7-membered ring compounds and methods of using the same

Abstract

The present disclosure relates to the use of a therapeutically effective amount of a compound of general formula (I): TIFF2025519608000022.tif42150(wherein the variables R 1 , R 2 , Ar, X, Z and W have the meanings described herein) or a pharmaceutically acceptable salt or solvate thereof, for treating or preventing various diseases or conditions in a subject, particularly hepatobiliary diseases, gastrointestinal diseases associated with hepatobiliary diseases and / or eosinophilic diseases, and relates to the use of a compound of formula (I) in such treatment or prevention.

Description

Technical Field

[0001] Cross-reference This application claims the benefit of U.S. Provisional Application No. 63 / 350,961, filed Jun. 10, 2022, and U.S. Provisional Application No. 63 / 429,004, filed Nov. 30, 2022, the contents of each of which are hereby incorporated by reference in their entirety.

[0002] Field The present disclosure provides 7-membered nitrogen-containing ring compounds having chymase inhibitory activity and their use in the treatment of hepatobiliary diseases.

[0003] Background Art Hepatobiliary diseases include a heterogeneous group of diseases of the liver and biliary system. They are caused by disorders in bile formation or flow. Clinical consequences can include jaundice, pruritus, and fatigue. Left untreated, they can lead to fibrosis, biliary cirrhosis, and end-stage liver disease. Hepatobiliary diseases and hepatobiliary-related diseases include acute hepatitis, alcoholic hepatitis, alcoholic liver disease, extrahepatic cholestasis, colitis, hepatic fibrosis, liver abscess, cirrhosis, neonatal jaundice, obstructive jaundice, primary bile acid malabsorption, acute cholecystitis, autoimmune hepatitis, benign recurrent intrahepatic cholestasis, biliary obstruction, cholestatic liver disease, Crigler-Najjar syndrome, drug-induced hepatitis, Gilbert syndrome, intrahepatic cholestasis of pregnancy, liver rejection, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, polycystic liver disease, primary biliary cirrhosis, veno-occlusive disease, Wilson's disease. The two most common hepatobiliary diseases are primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC).

[0004] PSC is estimated to affect approximately 53,000 people in the United States and approximately 126,000 people in the 7MM countries. The market size of PSC is estimated to be $46 million in the United States and $126 million globally in 2020, and is expected to expand to approximately $157 million in the United States by 2026. PSC is characterized by a progressive course of cholestasis with inflammation and fibrosis of the intrahepatic and extrahepatic bile ducts. Symptoms associated with PSC include fatigue, pruritus, jaundice, dark urine, pale stools, abdominal pain, and / or nausea, hepatomegaly, and cirrhosis. Mast cells are known to play an active role in the pathogenesis of PSC. Chymase-positive mast cells have been detected in portal areas and sinusoidal walls in sections from affected livers, coinciding with fibrotic areas associated with extensive hepatic fibrosis. 80% of PSC patients have underlying inflammatory bowel disease (IBD) and show an increased risk of colorectal cancer compared to non-PSC-IBD.

[0005] PBC is characterized by inflammation and scarring of the small bile ducts. In severe cases, PBC can lead to jaundice, cirrhosis, and ultimately liver failure. PBC is divided into four stages, from stage 1, an early disease without significant scarring of the liver, to stage 4. The exact prevalence of PBC is estimated to be approximately 131,000 people in the United States and approximately 304,000 people worldwide.

[0006] Colitis is a chronic digestive disease characterized by inflammation of the inner lining of the colon. Infections, loss of blood supply in the colon, inflammatory bowel disease (IBD), and infiltration of the colon wall by collagen or lymphocytic white blood cells are all possible causes of colon inflammation. Common tests for colitis include X-rays of the colon, tests of the stool for blood and pus, sigmoidoscopy, and colonoscopy. Further tests include stool cultures and blood tests, including blood chemistry tests. An elevated erythrocyte sedimentation rate (ESR), a measure of the time it takes for red blood cells to settle in a blood sample, is typical of acute colitis. Colitis encompasses both ulcerative colitis (UC) and Crohn's disease (CD). Ulcerative colitis (UC), an inflammatory bowel disease (IBD), is characterized by chronic inflammation of the colon and rectum. This is a lifelong condition of the gastrointestinal tract with a high unmet medical need. The etiology of IBD is multifactorial and includes genetic predisposition, epithelial barrier defects, dysregulated immune responses, and environmental factors.

[0007] There are many treatments and therapies for these conditions, but none are ideal. Current therapies can only provide supportive and symptomatic improvements. For example, OCALIVA, obeticholic acid, a chemical structure of a semi-synthetic bile acid analogue: 6α-ethyl-chenodeoxycholic acid, is an approved drug for treating chronic cholestatic diseases but has a black box warning. Liver transplantation is the only proven long-term treatment for cholestatic diseases.

[0008] Therefore, there is a high unmet need in cholestatic diseases for the development of an economical and orally available drug therapy that exerts a disease-modifying effect.

[0009] SUMMARY OF THE INVENTION The present disclosure is a method for treating or preventing a cholestatic disease in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound of formula (I):

Chemical formula

[0010] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is (1) 4-{(1R)-1-[({(6R)-6-(5-chloro-2-methoxybenzyl)-7-oxo-3-[(pyridin-2-yloxy)imino]-1,4-diazepan-1-yl}carbonyl)amino]propyl}benzoic acid, (2) 2-amino-4-[(1R)-1-({[(6S)-6-(5-chloro-2-methoxybenzyl)-3-(ethoxyimino)-7-oxo-1,4-diazepan-1-yl]carbonyl}amino)butyl]benzoic acid, (3) 2-amino-4-{(1R)-1-[({(6S)-6-(5-chloro-2-methoxybenzyl)-7-oxo-3-[(2,2,2-trifluoroethoxy)imino]-1,4-diazepan-1-yl}carbonyl)amino]butyl}benzoic acid, (4) 2-amino-4-{(1R)-1-[({(6R)-6-(5-chloro-2-methoxybenzyl)-3-[(3,5-difluorophenoxy)imino]-7-oxo-1,4-diazepan-1-yl}carbonyl)amino]ethyl}benzoic acid, (5) 2-amino-4-[(1R)-1-({[(6S)-6-(5-chloro-2-methoxybenzyl)-3-(methoxyimino)-4-methyl-7-oxo-1,4-diazepan-1-yl]carbonyl}amino)butyl]benzoic acid, (6) (4-{(1R)-1-[({(6R)-6-(5-chloro-2-methoxybenzyl)-3-[(3,5-difluorophenoxy)imino]-7-oxo-1,4-diazepan-1-yl}carbonyl)amino]ethyl}phenyl)acetic acid, (7) 2-amino-4-{[({(6R)-6-(5-chloro-2-methoxybenzyl)-3-[(3,5-difluorophenoxy)imino]-7-oxo-1,4-diazepan-1-yl}carbonyl)amino]methyl}benzoic acid, (8) {4-[(1R)-1-({[(6R)-6-(5-chloro-2-methoxybenzyl)-7-oxo-3-(phenoxyimino)-1,4-diazepan-1-yl]carbonyl}amino)propyl]phenyl}acetic acid, (9) 2-Amino-4-[(1R)-1-({[(6R)-6-(5-chloro-2-methoxybenzyl)-7-oxo-3-(phenoxyimino)-1,4-diazepan-1-yl]carbonyl}amino)propyl]benzoic acid, or (10) 2-Amino-4-[(1R)-1({[(6R)-6-(5-chloro-2-methoxybenzyl)-3-(ethoxyimino)-7-oxo-1,4-diazepan-1-yl]carbonyl}amino)butyl]benzoic acid selected from the group consisting of.

[0011] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is 2-amino-4-[(1R)-1-({[(3Z,6S)-6-(5-chloro-2-methoxybenzyl)-3-(ethoxyimino)-7-oxo-1,4-diazepan-1-yl]carbonyl}amino)butyl]benzoic acid (referred to herein as "Compound 1").

Chemical formula

[0012] In a preferred embodiment, Compound 1 is a monoacetic acid solvate (referred to herein as "monoacetic acid solvate of Compound 1") known as 2-amino-4-[(1R)-1-({[(3Z,6S)-6-(5-chloro-2-methoxybenzyl)-3-(ethoxyimino)-7-oxo-1,4-diazepan-1-yl]carbonyl}amino)butyl]benzoic acid monoacetic acid solvate.

Chemical formula

[0013] In some embodiments, the present disclosure includes a compound of formula I or Compound 1 or a pharmaceutically acceptable salt or solvate thereof as a highly selective kimerase inhibitor.

[0014] In some embodiments, the present disclosure encompasses a method of treating a hepatobiliary disease in a subject in need of treatment for the hepatobiliary disease, the method comprising administering a therapeutically effective amount of a compound of formula (I) comprising Compound 1 or a pharmaceutically acceptable salt or solvate thereof to treat the disease.

[0015] In some embodiments, the present disclosure encompasses a method of treating a gastrointestinal disease in a subject in need of treatment for the gastrointestinal disease, the method comprising administering a therapeutically effective amount of a compound of formula (I) comprising Compound 1 or a pharmaceutically acceptable salt or solvate thereof to treat the disease.

[0016] In some embodiments, the present disclosure encompasses a method of treating an eosinophilic disease including eosinophilic esophagitis (EoE) in a subject in need of treatment for the eosinophilic disease, the method comprising administering a therapeutically effective amount of a compound of formula (I) comprising Compound 1 or a pharmaceutically acceptable salt or solvate thereof to treat the disease.

[0017] In some embodiments, the present disclosure encompasses a method of treating a hepatobiliary disease in a subject, the method comprising administering a therapeutically effective amount of a compound of formula (I) comprising Compound 1 or a pharmaceutically acceptable salt or solvate thereof to treat the disease.

[0018] In some embodiments, the present disclosure encompasses a method of treating a hepatobiliary disease in a subject, the method comprising administering a therapeutically effective amount of a compound of formula (I) comprising Compound 1 or a pharmaceutically acceptable salt or solvate thereof to improve pruritus.

[0019] In some embodiments, the present disclosure provides a method for treating hepatobiliary diseases in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of formula (I), which comprises compound 1 or a pharmaceutically acceptable salt or solvate thereof, so as to improve one or more of occult blood in feces, fecal incontinence, fever, fatigue, weight loss, number of mast cells and eosinophils, dysphagia, gastroesophageal reflux disease (GERD), bloating, early satiety, anorexia, jaundice, pruritus, hepatomegaly, cirrhosis, biliary obstruction, abdominal pain, nausea, diarrhea, cramps, and inflammation in the subject suffering from hepatobiliary diseases.

[0020] In some embodiments, the present disclosure provides a method for treating hepatobiliary diseases in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, so as to improve inflammation.

[0021] In various embodiments, the present disclosure provides a method for treating or preventing hepatobiliary diseases in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt or solvate thereof.

[0022] In some embodiments, the present disclosure provides a method for reducing infiltration of mast cells in a subject suffering from hepatobiliary diseases, comprising administering to the subject a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt or solvate thereof.

[0023] In some embodiments, the present disclosure provides a method for treating or preventing jaundice in a subject suffering from hepatobiliary diseases, comprising administering to the subject a therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt or solvate thereof.

[0024] In some embodiments, the present disclosure encompasses a method for treating or preventing pruritus in a subject suffering from a hepatobiliary disorder, the method comprising administering to the subject a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt or solvate thereof.

[0025] In some embodiments, the present disclosure encompasses a method for reducing inflammation in a subject suffering from a hepatobiliary disorder, the method comprising administering to the subject a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt or solvate thereof.

[0026] In some embodiments, the present disclosure encompasses a method for reducing bile acid accumulation in a subject suffering from a hepatobiliary disorder, the method comprising administering to the subject a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt or solvate thereof.

[0027] In some embodiments, the method treats a gastrointestinal disorder that may be associated with a hepatobiliary disorder. Such gastrointestinal disorders are selected from the group consisting of acute hepatitis, alcoholic hepatitis, alcoholic liver disease, colitis, extrahepatic cholestasis, liver fibrosis, liver abscess, cirrhosis, ulcerative colitis, Crohn's disease, irritable bowel syndrome (IBS), proctitis, celiac disease, ileitis, duodenitis, diverticulitis, neonatal jaundice, obstructive jaundice, primary bile acid malabsorption, acute cholecystitis, autoimmune hepatitis, benign recurrent intrahepatic cholestasis, biliary obstruction, cholestatic liver disease, Crigler-Najjar syndrome, drug-induced hepatitis, Dubin-Johnson syndrome, intrahepatic cholestasis of pregnancy, liver rejection, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, polycystic liver disease, veno-occlusive disease, and Wilson's disease. In an embodiment, the hepatobiliary disorder is PSC. In another embodiment, the hepatobiliary disorder is PBC. In yet another embodiment, the gastrointestinal disorder is colitis.

[0028] In one embodiment, the therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt or solvate thereof is about 10 mg to about 1000 mg per unit dose (for example, about 50 mg to about 950 mg per unit dose, about 50 mg to about 900 mg per unit dose, about 50 mg to about 850 mg per unit dose, about 50 mg to about 800 mg per unit dose, about 50 mg to about 750 mg per unit dose, about 50 mg to about 700 mg per unit dose, about 50 mg to about 650 mg per unit dose, about 50 mg to about 600 mg per unit dose, about 50 mg to about 550 mg per unit dose, about 50 mg to about 500 mg per unit dose, about 50 mg to about 450 mg per unit dose, about 50 mg to about 400 mg per unit dose, about 50 mg to about 350 mg per unit dose, about 50 mg to about 300 mg per unit dose, about 50 mg to about 250 mg per unit dose, about 50 mg to about 200 mg per unit dose, about 50 mg to about 150 mg per unit dose, about 50 mg to about 100 mg per unit dose). In embodiments, the therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt or solvate thereof is administered once a day, twice a day, three times a day, once every two days, or once every three days, or once a week.

[0029] In some embodiments, the therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof is formulated as a pellet, a multiunit particulate system (MUPS), a tablet, a troche, a lozenge, a dispersible powder or granule, or a hard or soft capsule, a powder, a sustained release formulation, a microcapsule, and orally administered to a subject in a unit dosage form.

[0030] In some embodiments, it is a method for treating or preventing PSC in a subject in need of treatment or prevention of PSC, the method comprising the step of administering to the subject a therapeutically effective amount of the monoacetate solvate of Compound 1.

[0031] In some embodiments, it is a method for treating or preventing PSC in a subject in need of treatment or prevention of PSC, the method comprising administering to the subject a monoacetate solvate of Compound 1 in the range of about 10 mg to 1000 mg per unit dose.

[0032] In some embodiments, the present disclosure encompasses a method for reducing angiogenesis in a subject with PSC in need of reducing angiogenesis, the method comprising administering to the subject a therapeutically effective amount of a monoacetate solvate of Compound 1.

[0033] In some embodiments, the present disclosure encompasses a method for reducing biliary tract senescence in a subject with PSC in need of reducing biliary tract senescence, the method comprising administering to the subject a therapeutically effective amount of a monoacetate solvate of Compound 1.

[0034] In some embodiments, the present disclosure encompasses a method for reducing the proliferation of cholangiocytes in a subject with PSC in need of reducing the proliferation of cholangiocytes, the method comprising administering to the subject a therapeutically effective amount of a monoacetate solvate of Compound 1.

[0035] In some embodiments, it is a method for treating or preventing PBC in a subject in need of treatment or prevention of PBC, the method comprising administering to the subject a therapeutically effective amount of a monoacetate solvate of Compound 1.

[0036] In some embodiments, the present disclosure encompasses a method for treating or preventing EGID and / or EoE in a subject in need of treatment or prevention of EGID and / or EoE, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

[0037] In some embodiments, the present disclosure provides a method for treating or preventing colitis in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the invention, comprising a monoacetate solvate of Compound 1.

[0038] In some embodiments, the present invention provides a method for treating or preventing colitis in a subject in need thereof, the method comprising administering to the subject a monoacetate solvate of Compound 1 in the range of about 10 mg to 1000 mg per unit dose.

[0039] In an embodiment, the present disclosure provides a method for reducing one or more of weight loss, diarrhea, and rectal bleeding in a subject suffering from colitis, the subject in need of reducing one or more of weight loss, diarrhea, and rectal bleeding, the method comprising administering to the subject a therapeutically effective amount of a compound of the invention, comprising a monoacetate solvate of Compound 1.

Chemical formula

[0040] In an embodiment, the present disclosure provides a method for treating or preventing EGID in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt or solvate thereof. In a preferred embodiment, Compound 1 is a monoacetate solvate.

[0041] In an embodiment, EGID is selected from the group consisting of eosinophilic gastroenteritis, eosinophilic esophagitis (EoE), eosinophilic duodenitis (EoD), and eosinophilic gastritis (EoG).

[0042] In one aspect, the present disclosure provides the following structure:

Chemical formula

[0043] In another aspect, the present disclosure provides a composition comprising 2-amino-4-[(1R-1-({[(3Z,6S)-6-(5-chloro-2-methoxybenzyl)-3-(ethoxyimino)-7-oxo-1,4-diazepan-1-yl]carbonyl}amino)butyl]benzoic acid (Compound 1) or a pharmaceutically acceptable salt or solvate thereof.

[0044] In another aspect, the present disclosure provides a method for treating a hepatobiliary disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of 2-amino-4-[(1R-1-({[(3Z,6S)-6-(5-chloro-2-methoxybenzyl)-3-(ethoxyimino)-7-oxo-1,4-diazepan-1-yl]carbonyl}amino)butyl]benzoic acid (Compound 1) or a pharmaceutically acceptable salt or solvate thereof.

[0045] In some embodiments of any of the foregoing methods, administration of the therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt or solvate thereof improves one or more of infiltration of at least one of mast cells or macrophages, bile acid accumulation, cholangiocyte proliferation, biliary tract senescence, fibrosis, and collagen deposition in the subject suffering from a hepatobiliary disease.

[0046] In some embodiments of any of the foregoing methods, administration of the therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt or solvate thereof improves one or more of jaundice, pruritus, hepatomegaly, cirrhosis, biliary obstruction, abdominal pain, nausea, diarrhea, spasm, and inflammation in the subject suffering from a hepatobiliary disease.

[0047] In some embodiments of any of the foregoing methods, the method for treatment comprises preventing the hepatobiliary disease in the subject.

[0048] In another aspect, the present disclosure provides a method for treating primary sclerosing cholangitis in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of 2-amino-4-[(1R-1-({[(3Z,6S)-6-(5-chloro-2-methoxybenzyl)-3-(ethoxyimino)-7-oxo-1,4-diazepan-1-yl]carbonyl}amino)butyl]benzoic acid (Compound 1) or a pharmaceutically acceptable salt or solvate thereof.

[0049] In some embodiments of any of the foregoing methods, administration of the therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt or solvate thereof improves one or more of infiltration of at least one of mast cells or macrophages, bile acid accumulation, cholangiocyte proliferation, biliary tract senescence, fibrosis, and collagen deposition in the subject suffering from primary sclerosing cholangitis.

[0050] In some embodiments of any of the foregoing methods, administration of the therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt or solvate thereof improves one or more of occult blood in stool, fecal incontinence, fever, fatigue, weight loss, mast cell and eosinophil counts, dysphagia, gastroesophageal reflux disease (GERD), fullness, early satiety, loss of appetite, jaundice, pruritus, hepatomegaly, cirrhosis, biliary obstruction, abdominal pain, nausea, diarrhea, spasm, and inflammation in the subject suffering from PSC.

[0051] In some embodiments of any of the foregoing methods, the method for treatment comprises preventing PSC in the subject.

[0052] In some embodiments of any of the foregoing methods, the administration of the therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt or solvate thereof treats at least one of inflammatory bowel disease and colitis in the subject.

[0053] In another aspect, the present disclosure provides a method for treating PBC in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of 2-amino-4-[(1R-1-({[(3Z,6S)-6-(5-chloro-2-methoxybenzyl)-3-(ethoxyimino)-7-oxo-1,4-diazepan-1-yl]carbonyl}amino)butyl]benzoic acid (Compound 1) or a pharmaceutically acceptable salt or solvate thereof.

[0054] In some embodiments of any of the foregoing methods, administration of the therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt or solvate thereof improves one or more of infiltration of at least one of mast cells or macrophages, bile acid accumulation, cholangiocyte proliferation, biliary tract senescence, fibrosis, and collagen deposition in the subject suffering from primary biliary cholangitis.

[0055] In some embodiments of any of the foregoing methods, administration of the therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt or solvate thereof improves one or more of occult blood in feces, fecal incontinence, fever, fatigue, weight loss, mast cell count and eosinophil count, dysphagia, gastroesophageal reflux disease (GERD), bloating, early satiety, anorexia, jaundice, pruritus, hepatomegaly, cirrhosis, biliary obstruction, abdominal pain, nausea, diarrhea, ulcerative colitis, Crohn's disease, irritable bowel syndrome (IBS), proctitis, celiac disease, ileitis, duodenitis, diverticulitis, spasm and inflammation in the subject suffering from primary biliary cholangitis.

[0056] In some embodiments of any of the foregoing methods, the method for treatment comprises preventing PBC in the subject.

[0057] In some embodiments of any of the foregoing methods, the administration of the therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt or solvate thereof treats at least one of inflammatory bowel disease and colitis in the subject.

[0058] In some embodiments of any of the foregoing methods, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is selective for chymase over cathepsin G. The compound of formula I has an IC50 value of 0.029 μM against human chymase, but an IC50 value of 32 μM against cathepsin. Thus, the compound of formula I is highly selective and specific for the inhibition of chymase.

[0059] In some embodiments of any of the foregoing methods, the hepatobiliary disease is selected from the group consisting of acute hepatitis, alcoholic hepatitis, alcoholic liver disease, extrahepatic cholestasis, liver fibrosis, liver abscess, cirrhosis, colitis, neonatal jaundice, obstructive jaundice, primary bile acid malabsorption, acute cholecystitis, autoimmune hepatitis, benign recurrent intrahepatic cholestasis, biliary obstruction, cholestatic liver disease, Crigler-Najjar syndrome, drug-induced hepatitis, Gilbert's syndrome, intrahepatic cholestasis of pregnancy, liver rejection, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, polycystic liver disease, veno-occlusive disease, and Wilson's disease.

[0060] In other embodiments, the gastrointestinal disease is selected from the group consisting of ulcerative colitis, Crohn's disease, irritable bowel syndrome (IBS), proctitis, celiac disease, ileitis, duodenitis, and diverticulitis.

[0061] In some embodiments of any of the foregoing methods, the therapeutically effective amount of the compound 1 or a pharmaceutically acceptable salt or solvate thereof is from about 20 mg to about 400 mg per unit dose. In some embodiments, the therapeutically effective amount of the compound 1 or a pharmaceutically acceptable salt or solvate thereof is from about 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, and 400 mg.

[0062] In some embodiments of any of the foregoing methods, a therapeutically effective amount of the compound 1 or a pharmaceutically acceptable salt or solvate thereof is orally administered to a subject once a day, twice a day, three times a day, once every two days, once every three days, or once a week.

[0063] In some embodiments of any of the foregoing methods, the compound 1 is [Chemical formula] as follows.

