Benzothia (di) azepin compounds and their use as bile acid modulators

Abstract

The present invention relates to 1, 5-benzothiazepin and to 1, 2, 5-benzothiazepin derivatives of the formula (I), and to the use thereof. These compounds are bile acid modulators having apical sodium dependent bile acid transporter (ASBT) and / or liver bile acid transporter (LBAT) inhibitory activity. The invention also relates to pharmaceutical compositions comprising these compounds and to the use of these compounds in the treatment of cardiovascular diseases, fatty acid metabolism and glucose utilization disorders, gastrointestinal diseases and liver diseases. # imgabs0 #

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to Indian Patent Application No. 202211038517 filed on July 5, 2022, the disclosure of which is incorporated herein by reference in its entirety. Technical Field

[0003] The present invention relates to 1,5-benzothiazepine and 1,2,5-benzothiadiazepine derivatives of formula (I). These compounds are bile acid regulators with apical sodium-dependent bile acid transporter (ASBT) and / or liver bile acid transporter (LBAT) inhibitory activity. The present invention also relates to pharmaceutical compositions containing these compounds, and the use of these compounds in the treatment of cardiovascular diseases, fatty acid metabolism and glucose utilization disorders, gastrointestinal diseases and liver diseases. Background Art

[0004] Bile acid is a physiological detergent that plays an important role in intestinal absorption and the transport of lipids, nutrients and vitamins. It is also a signaling molecule that activates nuclear receptors and regulates cell signaling pathways of lipid, glucose and energy metabolism. Bile acid is a steroid acid that is synthesized by cholesterol in the liver and stored in the gallbladder in the form of mixed micelles. During digestion, the duodenum triggers the release of hormones that cause gallbladder contraction, thereby releasing bile acid in the small intestine, which enables the absorption of fat-soluble vitamins and cholesterol in the small intestine. When it reaches the ileum, bile acid is reabsorbed from the intestine and secreted into the portal blood, returning to the liver via the portal circulation. Therefore, more than 90% of bile acid recirculates and returns to the liver. These bile acids are then transported through the sinusoidal membrane of the hepatocytes and secreted through the tubular membrane into the bile. In this first pass, 75-90% of bile acid is absorbed by the hepatocytes, completing a round of enterohepatic circulation. The bile acids that escape liver clearance partially enter the systemic circulation, where free bile acids are filtered by the glomeruli, effectively recovered in the proximal tubules and exported back to the systemic circulation. Interestingly, most of the bile acids that cross the tubular membrane and are secreted into bile come from the recycling pool, while less than 10% come from new de novo liver synthesis. A small portion of bile acids that are not reabsorbed in the ileum reach the colon. In the intestinal lumen, primary bile acids are converted into secondary bile acids under the action of intestinal bacteria, mainly via mono- or di-dehydroxylation reactions of the steroid nucleus. Bile acids that escape intestinal absorption are then excreted in the feces.

[0005] Overall, an efficient transport system helps maintain a constant bile acid pool, ensuring sufficiently high levels of conjugated bile acids in the intestine to promote lipid absorption and reduce small intestinal bacterial load. The system also minimizes fecal and urinary bile acid losses and protects the intestinal and hepatobiliary compartments by eliminating potentially cytotoxic detergents (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] It has been found that the regulation of bile acid pool size plays a key role in cholesterol homeostasis by converting cholesterol into bile acids via the liver, which represents the main pathway for the body to eliminate cholesterol. The liver plays a vital role in removing endogenous and exogenous compounds from the body. Normal hepatobiliary secretion and enterohepatic circulation are necessary for the body to eliminate 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] Reabsorption of bile acids in the ileum can be inhibited by apical sodium-dependent bile acid transporter (ASBT) inhibitor compounds. Inhibition of bile acid reabsorption has been reported for the treatment of several diseases, including dyslipidemia, diabetes, obesity, constipation, cholestatic liver disease, nonalcoholic 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, 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.

[0008] Although many ASBT inhibitor compounds have been previously reported, there remains a need for additional bile acid modulating compounds with optimized characteristics in terms of potency, selectivity and bioavailability. DETAILED DESCRIPTION OF THE INVENTION

[0010] It has been found that certain 1,5-benzothiazepine and 1,2,5-benzothiadiazepine derivatives are effective inhibitors of the apical sodium-dependent bile acid transporter (ASBT) and / or the liver bile acid transporter (LBAT) and can be used to treat diseases requiring inhibition of bile acid circulation.

[0011]

[0012] in

[0013] M is -CH 2 -or-NR 6 -;

[0014] R 1 C 1-4 alkyl;

[0015] R 2 Selected from hydrogen and C 1-4 alkyl;

[0016] R 3 are independently selected from hydrogen, halogen, hydroxyl, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, cyano, nitro, amino, N-(C 1-4 Alkyl)amino and N,N-di(C 1-4 Alkyl)amino;

[0017] n is an integer 1, 2 or 3;

[0018] R 4 Selected from hydrogen, halogen, cyano, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyloxy, C 1-4 Alkylthio, C 3-6 Cycloalkylthio, C 1-4 Alkylsulfonyl, C 3-6 Cycloalkylsulfonyl, amino, N-(C 1-4 Alkyl)amino and N,N-di(C 1-4 Alkyl)amino;

[0019] R 5A and R 5B are independently selected from hydrogen, halogen, hydroxyl, C 1-4 Alkyl and C 1-4 Alkoxy; or R 5A and R 5BTogether with the carbon atoms to which they are attached, they form a 3- to 5-membered saturated carbocyclic ring; and

[0020] R 6 Selected from hydrogen and C 1-4 alkyl;

[0021] or a pharmaceutically acceptable salt thereof.

[0022] In some embodiments, R 1 C 2-4 In a preferred embodiment, R 1 It is n-butyl.

[0023] In some embodiments, R 2 In some embodiments, R 2 It is methyl, ethyl or n-butyl.

[0024] In some embodiments, R 3 In a preferred embodiment, n is 1, i.e., the benzene ring is substituted with only one substituent R 3 In another preferred embodiment, R 3 Located in the opposite position.

[0025] In some embodiments, R 4 is selected from the group consisting of fluoro, chloro, bromo, methyl, ethyl, cyclopropyl, methoxy, ethoxy, methylthio, ethylthio, methylsulfonyl, amino, methylamino, and dimethylamino. 4 is methoxy, methylthio, methylsulfonyl or dimethylamino. 4 It is methoxy or methylthio.

[0026] In some embodiments, R 5A and R 5B are independently hydrogen or C 1-4 alkyl, or together with the carbon atom to which they are attached, form a cyclopropyl ring. 5A and R 5B are each independently hydrogen or methyl.

[0027] In some embodiments, R 6 In some embodiments, R 6 It is methyl.

[0028] In a preferred embodiment, the compound of formula (I) is a compound of formula (Ia):

[0029]

[0030] in

[0031] M is selected from -CH 2 -, -NH-, and -NCH 3 -;

[0032] R 1 C 2-4 alkyl;

[0033] R 2 Selected from hydrogen and C 1-4 alkyl;

[0034] R 3 Selected from hydrogen, fluorine, chlorine, bromine, hydroxy, methoxy, amino, methylamino, dimethylamino;

[0035] R 4 is selected from the group consisting of fluorine, chlorine, bromine, methyl, cyclopropyl, methoxy, ethoxy, methylthio, ethylthio, methylsulfonyl, amino, methylamino and dimethylamino;

[0036] R 5A and R 5B are independently hydrogen or C 1-4 alkyl, or together with the carbon atom to which they are attached, form a cyclopropyl ring;

[0037] or a pharmaceutically acceptable salt thereof.

[0038] In another preferred embodiment, the compound of formula (I) is a compound of formula (Ia), wherein

[0039] M is selected from -CH 2 -, -NH- and -N(CH 3 )-;

[0040] R 1 is n-butyl;

[0041] R 2 Selected from hydrogen and C 1-4 alkyl;

[0042] R 3 is selected from hydrogen and fluorine;

[0043] R 4 is methoxy, methylthio, methylsulfonyl or dimethylamino;

[0044] R 5A and R 5B are each independently hydrogen or methyl;

[0045] or a pharmaceutically acceptable salt thereof.

[0046] In one embodiment, the compound of formula (I) is selected from:

[0047] 2-(((3-Butyl-3-ethyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)acetic acid;

[0048] (S)-2-(((3-butyl-3-ethyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)acetic acid;

[0049] (R)-2-(((3-butyl-3-ethyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)acetic acid;

[0050] 2-(((3,3-dibutyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)acetic acid;

[0051] 2-(((3-butyl-3-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)acetic acid;

[0052] (S)-2-(((3-butyl-3-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)acetic acid;

[0053] (R)-2-(((3-butyl-3-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)acetic acid;

[0054] 2-(((3-Butyl-3-ethyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxido-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)acetic acid;

[0055] (S)-2-(((3-butyl-3-ethyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxido-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)acetic acid;

[0056] (R)-2-(((3-butyl-3-ethyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxido-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)acetic acid;

[0057] 2-(((3,3-dibutyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetic acid;

[0058] 2-(((3-Butyl-3-ethyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetic acid;

[0059] (S)-2-(((3-butyl-3-ethyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetic acid;

[0060] (R)-2-(((3-butyl-3-ethyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetic acid;

[0061] 2-(((3-Butyl-2-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetic acid;

[0062] (S)-2-(((3-butyl-2-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetic acid;

[0063] (R)-2-(((3-butyl-2-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetic acid;

[0064] 2-(((3-Butyl-3-ethyl-7-methoxy-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)acetic acid;

[0065] (S)-2-(((3-butyl-3-ethyl-7-methoxy-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)acetic acid;

[0066] (R)-2-(((3-butyl-3-ethyl-7-methoxy-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)acetic acid;

[0067] 2-(((3-Butyl-3-ethyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxido-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)-2-methylpropanoic acid;

[0068] (S)-2-(((3-butyl-3-ethyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxido-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)-2-methylpropanoic acid;

[0069] (R)-2-(((3-butyl-3-ethyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxido-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)-2-methylpropanoic acid;

[0070] 2-(((3,3-dibutyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)-2-methylpropanoic acid;

[0071] 2-(((3-butyl-3-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)-2-methylpropanoic acid;

[0072] (S)-2-(((3-butyl-3-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)-2-methylpropanoic acid;

[0073] (R)-2-(((3-butyl-3-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)-2-methylpropanoic acid;

[0074] 2-(((3-butyl-3-ethyl-2-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetic acid;

[0075] (S)-2-(((3-butyl-3-ethyl-2-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetic acid;

[0076] (R)-2-(((3-butyl-3-ethyl-2-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetic acid;

[0077] 2-(((3,3-dibutyl-2-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetic acid;

[0078] 2-(((3,3-dibutyl-2-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)-2-methylpropanoic acid;

[0079] 2-(((3,3-dibutyl-2-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)-2-methylpropanoic acid;

[0080] 2-(((3-Butyl-3-ethyl-7-methoxy-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)-2-methylpropanoic acid;

[0081] (S)-2-(((3-butyl-3-ethyl-7-methoxy-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)-2-methylpropanoic acid;

[0082] (R)-2-(((3-butyl-3-ethyl-7-methoxy-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)-2-methylpropanoic acid;

[0083] 2-(((3-butyl-7-methoxy-3-methyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)acetic acid;

[0084] (S)-2-(((3-butyl-7-methoxy-3-methyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)acetic acid;

[0085] (R)-2-(((3-butyl-7-methoxy-3-methyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)acetic acid;

[0086] 2-(((3-Butyl-5-(4-fluorophenyl)-7-methoxy-2-methyl-1,1-dioxido-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetic acid;

[0087] (S)-2-(((3-butyl-5-(4-fluorophenyl)-7-methoxy-2-methyl-1,1-dioxido-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetic acid;

[0088] (R)-2-(((3-butyl-5-(4-fluorophenyl)-7-methoxy-2-methyl-1,1-dioxido-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetic acid;

[0089] 2-(((3,3-dibutyl-7-methoxy-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)acetic acid;

[0090] 2-(((3,3-dibutyl-5-(4-fluorophenyl)-7-methoxy-1,1-dioxido-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)acetic acid;

[0091] 2-(((3-Butyl-3-ethyl-5-(4-fluorophenyl)-7-methoxy-1,1-dioxido-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)-2-methylpropanoic acid;

[0092] (S)-2-(((3-Butyl-3-ethyl-5-(4-fluorophenyl)-7-methoxy-1,1-dioxido-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)-2-methylpropanoic acid;

[0093] (R)-2-(((3-butyl-3-ethyl-5-(4-fluorophenyl)-7-methoxy-1,1-dioxido-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)-2-methylpropanoic acid;

[0094] 2-(((3-butyl-7-methoxy-2-methyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetic acid;

[0095] (S)-2-(((3-butyl-7-methoxy-2-methyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetic acid;

[0096] (R)-2-(((3-butyl-7-methoxy-2-methyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetic acid;

[0097] 2-(((3-butyl-7-methoxy-2-methyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)-2-methylpropanoic acid;

[0098] (S)-2-(((3-butyl-7-methoxy-2-methyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)-2-methylpropanoic acid;

[0099] (R)-2-(((3-butyl-7-methoxy-2-methyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)-2-methylpropanoic acid;

[0100] 2-(((3-Butyl-3-ethyl-5-(4-fluorophenyl)-7-methoxy-1,1-dioxido-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)acetic acid;

[0101] (S)-2-(((3-butyl-3-ethyl-5-(4-fluorophenyl)-7-methoxy-1,1-dioxido-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)acetic acid;

[0102] (R)-2-(((3-butyl-3-ethyl-5-(4-fluorophenyl)-7-methoxy-1,1-dioxido-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)acetic acid;

[0103] 2-(((3-butyl-7-methoxy-3-methyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)-2-methylpropanoic acid;

[0104] (S)-2-(((3-butyl-7-methoxy-3-methyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)-2-methylpropanoic acid;

[0105] (R)-2-(((3-butyl-7-methoxy-3-methyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)-2-methylpropanoic acid;

[0106] 2-(((3,3-dibutyl-7-methoxy-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)-2-methylpropanoic acid;

[0107] 2-(((3-Butyl-3-ethyl-7-methoxy-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetic acid;

[0108] (R)-2-(((3-butyl-3-ethyl-7-methoxy-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetic acid;

[0109] (S)-2-(((3-butyl-3-ethyl-7-methoxy-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetic acid;

[0110] 2-(((3-butyl-7-(dimethylamino)-3-ethyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetic acid;

[0111] 2-(((3-butyl-3-ethyl-7-(methylsulfonyl)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetic acid;

[0112] (S)-2-(((3-butyl-3-ethyl-7-(methylsulfonyl)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetic acid;

[0113] (R)-2-(((3-butyl-3-ethyl-7-(methylsulfonyl)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetic acid;

[0114] (R)-2-(((3-butyl-7-(dimethylamino)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetic acid;

[0115] (R)-2-(((3-butyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetic acid;

[0116] (R)-2-(((3-butyl-7-methoxy-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetic acid;

[0117] 2-(((3-butyl-7-(dimethylamino)-3-methyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetic acid;

[0118] 2-(((3-butyl-7-methoxy-3-methyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetic acid; and

[0119] 2-(((3-butyl-3-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetic acid;

[0120] or a pharmaceutically acceptable salt thereof.

[0121] As used herein, the term "halogen" refers to fluorine, chlorine, bromine and iodine.

[0122] As used herein, the term “C 1-6 "Alkyl" refers to a straight or branched chain alkyl group having 1 to 6 carbon atoms, and the term "C 1-4 "Alkyl" refers to a straight or branched chain alkyl group having 1 to 4 carbon atoms. 1-4 Examples of the alkyl group include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

[0123] As used herein, the term “C 3-6 "Cycloalkyl" refers to a monocyclic saturated hydrocarbon ring having 3 to 6 carbon atoms. 3-6 Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0124] As used herein, the term “C 1-4 "Haloalkyl" refers to a straight or branched chain C 1-4 Alkyl in which one or more hydrogen atoms have been replaced by halogen. 1-4 Examples of haloalkyl groups include chloromethyl, fluoroethyl and trifluoromethyl.

[0125] As used herein, the term “C 1-4 Alkoxy" and "C 1-4 "Alkylthio" refers to a straight or branched C 1-4 alkyl.

[0126] As used herein, the term “C 1-4 "Alkylsulfonyl" refers to a sulfonyl (-S(O) 2 -) group is connected to the rest of the molecule by a straight or branched C 1-4 alkyl.

[0127] The term "amino" refers to -NH 2 As used herein, the term "N-(C 1-4 Alkyl)amino" and "N,N-di(C 1-4 "Alkyl)amino" refers to one or two hydrogen atoms connected by a straight or branched C 1-4 Alkyl-substituted amino group. N-(C 1-4Examples of the N,N-di(C 1-4 Examples of the alkyl)amino group include dimethylamino and diethylamino.

[0128] As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms that are useful for human pharmaceutical use and that are generally safe, non-toxic, and neither biologically nor otherwise undesirable.

[0129] As used herein, the term "about" refers to a value or parameter herein, including (and describing) embodiments for that value or parameter itself. For example, a description referring to "about 20" includes a description of "20". Numerical ranges include the values ​​defining the range. In general, 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.

[0130] The 1,5-benzothiazepine and 1,2,5-benzothiadiazepine compounds of formula (I) or their pharmaceutically acceptable salts are inhibitors of apical sodium-dependent bile acid transporters (ASBT inhibitors), inhibitors of liver bile acid transporters (LBAT inhibitors), or inhibitors of both apical sodium-dependent bile acid and liver bile acid transporters (dual ASBT / LBAT inhibitors). Therefore, they are used to treat or prevent conditions, disorders and diseases that require inhibition of bile acid circulation, such as cardiovascular diseases, fatty acid metabolism and glucose utilization disorders, gastrointestinal diseases and liver diseases.

[0131] Cardiovascular disease and disorders of fatty acid metabolism and glucose utilization include, but are not limited to, hypercholesterolemia; disorders of fatty acid metabolism; type 1 and type 2 diabetes; complications of diabetes, including cataracts, microvascular disease and macrovascular disease, retinopathy, neuropathy, nephropathy and delayed wound healing, tissue ischemia, diabetic foot, atherosclerosis, myocardial infarction, acute coronary syndrome, unstable angina, stable angina, stroke, peripheral arterial occlusive disease, cardiomyopathy, heart failure, arrhythmias and vascular 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.

[0132] Gastrointestinal diseases and disorders 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, medication-induced constipation, irritable bowel syndrome with constipation (IBS-C), mixed irritable bowel syndrome (IBS-M), pediatric functional constipation, and opioid-induced constipation); Crohn's disease; primary bile acid malabsorption; irritable bowel syndrome (IBS); inflammatory bowel disease (IBD); ileal inflammation; and reflux disease and its complications, such as Barrett's esophagus (Barrett's esophagus). esophagus), bile reflux esophagitis, and bile reflux gastritis.

[0133] Liver disease as defined herein is any disease in the liver and organs connected thereto, such as the pancreas, portal vein, liver parenchyma, intrahepatic biliary tree, extrahepatic biliary tree, and gallbladder. In some cases, the liver disease is a bile acid-dependent liver disease. Liver diseases and disorders include, but are not limited to, inherited liver metabolic disorders; inborn errors of bile acid synthesis; congenital bile duct anomalies; biliary atresia; post-Kasai biliary atresia; post-liver transplant biliary atresia; neonatal hepatitis; neonatal cholestasis; inherited forms of cholestasis; cerebrotendinous xanthomatosis; secondary BA synthesis defects; Zellweger's syndrome; cystic fibrosis-related liver disease; alpha 1-antitrypsin deficiency; Alagilles syndrome (ALGS); Byler syndrome (Byler syndrome); primary bile acid (BA) synthesis defect; progressive familial intrahepatic cholestasis (PFIC), including PFIC-1, PFIC-2, PFIC-3 and nonspecific PFIC, PFIC after bile shunt and PFIC after liver transplantation; benign recurrent intrahepatic cholestasis (BRIC), including BRIC1, BRIC2 and nonspecific BRIC, BRIC after bile shunt and BRIC after liver transplantation; autoimmune hepatitis; primary biliary cirrhosis (PBC); liver fibrosis; nonalcoholic fatty liver disease (NAFLD); nonalcoholic steatohepatitis (NASH); portal hypertension; cholestasis; Down syndrome cholestasis 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); biliary stones; common bile duct stones; cholelithiasis pancreatitis; Caroli's disease disease); bile duct malignancies; malignancies causing biliary tree obstruction; biliary strictures; AIDS cholangiopathy; ischemic cholangiopathy; pruritus due to cholestasis or jaundice; pancreatitis; chronic autoimmune liver disease causing progressive cholestasis; hepatic steatosis; alcoholic hepatitis; acute fatty liver; fatty liver of pregnancy; drug-induced hepatitis; iron overload; inborn error of bile acid synthesis type 1 (BAS defect type 1); drug-induced liver injury (DILI); hepatic fibrosis; congenital hepatic fibrosis; cirrhosis; Langerhans cell histiocytosis (LCH); neonatal ichthyosis sclerosing cholangitis (NISCH);Erythropoietic protoporphyria (EPP); idiopathic adult-onset bile duct deficiency (IAD); idiopathic neonatal hepatitis (INH); non-symptomatic interlobular bile duct deficiency (NSPILBD); North American Indian childhood cirrhosis (NAIC); hepatic sarcoidosis; amyloidosis; necrotizing enterocolitis; serum bile acid-induced toxicity, including arrhythmias with abnormal serum bile acid profiles (e.g., atrial fibrillation), cardiomyopathy ("cholecardia") associated with cirrhosis, and skeletal muscle atrophy associated with cholestatic liver disease; polycystic liver disease; viral hepatitis (including hepatitis A, B, C, D, and E); hepatocellular carcinoma (liver cancer); bile duct cancer; bile acid-related gastrointestinal cancers; and cholestasis caused by liver, bile duct, and pancreatic tumors and neoplasms. The compounds of formula (I) or pharmaceutically acceptable salts thereof are also useful for augmenting corticosteroid therapy for liver disease. ;

[0134] Other diseases that can be treated or prevented by the compounds of formula (I) or their pharmaceutically acceptable salts include hyperabsorption syndrome (including abetalipoproteinemia, familial hypobetalipoproteinemia (FHBL), chylomicron retention disease (CRD) and sitosterolemia); hypervitaminosis and osteopetrosis; hypertension; glomerular hyperfiltration; polycystic kidney disease (PKD) (including autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD)); and pruritus of renal failure. The compounds are also used in the protection of renal damage associated with liver disease or metabolic disease.

[0135] The transport of bile acids in the human body is controlled by members of the SLC10 solute carrier protein family, especially Na + - Taurocholate cotransporting 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), which is expressed in the apical membrane of ileal epithelial cells, proximal tubular cells, biliary epithelial cells, large bile duct cells and gallbladder epithelial cells. In the liver, bile acids are efficiently extracted from portal blood via the liver bile acid transporter (LBAT) and re-secreted across the tubular membrane via the bile salt export pump (BSEP; gene symbol ABCB11). Reabsorption of bile acids in the ileum is handled by the apical sodium-dependent bile acid transporter (ASBT), which is commonly referred to as the ileal bile acid transporter (IBAT). Both LBAT and ASBT act as sodium-solute cotransporters, moving two or more Na per molecule of solute. + ion.

[0136] Exogenous substances and endogenous substances, including bile acid, are absorbed by the liver from portal blood and secreted in bile via different transporters with individualized substrate specificity. The bile acid conjugated by glycine and the bile acid conjugated by taurine exist in anionic form and cannot pass through the membrane via diffusion, so they are completely dependent on membrane transporters to enter or leave hepatocytes (Kosters and Karpen, Xenobiotica 2008, Vol. 38, pp. 1043-1071). ASBT and LBAT prefer the bile salts conjugated by glycine and taurine to exceed their unconjugated counterparts, and show an affinity for dihydroxy bile salts higher than that for trihydroxy bile salts. Non-bile acid substrates of ASBT have not yet been identified, but LBAT has also been found to transport a variety of steroid sulfates, hormones and exogenous substances.

[0137] In terms of drug inhibition requirements, LBAT is not as thoroughly characterized as ASBT. Dong et al. have identified FDA-approved drugs that inhibit human LBAT and compared LBAT and ASBT inhibition requirements. A series of LBAT inhibition studies were conducted using FDA-approved drugs in conjunction with iterative computational model development. Screening studies identified 27 drugs as novel LBAT inhibitors, including irbesartan (Ki=11.9μM) and ezetimibe (Ki=25.0μM). Common characteristic pharmacophores indicate that two hydrophobes and one hydrogen bond receptor are important for inhibiting LBAT. Of the 72 drugs screened in vitro, a total of 31 drugs inhibited LBAT, while 51 drugs (i.e., more than half) inhibited ASBT. Therefore, despite the existence of inhibitor overlap, ASBT is unexpectedly more permissive to drug inhibition than LBAT, and this may be related to the less pharmacophore features of LBAT (Dong et al., Mol. Pharm. 2013, Vol. 10, pp. 1008-1019).

[0138] Vaz et al. describe the identification of LBAT deficiency as a new inborn error of metabolism with a relatively mild clinical phenotype. The identification of LBAT deficiency confirms that this transporter is the main input system for conjugating bile salts into the liver, and also shows that auxiliary transporters can maintain enterohepatic circulation when it is absent (Vaz et al., Hepatology 2015, Vol. 61, pp. 260-267). These findings support the hypothesis that LBAT inhibition is a safe mechanism of action, because hepatocytes are still likely to absorb the necessary amount of bile acid.

[0139] Liu et al. describe the identification of a novel hypercholanemia associated with homozygosity for the p.Ser267Phe mutation in SLC10A1 (LBAT). The allele frequency of this mutation in the gene SLC10A1 varies in different populations, with the highest incidence occurring in southern China (8% and 12% in Han and Dai Chinese, respectively) and Vietnam (11%). This "hidden" hypercholanemia is believed to affect 0.64% of the southern Han population, 1.44% of the Dai population in China, and 1.21% of the Vietnamese population. Increased levels of conjugated and unconjugated serum BAs were also observed in homozygous individuals. Liu et al. proposed that this finding is most likely due to reduced BA transport from the portal circulation to hepatocytes. This supports the hypothesis that the physiological function of the enterohepatic circulation is not only to recycle bile acids, but also to clear bile acids from the circulation to achieve homeostasis (Karpen and Dawson, Hepatology 2015, Vol. 61, pp. 24-27). Alternatively, the liver may synthesize increased levels of bile acids to compensate for the reduced enterohepatic recycling in the homozygous carrier. Since LBAT also transports unconjugated bile acids, the increase in unconjugated bile acids in this study is not surprising (Liu et al., Scientific Reports 2017, 7:9214, pp. 1-7).

[0140] LBAT has been found to be downregulated in several forms of cholestatic liver injury and cholestasis, whereas ASBT has been found to be downregulated in a variety of gastrointestinal disorders, such as Crohn's disease, primary bile acid malabsorption, inflammatory bowel disease, and ileal inflammation, but upregulated in cholestasis. LBAT also serves as a cellular receptor for viral entry of hepatitis B virus (HBV) and hepatitis D virus (HDV), which in turn are the main causes of liver disease and hepatocellular carcinoma.

[0141] ASBT inhibition has been studied for lowering plasma cholesterol levels and improving insulin resistance, as well as reducing hepatic bile acid load in cholestatic liver disease. In addition, ASBT inhibition has been found to restore normal insulin levels 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.

[0142] Since ASBT is mainly expressed in the ileum (here it is generally referred to as IBAT), ASBT inhibitors do not have to be systemically available. On the other hand, ASBT is also expressed in the proximal tubule cells of the kidney. Therefore, systemically available ASBT inhibitors can also inhibit the reabsorption of bile acids in the kidney. It is believed that this will lead to an increase in bile acid content in urine, and increase the removal of bile acid from the body via urine. Therefore, it is expected that systemically available ASBT inhibitors that play a role not only in the ileum but also in the kidney will lead to a greater reduction in bile acid content than non-systemically available ASBT inhibitors that only play a role in the ileum.

[0143] Compounds with high ASBT inhibitory potency are particularly useful in the treatment of liver diseases causing cholestasis, such as progressive familial intrahepatic cholestasis (PFIC), Alagille syndrome, biliary atresia and nonalcoholic steatohepatitis (NASH).

[0144] Biliary atresia is a rare pediatric liver disease that involves partial or complete obstruction (or even absence) of a large bile duct. This obstruction or absence causes cholestasis, leading to accumulation of bile acids, which damages the liver. In some embodiments, accumulation of bile acids occurs in the extrahepatic bile duct tree. In some embodiments, accumulation of bile acids occurs in the intrahepatic bile duct tree. The current standard of care is the Kasai procedure, which is a surgery to remove the obstructed bile duct and connect a portion of the small intestine directly to the liver. There is currently no approved drug therapy for this disorder.

[0145] Provided herein is a method for treating biliary atresia in an individual in need thereof, 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 administering a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is administered a compound of formula (I) or a pharmaceutically acceptable salt thereof prior to performing a Kasai procedure. In some embodiments, the treatment of biliary atresia reduces the subject's serum bile acid level. In some embodiments, serum bile acid content is determined via, for example, an ELISA enzyme assay or an assay that measures total bile acid, 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 can be reduced, for example, by 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 of biliary atresia includes treatment of pruritus.

[0146] PFIC is a rare genetic disorder that is estimated to affect one in every 50,000 to 100,000 children born worldwide and causes progressive, life-threatening liver disease.

[0147] One manifestation of PFIC is pruritus, which often leads to a severe reduction in quality of life. In some cases, PFIC leads to cirrhosis and liver failure. Current treatments include partial extrabiliary diversion (PEBD) and liver transplantation, however, these options may carry a considerable risk of postoperative complications, as well as psychological and social issues.

[0148] Three alternative gene defects have been identified that are associated with three separate subtypes of PFIC called Type 1, Type 2, and Type 3:

[0149] PFIC type 1, which is sometimes called "Bayer disease," is caused by impaired bile secretion due to mutations in the ATP8B1 gene, which encodes a protein that helps maintain the proper balance of fats called phospholipids in the membranes of bile duct cells. An imbalance in these phospholipids is associated with cholestasis and elevated bile acids in the liver. Subjects affected by PFIC type 1 typically develop cholestasis in the first few months of life and, without surgical treatment, progress to cirrhosis and end-stage liver disease by the end of the first decade of life.

[0150] PFIC type 2, which is sometimes called "Bayer syndrome," is caused by impaired bile salt secretion due to mutations in the ABCB11 gene, which encodes a protein called the bile salt export pump, which moves bile acids out of the liver. Subjects 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.

[0151] PFIC type 3, which usually presents with progressive cholestasis in the first few years of childhood, is caused by mutations in the ABCB4 gene, which encodes a transporter protein that moves phospholipids across cell membranes.

[0152] In addition, mutations in the TJP2 gene, NR1H4 gene, or Myo5b gene have been proposed as causes of PFIC. In addition, 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.

[0153] Exemplary mutations of the ATP8B1 gene or the resulting protein are listed in Tables 2 and 3, where the numbering is based on the human wild-type ATP8B1 protein (e.g., SEQ ID NO: 1) or gene (e.g., SEQ ID NO: 2). Exemplary mutations of the ABCB11 gene or the resulting protein are listed in Tables 4 and 5, where the numbering is based on the human wild-type ABCB11 protein (e.g., SEQ ID NO: 3) or gene (e.g., SEQ ID NO: 4).

[0154] As will be appreciated by those skilled in the art, the amino acid position of a reference protein sequence corresponding to a particular amino acid position of SEQ ID NO: 1 or 3 can be determined by aligning the reference protein sequence with SEQ ID NO: 1 or 3 (e.g., using a software program such as ClustalW2). Changes in these residues (referred to herein as "mutations") may include single or multiple amino acid substitutions, insertions within or flanking the sequence, and deletions within or flanking the sequence. As will be appreciated by those skilled in the art, the nucleotide position of a reference gene sequence corresponding to a particular nucleotide position of SEQ ID NO: 2 or 4 can be determined by aligning the reference gene sequence with SEQ ID NO: 2 or 4 (e.g., using a software program such as ClustalW2). Changes in these residues (referred to herein as "mutations") may include single or multiple nucleotide substitutions, insertions within or flanking the sequence, and deletions within or flanking the sequence. See also Kooistra et al., “KLIFS: A structural kinase-ligand interaction database”, Nucleic Acids Res. 2016, Vol. 44, No. D1, pp. D365-D371, which is incorporated herein by reference in its entirety.

[0155] Typical protein sequence of ATP8B1 (SEQ ID NO: 1) - Uniprot ID O43520

[0156]

[0157] Typical DNA sequence of ATP8B1 (SEQ ID NO: 2)

[0158]

[0159]

[0160] Table 2. Exemplary ATP8B1 mutations

[0161]

[0162]

[0163]

[0164]

[0165]

[0166]

[0167]

[0168]

[0169] Table 3. Selected ATP8B1 mutations associated with PFIC-1

[0170]

[0171]

[0172]

[0173]

[0174] A Mutation "X" indicates an early stop codon

[0175] References in Tables 2 and 3

[0176] 1 Folmer et al., Hepatology. 2009, Vol. 50(5), pp. 1597-1605

[0177] 2 Hsu et al., Hepatol Res. 2009, Vol. 39(6), pp. 625-631

[0178] 3 Alvarez et al., Hum Mol Genet. 2004, Vol. 13(20), pp. 2451-2460

[0179] 4 Davit-Spraul et al., Hepatology 2010, Vol. 51(5), pp. 1645-1655

[0180] 5 Vitale et al., J Gastroenterol. 2018, Vol. 53(8), pp. 945-958

[0181] 6 Klomp et al., Hepatology 2004, Vol. 40(1), pp. 27-38

[0182] 7 Zarenezhad et al., Hepatitis Monthly:2017,vol.17(2);e43500.

