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 with apical sodium-dependent bile acid transporter (ASBT) and / or hepatic bile acid transport (LBAT) inhibitory activity. The present invention also relates to pharmaceutical compositions comprising these compounds and the use of these compounds in the treatment of cardiovascular diseases, fatty acid metabolism and glucose utilization disorders, gastrointestinal diseases, and liver diseases.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to Indian Patent Application No. 202111024711 filed on June 3, 2021, the disclosure of which is incorporated herein 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 with apical sodium-dependent bile acid transporter (ASBT) and / or hepatic bile acid transport (LBAT) inhibitory activity. The present invention also relates to pharmaceutical compositions comprising these compounds and the use of these compounds in the treatment of cardiovascular diseases, fatty acid metabolism and glucose utilization disorders, gastrointestinal diseases, and liver diseases. [Background technology]

[0003] Bile acids are physiological surfactants that play an important role 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 that are synthesized from cholesterol in the liver and stored in the gallbladder as mixed micelles. During digestion, the duodenum triggers 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. Once bile acids reach the ileum, they are reabsorbed from the intestine and secreted into the portal blood and returned to the liver via the portal circulation. In this way, more than 90% of the bile acids are recycled back to the liver. These bile acids are then transported across the sinusoidal membrane of hepatocytes and resecreted across the canalicular membrane into the bile. During this first pass, 75-90% of the bile acids are taken up by hepatocytes, completing one enterohepatic circulation. Some bile acids that are not removed by the liver enter the systemic circulation, where free bile acids are filtered by the renal glomerulus and efficiently collected by the proximal tubule and returned to the systemic circulation. Interestingly, the majority of bile acids secreted across the canalicular membrane into bile originate from the recycling pool, with less than 10% resulting from de novo hepatic synthesis. Few bile acids that are not reabsorbed in the ileum reach the colon. In the intestinal lumen, primary bile acids are converted into secondary bile acids under the action of intestinal bacteria, mainly by single or double dehydroxylation of the steroid nucleus. Bile acids that are not absorbed in the intestine are then excreted in the 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 facilitate lipid absorption and reduce bacterial load in the small intestine. This system also protects the intestine and hepatobiliary compartment by minimizing bile acid losses in feces and urine, and eliminating potentially cytotoxic surfactants (as reviewed by Kosters and Karpen (Xenobiotica 2008, vol. 38, pp. 1043-1071); Chiang (J. Lipid Res. 2009, vol. 50, pp. 1955-1966); and Dawson (Handb. Exp. Pharmacol. 2011, vol. 201, pp. 169-203)).

[0005] Regulation of the bile acid pool size by converting cholesterol to bile acids in the liver has been found to play an important role in cholesterol homeostasis, which represents the main route of 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 in the treatment of several diseases, including dyslipidemia, diabetes, obesity, constipation, cholestatic liver disease, non-alcoholic steatohepatitis, and other liver diseases. Several ASBT inhibitor compounds have been disclosed over the past several decades. For example, WO 93 / 16055, WO 94 / 18183, WO 94 / 18184, WO 96 / 05188, WO 96 / 08484, WO 96 / 16051, WO 97 / 33882, WO 98 / 03818, WO 98 / 07449, WO 98 / 40375, WO 99 / 35135, WO 99 / 64409, WO 99 / 64410, WO 00 / 47568, WO 00 / 61568, WO 00 / 38725, WO 00 / 38726, WO 00 / 38727, WO 00 / 38728, WO 00 / 38729, WO 01 / 66533, WO 01 / 68096, WO 02 / 32428, WO 02 / 50051, WO 03 / 020710, WO 03 / 022286, WO 03 / 022825, WO 03 / 022830, WO 03 / 061663, WO 03 / 091232, WO 03 / 106482, WO 2004 / 006899, WO 2004 / 076430, WO 2007 / 009655, WO 2007 / 009656, WO 2011 / 137135, WO 2019 / 234077, WO 2020 / 161216, WO See 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] US Patent Application Publication No. 2018 / 0140219 [Patent Document 60] US Patent Application Publication No. 2016 / 146715 [Patent Document 61] US 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 literature]

[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, 61, 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, Volume 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, pp. 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, 67(1), 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, 44(8), 1585-1596; [Non-Patent Document 15] Lv et al., J Clin Transl Hepatol. 2018, No. 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, 31(4), 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, 45(4), 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, 59(9), 1265-9 [Non-Patent Document 22] Adams et al., Clin. Chem. 2005, 51(10), 1867-1873 [Non-Patent Document 23] Lichtinghagen R et al. J Hepatol. 2013 Aug;59(2):236-42 [Non-Patent Document 24] Neuman et al., Can. J. Gastroenterol. Hepatol. 2014, vol. 28(11), pp. 607-618 [Non-Patent Document 25] Perez MJ, Briz O. World J. Gastroenterol. 2009, No. 15(14), pp. 1677-1689 [Non-Patent Document 26] Sorrentino P et al., Dig. Dis. Sci. 2005, 50(6), 1130-1135 [Non-Patent Document 27] Satapathy SK and Sanyal AJ. Semin. Liver Dis. 2015, 35(3), 221-235. [Non-Patent Document 28] PGM Wutz and TW Greene, Greene's Protective Groups in Organic Synthesis, 4th ed., John Wiley & Sons, Hoboken, 2006 Summary of the Invention

[0009] Despite the number of previously reported ASBT inhibitor compounds, there remains a need for additional bile acid modulating compounds with an optimized profile in terms of potency, selectivity, and bioavailability. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] It has been discovered that certain 1,5-benzothiazepine and 1,2,5-benzothiadiazepine derivatives are potent inhibitors of the apical sodium-dependent bile acid transporter (ASBT) and / or the hepatic bile acid transporter (LBAT) and may be useful in treating diseases in which inhibition of bile acid cycling is desirable.

[0011] In a first aspect, the present invention provides a compound of formula (I)

[0012] [ka]

[0013] (In the formula, M is -CH2- or -NR 5 - Selected from; R 1 is C 1~4 is alkyl; R 2 are independently 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, N,N-di(C 1~4 Alkyl)amino, C 1~6 Alkylcarbonylamino, C 3~6 Cycloalkylcarbonylamino, N-(C 1~4 Alkyl)aminocarbonyl, N,N-di(C 1~4 Alkyl)aminocarbonyl, C 1~4 Alkyloxycarbonylamino, C 3~6 Cycloalkyloxycarbonylamino, C 1~4 Alkyl sulfonamides, and C 3~6 cycloalkylsulfonamides; n is an integer of 1, 2, or 3; R 3 is 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, amino, N-(C 1~4 alkyl)amino, and N,N-di(C 1~4 (alkyl)amino; R4A and R 4B are each independently hydrogen, halogen, hydroxy, C 1~4 Alkyl, and C 1~4 alkoxy; or R 4A and R 4B together with the carbon atoms to which they are attached form a 3- to 5-membered saturated carbocyclic ring; R 4C and R 4D are each independently hydrogen and C 1~4 selected from the group consisting of alkyl; R 5 is hydrogen and C 1~4 alkyl) or a pharma- ceutical acceptable salt thereof.

[0014] In some embodiments, R 1 is C 2~4 In a preferred embodiment, R 1 is n-propyl. In another preferred embodiment, R 1 is n-butyl.

[0015] In some embodiments, R 2 is 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 contains only one substituent R 2 In another preferred embodiment, R 2 is in para rank.

[0016] In some embodiments, R 3 is selected from the group consisting of fluoro, chloro, bromo, methyl, cyclopropyl, methoxy, ethoxy, methylthio, ethylthio, amino, methylamino, and dimethylamino.

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

[0018] In some embodiments, R 4C and R 4D are each independently hydrogen or methyl. In some embodiments, R 4C and R 4D are each hydrogen.

[0019] In some embodiments, R 5 is hydrogen. In some embodiments, R 5 is methyl.

[0020] In a preferred embodiment, the compound of formula (I) is a compound of formula (Ia):

[0021] [ka]

[0022] (In the formula, M is selected from the group consisting of -CH2-, -NH-, and -NCH3-; R 1 is C 2~4 is alkyl; R 2 are independently hydrogen, halogen, hydroxy, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, Amino, N-(C 1~4 Alkyl)amino, N,N-di(C 1~4 (alkyl)amino; n is an integer of 1 or 2; R 3 is a halogen, C 1~4 Alkyl, C 3~6 Cycloalkyl, C 1~4 Alkoxy, C 1~4 Alkylthio, amino, N-(C 1~4 alkyl)amino, and N,N-di(C 1~4 (alkyl)amino; R 4A and R 4B are each independently hydrogen, halogen, hydroxy, C 1~4 Alkyl, and C 1~4 alkoxy or R 4A and R 4B together with the carbon atom to which they are attached form a cyclopropyl ring. or a pharma- ceutical acceptable salt thereof.

[0023] In a preferred embodiment, the compound of formula (I) is a compound of formula (Ib):

[0024] [ka]

[0025] (In the formula, M is selected from the group consisting of -CH2-, -NH-, and -N(CH3)-; R 1 is C 2~4 alkyl, more preferably n-propyl or n-butyl; R 2 are independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, hydroxy, methoxy, amino, methylamino, and dimethylamino; R 3 is selected from the group consisting of fluoro, chloro, bromo, methyl, cyclopropyl, methoxy, ethoxy, methylthio, ethylthio, amino, methylamino, and dimethylamino; R 4A and R 4Bare each independently hydrogen, fluoro, methyl, methoxy, or ethoxy, or together with the carbon atom to which they are attached form a cyclopropyl ring. or a pharma- ceutical acceptable salt thereof.

[0026] Preferred compounds of the present invention are compounds of formula (Ib) as defined above, 1 , R 2 , R 3 , R 4A , and R 4B is as shown in Table 1 below), or a pharma- ceutically acceptable salt thereof:

[0027] [Table 1A]

[0028] [Table 1B]

[0029] [Table 1C]

[0030] In certain embodiments, the compound of formula (I) is 3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2,2-dimethylpropanoic acid; (S)-3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2,2-dimethylpropanoic acid; (R)-3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2,2-dimethylpropanoic acid; 1-(((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid; (S)-1-(((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid; (R)-1-(((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid; 3-((3-butyl-7-(ethylthio)-2-methyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2,2-dimethylpropanoic acid; (S)-3-((3-butyl-7-(ethylthio)-2-methyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2,2-dimethylpropanoic acid; (R)-3-((3-butyl-7-(ethylthio)-2-methyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2,2-dimethylpropanoic acid; 1-(((3-butyl-7-(ethylthio)-2-methyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid; (S)-1-(((3-butyl-7-(ethylthio)-2-methyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid; (R)-1-(((3-butyl-7-(ethylthio)-2-methyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid; 3-((3-butyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy)-2,2-dimethylpropanoic acid; 1-(((3-butyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid; 1-(((3-butyl-5-(4-fluorophenyl)-2-methyl-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid; (S)-1-(((3-butyl-5-(4-fluorophenyl)-2-methyl-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid; (R)-1-(((3-butyl-5-(4-fluorophenyl)-2-methyl-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid; 3-((3-butyl-5-(4-fluorophenyl)-2-methyl-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2,2-dimethylpropanoic acid; (S)-3-((3-butyl-5-(4-fluorophenyl)-2-methyl-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2,2-dimethylpropanoic acid; (R)-3-((3-butyl-5-(4-fluorophenyl)-2-methyl-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2,2-dimethylpropanoic acid; 1-(((3-butyl-7-(ethylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid; 1-(((3-butyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid; (S)-1-(((3-butyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid; (R)-1-(((3-butyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid; 1-(((3-butyl-7-(ethylthio)-5-(4-fluorophenyl)-1,1-dioxide-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid; (S)-1-(((3-butyl-7-(ethylthio)-5-(4-fluorophenyl)-1,1-dioxide-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid; (R)-1-(((3-butyl-7-(ethylthio)-5-(4-fluorophenyl)-1,1-dioxide-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid; 3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2,2-difluoropropanoic acid; (S)-3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2,2-difluoropropanoic acid; (R)-3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2,2-difluoropropanoic acid; 3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2-methoxy-2-methylpropanoic acid; (S)-3-(((R)-3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2-methoxy-2-methylpropanoic acid; (S)-3-(((S)-3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2-methoxy-2-methylpropanoic acid; (R)-3-(((R)-3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2-methoxy-2-methylpropanoic acid; (R)-3-(((S)-3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2-methoxy-2-methylpropanoic acid; 3-((3-butyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy)propanoic acid; (S)-3-((3-butyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy)propanoic acid; (R)-3-((3-butyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy)propanoic acid; 3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2-ethoxypropanoic acid; 3-((3-butyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy)-2-hydroxypropanoic acid; 3-((3-ethyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy)propanoic acid; 3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2-methoxypropanoic acid; 3-(((S)-3-Butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2-methoxypropanoic acid; 3-(((R)-3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2-methoxypropanoic acid; (S)-3-(((R)-3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2-methoxypropanoic acid; (R)-3-(((R)-3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2-methoxypropanoic acid; (S)-3-(((S)-3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2-methoxypropanoic acid; (R)-3-(((S)-3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2-methoxypropanoic acid; and 3-((3-butyl-7-(ethylthio)-5-(4-fluorophenyl)-2-methyl-1,1-dioxide-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2-hydroxypropanoic acid; or a pharma- ceutical acceptable salt thereof.

[0031] As used herein, the term "halo" refers to fluoro, chloro, bromo, and iodo.

[0032] As used herein, "C 1~6 The term "alkyl" refers to a straight or branched alkyl group having 1 to 6 carbon atoms, 1~4 The term "alkyl" refers to a straight or branched alkyl group having 1 to 4 carbon atoms. 1~4 Examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0033] As used herein, "C 1~4 The term "haloalkyl" refers to a straight or branched C alkyl group, as defined herein. 1~4 C refers to an alkyl group in which one or more hydrogen atoms have been replaced with halogen. 1~4 Examples of haloalkyl include chloromethyl, fluoroethyl, and trifluoromethyl.

[0034] As used herein, "C 1~4 Alkoxy" and "C 1~4 The term "alkylthio" refers to a straight or branched C alkyl group bonded to the remainder of the molecule through an oxygen or sulfur atom, respectively. 1~4 Refers to an alkyl group.

[0035] As used herein, "C 3~6 The term "cycloalkyl" refers to a monocyclic saturated hydrocarbon ring having 3 to 6 carbon atoms. 3~6 Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0036] The term "aryl" refers to an aromatic monocyclic ring of 6 carbon atoms or an aromatic bicyclic ring system of 10 carbon atoms. Examples of aryl include phenyl, naphthyl, and azulenyl.

[0037] The term "amino" refers to the -NH group. As used herein, "N-(C 1~4 "N,N-di(C 1~4 The term "amino" refers to a straight or branched C 1~4 Refers to an amino group replaced by an alkyl group. N-(C 1~4 Examples of N,N-di-(C alkyl)amino include methylamino, ethylamino, and tert-butylamino. 1~4 Examples of alkyl)amino include dimethylamino and diethylamino.

[0038] As used herein, “N-(aryl-C 1~4 The term "aryl)amino" refers to a hydrogen atom attached to an aryl-C 1~4 Refers to an amino group replaced by an alkyl group. N-(aryl-C 1~4 Examples of "C alkyl" amino include benzylamino and phenylethylamino. 1~6 The term "alkylcarbonylamino" refers to a group in which the hydrogen atom is C 1~6 It refers to an amino group replaced with an alkylcarbonyl group. 1~6 Examples of alkanoylamino include acetylamino and tert-butylcarbonylamino. 1~4 The term "alkyloxycarbonylamino" means that the hydrogen atom is C 1~4 It refers to an amino group replaced with an alkyloxycarbonyl group. 1~4 An example of an alkyloxycarbonylamino is tert-butoxycarbonylamino. 1~4 Alkyl sulfonamide" and "C 3~6 The term "cycloalkylsulfonamide" refers to a group in which the hydrogen atom is C 1~4 Alkylsulfonyl or C 3~6 It refers to an amino group each replaced by a cycloalkylsulfonyl group.

[0039] As used herein, the term "pharmaceutical acceptable" refers to compounds, materials, compositions and / or dosage forms that are suitable for human pharmaceutical use and are generally safe, non-toxic, and not biologically or otherwise undesirable.

[0040] As used herein, the term "about" refers to a value or parameter, including (and describing) embodiments directed to the value or parameter itself. For example, a statement referring to "about 20" includes the statement "20." Numerical ranges include the numbers that define the range. Generally speaking, the term "about" refers to the value recited by the variable, to any value within the experimental error of the value recited by the variable (e.g., within a 95% confidence interval of the mean), or within 10 percent of the value recited by the variable, whichever is greater.

[0041] The 1,5-benzothiazepine and 1,2,5-benzothiadiazepine compounds of formula (I), or pharma- ceutically acceptable salts thereof, are inhibitors of the apical sodium-dependent bile acid transporter, the hepatic bile acid transporter, or both the apical sodium-dependent bile acid transporter and the hepatic bile acid transporter (ASBT inhibitors, LBAT inhibitors, and dual ASBT / LBAT inhibitors, respectively).As such, they are useful in the treatment or prevention of conditions, disorders, and diseases in which inhibition of bile acid circulation is desirable, such as cardiovascular diseases, disorders of fatty acid metabolism and glucose utilization, gastrointestinal diseases, and hepatic diseases.

[0042] Cardiovascular diseases and disorders of fatty acid metabolism and glucose utilization include, but are not limited to, hypercholesterolemia; disorders of fatty acid metabolism; diabetes mellitus type 1 and type 2; complications of diabetes, such as cataracts, small and large vessel disease, retinopathy, neuropathy, nephropathy, and delayed wound healing, tissue ischemia, diabetic foot, arteriosclerosis, myocardial infarction, acute coronary syndrome, unstable angina, stable angina, stroke, peripheral arterial occlusive disease, cardiomyopathy, heart failure, heart rhythm disorders, and vascular restenosis; diabetes-related disorders, such as insulin resistance (impaired glucose homeostasis), hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, obesity, dyslipidemia, hyperlipidemia, such as hypertriglyceridemia, metabolic syndrome (syndrome X), atherosclerosis, and hypertension; and increased high density lipoprotein levels.

[0043] Gastrointestinal diseases and disorders include 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 irritable bowel syndrome (IBS-M), pediatric functional constipation, and opioid-induced constipation); Crohn's disease; primary bile acid malabsorption; irritable bowel syndrome (IBS); inflammatory bowel disease (IBD); ileal inflammation; and reflux disease and its complications, such as Barrett's esophagus, bile reflux esophagitis, and bile reflux gastritis.

[0044] A liver disease, as defined herein, is any disease of the liver and its associated 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, including hereditary metabolic disorders of the liver; congenital anomalies of bile acid synthesis; congenital abnormalities of bile duct course; biliary atresia; biliary atresia after Kasai operation; biliary atresia after liver transplantation; neonatal hepatitis; neonatal cholestasis; inherited forms of cholestasis; cerebrotendinous xanthomatosis; secondary defects of BA synthesis; Zellweger syndrome; cystic fibrosis-related liver disease; alpha 1-antitrypsin deficiency; Alagille syndrome (ALGS); Byler syndrome; primary defects of bile acid (BA) synthesis; progressive familial intrahepatic cholestasis (PFIC), e.g., PFIC-1, PFIC-2, PFIC-3, and non-specific PFIC, PFIC after bile diversion, and PFIC after liver transplantation; benign recurrent intrahepatic cholestasis (BRIC), e.g., BRIC1 , BRIC2, and non-specific BRIC, BRIC after bile diversion, and BRIC after liver transplant;autoimmune hepatitis;primary biliary cirrhosis (PBC);liver fibrosis;nonalcoholic fatty liver disease (NAFLD);nonalcoholic steatohepatitis (NASH);portal hypertension;cholestasis;Down syndrome cholestasis;drug-induced cholestasis;intrahepatic cholestasis of pregnancy (jaundice in pregnancy);intrahepatic cholestasis;extrahepatic cholestasis;cholestasis associated with parenteral nutrition (PNAC);hypophospholipid-associated cholestasis;lymphoedema cholestasis syndrome 1 (LCS1);primary sclerosing cholangitis (PSC);immunoglobulin G4-associated cholangitis;primary biliary cholangitis;cholelithiasis (gallstones);biliary cholangitis (biliary lithiasis);choledocholithiasis;gallstone pancreatitis;Caroli's disease;malignant tumors of the bile duct;malignant tumors causing obstruction of the biliary tree;bile duct stenosis;AIDS cholangiopathy;ischemic cholangiopathy;pruritus due to cholestasis or jaundice;pancreatitis;chronic autoimmune liver disease leading to progressive cholestasis;hepatic steatosis;alcoholic hepatitis;acute fatty liver;fatty liver of pregnancy;drug-induced hepatitis;iron overload;inborn errors of bile acid metabolism type 1 (BAS type 1);drug-induced liver injury (DILI);hepatic fibrosis;congenital hepatic fibrosis;cirrhosis;Langerhans cell histiocytosis (LCH);neonatal ichthyotic sclerosing cholangitis (NISCH);erythropoietic protoporphyria (EPP);idiopathic adult bile duct paucity (IAD);idiopathic neonatal hepatitis (INH);These include, but are not limited to, nonsyndromic intrahepatic cholangiocytosis (NS PILBD); autosomal recessive hereditary intrahepatic cholestasis (North American Indian childhood cirrhosis) (NAIC); hepatic sarcoidosis; amyloidosis; necrotizing enterocolitis; toxicity caused by serum bile acids, such as cardiac rhythm disorders (e.g., atrial fibrillation) in the setting of abnormal serum bile acid profiles, cardiomyopathy associated with cirrhosis ("cholecardia"), and skeletal muscle wasting associated with cholestatic liver disease; polycystic hepatic disease; viral hepatitis (including hepatitis A, hepatitis B, hepatitis C, hepatitis D, and hepatitis E); hepatocellular carcinoma (hepatocellular carcinoma); cholangiocarcinoma; gastrointestinal cancers related to bile acids; and cholestasis caused by tumors and neoplasms of the liver, biliary tract, and pancreas. The compounds of formula (I) or pharma- ceutically acceptable salts thereof are also useful for augmenting corticosteroid therapy in liver disease;

[0045] Other diseases that may be treated or prevented by the compounds of formula (I) or their pharma- ceutically acceptable salts include hyperabsorption syndromes (including abetalipoproteinemia, familial hypobetalipoproteinemia (FHBL), chylomicron retention disease (CRD), and sitosterolemia); hypervitaminosis and osteopetrosis; hypertension; glomerular hyperfiltration; polycystic kidney disease (PKD), such as autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD); and pruritus in renal failure. The compounds are also useful for protection against kidney damage associated with liver or metabolic disease.

[0046] The transport of bile acids in the human body is mediated by members of the SLC10 family of solute carrier proteins, particularly Na +It is regulated by the apical sodium-dependent bile acid transporter (ASBT, also called ileal bile acid transporter (IBAT), ISBT, ABAT, or NTCP2; gene symbol SLC10A2), which is expressed in the apical membrane of ileal enterocytes, proximal tubule cells, bile duct epithelium, large duct cells, and gallbladder epithelial cells. In the liver, bile acids are efficiently extracted from the portal blood by the hepatic bile acid transporter (LBAT) and resecreted across the canalicular membrane by the bile salt export pump (BSEP; gene symbol ABCB11). Reabsorption of bile acids in the ileum is handled by the apical sodium-dependent bile acid transporter (ASBT), commonly referred to in the ileum as the ileal bile acid transporter (IBAT). Both LBAT and ASBT transport more than two Na per molecule of solute. + It functions as an electrogenic sodium-solute cotransporter to move ions.

[0047] Endobiotics, including xenobiotics and bile acids, are taken up by the liver from portal blood and secreted into bile by distinct transport proteins with individualized substrate specificity. Glycine- and taurine-conjugated bile acids exist in anionic form and cannot cross the membrane by diffusion, and are therefore entirely dependent 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 higher affinity for dihydroxy bile salts over trihydroxy bile salts. Although the non-bile acid substrates of ASBT have yet to be identified, LBAT has also been found to transport various steroid sulfates, hormones, and xenobiotics.

[0048] LBAT has not been as thoroughly characterized as ASBT in terms of drug inhibition requirements. identified FDA-approved drugs that inhibit human LBAT and compared the inhibition requirements of LBAT and ASBT. A series of LBAT inhibition studies were performed using FDA-approved drugs in conjunction with the development of an iterative computational model. From the screening studies, 27 drugs were identified as novel LBAT inhibitors, including irbesartan (Ki=11.9 μM) and ezetimibe (Ki=25.0 μM). Common features in the pharmacophore indicated that two hydrophobes and one hydrogen-bonding receptor are important for the inhibition of LBAT. From the 72 drugs screened in vitro, a total of 31 drugs inhibited LBAT, whereas 51 drugs (i.e., more than half) inhibited ASBT. Thus, despite the inhibitor overlap, ASBT is unexpectedly more tolerant to drug inhibition than LBAT, which may be related to LBAT having fewer pharmacophore features (Dong et al., Mol. Pharm. 2013, vol. 10, pp. 1008-1019).

[0049] Vaz et al. describe the identification of LBAT deficiency as a new congenital anomaly with a relatively mild clinical phenotype. Identification of LBAT deficiency confirms this transporter as the major import system for conjugated bile salts into the liver, but also shows that in its absence, auxiliary transporters can sustain the enterohepatic circulation (Vaz et al., Hepatology 2015, vol. 61, pp. 260-267). These findings support the hypothesis that LBAT inhibition is a safe mechanism of action, since hepatocytes still have the potential to take up the necessary amounts of bile acids.

[0050] Liu et al. describe the identification of a new type of hypercholanic acidemia 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 occurring in Southern China (8% and 12% in Chinese Han and Dai populations, respectively) and Vietnam (11%). This "hidden" hypercholanic acidemia was thought to affect 0.64% of the Southern Chinese Han population, 1.44% of the Dai population, and 1.21% of the Vietnamese population. Increased conjugated and unconjugated serum BA levels in homozygous individuals were also observed. Liu et al. suggest that this finding is most likely due to reduced BA transport from the portal circulation to hepatocytes. This supports the hypothesis that the physiological function of the enterohepatic circulation is not only to recycle bile acids but also to remove them from the 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).

[0051] LBAT has been found to be downregulated in some forms of cholestatic liver injury and cholestasis, whereas 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 is a major cause of liver disease and hepatocellular carcinoma.

[0052] ASBT inhibition has been investigated for reducing plasma cholesterol levels and improving insulin resistance, as well as reducing the burden of bile acids on the liver in cholestatic liver disease.In addition, ASBT inhibition has been found to restore insulin levels and normal blood glucose levels, thereby establishing ASBT inhibition as a promising treatment for type 2 diabetes mellitus.ASBT inhibitors are also used to treat functional constipation.

[0053] Since ASBT is primarily expressed in the ileum (often referred to as IBAT in the ileum), ASBT inhibitors do not need to be systemically absorbed. However, ASBT is also expressed in the proximal tubule cells of the kidney. Therefore, a systemically absorbed ASBT inhibitor may also inhibit reuptake of bile acids in the kidney. This would increase urinary bile acid levels and increase removal of bile acids from the body via urine. Therefore, a systemically absorbed ASBT inhibitor that has an effect not only in the ileum but also in the kidney would be predicted to lead to a greater reduction in bile acid levels than a non-systemically absorbed ASBT inhibitor that has an effect only in the ileum.

[0054] Compounds with high ASBT inhibitory potency are particularly suitable for the treatment of liver diseases causing cholestasis, such as progressive familial intrahepatic cholestasis (PFIC), Alagille syndrome, biliary atresia, and non-alcoholic steatohepatitis (NASH).

[0055] Biliary atresia is a rare pediatric liver disease involving partial or total blockage (or even absence) of the bile duct. This blockage or absence causes cholestasis leading to the accumulation of bile acids that damage the liver. In some embodiments, the accumulation of bile acids occurs in the extrahepatic bile duct system. In some embodiments, the accumulation of bile acids occurs in the intrahepatic bile duct system. The current standard of care is the Kasai procedure, a surgical procedure that removes the blocked bile duct and connects a portion of the small intestine directly to the liver. There is currently no approved drug therapy for this disorder.

[0056] Provided herein is a method for treating biliary atresia in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof. In some embodiments, the subject is administered a compound of formula (I) or a pharma- ceutically acceptable salt thereof after undergoing Kasai's maneuver. In some embodiments, the subject is administered a compound of formula (I) or a pharma- ceutically acceptable salt thereof before undergoing Kasai's maneuver. In some embodiments, treating biliary atresia reduces serum bile acid levels in the subject. In some embodiments, serum bile acid levels are 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, serum bile acid levels may be reduced by, for example, 10% to 40%, 20% to 50%, 30% to 60%, 40% to 70%, 50% to 80%, or greater than 90% of the serum bile acid levels prior to administration of the compound of Formula (I) or a pharma- ceutically acceptable salt thereof. In some embodiments, treating biliary atresia includes treating pruritus.

[0057] PFIC is a rare genetic disorder that is estimated to affect one in 50,000-100,000 live births worldwide and causes progressive, life-threatening liver disease.

