Crystalline forms of farnesoid x receptor agonist

Abstract

To provide compounds useful as farnesoid X receptor agonist.SOLUTION: The invention provides crystalline forms 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, and pharmaceutically acceptable salts and solvates.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. Provisional Patent Application No. 62 / 991,213, filed March 18, 2020. No. 6,299,499, filed on Oct. 1, 2004, which is hereby incorporated by reference in its entirety.

[0002] Described herein are compounds that are farnesoid X receptor agonists, compounds of such compounds Methods of preparation, pharmaceutical compositions and medicaments containing such compounds, and farnesoid X receptors Methods of using such compounds in the treatment of conditions, diseases, or disorders associated with receptor activity BACKGROUND OF THE INVENTION

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

[0004] Described herein are farnesoid X receptor agonists, 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 pharmaceutically acceptable solvates (including hydrates), polymorphs, and and amorphous phases, and methods for their use are described. 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-carboxy and pharmaceutically acceptable solvates (including hydrates), polymorphs, and non-solvates thereof. The crystalline phase is useful for the treatment of mammalian diseases or conditions that would benefit from treatment with FXR agonists. is used in the manufacture of a medicament for the treatment of a condition.

[0005] 4-((4-(1-(tert-butyl)-1H-pyrazol-4-yl)pyridine- 2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octyl) Tan-1-yl)methyl)carbamoyl)cyclohexyl 3-hydroxyazetidin- Methods for preparing crystalline forms of tetrahydrofuran-1-carboxylate are also described herein. Additionally, pharmaceutical compositions comprising the crystalline forms and methods for treating diseases or conditions are also disclosed. Methods of using FXR agonists are described.

[0006] One embodiment is 4-((4-(1-(tert-butyl)-1H-pyrazole-4 -yl)pyridin-2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo [2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl 3-hydro A crystalline form of azetidine-trans-1-carboxylate, or a pharmaceutically acceptable salt thereof It is an acceptable salt or solvate.

[0007] Another embodiment is the crystalline form of claim 1, wherein the 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)carba cyclohexyl 3-hydroxyazetidine-trans-1-carboxylate It is a free base.

[0008] In another embodiment described herein, 4-((4-(1-(tert-butyl) (4-(4-methoxy-3-yl)-1H-pyrazol-4-yl)pyridin-2-yl) -methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl )Crystalline Cyclohexyl 3-hydroxyazetidine-trans-1-carboxylate The morphology has the following characteristics: (a) An X-ray powder diffraction (XRPD) pattern substantially the same as that shown in Figure 1; (b)7.4°(2-θ), 8.4°(2-θ), 14.6°(2-θ), 15.4° (2-θ), 16.8°(2-θ), 17.0°(2-θ), 17.3°(2-θ), 1 Characteristic peaks at 7.6° (2-θ), 18.9° (2-θ), and 19.3° (2-θ) X-ray powder diffraction (XRPD) pattern with a peak, (c) Thermogravimetric analysis (TGA) substantially similar to that shown in Figure 2; (d) A DSC thermogram substantially similar to that shown in Figure 3; (e) a DSC thermogram with an endotherm that begins at approximately 213°C; or (f) any combination thereof; This is form 1, which has at least one of the following:

[0009] In some embodiments, the crystalline form has an x-ray diffraction pattern substantially identical to that shown in FIG. In some embodiments, the crystalline form has a powder diffraction (XRPD) pattern of: 7.4°(2-θ), 8.4°(2-θ), 14.6°(2-θ), 15.4°(2-θ ), 16.8°(2-θ), 17.0°(2-θ), 17.3°(2-θ), 17.6° (2-θ), 18.9°(2-θ), and 19.3°(2-θ). In some embodiments, the crystalline The form has a thermogravimetric analysis (TGA) substantially similar to that shown in Figure 2. In this embodiment, the crystalline form has a DSC thermogram substantially similar to that shown in FIG. In some embodiments, the crystalline form has an absorption peak with an onset of about 213°C. In some embodiments, the crystalline form has a DSC thermogram with heat. Characterized by properties (a), (b), (c), (d), and (e). In this embodiment, the crystalline form is obtained by dissolving in acetonitrile, ethanol, methanol, 2-propanol, or the like. Alcohol, ethyl acetate, ethanol / heptane (1:1 v / v), acetone, or In some embodiments, the crystalline The form is not solvated. In some embodiments, the crystalline form is anhydrous.

[0010] In another embodiment described herein, 4-((4-(1-(tert-butyl) (4-(4-methoxy-3-yl)-1H-pyrazol-4-yl)pyridin-2-yl) -methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl )Crystalline Cyclohexyl 3-hydroxyazetidine-trans-1-carboxylate The morphology has the following characteristics: (a) X-ray powder diffraction (XRPD) pattern substantially the same as that shown in Figure 4; (b) 8.5°(2-θ), 12.8°(2-θ), 13.4°(2-θ), 16.2 °(2-θ), 17.0°(2-θ), 18.8°(2-θ), 19.5°(2-θ), and X-ray powder diffraction (XRPD) patterns with characteristic peaks at 20.5° (2-θ). hmm, (c) Thermogravimetric analysis (TGA) substantially similar to that shown in Figure 5; (d) A DSC thermogram substantially similar to that shown in Figure 6; (e) a DSC thermogram with an endotherm that begins at approximately 212°C; or (f) any combination thereof; and Form 2, which has at least one of:

[0011] In some embodiments, the crystalline form has an X-ray diffraction pattern substantially similar to that shown in FIG. In some embodiments, the crystalline form has a powder diffraction (XRPD) pattern of: 8.5°(2-θ), 12.8°(2-θ), 13.4°(2-θ), 16.2°(2-θ) θ), 17.0°(2-θ), 18.8°(2-θ), 19.5°(2-θ), and 2 It has an X-ray powder diffraction (XRPD) pattern with a characteristic peak at 0.5° (2-θ). In some embodiments, the crystalline form has a structure substantially similar to that shown in FIG. In some embodiments, the crystalline form has a thermogravimetric analysis (TGA) as shown in FIG. In some embodiments, the DSC thermogram is substantially similar to that shown in FIG. The crystalline form has a DSC thermogram with an endotherm that begins at about 212°C. In some embodiments, the crystalline form has properties (a), (b), (c), (d), and (e). e). In some embodiments, the crystalline form is characterized by having ethyl acetate. In some embodiments, the crystalline form is obtained from alcohol / water (97:3 v / v). In some embodiments, the crystalline form is obtained from acetonitrile. In some embodiments, the crystalline form is unsolvated. In embodiments, the crystalline form is anhydrous.

[0012] In another embodiment described herein, 4-((4-(1-(tert-butyl) (4-(4-methoxy-3-yl)-1H-pyrazol-4-yl)pyridin-2-yl) -methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl )Crystalline Cyclohexyl 3-hydroxyazetidine-trans-1-carboxylate The morphology has the following characteristics: (a) An X-ray powder diffraction (XRPD) pattern substantially the same as that shown in Figure 7; (b)7.5°(2-θ), 15.1°(2-θ), 16.6°(2-θ), 16.9 °(2-θ), 17.2°(2-θ), 17.5°(2-θ), and 18.7°(2- X-ray powder diffraction (XRPD) pattern with characteristic peaks at θ (c) Thermogravimetric analysis (TGA) substantially similar to that shown in Figure 8; (d) A DSC thermogram substantially similar to that shown in Figure 9; (e) a DSC thermogram with an endotherm that begins at approximately 214°C; or (f) any combination thereof; and Form 3, which has at least one of:

[0013] In some embodiments, the crystalline form has an X-ray diffraction pattern substantially similar to that shown in FIG. In some embodiments, the crystalline form has a powder diffraction (XRPD) pattern of: 7.5°(2-θ), 15.1°(2-θ), 16.6°(2-θ), 16.9°(2-θ) θ), 17.2°(2-θ), 17.5°(2-θ), and 18.7°(2-θ) In some embodiments, the compound has an X-ray powder diffraction (XRPD) pattern with characteristic peaks. In the crystalline form, a thermogravimetric analysis (TGA) substantially similar to that shown in FIG. In some embodiments, the crystalline form has substantially the same structure as that shown in FIG. In some embodiments, the crystalline form has a DSC thermogram similar to that of about 21 It has a DSC thermogram with an endotherm onset at 4° C. In some embodiments, The crystalline form is characterized by having properties (a), (b), (c), (d), and (e). In some embodiments, the crystalline form is methyl t-butyl ether (TB ME). In some embodiments, the crystalline form is unsolvated. In some embodiments, the crystalline form is anhydrous.

[0014] In another embodiment described herein, 4-((4-(1-(tert-butyl) (4-(4-methoxy-3-yl)-1H-pyrazol-4-yl)pyridin-2-yl) -methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl )Crystalline Cyclohexyl 3-hydroxyazetidine-trans-1-carboxylate The morphology has the following characteristics: (a) An X-ray powder diffraction (XRPD) pattern substantially the same as that shown in FIG. 10; (b) 5.4°(2-θ), 8.9°(2-θ), 9.9°(2-θ), 14.8°( 2-θ), 15.9°(2-θ), 16.2°(2-θ), 16.8°(2-θ), 17 Characteristic peaks at 0.5° (2-θ), 18.5° (2-θ), and 20.1° (2-θ) X-ray powder diffraction (XRPD) pattern with (c) Thermogravimetric analysis (TGA) substantially similar to that shown in Figure 11; (d) A DSC thermogram substantially similar to that shown in Figure 12; (e) a first endotherm with an onset at about 164°C and a second endotherm with an onset at about 209°C DSC thermogram, or (f) any combination thereof; and Form 4, which has at least one of:

[0015] In some embodiments, the crystalline form has substantially the same X structure as shown in FIG. In some embodiments, the crystalline form has a linear powder diffraction (XRPD) pattern. , 5.4°(2-θ), 8.9°(2-θ), 9.9°(2-θ), 14.8°(2-θ ), 15.9°(2-θ), 16.2°(2-θ), 16.8°(2-θ), 17.5° (2-θ), 18.5°(2-θ), and 20.1°(2-θ). In some embodiments, the crystalline The form has a thermogravimetric analysis (TGA) substantially similar to that shown in Figure 11. In some embodiments, the crystalline form exhibits a DSC profile substantially similar to that shown in FIG. In some embodiments, the crystalline form has an onset of about 214°C. In some embodiments, the crystalline form has a DSC thermogram with an endotherm. , characterized by having properties (a), (b), (c), (d), and (e). In some embodiments, the crystalline form is derived from methyl t-butyl ether (TBME). In some embodiments, the crystalline form is unsolvated. In embodiments, the crystalline form is anhydrous.

[0016] In a further embodiment, crystalline 4-((4-(1-(tert-butyl)-1H- pyrazol-4-yl)pyridin-2-yl)((4-(4-methoxy-3-methylphenyl) Nyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl Silyl 3-hydroxyazetidine-trans-1-carboxylate, or its pharmaceutical Acceptable salts or solvates, as well as pharmaceutically acceptable carriers, diluents and excipients and at least one inactive ingredient selected from the group consisting of: In some embodiments, the pharmaceutical composition comprises crystalline 4-((4-(1-(tert-butyl) -1H-pyrazol-4-yl)pyridin-2-yl)((4-(4-methoxy-3-methyl- (methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl) Contains cyclohexyl 3-hydroxyazetidine-trans-1-carboxylate free base nothing.

[0017] In another embodiment, 4-((4-(1-(te rt-butyl)-1H-pyrazol-4-yl)pyridin-2-yl)((4-(4-methyl)-pyridin-2-yl) (3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl) (rubamoyl)cyclohexyl 3-hydroxyazetidine-trans-1-carboxylate or a pharmaceutically acceptable salt or solvate thereof. It is served.

[0018] In another embodiment, a method for treating or preventing a liver disease or condition in a mammal. Therefore, the 4-((4-(1-(tert- butyl)-1H-pyrazol-4-yl)pyridin-2-yl)((4-(4-methoxy -3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamo (yl)cyclohexyl 3-hydroxyazetidine-trans-1-carboxylate Methods are provided herein that include administering a therapeutically effective amount of a crystalloid form. In some embodiments, the disease or condition is a metabolic condition. wherein the disease or condition is a liver condition.

[0019] In some embodiments, the 4-((4-(1-(tert-butyl) (4-(4-methoxy-3-yl)-1H-pyrazol-4-yl)pyridin-2-yl) -methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl )Crystalline Cyclohexyl 3-hydroxyazetidine-trans-1-carboxylate The dosage forms may be intravenous, subcutaneous, oral, inhaled, intranasal, transdermal, or ophthalmic. The compound is administered to a mammal by

[0020] In another embodiment, any one of the diseases or conditions described herein is treated or prevented. 4-((4-(1-(tert-butyl)-1H- pyrazol-4-yl)pyridin-2-yl)((4-(4-methoxy-3-methylphenyl) Nyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl a crystalline form of silyl 3-hydroxyazetidine-trans-1-carboxylate, or administering a therapeutically effective amount of the pharmaceutically acceptable salt or solvate thereof to a mammal in need thereof; Methods for administering to a subject are described herein.

[0021] In another embodiment, for treating or preventing a metabolic or hepatic condition in a mammal. The method of claim 1, wherein the 4-((4-(1-(tert-butyl)-1H-pyridinyl)-4-methyl ... isopropyl or propyl. pyrazol-4-yl)pyridin-2-yl)((4-(4-methoxy-3-methylphenyl) bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl crystalline form of 3-hydroxyazetidine-trans-1-carboxylate, or administering to a mammal in need thereof a therapeutically effective amount of a pharmaceutically acceptable salt or solvate of In other embodiments, methods are described herein that involve administering a compound to a subject, such as a mammal, a mammalian cell, or a mammalian cell. or liver conditions amenable to treatment with FXR agonists. In this case, the method may comprise the step of preparing 4-((4-(1-(tert-butyl)-1H-pyrazol-2-yl)methyl)- ... 4-(4-methoxy-3-methylphenyl)-2-azol-4-yl)pyridin-2-yl) )bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl A crystalline form of 3-hydroxyazetidine-trans-1-carboxylate, or In addition to the pharmaceutically acceptable salt or solvate, a second therapeutic agent may be administered to the mammal. and further including.

