Formulations of farnesoid X receptor agonists

Abstract

The present application relates to formulations of farnesol X receptor agonists. Specifically, described herein are pharmaceutical formulations of the farnesoid X receptor agonist 3-hydroxyazetidine-trans-1-carboxylic acid 4-((4-(1-(tert-butyl)-1H-pyrazol-4-yl) pyridin-2-yl) ((4-(4-methoxy-3-methylphenyl) bicyclo [2.2. 2] octane-1-yl) methyl) carbamoyl) cyclohexyl, and methods for preparing the pharmaceutical formulations of the farnesoid X receptor agonist 3-hydroxyazetidine-trans-1-carboxylic acid. And methods of treating conditions, diseases, or conditions associated with farnesoid X receptor activity using such pharmaceutical formulations.

Description

This application is a divisional application of the invention patent application with the application date of March 17, 2021, application number 202180036385.5, and title "Formulations of Farnesoid X Receptor Agonists". Cross-reference

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 991,216, filed on March 18, 2020, the entire content of which is incorporated herein by reference. Technical Field

[0002] Described herein are spray-dried solid dispersions of farnesoid X receptor agonists, pharmaceutical formulations comprising such spray-dried solid dispersions, and methods of using such spray-dried solid dispersions and pharmaceutical formulations to treat conditions, diseases, or disorders associated with farnesoid X receptor activity. Background Art

[0003] The farnesoid X receptor (FXR) is a nuclear receptor highly expressed in the liver, intestine, kidney, adrenal gland, and adipose tissue. FXR regulates multiple target genes involved in controlling bile acid synthesis and transport, lipid metabolism, and glucose homeostasis. FXR agonism is a therapeutic modality for many metabolic disorders, liver diseases or conditions, inflammatory conditions, gastrointestinal diseases, or diseases of cell proliferation. Summary of the Invention

[0004] In one aspect, the present disclosure provides a spray-dried solid dispersion comprising: (a) 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 (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-hydroxyazetidine-trans-1-carboxylate is dispersed in a polymer matrix formed by the pharmaceutically acceptable polymer. In some embodiments, 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 Soluplus. In some embodiments, the pharmaceutically acceptable polymer is selected from PVP / VA 64 and HPMCAS-M. In some embodiments, the pharmaceutically acceptable polymer is PVP / VA 64. In some embodiments, the pharmaceutically acceptable polymer is HPMCAS-M. In some embodiments, the weight ratio 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-carboxylate to the pharmaceutically acceptable polymer is from 9:1 to 1:9. In some embodiments, the weight ratio 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-carboxylate to the pharmaceutically acceptable polymer is from 3:1 to 1:3. In some embodiments, the weight ratio 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-carboxylate to the pharmaceutically acceptable polymer is about 2:1.In some embodiments, the weight ratio 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-carboxylate to a pharmaceutically acceptable polymer is about 1.5:1. In some embodiments, the weight ratio 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-carboxylate to a pharmaceutically acceptable polymer is about 1:1. In some embodiments, the spray-dried solid dispersion further comprises a non-aqueous solvent. In some embodiments, the non-aqueous solvent is selected from tert-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, carbon tetrachloride, dimethyl sulfoxide, hexafluoroacetone, chlorobutanol, dimethyl sulfone, acetic acid, cyclohexane, and mixtures thereof. In some embodiments, the non-aqueous solvent is selected from ethanol, methanol, propanol, butanol, isopropanol, tert-butanol, dichloromethane, and mixtures thereof. In some embodiments, the non-aqueous solvent is a mixture of dichloromethane and methanol. In some embodiments of the spray-dried solid dispersion, 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 is substantially amorphous. In some embodiments of the spray-dried solid dispersion, 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 is substantially crystalline.

[0005] On the other hand, the present disclosure provides a pharmaceutical formulation comprising the spray-dried solid dispersion described herein, which further comprises one or more pharmaceutically acceptable ingredients selected from one or more diluents, one or more disintegrants, one or more binders, one or more lubricants, one or more glidants, and one or more surfactants. In some embodiments, the one or more pharmaceutically acceptable ingredients are selected from microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, magnesium stearate, colloidal silicon dioxide, mannitol, crospovidone, and sodium stearyl fumarate. In some embodiments, the one or more pharmaceutically acceptable ingredients are selected from microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, magnesium stearate, and colloidal silicon dioxide. In some embodiments, the pharmaceutical formulation is in the form of a tablet. In some embodiments, the tablet comprises from about 1 wt% to about 30 wt% of the spray-dried solid dispersion. In some embodiments, the tablet comprises from about 5 wt% to about 25 wt% of the spray-dried solid dispersion. In some embodiments, the tablet comprises from about 1 wt% to about 20 wt% 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-carboxylate. In some embodiments, the tablet comprises 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-carboxylate. In some embodiments, the pharmaceutical formulation is in the form of a capsule.

[0006] On the other hand, the present disclosure provides a method of treating or preventing a liver disease or condition in a mammal, the method comprising administering to the mammal in need thereof a therapeutically effective amount of the spray-dried solid dispersion or pharmaceutical formulation described herein. In some embodiments, the disease or condition is a metabolic condition. In some embodiments, the disease or condition is a liver condition.

[0007] In some embodiments, the spray-dried solid dispersion described herein is administered to the mammal by intravenous administration, subcutaneous administration, oral administration, inhalation, nasal administration, topical administration, or ocular administration. In some embodiments, the pharmaceutical formulation described herein is administered to the mammal by intravenous administration, subcutaneous administration, oral administration, inhalation, nasal administration, topical administration, or ocular administration.

[0008] In another aspect, the present disclosure describes a method of treating or preventing any one of the diseases or conditions described herein, the method comprising administering to a mammal in need thereof a therapeutically effective amount of the spray-dried solid dispersion or pharmaceutical formulation described herein.

[0009] In another aspect, the present disclosure describes a method of treating or preventing a metabolic or hepatic condition in a mammal, the method comprising administering to a mammal in need thereof a therapeutically effective amount of the spray-dried solid dispersion or pharmaceutical formulation described herein. In other embodiments, the metabolic or hepatic condition is suitable for treatment with an FXR agonist. In some embodiments, the method further comprises administering to the mammal a second therapeutic agent in addition to the spray-dried solid dispersion or a pharmaceutically acceptable salt or solvate thereof described herein.

[0010] In another aspect, the present disclosure describes a method of treating or preventing a liver disease or condition in a mammal, the method comprising administering to the mammal the spray-dried solid dispersion or pharmaceutical formulation described herein. In some embodiments, the liver disease or condition is alcoholic or non-alcoholic liver disease. In some embodiments, the liver disease or condition is primary biliary cirrhosis, primary sclerosing cholangitis, cholestasis, non-alcoholic steatohepatitis (NASH) or non-alcoholic fatty liver disease (NAFLD). In some embodiments, the alcoholic liver disease or condition is fatty liver (steatosis), cirrhosis or alcoholic hepatitis. In some embodiments, the non-alcoholic liver disease or condition is non-alcoholic steatohepatitis (NASH) or non-alcoholic fatty liver disease (NAFLD). In some embodiments, the non-alcoholic liver disease or condition is non-alcoholic steatohepatitis (NASH). In some embodiments, the non-alcoholic liver disease or condition is non-alcoholic steatohepatitis (NASH) and is accompanied by liver fibrosis. In some embodiments, the non-alcoholic liver disease or condition is non-alcoholic steatohepatitis (NASH) without liver fibrosis. In some embodiments, the non-alcoholic liver disease or condition is intrahepatic cholestasis or extrahepatic cholestasis. In some embodiments, the liver disease or condition is steatohepatitis, cholangitis, fatty liver disease, cholestasis, cirrhosis, fibrotic liver disease, liver inflammation, primary biliary cholangitis, biliary atresia, Alagille 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, the present disclosure describes a method of treating or preventing liver fibrosis in a mammal, the method comprising administering to the mammal a spray-dried solid dispersion or pharmaceutical formulation described herein. In some embodiments, the mammal is diagnosed with hepatitis C virus (HCV), non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis (PSC), cirrhosis, Wilson's disease, hepatitis B virus (HBV), HIV-associated steatohepatitis and cirrhosis, chronic viral hepatitis, non-alcoholic fatty liver disease (NAFLD), alcoholic steatohepatitis (ASH), primary biliary cirrhosis (PBC), or biliary cirrhosis. In some embodiments, the mammal is diagnosed with non-alcoholic steatohepatitis (NASH).

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

[0013] In another aspect, the present disclosure describes a method of treating or preventing a gastrointestinal disease or condition in a mammal, the method comprising administering to the mammal a spray-dried solid dispersion or pharmaceutical formulation described herein. In some embodiments, the gastrointestinal disease or condition is 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 (GERD), peptic ulcer, non-ulcer dyspepsia (NUD), celiac disease, intestinal celiac disease, postoperative inflammation, gastric carcinogenesis, graft-versus-host disease, or any combination thereof. In some embodiments, the gastrointestinal disease is irritable bowel syndrome (IBS), IBS with diarrhea (IBS-D), IBS with constipation (IBS-C), mixed IBS (IBS-M), unclassified IBS (IBS-U), or bile acid diarrhea (BAD).

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

[0015] In another aspect, a method of treating or preventing a metabolism inflammation-mediated disease or disorder in a mammal is described herein, the method comprising administering to the mammal a spray-dried solid dispersion or pharmaceutical formulation described herein. In some embodiments, the metabolism inflammation-mediated disease or disorder is diabetes.

[0016] In another aspect, a method of treating or preventing a lipid disease or disorder in a mammal is described herein, the method comprising administering to the mammal a spray-dried solid dispersion or pharmaceutical formulation described herein. In some embodiments, the lipid disease or disorder in the mammal is dyslipidemia.

[0017] In another aspect, a method of treating or preventing cancer in a mammal is described herein, the method comprising administering to the mammal a spray-dried solid dispersion or pharmaceutical formulation described herein. In some embodiments, the cancer is prostate cancer, colorectal cancer, or hepatocellular carcinoma.

[0018] In another aspect, a method of treating or preventing a disease or condition in a mammal that would benefit from treatment with an FXR agonist is described herein, the method comprising administering to the mammal a spray-dried solid dispersion or pharmaceutical formulation described herein. In some embodiments, in addition to the spray-dried solid dispersion or pharmaceutical formulation described herein, the methods described herein further comprise administering at least one additional therapeutic agent. Incorporation by reference

[0019] All publications and patent applications mentioned in this specification are incorporated herein by reference to the extent applicable and relevant. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 The pharmacokinetic curves of Compound 1 tablets A and C in monkeys are described.