[0058] One symptom of PFIC is pruritus, which often significantly reduces quality of life. In some cases, PFIC leads to cirrhosis and liver failure. Current therapies include partial external biliary diversion (PEFD) and liver transplantation, but these options carry substantial risks of postoperative complications as well as potential psychological and social problems.

[0059] Three alternative genetic defects have been identified that correlate with three distinct PFIC subtypes, known as types 1, 2, and 3. · PFIC type 1, sometimes called "Byler's disease," is caused by impaired bile secretion due to mutations in the ATP8B1 gene, which codes for a protein that helps maintain the proper balance of fats known as phospholipids in cell membranes in the bile ducts. An imbalance of these phospholipids is associated with cholestasis and elevated bile acids in the liver. Subjects affected with PFIC type 1 usually develop cholestasis in the first month of life and, without surgical treatment, progress to cirrhosis and end-stage liver disease before the first decade of life. PFIC type 2, sometimes called "Byler syndrome," is caused by impaired bile salt secretion due to mutations in the ABCB11 gene, which codes for a protein known as the bile salt export pump, which moves bile acids out of the liver. Subjects with PFIC type 2 often develop liver failure within the first few years of life and are at high risk of developing a type of liver cancer known as hepatocellular carcinoma. PFIC type 3 typically presents with progressive cholestasis during the first few years of childhood and is caused by mutations in the ABCB4 gene, which codes for a transporter that moves phospholipids across cell membranes.

[0060] In addition, mutations in the TJP2, NR1H4, or Myo5b genes have been proposed as causes of PFIC. In addition, some subjects with PFIC do not have mutations in any of the ATP8B1, ABCB11, ABCB4, TJP2, NR1H4, or Myo5b genes. In these cases, the cause of the condition is unknown.

[0061] Exemplary mutations of the ATP8B1 gene or 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 are listed in Tables 2 and 3. Exemplary mutations of the ABCB11 gene or 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 are listed in Tables 4 and 5.

[0062] As can be appreciated by one of skill in the art, amino acid positions in a reference protein sequence that correspond to 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 can be appreciated by one of skill in the art, nucleotide positions in a reference gene sequence that correspond to 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 by reference in its entirety.

[0063] Canonical protein sequence of ATP8B1 (SEQ ID NO:1) - Uniprot ID O43520

[0064] [ka]

[0065] Canonical DNA sequence of ATP8B1 (SEQ ID NO:2)

[0066] [ka]

[0067] [ka]

[0068]

change

[0069]

Table 2A

[0070]

Table 2B

[0071]

Table 2C

[0072]

Table 2D

[0073]

Table 2E

[0074]

Table 2F

[0075]

Table 2G

[0076]

Table 2H

[0077]

Table 2I

[0078]

Table 3A

[0079]

Table 3B

[0080]

Table 3C

[0081]

Table 3D

[0082] References for 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. 7Zarenezhad 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., Journal of Gastroenterology 2015, vol. 53, no. 12. Abstract Number: A3-27. Meeting info: 32nd annual meeting of the German Working Group for the Study of the Liver. 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 Word 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 Word et al., Hepatology 2015, vol. 61(4), p. 1382-1391.

[0083] In some embodiments, the mutation in ATP8B1 is selected from L127P, G308V, T456M, D554N, F529del, I661T, E665X, R930X, R952X, R1014X, and G1040R.

[0084] Canonical protein sequence of ABCB11 (SEQ ID NO:3) - Uniprot ID O95342

[0085] [ka]

[0086] Canonical DNA sequence of ABCB11 (SEQ ID NO:4)

[0087] [ka]

[0088] [ka]

[0089] [Table 4A]

[0090] [Table 4B]

[0091] [Table 4C]

[0092] [Table 4D]

[0093] [Table 4E]

[0094] [Table 4F]

[0095] Table 4G

[0096]

Table 4H

[0097]

Table 4I

[0098]

Table 4J

[0099]

Table 4K

[0100]

Table 4L

[0101]

Table 4M

[0102]

Table 4N

[0103]

Table 5A

[0104]

Table 5B

[0105]

Table 5C

[0106]

Table 5D

[0107]

Table 5E

[0108]

Table 5F

[0109] Table 5G

[0110]

Table 5H

[0111] References for 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,. 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[0112] 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.

[0113] Methods of treating PFIC (e.g., PFIC-1 and PFIC-2) in a subject are provided, the methods including performing an assay on a sample obtained from the subject to determine whether the subject has a PFIC-associated mutation (e.g., an ATP8B1, ABCB11, ABCB4, TJP2, NR1H4, or Myo5b mutation), and administering (e.g., specifically or selectively administering) a therapeutically effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof to the subject determined to have a PFIC-associated mutation. In some embodiments, the mutation is an ATP8B1 or ABCB11 mutation, such as 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.

[0114] Also provided is a method for treating PFIC (e.g., PFIC-1 and PFIC-2) in a subject in need of treatment of PFIC, 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 pharma- ceutically 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 pharma- ceutically 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.

[0115] In some embodiments, the subject is determined to have a mutation associated with PFIC in the subject or in a biopsy specimen from the subject through the use of a test recognized by those skilled in the art, including next generation sequencing (NGS). In some embodiments, the subject is determined to have a mutation associated with PFIC using a regulatory approved, e.g., FDA approved, test or assay for identifying a mutation associated with PFIC in the subject or in a biopsy specimen from the subject, or by performing any of the non-limiting examples of assays described herein. Further methods of diagnosing PFIC are described in Gunaydin, M. et al., Hepat Med. 2018, Vol. 10, pp. 95-104 (incorporated herein by reference in its entirety).

[0116] In some embodiments, treatment of PFIC (e.g., PFIC-1 or PFIC-2) reduces serum bile acid levels in the subject. In some embodiments, serum bile acid levels are determined, for example, by ELISA enzyme assay or by an assay for measuring total bile acid as described in Danese et al., PLoS One. 2017, Vol. 12(6): e0179200, which is incorporated herein by reference in its entirety. In some embodiments, serum bile acid levels can be reduced, for example, by 10% to 40%, 20% to 50%, 30% to 60%, 40% to 70%, 50% to 80%, or more than 90% of serum bile acid levels prior to administration of a compound of Formula (I) or a pharma- ceutical acceptable salt thereof. In some embodiments, treatment of PFIC includes treatment of pruritus.

[0117] Since LBAT is expressed in hepatocytes, LBAT and dual ASBT / LBAT inhibitor substances should have at least some degree of bioavailability and free fraction in blood. Since LBAT inhibitor compounds only need to survive from the intestine to the liver, it is expected that relatively low systemic exposure of such compounds will be sufficient, thereby minimizing the potential risk of any side effects in other parts of the body. It is expected that the inhibition of LBAT and ASBT will have at least an additive effect on reducing bile acid concentrations in the liver. It is also expected that dual ASBT / LBAT inhibitors may be able to reduce bile acid levels without inducing diarrhea, as is sometimes observed with ASBT inhibitors.

[0118] Compounds with high LBAT inhibitory potency and sufficient bioavailability are expected to be particularly suitable for the treatment of hepatitis. Compounds with dual ASBT / LBAT inhibitory potency and sufficient bioavailability are expected to be particularly suitable for the treatment of non-alcoholic steatohepatitis (NASH).

[0119] NASH is a common and serious chronic liver disease that resembles alcoholic liver disease, but occurs in people who drink little or no alcohol. In patients with NASH, fat accumulation in the liver, known as nonalcoholic fatty liver disease (NAFLD) or steatosis, and other factors such as high LDL cholesterol and insulin resistance, can induce chronic inflammation in the liver, leading to progressive scarring of tissue, known as fibrosis, and cirrhosis, and then ultimately 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 than healthy subjects (2.2-2.4-fold increase in NASH at fasting and 1.7-2.2-fold increase in NASH at all postprandial time points). These are driven by an increase in taurine- and glycine-conjugated primary and secondary bile acids. Patients with NASH exhibited large variations in their fasting and postprandial bile acid profiles. These results indicate that patients with NASH are more exposed to bile acids during fasting and after meals, including more hydrophobic and cytotoxic secondary species.Increased exposure to bile acids may contribute to liver injury and the pathogenesis of NAFLD and NASH (Ferslew et al., Dig Dis Sci. 2015, vol. 60, pp. 3318-3328).Therefore, ASBT and / or LBAT inhibition is likely to be beneficial for the treatment of NASH.

[0120] 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 medications (Chalasani et al., Hepatology 2018, vol. 67(1), pp. 328-357). NAFLD can be classified into nonalcoholic fatty liver (NAFL) and nonalcoholic 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 hepatocyte ballooning. NASH is defined as the presence of ≥5% hepatic steatosis and inflammation with hepatocellular injury (e.g., ballooning) with or without any hepatic fibrosis. NASH is also commonly associated with liver inflammation and hepatic fibrosis, which can progress to cirrhosis, end-stage liver disease, and hepatocellular carcinoma. Liver fibrosis is not always present in NASH, but when present, the severity of fibrosis may be related to long-term outcome.

[0121] There are many techniques that can be used to evaluate and assess the severity of disease, including whether a subject has NAFLD, and if so, whether the NAFLD is NAFL or NASH. In some embodiments, the severity of NAFLD can be evaluated 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 from Kleiner.

[0122] [Table 6]

[0123] In some embodiments, the 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, the NAS is determined for a sample from a subject prior to administration of a compound of formula (I) or a pharma- ceutically acceptable salt thereof. In some embodiments, the NAS is determined during or after a period of administration of a compound of formula (I) or a pharma- ceutically acceptable salt thereof. In some embodiments, a lower NAS score during or after a period of administration of a compound of formula (I) or a pharma- ceutically acceptable salt thereof compared to before administration of a compound of formula (I) or a pharma- ceutical acceptable salt thereof indicates treatment of NAFLD (e.g., NASH). For example, a decrease in NAS of 1, 2, 3, 4, 5, 6, or 7 indicates treatment of NAFLD (e.g., NASH). In some embodiments, the NAS after administration of a compound of formula (I) or a pharma- ceutical acceptable salt thereof is 7 or less. In some embodiments, the NAS during administration of the compound of formula (I) or a pharma- ceutically acceptable salt thereof is 5 or less, 4 or less, 3 or less, or 2 or less. In some embodiments, the NAS during administration of the compound of formula (I) or a pharma- ceutically acceptable salt thereof is 7 or less. In some embodiments, the NAS during administration of the compound of formula (I) or a pharma- ceutical acceptable salt thereof is 5 or less, 4 or less, 3 or less, or 2 or less. In some embodiments, the NAS after administration of the compound of formula (I) or a pharma- ceutical acceptable salt thereof is 7 or less. In some embodiments, the NAS after administration of the compound of formula (I) or a pharma- ceutical acceptable salt thereof is 5 or less, 4 or less, 3 or less, or 2 or less.

[0124] Further methods of evaluating or assessing NASH in a subject include determining one or more biomarkers (e.g., serum markers and panels) that indicate one or more of hepatic steatosis (e.g., fat accumulation in liver); liver inflammation; liver damage, liver inflammation, liver fibrosis, and / or liver cirrhosis.Further examples of physiological indicators of NASH can include liver morphology, liver stiffness, and size or mass of the liver of the subject.In some embodiments, NASH in a subject is demonstrated by detecting biomarkers that indicate hepatic fat accumulation and liver damage.For example, elevated serum ferritin and low titer of serum autoantibodies can be common features of NASH.

[0125] In some embodiments, methods for assessing NASH include magnetic resonance imaging (either by spectroscopy or proton density fat fraction measurement (MRI-PDFF)) to quantify steatosis, transient elastography (FIBROSCAN®) to diagnose significant liver fibrosis and / or cirrhosis, hepatic venous pressure gradient (HPVG), liver stiffness measurement on MRE, and evaluation of histological features of liver biopsy. In some embodiments, magnetic resonance imaging is used to detect one or more of 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.

[0126] In some embodiments, treatment of NASH can include a reduction in one or more symptoms associated with NASH; a reduction in the amount of hepatic steatosis; a reduction in NAS; a reduction in liver inflammation; a reduction in the level of a biomarker indicative of one or more of liver damage, inflammation, liver fibrosis, and / or cirrhosis; and a reduction in fibrosis and / or cirrhosis, a lack of further progression of fibrosis and / or cirrhosis, or a delay in the progression of fibrosis and / or cirrhosis in a subject following administration of one or more doses of a compound of Formula (I) or a pharmacologic acceptable salt thereof.

[0127] In some embodiments, treating NASH includes reducing one or more symptoms associated with NASH in a subject. Exemplary symptoms may include one or more of: liver enlargement, fatigue, pain in the upper right quadrant, abdominal distension, enlargement of blood vessels just below the surface of the skin, breast enlargement in men, spleen enlargement, palmar erythema, jaundice, and pruritus. In some embodiments, the subject is asymptomatic. In some embodiments, the subject's overall weight does not increase. In some embodiments, the subject's overall weight decreases. In some embodiments, the subject's body mass index (BMI) does not increase. In some embodiments, the subject's body mass index (BMI) decreases. In some embodiments, the subject's waist-to-hip ratio (WTH) does not increase. In some embodiments, the subject's waist-to-hip ratio (WTH) decreases.

[0128] In some embodiments, the treatment of NASH can be evaluated by measuring hepatic steatosis.In some embodiments, the treatment of NASH comprises reducing hepatic steatosis after administration of the compound of formula (I) or a pharma- ceutical acceptable salt thereof as described herein. In some embodiments, hepatic steatosis is determined by one or more methods selected from the group consisting of ultrasonography, computed tomography (CT), magnetic resonance imaging, magnetic resonance spectroscopy (MRS), magnetic resonance elastography (MRE), transient elastography (TE) (e.g., FIBROSCAN®), measurement of liver size or mass, or by liver biopsy (see, e.g., Di Lascio et al., Ultrasound Med Biol. 2018, 44(8), 1585-1596; Lv et al., J Clin Transl Hepatol. 2018, 6(2), 217-221; Reeder et al., J Magn Reson Imaging. 2011, 34(4), spcone; and de Ledinghen V et al., J Gastroenterol Hepatol. 2016, vol. 31(4), pp. 848-855, each of which is incorporated herein by reference in its entirety. A subject diagnosed with NASH may have greater than about 5% hepatic steatosis, e.g., greater than about 5% to about 25%, about 25% to about 45%, about 45% to about 65%, or greater than about 65% hepatic steatosis. In some embodiments, a subject with greater than about 5% to about 33% hepatic steatosis has stage 1 hepatic steatosis, a subject with about 33% to about 66% hepatic steatosis has stage 2 hepatic steatosis, and a subject with greater than about 66% hepatic steatosis has stage 3 hepatic steatosis.

[0129] In some embodiments, the amount of hepatic steatosis is determined before administration of the compound of formula (I) or a pharma- ceutically 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 pharma- ceutically 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 pharma- ceutically acceptable salt thereof compared to before administration of the compound of formula (I) or a pharma- ceutical 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 by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% indicates treatment of NASH.

[0130] 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 a liver biopsy sample 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 pharma- ceutical acceptable salt thereof. In some embodiments, the severity of liver inflammation is determined during or after administration of the compound of formula (I) or a pharma- ceutical acceptable salt thereof. In some embodiments, a reduction in the severity of liver inflammation during or after administration of a compound of Formula (I) or a pharma- ceutically acceptable salt thereof, compared to before administration of the compound of Formula (I) or a pharma- ceutically acceptable salt thereof, indicates treatment of NASH. For example, a reduction 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 reduction 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.

[0131] In some embodiments, the treatment of NASH includes treating fibrosis and / or cirrhosis, such as reducing the severity of fibrosis, lack of further progression of fibrosis and / or cirrhosis, or delaying 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 liver fibrosis, and histological features of 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®), fibrosis-scoring systems, biomarkers of liver 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. 846-54), 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.

[0132] In some embodiments, the severity of fibrosis is determined before administration of the compound of formula (I) or a pharma- ceutically acceptable salt thereof. In some embodiments, the severity of fibrosis is determined during or after administration of the compound of formula (I) or a pharma- ceutically acceptable salt thereof. In some embodiments, a reduction in the severity of fibrosis during or after administration of the compound of formula (I) or a pharma- ceutically acceptable salt thereof compared to before administration of the compound of formula (I) or a pharma- cically acceptable salt thereof indicates treatment of NASH. In some embodiments, a reduction in the severity of fibrosis, a lack of further progression of fibrosis and / or cirrhosis, or a 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, the reduction in the stage of fibrosis is a reduction in the severity of fibrosis. For example, a reduction of 1, 2, 3, or 4 stages is a reduction in the severity of fibrosis. In some embodiments, a reduction 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 is reduced from stage 4 to stage 3, from stage 4 to stage 2, from stage 4 to stage 1, from stage 4 to stage 0, from stage 3 to stage 2, from stage 3 to stage 1, from stage 3 to stage 0, from stage 2 to stage 1, from stage 2 to stage 0, or from stage 1 to stage 0, after administration of a compound of formula (I) or a pharma- ceutically acceptable salt thereof, compared to before administration of a compound of formula (I) or a pharma-ceutically acceptable salt thereof. In some embodiments.The stage of fibrosis is reduced from stage 4 to stage 3, stage 4 to stage 2, stage 4 to stage 1, stage 4 to stage 0, stage 3 to stage 2, stage 3 to stage 1, stage 3 to stage 0, stage 2 to stage 1, stage 2 to stage 0, or stage 1 to stage 0, during the period of administration of the compound of Formula (I) or a pharma- ceutically acceptable salt thereof, as compared to before administration of the compound of Formula (I) or a pharma- ceutically acceptable salt thereof. In some embodiments, the stage of fibrosis is reduced from stage 4 to stage 3, stage 4 to stage 2, stage 4 to stage 1, stage 4 to stage 0, stage 3 to stage 2, stage 3 to stage 1, stage 3 to stage 0, stage 2 to stage 1, stage 2 to stage 0, or stage 1 to stage 0, during the period of administration of the compound of Formula (I) or a pharma- ceutically acceptable salt thereof, as compared to before administration of the compound of Formula (I) or a pharma- ceutically acceptable salt thereof.

[0133] In some embodiments, the presence of NASH is determined by one or more biomarkers that indicate one or more of liver damage, inflammation, liver fibrosis, and / or liver cirrhosis, or a scoring system thereof.In some embodiments, the severity of NASH is determined by one or more biomarkers that indicate one or more of liver damage, inflammation, liver fibrosis, and / or liver 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 that encodes the biomarker and / or the peptide or protein of the biomarker.Non-limiting examples of biomarkers indicative of one or more liver damage, inflammation, liver fibrosis, and / or cirrhosis and / or scoring systems thereof include the aspartate aminotransferase (AST) to platelet ratio index (APRI); the aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio (AAR); the FIB-4 score (see, e.g., McPherson et al., Gut score), based on the APRI, alanine aminotransferase (ALT) level, and the age of the subject. 2010, 59(9), 1265-9, which is incorporated herein by reference in its entirety); hyaluronic acid; proinflammatory cytokines; a panel of biomarkers consisting of α2-macroglobulin, haptoglobin, apolipoprotein A1, bilirubin, gamma glutamyl transpeptidase (GGT) 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 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, 51(10):1867-1873), and a panel of biomarkers consisting of tissue inhibitor of metalloproteinase-1, hyaluronic acid, and alpha2-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. 2013 Aug;59(2):236-42, which is incorporated herein by reference in its entirety).In some embodiments, the presence of fibrosis is determined by a panel of biomarkers consisting of α2-macroglobulin, haptoglobin, apolipoprotein A1, bilirubin, gamma glutamyl transpeptidase (GGT) in combination with the subject's age and sex to generate a FIB-4 score, a measure of fibrosis and necroinflammatory activity in the liver (e.g., FIBROTEST®, FIBROSURE®), a panel of biomarkers consisting of bilirubin, gamma glutamyl transferase, hyaluronic acid, α2-macroglobulin in combination with the subject's age and sex (e.g., HEPASCORE®; see, e.g., Adams et al., Clin. Chem. 2005, 51(10), pp. 1867-1873), and a panel of biomarkers consisting of tissue inhibitor of metalloproteinase 1, hyaluronic acid, and alpha2-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) is not increased. In some embodiments, the level of aspartate aminotransferase (AST) is decreased. In some embodiments, the level of alanine aminotransferase (ALT) is not increased. In some embodiments, the level of alanine aminotransferase (ALT) is decreased. In some embodiments, the "level" of an enzyme refers to the concentration of the enzyme, e.g., in blood. For example, AST or ALT levels can be expressed as units / L.

[0134] In some embodiments, the severity of fibrosis is assessed using the FIB-4 score, a panel of biomarkers consisting of α2-macroglobulin, haptoglobin, apolipoprotein A1, bilirubin, gamma glutamyl transpeptidase (GGT) in combination with the subject's age and sex to generate a measure of fibrosis and necroinflammatory activity in the liver (e.g., FIBROTEST®, FIBROSURE®), a panel of biomarkers consisting of bilirubin, gamma glutamyl transferase, hyaluronic acid, α2-macroglobulin in combination with the subject's age and sex (e.g., HEPASCORE®; see, e.g., Adams et al., Clin. Chem. 2005, 51(10), 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).

[0135] In some embodiments, liver inflammation is determined by the level of liver inflammation biomarkers, for example, the level of proinflammatory cytokines. Non-limiting examples of biomarkers indicative of liver inflammation include interleukin-(IL)6, interleukin-(IL)1β, tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β, monocyte chemotactic protein (MCP)-1, C-reactive protein (CRP), PAI-1, and collagen isoforms, for example, Col1a1, Col1a2, and Col4a1 (see, for example, 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 assessed by changes in macrophage infiltration, for example, by measuring changes in CD68 expression levels. In some embodiments, liver inflammation can be determined by measuring or monitoring serum or circulating levels of one or more of interleukin-(IL)6, interleukin-(IL)1β, tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β, monocyte chemotactic protein (MCP)-1, and C-reactive protein (CRP).

[0136] In some embodiments, the level of one or more biomarkers indicative of one or more of liver damage, inflammation, liver fibrosis, and / or liver cirrhosis is determined for a sample from a subject before administration of a compound of formula (I) or a pharma- ceutically acceptable salt thereof. In some embodiments, the level of one or more biomarkers indicative of one or more of liver damage, inflammation, liver fibrosis, and / or liver cirrhosis is determined during or after administration of a compound of formula (I) or a pharma- ceutically acceptable salt thereof. In some embodiments, a decrease in the level of one or more biomarkers indicative of one or more of liver damage, inflammation, liver fibrosis, and / or liver cirrhosis during or after administration of a compound of formula (I) or a pharma- ceutically acceptable salt thereof compared to before administration of a compound of formula (I) or a pharma- ceutically acceptable salt thereof indicates treatment of NASH. For example, a reduction 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% in the level of one or more biomarkers indicative of one or more of liver damage, inflammation, liver fibrosis, and / or cirrhosis is indicative of treatment of NASH. In some embodiments, the reduction in the level of one or more biomarkers indicative of one or more of liver damage, inflammation, liver fibrosis, and / or cirrhosis following administration of a compound of Formula (I) or a pharma- ceutically 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 reduction in the level of one or more biomarkers indicative of one or more of liver damage, inflammation, liver fibrosis, and / or cirrhosis during administration of a compound of Formula (I) or a pharma- ceutically 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 reduction in the level of one or more biomarkers indicative of one or more of liver damage, inflammation, liver fibrosis, and / or cirrhosis after a period of administration of a compound of Formula (I) or a pharma- ceutically 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%.

[0137] In some embodiments, treating NASH reduces the level of serum bile acids in the 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, for example, by 10% to 40%, 20% to 50%, 30% to 60%, 40% to 70%, 50% to 80%, or more than 90% of the level of serum bile acids before administration of the compound of formula (I) or a pharma- ceutical acceptable salt thereof. In some embodiments, the NASH is NASH with associated cholestasis. In cholestasis, release of bile, including bile acids, from the liver is blocked. Bile acids can cause hepatocellular damage (see, e.g., Perez MJ, Briz O. World J. Gastroenterol. 2009, vol. 15(14), pp. 1677-1689), which can lead to or increase the development of fibrosis (e.g., cirrhosis) and increase the risk of hepatocellular carcinoma (see, e.g., Sorrentino P et al., Dig. Dis. Sci. 2005, vol. 50(6), pp. 1130-1135, and Satapathy SK and Sanyal AJ. Semin. Liver Dis. 2015, vol. 35(3), pp. 221-235, each of which is incorporated herein by reference in its entirety). In some embodiments, the treatment of NASH includes treating pruritus. In some embodiments, the treatment of NASH with associated cholestasis includes treating pruritus. In some embodiments, subjects with NASH with associated cholestasis have pruritus.

[0138] Exemplary biomarkers for NASH are shown in Table 7.

[0139] [Table 7]

[0140] References for 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 US Patent No. 9,872,844

[0141] Some compounds of formula (I) or pharma- ceutically acceptable salts thereof may exhibit a higher free fraction in plasma. In some embodiments, the free fraction is greater than about 0.2%, such as greater than about 0.4%, for example greater than about 0.6%, for example greater than about 0.8%, for example greater than about 1.0%, for example greater than about 1.25%, for example greater than about 1.5%, for example greater than about 1.75%, for example greater than about 2.0%, for example greater than about 2.5%, for example greater than about 3%, for example greater than about 4%, for example greater than about 5%, for example greater than about 7.5%, for example greater than about 10%, or for example greater than about 20%.

[0142] Some compounds of formula (I) or pharma- ceutically 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%, for example greater than about 0.6%, such as greater than about 0.8%, for example greater than about 1.0%, such as greater than about 2%, for example greater than about 3%, such as greater than about 5%, for example greater than about 7.5%, such as greater than about 10%, for example greater than about 15%, for example greater than about 20%, for example greater than about 30%, or for example greater than about 50%.

[0143] After absorption from the intestine, some compounds of formula (I) or pharma- ceutically acceptable salts thereof can circulate through the enterohepatic circulation.In some embodiments, the fraction of the compound circulating through the enterohepatic circulation is greater than about 0.1%, such as greater than about 0.2%, for example greater than about 0.3%, for example greater than about 0.5%, for example greater than about 1.0%, for example greater than about 1.5%, for example greater than about 2%, for example greater than about 3%, for example greater than about 5%, for example greater than about 7%, for example greater than about 10%, for example greater than about 15%, for example greater than about 20%, for example greater than about 30%, or for example greater than about 50%.

[0144] Some compounds of formula (I) or pharma- ceutically acceptable salts thereof may cause renal excretion of bile salts. In some embodiments, the fraction of circulating bile acids excreted by the renal route is greater than about 1%, such as greater than about 2%, for example greater than about 5%, for example greater than about 7%, for example greater than about 10%, for example greater than about 15%, for example greater than about 20%, or for example greater than about 25%.

[0145] Some compounds of formula (I) or pharma- ceutically acceptable salts thereof may exhibit improved or optimal permeability. Permeability may be measured in Caco2 cells, and values ​​are given as Papp (apparent permeability) values ​​in cm / s. In some embodiments, the permeability is at least about 0.1 x 10 -6 cm / s, e.g., about 0.2×10 -6 cm / s, e.g., about 0.4×10 -6 cm / s, e.g., about 0.7×10 -6 cm / s, e.g., about 1.0×10 -6 cm / s, e.g., about 2×10 -6 cm / s, e.g., about 3×10 -6 cm / s, e.g., about 5×10 -6 cm / s, e.g., about 7×10 -6 cm / s, e.g., about 10×10 -6 cm / s, e.g., about 15×10 -6 Over cm / s.

[0146] Some compounds of formula (I) or pharma- ceutically 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%, for example greater than about 10%, for example greater than about 15%, for example greater than about 20%, for example greater than about 30%, for example greater than about 40%, for example greater than about 50%, for example greater than about 60%, for example greater than about 70%, or for example greater than about 80%. In other embodiments, the oral bioavailability is between about 10% and about 90%, for example between about 20% and about 80%, for example between about 30% and about 70%, or for example between about 40% and about 60%.

[0147] Some of the compounds of formula (I), or pharma- ceutically acceptable salts thereof, may be substrates for relevant transporters in the kidney.

[0148] Some compounds of formula (I) or pharma- ceutically acceptable salts thereof may produce concentrations of bile acids in the intestine, liver and serum that do not cause adverse gastrointestinal effects.

[0149] Some compounds of formula (I) or pharma- ceutical acceptable salts thereof can reduce the concentration of bile acids in the liver without causing gastrointestinal disorders such as diarrhea.

[0150] As used herein, the terms "treatment", "treat" and "treating" refer to the regression, alleviation, delay of onset, or inhibition of progression of a disease or disorder as described herein, or one or more symptoms thereof. 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., taking into account a history of the condition and / or taking into account genetic or other susceptibility factors) prior to the onset of symptoms. Treatment may also be continued after the condition has resolved, e.g., to prevent or delay its recurrence.

[0151] Suitable pharma- ceutically acceptable salts of the compounds of the invention are, for example, base addition salts of compounds of the invention which are sufficiently acidic, such as alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts), ammonium salts, or salts with organic bases which provide a physiologically acceptable cation, such as, for example, salts with methylamine, dimethylamine, trimethylamine, piperidine, morpholine, or tris-(2-hydroxyethyl)amine.

