TREATMENT OF TYPE 2 DIABETES OR WEIGHT MANAGEMENT CONTROL WITH 2-((4-((S)-2-(5-CHLOROPYRIDIN-2-YL)-2-METHYLBENZO[D][1,3]DIO XOL-4-YL)PIPERIDIN- 1-YL)METHYL)-1-(((S)-OXETAN-2-YL)METHYL)-1H-BENZO[D]IMIDAZOL E-6-CARBOXYLIC ACID OR A PHARMACEUTICALLY SALT THEREOF

FIELD OF INVENTION

The invention provides a method for treating type 2 diabetes mellitus or for weight management control (e.g. treating obesity or overweight) by administering to a mammal (e.g. a human) in need thereof a pharmaceutical composition as an oral dosage form once-daily, wherein the pharmaceutical composition contains 2-((4-((S)-2-(5-chloropyridin-2-yl)-2- methylbenzo[d][1 ,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)me thyl)-1 H- benzo[d]imidazole-6-carboxylic acid, or a pharmaceutically salt thereof [such as its 2-amino-2- (hydroxymethyl)propane-1 ,3-diol salt, also known as its tris salt]. Moreover, the invention provides oral compositions/formulations for the methods of treatment described herein.

BACKGROUND OF THE INVENTION

Diabetes is a major public health concern because of its increasing prevalence and associated health risks. The disease is characterized by high levels of blood glucose resulting from defects in insulin production, insulin action, or both. Two major forms of diabetes are recognized, Type 1 and Type 2. Type 1 diabetes (T1D) develops when the body's immune system destroys pancreatic beta cells, the only cells in the body that make the hormone insulin that regulates blood glucose. To survive, people with Type 1 diabetes must have insulin administered by injection or a pump. Type 2 diabetes mellitus (referred to generally as T2DM) usually begins with either insulin resistance or when there is insufficient production of insulin to maintain an acceptable glucose level.

Currently, various pharmacological approaches are available for treating hyperglycemia and subsequently, T2DM (Hampp, C. et al. Use of Antidiabetic Drugs in the U.S., 2003-2012, Diabetes Care 2014, 37, 1367-1374). These may be grouped into six major classes, each acting through a different primary mechanism: (A) Insulin secretogogues, including sulphonyl-ureas (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-1 R) agonists (e.g., liraglutide, al biglutide, exenatide, lixisenatide, dulaglutide, semaglutide), which enhance secretion of insulin by acting on the pancreatic beta-cells. Sulphonyl-ureas and meglitinides have limited efficacy and tolerability, cause weight gain and often induce hypoglycemia. DPP-IV inhibitors have limited efficacy. Marketed GLP-1R agonists are peptides primarily administered by subcutaneous injection. Semaglutide and liraglutide are additionally approved for the treatment of obesity. (B) Biguanides (e.g., metformin) are thought to act primarily by decreasing hepatic glucose production. Biguanides often cause gastrointestinal disturbances and lactic acidosis.

(C) Inhibitors of alpha-glucosidase (e.g., acarbose) decrease intestinal glucose absorption. These agents often cause gastrointestinal disturbances. (D) Thiazolidinediones (e.g., pioglitazone, rosiglitazone) act on a specific receptor (peroxisome prol iterator-activated receptor-gamma) in the liver, muscle and fat tissues. They regulate lipid metabolism, subsequently enhancing the response of these tissues to the actions of insulin. Frequent use of these drugs may lead to weight gain and may induce edema and anemia. (E) Insulin is used in more severe cases, either alone or in combination with the above agents, and frequent use may also lead to weight gain and carries a risk of hypoglycemia. (F) sodium-glucose linked transporter cotransporter 2 (SGLT2) inhibitors (e.g., dapagliflozin, empagliflozin, canagliflozin, ertugliflozin) inhibit reabsorption of glucose in the kidneys and thereby lower glucose levels in the blood. This emerging class of drugs may be associated with ketoacidosis and urinary tract infections.

With the exception of GLP-1 R agonists and SGLT2 inhibitors, the currently available drugs have limited efficacy and do not address the most important problems, the declining p-cell function and the associated obesity.

Obesity is a chronic disease that is highly prevalent in modern society and is associated with numerous medical problems including hypertension, hypercholesterolemia, and coronary heart disease. It is further highly correlated with T2DM and insulin resistance, the latter of which is generally accompanied by hyperinsulinemia or hyperglycemia, or both. In addition, T2DM is associated with a two to fourfold increased risk of coronary artery disease. Presently, the only treatment that eliminates obesity with high efficacy is bariatric surgery, but this treatment is costly and risky. Pharmacological intervention is generally less efficacious and associated with side effects. There is therefore an obvious need for more efficacious pharmacological intervention with fewer side effects and convenient administration.

Although T2DM is most commonly associated with hyperglycemia and insulin resistance, other diseases, disorders, and/or conditions associated with T2DM include, for example, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, obesity, dyslipidemia, hypertension, hyperinsulinemia, and nonalcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).

NAFLD is the hepatic manifestation of metabolic syndrome, and is a spectrum of hepatic conditions encompassing steatosis, NASH, fibrosis, cirrhosis and ultimately hepatocellular carcinoma. NAFLD and NASH are considered the primary fatty liver diseases as they account for the greatest proportion of individuals with elevated hepatic lipids. The severity of NAFLD/NASH is based on the presence of lipid, inflammatory cell infiltrate, hepatocyte ballooning, and the degree of fibrosis. Although not all individuals with fatty liver disease (e.g. steatosis or NAFLD) progress to NASH, a substantial proportion do.

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

In a healthy individual, GLP-1 plays an important role regulating post-prandial blood glucose levels by stimulating glucose-dependent insulin secretion by the pancreas resulting in increased glucose absorption in the periphery. GLP-1 also suppresses glucagon secretion, leading to reduced hepatic glucose output. In addition, GLP-1 delays gastric emptying and slows small bowel motility delaying food absorption. In people with T2DM, the normal postprandial rise in GLP-1 is absent or reduced (Vilsboll T, et al. Diabetes. 2001. 50; 609-613).

Holst (Physiol. Rev. 2007, 87, 1409) and Meier (Nat. Rev. Endocrinol. 2012, 8, 728) describe that GLP-1 receptor agonists, such as GLP-1 , liraglutide and exendin-4, have 3 major pharmacological activities to improve glycemic control in patients with T2DM by reducing fasting and postprandial glucose (FPG and PPG): (i) increased glucose-dependent insulin secretion (improved first- and second-phase), (ii) glucagon suppressing activity under hyperglycemic conditions, (iii) delay of gastric emptying rate resulting in retarded absorption of meal-derived glucose.

2-((4-((S)-2-(5-Chloropyridin-2-yl)-2-methylbenzo[c(][1 ,3]dioxol-4-yl)piperidin-1-yl)methyl)- 1-(((S)-oxetan-2-yl)methyl)-1 H-benzo[d]imidazole-6-carboxylic acid (referred to herein as “Compound 1”) is a GLP1 agonist.

Compound 1

Compound 1 (both in the forms the free acid and as its tris salt) was prepared in Example 10 of US Patent Application No. 16/436,311 filed June 10, 2019 (granted as U.S. Patent No. 10934279) and of International Application No. PCT/IB2019/054867 filed June 11 , 2019 (published as WO2019239319), each of which is hereby incorporated herein by reference in its entirety. There, Compound 1 was designated as 2-({4-[2-(5-chloropyridin-2-yl)-2-methyl- 1,3-benzodioxol-4-yl]piperidin-1-yl}methyl)-1-[(2S)-oxetan-2 -ylmethyl]-1 H-benzimidazole-6- carboxylic acid, DIAST-X2:

DIAST-X2, wherein the chiral center on the left part of the compound structure is marked as “abs” to indicate that chiral center has only one stereo-configuration (i.e. , not a racemate with respect to that chiral center).

In addition, US Patent Application No. 16/436,311 filed June 10, 2019 (granted as U.S. Patent No. 10934279) and International Application No. PCT/IB2019/054867, filed June 11 , 2019 (published as WO2019239319) reported an anhydrous crystalline form (designed as Form A) of the tris salt of Compound 1.

Moreover, WO2021116874 (International Application No. PCT/IB2020/061585 filed December 07, 2020) reported a hydrate crystalline form (for example, a monohydrate crystalline form, such as Form 2 or Form 3) and an amorphous form of tris salt of Compound 1.

There remains a need for a safe and efficacious treatment for cardiometabolic and associated diseases and/or conditions, such as T2DM, obesity, and overweight.

The novel methods of treatment and compositions/formulations described herein are directed toward this and other important ends.

SUMMARY OF THE INVENTION

The present invention provides, in part, a method for treating type 2 diabetes mellitus (T2DM) comprising once-daily administering to a human in need thereof a pharmaceutical composition, wherein: the pharmaceutical composition is in the form of an oral dosage form; and the pharmaceutical composition comprises 2-((4-((S)-2-(5-chloropyridin-2-yl)-2- methylbenzo[c(][1 ,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)me thyl)-1 H- benzo[d]imidazole-6-carboxylic acid or a pharmaceutically salt thereof in an amount equivalent to about 10 mg to about 300 mg of 2-((4-((S)-2-(5-chloropyridin-2-yl)-2- methylbenzo[c(][1 ,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)me thyl)-1 H- benzo[d]imidazole-6-carboxylic acid. The present invention further provides a method for weight management control (such as for treating obesity or overweight) comprising once-daily administering to a human in need thereof a pharmaceutical composition, wherein: the pharmaceutical composition is in the form of an oral dosage form; and the pharmaceutical composition comprises 2-((4-((S)-2-(5-chloropyridin-2-yl)-2- methylbenzo[c(][1 ,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)me thyl)-1 H- benzo[d]imidazole-6-carboxylic acid or a pharmaceutically salt thereof in an amount equivalent to about 10 mg to about 300 mg of 2-((4-((S)-2-(5-chloropyridin-2-yl)-2- methylbenzo[c(][1 ,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)me thyl)-1 H- benzo[d]imidazole-6-carboxylic acid.

The present invention further provides an immediate-release oral pharmaceutical composition (e.g. a tablet) comprising: 2-((4-((S)-2-(5-chloropyridin-2-yl)-2- methylbenzo[c(][1 ,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)me thyl)-1 H- benzo[d]imidazole-6-carboxylic acid, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof; a filler; a disintegrant; and a lubricant. This immediate-release oral pharmaceutical composition of the invention can also be used in the methods of treatment of the invention provided herein.

BRIEF DESCRIPTION OF FIGURES

FIG. 1 shows a flow diagram of the preparation process of tris salt of Compound 1 immediate release tablets (strength equivalent to 1 mg, 10 mg, 20 mg, 60 mg, or 100 mg Compound 1) in Example 1.

