Treatment of type 2 diabetes or obesity or overweight using 2-[(4-{6-[(4-cyano-2-fluorobenzyl)oxy]pyridin-2-yl}piperidin-1-yl)methyl]-1-[(2S)-oxetan-2-ylmethyl]-1h-benzimidazole-6-carboxylic acid or pharmaceutical salt thereof

Abstract

To provide required safe and effective treatment for cardiovascular metabolism and related diseases such as T2DM, obesity and overweight.SOLUTION: The invention provides a method for treating T2DM, obesity or overweight, or for controlling weight by administering, twice a day, a pharmaceutical composition in an oral dosage form to a mammal (e.g., human) in need thereof, where the pharmaceutical composition comprises 2-[(4-{6-[(4-cyano-2-fluorobenzyl)oxy]pyridin-2-yl}piperidin-1-yl)methyl]-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid or a pharmaceutical salt thereof (e.g., tris salt thereof). Further, the invention provides an oral composition / formulation for the therapeutic method disclosed herein.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention provides methods for treating type 2 diabetes mellitus, obesity, or overweight, or for controlling weight management, by administering twice daily to a mammal (e.g., a human) in need thereof a pharmaceutical composition in an oral dosage form, the pharmaceutical composition comprising 2-[(4-{6-[(4-cyano-2-fluorobenzyl)oxy]pyridin-2-yl}piperidin-1-yl)methyl]-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid or a pharmaceutical salt thereof (e.g., the 2-amino-2-(hydroxymethyl)propane-1,3-diol salt thereof, also known as the Tris salt thereof). Additionally, the present invention also provides oral compositions / formulations for the therapeutic methods described herein. [Background technology]

[0002] Diabetes mellitus (DM) is a significant public health concern due to its increasing prevalence and associated health risks. The disease is characterized by high blood glucose levels resulting from defects in insulin production, insulin action, or both. Two major forms of diabetes mellitus are identified: type 1 and type 2. Type 1 diabetes mellitus (T1DM) develops when the body's immune system destroys pancreatic beta cells, the only cells in the body that produce the insulin hormone that regulates blood glucose. Patients with type 1 diabetes must receive insulin via injections or a pump to survive. Type 2 diabetes mellitus (commonly referred to as T2DM) typically results from insulin resistance and insufficient insulin production to maintain acceptable glucose levels.

[0003] Currently, various pharmacological approaches are available to treat hyperglycemia in T2DM (Hampp, C. et al., Use of Antidiabetic Drugs in the US, 2003-2012, Diabetes Care 2014, 37, 1367-1374). These approaches can be grouped into six major classes, each acting by a different primary mechanism: insulin secretagogues, biguanides, alpha-glucosidase inhibitors, thiazolidinediones (TZDs), insulin, and sodium-glucose-linked transporter cotransporter 2 (SGLT2) inhibitors. (A) Insulin secretagogues include sulfonylureas (e.g., glipizide, glimepiride, glyburide), meglitinides (e.g., nateglidine, repaglinide), dipeptidyl peptidase IV (DPP-IV) inhibitors (e.g., sitagliptin, vildagliptin, alogliptin, dutogliptin, linagliptin, saxogliptin), and glucagon-like peptide 1 receptor (GLP-1R) agonists (e.g., liraglutide, albiglutide, exenatide, lixisenatide, dulaglutide, semaglutide), which act on pancreatic beta cells to enhance insulin secretion. Sulfonylureas and meglitinides have limited efficacy and tolerability, cause weight gain, and often induce hypoglycemia. DPP-IV inhibitors have limited effectiveness. Marketed GLP-1R agonists are peptides administered primarily by subcutaneous injection. Liraglutide has additionally been approved for the treatment of obesity. (B) Biguanides (e.g., metformin) are thought to act primarily by reducing hepatic glucose production. Biguanides often cause gastrointestinal upset and lactic acidosis, further limiting their use. (C) Alpha-glucosidase inhibitors (e.g., acarbose) reduce intestinal glucose absorption. These agents often cause gastrointestinal upset and / or have limited effectiveness.(D) Thiazolidinediones (e.g., pioglitazone, rosiglitazone) act on specific receptors (peroxisome proliferator-activated receptor gamma) in the liver, muscle, and adipose tissue. They regulate lipid metabolism and subsequently enhance the response of these tissues to insulin action. Frequent use of these drugs can lead to weight gain and can induce edema and anemia. (E) Insulin is used alone or in combination with the above drugs in more severe cases; frequent use can lead to weight gain and is associated with the risk of hypoglycemia. (F) Sodium-glucose-linked transporter cotransporter 2 (SGLT2) inhibitors (e.g., dapagliflozin, empagliflozin, canagliflozin, ertugliflozin) inhibit glucose reabsorption in the kidney, thereby lowering blood glucose levels. This emerging class of drugs can be associated with ketoacidosis and urinary tract infections.

[0004] However, drugs, with the exception of GLP-1R agonists and SGLT2 inhibitors, have limited efficacy and do not address the most important problem: declining beta-cell function and associated obesity.

[0005] Excessive fat storage can impair movement, flexibility, and alter the body's appearance. Both overweight and obesity can be associated with or cause health problems.

[0006] Obesity is a highly prevalent chronic disease in modern society and is associated with numerous medical problems, including hypertension, hypercholesterolemia, and coronary heart disease. Obesity is also strongly correlated with T2DM and insulin resistance, which is generally accompanied by hyperinsulinemia, hyperglycemia, or both. Additionally, T2DM is associated with a two- to four-fold increased risk of coronary artery disease. Currently, the only highly effective treatment for obesity is bariatric surgery, which is invasive and expensive. Pharmacological interventions are generally less effective and associated with side effects. Therefore, there is a clear need for more effective pharmacological interventions with fewer side effects and easier administration.

[0007] Although T2DM is most commonly associated with hyperglycemia and insulin resistance, other diseases, conditions, symptoms, and complications associated with T2DM include diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, obesity, dyslipidemia, hypertension, hyperinsulinemia, and increased risk of nonalcoholic fatty liver disease (NAFLD), cardiovascular disease, and cancer.

[0008] NAFLD is a hepatic manifestation of metabolic syndrome and is a spectrum of liver conditions including steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and ultimately hepatocellular carcinoma. NAFLD and NASH are considered the major fatty liver diseases because they account for the highest percentage of individuals with elevated liver lipids. The severity of NAFLD / NASH is based on the presence of lipids, inflammatory cell infiltrates, hepatocyte ballooning, and the degree of fibrosis. Although not all individuals with steatosis progress to NASH, a significant proportion do.

[0009] GLP-1 is a 30-amino acid incretin hormone secreted by L-cells in the intestine in response to food ingestion. GLP-1 has been shown to stimulate insulin secretion in a physiological, glucose-dependent manner, decrease glucagon secretion, inhibit gastric emptying, reduce appetite, and stimulate beta-cell proliferation. In preclinical studies, GLP-1 promotes continued beta-cell responsiveness by stimulating the transcription of genes important for glucose-dependent insulin secretion and promoting beta-cell neogenesis (Meier et al., Biodrugs. 2003;17(2):93-102).

[0010] In healthy individuals, GLP-1 plays a key role in regulating postprandial blood glucose levels by stimulating glucose-dependent insulin secretion by the pancreas, resulting in increased peripheral glucose absorption. GLP-1 also suppresses glucagon secretion and reduces hepatic glucose output. In addition, GLP-1 slows gastric emptying and small intestinal motility, slowing food absorption. In patients with T2DM, the normal postprandial rise in GLP-1 is absent or attenuated (Vilsboll T et al., Diabetes. 2001.50;609-613).

[0011] Holst (Physiol.Rev.2007, 87, 1409) and Meier (Nat.Rev.Endocrinol.2012, 8, 728) have described that GLP-1 receptor agonists, such as GLP-1, liraglutide, and exendin-4, exhibit three major pharmacological activities that improve glycemic control in patients with T2DM by lowering fasting and postprandial glucose (FPG and PPG): (i) increasing glucose-dependent insulin secretion (improving phases 1 and 2), (ii) glucagon suppression under hyperglycemic conditions, and (iii) slowing gastric emptying, which slows the absorption of meal-derived glucose. [Prior art documents] [Patent documents]

[0012] [Patent Document 1] U.S. Patent No. 10,208,019 [Patent Document 2] International Application No. PCT / IB2011 / 054119 [Patent Document 3] U.S. Patent No. 8,859,577 [Patent Document 4] International PCT Application No. PCT / IB2018 / 058966 [Patent Document 5] U.S. Patent No. 10,071,992 [Patent Document 6] U.S. Patent No. 9,809,579 [Patent Document 7] U.S. Patent No. 9,150,568 [Patent Document 8] U.S. Patent No. 4,485,045 [Patent Document 9] U.S. Patent No. 5,013,556 [Patent Document 10] U.S. Patent No. 3,773,919 [Non-patent literature]

[0013] [Non-Patent Document 1] Hampp, C. et al., Use of Antidiabetic Drugs in the US, 2003~2012, Diabetes Care 2014, 37, 1367~1374 [Non-patent document 2] Meier et al., Biodrugs.2003;17(2):93-102 [Non-patent document 3] Vilsboll T et al., Diabetes.2001.50;609-613 [Non-patent document 4] Holst(Physiol.Rev.2007, 87, 1409) [Non-patent document 5] Meier (Nat.Rev.Endocrinol.2012, 8, 728) [Non-patent document 6] European Pharmacopeia 6.0, Part 01 / 2008:1502 [Non-Patent Document 7] Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use (Wiley-VCH, 2002) [Non-patent document 8] Polymorphism in Pharmaceutical Solids by KR Morris (ed. HG Brittain, Marcel Dekker, 1995) [Non-Patent Document 9] O. Almarsson and M.J. Zaworotko, Chem Commun, 17, 1889–1896 (2004) [Non-Patent Document 10] Haleblian, J Pharm Sci, 64(8), 1269–1288 (August 1975) [Non-Patent Document 11] Crystals and the Polarizing Microscope, 4th ed., by N.H. Hartshorne and A. Stuart (Edward Arnold, 1970) [Non-Patent Document 12] ACLMCarvaho et al., Int J Mol Sci 29682~29716 (2015) [Non-Patent Document 13] Smith, Roger M., Loughborough University, Loughborough, UK, Chromatographic Science Series (1998), 75 (SFC with Packed Columns), pp. 223-249 [Non-Patent Document 14] Stereochemistry of Organic Compounds by E.L. Liel and S.H. Wilen (Wiley, 1994) [Non-Patent Document 15] Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 1975 [Non-Patent Document 16] Liberman et al., eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980 [Non-Patent Document 17] Kibbe et al., eds., Handbook of Pharmaceutical Excipients (3rd ed.), American Pharmaceutical Association, Washington, 1999 [Non-Patent Document 18] Remington, The Science and Practice of Pharmacy, 20th edition, Mack Publishing (2000). Summary of the Invention [Problem to be solved by the invention]

[0014] There remains a need for safe and effective treatments for cardiometabolic and related diseases, such as T2DM, obesity, and overweight.

[0015] 2-[(4-{6-[(4-cyano-2-fluorobenzyl)oxy]pyridin-2-yl}piperidin-1-yl)methyl]-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid or a pharmaceutical salt thereof (e.g., its 2-amino-2-(hydroxymethyl)propane-1,3-diol salt, also known as its Tris salt or its tris(hydroxyethyl)methylamine salt) is a GLP-1R agonist described in U.S. Pat. No. 10,208,019 (see Example 4A-01 of this patent), which is incorporated herein by reference in its entirety for all purposes.