[0183] 8Dixon et al., Scientific Reports 2017, Vol. 7, 11823.

[0184] 9 Painter et al., Eur J Hum Genet. 2005, Vol. 13(4), pp. 435-439

[0185] 10 Deng et al., World J Gastroenterol. 2012, Vol. 18(44), pp. 6504-6509

[0186] 11 Giovannoni et al., PLoS One. 2015, Vol. 10(12): e0145021.

[0187] 12 Li et al., Hepatology International 2017, Vol. 11, No. 1, Supp. 1, pp. S180. Abstract No. OP284.

[0188] 13 Togawa et al., Journal of Pediatric Gastroenterology and Nutrition 2018, Vol. 67, Supp. 1, pp. S363. Abstract No. 615.

[0189] 14 Miloh et al., Gastroenterology 2006, Vol. 130, No. 4, Suppl. 2, pp. A759-A760. Conference information: Digestive Disease Week Meeting / 107th Annual Meeting of the American-Gastroenterological-Association. Los Angeles, California, USA, May 19

[0190] 15 et al., Zeitschrift fur Gastroenterologie 2015, Volume 53, Issue 12. Abstract No. A3-27. Conference Information: 32. Jahrestagung der Deutschen Arbeitsgemeinschaft zum Studium der Leber, Düsseldorf, Germany, January 22, 2016 - January 23, 2016

[0191] 16 Mizuochi et al., Clin Chim Acta. 2012, Vol. 413(15-16), pp. 1301-1304

[0192] 17 Liu et al., Hepatology International 2009, Vol. 3, No. 1, pp. 184-185. Abstract No. PE405. Conference Information: 19th Conference of the Asian Pacific Association for the Study of the Liver. Hong Kong, China, February 13, 2009 - February 16, 2009

[0193] 18 McKay et al., Version 2. F1000Res.2013;2:32. DOI:10.12688 / f1000research.2-32.v2

[0194] 19 Hasegawa et al., Orphanet J Rare Dis. 2014, Vol. 9:89

[0195] 20 Stone et al., J Biol Chem. 2012, Vol. 287(49), pp. 41139-51

[0196] 21 Kang et al., J Pathol Transl Med. 2019 May 16. doi:10.4132 / jptm.2019.05.03. [Epub ahead of print]

[0197] 22 Sharma et al., BMC Gastroenterol. 2018, Vol. 18(1), p. 107

[0198] 23 Uegaki et al., Intern Med. 2008, Vol. 47(7), pp. 599-602

[0199] 24 Goldschmidt et al., Hepatol Res. 2016, Vol. 46(4), pp. 306-311

[0200] 25Liu et al., J Pediatr Gastroenterol Nutr. 2010, Vol. 50(2), pp. 179-183

[0201] 26 Jung et al., J Pediatr Gastroenterol Nutr. 2007, Vol. 44(4), pp. 453-458

[0202] 27 Bounford. University of Birmingham. Dissertation Abstracts International, (2016) Volume 75, Issue 1C, Subscription Number: AAI10588329. ProQuest Dissertations & Theses.

[0203] 28 Stolz et al., Aliment Pharmacol Ther. 2019, Vol. 49(9), pp. 1195-1204

[0204] 29 Ivashkin et al., Hepatology International 2016, Vol. 10, No. 1, Supp. SUPPL. 1, pp. S461. Abstract No. LBO-38. Conference Information: 25th Annual Conference of the Asian Pacific Association for the Study of the Liver, APASL 2016. Tokyo, Japan, February 20, 2016 - February 24, 2016

[0205] 30 Blackmore et al., J Clin Exp Hepatol. 2013, Vol. 3(2), pp. 159-161

[0206] 31 Matte et al., J Pediatr Gastroenterol Nutr. 2010, Vol. 51(4), pp. 488-493

[0207] 32 Squires et al., J Pediatr Gastroenterol Nutr. 2017, Vol. 64(3), pp. 425-430

[0208] 33Hayshi et al., EBioMedicine. 2018, Vol. 27, pp. 187-199

[0209] 34 Nagasaka et al., J Pediatr Gastroenterol Nutr. 2007, Vol. 45(1), pp. 96-105

[0210] 35 Wang et al., PLoS One. 2016; Vol. 11(4):e0153114.

[0211] 36 Narchi et al., Saudi J Gastroenterol. 2017, Vol. 23(5), pp. 303-305

[0212] 37 Alashkar et al., Blood 2015, Vol. 126, No. 23. Conference information: 57th Annual Meeting of the American-Society-of-Hematology. Amer Soc Hematol, Orlando, Florida, USA, December 5-8, 2015.

[0213] 38 Ferreira et al., Pediatric Transplantation 2013, Vol. 17, Supp. SUPPL. 1, pp. 99. Abstract No. 239. Conference information: IPTA 7th Congress on Pediatric Transplantation. Warsaw, Poland, July 13, 2013 - July 16, 2013.

[0214] 39 Pauli-Magnus et al., J Hepatol. 2005, Vol. 43(2), pp. 342-

[0215] 357 pages

[0216] 40 Jericho et al., Journal of Pediatric Gastroenterology and Nutrition 2015, Vol. 60(3), pp. 368-374

[0217] 41 van der Woerd et al., PLoS One. 2013, Vol. 8(11): e80553.

[0218] 42 Copeland et al., J Gastroenterol Hepatol. 2013, Vol. 28(3), pp. 560-564

[0219] 43 et al., J Hepatol. 2017, Vol. 67(6), pp. 1253-1264

[0220] 44 Chen et al., Journal of Pediatrics 2002, Vol. 140(1), pp. 119-124

[0221] 45 Jirsa et al., Hepatol Res. 2004, Vol. 30(1), pp. 1-3

[0222] 46 van der Woerd et al., Hepatology 2015, Vol. 61(4), pp. 1382-1391

[0223] In some embodiments, the mutation in ATP8B1 is selected from L127P, G308V, T456M, D554N, F529del, I661T, E665X, R930X, R952X, R1014X, and G1040R.

[0224] Typical protein sequence of ABCB11 (SEQ ID NO:3) - Uniprot ID O95342

[0225]

[0226] Typical DNA sequence of ABCB11 (SEQ ID NO:4)

[0227]

[0228]

[0229]

[0230] Table 4. Exemplary ABCB11 mutations

[0231]

[0232]

[0233]

[0234]

[0235]

[0236]

[0237]

[0238]

[0239]

[0240]

[0241]

[0242]

[0243]

[0244]

[0245]

[0246]

[0247]

[0248]

[0249]

[0250]

[0251] Table 5. Selected ABCB11 mutations associated with PFIC-2

[0252]

[0253]

[0254]

[0255]

[0256]

[0257]

[0258]

[0259]

[0260]

[0261]

[0262]

[0263] A Mutation "X" indicates an early stop codon

[0264] References in Tables 4 and 5

[0265] 1 Noe et al., J Hepatol. 2005, Vol. 43(3), pp. 536-543

[0266] 2 Lam et al., Am J Physiol Cell Physiol. 2007, Vol. 293(5), pp. C1709-16

[0267] 3 Stindt et al., Liver Int. 2013, Vol. 33(10), pp. 1527-1735

[0268] 4 Gao et al., Shandong Yiyao 2012, Vol. 52(10), pp. 14-16

[0269] 5 Strautnieks et al., Gastroenterology. 2008, Vol. 134(4), pp. 1203-1214

[0270] 6 Kagawa et al., Am J Physiol Gastrointest Liver Physiol. 2008, Vol. 294(1), pp. G58-67

[0271] 7 Byrne et al., Hepatology. 2009, Vol. 49(2), pp. 553-567

[0272] 8 Chen et al., J Pediatr. 2008, Vol. 153(6), pp. 825-832

[0273] 9Davit-Spraul et al., Hepatology 2010, Vol. 51(5), pp. 1645-1655

[0274] 10 et al., Sci Rep. 2016, Vol. 6: 24827.

[0275] 11 Lang et al., Pharmacogenet Genomics. 2007, Vol. 17(1), pp. 47-60

[0276] 12 Ellinger et al., World J Gastroenterol. 2017, Vol. 23(29), pp. 5295-5303

[0277] 13 Vitale et al., J Gastroenterol. 2018, Vol. 53(8), pp. 945-958

[0278] 14 Knisely et al., Hepatology. 2006, Vol. 44(2), pp. 478-86

[0279] 15 Ellis et al., Hepatology. 2018, Vol. 67(4), pp. 1531-1545

[0280] 16 Lam et al., J Hepatol. 2006, Vol. 44(1), pp. 240-242

[0281] 17 Varma et al., Hepatology 2015, Vol. 62(1), pp. 198-206

[0282] 18 Treepongkaruna et al., World J Gastroenterol. 2009, Vol. 15(34), pp. 4339-4342

[0283] 19 Zarenezhad et al., Hepatitis Monthly:2017, Vol. 17(2);

[0284] e43500.

[0285] 20Hayashi et al., Hepatol Res. 2016, Vol. 46(2), pp. 192-200

[0286] 21 Guorui et al., Linchuang Erke Zazhi 2013, Vol. 31(10), pp. 905-909

[0287] 22 van Mil et al., Gastroenterology. 2004, Vol. 127(2), pp. 379-384

[0288] 23 Anzivino et al., Dig Liver Dis. 2013, Vol. 45(3), pp. 226-232

[0289] 24 Park et al., World J Gastroenterol. 2016, Vol. 22(20), pp. 4901-4907

[0290] 25 Imagawa et al., J Hum Genet. 2018, Vol. 63(5), pp. 569-577

[0291] 26 Giovannoni et al., PLoS One. 2015, Vol. 10(12): e0145021.

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[0357] 91 U.S. Patent 9,295,677

[0358] In some embodiments, the mutation in ABCB11 is selected from A167T, G238V, V284L, E297G, R470Q, R470X, D482G, R487H, A570T, N591S, A865V, G982R, R1153C, and R1268Q.

[0359] Provided are methods for treating PFIC (e.g., PFIC-1 and PFIC-2) in a subject, comprising analyzing a sample obtained from the subject to determine whether the subject has a mutation associated with PFIC (e.g., ATP8B1, ABCB11, ABCB4, TJP2, NR1H4, or Myo5b mutation), and administering (e.g., specifically or selectively administering) a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject determined to have a mutation associated with PFIC. In some embodiments, the mutation is an ATP8B1 or ABCB11 mutation. For example, a mutation as provided in any one of Tables 2 to 5. In some embodiments, the mutation in ATP8B1 is selected from L127P, G308V, T456M, D554N, F529del, I661T, E665X, R930X, R952X, R1014X, and G1040R. In some embodiments, the mutation in ABCB11 is selected from A167T, G238V, V284L, E297G, R470Q, R470X, D482G, R487H, A570T, N591S, A865V, G982R, R1153C, and R1268Q.

[0360] Also provided is a method for treating PFIC (e.g., PFIC-1 and PFIC-2) in a subject in need thereof, the method comprising: (a) detecting a mutation associated with PFIC (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 mutation associated with PFIC (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. For example, a mutation as provided in any one of Tables 2 to 5. In some embodiments, the mutation in ATP8B1 is selected from L127P, G308V, T456M, D554N, F529del, I661T, E665X, R930X, R952X, R1014X and G1040R. In some embodiments, the mutation in ABCB11 is selected from A167T, G238V, V284L, E297G, R470Q, R470X, D482G, R487H, A570T, N591S, A865V, G982R, R1153C and R1268Q.

[0361] In some embodiments, the subject is determined to have a mutation associated with PFIC in a subject or in a biopsy sample from a subject using any art-recognized test, including next-generation sequencing (NGS). In some embodiments, a test or analysis of a mutation associated with PFIC in a subject or in a biopsy sample from a subject approved by a regulatory agency (e.g., FDA-approved) is used to identify a subject or a subject, or via any of the non-limiting examples of the analysis described herein to determine that the subject has a mutation associated with PFIC. Additional methods for diagnosing PFIC are described in Gunaydin, M. et al., Hepat Med. 2018, Vol. 10, pp. 95-104, which is incorporated herein by reference in its entirety.

[0362] In some embodiments, treatment with PFIC (e.g., PFIC-1 or PFIC-2) reduces serum bile acid content in a subject. In some embodiments, serum bile acid content is determined via, for example, an ELISA enzyme assay or an assay that measures total bile acid, 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 content 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 serum bile acid content prior to administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, treatment of PFIC includes treatment of pruritus.

[0363] Because LBAT is expressed on hepatocytes, LBAT and dual ASBT / LBAT inhibitor substances need to have at least certain bioavailability and free fraction in blood. Because LBAT inhibitor compounds only need to survive from the intestinal tract to the liver, it is expected that the relatively low systemic exposure of such compounds will be sufficient, thereby minimizing the potential risk of any side effect in the rest of the body. It is expected that the inhibition of LBAT and ASBT will have an additive effect at least in reducing intrahepatic bile acid concentration. It is also expected that dual ASBT / LBAT inhibitors may be able to reduce bile acid content without inducing diarrhea, which is sometimes also observed under ASBT inhibitors.

[0364] Compounds with high LBAT inhibitory potency and adequate bioavailability are expected to be particularly useful in the treatment of hepatitis.Compounds with dual ASBT / LBAT inhibitory potency and adequate bioavailability are expected to be particularly useful in the treatment of non-alcoholic steatohepatitis (NASH).

[0365] NASH is a common and serious chronic liver disease that is similar to alcoholic liver disease, but occurs in people who drink little or no alcohol. In NASH patients, fat accumulation in the liver, called non-alcoholic fatty liver disease (NAFLD) or steatosis, and other factors such as high LDL cholesterol and insulin resistance induce chronic inflammation in the liver and may lead to progressive scarring of the tissue, called fibrosis and cirrhosis, ultimately leading to liver failure and death. It has been found that NASH patients have significantly higher total serum bile acid concentrations under fasting conditions (NASH increased 2.2 to 2.4 times) and all postprandial time points (NASH increased 1.7 to 2.2 times) than healthy subjects. These are driven by increases in taurine-conjugated and glycine-conjugated primary and secondary bile acids. NASH patients show greater variability in their fasting and postprandial bile acid profiles. These results indicate that NASH patients are more exposed to bile acids, including more hydrophobic and cytotoxic secondary species, both fasting and postprandial. Increased bile acid exposure may be involved in liver damage 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.

[0366] NAFLD is characterized by hepatic steatosis without secondary causes of hepatic 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 non-alcoholic fatty liver disease (NAFL) and non-alcoholic 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 the presence of ≥5% hepatic steatosis and inflammation of hepatocellular damage (e.g., swelling), with or without any hepatic fibrosis. NASH is also commonly associated with hepatic inflammation and hepatic fibrosis, which can progress to cirrhosis, end-stage liver disease, and hepatocellular carcinoma. Although hepatic fibrosis is not always present in NASH, the severity of fibrosis (when present) may be associated with long-term outcomes.

[0367] There are many methods for assessing and evaluating whether a subject suffers from NAFLD, and if so, assessing and evaluating the severity of the disease, including distinguishing NAFLD as NAFL or NASH. In some embodiments, NAS can be used to assess the severity of NAFLD. In some embodiments, NAS can be used to assess the treatment of NAFLD. In some embodiments, NAS can be determined as described in Kleiner et al., Hepatology. 2005, 41 (6): 1313-1321, which is incorporated herein by reference in its entirety. For a simplified NAS protocol adapted from Kleiner, see, for example, Table 6.

[0368] Table 6. Example of NAFLD Activity Score (NAS) with fibrosis stage

[0369]

[0370]

[0371] In some embodiments, NAS is determined non-invasively, for example, as described in U.S. Application Publication No. 2018 / 0140219, which is incorporated herein by reference in its entirety. In some embodiments, before administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, the NAS of a sample from a subject is determined. In some embodiments, NAS is determined during or after the time period of administering a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, compared to before administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, a NAS score during or after the time period of administering a compound of formula (I) or a pharmaceutically acceptable salt thereof is lower, indicating the treatment of NAFLD (eg, NASH). For example, NAS is reduced by 1, 2, 3, 4, 5, 6 or 7 indicating the treatment of NAFLD (eg, NASH). In some embodiments, after administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, NAS is 7 or less. In some embodiments, during the period of administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, the NAS is 5 or less, 4 or less, 3 or less, or 2 or less. In some embodiments, during the period of administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, the NAS is 7 or less. In some embodiments, during the period of administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, the NAS is 5 or less, 4 or less, 3 or less, or 2 or less. In some embodiments, after the period of administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, the NAS is 7 or less. In some embodiments, after the period of administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, the NAS is 5 or less, 4 or less, 3 or less, or 2 or less.

[0372] Other methods of assessing and evaluating NASH in a subject include determining liver steatosis (e.g., fat accumulation in the liver); liver inflammation; one or more of biomarkers (e.g., serum markers and panels) indicative of one or more of liver damage, liver inflammation, liver fibrosis, and / or cirrhosis. Other examples of physiological indicators of NASH may include liver morphology, liver stiffness, and the size or weight of a subject's liver.

[0373] In some embodiments, NASH in a subject is demonstrated by the accumulation of liver fat and the detection of biomarkers indicative of liver damage. For example, elevated serum ferritin and low titers of serum autoantibodies can be common features of NASH.

[0374] In some embodiments, methods of assessing NASH include magnetic resonance imaging, quantification of steatosis via spectroscopy or via proton density fat fraction (MRI-PDFF), transient elastography Hepatic venous pressure gradient (HPVG), liver stiffness measurement using MRE to diagnose significant liver fibrosis and / or cirrhosis, and to assess the histological features of liver biopsies. In some embodiments, magnetic resonance imaging is used to detect one or more of steatosis hepatitis (NASH-MRI), liver fibrosis (Fibro-MRI), and steatosis. See, e.g., U.S. Application Publication Nos. 2016 / 146715 and 2005 / 0215882, each of which is incorporated herein by reference in its entirety.

[0375] In some embodiments, the treatment of NASH may include a reduction in one or more symptoms associated with NASH in a subject after administration of one or more doses of a compound of Formula (I) or a pharmaceutically acceptable salt thereof; a reduction in the amount of liver steatosis; a reduction in NAS; a reduction in liver inflammation; a reduction in the level of a biomarker indicative of one or more of liver damage, 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.

[0376] In some embodiments, treatment of NASH comprises a reduction in one or more symptoms associated with NASH in a subject. Exemplary symptoms may include one or more of an enlarged liver, fatigue, right upper quadrant pain, abdominal swelling, enlarged blood vessels just below the surface of the skin, enlarged male breasts, enlarged spleen, red palms, jaundice, and pruritus. In some embodiments, the subject is asymptomatic. In some embodiments, the subject's total weight does not increase. In some embodiments, the subject's total weight decreases. In some embodiments, the subject's body mass index (BMI) does not increase. In some embodiments, the subject's body mass index (BMI) decreases. In some embodiments, the subject's waist-to-hip (WTH) ratio does not increase. In some embodiments, the subject's waist-to-hip (WTH) ratio decreases.

[0377] In some embodiments, treatment of NASH can be assessed by measuring liver steatosis. In some embodiments, treatment of NASH comprises reducing liver steatosis after administration of a compound of Formula (I) as described herein or a pharmaceutically acceptable salt thereof. In some embodiments, liver steatosis is determined by one or more methods selected from the group consisting of ultrasonography, computed tomography (CT), magnetic resonance imaging, magnetic resonance spectroscopy (MRS), magnetic resonance elastography (MRE), transient elastography (TE) (e.g. ), measuring liver size or weight, or via liver biopsy (see, e.g., Di Lascio et al., Ultrasound Med Biol. 2018, Vol. 44(8), pp. 1585-1596; Lv et al., J Clin Transl Hepatol. 2018, Vol. 6(2), pp. 217-221; Reeder et al., J MagnReson Imaging. 2011, Vol. 34(4), spcone; and de Lédinghen V et al., J Gastroenterol Hepatol. 2016, Vol. 31(4), pp. 848-855, each of which is incorporated herein by reference in its entirety). A subject diagnosed with NASH may have greater than about 5% hepatic steatosis, e.g., greater than about 5% to about 25%, about 25% to about 45%, about 45% to about 65%, or greater than about 65% hepatic steatosis. In some embodiments, a subject with greater than about 5% to about 33% liver steatosis has stage 1 liver steatosis, a subject with about 33% to about 66% liver steatosis has stage 2 liver steatosis, and a subject with greater than about 66% liver steatosis has stage 3 liver steatosis.

[0378] In some embodiments, the amount of hepatic steatosis is determined before administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the amount of hepatic steatosis is determined during or after a period of administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, a reduction in the amount of hepatic steatosis during or after a period of administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as compared to before administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof, indicates treatment of NASH. For example, a reduction in the amount of hepatic steatosis by about 1% to about 50%, about 25% to about 75%, or about 50% to about 100% indicates treatment of NASH. In some embodiments, a decrease in the amount of hepatic steatosis by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% is indicative of treatment of NASH.

[0379] In some embodiments, the presence of liver inflammation is determined via one or more methods selected from the following: biomarkers indicating liver inflammation and liver biopsy samples from subjects. In some embodiments, the severity of liver inflammation is determined by liver biopsy samples from subjects. For example, liver inflammation in liver biopsy samples can be assessed as described in Kleiner et al., Hepatology 2005, Vol. 41 (6), pp. 1313-1321 and Brunt et al., Am J Gastroenterol 1999, Vol. 94, pp. 2467-2474, each of which is hereby incorporated by reference in its entirety. In some embodiments, the severity of liver inflammation is determined before administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the severity of liver inflammation is determined during or after the time period of administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, a decrease in the severity of liver inflammation during or after the period of time of administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, as compared to before administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, indicates treatment of NASH. For example, a decrease in the severity of liver inflammation of about 1% to about 50%, about 25% to about 75%, or about 50% to about 100% indicates treatment of NASH. In some embodiments, a decrease in the severity of liver inflammation of about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% indicates treatment of NASH.

[0380] In some embodiments, treatment of NASH comprises treatment of fibrosis and / or cirrhosis, such as reduction in severity of fibrosis, no further progression of fibrosis and / or cirrhosis, or slowed progression of fibrosis and / or cirrhosis. In some embodiments, the presence of fibrosis and / or cirrhosis is determined by one or more methods selected from the following: transient elastography (e.g. ), non-invasive markers of liver fibrosis, and histological features of liver biopsies. In some embodiments, the severity of fibrosis (e.g., stage) is determined by one or more methods selected from the following: transient elastography (e.g., ), fibrosis scoring system, biomarkers of liver fibrosis (e.g., non-invasive biomarkers) and hepatic venous pressure gradient (HVPG). Non-limiting examples of fibrosis scoring systems include NAFLD fibrosis scoring system (see, e.g., Angulo et al., Hepatology 2007, Vol. 45(4), pp. 846-54), Brunt et al., Am. J. Gastroenterol. 1999, Vol. 94, pp. 2467-2474, Kleiner et al., Hepatology 2005, Vol. 41(6), pp. 1313-1321, and ISHAK fibrosis scoring system (see Ishak et al., J. Hepatol. 1995, Vol. 22, pp. 696-699), each of which is incorporated herein by reference in its entirety.

[0381] In some embodiments, the severity of fibrosis is determined before administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the severity of fibrosis is determined during or after the time period of administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the severity of fibrosis is reduced during or after the time period of administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof, indicating the treatment of NASH. In some embodiments, the severity of fibrosis is reduced, fibrosis and / or cirrhosis is not further advanced, or the progression of fibrosis and / or cirrhosis is slowed, indicating the treatment of NASH. In some embodiments, a scoring system is used, such as any one of the fibrosis scoring systems described herein to determine the severity of fibrosis, for example, a score may indicate the stage of fibrosis, such as stage 0 (no fibrosis), stage 1, stage 2, stage 3, and stage 4 (cirrhosis) (see, for example, Kleiner et al.). In some embodiments, the reduction in the stage of fibrosis is a reduction in the severity of fibrosis. For example, the reduction in stage 1, 2, 3, or 4 is a reduction in the severity of fibrosis. In some embodiments, a decrease in stage, e.g., from stage 4 to stage 3, from stage 4 to stage 2, from stage 4 to stage 1, from stage 4 to stage 0, from stage 3 to stage 2, from stage 3 to stage 1, from stage 3 to stage 0, from stage 2 to stage 1, from stage 2 to stage 0, or from stage 1 to stage 0, indicates treatment of NASH. In some embodiments, the stage of fibrosis is decreased from stage 4 to stage 3, from stage 4 to stage 2, from stage 4 to stage 1, from stage 4 to stage 0, from stage 3 to stage 2, from stage 3 to stage 1, from stage 3 to stage 0, from stage 2 to stage 1, from stage 2 to stage 0, or from stage 1 to stage 0 after administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, compared to before administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the stage of fibrosis decreases from stage 4 to stage 3, from stage 4 to stage 2, from stage 4 to stage 1, from stage 4 to stage 0, from stage 3 to stage 2, from stage 3 to stage 1, from stage 3 to stage 0, from stage 2 to stage 1, from stage 2 to stage 0, or from stage 1 to stage 0 during the period of time during which the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered, compared to before the administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the stage of fibrosis decreases from stage 4 to stage 3, from stage 4 to stage 2, from stage 4 to stage 1, from stage 4 to stage 0, from stage 3 to stage 2, from stage 3 to stage 1, from stage 3 to stage 0, from stage 2 to stage 1, from stage 2 to stage 0, or from stage 1 to stage 0 after the administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, compared to before the administration of the compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0382] In some embodiments, the presence of NASH is determined by one or more biomarkers indicating liver damage, inflammation, liver fibrosis and / or liver cirrhosis, or a scoring system thereof. In some embodiments, the severity of NASH is determined by one or more biomarkers indicating liver damage, inflammation, liver fibrosis and / or liver cirrhosis, or a scoring system thereof. The content of the biomarker can be determined by, for example, measuring, quantifying and monitoring the expression of the gene or mRNA encoding the biomarker and / or the peptide or protein of the biomarker. Non-limiting examples of biomarkers indicative of one or more of liver damage, inflammation, liver fibrosis and / or cirrhosis and / or their scoring systems include aspartate aminotransferase (AST) to platelet ratio index (APRI); aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio (AAR); FIB-4 score, which is based on APRI, alanine aminotransferase (ALT) level and subject age (see, e.g., McPherson et al., Gut 2010, Vol. 59(9), pp. 1265-9, which is incorporated herein by reference in its entirety); hyaluronic acid; proinflammatory cytokines; a panel of biomarkers consisting of α2-macroglobulin, haptoglobin, apolipoprotein A1, bilirubin, gamma glutamyl transpeptidase (GGT) combined with the subject's age and sex to generate a measure of fibrotic and necroinflammatory activity in the liver (e.g., ), a panel of biomarkers consisting of bilirubin, gamma-glutamyl transferase, hyaluronic acid, α2-macroglobulin combined with the age and sex of the subjects (e.g. See, e.g., Adams et al., Clin. Chem. 2005, Vol. 51(10), pp. 1867-1873), and a panel of biomarkers consisting of tissue inhibitor of metalloproteinase-1, hyaluronic acid, and α2-macroglobulin (e.g. ); a panel of biomarkers consisting of tissue inhibitor of metalloproteinase 1 (TIMP-1), amino-terminal propeptide of type III procollagen (PIIINP), and hyaluronic acid (HA) (e.g., enhanced liver fibrosis (ELF) score, see, e.g., Lichtinghagen R et al., J Hepatol. 2013 Aug;59(2):236-42, which is incorporated herein by reference in its entirety). In some embodiments, the presence of fibrosis is scored via the FIB-4, a panel of biomarkers consisting of α2-macroglobulin, haptoglobin, apolipoprotein A1, bilirubin, gamma glutamyl transpeptidase (GGT) combined with the age and sex of the subject to generate a measure of fibrotic and necroinflammatory activity in the liver (e.g., ), a panel of biomarkers consisting of bilirubin, gamma-glutamyl transferase, hyaluronic acid, α2-macroglobulin combined with the age and sex of the subjects (e.g. See, e.g., Adams et al., Clin. Chem. 2005, Vol. 51(10), pp. 1867-1873), and a panel of biomarkers consisting of tissue inhibitor of metalloproteinase-1, hyaluronic acid, and α2-macroglobulin (e.g. ); and a panel of biomarkers consisting of tissue inhibitor of metalloproteinase 1 (TIMP-1), amino-terminal propeptide of type III procollagen (PIIINP), and hyaluronic acid (HA), such as enhanced liver fibrosis (ELF) score, one or more of which are determined.

[0383] In some embodiments, the level of aspartate aminotransferase (AST) is not increased. In some embodiments, the level of aspartate aminotransferase (AST) is reduced. In some embodiments, the level of alanine aminotransferase (ALT) is not increased. In some embodiments, the level of alanine aminotransferase (ALT) is reduced. In some embodiments, the "level" of an enzyme refers to the concentration of the enzyme, such as in the blood. For example, the level of AST or ALT can be expressed as units / L.

[0384] In some embodiments, the severity of fibrosis is assessed by the FIB-4 score, a panel of biomarkers consisting of α2-macroglobulin, haptoglobin, apolipoprotein A1, bilirubin, gamma glutamyl transpeptidase (GGT) combined with the age and sex of the subject to generate a measure of fibrotic and necroinflammatory activity in the liver (e.g. ), a panel of biomarkers consisting of bilirubin, gamma-glutamyl transferase, hyaluronic acid, α2-macroglobulin combined with the age and sex of the subjects (e.g. See, e.g., Adams et al., Clin. Chem. 2005, Vol. 51(10), pp. 1867-1873, which is incorporated herein by reference in its entirety), and a panel of biomarkers consisting of tissue inhibitor of metalloproteinase-1, hyaluronic acid, and α2-macroglobulin (e.g. ); and a panel of biomarkers consisting of tissue inhibitor of metalloproteinase 1 (TIMP-1), amino-terminal propeptide of type III procollagen (PIIINP), and hyaluronic acid (HA), such as enhanced liver fibrosis (ELF) score, one or more of which are determined.

[0385] In some embodiments, liver inflammation is determined by the level of liver inflammation biomarkers (e.g., proinflammatory cytokines). Non-limiting examples of biomarkers indicative of liver inflammation include interleukin-(IL) 6, interleukin-(IL) 1β, tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β, monocyte chemoattractant protein (MCP)-1, C-reactive protein (CRP), PAI-1, and collagen subtypes such as Col1a1, Col1a2, and Col4a1 (see, e.g., Neuman et al., Can. J. Gastroenterol. Hepatol. 2014, Vol. 28 (11), pp. 607-618 and U.S. Pat. No. 9,872,844, each of which is incorporated herein by reference in its entirety). Liver inflammation can also be assessed by changes in macrophage infiltration, such as measuring changes in CD68 expression. In some embodiments, liver inflammation can be determined by measuring or monitoring serum or circulating levels of one or more of interleukin-(IL)6, interleukin-(IL)1β, tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β, monocyte chemoattractant protein (MCP)-1, and C-reactive protein (CRP).

[0386] In some embodiments, before administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, the level of one or more biomarkers indicating liver damage, inflammation, liver fibrosis and / or liver cirrhosis in a sample from a subject is determined. In some embodiments, during or after the period of administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof, the level of one or more biomarkers indicating liver damage, inflammation, liver fibrosis and / or liver cirrhosis is determined. In some embodiments, a decrease in the level of one or more biomarkers indicating liver damage, inflammation, liver fibrosis and / or liver cirrhosis during or after the period of administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as compared to before administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof, indicates treatment of NASH. For example, a decrease in the level of one or more biomarkers indicative of one or more of liver damage, inflammation, liver fibrosis, and / or cirrhosis by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 99% is indicative of treatment of NASH. In some embodiments, after administration of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, the level of one or more biomarkers indicative of one or more of liver damage, inflammation, liver fibrosis and / or cirrhosis is reduced by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 99%. In some embodiments, the levels of one or more biomarkers indicative of one or more of liver damage, inflammation, liver fibrosis and / or cirrhosis are reduced by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 99% during the period of administration of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.In some embodiments, the levels of one or more biomarkers indicative of one or more of liver damage, inflammation, liver fibrosis and / or cirrhosis are reduced by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 99% over a period of time following administration of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0387] In some embodiments, treatment of NASH reduces the serum bile acid content of the subject. In some embodiments, serum bile acid content is determined via, for example, an ELISA enzyme assay or an assay that measures total bile acid, 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 content may be reduced by, for example, 10% to 40%, 20% to 50%, 30% to 60%, 40% to 70%, 50% to 80%, or more than 90% of the serum bile acid content before administration of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, NASH is NASH associated with cholestasis. In cholestasis, the release of bile (including bile acid) from the liver is blocked. Bile acids can cause liver cell damage (see, e.g., 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, e.g., 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, subjects with NASH with cholestasis suffer from pruritus.