FIG. 2 shows a diagram for the Compounding Process of tris salt of Compound 1 oral solutions in Example 2.

FIG. 3 shows overall study design with actual implementation of the clinical study in Example 3.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment (Embodiment A1), the present invention provides a method for treating T2DM comprising once-daily administering to a human in need thereof a pharmaceutical composition, wherein: the pharmaceutical composition is in the form of an oral dosage form; and the pharmaceutical composition comprises 2-((4-((S)-2-(5-chloropyridin-2-yl)-2- methylbenzo[c(][1 ,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)me thyl)-1 H- benzo[d]imidazole-6-carboxylic acid or a pharmaceutically salt thereof in an amount equivalent to about 10 mg to about 300 mg of 2-((4-((S)-2-(5-chloropyridin-2-yl)-2- methylbenzo[d][1 ,3]dioxol-4-yl)piperidin-1 -yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1 H- benzo[d]imidazole-6-carboxylic acid.

Embodiment A2 is a further embodiment of Embodiment A1 , wherein the pharmaceutical composition is present in an oral solution form or in a solid oral dosage form.

Embodiment A3 is a further embodiment of Embodiment A1 or A2, wherein the pharmaceutical composition is present in a solid oral dosage form, which includes, for example, tablets, capsules, caplets, sachets, powders, granules, or orally dispersible films.

Embodiment A4 is a further embodiment of any one of Embodiments A1 to A3, wherein the pharmaceutical composition is in an immediate-release solid dosage form.

As use herein, the term "immediate release" or its abbreviated term "IR" [for example, in "immediate release tablet"] corresponds to the definition provided in European Pharmacopeia 6.0, part 01/2008: 1502 as relating to "conventional-release dosage forms" or "immediate- release dosage forms" in the form of a tablet showing a release of the active substance, which is not deliberately modified by a special formulation design and/or manufacturing method, thereby being 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 a release quantity of the active pharmacological ingredient of at least 75% within 30 minutes, as determined according to the USP release method using apparatus 2 (paddle), i.e. having a Q value (30 minutes) of at least 75 %.

Embodiment A5 is a further embodiment of any one of Embodiments A1 to A4, wherein the pharmaceutical composition is in an immediate-release tablet dosage form.

Embodiment A6 is a further embodiment of any one of Embodiments A1 to A5, wherein the pharmaceutical composition includes one or more tablets.

Embodiment A7 is a further embodiment of any one of Embodiments A1 to A6, wherein the pharmaceutical composition contains Compound 1 or a pharmaceutically salt thereof in an amount equivalent to about 10 mg to about 300 mg of Compound 1, for example, about 20 mg to about 280 mg of Compound 1 , about 20 mg to about 260 mg of Compound 1 , about 20 mg to about 240 mg of Compound 1 , about 20 mg to about 220 mg of Compound 1 , about 20 mg to about 200 mg of Compound 1 , about 20 mg to about 180 mg of Compound 1 , about 20 mg to about 120 mg of Compound 1 , about 20 mg to about 100 mg of Compound 1 , about 20 mg to about 80 mg of Compound 1 , about 20 mg to about 60 mg of Compound 1 , about 20 mg to about 40 mg of Compound 1 , about 20 mg to about 30 mg of Compound 1 , about 30 mg to about 260 mg of Compound 1 , about 30 mg to about 240 mg of Compound 1 , about 30 mg to about 180 mg of Compound 1, about 30 mg to about 120 mg of Compound 1 , about 30 mg to about 100 mg of Compound 1 , about 30 mg to about 60 mg of Compound 1 , about 60 mg to about 280 mg of Compound 1 , about 60 mg to about 260 mg of Compound 1 , about 60 mg to about 240 mg of Compound 1 , about 60 mg to about 220 mg of Compound 1 , about 60 mg to about 200 mg of Compound 1 , about 60 mg to about 180 mg of Compound 1 , about 60 mg to about 160 mg of Compound 1, about 60 mg to about 140 mg of Compound 1 , about 60 mg to about 120 mg of Compound 1 , about 60 mg to about 100 mg of Compound 1 , about 80 mg to about 280 mg of Compound 1 , about 80 mg to about 260 mg of Compound 1 , about 80 mg to about 240 mg of Compound 1 , about 80 mg to about 220 mg of Compound 1 , about 80 mg to about 220 mg of Compound 1 , about 80 mg to about 200 mg of Compound 1 , about 100 mg to about 280 mg of Compound 1, about 100 mg to about 260 mg of Compound 1, about 100 mg to about 240 mg of Compound 1, about 100 mg to about 220 mg of Compound 1, about 100 mg to about 220 mg of Compound 1, about 100 mg to about 200 mg of Compound 1, about 120 mg to about 280 mg of Compound 1, about 120 mg to about 260 mg of Compound 1, about 120 mg to about 240 mg of Compound 1, about 120 mg to about 220 mg of Compound 1, about 120 mg to about 220 mg of Compound 1, about 120 mg to about 200 mg of Compound 1, about 140 mg to about 280 mg of Compound 1, about 140 mg to about 260 mg of Compound 1, about 140 mg to about 240 mg of Compound 1, about 140 mg to about 220 mg of Compound 1, about 140 mg to about 220 mg of Compound 1 , about 140 mg to about 200 mg of Compound 1 , about 20 mg of Compound 1, about 30 mg of Compound 1, about 40 mg of Compound 1, about 50 mg of Compound 1 , about 60 mg of Compound 1 , about 70 mg of Compound 1 , about 80 mg of Compound 1, about 90 mg of Compound 1, about 100 mg of Compound 1 , about 110 mg of Compound 1, about 120 mg of Compound 1, about 130 mg of Compound 1, about 140 mg of Compound 1, about 150 mg of Compound 1, about 160 mg of Compound 1, about 170 mg of Compound 1, about 180 mg of Compound 1, about 190 mg of Compound 1, about 200 mg of

Compound 1, about 210 mg of Compound 1, about 220 mg of Compound 1, about 230 mg of

Compound 1, about 240 mg of Compound 1, about 250 mg of Compound 1, about 260 mg of

Compound 1, about 270 mg of Compound 1, about 280 mg of Compound 1, about 290 mg of

Compound 1 , or about 300 mg of Compound 1. In some further embodiments, the pharmaceutical composition contains Compound 1 or a pharmaceutically salt thereof in an amount equivalent to about 10 mg to about 300 mg of Compound 1, about 20 mg to about 260 mg of Compound 1 , or about 60 mg to about 200 mg of Compound 1. In some yet further embodiments, the pharmaceutical composition contains Compound 1 or a pharmaceutically salt thereof in an amount equivalent to about 20 mg to about 260 mg of Compound 1 , or about 60 mg to about 200 mg of Compound 1.

Embodiment A8 is a further embodiment of any one of Embodiments A1 to A7, wheren the Compound 1 or pharmaceutically salt thereof in the pharmaceutical composition is a pharmaceutical salt of Compound 1, for example, tris salt of Compound 1 Embodiment A9 is a further embodiment of any one of Embodiments A1 to A7, wheren the Compound 1 or pharmaceutically salt thereof in the pharmaceutical composition is tris salt of Compound 1.

Embodiment A10 is a further embodiment of Embodiment A9, wheren the tris salt of Compound 1 is in a crystalline form.

Embodiment A11 is a further embodiment of Embodiment A9, wheren the tris salt of Compound 1 is in a monohydrate crystalline form.

Embodiment A12 is a further embodiment of Embodiment A9, wheren the tris salt of Compound 1 is in Form 3, wherein Form 3 is a monohydrate form which has a PXRD comprising two peaks, in terms of 20 + 0.2° 20, at 7.4 and 14.8; and Form 3 has a ¹³ C ssNMR spectrum comprising chemical shifts at 54.7 and 138.4 ± 0.2 ppm.

The term "treating", as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term "treatment", as used herein, unless otherwise indicated, refers to the act of treating as "treating" is defined herein. The term “treating” also includes adjuvant and neo-adjuvant treatment of a subject (e.g. a human).

Embodiment A13 is a further embodiment of any one of Embodiments A1 to A12, wherein the method for treating T2DM includes improving glycemic control.

Embodiment A14 is a further embodiment of any one of Embodiments A1 to A13, wherein the method for treating T2DM includes reducing the fasting plasma glucose level of the human, for example, to about 126 mg/dL or lower.

Embodiment A15 is a further embodiment of any one of Embodiments A1 to A14, wherein the method 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.

Embodiment A16 is a further embodiment of any one of Embodiments A1 to A15, wherein the method treating T2DM includes reducing the mean daily glucose level to about 157 mg/dL or less.

Embodiment A17 is a further embodiment of any one of Embodiments A1 to A16, wherein the method for treating T2DM has low risk of hypoglycemia.

Embodiment A18 is a further embodiment of any one of Embodiments A1 to A17, wherein the method further includes administering to the human an additional therapeutic agent.

Embodiment A19 is a further embodiment of any one of Embodiments A1 to A18, wherein the method is an adjunct to a reduced-calorie diet and/or increased physical activity. In one embodiment (Embodiment B1), the invention provides a method for weight management control (including e.g. a method for treating obesity or overweight) comprising once-daily administering to a human in need thereof a pharmaceutical composition, wherein: the pharmaceutical composition is in the form of an oral dosage form; and the pharmaceutical composition comprises 2-((4-((S)-2-(5-chloropyridin-2-yl)-2- methylbenzo[c(][1 ,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)me thyl)-1 H- benzo[d]imidazole-6-carboxylic acid or a pharmaceutically salt thereof in an amount equivalent to about 10 mg to about 180 mg of 2-((4-((S)-2-(5-chloropyridin-2-yl)-2- methylbenzo[c(][1 ,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)me thyl)-1 H- benzo[d]imidazole-6-carboxylic acid.

Embodiment B2 is a further embodiment of Embodiment B1, wherein the pharmaceutical composition is present in an oral solution form or in a solid oral dosage form.

Embodiment B3 is a further embodiment of Embodiment B1 or B2, wherein the pharmaceutical composition is present in a solid oral dosage form, which includes, for example, tablets, capsules, caplets, sachets, powders, granules, or orally dispersible films.

Embodiment B4 is a further embodiment of any one of Embodiments B1 to B3, wherein the pharmaceutical composition is in an immediate-release solid dosage form.

Embodiment B5 is a further embodiment of any one of Embodiments B1 to B4, wherein the pharmaceutical composition is in an immediate-release tablet dosage form.

Embodiment B6 is a further embodiment of any one of Embodiments B1 to B5, wherein the pharmaceutical composition includes one or more tablets.