[0021] Figure 2 The release curves of 12 mg tablets of Compound 1 containing 5% and 10% sodium croscarmellose are described. DETAILED DESCRIPTION

[0022] The nuclear hormone receptor farnesoid X receptor (also known as FXR or nuclear receptor subfamily 1, group H, member 4 (NR1H4)) (OMIM: 603826) functions as a bile acid metabolism regulator. FXR is a ligand-activated transcription receptor expressed in diverse tissues including the adrenal gland, kidney, stomach, duodenum, jejunum, ileum, colon, gallbladder, liver, macrophages, and white and brown adipose tissues. FXR is highly expressed in tissues involved in bile acid metabolism such as the liver, intestine, and kidney. Bile acids act as endogenous ligands for FXR, such that the intestinal and systemic release of bile acids induces FXR-directed alterations in the gene expression network. Bile acids are the major oxidative products of cholesterol and, in some instances, are regulators of cholesterol absorption when secreted into the intestine. The rate-limiting step in the conversion of cholesterol to bile acids is catalyzed by the cytochrome p450 enzyme cholesterol 7-α-hydroxylase (CYP7A1) and occurs in the liver. The cytochrome p450 enzyme sterol 12-α-hydroxylase (CYP8B1) mediates the production of cholic acid and determines the relative amounts of the two major bile acids, cholic acid and chenodeoxycholic acid. Activation of FXR can inhibit the transcription of CYP7A1 and CYP8B1 by increasing the expression level of small heterodimer partner (SHP) (also known as nuclear receptor subfamily 0, group B, member 2; or NR0B2) in mice and the intestinal expression of fibroblast growth factor 15 (FGF15) and human fibroblast growth factor 19 (FGF19). SHP inhibits liver receptor homolog (LRH-1) and hepatocyte nuclear factor 4α (HNFα4), transcription factors that regulate CYP7A1 and CYP8B1 gene expression. The inhibition of CYP8B1 by FXR can be species-specific, and FXR activation can, in some cases, increase the expression of human CYP8B1 (Sanyal et al. PNAS, 2007, 104, 15665). In some cases, FGF15 / 19 released from the intestine then activates fibroblast growth factor receptor 4 in the liver, leading to the activation of the mitogen-activated protein kinase (MAPK) signaling pathway, which inhibits CYP7A1 and CYP8B1.

[0023] In some embodiments, elevated bile acid levels are associated with insulin resistance. For example, insulin resistance sometimes results in reduced glucose uptake in the blood and increased de novo glucose production in the liver. In some cases, intestinal sequestration of bile acids has been shown to improve insulin resistance by promoting the secretion of glucagon-like peptide-1 (GLP1) by intestinal L-cells. GLP-1 is an incretin derived from the proglucagon gene transcript. It is released in response to food intake and controls appetite and gastrointestinal function, and promotes pancreatic insulin secretion. The bioactive forms of GLP-1 include GLP-1-(7-37) and GLP-1-(7-36)NH2, which are produced by selective cleavage of the proglucagon molecule. In this context, FXR activation leading to reduced bile acid production is associated with a reduction in insulin resistance.

[0024] In some embodiments, activation of FXR is also associated with the secretion of pancreatic polypeptides such as peptide YY (PYY or PYY3-36). In some cases, peptide YY is a gastrointestinal hormone peptide that regulates the neuronal activity within the hypothalamus and brainstem, brain regions involved in reward processing. In some cases, reduced PYY levels are associated with increased appetite and weight gain.

[0025] In some cases, activation of FXR indirectly results in a reduction in plasma triglycerides. The clearance of triglycerides from the bloodstream is due to lipoprotein lipase (LPL). LPL activity is enhanced by the induction of its activator apolipoprotein CII, and the inhibition of its inhibitor apolipoprotein CIII in the liver occurs upon FXR activation.

[0026] In some cases, activation of FXR further regulates energy expenditure, such as adipocyte differentiation and function. Adipose tissue consists of adipocytes (adipocytes or fat cell). In some cases, adipocytes further differentiate into brown adipose tissue (BAT) or white adipose tissue (WAT). The function of BAT is to generate body heat, while the function of WAT is to be a fat storage tissue.

[0027] In some cases, FXR is widely expressed in the intestine. In some cases, activation of FXR has been shown to induce the expression and secretion of FGF19 (or FGF15 in mice) in the intestine. FGF19 is a hormone that regulates bile acid synthesis and plays a role in glucose metabolism, lipid metabolism, and energy expenditure. In some cases, FGF19 has also been observed to regulate adipocyte function and differentiation. Indeed, one study showed that administration of FGF19 to mice fed a high-fat diet increased energy expenditure, regulated adipocyte differentiation and function, reversed weight gain, and improved insulin resistance (see, Fu et al., “Fibroblast growth factor 19 increases metabolic rate and reverses dietary and leptin-deficient diabetes” Endocrinology 145:2594-2603 (2004)).

[0028] In some cases, intestinal FXR activity has also been shown to be involved in reducing the overgrowth of microbiota, for example, during feeding (Li et al., Nat Commun 4:2384, 2013). For example, studies have shown that activation of FXR is associated with increased expression of several genes in the ileum, such as Ang2, iNos, and Il18, which have been identified to have antimicrobial effects (Inagaki et al., Proc Natl Acad Sci U S A 103:3920-3925, 2006).

[0029] In some cases, FXR is involved in barrier function and immune regulation in the intestine. FXR regulates the transcription of genes involved in bile salt synthesis, transport, and metabolism in the liver and intestine, and in some cases has been shown to result in the improvement of intestinal inflammation and the prevention of bacterial translocation into the gut (Gadaleta et al., Gut. 2011 Apr; 60(4):463-72).

[0030] In some cases, overproduction of bile acids or improper transport and recycling of bile acids can lead to diarrhea. FXR regulates the transcription of genes involved in bile salt synthesis, transport, and metabolism in the liver and intestine, and in some cases can improve diarrhea (Camilleri, Gut Liver. 2015 May; 9(3):332–339).

[0031] G protein-coupled bile acid receptor 1 (also known as GPBAR2, GPCR19, membrane-type receptor for bile acids or M-BAR or TGR5) is a cell surface receptor for bile acids. When activated by bile acids, TGR5 induces the production of intracellular cAMP, which then triggers an increase in triiodothyronine due to the activation of deiodinase (DIO2) in BAT, resulting in increased energy expenditure.

[0032] Thus, in some embodiments, metabolic processes such as regulation of bile acid synthesis, bile acid cycling, glucose metabolism, lipid metabolism or insulin sensitivity are regulated by activation of FXR. Additionally, in some embodiments, dysregulation of metabolic processes such as bile acid synthesis, bile acid cycling, glucose metabolism, lipid metabolism or insulin sensitivity results in metabolic diseases such as diabetes or diabetes-related conditions or disorders, alcoholic or non-alcoholic liver diseases or conditions, intestinal inflammation or cell proliferative disorders.

[0033] In certain embodiments, compounds having activity as FXR agonists are disclosed herein. In some embodiments, the FXR agonists described herein are structurally distinct from bile acids, other synthetic FXR ligands and other natural FXR ligands.

[0034] In some embodiments, methods of treating or preventing metabolic disorders such as diabetes, obesity, impaired glucose tolerance, dyslipidemia or insulin resistance by administering a therapeutically effective amount of an FXR agonist are also disclosed herein. In some instances, the compound is administered to the GI tract of the subject.

[0035] In additional embodiments, methods for treating or preventing alcoholic or non-alcoholic liver diseases or conditions (e.g., cholestasis, primary biliary cirrhosis, steatosis, cirrhosis, alcoholic hepatitis, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), primary sclerosing cholangitis (PSC), or elevated liver enzymes) are disclosed herein, which are carried out by administering to a subject in need thereof a therapeutically effective amount of an FXR agonist (e.g., via the GI tract). In additional embodiments, methods are disclosed herein for treating or preventing cholestasis, cirrhosis, primary biliary cirrhosis, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), or primary sclerosing cholangitis (PSC) by administering to a subject in need thereof a therapeutically effective amount of an FXR agonist. In some embodiments, methods are disclosed herein for treating or preventing cholestasis by administering to a subject in need thereof a therapeutically effective amount of an FXR agonist. In some embodiments, methods are disclosed herein for treating or preventing primary biliary cirrhosis by administering to a subject in need thereof a therapeutically effective amount of an FXR agonist. In some embodiments, methods are disclosed herein for treating or preventing NASH by administering to a subject in need thereof a therapeutically effective amount of an FXR agonist. In some embodiments, methods are disclosed herein for treating or preventing NAFLD by administering to a subject in need thereof a therapeutically effective amount of an FXR agonist.

[0036] In further embodiments, methods are disclosed herein for treating or preventing intestinal inflammation and / or cell proliferative disorders such as cancer by administering to a subject in need thereof a therapeutically effective amount of an FXR agonist (e.g., via the GI tract).

[0037] In still further embodiments, FXR agonists are disclosed herein that modulate one or more proteins or genes associated with metabolic processes such as bile acid synthesis, glucose metabolism, lipid metabolism, or insulin sensitivity, such as an increase in FGF19 (FGF15 in mice) activity, an increase in GLP-1 secretion, or an increase in PYY secretion. 3-Hydroxyazetidine-trans-1-carboxylic acid 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 ester (Compound 1)

[0038] This text describes the FXR agonist compound 3-hydroxyazetidine-trans-1-carboxylic acid 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 ester (Compound 1). "Compound 1" or "3-hydroxyazetidine-trans-1-carboxylic acid 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 ester" refers to the compound having the following structure:

[0039] In some embodiments, Compound 1 is in the form of a pharmaceutically acceptable salt. In some embodiments, Compound 1 is the free base. Additionally, Compound 1 can exist in a non-solvated form as well as in a solvated form with a pharmaceutically acceptable solvent such as water, ethanol, etc. The solvated forms of Compound 1 provided herein are also considered to be disclosed herein. In some embodiments, Compound 1 is solvated. In some embodiments, Compound 1 is non-solvated. 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 has sustained exposure when administered to a mammal. In some embodiments, Compound 1 has 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 containing a bile acid chemical structure. In published clinical studies, OCA has demonstrated clinical efficacy as an FXR agonist, but is associated with adverse side effects such as pruritus, increased LDL cholesterol, and hepatotoxicity at higher administration doses. In some embodiments, in a suitable in vitro assay evaluating the binding of an FXR agonist to FXR, Compound 1 shows at least 30-fold greater potency than OCA. In some embodiments, the increased potency of Compound 1 indicates a wider potential therapeutic window relative to OCA.

[0042] In some embodiments, Compound 1 shows sustained FXR engagement in preclinical animal models based on pharmacokinetic and pharmacodynamic markers. In some embodiments, Compound 1 demonstrates sustained FXR engagement that permits once-daily dosing of Compound 1.

[0043] As used herein, "pharmaceutically acceptable" refers to materials, such as a carrier or diluent, which do not abrogate the biological activity or properties of a compound and which are relatively non-toxic, i.e., the material can be administered to an individual without causing undesirable biological effects or interacting in a harmful manner with any component of the composition in which it is contained.

[0044] The term "pharmaceutically acceptable salt" refers to forms of the therapeutically active agent that are formed by the combination of the cationic form of the therapeutically active agent with a suitable anion or, in alternative embodiments, the anionic form of the therapeutically active agent with a suitable cation. Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. S.M. Berge, L.D. Bighley, D.C. Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. Handbook of Pharmaceutical Salts: Properties, Selection and Use, edited by P.H. Stahl and C.G. Wermuth, Weinheim / Zürich: Wiley-VCH / VHCA, 2002. Medicinal salts are generally more soluble and dissolve more rapidly in gastric and intestinal fluids than the non-ionic substances and can thus be used in solid dosage forms. In addition, because their solubility is generally a function of pH, selective dissolution in one or another part of the digestive tract is possible and this ability can be manipulated as an aspect of delayed and sustained release behavior. Moreover, since the salt-forming molecules can be in equilibrium with the neutral form, the passage through biological membranes can be modulated.

