Combination therapy for treatment of metabolic disease

Abstract

Provided herein are methods and compositions for the treatment of conditions or disorders involving the gut-brain axis. In some embodiments, the condition or disorder is: a metabolic disorder, such as type 2 diabetes, hyperglycemia, metabolic syndrome, obesity, hypercholesterolemia, or nonalcoholic steatohepatitis; a nutritional disorder, such as short bowel syndrome, intestinal failure, or intestinal insufficiency; or an eating disorder, such as hyperphagia or binge eating disorder.

Description

COMBINATION THERAPY FOR TREATMENT OF METABOLIC DISEASECROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of US Provisional Application No. 63 / 613,964 filed on December 22, 2023, which is incorporated herein by reference in its entirety.FIELD OF THE INVENTION

[0002] Described herein is a combination comprising a GPR119 agonist and a GPR40 agonist useful for the treatment of conditions or disorders involving the gut -brain axis. In some embodiments, the condition or disorder is: a metabolic disorder, such as type 2 diabetes, hyperglycemia, metabolic syndrome, obesity, hypercholesterolemia, or nonalcoholic steatohepatitis; a nutritional disorder, such as short bowel syndrome, intestinal failure, or intestinal insufficiency; or an eating disorder, such as hyperphagia or binge eating disorder.BRIEF SUMMARY OF THE INVENTION

[0003] Disclosed herein, in certain embodiments, are combination therapies useful for the treatment of conditions or disorders involving the gut -brain axis comprising a GPR119 agonist and a GPR40 agonist compound. In some embodiments, the GPR119 and / or GPR40 agonists are gut-restricted or selectively modulate GPR119 and / or GPR40 located in the gut. In some embodiments, the condition is selected from the group consisting of: central nervous system (CNS) disorders including mood disorders, anxiety, depression, affective disorders, schizophrenia, malaise, cognition disorders, addiction, autism, epilepsy, neurodegenerative disorders, Alzheimer’s disease, and Parkinson’s disease, Lewy Body dementia, episodic cluster headache, migraine, pain; metabolic conditions including diabetes and its complications such as chronic kidney disease / diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, and cardiovascular disease, metabolic syndrome, obesity, dyslipidemia, and nonalcoholic steatohepatitis (NASH); eating and nutritional disorders including hyperphagia, cachexia, binge eating disorder, short bowel syndrome, intestinal failure, intestinal insufficiency and other eating disorders; inflammatory disorders and autoimmune diseases such as inflammatory bowel disease, ulcerative colitis, Crohn’s disease, psoriasis, and celiac disease; necrotizing enterocolitis; diseases / disorders of gastrointestinal barrier dysfunction including environmental enteric dysfunction, spontaneous bacterial peritonitis; functional gastrointestinal disorders such as irritable bowel syndrome, functional dyspepsia, functional abdominal bloating / distension, functional diarrhea, functional constipation, andopioid-induced constipation; gastroparesis; nausea and vomiting; disorders related to microbiome dysbiosis, and other conditions involving the gut-brain axis.

[0004] In one aspect, described herein is a method of treating a metabolic disorder, nutritional disorder, eating disorder, or a combination thereof in a human in need thereof, the method comprising administering to the human in need thereof:(a) 2-(4-(3-(l-(5-chloropyrimidin-2-yl)piperidin-4-yl)propoxy)-2-fluorophenyl)- l-(3 -((((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)methyl)azetidin-l- yl)ethan-l-one (Compound 1), which has the following structure:(Compound 1), or a pharmaceutically acceptable salt or solvate thereof; and(b) ((2S)-2-cyclopropyl-2-(3-((l-(2-(4,4-dimethylpentyl)-5- methoxyphenyl)piperidin-4-yl)methoxy)phenyl)ethyl)(methyl)phosphinicacid(Compound 2), which has the following structure:(Compound 2), or a pharmaceutically acceptable salt or solvate thereof; wherein Compound 1, or a pharmaceutically acceptable salt or solvate thereof, and Compound 2, or a pharmaceutically acceptable salt or solvate thereof, are administered to the human in need thereof by oral administration.

[0005] In some embodiments, the metabolic disorder is type 2 diabetes, hyperglycemia, metabolic syndrome, obesity, hypercholesterolemia, or nonalcoholic steatohepatitis. In some embodiments, metabolic disorder is type 2 diabetes. In some embodiments, the metabolic disorder is obesity. In some embodiments, the nutritional disorder is short bowel syndrome, intestinal failure, or intestinal insufficiency. In some embodiments, the eating disorder is hyperphagia or binge eating disorder.

[0006] In some embodiments, treating the metabolic disorder, nutritional disorder, eating disorder, or a combination thereof comprises an increase in plasma levels of CCK, oxyntomodulin, total GLP-1, active GLP-1, PYY, or a combination thereof. In some embodiments, treating the metabolic disorder, nutritional disorder, eating disorder, or a combination thereof comprises an increase in plasma levels of total GLP-1, active GLP-1, PYY, or a combination thereof.

[0007] In some embodiments, treating the metabolic disorder, nutritional disorder, eating disorder, or combination thereof comprises a decrease in body weight.

[0008] In some embodiments, the dose of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is between about 3 mg and about 500 mg. In some embodiments, the dose of Compound 1 , or a pharmaceutically acceptable salt or solvate thereof, is about 3 mg, about 10 mg, about20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 80 mg, about 100 mg, about 120 mg, about 150 mg, about200 mg, about250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, or about 500 mg. In some embodiments, the dose of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is between about 20 mg and about 100 mg. In some embodiments, dose of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, or about 100 mg.

[0009] In some embodiments, the dose of Compound 2, or a pharmaceutically acceptable salt or solvate thereof, is between about 10 mg and about 500 mg. In some embodiments, the dose of Compound 2, or a pharmaceutically acceptable salt or solvate thereof, is about 10 mg about20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 80 mg, about 100 mg, about 120 mg, about 150 mg, about 200 mg, about250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, or about 500 mg. In some embodiments, the dose of Compound 2, or a pharmaceutically acceptable salt or solvate thereof, is between about 20 mg and about 120 mg. In some embodiments, the dose of Compound 2, or a pharmaceutically acceptable salt or solvate thereof, is about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, or about 120 mg.

[0010] In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, and Compound 2, or a pharmaceutically acceptable salt or solvate thereof, are administered sequentially. In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, and Compound 2, or a pharmaceutically acceptable salt or solvate thereof, are administered simultaneously.

[0011] In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, and Compound 2, or a pharmaceutically acceptable salt or solvate thereof, are administered once daily, twice daily, three times daily, or four times daily. In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, and Compound 2, or a pharmaceutically acceptable salt or solvate thereof, are administered once or twice daily.

[0012] In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, and Compound 2, or a pharmaceutically acceptable salt or solvate thereof, are administered with food. In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, and Compound 2, or a pharmaceutically acceptable salt or solvate thereof, are administered without food.

[0013] In some embodiments, the method comprises administering to the human in need thereof :(a) between about 20 mg and about 100 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof; and(b) between about 20 mg and about 120 mg of Compound 2, or a pharmaceutically acceptable salt or solvate thereof; wherein Compound 1 and Compound 2 are simultaneously administered to the human in need thereof once or twice daily.

[0014] In another aspect, described herein is a method of treating a metabolic disorder, nutritional disorder, eating disorder, or a combination thereof in a human, the method comprising administering to the human in need thereof:(a) between about 20 mg and about 100 mg 2-(4-(3-(l-(5-chloropyrimidin-2- yl)piperidin-4-yl)propoxy)-2-fluorophenyl)-l-(3-((((2S,3R,4R,5R)-2,3,4,5,6- pentahy droxyhexy l)amino)methy l)azetidin - 1 -y l)ethan- 1 -one (Compound 1 ), which has the following structure:(Compound 1), or a pharmaceutically acceptable salt or solvate thereof; and(b) between about 20 mg and about 120 mg of ((2S)-2-cyclopropyl-2-(3-((l-(2- (4,4-dimethylpentyl)-5-methoxyphenyl)piperidin-4- yl)methoxy)phenyl)ethyl)(methyl)phosphinic acid (Compound 2), which has the following structure:(Compound 2), or a pharmaceutically acceptable salt or solvate thereof;wherein Compound 1, or a pharmaceutically acceptable salt or solvate thereof, and Compound 2, or a pharmaceutically acceptable salt or solvate thereof, are administered to the human in need thereof by oral administration.