[0022] In another embodiment, a method for treating or preventing a liver disease or condition in a mammal. 4-((4-(1-(tert-butyl)-1H-pyrazol-4-yl)pyridin phenyl-2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2] Octan-1-yl)methyl)carbamoyl)cyclohexyl 3-hydroxyazetidine crystalline form of α-trans-1-carboxylate, or a pharmaceutically acceptable salt thereof; Methods are described herein that include administering a compound or a solvate thereof to a mammal. In some embodiments, the liver disease or condition is primary biliary cirrhosis, primary sclerosing cholangitis. , cholestasis, nonalcoholic steatohepatitis (NASH), or nonalcoholic fatty liver disease In some embodiments, the patient is suffering from alcoholic liver disease or condition (NAFLD). In some embodiments, the condition is fatty liver (steatosis), cirrhosis, or alcoholic hepatitis. In this context, non-alcoholic liver disease or condition is referred to as non-alcoholic steatohepatitis (NASH) or or non-alcoholic fatty liver disease (NAFLD). An alcoholic liver disease or condition is nonalcoholic steatohepatitis (NASH). In some embodiments, the non-alcoholic liver disease or condition is non-alcoholic fatty liver disease. In some embodiments, nonalcoholic steatohepatitis (NASH) is associated with liver fibrosis. The liver disease or condition is nonalcoholic steatohepatitis (NASH) without liver fibrosis In some embodiments, the non-alcoholic liver disease or condition is intrahepatic cholestasis or In some embodiments, the liver disease or condition is fatty liver disease or extrahepatic cholestasis. Hepatitis, cholangitis, fatty liver disease, cholestasis, cirrhosis, fibrotic liver disease, liver inflammation, bile duct obstruction Alagille syndrome, IFALD (intestinal failure-associated liver disease), parenteral nutrition-associated liver disease (PNA) LD), hepatitis, hepatocellular carcinoma, cholangiocarcinoma, or a combination thereof. In this condition, cholestasis may be caused by intrahepatic cholestasis of pregnancy or progressive familial intrahepatic cholestasis ( PFIC).

[0023] In another embodiment, there is provided a method for treating or preventing liver fibrosis in a mammal, comprising administering to said mammal a 4 -((4-(1-(tert-butyl)-1H-pyrazol-4-yl)pyridine-2- yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octane -1-yl)methyl)carbamoyl)cyclohexyl 3-hydroxyazetidine-trans Crystalline forms of benzophenone-1-carboxylate, or pharmaceutically acceptable salts or solvents thereof Methods are described herein that include administering a compound of formula (I) to a mammal. In this form, mammals are infected with hepatitis C virus (HCV), non-alcoholic steatohepatitis ( NASH), primary sclerosing cholangitis (PSC), liver 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 ( In some embodiments, the mammal has been diagnosed with PBC, or biliary cirrhosis. The patient has been diagnosed with nonalcoholic steatohepatitis (NASH).

[0024] In another aspect, there is provided a method of treating or preventing liver inflammation in a mammal, comprising: 4-((4-(1-(tert-butyl)-1H-pyrazol-4-yl)pyridine-2 -yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octa (1-methyl)carbamoyl)cyclohexyl 3-hydroxyazetidine-tra crystalline form of acetonitrile-1-carboxylate, or a pharmaceutically acceptable salt or solution thereof Methods are described herein that include administering the vehicle to a mammal. In embodiments, the mammal is a patient with hepatitis C virus (HCV), non-alcoholic steatohepatitis (NSHIP), or (NASH), primary sclerosing cholangitis (PSC), liver cirrhosis, Wilson's disease, hepatitis B virus Hepatitis B virus (HBV), HIV-associated steatohepatitis and cirrhosis, chronic viral hepatitis, non-alcoholic fatty liver disease (NAFLD), alcoholic steatohepatitis (ASH), primary biliary cirrhosis In some embodiments, the patient is breastfeeding and has been diagnosed with primary biliary cirrhosis (PBC), or biliary cirrhosis. The animal has been diagnosed with non-alcoholic steatohepatitis (NASH). In some embodiments, liver inflammation is associated with inflammation of the gastrointestinal tract. Dairy animals have been diagnosed with inflammatory bowel disease.

[0025] In another aspect, a method for treating or preventing a gastrointestinal disease or condition in a mammal. 4-((4-(1-(tert-butyl)-1H-pyrazol-4-yl)pyrazole) Lysin-2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2. 2]Octan-1-yl)methyl)carbamoyl)cyclohexyl 3-hydroxyazetyl Crystalline forms of cin-trans-1-carboxylate, or pharmaceutically acceptable salts thereof or a solvate thereof to a mammal. 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 colon inflammation, 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 In some embodiments, the gastrointestinal disorder is irritable bowel syndrome. IBS, IBS with diarrhea (IBS-D), IBS with constipation IBS-C, mixed IBS (IBS-M), unclassifiable IBS (IBS-U), or or bile acid diarrhea (BAD).

[0026] In another embodiment, a mammal that would benefit from treatment with an FXR agonist. 1. A method for treating or preventing a disease or condition, comprising administering to a patient a compound selected from the group consisting of 4-((4-(1-(tert-butyl 4-hydroxybenzoates, 4-((4-(1- ... (4-(4-methoxy-)-1H-pyrazol-4-yl)pyridin-2-yl) 3-Methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl Crystals of (phenyl)cyclohexyl 3-hydroxyazetidine-trans-1-carboxylate and administering to a mammal a pharmaceutical form, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the methods described herein include The method is to prepare 4-((4-(1-(tert-butyl)-1H-pyrazol-4-yl)pyrazole 4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2 ]octan-1-yl)methyl)carbamoyl)cyclohexyl 3-hydroxyazetidinyl The crystalline form of benzophenone-trans-1-carboxylate, or a pharmaceutically acceptable salt thereof, is also or further comprising administering, in addition to the solvate, at least one additional therapeutic agent.

[0027] Incorporation by Reference All publications and patent applications mentioned herein are incorporated by reference in their entirety, to the extent applicable and relevant. It is incorporated herein by reference. [Brief explanation of the drawings]

[0028] [Figure 1] Figure 1 shows the X-ray powder diffraction (XRPD) pattern of Form 1 of crystalline 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 free base. [Figure 2] Figure 1 shows a thermogravimetric analysis (TGA) thermogram of Form 1 of crystalline 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 free base. [Figure 3] FIG. 1 shows a differential scanning calorimetry (DSC) thermogram of Form 1 of crystalline 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 free base. [Figure 4] Figure 1 shows the X-ray powder diffraction (XRPD) pattern of Form 2 of crystalline 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 free base. [Figure 5]Figure 1 shows a thermogravimetric analysis (TGA) thermogram of Form 2 of crystalline 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 free base. [Figure 6] Crystalline 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 [Figure 7] Figure 1 shows the X-ray powder diffraction (XRPD) pattern of Form 3 of crystalline 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 free base. [Figure 8] Figure 1 shows a thermogravimetric analysis (TGA) thermogram of Form 3 of crystalline 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 free base. [Figure 9] Figure 1 shows a differential scanning calorimetry (DSC) thermogram of Form 3 of crystalline 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 free base. [Figure 10]Figure 1 shows the X-ray powder diffraction (XRPD) pattern of Form 4 of crystalline 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 free base. [Figure 11] Figure 1 shows a thermogravimetric analysis (TGA) thermogram of Form 4 of crystalline 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 free base. [Figure 12] Figure 1 shows a differential scanning calorimetry (DSC) thermogram of Form 4 of crystalline 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 free base. [Figure 13] Figure 1 shows the dynamic vapor sorption (DVS) isotherm (DVS isotherm plot) of Form 1 of crystalline 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 free base over two complete sorption / desorption cycles. [Figure 14]Figure 1 shows the dynamic vapor sorption (DVS) isotherm (DVS isotherm plot) of Form 2 of crystalline 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 free base over two complete sorption / desorption cycles. [Figure 15] Figure 1 shows the dynamic vapor sorption (DVS) isotherm (DVS isotherm plot) of Form 3 of crystalline 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 free base over two complete sorption / desorption cycles. [Figure 16] Figure 1 shows the dynamic vapor sorption (DVS) isotherm (DVS isotherm plot) of Form 4 of crystalline 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 free base over two complete sorption / desorption cycles.

[0029] Detailed Description of the Invention Nuclear hormone receptor farnesoid X receptor (FXR or nuclear receptor subfamily 1, Group H, member 4 (also known as NR1H4) (OMIM: 603826) FXR functions as a modulator of bile acid metabolism. , jejunum, ileum, colon, gallbladder, liver, macrophages, white and brown adipose tissue, etc. FXR is a ligand-activated transcriptional receptor expressed in various tissues, including the liver, intestine, and kidney. It is highly expressed in tissues involved in bile acid metabolism. Bile acids act as endogenous ligands for FXR. It functions by allowing intestinal and systemic release of bile acids to induce FXR-directed changes in gene expression networks. Bile acids are the major oxidation products of cholesterol and, in some cases, are transported to the intestine. Once secreted, it acts as a modulator of cholesterol absorption. Cholesterol to bile acids The rate-limiting step in the conversion of cholesterol to hydroxybenzoate is the cytochrome p450 enzyme cholesterol 7-α-hydroxybenzoate. It is generated in the liver and is catalyzed by the cytochrome p450 enzyme steroid. Cholic acid 12-β-hydroxylase (CYP8B1) mediates the production of cholic acid and Determine the relative amounts of the major bile acids, cholic acid and chenodeoxycholic acid. FXR activity The activation of small heterodimer partner (SHP) (nuclear receptor subfamily 0, GlcNAc) in the liver The expression levels of NR0B2 (also known as loop B, member 2, or NR0B2) and the mouse Fibroblast growth factor 15 (FGF15) in humans and fibroblast growth factor 19 (FG F19) in the intestine, thereby inhibiting the transcription of CYP7A1 and CYP8B1. SHP regulates CYP7A1 and CYP8B1 gene expression. The transcription factors liver receptor homologue 1 (LRH-1) and hepatocyte nuclear factor 4α (HNFα) 4) The inhibition of CYP8B1 by FXR may be species-specific, and FX Activation of R may increase CYP8B1 expression in humans in some cases (Sanyal et al.,PNAS,2007,104,15665). Some examples In this study, FGF15 / 19 released from the intestine then activates fibroblast growth factor receptors in the liver. Mitogen-activated protein 4 activates CYP7A1 and inhibits CYP8B1 This leads to activation of the MAPK signaling pathway.

[0030] In some embodiments, elevated bile acid levels are associated with insulin resistance. For example, insulin resistance is caused by a decrease in glucose uptake from the blood and a decrease in liver This can lead to increased novo glucose production. In some cases, bile acid Intestinal sequestration enhances secretion of glucagon-like peptide-1 (GLP1) from intestinal L cells It has been shown that GLP-1 improves insulin resistance by inhibiting proglucosamine. It is an incretin derived from the transcription product of the vasopressin gene. It is released in response to food intake. GLP-1 regulates appetite and gastrointestinal function and stimulates insulin secretion from the pancreas. The therapeutically active form is GLP-1-(7-3), which results from selective cleavage of the proglucagon molecule. 7) and GLP-1-(7-36)NH2. In such cases, the production of bile acids Activation of FXR, leading to a decrease in insulin resistance, is associated with decreased insulin resistance.

[0031] In some embodiments, activation of FXR is mediated by peptide YY (PYY or PYY It is also involved in the secretion of folded pancreatic polypeptides such as 3-36. In this study, peptide YY acts on neurons in the hypothalamus and brainstem, areas of the brain involved in reward processing. PY is a gastrointestinal hormone peptide that regulates neuronal activity. Decreased Y concentrations are associated with increased appetite and weight gain.

[0032] In some cases, activation of FXR indirectly leads to a decrease in plasma triglycerides. The clearance of triglycerides from the bloodstream is mediated by lipoprotein lipase (LPL). LPL activity is due to the induction of its activator, apolipoprotein CII. This is enhanced by induction, and suppression of its inhibitor, apolipoprotein CIII, in the liver is , which occurs upon FXR activation.

[0033] In some cases, activation of FXR may increase energy expenditure, such as adipocyte differentiation and function. Adipose tissue is made up of adipocytes or fat cells. In some cases, adipocytes are also called brown adipose tissue (BAT) or The function of BAT is to generate body heat. WAT functions as a fat storage tissue.

[0034] In some cases, FXR is widely expressed in the intestine. Activation induces the expression and secretion of FGF19 (or FGF15 in mice) in the intestine. FGF19 regulates bile acid synthesis, as well as glucose metabolism, lipid metabolism, and enzyme metabolism. In some cases, FGF19 is a hormone that affects the metabolism of fat. It has also been observed to regulate the function and differentiation of adipocytes. In fact, one study showed that a high-fat diet Administration of FGF19 to mice increased energy expenditure and fat cell differentiation. It has been shown that this regulates the function of the omega-3 fatty acids, reverses weight gain, and improves insulin resistance. (Fu et al., “Fibroblast growth factor 19 increases metabolic rate and reverses d ietary and leptin-deficient diabetes.”En (See Docrinology 145:2594-2603 (2004)).

[0035] In some cases, intestinal FXR activity may contribute to microbiome overgrowth, such as during feeding. It has been shown that this is involved in the decline of ATP (Li et al., NatCommun4: 2384, 2013). For example, one study demonstrated that activation of FXR was associated with antibacterial activity. associated with increased expression of several genes in the ileum, including Ang2, iNos, and Il18. It has been shown that (Inagaki et al., Proc Natl Acad Sci USA 103:3920~3925, 2006).

[0036] In some instances, FXR is involved in intestinal barrier function and immune regulation. It regulates the transcription of genes involved in the synthesis, transport, and metabolism of bile salts in the liver and intestine, and in some cases It has been shown that this improves intestinal inflammation and prevents bacterial migration into the intestinal tract (Ga Daleta et al., Gut., April 2011, 60(4):463~72) .

[0037] In some cases, overproduction of bile acids or inadequate transport and recycling of bile acids can lead to diarrhea. FXR regulates bile salt synthesis, transport, and metabolism in the liver and intestine. It regulates the transcription of the genes involved, leading to an improvement in diarrhea in some cases (Camil leri, Gut Liver, May 2015, 9(3):332~339).