[0045] It should be understood that reference to pharmaceutically acceptable salts includes solvate addition forms. In some embodiments, the solvate contains a stoichiometric or non-stoichiometric amount of the solvent and is formed during the process of isolating or purifying the compound with a pharmaceutically acceptable solvent such as water, ethanol, etc. Hydrates are formed when the solvent is water or alcoholates are formed when the solvent is an alcohol. Solvates of the compounds described herein are conveniently prepared or formed in the methods described herein. In addition, the compounds provided herein optionally exist in unsolvated as well as solvated forms. Certain terms

[0046] Unless otherwise indicated, the following terms used in this application have the definitions given below. The use of the term "including" and other forms thereof, such as "include", "includes", and "included", is not limiting. When referring to a number or numerical range, the term "about" means that the number or numerical range so referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range can vary between 1% and 15% of that number or numerical range. The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described.

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

[0048] As used herein, the term "modulate" means to interact directly or indirectly with a target to alter the activity of the target, including (by way of example only) enhancing the activity of the target, inhibiting the activity of the target, restricting the activity of the target, or prolonging the activity of the target.

[0049] As used herein, the term "modulator" means a molecule that interacts directly or indirectly with a target. The interaction includes, but is not limited to, the interaction of an agonist, partial agonist, inverse agonist, antagonist, degrader, or a combination thereof. In some embodiments, the modulator is an agonist.

[0050] As used herein, the terms "administer", "administering", "administration", etc. mean methods that can be used to deliver a compound or composition to a desired biological site of action. These methods include, but are not limited to, oral route, duodenal route, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intra-arterial, or infusion), topical, and rectal administration. Those skilled in the art are familiar with the administration techniques that can be used in conjunction with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

[0051] As used herein, the terms "co-administer", etc. mean to encompass the administration of a selected therapeutic agent to a single patient and are intended to include treatment regimens in which the agents are administered by the same or different routes of administration or at the same or different times.

[0052] As used herein, the term "effective amount" or "therapeutically effective amount" refers to an amount of an agent or compound administered that will, to some extent, alleviate one or more symptoms of the disease or condition being treated. The results include reduction and / or alleviation of the signs, symptoms or causes of the disease and / or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a compound disclosed herein required to provide a clinically significant reduction of the symptoms of the disease. In any individual case, a suitable "effective" amount is optionally determined using techniques such as dose escalation studies.

[0053] As used herein, the term "enhance (enhance or enhancing)" means to increase or prolong the potency or duration of a desired effect. Thus, with respect to enhancing the action of a therapeutic agent, the term "enhance" means the ability to increase or prolong the action of another therapeutic agent on a system, either in potency or duration. An "enhancing effective amount" as used herein is an amount sufficient to enhance the action of another therapeutic agent in a desired system.

[0054] As used herein, the term "drug combination" refers to a product resulting from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term "fixed combination" refers to the active ingredient (e.g., Compound 1 or a pharmaceutically acceptable salt thereof) and the co-administered drug being administered to a patient simultaneously in the form of a single entity or dose. The term "non-fixed combination" refers to the active ingredient (e.g., Compound 1 or a pharmaceutically acceptable salt thereof) and the co-administered drug being administered to a patient simultaneously, concurrently or sequentially as separate entities without a specific time interval limit, where such administration provides effective levels of both compounds in the patient. The latter also applies to combination therapies, such as the administration of three or more active ingredients.

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

[0056] The term "subject" or "patient" includes mammals. Examples of mammals include, but are not limited to, any member of the mammalian class: humans, non-human primates such as chimpanzees and other ape and monkey species; farm animals such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs and cats; laboratory animals including rodents such as rats, mice and guinea pigs, etc. In one embodiment, the subject is a human.

[0057] As used herein, the terms "treat", "treating", or "treatment" include alleviating, reducing, or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, alleviating the disease or condition, causing regression of the disease or condition, alleviating the condition caused by the disease or condition, or prophylactically and / or therapeutically halting the symptoms of the disease or condition. Pharmaceutical composition

[0058] In some embodiments, the spray-dried solid dispersion of Compound 1 described herein is formulated into a pharmaceutical composition. The pharmaceutical composition is formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that aid in processing the active compound into a pharmaceutically useful formulation. Suitable formulations depend on the chosen route of administration. An overview of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Remington’s Pharmaceutical Sciences by Hoover, John E., Mack Publishing Co., Easton, Pennsylvania 1975; Pharmaceutical Dosage Forms, edited by Liberman, H.A. and Lachman, L., Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), the disclosures of which are incorporated herein by reference.

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

[0060] In some embodiments, the pharmaceutical composition of Compound 1 suitable for oral administration is present in discrete units, such as capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient; powders or granules.

[0061] Pharmaceutical compositions for oral use include tablets, push-fit capsules made of gelatin, and soft sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Tablets can be prepared by compressing or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing the active ingredient in free-flowing form, such as a powder or granules optionally mixed with a binder, an inert diluent or lubricant, a surfactant or a dispersant, in a suitable machine. Molded tablets can be prepared by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine. In some embodiments, the tablets are coated or scored and formulated to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be in doses suitable for such administration. Push-fit capsules can contain the active ingredient mixed with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally a stabilizer. In soft capsules, the active compound can be dissolved or suspended in a suitable liquid such as a fatty oil, liquid paraffin, or liquid polyethylene glycol. In some embodiments, a stabilizer is added. The dragee core has a suitable coating. For this purpose, concentrated sugar solutions can be used, which can optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyes or pigments can be added to the tablet or dragee coating for identification or characterization of different combinations of the active compound dose.

[0062] Conventional techniques for manufacturing solid oral dosage forms include, but are not limited to, one or a combination of the following methods: (1) dry blending; (2) direct compression; (3) milling; (4) dry granulation or non-aqueous granulation; or (5) wet granulation. See, e.g., Lachman et al., The Theory and Practice of Industrial 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, top spray, tableting, extrusion, etc.

[0063] It should be understood that, in addition to the ingredients specifically mentioned above, the compounds and compositions described herein can include other conventional pharmaceutically agents in the art, taking into account the type of formulation being discussed. For example, those suitable for oral administration can include flavoring agents.

[0064] This text provides tablets comprising Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the tablets comprise: Compound 1 dispersed in a polymer matrix formed from a pharmaceutically acceptable polymer; one or more pharmaceutically acceptable ingredients selected from one or more diluents, one or more disintegrants, one or more lubricants, one or more glidants; and optionally one or more film coating agents.

[0065] In some embodiments, the present text describes a spray-dried solid dispersion comprising (a) Compound 1; and (b) a pharmaceutically acceptable polymer; wherein Compound 1 is dispersed in a polymer matrix formed from a pharmaceutically acceptable polymer.

[0066] In some embodiments, the present text describes tablets prepared with the spray-dried solid dispersion described herein. Formulation of spray-dried solid dispersion of Compound 1

[0067] In some embodiments described herein, the Compound 1 pharmaceutical composition is a spray-dried solid dispersion formulation. In some embodiments, provided herein is a spray-dried solid dispersion comprising: (a) 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 (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-hydroxyazetidine-trans-1-carboxylate is dispersed in a polymer matrix formed by a pharmaceutically acceptable polymer. In some embodiments, 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 Soluplus. In some embodiments, the pharmaceutically acceptable polymer is selected from PVP / VA 64 and HPMCAS-M. In some embodiments, the pharmaceutically acceptable polymer is PVP / VA 64. In some embodiments, the pharmaceutically acceptable polymer is HPMC-AS-M. In some embodiments, the pharmaceutically acceptable polymer is PVP 30. In some embodiments, the pharmaceutically acceptable polymer is HPMC-AS-L. In some embodiments, the pharmaceutically acceptable polymer is HPMC-AS-H. In some embodiments, the pharmaceutically acceptable polymer is Eudragit L100-55. In some embodiments, the pharmaceutically acceptable polymer is Eudragit L100. In some embodiments, the pharmaceutically 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. In some embodiments, the weight ratio of Compound 1 to the pharmaceutically acceptable polymer is from 9:1 to 1:9. In some embodiments, the weight ratio of Compound 1 to the pharmaceutically acceptable polymer is from 7:1 to 1:7.In some embodiments, the weight ratio of Compound 1 to the pharmaceutically acceptable polymer is from 5:1 to 1:5. In some embodiments, the weight ratio of Compound 1 to the pharmaceutically acceptable polymer is from 4:1 to 1:4. In some embodiments, the weight ratio of Compound 1 to the pharmaceutically acceptable polymer is from 3:1 to 1:3. In some embodiments, the weight ratio of Compound 1 to the pharmaceutically acceptable polymer is from 2:1 to 1:2. In some embodiments, the weight ratio of Compound 1 to the pharmaceutically acceptable polymer is 4:1. In some embodiments, the weight ratio of Compound 1 to the pharmaceutically acceptable polymer is 3:1. In some embodiments, the weight ratio of Compound 1 to the pharmaceutically acceptable polymer is 2:1. In some embodiments, the weight ratio of Compound 1 to the pharmaceutically acceptable polymer is 1.5:1. In some embodiments, 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 1:1.5. In some embodiments, the weight ratio of Compound 1 to the pharmaceutically acceptable polymer is 1:2. In some embodiments, the spray-dried solid dispersion further comprises a non-aqueous solvent. In some embodiments, the non-aqueous solvent is selected from tert-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, carbon tetrachloride, dimethyl sulfoxide, hexafluoroacetone, chlorobutanol, dimethyl sulfone, acetic acid, cyclohexane, and mixtures thereof. In some embodiments, the non-aqueous solvent is selected from ethanol, methanol, propanol, butanol, isopropanol, tert-butanol, dichloromethane, and mixtures thereof. In some embodiments, the non-aqueous solvent is a mixture of dichloromethane and methanol. In some embodiments, the non-aqueous solvent is a mixture of dichloromethane and methanol, wherein 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, wherein the weight ratio of dichloromethane to methanol is about 14 / 1. In some embodiments, the non-aqueous solvent is a mixture of dichloromethane and methanol, wherein the weight ratio of dichloromethane to methanol is about 13 / 1. In some embodiments, the non-aqueous solvent is a mixture of dichloromethane and methanol, wherein the weight ratio of dichloromethane to methanol is about 12 / 1. In some embodiments, the non-aqueous solvent is a mixture of dichloromethane and methanol, wherein 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, wherein the weight ratio of dichloromethane to methanol is about 10 / 1. In some embodiments, the non-aqueous solvent is a mixture of dichloromethane and methanol, wherein the weight ratio of dichloromethane to methanol is about 9 / 1. In some embodiments, the non-aqueous solvent is a mixture of dichloromethane and methanol, wherein the weight ratio of dichloromethane to methanol is about 8 / 1.In some embodiments, the non-aqueous solvent is a mixture of dichloromethane and methanol, wherein the weight ratio of dichloromethane to methanol is about 7 / 1. In some embodiments, the non-aqueous solvent is a mixture of dichloromethane and methanol, wherein the weight ratio of dichloromethane to methanol is about 6 / 1. In some embodiments, the non-aqueous solvent is a mixture of dichloromethane and methanol, wherein the weight ratio of dichloromethane to methanol is about 5 / 1. In some embodiments, the non-aqueous solvent is a mixture of dichloromethane and methanol, wherein 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, wherein the weight ratio of dichloromethane to methanol is about 3 / 1. In some embodiments, the non-aqueous solvent is a mixture of dichloromethane and methanol, wherein the weight ratio of dichloromethane to methanol is about 2 / 1. In some embodiments, the non-aqueous solvent is a mixture of dichloromethane and methanol, wherein the weight ratio of dichloromethane to methanol is about 1 / 1. In some embodiments of the spray-dried solid dispersion, Compound 1 is substantially amorphous.