[0015] In some embodiments, the metabolic disorder is type 2 diabetes, hyperglycemia, metabolic syndrome, obesity, hypercholesterolemia, or nonalcoholic steatohepatitis. In some embodiments, the metabolic disorder is type 2 diabetes. In some embodiments, the metabolic disorder is obesity. In some embodiments, the nutritional disorder is short bowel syndrome, intestinal failure, or intestinal insufficiency. In some embodiments, the eating disorder is hyperphagia or binge eating disorder.

[0016] In some embodiments, treating the metabolic disorder, nutritional disorder, eating disorder, or a combination thereof comprises an increase in plasma levels of total GLP-1, active GLP-1, PYY, or a combination thereof.

[0017] In some embodiments, treating the metabolic disorder, nutritional disorder, eating disorder, or combination thereof comprises a decrease in body weight.

[0018] In some embodiments, the dose of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, or about 100 mg; and the dose of Compound 2, or a pharmaceutically acceptable salt or solvate thereof, is about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, or about 120 mg.

[0019] In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, and Compound 2, or a pharmaceutically acceptable salt or solvate thereof, are administered once or twice daily.

[0020] In another aspect, described herein is a method of treating obesity in a human, the method comprising administering to the human in need thereof:(a) between about 20 mg and about 100 mg 2-(4-(3-(l-(5-chloropyrimidin-2- yl)piperidin-4-yl)propoxy)-2-fhrorophenyl)-l-(3-((((2S,3R,4R,5R)-2,3,4,5,6- pentahy droxyhexy l)amino)methy l)azetidin - 1 -y l)ethan- 1 -one (Compound 1 ), which has the following structure:(Compound 1), or a pharmaceutically acceptable salt or solvate thereof; and(b) between about 20 mg and about 120 mg of ((2S)-2-cyclopropyl-2-(3-((l-(2- (4,4-dimethylpentyl)-5-methoxyphenyl)piperidin-4- yl)methoxy)phenyl)ethyl)(methyl)phosphinic acid (Compound 2), which has the following structure:(Compound 2), or a pharmaceutically acceptable salt or solvate thereof; wherein Compound 1, or a pharmaceutically acceptable salt or solvate thereof, and Compound 2, or a pharmaceutically acceptable salt or solvate thereof, are administered to the human in need thereof by oral administration.

[0021] In some embodiments, treating obesity comprises a decrease in body weight.

[0022] In some embodiments, the dose of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, or about 100 mg; and the dose of Compound 2, or a pharmaceutically acceptable salt or solvate thereof, is about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, or about 120 mg.

[0023] In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, and Compound 2, or a pharmaceutically acceptable salt or solvate thereof, are administered once or twice daily.

[0024] In another aspect, described herein is a method of treating obesity in a human, the method comprising orally administering to the human in need thereof ((2S)-2-cyclopropyl-2- (3-((l-(2-(4,4-dimethylpentyl)-5-methoxyphenyl)piperidin-4- yl)methoxy)phenyl)ethyl)(methyl)phosphinic acid (Compound 2), which has the following structure:(Compound 2), or a pharmaceutically acceptable salt or solvate thereof.

[0025] In some embodiments, treating obesity comprises a decrease in body weight.

[0026] In some embodiments, the dose of Compound 2, or a pharmaceutically acceptable salt or solvate thereof, is between about 10 mg and about 500 mg. In some embodiments, thedose of Compound 2, or a pharmaceutically acceptable salt or solvate thereof, is about 10 mg about20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 80 mg, about 100 mg, about 120 mg, about 150 mg, about 200 mg, about250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, or about 500 mg. In some embodiments, the dose of Compound 2, or a pharmaceutically acceptable salt or solvate thereof, is between about 20 mg and about 120 mg. In some embodiments, the dose of Compound 2, or a pharmaceutically acceptable salt or solvate thereof, is about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, or about 120 mg.

[0027] In some embodiments, Compound 2, or a pharmaceutically acceptable salt or solvate thereof, are administered once or twice daily.

[0028] In some embodiments, the method further comprises orally administering to the human in need thereof 2-(4-(3-(l-(5-chloropyrimidin-2-yl)piperidin-4-yl)propoxy)-2- fluorophenyl)-l-(3-((((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)methyl)azetidin-l- yl)ethan-l-one (Compound 1), which has the following structure:or a pharmaceutically acceptable salt or solvate thereof.

[0029] In some embodiments, the dose of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is between about 3 mg and about 500 mg. In some embodiments, the dose of Compound 1 , or a pharmaceutically acceptable salt or solvate thereof, is about 3 mg, about 10 mg, about20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 80 mg, about 100 mg, about 120 mg, about 150 mg, about200 mg, about250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, or about 500 mg. In some embodiments, the dose of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is between about 20 mg and about 100 mg. In some embodiments, the dose of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, or about 100 mg.

[0030] In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered once or twice daily.

[0031] In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, and Compound 2, or a pharmaceutically acceptable salt or solvate thereof, are administered sequentially. In some embodiments, Compound 1, or a pharmaceuticallyacceptable salt or solvate thereof, and Compound 2, or a pharmaceutically acceptable salt or solvate thereof, are administered simultaneously.

[0032] In another aspect, described herein is a method of treating type 2 diabetes in a human, the method comprising administering to the human in need thereof:(a) between about 20 mg and about 100 mg 2-(4-(3-(l-(5-chloropyrimidin-2- yl)piperidin-4-yl)propoxy)-2-fluorophenyl)-l-(3-((((2S,3R,4R,5R)-2,3,4,5,6- pentahy droxyhexy l)amino)methy l)azetidin - 1 -y l)ethan- 1 -one (Compound 1 ), which has the following structure:(Compound 1), or a pharmaceutically acceptable salt or solvate thereof; and(b) between about 20 mg and about 60 mg of ((2S)-2-cyclopropyl-2-(3-((l-(2- (4,4-dimethylpentyl)-5-methoxyphenyl)piperidin-4- yl)methoxy)phenyl)ethyl)(methyl)phosphinic acid (Compound 2), which has the following structure:(Compound 2), or a pharmaceutically acceptable salt or solvate thereof; wherein Compound 1, or a pharmaceutically acceptable salt or solvate thereof, and Compound 2, or a pharmaceutically acceptable salt or solvate thereof, are administered to the human in need thereof by oral administration.

[0033] In some embodiments, treating type 2 diabetes comprises an increase in plasma levels of total GLP-1, active GLP-1, PYY, or a combination thereof.

[0034] In some embodiments, treating type 2 diabetes comprises a decrease in body weight.

[0035] In some embodiments, the dose of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, or about 100 mg.

[0036] In some embodiments, the dose of Compound 2, or a pharmaceutically acceptable salt or solvate thereof, is about 20 mg, about 30 mg, about 40 mg, about 50 mg, or about 60 mg.

[0037] In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, and Compound 2, or a pharmaceutically acceptable salt or solvate thereof, are administered once or twice daily.

[0038] In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, and Compound 2, or a pharmaceutically acceptable salt or solvate thereof, are administered sequentially. In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, and Compound 2, or a pharmaceutically acceptable salt or solvate thereof, are administered simultaneously.