[0152] Some compounds of formula (I) or pharma- ceutically 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 that possess ASBT and / or LBAT inhibitory activity. The present invention also encompasses any and all tautomers of compounds of formula (I) or pharma- ceutically acceptable salts thereof that possess ASBT and / or LBAT inhibitory activity. Certain compounds of formula (I) or pharma- ceutically acceptable salts thereof may exist in solvated forms, such as, for example, hydrated forms, as well as unsolvated forms. It should be understood that the present invention encompasses all such solvated forms that possess ASBT and / or LBAT inhibitory activity.

[0153] In another aspect, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (I) or its pharma- ceutical acceptable salt and one or more pharma- ceutical acceptable excipients.The excipients can include, for example, fillers, binders, disintegrants, glidants, and lubricants.In general, the pharmaceutical composition can be prepared in a conventional manner using conventional excipients.

[0154] Examples of suitable fillers include, but are not limited to, dicalcium phosphate dihydrate, calcium sulfate, lactose (such as lactose monohydrate), sucrose, mannitol, sorbitol, cellulose, microcrystalline cellulose, dry starch, hydrolyzed starch, and pregelatinized starch.

[0155] Examples of suitable binders include, but are not limited to, starch, pregelatinized starch, gelatin, sugars (such as sucrose, glucose, dextrose, lactose, and sorbitol), polyethylene glycol, waxes, natural and synthetic gums (such as gum arabic and gum tragacanth), sodium alginate, cellulose derivatives (such as hydroxypropylmethylcellulose (or hypromellose), hydroxypropylcellulose, and ethylcellulose), and synthetic polymers (such as acrylic acid and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, aminoalkyl methacrylate copolymers, polyacrylic acid / polymethacrylic acid copolymers, and polyvinylpyrrolidone (povidone)).

[0156] Examples of suitable disintegrants include, but are not limited to, dry starch, modified starches (such as (partially) pregelatinized starch, sodium starch glycolate, and sodium carboxymethyl starch), alginic acid, cellulose derivatives (such as sodium carboxymethylcellulose, hydroxypropylcellulose, and low-substituted hydroxypropylcellulose (L-HPC)), and crosslinked polymers (such as carmellose, croscarmellose sodium, carmellose calcium, and crosslinked PVP (crospovidone)).

[0157] 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 oxide, starch, sodium lauryl sulfate, boric acid, magnesium oxide, waxes (such as carnauba wax), hydrogenated oils, polyethylene glycol, sodium benzoate, polyethylene glycol, and mineral oil.

[0158] The pharmaceutical composition may be conventionally coated with one or more coating layers. An enteric coating layer or a coating layer for delayed or targeted release of the compound of formula (I) or its pharma- ceutical acceptable salt is also contemplated. The coating layer may include one or more coating agents, and may optionally include a plasticizer and / or a pigment (or colorant).

[0159] Examples of suitable coating agents include, but are not limited to, cellulosic 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), vinylic polymers (such as polyvinyl alcohol), 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.).

[0160] Examples of suitable plasticizers include, but are not limited to, triethyl citrate, glyceryl triacetate, tributyl citrate, diethyl phthalate, acetyl tributyl citrate, dibutyl phthalate, dibutyl sebacate, and polyethylene glycol.

[0161] Examples of suitable pigments include, but are not limited to, titanium dioxide, iron oxide (such as yellow, brown, red, or black iron oxide), and barium sulfate.

[0162] The pharmaceutical composition may be in a form suitable for oral administration, injection (including intravenous, subcutaneous, intramuscular, and intravascular injection), topical administration for rectal administration, etc. In a preferred embodiment, the pharmaceutical composition is in a form suitable for oral administration, such as a tablet or capsule.

[0163] 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, as well as other factors normally considered by the attending physician when determining the regimen and dosage level appropriate for a particular patient.

[0164] The amount of compound to be administered will vary depending on the patient being treated and can range from about 1 μg / kg body weight to about 50 mg / kg body weight per day. A unit dosage form such as a tablet or capsule will usually contain about 1 to about 250 mg of active ingredient, for example about 1 to about 100 mg, or for example about 1 to about 50 mg, or for example 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 active ingredient. The daily dose can be administered as a single dose or divided into one, two, three or more unit doses. The daily dose of the orally administered bile acid modulator 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.

[0165] In another aspect, the present invention relates to a compound of formula (I) or a pharma- ceutically acceptable salt thereof for use as a medicament. The present invention also relates to the use of a compound of formula (I) or a pharma-ceutically acceptable salt thereof as a medicament.

[0166] In another aspect, the present invention relates to a compound of formula (I) or a pharma- ceutically 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 pharma- ceutically 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, comprising administering to a subject in need of such treatment or prevention a therapeutically effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof.

[0167] Combination therapy In one aspect of the present invention, the compound of formula (I) or its pharma- ceutical acceptable salt 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 its pharma-ceutical acceptable salt and at least one other therapeutically active agent may be administered simultaneously, sequentially, or separately.The therapeutically active agents suitable for combination with the compound of formula (I) include, but are not limited to, known active agents useful for treating any of the above-mentioned conditions, disorders, and diseases.

[0168] In one embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in combination with another ASBT inhibitor. Suitable ASBT inhibitors include 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 No. 3210977, all of which are incorporated herein by reference in their entireties.Specific examples of suitable ASBT inhibitors include 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-1'-phenyl-1'-[N'-(carboxymethyl)carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-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 (odebixibat).

[0169] In another embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in combination with a bile acid binder (also called 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 incorporated herein by reference in their entirety.

[0170] In another embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in combination with a DPP-IV inhibitor, such as a gliptin, such as sitagliptin, vildagliptin, saxagliptin, linagliptin, gemigliptin, anagliptin, teneligliptin, alogliptin, trelagliptin, omarigliptin, evogliptin, gosogliptin, and dutogliptin, or a pharma- ceutically acceptable salt thereof.

[0171] In another embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in combination with an HMG CoA reductase inhibitor, such as fluvastatin, lovastatin, pravastatin, simvastatin, atorvastatin, pitavastatin, cerivastatin, mevastatin, rosuvastatin, bervastatin, or dalvastatin, or a pharma- ceutically acceptable salt thereof.

[0172] In another embodiment, the compounds of formula (I) or a pharma- ceutically acceptable salt thereof are administered in combination with a cholesterol absorption inhibitor, such as, for example, ezetimibe, or a pharma- ceutically acceptable salt thereof.

[0173] In another embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in combination with a PPARα agonist, such as a fibrate, for example, clofibrate, bezafibrate, ciprofibrate, clinofibrate, clofibrate, fenofibrate, gemfibrozil, lonifibrate, and simfribrate, or a pharma- ceutically acceptable salt thereof.

[0174] In another embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in combination with a PPARγ agonist, such as a thiazolidinedione, for example, pioglitazone, rosiglitazone, and lobeglitazone, or a pharma- ceutically acceptable salt thereof.

[0175] In another embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in combination with a dual PPAR α / γ agonist, such as a glitazar, for example saroglitazar, aleglitazar, muraglitazar, or tesaglitazar, or a pharma- ceutically acceptable salt thereof.

[0176] In another embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in combination with a dual PPAR alpha / delta agonist, such as elafibranor.

[0177] In yet another embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in combination with a pan-PPAR agonist (i.e., a PPAR agonist with activity across all subtypes: alpha, gamma, and delta), such as IVA337.

[0178] In another embodiment, the compound of formula (I) or a pharma- ceutically 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.

[0179] In another embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in combination with a TGR5 receptor modulator, for example a TGR5 agonist, for example 6α-ethyl-23(S)-methylcholic acid (INT-777).

[0180] In another embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in combination with a dual FXR / TGR5 agonist, such as INT-767.

[0181] In another embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in combination with ursodeoxycholic acid (UDCA).In yet another embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in combination with norursodeoxycholic acid (norUDCA).

[0182] In another embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in combination with an FGF19 modulator, such as NGM282.

[0183] In another embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in combination with an FGF21 agonist, such as BMS-986036.

[0184] In another embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in combination with an integrin inhibitor, such as PLN-74809 and PLN-1474.

[0185] In another embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in combination with a CCR2 / CCR5 inhibitor, such as, for example, cenicriviroc.

[0186] In another embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in combination with a caspase protease inhibitor, such as emricasan.

[0187] In another embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in combination with a galectin-3 inhibitor, such as GR-MD-02.

[0188] In another embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in combination with a stearoyl-CoA desaturase (SCD) inhibitor, such as aramchol (arachidylamide cholanic acid).

[0189] In another embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in combination with an apoptosis signal-regulating kinase 1 (ASK1) inhibitor, such as selonsertib.

[0190] In another embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in combination with a LOXL2 inhibitor, such as simtuzumab.

[0191] In another embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in combination with an ACC inhibitor, such as GS-0976.

[0192] In another embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in combination with a thyroid hormone receptor beta agonist, such as MGL3196.

[0193] In another embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in combination with a GLP-1 agonist, such as liraglutide.

[0194] In another embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in combination with a glucagon-like peptide and a dual agonist of the glucagon receptor, such as SAR425899.

[0195] In another embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in combination with a mitochondrial pyruvate transporter inhibitor, such as MSDC-0602K.

[0196] In another embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in combination with an antioxidant, such as vitamin E.

[0197] In another embodiment, the compound of formula (I) or a pharma- ceutically 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.

[0198] In another embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in combination with a diacylglycerol O-acyltransferase 2 (DGAT2) inhibitor, such as DGAT2RX and PF-06865571.

[0199] In another embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in combination with a fatty acid synthase (FASN) inhibitor, such as TVB-2640.

[0200] In another embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in combination with an AMP-activated protein kinase (AMPK) activator, such as PXL-770.

[0201] In another embodiment, the compound of formula (I) or a pharma- ceutically 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.

[0202] In another embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in combination with a cannabinoid receptor 1 (CB1) antagonist, such as IM102.

[0203] In another embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in combination with Klotho-beta (KLB) and a fibroblast growth factor receptor (FGFR) activator, such as MK-3655 (formerly known as NGM-313).

[0204] In another embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in combination with a chemokine (cc motif) ligand 24 (CCL24) inhibitor, such as CM101.

[0205] In another embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in combination with an A3 antagonist, such as PBF-1650.

[0206] In another embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in combination with a P2x7 receptor antagonist, such as SGM1019.

[0207] In another embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in combination with a P2Y13 receptor agonist, such as CER-209.

[0208] In another embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in combination with a sulfated oxysterol, such as Dur-928.

[0209] In another embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in combination with a leukotriene D4 (LTD4) receptor antagonist, such as MN-001.

[0210] In another embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in combination with a type 1 natural killer T cell (NKT1) inhibitor, such as GRI-0621.

[0211] In another embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in combination with an anti-lipopolysaccharide (LPS) compound, such as IMM-124E.

[0212] In another embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in combination with a VAP1 inhibitor, such as, for example, BI1467335.

[0213] In another embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in combination with an A3 adenosine receptor agonist, such as CF-102.

[0214] In another embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in combination with a SIRT-1 activator, such as NS-20.

[0215] In another embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in combination with a nicotinic acid receptor 1 agonist, such as ARI-3037MO.

[0216] In another embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in combination with a TLR4 antagonist, such as JKB-121.

[0217] In another embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in combination with a ketohexokinase inhibitor, such as PF-06835919.

[0218] In another embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in combination with an adiponectin receptor agonist, such as ADP-335.

[0219] In another embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in combination with an autotaxin inhibitor, such as PAT-505 and PF8380.

[0220] In another embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in combination with a chemokine (cc motif) receptor 3 (CCR3) antagonist, such as bertilimumab.

[0221] In another embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in combination with a chloride channel agonist such as cobiprostone and lubiprostone.

[0222] In another embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in combination with a heat shock protein 47 (HSP47) inhibitor, such as ND-L02-s0201.

[0223] In another embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in combination with a sterol regulatory region binding protein (SREBP) transcription factor inhibitor, such as CAT-2003 and MDV-4463.

[0224] In another embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in combination with a biguanidine, such as metformin.

[0225] In another embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in combination with insulin.

[0226] In another embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in combination with a glycogen phosphorylase inhibitor and / or a glucose-6-phosphatase inhibitor.

[0227] In another embodiment, the compounds of formula (I) or a pharma- ceutically acceptable salt thereof are administered in combination with a sulfonylurea such as, for example, glipizide, glibenclamide, and glimepiride.

[0228] In another embodiment, the compounds of formula (I) or a pharma- ceutically acceptable salt thereof are administered in combination with a meglitinide, such as repaglinide, nateglinide, and ormiglitinide.

[0229] In another embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in combination with a glucosidase inhibitor such as, for example, acarbose or miglitol.

[0230] In another embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in combination with a squalene synthase inhibitor, such as TAK-475.

[0231] In another embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in combination with a PTPB1 inhibitor, such as, for example, trodusquemine, eltiprotafib, JTT-551, and claramine.

[0232] Preparation of compounds The compounds of the present invention can be prepared by the processes described below as free acids or pharma- ceutical acceptable salts thereof. Throughout the following description of such processes, it is understood that, where appropriate, suitable protecting groups will be added and subsequently removed from various reactants and intermediates in a manner that is easily understood by those skilled in the art of organic synthesis. 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 PGM Wutz and TW Greene, John Wiley & Sons, Hoboken, 2006.

[0233] General method All solvents used were of analytical grade. Commercially available anhydrous solvents were routinely used in the reactions. Starting materials were available from commercial sources or prepared according to literature procedures. 3-Butyl-8-hydroxy-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide and 3-ethyl-8-hydroxy-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide can be prepared as described in WO 2021 / 110883 (intermediates 7 and 18, respectively). Room temperature refers to 20-25°C. Compositions of solvent mixtures are given as volume percentages or volume ratios.

[0234] LCMS: Instrument name: Agilent 1290 infinity II. Method A: Mobile phase: A: 0.1% HCOOH:ACN (95:5) in water, B: ACN; flow rate: 1.5 mL / min; column: ZORBAX XDB C-18 (50 x 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 x 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: ACN; Flow rate: 1.0 mL / min; Column: Zorbax Extend C18 (50×4.6 mm), 5 μM. Method K: 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.

[0235] 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. Device name: Shimadzu Nexera X2 LC / 2020 MSD Method B: Mobile phase: A: 0.1% HCOOH in water, B: ACN; flow rate: 0.8 mL / min; column: Acquity UPLC BEH C18 (2.1 × 50) mm; 1.7 μm.

[0236] HPLC: Instrument Name: Agilent 1260 Infinity II Series Instrument (Use % with UV detection (max plot) as below). 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 x 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).

[0237] Chiral SFC: Equipment name: PIC SFC 10 (for analysis) The ratio of CO2 to 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 x 4.6 mm, 5 μm). Method D: Mobile phase: methanol; flow rate: 3 mL / min; column: Lux A1 (250 x 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 x 4.6 mm, 5 μm). Method M: Mobile phase: 0.5% isopropylamine in IPA; flow rate: 5 mL / min; column: YMC Cellulose-SC (250 x 4.6 mm, 5 μm). Method N: Mobile phase: methanol, flow rate: 5 mL / min; column: Chiralcel OX-H (250 x 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 x 4.6 mm, 5 μm). Method P: Mobile phase: 0.5% isopropylamine in methanol, flow rate: 3 mL / min; column: Chiralpak AS-H (250 x 4.6 mm, 5 μm). Method Q: Mobile phase: IPA, flow rate: 3 mL / min; Column: Lux A1 (250 x 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 x 4.6 mm, 5 μm). Method S: Mobile phase: 0.5% isopropylamine in methanol, flow rate: 3 mL / min; column: Chiralpak OX-H (250 x 4.6 mm, 5 μm). Method T: Mobile phase: 0.5% isopropylamine in IPA, flow rate: 4 mL / min; column: YMC Cellulose-SB (250×4.6 mm, 5 μm). Method U: Mobile phase: 0.5% isopropylamine in IPA, flow rate: 3 mL / min; column: Chiralpak AS-H (250 x 4.6 mm, 5 μm).

[0238] Preparative HPLC: Instrument 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: 10mM NH4OAc in water; B: ACN; flow rate: 35mL / min; column: X select C18 (30 x 150mm, 5μm). Method C: Mobile phase: A: 10 mM NH4HCO3 in water; B: ACN; Flow rate: 1.0 mL / min; Column: XBridge C8 (50 x 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).

[0239] Chiral Prep SFC: Device name: PIC SFC 100 and PSC SFC 400 The ratio of CO2 to 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 x 30 mm, 5 μm). Method D: Mobile phase: methanol; flow rate: 3 mL / min; column: Chiral CCS (250 x 30 mm, 5 μm). Method E: Mobile phase: methanol; flow rate: 3 mL / min; column: Lux A1 (250 x 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 x 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 x 30 mm, 5 μm).

[0240] Abbreviation ACN Acetonitrile BOC tert-butoxycarbonyl DBAD Di-tert-butyl azodicarboxylate DCM Dichloromethane DMF Dimethylformamide HPLC High Performance Liquid Chromatography IPA Isopropyl Alcohol LCMS Liquid Chromatography Mass Spectrometry NMP N-Methyl-2-pyrrolidone PE Petroleum Ether SFC Supercritical Fluid Chromatography TFA Trifluoroacetic acid THF Tetrahydrofuran TLC Thin Layer Chromatography UPLC Ultra High Performance Liquid Chromatography

[0241] The present invention will now be illustrated by the following examples, which are not intended to limit the invention in any way. All citations and references are incorporated by reference. EXAMPLES

[0242] Intermediate 1 2-((tert-butoxycarbonyl)amino)hexanoic acid

[0243] [ka]

[0244] To a solution of 2-aminohexanoic acid (25 g, 0.19 mol) in water (250 mL) and THF (250 mL), NaHCO3 (48 g, 0.57 mol) and Boc anhydride (52.2 mL, 0.23 mol) were added and the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was cooled, quenched and acidified using 1.5 N HCl. The reaction mixture was extracted with EtOAc (2 x 150 mL). The combined organic layers were washed with ice-cold water (150 mL) and brine (150 mL), dried over anhydrous Na2SO4 and concentrated to give the title compound. Yield: 45.5 g (crude, white solid). 1 H NMR (400 MHz, DMSO-d6): δ 5.10-4.98 (m, 1H), 4.33-4.30 (m, 1H), 1.95-1.81 (m, 1H), 1.75-1.55 (m, 1H), 1.46 (s, 10H), 1.45-1.31 (m, 4H), 0.93 (t, J = 7.2 Hz, 3H). LCMS: (Method E) 132.2 (M + -Boc+H), Rt. 2.36 minutes, 99.98% (max).

[0245] Intermediate 2 tert-Butyl (1-oxo-1-(phenylamino)hexan-2-yl)carbamate

[0246] [ka]

[0247] To a stirred solution of 2-((tert-butoxycarbonyl)amino)hexanoic acid (Intermediate 1; 45.5 g, 0.196 mol) in DMF (150 mL), triethylamine (54.83 mL, 0.39 mol) was added and the reaction mixture was cooled to 0° C. 1-Propanephosphonic anhydride solution (50% in EtOAc; 75.1 g, 0.23 mol) and aniline (18 g, 0.196 mol) were added 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 ice-cold water (50 mL) and diluted with EtOAc (200 mL). The aqueous layer was washed with ice-cold water (200 mL) and brine (200 mL), then dried over anhydrous Na2SO4 and filtered off. The organic portion was concentrated under vacuum to give the title compound. Yield: 82% (49.7 g, white solid). 1 H NMR (400 MHz, DMSO-d6): δ 9.93 (s, 1H), 7.60 (d, J = 7.6 Hz, 2H), 7.30 (t, J = 8.0 Hz, 2H), 7.06-6.99 (m, 2H), 4.07-4.02 (m, 1H), 1.63-1.56 (m, 2H), 1.46-1.28 (m, 13H), 0.86 (t, J = 6.8 Hz, 3H). LCMS: (Method E) 207.0 (M + -Boc+H), Rt. 2.69 minutes, 91.20% (max).

[0248] Intermediate 3 2-Amino-N-phenylhexanamide

[0249] [ka]

[0250] To a solution of tert-butyl (1-oxo-1-(phenylamino)hexan-2-yl)carbamate (Intermediate 2; 49.7 g, 0.162 mol) in 1,4-dioxane (500 mL) at 0° C. was added a solution of HCl in 1,4-dioxane (4 M, 199 mL) and the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under vacuum and the resulting residue was quenched with saturated NaHCO3 solution. The aqueous layer was extracted with EtOAc (2×200 mL). The combined organic layers were washed with brine (200 mL) and dried over anhydrous Na2SO4. The organic portion was filtered and concentrated under vacuum to give the title compound. Yield: 95% (32 g, colorless gum). 1 H NMR (400 MHz, DMSO-d6): δ 10.20-9.66 (m, 1H), 7.64 (dd, J = 4.8, 2.4 Hz, 2H), 7.32-7.27 (m, 2H), 7.06-7.02 (m, 1H), 3.29-3.26 (m, 1H), 1.67-1.61 (m, 1H), 1.46-1.27 (m, 5H), 0.89-0.85 (m, 3H). LCMS: (Method B) 207.2 (M + +H), Rt. 2.03 minutes, 84.36% (max).

[0251] Intermediate 4 N1-Phenylhexane-1,2-diamine

[0252] [ka]

[0253] To a solution of 2-amino-N-phenylhexanamide (Intermediate 3; 32 g, 0.15 mol) in THF (320 mL) at 0° C., borane dimethylsulfide (2M solution in THF, 117 mL, 0.23 mol) was added and the reaction mixture was heated at 75° C. for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to 0° C., quenched with methanol (150 mL), and then heated at 60° C. for 2 h. The reaction mixture was cooled to room temperature and concentrated under vacuum. The resulting residue was partitioned between water (50 mL) and EtOAc (50 mL). The aqueous layer was extracted with EtOAc (2×250 mL). The combined organic layers were washed with water (250 mL) and brine (250 mL). The organic portion was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The resulting crude material was purified by Isolera column chromatography (eluent: 10% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 93% (28 g, yellow oil). LCMS: (Method B) 193.3 (M + +H), Rt.1.98 min, 76.9% (max).

[0254] Intermediate 5 2,4-Dibromo-5-methoxy-N-(1-(phenylamino)hexan-2-yl)benzenesulfonamide

[0255] [ka]

[0256] To a solution of 2,4-dibromo-5-methoxybenzenesulfonyl chloride (3.2 g, 8.79 mmol) in THF (50 mL) at 0° C., N1-phenylhexane-1,2-diamine (Intermediate 4; 1.3 g, 6.76 mmol) and triethylamine (2.8 mL, 20.3 mmol) were added and the reaction mixture was stirred at room temperature for 4 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under vacuum and the resulting residue was dissolved in EtOAc (60 mL). The organic layer was washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, and concentrated under vacuum. The resulting crude material was purified by Isolera column chromatography (eluent: 18% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 97% (3.5 g, brown gum). LCMS: (Method E) 521.0 (M + +H), Rt.3.14 minutes, 93.57% (maximum).

[0257] Intermediate 6 7-Bromo-3-butyl-8-methoxy-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide

[0258] [ka]

[0259] To a solution of 2,4-dibromo-5-methoxy-N-(1-(phenylamino)hexan-2-yl)benzenesulfonamide (Intermediate 5; 3.5 g, 6.72 mmol) in DMF (30 mL) was added K2CO3 (1.73 g, 12.5 mmol) and copper powder (0.42 g, 6.72 mmol). The reaction mixture was degassed under N2 atmosphere for 5 min, then the reaction mixture was heated at 115 °C for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice-cold water (25 mL) and the aqueous layer was extracted with a 1:1 mixture of EtOAc and PE (2 x 50 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated under vacuum. The resulting crude material was purified by Isolera column chromatography (eluent: 25% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 51% (1.5g, brown gum). LCMS: (Method A) 439.0(M + +H), Rt.2.83 min, 82.06% (max).

[0260] Intermediate 7 7-Bromo-3-butyl-8-methoxy-2-methyl-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide

[0261] [ka]

[0262] To a stirred solution of 7-bromo-3-butyl-8-methoxy-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (intermediate 6; 4.5 g, 10.24 mmol) in N-methyl-2-pyrrolidone (20 mL), Cs2CO3 (6.7 g, 20.5 mmol) was added followed by iodomethane (3.2 mL, 51.2 mmol) 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 (25 mL) and the aqueous layer was extracted with a mixture of EtOAc and PE (30%, 2×75 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated under vacuum. The crude material obtained was directly sent to the next step without further purification. Yield: 4.5 g (crude, light brown solid). LCMS: (Method E) 452.8(M + +H), Rt.3.19 minutes, 95.26% (maximum).

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

[0264] [ka]

[0265] To a solution of 7-bromo-3-butyl-8-methoxy-2-methyl-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (intermediate 7; 4.5 g, 9.92 mmol) in DMF (50 mL) was added sodium thiomethoxide (3.5 g, 49.6 mmol) and the reaction mixture was heated at 80° C. for 16 h. After completion of the reaction (monitored by UPLC), the reaction mixture was quenched with ice-cold water (25 mL) and the aqueous layer was extracted with EtOAc (4×50 mL). The combined organic layers were washed with water (2×100 mL) and brine (100 mL) and dried over anhydrous Na2SO4. The organic portion was concentrated under vacuum and the resulting crude material was purified by Isolera column chromatography (eluent: 26% EtOAc PE; silica gel: 230-400 mesh) to give the title compound. Yield: 77% (3.1 g, off-white solid). 1 H NMR (400 MHz, DMSO-d6): δ 10.73 (s, 1H), 7.29 (s, 1H), 7.12-7.16 (m, 2H), 6.99 (s, 1H), 6.67 (t, J = 7.2 Hz, 1H), 6.54 (d, J = 8.0 Hz, 2H), 4.06-3.89 (m, 2H), 3.21-3.09 (m, 1H), 2.42 (s, 3H), 2.34 (s, 3H), 1.68-1.55 (m, 1H), 1.54-1.42 (m, 1H), 1.41-1.25 (m, 4H), 0.93-0.90 (m, 3H).LCMS: (Method A) 406.9 (M + +H), Rt. 2.65 minutes, 92.05% (max.).

[0266] Intermediate 9 (S)-3-Butyl-8-hydroxy-2-methyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide and (R)-3-Butyl-8-hydroxy-2-methyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide

[0267] [ka]

[0268] The two enantiomers of racemic 3-butyl-8-hydroxy-2-methyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (Intermediate 8; 10.0 g, 24.59 mmol) were separated by SFC instrumentation (Method E). The material was concentrated under vacuum at 40° C. The first eluting fraction corresponded to enantiomer 1 and the second to enantiomer 2. The absolute configurations of the two enantiomers are unknown. Enantiomer 1: Yield: 42% (4.3 g, off-white solid). 1 H NMR (400 MHz, DMSO-d6): δ 10.69 (s, 1H), 7.28 (s, 1H), 7.13 (t, J = 10.8 Hz, 2H), 6.99 (s, 1H), 6.66 (t, J = 9.6 Hz, 1H), 6.53 (d, J = 10.8 Hz, 2H), 4.00-3.89 (m, 2H), 3.19-3.14 (m, 1H), 2.42 (s, 3H), 2.34 (s, 3H), 1.68-1.55 (m, 1H), 1.55-1.45 (m, 1H), 1.40-1.25 (m, 4H), 0.95-0.85 (m, 3H). LCMS: (Method A) 407.1 (M + +H), Rt. 2.56 min, 98.41% (max). HPLC: (Method E) Rt. 5.43 min, 98.58% (max).Chiral SFC: (Method D) Rt. 1.83 min, 100% (max). Enantiomer 2: Yield: 34% (4.2 g, off-white solid). 1H NMR (400 MHz, DMSO-d6): δ 10.58 (s, 1H), 7.27 (s, 1H), 7.13 (t, J = 10.0 Hz, 2H), 6.98 (s, 1H), 6.66 (t, J = 10.0 Hz, 1H), 6.53 (d, J = 10.8 Hz, 2H), 4.10-3.80 (m, 2H), 3.25-3.05 (m, 1H), 2.42 (s, 3H), 2.34 (s, 3H), 1.68-1.45 (m, 2H), 1.45-1.25 (m, 4H), 0.98-0.85 (m, 3H). LCMS: (Method A) 407.2 (M + +H), Rt. 2.56 min, 98.25% (max). HPLC: (Method E) Rt. 5.43 min, 97.49% (max).Chiral SFC: (Method D) Rt. 3.06 min, 99.76% (max).

[0269] Intermediate 10 Methyl 3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2,2-dimethylpropanoate

[0270] [ka]

[0271] 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 (Intermediate 8; 0.2 g, 0.49 mmol) in THF (5 mL) at 0° C., methyl 3-hydroxy-2,2-dimethylpropanoate (0.07 g, 0.49 mmol) and triphenylphosphine (0.19 g, 0.73 mmol) were added and the reaction mixture was stirred for 10 min. Then, DBAD (0.22 g, 0.98 mmol) was added at 0° C. and the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water (5 mL) and the aqueous layer was extracted with ethyl acetate (2×5 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 and concentrated under vacuum. The crude material obtained was purified by Isolera column chromatography (eluent: 20-22% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 60% (0.15 g, white solid). LCMS: (Method K) 521.1(M + +H), Rt.3.23 min, 75.58% (max).