[0064] In one aspect, the present disclosure provides a method for treating at least one of primary sclerosing cholangitis and primary biliary cholangitis in a subject in need of treatment for at least one of primary sclerosing cholangitis and primary biliary cholangitis, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I): [Chemical formula] (wherein Ar is (1) a C6-C14 aromatic hydrocarbon group, (2) a 5- to 8-membered aromatic heterocyclic group having 1 to 4 heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom, and an oxygen atom in place of a carbon atom, or (3) a bicyclic or tricyclic aromatic group formed by condensation of the above aromatic heterocyclic group and a C6-C14 aromatic hydrocarbon ring, The above groups (1)-(3) of Ar are (viii) a halogen atom, (ix) nitro, (x) cyano, (xi) C1-C6 alkyl optionally substituted with 1 to 3 halogen atoms, (xii) C2-C6 alkenyl optionally substituted with 1 to 3 halogen atoms, (xiii) C2-C6 alkynyl optionally substituted with 1 to 3 halogen atoms, (xiv) C3-C6 cycloalkyl, (ix) hydroxyl, (xiii) C1-C6 alkoxy which may be substituted with 1-3 groups selected from the group consisting of a halogen atom, mono- or di-C1-C6 alkylamino, C1-C6 alkoxy, mono- or di-C1-C6 alkylcarbamoyl, mono- or di-C7-C16 aralkylcarbamoyl, mono- or di-C1-C10 heteroaryl-C1-C6 alkylcarbamoyl, carboxyl, and C1-C6 alkoxycarbonyl, or may be substituted with 1-13 deuterium atoms, (xiv) C1-C5 alkylenedioxy, (xv) C1-C6 alkylthio which may be substituted with 1-3 groups selected from the group consisting of a halogen atom, mono- or di-C1-C6 alkylamino, C1-C6 alkoxy, mono- or di-C1-C6 alkylcarbamoyl, mono- or di-C7-C16 aralkylcarbamoyl, mono- or di-C1-C10 heteroaryl-C1-C6 alkylcarbamoyl, carboxyl, and C1-C6 alkoxycarbonyl, or may be substituted with 1-13 deuterium atoms, (xvi) Amino, (xix) Mono-C1-C6 alkylamino, (xx) Di-C1-C6 alkylamino, (xxi) 5-6 membered ring amino, (xxii) C1-C6 alkylcarbonyl, (xxiii) Carboxyl, (xxiv) C1-C6 alkoxycarbonyl, (xxviii) Carbamoyl, (xxix) Thiocarbamoyl, (xxx) Mono-C1-C6 alkylcarbamoyl, (xxxi) Di-C1-C6 alkylcarbamoyl, (xxxii) 5-6 membered ring aminocarbonyl, (xxxiii) Sulfo, (xxxiv) C1-C6 alkylsulfonyl, (xxxv) C1-C6 alkoxycarbonylamino, (xxxvi)C1-C6 alkylcarbonylamino, (xxxi) mono- or di-C1-C6 alkylaminocarbonylamino, (xxxii) aminosulfonyl, and (xxxiii) mono- or di-C1-C6 alkylaminosulfonyl substituted with 1 to 5 groups selected from the group consisting of, or optionally substituted with 1 to 9 deuterium atoms, X is (1) a connecting bond, (2) a linear or branched C1-C6 alkylene optionally substituted with 1 to 12 deuterium atoms, (3) an oxygen atom, (4) NR3 (wherein R3 is a hydrogen atom or a C1-C6 alkyl group), or (5) -S(O)m- (wherein m is an integer from 0 to 2), Z is (1) a connecting bond or (2) CR4R5 (wherein R4 and R5 are independently (G) a hydrogen atom, (H) a deuterium atom, (I) (i) carboxyl, (ii) C1-C6 alkoxycarbonyl, (iii) phenyl, (iv) hydroxyl, (v) C1-C6 alkoxy, (vi) a halogen atom, and (vii) a C1-C6 alkyl optionally substituted with 1 to 5 groups selected from the group consisting of C3-C6 cycloalkyl or optionally substituted with 1 to 13 deuterium atoms, (J) (i) a halogen atom and (ii) a C3-C6 cycloalkyl optionally substituted with 1 to 5 groups selected from the group consisting of an alkyl group optionally substituted with 1 to 3 halogen atoms or optionally substituted with 1 to 11 deuterium atoms, (K) COOR6 (wherein R6 is a hydrogen atom or C1-C6 alkyl), or (L) CONR7R8 (wherein R7 and R8 are independently (d) a hydrogen atom, (e)(i) a halogen atom, (ii) C3-C6 cycloalkyl, (iii) carboxyl, (iv) C1-C6 alkoxycarbonyl, (v) C1-C6 alkylcarbonyl, (vi) carbamoyl, (vii) mono-C1-C6 alkylcarbamoyl, (viii) di-C1-C6 alkylcarbamoyl, (ix) C6-C12 aryl, and (x) C1-C10 heteroaryl, which may be substituted with 1 to 3 groups selected from the group consisting of C1-C6 alkyl, (f) a C6-C14 aromatic hydrocarbon group, (f) instead of a carbon atom, a 5- to 8-membered aromatic heterocyclic group having 1 to 4 heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom, or (g) a bicyclic or tricyclic aromatic group formed by the condensation of the above aromatic heterocyclic group and a C6-C14 aromatic hydrocarbon ring and the groups (c) to (e) are each independently selected from the group consisting of (i) a halogen atom, (ii) nitro, (iii) cyano, (iv) C1-C6 alkyl optionally substituted with 1 to 3 halogen atoms, (v) C2-C6 alkenyl optionally substituted with 1 to 3 halogen atoms, (vi) C2-C6 alkynyl optionally substituted with 1 to 3 halogen atoms, (vii) C3-C6 cycloalkyl, (viii) hydroxyl, (ix) C1-C6 alkoxy optionally substituted with 1 to 3 halogen atoms, (x) C1-C5 alkylenedioxy, (xi) C1-C6 alkylthio optionally substituted with 1 to 3 halogen atoms, (xii) amino, (xiii) mono-C1-C6 alkylamino, (xiv) di-C1-C6 alkylamino, (xv) 5- to 6-membered ring amino, (xvi) C1-C6 alkylcarbonyl, (xvii) carboxyl, (xviii) C1-C6 alkoxycarbonyl, (xix) carbamoyl, (xx) thiocarbamoyl, (xxi) mono-C1-C6 alkylcarbamoyl, (xxii) di-C1-C6 alkylcarbamoyl, (xxiii) C6-C10 arylcarbamoyl, (xxiv) C1-C10 heteroarylcarbamoyl, (xxv) sulfo, (xxvi) C1-C6 alkylsulfonyl, (xxvii) aminosulfonyl, and (xxviii) mono- or di-C1-C6 alkylaminosulfonylamino, and may be substituted with 1 to 5 groups selected from the group or with 1 to 9 deuterium atoms) is) and W is (1) a hydrogen atom, (2) a C6-C14 aromatic hydrocarbon group, (3) a 5- to 8-membered aromatic heterocyclic group having 1 to 4 heteroatoms selected from nitrogen, sulfur, and oxygen atoms in place of a carbon atom, (4) a bicyclic or tricyclic aromatic group formed by condensation of the aromatic heterocyclic group and a C6-C14 aromatic hydrocarbon ring, or a deuterium atom Each of the groups (2) to (4) of W above is (i) a halogen atom, (ii) nitro, (iii) cyano, (iv) C1-C6 alkyl optionally substituted with 1 to 3 groups selected from the group consisting of a halogen atom, amino, C1-C6 alkoxycarbonyl, C1-C6 alkoxycarbonylamino and carboxyl, (v) C2-C6 alkenyl optionally substituted with 1 to 3 halogen atoms, (vi) C2-C6 alkynyl optionally substituted with 1 to 3 halogen atoms, (vii) C3-C6 cycloalkyl, (viii) hydroxyl, (ix) C1-C6 alkoxy optionally substituted with 1 to 3 groups selected from the group consisting of a halogen atom, hydroxyl, C1-C6 alkoxy, amino and mono- or di-C1-C6 alkylamino, (x) C1-C5 alkylenedioxy, (xi) C1-C6 alkylthio optionally substituted with 1 to 3 groups selected from the group consisting of a halogen atom, hydroxyl, C1-C6 alkoxy, amino and mono- or di-C1-C6 alkylamino, (xii) amino, (xiii) mono-C1-C6 alkylamino, (xiv) di-C1-C6 alkylamino, (xv) a 5- or 6-membered ring amino, (xvi) C1-C6 alkyl-carbonyl, (xvii) carboxyl, (xviii) C1-C6 alkoxycarbonyl optionally substituted with a halogen atom, (xix) C7-C16 aralkyloxycarbonyl optionally substituted with a halogen atom, (xx) carbamoyl, (xxi) a mono-C1-C6 alkylcarbamoyl optionally substituted with 1-3 groups selected from the group consisting of a halogen atom, hydroxyl, carboxyl, C1-C6 alkoxy, amino, and mono- or di-C1-C6 alkylamino, (xxii) a di-C1-C6 alkylcarbamoyl optionally substituted with hydroxyl, (xxiii) a 5- or 6-membered ring aminocarbonyl optionally substituted with C1-C6 alkoxycarbonyl, (xxiv) C6-C10 arylcarbamoyl, (xxv) C1-C10 heteroarylcarbamoyl, (xxvi) C7-C16 aralkylcarbamoyl, (xxvii) C1-C10 heteroaryl-C1-C6 alkylcarbamoyl, (xxviii) N-C1-C6 alkyl-N-C6-C12 arylcarbamoyl, (xxix) C3-C6 cycloalkylcarbamoyl, (xxx) sulfo, (xxxi) C1-C6 alkylsulfonyl, (xxxii) C1-C6 alkylsulfonylamino, (xxxiii) C6-C12 arylsulfonylamino optionally substituted with C1-C6 alkyl, (xxxiv) C1-C10 heteroarylsulfonylamino, (xxxv) C1-C6 alkoxycarbonylamino, (xxxvi) C1-C6 alkylcarbonylamino, (xxxvii) mono- or di-C1-C6 alkylaminocarbonylamino, (xxxviii) C6-C12 aryl, (xxxix) C1-C10 heteroaryl, (xl) C6-C10 aryloxy, (xli) C1-C10 heteroaryloxy, (xlii) C7-C16 arakyloxy, (xliii) C1-C10 heteroaryl-C1-C6 alkyloxy, (xliv) aminosulfonyl, (xlv) mono- or di-C1-C6 alkylaminosulfonyl, (xlvi) C7-C16 aralkyloxycarbamoyl,and may be substituted with 1 to 5 groups selected from the group consisting of (xlvii) C1-C10 heteroaryl-C1-C6 alkyloxycarbonyl, or may be substituted with 1 to 9 deuterium atoms, R1 is (6) a hydrogen atom, (7) C1-C6 alkyl which may be substituted with 1 to 3 (i) halogen atoms or (ii) C3-C6 cycloalkyl, or (iii) may be substituted with 1 to 13 deuterium atoms, (8) C2-C6 alkenyl which may be substituted with 1 to 3 (i) halogen atoms or (ii) C3-C6 cycloalkyl, or (iii) may be substituted with 1 to 11 deuterium atoms, (9) C2-C6 alkynyl which may be substituted with 1 to 3 (i) halogen atoms or (ii) C3-C6 cycloalkyl, or (iii) may be substituted with 1 to 9 deuterium atoms, or (10) C3-C6 cycloalkyl which may be substituted with 1 to 3 (i) halogen atoms or (ii) C3-C6 cycloalkyl, or (iii) may be substituted with 1 to 11 deuterium atoms and R2 is (1) OR9 or (2) NR10R11 (wherein R9, R10, and R11 are independently (E) a hydrogen atom, (F) C1-C6 alkyl, (G) C2-C6 alkenyl, (H) C3-C6 alkynyl, (I) C3-C6 cycloalkyl, (J) a C6-C14 aromatic hydrocarbon group, (K) instead of a carbon atom, a 5- to 8-membered aromatic heterocyclic group having 1 to 4 heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom, and an oxygen atom, or (L) a bicyclic or tricyclic aromatic group formed by condensation of the above aromatic heterocyclic group and a C6-C14 aromatic hydrocarbon ring is shown, Each of the groups (B) to (E) above may be substituted with 1 to 3 groups selected from the group consisting of (i) a halogen atom, (ii) C3-C6 cycloalkyl, (iii) hydroxyl, (iv) C1-C6 alkoxy which may be substituted with 1 to 3 halogen atoms, (v) amino, (vi) mono-C1-C6 alkylamino, (vii) di-C1-C6 alkylamino, (viii) 5- to 6-membered ring amino, (ix) carboxyl, (x) C1-C6 alkoxycarbonyl, (xi) C1-C6 alkylcarbonyl, (xii) carbamoyl, (xiii) mono-C1-C6 alkylcarbamoyl, (xiv) di-C1-C6 alkylcarbamoyl, (xv) C6-C12 aryl, and (xvi) C1-C10 heteroaryl, or may be substituted with 1 to 13 deuterium atoms. Furthermore, each of the groups (F) to (H) above may be substituted with 1 to 5 groups selected from the group consisting of (i) a halogen atom, (ii) nitro, (iii) cyano, (iv) C1-C6 alkyl which may be substituted with 1 to 3 halogen atoms, (v) C3-C6 cycloalkyl which may be substituted with 1 to 3 halogen atoms, (vi) hydroxyl, (vii) C1-C6 alkoxy which may be substituted with 1 to 3 halogen atoms, (viii) amino, (ix) mono-C1-C6 alkylamino, (x) di-C1-C6 alkylamino, (xi) 5- to 6-membered ring amino, (xii) C1-C6 alkylcarbonyl, (xiii) carboxyl, (xiv) C1-C6 alkoxycarbonyl, (xv) carbamoyl, (xvi) mono-C1-C6 alkylcarbamoyl, (xvii) di-C1-C6 alkylcarbamoyl, (xviii) C1-C6 alkylsulfonyl, (xix) aminosulfonyl, and (xx) mono- or di-C1-C6 alkylaminosulfonyl, or may be substituted with 1 to 9 deuterium atoms, or R1 and R2 may together with the atoms to which they are attached form a 5- or 6-membered heterocyclic ring. The above 5- or 6-membered heterocyclic ring (I) a halogen atom (J) oxo (K) hydroxyl (L) C1-C6 alkyl (M) C2 - C6 alkenyl, (N) C2 - C6 alkynyl, (O) C3 - C6 cycloalkyl, (P) C6 - C14 aromatic hydrocarbon group, (L) Instead of a carbon atom, a 5 - to 8 - membered aromatic heterocyclic group having 1 to 4 heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom, and an oxygen atom, and (M) A bicyclic or tricyclic aromatic group formed by the condensation of the above aromatic heterocyclic group and a C6 - C14 aromatic hydrocarbon ring even if it is substituted with 1 to 3 groups selected from the group consisting of, or (N) 1 to 6 deuterium atoms may be substituted, Each of the groups (D) to (G) above may be substituted with 1 to 3 groups selected from the group consisting of (i) a halogen atom, (ii) C3-C6 cycloalkyl, (iii) hydroxyl, (iv) C1-C6 alkoxy which may be substituted with 1 to 3 halogen atoms, (v) amino, (vi) mono-C1-C6 alkylamino, (vii) di-C1-C6 alkylamino, (viii) 5- to 6-membered ring amino, (ix) carboxyl, (x) C1-C6 alkoxycarbonyl, (xi) C1-C6 alkyl-carbonyl, (xii) carbamoyl, (xiii) mono-C1-C6 alkylcarbamoyl, (xiv) di-C1-C6 alkylcarbamoyl, (xv) C6-C12 aryl, and (xvi) C1-C10 heteroaryl, or may be substituted with 1 to 13 deuterium atoms. Each of the groups (H) to (J) above may be substituted with 1 to 5 groups selected from the group consisting of (i) a halogen atom, (ii) nitro, (iii) cyano, (iv) C1-C6 alkyl which may be substituted with 1 to 3 halogen atoms, (v) C3-C6 cycloalkyl which may be substituted with 1 to 3 halogen atoms, (vi) hydroxyl, (vii) C1-C6 alkoxy which may be substituted with 1 to 3 halogen atoms, (viii) amino, (ix) mono-C1-C6 alkylamino, (x) di-C1-C6 alkylamino, (xi) 5- to 6-membered ring amino, (xii) C1-C6 alkylcarbonyl, (xiii) carboxyl, (xiv) C1-C6 alkoxycarbonyl, (xv) carbamoyl, (xvi) mono-C1-C6 alkylcarbamoyl, (xvii) di-C1-C6 alkylcarbamoyl, (xviii) C1-C6 alkylsulfonyl, (xix) aminosulfonyl, and (xx) mono- or di-C1-C6 alkylaminosulfonyl, or may be substituted with 1 to 9 deuterium atoms) is) or a pharmaceutically acceptable salt or solvate thereof to a subject, which includes a method.

[0065] In some embodiments of any of the foregoing methods, administration of the therapeutically effective amount of the compound of formula I or a pharmaceutically acceptable salt or solvate thereof improves one or more of infiltration of at least one of mast cells or macrophages, bile acid accumulation, cholangiocyte proliferation, biliary tract aging, fibrosis, and collagen deposition in the subject suffering from a hepatobiliary disease.

[0066] In some embodiments of any of the foregoing methods, administration of the therapeutically effective amount of the compound of formula I or a pharmaceutically acceptable salt or solvate thereof improves one or more of occult blood in stool, fecal incontinence, fever, fatigue, weight loss, number of mast cells and eosinophils, dysphagia, gastroesophageal reflux disease (GERD), a feeling of fullness, early satiety, anorexia, jaundice, pruritus, hepatomegaly, cirrhosis, biliary obstruction, abdominal pain, nausea, diarrhea, spasm, ulcerative colitis, Crohn's disease, irritable bowel syndrome (IBS), proctitis, celiac disease, ileitis, duodenitis, diverticulitis, and inflammation in the subject suffering from a hepatobiliary disease.

[0067] In some embodiments of any of the foregoing methods, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is more selective for chymase than for cathepsin G.

[0068] In some embodiments of any of the foregoing methods, the hepatobiliary disease is selected from the group consisting of acute hepatitis, alcoholic hepatitis, alcoholic liver disease, extrahepatic biliary stasis, hepatic fibrosis, liver abscess, cirrhosis, colitis, neonatal jaundice, obstructive jaundice, primary bile acid malabsorption, acute cholecystitis, autoimmune hepatitis, benign recurrent intrahepatic cholestasis, biliary obstruction, cholestatic liver disease, Crigler-Najjar syndrome, drug-induced hepatitis, Dubin-Johnson syndrome, intrahepatic cholestasis of pregnancy, liver rejection, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, polycystic liver disease, veno-occlusive disease, and Wilson's disease.

[0069] In some embodiments of any of the foregoing methods, the therapeutically effective amount of the compound of formula I or a pharmaceutically acceptable salt or solvate thereof is about 20 mg to about 400 mg per unit dose.

Brief Description of the Drawings

[0070]

Figure 1

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Figure 8

Figure 9

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Figure 12

Figure 13

Figure 14

Figure 15

[0071] Mode for Carrying Out the Invention In the following sections, various embodiments of the present disclosure are defined in more detail. Each embodiment so defined can be combined with any other aspect unless it is clearly shown otherwise. In particular, any feature shown as being preferred or advantageous can be combined with any other feature shown as being preferred or advantageous.

[0072] I. Abbreviations As used herein, the following abbreviations have the following meanings. mg Milligram i.p. Intraperitoneal OD Once a day PBC Primary biliary cholangitis / primary biliary cirrhosis PSC Primary sclerosing cholangitis MC mast cell Mdr2 - multidrug resistance 2 gene, also known as adenosine triphosphate - binding cassette B4 (ABCB4) MUPS multi - unit particulate system IBD inflammatory bowel disease UC ulcerative colitis CD Crohn's disease GI gastrointestinal GBA gut - brain axis MMP - 9 matrix metalloproteinase 9 TGF transforming growth factor SCF stem cell factor EGID eosinophilic gastrointestinal disease BDL bile duct ligation TBA total bile acid NAD nicotinamide adenine dinucleotide EIA enzyme immunoassay KO knockout WT untreated TNF tumor necrosis factor IL - 1β interleukin - 1β IL - 18 interleukin - 18 IL - 6 interleukin - 6 MCP - 1 mast cell protease IL - 33 interleukin - 33

[0073] II. Definitions It should be understood that the terms used in this specification are for the sole purpose of describing embodiments and are not intended to be limiting. As used herein, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise.

[0074] As used herein, the term "about" refers to ±10% of the indicated numerical value, unless otherwise specified or clear from the context, and except where such a range exceeds 100% of the possible value or is less than 0% of the possible value, e.g., a content of less than 0% of a component or more than 100% of the total content of the composition.

[0075] As used herein, the term "solvate" refers to a crystalline form containing either a compound of formula (I) or a pharmaceutically acceptable salt thereof and either a stoichiometric or non-stoichiometric amount of a solvent. Examples of solvents include water, methanol, ethanol, 1-propanol, 2-propanol, formic acid, ethyl formate, acetic acid, methyl acetate, ethyl acetate, propyl acetate, and isobutyl acetate. Hereinafter, references to the compound of formula (I) are to any physical form of the compound, unless a particular form, salt, or solvate is specified.

[0076] As used herein, the term "active agent" or "therapeutic agent" refers to a chemical agent capable of having activity.

[0077] As used herein, the terms "comprises", "comprising", "includes", "including", "having" mean "including but not limited to".

[0078] As used herein, the terms "formulation" and "composition" are used interchangeably, unless clearly intended to have different meanings.

[0079] As used herein, the term "Hepatobiliary disease" refers to a medical condition in which there is an impairment in bile excretion from the liver or bile excretion is blocked. Clinical symptoms and signs include fatigue, jaundice, itching (pruritus), fibrosis, and the inability to digest certain foods, nausea, vomiting, dark and light-colored urine. Hepatobiliary disease according to the present teachings refers to any stage or severity of hepatobiliary disease (e.g., disease remission or acute disease).

[0080] As used herein, the term "Eosinophilic Gastrointestinal disease" refers to a medical condition in which there is an increase in the number of eosinophils in any part of the gastrointestinal tract from the esophagus to the colon. EGID according to the present teachings refers to any stage or severity of eosinophilic gastrointestinal disease (e.g., disease remission or acute disease).

[0081] The present disclosure also includes all stereoisomers of a compound, including diastereomers and enantiomers. The present disclosure also includes mixtures of stereoisomers in any ratio, including but not limited to racemic mixtures. Unless stereochemistry is explicitly shown in the structure, the structure is intended to encompass all possible stereoisomers of the indicated compound. If stereochemistry is explicitly shown for one or more parts of a molecule but not for another one or more parts of the molecule, the structure is intended to encompass all possible stereoisomers for the one or more parts for which stereochemistry is not explicitly shown.

[0082] As used herein, the term "inhibit" refers to the ability of a compound or any agent to reduce or interfere with the described function, level, activity, synthesis, release, binding, etc., based on the context in which the term "inhibit" is used. The term "inhibit" is used interchangeably with "reduce", "block", and "decrease".

[0083] As used herein, the terms "patient" or "subject" refer to an organism that is suffering from or is predisposed to a condition that can be treated by administration of the pharmaceutical compositions provided herein. Non-limiting examples include humans, other mammals, and other non-mammals.

[0084] As used herein, the term "pharmaceutically acceptable salt" refers to salts that are known to be non-toxic and are commonly used in the pharmaceutical literature. When a compound having formula (I) has an amine or other basic group as a substituent, examples include salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and other mineral acids, formic acid, acetic acid, fumaric acid, maleic acid, oxalic acid, citric acid, malic acid, tartaric acid, aspartic acid, glutamic acid, and other organic carboxylic acids, or salts with methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydroxybenzenesulfonic acid, and other sulfonic acids. When a compound having formula (I) has a carboxylic acid or other acid group as a substituent, examples include salts with sodium, potassium, or other alkali metal salts, calcium, magnesium, or other alkaline earth metal salts, ammonia, triethylamine, or ethylenediamine, propanediamine, pyrrolidine, piperidine, piperazine, pyridine, lysine, choline, ethanolamine, N,N-dimethylethanolamine, 4-hydroxypiperidine, glucosamine, N-methylglucosamine, or other organic bases, and hydroxylalkane diacids, aromatic acids, aliphatic and aromatic sulfonic acids may also be used.

