H), 1.12-1.07 (m, 4H), 0.75-0.66 (m,6H). LCMS: (Method O) 504.2 (M + -H), Rt. 5.74 min, 99.23% (maximum). HPLC: (Method F) Rt. 6.58 min, 99.85% (maximum). Chiral SFC: (Method P) Rt. 3.87 min, 100% (maximum).

[0532] Bioanalysis

[0533] IBAT (h / m) analysis scheme

[0534] 10,000 cells (human or mouse IBAT-overexpressing cells) were seeded in 200 µL of MEM-α medium (Gibco 12571-063) supplemented with 10% FBS (Gibco10438026) and puromycin (Gibco A1113803) (10 µg / mL) in 96-well plates (Corning CLS3809) and incubated at 37°C in 5% CO2 for 48 h. After incubation, the medium was decanted from the wells and the cells were washed twice with 300 µL of basal MEM-α medium (FBS-free). After each decanting of the basal MEM-α medium, the plate was gently tapped against a paper towel to ensure maximum removal of residual medium.

[0535] The test inhibitor dilution (maximum test concentration 10 µM, 3-fold serial dilution, 10 spots) prepared in DMSO (Sigma D2650) was added to an incubation mixture (maintaining a final DMSO concentration of 0.2%) containing 0.25 µM 3H-taurocholic acid (ARC ART-1368) and 5 µM cold taurocholic acid (Sigma T4009). Then, 50 µL of the incubation mixture containing the test inhibitor was added to each well (in duplicate), and the plate was incubated in a CO2 incubator at 37°C for 20 minutes. After incubation, the reaction was stopped by holding the plate on an ice-water mixture for 2–3 minutes, and the incubation mixture was then completely aspirated from the wells. Wash the wells twice with 250 µL of cooled, unlabeled 1 mM taurine dissolved in (10 mM) HBSS (Gibco 14175079) (pH 7.4) buffered with HEPES (Gibco 15630080). After each wash, gently pat the plate against a paper towel to ensure maximum removal of the blocking buffer.

[0536] 100 µL of MicroScint-20 (PerkinElmer 6013621) was added to the wells and left overnight at room temperature. The board was then read using a PerkinElmer TopCount NXT™ microplate scintillation and luminescence counter according to the 3H test protocol (set to 120 seconds per well).

[0537] LBAT (h / m) analysis scheme

[0538] 20,000 cells (human or mouse LBAT-overexpressing cells) were seeded in 100 µL of MEM-α medium (Gibco 12571-063) supplemented with 10% FBS (Gibco10438026) and containing genistein (Gibco 10131-027) (1 mg / mL) in 96-well plates (Corning CLS3809) and incubated at 37°C in 5% CO2 for 24 h. After incubation, the medium was decanted from the wells and the cells were washed twice with 300 µL of basal MEM-α medium (FBS-free). After each decanting of the basal MEM-α medium, the plate was gently tapped against a paper towel to ensure maximum removal of residual medium.

[0539] For human LBAT, the incubation mixture was prepared by adding the test inhibitor dilution (3-fold serial dilution in DMSO (Sigma D2650), 10 spots) to MEM-α (FBS-free) (maintaining a final DMSO concentration of 0.2%) containing 0.3 µM 3H-taurocholic acid (ARC ART-1368) and 7.5 µM cold taurocholic acid (Sigma T4009). For mouse LBAT, the incubation mixture was prepared by adding the test inhibitor dilution (3-fold serial dilution in DMSO, 10 spots) to MEM-α (FBS-free) (maintaining a final DMSO concentration of 0.2%) containing 0.3 µM 3H-taurocholic acid and 25 µM cold taurocholic acid.

[0540] Next, 50 µL of the incubation mixture containing the test inhibitor was added to each well (in duplicate), and the plate was incubated in a CO2 incubator at 37°C for 20 minutes. After incubation, the reaction was stopped by holding the plate on an ice-water mixture for 2–3 minutes, and then the incubation mixture was completely aspirated from the wells. The wells were washed twice with 250 µL of cooled, unlabeled 1 mM taurine dissolved in (10 mM) HBSS (Gibco 14175079) (pH 7.4) in HEPES (Gibco 15630080) buffer. After each wash, the plate was gently patted against a paper towel to ensure maximum removal of the blocking buffer.