[0272] Intermediate 11 Methyl (S)-3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2,2-dimethylpropanoate and Methyl (R)-3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2,2-dimethylpropanoate

[0273] [ka]

[0274] To a stirred solution of enantiomer 1 of 3-butyl-8-hydroxy-2-methyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (intermediate 9; 0.1 g, 0.24 mmol) in THF (5 mL) at 0° C., methyl 3-hydroxy-2,2-dimethylpropanoate (0.04 g, 0.24 mmol) and triphenylphosphine (0.09 g, 0.36 mmol) were added and the reaction mixture was stirred for 10 min. Then, DBAD (0.11 g, 0.48 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under vacuum. The crude material obtained was purified by Isolera column chromatography (eluent: 20% EtOAc / PE; silica gel: 230-400 mesh) to give enantiomer 1 of the title compound. Starting from 0.3 g of enantiomer 2 of intermediate 9, the same procedure was followed to obtain enantiomer 2 of the title compound. After completion of the reaction, the reaction mixture was concentrated under vacuum and the crude obtained was purified by Isolera column chromatography (eluent: 8% EtOAc / PE; silica gel: 230-400 mesh) to obtain the title compound. The absolute configuration of the two enantiomers is unknown. Enantiomer 1: Yield: 80% (80 mg, white solid). LCMS: (Method K) 521.0 (M + +H), Rt.3.24 minutes, 91.11% (maximum). Enantiomer 2: Yield: 99% (0.4 g, yellow solid). LCMS: (Method K) 521.0 (M + +H), Rt.3.26 min, 95.22% (max).

[0275] Intermediate 12 Ethyl 1-(((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylate

[0276] [ka]

[0277] 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 (Intermediate 8; 0.1 g, 0.25 mmol) in THF (5 mL) at 0° C., ethyl 1-(hydroxymethyl)cyclopropane-1-carboxylate (0.04 g, 0.25 mmol) and triphenylphosphine (0.09 g, 0.37 mmol) were added and the reaction mixture was stirred for 10 min. Then, DBAD (0.09 g, 0.37 mmol) was added at 0° C. and the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water (5 mL) and the aqueous layer was extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with water (5 mL) and brine (5 mL), dried over anhydrous Na2SO4, and concentrated under vacuum. The resulting crude material was purified by Isolera column chromatography (eluent: 30% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 46% (0.12 g, white solid). LCMS: (Method K) 533.3(M + +H), Rt.3.10 minutes, 39.60%.

[0278] Intermediate 13 Ethyl (S)-1-(((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylate and Ethyl (R)-1-(((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylate

[0279] [ka]

[0280] Starting from 0.1 g of enantiomer 1 of intermediate 9, enantiomer 1 of the title compound was obtained according to the procedure as described above for intermediate 12. Following the same procedure but starting from 0.1 g of enantiomer 2 of intermediate 9, enantiomer 2 of the title compound was obtained. The absolute configuration of the two enantiomers is unknown. Enantiomer 1: Yield: 72% (0.12 g, white solid). LCMS: (Method K) 533.0 (M + +H), Rt.3.29 minutes, 78.91% (maximum). Enantiomer 2: Yield: 66% (0.13 g, white solid). LCMS: (Method K) 533.0 (M + +H), Rt.3.29 min, 66.72% (max).

[0281] Intermediate 14 3-Butyl-7-(ethylthio)-8-hydroxy-2-methyl-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide

[0282] [ka]

[0283] To a solution of 7-bromo-3-butyl-8-methoxy-2-methyl-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (intermediate 7; 0.3 g, 0.66 mmol) in N-methyl-2-pyrrolidone (5 mL), sodium ethanethiolate (0.27 g, 3.31 mmol) was added and the reaction mixture was stirred at 100° C. for 12 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice-cold water (25 mL) and the aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layers were washed with ice-cold water (50 mL) and brine (50 mL) and dried over anhydrous Na2SO4. The organic portion was concentrated under vacuum and the resulting crude material was purified by Isolera column chromatography (eluent: 30% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 69% (0.2 g, off-white solid). 1 H NMR (400 MHz, DMSO-d6): δ 7.63 (s, 1H), 7.42 (s, 1H), 7.23-7.21 (m, 2H), 6.83 (t, J = 7.6 Hz, 1H), 6.68-6.64 (m, 3H), 4.05-4.01 (m, 2H), 3.23-3.21 (m, 1H), 2.80 (q, J = 7.2 Hz, 2H), 2.60 (s, 3H), 1.57-1.31 (m, 6H), 1.27 (t, J = 7.20 Hz, 3H), 0.96 (t, J = 7.20 Hz, 3H). LCMS: (Method E) 421.0 (M + +H), Rt. 3.04 minutes, 95.23% (max).

[0284] Intermediate 15 Methyl 3-((3-butyl-7-(ethylthio)-2-methyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2,2-dimethylpropanoate

[0285] [ka]

[0286] To a stirred solution of 3-butyl-7-(ethylthio)-8-hydroxy-2-methyl-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (Intermediate 14; 0.15 g, 0.36 mmol) in THF (5 mL) at 0° C., methyl 3-hydroxy-2,2-dimethylpropanoate (0.05 g, 0.36 mmol) and triphenylphosphine (0.14 g, 0.54 mmol) were added and the reaction mixture was stirred for 10 min. Then, DBAD (0.12 g, 0.54 mmol) was added at 0° C. and the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water (5 mL) and the aqueous layer was extracted with ethyl acetate (2×5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, then filtered and concentrated under vacuum. The resulting crude material was purified by Isolera column chromatography (eluent: 22% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 32% (0.16 g, white solid). LCMS: (Method A) 535.2(M + +H), Rt.3.08 min, 38.01% (max).

[0287] Intermediate 16 Ethyl 1-(((3-butyl-7-(ethylthio)-2-methyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylate

[0288] [ka]

[0289] To a stirred solution of 3-butyl-7-(ethylthio)-8-hydroxy-2-methyl-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (Intermediate 14; 0.15 g, 0.36 mmol) in THF (10 mL) at 0° C., ethyl 1-(hydroxymethyl)cyclopropane-1-carboxylate (0.05 g, 0.36 mmol) and triphenylphosphine (0.14 g, 0.54 mmol) were added and the reaction mixture was stirred for 10 min. Then, DBAD (0.12 g, 0.54 mmol) was added at 0° C. and the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water (5 mL) and the aqueous layer was extracted with ethyl acetate (2×5 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 and concentrated under vacuum. The crude material obtained was purified by Isolera column chromatography (eluent: 22% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 81% (0.16 g, white solid). LCMS: (Method A) 547.2(M + +H), Rt.3.06 min, 98.17% (max).

[0290] Intermediate 17 3-Butyl-7-chloro-5-(4-fluorophenyl)-8-methoxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one

[0291] [ka]

[0292] To a stirred solution of 3-butyl-7-chloro-8-methoxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one (6 g, 20.01 mmol) in 1-bromo-4-fluorobenzene (88 g, 500 mmol), copper(I) iodide (0.38 g, 2.00 mmol) and K2CO3 (5.53 g, 40.0 mmol) were added and the solution was purged with nitrogen for degassing for 20 minutes. Then, tris[2-(2-methoxyethoxy)ethyl]amine (1.30 g, 4.00 mmol) was added under nitrogen atmosphere and the resulting reaction mixture was heated at 135° C. for 40 hours. After completion of the reaction (monitored by UPLC), the reaction mixture was filtered through Celite and the Celite pad was washed with EtOAc (100 mL). The filtrate was concentrated under vacuum and the crude material obtained was purified by Isolera column chromatography (eluent: 15-20% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 64% (5.5 g, off-white solid). LCMS: (Method E) 394.0(M + +H), Rt.3.19 min, 91.57%.

[0293] Intermediate 18 3-Butyl-7-chloro-5-(4-fluorophenyl)-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

[0294] [ka]

[0295] To a stirred solution of 3-butyl-7-chloro-5-(4-fluorophenyl)-8-methoxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one (Intermediate 17; 5.5 g, 13.96 mmol) in THF (60 mL) at 0° C., borane dimethylsulfide (140 mL, 140 mmol) was added dropwise and the reaction mixture was refluxed at 75° C. for 40 h. After completion of the reaction (monitored by UPLC), the reaction mixture was cooled to 0° C. and quenched with methanol (100 mL). The resulting solution was heated at 65° C. for 2 h, then cooled to room temperature and concentrated under vacuum. The resulting crude material was purified by Isolera column chromatography (eluent: 15-20% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 77% (4.5 g, colorless liquid). LCMS: (Method A) 380.0(M + ) Rt.3.61 minutes, 90.76% (max).

[0296] Intermediate 19 3-Butyl-7-chloro-5-(4-fluorophenyl)-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide

[0297] [ka]

[0298] To a stirred solution of 3-butyl-7-chloro-5-(4-fluorophenyl)-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (Intermediate 18; 4.5 g, 11.84 mmol) in THF (45 mL) and water (10 mL), oxone (36.4 g, 59.2 mmol) was added and the reaction mixture was stirred at room temperature for 24 h. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a Buchner funnel and the filtrate was extracted with EtOAc (2×200 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, and concentrated under vacuum. The crude material was purified by Isolera column chromatography (eluent: 10-13% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 84% (4.1 g, colorless solid). LCMS: (Method A) 412.1(M + +H), Rt.2.83 min, 96.78% (max).

[0299] Intermediate 20 3-Butyl-5-(4-fluorophenyl)-8-hydroxy-7-(methylthio)-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide

[0300] [ka]

[0301] To a stirred solution of 3-butyl-7-chloro-5-(4-fluorophenyl)-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide (Intermediate 19; 1 g, 2.42 mmol) in DMF (12 mL) was added sodium thiomethoxide (0.85 g, 12.14 mol) at room temperature and the resulting mixture was stirred at 100 °C overnight. 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 x 20 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated under vacuum. The resulting crude material was purified by Isolera column chromatography (eluent: 30-35% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 30% (0.300 g, off-white solid). 1 H NMR (400 MHz, CDCl3): δ 7.66 (s, 1H), 7.27 (s, 1H), 6.94-6.94 (m, 2H), 6.62-6.64 (m, 2H), 4.14-4.16 (m, 1H), 3.41-3.42 (m, 1H), 2.96-2.96 (m, 1H), 2.50 (s, 1H), 2.40 (s, 3H), 1.37-1.37 (m, 4H), 1.29-1.30 (m, 4H), 0.95 (t, J = 7.20 Hz, 3H). LCMS: (Method A) 408.2 (M +_ H), Rt. 2.54 minutes, 98.39% (max).

[0302] Intermediate 21 Methyl 3-((3-butyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy)-2,2-dimethylpropanoate

[0303] [ka]

[0304] To a stirred solution of 3-butyl-5-(4-fluorophenyl)-8-hydroxy-7-(methylthio)-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide (Intermediate 20; 0.1 g, 0.25 mmol) in THF (5 mL) at 0° C., methyl 3-hydroxy-2,2-dimethylpropanoate (0.03 g, 0.25 mmol) and triphenylphosphine (0.09 g, 0.37 mmol) were added and the reaction mixture was stirred for 10 min. Then, DBAD (0.08 g, 0.37 mmol) was added at 0° C. and the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water (5 mL) and the aqueous layer was extracted with ethyl acetate (2×5 mL). The combined organic layers were washed with brine (5 mL) and dried over anhydrous Na2SO4. The organic portion was filtered and concentrated in vacuo, and the crude material obtained was purified by Isolera column chromatography (eluent: 22% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 73% (0.12 g, white solid). LCMS: (Method A) 524.1(M + +H), Rt.3.33 minutes, 77.91% (maximum).

[0305] Intermediate 22 Ethyl 1-(((3-butyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylate

[0306] [ka]

[0307] To a stirred solution of 3-butyl-5-(4-fluorophenyl)-8-hydroxy-7-(methylthio)-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide (Intermediate 20; 0.1 g, 0.25 mmol) in THF (5 mL) at 0° C., ethyl 1-(hydroxymethyl)cyclopropane-1-carboxylate (0.04 g, 0.25 mmol) and triphenylphosphine (0.09 g, 0.37 mmol) were added and the reaction mixture was stirred for 10 min. Then, DBAD (0.08 g, 0.37 mmol) was added at 0° C. and the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water (5 mL) and the aqueous layer was extracted with ethyl acetate (2×5 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 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: 82% (0.11 g, white solid). LCMS: (Method A) 536.2(M + +H), Rt.3.35 minutes, 97.37% (max).

[0308] Intermediate 23 tert-Butyl (1-((4-fluorophenyl)amino)-1-oxohexan-2-yl)carbamate

[0309] [ka]

[0310] To a stirred solution of 2-((tert-butoxycarbonyl)amino)hexanoic acid (93.0 g, 402 mmol) in DMF (930 mL) at 0° C., triethylamine (112 mL, 804 mmol) was added dropwise. Then, 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (307 g, 483 mmol) was added and the reaction mixture was stirred at 0° C. for 10 min. Then, 4-fluoroaniline (44.7 g, 402 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 diluted with ice-cold water (500 mL) to precipitate the solid product. The obtained solid was filtered, washed with water (2×100 mL) and dried under vacuum to obtain the title compound. The obtained crude product was directly carried to the next step without further purification. Yield: 69% (90 g, pale yellow solid). LCMS:(Method K)225.2(M + +H-Boc), Rt.2.66 min, 99.41% (max).

[0311] Intermediate 24 2-Amino-N-(4-fluorophenyl)hexanamide

[0312] [ka]

[0313] To a stirred solution of tert-butyl (1-((4-fluorophenyl)amino)-1-oxohexan-2-yl)carbamate (Intermediate 23; 90 g, 277 mmol) in 1,4-dioxane (900 mL) was added HCl in dioxane (4 M in 1,4-dioxane, 360 mL, 1280 mmol) at 0° C., and the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under vacuum and the resulting residue was basified with 10% NaHCO3 solution (400 mL). The aqueous layer was extracted with EtOAc (2×500 mL), and the combined organic layers were washed with water (2×100 mL) and dried over anhydrous Na2SO4. The organic portion was concentrated under vacuum, and the resulting crude was directly sent to the next step without further purification. Yield: 91% (60 g, light brown liquid). LCMS:(Method K)225.1(M + +H), Rt.1.97 min, 94.23% (maximum).

[0314] Intermediate 25 N1-(4-fluorophenyl)hexane-1,2-diamine

[0315] [ka]

[0316] To a stirred solution of 2-amino-N-(4-fluorophenyl)hexanamide (Intermediate 24; 60 g, 268 mmol) in THF (300 mL) was added borane dimethylsulfide (1 M in THF, 401 mL, 401 mmol) at 0° C. and the reaction mixture was heated at 75° C. for 24 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with methanol (200 mL) at 0° C. and the reaction mixture was heated at 75° C. for 2 h. The reaction mixture was concentrated under vacuum and the resulting residue was dissolved in DCM (500 mL). The organic layer was washed with water (2×200 mL), dried over anhydrous Na2SO4, and then concentrated under vacuum. The resulting crude was purified by Isolera column chromatography (eluent: 5-20% MeOH in DCM; silica gel: 230-400 mesh) to give the title compound. Yield: 87% (53 g, brown liquid). LCMS: (Method K) 211.2(M + +H), Rt.1.97 min, 92.44% (max).

[0317] Intermediate 26 2,4-Dibromo-N-(1-((4-fluorophenyl)amino)hexan-2-yl)-5-methoxybenzenesulfonamide

[0318] [ka]

[0319] To a stirred solution of N1-(4-fluorophenyl)hexane-1,2-diamine (Intermediate 25; 20 g, 95 mmol) in THF (200 mL), 2,4-dibromo-5-methoxybenzenesulfonyl chloride (41.6 g, 114 mmol) and triethylamine (39.8 mL, 285 mmol) were added at 0° C. and the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc (400 mL). The organic layer was washed with water (2×100 mL) and dried over anhydrous Na2SO4. The organic portion was 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: 86% (45.5 g, brown solid). 1 H NMR (400 MHz, DMSO-d6): δ 8.02-7.90 (m, 2H), 7.55 (s, 1H), 6.82 (m, 2H), 6.31-6.26 (m, 2H), 5.45-5.30 (m, 1H), 3.90 (s, 3H), 3.30-3.15 (m, 1H), 3.05-2.82 (m, 2H), 1.60-1.40 (m, 1H), 1.40-1.30 (m, 1H), 1.30-1.20 (m, 1H), 1.15-0.98 (m, 3H), 0.73 (t, J = 8.80 Hz, 3H). LCMS: (Method A) 538.9 (M + +H), Rt. 3.04 minutes, 85.57% (max).

[0320] Intermediate 27 7-Bromo-3-butyl-5-(4-fluorophenyl)-8-methoxy-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide

[0321] [ka]

[0322] To a stirred solution of 2,4-dibromo-N-(1-((4-fluorophenyl)amino)hexan-2-yl)-5-methoxybenzenesulfonamide (Intermediate 26; 45 g, 84 mmol) in DMF (450 mL) was added potassium carbonate (23.11 g, 167 mmol) and copper iodide (1.59 g, 8.36 mmol) at room temperature. The reaction mixture was degassed with nitrogen for 15 min. Tris[2-(2-methoxyethoxy)ethyl]amine (5.41 g, 16.72 mmol) was then added at room temperature and the reaction mixture was heated at 130° C. for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a Celite pad and the Celite pad was washed with EtOAc (50 mL). The filtrate portion was concentrated under vacuum. The resulting residue was diluted with EtOAc (400 mL) and the organic layer was washed with water (2×100 mL). The organic portion was dried over anhydrous Na2SO4 and the resulting crude was purified by Isolera column chromatography (eluent: 12% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 55% (22.0 g, white solid). 1 H NMR (400 MHz, DMSO-d6): δ 7.57 (s, 1H), 7.50-7.42 (d, J = 6.6 Hz, 2H), 7.02 (t, J = 9.0 Hz, 2H), 6.70-6.50 (m, 2H), 4.38-4.22 (m, 1H), 3.95 (s, 3H), 3.33 (m, 1H), 2.95-2.80 (m, 1H), 1.65-1.15 (m, 6H), 0.89 (t, J = 9.2 Hz, 3H). LCMS: (Method A) 455.0 (M + -H), Rt. 2.71 minutes, 95.55% (max).

[0323] Intermediate 28 7-Bromo-3-butyl-5-(4-fluorophenyl)-8-methoxy-2-methyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide

[0324] [ka]

[0325] To a stirred solution of 7-bromo-3-butyl-5-(4-fluorophenyl)-8-methoxy-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (Intermediate 27; 5.8 g, 12.68 mmol) in N-methyl-2-pyrrolidone (24 mL), Cs2CO3 (8.26 g, 25.4 mmol) was added at 0° C. and the reaction mixture was stirred for 15 min. Then, methyl iodide (1.58 mL, 25.4 mmol) was added dropwise at 0° C. and the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc (100 mL) and the organic layer was washed with water (50 mL). The organic portion was dried over anhydrous Na2SO4 and concentrated under vacuum. The resulting crude product was purified by Isolera column chromatography (eluent: 15% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 75% (5.1 g, white solid). 1 H NMR (400 MHz, DMSO-d6): δ 7.47 (s, 1H), 7.41 (s, 1H), 6.98-6.94 (m, 2H), 6.72-6.69 (m, 2H), 3.99-3.92 (m, 5H), 3.40-3.22 (m, 1H), 2.63 (s, 3H), 1.68-1.60 (m, 1H), 1.50-1.35 (m, 5H), 0.95 (t, J = 7.2 Hz, 3H). LCMS: (Method A) 471.0 (M + +H), Rt. 2.89 minutes, 88.26% (max).

[0326] Intermediate 29 3-Butyl-5-(4-fluorophenyl)-8-hydroxy-2-methyl-7-(methylthio)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide

[0327] [ka]

[0328] 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 (Intermediate 28; 2.0 g, 4.24 mmol) in DMF (20 mL) was added sodium thiomethoxide (1.48 g, 21.21 mmol) at room temperature and the reaction mixture was stirred at 100 °C for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature and quenched with water (20 mL). The aqueous layer was extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na2SO4. The organic portion was concentrated under vacuum and the resulting crude material was purified by Isolera column chromatography (eluent: 15-20% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 81% (1.6 g, pale yellow solid). 1 H NMR (400 MHz, DMSO-d6): δ 10.72 (s, 1H), 7.27 (s, 1H), 6.97 (t, J = 11.2 Hz, 3H), 6.55-6.50 (m, 2H), 3.98-3.86 (m, 2H), 3.30-3.05 (m, 1H), 2.42 (s, 3H), 2.34 (s, 3H), 1.70-1.45 (m, 2H), 1.40-1.25 (m, 4H), 1.00-0.80 (m, 3H). LCMS: (Method A) 425.2 (M + +H), Rt. 2.56 minutes, 90.64% (max).

[0329] Intermediate 30 Ethyl 1-(((3-butyl-5-(4-fluorophenyl)-2-methyl-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylate

[0330] [ka]

[0331] To a stirred solution of 3-butyl-5-(4-fluorophenyl)-8-hydroxy-2-methyl-7-(methylthio)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (Intermediate 29; 0.06 g, 0.14 mmol) in THF (3 mL) at 0° C., ethyl 1-(hydroxymethyl)cyclopropane-1-carboxylate (0.02 g, 0.14 mmol) and triphenylphosphine (0.056 g, 0.212 mmol) were added and the reaction mixture was stirred for 10 min. Then, DBAD (0.05 g, 0.21 mmol) was added at 0° C. and the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water (5 mL) and the aqueous layer was extracted with ethyl acetate (2×5 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 and concentrated under vacuum. The crude material obtained was purified by Isolera column chromatography (eluent: 22-25% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 69% (70 mg, off-white solid). LCMS: (Method A) 551.2(M + +H), Rt.2.96 min, 77.38% (max).

[0332] Intermediate 31 Methyl 3-((3-butyl-5-(4-fluorophenyl)-2-methyl-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2,2-dimethylpropanoate

[0333] [ka]

[0334] To a stirred solution of 3-butyl-5-(4-fluorophenyl)-8-hydroxy-2-methyl-7-(methylthio)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (Intermediate 29; 0.05 g, 0.12 mmol) in THF (3 mL) at 0° C., methyl 3-hydroxy-2,2-dimethylpropanoate (0.02 g, 0.12 mmol) and triphenylphosphine (0.05 g, 0.18 mmol) were added and the reaction mixture was stirred for 30 min. Then, DBAD (0.04 g, 0.18 mmol) was added at 0° C. and the reaction mixture was stirred at room temperature for 12 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water (5 mL) and the aqueous layer was extracted with ethyl acetate (2×5 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 and concentrated under vacuum. The crude material obtained was purified by Isolera column chromatography (eluent: 30% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 57% (60 mg, brown solid). LCMS: (Method A) 538.8(M + ), Rt.3.03 minutes, 60.90% (max).

[0335] Intermediate 32 2-((tert-butoxycarbonyl)amino)hexanoic acid

[0336] [ka]

[0337] To a solution of 2-aminohexanoic acid (25 g, 0.19 mol) in water (250 mL) and THF (250 mL), NaHCO3 (48 g, 0.57 mol) and Boc anhydride (52.2 mL, 0.23 mol) were added and the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was cooled, quenched and acidified using 1.5 N HCl. The reaction mixture was extracted with EtOAc (2 x 150 mL). The combined organic layers were washed with ice-cold water (150 mL) and brine (150 mL), dried over anhydrous Na2SO4 and concentrated to give the title compound. Yield: 45.5 g (crude, white solid). 1 H NMR (400 MHz, DMSO-d6): δ 5.10-4.98 (m, 1H), 4.33-4.30 (m, 1H), 1.95-1.81 (m, 1H), 1.75-1.55 (m, 1H), 1.46 (s, 10H), 1.45-1.31 (m, 4H), 0.93 (t, J = 7.2 Hz, 3H). LCMS: (Method E) 132.2 (M + -Boc+H), Rt. 2.36 minutes, 99.98% (max).

[0338] Intermediate 33 tert-Butyl (1-oxo-1-(phenylamino)hexan-2-yl)carbamate

[0339] [ka]

[0340] To a stirred solution of 2-((tert-butoxycarbonyl)amino)hexanoic acid (Intermediate 32; 45.5 g, 0.196 mol) in DMF (150 mL), triethylamine (54.83 mL, 0.39 mol) was added and the reaction mixture was cooled to 0° C. 1-Propanephosphonic anhydride solution (50% in EtOAc; 75.1 g, 0.23 mol) and aniline (18 g, 0.196 mol) were added 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 ice-cold water (50 mL) and diluted with EtOAc (200 mL). The aqueous layer was washed with ice-cold water (200 mL) and brine (200 mL), then dried over anhydrous Na2SO4 and filtered off. The organic portion was concentrated under vacuum to give the title compound. Yield: 82% (49.7 g, white solid). 1 H NMR (400 MHz, DMSO-d6): δ 9.93 (s, 1H), 7.60 (d, J = 7.6 Hz, 2H), 7.30 (t, J = 8.0 Hz, 2H), 7.06-6.99 (m, 2H), 4.07-4.02 (m, 1H), 1.63-1.56 (m, 2H), 1.46-1.28 (m, 13H), 0.86 (t, J = 6.8 Hz, 3H). LCMS: (Method E) 207.0 (M + -Boc+H), Rt. 2.69 minutes, 91.20% (max).

[0341] Intermediate 34 2-Amino-N-phenylhexanamide

[0342] [ka]

[0343] To a solution of tert-butyl (1-oxo-1-(phenylamino)hexan-2-yl)carbamate (Intermediate 33; 49.7 g, 0.162 mol) in 1,4-dioxane (500 mL) at 0° C. was added a solution of HCl in 1,4-dioxane (4 M, 199 mL) and the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under vacuum and the resulting residue was quenched with saturated NaHCO3 solution. The aqueous layer was extracted with EtOAc (2×200 mL). The combined organic layers were washed with brine (200 mL) and dried over anhydrous Na2SO4. The organic portion was filtered and concentrated under vacuum to give the title compound. Yield: 95% (32 g, colorless gum). 1 H NMR (400 MHz, DMSO-d6): δ 10.20-9.66 (m, 1H), 7.64 (dd, J = 4.8, 2.4 Hz, 2H), 7.32-7.27 (m, 2H), 7.06-7.02 (m, 1H), 3.29-3.26 (m, 1H), 1.67-1.61 (m, 1H), 1.46-1.27 (m, 5H), 0.89-0.85 (m, 3H). LCMS: (Method B) 207.2 (M + +H), Rt. 2.03 minutes, 84.36% (max).

[0344] Intermediate 35 N1-Phenylhexane-1,2-diamine

[0345] [ka]

[0346] To a solution of 2-amino-N-phenylhexanamide (Intermediate 34; 32 g, 0.15 mol) in THF (320 mL) at 0° C., borane dimethylsulfide (2M solution in THF, 117 mL, 0.23 mol) was added and the reaction mixture was heated at 75° C. for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to 0° C., quenched with methanol (150 mL), and then heated at 60° C. for 2 h. The reaction mixture was cooled to room temperature and concentrated under vacuum. The resulting residue was partitioned between water (50 mL) and EtOAc (50 mL). The aqueous layer was extracted with EtOAc (2×250 mL). The combined organic layers were washed with water (250 mL) and brine (250 mL). The organic portion was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The resulting crude material was purified by Isolera column chromatography (eluent: 10% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 93% (28 g, yellow oil). LCMS: (Method B) 193.3 (M + +H), Rt.1.98 min, 76.9% (max).

[0347] Intermediate 36 2,4-Dibromo-5-methoxy-N-(1-(phenylamino)hexan-2-yl)benzenesulfonamide

[0348] [ka]

[0349] To a solution of 2,4-dibromo-5-methoxybenzenesulfonyl chloride (3.2 g, 8.79 mmol) in THF (50 mL) at 0° C., N1-phenylhexane-1,2-diamine (Intermediate 35; 1.3 g, 6.76 mmol) and triethylamine (2.8 mL, 20.3 mmol) were added and the reaction mixture was stirred at room temperature for 4 h. After completion of the reaction (monitored by TLC), the reaction mixture was concentrated under vacuum and the resulting residue was dissolved in EtOAc (60 mL). The organic layer was washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4 and concentrated under vacuum. The resulting crude material was purified by Isolera column chromatography (eluent: 18% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 97% (3.5 g, brown gum). LCMS: (Method E) 521.0 (M + +H), Rt.3.14 minutes, 93.57% (maximum).

[0350] Intermediate 37 7-Bromo-3-butyl-8-methoxy-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide

[0351] [ka]

[0352] To a solution of 2,4-dibromo-5-methoxy-N-(1-(phenylamino)hexan-2-yl)benzenesulfonamide (Intermediate 36; 3.5 g, 6.72 mmol) in DMF (30 mL) was added K2CO3 (1.73 g, 12.5 mmol) and copper powder (0.42 g, 6.72 mmol). The reaction mixture was degassed under N2 atmosphere for 5 min, then the reaction mixture was heated at 115 °C for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice-cold water (25 mL) and the aqueous layer was extracted with a 1:1 mixture of EtOAc and PE (2 x 50 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated under vacuum. The resulting crude material was purified by Isolera column chromatography (eluent: 25% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 51% (1.5g, brown gum). LCMS: (Method A) 439.0(M + +H), Rt.2.83 min, 82.06% (max).