[0016] [ka] 2-[(4-{6-[(4-cyano-2-fluorobenzyl)oxy]pyridin-2-yl}piperidin-1-yl)methyl]-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid ("Compound 1")

[0017] The Tris salt of 2-[(4-{6-[(4-cyano-2-fluorobenzyl)oxy]pyridin-2-yl}piperidin-1-yl)methyl]-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid refers to a salt of Compound 1 generated using 1,3-dihydroxy-2-(hydroxymethyl)propan-2-amine. The Tris is associated with the carboxylic acid moiety of Compound 1. Unless otherwise specified, when referring to the Tris salt of Compound 1, the counterion and Compound 1 are in a stoichiometric ratio of about 1:1 (i.e., 0.9:1.0 to 1.0:0.9, e.g., 0.95:1.00 to 1.00:0.95, or 0.99:1.00 to 1.00:1.01). Another chemical name for the tris salt of compound 1 is 1,3-dihydroxy-2-(hydroxymethyl)propan-2-aminium 2-[(4-{6-[(4-cyano-2-fluorobenzyl)oxy]pyridin-2-yl}piperidin-1-yl)methyl]-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylate, which may also be represented, for example, by one of the following structures:

[0018] [ka]

[0019] The novel therapeutic methods and compositions / formulations described herein are directed to this and other important ends. [Means for solving the problem]

[0020] The invention provides, in part, a method of treating T2DM comprising administering to a human being in need thereof a pharmaceutical composition, wherein the pharmaceutical composition is in an oral dosage form and comprises 2-[(4-{6-[(4-cyano-2-fluorobenzyl)oxy]pyridin-2-yl}piperidin-1-yl)methyl]-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid or a pharmaceutical salt thereof.

[0021] The present invention further provides a method for controlling weight management, comprising administering a pharmaceutical composition to a human being in need thereof, wherein the pharmaceutical composition is in an oral dosage form, and the pharmaceutical composition comprises 2-[(4-{6-[(4-cyano-2-fluorobenzyl)oxy]pyridin-2-yl}piperidin-1-yl)methyl]-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid or a pharmaceutical salt thereof.

[0022] The present invention further provides an immediate release oral pharmaceutical composition containing 2-[(4-{6-[(4-cyano-2-fluorobenzyl)oxy]pyridin-2-yl}piperidin-1-yl)methyl]-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid or a pharmaceutical salt thereof. The immediate release oral pharmaceutical composition of the present invention can be used in the treatment methods of the present invention provided herein.

[0023] The present invention further provides an immediate release oral pharmaceutical composition comprising 2-[(4-{6-[(4-cyano-2-fluorobenzyl)oxy]pyridin-2-yl}piperidin-1-yl)methyl]-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, a filler, a disintegrant, and a lubricant. This immediate release oral pharmaceutical composition of the present invention can also be used in the treatment methods of the present invention provided herein. [Brief explanation of the drawings]

[0024] [Figure 1] 1 is a flow chart showing the steps for preparing an immediate-release tablet of the tris salt of Compound 1. [Figure 2] 1 is a flow chart showing the process for preparing a Compound 1 Tris salt controlled-release tablet (equivalent to 50 mg of Compound 1). DETAILED DESCRIPTION OF THE INVENTION

[0025] In a first aspect, the present invention provides a method of treating T2DM, comprising administering a pharmaceutical composition to a human being in need thereof, wherein the pharmaceutical composition is in an oral dosage form, and the pharmaceutical composition comprises 2-[(4-{6-[(4-cyano-2-fluorobenzyl)oxy]pyridin-2-yl}piperidin-1-yl)methyl]-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid ("Compound 1") or a pharmaceutical salt thereof.

[0026] In some embodiments, the pharmaceutical composition is in an oral solution form or a solid oral dosage form.

[0027] In some embodiments, the pharmaceutical composition is in a solid oral dosage form, including, for example, a tablet, capsule, caplet, sachet, powder, granules, or orally dispersible film.

[0028] In some embodiments, the pharmaceutical composition is an immediate release solid dosage form.

[0029] As used herein, the term "immediate release" or its abbreviation "IR" [e.g., in "immediate release tablet"] corresponds to the definition given in European Pharmacopeia 6.0, Part 01 / 2008:1502 for a "conventional-release dosage form" or "immediate-release dosage form," which is a tablet form that indicates the release of the active substance not intentionally altered by special formulation and / or manufacturing methods, and is therefore distinct from "modify-release," "prolong-release," "delayed-release," and "pulsatile-release" dosage forms, as defined in European Pharmacopeia 6.0, Part 01 / 2008:1502. For example, more specifically, "immediate release" or "IR" means the release of at least 70%, 75%, or 80% of the active pharmacological ingredient within a given time, such as 60 minutes, 45 minutes, or 30 minutes, as determined according to the USP release method using Apparatus 2 (paddles), where the Q value (30 minutes) is at least 75%.

[0030] In some embodiments, the pharmaceutical composition is in an immediate release tablet dosage form.

[0031] In some embodiments, the pharmaceutical composition comprises one or more tablets.

[0032] In some embodiments, the pharmaceutical composition comprises Compound 1 or a pharmaceutical salt thereof in an amount equivalent to about 10 mg to about 140 mg of Compound 1, e.g., about 10 mg to about 120 mg of Compound 1, about 10 mg to about 50 mg of Compound 1, about 10 mg to about 40 mg of Compound 1, about 10 mg to about 20 mg of Compound 1, about 15 mg to about 25 mg of Compound 1, about 15 mg to about 40 mg of Compound 1, about 15 mg to about 50 mg of Compound 1, about 20 mg to about 30 mg of Compound 1, about 30 mg to about 40 mg of Compound 1, about 30 mg to about 50 mg of Compound 1, about 30 mg to about 60 mg of Compound 1, about 30 mg to about 70 mg of Compound 1, about 30 mg to about 80 mg of Compound 1, about 30 mg to about 90 mg of Compound 1, about 30 mg to about 90 mg of Compound 1, about 30 mg to about 100 mg of Compound 1, about 30 mg to about 120 mg of Compound 1, about 30 mg to about 15 ... The compound 1 may contain an amount equivalent to 0 mg to about 30 mg of compound 1, about 30 mg to about 100 mg of compound 1, about 40 mg to about 70 mg of compound 1, about 40 mg to about 50 mg of compound 1, about 70 mg to about 130 mg of compound 1, about 70 mg to about 120 mg of compound 1, about 100 mg to about 140 mg of compound 1, about 110 mg to about 130 mg of compound 1, about 115 mg to about 125 mg of compound 1, or about 120 mg of compound 1.

[0033] In some embodiments, Compound 1 or a pharmaceutical salt thereof in the pharmaceutical composition is a pharmaceutical salt of Compound 1, for example, a tris salt of Compound 1.

[0034] In some embodiments, the pharmaceutical composition is administered twice daily. In some embodiments, the twice daily administrations are separated by at least 4, 5, or 6 hours. In some embodiments, the twice daily administrations are separated by at least 6, 7, or 8 hours. In some embodiments, the twice daily administrations are separated by at least 8, 9, or 10 hours.

[0035] In some embodiments, the twice daily doses are separated by 4 to 16 hours, 8 to 16 hours, or 10 to 14 hours, hi some further embodiments, the twice daily doses are separated by 11 to 13 hours, or about 12 hours.

[0036] As used herein, the term "treating," unless otherwise indicated, means to reverse, alleviate, inhibit the progression of, or prevent the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. As used herein, the term "treatment," unless otherwise indicated, refers to the act of treating, as defined herein. The term "treating" also includes adjuvant and neoadjuvant treatment of a subject (e.g., a human).

[0037] In some embodiments, the methods of treating T2DM include improving glycemic control.

[0038] In some embodiments, the method of treating T2DM includes lowering a human's fasting plasma glucose level, for example, to about 126 mg / dL or less. In some embodiments, the method of treating T2DM includes reducing glycated hemoglobin (HbA1c), for example, to about 7.0% or less, about 6.5% or less, or about 5.7% or less. In some embodiments, the method of treating T2DM includes lowering average daily glucose levels to about 157 mg / dL or less. In some embodiments, the method of treating T2DM includes low or no glycemic risk.

[0039] In some embodiments, the method further comprises administering an additional therapeutic agent to the human.

[0040] In some embodiments, the methods are in addition to a reduced calorie diet and / or increased physical activity.

[0041] In a second aspect, the present invention provides a method for controlling weight management or treating obesity or overweight, comprising administering a pharmaceutical composition to a human being in need thereof, wherein the pharmaceutical composition is in an oral dosage form, and the pharmaceutical composition comprises 2-[(4-{6-[(4-cyano-2-fluorobenzyl)oxy]pyridin-2-yl}piperidin-1-yl)methyl]-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid or a pharmaceutical salt thereof.

[0042] In some embodiments, the pharmaceutical composition is in an oral solution form or a solid oral dosage form.

[0043] In some embodiments, the pharmaceutical composition is in a solid oral dosage form, including, for example, a tablet, capsule, caplet, sachet, powder, granules, or orally dispersible film.

[0044] In some embodiments, the pharmaceutical composition is an immediate release solid dosage form.

[0045] In some embodiments, the pharmaceutical composition is an immediate release tablet dosage form.

[0046] In some embodiments, the pharmaceutical composition comprises one or more tablets.

[0047] In some embodiments, the pharmaceutical composition contains Compound 1 or a pharmaceutical salt thereof in an amount equivalent to about 10 mg to about 140 mg of Compound 1, e.g., about 10 mg to about 120 mg of Compound 1, about 10 mg to about 40 mg of Compound 1, about 10 mg to about 20 mg of Compound 1, about 15 mg to about 25 mg of Compound 1, about 15 mg to about 40 mg of Compound 1, about 15 mg to about 50 mg of Compound 1, about 40 mg to about 70 mg of Compound 1, about 40 mg to about 50 mg of Compound 1, about 70 mg to about 130 mg of Compound 1, about 70 mg to about 120 mg of Compound 1, about 100 mg to about 140 mg of Compound 1, about 110 mg to about 130 mg of Compound 1, about 115 mg to about 125 mg of Compound 1, or about 120 mg of Compound 1.

[0048] In some embodiments, Compound 1 or a pharmaceutical salt thereof in the pharmaceutical composition is an amount equivalent to about 10 mg to about 120 mg of Compound 1, about 10 mg to about 40 mg of Compound 1, about 40 mg to about 70 mg of Compound 1, about 70 mg to about 120 mg of Compound 1, or about 120 mg of Compound 1.

[0049] In some embodiments, Compound 1 or a pharmaceutical salt thereof in the pharmaceutical composition is an amount equivalent to about 10 mg to about 100 mg of Compound 1, about 10 mg to about 40 mg of Compound 1, about 20 mg to about 100 mg of Compound 1, about 20 mg to about 80 mg of Compound 1, or about 40 mg to about 80 mg of Compound 1.

[0050] In some embodiments, Compound 1 or a pharmaceutical salt thereof in the pharmaceutical composition is a pharmaceutical salt of Compound 1, for example, a tris salt of Compound 1.

[0051] In some embodiments, the pharmaceutical composition is administered twice daily. In some embodiments, the twice daily administrations are separated by at least 4, 5, or 6 hours. In some embodiments, the twice daily administrations are separated by at least 6, 7, or 8 hours. In some embodiments, the twice daily administrations are separated by at least 8, 9, or 10 hours.

[0052] In some embodiments, the twice daily doses are separated by 4 to 16 hours, 8 to 16 hours, or 10 to 14 hours, hi some further embodiments, the twice daily doses are separated by 11 to 13 hours, or about 12 hours.

