ASBT inhibitors in the treatment of kidney diseases

Abstract

The present invention relates to inhibitors of apical sodium-dependent bile acid transport (ASBT) for use in the treatment of kidney diseases and disorders, such as bile nephropathy. Such treatment can include reducing serum bile acid concentrations, increasing urinary bile acid concentrations, and improving hepatic and renal parameters.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to Swedish Patent Application No. 2251441-8, filed December 9, 2022, the disclosure of which is incorporated herein by reference in its entirety.

[0002] The present invention relates to inhibitors of apical sodium-dependent bile acid transport (ASBT) for use in the treatment of kidney diseases and disorders, such as bile nephropathy. Such treatment can include reducing serum bile acid concentrations, increasing urinary bile acid concentrations, and improving hepatic and renal parameters. [Background technology]

[0003] Cholemic nephropathy is a condition of kidney damage / failure in patients with obstructive jaundice. Also known as bile cast nephropathy, bile acid nephropathy, icteric nephrosis / nephropathy, or jaundice-associated nephropathy, cholecystic nephropathy is an underappreciated but important cause of renal dysfunction in jaundiced cholestatic or advanced liver disease. It is a common complication in patients with liver diseases such as cirrhosis, alcoholic steatohepatitis, drug-induced cholestatic liver injury, and fulminant hepatitis, and is associated with high morbidity and mortality. Cholemic nephropathy is characterized by hemodynamic changes in the liver, kidneys, and systemic circulation, intratubular cast formation, and renal tubular epithelial cell injury, but the underlying pathophysiological mechanisms remain poorly understood.

[0004] Toxic bile acids have been suggested to play a role in the development of renal injury in cholestasis (Fickert et al., Hepatology 2013, Vol. 58, pp. 2056–2069; Krones et al., Dig. Dis. 2015, Vol. 33, pp. 367–375; Tinti et al., Life 2021, Vol. 11, pp. 1200). Norursodeoxycholic acid, a less toxic bile acid, has been shown to ameliorate renal injury and has been proposed as a treatment for bile vascular nephropathy (Krones et al., J Hepatol. 2017, Vol. 67, pp. 110–119). [Prior art documents] [Patent documents]

[0005] [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 / 01687 [Patent Document 15] WO 00 / 47568 [Patent Document 16] WO 00 / 61568 [Patent Document 17] WO 00 / 38725 [Patent Document 18] WO 00 / 38726 [Patent Document 19] WO 00 / 38727 [Patent Document 20] WO 00 / 38728 [Patent Document 21] WO 00 / 38729 [Patent Document 22] WO 01 / 66533 [Patent Document 23] WO 01 / 68096 [Patent Document 24] WO 02 / 32428 [Patent Document 25] WO 02 / 50051 [Patent Document 26] WO 03 / 020710 [Patent Document 27] WO 03 / 022286 [Patent Document 28] WO 03 / 022825 [Patent Document 29] WO 03 / 022830 [Patent Document 30] WO 03 / 061663 [Patent Document 31] WO 03 / 091232 [Patent Document 32] WO 03 / 106482 [Patent Document 33] WO 2004 / 006899 [Patent Document 34] WO 2004 / 076430 [Patent Document 35] WO 2007 / 009655 [Patent Document 36] WO 2007 / 009656 [Patent Document 37] WO 2008 / 058628 [Patent Document 38] WO 2008 / 058630 [Patent Document 39] WO 2011 / 137135 [Patent Document 40] WO 2019 / 234077 [Patent Document 41] WO 2020 / 161216 [Patent Document 42] WO 2020 / 161217 [Patent Document 43] WO 2021 / 110884 [Patent Document 44] WO 2021 / 110885 [Patent Document 45] WO 2021 / 110886 [Patent Document 46] WO 2021 / 110887 [Patent Document 47] WO 2022 / 029101 [Patent Document 48] DE 19825804 [Patent Document 49] EP 864582 [Patent Document 50] EP 489423 [Patent Document 51] EP 549967 [Patent Document 52] EP 573848 [Patent Document 53] EP 624593 [Patent Document 54] EP 624594 [Patent Document 55] EP 624595 [Patent Document 56] EP 624596 [Patent Document 57] EP 0864582 [Patent Document 58] EP 1173205 [Patent Document 59] EP 1535913 [Patent Document 60] EP 1719768 [Patent Document 61] EP 3210977 [Patent Document 62] PCT / EP2023 / 068476 [Non-patent literature]

[0006] [Non-Patent Document 1] Fickert et al., Hepatology 2013, Vol. 58, pp. 2056-2069 [Non-patent document 2] Krones et al., Dig. Dis. 2015, Vol. 33, pp. 367-375 [Non-patent document 3] Tinti et al., Life 2021, Volume 11, 1200 [Non-patent document 4] Krones et al., J Hepatol. 2017, Vol. 67, pp. 110-119 [Non-Patent Document 5] Lala et al., "Liver Function Tests." StatPearls, StatPearls Publishing, October 5, 2022 (PMID: 29494096) Summary of the Invention

[0007] Despite growing interest in biliary nephropathy and an improved mechanistic understanding of the disease, there are currently no specific treatments available for this condition. [Brief explanation of the drawings]

[0008] [Figure 1A] Figure 1 shows plots of blood chemistry analysis in mice 12 weeks after bile duct ligation (BDL) or sham surgery: Alanine transaminase (ALT) levels. [Figure 1B]Figure 1 shows plots of blood chemistry analysis in mice 12 weeks after bile duct ligation (BDL) or sham surgery: Aspartate transferase (AST) levels. [Figure 1C] Figure 1 shows plots of blood chemistry analysis in mice 12 weeks after bile duct ligation (BDL) or sham surgery: alkaline phosphatase (ALP) levels. [Figure 1D] Figure 1 shows plots of blood chemistry analysis in mice 12 weeks after bile duct ligation (BDL) or sham surgery. Total bilirubin levels. [Figure 2A] Figure 1 shows plots of bile acid transporter expression 12 weeks after BDL or sham surgery. Sinusoidal uptake transporter NTCP. [Figure 2B] Figure 1 shows plots of bile acid transporter expression 12 weeks after BDL or sham surgery. Sinusoidal uptake transporter Cyp7a1. [Figure 2C] Figure 1 shows plots of bile acid transporter expression 12 weeks after BDL or sham surgery. Apical transporter Bsep. [Figure 2D] Figure 1 shows plots of bile acid transporter expression 12 weeks after BDL or sham surgery.Sinusoidal efflux transporter MRP4. [Figure 3A] FIG. 1 shows plots of expression of the apical uptake transporter ASBT 12 weeks after BDL or sham surgery. [Figure 3B] FIG. 1 shows plots of expression of the apical uptake transporter OATP1a1 12 weeks after BDL or sham surgery. [Figure 3C] FIG. 1 shows plots of the expression of the apical efflux transporter MRP4 12 weeks after BDL or sham surgery. [Figure 3D] FIG. 1 shows plots of the expression of the basolateral efflux transporter MRP3 12 weeks after BDL or sham surgery. [Figure 3E] FIG. 1 shows plots of the expression of the basolateral efflux transporter OSTα 12 weeks after BDL or sham surgery. [Figure 4] FIG. 1 shows plots of total urinary bile acid concentrations after treatment of BDL mice with different doses of Compound 1. [Figure 5A] Figure 1 shows plots of concentrations of individual urinary bile acids following treatment of BDL mice with different doses of Compound 1. Tauro-α / β-muricholic acid. [Figure 5B] Figure 1 shows plots of concentrations of individual urinary bile acids following treatment of BDL mice with different doses of Compound 1. Taurocholic acid. [Figure 5C] Figure 1 shows plots of concentrations of individual urinary bile acids following treatment of BDL mice with different doses of Compound 1. Taurocholate sulfate. [Figure 6] FIG. 1 shows plots of total urinary bile acid concentrations after treatment of mice (BDL or Sham) with vehicle or Compound 1 for 6 weeks. [Figure 7] 1 is a plot of the concentrations of individual bile acids (ω-muricholic acid, tauro-ω-muricholic acid, tauro-α / β-muricholic acid, and β-muricholic acid) in urine after treatment of mice (BDL or Sham) with vehicle or Compound 1 for 6 weeks. [Figure 8] 1 is a plot of the concentrations of individual bile acids (glycocholate, tauroursodeoxycholic acid, taurocholic acid, and cholic acid) in urine after treatment of mice (BDL or Sham) with vehicle or Compound 1 for 6 weeks. [Figure 9] 1 is a plot of the concentrations of individual bile acids (ursodeoxycholic acid, hyodeoxycholic acid, taurochenodeoxycholic acid, and taurodeoxycholic acid) in urine after treatment of mice (BDL or Sham) with vehicle or Compound 1 for 6 weeks. [Figure 10] 1 is a plot of the concentrations of individual bile acids (chenodeoxycholic acid, deoxycholic acid, taurolithocholic acid, and taurocholic acid sulfate) in urine after treatment of mice (BDL or Sham) with vehicle or Compound 1 for 6 weeks. [Figure 11] FIG. 1 shows a plot of the change in body weight of mice (BDL or Sham) during 6 weeks of treatment with vehicle or Compound 1. [Figure 12]FIG. 1 shows plots of survival of mice (BDL or Sham) during 6 weeks of treatment with vehicle or Compound 1. [Figure 13] 1 is a plot of the concentration of the urinary biomarker neutrophil gelatinase-associated lipocalin (NGAL) during treatment of mice (BDL or Sham) with vehicle or Compound 1 for 6 weeks. [Figure 14] 1 is a plot of the concentration of the urinary biomarker kidney injury molecule-1 (KIM-1) during treatment of mice (BDL or Sham) with vehicle or Compound 1 for 6 weeks. [Figure 15A] Figure 1 shows plots of blood chemistry analysis of mice (BDL or Sham) during 6 weeks of treatment with vehicle or Compound 1. Alanine transaminase (ALT) levels. [Figure 15B] Figure 1 shows plots of blood chemistry analysis of mice (BDL or Sham) during 6 weeks of treatment with vehicle or Compound 1. Aspartate transferase (AST) levels. [Figure 15C] Figure 1 shows plots of blood chemistry analysis of mice (BDL or Sham) during 6 weeks of treatment with vehicle or Compound 1. Alkaline phosphatase (ALP) levels. [Figure 15D] Figure 1 shows plots of blood chemistry analysis of mice (BDL or Sham) during 6 weeks of treatment with vehicle or Compound 1. Total bilirubin levels. [Figure 15E] Figure 1 shows plots of blood chemistry analysis of mice (BDL or Sham) during 6 weeks of treatment with vehicle or Compound 1. Blood urea nitrogen (BUN) levels. [Figure 16A] Figure 1 shows plots of the expression of different bile acid transporters after 6 weeks of treatment of mice (BDL or Sham) with vehicle or Compound 1. NTCP. [Figure 16B] Figure 1 shows plots of the expression of different bile acid transporters after 6 weeks of treatment of mice (BDL or Sham) with vehicle or Compound 1. Bsep. [Figure 16C]Figure 1 shows plots of the expression of different bile acid transporters after 6 weeks of treatment of mice (BDL or Sham) with vehicle or Compound 1. OATP. [Figure 16D] Figure 1 shows plots of the expression of different bile acid transporters after 6 weeks of treatment of mice (BDL or Sham) with vehicle or Compound 1. MRP2. [Figure 16E] Figure 1 shows plots of the expression of different bile acid transporters after 6 weeks of treatment of mice (BDL or Sham) with vehicle or Compound 1. MRP3. [Figure 16F] Figure 1 shows plots of the expression of different bile acid transporters after 6 weeks of treatment of mice (BDL or Sham) with vehicle or Compound 1. Cyp7a1. [Figure 16G] Figure 1 shows plots of the expression of different bile acid transporters after 6 weeks of treatment of mice (BDL or Sham) with vehicle or Compound 1. MRP4. [Figure 17A] Figure 1 shows plots of the expression of different bile acid transporters after 6 weeks of treatment of mice (BDL or Sham) with vehicle or Compound 1. ASBT. [Figure 17B] Figure 1 shows plots of the expression of different bile acid transporters after 6 weeks of treatment of mice (BDL or Sham) with vehicle or Compound 1. OATP2b1. [Figure 17C] Figure 1 shows plots of the expression of different bile acid transporters after 6 weeks of treatment of mice (BDL or Sham) with vehicle or Compound 1. OATP1a1. [Figure 17D] Figure 1 shows plots of the expression of different bile acid transporters after 6 weeks of treatment of mice (BDL or Sham) with vehicle or Compound 1. MRP2. [Figure 17E] Figure 1 shows plots of the expression of different bile acid transporters after 6 weeks of treatment of mice (BDL or Sham) with vehicle or Compound 1. MRP3. [Figure 17F] Figure 1 shows plots of the expression of different bile acid transporters after 6 weeks of treatment of mice (BDL or Sham) with vehicle or Compound 1. MRP4. [Figure 17G] Figure 1 shows plots of the expression of different bile acid transporters after 6 weeks of treatment of mice (BDL or Sham) with vehicle or Compound 1. OST-α. [Figure 18A] Figure 1 shows a plot of % survival after treatment of mice (BDL or Sham) with vehicle or Compound 1 for 28 days starting at different times from BDL or Sham. Treatment from day 3. [Figure 18B] Figure 1 shows a plot of % survival after treatment of mice (BDL or Sham) with vehicle or Compound 1 for 28 days starting at different times from BDL or Sham. Treatment from day 21. [Figure 18C] Figure 1 shows a plot of % survival after treatment of mice (BDL or Sham) with vehicle or Compound 1 for 28 days starting at different times from BDL or Sham. Treatment from day 42. [Figure 18D] Figure 1 shows a plot of % survival after treatment of mice (BDL or Sham) with vehicle or Compound 1 for 28 days starting at different times from BDL or Sham. Treatment from day 63. [Figure 19A] Figure 1 shows a plot of the change in body weight (%) after treatment of mice (BDL or Sham) with vehicle or Compound 1 for 28 days starting at different times from BDL or Sham. Treatment from day 3. [Figure 19B] Figure 1 shows a plot of the change in body weight (%) after treatment of mice (BDL or Sham) with vehicle or Compound 1 for 28 days starting at different times from BDL or Sham. Treatment from day 21. [Figure 19C] Figure 1 shows a plot of the change in body weight (%) after 28 days of treatment of mice (BDL or Sham) with vehicle or Compound 1 starting at different times from BDL or Sham. Treatment from day 42. [Figure 19D] Figure 1 shows a plot of the change in body weight (%) after treatment of mice (BDL or Sham) with vehicle or Compound 1 for 28 days starting at different times from BDL or Sham. Treatment from day 63. [Figure 20A]FIG. 1 shows plots of total bile acid concentrations in serum after treatment of mice (BDL or Sham) with vehicle, Compound 1, or Compound 2 for 19 days. [Figure 20B] FIG. 1 shows plots of total bile acid concentrations in urine after treatment of mice (BDL or Sham) with vehicle, Compound 1, or Compound 2 for 19 days. [Figure 21] Figure 1 shows plots of the concentration of the urinary biomarker NGAL after 19 days of treatment of mice (BDL or Sham) with vehicle, Compound 1, or Compound 2. (Data are presented as mean ± SEM). [Figure 22A] Figure 1 shows plots of total bile acid concentrations in serum after treatment of BDL mice with vehicle or different ASBT inhibitors for 5 days (data are expressed as mean ± SEM; **p<0.01 and ****p>0.001 vs. BDL control group by one-way ANOVA followed by Dunnett's multiple comparison test; $$$$p>0.0001 vs. BDL control group by Student's unpaired t-test). [Figure 22B] Figure 1 shows plots of total bile acid concentrations in urine after treatment of BDL mice with vehicle or different ASBT inhibitors for 5 days (data are expressed as mean ± SEM; **p<0.01 and ****p>0.001 vs. BDL control group by one-way ANOVA followed by Dunnett's multiple comparison test; $$$$p>0.0001 vs. BDL control group by Student's unpaired t-test). [Figure 23] Figure 1 shows plots of the concentration of the urinary biomarker NGAL after treatment of BDL mice with vehicle or different ASBT inhibitors for 5 days (data are presented as mean ± SEM; *p<0.05 vs. BDL control group by one-way ANOVA followed by Dunnett's multiple comparison test; $p>0.05 and $$p<0.01 vs. BDL control group by Student's unpaired t-test). [Figure 24A] Figure 1 shows plots of serum concentrations of ASBT inhibitor Compound X at 2 and 6 hours after dosing on day 8. (Data are expressed as mean ± SEM). [Figure 24B]Figure 1 shows plots of the concentration of ASBT inhibitor in serum at 2 and 6 hours after dosing on day 8. Compound 5. (Data are expressed as mean ± SEM). [Figure 25] Figure 1 shows plots of concentrations of Compound X and Compound 5 in urine on day 8. (Data are expressed as mean ± SEM). DETAILED DESCRIPTION OF THE INVENTION

[0009] The apical sodium-dependent bile acid transporter (ASBT, also known as ileal bile acid transporter (IBAT), ISBT, ABAT, or NTCP2; gene symbol SLC10A2) is expressed in the apical membrane of ileal enterocytes, renal proximal tubular epithelial cells, bile duct epithelial cells, large duct cells, and gallbladder epithelial cells. ASBT is primarily expressed in the ileum, where it mediates the reabsorption of conjugated bile acids for recirculation to the liver. Inhibition of ASBT disrupts the enterohepatic circulation, resulting in fecal release of bile acids similar to surgical interruption of the enterohepatic circulation. Removal of bile acids from the enterohepatic circulation results in decreased serum and liver bile acid levels. Therefore, ASBT inhibitors have been developed for the treatment of liver diseases associated with elevated bile acid levels.

