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

Abstract

The present invention relates to 1,5-benzothiazepine and 1,2,5-benzothiadiazepine derivatives of formula (I). These compounds are bile acid modulators having 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, as well as the use of these compounds in the treatment of cardiovascular diseases, disorders of fatty acid metabolism and glucose utilization, gastrointestinal diseases, and liver diseases. JPEG2025521736000270.jpg42170

Description

Technical Field

[0001] Cross - reference to related applications This application claims priority to Indian Patent Application No. 202211038517, filed on July 5, 2022 (the disclosure of which is hereby incorporated by reference in its entirety).

[0002] The present invention relates to 1,5 - benzothiazepine and 1,2,5 - benzothiadiazepine derivatives of formula (I). These compounds are bile acid modulators having 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

[0003] Bile acids are physiological surfactants that play important roles in the intestinal absorption and transport of lipids, nutrients, and vitamins. They are also signaling molecules that activate nuclear receptors and cell signaling pathways that regulate lipid, glucose, and energy metabolism. Bile acids are steroid acids synthesized from cholesterol in the liver and stored in the gallbladder as mixed micelles. During digestion, the duodenum induces the release of hormones that cause the gallbladder to contract, thereby releasing bile acids into the small intestine, where they enable the absorption of fat-soluble vitamins and cholesterol. When bile acids reach the ileum, they are reabsorbed from the intestine, secreted into the portal blood, and returned to the liver via the portal circulation. Thus, more than 90% of bile acids are recycled and returned to the liver. These bile acids are then transported across the sinusoidal cell membrane of hepatocytes and re-secreted into bile across the canalicular membrane. In this first pass, 75-90% of bile acids are taken up by hepatocytes, completing one enterohepatic circulation. A portion of bile acids that are not removed by the liver enters the systemic circulation, where free bile acids are filtered by the renal glomeruli, efficiently reabsorbed in the proximal tubule, and returned to the systemic circulation. Interestingly, most of the bile acids secreted into bile across the canalicular membrane are derived from the recycling pool, and less than 10% arise from de novo hepatic synthesis. The small amount of bile acids that are not reabsorbed in the ileum reaches the colon. In the intestinal lumen, primary bile acids are converted to secondary bile acids mainly by mono- or di-dehydroxylation reactions of the steroid nucleus under the action of intestinal bacteria. Bile acids that are not absorbed by the intestine are then excreted in feces.

[0004] Overall, an efficient transport system helps maintain a constant bile acid pool, thereby ensuring a sufficiently high level of conjugated bile acids in the intestine to promote lipid absorption and reducing the bacterial load in the small intestine. This system also minimizes losses of bile acids into feces and urine and protects the intestine and hepatobiliary tract by eliminating potentially cytotoxic surfactants (as outlined 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)).

[0005] Regulation of the size of the bile acid pool by conversion of cholesterol to bile acids in the liver has been found to play an important role in cholesterol homeostasis, which corresponds to a major route for cholesterol excretion from the body. The liver plays an essential role in removing endogenous and xenobiotic compounds from the body. Normal hepatic bile secretion and enterohepatic circulation are required to excrete endogenous compounds such as cholesterol and bilirubin and their metabolites from the body, thereby maintaining lipid and bile acid homeostasis. (Kosters and Karpen, Xenobiotica 2008, Vol. 38, pp. 1043-1071).

[0006] Ileal reabsorption of bile acids can be inhibited by apical sodium-dependent bile acid transporter (ASBT) inhibitor compounds. Inhibition of bile acid reabsorption has been reported to be useful for the treatment of several diseases, including dyslipidemia, diabetes, obesity, constipation, cholestatic liver diseases, non-alcoholic steatohepatitis, and other liver diseases. Numerous ASBT inhibitor compounds have been disclosed over the past several decades. For example, see 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, EP 624593, EP 624594, EP 624595, EP 624596, EP 0864582, EP 1173205, EP 1535913 and EP 3210977.

Prior Art Documents

Patent Documents

[0007] [Patent Document 1] WO 93 / 16055 [Patent Document 2] WO 94 / 18183 [Patent Document 3] WO 94 / 18184 [Patent Document 4] WO 96 / 05188 [Patent Document 5] WO 96 / 08484 [Patent Document 6] WO 96 / 16051 [Patent Document 7] WO 97 / 33882 [Patent Document 8] WO 98 / 03818 [Patent Document 9] WO 98 / 07449 [Patent Document 10] WO 98 / 40375 [Patent Document 11] WO 99 / 35135 [Patent Document 12] WO 99 / 64409 [Patent Document 13] WO 99 / 64410 [Patent Document 14] WO 00 / 47568 [Patent Document 15] WO 00 / 61568 [Patent Document 16] WO 00 / 38725 [Patent Document 17] WO 00 / 38726 [Patent Document 18] WO 00 / 38727 [Patent Document 19] WO 00 / 38728 [Patent Document 20] WO 00 / 38729 [Patent Document 21] WO 01 / 66533 [Patent Document 22] WO 01 / 68096 [Patent Document 23] WO 02 / 32428 [Patent Document 24] WO 02 / 50051 [Patent Document 25] WO 03 / 020710 [Patent Document 26] WO 03 / 022286 [Patent Document 27] WO 03 / 022825 [Patent Document 28] WO 03 / 022830 [Patent Document 29] WO 03 / 061663 [Patent Document 30] WO 03 / 091232 [Patent Document 31] WO 03 / 106482 [Patent Document 32] WO 2004 / 006899 [Patent Document 33] WO 2004 / 076430 [Patent Document 34] WO 2007 / 009655 [Patent Document 35] WO 2007 / 009656 [Patent Document 36] WO 2011 / 137135 [Patent Document 37] WO 2019 / 234077 [Patent Document 38] WO 2020 / 161216 [Patent Document 39] WO 2020 / 161217 [Patent Document 40] WO 2021 / 110883 [Patent Document 41] WO 2021 / 110884 [Patent Document 42] WO 2021 / 110885 [Patent Document 43] WO 2021 / 110886 [Patent Document 44] WO 2021 / 110887 [Patent Document 45] WO 2022 / 029101 [Patent Document 46] DE 19825804 [Patent Document 47] EP 864582 [Patent Document 48] EP 489423 [Patent Document 49] EP 549967 [Patent Document 50] EP 573848 [Patent Document 51] EP 624593 [Patent Document 52] EP 624594 [Patent Document 53] EP 624595 [Patent Document 54] EP 624596 [Patent Document 55] EP 0864582 [Patent Document 56] EP 1173205 [Patent Document 57] EP 1535913 [Patent Document 58] EP 3210977 [Patent Document 59] U.S. Patent Application Publication No. 2018 / 0140219 [Patent Document 60] U.S. Patent Application Publication No. 2016 / 146715 [Patent Document 61] U.S. Patent Application Publication No. 2005 / 0215882 [Patent Document 62] U.S. Patent No. 9,872,844 [Patent Document 63] WO 2017 / 138877 [Patent Document 64] WO 2017 / 138878 [Patent Document 65] WO 2019 / 032026 [Patent Document 66] WO 2019 / 032027 [Non-Patent Document]

[0008] [Non-Patent Document 1] Kosters and Karpen (Xenobiotica 2008, Vol. 38, pp. 1043 - 1071) [Non-Patent Document 2] Chiang (J. Lipid Res. 2009, Vol. 50, pp. 1955 - 1966) [Non-Patent Document 3] Dawson (Handb. Exp. Pharmacol. 2011, Vol. 201, pp. 169 - 203) [Non-Patent Document 4] Dong et al., Mol. Pharm. 2013, Vol. 10, pp. 1008 - 1019 [Non-Patent Document 5] Vaz et al., Hepatology 2015, Vol. 61, pp. 260 - 267 [Non-Patent Document 6] Karpen and Dawson, Hepatology 2015, Vol. 61, pp. 24 - 27 [Non-Patent Document 7] Liu et al., Scientific Reports 2017, 7: 9214, pp. 1 - 7 [Non-Patent Document 8] Danese et al., PLoS One. 2017, Vol. 12(6): e0179200 [Non-Patent Document 9] Kooistra et al., "KLIFS: A structural kinase-ligand interaction database", Nucleic Acids Res. 2016, Vol. 44, No. D1, D365 - D371 [Non-Patent Document 10] Gunaydin, M. et al., Hepat Med. 2018, Vol. 10, pp. 95 - 104 [Non-Patent Document 11] Ferslew et al., Dig Dis Sci. 2015, Vol. 60, pp. 3318 - 3328 [Non - Patent Document 12] Chalasani et al., Hepatology 2018, Vol. 67(1), pp. 328 - 357 [Non - Patent Document 13] Kleiner et al., Hepatology. 2005, 41(6):1313 - 1321 [Non - Patent Document 14] Di Lascio et al., Ultrasound Med Biol. 2018, Vol. 44(8), pp. 1585 - 1596; [Non - Patent Document 15] Lv et al., J Clin Transl Hepatol. 2018, Vol. 6(2), pp. 217 - 221; [Non - Patent Document 16] Reeder et al., J Magn Reson Imaging. 2011, Vol. 34(4), spcone; [Non - Patent Document 17] de Ledinghen V et al., J Gastroenterol Hepatol. 2016, Vol. 31(4), pp. 848 - 855 [Non - Patent Document 18] Brunt et al., Am J Gastroenterol 1999, Vol. 94, pp. 2467 - 2474 [Non - Patent Document 19] Angulo et al., Hepatology 2007, Vol. 45(4), pp. 846 - 54 [Non - Patent Document 20] Ishak et al., J. Hepatol. 1995, Vol. 22, pp. 696 - 699 [Non - Patent Document 21] McPherson et al., Gut 2010, Vol. 59(9), pp. 1265 - 9 [Non - Patent Document 22] Adams et al., Clin. Chem. 2005, Vol. 51(10), pp. 1867 - 1873 [Non - Patent Document 23] Lichtinghagen R et al., J Hepatol. August 2013;59(2):236-42

Non-Patent Document 24

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Summary of the Invention

Problems to be Solved by the Invention

[0009] Despite several previously reported ASBT inhibitor compounds, there is a need for further bile acid modulating compounds having an optimized profile with respect to potency, selectivity, and bioavailability.

Means for Solving the Problems

[0010] Certain 1,5-benzothiazepine and 1,2,5-benzothiadiazepine derivatives have been found to be potent inhibitors of the apical sodium-dependent bile acid transporter (ASBT) and / or the liver bile acid transporter (LBAT) and may be useful in treating diseases where inhibition of bile acid circulation is desirable. Accordingly, in a first aspect, the present invention provides a compound of formula (I)

[0011]

Chemical formula

[0012] (wherein M is -CH2- or -NR 6 -, R 1 is C 1~4 alkyl, R 2 is selected from the group consisting of hydrogen and C 1~4 alkyl, R 3 is independently selected from the group consisting of hydrogen, halogen, hydroxy, 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 of 1, 2 or 3, R 4 is selected from the group consisting of 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 R5B is independently selected from the group consisting of hydrogen, halogen, hydroxy, C 1~4 alkyl and C 1~4 alkoxy, or R 5A and R 5B together with the carbon atom to which they are attached form a 3- to 5-membered saturated carbon ring, R 6 is selected from the group consisting of hydrogen and C 1~4 alkyl) or a pharmaceutically acceptable salt thereof.

[0013] In some embodiments, R 1 is C 2~4 alkyl. In a preferred embodiment, R 1 is n-butyl.

[0014] In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is methyl, ethyl or n-butyl.

[0015] In some embodiments, R 3 is independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, hydroxy, methoxy, amino, methylamino and dimethylamino. In a preferred embodiment, n is 1, i.e., the phenyl ring is substituted with only one substituent R 3 . In another preferred embodiment, R 3 is in the para position.

[0016] 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. In some embodiments, R 4 is methoxy, methylthio, methylsulfonyl or dimethylamino. In some embodiments, R 4 is methoxy or methylthio.

[0017] In some embodiments, R 5A and R 5B are each independently hydrogen or C 1~4 alkyl, or together with the carbon atom to which they are attached, form a cyclopropyl ring. In some embodiments, R 5A and R 5B are each independently hydrogen or methyl.

[0018] In some embodiments, R 6 is hydrogen. In some embodiments, R 6 is methyl.

[0019] In a preferred embodiment, the compound of formula (I) is a compound of formula (I-a):

[0020]

Chemical formula

[0021] (wherein M is selected from the group consisting of -CH2-, -NH-, and -NCH3-, R 1 is C 2~4 alkyl, R 2 is selected from the group consisting of hydrogen and C 1~4 alkyl, R 3 is selected from the group consisting of hydrogen, fluoro, chloro, bromo, hydroxy, methoxy, amino, methylamino, and dimethylamino, R 4 is selected from the group consisting of fluoro, chloro, bromo, methyl, cyclopropyl, methoxy, ethoxy, methylthio, ethylthio, methylsulfonyl, amino, methylamino, and dimethylamino, R 5A and R 5B are each independently hydrogen or C 1~4 alkyl, or together with the carbon atom to which they are attached, form a cyclopropyl ring) or a pharmaceutically acceptable salt thereof.

[0022] In another preferred embodiment, the compound of formula (I) is a compound of formula (I-a), wherein M is selected from the group consisting of -CH2-, -NH-, and -N(CH3)-, R 1 is n-butyl, R 2 is selected from the group consisting of hydrogen and C 1~4 alkyl, R 3 is selected from the group consisting of hydrogen and fluoro, R 4 is methoxy, methylthio, methylsulfonyl, or dimethylamino, R 5A and R 5B are each independently hydrogen or methyl) or a pharmaceutically acceptable salt thereof.

[0023] In certain embodiments, the compound of formula (I) is 2-(((3-butyl-3-ethyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)methyl)thio)acetic acid; (S)-2-(((3-butyl-3-ethyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)methyl)thio)acetic acid; (R)-2-(((3-butyl-3-ethyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)methyl)thio)acetic acid; 2-(((3,3-dibutyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)methyl)thio)acetic acid; 2-(((3-butyl-3-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)methyl)thio)acetic acid; (S)-2-(((3-butyl-3-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)methyl)thio)acetic acid; (R)-2-(((3-butyl-3-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)methyl)thio)acetic acid; 2-(((3-butyl-3-ethyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)methyl)thio)acetic acid; (S)-2-(((3-butyl-3-ethyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)methyl)thio)acetic acid; (R)-2-(((3-butyl-3-ethyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)methyl)thio)acetic acid; 2-(((3,3-dibutyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)methyl)thio)acetic acid; 2-(((3-butyl-3-ethyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)methyl)thio)acetic acid; (S)-2-(((3-butyl-3-ethyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)methyl)thio)acetic acid; (R)-2-(((3-butyl-3-ethyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)methyl)thio)acetic acid; 2-(((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)methyl)thio)acetic acid; (S)-2-(((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)methyl)thio)acetic acid; (R)-2-(((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)methyl)thio)acetic acid; 2-(((3-butyl-3-ethyl-7-methoxy-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiadiazepin-8-yl)methyl)thio)acetic acid; (S)-2-(((3-butyl-3-ethyl-7-methoxy-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiadiazepin-8-yl)methyl)thio)acetic acid; (R)-2-(((3-butyl-3-ethyl-7-methoxy-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiadiazepin-8-yl)methyl)thio)acetic acid; 2-(((3-butyl-3-ethyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,5-benzothiadiazepin-8-yl)methyl)thio)-2-methylpropanoic acid; (S)-2-(((3-butyl-3-ethyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,5-benzothiadiazepin-8-yl)methyl)thio)-2-methylpropanoic acid; (R)-2-(((3-butyl-3-ethyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)methyl)thio)-2-methylpropanoic acid; 2-(((3,3-dibutyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)methyl)thio)-2-methylpropanoic acid; 2-(((3-butyl-3-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)methyl)thio)-2-methylpropanoic acid; (S)-2-(((3-butyl-3-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)methyl)thio)-2-methylpropanoic acid; (R)-2-(((3-butyl-3-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)methyl)thio)-2-methylpropanoic acid; 2-(((3-butyl-3-ethyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)methyl)thio)acetic acid; (S)-2-(((3-butyl-3-ethyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)methyl)thio)acetic acid; (R)-2-(((3-butyl-3-ethyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)methyl)thio)acetic acid; 2-(((3,3-dibutyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)methyl)thio)acetic acid; 2-(((3,3-Dibutyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)methyl)thio)-2-methylpropanoic acid; 2-(((3,3-Dibutyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)methyl)thio)-2-methylpropanoic acid; 2-(((3-Butyl-3-ethyl-7-methoxy-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)methyl)thio)-2-methylpropanoic acid; (S)-2-(((3-Butyl-3-ethyl-7-methoxy-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)methyl)thio)-2-methylpropanoic acid; (R)-2-(((3-Butyl-3-ethyl-7-methoxy-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)methyl)thio)-2-methylpropanoic acid; 2-(((3-Butyl-7-methoxy-3-methyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)methyl)thio)acetic acid; (S)-2-(((3-Butyl-7-methoxy-3-methyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)methyl)thio)acetic acid; (R)-2-(((3-Butyl-7-methoxy-3-methyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)methyl)thio)acetic acid; 2-(((3-Butyl-5-(4-fluorophenyl)-7-methoxy-2-methyl-1,1-dioxide-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)methyl)thio)acetic acid; (S)-2-(((3-butyl-5-(4-fluorophenyl)-7-methoxy-2-methyl-1,1-dioxide-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)methyl)thio)acetic acid; (R)-2-(((3-butyl-5-(4-fluorophenyl)-7-methoxy-2-methyl-1,1-dioxide-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)methyl)thio)acetic acid; 2-(((3,3-dibutyl-7-methoxy-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiadiazepin-8-yl)methyl)thio)acetic acid; 2-(((3,3-dibutyl-5-(4-fluorophenyl)-7-methoxy-1,1-dioxide-2,3,4,5-tetrahydro-1,5-benzothiadiazepin-8-yl)methyl)thio)acetic acid; 2-(((3-butyl-3-ethyl-5-(4-fluorophenyl)-7-methoxy-1,1-dioxide-2,3,4,5-tetrahydro-1,5-benzothiadiazepin-8-yl)methyl)thio)-2-methylpropanoic acid; (S)-2-(((3-butyl-3-ethyl-5-(4-fluorophenyl)-7-methoxy-1,1-dioxide-2,3,4,5-tetrahydro-1,5-benzothiadiazepin-8-yl)methyl)thio)-2-methylpropanoic acid; (R)-2-(((3-butyl-3-ethyl-5-(4-fluorophenyl)-7-methoxy-1,1-dioxide-2,3,4,5-tetrahydro-1,5-benzothiadiazepin-8-yl)methyl)thio)-2-methylpropanoic acid; 2-(((3-butyl-7-methoxy-2-methyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)methyl)thio)acetic acid; (S)-2-(((3-butyl-7-methoxy-2-methyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)methyl)thio)acetic acid; (R)-2-(((3-Butyl-7-methoxy-2-methyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)methyl)thio)acetic acid; 2-(((3-Butyl-7-methoxy-2-methyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)methyl)thio)-2-methylpropanoic acid; (S)-2-(((3-Butyl-7-methoxy-2-methyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)methyl)thio)-2-methylpropanoic acid; (R)-2-(((3-Butyl-7-methoxy-2-methyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)methyl)thio)-2-methylpropanoic acid; 2-(((3-Butyl-3-ethyl-5-(4-fluorophenyl)-7-methoxy-1,1-dioxide-2,3,4,5-tetrahydro-1,5-benzothiadiazepin-8-yl)methyl)thio)acetic acid; (S)-2-(((3-Butyl-3-ethyl-5-(4-fluorophenyl)-7-methoxy-1,1-dioxide-2,3,4,5-tetrahydro-1,5-benzothiadiazepin-8-yl)methyl)thio)acetic acid; (R)-2-(((3-Butyl-3-ethyl-5-(4-fluorophenyl)-7-methoxy-1,1-dioxide-2,3,4,5-tetrahydro-1,5-benzothiadiazepin-8-yl)methyl)thio)acetic acid; 2-(((3-Butyl-7-methoxy-3-methyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiadiazepin-8-yl)methyl)thio)-2-methylpropanoic acid; (S)-2-(((3-Butyl-7-methoxy-3-methyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiadiazepin-8-yl)methyl)thio)-2-methylpropanoic acid; (R)-2-(((3-Butyl-7-methoxy-3-methyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)methyl)thio)-2-methylpropanoic acid; 2-(((3,3-Dibutyl-7-methoxy-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)methyl)thio)-2-methylpropanoic acid; 2-(((3-Butyl-3-ethyl-7-methoxy-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)methyl)thio)acetic acid; (R)-2-(((3-Butyl-3-ethyl-7-methoxy-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)methyl)thio)acetic acid; (S)-2-(((3-Butyl-3-ethyl-7-methoxy-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)methyl)thio)acetic acid; 2-(((3-Butyl-7-(dimethylamino)-3-ethyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)methyl)thio)acetic acid; 2-(((3-Butyl-3-ethyl-7-(methylsulfonyl)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)methyl)thio)acetic acid; (S)-2-(((3-Butyl-3-ethyl-7-(methylsulfonyl)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)methyl)thio)acetic acid; (R)-2-(((3-Butyl-3-ethyl-7-(methylsulfonyl)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)methyl)thio)acetic acid; (R)-2-(((3-Butyl-7-(dimethylamino)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)methyl)thio)acetic acid; (R)-2-(((3-Butyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)methyl)thio)acetic acid; (R)-2-(((3-Butyl-7-methoxy-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)methyl)thio)acetic acid; 2-(((3-Butyl-7-(dimethylamino)-3-methyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)methyl)thio)acetic acid; 2-(((3-Butyl-7-methoxy-3-methyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)methyl)thio)acetic acid; and 2-(((3-Butyl-3-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)methyl)thio)acetic acid; or a salt thereof acceptable as a medicament, selected from the group consisting of.

BEST MODE FOR CARRYING OUT THE INVENTION

[0024] As used herein, the term "halo" refers to fluoro, chloro, bromo and iodo.

[0025] As used herein, "C 1~6 alkyl" refers to a straight or branched alkyl group having 1 to 6 carbon atoms, and "C 1~4 alkyl" refers to a straight or branched alkyl group having 1 to 4 carbon atoms. C 1~4Examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0026] As used herein, the term "C" 3~6 "cycloalkyl" refers to a monocyclic saturated hydrocarbon ring having 3 to 6 carbon atoms. C 3~6 Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0027] As used herein, the term "C" 1~4 "haloalkyl", as defined herein, refers to a straight or branched C in which one or more hydrogen atoms are replaced by halogen 1~4 alkyl group. C 1~4 Examples of haloalkyl include chloromethyl, fluoroethyl, and trifluoromethyl.

[0028] As used herein, the terms "C" 1~4 "alkoxy" and "C" 1~4 "alkylthio", etc., each refer to a straight or branched C bonded to the rest of the molecule through an oxygen or sulfur atom 1~4 alkyl group.

[0029] As used herein, the term "C" 1~4 "alkylsulfonyl" refers to a straight or branched C bonded to the rest of the molecule through a sulfonyl (-S(O)2-) group 1~4 alkyl group.

[0030] The term "amino" refers to the -NH2 group. As used herein, the terms "N-(C" 1~4 "alkyl)amino" and "N,N-di(C" 1~4 "alkyl)amino" refer to an amino group in which one or both hydrogen atoms are each replaced by a straight or branched C 1~4 alkyl group. N-(C 1~4Examples of (alkyl)amino include methylamino, ethylamino, and tert-butylamino, and N,N-di-(C 1~4 Examples of (alkyl)amino include dimethylamino and diethylamino.

[0031] As used herein, the term "pharmaceutically acceptable" refers to compounds, materials, compositions, and / or dosage forms that are suitable for human pharmaceutical use, are generally safe, non-toxic, and neither biologically nor otherwise undesirable.

[0032] As used herein, the term "about" refers, in this specification, to a value or parameter that includes (and describes) embodiments that target the value or parameter itself. For example, a description that refers to "about 20" includes a description of "20". Numerical ranges include the numbers that define the range. Generally speaking, the term "about" refers to either the value indicated by the variable, all values within the experimental error of the value indicated by the variable (e.g., within the 95% confidence interval of the mean), or within 10 percent of the value indicated by the variable, whichever is greater.

[0033] The 1,5-benzothiazepine and 1,2,5-benzothiadiazepine compounds of formula (I), or pharmaceutically acceptable salts thereof, are inhibitors of the apical sodium-dependent bile acid transporter, the liver bile acid transporter, or both the apical sodium-dependent bile acid transporter and the liver bile acid transporter (an ASBT inhibitor, an LBAT inhibitor, and a dual ASBT / LBAT inhibitor, respectively). Accordingly, they are useful for the treatment or prevention of conditions, disorders, and diseases such as cardiovascular diseases, fatty acid metabolism and glucose utilization disorders, gastrointestinal diseases, and liver diseases, where inhibition of bile acid circulation is desirable.

[0034] As circulatory diseases and fatty acid metabolism and glucose utilization disorders, hypercholesterolemia; disorders of fatty acid metabolism; type 1 and type 2 true diabetes; cataracts, microvascular and macrovascular diseases, retinopathy, neuropathy, nephropathy, and delayed wound healing, tissue ischemia, diabetic foot lesions, atherosclerosis, myocardial infarction, acute coronary syndrome, unstable angina, stable angina, stroke, peripheral arterial occlusive disease, cardiomyopathy, heart failure, cardiac arrhythmias, and vascular restenosis, complications of diabetes including; diabetes-related diseases, such as insulin resistance (disorders of glucose homeostasis), hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, obesity, dyslipidemia, hypertriglyceridemia, hyperlipidemia including metabolic syndrome (syndrome X), atherosclerosis, and hypertension; and increases in high-density lipoprotein levels, but not limited to these.

[0035] As gastrointestinal diseases and disorders, constipation (including chronic constipation, functional constipation, chronic idiopathic constipation (CIC), intermittent / sporadic constipation, constipation secondary to type 1 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, constipation-predominant irritable bowel syndrome (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); inflammation of the ileum; and reflux disease and its complications, such as Barrett's esophagus, bile reflux esophagitis, and bile reflux gastritis.