[0085] As used herein, the terms "pharmaceutically acceptable excipient" and "pharmaceutically acceptable carrier" refer to substances that assist in the administration of an active agent to a subject and its absorption by the subject. It also refers to excipients that can be included in the compositions of the present disclosure and that do not cause significant harmful toxic effects in patients.

[0086] As used herein, the term "infiltration of mast cells" refers to an increase in mast cells in the liver that results in hepatobiliary disease.

[0087] As used herein, the term "inflammation" refers to signs such as redness and swelling when the body reacts to a stimulant.

[0088] As used herein, the term "jaundice" refers to a medical condition in which the skin, mucous membranes, and sclera become yellow due to an increase in bilirubin levels.

[0089] As used herein, the term "pruritis" refers to a medical condition characterized by itching.

[0090] As used herein, the term "angiogenesis" refers to the formation of blood vessels as an important process for wound healing.

[0091] As used herein, the term "biliary senescence" refers to a pathophysiological phenomenon in which proliferating cells enter cell cycle arrest following DNA damage and other stress signals. Although natural permanent DNA damage can occur after repeated cell divisions, however, acute stress or other injuries can push cells into premature aging and ultimately the senescence-associated secretory phenotype (SASP).

[0092] As used herein, the term "bile acid accumulation" refers to the accumulation of bile acids in the liver due to blood flow disorders. This refers to the accumulation of toxic bile acids in the hepatobiliary system that damages cholangiocytes and hepatocytes, causing liver injury and inflammation. Excessive accumulation of bile acids leads to chronic cholestasis, which then progresses to fibrosis, cirrhosis, and ultimately liver failure or hepatocellular or cholangiocarcinoma.

[0093] As used herein, the term "proliferation of ductular hepatocytes" refers to a cellular liver reaction that occurs in chronic liver disease and results in an increase in ductular mass.

[0094] As used herein, the term "preventing" or "prevention" means preventing the occurrence of a disease, condition, or associated symptoms, or preventing its recurrence, for example, after a period of improvement.

[0095] As used herein, the term "Fibrosis" refers to the development of fibrous connective tissue as a repair response to injury or damage. Fibrosis can refer to connective tissue deposition that occurs as part of normal healing or excessive tissue deposition that occurs as a pathological process.

[0096] As used herein, the term "Cholangiocyte activation" refers to the process by which cholangiocytes are activated, which can occur via one or more of infection, cholestasis, ischemia, and foreign bodies. In many cholangiopathies, including PSC and PBC, the activation injury is unknown. Characteristics that characterize activated cholangiocytes include increased proliferation and pro-fibrotic and pro-inflammatory secretions. Activated cholangiocytes are also involved in the recruitment and crosstalk with immune cells, vascular cells, and mesenchymal cells, and when chronically activated, are involved in the development of biliary fibrosis and cholangiocarcinoma. Extensive changes in protein expression and the activated cholangiocyte secretome make cholangiocytes active participants in the ongoing immunological response to biliary injury via multifaceted autocrine and paracrine mechanisms.

[0097] As used herein, the term "therapeutic effective amount" means the following: (1) Preventing a disease, e.g., preventing a disease, condition, or disorder in an individual who may have a predisposition to the disease, condition, or disorder but has not yet experienced or exhibited the pathology or general symptoms of the disease, (2) Inhibiting a disease, e.g., inhibiting a disease, condition, or disorder in an individual who is experiencing or exhibiting the pathology or general symptoms of the disease, condition, or disorder (i.e., preventing further progression of the pathology and / or general symptoms), and (3) Improving a disease, e.g., improving a disease, condition, or disorder in an individual who is experiencing or exhibiting the pathology or general symptoms of the disease, condition, or disorder (i.e., reversing the pathology and / or general symptoms) Refers to the amount of an agent or pharmaceutical that induces a biological or medical response in a tissue, system, animal, individual, or human being required by a researcher, veterinarian, physician, or other clinician or caregiver, or by an individual, and includes one or more of the following.

[0098] As used herein, the term "treatment" means the following: (1) Preventing a disease, e.g., preventing a disease, condition or disorder in an individual who may have a predisposition to the disease, condition or disorder but has not yet experienced or exhibited the pathological state or overall symptoms of the disease, (2) Inhibiting a disease, e.g., inhibiting a disease, condition or disorder in an individual who is experiencing or exhibiting the pathological state or overall symptoms of the disease, condition or disorder (i.e., preventing further progression of the pathological state and / or overall symptoms), and (3) Improving a disease, e.g., improving a disease, condition or disorder in an individual who is experiencing or exhibiting the pathological state or overall symptoms of the disease, condition or disorder (i.e., reversing the pathological state and / or overall symptoms) refers to one or more of the above.

[0099] As used herein, the term "unit dosage form" refers to physically discrete units suitable as unit doses for human subjects and other mammals (e.g., dogs), each unit containing a predetermined amount of an active material calculated to produce the desired onset, tolerance and / or therapeutic effect in combination with a suitable pharmaceutical excipient (e.g., a tablet or capsule).

[0100] The "C6-C14 aromatic hydrocarbon group" represented by Ar may include a monocyclic or polycyclic aromatic hydrocarbon group, more specifically, phenyl, biphenyl, naphthyl, indenyl, anthryl, phenanthryl (preferably phenyl, biphenyl, naphthyl, etc., particularly preferably phenyl, etc.), or other 6-14 membered monocyclic or polycyclic aromatic hydrocarbon groups, etc.

[0101] Furthermore, the "5- to 8-membered aromatic heterocyclic group containing 1 to 4 heteroatoms selected from nitrogen, sulfur, and oxygen atoms other than carbon atoms" represented by Ar is, for example, a monocyclic group preferably composed of one or two heteroatoms selected from nitrogen, oxygen, and sulfur atoms other than carbon atoms and containing one or more (for example, 1 to 4, preferably 1 to 3) heteroatoms, or a condensed aromatic heterocyclic group thereof. More specifically, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, naphthyridinyl, purinyl, and other aromatic heterocyclic groups (preferably pyridyl, thienyl, and furyl) may be mentioned.

[0102] Furthermore, the "bicyclic or tricyclic aromatic group formed by condensation of the above aromatic heterocyclic group and a C6-C14 aromatic hydrocarbon ring group" represented by Ar includes benzothienyl, benzofuryl, indolyl, isoindolyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, benzodioxolyl, quinolyl, isoquinolyl, quinoxalinyl, phthalazinyl (preferably benzothienyl, benzofuryl, benzodioxolyl, and quinolyl), etc. may be mentioned.

[0103] As used herein, "compound" means including all stereoisomers, geometric isomers, tautomers, and isotopes of the indicated structure. Compounds in this specification identified by name or structure as a particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.

[0104] As used herein, "SASP" refers to the senescence-associated secretory phenotype (SASP), a phenotype associated with senescent cells, which secrete high levels of inflammatory cytokines, immunomodulatory factors, growth factors, and proteases. SASP factors can be generally grouped into the following major categories: soluble signaling factors (interleukins, chemokines, and growth factors), secreted proteases, and secreted insoluble proteins / extracellular matrix (ECM) components.

[0105] As used herein, the term "Primary biliary cholangitis", also known as "Primary biliary cirrhosis" (PBC), refers to a chronic liver disease caused by the progressive destruction of the bile ducts in the liver. This disease is often incidentally discovered due to abnormal results in routine liver blood tests. When primary biliary cholangitis (PBC) is suspected, a blood test to examine anti-mitochondrial antibodies (AMA) can be performed. This test is positive in almost all people with primary biliary cholangitis (PBC). A liver biopsy, which removes a small sample of liver tissue with a small needle, can be helpful in confirming the diagnosis. For example, various co-existing conditions, including inflammatory bowel disease and colitis, can occur in PBC and PSC.

[0106] As used herein, the term "Primary sclerosing cholangitis" (PSC) refers to a chronic liver disease in which the intrahepatic and extrahepatic bile ducts of the liver become inflamed and scarred, eventually leading to stricture or obstruction. This results in the accumulation of bile in the liver, causing further liver damage. PSC causes progressive fibrosis, inflammatory destruction of the intrahepatic and extrahepatic bile ducts, and subsequent bile stasis. Patients often progress to cirrhosis, requiring liver transplantation. Genetic susceptibility, environmental triggers, a disrupted gut / liver axis, abnormal composition of the gut microbiota, and overproduction of bile / bile acids are thought to be some of the causes of PSC. This is often characterized by the presence of hyperactivated interactions between bile duct cells and immune cells such as mast cells. (Vesterhus. J Hep. 2017;67:6,1298 - 1323).

[0107] As used herein, the term "Ductular reaction" (DR) refers to a series of protein changes in liver tissue in response to either acute or chronic injury. This is characterized by the proliferation of reactive bile ducts induced by liver injury. DR is pathologically recognized as ductular hyperplasia and is commonly observed in biliary disorders.

[0108] As used herein, the term "Mast cell" (MC) refers to those found in connective tissues throughout the body, particularly under the skin, near blood vessels and lymphatic vessels, nerves, as well as in the lungs and intestines. Mast cells play an important role in how the immune system responds to certain bacteria and parasites and help to regulate other types of immune responses. Mast cells secrete chemokines and other factors (such as histamine) that promote the inflammatory response. In human PSCs, MCs infiltrate the liver and contribute to liver injury. MCs interact and are present near cholangiocytes. Evidence from the scientific literature suggests an important role for mast cells and chymase in eosinophilia. For example, gastric and duodenal biopsy specimens from patients with EoE and / or EG / EoD showed a significant increase in the mean mast cell count compared to biopsy specimens from patients without the disease. The mean mast cell count also correlated very well with the eosinophil count observed in esophageal and duodenal biopsy specimens from EoE patients. Furthermore, a high mast cell count has been associated with the presence of several EG / EoD symptoms (such as dysphagia, abdominal pain, diarrhea) and endoscopic features (i.e., duodenal erosions and granularity).

[0109] Chymase, an important mediator released after mast cell degradation, has been shown to promote eosinophil survival, infiltration and activation under these conditions. Therefore, chymase inhibition is an attractive target for EoE therapy.

[0110] As used herein, the term "Cholangiocyte proliferation" refers to the proliferation or regeneration of cholangiocytes that results in the expansion of the cholangiocyte population. Cholangiocytes are epithelial cells that are part of the bile ducts. Cholangiocytes contribute to bile secretion via the net release of bicarbonate and water. Cholangiocyte proliferation is induced during extrahepatic bile duct obstruction. The proliferative response of cholangiocytes during cholestasis is regulated by the complex interaction of several factors, including gastrointestinal hormones, neuroendocrine hormones and autocrine or paracrine signaling mechanisms.

[0111] As used herein, the term "Fibrosis" refers to the development of fibrous connective tissue as a repair response to injury or damage. Fibrosis can refer to connective tissue deposition that occurs as part of normal healing, or excessive tissue deposition that occurs as a pathological process.

[0112] As used herein, the term "Biliary obstruction" refers to the obstruction of any duct that transports bile from the liver to the gallbladder, or from the gallbladder to the small intestine. This can be caused by one or more of inflammatory lymph nodes, gallstones, cysts, injury from gallbladder surgery, tumors that have spread to the gallbladder, liver, pancreas or bile duct, inflammation of the bile duct or liver injury.

[0113] As used herein, the term "Hepatic fibrosis" refers to the wound healing response of the liver after acute or chronic injury that often results in the formation of scar tissue.

[0114] As used herein, the term "Liver abscess" refers to a mass filled with pus in the liver that can occur from injury to the liver or intra-abdominal infection spreading from the portal circulation.

[0115] As used herein, the term "Liver cirrhosis" refers to a late-stage liver disease in which healthy liver tissue is replaced by scar tissue and the liver is permanently damaged.

[0116] As used herein, the term "Colitis" refers to inflammation of the large intestine or colon. Common symptoms include abdominal pain and distension, bloody stools, the urge to have frequent bowel movements (tenesmus), dehydration and diarrhea.

[0117] As used herein, the term "Neonatal jaundice" refers to a liver condition that causes yellowing of the skin and eyes in newborns. Neonatal jaundice is common in premature infants. The cause is often immaturity of the liver, infection, medication, or blood disorders.

[0118] As used herein, the term "Obstructive jaundice" refers to a specific type of jaundice in which symptoms occur due to stenosis or obstruction of the bile duct or pancreatic duct, preventing the normal excretion of bile from the bloodstream into the intestine.

[0119] As used herein, the term "Primary bile acid malabsorption" refers to a idiopathic intestinal disorder associated with congenital diarrhea, steatorrhea, interruption of the enterohepatic circulation of bile acids, and a decrease in plasma cholesterol levels.

[0120] As used herein, the term "Acute cholecystitis" refers to inflammation of the gallbladder that occurs due to obstruction of the cystic duct or impaired gallbladder emptying.

[0121] As used herein, the term "Autoimmune hepatitis" refers to inflammation of the gallbladder that occurs due to obstruction of the cystic duct or impaired gallbladder emptying.

[0122] As used herein, the term "Benign recurrent intrahepatic cholestasis" (BRIC) refers to a rare genetic disorder characterized by intermittent episodes of jaundice and pruritus due to reduced ability of hepatocytes to secrete bile.

[0123] As used herein, the term "Cholestatic liver disease" refers to a group of diseases characterized by jaundice and cholestasis as the main symptoms, with various complications that can significantly affect the liver and lead to end-stage liver disease, cirrhosis, and liver-related complications.

[0124] As used herein, the term "Crigler-najjar syndrome" refers to a rare autosomal recessive genetic disorder characterized by the absence or reduced activity of UDP-glucuronosyltransferase, an enzyme required for the glucuronidation of unconjugated bilirubin in the liver. This is one of the main causes of congenital non-hemolytic jaundice.

[0125] As used herein, the term "Drug-induced hepatitis" refers to acute or chronic liver injury secondary to a drug or herb compound. This can be classified based on clinical symptoms (hepatocellular, cholestatic, or mixed), the mechanism of hepatotoxicity, or the histological appearance from a liver biopsy.

[0126] As used herein, the term "Gilbert’s syndrome" refers to a hereditary (genetic) liver disorder that affects the body's ability to process bilirubin. Bilirubin is a yellowish liquid waste product that occurs naturally when the body breaks down old red blood cells. Patients with Gilbert’s syndrome do not produce enough liver enzymes to keep bilirubin at normal levels. As a result, excess bilirubin accumulates in the body. Excess bilirubin is known as hyperbilirubinemia.

[0127] As used herein, the term "Intrahepatic cholestasis of pregnancy" refers to liver disorders in the late second and early third trimesters of pregnancy. This is also known as obstetric cholestasis (OC) and is characterized by pruritus and other liver function tests associated with increased serum bile acids.

[0128] As used herein, the term "Liver rejection" refers to the body's physiological reaction to foreign substances. When a new liver is placed in a person's body, the body perceives the transplanted organ as a threat and attempts to attack it. The immune system produces antibodies that try to kill the new organ without recognizing that the transplanted liver is beneficial. In many cases, drugs are given to trick the immune system into accepting the transplant in order for the organ to survive well in the new body.

[0129] As used herein, the term "Non-alcoholic fatty liver disease" (NAFLD) refers to an umbrella term for various liver conditions that affect people who consume little or no alcohol. The main feature of NAFLD is too much fat stored in liver cells.

[0130] As used herein, the term "Non-alcoholic steatohepatitis" (NASH) refers to a type of liver disease in which fat accumulates in the livers of people who consume little or no alcohol. This causes inflammation of the liver and damage to liver cells, which can lead to cirrhosis (scarring of the liver) and liver failure. People with non-alcoholic steatohepatitis are at high risk of developing liver cancer. This is more common in middle-aged adults, especially those who are overweight or obese, or have diabetes, or have high levels of cholesterol and triglycerides (a type of fat) in their blood.

[0131] As used herein, the term "Polycystic liver disease" refers to a rare condition in which cysts or fluid-filled sacs grow throughout the liver. The main symptom of polycystic liver disease is abdominal distension due to large masses of cysts in the liver. Other symptoms, also caused by most of the cysts in the abdomen, include shortness of breath, early satiety, abdominal discomfort, and back discomfort.

[0132] As used herein, the term "Veno-occlusive disease" refers to a condition in which some of the veins in the liver are blocked. This can reduce blood flow in the liver and lead to liver damage. Signs and symptoms include weight gain, yellowing of the skin and whites of the eyes, dark urine, and an increase in the size of the liver. This can occur at some point after radiation therapy to the liver and bile ducts, or after high-dose chemotherapy drugs are administered before a stem cell transplant. It is also called sinusoidal obstruction syndrome.

[0133] As used herein, the term "Wilson’s disease" refers to a genetic disorder in which excessive amounts of copper accumulate in the body, particularly in the liver, brain, and eyes. The signs and symptoms of Wilson’s disease usually first appear between the ages of 6 and 45, but most often begin during the teenage years. The features of this condition include a combination of liver disease and neurological and psychiatric problems.

[0134] As used herein, the term "EGID: Eosinophilic gastrointestinal disorder" refers to a group of rare gastrointestinal (GI) diseases that include eosinophilic gastritis (EoG), eosinophilic enteritis (EoN), and eosinophilic colitis (EoC). All of these are characterized by the presence of large numbers of eosinophils in the stomach or small intestine or large intestine. They affect different parts of the digestive tract from the esophagus to the large intestine. Common symptoms include heartburn, vomiting, stomach pain, weight loss, growth retardation in children, and diarrhea.

[0135] As used herein, the term "eosinophilic gastritis and / or eosinophilic duodenitis (EG / EoD)" refers to a condition that causes inflammation throughout the digestive system. Symptoms associated with EG / EoD vary from person to person and may include vomiting, abdominal pain, nausea, fullness, constipation, diarrhea, difficulty swallowing (dysphagia), ascites (fluid in the abdomen), heartburn, and a feeling of fullness.

[0136] As used herein, the term "eosinophilic esophagitis (EoE)" refers to a chronic and progressive condition in which immune cells (eosinophils) accumulate in the esophagus and ultimately damage the esophagus. Common symptoms include difficulty swallowing (dysphagia), even after taking a proton pump inhibitor (PPI), food getting stuck in the esophagus (impaction), feeling stuck, vomiting, and chest pain / heartburn.