[0038] G protein-coupled bile acid receptor 1 (GPBAR2, GPCR19, membrane receptor for bile acids) or M-BAR, or TGR5) is a cell surface receptor for bile acids. Upon activation by bile acids, TGR5 induces the production of intracellular cAMP, which stimulates BAT proliferation. Activation of deiodinase (DIO2) causes an increase in triiodothyronine, Energy consumption increases.

[0039] Thus, in some embodiments, bile acid synthesis, bile acid circulation, glucose metabolism Regulation of metabolic processes such as oxidative stress, lipid metabolism, or insulin sensitivity is mediated by FXR activation. Furthermore, in some embodiments, bile acid synthesis, bile acid circulation, glutamic acid synthesis, and glutamic acid synthesis are regulated by Dysregulation of metabolic processes such as course metabolism, lipid metabolism, or insulin sensitivity can lead to diabetes. or diabetes-related conditions or disorders, alcoholic or non-alcoholic liver disease or This can result in metabolic disorders such as inflammatory bowel disease, intestinal inflammation, or cell proliferative disorders.

[0040] Disclosed herein, in certain embodiments, are compounds that can be used as FXR agonists. In some embodiments, the compounds described herein are compounds having FXR antagonist activity. The FXR ligands are structurally distinct from bile acids, other synthetic FXR ligands, and other natural FXR ligands. varies.

[0041] In some embodiments, administering a therapeutically effective amount of an FXR agonist Treat metabolic disorders such as diabetes, obesity, impaired glucose tolerance, dyslipidemia, or insulin resistance Also disclosed herein are methods for preventing or preventing a gastrointestinal tract infection in a subject. It is administered into the tube.

[0042] In further embodiments, disclosed herein is a therapeutically effective amount of an FXR antagonist. by administering the compound to a subject in need thereof (e.g., via the gastrointestinal tract), Alcoholic or non-alcoholic liver disease or condition (e.g., cholestasis, primary biliary Cirrhosis, steatosis, cirrhosis, alcoholic hepatitis, non-alcoholic steatohepatitis (NASH) , nonalcoholic fatty liver disease (NAFLD), primary sclerosing cholangitis (PSC) or liver enzymes In a further embodiment, the present invention provides a method for treating or preventing a condition described herein. What is disclosed is a method for administering a therapeutically effective amount of an FXR agonist to a subject in need thereof. By administering this product, cholestasis, liver cirrhosis, primary biliary cirrhosis, and non-alcoholic fatty liver disease can be improved. NASH, nonalcoholic fatty liver disease (NAFLD), or primary sclerosing cholangitis In some embodiments, the present invention provides a method for treating or preventing PSC. What is disclosed is a method for administering a therapeutically effective amount of an FXR agonist to a subject in need thereof. In some embodiments, the method includes administering a compound to treat or prevent cholestasis. Disclosed herein is a method for administering a therapeutically effective amount of an FXR agonist to a patient in need thereof. and a method for treating or preventing primary biliary cirrhosis by administering the compound to a subject. In some embodiments, disclosed herein is a therapeutically effective amount of FX and administering an R agonist to a subject in need thereof to treat or In some embodiments, disclosed herein are methods for preventing NA is achieved by administering a therapeutically effective amount of an FXR agonist to a subject in need thereof. Methods for treating or preventing FLD are included.

[0043] In further embodiments, disclosed herein is a therapeutically effective amount of an FXR antagonist. by administering the agonist to a subject in need thereof (e.g., via the gastrointestinal tract) and a method for treating or preventing inflammation and / or cell proliferative disorders such as cancer in the intestine. include.

[0044] In further embodiments, disclosed herein are methods for inhibiting bile acid synthesis, glucose synthesis, and the like. metabolism, lipid metabolism, or insulin sensitivity, e.g., FGF19 (FGF1 in mice) 5) Increased activity of α-glucan, increased secretion of GLP-1, or increased secretion of PYY FXR agonists that regulate one or more of the proteins or genes associated with include.

[0045] 4-((4-(1-(tert-butyl)-1H-pyrazol-4-yl)pyridine- 2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octyl) Tan-1-yl)methyl)carbamoyl)cyclohexyl 3-hydroxyazetidin- lance-1-carboxylate (compound 1)

[0046] Described herein are FXR agonist compounds 4-((4-(1-(ter t-butyl)-1H-pyrazol-4-yl)pyridin-2-yl)((4-(4-meth (3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)carboxamide Bamoyl)cyclohexyl 3-hydroxyazetidine-trans-1-carboxylate (Compound 1). "Compound 1" or "4-((4-(1-(tert-butyl)- 1H-pyrazol-4-yl)pyridin-2-yl)((4-(4-methoxy-3-methyl) (phenyl)bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclo "Dihexyl 3-hydroxyazetidine-trans-1-carboxylate" has the following structure: It refers to a compound having

[0047] [ka]

[0048] 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 may be in the unsolvated form. It may exist in a solvated form with pharmaceutically acceptable solvents such as water, ethanol, etc. The solvated forms of Compound 1 presented herein are also disclosed herein. In some embodiments, Compound 1 is solvated.

[0049] As used herein, "pharmaceutically acceptable" means a compound that is soluble in water and that exhibits the biological activity or properties of the compound. This refers to a material, such as a carrier or diluent, that does not destroy the product and is relatively non-toxic; The material may be used without causing any undesirable biological effects or in the composition in which it is contained. administered to an individual without interacting in any adverse way with any of the components of

[0050] The term "pharmaceutically acceptable salt" refers to a therapeutically active agent in combination with a suitable anion. or in another embodiment, in combination with a suitable cation. refers to a form of a therapeutically active agent that consists of the anionic form of the therapeutically active agent. Pharmaceutical Salts:Properties,Selecti on and Use. International Union of Pure a nd Applied Chemistry,Wiley-VCH2002. SMB erge,LDBighley,DCMonkhouse,J.Pharm.S ci.1977,66,1-19. By P.H. Stahl and C.G. Wermuth ,Handbook of Pharmaceutical Salts: Prope rties,Selection and Use,Weinheim / Zuerich :Wiley-VCH / VHCA, 2002. Pharmaceutical salts are typically more soluble than non-ionic species. It is more soluble in gastric and intestinal fluids than steroids and dissolves rapidly, making it useful in solid dosage forms. , their solubility is often a function of pH, so their solubility in one part of the digestive tract or another Selective dissolution is possible, and this ability can be manipulated as one aspect of delayed and sustained release behavior. In addition, salt-forming molecules can be in equilibrium with the neutral form, allowing for easier transport through biological membranes. The excess can be adjusted.

[0051] It should be understood that a reference to a pharmaceutically acceptable salt includes the solvent addition forms. In some embodiments, the solvate may be in either stoichiometric or non-stoichiometric amounts. The compounds are isolated or purified using pharmaceutically acceptable solvents such as water, ethanol, etc. are formed during the purification process. When the solvent is water, hydrates are formed, and when the solvent is alcohol, In the case of alcohols, alcoholates are formed. Solvates of the compounds described herein are also used herein. Further, the present invention provides a method for preparing or forming a compound of formula (I) or (II) in a form that is conveniently prepared or formed during the process described herein. Compounds optionally exist in unsolvated and solvated forms.

[0052] Amorphous compound 1 In some embodiments, Compound 1 is amorphous. Thus, Compound 1 is amorphous and anhydrous. In some embodiments, amorphous Compound 1 has an X-ray powder diffraction (XRPD) pattern that indicates a lack of crystalline material.

[0053] Crystalline Form of Compound 1 Changes in solid form can affect various physical and chemical properties, This allows for improved processing, formulation, stability, bioavailability, among other important pharmaceutical properties. may pose advantages or disadvantages in terms of product availability, storage, and handling (e.g., transportation). Identifying and selecting solid forms of pharmaceutical compounds is complex. Useful pharmaceutical solids include products and Depending on the mode of administration, these include crystalline solids and amorphous solids. Amorphous solids fall into a broad category. A crystalline solid is characterized by a lack of structural order around the molecule, whereas a crystalline solid is characterized by structural periodicity. The desired class of pharmaceutical solids will depend on the particular application, and amorphous solids may be used in, for example, Crystalline solids may be selected based on, for example, an enhanced dissolution profile. For example, it may be desirable for properties such as physical or chemical stability.

[0054] Solid forms of pharmaceutical compounds, whether crystalline or amorphous, include single and multiple components. Single-component solids include pharmaceutical compounds in the absence of other compounds. The variety of single-component crystalline substances is This may arise from polymorphism, the phenomenon of multiple three-dimensional configurations for a pharmaceutical compound.

[0055] However, even if crystalline forms of the compounds exist, there are no known methods for successfully preparing them. Of course, it is impossible to predict priorities (e.g., Braga and Gre pioni, 2005, “Making crystals from crystal s:a green route to crystal engineering a nd polymorphism”, Chem.Commun.:3635~3645( When it comes to crystal engineering, if the instructions are not very precise and / or other external factors affect the process, (If the effect of the serotonin receptors on the serotonin receptors is significant, the results may be unpredictable.) Jones et al. ., 2006, “Pharmaceutical Cocrystals: An Eme ging Approach to Physical Property Enha ncement”, MRS Bulletin 31:875~879 (currently, It is generally not possible to computationally predict the number of observable polymorphs even for the simplest molecules. ), Price, 2004, “The computational prediction on of pharmaceutical crystal structures and polymorphism”, Advanced Drug Delivery Reviews 56:301–319 (“Price”), and Bernstei n, 2004, “Crystal Structure Prediction an d Polymorphism”, ACA Transactions 39:14~2 3 (Before we could state with any degree of confidence the ability to predict crystal structures) There is still much to learn and do.

[0056] The variety of possible solid forms represents a potential variation in the physical and chemical properties of a particular pharmaceutical compound. Solid form discovery and selection creates potential diversity for effective, stable, and marketable pharmaceuticals. This is extremely important in product development.

[0057] 4-((4-(1-(tert-butyl)-1H-pyrazol-4-yl)pyridine- 2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octyl) Tan-1-yl)methyl)carbamoyl)cyclohexyl 3-hydroxyazetidin- Crystalline Form 1 of lance-1-carboxylate (Compound 1)

[0058] In some embodiments, 4-((4-(1-(tert-butyl)-1H-pyra 4-(4-methoxy-3-methylphenyl)-2-azol-4-yl)pyridin-2-yl) )bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl 3-Hydroxyazetidine-trans-1-carboxylate (Compound 1) is available in crystalline form. In some embodiments, crystalline Compound 1 has the following properties: (a) An X-ray powder diffraction (XRPD) pattern substantially the same as that shown in Figure 1; (b)7.4°(2-θ), 8.4°(2-θ), 14.6°(2-θ), 15.4° (2-θ), 16.8°(2-θ), 17.0°(2-θ), 17.3°(2-θ), 1 Characteristic peaks at 7.6° (2-θ), 18.9° (2-θ), and 19.3° (2-θ) X-ray powder diffraction (XRPD) pattern with a peak, (c) Thermogravimetric analysis (TGA) substantially similar to that shown in Figure 2; (d) A DSC thermogram substantially similar to that shown in Figure 3; (e) a DSC thermogram with an endotherm that begins at approximately 213°C; or (f) any combination thereof; The present invention is characterized by having at least one of the following:

[0059] In some embodiments, Form 1 of crystalline Compound 1 is selected from (a) through (e): In some embodiments, the composition is characterized by having at least two properties: Form 1 of crystalline Compound 1 has at least three properties selected from (a) through (e). In some embodiments, Form 1 of crystalline Compound 1 is characterized by: (e) to (f) In one embodiment, Form 1 of crystalline Compound 1 is characterized as having properties (a) through (e). It is characterized by:

[0060] In some embodiments, Form 1 of crystalline Compound 1 is (a) Form 1 of crystalline Compound 1 shown in FIG. In some embodiments, the compound has an X-ray powder diffraction (XRPD) pattern substantially the same as Form 1 of crystalline Compound 1 exhibits 7.4° (2-θ), 8.4° (2-θ), and 14.6° (2-θ). (2-θ), 15.4°(2-θ), 16.8°(2-θ), 17.0°(2-θ), 1 7.3°(2-θ), 17.6°(2-θ), 18.9°(2-θ), and 19.3° It has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at (2-θ). In some embodiments, Form 1 of crystalline Compound 1 is substantially identical to that shown in FIG. In some embodiments, the crystalline Form 1 of Compound 1 has a DSC thermogram substantially similar to that shown in Figure 3. In some embodiments, Form 1 of crystalline Compound 1 exhibits an endotherm with an onset of about 213° C. In some embodiments, the crystalline form of Compound 1 has a DSC thermogram with Form 1 is acetonitrile, ethanol, methanol, 2-propanol, ethyl acetate, methanol / heptane (1:1 v / v), acetone, or acetonitrile / water (1:2 v / v). In some embodiments, Form 1 of crystalline Compound 1 is obtained from acetonitrile. In some embodiments, Form 1 of crystalline Compound 1 is obtained from ethanol. In some embodiments, Form 1 of crystalline Compound 1 is obtained from methanol. In some embodiments, Form 1 of crystalline Compound 1 is obtained from 2-propanol. In some embodiments, Form 1 of crystalline Compound 1 is obtained from acetic acid. In some embodiments, Form 1 of crystalline Compound 1 is obtained from ethanol. In some embodiments, the crystallization is performed using a 1:1 v / v alcohol / heptane mixture. Form 1 of Compound 1 is obtained from acetone. In some embodiments, the crystalline compound Form 1 of 1 is obtained from acetonitrile / water (1:2 v / v). In some embodiments, Form 1 of crystalline Compound 1 is solvated. In some embodiments, crystalline Form 1 of Compound 1 is unsolvated. Form 1 of crystalline Compound 1 is hydrated. In some embodiments, Form 1 of crystalline Compound 1 is Form 1 is anhydrous.

