Formulations of farnesoid x receptor agonist

Abstract

To provide pharmaceutical formulations and methods of use thereof in the treatment of conditions, diseases, or disorders associated with farnesoid X receptor activity.SOLUTION: Pharmaceutical formulations of a farnesoid X receptor agonist, 4-((4-(1-(tert-butyl)-1H-pyrazol-4-yl)pyridin-2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl 3-hydroxyazetidine-trans-1-carboxylate, and methods of using such pharmaceutical formulations in the treatment of conditions, diseases, or disorders associated with farnesoid X receptor activity are disclosed.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] This application is a continuation of U.S. Provisional Patent Application No. 62 / 991,216, filed March 18, 2020. No. 6,299,499, filed on Oct. 1, 2004, which is hereby incorporated by reference in its entirety.

[0002] Described herein are spray-dried solid dispersions of farnesoid X receptor agonists, such as Pharmaceutical formulations containing spray-dried solid dispersions and conditions associated with farnesoid X receptor activity Use of such spray-dried solid dispersions and pharmaceutical formulations in the treatment of conditions, diseases, or disorders. The method of use is described. [Background technology]

[0003] Farnesoid X receptor (FXR) is highly expressed in the liver, intestine, kidney, adrenal gland, and adipose tissue. FXR is a nuclear receptor expressed in the ovarian murine lining. It mediates bile acid synthesis and transport, lipid metabolism, and glucoside FXR regulates various target genes involved in the control of blood glucose homeostasis. a metabolic disorder, a liver disease or condition, an inflammatory condition, a gastrointestinal disorder, or a cell proliferative disorder. do. Summary of the Invention

[0004] In one embodiment, (a) 4-((4-(1-(tert-butyl)-1H-pyrazoline) (4-(4-methoxy-3-methylphenyl)-4-yl)pyridin-2-yl) Bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl 3 -hydroxyazetidine-trans-1-carboxylate and (b) a pharmaceutically acceptable and a polymer, wherein the polymer is 4-((4-(1-(tert- butyl)-1H-pyrazol-4-yl)pyridin-2-yl)((4-(4-methoxy -3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamo yl)cyclohexyl 3-hydroxyazetidine-trans-1-carboxylate, Dispersed in a polymer matrix formed from a pharmaceutically acceptable polymer. In some embodiments, pharmaceutically acceptable The polymers are PVP / VA 64, PVP 30, HPMCAS-L, and HPMCAS-M. , HPMCAS-H, Eudragit L100-55, Eudragit L100 , Eudragit EPO, HPMC E15, HPMC E3, HPMC E5, H Selected from PMCP-HP55 and Soluplus. In an embodiment, the pharmaceutically acceptable polymer is PVP / VA 64 and HPMC. In some embodiments, the pharmaceutically acceptable polymer is selected from AS-M. PVP / VA 64. In some embodiments, the pharmaceutically acceptable polymer is HPMCAS-M. In some embodiments, 4-((4-(1-(ter t-butyl)-1H-pyrazol-4-yl)pyridin-2-yl)((4-(4-meth (3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)carboxamide Bamoyl)cyclohexyl 3-hydroxyazetidine-trans-1-carboxylate The weight ratio of the pharmaceutically acceptable polymer to the hydroxybenzoate is 9:1 to 1:9. In the embodiment, 4-((4-(1-(tert-butyl)-1H-pyrazol-4-yl) pyridin-2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2 .2]octan-1-yl)methyl)carbamoyl)cyclohexyl 3-hydroxyazetate The weight ratio of thididine-trans-1-carboxylate to the pharmaceutically acceptable polymer is In some embodiments, the ratio is 3:1 to 1:3. butyl)-1H-pyrazol-4-yl)pyridin-2-yl)((4-(4-methoxy -3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamo (yl)cyclohexyl 3-hydroxyazetidine-trans-1-carboxylate and drugs In some embodiments, the weight ratio of the polymer to the biologically acceptable polymer is about 2:1. 4-((4-(1-(tert-butyl)-1H-pyrazol-4-yl)pyridine-2 -yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octa (1-methyl)carbamoyl)cyclohexyl 3-hydroxyazetidine-tra The weight ratio of acetophenone-1-carboxylate to the pharmaceutically acceptable polymer is about 1.5:1 In some embodiments, 4-((4-(1-(tert-butyl)-1H -pyrazol-4-yl)pyridin-2-yl)((4-(4-methoxy-3-methyl- Phenyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohe 3-hydroxyazetidine-trans-1-carboxylate and pharmaceutically acceptable salts thereof In some embodiments, the weight ratio of the spray-dried solids to the polymer is about 1:1. The dispersion further comprises a non-aqueous solvent. In some embodiments, the non-aqueous solvent is ter t-butanol, n-propanol, n-butanol, isopropanol, ethanol, Methanol, acetone, ethyl acetate, dimethyl carbonate, acetonitrile, dichloromethane, Methyl ethyl ketone, methyl isobutyl ketone, 1-pentanol, methyl acetate, tetrachloride Carbon, dimethyl sulfoxide, hexafluoroacetone, chlorobutanol, dimethyl sulfoxide The solvent is selected from the group consisting of methyl methylcellulose, methyl cellulose, methyl cellulose acetate, methyl cellulose ester ... In some embodiments, the non-aqueous solvent is ethanol, methanol, propanol, butyl alcohol, or the like. alcohol, isopropanol, tert-butanol, dichloromethane, and mixtures thereof In some embodiments, the non-aqueous solvent is selected from the group consisting of dichloromethane, ... A mixture of methane and methanol. In some embodiments of the spray-dried solid dispersion , 4-((4-(1-(tert-butyl)-1H-pyrazol-4-yl)pyridine- 2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octyl) Tan-1-yl)methyl)carbamoyl)cyclohexyl 3-hydroxyazetidin- The lanth-1-carboxylate is substantially amorphous. In some embodiments, 4-((4-(1-(tert-butyl)-1H-pyrazole -4-yl)pyridin-2-yl)((4-(4-methoxy-3-methylphenyl)bis( Chloro[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl 3-hydroxybenzoate Hydroxazetidine-trans-1-carboxylate is substantially crystalline.

[0005] In another aspect, provided herein is a spray-dried solid dispersion described herein. 1. A pharmaceutical formulation comprising one or more diluents, one or more disintegrants, one or more may comprise a plurality of binders, one or more lubricating agents, one or more glidants, and one or more one or more pharmaceutically acceptable components selected from the group consisting of surfactants In some embodiments, the pharmaceutical formulation further comprises one or more pharmaceutical components. Acceptable ingredients are microcrystalline cellulose, lactose monohydrate, croscarmellose Thorium, Magnesium Stearate, Colloidal Silicon Dioxide, Mannitol, Cross povidone, and sodium stearyl fumarate. In embodiments, the one or more pharmaceutically acceptable ingredients include microcrystalline cellulose, Lactose monohydrate, croscarmellose sodium, magnesium stearate, and and colloidal silicon dioxide. The pharmaceutical formulation is in the form of a tablet. In some embodiments, the tablet contains from about 1% by weight to about 30% by weight of In some embodiments, the tablet comprises about 5% by weight of the spray-dried solid dispersion. In some embodiments, the tablet comprises from about 25% by weight of the spray-dried solid dispersion. About 1% by weight to about 20% by weight of 4-((4-(1-(tert-butyl)-1H-pyrazoline) (4-(4-methoxy-3-methylphenyl)biphenyl-4-yl)pyridin-2-yl)( ... Cyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl 3- In some embodiments, the compound includes hydroxyazetidine-trans-1-carboxylate. In the present invention, the tablets contain about 1 mg, about 5 mg, about 12 mg, or about 25 mg of 4-((4-( 1-(tert-butyl)-1H-pyrazol-4-yl)pyridin-2-yl)((4 -(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl) Methyl)carbamoyl)cyclohexyl 3-hydroxyazetidine-trans-1-carboxamide In some embodiments, the pharmaceutical formulation is in capsule form.

[0006] In another embodiment, a method for treating or preventing a liver disease or condition in a mammal. Thus, a therapeutically effective amount of the spray-dried solid dispersion or pharmaceutical formulation described herein is administered to a patient in need thereof. In some embodiments, methods are provided herein that include administering to a mammal suffering from the disease. In some embodiments, the disease or condition is a metabolic condition. Or the condition is a liver condition.

[0007] In some embodiments, the spray-dried solid dispersions described herein are administered intravenously, Administered to mammals by subcutaneous, oral, inhalation, nasal, dermal, or ocular administration In some embodiments, the pharmaceutical formulations described herein are administered intravenously, subcutaneously, or intravenously. administered to a mammal by oral administration, inhalation, nasal administration, dermal administration, or ocular administration. do.

[0008] In another embodiment, any one of the diseases or conditions described herein is treated or prevented. a therapeutically effective amount of the spray-dried solid dispersion or pharmaceutical formulation described herein. The methods described herein include administering to a mammal in need thereof .

[0009] In another embodiment, a method for the treatment or prevention of a metabolic or hepatic condition in a mammal A method for spray-drying a solid dispersion or pharmaceutical formulation described herein, comprising the steps of: Methods are described herein that include administering to a mammal in need thereof. In embodiments, the metabolic or liver condition is amenable to treatment with an FXR agonist. In some embodiments, the method comprises spray-drying a solid dispersion described herein or In addition to the pharmaceutically acceptable salt or solvate, a second therapeutic agent may be administered to the mammal. and further including.

[0010] In another aspect, there is provided a method of treating or preventing a liver disease or condition in a mammal, comprising: A method comprising administering to a mammal a spray-dried solid dispersion or pharmaceutical formulation as described herein. In some embodiments, the liver disease or condition is In some embodiments, the liver disease is alcoholic or non-alcoholic. or conditions include primary biliary cirrhosis, primary sclerosing cholangitis, cholestasis, nonalcoholic Fatty liver disease (NASH) or nonalcoholic fatty liver disease (NAFLD). In some embodiments, the alcoholic liver disease or condition is fatty liver (steatosis), cirrhosis or alcoholic hepatitis. In some embodiments, non-alcoholic liver disease or the condition is nonalcoholic steatohepatitis (NASH) or nonalcoholic fatty liver disease In some embodiments, the non-alcoholic liver disease or condition is NAFLD. In some embodiments, the non-alcoholic steatohepatitis is non-alcoholic steatohepatitis (NASH). The alcoholic liver disease or condition is nonalcoholic steatohepatitis (NASH) and In some embodiments, the non-alcoholic liver disease or condition is associated with hepatic fibrosis. In some embodiments, the disease is non-alcoholic steatohepatitis (NASH) without fibrosis. In this case, the nonalcoholic liver disease or condition can be intrahepatic or extrahepatic cholestasis. In some embodiments, the liver disease or condition is steatohepatitis, cholangitis, fatty liver disease , cholestasis, cirrhosis, fibrotic liver disease, hepatitis, primary biliary cholangitis, biliary atresia, ala Ziel's syndrome, IFALD (intestinal failure-associated liver disease), parenteral nutrition-associated liver disease (PNALD) , hepatitis, hepatocellular carcinoma, cholangiocarcinoma, or a combination thereof.

[0011] In another aspect, there is provided a method of treating or preventing liver fibrosis in a mammal, comprising administering to said mammal a method comprising administering to said mammal a method of treating or preventing liver fibrosis in a mammal, the method comprising administering to said mammal a method of treating ... a method comprising administering to a mammal a spray-dried solid dispersion or pharmaceutical formulation according to the present invention; In some embodiments, the mammal is infected with hepatitis C virus. (HCV), nonalcoholic steatohepatitis (NASH), primary sclerosing cholangitis (PSC), Cirrhosis of the liver, Wilson's disease, Hepatitis B virus (HBV), HIV-associated steatohepatitis and liver cirrhosis Hepatitis, chronic viral hepatitis, nonalcoholic fatty liver disease (NAFLD), alcoholic fatty liver disease have been diagnosed with ASH, primary biliary cirrhosis (PBC), or biliary cirrhosis In some embodiments, the mammal is diagnosed with non-alcoholic steatohepatitis (NASH). He has been diagnosed with:

[0012] In another aspect, there is provided a method of treating or preventing hepatitis in a mammal, comprising administering to a mammal a compound as described herein. The method of the present invention comprises administering the spray-dried solid dispersion or pharmaceutical formulation described above to a mammal. In some embodiments, the mammal is infected with hepatitis C virus ( HCV), nonalcoholic steatohepatitis (NASH), primary sclerosing cholangitis (PSC), liver Cirrhosis, Wilson's disease, Hepatitis B virus (HBV), HIV-associated steatohepatitis and cirrhosis , chronic viral hepatitis, nonalcoholic fatty liver disease (NAFLD), alcoholic fatty liver disease Diagnosed with hepatitis (ASH), primary biliary cirrhosis (PBC), or biliary cirrhosis In some embodiments, the mammal is diagnosed with non-alcoholic steatohepatitis (NASH). In some embodiments, the hepatitis is associated with inflammation of the gastrointestinal tract. In some embodiments, the mammal has been diagnosed with inflammatory bowel disease.

[0013] In another embodiment, a method of treating or preventing a gastrointestinal disease or condition in a mammal, comprising: administering to a mammal a spray-dried solid dispersion or pharmaceutical formulation described herein. In some embodiments, the method is for treating a gastrointestinal disease or condition. Symptoms include necrotizing enterocolitis, gastritis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, irritable bowel syndrome, Gastroenteritis, radiation-induced enteritis, pseudomembranous colitis, chemotherapy-induced enteritis, gastroesophageal reflux disease (GER) D), peptic ulcer, non-ulcer dyspepsia (NUD), celiac disease, intestinal celiac disease, postoperative inflammation, gastric carcinogenesis, graft-versus-host disease, or any combination thereof. In an embodiment, the gastrointestinal disorder is irritable bowel syndrome (IBS), irritable bowel syndrome with diarrhea ( IBS-D), irritable bowel syndrome with constipation (IBS-C), mixed IBS (IBS-M) , unclassifiable IBS (IBS-U), or bile acid diarrhea (BAD).