[0010] ASBT is also expressed in renal proximal tubule epithelial cells. Therefore, systemically absorbable ASBT inhibitors may also inhibit renal bile acid reuptake. This would increase urinary bile acid levels and enhance bile acid removal from the body via urine. Therefore, targeting renal ASBT may be an additional means to increase bile acid excretion, thereby further reducing bile acid load in serum and liver.

[0011] Many drugs that are not eliminated by a diseased liver end up in kidney tissue and can cause kidney disease. While it is currently unknown which mediators cause kidney damage in a diseased liver, candidates include bile acids, bilirubin, and inflammatory mediators such as cytokines. It has now been discovered that ASBT inhibitors may also play an important role in mediating the toxic effects of bile acids in the kidney. The inventors observed that ASBT is strongly downregulated after bile duct ligation (BDL) in mice (see Figures 2 and 3), and that inhibition of renal ASBT dramatically improved bilemic nephropathy in mice. Renal proximal tubule epithelial cells, in particular, have been found to be involved in kidney disease because they accumulate bile acids via the transporter ASBT. ASBT inhibition was found to almost completely inhibit bile acid uptake into proximal tubule epithelial cells, thereby preventing bile casts and kidney disease. This was unexpected because ASBT is primarily expressed in the proximal tubules, whereas bile casts form in the distal tubules. Given the many potential mediators involved in the pathogenesis of kidney disease, it is surprising that an ASBT inhibitor would have such a profound effect. The similarity of the essential histological features and ASBT expression in the kidneys of patients with bile nephropathy suggests therapeutic potential in humans. Therefore, ASBT inhibition may have a protective effect on the kidney, especially in patients with advanced liver disease.

[0012] Thus, in a first aspect, the present invention relates to an ASBT inhibitor (e.g., any of the ASBT inhibitors described herein) or a pharmaceutically acceptable salt thereof for use in treating a kidney disease or disorder. In some embodiments, the kidney disease or disorder is selected from the group consisting of bilemic nephropathy, chronic nephropathy, hyperbilirubinemia, obstructive jaundice renal dysfunction, age-related impairment of mitochondrial function in the kidney, kidney inflammation, acute kidney injury (AKI), renal ischemia / reperfusion injury (IRI), chronic kidney disease (CKD), chronic renal failure, end-stage renal disease (ESRD), proximal tubule injury in the kidney, type 1 hepatorenal syndrome, type 2 hepatorenal syndrome, and acute exacerbation of chronic liver disease.

[0013] In some embodiments, the renal disease or disorder is a bile acid-dependent renal disease or disorder, such as a renal disease or disorder that may benefit from partial or complete inhibition of renal ASBT. Non-limiting examples of bile acid-dependent renal diseases or disorders include bile nephropathy, chronic nephropathy, hyperbilirubinemia, obstructive jaundice renal dysfunction, age-related impairment of mitochondrial function in the kidney, renal inflammation, acute kidney injury (AKI), renal ischemia / reperfusion injury (IRI), chronic kidney disease (CKD), chronic renal failure, end-stage renal disease (ESRD), proximal tubule injury in the kidney, type 1 hepatorenal syndrome, type 2 hepatorenal syndrome, and acute exacerbation of chronic liver disease.

[0014] In some embodiments, the present invention relates to an ASBT inhibitor (eg, any of the ASBT inhibitors described herein) or a pharmaceutically acceptable salt thereof, for use in the treatment of biliary nephropathy.

[0015] ASBT inhibitors In some embodiments, the ASBT inhibitor is selected from the group consisting of compounds described in WO 93 / 16055, WO 94 / 18183, WO 94 / 18184, WO 96 / 05188, WO 96 / 08484, WO 96 / 16051, WO 97 / 33882, WO 98 / 03818, WO 98 / 07449, WO 98 / 40375, WO 99 / 35135, WO 99 / 64409, WO 99 / 64410, WO 00 / 01687, 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 2008 / 058628, WO 2008 / 058630, WO 2011 / 137135, WO 2019 / 234077, WO 2020 / 161216, WO 2020 / 161217, 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, EP 1719768 or EP 3210977.

[0016] In some embodiments, the ASBT inhibitor is a compound of formula (I):

[0017] [ka]

[0018] (In the formula, R v is hydrogen or C 1~6 alkyl; R 1 and R 2 One of them is hydrogen, C 1~6 Alkyl or C 2~6 alkenyl, and the other is selected from C 1~6 Alkyl or C 2~6 alkenyl; R x and R y are independently hydrogen, hydroxy, amino, mercapto, C 1~6 Alkyl, C 1~6 Alkoxy, N-(C 1~6 alkyl)amino, N,N-(C 1~6 alkyl)2amino, C where a is 0 to 2 1~6 AlkylS(O) a selected from the group consisting of: M is selected from -N- or -CH-; R z is halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, C 1~6 Alkanoyl, C 1~6 Alkanoyloxy, N-(C 1~6 alkyl)amino, N,N-(C 1~6 Alkyl)2amino, C 1~6 Alkanoylamino, N-(C 1~6 alkyl)carbamoyl, N,N-(C 1~6 alkyl)2carbamoyl, C where a is 0 to 2 1~6 AlkylS(O) a , C 1~6 Alkoxycarbonyl, N-(C 1~6 alkyl)sulfamoyl and N,N-(C 1~6 alkyl)sulfamoyl; v is 0 to 5; R 4 and R5 one of which is a group of formula (IA):

[0019] [ka]

[0020] and R 3 and R 6 , and R 4 and R 5 The other is independently hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C 1~4 Alkyl, C 2~4 Alkenyl, C 2~4 Alkynyl, C 1~4 Alkoxy, C 1~4 Alkanoyl, C 1~4 Alkanoyloxy, N-(C 1~4 alkyl)amino, N,N-(C 1~4 Alkyl)2amino, C 1~4 Alkanoylamino, N-(C 1~4 alkyl)carbamoyl, N,N-(C 1~4 alkyl)2carbamoyl, C where a is 0 to 2 1~4 AlkylS(O) a , C 1~4 Alkoxycarbonyl, N-(C 1~4 alkyl)sulfamoyl and N,N-(C 1~4 alkyl)2sulfamoyl; 3 and R 6 , and R 4 and R 5 The other has one or more R 16 optionally substituted by; X is -O-, -N(R a )-, -S(O) b - or -CH(R a )-where R a is hydrogen or C 1~6 alkyl and b is 0 to 2; Ring A is aryl or heteroaryl; where Ring A is R 17 optionally substituted with one or more substituents selected from: R 7 is hydrogen, C 1~4 alkyl, carbocyclyl, or heterocyclyl; where R 7 is R 18 optionally substituted with one or more substituents selected from: R 8 is hydrogen or C 1~4 is alkyl; R 9 is hydrogen or C 1~4 is alkyl; R 10 is hydrogen, C 1~4 alkyl, carbocyclyl, or heterocyclyl; where R 10 is R 19 optionally substituted with one or more substituents selected from: R 11 is carboxy, sulfo, sulfino, phosphono, -P(O)(OR c )(OR d ), -P(O)(OH)(OR c ), -P(O)(OH)(R d ) or -P(O)(OR c )(R d ), where R c and R d are independent, C 1~6 alkyl; or R 11 is a group of formula (IB) or (IC):

[0021] [ka]

[0022] (In the formula, Y is -N(R n )-, -N(R n )C(O)-, -N(R n )C(O)(CR s R t )v N(R n )C(O)—, —O—, and —S(O)a-; where a is 0 to 2, v is 1 to 2, and R s and R t are independently selected from hydrogen or R 26 C optionally substituted by 1~4 alkyl, and R n is hydrogen or C 1~4 is alkyl; R 12 is hydrogen or C 1~4 is alkyl; R 13 and R 14 are independently hydrogen, C 1~6 alkyl, carbocyclyl, or heterocyclyl; when q is 0, R 14 may further be selected from hydroxy; 13 and R 14 are independent, R 20 optionally substituted with one or more substituents selected from: R 15 is carboxy, sulfo, sulfino, phosphono, -P(O)(OR e )(OR f ), -P(O)(OH)(OR e ), -P(O)(OH)(R e ) or -P(O)(OR e )(R f ), where R e and R f are independent, C 1~6 alkyl; p is 1 to 3; where R 13 The values ​​of may be the same or different; q is between 0 and 1; r is 0 to 3; where R 14 The values ​​of can be the same or different) and m is 0 to 2; where R 10 The values ​​of may be the same or different; n is 1 to 3; where R7 The values ​​of may be the same or different; Ring B has R on the carbon 23 and a nitrogen-linked heterocyclyl substituted on a carbon by one or more groups selected from 24 wherein when said nitrogen-linked heterocyclyl contains an —NH— moiety, the nitrogen is optionally further substituted by R 25 optionally substituted with a group selected from R 16 , R 17 and R 18 are independently halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C 1~4 Alkyl, C 2~4 Alkenyl, C 2~4 Alkynyl, C 1~4 Alkoxy, C 1~4 Alkanoyl, C 1~4 Alkanoyloxy, N-(C 1~4 alkyl)amino, N,N-(C 1~4 Alkyl)2amino, C 1~4 Alkanoylamino, N-(C 1~4 alkyl)carbamoyl, N,N-(C 1~4 alkyl)2carbamoyl, C where a is 0 to 2 1~4 AlkylS(O) a , C 1~4 Alkoxycarbonyl, N-(C 1~4 alkyl)sulfamoyl and N,N-(C 1~4 alkyl)2sulfamoyl; 16 , R 17 and R 18 independently, one or more R 21 optionally substituted by; R 19 , R 20 , R 24 and R 26 are independently halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C 1~4 Alkyl, C 2~4Alkenyl, C 2~4 Alkynyl, C 1~4 Alkoxy, C 1~4 Alkanoyl, C 1~4 Alkanoyloxy, N-(C 1~4 alkyl)amino, N,N-(C 1~4 Alkyl)2amino, C 1~4 Alkanoylamino, N-(C 1~4 alkyl)carbamoyl, N,N-(C 1~4 alkyl)2carbamoyl, C where a is 0 to 2 1~4 AlkylS(O) a , C 1~4 Alkoxycarbonyl, N-(C 1~4 alkyl)sulfamoyl, N,N-(C 1~4 alkyl)2sulfamoyl, carbocyclyl, heterocyclyl, benzyloxycarbonylamino, (C 1~4 alkyl) 3 silyl, sulfo, sulfino, amidino, phosphono, -P(O)(OR a )(OR b ), -P(O)(OH)(OR a ), -P(O)(OH)(R a ) or -P(O)(OR a )(R b ), wherein R a and R b are independent, C 1~6 alkyl; where R 19 , R 20 , R 24 and R 26 independently, one or more R 22 optionally substituted by; R 21 and R 22are independently selected from the group consisting of halo, hydroxy, cyano, carbamoyl, ureido, amino, nitro, carboxy, carbamoyl, mercapto, sulfamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, vinyl, allyl, ethynyl, methoxycarbonyl, formyl, acetyl, formamido, acetylamino, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl, N,N-dimethylcarbamoyl, methylthio, methylsulfinyl, mesyl, N-methylsulfamoyl, and N,N-dimethylsulfamoyl; R 23 is carboxy, sulfo, sulfino, phosphono, -P(O)(OR g )(OR h ), -P(O)(OH)(OR g ), -P(O)(OH)(R g ) or -P(O)(OR g )(R h ), where R g and R h are independent, C 1~6 alkyl; R 25 is C 1~6 Alkyl, C 1~6 Alkanoyl, C 1~6 Alkylsulfonyl, C 1~6 Alkoxycarbonyl, carbamoyl, N-(C 1~6 alkyl)carbamoyl, N,N-(C 1~6 alkyl) selected from the group consisting of carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulfonyl or a pharmaceutically acceptable salt thereof.

[0023] In some embodiments, the ASBT inhibitor is a compound of formula (II):

[0024] [ka]

[0025] (In the formula, Rv and R w are independently hydrogen or C 1~6 alkyl; R 1 and R 2 are independent, C 1~6 alkyl; R x and R y are independently hydrogen or C 1~6 alkyl, or R x and R y One of the two is hydrogen or C 1~6 alkyl, and the other is hydroxy or C 1~6 is alkoxy; R z is halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkoxy, C 1~6 Alkanoyl, C 1~6 Alkanoyloxy, N-(C 1~6 alkyl)amino, N,N-(C 1~6 Alkyl)2amino, C 1~6 Alkanoylamino, N-(C 1~6 alkyl)carbamoyl, N,N-(C 1~6 alkyl)2carbamoyl, C where a is 0 to 2 1~6 AlkylS(O) a , C 1~6 Alkoxycarbonyl, C 1~6 Alkoxycarbonylamino, ureido, N'-(C 1~6 alkyl)ureido, N-(C 1~6 alkyl)ureido, N',N'-(C 1~6 alkyl) 2 ureido, N'-(C 1~6 alkyl)-N-(C 1~6 alkyl)ureido, N',N'-(C 1~6 alkyl)2-N-(C 1~6 alkyl)ureido, N-(C 1~6 alkyl)sulfamoyl and N,N-(C 1~6alkyl)sulfamoyl; v is 0 to 5; R 4 and R 5 one of which is a group of formula (IIA):

[0026] [ka]

[0027] and R 3 and R 6 , and R 4 and R 5 The other is independently hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C 1~4 Alkyl, C 2~4 Alkenyl, C 2~4 Alkynyl, C 1~4 Alkoxy, C 1~4 Alkanoyl, C 1~4 Alkanoyloxy, N-(C 1~4 alkyl)amino, N,N-(C 1~4 Alkyl)2amino, C 1~4 Alkanoylamino, N-(C 1~4 alkyl)carbamoyl, N,N-(C 1~4 alkyl)2carbamoyl, C where a is 0 to 2 1~4 AlkylS(O) a , C 1~4 Alkoxycarbonyl, N-(C 1~4 alkyl)sulfamoyl and N,N-(C 1~4 alkyl)sulfamoyl; where R 3 and R 6 , and R 4 and R 5 The other has one or more R 16 optionally substituted by; D is -O-, -N(R a )-, -S(O) b - or -CH(R a)-where R a is hydrogen or C 1~6 alkyl and b is 0 to 2; Ring A is aryl or heteroaryl; where Ring A is R 17 optionally substituted with one or more substituents selected from: R 7 is hydrogen, C 1~4 alkyl, carbocyclyl, or heterocyclyl; where R 7 is R 18 optionally substituted with one or more substituents selected from: R 8 is hydrogen or C 1~4 is alkyl; R 9 is hydrogen or C 1~4 is alkyl; R 10 is hydrogen, C 1~4 alkyl, carbocyclyl, or heterocyclyl; where R 10 is R 19 optionally substituted with one or more substituents selected from: R 11 is carboxy, sulfo, sulfino, phosphono, tetrazolyl, -P(O)(OR c )(OR d ), -P(O)(OH)(OR c ), -P(O)(OH)(R d ) and -P(O)(OR c )(R d ), wherein R c and R d are independent, C 1~6 alkyl; or R 11 is a group of formula (IIB):