[0137] III. Treatment Methods In an embodiment, the present disclosure is a method for treating or preventing hepatobiliary diseases in a subject in need of treatment or prevention of hepatobiliary diseases, the method comprising administering a therapeutically effective amount of a compound of formula (I): [Chemical formula] (wherein, Ar is (1) a C6-C14 aromatic hydrocarbon group, (2) a 5- to 8-membered aromatic heterocyclic group having 1 to 4 heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom, and an oxygen atom in place of a carbon atom, or (3) a bicyclic or tricyclic aromatic group formed by condensation of the above aromatic heterocyclic group and a C6-C14 aromatic hydrocarbon ring, The above groups (1)-(3) of Ar are (i) a halogen atom, (ii) nitro, (iii) cyano, (iv) C1-C6 alkyl optionally substituted with 1 to 3 halogen atoms, (v) C2-C6 alkenyl which may be substituted with 1 to 3 halogen atoms, (vi) C2-C6 alkynyl which may be substituted with 1 to 3 halogen atoms, (vii) C3-C6 cycloalkyl, (xviii) hydroxyl, (ix) halogen atom, mono- or di-C1-C6 alkylamino, C1-C6 alkoxy, mono- or di-C1-C6 alkylcarbamoyl, mono- or di-C7-C16 aralkylcarbamoyl, mono- or di-C1-C10 heteroaryl-C1-C6 alkylcarbamoyl, carboxyl, and C1-C6 alkoxycarbonyl, or C1-C6 alkoxy which may be substituted with 1 to 3 groups selected from the group consisting of 1 to 13 deuterium atoms, (x) C1-C5 alkylenedioxy, (xi) halogen atom, mono- or di-C1-C6 alkylamino, C1-C6 alkoxy, mono- or di-C1-C6 alkylcarbamoyl, mono- or di-C7-C16 aralkylcarbamoyl, mono- or di-C1-C10 heteroaryl-C1-C6 alkylcarbamoyl, carboxyl, and C1-C6 alkoxycarbonyl, or C1-C6 alkylthio which may be substituted with 1 to 3 groups selected from the group consisting of 1 to 13 deuterium atoms, (xii) amino, (xiii) mono-C1-C6 alkylamino, (xiv) di-C1-C6 alkylamino, (xv) 5- to 6-membered ring amino, (xvi) C1-C6 alkylcarbonyl, (xvii) carboxyl, (xviii) C1-C6 alkoxycarbonyl, (xix) carbamoyl, (xx) thiocarbamoyl, (xxi) mono-C1-C6 alkylcarbamoyl, (xxii) di-C1-C6 alkylcarbamoyl, (xxii) 5- or 6-membered ring aminocarbonyl, (xxiv) sulfo, (xxv) C1-C6 alkylsulfonyl, (xxvi) C1-C6 alkoxycarbonylamino, (xxvii) C1-C6 alkylcarbonylamino, (xxviii) mono- or di-C1-C6 alkylaminocarbonylamino, (xxix) aminosulfonyl, and (xxx) mono- or di-C1-C6 alkylaminosulfonyl which may be substituted with 1 to 5 groups selected from the group consisting of, or which may be substituted with 1 to 9 deuterium atoms, X is (1) a connecting bond, (2) a linear or branched C1-C6 alkylene which may be substituted with 1 to 12 deuterium atoms, (3) an oxygen atom, (4) NR 3 (wherein R 3 is a hydrogen atom or a C1-C6 alkyl group), or (5) -S(O)m- (wherein m is an integer from 0 to 2), Z is (1) a connecting bond or (2) CR 4 R 5 (wherein R 4 and R 5 are independently (A) a hydrogen atom, (B) a deuterium atom, (C) (i) carboxyl, (ii) C1-C6 alkoxycarbonyl, (iii) phenyl, (iv) hydroxyl, (v) C1-C6 alkoxy, (vi) a halogen atom, and (vii) a C1-C6 alkyl which may be substituted with 1 to 5 groups selected from the group consisting of or which may be substituted with 1 to 13 deuterium atoms, (D) (i) a halogen atom and (ii) a C3-C6 cycloalkyl which may be substituted with 1 to 5 groups selected from the group consisting of an alkyl group which may be substituted with 1 to 3 halogen atoms or which may be substituted with 1 to 11 deuterium atoms, (E) COOR6 (wherein, R 6 is a hydrogen atom or C1-C6 alkyl), or (F)CONR 7 R 8 (wherein, R 7 and R 8 are, independently, (a) a hydrogen atom, (b) (i) a halogen atom, (ii) C3-C6 cycloalkyl, (iii) carboxyl, (iv) C1-C6 alkoxycarbonyl, (v) C1-C6 alkylcarbonyl, (vi) carbamoyl, (vii) mono-C1-C6 alkylcarbamoyl, (viii) di-C1-C6 alkylcarbamoyl, (ix) C6-C12 aryl, and (x) C1-C10 heteroaryl, and may be substituted with 1 to 3 groups selected from the group consisting of C1-C6 alkyl optionally substituted with (c) a C6-C14 aromatic hydrocarbon group, (d) a 5- to 8-membered aromatic heterocyclic group having 1 to 4 heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom, and an oxygen atom in place of a carbon atom, or (e) a bicyclic or tricyclic aromatic group formed by condensation of the above aromatic heterocyclic group and a C6-C14 aromatic hydrocarbon ring and the groups (c) to (e) are each independently selected from the group consisting of (i) a halogen atom, (ii) nitro, (iii) cyano, (iv) C1-C6 alkyl optionally substituted with 1 to 3 halogen atoms, (v) C2-C6 alkenyl optionally substituted with 1 to 3 halogen atoms, (vi) C2-C6 alkynyl optionally substituted with 1 to 3 halogen atoms, (vii) C3-C6 cycloalkyl, (viii) hydroxyl, (ix) C1-C6 alkoxy optionally substituted with 1 to 3 halogen atoms, (x) C1-C5 alkylenedioxy, (xi) C1-C6 alkylthio optionally substituted with 1 to 3 halogen atoms, (xii) amino, (xiii) mono-C1-C6 alkylamino, (xiv) di-C1-C6 alkylamino, (xv) 5- to 6-membered ring amino, (xvi) C1-C6 alkylcarbonyl, (xvii) carboxyl, (xviii) C1-C6 alkoxycarbonyl, (xix) carbamoyl, (xx) thiocarbamoyl, (xxi) mono-C1-C6 alkylcarbamoyl, (xxii) di-C1-C6 alkylcarbamoyl, (xxiii) C6-C10 arylcarbamoyl, (xxiv) C1-C10 heteroarylcarbamoyl, (xxv) sulfo, (xxvi) C1-C6 alkylsulfonyl, (xxvii) aminosulfonyl, and (xxviii) mono- or di-C1-C6 alkylaminosulfonylamino, and may be substituted with 1 to 5 groups selected from the group or with 1 to 9 deuterium atoms) is) and W is (1) a hydrogen atom, (2) a C6-C14 aromatic hydrocarbon group, (3) a 5- to 8-membered aromatic heterocyclic group having 1 to 4 heteroatoms selected from nitrogen, sulfur, and oxygen atoms in place of carbon atoms, (4) a bicyclic or tricyclic aromatic group formed by condensation of the aromatic heterocyclic group and a C6-C14 aromatic hydrocarbon ring, or a deuterium atom Each of the groups (2) to (4) of W above is (i) a halogen atom, (ii) nitro, (iii) cyano, (iv) a C1-C6 alkyl optionally substituted with 1 to 3 groups selected from the group consisting of a halogen atom, amino, C1-C6 alkoxycarbonyl, C1-C6 alkoxycarbonylamino and carboxyl, (v) a C2-C6 alkenyl optionally substituted with 1 to 3 halogen atoms, (vi) a C2-C6 alkynyl optionally substituted with 1 to 3 halogen atoms, (vii) a C3-C6 cycloalkyl, (viii) hydroxyl, (ix) a C1-C6 alkoxy optionally substituted with 1 to 3 groups selected from the group consisting of a halogen atom, hydroxyl, C1-C6 alkoxy, amino and mono- or di-C1-C6 alkylamino, (x) a C1-C5 alkylenedioxy, (xi) a C1-C6 alkylthio optionally substituted with 1 to 3 groups selected from the group consisting of a halogen atom, hydroxyl, C1-C6 alkoxy, amino and mono- or di-C1-C6 alkylamino, (xii) amino, (xiii) mono-C1-C6 alkylamino, (xiv) di-C1-C6 alkylamino, (xv) a 5- to 6-membered ring amino, (xvi) a C1-C6 alkyl-carbonyl, (xvii) carboxyl, (xviii) a C1-C6 alkoxycarbonyl optionally substituted with a halogen atom, (xix) a C7-C16 aralkyloxycarbonyl optionally substituted with a halogen atom, (xx) carbamoyl, (xxi) a mono-C1-C6 alkylcarbamoyl optionally substituted with 1 to 3 groups selected from the group consisting of a halogen atom, hydroxyl, carboxyl, C1-C6 alkoxy, amino, and mono or di-C1-C6 alkylamino, (xxii) a di-C1-C6 alkylcarbamoyl optionally substituted with hydroxyl, (xxiii) a 5- to 6-membered ring aminocarbonyl optionally substituted with a C1-C6 alkoxycarbonyl, (xxiv) a C6-C10 arylcarbamoyl, (xxv) a C1-C10 heteroarylcarbamoyl, (xxvi) a C7-C16 aralkylcarbamoyl, (xxvii) a C1-C10 heteroaryl-C1-C6 alkylcarbamoyl, (xxviii) an N-C1-C6 alkyl-N-C6-C12 arylcarbamoyl,(xxix) C3-C6 cycloalkylcarbamoyl, (xxx) sulfo, (xxxi) C1-C6 alkylsulfonyl, (xxxii) C1-C6 alkylsulfonylamino, (xxxiii) C6-C12 arylsulfonylamino optionally substituted with C1-C6 alkyl, (xxxiv) C1-C10 heteroarylsulfonylamino, (xxxv) C1-C6 alkoxycarbonylamino, (xxxvi) C1-C6 alkylcarbonylamino, (xxxvii) mono- or di-C1-C6 alkylaminocarbonylamino, (xxxviii) C6-C12 aryl, (xxxix) C1-C10 heteroaryl, (xl) C6-C10 aryloxy, (xli) C1-C10 heteroaryloxy, (xlii) C7-C16 aralkyloxy, (xliii) C1-C10 heteroaryl-C1-C6 alkyloxy, (xliv) aminosulfonyl, (xlv) mono- or di-C1-C6 alkylaminosulfonyl, (xlvi) C7-C16 aralkyloxycarbonyl, and (xlvii) C1-C10 heteroaryl-C1-C6 alkyloxycarbonyl, and may be substituted with 1 to 5 groups selected from the group consisting of, or may be substituted with 1 to 9 deuterium atoms, R1 is (1) a hydrogen atom, (2) C1-C6 alkyl optionally substituted with 1 to 3 (i) halogen atoms or (ii) C3-C6 cycloalkyl, or (iii) 1 to 13 deuterium atoms, (3) C2-C6 alkenyl optionally substituted with 1 to 3 (i) halogen atoms or (ii) C3-C6 cycloalkyl, or (iii) 1 to 11 deuterium atoms, (4) C2-C6 alkynyl optionally substituted with 1 to 3 (i) halogen atoms or (ii) C3-C6 cycloalkyl, or (iii) 1 to 9 deuterium atoms, or (5) C3-C6 cycloalkyl optionally substituted with 1 to 3 (i) halogen atoms or (ii) C3-C6 cycloalkyl, or (iii) 1 to 11 deuterium atoms and R2 is (1) OR 9 or (2) NR 10 R 11 (wherein R 9 R 10 and R 11 are each independently (A) a hydrogen atom, (B) C1-C6 alkyl, (C) C2-C6 alkenyl, (D) C3-C6 alkynyl, (E) C3-C6 cycloalkyl, (F) a C6-C14 aromatic hydrocarbon group, (G) a 5- to 8-membered aromatic heterocyclic group having 1 to 4 heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom in place of a carbon atom, or (H) a bicyclic or tricyclic aromatic group formed by condensation of the above aromatic heterocyclic group and a C6-C14 aromatic hydrocarbon ring and Each of the groups (B) to (E) is substituted with 1 to 3 groups selected from the group consisting of (i) a halogen atom, (ii) C3-C6 cycloalkyl, (iii) hydroxyl, (iv) C1-C6 alkoxy optionally substituted with 1 to 3 halogen atoms, (v) amino, (vi) mono-C1-C6 alkylamino, (vii) di-C1-C6 alkylamino, (viii) 5- to 6-membered ring amino, (ix) carboxyl, (x) C1-C6 alkoxycarbonyl, (xi) C1-C6 alkylcarbonyl, (xii) carbamoyl, (xiii) mono-C1-C6 alkylcarbamoyl, (xiv) di-C1-C6 alkylcarbamoyl, (xv) C6-C12 aryl, and (xvi) C1-C10 heteroaryl, or may be substituted with 1 to 13 deuterium atoms. Further, each of the groups (F) to (H) is (i) a halogen atom, (ii) nitro, (iii) cyano, (iv) C1-C6 alkyl optionally substituted with 1 to 3 halogen atoms, (v) C3-C6 cycloalkyl optionally substituted with 1 to 3 halogen atoms, (vi) hydroxyl, (vii) C1-C6 alkoxy optionally substituted with 1 to 3 halogen atoms, (viii) amino, (ix) mono-C1-C6 alkylamino, (x) di-C1-C6 alkylamino, (xi) 5- to 6-membered ring amino, (xii) C1-C6 alkylcarbonyl, (xiii) carboxyl, (xiv) C1-C6 alkoxycarbonyl, (xv) mono-C1-C6 alkylcarbamoyl, (xvii) di-C1-C6 alkylcarbamoyl, (xviii) C1-C6 alkylsulfonyl, (xix) aminosulfonyl, and (xx) mono- or di-C1-C6 alkylaminosulfonyl, or may be substituted with 1 to 5 groups selected from the group consisting of 1 to 9 deuterium atoms, or R1 and R2 may together with the atoms to which they are attached form a 5- or 6-membered heterocyclic ring. The above 5- or 6-membered heterocyclic ring is (A) a halogen atom, (B) oxo, (C) hydroxyl (D) C1-C6 alkyl, (E) C2-C6 alkenyl, (F) C2 - C6 alkynyl, (G) C3 - C6 cycloalkyl (H) C6 - C14 aromatic hydrocarbon group, (I) Instead of a carbon atom, a 5 - 8 membered aromatic heterocyclic group having 1 - 4 heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom, and (J) A bicyclic or tricyclic aromatic group formed by the condensation of the above aromatic heterocyclic group and a C6 - C14 aromatic hydrocarbon ring substituted with 1 - 3 groups selected from the group consisting of, or (K) may be substituted with 1 - 6 deuterium atoms, Each of the groups (D) to (G) above is optionally substituted with 1 to 3 groups selected from the group consisting of (i) a halogen atom, (ii) C3-C6 cycloalkyl, (iii) hydroxyl, (iv) C1-C6 alkoxy optionally substituted with 1 to 3 halogen atoms, (v) amino, (vi) mono-C1-C6 alkylamino, (vii) di-C1-C6 alkylamino, (viii) 5- to 6-membered ring amino, (ix) carboxyl, (x) C1-C6 alkoxycarbonyl, (xi) C1-C6 alkyl-carbonyl, (xii) carbamoyl, (xiii) mono-C1-C6 alkylcarbamoyl, (xiv) di-C1-C6 alkylcarbamoyl, (xv) C6-C12 aryl, and (xvi) C1-C10 heteroaryl, or is optionally substituted with 1 to 13 deuterium atoms. Each of the groups (H) to (J) above is optionally substituted with 1 to 5 groups selected from the group consisting of (i) a halogen atom, (ii) nitro, (iii) cyano, (iv) C1-C6 alkyl optionally substituted with 1 to 3 halogen atoms, (v) C3-C6 cycloalkyl optionally substituted with 1 to 3 halogen atoms, (vi) hydroxyl, (vii) C1-C6 alkoxy optionally substituted with 1 to 3 halogen atoms, (viii) amino, (ix) mono-C1-C6 alkylamino, (x) di-C1-C6 alkylamino, (xi) 5- to 6-membered ring amino, (xii) C1-C6 alkylcarbonyl, (xiii) carboxyl, (xiv) C1-C6 alkoxycarbonyl, (xv) carbamoyl, (xvi) mono-C1-C6 alkylcarbamoyl, (xvii) di-C1-C6 alkylcarbamoyl, (xviii) C1-C6 alkylsulfonyl, (xix) aminosulfonyl, and (xx) mono- or di-C1-C6 alkylaminosulfonyl, or is optionally substituted with 1 to 9 deuterium atoms) is) Also included is a method comprising administering to a subject the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is (1) 4-{ (1R)-1-[({(6R)-6-(5-chloro-2-methoxybenzyl)-7-oxo-3-[(pyridin-2-yl)oxy]imino}-1,4-diazepan-1-yl)carbonyl]amino}propyl]benzoic acid, (2) 2-amino-4-[(1R)-1-({[(6S)-6-(5-chloro-2-methoxybenzyl)-3-(ethoxyimino)-7-oxo-1,4-diazepan-1-yl]carbonyl}amino)butyl]benzoic acid, (3) 2-amino-4-{ (1R)-1-[({(6S)-6-(5-chloro-2-methoxybenzyl)-7-oxo-3-[(2,2,2-trifluoroethoxy)imino]-1,4-diazepan-1-yl}carbonyl)amino]butyl}benzoic acid, (4) 2-amino-4-{ (1R)-1-[({(6R)-6-(5-chloro-2-methoxybenzyl)-3-[(3,5-difluorophenoxy)imino]-7-oxo-1,4-diazepan-1-yl}carbonyl)amino]ethyl}benzoic acid, (5) 2-amino-4-[(1R)-1-({[(6S)-6-(5-chloro-2-methoxybenzyl)-3-(methoxyimino)-4-methyl-7-oxo-1,4-diazepan-1-yl]carbonyl}amino)butyl]benzoic acid, (6) (4-{ (1R)-1-[({(6R)-6-(5-chloro-2-methoxybenzyl)-3-[(3,5-difluorophenoxy)imino]-7-oxo-1,4-diazepan-1-yl}carbonyl)amino]ethyl}phenyl)acetic acid, (7) 2-amino-4-{ [({(6R)-6-(5-chloro-2-methoxybenzyl)-3-[(3,5-difluorophenoxy)imino]-7-oxo-1,4-diazepan-1-yl}carbonyl)amino]methyl}benzoic acid, (8) {4-[(1R)-1-({[(6R)-6-(5-chloro-2-methoxybenzyl)-7-oxo-3-(phenoxyimino)-1,4-diazepan-1-yl]carbonyl}amino)propyl]phenyl}acetic acid, (9) 2-Amino-4-[(1R)-1-({[(6R)-6-(5-chloro-2-methoxybenzyl)-7-oxo-3-(phenoxyimino)-1,4-diazepan-1-yl]carbonyl}amino)propyl]benzoic acid, or (10) 2-Amino-4-[(1R)-1({[(6R)-6-(5-chloro-2-methoxybenzyl)-3-(ethoxyimino)-7-oxo-1,4-diazepan-1-yl]carbonyl}amino)butyl]benzoic acid selected from the group consisting of.

[0138] In an embodiment, the compound of formula (I) is a highly selective inhibitor for chymase over cathepsin G. Due to the high selectivity, the compound of formula (I) has fewer side effects after long-term use in the treatment of hepatobiliary diseases compared to non-selective chymase inhibitors.

[0139] In an embodiment, the compound of formula (I) is 2-amino-4-[(1R)-1-({[(3Z,6S)-6-(5-chloro-2-methoxybenzyl)-3-(ethoxyimino)-7-oxo-1,4-diazepan-1-yl]carbonyl}amino)butyl]benzoic acid (Compound 1):

Chemical formula

[0140] In a preferred embodiment, Compound 1 is the monoacetic acid solvate of Compound 1:

Chemical formula

[0141] In an embodiment, the monoacetic acid solvate of Compound 1 is about 1600 times more selective for chymase than cathepsin G. In an embodiment, the monoacetic acid solvate of Compound 1 has fewer side effects than other non-selective chymase inhibitors in the treatment of hepatobiliary diseases.

[0142] In embodiments, hepatobiliary diseases are selected from the group consisting of acute hepatitis, alcoholic hepatitis, alcoholic liver disease, extrahepatic biliary stasis, hepatic fibrosis, liver abscess, cirrhosis, neonatal jaundice, obstructive jaundice, primary bile acid malabsorption, acute cholecystitis, autoimmune hepatitis, benign recurrent intrahepatic cholestasis, biliary obstruction, cholestatic liver disease, Crigler-Najjar syndrome, drug-induced hepatitis, Gilbert syndrome, intrahepatic cholestasis of pregnancy, liver rejection, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, polycystic liver disease, PBC, PSC, veno-occlusive disease, Wilson's disease. In embodiments, hepatobiliary diseases include PSC. In embodiments, hepatobiliary diseases include PBC.

[0143] In embodiments, the present disclosure includes a method of treating a hepatobiliary disease in a subject in need of treatment of a hepatobiliary disease, the method comprising improving jaundice by administering a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

[0144] In embodiments, the present disclosure includes a method of treating a hepatobiliary disease in a subject in need of treatment of a hepatobiliary disease, the method comprising improving pruritus by administering a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

[0145] In embodiments, the present disclosure includes a method of treating a hepatobiliary disease in a subject in need of treatment of a hepatobiliary disease, the method comprising improving inflammation by administering a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

[0146] In various embodiments, the present disclosure includes treatment regimens involving administration of a pharmaceutical formulation once a day, twice a day, three times a day, once every two days, or once every three days, or once a week to a patient in need of administration of the pharmaceutical formulation. Administration is preferably oral, but other routes including, for example, rectal or intracolonic administration are contemplated.

[0147] In embodiments, the pharmaceutical formulation includes one or more second therapeutic agents.

[0148] In certain embodiments, the method includes administering to the subject, as adjuvant therapy, one or more additional second formulations comprising one or more second therapeutic agents. In various embodiments, the second formulations may be administered simultaneously or sequentially for a specified period of time. In embodiments, the second formulations may be administered by the same route of administration as the first formulation or by a different route of administration than the first formulation. In embodiments, the second formulations are immediate release formulations, sustained release formulations, or delayed release formulations.

[0149] In embodiments, the one or more second therapeutic agents are steroids (such as betamethasone), immunosuppressants (such as tacrolimus and pimecrolimus), anti-allergy agents (clemastine fumarate, d-chlorpheniramine maleate, cyproheptadine hydrochloride, promethazine hydrochloride, homochlorcyclizine hydrochloride, mequitazine, diphenhydramine hydrochloride, ebastine, cetirizine hydrochloride, olopatadine hydrochloride, fexofenadine hydrochloride, sodium cromoglicate, emedastine fumarate, sprastin tosylate, and epinastine hydrochloride, etc.).

[0150] In embodiments, the present disclosure encompasses a method for treating or preventing hepatobiliary diseases in a subject, the method comprising administering to the subject a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt or solvate thereof.

[0151] In embodiments, the present disclosure encompasses a method for treating or preventing jaundice in a subject suffering from hepatobiliary diseases in the subject, the method comprising administering to the subject a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt or solvate thereof.

[0152] In some embodiments, the present disclosure encompasses a method for treating or preventing one or more of hepatomegaly, cirrhosis, biliary obstruction, occult blood in feces, fecal incontinence, fever, fatigue, weight loss, abdominal pain, diarrhea, nausea, cramps, number of mast cells and eosinophils, dysphagia, gastroesophageal reflux disease (GERD), a feeling of fullness, early satiety, loss of appetite, and pruritus in a subject suffering from a target hepatobiliary disease, the method comprising administering to the subject a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt or solvate thereof.

[0153] In an embodiment, the present disclosure encompasses a method for treating or preventing inflammation in a subject suffering from a hepatobiliary disease, the method comprising administering to the subject a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt or solvate thereof.

[0154] In an embodiment, the present disclosure encompasses a method for reducing mast cell infiltration in a subject suffering from a hepatobiliary disease, the method comprising administering to the subject a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt or solvate thereof.

[0155] In an embodiment, the present disclosure is a method for treating or preventing hepatobiliary diseases in a subject, comprising administering to the subject a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt or solvate thereof in an amount of about 10 mg to about 1000 mg per unit dose, for example, about 50 mg to about 950 mg per unit dose, about 10 mg to about 900 mg per unit dose, about 10 mg to about 850 mg per unit dose, about 10 mg to about 800 mg per unit dose, about 10 mg to about 750 mg per unit dose, about 10 mg to about 700 mg per unit dose, about 10 mg to about 650 mg per unit dose, about 10 mg to about 600 mg per unit dose, about 50 mg to about 550 mg per unit dose, about 50 mg to about 500 mg per unit dose, about 50 mg to about 450 mg per unit dose, about 50 mg to about 400 mg per unit dose, about 50 mg to about 350 mg per unit dose, about 50 mg to about 300 mg per unit dose, about 50 mg to about 250 mg per unit dose, about 50 mg to about 200 mg per unit dose, about 50 mg to about 150 mg per unit dose, about 50 mg to about 100 mg per unit dose.

[0156] In an embodiment, the hepatobiliary disease is selected from the group consisting of acute hepatitis, alcoholic hepatitis, alcoholic liver disease, extrahepatic biliary stasis, liver fibrosis, liver abscess, cirrhosis, neonatal jaundice, obstructive jaundice, primary bile acid malabsorption, acute cholecystitis, autoimmune hepatitis, benign recurrent intrahepatic cholestasis, biliary obstruction, cholestatic liver disease, Crigler-Najjar syndrome, drug-induced hepatitis, Gilbert's syndrome, intrahepatic cholestasis of pregnancy, liver rejection, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, polycystic liver disease, PBC, PSC, veno-occlusive disease, Wilson's disease. In an embodiment, the hepatobiliary disease includes PSC. In an embodiment, the hepatobiliary disease includes PBC.

[0157] In an embodiment, the present disclosure encompasses a method for treating or preventing PSC in a subject in need of treatment or prevention of PSC, the method comprising administering to the subject a therapeutically effective amount of a monoacetate solvate of Compound 1. In an embodiment, the monoacetate solvate of Compound 1 is in the range of about 10 mg to 100 mg per unit dose.

[0158] In an embodiment, the present disclosure encompasses a method for treating or preventing PBC in a subject in need of treatment or prevention of PBC, the method comprising administering to the subject a therapeutically effective amount of a monoacetate solvate of Compound 1. In an embodiment, the monoacetate solvate of Compound 1 is in the range of about 10 mg to 100 mg per unit dose.

[0159] In an embodiment, the present disclosure encompasses a method for treating or preventing EGID in a subject in need of treatment or prevention of EGID, the method comprising administering to the subject a therapeutically effective amount of a compound according to formula (I) or a pharmaceutically acceptable salt or solvate thereof.

[0160] In an embodiment, the present disclosure encompasses a method for treating or preventing colitis in a subject in need of treatment or prevention of colitis, the method comprising administering to the subject a therapeutically effective amount of a compound of the present invention comprising a monoacetate solvate of Compound 1. In an embodiment, such a compound comprising a monoacetate solvate of Compound 1 is in the range of about 10 mg to 100 mg per unit dose. In an embodiment, the present disclosure further encompasses a method for treating or preventing ulcerative colitis (UC) in a subject in need of treatment or prevention of ulcerative colitis (UC), the method comprising administering to the subject a therapeutically effective amount of a compound of the present invention comprising a monoacetate solvate of Compound 1. In an embodiment, such a compound comprising a monoacetate solvate of Compound 1 is in the range of about 10 mg to 100 mg per unit dose.

[0161] In an embodiment, the present disclosure is a method for treating or preventing Crohn's disease (CD) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the present invention comprising a monoacetate solvate of Compound 1. In an embodiment, such a compound comprising a monoacetate solvate of Compound 1 is in the range of about 10 mg to 100 mg per unit dose.

[0162] In an embodiment, the present disclosure is a method for treating or preventing EGID in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt or solvate thereof.

[0163] In certain embodiments, EGID is selected from the group consisting of eosinophilic gastroenteritis, eosinophilic esophagitis, eosinophilic duodenitis, and eosinophilic gastritis.

[0164] IV. Synthesis of Compounds The compounds of the present disclosure can be readily synthesized by various methods known in the art. The synthesis of the 7-membered ring compounds of the present disclosure is disclosed in U.S. Patent No. 8,846,660, which is hereby incorporated by reference in its entirety and relied upon.

[0165] V. Dosage and Administration: In various embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is administered in an amount in the range of about 10 mg to 1000 mg per unit dose (about 50 mg to about 950 mg per unit dose, about 10 mg to about 900 mg per unit dose, about 10 mg to about 850 mg per unit dose, about 10 mg to about 800 mg per unit dose, about 10 mg to about 750 mg per unit dose, about 10 mg to about 700 mg per unit dose, about 10 mg to about 650 mg per unit dose, about 10 mg to about 600 mg per unit dose, about 50 mg to about 550 mg per unit dose, about 50 mg to about 500 mg per unit dose, about 50 mg to about 450 mg per unit dose, about 50 mg to about 400 mg per unit dose, about 50 mg to about 350 mg per unit dose, about 50 mg to about 300 mg per unit dose, about 50 mg to about 250 mg per unit dose, about 50 mg to about 200 mg per unit dose, about 50 mg to about 150 mg per unit dose, about 50 mg to about 100 mg per unit dose). In some embodiments, the compound of formula (I) (milligrams per kilogram of the subject's body weight) is in the range of about 0.1 mg / kg to about 100 mg / kg.