[0353] Intermediate 38 7-Bromo-3-butyl-8-methoxy-2-(4-methoxybenzyl)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide

[0354] [ka]

[0355] To a stirred solution of 7-bromo-3-butyl-8-methoxy-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (Intermediate 37; 2 g, 4.55 mmol) in NMP (15 mL) was added Cs2CO3 (1.78 g, 5.46 mmol) at 0° C. and the reaction mixture was stirred for 15 min. Then 1-(bromomethyl)-4-methoxybenzene (1.37 g, 6.83 mmol) was added dropwise at 0° C. and the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc (50 mL) and the organic layer was washed with water (2×10 mL). The organic portion was dried over anhydrous Na2SO4 and concentrated under vacuum. The resulting crude was purified by Isolera column chromatography (eluent: 20-22% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 46% (2.1 g, white solid). LCMS: (Method K) 559.1(M + ), Rt.2.99 min, 56.12% (max).

[0356] Intermediate 39 3-Butyl-7-(ethylthio)-8-hydroxy-2-(4-methoxybenzyl)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide

[0357] [ka]

[0358] 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 38; 1.0 g, 1.79 mmol) in NMP (10 mL) was added sodium ethanethiolate (0.75 g, 8.94 mmol) at room temperature and the reaction mixture was heated at 100 °C for 12 h. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature and quenched with water (20 mL). The aqueous layer was extracted with EtOAc (2 x 30 mL) and the combined organic layers were washed with brine (10 mL) and then dried over anhydrous Na2SO4. The organic portion was concentrated under vacuum and the resulting crude material was purified by Isolera column chromatography (eluent: 20-22% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 29% (0.3 g, white solid). LCMS: (Method A) 527.1(M + +H), Rt.2.89 min, 91.85% (maximum).

[0359] Intermediate 40 3-Butyl-7-(ethylthio)-8-hydroxy-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide

[0360] [ka]

[0361] To a stirred solution of 3-butyl-7-(ethylthio)-8-hydroxy-2-(4-methoxybenzyl)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (Intermediate 39; 0.4 g, 0.76 mmol) in toluene (5 mL) at 0° C., triphenylamine (0.09 g, 0.38 mmol) and 2,2,2-trifluoroacetic acid (1.73 g, 15.19 mmol) were added. 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 (10 mL) and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated under vacuum. The resulting crude material was purified by Isolera column chromatography (eluent: 25% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 30% (0.2 g, white solid). LCMS: (Method B) 407.1(M + +H), Rt.2.58 min, 47.18% (max).

[0362] Intermediate 41 Ethyl 1-(((3-butyl-7-(ethylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylate

[0363] [ka]

[0364] To a stirred solution of 3-butyl-7-(ethylthio)-8-hydroxy-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (Intermediate 40; 0.05 g, 0.12 mmol) in THF (5 mL) at 0° C., ethyl 1-(hydroxymethyl)cyclopropane-1-carboxylate (0.03 g, 0.18 mmol) and triphenylphosphine (0.05 g, 0.18 mmol) were added and the reaction mixture was stirred for 10 min. Then, DBAD (0.04 g, 0.19 mmol) was added at 0° C. and the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water (5 mL) and the aqueous layer was extracted with ethyl acetate (2×5 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 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: 76% (50 mg, white solid). LCMS: (Method A) 532.7(M + ), Rt.3.00 min, 98.06% (max).

[0365] Intermediate 42 7-Bromo-3-butyl-5-(4-fluorophenyl)-8-methoxy-2-(4-methoxybenzyl)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide

[0366] [ka]

[0367] To a stirred solution of 7-bromo-3-butyl-5-(4-fluorophenyl)-8-methoxy-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (Intermediate 27; 5 g, 10.93 mmol) in NMP (50 mL) was added Cs2CO3 (7.12 g, 21.86 mmol) and the reaction mixture was stirred at 0 °C for 30 min. Then 1-(bromomethyl)-4-methoxybenzene (3.30 g, 16.40 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a Celite bed and the Celite bed was washed with EtOAc (2 x 20 mL). The filtrate was concentrated under vacuum and the crude was purified by Isolera column chromatography (eluent: 15-20% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 73% (6 g, off-white solid). LCMS: (Method A) 578.1(M + +H), Rt.3.49 min, 75.44%.

[0368] Intermediate 43 3-Butyl-5-(4-fluorophenyl)-8-hydroxy-2-(4-methoxybenzyl)-7-(methylthio)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide

[0369] [ka]

[0370] To a stirred solution of 7-bromo-3-butyl-5-(4-fluorophenyl)-8-methoxy-2-(4-methoxybenzyl)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (Intermediate 42; 1 g, 1.23 mmol) in DMF (20 mL) was added sodium thiomethoxide (0.43 g, 6.14 mmol) at room temperature and the resulting mixture was stirred at 100 °C for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with water (50 mL) and the aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated under vacuum. 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: 66% (500 g, off-white solid). LCMS: (Method B) 529.1(M +_ H), Rt.3.20 minutes, 85.70% (maximum).

[0371] Intermediate 44 3-Butyl-5-(4-fluorophenyl)-8-hydroxy-7-(methylthio)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide

[0372] [ka]

[0373] To a stirred solution of 3-butyl-5-(4-fluorophenyl)-8-hydroxy-2-(4-methoxybenzyl)-7-(methylthio)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (Intermediate 43; 0.2 g, 0.37 mmol) in toluene (10 ml), triphenylamine (0.09 g, 0.37 mmol) and 2,2,2-trifluoroacetic acid (0.04 g, 0.37 mmol) were added at 0° C. and the reaction mixture was stirred at room temperature for 4 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 (2×20 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4 and concentrated under vacuum. 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: 90% (0.15 g, white solid). LCMS: (Method A) 411.0(M + +H), Rt.2.26 min, 93.21% (maximum).

[0374] Intermediate 45 Ethyl 1-(((3-butyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylate

[0375] [ka]

[0376] To a stirred solution of 3-butyl-5-(4-fluorophenyl)-8-hydroxy-7-(methylthio)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (Intermediate 44; 0.05 g, 0.12 mmol) in THF (5 mL) at 0° C., ethyl 1-(hydroxymethyl)cyclopropane-1-carboxylate (0.02 g, 0.12 mmol) and triphenylphosphine (0.05 g, 0.18 mmol) were added and the reaction mixture was stirred for 10 min. Then, DBAD (0.04 g, 0.18 mmol) was added at 0° C. and the reaction mixture was stirred at room temperature for 1 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water (5 mL) and the aqueous layer was extracted with ethyl acetate (2×5 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 and concentrated under vacuum. The crude material obtained was purified by Isolera column chromatography (eluent: 20-22% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 51% (0.1 g, white solid). LCMS: (Method B) 536.2(M + ), Rt.2.79 min, 96.56% (max).

[0377] Intermediate 46 3-Butyl-7-(ethylthio)-5-(4-fluorophenyl)-8-hydroxy-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide

[0378] [ka]

[0379] To a stirred solution of 7-bromo-3-butyl-5-(4-fluorophenyl)-8-methoxy-2-(4-methoxybenzyl)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (Intermediate 42; 0.3 g, 0.52 mmol) in DMF (5 mL) was added sodium ethanethiolate (0.22 g, 2.60 mmol) at room temperature and the reaction mixture was stirred at 100 °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 (2 x 30 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4 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: 97% (0.23 g, white solid). LCMS: (Method A) 425.1(M + +H), Rt.2.97 min, 92.88% (maximum).

[0380] Intermediate 47 Ethyl 1-(((3-butyl-7-(ethylthio)-5-(4-fluorophenyl)-1,1-dioxide-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylate

[0381] [ka]

[0382] To a stirred solution of 3-butyl-7-(ethylthio)-5-(4-fluorophenyl)-8-hydroxy-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (Intermediate 46; 0.1 g, 0.24 mmol) in THF (5 mL) at 0° C., ethyl 1-(hydroxymethyl)cyclopropane-1-carboxylate (0.102 g, 0.71 mmol) and triphenylphosphine (0.19 g, 0.71 mmol) were added and the reaction mixture was stirred for 10 min. Then, DBAD (0.16 g, 0.71 mmol) was added at 0° C. and the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water (5 mL) and the aqueous layer was extracted with ethyl acetate (2×5 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 and concentrated under vacuum. The crude material obtained was purified by Isolera column chromatography (eluent: 22-25% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 49% (70 mg, brown solid). LCMS: (Method A) 551.1(M + +H), Rt.2.93 minutes, 90.19% (maximum).

[0383] Intermediate 48 Ethyl 3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2,2-difluoropropanoate

[0384] [ka]

[0385] 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 (Intermediate 8; 0.1 g, 0.25 mmol) in DMF (3 mL) at 0° C., Cs2CO3 (0.12 g, 0.37 mmol) was added and the reaction mixture was stirred at room temperature for 30 min. Ethyl 3-bromo-2,2-difluoropropanoate (0.07 g, 0.30 mmol) was then added and the reaction mixture was stirred at room temperature for 16 h. After TLC revealed that the starting material was not completely consumed, the reaction mixture was heated at 60° C. for 2 h. The reaction mixture was then diluted with water (5 mL) and the aqueous layer was extracted with ethyl acetate (2×10 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 and concentrated under vacuum. The resulting crude material was purified by Isolera column chromatography (eluent: 8-10% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 33% (0.1 g, brown solid). UPLC: (Method B) 543.2(M + +H), Rt.2.55 minutes, 43.90% (max).

[0386] Intermediate 49 Methyl 3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2-hydroxy-2-methylpropanoate

[0387] [ka]

[0388] 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 (Intermediate 8; 0.5 g, 1.22 mmol) in DMF (5 mL) was added Cs2CO3 (0.78 g, 2.4 mmol) and methyl 2-methyloxirane-2-carboxylate (0.42 g, 3.6 mmol) at 0° C. The reaction mixture was stirred at room temperature for 72 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with dilute HCl (1.5 N, 5 mL). The aqueous layer was extracted with ethyl acetate (2×20 mL) and the combined organic layers were washed with water (10 mL) and brine (10 mL). The organic portion was 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: 27% (0.17 g, brown solid). 1 H NMR (400 MHz, CDCl3): δ 7.36 (s, 1H), 7.29-7.25 (m, 2H), 6.97 (s, 1H), 6.83-6.80 (m, 1H), 6.68-6.65 (m, 2H), 4.37-4.36 (m, 1H), 4.15 (m, 1H), 4.04 (s, 1H), 4.00 (s, 1H), 3.88 (s, 3H), 3.65 (bs, 1H), 3.15 (bs, 1H), 2.59 (s, 3H), 2.33 (s, 3H), 1.66 (m, 2H), 1.6 (m, 6H), 1.3 (m, 1H), 0.98-0.96 (m, 3H). LCMS: (Method K) 523.1 (M + +H), Rt. 2.97 minutes, 94.53% (max).

[0389] Intermediate 50 Methyl 3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2-hydroxy-2-methylpropanoate

[0390] [ka]

[0391] Starting from 0.15 g of enantiomer 2 of 3-butyl-8-hydroxy-2-methyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (intermediate 9), the title compound was obtained following the same procedure as described above for intermediate 49. The crude material was purified by Isolera column chromatography (eluent: 10-15% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. The absolute configuration of the compound is unknown. Yield: 47% (90 mg, brown solid). 1 H NMR (400 MHz, CDCl3): δ 7.37 (s, 1H), 7.29 (m, 2H), 6.98 (s, 1H), 6.84 (t, J = 4.4 Hz, 1H), 6.68-6.66 (m, 2H), 4.37-4.36 (m, 1H), 4.13 (m, 1H), 4.04 (m, 2H), 3.88 (s, 3H), 3.30 (bs, 1H), 2.98 (s, 2H), 2.59 (s, 3H), 2.33 (s, 3H), 1.60-1.57 (m, 3H), 1.56-1.49 (m, 4H), 0.98-0.96 (m, 3H). LCMS: (Method K) 522.9 (M + +H), Rt. 2.78 minutes, 92.89% (max).

[0392] Intermediate 51 Methyl (S)-3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2-hydroxy-2-methylpropanoate and methyl (R)-3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2-hydroxy-2-methylpropanoate (individual diastereomers)

[0393] [ka]

[0394] The two diastereoisomers of intermediate 50 (0.3 g, 0.58 mmol) were separated by chiral SFC instrumentation (Method N). The material was concentrated under vacuum at 40° C. The first eluting fraction corresponded to diastereomer 1 and the second eluting fraction corresponded to diastereomer 2. Each of the two fractions was then processed separately for further purification. The resulting residue was diluted with ethyl acetate (30 ml) and washed with dilute HCl (1.5N, 10 mL) and water (10 mL). The organic portion was then dried over anhydrous Na2SO4, filtered and concentrated under vacuum to give the purified diastereomer of the title compound. The absolute configuration of the two diastereomers is unknown. Diastereoisomer 1: Yield: 43% (0.13 g, off-white gum). 1H NMR (400 MHz, DMSO-d6): δ 7.30 (s, 1H), 7.16 (t, J = 8.4 Hz, 2H), 7.05 (s, 1H), 6.70 (t, J = 7.2 Hz, 1H), 6.57 (d, J = 8.0 Hz, 2H), 5.74 (s, 1H), 4.21 (m, 2H), 3.88 (bs, 1H), 3.69 (s, 3H), 3.20 (bs, 1H), 2.46 (s, 3H), 2.34 (s, 3H), 1.64 (m, 1H), 1.50 (m, 1H), 1.49 (s, 3H), 1.36 (m, 4H), 0.93-0.92 (m, 3H). LCMS: (Method H) 523.0 (M + +H), Rt. 2.50 points, 96.90% (maximum). HPLC: (Method E) Rt. 5.62 points, 98.27% (maximum). KuraSFC: (Method L) Rt. 3.73 points, 98.36% (maximum). Sesame heterosexual body 2: Yield: 41% (0.13g, sesame-like substance). 1 H NMR (400 MHz, DMSO-d6): δ 7.30 (s, 1H), 7.16 (t, J = 8.4 Hz, 2H), 7.04 (s, 1H), 6.69 (t, J = 7.2 Hz, 1H), 6.57 (d, J = 8.0 Hz, 2H), 5.73 (s, 1H), 4.20 (m, 2H), 4.04 (bs, 2H), 3.90 (bs, 1H), 3.69 (s, 4H), 1.99 (m, 1H), 1.44 (m, 4H), 1.35-1.30 (m, 7H), 0.91 (m, 4H). LCMS: (Method H) 523.0 (M + +H), Rt. 2.50 minutes, 93.08% (maximum). HPLC: (Method E) Rt. 5.63 minutes, 94.12% (maximum). KuraSFC: (Method L) Rt. 4.68 minutes, 98.75% (maximum).

[0395] Intermediate 52 Methyl 3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2-methoxy-2-methylpropanoate

[0396] [ka]

[0397] To a stirred solution of methyl 3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2-hydroxy-2-methylpropanoate (Intermediate 49; 0.17 g, 0.32 mmol) in DMF (5 mL) at 0° C., sodium hydride (6.5 mg, 0.16 mmol) was added and the reaction mixture was stirred for 10 min. Then, methyl iodide (0.23 g, 1.62 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 3 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with dilute HCl (1.5 N, 5 mL) and the aqueous layer was extracted with ethyl acetate (2×20 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 crude material obtained was purified by Isolera column chromatography (eluent: 10-12% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 75% (0.13 g, brown solid). LCMS: (Method K) 537.2(M + +H), Rt.2.98 min, 96.48% (max).

[0398] Intermediate 53 Methyl 3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2-methoxy-2-methylpropanoate

[0399] [ka]

[0400] Starting from 0.08 g of intermediate 50, the title compound was obtained following the same procedure as described for intermediate 52. After work-up of the reaction mixture, the crude material was purified by Isolera column chromatography (eluent: 10-15% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. The absolute configuration of the compound is unknown. Yield: 57% (50 mg, off-white solid). LCMS:(Method K)537.0(M + +H), Rt.3.12 minutes, 93.30% (maximum).

[0401] Intermediate 54 Methyl (S)-3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2-methoxy-2-methylpropanoate and methyl (R)-3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2-methoxy-2-methylpropanoate (individual diastereomers)

[0402] [ka]

[0403] Diastereoisomers 1 and 2 of the title compound were prepared from diastereoisomer 1 (0.13 g) and diastereoisomer 2 (0.13 g) of intermediate 51, respectively, following the same procedure as described for intermediate 52. After workup of the reaction mixture, the crude material was purified by Isolera column chromatography (eluent: 22% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. The absolute configurations of the two diastereomers are unknown. Diastereoisomer 1: Yield: 69% (95 mg, pale yellow solid). 1 H NMR (400 MHz, DMSO-d6): δ 7.32 (s, 1H), 7.16 (t, J = 8.0 Hz, 2H), 7.05 (s, 1H), 6.71 (t, J = 7.2 Hz, 1H), 6.58 (d, J = 8.0 Hz, 2H), 4.36 (m, 2H), 4.04-4.03 (m, 1H), 3.90 (bs, 1H), 3.73 (s, 3H), 3.30 (s, 3H), 2.46 (s, 3H), 2.35 (s, 4H), 1.61 (m, 1H), 1.49 (s, 4H), 1.36 (m, 4H), 0.94-0.92 (m, 3H). LCMS: (Method A) 537.1 (M + +H), Rt. 2.89 minutes, 96.63% (max). Diastereoisomer 2: Yield: 64% (90 mg, pale yellow solid). LCMS: (Method A) 537.1 (M + +H), Rt.2.89 min, 95.04% (maximum).

[0404] Intermediate 55 Methyl 3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2-hydroxypropanoate

[0405] [ka]

[0406] To a solution of 3-butyl-8-hydroxy-2-methyl-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (Intermediate 8; 0.5 g, 1.22 mmol) in DMF (10 mL), Cs2CO3 (0.79 g, 2.45 mmol) was added and the reaction mixture was stirred at room temperature for 15 min. Then, methyloxirane-2-carboxylate (0.37 g, 3.68 mmol) was added and the reaction mixture was stirred at room temperature for 72 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with dilute HCl (1.5 N, 15 mL) and diluted with water (10 mL). The aqueous layer was extracted with EtOAc (2×15 mL) and the combined organic layers were washed with water (15 mL) and brine (15 mL). The organic portion was dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude material obtained was purified by Isolera column chromatography (eluent: 10% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 29% (0.18 g, colorless gum). 1 H NMR (400 MHz, DMSO-d6): δ 7.33 (s, 1H), 7.17-7.05 (m, 3H), 6.72-6.56 (m, 2H), 5.91-5.89 (m, 1H), 4.51-4.49 (m, 1H), 4.32-4.27 LCMS: (Method B) 509.0 (M + +H), Rt. 2.57 minutes, 99.63% (max).

[0407] Intermediate 56 Methyl 3-(((S)-3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2-hydroxypropanoate and methyl 3-(((R)-3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2-hydroxypropanoate

[0408] [ka]

[0409] Stereoisomers 1 and 2 of the title compound were prepared from enantiomer 1 (0.3 g) and enantiomer 2 (0.3 g) of intermediate 9, respectively, following the same procedure as described for intermediate 55. The absolute configurations of the two stereoisomers are unknown. Stereoisomer 1: Yield: 47.1% (0.18 g, brown solid). 1 H-NMR (400 MHz, CDCl3): δ 7.39 (s, 1H), 7.29-7.20 (m, 2H), 6.98 (s, 1H), 6.83-6.78 (m, 1H), 6.67-6.65 (m, 2H), 4.60-4.59 (m, 1H), 4.44-4.42 (m, 2H), 4.04-4.00 (m, 2H), 3.90-3.85 (m, 3H), 3.26-3.24 (m, 1H), 2.99-2.90 (m, 1H), 2.58 (s, 3H), 2.33 (s, 3H), 1.49-1.24 (m, 6H), 0.98-0.94 (m, 3H). LCMS: (Method A) 509.1 (M + +H) Rt. 2.92 minutes, 98.11% (max). Stereoisomer 2: Yield: 44.8% (0.17 g, off-white solid). 1H-NMR (400 MHz, DMSO-d6): δ 7.39 (s, 1H), 7.29-7.21 (m, 2H), 6.98 (s, 1H), 6.85-6.83 (m, 1H), 6.68-6.67 (m, 2H), 4.60-4.58 (m, 1H), 4.46-4.42 (m, 2H), 4.04-4.00 (m, 2H), 3.90-3.85 (m, 3H), 3.26-3.24 (m, 1H), 2.98-2.91 (m, 1H), 2.58 (s, 3H), 2.33 (s, 3H), 1.49-1.24 (m, 6H), 0.98-0.94 (m, 3H). LCMS: (Method E) 508.9 (M + +H) Rt. 2.72 minutes, 98.85% (max).

[0410] Intermediate 57 Methyl 3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2-methoxypropanoate

[0411] [ka]

[0412] To a stirred solution of methyl 3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2-hydroxypropanoate (Intermediate 55; 180 mg, 0.35 mmol) in DMF (2 mL) at 0° C., a suspension of sodium hydride (7.06 mg, 0.17 mmol) in DMF (2 mL) at 0° C. was added dropwise and the reaction mixture was stirred at room temperature for 10 min. Then, methyl iodide (109 mL, 1.76 mmol) in DMF (1 mL) was added dropwise at 0° C. 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 dilute HCl (1.5 N, 1 mL), diluted with water (5 mL) and the aqueous layer was extracted with EtOAc (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 crude material obtained was purified by Isolera column chromatography (eluent: 20-30% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 31.4% (55 mg, brown solid). 1 H NMR (400 MHz, DMSO-d6): δ 7.34 (s, 1H), 7.15 (t, J = 7.6 Hz, 2H), 7.13 (s, 1H), 6.69 (t, J = 7.2 Hz, 1H), 6.58 (d, J = 8.4 Hz, 2H), 4.44-4.42 (m, 1H), 4.37-4.35 (m, 2H), 4.00-3.95 (m, 1H), 3.73-3.73 (m, 1H), 3.43 (s, 3H), 3.41 (s, 3H), 3.20-3.19 (m, 1H), 2.37 (s, 3H), 2.28 (s, 3H), 1.36-1.34 (m, 2H), 1.27-1.24 (m, 4H), 0.9 (t, J = 6.8 Hz, 3H). LCMS: (Method E) 522.8 (M + +H), Rt. 2.87 minutes, 95.53% (max).

[0413] Intermediate 58 Methyl 3-(((S)-3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2-methoxypropanoate and methyl 3-(((R)-3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2-methoxypropanoate

[0414] [ka]

[0415] Stereoisomers 1 and 2 of the title compound were prepared from stereoisomer 1 (0.25 g) and stereoisomer 2 (0.24 g) of intermediate 56, respectively, following the same procedure as described for intermediate 57. The absolute configurations of the two stereoisomers are unknown. Stereoisomer 1: Yield: 54.9% (0.15 g, white solid). 1 H-NMR (400 MHz, CDCl3): δ 7.39 (s, 1H), 7.22-7.20 (m, 2H), 6.98 (s, 1H), 6.83-6.78 (m, 1H), 6.67-6.65 (m, 2H), 4.44-4.38 (m, 2H), 427-4.25 (m,1H), 4.09-4.04 (m, 2H), 3.87-3.80 (m, 5H), 3.61 (s, 3H), 3.23 (s, 1H), 2.57 (s, 3H), 2.33 (s, 3H), 1.75-1.70 (m, 1H), 1.58 (s, 3H), 1.50-1.28 (m, 3H). LCMS: (Method B) 523.1(M + +H) Rt.2.71 min, 94.97% (max). Stereoisomer 2: Yield: 38.6% (0.1 g, white solid). LCMS: (Method B) 523.0(M + +H) Rt.2.71 minutes, 95.14% (maximum).

[0416] Intermediate 59 Methyl 3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2-ethoxypropanoate

[0417] [ka]

[0418] To a stirred solution of methyl 3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2-hydroxypropanoate (Intermediate 55; 140 mg, 0.28 mmol) in DMF (3 mL) at 0° C., sodium hydride (5.5 mg, 0.14 mmol) was added and the reaction mixture was stirred for 5 min. Then, ethyl iodide (0.11 mL, 1.38 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 1 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with dilute HCl (1.5 N, 1 mL) and the aqueous layer was extracted with EtOAc (2×10 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 in vacuo and the crude material obtained was purified by Isolera column chromatography (eluent: 30-45% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 20% (0.03 g, off-white gum). LCMS: (Method E) 537.0(M + +H) Rt.3.12 minutes, 73.10% (max).

[0419] Intermediate 60 Methyl 3-((3-butyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy)-2-hydroxypropanoate

[0420] [ka]

[0421] To a stirred solution of 3-butyl-8-hydroxy-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide (0.2 g, 0.51 mmol) in DMF (5 mL) at 0° C., methyloxirane-2-carboxylate (0.16 g, 1.53 mmol) and Cs2CO3 (0.33 g, 1.02 mmol) were added and the reaction mixture was stirred at room temperature for 16 h. TLC showed incomplete conversion, so additional methyloxirane-2-carboxylate (0.16 g, 1.53 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. Although TLC showed that not all starting material had been consumed, the reaction mixture was quenched with dilute HCl (1.5 N, 5 mL) and the aqueous layer was extracted with EtOAc (2×15 mL). The combined organic layers were washed with water (5 mL), brine (10 mL) and dried over anhydrous Na2SO4. The organic portion was filtered and concentrated in vacuo and the crude material obtained was purified by Isolera column chromatography (eluent: 40% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound, yield: 67% (0.17 g, brown gum). 1 H NMR (400 MHz, DMSO-d6): δ 7.42 (s, 1H), 7.28 (t, J = 6.04 Hz, 2H), 7.17 (s, 1H), 6.68 (t, J = 7.32 Hz, 1H), 6.55 (d, J = 8.04 Hz, 2H), 5.91 (m, 1H), 4.52-4.49 (m, 1H), 4.37-4.31 (m, 2H), 4.29-4.26 (m, 1H), 3.72 (s, 3H), 3.69-3.68 (m, 1H), 3.34 -3.32 (m,1H), 3.18-3.01 (m, 1H), 2.34 (s, 3H), 1.39-1.18 (m, 7H), 0.92-0.89 (m, 3H). LCMS: (Method E) 494.1 (M + +H) Rt. 2.44 minutes, 95.67% (max).

[0422] Intermediate 61 3-Butyl-7-(ethylthio)-5-(4-fluorophenyl)-8-hydroxy-2-methyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide

[0423] [ka]

[0424] 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 (Intermediate 28; 0.500 g, 1.06 mmol) in NMP (4 mL) was added sodium ethanethiolate (0.45 g, 5.30 mmol) and the reaction mixture was heated at 100 °C for 16 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 EtOAc (2 x 20 mL). The combined organic layers were washed with water (5 mL), brine (5 mL) and the organic portion was dried over anhydrous Na2SO4. The organic portion was filtered and concentrated under vacuum and the resulting crude was purified by Isolera column chromatography (eluent: 30-50% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 86% (0.4 g, yellowish solid). LCMS: (Method A) 439.1(M + +H)Rt.2.69 minutes, 54.66% (max).

[0425] Intermediate 62 Methyl 3-((3-butyl-7-(ethylthio)-5-(4-fluorophenyl)-2-methyl-1,1-dioxide-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2-hydroxypropanoate

[0426] [ka]

[0427] To a stirred solution of 3-butyl-7-(ethylthio)-5-(4-fluorophenyl)-8-hydroxy-2-methyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine 1,1-dioxide (Intermediate 61; 100 mg, 0.23 mmol) in DMF (1 mL), Cs2CO3 (153 mg, 0.47 mmol) was added and the reaction mixture was stirred at room temperature for 10 min. Then, methyloxirane-2-carboxylate (68.4 mg, 0.69 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 24 h. After completion of the reaction (monitored by TLC), the reaction mixture was acidified with dilute HCl (1.5 N, 2 mL) and the aqueous layer was extracted with EtOAc (2 x 10 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 in vacuo, and the crude material obtained was purified by Isolera column chromatography (eluent: 0-20% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 79.6% (55 mg, white solid). LCMS: (Method B) 541.2(M + +H)Rt.2.65 minutes, 79.63% (max).