[0541] 100 µL of MicroScint-20 (PerkinElmer 6013621) was added to the well and left overnight at room temperature. The board was then read in a PerkinElmer TopCount NXT™ microboard scintillation and luminescence counter according to the 3H test protocol (set to 120 seconds of reading time per well, normal board orientation).

[0542] Two-way permeability analysis (Caco-2 cells)

[0543] Caco-2 cells (Evotec) were seeded at a density of 70,000 cells / well in Millicell® 24-well insert cell culture plates and maintained in an incubator (37°C, 5% CO2, 95% RH) for 21 days, with the culture medium changed every other day.

[0544] Stock solutions (10 mM) of the test compounds atenolol (a low-permeability marker), propranolol (a high-permeability marker), and digoxin (a substrate for the P-gp transport pathway) were prepared in dimethyl sulfoxide (DMSO). Intermediate stock solutions (1 mM) were prepared by diluting 10 µL of the 10 mM mother stock solution with 90 µL of pure DMSO. Working stock solutions (10 µM) were prepared by diluting 50 µL of the 1 mM intermediate stock solution with 4950 µL of FaSSIF buffer. The compounds were added after FaSSIF, and the samples were subjected to acoustic treatment for 2 hours followed by centrifugation at 4000 RPM for 30 minutes at 37°C. 4 mL of the supernatant was used directly for analysis. The final DMSO concentration in the transport experiments was 1%.

[0545] On the day of analysis, the Caco-2 monolayer was washed twice with transport buffer (HBSS, pH 7.4) and pre-incubated in an incubator for 30 minutes (37°C, 5% CO2, 95% RH). The transepithelial resistance (TEER) of the monolayer was measured using the Millicell®-ERS system. A TEER value exceeding 350 ohms / cm was considered acceptable. 2 Single-cell layers were selected for analysis.

[0546] Analysis was performed along the absorption (A2B) and secretion (B2A) directions. The transport assay was initiated by adding a transport analysis buffer (FaSSIF buffer prepared in HBSS) consisting of the compound to the donor chamber (top chamber AB; basal-side chamber BA) in two copies (n=2) of each well. Drug-free HBSS buffer (pH 7.4) containing 1% bovine serum albumin (BSA) was introduced into the recipient chamber (AB-basal-side chamber; BA-top chamber). The volumes of the top and basal-side chambers were 0.4 mL and 0.8 mL, respectively. After adding the preparation solution, the plates were incubated at 37°C for 120 minutes. After 120 minutes, donor and recipient samples were collected and matrix-matched with the opposite buffer (1:1, 30 µL study sample + 30 µL blank buffer). The sample matrix was then prepared with the opposite buffer (1:1, 30 µL study sample + 30 µL blank buffer). Samples were treated with acetonitrile containing the internal standard (60 µL study sample + 200 µL acetonitrile containing tolbutamide, 500 ng / mL). The samples were vortexed and centrifuged at 4000 rpm for 10 min. The resulting supernatant (100 µL) was diluted with 100 µL of water and transferred to freshly prepared 96-well plates. If applicable, the concentrations of compounds in the samples were analyzed using discovery-grade bioanalytical methods via liquid chromatography-tandem mass spectrometry (LC-MS / MS).

[0547] The average apparent permeability (P) of the compounds atenolol, propranolol and digoxin was tested. app , ×10 -6 The speed (cm / s) is calculated as follows:

[0548] Where dq / dt = transport rate (the rate at which the compound is transported in the acceptor chamber), C0 = initial concentration in the donor chamber, and A = surface area of ​​the effective filter membrane.