[0166] In certain embodiments, the dosage (in milligrams per kilogram of the subject's body weight) of the compound of formula (I) or a pharmaceutically acceptable salt thereof is in the range of about 0.1 to about 100 mg / kg, preferably about 1 to 50 mg / kg, more preferably about 1 to about 10 mg / kg, and is administered once a day, twice a day, three times a day, once every two days, or once every three days, or once a week. In some embodiments, the unit dose (total unit dose) of Compound 1 or a pharmaceutically acceptable salt thereof is in the range of about 10 mg to about 1000 mg per unit dose, for example, about 50 mg to about 500 mg per unit dose.

[0167] In certain embodiments, the dosage of Compound 1 or a pharmaceutically acceptable salt or solvate thereof (based on the amount of the active ingredient, in milligrams per kilogram of the subject's body weight) is from about 0.1 mg / kg to about 100 mg / kg, such as, for example, about 0.2 mg / kg, about 0.4 mg / kg, about 0.6 mg / kg, about 0.8 mg / kg, about 1.0 mg / kg, about 1.2 mg / kg, about 1.4 mg / kg, about 1.6 mg / kg, about 1.8 mg / kg, about 2.0 mg / kg, about 2.2 mg / kg, about 2.4 mg / kg, about 2.6 mg / kg, about 2.8 mg / kg, about 3.0 mg / kg, about 3.2 mg / kg, about 3.4 mg / kg, about 3.6 mg / kg, about 3.8 mg / kg, about 4.0 mg / kg, about 4.2 mg / kg, about 4.4 mg / kg, about 4.6 mg / kg, about 4.8 mg / kg, about 5.0 mg / kg, about 5.2 mg / kg, about 5.4 mg / kg, about 5.6 mg / kg, about 5.8 mg / kg, about 6.0 mg / kg, about 6.2 mg / kg, about 6.4 mg / kg, about 6.6 mg / kg, about 6.8 mg / kg, about 7.0 mg / kg, about 7.2 mg / kg, about 7.4 mg / kg, about 7.6 mg / kg, about 7.8 mg / kg, about 8.0 mg / kg, about 8.2 mg / kg, about 8.4 mg / kg, about 8.6 mg / kg, about 8.8 mg / kg, about 9.0 mg / kg, about 9.2 mg / kg, about 9.4 mg / kg, about 9.6 mg / kg, about 9.8 mg / kg, or about 10.0 mg / kg, about 12 mg / kg, about 14 mg / kg, about 16 mg / kg, about 18 mg / kg, about 20 mg / kg, about 22 mg / kg, about 24 mg / kg, about 26 mg / kg, about 28 mg / kg, about 30 mg / kg, about 32 mg / kg, about 34 mg / kg, about 36 mg / kg, about 38 mg / kg, about 40 mg / kg, about 42 mg / kg, about 44 mg / kg, about 46 mg / kg, about 48 mg / kg, about 50 mg / kg, about 52 mg / kg, about 54 mg / kg, about 56 mg / kg, about 58 mg / kg, about 60 mg / kg, about 62 mg / kg, about 64 mg / kg, about 66 mg / kg, about 68 mg / kg, about 70 mg / kg, about 72 mg / kg, about 74 mg / kg, about 76 mg / kg, about 78 mg / kg, about 80 mg / kg, about 82 mg / kg, about 84 mg / kg, about 86 mg / kg, about 88 mg / kg, about 90 mg / kg, about 92 mg / kg, about 94 mg / kg, about 96 mg / kg, about 98 mg / kg, or about 100 mg / kg (including all values and ranges therebetween).

[0168] The unit dose (total unit dose) of Compound 1 or a pharmaceutically acceptable salt or solvate thereof is from about 10 mg to 1000 mg, for example, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, or about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, about 800 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 860 mg, about 870 mg, about 880 mg, about 890 mg, about 900 mg, about 910 mg, about 920 mg, about 930 mg, about 940 mg, about 950 mg, about 960 mg, about 970 mg, about 980 mg, about 990 mg, about 1000 mg (including all values and ranges therebetween). In embodiments, the unit dose of Compound 1 or a pharmaceutically acceptable salt or solvate thereof in a pharmaceutical formulation is administered once a day, twice a day, three times a day, once every two days, or once every three days, or once a week. In embodiments, the unit dose of ondansetron is administered once a day. In embodiments, the unit dose of ondansetron is administered twice a day.In various embodiments, the pharmaceutical composition, formulation, and dosage form can be administered once or more per day, for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 days, can be extended for more than 1 month, or can be administered at various intervals within the above time frame.

[0169] In various embodiments, the unit dosage range of Compound 1 or a pharmaceutically acceptable salt or solvate thereof used in the pharmaceutical formulations of the present disclosure is from about 10 mg to about 1000 mg, from about 50 mg to about 950 mg, from about 50 mg to about 900 mg, from about 50 mg to about 850 mg, from 50 mg to about 800 mg, from about 50 mg to about 750 mg, from about 50 mg to about 700 mg, from about 50 mg to about 650 mg, from about 50 mg to about 600 mg, from about 50 mg to about 550 mg, from about 50 mg to about 500 mg, from about 50 mg to about 450 mg, from about 50 mg to about 400 mg, from about 50 mg to about 350 mg, from about 50 mg to about 300 mg, from about 50 mg to about 250 mg, from about 50 mg to about 200 mg, from about 50 mg to about 150 mg, from about 50 mg to about 100 mg. In embodiments, the dosage is administered once a day, twice a day, three times a day, once every two days, or once every three days or once a week.

[0170] In various embodiments, the unit dosage of Compound 1 or a pharmaceutically acceptable salt or solvate thereof included in the present disclosure is about 10 mg, about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 900 mg, about 950 mg, about 1000 mg. The dosage can be administered once a day, twice a day, three times a day, once every two days, or once every three days or once a week.

[0171] In an embodiment, the preferred dosages of Compound 1 or its pharmaceutically acceptable salt or solvate are about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg or about 100 mg, about 150 mg. The dosages can be administered once a day, twice a day, three times a day, once every two days, once every three days or once a week.

[0172] VI. Pharmaceutical Composition In an embodiment, the present disclosure provides a pharmaceutical composition comprising a compound of formula (I) or its pharmaceutically acceptable salt or solvate for treating hepatobiliary diseases. In an embodiment, the diseases are selected from acute hepatitis, alcoholic hepatitis, alcoholic liver disease, colitis, extrahepatic cholestasis, liver fibrosis, liver abscess, cirrhosis, neonatal jaundice, obstructive jaundice, primary bile acid malabsorption, acute cholecystitis, autoimmune hepatitis, benign recurrent intrahepatic cholestasis, biliary obstruction, cholestatic liver disease, Crigler-Najjar syndrome, drug-induced hepatitis, Gilbert's syndrome, intrahepatic cholestasis of pregnancy, liver rejection, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, polycystic liver disease, PBC, PSC, veno-occlusive disease, Wilson's disease.

[0173] In another embodiment, the present disclosure provides a pharmaceutical composition comprising a compound of formula (I) or its pharmaceutically acceptable salt or solvate for treating EGID. In an embodiment, EGID is selected from the group consisting of eosinophilic gastroenteritis, and eosinophilic esophagitis, eosinophilic duodenitis, eosinophilic gastritis.

[0174] In one embodiment, the compound of formula (I) is Compound 1 or its pharmaceutically acceptable salt or solvate. In an embodiment, Compound 1 or its pharmaceutically acceptable salt or solvate is 2-amino-4-[(1R)-1-({[(3Z,6S)-6-(5-chloro-2-methoxybenzyl)-3-(ethoxyimino)-7-oxo-1,4-diazepan-1-yl]carbonyl}amino)butyl]benzoic acid monoacetate solvate.

[0175] In an embodiment, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, together with one or more acceptable adjuvants (e.g., a carrier or an excipient).

[0176] The pharmaceutical composition of the present disclosure can be administered by any convenient route suitable for the desired treatment. Oral or parenteral routes are suitable for administering the pharmaceutical composition for treating hepatobiliary diseases (e.g., PSC, PBC).

[0177] The pharmaceutical composition of the present disclosure can also be administered orally with site-specific or targeted delivery of the compound of formula (I) or Compound 1 as an active agent. In some embodiments, the composition is designed for targeted delivery, e.g., intestinal targeted delivery, liver targeted delivery. In an embodiment, the oral composition can be immediate release or modified release or delayed release or timed release. In some embodiments, the oral composition for specific site delivery can include tablets, troches, lozenges, dispersible powders, pellets, multi-unit particle systems (MUPS) granules, hard or soft capsules, suspensions, solutions, etc. In some embodiments, the pharmaceutical formulation can be in unit dosage form.

[0178] Accordingly, the present disclosure also provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and either a conjugate of the present disclosure or a pharmaceutically acceptable salt of a compound of the present disclosure. Suitable excipients can be tailored to the specific composition and route of administration by methods well known in the art, e.g., REMINGTON'S PHARMACEUTICAL SCIENCES.

[0179] The oral pharmaceutical composition may further contain a carrier, such as a diluent, wax, flavoring agent, binder, preservative, tablet disintegrant, bioadhesive polymer, polymer or encapsulating or coating material (e.g., enteric coating material), etc. In some embodiments, the polymer can be an immediate release polymer, sustained release polymer, controlled release polymer, enteric coating polymer or colon release polymer, etc. Details regarding the techniques for formulation and administration are well described in the scientific and patent literature. See, for example, the latest edition of Remington’s Pharmaceutical Sciences, Maack Publishing Co, Easton Pa (“Remington’s”).

[0180] In some embodiments, in a solid composition such as a tablet, the active agent is mixed with a pharmaceutical carrier. Examples of pharmaceutical carriers that can be incorporated into the tablets of the present disclosure include one or more of the following: diluents, waxes, flavoring agents, binders, preservatives, tablet disintegrants, polymers or capsule materials or coating materials (e.g., enteric coating materials), and the like.Conventional tablet-forming ingredients include binders such as starch, corn starch, polyvinylpyrrolidone, gums, gum arabic, gelatin, cellulose derivatives and combinations thereof; diluents such as microcrystalline cellulose, lactose, dibasic or tribasic calcium phosphate, confectioner's sugar, compressible sugar, dextrate, dextrin, dextrose, fructose, lactitol, mannitol, sucrose, starch xylitol, sorbitol, talc, calcium carbonate, calcium sulfate and combinations thereof; lubricants such as magnesium, aluminum, calcium or zinc stearate, polyethylene glycol, glyceryl behenate, glyceryl monostearate, mineral oil sodium stearyl fumarate, stearic acid, hydrogenated vegetable oil, talc, hydrogenated soybean oil, stearyl alcohol and combinations thereof; glidants such as magnesium trisilicate, powdered cellulose, starch, talc, tribasic calcium phosphate, calcium silicate, magnesium stearate, magnesium silicate, colloidal silicon dioxide, or silicon hydrogel and combinations thereof; surfactants; waxes; disintegrants; bioadhesive polymers such as proteins such as pectin, zein, etc., polysaccharides such as cellulose, dextran, etc., polyamides, polycarbonates, polyalkylenes, polyalkylene glycols, polyalkylene oxides, polyalkylene terephthalates, polyvinyl alcohol, polyvinyl ethers, polyvinyl esters, polyvinyl halides, polyvinylpyrrolidone, polyglycolide, polysiloxanes, polyurethanes, polystyrenes, polymers of acrylic and methacrylic esters, polylactide, polyanhydrides, polyorthoesters, and combinations thereof; controlled release polymers which can be, but are not limited to, individual and combinations of ethyl acrylate and methyl methacrylate copolymer dispersions; modified release polymers such as cellulose derivative vinylpyrrolidone polymers and copolymers; alkylene oxides and water. These can be used to form solid dosage forms containing a homogeneous mixture of the compounds of the present disclosure or non-toxic pharmaceutically acceptable salts thereof.Next, the solid pre-formulation composition is subdivided into the above types of unit dosage forms. Tablets, pills, etc. of the formulation or composition can be formulated by coating or other means to provide a dosage form for site-specific drug delivery, and the advantages of long-term action can be obtained. For example, a tablet or pill can include an inner composition covered by an outer component. Further, the two components can be separated by an enteric coating that functions to resist disintegration and allows the inner component to pass through the stomach intact or allows the release to be delayed. In some embodiments, the pharmaceutical formulation can be in the form of a suspension.

[0181] Furthermore, pigments and colorants may be added.

[0182] In some embodiments, the pharmaceutical formulation comprises a drug targeting molecular conjugate of the present disclosure complexed with liposomes. Methods for producing liposomes are known to those skilled in the art.

[0183] In some embodiments, sustained release preparations comprising the drug targeting molecular conjugates described herein can be manufactured. Suitable examples of sustained release preparations include a semipermeable matrix of a solid hydrophobic polymer containing the drug conjugate, and the matrix is in the form of a shaped article (e.g., a film or microcapsule). Methods for producing sustained release preparations are known to those skilled in the art. In some embodiments, pharmaceutical compositions suitable for parenteral injection can include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as propylene glycol, polyethylene glycol, glycerol, etc.), suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters (such as ethyl oleate). Suitable fluidity can be maintained, for example, by the use of coatings such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants.

[0184] VII. Hepatobiliary diseases: In embodiments, the methods of the present disclosure are useful for treating various hepatobiliary diseases and hepatobiliary-related diseases. In embodiments, the diseases are selected from the group consisting of acute hepatitis, alcoholic hepatitis, alcoholic liver disease, extrahepatic cholestasis, liver fibrosis, liver abscess, cirrhosis, neonatal jaundice, obstructive jaundice, primary bile acid malabsorption, acute cholecystitis, autoimmune hepatitis, benign recurrent intrahepatic cholestasis, colitis, biliary obstruction, cholestatic liver disease, Crigler-Najjar syndrome, drug-induced hepatitis, Dubin-Johnson syndrome, intrahepatic cholestasis of pregnancy, liver rejection, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, polycystic liver disease, PBC, PSC, veno-occlusive disease, Wilson's disease. In embodiments, the hepatobiliary disease is PSC. In embodiments, the hepatobiliary disease is PBC.

[0185] In embodiments, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is useful in the treatment of acute hepatitis. In embodiments, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is useful in the treatment of alcoholic hepatitis. In embodiments, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is useful in the treatment of alcoholic liver disease. In embodiments, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is useful in the treatment of extrahepatic cholestasis. In embodiments, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is useful in the treatment of liver fibrosis. In embodiments, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is useful in the treatment of liver abscess. In embodiments, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is useful in the treatment of liver cirrhosis. In embodiments, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is useful in the treatment of neonatal jaundice. In embodiments, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is useful in the treatment of obstructive jaundice. In embodiments, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is useful in the treatment of primary bile acid malabsorption. In embodiments, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is useful in the treatment of acute cholecystitis. In embodiments, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is useful in the treatment of autoimmune hepatitis. In embodiments, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is useful in the treatment of benign recurrent intrahepatic cholestasis. In embodiments, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is useful in the treatment of biliary obstruction. In embodiments, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is useful in the treatment of cholestatic liver disease.In embodiments, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is useful in the treatment of Crigler-Najjar syndrome. In embodiments, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is useful in the treatment of drug-induced hepatitis. In embodiments, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is useful in the treatment of Dubin-Johnson syndrome. In embodiments, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is useful in the treatment of intrahepatic cholestasis of pregnancy. In embodiments, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is useful in the treatment of liver rejection. In embodiments, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is useful in the treatment of non-alcoholic fatty liver disease. In embodiments, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is useful in the treatment of non-alcoholic steatohepatitis. In embodiments, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is useful in the treatment of polycystic liver disease. In embodiments, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is useful in the treatment of PBC. In embodiments, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is useful in the treatment of PSC. In embodiments, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is useful in the treatment of veno-occlusive disease. In embodiments, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is useful in the treatment of Wilson's disease, ulcerative colitis, Crohn's disease, irritable bowel syndrome (IBS), proctitis, celiac disease, ileitis, duodenitis and diverticulitis.

[0186] In an embodiment, a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt or solvate thereof is useful in the treatment of acute hepatitis. In an embodiment, a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt or solvate thereof is useful in the treatment of alcoholic hepatitis. In an embodiment, a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt or solvate thereof is useful in the treatment of alcoholic liver disease. In an embodiment, a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt or solvate thereof is useful in the treatment of extrahepatic cholestasis. In an embodiment, a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt or solvate thereof is useful in the treatment of liver fibrosis. In an embodiment, a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt or solvate thereof is useful in the treatment of liver abscess. In an embodiment, a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt or solvate thereof is useful in the treatment of cirrhosis. In an embodiment, a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt or solvate thereof is useful in the treatment of neonatal jaundice. In an embodiment, a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt or solvate thereof is useful in the treatment of obstructive jaundice. In an embodiment, a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt or solvate thereof is useful in the treatment of primary bile acid malabsorption. In an embodiment, a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt or solvate thereof is useful in the treatment of acute cholecystitis. In an embodiment, a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt or solvate thereof is useful in the treatment of autoimmune hepatitis. In an embodiment, a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt or solvate thereof is useful in the treatment of benign recurrent intrahepatic cholestasis. In an embodiment, a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt or solvate thereof is useful in the treatment of biliary obstruction. In an embodiment, a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt or solvate thereof is useful in the treatment of cholestatic liver disease. In an embodiment, a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt or solvate thereof is useful in the treatment of Crigler-Najjar syndrome.In embodiments, a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt or solvate thereof is useful in the treatment of drug-induced hepatitis. In embodiments, a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt or solvate thereof is useful in the treatment of Gilberts syndrome. In embodiments, a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt or solvate thereof is useful in the treatment of intrahepatic cholestasis of pregnancy. In embodiments, a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt or solvate thereof is useful in the treatment of liver rejection. In embodiments, a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt or solvate thereof is useful in the treatment of non-alcoholic fatty liver disease. In embodiments, a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt or solvate thereof is useful in the treatment of non-alcoholic steatohepatitis. In embodiments, a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt or solvate thereof is useful in the treatment of polycystic liver disease. In embodiments, a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt or solvate thereof is useful in the treatment of PBC. In embodiments, a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt or solvate thereof is useful in the treatment of PSC. In embodiments, a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt or solvate thereof is useful in the treatment of colitis. In embodiments, a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt or solvate thereof is useful in the treatment of ulcerative colitis (UC) and / or Crohn's disease (CD). In embodiments, a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt or solvate thereof is useful in the treatment of veno-occlusive disease. In embodiments, a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt or solvate thereof is useful in the treatment of Wilson's disease. In some embodiments, the present disclosure encompasses a method for treating or preventing IBD in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the invention comprising Compound 1 or a pharmaceutically acceptable salt or solvate thereof.In an embodiment, the present disclosure encompasses a method for treating or preventing PSC in a subject suffering from IBD and in need of treatment or prevention of PSC, the method comprising administering to the subject a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt or solvate thereof.