[0061] 4-((4-(1-(tert-butyl)-1H-pyrazol-4-yl)pyridine- 2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octyl) Tan-1-yl)methyl)carbamoyl)cyclohexyl 3-hydroxyazetidin- Crystalline Form 2 of lance-1-carboxylate (Compound 1)

[0062] In some embodiments, 4-((4-(1-(tert-butyl)-1H-pyra 4-(4-methoxy-3-methylphenyl)-2-azol-4-yl)pyridin-2-yl) )bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl 3-Hydroxyazetidine-trans-1-carboxylate (Compound 1) is available in crystalline form. In some embodiments, crystalline Compound 1 has the following properties: (a) X-ray powder diffraction (XRPD) pattern substantially the same as that shown in Figure 4; (b) 8.5°(2-θ), 12.8°(2-θ), 13.4°(2-θ), 16.2 °(2-θ), 17.0°(2-θ), 18.8°(2-θ), 19.5°(2-θ), and X-ray powder diffraction (XRPD) patterns with characteristic peaks at 20.5° (2-θ). hmm, (c) Thermogravimetric analysis (TGA) substantially similar to that shown in Figure 5; (d) A DSC thermogram substantially similar to that shown in Figure 6; (e) a DSC thermogram with an endotherm that begins at approximately 212°C; or (f) any combination thereof; The present invention is characterized by having at least one of the following:

[0063] In some embodiments, Form 2 of crystalline Compound 1 is selected from (a) through (e): In some embodiments, the composition is characterized by having at least two properties: Form 2 of crystalline Compound 1 has at least three properties selected from (a) through (e). In some embodiments, Form 2 of crystalline Compound 1 is characterized by: (e) to (f) In one embodiment, Form 2 of crystalline Compound 1 is characterized as having properties (a) through (e). It is characterized by:

[0064] In some embodiments, Form 2 of crystalline Compound 1 is substantially similar to that shown in FIG. In some embodiments, the results are similar in X-ray powder diffraction (XRPD) patterns. Form 2 of crystalline compound 1 exhibits 8.5° (2-θ), 12.8° (2-θ), and 13.4° (2 -θ), 16.2°(2-θ), 13.4°(2-θ), 16.2°(2-θ), 17. 0°(2-θ), 18.8°(2-θ), 19.5°(2-θ), and 20.5°(2 -θ) have X-ray powder diffraction (XRPD) patterns with characteristic peaks. In this embodiment, Form 2 of crystalline Compound 1 is substantially similar to that shown in FIG. In some embodiments, the crystalline compound has a thermogravimetric analysis (TGA) thermogram. Form 2 of Product 1 has a DSC thermogram substantially similar to that shown in Figure 6. In some embodiments, Form 2 of crystalline Compound 1 exhibits an endotherm with an onset at about 212°C. In some embodiments, Form 2 of crystalline Compound 1 has a DSC thermogram similar to that of Form 2 of crystalline Compound 1. In some embodiments, the resulting solution is obtained from ethyl acetate / water (97:3 v / v). Form 2 of crystalline Compound 1 is obtained from acetonitrile. In some embodiments, Crystalline Form 2 of Compound 1 is obtained from acetone. In some embodiments, the crystalline Form 2 of crystalline Compound 1 is solvated. In some embodiments, crystalline Compound 1 is solvated. Form 2 of 1 is unsolvated. In some embodiments, Form 2 of crystalline Compound 1 In some embodiments, Form 2 of crystalline Compound 1 is anhydrous. do.

[0065] 4-((4-(1-(tert-butyl)-1H-pyrazol-4-yl)pyridine- 2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octyl) Tan-1-yl)methyl)carbamoyl)cyclohexyl 3-hydroxyazetidin- Crystalline Form 3 of lance-1-carboxylate (Compound 1)

[0066] In some embodiments, 4-((4-(1-(tert-butyl)-1H-pyra 4-(4-methoxy-3-methylphenyl)-2-azol-4-yl)pyridin-2-yl) )bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl 3-Hydroxyazetidine-trans-1-carboxylate (Compound 1) is available in crystalline form. In some embodiments, crystalline Compound 1 has the following properties: (a) An X-ray powder diffraction (XRPD) pattern substantially the same as that shown in Figure 7; (b)7.5°(2-θ), 15.1°(2-θ), 16.6°(2-θ), 16.9 °(2-θ), 17.2°(2-θ), 17.5°(2-θ), and 18.7°(2- X-ray powder diffraction (XRPD) pattern with characteristic peaks at θ (c) Thermogravimetric analysis (TGA) substantially similar to that shown in Figure 8; (d) A DSC thermogram substantially similar to that shown in Figure 9; (e) a DSC thermogram with an endotherm that begins at approximately 214°C; or (f) any combination thereof; The present invention is characterized by having at least one of the following:

[0067] In some embodiments, Form 3 of crystalline Compound 1 is selected from (a) through (e): In some embodiments, the composition is characterized by having at least two properties: Form 3 of crystalline Compound 1 has at least three properties selected from (a) through (e). In some embodiments, Form 3 of crystalline Compound 1 is characterized by: (e) to (f) In one embodiment, Form 3 of crystalline Compound 1 is characterized as having properties (a) through (e). It is characterized by:

[0068] In some embodiments, Form 3 of crystalline Compound 1 is substantially similar to that shown in FIG. In some embodiments, the results are similar in X-ray powder diffraction (XRPD) patterns. Form 3 of crystalline compound 1 exhibits 7.5° (2-θ), 15.1° (2-θ), and 16.6° (2 -θ), 16.9°(2-θ), 17.2°(2-θ), 17.5°(2-θ), and The X-ray powder diffraction (XRPD) pattern had a characteristic peak at 18.7° (2-θ). In some embodiments, Form 3 of crystalline Compound 1 is as shown in FIG. have substantially similar thermogravimetric analysis (TGA) thermograms. Thus, Form 3 of crystalline Compound 1 exhibits a DSC thermogram substantially similar to that shown in FIG. In some embodiments, Form 3 of crystalline Compound 1 has an opening temperature of about 214°C. In some embodiments, the crystallization has a DSC thermogram with an endotherm at the onset of crystallization. Form 3 of Compound 1 is obtained from methyl t-butyl ether (TBME). In some embodiments, Form 3 of crystalline Compound 1 is solvated. In some embodiments, Form 3 of crystalline Compound 1 is unsolvated. Form 3 of crystalline Compound 1 is hydrated. In some embodiments, crystalline Compound 1 Form 3 of 1 is anhydrous.

[0069] 4-((4-(1-(tert-butyl)-1H-pyrazol-4-yl)pyridine- 2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octyl) Tan-1-yl)methyl)carbamoyl)cyclohexyl 3-hydroxyazetidin- Crystalline Form 4 of lance-1-carboxylate (Compound 1)

[0070] In some embodiments, 4-((4-(1-(tert-butyl)-1H-pyra 4-(4-methoxy-3-methylphenyl)-2-azol-4-yl)pyridin-2-yl) )bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl 3-Hydroxyazetidine-trans-1-carboxylate (Compound 1) is available in crystalline form. In some embodiments, crystalline Compound 1 has the following properties: (a) An X-ray powder diffraction (XRPD) pattern substantially the same as that shown in FIG. 10; (b) 5.4°(2-θ), 8.9°(2-θ), 9.9°(2-θ), 14.8°( 2-θ), 15.9°(2-θ), 16.2°(2-θ), 16.8°(2-θ), 17 Characteristic peaks at 0.5° (2-θ), 18.5° (2-θ), and 20.1° (2-θ) X-ray powder diffraction (XRPD) pattern with (c) Thermogravimetric analysis (TGA) substantially similar to that shown in Figure 11; (d) A DSC thermogram substantially similar to that shown in Figure 12; (e) a first endotherm with an onset at about 164°C and a second endotherm with an onset at about 209°C DSC thermogram, or (f) any combination thereof; The present invention is characterized by having at least one of the following:

[0071] In some embodiments, Form 4 of crystalline Compound 1 is selected from (a) through (e): In some embodiments, the composition is characterized by having at least two properties: Form 4 of crystalline Compound 1 has at least three properties selected from (a) through (e). In some embodiments, Form 4 of crystalline Compound 1 is characterized by: (e) to (f) In one embodiment, Form 4 of crystalline Compound 1 is characterized as having properties (a) through (e). It is characterized by:

[0072] In some embodiments, Form 4 of crystalline Compound 1 is substantially similar to that shown in FIG. In some embodiments, the results are similar in X-ray powder diffraction (XRPD) patterns. Form 4 of crystalline Compound 1 exhibits 5.4° (2-θ), 8.9° (2-θ), and 9.9° (2-θ) ), 14.8°(2-θ), 15.9°(2-θ), 16.2°(2-θ), 16.8° (2-θ), 17.5°(2-θ), 18.5°(2-θ), and 20.1°(2-θ ) have X-ray powder diffraction (XRPD) patterns with characteristic peaks. In an embodiment, Form 4 of crystalline Compound 1 has a thermal gradient substantially similar to that shown in FIG. In some embodiments, crystalline Compound 1 has a thermogravimetric analysis (TGA) thermogram. Form 4 of the present invention has a DSC thermogram substantially similar to that shown in Figure 9. In some embodiments, Form 4 of crystalline Compound 1 exhibits a first endotherm with an onset at about 164° C. The DSC thermogram shows a first endotherm with an onset of about 209°C and a second endotherm with an onset of about 209°C. In some embodiments, Form 4 of crystalline Compound 1 is solvated. In some embodiments, Form 4 of crystalline Compound 1 is unsolvated. Form 4 of crystalline Compound 1 is hydrated. In some embodiments, crystalline Compound 1 Form 4 of 1 is anhydrous.

[0073] Preparation of crystalline forms In some embodiments, 4-((4-(1-(tert-butyl)-1H-pyra 4-(4-methoxy-3-methylphenyl)-2-azol-4-yl)pyridin-2-yl) )bicyclo[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl Crystalline form of 3-hydroxyazetidine-trans-1-carboxylate (compound 1) is prepared as outlined in the Examples. The solvents, temperatures, and other conditions presented herein are Note that the reaction and drying conditions may vary.

[0074] In another embodiment, the crystalline Compound 1 is substantially pure. In the present invention, substantially pure crystalline Compound 1 is obtained by mixing amorphous Compound 1 and other crystalline forms. In certain embodiments, the pure crystalline form of Compound 1 is substantially free. The degree is approximately 95% or more, approximately 96% or more, approximately 97% or more, approximately 98% or more, approximately 98.5% or more, It is about 99% or more, about 99.5% or more, or about 99.8% or more.

[0075] compound 1 cocrystal Cocrystals are two or more nonvolatile compounds bound in a crystalline lattice by nonionic interactions. Pharmaceutical cocrystals are crystalline molecular complexes of a therapeutic compound, e.g., Compound 1, and Cocrystals of one or more non-volatile compounds. Volatile compounds are typically used as, for example, food additives, preservatives, pharmaceutical excipients, or other A In some embodiments, the PI is selected from non-toxic, pharmaceutically acceptable molecules such as PIs. and a mixture of Compound 1 or a pharmaceutically acceptable salt or solvate thereof with a pharmaceutically acceptable salt or solvate thereof. and at least one inactive ingredient selected from a carrier, a diluent, and an excipient. In some embodiments, cocrystals are prepared by solid-state grinding and solvent dropletization. In some embodiments, the co-crystals are prepared using solid-state methods such as grinding. In some embodiments, the co-immunoassay is prepared using high-throughput screening. The crystals are prepared using solution-based crystallization. Crystal formation affects solubility, dissolution rate, bioavailability, physical stability, and chemical stability. , leading to improved physical properties of the resulting solid form, such as flowability, friability, or compressibility. In some embodiments, compound 1 forms different co-crystals with different counter molecules, Some of these co-crystals exhibit enhanced solubility or stability. In this study, pharmaceutical cocrystals of Compound 1 were used to improve the bioavailability or stability profile of Compound 1. Increase your profile.

[0076] Suitable solvent Therapeutic products that can be administered to mammals, including humans, must be prepared in accordance with regulatory guidelines. Such government regulatory guidelines are based on Good Manufacturing Practices (GGP). This is called Good Manufacturing Practice (GMP). Guidelines may also be issued regarding acceptable contamination of active therapeutic agents, such as the amount of residual solvents in the final product. The preferred solvents are suitable for use in GMP facilities and are industrial grade. The solvent category is based on, for example, the "Registered Pharmaceuticals for Human Use" International Conference on Harmonization of Technical Requirements for rence on Harmonization of Technical Requ irements for Registration of Pharmaceuti "ICH Guidelines for Human Use" and "Impurities: Residual Solvents" Impurities: Guidelines for Residual Solvents), Q3C(R3), (November 2005)

[0077] Solvents are divided into three classes: Class 1 solvents are toxic and should be avoided. Class 2 solvents are solvents whose use is restricted during the manufacture of therapeutic drugs. Class 3 solvents are toxic and Class 3 solvents are solvents with low toxicity and low risk to human health. It has been shown to have low toxicity in acute or short-term tests and negative results in genotoxicity tests.

[0078] Class 1 solvents to avoid include benzene, carbon tetrachloride, 1,2 dichloroethane, 1 ,1-dichloroethene, and 1,1,1-trichloroethane.

[0079] Examples of Class 2 solvents include acetonitrile, chlorobenzene, chloroform, and cyclohexane. San, 1,2-dichloroethene, dichloromethane, 1,2-dimethoxyethane, N,N- Dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane, 2-ethoxy Ethanol, ethylene glycol, formamide, hexane, methanol, 2-methoxy Ethanol, methyl butyl ketone, methylcyclohexane, N-methylpyrrolidine, Tromethane, pyridine, sulfolane, tetralin, toluene, 1,1,2-trichloroethane There are ten and xylene.

[0080] Less toxic Class 3 solvents include acetic acid, acetone, anisole, 1-butanol, 2-methylpropanol, and 2-methylpropanol. -butanol, butyl acetate, methyl t-butyl ether (MTBE), cumene, dimethyl Sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane , isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ethyl ketone, methyl isobutyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, and tetraethanol Hydrofuran is an example.

[0081] Residual solvents in active pharmaceutical ingredients (API) come from the manufacturing of the API. Depending on the manufacturing technique, the solvent may not be completely removed. The choice of solvent can improve yield and determine properties such as crystalline morphology, purity, and solubility. Therefore, the solvent is an important parameter in the synthesis process. is.