Embodiment B7 is a further embodiment of any one of Embodiments B1 to B6, wherein the pharmaceutical composition contains Compound 1 or a pharmaceutically salt thereof in an amount equivalent to about 10 mg to about 300 mg of Compound 1, for example, about 20 mg to about 280 mg of Compound 1 , about 20 mg to about 260 mg of Compound 1 , about 20 mg to about 240 mg of Compound 1 , about 20 mg to about 220 mg of Compound 1 , about 20 mg to about 200 mg of Compound 1 , about 20 mg to about 180 mg of Compound 1 , about 20 mg to about 120 mg of Compound 1 , about 20 mg to about 100 mg of Compound 1 , about 20 mg to about 80 mg of Compound 1 , about 20 mg to about 60 mg of Compound 1 , about 20 mg to about 40 mg of Compound 1 , about 20 mg to about 30 mg of Compound 1 , about 30 mg to about 260 mg of Compound 1 , about 30 mg to about 240 mg of Compound 1 , about 30 mg to about 180 mg of Compound 1, about 30 mg to about 120 mg of Compound 1 , about 30 mg to about 100 mg of Compound 1 , about 30 mg to about 60 mg of Compound 1 , about 60 mg to about 280 mg of Compound 1 , about 60 mg to about 260 mg of Compound 1 , about 60 mg to about 240 mg of Compound 1 , about 60 mg to about 220 mg of Compound 1 , about 60 mg to about 200 mg of Compound 1 , about 60 mg to about 180 mg of Compound 1 , about 60 mg to about 160 mg of Compound 1, about 60 mg to about 140 mg of Compound 1 , about 60 mg to about 120 mg of Compound 1 , about 60 mg to about 100 mg of Compound 1 , about 80 mg to about 280 mg of Compound 1 , about 80 mg to about 260 mg of Compound 1 , about 80 mg to about 240 mg of Compound 1 , about 80 mg to about 220 mg of Compound 1 , about 80 mg to about 220 mg of Compound 1 , about 80 mg to about 200 mg of Compound 1 , about 100 mg to about 280 mg of Compound 1, about 100 mg to about 260 mg of Compound 1, about 100 mg to about 240 mg of Compound 1, about 100 mg to about 220 mg of Compound 1, about 100 mg to about 220 mg of Compound 1, about 100 mg to about 200 mg of Compound 1, about 120 mg to about 280 mg of Compound 1, about 120 mg to about 260 mg of Compound 1, about 120 mg to about 240 mg of Compound 1, about 120 mg to about 220 mg of Compound 1, about 120 mg to about 220 mg of Compound 1, about 120 mg to about 200 mg of Compound 1, about 140 mg to about 280 mg of Compound 1, about 140 mg to about 260 mg of Compound 1, about 140 mg to about 240 mg of Compound 1, about 140 mg to about 220 mg of Compound 1, about 140 mg to about 220 mg of Compound 1 , about 140 mg to about 200 mg of Compound 1 , about 20 mg of Compound 1, about 30 mg of Compound 1, about 40 mg of Compound 1, about 50 mg of Compound 1 , about 60 mg of Compound 1 , about 70 mg of Compound 1 , about 80 mg of Compound 1, about 90 mg of Compound 1, about 100 mg of Compound 1 , about 110 mg of Compound 1, about 120 mg of Compound 1, about 130 mg of Compound 1, about 140 mg of Compound 1, about 150 mg of Compound 1, about 160 mg of Compound 1, about 170 mg of Compound 1, about 180 mg of Compound 1, about 190 mg of Compound 1, about 200 mg of

Compound 1, about 210 mg of Compound 1, about 220 mg of Compound 1, about 230 mg of

Compound 1, about 240 mg of Compound 1, about 250 mg of Compound 1, about 260 mg of

Compound 1, about 270 mg of Compound 1, about 280 mg of Compound 1, about 290 mg of

Compound 1 , or about 300 mg of Compound 1. In some further embodiments, the pharmaceutical composition contains Compound 1 or a pharmaceutically salt thereof in an amount equivalent to about 10 mg to about 300 mg of Compound 1, about 20 mg to about 260 mg of Compound 1 , or about 80 mg to about 260 mg of Compound 1. In some yet further embodiments, the pharmaceutical composition contains Compound 1 or a pharmaceutically salt thereof in an amount equivalent to about 20 mg to about 260 mg of Compound 1 , or about 80 mg to about 260 mg of Compound 1.

Embodiment B8 is a further embodiment of any one of Embodiments B1 to B7, wheren the Compound 1 or pharmaceutically salt thereof in the pharmaceutical composition is a pharmaceutical salt of Compound 1, for example, tris salt of Compound 1

Embodiment B9 is a further embodiment of any one of Embodiments B1 to B7, wheren the Compound 1 or pharmaceutically salt thereof in the pharmaceutical composition is tris salt of Compound 1. Embodiment B10 is a further embodiment of Embodiment B9, wheren the tris salt of Compound 1 is in a crystalline form.

Embodiment B11 is a further embodiment of Embodiment B9, wheren the tris salt of Compound 1 is in a monohydrate crystalline form.

Embodiment B12 is a further embodiment of Embodiment B9, wheren the tris salt of Compound 1 is in Form 3, wherein Form 3 is a monohydrate form which has a PXRD comprising two peaks, in terms of 20 + 0.2° 20, at 7.4 and 14.8; and Form 3 has a ¹³ C ssNMR spectrum comprising chemical shifts at 54.7 and 138.4 ± 0.2 ppm.

Embodiment B12 is a further embodiment of any one of Embodiments B1 to B12, wheren the initial body mass index (BMI) of the human is 24 kg/m ² or greater (the initial BMI is the BMI when the weight management control starts). In some further embodiments, the initial BMI of the human is 24 kg/m ² to 30 kg/m ² .

Embodiment B13 is a further embodiment of any one of Embodiments B1 to B12, wheren the initial BMI of the human is 27 kg/m ² or greater.

Embodiment B14 is a further embodiment of any one of Embodiments B1 to B12, wheren the initial BMI of the human is 30 kg/m ² or greater. In some further embodiments, the initial BMI of the human is 30.0 kg/m ² to 45 kg/m ² .

As used herein, a human with a BMI of 30 kg/m ² or greater is obese (i.e. suffering from obesity).

As used herein, a human with a BMI of 25.0 to 29.9 kg/m ² is overweight (i.e. suffering from overweight/having the condition of overweight).

The term "treating", as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term "treatment", as used herein, unless otherwise indicated, refers to the act of treating as "treating" is defined herein. The term “treating” also includes adjuvant and neo-adjuvant treatment of a subject (e.g. a human).

In some embodiments, weight management control includes treating obsesity or overweight.

Embodiment B15 is a further embodiment of any one of Embodiments B1 to B14, wherein the human has at least one weight-related comorbidity (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia).

Embodiment B16 is a further embodiment of any one of Embodiments B1 to B12, wherein the human is overweight and has at least one weight-related comorbidity (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Embodiment B17 is a further embodiment of any one of Embodiments B1 to B12, wherein the human has obesity and has at least one weight-related comorbidity (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia).

Embodiment B18 is a further embodiment of any one of Embodiments B1 to B17, wherein the method for weight management control includes reducing the body weight of the human, for example, greater than about 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10%.

Embodiment B19 is a further embodiment of any one of Embodiments B1 to B17, wherein the method for weight management control includes reducing the body weight of the human, for example, greater than about 5%, 6%, 7%, 8%, 9%, or 10%.

Embodiment B20 is a further embodiment of any one of Embodiments B1 to B17, wherein the method for weight management control includes reducing the body weight of the human, for example, greater than about 8%, 9%, 10%, 11 %, 12%, 13%, 14%, or 15%.

Embodiment B21 is a further embodiment of any one of Embodiments B1 to B17, wherein the method for weight management control includes reducing the body weight of the human, for example, greater than about 10%, 15%, 20%, 25%, or 30%.

Embodiment B22 is a further embodiment of any one of Embodiments B1 to B21 , wherein the method for weight management control includes the body mass index (BMI) of the human, for example, greater than about 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10%.

Embodiment B23 is a further embodiment of any one of Embodiments B1 to B21 , wherein the method for weight management control includes the body mass index (BMI) of the human, for example, greater than about 8%, 9%, 10%, 11 %, 12%, 13%, 14%, or 15%.

Embodiment B24 is a further embodiment of any one of Embodiments B1 to B21 , wherein the method for weight management control includes the body mass index (BMI) of the human, for example, greater than about 10%, 15%, 20%, 25%, or 30%.

Embodiment B25 is a further embodiment of any one of Embodiments B1 to B24, wherein the method further includes administering to the human an additional therapeutic agent.

Embodiment B26 is a further embodiment of any one of Embodiments B1 to B25, wherein the method is an adjunct to a reduced-calorie diet and/or increased physical activity.

In one embodiment (Embodiment C1), the present invention provides an immediate- release oral pharmaceutical composition comprising:

2-((4-((S)-2-(5-chloropyridin-2-yl)-2-methylbenzo[c(][1 ,3]dioxol-4-yl)piperidin-1-yl)methyl)- 1-(((S)-oxetan-2-yl)methyl)-1 H-benzo[d]imidazole-6-carboxylic acid, or a pharmaceutically acceptable salt thereof (e.g. tris salt of Compound 1); a filler [e.g. microcrystalline cellulose, lactose (e.g. in the form of lactose monohydrate), or a combination thereof, for example, a combination of microcrystalline cellulose and lactose monohydrate in about 2:1 weight ratio]; a disintegrant; and a lubricant.

Embodiment C2 is a further embodiment of Embodiment C1 , wherein the oral pharmaceutical composition comprises microcrystalline cellulose; lactose (e.g. in the form of lactose monohydrate); crospovidone (e.g. Crospovidone Type B); and a metallic stearate (such as magnesium stearate) or sodium stearyl fumarate.

In some embodiments, the oral pharmaceutical composition comprises microcrystalline cellulose; lactose (e.g. in the form of lactose monohydrate); Crospovidone Type B; and sodium stearyl fumarate.

Embodiment C3 is a further embodiment of Embodiment C1 or C2, wherein the oral pharmaceutical composition of the invention comprises:

1.0% to 35.0% by weight of Compound 1 or a pharmaceutically acceptable salt thereof (e.g. tris salt of Compound 1);

60% to 95% by weight of filler [e.g. microcrystalline cellulose, lactose (e.g. in the form of lactose monohydrate), or a combination thereof, for example, a combination of microcrystalline cellulose and lactose monohydrate in about 2:1 weight ratio];

1.0% to 5.0% by weight of disintegrant (e.g. crospovidone, starch, pregelatinized starch, carboxymethylcellulose, hydroxypropylcellulose, sodium starch glycolate or croscarmellose sodium); and

0.2% to 3.0% by weight lubricant [e.g. metallic stearate (such as magnesium stearate) or sodium stearyl fumarate].