[0187] In an embodiment, a therapeutically effective amount of 2-amino-4-[(1R)-1-({[(3Z,6S)-6-(5-chloro-2-methoxybenzyl)-3-(ethoxyimino)-7-oxo-1,4-diazepan-1-yl]carbonyl}amino)butyl]benzoic acid monoacetic acid solvate is useful in the treatment of acute hepatitis. In an embodiment, a therapeutically effective amount of 2-amino-4-[(1R)-1-({[(3Z,6S)-6-(5-chloro-2-methoxybenzyl)-3-(ethoxyimino)-7-oxo-1,4-diazepan-1-yl]carbonyl}amino)butyl]benzoic acid monoacetic acid solvate is useful in the treatment of alcoholic hepatitis. In an embodiment, a therapeutically effective amount of 2-amino-4-[(1R)-1-({[(3Z,6S)-6-(5-chloro-2-methoxybenzyl)-3-(ethoxyimino)-7-oxo-1,4-diazepan-1-yl]carbonyl}amino)butyl]benzoic acid monoacetic acid solvate is useful in the treatment of alcoholic liver disease. In an embodiment, a therapeutically effective amount of 2-amino-4-[(1R)-1-({[(3Z,6S)-6-(5-chloro-2-methoxybenzyl)-3-(ethoxyimino)-7-oxo-1,4-diazepan-1-yl]carbonyl}amino)butyl]benzoic acid monoacetic acid solvate is useful in the treatment of extrahepatic cholestasis. In an embodiment, a therapeutically effective amount of 2-amino-4-[(1R)-1-({[(3Z,6S)-6-(5-chloro-2-methoxybenzyl)-3-(ethoxyimino)-7-oxo-1,4-diazepan-1-yl]carbonyl}amino)butyl]benzoic acid monoacetic acid solvate is useful in the treatment of hepatic fibrosis. In an embodiment, a therapeutically effective amount of 2-amino-4-[(1R)-1-({[(3Z,6S)-6-(5-chloro-2-methoxybenzyl)-3-(ethoxyimino)-7-oxo-1,4-diazepan-1-yl]carbonyl}amino)butyl]benzoic acid monoacetic acid solvate is useful in the treatment of liver abscess. In an embodiment, a therapeutically effective amount of 2-amino-4-[(1R)-1-({[(3Z,6S)-6-(5-chloro-2-methoxybenzyl)-3-(ethoxyimino)-7-oxo-1,4-diazepan-1-yl]carbonyl}amino)butyl]benzoic acid monoacetic acid solvate is useful in the treatment of liver cirrhosis.In an embodiment, a therapeutically effective amount of 2-amino-4-[(1R)-1-({[(3Z,6S)-6-(5-chloro-2-methoxybenzyl)-3-(ethoxyimino)-7-oxo-1,4-diazepan-1-yl]carbonyl}amino)butyl]benzoic acid monoacetic acid solvate is useful in the treatment of neonatal jaundice. In an embodiment, a therapeutically effective amount of 2-amino-4-[(1R)-1-({[(3Z,6S)-6-(5-chloro-2-methoxybenzyl)-3-(ethoxyimino)-7-oxo-1,4-diazepan-1-yl]carbonyl}amino)butyl]benzoic acid monoacetic acid solvate is useful in the treatment of obstructive jaundice. In an embodiment, a therapeutically effective amount of 2-amino-4-[(1R)-1-({[(3Z,6S)-6-(5-chloro-2-methoxybenzyl)-3-(ethoxyimino)-7-oxo-1,4-diazepan-1-yl]carbonyl}amino)butyl]benzoic acid monoacetic acid solvate is useful in the treatment of primary bile acid malabsorption. In an embodiment, a therapeutically effective amount of 2-amino-4-[(1R)-1-({[(3Z,6S)-6-(5-chloro-2-methoxybenzyl)-3-(ethoxyimino)-7-oxo-1,4-diazepan-1-yl]carbonyl}amino)butyl]benzoic acid monoacetic acid solvate is useful in the treatment of acute cholecystitis. In an embodiment, a therapeutically effective amount of 2-amino-4-[(1R)-1-({[(3Z,6S)-6-(5-chloro-2-methoxybenzyl)-3-(ethoxyimino)-7-oxo-1,4-diazepan-1-yl]carbonyl}amino)butyl]benzoic acid monoacetic acid solvate is useful in the treatment of autoimmune hepatitis. In an embodiment, a therapeutically effective amount of 2-amino-4-[(1R)-1-({[(3Z,6S)-6-(5-chloro-2-methoxybenzyl)-3-(ethoxyimino)-7-oxo-1,4-diazepan-1-yl]carbonyl}amino)butyl]benzoic acid monoacetic acid solvate is useful in the treatment of benign recurrent intrahepatic cholestasis. In an embodiment, a therapeutically effective amount of 2-amino-4-[(1R)-1-({[(3Z,6S)-6-(5-chloro-2-methoxybenzyl)-3-(ethoxyimino)-7-oxo-1,4-diazepan-1-yl]carbonyl}amino)butyl]benzoic acid monoacetic acid solvate is useful in the treatment of biliary obstruction.In an embodiment, a therapeutically effective amount of 2-amino-4-[(1R)-1-({[(3Z,6S)-6-(5-chloro-2-methoxybenzyl)-3-(ethoxyimino)-7-oxo-1,4-diazepan-1-yl]carbonyl}amino)butyl]benzoic acid monoacetate solvate is useful in the treatment of cholestatic liver diseases. In an embodiment, a therapeutically effective amount of 2-amino-4-[(1R)-1-({[(3Z,6S)-6-(5-chloro-2-methoxybenzyl)-3-(ethoxyimino)-7-oxo-1,4-diazepan-1-yl]carbonyl}amino)butyl]benzoic acid monoacetate solvate is useful in the treatment of Crigler-Najjar syndrome. In an embodiment, a therapeutically effective amount of 2-amino-4-[(1R)-1-({[(3Z,6S)-6-(5-chloro-2-methoxybenzyl)-3-(ethoxyimino)-7-oxo-1,4-diazepan-1-yl]carbonyl}amino)butyl]benzoic acid monoacetate solvate is useful in the treatment of drug-induced hepatitis. In an embodiment, a therapeutically effective amount of 2-amino-4-[(1R)-1-({[(3Z,6S)-6-(5-chloro-2-methoxybenzyl)-3-(ethoxyimino)-7-oxo-1,4-diazepan-1-yl]carbonyl}amino)butyl]benzoic acid monoacetate solvate is useful in the treatment of Dubin-Johnson syndrome. In an embodiment, a therapeutically effective amount of 2-amino-4-[(1R)-1-({[(3Z,6S)-6-(5-chloro-2-methoxybenzyl)-3-(ethoxyimino)-7-oxo-1,4-diazepan-1-yl]carbonyl}amino)butyl]benzoic acid monoacetate solvate is useful in the treatment of intrahepatic cholestasis of pregnancy. In an embodiment, a therapeutically effective amount of 2-amino-4-[(1R)-1-({[(3Z,6S)-6-(5-chloro-2-methoxybenzyl)-3-(ethoxyimino)-7-oxo-1,4-diazepan-1-yl]carbonyl}amino)butyl]benzoic acid monoacetate solvate is useful in the treatment of liver rejection.In an embodiment, a therapeutically effective amount of 2-amino-4-[(1R)-1-({[(3Z,6S)-6-(5-chloro-2-methoxybenzyl)-3-(ethoxyimino)-7-oxo-1,4-diazepan-1-yl]carbonyl}amino)butyl]benzoic acid monoacetate solvate is useful in the treatment of non-alcoholic fatty liver disease. In an embodiment, a therapeutically effective amount of 2-amino-4-[(1R)-1-({[(3Z,6S)-6-(5-chloro-2-methoxybenzyl)-3-(ethoxyimino)-7-oxo-1,4-diazepan-1-yl]carbonyl}amino)butyl]benzoic acid monoacetate solvate is useful in the treatment of non-alcoholic steatohepatitis. In an embodiment, a therapeutically effective amount of 2-amino-4-[(1R)-1-({[(3Z,6S)-6-(5-chloro-2-methoxybenzyl)-3-(ethoxyimino)-7-oxo-1,4-diazepan-1-yl]carbonyl}amino)butyl]benzoic acid monoacetate solvate is useful in the treatment of polycystic liver disease. In an embodiment, a therapeutically effective amount of 2-amino-4-[(1R)-1-({[(3Z,6S)-6-(5-chloro-2-methoxybenzyl)-3-(ethoxyimino)-7-oxo-1,4-diazepan-1-yl]carbonyl}amino)butyl]benzoic acid monoacetate solvate is useful in the treatment of primary biliary cirrhosis. In an embodiment, a therapeutically effective amount of 2-amino-4-[(1R)-1-({[(3Z,6S)-6-(5-chloro-2-methoxybenzyl)-3-(ethoxyimino)-7-oxo-1,4-diazepan-1-yl]carbonyl}amino)butyl]benzoic acid monoacetate solvate is useful in the treatment of veno-occlusive disease. In an embodiment, a therapeutically effective amount of 2-amino-4-[(1R)-1-({[(3Z,6S)-6-(5-chloro-2-methoxybenzyl)-3-(ethoxyimino)-7-oxo-1,4-diazepan-1-yl]carbonyl}amino)butyl]benzoic acid monoacetate solvate is useful in the treatment of Wilson's disease.

[0188] Other diseases: In embodiments, the methods of the present disclosure are useful for the treatment of various EGIDs. In embodiments, EGIDs include eosinophilic gastroenteritis and eosinophilic esophagitis, eosinophilic duodenitis, and eosinophilic gastritis.

[0189] In embodiments, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is useful in the treatment of eosinophilic gastroenteritis. In embodiments, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is useful in the treatment of eosinophilic esophagitis. In embodiments, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is useful in the treatment of eosinophilic duodenitis. In embodiments, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is useful in the treatment of eosinophilic gastritis.

[0190] In embodiments, a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt or solvate thereof is useful in the treatment of eosinophilic gastroenteritis. In embodiments, a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt or solvate thereof is useful in the treatment of eosinophilic esophagitis. In embodiments, a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt or solvate thereof is useful in the treatment of eosinophilic duodenitis. In embodiments, a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt or solvate thereof is useful in the treatment of eosinophilic gastritis.

[0191] In an embodiment, a solvate of 2-amino-4-[(1R)-1-({[(3Z,6S)-6-(5-chloro-2-methoxybenzyl)-3-(ethoxyimino)-7-oxo-1,4-diazepan-1-yl]carbonyl}amino)butyl]benzoic acid monoacetic acid in a therapeutically effective amount is useful in the treatment of eosinophilic gastroenteritis. In an embodiment, a solvate of 2-amino-4-[(1R)-1-({[(3Z,6S)-6-(5-chloro-2-methoxybenzyl)-3-(ethoxyimino)-7-oxo-1,4-diazepan-1-yl]carbonyl}amino)butyl]benzoic acid monoacetic acid in a therapeutically effective amount is useful in the treatment of eosinophilic esophagitis. In an embodiment, a solvate of 2-amino-4-[(1R)-1-({[(3Z,6S)-6-(5-chloro-2-methoxybenzyl)-3-(ethoxyimino)-7-oxo-1,4-diazepan-1-yl]carbonyl}amino)butyl]benzoic acid monoacetic acid in a therapeutically effective amount is useful in the treatment of eosinophilic duodenitis. In an embodiment, a solvate of 2-amino-4-[(1R)-1-({[(3Z,6S)-6-(5-chloro-2-methoxybenzyl)-3-(ethoxyimino)-7-oxo-1,4-diazepan-1-yl]carbonyl}amino)butyl]benzoic acid monoacetic acid in a therapeutically effective amount is useful in the treatment of eosinophilic gastritis.

[0192] Specific embodiments of the present disclosure Embodiment 1: A method for treating or preventing a hepatobiliary disease in a subject in need of treating or preventing a hepatobiliary disease, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I): [Chemical formula] (wherein, Ar is (1) a C6-C14 aromatic hydrocarbon group, (2) a 5- to 8-membered aromatic heterocyclic group having 1 to 4 heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom, and an oxygen atom in place of a carbon atom, or (3) a bicyclic or tricyclic aromatic group formed by condensation of the above aromatic heterocyclic group and a C6-C14 aromatic hydrocarbon ring, The above groups (1) to (3) of Ar are (i) a halogen atom, (ii) nitro, (iii) cyano, (iv) C1-C6 alkyl which may be substituted with 1 to 3 halogen atoms, (v) C2-C6 alkenyl which may be substituted with 1 to 3 halogen atoms, (vi) C2-C6 alkynyl which may be substituted with 1 to 3 halogen atoms, (vii) C3-C6 cycloalkyl, (viii) hydroxyl, (ix) C1-C6 alkoxy which may be substituted with 1 to 3 groups selected from the group consisting of a halogen atom, mono- or di-C1-C6 alkylamino, C1-C6 alkoxy, mono- or di-C1-C6 alkylcarbamoyl, mono- or di-C7-C16 aralkylcarbamoyl, mono- or di-C1-C10 heteroaryl-C1-C6 alkylcarbamoyl, carboxyl, and C1-C6 alkoxycarbonyl, or which may be substituted with 1 to 13 deuterium atoms, (x) C1-C5 alkylenedioxy, (xi) C1-C6 alkylthio which may be substituted with 1 to 3 groups selected from the group consisting of a halogen atom, mono- or di-C1-C6 alkylamino, C1-C6 alkoxy, mono- or di-C1-C6 alkylcarbamoyl, mono- or di-C7-C16 aralkylcarbamoyl, mono- or di-C1-C10 heteroaryl-C1-C6 alkylcarbamoyl, carboxyl, and C1-C6 alkoxycarbonyl, or which may be substituted with 1 to 13 deuterium atoms, (xii) amino, (xiii) mono-C1-C6 alkylamino, (xiv) di-C1-C6 alkylamino, (xv) 5- to 6-membered ring amino, (xvi) C1-C6 alkylcarbonyl, (xvii) carboxyl, (xviii) C1-C6 alkoxycarbonyl, (xix) carbamoyl, (xx) Thiocarbamoyl, (xxi) Mono-C1-C6 alkylcarbamoyl, (xxii) Di-C1-C6 alkylcarbamoyl, (xxiii) 5- or 6-membered aminocarbonyl, (xxiv) Sulfo, (xxv) C1-C6 alkylsulfonyl, (xxvi) C1-C6 alkoxycarbonylamino, (xxvii) C1-C6 alkylcarbonylamino, (xxviii) Mono- or di-C1-C6 alkylaminocarbonylamino, (xxix) Aminosulfonyl, and (xxx) Mono- or di-C1-C6 alkylaminosulfonyl substituted with 1 to 5 groups selected from the group consisting of, or optionally substituted with 1 to 9 deuterium atoms, X is (1) a connecting bond, (2) a linear or branched C1-C6 alkylene optionally substituted with 1 to 12 deuterium atoms, (3) an oxygen atom, (4) NR 3 (wherein R 3 is a hydrogen atom or a C1-C6 alkyl group), or (5) -S(O)m- (wherein m is an integer from 0 to 2), Z is (1) a connecting bond or (2) CR 4 R 5 (wherein R 4 and R 5 are independently (A) a hydrogen atom, (B) a deuterium atom, (C) (i) carboxyl, (ii) C1-C6 alkoxycarbonyl, (iii) phenyl, (iv) hydroxyl, (v) C1-C6 alkoxy, (vi) a halogen atom, and (vii) C1-C6 alkyl optionally substituted with 1 to 5 groups selected from the group consisting of or optionally substituted with 1 to 13 deuterium atoms, (D) (i) a halogen atom and (ii) a C3-C6 cycloalkyl which may be substituted with 1 to 5 groups selected from the group consisting of an alkyl group which may be substituted with 1 to 3 halogen atoms, or which may be substituted with 1 to 11 deuterium atoms, (E) COOR 6 (wherein R 6 is a hydrogen atom or C1-C6 alkyl), or (F) CONR 7 R 8 (wherein R 7 and R 8 are, independently, (a) a hydrogen atom, (b) (i) a halogen atom, (ii) a C3-C6 cycloalkyl, (iii) carboxyl, (iv) C1-C6 alkoxycarbonyl, (v) C1-C6 alkylcarbonyl, (vi) carbamoyl, (vii) mono-C1-C6 alkylcarbamoyl, (viii) di-C1-C6 alkylcarbamoyl, (ix) C6-C12 aryl, and (x) a C1-C6 alkyl which may be substituted with 1 to 3 groups selected from the group consisting of a C1-C10 heteroaryl, (c) a C6-C14 aromatic hydrocarbon group, (d) a 5- to 8-membered aromatic heterocyclic group having 1 to 4 heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom in place of a carbon atom, or (e) a bicyclic or tricyclic aromatic group formed by condensation of the above aromatic heterocyclic group and a C6-C14 aromatic hydrocarbon ring and the groups (c) to (e) are each independently (i) a halogen atom, (ii) nitro, (iii) cyano, (iv) C1-C6 alkyl optionally substituted with 1 to 3 halogen atoms, (v) C2-C6 alkenyl optionally substituted with 1 to 3 halogen atoms, (vi) C2-C6 alkynyl optionally substituted with 1 to 3 halogen atoms, (vii) C3-C6 cycloalkyl, (viii) hydroxyl, (ix) C1-C6 alkoxy optionally substituted with 1 to 3 halogen atoms, (x) C1-C5 alkylenedioxy, (xi) C1-C6 alkylthio optionally substituted with 1 to 3 halogen atoms, (xii) amino, (xiii) mono-C1-C6 alkylamino, (xiv) di-C1-C6 alkylamino, (xv) 5- to 6-membered ring amino, (xvi) C1-C6 alkylcarbonyl, (xvii) carboxyl, (xviii) C1-C6 alkoxycarbonyl, (xix) carbamoyl, (xx) thiocarbamoyl, (xxi) mono-C1-C6 alkylcarbamoyl, (xxii) di-C1-C6 alkylcarbamoyl, (xxiii) C6-C10 arylcarbamoyl, (xxiv) C1-C10 heteroarylcarbamoyl, (xxv) sulfo, (xxvi) C1-C6 alkylsulfonyl, (xxvii) aminosulfonyl, and (xxviii) optionally substituted with 1 to 5 groups selected from the group consisting of mono- or di-C1-C6 alkylaminosulfonylamino or optionally substituted with 1 to 9 deuterium atoms) is), and W is (1) a hydrogen atom, (2) a C6-C14 aromatic hydrocarbon group, (3) a 5- to 8-membered aromatic heterocyclic group having 1 to 4 heteroatoms selected from nitrogen, sulfur, and oxygen atoms in place of carbon atoms, (4) a bicyclic or tricyclic aromatic group formed by condensation of the above aromatic heterocyclic group and a C6-C14 aromatic hydrocarbon ring, or a deuterium atom, Each of the groups (2) to (4) of W above is: (i) a C1-C6 alkyl which may be substituted with 1 to 3 groups selected from the group consisting of a halogen atom, (ii) nitro, (iii) cyano, (iv) a halogen atom, amino, C1-C6 alkoxycarbonyl, C1-C6 alkoxycarbonylamino and carboxyl; (v) a C2-C6 alkenyl which may be substituted with 1 to 3 halogen atoms; (vi) a C2-C6 alkynyl which may be substituted with 1 to 3 halogen atoms; (vii) a C3-C6 cycloalkyl; (viii) hydroxyl; (ix) a C1-C6 alkoxy which may be substituted with 1 to 3 groups selected from the group consisting of a halogen atom, hydroxyl, C1-C6 alkoxy, amino and mono- or di-C1-C6 alkylamino; (x) a C1-C5 alkylenedioxy; (xi) a C1-C6 alkylthio which may be substituted with 1 to 3 groups selected from the group consisting of a halogen atom, hydroxyl, C1-C6 alkoxy, amino and mono- or di-C1-C6 alkylamino; (xii) amino; (xiii) mono-C1-C6 alkylamino; (xiv) di-C1-C6 alkylamino; (xv) a 5- to 6-membered ring amino; (xvi) a C1-C6 alkyl-carbonyl; (xvii) carboxyl; (xviii) a C1-C6 alkoxycarbonyl which may be substituted with a halogen atom; (xix) a C7-C16 aralkyloxycarbonyl which may be substituted with a halogen atom; (xx) carbamoyl; (xxi) a mono-C1-C6 alkylcarbamoyl which may be substituted with 1 to 3 groups selected from the group consisting of a halogen atom, hydroxyl, carboxyl, C1-C6 alkoxy, amino, and mono or di-C1-C6 alkylamino; (xxii) a di-C1-C6 alkylcarbamoyl which may be substituted with hydroxyl; (xxiii) a 5- to 6-membered ring aminocarbonyl which may be substituted with a C1-C6 alkoxycarbonyl; (xxiv) a C6-C10 arylcarbamoyl; (xxv) a C1-C10 heteroarylcarbamoyl; (xxvi) a C7-C16 aralkylcarbamoyl; (xxvii) a C1-C10 heteroaryl-C1-C6 alkylcarbamoyl; (xxviii) an N-C1-C6 alkyl-N-C6-C12 arylcarbamoyl.(xxix) C3-C6 cycloalkylcarbamoyl, (xxx) sulfo, (xxxi) C1-C6 alkylsulfonyl, (xxxii) C1-C6 alkylsulfonylamino, (xxxiii) C6-C12 arylsulfonylamino optionally substituted with C1-C6 alkyl, (xxxiv) C1-C10 heteroarylsulfonylamino, (xxxv) C1-C6 alkoxycarbonylamino, (xxxvi) C1-C6 alkylcarbonylamino, (xxxvii) mono- or di-C1-C6 alkylaminocarbonylamino, (xxxviii) C6-C12 aryl, (xxxix) C1-C10 heteroaryl, (xl) C6-C10 aryloxy, (xli) C1-C10 heteroaryloxy, (xlii) C7-C16 aralkyloxy, (xliii) C1-C10 heteroaryl-C1-C6 alkyloxy, (xliv) aminosulfonyl, (xlv) mono- or di-C1-C6 alkylaminosulfonyl, (xlvi) C7-C16 aralkyloxycarbonyl, and (xlvii) C1-C10 heteroaryl-C1-C6 alkyloxycarbonyl, which may be substituted with 1 to 5 groups selected from the group consisting of, or may be substituted with 1 to 9 deuterium atoms, R1 is (1) a hydrogen atom, (2) C1-C6 alkyl which may be substituted with 1 to 3 (i) halogen atoms or (ii) C3-C6 cycloalkyl, or (iii) may be substituted with 1 to 13 deuterium atoms, (3) C2-C6 alkenyl which may be substituted with 1 to 3 (i) halogen atoms or (ii) C3-C6 cycloalkyl, or (iii) may be substituted with 1 to 11 deuterium atoms, (4) C2-C6 alkynyl which may be substituted with 1 to 3 (i) halogen atoms or (ii) C3-C6 cycloalkyl, or (iii) may be substituted with 1 to 9 deuterium atoms, or (5) C3-C6 cycloalkyl which may be substituted with 1 to 3 (i) halogen atoms or (ii) C3-C6 cycloalkyl, or (iii) may be substituted with 1 to 11 deuterium atoms and R2 is (1) OR 9 or (2) NR 10 R 11 (wherein R 9 R 10 and R 11 are independently (A) a hydrogen atom, (B) C1-C6 alkyl, (C) C2-C6 alkenyl, (D) C3-C6 alkynyl, (E) C3-C6 cycloalkyl, (F) a C6-C14 aromatic hydrocarbon group, (G) a 5- to 8-membered aromatic heterocyclic group having 1 to 4 heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom in place of a carbon atom, or (H) a bicyclic or tricyclic aromatic group formed by condensation of the above aromatic heterocyclic group and a C6-C14 aromatic hydrocarbon ring is shown, each of the above groups (B) to (E) may be substituted with 1 to 3 groups selected from the group consisting of (i) a halogen atom, (ii) C3-C6 cycloalkyl, (iii) hydroxyl, (iv) C1-C6 alkoxy optionally substituted with 1 to 3 halogen atoms, (v) amino, (vi) mono-C1-C6 alkylamino, (vii) di-C1-C6 alkylamino, (viii) 5- to 6-membered ring amino, (ix) carboxyl, (x) C1-C6 alkoxycarbonyl, (xi) C1-C6 alkylcarbonyl, (xii) carbamoyl, (xiii) mono-C1-C6 alkylcarbamoyl, (xiv) di-C1-C6 alkylcarbamoyl, (xv) C6-C12 aryl, and (xvi) C1-C10 heteroaryl, or may be substituted with 1 to 13 deuterium atoms, Furthermore, each of the groups (F) to (H) is independently selected from the group consisting of (i) a halogen atom, (ii) nitro, (iii) cyano, (iv) C1-C6 alkyl optionally substituted with 1 to 3 halogen atoms, (v) C3-C6 cycloalkyl optionally substituted with 1 to 3 halogen atoms, (vi) hydroxyl, (vii) C1-C6 alkoxy optionally substituted with 1 to 3 halogen atoms, (viii) amino, (ix) mono-C1-C6 alkylamino, (x) di-C1-C6 alkylamino, (xi) 5- or 6-membered ring amino, (xii) C1-C6 alkylcarbonyl, (xiii) carboxyl, (xiv) C1-C6 alkoxycarbonyl, (xv) mono-C1-C6 alkylcarbamoyl, (xvii) di-C1-C6 alkylcarbamoyl, (xviii) C1-C6 alkylsulfonyl, (xix) aminosulfonyl, and (xx) mono- or di-C1-C6 alkylaminosulfonyl, and may be substituted with 1 to 5 groups selected from this group, or may be substituted with 1 to 9 deuterium atoms, or R1 and R2 may together with the atoms to which they are attached form a 5- or 6-membered heterocyclic ring, and the above 5- or 6-membered heterocyclic ring is (A) a halogen atom, (B) oxo, (C) hydroxyl (D) C1-C6 alkyl, (E) C2-C6 alkenyl, (F) C2-C6 alkynyl, (G) C3-C6 cycloalkyl (H) C6-C14 aromatic hydrocarbon group, (I) a 5- to 8-membered aromatic heterocyclic group having 1 to 4 heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom in place of a carbon atom, and (J) a bicyclic or tricyclic aromatic group formed by condensation of the above aromatic heterocyclic group and a C6-C14 aromatic hydrocarbon ring and may be substituted with 1 to 3 groups selected from this group, or (K) may be substituted with 1 to 6 deuterium atoms, Each of the groups (D) to (G) above is optionally substituted with 1 to 3 groups selected from the group consisting of (i) a halogen atom, (ii) C3-C6 cycloalkyl, (iii) hydroxyl, (iv) C1-C6 alkoxy optionally substituted with 1 to 3 halogen atoms, (v) amino, (vi) mono-C1-C6 alkylamino, (vii) di-C1-C6 alkylamino, (viii) 5- to 6-membered ring amino, (ix) carboxyl, (x) C1-C6 alkoxycarbonyl, (xi) C1-C6 alkyl-carbonyl, (xii) carbamoyl, (xiii) mono-C1-C6 alkylcarbamoyl, (xiv) di-C1-C6 alkylcarbamoyl, (xv) C6-C12 aryl, and (xvi) C1-C10 heteroaryl, or is optionally substituted with 1 to 13 deuterium atoms. Each of the groups (H) to (J) above is optionally substituted with 1 to 5 groups selected from the group consisting of (i) a halogen atom, (ii) nitro, (iii) cyano, (iv) C1-C6 alkyl optionally substituted with 1 to 3 halogen atoms, (v) C3-C6 cycloalkyl optionally substituted with 1 to 3 halogen atoms, (vi) hydroxyl, (vii) C1-C6 alkoxy optionally substituted with 1 to 3 halogen atoms, (viii) amino, (ix) mono-C1-C6 alkylamino, (x) di-C1-C6 alkylamino, (xi) 5- to 6-membered ring amino, (xii) C1-C6 alkylcarbonyl, (xiii) carboxyl, (xiv) C1-C6 alkoxycarbonyl, (xv) carbamoyl, (xvi) mono-C1-C6 alkylcarbamoyl, (xvii) di-C1-C6 alkylcarbamoyl, (xviii) C1-C6 alkylsulfonyl, (xix) aminosulfonyl, and (xx) mono- or di-C1-C6 alkylaminosulfonyl, or is optionally substituted with 1 to 9 deuterium atoms) is) Also included is a method comprising administering to a subject the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof. Embodiment 2: The compound of formula (I) is (1) 4-{ (1R)-1-[({(6R)-6-(5-chloro-2-methoxybenzyl)-7-oxo-3-[(pyridin-2-yloxy)imino]-1,4-diazepan-1-yl}carbonyl)amino]propyl}benzoic acid, (2) 2-amino-4-[(1R)-1-({[(6S)-6-(5-chloro-2-methoxybenzyl)-3-(ethoxyimino)-7-oxo-1,4-diazepan-1-yl]carbonyl}amino)butyl]benzoic acid, (3) 2-amino-4-{ (1R)-1-[({(6S)-6-(5-chloro-2-methoxybenzyl)-7-oxo-3-[(2,2,2-trifluoroethoxy)imino]-1,4-diazepan-1-yl}carbonyl)amino]butyl}benzoic acid, (4) 2-amino-4-{ (1R)-1-[({(6R)-6-(5-chloro-2-methoxybenzyl)-3-[(3,5-difluorophenoxy)imino]-7-oxo-1,4-diazepan-1-yl}carbonyl)amino]ethyl}benzoic acid, (5) 2-amino-4-[(1R)-1-({[(6S)-6-(5-chloro-2-methoxybenzyl)-3-(methoxyimino)-4-methyl-7-oxo-1,4-diazepan-1-yl]carbonyl}amino)butyl]benzoic acid, (6) (4-{ (1R)-1-[({(6R)-6-(5-chloro-2-methoxybenzyl)-3-[(3,5-difluorophenoxy)imino]-7-oxo-1,4-diazepan-1-yl}carbonyl)amino]ethyl}phenyl)acetic acid, (7) 2-amino-4-{[({(6R)-6-(5-chloro-2-methoxybenzyl)-3-[(3,5-difluorophenoxy)imino]-7-oxo-1,4-diazepan-1-yl}carbonyl)amino]methyl}benzoic acid, (8) {4-[(1R)-1-({[(6R)-6-(5-chloro-2-methoxybenzyl)-7-oxo-3-(phenoxyimino)-1,4-diazepan-1-yl]carbonyl}amino)propyl]phenyl}acetic acid, (9) 2-Amino-4-[(1R)-1-({[(6R)-6-(5-chloro-2-methoxybenzyl)-7-oxo-3-(phenoxyimino)-1,4-diazepan-1-yl]carbonyl}amino)propyl]benzoic acid, or (10) 2-Amino-4-[(1R)-1({[(6R)-6-(5-chloro-2-methoxybenzyl)-3-(ethoxyimino)-7-oxo-1,4-diazepan-1-yl]carbonyl}amino)butyl]benzoic acid The method according to embodiment 1, selected from the group consisting of

[0193] Embodiment 3: The method according to embodiment 1 or 2, wherein the compound of formula (I) is 2-amino-4-[(1R)-1-({[(3Z,6S)-6-(5-chloro-2-methoxybenzyl)-3-(ethoxyimino)-7-oxo-1,4-diazepan-1-yl]carbonyl}amino)butyl]benzoic acid (Compound 1) or a pharmaceutically acceptable salt or solvate thereof.