[0036] A liver disease, as defined herein, is any disease in the liver and related organs such as the pancreas, portal vein, liver parenchyma, intrahepatic biliary system, extrahepatic biliary system, and gallbladder. In some cases, the liver disease is a bile acid-dependent liver disease. Liver diseases and disorders include: hereditary metabolic disorders of the liver; congenital abnormalities in bile acid synthesis; congenital biliary tract malformations; biliary atresia; biliary atresia after Kasai operation; biliary atresia after liver transplantation; neonatal hepatitis; neonatal cholestasis; genetic forms of cholestasis; cerebrotendinous xanthomatosis; secondary defects in BA synthesis; Zellweger syndrome; liver diseases associated with cystic fibrosis; alpha1-antitrypsin deficiency; Alagille syndrome (ALGS); Byler syndrome; primary defects in bile acid (BA) synthesis; progressive familial intrahepatic cholestasis (PFIC) including PFIC-1, PFIC-2, PFIC-3, and unspecified PFIC, PFIC after bile diversion, and PFIC after liver transplantation; benign recurrent intrahepatic cholestasis (BRIC) including BRIC1, BRIC2, and unspecified BRIC, BRIC after bile diversion, and BRIC after liver transplantation; autoimmune hepatitis; primary biliary cirrhosis (PBC); liver fibrosis; non-alcoholic fatty liver disease (NAFLD); non-alcoholic steatohepatitis (NASH); portal hypertension; cholestasis; cholestasis in Down syndrome; drug-induced cholestasis; intrahepatic cholestasis of pregnancy (jaundice during pregnancy); intrahepatic cholestasis; extrahepatic cholestasis; parenteral nutrition-associated cholestasis (PNAC); cholestasis associated with low phospholipids; lymphedema cholestasis syndrome 1 (LCS1); primary sclerosing cholangitis (PSC); cholangitis associated with immunoglobulin G4; primary biliary cholangitis; cholelithiasis (gallstones); biliary lithiasis; choledocholithiasis; gallstone pancreatitis; Caroli's disease; malignant tumors of the bile duct; malignant tumors causing obstruction of the biliary tree; biliary stricture; AIDS cholangiopathy; ischemic cholangiopathy; pruritus due to cholestasis or jaundice; pancreatitis; chronic autoimmune liver diseases leading to progressive cholestasis; hepatic steatosis; alcoholic hepatitis; acute fatty liver; fatty liver of pregnancy; drug-induced hepatitis; hemosiderosis; congenital bile acid metabolism disorder type 1 (BAS disorder type 1); drug-induced liver injury (DILI); liver fibrosis; congenital hepatic fibrosis; cirrhosis; Langerhans cell histiocytosis (LCH); neonatal ichthyosis sclerosing cholangitis (NISCH); erythropoietic protoporphyria (EPP); idiopathic adult ductopenia (IAD); idiopathic neonatal hepatitis (INH);Non-symptomatic intrahepatic bile ductopenia (NS PILBD); autosomal recessive hereditary intrahepatic cholestasis (North American Indian childhood cirrhosis) (NAIC); hepatic sarcoidosis; amyloidosis; necrotizing enterocolitis; cardiac arrhythmias (such as atrial fibrillation) in the context of abnormal serum bile acid profiles, cardiomyopathy associated with cirrhosis ("cholecardia"), and toxicity caused by serum bile acids including skeletal muscle wasting associated with cholestatic liver disease; polycystic liver disease; viral hepatitis (including hepatitis A, B, C, D, and E); hepatocellular carcinoma (hepatocellular tumor); cholangiocarcinoma; gastrointestinal cancers related to bile acids; and cholestasis caused by tumors and neoplasms of the liver, biliary tract, and pancreas, but not limited thereto. The compound of formula (I) or a pharmaceutically acceptable salt thereof is also useful for enhancing corticosteroid therapy in liver diseases.;

[0037] Other diseases that can be treated or prevented by the compound of formula (I) or a pharmaceutically acceptable salt thereof include malabsorption syndromes (including abetalipoproteinemia, familial hypobetalipoproteinemia (FHBL), chylomicron retention disease (CRD), and sitosterolemia); vitamin excess and marble bone disease; hypertension; glomerular hyperfiltration; polycystic kidney disease (PKD) including autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD); and uremic pruritus. The compound is also useful for protecting against kidney injury associated with liver or metabolic diseases.

[0038] Bile acid transport in the human body is mediated by the action of members of the SLC10 family of solute transporter proteins, particularly Na expressed on the sinusoidal cell membrane of hepatocytes +-Sodium taurocholate cotransporting polypeptide (NTCP, also known as liver bile acid transporter (LBAT); gene symbol SLC10A1), and apical sodium-dependent bile acid transporter (ASBT, also known as ileal bile acid transporter (IBAT), ISBT, ABAT, or NTCP2; gene symbol SLC10A2) expressed on the apical membranes of ileal enterocytes, proximal tubular cells, bile duct epithelium, large bile duct cells, and gallbladder epithelial cells. In the liver, bile acids are efficiently extracted from portal blood by the liver bile acid transporter (LBAT) and are resecreted across the canalicular membrane by the bile salt export pump (BSEP; gene symbol ABCB11). Ileal bile acid reabsorption is handled by the apical sodium-dependent bile acid transporter (ASBT), generally called the ileal bile acid transporter (IBAT) in the ileum. Both LBAT and ASBT function as electrogenic sodium-solute cotransporters that move more than two Na + ions per molecule of solute.

[0039] Endogenous substances, including xenobiotics and bile acids, are taken up from portal blood by the liver and secreted into bile by distinct transport proteins with individualized substrate specificities. Glycine- and taurine-conjugated bile acids exist in anionic form and cannot cross membranes by diffusion, thus relying entirely on membrane transport proteins to enter and exit hepatocytes (Kosters and Karpen, Xenobiotica 2008, Vol. 38, pp. 1043-1071). ASBT and LBAT prefer glycine- and taurine-conjugated bile salts over their unconjugated counterparts and show a higher affinity for dihydroxy bile salts than trihydroxy bile salts. The non-bile acid substrates of ASBT have not yet been identified, but LBAT has been found to transport various steroid sulfates, hormones, and xenobiotics as well.

[0040] LBAT has not been as fully characterized as ASBT with respect to drug inhibition requirements. Dong et al. identified FDA-approved drugs that inhibit human LBAT and compared the inhibition requirements of LBAT and ASBT. A series of LBAT inhibition tests were conducted using FDA-approved drugs in conjunction with the development of an iterative computational model. From the screening tests, 27 drugs, including irbesartan (Ki = 11.9 μM) and ezetimibe (Ki = 25.0 μM), were identified as novel LBAT inhibitors. Because there are common features in the pharmacophores, it was shown that two hydrophobic substances and one hydrogen bond acceptor are important for the inhibition of LBAT. From 72 drugs screened in vitro, a total of 31 drugs inhibited LBAT, whereas 51 drugs (i.e., more than half) inhibited ASBT. Thus, although there is inhibitor overlap, ASBT is unexpectedly more permissive than LBAT with respect to drug inhibition, which may be related to the fact that LBAT has fewer pharmacophore features (Dong et al., Mol. Pharm. 2013, Vol. 10, pp. 1008-1019).

[0041] Vaz et al. have described the identification of LBAT deficiency as a new congenital abnormality with a relatively mild clinical phenotype. The identification of LBAT deficiency confirms that this transporter is the major uptake system for conjugated bile salts into the liver, but also shows that auxiliary transporters can sustain the enterohepatic circulation in its absence (Vaz et al., Hepatology 2015, Vol. 61, pp. 260-267). These findings support the hypothesis that LBAT inhibition is a safe mechanism of action because hepatocytes still have the potential to take up the required amount of bile acids.

[0042] Liu et al. described the identification of a new type of hypercholanemia associated with homozygosity for the p.Ser267Phe mutation in SLC10A1 (LBAT). The allele frequency of this mutation in the gene SLC10A1 varies by ethnic group, with the highest incidence rates occurring in South China (8% and 12% in Han Chinese and Dai ethnic groups in China, respectively) and Vietnam (11%). This "hidden" hypercholanemia was thought to affect 0.64% of the South Han Chinese ethnic group, 1.44% of the Dai ethnic group, and 1.21% of the ethnic group in Vietnam. An increase in conjugated and unconjugated serum BA levels was also observed in homozygous individuals. Liu et al. suggested that this finding is most likely due to a reduction in BA transport from the portal circulation to hepatocytes. This supports the hypothesis that the physiological function of the enterohepatic circulation is not only the recirculation of bile acids but also the removal of bile acids from this circulation to achieve homeostasis (Karpen and Dawson, Hepatology 2015, Vol. 61, pp. 24 - 27). Alternatively, in homozygous carriers, the liver may synthesize increased levels of bile acids to compensate for the reduced enterohepatic recirculation. Since LBAT also transports unconjugated bile acids, the increase in unconjugated bile acids in this study was not surprising (Liu et al., Scientific Reports 2017, 7: 9214, pp. 1 - 7).

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

[0044] ASBT inhibition has been investigated for its ability to reduce plasma cholesterol levels, improve insulin resistance, and reduce the bile acid burden on the liver in cholestatic liver diseases. In addition, ASBT inhibition has been found to restore insulin levels and euglycemia, thereby establishing ASBT inhibition as a promising treatment for type 2 diabetes mellitus. ASBT inhibitors are also used in the treatment of functional constipation.

[0045] Since ASBT is mainly expressed in the ileum (often called IBAT in the ileum), ASBT inhibitors do not need to be systemically absorbed. On the other hand, ASBT is also expressed in proximal tubule cells of the kidney. Therefore, systemically absorbed ASBT inhibitors may also inhibit the reuptake of bile acids in the kidney. This is thought to increase the level of bile acids in the urine and enhance the removal of bile acids from the body via urine. Therefore, systemically absorbed ASBT inhibitors that act on both the ileum and the kidney are predicted to lead to a greater reduction in bile acid levels than non-systemically absorbed ASBT inhibitors that act only on the ileum.

[0046] Compounds with high ASBT inhibitory potency are particularly suitable for the treatment of liver diseases that cause cholestasis, such as progressive familial intrahepatic cholestasis (PFIC), Alagille syndrome, biliary atresia, and non-alcoholic steatohepatitis (NASH).

[0047] Biliary atresia is a rare pediatric liver disease that involves partial or complete obstruction (or even absence) of the large bile ducts. This obstruction or absence causes cholestasis, which leads to the accumulation of bile acids that damage the liver. In some embodiments, the accumulation of bile acids occurs in the extrahepatic biliary system. In some embodiments, the accumulation of bile acids occurs in the intrahepatic biliary system. The current standard treatment is the Kasai procedure, a surgical operation that removes the obstructed bile duct and connects a portion of the small intestine directly to the liver. Currently, there is no approved drug therapy for this disorder.

[0048] A method for treating biliary atresia in a subject in need of treatment for biliary atresia is provided herein, 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 is administered a compound of formula (I) or a pharmaceutically acceptable salt thereof after undergoing the Kasai procedure. In some embodiments, the subject is administered a compound of formula (I) or a pharmaceutically acceptable salt thereof prior to undergoing the Kasai procedure. In some embodiments, treatment of biliary atresia results in a decrease in the level of serum bile acids in the subject. In some embodiments, the level of serum bile acids is determined by, for example, an ELISA enzyme assay or a total bile acid measurement assay 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, the level of serum bile acids can be reduced by, for example, 10% - 40%, 20% - 50%, 30% - 60%, 40% - 70%, 50% - 80%, or more than 90% of the level of serum bile acids prior to administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, treatment of biliary atresia includes treatment of pruritus.

[0049] PFIC is a rare genetic disorder that is estimated to affect one in 50,000 - 100,000 births worldwide and causes a progressive, life - threatening liver disease.

[0050] One symptom of PFIC is pruritus, which often significantly reduces quality of life. In some cases, PFIC progresses to cirrhosis and liver failure. Current therapies include partial external biliary drainage (PEFD) and liver transplantation, but these options carry a substantial risk of postoperative complications as well as potential psychological and social problems.

[0051] Three alternative genetic defects have been identified that correlate with three separate PFIC subtypes known as type 1, type 2, and type 3: · Type 1 PFIC, also sometimes called "Byler's disease," is caused by a disorder of bile secretion resulting from mutations in the ATP8B1 gene, which encodes a protein that helps maintain the proper balance of fats known as phospholipids in the cell membranes within the bile ducts. These imbalances in phospholipids are associated with bile stasis and elevated bile acids in the liver. Subjects affected by type 1 PFIC typically develop bile stasis within one month of birth and, without surgical treatment, progress to cirrhosis and end-stage liver disease before 10 years of age. · Type 2 PFIC, also sometimes called "Byler syndrome," is caused by a disorder of bile salt secretion resulting from mutations in the ABCB11 gene, which encodes a protein known as the bile salt export pump that moves bile acids out of the liver. Subjects with type 2 PFIC often develop liver failure within several years after birth and have a high risk of developing a certain type of liver cancer known as hepatocellular carcinoma. · Type 3 PFIC typically presents with progressive bile stasis in the first few years of childhood and is caused by mutations in the ABCB4 gene, which encodes a transporter that moves phospholipids across the cell membrane.

[0052] In addition, mutations in the TJP2 gene, NR1H4 gene, or Myo5b gene have been proposed as causes of PFIC. In addition, there are subjects with PFIC who do not have mutations in any of the ATP8B1, ABCB11, ABCB4, TJP2, NR1H4, or Myo5b genes. In these cases, the cause of this condition is unknown.

[0053] Exemplary mutations of the ATP8B1 gene or the resulting protein are numbered based on the human wild-type ATP8B1 protein (e.g., SEQ ID NO: 1) or gene (e.g., SEQ ID NO: 2) and listed in Tables 2 and 3. Exemplary mutations of the ABCB11 gene or the resulting protein are numbered based on the human wild-type ABCB11 protein (e.g., SEQ ID NO: 3) or gene (e.g., SEQ ID NO: 4) and listed in Tables 4 and 5.

[0054] As will be understood by those skilled in the art, the amino acid positions in the reference protein sequence corresponding to the specific amino acid positions in 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 to these residues (referred to herein as "mutations") can include single or multiple amino acid substitutions, insertions, and deletions within or adjacent to the sequence. As will be understood by those skilled in the art, the nucleotide positions in the reference gene sequence corresponding to the specific nucleotide positions in 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 to these residues (referred to herein as "mutations") can include single or multiple nucleotide substitutions, insertions, and deletions within or adjacent to 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.

[0055] Canonical protein sequence of ATP8B1 (SEQ ID NO: 1) - Uniprot ID O43520

[0056]

Chem.

[0057] Canonical DNA sequence of ATP8B1 (SEQ ID NO: 2)

[0058]

Chem.

[0059]

Chem.

[0060]

Table 1A

[0061]

Table 1B

[0062]

Table 1C

[0063]

Table 1D

[0064]

Table 1E

[0065]

Table 1F

[0066]

Table 1G

[0067]

Table 1H

[0068]

Table 1I

[0069]

Table 2A

[0070]

Table 2B

[0071]

Table 2C

[0072]

Table 2D

[0073] References related to Table 2 and Table 3 1 Folmer et al., Hepatology. 2009, vol. 50(5), p. 1597-1605. 2 Hsu et al., Hepatol Res. 2009, vol. 39(6), p. 625-631. 3 Alvarez et al., Hum Mol Genet. 2004, vol. 13(20), p. 2451-2460. 4 Davit-Spraul et al., Hepatology 2010, vol. 51(5), p. 1645-1655. 5 Vitale et al., J Gastroenterol. 2018, vol. 53(8), p. 945-958. 6 Klomp et al., Hepatology 2004, vol. 40(1), p. 27-38. 7 Zarenezhad et al., Hepatitis Monthly: 2017, vol. 17(2); e43500. 8 Dixon et al., Scientific Reports 2017, vol. 7, 11823. 9 Painter et al., Eur J Hum Genet. 2005, vol. 13(4), p. 435-439. 10 Deng et al., World J Gastroenterol. 2012, vol. 18(44), p. 6504-6509. 11 Giovannoni et al., PLoS One. 2015, vol. 10(12): e0145021. 12 Li et al., Hepatology International 2017, vol. 11, No. 1, Supp. Supplement 1, pp. S180. Abstract Number: OP284. 13 Togawa et al., Journal of Pediatric Gastroenterology and Nutrition 2018, vol. 67, Supp. Supplement 1, pp. S363. Abstract Number: 615. 14 Miloh et al., Gastroenterology 2006, vol. 130, No. 4, Suppl. 2, pp. A759-A760. Meeting Info.: Digestive Disease Week Meeting / 107th Annual Meeting of the American-Gastroenterological-Association. Los Angeles, CA, USA. May 19. 15Droege et al., Zeitschrift fur Gastroenterologie 2015, vol. 53, No. 12. Abstract Number: A3-27. Meeting Info: 32. Jahrestagung der Deutschen Arbeitsgemeinschaft zum Studium der Leber. Dusseldorf, Germany. 22 Jan 2016-23 Jan 2016 16 Mizuochi et al., Clin Chim Acta. 2012, vol. 413(15-16), p. 1301-1304. 17 Liu et al., Hepatology International 2009, vol. 3, No. 1, p. 184-185. Abstract Number: PE405. Meeting Info: 19th Conference of the Asian Pacific Association for the Study of the Liver. Hong Kong, China. 13 Feb 2009-16 Feb 2009 18 McKay et al., Version 2. F1000Res. 2013; 2: 32. DOI: 10.12688 / f1000research.2-32.v2 19 Hasegawa et al., Orphanet J Rare Dis. 2014, vol. 9:89. 20 Stone et al., J Biol Chem. 2012, vol. 287(49), p. 41139-51. 21 Kang et al., J Pathol Transl Med. 2019 May 16. doi: 10.4132 / jptm.2019.05.03. [Epub ahead of print] 22Sharma et al., BMC Gastroenterol. 2018, vol. 18(1), p. 107. 23 Uegaki et al., Intern Med. 2008, vol. 47(7), p. 599-602. 24 Goldschmidt et al., Hepatol Res. 2016, vol. 46(4), p. 306-311. 25 Liu et al., J Pediatr Gastroenterol Nutr. 2010, vol. 50(2), p. 179-183. 26 Jung et al., J Pediatr Gastroenterol Nutr. 2007, vol. 44(4), p. 453-458. 27 Bounford. University of Birmingham. Dissertation Abstracts International, (2016) Vol. 75, No. 1C. Order No.: AAI10588329. ProQuest Dissertations & Theses. 28 Stolz et al., Aliment Pharmacol Ther. 2019, vol. 49(9), p. 1195-1204. 29 Ivashkin et al., Hepatology International 2016, vol. 10, No. 1, Supp. SUPPL. 1, pp. S461. Abstract Number: LBO-38. Meeting Info: 25th Annual Conference of the Asian Pacific Association for the Study of the Liver, APASL 2016. Tokyo, Japan. 20 Feb 2016-24 Feb 2016 30 Blackmore et al., J Clin Exp Hepatol. 2013, vol. 3(2), p. 159-161. 31 Matte et al., J Pediatr Gastroenterol Nutr. 2010, vol. 51(4), p. 488-493. 32 Squires et al., J Pediatr Gastroenterol Nutr. 2017, vol. 64(3), p. 425-430. 33 Hayshi et al., EBioMedicine. 2018, vol. 27, p. 187-199. 34 Nagasaka et al., J Pediatr Gastroenterol Nutr. 2007, vol. 45(1), p. 96-105. 35 Wang et al., PLoS One. 2016; vol. 11(4): e0153114. 36 Narchi et al., Saudi J Gastroenterol. 2017, vol. 23(5), p. 303-305. 37 Alashkar et al., Blood 2015, vol. 126, No. 23. Meeting Info.: 57th Annual Meeting of the American-Society-of-Hematology. Orlando, FL, USA. December 05 -08, 2015. Amer Soc Hematol. 38Ferreira et al., Pediatric Transplantation 2013, vol. 17, Supp. SUPPL. 1, pp. 99. Abstract Number: 239. Meeting Info: IPTA 7th Congress on Pediatric Transplantation. Warsaw, Poland. 13 Jul 2013-16 Jul 2013. 39 Pauli-Magnus et al., J Hepatol. 2005, vol. 43(2), p. 342-357. 40 Jericho et al., Journal of Pediatric Gastroenterology and Nutrition 2015, vol. 60(3), p. 368-374. 41 van der Woerd et al., PLoS One. 2013, vol. 8(11): e80553. 42 Copeland et al., J Gastroenterol Hepatol. 2013, vol. 28(3), p. 560-564. 43 Droege et al., J Hepatol. 2017, vol. 67(6), p. 1253-1264. 44 Chen et al., Journal of Pediatrics 2002, vol. 140(1), p. 119-124. 45 Jirsa et al., Hepatol Res. 2004, vol. 30(1), p. 1-3. 46 van der Woerd et al., Hepatology 2015, vol. 61(4), p. 1382-1391.

[0074] In some embodiments, the mutations in ATP8B1 are selected from L127P, G308V, T456M, D554N, F529del, I661T, E665X, R930X, R952X, R1014X, and G1040R.

[0075] Canonical protein sequence of ABCB11 (SEQ ID NO: 3) - Uniprot ID O95342

[0076]

Chemical formula

[0077] Canonical DNA sequence of ABCB11 (SEQ ID NO: 4)

[0078]

Chemical formula

[0079]

Chemical formula

[0080]

Table 3A

[0081]

Table 3B

[0082]

Table 3C

[0083]

Table 3D

[0084]

Table 3E

[0085]

Table 3F

[0086]

Table 3G

[0087]

Table 3H

[0088]

Table 3I

[0089]

Table 3J

[0090]

Table 3K

[0091]

Table 3L

[0092]

Table 3M

[0093]

Table 3N

[0094]

Table 4A

[0095]

Table 4B

[0096]

Table 4C

[0097]

Table 4D

[0098]

Table 4E

[0099]

Table 4F

[0100]

Table 4G

[0101]

Table 4H

[0102] References related to Table 4 and Table 5 1 Noe et al., J Hepatol. 2005, vol. 43(3), p. 536-543. 2 Lam et al., Am J Physiol Cell Physiol. 2007, vol. 293(5), p. C1709-16. 3 Stindt et al., Liver Int. 2013, vol. 33(10), p. 1527-1735. 4Gao et al., Shandong Yiyao 2012, vol. 52(10), p. 14-16. 5 Strautnieks et al., Gastroenterology. 2008, vol. 134(4), p. 1203-1214. 6 Kagawa et al., Am J Physiol Gastrointest Liver Physiol. 2008, vol. 294(1), p. G58-67. 7 Byrne et al., Hepatology. 2009, vol. 49(2), p. 553-567. 8 Chen et al., J Pediatr. 2008, vol. 153(6), p. 825-832. 9 Davit-Spraul et al., Hepatology 2010, vol. 51(5), p. 1645-1655. 10 Droege et al., Sci Rep. 2016, vol. 6: 24827. 11 Lang et al., Pharmacogenet Genomics. 2007, vol. 17(1), p. 47-60. 12 Ellinger et al., World J Gastroenterol. 2017, vol. 23(29), p. :5295-5303. 13 Vitale et al., J Gastroenterol. 2018, vol. 53(8), p. 945-958. 14 Knisely et al., Hepatology. 2006, vol. 44(2), p. 478-86. 15Ellis et al., Hepatology. 2018, vol. 67(4), p. 1531-1545. 16 Lam et al., J Hepatol. 2006, vol. 44(1), p. 240-242. 17 Varma et al., Hepatology 2015, vol. 62(1), p. 198-206. 18 Treepongkaruna et al., World J Gastroenterol. 2009, vol. 15(34), p. 4339-4342. 19 Zarenezhad et al., Hepatitis Monthly: 2017, vol. 17(2); e43500. 20 Hayashi et al., Hepatol Res. 2016, vol. 46(2), p. 192-200. 21 Guorui et al., Linchuang Erke Zazhi 2013, vol. 31(10), 905-909. 22 van Mil et al., Gastroenterology. 2004, vol. 127(2), p. 379-384. 23 Anzivino et al., Dig Liver Dis. 2013, vol. 45(3), p. 226-232. 24 Park et al., World J Gastroenterol. 2016, vol. 22(20), p. 4901-4907. 25 Imagawa et al., J Hum Genet. 2018, vol. 63(5), p. 569-577. 26Giovannoni et al., PLoS One. 2015, vol. 10(12): e0145021. 27 Hu et al., Mol Med Rep. 2014, vol. 10(3), p. 1264-1274. 28 Lang et al,. Drug Metab Dispos. 2006, vol. 34(9), p. 1582-1599. 29 Masahata et al., Transplant Proc. 2016, vol. 48(9), p. 3156-3162. 30 Holz et al., Hepatol Commun. 2018, vol. 2(2), p. 152-154. 31 Li et al., Hepatology International 2017, vol. 11, No. 1, Supp. Supplement 1, pp. S180. Abstract Number: OP284. 32 Francalanci et al., Laboratory Investigation 2011, vol. 91, Supp. SUPPL. 1, pp. 360A. Abstract Number: 1526. 33 Francalanci et al., Digestive and Liver Disease 2010, vol. 42, Supp. SUPPL. 1, pp. S16. Abstract Number: T.N.5. 34 Shah et al., J Pediatr Genet. 2017, vol. 6(2), p. 126-127. 35 Gao et al., Hepatitis Monthly 2017, vol. 17(10), e55087 / 1-e55087 / 6. 36 Evason et al., Am J Surg Pathol. 2011, vol. 35(5), p. 687-696. 37 Davit-Spraul et al., Mol Genet Metab. 2014, vol. 113(3), p. 225-229. 38 Maggiore et al., J Hepatol. 2010, vol. 53(5), p. 981-6. 39 McKay et al., Version 2. F1000Res. 2013; 2: 32. DOI: 10.12688 / f1000research.2-32.v2 40 Liu et al., Pediatr Int. 2013, vol. 55(2), p. 138-144. 41 Waisbourd-Zinman et al., Ann Hepatol. 2017, vol. 16(3), p. 465-468. 42 Griffin, et al., Canadian Journal of Gastroenterology and Hepatology 2016, vol. 2016. Abstract Number: A200. Meeting Info: 2016 Canadian Digestive Diseases Week, CDDW 2016. Montreal, QC, United States. 26 Feb 2016-29 Feb 2016 43 Qiu et al., Hepatology 2017, vol. 65(5), p. 1655-1669. 44 Imagawa et al., Sci Rep. 2017, 7:41806. 45Kang et al., J Pathol Transl Med. 2019 May 16. doi: 10.4132 / jptm.2019.05.03. [Epub ahead of print] 46 Takahashi et al., Eur J Gastroenterol Hepatol. 2007, vol. 19(11), p. 942-6. 47 Shimizu et al., Am J Transplant. 2011, vol. 11(2), p. 394-398. 48 Krawczyk et al., Ann Hepatol. 2012, vol. 11(5), p. 710-744. 49 Sharma et al., BMC Gastroenterol. 2018, vol. 18(1), p. 107. 50 Sattler et al., Journal of Hepatology 2017, vol. 66, No. 1, Suppl. S, pp. S177. Meeting Info.: International Liver Congress / 52nd Annual Meeting of the European-Association-for-the-Study-of-the-Liver. Amsterdam, NETHERLANDS. April 19 -23, 2017. European Assoc Study Liver. 51 Jung et al., J Pediatr Gastroenterol Nutr. 2007, vol. 44(4), p. 453-458. 52Sciveres. Digestive and Liver Disease 2010, vol. 42, Supp. SUPPL. 5, pp. S329. Abstract Number: CO18. Meeting Info: 17th National Congress SIGENP. Pescara, Italy. 07 Oct 2010-09 Oct 2010 53 Sohn et al., Pediatr Gastroenterol Hepatol Nutr. 2019, vol. 22(2), p. 201-206. 54 Ho et al., Pharmacogenet Genomics. 2010, vol. 20(1), p. 45-57. 55 Wang et al., Hepatol Res. 2018, vol. 48(7), p. 574-584. 56 Shaprio et al., J Hum Genet. 2010, vol. 55(5), p. 308-313. 57 Bounford. University of Birmingham. Dissertation Abstracts International, (2016) Vol. 75, No. 1C. Order No.: AAI10588329. ProQuest Dissertations & Theses. 58 Stolz et al., Aliment Pharmacol Ther. 2019, vol. 49(9), p. 1195-1204. 59 Jankowska et al., J Pediatr Gastroenterol Nutr. 2014, vol. 58(1), p. 92-95. 60Kim. Journal of Pediatric Gastroenterology and Nutrition 2016, vol. 62, Supp. SUPPL. 1, pp. 620. Abstract Number: H-P-045. Meeting Info: 49th Annual Meeting of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition, ESPGHAN 2016. Athens, Greece. 25 May 2016-28 May 2016. 61 Pauli-Magnus et al., Hepatology 2003, vol. 38, No. 4 Suppl. 1, pp. 518A. print. Meeting Info.: 54th Annual Meeting of the American Association for the Study of Liver Diseases. Boston, MA, USA. October 24-28, 2003. American Association for the Study of Liver Diseases. 62 Li et al., Hepatology International 2017, vol. 11, No. 1, Supp. Supplement 1, pp. S362. Abstract Number: PP0347. Meeting Info: 26th Annual Conference of the Asian Pacific Association for the Study of the Liver, APASL 2017. Shanghai, China. 15 Feb 2017-19 Feb 2017. 63Rumbo et al., Transplantation 2018, vol. 102, No. 7, Supp. Supplement 1, pp. S848. Abstract Number: P.752. Meeting Info: 27th International Congress of The Transplantation Society, TTS 2018. Madrid, Spain. 30 Jun 2018-05 Jul 2018. 64 Lee et al., Pediatr Gastroenterol Hepatol Nutr. 2017, vol. 20(2), p. 114-123. 65 Sherrif et al., Liver international: official journal of the International Association for the Study of the Liver 2013, vol. 33, No. 8, pp. 1266-1270. 66 Blackmore et al., J Clin Exp Hepatol. 2013, vol. 3(2), p. 159-161. 67 Matte et al., J Pediatr Gastroenterol Nutr. 2010, vol. 51(4), p. 488-493. 68 Lin et al., Zhongguo Dang Dai Er Ke Za Zhi. 2018, vol. 20(9), p. 758-764. 69Harmanci et al., Experimental and Clinical Transplantation 2015, vol. 13, Supp. SUPPL. 2, pp. 76. Abstract Number: P62. Meeting Info: 1st Congress of the Turkic World Transplantation Society. Astana, Kazakhstan. 20 May 2015-22 May 2015. 70 Herbst et al., Mol Cell Probes. 2015, vol. 29(5), p. 291-298. 71 Moghadamrad et al., Hepatology. 2013, vol. 57(6), p. 2539-2541. 72 Holz et al., Zeitschrift fur Gastroenterologie 2016, vol. 54, No. 8. Abstract Number: KV275. Meeting Info: Viszeralmedizin 2016, 71. Jahrestagung der Deutschen Gesellschaft fur Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten mit Sektion Endoskopie - 10. Herbsttagung der Deutschen Gesellschaft fur Allgemein- und Viszeralchirurgie. Hamburg, Germany. 21 Sep 2016-24 Sep 2016. 73 Wang et al., PLoS One. 2016; vol. 11(4): e0153114. 74Hao et al., International Journal of Clinical and Experimental Pathology 2017, vol. 10(3), p. 3480-3487. 75 Arnell et al., J Pediatr Gastroenterol Nutr. 2010, vol. 51(4), p. 494-499. 76 Sharma et al., Indian Journal of Gastroenterology 2017, vol. 36, No. 1, Supp. Supplement 1, pp. A99. Abstract Number: M-20. Meeting Info: 58th Annual Conference of the Indian Society of Gastroenterology, ISGCON 2017. Bhubaneswar, India. 14 Dec 2017-17 Dec 2017. 77 Beausejour et al., Can J Gastroenterol. 2011, vol. 25(6), p. 311-314. 78 Imagawa et al., Journal of Pediatric Gastroenterology and Nutrition 2016, vol. 63, Supp. Supplement 2, pp. S51. Abstract Number: 166. Meeting Info: World Congress of Pediatric Gastroenterology, Hepatology and Nutrition 2016. Montreal, QC, Canada. 05 Oct 2016-08 Oct 2016. 79Peng et al., Zhonghua er ke za zhi (Chinese journal of pediatrics) 2018, vol. 56, No. 6, pp. 440-444. 80 Tibesar et al., Case Rep Pediatr. 2014, vol. 2014: 185923. 81 Ng et al., Journal of Pediatric Gastroenterology and Nutrition 2018, vol. 66, Supp. Supplement 2, pp. 860. Abstract Number: H-P-127. Meeting Info: 51st Annual Meeting European Society for Paediatric Gastroenterology, Hepatology and Nutrition, ESPGHAN 2018. Geneva, Switzerland. 09 May 2018-12 May 2018. 82 Wong et al., Clin Chem. 2008, vol. 54(7), p. 1141-1148. 83 Pauli-Magnus et al., J Hepatol. 2005, vol. 43(2), p. 342-357. 84 Jericho et al., Journal of Pediatric Gastroenterology and Nutrition. 60, vol. 3, p. 368-374. 85Scheimann et al., Gastroenterology 2007, vol. 132, No. 4, Suppl. 2, pp. A452. Meeting Info.: Digestive Disease Week Meeting / 108th Annual Meeting of the American-Gastroenterological-Association. Washington, DC, USA. May 19 -24, 2007. Amer Gastroenterol Assoc; Amer Assoc Study Liver Dis; Amer Soc Gastrointestinal Endoscopy; Soc Surg Alimentary Tract. 86 Jaquotot-Haerranz et al., Rev Esp Enferm Dig. 2013, vol. 105(1), p. 52-54. 87 Khosla et al., American Journal of Gastroenterology 2015, vol. 110, No. Suppl. 1, pp. S397. Meeting Info.: 80th Annual Scientific Meeting of the American-College-of-Gastroenterology. Honolulu, HI, USA. October 16 -21, 2015. 88 Droege et al., J Hepatol. 2017, vol. 67(6), p. 1253-1264. 89 Liu et al., Liver International 2010, vol. 30(6), p. 809-815. 90 Chen et al., Journal of Pediatrics 2002, vol. 140(1), p. 119-124. 91U.S. Patent No. 9,295,677