[0428] Example 1 3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2,2-dimethylpropanoic acid

[0429] [ka]

[0430] To a stirred solution of methyl 3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2,2-dimethylpropanoate (Intermediate 10; 0.15 g, 0.28 mmol) in a mixture of 1,4-dioxane and water (3:2; 5 mL) at 0° C., lithium hydroxide (24 mg, 0.50 mmol) was added and the reaction mixture was stirred at room temperature for 3 h. After completion of the reaction (monitored by TLC), the reaction mixture was acidified with dilute HCl (1.5 N, 5 mL) and the aqueous layer was extracted with ethyl acetate (2×10 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 and concentrated under vacuum. The resulting crude was purified by preparative HPLC purification (Method A) to give the title compound. Yield: 7% (10 mg, white solid). 1 H NMR (400 MHz, DMSO-d6): δ 12.46 (s, 1H), 7.28 (s, 1H), 7.15 (t, J = 8.8 Hz, 2H), 7.05 (s, 1H), 6.69 (t, J = 7.2 Hz, 1H), 6.57 (d, J = 8.4 Hz, 2H), 4.12 (s, 2H), 4.08-3.92 (m, 1H), 3.92-3.82 (m, 1H), 3.25-3.12 (m, 1H), 2.46 (s, 3H), 2.34 (s, 3H), 1.70-1.60 (m, 1H), 1.58-1.42 (m, 1H), 1.42-1.32 (m, 4H), 1.28-1.25 (m, 6H), 0.9 (t, J = 7.2 Hz, 3H). LCMS: (Method K) 506.9 (M + +H), Rt. 2.85 min, 95.20% (max). HPLC: (Method E) Rt. 5.85 min, 97.92% (max).

[0431] Example 2 (S)-3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2,2-dimethylpropanoic acid and (R)-3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2,2-dimethylpropanoic acid

[0432] [ka]

[0433] To a stirred solution of methyl 3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2,2-dimethylpropanoate enantiomer 1 (intermediate 11; 80 mg, 0.06 mmol) in a mixture of 1,4-dioxane and water (3:2; 5 mL) at 0° C., lithium hydroxide (15 mg, 0.11 mmol) was added and the reaction mixture was stirred at room temperature for 3 h. After completion of the reaction (monitored by TLC), the reaction mixture was acidified with dilute HCl (1.5 N, 5 mL) and the aqueous layer was extracted with ethyl acetate (2×20 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 in vacuo and the resulting crude was purified by preparative HPLC purification (Method A) to afford enantiomer 1 of the title compound. Starting from 0.4 g of enantiomer 2 of intermediate 11, the same procedure was followed to obtain enantiomer 2 of the title compound. The crude obtained was purified by preparative HPLC purification (method B) to give the title compound. The absolute configuration of the two enantiomers is unknown. Enantiomer 1: Yield: 75% (15 mg, white solid). 11H NMR (400 MHz, DMSO-d6): δ 12.45 (s, 1H), 7.28 (s, 1H), 7.16 (t, J = 7.6 Hz, 2H), 7.05 (, 1H), 6.70 (t, J = 7.2 Hz, 1H), 6.58 (d, J = 8.4 Hz, 2H), 4.12 (s, 2H), 4.1 - 3.98 (m, 1H), 3.98 - 3.8 (m, 1H), 3.3 - 3.1 (m, 1H), 2.46 (s, 3H), 2.34 (s, 3H), 1.65 - 1.64 (m, 1H), 1.51 - 1.49 (m, 1H), 1.28 (m, 10H), 0.94 - 0.90 (m, 3H). LCMS: (Method K) 507.0 (M + +H), Rt. 3.04 min, 98.00% (max). HPLC: (Method E) Rt. 6.02 min, 99.04% (max). Chiral purity: (Method D) Rt. 1.90 min, 100.00% (max). Enantiomer 2: Yield: 13% (50 mg, off-white solid). 1 1H NMR (400 MHz, DMSO-d6): δ 12.46 (s, 1H), 7.28 (s, 1H), 7.16 (t, J = 7.6 Hz, 2H), 7.05 (s, 1H), 6.70 (t, J = 7.6 Hz, 1H), 6.58 (d, J = 8.0 Hz, 2H), 4.12 (s, 2H), 4.1 - 3.98 (m, 1H), 3.98 - 3.8 (m, 1H), 3.25 - 3.1 (bs, 1H), 2.46 (s, 3H), 2.34 (s, 3H), 1.7 - 1.45 (m, 2H), 1.4 - 1.2 (m, 10H), 0.94 - 0.92 (m, 3H). LCMS: (Method H) 507.0 (M + +H), Rt. 2.82 min, 96.15% (max). HPLC: (Method D) Rt. 5.94 min, 95.57% (max). Chiral purity: (Method D) Rt. 2.61 min, 97.52% (max).

[0434] (Example 3) 1-(((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid

[0435] [ka]

[0436] To a stirred solution of ethyl 1-(((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylate (Intermediate 12; 0.12 g, 0.23 mmol) in a mixture of 1,4-dioxane and water (3:2, 5 mL) at 0° C., lithium hydroxide (10.79 mg, 0.45 mmol) was added and the reaction mixture was stirred at room temperature for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was acidified with dilute HCl (1.5 N, 3 mL) and the aqueous layer was extracted with ethyl acetate (2×10 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 and concentrated in vacuo and the resulting crude material was purified by preparative HPLC purification (Method A) to give the title compound. Yield: 22% (25 mg, white solid). 1H NMR (400 MHz, DMSO-d6) δ 12.40 (s, 1H), 7.28 (s, 1H), 7.16 (t, J = 8.4 Hz, 2H), 7.05 (s, 1H), 6.70 (t, J = 7.6 Hz, 1H), 6.58 (d, J = 8.0 Hz, 2H), 4.27 (dd, J = 3.6, 10.0 Hz, 2H), 4.04-3.99 (m, 1H), 3.90 (bs, 1H), 3.15 (bs, 1H), 2.40 (s, 3H), 2.29 (s, 3H), 1.65-1.62 (m, 1H), 1.51-1.50 (m, 1H), 1.47-1.45 (m, 4H), 1.24-1.23 (m, 2H), 1.15-1.12 (m, 2H), 0.94-0.92 (m, 3H). LCMS: (Method K) 505.3 (M + +H), Rt. 2.76 min, 99.10% (max). HPLC: (Method E) Rt. 5.70 min, 98.59% (max).

[0437] Example 4 (S)-1-(((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid and (R)-1-(((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid

[0438] [ka]

[0439] To a stirred solution of ethyl 1-(((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylate enantiomer 1 (Intermediate 13; 0.12 g, 0.23 mmol) in a mixture of 1,4-dioxane and water (3:2; 5 mL), lithium hydroxide (10.79 mg, 0.45 mmol) was added at 0° C. The reaction mixture was stirred at room temperature for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was acidified with dilute HCl (1.5 N, 3 mL). The aqueous layer was extracted with ethyl acetate (2×10 mL) and the combined organic layers were washed with water (5 mL) and brine (5 mL) and dried over anhydrous Na2SO4. The organic portion was filtered and concentrated under vacuum. The resulting crude material was purified by preparative HPLC purification (Method A) to afford the title compound. Following the same procedure, starting from 0.13 g of enantiomer 2 of intermediate 13, enantiomer 2 of the title compound was obtained. The absolute configuration of the two enantiomers is unknown. Enantiomer 1: Yield: 26% (30 mg, white solid). 1 H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 7.28 (s, 1H), 7.16 (t, J = 8.4 Hz, 2H), 7.05 (s, 1H), 6.70 (t, J = 7.2 Hz, 1H), 6.57 (d, J = 8.0 Hz, 2H), 4.28 - 4.26 (m, 2H), 4.02 (m, 1H), 3.89 (bs, 1H), 3.47 (bs, 1H), 2.46 (s, 3H), 2.34 (s, 3H), 1.63-1.62 (m, 1H), 1.51-1.50 (m, 1H), 1.36-1.35 (m, 4H), 1.23-1.22 (m, 2H), 1.10-1.09 (m, 2H), 0.94-0.92 (m, 3H). LCMS: (Method K) 505.0 (M ++H), Rt. 3.01 min, 96.72% (max). HPLC: (Method E) Rt. 5.61 min, 97.75% (max).Chiral purity: (Method H) Rt. 3.19 min, 99.69% (max). Enantiomer 2: Yield: 20% (25 mg, white solid). 1 H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 7.28 (s, 1H), 7.16 (t, J = 7.2 Hz, 2H), 7.05 (s, 1H), 6.71 (t, J = 7.2 Hz, 1H), 6.58 (d, J = 8.4 Hz, 2H), 4.27 (m, 2H), 4.02 (m, 1H), 3.90 (bs, 1H), 3.21 (bs, 1H), 2.46 (s, 3H), 2.34 (s, 3H), 1.65-1.62 (m, 1H), 1.50-1.49 (m, 1H), 1.37-1.35 (m, 4H), 1.24-1.23 (m, 2H), 1.11-1.10 (m, 2H), 0.94-0.92 (m, 3H). LCMS: (Method K) 505.0 (M + +H), Rt. 3.01 min, 97.62% (max). HPLC: (Method E) Rt. 5.61 min, 98.84% (max).Chiral purity: (Method H) Rt. 4.18 min, 99.55% (max).

[0440] Example 5 3-((3-butyl-7-(ethylthio)-2-methyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2,2-dimethylpropanoic acid

[0441] [ka]

[0442] To a stirred solution of methyl 3-((3-butyl-7-(ethylthio)-2-methyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2,2-dimethylpropanoate (Intermediate 15; 0.16 g, 0.30 mmol) in a mixture of 1,4-dioxane and water (3:2, 5 mL) at 0° C., lithium hydroxide (0.02 g, 0.60 mmol) was added and the reaction mixture was stirred at room temperature for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was acidified with dilute HCl (1.5 N, 5 mL) and the aqueous layer was extracted with ethyl acetate (2×10 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 preparative HPLC purification (Method A) to give the title compound. Yield: 38% (60 mg, white solid). 1 H NMR (400 MHz, DMSO-d6): δ 12.45 (s, 1H), 7.29 (s, 1H), 7.16 (t, J = 7.6 Hz, 2H), 7.08 (s, 1H), 6.71 (t, J = 7.6 Hz, 1H), 6.59 (d, J = 7.6 Hz, 2H), 4.11 (s, 2H), 4.05-3.85 (m, 2H), 3.25-3.15 (m, 1H), 3.02-2.8 (m, 2H), 2.60 (m, 1H), 2.47 (s, 3H), 1.7-1.45 (m, 2H), 1.42-1.3 (m, 5H), 1.28 (m, 1H), 1.27 (s, 6H), 1.21 (t, J = 7.60 Hz, 3H), 0.92 (t, J = 6.8 Hz, 3H). LCMS: (Method B) 521.0 (M + +H), Rt. 2.05 min, 96.18% (max). HPLC: (Method E) Rt. 5.94 min, 97.88% (max).

[0443] Example 6 (S)-3-((3-butyl-7-(ethylthio)-2-methyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2,2-dimethylpropanoic acid and (R)-3-((3-butyl-7-(ethylthio)-2-methyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2,2-dimethylpropanoic acid

[0444] [ka]

[0445] The two enantiomers of racemic 3-((3-butyl-7-(ethylthio)-2-methyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2,2-dimethylpropanoic acid (Example 5; 50 mg, 0.09 mmol) were separated by chiral SFC instrumentation (Method F). The material was concentrated under vacuum at 40° C. The first eluting fraction corresponded to enantiomer 1 and the second to enantiomer 2. The absolute configurations of the two enantiomers are unknown. Enantiomer 1: Yield: 37% (20 mg, off-white solid). 1 H NMR (400 MHz, DMSO-d6): δ 7.29 (s, 1H), 7.15 (t, J = 8.8 Hz, 2H), 7.08 (s, 1H), 6.70 (t, J = 7.2 Hz, 1H), 6.59 (d, J = 8.0 Hz, 2H), 4.11 (s, 2H), 4.05-3.83 (m, 2H), 3.28-3.12 (m, 1H), 2.95-2.82 (m, 2H), 2.47 (s, 3H), 1.68-1.55 (m, 1H), 1.55-1.45 (m, 1H), 1.42-1.32 (m, 4H), 1.32-1.22 (m, 6H), 1.20 (t, J = 7.20 Hz, 3H), 0.95-0.88 (m, 3H). LCMS: (Method K) 521.2 (M+ +H), Rt. 3.13 min, 98.08% (max). HPLC: (Method E) Rt. 5.91 min, 91.39% (max).Chiral SFC: (Method H) Rt. 1.72 min, 95.81% (max). Enantiomer 2: Yield: 23% (15 mg, off-white solid). 1 H NMR (400 MHz, DMSO-d6): δ 12.45 (s, 1H), 7.29 (s, 1H), 7.15 (t, J = 8.8 Hz, 2H), 7.08 (s, 1H), 6.70 (t, J = 7.6 Hz, 1H), 6.59 (d, J = 8.0 Hz, 2H), 4.11 (s, 2H), 4.08-3.80 (m, 2H), 3.28-3.12 (m, 1H), 2.92-2.82 (m, 2H), 2.47 (s, 3H), 1.68-1.58 (m, 1H), 1.58-1.45 (m, 1H), 1.42-1.32 (m, 4H), 1.32-1.22 (m, 6H), 1.2 (t, J = 7.2 Hz, 3H), 0.95-0.88 (m, 3H). LCMS: (Method D) 521.0 (M + +H), Rt. 3.13 min, 94.38% (max). HPLC: (Method E) Rt. 5.93 min, 94.93% (max).Chiral SFC: (Method H) Rt. 2.30 min, 95.03% (max).

[0446] Example 7 1-(((3-butyl-7-(ethylthio)-2-methyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid

[0447] [ka]

[0448] To a stirred solution of ethyl 1-(((3-butyl-7-(ethylthio)-2-methyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylate (Intermediate 16; 0.05 g, 0.091 mmol) in a mixture of 1,4-dioxane and water (3:2, 5 mL) at 0° C., lithium hydroxide (4.38 mg, 0.18 mmol) was added and the reaction mixture was stirred at room temperature for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was acidified with dilute HCl (1.5 N, 3 mL) and the aqueous layer was extracted with ethyl acetate (2×10 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 and concentrated under vacuum. The resulting crude material was purified by preparative HPLC purification (Method A) to give the title compound. Yield: 30% (15 mg, white solid). 1 H NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 7.28 (s, 1H), 7.15 (t, J = 7.6 Hz, 2H), 7.08 (s, 1H), 6.70 (t, J = 7.2 Hz, 1H), 6.58 (d, J = 8.0 Hz, 2H), 4.29-4.20 (m, 2H), 4.04-4.00 (m, 1H), 3.88 (m, 1H), 3.22 (m, 1H), 2.88 (m, 2H), 2.46 (s, 3H), 1.65-1.60 (m, 1H), 1.54-1.49 (m, 1H), 1.35 (m, 4H), 1.24-1.18 (m, 5H), 1.09 (m, 2H), 0.93 (m, 3H). LCMS: (Method K) 519.2 (M + +H), Rt. 2.83 min, 94.83% (max). HPLC: (Method E) Rt. 5.79 min, 94.74% (max).

[0449] Example 8 (S)-1-(((3-butyl-7-(ethylthio)-2-methyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid and (R)-1-(((3-butyl-7-(ethylthio)-2-methyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid

[0450] [ka]

[0451] The two enantiomers of racemic 1-(((3-butyl-7-(ethylthio)-2-methyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid (Example 7; 60 mg, 0.12 mmol) were separated by chiral SFC instrumentation (Method H). The material was concentrated under vacuum at 40° C. The first eluting fraction corresponded to enantiomer 1 and the second to enantiomer 2. The absolute configurations of the two enantiomers are unknown. Enantiomer 1: Yield: 24% (15 mg, off-white solid). 1H NMR (400 MHz, DMSO-d6): δ 12.43 (s, 1H), 7.28 (s, 1H), 7.15 (t, J = 8.8 Hz, 2H), 7.08 (s, 1H), 6.70 (t, J = 7.2 Hz, 1H), 6.58 (d, J = 8.4 Hz, 2H), 4.24 (m, 2H), 4.10-3.95 (m, 1H), 3.95-3.80 (m, 1H), 3.28-3.12 (m, 1H), 2.98-2.84 (m, 2H), 2.46 (s, 3H), 1.70-1.58 (m, 1H), 1.58-1.45 (m, 1H), 1.40-1.32 (m, 4H), 1.28-1.18 (m, 5H), 1.15-1.05 (m, 2H), 0.9 (t, J = 6.8 Hz, 3H). LCMS: (Method A) 519.2 (M + +H), Rt. 3.15 points, 97.05% (maximum). HPLC: (Method E) Rt. 5.94 points, 97.46% (maximum). KuraSFC: (Method K) Rt. 2.87 points, 99.75% (maximum). Enatoplast 2: Yield: 23% (15 mg, Enatoplast solid). 1 H NMR (400 MHz, DMSO-d6): δ 12.43 (s, 1H), 7.28 (s, 1H), 7.15 (t, J = 7.6 Hz, 2H), 7.08 (s, 1H), 6.70 (t, J = 7.6 Hz, 1H), 6.58 (d, J = 8.0 Hz, 2H), 4.35-4.12 (m, 2H), 4.10-3.98 (m, 1H), 3.98-3.80 (m, 1H), 3.28-3.10 (m, 1H), 2.89 (m, 2H), 2.47 (s, 3H), 1.68-1.58 (m, 1H), 1.58-1.45 (m, 1H), 1.45-1.30 (m, 4H), 1.28-1.18 (m, 5H), 1.15-1.05 (m, 2H), 1.00-0.85 (m, 3H). LCMS: (Method A) 519.1 (M ++H), Rt. 2.70 min, 95.84% (max). HPLC: (Method E) Rt. 5.79 min, 94.28% (max).Chiral SFC: (Method K) Rt. 3.61 min, 99.46% (max).

[0452] Example 9 3-((3-butyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy)-2,2-dimethylpropanoic acid

[0453] [ka]

[0454] To a stirred solution of methyl 3-((3-butyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy)-2,2-dimethylpropanoate (Intermediate 21; 0.12 g, 0.23 mmol) in a mixture of 1,4-dioxane and water (3:2; 5 mL) at 0° C., lithium hydroxide (10.97 mg, 0.46 mmol) was added and the reaction mixture was stirred at room temperature for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was acidified with dilute HCl (1.5 N, 5 mL) and the aqueous layer was extracted with ethyl acetate (2×10 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 resulting crude material was purified by preparative HPLC purification (Method A) to give the title compound. Yield: 17% (20 mg, white solid). 1H NMR (400 MHz, DMSO-d6): δ 12.43 (s, 1H), 7.35 (s, 1H), 7.03-6.97 (m, 3H), 6.58-6.54 (m, 2H), 4.25-4.08 (m, 3H), 3.50-3.35 (m, 1H), 3.25-3.02 (m, 2H), 2.34 (s, 3H), 2.32-2.20 (m, 1H), 1.38-1.35 (m, 4H), 1.32-1.27 (m, 8H), 0.91 (t, J = 7.20 Hz, 3H). LCMS: (Method A) 510.0 (M + +H), Rt. 3.03 min, 98.51% (max). HPLC: (Method E) Rt. 5.67 min, 99.12% (max).

[0455] Example 10 1-(((3-butyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid

[0456] [ka]

[0457] To a stirred solution of ethyl 1-(((3-butyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylate (Intermediate 22; 0.1 g, 0.19 mmol) in a mixture of 1,4-dioxane and water (5:1, 6 mL) at 0° C., lithium hydroxide (8.94 mg, 0.373 mmol) was added and the reaction mixture was stirred at room temperature for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was acidified with dilute HCl (1.5 N, 3 mL) and the aqueous layer was extracted with ethyl acetate (2×10 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 and concentrated under vacuum. The resulting crude material was purified by preparative HPLC purification (Method A) to give the title compound. Yield: 15% (15 mg, white solid). 1 H NMR (400 MHz, DMSO-d6): δ 12.43 (s, 1H), 7.35 (s, 1H), 7.03-6.97 (m, 3H), 6.57-6.54 (m, 2H), 4.32-4.12 (m, 3H), 3.50-3.38 (m, 1H), 3.25-3.00 (m, 2H), 2.34 (s, 3H), 2.32-2.20 (m, 1H), 1.45-1.20 (m, 8H), 1.12-1.08 (m, 2H), 0.90 (t, J = 7.20 Hz, 3H). LCMS: (Method A) 508.1 (M + +H), Rt. 2.96 min, 94.20% (max). HPLC: (Method E) Rt. 5.53 min, 94.35% (max).

[0458] Example 11 1-(((3-butyl-5-(4-fluorophenyl)-2-methyl-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid

[0459] [ka]

[0460] To a stirred solution of ethyl 1-(((3-butyl-5-(4-fluorophenyl)-2-methyl-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylate (Intermediate 30; 80 mg, 0.15 mmol) in a mixture of 1,4-dioxane and water (3:2, 5 mL) at 0° C., lithium hydroxide (6.96 mg, 0.29 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was acidified with dilute HCl (1.5 N, 3 mL) and the aqueous layer was extracted with ethyl acetate (2×10 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 and concentrated under vacuum. The resulting crude material was purified by preparative HPLC purification (Method A) to give the title compound. Yield: 29% (22 mg, white solid). 1 H NMR (400 MHz, DMSO-d6): δ 12.45 (s, 1H), 7.27 (s, 1H), 7.10-6.82 (m, 3H), 6.72-6.48 (m, 2H), 4.25 (m, 2H), 4.05-3.92 (m, 1H), 3.92-3.80 (m, 1H), 3.28-3.10 (m, 1H), 2.45 (s, 3H), 2.34 (s, 3H), 1.68-1.55 (m, 1H), 1.55-1.42 (m, 1H), 1.42-1.28 (m, 4H), 1.28-1.18 (m, 2H), 1.18-1.02 (m, 2H), 1.00-0.82 (m, 3H). LCMS: (Method B) 523.0 (M + +H), Rt. 2.10 min, 98.06% (max). HPLC: (Method E) Rt. 5.75 min, 99.00% (max).

[0461] Example 12 (S)-1-(((3-butyl-5-(4-fluorophenyl)-2-methyl-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid and (R)-1-(((3-butyl-5-(4-fluorophenyl)-2-methyl-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid

[0462] [ka]

[0463] The two enantiomers of racemic 1-(((3-butyl-5-(4-fluorophenyl)-2-methyl-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid (Example 11; 40 mg, 0.077 mmol) were separated by chiral SFC instrumentation (Method A). The material was concentrated under vacuum at 40° C. The first eluting fraction corresponded to enantiomer 1 and the second to enantiomer 2. The absolute configurations of the two enantiomers are unknown. Enantiomer 1: Yield: 25% (10 mg, white solid). 1 H NMR (400 MHz, DMSO-d6): δ 12.44 (s, 1H), 7.27 (s, 1H), 7.02-7.01 (m, 3H), 6.59 (m, 2H), 4.26 (m, 2H), 4.05-3.98 (m, 1H), 3.92-3.82 (m, 1H), 3.2-3.15 (m, 1H), 2.46 (s, 3H), 2.34 (s, 3H), 1.68-1.55 (m, 1H), 1.55-1.48 (m, 1H), 1.4-1.3 (m, 4H), 1.25-1.18 (m, 2H), 1.12-1.05 (m, 2H), 0.98-0.88 (m, 3H). LCMS: (Method A) 523.1 (M ++H), Rt. 3.05 min, 97.58% (max). HPLC: (Method E) Rt. 5.66 min, 99.56% (max).Chiral SFC: (Method U) Rt. 2.37 min, 99.39% (max). Enantiomer 2: Yield: 36% (15 mg, white solid). 1 H NMR (400 MHz, DMSO-d6): δ 12.45 (s, 1H), 7.27 (s, 1H), 7.10-6.90 (m, 3H), 6.65-6.48 (m, 2H), 4.32-4.18 (m, 2H), 4.05-3.95 (m, 1H), 3.90-3.82 (m, 1H), 3.25-3.15 (m, 1H), 2.47 (s, 3H), 2.34 (s, 3H), 1.65-1.55 (m, 1H), 1.55-1.45 (m, 1H), 1.42-1.28 (m, 4H), 1.28-1.20 (m, 2H), 1.15-1.05 (m, 2H), 0.9 (t, J = 6.8 Hz, 3H). LCMS: (Method A) 523.1 (M + +H), Rt. 3.05 min, 96.30% (max). HPLC: (Method E) Rt. 5.62 min, 95.65% (max).Chiral SFC: (Method U) Rt. 2.93 min, 99.67% (max).

[0464] (Example 13) 3-((3-butyl-5-(4-fluorophenyl)-2-methyl-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2,2-dimethylpropanoic acid

[0465] [ka]

[0466] To a stirred solution of methyl 3-((3-butyl-5-(4-fluorophenyl)-2-methyl-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2,2-dimethylpropanoate (Intermediate 31; 0.04 g, 0.074 mmol) in a mixture of 1,4-dioxane and water (5:1, 6 mL) at 0° C., lithium hydroxide (3.56 mg, 0.15 mmol) was added and the reaction mixture was stirred at room temperature for 12 h. After completion of the reaction (monitored by TLC), the reaction mixture was acidified with dilute HCl (1.5 N, 5 mL) and the aqueous layer was extracted with ethyl acetate (2×10 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 and concentrated under vacuum. The resulting crude material was purified by preparative HPLC purification (Method A) to give the title compound. Yield: 25% (10 mg, white solid). 1 H NMR (400 MHz, DMSO-d6): δ 12.46 (s, 1H), 7.27 (s, 1H), 7.13-6.82 (m, 3H), 6.70-6.40 (m, 2H), 4.11 (s, 2H), 4.05-3.95 (m, 1H), 3.95-3.75 (m, 1H), 3.30-3.15 (m, 1H), 2.46 (s, 3H), 2.34 (s, 3H), 1.72-1.55 (m, 1H), 1.55-1.42 (m, 1H), 1.40-1.30 (m, 4H), 1.30-1.25 (m, 6H), 0.95-0.88 (m, 3H). LCMS: (Method A) 524.8 (M + ), Rt. 2.74 min, 95.76% (max). HPLC: (Method E) Rt. 5.75 min, 96.44% (max).

[0467] Example 14 (S)-3-((3-butyl-5-(4-fluorophenyl)-2-methyl-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2,2-dimethylpropanoic acid and (R)-3-((3-butyl-5-(4-fluorophenyl)-2-methyl-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2,2-dimethylpropanoic acid

[0468] [ka]

[0469] The two enantiomers of racemic 3-((3-butyl-5-(4-fluorophenyl)-2-methyl-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2,2-dimethylpropanoic acid (Example 13; 0.025 g, 0.143 mmol) were separated by chiral SFC (Method G). The material was concentrated under vacuum at 40° C. The first eluting fraction corresponded to enantiomer 1 and the second to enantiomer 2. The absolute configurations of the two enantiomers are unknown. Enantiomer 1: Yield: 33.2% (0.025 g, off-white solid). 1 H-NMR (400 MHz, DMSO-d6): δ 12.46 (s, 1H), 7.27 (s, 1H), 7.02-7.01 (m, 1H), 6.98-6.96 (m, 2H), 6.59-6.56 (m, 2H), 4.11 (s, 2H), 4.01-3.97 (m, 1H), 3.86 (s, 1H), 3.24-3.21 (m, 1H), 2.46 (s, 3H), 2.34 (s, 3H), 1.60-1.41 (m, 2H), 1.35-1.34 (m, 4H), 1.27 (s, 6H), 0.93-0.91 (m, 3H). LCMS: (Method A) 525.1 (M ++H), Rt. 3.18 min, 99.48% (max). HPLC: (Method B) Rt. 5.88 min, 99.62% (max).Chiral HPLC: (Method G) Rt. 1.65 min, 100% (max) Enantiomer 2: Yield: 26.6% (0.020 g, off-white solid). 1 H-NMR (400 MHz, DMSO-d6): δ 12.46 (s, 1H), 7.27 (s, 1H), 7.02-7.01 (m, 1H), 6.98-6.96 (m, 2H), 6.59-6.57 (m, 2H), 4.11 (s, 2H), 4.01-3.97 (m, 1H), 3.87 (s, 1H), 3.24-3.23 (m, 1H), 2.46 (s, 3H), 2.34 (s, 3H), 1.60 (s, 2H), 1.35 (s, 4H), 1.27-1.24 (m, 6H), 0.93-0.91 (m, 3H). LCMS: (Method A) 525.2 (M + +H), Rt. 3.17 min, 98.37% (max). HPLC: (Method B) Rt. 5.88 min, 99.71% (max).Chiral HPLC (Method G) Rt. 2.22 min, 99.76% (max)

[0470] Example 15 1-(((3-Butyl-7-(ethylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid

[0471] [ka]

[0472] To a stirred solution of ethyl 1-(((3-butyl-7-(ethylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylate (Intermediate 41; 0.05 g, 0.09 mmol) in a mixture of 1,4-dioxane and water (5:1, 6 mL) at 0° C., lithium hydroxide (4.50 mg, 0.19 mmol) was added and the reaction mixture was stirred at room temperature for 12 h. After completion of the reaction (monitored by TLC), the reaction mixture was acidified with dilute HCl (1.5 N, 3 mL) and the aqueous layer was extracted with ethyl acetate (2×10 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 and concentrated under vacuum. The resulting crude material was purified by preparative HPLC purification (Method A) to give the title compound. Yield: 20% (10 mg, white solid). 1 H NMR (400 MHz, DMSO-d6): δ 12.45 (s, 1H), 7.32 (s, 1H), 7.25 (d, J = 9.2 Hz, 1H), 7.14 (t, J = 8.4 Hz, 2H), 7.08 (s, 1H), 6.69 (t, J = 7.2 Hz, 1H), 6.57 (d, J = 8.4 Hz, 2H), 4.45-4.30 (m, 1H), 4.30-4.15 (m, 2H), 3.52-3.42 (m, 1H), 2.95-2.80 (m, 3H), 1.70-1.52 (m, 2H), 1.52-1.38 (m, 4H), 1.35-1.28 (m, 2H), 1.25-1.22 (m, 3H), 1.12-1.08 (m, 2H), 0.9 (t, J = 7.2 Hz, 3H). LCMS: (Method A) 505.1 (M + +H), Rt. 2.52 min, 92.00% (max). HPLC: (Method E) Rt. 5.55 min, 92.07% (max).