[0039] In some embodiments for the methods described herein, treatment further comprises administering one or more additional therapeutic agents to the human in need thereof; wherein the one or more additional therapeutic agents are selected from: a TGR5 agonist, an SSTR5 antagonist, an SSTR5 inverse agonist, a CCK1 agonist, a PDE4 inhibitor, a DPP -4 inhibitor, a GLP-1 receptor agonist, a GOAT inhibitor, metformin, sitagliptin, and combinations thereof. In some embodiments, the one or more additional therapeutic agents are selected from: metformin, sitagliptin, and combinations thereof.

[0040] Other objects, features and advantages of the compounds, methods and compositions described herein will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the instant disclosure will become apparent to those skilled in the art from this detailed description.DETAILED DESCRIPTION OF THE INVENTION

[0041] This disclosure is directed, at least in part, to combination therapies useful for the treatment of conditions or disorders involving the gut -brain axis comprising a GPR119 agonist and a GPR40 agonist compound.Gut-Brain Axis

[0042] The gut-brain axis refers to the bidirectional biochemical signaling that connects the gastrointestinal tract (GI tract) with the central nervous system (CNS) through the peripheral nervous system (PNS) and endocrine, immune, and metabolic pathways.

[0043] In some instances, the gut-brain axis comprises the GI tract; the PNS including the dorsal root ganglia (DRG) and the sympathetic and parasympathetic arms of the autonomic nervous system including the enteric nervous system and the vagus nerve; the CNS; and the neuroendocrine and neuroimmune systems including the hypothalamic-pituitary-adrenal axis(HPA axis). The gut-brain axis is important for maintaining homeostasis of the body and is regulated and modulates physiology through the central and peripheral nervous systems and endocrine, immune, and metabolic pathways.

[0044] The gut-brain axis modulates several important aspects of physiology and behavior. Modulation by the gut-brain axis occurs via hormonal and neural circuits. Key components of these hormonal and neural circuits of the gut-brain axis include highly specialized, secretory intestinal cells that release hormones (enteroendocrine cells or EECs), the autonomic nervous system (including the vagus nerve and enteric nervous system), and the central nervous system. These systems work together in a highly coordinated fashion to modulate physiology and behavior.

[0045] Defects in the gut-brain axis are linked to a number of diseases, including those of high unmet need.

[0046] In some embodiments of the methods described herein, the condition or disorder involving the gut-brain axis is selected from the group consisting of: central nervous system (CNS) disorders including mood disorders, anxiety, depression, affective disorders, schizophrenia, malaise, cognition disorders, addiction, autism, epilepsy, neurodegenerative disorders, Alzheimer’s disease, and Parkinson’s disease, Lewy Body dementia, episodic cluster headache, migraine, pain; metabolic conditions including diabetes and its complications such as chronic kidney disease / diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, and cardiovascular disease, metabolic syndrome, obesity, dyslipidemia, and nonalcoholic steatohepatitis (NASH); eating and nutritional disorders including hyperphagia, cachexia, binge eating disorder, short bowel syndrome, intestinal failure, intestinal insufficiency and other eating disorders; inflammatory disorders and autoimmune diseases such as inflammatory bowel disease, ulcerative colitis, Crohn’s disease, psoriasis, and celiac disease; necrotizing enterocolitis; gastrointestinal injury resulting from toxic insults such as radiation or chemotherapy; diseases / disorders of gastrointestinal barrier dysfunction including environmental enteric dysfunction, spontaneous bacterial peritonitis; functional gastrointestinal disorders such as irritable bowel syndrome, functional dyspepsia, functional abdominal bloating / distension, functional diarrhea, functional constipation, and opioid-induced constipation; gastroparesis; nausea and vomiting; disorders related to microbiome dysbiosis, other conditions involving the gut-brain axis. In some embodiments, the condition is a metabolic disorder. In some embodiments, the metabolic disorder is type 2 diabetes, hyperglycemia, metabolic syndrome, obesity, hypercholesterolemia, or nonalcoholic steatohepatitis. In some embodiments, the metabolic disorder is diabetes. In otherembodiments, the metabolic disorder is obesity. In other embodiments, the metabolic disorder is nonalcoholic steatohepatitis. In some embodiments, the condition involving the gut-brain axis is a nutritional disorder. In some embodiments, the nutritional disorder is short bowel syndrome, intestinal failure, or intestinal insufficiency. In some embodiments, the nutritional disorder is short bowel syndrome. In some embodiments, the condition involving the gutbrain axis is weight loss or preventing weight gain or weight regain. In some embodiments, the condition involving the gut-brain axis is weight loss or preventing weight gain or weight regain post-bariatric surgery. In some embodiments, the condition involving the gut-brain axis is weight loss or preventing weight gain or weight regain, wherein the subject has had bariatric surgery.GPR119 in the Gut-Brain Axis

[0047] In some instances, GPR119 is expressed in the pancreas and in enteroendocrine cells of the gastrointestinal tract. In some instances, GPR119 is expressed in enteroendocrine cells. GPR119 is activated by oleoylethanolamide (OEA) and other oleic acid derivatives and N-acylethanolamides. GPR119 agonists may be useful in the treatment of metabolic diseases such as diabetes and obesity, and other diseases involving the gut-brain axis.

[0048] In some instances, modulators of GPR119, for example, GPR119 agonists, induce the production of intracellular cAMP. In some instances, modulators of GPR119, for example, GPR119 agonists, induce the secretion of GLP-1, GLP-2, GIP, PYY, CCK, or other hormones. In some instances, modulators of GPR119, for example, GPR119 agonists, induce the secretion of GLP-1, GIP, CCK or PYY. In some instances, modulators of GPR119, for example, GPR119 agonists, induce the secretion of GLP-1 . In some instances, modulators of GPR119, for example, GPR119 agonists, induce the secretion of PYY.GPR40 in the Gut-Brain Axis

[0049] Free fatty acid receptor 1 (FFA1, FFAR1), also known as GPR40, is a class A G- protein coupled receptor. This membrane protein binds free fatty acids, acting as a nutrient sensor for regulating energy homeostasis. In some instances, GPR40 is expressed in enteroendocrine cells and pancreatic islet P cells. In some instances, GPR40 is expressed in enteroendocrine cells. Several naturally occurring medium to long-chain fatty acids act as ligands for GPR40. GPR40 agonists or partial agonists may be useful in the treatment of metabolic diseases such as obesity, diabetes, and NASH, and other diseases involving the gut-brain axis.

[0050] In some instances, modulators of GPR40, for example, GPR40 agonists or partial agonists, induce insulin secretion. In some instances, modulators of GPR40, for example,GPR40 agonists or partial agonists, induce an increase in cytosolic Ca2+. In some instances, modulators of GPR40, for example, GPR40 agonists or partial agonists, induce higher levels of intracellular cAMP. In some instances, GPR40 modulation is in enteroendocrine cells. In some instances, modulators of GPR40, for example, GPR40 agonists, induce the secretion of GLP-1, GIP, CCK or PYY. In some instances, modulators of GPR40, for example, GPR40 agonists, induce the secretion of GLP-1.Peptide Hormones of the Gut-Brain Axis

[0051] Incretins are a group of metabolic hormones released in the gut that stimulate a decrease in blood glucose levels in a glucose-dependent manner. Incretins include the peptide hormones GLP-1 and GIP. In some instances, incretin hormones are released in enteroendocrine cells after eating. In some instances, incretin hormones augment the secretion of insulin released from pancreatic beta cells of the islets of Langerhans by a blood glucose-dependent mechanism. In some instances, incretin hormones (such as GLP-1) also inhibit glucagon release from the alpha cells of the islets of Langerhans. Beside insulinotropic effects, GLP-1 has been associated with numerous regulatory and protective effects. GLP-1 inhibits gastric emptying, acid secretion, motility, decreases appetite and promotes satiety. GLP-1 receptor activation hasbeen linked with neurotrophic effects including neurogenesis and neuroprotective effects including reduced necrotic and apoptotic signaling and cell death. GLP-1 receptor agonist treatment is associated with protection against a range of experimental disease models such as Parkinson's disease, Alzheimer's disease, stroke, traumatic brain injury, and multiple sclerosis. Other peptide hormones released in the gut include CCK, PYY, GLP-2, oxyntomdulin, gastrin, secretin, vasoactive intestinal peptide (VIP), motilin, ghrelin, bombesin, calcitonin gene-related peptide (CGRP), chromogranin A, enkephalins, enteroglucagon, galanin, ghrelin, growth factors, growth hormone-releasing factor, leptin, motilin, amylin, neuropeptide Y (NPY), neurotensin, pancreatic polypeptide, somatostatin, substance P and trefoil peptides. These peptides regulate a wide variety of processes including food intake, metabolic rate, glucose homeostasis, gastric emptying, gut motility, gall bladder contraction, pancreatic secretion, intestinal mucosal growth, muscosal protection and repair, pain, cell proliferation and differentiation, water and electrolyte secretion, and intestinal blood flow.