[0014] In another aspect, there is provided a method of treating or preventing a renal disease or condition in a mammal, comprising: A method comprising administering to a mammal a spray-dried solid dispersion or pharmaceutical formulation as described herein. In some embodiments, the renal disease or condition is Renal fibrosis, acute kidney injury, chronic kidney injury, ischemic nephropathy, diabetic nephropathy, tubulointerstitial nephritis / nephropathy nephropathy, glomerulonephritis / nephropathy, or a combination.

[0015] In another embodiment, a method for treating or preventing a metabolic inflammation-mediated disease or disorder in a mammal is provided. The method comprises administering to a mammal a spray-dried solid dispersion or pharmaceutical formulation described herein. In some embodiments, methods are described herein that include administering: The metabolic inflammation-mediated disease or disorder is diabetes.

[0016] In another embodiment, there is provided a method of treating or preventing a lipid disease or disorder in a mammal, comprising: administering to a mammal a spray-dried solid dispersion or pharmaceutical formulation described herein. In some embodiments, methods are described herein for detecting lipids in a mammal. The quality disease or disorder is dyslipidemia.

[0017] In another aspect, a method for treating or preventing cancer in a mammal is provided, comprising administering to a mammal a compound as described herein. The method of claim 1, further comprising administering to a mammal a spray-dried solid dispersion or pharmaceutical formulation of the present invention. In some embodiments, the cancer is prostate cancer, colon cancer, or hepatocellular carcinoma. It is a cystic carcinoma.

[0018] In another embodiment, a mammalian disease or condition that may benefit from treatment with an FXR agonist is provided. A method for treating or preventing a condition comprising administering to a subject a spray-dried solid dispersion or Methods are described herein that include administering the pharmaceutical formulation to a mammal. In some embodiments, the methods described herein comprise spray-dried solid dispersions described herein. Or further comprising administering at least one additional therapeutic agent in addition to the pharmaceutical formulation.

[0019] (Incorporated by reference) All publications and patent applications mentioned herein are incorporated by reference in their entirety, to the extent applicable and relevant. It is incorporated herein by reference. [Brief explanation of the drawings]

[0020] [Figure 1] FIG. 1 shows the pharmacokinetic profiles of Compound 1 tablets A and C in monkeys. [Figure 2] FIG. 1 shows the release profiles of 12 mg tablets of Compound 1 containing 5% and 10% croscarmellose sodium. DETAILED DESCRIPTION OF THE INVENTION

[0021] Nuclear hormone receptor farnesoid X receptor (FXR or nuclear receptor subfamily 1, Group H, member 4 (also known as NR1H4) (OMIM: 603826) FXR functions as a modulator of bile acid metabolism. , jejunum, ileum, colon, gallbladder, liver, macrophages, white and brown adipose tissue, etc. FXR is a ligand-activated transcriptional receptor expressed in various tissues, including the liver, intestine, and kidney. It is highly expressed in tissues involved in bile acid metabolism. Bile acids act as endogenous ligands for FXR. It functions by allowing intestinal and systemic release of bile acids to induce FXR-directed changes in gene expression networks. Bile acids are the major oxidation products of cholesterol and, in some cases, are transported to the intestine. Once secreted, it acts as a modulator of cholesterol absorption. Cholesterol to bile acids The rate-limiting step in the conversion of cholesterol to hydroxybenzoate is the cytochrome p450 enzyme cholesterol 7-α-hydroxybenzoate. It is generated in the liver and is catalyzed by the cytochrome p450 enzyme steroid. Cholic acid 12-β-hydroxylase (CYP8B1) mediates the production of cholic acid and Determine the relative amounts of the major bile acids, cholic acid and chenodeoxycholic acid. FXR activity The activation of small heterodimer partner (SHP) (nuclear receptor subfamily 0, GlcNAc) in the liver The expression levels of NR0B2 (also known as loop B, member 2, or NR0B2) and the mouse Fibroblast growth factor 15 (FGF15) in humans and fibroblast growth factor 19 (FG F19) in the intestine, thereby inhibiting the transcription of CYP7A1 and CYP8B1. SHP regulates CYP7A1 and CYP8B1 gene expression. The transcription factors liver receptor homologue 1 (LRH-1) and hepatocyte nuclear factor 4α (HNFα) 4) The inhibition of CYP8B1 by FXR may be species-specific, and FX Activation of R may increase CYP8B1 expression in humans in some cases (Sanyal et al.,PNAS,2007,104,15665). Some examples In this study, FGF15 / 19 released from the intestine then activates fibroblast growth factor receptors in the liver. Mitogen-activated protein 4 activates CYP7A1 and inhibits CYP8B1 This leads to activation of the MAPK signaling pathway.

[0022] In some embodiments, elevated bile acid levels are associated with insulin resistance. For example, insulin resistance is caused by a decrease in glucose uptake from the blood and a decrease in liver This can lead to increased novo glucose production. In some cases, bile acid Intestinal sequestration enhances secretion of glucagon-like peptide-1 (GLP1) from intestinal L cells It has been shown that GLP-1 improves insulin resistance by inhibiting proglucosamine. It is an incretin derived from the transcription product of the vasopressin gene. It is released in response to food intake. GLP-1 regulates appetite and gastrointestinal function and stimulates insulin secretion from the pancreas. The therapeutically active form is GLP-1-(7-3), which results from selective cleavage of the proglucagon molecule. 7) and GLP-1-(7-36)NH2. In such cases, the production of bile acids Activation of FXR, leading to a decrease in insulin resistance, is associated with decreased insulin resistance.

[0023] In some embodiments, activation of FXR is mediated by peptide YY (PYY or PYY It is also associated with the secretion of folded pancreatic polypeptides such as erythropoietin (3-36). In this case, peptide YY is secreted in the hypothalamus and brainstem, areas of the brain involved in reward processing. It is a gastrointestinal hormone peptide that regulates neuronal activity in the Decreased PYY levels are associated with increased appetite and weight gain.

[0024] In some cases, activation of FXR indirectly leads to a decrease in plasma triglycerides. The clearance of triglycerides from the bloodstream is mediated by lipoprotein lipase (LPL). LPL activity is due to the induction of its activator, apolipoprotein CII. This is enhanced by induction, and suppression of its inhibitor, apolipoprotein CIII, in the liver is , which occurs upon FXR activation.

[0025] In some cases, activation of FXR may increase energy expenditure, such as adipocyte differentiation and function. Adipose tissue is made up of adipocytes or fat cells. In some cases, adipocytes are also called brown adipose tissue (BAT) or The function of BAT is to generate body heat. WAT functions as a fat storage tissue.

[0026] In some cases, FXR is widely expressed in the intestine. Activation induces the expression and secretion of FGF19 (or FGF15 in mice) in the intestine. FGF19 regulates bile acid synthesis, as well as glucose metabolism, lipid metabolism, and enzyme metabolism. In some cases, FGF19 is a hormone that affects the metabolism of fat. It has also been observed to regulate the function and differentiation of adipocytes. In fact, one study showed that a high-fat diet Administration of FGF19 to mice increased energy expenditure and fat cell differentiation. It has been shown that this regulates the function of the omega-3 fatty acids, reverses weight gain, and improves insulin resistance. (Fu et al., “Fibroblast growth factor 19 increases metabolic rate and reverses d ietary and leptin-deficient diabetes.”En (See Docrinology 145:2594-2603 (2004)).

[0027] In some cases, intestinal FXR activity may contribute to microbiome overgrowth, such as during feeding. It has been shown that it is involved in the decline of 2384, 2013). For example, one study demonstrated that activation of FXR was associated with antibacterial activity. associated with increased expression of several genes in the ileum, including Ang2, iNos, and Il18. It has been shown that (Inagaki et al., Proc Natl Acad Sci USA103:3920~3925,2006).

[0028] In some instances, FXR is involved in intestinal barrier function and immune regulation. It regulates the transcription of genes involved in the synthesis, transport, and metabolism of bile salts in the liver and intestine, and in some cases It has been shown that this improves intestinal inflammation and prevents bacterial migration into the intestinal tract (Ga Daleta et al., Gut., April 2011, 60(4):463~72) .

[0029] In some cases, overproduction of bile acids or inadequate transport and recycling of bile acids can lead to diarrhea. FXR regulates bile salt synthesis, transport, and metabolism in the liver and intestine. It regulates the transcription of the genes involved, leading to an improvement in diarrhea in some cases (Camil leri, Gut Liver. May 2015, 9(3):332~339).

[0030] G protein-coupled bile acid receptor 1 (GPBAR2, GPCR19, membrane receptor for bile acids) or M-BAR, or TGR5) is a cell surface receptor for bile acids. Upon activation by bile acids, TGR5 induces the production of intracellular cAMP, which stimulates BAT proliferation. Activation of deiodinase (DIO2) causes an increase in triiodothyronine, Energy consumption increases.

[0031] Thus, in some embodiments, bile acid synthesis, bile acid circulation, glucose metabolism Regulation of metabolic processes such as oxidative stress, lipid metabolism, or insulin sensitivity is mediated by FXR activation. Furthermore, in some embodiments, bile acid synthesis, bile acid circulation, glutamic acid synthesis, and glutamic acid synthesis are regulated by Dysregulation of metabolic processes such as course metabolism, lipid metabolism, or insulin sensitivity can lead to diabetes. or diabetes-related conditions or disorders, alcoholic or non-alcoholic liver disease or This can result in metabolic disorders such as inflammatory bowel disease, intestinal inflammation, or cell proliferative disorders.

[0032] Disclosed herein, in certain embodiments, are compounds that can be used as FXR agonists. In some embodiments, the compounds described herein are compounds having FXR antagonist activity. The FXR ligands are structurally distinct from bile acids, other synthetic FXR ligands, and other natural FXR ligands. varies.

[0033] In some embodiments, administering a therapeutically effective amount of an FXR agonist Treat metabolic disorders such as diabetes, obesity, impaired glucose tolerance, dyslipidemia, or insulin resistance Also disclosed herein are methods for preventing or preventing a gastrointestinal tract infection in a subject. It is administered into the tube.

[0034] In further embodiments, disclosed herein is a therapeutically effective amount of an FXR antagonist. by administering the compound to a subject in need thereof (e.g., via the gastrointestinal tract), Alcoholic or non-alcoholic liver disease or condition (e.g., cholestasis, primary biliary Cirrhosis, steatosis, cirrhosis, alcoholic hepatitis, non-alcoholic steatohepatitis (NASH) , nonalcoholic fatty liver disease (NAFLD), primary sclerosing cholangitis (PSC) or liver enzymes In a further embodiment, the present invention provides a method for treating or preventing a condition described herein. What is disclosed is a method for administering a therapeutically effective amount of an FXR agonist to a subject in need thereof. By administering this product, cholestasis, liver cirrhosis, primary biliary cirrhosis, and non-alcoholic fatty liver disease can be improved. NASH, nonalcoholic fatty liver disease (NAFLD), or primary sclerosing cholangitis In some embodiments, the present invention provides a method for treating or preventing PSC. What is disclosed is a method for administering a therapeutically effective amount of an FXR agonist to a subject in need thereof. In some embodiments, the method includes administering a compound to treat or prevent cholestasis. Disclosed herein is a method for administering a therapeutically effective amount of an FXR agonist to a patient in need thereof. and a method for treating or preventing primary biliary cirrhosis by administering the compound to a subject. In some embodiments, disclosed herein is a therapeutically effective amount of FX and administering an R agonist to a subject in need thereof to treat or In some embodiments, disclosed herein are methods for preventing NA is achieved by administering a therapeutically effective amount of an FXR agonist to a subject in need thereof. Methods for treating or preventing FLD are included.

[0035] In further embodiments, disclosed herein is a therapeutically effective amount of an FXR antagonist. by administering the agonist to a subject in need thereof (e.g., via the gastrointestinal tract) and a method for treating or preventing inflammation and / or cell proliferative disorders such as cancer in the intestine. include.

[0036] In further embodiments, disclosed herein are methods for inhibiting bile acid synthesis, glucose synthesis, and the like. metabolism, lipid metabolism, or insulin sensitivity, e.g., FGF19 (FGF1 in mice) 5) Increased activity of α-glucan, increased secretion of GLP-1, or increased secretion of PYY FXR agonists that regulate one or more of the proteins or genes associated with include.

[0037] 4-((4-(1-(tert-butyl)-1H-pyrazol-4-yl)pyridine-2 -yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octa (1-methyl)carbamoyl)cyclohexyl 3-hydroxyazetidine-tra ace-1-carboxylate (compound 1) Described herein are FXR agonist compounds 4-((4-(1-(ter t-butyl)-1H-pyrazol-4-yl)pyridin-2-yl)((4-(4-meth (3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)carboxamide Bamoyl)cyclohexyl 3-hydroxyazetidine-trans-1-carboxylate (Compound 1). "Compound 1" or "4-((4-(1-(tert-butyl)- 1H-pyrazol-4-yl)pyridin-2-yl)((4-(4-methoxy-3-methyl) (phenyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclo "Dihexyl 3-hydroxyazetidine-trans-1-carboxylate" has the following structure: It refers to a compound having

[0038] [ka]

[0039] In some embodiments, Compound 1 is in the form of a pharmaceutically acceptable salt. In this embodiment, Compound 1 is the free base. Additionally, Compound 1 may be present in unsolvated and and may exist in solvated forms with pharmaceutically acceptable solvents such as water, ethanol, etc. The solvated forms of Compound 1 presented herein are also disclosed herein. In some embodiments, Compound 1 is solvated. In the form, Compound 1 is unsolvated. In some embodiments, Compound 1 is crystalline. In some embodiments, compound 1 is amorphous.