[0082] In some embodiments, the composition comprising Compound 1 includes an organic solvent. In embodiments, the composition comprising Compound 1 contains a residual amount of organic solvent. In some embodiments, the organic solvent is a Class 3 solvent. In some embodiments, the composition comprises a residual amount of a Class 3 solvent. The solvents were acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, Methyl t-butyl ether, cumene, dimethyl sulfoxide, ethanol, ethyl acetate, Ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, vinegar Methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, methyl isobutyl ketone , 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2 -propanol, propyl acetate, and tetrahydrofuran. In some embodiments, Class 3 solvents include ethyl acetate, isopropyl acetate, tert-butyl acetate, ethyl acetate, methyl ... t-butyl methyl ether, heptane, isopropanol, and ethanol. can be.

[0083] Specific Terms Unless otherwise stated, the following terms used in this application have the definitions set forth below: The terms "including" and "include" and "including" Use of other forms such as "includes" and "included" The section headings used herein are for organizational purposes only and are not intended to be limiting. and should not be construed as limiting the subject matter described.

[0084] The term "acceptable" as used herein with respect to a formulation, composition, or ingredient means that the treatment will have no lasting adverse effect on the general health of the subject being treated. .

[0085] As used herein, the term "modulate" refers to directly altering the activity of a target. This means that the compound interacts with a target directly or indirectly, by way of example only, to enhance the activity of the target. inhibiting the activity of a target, limiting the activity of a target, or enhancing the activity of a target This includes extending the

[0086] As used herein, the term "modulator" refers to a compound that interacts directly or indirectly with a target. This refers to molecules that interact with each other. Interactions include agonists, partial agonists, inverse agonists, These interactions include interactions of antagonists, degraders, or combinations thereof. In some embodiments, the modulator is an agonist. .

[0087] As used herein, the terms "administer," "administering," "administration," and the like refer to a biological methods that can be used to enable delivery of a compound or composition to a desired site of therapeutic action. These methods include oral route, intraduodenal route, parenteral injection (intravenous, subcutaneous, including intraperitoneal, intramuscular, intravenous or infusion), topical and rectal administration, but Those skilled in the art will be familiar with administration techniques that can be used with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered intravenously. It is administered orally.

[0088] As used herein, the term "co-administration" and the like refers to the administration of selected therapeutic agents to a single patient. It is meant to encompass administration of drugs by the same or different routes or simultaneously or differently. The term "therapeutic regimen" is intended to include a therapeutic regimen administered over a period of time.

[0089] As used herein, the term "effective amount" or "therapeutically effective amount" refers to the amount of the disease being treated. or of an administered drug or compound that relieves to some extent one or more of the symptoms of a condition A sufficient amount of the drug, the result of which may include reduction and / or alleviation of the signs, symptoms, or causes of disease. These include the synthesis, synthesis of, or other desired modification of a biological system, e.g., for therapeutic use. An "effective amount" for purposes of this invention is the amount required to provide a clinically significant reduction in disease symptoms. The amount of a composition containing a compound disclosed herein. An "effective" amount is optionally determined using techniques, such as a dose escalation study.

[0090] As used herein, "enhance" or "enhance" The term "aging" refers to increasing or prolonging the potency or duration of a desired effect. Therefore, in regard to enhancing the effect of a therapeutic agent, "enhanced" means The term "g)" refers to a system that is significantly different in either potency or duration from other therapeutic agents. As used herein, an "enhancing-effective amount" refers to the ability to increase or prolong the effect of a desired An amount sufficient to enhance the effect of another therapeutic agent on a system.

[0091] As used herein, the term "pharmaceutical combination" refers to a mixture or administration of two or more active ingredients. means the product resulting from the combination, both fixed and non-fixed combinations of active ingredients The term "fixed combination" refers to a combination of active ingredients, e.g. Compound 1 or The pharmaceutically acceptable salt and the co-agent may both be administered to the patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredient is administered to a subject. component, e.g., Compound 1 or a pharmaceutically acceptable salt thereof, and an auxiliary agent, as separate entities. It is intended to be administered to a patient simultaneously, in parallel, or consecutively without a specific intervening time. Such administration provides effective levels of the two compounds in the patient's body. It also applies to cocktail therapy, for example the administration of three or more active ingredients.

[0092] The terms "kit" and "article of manufacture" are used synonymously.

[0093] The term "subject" or "patient" includes mammals. Examples of mammals include mammals Any member of the class Animal: i.e., humans, chimpanzees and other apes and rhinoceroses non-human primates such as the genus Pseudomonas aeruginosa, livestock such as cattle, horses, sheep, goats, and pigs, and rabbits, dogs, and cats. This includes domestic animals, laboratory animals including rodents such as rats, mice, and guinea pigs. In one embodiment, the mammal is a human.

[0094] As used herein, the terms "treat," "treating," or "treatment" mean Alleviating, reducing, or ameliorating at least one symptom of a disease or condition, and / or reducing additional symptoms Preventing, inhibiting a disease or condition, e.g., halting the progression of a disease or condition alleviating a disease or condition; causing regression of a disease or condition; or to alleviate a condition caused by, or be preventative and / or therapeutic This includes effectively arresting the symptoms of a disease or condition.

[0095] Pharmaceutical Composition In some embodiments, Compound 1 described herein is formulated into a pharmaceutical composition. A pharmaceutical composition is one or more compounds that facilitate the processing of an active compound into a pharmaceutical preparation. It is formulated in a conventional manner using a number of pharmaceutically acceptable inactive ingredients. The dosage will depend on the chosen route of administration. minton:The Science and Practice of Phar Macy, 19th ed. (Easton, Pa.: Mack Publishing Com pany, 1995), Hoover, John E., Remington's P. Pharmaceutical Sciences(Mack Publishing C o., Easton, Pennsylvania 1975), Liberman, H. Pharmaceutical Dosage by .A. and Lachman, L. Forms (Marcel Decker, New York, NY, 1980), and and Pharmaceutical Dosage Forms and Drug De livery Systems, 7th edition (Lippincott Williams&W ilkins, 1999), which is incorporated herein by reference for such disclosure. be absorbed.

[0096] In some embodiments, Compound 1 described herein is administered alone or in a pharmaceutical composition. It is administered in combination with a pharmaceutically acceptable carrier, excipient, or diluent in a Administration of Compound 1 and pharmaceutical compositions thereof as described herein provides for the delivery of the compound to the site of action. It can be affected by any method that allows for delivery. These methods include, but are not limited to: Not limited to, but includes enteral routes (oral, gastric or duodenal feeding tubes, rectal suppositories and including enemas), parenteral routes (injection or infusion, e.g., intra-arterial, intracardiac, intradermal, duodenal Intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural, and and subcutaneous), inhalation, transdermal, transmucosal, sublingual, buccal and topical (e.g., epidermal, dermal, enema) administration (eye drops, ear drops, intranasal, intravaginal), but the most suitable route is e.g. By way of example only, Compound 1 may be used in, for example, Local infusion, topical application such as a cream or ointment, injection, catheter, or implant Administration can also be localized to the area in need of treatment by The administration may be by direct injection into the site of the affected tissue or organ.

[0097] In some embodiments, pharmaceutical compositions of Compound 1 suitable for oral administration each comprise It may be presented as a powder or as discrete units such as capsules, cachets or tablets containing a predetermined amount of the active ingredient. or as granules, as a solution or suspension in an aqueous or non-aqueous liquid, or in an oil-in-water In some embodiments, the emulsion is provided as a water-in-oil liquid emulsion. In dosage form, the active ingredient is presented as a bolus, electuary or paste.

[0098] Orally available pharmaceutical compositions include tablets, push-fit gelatin capsules, and Soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be made without the use of binders, inert diluents, or lubricants, surfactants. or the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a dispersing agent. Molded tablets can be prepared by compressing the tablet in a suitable machine. It can be made by molding in a suitable machine a mixture of the powdered compound moistened with water. In some embodiments, the tablet provides a sustained or controlled release of the active ingredient therein. All oral administration The formulation must be in a dosage suitable for such administration. may contain fillers such as lactose, binders such as starch, and / or talc or stearyl alcohol. It contains the active ingredient mixed with a lubricating agent, such as magnesium phosphate, and optionally a stabilizer. In soft capsules, the active compounds can be coated with fatty oils, liquid paraffin, or It can be dissolved or suspended in a suitable liquid, such as liquid polyethylene glycol. In some embodiments, stabilizers are added. The dragee cores may be coated with a suitable coating. For this purpose, gum arabic, talc, polyvinylpyrrolidone, calcium carbonate, vopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solution, and using a concentrated sugar solution which may optionally contain a suitable organic solvent or solvent mixture. To identify or characterize different combinations of active compound doses. For this purpose, dyestuffs or pigments can be added to the tablets or dragee coatings.

[0099] In some embodiments, the pharmaceutical composition is administered by injection, e.g., by bolus injection or It is formulated for parenteral administration by continuous infusion. The formulation for injection is formulated in unit dosage form with the addition of a preservative. The compositions may be provided in oil-based or water-based formulations, for example in ampoules or multi-dose containers. The composition may take such forms as suspensions, solutions or emulsions in aqueous media, and may contain suspending agents, stabilizers and The compositions may contain formulating agents such as a dispersing agent and / or a dispersing agent. The compositions may be provided in small quantity containers, such as sealed ampoules and vials, and can be dispensed immediately prior to use. Requires only the addition of a bacterial liquid carrier, such as saline or sterile pyrogen-free water It can be stored in powder form or freeze-dried (lyophilized). and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

[0100] Pharmaceutical compositions for parenteral administration may contain antioxidants, buffers, bacteriostats, and other additives intended for formulation. Aqueous and non-aqueous (e.g., 100 mg / kg) solutions of the active compound may contain solutes that render them isotonic with the patient's blood. Sterile injection solutions (oil-based) and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils, such as sesame oil, ethyl oleate, or hexane. These include synthetic fatty acid esters such as glycols or triglycerides, or liposomes. Injection suspensions may be prepared with sodium carboxymethylcellulose, sorbitol, or dextrose. The suspension may contain a substance that increases the viscosity of the suspension, such as orchid. Contains suitable stabilizers or agents that increase the solubility of the compound and allow for the preparation of highly concentrated solutions. Good too.

[0101] For buccal or sublingual administration, the compositions may be administered in the form of tablets, lozenges, troches, or the like formulated in a conventional manner. Such compositions may be in the form of a gel, a sucrose, or a gel. The active ingredient may be contained in a flavored base such as cassia or tragacanth.

[0102] In addition to the ingredients specifically mentioned above, the compounds and compositions described herein may be used in conjunction with the formulation type in question. In consideration of the above, the composition may contain other agents conventional in the art, for example, It should be understood that the composition may also include flavoring agents.

[0103] Administration Methods and Treatment Regimen In one embodiment, Compound 1 as described herein or a pharmaceutically acceptable salt thereof for treating a disease or condition in a mammal that would benefit from the administration of an FXR agonist. The present invention relates to the preparation of a medicament for treating any of the diseases or conditions described herein. The method of treatment in a mammal in need thereof comprises administering to a mammal a compound of formula I described herein, is a pharmaceutically acceptable salt, active metabolite, prodrug, or pharmaceutically acceptable salt thereof. and administering to said mammal a therapeutically effective amount of a pharmaceutical composition comprising the solvate. nothing.

[0104] Disclosed herein are methods of administering an FXR agonist in combination with an additional therapeutic agent. In some embodiments, the additional therapeutic agent is a treatment for diabetes or a diabetes-related disorder or or condition, alcoholic or non-alcoholic liver disease, inflammation-related bowel conditions, or Includes therapeutic agents for the treatment of cell proliferative disorders.

[0105] In certain embodiments, compositions containing the compounds described herein are used for the prevention and / or treatment of In certain therapeutic applications, the compositions are administered to treat a disease or condition. in an amount sufficient to cure or at least partially arrest at least one symptom of the disease. An amount effective for this use is administered to a patient already suffering from a disease or condition. The severity and course of the condition, previous treatment, the patient's general health, weight, and response to medications, etc. A therapeutically effective amount may be determined through dose escalation and / or dose ranging clinical trials. Optionally determined by methods including, but not limited to, floor testing.

[0106] In prophylactic applications, compositions containing the compounds described herein are used to treat a particular disease, disorder, or condition. are administered to patients who are susceptible to or otherwise at risk for the condition. A prophylactically effective amount or dose is defined as a "prophylactically effective amount or dose." The amount of the drug that is effective for this use will depend on the patient's health condition, weight, etc. The appropriate amount will depend on the severity and course of the disease, disorder or condition, previous treatment, the patient's health status and Depending on the response to the medication and the judgment of the treating physician. Treatment is administered to breastfeeding patients who have previously experienced and are currently in remission of at least one symptom of the disease being treated. The animal is administered Compound 1 or a pharmaceutically acceptable salt thereof to prevent the recurrence of symptoms of the disease or condition. This includes administering a pharmaceutical composition containing an acceptable salt thereof.

[0107] In certain embodiments where the patient's condition does not improve, at the physician's discretion, the patient's illness or Compound 1 is administered chronically, i.e., to improve or control or limit the symptoms of the condition. , administered for an extended period of time, including for the patient's lifetime.

[0108] In certain embodiments where the patient's condition improves, the dose of the drug administered may be temporarily reduced. The drug is administered at a reduced dose or temporarily suspended for a period of time (i.e., a "drug holiday"). In embodiments, the length of the drug holiday period is between 2 days and 1 year, and by way of example only, 2 days , 3rd, 4th, 5th, 6th, 7th, 10th, 12th, 15th, 20th, 28th, or 2 Dose reduction during the drug holiday period may be, by way of example only, 10% to 100%. Examples include 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% and and 100%.

[0109] Once the patient's condition has improved, a maintenance dose is administered if necessary. The dosage or frequency of administration, or both, is adjusted as a function of the symptoms to determine the degree of improvement in the disease. However, in certain embodiments, Therefore, patients require intermittent treatment on a long-term basis upon recurrence of symptoms.