Embodiment C4 is a further embodiment of any one of Embodiments C1 or C3, wherein the oral pharmaceutical composition of the invention comprises:

1.0% to 30.0% by weight of Compound 1 or a pharmaceutically acceptable salt thereof (e.g. tris salt of Compound 1);

60% to 95% by weight of filler [e.g. microcrystalline cellulose, lactose (e.g. in the form of lactose monohydrate), or a combination thereof, for example, a combination of microcrystalline cellulose and lactose monohydrate in about 2:1 weight ratio];

1.0% to 5.0% by weight of disintegrant (e.g. sodium starch glycolate or croscarmellose sodium); and

0.2% to 2.5% by weight lubricant [e.g. metallic stearate (such as magnesium stearate) or sodium stearyl fumarate].

Embodiment C5 is a further embodiment of any one of Embodiments C1 or C3, wherein the oral pharmaceutical composition of the invention comprises:

1.0% to 20.0% by weight of Compound 1 or a pharmaceutically acceptable salt thereof (e.g. tris salt of Compound 1); 60% to 95% by weight of filler [e.g. microcrystalline cellulose, lactose (e.g. in the form of lactose monohydrate), or a combination thereof, for example, a combination of microcrystalline cellulose and lactose monohydrate in about 2:1 weight ratio];

2.0% to 4.0% by weight of disintegrant (e.g. crospovidone, starch, pregelatinized starch, carboxymethylcellulose, hydroxypropylcellulose, sodium starch glycolate or croscarmellose sodium); and

1.0% to 2.5% by weight lubricant [e.g. metallic stearate (such as magnesium stearate) or sodium stearyl fumarate].

Embodiment C6 is a further embodiment of any one of Embodiments C1 or C3, wherein the oral pharmaceutical composition of the invention comprises:

1.0% to 20.0% by weight of Compound 1 or a pharmaceutically acceptable salt thereof (e.g. tris salt of Compound 1);

75% to 95% by weight of filler [e.g. microcrystalline cellulose, lactose (e.g. in the form of lactose monohydrate), or a combination thereof, for example, a combination of microcrystalline cellulose and lactose monohydrate in about 2:1 weight ratio];

2.0% to 4.0% by weight of disintegrant (e.g. crospovidone, starch, pregelatinized starch, carboxymethylcellulose, hydroxypropylcellulose, sodium starch glycolate or croscarmellose sodium); and

1.0% to 2.5% by weight lubricant [e.g. metallic stearate (such as magnesium stearate) or sodium stearyl fumarate].

Embodiment C7 is a further embodiment of any one of Embodiments C1 or C3, wherein the oral pharmaceutical composition of the invention comprises:

1.0% to 20.0% by weight of tris salt of Compound 1 (e.g. Form 3 of tris salt of Compound 1);

75% to 95% by weight of filler [e.g. a combination of microcrystalline cellulose and lactose (e.g. in the form of lactose monohydrate)];

2.0% to 4.0% by weight of disintegrant (e.g. crospovidone such as Crospovidone Type B); and

1.0% to 2.5% by weight lubricant [e.g. metallic stearate (such as magnesium stearate) or sodium stearyl fumarate].

Embodiment C8 is a further embodiment of any one of Embodiments C1 or C3, wherein the oral pharmaceutical composition of the invention comprises:

8.0% to 20.0% by weight of tris salt of Compound 1 (e.g. Form 3 of tris salt of Compound 1);

75% to 87% by weight of filler [e.g. microcrystalline cellulose, lactose (e.g. in the form of lactose monohydrate), or a combination thereof]; 2.0% to 4.0% by weight of disintegrant (e.g. crospovidone such as Crospovidone Type

B); and

1.0% to 2.5% by weight lubricant [e.g. metallic stearate (such as magnesium stearate) or sodium stearyl fumarate].

Embodiment C9 is a further embodiment of any one of Embodiments C1 or C3, wherein the oral pharmaceutical composition of the invention comprises:

1.0% to 10.0% by weight of tris salt of Compound 1 (e.g. Form 3 of tris salt of Compound 1);

80% to 95% by weight of filler [e.g. microcrystalline cellulose, lactose (e.g. in the form of lactose monohydrate), or a combination thereof];

2.0% to 4.0% by weight of disintegrant (e.g. crospovidone such as Crospovidone Type B); and

1.0% to 2.5% by weight lubricant [e.g. metallic stearate (such as magnesium stearate) or sodium stearyl fumarate].

Embodiment C10 is a further embodiment of any one of Embodiments C1 or C9, wherein the Compound 1 or pharmaceutically salt thereof in the pharmaceutical composition is in an amount equivalent to about 1 .0 mg to about 300 mg of Compound 1 , for example, in an amount equivalent to about 1 .0 mg to about 260 mg of Compound 1 , about 1.0 mg to about 200 mg of Compound 1 , about 1.0 mg to about 180 mg of Compound 1 , about 1.0 mg to about 150 mg of Compound 1 , about 1.0 mg to about 125 mg of Compound 1 , about 1.0 mg to about 100 mg of Compound 1 , about 1 .0 mg to about 80 mg of Compound 1 , about 1 .0 mg to about 60 mg of Compound 1 , about 1 .0 mg to about 50 mg of Compound 1 , about 10 mg to about 100 mg of Compound 1 , about 10 mg to about 80 mg of Compound 1 , about 10 mg to about 60 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 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 , about 1 mg of Compound 1 , about 10 mg of Compound 1 , about 20 mg of Compound 1 , about 30 mg of Compound 1 , about 40 mg of Compound 1 , about 50 mg of Compound 1 , about 60 mg of Compound 1 , about 70 mg of Compound 1 , about 80 mg of Compound 1 , about 90 mg of Compound 1 , about 100 mg of Compound 1 , about 120 mg of Compound 1 , about 140 mg of Compound 1 , about 150 mg of Compound 1 , about 160 mg of Compound 1 , about 180 mg of Compound 1 , or about 200 mg of Compound 1. Embodiment C11 is a further embodiment of any one of Embodiments C1 or C9, wherein the Compound 1 or pharmaceutically salt thereof in the pharmaceutical composition is in an amount equivalent to about 10 mg to about 200 mg of Compound 1 , about 10 mg to about 120 mg of Compound 1, about 1 mg to about 10 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 , about 1 mg of Compound 1 , about 10 mg of Compound 1 , about 20 mg of Compound 1, about 50 mg of Compound 1, about 60 mg of Compound 1, about 80 mg of Compound 1, about 100 mg of Compound 1, about 120 mg of Compound 1, or about 150 mg of Compound 1.

Embodiment C12 is a further embodiment of any one of Embodiments C1 or C11 , wherein the immediate-release oral dosage form is a solid oral dosage form, which includes, for example, tablets, capsules, caplets, sachets, powders, granules, orally dispersible films. In some embodiments, the immediate-release oral dosage form is a tablet form.

Embodiment C13 is a further embodiment of any one of Embodiments C1 or C12, wherein the 2-((4-((S)-2-(5-chloropyridin-2-yl)-2-methylbenzo[d][1 , 3]dioxol-4-yl)pi peridi n- 1 - yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1 H-benzo[d]imidazole-6-carboxylic acid or a pharmaceutically acceptable salt thereof is tris salt of 2-((4-((S)-2-(5-chloropyridin-2-yl)-2- methylbenzo[d][1 ,3]dioxol-4-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)me thyl)-1 H- benzo[d]imidazole-6-carboxylic acid.

Embodiment C14 is a further embodiment of any one of Embodiments C1 or C12, wherein the tris salt of Compound 1 is in a crystalline form, for example, a monohydrate form (e.g. Form 3, wherein Form 3 has a PXRD comprising two peaks, in terms of 20 + 0.2° 20, at

7.4 and 14.8; and Form 3 has a ¹³ C ssNMR spectrum comprising chemical shifts at 54.7 and

138.4 ± 0.2 ppm).

Embodiment C15 is a further embodiment of any one of Embodiments C1 or C12, wherein the tris salt of Compound 1 is in an amorphous form.

In some embodiments, the immediate-release oral pharmaceutical composition in any one of Embodiments C1 to C15 can be used in the method of any one of Embodiments A1 to A19.

In some embodiments, the immediate-release oral pharmaceutical composition in any one of Embodiments C1 to C15 can be used in the method of any one of Embodiments B1 to B26.

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” means within an acceptable standard error of the mean, when considered by one skilled in the art. The term “tris” means 1,3-dihydroxy-2-(hydroxymethyl)propan-2-amine, also known as THAM, tromethamine, 2-amino-2-(hydroxymethyl)propane-1 ,3-diol, tris(hydroxymethyl)aminomethane.

Tris salt of Compound 1 means a salt of Compound 1 made using 1 ,3-dihydroxy-2- (hydroxymethyl)propan-2-amine. The tris is associated with the carboxylic acid moiety of Compound 1. Unless otherwise stated, when referencing the tris salt of Compound 1, the counterion and Compound 1 are in a stoichiometric ratio of about 1 :1 (i.e. from 0.9: 1.0 to 1.0:0.9, for example, from 0.95:1.00 to 1.00:0.95). Another chemical name for tris salt of Compound 1 is 1,3-dihydroxy-2-(hydroxymethyl)propan-2-aminium 2-((4-((S)-2-(5-Chloropyridin- 2-yl)-2-methylbenzo[d][1,3]dioxol-4-yl)piperidin-1-yl)methyl )-1-(((S)-oxetan-2-yl)methyl)-1 H- benzo[d]imidazole-6-carboxylate, which can also be represented, for example, by one of the following structures.

Those skilled in the art would readily understand that multiple nomenclatures can be used to name a same compound (including a same salt).

The term “monohydrate” when used to describe a crystalline form of a compound (or a salt) means that the stoichiometric ratio of the hydrate water to the compound (or salt) is about 1 : 1 (for example, from 0.9 : 1.0 to 1.1 : 1.0).

In some embodiments, the tris salt of Compound is present as a crystalline form, for example, a monohydrate crystalline form, such as Form 3. Preparation and characterization of Form 3 can be found in WO2021116874 (International Application No. PCT/IB2020/061585 filed December 07, 2020). As reported in WO2021116874 (including information on sample preparation and PXRD instrument and data collection), Form 3 has a PXRD comprising at least one, two, three, or four peaks, in terms of 20 + 0.2° 20, at 3.7, 7.4, 9.9, 14.8, and 20.6. In some embodiments, Form 3 has a PXRD comprising at least two or three peaks, in terms of 20 + 0.2° 20, at 3.7, 7.4, 9.9, 14.8, and 20.6. In some embodiments, Form 3 has a PXRD comprising two peaks, in terms of 20 + 0.2° 20, at 7.4 and 14.8. In some embodiments, Form 3 has a PXRD comprising three peaks, in terms of 20 + 0.2° 20, at 3.7, 7.4, and 14.8. In some embodiments, Form 3 has a PXRD comprising four peaks, in terms of 20 + 0.2° 20, at 3.7, 7.4, 14.8, and 20.6. In some embodiments, Form 3 has a PXRD comprising five peaks, in terms of 20 + 0.2° 20, at 3.7, 7.4, 9.9, 14.8, and 20.6. In some embodiments, Form 3 has a PXRD comprising peaks, in terms of 20 + 0.2° 20, at 3.7, 7.4, 9.9, 11.1 , 14.8, 18.2, 20.6, 23.5, 24.3, and 24.6. As reported in WO2021116874 (including information on sample preparation and NMR instrument and data collection), some characteristic ¹³ C ssNMR chemical shifts of Form 3, expressed as ppm, are at 42.8, 54.7, 128.2, 138.4 and 156.6 ± 0.2 ppm. In some embodiments, Form 3 has a ¹³ C ssNMR spectrum comprising chemical shifts at 54.7 and 138.4 ± 0.2 ppm. In some embodiments, Form 3 has a ¹³ C ssNMR spectrum comprising chemical shifts at 54.7, 138.4 and 156.6 ppm ± 0.2 ppm.