[0549] HepaRG-based analysis scheme

[0550] Following the protocol provided by Biopredic International, cryopreserved vials (Biopredic International HPR116080) of differentiated HepaRG cells were thawed in HepaRG thaw / inoculation / universal medium (Biopredic International ADD670C) supplemented with 200 mM glutamine (Gibco35050061). 70,000 cells per well were seeded into 100 µL of HepaRG thaw / inoculation / universal medium supplemented with 200 mM Glutamax in a 96-well plate (Corning CLS3809) and incubated at 37°C in 5% CO2 for 24 hours. After incubation, the inoculation medium was replaced with HepaRG maintenance / metabolism medium (Biopredic International ADD620C) and incubated for 6 days, with fresh HepaRG maintenance / metabolism medium added every 48 hours. Seven days after incubation, the incubation medium was decanted from the wells, and the cells were washed twice with 250 µL of Williams's E Basal Media (Gibco 12551032). After each decanting of Williams's E Basal Media, the plate was gently patted against a paper towel to ensure maximum removal of residual medium.

[0551] The incubation mixture was prepared by adding a 3-fold serial dilution of the test inhibitor (in DMSO (Sigma D2650)) to Williams E medium (basal) containing 0.3 µM 3H-taurocholic acid (ARC ART-1368) and 7.5 µM cold taurocholic acid (Sigma T4009) (maintaining a final DMSO concentration of 0.2%). Then, 50 µL of the incubation mixture containing the test inhibitor was added to each well (in duplicate), and the plates were incubated in a 5% CO2 incubator at 37°C for 30 minutes. After incubation, the reaction was stopped by holding the plates on an ice-water mixture for 2–3 minutes, and the incubation mixture was then completely aspirated from the wells. Wash the wells twice with 250 µL of cooled, unlabeled 1 mM taurine dissolved in (10 mM) HBSS (Gibco 14175079) (pH 7.4) buffered with HEPES (Gibco 15630080). After each wash, gently pat the plate against a paper towel to ensure maximum removal of the blocking buffer.

[0552] 100 µL of MicroScint-20 (PerkinElmer 6013621) was added to the well and left overnight at room temperature. The board was then read in a PerkinElmer TopCount NXT™ microboard scintillation and luminescence counter according to the 3H test protocol (set to 120 seconds of reading time per well, normal board orientation).

[0553] Preparation of diluent for test compounds

[0554] All test compounds were provided in powder form at room temperature. A 10 mM DMSO stock solution of each test compound was prepared, aliquoted, and stored at -20°C. Three-fold serial dilutions in DMSO were prepared from the 10 mM DMSO stock solutions of the compounds, resulting in a total of 10 test compound dilutions. 0.5 µL of this DMSO dilution was added to 250 µL of FBS-free basal medium containing 3H-taurocholic acid and cold taurocholic acid to prepare an incubation mixture.

[0555] Bioavailability study

[0556] Male mice (C57BL / 6 or CD1) aged 8 to 9 weeks or Wistar rats were used. For each test compound, two groups of three animals were used. One group received a single intravenous dose of 1 mg / kg (mediator 100% DMSO) via tail vein, and the other group received a single oral dose of 10 mg / kg via feeding tube. The group receiving the oral dose fasted overnight. Blood samples were collected 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after intravenous administration, and 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after oral administration. Blood samples were obtained from the saphenous vein. 0.2% EDTA was used as the anticoagulant. Samples were analyzed using an LC-MS / MS system, following the development of discovery-level bioanalytical methods for estimating the presence of test compounds in plasma.

[0557] result

[0558] Biological data of the compounds in the examples are shown in Table 2 below.

[0559] Table 2

[0560] PD model: Evaluation of the total bile acid content in male C57BL6 mice by testing compounds.

[0561] The effects of bile acid modulators on bile acid levels were investigated using 8- to 9-week-old C57BL / 6N Tac mice. After quarantine and acclimatization, animals were randomly assigned to x experimental groups based on body weight: (i) a control group and (ii) a group receiving oral administration of the test compound y mg / kg once daily. Animals were treated with the test compound for 7 days. On day 5, animals were isolated in new cages. On day 7, feces were collected from each cage, and blood was subsequently drawn from each animal via the retroorbital route. Animals were euthanized to collect liver and terminal ileum for further analysis. Body weight and food consumption were measured twice weekly. Serum lipid profiles were analyzed from serum samples taken on day 7. Total bile acids in serum were measured from serum samples taken on day 7. Fecal bile excretion was measured from fecal samples taken on day 7. Hepatic expression of CYP7A1 and SHP was quantified from liver samples taken on day 7. Hepatic triglycerides and total cholesterol were analyzed from liver samples taken on day 7.