[0052] In some instances, modulating the activity of the GPCRs described herein, e.g., GPR40 and GPR119, increases peptide hormone secretion. In some instances, the biological effect of peptide hormones is in enteroendocrine cells. In some instances, peptide hormones, e.g., GLP-1 and GIP, stimulate insulin release in a glucose dependent manner. In someinstances, GLP-1, for example, is necessary for normal glucose homeostasis. In some instances, peptide hormones, e.g., GLP-1, GLP-2 and GIP, contribute to beneficial effects for the treatment of diseases or conditions involving the gut-brain axis (e.g., diabetes, obesity or short bowel syndrome), including 1) increased insulin secretion, 2) increased glucose disposal, 3) suppression in glucose production, 4) reduced gastric emptying, 5) reduction in food intake, 6) body mass reduction, 7) increased cAMP levels, 8) increased nutrient absorption, 9) increased small intestinal length, 10) increased small intestinal weight, 11) increased villus height, and 12) increased villus height / crypt depth ratio.

[0053] Described herein is a method of treating a condition or disorder involving the gutbrain axis in an individual in need thereof, the method comprising administering to the individual Compound 1, or a pharmaceutically acceptable salt or solvate thereof.

[0054] Also described herein is a method of treating a condition or disorder involving the gut-brain axis in an individual in need thereof, the method comprising administering to the individual Compound 2, or a pharmaceutically acceptable salt or solvate thereof.

[0055] Described herein is a method of treating a condition or disorder involving the gutbrain axis in an individual in need thereof, the method comprising administering to the individual Compound 1, or a pharmaceutically acceptable salt or solvate thereof, in combination with Compound 2, or a pharmaceutically acceptable salt or solvate thereof.Compound 1

[0056] Compound 1 refers to 2-(4-(3-(l -(5-chloropyrimidin-2-yl)piperidin-4-yl)propoxy)- 2-fluorophenyl)-l-(3 -((((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)methyl)azetidin- l-yl)ethan-l-one, which has the chemical structure shown below.

[0057] Compound 1 is also referred to as 2-[4-[3-[l-(5-chloropyrimidin-2-yl)-4- piperidyl]propoxy]-2-fluorophenyl]-l-[3-[[[(2S,3R,4R,5R)-2,3,4,5,6- pentahydroxyhexyl]amino]methyl]azetidin-l-yl]ethanone.

[0058] Compound 1 is a potent, gut-restricted, small molecule full agonist of GPR119 being developed for the treatment of obesity and Type 2 diabetes mellitus. The pharmacokinetics of Compound 1 across non -clinical species are characterized by low clearances and volumes of distribution, and short terminal half -lives (<5 hours). The oral availability of Compound 1 is low in all species (< 5%). Compound 1 was found to be highly bound to plasma proteins in all species (> 99%) and does not distribute to red blood cells.Compound 2

[0059] Compound 2 refers to ((2S)-2-cyclopropyl-2-(3-((l-(2-(4,4-dimethylpentyl)-5- methoxyphenyl)piperidin-4-yl)methoxy)phenyl)ethyl)(methyl)phosphinic acid, which has the chemical structure shown below.(Compound 2).

[0060] Compound 2 is also referred to as ((S)-2-cyclopropyl-2-(3-((l-(2-(4,4- dimethylpentyl)-5-methoxyphenyl)piperidin-4-yl)methoxy)phenyl)ethyl)(methyl)phosphinic acid.

[0061] Compound 2 is a potent, gut-restricted, small molecule full agonist of GPR40 being developed for the treatment of obesity and Type 2 diabetes mellitus. Compound 2 demonstrated low clearance and low volumes of distribution in mice, rats, dogs, and monkey. The terminal half-life ranged from 1 to 11 h and was found to be higher in the non -rodent species. The oral bioavailability of Compound 2 in preclinical species was observed to be < 2% in mice, rats, and non-human primates and 13% in dogs. Compound 2 was found to be highly bound to plasma proteins in all species (> 99%) and did not distribute to red blood cells.

[0062] In preclinical studies activation of GPR40 alone with Compound 2 or GPR119 alone with Compound 1 elicits modest secretion of gut peptides, improvements in glycemic control, and body weight loss. Combination therapy results in more than additive effects on hormone secretion, glucose control and weight loss.Methods of Treatment

[0063] Described herein, in some embodiments, is a method of treating a condition or disorder involving the gut-brain axis in an individual in need thereof, the method comprising administering to the individual a GPR119 agonist (Compound 1, or a pharmaceutically acceptable salt or solvate thereof) and / or a GPR40 agonist (Compound 2, or a pharmaceutically acceptable salt or solvate thereof). In some embodiments, the condition or disorder involving the gut-brain axis is a metabolic disorder, nutritional disorder, eating disorder, or a combination thereof. In some embodiments, the individual is a human. In some embodiments, the methods described herein comprise administering to the individual a GPR40 agonist (Compound 2, or a pharmaceutically acceptable salt or solvate thereof). In other embodiments, the methods of treatment described herein comprise administering to theindividual both a GPR119 agonist (Compound 1, or a pharmaceutically acceptable salt or solvate thereof) and a GPR40 agonist (Compound 2, or a pharmaceutically acceptable salt or solvate thereof).

[0064] In some embodiments, the condition or disorder is selected from the group consisting of: central nervous system (CNS) disorders including mood disorders, anxiety, depression, affective disorders, schizophrenia, malaise, cognition disorders, addiction, autism, epilepsy, neurodegenerative disorders, Alzheimer’s disease, and Parkinson’s disease, Lewy Body dementia, episodic cluster headache, migraine, pain; metabolic conditions including diabetes and its complications such as chronic kidney disease / diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, and cardiovascular disease, metabolic syndrome, obesity, dyslipidemia, and nonalcoholic steatohepatitis (NASH); eating and nutritional disorders including hyperphagia, cachexia, binge eating disorder, short bowel syndrome, intestinal failure, intestinal insufficiency and other eating disorders; inflammatory disorders and autoimmune diseases such as inflammatory bowel disease, ulcerative colitis, Crohn’s disease, psoriasis, and celiac disease; necrotizing enterocolitis; gastrointestinal injury resulting from toxic insults such as radiation or chemotherapy; diseases / disorders of gastrointestinal barrier dysfunction including environmental enteric dysfunction, spontaneous bacterial peritonitis; functional gastrointestinal disorders such as irritable bowel syndrome, functional dyspepsia, functional abdominal bloating / distension, functional diarrhea, functional constipation, and opioid-induced constipation; gastroparesis; nausea and vomiting; disorders related to microbiome dysbiosis, other conditions involving the gut-brain axis.

[0065] In some embodiments, the condition is a metabolic disorder. In some embodiments, the metabolic disorder is type 2 diabetes, hyperglycemia, metabolic syndrome, obesity, hypercholesterolemia, or nonalcoholic steatohepatitis. In some embodiments, the metabolic disorder is type 2 diabetes. In other embodiments, the metabolic disorder is obesity. In other embodiments, the metabolic disorder is nonalcoholic steatohepatitis.