[0040] Compound 1 has a non-bile acid chemical structure. In some embodiments, Compound 1 is In some embodiments, the compound has sustained exposure when administered to a mammal. Compound 1 has a continuous target engagement with FXR. In some embodiments, Compound 1 is suitable for once-daily oral administration.

[0041] Obeticholic acid (OCA) is an FXR agonist that contains the chemical structure of a bile acid. In clinical studies, OCA has demonstrated clinical efficacy as an FXR agonist. Associated with harmful side effects at high doses, including itching, increased LDL cholesterol, and liver toxicity In some embodiments, the binding of an FXR agonist to FXR is assessed. In suitable in vitro assays, Compound 1 is at least 30-fold more potent than OCA. In some embodiments, the increased potency of Compound 1 is greater than that of OCA. This indicates a potentially wider therapeutic window.

[0042] In some embodiments, Compound 1 is a compound that is Preclinical animal models have demonstrated sustained FXR engagement. , Compound 1 demonstrates sustained FXR engagement allowing for once-daily administration of Compound 1.

[0043] As used herein, "pharmaceutically acceptable" means a compound that is soluble in water and that exhibits the biological activity or properties of the compound. This refers to a material, such as a carrier or diluent, that does not destroy the product and is relatively non-toxic; The material may be used without causing any undesirable biological effects or in the composition in which it is contained. administered to an individual without interacting in any adverse way with any of the components of

[0044] The term "pharmaceutically acceptable salt" refers to a therapeutically active agent in combination with a suitable anion. or in another embodiment, in combination with a suitable cation. refers to a form of a therapeutically active agent that consists of the anionic form of the therapeutically active agent. Pharmaceutical Salts:Properties,Selecti on and Use. International Union of Pure a nd Applied Chemistry, Wiley-VCH 2002. SM .Berge,LDBighley,DCMonkhouse,J.Pharm .Sci.1977,66,1-19. P.H.Stahl and C.G.Wermut Handbook of Pharmaceutical Salts: Pro parties,Selection and Use,Weinheim / Zueri ch:Wiley-VCH / VHCA, 2002. Pharmaceutical salts are typically non-ionic They are more soluble in gastric and intestinal fluids than the active species, dissolve rapidly, and are useful in solid dosage forms. Furthermore, their solubility is often a function of pH, so they may be present in one part of the gastrointestinal tract or another. This ability is one aspect of delayed-release and sustained-release behavior. In addition, salt-forming molecules can be in equilibrium with the neutral form, making them biocompatible. The passage through the membrane can be adjusted.

[0045] It should be understood that a reference to a pharmaceutically acceptable salt includes the solvent addition forms. In some embodiments, the solvate may be in either stoichiometric or non-stoichiometric amounts. The compounds are isolated or purified using pharmaceutically acceptable solvents such as water, ethanol, etc. are formed during the purification process. When the solvent is water, hydrates are formed, and when the solvent is alcohol, In the case of alcohols, alcoholates are formed. Solvates of the compounds described herein are also used herein. Further, the present invention provides a method for preparing or forming a compound of formula (I) or (II) in a form that is conveniently prepared or formed during the process described herein. Compounds optionally exist in unsolvated and solvated forms.

[0046] Specific Terms Unless otherwise stated, the following terms used in this application have the definitions set forth below: The terms "including" and "include" and "including" Use of other forms such as "includes" and "included" When referring to a number or range of numbers, the term "about" is intended to mean the It means that the numbers or numerical ranges given are approximations within experimental variation (or statistical experimental error). Therefore, a number or range of values ​​may be between 1% and 15% of the specified number or range of values. %. The section headings used herein are for organizational purposes only and They should not be construed as limiting the subject matter described.

[0047] The term "acceptable" as used herein with respect to a formulation, composition, or ingredient means that the treatment will have no lasting adverse effect on the general health of the subject being treated. .

[0048] As used herein, the term "modulate" refers to directly altering the activity of a target. This means that the compound interacts with a target directly or indirectly, by way of example only, to enhance the activity of the target. inhibiting the activity of a target, limiting the activity of a target, or enhancing the activity of a target This includes extending the

[0049] As used herein, the term "modulator" refers to a compound that interacts directly or indirectly with a target. This refers to molecules that interact with each other. Interactions include agonists, partial agonists, inverse agonists, These interactions include interactions of antagonists, degraders, or combinations thereof. In some embodiments, the modulator is an agonist. .

[0050] As used herein, the terms "administer," "administering," "administration," and the like refer to a biological methods that can be used to enable delivery of a compound or composition to a desired site of therapeutic action. These methods include oral route, intraduodenal route, parenteral injection (intravenous, subcutaneous, including intraperitoneal, intramuscular, intravenous or infusion), topical and rectal administration, but Those skilled in the art will be familiar with administration techniques that can be used with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered intravenously. It is administered orally.

[0051] As used herein, the term "co-administration" and the like refers to the administration of selected therapeutic agents to a single patient. It is meant to encompass administration of drugs by the same or different routes or simultaneously or differently. The term "therapeutic regimen" is intended to include a therapeutic regimen administered over a period of time.

[0052] As used herein, the term "effective amount" or "therapeutically effective amount" refers to the amount of the disease being treated. or of an administered drug or compound that relieves to some extent one or more of the symptoms of a condition A sufficient amount of the drug, the result of which may include reduction and / or alleviation of the signs, symptoms, or causes of disease. These include the synthesis, synthesis of, or other desired modification of a biological system, e.g., for therapeutic use. An "effective amount" for purposes of this invention is the amount required to provide a clinically significant reduction in disease symptoms. The amount of a composition containing a compound disclosed herein. An "effective" amount is optionally determined using techniques, such as a dose escalation study.

[0053] As used herein, "enhance" or "enhance" The term "aging" refers to increasing or prolonging the potency or duration of a desired effect. Therefore, in regard to enhancing the effect of a therapeutic agent, "enhanced" means The term "g)" refers to a system that is significantly different in either potency or duration from other therapeutic agents. As used herein, an "enhancing-effective amount" refers to the ability to increase or prolong the effect of a desired An amount sufficient to enhance the effect of another therapeutic agent on a system.

[0054] As used herein, the term "pharmaceutical combination" refers to a mixture or administration of two or more active ingredients. means the product resulting from the combination, both fixed and non-fixed combinations of active ingredients The term "fixed combination" refers to a combination of active ingredients, e.g. Compound 1 or The pharmaceutically acceptable salt and the co-agent may both be administered to the patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredient is administered to a subject. component, e.g., Compound 1 or a pharmaceutically acceptable salt thereof, and an auxiliary agent, as separate entities. It is intended to be administered to a patient simultaneously, in parallel, or consecutively without a specific intervening time. Such administration provides effective levels of the two compounds in the patient's body. It also applies to cocktail therapy, for example the administration of three or more active ingredients.

[0055] The terms "kit" and "article of manufacture" are used synonymously.

[0056] The term "subject" or "patient" includes mammals. Examples of mammals include mammals Any member of the animal class: humans, chimpanzees, and other ape and monkey species Non-human primates, livestock such as cattle, horses, sheep, goats, and pigs, and domestic animals such as rabbits, dogs, and cats , laboratory animals including rodents such as rats, mice, and guinea pigs, etc., but these In one embodiment, the mammal is a human.

[0057] As used herein, the terms "treat," "treating," or "treatment" mean Alleviating, reducing, or ameliorating at least one symptom of a disease or condition, and / or reducing additional symptoms Preventing, inhibiting a disease or condition, e.g., halting the progression of a disease or condition alleviating a disease or condition; causing regression of a disease or condition; or to alleviate a condition caused by, or be preventative and / or therapeutic This includes effectively arresting the symptoms of a disease or condition.

[0058] Pharmaceutical Composition In some embodiments, the spray-dried solid dispersion of Compound 1 described herein is The active compound is formulated into a pharmaceutical composition. Disposed in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate Proper formulation is dependent upon the route of administration chosen. The abstract, for example, is from Remington: The Science and Practice CE of Pharmacy, 19th Edition (Easton, Pa.: Mack Publ. ishing Company, 1995), Hoover, John E., Rem. ington's Pharmaceutical Sciences(Mack Pu blishing Co., Easton, Pennsylvania 1975), Pharmaceutic by Liberman, H.A. and Lachman, L. al Dosage Forms (Marcel Decker, New York, NY , 1980), and Pharmaceutical Dosage Forms a nd Drug Delivery Systems, 7th Edition (Lippincott Williams & Wilkins, 1999), and is incorporated herein by reference.

[0059] In some embodiments, the spray-dried solid dispersion of Compound 1 described herein is alone or in combination with a pharmaceutically acceptable carrier, excipient or diluent in a pharmaceutical composition. Spray-dried solid dispersions of Compound 1 and pharmaceutical compositions thereof as described herein Administration of the compound can be affected by any method that allows delivery of the compound to the site of action. These methods include, but are not limited to, delivery by oral administration.

[0060] In some embodiments, pharmaceutical compositions of Compound 1 suitable for oral administration each comprise Other formulations include capsules, cachets, or tablets containing a predetermined amount of the active ingredient as a powder or granules. Presented as individual units.

[0061] Orally available pharmaceutical compositions include tablets, push-fit gelatin capsules, and Soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be made without the use of a binder, an inert diluent, or a lubricant, an interfacial agent, or The active ingredient in free-flowing form, such as a powder or granules, optionally mixed with an activator or dispersant. Molded tablets can be prepared by compressing the ingredients in a suitable machine. Making the powdered compound moistened with a diluent by molding it in a suitable machine In some embodiments, the tablet provides a sustained or controlled release of the active ingredient therein. The tablets are coated or scored and formulated to provide a smooth release. All formulations should be in dosages suitable for such administration. may contain fillers such as lactose, binders such as starch, and / or talc or stearyl alcohol. It contains the active ingredient mixed with a lubricating agent, such as magnesium phosphate, and optionally a stabilizer. In soft capsules, the active compounds can be coated with fatty oils, liquid paraffin, or It can be dissolved or suspended in a suitable liquid, such as liquid polyethylene glycol. In some embodiments, stabilizers are added. The dragee cores may be coated with a suitable coating. For this purpose, gum arabic, talc, polyvinylpyrrolidone, calcium carbonate, vopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solution, and a concentrated sugar solution which may optionally contain a suitable organic solvent or solvent mixture. can be used to identify or characterize different combinations of active compound doses. Dyestuffs or pigments can be added to the tablets or dragee coatings to prevent the appearance of a visible toxin.

[0062] Conventional techniques for producing solid oral dosage forms include: (1) dry blending; (2) direct compression; (3) milling, (4) dry or non-aqueous granulation, or (5) wet granulation. These include, but are not limited to, combinations thereof. For example, Lachman et al. l.,The Theory and Practice of Industrial See Pharmacy (1986). Other methods include, for example, spray drying. , pan coating, melt granulation, granulation, fluidized bed spray drying or coating (e.g., Wurster coating, tangential coating, tops This includes pressing, tableting, extrusion, etc.

[0063] In addition to the ingredients specifically mentioned above, the compounds and compositions described herein may be used in conjunction with the formulation type in question. In consideration of the above, the composition may contain other agents conventional in the art, for example, It should be understood that the composition may also include flavoring agents.

[0064] Tablets containing Compound 1 or a pharmaceutically acceptable salt thereof are provided. In some embodiments, the tablet comprises a polymer matrix formed from a pharmaceutically acceptable polymer. Compound 1, one or more diluents, one or more disintegrants, one or one or more lubricants, one or more glidants A plurality of pharmaceutically acceptable ingredients, and optionally one or more film coatings. Contains a stimulating agent.

[0065] In some embodiments, (a) Compound 1 and (b) a pharmaceutically acceptable polymer Described herein is a spray-dried solid dispersion comprising Compound 1, It is dispersed in a polymer matrix formed from an acceptable polymer.

[0066] In some embodiments, a composition prepared using the spray-dried solid dispersion described herein Tablets containing the compound are described herein.