[0068] In another aspect, the present disclosure provides a pharmaceutical formulation comprising the spray-dried solid dispersion described herein, which further comprises one or more pharmaceutically acceptable ingredients selected from one or more diluents, one or more disintegrants, one or more binders, one or more lubricants, one or more glidants, and one or more surfactants. In some embodiments, the one or more pharmaceutically acceptable ingredients are selected from microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, magnesium stearate, colloidal silicon dioxide, mannitol, crospovidone, and sodium stearyl fumarate. In some embodiments, the one or more pharmaceutically acceptable ingredients are selected from microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, magnesium stearate, and colloidal silicon dioxide. In some embodiments, the pharmaceutical formulation is in the form of a tablet. In some embodiments, the pharmaceutical formulation is in the form of a capsule.

[0069] In one aspect, the present disclosure describes a tablet comprising: Compound 1 or a pharmaceutically acceptable salt thereof, dispersed in a polymer matrix formed from a pharmaceutically acceptable polymer; one or more pharmaceutically acceptable ingredients selected from one or more diluents, one or more disintegrants, one or more lubricants, one or more glidants; and optionally one or more film coating agents.

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

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

[0072] In some embodiments, the tablet comprises from about 1 wt% to about 15 wt% of Compound 1, dispersed in from about 0.5 wt% to about 10 wt% of a polymer matrix formed from a pharmaceutically acceptable polymer.

[0073] In some embodiments, the tablet comprises from about 1 wt% to about 15 wt% of Compound 1 dispersed in from about 0.5 wt% to about 10 wt% of a polymer matrix formed from a pharmaceutically acceptable polymer; from about 70 wt% to about 99 wt% of one or more pharmaceutically acceptable ingredients selected from one or more diluents, one or more disintegrants, one or more lubricants, one or more glidants; and optionally less than about 2 wt% of one or more film coating agents.

[0074] In some embodiments, the tablet comprises from about 1 wt% to about 30 wt% of a spray-dried solid dispersion. In some embodiments, the tablet comprises from about 5 wt% to about 25 wt% of a spray-dried solid dispersion. In some embodiments, the tablet comprises from about 5 wt% to about 20 wt% of a spray-dried solid dispersion. In some embodiments, the tablet comprises from about 5 wt% to about 15 wt% of a spray-dried solid dispersion. In some embodiments, the tablet comprises from about 5 wt% to about 10 wt% of a spray-dried solid dispersion.

[0075] In some embodiments, in addition to the spray-dried solid dispersion, the additional excipients in the tablet comprise one or more diluents, one or more disintegrants, one or more lubricants, one or more glidants or any combination thereof. In some embodiments, in addition to the spray-dried solid dispersion, the additional excipients in the tablet comprise microcrystalline cellulose, mannitol, crospovidone, colloidal silicon dioxide and magnesium stearate.

[0076] In some embodiments, the tablet comprises one or more fillers / binders / diluents. The filler / binder / diluent is selected from cellulose (e.g., microcrystalline cellulose, carboxymethyl cellulose, ethyl cellulose and methyl cellulose), starch, gelatin, sugars (e.g., sucrose, glucose, dextran, mannitol and lactose), natural and synthetic gums (e.g., acacia, sodium alginate, panwar gum and ghatti gum), polyvinylpyrrolidone, polyethylene glycol, waxes and any combination thereof. In some embodiments, the tablet comprises microcrystalline cellulose and lactose monohydrate.

[0077] In some embodiments, one or more fillers / binders / diluents in the tablets described herein account for about 40% to about 95% by weight of the total weight of the tablets. In some embodiments, one or more fillers / binders / diluents in the tablets described herein account for about 60% to about 95% by weight of the total weight of the tablets. In some embodiments, one or more fillers / binders / diluents in the tablets described herein account for about 65% to about 95% by weight of the total weight of the tablets. In some embodiments, one or more fillers / binders / diluents in the tablets described herein account for about 75% to about 95% by weight of the total weight of the tablets. In some embodiments, one or more fillers / binders / diluents in the tablets described herein account for about 50%, about 55%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90% or about 95% by weight of the total weight of the tablets. In some embodiments, one or more fillers / binders / diluents in the tablets described herein account for about 58% by weight of the total weight of the tablets. In some embodiments, one or more fillers / binders / diluents account for less than 95%, less than 85%, less than 75%, less than 65% or less than 60% by weight of the total weight of the tablets.

[0078] In some embodiments, the tablets contain one or more disintegrants. The disintegrants are selected from sodium croscarmellose, crospovidone, sodium starch glycolate, magnesium aluminum silicate HV, methylcellulose, agar, bentonite, cellulose, carboxymethylcellulose and any combination thereof. In some embodiments, the tablets contain sodium croscarmellose.

[0079] In some embodiments, one or more disintegrants in the tablets described herein account for about 2% to about 20% by weight of the total weight of the tablets. In some embodiments, one or more disintegrants in the tablets described herein account for about 5% to about 10% by weight of the total weight of the tablets. In some embodiments, one or more disintegrants in the tablets described herein account for 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% or about 20% by weight of the total weight of the tablets. In some embodiments, one or more disintegrants in the tablets described herein account for about 5% by weight of the total weight of the tablets. In some embodiments, one or more disintegrants in the tablets described herein account for about 10% by weight of the total weight of the tablets. In some embodiments, one or more disintegrants account for less than 20% by weight of the total weight of the tablets.

[0080] In some embodiments, the tablet comprises one or more lubricants. The lubricants are selected from talc, magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, glyceryl behenate, hydrogenated vegetable oil, polyethylene glycol, and any combination thereof. In some embodiments, the tablet comprises magnesium stearate.

[0081] In some embodiments, one or more of the lubricants in the tablets described herein are present in an amount of from about 0.1 wt% to about 5 wt% of the total weight of the tablet. In some embodiments, one or more of the lubricants in the tablets described herein are present in an amount of from about 0.1 wt% to about 2 wt% of the total weight of the tablet. In some embodiments, one or more of the lubricants in the tablets described herein are present in an amount of from about 0.1 wt% to about 1 wt% of the total weight of the tablet. In some embodiments, one or more of the lubricants in the tablets described herein are present in an amount of about 0.1 wt%, about 0.2 wt%, about 0.3 wt%, about 0.4 wt%, about 0.5 wt%, about 0.6 wt%, about 0.7 wt%, about 0.8 wt%, about 0.9 wt%, or about 1 wt% of the total weight of the tablet. In some embodiments, one or more of the lubricants in the tablets described herein are present in an amount of about 1 wt% of the total weight of the tablet. In some embodiments, one or more of the lubricants are present in an amount less than 2 wt% of the total weight of the tablet.

[0082] In some embodiments, the tablet comprises one or more glidants. A glidant is a substance added to a powder to improve its flowability. Examples of glidants include magnesium stearate, colloidal silicon dioxide, starch, and talc. In some embodiments, the tablet comprises colloidal silicon dioxide.

[0083] In some embodiments, one or more of the lubricants in the tablets described herein are present in an amount of from about 0.1 wt% to about 5 wt% of the total weight of the tablet. In some embodiments, one or more of the lubricants in the tablets described herein are present in an amount of from about 0.1 wt% to about 2 wt% of the total weight of the tablet. In some embodiments, one or more of the lubricants in the tablets described herein are present in an amount of from about 0.5 wt% to about 1.5 wt% of the total weight of the tablet. In some embodiments, one or more of the lubricants in the tablets described herein are present in an amount of about 0.1 wt%, about 0.2 wt%, about 0.3 wt%, about 0.4 wt%, about 0.5 wt%, about 0.6 wt%, about 0.7 wt%, about 0.8 wt%, about 0.9 wt%, about 1 wt%, about 1.1 wt%, about 1.2 wt%, about 1.3 wt%, about 1.4 wt%, about 1.5 wt%, about 1.6 wt%, about 1.7 wt%, about 1.8 wt%, about 1.9 wt%, or about 2 wt% of the total weight of the tablet. In some embodiments, one or more of the lubricants in the tablets described herein are present in an amount of about 1 wt% of the total weight of the tablet. In some embodiments, one or more of the lubricants are present in an amount less than 2 wt% of the total weight of the tablet. Additional Excipients

[0084] In some embodiments, the tablets described herein contain additional excipients, including but not limited to buffers, glidants, preservatives, and colorants. Additional excipients such as fillers, tonicity agents, and chelating agents are within the scope of the embodiments.

[0085] Non-limiting examples of buffers include, but are not limited to, sodium bicarbonate, potassium bicarbonate, magnesium hydroxide, magnesium lactate, magnesium glucomate, aluminum hydroxide, aluminum hydroxide / sodium bicarbonate coprecipitate, a mixture of an amino acid and a buffer, a mixture of aluminum glycinate and a buffer, a mixture of an acid salt of an amino acid and a buffer, and a mixture of an amino acid basic salt and a buffer. Other buffers include sodium citrate, sodium tartrate, sodium acetate, sodium carbonate, sodium polyphosphate, potassium polyphosphate, sodium pyrophosphate, potassium pyrophosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, trisodium phosphate, tripotassium phosphate, sodium acetate, potassium metaphosphate, magnesium oxide, magnesium hydroxide, magnesium carbonate, magnesium silicate, calcium acetate, calcium glycerophosphate, calcium chloride, calcium hydroxide, calcium lactate, calcium carbonate, calcium bicarbonate, and other calcium salts.

[0086] In some embodiments, tablets described herein include preservatives. Preservatives include antimicrobial agents, antioxidants, and agents that improve sterility. Exemplary preservatives include ascorbic acid, ascorbyl palmitate, BHA, BHT, citric acid, isoascorbic acid, fumaric acid, malic acid, propyl gallate, sodium ascorbate, sodium bisulfate, sodium metabisulfite, sodium sulfite, parabens (methyl, ethyl, butyl), benzoic acid, potassium sorbate, vanillin, etc.

[0087] In some embodiments, the tablets described herein contain colorants for identity and / or aesthetic purposes of the resulting liquid form. Suitable colorants illustratively include FD&C Red No. 3, FD&C Red No. 20, FD&C Red No. 40, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5, caramel, iron oxide, and mixtures thereof.

[0088] Additional excipients are contemplated in tablet embodiments. These additional excipients are selected based on their functionality and compatibility with the tablet compositions described herein, and reference may be made, for example, to Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Remington’s Pharmaceutical Sciences by Hoover and John E. (Easton, PA: Mack Publishing Co 1975); Pharmaceutical Dosage Forms edited by Liberman, H.A. and Lachman, L. (Marcel Decker, New York, N.Y., 1980); and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Edition (Lippincott Williams & Wilkins 1999), the disclosures of which are incorporated herein by reference in their entirety.