[0110] The amount of a given drug that corresponds to such an amount will vary depending on the particular compound, the condition and its severity, the treatment, and the dosage. Varies depending on factors such as the identity of the subject or host seeking treatment (e.g., weight, sex). However, the specific drug administered, the route of administration, and the type of treatment may nonetheless be varied. Determined according to the specific circumstances surrounding the case, including the condition and the subject or host being treated will be done.

[0111] However, in general, the dose used for adult treatment is typically 0. In one embodiment, the dosage used for the treatment of adults is in the range of 0.1 mg to 5000 mg. The amount is from about 1 mg to about 1000 mg per day. Doses may be administered in single or divided doses, simultaneously or at appropriate intervals, e.g., 2 doses per day. Conveniently, the dose may be administered in one, three, four or more sub-doses.

[0112] In one embodiment, Compound 1 as described herein or a pharmaceutically acceptable salt thereof A suitable daily dose is about 0.01 to about 50 mg per kg of body weight. In some cases, the daily dose or amount of active ingredient in the dosage form may vary depending on the individual treatment plan. Lower or higher than the ranges indicated herein, based on the variables. In this regard, the daily and unit dosages will depend on the activity of the compound used, the disease or condition to be treated, The dosage regimen will depend on the individual subject's needs, the severity of the disease or condition being treated, and the judgment of the practitioner. This may vary depending on many variables, including but not limited to:

[0113] The toxicity and therapeutic efficacy of such treatment regimens are evaluated by, but not limited to, LD 50 and E D 50 determined by standard pharmaceutical procedures in cell cultures or experimental animals, including the determination of The dose ratio between toxic and therapeutic effects is the therapeutic index, and the LD 50 and ED 50 Expressed as a ratio of In certain embodiments, data obtained from cell culture assays and animal studies a therapeutically effective daily dose range and / or therapeutically effective In some embodiments, the compounds described herein are used to formulate effective unit doses. The daily dose of the compound is the ED 50 The circulating concentration range includes In embodiments, the daily dose range and / or unit dose may vary depending on the dosage form and use. It will vary within this range depending on the route of administration chosen.

[0114] In a further embodiment of any of the foregoing aspects, an effective amount of a compound described herein 1 or a pharmaceutically acceptable salt thereof, (a) by systemically administering to a mammal, and / or (b) orally administered to a mammal, and / or (c) intravenously administered to a mammal, and and / or (d) by injection into a mammal, and / or (e) by topical administration to a mammal. and / or (f) administering non-systemically or locally to a mammal.

[0115] Further embodiments of any of the foregoing aspects include a single administration of an effective amount of Compound 1, This may involve (i) administering the compound once daily or (ii) administering the compound to the mammal multiple times daily. Further embodiments include administering

[0116] Further embodiments of any of the foregoing aspects include multiple administrations of an effective amount of Compound 1; This can include (i) administering the compound as a single dose, either continuously or intermittently; (ii) administering multiple doses of the compound; (iii) the compound is administered to the mammal every 8 hours; (iv) administering the compound to the mammal every 12 hours; (v) administering the compound every 24 hours. Further embodiments include administering to a mammal in a In this method, the administration of the compound is temporarily suspended or the amount of the compound administered is increased. At the end of the drug holiday, which includes a drug holiday during which the dose of the compound is temporarily reduced, administration of the compound is resumed. In one embodiment, the length of the drug holiday varies from 2 days to 1 year.

[0117] In some instances, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in combination with one or more other It is appropriate to administer the drug in combination with other therapeutic agents.

[0118] In one embodiment, the therapeutic efficacy of Compound 1 is enhanced by the administration of an adjuvant. (i.e., the adjuvant itself has minimal therapeutic effect, but when combined with another therapeutic agent, (When combined, this enhances the overall therapeutic effect on the patient.) Alternatively, several In some embodiments, the benefit experienced by a patient may be determined by administering one of the compounds described herein to a patient having a therapeutic benefit. The effect is increased by administering it with another drug (including a therapeutic regimen) that also has the same effect.

[0119] In one particular embodiment, Compound 1 or a pharmaceutically acceptable salt thereof is and a second therapeutic agent, wherein Compound 1 or a pharmaceutically acceptable salt thereof and a second therapeutic agent are co-administered. Therapeutic agents modulate different aspects of the disease, disorder or condition being treated, thereby This provides a greater overall benefit than administering either treatment alone. [Example]

[0120] List of Abbreviations In the foregoing description and throughout the description of the present invention, the following abbreviations are used unless otherwise indicated: It should be understood to have the following meanings: ACN or MeCN: acetonitrile Bn: Benzyl BOC or Boc:tert butylcarbamate t-butyl: tert-butyl Cy: Cyclohexyl DCE: dichloroethane (ClCH2CH2Cl) DCM: dichloromethane (CH2Cl2) DIPEA or DIEA: Diisopropylethylamine DMAP: 4-(N,N-dimethylamino)pyridine DMF: dimethylformamide DMA: N,N-dimethylacetamide DMSO: dimethyl sulfoxide equiv: equivalent amount Et: Ethyl Et2O: Diethyl ether EtOH: ethanol EtOAc: ethyl acetate HPLC: High-performance liquid chromatography Me: Methyl MeOH: Methanol MS: Mass spectrometry NMR: nuclear magnetic resonance RP HPLC: Reversed-phase high-pressure liquid chromatography T3P: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphospho Linane-2,4,6-trioxide TBME: Methyl tert-butyl ether TFA: Trifluoroacetic acid THF: tetrahydrofuran TLC: Thin Layer Chromatography

[0121] I. Chemical synthesis Unless otherwise stated, reagents and solvents were used as received from the supplier. For minute and / or oxygen-sensitive synthetic transformations, use anhydrous solvents and oven-dried glassware. The reaction times are approximate and not optimized. Unless otherwise specified, column chromatography and thin layer chromatography (TLC) It was carried out on silica gel.

[0122] Example 1: 4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octane Preparation of 1-carbaldehyde (Intermediate 1)

[0123] [ka]

[0124] Step 1: 8-(4-methoxy-3-methylphenyl)-1,4-dioxaspiro[4.5 ]Decan-8-ol Three batches were run in parallel: n-BuLi (762 mL, 1.90 mol, n- 2.5M in hexane) with 4-bromo-1-methoxy-2-methylbenzene (333g, To a solution of 1.66 mol) and dry THF (2 L) was added dropwise at -60°C under N2 for 1 hour. The reaction was stirred at -60 °C for 1 h and then added 1,4-dioxaspiro[4.5]deca A solution of thion-8-one (284.53 g, 1.82 mol) in dry THF (1 L) was The reaction was stirred at -60 °C for 1 h, then the three batches were added dropwise with saturated NH The mixture was poured into aqueous 4Cl (3 L). The mixture was extracted with EtOAc (5 L x 2). The combined organic layer was washed with brine (5 L), dried over Na2SO4, filtered, concentrated, and then The mixture was then triturated in n-hexane (1.2 L) at room temperature overnight. The mixture was filtered and the filter cake was Wash with cold n-hexane (200 mL × 2) and then vacuum dry to obtain 8-(4-methoxyphenyl)-2-(4-methyl-2-propanol). -3-methylphenyl)-1,4-dioxaspiro[4.5]decan-8-ol (11 00g, 82%) as a white solid. 1 H NMR (400 MHz, CDCl): δ7.30-7.20(m,2H),6.74(d,1H),4.02-3.87(m, 4H),3.78(s,3H),2.18(s,3H),2.15-2.00(m,4H ),1.82-1.73(m,2H),1.68-1.60(m,2H),1.48(s ,4H)1H).

[0125] Step 2: 8-allyl-8-(4-methoxy-3-methylphenyl)-1,4-dioxane pyro[4.5] decane Four batches were run in parallel: BF3·Et2O (376.95 g, 2.65 mo l) was reacted with 8-(4-methoxy-3-methylphenyl)-1,4-dioxaspiro[4.5 ]Decan-8-ol (275 g, 0.99 mol) and allyltrimethylsilane (18 A solution of 0.62 g (1.58 mol) and dry DCM (3 L) was heated at -65 °C under N2. The reaction mixture was stirred at -65°C for 1 hour, and then the four batches were carefully added with saturated NaHC The mixture was poured into an aqueous solution of O3 (10 L). The mixture was extracted with DCM (5 L x 3). The organic layer was washed with brine (5 L), dried over Na2SO4, filtered and concentrated to give 8- Allyl-8-(4-methoxy-3-methylphenyl)-1,4-dioxaspiro[4.5 ] Decane (1350 g) was obtained as a yellow oil. 1 H NMR (400 MHz, CDC) l3):δ7.17-7.01(m,2H),6.85-6.75(m,1H),5.5 3-5.37(m,1H),5.01-4.85(m,2H),3.99-3.87(m ,4H),3.82(s,3H),2.37-2.29(m,1H),2.28-2.2 1(m, 5H), 2.20-2.10(m, 2H), 1.82-1.71(m, 2H), 1.70-1.52(m, 3H).

[0126] Step 3: 4-Allyl-4-(4-methoxy-3-methylphenyl)cyclohexanone Three batches were run in parallel: water (450 mL), then formic acid (285.95 g, 5 0.95 mol) to 8-allyl-8-(4-methoxy-3-methylphenyl)-1,4- To a solution of dioxaspiro[4.5]decane (450 g) and THF (1.8 L) was added at room temperature. The reaction mixture was refluxed overnight, cooled to room temperature, and then three batches were added to saturated NaHCO The mixture was poured into aqueous 3 solution (3 L). The mixture was extracted with EA (3 L x 3). The combined organic layers was washed with brine (3 L), dried over Na2SO4, filtered, concentrated, and then evaporated onto silica Purification was performed by gel chromatography (petroleum ether / Et0Ac = 1 / 0 to 50 / 1). 4-allyl-4-(4-methoxy-3-methylphenyl)cyclohexanone (800 g, 69.3% over two steps) as a yellow oil. 1 H NMR (400 MHz, CD Cl3):δ7.16-7.06(m,2H),6.80-6.73(m,1H),5. 48-5.30(m,1H),4.96-4.79(m,2H),3.77(s,3H) ,2.48-2.35(m,2H),2.32-2.05(m,9H),1.89-1. 77(m,2H).

[0127] Step 4: 4-allyl-4-(4-methoxy-3-methylphenyl)cyclohexanecarbo Nitrile Three batches were run in parallel: t-BuOK (299.69 g, 2.67 mol) 4-allyl-4-(4-methoxy-3-methylphenyl)cyclohexanone (230 g, 890.25 mmol) and Tos-MIC (260.72 g, 1.34 mol) To a solution of DME (2 L) was added dropwise over 1 h at 0 °C under N2 (maintaining the internal temperature <5 °C). The mixture was stirred at room temperature for 2 hours, and then the three batches were washed with saturated aqueous NH4Cl ( The mixture was poured into 5 L of ethyl acetate. The mixture was extracted with EtOAc (5 L x 2). The combined organic layer was Wash with ethanol (5 L), dry with Na2SO4, filter, concentrate, and then load onto silica gel. Purification by chromatography (petroleum ether / EtOAc = 1 / 0 to 50 / 1) 4-Allyl-4-(4-methoxy-3-methylphenyl)cyclohexanecarbonitrile (508 g, 70.6%) was obtained as a yellow oil. 1 H NMR (400 MHz, CD Cl3):δ7.13-6.99(m,2H),6.83-6.75(m,1H),5. 51-5.31(m,1H),5.03-4.85(m,2H),3.84(s,3H) ,2.58-2.48(m, 1H),2.38-2.02(m, 7H),1.98-1. 79(m, 2H), 1.78-1.56(m, 3H), 1.54-1.40(m, 1H) .

[0128] Step 5: 4-(2,3-dihydroxypropyl)-4-(4-methoxy-3-methylphenyl)- (cyclohexanecarbonitrile) Three batches were run in parallel: NMO (242.66 g, 2.07 mol), then K2OsO4·2H2O (7.63 g, 20.71 mmol) was added to 4-allyl-4-(4 -methoxy-3-methylphenyl)cyclohexanecarbonitrile (1.86g, 690 A solution of 1.47 mmol) in acetone (2 L) and H2O (2.50 mL) was added at 0°C. The reaction was allowed to warm to room temperature and stirred for 2 hours. Three batches were added to a saturated aqueous solution of Na2SO3. (4 L), and then the mixture was extracted with EtOAc (3 L x 2). Wash with 3 L of lye, dry with Na2SO4, filter, concentrate, and then add silica gel Purify by chromatography (petroleum ether / EtOAc = 5 / 1 to 1 / 2) , 4-(2,3-dihydroxypropyl)-4-(4-methoxy-3-methylphenyl) Cyclohexanecarbonitrile (600 g, 95.4%) was obtained as a yellow oil. 1 H NMR(400MHz,CDCl3):δ7.21-7.01(m,2H),6.87 -6.74(m,1H),3.83(s,3H),3.65-3.49(m,1H),3 .35-3.17(m,2H),2.60-2.45(m,1H),2.41-2.11 (m,5H),2.01-1.81(m,4H),1.79-1.38(m,6H).

[0129] Step 6: 4-(4-methoxy-3-methylphenyl)-4-(2-oxoethyl)cyclo Hexanecarbonitrile Three batches were run in parallel: NaIO4 (169.20 g, 791.05 mmol); l) with 4-(2,3-dihydroxypropyl)-4-(4-methoxy-3-methylphenyl)- (cyclohexanecarbonitrile) (200 g, 659.21 mmol) and THF ( A solution of 2 L of ethanol and 1 L of H2O was added at 0 °C for 30 min (maintaining an internal temperature of <5 °C). The mixture was stirred at room temperature for 3 hours, and then poured in three batches into water (2 L). The mixture was extracted with EtOAc (2 L x 2). The combined organic layers were washed with brine (2 L). Wash, dry over Na2SO4, filter, and concentrate to give 4-(4-methoxy-3-methyl- (phenyl)-4-(2-oxoethyl)cyclohexanecarbonitrile (510 g) Obtained as an oil. 1H NMR(400MHz,CDCl3):δ9.43-9.22 (m,1H),7.20-6.99(m,2H),6.87-6.71(m,1H),3 .82(s,3H),2.63-2.48(m,2H),2.46-2.36(m,1H ),2.33-2.13(m,4H),2.02-1.71(m,5H),1.71-1 .57(m,2H).