[0028] [ka]

[0029] (In the formula, X is -N(R q)-, -N(R q )C(O)-, -O-, or -S(O) a where a is 0 to 2, and R q is hydrogen or C 1~4 is alkyl; R 12 is hydrogen or C 1~4 is alkyl; R 13 and R 14 are independently hydrogen, C 1~4 Alkyl, carbocyclyl, heterocyclyl and R 23 wherein said C is selected from the group consisting of 1~4 alkyl, carbocyclyl, or heterocyclyl independently represents R 20 optionally substituted with one or more substituents selected from: R 15 is carboxy, sulfo, sulfino, phosphono, tetrazolyl, -P(O)(OR e )(OR f ), -P(O)(OH)(OR e ), -P(O)(OH)(R e ) and -P(O)(OR e )(R f ), wherein R e and R f are independent, C 1~6 alkyl; or R 15 is a group of formula (IIC):

[0030] [ka]

[0031] (In the formula, R 24 is hydrogen or C 1~4 is alkyl; R 25 is hydrogen, C 1~4 Alkyl, carbocyclyl, heterocyclyl and R 27 wherein said C is selected from the group consisting of 1~4alkyl, carbocyclyl, or heterocyclyl independently represents R 28 optionally substituted with one or more substituents selected from: R 26 is carboxy, sulfo, sulfino, phosphono, tetrazolyl, -P(O)(OR g )(OR h ), -P(O)(OH)(OR g ), -P(O)(OH)(R g ) and -P(O)(OR g )(R h ), wherein R g and R h are independent, C 1~6 alkyl) and p is 1 to 3; where R 13 The values ​​of may be the same or different; q is between 0 and 1; r is 0 to 3; where R 14 The values ​​of can be the same or different) and m is 0 to 2; where R 10 The values ​​of may be the same or different; n is 1 to 3; where R 7 The values ​​of may be the same or different; z is 0 to 3; where R 25 The values ​​of may be the same or different; R 16 , R 17 and R 18 each independently represents halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C 1~4 Alkyl, C 2~4 Alkenyl, C 2~4 Alkynyl, C 1~4 Alkoxy, C 1~4 Alkanoyl, C 1~4 Alkanoyloxy, N-(C 1~4 alkyl)amino, N,N-(C 1~4Alkyl)2amino, C 1~4 Alkanoylamino, N-(C 1~4 alkyl)carbamoyl, N,N-(C 1~4 alkyl)2carbamoyl, C where a is 0 to 2 1~4 AlkylS(O) a , C 1~4 Alkoxycarbonyl, N-(C 1~4 alkyl)sulfamoyl and N,N-(C 1~4 alkyl)sulfamoyl; where R 16 , R 17 and R 18 independently, one or more R 21 optionally substituted by; R 19 , R 20 , R 23 , R 27 and R 28 each independently represents halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C 1~4 Alkyl, C 2~4 Alkenyl, C 2~4 Alkynyl, C 1~4 Alkoxy, C 1~4 Alkanoyl, C 1~4 Alkanoyloxy, N-(C 1~4 alkyl)amino, N,N-(C 1~4 Alkyl)2amino, C 1~4 Alkanoylamino, N-(C 1~4 alkyl)carbamoyl, N,N-(C 1~4 alkyl)2carbamoyl, C where a is 0 to 2 1~4 AlkylS(O) a , C 1~4 Alkoxycarbonyl, N-(C 1~4 alkyl)sulfamoyl, N,N-(C 1~4 alkyl)2sulfamoyl, carbocyclyl, heterocyclyl, sulfo, sulfino, amidino, phosphono, -P(O)(OR a )(OR b ), -P(O)(OH)(OR a), -P(O)(OH)(R a ) or -P(O)(OR a )(R b ), wherein R a and R b are independent, C 1~6 alkyl; where R 19 , R 20 , R 23 , R 27 and R 28 independently, one or more R 22 optionally substituted by; R 21 and R 22 are independently selected from the group consisting of halo, hydroxy, cyano, carbamoyl, ureido, amino, nitro, carboxy, carbamoyl, mercapto, sulfamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, vinyl, allyl, ethynyl, methoxycarbonyl, formyl, acetyl, formamido, acetylamino, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl, N,N-dimethylcarbamoyl, methylthio, methylsulfinyl, mesyl, N-methylsulfamoyl, and N,N-dimethylsulfamoyl. or a pharmaceutically acceptable salt thereof.

[0032] In some embodiments, the ASBT inhibitor is a compound of formula (III):

[0033] [ka]

[0034] (In the formula, q is an integer from 1 to 4; n is an integer from 0 to 2; R 1 and R 2is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl; where alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl are each independently selected from the group consisting of OR 9 , N.R. 9 R 10 , N + R 9 R 10 R w A - , S.R. 9 , S + R 9 R 10 A - .P + R 9 R 10 R 11 A - , S(O)R 9 , SO2R 9 , SO3R 9 , CO2R 9 , CN, halogen, oxo, and CONR 9 R 10 and optionally substituted with one or more substituents selected from the group consisting of: wherein alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl)aryl, and cycloalkyl optionally have one or more carbons substituted with O, NR 9 , N + R 9 R 10 A - ,S,SO,SO2,S + R 9 A - , P + R 9 R 10 A - or phenylene, R 9 , R 10 , and Rw is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammonium alkyl, aryl alkyl, carboxy alkyl, carboxy heteroaryl, carboxy heterocycle, carboalkoxy alkyl, carboxy alkyl amino, heteroaryl alkyl, heterocyclyl alkyl, and alkyl ammonium alkyl; or R 1 and R 2 together with the carbon to which they are attached, C 3~10 Forming a cycloalkyl; R 3 and R 4 are independently H, alkyl, alkenyl, alkynyl, acyloxy, aryl, heterocycle, OR 9 , N.R. 9 R 10 , S.R. 9 , S(O)R 9 , SO2R 9 , and SO3R 9 wherein R 9 and R 10 is as defined above; or R 3 and R 4 Together, =O, =NOR 11 , =S, =NNR 11 R 12 , =NR 9 , or =CR 11 R 12 Forming where R 11 and R 12 are independently H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR 9 , N.R. 9 R 10 , S.R. 9 , S(O)R 9 , SO2R 9 , SO3R 9 , CO2R 9, CN, halogen, oxo, and CONR 9 R 10 wherein R 9 and R 10 is as defined above, except that R 3 and R 4 cannot both be OH, NH2, and SH, or R 11 and R 12 together with the nitrogen or carbon atom to which they are attached form a cyclic ring; R 5 is one or more OR 13a is an aryl substituted with where R 13a is selected from the group consisting of alkylarylalkyl, alkylheteroarylalkyl, alkylheterocyclylalkyl, heterocyclylalkyl, heteroarylalkyl, quaternary heterocyclylalkyl, alkylammoniumalkyl, and carboxyalkylaminocarbonylalkyl; R 13a is hydroxy, amino, sulfo, carboxy, alkyl, carboxyalkyl, heterocycle, heteroaryl, sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, quaternary heterocyclylalkyl, quaternary heteroarylalkyl, guanidinyl, OR 9 , N.R. 9 R 10 , N + R 9 R 11 R 12 A - , S.R. 9 , S(O)R 9 , SO2R 9 , SO3R 9 , oxo, CO2R 9 , CN, halogen, CONR 9 R 10 , SO2OM, SO2NR 9 R 10 , PO(OR 16 ) OR 17 , P + R 9 R 10 R11 A - , S + R 9 R 10 A - and C(O)OM, where A - is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation, where R 16 and R 17 are independent, R 9 and the substituents comprising M; R 6 is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, OR 30 , S.R. 9 , S(O)R 9 , SO2R 9 , and SO3R 9 is selected from the group consisting of Here, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, and quaternary heteroaryl are alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen, oxo, OR 13 , N.R. 13 R 14 , S.R. 13 , S(O)R 13 , SO2R 13 , SO3R 13 , N.R. 13 OR 14 , N.R. 13 NR 14 R 15 , NO2, CO2R 13 , CN, OM, SO2OM, SO2NR 13 R 14 , C(O)NR 13 R 14 , C(O)OM, COR 13 , N.R. 13 C(O)R 14 , N.R. 13 C(O)NR 14 R 15, N.R. 13 CO2R 14 ,OC(O)R 13 , OC(O)NR 13 R 14 , N.R. 13 SOR 14 , N.R. 13 SO2R 14 , N.R. 13 SONR 14 R 15 , N.R. 13 SO2NR 14 R 15 , P(O)R 13 R 14 , P + R 13 R 14 R 15 A - , P(OR 13 ) OR 14 , S + R 13 R 14 A - , and N + R 9 R 11 R 12 A - and optionally substituted with one or more substituents independently selected from the group consisting of: A - is a pharmaceutically acceptable anion, M is a pharmaceutically acceptable cation, The alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle are selected from the group consisting of OR 7 , N.R. 7 R 8 , S.R. 7 , S(O)R 7 , SO2R 7 , SO3R 7 , CO2R 7 , CN, Oxo, CONR 7 R 8 , N + R 7 R 8 R 9 A -, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P(O)R 7 R 8 , P + R 7 R 8 R 9 A - , and P(O)(OR 7 ) OR 8 and optionally further substituted with one or more substituents selected from the group consisting of: wherein the alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle optionally have one or more carbons substituted by O, NR 7 , N + R 7 R 8 A - ,S,SO,SO2,S + R 7 A - , PR 7 , P(O)R 7 , P + R 7 R 8 A - or phenylene, R 13 , R 14 , and R 15 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, arylalkyl, alkylarylalkyl, alkylheteroarylalkyl, alkylheterocyclylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, heterocyclylalkyl, heteroarylalkyl, quaternary heterocyclylalkyl, quaternary heteroarylalkyl, alkylammoniumalkyl, and carboxyalkylaminocarbonylalkyl; wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl optionally have one or more carbons substituted with O, NR 9 , N + R 9 R 10 A- ,S,SO,SO2,S + R 9 A - , PR 9 , P + R 9 R 10 A - , P(O)R 9 phenylene, carbohydrate, amino acid, peptide, or polypeptide; R 13 , R 14 , and R 15 is hydroxy, amino, sulfo, carboxy, alkyl, carboxyalkyl, heterocycle, heteroaryl, sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, quaternary heterocyclylalkyl, quaternary heteroarylalkyl, guanidinyl, OR 9 , N.R. 9 R 10 , N + R 9 R 11 R 12 A - , S.R. 9 , S(O)R 9 , SO2R 9 , SO3R 9 , oxo, CO2R 9 , CN, halogen, CONR 9 R 10 , SO2OM, SO2NR 9 R 10 , PO(OR 16 ) OR 17 , P + R 9 R 10 R 11 A - , S + R 9 R 10 A - and C(O)OM, where R 16 and R 17 are independent, R 9 and the substituents comprising M; or R 13 and R 14together with the nitrogen atom to which they are attached form a monocyclic or polycyclic heterocycle optionally substituted with one or more groups selected from the group consisting of oxo, carboxy, and quaternary salts; or R 14 and R 15 together with the nitrogen atom to which they are attached form a cyclic ring; R 30 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammonium alkyl, alkylammonium alkyl, aryl alkyl, carboxyalkyl, carboxyheteroaryl, carboxyheterocycle, carboalkoxyalkyl, carboxyalkylamino, heteroaryl alkyl, heterocyclyl alkyl, and alkylammonium alkyl; R 7 and R 8 are independently selected from the group consisting of hydrogen and alkyl; One or more R x are independently H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl, polyether, quaternary heterocycle, quaternary heteroaryl, OR 13 , N.R. 13 R 14 , S.R. 13 , S(O)R 13 , S(O)2R 13 , SO3R 13 , S + R 13 R 14 A - , N.R. 13 OR 14 , N.R. 13 NR 14 R 15 , NO2, CO2R 13 , CN, OM, SO2OM, SO2NR 13 R 14 , N.R. 14 C(O)R 13 , C(O)NR 13 R 14 , N.R. 14 C(O)R13 , C(O)OM, COR 13 , OR 18 , S(O) n NR 18 , N.R. 13 R 18 , N.R. 18 OR 14 , N + R 9 R 11 R 12 A - , P + R 9 R 11 R 12 A - , amino acids, peptides, polypeptides, and carbohydrates; wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl, haloalkyl, polyether, quaternary heterocycle, and quaternary heteroaryl are OR 9 , N.R. 9 R 10 , N + R 9 R 11 R 12 A - , S.R. 9 , S(O)R 9 , SO2R 9 , SO3R 9 , oxo, CO2R 9 , CN, halogen, CONR 9 R 10 , SO2OM, SO2NR 9 R 10 , PO(OR 16 ) OR 17 , P + R 9 R 11 R 12 A - , S + R 9 R 10 A - or C(O)OM, where R 18 is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, and alkyl; wherein acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, quaternary heterocycle, and quaternary heteroaryl are OR 9 , N.R. 9 R 10 , N + R 9 R 11 R 12 A - , S.R. 9 , S(O)R 9 , SO2R 9 , SO3R 9 , oxo, CO2R 9 , CN, halogen, CONR 9 R 10 , SO3R 9 , SO2OM, SO2NR 9 R 10 , PO(OR 16 ) OR 17 and C(O)OM, where R x In the formula (I), one or more carbon atoms are O, NR 13 , N + R 13 R 14 A - ,S,SO,SO2,S + R 13 A - , PR 13 , P(O)R 13 , P + R 13 R 14 A - phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl; wherein one or more carbons in the polyalkyl, phenylene, amino acid, peptide, polypeptide, and carbohydrate are O, NR 9 , N + R 9 R 10 A - ,S,SO,SO2,S + R 9 A - , PR9 , P + R 9 R 10 A - , or P(O)R 9 has been replaced in some cases by; Here, the quaternary heterocycle and the quaternary heteroaryl are alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR 13 , N.R. 13 R 14 , S.R. 13 , S(O)R 13 , SO2R 13 , SO3R 13 , N.R. 13 OR 14 , N.R. 13 NR 14 R 15 , NO2, CO2R 13 , CN, OM, SO2OM, SO2NR 13 R 14 , C(O)NR 13 R 14 , C(O)OM, COR 13 , P(O)R 13 R 14 , P + R 13 R 14 R 15 A - , P(OR 13 ) OR 14 , S + R 13 R 14 A - , and N + R 9 R 11 R 12 A - and optionally substituted with one or more groups selected from the group consisting of or a pharmaceutically acceptable salt thereof.