[0388] Exemplary biomarkers for NASH are provided in Table 7.

[0389] Table 7. Exemplary NASH biomarkers

[0390] Liver fibrosis biomarkers

[0391] Aspartate aminotransferase (AST) to platelet ratio index (APRI)

[0392] Aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio (AAR)

[0393] FIB-4 Scoring 1

[0394] Hyaluronic acid

[0395] Pro-inflammatory cytokines

[0396] A panel of proteins, including α2-macroglobulin, haptoglobin, apolipoprotein A1, bilirubin, gamma glutamyl transpeptidase (GGT), combined with the age and sex of the subject, to generate a measure of fibrotic and necroinflammatory activity in the liver (e.g. )

[0397] A panel of factors combined with the age and sex of the subjects included bilirubin, gamma-glutamyl transferase, hyaluronic acid, α2-macroglobulin (e.g. )

[0398] These include tissue inhibitor of metalloproteinase-1, hyaluronic acid, and α2-macroglobulin (e.g. )

[0399] These include tissue inhibitor of metalloproteinase 1 (TIMP-1), amino-terminal propeptide of type III procollagen (PIIINP), and hyaluronic acid (HA) (e.g., enhanced liver fibrosis (ELF) score) 3 )

[0400] Biomarkers of liver inflammation 4,5

[0401] Interleukin-6

[0402] Interleukin-1β

[0403] Tumor necrosis factor (TNF)-α

[0404] Transforming Growth Factor (TGF)-β

[0405] Monocyte chemoattractant protein (MCP)-1

[0406] C-reactive protein (CRP)

[0407] PAI-1

[0408] Collagen subtypes (e.g. Col1a1, Col1a2, and Col4a1)

[0409] Changes in macrophage infiltration (e.g. changes in CD68 expression)

[0410] References in Table 7

[0411] 1 McPherson et al., Gut. 2010, Vol. 59(9), pp. 1265-1269.

[0412] 2 Adams et al., Clin Chem. 2005, Vol. 51(10), pp. 1867-1873.

[0413] 3 Lichtinghagen et al., J Hepatol. 2013, Vol. 59(2), pp. 236-242.

[0414] 4 Neuman et al., Can J Gastroenterol Hepatol. 2014, Vol. 28(11), pp. 607-618.

[0415] 5 U.S. Patent No. 9,872,844

[0416] Some formula (I) compounds or their pharmaceutically acceptable salts can show higher free fractions in blood 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%.

[0417] Some formula (I) compounds or their pharmaceutically acceptable salts can 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%.

[0418] After being absorbed by the intestine, some compounds of formula (I) or their pharmaceutically acceptable salts may circulate via the enterohepatic circulation. In some embodiments, the fraction of compounds circulating via the 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%.

[0419] Some compounds of formula (I) or pharmaceutically acceptable salts thereof can cause the kidney to secrete bile salts. In some embodiments, the fraction of circulating bile acids secreted by the kidney 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%.

[0420] Some compounds of Formula (I) or pharmaceutically acceptable salts thereof may exhibit improved or optimal permeability. Permeability can be measured in Caco2 cells and values ​​are given as apparent permeability (Papp) values ​​in cm / second. In some embodiments, the permeability is greater than at least about 0.1×10 -6 cm / sec, such as greater than about 0.2×10 -6 cm / sec, such as greater than about 0.4×10 - 6 cm / sec, such as greater than about 0.7×10 -6 cm / sec, such as greater than about 1.0×10 -6 cm / sec, such as greater than about 2×10 -6 cm / sec, such as greater than about 3×10 -6 cm / sec, such as greater than about 5×10 -6 cm / sec, such as greater than about 7×10 -6 cm / sec, such as greater than about 10×10 -6 cm / sec, such as greater than about 15×10 -6 cm / sec.

[0421] Some compounds of formula (I) or their pharmaceutically acceptable salts may show improved or optimal bioavailability. In some embodiments, the 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, the 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%.

[0422] Some compounds of formula (I) or pharmaceutically acceptable salts thereof may be substrates for relevant transport proteins in the kidney.

[0423] Some compounds of formula (I) or pharmaceutically acceptable salts thereof can produce bile acid concentrations in the intestine, liver and serum that do not cause adverse gastrointestinal effects.

[0424] Some compounds of formula (I) or pharmaceutically acceptable salts thereof can reduce the bile acid concentration in the liver without causing gastrointestinal disorders such as diarrhea.

[0425] As used herein, the term "treatment / treat / treating" refers to reversing, alleviating a disease or disorder as described herein or one or more symptoms thereof, delaying its onset or inhibiting its progression. In some embodiments, treatment may be administered after one or more symptoms have occurred. In other embodiments, treatment may be administered in the absence of symptoms. 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 hereditary or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.

[0426] Suitable pharmaceutically acceptable salts of the compounds of the invention are, for example, base addition salts of the compounds of the invention which are sufficiently acidic, 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 providing physiologically acceptable cations, for example salts with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

[0427] 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 the present invention encompasses all such optical isomers, diastereomers and geometric isomers having ASBT and / or LBAT inhibitory activity. The present invention also encompasses any and all tautomeric forms of compounds of formula (I) or pharmaceutically acceptable salts thereof having ASBT and / or LBAT inhibitory activity. Certain compounds of formula (I) or pharmaceutically acceptable salts thereof may exist in unsolvated as well as solvated forms, such as hydrated forms. It should be understood that the present invention encompasses all such solvated forms having ASBT and / or LBAT inhibitory activity.

[0428] 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. Excipients may, for example, include fillers, binders, disintegrants, glidants and lubricants. In general, pharmaceutical compositions can be prepared in a conventional manner using conventional excipients.

[0429] 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.

[0430] Examples of suitable binders 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 hypromellose), 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 (povidone)).

[0431] Examples of suitable disintegrants include, but are not limited to, dry starch, modified starches (such as (partially) pregelatinized starch, sodium starch glycolate and sodium carboxymethyl starch), alginic acid, cellulose derivatives (such as sodium carboxymethylcellulose, hydroxypropylcellulose and low-substituted hydroxypropylcellulose (L-HPC)), and cross-linked polymers (such as carboxymethylcellulose, cross-linked sodium carboxymethylcellulose, calcium carboxymethylcellulose and cross-linked PVP (crospovidone)).

[0432] Examples of suitable glidants and lubricants include, but are not limited to, talc, magnesium stearate, calcium stearate, stearic acid, glyceryl behenate, colloidal silicon dioxide, aqueous silicon dioxide, synthetic magnesium silicate, finely divided silicon dioxide, starch, sodium lauryl sulfate, boric acid, magnesium oxide, waxes (such as carnauba wax), hydrogenated oils, polyethylene glycol, sodium benzoate, polyethylene glycol, and mineral oil.

[0433] The pharmaceutical composition may be conventionally coated with one or more coating layers. Enteric coating layers or coating layers for delayed or targeted release of the compound of formula (I) or a pharmaceutically acceptable salt thereof are also contemplated. The coating layer may comprise one or more coating agents and may optionally comprise a plasticizer and / or a pigment (or colorant).

[0434] Examples of suitable coating agents include, but are not limited to, cellulose-based polymers (such as ethylcellulose, hydroxypropyl methylcellulose (or hypromellose), hydroxypropyl cellulose, cellulose acetate phthalate, cellulose acetate succinate, hydroxypropyl methylcellulose succinate acetate, and hydroxypropyl methylcellulose 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, and polyacrylic acid / polymethacrylic acid copolymers.

[0435] Examples of suitable plasticizers include, but are not limited to, triethyl citrate, glyceryl triacetate, tributyl citrate, diethyl phthalate, acetyl tributyl citrate, dibutyl phthalate, dibutyl sebacate, and polyethylene glycol.

[0436] Examples of suitable pigments include, but are not limited to, titanium dioxide, iron oxides (such as yellow, brown, red or black iron oxides), and barium sulfate.

[0437] 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 a tablet or capsule.

[0438] The dosage required for therapeutic or prophylactic treatment will depend on the route of administration, the severity of the disease, the age and weight of the patient and other factors normally considered by the attending physician when determining the appropriate regimen and dosage level for a particular patient.

[0439] The amount of the compound to be administered is different for the treated patient, and can vary between about 1 μg to about 50 mg per kg of body weight per day. Unit dosage forms such as tablets or capsules will generally contain about 1 to about 250 mg of 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 in a single dose form or divided into one, two, three or more unit doses. The daily dose of the bile acid regulator for oral administration is preferably in about 0.1 to about 250 mg, more preferably in about 1 to about 100 mg, such as in about 1 to about 5 mg, such as in about 1 to about 10 mg, such as in about 1 to about 15 mg, or such as in about 1 to about 20 mg.

[0440] In another aspect, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as a medicament. The present invention also relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as a medicament.

[0441] In another aspect, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is used to treat or prevent any disease listed herein. The present invention further relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing any disease listed herein. The present invention further relates to a method for treating or preventing any disease listed herein of a subject (such as a human being), comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject in need of such treatment or prevention.

[0442] Combination therapy

[0443] In one aspect of the invention, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with at least one other therapeutic agent, such as one, two, three or more other therapeutic agents. The compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one other therapeutic agent may be administered simultaneously, sequentially or separately. The therapeutic agents suitable for combination with the compound of formula (I) include, but are not limited to, known agents for treating any of the aforementioned conditions, disorders and diseases.

[0444] In one embodiment, the compound of the 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 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, all of which are incorporated herein by reference in their entirety.Specific examples of suitable ASBT inhibitors include 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylsulfanyl-8-(N-{(R)-1'-phenyl-1'-[N'-(carboxymethyl)carbamoyl]-methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine (eloxibat) and 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylsulfanyl-8-(N-{(R)-a-[N-((S)-1-carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine (orvixibat).

[0445] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a bile acid binder (also known as a bile acid sequestrant or resin), such as colesevelam, cholestyramine or cholestipol. In a preferred embodiment of such a combination, the bile acid binder 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.

[0446] 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.

[0447] 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, bervastatin or dalvastatin or a pharmaceutically acceptable salt thereof.

[0448] 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.

[0449] 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.

[0450] 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.

[0451] 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, aleglitazar, muraglitazar or tesaglitazar, or a pharmaceutically acceptable salt thereof.

[0452] In another embodiment, the compound of the formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a dual PPAR alpha / delta agonist such as elafibranor.

[0453] In another embodiment, the compound of the formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a pan-PPAR agonist (ie a PPAR agonist active against all the following isoforms: alpha, gamma and delta), such as, for example, IVA337.

[0454] 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 cafestol, chenodeoxycholic acid, 6α-ethyl-chenodeoxycholic acid (obeticholic acid; INT-747), fexaramine, tropifexor, cilofexor and MET409.

[0455] 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).

[0456] 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.

[0457] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with ursodeoxycholic acid (UDCA). In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with nor-ursodeoxycholic acid (nor-UDCA).

[0458] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a FGF19 modulator, such as NGM282.

[0459] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a FGF21 agonist, such as BMS-986036.

[0460] In another embodiment, the compound of the formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with an integrin inhibitor, such as PLN-74809 and PLN-1474.

[0461] In another embodiment, the compound of the formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a CCR2 / CCR5 inhibitor such as cenicriviroc.

[0462] In another embodiment, the compound of the formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a caspase inhibitor, such as emricasan.

[0463] In another embodiment, the compound of the formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a galectin-3 inhibitor, such as GR-MD-02.

[0464] In another embodiment, the compound of the formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a stearoyl-CoA desaturase (SCD) inhibitor, such as aramchol (aramchol) (eicosanylaminocholic acid).

[0465] In another embodiment, the compound of the formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with an inhibitor of apoptosis signal-regulating kinase 1 (ASK1), such as selonsertib.

[0466] In another embodiment, the compound of the formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a LOXL2 inhibitor, such as simtuzumab.

[0467] 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.

[0468] In another embodiment, the compound of the formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a thyroid hormone receptor-β agonist, such as MGL3196.

[0469] In another embodiment, the compound of the formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a GLP-1 agonist such as liraglutide.

[0470] In another embodiment, the compound of the 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.

[0471] 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.

[0472] 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.

[0473] 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 dual SGLT1 and SGLT2 inhibitor. Examples of such compounds are dapagliflozin, sotagliflozin, canagliflozin, empagliflozin, LIK066, and SGL5213.

[0474] In another embodiment, the compound of the 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.

[0475] In another embodiment, the compound of the formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a fatty acid synthase (FASN) inhibitor, such as TVB-2640.

[0476] In another embodiment, the compound of the formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with an AMP-activated protein kinase (AMPK) activator, such as PXL-770.

[0477] 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.

[0478] In another embodiment, the compound of the formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a cannabinoid receptor 1 (CB1) antagonist, such as IM102.

[0479] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with Klothoβ (KLB) and an activator of fibroblast growth factor receptor (FGFR), such as MK-3655 (formerly known as NGM-313).

[0480] In another embodiment, the compound of the formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a chemokine (cc motif) ligand 24 (CCL24) inhibitor, such as CM101.

[0481] 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.

[0482] 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.

[0483] In another embodiment, the compound of the formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a P2Y13 receptor agonist, such as CER-209.

[0484] In another embodiment, the compound of the formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a sulfated oxysterol, such as Dur-928.

[0485] 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.

[0486] In another embodiment, the compound of the formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with an inhibitor of natural killer T cells type 1 (NKT1), such as GRI-0621.

[0487] 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.

[0488] In another embodiment, the compound of the formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a VAP1 inhibitor, such as BI1467335.

[0489] 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.

[0490] 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.

[0491] In another embodiment, the compound of the formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a nicotinic acid receptor 1 agonist, such as ARI-3037MO.

[0492] 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.

[0493] In another embodiment, the compound of the formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a hexokinases inhibitor, such as PF-06835919.

[0494] 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.

[0495] In another embodiment, the compound of the formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with an autotaxin inhibitor, such as PAT-505 and PF8380.

[0496] In another embodiment, the compound of the formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a chemokine (cc motif) receptor 3 (CCR3) antagonist, such as bertilimumab.

[0497] In another embodiment, the compound of the formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a chloride channel stimulator, such as cobiprostone and lubiprostone.

[0498] In another embodiment, the compound of the 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.

[0499] In another embodiment, the compound of the formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with an inhibitor of sterol regulatory element binding protein (SREBP) transcription factors, such as CAT-2003 and MDV-4463.

[0500] In another embodiment, the compound of the formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a biguanide, such as metformin.

[0501] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with insulin.

[0502] In another embodiment, the compound of the formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a glycogen phosphorylase inhibitor and / or a glucose-6-phosphatase inhibitor.

[0503] In another embodiment, the compound of the formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a sulfonylurea such as glipizid, glibenklamid and glimepirid.

[0504] In another embodiment, the compound of the formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a meglitinide, such as repaglinide, nateglinide and ormiglitinide.

[0505] In another embodiment, the compound of the formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a glucosidase inhibitor, such as acarbose or miglitol.

[0506] In another embodiment, the compound of the formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a squalene synthase inhibitor, such as TAK-475.

[0507] In another embodiment, the compound of the formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a PTPB1 inhibitor, such as trodusquemine, ertiprotafib, JTT-551 and claramine.

[0508] Preparation of compounds

[0509] The compounds of the present invention can be prepared as free acids or pharmaceutically acceptable salts thereof via 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 various reactants and intermediates in a manner readily understood by those skilled in the art of organic synthesis, and subsequently removed from various reactants and intermediates. The conventional procedures using such protecting groups and examples of suitable protecting groups are described, for example, in PGM Wutz and TW Greene's Protective Groups in Organic Synthesis, 4th edition, John Wiley & Sons, Hoboken, 2006.

[0510] General approach

[0511] All solvents used were of analytical grade. Commercially available anhydrous solvents were routinely used for the reactions. Starting materials can be purchased from commercial sources or prepared according to literature procedures. 7-Bromo-3,3-dibutyl-8-methoxy-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide and 3,3-dibutyl-8-hydroxy-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide can be prepared as described in WO 02 / 50051 (Method 26). 7-Bromo-3-butyl-3-ethyl-8-methoxy-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide, 3-butyl-3-ethyl-8-hydroxy-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide, 7-Bromo-3-butyl-3-ethyl-8-methoxy-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiazepine Diazepine 1,1-dioxide, 3-butyl-3-ethyl-8-hydroxy-2-(4-methoxybenzyl)-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide and 3-butyl-3-ethyl-8-hydroxy-2-methyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide can be prepared according to the method described in WO 2019 / 234077 (intermediates 22, 23, 26, 128 and 152, respectively). 3,3-Dibutyl-8-hydroxy-2-(4-methoxybenzyl)-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide can be prepared according to the method described in WO 03 / 022286 (Method 24). 7-Bromo-3,3-dibutyl-5-(4-fluorophenyl)-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide, 7-bromo-3-butyl-3-ethyl-5-(4-fluorophenyl)-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide and 3-butyl-3-ethyl-5-(4-fluorophenyl)-8-hydroxy-7-(methylthio)-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide can be prepared according to the method described in WO 2020 / 161216 (intermediates 43, 69 and 70, respectively).7-Bromo-3-butyl-8-methoxy-2-methyl-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide, 3-butyl-8-hydroxy-2-methyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide and 7-bromo-3-butyl-5-(4-fluorophenyl)-8-methoxy-2-methyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide can be prepared according to the method described in WO 2021 / 110883 (intermediates 32, 33 and 45, respectively). Enantiomerically pure (R)-7-bromo-3-butyl-8-methoxy-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide can be prepared according to the steps described in WO 2021 / 110883 (see intermediates 21 to 26), starting from a single enantiomer of 2-aminohexanoic acid (D-norleucine). 7-Bromo-3-butyl-8-methoxy-3-methyl-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide and 3-butyl-8-hydroxy-3-methyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide can be prepared as described in WO2021 / 110884 (intermediates 5 and 6, respectively). Room temperature refers to 20-25° C. The solvent mixture composition is given in volume percentage or volume ratio.

[0512] LCMS:

[0513] Instrument name: Agilent 1290infinity II.

[0514] Method A: Mobile phase: A: 0.1% HCOOH / water:ACN (95:5), B: ACN; Flow rate: 1.5 mL / min; Column: ZORBAX XDB C-18 (50×4.6 mm) 3.5 μM.

[0515] Method B: Mobile phase: A: 10 mM NH 4 HCO 3 / water, B: ACN; flow rate: 1.2 mL / min; column: XBridge C8 (50×4.6 mm), 3.5 μM.

[0516] Method C: Mobile phase: A: 0.1% HCOOH / water:ACN (95:5), B: ACN; Flow rate: 1.5 mL / min; Column: ATLANTIS dC18 (50×4.6 mm), 5 μM.

[0517] Method D: Mobile phase: A: 10 mM NH 4 OAc / water, B: ACN; flow rate: 1.2 mL / min; column: Zorbax ExtendC18 (50×4.6 mm) 5 μM.

[0518] Method E: Mobile phase: A: 0.1% TFA / water:ACN (95:5), B: 0.1% TFA / ACN; Flow rate: 1.5 mL / min; Column: XBridge C8 (50×4.6 mm), 3.5 μM.

[0519] Method F: Mobile phase: A: 0.1% TFA / water, B: 0.1% TFA / ACN; flow rate: 0.8 mL / min; column: ZORBAXECLIPSE PLUS C18 (50×2.1 mm), 1.8 μm.

[0520] Method G: Mobile phase: A: 0.1% TFA / water, B: 0.1% TFA / ACN; Flow rate: 0.8 mL / min; Column: Acquity UPLC BEH C18 (2.1×50 mm), 1.7 μm.

[0521] Method H: Mobile phase: A: 10 mM NH 4 OAc, B: 100% ACN; flow rate: 0.8 mL / min; column: AcquityUPLC BEH C18 (2.1×50) mm; 1.7 μm.

[0522] Method I: Mobile phase: A: 0.1% HCOOH / water:ACN (95:5), B: ACN; Flow rate: 0.8 mL / min; Column: ZORBAX ECLIPSE PLUS C18 (2.1×50) mm, 1.8 μm.

[0523] Method J: Mobile phase: A: 0.1% TFA / water, B: 0.1% TFA / ACN; Flow rate: 1.5 mL / min; Column: XBridge C8 (50 x 4.6 mm), 3.5 μM.

[0524] Instrument name: Waters Acquity UPLC I Class / SQ Detector 2

[0525] Method K: Mobile phase: A: 0.1% HCOOH / water:ACN (95:5), B: ACN; Flow rate: 0.8 mL / min; Column: BEHC18 (50x2.1 mm), 1.7 μm.

[0526] UPLC:

[0527] Instrument name: Waters Acquity I Class

[0528] Method A: Mobile phase: A: 0.1% HCOOH / water, B: 0.1% HCOOH in ACN; Flow rate: 0.8 mL / min; Column: Acquity UPLC HSS T3 (2.1×50) mm; 1.8 μm.

[0529] HPLC:

[0530] Instrument name: Agilent 1260 Infinity II series instrument, % and UV detection (maxplot) were used as follows.

[0531] Method A: Mobile phase: A: 10 mM NH 4 HCO 3 / water, B: ACN; flow rate: 1.0 mL / min; column: XBridge C8 (50×4.6 mm, 3.5 μm).

[0532] Method B: Mobile phase: A: 0.1% TFA / water, B: 0.1% TFA / ACN; Flow rate: 2.0 mL / min; Column: XBridge C8 (50×4.6 mm, 3.5 μm).

[0533] Method C: Mobile phase: A: 10 mM NH 4 Oac / milli-q water, B: ACN; flow rate: 1.0 ml / min; column: Phenomenex Gemini C18 (150×4.6 mm, 3.0 μm).

[0534] Method D: Mobile phase: A: 0.1% TFA / water, B: ACN; Flow rate: 1.0 mL / min; Column: ATLANTIS dC18 (250×4.6 mm, 5.0 μm).

[0535] Method E: Mobile phase: A: 0.1% TFA / water, B: ACN, flow rate: 2.0 mL / min; column: X-Bridge C8 (50×4.6 mm, 3.5 μm).

[0536] Chiral SFC:

[0537] Instrument name: PIC SFC 10 (analytical)

[0538] CO 2 The ratio between co-solvent is between 60:40 and 80:20

[0539] Method A: Mobile phase: 0.5% isopropylamine / IPA; Flow rate: 3 mL / min; Column: YMC amylose-SA (250×4.6 mm, 5 μm).

[0540] Method B: Mobile phase: 0.5% isopropylamine / IPA; Flow rate: 3 mL / min; Column: Chiralpak AD-H (250×4.6 mm, 5 μm).

[0541] Method C: mobile phase: 20 mM ammonia / methanol; flow rate: 3 mL / min; column: YMC cellulose-SC (250×4.6 mm, 5 μm).

[0542] Method D: Mobile phase: methanol; Flow rate: 3 mL / min; Column: Lux A1 (250×4.6 mm, 5 μm).

[0543] Method E: Mobile phase: 0.5% isopropylamine / methanol; Flow rate: 5 mL / min; Column: Lux C4.

[0544] Method F: Mobile phase: 0.5% isopropylamine / methanol; Flow rate: 3 mL / min; Column: YMC cellulose-SC.

[0545] Method G: Mobile phase: 0.5% isopropylamine / methanol; Flow rate: 3 mL / min; Column: Lux A1.

[0546] Method H: mobile phase: 0.5% isopropylamine / IPA; flow rate: 3 mL / min; column: Lux A1 (250×4.6 mm, 5 μm).

[0547] Method I: Mobile phase: 0.5% isopropylamine / methanol; Flow rate: 3 mL / min; Column: chiral CCS (250×4.6 mm, 5 μm).

[0548] Method J: mobile phase: 0.5% isopropylamine / IPA; flow rate: 5 mL / min; column: YMC cellulose-SC AD-H (250×4.6 mm, 5 μm).

[0549] Method K: Mobile phase: 0.5% isopropylamine / methanol; Flow rate: 4 mL / min; Column: (R,R)-Whelk-01 (250×4.6 mm, 5 μm).

[0550] Method L: Mobile phase: 0.5% isopropylamine / IPA; Flow rate: 3 mL / min; Column: Chiralcel OX-H (250×4.6 mm, 5 μm).

[0551] Method M: mobile phase: 0.5% isopropylamine / IPA; flow rate: 5 mL / min; column: YMC cellulose-SC (250×4.6 mm, 5 μm).

[0552] Method N: Mobile phase: methanol, flow rate: 5 mL / min; column: Chiralcel OX-H (250×4.6 mm, 5 μm).

[0553] Method O: Mobile phase: 0.1% isopropylamine / IPA:methanol (1:1), flow rate: 3 mL / min; column: Chiralpak AS-H (250×4.6 mm, 5 μm).

[0554] Method P: Mobile phase: 0.5% isopropylamine / methanol, flow rate: 3 mL / min; column: Chiralpak AS-H (250×4.6 mm, 5 μm).

[0555] Method Q: Mobile phase: IPA, flow rate: 3 mL / min; column: Lux A1 (250×4.6 mm, 5 μm).

[0556] Method R: Mobile phase: 0.1% isopropylamine / IPA:methanol (1:1), flow rate: 3 mL / min; column: Lux A1 (250×4.6 mm, 5 μm).

[0557] Method S: mobile phase: 0.5% isopropylamine / IPA (1:1), flow rate: 3 mL / min; column: Chiralpak AS-H (250 x 4.6 mm, 5 μm).

[0558] Method T: Mobile phase: 0.5% isopropylamine / IPA (1:1), flow rate: 4 mL / min; column: Chiralpak OX-H (250 x 4.6 mm, 5 μm).

[0559] Method U: Mobile phase: IPA, flow rate: 3 mL / min; column: Chiralpak AS-H (250 x 4.6 mm, 5 μm).

[0560] Method V: Mobile phase: 0.5% isopropylamine / methanol, flow rate: 3 mL / min; column: Chiralpak OX-H (250 x 4.6 mm, 5 μm).

[0561] Preparative HPLC:

[0562] Instrument name: Agilent 1290Infinity II

[0563] Method A: Mobile phase: A: 0.1% TFA / water; Mobile phase; B: 0.1% TFA / ACN; Flow rate: 2.0 mL / min; Column: X-Bridge C8 (50×4.6 mm, 3.5 μM).

[0564] Method B: Mobile phase: A: 10 mM NH 4 OAc / water; B: ACN; flow rate: 35 mL / min; column: X select C18 (30×150 mm, 5 μm).

[0565] Method C: Mobile phase: A: 10 mM NH 4 HCO 3 / water; B: ACN; flow rate: 1.0 mL / min; column: XBridge C8 (50×4.6 mm, 3.5 μm).

[0566] Method D: Mobile phase: A: 0.1% HCOOH / water; B: ACN; Flow rate: 1.0 mL / min; Column: X-select C18 (30×150 mm, 5 μm).

[0567] Method E: Mobile phase: A: 0.1% TFA / water, B: ACN; Flow rate: 15 mL / min; Column: sunfire C18 (19x150 mm, 5 μm).

[0568] Chiral Preparative SFC:

[0569] Instrument name: PIC SFC 100 and PSC SFC 400

[0570] CO 2 The ratio between co-solvent is between 60:40 and 80:20

[0571] Method A: Mobile phase: 0.5% isopropylamine / IPA; Flow rate: 3 mL / min; Column: YMC amylose-SA (250×30 mm, 5 μm).

[0572] Method B: mobile phase: 0.5% isopropylamine / IPA; flow rate: 3 mL / min; column: Chiralpak AD-H (250×30 mm, 5 μm).

[0573] Method C: mobile phase: 20 mM ammonia / methanol; flow rate: 3 mL / min; column: YMC cellulose-SC (250×30 mm, 5 μm).

[0574] Method D: Mobile phase: methanol; Flow rate: 3 mL / min; Column: chiral CCS (250×30 mm, 5 μm).

[0575] Method E: Mobile phase: methanol; Flow rate: 3 mL / min; Column: Lux A1 (250×30 mm, 5 μm).

[0576] Method F: mobile phase: 0.5% isopropylamine / IPA; flow rate: 3 mL / min; column: Lux A1 (250×30 mm, 5 μm).

[0577] Method G: mobile phase: 0.5% isopropylamine / methanol; flow rate: 3 mL / min; column: chiral CCS (250×30 mm, 5 μm).

[0578] Method H: Mobile phase: 0.5% isopropylamine / methanol; Flow rate: 4 mL / min; Column: (R,R)-Whelk-01 (250x30 mm, 5 μm).

[0579] Method I: Mobile phase: 0.5% isopropylamine / IPA; Flow rate: 5 mL / min; Column: YMC Cellulose-SC (250x30 mm, 5 μm).

[0580] Method J: Mobile phase: 0.5% isopropylamine / IPA; Flow rate: 3 mL / min; Column: Chiralcel OX-H (250x30 mm, 5 μm).

[0581] Method K: mobile phase: 0.5% isopropylamine / methanol; flow rate: 5 mL / min; column: YMC Cellulose-SC (250x30 mm, 5 μm).

[0582] Method L: Mobile phase: methanol; Flow rate: 5 mL / min; Column: Chiralcel OX-H (250x30 mm, 5 μm).

[0583] Method M: Mobile phase: 0.5% isopropylamine / methanol, flow rate: 3 mL / min; Column: Chiralpak AS-H (250 x 4.6 mm, 5 μm).

[0584] Method N: mobile phase: 0.1% isopropylamine / IPA:MeOH (1:1), flow rate: 3 mL / min; column: Chiralpak AS-H (250x4.6 mm, 5 μm).

[0585] abbreviation

[0586] ACN Acetonitrile

[0587] DCM Dichloromethane

[0588] DMF Dimethylformamide

[0589] dppf 1,1'-Bis(diphenylphosphino)ferrocene

[0590] HPLC High Performance Liquid Chromatography

[0591] IPA Isopropyl Alcohol

[0592] LCMS liquid chromatography-mass spectrometry

[0593] NMP N-Methyl-2-pyrrolidone

[0594] PE Petroleum Ether

[0595] Pd 2 (dba) 3 Tris(dibenzylideneacetone)dipalladium(0)

[0596] PMB p-Methoxybenzyl

[0597] RT Room temperature

[0598] RuPhos 2-Dicyclohexylphosphino-2',6'-diisopropoxybiphenyl

[0599] SFC Supercritical Fluid Chromatography

[0600] TFA Trifluoroacetic acid

[0601] THF Tetrahydrofuran

[0602] TLC Thin Layer Chromatography

[0603] UPLC Ultra-Performance Liquid Chromatography

[0604] The present invention will now be described by way of the following examples, which are not intended to limit the present invention in any respect. All cited documents and references are incorporated by reference. Example

[0605] Intermediate 1

[0606] 3-Butyl-3-ethyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl trifluoromethanesulfonate

[0607]

[0608] To a stirred solution of 3-butyl-3-ethyl-8-hydroxy-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide (500 mg, 1.19 mmol) in dry DCM (10 mL) at 0 ° C, pyridine (0.2 mL, 2.38 mmol) and trifluoromethanesulfonic anhydride (0.3 mL, 1.78 mmol) were added dropwise, and the reaction mixture was stirred at RT for 1 hour. After the reaction was completed (monitored by TLC), the reaction mixture was diluted with water (10 mL) and the aqueous layer was extracted with DCM (2x20 mL). The combined organic layer was washed with water (5 mL) and brine (5 mL), and then anhydrous Na2 SO 4 Dry. Filter the organic portion, concentrate in vacuo, and purify the resulting crude material by Isolera column chromatography (eluent: 9-10% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 46% (480 mg, white solid).

[0609] 1 H NMR (400 MHz, DMSO-d 6 ): δ7.70(s,1H),7.40(t,J=9.6Hz,4H),7.17(t,J=9.2Hz,1H),6.53(s,1H),3.88-3.80(m,2H),3.53-3.48(m,2H ),2.18(s,3H),1.58-1.51(m,1H),1.45-1.35(m,3H),0.89-0.83(m,4H),0.69-0.79(m,6H).LCMS:(Method B)552.2(M + +H), Rt.3.21min, 98.21% (Max).

[0610] Intermediate 2

[0611] 3-Butyl-3-ethyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-carboxylic acid methyl ester 1,1-dioxide

[0612]

[0613] To a stirred solution of 3-butyl-3-ethyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl trifluoromethanesulfonate (Intermediate 1; 500 mg, 0.90 mmol) in degassed methanol (10 mL) and DMF (5 mL) were added triethylamine (0.18 mL, 1.35 mmol), dppf (126 mg, 0.20 mmol) and Pd 2 (dba) 3 (104 mg, 0.10 mmol). The resulting reaction mixture was stirred at 70 ° C for 16 hours in an autoclave under 5 kg carbon monoxide pressure. After the reaction was completed (monitored by TLC), the reaction mixture was diluted with water (20 mL), and the aqueous layer was extracted with EtOAc (2x50 mL). The combined organic layer was washed with water (15 mL) and brine (15 mL), and then washed with anhydrous Na 2 SO 4Dry. Filter the organic portion, concentrate in vacuo, and purify the resulting crude material by Isolera column chromatography (eluent: 10-15% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 52% (215 mg, off-white solid).