Pharmaceutically acceptable salts include acid addition and base salts.

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

Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, 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.

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

Pharmaceutically acceptable salts may be prepared by one or more of three methods:

(i) by reacting a compound with the desired acid or base;

(ii) by removing an acid- or base-labile protecting group from a suitable precursor of a compound or by ring-opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid or base; or (iii) by converting one salt of a compound to another by reaction with an appropriate acid or base or by means of a suitable ion exchange column.

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

Compounds and 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, for example, ethanol. The term ‘hydrate’ is employed when said solvent is water. For example, a hydrate crystalline form of tris salt of Compound 1 disclosed herein refers to a crystalline material/complex that includes both tris salt of Compond 1 and water (hydrate water) in the crystal lattice of the crystalline material/complex.

A currently accepted classification system for organic hydrates is one that defines isolated site, channel, or metal-ion coordinated hydrates - see Polymorphism in Pharmaceutical Solids by K. R. Morris (Ed. H. G. Brittain, Marcel Dekker, 1995). Isolated site hydrates are ones in which the water molecules are isolated from direct contact with each other by intervening organic molecules. In channel hydrates, the water molecules lie in lattice channels where they are next to other water molecules. In metal-ion coordinated hydrates, the water molecules are bonded to the metal ion.

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

Also included within the scope of the invention are multi-component complexes (other than salts and solvates) wherein the drug and at least one other component are present in stoichiometric or non-stoichiometric amounts. Complexes of this type include clathrates (drughost inclusion complexes) and co-crystals. The latter are typically defined as crystalline complexes of neutral molecular constituents which are bound together through non-covalent interactions, but could also be a complex of a neutral molecule with a salt. Co-crystals may be prepared by melt crystallisation, by recrystallisation from solvents, or by physically grinding the components together - see Chem Commun, 17, 1889-1896, by O. Almarsson and M. J. Zaworotko (2004). For a general review of multi-component complexes, see J Pharm Sci, 64 (8), 1269-1288, by Haleblian (August 1975).

The compounds of the invention may exist in a continuum of solid states ranging from fully amorphous to fully crystalline. The term ‘amorphous’ refers to a state in which the material lacks long range order at the molecular level and, depending upon temperature, may exhibit the physical properties of a solid or a liquid. Typically such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid. Upon heating, a change from solid to liquid properties occurs which is characterised by a change of state, typically second order (‘glass transition’). The term ‘crystalline’ refers to a solid phase in which the material has a regular ordered internal structure at the molecular level and gives a distinctive X-ray diffraction pattern with defined peaks. Such materials when heated sufficiently will also exhibit the properties of a liquid, but the change from solid to liquid is characterised by a phase change, typically first order (‘melting point’).

A compound may also exist in a mesomorphic state (mesophase or liquid crystal) when subjected to suitable conditions. The mesomorphic state is intermediate between the true crystalline state and the true liquid state (either melt or solution). Mesomorphism arising as the result of a change in temperature is described as ‘thermotropic’ and that resulting from 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 consist of molecules which possess an ionic (such as -COONa ⁺ , -COOK ⁺ , or -SOs'Na ⁺ ) or non-ionic (such as -N'N CHsh) polar head group. For more information, see Crystals and the Polarizing Microscope by N. H. Hartshorne and A. Stuart, 4 ^th Edition (Edward Arnold, 1970).

Some compounds may exhibit polymorphism and/or one or more kinds of isomerism (e.g. optical, geometric or tautomeric isomerism). The crystalline forms of the invnetions may also be isotopically labelled. Such variation is implicit to Compound 1 or its salt defined as they are by reference to their structural features and therefore within the scope of the invention.

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

Certain pharmaceutically acceptable salts of Compound 1 may also contain a counterion which is optically active (e.g. d-lactate or l-lysine) or racemic (e.g. dl-tartrate or dl-arginine).

Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallisation.

Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). Alternatively, a racemic precursor containing a chiral ester may be separated by enzymatic resolution (see, for example, Int J Mol Sci 29682-29716 by A. C. L. M. Carvaho et. al. (2015)). In the case where a compound contains an acidic or basic moiety, a salt may be formed with an optically pure base or acid such as 1 -phenylethylamine or tartaric acid. The resulting diastereomeric mixture may be separated by fractional crystallization and one or both of the diastereomeric salts converted to the corresponding pure enantiomer(s) by means well known to a skilled person. Alternatively, the racemate (or a racemic precursor) may be covalently reacted with a suitable optically active compound, for example, an alcohol, amine or benzylic chloride. The resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization by means well known to a skilled person to give the separated diastereomers as single enantiomers with 2 or more chiral centers. Chiral compounds (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2% to 20%, and from 0 to 5% by volume of an alkylamine, typically 0.1% diethylamine. Concentration of the eluate affords the enriched mixture. Chiral chromatography using sub-and supercritical fluids may be employed. Methods for chiral chromatography 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, Pennsylvania, USA, a subsidiary of Daicel® Chemical Industries, Ltd., Tokyo, Japan.

When any racemate crystallises, crystals of two different types are possible. The first type is the racemic compound (true racemate) referred to above wherein one homogeneous form of crystal is produced containing both enantiomers in equimolar amounts. The second type is the racemic mixture or conglomerate wherein two forms of crystal are produced in equimolar amounts each comprising a single enantiomer. While both of the crystal forms present in a racemic mixture have identical physical properties, they may have different physical properties compared to the true racemate. Racemic mixtures may be separated by conventional techniques known to those skilled in the art - see, for example, Stereochemistry of Organic Compounds by E. L. Eliel and S. H. Wilen (Wiley, 1994).

Although Compound 1 and its salts have been drawn herein in a single tautomeric form, all possible tautomeric forms are included within the scope of the invention.

The present invention includes all pharmaceutically acceptable isotopically-labeled Compound 1 or a salt thereof wherein 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 which predominates in nature. Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as ² H and ³ H, carbon, such as ¹¹ C, ¹³ C and ¹⁴ C, chlorine, such as ³⁶ CI, nitrogen, such as ¹³ N and ¹⁵ N, and oxygen, such as ¹⁵ 0, ¹⁷ O and ¹⁸ O.

Certain isotopically-labelled Compound 1 or a salt thereof, for example those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. ³ H, and carbon-14, i.e. ¹⁴ C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.

Substitution with heavier isotopes such as deuterium, i.e. ² H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.

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

Isotopically-labeled compounds can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.

Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D2O, de-acetone, de- DMSO.

Administration and Dosing

Typically, a compound of the invention is administered in an amount effective to treat a condition as described herein. The compounds of the invention may be administered as compound per se, or alternatively, as a pharmaceutically acceptable salt. For administration and dosing purposes, the compound per se or pharmaceutically acceptable salt thereof will simply be referred to as the compounds of the invention.

The compounds of the invention may be administered by any suitable route in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended.

The compounds of the invention may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the bloodstream directly from the mouth.

The dosage regimen for the compounds of the invention and/or compositions containing said compounds is based on a variety of 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 employed. Multiple doses per day may be used to increase the total daily dose, if desired.

For oral administration, the compositions may be provided, for example, in the form of tablets containing the active ingredient for the symptomatic adjustment of the dosage to the patient.

Suitable subjects according to the invention include mammalian subjects. In one embodiment, humans are suitable subjects. Human subjects may be of either sex and at any stage of development.

Pharmaceutical Compositions

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

In some embodiments, pharmaceutically acceptable carriers include one or more components select from diluents/fi Ilers, disintegrants, binders, wetting agents, and lubricants.

As used herein, the term “diluent or filler” refers to a substance that acts to dilute the active pharmacological agent to the desired dosage and/or that acts as a carrier for the active pharmacological agent. Examples of diluent or filler include mannitol, lactose (including e.g. lactose monohydrate), sucrose, maltodextrin, sorbitol, xylitol, powdered cellulose, microcrystalline cellulose, carboxymethylcellulose, carboxyethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, methylhydroxyethylcellulose, starch, sodium starch glycolate, pregelatinized starch, a calcium phosphate, a metal carbonate, a metal oxide, and/or a metal aluminosilicate.

As used herein, the term “disintegrant” refers to a substance that encourages disintegration in water (or water-containing fluid in vivo) of a pharmaceutical composition/formulation of the invention. Examples of disintegrant include croscarmellose sodium, carmellose calcium, crospovidone, alginic acid, sodium alginate, potassium alginate, calcium alginate, an ion exchange resin, an effervescent system based on food acids and an alkaline carbonate component, clay, talc, starch, pregelatinized starch, sodium starch glycolate, cellulose floc, carboxymethylcellulose, hydroxypropylcellulose, calcium silicate, a metal carbonate, sodium bicarbonate, calcium citrate, and/or calcium phosphate.

As used herein, the term “binder” refers to a substance that increases the mechanical strength and/or compressibility of a pharmaceutical composition/formulation of the invention. Examples of binder include polyvinylpyrrolidone, copovidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, crosslinked poly(acrylic acid), gum arabic, gum acacia, gum tragacanath, lecithin, casein, polyvinyl alcohol, gelatin, kaolin, cellulose, methylcellulose, hydroxymethylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, hydroxyethylcellulose, methylhydroxyethylcellulose, silicified microcrystalline cellulose, starch, maltodextrin, dextrins, microcrystalline cellulose, and/or sorbitol.