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

[0090] In one embodiment, the single unit dose further includes a film coating that disintegrates upon oral ingestion or upon contact with a diluent. In one embodiment, these formulations are prepared by conventional techniques.

[0091] Compressed tablets are solid dosage forms prepared by compressing the above-described bulk blend formulations. In various embodiments, compressed tablets designed to dissolve in the mouth will contain one or more flavoring agents. In other embodiments, the compressed tablets will include a film surrounding the final compressed tablet. In some embodiments, the film coating aids patient compliance (e.g., coating or sugar coating). The film coating containing is generally about 1% to about 5% of the tablet weight. In other embodiments, the compressed tablets contain one or more excipients.

[0092] The present disclosure provides a film-coated tablet form that contains: a combination of an active ingredient (e.g., Compound 1 or a pharmaceutically acceptable salt thereof) and one or more tableting excipients to form a tablet core and subsequently coat the tablet core. The tablet core is prepared using conventional tableting methods and subsequent compression and coating.

[0093] An enteric coating is a coating that resists the action of gastric acid but dissolves or disintegrates in the intestine.

[0094] In one aspect, the oral solid dosage forms disclosed herein include an enteric coating. The enteric coating includes one or more of the following: cellulose acetate phthalate; methyl acrylate-methyl methacrylate copolymer; cellulose acetate succinate; hydroxypropyl methylcellulose phthalate; hydroxypropyl methylcellulose acetate succinate (hypromellose acetate succinate); polyvinyl acetate phthalate (PVAP); methyl methacrylate-methyl methacrylate copolymer; methacrylic acid copolymer, cellulose acetate (and its succinate and phthalate forms); styrene maleic acid copolymer; polymethacrylic acid / acrylic acid copolymer; hydroxyethyl ethylcellulose phthalate; hydroxypropyl methylcellulose acetate succinate; cellulose acetate tetrahydrophthalate; acrylic resin; shellac.

[0095] The enteric coating is a coating placed on tablets, pills, capsules, pellets, beads, granules, particles, etc., such that it does not dissolve until it reaches the small intestine.

[0096] A sugar-coated tablet is a compressed tablet surrounded by a sugar coating, which can be beneficial for masking an unpleasant taste or odor and protecting the tablet from oxidation.

[0097] A film-coated tablet is a compressed tablet covered with a thin layer or film of a water-soluble material. The film coating includes, but is not limited to, hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000, and cellulose acetate phthalate. The film coating imparts the same general properties as the sugar coating. A multiple-compressed tablet is a compressed tablet prepared by more than one compression cycle, including layered tablets and compressed-coated or dry-coated tablets. In some embodiments, the tablet is coated with a water-soluble, pH-independent film coating that allows for rapid disintegration for rapid release of the active ingredient (e.g., Opadry products). Dosage in the tablet

[0098] In some embodiments, the amount of Compound 1 in the tablet is from about 1 mg to 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. In some embodiments, the amount of Compound 1 in the tablet is about 25 mg. Administration methods and treatment regimens

[0099] In one embodiment, Compound 1 described herein or a pharmaceutically acceptable salt thereof is used to prepare a medicament for treating a disease or condition in a mammal that would benefit from administration of an FXR agonist. A method of treating any disease or condition described herein in a mammal in need of such treatment involves administering to the mammal a therapeutically effective amount of a pharmaceutical composition (i.e., formulation) comprising Compound 1 described herein or a pharmaceutically acceptable salt thereof, an active metabolite, a prodrug, or a pharmaceutically acceptable solvate.

[0100] Methods of administering an FXR agonist in combination with an additional therapeutic agent are disclosed herein. In some embodiments, the additional therapeutic agent includes a therapeutic agent for treating diabetes or diabetes-related disorders or conditions, alcoholic or non-alcoholic liver disease, inflammation-related bowel conditions, or proliferative disorders.

[0101] In certain embodiments, administering a composition containing a compound described herein is for prophylactic and / or therapeutic treatment. In certain therapeutic applications, the composition is administered to a patient having a disease or condition in an amount sufficient to cure or at least partially inhibit at least one symptom of the disease or condition. The effective amount for such use depends on the severity and course of the disease or condition, previous treatment, the health status, body weight, and response of the patient to the drug, and the judgment of the treating physician. The therapeutically effective amount is optionally determined by methods including, but not limited to, dose escalation and / or dose range clinical trials.

[0102] In a prophylactic application, a composition containing a compound described herein is administered to a patient susceptible to or at risk of a particular disease, disorder, or condition. Such an amount is defined as a "prophylactically effective amount or dose". In this use, the exact amount also depends on the health status, body weight, etc. of the patient. When used in a patient, the effective amount for this use will depend on the severity and course of the disease, disorder, or condition, previous treatment, the health status of the patient, and response to the drug, and the judgment of the treating physician. In one aspect, prophylactic treatment includes administering a pharmaceutical composition comprising Compound 1 or a pharmaceutically acceptable salt thereof to a mammal that has previously experienced at least one symptom of the disease being treated and is currently in remission to prevent recurrence of symptoms of the disease or condition.

[0103] In certain embodiments where the patient's condition does not improve, Compound 1 is administered chronically, i.e., for a prolonged period of time, including for the duration of the patient's life, at the discretion of the physician, in order to improve or otherwise control or limit the symptoms of the patient's disease or condition.

[0104] In certain embodiments in which the patient's condition does improve, the dose of the administered drug is temporarily reduced or temporarily discontinued for a period of time (i.e., a "drug holiday"). In specific embodiments, the length of the drug holiday is between 2 days and 1 year, including by way of example only 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, or more than 28 days. By way of example only, the dose reduction during the drug holiday is 10%-100%, including by way of example only 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.

[0105] Once the patient's condition has improved, a maintenance dose is administered if necessary. Subsequently, in specific embodiments, the dose or frequency or both of the administered drug are reduced to a level that maintains the improved disease, disorder, or condition, depending on the symptoms. However, in certain embodiments, the patient requires long-term intermittent treatment upon any recurrence of symptoms.

[0106] The amount of a given pharmaceutical agent corresponding to such an amount varies depending on factors such as the specific compound, the disease state and its severity, the identity of the subject or host to be treated (e.g., weight, gender), but is still determined according to the specific circumstances surrounding the case, including for example the specific pharmaceutical agent administered, the route of administration, the condition being treated, and the subject or host being treated.

[0107] However, generally speaking, the dose for adult treatment is usually from 0.01 mg to 500 mg per day. In one aspect, the dose for adult treatment is from about 1 mg to about 500 mg per day. In one embodiment, the required dose is conveniently presented as a single dose or as separate doses administered simultaneously or at appropriate intervals, e.g., as twice, three times, four times, or more sub-doses per day.

[0108] In one embodiment, the daily dose suitable for Compound 1 or a pharmaceutically acceptable salt thereof described herein is from about 0.01 to about 50 mg / kg body weight. In some embodiments, based on many variables regarding an individual treatment regimen, the daily dose or the amount of the active ingredient in the dosage form is lower or higher than the ranges shown herein. In various embodiments, the daily dose and unit dose vary according to many variables, including but not limited to the activity of the compound used, the disease or condition to be treated, the mode of administration, the needs of the individual subject, the severity of the disease or condition to be treated, and the judgment of the physician.

[0109] The toxicity and therapeutic efficacy of such treatment regimens are determined in cell cultures or experimental animals by standard pharmaceutical procedures, including but not limited to determination of LD 50 and ED 50。The dose ratio between toxicity and therapeutic effect is the therapeutic index, which is expressed as the ratio between LD 50 and ED 50 In certain embodiments, data obtained from cell culture assays and animal studies are used to formulate a therapeutically effective daily dose range and / or a therapeutically effective unit dose for mammals, including humans. In some embodiments, the daily dose of the compounds described herein is within the circulating concentration range including the ED 50 with minimal toxicity. In certain embodiments, the daily dose range and / or unit dose vary within this range depending on the dosage form used and the route of administration employed.

[0110] In a further embodiment of any of the above aspects, an effective amount of Compound 1 described herein or a pharmaceutically acceptable salt thereof: (a) is administered systemically to a mammal; and / or (b) is administered orally to a mammal; and / or (c) is administered intravenously to a mammal; and / or (d) is administered by injection to a mammal; and / or (e) is administered topically to a mammal; and / or (f) is administered non-systemically or topically to a mammal.

[0111] In a further embodiment of any of the above aspects, it includes a single administration of an effective amount of Compound 1, including further embodiments where (i) the compound is administered once a day; or (ii) the compound is administered to the mammal multiple times over a time span of one day.

[0112] In a further embodiment of any of the above aspects, it includes multiple administrations of an effective amount of Compound 1, including further embodiments where (i) the compound is administered continuously or intermittently as a single dose; (ii) the time between multiple administrations is every 6 h; (iii) the compound is administered to the mammal every 8 h; (iv) the compound is administered to the mammal every 12 h; (v) the compound is administered to the mammal every 24 h. In a further or alternative embodiment, the method includes a drug holiday, where the administration of the compound is temporarily suspended or the dose of the administered compound is temporarily reduced; at the end of the drug holiday, the administration of the compound is resumed. In one embodiment, the length of the drug holiday is from 2 days to 1 year.

[0113] In certain cases, it is appropriate to administer Compound 1 or a pharmaceutically acceptable salt thereof in combination with one or more 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 benefit, but when combined with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Alternatively, in some embodiments, the benefit experienced by the patient is increased by administering one of the compounds described herein in combination with another agent that also has therapeutic benefit (which also includes a treatment regimen).