[0053] In some embodiments, controlling weight management includes controlling weight management over time.

[0054] In some embodiments, the initial body mass index (BMI) of a human is 24 kg / m 2 (Initial BMI is the BMI at which weight management control begins.) In some embodiments, a person's initial BMI is 24 kg / m or greater. 2 ~30kg / m2 is.

[0055] In some embodiments, the human's initial BMI is 27 kg / m 2 That's all.

[0056] In some embodiments, the human's initial BMI is 30 kg / m 2 In some embodiments, the human's initial BMI is 30.0 kg / m or greater. 2 ~45kg / m 2 is.

[0057] As used herein, a BMI of 30 kg / m 2 A person who is above this is obese (ie, has obesity).

[0058] As used herein, a BMI of 25.0 to 29.9 kg / m 2 A person is overweight (ie, has excess body weight) if:

[0059] As used herein, the term "treating," unless otherwise indicated, means to reverse, alleviate, inhibit the progression of, or prevent the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. As used herein, the term "treatment," unless otherwise indicated, refers to the act of treating, as defined herein. The term "treating" also encompasses adjuvant and neoadjuvant treatment of a subject (e.g., a human).

[0060] In some embodiments, treating obesity or overweight includes controlling weight management.

[0061] In some embodiments, the human has at least one weight-related comorbidity (eg, hypertension, type 2 diabetes mellitus, or dyslipidemia).

[0062] In some embodiments, the human is overweight and has at least one weight-related comorbidity (eg, hypertension, type 2 diabetes mellitus, or dyslipidemia).

[0063] In some embodiments, the human is obese and has at least one weight-related comorbidity (eg, hypertension, type 2 diabetes mellitus, or dyslipidemia).

[0064] In some embodiments, the method of controlling weight management comprises reducing a person's body weight by, for example, more than about 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10%.

[0065] In some embodiments, the method of controlling weight management comprises reducing a person's body weight by, for example, more than 10%, 15%, 20%, 25%, or 30%.

[0066] In some embodiments, the method of controlling weight management comprises reducing a person's body weight by, for example, more than about 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10%.

[0067] In some embodiments, the method of controlling weight management comprises lowering a person's body mass index (BMI), for example, by more than about 10%, 15%, 20%, 25%, or 30%.

[0068] In some embodiments, the method further comprises administering an additional therapeutic agent to the human.

[0069] In some embodiments, the methods are in addition to a reduced calorie diet and / or increased physical activity.

[0070] In a third aspect, the present invention provides an immediate release oral pharmaceutical composition comprising Compound 1 or a pharmaceutical salt thereof.

[0071] In some embodiments, Compound 1 or a pharmaceutical salt thereof is a tris salt of Compound 1.

[0072] In some embodiments, Compound 1 or a pharmaceutical salt thereof in the pharmaceutical composition is present in an amount equivalent to about 10 mg to about 140 mg of Compound 1, e.g., about 10 mg to about 120 mg of Compound 1, about 10 mg to about 40 mg of Compound 1, about 10 mg to about 20 mg of Compound 1, about 15 mg to about 25 mg of Compound 1, about 15 mg to about 40 mg of Compound 1, about 15 mg to about 50 mg of Compound 1, about 40 mg to about 70 mg of Compound 1, about 40 mg to about 50 mg of Compound 1, about 70 mg to about 130 mg of Compound 1, about 70 mg to about 120 mg of Compound 1, about 100 mg to about 140 mg of Compound 1, about 110 mg to about 130 mg of Compound 1, about 115 mg to about 125 mg of Compound 1, or about 120 mg of Compound 1.

[0073] In some embodiments, Compound 1 or a pharmaceutical salt thereof in the pharmaceutical composition is an amount equivalent to about 10 mg to about 120 mg of Compound 1, about 10 mg to about 40 mg of Compound 1, about 40 mg to about 70 mg of Compound 1, about 70 mg to about 120 mg of Compound 1, or about 120 mg of Compound 1.

[0074] In some embodiments, the immediate release oral dosage form is a solid oral dosage form, including, for example, tablets, capsules, caplets, sachets, powders, granules, orally dispersible films, hi some embodiments, the immediate release oral dosage form is in tablet form.

[0075] In some embodiments, the immediate release oral pharmaceutical composition of the third aspect may be used in the method of the first or second aspects of the invention.

[0076] In a fourth aspect, the present invention provides a method for producing a composition comprising: Compound 1 or a pharmaceutical salt thereof (e.g., the tris salt of Compound 1); a filler (e.g., microcrystalline cellulose, lactose (e.g., in the form of lactose monohydrate), or a combination thereof, e.g., a combination of microcrystalline cellulose and lactose monohydrate in a weight ratio of about 2:1); disintegrants (e.g., crospovidone, starch, pregelatinized starch, carboxymethylcellulose, hydroxypropylcellulose, sodium alginate, croscarmellose sodium, or sodium starch glycolate); and lubricants [e.g., metal stearates (such as magnesium stearate or sodium stearyl fumarate)]. An immediate release oral pharmaceutical composition comprising:

[0077] In some embodiments, oral pharmaceutical compositions comprise microcrystalline cellulose, lactose (eg, in the form of lactose monohydrate), sodium starch glycolate, and magnesium stearate.

[0078] In some embodiments, the oral pharmaceutical composition comprises microcrystalline cellulose, lactose (eg, in the form of lactose monohydrate), sodium starch glycolate, and sodium stearyl fumarate.

[0079] In some embodiments, the oral pharmaceutical composition of the present invention comprises: 1.0% to 35.0% by weight of Compound 1 or a pharmaceutically acceptable salt thereof (e.g., the Tris salt of Compound 1); 60% to 95% by weight of a filler (e.g., microcrystalline cellulose, lactose (e.g., in the form of lactose monohydrate), or a combination thereof, e.g., a combination of microcrystalline cellulose and lactose monohydrate in a weight ratio of about 2:1); 0.2% to 2.5% by weight of a lubricant (e.g., a metal stearate (such as magnesium stearate or sodium stearyl fumarate)), and 1.0% to 5.0% by weight of a disintegrant (e.g., crospovidone, starch, pregelatinized starch, carboxymethylcellulose, hydroxypropylcellulose, sodium starch glycolate, or croscarmellose sodium) Includes:

[0080] In some embodiments, the oral pharmaceutical composition of the present invention comprises: 1.0% to 35.0% by weight of Compound 1 or a pharmaceutically acceptable salt thereof (e.g., the Tris salt of Compound 1); 60% to 95% by weight of a filler (e.g., microcrystalline cellulose, lactose (e.g., in the form of lactose monohydrate), or a combination thereof, e.g., a combination of microcrystalline cellulose and lactose monohydrate in a weight ratio of about 2:1); 0.2% to 2.5% by weight of a lubricant (e.g., a metal stearate (such as magnesium stearate or sodium stearyl fumarate)), and 1.0% to 5.0% by weight of a disintegrant (e.g., sodium starch glycolate or croscarmellose sodium) Includes:

[0081] In some embodiments, the oral pharmaceutical composition of the present invention comprises: 10.0% to 35.0% by weight of Compound 1 or a pharmaceutically acceptable salt thereof (e.g., the Tris salt of Compound 1); 60% to 90% by weight of a filler (e.g., microcrystalline cellulose, lactose (e.g., in the form of lactose monohydrate), or a combination thereof, e.g., a combination of microcrystalline cellulose and lactose monohydrate in a weight ratio of about 2:1); 0.2% to 2.5% by weight of a lubricant (e.g., a metal stearate (such as magnesium stearate or sodium stearyl fumarate)), and 1.0% to 5.0% by weight of a disintegrant (e.g., crospovidone, starch, pregelatinized starch, carboxymethylcellulose, hydroxypropylcellulose, sodium starch glycolate, or croscarmellose sodium) Includes:

[0082] In some embodiments, the oral pharmaceutical composition of the present invention comprises: 1.0% to 20.0% by weight of Compound 1 or a pharmaceutically acceptable salt thereof (e.g., the Tris salt of Compound 1); 70% to 95% by weight of a filler (e.g., microcrystalline cellulose, lactose (e.g., in the form of lactose monohydrate), or a combination thereof, e.g., a combination of microcrystalline cellulose and lactose monohydrate in a weight ratio of about 2:1); 0.2% to 2.0% by weight of a lubricant (e.g., a metal stearate (such as magnesium stearate or sodium stearyl fumarate)), and 1.0% to 5.0% by weight of a disintegrant (e.g., sodium starch glycolate or croscarmellose sodium) Includes:

[0083] In some embodiments, the oral pharmaceutical composition of the present invention comprises: 1.0% to 20.0% by weight of Compound 1 or a pharmaceutically acceptable salt thereof (e.g., the Tris salt of Compound 1); 70% to 95% by weight of a filler (e.g., microcrystalline cellulose, lactose (e.g., in the form of lactose monohydrate), or a combination thereof); 0.5% to 1.5% by weight of a lubricant (e.g., a metal stearate (such as magnesium stearate or sodium stearyl fumarate)), and 2.0% to 4.0% by weight of a disintegrant (e.g., sodium starch glycolate or croscarmellose sodium) Includes:

[0084] In some embodiments, the oral pharmaceutical composition of the present invention comprises: 7.0% to 18.0% by weight of Compound 1 or a pharmaceutically acceptable salt thereof (e.g., the Tris salt of Compound 1); 75% to 90% by weight of a filler (e.g., microcrystalline cellulose, lactose (e.g., in the form of lactose monohydrate), or a combination thereof); 0.5% to 1.5% by weight of a lubricant (e.g., a metal stearate (such as magnesium stearate or sodium stearyl fumarate)), and 2.5% to 3.5% by weight of a disintegrant (e.g., sodium starch glycolate or croscarmellose sodium) Includes:

[0085] In some embodiments, the oral pharmaceutical composition of the present invention comprises: 15.0% to 35.0% by weight of Compound 1 or a pharmaceutically acceptable salt thereof (e.g., 15.0% to 35.0% by weight of the Tris salt of Compound 1); 60.0% to 80.0% by weight of a filler (e.g., microcrystalline cellulose, lactose (e.g., in the form of lactose monohydrate), or a combination thereof); 1.5% to 2.5% by weight of a lubricant (e.g., a metal stearate (such as magnesium stearate or sodium stearyl fumarate)), and 2.5% to 3.5% by weight of a disintegrant (e.g., sodium starch glycolate or croscarmellose sodium) Includes:

[0086] In some embodiments, the oral pharmaceutical composition comprises: Compound 1 or a pharmaceutical salt thereof (e.g., the tris salt of Compound 1); a filler (e.g., microcrystalline cellulose, lactose (e.g., in the form of lactose monohydrate), or a combination thereof, e.g., a combination of microcrystalline cellulose and lactose monohydrate in a weight ratio of about 2:1); Disintegrants (e.g., crospovidone, starch, pregelatinized starch, carboxymethylcellulose, hydroxypropylcellulose), and Lubricants [e.g., metal stearates (such as magnesium stearate or sodium stearyl fumarate)] Includes:

[0087] In some embodiments, the oral pharmaceutical composition comprises microcrystalline cellulose, lactose (eg, in the form of lactose monohydrate), crospovidone, and magnesium stearate.