[0035] In some embodiments, the ASBT inhibitor is a compound of formula (IV):

[0036] [ka]

[0037] (In the formula, X is O, NH, CH or a bond; R 1 is C 1~6 is alkyl; R 2 , R 2' , R 3 , R 3' , R 4 , R 4' , R 5 and R 5' are each independently H, Cl, Br, I, OH, -(CH2)-OH, CF3, NO2, N3, CN, S(O) p -R 6 , OS(O) p -R 6 , C 1~6 Alkylene-S(O) p -R 6 , C 1~6 Alkylene-OS(O) p -R 6 , COOH, COOC 1~6 Alkyl, CONH2, CONHC 1~6 Alkyl, CON(C 1~6 Alkyl)2, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl and OC 1~6 alkyl, where one or more of the alkyl hydrogens are fluorine; and phenyl, —(CH)-phenyl, —(CH) n -phenyl, O-phenyl, O-(CH2) m -phenyl, -(CH2)-O-(CH2) m -phenyl, where the phenyl ring is not affected by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, OC 1~6 Alkyl, C 1~6 Alkyl, NH2, NHC 1~6 Alkyl, N(C 1~6 Alkyl)2, SO2-CH3, COOH, COOC 1~6may be substituted 1 to 3 times with alkyl or CONH2; where, always, R 2 , R 2' , R 3 , R 3' , R 4 , R 4' , R 5 , R 5' At least one of the following is -O-(CH2) m -phenyl or -(CH2)-O-(CH2) m -phenyl, where the phenyl ring is free of F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, OC 1~6 Alkyl, C 1~6 Alkyl, NH2, NHC 1~6 Alkyl, N(C 1~6 Alkyl)2, SO2-CH3, COOH, COOC 1~6 alkyl, optionally substituted 1 to 3 times by CONH2; R 6 are H, OH, and C 1~6 Alkyl, NH2, NHC 1~6 Alkyl and N(C 1~6 alkyl)2; n is an integer of 2, 3, 4, 5, or 6; m is an integer of 1, 2, 3, 4, 5, or 6; p is an integer of 0, 1 or 2. or a pharmaceutically acceptable salt thereof.

[0038] In some embodiments, the ASBT inhibitor is a compound of formula (V):

[0039] [ka]

[0040] (In the formula, R 1 is selected from the group consisting of H, Cl, Br, N(CH3)2 and methoxy; R 2 is H or OH; Each R3 are independent, C 1~6 is alkyl; X is CH2, C(O) or CH=CH; Q is C 0~6 is alkyl; R 4 OH, SO3H, CO2H, PO3H2, CONR 5 R 5 , N.R. 5 R 5 and NHC(O)CH2NR 5 R 5 selected from the group consisting of: Each R 5 are independently H, OH, C 1~6 Alkyl, C 0~6 AlkylCO2H,C 0~6 AlkylSO3H,C 0~6 AlkylPO3H2, C(O)C 0~6 AlkylCO2H, C(O)C 0~6 AlkylSO3H, C(O)C 0~6 AlkylPO3H2 and CH(R 6 )C 0~6 alkylCOH; R 6 is C 0~6 AlkylCO2H,C 0~6 Alkyl OH, C 0~6 Alkyl SO3H and C 0~6 alkylPO3H2) or a pharmaceutically acceptable salt thereof.

[0041] In some embodiments, the ASBT inhibitor is a compound of formula (VI):

[0042] [ka]

[0043] (In the formula, M is -CH2- and -NR 7 -Selected from; R 1 and R 2are each independently, C 1~4 is alkyl; R 3 is hydrogen, halogen, hydroxy, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, cyano, nitro, amino, N-(C 1~4 alkyl)amino, N,N-di(C 1~4 alkyl)amino, N-(aryl-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 sulfonamide and C 3~6 cycloalkylsulfonamides; n is an integer of 1, 2, or 3; R 4 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 selected from the group consisting of (alkyl)amino; R 5 and R 6 is carboxy and R 5 and R 6 The other is hydrogen, fluoro, C 1~4 Alkyl and C 1~4 haloalkyl; R 7 is hydrogen and C 1~4 selected from the group consisting of alkyl; R 8is hydrogen and C 1~4 alkyl) or a pharmaceutically acceptable salt thereof.

[0044] In some embodiments, the ASBT inhibitor is a compound of formula (VII):

[0045] [ka]

[0046] (In the formula, M is -CH2- or -NR 6 - and; R 1 and R 2 are each independently, C 1~4 is alkyl; R 3 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 N-(aryl-C 1~4 selected from the group consisting of (alkyl)amino; n is an integer of 1, 2, or 3; R 4 is hydrogen, halogen, hydroxy, 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 selected from the group consisting of (alkyl)amino; R 5A , R 5B , R 5C and R 5Dare each independently hydrogen, halogen, hydroxy, amino, C 1~4 Alkyl and C 1~4 selected from the group consisting of alkoxy; R 6 is hydrogen and C 1~4 alkyl) or a pharmaceutically acceptable salt thereof.

[0047] In some embodiments, the ASBT inhibitor is a compound of formula (VIII):

[0048] [ka]

[0049] (In the formula, M is -CH2- or -NH-; R 1 and R 2 are each independently, C 1~4 is alkyl; R 3 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 N-(aryl-C 1~4 selected from the group consisting of (alkyl)amino; n is an integer of 1, 2, or 3; R 4 is hydrogen, halogen, hydroxy, 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) or a pharmaceutically acceptable salt thereof.

[0050] In some embodiments, the ASBT inhibitor is a compound of formula (IX):

[0051] [ka]

[0052] (In the formula, M is -CH2- and -NR 6 -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, cyano, nitro, amino, N-(C 1~4 alkyl)amino, N,N-di(C 1~4 alkyl)amino, N-(aryl-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 sulfonamide 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-(C1~4 alkyl)amino and N,N-di(C 1~4 selected from the group consisting of (alkyl)amino; R 4 and R 5 is carboxyl, and R 4 and R 5 The other is hydrogen, fluoro, C 1~4 Alkyl and C 1~4 haloalkyl; R 6 is hydrogen and C 1~4 selected from the group consisting of alkyl; R 7 is hydrogen and C 1~4 alkyl) or a pharmaceutically acceptable salt thereof.

[0053] In some embodiments, the ASBT inhibitor is a compound of formula (X):

[0054] [ka]

[0055] (In the formula, M is -CH2- or -NR 6 - and; R 1 is C 1~4 is alkyl; R 2 is hydrogen and C 1~4 selected from the group consisting of alkyl; R 3 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 and N,N-di(C 1~4 selected from the group consisting of (alkyl)amino; n is an integer of 1, 2, or 3; R 4is 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 selected from the group consisting of (alkyl)amino; R 5A and R 5B are each independently hydrogen, halogen, hydroxy, C 1~4 Alkyl and C 1~4 or R is selected from the group consisting of alkoxy; 5A and R 5B together with the carbon atoms to which they are attached form a 3- to 5-membered saturated carbocyclic ring; R 6 is hydrogen and C 1~4 alkyl) or a pharmaceutically acceptable salt thereof.

[0056] In some embodiments, the ASBT inhibitor is: 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; 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; 1-{[4-({4-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-1λ 6-benzothiepin-5-yl]phenoxy}methyl)phenyl]methyl}-1,4-diazabicyclo[2.2.2]octan-1-ium chloride; N-(3-O-benzyl-6-O-sulfo-β-D-glucopyranosyl)-N'-{3-[(3S,4R,5R)-3-butyl-7-(dimethylamino)-3-ethyl-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-1λ] 6 -benzothiepin-5-yl]phenyl}urea; 3-({[(3R,5R)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1λ 6 ,4-benzothiazepin-8-yl]methyl}amino)pentanedioic acid; (Z)-3-((3,3-dibutyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy)-2-fluoroacrylic acid; (Z)-3-((3-butyl-3-ethyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy)-2-fluoroacrylic acid; 3-((7-bromo-3-butyl-3-ethyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy)propanoic acid; 3-((3,3-dibutyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy)-2-hydroxypropanoic acid; 3-((3-butyl-3-ethyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy)propanoic acid; 3-((3,3-dibutyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)propanoic acid; 3-((3-butyl-3-ethyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)propanoic acid; 2-((3-butyl-7-(dimethylamino)-3-ethyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy)acetic acid; 2-((3-butyl-3-ethyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydrobenzo-1,2,5-thiadiazepin-8-yl)oxy)acetic acid; and (E)-3-((3-butyl-3-ethyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy)acrylic acid or a pharmaceutically acceptable salt thereof.

[0057] In some embodiments, the ASBT inhibitor is (Z)-3-((3-butyl-3-ethyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy)-2-fluoroacrylic acid:

[0058] [ka]

[0059] or a pharmaceutically acceptable salt thereof, also referred to herein as "Compound 1." In some embodiments, the ASBT inhibitor is (S)-(Z)-3-((3-butyl-3-ethyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy)-2-fluoroacrylic acid, or a pharmaceutically acceptable salt thereof. In some embodiments, Compound 1 is (S)-(Z)-3-((3-butyl-3-ethyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy)-2-fluoroacrylic acid. In some embodiments, the ASBT inhibitor is (R)-(Z)-3-((3-butyl-3-ethyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy)-2-fluoroacrylic acid, or a pharmaceutically acceptable salt thereof. In some embodiments, compound 1 is (R)-(Z)-3-((3-butyl-3-ethyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy)-2-fluoroacrylic acid. Compound 1 can be prepared as described in WO 2019 / 234077.

[0060] In some embodiments, the ASBT inhibitor is 3-((3,3-dibutyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-8-yl)oxy)propanoic acid:

[0061] [ka]

[0062] or a pharmaceutically acceptable salt thereof, also referred to herein as "Compound 2." Compound 2 can be prepared as described in WO 2020 / 161217.

[0063] In some embodiments, the ASBT inhibitor is 2-(((3-butyl-3-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)methyl)thio)acetic acid:

[0064] [ka]

[0065] or a pharmaceutically acceptable salt thereof, also referred to herein as "Compound 3." In some embodiments, the ASBT inhibitor is (S)-2-(((3-butyl-3-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)methyl)thio)acetic acid, or a pharmaceutically acceptable salt thereof. In some embodiments, Compound 3 is (S)-2-(((3-butyl-3-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)methyl)thio)acetic acid. In some embodiments, the ASBT inhibitor is (R)-2-(((3-butyl-3-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)methyl)thio)acetic acid, or a pharmaceutically acceptable salt thereof. In some embodiments, compound 3 is (R)-2-(((3-butyl-3-methyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)methyl)thio)acetic acid. Compound 2 can be prepared as described in PCT / EP2023 / 068476.

[0066] In some embodiments, the ASBT inhibitor is 2-(((3-butyl-7-methoxy-3-methyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)methyl)thio)acetic acid:

[0067] [ka]

[0068] or a pharmaceutically acceptable salt thereof, also referred to herein as "Compound 4." In some embodiments, the ASBTI inhibitor is (S)-2-(((3-butyl-7-methoxy-3-methyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)methyl)thio)acetic acid, or a pharmaceutically acceptable salt thereof. In some embodiments, Compound 4 is (S)-2-(((3-butyl-7-methoxy-3-methyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)methyl)thio)acetic acid. In some embodiments, the ASBTI inhibitor is (R)-2-(((3-butyl-7-methoxy-3-methyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)methyl)thio)acetic acid, or a pharmaceutically acceptable salt thereof. In some embodiments, compound 4 is (R)-2-(((3-butyl-7-methoxy-3-methyl-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)methyl)thio)acetic acid. Compound 4 can be prepared as described in PCT / EP2023 / 068476.

[0069] In some embodiments, the ASBT inhibitor is 2-((3-butyl-3-ethyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy)acetic acid:

[0070] [ka]

[0071] or a pharmaceutically acceptable salt thereof, also referred to herein as "Compound 5." In some embodiments, the ASBTI inhibitor is (S)-2-((3-butyl-3-ethyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy)acetic acid, or a pharmaceutically acceptable salt thereof. In some embodiments, Compound 5 is (S)-2-((3-butyl-3-ethyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy)acetic acid. In some embodiments, the ASBTI inhibitor is (R)-2-((3-butyl-3-ethyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy)acetic acid, or a pharmaceutically acceptable salt thereof. In some embodiments, compound 5 is (R)-2-((3-butyl-3-ethyl-5-(4-fluorophenyl)-7-(methylthio)-1,1-dioxide-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy)acetic acid. Compound 5 can be prepared as described in WO 2021 / 110887.

[0072] In some embodiments, the ASBT inhibitor is

[0073] [ka]

[0074] [ka]

[0075] or a pharmaceutically acceptable salt thereof.

[0076] In some embodiments, the ASBT inhibitor is elobixibat or a pharmaceutically acceptable salt thereof. In some embodiments, the ASBT inhibitor is odebixibat or a pharmaceutically acceptable salt thereof. In some embodiments, the ASBT inhibitor is maralixibat or a pharmaceutically acceptable salt thereof. In some embodiments, the ASBT inhibitor is vorixibat or a pharmaceutically acceptable salt thereof. In some embodiments, the ASBT inhibitor is linelixibat or a pharmaceutically acceptable salt thereof. In some embodiments, the ASBT inhibitor comprises a combination of two or more of elobixibat, odebixibat, maralixibat, vorixibat, and linelixibat, or pharmaceutically acceptable salts thereof.

[0077] As used herein, the term "halo" refers to fluoro, chloro, bromo and iodo.

[0078] As used herein, "C 1~6 The term "alkyl" refers to a straight or branched chain alkyl group having 1 to 6 carbon atoms, and "C 1~4 The term "alkyl" refers to a straight or branched chain 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.

[0079] 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.

[0080] As used herein, "C 1~4 Alkoxy" and "C 1~4The term "alkylthio" refers to a straight or branched C alkyl group bonded to the rest of the molecule through an oxygen or sulfur atom, respectively. 1~4 Refers to an alkyl group.

[0081] 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.

[0082] The term "amino" refers to the group -NH. As used herein, "N-(C 1~4 alkyl)amino" and "N,N-di(C 1~4 The term "(alkyl)amino" refers to a group in which one or both hydrogen atoms are replaced by a straight or branched C 1~4 It refers to an amino group substituted with 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.

[0083] 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.

[0084] As used herein, "N-(aryl-C 1~4 The term "(alkyl)amino" refers to a group in which a hydrogen atom is bonded to an aryl-C 1~4 Refers to an amino group substituted with an alkyl group. N-(aryl-C 1~4 Examples of "C alkyl" amino include benzylamino and phenylethylamino. 1~6 The term "alkylcarbonylamino" refers to the amino group of a hydrogen atom in which the C 1~6 Refers to an amino group substituted with an alkylcarbonyl group. 1~6Examples of alkanoylamino include acetylamino and tert-butylcarbonylamino. 1~4 The term "alkyloxycarbonylamino" refers to the amino group of a hydrogen atom. 1~4 It refers to an amino group substituted 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 substituted with a cycloalkylsulfonyl group.

[0085] Some ASBT inhibitors or pharmaceutically acceptable salts thereof may have chiral centers and / or centers of geometric isomeric form (E- and Z-isomers). It should be understood that the present invention encompasses all such optical isomers, diastereoisomers, and geometric isomers that retain ASBT inhibitory activity. The present invention also encompasses any and all tautomers that retain ASBT inhibitory activity. Certain ASBT inhibitors or pharmaceutically 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 retain ASBT inhibitory activity.

[0086] As used herein, the term "pharmaceutically 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.

[0087] Suitable pharmaceutically acceptable salts of ASBT inhibitors are, for example, base addition salts of the compound that are sufficiently acidic, such as alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts), ammonium salts, or salts with organic bases that provide physiologically acceptable cations, such as salts with methylamine, dimethylamine, trimethylamine, piperidine, morpholine, or tris-(2-hydroxyethyl)amine.

[0088] Administration of ASBT inhibitors In some embodiments, after administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof, the subject exhibits a reduction in serum bile acid concentrations of at least 50% (e.g., at least 55%; at least 60%; at least 65%; at least 70%; at least 75%; at least 80%; at least 85%; at least 90%; or at least 95%) relative to baseline. In some embodiments, the subject exhibits a reduction in serum bile acid concentrations of at least 60%, at least 70%, at least 80%, or at least 90% relative to baseline.

[0089] In some embodiments, the subject exhibits a reduction in serum bile acid concentration of about 50% to about 100% (e.g., about 50% to about 60%; about 50% to about 70%; about 50% to about 80%; about 50% to about 90%; about 60% to about 70%; about 60% to about 80%; about 60% to about 90%; about 60% to about 100%; about 70% to about 80%; about 70% to about 90%; about 70% to about 100%; about 80% to about 90%; about 80% to about 100%; or about 90% to about 100%) relative to baseline after administration of the ASBT inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the subject exhibits a reduction in serum bile acid concentration of about 50%, about 60%, about 70%, about 80%, or about 90% relative to baseline.