[0473] Example 16 1-(((3-butyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid

[0474] [ka]

[0475] To a stirred solution of ethyl 1-(((3-butyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylate (Intermediate 45; 0.03 g, 0.06 mmol) in a mixture of 1,4-dioxane and water (5:1, 6 mL) at 0° C., lithium hydroxide (2.68 mg, 0.11 mmol) was added and the reaction mixture was stirred at room temperature for 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was acidified with dilute HCl (1.5 N, 3 mL) and the aqueous layer was extracted with ethyl acetate (2×10 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 and concentrated under vacuum. The resulting crude was purified by preparative HPLC purification (Method A) to give the title compound. Yield: 33% (10 mg, white solid). 1 H NMR (400 MHz, DMSO-d6): δ 12.51 (s, 1H), 7.36 (s, 1H), 7.32 (d, J = 9.6 Hz, 1H), 7.12-6.98 (m, 3H), 6.72-6.55 (m, 2H), 4.42-4.22 LCMS: (Method A) 509.1 (M + +H), Rt. 2.41 min, 91.15% (max). HPLC: (Method E) Rt. 5.40 min, 93.38% (max).

[0476] (Example 17) (S)-1-(((3-butyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid and (R)-1-(((3-butyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid

[0477] [ka]

[0478] The two enantiomers of racemic 1-(((3-butyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid (Example 16; 0.1 g, 0.19 mmol) were separated by chiral SFC instrumentation (Method M). The material was concentrated under vacuum at 40° C. The first eluting fraction corresponded to enantiomer 1 and the second to enantiomer 2. The absolute configurations of the two enantiomers are unknown. Enantiomer 1: Yield: 40% (40 mg, off-white solid). 1H NMR (400 MHz, DMSO-d6): δ 12.45 (s, 1H), 7.30 (s, 1H), 7.26 (d, J = 9.2 Hz, 1H), 7.05-6.95 (m, 3H), 6.62-6.48 (m, 2H), 4.38-4.15 (m, 3H), 3.48-3.40 (m, 1H), 2.95-2.78 (m, 1H), 2.33 (s, 3H), 1.65-1.42 (m, 2H), 1.42-1.28 (m, 4H), 1.28-1.20 (m, 2H), 1.15-1.05 (m, 2H), 0.90 (t, J = 7.20 Hz, 3H). LCMS: (Method K) 509.2 (M + +H), Rt. 2.40 minutes, 98.25% (maximum). HPLC: (Method E) Rt. 5.51 minutes, 99.22% (maximum). SFC: (Method G) Rt. 1.41 minutes, 100% (maximum). Enomax 2: Yield: 40% (40 mg, Enotomo solid). 1 H NMR (400 MHz, DMSO-d6): δ 12.45 (s, 1H), 7.30 (s, 1H), 7.26 (d, J = 8.8 Hz, 1H), 7.10-7.92 (m, 3H), 6.65-6.48 (m, 2H), 4.38-4.18 (m, 3H), 3.52-3.42 (m, 1H), 2.95-2.78 (m, 1H), 2.33 (s, 3H), 1.65-1.45 (m, 2H), 1.45-1.30 (m, 4H), 1.28-1.20 (m, 2H), 1.15-1.05 (m, 2H), 0.90 (t, J = 6.80 Hz, 3H). LCMS: (Method B) 508.9 (M + +H), Rt. 1.88 points, 96.57% (maximum). HPLC: (Method E) Rt. 5.51 points, 98.55% (maximum). KuraSFC: (Method G) Rt. 2.13 points, 99.05% (maximum).

[0479] (Example 18) 1-(((3-butyl-7-(ethylthio)-5-(4-fluorophenyl)-1,1-dioxide-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid

[0480] [ka]

[0481] To a stirred solution of ethyl 1-(((3-butyl-7-(ethylthio)-5-(4-fluorophenyl)-1,1-dioxide-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylate (Intermediate 47; 0.07 g, 0.13 mmol) in a mixture of 1,4-dioxane and water (5:1, 6 mL) at 0° C., lithium hydroxide (6.09 mg, 0.25 mmol) was added and the reaction mixture was stirred at room temperature for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was acidified with dilute HCl (1.5 N, 3 mL) and the aqueous layer was extracted with ethyl acetate (2×10 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 and concentrated under vacuum. The resulting crude was purified by preparative HPLC purification (Method A) to give the title compound. Yield: 58% (40 mg, white solid). 1H NMR (400 MHz, DMSO-d6): δ 12.45 (s, 1H), 7.31 (s, 1H), 7.26 (d, J = 9.2 Hz, 1H), 7.05 (s, 1H), 6.99 (t, J = 8.8 Hz, 2H), 6.68-6.45 (m, 2H), 4.42-4.22 (m, 2H), 4.22-4.10 (m, 1H), 3.50-3.40 (m, 1H), 2.87 (m, 3H), 1.65-1.52 (m, 1H), 1.48-1.22 (m, 7H), 1.22-1.18 (m, 3H), 1.15-1.05 (m, 2H), 0.90 (t, J = 7.20 Hz, 3H). LCMS: (Method A) 521.3 (M + -H), Rt. 3.02 min, 95.10% (max). HPLC: (Method E) Rt. 5.61 min, 97.11% (max).

[0482] (Example 19) (S)-1-(((3-butyl-7-(ethylthio)-5-(4-fluorophenyl)-1,1-dioxide-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid and (R)-1-(((3-butyl-7-(ethylthio)-5-(4-fluorophenyl)-1,1-dioxide-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid

[0483] [ka]

[0484] The two enantiomers of racemic 1-(((3-butyl-7-(ethylthio)-5-(4-fluorophenyl)-1,1-dioxide-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid (Example 18; 30 mg, 0.06 mmol) were separated by chiral SFC instrumentation (Method M). The material was concentrated under vacuum at 40° C. The first eluting fraction corresponded to enantiomer 1 and the second to enantiomer 2. The absolute configurations of the two enantiomers are unknown. Enantiomer 1: Yield: 30% (9 mg, off-white solid). 1 H NMR (400 MHz, DMSO-d6): δ 12.43 (s, 1H), 7.31 (s, 1H), 7.26 (d, J = 9.6 Hz, 1H), 7.05 (s, 1H), 6.99 (t, J = 8.8 Hz, 2H), 6.65-6.52 (m, 2H), 4.38-4.12 (m, 3H), 3.42-3.38 (m, 1H), 2.92-2.85 (m, 3H), 1.65-1.52 (m, 2H), 1.45-1.38 (m, 2H), 1.25-1.20 (m, 3H), 1.20-1.18 (m, 3H), 1.12-1.02 (m, 3H), 0.95-0.88 (m, 3H). LCMS: (Method A) 521.2 (M + -H), Rt. 3.01 min, 95.40% (max). HPLC: (Method E) Rt. 5.63 min, 99.21% (max).Chiral SFC: (Method G) Rt. 2.2 min, 99.74% (max). Enantiomer 2: Yield: 23% (7 mg, off-white solid). 1H NMR (400 MHz, DMSO-d6): δ 12.44 (s, 1H), 7.31 (s, 1H), 7.26 (d, J = 9.6 Hz, 1H), 7.05 (s, 1H), 6.99 (t, J = 8.8 Hz, 2H), 6.68-6.50 (m, 2H), 4.35-4.15 (m, 3H), 3.42-3.38 (m, 1H), 2.92-2.85 (m, 3H), 1.65-1.55 (m, 1H), 1.50-1.32 (m, 4H), 1.28-1.15 (m, 6H), 1.12-1.08 (m, 2H), 0.95-0.85 (m, 3H). LCMS: (Method A) 521.1 (M + -H), Rt. 3.00 min, 97.25% (max). HPLC: (Method E) Rt. 5.70 min, 97.41% (max).Chiral SFC: (Method G) Rt. 3.45 min, 99.49% (max).

[0485] (Example 20) 3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2,2-difluoropropanoic acid

[0486] [ka]

[0487] To a stirred solution of ethyl 3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2,2-difluoropropanoate (Intermediate 48; 0.1 g, 0.18 mmol) in a mixture of 1,4-dioxane and water (3:1, 4 mL) at 0° C., lithium hydroxide (8.83 mg, 0.37 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was acidified with dilute HCl (1.5 N, 5 mL) and the aqueous layer was extracted with ethyl acetate (2×10 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 and concentrated under vacuum. The resulting crude was purified by preparative HPLC purification (Method A) to give the title compound. Yield: 14% (14 mg, off-white solid). 1 H NMR (400 MHz, DMSO-d6): δ 7.33 (s, 1H), 7.15 (t, J = 8.4 Hz, 2H), 7.06 (s, 1H), 6.70 (t, J = 7.2 Hz, 1H), 6.58 (d, J = 8.4 Hz, 2H), 4.51 (t, J = 14.4 Hz, 2H), 4.08-3.98 (m, 1H), 3.95-3.85 (m, 1H), 3.25-3.15 (m, 1H), 2.46 (s, 3H), 2.36 (s, 3H), 1.68-1.58 (m, 1H), 1.55-1.45 (m, 1H), 1.40-1.28 (m, 4H), 0.95-0.88 (m, 3H). LCMS: (Method K) 515.2 (M + +H), Rt. 2.46 min, 95.16% (max). HPLC: (Method E) Rt. 5.57 min, 96.09% (max).

[0488] Example 21 (S)-3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2,2-difluoropropanoic acid and (R)-3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2,2-difluoropropanoic acid

[0489] [ka]

[0490] The two enantiomers of racemic 3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2,2-difluoropropanoic acid (Example 20; 40 mg, 0.08 mmol) were separated by chiral SFC instrumentation (Method F). The material was concentrated under vacuum at 40° C. The first eluting fraction corresponded to enantiomer 1 and the second to enantiomer 2. The absolute configurations of the two enantiomers are unknown. Enantiomer 1: Yield: 12% (5 mg, off-white solid). 1 H NMR (400 MHz, DMSO-d6): δ 7.34 (s, 1H), 7.15 (t, J = 8.4 Hz, 2H), 7.06 (s, 1H), 6.70 (t, J = 7.2 Hz, 1H), 6.58 (d, J = 8.0 Hz, 2H), 4.52 (t, J = 14.0 Hz, 2H), 4.05-3.95 (m, 1H), 3.95-3.80 (m, 1H), 3.25-3.15 (m, 1H), 2.46 (s, 3H), 2.36 (s, 3H), 1.68-1.58 (m, 1H), 1.55-1.45 (m, 1H), 1.42-1.32 (m, 4H), 0.98-0.88 (m, 3H). LCMS: (Method B) 515.0 (M ++H), Rt. 2.09 min, 94.41% (max). HPLC: (Method E) Rt. 5.52 min, 98.13% (max).Chiral SFC: (Method H) Rt. 3.26 min, 100% (max). Enantiomer 2: Yield: 13% (5 mg, off-white solid). 1 H NMR (400 MHz, DMSO-d6): δ 7.34 (s, 1H), 7.15 (t, J = 8.8 Hz, 2H), 7.06 (s, 1H), 6.70 (t, J = 7.2 Hz, 1H), 6.58 (d, J = 8.4 Hz, 2H), 4.50 (t, J = 14.4 Hz, 2H), 4.05-3.98 (m, 1H), 3.95-3.82 (m, 1H), 3.25-3.12 (m, 1H), 2.46 (s, 3H), 2.36 (s, 3H), 1.68-1.58 (m, 1H), 1.50-1.45 (m, 1H), 1.42-1.30 (m, 4H), 0.92 (t, J = 6.80 Hz, 3H). LCMS: (Method B) 515.1 (M + +H), Rt. 2.09 min, 93.89% (max). HPLC: (Method E) Rt. 5.53 min, 99.76% (max).Chiral SFC: (Method H) Rt. 5.93 min, 100% (max).

[0491] Example 22 3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2-methoxy-2-methylpropanoic acid

[0492] [ka]

[0493] To a stirred solution of methyl 3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2-methoxy-2-methylpropanoate (Intermediate 52; 0.13 g, 0.24 mmol) in a mixture of 1,4-dioxane and water (2:1, 3 mL) at 0° C., lithium hydroxide (0.02 g, 0.48 mmol) was added and the reaction mixture was stirred at room temperature for 3 h. After completion of the reaction (monitored by TLC), the reaction mixture was acidified with dilute HCl (1.5 N, 5 mL) and the aqueous layer was extracted with ethyl acetate (2×20 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 in vacuo and the resulting crude was purified by preparative HPLC purification (Method A) to give the title compound. Yield: 25% (30 mg, white solid). 1 H NMR (400 MHz, DMSO-d6): δ 13.0 (s, 1H), 7.32 (s, 1H), 7.16 (t, J = 7.6 Hz, 2H), 7.05 (s, 1H), 6.71 (t, J = 7.2 Hz, 1H), 6.58 (d, J = 8.4 Hz, 2H), 4.36 (m, 1H), 4.27 (m, 1H), 4.02 (m, 1H), 3.95-3.85 (m, 1H), 3.31 (s, 3H), 3.25-3.15 (bs, 1H), 2.46 (s, 3H), 2.34 (s, 3H), 1.7-1.3 (m, 9H), 0.94-0.92 (m, 3H). LCMS: (Method K) 522.9 (M + +H), Rt. 2.94 min, 98.59% (max). HPLC: (Method E) Rt. 5.54 min, 98.79% (max).

[0494] (Example 23) 3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2-methoxy-2-methylpropanoic acid

[0495] [ka]

[0496] Starting from 0.05 g of intermediate 53, the title compound was obtained according to the same procedure as described for example 21. After workup of the reaction mixture, the crude material was purified by Isolera column chromatography (eluent: 10-15% EtOAc / PE; silica gel: 230-400 mesh) to obtain the title compound. The absolute configuration of the compound is unknown. Yield: 50% (25 mg, off-white solid). 1 H NMR (400 MHz, DMSO-d6): δ 13.0 (s, 1H), 7.33 (s, 1H), 7.16 (t, J = 7.2 Hz, 2H), 7.05 (s, 1H), 6.70 (t, J = 7.6 Hz, 1H), 6.58 (d, J = 8.4 Hz, 2H), 4.36 (t, J = 9.6 Hz, 1H), 4.27 (t, J = 8.0 Hz, 1H), 4.02 (m, 1H), 3.89-3.88 (m, 1H), 3.30 (s, 3H), 3.25-3.15 (m, 1H), 2.46 (s, 3H), 2.35 (s, 3H), 1.7-1.6 (m, 1H), 1.6-1.42 (m, 4H), 1.42-1.28 (m, 4H), 1.0-0.85 (m, 3H). LCMS: (Method K) 522.9 (M + +H), Rt. 2.73 min, 99.48% (max). HPLC: (Method E) Rt. 5.51 min, 99.35% (max).

[0497] (Example 24) (S)-3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2-methoxy-2-methylpropanoic acid and (R)-3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2-methoxy-2-methylpropanoic acid (individual diastereomers)

[0498] [ka]

[0499] Diastereoisomers 1 and 2 of the title compound were prepared from diastereoisomer 1 (95 mg) and diastereoisomer 2 (90 mg) of intermediate 54, respectively, following the same procedure as described for Example 21. After workup of the reaction mixture, the crude material was purified by Isolera column chromatography (eluent: 4% MeOH / DCM; silica gel: 230-400 mesh) to give the title compound. The absolute configuration of the two diastereomers is unknown. Diastereoisomer 1: Yield: 57% (55 mg, white solid). 1 H NMR (400 MHz, DMSO-d6): δ 7.33 (s, 1H), 7.16 (t, J = 7.2 Hz, 2H), 7.05 (s, 1H), 6.71 (t, J = 7.6 Hz, 1H), 6.58 (d, J = 8.0 Hz, 2H), 4.42-4.32 (m, 1H), 4.3-4.2 (m, 1H), 4.1-3.8 (m, 2H), 3.31 (s, 3H), 3.25-3.15 (m, 1H), 2.46 (s, 3H), 2.35 (s, 3H), 1.7-1.58 (m, 1H), 1.55 - 1.28 (m, 8H), 0.95-0.88 (m, 3H). LCMS: (Method K) 523.3 (M ++H), Rt. 2.71 min, 98.96% (max). HPLC: (Method E) Rt. 5.45 min, 97.51% (max).Chiral purity: (Method H) Rt. 9.02 min, 98.10% (max). Diastereoisomer 2: Yield: 49% (45 mg, white solid). 1 H NMR (400 MHz, DMSO-d6): δ 13.08 (s, 1H), 7.33 (s, 1H), 7.16 (t, J = 8.0 Hz, 2H), 7.06 (s, 1H), 6.71 (t, J = 7.2 Hz, 1H), 6.58 (d, J = 8.4 Hz, 2H), 4.42-4.32 (m, 1H), 4.3-4.18 (m, 1H), 4.1-3.85 (m, 2H), 3.30 (s, 3H), 3.25-3.15 (m, 1H), 2.47 (s, 3H), 2.35 (s, 3H), 1.7-1.45 (m, 5H), 1.45-1.28 (m, 4H), 0.95-0.88 (m, 3H). LCMS: (Method K) 523.3 (M + +H), Rt. 2.71 min, 98.20% (max). HPLC: (Method E) Rt. 5.45 min, 98.01% (max).Chiral purity: (Method H) Rt. 7.83 min, 98.92% (max).

[0500] (Example 25) 3-((3-butyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy)propanoic acid

[0501] [ka]

[0502] To a stirred solution of 3-butyl-8-hydroxy-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide (0.2 g, 0.05 mmol) in THF (5 mL) was added potassium tert-butoxide (0.063 g, 0.06 mmol) and oxetan-2-one (0.04 g, 0.06 mmol) and the reaction mixture was stirred at 50° C. for 3 h. As TLC showed incomplete conversion, additional oxetan-2-one (0.04 g, 0.06 mmol) was added and the reaction mixture was stirred at 50° C. for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was acidified with dilute HCl (5 mL, 1.5 N HCl) 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 and concentrated in vacuo and the resulting material was purified by Isolera column chromatography (eluent: 20% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. Yield: 31% (75 mg, white solid). 1 H-NMR (400 MHz, DMSO-d6): δ 7.51 (s, 1H), 7.18 (t, J = 8.00 Hz, 2H), 7.06 (s, 1H), 6.75 (t, J = 7.20 Hz, 1H), 6.67 (d, J = 8.00 Hz, 2H), 4.40 (s, 2H), 4.35-4.31 (m, 1H), 3.44-3.40 (m, 1H), 3.14-3.05 (m, 2H), 2.87-2.85 (m, 2H), 2.45 (s, 1H), 2.33 (s, 3H), 1.47-1.40 (m, 6H), 1.00-0.89 (m, 3H). LCMS: (Method E) 464.1 (M + +H) Rt. 4.81 min, 95.14% (max). HPLC: (Method B) Rt. 5.36 min, 95.27% (max).

[0503] (Example 26) (S)-3-((3-butyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy)propanoic acid and (R)-3-((3-butyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy)propanoic acid

[0504] [ka]

[0505] The two enantiomers of racemic 3-((3-butyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy)propanoic acid (Example 25; 68 mg, 0.15 mmol) were separated by chiral SFC (Method D). The material was concentrated under vacuum at 40° C. The first eluting fraction corresponded to enantiomer 1 and the second to enantiomer 2. The absolute configurations of the two enantiomers are unknown. Enantiomer 1: Yield: 35% (0.024 g, white solid). 1 H NMR (400 MHz, DMSO-d6): δ 12.47 (s, 1H), 7.39 (s, 1H), 7.15 (t, J = 7.60 Hz, 2H), 7.06 (s, 1H), 6.68 (t, J = 7.20 Hz, 1H), 6.56 (d, J = 8.00 Hz, 2H), 4.34-4.21 (m, 3H), 3.34 (s, 1H), 3.14 (s, 1H), 3.10-3.04 (m, 1H), 2.72 (s, 2H), 2.34 (s, 4H), 1.40-1.30 (m, 6H), 0.93-0.89 (m, 3H). LCMS: (Method A) 464.1 (M + +H) Rt. 2.54 min, 94.45% (max). HPLC: (Method B) Rt. 5.36 min, 97.37% (max).Chiral HPLC: (Method D) Rt. 2.07 min, 100% (max). Enantiomer 2: Yield: 12% (0.008 g, white solid). 1 H NMR (400 MHz, DMSO-d6): δ 7.39 (s, 1H), 7.17-7.15 (m, 2H), 7.06 (s, 1H), 6.68 (t, J = 7.20 Hz, 1H), 6.55 (d, J = 8.00 Hz, 2H), 4.34-4.30 (m, 3H), 3.44-3.41 (m, 1H), 3.40-3.33 (m, 1H), 3.29-3.23 (m, 1H), 2.76-2.73 (m, 2H), 2.34 (s, 4H), 1.40-1.30 (m, 6H), 0.93-0.89 (m, 3H). LCMS: (Method A) 464.2 (M + +H) Rt. 2.55 min, 99.61% (max). HPLC: (Method B) Rt. 5.35 min, 99.92% (max).Chiral HPLC: (Method D) Rt. 3.28 min, 99.26% (max).

[0506] Example 27 3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2-ethoxypropanoic acid

[0507] [ka]

[0508] To a stirred solution of methyl 3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2-ethoxypropanoate (Intermediate 59; 30 mg, 0.06 mmol) in 1,4-dioxane (1 mL) at 0° C., lithium hydroxide (4.69 mg, 0.11 mmol) was added and the reaction mixture was stirred at room temperature for 30 min. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with dilute HCl (1.5 N, 1 mL) and the aqueous layer was extracted with EtOAc (2×5 mL). The combined organic layers were washed with water (5 mL), brine (5 mL) and dried over anhydrous Na2SO4. The organic portion was filtered, concentrated under vacuum and the resulting crude material was purified by preparative HPLC (Method A) to give the title compound. Yield: 13% (4 mg, off-white solid). 1 H NMR (400 MHz, DMSO-d6): δ 13.21 (s, 1H), 7.38 (s, 1H), 7.15 (t, J = 8.00 Hz, 2H), 7.05 (s, 1H), 6.70 (t, J = 4.00 Hz, 1H), 6.58 (d, J = 6.80 Hz, 2H), 4.43-4.41 (m, 1H), 4.33-4.25 (m, 2H), 4.03-3.87 (m, 2H), 3.74-3.70 (m, 1H), 3.58-3.54 (m, 1H), 3.23-3.11 (m, 1H), 2.51 (s, 3H), 2.34 (s, 3H), 1.61-1.48 (m, 2H), 1.36-1.30 (m, 4H), 1.17-1.13 (m, 3H), 0.94-0.90 (m, 3H). LCMS: (Method E) 523.0 (M + +H) Rt. 2.89 min, 95.56% (max). HPLC: (Method B) Rt. 5.59 min, 93.21% (max).

[0509] (Example 28) 3-((3-butyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy)-2-hydroxypropanoic acid

[0510] [ka]

[0511] To a stirred solution of methyl 3-((3-butyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy)-2-hydroxypropanoate (Intermediate 60; 0.17 g, 0.34 mmol) in 1,4-dioxane (2 mL) at 0° C., dilute HCl (6N, 2 mL) was added dropwise and the reaction mixture was heated at 80° C. for 3 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water (5 mL) and the aqueous layer was extracted with EtOAc (2×5 mL). The combined organic layers were washed with water (5 mL), brine (5 mL) and the organic portion was dried over anhydrous Na2SO4. The organic portion was filtered and concentrated under vacuum, and the crude material obtained was purified by Isolera column chromatography (eluent: 3-10% MeOH in DCM; silica gel: 230-400 mesh) to give the title compound. Yield: 30% (50 mg, light brown solid). 1 H NMR (400 MHz, DMSO-d6): δ 7.42 (s, 1H), 7.14 (t, J = 8.00 Hz, 2H), 7.04 (s, 1H), 6.67 (t, J = 7.60 Hz, 1H), 6.55 (d, J = 8.00 Hz, 2H), 4.37-4.32 (m, 1H), 4.27-4.19 (m, 3H), 3.43-3.39 (m, 1H), 3.33-3.20 (m, 1H), 3.08-3.02 (m, 1H), 2.34 (s, 3H), 2.33-2.27 (m, 1H), 1.38-1.35 (m, 4H), 1.33-1.25 (m, 3H), 0.91-0.88 (m, 3H). LCMS: (Method E) 480.1 (M+ +H) Rt. 2.68 min, 98.95% (max). HPLC: (Method B) Rt. 4.91 min, 97.58% (max).

[0512] (Example 29) 3-((3-ethyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy)propanoic acid

[0513] [ka]

[0514] To a stirred solution of 3-ethyl-8-hydroxy-7-(methylthio)-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine 1,1-dioxide (0.2 g, 0.55 mmol) in THF (5 mL) at 0 °C was added KO t Bu (0.07 g, 0.60 mmol) and oxetan-2-one (0.04 g, 0.60 mmol) were added and the reaction mixture was stirred at 50 °C for 3 h. As TLC showed incomplete conversion, additional oxetan-2-one (0.04 g, 0.06 mmol) was added and the reaction mixture was stirred at 50 °C for 16 h. After completion of the reaction, the reaction mixture was acidified with dilute HCl (1.5 N, 5 mL) and the aqueous layer was extracted with EtOAc (2 x 15 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 crude material obtained was purified by Isolera column chromatography (eluent: 45% EtOAc:PE; silica gel: 230-400 mesh). The material obtained was re-purified by preparative HPLC purification (Method A) to give the title compound. Yield: 6.2% (15 mg, light brown solid). 1H NMR (400 MHz, DMSO-d6): δ 7.39 (s, 1H), 7.17-7.13 (m, 2H), 7.06 (s, 1H), 6.68 (t, J = 7.20 Hz, 1H), 6.57 (d, J = 8.00 Hz, 2H), 4.31-4.25 (m, 3H), 3.47-3.43 (m, 1H), 3.43-3.26 (m, 1H), 3.10-3.04 (m, 1H), 2.72-2.68 (m, 2H), 2.34 (s, 3H), 2.24 (s, 1H), 1.48-1.38 (m, 2H), 0.99 (t, J = 7.60 Hz, 3H). LCMS: (Method A) 436.1(M + +H) Rt. 2.10 min, 98.88% (max). HPLC: (Method B) Rt. 4.33 min, 99.77% (max).

[0515] (Example 30) 3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2-methoxypropanoic acid

[0516] [ka]

[0517] To a stirred solution of methyl 3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2-methoxypropanoate (Intermediate 57; 55 mg, 0.10 mmol) in a mixture of 1,4-dioxane and water (2:1, 3 mL) at 0° C., lithium hydroxide (10 mg, 0.21 mmol) was added and the reaction mixture was stirred at room temperature for 1 h. After completion of the reaction (monitored by TLC), the reaction mixture was acidified with dilute HCl (1.5 N, pH approx. 4) and diluted with ice-cold water (2 mL). The aqueous layer was extracted with EtOAc (2×5 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 to give the title compound. Yield: 28% (15 mg, white solid). 1 H NMR (400 MHz, DMSO-d6): δ 13.02 (bs, 1H), 7.34 (s, 1H), 7.15 (t, J = 8.0 Hz, 2H), 7.05 (s, 1H), 6.70 (t, J = 7.2 Hz, 1H), 6.58 (d, J = 8.0 Hz, 2H), 4.43 (t, J = 3.2 Hz, 1H), 4.37-4.31 (m, 1H), 4.19-4.15 (m, 1H), 4.04-4.01 (m, 1H), 4.00-3.90 (m, 1H), 3.43 (s, 3H), 3.20-3.19 (m, 1H), 2.45 (s, 3H), 2.35 (s, 3H), 1.62-1.60 (m, 1H), 1.52-1.50 (m, 1H), 1.36-1.31 (m, 4H), 0.93-0.92 (m, 3H). LCMS: (Method E) 508.9 (M + +H), Rt. 2.87 min, 96.57% (max). HPLC: (Method B) Rt. 5.44 min, 98.31% (max).