[0614] 1 H NMR (400 MHz, DMSO-d 6 ): δ8.41(s,1H),7.51-7.45(m,4H),7.30-7.26(m,1H),6.28(s,1H),3.98-3.95(m,2H),3.82(s,3H),3.56-3.53(m,2H),1.89 (s,3H),1.59-1.56(m,1H),1.43-1.31(m,3H),1.24-1.04(m,2H),0.94-0.87(m,2H),0.72-0.65(m,6H).LCMS: (Method A) 462.9(M + +H), Rt.3.23min, 77.43% (Max).

[0615] Intermediate 3

[0616] 3-Butyl-3-ethyl-8-(hydroxymethyl)-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide

[0617]

[0618] To a stirred solution of 3-butyl-3-ethyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-carboxylic acid methyl ester 1,1-dioxide (Intermediate 2; 200 mg, 0.43 mmol) in dry THF (10 mL) at 0 ° C, lithium aluminum hydride (2M in THF, 0.4 mL, 0.86 mmol) was added dropwise, and the reaction mixture was stirred at RT for 1 hour. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with saturated aqueous ammonium chloride (5 mL) and the aqueous layer was extracted with EtOAc (2x15 mL). The combined organic layer was washed with water (10 mL), brine (10 mL), and anhydrous Na 2 SO 4 Dry. Filter the organic portion, concentrate in vacuo and use the resulting crude material in the next step without further purification. Yield: 83% (210 mg, white solid).

[0619] 1 H NMR (400 MHz, DMSO-d 6): δ7.92(s,1H),7.32-7.30(m,3H),7.19-7.16(m,2H),7.20-6.99(m,1H),6.61(s,1H),5.47(s,2H ),4.45(s,2H),3.76(s,2H),2.16(s,3H),1.54-1.36(m,4H),1.17-1.06(m,4H),0.73-0.65(m,6H).

[0620] Intermediate 4

[0621] Ethyl 2-(((3-butyl-3-ethyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)acetate

[0622]

[0623] To a stirred solution of 3-butyl-3-ethyl-8-(hydroxymethyl)-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide (intermediate 3; 50 mg, 0.11 mmol) in DCM (10 mL) at 0 ° C, zinc iodide (17.3 mg, 0.05 mmol) and ethyl 2-mercaptoacetate (34 mg, 0.28 mmol) were added successively, and the reaction mixture was stirred at RT for 1 hour. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with water (10 mL) and the aqueous layer was extracted with DCM (2x10 mL). The combined organic layer was washed with water (10 mL), brine (10 mL), and anhydrous Na 2 SO 4 Dry. Filter the organic portion, concentrate in vacuo and use the resulting crude material in the next step without further purification. Yield: 70 mg (crude, light yellow solid).

[0624] 1 H NMR (400 MHz, DMSO-d 6): δ7.74(s,1H),7.33(t,J=8.4Hz,2H),7.22(d,J=7.6Hz,2H),7.04(t,J= 7.6Hz,1H),6.58(s,1H),4.14-4.07(m,2H),3.88(s,2H),3.77-3.73(m,2H ),3.35-3.34(m,2H),3.31-3.30(m,2H),2.15(s,3H),1.55-1.50(m,1H),1 .49-.39(m,3H),1.38-1.34(m,3H),1.27-1.18(m,4H),0.75-0.70(m,6H).

[0625] Intermediate 5

[0626] 3,3-Dibutyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl trifluoromethanesulfonate

[0627]

[0628] To a stirred solution of 3,3-dibutyl-8-hydroxy-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide (1.0 g, 2.23 mmol) in dry DCM (10 mL) at 0 ° C, pyridine (0.35 mL, 4.46 mmol) and trifluoromethanesulfonic anhydride (0.56 mL, 3.35 mmol) were added dropwise, and the reaction mixture was stirred at RT for 1 hour. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with ice-cold water (20 mL) and the aqueous layer was extracted with DCM (2x50 mL). The combined organic layer was washed with water (10 mL), brine (10 mL), and then anhydrous Na 2 SO 4 Dry. Filter the organic portion, concentrate in vacuo, and purify the resulting crude material by Isolera column chromatography (eluent: 20% EtOAc / PE; silica gel: 230-400 mesh). The resulting solid was triturated with petroleum ether (2x10 mL) and dried in vacuo to afford the title compound. Yield: 85% (1.1 g, off-white solid).

[0629] 1 H NMR (400 MHz, DMSO-d 6): δ7.70 (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.3.52min, 96.63% (Max).

[0630] Intermediate 6

[0631] 3,3-Dibutyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-carboxylic acid methyl ester 1,1-dioxide

[0632]

[0633] To a solution of 3,3-dibutyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl trifluoromethanesulfonate (Intermediate 5; 1.10 g, 1.80 mmol) in degassed methanol (10 mL) and DMF (5 mL) were added triethylamine (0.4 mL, 2.80 mmol), dppf (126 mg, 0.20 mmol) and Pd 2 (dba) 3 (104 mg, 0.10 mmol). The resulting reaction mixture was stirred at 70 ° C for 16 hours in an autoclave under 5 kg carbon monoxide pressure. After the reaction was completed (monitored by TLC), the reaction mixture was diluted with water (20 mL) and the aqueous layer was extracted with EtOAc (2x50 mL). The combined organic layer was washed with water (15 mL), brine (15 mL), and then washed with anhydrous Na 2 SO 4 Dry. Filter the organic portion, concentrate in vacuo, and purify the resulting crude material by Isolera column chromatography (eluent: 15% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 67% (0.62 g, off-white solid).

[0634] 1 H NMR (400 MHz, DMSO-d 6):δ8.41(s,1H),7.51-7.45(m,4H),7.27(s,1H),6.29(s,1H),4.05-3.90(m,2H),3.82(s,3H),3.62-3.48(m,2H),1.89(s,3H),1.60-1.20(m,4H),1.20-0.80(m,8H),0.78-0.55(m,6H).LCMS:(Method E)489.9(M + +H), Rt.3.37min, 94.23% (Max).

[0635] Intermediate 7

[0636] 3,3-Dibutyl-8-(hydroxymethyl)-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide

[0637]

[0638] To a stirred solution of 3,3-dibutyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-carboxylic acid methyl ester 1,1-dioxide (Intermediate 6; 0.3 g, 0.6 mmol) in dry THF (6 mL) was added lithium aluminum hydride (1 M in THF, 0.9 mL, 0.9 mmol) at 0 ° C, and the reaction mixture was stirred at RT for 1 hour. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with saturated aqueous ammonium chloride (5 mL) and the aqueous layer was extracted with EtOAc (2x15 mL). The combined organic layer was washed with water (10 mL), brine (10 mL), and then anhydrous Na 2 SO 4 Dry. Filter the organic portion, concentrate in vacuo, and use the crude product in the next step without any purification. Yield: 300 mg (crude, off-white solid).

[0639] 1 H NMR (400 MHz, DMSO-d 6): δ7.91(s,1H),7.32-7.28(m,2H),7.19-7.17(m,2H),7.02-6.99(m,1H),6.59(s,1H),5.47(t,J=5.6Hz,1H),4.43(d,J=5.2Hz,2H),3.90-3 .65(m,2H),3.40-3.30(m,2H),2.15(s,3H),1.50-1.40(m,2H),1.40-1.30(m,2H),1.20-0.98(m,8H),0.80-0.70(m,6H).LCMS: (Method A) 462.1(M + +H), Rt.2.94min, 97.01% (Max).

[0640] Intermediate 8

[0641] Ethyl 2-(((3,3-dibutyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)acetate

[0642]

[0643] To a stirred solution of 3,3-dibutyl-8-(hydroxymethyl)-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide (intermediate 7; 0.08 g, 0.17 mmol) in DCM (3 mL) at 0 ° C, zinc iodide (0.03 g, 0.09 mmol) was added, followed by ethyl 2-mercaptoacetate (0.04 g, 0.35 mmol), and the reaction mixture was stirred at RT for 1 hour. After the reaction was completed (monitored by TLC), the reaction mixture was diluted with water (10 mL) and the aqueous layer was extracted with DCM (2x20 mL). The combined organic layers were washed with water (5 mL) and brine (5 mL), then purified by anhydrous Na 2 SO 4 Dry. Filter the organic portion, concentrate in vacuo, and use the resulting material in the next step without further purification. Yield: 80% (90 mg, brown solid).

[0644] LCMS: (Method E) 581.0 (M + +18), Rt.3.44min, 80.16% (Max).

[0645] Intermediate 9

[0646] 3-Butyl-3-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl trifluoromethanesulfonate

[0647]

[0648] To a stirred solution of 3-butyl-8-hydroxy-3-methyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide (1.0 g, 2.46 mmol) in dry DCM (10 mL) at 0 ° C, pyridine (0.24 g, 4.93 mmol) was added dropwise. Trifluoromethanesulfonic anhydride (0.65 g, 3.69 mmol) was then added dropwise at 0 ° C, and the reaction mixture was stirred at RT for 1 hour. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with ice-cold water (20 mL). The aqueous layer was extracted with DCM (2x50 mL) and the combined organic layer was washed with water (10 mL) and brine (10 mL). The organic layer was purified by anhydrous Na 2 SO 4 The mixture was dried, filtered and concentrated under vacuum. The crude material was purified by Isolera column chromatography (eluent: 20% EtOAc / PE; silica gel: 230-400 mesh) to give a sticky solid. The sticky solid was further purified and dried by grinding with petroleum ether (2x10 mL) to give the title compound. Yield: 68% (0.9 g, off-white solid).

[0649] LCMS: (Method E) 538.0 (M + +H), Rt.3.30min, 97.12% (Max).

[0650] Intermediate 10

[0651] 3-Butyl-3-methyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-carboxylic acid methyl ester 1,1-dioxide

[0652]

[0653] To a solution of 3-butyl-3-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl trifluoromethanesulfonate (Intermediate 9; 0.9 g, 1.67 mmol) in degassed methanol (15 mL) and DMF (10 mL) were added triethylamine (0.32 mL, 2.51 mmol), dppf (0.10 g, 2.00 mmol) and Pd 2 (dba) 3(0.09 g, 1.01 mmol). The resulting reaction mixture was stirred at 75 ° C for 16 hours in an autoclave under 5 kg carbon monoxide pressure. After the reaction was completed (monitored by TLC), the reaction mixture was diluted with water (20 mL) and the aqueous layer was extracted with EtOAc (2x50 mL). The combined organic layer was washed with water (15 mL) and brine (15 mL), and then washed with anhydrous Na 2 SO 4 Dry. Filter the organic layer, concentrate in vacuo and purify the crude material by Isolera column chromatography (eluent: 15% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 67.5% (0.5 g, off-white solid).

[0654] LCMS: (Method E) 448.3 (M + +H), Rt.2.93min, 96.13% (Max).

[0655] Intermediate 11

[0656] 3-Butyl-8-(hydroxymethyl)-3-methyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide

[0657]

[0658] To a stirred solution of 3-butyl-3-methyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-carboxylic acid methyl ester 1,1-dioxide (Intermediate 10; 0.25 g, 0.56 mmol) in dry THF (10 mL) was added lithium aluminum hydride (2M solution in THF, 0.27 mL, 0.56 mmol) dropwise at 0°C and the reaction mixture was stirred at RT for 1 hour. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with saturated aqueous ammonium chloride solution (10 mL) and the aqueous layer was extracted with EtOAc (2x15 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), and washed with anhydrous Na 2 SO 4 Dry. Filter the organic portion and concentrate in vacuo to afford the title compound which is used in the next step without further purification. Yield: 92% (0.22 g, off-white solid).

[0659] LCMS: (Method A) 419.9 (M + +H), Rt.2.72min,98.23%(Max).

[0660] Intermediate 12

[0661] Ethyl 2-(((3-butyl-3-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)acetate

[0662]

[0663] To a stirred solution of 3-butyl-8-(hydroxymethyl)-3-methyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide (intermediate 11; 0.15 g, 0.36 mmol) in DCM (5 mL) at 0 ° C, zinc iodide (0.06 g, 0.18 mmol) and ethyl 2-mercaptoacetate (0.08 g, 0.72 mmol) were added, and the reaction mixture was stirred at RT for 2 hours. After the reaction was completed (monitored by TLC), the reaction mixture was diluted with water (10 mL) and the aqueous layer was extracted with DCM (2x20 mL). The combined organic layer was washed with water (5 mL) and brine (5 mL), and then anhydrous Na 2 SO 4 The organic portion was concentrated in vacuo and the resulting crude material was purified by Isolera column chromatography (eluent: 20% EtOAc / PE; silica gel: 230-400 mesh) to afford the title compound. Yield: 75.26%, (0.14 g, white solid).

[0664] LCMS: (Method B) 539.0 (M + +18), Rt.2.86min, 97.00% (Max).

[0665] Intermediate 13

[0666] 3-Butyl-3-ethyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxido-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl trifluoromethanesulfonate

[0667]

[0668] To a stirred solution of 3-butyl-3-ethyl-5-(4-fluorophenyl)-8-hydroxy-7-(methylthio)-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide (3 g, 6.85 mmol) in DCM (30 mL) at 0 ° C, pyridine (1.08 mL, 13.71 mmol) and trifluoromethanesulfonic anhydride (1.36 mL, 8.22 mmol) were added dropwise, and the reaction mixture was stirred at RT for 1 hour. After the reaction was completed (monitored by TLC), the reaction mixture was diluted with water (20 mL) and the aqueous layer was extracted with DCM (2x50 mL). The combined organic layer was washed with water (20 mL), brine (20 mL), and then anhydrous Na 2 SO 4 Dry. Filter the organic portion, concentrate in vacuo, and purify the resulting crude material by Isolera column chromatography (eluent: 10-20% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 89.7% (3.5 g, white solid).

[0669] Intermediate 14

[0670] 3-Butyl-3-ethyl-5-(4-fluorophenyl)-7-(methylthio)-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-carboxylic acid methyl ester 1,1-dioxide

[0671]

[0672] To a solution of 3-butyl-3-ethyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxido-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl trifluoromethanesulfonate (Intermediate 13; 3.5 g, 6.15 mmol) in degassed methanol (35 mL) and DMF (20 mL) were added triethylamine (1.28 mL, 9.22 mmol), dppf (0.41 g, 0.73 mmol) and Pd 2 (dba) 3 (0.34 g, 0.37 mmol). The resulting reaction mixture was stirred at 75 ° C for 16 hours in an autoclave under 5 kg carbon monoxide pressure. After the reaction was completed (monitored by TLC), the reaction mixture was diluted with water (20 mL) and the aqueous layer was extracted with EtOAc (2x50 mL). The combined organic layer was washed with water (15 mL), brine (15 mL), and then washed with anhydrous Na 2 SO 4Dry. Filter the organic layer, concentrate in vacuo, and purify the resulting crude material by Isolera column chromatography (eluent: 20% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 16% (0.45 g, off-white solid).

[0673] 1 H NMR (400 MHz, DMSO-d 6 ):δ8.40(s,1H),7.60-7.57(m,2H),7.32(t,J=8.80Hz,2H),6.21(s,1H),3.95-3.92(m,2H),3.81(s,3H),3.58(s,2H),1.93(s,3H),1.58-1.50(m,1H),1.40-1.32(m,3H),1.19-1.16(m,2H),1.09-1.08(m,1H),0.86-0.84(m,1H),0.73-0.64(m,6H).LCMS:(Method E)480.0(M + +H), Rt.3.17min, 91.42% (Max).

[0674] Intermediate 15

[0675] 3-Butyl-3-ethyl-5-(4-fluorophenyl)-8-(hydroxymethyl)-7-(methylthio)-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide

[0676]

[0677] To a stirred solution of 3-butyl-3-ethyl-5-(4-fluorophenyl)-7-(methylthio)-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-carboxylic acid methyl ester 1,1-dioxide (Intermediate 14; 1.7 g, 3.54 mmol) in THF (20 mL) was added lithium aluminum hydride (2M solution in THF, 2.6 mL, 5.32 mmol) dropwise at 0°C and the reaction mixture was stirred at RT for 1 hour. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with saturated aqueous ammonium chloride solution (10 mL) and the aqueous layer was extracted with EtOAc (2x25 mL). The combined organic layers were washed with water (15 mL), brine (15 mL), and washed with anhydrous Na 2 SO 4 Dry. Filter the organic portion, concentrate in vacuo and use the resulting crude material in the next step without further purification. Yield: 1.7 g (crude, off-white solid).

[0678] 1H NMR (400 MHz, DMSO-d 6 ):δ7.89(s,1H),7.14-7.24(m,5H),6.51(s,1H),5.45-5.48(m,2H),4.43-4.42(m,2H),3.78-3.71(m,2H),1.53(s,3H),1.51-1.50(m,4H),1.38-1.30(m,4H),1.24-1.00(m,6H).LCMS:(Method G)451.0(M + +H), Rt.2.57min, 94.36% (Max).

[0679] Intermediate 16

[0680] Ethyl 2-(((3-butyl-3-ethyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxido-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)acetate

[0681]

[0682] To a stirred solution of 3-butyl-3-ethyl-5-(4-fluorophenyl)-8-(hydroxymethyl)-7-(methylthio)-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide (intermediate 15; 0.3 g, 0.66 mmol) in DCM (10 mL) at 0 ° C, zinc iodide (0.11 g, 0.33 mmol) and ethyl 2-mercaptoacetate (0.16 g, 1.33 mmol) were added, and the reaction mixture was stirred at RT for 2 hours. After the reaction was completed (monitored by TLC), the reaction mixture was diluted with water (50 mL) and the aqueous layer was extracted with DCM (2x25 mL). The combined organic layer was washed with water (5 mL) and brine (5 mL), and then filtered through anhydrous Na 2 SO 4 Dry. The organic portion was concentrated in vacuo and the resulting crude product was used in the next step without any purification. Yield: 368 mg (crude, light yellow solid).

[0683] LCMS: (Method B) 571.1 (M + +18), Rt.2.91min, 64.26% (Max).

[0684] Intermediate 17

[0685] 3,3-Dibutyl-2-(4-methoxybenzyl)-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl trifluoromethanesulfonate

[0686]

[0687] To a stirred solution of 3,3-dibutyl-8-hydroxy-2-(4-methoxybenzyl)-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (0.5 g, 0.88 mmol) in dry DCM (5 mL) at 0 ° C, pyridine (0.14 mL, 1.76 mmol) was added. Trifluoromethanesulfonic anhydride (0.22 mL, 1.32 mmol) was then added dropwise, and the reaction mixture was stirred at RT for 1 hour. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with ice-cold water (20 mL) and the aqueous layer was extracted with DCM (2x20 mL). The combined organic layer was washed with water (10 mL) and brine (10 mL), and then anhydrous Na 2 SO 4 Dry. Filter the organic portion, concentrate in vacuo, and purify the resulting crude material by Isolera column chromatography (eluent: 20% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 91% (0.6 g, white solid).

[0688] LCMS: (Method J) 701.3 (M + +H), Rt.3.49min, 93.52% (Max).

[0689] Intermediate 18

[0690] 3,3-Dibutyl-2-(4-methoxybenzyl)-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-carboxylic acid methyl ester 1,1-dioxide

[0691]

[0692] To a solution of 3,3-dibutyl-2-(4-methoxybenzyl)-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl trifluoromethanesulfonate (Intermediate 17; 0.6 g, 0.86 mmol) in degassed methanol (10 mL) and DMF (5 mL) were added triethylamine (0.18 mL, 1.28 mmol), dppf (57 mg, 0.10 mmol) and Pd 2 (dba) 3(47 mg, 0.05 mmol). The resulting reaction mixture was stirred at 70 ° C for 16 hours in an autoclave under 5 kg carbon monoxide pressure. After the reaction was completed (monitored by TLC), the reaction mixture was diluted with water (20 mL) and the aqueous layer was extracted with EtOAc (2x50 mL). The combined organic layer was washed with water (15 mL) and brine (15 mL), and then washed with anhydrous Na 2 SO 4 Dry. Filter the organic portion, concentrate in vacuo, and purify the resulting crude material by Isolera column chromatography (eluent: 12% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 28% (0.17 g, off-white solid).

[0693] LCMS: (Method J) 610.9 (M + +H), Rt.3.51min, 87.25% (Max).

[0694] Intermediate 19

[0695] 3,3-Dibutyl-8-(hydroxymethyl)-2-(4-methoxybenzyl)-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide

[0696]

[0697] To a stirred solution of 3,3-dibutyl-2-(4-methoxybenzyl)-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-carboxylic acid methyl ester 1,1-dioxide (Intermediate 18; 0.17 g, 0.28 mmol) in dry THF (4 mL) was added lithium aluminum hydride (1 M solution in THF, 0.41 mL, 0.42 mmol) dropwise at 0 °C, and the reaction mixture was stirred at RT for 20 minutes. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with saturated aqueous ammonium chloride solution (10 mL) and the aqueous layer was extracted with EtOAc (2x20 mL). The combined organic layers were washed with water (10 mL) and brine (10 mL), then dried over anhydrous Na 2 SO 4 Dry. Filter the organic portion, concentrate in vacuo and use the resulting crude material in the next step without further purification. Yield: 87% (0.15 g, off-white solid).

[0698] Intermediate 20

[0699] Ethyl 2-(((3,3-dibutyl-2-(4-methoxybenzyl)-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetate

[0700]

[0701] To a stirred solution of 3,3-dibutyl-8-(hydroxymethyl)-2-(4-methoxybenzyl)-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (Intermediate 19; 0.15 g, 0.26 mmol) in DCM (5 mL) at 0 ° C, zinc iodide (0.04 g, 0.13 mmol) and ethyl 2-mercaptoacetate (0.06 g, 0.52 mmol) were added, and the reaction mixture was stirred at RT for 1 hour. After the reaction was completed (monitored by TLC), the reaction mixture was diluted with water (10 mL) and the aqueous layer was extracted with DCM (2x20 mL). The combined organic layer was washed with water (10 mL) and brine (10 mL), and then washed with anhydrous Na 2 SO 4 Dry. The organic portion was concentrated in vacuo and the resulting crude material was purified by Isolera column chromatography (eluent: 12% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 59.2%, (0.16 g, white sticky solid).

[0702] LCMS: (Method B) 702.0 (M + +18), Rt.3.24min, 54.22% (Max).

[0703] Intermediate 21

[0704] Ethyl 2-(((3,3-dibutyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetate

[0705]

[0706] To a stirred solution of ethyl 2-(((3,3-dibutyl-2-(4-methoxybenzyl)-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetate (Intermediate 20; 0.16 g, 0.23 mmol) in toluene (3 mL) at 0°C, triphenylamine (0.12 g, 0.47 mmol) and 2,2,2-trifluoroacetic acid (0.18 mL, 2.34 mmol) were added dropwise and the resulting reaction mixture was stirred at RT for 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with ice-cold water (10 mL) and the aqueous layer was extracted with EtOAc (2x10 mL). The combined organic layers were washed with water (5 mL) and brine (5 mL) and then purified by anhydrous Na 2 SO 4 Dry. The organic portion was concentrated in vacuo and the resulting crude material was purified by Isolera column chromatography (eluent: 20% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 58% (85 mg, light brown solid).

[0707] 1 H NMR (400 MHz, DMSO-d 6 ): δ7.51(s,1H),7.55-7.20(m,5H),7.20-7.05(m,1H),6.44(s,1H),4. 12(q,J=6.8Hz,2H),4.10-3.90(m,2H),3.83(s,2H),3.27(s,2H),2.08 (s,3H),1.62-1.45(m,2H),1.45-1.28(m,2H),1.28-1.15(m,6H),1.15-1.00(m,2H),1.00-0.82(m,3H),0.82-0.68(m,6H)LCMS: (Method A) 563.2(M) + -H), Rt.3.23min, 89.96% (Max).

[0708] Intermediate 22

[0709] 3-Butyl-3-ethyl-2-(4-methoxybenzyl)-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl trifluoromethanesulfonate

[0710]

[0711] To a stirred solution of 3-butyl-3-ethyl-8-hydroxy-2-(4-methoxybenzyl)-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (1.60 g, 2.96 mmol) in dry DCM (10 mL) at 0 ° C, pyridine (0.72 mL, 8.88 mmol) and trifluoromethanesulfonic anhydride (0.75 mL, 4.44 mmol) were added dropwise, and the reaction mixture was stirred at RT for 1 hour. After the reaction was completed (monitored by TLC), the reaction mixture was diluted with water (10 mL) and the aqueous layer was extracted with DCM (2x20 mL). The combined organic layer was washed with brine (5 mL) and anhydrous Na 2 SO 4 Dry, filter and concentrate under vacuum. The crude material was purified by Isolera column chromatography (eluent: 20-22% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 62.8% (1.4 g, white solid).

[0712] LCMS: (Method A) 673.0 (M + +H), Rt.3.53min, 89.35% (Max).

[0713] Intermediate 23

[0714] 3-Butyl-3-ethyl-2-(4-methoxybenzyl)-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-carboxylic acid methyl ester 1,1-dioxide

[0715]

[0716] To a stirred solution of 3-butyl-3-ethyl-2-(4-methoxybenzyl)-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl trifluoromethanesulfonate (Intermediate 22; 1.4 g, 2.08 mmol) in degassed methanol (20 mL) and DMF (5 mL) were added triethylamine (0.29 mL, 2.08 mmol), dppf (138 mg, 0.25 mmol) and Pd 2 (dba) 3 (110 mg, 0.13 mmol). The resulting reaction mixture was stirred at 70 ° C for 16 hours in an autoclave under 10 kg carbon monoxide pressure. After the reaction was completed (monitored by TLC), the reaction mixture was diluted with water (20 mL) and the aqueous layer was extracted with EtOAc (2x50 mL). The combined organic layer was washed with water (15 mL) and brine (15 mL), and then washed with anhydrous Na2 SO 4 Dry. Filter the organic portion, concentrate in vacuo, and purify the resulting crude material by Isolera column chromatography (eluent: 10-12% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 67% (1 g, off-white solid).

[0717] LCMS: (Method A) 583.2 (M + +H), Rt.3.26min, 81.20% (Max).

[0718] Intermediate 24

[0719] 3-Butyl-3-ethyl-8-(hydroxymethyl)-2-(4-methoxybenzyl)-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide

[0720]

[0721] To a stirred solution of 3-butyl-3-ethyl-2-(4-methoxybenzyl)-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-carboxylic acid methyl ester 1,1-dioxide (Intermediate 23; 1 g, 1.72 mmol) in dry THF (10 mL) was added lithium aluminum hydride (2M in THF, 1.27 mL, 2.54 mmol) at 0 ° C, and the reaction mixture was stirred at RT for 1 hour. After the reaction was completed (monitored by TLC), the reaction mixture was cooled to 0 ° C and quenched with saturated aqueous ammonium chloride solution (10 mL). The aqueous layer was extracted with EtOAc (2x20 mL), and the combined organic layers were washed with water (10 mL) and brine (10 mL), and then washed with anhydrous Na 2 SO 4 Dry. Filter the organic portion, concentrate in vacuo, and purify the resulting crude material by Isolera column chromatography (eluent: 20-25% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 51% (550 mg, off-white solid).

[0722] Intermediate 25

[0723] Ethyl 2-(((3-butyl-3-ethyl-2-(4-methoxybenzyl)-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetate

[0724]

[0725] To a stirred solution of 3-butyl-3-ethyl-8-(hydroxymethyl)-2-(4-methoxybenzyl)-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (intermediate 24; 200 mg, 0.36 mmol) in DCM (5 mL) at 0 ° C, zinc iodide (60 mg, 0.18 mmol) and ethyl 2-mercaptoacetate (43.3 mg, 0.36 mmol) were added, and the reaction mixture was stirred at RT for 2 hours. After the reaction was completed (monitored by TLC), the reaction mixture was diluted with water (10 mL) and the aqueous layer was extracted with EtOAc (2x15 mL). The combined organic layer was washed with water (5 mL) and brine (5 mL) and dried over anhydrous Na 2 SO 4 Dry. Filter the organic portion, concentrate in vacuo and use the resulting crude material in the next step without further purification. Yield: 32.8% (160 mg, light yellow sticky solid).

[0726] Intermediate 26

[0727] Ethyl 2-(((3-butyl-3-ethyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetate

[0728]

[0729] To a stirred solution of ethyl 2-(((3-butyl-3-ethyl-2-(4-methoxybenzyl)-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetate (Intermediate 25; 160 mg, 0.24 mmol) in toluene (10 mL) at 0°C, triphenylamine (120 mg, 0.48 mmol) and trifluoroacetic acid (0.19 mL, 2.44 mmol) were added dropwise, and the reaction mixture was stirred at RT for 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice-cold water (10 mL) and the aqueous layer was extracted with EtOAc (2x10 mL). The combined organic layers were washed with water (10 mL) and brine (10 mL), then purified by anhydrous Na 2 SO 4 Dry. Filter the organic portion, concentrate in vacuo, and purify the resulting crude material by Isolera column chromatography (eluent: 20-25% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 73.2% (100 mg, light brown solid).

[0730] LCMS: (Method A) 535.21 (M + -H), Rt.2.96min, 95.72% (Max).

[0731] Intermediate 27

[0732] 3-Butyl-2-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl trifluoromethanesulfonate

[0733]

[0734] To a stirred solution of 3-butyl-8-hydroxy-2-methyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (1.0 g, 2.460 mmol) in dry DCM (10 mL) at 0 ° C, pyridine (0.38 mL, 4.92 mmol) was added dropwise. Trifluoromethanesulfonic anhydride (0.83 mL, 2.95 mmol) was then added, and the reaction mixture was stirred at RT for 1 hour. After the reaction was completed (monitored by TLC), the reaction mixture was diluted with water (10 mL) and the aqueous layer was extracted with DCM (2x20 mL). The combined organic layers were washed with brine (5 mL) and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate under vacuum. The crude material was purified by Isolera column chromatography (eluent: 20-22% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 63% (1.0 g, white solid).

[0735] UPLC-MS: (Method A) 539.1 (M + +H), Rt.2.64min, 92.69% (Max).

[0736] Intermediate 28

[0737] 3-Butyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-carboxylic acid methyl ester 1,1-dioxide

[0738]

[0739] To a stirred solution of 3-butyl-2-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl trifluoromethanesulfonate (Intermediate 27; 1.0 g, 1.85 mmol) in degassed methanol (15 mL) and DMF (10 mL) were added triethylamine (0.38 mL, 2.78 mmol), dppf (0.13 g, 0.22 mmol) and Pd 2 (dba) 3 (0.102 g, 0.11 mmol). The resulting reaction mixture was then stirred at 70 °C for 16 hours in an autoclave under 10 kg carbon monoxide pressure. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water (20 mL) and the aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with water (15 mL), brine (15 mL), and then washed with anhydrous Na 2 SO 4 Dry. Filter the organic portion, concentrate in vacuo, and purify the resulting crude material by Isolera column chromatography (eluent: 10-12% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 50.4% (600 mg, off-white solid).

[0740] UPLC-MS: (Method A) 449.1 (M + +H), Rt.2.46min, 69.04% (Max).

[0741] Intermediate 29

[0742] 3-Butyl-8-(hydroxymethyl)-2-methyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide

[0743]

[0744] To a stirred solution of 3-butyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-carboxylic acid methyl ester 1,1-dioxide (Intermediate 28; 0.6 g, 1.34 mmol) in dry THF (10 mL) at 0 ° C, lithium aluminum hydride (2M in THF, 1.05 mL, 2.10 mmol) was added dropwise, and the reaction mixture was stirred at RT for 1 hour. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with saturated aqueous ammonium chloride (10 mL) and the aqueous layer was extracted with EtOAc (2x20 mL). The combined organic layer was washed with water (10 mL) and brine (10 mL), and then dried over anhydrous Na 2 SO4 Dry. Filter the organic portion, concentrate in vacuo, and purify the resulting crude product by Isolera column chromatography (eluent: 20-25% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 86% (500 mg, off-white solid).

[0745] Intermediate 30

[0746] Ethyl 2-(((3-butyl-2-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetate

[0747]

[0748] To a stirred solution of 3-butyl-8-(hydroxymethyl)-2-methyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (intermediate 29; 0.25 g, 0.59 mmol) in DCM (5 mL) at 0 ° C, zinc iodide (II) (0.09 g, 0.29 mmol) and ethyl 2-mercaptoacetate (0.14 g, 1.19 mmol) were added, and the reaction mixture was stirred at RT for 1 hour. After the reaction was completed (monitored by TLC), the reaction mixture was diluted with water (10 mL) and the aqueous layer was extracted with EtOAc (2x10 mL). The combined organic layer was washed with water (10 mL) and brine (10 mL), and then dried over anhydrous Na 2 SO 4 Dry. Filter the organic portion, concentrate in vacuo and carry the resulting crude material to the next step without any purification. Yield: 48% (0.2 g, light yellow solid).

[0749] Intermediate 31

[0750] 7-Bromo-3-butyl-3-ethyl-8-hydroxy-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide

[0751]

[0752] To a stirred solution of 7-bromo-3-butyl-3-ethyl-8-methoxy-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide (3 g, 6.43 mmol) in DCM (10 mL) at -15 °C was added BBr dropwise 3(1M in DCM, 12.86mL, 12.86mmol), and the reaction mixture was stirred for 10 minutes. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with methanol (10mL) at 0°C and concentrated under vacuum. The resulting crude material was purified by Isolera column chromatography (eluent: 0-30% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 48% (2.9g, brown solid).