[0090] In some embodiments, serum bile acid concentrations are normalized after administration of the ASBT inhibitor or a pharmaceutically acceptable salt thereof, hi some embodiments, serum bile acid concentrations are normalized after administration of the ASBT inhibitor or a pharmaceutically acceptable salt thereof for at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, at least 44 weeks, at least 48 weeks, etc.

[0091] In some embodiments, serum bile acid concentrations are measured after about 1 week to about 72 weeks (e.g., about 1 week to about 4 weeks, about 1 week to about 8 weeks, about 1 week to about 12 weeks, about 1 week to about 16 weeks, about 1 week to about 20 weeks, about 1 week to about 24 weeks, about 1 week to about 36 weeks, about 1 week to about 40 weeks, about 1 week to about 48 weeks, about 1 week to about 52 weeks, about 1 week to about 60 weeks, about 4 weeks to about 8 weeks). , about 4 weeks to about 16 weeks, about 4 weeks to about 24 weeks, about 4 weeks to about 40 weeks, about 4 weeks to about 52 weeks, about 4 weeks to about 72 weeks, about 8 weeks to about 16 weeks, about 8 weeks to about 24 weeks, about 8 weeks to about 36 weeks, about 8 weeks to about 48 weeks, about 8 weeks to about 60 weeks, about 12 weeks to about 20 weeks, about 12 weeks to about 28 weeks, about 12 weeks to about 40 weeks, about 12 weeks to about 52 weeks, about 12 weeks to Approximately 72 weeks, approximately 16 weeks to approximately 24 weeks, approximately 16 weeks to approximately 36 weeks, approximately 16 weeks to approximately 48 weeks, approximately 16 weeks to approximately 60 weeks, approximately 20 weeks to approximately 28 weeks, approximately 20 weeks to approximately 40 weeks, approximately 20 weeks to approximately 52 weeks, approximately 20 weeks to approximately 72 weeks, approximately 24 weeks to approximately 36 weeks, approximately 24 weeks to approximately 48 weeks, approximately 24 weeks to approximately 60 weeks, approximately 28 weeks to approximately 40 weeks, approximately 28 weeks to approximately 52 weeks, approximately 28 The ASBT inhibitor or a pharmaceutically acceptable salt thereof is normalized after administration of the ASBT inhibitor or a pharmaceutically acceptable salt thereof for about 72 weeks, about 36 weeks to about 48 weeks, about 36 weeks to about 60 weeks, about 40 weeks to about 44 weeks, about 40 weeks to about 52 weeks, about 40 weeks to about 72 weeks, about 44 weeks to about 52 weeks, about 44 weeks to about 72 weeks, about 48 weeks to about 60 weeks, about 52 weeks to about 72 weeks, or about 60 weeks to about 72 weeks.

[0092] In some embodiments, after administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof, the subject exhibits an increase in urinary bile acids of at least 50% (e.g., at least 55%; at least 60%; at least 65%; at least 70%; at least 75%; at least 80%; at least 85%; at least 90%; or at least 95%) relative to baseline. In some embodiments, the subject exhibits an increase in urinary bile acids of at least 60%, at least 70%, at least 80%, or at least 90% relative to baseline.

[0093] In some embodiments, the subject exhibits an increase in urinary bile acids of about 50% to about 100% (e.g., about 50% to about 60%; about 50% to about 70%; about 50% to about 80%; about 50% to about 90%; about 60% to about 70%; about 60% to about 80%; about 60% to about 90%; about 60% to about 100%; about 70% to about 80%; about 70% to about 90%; about 70% to about 100%; about 80% to about 90%; about 80% to about 100%; or about 90% to about 100%) relative to baseline following administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the subject exhibits an increase in urinary bile acids of about 50%, about 60%, about 70%, about 80%, or about 90% relative to baseline.

[0094] In some embodiments, the presence of a disease enumerated herein, such as biliary nephropathy, is determined by one or more biomarkers indicative of one or more of bile duct obstruction, cholestasis, inflammation, liver fibrosis, and cirrhosis, and / or a scoring system thereof. In some embodiments, the severity of a disease enumerated herein, such as biliary nephropathy, is determined by one or more biomarkers indicative of one or more of bile duct obstruction, cholestasis, inflammation, liver fibrosis, and cirrhosis, and / or a scoring system thereof. In some embodiments, the outcome of treatment of a disease enumerated herein, such as biliary nephropathy, is determined by one or more biomarkers indicative of one or more of bile duct obstruction, cholestasis, inflammation, liver fibrosis, and cirrhosis, and / or a scoring system thereof. Non-limiting examples of biomarkers indicative of one or more of bile duct obstruction, cholestasis, inflammation, liver fibrosis, and cirrhosis, and / or their scoring systems, include alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), gamma glutamyltransferase (GGT), serum bilirubin, prothrombin time (PT), international normalized ratio (INR), total protein, and albumin levels (see, e.g., Lala et al., "Liver Function Tests." StatPearls, StatPearls Publishing, October 5, 2022 (PMID: 29494096), which is incorporated herein by reference in its entirety). In some embodiments, a subject shows improvement in liver parameters (biomarkers) after administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, the level of aspartate aminotransferase (AST) does not increase. 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., the concentration in the blood.For example, AST or ALT levels can be expressed as units / L.

[0095] In some embodiments, serum total bilirubin levels are reduced after administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, total bilirubin levels are reduced from baseline by about 0.5 mg / dL to about 5.0 mg / dL, about 1 mg / dL to about 5.0 mg / dL, about 1.5 mg / dL to about 5.0 mg / dL, or about 2.0 mg / dL to about 5.0 mg / dL after administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof for at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, at least 44 weeks, at least 48 weeks, etc. For example, total bilirubin can be reduced by at least 70% (e.g., approximately 99%) after administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof for at least 24 weeks.

[0096] In some embodiments, the total bilirubin level increases from baseline to about 0.5 mg / dL to about 5.0 mg / dL, about 0.5 mg / dL to about 4.0 mg / dL, about 0.5 mg / dL to about 3.0 mg / dL, about 0.5 mg / dL to about 2.0 mg / dL, about 0.5 mg / dL to about 1.5 mg / dL, about 1.0 mg / dL to about 5.0 mg / dL, about 1.0 mg / dL to about 4.0 mg / dL, about 1.0 mg / dL to about 3.0 mg / dL, or about 1.0 mg / dL to about 2.0 mg / dL after administration of the ASBT inhibitor or a pharmaceutically acceptable salt thereof. A decrease of 0 mg / dL, about 1.0 mg / dL to about 1.5 mg / dL, about 1.5 mg / dL to about 5.0 mg / dL, about 1.5 mg / dL to about 4.0 mg / dL, about 1.5 mg / dL to about 3.0 mg / dL, about 1.5 mg / dL to about 2.0 mg / dL, about 2.0 mg / dL to about 5.0 mg / dL, about 2.0 mg / dL to about 4.0 mg / dL, about 2.0 mg / dL to about 3.0 mg / dL, about 3.0 mg / dL to about 5.0 mg / dL, about 3.0 mg / dL to about 4.0 mg / dL, or 4.0 mg / dL to about 5.0 mg / dL. For example, total bilirubin can be reduced by about 50% to about 100% (e.g., about 50% to about 60%; about 50% to about 70%; about 50% to about 80%; about 50% to about 90%; about 60% to about 70%; about 60% to about 80%; about 60% to about 90%; about 60% to about 100%; about 70% to about 80%; about 70% to about 90%; about 70% to about 100%; about 80% to about 90%; about 80% to about 100%; or about 90% to about 100%) after administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, serum total bilirubin levels are reduced by about 50%, about 60%, about 70%, about 80%, or about 90% relative to baseline after administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof.In some embodiments, serum total bilirubin levels are maintained for about 1 week to about 72 weeks (e.g., about 1 week to about 4 weeks, about 1 week to about 8 weeks, about 1 week to about 12 weeks, about 1 week to about 16 weeks, about 1 week to about 20 weeks, about 1 week to about 24 weeks, about 1 week to about 36 weeks, about 1 week to about 40 weeks, about 1 week to about 48 weeks, about 1 week to about 52 weeks, about 1 week to about 60 weeks, about 4 weeks to about 8 weeks, about 4 weeks to about 16 weeks, about 4 weeks to about 24 weeks, about 4 weeks to about 40 weeks, about 4 weeks to about 52 weeks, about 4 weeks to about 72 weeks, about 8 weeks to about 16 weeks, about 8 weeks to about 24 weeks, about 8 weeks to about 36 weeks, about 8 weeks to about 48 weeks, about 8 weeks to about 60 weeks, about 12 weeks to about 20 weeks, about 12 weeks to about 28 weeks, about 12 weeks to about 40 weeks, about 12 weeks to about 52 weeks, about 12 weeks to about 72 weeks, about 16 weeks to about 24 weeks, about 16 weeks to about 36 weeks, about 16 weeks to about 48 weeks, about 16 weeks to about 60 weeks, about 20 weeks to about 28 weeks, about 20 weeks to about 40 weeks, about 20 weeks to about 52 weeks, about 20 weeks to about 72 weeks, about 2 After administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof for 4 weeks to about 36 weeks, about 24 weeks to about 48 weeks, about 24 weeks to about 60 weeks, about 28 weeks to about 40 weeks, about 28 weeks to about 52 weeks, about 28 weeks to about 72 weeks, about 36 weeks to about 48 weeks, about 36 weeks to about 60 weeks, about 40 weeks to about 44 weeks, about 40 weeks to about 52 weeks, about 40 weeks to about 72 weeks, about 44 weeks to about 52 weeks, about 44 weeks to about 72 weeks, about 48 weeks to about 60 weeks, about 52 weeks to about 72 weeks, or about 60 weeks to about 72 weeks For example, total bilirubin can be reduced by about 50% to about 100% (e.g., about 50% to about 60%; about 50% to about 70%; about 50% to about 80%; about 50% to about 90%; about 60% to about 70%; about 60% to about 80%; about 60% to about 90%; about 60% to about 100%; about 70% to about 80%; about 70% to about 90%; about 70% to about 100%; about 80% to about 90%; about 80% to about 100%; or about 90% to about 100%) after administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof.

[0097] In some embodiments, serum alkaline phosphatase (ALP) levels are improved after administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, ALP levels are decreased after administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, ALP levels are decreased from baseline by about 50 U / L to about 175 U / L, about 50 U / L to about 150 U / L, about 50 U / L to about 125 U / L, or about 100 U / L to about 150 U / L after administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof for at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, at least 44 weeks, at least 48 weeks, etc. For example, ALP levels can be reduced by approximately 50%, approximately 60%, or approximately 70% after administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof for at least 24 weeks.

[0098] In some embodiments, the ALP level is measured over a period of about 1 week to about 72 weeks (e.g., about 1 week to about 4 weeks, about 1 week to about 8 weeks, about 1 week to about 12 weeks, about 1 week to about 16 weeks, about 1 week to about 20 weeks, about 1 week to about 24 weeks, about 1 week to about 36 weeks, about 1 week to about 40 weeks, about 1 week to about 48 weeks, about 1 week to about 52 weeks, about 1 week to about 60 weeks, about 4 weeks to about 8 weeks, about 4 weeks to about 16 weeks, about 4 weeks to about 24 weeks, about 4 weeks to about 40 weeks, about 4 weeks to about 52 weeks, about 4 weeks to about 72 weeks, about 8 weeks to about 16 weeks, About 8 weeks to about 24 weeks, about 8 weeks to about 36 weeks, about 8 weeks to about 48 weeks, about 8 weeks to about 60 weeks, about 12 weeks to about 20 weeks, about 12 weeks to about 28 weeks, about 12 weeks to about 40 weeks, about 12 weeks to about 52 weeks, about 12 weeks to about 72 weeks, about 16 weeks to about 24 weeks, about 16 weeks to about 36 weeks, about 16 weeks to about 48 weeks, about 16 weeks to about 60 weeks, about 20 weeks to about 28 weeks, about 20 weeks to about 40 weeks, about 20 weeks to about 52 weeks, about 20 weeks to about 72 weeks, about 24 weeks to about 36 weeks, about 24 weeks to about 48 weeks, about 24 weeks about 52 to about 72 weeks, about 60 to about 72 weeks, about 28 to about 40 weeks, about 28 to about 52 weeks, about 28 to about 72 weeks, about 36 to about 48 weeks, about 36 to about 60 weeks, about 40 to about 44 weeks, about 40 to about 52 weeks, about 40 to about 72 weeks, about 44 to about 52 weeks, about 44 to about 72 weeks, about 48 to about 60 weeks, about 52 to about 72 weeks, or about 60 to about 72 weeks of administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof, / L, about 50 U / L to about 125 U / L, about 50 U / L to about 75 U / L, about 75 U / L to about 175 U / L, about 75 U / L to about 150 U / L, about 75 U / L to about 125 U / L, about 75 U / L to about 100 U / L, about 100 U / L to about 175 U / L, about 100 U / L to about 150 U / L, about 100 U / L to about 125 U / L, or about 150 U / L to about 175 U / L. For example, ALP levels can be reduced by about 50%, about 60%, or about 70% after administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof.

[0099] In some embodiments, serum alanine aminotransferase (ALT) levels are improved after administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, ALT levels are decreased after administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof. In some embodiments, ALT levels are decreased from baseline by about 50 U / L to about 175 U / L, about 50 U / L to about 150 U / L, about 50 U / L to about 125 U / L, or about 100 U / L to about 150 U / L after administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof for at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, at least 44 weeks, at least 48 weeks, etc. For example, ALT levels can be reduced by approximately 50%, approximately 60%, or approximately 70% after administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof for at least 24 weeks.

[0100] In some embodiments, serum aspartate aminotransferase (AST) levels are improved following administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof.

[0101] In some embodiments, ALT levels are measured over a period of about 1 week to about 72 weeks (e.g., about 1 week to about 4 weeks, about 1 week to about 8 weeks, about 1 week to about 12 weeks, about 1 week to about 16 weeks, about 1 week to about 20 weeks, about 1 week to about 24 weeks, about 1 week to about 36 weeks, about 1 week to about 40 weeks, about 1 week to about 48 weeks, about 1 week to about 52 weeks, about 1 week to about 60 weeks, about 4 weeks to about 8 weeks, about 4 weeks to about 16 weeks, about 4 weeks to about 24 weeks, about 4 weeks to about 40 weeks, about 4 weeks to about 52 weeks, about 4 weeks to about 72 weeks, about 8 weeks to about 16 weeks, About 8 weeks to about 24 weeks, about 8 weeks to about 36 weeks, about 8 weeks to about 48 weeks, about 8 weeks to about 60 weeks, about 12 weeks to about 20 weeks, about 12 weeks to about 28 weeks, about 12 weeks to about 40 weeks, about 12 weeks to about 52 weeks, about 12 weeks to about 72 weeks, about 16 weeks to about 24 weeks, about 16 weeks to about 36 weeks, about 16 weeks to about 48 weeks, about 16 weeks to about 60 weeks, about 20 weeks to about 28 weeks, about 20 weeks to about 40 weeks, about 20 weeks to about 52 weeks, about 20 weeks to about 72 weeks, about 24 weeks to about 36 weeks, about 24 weeks to about 48 weeks, about 24 weeks about 52 to about 72 weeks, about 60 to about 72 weeks, about 28 to about 40 weeks, about 28 to about 52 weeks, about 28 to about 72 weeks, about 36 to about 48 weeks, about 36 to about 60 weeks, about 40 to about 44 weeks, about 40 to about 52 weeks, about 40 to about 72 weeks, about 44 to about 52 weeks, about 44 to about 72 weeks, about 48 to about 60 weeks, about 52 to about 72 weeks, or about 60 to about 72 weeks of administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof, / L, about 50 U / L to about 125 U / L, about 50 U / L to about 75 U / L, about 75 U / L to about 175 U / L, about 75 U / L to about 150 U / L, about 75 U / L to about 125 U / L, about 75 U / L to about 100 U / L, about 100 U / L to about 175 U / L, about 100 U / L to about 150 U / L, about 100 U / L to about 125 U / L, or about 150 U / L to about 175 U / L. For example, ALT levels can be reduced by about 50%, about 60%, or about 70% after administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof.