[0518] (Example 31) 3-(((S)-3-Butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2-methoxypropanoic acid and 3-(((R)-3-Butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2-methoxypropanoic acid

[0519] [ka]

[0520] Stereoisomers 1 and 2 of the title compound were prepared from stereoisomer 1 (0.15 g) and stereoisomer 2 (0.1 g) of intermediate 58, respectively, following the same procedure as described for example 30. After workup of the reaction mixture, the crude material was purified by Isolera column chromatography (eluent: 0-30% EtOAc / PE; silica gel: 230-400 mesh) to give the title compound. The absolute configuration of the two stereoisomers is unknown. Stereoisomer 1: Yield: 71.3% (0.11 g, brown solid). 1 H-NMR (400 MHz, DMSO-d6): δ 12.64 (s, 1H), 7.35 (s, 1H), 7.15 (t, J = 8.00 Hz, 2H), 7.06 (s, 1H), 6.70 (t, J = 7.60 Hz, 1H), 6.58 (d, J = 8.40 Hz, 2H), 4.44-4.41 (m, 2H), 4.37-4.34 (m, 1H), 4.19-4.19 (m, 1H), 4.03-4.00 (m, 1H), 3.43 (s, 3H), 3.18-3.17 (m, 1H), 2.46 (s, 3H), 2.35-2.33 (m, 3H), 1.60-1.62 (m, 2H), 1.36-1.31 (m, 4H), 0.94-0.90 (m, 3H). LCMS: (Method E) 509.2 (M ++H) Rt. 2.64 min, 94.06% (max). HPLC: (Method B) Rt. 5.33 min, 94.60% (max). Stereoisomer 2: Yield: 66.7% (0.07 g, white solid). 1 H-NMR (400 MHz, DMSO-d6): δ 13.03 (s, 1H), 7.35 (s, 1H), 7.15 (t, J = 8.00 Hz, 2H), 7.06 (s, 1H), 6.70 (t, J = 7.20 Hz, 1H), 6.58 (d, J = 8.40 Hz, 2H), 4.44-4.39 (m, 2H), 4.33-4.33 (m, 1H), 4.19-4.04 (m, 1H), 4.00-3.90 (m, 1H), 3.38 (s, 3H), 3.19-3.17 (m, 1H), 2.46 (s, 3H), 2.33 (s, 3H), 1.62-1.51 (m, 2H), 1.36-1.31 (m, 4H), 0.94-0.92 (m, 3H). LCMS: (Method A) 509.0(M + +H) Rt. 2.90 min, 99.65% (max). HPLC: (Method B) Rt. 5.29 min, 99.81% (max).

[0521] Example 32 (S)-3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2-methoxypropanoic acid and (R)-3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2-methoxypropanoic acid (individual diastereomers)

[0522] [ka]

[0523] The two diastereomers of stereoisomer 2 of Example 31 were separated by SFC (Method H). The material was concentrated under vacuum at 40° C. The first eluting fraction corresponded to diastereomer 1 and the second eluting fraction corresponded to diastereomer 2. The absolute configurations of the two diastereomers are unknown. Diastereomer 1: Yield: 15.37% (0.01 g, white solid). 1 H-NMR (400 MHz, DMSO-d6): δ 7.34 (s, 1H), 7.15 (t, J = 7.20 Hz, 2H), 7.05 (s, 1H), 6.70 (t, J = 6.80 Hz, 1H), 6.58 (d, J = 8.00 Hz, 2H), 4.48-4.42 (m, 1H), 4.22 (m, 1H), 4.03-3.89 (m, 3H), 3.55-3.51 (m, 1H), 3.33 (s, 3H), 2.51 (s, 3H), 2.35 (s, 3H), 1.63-1.60 (m, 2H), 1.36-1.31 (m, 4H), 0.94-0.86 (m, 3H). LCMS: (Method E) 508.9 (M + +H) Rt. 2.91 min, 98.24% (max). HPLC: (Method B) Rt. 5.30 min, 99.93% (max).Chiral HPLC (Method H) Rt. 4.33 min, 100% (max). Diastereomer 2: Yield: 22.96% (0.02 g, white solid). 1H-NMR (400 MHz, DMSO-d6): δ 7.33 (s, 1H), 7.15 (t, J = 7.60 Hz, 2H), 7.05 (s, 1H), 6.69 (t, J = 7.20 Hz, 1H), 6.58 (d, J = 8.40 Hz, 2H), 4.48-4.42 (m, 1H), 4.29-4.21 (m, 1H), 3.99-3.90 (m, 3H), 3.45-3.40 (m, 1H), 3.23 (s, 3H), 2.46 (s, 3H), 2.35 (s, 3H), 1.63-1.51 (m, 2H), 1.50-1.35 (m, 4H), 0.94-0.86 (m, 3H). LCMS: (Method A) 508.9 (M + +H) Rt. 2.91 min, 98.61% (max). HPLC: (Method B) Rt. 5.30 min, 99.48% (max).Chiral HPLC (Method H) Rt. 5.41 min, 99.23% (max).

[0524] (Example 33) 3-((3-butyl-7-(ethylthio)-5-(4-fluorophenyl)-2-methyl-1,1-dioxide-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2-hydroxypropanoic acid

[0525] [ka]

[0526] To a stirred solution of methyl 3-((3-butyl-7-(ethylthio)-5-(4-fluorophenyl)-2-methyl-1,1-dioxide-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2-hydroxypropanoate (Intermediate 63; 55 mg, 0.10 mmol) in 1,4-dioxane at 0° C., dilute HCl (6N, 3 mL) was added dropwise and the reaction mixture was heated at 80° C. for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with cold water (5 mL) and the aqueous layer was extracted with EtOAc (2×5 mL). The combined organic layers were washed with water (5 mL), brine (5 mL) and dried over anhydrous Na2SO4. The organic portion was filtered, concentrated under vacuum and the resulting crude material was purified by preparative HPLC (Method C) to give the title compound. Yield: 18.11% (0.01 g, white solid). 1 H-NMR (400 MHz, DMSO-d6): δ 12.84 (s, 1H), 7.34 (s, 1H), 7.06 (s, 1H), 6.99 (t, J = 8.80 Hz, 2H), 6.60-6.57 (m, 2H), 5.62-5.60 (m,1H), 4.32-4.29 (m, 1H), 4.27-4.25 (m, 2H), 4.01-3.97 (m, 1H), 3.86-3.85 (m, 1H), 3.23-3.22 (m, 1H), 2.91-2.85 (m, 2H), 2.52 (s, 3H), 1.62-1.58 (m, 1H), 1.58-1.50 (m, 1H),1.35-1.34 (m, 4H), 1.24-1.17 (m, 3H), 0.91 (t, J = 6.80 Hz, 3H). LCMS: (Method A) 527.1 (M + +H) Rt. 2.42 min, 93.98% (max). HPLC: (Method B) Rt. 5.31 min, 95.21% (max).

[0527] Biological assays IBAT(h / m) assay protocol 10,000 cells (human or mouse IBAT overexpressing cells) were seeded in 200 μL MEM-alpha medium (Gibco 12571-063) supplemented with 10% FBS (Gibco 10438026) containing puromycin (Gibco A1113803) (10 μg / mL) in 96-well plates (Corning CLS3809) and incubated for 48 hours at 37° C. in 5% CO2. After incubation, the medium was decanted from the wells and the cells were washed twice with 300 μL basal MEM-alpha medium (without FBS). After each decantation of basal MEM-alpha medium, the plate was tapped against a paper towel to ensure maximum removal of residual medium. Dilutions of test inhibitors (highest test concentration 10 μM, 3-fold serial dilutions, 10 points) prepared in DMSO (Sigma D2650) were added to incubation mixtures containing 0.25 μM 3H-taurocholic acid (ARC ART-1368) and 5 μM cold taurocholic acid (Sigma T4009) (maintaining a final DMSO concentration of 0.2%). Then, 50 μL of incubation mixtures containing test inhibitors were added to the wells (in duplicate) and the plate was incubated at 37°C in a CO2 incubator for 20 min. After incubation, the reaction was stopped by keeping the plate on ice-water mixture for 2-3 min, and then the incubation mixture was completely aspirated from the wells. Wells were washed twice with 250 μL of cold unlabeled 1 mM taurocholate dissolved in HEPES (Gibco 15630080) buffered (10 mM) HBSS (Gibco 14175079), pH 7.4. After each wash, plates were tapped against a paper towel to ensure maximum removal of blocking buffer. 100 μL of MicroScint-20 (PerkinElmer 6013621) was added to the wells and kept at room temperature overnight, after which the plates were read in a PerkinElmer TopCount NXT™ Microplate Scintillation and Luminescence Counter under the 3H Test protocol (set at 120 second read time per well).

[0528] LBAT(h / m) assay protocol 20,000 cells (human or mouse LBAT overexpressing cells) were seeded in 100 μL MEM-alpha medium (Gibco 12571-063) supplemented with 10% FBS (Gibco 10438026) containing Geneticin (Gibco 10131-027) (1 mg / mL) in 96-well plates (Corning CLS3809) and incubated for 24 hours at 37° C. in 5% CO2. After incubation, the medium was decanted from the wells and the cells were washed twice with 300 μL basal MEM-alpha medium (without FBS). After each decantation of basal MEM-alpha medium, the plate was tapped against a paper towel to ensure maximum removal of residual medium. For human LBAT, incubation mixtures were prepared by adding dilutions of test inhibitors (10-point 3-fold serial dilutions in DMSO (Sigma D2650)) into MEM-alpha (without FBS) containing 0.3 μM 3H-taurocholic acid (ARC ART-1368) and 7.5 μM cold taurocholic acid (Sigma T4009) (maintaining a final DMSO concentration of 0.2%). For mouse LBAT, incubation mixtures were prepared by adding dilutions of test inhibitors (10-point 3-fold serial dilutions in DMSO) into MEM-alpha (without FBS) containing 0.3 μM 3H-taurocholic acid and 25 μM cold taurocholic acid (maintaining a final DMSO concentration of 0.2%). Then, 50 μL of incubation mixture containing the test inhibitor was added to the wells (in duplicate) and the plate was incubated for 20 min at 37 °C in a CO2 incubator. After incubation, the reaction was stopped by keeping the plate on ice-water mixture for 2-3 min, and then the incubation mixture was completely aspirated from the wells. The wells were washed twice with 250 μL of chilled unlabeled 1 mM taurocholate dissolved in HEPES (Gibco 15630080) buffered (10 mM) HBSS (Gibco 14175079) (pH 7.4). After each wash, the plate was tapped against a paper towel to ensure maximum removal of blocking buffer. 100 μL of MicroScint-20 (PerkinElmer 6013621) was added to the wells and kept at room temperature overnight, after which the plates were read in a PerkinElmer TopCount NXT™ Microplate Scintillation and Luminescence Counter under the 3H Test protocol (set to 120 second read time per well in normal plate orientation).

[0529] Bidirectional permeability assay (Caco-2 cells) Caco-2 cells (Evotec) were seeded at a density of 70,000 cells / well in Millicell® 24-well cell culture insert plates and maintained in an incubator (37° C., 5% CO2, 95% RH) for 21 days with medium changes every other day. Stock solutions (10 mM) of test compounds, atenolol (low permeability marker), propranolol (high permeability marker) and digoxin (substrate for P-gp transport pathway) were prepared in dimethyl sulfoxide (DMSO). Intermediate stock solutions (1 mM) were prepared by diluting 10 μL of 10 mM master stock solution with 90 μL of neat DMSO. Working stock solutions (10 μM) were prepared by diluting 50 μL of 1 mM with 4950 μL of FaSSIF buffer. After addition of compounds to FaSSIF, samples were subjected to sonication for 2 hours and centrifuged at 4000 RPM for 30 minutes at 37°C. 4 mL of the resulting supernatant was used directly in the assay. The final DMSO concentration in the transport experiments was 1%. On the day of the assay, Caco-2 monolayers were washed twice with transport buffer (HBSS, pH 7.4) and pre-incubated for 30 min in an incubator (37° C., 5% CO2, 95% RH). The electrical resistance of the monolayers was measured using a Millicell®-ERS system. 350 ohm.cm 2 Monolayers with transepithelial electrical resistance (TEER) values ​​above 100 nm were selected for the assay. Assays were performed in the absorptive (A2B) and secretory (B2A) directions. Transport experiments were initiated by the addition of compound-based transport assay buffer (FaSSIF buffer prepared in HBSS) to the donor compartments (apical chamber AB; basolateral chamber BA) in duplicate (n=2) wells. Drug-free HBSS buffer (pH 7.4) containing 1% bovine serum albumin (BSA) was introduced to the receiver (AB-basolateral; BA-apical) compartments. The volumes of the apical and basolateral compartments were 0.4 and 0.8 mL, respectively. After addition of dosing solutions, plates were incubated for 120 min at 37° C. in an incubator. After 120 min, donor and receiver samples were taken and matrix-matched with the buffer on the opposite side (1:1, 30 μL test sample + 30 μL blank buffer). The dosed samples were matrix matched with the opposing buffer (1:1, 30 μL test sample + 30 μL blank buffer). Samples were processed by adding acetonitrile containing an internal standard (60 μL test sample + 200 μL acetonitrile containing internal standard-tolbutamide, 500 ng / mL). Samples were vortexed and centrifuged at 4000 rpm for 10 min. The resulting supernatant (100 μL) was diluted with 100 μL water and transferred to a new 96-well plate. The concentrations of compounds in the samples were analyzed, when applicable, by liquid chromatography tandem mass spectrometry (LC-MS / MS) method using discovery grade bioanalytical methods. The mean apparent permeability (P app , ×10 -6 The velocity (cm / sec) was calculated as follows:

[0530]

number

[0531] (where dq / dt = transport rate (rate of transport of compound in the receiver compartment), C0 = initial concentration in the donor compartment, and A = effective filtration membrane surface area).

[0532] HepaRG-based assay protocol A cryopreserved vial of differentiated HepaRG cells (Biopredic International HPR116080) is thawed in HepaRG Thawing / Plating / General Purpose Medium (Biopredic International ADD670C) supplemented with 200 mM Glutamax (Gibco 35050061) according to the protocol provided by Biopredic International. 70,000 cells per well are seeded in 100 μL of HepaRG Thawing / Plating / General Purpose Medium supplemented with 200 mM Glutamax in a 96-well plate (Corning CLS3809) and incubated for 24 hours at 37° C. in 5% CO2. After incubation, the seeding medium is replaced with HepaRG Maintenance / Metabolism Medium (Biopredic International ADD620C) and replenished with fresh HepaRG Maintenance / Metabolism Medium every 48 hours and incubated for 6 days. After 7 days of incubation post-seeding, the incubation medium is decanted from the wells and the cells are washed twice with 250 μL of William's E Basal Media (Gibco 12551032). After each decantation of William's E Basal Media, the plate is tapped against a paper towel to ensure maximum removal of residual medium. Incubation mixtures are prepared by adding dilutions of test inhibitors (3-fold serial dilutions in DMSO (Sigma D2650)) in William's E medium (basal) containing 0.3 μM 3H-taurocholic acid (ARC ART-1368) and 7.5 μM cold taurocholic acid (Sigma T4009) (maintaining a final DMSO concentration of 0.2%). 50 μL of incubation mixture containing the test inhibitor is then added to the wells (in duplicate) and the plate is incubated for 30 min at 37°C in a 5% CO2 incubator. After incubation, the reaction is stopped by keeping the plate on an ice-water mixture for 2-3 min, and then the incubation mixture is completely aspirated from the wells. Wash wells twice with 250 μL of cold unlabeled 1 mM taurocholate dissolved in HEPES (Gibco 15630080) buffered (10 mM) HBSS (Gibco 14175079), pH 7.4. Tap plate against paper towel after each wash to ensure maximum removal of blocking buffer. 100 μL of MicroScint-20 (PerkinElmer 6013621) is added to the wells and kept at room temperature overnight, after which the plates are read in a PerkinElmer TopCount NXT™ Microplate Scintillation and Luminescence Counter under the 3H Test protocol (set at 120 second read time per well in normal plate orientation).

[0533] Preparation of test compound dilutions All test compounds were prepared in powder form at room temperature. 10 mM DMSO stock solutions of test compounds were prepared, aliquoted, and stored at -20°C. From the 10 mM DMSO stock solutions of compounds, 3-fold serial dilutions in DMSO were prepared to obtain a total of 10 dilutions of test compounds. 0.5 μL of this dilution in DMSO was added to 250 μL of basal medium without FBS containing 3H-taurocholate and cold taurocholate to prepare the incubation mixture.

[0534] Bioavailability test Male mice (C57BL / 6 or CD1) or Wistar rats aged 8-9 weeks were used. For each test compound, two groups of 3 animals each were used. One group received a single intravenous dose of 1 mg / kg (vehicle 100% DMSO) through the tail vein, and the other group received a single oral dose of 10 mg / kg through a gavage needle. The group receiving the oral dose was fasted overnight. Blood samples were taken at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after intravenous dosing, and 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after oral dosing. Blood samples were taken from the saphenous vein. 0.2% EDTA was used as the anticoagulant. Samples were analyzed by a discovery grade bioanalytical method developed for the estimation of test compounds in plasma using an LC-MS / MS system.

[0535] result Biological data for example compounds is shown in Table 8 below.

[0536] [Table 8A]

[0537] [Table 8B]

[0538] PD model: Evaluation of test compounds on total bile acid levels in male C57BL6 mice Eight to nine week old C57BL / 6N Tac mice are used to test the effect of bile acid modulators on bile acid levels. After completion of the quarantine and acclimation period, animals are randomly divided based on body weight into x experimental groups: (i) vehicle control, and (ii) test compound y mg / kg orally once daily. Animals are treated with test compound for 7 days. On the fifth day of the study, animals are individually housed in new cages. On the seventh day, feces are collected from each cage, and then blood is collected from each animal via the retro-orbital route. Animals are euthanized and liver and terminal ileum are collected from each animal for further analysis. Body weight and food intake are measured twice weekly. Serum lipid profile is analyzed in serum samples on day 7. Total bile acids in serum are measured in serum samples on day 7. Fecal bile excretion is measured in fecal samples on day 7. Hepatic expression of CYP7A1 and SHP will be quantified in liver samples on day 7. Hepatic triglycerides and total cholesterol will be analyzed in liver samples on day 7.

[0539] Urinary bile acid model: Evaluation of test compounds on urinary bile acid levels in male C57BL / 6N mice Eight to nine week old C57BL / 6N Tac mice are used to test the effect of bile acid modulators on bile acid levels. After completion of the quarantine and acclimation period, animals are randomly divided based on body weight into x experimental groups: (i) vehicle control, and (ii) test compound y mg / kg orally once daily. Animals are treated with test compound for 7 days. On the sixth day of the study, animals are transferred to metabolic cages. On the seventh day, feces and urine are collected from each metabolic cage, and then blood is collected from each animal via the retro-orbital route. Animals are euthanized and kidneys are collected from each animal for further analysis. Body weight is measured twice weekly. Total bile acids in serum are measured in the day 7 serum sample. Fecal bile acid excretion is measured in the day 7 fecal sample. Urinary excretion of bile acids is measured in the day 7 sample. Renal expression of ASBT, OSTa, OSTAb, and MRP2 will be quantified in day 7 samples.

Claims

1. Compounds of formula (I) 【Chemistry 1】 (In the formula, M is -CH 2 - and -NR 5 - Selected from; R 1 is C 1～4 is alkyl; R 2 are independently 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, N,N-di(C 1～4 Alkyl)amino, C 1～6 Alkylcarbonylamino, C 3～6 Cycloalkylcarbonylamino, N-(C 1～4 Alkyl)aminocarbonyl, N,N-di(C 1～4 Alkyl)aminocarbonyl, C 1～4 Alkyloxycarbonylamino, C 3～6 Cycloalkyloxycarbonylamino, C 1～4 Alkyl sulfonamides, and C 3～6 cycloalkylsulfonamides; n is an integer of 1, 2, or 3; R 3 is 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, amino, N-(C 1～4 alkyl)amino, and N,N-di(C 1～4 (alkyl)amino; R 4A and R 4B are each independently hydrogen, halogen, hydroxy, C 1～4 Alkyl, and C 1～4 alkoxy; or R 4A and R 4B together with the carbon atoms to which they are attached form a 3- to 5-membered saturated carbocyclic ring; R 4C and R 4D are each independently hydrogen and C 1～4 selected from the group consisting of alkyl; R 5 is hydrogen and C 1～4 alkyl) or a pharma- ceutical acceptable salt thereof.

2. R 1 C 2～4 2. The compound of claim 1, wherein the compound is alkyl.

3. R 1 The compound of claim 1, wherein is n-propyl or n-butyl.

4. R 2 2. The compound of claim 1, wherein is independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, hydroxy, methoxy, amino, methylamino, and dimethylamino.

5. R 3 2. The compound of claim 1, wherein is selected from the group consisting of fluoro, chloro, bromo, methyl, cyclopropyl, methoxy, ethoxy, methylthio, ethylthio, amino, methylamino, and dimethylamino.

6. R 4A and R 4B are each independently hydrogen, halogen, hydroxy, C 1～4 Alkyl, and C 1～4 alkoxy or R 4A and R 4B and together with the carbon atom to which they are attached form a cyclopropyl ring.

7. R 4C and R 4D 2. The compound of claim 1, wherein each is independently hydrogen or methyl.

8. R 5 is hydrogen or methyl.

9. 3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2,2-dimethylpropanoic acid; (S)-3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2,2-dimethylpropanoic acid; (R)-3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2,2-dimethylpropanoic acid; 1-(((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid; (S)-1-(((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid; (R)-1-(((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid; 3-((3-butyl-7-(ethylthio)-2-methyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2,2-dimethylpropanoic acid; (S)-3-((3-butyl-7-(ethylthio)-2-methyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2,2-dimethylpropanoic acid; (R)-3-((3-butyl-7-(ethylthio)-2-methyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2,2-dimethylpropanoic acid; 1-(((3-butyl-7-(ethylthio)-2-methyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid; (S)-1-(((3-butyl-7-(ethylthio)-2-methyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid; (R)-1-(((3-butyl-7-(ethylthio)-2-methyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid; 3-((3-butyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy)-2,2-dimethylpropanoic acid; 1-(((3-butyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid; 1-(((3-butyl-5-(4-fluorophenyl)-2-methyl-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid; (S)-1-(((3-butyl-5-(4-fluorophenyl)-2-methyl-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid; (R)-1-(((3-butyl-5-(4-fluorophenyl)-2-methyl-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid; 3-((3-butyl-5-(4-fluorophenyl)-2-methyl-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2,2-dimethylpropanoic acid; (S)-3-((3-butyl-5-(4-fluorophenyl)-2-methyl-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2,2-dimethylpropanoic acid; (R)-3-((3-butyl-5-(4-fluorophenyl)-2-methyl-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2,2-dimethylpropanoic acid; 1-(((3-butyl-7-(ethylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid; 1-(((3-butyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid; (S)-1-(((3-butyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid; (R)-1-(((3-butyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid; 1-(((3-butyl-7-(ethylthio)-5-(4-fluorophenyl)-1,1-dioxide-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid; (S)-1-(((3-butyl-7-(ethylthio)-5-(4-fluorophenyl)-1,1-dioxide-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid; (R)-1-(((3-butyl-7-(ethylthio)-5-(4-fluorophenyl)-1,1-dioxide-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)methyl)cyclopropane-1-carboxylic acid; 3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2,2-difluoropropanoic acid; (S)-3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2,2-difluoropropanoic acid; (R)-3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2,2-difluoropropanoic acid; 3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2-methoxy-2-methylpropanoic acid; (S)-3-(((R)-3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2-methoxy-2-methylpropanoic acid; (S)-3-(((S)-3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2-methoxy-2-methylpropanoic acid; (R)-3-(((R)-3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2-methoxy-2-methylpropanoic acid; (R)-3-(((S)-3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2-methoxy-2-methylpropanoic acid; 3-((3-butyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy)propanoic acid; (S)-3-((3-butyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy)propanoic acid; (R)-3-((3-butyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy)propanoic acid; 3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2-ethoxypropanoic acid; 3-((3-butyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy)-2-hydroxypropanoic acid; 3-((3-ethyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy)propanoic acid; 3-((3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2-methoxypropanoic acid; 3-(((S)-3-Butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2-methoxypropanoic acid; 3-(((R)-3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2-methoxypropanoic acid; (S)-3-(((R)-3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2-methoxypropanoic acid; (R)-3-(((R)-3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2-methoxypropanoic acid; (S)-3-(((S)-3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2-methoxypropanoic acid; (R)-3-(((S)-3-butyl-2-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2-methoxypropanoic acid; and 3-((3-butyl-7-(ethylthio)-5-(4-fluorophenyl)-2-methyl-1,1-dioxide-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)-2-hydroxypropanoic acid; or a pharma- ceutically acceptable salt thereof.

10. 10. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 9 and one or more pharma- ceutically acceptable excipients.

11. A pharmaceutical comprising a compound according to any one of claims 1 to 9.

12. 12. The medicament according to claim 11, for use in the treatment or prevention of cardiovascular diseases or disorders of fatty acid metabolism or disorders of glucose utilization, such as hypercholesterolemia; disorders of fatty acid metabolism; type 1 and type 2 diabetes mellitus; diabetic complications, such as cataracts, small and large vessel disease, retinopathy, neuropathy, nephropathy, and delayed wound healing, tissue ischemia, diabetic foot, arteriosclerosis, myocardial infarction, acute coronary syndrome, unstable angina, stable angina, stroke, peripheral arterial occlusive disease, cardiomyopathy, heart failure, heart rhythm disorders, and vascular restenosis; diabetes-related diseases, such as insulin resistance (disorders of glucose homeostasis), hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, obesity, dyslipidemia, hyperlipidemia, such as hypertriglyceridemia, metabolic syndrome (syndrome X), atherosclerosis, and hypertension; and increased high density lipoprotein levels.

13. 12. The medicament according to claim 11 for use in the treatment or prevention of a gastrointestinal disease or disorder, 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 irritable bowel syndrome (IBS-M), paediatric functional constipation, and opioid-induced constipation); Crohn's disease; primary bile acid malabsorption; irritable bowel syndrome (IBS); inflammatory bowel disease (IBD); ileal inflammation; and reflux disease and its complications, such as Barrett's esophagus, bile reflux esophagitis, and bile reflux gastritis.

14. Liver diseases or disorders, e.g., hereditary metabolic disorders of the liver; congenital anomalies of bile acid synthesis; congenital abnormalities of bile duct course; biliary atresia; biliary atresia after Kasai operation; biliary atresia after liver transplantation; neonatal hepatitis; neonatal cholestasis; inherited forms of cholestasis; cerebrotendinous xanthomatosis; secondary defects of BA synthesis; Zellweger syndrome; liver disease associated with cystic fibrosis; alpha 1-antitrypsin deficiency; Alagille syndrome (ALGS); Byler syndrome; primary defects of bile acid (BA) synthesis; progressive familial intrahepatic cholestasis (PFIC), e.g., PFIC-1, PFIC-2, PFIC-3, and non-specific PFIC, PFIC after bile diversion, and PFIC after liver transplantation; benign recurrent intrahepatic cholestasis (BRIC), e.g., BRIC BRIC 1, BRIC2, and non-specific BRIC, BRIC after bile diversion, and BRIC after liver transplant;autoimmune hepatitis;primary biliary cirrhosis (PBC);liver fibrosis;nonalcoholic fatty liver disease (NAFLD);nonalcoholic steatohepatitis (NASH);portal hypertension;cholestasis;Down syndrome cholestasis;drug-induced cholestasis;intrahepatic cholestasis of pregnancy (jaundice in pregnancy);intrahepatic cholestasis;extrahepatic cholestasis;cholestasis associated with parenteral nutrition (PNAC);hypophospholipid-associated cholestasis;lymphoedema cholestasis syndrome 1 (LCS1);primary sclerosing cholangitis (PSC);immunoglobulin G4-associated cholangitis;primary biliary cholangitis;cholelithiasis (gallstones);biliary cholangitis (biliary lithiasis);choledocholithiasis;gallstone pancreatitis;Caroli's disease;malignant tumors of the bile duct;malignant tumors causing obstruction of the biliary tree;bile duct stenosis;AIDS cholangiopathy;ischemic cholangiopathy;pruritus due to cholestasis or jaundice;pancreatitis;chronic autoimmune liver disease leading to progressive cholestasis;hepatic steatosis;alcoholic hepatitis;acute fatty liver;fatty liver of pregnancy;drug-induced hepatitis;iron overload;inborn errors of bile acid metabolism type 1 (BAS type 1);drug-induced liver injury (DILI);hepatic fibrosis;congenital hepatic fibrosis;cirrhosis;Langerhans cell histiocytosis (LCH);neonatal ichthyotic sclerosing cholangitis (NISCH);erythropoietic protoporphyria (EPP);idiopathic adult bile duct paucity (IAD);idiopathic neonatal hepatitis (INH);nonsyndromic intrahepatic cholangiopaucity (NS PILBD); North American Indian childhood cirrhosis (NAIC);12. The medicament according to claim 11 for use in the treatment or prevention of cholestasis caused by hepatic sarcoidosis; amyloidosis; necrotizing enterocolitis; toxicity caused by serum bile acids, such as cardiac rhythm disorders (e.g. atrial fibrillation) in the setting of abnormal serum bile acid profiles, 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 carcinoma); cholangiocarcinoma; gastrointestinal cancers associated with bile acids; and tumors and neoplasms of the liver, biliary tract, and pancreas; or for use in augmenting corticosteroid therapy in liver disease.

15. 12. The medicament according to claim 11, for use in the treatment or prevention of hyperabsorption syndromes (including abetalipoproteinemia, familial hypobetalipoproteinemia (FHBL), chylomicron retention disease (CRD), and sitosterolemia); hypervitaminosis and osteopetrosis; hypertension; glomerular hyperfiltration; polycystic kidney disease (PKD), such as autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD); and pruritus in renal failure; or for use in protection against kidney damage associated with liver or metabolic disease.

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