[0753] Intermediate 32

[0754] 3-Butyl-3-ethyl-8-hydroxy-7-methoxy-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide

[0755]

[0756] To a stirred solution of 7-bromo-3-butyl-3-ethyl-8-hydroxy-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide (Intermediate 31; 2.0 g, 4.42 mmol) in sodium methoxide (28% in methanol, 15 mL) was added copper (I) bromide (0.63 g, 4.42 mmol) at RT, and the reaction mixture was heated at 85 ° C for 6 hours. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with water (10 mL) and the aqueous layer was extracted with EtOAc (2x25 mL). The combined organic layer was washed with water (15 mL) and brine (15 mL), and the mixture was purified by anhydrous Na 2 SO 4 The organic layer was concentrated in vacuo and the resulting crude material was purified by Isolera column chromatography (eluent: 0-30% EtOAc / PE; silica gel: 230-400 mesh) to afford the title compound. Yield: 48% (2 g, brown solid).

[0757] LCMS: (Method A) 404.1 (M + +H), Rt.2.94min, 98.03% (Max).

[0758] Intermediate 33

[0759] 3-Butyl-3-ethyl-7-methoxy-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl trifluoromethanesulfonate

[0760]

[0761] To a stirred solution of 3-butyl-3-ethyl-8-hydroxy-7-methoxy-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide (Intermediate 32; 1.0 g, 2.48 mmol) in dry DCM (10 mL) at 0 ° C, pyridine (0.2 mL, 2.48 mmol) and trifluoromethanesulfonic anhydride (0.41 mL, 2.48 mmol) were added, and the reaction mixture was stirred at RT for 1 hour. After the reaction was completed (monitored by TLC), the reaction mixture was diluted with water (10 mL) and the aqueous layer was extracted with DCM (2x20 mL). The combined organic layers were washed with brine (5 mL) and brine (10 mL), and then washed with anhydrous Na 2 SO 4 Dry. The organic portion was concentrated in vacuo and the resulting crude material was purified by Isolera column chromatography (eluent: 7-8% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 68% (900 mg, white solid).

[0762] LCMS: (Method A) 536.1 (M + +H), Rt.3.10min, 97.27% (Max).

[0763] Intermediate 34

[0764] 3-Butyl-3-ethyl-7-methoxy-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-carboxylic acid methyl ester 1,1-dioxide

[0765]

[0766] To a stirred solution of 3-butyl-3-ethyl-7-methoxy-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl trifluoromethanesulfonate (Intermediate 33; 0.9 g, 1.68 mmol) in degassed methanol (15 mL) and DMF (5 mL) was added triethylamine (0.35 mL, 2.52 mmol), Pd 2 (dba) 3 (0.08 g, 0.08 mmol) and dppf (0.11 g, 0.20 mmol). The resulting reaction mixture was stirred at 70 ° C for 16 hours in an autoclave under 5 kg carbon monoxide pressure. After the reaction was completed (monitored by TLC), the reaction mixture was diluted with water (20 mL) and the aqueous layer was extracted with EtOAc (2x50 mL). The combined organic layer was washed with water (15 mL) and brine (15 mL), and then washed with anhydrous Na 2 SO 4Dry. Filter the organic portion, concentrate in vacuo, and purify the resulting crude material by Isolera column chromatography (eluent: 0-30% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 16% (0.6 g, off-white solid).

[0767] Intermediate 35

[0768] 3-Butyl-3-ethyl-8-(hydroxymethyl)-7-methoxy-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide

[0769]

[0770] To a stirred solution of 3-butyl-3-ethyl-7-methoxy-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-carboxylic acid methyl ester 1,1-dioxide (Intermediate 34; 0.2 g, 0.45 mmol) in THF (5 mL) at 0 ° C, lithium aluminum hydride (2M in THF, 0.22 mL, 0.44 mmol) was added dropwise, and the reaction mixture was stirred at RT for 1 hour. After the reaction was completed (monitored by TLC), the reaction mixture was cooled to 0 ° C and quenched with saturated aqueous ammonium chloride solution (10 mL). The aqueous layer was extracted with EtOAc (2x20 mL), and the combined organic layers were washed with water (10 mL) and brine (10 mL), and then washed with anhydrous Na 2 SO 4 Dry. Filter the organic portion, concentrate in vacuo, and purify the resulting crude product by Isolera column chromatography (eluent: 20% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 95% (190 mg, white solid).

[0771] Intermediate 36

[0772] Ethyl 2-(((3-butyl-3-ethyl-7-methoxy-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)acetate

[0773]

[0774] To a stirred solution of 3-butyl-3-ethyl-8-(hydroxymethyl)-7-methoxy-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide (intermediate 35; 0.19g, 0.46mmol) in DCM at 0°C, ethyl 2-mercaptoacetate (0.11g, 0.91mmol) was added, followed by zinc (II) iodide (0.07g, 0.23mmol), and the reaction mixture was stirred at RT for 3 hours. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with water (5mL) and the aqueous layer was extracted with DCM (2x10mL). The combined organic layer was washed with water (5mL) and brine (5mL), then filtered through anhydrous Na 2 SO 4 Dry. Filter the organic layer, concentrate in vacuo and purify the crude material by Isolera column chromatography (eluent: 0-30% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 60% (0.15 g, white solid).

[0775] Intermediate 37

[0776] 2-(((3-Butyl-3-ethyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxido-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)-2-methylpropanoic acid methyl ester

[0777]

[0778] To a stirred solution of 3-butyl-3-ethyl-5-(4-fluorophenyl)-8-(hydroxymethyl)-7-(methylthio)-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide (intermediate 15; 250mg, 0.58mmol) in DCM (5mL) at 0°C, 2-mercapto-2-methylpropionic acid methyl ester (81mg, 0.61mmol) and zinc iodide (70mg, 0.22mmol) were added, and the reaction mixture was stirred at RT for 3 hours. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with water (5mL) and the aqueous layer was extracted with DCM (2x10mL). The combined organic layer was washed with brine (10mL) and dried over anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo to afford the title compound. Yield: 76.2% (230 mg, brown gum).

[0779] Intermediate 38

[0780] 2-(((3,3-dibutyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)-2-methylpropanoic acid methyl ester

[0781]

[0782] To a stirred solution of 3,3-dibutyl-8-(hydroxymethyl)-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide (intermediate 7, 0.15g, 0.33mmol) in DCM (5mL) at 0°C, 2-mercapto-2-methylpropionic acid methyl ester (0.05g, 0.36mmol) and zinc iodide (II) (0.05g, 0.16mmol) were added, and the reaction mixture was stirred at RT for 1 hour. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with water (5mL) and the aqueous layer was extracted with DCM (2x10mL). The combined organic layer was washed with brine (10mL) and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo to afford the title compound. Yield: 48% (0.09 g, brown gum).

[0783] Intermediate 39

[0784] 2-(((3-butyl-3-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)-2-methylpropanoic acid methyl ester

[0785]

[0786] To a stirred solution of 3-butyl-8-(hydroxymethyl)-3-methyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide (intermediate 11; 0.07g, 0.17mmol) in DCM (5mL) at 0°C, 2-mercapto-2-methylpropionic acid methyl ester (0.05g, 0.33mmol) and zinc (II) iodide (16mg, 0.09mmol) were added, and the reaction mixture was stirred at RT for 1 hour. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with water (5mL) and the aqueous layer was extracted with DCM (2x15mL). The combined organic layer was washed with brine (20mL) and dried over anhydrous Na 2 SO 4Dry, filter and concentrate under vacuum. The crude material was purified by Isolera column chromatography (eluent: 20% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 75% (0.05 g, white solid).

[0787] Intermediate 40

[0788] 3-Butyl-3-ethyl-2-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl trifluoromethanesulfonate

[0789]

[0790] To a stirred solution of 3-butyl-3-ethyl-8-hydroxy-2-methyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (1.5 g, 2.77 mmol) in DCM (10 mL) at 0 ° C, pyridine (0.67 mL, 8.32 mmol) and trifluoromethanesulfonic anhydride (0.14 mL, 1.76 mmol) were added dropwise, and the reaction mixture was stirred at RT for 1 hour. After the reaction was completed (monitored by TLC), the reaction mixture was diluted with water (20 mL) and the aqueous layer was extracted with DCM (2x20 mL). The combined organic layer was washed with water (20 mL), brine (20 mL), and then anhydrous Na 2 SO 4 Dry. Filter the organic portion, concentrate in vacuo, and purify the resulting crude material by Isolera column chromatography (eluent: 20% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 97% (1.85 g, white solid).

[0791] LCMS: (Method A) 567.1 (M + +H), Rt.3.32min, 97.97% (Max).

[0792] Intermediate 41

[0793] 3-Butyl-3-ethyl-2-methyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-carboxylic acid methyl ester 1,1-dioxide

[0794]

[0795] To a solution of 3-butyl-3-ethyl-2-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl trifluoromethanesulfonate (Intermediate 40; 1.85 g, 3.26 mmol) in degassed methanol (10 mL) and DMF (5 mL) was added triethylamine (0.45 mL, 3.26 mmol), dppf (0.22 g, 0.39 mmol) and Pd 2 (dba) 3 (0.18 g, 0.19 mmol). The resulting reaction mixture was stirred at 75 ° C for 16 hours in an autoclave under 5 kg carbon monoxide pressure. After the reaction was completed (monitored by TLC), the reaction mixture was diluted with water (20 mL) and the aqueous layer was extracted with EtOAc (2x20 mL). The combined organic layer was washed with water (10 mL), brine (10 mL), and then washed with anhydrous Na 2 SO 4 Dry. Filter the organic layer, concentrate in vacuo, and purify the resulting crude material by Isolera column chromatography (eluent: 12% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 48.5% (1 g, off-white solid).

[0796] LCMS: (Method A) 477.1 (M + +H), Rt.3.16min, 75.49% (Max).

[0797] Intermediate 42

[0798] 3-Butyl-3-ethyl-8-(hydroxymethyl)-2-methyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide

[0799]

[0800] To a stirred solution of 3-butyl-3-ethyl-2-methyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-carboxylic acid methyl ester 1,1-dioxide (Intermediate 41; 1 g, 2.09 mmol) in THF (10 mL) was added lithium aluminum hydride (2M solution in THF, 1.57 mL, 3.15 mmol) dropwise at 0 ° C, and the reaction mixture was stirred at RT for 1 hour. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with saturated aqueous ammonium chloride (5 mL) and the aqueous layer was extracted with EtOAc (2x20 mL). The combined organic layer was washed with water (15 mL), brine (15 mL), and then anhydrous Na 2 SO4 Dry. Filter the organic portion, concentrate in vacuo, and purify the resulting crude product by Isolera column chromatography (eluent: 20% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 53% (0.5 g, off-white solid).

[0801] 1 H NMR (400 MHz, CDCl 3 ): δ7.83(s,1H),7.42-7.38(m,2H),724-7.19(m,3H),6.40(s,1H),4.67-4.65(d,J=6.4Hz,2H),4.40-4.28(m,2H),3.04( s,3H),2.11-2.07(m,4H),1.90-1.87(m,2H),1.56-1.55(m,1H),1.28-1.11(m,2H),1.02-0.95(m,2H),0.82-0.75(m,6H).

[0802] Separation of enantiomers:

[0803] (S)-3-Butyl-3-ethyl-8-(hydroxymethyl)-2-methyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide and (R)-3-Butyl-3-ethyl-8-(hydroxymethyl)-2-methyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide

[0804]

[0805] The two enantiomers of racemic 3-butyl-3-ethyl-8-(hydroxymethyl)-2-methyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (0.3 g, 0.67 mmol) were separated by chiral SFC (Method H). The material was concentrated in vacuo at 45°C. The first eluting fraction corresponded to enantiomer 1 and the second eluting fraction to enantiomer 2. The absolute configuration of the two enantiomers is unknown.

[0806] Enantiomer 1: Yield: 39% (0.12 g, white solid). Chiral HPLC (Method H) Rt. 3.16 min, 99.85% (Max).

[0807] Enantiomer 2: Yield: 32.9% (0.1 g, white solid). Chiral HPLC (Method H) Rt. 3.84 min, 98.34% (Max).

[0808] Intermediate 43

[0809] Ethyl 2-(((3-butyl-3-ethyl-2-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetate

[0810]

[0811] To a stirred solution of 3-butyl-3-ethyl-8-(hydroxymethyl)-2-methyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (intermediate 42; 500mg, 1.11mmol) in DCM (5mL) at 0°C, zinc iodide (356mg, 1.11mmol) and ethyl 2-mercaptoacetate (134mg, 1.11mmol) were added, and the reaction mixture was stirred at RT for 2 hours. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with water (5mL) and the aqueous layer was extracted with DCM (2x15mL). The combined organic layer was washed with brine (20mL) and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate under vacuum. The crude material was purified by Isolera column chromatography (eluent: 12% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 25.7% (0.15 g, colorless gum).

[0812] 1 H NMR (400 MHz, DMSO-d 6 ): δ7.59(s,1H),7.42-7.38(m,2H),7.34-7.32(m,2H),7.18-7.14(m,1H),6. 41(s,1H),4.38-4.2(m,1H),4.17-4.13(m,3H),3.82(s,2H),3.28(s,3H),3. 17(s,2H),2.89(s,3H),2.07(s,3H),1.92-1.80(m,2H),1.46-1.49(m,2H),1 .21-1.18(m,2H),0.96-0.90(m,2H),0.75-0.69(m,6H).LCMS:(Method A)549.2(M + -H), Rt. 3.23min, 99.79% (Max). HPLC: (Method B) Rt. 6.67min, 99.83% (Max).

[0813] Intermediate 44

[0814] Ethyl (S)-2-(((3-butyl-3-ethyl-2-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetate and Ethyl (R)-2-(((3-butyl-3-ethyl-2-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetate

[0815]

[0816] Following the same procedure as described for intermediate 43, but starting from 50 mg of enantiomers 1 and 2 of intermediate 42, respectively, enantiomers 1 and 2 of the title compound were obtained. The absolute configuration of the two enantiomers is unknown.

[0817] Enantiomer 1: Yield: 73% (45 mg, colorless gum). 1 H NMR (400 MHz, DMSO-d 6 ): δ7.59(s,1H),7.42-7.38(m,2H),7.35-7.33(m,2H),7.18-7.16(m,1H) ,6.41(s,1H),4.20-4.13(m,2H),4.12-4.08(m,2H),3.82(s,2H),3.28(s ,2H),2.90(s,3H),2.07(s,3H),1.99-1.82(m,1H),1.80-1.78(m,1H),1. 55-1.48(m,2H),1.23-1.16(m,5H),1.02-0.99(m,2H),0.74-0.69(m,6H).

[0818] Enantiomer 2: Yield: 74% (45 mg, colorless gum). 1 H NMR (400 MHz, DMSO-d 6): δ7.60(s,1H),7.42-7.38(m,2H),7.33-7.31(m,2H),7.18-7.14(m,1H) ,6.41(s,1H),4.20-4.13(m,2H),4.12-4.08(m,2H),3.82(s,2H),3.28(s ,2H),2.90(s,3H),2.07(s,3H),1.99-1.82(m,1H),1.80-1.78(m,1H),1. 55-1.48(m,2H),1.24-1.16(m,5H),1.02-0.99(m,2H),0.74-0.69(m,6H).

[0819] Intermediate 45

[0820] 3,3-Dibutyl-8-methoxy-2-methyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide

[0821]

[0822] To a stirred solution of 3,3-dibutyl-8-hydroxy-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (0.38 g, 0.85 mmol) in NMP (5 mL) at 0°C was added Cs 2 CO 3 (0.55 g, 1.69 mmol). Iodomethane (0.11 mL, 1.69 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with water (20 mL) and the aqueous layer was extracted with EtOAc (2x20 mL). The combined organic layer was washed with water (15 mL) and brine (15 mL), and then purified by anhydrous Na 2 SO 4 Dry. Filter the organic portion, concentrate in vacuo, and purify the resulting crude material by Isolera column chromatography (eluent: 15% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 84% (0.34 g, off-white solid).

[0823] LCMS: (Method E) 477.3 (M + +H), Rt.3.30min, 99.44% (Max).

[0824] Intermediate 46

[0825] 3,3-Dibutyl-8-hydroxy-2-methyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide

[0826]

[0827] To a stirred solution of 3,3-dibutyl-8-methoxy-2-methyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (Intermediate 45; 0.34 g, 0.71 mmol) in DMF (5 mL), sodium thiomethoxide (0.25 g, 3.57 mmol) was added at room temperature, and the reaction mixture was heated at 100 ° C for 16 hours. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with water (20 mL) and the aqueous layer was extracted with EtOAc (2x25 mL). The combined organic layer was washed with water (15 mL) and brine (15 mL), and the mixture was purified by anhydrous Na 2 SO 4 Dry. Filter the organic layer and concentrate under vacuum. The crude material was purified by Isolera column chromatography (eluent: 0-30% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 62.4% (0.3 g, white solid).

[0828] LCMS: (Method A) 463.1 (M + +H), Rt.4.18min, 68.61% (Max).

[0829] Intermediate 47

[0830] 3,3-Dibutyl-2-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl trifluoromethanesulfonate

[0831]

[0832] To a stirred solution of 3,3-dibutyl-8-hydroxy-2-methyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (Intermediate 46; 0.3 g, 0.65 mmol) in DCM (5 mL) at 0 ° C, pyridine (0.10 mL, 1.29 mmol) and trifluoromethanesulfonic anhydride (0.16 mL, 0.97 mmol) were added dropwise, and the reaction mixture was stirred at RT for 30 minutes. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water (10 mL) and the aqueous layer was extracted with DCM (2x20 mL). The combined organic layer was washed with water (20 mL), brine (20 mL), and then anhydrous Na 2 SO 4 Dry. Filter the organic portion, concentrate in vacuo, and purify the resulting crude material by Isolera column chromatography (eluent: 20% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 89% (0.35 g, off-white solid).

[0833] LCMS: (Method A) 595.1 (M + +H), Rt.3.65min,98.61%(Max).

[0834] Intermediate 48

[0835] 3,3-Dibutyl-2-methyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-carboxylic acid methyl ester 1,1-dioxide

[0836]

[0837] To a solution of 3,3-dibutyl-2-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl trifluoromethanesulfonate (Intermediate 47; 0.35 g, 0.59 mmol) in degassed methanol (10 mL) and DMF (5 mL) was added triethylamine (0.12 mL, 0.88 mmol), dppf (0.03 g, 0.04 mmol) and Pd 2 (dba) 3 (0.04 g, 0.07 mmol). The resulting reaction mixture was stirred at 75 ° C for 16 hours in an autoclave under 5 kg carbon monoxide pressure. After the reaction was completed (monitored by TLC), the reaction mixture was diluted with water (20 mL) and the aqueous layer was extracted with EtOAc (2x20 mL). The combined organic layer was washed with water (10 mL), brine (10 mL), and then washed with anhydrous Na 2SO 4 Dry. Filter the organic layer, concentrate in vacuo, and purify the resulting crude material by Isolera column chromatography (eluent: 12% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 39.3% (0.18 g, white solid).

[0838] LCMS: (Method A) 505.2 (M + +H), Rt.3.41min, 64.78% (Max).

[0839] Intermediate 49

[0840] 3,3-Dibutyl-8-(hydroxymethyl)-2-methyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide

[0841]

[0842] To a stirred solution of 3,3-dibutyl-2-methyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-carboxylic acid methyl ester 1,1-dioxide (Intermediate 48; 0.18 g, 0.36 mmol) in THF (5 mL) was added lithium aluminum hydride (2.4 M in THF, 0.22 mL, 0.54 mmol) at 0 ° C, and the reaction mixture was stirred at RT for 1 hour. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with saturated aqueous ammonium chloride (5 mL) and the aqueous layer was extracted with EtOAc (3x20 mL). The combined organic layer was washed with water (15 mL), brine (15 mL), and anhydrous Na 2 SO 4 Dry. Filter the organic portion, concentrate in vacuo, and purify the resulting crude product by Isolera column chromatography (eluent: 25% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 64.3% (0.11 g, off-white solid).

[0843] 1 H NMR (400 MHz, DMSO-d 6):δ7.75(s,1H),7.4-7.36(m,2H),730-7.28(m,2H),7.14-7.11(m,1H),6.43(s,1H),5.36-5.33(m,1H),4.04-4.39(m,2H),4.16-4.04(m,2H),2.87(s,3H),2.07(s,3H),1.99-1.79(m,2H),1.50-1.45(m,2H),1.24-1.09(m,8H),0.98-0.97(m,6H).LCMS:(Method A)477.0(M + +H), Rt.3.29min, 99.42% (Max).

[0844] Intermediate 50

[0845] Ethyl 2-(((3,3-dibutyl-2-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetate

[0846]

[0847] To a stirred solution of 3,3-dibutyl-8-(hydroxymethyl)-2-methyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (intermediate 49; 0.11 g, 0.23 mmol) in DCM (5 mL) at 0 ° C, zinc iodide (II) (0.037 g, 0.12 mmol) and ethyl 2-mercaptoacetate (0.05 g, 0.46 mmol) were added, and the reaction mixture was stirred at RT for 1 hour. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with water (5 mL) and the aqueous layer was extracted with DCM (2x10 mL). The combined organic layer was washed with brine (20 mL) and dried over anhydrous Na 2 SO 4 Dry, filter and concentrate under vacuum. The crude material was purified by Isolera column chromatography (eluent: 12% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 82% (0.11 g, off-white solid).

[0848] 1 H NMR (400 MHz, DMSO-d 6): δ7.59(s,1H),7.42-7.38(m,2H),7.35-7.33(m,2H),7.18-7.16(m,1H) ,6.41(s,1H),4.20-4.13(m,2H),4.12-4.10(m,2H),3.82(s,2H),3.28(s, 2H),2.90(s,3H),2.07(s,3H),1.99-1.82(m,2H),1.54-1.47(m,2H),1.24 -1.00 (m, 11H), 0.75-0.72 (m, 6H). HPLC: (Method B) Rt. 6.67min, 99.83% (Max).

[0849] Intermediate 51

[0850] 2-(((3,3-dibutyl-2-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)-2-methylpropanoic acid methyl ester

[0851]

[0852] To a stirred solution of 3,3-dibutyl-8-(hydroxymethyl)-2-methyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (intermediate 49; 0.38 g, 0.79 mmol) in DCM (10 mL) at 0 ° C, 2-mercapto-2-methylpropionic acid methyl ester (0.21 g, 1.59 mmol) and zinc iodide (0.13 g, 0.39 mmol) were added, and the reaction mixture was stirred at RT for 2 hours. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with water (5 mL) and the aqueous layer was extracted with DCM (2x15 mL). The combined organic layer was washed with brine (20 mL) and dried over anhydrous Na 2 SO 4 Dry, filter and concentrate under vacuum. The crude material was purified by Isolera column chromatography (eluent: 17% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 87% (0.4 g, white solid).

[0853] 1 H NMR (400 MHz, DMSO-d 6): δ7.57(s,1H),7.32-7.42(m,4H),7.16-7.18(m,1H),6.37(s,1H),4.18-4.26(m,2H),3.82(s,2H),3.64(s,3H),2 .89(s,3H),2.06(s,3H),1.82-1.89(m,2H),1.48(s,7H),1.42-1.43(m,1H),1.10-1.23(m,8H),0.67-0.75(m,6H).

[0854] Intermediate 52

[0855] 2-(((3-Butyl-3-ethyl-2-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)-2-methylpropanoic acid methyl ester

[0856]

[0857] To a stirred solution of 3-butyl-3-ethyl-8-(hydroxymethyl)-2-methyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (intermediate 42; 0.4g, 0.89mmol) in DCM (10mL) at 0°C, 2-mercapto-2-methylpropionic acid methyl ester (0.24g, 1.78mmol) and zinc iodide (0.14g, 0.45mmol) were added and the reaction mixture was placed at room temperature for 2 hours. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with water (5mL) and the aqueous layer was extracted with DCM (2x15mL). The combined organic layer was washed with brine (20mL) and dried over anhydrous Na 2 SO 4 Dry, filter and concentrate under vacuum. The crude material was purified by Isolera column chromatography (eluent: 17% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 83.3% (0.42 g, white solid).

[0858] 1 H NMR (400 MHz, DMSO-d 6): δ7.58(s,1H),7.43-7.30(m,4H),7.18-7.16(m,1H),6.37(s,1H),4.16(s,2H),3.82(s,2H),3.65(s,3H),2.8 9(s,3H),2.07(s,3H),1.87-1.84(m,2H),1.48(s,8H),1.18-1.11(m,2H),0.91-0.72(m,2H),0.69-0.51(m,6H).

[0859] Intermediate 53

[0860] 2-(((3-Butyl-3-ethyl-7-methoxy-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)-2-methylpropanoic acid methyl ester

[0861]

[0862] To a stirred solution of 3-butyl-3-ethyl-8-(hydroxymethyl)-7-methoxy-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide (intermediate 35; 0.35 g, 0.83 mmol) in DCM (5 mL) at 0 ° C, 2-mercapto-2-methylpropionic acid methyl ester (0.22 g, 1.68 mmol) and zinc (II) iodide (0.13 g, 0.42 mmol) were added, and the reaction mixture was stirred at RT for 1 hour. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with water (15 mL), and the aqueous layer was extracted with DCM (2X 15 mL). The combined organic layer was washed with brine (20 mL) and dried over anhydrous Na 2 SO 4 Dry. Filter the organic portion and concentrate in vacuo. The crude material obtained is purified by Isolera column chromatography (eluent: 20% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 67.3% (0.35 g, white solid).

[0863] Intermediate 54

[0864] 7-Bromo-3-butyl-8-hydroxy-3-methyl-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide

[0865]

[0866] To a stirred solution of 7-bromo-3-butyl-8-methoxy-3-methyl-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide (2.5 g, 5.53 mmol) in DCM (10 mL) at -15 °C was added BBr dropwise 3 (1M in DCM, 11.05mL, 11.05mmol), and the reaction mixture was stirred for 10 minutes. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with methanol (10mL) and concentrated in vacuo. The resulting crude material was purified by Isolera column chromatography (eluent: 0-30% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 89% (2.1g, brown solid).

[0867] LCMS: (Method E) 440.1 (M + +2), Rt.2.57min, 96.55% (Max).

[0868] Intermediate 55

[0869] 3-Butyl-8-hydroxy-7-methoxy-3-methyl-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide

[0870]

[0871] To a stirred solution of 7-bromo-3-butyl-8-hydroxy-3-methyl-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide (Intermediate 54; 2.1 g, 4.79 mmol) in sodium methoxide (30% in methanol, 20 mL) was added copper (I) bromide (0.69 g, 4.79 mmol) at RT and the reaction mixture was heated at 85 °C for 6 hours. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with water (10 mL) and the aqueous layer was extracted with EtOAc (2x25 mL). The combined organic layers were washed with water (15 mL), brine (15 mL) and purified by anhydrous Na 2 SO 4 Dry. Filter the organic layer, concentrate in vacuo and purify the crude material by Isolera column chromatography (eluent: 0-30% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 85% (1.6 g, brown solid).

[0872] LCMS: (Method A) 390.1 (M + +H), Rt.2.94min, 99.05% (Max).

[0873] Intermediate 56

[0874] 3-Butyl-7-methoxy-3-methyl-1,1-dioxy-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl trifluoromethanesulfonate

[0875]

[0876] To a stirred solution of 3-butyl-8-hydroxy-7-methoxy-3-methyl-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide (Intermediate 55; 1.3 g, 3.34 mmol) in DCM (10 mL) at 0°C, pyridine (0.26 mL, 3.34 mmol) and trifluoromethanesulfonic anhydride (0.55 mL, 3.34 mmol) were added dropwise, and the reaction mixture was stirred at RT for 1 hour. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water (20 mL) and the aqueous layer was extracted with DCM (2x50 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), and washed with anhydrous Na 2 SO 4 The organic portion was filtered, concentrated in vacuo, and the crude material was purified by Isolera column chromatography (eluent: 20% EtOAc / PE; silica gel: 230-400 mesh). The sticky solid was triturated with petroleum ether (2x10 mL) and dried under vacuum to give the title compound. Yield: 73.9% (1.3 g, off-white solid).

[0877] 1 H NMR (400 MHz, CDCl 3 ):δ7.87(s,1H),7.41-7.37(m,2H),7.20-7.14(m,3H),6.33(s,1H),3.97-3.96(m,1H),3.79-3.76(m,1H),3.66(s,3H),3.28-3.18(m,2H),1.56-1.52(m,1H),1.49-1.39(m,1H),1.38-1.32(m,2H),1.27-1.22(m,5H),0.87-0.79(m,3H).LCMS:(Method E)522.2(M + +H), Rt.2.77min, 99.09% (Max).

[0878] Intermediate 57

[0879] 3-Butyl-7-methoxy-3-methyl-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-carboxylic acid methyl ester 1,1-dioxide

[0880]

[0881] To a solution of 3-butyl-7-methoxy-3-methyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl trifluoromethanesulfonate (Intermediate 56; 1.30 g, 2.49 mmol) in degassed methanol (15 mL) and DMF (10 mL) was added triethylamine (0.51 mL, 3.74 mmol), dppf (0.17 g, 0.29 mmol) and Pd 2 (dba) 3 (0.11 g, 0.13 mmol). The resulting reaction mixture was stirred at 75 ° C for 16 hours in an autoclave under 5 kg carbon monoxide pressure. After the reaction was completed (monitored by TLC), the reaction mixture was diluted with water (20 mL) and the aqueous layer was extracted with EtOAc (2x50 mL). The combined organic layer was washed with water (15 mL), brine (15 mL), and anhydrous Na 2 SO 4 Dry. Filter the organic portion, concentrate in vacuo, and purify the resulting crude material by Isolera column chromatography (eluent: 15% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 64.24% (0.7 g, off-white solid).

[0882] 1 H NMR (400 MHz, CDCl 3 ): δ8.58(s,1H),7.44-7.41(m,2H),7.25-7.20(m,3H),6.12(s,1H),4.07-4.04(m,1H),3.91(s,1H),3.86(s,3H),3.59(s,3H),3.3 7-3.34(m,1H),3.26-3.22(m,1H),1.62-1.52(m,1H),1.38-1.36(m,1H),1.22-1.04(m,7H),0.80-0.77(m,3H).LCMS: (Method A) 432.1(M + +H), Rt.2.72min, 99.28% (Max).

[0883] Intermediate 58

[0884] 3-Butyl-8-(hydroxymethyl)-7-methoxy-3-methyl-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide

[0885]

[0886] To a stirred solution of 3-butyl-7-methoxy-3-methyl-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-carboxylic acid methyl ester 1,1-dioxide (Intermediate 57; 0.7 g, 1.62 mmol) in THF (10 mL) was added lithium aluminum hydride (2M in THF, 0.81 mL, 1.62 mmol) at 0°C, and the reaction mixture was stirred at RT for 1 hour. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with saturated aqueous ammonium chloride (10 mL) and the aqueous layer was extracted with EtOAc (2x25 mL). The combined organic layers were washed with water (15 mL), brine (15 mL), and anhydrous Na 2 SO 4 Dry. Filter the organic portion, concentrate in vacuo and use the resulting crude material in the next step without further purification. Yield: 600 mg (crude, off-white solid).

[0887] 1 H NMR (400 MHz, CDCl 3 ): δ7.94(s,1H),7.34-7.30(m,2H),7.29-7.28(m,2H),7.14-7.03(m,1H),6.36(s,1H),4.66(s,2H),3.87-3.78(m,1H),3.67 (s,4H),3.26-3.22(m,1H),3.26-3.22(m,1H),1.45-1.30(m,6H),1.28-1.12(m,3H),0.84-0.81(m,3H).LCMS: (Method A) 404.1(M + +H), Rt.2.44min, 99.91% (Max).

[0888] Intermediate 59

[0889] Ethyl 2-(((3-butyl-7-methoxy-3-methyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)acetate

[0890]

[0891] To a stirred solution of 3-butyl-8-(hydroxymethyl)-7-methoxy-3-methyl-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide (intermediate 58; 0.3g, 0.74mmol) in DCM (10mL) at 0°C, ethyl 2-mercaptoacetate (0.18g, 1.49mmol) and zinc (II) iodide (0.12g, 0.37mmol) were added, and the reaction mixture was stirred at RT for 1 hour. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with water (20mL) and the aqueous layer was extracted with DCM (2x20mL). The combined organic portion was washed with brine (10mL) and dried over anhydrous Na 2 SO 4 Dry. Filter the organic portion and concentrate in vacuo. The crude material obtained is purified by Isolera column chromatography (eluent: 20% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 66.5% (0.25 g, white solid).

[0892] Intermediate 60

[0893] 7-Bromo-3-butyl-5-(4-fluorophenyl)-8-hydroxy-2-methyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide

[0894]

[0895] To a stirred solution of 7-bromo-3-butyl-5-(4-fluorophenyl)-8-methoxy-2-methyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (2.0 g, 4.24 mmol) in DCM (20 mL) at -15 °C was added BBr dropwise 3 (1M in DCM, 4.24mL, 4.24mmol), and the reaction mixture was stirred at this temperature for 10 minutes. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with methanol (15mL) and the reaction mixture was concentrated under vacuum. The resulting crude material was purified by Isolera column chromatography (eluent: 0-30% EtOAc / PE; silica gel: 230-400 mesh) to obtain the title compound. Yield: 80% (1.6g, brown solid).