[0088] In some embodiments, the oral pharmaceutical composition of the present invention comprises: 1.0% to 35.0% by weight of Compound 1 or a pharmaceutically acceptable salt thereof (e.g., the Tris salt of Compound 1); 60% to 95% by weight of a filler (e.g., microcrystalline cellulose, lactose (e.g., in the form of lactose monohydrate), or a combination thereof, e.g., a combination of microcrystalline cellulose and lactose monohydrate in a weight ratio of about 2:1); 0.2% to 2.5% by weight of a lubricant (e.g., a metal stearate (such as magnesium stearate or sodium stearyl fumarate)), and 1.0% to 5.0% by weight of a disintegrant (e.g., crospovidone) Includes:

[0089] In some embodiments, the oral pharmaceutical composition of the present invention comprises: 10.0% to 35.0% by weight of Compound 1 or a pharmaceutically acceptable salt thereof (e.g., the Tris salt of Compound 1); 60% to 70% by weight of a filler (e.g., microcrystalline cellulose, lactose (e.g., in the form of lactose monohydrate), or a combination thereof, e.g., a combination of microcrystalline cellulose and lactose monohydrate in a weight ratio of about 2:1); 0.2% to 2.5% by weight of a lubricant (e.g., a metal stearate (such as magnesium stearate or sodium stearyl fumarate)), and 1.0% to 5.0% by weight of a disintegrant (e.g., crospovidone) Includes:

[0090] In some embodiments, the oral pharmaceutical composition of the present invention comprises: 23.0% to 35.0% by weight of Compound 1 or a pharmaceutically acceptable salt thereof (e.g., 29.0% to 32.0% by weight of the Tris salt of Compound 1); 60% to 70% by weight of a filler (e.g., microcrystalline cellulose, lactose (e.g., in the form of lactose monohydrate), or a combination thereof, e.g., a combination of microcrystalline cellulose and lactose monohydrate in a weight ratio of about 2:1); 1.0% to 2.5% by weight of a lubricant (e.g., a metal stearate (such as magnesium stearate or sodium stearyl fumarate)), and 2.0% to 4.0% by weight of a disintegrant (e.g., crospovidone) Includes:

[0091] In some embodiments, the oral pharmaceutical composition of the present invention comprises: 24.0% to 33.0% by weight of Compound 1 or a pharmaceutically acceptable salt thereof (e.g., 29.0% to 32.0% by weight of the Tris salt of Compound 1); 62.0% to 68.0% by weight of a filler (e.g., microcrystalline cellulose, lactose (e.g., in the form of lactose monohydrate), or a combination thereof, e.g., a combination of microcrystalline cellulose and lactose monohydrate in a weight ratio of about 2:1); 1.5% to 2.5% by weight of a lubricant (e.g., a metal stearate (such as magnesium stearate or sodium stearyl fumarate)), and 2.5% to 3.5% by weight of a disintegrant (e.g., crospovidone) Includes:

[0092] In some embodiments, Compound 1 or a pharmaceutical salt thereof in the pharmaceutical composition is present in an amount equivalent to about 10 mg to about 140 mg of Compound 1, e.g., about 10 mg to about 120 mg of Compound 1, about 10 mg to about 40 mg of Compound 1, about 10 mg to about 20 mg of Compound 1, about 15 mg to about 25 mg of Compound 1, about 15 mg to about 40 mg of Compound 1, about 15 mg to about 50 mg of Compound 1, about 40 mg to about 70 mg of Compound 1, about 40 mg to about 50 mg of Compound 1, about 70 mg to about 130 mg of Compound 1, about 70 mg to about 120 mg of Compound 1, about 100 mg to about 140 mg of Compound 1, about 110 mg to about 130 mg of Compound 1, about 115 mg to about 125 mg of Compound 1, or about 120 mg of Compound 1.

[0093] In some embodiments, Compound 1 or a pharmaceutical salt thereof in the pharmaceutical composition is an amount equivalent to about 10 mg to about 120 mg of Compound 1, about 10 mg to about 40 mg of Compound 1, about 40 mg to about 70 mg of Compound 1, about 70 mg to about 120 mg of Compound 1, or about 120 mg of Compound 1.

[0094] In some embodiments, the immediate release oral dosage form is a solid oral dosage form, including, for example, tablets, capsules, caplets, sachets, powders, granules, orally dispersible films, hi some embodiments, the immediate release oral dosage form is in tablet form.

[0095] In some embodiments, the tris salt of Compound 1 in the pharmaceutical compositions of the invention (or methods of the invention) is present in a crystalline form, such as the crystalline form disclosed in U.S. Pat. No. 10,208,019 (Example 4A-01 therein).

[0096] In some embodiments, Compound 1 in the pharmaceutical compositions of the invention (or methods of the invention) is present in the amorphous form of Compound 1 or the amorphous form of a Tris salt of Compound 1. The amorphous form of Compound 1 or the amorphous form of a Tris salt of Compound 1 can be prepared, for example, by lyophilization (freeze-drying).

[0097] In some embodiments, pharmaceutical compositions of the invention (including those used in methods of the invention) are oral solutions prepared using an amorphous form of Compound 1 or an amorphous form of a Tris salt of Compound 1.

[0098] In some embodiments, the immediate release oral pharmaceutical composition of the fourth aspect may be used in the method of the first or second aspects of the invention.

[0099] The term "about" generally means within 5%, preferably within 3%, and more preferably within 1% of a given value or range. Alternatively, the term "about" can mean within an acceptable standard error of the mean when considered by one of ordinary skill in the art.

[0100] The term "Tris" refers to 1,3-dihydroxy-2-(hydroxymethyl)propan-2-amine, also known as THAM, tromethamine, 2-amino-2-(hydroxymethyl)propane-1,3-diol, tris(hydroxymethyl)aminomethane.

[0101] The Tris salt of Compound 1 refers to a salt of Compound 1 produced using 1,3-dihydroxy-2-(hydroxymethyl)propan-2-amine. The Tris is associated with the carboxylic acid moiety of Compound 1. Unless otherwise specified, when referring to the Tris salt of Compound 1, the counterion and Compound 1 are in a stoichiometric ratio of about 1:1 (i.e., 0.9:1.0 to 1.0:0.9, e.g., 0.95:1.00 to 1.00:0.95). Another chemical name for the tris salt of compound 1 is 1,3-dihydroxy-2-(hydroxymethyl)propan-2-aminium 2-[(4-{6-[(4-cyano-2-fluorobenzyl)oxy]pyridin-2-yl}piperidin-1-yl)methyl]-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylate, which may also be represented, for example, by one of the following structures:

[0102] [ka]

[0103] Those skilled in the art will readily appreciate that multiple nomenclature systems may be used to name the same compound (including the same salt).

[0104] Pharmaceutically acceptable salts include acid addition and base salts.

[0105] Suitable acid addition salts are those formed from acids which form non-toxic salts, examples of which include acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, hydrogensulfate / sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hybenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, and lactate. , malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, 1,5-naphthalenedisulfonate, and xinafoate.

[0106] Suitable base salts are those formed from bases which form non-toxic salts, examples of which include aluminum, arginine, benzathine, calcium, choline, diethylamine, bis(2-hydroxyethyl)amine (diolamine), glycine, lysine, magnesium, meglumine, 2-aminoethanol (olamine), potassium, sodium, 2-amino-2-(hydroxymethyl)propane-1,3-diol (tris or tromethamine), and zinc salts.

[0107] Hemisalts of acids and bases may also be formed, such as hemisulfate and hemicalcium salts. For a review of suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002).

[0108] Pharmaceutically acceptable salts include (i) by reacting the compound with a desired acid or base; (ii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound, or by ring-opening a suitable cyclic precursor, e.g., a lactone or lactam, using a desired acid or base; or (iii) by converting one salt of the compound to another salt by reaction with an appropriate acid or base or by means of a suitable ion exchange column; It can be prepared by one or more of three methods.

[0109] All three reactions are typically carried out in solution. The resulting salt may precipitate and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the resulting salt may vary from completely ionized to almost non-ionized.

[0110] The compound and its pharmaceutically acceptable salts may exist in unsolvated and solvated forms. The term "solvate" is used herein to describe a molecular complex comprising a compound or its salt and one or more pharmaceutically acceptable solvent molecules, such as ethanol. The term "hydrate" is used when the solvent is water. For example, the hydrate crystalline form of the tris salt of Compound 1 disclosed herein refers to a crystalline material / complex that contains both the tris salt of Compound 1 and water (hydration water) in the crystal lattice of the crystalline material / complex.

[0111] The currently accepted classification system for organic hydrates defines isolated site, channel, or metal ion coordinated hydrates. See Polymorphism in Pharmaceutical Solids by KR Morris (HGBrittain, ed., Marcel Dekker, 1995). Isolated site hydrates are hydrates in which the water molecules are isolated from direct contact with each other by intervening organic molecules. In channel hydrates, the water molecules reside in lattice channels where they are next to other water molecules. In metal ion coordinated hydrates, the water molecules are bound to the metal ion.

[0112] When the solvent or water is tightly bound, the complex can have a well-defined stoichiometry independent of humidity. However, when the solvent or water is weakly bound, such as in channel solvates or hygroscopic compounds, the water / solvent content can be dependent on humidity and drying conditions. In such cases, non-stoichiometry becomes the norm.

[0113] The scope of the present invention also includes multicomponent complexes (other than salts and solvates) in which a drug and at least one other component are present in stoichiometric or non-stoichiometric amounts. This type of complex includes clathrates (drug-host inclusion complexes) and cocrystals. The latter are typically defined as crystalline complexes of neutral molecular components bound together by noncovalent interactions, although complexes with salts of neutral molecules are also possible. Cocrystals may be prepared by melt crystallization, recrystallization from solvents, or by physically grinding the components together. See O. Almarsson and MJ Zaworotko, Chem Commun, 17, 1889-1896 (2004). For a review of multicomponent complexes, see Haleblian, J Pharm Sci, 64(8), 1269-1288 (August 1975).

[0114] The compounds of the present invention may exist in a range of solid states, ranging from completely amorphous to completely crystalline. The term "amorphous" refers to a state in which a material lacks long-range order at the molecular level and, depending on temperature, may exhibit the physical properties of either a solid or a liquid. Typically, such materials exhibit the properties of a solid but do not exhibit a distinctive X-ray diffraction pattern and are more formally described as liquids. Upon heating, a change from solid to liquid properties occurs, usually characterized by a second-order change of state ("glass transition"). The term "crystalline" refers to a solid phase in which the material has a regular, well-ordered internal structure at the molecular level and exhibits a distinctive X-ray diffraction pattern with distinct peaks. When heated sufficiently, such materials also exhibit the properties of a liquid, but the change from solid to liquid is usually characterized by a first-order phase transition ("melting point").

[0115] Compounds may also exist in a mesomorphic state (mesophase or liquid crystal) when subjected to the appropriate conditions. A mesomorphic state is intermediate between a true crystalline state and a true liquid state (melt or solution). Mesomorphism that occurs as a result of a change in temperature is described as "thermotropic," while that that occurs as a result of the addition of a second component, such as water or another solvent, is described as "lyotropic." Compounds that have the potential to form lyotropic mesophases are described as "amphiphilic" and are ionic (-COO - Na + , -COO - K + , or -SO3 - Na + ) or non-ionic (-N - N + They consist of molecules with polar head groups such as (CH3)3. For more information, see Crystals and the Polarizing Microscope, 4th Edition, by N.H. Hartshorne and A. Stuart (Edward Arnold, 1970).

[0116] Some compounds may exhibit polymorphism and / or one or more types of isomerism (e.g., optical, geometric, or tautomerism). The inventors' crystalline forms may also be isotopically labeled. Such variations are inherently included in Compound 1 or its salts as defined herein with respect to its structural features, and therefore are within the scope of the present invention.