[0103] 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.

[0104] A method for treating PFIC (e.g., PFIC-1 and PFIC-2) in a subject is provided, the method comprising assaying a sample obtained from the subject to determine whether the subject has a mutation associated with PFIC (e.g., an ATP8B1, ABCB11, ABCB4, TJP2, NR1H4, or Myo5b mutation), and administering to the subject determined to have a mutation associated with PFIC a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., administering specifically or selectively). In some embodiments, the mutation is an ATP8B1 or ABCB11 mutation. For example, a mutation as shown in any one of Tables 1-4. 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.

[0105] Methods for treating PFIC (e.g., PFIC-1 and PFIC-2) in a subject in need of treatment for PFIC are also provided, the method comprising: (a) detecting a mutation associated with PFIC in the subject (e.g., an ATP8B1, ABCB11, ABCB4, TJP2, NR1H4, or Myo5b mutation); 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 comprise administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject having a mutation associated with PFIC (e.g., an ATP8B1, ABCB11, ABCB4, TJP2, NR1H4, or Myo5b mutation). In some embodiments, the mutation is an ATP8B1 or ABCB11 mutation. For example, a mutation as shown in any one of Tables 1-4. 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.

[0106] In some embodiments, a subject is determined to have a mutation associated with PFIC in the subject or a biopsy specimen from the subject through the use of assays recognized by those of skill in the art, including next generation sequencing (NGS). In some embodiments, a subject is determined to have a mutation associated with PFIC by using an assay or assay kit approved by a regulatory agency, such as an assay approved by the FDA, for identifying a mutation associated with PFIC in the subject or a biopsy specimen from the subject, or by performing any of the non-limiting examples of assays described herein. Further 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).

[0107] In some embodiments, treatment of PFIC (e.g., PFIC-1 or PFIC-2) reduces the level of bile acids in the serum of a subject. In some embodiments, the level of bile acids in the serum is determined, for example, by an ELISA enzyme assay or by an assay for measuring total bile acids as described in Danese et al., PLoS One. 2017, Vol. 12(6): e0179200 (which is incorporated herein by reference in its entirety). In some embodiments, the level of bile acids in the serum can be reduced by, for example, 10% - 40%, 20% - 50%, 30% - 60%, 40% - 70%, 50% - 80%, or more than 90% of the level of bile acids in the serum 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.

[0108] Since LBAT is expressed in hepatocytes, LBAT and dual ASBT / LBAT inhibitor substances need to have at least some degree of bioavailability and free fraction in the blood. Since LBAT inhibitor compounds only need to remain from the intestine to the liver, relatively low systemic exposure of such compounds is sufficient, thereby potentially minimizing any risk of side effects at other sites of the body. Inhibition of LBAT and ASBT is expected to have at least an additive effect on the reduction of bile acid concentration in the liver. It is also expected that dual ASBT / LBAT inhibitors may be able to reduce bile acid levels without inducing diarrhea as sometimes observed with ASBT inhibitors.

[0109] Compounds having high LBAT inhibitory potency and sufficient bioavailability are expected to be particularly suitable for the treatment of hepatitis. Compounds having dual ASBT / LBAT inhibitory potency and sufficient bioavailability are expected to be particularly suitable for the treatment of non-alcoholic steatohepatitis (NASH).

[0110] NASH is a common and severe chronic liver disease similar to alcoholic liver disease, but it occurs in people who rarely or never drink alcohol. In patients with NASH, fat accumulation in the liver known as 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, leading to progressive scarring of tissue known as fibrosis, and cirrhosis, and ultimately potentially liver failure and death. Patients with NASH have been found to have significantly higher total serum bile acid concentrations at fasting and all postprandial time points compared to healthy subjects (a 2.2 - 2.4-fold increase in NASH at fasting and a 1.7 - 2.2-fold increase in NASH at all postprandial time points). These are driven by increases in taurine- and glycine-conjugated primary and secondary bile acids. Patients with NASH exhibited large variations in their fasting and postprandial bile acid profiles. From these results, it is shown that patients with NASH are more exposed to bile acids, including more hydrophobic and cytotoxic secondary species, at fasting and postprandially. The increased exposure to bile acids may be involved in liver injury and the development of NAFLD and NASH (Ferslew et al., Dig Dis Sci. 2015, Vol. 60, pp. 3318 - 3328). Therefore, ASBT and / or LBAT inhibition is likely to be beneficial for the treatment of NASH.

[0111] 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 pharmacotherapies (Chalasani et al., Hepatology 2018, Vol. 67(1), pp. 328-357). NAFLD can be classified into non-alcoholic fatty liver (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 injury in the form of ballooning hepatocyte enlargement. NASH is defined as the presence of ≥5% hepatic steatosis and inflammation with hepatocyte injury (e.g., ballooning) regardless of the presence or absence of any hepatic fibrosis. NASH is generally also associated with liver inflammation and hepatic fibrosis, which can progress to cirrhosis, end-stage liver disease, and hepatocellular carcinoma. Hepatic fibrosis does not necessarily exist in NASH, but when present, the severity of fibrosis can be associated with long-term outcomes.

[0112] There are many techniques used to assess and score disease severity, including determining whether a subject has NAFLD and, if so, distinguishing whether the NAFLD is NAFL or NASH. In some embodiments, the severity of NAFLD can be assessed using NAS. In some embodiments, the treatment of NAFLD can be evaluated using NAS. 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). See, for example, Table 6 for a simplified NAS scheme based on Kleiner.

[0113] [Table 5]

[0114] In some embodiments, NAS is determined non-invasively, for example, as described in U.S. Patent Application Publication No. 2018 / 0140219, which is incorporated herein by reference in its entirety. In some embodiments, NAS is determined on a sample from a subject prior to administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, NAS is determined during or after the administration period of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, a lower NAS score during or after the administration period of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as compared to prior to administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof, indicates treatment of NAFLD (e.g., NASH). For example, a decrease in NAS by 1, 2, 3, 4, 5, 6, or 7 indicates treatment of NAFLD (e.g., NASH). In some embodiments, NAS after administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof is 7 or less. In some embodiments, NAS during the administration period of a compound of formula (I) or a pharmaceutically acceptable salt thereof is 5 or less, 4 or less, 3 or less, or 2 or less. In some embodiments, NAS during the administration period of a compound of formula (I) or a pharmaceutically acceptable salt thereof is 7 or less. In some embodiments, NAS during the administration period of a compound of formula (I) or a pharmaceutically acceptable salt thereof is 5 or less, 4 or less, 3 or less, or 2 or less. In some embodiments, NAS after the administration period of a compound of formula (I) or a pharmaceutically acceptable salt thereof is 7 or less. In some embodiments, NAS after the administration period of a compound of formula (I) or a pharmaceutically acceptable salt thereof is 5 or less, 4 or less, 3 or less, or 2 or less.

[0115] Additional methods for assessing or assaying NASH in a subject include determining one or more of hepatic steatosis (e.g., accumulation of fat in the liver); inflammation of the liver; and one or more biomarkers (e.g., serum markers and panels) indicative of one or more of liver injury, liver inflammation, liver fibrosis, and / or cirrhosis. Further examples of physiological indicators of NASH can include the liver morphology, liver stiffness, and size or mass of the subject's liver. In some embodiments, NASH in a subject is demonstrated by detection of accumulation of liver fat and a biomarker indicative of liver injury. For example, elevated serum ferritin and low titers of serum autoantibodies can be common features of NASH.

[0116] In some embodiments, methods for assessing NASH include magnetic resonance imaging (either by spectroscopy or proton density fat fraction measurement (MRI-PDFF)) for quantifying steatosis, transient elastography (FIBROSCAN®) for diagnosing significant liver fibrosis and / or cirrhosis, hepatic venous pressure gradient (HVPG), measurement of liver stiffness by MRE, and evaluation of histological features of a liver biopsy. In some embodiments, magnetic resonance imaging is used to detect one or more of non-alcoholic steatohepatitis (NASH-MRI), liver fibrosis (Fibro-MRI), and steatosis. See, for example, U.S. Patent Application Publication Nos. 2016 / 146715 and 2005 / 0215882, each of which is incorporated herein by reference in its entirety.

[0117] In some embodiments, treatment of NASH includes a decrease in one or more symptoms associated with NASH in a subject following administration of one or more doses of a compound of formula (I) or a pharmaceutically acceptable salt thereof; a reduction in the amount of hepatic steatosis; a reduction in NAS; a reduction in liver inflammation; a reduction in the level of one or more biomarkers indicative of one or more of liver injury, inflammation, liver fibrosis, and / or cirrhosis; and a reduction in fibrosis and / or cirrhosis, absence of further progression of fibrosis and / or cirrhosis, or delay in the progression of fibrosis and / or cirrhosis.

[0118] In some embodiments, the treatment of NASH includes a reduction in one or more symptoms associated with NASH in a subject. Exemplary symptoms can include one or more of liver hypertrophy, fatigue, pain in the upper right abdomen, abdominal distension, hypertrophy of blood vessels just under the surface of the skin, gynecomastia in males, splenomegaly, palmar erythema, jaundice, and pruritus. In some embodiments, the subject is asymptomatic. In some embodiments, the total weight of the subject does not increase. In some embodiments, the total weight of the subject decreases. In some embodiments, the body mass index (BMI) of the subject does not increase. In some embodiments, the body mass index (BMI) of the subject decreases. In some embodiments, the waist-to-hip ratio (WTH) of the subject does not increase. In some embodiments, the waist-to-hip ratio (WTH) of the subject decreases.

[0119] In some embodiments, the treatment of NASH can be evaluated by measuring hepatic steatosis. In some embodiments, the treatment of NASH comprises a reduction in hepatic steatosis after administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein. In some embodiments, hepatic steatosis is determined by one or more methods selected from the group consisting of ultrasound examination, computed tomography (CT), magnetic resonance imaging, magnetic resonance spectroscopy (MRS), magnetic resonance elastography (MRE), transient elastography (TE) (e.g., FIBROSCAN®), measurement of liver size or mass, or by liver biopsy (see, e.g., Di Lascio et al., Ultrasound Med Biol. 2018, Vol. 44(8), 1585-1596; Lv et al., J Clin Transl Hepatol. 2018, Vol. 6(2), 217-221; Reeder et al., J Magn Reson Imaging. 2011, Vol. 34(4), spcone; and de Ledinghen V et al., J Gastroenterol Hepatol. 2016, Vol. 31(4), 848-855, each of which is incorporated herein by reference in its entirety). A subject diagnosed with NASH can have more than about 5% hepatic steatosis, e.g., more than about 5% to about 25%, about 25% to about 45%, about 45% to about 65%, or more than about 65% hepatic steatosis. In some embodiments, a subject having more than about 5% to about 33% hepatic steatosis has stage 1 hepatic steatosis, a subject having about 33% to about 66% hepatic steatosis has stage 2 hepatic steatosis, and a subject having more than about 66% hepatic steatosis has stage 3 hepatic steatosis.

[0120] In some embodiments, the amount of hepatic steatosis is determined prior to administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the amount of hepatic steatosis is determined during or after the administration period of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, a reduction in the amount of hepatic steatosis during or after the administration period of the compound of formula (I) or a pharmaceutically acceptable salt thereof, compared to prior to administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof, indicates treatment of NASH. For example, a reduction in the amount of hepatic steatosis 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 reduction in the amount of hepatic steatosis 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.

[0121] In some embodiments, the presence of liver inflammation is determined by one or more methods selected from the group consisting of biomarkers indicative of liver inflammation and liver biopsy samples from the subject. In some embodiments, the severity of liver inflammation is determined from a liver biopsy sample from the subject. For example, liver inflammation in a liver biopsy specimen can be evaluated 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 incorporated herein by reference in its entirety). In some embodiments, the severity of liver inflammation is determined prior to administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the severity of liver inflammation is determined during or after the administration period of the 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 administration period of the compound of formula (I) or a pharmaceutically acceptable salt thereof as compared to prior to administration of the 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.

[0122] In some embodiments, treatment of NASH includes treatment of fibrosis and / or cirrhosis, e.g., a decrease in the severity of fibrosis, absence of further progression of fibrosis and / or cirrhosis, or delay in the 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 group consisting of transient elastography (e.g., FIBROSCAN®), non-invasive markers of fibrosis, and histological features of a liver biopsy. In some embodiments, the severity (e.g., stage) of fibrosis is determined by one or more methods selected from the group consisting of transient elastography (e.g., FIBROSCAN®), a fibrosis-scoring system, biomarkers of fibrosis (e.g., non-invasive biomarkers), and hepatic venous pressure gradient (HVPG). Non-limiting examples of fibrosis-scoring systems include the NAFLD fibrosis-scoring system (see, e.g., Angulo et al., Hepatology 2007, vol. 45(4), pp. 846-854), the fibrosis-scoring system of Brunt et al., Am. J. Gastroenterol. 1999, vol. 94, pp. 2467-2474, the fibrosis-scoring system of Kleiner et al., Hepatology 2005, vol. 41(6), pp. 1313-1321, and the Ishak fibrosis-scoring system (see Ishak et al., J. Hepatol. 1995, vol. 22, pp. 696-699) (the contents of each of which are incorporated herein by reference in their entirety).

[0123] In some embodiments, the severity of fibrosis is determined before administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the severity of fibrosis is determined during or after the administration period of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, a decrease in the severity of fibrosis during or after the administration period of the compound of formula (I) or a pharmaceutically acceptable salt thereof, compared to before administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof, indicates treatment of NASH. In some embodiments, a decrease in the severity of fibrosis, absence of further progression of fibrosis and / or cirrhosis, or delay in the progression of fibrosis and / or cirrhosis indicates treatment of NASH. In some embodiments, the severity of fibrosis is determined using a scoring system such as any of the fibrosis scoring systems described herein, for example, the score can indicate the stage of fibrosis, for example, stage 0 (no fibrosis), stage 1, stage 2, stage 3, and stage 4 (cirrhosis) (see, e.g., Kleiner et al.). In some embodiments, a decrease in the stage of fibrosis is a decrease in the severity of fibrosis. For example, a decrease of 1, 2, 3, or 4 stages is a decrease in the severity of fibrosis. In some embodiments, a decrease in stage, for example, 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 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 administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof, compared to before 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 during the administration period of the compound of formula (I) or a salt thereof acceptable as a medicament, as compared to before the administration of the compound of formula (I) or a salt thereof acceptable as a medicament. 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 period of the compound of formula (I) or a salt thereof acceptable as a medicament, as compared to before the administration of the compound of formula (I) or a salt thereof acceptable as a medicament.

[0124] In some embodiments, the presence of NASH is determined by one or more biomarkers indicative of one or more of liver injury, inflammation, liver fibrosis, and / or cirrhosis, or a scoring system thereof. In some embodiments, the severity of NASH is determined by one or more biomarkers indicative of one or more of liver injury, inflammation, liver fibrosis, and / or cirrhosis, or a scoring system thereof. The level of a biomarker can be determined, for example, by measuring, quantifying, and monitoring the expression level of the gene or mRNA encoding the biomarker and / or the peptide or protein of the biomarker.Non-limiting examples of one or more biomarkers indicative of liver impairment, inflammation, liver fibrosis, and / or cirrhosis, and / or their scoring systems include the ratio index of aspartate aminotransferase (AST) to platelets (APRI); the ratio of aspartate aminotransferase (AST) to alanine aminotransferase (ALT) (AAR); the FIB-4 score based on APRI, alanine aminotransferase (ALT) level, and the age of the subject (see, e.g., McPherson et al., Gut 2010, Vol. 59(9), pp. 1265-1269, which is incorporated herein by reference in its entirety); hyaluronic acid; pro-inflammatory cytokines; a panel of biomarkers consisting of α2-macroglobulin, haptoglobin, apolipoprotein A1, bilirubin, gamma-glutamyl transpeptidase (GGT) in combination with the age and sex of the subject to generate a measure of fibrotic and necroinflammatory activity in the liver (e.g., FIBROTEST®, FIBROSURE®); a panel of biomarkers consisting of bilirubin, gamma-glutamyl transpeptidase, hyaluronic acid, α2-macroglobulin in combination with the age and sex of the subject (e.g., HEPASCORE®; 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., FIBROSPECT®); 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. August 2013; 59(2):236-242, which is incorporated herein by reference in its entirety).In some embodiments, the presence of fibrosis is determined by one or more of a panel of biomarkers consisting of α2-macroglobulin, haptoglobin, apolipoprotein A1, bilirubin, gamma-glutamyltransferase (GGT) (e.g., FIBROTEST®, FIBROSURE®) in combination with the age and sex of the subject to generate a measure of fibrosis and necroinflammatory activity in the liver, a panel of biomarkers consisting of bilirubin, gamma-glutamyltransferase, hyaluronic acid, α2-macroglobulin in combination with the age and sex of the subject (e.g., HEPASCORE®; 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., FIBROSPECT®); 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) (e.g., Enhanced Liver Fibrosis (ELF) score). In some embodiments, the level of aspartate aminotransferase (AST) does not increase. In some embodiments, the level of aspartate aminotransferase (AST) decreases. In some embodiments, the level of alanine aminotransferase (ALT) does not increase. In some embodiments, the level of alanine aminotransferase (ALT) decreases. In some embodiments, the "level" of an enzyme refers to the concentration of the enzyme, e.g., the concentration in the blood. For example, the level of AST or ALT can be expressed in units / L.

[0125] In some embodiments, the severity of fibrosis is determined by one or more of the FIB-4 score, a panel of biomarkers consisting of α2-macroglobulin, haptoglobin, apolipoprotein A1, bilirubin, gamma glutamyl transpeptidase (GGT) (e.g., FIBROTEST®, FIBROSURE®) in combination with the age and sex of the subject to generate a measure of fibrosis and necroinflammatory activity in the liver, a panel of biomarkers consisting of bilirubin, gamma glutamyl transferase, hyaluronic acid, α2-macroglobulin in combination with the age and sex of the subject (e.g., HEPASCORE®; 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., FIBROSPECT®); 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) (e.g., Enhanced Liver Fibrosis (ELF) score).

[0126] In some embodiments, liver inflammation is determined by the level of biomarkers of liver inflammation, such as the level of pro-inflammatory 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 isoforms, 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. Patent No. 9,872,844, each of which is incorporated herein by reference in its entirety). Liver inflammation can also be evaluated by changes in macrophage infiltration, such as by measuring changes in CD68 expression levels. In some embodiments, liver inflammation can be determined by measuring or monitoring the 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).

[0127] In some embodiments, the level of one or more biomarkers indicative of one or more of liver injury, inflammation, liver fibrosis, and / or cirrhosis is determined on a sample from a subject prior to administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of one or more biomarkers indicative of one or more of liver injury, inflammation, liver fibrosis, and / or cirrhosis is determined during or after the administration period of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, a decrease in the level of one or more biomarkers indicative of one or more of liver injury, inflammation, liver fibrosis, and / or cirrhosis during or after the administration period of the compound of formula (I) or a pharmaceutically acceptable salt thereof as compared to prior to administration of the 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 injury, inflammation, liver fibrosis, and / or cirrhosis of 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% indicates treatment of NASH. In some embodiments, the decrease in the level of one or more biomarkers indicative of one or more of liver injury, inflammation, liver fibrosis, and / or cirrhosis after administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 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 decrease in the level of one or more biomarkers indicative of one or more of liver injury, inflammation, liver fibrosis, and / or cirrhosis during the administration period of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 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 decrease in the level of one or more biomarkers indicative of one or more of liver injury, inflammation, liver fibrosis, and / or cirrhosis after the administration period of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 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%.

[0128] In some embodiments, treatment of NASH results in a decrease in the level of serum bile acids in a subject. In some embodiments, the level of serum bile acids is determined, for example, by an ELISA enzyme assay or a total bile acid measurement assay 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, the level of serum bile acids can be reduced by, for example, 10% - 40%, 20% - 50%, 30% - 60%, 40% - 70%, 50% - 80%, or more than 90% of the level of serum bile acids prior to administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, NASH is NASH with accompanying cholestasis. In cholestasis, the release of bile, including bile acids, from the liver is blocked. Bile acids can cause damage to hepatocytes (see, for example, Perez MJ, Briz O. World J. Gastroenterol. 2009, Vol. 15(14), pp. 1677 - 1689), which can lead to or increase the progression of fibrosis (such as cirrhosis) and increase the risk of hepatocellular carcinoma (see, for example, Sorrentino P et al., Dig. Dis. Sci. 2005, Vol. 50(6), pp. 1130 - 1135, and Satapathy SK and Sanyal AJ. Semin. Liver Dis. 2015, Vol. 35(3), pp. 221 - 235, each of which is incorporated herein by reference in its entirety). In some embodiments, treatment of NASH includes treatment of pruritus. In some embodiments, treatment of NASH with accompanying cholestasis includes treatment of pruritus. In some embodiments, a subject having NASH with accompanying cholestasis has pruritus.

[0129] Exemplary biomarkers for NASH are shown in Table 7.

[0130] [Table 6]

[0131] References related to Table 7 1 McPherson et al., Gut. 2010, vol. 59(9), p. 1265 - 1269. 2 Adams, et al. Clin Chem. 2005, vol. 51(10), p. 1867 - 1873. 3 Lichtinghagen, et al. J Hepatol. 2013, vol. 59(2), p. 236 - 242. 4 Neuman, et al. Can J Gastroenterol Hepatol. 2014, vol. 28(11), p. 607 - 618. 5 U.S. Patent No. 9,872,844

[0132] Some compounds of formula (I) or pharmaceutically acceptable salts thereof may exhibit a greater free fraction in plasma. In some embodiments, the free fraction is greater than about 0.2%, such as greater than about 0.4%, such as greater than about 0.6%, such as greater than about 0.8%, such as greater than about 1.0%, such as greater than about 1.25%, such as greater than about 1.5%, such as greater than about 1.75%, such as greater than about 2.0%, such as greater than about 2.5%, such as greater than about 3%, such as greater than about 4%, such as greater than about 5%, such as greater than about 7.5%, such as greater than about 10%, or such as greater than about 20%.