[0562] Urinary bile acid model: Evaluation of the effect of test compounds on urinary bile acid levels in male C57BL / 6N mice.

[0563] The effects of bile acid modulators on bile acid levels were investigated using 8- to 9-week-old C57BL / 6N Tac mice. After quarantine and acclimatization, animals were randomly assigned to x experimental groups based on body weight: (i) a control group and (ii) a group receiving oral administration of the test compound y mg / kg once daily. Animals were treated with the test compound for 7 days. On day 6, animals were transferred to metabolic cages. On day 7, feces and urine were collected from each metabolic cage, followed by blood collection via the retroorbital route. Animals were euthanized to collect kidneys for further analysis. Body weight was measured twice weekly. Total bile acids in serum were measured in day 7 serum samples. Fecal bile acid excretion was measured in day 7 fecal samples. Urinary bile acid excretion was measured in day 7 samples. Kidney expression of ASBT, OTa, OSTAb, and MRP2 was quantified in day 7 samples.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, (I) in M is -CH2- or -NH-; R 1 and R 2 Each independently is C 1-4 alkyl; R 3 Independently selected from hydrogen, halogen, hydroxyl, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, cyano, nitro, amino N -(C 1-4 alkyl)amino and N,N -two(C) 1-4 alkyl)amino; n is an integer, 1, 2, or 3; R 4 Selected from hydrogen, halogen, cyano, C 1-4 Alkyl, C 3-6 cycloalkyl, C 1-4 Alkoxy, C 3-6 Cycloalkoxy, C 1-4 Alkylthio, C 3-6 cycloalkylthio, C 1-4 alkyl sulfinyl, hydroxy-C 1-4 Alkoxy, hydroxy-C 1-4 Alkylthio, amino N -(C 1-4 alkyl)amino and N,N -two(C) 1-4 alkyl)amino; and R 5A and R 5B Each is independently selected from hydrogen and C. 1-4 Alkyl; or R 5A and R 5B Together with the carbon atoms they are attached to, they form 3- to 5-membered saturated carbon rings.

2. The compound according to claim 1, wherein R 1 It is n-butyl.

3. The compound according to claim 1, wherein R 2 It can be methyl, ethyl, or n-butyl.

4. The compound according to claim 1, wherein R 3 It is either hydrogen or fluorine.

5. The compound according to claim 1, wherein R 4 Selected from C 1-4 Alkoxy, C 1-4 Alkyl thiols, hydroxyl -C 1-4 Alkoxy and hydroxy-C 1-4 Alkylthio group.