[0117] Compounds containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Where compounds contain an alkenyl or alkenylene group, cis / trans (or Z / E) geometric isomers are possible. Where structural isomers are interconvertible via a low energy barrier, tautomeric isomerism ("tautomerism") can occur. Tautomerism can take the form of, for example, proton tautomerism in compounds containing imino, keto, or oxime groups, or so-called valence tautomerism in compounds containing aromatic moieties. This means that a single compound may exhibit more than one type of isomerism.

[0118] Certain pharmaceutically acceptable salts of Compound 1 may contain counterions that are optically active (e.g., d-lactate or l-lysine) or racemic (e.g., dl-tartrate or dl-arginine).

[0119] Cis / trans isomers can be separated by conventional techniques well known to those skilled in the art, such as chromatography and fractional crystallization.

[0120] Conventional techniques for preparing / isolating individual enantiomers include chiral synthesis from appropriate optically pure precursors or resolution of the racemate (or racemate of a salt or derivative) using, for example, chiral high-performance liquid chromatography (HPLC). Alternatively, racemic precursors containing chiral esters can be separated by enzymatic resolution (see, for example, ACLM Carvaho et al., Int J Mol Sci 29682-29716 (2015)). In cases where the compound contains an acidic or basic moiety, a salt can be formed with an optically pure base or acid, such as 1-phenylethylamine or tartaric acid. The resulting diastereomeric mixture can be separated by fractional crystallization, and one or both of the diastereomeric salts can be converted to the corresponding pure enantiomer by means well known to those skilled in the art. Alternatively, the racemate (or racemic precursor) can be covalently reacted with an appropriate optically active compound, such as an alcohol, amine, or benzyl chloride. The resulting diastereomeric mixture can be separated by chromatography and / or fractional crystallization by means well known to those skilled in the art to separate diastereomers as single enantiomers having two or more chiral centers. Chiral compounds (and their chiral precursors) can be obtained in enantiomerically enriched form using chromatography, usually HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, usually heptane or hexane, containing 0-50% by volume, usually 2%-20% isopropanol, and 0-5% by volume of an alkylamine, usually 0.1% diethylamine. Concentration of the eluate yields the enriched mixture. Chiral chromatography using subcritical and supercritical fluids may also be used. Chiral chromatography methods useful in some embodiments of the present invention are known in the art (see, for example, Smith, Roger M., Loughborough University, Loughborough, UK, Chromatographic Science Series (1998), 75 (SFC with Packed Columns), pp. 223-249, and references cited therein).In some relevant examples herein, columns were obtained from Chiral Technologies, Inc. (West Chester, PA, USA), a subsidiary of Daicel® Chemical Industry Co., Ltd. (Tokyo, Japan).

[0121] When a racemate crystallizes, two different types of crystals are possible. The first type is the racemate (true racemate) mentioned above, in which one homogeneous form of crystals containing both enantiomers in equimolar amounts occurs. The second type is a racemic mixture or conglomerate, in which two forms of crystals, each containing a single enantiomer, occur in equimolar amounts. The crystalline forms present in a racemic mixture both have the same physical properties, but they may have different physical properties compared to a true racemate. Racemic mixtures can be separated by conventional techniques known to those skilled in the art. See, for example, Stereochemistry of Organic Compounds by EL Eliel and SH Wilen (Wiley, 1994).

[0122] Although Compound 1 and its salts are depicted herein as a single tautomeric form, all possible tautomeric forms are included within the scope of the present invention.

[0123] The present invention includes all isotopically labeled pharmaceutically acceptable compounds 1 or salts thereof in which one or more atoms are replaced by atoms having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominant in nature.

[0124] Examples of isotopes suitable for inclusion in compounds of the invention include: 2 H and 3 Hydrogen such as H 11 C. 13 C, and 14 Carbon, such as C 36 chlorine such as Cl, 13 N and 15 Nitrogen such as N 15 O. 17 O, and18 Examples include isotopes of oxygen such as O.

[0125] Certain isotopically labeled Compound 1 or salts thereof, for example, Compound 1 or salts thereof incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotope tritium, i.e. 3 H, and carbon-14, i.e. 14 C is particularly useful for this purpose given its ease of incorporation and readily available means of detection.

[0126] Deuterium, i.e. 2 Substitution with heavier isotopes such as 3H may offer certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements.

[0127] 11 C. 18 F, 15 O, and 13 Substitution with positron emitting isotopes, such as N, can be useful in examining substrate receptor occupancy in Positron Emission Topography (PET) studies.

[0128] Isotopically labeled compounds can generally be prepared by conventional techniques known to those skilled in the art or by methods analogous to those described in the accompanying Examples and Preparations, substituting the appropriate isotopically labeled reagent for the previously used unlabeled reagent.

[0129] Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, eg, D2O, d6-acetone, d6-DMSO.

[0130] Administration and Dosage The compound of the present invention is usually administered in an amount effective for treating the conditions described herein.The compound of the present invention can be administered as a compound itself or alternatively as a pharmaceutically acceptable salt.For the purpose of administration and dosage, the compound itself or its pharmaceutically acceptable salt is simply referred to as the compound of the present invention.

[0131] The compounds of the present invention are administered by any suitable route in the form of a pharmaceutical composition adapted to such route, in a dose effective for the intended treatment. The compounds of the present invention may be administered orally, rectally, vaginally, parenterally, or topically.

[0132] The compounds of the present invention can be administered orally, either by swallowing, so that the compound enters the gastrointestinal tract, or by buccal or sublingual administration by which the compound enters the blood stream directly from the mouth.

[0133] The dosage regimen for the compounds of the present invention and / or compositions containing said compounds is based on various factors, including the type, age, weight, sex, and medical condition of the patient, the severity of the condition, the route of administration, and the activity of the particular compound used. Typically, multiple doses per day may be used, if necessary, to increase the total daily dose.

[0134] For oral administration, the composition may be provided, for example, in the form of a tablet containing the active ingredient, the dosage to the patient being adjusted based on symptoms.

[0135] Suitable subjects according to the present invention include mammalian subjects. In one embodiment, a human is a suitable subject. Human subjects may be of either gender and at any stage of development.

[0136] Pharmaceutical Composition In another embodiment, the present invention includes pharmaceutical compositions. Such pharmaceutical compositions include compounds of the present invention formulated with a pharmaceutically acceptable carrier. Other pharmacologically active substances may also be present. As used herein, "pharmaceutically acceptable carrier" includes any and all physiologically compatible solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. Examples of pharmaceutically acceptable carriers include one or more of water, saline, phosphate-buffered saline, dextrose, glycerol, ethanol, and the like, and combinations thereof. Isotonic agents, for example, sugars, sodium chloride, or polyalcohols such as mannitol or sorbitol, may also be included in the composition. Wetting agents or minor amounts of auxiliary substances, such as wetting or emulsifying agents, preservatives, buffers, and the like, which enhance the shelf life or effectiveness of the antibody or antibody portion, are pharmaceutically acceptable.

[0137] In some embodiments, the pharmaceutically acceptable carrier comprises one or more components selected from a diluent / filler, a disintegrant, a binder, a wetting agent, and a lubricant.

[0138] As used herein, the term "diluent or filler" refers to a substance that serves to dilute a pharmacologically active agent to a desired dosage and / or acts as a carrier for the pharmacologically active agent. Examples of diluents or fillers include mannitol, lactose (including, for example, lactose monohydrate), sucrose, maltodextrin, sorbitol, xylitol, powdered cellulose, microcrystalline cellulose, carboxymethyl cellulose, carboxyethyl cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, methylhydroxyethyl cellulose, starch, sodium starch glycolate, pregelatinized starch, calcium phosphate, metal carbonates, metal oxides, and / or metal aluminosilicates.

[0139] As used herein, the term "disintegrant" refers to a substance that promotes the disintegration of the pharmaceutical composition / formulation of the present invention in water (or in vivo in a fluid containing water). Examples of disintegrants include croscarmellose sodium, carmellose calcium, crospovidone, alginic acid, sodium alginate, potassium alginate, calcium alginate, ion exchange resins, effervescent systems based on food acid and alkali carbonate components, clay, talc, starch, pregelatinized starch, sodium starch glycolate, cellulose floc, carboxymethylcellulose, hydroxypropylcellulose, calcium silicate, metal carbonates, sodium bicarbonate, calcium citrate, and / or calcium phosphate.

[0140] As used herein, the term "binder" refers to a substance that increases the mechanical strength and / or compressibility of the pharmaceutical composition / preparation of the present invention.Examples of binders include polyvinylpyrrolidone, copovidone, hydroxypropyl cellulose, hydroxypropylmethylcellulose, cross-linked poly(acrylic acid), gum arabic, gum acacia, gum tragacanth, lecithin, casein, polyvinyl alcohol, gelatin, kaolin, cellulose, methylcellulose, hydroxymethylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, hydroxyethylcellulose, methylhydroxyethylcellulose, silicified microcrystalline cellulose, starch, maltodextrin, dextrin, microcrystalline cellulose, and / or sorbitol.

[0141] As used herein, the term "wetting agent" refers to a substance that increases the water permeability of a pharmaceutical composition / formulation of the present invention. In another aspect, the term "wetting agent" refers to a substance that enhances the dissolution of a pharmacologically active agent in water (or in vivo, in a fluid containing water). In yet another aspect, the term "wetting agent" refers to a substance that increases the bioavailability of a pharmacologically active agent after the pharmaceutical composition / formulation of the present invention is administered. Examples of humectants include metallic lauryl sulfates, polyethylene glycol, fatty acid glyceride esters, polyoxyethylene-polyoxypropylene copolymers, polyoxyethylene-alkyl ethers, metallic alkyl sulfates, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene castor oil derivatives, sugar esters of fatty acids, polyglycolized glycerides, quaternary ammonium amine compounds, lauroyl macrogolglycerides, caprylocaproyl macrogolglycerides, stearoyl macrogolglycerides, linoleoyl macrogolglycerides, oleoyl macrogolglycerides, polyethoxylated vegetable oils, polyethoxylated sterols, polyethoxylated cholesterol, polyethoxylated glycerol fatty acid esters, polyethoxylated fatty acid esters, sulfosuccinates, taurates, and / or sodium docusate.

[0142] As used herein, the term "lubricant" refers to a substance that helps prevent a pharmaceutical formulation / composition from sticking to equipment during processing and / or improves powder flow of the composition / formulation during processing. Examples of lubricants include stearic acid, metal stearates (e.g., magnesium stearate), sodium stearyl fumarate, fatty acids, fatty alcohols, fatty acid esters, glyceryl behenate, mineral oil, vegetable oil, paraffin, leucine, silica, silicic acid, talc, propylene glycol fatty acid esters, polyethylene glycol, polypropylene glycol, polyalkylene glycol, and / or sodium chloride.

[0143] In some embodiments, the compositions of the present invention comprise a filler (e.g., microcrystalline cellulose, lactose (e.g., in the form of lactose monohydrate), or a combination thereof), a disintegrant (e.g., croscarmellose sodium, sodium alginate, potassium alginate, or sodium starch glycolate), and a lubricant (e.g., a metal stearate, such as magnesium stearate). In some embodiments, the compositions of the present invention comprise microcrystalline cellulose, lactose (e.g., in the form of lactose monohydrate), sodium starch glycolate, and magnesium stearate.

[0144] The compositions of the present invention may be in a variety of forms, including, for example, liquid, semi-solid, and solid dosage forms, such as liquid solutions, dispersions or suspensions, tablets, pills, powders, liposomes, and suppositories, depending on the intended mode of administration and therapeutic application.