[0115] In one specific embodiment, Compound 1 or a pharmaceutically acceptable salt thereof is co-administered with a second therapeutic agent, wherein Compound 1 or a pharmaceutically acceptable salt thereof and the second therapeutic agent modulate different aspects of the disease, disorder, or condition being treated, thereby providing a greater overall benefit than either therapeutic agent alone. Examples List of Abbreviations

[0116] As used above and throughout the description of the present invention, unless otherwise indicated, the following abbreviations shall be understood to have the following meanings: ACN or MeCN Acetonitrile Bn Benzyl BOC or Boc tert-Butyl carbamate t-Bu tert-Butyl Cy Cyclohexyl DCE Dichloroethane (ClCH2CH2Cl) DCM Dichloromethane (CH2Cl2) DIPEA or IEA Diisopropylethylamine DMAP 4-(N,N-Dimethylamino)pyridine DMF N,N-Dimethylformamide DMA N,N-Dimethylacetamide DMSO Dimethyl sulfoxide equiv Equivalent 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 Reverse-phase high-pressure liquid chromatography T3P 2,4,6-Tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide TBME Methyl tert-butyl ether TFA Trifluoroacetic acid THF Tetrahydrofuran TLC Thin layer chromatography I. Chemical synthesis

[0117] Unless otherwise stated, reagents and solvents were used as received from commercial suppliers. Anhydrous solvents and oven-dried glassware were used for synthetic transformations sensitive to moisture and / or oxygen. Yields were not optimized. Reaction times are approximate and not optimized. Unless otherwise stated, column chromatography and thin layer chromatography (TLC) were performed on silica gel. Example 1: Preparation of 4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octane-1-carbaldehyde (Intermediate 1) Step 1: 8-(4-Methoxy-3-methylphenyl)-1,4-dioxaspiro[4.5]decan-8-ol

[0118] Three batches were run in parallel: At -60 °C under N2, n-BuLi (762 mL, 1.90 mol, 2.5 M solution in n-hexane) was added dropwise over 1 h to a solution of 4-bromo-1-methoxy-2-methylbenzene (333 g, 1.66 mol) and anhydrous THF (2 L). The reaction was stirred at -60 °C for 1 h, then a solution of 1,4-dioxaspiro[4.5]decan-8-one (284.53 g, 1.82 mol) and anhydrous THF (1 L) was added dropwise over 45 min. The reaction was stirred at -60 °C for 1 h, then the three batches were poured into saturated aqueous NH4Cl (3 L). The mixture was extracted with EtOAc (5 L × 2). The combined organic layers were washed with brine (5 L), dried over Na2SO4, filtered, concentrated, and then triturated in n-hexane (1.2 L) at room temperature overnight. The mixture was filtered, the filter cake was washed with cold n-hexane (200 mL × 2), and then dried in vacuo to give 8-(4-methoxy-3-methylphenyl)-1,4-dioxaspiro[4.5]decan-8-ol (1100 g, 82%) as a white solid. 1 1H NMR (400 MHz, CDCl3): δ 7.30 - 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, 1H). Step 2: 8-Allyl-8-(4-methoxy-3-methylphenyl)-1,4-dioxaspiro[4.5]decane

[0119] Run 4 batches in parallel: At -65 °C in N2, add BF3·Et2O (376.95 g, 2.65 mol) to a solution of 8-(4-methoxy-3-methylphenyl)-1,4-dioxaspiro[4.5]decan-8-ol (275 g, 0.99 mol), allyltrimethylsilane (180.62 g, 1.58 mol), and anhydrous DCM (3 L). Stir the reaction mixture at -65 °C for 1 h, then carefully pour the 4 batches into saturated aqueous NaHCO3 (10 L). Extract the mixture with DCM (5 L × 3). Wash the combined organic layers with brine (5 L), dry over Na2SO4, filter, and concentrate to obtain 8-allyl-8-(4-methoxy-3-methylphenyl)-1,4-dioxaspiro[4.5]decane as a yellow oil (1350 g). 1 1H NMR (400 MHz, CDCl3): δ 7.17 - 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). Step 3: 4-Allyl-4-(4-methoxy-3-methylphenyl)cyclohexanone

[0120] Run 3 batches in parallel: Add water (450 mL) and formic acid (285.95 g, 5.95 mol) successively at room temperature to a solution of 8-allyl-8-(4-methoxy-3-methylphenyl)-1,4-dioxaspiro[4.5]decane (450 g) and THF (1.8 L). Reflux the reaction mixture overnight, cool it to room temperature, then pour the 3 batches into saturated aqueous NaHCO3 (3 L). Extract the mixture with EA (3 L × 3). Wash the combined organic layers with brine (3 L), dry over Na2SO4, filter, concentrate, and then purify by silica gel chromatography (petroleum ether / EtOAc = 1 / 0 - 50 / 1) to obtain 4-allyl-4-(4-methoxy-3-methylphenyl)cyclohexanone as a yellow oil (800 g, 69.3%, over 2 steps). 11H NMR (400 MHz, CDCl3): δ 7.16 - 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). Step 4: 4 - Allyl - 4-(4 - methoxy - 3 - methylphenyl)cyclohexanecarbonitrile

[0121] Run 3 batches in parallel: At 0 °C under N2, add t - BuOK (299.69 g, 2.67 mol) (maintaining the internal temperature < 5 °C) portionwise over 1 h to a solution of 4 - allyl - 4-(4 - methoxy - 3 - methylphenyl)cyclohexanone (230 g, 890.25 mmol), Tos - MIC (260.72 g, 1.34 mol), and DME (2 L). Stir the mixture at room temperature for 2 h, then pour it into saturated aqueous NH4Cl solution (5 L) in 3 portions. Extract the mixture with EtOAc (5 L × 2). Wash the combined organic layers with brine (5 L), dry over Na2SO4, filter, concentrate, and then purify by silica gel chromatography (petroleum ether / EtOAc = 1 / 0 - 50 / 1) to obtain 4 - allyl - 4-(4 - methoxy - 3 - methylphenyl)cyclohexanecarbonitrile as a yellow oil (508 g, 70.6%). 1 1H NMR (400 MHz, CDCl3): δ 7.13 - 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). Step 5: 4-(2,3 - Dihydroxypropyl)-4-(4 - methoxy - 3 - methylphenyl)cyclohexanecarbonitrile

[0122] Run 3 batches in parallel: At 0 °C, NMO (242.66 g, 2.07 mol) and then K2OsO4·2H2O (7.63 g, 20.71 mmol) were added to a solution of 4-allyl-4-(4-methoxy-3-methylphenyl)cyclohexanecarbonitrile (186 g, 690.47 mmol), acetone (2 L), and H2O (250 mL). The reaction was warmed to room temperature and stirred for 2 h. The 3 batches were poured into saturated aqueous Na2SO3 (4 L), and the mixture was extracted with EtOAc (3 L × 2). The combined organic layers were washed with brine (3 L), dried over Na2SO4, filtered, concentrated, and then purified by silica gel chromatography (petroleum ether / EtOAc = 5 / 1 - 1 / 2) to give 4-(2,3-dihydroxypropyl)-4-(4-methoxy-3-methylphenyl)cyclohexanecarbonitrile as a yellow oil (600 g, 95.4%). 1 1H NMR (400 MHz, CDCl3): δ 7.21 - 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). Step 6: 4-(4-Methoxy-3-methylphenyl)-4-(2-oxoethyl)cyclohexanecarbonitrile

[0123] Run 3 batches in parallel: At 0 °C, NaIO4 (169.20 g, 791.05 mmol) (maintaining an internal temperature < 5 °C) was added portionwise over 30 min to a solution of 4-(2,3-dihydroxypropyl)-4-(4-methoxy-3-methylphenyl)cyclohexanecarbonitrile (200 g, 659.21 mmol), THF (2 L), and H2O (1 L). The mixture was stirred at room temperature for 3 h and then the 3 batches were poured into water (2 L). The mixture was extracted with EtOAc (2 L × 2). The combined organic layers were washed with brine (2 L), dried over Na2SO4, filtered, and concentrated to give 4-(4-methoxy-3-methylphenyl)-4-(2-oxoethyl)cyclohexanecarbonitrile as a colorless oil (510 g). 1 1H NMR (400 MHz, CDCl3): δ 9.43 - 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). Step 7: 4-(2-Hydroxyethyl)-4-(4-methoxy-3-methylphenyl)cyclohexanecarbonitrile

[0124] Run 3 batches in parallel: At 0 °C under N2, add NaBH4 (35.55 g, 939.73 mmol) to a solution of 4-(4-methoxy-3-methylphenyl)-4-(2-oxoethyl)cyclohexanecarbonitrile (170 g) and THF (1.7 L). Stir the mixture at room temperature for 3 h, then pour the 3 batches into ice water (3 L). Extract the mixture with EtOAc (1.5 L × 2). Wash the combined organic layers with brine (2 L), dry over Na2SO4, filter, concentrate, and obtain 4-(2-hydroxyethyl)-4-(4-methoxy-3-methylphenyl)cyclohexanecarbonitrile (495 g) as a colorless oil. 1 1H NMR (400 MHz, CDCl3): δ 7.18 - 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). Step 8: 4-(2-Bromoethyl)-4-(4-methoxy-3-methylphenyl)cyclohexanecarbonitrile

[0125] Run 3 batches in parallel: At 0 °C under N2, dropwise add a solution of PPh3 (316.62 g, 1.21 mol) and DCM (1 L) to a solution of 4-(2-hydroxyethyl)-4-(4-methoxy-3-methylphenyl)cyclohexanecarbonitrile (165 g), CBr4 (300.24 g, 905.37 mmol), and DCM (1.5 L) over 1 h. Stir the mixture at room temperature for 1.5 h, combine with another 2 batches, and concentrate. Grind the crude product in MTBE (5 L) at room temperature overnight. Remove the solid by filtration, wash the filter cake with MTBE (500 mL × 2), concentrate the filtrate, and then purify by silica gel chromatography (petroleum ether / EtOAc = 30 / 1) to obtain 4-(2-bromoethyl)-4-(4-methoxy-3-methylphenyl)cyclohexanecarbonitrile (530 g, 80%) as a white solid. 11H NMR (400 MHz, CDCl3): δ 7.11 - 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, 1H), 1.99 - 1.79 (m, 3H), 1.77 - 1.45 (m, 3H). Step 9: 4-(4-Methoxy-3-methylphenyl)bicyclo[2.2.2]octane-1-carbonitrile

[0126] Run 3 batches in parallel: At -65 °C under N2, add dropwise LDA (420 mL, 840 mmol, 2 M solution in THF) over 1 h to a solution of 4-(2-bromoethyl)-4-(4-methoxy-3-methylphenyl)cyclohexanecarbonitrile (143 g, 425.26 mmol), HMPA (381.03 g, 2.13 mol), and THF (1430 mL). Stir the mixture at -65 °C for 3 h, then pour it into saturated aqueous NH4Cl solution (5 L) in 3 batches. Extract the mixture with EtOAc (3 L × 2). Wash the combined organic layers with water (3 L), wash with brine (3 L), dry over Na2SO4, filter, concentrate, and then triturate overnight at room temperature in EA:hexane (1:30, 775 mL). Filter the mixture and wash the filter cake with EA:hexane (1:30, 150 mL), dry in vacuo to obtain 4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octane-1-carbonitrile (240 g, 73%) as a yellow solid. 1 1H NMR (400 MHz, CDCl3): δ 7.13 - 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). Step 10: 4-(4-Methoxy-3-methylphenyl)bicyclo[2.2.2]octane-1-carbaldehyde

[0127] Run 3 batches in parallel: At -65 °C in N2, add DIBAL-H (1 M PhMe, 830 mL, 830 mmol) to a solution of 4-(4-methoxy-3-methyl-phenyl)bicyclo[2.2.2]octane-1-carbonitrile (106 g, 415.11 mmol) in DCM (1 L). Stir the mixture at -65 °C for 1 h, then pour it into a saturated aqueous solution of NaK tartrate (3 L) in 3 batches and dilute with DCM (1.5 L). Stir the mixture at room temperature for 3 h. Separate the organic layer, and extract the aqueous phase with DCM (2 L × 2). Combine the organic layers, wash with brine (3 L), dry over Na2SO4, filter and concentrate to obtain 4-(4-methoxyphenyl-3-methyl)phenylbicyclo[2.2.2]octane-1-carbaldehyde (336 g) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6): δ 9.50 - 9.43 (m, 1H), 7.11 - 7.00 (m, 2H), 6.83 - 6.79 (m, 1H), 3.77 - 3.68 (m, 3H), 2.18 - 2.02 (m, 3H), 1.82 - 1.72 (m, 6H), 1.71 - 1.60 (m, 6H). Step 11: Potassium hydroxy(4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methanesulfonate