[0067] Compound 1: Spray-dried solid dispersion formulation In some embodiments described herein, the pharmaceutical composition of Compound 1 is a spray-dried solid. In some embodiments, the (a) 4-((4-(1-(tert-butyl)-2-methyl-2-propanol-2-one ... t-butyl)-1H-pyrazol-4-yl)pyridin-2-yl)((4-(4-meth (3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)carboxamide Bamoyl)cyclohexyl 3-hydroxyazetidine-trans-1-carboxylate and (b) a pharmaceutically acceptable polymer. wherein 4-((4-(1-(tert-butyl)-1H-pyrazol-4-yl) pyridin-2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2 .2]octan-1-yl)methyl)carbamoyl)cyclohexyl 3-hydroxyazetate The thiamine-trans-1-carboxylate is formed from a pharmaceutically acceptable polymer. In some embodiments, the pharmaceutically acceptable carrier is dispersed in a polymer matrix. Accepted polymers are PVP / VA 64, PVP 30, HPMCAS-L, and HPMC AS-M, HPMCAS-H, Eudragit L100-55, Eudragit L100, Eudragit EPO, HPMC E15, HPMC E3, HPMC E5, HPMCP-HP55, and Solplus. In this study, the pharmaceutically acceptable polymers were PVP / VA 64 and HPMCAS-M. In some embodiments, the pharmaceutically acceptable polymer is selected from PVP / V A 64. In some embodiments, the pharmaceutically acceptable polymer is HPMC In some embodiments, the pharmaceutically acceptable polymer is PVP. 30. In some embodiments, the pharmaceutically acceptable polymer is HPMC- In some embodiments, the pharmaceutically acceptable polymer is HPMC. In some embodiments, the pharmaceutically acceptable polymer is Eu In some embodiments, the pharmaceutically acceptable salt is drugit L100-55. The polymer is Eudragit L100. A commercially acceptable polymer is Eudragit EPO. In some embodiments, the pharmaceutically acceptable polymer is HPMC E15. In some embodiments, the pharmaceutically acceptable polymer is HPMC E3. In some embodiments, the pharmaceutically acceptable polymer is HPMC E5. In some embodiments, the pharmaceutically acceptable polymer is HPMCP-HP55. In some embodiments, the pharmaceutically acceptable polymer is Soluplus. The weight ratio of Compound 1 to the pharmaceutically acceptable polymer is 9:1 to 1:9. In some embodiments, the weight ratio of Compound 1 to the pharmaceutically acceptable polymer is 7:1 In some embodiments, the ratio of Compound 1 to a pharmaceutically acceptable polymer is 1:7. In some embodiments, the weight ratio of Compound 1 to the drug is 5:1 to 1:5. The weight ratio of the biologically acceptable polymer to the polymer is 4:1 to 1:4. wherein the weight ratio of Compound 1 to the pharmaceutically acceptable polymer is 3:1 to 1:3. In some embodiments, the weight ratio of Compound 1 to the pharmaceutically acceptable polymer is In some embodiments, the ratio of Compound 1 to a pharmaceutically acceptable salt is 2:1 to 1:2. In some embodiments, the weight ratio of Compound 1 to the pharmaceutical polymer is 4:1. In some embodiments, the weight ratio of the compound to a polymer acceptable for the compound is 3:1. The weight ratio of 1 to the pharmaceutically acceptable polymer is 2:1. In this case, the weight ratio of Compound 1 to the pharmaceutically acceptable polymer is 1.5:1. In this embodiment, the weight ratio of Compound 1 to the pharmaceutically acceptable polymer is 1:1. In some embodiments, the weight ratio of Compound 1 to the pharmaceutically acceptable polymer is In some embodiments, the ratio of Compound 1 to a pharmaceutically acceptable polymer is 1:1.5. In some embodiments, the weight ratio of the non- In some embodiments, the non-aqueous solvent is tert-butanolic acid. alcohol, n-propanol, n-butanol, isopropanol, ethanol, methanol , acetone, ethyl acetate, dimethyl carbonate, acetonitrile, dichloromethane, methyl ethyl methyl isobutyl ketone, 1-pentanol, methyl acetate, carbon tetrachloride, dimethicone ethyl sulfoxide, hexafluoroacetone, chlorobutanol, dimethyl sulfone, vinegar In some embodiments, the hydroxybenzoate is selected from the group consisting of hydroxybenzoates, ... Non-aqueous solvents include ethanol, methanol, propanol, butanol, and isopropanol. tert-butanol, dichloromethane, and mixtures thereof. In some embodiments, the non-aqueous solvent is selected from dichloromethane and methanol. In some embodiments, the non-aqueous solvent is a mixture of dichloromethane and methanol. The weight ratio of dichloromethane to methanol is about 15 / 1. In some embodiments, the non-aqueous solvent is a mixture of dichloromethane and methanol; The weight ratio of dichloromethane to methanol is about 14 / 1. The non-aqueous solvent is a mixture of dichloromethane and methanol. In some embodiments, the non-aqueous solvent is dicyanol, and the weight ratio is about 13 / 1. It is a mixture of dichloromethane and methanol, and the weight ratio of dichloromethane to methanol is about In some embodiments, the non-aqueous solvent is dichloromethane and methanol. The weight ratio of dichloromethane to methanol is about 11 / 1. In some embodiments, the non-aqueous solvent is a mixture of dichloromethane and methanol; The weight ratio of dichloromethane to methanol is about 10 / 1. The non-aqueous solvent is a mixture of dichloromethane and methanol. In some embodiments, the non-aqueous solvent is dichloromethane. It is a mixture of dichloromethane and methanol, and the weight ratio of dichloromethane to methanol is about 8 In some embodiments, the non-aqueous solvent is a mixture of dichloromethane and methanol. It is a mixture of dichloromethane and methanol in a weight ratio of about 7:1. In an embodiment, the non-aqueous solvent is a mixture of dichloromethane and methanol; The weight ratio of methyl ether to methanol is about 6 / 1. The solvent is a mixture of dichloromethane and methanol. In some embodiments, the non-aqueous solvent is dichloromethane The weight ratio of dichloromethane to methanol is about 4 / 1. In some embodiments, the non-aqueous solvent is a mixture of dichloromethane and methanol. and the weight ratio of dichloromethane to methanol is about 3 / 1. In the above formula, the non-aqueous solvent is a mixture of dichloromethane and methanol, and dichloromethane and methanol in a weight ratio of about 2 / 1. In some embodiments, the non-aqueous solvent is A mixture of dichloromethane and methanol, with a weight ratio of dichloromethane to methanol of In some embodiments of the spray-dried solid dispersion, Compound 1 is It is amorphous in nature.

[0068] In another aspect, provided herein is a spray-dried solid dispersion described herein. and one or more diluents, one or more disintegrants, one or more binders. a combination agent, one or more lubricating agents, one or more glidants, and one or more and further comprising one or more pharmaceutically acceptable ingredients selected from the group consisting of surfactants. In some embodiments, the pharmaceutical formulation comprises one or more pharmaceutically acceptable salts. The ingredients are microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, Magnesium stearate, colloidal silicon dioxide, mannitol, crospovidone, and sodium stearyl fumarate. wherein the one or more pharmaceutically acceptable ingredients are microcrystalline cellulose, lactose Monohydrate, Croscarmellose Sodium, Magnesium Stearate, and Colloids In some embodiments, the pharmaceutical formulation is selected from the group consisting of: silicon dioxide, silica, silica gel, silica gel, silica gel powder ... In some embodiments, the pharmaceutical formulation is in capsule form.

[0069] In one embodiment, the polymer matrix is ​​formed from a pharmaceutically acceptable polymer. Compound 1 or a pharmaceutically acceptable salt thereof, one or more diluents dispersed therein. a diluent, one or more disintegrants, one or more lubricants, one or more glidants and optionally one or more pharmaceutically acceptable ingredients selected from the group consisting of and one or more film coatings. .

[0070] In some embodiments, the polymer matrix is ​​formed from a pharmaceutically acceptable polymer. Compound 1 or a pharmaceutically acceptable salt thereof dispersed in the sorbitol is a compound as described herein. is a spray-dried solid dispersion of

[0071] In some embodiments, the tablet contains about 1% to about 15% Compound 1 by weight. In some embodiments, the tablet comprises a polymer formed from a pharmaceutically acceptable polymer. It contains about 1% to about 20% by weight of polymer matrix.

[0072] In some embodiments, the tablet comprises a polymer formed from a pharmaceutically acceptable polymer. Compound 1 is dispersed in a polymer matrix at about 0.5% by weight to about 10% by weight. It contains about 15% by weight to about 15% by weight.

[0073] In some embodiments, the tablet comprises a polymer formed from a pharmaceutically acceptable polymer. Approximately 1% by weight to approximately 10% by weight of the polymer matrix is ​​dispersed in approximately 0.5% by weight to approximately 10% by weight of the polymer matrix. About 15% by weight of Compound 1, one or more diluents, one or more disintegrants, one or more is selected from the group consisting of a plurality of lubricating agents, one or more glidants, About 99% by weight of one or more pharmaceutically acceptable ingredients, and optionally about 2% by weight % of one or more film coating agents.

[0074] In some embodiments, the tablet contains about 1% to about 30% spray-dried solids by weight. In some embodiments, the tablet contains about 5% to about 25% by weight of a spray. In some embodiments, the tablet comprises about 5% by weight to about 20% by weight of a dry solid dispersion. In some embodiments, the tablet comprises about 5% by weight of the spray-dried solid dispersion. In some embodiments, the tablet comprises about 15% by weight of the spray-dried solid dispersion. It contains 5% to about 10% by weight of the spray-dried solid dispersion.

[0075] In some embodiments, additional excipients in the tablet in addition to the spray-dried solid dispersion are , one or more diluents, one or more disintegrants, one or more lubricants, one or more In some embodiments, the formulation comprises a glidant or glidants, or any combination thereof. In addition to the spray-dried solid dispersion, additional excipients in the tablet include microcrystalline cellulose, Mannitol, crospovidone, colloidal silicon dioxide, and magnesium stearate Includes Umu.

[0076] In some embodiments, tablets contain one or more fillers / binders / diluents. Fillers / binders / diluents include cellulose (e.g., microcrystalline cellulose, carboxymethylcellulose, methylcellulose, ethylcellulose, and methylcellulose), starch, gelatin , sugars (e.g., sucrose, glucose, dextrose, mannitol, and lactose) natural and synthetic gums (e.g., acacia, sodium alginate, bread gum) , and Gum Gatti), Polyvinylpyrrolidinone, Polyethylene glycol, Wax and any combination thereof. In some embodiments, the tablet Contains microcrystalline cellulose, and lactose monohydrate.

[0077] In some embodiments, one or more fillers / binding agents in the tablets described herein The excipient / diluent comprises about 40% to about 95% by weight of the total weight of the tablet. In embodiments, one or more fillers / binders / diluents in the tablets described herein The tablet comprises about 60% to about 95% by weight of the total weight of the tablet. Therefore, one or more fillers / binders / diluents in the tablets described herein may comprise more than one filler / binder / diluent in the total weight of the tablet. In some embodiments, the amount of the hydroxybenzoates used herein comprises about 65% to about 95% by weight of the total amount of the hydroxybenzoates used herein. The one or more fillers / binders / diluents in the tablet described in claim 1 account for about 75% of the total weight of the tablet. In some embodiments, the tablet composition described herein comprises from about 95% to about 95% by weight of the tablet. The one or more fillers / binders / diluents in the tablet may comprise about 50% by weight, about 5% by weight, of the total weight of the tablet. 5% by weight, about 65% by weight, about 70% by weight, about 75% by weight, about 80% by weight, about 85% by weight, In some embodiments, the compositions described herein comprise about 90% or about 95% by weight. The one or more fillers / binders / diluents in the described tablets comprise about 58% by weight of the total weight of the tablet. In some embodiments, the tablet comprises less than 95% by weight, 85% by weight, or less than 95% by weight of the total tablet weight. less than 75% by weight, less than 65% by weight, or less than 60% by weight of one or more It constitutes a filler / binder / diluent.

[0078] In some embodiments, the tablet comprises one or more disintegrants. Roscarmellose sodium, crospovidone, sodium starch glycolate, B Gum HV, methylcellulose, agar, bentonite, cellulose, carboxymethylcellulose In some embodiments, the protein is selected from the group consisting of riboflavin, sucrose ... , the tablets contain croscarmellose sodium.

[0079] In some embodiments, one or more disintegrants in the tablets described herein are It comprises about 2% to about 20% by weight of the total weight of the tablet. The disintegrant(s) in the tablets described herein comprise from about 5% to about 10% by weight of the total weight of the tablet. In some embodiments, one or more of the tablets described herein comprise 100% by weight. The disintegrants may comprise about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 9% by weight, approximately 10% by weight, approximately 11% by weight, approximately 12% by weight, approximately 13% by weight, approximately 14% by weight, about 15% by weight, about 16% by weight, about 17% by weight, about 18% by weight, about 19% by weight, or about 2% by weight In some embodiments, one or more of the tablets described herein comprise 0% by weight. In some embodiments, the disintegrants comprise about 5% by weight of the total weight of the tablet. The one or more disintegrants in the tablets described herein comprise about 10% by weight of the total weight of the tablet. In some embodiments, less than 20% by weight of the total weight of the tablet comprises one or more Contains several disintegrants.

[0080] In some embodiments, the tablet comprises one or more lubricants. Calcium stearate, magnesium stearate, stearic acid, fumaric acid Sodium tearyl alcohol, glyceryl behenate, hydrogenated vegetable oil, polyethylene glycol, and and any combination thereof. In some embodiments, the tablet comprises Contains magnesium phosphate.

[0081] In some embodiments, one or more lubricating agents in the tablets described herein are It comprises about 0.1% to about 5% by weight of the total weight of the tablet. The one or more lubricants in the tablets described herein may comprise from about 0.1% to about 10% by weight of the total weight of the tablet. In some embodiments, one or more of the tablets described herein comprise about 2% by weight. The lubricant or lubricants comprise about 0.1% to about 1% by weight of the total weight of the tablet. In some embodiments, one or more lubricants in the tablets described herein comprise more than one lubricant in the total weight of the tablet. Amounts of about 0.1 wt%, about 0.2 wt%, about 0.3 wt%, about 0.4 wt%, about 0.5 wt% %, about 0.6% by weight, about 0.7% by weight, about 0.8% by weight, about 0.9% by weight, or about 1% by weight In some embodiments, one or more of the tablets described herein comprise 100% by weight. The lubricant comprises about 1% by weight of the total weight of the tablet. Less than 2% by weight of the total weight of the agent comprises one or more lubricants.

[0082] In some embodiments, the tablet comprises one or more glidants. Glidants are substances added to powders to improve flowability. Examples of glidants include stearyl alcohol, PEG-14, PEG-18, PEG-19, PEG-20, PEG-21, PEG-22, PEG-23, PEG-24, PEG-25, PEG-26, PEG-27, PEG-28, PEG-29, PEG-30, PEG-31, PEG-32, PEG-33, Contains magnesium phosphate, colloidal silicon dioxide, starch and talc. In some embodiments, the tablet comprises colloidal silicon dioxide.