As used herein, the term “wetting agent” refers to a substance that increases the water permeability of a pharmaceutical composition/formulation of the invention. In another aspect, the term, “wetting agent” refers to a substance that increases dissolution of the active pharmacological agent in water (or water containing fluid in vivo). In yet another aspect, the term “wetting agent” refers to a substance that increases the bioavailability of the active pharmacological agent after administration of a pharmaceutical composition/formulation of the invention. Examples of wetting agent include metallic lauryl sulfate, polyethylene glycol, glycerides of fatty ester, polyoxyethylene-polyoxypropylene copolymer, polyoxyethylene-alkyl ether, metal alkyl sulfate, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil derivative, sugar ester of fatty acid, polyglycolized glyceride, quaternary ammonium amine compound, lauroyl macrogol glycerides, caprylocaproyl macrogolglycerides, stearoyl macrogol glycerides, linoleoyl macrogol glycerides, oleoyl macrogol glycerides, polyethoxylated vegetable oil, polyethoxylated sterol, polyethoxylated cholesterol, polyethoxylated glycerol fatty acid ester, polyethoxylated fatty acid ester, sulfosuccinate, taurate, and/or docusate sodium.

As used herein, the term “lubricant” refers to a substance that aids in preventing sticking to the equipment of the pharmaceutical formulations/composition during processing and/or that improves powder flow of the composition/formulation during processing. Examples of lubricant include stearic acid, metallic stearate (e.g. magnesium stearate), sodium stearyl fumarate, fatty acid, fatty alcohol, fatty acid ester, glyceryl behenate, mineral oil, vegetable oil, paraffin, leucine, silica, silicic acid, talc, propylene glycol fatty acid ester, polyethylene glycol, polypropylene glycol, polyalkylene glycol, and/or sodium chloride.

In some embodiments, a composition of the invention comprises 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. metallic stearate (such as magnesium stearate) or sodium stearyl fumarate]. In some embodiments, a composition of the invention comprises microcrystalline cellulose, lactose (e.g. in the form of lactose monohydrate), sodium starch glycolate, and sodium stearyl fumarate.

The compositions of this invention may be in a variety of forms. These include, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions, dispersions or suspensions, tablets, pills, powders, liposomes and suppositories. The form depends on the intended mode of administration and therapeutic application.

Oral administration of a solid dose form may be, for example, presented in discrete units, such as hard or soft capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of a pharmacological active ingredient (API, for example, Compound 1 or a pharmaceutical acceptable salt thereof such as tris salt of Compound 1). In one embodiment, the oral administration may be in tablet form. In one embodiment, the oral administration may be in capsule form. In one embodiment, the oral administration may be in a powder or granule form. In one embodiment, the oral dose form is sub-lingual, such as, for example, a lozenge. In such solid dosage forms, the compounds of the invention are ordinarily 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 also may comprise buffering agents or may be prepared with enteric coatings.

In another embodiment, oral administration may be in a liquid dose form. 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 also may comprise adjuvants, such as wetting, emulsifying, suspending, flavoring (e.g., sweetening), and/or perfuming agents.

Other carrier materials and modes of administration known in the pharmaceutical art may also be used. Pharmaceutical compositions of the invention may be prepared by any of the well-known techniques of pharmacy, such as effective formulation and administration procedures. The above considerations in regard to effective formulations and administration procedures are well known in the art and are described in standard textbooks. Formulation of drugs is discussed in, for example, Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania, 1975; Liberman et al., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Kibbe et al., Eds., Handbook of Pharmaceutical Excipients (3rd Ed.), American Pharmaceutical Association, Washington, 1999.

Co-administration The compositions of the invention can be used alone, or in combination with other therapeutic agents. The invention provides any of the uses, methods or compositions as defined herein wherein the compound of any embodiment herein, or pharmaceutically acceptable salt thereof, or pharmaceutically acceptable solvate of said compound or salt, is used in combination with one or more other therapeutic agent discussed herein. This would include a pharmaceutical composition for the treatment of a disease or condition for which an agonist of the GLP-1R is indicated, comprising a composition of the invention, as defined in any of the embodiments described herein, and one or more other therapeutic agent discussed herein.

The administration of two or more compounds “in combination” means that all of the compounds are administered closely enough in time that each may generate a biological effect in the same time frame. The presence of one agent may alter the biological effects of the other compound(s). The two or more compounds may be administered simultaneously, concurrently or sequentially. Additionally, simultaneous administration may be carried out by mixing the compounds prior to administration or by administering the compounds at the same point in time but as separate dosage forms at the same or different site of administration.

The phrases “concurrent administration,” “co-administration,” “simultaneous administration,” and “administered simultaneously” mean that the compounds are administered in combination.

In another embodiment, the invention provides methods of treatment that include administering compounds of the present invention in combination with one or more other pharmaceutical agents, wherein the one or more other pharmaceutical agents may be selected from the agents discussed herein.

In one embodiment, the compounds of this invention are administered with an antidiabetic agent including but not limited to a biguanide (e.g., metformin), a sulfonylurea (e.g., tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride, or glipizide), a thiazolidinedione (e.g., pioglitazone, rosiglitazone, or lobeglitazone), a glitazar (e.g., saroglitazar, aleglitazar, muraglitazar or tesaglitazar), a meglitinide (e.g., nateglinide, repaglinide), a dipeptidyl peptidase 4 (DPP-4) inhibitor (e.g., sitagliptin, vildagliptin, saxagliptin, linagliptin, gemigliptin, anagliptin, teneligliptin, alogliptin, trelagliptin, dutogliptin, or omarigliptin), a glitazone (e.g., pioglitazone, rosiglitazone, balaglitazone, rivoglitazone, or lobeglitazone), a sodium-glucose linked transporter 2 (SGLT2) inhibitor (e.g., empagliflozin, canagliflozin, dapagliflozin, ipragliflozin, Ipragliflozin, tofogliflozin, sergliflozin etabonate, remogliflozin etabonate, or ertugliflozin), an SGLTL1 inhibitor, a GPR40 agonist (FFAR1/FFA1 agonist, e.g. fasiglifam), glucose-dependent insulinotropic peptide (GIP) and analogues thereof, an alpha glucosidase inhibitor (e.g. voglibose, acarbose, or miglitol) , or an insulin or an insulin analogue, including the pharmaceutically acceptable salts of the specifically named agents and the pharmaceutically acceptable solvates of said agents and salts.

In another embodiment, the compounds of this invention are administered with an antiobesity or other agent including but not limited to peptide YY or an analogue thereof, a neuropeptide Y receptor type 2 (NPYR2) agonist, a NPYR1 or NPYR5 antagonist, a cannabinoid receptor type 1 (CB1R) antagonist, a lipase inhibitor (e.g., orlistat), a human proislet peptide (HIP), a melanocortin receptor 4 agonist (e.g., setmelanotide), a melanin concentrating hormone receptor 1 antagonist, a farnesoid X receptor (FXR) agonist (e.g. obeticholic acid), zonisamide, phentermine (alone or in combination with topiramate), a norepinephrine/dopamine reuptake inhibitor (e.g., buproprion), an opioid receptor antagonist (e.g., naltrexone), a combination of norepinephrine/dopamine reuptake inhibitor and opioid receptor antagonist (e.g., a combination of bupropion and naltrexone), a GDF-15 analog, sibutramine, a cholecystokinin agonist, amylin and analogues therof (e.g., pramlintide), leptin and analogues thereof (e.g., metroleptin), a serotonergic agent (e.g., lorcaserin), a methionine aminopeptidase 2 (MetAP2) inhibitor (e.g., beloranib or ZGN-1061), phendimetrazine, diethylpropion, benzphetamine, an SGLT2 inhibitor (e.g., empagliflozin, canagliflozin, dapagliflozin, ipragliflozin, Ipragliflozin, tofogliflozin, sergliflozin etabonate, remogliflozin etabonate, or ertugliflozin), an SGLTL1 inhibitor, a dual SGLT2/SGLT1 inhibitor, a fibroblast growth factor receptor (FGFR) modulator, an AMP-activated protein kinase (AMPK) activator, biotin, a MAS receptor modulator, a GIP (gastric inhibitory polypeptide, also called glucosedependent insulinotropic polypeptide) receptor antagonist or agonist, or a glucagon receptor agonist (alone or in combination with another GLP-1R agonist, e.g., liraglutide, exenatide, dulaglutide, albiglutide, lixisenatide, or semaglutide), including the pharmaceutically acceptable salts of the specifically named agents and the pharmaceutically acceptable solvates of said agents and salts.

In another embodiment, the compounds of this invention are administered in combination with one or more of the following: an agent to treat NASH including but not limited to PF-05221304, an FXR agonist (e.g., obeticholic acid), a PPAR a/5 agonist (e.g., elafibranor), a synthetic fatty acid-bile acid conjugate (e.g., aramchol), a caspase inhibitor (e.g., emricasan), an anti-lysyl oxidase homologue 2 (LOXL2) monoclonal antibody (e.g., simtuzumab), a galectin 3 inhibitor (e.g., GR-MD-02), a MAPK5 inhibitor (e.g., GS-4997), a dual antagonist of chemokine receptor 2 (CCR2) and CCR5 (e.g., cenicriviroc), a fibroblast growth factor 21 (FGF21) agonist (e.g., BMS-986036), a leukotriene D4 (LTD4) receptor antagonist (e.g., tipelukast), a niacin analogue (e.g., ARI 3037MO), an ASBT inhibitor (e.g., volixibat), an acetyl-CoA carboxylase (ACC) inhibitor (e.g., NDI 010976 or PF-05221304), a ketohexokinase (KHK) inhibitor, a diacylglyceryl acyltransferase 2 (DGAT2) inhibitor, a CB1 receptor antagonist, an anti-CB1 R antibody, or an apoptosis signal-regulating kinase 1 (ASK1) inhibitor, including the pharmaceutically acceptable salts of the specifically named agents and the pharmaceutically acceptable solvates of said agents and salts.

Some specific compounds that can be used in combination with the compounds of the present invention for treating diseases or disorders described herein include:

4-(4-(1-lsopropyl-7-oxo-1 ,4,6,7-tetrahydrospiro[indazole-5,4'-piperidine]-1'-carbonyl )-6- methoxypyridin-2-yl)benzoic acid, which is an example of a selective ACC inhibitor and was prepared as the free acid in Example 9 of U.S. Patent No. 8,859,577, which is the U.S. national phase of International Application No. PCT/IB2011/054119, the disclosures of which are hereby incorporated herein by reference in their entireties for all purposes. Crystal forms of 4-(4-(1- lsopropyl-7-oxo-1 ,4,6,7-tetrahydrospiro[indazole-5,4'-piperidine]-1'-carbonyl )-6-methoxypyridin- 2-yl)benzoic acid, including an anhydrous mono-tris form (Form 1) and a trihydrate of the monotris salt (Form 2), are described in International PCT Application No. PCT/IB2018/058966, the disclosure of which is hereby incorporated herein by reference in its entirety for all purposes;

(S)-2-(5-((3-Ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(tetr ahydrofuran-3-yl)pyrimidine-5- carboxamide, or a pharmaceutically acceptable salt thereof, and its crystalline solid forms (Form 1 and Form 2) is an example of a DGAT2 inhibitor described in Example 1 of U.S. Patent No. 10,071 ,992, the disclosure of which is hereby incorporated herein by reference in its entirety for all purposes;

[(1 R,5S,6R)-3-{2-[(2S)-2-methylazetidin-1-yl]-6-(trifluoromethy l)pyrimidin-4-yl}-3- azabicyclo[3.1.0]hex-6-yl]acetic acid, or a pharmaceutically acceptable salt thereof, (including a crystalline free acid form thereof) is an example of a ketohexokinase (KHK) inhibitor and is described in Example 4 of U.S. Patent No. 9,809,579, the disclosure of which is hereby incorporated herein by reference in its entirety for all purposes; and the FXR agonist Tropifexor or a pharmaceutically acceptable salt thereof is described in Example 1-1 B of U.S. Patent No. 9,150,568, the disclosure of which is hereby incorporated herein by reference in its entirety for all purposes.