[0194] Embodiment 4: The method according to embodiment 3, wherein Compound 1 is a monoacetic acid solvate. [Chemical formula]

[0195] Embodiment 5: The method according to embodiment 1, wherein the compound of formula I or a pharmaceutically acceptable salt or solvate thereof is more selective for chymase than for cathepsin G.

[0196] Embodiment 6: The method according to embodiment 1, wherein the compound of formula I or a pharmaceutically acceptable salt or solvate thereof has fewer side effects after long-term use in the treatment of hepatobiliary diseases than non-selective chymase inhibitors.

[0197] Embodiment 7: The method according to embodiment 1, wherein administration of a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof improves jaundice.

[0198] Embodiment 8: The method according to embodiment 1, wherein administration of a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof improves pruritus.

[0199] Embodiment 9: The method according to embodiment 1, wherein administration of a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof improves inflammation.

[0200] Embodiment 10: The method according to any one of embodiments 1 to 9, wherein the hepatobiliary disease is selected from the group consisting of acute hepatitis, alcoholic hepatitis, alcoholic liver disease, extrahepatic cholestasis, liver fibrosis, liver abscess, cirrhosis, neonatal jaundice, obstructive jaundice, primary bile acid malabsorption, acute cholecystitis, autoimmune hepatitis, benign recurrent intrahepatic cholestasis, biliary obstruction, cholestatic liver disease, Crigler-Najjar syndrome, drug-induced hepatitis, Gilbert's syndrome, intrahepatic cholestasis of pregnancy, liver rejection, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, polycystic liver disease, PBC, PSC, veno-occlusive disease, and Wilson's disease.

[0201] Embodiment 11: A method for treating or preventing a hepatobiliary disease in a subject in need of treatment or prevention of a hepatobiliary disease, the method comprising administering to the subject a therapeutically effective amount of 2-amino-4-[(1R)-1-({[(3Z,6S)-6-(5-chloro-2-methoxybenzyl)-3-(ethoxyimino)-7-oxo-1,4-diazepan-1-yl]carbonyl}amino)butyl]benzoic acid (Compound 1) or a pharmaceutically acceptable salt or solvate thereof.

[0202] Embodiment 12: A method for reducing mast cell infiltration in a subject suffering from a hepatobiliary disease, the method comprising administering to the subject a therapeutically effective amount of 2-amino-4-[(1R)-1-({[(3Z,6S)-6-(5-chloro-2-methoxybenzyl)-3-(ethoxyimino)-7-oxo-1,4-diazepan-1-yl]carbonyl}amino)butyl]benzoic acid (Compound 1) or a pharmaceutically acceptable salt or solvate thereof.

[0203] Embodiment 13: A method for treating or preventing pruritus in a subject suffering from hepatobiliary disease, the method comprising administering to the subject a therapeutically effective amount of 2-amino-4-[(1R)-1-({[(3Z,6S)-6-(5-chloro-2-methoxybenzyl)-3-(ethoxyimino)-7-oxo-1,4-diazepan-1-yl]carbonyl}amino)butyl]benzoic acid (Compound 1) or a pharmaceutically acceptable salt or solvate thereof.

[0204] Embodiment 14: A method for treating or preventing jaundice in a subject suffering from hepatobiliary disease, the method comprising administering to the subject a therapeutically effective amount of 2-amino-4-[(1R)-1-({[(3Z,6S)-6-(5-chloro-2-methoxybenzyl)-3-(ethoxyimino)-7-oxo-1,4-diazepan-1-yl]carbonyl}amino)butyl]benzoic acid (Compound 1) or a pharmaceutically acceptable salt or solvate thereof.

[0205] Embodiment 15: A method for reducing inflammation in a subject suffering from hepatobiliary disease, the method comprising administering to the subject a therapeutically effective amount of 2-amino-4-[(1R)-1-({[(3Z,6S)-6-(5-chloro-2-methoxybenzyl)-3-(ethoxyimino)-7-oxo-1,4-diazepan-1-yl]carbonyl}amino)butyl]benzoic acid (Compound 1) or a pharmaceutically acceptable salt or solvate thereof.

[0206] Embodiment 16: A method for reducing bile acid accumulation in a subject suffering from hepatobiliary disease, the method comprising administering to the subject a therapeutically effective amount of 2-amino-4-[(1R)-1-({[(3Z,6S)-6-(5-chloro-2-methoxybenzyl)-3-(ethoxyimino)-7-oxo-1,4-diazepan-1-yl]carbonyl}amino)butyl]benzoic acid (Compound 1) or a pharmaceutically acceptable salt or solvate thereof.

[0207] Embodiment 17: The method according to any one of Embodiments 1 to 16, wherein the hepatobiliary disease is selected from the group consisting of acute hepatitis, alcoholic hepatitis, alcoholic liver disease, extrahepatic biliary stasis, hepatic fibrosis, liver abscess, cirrhosis, neonatal jaundice, obstructive jaundice, colitis, primary bile acid malabsorption, acute cholecystitis, autoimmune hepatitis, benign recurrent intrahepatic cholestasis, biliary obstruction, cholestatic liver disease, Crigler-Najjar syndrome, drug-induced hepatitis, Gilbert syndrome, intrahepatic cholestasis of pregnancy, liver rejection, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, polycystic liver disease, PBC, PSC, venous occlusive disease, Wilson's disease.

[0208] Embodiment 18: The method according to Embodiment 17, wherein the hepatobiliary disease is PSC or PBC.

[0209] Embodiment 19: The method according to Embodiment 17, wherein the hepatobiliary disease is related to various gastrointestinal disorders including colitis, ulcerative colitis, Crohn's disease, irritable bowel syndrome (IBS), proctitis, celiac disease, ileitis, duodenitis and diverticulitis.

[0210] Embodiment 20: The method according to any one of Embodiments 8 to 18, wherein the therapeutically effective amount of Compound 1 is about 10 mg to about 1000 mg per unit dose (for example, about 50 mg to about 950 mg per unit dose, about 10 mg to about 900 mg per unit dose, about 10 mg to about 850 mg per unit dose, about 10 mg to about 800 mg per unit dose, about 10 mg to about 750 mg per unit dose, about 10 mg to about 700 mg per unit dose, about 10 mg to about 650 mg per unit dose, about 10 mg to about 600 mg per unit dose, about 50 mg to about 550 mg per unit dose, about 50 mg to about 500 mg per unit dose, about 50 mg to about 450 mg per unit dose, about 50 mg to about 400 mg per unit dose, about 50 mg to about 350 mg per unit dose, about 50 mg to about 300 mg per unit dose, about 50 mg to about 250 mg per unit dose, about 50 mg to about 200 mg per unit dose, about 50 mg to about 150 mg per unit dose, about 50 mg to about 100 mg per unit dose).

[0211] Embodiment 21: The method according to any one of Embodiments 11 to 16, wherein a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof is administered once a day, twice a day, three times a day, once every two days, or once every three days, or once a week.

[0212] Embodiment 22: The method according to any one of Embodiments 11 to 16, wherein a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt or solvate thereof is orally administered to a subject.

[0213] Embodiment 23: The method according to Embodiment 22, wherein a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt or solvate thereof is administered in a unit dosage form for oral administration formulated as a pellet, a multi-unit particle system (MUPS), a tablet, a troche, a lozenge, a dispersible powder or granule, or a hard or soft capsule, a powder, a sustained-release formulation, a microcapsule.

[0214] Embodiment 24: The method according to any one of the foregoing embodiments, wherein the subject is a mammal, preferably a human.

[0215] Embodiment 25: A method for treating PSC in a subject, comprising the step of administering to the subject 2-amino-4-[(1R)-1-({[(3Z,6S)-6-(5-chloro-2-methoxybenzyl)-3-(ethoxyimino)-7-oxo-1,4-diazepan-1-yl]carbonyl}amino)butyl]benzoic acid monoacetate in the range of about 10 mg to about 1000 mg per unit dose.

[0216] Embodiment 26: A method for reducing biliary tract aging in a subject suffering from PSC, comprising the step of administering to the subject a therapeutically effective amount of 2-amino-4-[(1R)-1-({[(3Z,6S)-6-(5-chloro-2-methoxybenzyl)-3-(ethoxyimino)-7-oxo-1,4-diazepan-1-yl]carbonyl}amino)butyl]benzoic acid monoacetate.

[0217] Embodiment 27: A method for reducing the proliferation of cholangiocytes in a subject suffering from PSC, comprising the step of administering to the subject a therapeutically effective amount of 2-amino-4-[(1R)-1-({[(3Z,6S)-6-(5-chloro-2-methoxybenzyl)-3-(ethoxyimino)-7-oxo-1,4-diazepan-1-yl]carbonyl}amino)butyl]benzoic acid monoacetate.

[0218] Embodiment 28: A method for reducing angiogenesis in a subject suffering from PSC, comprising the step of administering to the subject a therapeutically effective amount of 2-amino-4-[(1R)-1-({[(3Z,6S)-6-(5-chloro-2-methoxybenzyl)-3-(ethoxyimino)-7-oxo-1,4-diazepan-1-yl]carbonyl}amino)butyl]benzoic acid monoacetate.

[0219] Embodiment 29: A method for treating PBC in a subject, comprising the step of administering to the subject from about 10 mg to about 1000 mg per unit of 2-amino-4-[(1R)-1-({[(3Z,6S)-6-(5-chloro-2-methoxybenzyl)-3-(ethoxyimino)-7-oxo-1,4-diazepan-1-yl]carbonyl}amino)butyl]benzoic acid monoacetate.

[0220] Embodiment 30: A pharmaceutical composition for treating hepatobiliary diseases in a subject, comprising a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt or solvate thereof.

[0221] Embodiment 31: The pharmaceutical composition according to Embodiment 30, wherein the therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt or solvate thereof is from about 10 mg to about 1000 mg per unit dose.

[0222] Embodiment 32: The pharmaceutical composition according to Embodiment 30, wherein the hepatobiliary disease is selected from the group consisting of acute hepatitis, alcoholic hepatitis, alcoholic liver disease, extrahepatic cholestasis, hepatic fibrosis, liver abscess, cirrhosis, neonatal jaundice, obstructive jaundice, primary bile acid malabsorption, acute cholecystitis, autoimmune hepatitis, benign recurrent intrahepatic cholestasis, biliary obstruction, cholestatic liver disease, Crigler-Najjar syndrome, drug-induced hepatitis, Gilbert syndrome, intrahepatic cholestasis of pregnancy, liver rejection, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, polycystic liver disease, PBC, PSC, veno-occlusive disease, Wilson's disease.

[0223] Embodiment 33: The pharmaceutical composition according to Embodiment 30, wherein the hepatobiliary disease is PSC or PBC.

[0224] Embodiment 34: The pharmaceutical composition according to Embodiment 30, wherein the hepatobiliary disease is colitis.

[0225] Embodiment 35: A pharmaceutical composition for treating PSC or PBC in a subject, comprising about 10 mg to about 1000 mg of Compound 1 or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier or excipient.

[0226] Embodiment 36: A pharmaceutical composition for treating colitis in a subject, comprising about 10 mg to about 1000 mg of Compound 1 or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier or excipient.

[0227] Embodiment 37: A method for treating or preventing EGID in a subject in need of treatment or prevention of EGID, comprising administering a therapeutically effective amount of a compound of formula (I):

Chemical formula

[0228] Embodiment 38: The compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is (1) 4-{(1R)-1-[({(6R)-6-(5-chloro-2-methoxybenzyl)-7-oxo-3-[(pyridin-2-yloxy)imino]-1,4-diazepan-1-yl}carbonyl)amino]propyl}benzoic acid, (2) 2-amino-4-[(1R)-1-({[(6S)-6-(5-chloro-2-methoxybenzyl)-3-(ethoxyimino)-7-oxo-1,4-diazepan-1-yl]carbonyl}amino)butyl]benzoic acid, (3) 2-amino-4-{(1R)-1-[({(6S)-6-(5-chloro-2-methoxybenzyl)-7-oxo-3-[(2,2,2-trifluoroethoxy)imino]-1,4-diazepan-1-yl}carbonyl)amino]butyl}benzoic acid, (4) 2-amino-4-{(1R)-1-[({(6R)-6-(5-chloro-2-methoxybenzyl)-3-[(3,5-difluorophenoxy)imino]-7-oxo-1,4-diazepan-1-yl}carbonyl)amino]ethyl}benzoic acid, (5) 2-amino-4-[(1R)-1-({[(6S)-6-(5-chloro-2-methoxybenzyl)-3-(methoxyimino)-4-methyl-7-oxo-1,4-diazepan-1-yl]carbonyl}amino)butyl]benzoic acid, (6) (4-{(1R)-1-[({(6R)-6-(5-chloro-2-methoxybenzyl)-3-[(3,5-difluorophenoxy)imino]-7-oxo-1,4-diazepan-1-yl}carbonyl)amino]ethyl}phenyl)acetic acid, (7) 2-amino-4-{[({(6R)-6-(5-chloro-2-methoxybenzyl)-3-[(3,5-difluorophenoxy)imino]-7-oxo-1,4-diazepan-1-yl}carbonyl)amino]methyl}benzoic acid, (8) {4-[(1R)-1-({[(6R)-6-(5-chloro-2-methoxybenzyl)-7-oxo-3-(phenoxyimino)-1,4-diazepan-1-yl]carbonyl}amino)propyl]phenyl}acetic acid, (9) 2-Amino-4-[(1R)-1-({[(6R)-6-(5-chloro-2-methoxybenzyl)-7-oxo-3-(phenoxyimino)-1,4-diazepan-1-yl]carbonyl}amino)propyl]benzoic acid, or (10) 2-Amino-4-[(1R)-1({[(6R)-6-(5-chloro-2-methoxybenzyl)-3-(ethoxyimino)-7-oxo-1,4-diazepan-1-yl]carbonyl}amino)butyl]benzoic acid The method according to embodiment 37, selected from the group consisting of.

[0229] Embodiment 39: The compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is 2-amino-4-[(1R)-1-({[(3Z,6S)-6-(5-chloro-2-methoxybenzyl)-3-(ethoxyimino)-7-oxo-1,4-diazepan-1-yl]carbonyl}amino)butyl]benzoic acid (Compound 1), the method according to embodiment 30 or 31.

[0230] Embodiment 40: The solvate of Compound 1 is 2-amino-4-[(1R)-1-({[(3Z,6S)-6-(5-chloro-2-methoxybenzyl)-3-(ethoxyimino)-7-oxo-1,4-diazepan-1-yl]carbonyl}amino)butyl]benzoic acid monoacetate, the method according to embodiment 30 or 31. [Chemical formula]

[0231] Embodiment 41: The method according to embodiment 38, wherein the EGID is selected from the group consisting of eosinophilic gastroenteritis and eosinophilic esophagitis, eosinophilic duodenitis, eosinophilic gastritis.

[0232] Embodiment 42: A method for treating or preventing EGID in a subject in need of treatment or prevention of EGID, comprising the step of administering to the subject a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt or solvate thereof.

[0233] Embodiment 43: The method according to embodiment 42, wherein the EGID is selected from eosinophilic gastroenteritis, eosinophilic esophagitis, eosinophilic duodenitis, and eosinophilic gastritis.

[0234] Embodiment 44: The method according to embodiment 42, wherein the therapeutically effective amount of Compound 1 is from about 10 mg to about 1000 mg (e.g., from about 50 mg to about 500 mg) per unit dose.

[0235] Embodiment 45: The method according to any one of embodiments 42 to 44, wherein the therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof is administered once a day, twice a day, three times a day, once every two days, once every three days, or once a week.

[0236] Embodiment 46: The method according to any one of embodiments 42 to 44, wherein the therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt thereof is administered orally to the subject.

[0237] Embodiment 47: The method according to any one of embodiments 42 to 44, wherein the therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt or solvate thereof is administered in a unit dosage form for oral administration formulated as pellets, multi-unit particle systems (MUPS), tablets, troches, lozenges, dispersible powders or granules, or hard or soft capsules, powders, sustained release formulations, microcapsules.

[0238] Embodiment 48: The method according to any one of the foregoing embodiments, wherein the subject is a mammal, preferably a human.

[0239] Embodiment 49: A pharmaceutical composition for treating EGID in a subject, comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

[0240] Embodiment 50: A pharmaceutical composition for treating EGID in a subject, comprising a therapeutically effective amount of Compound 1 or a pharmaceutically acceptable salt or solvate thereof.

[0241] Embodiment 51: The pharmaceutical composition according to embodiment 48, wherein the therapeutically effective amount of compound 1 or a pharmaceutically acceptable salt or solvate thereof is about 10 mg to about 1000 mg per unit dose.

[0242] Embodiment 52: The pharmaceutical composition according to embodiment 49 or 50, wherein the EGID is selected from the group consisting of eosinophilic gastroenteritis, eosinophilic esophagitis, eosinophilic duodenitis, and eosinophilic gastritis.

[0243] Embodiment 53: A pharmaceutical composition for treating eosinophilic gastroenteritis in a subject, comprising a monoacetic acid solvate of 2-amino-4-[(1R)-1-({[(3Z,6S)-6-(5-chloro-2-methoxybenzyl)-3-(ethoxyimino)-7-oxo-1,4-diazepan-1-yl]carbonyl}amino)butyl]benzoic acid, and optionally a pharmaceutically acceptable carrier or excipient.

[0244] Embodiment 54: A pharmaceutical composition for treating eosinophilic esophagitis in a subject, comprising a monoacetic acid solvate of 2-amino-4-[(1R)-1-({[(3Z,6S)-6-(5-chloro-2-methoxybenzyl)-3-(ethoxyimino)-7-oxo-1,4-diazepan-1-yl]carbonyl}amino)butyl]benzoic acid, and optionally a pharmaceutically acceptable carrier or excipient.

[0245] Embodiment 55: A pharmaceutical composition for treating eosinophilic duodenitis in a subject, comprising a monoacetic acid solvate of 2-amino-4-[(1R)-1-({[(3Z,6S)-6-(5-chloro-2-methoxybenzyl)-3-(ethoxyimino)-7-oxo-1,4-diazepan-1-yl]carbonyl}amino)butyl]benzoic acid, and optionally a pharmaceutically acceptable carrier or excipient.

[0246] Pharmaceutical composition for treating eosinophilic gastritis in a subject, comprising 2-amino-4-[(1R)-1-({[(3Z,6S)-6-(5-chloro-2-methoxybenzyl)-3-(ethoxyimino)-7-oxo-1,4-diazepan-1-yl]carbonyl}amino)butyl]benzoic acid monoacetic acid solvate, and optionally a pharmaceutically acceptable carrier or excipient.

[0247] Examples The present disclosure has been described and illustrated with reference to specific embodiments thereof, but those skilled in the art will understand that various adaptations, changes, modifications, substitutions, deletions, or additions to the procedures and protocols can be made without departing from the spirit and scope of the present disclosure. For example, effective dosages other than the specific dosages described above may be applicable as a result of variations in the responsiveness of the subject. The specific pharmacological responses observed may vary according to and in response to the active compound selected with the pharmaceutical carrier of the present invention. Further, the response may vary depending on the type of formulation used and the mode of administration, and such expected variations or differences in results are contemplated in accordance with the objectives and practice of the present disclosure. Accordingly, the present disclosure is defined by the following claims, and such claims are intended to be construed broadly as reasonably possible.

[0248] Mouse model The Mdr2 knockout (Mdr2 KO) mouse is a genetic mouse model of PSC and exhibits a phenotype similar to that of human PSC. Collagen content, cholangiolar reaction, and inflammation are increased in Mdr2 knockout mice. The Mdr2 KO mouse also has an enhanced presence of mast cells (MCs). The total bile acid (TBA) content is increased in Mdr2 knockout mice. The accumulation of chymase- and tryptase-positive mast cells (MCs) in the liver was evaluated by immunohistochemistry. Metabolic parameters, such as total bile acids (serum and liver), cholangiolar reaction (CK-19), hepatic fibrosis (Fast Green Sirius Red staining), collagen deposition, hydroxyproline levels, fibrosis gene markers, cholangiocyte activation (desmin), inflammation, and mast cell products (F4 / 80, a macrophage marker), as well as aging and SASP markers (TGF-β1, p21, p16), were measured to determine the effect of Compound 1 in a mouse model of hepatobiliary disease.

[0249] Example 1: Measurement of the Efficacy of a Test Compound in the Treatment of Primary Sclerosing Cholangitis Objective: The objective of this experiment was to evaluate the potential of the test compounds of the present disclosure in the treatment of the progression of primary sclerosing cholangitis in a model of multidrug resistance 2 MDr2 knockout (Mdr2 KO) mice. This model recapitulates the clinical features of PSC, such as the accumulation of bile salts and triglycerides in the liver, hepatic steatosis, inflammation, and fibrosis.