[0145] Oral solid dosage forms may be presented in discrete units, such as, for example, hard or soft capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of the pharmacologically active ingredient (API, e.g., Compound 1 or a pharmaceutically acceptable salt thereof, such as the Tris salt of Compound 1). In one embodiment, the oral dosage may be in tablet form. In one embodiment, the oral dosage may be in capsule form. In one embodiment, the oral dosage may be in powder or granule form. In one embodiment, the oral dosage form is sublingual, such as a lozenge. In such solid dosage forms, the compounds of the present invention are typically combined with one or more adjuvants. Such capsules or tablets may contain an immediate-release formulation. In other embodiments, such capsules or tablets may contain a controlled-release formulation. In the case of capsules, tablets, and pills, the dosage forms may include buffering agents or be prepared with an enteric coating.

[0146] In another embodiment, oral administration may be in the form of a liquid dosage. Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art (e.g., water). Such compositions may also contain adjuvants such as wetting agents, emulsifying agents, suspending agents, flavoring agents (e.g., sweeteners), and / or flavoring agents.

[0147] Other carrier materials and modes of administration known in the pharmaceutical industry may also be used. The pharmaceutical compositions of the present invention can be prepared by any well-known pharmaceutical technique, such as effective formulation and administration procedures. The above considerations regarding effective formulation and administration procedures are well known in the art and are described in standard textbooks. Drug formulation is discussed, for example, in Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 1975; Liberman et al., eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Kibbe et al., eds., Handbook of Pharmaceutical Excipients (3rd ed.), American Pharmaceutical Association, Washington, 1999.

[0148] Coadministration The composition of the present invention can be used alone or in combination with other therapeutic agents.The present invention also provides any use, method or composition as defined herein, wherein the compound of any embodiment herein or its pharmaceutically acceptable salt or the pharmaceutically acceptable solvate of said compound or salt is used in combination with one or more other therapeutic agents as discussed herein.This includes the pharmaceutical composition for treating the disease or condition for which GLP-1R agonist is indicated, comprising the composition of the present invention as defined in any embodiment herein and one or more other therapeutic agents as discussed herein.

[0149] Administration of two or more compounds "in combination" means that all of the compounds are administered close enough in time to produce their respective biological effects within the same time frame. The presence of one agent may alter the biological effect of the other compound. Two or more compounds may be administered simultaneously, concurrently, or sequentially. Additionally, simultaneous administration may be achieved by mixing the compounds prior to administration, or by administering the compounds at the same or different administration sites, at the same time, but in separate dosage forms.

[0150] The terms "concurrent administration," "co-administration," "simultaneous administration," and "administration at the same time" mean that compounds are administered in combination.

[0151] In another embodiment, the present invention provides a method of treatment that includes administering a compound of the present invention in combination with one or more other pharmaceutical agents, which can be selected from the agents discussed herein.

[0152] In one embodiment, the compounds of the present invention include, but are not limited to, biguanides (e.g., metformin), sulfonylureas (e.g., tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride, or glipizide), thiazolidinediones (e.g., pioglitazone, rosiglitazone, or lobeglitazone), glitazars (e.g., saroglitazar, aleglitazar, muraglitazar, or tesaglitazar), meglitinides (e.g., nateglinide, repag, linid), dipeptidyl peptidase 4 (DPP-4) inhibitors (e.g., sitagliptin, vildagliptin, saxagliptin, linagliptin, gemigliptin, anagliptin, teneligliptin, alogliptin, trelagliptin, dutogliptin, or omarigliptin), glitazones (e.g., pioglitazone, rosiglitazone, balaglitazone, rivoglitazone, or lobeglitazone), sodium-glucose cotransporter 2 (sodium-glucose and antidiabetic agents, including SGLT2 (sodium-linked transporter 2) inhibitors (e.g., empagliflozin, canagliflozin, dapagliflozin, ipragliflozin, ipragliflozin, tofogliflozin, sergliflozin etabonate, remogliflozin etabonate, or ertugliflozin), SGLTL1 inhibitors, GPR40 agonists (FFAR1 / FFA1 agonists, e.g., fasiglifam), glucose-dependent insulinotropic peptide (GIP) and analogs thereof, alpha-glucosidase inhibitors (e.g., voglibose, acarbose, or miglitol), or insulin or insulin analogs, including pharmaceutically acceptable salts of the specifically named agents and pharmaceutically acceptable solvates of said agents and salts.

[0153] In another embodiment, the compounds of the present invention are selected from the group consisting of, but not limited to, peptide YY or an analog thereof, a type 2 neuropeptide Y receptor (NPYR2) agonist, a NPYR1 or NPYR5 antagonist, a type 1 cannabinoid receptor (CB1R) antagonist, a lipase inhibitor (e.g., orlistat), a human proislet peptide (HPL), a steroid hormone receptor antagonist (HSR ... peptide (HIP), melanocortin receptor 4 agonists (e.g., setmelanotide), melanin-concentrating hormone receptor 1 antagonists, farnesoid X receptor (FXR) agonists (e.g., obeticholic acid), zonisamide, phentermine (alone or in combination with topiramate), norepinephrine / dopamine reuptake inhibitors (e.g., buproprion), opioid receptor antagonists (e.g., naltrexone), combinations of norepinephrine / dopamine reuptake inhibitors and opioid receptor antagonists (e.g., buproprion and naltrexone), GDF -15 analogs, sibutramine, cholecystokinin agonists, amylin and its analogs (e.g., pramlintide), leptin and its analogs (e.g., metroleptin), serotonergic agents (e.g., lorcaserin), methionine aminopeptidase 2 (MetAP2) inhibitors (e.g., beloranib or ZGN-1061), phendimetrazine, diethylpropion, benzphetamine, SGLT2 inhibitors (e.g., empagliflozin, canagliflozin, dapagliflozin, ipragliflozin, tofogliflozin, sergliflozin etabonate, remogliflozinetabonate, or ertugliflozin), SGLTL1 inhibitors, SGLT2 / SGLT1 dual inhibitors, fibroblast growth factor receptor (FGFR) modulators, AMP-activated protein kinase (AMPK) activators, biotin, MAS receptor modulators, or glucagon receptor agonists (alone or in combination with another GLP-1R agonist, e.g., liraglutide, exenatide, dulaglutide, albiglutide, lixisenatide, or semaglutide), including pharmaceutically acceptable salts of the specifically named agents and pharmaceutically acceptable solvates of said agents and salts.

[0154] In another embodiment, the compounds of the present invention include, but are not limited to, PF-05221304, FXR agonists (e.g., obeticholic acid), PPARα / δ agonists (e.g., elafibranor), synthetic fatty acid-bile acid conjugates (e.g., aramchol), caspase inhibitors (e.g., emricasan), anti-lysyl oxidase homolog 2 (LOXL2) monoclonal antibodies (e.g., simtuzumab), galectin 3 inhibitors (e.g., GR-MD-02), MAPK5 inhibitors (e.g., GS-4997), dual antagonists of chemokine receptor 2 (CCR2) and CCR5 (e.g., cenicriviroc), fibroblast growth factor 21 (FGF21) agonists (e.g., BMS-986036), and the like. ), a leukotriene D4 (LTD4) receptor antagonist (e.g., tipelukast), a niacin analog (e.g., ARI3037MO), an ASBT inhibitor (e.g., volixibat), an acetyl-CoA carboxylase (ACC) inhibitor (e.g., NDI010976 or PF-05221304), a ketohexokinase (KHK) inhibitor, a diacylglyceryl acyltransferase 2 (DGAT2) inhibitor, a CB1 receptor antagonist, an anti-CB1R antibody, or an apoptosis signal-regulating kinase 1 (ASK1) inhibitor, including pharmaceutically acceptable salts of the specifically named agents and pharmaceutically acceptable solvates of said agents and salts, when administered in combination with one or more agents for treating NASH.

[0155] Some particular compounds that can be used in combination with the compounds of the present invention to treat the diseases or disorders described herein include the following: 4-(4-(1-Isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4′-piperidine]-1′-carbonyl)-6-methoxypyridin-2-yl)benzoic acid (an example of a selective ACC inhibitor, prepared as the free acid in Example 9 of U.S. Pat. No. 8,859,577, the U.S. national phase of International Application No. PCT / IB2011 / 054119, the disclosures of which are incorporated herein by reference in their entireties for all purposes). Crystalline forms of 4-(4-(1-isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4′-piperidine]-1′-carbonyl)-6-methoxypyridin-2-yl)benzoic acid, including the anhydrous monotris form (Form 1) and the monotris salt trihydrate (Form 2), are described in International PCT Application No. PCT / IB2018 / 058966, the disclosure of which is incorporated herein by reference in its entirety for all purposes; (S)-2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(tetrahydrofuran-3-yl)pyrimidine-5-carboxamide or a pharmaceutically acceptable salt thereof, and its crystalline solid forms (Form 1 and Form 2) [an example of a DGAT2 inhibitor described in Example 1 of U.S. Pat. No. 10,071,992, the disclosure of which is incorporated herein by reference in its entirety for all purposes]; [(1R,5S,6R)-3-{2-[(2S)-2-methylazetidin-1-yl]-6-(trifluoromethyl)pyrimidin-4-yl}-3-azabicyclo[3.1.0]hex-6-yl]acetic acid or a pharmaceutically acceptable salt thereof (including its crystalline free acid form) (an example of a ketohexokinase (KHK) inhibitor, which is described in Example 4 of U.S. Pat. No. 9,809,579, the disclosure of which is incorporated herein by reference in its entirety for all purposes), and The FXR agonist tropifexor or a pharmaceutically acceptable salt thereof (described in Examples 1-1B of US Pat. No. 9,150,568, the disclosure of which is incorporated herein by reference in its entirety for all purposes).

[0156] Such agents and compounds of the present invention can be combined with a pharmaceutically acceptable vehicle, such as saline, Ringer's solution, dextrose solution, etc. The particular dosage regimen, i.e., dose, timing, and repetition, will depend on the particular individual and their individual medical history.

[0157] Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed and include buffers such as phosphate, citric acid, and other organic acids; salts such as sodium chloride; antioxidants including ascorbic acid and methionine; preservatives (e.g., octadecyldimethylbenzylammonium chloride, hexamethonium chloride, benzalkonium chloride, benzethonium chloride, phenol, butyl or benzyl alcohol, alkyl parabens such as methyl or propyl paraben, catechol, resorcinol, cyclohexanol, 3-pentanol, and m-cresol); low molecular weight (less than about 10 residues) polypeptides; serum albumin; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrin; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose, or sorbitol; counterions that form salts, such as sodium; metal complexes (e.g., Zn-protein complexes); and / or non-ionic surfactants such as TWEEN™, PLURONICS™, or polyethylene glycol (PEG).

[0158] Liposomes containing such drugs and / or compounds of the present invention can be prepared by methods known in the art, such as those described in U.S. Patent Nos. 4,485,045 and 4,544,545. Liposomes with improved circulation time are disclosed in U.S. Patent No. 5,013,556. Particularly useful liposomes can be produced by reverse-phase evaporation using a lipid composition containing phosphatidylcholine, cholesterol, and PEG-derivatized phosphatidylethanolamine (PEG-PE). Liposomes are extruded through filters with defined pore sizes to yield liposomes with the desired diameter.

[0159] Such agents and / or compounds of the invention can also be entrapped in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules), or macroemulsions, in microcapsules prepared, for example, by coacervation techniques or interfacial polymerization, e.g., hydroxymethylcellulose or gelatin microcapsules, and poly(methyl methacrylate) microcapsules, respectively. Such techniques are disclosed in Remington, The Science and Practice of Pharmacy, 20th Edition, Mack Publishing (2000).