[0083] In some embodiments, one or more lubricating agents in the tablets described herein are It comprises about 0.1% to about 5% by weight of the total weight of the tablet. The one or more lubricants in the tablets described herein may be from about 0.1% to about 10% by weight of the total weight of the tablet. In some embodiments, one or more of the tablets described herein comprise about 2% by weight. The lubricant or lubricants comprise about 0.5% to about 1.5% by weight of the total weight of the tablet. In some embodiments, one or more lubricants in the tablets described herein may be present in the tablet. About 0.1% by weight, about 0.2% by weight, about 0.3% by weight, about 0.4% by weight, about 0.5% by weight of the total weight Weight%, approx. 0.6% by weight, approx. 0.7% by weight, approx. 0.8% by weight, approx. 0.9% by weight, approx. 1% by weight %, approximately 1.1% by weight, approximately 1.2% by weight, approximately 1.3% by weight, approximately 1.4% by weight, approximately 1.5% by weight %, about 1.6% by weight, about 1.7% by weight, about 1.8% by weight, about 1.9% by weight, or about 2 times In some embodiments, one or more of the tablets described herein comprise 100% by weight. The lubricant comprises about 1% by weight of the total weight of the tablet. Less than 2% by weight of the total weight of the agent comprises one or more lubricants.

[0084] Additional excipients In some embodiments, the tablets described herein may contain additives such as, but not limited to, buffers, Additional excipients include stimulants, preservatives, and coloring agents. Additional excipients such as chelating agents are within the scope of the embodiments.

[0085] Non-limiting examples of buffering agents include sodium bicarbonate, potassium bicarbonate, magnesium hydroxide, Um, magnesium lactate, magnesium gluconate, aluminum hydroxide, aluminum hydroxide Aluminum / sodium bicarbonate coprecipitate, amino acid and buffer mixture, aluminum glycinate Mixture of amino acid and buffer solution, Mixture of acid salt of amino acid and buffer solution, Alkaline salt of amino acid and buffer solution Additional buffering agents include, but are not limited to, sodium citrate, Sodium tartrate, sodium acetate, sodium carbonate, sodium polyphosphate, poly Potassium phosphate, sodium pyrophosphate, potassium pyrophosphate, disodium hydrogen phosphate , dipotassium hydrogen phosphate, trisodium phosphate, tripotassium phosphate, sodium acetate, Potassium phosphate, magnesium oxide, magnesium hydroxide, magnesium carbonate Calcium, magnesium silicate, calcium acetate, calcium glycerophosphate, calcium chloride Calcium hydroxide, calcium lactate, calcium carbonate, calcium bicarbonate, and other Contains calcium salts.

[0086] In some embodiments, the tablets described herein include a preservative. Examples of preservatives include antibacterial agents, antioxidants, and agents that enhance sterility. Corbic acid, ascorbyl palmitate, BHA, BHT, citric acid, erythorbic acid , Fumaric acid, Malic acid, Propyl gallate, Sodium ascorbate, Sodium bisulfate Sodium metabisulfite, sodium sulfite, parabens (methyl-, ethyl-, butyl Examples include benzoic acid, potassium sorbate, and vanillin.

[0087] In some embodiments, the tablets described herein are used to identify and administer the resulting liquid form. Suitable coloring agents include, for example, FD&C raffinate ... Red No. 3, FD&C Red No. 20, FD&C Red No. 40, FD&C Yellow No. 6, FD D&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5, Caramel, Iron Oxides and Mixtures thereof may also be mentioned.

[0088] In tablet embodiments, additional excipients are contemplated. These additional excipients have functional properties. and are selected based on their compatibility with the tablet compositions described herein, e.g., Remin gton:The Science and Practice of Pharmac y, 19th ed. (Easton, PA: Mack Publishing Company , 1995), Hoover, John E., Remington's Pharm. aceutical Sciences(Easton, PA:Mack Publicis) hing Co 1975), Liberman, HA and Lachman, L Author: Pharmaceutical Dosage Forms (New York, NY: Marcel Decker 1980), and Pharmaceutica l Dosage Forms and Drug Delivery Systems , 7th edition (Lippincott Williams & Wilkins 1999) ), which is incorporated herein by reference in its entirety.

[0089] In further embodiments, the tablets described herein are enteric coated tablets, sugar coated tablets, or coated tablets such as film-coated tablets.

[0090] In one embodiment, the individual unit doses are disintegrable by oral ingestion or contact with a diluent. In one embodiment, these formulations contain a conventional film coating. Manufactured by technology.

[0091] Compressed tablets are solid dosage forms prepared by compressing the bulk blend formulations described above. In various embodiments, compressed tablets designed to dissolve in the mouth may contain one or more In another embodiment, the compressed tablets contain a flavoring agent or agents. In some embodiments, the film coating is coating or sugar coating Film coatings, including Opadry®, are typically applied to the tablet weight. In other embodiments, the amount of the compressed tablet ranges from about 1% to about 5%. Contains several excipients.

[0092] Provided herein are compounds containing an active ingredient (e.g., Compound 1 or a pharmaceutically acceptable salt thereof). a salt thereof) to form a tablet core, followed by one or more tablet coatings to coat the core. It is in the form of a film-coated tablet containing a combination of formulation excipients. The tablets are manufactured using a conventional tableting process, followed by compression and coating. It can be done.

[0093] Enteric coatings are coatings that resist the action of stomach acid but dissolve or disintegrate in the intestine. It is.

[0094] In one embodiment, the oral solid dosage forms disclosed herein include an enteric coating. Enteric coatings include cellulose acetate phthalate, methyl acrylate, Acrylic acid copolymer, cellulose acetate succinate, hydroxypropyl methylcellulose cellulose phthalate, hydroxypropyl methylcellulose acetate succinate (hydroxypropyl methylcellulose acetate succinate) Promellose acetate succinate), polyvinyl acetate phthalate (PVAP) , methyl methacrylate-methacrylic acid copolymer, methacrylic acid copolymer, cellulose acetate (and its succinic and phthalic versions), styrene maleic acid copolymer , polymethacrylic acid / acrylic acid copolymer, hydroxyethyl ethyl cellulose phthalate cellulose acetate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate Contains one or more of the following: tetrahydrophthalate, acrylic resin, shellac can be.

[0095] Enteric coating is used to coat tablets, pills, capsules, pellets, beads, granules, particles, etc. This is a coating that is applied to the drug to prevent it from dissolving until it reaches the small intestine.

[0096] Sugar-coated tablets are compressed tablets coated with sugar to prevent unpleasant taste or It helps mask odors and protects the tablets from oxidation.

[0097] Film-coated tablets are compressed tablets covered with a thin layer or film of a water-soluble substance. The film coating contains hydroxyethyl cellulose, carboxymethyl cellulose, Contains sodium phosphate, polyethylene glycol 4000, and cellulose acetate phthalate. Film coatings are used in the same way as sugar coatings. Multiple compression tablets are produced by multiple compression cycles. Tablets, including layered tablets and press-coated or dry-coated tablets In some embodiments, the tablets are capable of immediate disintegration for rapid active release. The solution is coated with a water-soluble, pH-independent film coating (e.g., Op adry products).

[0098] Tablet dosage In some embodiments, the amount of Compound 1 in the tablet is between about 1 mg and about 25 mg. In some embodiments, the amount of Compound 1 in the tablet is about 1 mg. In some embodiments, the amount of Compound 1 in the tablet is about 5 mg. In some embodiments, the amount of Compound 1 in the tablet is about 12 mg. The amount of Compound 1 is about 25 mg.

[0099] Administration Methods and Treatment Regimen In one embodiment, Compound 1 as described herein or a pharmaceutically acceptable salt thereof The present invention relates to a method for treating a mammalian disease or condition that may benefit from the administration of an FXR agonist. The compounds of the present invention are used in the preparation of a medicament for treating any of the diseases or conditions described herein. The method of treatment in a mammal in need thereof comprises administering to a mammal a compound described herein, or or a pharmaceutically acceptable salt, active metabolite, prodrug, or pharmaceutically acceptable salt thereof and administering to the mammal a therapeutically effective amount of a pharmaceutical composition (i.e., formulation) containing the solvate of This includes administering the drug.

[0100] Disclosed herein are methods of administering an FXR agonist in combination with an additional therapeutic agent. In some embodiments, the additional therapeutic agent is a treatment for diabetes or a diabetes-related disorder or or condition, alcoholic or non-alcoholic liver disease, inflammation-related bowel conditions, or Includes therapeutic agents for the treatment of cell proliferative disorders.

[0101] In certain embodiments, compositions containing the compounds described herein are used for the prevention and / or treatment of In certain therapeutic applications, the compositions are administered to treat a disease or condition. in an amount sufficient to cure or at least partially arrest at least one symptom of the disease. An amount effective for this use is administered to a patient already suffering from a disease or condition. The severity and course of the condition, previous treatment, the patient's general health, weight, and response to medications, etc. A therapeutically effective amount may be determined through dose escalation and / or dose ranging clinical trials. Optionally determined by methods including, but not limited to, floor testing.

[0102] In prophylactic applications, compositions containing the compounds described herein are used to treat a particular disease, disorder, or condition. are administered to patients who are susceptible to or otherwise at risk for the condition. A prophylactically effective amount or dose is defined as a "prophylactically effective amount or dose." The amount of the drug that is effective for this use will depend on the patient's health condition, weight, etc. The appropriate amount will depend on the severity and course of the disease, disorder or condition, previous treatment, the patient's health status and Depending on the response to the medication and the judgment of the treating physician. Treatment is administered to breastfeeding patients who have previously experienced and are currently in remission of at least one symptom of the disease being treated. The animal is administered Compound 1 or a pharmaceutically acceptable salt thereof to prevent the recurrence of symptoms of the disease or condition. This includes administering a pharmaceutical composition containing an acceptable salt thereof.

[0103] In certain embodiments where the patient's condition does not improve, at the physician's discretion, the patient's illness or Compound 1 is administered chronically, i.e., to improve or control or limit the symptoms of the condition. , administered for an extended period of time, including for the patient's lifetime.

[0104] In certain embodiments where the patient's condition improves, the dose of the drug administered may be temporarily reduced. The drug is administered at a reduced dose or temporarily suspended for a period of time (i.e., a "drug holiday"). In embodiments, the length of the drug holiday period is between 2 days and 1 year, and by way of example only, 2 days , 3rd, 4th, 5th, 6th, 7th, 10th, 12th, 15th, 20th, 28th, or 2 Dose reduction during the drug holiday period may be, by way of example only, 10% to 100%. Examples include 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% and and 100%.

[0105] Once the patient's condition has improved, a maintenance dose is administered if necessary. The dosage or frequency of administration, or both, is adjusted as a function of the symptoms to determine the degree of improvement in the disease. However, in certain embodiments, Therefore, patients require intermittent treatment on a long-term basis upon recurrence of symptoms.

[0106] The amount of a given drug that corresponds to such an amount will vary depending on the particular compound, the condition and its severity, the treatment, and the dosage. Varies depending on factors such as the identity of the subject or host seeking treatment (e.g., weight, sex). However, the specific drug administered, the route of administration, and the type of treatment may nonetheless be varied. Determined according to the specific circumstances surrounding the case, including the condition and the subject or host being treated will be done.

[0107] However, in general, the dose used for adult treatment is typically 0. In one embodiment, the dose used to treat adults is in the range of 0.1 mg to 500 mg. is from about 1 mg to about 500 mg per day. In one embodiment, the desired dose may be administered in a single or divided dose simultaneously or at appropriate intervals, e.g., twice daily; Conveniently, three, four or more sub-doses may be administered.

[0108] In one embodiment, Compound 1 as described herein or a pharmaceutically acceptable salt thereof A suitable daily dose is about 0.01 to about 50 mg per kg of body weight. In some cases, the daily dose or amount of active ingredient in the dosage form may vary depending on the individual treatment plan. Lower or higher than the ranges indicated herein, based on the variables. In this regard, the daily and unit dosages will depend on the activity of the compound used, the disease or condition to be treated, The dosage regimen will depend on the individual subject's needs, the severity of the disease or condition being treated, and the judgment of the practitioner. This may vary depending on many variables, including but not limited to:

[0109] The toxicity and therapeutic efficacy of such treatment regimens are evaluated by, but not limited to, LD 50 and E D 50 determined by standard pharmaceutical procedures in cell cultures or experimental animals, including the determination of The dose ratio between toxic and therapeutic effects is the therapeutic index, and the LD 50 and ED 50 Expressed as a ratio of In certain embodiments, data obtained from cell culture assays and animal studies a therapeutically effective daily dose range and / or therapeutically effective In some embodiments, the compounds described herein are used to formulate effective unit doses. The daily dose of the compound is the ED 50 The circulating concentration range includes In embodiments, the daily dose range and / or unit dose may vary depending on the dosage form and use. It will vary within this range depending on the route of administration chosen.

[0110] In a further embodiment of any of the foregoing aspects, an effective amount of a compound described herein 1 or a pharmaceutically acceptable salt thereof, (a) by systemically administering to a mammal, and / or (b) orally administered to a mammal, and / or (c) intravenously administered to a mammal, and and / or (d) by injection into a mammal, and / or (e) by topical administration to a mammal. and / or (f) administering non-systemically or locally to a mammal.