6. The compound according to claim 1, wherein R 5A and R 5B Each is hydrogen.

7. The compound according to claim 1, wherein the compound is selected from: 2-((3-Butyl-3-ethyl-5-(4-fluorophenyl)-7-methoxy-1,1-dioxo-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; (S)-2-((3-Butyl-3-ethyl-5-(4-fluorophenyl)-7-methoxy-1,1-dioxo-2,3,4,5-tetrahydro-1,5-benzothiazazatrien-8-yl)methoxy)acetic acid; (R)-2-((3-Butyl-3-ethyl-5-(4-fluorophenyl)-7-methoxy-1,1-dioxo-2,3,4,5-tetrahydro-1,5-benzothiazazatrien-8-yl)methoxy)acetic acid; 2-((3-Butyl-3-ethyl-7-(methylthio)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; (S)-2-((3-Butyl-3-ethyl-7-(methylthio)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazazazetrin-8-yl)methoxy)acetic acid; (R)-2-((3-Butyl-3-ethyl-7-(methylthio)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazazazetrin-8-yl)methoxy)acetic acid; 2-((3-Butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; (S)-2-((3-Butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; (R)-2-((3-Butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; 2-((3-Butyl-3-ethyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxo-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; (S)-2-((3-Butyl-3-ethyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxo-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; (R)-2-((3-Butyl-3-ethyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxo-2,3,4,5-tetrahydro-1,5-benzothiazazatrien-8-yl)methoxy)acetic acid; 2-((3,3-dibutyl-7-(methylthio)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; 2-((3-Butyl-3-ethyl-7-(methylthio)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; (S)-2-((3-Butyl-3-ethyl-7-(methylthio)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; (R)-2-((3-Butyl-3-ethyl-7-(methylthio)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; 2-((3-Butyl-3-methyl-7-(methylthio)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; (S)-2-((3-Butyl-3-methyl-7-(methylthio)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; (R)-2-((3-Butyl-3-methyl-7-(methylthio)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; 2-((3-Butyl-3-ethyl-7-methoxy-5-(4-methoxyphenyl)-1,1-dioxo-2,3,4,5-tetrahydro-1,5-benzothiazazacycloheptatrien-8-yl)methoxy)acetic acid; (S)-2-((3-Butyl-3-ethyl-7-methoxy-5-(4-methoxyphenyl)-1,1-dioxo-2,3,4,5-tetrahydro-1,5-benzothiazazonyl-8-yl)methoxy)acetic acid; and (R)-2-((3-Butyl-3-ethyl-7-methoxy-5-(4-methoxyphenyl)-1,1-dioxo-2,3,4,5-tetrahydro-1,5-benzothiazazatrien-8-yl)methoxy)acetic acid; Or its pharmaceutically acceptable salt.

8. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 7 and one or more pharmaceutically acceptable excipients.

9. The compound according to any one of claims 1 to 7, used as a medicine.

10. The compound according to any one of claims 1 to 7, for the treatment or prevention of cardiovascular diseases or fatty acid metabolism disorders or glucose utilization disorders, such as hypercholesterolemia; fatty acid metabolism disorders; type 1 and type 2 diabetes; complications of diabetes, including cataracts, microvascular and macrovascular diseases, retinopathy, neuropathy, nephropathy and delayed wound healing, tissue ischemia, diabetic foot, arteriosclerosis, myocardial infarction, acute coronary syndrome, unstable angina, stable angina, stroke, peripheral artery occlusion, cardiomyopathy, heart failure, arrhythmia and restenosis; diabetes-related diseases, such as insulin resistance (impaired glucose homeostasis), hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, obesity, dyslipidemia, hyperlipidemia including hypertriglyceridemia, metabolic syndrome (syndrome X), atherosclerosis and hypertension; and for increasing high-density lipoprotein levels.

11. The compound according to any one of claims 1 to 7, for the treatment or prevention of gastrointestinal diseases or disorders, such as constipation (including chronic constipation, functional constipation, chronic idiopathic constipation (CIC), intermittent / occasional constipation, constipation secondary to diabetes, constipation secondary to stroke, constipation secondary to chronic kidney disease, constipation secondary to multiple sclerosis, constipation secondary to Parkinson's disease, constipation secondary to systemic sclerosis, drug-induced constipation, irritable bowel syndrome with constipation (IBS-C), mixed irritable bowel syndrome (IBS-M), functional constipation in children, and opioid-induced constipation); Crohn's disease; primary bile acid malabsorption; irritable bowel syndrome (IBS); inflammatory bowel disease (IBD); ileitis; and reflux diseases and their complications, such as Barrett's esophagus, bile reflux esophagitis, and bile reflux gastritis.