[0896] 1 H NMR (400 MHz, DMSO-d 6):δ11.09(s,1H),7.50(s,1H),7.45(s,1H),7.01(t,J=8.8Hz,2H),6.59-6.56(m,2H),4.04-3.97(m,1H),3.86-3.82(m,1H),3.25-3.22(m,1H),2.46(s,3H),1.49-1.46(m,1H),1.30-1.32(m,5H),0.92-0.90(m,3H).LCMS:(Method A)455(M + -2), Rt.2.67min, 97.17% (Max).

[0897] Intermediate 61

[0898] 3-Butyl-5-(4-fluorophenyl)-8-hydroxy-7-methoxy-2-methyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide

[0899]

[0900] To a stirred solution of 7-bromo-3-butyl-5-(4-fluorophenyl)-8-hydroxy-2-methyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (Intermediate 60; 1.6 g, 3.50 mmol) in sodium methoxide (30% solution in methanol, 10 mL) was added copper (I) bromide (0.50 g, 3.50 mmol) at RT and the reaction mixture was heated at 85 °C for 6 hours. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with water (10 mL) and the aqueous layer was extracted with EtOAc (2x25 mL). The combined organic layers were washed with water (15 mL), brine (15 mL) and purified by anhydrous Na 2 SO 4 Dry. Filter the organic layer, concentrate in vacuo and purify the crude material by Isolera column chromatography (eluent: 0-30% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 85% (1.4 g, brown solid).

[0901] 1 H NMR (400 MHz, DMSO-d 6): δ9.87(s,1H),7.26(s,1H),6.99-6.95(m,2H),6.88(s,1H),6.56-6.53(m,2H),4.06-3.97(m,1H),3.92-3.86(m,1H),3.33(s,3H ),3.21-3.16(m,1H),2.40(s,3H),1.6-1.56(m,1H),1.48-1.45(m,1H),1.34-1.29(m,4H),0.92-0.89(m,3H).LCMS: (Method K) 409.2(M + +H), Rt.2.27min, 86.65% (Max).

[0902] Intermediate 62

[0903] 3-Butyl-5-(4-fluorophenyl)-7-methoxy-2-methyl-1,1-dioxido-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl trifluoromethanesulfonate

[0904]

[0905] To a stirred solution of 3-butyl-5-(4-fluorophenyl)-8-hydroxy-7-methoxy-2-methyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (intermediate 61; 1.4 g, 3.43 mmol) in DCM (15 mL) at 0 ° C, pyridine (0.55 mL, 6.85 mmol) and trifluoromethanesulfonic anhydride (0.86 mL, 5.14 mmol) were added dropwise, and the reaction mixture was stirred at RT for 1 hour. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with ice-cold water (20 mL) and the aqueous layer was extracted with DCM (2x50 mL). The combined organic layer was washed with water (10 mL), brine (10 mL), and anhydrous Na 2 SO 4 The organic portion was filtered, concentrated in vacuo, and the crude material was purified by Isolera column chromatography (eluent: 20% EtOAc / PE; silica gel: 230-400 mesh) to give a sticky solid. The sticky solid was triturated with petroleum ether (2x10 mL) and dried under vacuum to give the title compound. Yield: 76% (1.5 g, off-white solid).

[0906] 1 H NMR (400 MHz, DMSO-d 6): δ7.78(s,1H),7.13-7.17(m,3H),6.92-6.89(m,2H),4.08-4.02(m,1H),3.83(s,3H),3.73-3.71(m,1H),3 .59-3.51(m,1H),2.68(s,3H),1.56-1.55(m,2H),1.37-1.33(m,4H),0.91-0.88(m,3H).LCMS: (Method E) 541.2(M + +H), Rt.2.74min, 94.32% (Max).

[0907] Intermediate 63

[0908] 3-Butyl-5-(4-fluorophenyl)-7-methoxy-2-methyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-carboxylic acid methyl ester 1,1-dioxide

[0909]

[0910] To a solution of 3-butyl-5-(4-fluorophenyl)-7-methoxy-2-methyl-1,1-dioxido-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl trifluoromethanesulfonate (Intermediate 62; 1.5 g, 2.77 mmol) in degassed methanol (15 mL) and DMF (10 mL) at RT were added triethylamine (0.58 mL, 4.16 mmol), dppf (0.18 g, 0.33 mmol) and Pd 2 (dba) 3 (0.15 g, 0.16 mmol). The resulting reaction mixture was stirred at 75 ° C for 16 hours in an autoclave under 5 kg carbon monoxide pressure. After the reaction was completed (monitored by TLC), the reaction mixture was diluted with water (20 mL) and the aqueous layer was extracted with EtOAc (2x50 mL). The combined organic layer was washed with water (15 mL), brine (15 mL), and anhydrous Na 2 SO 4 Dry. Filter the organic portion, concentrate in vacuo, and purify the resulting crude material by Isolera column chromatography (eluent: 15% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 86% (1.1 g, off-white solid).

[0911] 1 H NMR (400 MHz, DMSO-d 6): δ8.15(s,1H),7.18-7.06(m,4H),6.60(s,1H),4.05-4.00(m,1H),3.79(s,4H),3.66(s,4H ),2.68(s,3H),1.57-1.53(m,2H),1.38-1.26(m,4H),0.91-0.87(m,3H).LCMS: (Method A) 451.1(M + +H), Rt.3.08min, 97.59% (Max).

[0912] Intermediate 64

[0913] 3-Butyl-5-(4-fluorophenyl)-8-(hydroxymethyl)-7-methoxy-2-methyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide

[0914]

[0915] To a stirred solution of 3-butyl-5-(4-fluorophenyl)-7-methoxy-2-methyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-carboxylic acid methyl ester 1,1-dioxide (Intermediate 63; 1.1 g, 2.44 mmol) in THF (10 mL) was added lithium aluminum hydride (1M in THF, 2.44 mL, 2.44 mmol) at 0°C, and the reaction mixture was stirred at RT for 1 hour. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with saturated aqueous ammonium chloride (10 mL) and the aqueous layer was extracted with EtOAc (2x15 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), and anhydrous Na 2 SO 4 Dry. Filter the organic portion, concentrate in vacuo and use the resulting crude material in the next step without further purification. Yield: 87% (0.9 g, off-white solid).

[0916] 1 H NMR (400 MHz, DMSO-d 6 ): δ7.89(s,1H),7.02(t,J=8.8Hz,2H),6.85(s,1H),6.70-6.67(m,2H),5.33-5.30(m,1H),4.53-4.50(m,2H),4.04- 3.99(m,1H),3.77(s,4H),3.34-3.32(m,1H),2.45(s,3H),1.57-1.56(m,2H),1.35-1.31(m,4H),0.92-0.89(m,3H).

[0917] Intermediate 65

[0918] Ethyl 2-(((3-butyl-5-(4-fluorophenyl)-7-methoxy-2-methyl-1,1-dioxido-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetate

[0919]

[0920] To a stirred solution of 3-butyl-5-(4-fluorophenyl)-8-(hydroxymethyl)-7-methoxy-2-methyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (intermediate 64; 0.35 g, 0.83 mmol) in DCM (10 mL) at 0 ° C, ethyl 2-mercaptoacetate (0.199 g, 1.66 mmol) and zinc iodide (0.13 g, 0.41 mmol) were added, and the reaction mixture was stirred at RT for 2 hours. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with water (5 mL) and the aqueous layer was extracted with DCM (2x15 mL). The combined organic layer was washed with brine (20 mL) and dried over anhydrous Na 2 SO 4 Dry, filter and concentrate under vacuum. The crude material was purified by Isolera column chromatography (eluent: 15% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 79% (0.37 g, white gum).

[0921] 1 H NMR (400 MHz, DMSO-d 6 ): δ7.74(s,1H),7.03(s,2H),6.88(s,1H),6.73(s,2H),4.12-4.00(m,3H),3.83(s,2H),3.77(s,3H ),3.38(s,2H),2.51-2.47(m,3H),1.54(s,2H),1.34(s,3H),1.23-1.21(m,4H),0.91-0.93(m,3H).

[0922] Intermediate 66

[0923] 7-Bromo-3,3-dibutyl-8-hydroxy-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide

[0924]

[0925] To a stirred solution of 7-bromo-3,3-dibutyl-8-methoxy-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide (3.3 g, 6.67 mmol) in DCM (5 mL) at -15 °C was added BBr dropwise 3 (1M in DCM, 12.86mL, 12.86mmol), and the reaction mixture was stirred for 10 minutes. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with methanol (10mL) at 0°C and concentrated in vacuo. The resulting crude material was purified by Isolera column chromatography (eluent: 0-30% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 86% (2.5g, brown solid).

[0926] LCMS: (Method A) 480.0 (M + +H), Rt.3.16min, 70.09% (Max).

[0927] Intermediate 67

[0928] 3,3-Dibutyl-8-hydroxy-7-methoxy-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide

[0929]

[0930] To a stirred solution of 7-bromo-3,3-dibutyl-8-hydroxy-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide (Intermediate 66; 2 g, 4.16 mmol) in sodium methoxide (28% in methanol, 20 mL) was added copper (I) bromide (0.59 g, 4.16 mmol) at RT, and the reaction mixture was heated at 85 ° C for 6 hours. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with water (10 mL) and the aqueous layer was extracted with EtOAc (2x50 mL). The combined organic layers were washed with water (25 mL), brine (25 mL), and anhydrous Na 2 SO 4 Dry. Filter the organic layer, concentrate in vacuo, and purify the resulting crude material by Isolera column chromatography (eluent: 0-30% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 59.4% (1.2 g, brown solid).

[0931] LCMS: (Method A) 430.1 (M + +H), Rt.2.70min, 89.19% (Max).

[0932] Intermediate 68

[0933] 3,3-Dibutyl-7-methoxy-1,1-dioxy-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl trifluoromethanesulfonate

[0934]

[0935] To a stirred solution of 3,3-dibutyl-8-hydroxy-7-methoxy-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide (Intermediate 67; 1.2 g, 2.78 mmol) in dry DCM (10 mL) at 0°C, pyridine (0.11 mL, 1.39 mmol) and trifluoromethanesulfonic anhydride (0.46 mL, 2.78 mmol) were added dropwise, and the reaction mixture was stirred at RT for 1 hour. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water (10 mL) and the aqueous layer was extracted with DCM (2x50 mL). The combined organic layers were washed with water (5 mL), brine (5 mL), and purified by anhydrous Na 2 SO 4 The organic portion was filtered, concentrated in vacuo, and the crude material was purified by Isolera column chromatography (eluent: 20% EtOAc / PE; silica gel: 230-400 mesh). The sticky solid of the resulting compound was triturated with petroleum ether (2x10 mL) and dried under vacuum to give the title compound. Yield: 61% (1.1 g, off-white solid).

[0936] LCMS: (Method A) 564.1 (M + +H), Rt.3.31min, 89.09% (Max).

[0937] Intermediate 69

[0938] 3,3-Dibutyl-7-methoxy-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-carboxylic acid methyl ester 1,1-dioxide

[0939]

[0940] To a solution of 3,3-dibutyl-7-methoxy-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl trifluoromethanesulfonate (Intermediate 68; 1.10 g, 1.95 mmol) in degassed methanol (10 mL) and DMF (15 mL) were added triethylamine (0.29 g, 2.93 mmol), dppf (0.13 g, 0.23 mmol) and Pd 2 (dba) 3(0.09 g, 0.09 mmol). The resulting reaction mixture was stirred at 70 ° C for 16 hours in an autoclave under 5 kg carbon monoxide pressure. After the reaction was completed (monitored by TLC), the reaction mixture was diluted with water (20 mL) and the aqueous layer was extracted with EtOAc (2x50 mL). The combined organic layer was washed with water (15 mL), brine (15 mL), and anhydrous Na 2 SO 4 Dry. Filter the organic portion, concentrate in vacuo, and purify the resulting crude material by Isolera column chromatography (eluent: 15% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 74.4% (0.8 g, off-white solid).

[0941] LCMS: (Method A) 474.1 (M + +H), Rt.3.08min, 86.01% (Max).

[0942] Intermediate 70

[0943] 3,3-Dibutyl-8-(hydroxymethyl)-7-methoxy-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide

[0944]

[0945] To a stirred solution of 3,3-dibutyl-7-methoxy-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-carboxylic acid methyl ester 1,1-dioxide (Intermediate 69; 0.8 g, 1.69 mmol) in THF (10 mL) was added lithium aluminum hydride (2M in THF, 1.69 mL, 1.69 mmol) at 0°C, and the reaction mixture was stirred at RT for 1 hour. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with saturated aqueous ammonium chloride (10 mL) and the aqueous layer was extracted with EtOAc (2x50 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), and washed with anhydrous Na 2 SO 4 Dry. Filter the organic portion, concentrate in vacuo and use the resulting crude material in the next step without further purification. Yield: 95% (0.75 g, off-white solid).

[0946] LCMS: (Method E) 446.3 (M + +H), Rt.2.66min, 95.15% (Max).

[0947] Intermediate 71

[0948] Ethyl 2-(((3,3-dibutyl-7-methoxy-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)acetate

[0949]

[0950] To a stirred solution of 3,3-dibutyl-8-(hydroxymethyl)-7-methoxy-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide (intermediate 70; 0.2g, 0.45mmol) in DCM (5mL) at 0°C, ethyl 2-mercaptoacetate (0.108g, 0.89mmol) and zinc (II) iodide (0.07g, 0.22mmol) were added, and the reaction mixture was stirred at RT for 1 hour. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with water (15mL) and the aqueous layer was extracted with DCM (2x20mL). The combined organic layer was washed with brine (20mL) and dried over anhydrous Na 2 SO 4 Dry. Filter the organic portion and concentrate in vacuo. The crude material obtained is purified by Isolera column chromatography (eluent: 20% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 61% (0.15 g, white solid).

[0951] Intermediate 72

[0952] 7-Bromo-3,3-dibutyl-5-(4-fluorophenyl)-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide

[0953]

[0954] To a stirred solution of 7-bromo-3,3-dibutyl-5-(4-fluorophenyl)-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide (2 g, 3.90 mmol) in DCM (20 mL) at 0°C was added BBr dropwise at -15°C. 3 (1M solution in DCM, 3.90mL, 3.90mmol), and the reaction mixture was stirred for 10 minutes. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with methanol (20mL), and the organic part was concentrated under vacuum. The resulting solid was distributed between water (5mL) and EtOAc (5mL), and the aqueous layer was extracted with EtOAc (2x15mL). The combined organic layer was washed with water (10mL) and brine (15mL), then filtered through anhydrous Na 2 SO 4Dry. Filter the organic portion, concentrate in vacuo, and purify the resulting crude material by Isolera column chromatography (eluent: 20% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 87% (1.69 g, white solid).

[0955] LCMS: (Method A) 496.1 (M + -H), Rt.3.07min, 94.28% (Max).

[0956] Intermediate 73

[0957] 3,3-Dibutyl-5-(4-fluorophenyl)-8-hydroxy-7-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide

[0958]

[0959] To a stirred solution of 7-bromo-3,3-dibutyl-5-(4-fluorophenyl)-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide (Intermediate 72; 1.69 g, 3.39 mmol) in sodium methoxide (28% in methanol, 20 mL) was added cuprous bromide (0.59 g, 4.16 mmol) at room temperature and the reaction mixture was heated at 85 °C for 6 hours. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with water (10 mL) and the aqueous layer was extracted with EtOAc (2x25 mL). The combined organic layers were washed with water (15 mL) and brine (15 mL) and purified by anhydrous Na 2 SO 4 The organic layer was filtered and concentrated in vacuo and the resulting crude material was purified by Isolera column chromatography (eluent: 0-30% EtOAc / PE; silica gel: 230-400 mesh) to afford the title compound.

[0960] Yield: 97% (1.5 g, brown solid). LCMS: (Method A) 450.2 (M + +H), Rt.3.26min, 98.43% (Max).

[0961] Intermediate 74

[0962] 3,3-Dibutyl-5-(4-fluorophenyl)-7-methoxy-1,1-dioxido-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl trifluoromethanesulfonate

[0963]

[0964] To a stirred solution of 3,3-dibutyl-5-(4-fluorophenyl)-8-hydroxy-7-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide (Intermediate 73; 1.5 g, 3.34 mmol) in DCM (10 mL) at 0°C, pyridine (0.27 mL, 3.34 mmol) and trifluoromethanesulfonic anhydride (0.56 mL, 0.33 mmol) were added dropwise, and the reaction mixture was stirred at RT for 30 minutes. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water (5 mL) and the aqueous layer was extracted with DCM (2x20 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), and washed with anhydrous Na 2 SO 4 Dry. Filter the organic portion, concentrate in vacuo, and purify the resulting crude material by Isolera column chromatography (eluent: 8-10% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 77% (1.5 g, off-white solid).

[0965] LCMS: (Method G) 582.0 (M + +H), Rt.2.76min, 99.01% (Max).

[0966] Intermediate 75

[0967] 3,3-Dibutyl-5-(4-fluorophenyl)-7-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-carboxylic acid methyl ester 1,1-dioxide

[0968]

[0969] To a solution of 3,3-dibutyl-5-(4-fluorophenyl)-7-methoxy-1,1-dioxido-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl trifluoromethanesulfonate (Intermediate 74; 1.50 g, 2.58 mmol) in degassed methanol (15 mL) and DMF (10 mL) was added triethylamine (0.75 mL, 5.42 mmol), dppf (0.24 g, 0.43 mmol) and Pd 2 (dba) 3 (0.16 g, 0.18 mmol). The resulting reaction mixture was stirred at 75 ° C for 16 hours in an autoclave under 5 kg carbon monoxide pressure. After the reaction was completed (monitored by TLC), the reaction mixture was diluted with water (20 mL) and the aqueous layer was extracted with EtOAc (2x20 mL). The combined organic layer was washed with water (10 mL), brine (10 mL), and anhydrous Na 2 SO 4Dry. Filter the organic layer, concentrate in vacuo and purify the crude material by Isolera column chromatography (eluent: 10-15% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 77% (1 g, white solid).

[0970] 1 H NMR (400 MHz, DMSO-d 6 ):δ8.25(s,1H),7.54-7.51(m,2H),730-7.26(m,2H),6.03(s,1H),3.95-3.90(m,2H),3.76(s,3H),3.50(s,5H),1.45-1.42(m,2H),1.33-1.26(m,2H),1.13-1.08(m,4H),0.99-0.92(m,4H),0.75-0.72(m,6H).LCMS:(Method A)492.2(M + +H), Rt.3.05min, 97.78% (Max).

[0971] Intermediate 76

[0972] 3,3-Dibutyl-5-(4-fluorophenyl)-8-(hydroxymethyl)-7-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide

[0973]

[0974] To a stirred solution of 3,3-dibutyl-5-(4-fluorophenyl)-7-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-carboxylic acid methyl ester 1,1-dioxide (Intermediate 75; 1.5 g, 3.05 mmol) in THF (10 mL) was added lithium aluminum hydride (2M in THF, 1.53 mL, 3.05 mmol) at 0 °C, and the reaction mixture was stirred at RT for 30 minutes. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with saturated aqueous ammonium chloride solution (5 mL) and the aqueous layer was extracted with EtOAc (3x20 mL). The combined organic layers were washed with water (15 mL), brine (15 mL), and anhydrous Na 2 SO 4 Dry. Filter the organic portion, concentrate in vacuo, and purify the resulting crude product by Isolera column chromatography (eluent: 25% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 71% (1 g, off-white solid).

[0975] Intermediate 77

[0976] Ethyl 2-(((3,3-dibutyl-5-(4-fluorophenyl)-7-methoxy-1,1-dioxido-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)acetate

[0977]

[0978] To a stirred solution of 3,3-dibutyl-5-(4-fluorophenyl)-8-(hydroxymethyl)-7-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide (intermediate 76; 100 mg, 0.22 mmol) in DCM (10 mL) at 0 ° C, ethyl 2-mercaptoacetate (25.9 mg, 0.22 mmol) and zinc iodide (68.8 mg, 0.22 mmol) were added, and the reaction mixture was stirred at RT for 1 hour. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with water (5 mL) and the aqueous layer was extracted with DCM (2x10 mL). The combined organic layer was washed with brine (10 mL) and dried over anhydrous Na 2 SO 4 Dry, filter and concentrate under vacuum. The crude material was purified by Isolera column chromatography (eluent: 0-30% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 82% (0.1 g, brown gum).

[0979] Intermediate 78

[0980] 7-Bromo-3-butyl-3-ethyl-5-(4-fluorophenyl)-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide

[0981]

[0982] To a stirred solution of 7-bromo-3-butyl-3-ethyl-5-(4-fluorophenyl)-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide (3 g, 6.19 mmol) in DCM (20 mL) at -15 °C was added BBr dropwise 3 (1M in DCM, 12.39mL, 12.39mmol), and the reaction mixture was stirred for 10 minutes. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with methanol (15mL) and the reaction mixture was concentrated under vacuum. The resulting crude material was purified by Isolera column chromatography (eluent: 0-30% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 82% (2.38g, brown solid).

[0983] 1 H NMR (400 MHz, DMSO-d 6 ):δ10.83(s,1H),7.59(s,1H),7.12-7.05(m,5H),3.65-3.35(m,2H),3.25(s,2H),1.47-1.45(m,1H),1.37-1.33(m,3H),1.18-1.01(m,4H),0.77-0.71(m,6H).LCMS:(Method K)471.1(M + +H), Rt.2.46min, 97.17% (Max).

[0984] Intermediate 79

[0985] 3-Butyl-3-ethyl-5-(4-fluorophenyl)-8-hydroxy-7-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide

[0986]

[0987] To a stirred solution of 7-bromo-3-butyl-3-ethyl-5-(4-fluorophenyl)-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide (Intermediate 78; 2.3 g, 4.89 mmol) in sodium methoxide (30% solution in methanol, 20 mL) was added copper (I) bromide (0.70 g, 4.89 mmol) at RT and the reaction mixture was heated at 85 °C for 6 hours. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with water (10 mL) and the aqueous layer was extracted with EtOAc (2x25 mL). The combined organic layers were washed with water (15 mL), brine (15 mL), and washed with anhydrous Na 2 SO 4 Dry. Filter the organic layer, concentrate in vacuo and purify the crude material by Isolera column chromatography (eluent: 0-30% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 95% (2.0 g, brown solid).

[0988] LCMS: (Method E) 422.3 (M + +H), Rt.2.45min, 98.53% (Max).

[0989] Intermediate 80

[0990] 3-Butyl-3-ethyl-5-(4-fluorophenyl)-7-methoxy-1,1-dioxido-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl trifluoromethanesulfonate

[0991]

[0992] To a stirred solution of 3-butyl-3-ethyl-5-(4-fluorophenyl)-8-hydroxy-7-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide (Intermediate 79; 2 g, 4.74 mmol) in dry DCM (15 mL) at 0°C, pyridine (0.37 mL, 4.74 mmol) and trifluoromethanesulfonic anhydride (0.8 mL, 4.74 mmol) were added dropwise, and the reaction mixture was stirred at RT for 1 hour. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water (20 mL) and the aqueous layer was extracted with DCM (2x50 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), and washed with anhydrous Na 2 SO 4 The organic portion was filtered, concentrated in vacuo, and the crude material was purified by Isolera column chromatography (eluent: 20% EtOAc / PE; silica gel: 230-400 mesh) to give a sticky solid. The sticky solid was triturated with petroleum ether (2x10 mL) and dried under vacuum to give the title compound. Yield: 74.6% (2 g, off-white solid).

[0993] LCMS: (Method E) 554.2 (M + +H), Rt.2.82min, 98.24% (Max).

[0994] Intermediate 81

[0995] 3-Butyl-3-ethyl-5-(4-fluorophenyl)-7-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-carboxylic acid methyl ester 1,1-dioxide

[0996]

[0997] To a solution of 3-butyl-3-ethyl-5-(4-fluorophenyl)-7-methoxy-1,1-dioxido-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl trifluoromethanesulfonate (Intermediate 80; 2 g, 3.61 mmol) in degassed methanol (15 mL) and DMF (10 mL) was added triethylamine (0.75 mL, 5.42 mmol), dppf (0.24 g, 0.43 mmol) and Pd 2 (dba) 3(0.17 g, 0.18 mmol). The resulting reaction mixture was stirred at 75 ° C for 16 hours in an autoclave under 5 kg carbon monoxide pressure. After the reaction was completed (monitored by TLC), the reaction mixture was diluted with water (20 mL) and the aqueous layer was extracted with EtOAc (2x50 mL). The combined organic layer was washed with water (15 mL), brine (15 mL), and anhydrous Na 2 SO 4 Dry. Filter the organic portion, concentrate in vacuo, and purify the resulting crude material by Isolera column chromatography (eluent: 15% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 90% (1.5 g, off-white solid).

[0998] 1 H NMR (400 MHz, CDCl 3 ):δ8.58(s,1H),7.28-7.27(m,2H),7.24-7.13(m,2H),5.99(s,1H),3.94(s,2H),3.87(s,3H),3.59(s,3H),3.29(s,2H),1.68-1.65(m,1H),1.59-1.50(m,3H),1.27-1.11(m,4H),0.84-0.73(m,6H).LCMS:(Method A)464.2(M + +H), Rt.2.78min, 98.72% (Max).

[0999] Intermediate 82

[1000] 3-Butyl-3-ethyl-5-(4-fluorophenyl)-8-(hydroxymethyl)-7-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide

[1001]

[1002] To a stirred solution of 3-butyl-3-ethyl-5-(4-fluorophenyl)-7-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-carboxylic acid methyl ester 1,1-dioxide (Intermediate 81; 1.5 g, 3.24 mmol) in THF (10 mL) was added lithium aluminum hydride (2M in THF, 1.62 mL, 3.24 mmol) at 0 ° C, and the reaction mixture was stirred at RT for 1 hour. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with saturated aqueous ammonium chloride (10 mL) and the aqueous layer was extracted with EtOAc (2x15 mL). The combined organic layer was washed with water (10 mL), brine (10 mL), and anhydrous Na 2 SO4 Dry. Filter the organic portion, concentrate in vacuo and use the resulting crude material in the next step without further purification. Yield: 98% (1.4 g, off-white solid).

[1003] 1 H NMR (400 MHz, CDCl 3 ): δ7.94(s,1H),7.29-7.27(m,2H),7.19-7.15(m,2H),6.17(s,1H),4.64(s,2H),3.78-3.74(m,2H),3.6 3(s,3H),3.21-3.20(s,2H),1.66-1.61(m,2H),1.50-1.41(m,2H),1.30-1.09(m,4H),0.83-0.76(m,6H).

[1004] Intermediate 83

[1005] 2-(((3-Butyl-3-ethyl-5-(4-fluorophenyl)-7-methoxy-1,1-dioxido-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)-2-methylpropanoic acid methyl ester

[1006]

[1007] To a stirred solution of 3-butyl-3-ethyl-5-(4-fluorophenyl)-8-(hydroxymethyl)-7-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide (intermediate 82; 500mg, 1.15mmol) in DCM (5mL) at 0°C, 2-mercapto-2-methylpropionic acid methyl ester (308mg, 2.29mmol) and zinc (II) iodide (183mg, 0.57mmol) were added, and the reaction mixture was stirred at RT for 1 hour. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with water (15mL) and the aqueous layer was extracted with DCM (2x20mL). The combined organic layer was washed with brine (20mL) and dried over anhydrous Na 2 SO 4 Dry. Filter the organic portion and concentrate in vacuo. The crude material obtained is purified by Isolera column chromatography (eluent: 20% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 79% (0.5 g, white solid).

[1008] Intermediate 84

[1009] 7-Bromo-3-butyl-8-hydroxy-2-methyl-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide

[1010]

[1011] To a stirred solution of 7-bromo-3-butyl-8-methoxy-2-methyl-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (2.8 g, 6.18 mmol) in DCM (20 mL) at -15 °C was added BBr dropwise 3 (1M in DCM, 1.17mL, 12.35mmol), and the reaction mixture was stirred for 10 minutes. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with methanol (10mL) at 0°C and concentrated in vacuo. The resulting crude material was purified by Isolera column chromatography (eluent: 0-30% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 75% (2.1g, brown solid.

[1012] LCMS: (Method A) 439.0 (M + ),Rt.2.50min,97.55%(Max).

[1013] Intermediate 85

[1014] 3-Butyl-8-hydroxy-7-methoxy-2-methyl-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide

[1015]

[1016] To a stirred solution of 7-bromo-3-butyl-8-hydroxy-2-methyl-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (Intermediate 84; 2.1 g, 4.78 mmol) in sodium methoxide (30% in methanol, 20 mL) was added copper (I) bromide (0.69 g, 4.78 mmol) at RT, and the reaction mixture was heated at 85 ° C for 6 hours. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with water (10 mL) and the aqueous layer was extracted with EtOAc (2x25 mL). The combined organic layers were washed with water (15 mL) and brine (15 mL), and the mixture was dried over anhydrous Na 2 SO 4Dry. Filter the organic layer, concentrate in vacuo and purify the crude material by Isolera column chromatography (eluent: 0-30% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 79% (1.45 g, brown solid).

[1017] LCMS: (Method A) 391.2 (M + +H), Rt.2.46min, 98.62% (Max).

[1018] Intermediate 86

[1019] 3-Butyl-7-methoxy-2-methyl-1,1-dioxy-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl trifluoromethanesulfonate

[1020]

[1021] To a stirred solution of 3-butyl-8-hydroxy-7-methoxy-2-methyl-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (Intermediate 85; 1.5 g, 3.84 mmol) in DCM (10 mL) at 0°C, pyridine (0.30 mL, 3.84 mmol) and trifluoromethanesulfonic anhydride (0.64 mL, 3.84 mmol) were added dropwise, and the reaction mixture was stirred at RT for 1 hour. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water (20 mL) and the aqueous layer was extracted with DCM (2x50 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), and washed with anhydrous Na 2 SO 4 The organic portion was filtered, concentrated in vacuo, and the crude material was purified by Isolera column chromatography (eluent: 20% EtOAc / PE; silica gel: 230-400 mesh) to give a sticky solid. The solid was triturated with petroleum ether (2x10 mL) and dried in vacuo to give the title compound. Yield: 74.6% (1.5 g, off-white solid).

[1022] 1 H NMR (400 MHz, CDCl 3): δ7.80(s,1H),7.36-7.34(m,2H),7.06-7.04(m,1H),6.98-6.97(m,2H),6.65(s,1H),4.05-4.02(m,1H ),3.77(s,5H),2.75(s,3H),1.78-1.67(m,1H),1.57-1.50(m,3H),1.48-1.30(m,2H),0.95-0.85(m,3H).

[1023] Intermediate 87

[1024] 3-Butyl-7-methoxy-2-methyl-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-carboxylic acid methyl ester 1,1-dioxide

[1025]

[1026] To a solution of 3-butyl-7-methoxy-2-methyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl trifluoromethanesulfonate (Intermediate 86; 1.5 g, 2.87 mmol) in degassed methanol (15 mL) and dry DMF (10 mL) were added triethylamine (0.39 mL, 2.87 mmol), dppf (0.19 g, 0.34 mmol) and Pd 2 (dba) 3 (0.13 g, 0.14 mmol). The resulting reaction mixture was stirred at 75 ° C for 16 h in an autoclave under 5 kg carbon monoxide pressure. After the reaction was completed (monitored by TLC), the reaction mixture was diluted with water (20 mL) and the aqueous layer was extracted with EtOAc (2x50 mL). The combined organic layer was washed with water (15 mL), brine (15 mL), and anhydrous Na 2 SO 4 Dry. Filter the organic layer, concentrate in vacuo, and purify the crude material by Isolera column chromatography (eluent: 15% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 70.6% (0.9 g, off-white solid).

[1027] LCMS: (Method B) 433.1 (M + +H), Rt.2.45min, 97.35% (Max).

[1028] Intermediate 88

[1029] 3-Butyl-8-(hydroxymethyl)-7-methoxy-2-methyl-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide

[1030]

[1031] To a stirred solution of 3-butyl-7-methoxy-2-methyl-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-carboxylic acid methyl ester 1,1-dioxide (Intermediate 87; 0.9 g, 2.08 mmol) in THF (10 mL) was added lithium aluminum hydride (2M in THF, 2.08 mL, 4.16 mmol) dropwise at 0°C and the reaction mixture was stirred at RT for 1 hour. After completion of the reaction (monitored by TLC), the mixture was heated with saturated NH 4 The reaction mixture was quenched with Cl solution (10 mL) and the aqueous layer was extracted with EtOAc (2 x 25 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), and dried over anhydrous Na 2 SO 4 Dry. Filter the organic portion, concentrate in vacuo and use the resulting crude material in the next step without further purification. Yield: 87% (0.8 g, off-white solid).

[1032] 1 H NMR (400 MHz, CDCl 3 ): δ7.92(s,1H),7.28-7.25(m,2H),6.93-6.90(m,1H),6.86-6.84(m,2H),6.68(s,1H),4.75-4.72(m,2H),4.15-4.13(m,1H ),4.06-3.99(m,1H),3.51(s,3H),3.47-3.46(m,1H),2.65(s,3H),1.6-1.36(m,3H),1.30-1.26(m,3H),0.96-0.85(m,3H).