[0133] Some compounds of formula (I) or pharmaceutically acceptable salts thereof may be excreted in urine. In some embodiments, the fraction of the compound excreted in urine is greater than about 0.2%, such as greater than about 0.4%, such as greater than about 0.6%, such as greater than about 0.8%, such as greater than about 1.0%, such as greater than about 2%, such as greater than about 3%, such as greater than about 5%, such as greater than about 7.5%, such as greater than about 10%, such as greater than about 15%, such as greater than about 20%, such as greater than about 30%, or such as greater than about 50%.

[0134] After absorption from the intestine, some compounds of formula (I) or pharmaceutically acceptable salts thereof can be circulated via the enterohepatic circulation. In some embodiments, the fraction of the compound circulated 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%.

[0135] Some compounds of formula (I) or pharmaceutically acceptable salts thereof may cause the renal excretion of bile salts. In some embodiments, the fraction of the circulating bile acids excreted via the renal pathway is greater than about 1%, such as greater than about 2%, such as greater than about 5%, such as greater than about 7%, such as greater than about 10%, such as greater than about 15%, such as greater than about 20%, or such as greater than about 25%.

[0136] Some compounds of formula (I) or pharmaceutically acceptable salts thereof may exhibit improved or optimal permeability. Permeability can be measured in Caco2 cells, and the value is shown in cm / s as the Papp (apparent permeability) value. In some embodiments, the permeability is at least greater than about 0.1×10 -6 cm / s, such as greater than about 0.2×10 -6 cm / s, such as greater than about 0.4×10 -6 cm / s, such as greater than about 0.7×10 -6 cm / s, such as greater than about 1.0×10 -6 cm / s, such as greater than about 2×10 -6 cm / s, such as greater than about 3×10 -6 cm / s, such as greater than about 5×10 -6 cm / s, such as greater than about 7×10 -6 cm / s, such as greater than about 10×10 -6 cm / s, such as greater than about 15×10 -6 cm / s.

[0137] Some compounds of formula (I) or pharmaceutically acceptable salts thereof may exhibit 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%.

[0138] Some compounds of formula (I) or pharmaceutically acceptable salts thereof can serve as substrates for relevant transporters in the kidney.

[0139] Some compounds of formula (I) or pharmaceutically acceptable salts thereof can result in concentrations of bile acids in the intestine, liver, and serum without causing adverse gastrointestinal effects.

[0140] Some compounds of formula (I) or pharmaceutically acceptable salts thereof can reduce the concentration of bile acids in the liver without causing gastrointestinal disorders such as diarrhea.

[0141] As used herein, the terms "treatment", "treating", and "treatment" refer to the regression, alleviation, delay in the onset, or inhibition of the progression of a disease, disorder, or one or more symptoms thereof as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual (e.g., considering a medical history of symptoms and / or genetic or other susceptibility factors) prior to the onset of symptoms. Treatment may also be continued after the symptoms have resolved, for example, to prevent or delay their recurrence.

[0142] Suitable pharmaceutically acceptable salts of the compounds of the present invention include, for example, base addition salts of the compounds of the present invention that 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 that provide physiologically acceptable cations, such as salts with methylamine, dimethylamine, trimethylamine, piperidine, morpholine, or tris-(2-hydroxyethyl)amine.

[0143] Some compounds of formula (I) or pharmaceutically acceptable salts thereof may have chiral centers and / or geometric isomeric centers (E- and Z-isomers). It should be understood that the present invention encompasses all such optical isomers, diastereoisomers, and geometric isomers possessing ASBT and / or LBAT inhibitory activity. The present invention also encompasses all tautomers of the compounds of formula (I) or pharmaceutically acceptable salts thereof possessing ASBT and / or LBAT inhibitory activity. Some compounds of formula (I) or pharmaceutically acceptable salts thereof may exist not only in the unsolvated form but also, for example, in solvated forms such as the hydrated form. It should be understood that the present invention encompasses all such solvated forms possessing ASBT and / or LBAT inhibitory activity.

[0144] 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. Examples of excipients include, for example, fillers, binders, disintegrants, glidants, and lubricants. Generally, the pharmaceutical composition can be prepared in a conventional manner using conventional excipients.

[0145] 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, dried starch, hydrolyzed starch, and pregelatinized starch.

[0146] 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 rubbers (such as gum arabic and tragacanth gum), sodium alginate, cellulose derivatives (such as hydroxypropylmethylcellulose (or hypromellose), hydroxypropylcellulose, and ethylcellulose), and synthetic polymers (such as copolymers of acrylic acid and methacrylic acid, methacrylic acid copolymers, methyl methacrylate copolymers, aminoalkyl methacrylate copolymers, polyacrylic acid / polymethacrylic acid copolymers, and polyvinylpyrrolidone (povidone)).

[0147] Examples of suitable disintegrants include, but are not limited to, dried starch, modified starch ((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 crosslinked polymers (such as carmellose, croscarmellose sodium, carmellose calcium, and crosslinked PVP (cross-povidone)).

[0148] Examples of suitable glidants and lubricants include, but are not limited to, talc, magnesium stearate, calcium stearate, stearic acid, glyceryl behenate, colloidal silica, aqueous silicon dioxide, synthetic magnesium silicate, micronized silicon dioxide, starch, sodium lauryl sulfate, boric acid, magnesium oxide, waxes (such as carnauba wax), hardened oils, polyethylene glycol, sodium benzoate, polyethylene glycol, and mineral oil.

[0149] The pharmaceutical composition may be conventionally coated with one or more coating layers. An enteric coating layer of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a coating layer for delayed release or targeted release is also contemplated. The coating layer may comprise one or more coating agents and optionally a plasticizer and / or a pigment (or colorant).

[0150] Examples of suitable coating agents include cellulose-based polymers (such as ethyl cellulose, hydroxypropyl methylcellulose (or hypromellose), hydroxypropyl cellulose, cellulose acetate phthalate, cellulose acetate succinate, hydroxypropyl methylcellulose acetate succinate, and hydroxypropyl methylcellulose phthalate, etc.), vinyl-based polymers (such as polyvinyl alcohol, etc.), and polymers based on acrylic acid and its derivatives (such as copolymers of acrylic acid and methacrylic acid, methacrylic acid copolymers, methyl methacrylate copolymers, aminoalkyl methacrylate copolymers, polyacrylic acid / polymethacrylic acid copolymers, etc.), but are not limited thereto.

[0151] Examples of suitable plasticizers include triethyl citrate, glyceryl triacetate, tributyl citrate, diethyl phthalate, tributyl acetyl citrate, dibutyl phthalate, dibutyl sebacate, and polyethylene glycol, but are not limited thereto.

[0152] Examples of suitable pigments include titanium dioxide, iron oxides (such as yellow, brown, red, or black iron oxides, etc.), and barium sulfate, but are not limited thereto.

[0153] The pharmaceutical composition may be in a form suitable for oral administration, injection (including intravenous, subcutaneous, intramuscular, and intraarterial injection), or topical administration for rectal administration. In a preferred embodiment, the pharmaceutical composition is in a form suitable for oral administration such as tablets or capsules.

[0154] 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 a regimen and dosage level suitable for a particular patient.

[0155] The amount of the compound to be administered will vary depending on the patient being treated and can vary from about 1 μg / kg body weight to about 50 mg / kg body weight per day. Unit dosage forms such as tablets or capsules will usually contain from about 1 to about 250 mg of the active ingredient, for example from about 1 to about 100 mg, or for example from about 1 to about 50 mg, or for example from about 1 to about 20 mg, for example about 2.5 mg, or about 5 mg, or about 10 mg, or about 15 mg of the active ingredient. The daily dosage can be administered as a single dose or divided into one, two, three, or more unit doses. The daily dosage of the bile acid modulator administered orally is preferably within about 0.1 to about 250 mg, more preferably within about 1 to about 100 mg, for example within about 1 to about 5 mg, for example within about 1 to about 10 mg, for example within about 1 to about 15 mg, or for example within about 1 to about 20 mg.

[0156] 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.

[0157] In another aspect, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of any of the diseases described herein. The present invention also relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing any of the diseases described herein. The present invention also relates to a method of treating or preventing any of the diseases described herein in a subject such as a human, the method comprising administering to a subject in need of such treatment or prevention a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0158] Combination therapy 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 therapeutically active agent, for example, one, two, three, or more other therapeutically active agents. The compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one other therapeutically active agent may be administered simultaneously, sequentially, or separately. Suitable therapeutically active agents for combination with the compound of formula (I) include, but are not limited to, known active agents useful for the treatment of any of the aforementioned conditions, disorders, and diseases.

[0159] In one embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with another ASBT inhibitor. Suitable ASBT inhibitors are disclosed in WO 93 / 16055, WO 94 / 18183, WO 94 / 18184, WO 96 / 05188, 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, EP 624593, EP 624594, EP 624595, EP 624596, EP 0864582, EP 1173205, EP 1535913, and EP 3210977 (all of which are incorporated herein by reference in their entirety).As specific examples of suitable ASBT inhibitors, 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{ (R)-1'-phenyl-1'-[N'-(carboxymethyl)carbamoyl]-methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine (elobixibat) and 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{ (R)-α-[N-((S)-1-carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine (odevixibat) can be mentioned.

[0160] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a bile acid binder (also referred to as a bile acid sequestrant or resin), such as colesevelam, cholestyramine, or colestipol. 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 hereby incorporated by reference in their entirety).

[0161] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a DPP-IV inhibitor, such as gliptins, for example sitagliptin, vildagliptin, saxagliptin, linagliptin, gemigliptin, anagliptin, teneligliptin, alogliptin, treagliptin, omarigliptin, evogliptin, gosogliptin, and dutogliptin, or a pharmaceutically acceptable salt thereof.

[0162] 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, besivastatin, or dalvastatin, or a pharmaceutically acceptable salt thereof.

[0163] 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.

[0164] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a PPARα agonist, such as a fibrate, such as clofibrate, bezafibrate, ciprofibrate, clinofibrate, clofibric acid, fenofibrate, gemfibrozil, ronifibrate, and simfribrate, or a pharmaceutically acceptable salt thereof.

[0165] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a PPARγ agonist, such as a thiazolidinedione, such as pioglitazone, rosiglitazone, and lobeglitazone, or a pharmaceutically acceptable salt thereof.

[0166] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a dual PPARα / γ agonist, such as a glitazar, such as saroglitazar, aleglitazar, muraglitazar, or tesaglitazar, or a pharmaceutically acceptable salt thereof.

[0167] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a dual PPARα / δ agonist, such as elafibranor.

[0168] In yet another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a pan-PPAR agonist (i.e., a PPAR agonist having activity across all subtypes: α, γ, and δ), such as IVA337.

[0169] 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, such as an FXR agonist, such as cafestol, chenodeoxycholic acid, 6α-ethyl-chenodeoxycholic acid (obeticholic acid; INT-747), fexaramine, tropifexor, cilofexor, and MET409.

[0170] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a TGR5 receptor modulator, such as a TGR5 agonist, such as 6α-ethyl-23(S)-methylcholic acid (INT-777).

[0171] 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.

[0172] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with ursodeoxycholic acid (UDCA). In yet another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with norursodeoxycholic acid (norUDCA).

[0173] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with an FGF19 modulator, such as NGM282.

[0174] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with an FGF21 agonist, such as BMS-986036.

[0175] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with an integrin inhibitor, such as PLN-74809 and PLN-1474.

[0176] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a CCR2 / CCR5 inhibitor, such as cenicriviroc.

[0177] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a caspase protease inhibitor, such as emricasan.

[0178] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a galectin-3 inhibitor, such as GR-MD-02.

[0179] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a stearoyl-CoA desaturase (SCD) inhibitor, such as arachidylamide colanic acid.

[0180] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with an apoptosis signal-regulating kinase 1 (ASK1) inhibitor, such as selonsertib.

[0181] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a LOXL2 inhibitor, such as simtuzumab.

[0182] 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.

[0183] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a thyroid hormone receptor β agonist, such as MGL3196.

[0184] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a GLP-1 agonist, such as liraglutide.

[0185] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a dual agonist of glucagon-like peptide and the glucagon receptor, such as SAR425899.

[0186] 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.

[0187] 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.

[0188] 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 inhibitor of SGLT1 and SGLT2. Examples of such compounds are dapagliflozin, sotagliflozin, canagliflozin, empagliflozin, LIK066, and SGL5213.

[0189] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a diacylglycerol O-acyltransferase 2 (DGAT2) inhibitor, such as DGAT2RX and PF-06865571.

[0190] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a fatty acid synthase (FASN) inhibitor, such as TVB-2640.

[0191] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with an AMP-activated protein kinase (AMPK) activator, such as PXL-770.

[0192] 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.

[0193] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a cannabinoid receptor 1 (CB1) antagonist, such as IM102.

[0194] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with β-Klotho (KLB) and a fibroblast growth factor receptor (FGFR) activator, such as MK-3655 (previously known as NGM-313).

[0195] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a chemokine (C-C motif) ligand 24 (CCL24) inhibitor, such as CM101.

[0196] 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.

[0197] 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.

[0198] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a P2Y13 receptor agonist, such as CER-209.

[0199] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a sulfated oxysterol, such as Dur-928.

[0200] 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.

[0201] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a type 1 natural killer T cell (NKT1) inhibitor, such as GRI-0621.

[0202] 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.

[0203] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a VAP1 inhibitor, such as BI1467335.

[0204] 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.

[0205] 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.

[0206] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a nicotinic acid receptor 1 agonist, such as ARI-3037MO.

[0207] 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.

[0208] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a ketohexokinase inhibitor, such as PF-06835919.

[0209] 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.

[0210] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with an autotaxin inhibitor, such as PAT-505 and PF8380.

[0211] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a chemokine (C-C motif) receptor 3 (CCR3) antagonist, such as belrimumab.

[0212] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a chloride ion channel stimulant, such as cobiprostone and lubiprostone.

[0213] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a heat shock protein 47 (HSP47) inhibitor, such as ND-L02-s0201.

[0214] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a sterol regulatory element-binding protein (SREBP) transcription factor inhibitor, such as CAT-2003 and MDV-4463.

[0215] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a biguanide, such as metformin.

[0216] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with insulin.

[0217] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a glycogen phosphorylase inhibitor and / or a glucose-6-phosphatase inhibitor.

[0218] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a sulfonylurea, such as glipizide, glyburide, and glimepiride.

[0219] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a meglitinide, such as repaglinide, nateglinide, and ormiglitinide.

[0220] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a glucosidase inhibitor, such as acarbose or miglitol.

[0221] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a squalene synthase inhibitor, such as TAK-475.

[0222] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with a PTPB1 inhibitor, such as trodusquemine, ertiprotafib, JTT-551, and claramine.

[0223] Preparation of the compound The compounds of the present invention can be prepared by the processes described below, as the free acids or their pharmaceutically acceptable salts. Throughout the following description of such processes, it will be understood that, where appropriate, suitable protecting groups will be added in a manner readily understood by those skilled in organic synthesis and subsequently removed from the various reactants and intermediates. Conventional procedures for using such protecting groups, and examples of suitable protecting groups, are described, for example, in Greene's Protective Groups in Organic Synthesis, 4th Edition, by P.G.M Wutz and T.W. Greene, John Wiley & Sons, Hoboken, 2006.

[0224] General method All solvents used were of analytical grade. Commercially available anhydrous solvents were routinely used in the reactions. The starting materials were either available from commercial suppliers 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 WO02 / 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-benzothiadiazepine 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 as described in WO2019 / 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 as described in WO03 / 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 as described in WO2020 / 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 as described in WO2021 / 110883 (Intermediates 32, 33, and 45, respectively). Enantiopure (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 procedure described in WO2021 / 110883 starting from the single enantiomer of 2-aminohexanoic acid (D-norleucine) (see Intermediates 21-26). 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 composition of the solvent mixture is indicated as volume percentage or volume ratio.

[0225] LCMS: Machine name: Agilent 1290 infinity II. Method A: Mobile phase: A: 0.1% HCOOH in water: ACN (95:5), B: ACN; Flow rate: 1.5 mL / min; Column: ZORBAX XDB C-18 (50×4.6 mm), 3.5 μM. Method B: Mobile phase: A: 10 mM NH4HCO3 in water, B: ACN; Flow rate: 1.2 mL / min; Column: XBridge C8 (50×4.6 mm), 3.5 μM. Method C: Mobile phase: A: 0.1% HCOOH in water: ACN (95:5), B: ACN; Flow rate: 1.5 mL / min; Column: ATLANTIS dC18 (50×4.6 mm), 5 μM. Method D: Mobile phase: A: 10 mM NH4OAc in water, B: ACN; Flow rate: 1.2 mL / min; Column: Zorbax Extend C18 (50×4.6 mm), 5 μM. Method E: Mobile phase: A: 0.1% TFA in water: ACN (95:5), B: 0.1% TFA in ACN; Flow rate: 1.5 mL / min; Column: XBridge C8 (50×4.6 mm), 3.5 μM. Method F: Mobile phase: A: 0.1% TFA in water, B: 0.1% TFA in ACN; Flow rate: 0.8 mL / min; Column: ZORBAX ECLIPSE PLUS C18 (50×2.1 mm), 1.8 μm. Method G: Mobile phase: A: 0.1% TFA in water, B: 0.1% TFA in ACN; Flow rate: 0.8 mL / min; Column: Acquity UPLC BEH C18 (2.1×50 mm), 1.7 μm. Method H: Mobile phase: A: 10 mM NH4OAc, B: 100% ACN; Flow rate: 0.8 mL / min; Column: Acquity UPLC BEH C18 (2.1×50) mm; 1.7 μm. Method I: Mobile phase: A: 0.1% HCOOH in water: ACN (95:5), B: ACN; Flow rate: 0.8 mL / min; Column: ZORBAX ECLIPSE PLUS C18 (2.1×50) mm, 1.8 μm. Method J: Mobile phase: A: 0.1% TFA in water, B: 0.1% TFA in ACN; Flow rate: 1.5 mL / min; Column: XBridge C8 (50×4.6 mm), 3.5 μM. Instrument name: Waters Acquity UPLC I Class / SQ Detector 2 Method K: Mobile phase: A: 0.1% HCOOH in water:ACN (95:5), B: ACN; Flow rate: 0.8 mL / min; Column: BEH C18 (50×2.1 mm), 1.7 μm.

[0226] UPLC: Instrument name: waters Acquity I Class Method A: Mobile phase: A: 0.1% HCOOH in 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.

[0227] HPLC: Instrument name: Agilent 1260 Infinity II series instrument (as follows, using % in UV detection (max plot)). Method A: Mobile phase: A: 10 mM NH4HCO3 in water, B: ACN; Flow rate: 1.0 mL / min; Column: XBridge C8 (50×4.6 mm, 3.5 μm). Method B: Mobile phase: A: 0.1% TFA in water, B: 0.1% TFA in ACN; Flow rate: 2.0 mL / min; Column: XBridge C8 (50×4.6 mm, 3.5 μm). Method C: Mobile phase: A: 10 mM NH4OAc in Milli-Q water, B: ACN; Flow rate: 1.0 ml / min; Column: Phenomenex Gemini C18 (150×4.6 mm, 3.0 μm). Method D: Mobile phase: A: 0.1% TFA in water, B: ACN; Flow rate: 1.0 mL / min; Column: ATLANTIS dC18 (250×4.6 mm, 5.0 μm). Method E: Mobile phase: A: 0.1% TFA in water, B: ACN, Flow rate: 2.0 mL / min; Column: X-Bridge C8 (50×4.6 mm, 3.5 μm).

[0228] Chiral SFC: Equipment name: PIC SFC 10 (for analysis) The ratio of CO2 to the co-solvent is in the range of 60:40 to 80:20 Method A: Mobile phase: 0.5% isopropylamine in IPA; Flow rate: 3 mL / min; Column: YMC Amylose-SA (250×4.6 mm, 5 μm). Method B: Mobile phase: 0.5% isopropylamine in IPA; Flow rate: 3 mL / min; Column: Chiralpak AD-H (250×4.6 mm, 5 μm). Method C: Mobile phase: 20 mM ammonia in methanol; Flow rate: 3 mL / min; Column: YMC Cellulose-SC (250×4.6 mm, 5 μm). Method D: Mobile phase: Methanol; Flow rate: 3 mL / min; Column: Lux A1 (250×4.6 mm, 5 μm). Method E: Mobile phase: 0.5% isopropylamine in methanol; Flow rate: 5 mL / min; Column: Lux C4. Method F: Mobile phase: 0.5% isopropylamine in methanol; Flow rate: 3 mL / min; Column: YMC Cellulose-SC. Method G: Mobile phase: 0.5% isopropylamine in methanol; Flow rate: 3 mL / min; Column: Lux A1. Method H: Mobile phase: 0.5% isopropylamine in IPA; Flow rate: 3 mL / min; Column: Lux A1 (250×4.6 mm, 5 μm). Method I: Mobile phase: 0.5% isopropylamine in methanol; Flow rate: 3 mL / min; Column: Chiral CCS (250×4.6 mm, 5 μm). Method J: Mobile phase: 0.5% isopropylamine in IPA; Flow rate: 5 mL / min; Column: YMC Cellulose-SC AD-H (250×4.6 mm, 5 μm). Method K: Mobile phase: 0.5% isopropylamine in methanol; Flow rate: 4 mL / min; Column: (R,R)-Whelk-01 (250×4.6 mm, 5 μm). Method L: Mobile phase: 0.5% isopropylamine in IPA; Flow rate: 3 mL / min; Column: Chiralcel OX-H (250×4.6 mm, 5 μm). Method M: Mobile phase: 0.5% isopropylamine in IPA; Flow rate: 5 mL / min; Column: YMC Cellulose-SC (250×4.6 mm, 5 μm). Method N: Mobile phase: Methanol, Flow rate: 5 mL / min; Column: Chiralcel OX-H (250×4.6 mm, 5 μm). Method O: Mobile phase: 0.1% isopropylamine in IPA:Methanol (1:1), Flow rate: 3 mL / min; Column: Chiralpak AS-H (250×4.6 mm, 5 μm). Method P: Mobile phase: 0.5% isopropylamine in methanol, Flow rate: 3 mL / min; Column: Chiralpak AS-H (250×4.6 mm, 5 μm). Method Q: Mobile phase: IPA, Flow rate: 3 mL / min; Column: Lux A1 (250×4.6 mm, 5 μm). Method R: Mobile phase: 0.1% isopropylamine in IPA:Methanol (1:1), Flow rate: 3 mL / min; Column: Lux A1 (250×4.6 mm, 5 μm). Method S: Mobile phase: 0.5% isopropylamine in IPA (1:1), Flow rate: 3 mL / min; Column: Chiralpak AS-H (250×4.6 mm, 5 μm). Method T: Mobile phase: 0.5% isopropylamine in IPA (1:1), Flow rate: 4 mL / min; Column: Chiralpak OX-H (250×4.6 mm, 5 μm). Method U: Mobile phase: IPA, Flow rate: 3 mL / min; Column: Chiralpak AS-H (250×4.6 mm, 5 μm). Method V: Mobile phase: 0.5% isopropylamine in methanol, Flow rate: 3 mL / min; Column: Chiralpak OX-H (250×4.6 mm, 5 μm).

[0229] Preparative HPLC: Equipment name: Agilent 1290 Infinity II Method A: Mobile phase: A: 0.1% TFA in water; Mobile phase; B: 0.1% TFA in ACN; Flow rate: 2.0 mL / min; Column: X-Bridge C8 (50×4.6 mm, 3.5 μM). Method B: Mobile phase: A: 10 mM NH4OAc in water; B: ACN; Flow rate: 35 mL / min; Column: X select C18 (30×150 mm, 5 μm). Method C: Mobile phase: A: 10 mM NH4HCO3 in water; B: ACN; Flow rate: 1.0 mL / min; Column: XBridge C8 (50×4.6 mm, 3.5 μm). Method D: Mobile phase: A: 0.1% HCOOH in water; B: ACN; Flow rate: 1.0 mL / min; Column: X-select C18 (30×150 mm, 5 μm). Method E: Mobile phase: A: 0.1% TFA in water, B: ACN; Flow rate: 15 mL / min; Column: sunfire C18 (19×150 mm, 5 μm).

[0230] Chiral preparative SFC: Equipment name: PIC SFC 100 and PSC SFC 400 The ratio of CO2 to the co-solvent is in the range of 60:40 to 80:20 Method A: Mobile phase: 0.5% isopropylamine in IPA; Flow rate: 3 mL / min; Column: YMC Amylose-SA (250×30 mm, 5 μm). Method B: Mobile phase: 0.5% isopropylamine in IPA; Flow rate: 3 mL / min; Column: Chiralpak AD-H (250×30 mm, 5 μm). Method C: Mobile phase: 20 mM ammonia in methanol; Flow rate: 3 mL / min; Column: YMC Cellulose-SC (250×30 mm, 5 μm). Method D: Mobile phase: methanol; Flow rate: 3 mL / min; Column: Chiral CCS (250×30 mm, 5 μm). Method E: Mobile phase: methanol; Flow rate: 3 mL / min; Column: Lux A1 (250×30 mm, 5 μm). Method F: Mobile phase: 0.5% isopropylamine in IPA; Flow rate: 3 mL / min; Column: Lux A1 (250×30 mm, 5 μm). Method G: Mobile phase: 0.5% isopropylamine in methanol; Flow rate: 3 mL / min; Column: Chiral CCS (250×30 mm, 5 μm). Method H: Mobile phase: 0.5% isopropylamine in methanol; Flow rate: 4 mL / min; Column: (R,R)-Whelk-01 (250×30 mm, 5 μm). Method I: Mobile phase: 0.5% isopropylamine in IPA; Flow rate: 5 mL / min; Column: YMC Cellulose-SC (250×30 mm, 5 μm). Method J: Mobile phase: 0.5% isopropylamine in IPA; Flow rate: 3 mL / min; Column: Chiralcel OX-H (250×30 mm, 5 μm). Method K: Mobile phase: 0.5% isopropylamine in methanol; Flow rate: 5 mL / min; Column: YMC Cellulose-SC (250×30 mm, 5 μm). Method L: Mobile phase: Methanol; Flow rate: 5 mL / min; Column: Chiralcel OX-H (250×30 mm, 5 μm). Method M: Mobile phase: 0.5% isopropylamine in methanol, Flow rate: 3 mL / min; Column: Chiralpak AS-H (250×4.6 mm, 5 μm). Method N: Mobile phase: 0.1% isopropylamine in IPA:MeOH (1:1), Flow rate: 3 mL / min; Column: Chiralpak AS-H (250×4.6 mm, 5 μm).

[0231] Abbreviations ACN Acetonitrile DCM Dichloromethane DMF Dimethylformamide dppf 1,1'-Bis(diphenylphosphino)ferrocene HPLC High Performance Liquid Chromatography IPA Isopropyl Alcohol LCMS Liquid Chromatography Mass Spectrometry NMP N-Methyl-2-pyrrolidone PE Petroleum Ether Pd2(dba)3 Tris(dibenzylideneacetone)dipalladium(0) PMB para-Methoxybenzyl RT Room temperature RuPhos 2-Dicyclohexylphosphino-2',6'-diisopropoxybiphenyl SFC Supercritical fluid chromatography TFA Trifluoroacetic acid THF Tetrahydrofuran TLC Thin layer chromatography UPLC Ultra performance liquid chromatography

[0232] The present invention will now be described by the following examples, which do not limit the present invention in any way. All cited documents and references are incorporated by reference.