[0250] Materials and Methods Test Compound: The monoacetate solvate of Compound 1 procured from Daiichi Sankyo.

[0251] Formulation for IP Injection: The monoacetate solvate of Compound 1 was suspended in 0.5% w / v hydroxypropyl cellulose.

[0252] Animals: Mdr2 homozygous knockout (Mdr2 KO) mice at 10 - 12 weeks of age were bred on an FVB / NJ background. All mice were maintained in a temperature - controlled environment (20°C - 22°C) on a 12:12 - hour light / dark cycle, fed a standard solid diet, and given free access to drinking water.

[0253] Experimental procedures: Drug administration The monohydrate acetate of compound 1 at 10 and 20 mg / kg was administered intraperitoneally daily from 10 weeks of age to 12 weeks of age. Mdr2 knockout (Mdr2 KO) mice were randomized into different groups as shown in Table 1. [Table 1]

[0254] Evaluation procedures Reduction of chymase - and tryptase - positive mast cells The levels of chymase - and tryptase - positive cells were observed by measuring the reduction in the expression of inflammatory markers such as mMCP1 and Tpbs2.

[0255] Liver bile acid accumulation Liver and serum bile acid accumulation was evaluated by using a colorimetric assay from Crystal Chem Inc (Catalog number 80471). For the liver, total bile acid (TBA) was extracted from the homogenized liver. For serum, (TBA) in the serum was measured by enzyme - immunoassay (EIA). 3 - alpha - hydroxysteroid dehydrogenase and nicotinamide adenine dinucleotide (NAD) converted TBA to 3 - ketosteroid and NADH. NADH reacted with nitroblue tetrazolium (NBT) to form a dye, which was measured at an absorbance of 540 nm.

[0256] Liver inflammation, fibrosis, and biliary senescence Liver inflammation, fibrosis, and biliary senescence were evaluated in liver sections by quantitative real-time PCR for mast cell markers such as Mcpt1, Fcer1α, Tpsb2 (see Figure 3), fibrosis-promoting markers such as Col1α1, Timp2, and Tgfb1 (see Figure 8), and biliary senescence markers such as Cdkn2a, Cdkn2c, Tgfb1, and Gl1bl (see Figure 10). Liver tissues were lysed, total RNA was isolated using Trizol, and fold changes were calculated using the ΔΔCt method.

[0257] Liver fibrosis was evaluated by quantitatively estimating collagen deposition using fast green and Sirius red staining of formalin-fixed paraffin-embedded liver sections (4 - 5 mm thick). Liver fibrosis and collagen deposition were evaluated by quantitative fast green / Sirius red staining. Macrophage accumulation was determined by staining for the F4 / 80 antibody (see Figure 4). Biliary epithelial cell activation was analyzed by immunofluorescence for desmin (see Figure 5) and CK19 (a marker for biliary epithelial cells) (see Figure 9).

[0258] Canalicular reaction / ductular reaction Changes in the intrahepatic bile duct mass (i.e., canalicular reaction) and the degree of cancer progression in the liver were also evaluated by quantitative immunohistochemistry in paraffin-embedded liver sections (4 - 5 mm thick) for CK19 (a marker for proliferating ducts and lobular hepatocytes) (see Figure 9).

[0259] Statistical analysis All data are presented as mean ± SEM. Groups were analyzed by Student's unpaired t-test when analyzing two groups or by two-way ANOVA when analyzing three or more groups, followed by appropriate post hoc tests. p < 0.05 was considered significant.

[0260] Results Treatment with Compound I in Mdr2 knockout (Mdr2 KO) mice resulted in a reduction in the accumulation of chymase- and tryptase-positive mast cells (MCs) in the liver Reduction of chymase- and tryptase-positive mast cells Treatment with the monoacetate solvate of compound 1 reduced the levels of chymase- and tryptase-positive cells, which was observed by a decrease in the expression of inflammatory markers such as mMCP1 and Tpbs2 (see Figure 1). Mdr2 KO mice were treated with 20 mg / kg of the monoacetate solvate of compound 1 and compared to untreated Mdr2 KO mice and FVBNJ wild-type mice. The levels of both inflammatory markers (mMCP1 and Tpbs2) were significantly decreased, indicating a reduction in chymase- and tryptase-positive cells.

[0261] Liver bile acid accumulation: The total liver bile acid content (Mdr2 knockout = 3.498252 μM, Mdr2 knockout, monoacetate solvate of compound 1 (20 mg / kg) = 1.796678, p < 0.0001) and serum bile acid content (Mdr2 KO = 62.04502 μM, Mdr2 KO, monoacetate solvate of compound 1 (20 mg / kg) = 26.23794, p < 0.0001) were significantly decreased in Mdr2 knockout (Mdr2 KO) mice treated with 20 mg / kg of the monoacetate solvate of compound 1, as shown in Figure 2.

[0262] Liver inflammation, fibrosis, and biliary senescence Mast cell markers Treatment with the monoacetate solvate of Compound 1 reduced the expression of inflammatory mast cell (MC) markers such as Mcpt1 (Mdr2 KO = 2.33385383; Mdr2 KO, monoacetate solvate of Compound 1, 10 mg / kg = 0.80944494, p = 0.0237; Mdr2 KO, monoacetate solvate of Compound 1, 20 mg / kg = 0.72297218, p = 0.0178), Fcer1 (Mdr2 KO = 2.20989385; Mdr2 KO, monoacetate solvate of Compound 1, 10 mg / kg = 1.5318546, p = 0.0058; Mdr2 KO, monoacetate solvate of Compound 1, 20 mg / kg = 0.88660902, p < 0.0001), and Tpsb2 (Mdr2 KO = 2.21107066; Mdr2 KO, monoacetate solvate of Compound 1, 10 mg / kg = 1.52950338, p = 0.8750; Mdr2 KO, monoacetate solvate of Compound 1, 20 mg / kg = 1.34093401, p = 0.7774), as shown in Figure 3. The fold change and p-value of each determined marker are shown in the table of Figure 3.

[0263] Similarly, treatment of Mdr2 knockout (Mdr2 KO) mice with Compound 1 also decreased the portal area F4 / 80 immunoreactivity (see Figure 4). Treatment of Mdr2 knockout - / - mice with Compound 1 also decreased the portal area F4 / 80 immunoreactivity. Mdr2 KO mice were treated with 20 mg / kg of the monoacetate solvate of Compound 1 and compared with untreated Mdr2 KO mice and FVBNJ wild-type mice. The determined p-values and F4 / 80 levels are shown in the table of Figure 4.

[0264] Biliary epithelial cell activation Biliary epithelial cell activation was analyzed by observing the immunofluorescence of desmin (see Figure 5) and CK19 (a marker of biliary epithelial cells) (see Figure 9). Treatment of Mdr2 knockout mice with Compound 1 showed a reduction in the expression of desmin levels when compared with untreated Mdr2 KO mice. The p-values and the % of desmin-positive cells are shown in the table of Figure 5.

[0265] Collagen deposition and hydroxyproline levels As shown in Figs. 6 to 7, treatment with the monoacetate solvate of Compound 1 restricted collagen deposition and hydroxyproline accumulation (Mdr2 KO = 4.871969; Mdr2 KO, monoacetate solvate of Compound 1, 10 mg / kg = 4.21926, p = 0.6426; Mdr2 KO, monoacetate solvate of Compound 1, 20 mg / kg = 2.971953, p = 0.0078). The determined p-values and the amount of collagen deposition are shown in the table of Fig. 6. The determined p-values and hydroxyproline levels are shown in the table of Fig. 7.

[0266] Fibrosis As shown in Fig. 8, treatment with the monoacetate solvate of Compound 1 reduced the expression of fibrosis-promoting fibrosis markers such as Col1a1 (Mdr2 KO = 3.28243911; Mdr2 KO, monoacetate solvate of Compound 1, 10 mg / kg = 1.50945703, p = 0.0005; Mdr2 KO, monoacetate solvate of Compound 1, 20 mg / kg = 0.9248071, p < 0.0001), Timp2 (Mdr2 KO = 3.41885191; Mdr2 KO, monoacetate solvate of Compound 1, 10 mg / kg = 1.53876217, p < 0.0001; Mdr2 KO, monoacetate solvate of Compound 1, 20 mg / kg = 0.94938034, p < 0.0001) and Tgfb1 (Mdr2 KO = 1.72254177; Mdr2 KO, monoacetate solvate of Compound 1, 10 mg / kg = 1.13268379, p = 0.0138; Mdr2 KO, monoacetate solvate of Compound 1, 20 mg / kg = 0.89864053, p = 0.0018) in Mdr2 knockout (Mdr2 KO) mice. The fold change and p-value of each determined marker are shown in the table of Fig. 8.

[0267] Ductular reaction / Increased ductal mass As evaluated by immunohistochemistry, treatment with the monoacetate solvate of compound 1 reduced the number of proliferating ducts and lobular hepatocytes (as well as CK19, a marker of cancer progression), as shown in Figure 9 (Mdr2 KO = 2.27623 μM; Mdr2 KO, monoacetate solvate of compound 1, 10 mg / kg = 1.113798 μM, p = 0.1970; Mdr2 KO, monoacetate solvate of compound 1, 20 mg / kg = 1.007429, p = 0.0122). The determined p-values and Ck-19 levels are shown in the table of Figure 9.

[0268] Biliary tract senescence: Administration of the monoacetate solvate of compound 1 (20 mg / kg) restricted the expression of senescence markers Cdkn2a (Mdr2 KO = 21.49752; Mdr2 KO, monoacetate solvate of compound 1, 20 mg / kg = 3.739189, p < 0.0001), Cdkn2c (Mdr2 KO = 16.05029; Mdr2 KO, monoacetate solvate of compound 1, 20 mg / kg = 12.66238, p = 0.0050), Tgfb1 (Mdr2 KO = 4.188847; Mdr2 KO, monoacetate solvate of compound 1, 20 mg / kg = 1.821263, p = 0.0002), Glb1l (Mdr2 KO = 13.02486; Mdr2 KO, monoacetate solvate of compound 1, 20 mg / kg = 3.319003, p = 0.0001) in Mdr2 knockout mice (Mdr2 KO), as shown in Figure 10. The fold change and p-value of each determined marker are shown in the table of Figure 10.

[0269] Conclusion: This data demonstrated that administration of the monoacetate solvate of Compound 1 to PSC animal models significantly reduced the expression of inflammatory mast cells (MCs) and macrophage accumulation, restricted cholangiocyte activation, reduced the expression of fibrosis-promoting gene s, restricted the deposition of collagen and hydroxyproline, reduced the number of proliferating ducts and lobular hepatocytes, and restricted the expression of senescence markers. Administration of Compound 1 improved cholangiolar reaction (DR), liver injury, senescence / SASP, and fibrosis, along with mast cell (MC) infiltration and activation in Mdr2 knockout (Mdr2 KO) mice. Inhibition of kinases by the monoacetate solvate of Compound 1 targets the PSC phenotype and improves pathogenesis by reducing biliary senescence and senescence-associated secretory phenotype (SASP) factors, thereby providing a therapeutic benefit to subjects with liver diseases, where MCs promote pathogenesis.

[0270] Human PSC and Mdr2 knockout (Mdr2 KO) mice exhibit enhanced cholangiolar reaction and biliary senescence. Without being bound by theory, senescence is thought to trigger cholangiocytes into a senescence-associated secretory phenotype (SASP) that increases factors such as TGF-b1. The increase in biliary senescence / SASP induces mast cell (MC) mobilization in the progression of PSC.

[0271] Administration of Compound 1 results in a decrease in cholangiocyte proliferation, a reduction in angiogenesis and inflammation, inhibition of TGF-b- and collagen-mediated liver fibrosis, and a decrease in HSC activation.

[0272] Mast cells positive for kinases (MCs) are significantly upregulated in human PSC and Mdr2 knockout (Mdr2 KO) mice. Treatment with Compound 1, a specific kinase inhibitor, decreases the presence of MCs and MC marker gene expression. In Mdr2 knockout (Mdr2 KO) mice treated with Compound 1, the PSC phenotype is improved, including liver injury, cholangiolar reaction, TGF-b1, biliary senescence, liver fibrosis, and portal inflammation. Thus, 14-day treatment with Compound 1 improves PSC-related phenotypes in Mdr2 knockout (Mdr2 KO) mice.

[0273] Example 2: Measurement of the Efficacy of a Test Compound in the Treatment of Ulcerative Colitis The purpose of this experiment was to evaluate the potential of the test compounds of the present disclosure in the treatment of ulcerative colitis (UC) in a dextran sulfate sodium (DSS)-induced colitis model. Dextran sulfate sodium (DSS) is a sulfated polysaccharide with variable molecular weight. Administration of DSS to mice causes human ulcerative colitis-like lesions due to its toxicity to colonic epithelial cells, resulting in defects in mucosal barrier function. DSS-induced colitis is a well-studied animal model for ulcerative colitis. This model reproduces clinical features of UC such as weight loss, diarrhea, and occult blood in the feces.

[0274] Materials and Methods Test compound: The monoacetate solvate of Compound 1 procured from Daiichi Sankyo. Formulation for IP injection: The monoacetate solvate of Compound 1 was suspended in 0.5% w / v hydroxypropyl cellulose.

[0275] Animals: For the DSS-induced acute model of experimental colitis, 8-week-old C57Bl / 6N mice (weighing 17 - 20 grams, all females from Charles River Laboratories) were used. All mice were maintained in a temperature-controlled environment (20°C ± 4°C) with a 12:12 hour light / dark cycle, relative humidity maintained at 55% ± 10%, ventilation performed 8 - 10 times per hour, provided with standard solid feed, and allowed free access to drinking water.

[0276] The experimental protocol for handling the mice was submitted and approved by the Italian Ministry of Health (IACUC#1174; approval number: 1144 / 2020-PR (prot.DC8BD.226)). Regular use of environmental enrichment was carried out to reduce animal stress. To obtain an environment that takes into account the physiological needs of the mice, the following parameters were observed.

[0277] Animal handling was minimized to what was necessary to reduce stress. For the proposed model, results for organs other than the colon were not described in the literature. One week before the start of the study, mice were randomly grouped and randomly assigned to groups of four mice in standard rectangular cages.

[0278] Mice were treated with a single oral cycle of 2.5% DSS (weight / volume) (DSS, molecular weight, 40 kDa; MP Biomedicals) characterized by 7 days of DSS exposure in drinking water, followed by 3 days of treatment with normal drinking water.

[0279] Experimental procedures Drug administration: Three days after the start of DSS administration, mice were treated with the test drug until day 9 according to the experimental groups and dosage regimens described in the following table. 0.5% (w / v) hydroxypropyl cellulose was used as the vehicle.

Table 2

[0280] Induction of colitis From day 0 to day 7, animals were given DSS in drinking water, and drugs were administered from day 3 to day 9. Body weight and clinical findings such as diarrhea and bleeding from the rectum were recorded daily until day 10 after induction of colitis.

[0281] Evaluation procedures The disease activity index (DAI) and weight loss were measured. The severity of colitis was determined using a Hemoccult SENSA card (Beckman Coulter) and calculated using the disease activity index (DAI) score based on daily evaluations of body weight, stool consistency, and the presence of blood in the stool.

[0282] The grade of intestinal inflammation was determined according to the criteria proposed by Cooper et al. (Cooper HS et al., Clinicopathologic study of dextran sulfate sodium experimental murine colitis. Lab Invest., 1993 Aug;69(2):238-49), and the DAI was determined by scoring changes in various factors such as weight loss, stool consistency, and occult blood. The weight loss score ranged from 0 to 4, where 0 indicated no weight loss, a score of 1 indicated the presence of a 1-5% weight loss, a score of 2 indicated the presence of a 5-10% weight loss, a score of 3 indicated the presence of a 10-20% weight loss, and a score of 4 represented a weight loss of more than 20%. Similarly, the stool consistency score ranged from 0 to 4, where a score of 0 represented normal stools, a score of 2 represented soft stools, and a score of 4 represented diarrhea. Rectal bleeding was observed by a score ranging from 0 to 4, where a score of 0 represented normal or no significant bleeding, a score of 2 indicated the presence of occult blood, and a score of 4 indicated the presence of gross bleeding. A 5-point (0-4) DAI was obtained by calculating the average of the weight score, stool consistency, and rectal bleeding.

[0283] Results Intraperitoneal treatment with Compound 1 in the DSS-induced colitis model significantly attenuated the pathological symptoms of DSS-induced colitis, such as weight loss, diarrhea, rectal bleeding, and DAI score, with an efficiency comparable to that of anti-TNF antibody. The results indicate that the monoacetate solvate of Compound 1 is as efficient as anti-TNF antibody for treating UC.

[0284] The weight loss graph is shown in Figure 12. Mice not exposed to DSS had no weight loss during the 0- to 10-day observation period. Mice exposed to DSS developed colitis and showed weight loss. DSS-exposed mice treated with the monoacetate solvate of Compound 1 showed a reduction in weight loss, comparable to the improvement seen in DSS-exposed mice treated with TNF.

[0285] The occult blood score graph is shown in Fig. 13. Mice not exposed to DSS had no measurable blood loss during the 0 - 10 day observation period. Mice exposed to DSS developed colitis and showed significant bleeding. DSS - exposed mice treated with the mono - acetate solvate of Compound 1 showed a reduction in bleeding, comparable to the improvement seen in DSS - exposed mice treated with TNF. Administration of Compound 1 significantly inhibited the reduction in colon length and improved the colon weight / length ratio.

[0286] The graph of the fecal hardness score is shown in Fig. 14. Mice not exposed to DSS had no diarrhea during the 0 - 10 day observation period. Mice exposed to DSS developed colitis and showed significant diarrhea and soft stools. DSS - exposed mice treated with the mono - acetate solvate of Compound 1 showed a reduction in diarrhea, comparable to the improvement seen in DSS - exposed mice treated with TNF.

[0287] The DAI score graph is shown in Fig. 15. Mice not exposed to DSS had a low DAI score of 0 during the 0 - 10 day observation period. Mice exposed to DSS developed colitis and showed significant DAI scores of 3 or more. DSS - exposed mice treated with Compound 1 showed a decrease in DAI score (<2). Fig. 16 shows the protective effect of administration of Compound 1 in DSS - induced colitis mice.

[0288] Conclusion: This data shows that administration of the mono - acetate solvate of Compound 1 to the DSS - induced colitis model significantly reduces weight loss, reduces blood loss, reduces diarrhea, reduces the DAI score, and shows a significant improvement in the colitis state. These results indicate that Compound 1 has a protective effect against DSS - induced acute colitis and suggest that Compound 1 may serve as an effective treatment for IBD.

[0289] Other Embodiments While specific embodiments of the subject matter have been described, the above specification is exemplary and not limiting. Upon review of this specification and the following claims, many variations will become apparent to those skilled in the art.

[0290] The recitation of a list of elements in any definition of a variable herein includes the definition of that variable as any single element or combination (or sub-combination) of elements of the list. The recitation of embodiments herein includes that embodiment as any single embodiment, or in combination with any other embodiment or portion thereof. The full scope of the present invention should be determined by reference to the claims, the full scope of their equivalents, and the specification, as well as such variations.

Claims

1. A pharmaceutical composition for the treatment or prevention of hepatobiliary tract disease, comprising 2-amino-4-[(1R-1-({[(3Z,6S)-6-(5-chloro-2-methoxybenzyl)-3-(ethoxyimino)-7-oxo-1,4-diazepan-1-yl]carbonyl}amino)butyl]benzoic acid (compound 1) or a pharmaceutically acceptable salt or solvate thereof as an active ingredient.

2. The pharmaceutical composition according to claim 1, used to improve one or more of the following in subjects suffering from hepatobiliary disease: infiltration of at least one of mast cells or macrophages, bile acid accumulation, bile duct cell proliferation, biliary senescence, fibrosis, and collagen deposition, or to improve one or more of the following: occult blood in the stool, fecal incontinence, fever, fatigue, weight loss, mast cell count and eosinophil count, dysphagia, gastroesophageal reflux disease (GERD), bloating, early satiety, loss of appetite, jaundice, pruritus, hepatomegaly, cirrhosis, bile duct obstruction, abdominal pain, nausea, diarrhea, ulcerative colitis, Crohn's disease, irritable bowel syndrome (IBS), proctitis, celiac disease, ileitis, duodenitis, diverticulitis, spasms, and inflammation.

3. The pharmaceutical composition according to claim 1, wherein the compound 1 or a pharmaceutically acceptable salt or solvate thereof is more selective to chymase than to cathepsin G.

4. The pharmaceutical composition according to claim 1, wherein the hepatobiliary disease is selected from the group consisting of acute hepatitis, alcoholic hepatitis, alcoholic liver disease, extrahepatic cholestasis, hepatic fibrosis, hepatic abscess, cirrhosis, colitis, neonatal jaundice, obstructive jaundice, primary bile acid malabsorption, acute cholecystitis, autoimmune hepatitis, benign recurrent intrahepatic cholestasis, bile duct obstruction, cholestatic liver disease, Crigler-Nadjar syndrome, drug-induced hepatitis, Gilbert's syndrome, pregnancy-related intrahepatic cholestasis, liver rejection, non-alcoholic fatty liver disease, non-alcoholic fatty liver disease, polycystic liver disease, veno-occlusive disease, and Wilson's disease.

5. The pharmaceutical composition according to claim 1, comprising about 20 mg to about 400 mg per unit dose of the compound 1 or a pharmaceutically acceptable salt or solvate thereof.

6. The aforementioned compound 1 is 【Chemistry 1】 The pharmaceutical composition according to claim 1.

7. The pharmaceutical composition according to claim 1, which is administered orally to a subject once a day, twice a day, three times a day, once every two days, once every three days, or once a week.

8. A pharmaceutical composition for the treatment or prevention of primary sclerosing cholangitis or primary biliary cholangitis, comprising 2-amino-4-[(1R-1-({[(3Z,6S)-6-(5-chloro-2-methoxybenzyl)-3-(ethoxyimino)-7-oxo-1,4-diazepan-1-yl]carbonyl}amino)butyl]benzoic acid (compound 1) or a pharmaceutically acceptable salt or solvate thereof as an active ingredient.

9. The pharmaceutical composition according to claim 8, used to reduce one or more of the following in a subject suffering from primary sclerosing cholangitis or primary biliary cholangitis: infiltration of at least one of mast cells or macrophages, bile acid accumulation, cholangiocarcinoma proliferation, biliary senescence, fibrosis, and collagen deposition, or to improve one or more of the following in a subject suffering from primary sclerosing cholangitis: occult blood in the stool, fecal incontinence, fever, fatigue, weight loss, mast cell count and eosinophil count, dysphagia, gastroesophageal reflux disease (GERD), bloating, early satiety, loss of appetite, jaundice, pruritus, hepatomegaly, cirrhosis, bile duct obstruction, abdominal pain, nausea, diarrhea, ulcerative colitis, Crohn's disease, irritable bowel syndrome (IBS), proctitis, celiac disease, ileitis, duodenitis, diverticulitis, spasms, and inflammation.

10. The pharmaceutical composition according to claim 8, used to treat or prevent at least one of inflammatory bowel disease and colitis in a subject.

11. The pharmaceutical composition according to claim 8, comprising about 20 mg to about 400 mg per unit dose of the compound 1 or a pharmaceutically acceptable salt or solvate thereof.

12. The aforementioned compound 1 is 【Chemistry 2】 The pharmaceutical composition according to claim 8.

13. The pharmaceutical composition according to claim 8, which is administered orally once a day, twice a day, three times a day, once every two days, once every three days, or once a week.

14. A pharmaceutical composition according to any one of claims 1 to 13, provided as pellets, multi-unit particle systems (MUPS), tablets, lozenges, dispersible powders or granules, or hard or soft capsules, powders, sustained-release formulations, or microcapsules.

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