[1033] Intermediate 89

[1034] Ethyl 2-(((3-butyl-7-methoxy-2-methyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetate

[1035]

[1036] To a stirred solution of 3-butyl-8-(hydroxymethyl)-7-methoxy-2-methyl-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (intermediate 88; 0.4g, 0.98mmol) in DCM (5mL) at 0°C, ethyl 2-mercaptoacetate (0.12g, 0.99mmol) and zinc (II) iodide (0.32g, 0.99mmol) were added, and the reaction mixture was stirred at RT for 1 hour. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with water (15mL) and the aqueous layer was extracted with DCM (2x20mL). The combined organic layer was washed with brine (20mL) and dried over anhydrous Na 2 SO 4 Dry. Filter the organic portion and concentrate in vacuo. The crude material obtained is purified by Isolera column chromatography (eluent: 20% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 69.9% (0.35 g, white solid).

[1037] Intermediate 90

[1038] 2-(((3-Butyl-7-methoxy-2-methyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)-2-methylpropanoic acid methyl ester

[1039]

[1040] To a stirred solution of 3-butyl-8-(hydroxymethyl)-7-methoxy-2-methyl-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (intermediate 88; 0.4g, 0.99mmol) in DCM (5mL) at 0°C, ethyl 2-mercaptoacetate (0.12g, 0.99mmol) and zinc (II) iodide (0.32g, 0.99) were added, and the reaction mixture was stirred at RT for 1 hour. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with water (5mL) and the aqueous layer was extracted with DCM (2x20mL). The combined organic portion was washed with brine (10mL) and dried over anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo. The crude material was purified by Isolera column chromatography (eluent: 20% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 58.3% (0.3 g, white solid).

[1041] Intermediate 91

[1042] Ethyl 2-(((3-butyl-3-ethyl-5-(4-fluorophenyl)-7-methoxy-1,1-dioxido-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)acetate

[1043]

[1044] To a stirred solution of 3-butyl-3-ethyl-5-(4-fluorophenyl)-8-(hydroxymethyl)-7-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide (intermediate 82; 0.5 g, 1.15 mmol) in DCM (10 mL) at 0 ° C, ethyl 2-mercaptoacetate (0.28 g, 2.29 mmol) and zinc (II) iodide (0.18 g, 0.57 mmol) were added, and the reaction mixture was stirred at RT for 1 hour. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with water (5 mL) and the aqueous layer was extracted with DCM (2x15 mL). The combined organic layer was washed with brine (20 mL) and dried over anhydrous Na 2 SO 4 Dry. Filter the organic portion and concentrate in vacuo. The crude material was purified by Isolera column chromatography (eluent: 20% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 81% (500 mg, white solid).

[1045] Intermediate 92

[1046] 2-(((3-butyl-7-methoxy-3-methyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)-2-methylpropanoic acid methyl ester

[1047]

[1048] To a stirred solution of 3-butyl-8-(hydroxymethyl)-7-methoxy-3-methyl-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide (intermediate 58; 0.25g, 0.62mmol) in DCM (10mL) at 0°C, 2-mercapto-2-methylpropionic acid methyl ester (0.083g, 0.62mmol) and zinc (II) iodide (0.39g, 1.24mmol) were added, and the reaction mixture was stirred at RT for 1 hour. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with water (5mL) and the aqueous layer was extracted with DCM (2x15mL). The combined organic layer was washed with brine (20mL) and dried over anhydrous Na 2 SO 4Dry, filter and concentrate under vacuum. The crude material was purified by Isolera column chromatography (eluent: 20% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 78% (0.25 g, white solid).

[1049] Intermediate 93

[1050] 2-(((3,3-dibutyl-7-methoxy-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)-2-methylpropanoic acid methyl ester

[1051]

[1052] To a stirred solution of 3,3-dibutyl-8-(hydroxymethyl)-7-methoxy-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide (intermediate 70; 200 mg, 0.45 mmol) in DCM (5 mL) at 0 ° C, 2-mercapto-2-methylpropionic acid methyl ester (60.2 mg, 0.45 mmol) and zinc (II) iodide (143 mg, 0.45 mmol) were added, and the reaction mixture was stirred at RT for 1 hour. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with water (5 mL) and the aqueous layer was extracted with DCM (2x15 mL). The combined organic layer was washed with brine (20 mL) and dried over anhydrous Na 2 SO 4 Dry, filter and concentrate under vacuum. The crude material was purified by Isolera column chromatography (eluent: 20% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 91% (230 mg, white solid).

[1053] Intermediate 94

[1054] 7-Bromo-3-butyl-3-ethyl-8-methoxy-2-(4-methoxybenzyl)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide

[1055]

[1056] At 0°C, 7-bromo-3-butyl-3-ethyl-8-methoxy-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (4 g, 8.56 mmol) was dissolved in NMP (40 mL), Cs 2 CO 3(5.56g, 17.13mmol) in a stirred solution, then 1-(chloromethyl)-4-methoxybenzene (2.01g, 12.84mmol) was added dropwise, and the reaction mixture was stirred at RT for 16 hours. After the reaction was completed (monitored by TLC), the reaction mixture was diluted with water (50mL) and the aqueous layer was extracted with ethyl acetate (2x50mL). The combined organic layer was washed with brine (30mL) and filtered through anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The crude product was purified by Isolera column chromatography (eluent: 0-50% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 63% (5 g, yellow gum).

[1057] LCMS: (Method G) 587.1 (M + +H), Rt.2.92min,63.50%(Max).

[1058] Intermediate 95

[1059] 7-Bromo-3-butyl-3-ethyl-8-hydroxy-2-(4-methoxybenzyl)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide

[1060]

[1061] To a stirred solution of 7-bromo-3-butyl-3-ethyl-8-methoxy-2-(4-methoxybenzyl)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (Intermediate 94; 5 g, 8.51 mmol) in DMSO (50 mL) was added lithium chloride (1.80 g, 42.5 mmol) at 0°C, and the reaction mixture was stirred at 140°C for 24 hours. After completion of the reaction (monitored by UPLC), the reaction mixture was quenched with ice-cold water (25 mL) and the resulting solid was filtered off. The resulting crude product was purified by Isolera column chromatography (eluent: 0-15% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 28% (1.4 g, off-white solid).

[1062] LCMS: (Method E) 575.1 (M + +2), Rt.2.71min, 97.53% (Max).

[1063] Intermediate 96

[1064] 3-Butyl-3-ethyl-8-hydroxy-7-methoxy-2-(4-methoxybenzyl)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide

[1065]

[1066] To a stirred solution of 7-bromo-3-butyl-3-ethyl-8-hydroxy-2-(4-methoxybenzyl)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (Intermediate 95; 1 ​​g, 1.74 mmol) in methanol (15 mL) was added sodium methoxide (25% in methanol, 2 mL, 8.72 mmol) and copper (I) bromide (0.25 g, 1.74 mmol) at 0°C and the reaction mixture was stirred at 75°C for 16 hours. After completion of the reaction (monitored by UPLC), the reaction mixture was diluted with water (20 mL) and the aqueous layer was extracted with EtOAc (50 mL). The combined organic layers were washed with brine (30 mL) and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure. 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: 62% (0.66 g, off-white solid).

[1067] LCMS: (Method B) 523.1 (M + -H), Rt.2.71min, 85.40% (Max).

[1068] Intermediate 97

[1069] 3-Butyl-3-ethyl-7-methoxy-2-(4-methoxybenzyl)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl trifluoromethanesulfonate

[1070]

[1071] To a stirred solution of 3-butyl-3-ethyl-8-hydroxy-7-methoxy-2-(4-methoxybenzyl)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (Intermediate 96; 660 mg, 1.26 mmol) in DCM (10 mL) at 0 ° C, pyridine (0.21 mL, 2.52 mmol) was added, followed by trifluoromethanesulfonic anhydride (0.32 mL, 1.89 mmol), and the reaction mixture was stirred at RT for 1 hour. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water (25 mL) and the aqueous layer was extracted with DCM (2x25 mL). The combined organic layers were washed with brine (30 mL) and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure. 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: 76% (0.65 g, off-white solid).

[1072] Intermediate 98

[1073] 3-Butyl-3-ethyl-7-methoxy-2-(4-methoxybenzyl)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-carboxylic acid methyl ester 1,1-dioxide

[1074]

[1075] A stirred solution of 3-butyl-3-ethyl-7-methoxy-2-(4-methoxybenzyl)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl trifluoromethanesulfonate (Intermediate 97; 650 mg, 0.99 mmol) in methanol (10 mL) and DMF (5 mL) was purged with nitrogen for 15 minutes. Pd was then added. 2 (dba) 3 (91 mg, 0.10 mmol), triethylamine (0.27 mL, 1.98 mmol) and dppf (54.9 mg, 0.10 mmol), and the reaction mixture was stirred at 70 ° C in a micro pressure reactor under 5 kg carbon monoxide pressure for 16 hours. After the reaction was completed (monitored by UPLC), the reaction mixture was filtered through a diatomaceous earth bed and the filtrate was concentrated to obtain a crude compound. 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: 34% (0.21 g, white solid).

[1076] LCMS: (Method B) 567.3 (M + +H)Rt.2.74Min,91.55%(Max).

[1077] Intermediate 99

[1078] 3-Butyl-3-ethyl-8-(hydroxymethyl)-7-methoxy-2-(4-methoxybenzyl)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide

[1079]

[1080] To a stirred solution of 3-butyl-3-ethyl-7-methoxy-2-(4-methoxybenzyl)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-carboxylic acid methyl ester 1,1-dioxide (Intermediate 98; 20 mg, 0.04 mmol) in THF (10 mL) was added dropwise LiAlH 4 (2M solution in THF, 0.035 mL, 0.04 mmol), and the reaction mixture was stirred at RT for 30 minutes. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with saturated aqueous ammonium chloride (25 mL) at 0°C and the aqueous layer was extracted with EtOAc (15 mL). The organic layer was washed with anhydrous Na 2 SO 4 Dry and concentrate in vacuo. The crude product was used in the next step without further purification. Yield: 89% (19 mg, crude).

[1081] LCMS: (Method B) 539.1 (M + +H), Rt.2.60Min, 92.50%(Max)

[1082] Intermediate 100

[1083] Ethyl 2-(((3-butyl-3-ethyl-7-methoxy-2-(4-methoxybenzyl)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetate

[1084]

[1085] To a stirred solution of 3-butyl-3-ethyl-8-(hydroxymethyl)-7-methoxy-2-(4-methoxybenzyl)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (Intermediate 99; 180 mg, 0.32 mmol) in DCM (5 mL) at 0 ° C, ethyl 2-mercaptoacetate (39.0 mg, 0.32 mmol) was added, followed by zinc iodide (104 mg, 0.32 mmol). The reaction mixture was then stirred at room temperature for 3 hours. After the reaction was completed (monitored by TLC), the reaction mixture was concentrated and quenched with water (30 mL). The aqueous layer was extracted with EtOAc (2x15 mL). The combined organic layers were separated and washed with anhydrous Na 2 SO 4 Dry and concentrate under high vacuum. The crude product was used directly in the next step without further purification. Yield: 250 mg (crude, off-white solid).

[1086] Intermediate 101

[1087] 2-(((3-Butyl-3-ethyl-7-methoxy-2-(4-methoxybenzyl)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetic acid

[1088]

[1089] To a stirred solution of ethyl 2-(((3-butyl-3-ethyl-7-methoxy-2-(4-methoxybenzyl)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetate (Intermediate 100; 200 mg, 0.31 mmol) in a mixture of 1,4-dioxane and water (1:1; 4 mL) was added LiOH (74.7 mg, 3.12 mmol) and the reaction mixture was stirred at RT for 1 hour. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with dilute HCl (1.5 N, 10 mL) and the aqueous layer was extracted with EtOAc (2×15 mL). The combined organic layers were separated and washed with anhydrous NaHCO 3 40% water. 2 SO 4 Dry and concentrate under high 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: 42% (0.2 g, off-white solid).

[1090] UPLC: (Method B) 611.0 (M +-H),Rt.1.51Min,50.26%(Max).

[1091] Intermediate 102

[1092] 3-Butyl-7-(dimethylamino)-3-ethyl-8-methoxy-2-(4-methoxybenzyl)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide

[1093]

[1094] To a stirred solution of 7-bromo-3-butyl-3-ethyl-8-methoxy-2-(4-methoxybenzyl)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (Intermediate 94; 0.5 g, 0.85 mmol) in 1,4-dioxane (5 mL) was added dimethylamine (40% aqueous solution, 0.2 mL, 1.70 mmol), sodium tert-butoxide (0.49 g, 5.11 mmol), Pd 2 (dba) 3 (0.08 g, 0.09 mmol) and RuPhos (0.08 g, 0.17 mmol), and the reaction mixture was stirred at 70 ° C for 2 hours. After the reaction was completed (monitored by TLC), the reaction mixture was diluted with water (25 mL), and the aqueous layer was extracted with EtOAc (2x25 mL). The organic layer was washed with brine (25 mL) and washed with anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure. 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: 98% (0.5 g, off-white solid).

[1095] LCMS: (Method A) 552.3 (M + +H), Rt.2.29min, 92.37% (Max).

[1096] Intermediate 103

[1097] 3-Butyl-7-(dimethylamino)-3-ethyl-8-hydroxy-2-(4-methoxybenzyl)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide

[1098]

[1099] To a stirred solution of 3-butyl-7-(dimethylamino)-3-ethyl-8-methoxy-2-(4-methoxybenzyl)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (Intermediate 102; 1.0 g, 1.81 mmol) in DMF (10 mL) was added sodium thiomethoxide (0.64 g, 9.06 mmol) and the reaction mixture was stirred at 70 ° C for 6 hours. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with water (25 mL) and the aqueous layer was extracted with EtOAc (2x25 mL). The organic layer was separated and washed with anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo. 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: 75% (0.8 g, off-white solid).

[1100] LCMS: (Method B) 538.3 (M + +H), Rt.2.49min, 91.11% (Max).

[1101] Intermediate 104

[1102] 3-Butyl-7-(dimethylamino)-3-ethyl-2-(4-methoxybenzyl)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl trifluoromethanesulfonate

[1103]

[1104] To a stirred solution of 3-butyl-7-(dimethylamino)-3-ethyl-8-hydroxy-2-(4-methoxybenzyl)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (intermediate 103; 1.3 g, 2.42 mmol) in DCM (10 mL) at 0 ° C, pyridine (0.39 mL, 4.84 mmol) and trifluoromethanesulfonic anhydride (0.4 mL, 2.418 mmol) were added dropwise, and the reaction mixture was stirred at RT for 30 minutes. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with water (25 mL) and the aqueous layer was extracted with DCM (2x25 mL). The combined organic layer was separated and the anhydrous Na 2 SO 4 Dry, filter and concentrate under high 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: 45% (1.0 g, brown solid).

[1105] LCMS: (Method B), 670.3 (M + +H), Rt.2.82min, 72.59% (Max).

[1106] Intermediate 105

[1107] 3-Butyl-7-(dimethylamino)-3-ethyl-2-(4-methoxybenzyl)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-carboxylic acid methyl ester 1,1-dioxide

[1108]

[1109] To a stirred solution of 3-butyl-7-(dimethylamino)-3-ethyl-2-(4-methoxybenzyl)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl trifluoromethanesulfonate (Intermediate 104; 0.4 g, 0.59 mmol) in methanol (15 mL) and DMF (10 mL) under nitrogen was added triethylamine (0.08 mL, 0.59 mmol), Pd 2 (dba) 3 (0.03 g, 0.03 mmol) and dppf (0.04 g, 0.07 mmol) were added, and the reaction mixture was stirred at 80 ° C for 16 hours in a micro pressure reactor under 5 kg carbon monoxide pressure. After the reaction was completed (monitored by TLC), the reaction mixture was concentrated in vacuo and quenched with water (25 mL). The aqueous layer was extracted with EtOAc (2x25 mL), and the combined organic layer was washed with anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo. 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: 11% (0.06 g, brown solid). LCMS: (Method B) 580.3 (M + +H), Rt.2.62min, 44.08% (Max).

[1110] Intermediate 106

[1111] 3-Butyl-7-(dimethylamino)-3-ethyl-8-(hydroxymethyl)-2-(4-methoxybenzyl)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide

[1112]

[1113] To a stirred solution of methyl 3-butyl-7-(dimethylamino)-3-ethyl-2-(4-methoxybenzyl)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-carboxylate 1,1-dioxide (Intermediate 105; 0.8 g, 1.38 mmol) in THF (10 mL) was added dropwise LiALH 4 (2M in THF, 0.69 mL, 1.38 mmol), the reaction mixture was stirred at RT for 30 minutes. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with saturated ammonium chloride solution (25 mL) at 0 ° C and the aqueous layer was extracted with EtOAc (2x25 mL). The organic layer was separated and washed with anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo. The crude product was used in the next step without further purification. Yield: 47% (0.6 g, brown gum).

[1114] LCMS: (Method B) 552.3 (M + +H),Rt.2.63Min,59.0%(Max).

[1115] Intermediate 107

[1116] Ethyl 2-(((3-butyl-7-(dimethylamino)-3-ethyl-2-(4-methoxybenzyl)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetate

[1117]

[1118] To a stirred solution of 3-butyl-7-(dimethylamino)-3-ethyl-8-(hydroxymethyl)-2-(4-methoxybenzyl)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (intermediate 106; 0.4 g, 0.73 mmol) in DCM (5 mL) at 0 ° C, ethyl 2-mercaptoacetate (0.09 g, 0.73 mmol) and zinc (II) iodide (0.23 g, 0.73 mmol) were added, and the reaction mixture was stirred at RT for 3 hours. After the reaction was completed (monitored by TLC), the reaction mixture was concentrated in vacuo. The resulting solid was quenched with water (20 mL), and the aqueous layer was extracted with EtOAc (2x25 mL). The combined organic layers were separated and the anhydrous Na 2 SO 4 Dry, filter and concentrate under high vacuum. The crude compound was used directly in the next step without further purification. Yield: 400 mg (crude, light brown solid).

[1119] Intermediate 108

[1120] 2-(((3-Butyl-7-(dimethylamino)-3-ethyl-2-(4-methoxybenzyl)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetic acid

[1121]

[1122] To a stirred solution of ethyl 2-(((3-butyl-7-(dimethylamino)-3-ethyl-2-(4-methoxybenzyl)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetate (Intermediate 107; 0.4 g, 0.61 mmol) in 1,4-dioxane (10 mL) was added lithium hydroxide (0.03 g, 1.22 mmol) in water (2 mL) at 0°C and the reaction mixture was stirred at RT for 1 hour. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with dilute HCl solution (1.5 N, 10 mL) and the aqueous layer was extracted with EtOAc (2 x 25 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo. 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: 28% (0.3 g, off-white solid).

[1123] LCMS: (Method E) 626.2 (M + +H), Rt 2.13min, 35.5% (Max).

[1124] Intermediate 109

[1125] 3-Butyl-3-ethyl-8-hydroxy-2-(4-methoxybenzyl)-7-(methylsulfonyl)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide

[1126]

[1127] To a stirred solution of 3-butyl-3-ethyl-8-hydroxy-2-(4-methoxybenzyl)-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (3.2 g, 5.92 mmol) in THF (30 mL) and water (3 mL) at 0°C, potassium monopersulfate (oxone) (18.19 g, 59.2 mmol) was added and the reaction mixture was stirred at RT for 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water (100 mL) and the aqueous layer was extracted with EtOAc (3x100 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure. 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: 63% (2.7 g, off-white solid).

[1128] LCMS: (Method E) 573.2 (M + +H), Rt 2.44min, 79.19% (Max).

[1129] Intermediate 110

[1130] 3-Butyl-3-ethyl-2-(4-methoxybenzyl)-7-(methylsulfonyl)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl trifluoromethanesulfonate

[1131]

[1132] To a stirred solution of 3-butyl-3-ethyl-8-hydroxy-2-(4-methoxybenzyl)-7-(methylsulfonyl)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (intermediate 109; 1.70 g, 2.97 mmol) in DCM (10 mL) at 0 ° C, pyridine (0.48 mL, 5.94 mmol) and trifluoromethanesulfonic anhydride (0.5 mL, 2.97 mmol) were added dropwise, and the reaction mixture was stirred at RT for 30 minutes. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with water (20 mL) and the aqueous layer was extracted with DCM (2x25 mL). The organic layer was separated and washed with anhydrous Na 2 SO 4Dry, filter and concentrate in vacuo. The crude material was purified by Isolera column chromatography (eluent: 0-30% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 63% (1.5 g, off-white solid).

[1133] Intermediate 111

[1134] 3-Butyl-3-ethyl-2-(4-methoxybenzyl)-7-(methylsulfonyl)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-carboxylic acid methyl ester 1,1-dioxide

[1135]

[1136] To a stirred solution of 3-butyl-3-ethyl-2-(4-methoxybenzyl)-7-(methylsulfonyl)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl trifluoromethanesulfonate (Intermediate 110; 3.0 g, 4.26 mmol) in MeOH (20 mL) and DMF (15 mL) under nitrogen was added triethylamine (0.6 mL, 4.26 mmol), Pd 2 (dba) 3 (0.19 g, 0.21 mmol) and dppf (0.28 g, 0.51 mmol), and the reaction mixture was stirred at 75 ° C in a micro pressure reactor under 5 kg carbon monoxide gas pressure for 16 h. After the reaction was completed (monitored by TLC), the reaction mixture was concentrated in vacuo. The resulting crude product was quenched with water (20 mL), and the aqueous layer was extracted with EtOAc (2x25 mL). The combined organic layer was separated and washed with anhydrous Na 2 SO 4 Dry, filter and concentrate under high vacuum. The crude material was purified by Isolera column chromatography (eluent: 0-30% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 38% (1.8 g, brown solid).

[1137] Intermediate 112

[1138] 3-Butyl-3-ethyl-8-(hydroxymethyl)-2-(4-methoxybenzyl)-7-(methylsulfonyl)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide

[1139]

[1140] To a stirred solution of 3-butyl-3-ethyl-2-(4-methoxybenzyl)-7-(methylsulfonyl)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-carboxylic acid methyl ester 1,1-dioxide (Intermediate 111; 1.8 g, 2.93 mmol) in THF (10 mL) at 0°C was added LiAlH 4 (2M in THF, 1.47 ml, 2.93 mmol), and the reaction mixture was stirred at RT for 30 minutes. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with saturated ammonium chloride solution (15 mL) at 0°C and the aqueous layer was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo. The crude product was used as is in the next step without further purification. Yield: 1.8 g (crude, light brown liquid).

[1141] Intermediate 113

[1142] Ethyl 2-(((3-butyl-3-ethyl-2-(4-methoxybenzyl)-7-(methylsulfonyl)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetate

[1143]

[1144] To a stirred solution of 3-butyl-3-ethyl-8-(hydroxymethyl)-2-(4-methoxybenzyl)-7-(methylsulfonyl)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (intermediate 112; 0.5 g, 0.85 mmol) in DCM (10 mL) at 0 ° C, ethyl 2-mercaptoacetate (0.10 g, 0.85 mmol) was added, followed by zinc (II) iodide (0.27 g, 0.85 mmol), and the reaction mixture was stirred at RT for 3 hours. After the reaction was completed (monitored by TLC), the reaction mixture was concentrated in vacuo, the crude product was quenched with water (10 mL), and the aqueous layer was extracted with EtOAc (3x20 mL). The combined organic layers were separated and the anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo. The crude product was used as is in the next step without further purification. Yield: 500 mg (crude, light brown liquid).

[1145] Intermediate 114

[1146] 2-(((3-Butyl-3-ethyl-2-(4-methoxybenzyl)-7-(methylsulfonyl)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetic acid

[1147]

[1148] To a stirred solution of ethyl 2-(((3-butyl-3-ethyl-2-(4-methoxybenzyl)-7-(methylsulfonyl)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetate (Intermediate 1113; 0.5 g, 0.73 mmol) in 1,4-dioxane (6 mL) was added lithium hydroxide (0.04 g, 1.45 mmol) in water (4 mL) at 0°C and the reaction mixture was stirred at RT for 1 hour. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with dilute HCl (1.5 N, 15 mL) and the aqueous layer was extracted with EtOAc (2 x 25 mL). The combined organic layers were separated and washed with anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo. The crude material was purified by Isolera column chromatography (eluent: 0-30% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 38% (0.3 g, off-white solid).

[1149] Intermediate 115

[1150] (R)-7-Bromo-3-butyl-8-methoxy-2-(4-methoxybenzyl)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide

[1151]

[1152] To a stirred solution of (R)-7-bromo-3-butyl-8-methoxy-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (2.5 g, 5.69 mmol) in DMF (20 mL) at 0°C was added Cs 2 CO 3 (3.71g, 11.38mmol), then 1-(chloromethyl)-4-methoxybenzene (1.34g, 8.53mmol) was added dropwise, and the reaction mixture was stirred at RT for 16 hours. After the reaction was completed (monitored by TLC), the reaction mixture was diluted with water (50mL), and the aqueous layer was extracted with EtOAc (3x50mL). The combined organic layer was washed with brine (50mL) and dried over anhydrous Na2 SO 4 Dry, filter and concentrate under reduced pressure. 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: 69% (2.2 g, brown solid).

[1153] LCMS: (Method B) 558.8 (M + ),Rt.1.91min,56.52%(Max).

[1154] Intermediate 116

[1155] (R)-3-Butyl-7-(dimethylamino)-8-methoxy-2-(4-methoxybenzyl)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide

[1156]

[1157] To a stirred solution of (R)-7-bromo-3-butyl-8-methoxy-2-(4-methoxybenzyl)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (Intermediate 115; 2 g, 3.57 mmol) in 1,4-dioxane (20 mL) was added dimethylamine (0.08 g, 1.70 mmol) and sodium tert-butoxide (0.49 g, 5.11 mmol) and the solution was purged with nitrogen for 10 minutes. Pd was then added 2 (dba) 3 (0.08 g, 0.09 mmol) and RuPhos (0.08 g, 0.17 mmol) were added and the reaction mixture was heated at 80 °C for 2 hours. After completion of the reaction (monitored by LCMS), the reaction mixture was diluted with water (20 mL) and the aqueous layer was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (20 mL) and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure. The crude product was purified by Isolera column chromatography (eluent: 20-30% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 52% (1.4 g, brown solid).

[1158] LCMS: (Method B) 524.3 (M + +H), Rt.2.87min, 43.87% (Max).

[1159] Intermediate 117

[1160] (R)-3-Butyl-7-(dimethylamino)-8-hydroxy-2-(4-methoxybenzyl)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide

[1161]

[1162] To a stirred solution of (R)-3-butyl-7-(dimethylamino)-8-methoxy-2-(4-methoxybenzyl)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (Intermediate 116; 2.0 g, 3.82 mmol) in DMF (10 mL) was added NaSMe (1.34 g, 19.10 mmol) and the reaction mixture was stirred at 70 ° C for 12 hours. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with water (20 mL) and the aqueous layer was extracted with EtOAc (3x50 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na 2 SO 4 Dry, filter and concentrate under reduced pressure. 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: 42% (1.2 g, off-white solid).

[1163] LCMS: (Method E) 510.2 (M + +H), Rt 1.97min, 68.55% (Max).

[1164] Intermediate 118

[1165] (R)-3-Butyl-7-(dimethylamino)-2-(4-methoxybenzyl)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl trifluoromethanesulfonate

[1166]

[1167] To a stirred solution of (R)-3-butyl-7-(dimethylamino)-8-hydroxy-2-(4-methoxybenzyl)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (intermediate 117; 1.5 g, 2.94 mmol) in DCM (10 mL) at 0 ° C, pyridine (0.47 mL, 5.89 mmol) and trifluoromethanesulfonic anhydride (0.5 mL, 2.94 mmol) were added dropwise, and the reaction mixture was stirred at RT for 30 minutes. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with water (20 mL) and the aqueous layer was extracted with DCM (2x20 mL). The combined organic layer was washed with brine (20 mL) and dried over anhydrous Na 2 SO 4 Dry, filter and concentrate 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: 59% (1.4 g, brown solid).

[1168] LCMS: (Method E) 642.2 (M + +H), Rt 2.80min, 79.5% (Max).

[1169] Intermediate 119

[1170] (R)-3-Butyl-7-(dimethylamino)-2-(4-methoxybenzyl)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-carboxylic acid methyl ester 1,1-dioxide

[1171]

[1172] To a stirred solution of (R)-3-butyl-7-(dimethylamino)-2-(4-methoxybenzyl)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl trifluoromethanesulfonate (Intermediate 118; 2.8 g, 4.36 mmol) in MeOH (20 mL) and DMF (15 mL) was added triethylamine (0.61 mL, 4.36 mmol), Pd 2 (dba) 3(0.20g, 0.22mmol) and dppf (0.29g, 0.52mmol), and the reaction mixture was stirred at 75°C in a micro pressure reactor under 5kg carbon monoxide gas pressure for 16h. After the reaction was completed (monitored by TLC), the reaction mixture was concentrated and the resulting mixture was quenched with water (20mL). The aqueous layer was extracted with EtOAc (2x15mL), the combined organic layer was separated and the anhydrous Na 2 SO 4 Dry. Filter the organic portion, concentrate in vacuo, and purify the resulting crude product by Isolera column chromatography (eluent: 0-30% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 54% (1.3 g, white solid).

[1173] LCMS: (Method E) 552.3 (M + +H), Rt.2.36min, 62.07% (Max).

[1174] Intermediate 120

[1175] (R)-3-Butyl-7-(dimethylamino)-8-(hydroxymethyl)-2-(4-methoxybenzyl)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide

[1176]

[1177] To a stirred solution of (R)-3-butyl-7-(dimethylamino)-2-(4-methoxybenzyl)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-carboxylic acid methyl ester 1,1-dioxide (Intermediate 119; 600 mg, 1.09 mmol) in THF (10 mL) at 0°C was added dropwise LiAlH 4 (2M in THF, 0.54 mL, 1.09 mmol), and the reaction mixture was stirred at RT for 30 minutes. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with saturated ammonium chloride solution (10 mL) at 0 ° C and the aqueous layer was extracted with EtOAc (2x20 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 Dry and concentrate in vacuo. The crude product was used as is in the next step without further purification.

[1178] 1 H-NMR (400 MHz, DMSO-d 6): δ7.96(s,1H),7.24-7.21(m,5H),6.89-6.81(m,5H),5.37(t,J=5.6Hz,1H),4.53(d,J=5.6Hz,2H),4.15(bs,2H),3.75(s,1 H),3.72(s,2H),3.71(s,3H),2.68(s,6H),1.43-1.36(m,2H),0.95-0.91(m,4H),0.62(t,J=6.80Hz,3H).LCMS:(Method B)524.2(M + +H), Rt 2.63min, 54.42% (Max).

[1179] Intermediate 121

[1180] (R)-ethyl 2-(((3-butyl-7-(dimethylamino)-2-(4-methoxybenzyl)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetate

[1181]

[1182] To a stirred solution of (R)-3-butyl-7-(dimethylamino)-8-(hydroxymethyl)-2-(4-methoxybenzyl)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (intermediate 120; 300mg, 0.57mmol) in DCM (10mL) at 0°C, ethyl 2-mercaptoacetate (68.8mg, 0.57mmol) and zinc (II) iodide (183mg, 0.57mmol) were added, and the reaction mixture was stirred at RT for 3 hours. After the reaction was completed (monitored by TLC), the reaction mixture was concentrated in vacuo and quenched with water (20mL). The aqueous layer was extracted with EtOAc (2x25mL) and washed with anhydrous Na 2 SO 4 Dry and concentrate in vacuo. The crude product was used as is in the next step without further purification.

[1183] Intermediate 122

[1184] (R)-2-(((3-Butyl-7-(dimethylamino)-2-(4-methoxybenzyl)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetic acid

[1185]

[1186] To a stirred solution of (R)-ethyl 2-(((3-butyl-7-(dimethylamino)-2-(4-methoxybenzyl)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetate (Intermediate 121; 300 mg, 0.48 mmol) in 1,4-dioxane (6 mL) was added lithium hydroxide (22.96 mg, 0.96 mmol) in water (1 mL) at 0°C and the reaction mixture was stirred at RT for 1 hour. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with dilute HCl (1.5 N, 15 mL) and the aqueous layer was extracted with EtOAc (2 x 25 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 Dry and concentrate under high vacuum. The crude product was purified by Isolera column chromatography (eluent: 0-50% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 47% (250 mg, white solid).

[1187] LCMS: (Method B) 598.2 (M + +H), Rt 2.05min, 54.26% (Max).

[1188] Intermediate 123

[1189] (R)-3-Butyl-8-hydroxy-2-(4-methoxybenzyl)-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide

[1190]

[1191] To a stirred solution of (R)-7-bromo-3-butyl-8-methoxy-2-(4-methoxybenzyl)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (Intermediate 115; 2.5 g, 4.47 mmol) in DMF (10 mL), NaSMe (1.57 g, 22.34 mmol) was added at RT, and the reaction mixture was stirred at 90 ° C for 12 hours. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with water (25 mL) and the aqueous layer was extracted with EtOAc (2x25 mL). The organic layer was separated and washed with anhydrous Na 2 SO 4 Dry and concentrate under high 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: 57% (1.5 g, off-white solid).