[0102] In some embodiments, after administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof, the subject exhibits a reduction in serum blood urea nitrogen (BUN). In some embodiments, BUN levels are reduced from baseline by about 0.5 mg / dL to about 5.0 mg / dL, about 1 mg / dL to about 5.0 mg / dL, about 1.5 mg / dL to about 5.0 mg / dL, or about 2.0 mg / dL to about 5.0 mg / dL after administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof for at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, at least 44 weeks, at least 48 weeks, etc. For example, BUN levels can be reduced by about 50%, about 60%, or about 70% after administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof for at least 24 weeks.

[0103] In some embodiments, BUN levels are measured over a period of about 1 week to about 72 weeks (e.g., about 1 week to about 4 weeks, about 1 week to about 8 weeks, about 1 week to about 12 weeks, about 1 week to about 16 weeks, about 1 week to about 20 weeks, about 1 week to about 24 weeks, about 1 week to about 36 weeks, about 1 week to about 40 weeks, about 1 week to about 48 weeks, about 1 week to about 52 weeks, about 1 week to about 60 weeks, about 4 weeks to about 8 weeks, about 4 weeks to about 16 weeks, about 4 weeks to about 24 weeks, about 4 weeks to about 40 weeks, about 4 weeks to about 52 weeks, about 4 weeks to about 72 weeks, about 8 weeks to about 16 weeks, about 8 weeks to about 24 weeks, about 8 weeks to about 36 weeks, About 8 weeks to about 48 weeks, about 8 weeks to about 60 weeks, about 12 weeks to about 20 weeks, about 12 weeks to about 28 weeks, about 12 weeks to about 40 weeks, about 12 weeks to about 52 weeks, about 12 weeks to about 72 weeks, about 16 weeks to about 24 weeks, about 16 weeks to about 36 weeks, about 16 weeks to about 48 weeks, about 16 weeks to about 60 weeks, about 20 weeks to about 28 weeks, about 20 weeks to about 40 weeks, about 20 weeks to about 52 weeks, about 20 weeks to about 72 weeks, about 24 weeks to about 36 weeks, about 24 weeks to about 48 weeks, about 24 weeks to about 60 weeks, about 28 weeks to about 40 weeks, about 28 weeks to about 52 weeks, about 28 weeks to about 72 weeks, After administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof for about 36 weeks to about 48 weeks, about 36 weeks to about 60 weeks, about 40 weeks to about 44 weeks, about 40 weeks to about 52 weeks, about 40 weeks to about 72 weeks, about 44 weeks to about 52 weeks, about 44 weeks to about 72 weeks, about 48 weeks to about 60 weeks, about 52 weeks to about 72 weeks, or about 60 weeks to about 72 weeks, a change in serum cholesterol level from baseline of about 0.5 mg / dL to about 5.0 mg / dL, about 0.5 mg / dL to about 4.0 mg / dL, about 0.5 mg / dL to about 3.0 mg / dL, about 0.5 mg / dL to about 2.0 mg / dL, about 0.5 mg / dL to about 1.0 mg / dL .5mg / dL, about 1.0mg / dL to about 5.0mg / dL, about 1.0mg / dL to about 4.0mg / dL, about 1.0mg / dL to about 3.0mg / dL, about 1.0mg / dL to about 2.0mg / dL, about 1.0mg / dL to about 1.5mg / dL, about 1.5mg / dL to about 5.0mg / dL dL, about 1.5 mg / dL to about 4.0 mg / dL, about 1.5 mg / dL to about 3.0 mg / dL, about 1.5 mg / dL to about 2.0 mg / dL, about 2.0 mg / dL to about 5.0 mg / dL, about 2.0 mg / dL to about 4.0 mg / dL, about 2.0 mg / dL to about 3.0 mg / dL, about 3.The BUN level may be reduced by about 0 mg / dL to about 5.0 mg / dL, about 3.0 mg / dL to about 4.0 mg / dL, or 4.0 mg / dL to about 5.0 mg / dL. For example, the BUN level may be reduced by about 50%, about 60%, or about 70% after administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof for at least 24 weeks.

[0104] In some embodiments, after administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof, the subject exhibits a reduction in urinary neutrophil gelatinase-associated lipocalin (NGAL). In some embodiments, the subject exhibits a reduction in urinary NGAL of between about 5% and about 100%, e.g., between about 10% and about 100%, between about 15% and about 100%, between about 25% and about 100%, between about 50% and about 100%, between about 75% and about 100%, between about 10% and about 75%, between about 25% and about 75%, or between about 50% and about 75%. In some embodiments, the subject exhibits a reduction in urinary NGAL of at least about 50% (e.g., 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%; or at least about 95%). In some embodiments, the subject exhibits a reduction in urinary NGAL of at least about 60%, at least about 70%, at least about 80%, or at least about 90%. In some embodiments, the subject exhibits a reduction in urinary NGAL of at least about 60%, at least about 70%, at least about 80%, or at least about 90%.

[0105] In some embodiments, after administration of an ASBT inhibitor or a pharmaceutically acceptable salt thereof, the subject exhibits a reduction in urinary kidney injury molecule-1 (KIM-1). In some embodiments, the subject exhibits a reduction in urinary KIM-1 of between about 5% and about 100%, e.g., between about 10% and about 100%, between about 15% and about 100%, between about 25% and about 100%, between about 50% and about 100%, between about 75% and about 100%, between about 10% and about 75%, between about 25% and about 75%, or between about 50% and about 75%. In some embodiments, the subject exhibits a reduction in urinary KIM-1 of at least 50% (e.g., at least 55%; at least 60%; at least 65%; at least 70%; at least 75%; at least 80%; at least 85%; at least 90%; or at least 95%). In some embodiments, the subject exhibits a reduction in urinary KIM-1 of at least 60%, at least 70%, at least 80%, or at least 90%. In some embodiments, the subject exhibits a reduction in urinary KIM-1 of about 60%, about 70%, about 80%, or about 90%.

[0106] In some embodiments, the ASBT inhibitor is administered orally. Because ASBT is primarily expressed in the ileum (often referred to as IBAT in the ileum), ASBT inhibitors do not need to be systemically absorbable. In fact, the systemic absorption of most known ASBT inhibitors is low, e.g., less than 10%. However, because ASBT is also expressed in proximal tubule cells in the kidney, systemically absorbable ASBT inhibitors may also inhibit renal bile acid reuptake. This may increase urinary bile acid levels and enhance bile acid removal from the body via urine. Therefore, systemically absorbable ASBT inhibitors that exert their effects not only in the ileum but also in the kidney are predicted to lead to greater reductions in bile acid levels than non-systemically absorbed ASBT inhibitors that exert their effects only in the ileum. Therefore, targeting ASBT in the kidney may be an alternative or additional means of increasing bile acid excretion and reducing bile acid load in serum, the liver, and the kidney. Thus, in some embodiments, the ASBT inhibitor is systemically absorbable. In some embodiments, the systemic absorption of the ASBT inhibitor is between about 10% and about 100%, e.g., between about 10% and about 75%, between about 10% and about 50%, between about 10% and about 25%, between about 25% and about 100%, between about 25% and about 75%, between about 25% and about 50%, between about 50% and about 100%, between about 50% and about 75%, or between about 75% and about 100%. In some embodiments, the systemic absorption of the ASBT inhibitor is greater than about 10%, e.g., greater than about 15%, e.g., greater than about 20%, e.g., greater than about 25%, or e.g., greater than about 30%. In some embodiments, the systemic absorption of the ASBT inhibitor is about 10%, about 15%, about 20%, about 25%, about 30%, about 40%, or about 50% or more.

[0107] In some embodiments, the ASBT inhibitor is administered subcutaneously. It has been found that subcutaneous administration of ASBT inhibitors can result in high bioavailability with consistent exposure lasting for more than 24 hours. Therefore, subcutaneous administration of ASBT inhibitors can result in bile acid regulation effects that are different from, and possibly longer-lasting than, oral administration of ASBT inhibitors. Such effects can be useful for treating diseases that require stronger inhibition of bile acid circulation or when oral administration may not be beneficial (i.e., when bile flow is blocked).

[0108] In some embodiments, oral administration of an ASBT inhibitor is combined with subcutaneous administration of an ASBT inhibitor. Such combined treatment may have additive or synergistic effects and may result in greater excretion of bile acids. Examples of non-systemically absorbed ASBT inhibitors include, but are not limited to, elobixibat, odebixibat, maralixibat, vorixibat, and linelixibat. These ASBT inhibitors have a systemic absorption rate of less than 10% after oral administration. Further examples of suitable ASBT inhibitors are disclosed, for example, in WO 2019 / 234077, WO 2020 / 161216, WO 2020 / 161217, WO 2021 / 110884, WO 2021 / 110885, WO 2021 / 110886, WO 2021 / 110887, and WO 2022 / 029101.

[0109] In some embodiments, a patient does not respond to treatment with an orally administered, non-systemically absorbed ASBT inhibitor. Because subcutaneous administration of an ASBT inhibitor leads to modulation of ASBT in the kidney, it is believed that subcutaneous administration of an ASBT inhibitor may result in a more potent ASBT-modulating effect than oral administration of the compound.

[0110] In some embodiments, for example, if a patient experiences severe side effects such as severe diarrhea, the patient cannot tolerate treatment with an orally administered non-systemically absorbed ASBT inhibitor. Subcutaneous administration of an ASBT inhibitor also regulates ASBT in the kidney, so that bile acids are excreted not only in feces but also in urine. This is expected to reduce the incidence of diarrhea.

[0111] Also provided herein is a method for treating a kidney disease or disorder as defined herein in a subject, the method comprising administering to the subject a therapeutically effective amount of an ASBT inhibitor (e.g., any of the ASBT inhibitors described herein) or a pharmaceutically acceptable salt thereof. Also provided herein is the use of an ASBT inhibitor (e.g., any of the ASBT inhibitors described herein) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a kidney disease or disorder as defined herein. In some embodiments, the kidney disease or disorder is selected from the group consisting of bile vascular nephropathy, chronic nephropathy, hyperbilirubinemia, obstructive jaundice renal dysfunction, age-related impairment of mitochondrial function in the kidney, kidney inflammation, acute kidney injury (AKI), renal ischemia / reperfusion injury (IRI), chronic kidney disease (CKD), chronic renal failure, end-stage renal disease (ESRD), proximal tubule injury in the kidney, type 1 hepatorenal syndrome, type 2 hepatorenal syndrome, and acute exacerbation of chronic liver disease.

[0112] Combination therapy In one aspect of the present invention, an ASBT inhibitor or a pharmaceutically acceptable salt thereof is administered in combination with at least one other therapeutically active agent, for example, one, two, three, or more other therapeutically active agents. The ASBT inhibitor or a pharmaceutically acceptable salt thereof and the at least one other therapeutically active agent may be administered simultaneously, sequentially, or separately. Therapeutic active agents suitable for combination with an ASBT inhibitor include, but are not limited to, known active agents useful in treating any of the diseases and disorders discussed herein.

[0113] In one embodiment, the ASBT inhibitor or a pharmaceutically acceptable salt thereof is administered in combination with another ASBT inhibitor. Suitable ASBT inhibitors are described in WO 93 / 16055, WO 94 / 18183, WO 94 / 18184, WO 96 / 05188, WO 96 / 08484, WO 96 / 16051, WO 97 / 33882, WO 98 / 03818, WO 98 / 07449, WO 98 / 40375, WO 99 / 35135, WO 99 / 64409, WO 99 / 64410, WO 00 / 01687, 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 / 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.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 (odevixibat), 1-{[4-({4-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-1λ. 6 -benzothiepin-5-yl]phenoxy}methyl)phenyl]methyl}-1,4-diazabicyclo[2.2.2]octan-1-ium chloride (malalixibat), N-(3-O-benzyl-6-O-sulfo-β-D-glucopyranosyl)-N'-{3-[(3S,4R,5R)-3-butyl-7-(dimethylamino)-3-ethyl-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-1λ 6 -benzothiepin-5-yl]phenyl}urea (borixibat) and 3-({[(3R,5R)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1λ 6 ,4-benzothiazepin-8-yl]methyl}amino)pentanedioic acid (linelixibat).

[0114] Some ASBT inhibitors may exhibit a higher plasma free fraction, hi some embodiments, the free fraction is from about 0% to about 100%, e.g., from about 0% to about 75%, from about 0% to about 50%, from about 0% to about 25%, from about 0% to about 10%, or from about 0% to about 5%. In some embodiments, the free fraction is about 0.1% to about 100%, e.g., about 0.1% to about 75%, about 0.1% to about 50%, about 0.1% to about 25%, about 0.1% to about 15%, about 0.1% to about 10%, about 0.1% to about 5%, about 0.1% to about 1%, about 1% to about 100%, about 1% to about 75%, about 1% to about 50%, about 1% to about 25%, about 1% to about 15%, about 1% to about 10%, about 1% to about 5%, or about 5% to about 1. 00%, about 5% to about 75%, about 5% to about 50%, about 5% to about 25%, about 5% to about 15%, about 5% to about 10%, about 10% to about 100%, about 10% to about 75%, about 10% to about 50%, about 10% to about 25%, about 10% to about 15%, about 15% to about 100%, about 15% to about 75%, about 15% to about 50%, about 15% to about 25%, about 25% to about 100%, about 25% to about 75%, or about 25% to about 50%. 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%, such as greater than about 0.8%, for example greater than about 1.0%, such as greater than about 1.25%, for example greater than about 1.5%, such as greater than about 1.75%, for example greater than about 2.0%, such as greater than about 2.5%, for example greater than about 3%, such as greater than about 4%, for example greater than about 5%, such as greater than about 7.5%, for example greater than about 10%, or such as greater than about 20%.

[0115] Some ASBT inhibitors may be excreted in urine, in some embodiments, the fraction of the compound excreted in urine is between about 0% and about 100%, or, for example, between about 0% and about 75%, between about 0% and about 50%, between about 0% and up to about 25%, between about 0% and up to about 10%, or between about 0% and up to about 5%. In some embodiments, the fraction of the compound excreted in urine is between about 0.1% and about 100%, e.g., between about 0.1% and about 75%, between about 0.1% and about 50%, between about 0.1% and about 25%, between about 0.1% and about 15%, between about 0.1% and about 10%, between about 0.1% and about 5%, between about 0.1% and about 1%, between about 1% and about 100%, between about 1% and about 75%, between about 1% and about 50%, between about 1% and about 25%, between about 1% and about 15%, between about 1% and about 10%, between about 1% and about 5%, between about 5% to about 100%, about 5% to about 75%, about 5% to about 50%, about 5% to about 25%, about 5% to about 15%, about 5% to about 10%, about 10% to about 100%, about 10% to about 75%, about 10% to about 50%, about 10% to about 25%, about 10% to about 15%, about 15% to about 100%, about 15% to about 75%, about 15% to about 50%, about 15% to about 25%, about 25% to about 100%, about 25% to about 75%, or about 25% to about 50%. In some embodiments, the fraction of the compound excreted in the urine 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 2%, for example greater than about 3%, for example greater than about 5%, for example greater than about 7.5%, 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%.