Example

[0233] Intermediate 1 3-Butyl-3-ethyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl trifluoromethanesulfonate

[0234]

Chemical formula

[0235] 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) was added dropwise, followed by dropwise addition of trifluoromethanesulfonic anhydride (0.3 mL, 1.78 mmol). The reaction mixture was stirred at RT for 1 h. 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 (2 × 20 mL). The combined organic layers were washed with water (5 mL) and brine (5 mL), and then dried over anhydrous Na2SO4. The organic portion was filtered and concentrated under vacuum, and the resulting crude material was purified 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). 1 H NMR (400 MHz, DMSO-d6): δ 7.70 (s, 1H), 7.40 (t, J = 9.6 Hz, 4H), 7.17 (t, J = 9.2 Hz, 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. 3.21 min, 98.21% (max).

[0236] Intermediate 2 Methyl 3-butyl-3-ethyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-carboxylate 1,1-dioxide

[0237]

Chemical Structure

[0238] To a stirred solution of 3-butyl-3-ethyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-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 Pd2(dba)3 (104 mg, 0.10 mmol) at RT. The resulting reaction mixture was stirred in an autoclave at 70 °C for 16 h under a carbon monoxide gas pressure of 5 kg. 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 × 50 mL). The combined organic layers were washed with water (15 mL) and brine (15 mL), then dried over anhydrous Na2SO4. The organic portion was filtered and concentrated under vacuum, and the resulting crude material was purified by Isolera column chromatography (eluent: 10 - 15% EtOAc / PE; silica gel: 230 - 400 mesh) to afford the title compound. Yield: 52% (215 mg, off-white solid). 1 H NMR (400 MHz, DMSO-d6): δ 8.41 (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. 3.23 min, 77.43% (max).

[0239] Intermediate 3 3-Butyl-3-ethyl-8-(hydroxymethyl)-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide

[0240]

Chem.

[0241] To a stirred solution of methyl 3-butyl-3-ethyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-carboxylate 1,1-dioxide (Intermediate 2; 200 mg, 0.43 mmol) in dry THF (10 mL) was added dropwise lithium aluminum hydride (2 M in THF, 0.4 mL, 0.86 mmol) at 0 °C, and the reaction mixture was stirred at RT for 1 h. 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 (2×15 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), and dried over anhydrous Na2SO4. The organic portion was filtered and concentrated under vacuum, and the resulting crude product was sent to the next step without further purification. Yield: 83% (210 mg, white solid). 1 H NMR (400 MHz, DMSO-d6): δ 7.92 (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).

[0242] Intermediate 4 Ethyl-2-(((3-butyl-3-ethyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)methyl)thio)acetate

[0243]

Chem.

[0244] 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 was added zinc iodide (17.3 mg, 0.05 mmol), followed by ethyl 2-mercaptoacetate (34 mg, 0.28 mmol), and the reaction mixture was stirred at RT for 1 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with water (10 mL), and the aqueous layer was extracted with DCM (2 × 10 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), and dried over anhydrous Na2SO4. The organic portion was filtered and concentrated under vacuum, and the resulting crude material was sent to the next step without further purification. Yield: 70 mg (crude, pale yellow solid). 1 H NMR (400 MHz, DMSO-d6): δ 7.74 (s, 1H), 7.33 (t, J = 8.4 Hz, 2H), 7.22 (d, J = 7.6 Hz, 2H), 7.04 (t, J = 7.6 Hz, 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 - 1.39 (m, 3H), 1.38 - 1.34 (m, 3H), 1.27 - 1.18 (m, 4H), 0.75 - 0.70 (m, 6H).

[0245] Intermediate 5 3,3-Dibutyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl trifluoromethanesulfonate

[0246]

Chemical Structure

[0247] 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) was added dropwise, followed by dropwise addition of trifluoromethanesulfonic anhydride (0.56 mL, 3.35 mmol). The reaction mixture was stirred at RT for 1 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice-cold water (20 mL), and the aqueous layer was extracted with DCM (2 × 50 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), and then dried over anhydrous Na2SO4. The organic portion was filtered and concentrated under vacuum, and the resulting crude material was purified by Isolera column chromatography (eluent: 20% EtOAc / PE; silica gel: 230 - 400 mesh). The obtained solid was triturated with petroleum ether (2 × 10 mL) and dried under vacuum to give the title compound. Yield: 85% (1.1 g, off-white solid). 1 H NMR (400 MHz, DMSO-d6): δ 7.70 (s, 1H), 7.43 - 7.30 (m, 4H), 7.18 (t, J = 6.8 Hz, 1H), 6.53 (s, 1H), 3.90 - 3.88 (m, 2H), 3.54 (s, 2H), 2.18 (s, 3H), 1.65 - 1.20 (m, 4H), 1.20 - 0.90 (m, 8H), 0.80 - 0.62 (m, 6H). LCMS: (method E) 579.9 (M + +H), Rt. 3.52 min, 96.63% (max).

[0248] Intermediate 6 Methyl 3,3-dibutyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-carboxylate 1,1-dioxide

[0249]

Chemical Structure

[0250] To a solution of 3,3-dibutyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-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 Pd2(dba)3 (104 mg, 0.10 mmol) at RT. The resulting reaction mixture was stirred at 70 °C for 16 h in an autoclave under a carbon monoxide gas pressure of 5 kg. 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 × 50 mL). The combined organic layers were washed with water (15 mL), brine (15 mL) and then dried over anhydrous Na2SO4. The organic portion was filtered and concentrated under vacuum, and the resulting crude material was purified 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). 1 H NMR (400 MHz, DMSO-d6): δ 8.41 (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. 3.37 min, 94.23% (max).

[0251] Intermediate 7 3,3-Dibutyl-8-(hydroxymethyl)-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide

[0252]

Chem.

[0253] To a stirred solution of methyl 3,3-dibutyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-carboxylate 1,1-dioxide (Intermediate 6; 0.3 g, 0.6 mmol) in dry THF (6 mL) was added dropwise 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 h. 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 (2 × 15 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), and then dried over anhydrous Na2SO4. The organic portion was filtered and concentrated under vacuum, and the resulting crude was sent to the next step without purification. Yield: 300 mg (crude, off-white solid). 1 H NMR (400 MHz, DMSO-d6): δ 7.91 (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 = 5.6 Hz, 1H), 4.43 (d, J = 5.2 Hz, 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. 2.94 min, 97.01% (max).

[0254] Intermediate 8 Ethyl 2-(((3,3-dibutyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)methyl)thio)acetate

[0255]

Chem.

[0256] 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 h. 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 (2 × 20 mL). The combined organic layers were washed with water (5 mL) and brine (5 mL), then dried over anhydrous Na2SO4. The organic portion was filtered and concentrated under vacuum, and the resulting material was sent to the next step without further purification. Yield: 80% (90 mg, brown solid). LCMS: (Method E) 581.0 (M + +18), Rt. 3.44 min, 80.16% (max).

[0257] Intermediate 9 3-Butyl-3-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl trifluoromethanesulfonate

[0258]

Chem.

[0259] 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) was added dropwise pyridine (0.24 g, 4.93 mmol) at 0 °C. Then trifluoromethanesulfonic anhydride (0.65 g, 3.69 mmol) was added dropwise at 0 °C and the reaction mixture was stirred at RT for 1 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold water (20 mL). The aqueous layer was extracted with DCM (2 × 50 mL) and the combined organic layers were washed with water (10 mL) and brine (10 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The obtained crude was purified by Isolera column chromatography (eluent: 20% EtOAc / PE; silica gel: 230 - 400 mesh) to give a sticky solid. This sticky solid was further purified by trituration with petroleum ether (2 × 10 mL) and dried to give the title compound. Yield: 68% (0.9 g, off-white solid). LCMS: (Method E) 538.0 (M + +H), Rt. 3.30 min, 97.12% (max).

[0260] Intermediate 10 Methyl 3-butyl-3-methyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-carboxylate 1,1-dioxide

[0261]

Chem.

[0262] A solution of 3-butyl-3-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl trifluoromethanesulfonate (Intermediate 9; 0.9 g, 1.67 mmol) in degassed methanol (15 mL) and DMF (10 mL) was added with triethylamine (0.32 mL, 2.51 mmol), dppf (0.10 g, 2.00 mmol) and Pd2(dba)3 (0.09 g, 1.01 mmol) at RT. The resulting reaction mixture was stirred at 75 °C for 16 h in an autoclave under a carbon monoxide gas pressure of 5 kg. 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 × 50 mL). The combined organic layers were washed with water (15 mL) and brine (15 mL), then dried over anhydrous Na2SO4. The organic layer was filtered and concentrated under vacuum, and the resulting crude material was purified 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). LCMS: (Method E) 448.3 (M + +H), Rt. 2.93 min, 96.13% (max).

[0263] Intermediate 11 3-Butyl-8-(hydroxymethyl)-3-methyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide

[0264]

Chem.

[0265] A stirred solution of methyl 3-butyl-3-methyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-carboxylate 1,1-dioxide (Intermediate 10; 0.25 g, 0.56 mmol) in dry THF (10 mL) was added dropwise with lithium aluminum hydride (2 M solution in THF, 0.27 mL, 0.56 mmol) at 0 °C, and the reaction mixture was stirred at RT for 1 h. 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 (2 × 15 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), and dried over anhydrous Na2SO4. The organic portion was filtered and concentrated under vacuum to give the title compound, which was carried on to the next step without further purification. Yield: 92% (0.22 g, off-white solid). LCMS: (Method A) 419.9 (M + +H), Rt. 2.72 min, 98.23% (max).

[0266] Intermediate 12 Ethyl 2-(((3-butyl-3-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)methyl)thio)acetate

[0267]

Chemical Structure

[0268] 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 h. 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 (2 × 20 mL). The combined organic layers were washed with water (5 mL) and brine (5 mL) and then dried over anhydrous Na2SO4. The organic portion was concentrated under vacuum and the resulting crude 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). LCMS: (Method B) 539.0 (M + +18), Rt. 2.86 min, 97.00% (max).

[0269] Intermediate 13 3-Butyl-3-ethyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl trifluoromethanesulfonate

[0270]

Chem.

[0271] 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) was added dropwise, followed by trifluoromethanesulfonic anhydride (1.36 mL, 8.22 mmol). The reaction mixture was stirred at RT for 1 h. 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 (2 × 50 mL). The combined organic layers were washed with water (20 mL), brine (20 mL) and then dried over anhydrous Na2SO4. The organic portion was filtered and concentrated under vacuum. The resulting crude material was purified 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).

[0272] Intermediate 14 Methyl 3-butyl-3-ethyl-5-(4-fluorophenyl)-7-(methylthio)-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-carboxylate 1,1-dioxide

[0273] [Chemical formula]

[0274] A solution of 3-butyl-3-ethyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl trifluoromethanesulfonate (Intermediate 13; 3.5 g, 6.15 mmol) in degassed methanol (35 mL) and DMF (20 mL) was added with triethylamine (1.28 mL, 9.22 mmol), dppf (0.41 g, 0.73 mmol) and Pd2(dba)3 (0.34 g, 0.37 mmol) at RT. The resulting reaction mixture was stirred at 75 °C for 16 h in an autoclave under a carbon monoxide gas pressure of 5 kg. 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 × 50 mL). The combined organic layers were washed with water (15 mL), brine (15 mL), and then dried over anhydrous Na2SO4. The organic layer was filtered and concentrated under vacuum, 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: 16% (0.45 g, off-white solid). 1 H NMR (400 MHz, DMSO-d6): δ 8.40 (s, 1H), 7.60 - 7.57 (m, 2H), 7.32 (t, J = 8.80 Hz, 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. 3.17 min, 91.42% (max).

[0275] Intermediate 15 3-Butyl-3-ethyl-5-(4-fluorophenyl)-8-(hydroxymethyl)-7-(methylthio)-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide

[0276]

Chem.

[0277] To a stirred solution of methyl 3-butyl-3-ethyl-5-(4-fluorophenyl)-7-(methylthio)-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-carboxylate 1,1-dioxide (Intermediate 14; 1.7 g, 3.54 mmol) in THF (20 mL) at 0 °C was added dropwise lithium aluminum hydride (2 M solution in THF, 2.6 mL, 5.32 mmol), and the reaction mixture was stirred at RT for 1 h. 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 (2 × 25 mL). The combined organic layers were washed with water (15 mL), brine (15 mL), and dried over anhydrous Na2SO4. The organic portion was filtered and concentrated under vacuum, and the resulting crude product was sent to the next step without further purification. Yield: 1.7 g (crude, off-white solid). 1 1H NMR (400 MHz, DMSO-d6): δ 7.89 (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. 2.57 min, 94.36% (max).

[0278] Intermediate 16 Ethyl 2-(((3-butyl-3-ethyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)methyl)thio)acetate

[0279]

Chem.

[0280] 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) was added zinc iodide (0.11 g, 0.33 mmol) and ethyl 2-mercaptoacetate (0.16 g, 1.33 mmol) at 0 °C, and the reaction mixture was stirred at RT for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water (50 mL), and the aqueous layer was extracted with DCM (2 × 25 mL). The combined organic layers were washed with water (5 mL) and brine (5 mL), and then dried over anhydrous Na2SO4. The organic portion was concentrated under vacuum, and the resulting crude material was sent to the next step without purification. Yield: 368 mg (crude, pale yellow solid). LCMS: (Method B) 571.1 (M + +18), Rt. 2.91 min, 64.26% (max).

[0281] Intermediate 17 3,3-Dibutyl-2-(4-methoxybenzyl)-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl trifluoromethanesulfonate

[0282]

Chem.

[0283] 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) was added pyridine (0.14 mL, 1.76 mmol) at 0 °C. Then trifluoromethanesulfonic anhydride (0.22 mL, 1.32 mmol) was added dropwise and the reaction mixture was stirred at RT for 1 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice-cold water (20 mL) and the aqueous layer was extracted with DCM (2 × 20 mL). The combined organic layers were washed with water (10 mL) and brine (10 mL) and then dried over anhydrous Na2SO4. The organic portion was filtered and concentrated under vacuum and the resulting crude was purified 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). LCMS: (method J) 701.3 (M + +H), Rt. 3.49 min, 93.52% (max).

[0284] Intermediate 18 Methyl 3,3-dibutyl-2-(4-methoxybenzyl)-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-carboxylate 1,1-dioxide

[0285]

Chemical Structure

[0286] A solution of 3,3-dibutyl-2-(4-methoxybenzyl)-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl trifluoromethanesulfonate (Intermediate 17; 0.6 g, 0.86 mmol) in degassed methanol (10 mL) and DMF (5 mL) was added with triethylamine (0.18 mL, 1.28 mmol), dppf (57 mg, 0.10 mmol) and Pd2(dba)3 (47 mg, 0.05 mmol) at RT. The resulting reaction mixture was stirred at 70 °C for 16 h in an autoclave under a carbon monoxide gas pressure of 5 kg. 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 × 50 mL). The combined organic layers were washed with water (15 mL) and brine (15 mL), then dried over anhydrous Na2SO4. The organic portion was filtered and concentrated under vacuum, 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: 28% (0.17 g, off-white solid). LCMS: (Method J) 610.9 (M + +H), Rt. 3.51 min, 87.25% (max).

[0287] Intermediate 19 3,3-Dibutyl-8-(hydroxymethyl)-2-(4-methoxybenzyl)-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide

[0288]

Chem.

[0289] A stirred solution of methyl 3,3-dibutyl-2-(4-methoxybenzyl)-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-carboxylate 1,1-dioxide (Intermediate 18; 0.17 g, 0.28 mmol) in dry THF (4 mL) was added dropwise with lithium aluminum hydride (1 M solution in THF, 0.41 mL, 0.42 mmol) at 0 °C and the reaction mixture was stirred at RT for 20 min. 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 (2 × 20 mL). The combined organic layers were washed with water (10 mL) and brine (10 mL) and then dried over anhydrous Na2SO4. The organic portion was filtered and concentrated under vacuum and the resulting crude was carried on to the next step without further purification. Yield: 87% (0.15 g, off-white solid).

[0290] Intermediate 20 Ethyl 2-(((3,3-dibutyl-2-(4-methoxybenzyl)-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)methyl)thio)acetate

[0291] [Chemical Structure]

[0292] 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 was added zinc iodide (0.04 g, 0.13 mmol) and ethyl 2-mercaptoacetate (0.06 g, 0.52 mmol), and the reaction mixture was stirred at RT for 1 h. 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 (2 × 20 mL). The combined organic layers were washed with water (10 mL) and brine (10 mL), then dried over anhydrous Na2SO4. The organic portion was concentrated under vacuum and the resulting crude material was purified by Isolera column chromatography (eluent: 12% EtOAc / PE; silica gel: 230 - 400 mesh) to afford the title compound. Yield: 59.2%, (0.16 g, sticky white solid). LCMS: (Method B) 702.0 (M + +18), Rt. 3.24 min, 54.22% (max).

[0293] Intermediate 21 Ethyl 2-(((3,3-dibutyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)methyl)thio)acetate

[0294]

Chem.

[0295] To a stirred solution of ethyl 2-(((3,3-dibutyl-2-(4-methoxybenzyl)-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)methyl)thio)acetate (Intermediate 20; 0.16 g, 0.23 mmol) in toluene (3 mL) was added dropwise triphenylamine (0.12 g, 0.47 mmol) and 2,2,2-trifluoroacetic acid (0.18 mL, 2.34 mmol) at 0 °C, and the resulting reaction mixture was stirred at RT for 16 h. 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 (2 × 10 mL). The combined organic layers were washed with water (5 mL) and brine (5 mL), then dried over anhydrous Na2SO4. The organic portion was concentrated under vacuum, 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: 58% (85 mg, light brown solid). 1 H NMR (400 MHz, DMSO-d6): δ 7.51 (s, 1H), 7.55 - 7.20 (m, 5H), 7.20 - 7.05 (m, 1H), 6.44 (s, 1H), 4.12 (q, J = 6.8 Hz, 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. 3.23 min, 89.96% (max).

[0296] Intermediate 22 3-Butyl-3-ethyl-2-(4-methoxybenzyl)-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl trifluoromethanesulfonate

[0297]

Chem.

[0298] 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) was added dropwise pyridine (0.72 mL, 8.88 mmol) and trifluoromethanesulfonic anhydride (0.75 mL, 4.44 mmol) at 0 °C, and the reaction mixture was stirred at RT for 1 h. 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 (2 × 20 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The resulting 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). LCMS: (Method A) 673.0 (M + +H), Rt. 3.53 min, 89.35% (max).

[0299] Intermediate 23 Methyl 3-butyl-3-ethyl-2-(4-methoxybenzyl)-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-carboxylate 1,1-dioxide

[0300]

Chem.

[0301] To a stirred solution of 3-butyl-3-ethyl-2-(4-methoxybenzyl)-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-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 Pd2(dba)3 (110 mg, 0.13 mmol) at RT. The resulting reaction mixture was stirred at 70 °C for 16 h in an autoclave under a carbon monoxide gas pressure of 10 kg. 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 × 50 mL). The combined organic layers were washed with water (15 mL) and brine (15 mL) and then dried over anhydrous Na2SO4. The organic portion was filtered and concentrated under vacuum and the resulting crude material was purified by Isolera column chromatography (eluent: 10 - 12% EtOAc / PE; silica gel: 230 - 400 mesh) to afford the title compound. Yield: 67% (1 g, off-white solid). LCMS: (Method A) 583.2 (M + +H), Rt. 3.26 min, 81.20% (max).

[0302] Intermediate 24 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

[0303]

Chemical Structure

[0304] A stirred solution of methyl 3-butyl-3-ethyl-2-(4-methoxybenzyl)-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-carboxylate 1,1-dioxide (Intermediate 23; 1 g, 1.72 mmol) in dry THF (10 mL) was added dropwise with lithium aluminum hydride (2 M in THF, 1.27 mL, 2.54 mmol) at 0 °C, and the reaction mixture was stirred at RT for 1 h. After completion of the reaction (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 (2 × 20 mL), and the combined organic layers were washed with water (10 mL), brine (10 mL), and then dried over anhydrous Na2SO4. The organic portion was filtered and concentrated under vacuum, and the resulting crude material was purified 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).

[0305] Intermediate 25 Ethyl 2-(((3-butyl-3-ethyl-2-(4-methoxybenzyl)-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)methyl)thio)acetate

[0306] [Chemical Structure]

[0307] 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 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water (10 mL) and the aqueous layer was extracted with EtOAc (2 × 15 mL). The combined organic layers were washed with water (5 mL) and brine (5 mL) and dried over anhydrous Na2SO4. The organic portion was filtered, concentrated under vacuum and the crude obtained was sent to the next step without further purification. Yield: 32.8% (160 mg, pale yellow sticky solid).

[0308] Intermediate 26 Ethyl 2-(((3-butyl-3-ethyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)methyl)thio)acetate

[0309]

Chem.

[0310] To a stirred solution of ethyl 2-(((3-butyl-3-ethyl-2-(4-methoxybenzyl)-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)methyl)thio)acetate (Intermediate 25; 160 mg, 0.24 mmol) in toluene (10 mL) at 0 °C was added dropwise triphenylamine (120 mg, 0.48 mmol) and trifluoroacetic acid (0.19 mL, 2.44 mmol), and the reaction mixture was stirred at RT for 16 h. 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 (2 × 10 mL). The combined organic layers were washed with water (10 mL) and brine (10 mL), then dried over anhydrous Na2SO4. The organic portion was filtered and concentrated under vacuum, and the resulting crude material was purified by Isolera column chromatography (eluent: 20 - 25% EtOAc / PE; silica gel: 230 - 400 mesh) to afford the title compound. Yield: 73.2% (100 mg, light brown solid). LCMS: (Method A) 535.21 (M + -H), Rt. 2.96 min, 95.72% (max).

[0311] Intermediate 27 3-Butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl trifluoromethanesulfonate

[0312]

Chem.

[0313] 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) was added dropwise pyridine (0.38 mL, 4.92 mmol) at 0 °C. Then trifluoromethanesulfonic anhydride (0.83 mL, 2.95 mmol) was added and the reaction mixture was stirred at RT for 1 h. 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 (2 × 20 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The resulting 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). UPLC-MS: (Method A) 539.1 (M + +H), Rt. 2.64 min, 92.69% (max).

[0314] Intermediate 28 Methyl 3-butyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-carboxylate 1,1-dioxide

[0315]

Chemical Structure

[0316] To a stirred solution of 3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-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 Pd2(dba)3 (0.102 g, 0.11 mmol) at RT. The resulting reaction mixture was then stirred at 70 °C for 16 h in an autoclave under a carbon monoxide gas pressure of 10 kg. 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 × 50 mL). The combined organic layers were washed with water (15 mL), brine (15 mL) and then dried over anhydrous Na2SO4. The organic portion was filtered and concentrated under vacuum and the resulting crude material was purified by Isolera column chromatography (eluent: 10–12% EtOAc / PE; silica gel: 230–400 mesh) to afford the title compound. Yield: 50.4% (600 mg, off-white solid). UPLC-MS: (Method A) 449.1 (M + +H), Rt. 2.46 min, 69.04% (max).

[0317] Intermediate 29 3-Butyl-8-(hydroxymethyl)-2-methyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide

[0318]

Chem.

[0319] A stirred solution of methyl 3-butyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-carboxylate 1,1-dioxide (Intermediate 28; 0.6 g, 1.34 mmol) in dry THF (10 mL) was added dropwise with lithium aluminum hydride (2 M in THF, 1.05 mL, 2.10 mmol) at 0 °C, and the reaction mixture was stirred at RT for 1 h. 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 (2 × 20 mL). The combined organic layers were washed with water (10 mL) and brine (10 mL), then dried over anhydrous Na2SO4. The organic portion was filtered and concentrated under vacuum, and the resulting crude product was purified by Isolera column chromatography (eluent: 20 - 25% EtOAc / PE; silica gel: 230 - 400 mesh) to afford the title compound. Yield: 86% (500 mg, off-white solid).

[0320] Intermediate 30 Ethyl 2-(((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetate

[0321] [Chemical Structure]

[0322] 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) was added zinc(II) iodide (0.09 g, 0.29 mmol) and ethyl 2-mercaptoacetate (0.14 g, 1.19 mmol) at 0 °C, and the reaction mixture was stirred at RT for 1 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water (10 mL), and the aqueous layer was extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with water (10 mL) and brine (10 mL), then dried over anhydrous Na2SO4. The organic portion was filtered and concentrated under vacuum, and the resulting crude material was sent directly to the next step without purification. Yield: 48% (0.2 g, pale yellow solid).

[0323] Intermediate 31 7-Bromo-3-butyl-3-ethyl-8-hydroxy-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiadiazepine 1,1-dioxide

[0324] [Chemical formula]

[0325] To a stirred solution of 7-bromo-3-butyl-3-ethyl-8-methoxy-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiadiazepine 1,1-dioxide (3 g, 6.43 mmol) in DCM (10 mL) was added dropwise BBr3 (1 M in DCM, 12.86 mL, 12.86 mmol) at -15 °C, and the reaction mixture was stirred for 10 min. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with methanol (10 mL) 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% (2.9 g, brown solid).

[0326] Intermediate 32 3-Butyl-3-ethyl-8-hydroxy-7-methoxy-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide

[0327]

Chem.

[0328] 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 h. 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 (2 × 25 mL). The combined organic layers were washed with water (15 mL) and brine (15 mL), and dried over anhydrous Na2SO4. The organic layer was concentrated under vacuum, and 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 g, brown solid). LCMS: (Method A) 404.1 (M + +H), Rt. 2.94 min, 98.03% (max).

[0329] Intermediate 33 3-Butyl-3-ethyl-7-methoxy-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl trifluoromethanesulfonate

[0330]

Chem.

[0331] 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) was added, followed by trifluoromethanesulfonic anhydride (0.41 mL, 2.48 mmol). The reaction mixture was stirred at RT for 1 h. 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 (2 × 20 mL). The combined organic layers were washed with brine (5 mL) and brine (10 mL), then dried over anhydrous Na2SO4. The organic portion was concentrated under vacuum and the resulting crude material was purified by Isolera column chromatography (eluent: 7 - 8% EtOAc / PE; silica gel: 230 - 400 mesh) to afford the title compound. Yield: 68% (900 mg, white solid). LCMS: (Method A) 536.1 (M + +H), Rt. 3.10 min, 97.27% (max).

[0332] Intermediate 34 Methyl 3-butyl-3-ethyl-7-methoxy-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-carboxylate 1,1-dioxide

[0333]

Chem.

[0334] A stirred solution of 3-butyl-3-ethyl-7-methoxy-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl trifluoromethanesulfonate (Intermediate 33; 0.9 g, 1.68 mmol) in degassed methanol (15 mL) and DMF (5 mL) was added with triethylamine (0.35 mL, 2.52 mmol), Pd2(dba)3 (0.08 g, 0.08 mmol) and dppf (0.11 g, 0.20 mmol) at RT. The resulting reaction mixture was stirred at 70 °C for 16 h in an autoclave under a carbon monoxide gas pressure of 5 kg. 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 × 50 mL). The combined organic layers were washed with water (15 mL) and brine (15 mL), then dried over anhydrous Na2SO4. The organic portion was filtered and concentrated under vacuum, and 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: 16% (0.6 g, off-white solid).