[0128] Run 6 batches in parallel: At 45 °C, add an aqueous solution of potassium metabisulfite (2 M, 54 mL, 108 mmol) to a solution of 4-(4-methoxy-3-methyl-phenyl)bicyclo[2.2.2]octane-1-carbaldehyde (56 g) in THF (300 mL) over 10 min. Stir the mixture at 45 °C for 3.5 h, cool it to room temperature, and then stir overnight at room temperature. Filter the 6 batches, and wash the filter cake with PE (400 mL) and dry under vacuum to obtain potassium hydroxy(4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methanesulfonate (381 g, 81%, in 2 steps) as a white solid. 1 H NMR (400 MHz, DMSO-d6) 7.12 - 6.97 (m, 2H), 6.88 - 6.71 (m, 1H), 4.51 (d, 1H), 3.73 (s, 3H), 3.56 (d, 1H), 2.11 (s, 3H), 1.88 - 1.56 (m, 12H). Step 12: 4-(4-Methoxy-3-methylphenyl)bicyclo[2.2.2]octane-1-carbaldehyde

[0129] Run 6 batches in parallel: At room temperature in N2, saturated aqueous Na2CO3 solution (300 mL) was added to a mixture of potassium (4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methanesulfonate (63.5 g, 167.76 mmol) and DCM (300 mL). The mixture was stirred for 1 h, then the 6 batches were poured into a mixture of DCM (1500 mL) and H2O (1500 mL). The organic layer was separated, and the aqueous phase was 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-methylphenyl)bicyclo[2.2.2]octane-1-carbaldehyde (240.3 g, 92%) as a white solid. 1 1H NMR (400 MHz, DMSO-d6): δ 9.52 - 9.41 (m, 1H), 7.14 - 7.02 (m, 2H), 6.84 - 7.80 (m, 1H), 3.73 (s, 3H), 2.12 (s, 3H), 1.83 - 1.72 (m, 6H), 1.71 - 1.56 (m, 6H); LCMS: 259.1 [M + H] + . Example 2: Preparation of 4-(1-(tert-butyl)-1H-pyrazol-4-yl)pyridin-2-amine (Intermediate 2)

[0130] 2-Methyltetrahydrofuran (10 mL), Pd(dppf)Cl2 and then aqueous K2CO3 solution (3 M, 10 mL, 30 mmol) were added to 4-bromopyridin-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) in a 40 mL vial. The reaction was degassed with 3 vacuum / N2 cycles, heated at 50 °C for 21 h, and then cooled to room temperature. The layers were separated, and the organic layer was washed with saturated aqueous NaK tartrate solution (25 mL), then with brine (25 mL). The aqueous layer was back-extracted with 2-methyltetrahydrofuran (25 mL). The combined organics were dried (MgSO4), filtered, concentrated, and then dried in vacuo for 1 h. A suspension of the crude material and MTBE (25 mL) was refluxed for 2 h, cooled to room temperature overnight, and then filtered. The filter cake was washed with MTBE (2 × 3 mL) and then dried in vacuo to give 4-(1-(tert-butyl)-1H-pyrazol-4-yl)pyridin-2-amine (1.15 g, 53%). 11H NMR (400 MHz, DMSO-d6): δ 8.27 (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] + 。 Example 3: Preparation of trans-4-((tert-butyldimethylsilyl)oxy)cyclohexanecarboxylic acid (Intermediate 3) Step 1: tert-Butyldimethylsilyl trans-4-((tert-butyldimethylsilyl)oxy)cyclohexanecarboxylate

[0131] Under N2 at room temperature, tert-butyldimethylchlorosilane (31.47 g, 208.8 mmol) was added to a mixture of trans-4-hydroxy-cyclohexanecarboxylic acid (10.03 g, 69.57 mmol), imidazole (18.96 g, 278.5 mmol) and DMF (140 mL) (the reaction exothermed to 32 °C). The reaction mixture was stirred at room temperature for 2 h and then diluted with diethyl ether (300 mL). The organic layer was washed (2 × 300 mL 1N HCl, then 300 mL brine), dried (Na2SO4), filtered and concentrated to give tert-butyldimethylsilyl trans-4-((tert-butyldimethylsilyl)oxy)cyclohexanecarboxylate (31.5 g) as a clear oil. 1 1H NMR (400 MHz, DMSO-d6): δ 3.61 - 3.53 (m, 1H), 2.26 - 2.18 (m, 1H), 2.04 - 1.96 (m, 2H), 1.92 - 1.85 (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). Step 2: trans-4-((tert-Butyldimethylsilyl)oxy)cyclohexanecarboxylic acid

[0132] In N2 at room temperature, a solution of potassium carbonate (58.01 g, 419.7 mmol) in H2O (300 mL) was added to a mixture of tert-butyl dimethylsilyl trans-4-((tert-butyldimethylsilyl)oxy)cyclohexanecarboxylate (31.5 g crude, 69.6 mmol), ethanol (1000 mL), and THF (300 mL). The reaction mixture was stirred at room temperature for 3 h, concentrated until 300 mL remained, diluted with brine (600 mL), and then acidified to pH 2 - 3 with 20% NaHSO4 (550 mL). The aqueous layer was extracted with ether (800 mL). The organic layer was washed (800 mL brine), dried (Na2SO4), filtered, concentrated, and dried under high vacuum (to remove silanol by-products) to give trans-4-((tert-butyldimethylsilyl)oxy)cyclohexanecarboxylic acid as a white solid (17.3 g, 96%, over 2 steps). 1 1H NMR (400 MHz, DMSO-d6): δ 12.30 (br s, 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). Example 4: Preparation of 3-hydroxyazetidine-trans-1-carboxylic acid 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)cyclo hexyl ester (Compound 1) 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

[0133] A mixture of intermediate 1 (1.0 equiv) and intermediate 2 (1.1 equiv) in methanol (7.5 vol) and acetic acid (0.33 equiv) was heated at 55 °C for at least 3 h. The reaction mixture was cooled to room temperature, and solid 2-methylpyridine borane complex (1.0 equiv) was added over at least 20 min. The reaction was stirred at room temperature overnight and water (12.0 vol) was added over at least 60 min. The suspension was stirred for at least 2 h. The solid was collected by filtration, washed with water / methanol (2:1) (2 × 1 vol), TBME (2 × 2 vol), and heptane (2 × 2 vol), and dried at 50 °C in a rotary evaporator to give 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. Steps 2 and 3: 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)methyl)cyclohexanecarboxamide

[0134] At 0 °C over 0.5 h, a solution of T3P in dichloromethane (2.0 eq) was added to a mixture of 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 (1.0 eq) and Intermediate 3 (1.2 eq) in dichloromethane (7.5 vol) and triethylamine (4.0 eq). The reaction mixture was warmed to room temperature and stirred for at least 12 h. The reaction mixture was cooled to 5 °C and quenched by addition of 2 portions of water (0.05 vol and 6.0 vol). The mixture was warmed to room temperature and stirred for at least 2 h. The organic layer was collected and washed with water. The dichloromethane solvent was replaced with 2-methyltetrahydrofuran (5.4 vol) in vacuo. Methanol (2.4 vol) and water (2 vol) were added to the solution, followed by aqueous HCl solution (32%) (1.9 eq). The reaction mixture was stirred at room temperature for at least 2 h. Aqueous 9.5% NaHCO3 solution (4 vol) was added to the mixture. The organic layer was collected, washed with brine, dried over Na2SO4, filtered and concentrated. 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 to give 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)methyl)cyclohexanecarboxamide. Step 4: 3-Hydroxyazetidine-trans-1-carboxylic acid 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 ester (Compound 1)

[0135] To a solution of 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)methyl)cyclohexanecarboxamide in dichloromethane (8.0 volumes) was added 1,1'-carbonyldiimidazole (1.5 equivalents). The mixture was stirred at room temperature for at least 3.5 h. At room temperature, 3-hydroxyazetidine hydrochloride (3.0 equivalents) was added to the solution, followed by iPr2NEt (7.0 equivalents). The reaction mixture was stirred at room temperature for at least 2.5 h. The reaction was quenched with 4.5% aqueous NaHCO3 (6.0 volumes). The organic layer was collected, and the aqueous layer was extracted once with dichloromethane (2.0 volumes). Methanol (0.8 volume) was added, and the combined organic layers were washed twice with 20% NH4Cl solution (4.0 volumes) and twice with water (4.0 volumes). The organic layer was dried (Na2SO4) and the dichloromethane solvent was changed to ethyl acetate (4 volumes). Heptane (4 volumes) was added slowly. The crude product was collected by filtration and washed with ethyl acetate:heptane (1:1). The crude product was dried in vacuo at 55 °C. The crude product was purified in a hot ethyl acetate slurry (5 volumes) and collected by filtration. The product was washed with ethyl acetate and dried in vacuo at 55 °C to give 3-hydroxyazetidine-trans-1-carboxylic acid 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 ester (Compound 1). II. Spray-dried dispersion of Compound 1 Example 5: Screening of Compound 1 / polymer combinations

[0136] A polymer-based spray-dried dispersion of Compound 1 was developed. Several Compound 1 / polymer combinations were screened and evaluated using computational models. The polymers evaluated were PVP / VA 64, PVP 30, HPMCAS-L, HPMCAS-M, HPMCAS-H, Eudragit L100-55, Eudragit L100, Eudragit EPO, HPMC E15, HPMC E3, HPMCE5, HPMCP-HP55, and Soluplus. The Compound 1 / polymer combinations were evaluated: 1) miscibility assessment - in silico at different stabilizer carriers and drug loads to evaluate the tendency for phase separation; 2) API / polymer solubility confirmation - for each lead condition, a series of compatible solvent systems were tested; 3) solvent casting - solvent casting experiments at different stabilizer carriers and drug loads to further narrow down formulation variables; and 4) supersaturation studies - precipitation inhibition of different stabilizer carriers was evaluated using the solvent shift method. Based on the screening studies, the scale-up of Compound 1 and PVP / VA 64 at 60% (w / w) and Compound 1 and HPMCAS-M at 60% (w / w) was carried out. Example 6: Laboratory-scale prototype manufacture of Compound 1 / polymer combinations

[0137] Spray drying. The feed solution was dried using a laboratory-scale spray dryer (Buchi B-290 spray dryer). The unit was equipped with a two-fluid nozzle with nozzle tips and caps of 0.7 mm and 1.5 mm, respectively. The spray drying unit was operated under nitrogen in an open-loop configuration (i.e., without recycle of the dried nitrogen), and the aspirator was blown at 100% capacity.

[0138] Secondary drying. A laboratory-scale vacuum tray dryer was used to reduce the residual solvent content of the wet spray-dried dispersion. Secondary drying was carried out at 50 °C for 48 h under vacuum and nitrogen purge.