[0066] In some embodiments, the condition involving the gut-brain axis is a nutritional disorder. In some embodiments, the nutritional disorder is short bowel syndrome, intestinal failure, or intestinal insufficiency. In some embodiments, the nutritional disorder is short bowel syndrome.

[0067] In some embodiments, the condition involving the gut-brain axis is an eating disorder. In some embodiments, the eating disorder is hyperphagia or binge eating disorder. In some embodiments, the eating disorder is binge eating disorder.

[0068] In some embodiments, the condition involving the gut-brain axis is weight loss or preventing weight gain or weight regain. In some embodiments, the condition involving the gut-brain axis is weight loss or preventing weight gain or weight regain post-bariatric surgery. In some embodiments, the condition involving the gut-brain axis is weight loss or preventing weight gain or weight regain, wherein the subject has had bariatric surgery.

[0069] Also described herein, in some embodiments, is a method of weight management in an individual in need thereof comprising administering to the individual a GPR119 agonist (Compound 1, or a pharmaceutically acceptable salt or solvate thereof) and / or a GPR40 agonist (Compound 2, or a pharmaceutically acceptable salt or solvate thereof). In some embodiments, the method comprises administering to the individual a GPR40 agonist (Compound 2, or a pharmaceutically acceptable salt or solvate thereof). In other embodiments, the method comprises administering to the individual both a GPR119 agonist (Compound 1, or a pharmaceutically acceptable salt or solvate thereof) and a GPR40 agonist (Compound 2, or a pharmaceutically acceptable salt or solvate thereof). In some embodiments, said weight management comprises one or more of: weight loss, maintenance of weight loss, decreased food consumption, increasing meal -related satiety, reducing premeal hunger, and reducing intra-meal food intake.

[0070] In some embodiments, modulating the activity of multiple receptors (e.g., GPR119 and GPR40) simultaneously as described herein results in elevated hormone levels. In some embodiments, modulating the activity of GPR119 and GPR40 simultaneously as described herein results in synergistically elevated hormone levels. In some embodiments, modulating the activity of GPR119 and GPR40 simultaneously as described herein results in elevated hormone secretion. In some embodiments, modulating the activity of GPR119 and GPR40 simultaneously as described herein results in synergistically elevated hormone secretion. In some embodiments, modulating the activity of GPR119 and GPR40 simultaneously as described herein results in hormone levels higher than those when modulating the activity of any single receptor. In some embodiments, modulating the activity of GPR119 and GPR40 simultaneously as described herein results in hormone secretion higher than that when modulating the activity of any single receptor. In some embodiments, modulating the activity of GPR119 and GPR40 simultaneously as described herein elicits a greater biological response, for example, increased insulin secretion, lower food consumption, increased body mass reduction, increased cAMP levels, increased nutrient absorption, increased small intestinal length, increased small intestinal weight, increased villus height, or increased villus height / crypt depth ratio than when modulating the activity of any single receptor. In someembodiments, modulating the activity of GPR119 and GPR40 simultaneously as described herein is preferred for the methods described herein relative to modulating the activity of a single receptor.

[0071] In certain aspects, disclosed herein is a method of increasing weight loss in a subject that is obese. In some embodiments, the subject has a body mass index (BMI) of 30.0 to <40.0 kg / m2. In some embodiments, the subject has a body mass index (BMI) of >40.0 kg / m2. In some embodiments, the subject has a body mass index (BMI) of >27.0 kg / m2. In some embodiments, the subject has at least one self -reported unsuccessful dietary effort to lose body weight. In some embodiments, the subject is weight stable (<5% variation) over the previous 3 months before treatment. In some embodiments, treatment comprises weight loss of 5% or more after 13 weeks of treatment.Subjects

[0072] In some embodiments, the subject is a human. In some embodiments, the subject is an adult. In some embodiments, the subject is aged 18 to 55 years. In some embodiments, the subject is aged 18 to 60 years. In some embodiments, the subject is aged 18 to 65 years. In some embodiments, the subject is aged 18 to 70 years. In some embodiments, the subject is a child. In some embodiments, the subject is aged 6 to 18 years. In some embodiments, the subject is aged 10 to 18 years. In some embodiments, the subject is aged 12 to 18 years. In some embodiments, the subject is 6 years old or older. In some embodiments, the subject is 10 years old or older. In some embodiments, the subject is 12 years old or older. In some embodiments, the subject is 18 years old or older.

[0073] In some embodiments, the subject is overweight. In some embodiments, the subject is overweight or obese. In some embodiments, the subject is obese.

[0074] In some embodiments, the subject has a BMI >18 and <30.0 (kg / m2). In some embodiments, the subject has a BMI >27.0 and <35.0 (kg / m2). In some embodiments, the subject has a BMI >27.0 and <35.0 (kg / m2). In some embodiments, the subject has a BMI >25.0 and <38.0 (kg / m2). In some embodiments, the subject has a BMI >30.0 and <40.0 (kg / m2). In some embodiments, the subject has a BMI >40.0 (kg / m2).

[0075] In some embodiments, the subject is overweight but otherwise healthy. In some embodiments, the subject is weight stable. In some embodiments, the subject is weight stable (<5% variation) over the last 3 months. In some embodiments, the subject has a history of at least one self -reported unsuccessful dietary effort to lose body weight.

[0076] In some embodiments, the subject is deemed to be healthy based on clinical evaluations including laboratory safety tests, medical history, physical examination, 12-lead electrocardiogram (ECG), and vital sign measurements.

[0077] In some embodiments, the subject is obese. In some embodiments, the subject has a BMI >30.0 and <40.0 (kg / m2). In some embodiments, the subject has a BMI >30.0. In some embodiments, the subject has a BMI >40.0. In some embodiments, the subject is weight stable. In some embodiments, the subject is weight stable (<5% variation) over the last 3 months. In some embodiments, the subject has a history of at least one self-reported unsuccessful dietary effort to lose body weight.

[0078] In some embodiments, the subject has Type 2 diabetes mellitus, in accordance with American Diabetes Association (ADA) guidelines. In some embodiments, the subject has a Body Mass Index (BMI) >25.0 and <38.0 (kg / m2). In some embodiments, the subject has a BMI >30.0 and <40.0 (kg / m2). In some embodiments, the subject has a BMI >30.0. In some embodiments, the subjecthas a BMI >40.0. In some embodiments, the subject has HbAlc of 7% to 10.5%. In some embodiments, the subject has HbAlc of over 6.5%. In some embodiments, the subject has HbAlc of > 6.5%. In some embodiments, the subject has HbAlc of > 5.7%. In some embodiments, the subject has a fasting plasma glucose level of >126 mg / dL in an oral glucose tolerance test. In some embodiments, the subjecthas a fasting plasma glucose level of >100 mg / dL in an oral glucose tolerance test. In some embodiments, the subject is weight stable. In some embodiments, the subject is weight stable (<5% variation) over the last 3 months. In some embodiments, the subject has a history of at least one self-reported unsuccessful dietary effort to lose body weight.

[0079] In some embodiments, the subject is on a stable metformin monotherapy. In some embodiments, the total daily dose of metformin is 500 to 2,000 mg / day. In some embodiments, the subject is on a stable metformin monotherapy (total daily dose of 500 to 2,000 mg / day) for at least 3 months. In some embodiments, the metformin is immediate release (IR) metformin. In other embodiments, the metformin is extended release (XR) metformin.Dosage and Administration

[0080] In one embodiment, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, and / or Compound 2, or a pharmaceutically acceptable salt or solvate thereof, is / are used in the preparation of medicaments for the treatment of a disease associated with the gutbrain axis. Methods for treating any of the diseases or conditions described herein in a subject in need of such treatment involves administration of pharmaceutical compositions thatinclude at least Compound 1 or a pharmaceutically acceptable salt, active metabolite, prodrug, or pharmaceutically acceptable solvate thereof, and / or Compound 2 or a pharmaceutically acceptable salt, active metabolite, prodrug, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said subject.