[0130] Step 7: 4-(2-hydroxyethyl)-4-(4-methoxy-3-methylphenyl)silyl cyclohexanecarbonitrile Three batches were run in parallel: NaBH4 (35.55 g, 939.73 mmol) ) to 4-(4-methoxy-3-methylphenyl)-4-(2-oxoethyl)cyclohexane To a solution of xanthanecarbonitrile (170 g) and THF (1.7 L) was added at 0°C under N2. The mixture was stirred at room temperature for 3 hours, and then the three batches were poured into ice-cold water (3 L). The mixture was extracted with EtOAc (1.5 L x 2). The combined organic layers were washed with brine (2 L). Wash, dry over Na2SO4, filter, and concentrate to give 4-(2-hydroxyethyl)-4 -(4-Methoxy-3-methylphenyl)cyclohexanecarbonitrile (495 g) Obtained as a colorless oil. 1 H 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).

[0131] Step 8: 4-(2-bromoethyl)-4-(4-methoxy-3-methylphenyl)cyclohexane Hexanecarbonitrile Three batches were run in parallel: PPh3 (316.62 g, 1.21 mol) and D The solution was diluted with CM (1 L) and 4-(2-hydroxyethyl)-4-(4-methoxy-3-methyl- (ethyl-phenyl)cyclohexanecarbonitrile (165g) and CBr4 (300.2 A solution of 4 g (905.37 mmol) and DCM (1.5 L) was added at 0 °C under N2 for 1 h. The mixture was stirred at room temperature for 1.5 hours, combined with the other two batches, and concentrated. The crude product was triturated in MTBE (5 L) at room temperature overnight. The solid was filtered off and the cake was The filtrate was washed with BE (500 mL × 2), concentrated, and then purified by chromatography on silica gel. Purification with (petroleum ether / EtOAc = 30 / 1) gave 4-(2-bromoethyl) -4-(4-methoxy-3-methylphenyl)cyclohexanecarbonitrile (530g , 80%) as a white solid. 1 H 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,2H ), 1.99-1.79(m,3H), 1.77-1.45(m,3H).

[0132] Step 9: 4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octane 1-carbonitrile Three batches were run in parallel: LDA (420 mL, 840 mmol, 2 in THF) M) with 4-(2-bromoethyl)-4-(4-methoxy-3-methylphenyl)cyclohexane Hydrohexanecarbonitrile (143 g, 425.26 mmol) and HMPA (381. A solution of 1003 g (2.13 mol) and THF (1430 mL) was heated at -65 °C under N The mixture was stirred at -65 °C for 3 min, and then the three batches were added with saturated NH The mixture was poured into aqueous Cl solution (5 L). The mixture was extracted with EtOAc (3 L x 2). The organic layer was washed with water (3 L), washed with brine (3 L), dried over Na2SO4, and It was filtered, concentrated, and then triturated in EA:hexane (1:30, 775 mL) at room temperature overnight. The mixture was filtered and the filter cake was washed with EA:hexane (1:30, 150 mL). The product was washed and dried under vacuum to give 4-(4-methoxy-3-methylphenyl)bicyclo[2. 2.2]Octane-1-carbonitrile (240 g, 73%) was obtained as a yellow solid. 1 H NMR(400MHz,CDCl3):δ7.13-6.98(m,2H),6.8 3-6.73(m,1H),3.82(s,3H),2.22(s,3H),2.12- 1.98(m,6H),1.94-1.80(m,6H).

[0133] Step 10: 4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octane -1-Carboxaldehyde Three batches were run in parallel: DIBAL-H (1 MPhMe, 830 mL, 83 0 mmol) in DCM (1 L) b) [2.2.2]octane-1-carbonitrile (106 g, 415.11 mmol) The solution was added under N2 at -65°C. The mixture was stirred at -65°C for 1 hour and then divided into three batches. The mixture was poured into saturated aqueous NaK tartrate (3 L) and diluted with DCM (1.5 L). The mixture was stirred at room temperature for 3 hours. The organic layer was separated and the aqueous layer was extracted with DCM (2 L x 2). The organic layers were combined, washed with brine (3 L), dried over Na2SO4, filtered, and concentrated. 4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octane-1- Carbaldehyde (336 g) was obtained as a yellow solid. 1 H NMR (400 MHz, DM SO-d6):δ9.50-9.43(m,1H),7.11-7.00(m,2H), 6.83-6.79(m,1H),3.77-3.68(m,3H),2.18-2.0 2(m,3H),1.82-1.72(m,6H),1.71-1.60(m,6H).

[0134] Step 11: Hydroxy(4-(4-methoxy-3-methylphenyl)bicyclo[2.2. 2] Potassium octan-1-yl methanesulfonate Six batches were run in parallel: aqueous potassium metabisulfite (2 M, 54 mL, 1 08 mmol) in THF (300 mL) (2.2.2)octane-1-carbaldehyde (56 g) at 45°C. The mixture was stirred at 45°C for 3.5 hours, cooled to room temperature, and then The mixture was stirred at room temperature overnight. Six batches were filtered and the filter cake was washed with PE (400 mL). It was washed, dried in vacuo, and then purified by filtration to obtain potassium hydroxy(4-(4-methoxy-3-methylphenyl) ) bicyclo[2.2.2]octan-1-yl) methanesulfonate (381g, 2 steps) The compound was obtained as a white solid (81%). 1 H NMR (400 MHz, DMSO-d): 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).

[0135] Step 12: 4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octane -1-Carboxaldehyde Six batches were run in parallel: Na2CO3 (300 mL) was added to potassium-hydrochloride 4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octane-1 -yl) methanesulfonate (63.5 g, 167.76 mmol) and DCM (300 m The mixture was stirred for 1 hour and then divided into six batches. The mixture was poured into a mixture of DCM (1500 mL) and H2O (1500 mL). The aqueous phase was separated and extracted with DCM (1500 mL × 3). The combined organic layers were washed with brine (2 L ), dried over Na2SO4, filtered, and concentrated to give 4-(4-methoxy-3-methyl- (ethylphenyl)bicyclo[2.2.2]octane-1-carbaldehyde (240.3g, 92%) as a white solid. 1 H NMR (400MHz, DMSO-d): δ .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]+.

[0136] Example 2: 4-(1-(tert-butyl)-1H-pyrazol-4-yl)pyridine- Preparation of 2-amine (intermediate 2)

[0137] [ka]

[0138] 2-Methyltetrahydrofuran (10 mL), Pd(dppf)Cl2, followed by K2C Aqueous O3 solution (3 M, 10 mL, 30 mmol) was added to a 40 mL vial containing 4-bromopyridine. Lysine-2-amine (1.87 g, 10.8 mmol) and 1-(tert-butyl) -4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1H-pyrazole (2.50 g, 10.0 mmol) was added. The reaction was vacuum / N Degassed in two cycles and heated at 50° C. for 21 hours, then allowed to cool to room temperature. The organic layer was washed with saturated aqueous NaK tartrate (25 mL) and then brine (25 mL). The aqueous layer was back-extracted with 2-methyltetrahydrofuran (25 mL). The organics were dried (MgSO4), filtered, concentrated, and then dried under vacuum for 1 hour. A suspension of the crude material in MTBE (25 mL) was refluxed for 2 hours, cooled to room temperature overnight, and then filtered. The filter cake was washed with MTBE (2 × 3 mL) and then dried under vacuum to give 4-(1-(tert-butyl)-1H-pyrazol-4-yl)pyridin-2-amine (1.15g, 53%) 1 H NMR (400 MHz, DMSO-d): δ .27(s,1H), 7.86-7.82(m,2H),6.74(d,1H),6.6 1(s, 1H), 5.77(s, 2H), 1.54(s, 9H), LCMS:217.1 [M+H]+.

[0139] Example 3: trans-4-((tert-butyldimethylsilyl)oxy)cyclohexa Preparation of carboxylic acid (intermediate 3)

[0140] [ka]

[0141] Step 1: trans-tert-butyldimethylsilyl 4-((tert-butyldimethyl Silyl)oxy)cyclohexanecarboxylate tert-Butyldimethylsilyl chloride (31.47 g, 208.8 mmol), trans-4-hydroxy-cyclohexanecarboxylic acid (10.03 g, 69.57 mm ol), imidazole (18.96 g, 278.5 mmol), and DMF (140 mL ) at room temperature under N2 (the reaction exothermed to 32 °C). The reaction was allowed to stand at room temperature for 2 h. The organic layer was stirred and then diluted with diethyl ether (300 mL). Wash with 1 mL of 1N HCl, then 300 mL of brine), dry (Na2SO4) , filtered, and concentrated to give trans-tert-butyldimethylsilyl 4-((tert-butyl) (Dimethylsilyl)oxy)cyclohexanecarboxylate was obtained as a clear oil. (31.5g). 1 H NMR(400MHz,DMSO-d6):δ3.61-3. 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).

[0142] Step 2: trans-4-((tert-butyldimethylsilyl)oxy)cyclohexane Carboxylic Acid Potassium carbonate (58.01 g, 419.7 mmol) in H2O (300 mL) was added to trans-tert-butyldimethylsilyl 4-((tert-butyldimethylsilyl)o (oxy)cyclohexanecarboxylate (crude 31.5 g, 69.6 mmol) and ethanol The mixture was added to a mixture of alcohol (1000 mL) and THF (300 mL) at room temperature under N2. The reaction was stirred at room temperature for 3 hours, concentrated until 300 mL remained, and washed with brine (600 mL). The aqueous layer was diluted and then acidified to pH 2-3 with 20% NaHSO4 (550 mL). Extract with ethyl ether (800 mL). Wash the organic layer with (800 mL brine). , dried (Na2SO4), filtered, concentrated, and dried under high vacuum (to remove silanol by-products). (To remove the substance), trans-4-((tert-butyldimethylsilyl)oxy) Cyclohexanecarboxylic acid (17.3 g, 96% over two steps) was obtained as a white solid. 1 H NMR (400MHz, DMSO-d6): δ12.30 (brs, 1H), 3.59 -3.51(m,1H), 2.15-2.05(m,1H), 1.88-1.74(m, 4H),1.41-1.29(m,2H),1.28-1.16(m,2H),0.84 (s,9H),0.02(s,6H).

[0143] Example 4: 4-((4-(1-(tert-butyl)-1H-pyrazol-4-yl)pyrazole) Lysin-2-yl)((4-(4-methoxy-3-methylphenyl)bicyclo[2.2. 2]Octan-1-yl)methyl)carbamoyl)cyclohexyl 3-hydroxyazetyl Preparation of diazine-trans-1-carboxylate (compound 1)

[0144] [ka]

[0145] Step 1: 4-(1-(tert-butyl)-1H-pyrazol-4-yl)-N-((4 -(4-methoxy-3-methylphenyl)bicyclo[2.2.2]octan-1-yl) Methyl)pyridin-2-amine Intermediate 1 (1.0 eq) in methanol (7.5 vol) and acetic acid (0.33 eq) A mixture of Intermediate 2 (1.1 equiv.) was heated at 55° C. for at least 3 hours. was cooled to room temperature and 2-methylpyridine borane complex (1.0 equivalent) was added as a solid to at least The reaction was stirred at room temperature overnight and water (12.0 vol) was added over 20 min. The suspension was stirred for at least 2 hours. The solid was collected by filtration and diluted with water. / methanol (2:1) (2 × 1 volume), TBME (2 × 2 volumes), and heptane (2 × 2 volumes), dried on a rotary evaporator at 50 °C, and rt-butyl)-1H-pyrazol-4-yl)-N-((4-(4-methoxy-3-methyl) (methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)pyridin-2-a Got Min.

[0146] Steps 2 and 3: trans-N-(4-(1-(tert-butyl)-1H-pyrazole) -4-yl)pyridin-2-yl)-4-hydroxy-N-((4-(4-methoxy-3 -methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)cyclohexa cincarboxamide 4-(1-methyl-2-methyl-1,3-dichloromethane) in dichloromethane (7.5 vol) and triethylamine (4.0 eq.) -(tert-butyl)-1H-pyrazol-4-yl)-N-((4-(4-methoxy -3-methylphenyl)bicyclo[2.2.2]octan-1-yl)methyl)pyridine A mixture of 1.0 equiv. of 2-amine and 1.2 equiv. of intermediate 3 was added to dichloromethane at 0° C. A solution of T3P in methane (2.0 equiv.) was added over 0.5 h. The reaction mixture was allowed to warm to room temperature. The reaction mixture was cooled to 5°C and added water twice (0.0 The mixture was quenched by the portionwise addition of 100 ml of ethanol (5.5 vol and 6.0 vol). The mixture was heated and stirred for at least 2 hours. The organic layer was collected and washed with water. The dichloromethane solvent was removed. Displaced in vacuo with 2-methyltetrahydrofuran (5.4 vol). Methanol (2. 4 vol) and water (2 vol) were added to the solution, followed by aqueous HCl (32%) (1.9 equiv. ) was added. The reaction mixture was stirred at room temperature for at least 2 hours. The mixture was added with 9.5% NaH Aqueous CO3 (4 volumes) was added. The organic layer was collected, washed with brine and It was dried and filtered through Celite. The filtrate was concentrated in vacuo and TBME (9 vol) was added. The solid was collected by filtration, washed with TBME and heptane, and dried in vacuo at 60°C. , trans-N-(4-(1-(tert-butyl)-1H-pyrazol-4-yl)pyrazole Lysin-2-yl)-4-hydroxy-N-((4-(4-methoxy-3-methylphenyl) (I)bicyclo[2.2.2]octan-1-yl)methyl)cyclohexanecarboxamide I got the Do.