[0160] Sustained-release preparations may also be used. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing Compound 1 or a pharmaceutically acceptable salt thereof, and such matrices are in the form of shaped articles, for example, films or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate) or poly(vinyl alcohol)), polylactide (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid and 7-ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers, such as those used in LUPRON DEPOT™ (injectable microspheres composed of lactic acid-glycolic acid copolymers and leuprolide acetate), sucrose acetate isobutyrate, and poly-D-(-)-3-hydroxybutyric acid.

[0161] Preparations used for intravenous administration must be sterile. This is readily accomplished, for example, by filtration through sterile filtration membranes. The compounds of the present invention are generally placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper that can be pierced by a hypodermic injection needle.

[0162] Suitable emulsions can be prepared using commercially available lipid emulsions, such as Intralipid™, Liposyn™, Infonutrol™, Lipofundin™, and Lipiphysan™. The active ingredient can be dissolved in a premixed emulsion composition, or alternatively, the active ingredient can be dissolved in oil (e.g., soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil, or almond oil) and mixed with phospholipids (e.g., egg phospholipids, soybean phospholipids, or soybean lecithin) and water to form an emulsion. It will be appreciated that other ingredients, such as glycerol or glucose, can be added to adjust the tonicity of the emulsion. Suitable emulsions typically contain up to 20% oil, e.g., between 5% and 20%. The fat emulsion may contain fat droplets between 0.1 μm and 1.0 μm, especially between 0.1 μm and 0.5 μm, and have a pH in the range of 5.5 to 8.0.

[0163] Emulsion compositions may be prepared by mixing a compound of the present invention with Intralipid™ or its constituent ingredients (soybean oil, egg phospholipids, glycerol, and water).

[0164] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as specified above. In some embodiments, the compositions are administered by oral or nasal respiratory route for local or systemic effect. Compositions in pharmaceutically acceptable solvents, preferably sterile, can be nebulized using a gas. Nebulized solutions can be inhaled directly from the nebulizing device, or the nebulizing device can be attached to a face mask, tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered, preferably orally or nasally, from a device that delivers the formulation in an appropriate manner.

[0165] kit Another aspect of the present invention provides kits comprising the pharmaceutical compositions of the present invention. The kits may include a diagnostic or therapeutic agent in addition to the pharmaceutical compositions of the present invention. The kits may also include instructions for use in a diagnostic or therapeutic method. In some embodiments, the kits include the pharmaceutical compositions of the present invention and a diagnostic agent. In other embodiments, the kits include the pharmaceutical composition and instructions for use in a therapeutic method.

[0166] In yet another embodiment, the present invention includes a kit suitable for use in carrying out the therapeutic methods described herein. In one embodiment, the kit contains one or more solid forms of the present invention in an amount sufficient to carry out the method of the present invention. In another embodiment, the kit includes one or more solid forms of the present invention in an amount sufficient to carry out the method of the present invention and a container for dosing. [Example]

[0167] The following examples illustrate the oral compositions / formulations and methods of the present invention.

[0168] Example 1 Preparation of immediate release (IR) tablets Non-film-coated immediate-release (IR) tablets of the Tris salt of Compound 1 were prepared in dosage strengths of 1 mg, 10 mg, 50 mg, and 100 mg (dose strength weights in milligrams are the equivalent weight of Compound 1).

[0169] The compositions of these tablets are shown in Tables 1-1 to 1-4.

[0170] [Table 1]

[0171] [Table 2]

[0172] [Table 3]

[0173] [Table 4]

[0174] Preparing IR tablets The following steps were performed in preparing the IR tablets. 1. Blend approximately half of the microcrystalline cellulose. 2. Add the Tris salt of Compound 1 to the microcrystalline cellulose, followed by lactose monohydrate and sodium starch glycolate and mix. 3. Mill the blend and pass the remaining amount of microcrystalline cellulose through a mill. Blend the milled powder. 4. Add intra-granular magnesium stearate and blend. 5. Compact and grind, then blend. 6. Add the extra-granular magnesium stearate and blend. 7. Compress using a suitable tablet press.

[0175] Example 1B Preparation of additional immediate release (IR) tablets Additional film-coated immediate-release (IR) tablets of the Tris salt of Compound 1 were prepared in a dosage strength of 100 mg (the dosage strength weight in milligrams is the equivalent weight of Compound 1). The compositions of these tablets are shown in Tables 1-5, 1-6, and 1-7. These tablets were prepared using a process similar to that in Example 1 (the disintegrants used were sodium starch glycolate or crospovidone).

[0176] [Table 5]

[0177] [Table 6]

[0178] [Table 7]

[0179] Example 2 Preparation of controlled-release (CR) tablets Film-coated controlled-release (CR) tablets of the Tris salt of Compound 1 were prepared in a dosage strength of 50 mg (weight in milligrams is the equivalent weight of Compound 1).

[0180] The composition of this CR tablet is shown in Table 2-1.

[0181] [Table 8]

[0182] CR tablet preparation process The following steps were performed in preparing the CR tablets (see Figure 2):

[0183] active layer 1. Using a 055R screen, perform a blend-mill-blend process of the Tris salt of Compound 1, polyethylene oxide, and a portion of the magnesium stearate. 2. The mixture from step 1 is subjected to dry granulation by roller compaction. 3. Add extragranular magnesium stearate and blend the mixture to achieve active layer granulation.

[0184] Swelling agent layer 4. Perform a blend-mill-blend process of polyethylene oxide, microcrystalline cellulose, sodium chloride, and FD&C Blue Aluminum Lake #2 using a 055R screen. 5. Add magnesium stearate and blend the mixture to obtain the leavening agent blend.

[0185] Bilayer tablets 6. The active layer and swelling agent layer are compressed into a bilayer core. 7. Film coat the bilayer core using a suitable pan coater to produce a permeable membrane. 8. The tablets are dried in a tray dryer to remove any remaining amounts of processing solvent. 9. Using a suitable laser, create delivery ports into the active layer surface of the bilayer tablet.

[0186] Example 3 Clinical study (dose-normalized study) of compound 1 (its tris salt form) This study was a randomized, double-blind (sponsor-open), parallel, placebo-controlled, multiple-ascending oral dose study of Compound 1 (in its Tris salt form) in participants with type 2 diabetes mellitus (T2DM) with metformin monotherapy as background treatment.

[0187] In this study, a total of 98 participants received oral doses of Compound 1 (in its tris salt form) or matching placebo for 28 days. Approximately 12 participants were enrolled in each cohort (9 active and 3 placebo) in a 3:1 randomization ratio, with eight cohorts enrolled in the study. Participants were allowed to enter the Clinical Investigation Unit (CRU) on or before Day -2, at the discretion of the principal investigator, and were released on Day 30 after completing all assessments. For each participant, the total participation period from the screening visit to the on-site follow-up visit was approximately 15 weeks. After the initial administration of the study product on Day 1, follow-up visits and follow-up contacts (conducted by telephone) occurred 35–42 and 56–63 days, respectively. Participants who discontinued before study completion could be replaced at the discretion of the principal investigator and sponsor. 92 participants completed the inpatient study.

[0188] The planned titration scheme and dosing paradigm for all cohorts is shown in Table 2-1. QD: Once a day BID: Twice a day

[0189] [Table 9]

[0190] Diagnosis and Primary Criteria for Participation: The study population was between 18 and 70 years of age with T2DM at the time of consent and screening, with an HbA1c of ≥7.0% and ≤10.5%, taking metformin as their only antihyperglycemic treatment, and a body mass index (BMI) of 24.5–45.4 kg / m 2 Participants were female and / or male participants of non-childbearing potential with T2DM, with a total body weight greater than 50 kg (110 lb). Metformin doses had to be ≥ 500 mg daily, stable for at least 2 months before the screening visit, and administered at the CRU according to the patient's baseline dosing regimen.

[0191] Study Treatment: Compound 1 (in the form of its Tris salt) was supplied as 1 mg, 10 mg, 50 mg, and 100 mg immediate-release (IR) or 50 mg controlled-release (CR) tablets for oral administration (see Examples 1 and 2). Matching placebo tablets (2:1, microcrystalline cellulose:lactose) were also provided.

[0192] result Subject Disposition and Demographics: A total of 98 participants were randomized and assigned to receive the study treatment, and 92 participants completed the study. Of the six participants who discontinued the study, two participants discontinued due to treatment-related treatment-emergent AEs (TEAEs). One participant in the Compound 1 (its Tris salt form) 15 mg twice daily (BID) group discontinued due to a moderate TEAE of headache, and one participant in the Compound 1 (its Tris salt form) 50 mg BID group discontinued due to moderate TEAEs of decreased appetite, nausea, vomiting, and fatigue. In addition, one participant in the Compound 1 (its Tris salt form) 50 mg BID group discontinued due to participant withdrawal, and three participants in the Compound 1 (its Tris salt form) 200 mg once daily (QD) CR group discontinued for other reasons. All study discontinuations occurred during the treatment phase.

[0193] Demographic characteristics and anthropometric measurements were generally comparable across all treatment groups. The 98 randomized participants consisted of 51 men (52%) and 47 women (48%). The majority of participants were Caucasian (70, 71.4%). 61 participants (62.2%) were Hispanic or Latino. The mean age of all participants was 57.4 years (range: 37-70 years). The mean weight was 92.4 kg (range: 50.2-138.9 kg). The mean BMI was 32.9 kg / m 2 (range: 25.0-43.0 kg / m 2 The mean T2DM duration for all participants was 9.5 years (range: 0.3-29.1 years), and the mean baseline HbA1c for the study population was 8.3% (range: 8.01-8.61%).

[0194] Safety Results: (A) Adverse events A total of 319 all-cause TEAEs were reported by 83 participants (84.7%) in the study, of which 262 (262 / 319: 82.1%) were considered treatment-related. Two participants experienced two severe TEAEs during the study, one of which occurred during the dosing period and was considered treatment-related, and the other occurred during the follow-up period (also an SAE) and was not considered treatment-related. There were no deaths. One SAE occurred during the study reporting period (not treatment-related, as previously described). Another SAE, also not treatment-related, was reported by the same participant outside the study reporting period and was not recorded in the clinical database. A total of two participants discontinued the study due to a TEAE, and two participants discontinued study drug due to a TEAE but continued in the study. Nine participants: 1 in the placebo group, 4 in the 50 mg BID group, 1 in the 120 mg BID group, 2 in the 120 mg BID slow titration group, and 1 in the 200 mg QD CR group had their dose reduced or temporarily discontinued due to TEAEs.

[0195] The Compound 1 (in its Tris salt form) 10 mg BID and 15 mg BID groups had the lowest number of all-cause-related TEAEs, with 8 and 16 events, respectively. The 120 mg BID slow-titration group had the highest number of all-cause-related TEAEs, with 50 events. The Compound 1 (in its Tris salt form) 120 mg BID slow-titration group reported one SAE (unrelated to treatment) and two severe TEAEs (one related to treatment and one unrelated). The placebo, 50 mg BID, 70 mg BID, 120 mg BID, 120 mg QD, and 200 mg QD CR groups reported 44, 45, 31, 43, 35, and 47 TEAEs, respectively.

[0196] The most frequently reported all-cause TEAEs by system organ class (SOC) were gastrointestinal disorders (reported in 73.5% of all participants) and nervous system disorders (33.7%). The most commonly reported all-cause TEAEs by preferred term (PT) were nausea (49.0%), dyspepsia (32.7%), vomiting (26.5%), diarrhea (24.5%), headache (23.5%), and constipation (20.4%). The incidence of all-cause TEAEs in the gastrointestinal disorders category in each dose group was higher than that in the placebo group (52.0%), except for the 10 mg BID group (33.3%).