These agents and compounds of the invention can be combined with pharmaceutically acceptable vehicles such as saline, Ringer’s solution, dextrose solution, and the like. The particular dosage regimen, i.e. , dose, timing and repetition, will depend on the particular individual and that individual’s medical history.

Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed, and may comprise buffers such as phosphate, citrate, and other organic acids; salts such as sodium chloride; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium 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; proteins, such as serum albumin, gelatin, or Igs; 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 dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g., Zn-protein complexes); and/or non-ionic surfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG).

Liposomes containing these agents and/or compounds of the invention are prepared by methods known in the art, such as described in U.S. Pat. Nos. 4,485,045 and 4,544,545. Liposomes with enhanced circulation time are disclosed in U.S. Patent No. 5,013,556. Particularly useful liposomes can be generated by the reverse phase evaporation method with a lipid composition comprising phosphatidylcholine, cholesterol and PEG-derivatized phosphatidylethanolamine (PEG-PE). Liposomes are extruded through filters of defined pore size to yield liposomes with the desired diameter.

These agents and/or the compounds of the invention may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and polymethylmethacrylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions. Such techniques are disclosed in Remington, The Science and Practice of Pharmacy, 20th Ed., Mack Publishing (2000).

Sustained-release preparations may be used. Suitable examples of sustained-release preparations include semi-permeable matrices of solid hydrophobic polymers containing Compound 1 or a pharmaceutically acceptable salt thereof, which matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or 'poly(vinylalcohol)), polylactides (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 copolymer and leuprolide acetate), sucrose acetate isobutyrate, and poly-D-(-)-3- hydroxybutyric acid.

The formulations to be used for intravenous administration must be sterile. This is readily accomplished by, for example, filtration through sterile filtration membranes. Compounds of the invention are generally placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle.

Suitable emulsions may be prepared using commercially available fat emulsions, such as Intralipid™, Liposyn™, Infonutrol™, Lipofundin™ and Lipiphysan™. The active ingredient may be either dissolved in a pre-mixed emulsion composition or alternatively it may be dissolved in an oil (e.g., soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil or almond oil) and an emulsion formed upon mixing with a phospholipid (e.g., egg phospholipids, soybean phospholipids or soybean lecithin) and water. It will be appreciated that other ingredients may be added, for example glycerol or glucose, to adjust the tonicity of the emulsion. Suitable emulsions will typically contain up to 20% oil, for example, between 5 and 20%. The fat emulsion can comprise fat droplets between 0.1 and 1.0 pm, particularly 0.1 and 0.5 pm, and have a pH in the range of 5.5 to 8.0.

The emulsion compositions can be those prepared by mixing a compound of the invention with Intralipid™ or the components thereof (soybean oil, egg phospholipids, glycerol and water).

Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as set out above. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably sterile pharmaceutically acceptable solvents may be nebulised by use of gases. Nebulised solutions may be breathed directly from the nebulising device or the nebulising device may be attached to a face mask, tent or intermittent positive pressure breathing machine. Solution, suspension or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.

KITS

Another aspect of the invention provides kits comprising a pharmaceutical composition of the invention. A kit may include, in addition to a pharmaceutical composition of the invention, diagnostic or therapeutic agents. A kit may also include instructions for use in a diagnostic or therapeutic method. In some embodiments, the kit includes a pharmaceutical composition of the invention and a diagnostic agent. In other embodiments, the kit includes a pharmaceutical composition and instructions for use in a therapeutic method.

In yet another embodiment, the invention comprises kits that are suitable for use in performing the methods of treatment described herein. In one embodiment, the kit contains one or more of solid forms of the invention in quantities sufficient to carry out the methods of the invention. In another embodiment, the kit comprises one or more solid forms of the invention in quantities sufficient to carry out the methods of the invention and a container for the dosage.

EXAMPLES

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

Example 1. Preparation of Immediate Release (IR) Tablets

Immediate release (IR), non-film-coated tablets of tris salt of Compound 1 (e.g. crystalline Form 3, a preparation thereof is provided in WO2021116874) in dosage strengths of 1 mg, 10 mg, 20 mg, 60 mg and 100 mg were prepared [the dosage strength weight expressed in milligram is the weight equivalent to Compound 1],

The compositions of these tablets are shown in Tables 1-1 to 1-5.

Table 1-1. Composition of tris salt of Compound 1 Tablet 1 mg

Table 1-2. Composition of tris salt of Compound 1 Tablet 10 mg Table 1-3. Composition of tris salt of Compound 1 Tablet 20 mg

Table 1-4. Composition of tris salt of Compound 1 Tablet 60 mg Table 1-5. Composition of tris salt of Compound 1 Tablet 100 mg

Process of preparing IR tablets

The following steps were carried out in preparing the IR tablets (See also Figure 1/FIG. 1).

1. Blend approximately half of the microcrystalline cellulose 2. Add tris salt of Compound 1 to the microcrystalline cellulose, followed by the lactose monohydrate and crospovidone type B and mix.

3. Mill the blend and pass the remaining amount of microcrystalline cellulose through the mill. Blend the milled powder.

4. Add the intra-granular sodium stearyl fumarate and blend. 5. Compact and mill, then blend.

6. Add the extra-granular sodium stearyl fumarate and blend.

7. Compress using a suitable tablet press.

Example 2. Preparation of oral solutions of tris salt of Compound 1

Oral solutions of tris salt of Compound 1 (containing the equivalent of 0.01 mg/mL to 12 mg/mL of Compound 1 in 0.1% v/v Polysorbate 80 in sterile water for irrigation vehicle) were prepared accodding to the following formula that is summarized in Table 2-1 (See Figure 2/FIG. 2 for a diagram for the compounding process of tris salt of compound 1 oral solutions). The solution concentration and volume were adjusted to give the required clinical dose (1- 1200 mg).

Table 2-1. Formulation Details for tris salt of Compound 1 Oral Solutions a. the dosage strength weight expressed in milligram is the weight equivalent to Compound 1 The required quantity of tris salt of Compound was weighed and dissolved in 0.1 % Polysorbate 80 in sterile water for irrigation vehicle to provide the final stock solution volume. Appropriate aliquots of the solutions were dispensed into a suitable drinking vessel to achieve the desired doses. The aliquots were administered without further dilution.

Example 3. A clinical study (dose escalating study) of Compound 1 (in the form of its tris salt)

Study Design

This study was a randomized, double-blind (investigator- and participant-blind), sponsor-open, placebo-controlled, multiple escalating oral doses study of Compound 1 (in the form of its tris salt). There were 2 participant populations enrolled in this study: participants with T2DM (as indicated by HbA1c level at Screening), and participants with Obesity, without diabetes, (as indicated by BMI at Screening). The study was conducted in 3 parts; Figure 3 shows an overview of the study, as it was conducted. As described in the protocol, dose levels were selected based on emerging data. Part A: adult participants with T2DM inadequately controlled on metformin who received Compound 1 (as its tris salt) or placebo daily for 28 days. As shown in Figure 3 (FIG. 3), 4 cohorts were enrolled to participate in Part A, with approximately 10 participants (8 Compound 1 : 2 placebo) per cohort. Participants in Part A were admitted to a clinical research unit 2 days before the first dose of study drug on day 1 and were discharged following completion of all assessments on day 31.

Part B: adult participants with Obesity (without diabetes) received Compound 1 (as its tris salt) or placebo daily for 42 days. As shown in Figure 3, 1 cohort, with approximately 15 participants (12 Compound 1 : 3 placebo), was enrolled to participate in Part B. Participants in Part B were admitted to a clinical research unit 3 days before the first dose of study drug on day 1 and were discharged following completion of all assessments on day 45.

Part C: adult participants with T2DM inadequately controlled on metformin received Compound 1 (as its tris salt) or placebo daily for 42 days. As shown in Figure 3, 1 cohort, with approximately 10 participants (8 Compound 1 : 2 placebo), was enrolled to participate in Part C. Participants in Part C were admitted to a clinical research unit 2 days before the first dose of study drug on day 1 and were discharged following completion of all assessments on day 45. For all participants (Parts A, B and C), there was a planned follow-up period of at least 28 days post last-dose.

Selection of Study Population

Adults, between 18 and 70 years of age, with inadequately controlled T2DM (as indicated by HbA1c at Screening) on metformin monotherapy, or with Obesity (without diabetes) were enrolled in this study. Females must have been of non-childbearing potential. Participants with Type 1 diabetes or secondary forms of diabetes were excluded from this study.

Key criteria for participants enrolling with T2DM (Part A and Part C):

T2DM, with an HbAlc of >7.0% and <10.5%, receiving a stable dose of metformin of at least 500 mg per day and use of no other medications for glycemic control and Participants were required to have a BMI of >24.5 to <45.5 kg/m ² and total body weight of >50 kg.

Key criteria for participants enrolling with Obesity (Part B): BMI of >30.5 to <45.5 kg/m ² . Participants did not have diabetes as indicated by laboratory tests including HbA1c of less than 6.5% .

Treatments

Treatments Administered

Participants received Compound 1 or matching placebo at approximately 0800 hours (±2 hours) each day from Day 1 to Day 28 (Part A) or Day 42 (Parts B and C). Investigator site personnel administered study intervention with approximately 240 mL ambient temperature water. Metformin was required for participants with T2DM. On all study days while in the clinical research unit (CRU), participants were given their morning dose of metformin at the same time as Compound 1/placebo. For participants taking metformin more frequently than once a day, the investigator determined the appropriate times during the day to administer those doses. For metformin and other permitted concomitant medications, the timing of administration should have been the same between inpatient days, and care should have been taken to minimize changes to the participants’ stable medication routine.

Identity of Study Intervention(s)

For this study, the investigational product was Compound 1 (as its tris salt), or matching placebo. Study intervention information is provided in Table 3-1. Compound 1 and matching placebo were supplied as tablets to the CRU in bulk along with individual dosing containers for unit dosing.

Table 3-1 A dose titration approach was taken in this study. Within a given cohort, the daily dose administered increased at set intervals over the dosing period up to a planned target dose. The target dose level for each cohort was adjusted based on data emerging from prior cohorts, in dose escalation fashion (Table 3-2 and Table 3-3).