[0081] In certain embodiments, the compositions containing the compounds described herein are administered for prophylactic and / or therapeutic treatments. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Therapeutically effective amounts can be determined by methods including, but not limited to, a dose escalation and / or dose ranging clinical trial.

[0082] In certain embodiments wherein the patient’s condition does not improve, upon the doctor’s discretion the administration of the compounds continue chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition.

[0083] Once improvement of the patient's conditions has occurred, a maintenance dose is administered if necessary. Subsequently, in some embodiments, the dosage or the frequency of administration, or both, is reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. In other embodiments, the dosage or the frequency of administration, or both, is maintained at the same level and is not reduced. In certain embodiments, however, the patient requires intermittent treatment on a long-term basis upon any recurrence of symptoms.

[0084] The amount of a given agent that corresponds to such an amount varies depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight, sex) of the subject or host in need of treatment, but nevertheless is determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.Dosage and Administration of Compound 1

[0085] In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered orally to the human. In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered to the human on a continuous dosing schedule. In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered to the human on a continuous d aily dosing schedule.

[0086] In some embodiments, Compound 1, or a pharmaceutically acceptable salt, or solvate thereof, is administered once daily, twice daily, three times daily, or four times daily . In some embodiments, Compound 1, or a pharmaceutically acceptable salt, or solvate thereof, is administered once daily or twice daily. In some embodiments, Compound 1, or a pharmaceutically acceptable salt, or solvate thereof, is administered once daily. In some embodiments, Compound 1, or a pharmaceutically acceptable salt, or solvate thereof, is administered twice daily.

[0087] In certain embodiments wherein sufficient improvement in the status of the disease or condition in the human is not observed, the daily dose of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is increased. In some embodiments, the frequency of administration is increased in order to provide maintained or more regular exposure to a GPR119 agonist (e.g., Compound 1, or a pharmaceutically acceptable salt or solvate thereof). In some embodiments, the frequency of administration is increased in order to provide repeat high Cmaxlevels on a more regular basis and / or provide maintained or more regular exposure to a GPR119 agonist (e.g., Compound 1, or a pharmaceutically acceptable salt or solvate thereof).

[0088] In any of the aforementioned aspects are further embodiments comprising multiple administrations of the effective amount of a GPR119 agonist (e.g., Compound 1, or a pharmaceutically acceptable salt or solvate thereof), including further embodiments in which (i) the GPR119 agonist is administered continuously or intermittently (as in a single dose of compound); (ii) the time between multiple administrations is every 6 hours; (iii) the GPR119 agonist is administered to the mammal every 8 hours; (iv) the GPR119 agonist is administered to the mammal every 12 hours; (v) the GPR119 agonist is administered to the mammal every 24 hours. In further or alternative embodiments, the method comprises a drug holiday, wherein the administration of the GPR119 agonist is temporarily suspended or the dose of the GPR119 agonist being administered is temporarily reduced; at the end of the drug holiday, dosing of the GPR119 agonist is resumed. In one embodiment, the length of the drug holiday varies from 2 days to 1 year.

[0089] In general, however, doses of Compound 1 , or a pharmaceutically acceptable salt or solvate thereof, employed for adult human treatment are typically in the range of 0.01 mg- 500 mg per day. In one embodiment, the desired dose is conveniently presented in a single dose or in divided doses administered simultaneously or at appropriate intervals, for example as two, three, four or more sub -doses per day.

[0090] In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered in an amount equivalent to a daily dose of about 3 mg to about 300 mg of Compound 1. In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered in an amount equivalent to a daily dose of about 5 mg to about 250 mg of Compound 1. In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered in an amount equivalent to a daily dose of about 20 mg to about 200 mg of Compound 1. In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered in an amount equivalent to a daily dose of about 20 mg to about 100 mg of Compound 1.

[0091] In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered in amount equivalent to a daily dose of about: 3 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 80 mg, 100 mg, 120 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, or 500 mg. In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered in amount equivalent to a daily dose of about: 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, or 300 mg of Compound 1. In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered in amount equivalent to a daily dose of about: 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, or 200 mg of Compound 1. In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered in amount equivalent to a daily dose of about: 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, or 100 mg of Compound 1.

[0092] In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered in a single dosage amount equivalent to about: 3 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 80 mg, 100 mg, 120 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, or 500 mg. In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered in a single dosage amountequivalent to about: 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, or 300 mg of Compound 1. In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered in a single dosage amount equivalent to about: 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, or 200 mg of Compound 1. In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered in a single dosage amount equivalent to about: 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, or 100 mg of Compound 1 . In some embodiments, Compound 1 is administered once or twice daily.

[0093] In some embodiments, Compound 1, or a pharmaceutically acceptable salt, or solvate thereof, is administered once daily or twice daily, with each dose having a dosage amount of about: 3 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 80 mg, 100 mg, 120 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, or 500 mg. In some embodiments, Compound 1, or a pharmaceutically acceptable salt, or solvate thereof, is administered once daily or twice daily, with each dose having a dosage amount of about: 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, or 300 mg of Compound 1. In some embodiments, Compound 1 , or a pharmaceutically acceptable salt, or solvate thereof, is administered once daily or twice daily, with each dose having a dosage amount of about: 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, or 100 mg of Compound 1.

[0094] In some embodiments, Compound 1, or a pharmaceutically acceptable salt, or solvate thereof, is administered once daily, with a dosage amount of about: 3 mg, 10 mg, 20mg, 30 mg, 40 mg, 50 mg, 60 mg, 80 mg, 100 mg, 120 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, or 500 mg. In some embodiments, Compound 1, or a pharmaceutically acceptable salt, or solvate thereof, is administered once daily, with a dosage amount of about: 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, or 300 mg of Compound 1. In some embodiments, Compound 1, or a pharmaceutically acceptable salt, or solvate thereof, is administered once daily, with a dosage amount of about: 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, or 100 mg of Compound 1.

[0095] In some embodiments, Compound 1, or a pharmaceutically acceptable salt, or solvate thereof, is administered twice daily, with each dose having a dosage amount of about: 3 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 80 mg, 100 mg, 120 mg, 150 mg, 200 mg 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, or 500 mg. In some embodiments, Compound 1, or a pharmaceutically acceptable salt, or solvate thereof, is administered twice daily, with each dose having a dosage amount of about: 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg,150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg,255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, or 300 mg ofCompound 1. In some embodiments, Compound 1, or a pharmaceutically acceptable salt, or solvate thereof, is administered twice daily, with each dose having a dosage amount of about: 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, or 100 mg of Compound 1.

[0096] In some embodiments, Compound 1, or a pharmaceutically acceptable salt, or solvate thereof, is administered once daily, with a dosage amount of about 3 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 80 mg, or 100 mg of Compound 1. In some embodiments, Compound 1, or a pharmaceutically acceptable salt, or solvate thereof, is administered once daily, with a dosage amount of about 10 mg of Compound 1. In some embodiments, Compound 1, or a pharmaceutically acceptable salt, or solvate thereof, is administered oncedaily, with a dosage amount of about 20 mg of Compound 1. In some embodiments, Compound 1, or a pharmaceutically acceptable salt, or solvate thereof, is administered once daily, with a dosage amount of about 30 mg of Compound 1. In some embodiments, Compound 1, or a pharmaceutically acceptable salt, or solvate thereof, is administered once daily, with a dosage amount of about 40 mg of Compound 1. In some embodiments, Compound 1, or a pharmaceutically acceptable salt, or solvate thereof, is administered once daily, with a dosage amount of about 50 mg of Compound 1. In some embodiments, Compound 1, or a pharmaceutically acceptable salt, or solvate thereof, is administered once daily, with a dosage amount of about 60 mg of Compound 1. In some embodiments, Compound 1, or a pharmaceutically acceptable salt, or solvate thereof, is administered once daily, with a dosage amount of about 70 mg of Compound 1. In some embodiments, Compound 1, or a pharmaceutically acceptable salt, or solvate thereof, is administered once daily, with a dosage amount of about 80 mg of Compound 1. In some embodiments, Compound 1, or a pharmaceutically acceptable salt, or solvate thereof, is administered once daily, with a dosage amount of about 90 mg of Compound 1. In some embodiments, Compound 1, or a pharmaceutically acceptable salt, or solvate thereof, is administered once daily, with a dosage amount of about 100 mg of Compound 1.