[0335] Intermediate 35 3-Butyl-3-ethyl-8-(hydroxymethyl)-7-methoxy-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide

[0336] [Chemical formula]

[0337] A stirred solution of methyl 3-butyl-3-ethyl-7-methoxy-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-carboxylate 1,1-dioxide (Intermediate 34; 0.2 g, 0.45 mmol) in THF (5 mL) was added dropwise with lithium aluminum hydride (2 M in THF, 0.22 mL, 0.44 mmol) at 0 °C, and the reaction mixture was stirred at RT for 1 h. After completion of the reaction (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 (2 × 20 mL), and the combined organic layers were washed with water (10 mL) and brine (10 mL), and then dried over anhydrous Na2SO4. The organic portion was filtered and 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: 95% (190 mg, white solid).

[0338] Intermediate 36 Ethyl 2-(((3-butyl-3-ethyl-7-methoxy-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)methyl)thio)acetate

[0339] [Chemical formula]

[0340] 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; 0.19 g, 0.46 mmol) in DCM at 0 °C, ethyl 2-mercaptoacetate (0.11 g, 0.91 mmol) was added followed by zinc(II) iodide (0.07 g, 0.23 mmol), and the reaction mixture was stirred at RT for 3 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with water (5 mL) and the aqueous layer was extracted with DCM (2 × 10 mL). The combined organic layers were washed with water (5 mL) and brine (5 mL), then dried over anhydrous Na2SO4. The organic layer was filtered and concentrated under vacuum, 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: 60% (0.15 g, white solid).

[0341] Intermediate 37 Methyl 2-(((3-butyl-3-ethyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)methyl)thio)-2-methylpropanoate

[0342] [Chemical formula]

[0343] 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; 250 mg, 0.58 mmol) in DCM (5 mL) was added methyl 2-mercapto-2-methylpropanoate (81 mg, 0.61 mmol) and zinc iodide (70 mg, 0.22 mmol) at 0 °C, and the reaction mixture was stirred at RT for 3 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with water (5 mL), and the aqueous layer was extracted with DCM (2 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to afford the title compound. Yield: 76.2% (230 mg, brown gum).

[0344] Intermediate 38 Methyl 2-(((3,3-dibutyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)methyl)thio)-2-methylpropanoate

[0345]

Chemical Structure

[0346] 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, 0.15 g, 0.33 mmol) in DCM (5 mL) was added methyl 2-mercapto-2-methylpropanoate (0.05 g, 0.36 mmol) and zinc iodide (II) (0.05 g, 0.16 mmol) at 0 °C, and the reaction mixture was stirred at RT for 1 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with water (5 mL), and the aqueous layer was extracted with DCM (2 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to afford the title compound. Yield: 48% (0.09 g, brown gum).

[0347] Intermediate 39 Methyl 2 - ((((3 - butyl - 3 - methyl - 7 - (methylthio) - 1,1 - dioxido - 5 - phenyl - 2,3,4,5 - tetrahydro - 1,5 - benzothiazepin - 8 - yl)methyl)thio)-2 - methylpropanoate

[0348]

Chem.

[0349] 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; 0.07 g, 0.17 mmol) in DCM (5 mL) at 0 °C, methyl 2 - mercapto - 2 - methylpropanoate (0.05 g, 0.33 mmol) and zinc(II) iodide (16 mg, 0.09 mmol) were added and the reaction mixture was stirred at RT for 1 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with water (5 mL) and the aqueous layer was extracted with DCM (2 × 15 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. 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: 75% (0.05 g, white solid).

[0350] Intermediate 40 3 - butyl - 3 - ethyl - 2 - methyl - 7 - (methylthio) - 1,1 - dioxido - 5 - phenyl - 2,3,4,5 - tetrahydro - 1,2,5 - benzothiadiazepin - 8 - yl trifluoromethanesulfonate

[0351]

Chem.

[0352] 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) was added dropwise, followed by trifluoromethanesulfonic anhydride (0.14 mL, 1.76 mmol). The reaction mixture was stirred at RT for 1 h. 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 (2 × 20 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), and then dried over anhydrous Na2SO4. The organic portion was filtered and concentrated under vacuum, 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: 97% (1.85 g, white solid). LCMS: (Method A) 567.1 (M + +H), Rt. 3.32 min, 97.97% (max).

[0353] Intermediate 41 Methyl 3-butyl-3-ethyl-2-methyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-carboxylate 1,1-dioxide

[0354]

Chem.

[0355] A solution of 3-butyl-3-ethyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl trifluoromethanesulfonate (Intermediate 40; 1.85 g, 3.26 mmol) in degassed methanol (10 mL) and DMF (5 mL) was added with triethylamine (0.45 mL, 3.26 mmol), dppf (0.22 g, 0.39 mmol) and Pd2(dba)3 (0.18 g, 0.19 mmol) at RT. The resulting reaction mixture was stirred at 75 °C for 16 h in an autoclave under a carbon monoxide gas pressure of 5 kg. 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 × 20 mL). The combined organic layers were washed with water (10 mL), brine (10 mL) and then dried over anhydrous Na2SO4. The organic layer was filtered and concentrated under vacuum, 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: 48.5% (1 g, off-white solid). LCMS: (Method A) 477.1 (M + +H), Rt. 3.16 min, 75.49% (max).

[0356] Intermediate 42 3-Butyl-3-ethyl-8-(hydroxymethyl)-2-methyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide

[0357]

Chem.

[0358] A stirred solution of methyl 3-butyl-3-ethyl-2-methyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-carboxylate 1,1-dioxide (Intermediate 41; 1 g, 2.09 mmol) in THF (10 mL) was added dropwise with lithium aluminum hydride (2 M solution in THF, 1.57 mL, 3.15 mmol) at 0 °C, and the reaction mixture was stirred at RT for 1 h. 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 (2 × 20 mL). The combined organic layers were washed with water (15 mL), brine (15 mL), and then dried over anhydrous Na2SO4. The organic portion was filtered and 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: 53% (0.5 g, off-white solid). 1 H NMR (400 MHz, CDCl3): δ 7.83 (s, 1H), 7.42 - 7.38 (m, 2H), 724 - 7.19 (m, 3H), 6.40 (s, 1H), 4.67 - 4.65 (d, J = 6.4 Hz, 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).

[0359] Separation of enantiomers: (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

[0360]

Chem.

[0361] 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 under vacuum at 45 °C. The first elution fraction corresponded to enantiomer 1 and the second elution fraction corresponded to enantiomer 2. The absolute configuration of the two enantiomers is unknown. Enantiomer 1: Yield: 39% (0.12 g, white solid). Chiral HPLC (Method H) Rt. 3.16 min, 99.85% (max). Enantiomer 2: Yield: 32.9% (0.1 g, white solid). Chiral HPLC (Method H) Rt. 3.84 min, 98.34% (max).

[0362] Intermediate 43 Ethyl 2-(((3-butyl-3-ethyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)methyl)thio)acetate

[0363]

Chem.

[0364] 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; 500 mg, 1.11 mmol) in DCM (5 mL) at 0 °C were added zinc iodide (356 mg, 1.11 mmol) and ethyl 2-mercaptoacetate (134 mg, 1.11 mmol), and the reaction mixture was stirred at RT for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with water (5 mL), and the aqueous layer was extracted with DCM (2 × 15 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The resulting crude material was purified by Isolera column chromatography (eluent: 12% EtOAc / PE; silica gel: 230 - 400 mesh) to afford the title compound. Yield: 25.7% (0.15 g, colorless gum). 1 H NMR (400 MHz, DMSO-d6): δ 7.59 (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. 3.23 min, 99.79% (max). HPLC: (Method B) Rt. 6.67 min, 99.83% (max).

[0365] Intermediate 44 Ethyl (S)-2-(((3-butyl-3-ethyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)methyl)thio)acetate and ethyl (R)-2-(((3-butyl-3-ethyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)methyl)thio)acetate

[0366]

Chem.

[0367] Following the same procedure as described for Intermediate 43, starting from 50 mg of each of enantiomers 1 and 2 of Intermediate 42, enantiomers 1 and 2 of the title compound were obtained. The absolute configuration of the two enantiomers is unknown. Enantiomer 1: Yield: 73% (45 mg, colorless gum). 1 H NMR (400 MHz, DMSO-d6): δ 7.59 (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). Enantiomer 2: Yield: 74% (45 mg, colorless gum). 11H NMR (400 MHz, DMSO-d6): δ 7.60 (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).

[0368] Intermediate 45 3,3 - Dibutyl - 8 - methoxy - 2 - methyl - 7 - (methylthio) - 5 - phenyl - 2,3,4,5 - tetrahydro - 1,2,5 - benzothiadiazepine 1,1 - dioxide

[0369] [Chemical Structure]

[0370] 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 Cs2CO3 (0.55 g, 1.69 mmol). Methyl iodide (0.11 mL, 1.69 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with water (20 mL) and the aqueous layer was extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with water (15 mL) and brine (15 mL) and then dried over anhydrous Na2SO4. The organic portion was filtered and concentrated in vacuo and the resulting crude material was purified 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). LCMS: (Method E) 477.3 (M + +H), Rt. 3.30 min, 99.44% (max).

[0371] Intermediate 46 3,3-Dibutyl-8-hydroxy-2-methyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide

[0372]

Chemical Structure

[0373] 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) was added sodium thiomethoxide (0.25 g, 3.57 mmol) at room temperature, and then the reaction mixture was heated at 100 °C for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with water (20 mL), and the aqueous layer was extracted with EtOAc (2 × 25 mL). The combined organic layers were washed with water (15 mL) and brine (15 mL), and dried over anhydrous Na2SO4. The organic layer was filtered 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: 62.4% (0.3 g, white solid). LCMS: (Method A) 463.1 (M + +H), Rt. 4.18 min, 68.61% (max).

[0374] Intermediate 47 3,3-Dibutyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl trifluoromethanesulfonate

[0375]

Chemical Structure

[0376] 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) was added dropwise, followed by dropwise addition of trifluoromethanesulfonic anhydride (0.16 mL, 0.97 mmol). 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 (2 × 20 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), and then dried over anhydrous Na2SO4. The organic portion was filtered and concentrated under vacuum, 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: 89% (0.35 g, off-white solid). LCMS: (Method A) 595.1 (M + +H), Rt. 3.65 min, 98.61% (max).

[0377] Intermediate 48 Methyl 3,3-dibutyl-2-methyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-carboxylate 1,1-dioxide

[0378]

Chem.

[0379] A solution of 3,3-dibutyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl trifluoromethanesulfonate (Intermediate 47; 0.35 g, 0.59 mmol) in degassed methanol (10 mL) and DMF (5 mL) was added with triethylamine (0.12 mL, 0.88 mmol), dppf (0.03 g, 0.04 mmol) and Pd2(dba)3 (0.04 g, 0.07 mmol) at RT. The resulting reaction mixture was stirred at 75 °C for 16 h in an autoclave under a carbon monoxide gas pressure of 5 kg. 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 × 20 mL). The combined organic layers were washed with water (10 mL), brine (10 mL) and then dried over anhydrous Na2SO4. The organic layer was filtered and concentrated under vacuum, 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: 39.3% (0.18 g, white solid). LCMS: (Method A) 505.2 (M + +H), Rt. 3.41 min, 64.78% (max).

[0380] Intermediate 49 3,3-Dibutyl-8-(hydroxymethyl)-2-methyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide

[0381]

Chem.

[0382] A stirred solution of methyl 3,3-dibutyl-2-methyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-carboxylate 1,1-dioxide (Intermediate 48; 0.18 g, 0.36 mmol) in THF (5 mL) was added dropwise with 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 h. 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 (3 × 20 mL). The combined organic layers were washed with water (15 mL), brine (15 mL), and dried over anhydrous Na2SO4. The organic portion was filtered and concentrated under vacuum, and the resulting crude product was purified by Isolera column chromatography (eluent: 25% EtOAc / PE; silica gel: 230 - 400 mesh) to afford the title compound. Yield: 64.3% (0.11 g, off-white solid). 1 1H NMR (400 MHz, DMSO-d6): δ 7.75 (s, 1H), 7.4 - 7.36 (m, 2H), 7.30 - 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. 3.29 min, 99.42% (max).

[0383] Intermediate 50 Ethyl 2-(((3,3-dibutyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)methyl)thio)acetate

[0384] [Chem.]

[0385] 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 were added zinc(II) iodide (0.037 g, 0.12 mmol) and ethyl 2-mercaptoacetate (0.05 g, 0.46 mmol), and the reaction mixture was stirred at RT for 1 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with water (5 mL), and the aqueous layer was extracted with DCM (2 × 10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. 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: 82% (0.11 g, off-white solid). 1 H NMR (400 MHz, DMSO-d6): δ 7.59 (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. 6.67 min, 99.83% (max).

[0386] Intermediate 51 Methyl 2-(((3,3-dibutyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)methyl)thio)-2-methylpropanoate

[0387]

Chem.

[0388] 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, methyl 2-mercapto-2-methylpropanoate (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 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with water (5 mL) and the aqueous layer was extracted with DCM (2 × 15 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The obtained crude material was purified by Isolera column chromatography (eluent: 17% EtOAc / PE; silica gel: 230 - 400 mesh) to afford the title compound. Yield: 87% (0.4 g, white solid). 1 H NMR (400 MHz, DMSO-d6): δ 7.57 (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).

[0389] Intermediate 52 Methyl 2-(((3-butyl-3-ethyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)methyl)thio)-2-methylpropanoate

[0390]

Chem.

[0391] 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; 0.4 g, 0.89 mmol) in DCM (10 mL) at 0 °C, methyl 2-mercapto-2-methylpropanoate (0.24 g, 1.78 mmol) and zinc iodide (0.14 g, 0.45 mmol) were added and the reaction mixture was stirred at RT for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with water (5 mL) and the aqueous layer was extracted with DCM (2 × 15 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The resulting 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). 1 H NMR (400 MHz, DMSO-d6): δ 7.58 (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), 2.89 (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).

[0392] Intermediate 53 Methyl 2-(((3-butyl-3-ethyl-7-methoxy-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)methyl)thio)-2-methylpropanoate

[0393]

Chem.

[0394] 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, methyl 2-mercapto-2-methylpropanoate (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 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with water (15 mL) and the aqueous layer was extracted with DCM (2 × 15 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na2SO4. The organic portion was filtered and concentrated under vacuum. The crude obtained was 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).

[0395] Intermediate 54 7-Bromo-3-butyl-8-hydroxy-3-methyl-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide

[0396]

Chem.

[0397] 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 dropwise BBr3 (1 M in DCM, 11.05 mL, 11.05 mmol), and the reaction mixture was stirred for 10 minutes. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with methanol (10 mL) 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 afford the title compound. Yield: 89% (2.1 g, brown solid). LCMS: (Method E) 440.1 (M + +2), Rt. 2.57 min, 96.55% (max).

[0398] Intermediate 55 3-Butyl-8-hydroxy-7-methoxy-3-methyl-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide

[0399]

Chemical Structure

[0400] 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 h. 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 (2 × 25 mL). The combined organic layers were washed with water (15 mL), brine (15 mL), and dried over anhydrous Na2SO4. The organic layer was filtered and concentrated under vacuum, 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: 85% (1.6 g, brown solid). LCMS: (Method A) 390.1 (M + +H), Rt. 2.94 min, 99.05% (max).

[0401] Intermediate 56 3-Butyl-7-methoxy-3-methyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl trifluoromethanesulfonate

[0402]

Chem.

[0403] 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) was added dropwise, followed by dropwise addition of trifluoromethanesulfonic anhydride (0.55 mL, 3.34 mmol). The reaction mixture was stirred at RT for 1 h. 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 (2 × 50 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), and dried over anhydrous Na2SO4. The organic portion was filtered and concentrated under vacuum, and the resulting crude material was purified by Isolera column chromatography (eluent: 20% EtOAc / PE; silica gel: 230 - 400 mesh). The obtained sticky solid was triturated with petroleum ether (2 × 10 mL) and dried under vacuum to give the title compound. Yield: 73.9% (1.3 g, off-white solid). 1 1H NMR (400 MHz, CDCl3): δ 7.87 (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. 2.77 min, 99.09% (max).

[0404] Intermediate 57 Methyl 3-butyl-7-methoxy-3-methyl-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-carboxylate 1,1-dioxide

[0405]

Chem.

[0406] To a solution of 3-butyl-7-methoxy-3-methyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-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 Pd2(dba)3 (0.11 g, 0.13 mmol) at RT. The resulting reaction mixture was stirred in an autoclave at 75 °C for 16 h under a carbon monoxide gas pressure of 5 kg. 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 × 50 mL). The combined organic layers were washed with water (15 mL), brine (15 mL) and dried over anhydrous Na2SO4. The organic portion was filtered and concentrated under vacuum, and the resulting crude material was purified by Isolera column chromatography (eluent: 15% EtOAc / PE; silica gel: 230 - 400 mesh) to afford the title compound. Yield: 64.24% (0.7 g, off-white solid). 1 H NMR (400 MHz, CDCl3): δ 8.58 (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), 3.37 - 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. 2.72 min, 99.28 % (max).

[0407] Intermediate 58 3-Butyl-8-(hydroxymethyl)-7-methoxy-3-methyl-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide

[0408]

Chem.

[0409] To a stirred solution of methyl 3-butyl-7-methoxy-3-methyl-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-carboxylate 1,1-dioxide (Intermediate 57; 0.7 g, 1.62 mmol) in THF (10 mL) was added dropwise lithium aluminum hydride (2 M in THF, 0.81 mL, 1.62 mmol) at 0 °C, and the reaction mixture was stirred at RT for 1 h. 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 (2 × 25 mL). The combined organic layers were washed with water (15 mL), brine (15 mL), and dried over anhydrous Na2SO4. The organic portion was filtered and concentrated under vacuum, and the resulting crude product was sent to the next step without further purification. Yield: 600 mg (crude, off-white solid). 1 H NMR (400 MHz, CDCl3): δ 7.94 (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. 2.44 min, 99.91% (max).

[0410] Intermediate 59 Ethyl 2-(((3-butyl-7-methoxy-3-methyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)methyl)thio)acetate

[0411]

Chem.

[0412] 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; 0.3 g, 0.74 mmol) in DCM (10 mL) at 0 °C, ethyl 2-mercaptoacetate (0.18 g, 1.49 mmol) and zinc(II) iodide (0.12 g, 0.37 mmol) were added and the reaction mixture was stirred at RT for 1 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with water (20 mL) and the aqueous layer was extracted with DCM (2 × 20 mL). The combined organic portions were washed with brine (20 mL) and dried over anhydrous Na2SO4. The organic portion was filtered and concentrated under vacuum. The obtained crude material was 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).

[0413] Intermediate 60 7-Bromo-3-butyl-5-(4-fluorophenyl)-8-hydroxy-2-methyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide

[0414]

Chem.

[0415] 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) was added dropwise BBr3 (1 M in DCM, 4.24 mL, 4.24 mmol) at -15 °C, and the reaction mixture was stirred at that temperature for 10 minutes. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with methanol (15 mL), and the reaction mixture was concentrated under vacuum. The obtained crude material was purified by Isolera column chromatography (eluent: 0 - 30% EtOAc / PE; silica gel: 230 - 400 mesh) to afford the title compound. Yield: 80% (1.6 g, brown solid). 1 1H NMR (400 MHz, DMSO-d6): δ 11.09 (s,1H), 7.50 (s, 1H), 7.45 (s, 1H), 7.01 (t, J = 8.8 Hz, 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. 2.67 min, 97.17% (max).

[0416] Intermediate 61 3-Butyl-5-(4-fluorophenyl)-8-hydroxy-7-methoxy-2-methyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide

[0417]

Chem.

[0418] 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 h. 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 (2 × 25 mL). The combined organic layers were washed with water (15 mL), brine (15 mL), and dried over anhydrous Na2SO4. The organic layer was filtered and concentrated under vacuum, and 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: 85% (1.4 g, brown solid). 1 1H NMR (400 MHz, DMSO-d6): δ 9.87 (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. 2.27 min, 86.65% (max).

[0419] Intermediate 62 3-Butyl-5-(4-fluorophenyl)-7-methoxy-2-methyl-1,1-dioxide-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl trifluoromethanesulfonate

[0420]

Chemical Structure

[0421] 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 were added dropwise pyridine (0.55 mL, 6.85 mmol) and trifluoromethanesulfonic anhydride (0.86 mL, 5.14 mmol), and the reaction mixture was stirred at RT for 1 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice-cold water (20 mL), and the aqueous layer was extracted with DCM (2 × 50 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), and dried over anhydrous Na2SO4. The organic portion was filtered and concentrated under vacuum, and the resulting crude material was purified by Isolera column chromatography (eluent: 20% EtOAc / PE; silica gel: 230 - 400 mesh) to afford a sticky solid. This sticky solid was triturated with petroleum ether (2 × 10 mL) and dried under vacuum to give the title compound. Yield: 76% (1.5 g, off-white solid). 1 H NMR (400 MHz, DMSO-d6): δ 7.78 (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. 2.74 min, 94.32% (max).

[0422] Intermediate 63 Methyl 3-butyl-5-(4-fluorophenyl)-7-methoxy-2-methyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-carboxylate 1,1-dioxide

[0423]

Chem.

[0424] To a solution of 3-butyl-5-(4-fluorophenyl)-7-methoxy-2-methyl-1,1-dioxide-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl trifluoromethanesulfonate (Intermediate 62; 1.5 g, 2.77 mmol) in degassed methanol (15 mL) and DMF (10 mL) was added triethylamine (0.58 mL, 4.16 mmol), dppf (0.18 g, 0.33 mmol) and Pd2(dba)3 (0.15 g, 0.16 mmol) at RT. The resulting reaction mixture was stirred at 75 °C for 16 h in an autoclave under a carbon monoxide gas pressure of 5 kg. 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 × 50 mL). The combined organic layers were washed with water (15 mL), brine (15 mL) and dried over anhydrous Na2SO4. The organic portion was filtered and concentrated under vacuum, and the resulting crude material was purified 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). 1 H NMR (400 MHz, DMSO-d6): δ 8.15 (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. 3.08 min, 97.59% (max).

[0425] Intermediate 64 3-Butyl-5-(4-fluorophenyl)-8-(hydroxymethyl)-7-methoxy-2-methyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide

[0426]

Chem.

[0427] To a stirred solution of methyl 3-butyl-5-(4-fluorophenyl)-7-methoxy-2-methyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-carboxylate 1,1-dioxide (Intermediate 63; 1.1 g, 2.44 mmol) in THF (10 mL) was added lithium aluminum hydride (1 M in THF, 2.44 mL, 2.44 mmol) at 0 °C and the reaction mixture was stirred at RT for 1 h. 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 (2 × 15 mL). The combined organic layers were washed with water (10 mL), brine (10 mL) and dried over anhydrous Na2SO4. The organic portion was filtered and concentrated under vacuum and the crude obtained was sent to the next step without further purification. Yield: 87% (0.9 g, off-white solid). 1 H NMR (400 MHz, DMSO-d6): δ 7.89 (s, 1H), 7.02 (t, J = 8.8 Hz, 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).

[0428] Intermediate 65 Ethyl 2-(((3-butyl-5-(4-fluorophenyl)-7-methoxy-2-methyl-1,1-dioxide-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)methyl)thio)acetate

[0429]

Chem.

[0430] 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) was added ethyl 2-mercaptoacetate (0.199 g, 1.66 mmol) and zinc iodide (0.13 g, 0.41 mmol) at 0 °C, and the reaction mixture was stirred at RT for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with water (5 mL), and the aqueous layer was extracted with DCM (2 × 15 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The resulting 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). 1 H NMR (400 MHz, DMSO-d6): δ 7.74 (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).

[0431] Intermediate 66 7-Bromo-3,3-dibutyl-8-hydroxy-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide

[0432]

Chem.

[0433] 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) was added dropwise BBr3 (1 M in DCM, 12.86 mL, 12.86 mmol) at -15 °C, and the reaction mixture was stirred for 10 minutes. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with methanol (10 mL) 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: 86% (2.5 g, brown solid). LCMS: (Method A) 480.0 (M + +H), Rt. 3.16 min, 70.09% (max).

[0434] Intermediate 67 3,3-Dibutyl-8-hydroxy-7-methoxy-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide

[0435]

Chem.

[0436] 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 h. 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 (2 × 50 mL). The combined organic layers were washed with water (25 mL), brine (25 mL) and dried over anhydrous Na2SO4. The organic layer was filtered and concentrated under vacuum, 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: 59.4% (1.2 g, brown solid). LCMS: (Method A) 430.1 (M + +H), Rt. 2.70 min, 89.19% (max).

[0437] Intermediate 68 3,3-Dibutyl-7-methoxy-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl trifluoromethanesulfonate

[0438] [Chemical Structure]

[0439] 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) was added dropwise, followed by dropwise addition of trifluoromethanesulfonic anhydride (0.46 mL, 2.78 mmol). The reaction mixture was stirred at RT for 1 h. 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 (2 × 50 mL). The combined organic layers were washed with water (5 mL), brine (5 mL), and dried over anhydrous Na2SO4. The organic portion was filtered and concentrated under vacuum, and the resulting crude material was purified by Isolera column chromatography (eluent: 20% EtOAc / PE; silica gel: 230 - 400 mesh). The sticky solid of the obtained compound was triturated with petroleum ether (2 × 10 mL) and dried under vacuum to give the title compound. Yield: 61% (1.1 g, off-white solid). LCMS: (Method A) 564.1 (M + +H), Rt. 3.31 min, 89.09% (max).

[0440] Intermediate 69 Methyl 3,3-dibutyl-7-methoxy-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-carboxylate 1,1-dioxide

[0441]

Chemical Structure

[0442] A solution of 3,3-dibutyl-7-methoxy-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl trifluoromethanesulfonate (Intermediate 68; 1.10 g, 1.95 mmol) in degassed methanol (10 mL) and DMF (15 mL) was added with triethylamine (0.29 g, 2.93 mmol), dppf (0.13 g, 0.23 mmol) and Pd2(dba)3 (0.09 g, 0.09 mmol) at RT. The resulting reaction mixture was stirred at 70 °C for 16 h in an autoclave under a carbon monoxide gas pressure of 5 kg. 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 × 50 mL). The combined organic layers were washed with water (15 mL), brine (15 mL), dried over anhydrous Na2SO4. The organic portion was filtered and concentrated under vacuum, and the resulting crude was purified 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). LCMS: (Method A) 474.1 (M + +H), Rt. 3.08 min, 86.01% (max).

[0443] Intermediate 70 3,3-Dibutyl-8-(hydroxymethyl)-7-methoxy-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide

[0444]

Chem.

[0445] To a stirred solution of methyl 3,3-dibutyl-7-methoxy-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-carboxylate 1,1-dioxide (Intermediate 69; 0.8 g, 1.69 mmol) in THF (10 mL) was added dropwise lithium aluminum hydride (2 M in THF, 1.69 mL, 1.69 mmol) at 0 °C and the reaction mixture was stirred at RT for 1 h. 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 (2 × 50 mL). The combined organic layers were washed with water (20 mL), brine (20 mL) and dried over anhydrous Na2SO4. The organic portion was filtered and concentrated under vacuum and the crude obtained was carried forward to the next step without further purification. Yield: 95% (0.75 g, off-white solid). LCMS: (Method E) 446.3 (M + +H), Rt. 2.66 min, 95.15% (max).