[0147] Step 4: 4-((4-(1-(tert-butyl)-1H-pyrazol-4-yl)pyrazole 4-(4-methoxy-3-methylphenyl)bicyclo[2.2.2 ]octan-1-yl)methyl)carbamoyl)cyclohexyl 3-hydroxyazetidinyl thiamin-trans-1-carboxylate (compound 1) trans-N-(4-(1-(tert-butyl)) -1H-pyrazol-4-yl)pyridin-2-yl)-4-hydroxy-N-((4- (4-Methoxy)-3-methylphenyl)bicyclo[2.2.2]octan-1-yl A solution of 1,1'-carbonyldiimidazole in methylcyclohexanecarboxamide (1.5 eq.) was added. The mixture was stirred at room temperature for at least 3.5 hours. Thiazetidine hydrochloride (3.0 equiv.) and then iPr2NEt (7.0 equiv.) were added to this at room temperature. The reaction mixture was stirred at room temperature for at least 2.5 hours. The reaction mixture was 4.5% The mixture was quenched with aqueous NaHCO3 (6.0 vol). The organic layer was collected and the aqueous layer was diluted with dichloromethane. The mixture was extracted once with methanol (2.0 vol). Methanol (0.8 vol) was added and the combined organic layer was The layer was washed twice with 20% NH4Cl solution (4.0 vol) and twice with water (4.0 vol). The organic layer was dried (Na2SO4) and the dichloromethane solvent was exchanged for ethyl acetate (4 volumes). Heptane was added slowly (4 volumes). The crude product was collected by filtration and diluted with ethyl acetate: The crude product was washed with heptane (1:1). The crude product was dried under vacuum at 55°C. The crude product was then purified by ethyl acetate. The product was purified by hot slurry in ethanol (5 volumes) and collected by filtration. The product was washed with ethyl acetate. , and dried under vacuum at 55°C to give 4-((4-(1-(tert-butyl)-1H-pyrazole -4-yl)pyridin-2-yl)((4-(4-methoxy-3-methylphenyl)bis( Chloro[2.2.2]octan-1-yl)methyl)carbamoyl)cyclohexyl 3-hydroxybenzoate Hydroxazetidine-trans-1-carboxylate (Compound 1, Form 1) was obtained.

[0148] II. Morphological characterization Example 5: X-ray powder diffraction (XRPD) Stoe Stadi PX-ray powder diffractometer Stoe Stadi P, Cu-Kal radiation equipped with MYTHEN 1K detector Standard measurement conditions: transmission type, 40kV and 40mA tube power supply, curved Ge monochromator rometer, 0.02°² step size, 12 sec or 48 sec step time, 1.5~ 50.5°2q scan range, detection mode: step scan, 1°2q detector step Standard sample preparation: 10-20 mg of sample is placed on two acetate foils, Myla Sample holder: Stoe permeable foil or Kapton foil placed between Through-type sample holder, the sample was rotated during the measurement.

[0149] XRPD analysis of Form 1 of Compound 1 (Figure 1) showed that Form 1 exhibited peaks of 7.4° (2-θ), 8.4 °(2-θ), 14.6°(2-θ), 15.4°(2-θ), 16.8°(2-θ), 17.0°(2-θ), 17.3°(2-θ), 17.6°(2-θ), 18.9°(2 -θ) and 19.3° (2-θ), indicating that it is crystalline. Ta.

[0150] XRPD analysis of Form 2 of Compound 1 (Figure 4) shows that Form 2 has a 2-θ angle of 8.5°, 12. 8°(2-θ), 13.4°(2-θ), 16.2°(2-θ), 17.0°(2-θ) , characteristic of 18.8°(2-θ), 19.5°(2-θ), and 20.5°(2-θ) It was shown to be crystalline with distinct peaks.

[0151] XRPD analysis of Form 3 of Compound 1 (Figure 7) shows that Form 3 has a 2-θ angle of 7.5°, 15. 1°(2-θ), 16.6°(2-θ), 16.9°(2-θ), 17.2°(2-θ) , 17.5°(2-θ), and 18.7°(2-θ) It was shown that

[0152] XRPD analysis of Form 4 of Compound 1 (Figure 10) showed that Form 4 exhibited a 5.4° (2-θ), 8. 9°(2-θ), 9.9°(2-θ), 14.8°(2-θ), 15.9°(2-θ), 16.2°(2-θ), 16.8°(2-θ), 17.5°(2-θ), 18.5°(2 -θ) and 20.1° (2-θ), indicating that it is crystalline. Ta.

[0153] Example 6: Thermogravimetric Analysis (TGA) TGA TG-FTIR is a Bruker FT-IR Spectrometer Netzsch Thermo-Microbalance connected to IFS 28 The measurements were carried out in a nitrogen atmosphere with heating rates ranging from 25°C to 300°C. The temperature was increased to 10°C / min in a room temperature environment using an aluminum crucible equipped with a micro-pinhole. was done.

[0154] The TGA of Form 1 of Compound 1 (Figure 2) showed a 0.14% increase from the start of the experiment up to about 100°C. A second mass loss of 0.43% was attributed to sample decomposition (approximately It was observed from 260°C onset.

[0155] The TGA of Form 2 of Compound 1 (FIG. 5) showed a 0.05% increase from the start of the experiment up to about 100°C. A second mass loss of 0.59% was attributed to sample decomposition (approximately It was observed from 250°C onwards.

[0156] TGA of Form 3 of Compound 1 (Figure 8) showed a small mass loss of 0.59%, corresponding to TBME. A second mass loss of 0.42% indicated the decomposition of the sample (approximately 275°C). This was observed from the start of

[0157] The TGA of Form 4 of Compound 1 (Figure 11) shows only 0.36% water starting at approximately 100°C. A second mass loss of 0.91% was observed due to sample decomposition (starting at approximately 250 °C). It has been observed since the beginning.

[0158] Example 7: Differential Scanning Calorimetry (DSC) DSC differential scanning calorimetry was performed on a TA Instruments DSCQ2000. Hermetically sealed gold crucibles or hermetically sealed aluminum Tzero crucibles The heating rate was 10°C per minute.

[0159] DSC analysis of Form 1 of Compound 1 (Figure 3) shows an onset of about 213°C and a peak at about 215°C. The compound exhibited a sharp melting endotherm with

[0160] DSC analysis of Form 2 of Compound 1 (FIG. 6) shows an onset of about 212° C. and a peak at about 214° C. The compound exhibited a sharp melting endotherm with

[0161] DSC analysis of Form 3 of Compound 1 (FIG. 9) shows an onset of about 214° C. and a peak at about 216° C. The compound exhibited a sharp melting endotherm with

[0162] DSC analysis of Form 4 of Compound 1 (FIG. 12) shows an endotherm at about 164° C. and an endotherm at about 209° C. It showed a second endotherm onset.

[0163] Example 8: Dynamic Vapor Sorption (DVS) DVS Intrinsic Control Software v1.0.1.2 (or SMS DVS Intrinsic Moisture Sorption Controlled by v1.0.1.3 Sorption isotherms were obtained using a spectrometer. The sample temperature was maintained at 25°C by instrument control. Humidity was achieved by mixing dry and moist nitrogen streams at a total flow rate of 200 ml / min. Relative humidity (RH) was controlled by a calibrated Rotro Measured by a nic probe (dynamic range 1.0-100% RH). %R The weight change of the sample (mass relaxation) as a function of H was constantly monitored with a microbalance (accuracy ±0.05). .005mg).

[0164] DVS analysis of Form 1 of Compound 1 (Figure 13) showed that the material was slightly hygroscopic and had a 95% R The sample after DVS showed a water content of 1.2%. No significant changes were observed.

[0165] DVS analysis of Form 2 of Compound 1 (Figure 14) showed that the material was slightly hygroscopic, with a 95% R The sample after DVS showed a water content of 1.0%. No significant changes were observed.

[0166] DVS analysis of Form 3 of Compound 1 (Figure 15) showed that the material was slightly hygroscopic, with a 95% R The sample after DVS showed a water content of 1.2%. No significant changes were observed.

[0167] DVS analysis of Form 4 of Compound 1 (Figure 16) showed that the material was slightly hygroscopic, with a 95% R The sample after DVS showed a water content of 1.9%. No significant changes were observed.

[0168] III. Crystallization Experiments Example 9: Suspension equilibrium experiments In the first series of experiments, amorphous compound 1 was dissolved in acetonitrile, ethanol, and HCl at room temperature. , methanol, 2-propanol, ethyl acetate, ethanol / heptane (1:1 v / v) Each suspension was suspended in either acetone or acetonitrile / water (1:2 v / v). The solid from the solution was collected by filtration and air-dried at room temperature. The solid was then vacuum-dried (approximately 20 min). (Rival, 80°C, overnight). The solid from each suspension gave Form 1 of crystalline Compound 1.

[0169] In another experiment, amorphous compound 1 (1.0 g) was dissolved in 5.0 mL of ethyl acetate / water at room temperature. (97:3 v / v) and heated to 50° C. The solution was stirred at 50° C. to obtain the compound 1 in the form After cooling the suspension to room temperature, it was filtered and centrifuged. The crystals were dried in air at rt and then vacuum dried at 80°C to give Form 2 of crystalline Compound 1.

[0170] In another experiment, amorphous compound 1 was suspended in TBME at room temperature. The solid was collected by filtration. The solid was then dried under vacuum at 80°C to obtain Form 3 of crystalline Compound 1. Ta.

[0171] In another experiment, amorphous Compound 1 was suspended in TBME at room temperature. Form 3 was seeded, followed by suspension equilibration for 2 hours. The suspension was then stirred for 4 days. The crystalline Compound 1 form was recovered by filtration, air-dried at room temperature, and then dried under vacuum at 80°C. I got 4.

[0172] IV. Compound 1FXR activity Example 10: In vitro FXR assay (TK) sowing CV-1 was cultured in a T175 flask containing DMEM + 10% charcoal-stripped FBS at 200°C. Seed at a density of 0,000 cells and incubate at 37°C, 5% CO for 18 hours (O / N). did.

[0173] Transfection After 18 hours of incubation, the medium in the T175 flask was replaced with fresh DMEM + 10% The serum was replaced with charcoal-stripped serum. MEM (Life Technologies, catalog number 31985-062) Expression plugs for hFXR, hRXR, TK-ECRE-luc, and pCMX-YFP The tube was then vortexed briefly and incubated at room temperature for 5 minutes. The transfection reagent (X-tremeGENE HP from Roche) was used. , Catalog No. 06 366 236 001) into vortexed OptiMEM The mixture was added to the plasmid and incubated at room temperature for 20 minutes. The transfection reagent / DNA mixture complex was added to the cells in the T175 flask. The cells were then incubated at 37°C in 5% CO2 for 18 hours (O / N).

[0174] Addition of Compound 1 Compound 1 was serially diluted in DMSO and added to the transfected CV-1 cells. The cells were then incubated for 18 hours. The next day, the cells were lysed and examined for luminescence. Compound 1 TK hFXR:EC 50 ≦0.01 μM.

Claims

1. A crystal 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, having the following properties: (a) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 8.5° (2-θ), 12.8° (2-θ), 13.4° (2-θ), 16.2° (2-θ), 17.0° (2-θ), 18.8° (2-θ), 19.5° (2-θ), and 20.5° (2-θ); or (b) DSC thermogram with an endotherm onset at approximately 212°C; The crystal is Form 2 having at least one of:

2. 2. The crystal of claim 1, wherein the crystal has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 8.5° (2-θ), 12.8° (2-θ), 13.4° (2-θ), 16.2° (2-θ), 17.0° (2-θ), 18.8° (2-θ), 19.5° (2-θ), and 20.5° (2-θ).

3. 2. The crystal of claim 1, wherein the crystal has a DSC thermogram with an endotherm with an onset of about 212°C.

4. A crystal 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, having the following properties: (a) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 7.5° (2-θ), 15.1° (2-θ), 16.6° (2-θ), 16.9° (2-θ), 17.2° (2-θ), 17.5° (2-θ), and 18.7° (2-θ); or (b) DSC thermogram with an endotherm onset at approximately 214°C; The crystal is Form 3 having at least one of:

5. 5. The crystal of claim 4, wherein the crystal has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 7.5° (2-θ), 15.1° (2-θ), 16.6° (2-θ), 16.9° (2-θ), 17.2° (2-θ), 17.5° (2-θ), and 18.7° (2-θ).

6. 5. The crystal of claim 4, wherein the crystal has a DSC thermogram with an endotherm with an onset of about 214°C.

7. A crystal 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, having the following properties: (a) an X-ray powder diffraction (XRPD) pattern having characteristic peaks at 5.4° (2-θ), 8.9° (2-θ), 9.9° (2-θ), 14.8° (2-θ), 15.9° (2-θ), 16.2° (2-θ), 16.8° (2-θ), 17.5° (2-θ), 18.5° (2-θ), and 20.1° (2-θ); or (b) a DSC thermogram with a first endotherm with an onset at about 164°C and a second endotherm with an onset at about 209°C; The crystal is Form 4 having at least one of:

8. 8. The crystal of claim 7, wherein the crystal has an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 5.4° (2-θ), 8.9° (2-θ), 9.9° (2-θ), 14.8° (2-θ), 15.9° (2-θ), 16.2° (2-θ), 16.8° (2-θ), 17.5° (2-θ), 18.5° (2-θ), and 20.1° (2-θ).

9. 8. The crystal of claim 7, wherein the crystal has a DSC thermogram with a first endotherm with an onset at about 164°C and a second endotherm with an onset at about 209°C.

10. A pharmaceutical composition comprising the crystal according to any one of claims 1 to 9 and at least one inactive ingredient selected from pharmaceutically acceptable carriers, diluents and excipients.

11. A crystal according to any one of claims 1 to 9 or a pharmaceutical composition according to claim 10 for treating or preventing a gastrointestinal disease or condition in a mammal.

12. 12. The crystal or pharmaceutical composition of claim 11, wherein the gastrointestinal disease or condition is necrotizing enterocolitis, gastritis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, irritable bowel syndrome, gastroenteritis, radiation-induced enterocolitis, pseudomembranous colitis, chemotherapy-induced enterocolitis, 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.

13. 12. The crystal or pharmaceutical composition of claim 11, wherein the gastrointestinal disease or condition is irritable bowel syndrome with diarrhea (IBS-D), irritable bowel syndrome with constipation (IBS-C), mixed IBS (IBS-M), undifferentiated IBS (IBS-U), or bile acid diarrhea (BAD).

14. The crystal or pharmaceutical composition of claim 11, wherein the gastrointestinal disease or condition is Crohn's disease.

15. The crystal or pharmaceutical composition of claim 11, wherein the gastrointestinal disease or condition is ulcerative colitis.

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