[0097] In some embodiments, Compound 1, or a pharmaceutically acceptable salt, or solvate thereof, is administered twice daily, with each dose having a dosage amount of about 3 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 80 mg, or 100 mg of Compound 1. In some embodiments, Compound 1 , or a pharmaceutically acceptable salt, or solvate thereof, is administered twice daily, with each dose having a dosage amount of about 10 mg of Compound 1. In some embodiments, Compound 1, or a pharmaceutically acceptable salt, or solvate thereof, is administered twice daily, with each dose having a dosage amount of about 20 mg of Compound 1. In some embodiments, Compound 1, or a pharmaceutically acceptable salt, or solvate thereof, is administered twice daily, with each dose having a dosage amount of about 30 mg of Compound 1. In some embodiments, Compound 1, or a pharmaceutically acceptable salt, or solvate thereof, is administered twice daily, with each dose having a dosage amount of about 40 mg of Compound 1. In some embodiments, Compound 1, or a pharmaceutically acceptable salt, or solvate thereof, is administered twice daily, with each dose having a dosage amount of about 50 mg of Compound 1. In some embodiments, Compound 1, or a pharmaceutically acceptable salt, or solvate thereof, is administered twice daily, with each dose having a dosage amount of about 60 mg of Compound 1. In some embodiments, Compound 1, or a pharmaceutically acceptable salt, orsolvate thereof, is administered twice daily, with each dose having a dosage amount of about 70 mg of Compound 1. In some embodiments, Compound 1, or a pharmaceutically acceptable salt, or solvate thereof, is administered twice daily, with each dose having a dosage amount of about 80 mg of Compound 1. In some embodiments, Compound 1, or a pharmaceutically acceptable salt, or solvate thereof, is administered twice daily, with each dose having a dosage amount of about 90 mg of Compound 1. In some embodiments, Compound 1, or a pharmaceutically acceptable salt, or solvate thereof, is administered twice daily, with each dose having a dosage amount of about 100 mg of Compound 1.

[0098] In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered in amount equivalent to about 100 mg of Compound 1 once daily. In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered in amount equivalent to about 100 mg of Compound 1 twice daily.

[0099] In some embodiments, Compound 1, or a pharmaceutically acceptable salt, or solvate thereof, is administered in a daily dose of at least about: 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg,195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, or 300 mg of Compound 1 .

[0100] In some embodiments, Compound 1, or a pharmaceutically acceptable salt, or solvate thereof, is administered in a daily dose of no more than about: 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg,190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg,295 mg, or 300 mg of Compound 1 .

[0101] In one embodiment, the daily dosages appropriate for the compound of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, described herein is from about 0.01 to about 50 mg / kg per body weight. In some embodiments, the daily dosage or the amount of active pharmaceutical ingredient in the dosage form is lower or higher than the ranges indicated herein, based on a number of variables in regard to an individual treatment regime. In various embodiments, the daily and unit dosages are altered depending on anumber of variables including, but not limited to, the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.

[0102] Toxicity and therapeutic efficacy of such therapeutic regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD50and the ED50. In certain embodiments, the therapeutic index is the dose ratio between the toxic and therapeutic effects, and it is expressed as the ratio between LD50and ED50. In certain embodiments, the data obtained from cell culture assays and animal studies are used in formulating the therapeutically effective daily dosage range and / or the therapeutically effective unit dosage amount for use in subjects, including humans. In some embodiments, the daily dosage amount of the compounds described herein lies within a range of circulating concentrations that include the ED50with minimal toxicity. In certain embodiments, the daily dosage range and / or the unit dosage amount varies within this range depending upon the dosage form employed and the route of administration utilized. In other certain embodiments, the therapeutic index is determined based on the tolerability of the compound due to adverse events. In some embodiments, the adverse events (AEs) are GI AEs, such as nausea, vomiting, diarrhea, constipation, and / or abdominal discomfort. In certain aspects, GI AEs are due to the enhanced secretion of gut hormones.

[0103] In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered on a dose titration schedule. In some embodiments, the dose titration schedule comprises: 1) an initial dose of Compound 1 , or a pharmaceutically acceptable salt or solvate thereof, which is dosed for an initial dosing period; 2) a first increased dose, which is calculated by increasing the initial dose by a first incremental dose, which is dosed for a second dosing period; 3) as required, additional increased dose(s), which have additional incremental doses and dosing periods; and 4) a final or optimized dose which is dosed for the remaining treatment time. An optimized dose provides efficacy of treatment while minimizes side effects with treatment.

[0104] In some embodiments, the initial dose of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is equivalent to about 3 mg to about 300 mg of Compound 1. In some embodiments, the initial dose of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is equivalent to about 5 mg to about 250 mg of Compound 1. In someembodiments, the initial dose of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is equivalent to about 20 mg to about 100 mg of Compound 1.

[0105] In some embodiments, the initial dose of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is equivalent to about: 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg,145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg,250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, or 300 mg of Compound 1.

[0106] In some embodiments, the first incremental value is equivalent to about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg of Compound 1.

[0107] In some embodiments, the second incremental value is equivalent to about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about lOOmg of Compound 1.

[0108] In some embodiments, the titration schedule is repeated until an optimized dose is obtained. An optimized dose provides efficacy of treatment while minimizes side effects with treatment.

[0109] In some embodiments, the optimized dose of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is equivalent to about: 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg,145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg,250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, or 300 mg of Compound 1 .

[0110] In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered in amount equivalent to about 100 mg of Compound 1 once daily. In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered in amount equivalent to about 100 mg of Compound 1 twice daily.

[0111] In some embodiments, Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered in an initial dose amount equivalent to about 100 mg of Compound 1 once daily for 1 day, 2 days, 3 days, 4 days, 5 days, 6, days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16, days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26, days, 27 days, 28 days, 29 days, or 30 days; followed by an optimized daily dose amount equivalent to about 200 mg of Compound 1 . In some embodiments, the optimized daily dose is administered once daily (for example, 200 mg once daily). In other embodiments, the optimized daily dose is administered in a divided dose twice daily (for example, 200 mg total daily dose administered as 100 mg dose twice daily). In some embodiments, Compound 1 , or a pharmaceutically acceptable salt or solvate thereof, is administered in an initial dose amount equivalent to about 100 mg of Compound 1 once daily for about 7 days; followed by an optimized dose amount equivalent to about 100 mg of Compound 1 twice daily.Dosage and Administration of Compound 2

[0112] In some embodiments, Compound 2, or a pharmaceutically acceptable salt or solvate thereof, is administered orally to the human. In some embodiments, Compound 2, or a pharmaceutically acceptable salt or solvate thereof, is administered to the human on a continuous dosing schedule. In some embodiments, Compound 2, or a pharmaceutically acceptable salt or solvate thereof, is administered to the human on a continuous daily dosing schedule.

[0113] In some embodiments, Compound 2, or a pharmaceutically acceptable salt, or solvate thereof, is administered once daily, twice daily, three times daily, or four times daily. In some embodiments, Compound 2, or a pharmaceutically acceptable salt, or solvate thereof, is administered once daily or twice daily. In some embodiments, Compound 2, or a pharmaceutically acceptable salt, or solvate thereof, is administered once daily. In some embodiments, Compound 2, or a pharmaceutically acceptable salt, or solvate thereof, is administered twice daily.