[1192] LCMS: (Method E) 513.2 (M + +H), Rt.2.49min, 87.85% (Max).

[1193] Intermediate 124

[1194] (R)-3-Butyl-2-(4-methoxybenzyl)-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl trifluoromethanesulfonate

[1195]

[1196] To a stirred solution of (R)-3-butyl-8-hydroxy-2-(4-methoxybenzyl)-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (intermediate 123; 1.5 g, 2.93 mmol) in DCM (10 mL) at 0 ° C, pyridine (0.47 mL, 5.85 mmol) and trifluoromethanesulfonic anhydride (0.5 mL, 2.93 mmol) were added dropwise, and the reaction mixture was stirred at RT for 30 minutes. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with water (20 mL) and the aqueous layer was extracted with DCM (2x20 mL). The organic portion was purified by anhydrous Na 2 SO 4 Dry and concentrate under high 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: 28% (0.6 g, brown solid).

[1197] Intermediate 125

[1198] (R)-3-Butyl-2-(4-methoxybenzyl)-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-carboxylic acid methyl ester 1,1-dioxide

[1199]

[1200] To a stirred solution of (R)-3-butyl-2-(4-methoxybenzyl)-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl trifluoromethanesulfonate (Intermediate 124; 1.2 g, 1.86 mmol) in methanol (20 mL) and DMF (15 mL) under nitrogen was added triethylamine (0.26 mL, 1.86 mmol), Pd2 (dba) 3 (0.09g, 0.09mmol) and dppf (0.12g, 0.22mmol), and the reaction mixture was stirred at 75 ° C for 16 hours in a micro pressure reactor under 5kg carbon monoxide pressure. After the reaction was completed (monitored by TLC), the reaction mixture was concentrated in vacuo and quenched with water (10mL). The aqueous layer was extracted with EtOAc (2x15mL), the organic layer was dried over anhydrous sodium sulfate and concentrated under high vacuum. The resulting crude product was purified by Isolera column chromatography (eluent: 0-30% EtOAc / PE; silica gel: 230-400 mesh) to obtain the title compound. Yield: 40% (0.6g, off-white solid).

[1201] LCMS: (Method B) 555.1 (M + +H), Rt 2.83min, 69.63% (Max).

[1202] Intermediate 126

[1203] (R)-3-Butyl-8-(hydroxymethyl)-2-(4-methoxybenzyl)-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide

[1204]

[1205] To a stirred solution of (R)-3-butyl-2-(4-methoxybenzyl)-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-carboxylic acid methyl ester 1,1-dioxide (Intermediate 125; 0.6 g, 1.08 mmol) in THF (10 mL) was added dropwise LiAlH 4 (2M in THF, 0.54mL, 1.08mmol), and the reaction mixture was stirred at RT for 30 minutes. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with saturated ammonium chloride solution (10mL) at 0°C and then extracted with ethyl acetate (2x20mL). The combined organic extracts were washed with brine (50mL) and washed with anhydrous Na 2 SO 4 Dry and concentrate in vacuo. The crude product was used as is in the next step without further purification.

[1206] Intermediate 127

[1207] (R)-ethyl 2-(((3-butyl-2-(4-methoxybenzyl)-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetate

[1208]

[1209] To a stirred solution of (R)-3-butyl-8-(hydroxymethyl)-2-(4-methoxybenzyl)-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (intermediate 126; 600mg, 1.14mmol) in DCM (5mL) at 0°C, ethyl 2-mercaptoacetate (137mg, 1.14mmol) and zinc (II) iodide (364mg, 1.14mmol) were added, and the reaction mixture was stirred at RT for 3 hours. After the reaction was completed (monitored by TLC), the reaction mixture was concentrated in vacuo and quenched with water (20mL). The aqueous layer was extracted with EtOAc (2x20mL) and anhydrous Na 2 SO 4 The combined organic layers were dried and concentrated under vacuum to give the crude product. The crude material was used directly in the next step without further purification.

[1210] Intermediate 128

[1211] (R)-2-(((3-Butyl-2-(4-methoxybenzyl)-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetic acid

[1212]

[1213] To a stirred solution of (R)-ethyl 2-(((3-butyl-2-(4-methoxybenzyl)-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetate (Intermediate 127; 500 mg, 0.79 mmol) in 1,4-dioxane (10 mL) was added lithium hydroxide (38.1 mg, 1.59 mmol) in water (2 mL) at 0 °C and the reaction mixture was stirred at RT for 1 hour. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with dilute HCl (15 mL, 1.5 N) and the aqueous layer was extracted with EtOAc (2 x 20 mL). The combined organic layers were separated and washed with anhydrous Na 2 SO 4Dry and concentrate in vacuo. The crude product was purified by Isolera column chromatography (eluent: 0-50% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 50% (0.45 g, off-white solid).

[1214] LCMS: (Method B), 599.1 (M + -H), Rt 2.0min, 53.31% (Max).

[1215] Intermediate 129

[1216] (R)-7-Bromo-3-butyl-8-hydroxy-2-(4-methoxybenzyl)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide

[1217]

[1218] To a stirred solution of 7-bromo-3-butyl-8-methoxy-2-(4-methoxybenzyl)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (intermediate 115; 1.5 g, 2.68 mmol) in DMSO (12 mL) at 0 ° C, lithium chloride (1.14 g, 26.8 mmol) was added, and the reaction mixture was stirred at 120 ° C for 24 hours. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with ice-cold water (20 mL). The resulting solid was collected by filtration and dried under vacuum. The resulting crude material was purified by Isolera column chromatography (eluent: 0-30% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 37% (1.0 g, off-white solid).

[1219] LCMS: (Method A), 544.0 (M + -H), Rt.2.65min, 54.3% (Max).

[1220] Intermediate 130

[1221] (R)-3-Butyl-8-hydroxy-7-methoxy-2-(4-methoxybenzyl)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide

[1222]

[1223] To a stirred solution of 7-bromo-3-butyl-8-hydroxy-2-(4-methoxybenzyl)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (Intermediate 129; 0.7 g, 1.28 mmol) in MeOH (10 mL) at 0°C, sodium methoxide (25% in methanol, 5.5 mL, 6.42 mmol) and copper (I) bromide (0.18 g, 1.28 mmol) were added and the reaction mixture was stirred at 75°C for 16 hours. After completion of the reaction (monitored by UPLC), the reaction mixture was diluted with water (50 mL) and the aqueous layer was extracted with EtOAc (3x100 mL). The combined organic layers were washed with brine (50 mL) and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate under vacuum. The crude material was purified by Isolera column chromatography (eluent: 0-30% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 69% (0.5 g, off-white solid).

[1224] LCMS: (Method C), 497.3 (M + +H), Rt.2.23min, 88.76% (Max).

[1225] Intermediate 131

[1226] (R)-3-Butyl-7-methoxy-2-(4-methoxybenzyl)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl trifluoromethanesulfonate

[1227]

[1228] To a stirred solution of (R)-3-butyl-8-hydroxy-7-methoxy-2-(4-methoxybenzyl)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (Intermediate 130; 1 g, 2.01 mmol) in DCM (5 mL) was added pyridine (0.32 mL, 4.03 mmol) and trifluoromethanesulfonic anhydride (0.5 mL, 3.02 mmol) dropwise at 0°C and the reaction mixture was stirred at RT for 30 minutes. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with water (25 mL) and the organic layer was extracted with DCM (2×25 mL). The combined organic layers were separated and washed with anhydrous Na 2 SO 4Dry, filter and concentrate in vacuo. 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: 41% (0.55 g, light yellow gum).

[1229] Intermediate 132

[1230] (R)-3-Butyl-7-methoxy-2-(4-methoxybenzyl)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-carboxylic acid methyl ester 1,1-dioxide

[1231]

[1232] To a stirred solution of 3-butyl-7-methoxy-2-(4-methoxybenzyl)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl trifluoromethanesulfonate (Intermediate 131; 550 mg, 0.88 mmol) in MeOH (10 mL) and DMF (10 mL) under nitrogen was added triethylamine (0.24 mL, 1.75 mmol), Pd 2 (dba) 3 (80 mg, 0.09 mmol) and dppf (48.5 mg, 0.09 mmol), and the reaction mixture was stirred at 75 ° C in a micro pressure reactor under 5 kg carbon monoxide gas pressure for 16 h. After the reaction was completed (monitored by TLC), the reaction mixture was concentrated in vacuo, and the resulting crude material was purified by Isolera column chromatography (eluent: 0-30% EtOAc / PE; silica gel: 230-400 mesh) to obtain the title compound. Yield: 56% (0.35 g, off-white solid).

[1233] LCMS: (Method E), 539.1 (M + +H), Rt.1.89Min, 75.4%(Max)

[1234] Intermediate 133

[1235] (R)-3-Butyl-8-(hydroxymethyl)-7-methoxy-2-(4-methoxybenzyl)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide

[1236]

[1237] To a stirred solution of (R)-3-butyl-7-methoxy-2-(4-methoxybenzyl)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-carboxylic acid methyl ester 1,1-dioxide (Intermediate 132; 350 mg, 0.65 mmol) in THF (4 mL) was added dropwise LiAlH 4 (2M in THF, 0.33 mL, 0.65 mmol), and the reaction mixture was stirred at RT for 30 minutes. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with saturated ammonium chloride solution (10 mL) at 0 ° C and the aqueous layer was extracted with EtOAc (2×20 mL). The organic layer was washed with anhydrous Na 2 SO 4 Dry, filter and concentrate under vacuum. The crude product was used as it is in the next step without further purification. Yield: 86% (0.31 g, brown solid).

[1238] LCMS: (Method C), 511.4 (M + +H), Rt.2.26Min, 92.18%(Max)

[1239] Intermediate 134

[1240] (R)-ethyl 2-(((3-butyl-7-methoxy-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetate

[1241]

[1242] To a stirred solution of (R)-3-butyl-8-(hydroxymethyl)-7-methoxy-2-(4-methoxybenzyl)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (Intermediate 133; 300 mg, 0.59 mmol) in DCM (6 mL) at 0 ° C, ethyl 2-mercaptoacetate (70.6 mg, 0.59 mmol) was added, followed by zinc iodide (188 mg, 0.59 mmol), and the reaction mixture was stirred at RT for 3 hours. The reaction mixture was then quenched with water (10 mL) and the aqueous layer was extracted with EtOAc (2x20 mL). The mixture was dried over anhydrous Na 2 SO 4 The combined organic layers were dried and concentrated in vacuo to afford the title compound. The compound was used as such in the next step without further purification. Yield: 55% (0.28 g, brown gum).

[1243] Intermediate 135

[1244] 2-Aminohexanoic acid ethyl ester hydrochloride

[1245]

[1246] To a stirred solution of 2-aminohexanoic acid (12 g, 91 mmol) in ethanol (130 mL) was added thionyl chloride (33 mL, 457 mmol) at 0 °C, 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 further purification. Yield: 94% (18 g, white solid).

[1247] LCMS: (Method B) 160.3 (M + +H), Rt.1.72min, 93.76% (max).

[1248] Intermediate 136

[1249] (E)-2-(Benzylideneamino)hexanoic acid ethyl ester

[1250]

[1251] To a stirred solution of ethyl 2-aminohexanoate hydrochloride (intermediate 135; 18 g, 92 mmol) in DCM (170 mL) at 0 ° C, triethylamine (25.6 mL, 184 mmol) was added over 30 minutes. Magnesium sulfate (11.07 g, 92 mmol) was then added in batches at 0 ° C. Benzaldehyde (9.37 mL, 92 mmol) was added to the reaction mixture at 0 ° C within 20 minutes, and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed (monitored by TLC), the reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated in vacuo. The resulting crude product was dissolved in petroleum ether (1000 mL), filtered through diatomaceous earth again, and the filtrate was concentrated in vacuo to give the title compound. The crude material was used in the next step without further purification. Yield: 73.5% (22 g, light brown liquid).

[1252] LCMS: (Method B) 248.2 (M + +H), Rt.2.48min, 93.76% (max).

[1253] Intermediate 137

[1254] (E)-2-(Benzylideneamino)-2-methylhexanoic acid ethyl ester

[1255]

[1256] To a stirred solution of NaH (60%, 3.23 g, 81 mmol) in DMF (50 mL) was slowly added a solution of (E)-ethyl 2-(benzylideneamino)hexanoate (Intermediate 136; 20 g, 81 mmol) in DMF (150 mL) at 0°C over 30 minutes, and 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 (2x500 mL). The organic layer was washed with brine (200 mL) and washed with anhydrous Na 2 SO 4 Dry. The organic portion was concentrated in vacuo and the crude product was used in the next step without further purification. Yield: 65.6% (21 g, yellow liquid).

[1257] LCMS: (Method B) 262.2 (M + +H), Rt.2.64min, 66.47% (max).

[1258] Intermediate 138

[1259] 2-Amino-2-methylhexanoic acid ethyl ester

[1260]

[1261] To a stirred solution of (E)-ethyl 2-(benzylideneamino)-2-methylhexanoate (Intermediate 137; 30 g, 115 mmol) in petroleum ether (100 mL) was added dilute HCl (150 mL, 1.5 N) at 0 °C and 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 basified (pH ~ 8.5) with solid sodium bicarbonate (5 g) and extracted with EtOAc (2 x 100 mL). The organic layer was then washed with water (2 x 25 mL). The combined organic portions were purified by anhydrous Na 2 SO 4 Dry and concentrate under vacuum to give the title compound. The crude material was used directly in the next step without further purification. Yield: 39.8% (8 g, light yellow liquid).

[1262] LCMS: (Method C) 174.3 (M + +1), Rt.1.1min, 99.74% (max).

[1263] Intermediate 139

[1264] 2-Amino-2-methyl-N-phenylhexanamide

[1265]

[1266] To a stirred solution of aniline (8.96 mL, 98 mmol) in THF (80 mL) at -78 ° C, n-BuLi (2.5 M in hexane) (41.6 mL, 104 mmol) was added dropwise over 30 minutes, and the reaction mixture was stirred at -25 ° C to -30 ° C for 45 minutes. Then 2-amino-2-methylhexanoic acid ethyl ester (intermediate 138; 10 g, 57.7 mmol) in THF (80 mL) was added at -78 ° C, and the reaction mixture was stirred at -78 ° C for 2 hours. After the reaction was completed (monitored by TLC), the reaction mixture was quenched with water (200 mL) at -78 ° C, and the reaction mixture was extracted with EtOAc (2x250 mL). The organic layer was washed with water (2x25 mL) and anhydrous Na 2 SO 4 Drying and concentration in vacuo afforded the crude title compound. The crude product was dissolved in petroleum ether (1000 mL), washed with 30% methanol in water (2 x 250 mL) and purified by anhydrous Na 2 SO 4 Dry. The organic portion was concentrated in vacuo and the resulting crude product was used as such in the next step without further purification. Yield: 72% (15 g, yellow liquid).

[1267] LCMS: (Method E) 221.3 (M + +1), Rt.1.15min, 61.25% (max).

[1268] Intermediate 140

[1269] 2-Methyl-N1-phenylhexane-1,2-diamine

[1270]

[1271] To a stirred solution of 2-amino-2-methyl-N-phenylhexanamide (Intermediate 139; 27 g, 123 mmol) in THF (250 mL) was added borane dimethyl sulfide complex (2M in THF, 61.3 mL, 123 mmol) at 0 °C, and the reaction mixture was heated at 70 °C for 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with methanol (65 mL) at 0 °C, and the reaction mixture was 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 (2x50 mL) and washed with anhydrous Na 2 SO 4Dry and concentrate in vacuo. The crude product was purified by Isolera column chromatography (eluent: 40% EtOAc in hexane; silica gel: 230-400 mesh) to give the title compound. Yield: 31.3% (8 g, yellow liquid).

[1272] 1 H NMR (400 MHz, DMSO-d 6 ): δ7.07-7.03(m,2H),6.62(dd,J=1.2,8.6Hz,2H),6.52-6.52(m,1H),5.30(t,J=5.6Hz,1H),2.85(d,J=6.0Hz,2 H), 2.26 (bs, 2H), 1.36-1.32 (m, 3H), 1.30-1.24 (m, 3H), 1.02 (s, 3H), 0.88 (t, J = 6.8Hz, 3H). LCMS: (Method C) 207.3 (M + +H), Rt.1.44min, 99.59% (max).

[1273] Intermediate 141

[1274] 1,2-Bis(2,4-dibromo-5-methoxyphenyl)disulfane

[1275]

[1276] To a stirred solution of 3-methoxybenzenethiol (100 g, 0.7 mol) in methanol (1000 mL), bromine (73 mL, 1.4 mol) was added dropwise at 0 °C, and the reaction mixture was stirred at RT for 24 hours. The reaction mixture was evaporated in vacuo, the resulting crude was diluted with EtOAc (2000 mL), and washed with water (2 x 500 mL). The organic layer was purified by anhydrous Na 2 SO 4 The resulting crude product was dissolved in glacial acetic acid (600 mL), bromine (20 mL) was added dropwise at room temperature, and the reaction mixture was stirred at RT for 2 hours. The resulting solid was filtered off, triturated with DCM and dried in vacuo to give the pure title compound. Yield: 37% (78 g, white solid).

[1277] 1 H NMR (400 MHz, DMSO-d 6 ): δ7.69(s,2H),7.17(s,2H),3.84(s,6H).

[1278] Intermediate 142

[1279] 2,4-Dibromo-5-methoxybenzenesulfonyl chloride

[1280]

[1281] To a stirred suspension of 1,2-bis(2,4-dibromo-5-methoxyphenyl)disulfane (Intermediate 141; 20.0 g, 33.67 mmol) and potassium nitrate (17.02 g, 168.35 mmol) in acetonitrile (200 mL) at 0°C was added sulfonyl chloride (13.6 mL, 168.35 mmol) dropwise and the reaction mixture was stirred at RT for 24 h. After completion of the reaction (monitored by TLC), the reaction mixture was poured onto crushed ice and the resulting solid was filtered off. The resulting solid was washed with water and dried under vacuum to give the pure title compound. Yield: 91% (22.5 g, white solid).

[1282] 1 H NMR (400 MHz, DMSO-d 6 ): δ8.05(s,1H),7.66(s,1H),4.01(s,3H).

[1283] Intermediate 143

[1284] 2,4-Dibromo-5-methoxy-N-(2-methyl-1-(phenylamino)hexan-2-yl)benzenesulfonamide

[1285]

[1286] To a stirred solution of 2-methyl-N1-phenylhexane-1,2-diamine (Intermediate 140; 10 g, 48.5 mmol) in THF (100 mL) was added 2,4-dibromo-5-methoxybenzenesulfonyl chloride (Intermediate 142; 21.2 g, 58.2 mmol) and triethylamine (20.3 mL, 145 mmol) at 0°C and the reaction mixture was stirred at RT for 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc (250 mL) - the organic layer was washed with water (2x50 mL) and dried over anhydrous Na 2 SO 4 Dry. The organic portion was concentrated in vacuo and the resulting 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).

[1287] LCMS: (Method C) 533.1 (M + +H), Rt.2.71min, 79.63% (max).

[1288] Intermediate 144

[1289] 7-Bromo-3-butyl-8-methoxy-3-methyl-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide

[1290]

[1291] To a stirred solution of 2,4-dibromo-5-methoxy-N-(2-methyl-1-(phenylamino)hex-2-yl)benzenesulfonamide (Intermediate 143; 15 g, 28.1 mmol) in DMF (100 mL) were added potassium carbonate (11.6 g, 84.3 mmol) and copper powder (885 mg, 14.05 mmol), and the reaction mixture was heated at 150 °C for 24 hours. The reaction mixture was then filtered through celite and washed with EtOAc (250 mL). The filtrate fraction was concentrated under vacuum, and the resulting 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).

[1292] 1 H NMR (400 MHz, DMSO-d 6 ): δ7.40-7.36 (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.2.54min, 94.22% (max).

[1293] Intermediate 145

[1294] 7-Bromo-3-butyl-8-methoxy-2-(4-methoxybenzyl)-3-methyl-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide

[1295]

[1296] To a stirred solution of 7-bromo-3-butyl-8-methoxy-3-methyl-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (Intermediate 144; 2.5 g, 5.51 mmol) in DMF (25 mL) at 0°C was added Cs2 CO 3 (3.59 g, 11.03 mmol). Then 1-(chloromethyl)-4-methoxybenzene (1.30 g, 8.27 mmol) was added dropwise, and the reaction mixture was stirred at RT for 16 hours. After the reaction was completed (monitored by TLC), the reaction mixture was diluted with water (50 mL), and the aqueous layer was extracted with EtOAc (3x50 mL). The combined organic layers were washed with brine (50 mL) and purified by anhydrous Na 2 SO 4 Dry, filter and concentrate 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).

[1297] LCMS: (Method C) 575.3 (M + +2), Rt.2.59min, 98.8% (Max).

[1298] Intermediate 146

[1299] 3-Butyl-7-(dimethylamino)-8-methoxy-2-(4-methoxybenzyl)-3-methyl-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide

[1300]

[1301] To a stirred solution of 7-bromo-3-butyl-8-methoxy-2-(4-methoxybenzyl)-3-methyl-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxid...

Claims

1. Compound of formula (I) in M is -CH2- or -NR 6 -; R 1 C 1-4 alkyl; R 2 Selected from hydrogen and C 1-4 alkyl; R 3 are independently selected from hydrogen, halogen, hydroxyl, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, cyano, nitro, amino, N-(C 1-4 Alkyl)amino and N,N-di(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 Cycloalkyloxy, C 1-4 Alkylthio, C 3-6 Cycloalkylthio, C 1-4 Alkylsulfonyl, C 3-6 Cycloalkylsulfonyl, amino, N-(C 1-4 Alkyl)amino and N,N-di(C 1-4 Alkyl)amino; R 5A and R 5B are independently selected from hydrogen, halogen, hydroxyl, C 1-4 Alkyl and C 1-4 Alkoxy; or R 5A and R 5B Together with the carbon atoms to which they are attached, they form a 3- to 5-membered saturated carbocyclic ring; R 6 Selected from hydrogen and C 1-4 alkyl; or a pharmaceutically acceptable salt thereof.

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

3. A compound according to claim 1 or 2, wherein R 2 For hydrogen.

4. A compound according to claim 1 or 2, wherein R 2 It is methyl, ethyl or n-butyl.

5. A compound according to any one of claims 1 to 4, wherein R 3 are independently selected from hydrogen, fluorine, chlorine, bromine, hydroxy, methoxy, amino, methylamino and dimethylamino.

6. A compound according to any one of claims 1 to 5, wherein R 4 is selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, cyclopropyl, methoxy, ethoxy, methylthio, ethylthio, methylsulfonyl, amino, methylamino and dimethylamino.

7. A compound according to any one of claims 1 to 6, wherein R 5A and R 5B are independently hydrogen or C 1-4 Alkyl groups, or together with the carbon atoms to which they are attached, form a cyclopropyl ring.

8. A compound according to any one of claims 1 to 7, wherein R 6 It is hydrogen or methyl.

9. A compound according to claim 1, selected from: 2-(((3-Butyl-3-ethyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)acetic acid; (S)-2-(((3-butyl-3-ethyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)acetic acid; (R)-2-(((3-butyl-3-ethyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)acetic acid; 2-(((3,3-dibutyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)acetic acid; 2-(((3-butyl-3-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)acetic acid; (S)-2-(((3-butyl-3-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)acetic acid; (R)-2-(((3-butyl-3-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)acetic acid; 2-(((3-Butyl-3-ethyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxido-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)acetic acid; (S)-2-(((3-butyl-3-ethyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxido-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)acetic acid; (R)-2-(((3-butyl-3-ethyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxido-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)acetic acid; 2-(((3,3-dibutyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetic acid; 2-(((3-Butyl-3-ethyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetic acid; (S)-2-(((3-butyl-3-ethyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetic acid; (R)-2-(((3-butyl-3-ethyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetic acid; 2-(((3-Butyl-2-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetic acid; (S)-2-(((3-butyl-2-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetic acid; (R)-2-(((3-butyl-2-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetic acid; 2-(((3-Butyl-3-ethyl-7-methoxy-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)acetic acid; (S)-2-(((3-butyl-3-ethyl-7-methoxy-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)acetic acid; (R)-2-(((3-butyl-3-ethyl-7-methoxy-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)acetic acid; 2-(((3-Butyl-3-ethyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxido-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)-2-methylpropanoic acid; (S)-2-(((3-butyl-3-ethyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxido-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)-2-methylpropanoic acid; (R)-2-(((3-butyl-3-ethyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxido-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)-2-methylpropanoic acid; 2-(((3,3-dibutyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)-2-methylpropanoic acid; 2-(((3-butyl-3-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)-2-methylpropanoic acid; (S)-2-(((3-butyl-3-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)-2-methylpropanoic acid; (R)-2-(((3-butyl-3-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)-2-methylpropanoic acid; 2-(((3-butyl-3-ethyl-2-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetic acid; (S)-2-(((3-butyl-3-ethyl-2-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetic acid; (R)-2-(((3-butyl-3-ethyl-2-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetic acid; 2-(((3,3-dibutyl-2-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetic acid; 2-(((3,3-dibutyl-2-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)-2-methylpropanoic acid; 2-(((3,3-dibutyl-2-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)-2-methylpropanoic acid; 2-(((3-Butyl-3-ethyl-7-methoxy-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)-2-methylpropanoic acid; (S)-2-(((3-butyl-3-ethyl-7-methoxy-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)-2-methylpropanoic acid; (R)-2-(((3-butyl-3-ethyl-7-methoxy-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)-2-methylpropanoic acid; 2-(((3-butyl-7-methoxy-3-methyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)acetic acid; (S)-2-(((3-butyl-7-methoxy-3-methyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)acetic acid; (R)-2-(((3-butyl-7-methoxy-3-methyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)acetic acid; 2-(((3-Butyl-5-(4-fluorophenyl)-7-methoxy-2-methyl-1,1-dioxido-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetic acid; (S)-2-(((3-butyl-5-(4-fluorophenyl)-7-methoxy-2-methyl-1,1-dioxido-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetic acid; (R)-2-(((3-butyl-5-(4-fluorophenyl)-7-methoxy-2-methyl-1,1-dioxido-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetic acid; 2-(((3,3-dibutyl-7-methoxy-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)acetic acid; 2-(((3,3-dibutyl-5-(4-fluorophenyl)-7-methoxy-1,1-dioxido-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)acetic acid; 2-(((3-Butyl-3-ethyl-5-(4-fluorophenyl)-7-methoxy-1,1-dioxido-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)-2-methylpropanoic acid; (S)-2-(((3-Butyl-3-ethyl-5-(4-fluorophenyl)-7-methoxy-1,1-dioxido-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)-2-methylpropanoic acid; (R)-2-(((3-butyl-3-ethyl-5-(4-fluorophenyl)-7-methoxy-1,1-dioxido-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)-2-methylpropanoic acid; 2-(((3-butyl-7-methoxy-2-methyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetic acid; (S)-2-(((3-butyl-7-methoxy-2-methyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetic acid; (R)-2-(((3-butyl-7-methoxy-2-methyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetic acid; 2-(((3-butyl-7-methoxy-2-methyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)-2-methylpropanoic acid; (S)-2-(((3-butyl-7-methoxy-2-methyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)-2-methylpropanoic acid; (R)-2-(((3-butyl-7-methoxy-2-methyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)-2-methylpropanoic acid; 2-(((3-Butyl-3-ethyl-5-(4-fluorophenyl)-7-methoxy-1,1-dioxido-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)acetic acid; (S)-2-(((3-butyl-3-ethyl-5-(4-fluorophenyl)-7-methoxy-1,1-dioxido-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)acetic acid; (R)-2-(((3-butyl-3-ethyl-5-(4-fluorophenyl)-7-methoxy-1,1-dioxido-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)acetic acid; 2-(((3-butyl-7-methoxy-3-methyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)-2-methylpropanoic acid; (S)-2-(((3-butyl-7-methoxy-3-methyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)-2-methylpropanoic acid; (R)-2-(((3-butyl-7-methoxy-3-methyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)-2-methylpropanoic acid; 2-(((3,3-dibutyl-7-methoxy-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)-2-methylpropanoic acid; 2-(((3-Butyl-3-ethyl-7-methoxy-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetic acid; (R)-2-(((3-butyl-3-ethyl-7-methoxy-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetic acid; (S)-2-(((3-butyl-3-ethyl-7-methoxy-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetic acid; 2-(((3-butyl-7-(dimethylamino)-3-ethyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetic acid; 2-(((3-butyl-3-ethyl-7-(methylsulfonyl)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetic acid; (S)-2-(((3-butyl-3-ethyl-7-(methylsulfonyl)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetic acid; (R)-2-(((3-butyl-3-ethyl-7-(methylsulfonyl)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetic acid; (R)-2-(((3-butyl-7-(dimethylamino)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetic acid; (R)-2-(((3-butyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetic acid; (R)-2-(((3-butyl-7-methoxy-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetic acid; 2-(((3-butyl-7-(dimethylamino)-3-methyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetic acid; 2-(((3-butyl-7-methoxy-3-methyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetic acid; and 2-(((3-butyl-3-methyl-7-(methylthio)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetic acid; or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 9 and one or more pharmaceutically acceptable excipients.

11. A compound according to any one of claims 1 to 9 for use as a medicament.

12. A compound according to any one of claims 1 to 9 for use in the treatment or prevention of cardiovascular disease 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 disease and macrovascular disease, retinopathy, neuropathy, nephropathy and delayed wound healing, tissue ischemia, diabetic foot, atherosclerosis, myocardial infarction, acute coronary syndrome, unstable angina, stable angina, stroke, peripheral arterial occlusive disease, cardiomyopathy, heart failure, arrhythmias and vascular 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.

13. A compound according to any one of claims 1 to 9 for use in 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); ileal inflammation; and reflux diseases and their complications, such as Barrett's esophagus, bile reflux esophagitis and bile reflux gastritis.

14. A compound according to any one of claims 1 to 9 for use in the treatment or prevention of liver diseases or disorders, such as inherited liver metabolic disorders; inborn errors of bile acid synthesis; inborn abnormalities of the bile duct; biliary atresia; post-Kasai postoperative biliary atresia; post-liver transplantation biliary atresia; neonatal hepatitis; neonatal cholestasis; inherited forms of cholestasis; cerebrotendinous xanthomatosis; secondary BA synthesis defects; Zellweger's syndrome; cystic fibrosis-related liver disease; alpha 1-antitrypsin deficiency; Alagille syndrome (ALGS); Byler syndrome; primary bile acid (BA) synthesis defects; progressive familial intrahepatic cholestasis (PFIC), including PFIC-1, PFIC-2, PFIC-3 and nonspecific PFIC, PFIC after bile shunt and PFIC after liver transplantation; benign recurrent intrahepatic cholestasis (BRIC), including BRIC1, BRIC2 and nonspecific BRIC, BRIC after bile shunt and B after liver transplantation RIC; 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 LSC1; primary sclerosing cholangitis (PSC); immunoglobulin G4-associated cholangitis; primary biliary cholangitis; cholelithiasis (gallstones); biliary stones; common bile duct stones; cholelithiasis pancreatitis; Caroli's disease; bile duct malignancies; malignancies causing biliary tree obstruction; biliary strictures; AIDS cholangiopathy; ischemic cholangiopathy; pruritus due to cholestasis or jaundice; pancreatitis; chronic autoimmune liver disease causing progressive cholestasis; fatty degeneration of the liver; Alcoholic hepatitis; Acute fatty liver; Fatty liver of pregnancy; Drug-induced hepatitis; Iron overload; Inborn error of bile acid synthesis type 1 (BAS deficiency type 1); Drug-induced liver injury (DILI); Hepatic fibrosis; Congenital hepatic fibrosis; Cirrhosis; Langerhans cell histiocytosis (LCH); Neonatal ichthyosis sclerosing cholangitis (NISCH); Erythropoietic protoporphyria (EPP); Idiopathic adult-onset bile duct deficiency (IAD); Idiopathic neonatal hepatitis (INH); Non-symptomatic interlobular bile duct deficiency (NSPILBD); North American Indian cirrhosis of childhood (NAIC); Hepatic sarcoidosis; Amyloid degeneration; necrotizing enterocolitis; serum bile acid-induced toxicity, including cardiac arrhythmias with abnormal serum bile acid profiles (e.g., atrial fibrillation), cardiomyopathy ("cholecardia") associated with cirrhosis, and skeletal muscle atrophy associated with cholestatic liver disease; polycystic liver disease; viral hepatitis (including hepatitis A, B, C, D, and E); hepatocellular carcinoma (liver cancer); cholangiocarcinoma; bile acid-related gastrointestinal cancers; and cholestasis caused by tumors and neoplasms of the liver, biliary tract, and pancreas; or corticosteroid therapy used to enhance liver disease.

15. A compound according to any one of claims 1 to 9 for use in the treatment or prevention of hyperabsorption syndrome (including abetalipoproteinemia, familial hypobetalipoproteinemia (FHBL), chylomicron retention disease (CRD) and sitosterolemia); hypervitaminosis and osteopetrosis; hypertension; glomerular hyperfiltration; polycystic kidney disease (PKD) (including autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD)); and pruritus in renal failure; or for protection against renal damage associated with liver disease or metabolic diseases.

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