[0111] Further embodiments of any of the foregoing aspects include a single administration of an effective amount of Compound 1, This may involve (i) administering the compound once daily or (ii) administering the compound to the mammal multiple times daily. Further embodiments include administering

[0112] Further embodiments of any of the foregoing aspects include multiple administrations of an effective amount of Compound 1; This can include (i) administering the compound as a single dose, either continuously or intermittently; (ii) administering multiple doses of the compound; (iii) the compound is administered to the mammal every 8 hours; (iv) administering the compound to the mammal every 12 hours; (v) administering the compound every 24 hours. Further embodiments include administering to a mammal in a In this method, the administration of the compound is temporarily suspended or the amount of the compound administered is increased. At the end of the drug holiday, which includes a drug holiday during which the dose of the compound is temporarily reduced, administration of the compound is resumed. In one embodiment, the length of the drug holiday varies from 2 days to 1 year.

[0113] In some instances, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in combination with one or more other It is appropriate to administer the drug in combination with other therapeutic agents.

[0114] In one embodiment, the therapeutic efficacy of Compound 1 is enhanced by the administration of an adjuvant. (i.e., the adjuvant itself has minimal therapeutic effect, but when combined with another therapeutic agent, (When combined, this enhances the overall therapeutic effect on the patient.) Alternatively, several In some embodiments, the benefit experienced by a patient may be determined by administering one of the compounds described herein to a patient having a therapeutic benefit. The effect is increased by administering it with another drug (including a therapeutic regimen) that also has the same effect.

[0115] In one particular embodiment, Compound 1 or a pharmaceutically acceptable salt thereof is and a second therapeutic agent, wherein Compound 1 or a pharmaceutically acceptable salt thereof and a second therapeutic agent are co-administered. Therapeutic agents modulate different aspects of the disease, disorder or condition being treated, thereby This provides a greater overall benefit than administering either treatment alone. [Example]

[0116] List of Abbreviations In the foregoing description and throughout the description of the present invention, the following abbreviations are used unless otherwise indicated: , should be understood to have the following meanings: ACN or MeCN: acetonitrile Bn: Benzyl BOC or Boc: tert-butylcarbamate t-butyl: tert-butyl Cy: Cyclohexyl DCE: dichloroethane (ClCH2CH2Cl) DCM: dichloromethane (CH2Cl2) DIPEA or DIEA: Diisopropylethylamine DMAP: 4-(N,N-dimethylamino)pyridine DMF: dimethylformamide DMA: N,N-dimethylacetamide DMSO: dimethyl sulfoxide equiv: equivalent amount Et: Ethyl Et2O: Diethyl ether EtOH: ethanol EtOAc: ethyl acetate HPLC: High-performance liquid chromatography Me: Methyl MeOH: Methanol MS: Mass spectrometry NMR: nuclear magnetic resonance RP-HPLC: Reversed-phase high-pressure liquid chromatography T3P: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphospho Linane-2,4,6-trioxide TBME: Methyl tert-butyl ether TFA: Trifluoroacetic acid THF: tetrahydrofuran TLC: Thin Layer Chromatography

[0117] I. Chemical synthesis Unless otherwise stated, reagents and solvents were used as received from the supplier. For minute and / or oxygen-sensitive synthetic transformations, use anhydrous solvents and oven-dried glassware. The reaction times are approximate and not optimized. Unless otherwise specified, column chromatography and thin layer chromatography (TLC) It was carried out on silica gel.

[0118] Example 1: 4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octane Preparation of 1-carbaldehyde (Intermediate 1)

[0119] [ka]

[0120] Step 1: 8-(4-Methoxy-3-methylphenyl)-1,4-dioxaspiro[4. 5]Decan-8-ol Three batches were run in parallel: n-BuLi (762 mL, 1.90 mol, n- 2.5M in hexane) with 4-bromo-1-methoxy-2-methylbenzene (333g, To a solution of 1.66 mol) and dry THF (2 L) was added dropwise at -60°C under N2 for 1 hour. The reaction was stirred at -60 °C for 1 h and then added 1,4-dioxaspiro[4.5]deca A solution of thion-8-one (284.53 g, 1.82 mol) in dry THF (1 L) was The reaction was stirred at -60 °C for 1 h, then the three batches were added dropwise with saturated NH The mixture was poured into aqueous 4Cl (3 L). The mixture was extracted with EtOAc (5 L x 2). The combined organic layer was washed with brine (5 L), dried over Na2SO4, filtered, concentrated, and then The mixture was then triturated in n-hexane (1.2 L) at room temperature overnight. The mixture was filtered and the filter cake was Wash with cold n-hexane (200 mL × 2) and then vacuum dry to obtain 8-(4-methoxyphenyl)-2-(4-methyl-2-propanol). -3-methylphenyl)-1,4-dioxaspiro[4.5]decan-8-ol (11 00g, 82%) as a white solid. 1 HNMR(400MHz,CDCl3):δ7.30-7.20(m,2H),6. 74(d,1H),4.02-3.87(m,4H),3.78(s,3H),2.18 (s,3H),2.15-2.00(m,4H),1.82-1.73(m,2H),1 .68-1.60(m,2H),1.48(s,4H).

[0121] Step 2: 8-Allyl-8-(4-methoxy-3-methylphenyl)-1,4-dioxane Spiro[4.5]decane Four batches were run in parallel: BF3Et2O (376.95 g, 2.65 mol ) with 8-(4-methoxy-3-methylphenyl)-1,4-dioxaspiro[4.5] Decane-8-ol (275 g, 0.99 mol) and allyltrimethylsilane (180 A solution of 1.62 g (1.58 mol) and dry DCM (3 L) was heated at -65°C under N2. The reaction mixture was stirred at -65 °C for 1 h, and then the four batches were carefully added with saturated NaHCO The mixture was poured into a 3 aqueous solution (10 L). The mixture was extracted with DCM (5 L x 3). The organic layer was washed with brine (5 L), dried over Na2SO4, filtered, and concentrated to give 8-aq. aryl-8-(4-methoxy-3-methylphenyl)-1,4-dioxaspiro[4.5] Decane (1350 g) was obtained as a yellow oil. 1 HNMR(400MHz,CDCl3):δ7.17-7.01(m,2H),6. 85-6.75(m,1H),5.53-5.37(m,1H),5.01-4.85( m,2H),3.99-3.87(m,4H),3.82(s,3H),2.37-2. 29(m,1H), 2.28-2.21(m,5H),2.20-2.10(m,2H) , 1.82-1.71(m,2H), 1.70-1.52(m,3H).

[0122] Step 3: 4-Allyl-4-(4-methoxy-3-methylphenyl)cyclohexanone Three batches were run in parallel: water (450 mL), then formic acid (285.95 g, 5 0.95 mol) to 8-allyl-8-(4-methoxy-3-methylphenyl)-1,4- To a solution of dioxaspiro[4.5]decane (450 g) and THF (1.8 L) was added at room temperature. The reaction mixture was refluxed overnight, cooled to room temperature, and then three batches were added to saturated NaHCO The mixture was poured into aqueous 3 solution (3 L). The mixture was extracted with EA (3 L x 3). The combined organic layers was washed with brine (3 L), dried over Na2SO4, filtered, concentrated, and then evaporated onto silica Purification was performed by gel chromatography (petroleum ether / Et0Ac = 1 / 0 to 50 / 1). 4-allyl-4-(4-methoxy-3-methylphenyl)cyclohexanone (800 g, 69.3% over two steps) as a yellow oil. 1 HNMR(400MHz,CDCl3):δ7.16-7.06(m,2H),6. 80-6.73(m,1H),5.48-5.30(m,1H),4.96-4.79( m,2H),3.77(s,3H),2.48-2.35(m,2H),2.32-2. 05(m,9H), 1.89-1.77(m,2H).

[0123] Step 4: 4-allyl-4-(4-methoxy-3-methylphenyl)cyclohexane Bonitrile Three batches were run in parallel: t-BuOK (299.69 g, 2.67 mol) 4-allyl-4-(4-methoxy-3-methylphenyl)cyclohexanone (230 g, 890.25 mmol) and Tos-MIC (260.72 g, 1.34 mol) To a solution of DME (2 L) was added dropwise over 1 h at 0 °C under N2 (maintaining the internal temperature <5 °C). The mixture was stirred at room temperature for 2 hours, and then the three batches were washed with saturated aqueous NH4Cl ( The mixture was poured into 5 L of ethyl acetate. The mixture was extracted with EtOAc (5 L x 2). The combined organic layer was Wash with ethanol (5 L), dry with Na2SO4, filter, concentrate, and then load onto silica gel. Purification by chromatography (petroleum ether / EtOAc = 1 / 0 to 50 / 1) 4-Allyl-4-(4-methoxy-3-methylphenyl)cyclohexanecarbonitrile (508 g, 70.6%) was obtained as a yellow oil. 1 HNMR(400MHz,CDCl3):δ7.13-6.99(m,2H),6. 83-6.75(m,1H),5.51-5.31(m,1H),5.03-4.85( m,2H),3.84(s,3H),2.58-2.48(m,1H),2.38-2. 02(m,7H), 1.98-1.79(m,2H), 1.78-1.56(m,3H) , 1.54-1.40(m,1H).

[0124] Step 5: 4-(2,3-dihydroxypropyl)-4-(4-methoxy-3-methylpropyl) (phenyl)cyclohexanecarbonitrile Three batches were run in parallel: NMO (242.66 g, 2.07 mol), then K2OsO4·2H2O (7.63 g, 20.71 mmol) was added to 4-allyl-4-( 4-Methoxy-3-methylphenyl)cyclohexanecarbonitrile (1.86g, 69 0.47 mmol), acetone (2 L), and H2O (2.50 mL) at 0 °C. The reaction was allowed to warm to room temperature and stirred for 2 hours. Three batches were added with saturated aqueous Na2SO3. The mixture was then extracted with EtOAc (3 L x 2). Washed with brine (3 L), dried over Na2SO4, filtered, concentrated, and then added to silica gel. The mixture was purified by chromatography on a column (petroleum ether / EtOAc = 5 / 1 to 1 / 2). 4-(2,3-dihydroxypropyl)-4-(4-methoxy-3-methylphenyl ) Cyclohexanecarbonitrile (600 g, 95.4%) was obtained as a yellow oil. 1 HNMR (400MHz, CDCl3): δ7.21-7.01(m,2H),6. 87-6.74(m,1H),3.83(s,3H),3.65-3.49(m,1H) ,3.35-3.17(m,2H),2.60-2.45(m,1H),2.41-2. 11(m,5H),2.01-1.81(m,4H),1.79-1.38(m,6H) .

[0125] Step 6: 4-(4-methoxy-3-methylphenyl)-4-(2-oxoethyl)cyclohexane Hexanecarbonitrile Three batches were run in parallel: NaIO 4( 169.20g, 791.05mmo l) with 4-(2,3-dihydroxypropyl)-4-(4-methoxy-3-methylphenyl)- (cyclohexanecarbonitrile) (200 g, 659.21 mmol) and THF ( A solution of 2 L of ethanol and 1 L of H2O was added at 0 °C for 30 min (maintaining an internal temperature of <5 °C). The mixture was stirred at room temperature for 3 hours, and then poured in three batches into water (2 L). The mixture was extracted with EtOAc (2 L x 2). The combined organic layers were washed with brine (2 L). Wash, dry over Na2SO4, filter, and concentrate to give 4-(4-methoxy-3-methyl- (phenyl)-4-(2-oxoethyl)cyclohexanecarbonitrile (510 g) Obtained as an oil. 1 HNMR(400MHz,CDCl3):δ9.43-9.22(m,1H),7. 20-6.99(m,2H),6.87-6.71(m,1H),3.82(s,3H) ,2.63-2.48(m,2H),2.46-2.36(m,1H),2.33-2. 13(m,4H), 2.02-1.71(m,5H), 1.71-1.57(m,2H) .

[0126] Step 7: 4-(2-hydroxyethyl)-4-(4-methoxy-3-methylphenyl) Cyclohexanecarbonitrile Three batches were run in parallel: NaBH4 (35.55 g, 939.73 mmol) ) to 4-(4-methoxy-3-methylphenyl)-4-(2-oxoethyl)cyclohexane To a solution of xanthanecarbonitrile (170 g) and THF (1.7 L) was added at 0°C under N2. The mixture was stirred at room temperature for 3 hours, and then the three batches were poured into ice-cold water (3 L). The mixture was extracted with EtOAc (1.5 L x 2). The combined organic layers were washed with brine (2 L). Wash, dry over Na2SO4, filter, and concentrate to give 4-(2-hydroxyethyl)-4 -(4-Methoxy-3-methylphenyl)cyclohexanecarbonitrile (495 g) Obtained as a colorless oil. 1HNMR(400MHz,CDCl3):δ7.18-6.97(m,2H),6. 88-6.71(m,1H),3.85-3.78(m,3H),3.76-3.70( m,1H),3.44-3.33(m,2H),2.71-2.69(m,0.5H), 2.60-2.48(m,0.5H),2.37-2.35(m,0.5H),2.27 -2.19(m,3H),2.14-2.12(m,0.5H),1.96-1.79( m,5H),1.78-1.61(m,3H),1.58-1.45(m,1H).