[0197] The majority of all-cause TEAEs (294 of 319) were mild in severity. Twenty-three TEAEs were moderate, of which 18 were considered treatment-related. Two severe TEAEs were reported in the 120 mg BID slow-dose group, one of which was considered treatment-related.

[0198] One participant in the 120 mg BID group experienced mild hypoglycemia after missing a meal or snack, which was considered self-limited and treatment-related.

[0199] (B) Clinical laboratory evaluation Regardless of baseline abnormalities, the most common laboratory abnormality was hemoglobin A1C (%) >1.3 above the upper limit of normal (ULN) (45 cases, 48.9%), which was expected due to the study's eligibility criteria. Other common laboratory abnormalities included activated partial thromboplastin time >1.1 times the ULN (40 cases, 40.8%) and urinary glucose >1 mg / dL (36 cases, 36.7%), but these did not appear to be disproportionate to placebo.

[0200] (C) Vital signs The most frequently reported postbaseline vital signs that met prespecified criteria for sectoral analysis were a ≥30 mmHg decrease in supine systolic blood pressure (BP) in 39 participants and a ≥20 mmHg decrease in supine diastolic BP in 24 participants across all treatment groups. No participants met the prespecified criterion for pulse rate greater than 40 bpm and less than 120 bpm. Sectoral analysis revealed no clear dose-related increase in the frequency of vital sign abnormalities.

[0201] Compound 1 (in its Tris salt form) treatment increased pulse rate compared to placebo on Days 1, 14, 21, and 28, with generally greater increases observed on Day 28 compared to Day 1. For all dosing intervals from Day 1 through Day 28, the mean time-matched double difference in pulse rate ranged from -6.4 to 11.8 bpm for all doses of Compound 1 (in its Tris salt form) compared to a range of -6.4 to -0.8 bpm for placebo. Despite these increases in pulse rate, no pulse rate-related AEs were reported, and no pulse rates above 120 bpm occurred.

[0202] (D) ECG A total of five participants reported post-baseline ECG (electrocardiogram) data meeting the prespecified criteria of a total QTcF (QT interval corrected for heart rate according to the Fridericia formula) interval of >450 but <480 or a change from baseline of >30 but <60; two of these events occurred in the placebo group and three of these events occurred in the planned Compound 1 (its tris salt form) treatment group. These events were self-limited and did not require intervention. No data met the criteria of a PR interval of >300 msec or a QRS duration of >140 msec, and a departmental analysis revealed no clear dose-related increase in the frequency of ECG abnormalities. No ECG abnormalities were observed in the optional Compound 1 (its tris salt form) groups (Compound 1 (its tris salt form) 120 mg BID slow-dose setting, 120 mg QD, and 200 mg QD CR groups). No ECG abnormalities were reported as AEs, and no ECG findings were reported by the investigator as clinically significant.

[0203] Ascending multiple oral doses of Compound 1 (in its Tris salt form) were generally safe and well tolerated in adult participants with T2DM. The most commonly reported all-cause TEAEs were nausea, dyspepsia, vomiting, diarrhea, headache, and constipation.

[0204] No clinically significant adverse trends in safety laboratory tests, vital signs, or ECG parameters were observed with increasing doses of Compound 1 (in its tris salt form).

[0205] Pharmacokinetic evaluation The plasma pharmacokinetic parameter of Compound 1 (in its tris salt form) was the area under the plasma concentration-time profile (AUC) from time 0 to 24 hours. 24 ), the maximum observed concentration over a 24-hour interval (C max ), and C max Time to max) was calculated after day 1 and multiple dose administration for each participant and treatment using non-compartmental analysis of concentration-time data.

[0206] [Table 10]

[0207] After a single oral dose of Compound 1 (in its tris salt form) on Day 1, absorption for the IR formulation for the QD and BID regimens was observed with a median T of 2.0 to 4.0 hours post-dose. max and T max1 This happened in.

[0208] Dose normalized mean AUC 24 Day 1 exposure, based on values, appeared to be roughly dose-proportional for all BID and QD treatments for the IR formulation. For the BID IR formulation-treated cohort, at day 28, AUC 24 and C max increased in a roughly dose-proportional manner.

[0209] For BID and QD IR treatments, mean C at day 28 max and C max1 The median T value was 3 to 10 hours after administration. max and T max1 While the CR formulation treatment (Cohort 7) achieved a median Tmax of 14 hours after dosing, absorption was slower. Mean t values across all treatments ranged between 4.7 and 8.1 hours, with no clear trends observed across the various treatments, regimens, or doses administered. The CR formulation resulted in approximately 50% lower exposure (AUC ) at Day 14 compared to that observed with the IR formulation. 24 and C max ), but by day 28, exposure was similar to that observed with IR formulation treatment. Urinary recovery of Compound 1 was low, with less than 0.1% of the dose still recovered in urine at day 28.

[0210] FPG, MDG, HbA1C, and weight measurements Measurements of fasting plasma glucose (FPG), 24-hour mean diurnal plasma glucose (MDG), HbA1C, and body weight (expressed as change from baseline) at baseline (day -1) and day 28 are shown in Tables 2-2 through 2-5.

[0211] Baseline was defined as the measurement (MDG, FPG, HbA1c, or body weight) on day -1. The randomized treatment represented the target dose at day 28. Baseline was restricted to subjects with non-missing values for change from baseline to time point of interest.

[0212] [Table 11] The observed data are shown. Mean diurnal blood glucose (MDG) was measured by AUC 24 / 24 was set.

[0213] [Table 12]

[0214] [Table 13]

[0215] [Table 14]

[0216] As shown in Tables 2-2 to 2-4, Compound 1 (in its tris salt form) demonstrated robust reductions in FPG, MDG, HbA1c, and body weight at 28 days, with increasing efficacy at higher doses of 70 mg to 120 mg twice daily.

[0217] All patents, patent applications, and references mentioned herein are hereby incorporated by reference in their entirety.

Claims

1. 1. A method of treating T2DM, comprising administering a pharmaceutical composition to a human being in need thereof; the pharmaceutical composition is in an oral dosage form; The pharmaceutical composition comprises 2-[(4-{6-[(4-cyano-2-fluorobenzyl)oxy]pyridin-2-yl}piperidin-1-yl)methyl]-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid or a pharmaceutical salt thereof. method.

2. 10. The method of claim 1, wherein the pharmaceutical composition is an immediate release solid dosage form.

3. 3. The method of claim 1 or 2, wherein the pharmaceutical composition is an immediate release tablet dosage form.

4. 4. The method of any one of claims 1 to 3, wherein the pharmaceutical composition comprises 2-[(4-{6-[(4-cyano-2-fluorobenzyl)oxy]pyridin-2-yl}piperidin-1-yl)methyl]-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid or a pharmaceutical salt thereof in an amount equivalent to about 10 mg to about 140 mg of 2-[(4-{6-[(4-cyano-2-fluorobenzyl)oxy]pyridin-2-yl}piperidin-1-yl)methyl]-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid.

5. 4. The method of any one of claims 1 to 3, wherein the 2-[(4-{6-[(4-cyano-2-fluorobenzyl)oxy]pyridin-2-yl}piperidin-1-yl)methyl]-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid or a pharmaceutical salt thereof in the pharmaceutical composition is a tris salt of 2-[(4-{6-[(4-cyano-2-fluorobenzyl)oxy]pyridin-2-yl}piperidin-1-yl)methyl]-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid.

6. 6. The method of any one of claims 1 to 5, wherein the pharmaceutical composition is administered twice daily.

7. 7. The method of claim 6, wherein the two daily doses are separated by at least about 8 hours.

8. 8. The method of any one of claims 1 to 7, wherein treating D2TM comprises improving glycemic control.

9. 1. A method for controlling weight management or treating obesity or overweight, comprising administering to a human in need thereof a pharmaceutical composition; the pharmaceutical composition is a solid oral dosage form; The pharmaceutical composition comprises 2-[(4-{6-[(4-cyano-2-fluorobenzyl)oxy]pyridin-2-yl}piperidin-1-yl)methyl]-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid or a pharmaceutical salt thereof. method.

10. 10. The method of claim 9, wherein the pharmaceutical composition comprises 2-[(4-{6-[(4-cyano-2-fluorobenzyl)oxy]pyridin-2-yl}piperidin-1-yl)methyl]-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid or a pharmaceutical salt thereof in an amount equivalent to about 10 mg to about 140 mg of 2-[(4-{6-[(4-cyano-2-fluorobenzyl)oxy]pyridin-2-yl}piperidin-1-yl)methyl]-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid.

11. 11. The method of claim 9 or 10, wherein the pharmaceutical composition is administered twice daily.

12. 12. The method of claim 11, wherein the two daily doses are separated by at least about 8 hours.

13. An immediate release oral pharmaceutical composition comprising 2-[(4-{6-[(4-cyano-2-fluorobenzyl)oxy]pyridin-2-yl}piperidin-1-yl)methyl]-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid or a pharmaceutical salt thereof.

14. 2-[(4-{6-[(4-cyano-2-fluorobenzyl)oxy]pyridin-2-yl}piperidin-1-yl)methyl]-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, Fillers, a disintegrant, and lubricant 1. An immediate release oral pharmaceutical composition comprising:

15. 2-[(4-{6-[(4-cyano-2-fluorobenzyl)oxy]pyridin-2-yl}piperidin-1-yl)methyl]-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof is a tris salt of 2-[(4-{6-[(4-cyano-2-fluorobenzyl)oxy]pyridin-2-yl}piperidin-1-yl)methyl]-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; the filler comprises microcrystalline cellulose, lactose, or a combination thereof; The disintegrant is sodium starch glycolate, The lubricant is magnesium stearate or sodium stearyl fumarate, 15. The pharmaceutical composition of claim 14.

16. 2-[(4-{6-[(4-cyano-2-fluorobenzyl)oxy]pyridin-2-yl}piperidin-1-yl)methyl]-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof is a tris salt of 2-[(4-{6-[(4-cyano-2-fluorobenzyl)oxy]pyridin-2-yl}piperidin-1-yl)methyl]-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid; the filler comprises microcrystalline cellulose, lactose, or a combination thereof; the disintegrant is crospovidone; The lubricant is magnesium stearate or sodium stearyl fumarate, 15. The pharmaceutical composition of claim 14.

17. 2-[(4-{6-[(4-cyano-2-fluorobenzyl)oxy]pyridin-2-yl}piperidin-1-yl)methyl]-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof, comprising from about 1.0% to about 35.0% by weight; the filler comprises from about 60% to about 95% by weight; the disintegrant comprises from about 1.0% to about 5.0% by weight; the lubricant comprises from about 0.2% to about 2.5% by weight; 16. The pharmaceutical composition according to claim 14 or 15.

18. 18. The pharmaceutical composition of any one of claims 13 to 17, comprising the tris salt of 2-[(4-{6-[(4-cyano-2-fluorobenzyl)oxy]pyridin-2-yl}piperidin-1-yl)methyl]-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid in an amount equivalent to about 10 mg to about 120 mg of 2-[(4-{6-[(4-cyano-2-fluorobenzyl)oxy]pyridin-2-yl}piperidin-1-yl)methyl]-1-[(2S)-oxetan-2-ylmethyl]-1H-benzimidazole-6-carboxylic acid.

19. 18. A pharmaceutical composition according to any one of claims 13 to 17 for use in the treatment of T2DM or in the control of weight management.

20. 20. The pharmaceutical composition of claim 19, which is administered twice daily.

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