[0139] Solution preparation. Solutions for the prototype fabrication of spray-dried dispersions using PVP / VA 64 and HPMCAS-M were prepared according to the following general procedure: The total amount of solvent was charged into an empty container; the total amount of polymer was slowly added with stirring; stirring was continued until the polymer was completely dissolved; the total amount of Compound 1 was slowly added with stirring; and stirring was continued until Compound 1 was completely dissolved. Representative solutions of Compound 1 and HPMCAS-M and Compound 1 and PVP / VA 64 were prepared according to the amounts and ratios in Table 1 below (where "C_feed" = solid content in the feed mixture [% w / w] and "C_Compound 1" = Compound 1 content in the feed mixture [% w / w]): Table 1. Solutions for the prototype fabrication of spray-dried dispersions Quantities and ratios Compound 1 / (HPMCAS-M) Compound 1 / (PVP / VA 64) Compound 1 g 19 24 HPMCAS Mg 12.66 - PVP / VA 64 g - 16 Dichloromethane g 254.4 324 Methanol g 28.5 36 Total solids g 31.66 40.0 Total liquid g 284.9 360 Compound 1 loading % w / w 60 60 C_feed % w / w 10 10 C_Compound 1 % w / w 6 6 Results

[0140] The main process data and analysis results are summarized in Table 2 below (where "T_feed" = the temperature of the feed solution [°C], "F_drying" = the flow rate of the drying gas in the spray dryer [kg / h], "F_atomization" = the flow rate of the atomizing gas [g / min], "T_outlet" = the temperature of the drying gas at the outlet of the drying chamber [°C], "F_feed" = the flow rate of the feed solution to the spray dryer [kg / h], "GC" = gas chromatography, "KF" = Karl Fisher, "TFN" = two-fluid nozzle, and "PSD" = particle size distribution): Table 2. Main process data and analysis results from the prototyping of spray-dried dispersions

[0141] Both spray-dried dispersions (Compound 1: HPMCAS-M and Compound 1: PVP / VA 64) were amorphous after secondary drying, as shown by the absence of crystallization peaks (XRPD) and the endothermic melting characteristics of crystalline material (DSC). Example 7: Stability study of Compound 1 spray-dried dispersion

[0142] Two Compound 1 spray-dried dispersions (Compound 1: HPMCAS-M and Compound 1: PVP / VA 64) were stored in capped vials at 40 °C / 75% RH for 1 month. No chemical degradation was observed for either spray-dried dispersion. Additionally, the amorphous state of each spray-dried dispersion was maintained. Example 8: Development of Compound 1 SDI tablet formulation

[0143] First, the compatibility of Compound 1 API (in amorphous form) was evaluated among various excipients. These compatibility studies were conducted in sealed containers at 40 °C / 75% RH for one month. At the end of the study, no detectable changes in assays, related substances, or appearance were detected. It was determined that Compound 1 API was compatible with the following: Avicel (microcrystalline cellulose), Tablettose (lactose monohydrate), Pearlitol (mannitol), Compitrol (glyceryl behenate), Acdisol (croscarmellose sodium), Polyplasdone XL (crospovidone), magnesium stearate, Cab-o-sil (colloidal silica).

[0144] As outlined in Table 3, four compound 1 formulation matrices were then prepared using spray-dried intermediate (SDI) PVP / VA and HPMCAS. Tablet formulation blends and tablets were prepared and their tabletability profiles, compressibility characteristics, disintegration times, friability, and biorelevant dissolution were evaluated. The only difference between the two formulations tested with each SDI was the disintegrant. The disintegrant is an important component in tablets containing SDI because the SDI polymer can also be used as a binder. The disintegrant may be key to overcoming the binding action of the SDI polymer to facilitate drug release. Table 3. Formulation matrices of compound 1 tablet formulations SDI: Spray-dried intermediate; API: Active pharmaceutical ingredient

[0145] Tabletability and compressibility curves were obtained for each of the four formulations. All four formulations produced tablets with high tensile strength (e.g., hardness ≥ 1.7 MPa) using typical compaction pressures such as 100 - 200 Mpa. The biorelevant dissolution curves of the four tablet formulations showed that all formulations could be compressed into high-quality tablets.

[0146] Two prototype 5 mg tablets were prepared from tablet formulations A and C. These tablets were used for pharmacokinetic studies in monkeys (n = 12 / formulation). From both tablet formulations, compound 1 was well absorbed ( Figure 1 ). Example 9: Compound 1 SDI tablet formulation – 5 mg and 25 mg tablets

[0147] The ingredients in Example 8 formulation A were increased by 5-fold to produce 25 mg tablets. Table 4. Formulations of 5 mg and 25 mg compound 1 tablet formulations API: Active pharmaceutical ingredient Example 10: Compound 1 SDI tablet formulation – 1 mg tablet

[0148] Since the amount of compound 1 SDI in the 1 mg blend was less than 2%, the blend was prepared by three-stage geometric dilution to provide a homogeneous mixture. This method requires the following steps: 1. Premix #1: Sieve the required amount of compound 1 SDI for the batch and double the amount of microcrystalline cellulose (MCC). Mix the premix #1. 2. Premix #2: Add MCC in an amount twice the weight of premix #1 and then mix. 3. Pre - blend #3: Add MCC in an amount twice the weight of Pre - blend #2 to the blend, and then mix. 4. Add the required amounts of MCC, lactose monohydrate, croscarmellose sodium, and colloidal silicon dioxide for the remaining batch to the blend and mix. Evaluate the blend using Blend Uniformity Analysis (BUA). 5. Once the BUA meets the requirements, sieve half of the batch of magnesium stearate, add it to the blend from Step 4, and mix. 6. Granulate the blend from Step 5 by roller compaction. Take samples to measure the bulk density (BD), tapped density (TD), and particle size distribution (PSD). Then, add the remaining half - batch amount of magnesium stearate to the blend from dry granulation and mix. 7. Compress the blend from Step 6 into tablets (round; 100 mg target weight). 8. Coat the compressed tablets in a pan coater. 9. Take samples of the final coated tablets for quality testing, stability, and bottle and cap the remaining bulk portion. Table 5. Formulation of 1 mg of Compound 1 Tablet Preparation Example 11: Compound 1 SDI tablet formulation – 12 mg tablet

[0149] When the tablet strength increases by more than 5 mg of Compound 1 and 3.3 mg of PVP / VA per 100 - mg tablet, the increase in the polymer inhibits drug release by acting as a binder. As a result, the amount of croscarmellose sodium increases from 5% to 10%, and the percentages of microcrystalline cellulose and lactose monohydrate decrease, resulting in an improved release profile of Compound 1 ( Figure 2 ). Table 6. Formulation of 12 mg of Compound 1 Tablet Preparation II. Compound 1 FXR Activity Example 12: In vitro FXR assay (TK) Seeding

[0150] Seed CV - 1 cells at a density of 2,000,000 cells in a T175 flask with DMEM + 10% charcoal - stripped FBS and incubate at 37 °C in 5% CO2 for 18 h (O / N). Transfection

[0151] After culturing for 18 h, the medium in the T175 flask was replaced with fresh DMEM + 10% activated charcoal stripped serum. In a polypropylene tube, 2500 μL of OptiMEM (Life Technologies, Cat# 31985-062) was combined with the expression plasmids of hFXR, hRXR, TK-ECRE-luc and pCMX-YFP. The tube was then vortexed briefly and incubated at room temperature for 5 min. The transfection reagent (X-tremeGENE HP from Roche, catalog number 06366236001) was added to the vortexed OptiMEM / plasmid mixture and incubated at room temperature for 20 min. After incubation, the transfection reagent / DNA mixture complex was added to the cells in the T175 flask, and the cells were incubated at 37 °C in 5% CO2 for 18 h (O / N). Add compound 1

[0152] Compound 1 was serially diluted in DMSO and added to the transfected CV-1 cells. The cells were then incubated for 18 h. The next day, the cells were lysed and luminescence was examined. Compound 1 TK hFXR:EC 50 ≤0.01 μM.

Claims

1. A spray-dried solid dispersion comprising: (a) 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 (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-hydroxyazetidine-trans-1-carboxylate is dispersed in a polymer matrix formed by the pharmaceutically acceptable polymer; wherein the pharmaceutically acceptable polymer is selected from the group consisting of 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 Soluplus; wherein the weight ratio 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-carboxylate to the pharmaceutically acceptable polymer is from 9:1 to 1:

9.

2. The spray-dried solid dispersion according to claim 1, further comprising a non-aqueous solvent.

3. The spray-dried solid dispersion according to claim 2, wherein the non-aqueous solvent is selected from the group consisting of tert-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, carbon tetrachloride, dimethyl sulfoxide, hexafluoroacetone, chlorobutanol, dimethyl sulfone, acetic acid, cyclohexane, and mixtures thereof.

4. The spray-dried solid dispersion according to claim 1, 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-hydroxyazetidine-trans-1-carboxylate is substantially amorphous.

5. The spray-dried solid dispersion according to claim 1, 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-hydroxyazetidine-trans-1-carboxylate is crystalline.

6. A pharmaceutical preparation comprising the spray-dried solid dispersion according to any one of claims 1-5 and optionally one or more pharmaceutically acceptable ingredients, said optionally one or more pharmaceutically acceptable ingredients being selected from the group consisting of: one or more diluents, one or more disintegrants, one or more binders, one or more lubricants, one or more glidants and one or more surfactants.

7. The pharmaceutical preparation according to claim 6, wherein said one or more pharmaceutically acceptable ingredients are selected from the group consisting of: microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, magnesium stearate, colloidal silicon dioxide, mannitol, crospovidone and sodium stearyl fumarate.

8. The pharmaceutical preparation according to claim 6 or 7, wherein the pharmaceutical preparation is in the form of a tablet.

9. The pharmaceutical preparation according to claim 8, wherein the tablet comprises from 1% to 30% by weight of the spray-dried solid dispersion.

10. The pharmaceutical preparation according to claim 8, wherein the tablet comprises from 1% to 20% by weight 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-carboxylate.

11. The pharmaceutical preparation according to claim 8, wherein the tablet comprises 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-carboxylate, "about" meaning that the recited number or numerical range is an approximation within experimental variability or within statistical experimental error and that the number or numerical range thus has a variation between 1% and 15% of that number or numerical range.

12. The pharmaceutical preparation according to claim 6 or 7, wherein the pharmaceutical preparation is in the form of a capsule.

13. Use of the spray-dried solid dispersion according to claim 1 or the pharmaceutical preparation according to any one of claims 2-7 in the manufacture of a medicament for the treatment of a disease or condition in a mammal, wherein the disease or condition is selected from the group consisting of: alcoholic liver disease, primary sclerosing cholangitis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), primary biliary cholangitis and inflammatory bowel disease.

14. Use of the spray-dried solid dispersion according to claim 1 or the pharmaceutical preparation according to any one of claims 2-7 in the manufacture of a medicament for the treatment of a disease or condition in a mammal that benefits from FXR agonist treatment.

15. Use of the spray-dried solid dispersion according to claim 1 or the pharmaceutical preparation according to any one of claims 2-7 in the manufacture of a medicament for the treatment of a liver disease or condition in a mammal.

16. Use of the spray-dried solid dispersion according to claim 1 or the pharmaceutical preparation according to any one of claims 2-7 in the manufacture of a medicament for treating gastrointestinal diseases or conditions in a mammal.

17. Use of the spray-dried solid dispersion according to claim 1 or the pharmaceutical preparation according to any one of claims 2-7 in the manufacture of a medicament for treating renal diseases or conditions, metabolic inflammation-mediated diseases or disorders, lipid diseases or disorders or cancer in a mammal.

18. Use according to any one of claims 13-17, wherein the method further comprises administering at least one additional therapeutic agent in addition to the spray-dried solid dispersion.

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