[0116] After absorption from the intestine, some ASBT inhibitors may circulate via the enterohepatic circulation. In some embodiments, the fraction of the compound circulating via the enterohepatic circulation is about 0% to about 100%, e.g., about 0% to about 75%, about 0% to about 50%, about 0% to up to about 25%, about 0% to up to about 10%, or about 0% to up to about 5%. In some embodiments, the fraction of a compound circulating via the enterohepatic circulation is between about 0.1% and about 100%, e.g., between about 0.1% and about 75%, between about 0.1% and about 50%, between about 0.1% and about 25%, between about 0.1% and about 15%, between about 0.1% and about 10%, between about 0.1% and about 5%, between about 0.1% and about 1%, between about 1% and about 100%, between about 1% and about 75%, between about 1% and about 50%, between about 1% and about 25%, between about 1% and about 15%, between about 1% and about 10%, between about 1% and about 5%. , about 5% to about 100%, about 5% to about 75%, about 5% to about 50%, about 5% to about 25%, about 5% to about 15%, about 5% to about 10%, about 10% to about 100%, about 10% to about 75%, about 10% to about 50%, about 10% to about 25%, about 10% to about 15%, about 15% to about 100%, about 15% to about 75%, about 15% to about 50%, about 15% to about 25%, about 25% to about 100%, about 25% to about 75%, or about 25% to about 50%. In some embodiments, the fraction of the compound that circulates via 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%, such as greater than about 1.0%, for example greater than about 1.5%, such as greater than about 2%, for example greater than about 3%, for example greater than about 5%, such as greater than about 7%, for example greater than about 10%, such as greater than about 15%, for example greater than about 20%, for example greater than about 30%, or for example greater than about 50%.

[0117] Some ASBT inhibitors can cause renal excretion of bile salts. In some embodiments, the fraction of circulating bile acids excreted via the renal pathway is between about 0% and about 100%, e.g., between about 0% and about 75%, between about 0% and about 50%, between about 0% and up to about 25%, between about 0% and up to about 10%, or between about 0% and up to about 5%. In some embodiments, the fraction of circulating bile acids excreted via the renal pathway is between about 0.1% and about 100%, e.g., between about 0.1% and about 75%, between about 0.1% and about 50%, between about 0.1% and about 25%, between about 0.1% and about 15%, between about 0.1% and about 10%, between about 0.1% and about 5%, between about 0.1% and about 1%, between about 1% and about 100%, between about 1% and about 75%, between about 1% and about 50%, between about 1% and about 25%, between about 1% and about 15%, between about 1% and about 10%, between about 1% and about 5 %, about 5% to about 100%, about 5% to about 75%, about 5% to about 50%, about 5% to about 25%, about 5% to about 15%, about 5% to about 10%, about 10% to about 100%, about 10% to about 75%, about 10% to about 50%, about 10% to about 25%, about 10% to about 15%, about 15% to about 100%, about 15% to about 75%, about 15% to about 50%, about 15% to about 25%, about 25% to about 100%, about 25% to about 75%, or about 25% to about 50%. In some embodiments, the fraction of circulating bile acids excreted via the renal pathway is greater than about 1%, such as greater than about 2%, such as greater than about 5%, such as greater than about 7%, such as greater than about 10%, such as greater than about 15%, such as greater than about 20%, or such as greater than about 25%.

[0118] Some ASBT inhibitors may exhibit improved or optimal permeability. Permeability may be measured in Caco2 cells, with values ​​expressed as Papp (apparent permeability) values ​​in cm / s. In some embodiments, the permeability is about 0.01 x 10 -6 cm / s~approx. 50×10 -6 cm / s, e.g., about 0.05 × 10 -6 cm / s ~ approx. 40×10 -6 cm / s, or for example, about 0.1×10 -6 cm / s ~ approx. 30×10 -6 In some embodiments, the permeability is at least about 0.1×10 cm / s. -6cm / 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 greater than cm / s.

[0119] Some ASBT inhibitors may exhibit improved or optimal oral bioavailability, such as from about 0% to about 100%, for example, from about 1% to about 100%, from about 1% to about 90%, from about 1% to about 80%, from about 1% to about 75%, from about 1% to about 60%, from about 1% to about 50%, from about 1% to about 40%, from about 1% to about 30%, from about 1% to about 20%, from about 1% to about 10%, from about 2% to about 50%, from about 10% to about 100%, from about 10% to about 90%, or from about 10% to approximately 80%, approximately 10% to approximately 75%, approximately 10% to approximately 60%, approximately 10% to approximately 50%, approximately 10% to approximately 40%, approximately 10% to approximately 30%, approximately 10% to approximately 20%, approximately 20% to approximately 100%, approximately 20% to approximately 90%, approximately 20% to approximately 80%, approximately 20% to approximately 75%, approximately 20% to approximately 60%, approximately 20% to approximately 50%, approximately 20% to approximately 40%, approximately 20% to approximately 30% , about 30% to about 100%, about 30% to about 90%, about 30% to about 80%, about 30% to about 75%, about 30% to about 60%, about 30% to about 50%, about 30% to about 40%, about 40% to about 100%, about 40% to about 90%, about 40% to about 80%, about 40% to about 75%, about 40% to about 60%, about 40% to about 50%, about 50% to about 100%, about 50% In some embodiments, the oral bioavailability may be greater than about 5%, such as greater than about 7%, such as greater than about 10%, such as greater than about 15%, such as greater than about 20%, such as greater than about 30%, such as greater than about 40%, such as greater than about 50%, such as greater than about 60%, such as greater than about 70%, or such as greater than about 80%. In other embodiments, the oral bioavailability is between about 10 and about 90%, such as between about 20 and about 80%, such as between about 30 and about 70%, or such as between about 40 and about 60%.

[0120] formulation The ASBT inhibitor may be administered as a pharmaceutical composition comprising a therapeutically effective amount of the ASBT inhibitor or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. Generally, the pharmaceutical composition may be prepared in a conventional manner using conventional excipients. The pharmaceutical composition may be in a form suitable for oral administration, parenteral injection (including intravenous, subcutaneous, intramuscular, and intravascular injections), topical administration, or rectal administration.

[0121] In some embodiments, the pharmaceutical composition may be in a form suitable for oral administration, such as a tablet or capsule. Such formulations may include excipients, such as fillers, binders, disintegrants, glidants, and lubricants, in addition to the ASBT inhibitor.

[0122] Examples of suitable fillers include, but are not limited to, calcium hydrogen phosphate dihydrate, calcium sulfate, lactose (e.g., lactose monohydrate), sucrose, mannitol, sorbitol, cellulose, microcrystalline cellulose, dry starch, hydrolyzed starch, and pregelatinized starch.

[0123] Examples of suitable binders include, but are not limited to, starch, pregelatinized starch, gelatin, sugars (e.g., sucrose, glucose, dextrose, lactose, and sorbitol), polyethylene glycol, waxes, natural and synthetic gums (e.g., gum acacia and gum tragacanth), sodium alginate, cellulose derivatives (e.g., hydroxypropylmethylcellulose (or hypromellose), hydroxypropylcellulose, and ethylcellulose), and synthetic polymers (e.g., acrylic and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, aminoalkyl methacrylate copolymers, polyacrylic acid / methacrylic acid copolymers, and polyvinylpyrrolidone (povidone)).

[0124] Examples of suitable disintegrants include, but are not limited to, dry starch, modified starches (e.g., (partially) pregelatinized starch, sodium starch glycolate, and sodium carboxymethyl starch), alginic acid, cellulose derivatives (e.g., sodium carboxymethylcellulose, hydroxypropylcellulose, and low-substituted hydroxypropylcellulose (L-HPC)), and cross-linked polymers (e.g., carmellose, croscarmellose sodium, carmellose calcium, and cross-linked PVP (crospovidone)).

[0125] Suitable examples of 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 (e.g., carnauba wax), hydrogenated oils, polyethylene glycol, sodium benzoate, polyethylene glycol, and mineral oil.

[0126] The pharmaceutical composition may be conventionally coated with one or more coating layers. Enteric coating layers, or coating layers for delayed or targeted release of the compound of formula (I) or a pharmaceutically acceptable salt thereof, are also contemplated. The coating layer may comprise one or more coating agents, and may optionally comprise a plasticizer and / or a pigment (e.g., a colorant).

[0127] Examples of suitable coating agents include, but are not limited to, cellulosic polymers (e.g., ethyl cellulose, hydroxypropyl methylcellulose (or hypromellose), hydroxypropyl cellulose, cellulose acetate phthalate, cellulose acetate succinate, hydroxypropyl methylcellulose acetate succinate, and hydroxypropyl methylcellulose phthalate), vinyl polymers (e.g., polyvinyl alcohol), and acrylic acid-based polymers and their derivatives (e.g., acrylic acid and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, aminoalkyl methacrylate copolymers, polyacrylic acid / methacrylic acid copolymers).

[0128] 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, polyethylene glycol.

[0129] Examples of suitable pigments include, but are not limited to, titanium dioxide, iron oxide (eg, yellow, brown, red, or black iron oxide), and barium sulfate.

[0130] In some embodiments, the pharmaceutical composition may be in a form suitable for parenteral administration (e.g., subcutaneous administration), such as a liquid (aqueous) formulation. Such formulations may include, in addition to the ASBT inhibitor, solubilizing and stabilizing excipients, such as salts (e.g., saline), buffers, surfactants, cosolvents, antioxidants, and preservatives.

[0131] Buffering agents can include salts such as phosphate, citrate, acetate, gluconate, lactate, tartrate, aspartate, glutamate, and phthalate, or their corresponding acid forms, as well as histidine or tris(tris(hydroxymethyl)aminomethane). The pH of the liquid formulation is in the range of about 4 to about 9, more preferably in the range of about 5 to about 8, and even more preferably in the range of about 6 to about 7.

[0132] The surfactant may be a cationic surfactant, anionic surfactant, or nonionic surfactant. Examples of cationic surfactants include, but are not limited to, cetyltrimethylammonium bromide (cetrimonium bromide) and cetylpyridinium chloride. Examples of anionic surfactants include, but are not limited to, sodium dodecyl sulfate (sodium lauryl sulfate) and ammonium dodecyl sulfate (ammonium lauryl sulfate). Examples of nonionic surfactants include, but are not limited to, glycerol monooleate, glycerol monostearate, polyoxyl castor oil (Cremophor EL), poloxamers (e.g., poloxamer 407 or 188), polysorbate 80, and sorbitan esters (Tween). In a preferred embodiment, the surfactant is a cationic surfactant.

[0133] Examples of suitable co-solvents include, but are not limited to, ethanol, propylene glycol, polyethylene glycol 400 (PEG400), N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), and N,N-dimethylacetamide (DMA).

[0134] Examples of suitable antioxidants include, but are not limited to, butylhydroxytoluene (BHT), ascorbyl palmitate, propyl gallate, and ascorbic acid, and combinations thereof.

[0135] Examples of suitable preservatives include, but are not limited to, phenol, benzyl alcohol, methylparaben, ethylparaben, propylparaben, ethylenediaminetetraacetic acid (EDTA), potassium sorbate, and sodium benzoate, and combinations thereof.

[0136] In some embodiments, the concentration of the ASBT inhibitor in the liquid formulation is about 0.001 to about 30 mg / mL. In some embodiments, the concentration of the ASBT inhibitor in the liquid formulation is about 0.01 to about 10 mg / mL, e.g., about 0.01 to about 5 mg / mL, about 0.01 to about 2 mg / mL, about 0.01 to about 1.5 mg / mL, about 0.01 to about 1.0 mg / mL, about 1 to about 10 mg / mL, about 1 to about 5 mg / mL, about 1 to about 2 mg / mL, about 1 to about 1.5 mg / mL, about 2 to about 10 mg / mL, about 2 to about 5 mg / mL, about 5 to about 10 mg / mL, or for example, about 10 to about 30 mg / mL, e.g., about 10 to about 20 mg / mL, or for example, about 20 to about 30 mg / mL. In some embodiments, the concentration of the ASBT inhibitor in the liquid formulation is about 0.2 mg / mL, about 0.3 mg / mL, about 0.4 mg / mL, about 0.5 mg / mL, about 0.6 mg / mL, about 0.7 mg / mL, about 0.8 mg / mL, about 0.9 mg / mL, about 1.0 mg / mL, about 1.2 mg / mL, about 1.4 mg / mL, about 1.6 mg / mL, about 1.8 mg / mL, or about 2.0 mg / mL.

[0137] In some embodiments, the pharmaceutical composition optionally comprises one or more additional therapeutic agents described herein.

[0138] Dosage and frequency of administration The dosage required for therapeutic or prophylactic treatment will depend on the route of administration, the severity of the disease, the age and weight of the patient, and other factors normally considered by the attending physician when determining the appropriate regimen and dosage level for a particular patient.

[0139] The amount of ASBT inhibitor administered will vary depending on the patient being treated and can range from about 1 μg / kg to about 50 mg / kg of body weight per day. In some embodiments, patients receive from about 1 μg / kg / day to about 50 mg / kg / day of an ASBT inhibitor or a pharmaceutically acceptable salt thereof, e.g., from about 1 μg / kg / day to about 25 mg / kg / day, from about 1 μg / kg / day to about 10 mg / kg / day, from about 1 μg / kg / day to about 5 mg / kg / day, from about 1 μg / kg / day to about 1 mg / kg / day, from about 1 μg / kg / day to about 800 μg / kg / day, from about 1 μg / kg / day to about 400 μg / kg / day, from about 1 μg / kg / day to about 200 μg / kg / day, from about 1 μg / kg / day to about 160 μg / kg / day, Approximately 1μg / kg / day to approximately 140μg / kg / day, approximately 1μg / kg / day to approximately 120μg / kg / day, approximately 1μg / kg / day to approximately 100μg / kg / day, approximately 1μg / kg / day to approximately 75μg / kg / day, approximately 1μg / kg / day to approximately 50μg / kg / day, approximately 1μg / kg / day ~ approx. 25 μg / kg / day, approx. 1 μg / kg / day ~ approx. 10 μg / kg / day, approx. 50 μg / kg / day ~ approx. 50 mg / kg / day, approx. 50 μg / kg / day ~ approx. 25 mg / kg / day, approx. / kg / day, about 50μg / kg / day to about 1mg / kg / day, about 50μg / kg / day to about 800μg / kg / day, about 50μg / kg / day to about 400μg / kg / day, about 50μg / kg / day to about 200μg / kg / day, about 50μg / kg / day to about 160μg / k g / day, about 50μg / kg / day to about 140μg / kg / day, about 50μg / kg / day to about 120μg / kg / day, about 50μg / kg / day to about 100μg / kg / day, about 50μg / kg / day to about 75μg / kg / day, about 200μg / kg / day to about 50mg / kg / day day, about 200μg / kg / day to about 25mg / kg / day, about 200μg / kg / day to about 10mg / kg / day, about 200μg / kg / day to about 5mg / kg / day, about 200μg / kg / day to about 1mg / kg / day, about 200μg / kg / day to about 800μg / kg / day , about 200μg / kg / day to about 400μg / kg / day, about 400μg / kg / day to about 50mg / kg / day, about 400μg / kg / day to about 25mg / kg / day, about 400μg / kg / day to about 10mg / kg / day, about 400μg / kg / day to about 5mg / kg / day,About 400 μg / kg / day to about 1 mg / kg / day, about 400 μg / kg / day to about 800 μg / kg / day, about 800 μg / kg / day to about 50 mg / kg / day, about 800 μg / kg / day to about 25 mg / kg / day, about 800 μg / kg / day to about 10 mg / kg / day, about 800 μg / kg / day to about 5 mg / kg / day, about 800 μg / kg / day to about 1 mg / kg / day, about 5 mg / kg / day to about 50 mg / kg / day, about 5 mg / kg / day to about 25 mg / kg / day, or about 5 mg / kg / day to about 10 mg / kg / day of an ASBT inhibitor or a pharmaceutically acceptable salt thereof is administered.