Table 2-2. Titration Scheme and Dosing Paradigm of Compound 1 for Part A

Table 3-3. Titration Scheme and Dosing Paradigm of Compound 1 for Parts B and C

Results

Subject Disposition and Demography

A total of 66 participants (51 with T2DM and 15 with obesity) were assigned to treatment and received at least 1 dose of study intervention; of these, 61 participants completed the blinded treatment. Of the 5 participants who discontinued, 3 were due to treatment-related AEs: 1 participant from Part A Compound 1 60 mg group discontinued on Day 13 at a dose of 40 mg due to nausea; this participant did not complete the follow-up visit due to withdrawal by participant. One participant from Part A Compound 1 120 mg group discontinued on Day 5 at a dose of 40 mg due to hypoglycemia. One participant from Part B Compound 1 180 mg group discontinued study drug on Day 32 at a dose of 150 mg due to upper abdominal pain; this participant continued in the study. In addition, 1 participant from Part A placebo group and 1 participant from Part C Compound 1 180 mg group discontinued during the treatment phase due to other reasons.

Demographic characteristics were generally comparable across groups. The gender distribution of the 66 participants was well-balanced, with 53% male and 47% female. The majority (more than 80%) of the participants were White, and a majority had Hispanic or Latino ethnicity (approximately 75% of participants with T2DM, and 87% of participants with Obesity). Overall, the mean age of participants was 57.4 years (range: 29 to 70 years), with generally similar average age and range across the populations studied. The mean weight and BMI for participants enrolling with T2DM were 89.7 kg (range: 52 to 152 kg) and 32.7 kg/m ² (range: 25 to 45 kg/m ² ), respectively. The mean duration of T2DM for participants with T2DM was 10.7 years (range: 1.6 to 22.8 years) and the median HbA1c at Screening in these participants was 8.4% (range: 7.0% to 10.5 %). The mean weight and BMI for participants enrolling with Obesity was 98.2 kg (range: 74 to 122 kg) and 35.1 kg/m ² (range: 31 to 44 kg/m ² ), respectively.

Safety Results

A total of 240 all-causality treatment-emergent adverse events (TEAEs) were reported by 58 study participants. A majority of TEAEs (89%, 214 out of 240) were mild in intensity and considered treatment-related (78%, 187 of 240) [AEs described hereafter were all TEAEs if not specifically identified. The adverse event (AE) causality was assessed by the investigator unless specified]. Twenty-four AEs of moderate intensity (in 13 participants) and 2 events of severe intensity (in 1 participant in Compound 1 30 mg group) were reported. There were no deaths. .

In participants with T2DM, a total of 174 TEAEs were reported in 44 (86.3%) participants. The majority of AEs (128 occurred in 38 participants) were considered treatment-related by the investigator. In Compound 1 treatment groups, the 10 mg group had the lowest number of all-causality AEs with 5 events, and the 180 mg group had the highest number of all-causality AEs with 47 events. One participant in the 30 mg group had an SAE of obstructive pancreatitis in the follow-up period (considered treatment-related by the investigator but considered unrelated by the sponsor). Additional AEs, including 4 of moderate intensity and 2 of severe intensity (hypotension and increased transaminases) were reported in this participant during the follow-up period, in the setting of this SAE. No other participants experienced serious AEs or AEs of severe intensityTwo participants with T2DM discontinued from the study treatment due to AEs and one participant in Compound 1 , 120 mg group had a dose reduction to 100 mg due to AEs.

In participants with Obesity, a total of 66 AEs were reported in 14 (93.3%) participants. The majority of AEs (59 occurred in 13 participants) were considered treatment-related. No SAEs, severe AEs, or permanent discontinuation from study due to AEs were reported in these participants. In Compound 1 , 180 mg group, 1 participant discontinued study drug and 1 participant had a dose reduction to 150 mg due toAEs.

In this study, all-causality TEAEs in the system organ class (SOC) of Gastrointestinal Disorders were most frequently reported (56.1% of events in participants with T2DM, 56.4% of events in participants with Obesity). The most frequently reported all-causality TEAE by preferred term (PT) was nausea in participants with T2DM, and nausea and constipation in participants with Obesity. Higher incidences of gastrointestinal (Gl) TEAEs were observed in the higher dose groups of Compound 1 (120 mg and 180 mg) compared to placebo.

A total of 12 participants (6 participants with T2DM and 6 participants with Obesity) experienced hypoglycemic AEs (all treatment-related). All of these AEs were considered mild in severity, with the exception of 1 moderate documented symptomatic hypoglycemia reported in Part A Compound 1 , 120 mg group. No participant had blood glucose <55 mg/dL.

There were no clinically significant adverse trends in safety laboratory tests, vital signs or ECG parameters with increasing Compound 1 doses.

In Summary, oral doses of Compound 1 up to 180 mg per day in adult participants with T2DM or with obesity were considered safe, with a tolerability profile consistent with the mechanism of action.

Pharmacokinetic Evaluations

Compound 1 (in the form of its tris salt) plasma pharmacokinetic parameters (Table 3-4) area under the plasma concentration time profile from time 0 to time 24 hours (AIIC24), maximum observed concentration over a 24-hour interval (C _m ax), and time for C _m ax (T _m ax) were calculated for each participant and treatment following Day 1 and multiple dose administration, using noncompartmental analysis of concentration-time data. Following administration of Compound 1 , Cmax was observed at 1 to 2 hours on Day 1 , and 2 to 8 hours following last dose on Day 28 or 42. The half-life averaged 20.70 to 26.50 hours following the last dose on Day 28 or 42. Exposure (Cmax and ALICtau) generally increased in an approximately dose proportional manner across the dose range studied. No substantial differences in the plasma exposure of Compound 1 (Cmax and ALICtau) were observed between participants with T2DM and obesity either after single dose (Day 1 , 10 mg) or multiple dose (Day 28, 120 mg and Day 42, 180 mg) administration. Urinary recovery of unchanged Compound 1, with less than 0.2% of the dose recovered in the 24 hour dosing interval following last dose on Day 28 or 42 Table 3-4. Pharmacokinetic Parameters for Compound 1

Change From Baseline (CFB) in Mean Daily Glucose (MDG), Fasting Plasma Glucose (FPG), and HbA1c in participants with T2DM CFB in MDG Mean daily glucose (MDG) was assessed following MMTT (mixed meal tolerance test) in participants with T2DM at baseline at end of treatment (Day 28 or Day 42). Baseline mean values were generally similar across treatment groups. The observed mean CFB in MDG increased with Compound 1 dose are shown in Table 3-5, ranging from -41.9 mg/dL (10 mg, Day 28) to -89.4 mg/dL (120 mg, Day 28), and -110.6 mg/dL (180 mg, Day 42).

Table 3-5. Summary of Mean Daily Glucose Observed in Participants with T2DM

Baseline is defined as the value on Day -1 .

Mean Daily Glucose (MDG) is defined as AUC24/24. Fasting Plasma Glucose

In participants with T2DM, mean baseline values for fasting plasma glucose were generally similar across treatment groups. Reductions from baseline in fasting plasma glucose were observed for all Compound 1 treatment groups during the dosing period, with the greatest decrease occurring within the first 14 days of dosing. As shown in Table 3-6, by Day 28 all Compound 1 treatment groups, with the exception of 10 mg, had average fasting plasma glucose levels of <126 mg/dL. The largest reductions in mean CFB were reported for the 60 mg, 120 mg and 180 mg groups with values of -78.6 mg/dL (Day 28), -71.0 mg/dL (Day 28) and - 102.3 mg/dL (Day 36), respectively.

In participants with Obesity, mean baseline values for fasting plasma glucose were 106.7 mg/dL for placebo and 99.1 mg/dL for Compound 1 , 180 mg group. Modest reductions from baseline were observed in the placebo and Compound 1 treated group, with the maximum observed mean CFB in the placebo and 180 mg groups of -5.7 mg/dL (Day 45) and -11.2 mg/dL (Day 28), respectively.

Table 3-6. Change from Baseline for Fasting Plasma Glucose in Participants with T2DM a. Maximum mean decline observed during dosing period.

N, number of participants randomized; n, number of participants analyzed;

HbA1c

Mean baseline values for HbA1C were similar across all treatment groups in participants with T2DM and ranged from 8.3% to 9.0%.

Mean CFB for the placebo groups as assessed in Part A on Day 28 and in Part C on Day 42 were -0.60 % and -0.61%, respectively.

At the end of the dosing period (ie, Day 28 for Part A and Day 42 for Part C), all Compound 1 treatment groups had reductions in HbAlc from baseline, with modelled mean decreases of up to -1.61% (Compound 1 , 180 mg group, Table 3-7). Table 3-7. Statistical Summary of Change from Baseline for HbA1c in Participants with

T2DM

Baseline is defined as the measurement collected at Day -1 OH. Unplanned readings have been excluded from the presentation. ANCOVA or MMRM model, used as appropriate

In summary, administration of Compound 1 (in the form of its tris salt) orally once-daily showed robust reductions in glucose (e.g. as measured by FPG and MDG) and HbA1c in the participants with T2DM (inadequately controlled on metformin).

Body Weight

In participants with T2DM, mean baseline values for body weight ranged from 55.9 to 100.5 kg. Declines in body weight were observed across the dosing period for all treatment groups (See Table 3-8). The largest declines in body weight at the end of the dosing period were observed for the highest dose levels. On Day 29, the Part A 120 mg group had a statistically significant decline in mean body weight relative to placebo, with a modelled mean decline from baseline of -4.66 kg (90% Cl = -5.89 to -3.43), and an observed mean percent CFB of -5.0%. On Day 43, the Part C 180 mg group had a statistically significant decline in mean body weight relative to placebo, with a modelled mean decline from baseline of -5.10 kg (90% Cl = -6.62 to -3.58) and an observed mean percent CFB of -5.5%.

In non-diabetic participants with Obesity, the mean baseline body weight was 101.3 kg for placebo and 95.6 kg for Compound 1 180 mg group, respectively. The maximum observed mean reductions from baseline (percent CFB) for the placebo and 180 mg groups were -3.4 kg (-3.6%) and -5.0 kg (-5.2%), respectively, on Day 43. The modelled mean CFB for the 180 mg group of -4.97 kg (90% Cl= -6.29 to -3.64) was similar to that in participants with T2DM at the same dose level. Table 3-8. Summary of Body Weight in Participants with T2DM and Participants with Obesity

Baseline is defined as the value on Day -1.

In summary, administration of Compound 1 (in the form of its tris salt) orally once-daily showed robust reductions in body weight in non-diabetic participants with obesity, and also in participants with T2DM. All patents, patent applications and references referred to herein are hereby incorporated by reference in their entirety.