[0446] Intermediate 71 Ethyl 2-(((3,3-dibutyl-7-methoxy-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)methyl)thio)acetate

[0447]

Chemical Structure

[0448] 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; 0.2 g, 0.45 mmol) in DCM (5 mL) at 0 °C, ethyl 2-mercaptoacetate (0.108 g, 0.89 mmol) and zinc(II) iodide (0.07 g, 0.22 mmol) were added and the reaction mixture was stirred at RT for 1 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with water (15 mL) and the aqueous layer was extracted with DCM (2 × 20 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na2SO4. The organic portion was filtered and concentrated under vacuum. 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: 61% (0.15 g, white solid).

[0449] Intermediate 72 7-Bromo-3,3-dibutyl-5-(4-fluorophenyl)-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide

[0450] [Chemical formula]

[0451] 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, BBr3 (1 M solution in DCM, 3.90 mL, 3.90 mmol) was added dropwise at -15 °C and the reaction mixture was stirred for 10 minutes. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with methanol (20 mL) and the organic portion was concentrated under vacuum. The resulting solid was partitioned between water (5 mL) and EtOAc (5 mL) and the aqueous layer was extracted with EtOAc (2 × 15 mL). The combined organic layers were washed with water (10 mL) and brine (15 mL) and then dried over anhydrous Na2SO4. The organic portion was filtered and concentrated under vacuum 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: 87% (1.69 g, white solid). LCMS: (Method A) 496.1 (M + -H), Rt. 3.07 min, 94.28% (max).

[0452] Intermediate 73 3,3-Dibutyl-5-(4-fluorophenyl)-8-hydroxy-7-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide

[0453]

Chemical Structure

[0454] 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 copper(I) bromide (0.59 g, 4.16 mmol) at room temperature and the reaction mixture was heated at 85 °C for 6 h. 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 (2 × 25 mL). The combined organic layers were washed with water (15 mL) and brine (15 mL), dried over anhydrous Na2SO4. The organic layer was filtered and concentrated under vacuum 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: 97% (1.5 g, brown solid). LCMS: (Method A) 450.2 (M + +H), Rt. 3.26 min, 98.43% (max).

[0455] Intermediate 74 3,3-Dibutyl-5-(4-fluorophenyl)-7-methoxy-1,1-dioxide-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl trifluoromethanesulfonate

[0456]

Chem.

[0457] 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) was added dropwise, followed by dropwise addition of trifluoromethanesulfonic anhydride (0.56 mL, 0.33 mmol), and the reaction mixture was stirred at RT for 30 min. 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 (2 × 20 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), and dried over anhydrous Na2SO4. The organic portion was filtered and concentrated under vacuum, and the resulting crude material was purified by Isolera column chromatography (eluent: 8 - 10% EtOAc / PE; silica gel: 230 - 400 mesh) to afford the title compound. Yield: 77% (1.5 g, off-white solid). LCMS: (Method G) 582.0 (M + +H), Rt. 2.76 min, 99.01% (max).

[0458] Intermediate 75 Methyl 3,3-dibutyl-5-(4-fluorophenyl)-7-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-carboxylate 1,1-dioxide

[0459]

Chem.

[0460] To a solution of 3,3-dibutyl-5-(4-fluorophenyl)-7-methoxy-1,1-dioxide-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl trifluoromethanesulfonate (Intermediate 74; 1.50 g, 2.58 mmol) in degassed methanol (15 mL) and DMF (10 mL) were added triethylamine (0.75 mL, 5.42 mmol), dppf (0.24 g, 0.43 mmol) and Pd2(dba)3 (0.16 g, 0.18 mmol) at RT. The resulting reaction mixture was stirred at 75 °C for 16 h. In an autoclave under a carbon monoxide gas pressure of 5 kg. 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 × 20 mL). The combined organic layers were washed with water (10 mL), brine (10 mL) and dried over anhydrous Na2SO4. The organic layer was filtered and concentrated under vacuum, and the resulting crude material was purified 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). 1 1H NMR (400 MHz, DMSO-d6): δ 8.25 (s, 1H), 7.54 - 7.51 (m, 2H), 7.30 - 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. 3.05 min, 97.78% (max).

[0461] Intermediate 76 3,3-Dibutyl-5-(4-fluorophenyl)-8-(hydroxymethyl)-7-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide

[0462] [Chemistry]

[0463] To a stirred solution of methyl 3,3-dibutyl-5-(4-fluorophenyl)-7-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-carboxylate 1,1-dioxide (Intermediate 75; 1.5 g, 3.05 mmol) in THF (10 mL) at 0 °C was added dropwise lithium aluminum hydride (2 M in THF, 1.53 mL, 3.05 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 solution (5 mL), and the aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with water (15 mL), brine (15 mL), and dried over anhydrous Na2SO4. The organic portion was filtered and concentrated under vacuum, and the resulting crude product was purified 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).

[0464] Intermediate 77 Ethyl 2-(((3,3-dibutyl-5-(4-fluorophenyl)-7-methoxy-1,1-dioxide-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)methyl)thio)acetate

[0465] [Chemistry]

[0466] 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 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with water (5 mL) and the aqueous layer was extracted with DCM (2 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude obtained was purified by Isolera column chromatography (eluent: 0 - 30% EtOAc / PE; silica gel: 230 - 400 mesh) to afford the title compound. Yield: 82% (0.1 g, brown gum).

[0467] Intermediate 78 7-Bromo-3-butyl-3-ethyl-5-(4-fluorophenyl)-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide

[0468]

Chem.

[0469] 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 dropwise BBr3 (1 M in DCM, 12.39 mL, 12.39 mmol), and the reaction mixture was stirred for 10 minutes. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with methanol (15 mL), 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% (2.38 g, brown solid). 1 1H NMR (400 MHz, DMSO-d6): δ 10.83 (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. 2.46 min, 97.17% (max).

[0470] Intermediate 79 3-Butyl-3-ethyl-5-(4-fluorophenyl)-8-hydroxy-7-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide

[0471]

Chemical formula

[0472] 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 h. 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 (2 × 25 mL). The combined organic layers were washed with water (15 mL), brine (15 mL) and dried over anhydrous Na2SO4. The organic layer was filtered and concentrated under vacuum, 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: 95% (2.0 g, brown solid). LCMS: (Method E) 422.3 (M + +H), Rt. 2.45 min, 98.53% (max).

[0473] Intermediate 80 3-Butyl-3-ethyl-5-(4-fluorophenyl)-7-methoxy-1,1-dioxide-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl trifluoromethanesulfonate

[0474]

Chem.

[0475] 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) was added dropwise followed by trifluoromethanesulfonic anhydride (0.8 mL, 4.74 mmol). The reaction mixture was stirred at RT for 1 h. 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 (2 × 50 mL). The combined organic layers were washed with water (10 mL), brine (10 mL) and dried over anhydrous Na2SO4. The organic portion was filtered and concentrated under vacuum. The resulting crude material was purified by Isolera column chromatography (eluent: 20% EtOAc / PE; silica gel: 230 - 400 mesh) to afford a sticky solid. The obtained sticky solid was triturated with petroleum ether (2 × 10 mL) and dried under vacuum to give the title compound. Yield: 74.6% (2 g, off-white solid). LCMS: (Method E) 554.2 (M + +H), Rt. 2.82 min, 98.24% (max).

[0476] Intermediate 81 Methyl 3-butyl-3-ethyl-5-(4-fluorophenyl)-7-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-carboxylate 1,1-dioxide

[0477]

Chemical Structure

[0478] A solution of 3-butyl-3-ethyl-5-(4-fluorophenyl)-7-methoxy-1,1-dioxide-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl trifluoromethanesulfonate (Intermediate 80; 2 g, 3.61 mmol) in degassed methanol (15 mL) and DMF (10 mL) was added with triethylamine (0.75 mL, 5.42 mmol), dppf (0.24 g, 0.43 mmol) and Pd2(dba)3 (0.17 g, 0.18 mmol) at RT. The resulting reaction mixture was stirred at 75 °C for 16 h in an autoclave under a carbon monoxide gas pressure of 5 kg. 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 × 50 mL). The combined organic layers were washed with water (15 mL), brine (15 mL) and dried over anhydrous Na2SO4. The organic portion was filtered and concentrated under vacuum, and the resulting crude material was purified 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). 1 H NMR (400 MHz, CDCl3): δ 8.58 (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. 2.78 min, 98.72% (max).

[0479] Intermediate 82 3-Butyl-3-ethyl-5-(4-fluorophenyl)-8-(hydroxymethyl)-7-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide

[0480] [Chemistry]

[0481] To a stirred solution of methyl 3-butyl-3-ethyl-5-(4-fluorophenyl)-7-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-carboxylate 1,1-dioxide (Intermediate 81; 1.5 g, 3.24 mmol) in THF (10 mL) was added dropwise lithium aluminum hydride (2 M in THF, 1.62 mL, 3.24 mmol) at 0 °C, and the reaction mixture was stirred at RT for 1 h. 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 (2 × 15 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), and dried over anhydrous Na2SO4. The organic portion was filtered and concentrated under vacuum, and the resulting crude material was sent to the next step without further purification. Yield: 98% (1.4 g, off-white solid). 1 H NMR (400 MHz, CDCl3): δ 7.94 (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), 3.63 (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).

[0482] Intermediate 83 Methyl 2-(((3-butyl-3-ethyl-5-(4-fluorophenyl)-7-methoxy-1,1-dioxide-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)methyl)thio)-2-methylpropanoate

[0483] [Chemistry]

[0484] 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; 500 mg, 1.15 mmol) in DCM (5 mL) at 0 °C, methyl 2-mercapto-2-methylpropanoate (308 mg, 2.29 mmol) and zinc(II) iodide (183 mg, 0.57 mmol) were added and the reaction mixture was stirred at RT for 1 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with water (15 mL) and the aqueous layer was extracted with DCM (2 × 20 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na2SO4. The organic portion was filtered and concentrated under vacuum. 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: 79% (0.5 g, white solid).

[0485] Intermediate 84 7-Bromo-3-butyl-8-hydroxy-2-methyl-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide

[0486]

Chemical formula

[0487] 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 dropwise BBr3 (1 M in DCM, 1.17 mL, 12.35 mmol), and the reaction mixture was stirred for 10 minutes. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with methanol (10 mL) 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: 75% (2.1 g, brown solid). LCMS: (Method A) 439.0 (M + ), Rt. 2.50 min, 97.55% (max).

[0488] Intermediate 85 3-Butyl-8-hydroxy-7-methoxy-2-methyl-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide

[0489] [Chemical formula]

[0490] 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 h. 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 (2×25 mL). The combined organic layers were washed with water (15 mL) and brine (15 mL), and dried over anhydrous Na2SO4. The organic layer was filtered and concentrated under vacuum, 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: 79% (1.45 g, brown solid). LCMS: (Method A) 391.2 (M + +H), Rt. 2.46 min, 98.62% (max).

[0491] Intermediate 86 3-Butyl-7-methoxy-2-methyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl trifluoromethanesulfonate

[0492]

Chem.

[0493] 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) was added dropwise, followed by dropwise addition of trifluoromethanesulfonic anhydride (0.64 mL, 3.84 mmol). The reaction mixture was stirred at RT for 1 h. 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 (2 × 50 mL). The combined organic layers were washed with water (10 mL) and brine (10 mL), and dried over anhydrous Na2SO4. The organic portion was filtered and concentrated under vacuum. The resulting crude material was purified by Isolera column chromatography (eluent: 20% EtOAc / PE; silica gel: 230 - 400 mesh) to give a sticky solid. The obtained solid was triturated with petroleum ether (2 × 10 mL) and dried under vacuum to give the title compound. Yield: 74.6% (1.5 g, off-white solid). 1 1H NMR (400 MHz, CDCl3): δ 7.80 (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).

[0494] Intermediate 87 Methyl 3-butyl-7-methoxy-2-methyl-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-carboxylate 1,1-dioxide

[0495]

Chemical Structure

[0496] A solution of 3-butyl-7-methoxy-2-methyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl trifluoromethanesulfonate (Intermediate 86; 1.5 g, 2.87 mmol) in degassed methanol (15 mL) and dry DMF (10 mL) was added with triethylamine (0.39 mL, 2.87 mmol), dppf (0.19 g, 0.34 mmol) and Pd2(dba)3 (0.13 g, 0.14 mmol) at RT. The resulting reaction mixture was stirred at 75 °C for 16 h in an autoclave under a carbon monoxide gas pressure of 5 kg. 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 × 50 mL). The combined organic layers were washed with water (15 mL), brine (15 mL) and dried over anhydrous Na2SO4. The organic layer was filtered and concentrated under vacuum, and the resulting crude material was purified 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). LCMS: (Method B) 433.1 (M + +H), Rt. 2.45 min, 97.35% (max).

[0497] Intermediate 88 3-Butyl-8-(hydroxymethyl)-7-methoxy-2-methyl-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide

[0498]

Chem.

[0499] A stirred solution of methyl 3-butyl-7-methoxy-2-methyl-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-carboxylate 1,1-dioxide (Intermediate 87; 0.9 g, 2.08 mmol) in THF (10 mL) was added dropwise with lithium aluminum hydride (2 M in THF, 2.08 mL, 4.16 mmol) at 0 °C, and the reaction mixture was stirred at RT for 1 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with saturated NH4Cl solution (10 mL), and the aqueous layer was extracted with EtOAc (2 × 25 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), and dried over anhydrous Na2SO4. The organic portion was filtered and concentrated under vacuum, and the obtained crude product was sent to the next step without further purification. Yield: 87% (0.8 g, off-white solid). 1 1H NMR (400 MHz, CDCl3): δ 7.92 (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).

[0500] Intermediate 89 Ethyl 2-(((3-butyl-7-methoxy-2-methyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)methyl)thio)acetate

[0501]

Chemical Structure

[0502] 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; 0.4 g, 0.98 mmol) in DCM (5 mL) at 0 °C, ethyl 2-mercaptoacetate (0.12 g, 0.99 mmol) and zinc(II) iodide (0.32 g, 0.99 mmol) were added and the reaction mixture was stirred at RT for 1 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with water (15 mL) and the aqueous layer was extracted with DCM (2 × 20 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na2SO4. The organic portion was filtered and concentrated under vacuum. The obtained crude material was purified by Isolera column chromatography (eluent: 20% EtOAc / PE; silica gel: 230 - 400 mesh) to afford the title compound. Yield: 69.9% (0.35 g, white solid).

[0503] Intermediate 90 Methyl 2-(((3-butyl-7-methoxy-2-methyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)methyl)thio)-2-methylpropanoate

[0504] [Chemical Structure]

[0505] 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; 0.4 g, 0.99 mmol) in DCM (5 mL) at 0 °C, ethyl 2-mercaptoacetate (0.12 g, 0.99 mmol) and zinc(II) iodide (0.32 g, 0.99) were added and the reaction mixture was stirred at RT for 1 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with water (5 mL) and the aqueous layer was extracted with DCM (2 × 20 mL). The combined organic portions were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The obtained crude material was purified by Isolera column chromatography (eluent: 20% EtOAc / PE; silica gel: 230 - 400 mesh) to afford the title compound. Yield: 58.3% (0.3 g, white solid).

[0506] Intermediate 91 Ethyl 2-(((3-butyl-3-ethyl-5-(4-fluorophenyl)-7-methoxy-1,1-dioxide-2,3,4,5-tetrahydro-1,5-benzothiadiazepin-8-yl)methyl)thio)acetate

[0507]

Chem.

[0508] 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 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with water (5 mL) and the aqueous layer was extracted with DCM (2 × 15 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na2SO4. The organic portion was filtered and concentrated under vacuum. The obtained crude material was purified by Isolera column chromatography (eluent: 20% EtOAc / PE; silica gel: 230 - 400 mesh) to afford the title compound. Yield: 81% (500 mg, white solid).

[0509] Intermediate 92 Methyl 2-(((3-butyl-7-methoxy-3-methyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)methyl)thio)-2-methylpropanoate

[0510]

Chemical Structure

[0511] 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; 0.25 g, 0.62 mmol) in DCM (10 mL) at 0 °C was added methyl 2-mercapto-2-methylpropanoate (0.083 g, 0.62 mmol) and zinc(II) iodide (0.39 g, 1.24 mmol), and the reaction mixture was stirred at RT for 1 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with water (5 mL) and the aqueous layer was extracted with DCM (2 × 15 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. 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: 78% (0.25 g, white solid).

[0512] Intermediate 93 Methyl 2-(((3,3-dibutyl-7-methoxy-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)methyl)thio)-2-methylpropanoate

[0513] [Chemical formula]

[0514] 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 was added methyl 2-mercapto-2-methylpropanoate (60.2 mg, 0.45 mmol) and zinc(II) iodide (143 mg, 0.45 mmol), and the reaction mixture was stirred at RT for 1 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with water (5 mL), and the aqueous layer was extracted with DCM (2 × 15 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. 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: 91% (230 mg, white solid).

[0515] Intermediate 94 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

[0516] [Chemical formula]

[0517] To a stirred solution of 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) in NMP (40 mL) at 0 °C was added dropwise Cs2CO3 (5.56 g, 17.13 mmol), then 1-(chloromethyl)-4-methoxybenzene (2.01 g, 12.84 mmol), and the reaction mixture was stirred at RT for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water (50 mL), and the aqueous layer was extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting 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). LCMS: (Method G) 587.1 (M + +H), Rt. 2.92 min, 63.50% (max).

[0518] Intermediate 95 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

[0519]

Chemical Structure

[0520] 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 h. 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 crude product obtained was purified by Isolera column chromatography (eluent: 0 - 15% EtOAc / PE; silica gel: 230 - 400 mesh) to afford the title compound. Yield: 28% (1.4 g, off-white solid). LCMS: (Method E) 575.1 (M + +2), Rt. 2.71 min, 97.53% (max).

[0521] Intermediate 96 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

[0522]

Chemical Structure

[0523] 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) at 0 °C were added sodium methoxide (25% in methanol, 2 mL, 8.72 mmol) and copper(I) bromide (0.25 g, 1.74 mmol), and the reaction mixture was stirred at 75 °C for 16 h. 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), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The obtained 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). LCMS: (Method B) 523.1 (M + -H), Rt. 2.71 min, 85.40% (maximum).

[0524] Intermediate 97 3-Butyl-3-ethyl-7-methoxy-2-(4-methoxybenzyl)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl trifluoromethanesulfonate

[0525] [Chemical formula]

[0526] 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 was added pyridine (0.21 mL, 2.52 mmol), followed by triflic anhydride (0.32 mL, 1.89 mmol), and the reaction mixture was stirred at RT for 1 h. 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 (2 × 25 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product obtained was purified by Isolera column chromatography (eluent: 0 - 30% EtOAc / PE; silica gel: 230 - 400 mesh) to afford the title compound. Yield: 76% (0.65 g, off-white solid).

[0527] Intermediate 98 Methyl 3-butyl-3-ethyl-7-methoxy-2-(4-methoxybenzyl)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-carboxylate 1,1-dioxide

[0528] [Chemical formula]

[0529] A stirred solution of 3-butyl-3-ethyl-7-methoxy-2-(4-methoxybenzyl)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl trifluoromethanesulfonate (Intermediate 97; 650 mg, 0.99 mmol) in methanol (10 mL) and DMF (5 mL) was purged with nitrogen gas for 15 minutes. Then, Pd2(dba)3 (91 mg, 0.10 mmol), triethylamine (0.27 mL, 1.98 mmol) and dppf (54.9 mg, 0.10 mmol) were added and the reaction mixture was stirred at 70 °C for 16 h in a tinyclave under a carbon monoxide gas pressure of 5 kg. After completion of the reaction (monitored by UPLC), the reaction mixture was filtered through a bed of celite and the crude compound was produced by concentrating the filtrate. The obtained crude was purified by Isolera column chromatography (eluent: 0 - 30% EtOAc / PE; silica gel: 230 - 400 mesh) to give the title compound. Yield: 34% (0.21 g, white solid). LCMS: (Method B) 567.3 (M + +H) Rt. 2.74 min, 91.55% (max).

[0530] Intermediate 99 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

[0531]

Chemical Structure

[0532] A stirred solution of methyl 3-butyl-3-ethyl-7-methoxy-2-(4-methoxybenzyl)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-carboxylate 1,1-dioxide (Intermediate 98; 20 mg, 0.04 mmol) in THF (10 mL) was treated dropwise with LiAlH4 (2 M solution in THF, 0.035 mL, 0.04 mmol) at 0 °C and the reaction mixture was stirred at RT for 30 min. After completion of the reaction (monitored by TLC), the reaction mixture was quenched at 0 °C with saturated aqueous ammonium chloride solution (25 mL) and the aqueous layer was extracted with EtOAc (15 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product was carried on to the next step without further purification. Yield: 89% (19 mg, crude). LCMS: (Method B) 539.1 (M + +H), Rt. 2.60 min, 92.50% (max)

[0533] Intermediate 100 Ethyl 2-(((3-butyl-3-ethyl-7-methoxy-2-(4-methoxybenzyl)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)methyl)thio)acetate

[0534]

Chemical Structure

[0535] 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 was added ethyl 2-mercaptoacetate (39.0 mg, 0.32 mmol), followed by zinc iodide (104 mg, 0.32 mmol). The reaction mixture was then stirred at RT for 3 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated and quenched with water (30 mL). The aqueous layer was extracted with EtOAc (2 × 15 mL). The combined organic layers were separated, dried over anhydrous Na2SO4 and concentrated under high vacuum. The crude product obtained was carried on to the next step without further purification. Yield: 250 mg (crude, off-white solid).

[0536] Intermediate 101 2-(((3-Butyl-3-ethyl-7-methoxy-2-(4-methoxybenzyl)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)methyl)thio)acetic acid

[0537] [Chemical Structure]

[0538] To a stirred solution of ethyl 2-(((3-butyl-3-ethyl-7-methoxy-2-(4-methoxybenzyl)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-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), LiOH (74.7 mg, 3.12 mmol) was added and the reaction mixture was stirred at RT for 1 h. 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, dried over anhydrous Na2SO4 and concentrated under high vacuum. The crude product obtained was purified by Isolera column chromatography (eluent: 0 - 30% EtOAc / PE; silica gel: 230 - 400 mesh) to afford the title compound. Yield: 42% (0.2 g, off-white solid). UPLC: (Method B) 611.0 (M + -H), Rt. 1.51 min, 50.26% (max).

[0539] Intermediate 102 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

[0540]

Chem.

[0541] 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) were added dimethylamine (40% in aqueous solution, 0.2 mL, 1.70 mmol), sodium tert-butoxide (0.49 g, 5.11 mmol), Pd2(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 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water (25 mL) and the aqueous layer was extracted with EtOAc (2 × 25 mL). The organic layer was washed with brine (25 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The obtained 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). LCMS: (Method A) 552.3 (M + +H), Rt. 2.29 min, 92.37% (max).

[0542] Intermediate 103 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

[0543]

Chem.

[0544] 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 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with water (25 mL), and the aqueous layer was extracted with EtOAc (2 × 25 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The obtained 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). LCMS: (Method B) 538.3 (M + +H), Rt. 2.49 min, 91.11% (max).

[0545] Intermediate 104 3-Butyl-7-(dimethylamino)-3-ethyl-2-(4-methoxybenzyl)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl trifluoromethanesulfonate

[0546]

Chemical Structure

[0547] 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 min. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with water (25 mL), and the aqueous layer was extracted with DCM (2 × 25 mL). The combined organic layers were separated, dried over anhydrous Na2SO4, filtered, and concentrated under high vacuum. The obtained 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). LCMS: (Method B), 670.3 (M + +H), Rt. 2.82 min, 72.59% (max).

[0548] Intermediate 105 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

[0549]

Chem.

[0550] A stirred solution of 3-butyl-7-(dimethylamino)-3-ethyl-2-(4-methoxybenzyl)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl trifluoromethanesulfonate (Intermediate 104; 0.4 g, 0.59 mmol) in methanol (15 mL) and DMF (10 mL) was added with triethylamine (0.08 mL, 0.59 mmol), Pd2(dba)3 (0.03 g, 0.03 mmol) and dppf (0.04 g, 0.07 mmol) under nitrogen, and the reaction mixture was stirred at 80 °C for 16 h in a tinyclave under a carbon monoxide gas pressure of 5 kg. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under vacuum and quenched with water (25 mL). The aqueous layer was extracted with EtOAc (2 × 25 mL), the combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The obtained 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. 2.62 min, 44.08% (max).

[0551] Intermediate 106 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

[0552]

Chemical Structure

[0553] 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 with LiALH4 (2 M in THF, 0.69 mL, 1.38 mmol) at 0 °C, and the reaction mixture was stirred at RT for 30 min. 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 (2 × 25 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The resulting crude product was sent to the next step without further purification. Yield: 47% (0.6 g, brown gum). LCMS: (Method B) 552.3 (M + +H), Rt. 2.63 min, 59.0% (max).

[0554] Intermediate 107 Ethyl 2-(((3-butyl-7-(dimethylamino)-3-ethyl-2-(4-methoxybenzyl)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)methyl)thio)acetate

[0555] [Chemical Structure]

[0556] 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 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under vacuum. The resulting solid was quenched with water (20 mL) and the aqueous layer was extracted with EtOAc (2 × 25 mL). The combined organic layers were separated, dried over anhydrous Na2SO4, filtered and concentrated under high vacuum. The resulting crude compound was sent directly to the next step without further purification. Yield: 400 mg (crude, light brown solid).

[0557] Intermediate 108 2-(((3-Butyl-7-(dimethylamino)-3-ethyl-2-(4-methoxybenzyl)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)methyl)thio)acetic acid

[0558]

Chem.

[0559] A stirred solution of ethyl 2-(((3-butyl-7-(dimethylamino)-3-ethyl-2-(4-methoxybenzyl)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)methyl)thio)acetate (Intermediate 107; 0.4 g, 0.61 mmol) in 1,4-dioxane (10 mL) was treated with 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 h. 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 × 25 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude product obtained 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). LCMS: (Method E) 626.2 (M + +H), Rt 2.13 min, 35.5% (max).

[0560] Intermediate 109 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

[0561]

Chemical Structure

[0562] 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 was added oxone (18.19 g, 59.2 mmol), and the reaction mixture was stirred at RT for 16 h. 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 (3 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The obtained 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). LCMS: (Method E) 573.2 (M + +H), Rt 2.44 min, 79.19% (max).

[0563] Intermediate 110 3-Butyl-3-ethyl-2-(4-methoxybenzyl)-7-(methylsulfonyl)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl trifluoromethanesulfonate

[0564]

Chemical Structure

[0565] 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 completion of the reaction (monitored by TLC), the reaction mixture was quenched with water (20 mL), and the aqueous layer was extracted with DCM (2 × 25 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered, 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: 63% (1.5 g, off-white solid).

[0566] Intermediate 111 Methyl 3-butyl-3-ethyl-2-(4-methoxybenzyl)-7-(methylsulfonyl)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-carboxylate 1,1-dioxide

[0567] [Chemical formula]

[0568] A stirred solution of 3-butyl-3-ethyl-2-(4-methoxybenzyl)-7-(methylsulfonyl)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl trifluoromethanesulfonate (Intermediate 110; 3.0 g, 4.26 mmol) in MeOH (20 mL) and DMF (15 mL) was added with triethylamine (0.6 mL, 4.26 mmol), Pd2(dba)3 (0.19 g, 0.21 mmol) and dppf (0.28 g, 0.51 mmol) under nitrogen, and the reaction mixture was stirred at 75 °C for 16 h in a tinyclave under a carbon monoxide gas pressure of 5 kg. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under vacuum. The obtained crude product was quenched with water (20 mL), and the aqueous layer was extracted with EtOAc (2 × 25 mL). The combined organic layers were separated, dried over anhydrous Na2SO4, filtered and concentrated under high vacuum. The obtained 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).