[0127] Step 8: 4-(2-bromoethyl)-4-(4-methoxy-3-methylphenyl)cyclohexyl Hexanecarbonitrile Three batches were run in parallel: PPh3 (316.62 g, 1.21 mol) and D The solution was diluted with CM (1 L) and 4-(2-hydroxyethyl)-4-(4-methoxy-3-methyl- (ethyl-phenyl)cyclohexanecarbonitrile (165g) and CBr4 (300.2 A solution of 4 g (905.37 mmol) and DCM (1.5 L) was added at 0 °C under N2 for 1 h. The mixture was stirred at room temperature for 1.5 hours, combined with the other two batches, and concentrated. The crude product was triturated in MTBE (5 L) at room temperature overnight. The solid was filtered off and the cake was The filtrate was washed with BE (500 mL × 2), concentrated, and then purified by chromatography on silica gel. Purification with (petroleum ether / EtOAc = 30 / 1) gave 4-(2-bromoethyl) -4-(4-methoxy-3-methylphenyl)cyclohexanecarbonitrile (530g , 80%) as a white solid. 1 HNMR(400MHz,CDCl3):δ7.11-6.96(m,2H),6. 86-6.73(m,1H),3.87-3.73(m,3H),3.09-2.93( m,2H),2.78-2.68(m,0.5H),2.62-2.50(m,0.5H ),2.38-2.34(m,1H),2.28-2.18(m,3H),2.17-2 .10(m,2H),2.08-1.99(m,2H),1.99-1.79(m,3H ), 1.77-1.45(m,3H).

[0128] Step 9: 4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octane -1-carbonitrile Three batches were run in parallel: LDA (420 mL, 840 mmol, 2 in THF) M) with 4-(2-bromoethyl)-4-(4-methoxy-3-methylphenyl)cyclohexane Hydrohexanecarbonitrile (143 g, 425.26 mmol) and HMPA (381. A solution of 1003 g (2.13 mol) and THF (1430 mL) was heated at -65 °C under N The mixture was stirred at -65 °C for 3 min, and then the three batches were added with saturated NH The mixture was poured into aqueous Cl solution (5 L). The mixture was extracted with EtOAc (3 L x 2). The organic layer was washed with water (3 L), washed with brine (3 L), dried over Na2SO4, and It was filtered, concentrated, and then triturated in EA:hexane (1:30, 775 mL) at room temperature overnight. The mixture was filtered and the filter cake was washed with EA:hexane (1:30, 150 mL). The product was washed and dried under vacuum to give 4-(4-methoxy-3-methylphenyl)bicyclo[2. 2.2]Octane-1-carbonitrile (240 g, 73%) was obtained as a yellow solid. 1 HNMR(400MHz,CDCl3):δ7.13-6.98(m,2H),6. 83-6.73(m,1H),3.82(s,3H),2.22(s,3H),2.12 -1.98(m,6H),1.94-1.80(m,6H).

[0129] Step 10: 4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octadecanoate Benzene-1-carbaldehyde Three batches were run in parallel: DIBAL-H (1 MPhMe, 830 mL, 83 0 mmol) in DCM (1 L) b) [2.2.2]octane-1-carbonitrile (106 g, 415.11 mmol) The solution was added under N2 at -65°C. The mixture was stirred at -65°C for 1 hour and then divided into three batches. The mixture was poured into saturated aqueous NaK tartrate (3 L) and diluted with DCM (1.5 L). The mixture was stirred at room temperature for 3 hours. The organic layer was separated and the aqueous layer was extracted with DCM (2 L x 2). The organic layers were combined, washed with brine (3 L), dried over Na2SO4, filtered, and concentrated. 4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octane-1- Carbaldehyde (336 g) was obtained as a yellow solid. 1 HNMR(400MHz,DMSO-d6):δ9.50-9.43(m,1H), 7.11-7.00(m,2H),6.83-6.79(m,1H),3.77-3.6 8(m,3H),2.18-2.02(m,3H),1.82-1.72(m,6H), 1.71-1.60(m,6H).

[0130] Step 11: Hydroxy(4-(4-methoxy-3-methylphenyl)bicyclo[2.2 .2]octan-1-yl)methanesulfonate potassium Six batches were run in parallel: aqueous potassium metabisulfite (2 M, 54 mL, 1 08 mmol) in THF (300 mL) (2.2.2)octane-1-carbaldehyde (56 g) at 45°C. The mixture was stirred at 45°C for 3.5 hours, cooled to room temperature, and then The mixture was stirred at room temperature overnight. Six batches were filtered and the filter cake was washed with PE (400 mL). It was washed, dried in vacuo, and then purified by filtration to obtain potassium hydroxy(4-(4-methoxy-3-methylphenyl) ) bicyclo[2.2.2]octan-1-yl) methanesulfonate (381g, 2 steps) The compound was obtained as a white solid (81%). 1 HNMR(400MHz,DMSO-d6):7.12-6.97(m,2H),6 .88-6.71(m,1H),4.51(d,1H),3.73(s,3H),3.5 6(d,1H),2.11(s,3H),1.88-1.56(m,12H).

[0131] Step 12: 4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octadecanoate Benzene-1-carbaldehyde Six batches were run in parallel: Na2CO3 (300 mL) was added to potassium-hydrochloride 4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octane-1 -yl) methanesulfonate (63.5 g, 167.76 mmol) and DCM (300 m The mixture was stirred for 1 hour and then divided into six batches. The mixture was poured into a mixture of DCM (1500 mL) and H2O (1500 mL). The aqueous phase was separated and extracted with DCM (1500 mL × 3). The combined organic layers were washed with brine (2 L ), dried over Na2SO4, filtered, and concentrated to give 4-(4-methoxy-3-methyl- (ethylphenyl)bicyclo[2.2.2]octane-1-carbaldehyde (240.3g, 92%) as a white solid. 1 HNMR(400MHz,DMSO-d6):δ9.52-9.41(m,1H), 7.14-7.02(m,2H),6.84-7.80(m,1H),3.73(s,3 H),2.12(s,3H),1.83-1.72(m,6H),1.71-1.56( m,6H), LCMS: 259.1 [M+H] + .

[0132] Example 2: 4-(1-(tert-butyl)-1H-pyrazol-4-yl)pyridine- Preparation of 2-amine (intermediate 2)

[0133] [ka]

[0134] 2-Methyltetrahydrofuran (10 mL), Pd(dppf)Cl2, followed by K2C Aqueous O3 solution (3 M, 10 mL, 30 mmol) was added to a 40 mL vial containing 4-bromopyridine. Lysine-2-amine (1.87 g, 10.8 mmol) and 1-(tert-butyl) -4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1H-pyrazole (2.50 g, 10.0 mmol) was added. The reaction was vacuum / N Degassed in two cycles and heated at 50° C. for 21 hours, then allowed to cool to room temperature. The organic layer was washed with saturated aqueous NaK tartrate (25 mL) and then brine (25 mL). The aqueous layer was back-extracted with 2-methyltetrahydrofuran (25 mL). The organics were dried (MgSO4), filtered, concentrated, and then dried under vacuum for 1 hour. A suspension of the crude material in MTBE (25 mL) was refluxed for 2 hours, cooled to room temperature overnight, and then filtered. The filter cake was washed with MTBE (2 × 3 mL) and then dried under vacuum to give 4-(1-(tert-butyl)-1H-pyrazol-4-yl)pyridin-2-amine (1.15g, 53%) 1 HNMR(400MHz,DMSO-d6):δ8.27(s,1H),7.86- 7.82(m,2H),6.74(d,1H),6.61(s,1H),5.77(s, 2H), 1.54(s, 9H), LCMS:217.1[M+H] + .

[0135] Example 3: trans-4-((tert-butyldimethylsilyl)oxy)cyclohexa Preparation of carboxylic acid (intermediate 3)

[0136] [ka]

[0137] Step 1: trans-tert-butyldimethylsilyl 4-((tert-butyldimethylsilyl) (silyl)oxy)cyclohexanecarboxylate tert-Butyldimethylsilyl chloride (31.47 g, 208.8 mmol), trans-4-hydroxy-cyclohexanecarboxylic acid (10.03 g, 69.57 mm ol), imidazole (18.96 g, 278.5 mmol), and DMF (140 mL ) at room temperature under N2 (the reaction exothermed to 32 °C). The reaction was allowed to stand at room temperature for 2 h. The organic layer was stirred and then diluted with diethyl ether (300 mL). Wash with 1 mL of 1N HCl, then 300 mL of brine), dry (Na2SO4) , filtered, and concentrated to give trans-tert-butyldimethylsilyl 4-((tert-butyl) (Dimethylsilyl)oxy)cyclohexanecarboxylate was obtained as a clear oil. (31.5g). 1 HNMR(400MHz,DMSO-d6):δ3.61-3.53(m,1H), 2.26-2.18(m,1H),2.04-1.96(m,2H),1.92-1.8 5(m,2H),1.51-1.39(m,2H),1.39-1.27(m,2H), 0.94(s,9H), 0.89(s,9H),0.26(s,6H),0.06(s, 6H).

[0138] Step 2: trans-4-((tert-butyldimethylsilyl)oxy)cyclohexa carboxylic acid Potassium carbonate (58.01 g, 419.7 mmol) in H2O (300 mL) was trans-tert-butyldimethylsilyl 4-((tert-butyldimethylsilyl)o (oxy)cyclohexanecarboxylate (crude 31.5 g, 69.6 mmol) and ethanol The mixture was added to a mixture of alcohol (1000 mL) and THF (300 mL) at room temperature under N2. The reaction was stirred at room temperature for 3 hours, concentrated until 300 mL remained, and washed with brine (600 mL). The aqueous layer was diluted and then acidified to pH 2-3 with 20% NaHSO4 (550 mL). Extract with ethyl ether (800 mL). Wash the organic layer with (800 mL brine). , dried (Na2SO4), filtered, concentrated, and dried under high vacuum (to remove silanol by-products). (To remove the substance), trans-4-((tert-butyldimethylsilyl)oxy) Cyclohexanecarboxylic acid (17.3 g, 96% over two steps) was obtained as a white solid. 1 HNMR(400MHz,DMSO-d6):δ12.30(brs,1H),3. 59-3.51 (m, 1H), 2.15-2.05 (m, 1H), 1.88-1.74 ( m,4H), 1.41-1.29(m,2H),1.28-1.16(m,2H),0. 84(s,9H),0.02(s,6H).

[0139] Example 4: 4-((4-(1-(tert-butyl)-1H-pyrazol-4-yl)pyrazole) Lysin-2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2. 2]Octan-1-yl)methyl)carbamoyl)cyclohexyl 3-hydroxyazetyl Preparation of diazine-trans-1-carboxylate (compound 1)

[0140] [ka]

[0141] Step 1: 4-(1-(tert-butyl)-1H-pyrazol-4-yl)-N-(( 4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl )Methyl)pyridin-2-amine Intermediate 1 (1.0 eq) in methanol (7.5 vol) and acetic acid (0.33 eq) A mixture of Intermediate 2 (1.1 equiv.) was heated at 55° C. for at least 3 hours. was cooled to room temperature and 2-methylpyridine borane complex (1.0 equivalent) was added as a solid to at least The reaction was stirred at room temperature overnight and water (12.0 vol) was added over 20 min. The suspension was stirred for at least 2 hours. The solid was collected by filtration and diluted with water. / methanol (2:1) (2 × 1 volume), TBME (2 × 2 volumes), and heptane (2 × 2 volumes), dried on a rotary evaporator at 50 °C, and rt-butyl)-1H-pyrazol-4-yl)-N-((4-(4-methoxy-3-methyl) (methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)pyridin-2-a Got Min.

[0142] Steps 2 and 3: trans-N-(4-(1-(tert-butyl)-1H-pyrazole) -4-hydroxy-N-((4-(4-methoxy- 3-Methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)cyclohexyl Saccarboxamide 4-(1-methyl-2-methyl-1,3-dichloromethane) in dichloromethane (7.5 vol) and triethylamine (4.0 eq.) -(tert-butyl)-1H-pyrazol-4-yl)-N-((4-(4-methoxy -3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)pyridine A mixture of 1.0 equiv. of 2-amine and 1.2 equiv. of intermediate 3 was added to dichloromethane at 0° C. A solution of T3P in methane (2.0 equiv.) was added over 0.5 h. The reaction mixture was allowed to warm to room temperature. The reaction mixture was cooled to 5°C and added water twice (0.0 The mixture was quenched by the portionwise addition of 100 ml of ethanol (5.5 vol and 6.0 vol). The mixture was heated and stirred for at least 2 hours. The organic layer was collected and washed with water. The dichloromethane solvent was removed. Displaced in vacuo with 2-methyltetrahydrofuran (5.4 vol). Methanol (2. 4 vol) and water (2 vol) were added to the solution, followed by aqueous HCl (32%) (1.9 equiv. ) was added. The reaction mixture was stirred at room temperature for at least 2 hours. The mixture was added with 9.5% NaH Aqueous CO3 (4 volumes) was added. The organic layer was collected, washed with brine and It was dried and filtered through Celite. The filtrate was concentrated in vacuo and TBME (9 vol) was added. The solid was collected by filtration, washed with TBME and heptane, and dried in vacuo at 60°C. , trans-N-(4-(1-(tert-butyl)-1H-pyrazol-4-yl)pyrazole Lysin-2-yl)-4-hydroxy-N-((4-(4-methoxy-3-methylphenyl) (I)bicyclo[2.2.2]octan-1-yl)methyl)cyclohexanecarboxamide I got the Do.