12. A compound according to any one of claims 1 to 7, used for the treatment or prevention of liver diseases or disorders, such as hereditary liver metabolic disorders; congenital errors in bile acid synthesis; congenital bile duct abnormalities; biliary atresia; biliary atresia after Kasai procedure; biliary atresia after liver transplantation; neonatal hepatitis; neonatal cholestasis; hereditary forms of cholestasis; encephalotendinosis xanthoma; secondary BA synthesis deficiency; Zieweger syndrome; cystic fibrosis-associated liver disease; α1-antitrypsin deficiency; Alageri syndrome (ALGS); Bayer syndrome; primary bile acid (BA) synthesis deficiency; progressive familial intrahepatic cholestasis (PFIC), including PFIC-1, PFIC-2, PFIC-3 and nonspecific PFIC, PFIC after bile shunt surgery and PFIC after liver transplantation; benign recurrent intrahepatic cholestasis (BRIC), including BRIC1, BRIC2 and nonspecific BRIC, BRIC after bile shunt surgery and BRIC after liver transplantation. BRIC; Autoimmune hepatitis; Primary biliary cirrhosis (PBC); Liver fibrosis; Nonalcoholic fatty liver disease (NAFLD); Nonalcoholic steatohepatitis (NASH); Portal hypertension; Cholestasis; Down syndrome cholestasis; Drug-induced cholestasis; Intrahepatic cholestasis of pregnancy (jaundice of pregnancy); Intrahepatic cholestasis; Extrahepatic cholestasis; Parenteral nutrition-associated cholestasis (PNAC); Hypophospholipid-associated cholestasis; Lymphedema cholestasis syndrome Syndrome 1 (LSC1); Primary sclerosing cholangitis (PSC); Immunoglobulin G4-associated cholangitis; Primary biliary cholangitis; Cholelithiasis (gallstones); Bile duct stones; Common bile duct stones; Cholelithiasis pancreatitis; Carrolli disease; Malignant tumors of the bile duct; Malignant tumors leading to obstruction of the bile duct tree; Biliary stricture; AIDS-related cholangopathy; Ischemic cholangopathy; Pruritus due to cholestasis or jaundice; Pancreatitis; Chronic autoimmune liver disease leading to progressive cholestasis; Hepatic steatosis; Alcoholic hepatitis; acute fatty liver; fatty liver of pregnancy; Drug-induced hepatitis; iron overload; congenital bile acid synthesis deficiency type 1 (BAS deficiency type 1); drug-induced liver injury (DILI); liver fibrosis; congenital liver fibrosis; cirrhosis; Langerhans cell histiocytosis (LCH); neonatal ichthyosis-sclerosing cholangitis (NISCH); erythropoietic protoporphyria (EPP); idiopathic adult-onset bile duct agenesis (IAD); idiopathic neonatal hepatitis (INH); nonsymptomatic interlobular bile duct agenesis (NS) PILBD; North American Indian childhood cirrhosis (NAIC); hepatic sarcoidosis; amyloidosis; necrotizing enterocolitis; toxicity caused by serum bile acids, including arrhythmias with abnormal serum bile acid distribution patterns (e.g., atrial fibrillation), cirrhosis-related cardiomyopathy ("cholepathic heart disease") and skeletal muscle atrophy associated with cholestatic liver disease; polycystic liver disease; viral hepatitis (including hepatitis A, hepatitis B, hepatitis C, hepatitis D, and hepatitis E); hepatocellular carcinoma (liver cancer); cholangiocarcinoma; bile acid-related gastrointestinal cancers; and cholestasis caused by tumors and vegetations of the liver, bile ducts, and pancreas; or used to enhance corticosteroid therapy for liver diseases.

13. A compound according to any one of claims 1 to 7, for the treatment or prevention of kidney diseases or disorders selected from the following: choleretic nephropathy; chronic kidney disease; hyperbilirubinemia; renal dysfunction due to obstructive jaundice; age-related renal mitochondrial dysfunction; kidney inflammation; acute kidney injury (AKI); renal ischemia / reperfusion injury (IRI); chronic kidney disease (CKD); chronic renal insufficiency; end-stage renal disease (ESRD); proximal tubular injury of the kidney; type 1 hepatorenal syndrome; type 2 hepatorenal syndrome; acute-on-chronic liver disease; glomerular hyperfiltration; polycystic kidney disease (PKD), including autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD); and pruritus due to renal failure; or for the prevention of kidney injury associated with liver disease or kidney injury associated with metabolic diseases.

14. The compound according to any one of claims 1 to 7, for the treatment or prevention of malabsorption syndrome (including abeta-lipoproteinemia, familial hypobeta-lipoproteinemia (FHBL), chylomicron retention disease (CRD), and sitosterolemia); hypervitaminosis and osteosclerosis; and hypertension.

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