[0569] Intermediate 112 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

[0570] [Chemical formula]

[0571] To a stirred solution of methyl 3-butyl-3-ethyl-2-(4-methoxybenzyl)-7-(methylsulfonyl)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-carboxylate 1,1-dioxide (Intermediate 111; 1.8 g, 2.93 mmol) in THF (10 mL) was added dropwise LiAlH4 (2 M in THF, 1.47 mL, 2.93 mmol) at 0 °C and the reaction mixture was stirred at RT for 30 min. 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 × 20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The obtained crude product was sent directly to the next step without further purification. Yield: 1.8 g (crude, light brown liquid).

[0572] Intermediate 113 Ethyl 2-(((3-butyl-3-ethyl-2-(4-methoxybenzyl)-7-(methylsulfonyl)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)methyl)thio)acetate

[0573] [Chemical Structure]

[0574] 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 was added ethyl 2-mercaptoacetate (0.10 g, 0.85 mmol), followed by zinc(II) iodide (0.27 g, 0.85 mmol), and the reaction mixture was stirred at RT for 3 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under vacuum, the resulting crude was quenched with water (10 mL), and the aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic layers were separated, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The resulting crude was carried on to the next step without further purification. Yield: 500 mg (crude, light brown liquid).

[0575] Intermediate 114 2-(((3-Butyl-3-ethyl-2-(4-methoxybenzyl)-7-(methylsulfonyl)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)methyl)thio)acetic acid

[0576] [Chemical Structure]

[0577] A stirred solution of ethyl 2-(((3-butyl-3-ethyl-2-(4-methoxybenzyl)-7-(methylsulfonyl)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)methyl)thio)acetate (Intermediate 1113; 0.5 g, 0.73 mmol) in 1,4-dioxane (6 mL) was treated with 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 h. 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 × 25 mL). The combined organic layers were separated, dried over anhydrous Na2SO4, filtered, 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 afford the title compound. Yield: 38% (0.3 g, off-white solid).

[0578] Intermediate 115 (R)-7-Bromo-3-butyl-8-methoxy-2-(4-methoxybenzyl)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide

[0579] [Chemical formula]

[0580] 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 Cs2CO3 (3.71 g, 11.38 mmol), followed by dropwise addition of 1-(chloromethyl)-4-methoxybenzene (1.34 g, 8.53 mmol). The reaction mixture was stirred at RT for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water (50 mL) and the aqueous layer was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting 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). LCMS: (Method B) 558.8 (M + ), Rt. 1.91 min, 56.52% (max).

[0581] Intermediate 116 (R)-3-Butyl-7-(dimethylamino)-8-methoxy-2-(4-methoxybenzyl)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide

[0582]

Chem.

[0583] 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 with dimethylamine (0.08 g, 1.70 mmol) and sodium tert-butoxide (0.49 g, 5.11 mmol), and the solution was purged with nitrogen gas for 10 minutes. Then, Pd2(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 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The obtained crude product was purified by Isolera column chromatography (eluent: 20 - 30% EtOAc / PE; silica gel: 230 - 400 mesh) to obtain the title compound. Yield: 52% (1.4 g, brown solid). LCMS: (Method B) 524.3 (M + +H), Rt. 2.87 min, 43.87% (max).

[0584] Intermediate 117 (R)-3-Butyl-7-(dimethylamino)-8-hydroxy-2-(4-methoxybenzyl)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide

[0585]

Chemical Structure

[0586] 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 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with water (20 mL), and the aqueous layer was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The obtained 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). LCMS: (Method E) 510.2 (M + +H), Rt 1.97 min, 68.55% (max).

[0587] Intermediate 118 (R)-3-Butyl-7-(dimethylamino)-2-(4-methoxybenzyl)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl trifluoromethanesulfonate

[0588]

Chemical Structure

[0589] 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. 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 (20 mL), and the aqueous layer was extracted with DCM (2 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The obtained 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). LCMS: (Method E) 642.2 (M + +H), Rt 2.80 min, 79.5% (max).

[0590] Intermediate 119 Methyl (R)-3-butyl-7-(dimethylamino)-2-(4-methoxybenzyl)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-carboxylate 1,1-dioxide

[0591]

Chemical Structure

[0592] To a stirred solution of (R)-3-butyl-7-(dimethylamino)-2-(4-methoxybenzyl)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl trifluoromethanesulfonate (Intermediate 118; 2.8 g, 4.36 mmol) in MeOH (20 mL) and DMF (15 mL), triethylamine (0.61 mL, 4.36 mmol), Pd2(dba)3 (0.20 g, 0.22 mmol) and dppf (0.29 g, 0.52 mmol) were added under a nitrogen atmosphere, and the reaction mixture was stirred at 75 °C for 16 h in a tiny autoclave under a carbon monoxide gas pressure of 5 kg. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated and the resulting mixture was quenched with water (20 mL). The aqueous layer was extracted with EtOAc (2 × 15 mL), the combined organic layers were separated and dried over anhydrous Na2SO4. The organic portion was filtered and concentrated in vacuo, and the resulting crude product was purified 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). LCMS: (Method E) 552.3 (M + +H), Rt. 2.36 min, 62.07% (max).

[0593] Intermediate 120 (R)-3-Butyl-7-(dimethylamino)-8-(hydroxymethyl)-2-(4-methoxybenzyl)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide

[0594]

Chemical Structure

[0595] To a stirred solution of methyl (R)-3-butyl-7-(dimethylamino)-2-(4-methoxybenzyl)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-carboxylate 1,1-dioxide (Intermediate 119; 600 mg, 1.09 mmol) in THF (10 mL) was added dropwise LiAlH4 (2 M in THF, 0.54 mL, 1.09 mmol) at 0 °C, and the reaction mixture was stirred at RT for 30 min. 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 combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product obtained was sent directly to the next step without further purification. 1 1H-NMR (400 MHz, DMSO-d6): δ 7.96 (s, 1H), 7.24 - 7.21 (m, 5H), 6.89 - 6.81 (m, 5H), 5.37 (t, J = 5.6 Hz, 1H), 4.53 (d, J = 5.6 Hz, 2H), 4.15 (bs, 2H), 3.75 (s, 1H), 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 = 6.80 Hz, 3H). LCMS: (Method B) 524.2 (M + +H), Rt 2.63 min, 54.42% (max).

[0596] Intermediate 121 Ethyl (R)-2-(((3-butyl-7-(dimethylamino)-2-(4-methoxybenzyl)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)methyl)thio)acetate

[0597]

Chemical Structure

[0598] 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; 300 mg, 0.57 mmol) in DCM (10 mL) at 0 °C, ethyl 2-mercaptoacetate (68.8 mg, 0.57 mmol) and zinc(II) iodide (183 mg, 0.57 mmol) were added and the reaction mixture was stirred at RT for 3 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under vacuum and quenched with water (20 mL). The aqueous layer was extracted with EtOAc (2 × 25 mL), dried over anhydrous Na2SO4 and concentrated under vacuum. The crude obtained was directly carried on to the next step without further purification.

[0599] Intermediate 122 (R)-2-(((3-Butyl-7-(dimethylamino)-2-(4-methoxybenzyl)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)methyl)thio)acetic acid

[0600] [Chemical Structure]

[0601] A stirred solution of ethyl (R)-2-(((3-butyl-7-(dimethylamino)-2-(4-methoxybenzyl)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)methyl)thio)acetate (Intermediate 121; 300 mg, 0.48 mmol) in 1,4-dioxane (6 mL) was treated with 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 h. 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 × 25 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under high vacuum. The crude product obtained was purified by Isolera column chromatography (eluent: 0 - 50% EtOAc / PE; silica gel: 230 - 400 mesh) to afford the title compound. Yield: 47% (250 mg, white solid). LCMS: (Method B) 598.2 (M + +H), Rt 2.05 min, 54.26% (max).

[0602] Intermediate 123 (R)-3-Butyl-8-hydroxy-2-(4-methoxybenzyl)-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide

[0603]

Chem.

[0604] 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) was added with NaSMe (1.57 g, 22.34 mmol) at RT, and the reaction mixture was stirred at 90 °C for 12 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with water (25 mL), and the aqueous layer was extracted with EtOAc (2 × 25 mL). The organic layer was separated, dried over anhydrous Na2SO4, and concentrated under high vacuum. The obtained 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). LCMS: (Method E) 513.2 (M + +H), Rt. 2.49 min, 87.85% (max).

[0605] Intermediate 124 (R)-3-Butyl-2-(4-methoxybenzyl)-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl trifluoromethanesulfonate

[0606]

Chemical Structure

[0607] 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. The reaction mixture was stirred at RT for 30 min. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with water (20 mL) and the aqueous layer was extracted with DCM (2 × 20 mL). The organic portion was dried over anhydrous Na2SO4 and concentrated under high vacuum. The obtained crude product was purified by Isolera column chromatography (eluent: 0 - 30% EtOAc / PE; silica gel: 230 - 400 mesh) to afford the title compound. Yield: 28% (0.6 g, brown solid).

[0608] Intermediate 125 Methyl (R)-3-butyl-2-(4-methoxybenzyl)-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-carboxylate 1,1-dioxide

[0609] [Chemical formula]

[0610] A stirred solution of (R)-3-butyl-2-(4-methoxybenzyl)-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl trifluoromethanesulfonate (Intermediate 124; 1.2 g, 1.86 mmol) in methanol (20 mL) and DMF (15 mL) was added with triethylamine (0.26 mL, 1.86 mmol), Pd2(dba)3 (0.09 g, 0.09 mmol) and dppf (0.12 g, 0.22 mmol) under nitrogen, and the reaction mixture was stirred at 75 °C for 16 h in a tiny autoclave under a carbon monoxide gas pressure of 5 kg. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under vacuum and quenched with water (10 mL). The aqueous layer was extracted with EtOAc (2 × 15 mL), the organic layer was dried over anhydrous sodium sulfate and concentrated under high vacuum. The crude product obtained was purified by Isolera column chromatography (eluent: 0 - 30% EtOAc / PE; silica gel: 230 - 400 mesh) to give the title compound. Yield: 40% (0.6 g, off-white solid). LCMS: (Method B) 555.1 (M + +H), Rt 2.83 min, 69.63% (max).

[0611] Intermediate 126 (R)-3-Butyl-8-(hydroxymethyl)-2-(4-methoxybenzyl)-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide

[0612]

Chem.

[0613] A stirred solution of methyl (R)-3-butyl-2-(4-methoxybenzyl)-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-carboxylate 1,1-dioxide (Intermediate 125; 0.6 g, 1.08 mmol) in THF (10 mL) was added dropwise with LiAlH4 (2 M in THF, 0.54 mL, 1.08 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 ammonium chloride solution (10 mL) at 0 °C and then extracted with ethyl acetate (2 × 20 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated under vacuum. The obtained crude product was sent directly to the next step without further purification.

[0614] Intermediate 127 Ethyl (R)-2-(((3-butyl-2-(4-methoxybenzyl)-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetate

[0615] [Chemical formula]

[0616] 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; 600 mg, 1.14 mmol) in DCM (5 mL) at 0 °C was added ethyl 2-mercaptoacetate (137 mg, 1.14 mmol) and zinc(II) iodide (364 mg, 1.14 mmol), and the reaction mixture was stirred at RT for 3 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under vacuum and quenched with water (20 mL). The aqueous layer was extracted with EtOAc (2 × 20 mL), and the combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum to give the crude product. The crude material obtained was sent directly to the next step without further purification.

[0617] Intermediate 128 (R)-2-(((3-Butyl-2-(4-methoxybenzyl)-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)methyl)thio)acetic acid

[0618] [Chemical Structure]

[0619] To a stirred solution of ethyl (R)-2-(((3-butyl-2-(4-methoxybenzyl)-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-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 h. 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 × 20 mL). The combined organic layers were separated, dried over anhydrous Na2SO4, and concentrated under vacuum. The crude product obtained 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). LCMS: (Method B), 599.1 (M + -H), Rt. 2.0 min, 53.31% (max).

[0620] Intermediate 129 (R)-7-Bromo-3-butyl-8-hydroxy-2-(4-methoxybenzyl)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide

[0621]

Chemical Structure

[0622] 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) was added lithium chloride (1.14 g, 26.8 mmol) at 0 °C and the reaction mixture was stirred at 120 °C for 24 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold water (20 mL). The solid obtained was collected by filtration and dried under vacuum. The crude material obtained was purified by Isolera column chromatography (eluent: 0 - 30% EtOAc / PE; silica gel: 230 - 400 mesh) to afford the title compound. Yield: 37% (1.0 g, off-white solid). LCMS: (Method A), 544.0 (M + -H), Rt. 2.65 min, 54.3% (max).

[0623] Intermediate 130 (R)-3-Butyl-8-hydroxy-7-methoxy-2-(4-methoxybenzyl)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide

[0624]

Chemical Structure

[0625] 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) was added with sodium methoxide (25% in methanol, 5.5 mL, 6.42 mmol) and copper(I) bromide (0.18 g, 1.28 mmol) at 0 °C, and the reaction mixture was stirred at 75 °C for 16 h. 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 (3 × 100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The obtained crude material was purified by Isolera column chromatography (eluent: 0 - 30% EtOAc / PE; silica gel: 230 - 400 mesh) to afford the title compound. Yield: 69% (0.5 g, off-white solid). LCMS: (Method C), 497.3 (M + +H), Rt. 2.23 min, 88.76% (max).

[0626] Intermediate 131 (R)-3-Butyl-7-methoxy-2-(4-methoxybenzyl)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl trifluoromethanesulfonate

[0627]

Chem.

[0628] 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) at 0 °C, pyridine (0.32 mL, 4.03 mmol) and triflic anhydride (0.5 mL, 3.02 mmol) were added dropwise, and the reaction mixture was stirred at RT for 30 min. 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, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The obtained 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, pale yellow gum).

[0629] Intermediate 132 Methyl (R)-3-butyl-7-methoxy-2-(4-methoxybenzyl)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-carboxylate 1,1-dioxide

[0630]

Chemical Structure

[0631] A stirred solution of 3-butyl-7-methoxy-2-(4-methoxybenzyl)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl trifluoromethanesulfonate (Intermediate 131; 550 mg, 0.88 mmol) in MeOH (10 mL) and DMF (10 mL) was added with triethylamine (0.24 mL, 1.75 mmol), Pd2(dba)3 (80 mg, 0.09 mmol) and dppf (48.5 mg, 0.09 mmol) under nitrogen, and the reaction mixture was stirred at 75 °C for 16 h in a tinyclave under a carbon monoxide gas pressure of 5 kg. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under vacuum, 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: 56% (0.35 g, off-white solid). LCMS: (Method E), 539.1 (M + +H), Rt. 1.89 min, 75.4% (max)

[0632] Intermediate 133 (R)-3-Butyl-8-(hydroxymethyl)-7-methoxy-2-(4-methoxybenzyl)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide

[0633]

Chem.

[0634] A stirred solution of methyl (R)-3-butyl-7-methoxy-2-(4-methoxybenzyl)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-carboxylate 1,1-dioxide (Intermediate 132; 350 mg, 0.65 mmol) in THF (4 mL) was added dropwise with LiAlH4 (2 M in THF, 0.33 mL, 0.65 mmol) at 0 °C, and the reaction mixture was stirred at RT for 30 min. 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 dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The obtained crude product was sent directly to the next step without further purification. Yield: 86% (0.31 g, brown solid). LCMS: (Method C), 511.4 (M + +H), Rt. 2.26 min, 92.18% (max)

[0635] Intermediate 134 Ethyl (R)-2-(((3-butyl-7-methoxy-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)methyl)thio)acetate

[0636]

Chemical Structure

[0637] 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 was added ethyl 2-mercaptoacetate (70.6 mg, 0.59 mmol), followed by zinc iodide (188 mg, 0.59 mmol), and the reaction mixture was stirred at RT for 3 h. The reaction mixture was then quenched with water (10 mL), and the aqueous layer was extracted with EtOAc (2 × 20 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum to give the title compound, which was carried on to the next step without further purification. Yield: 55% (0.28 g, brown gum).

[0638] Intermediate 135 Ethyl 2-aminohexanoate hydrochloride

[0639]

Chem.

[0640] To a stirred solution of 2-aminohexanoic acid (12 g, 91 mmol) in ethanol (130 mL) at 0 °C was added thionyl chloride (33 mL, 457 mmol), and the reaction mixture was heated at 80 °C for 16 h. The reaction mixture was then concentrated under vacuum to give the crude title compound, which was used in the next step without further purification. Yield: 94% (18 g, white solid). LCMS: (Method B) 160.3 (M + +H), Rt. 1.72 min, 93.76% (max).

[0641] Intermediate 136 Ethyl (E)-2-(benzylideneamino)hexanoate

[0642]

Chem.

[0643] 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. Then, magnesium sulfate (11.07 g, 92 mmol) was added portionwise at 0 °C. Benzaldehyde (9.37 mL, 92 mmol) was added to the reaction mixture at 0 °C over 20 minutes, and the reaction mixture was stirred at RT for 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through Celite and the filtrate was concentrated under vacuum. The obtained crude product was dissolved in petroleum ether (1000 mL), filtered again through Celite, and the filtrate was concentrated under vacuum to give the title compound. The crude material was sent to the next step without further purification. Yield: 73.5% (22 g, light brown liquid). LCMS: (Method B) 248.2 (M + +H), Rt. 2.48 min, 93.76% (max).

[0644] Intermediate 137 Ethyl (E)-2-(benzylideneamino)-2-methylhexanoate

[0645]

Chemical Structure

[0646] A stirred solution of NaH (60%, 3.23 g, 81 mmol) in DMF (50 mL) was slowly added dropwise at 0 °C with a solution of ethyl (E)-2-(benzylideneamino)hexanoate (Intermediate 136; 20 g, 81 mmol) in DMF (150 mL) over 30 minutes, and the reaction mixture was stirred at RT for 1.5 hours. Then, methyl iodide (5 mL, 81 mmol) was added at 0 °C, and the reaction mixture was stirred at RT for 1 hour. Then, the reaction mixture was quenched with 2-propanol (10 mL) at 0 °C and diluted with water (500 mL). The aqueous layer was extracted with petroleum ether (2 × 500 mL). The organic layer was washed with brine (200 mL) and dried over anhydrous Na2SO4. The organic portion was concentrated under vacuum, and the resulting crude material was sent to the next step without further purification. Yield: 65.6% (21 g, yellow liquid). LCMS: (Method B) 262.2 (M + +H), Rt. 2.64 min, 66.47% (max).

[0647] Intermediate 138 Ethyl 2-amino-2-methylhexanoate

[0648]

Chemical Structure

[0649] To a stirred solution of ethyl (E)-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 stirred vigorously at RT for 16 hours. The organic layer was separated, and the aqueous layer was washed with EtOAc (2 × 100 mL). Then, the aqueous layer was basified (pH ~8.5) by using solid sodium bicarbonate (5 g) and extracted with EtOAc (2 × 100 mL). Then, the organic layer was washed with water (2 × 25 mL). The combined organic portions were dried over anhydrous Na2SO4 and concentrated under vacuum to afford the title compound. The crude material was sent to the next step as such without further purification. Yield: 39.8% (8 g, pale yellow liquid). LCMS: (Method C) 174.3 (M+ +1), Rt. 1.1 min, 99.74% (max).

[0650] Intermediate 139 2-Amino-2-methyl-N-phenylhexanamide

[0651] ...

Claims

1. Compound of formula (I) 【Chemistry 1】 (In the formula, M is -CH) 2 - or -NR 6 -and, R 1 is C 1～4 It is alkyl, R 2 is hydrogen and C 1～4 Selected from the group consisting of alkyl groups, R 3 is independently selected from the group consisting of hydrogen, halogen, hydroxy, 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, either 1, 2, or 3. R 4 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 Alkyl sulfonyl, C 3～6 Cycloalkylsulfonyl, amino, N-(C 1～4 Alkyl)amino and N,N-di(C 1～4 Selected from the group consisting of alkyl)amino, R 5A and R 5B These are, independently, hydrogen, halogen, hydroxyl, and C. 1～4 Alkyl and C 1～4 Selected from the group consisting of alkoxys, or R 5A and R 5B These, together with the carbon atoms to which they are bonded, form a 3- to 5-membered saturated carbon ring. R 6 is hydrogen and C 1～4 (Selected from the group consisting of alkyl groups) Or its salt as a medicine.

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

3. R 2 The compound according to claim 1, wherein the compound is hydrogen.

4. R 2 The compound according to claim 1, wherein is methyl, ethyl, or n-butyl.

5. R 3 The compound according to claim 1, wherein the compound is independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, hydroxy, methoxy, amino, methylamino, and dimethylamino.

6. R 4 The compound according to claim 1, wherein the compound is selected from the group consisting of fluoro, chloro, bromo, methyl, ethyl, cyclopropyl, methoxy, ethoxy, methylthio, ethylthio, methylsulfonyl, amino, methylamino, and dimethylamino.

7. R 5A and R 5B However, each independently, hydrogen or C 1～4 The compound according to claim 1, wherein it is alkyl or, together with a carbon atom to which it is bonded, forms a cyclopropyl ring.

8. R 6 The compound according to claim 1, wherein is hydrogen or methyl.

9. 2-(((3-butyl-3-ethyl-7-(methylthio)-1,1-dioxide-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-dioxide-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-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)acetic acid; 2-(((3,3-dibutyl-7-(methylthio)-1,1-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)acetic acid; 2-(((3,3-dibutyl-7-(methylthio)-1,1-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)-2-methylpropanoic acid; 2-(((3,3-dibutyl-7-(methylthio)-1,1-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetic acid; 2-(((3,3-dibutyl-7-methoxy-1,1-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)-2-methylpropanoic acid; 2-(((3-butyl-7-methoxy-2-methyl-1,1-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-2,3,4,5-tetrahydro-1,5-benzothiazepine-8-yl)methyl)thio)acetic acid; 2-(((3-butyl-7-methoxy-3-methyl-1,1-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-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-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine-8-yl)methyl)thio)acetic acid; A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of the above.

10. A pharmaceutical composition comprising a therapeutically effective amount of the compound described in any one of claims 1 to 9 and one or more pharmaceutically acceptable excipients.

11. A pharmaceutical product comprising the compound described in any one of claims 1 to 9.

12. Use in the treatment or prevention of cardiovascular diseases or disorders of fatty acid metabolism or glucose utilization, e.g., hypercholesterolemia; disorders of fatty acid metabolism; type 1 and type 2 diabetes mellitus; complications of diabetes including cataracts, microvascular diseases, retinopathy, neuropathy, nephropathy, and delayed wound healing, tissue ischemia, diabetic foot lesions, arteriosclerosis, myocardial infarction, acute coronary syndrome, unstable angina, stable angina, stroke, peripheral artery occlusive disease, cardiomyopathy, heart failure, heart rate disorders, and restenosis; diabetes-related diseases, e.g., insulin resistance (impaired glucose homeostasis), hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, obesity, dyslipidemia, hyperlipidemia including hypertriglyceridemia, metabolic syndrome (X syndrome), atherosclerosis, and hypertension; and for increasing high-density lipoprotein levels, according to claim 11.

13. The pharmaceutically acceptable agent according to claim 11 for use in the treatment or prevention of gastrointestinal disorders or conditions, such as constipation (including chronic constipation, functional constipation, chronic idiopathic constipation (CIC), intermittent / sporadic constipation, constipation secondary to diabetes mellitus, 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, constipation-predominant irritable bowel syndrome (IBS-C), mixed-type 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); inflammation of the ileum; and reflux disorders and their complications, such as Barrett's esophagus, bile reflux esophagitis, and bile reflux gastritis.

14. Liver diseases or disorders, e.g., hereditary metabolic disorders of the liver; congenital abnormalities of bile acid synthesis; congenital bile duct anomalies; biliary atresia; biliary atresia after Kasai procedure; biliary atresia after liver transplantation; neonatal hepatitis; neonatal cholestasis; inherited forms of cholestasis; cerebral tendon xanthomatous disease; secondary defects in BA synthesis; Zellweger syndrome; liver diseases associated with cystic fibrosis; α1 antitrypsin deficiency; Alagille syndrome (ALGS); Beiler syndrome; primary defects in bile acid (BA) synthesis; progressive familial intrahepatic cholestasis (PFIC), including PFIC-1, PFIC-2, PFIC-3, and unspecified PFIC, post-bile diversion PFIC, and post-liver transplant PFIC; BRIC1, BRIC2, and unspecified BRIC, post-bile diversion Benign recurrent intrahepatic cholestasis (BRIC), including BRIC after liver transplantation; autoimmune hepatitis; primary biliary cirrhosis (PBC); hepatic fibrosis; non-alcoholic fatty liver disease (NAFLD); non-alcoholic steatohepatitis (NASH); portal hypertension; cholestasis; cholestasis in Down syndrome; drug-induced cholestasis; intrahepatic cholestasis in pregnancy (jaundice during pregnancy); intrahepatic cholestasis; extrahepatic cholestasis; cholestasis associated with parenteral nutrition (PNAC); cholestasis associated with hypophospholipids; lymphedema cholestasis syndrome 1 (LCS1); primary sclerosing cholangitis (PSC); cholangitis associated with immunoglobulin G4; primary biliary cholangitis; cholelithiasis (gallstones); biliary tract stones (biliary gallstones) Lithiasis; common bile duct stones; gallstone pancreatitis; caloric disease; malignant neoplasm of the bile duct; malignant neoplasm causing obstruction of the bile duct; bile duct stenosis; AIDS cholangiopathies; ischemic cholangiopathies; pruritus due to cholestasis or jaundice; pancreatitis; chronic autoimmune liver disease leading to progressive cholestasis; fatty liver degeneration; alcoholic hepatitis; acute fatty liver; fatty liver during pregnancy; drug-induced hepatitis; iron overload; congenital bile acid metabolism disorder type 1 (BAS disorder type 1); drug-induced liver injury (DILI); hepatic fibrosis; congenital hepatic fibrosis; cirrhosis; Langerhans cell histiocytosis (LCH); neonatal ichthyosis sclerosing cholangitis (NISCH); myeloid protoporphyria (EPP); idiopathic adult bile duct depression (IAD); idiopathic neonatal hepatitis (INH); asymptomatic intrahepatic bile duct depression (NS) PILBD; Autosomal recessive inherited intrahepatic cholestasis (North American Indian childhood cirrhosis) (NAIC); Hepatic sarcoidosis;For use in the treatment or prevention of cholestasis caused by amyloidosis; necrotizing enterocolitis; toxicities caused by serum bile acids, including dyscardiopathy (e.g., atrial fibrillation), cardiomyopathy associated with cirrhosis ("cholecardia"), and skeletal muscle wasting associated with cholestatic liver disease; polycystic hepatic disease; viral hepatitis (including hepatitis A, B, C, D, and E); hepatocellular carcinoma (hepatocellular tumor); cholangiocarcinoma; gastrointestinal cancers related to bile acids; and tumors and neoplasms of the liver, biliary tract, and pancreas; or for use in augmenting corticosteroid therapy in liver disease, according to claim 11.

15. The pharmacopoeci of claim 11 for use in the treatment or prevention of pruritus in renal failure; or for use in the protection of kidney injury associated with hepatic or metabolic disease.

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