[0140] A unit dosage form, for example a tablet or capsule, typically contains about 0.1 to about 250 mg, for example, about 0.1 to about 150 mg, about 0.1 to about 100 mg, about 0.1 to about 75 mg, about 0.1 to about 50 mg, about 0.1 to about 20 mg, for example, about 0.2 mg, about 0.4 mg, about 0.6 mg, about 1.2 mg, about 2.5 mg, about 5 mg, about 10 mg, or about 15 mg of the active ingredient. In some embodiments, the unit dosage form, for example a tablet or capsule, contains about 10 mg to about 250 mg, 10 mg to about 200 mg, 10 mg to about 150 mg, 10 mg to about 100 mg, 10 mg to about 100 mg, 10 mg to about 75 mg, 10 mg to about 50 mg, about 50 mg to about 250 mg, 50 mg to about 200 mg, 50 mg to about 150 mg, 50 mg to about 100 mg, 5 ...50 mg, 50 mg to about 150 mg, 50 mg to about 100 mg, 50 mg to about 75 mg, 10 mg to about 50 mg, about 50 mg to about 250 mg, 50 mg to about 250 mg, 50 mg to about 150 mg, 50 mg to about 100 mg, 50 mg to about Contains about 100 mg, 50 mg to about 75 mg, about 75 mg to about 250 mg, 75 mg to about 200 mg, 75 mg to about 150 mg, 75 mg to about 100 mg, 75 mg to about 100 mg, about 100 mg to about 250 mg, 100 mg to about 200 mg, 100 mg to about 150 mg, about 150 mg to about 250 mg, 150 mg to about 200 mg, or about 200 mg to about 250 mg. The daily dose can be administered as a single dose or can be divided into 1, 2, 3, or more unit doses. The daily oral dose of the bile acid modifying agent is preferably within about 0.1 to about 250 mg, more preferably within about 0.1 to about 100 mg, for example, about 0.1 to about 20 mg, about 0.1 to about 15 mg, about 0.1 to about 10 mg, about 0.1 to about 9 mg, about 0.1 to about 8 mg, about 1 to about 7 mg, about 1 to about 6 mg, about 0.1 to about 5 mg, about 0.1 to about 4 mg, about 0.1 to about 3 mg, about 0.1 to about 2 mg, about 0.1 to about 1 mg, about 1 to about 10 mg, about 1 to about 9 mg, about 1 to about 8 mg, about 1 to about 7 mg, about 1 to about 6 mg, about 1 to about 5 mg, about 1 to about 4 mg, about 1 to about 3 mg, about 1 to about 2 mg, about 2 to about 5 mg, about 2 to about 8 mg, about 2 to about 10 mg, about 5 to about 10 mg, about 5 to about 8 mg, or about 8 to about 10 mg.

[0141] As used herein, the terms "treatment," "treat," and "treating" refer to the regression, alleviation, delay in 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 predisposing factors) before the onset of symptoms. Treatment may also be continued after symptoms have resolved, e.g., to prevent or delay their recurrence.

[0142] As used herein, the terms "subject," "individual," and "patient" are used interchangeably and refer to any animal, including mammals, e.g., mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, primates, and humans. In some embodiments, the subject is a human.

[0143] As used herein, the term "baseline" refers to information obtained before the first administration of the drug or intervention of interest (e.g., at the beginning of a study), or an initial known value used to compare with later data. The baseline value is taken at time "zero" (i.e., before subjects in the study receive the drug or intervention of interest or placebo).

[0144] As used herein, the term "normalized" refers to an age-specific value that is within the range corresponding to healthy individuals (ie, a normal or normalized value).

[0145] As used herein, the term "about" refers to a value or parameter herein, 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 defining the range. In general, the term "about" refers to the value recited by the variable, to any value within 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. [Example]

[0146] ASBT inhibitor compounds 1-5 were used in the experiments described herein. The potency of these compounds (hIBAT IC 50 ), permeability and bioavailability are shown in Table 1 below. Values ​​were determined using assays described, for example, in WO 2020 / 161217.

[0147] [Table 1]

[0148] Example 1 A mouse model of biliary nephropathy - Bile duct ligation (BDL) in mice Time-resolved events in the liver and kidney were assessed after ligation of the extrahepatic common bile duct.

[0149] Male mice (C57BL / 6n) were used. After completing the quarantine and acclimation period, animals were randomly assigned to experimental groups based on body weight (n = 5 mice per group and time point). On day 0, animals underwent bile duct ligation or sham surgery. After 1 or 3 days, or after 1, 3, 6, 9, or 12 weeks, animals were euthanized, and samples (bile, blood, urine, liver, and kidney tissue) were collected and analyzed.

[0150] BDL resulted in excessive bile accumulation in the gallbladder and increases in serum ALT and AST, which peaked on day 1 and then declined as the liver adapted to cholestasis but remained above control values ​​(Figure 1A and 1B). Alkaline phosphatase (ALP) enzyme activity showed a time-dependent increase after BDL (Figure 1C).

[0151] Analysis of bile acid transporter expression showed that ASBT was strongly downregulated after BDL. Figures 2A–D show compensatory changes in bile acid transporter expression 12 weeks after BDL or sham surgery. Figure 2A: sinusoidal uptake transporter NTCP; Figure 2B: sinusoidal uptake transporter Cyp7a1; Figure 2C: apical transporter Bsep; Figure 2D: sinusoidal efflux transporter MRP4. Figures 3A–E show the expression of the apical uptake transporter ASBT (Figure 3A) and apical uptake transporter OATP1a1 (Figure 3B), apical efflux transporter MRP4 (Figure 3C), and basolateral efflux transporters MRP3 (Figure 3D) and OSTα (Figure 3E) 12 weeks after BDL or sham surgery.

[0152] Similar studies were performed using female mice.

[0153] Example 2 Effect of ASBT inhibition in BDL mice The short-term effect of oral administration of Compound 1 to BDL mice on urinary excretion of bile acids was evaluated.

[0154] Female mice (C57BL / 6n) were used. After completing the quarantine and acclimation period, the animals were randomly assigned to experimental groups based on body weight (n = 4-7 mice each). On day 0, the animals underwent bile duct ligation. Starting on day 7, the animals were treated with vehicle or different doses of Compound 1 for 5 days, as shown in Table 2. Compound 1 was administered orally by gavage twice daily. Spontaneous urine samples were collected by bladder cannulation before BDL and on days 7, 8, 9, 10, 11, and 12 after BDL, and urinary bile acid concentrations were determined.

[0155] [Table 2]

[0156] Dose-dependent studies demonstrated a strong increase in urinary bile acids due to ASBT inhibition over the 5-day analysis period. Urinary excretion of bile acids increased dramatically after treatment with Compound 1, with bile acid concentrations at least approximately 20-fold higher in all treatment groups. The results are shown in Figure 4 (total concentrations of all bile acids) and Figures 5A-C (concentrations of the individual bile acids tauro-α / β-muricholic acid, taurocholic acid, and taurocholic acid sulfate, respectively).

[0157] Example 3 Effect of ASBT inhibition on bile duct-ligated mice with bile duct nephropathy The long-term effects of Compound 1 on kidney injury in BDL mice were examined by histology, clinical chemistry, and in vivo imaging.

[0158] Female mice (C57BL / 6n) were used. After completing the quarantine and acclimation period, animals were randomly assigned to experimental groups based on body weight (n = 15 mice per group). On day 0, animals underwent bile duct ligation or sham surgery. Animals were treated with vehicle or Compound 1 at a dose of 60 mg / kg, as shown in Table 3 below. Compound 1 was administered orally by gavage twice daily. Spontaneous urine samples were collected by bladder cannulation before BDL and on day 1 and weeks 1, 2, 3, 4, 5, and 6 after BDL. Blood, urine, bile, and tissue samples were collected at the end of the experiment (week 6).

[0159] [Table 3]

[0160] Severe tubular fibrosis and cystic dilatation were observed in BDL vehicle controls, which were antagonized by Compound 1 to levels close to those of control animals without BDL. Urinary kidney injury markers neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) were potently attenuated by Compound 1 (see Figures 13 and 14, respectively). In addition, serum BAs were reduced by approximately 90% (see Figure 6 for total bile acids and Figures 7–10 for individual bile acids), and urinary BAs were significantly increased. Intravital imaging using Evans blue demonstrated severe blood leakage in the kidney after BDL, which was completely reversed by Compound 1.

[0161] The levels of liver enzymes (ALT, AST and ALP), total bilirubin and blood urea nitrogen (BUN) after 6 weeks of treatment are shown in Figure 15. The expression of different bile acid transporters after 6 weeks of treatment is shown in Figures 16 and 17.

[0162] Approximately 50% of the mice in the BDL-vehicle group died during the 6-week period, while no deaths occurred in the group of BDL mice treated with Compound 1 (see Figure 12). ASBT inhibition also potently ameliorated BDL-induced weight loss (see Figure 11). A similarly designed study using male mice (6 per group) confirmed the therapeutic efficacy of Compound 1 observed in the female cohort.

[0163] Example 4 Examining treatment time windows The effect of a period prior to the initiation of treatment with Compound 1 on kidney injury in BDL mice was evaluated.

[0164] Male mice (C57BL / 6n) were used. After completion of the quarantine and acclimation period, the animals were randomly assigned to experimental groups based on body weight (n=7 mice per group). On day 0, the animals underwent bile duct ligation or sham surgery. Starting on days 3, 21, 42, or 63, as shown in Table 4 below, the animals were treated with either vehicle or Compound 1 at a dose of 60 mg / kg for 28 days. Compound 1 was administered p.o. twice daily. The animals were weighed daily. Blood, urine, bile, and tissue samples were collected at the end of the experiment.

[0165] [Table 4]

[0166] A plot of the survival rate (%) for the four groups is shown in Figure 18. A plot of the weight change (%) for the four groups after sham surgery or BDL is shown in Figure 19.

[0167] Four weeks of treatment with Compound 1 completely prevented kidney damage and reversed weight loss when dosing began on day 3. Compound 1 almost completely reversed kidney damage and reversed weight loss when dosing began on day 21. Compound 1 partially reversed kidney damage and reversed weight loss when dosing began on day 42. Compound 1 had minimal effect when dosing began on day 63.

[0168] Example 5 Comparison of different ASBT inhibitors Male mice (C57BL / 6n) were used. After completing the quarantine and acclimation period, the animals were randomly divided into experimental groups based on body weight (n=12 mice per bile duct ligation group, along with 5 sham-operated controls). On day 0, animals underwent bile duct ligation or sham surgery. Starting on day 3, animals were treated with vehicle or ASBT inhibitor for 19 days, as shown in Table 5 below. ASBT inhibitor was administered once daily p.o. Animals were weighed daily. On day 21, blood samples were collected 2 and 6 hours after the final dose. On day 24, animals were sacrificed, and samples (urine and blood; liver, kidney, heart, and spleen tissues) were collected and analyzed.

[0169] [Table 5]

[0170] Compounds 1 and 2 decreased serum bile acids and increased urinary bile acids after 19 days of treatment. The concentrations of total bile acids in blood and urine on day 21 (i.e., day 19 of treatment) are shown in Figures 20A and 20B, respectively. Compounds 1 and 2 also decreased urinary NGAL after 18 days of treatment. See Figure 21.

[0171] Example 6 Comparison of different ASBT inhibitors Male mice (C57BL / 6n) were used. After completing the quarantine and acclimation period, the animals were randomly assigned to experimental groups based on body weight (n = 10 mice per bile duct ligation group). On day 1, the animals underwent bile duct ligation. Starting on day 4, the animals were treated with vehicle or ASBT inhibitor for 5 days, as shown in Table 6 below. The ASBT inhibitor was administered p.o. once daily. The animals were weighed daily. On day 6, the animals were moved to individual cages for cumulative overnight fecal collection (days 6-7). On day 8, blood samples were collected 2 and 6 hours after the final dose. The animals were then sacrificed, and samples (urine and blood; liver, kidney, and ileum tissue) were collected and analyzed.

[0172] [Table 6]

[0173] For all compounds, a decrease in serum bile acids and an increase in urinary bile acids were observed after 5 days of treatment. The concentrations of total bile acids in blood and urine on day 8 (i.e., day 5 of treatment) are shown in Figures 22A and 22B, respectively. Compound X and Compound 5 significantly reduced urinary NGAL after 5 days of treatment. See Figure 23.

[0174] The concentrations of Compound X and Compound 5 in serum (ie, 2 and 6 hours post-dose) and urine (up to 6 hours post-dose) on day 8 are shown in Figures 24 and 25, respectively.

Claims

1. An ASBT inhibitor or a pharmaceutically acceptable salt thereof for use in the treatment of a kidney disease or disorder.

2. 2. The ASBT inhibitor for use according to claim 1, wherein the kidney disease or disorder is a bile acid-dependent kidney disease or disorder.

3. 2. The ASBT inhibitor for use according to claim 1, wherein the kidney disease or disorder is selected from the group consisting of bile vascular nephropathy, chronic nephropathy, hyperbilirubinemia, obstructive jaundice renal dysfunction, age-related disorders of mitochondrial function in the kidney, kidney inflammation, acute kidney injury (AKI), renal ischemia / reperfusion injury (IRI), chronic kidney disease (CKD), chronic renal failure, end-stage renal disease (ESRD), proximal tubule damage in the kidney, type 1 hepatorenal syndrome, type 2 hepatorenal syndrome, and acute exacerbation of chronic liver disease.

4. 2. The ASBT inhibitor for use according to claim 1, wherein the kidney disease or disorder is bile nephropathy.

5. 2. The ASBT inhibitor for use according to claim 1, which is (Z)-3-((3-butyl-3-ethyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl)oxy)-2-fluoroacrylic acid or a pharmaceutically acceptable salt thereof.

6. 2. The ASBT inhibitor or a pharmaceutically acceptable salt thereof for use according to claim 1, selected from the group consisting of elobixibat, odebixibat, maralixibat, vorixibat and linelixibat.

7. The ASBT inhibitor for use according to claim 1, which is administered orally.

8. 2. The ASBT inhibitor for use according to claim 1, wherein the systemic absorption of the ASBT inhibitor is greater than 10%.

9. 10. The ASBT inhibitor for use according to claim 1, which is administered subcutaneously.

10. 10. The ASBT inhibitor for use according to claim 8, wherein the patient is also receiving treatment with an orally administered, non-systemically absorbed ASBT inhibitor.

11. 10. The ASBT inhibitor for use according to claim 1, wherein the subject exhibits a reduction in serum bile acid concentration after administration of the ASBT inhibitor.

12. 12. The ASBT inhibitor for use according to claim 11, wherein the reduction in serum bile acid concentration is at least 60%, at least 70%, at least 80%, or at least 90% relative to baseline.

13. 12. The ASBT inhibitor for use according to claim 11, wherein serum bile acid levels are normalized after administration of the ASBT inhibitor.

14. 2. The ASBT inhibitor for use according to claim 1, wherein the subject exhibits an increase in urinary bile acids after administration of the ASBT inhibitor.

15. 15. The ASBT inhibitor for use according to claim 14, wherein the increase in urinary bile acids is at least 60%, at least 70%, at least 80%, or at least 90% over baseline.

16. 10. The ASBT inhibitor for use according to claim 1, wherein the subject shows improvement in liver parameters after administration of the ASBT inhibitor.

17. 17. The ASBT inhibitor for use according to claim 16, wherein the liver parameter is selected from the group consisting of serum total bilirubin level, serum alkaline phosphatase (ALP) level, serum alanine aminotransferase (ALT) level and serum aspartate aminotransferase (AST) level.

18. 17. The ASBT inhibitor for use according to claim 16, wherein the improvement in the liver parameter occurs after administration of the ASBT inhibitor for at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 40 weeks, or at least 48 weeks.

19. 2. The ASBT inhibitor for use according to claim 1, wherein the subject exhibits a reduction in urinary neutrophil gelatinase-associated lipocalin (NGAL) after administration of the ASBT inhibitor.

20. 20. The ASBT inhibitor for use according to claim 19, wherein the reduction in urinary NGAL is at least 60%, at least 70%, at least 80%, or at least 90%.

21. 2. The ASBT inhibitor for use according to claim 1, wherein the subject exhibits a reduction in urinary kidney injury molecule-1 (KIM-1) after administration of the ASBT inhibitor.

22. 22. The ASBT inhibitor for use according to claim 21, wherein the reduction of urinary KIM-1 is at least 60%, at least 70%, at least 80%, or at least 90%.

23. 2. The ASBT inhibitor for use according to claim 1, wherein the subject exhibits a reduction in serum blood urea nitrogen (BUN) after administration of the ASBT inhibitor.

24. 10. The ASBT inhibitor for use according to claim 1, which is administered once daily.

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