[0143] Step 4: 4-((4-(1-(tert-butyl)-1H-pyrazol-4-yl)pyrazole) Lysin-2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2. 2]Octan-1-yl)methyl)carbamoyl)cyclohexyl 3-hydroxyazetyl Din-trans-1-carboxylate (Compound 1) trans-N-(4-(1-(tert-butyl)) -1H-pyrazol-4-yl)pyridin-2-yl)-4-hydroxy-N-((4- (4-Methoxy)-3-methylphenyl)bicyclo[2.2.2]octan-1-yl A solution of 1,1'-carbonyldiimidazole in methylcyclohexanecarboxamide (1.5 eq.) was added. The mixture was stirred at room temperature for at least 3.5 hours. Thiazetidine hydrochloride (3.0 equiv.) and then iPr2NEt (7.0 equiv.) were added to this at room temperature. The reaction mixture was stirred at room temperature for at least 2.5 hours. The reaction mixture was 4.5% The mixture was quenched with aqueous NaHCO3 (6.0 vol). The organic layer was collected and the aqueous layer was diluted with dichloromethane. The extract was extracted once with methanol (2.0 vol). Methanol (0.8 vol) was added and the combined organic layer was The layer was washed twice with 20% NH4Cl solution (4.0 vol) and twice with water (4.0 vol). The organic layer was dried (Na2SO4) and the dichloromethane solvent was exchanged for ethyl acetate (4 volumes). Heptane was added slowly (4 volumes). The crude product was collected by filtration and diluted with ethyl acetate: The crude product was washed with heptane (1:1). The crude product was dried under vacuum at 55°C. The crude product was then purified by ethyl acetate. The product was purified by hot slurry in ethanol (5 volumes) and collected by filtration. The product was washed with ethyl acetate. , and dried under vacuum at 55°C to give 4-((4-(1-(tert-butyl)-1H-pyrazole -4-yl)pyridin-2-yl)((4-(4-methoxy-3-methylphenyl)bis( Chloro[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl 3-hydroxybenzoate Hydroxyazetidine-trans-1-carboxylate (Compound 1) was obtained.

[0144] II. Compound 1 spray-dried dispersion Example 5: Screening of Compound 1 / Polymer Combinations Polymer-based spray-dried dispersions of Compound 1 were developed. Several Compound 1 / polymer Combinations of polymers were screened and evaluated using computational models. PVP / VA 64, PVP 30, HPMCAS-L, HPMCAS-M, HPM CAS-H, Eudragit L100-55, Eudragit L100, Eudragit ragit EPO, HPMC E15, HPMC E3, HPMC E5, HPMCP The compound 1 / polymer combinations were as follows: The following were evaluated: 1) Miscibility evaluation - to evaluate the phase separation tendency with different stabilizing carriers and drug loadings. Computer simulation to confirm API / polymer solubility - each lead A series of compatible solvent systems were tested for the following conditions: 3) Solvent Casting -To further refine the formulation changes, solvent castings with different stabilizing carriers and drug loadings were performed. 4) Supersaturation studies - precipitation inhibition of different stabilizing carriers using solvent exchange method Based on screening studies, 60% ( 60% (w / w) of Compound 1 and HPMCAS-M were scaled up. Ta.

[0145] Example 6: Lab-scale prototyping of Compound 1 / polymer combination (Spray drying). A laboratory-scale spray dryer (Buchi B-290 spray dryer) was used. The unit had a nozzle tip and cap each 0.7 mm thick. The spray drying unit was equipped with a 1.5 mm two-fluid nozzle and an open loop configuration. The aspirator was operated with nitrogen (i.e., no recirculation of dry nitrogen) and insufflated at 100% capacity. That's right.

[0146] (Secondary drying). A laboratory-scale vacuum tray dryer was used to dry the residue of the wet spray-dried dispersion. The distillate content was reduced. Secondary drying was performed at 50°C for 48 hours under vacuum with a nitrogen sweep. went.

[0147] (Solution Preparation). Spray-dried dispersion using PVP / VA 64 and HPMCAS-M The prototyping solutions were prepared according to the following general procedure: The entire amount of polymer charged in the empty container was slowly added while stirring. Stirring was continued until dissolved. The entire amount of Compound 1 was slowly added while stirring. Stirring was continued until 1 was completely dissolved. A representative solution of PVP / VA 64 was prepared according to the amounts and ratios in Table 1 below (where "C_Feed" = solids in the feed mixture [% w / w], and "C_Compound 1" = solids in the feed mixture [% w / w]. Compound 1 content in the mixture [% w / w]).

[0148] [Table 1]

[0149] result The main process data and analytical results are summarized in Table 2 below ("T_Feed" = temperature of the feed solution). degree [℃], "F_Drying" = flow rate of drying gas in the spray dryer [kg / h], "F_Atomization" = Atomization gas flow rate [g / min], "T_outlet" = drying gas temperature at the outlet of the drying chamber [℃] "F_feed" = flow rate of the feed solution to the spray dryer [kg / h], "GC" = gas chromatography Graphy, "KF" = Karl Fischer, "TFN" = Two-Fluid Nozzle, and "P SD” = particle size distribution).

[0150] [Table 2]

[0151] Both spray-dried dispersions (Compound 1:HPMCAS-M and Compound 1:PVP / VA) 64) exhibits crystalline peaks (XRPD) and melting endotherms (DSC) characteristic of crystalline materials. It was amorphous after secondary drying as indicated by the absence of

[0152] Example 7: Stability Study of Spray-Dried Dispersions of Compound 1 Two spray-dried dispersions of Compound 1 (Compound 1:HPMCAS-M and Compound 1:PV P / VA 64) was stored in a capped vial at 40°C / 75% RH for one month. No chemical degradation was observed for any of the spray-dried dispersions. The amorphous state of the dried dispersion was maintained.

[0153] Example 8: Development of an SDI tablet formulation of Compound 1 First, the compatibility of Compound 1 API (amorphous form) was evaluated with various excipients. These compatibility studies were carried out in a closed container at 40°C / 75% RH for one month. No detectable changes in assay, related substances, or appearance were detected. APIs are Avicel (microcrystalline cellulose), Tabletose (lactose monohydrate) , Peritol (mannitol), Compitrol (glyceryl behenate), Acdyso Polyplasdone XL (crospovidone), steroids Compatible with magnesium phosphate and Cab-o-sil (colloidal silicon dioxide) It was decided that...

[0154] Four Compound 1 formulation matrices were then prepared using spray-dried intermediates ( SDI) PVP / VA and HPMCAS were used to prepare the tablet formulation blend and Tablets were prepared and analyzed for tabletability profile, compressibility profile, disintegration time, friability, and biodegradability. The only difference between the two formulations tested in each SDI was the disintegration time. The SDI polymer also functions as a binder, so the disintegrant was a tablet containing SDI. Disintegrants are an important component of the drug release system, overcoming the binder effect of the SDI polymer. It plays an important role in

[0155] [Table 3]

[0156] Tableting and compressibility curves were obtained for each of the four formulations. All four formulations Typical compression pressures such as 100-200 MPa are used to achieve high tensile strength (e.g., hardness). Tablets with a dissolution rate of 1.7 MPa or higher were produced. The biorelevant dissolution profiles of the four tablet formulations were: All formulations were shown to be compressible into high quality tablets.

[0157] Two prototype 5 mg tablets were prepared from tablet formulations A and C. These tablets Compound 1 was used in a pharmacokinetic study in monkeys (n=12 per formulation). The drug was well absorbed from the formulation (Figure 1).

[0158] Example 9: Compound 1 SDI Tablet Formulations—5 mg and 25 mg Tablets The ingredients of Formulation A in Example 8 were increased five-fold to produce 25 mg tablets.

[0159] [Table 4]

[0160] Example 10: Compound 1 SDI Tablet Formulation - 1 mg Tablet The amount of compound 1SDI in a 1 mg blend is less than 2%, providing a homogeneous mixture. To achieve this, blends were prepared by three-stage geometric dilution. This process involved the following steps: Things went smoothly. (1) Preblend #1: The required amount of Compound 1 SDI for the batch is sieved and microcrystalline Double the amount of cellulose (MCC). Mix Preblend #1. (2) Preblend #2: Add MCC equivalent to twice the weight of Preblend #1 and mix. Combine. (3) Preblend #3: Blended with MCC equivalent to twice the weight of Preblend #2 Add to and mix. (4) Add the required amounts of MCC, lactose monohydrate, and croscarmellose sodium for the remaining batch. The sodium, and colloidal silicon dioxide are added to the blend and mixed. Evaluate for blend uniformity analysis (BUA). (5) Once the BUA meets the requirements, sift half the batch amount of magnesium stearate. Add to the blend from step 4 and mix. (6) The blend from step 5 is granulated by roller compaction. Samples are taken for measuring the particle size distribution (PSD), particle size distribution (TD), and particle size distribution (PSD). Add the remaining half of the required batch of magnesium stearate to the dry granulation blend. Mix. (7) Compress the blend from step 6 into tablets (round, target weight 100 mg). (8) The compressed tablets are coated in a pan coater. (9) The final coated tablets are sampled for quality testing and stability. The remaining bulk is bottled and capped.

[0161] [Table 5]

[0162] Example 11: Compound 1 SDI Tablet Formulation - 12 mg Tablets The tablet strength was 5 mg of Compound 1 and 3.3 mg of PVP / VA per 100 mg tablet. As the amount of polymer increases above g, it acts as a binder, increasing the amount of drug As a result, the amount of croscarmellose sodium was increased from 5% to 10%. The ratio of microcrystalline cellulose to lactose monohydrate increased, and the ratio of lactose monohydrate decreased, resulting in the release process of Compound 1. The file has been improved (Figure 2).

[0163] [Table 6]

[0164] III. Compound 1FXR activity Example 12: In vitro FXR assay (TK)

[0165] sowing CV-1 cells were cultured in a T175 flask containing DMEM + 10% charcoal-stripped FBS for 2 days. The cells were seeded at a density of 0.000,000 cells and incubated at 37°C in 5% CO for 18 hours (O / N). I was invited.

[0166] Transfection After 18 hours of incubation, the medium in the T175 flask was replaced with fresh DMEM + 10% The serum was replaced with charcoal-stripped serum. MEM (Life Technologies, catalog number 31985-062) Expression plugs for hFXR, hRXR, TK-ECRE-luc, and pCMX-YFP The tube was then vortexed briefly and incubated at room temperature for 5 minutes. The transfection reagent (X-tremeGENE HP from Roche) was used. , Catalog No. 06 366 236 001) into vortexed OptiMEM The mixture was added to the plasmid and incubated at room temperature for 20 minutes. The transfection reagent / DNA mixture complex was added to the cells in the T175 flask. The cells were then incubated at 37°C in 5% CO2 for 18 hours (O / N).

[0167] Addition of Compound 1 Compound 1 was serially diluted in DMSO and added to the transfected CV-1 cells. The cells were then incubated for 18 hours. The next day, the cells were lysed and examined for luminescence. Compound 1 TK hFXR:EC 50 ≦0.01 μM.

Claims

1. Use of a pharmaceutical formulation comprising a spray-dried solid dispersion in the manufacture of a drug for treating or preventing inflammatory bowel disease, wherein the spray-dried solid dispersion comprises (a) 4-((4-(1-(tert-butyl)-1H-pyrazole-4-yl)pyridine-2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl 3-hydroxyazetidine-trans-1-carboxylate and (b) a pharmaceutically acceptable polymer, Uses 4-((4-(1-(tert-butyl)-1H-pyrazole-4-yl)pyridine-2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl 3-hydroxyazetidine-trans-1-carboxylate dispersed in a polymer matrix formed from the pharmaceutically acceptable polymer.

2. The use according to Claim 1, wherein the pharmaceutically acceptable polymer is selected from PVP / VA 64, PVP 30, HPMCAS-L, HPMCAS-M, HPMCAS-H, Eudragit® L100-55, Eudragit® L100, Eudragit® EPO, HPMC E15, HPMC E3, HPMC E5, HPMCP-HP55, and Solplus®.

3. The use according to claim 2, wherein the pharmaceutically acceptable polymer is PVP / VA 64.

4. The use according to claim 2, wherein the pharmaceutically acceptable polymer is HPMCAS-M.

5. The use according to claim 1, wherein the weight ratio of 4-((4-(1-(tert-butyl)-1H-pyrazole-4-yl)pyridine-2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl 3-hydroxyazetidine-trans-1-carboxylate to the pharmaceutically acceptable polymer is 9:1 to 1:

9.

6. The use according to claim 5, wherein the weight ratio of 4-((4-(1-(tert-butyl)-1H-pyrazole-4-yl)pyridine-2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl 3-hydroxyazetidine-trans-1-carboxylate to the pharmaceutically acceptable polymer is about 2:1, about 1.5:1, or about 1:

1.

7. The use according to claim 1, further comprising a non-aqueous solvent selected from the group consisting of ethanol, methanol, propanol, butanol, isopropanol, tert-butanol, dichloromethane, and mixtures thereof.

8. The use according to claim 7, wherein the non-aqueous solvent is a mixture of dichloromethane and methanol.

9. The use according to any one of claims 1 to 8, wherein the pharmaceutical formulation comprising a spray-dried solid dispersion comprises one or more pharmaceutically acceptable components selected from the group consisting of one or more diluents, one or more disintegrants, one or more binders, one or more smoothing agents, one or more flow promoters, and one or more surfactants.

10. The use according to claim 9, wherein the one or more pharmaceutically acceptable components are selected from the group consisting of microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, magnesium stearate, colloidal silicon dioxide, mannitol, crospovidone, and stearyl fumarate sodium.

11. The use according to claim 9, in the form of a tablet.

12. The use according to claim 11, wherein the tablet comprises about 1% to about 30% by weight of a spray-dried solid dispersion.

13. The use according to claim 12, wherein the tablet contains about 1% to about 20% by weight of 4-((4-(1-(tert-butyl)-1H-pyrazole-4-yl)pyridine-2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl 3-hydroxyazetidine-trans-1-carboxylate.

14. The use according to claim 12, wherein the tablet contains about 1 mg, about 5 mg, about 6 mg, about 12 mg, or about 25 mg of 4-((4-(1-(tert-butyl)-1H-pyrazole-4-yl)pyridine-2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl 3-hydroxyazetidine-trans-1-carboxylate.

15. The use according to any one of claims 1 to 14, wherein the inflammatory bowel disease is Crohn's disease.

16. The use according to any one of claims 1 to 14, wherein the inflammatory bowel disease is ulcerative colitis.

Images