[0114] In certain embodiments wherein sufficient improvement in the status of the disease or condition in the human is not observed, the daily dose of Compound 2, or a pharmaceutically acceptable salt or solvate thereof, is increased. In some embodiments, the frequency of administration is increased in order to provide maintained or more regular exposure to a GPR40 agonist (e.g., Compound 2, or a pharmaceutically acceptable salt or solvate thereof). In some embodiments, the frequency of administration is increased in order to provide repeat high Cmaxlevels on a more regular basis and / or provide maintained or moreregular exposure to a GPR40 agonist (e.g., Compound 2, or a pharmaceutically acceptable salt or solvate thereof).

[0115] In any of the aforementioned aspects are further embodiments comprising multiple administrations of the effective amount of a GPR40 agonist (e.g., Compound 2, or a pharmaceutically acceptable salt or solvate thereof), including further embodiments in which (i) the GPR40 agonist is administered continuously or intermittently (as in a single dose of compound); (ii) the time between multiple administrations is every 6 hours; (iii) the GPR40 agonist is administered to the mammal every 8 hours; (iv) the GPR40 agonist is administered to the mammal every 12 hours; (v) the GPR40 agonist is administered to the mammal every 24 hours. In further or alternative embodiments, the method comprises a drug holiday, wherein the administration of the GPR40 agonist is temporarily suspended or the dose of the GPR40 agonist being administered is temporarily reduced; at the end of the drug holiday, dosing of the GPR40 agonist is resumed. In one embodiment, the length of the drug holiday varies from 2 days to 1 year.

[0116] In general, however, doses of Compound 2, or a pharmaceutically acceptable salt or solvate thereof, employed for adult human treatment are typically in the range of 0.01 mg- 500 mg per day. In one embodiment, the desired dose is conveniently presented in a single dose or in divided doses administered simultaneously or at appropriate intervals, for example as two, three, four or more sub -doses per day.

[0117] In some embodiments, Compound 2, or a pharmaceutically acceptable salt or solvate thereof, is administered in an amount equivalent to a daily dose of about 10 mg to about 500 mg of Compound 2. In some embodiments, Compound 2, or a pharmaceutically acceptable salt or solvate thereof, is administered in an amount equivalent to a daily dose of about 10 mg to about 250 mg of Compound 2. In some embodiments, Compound 2, or a pharmaceutically acceptable salt or solvate thereof, is administered in an amount equivalent to a daily dose of about 10 mg to about 240 mg of Compound 2. In some embodiments, Compound 2, or a pharmaceutically acceptable salt or solvate thereof, is administered in an amount equivalent to a daily dose of about 20 mg to about 120 mg of Compound 2. In some embodiments, Compound 2, or a pharmaceutically acceptable salt or solvate thereof, is administered in an amount equivalent to a daily dose of about 20 mg to about 60 mg of Compound 2.

[0118] In some embodiments, particularly for the methods of treating of type 2 diabetes, Compound 2, or a pharmaceutically acceptable salt or solvate thereof, is administered in an amount equivalent to a daily dose of about 20 mg to about 120 mg of Compound 2. In somesuch embodiments, Compound 2, or a pharmaceutically acceptable salt or solvate thereof, is administered in an amount equivalent to a daily dose of about 20 mg to about 60 mg of Compound 2.

[0119] In some embodiments, Compound 2, or a pharmaceutically acceptable salt or solvate thereof, is administered in amount equivalent to a daily dose of about: 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 80 mg, 100 mg, 120 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, or 500 mg. In some embodiments, Compound 2, or a pharmaceutically acceptable salt or solvate thereof, is administered in amount equivalent to a daily dose of about: 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, or 250 mg of Compound 2. In some embodiments, Compound 2, or a pharmaceutically acceptable salt or solvate thereof, is administered in amount equivalent to a daily dose of about: 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, or 240 mg of Compound 2. In some embodiments, Compound 2, or a pharmaceutically acceptable salt or solvate thereof, is administered in amount equivalent to a daily dose of about: 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, or 120 mg of Compound 2. In some embodiments, Compound 2, or a pharmaceutically acceptable salt or solvate thereof, is administered in amount equivalentto a daily dose of about: 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, or 60 mg of Compound 2.

[0120] In some embodiments, Compound 2, or a pharmaceutically acceptable salt or solvate thereof, is administered in a single dosage amount equivalent to about: 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 80 mg, 100 mg, 120 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, or 500 mg. In some embodiments, Compound 2, or a pharmaceutically acceptable salt or solvate thereof, is administered in a single dosage amount equivalentto about: 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, or 250 mg of Compound 2. In some embodiments, Compound 2, or a pharmaceutically acceptable salt or solvate thereof, is administered in a single dosage amount equivalent to about: 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, or 240 mg of Compound 2. In some embodiments, Compound 2, or a pharmaceutically acceptable salt or solvate thereof, is administered in a single dosage amount equivalent to about: 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, or 120 mg of Compound 2. In some embodiments, Compound 2, or a pharmaceutically acceptable salt or solvate thereof, is administered in a single dosage amount equivalent to about: 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, or 60 mg of Compound 2. In some embodiments, Compound 1 is administered once or twice daily.

[0121] In some embodiments, Compound 2, or a pharmaceutically acceptable salt, or solvate thereof, is administered once daily or twice daily, with each dose having a dosage amount of about: 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 80 mg, 100 mg, 120 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, or 500 mg. In some embodiments, Compound 2, or a pharmaceutically acceptable salt, or solvate thereof, is administered once daily or twice daily, with each dose having a dosage amount of about: 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, or 250 mg of Compound 2. In some embodiments, Compound 2, or a pharmaceutically acceptable salt, or solvate thereof, is administered once daily or twice daily, with each dose having a dosage amount of about: 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, or 240 mg of Compound 2. In some embodiments, Compound 2, or a pharmaceutically acceptable salt, or solvate thereof, is administered oncedaily or twice daily, with each dose having a dosage amount of about: 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, or 120 mg of Compound 2. In some embodiments, Compound 2, or a pharmaceutically acceptable salt, or solvate thereof, is administered once daily or twice daily, with each dose having a dosage amount of about: 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, or 60 mg of Compound 2.

[0122] In some embodiments, Compound 2, or a pharmaceutically acceptable salt, or solvate thereof, is administered once daily, with a dosage amount of about: 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 80 mg, 100 mg, 120 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, or 500 mg. In some embodiments, Compound 2, or a pharmaceutically acceptable salt, or solvate thereof, is administered once daily, with a dosage amount of about: 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, or 250 mg of Compound 2. In some embodiments, Compound 2, or a pharmaceutically acceptable salt, or solvate thereof, is administered once daily, with a dosage amount of about: 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, or 240 mg of Compound 2. In some embodiments, Compound 2, or a pharmaceutically acceptable salt, or solvate thereof, is administered once daily, with a dosage amount of about: 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, or 120 mg of Compound 2. In some embodiments, Compound 2, or a pharmaceutically acceptable salt, or solvate thereof, is administered once daily, with a dosage amount of about: 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, or 60 mg of Compound 2.

[0123] In some embodiments, Compound 2, or a pharmaceutically acceptable salt, or solvate thereof, is administered twice daily, with each dose having a dosage amount of about: 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 80 mg, 100 mg, 120 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, or 500 mg. In some embodiments, Compound 2, or a pharmaceutically acceptable salt, or solvate thereof, is administered twice daily, with each dose having a dosage amount of about: 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg,45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, or 250 mg of Compound 2. In some embodiments, Compound 2, or a pharmaceutically acceptable salt, or solvate thereof, is administered twice daily, with each dose having a dosage amount of about: 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, or 240 mg of Compound 2. In some embodiments, Compound 2, or a pharmaceutically acceptable salt, or solvate thereof, is administered twice daily, with each dose having a dosage amount of about: 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, or 120 mg of Compound 2. In some embodiments, Compound 2, or a pharmaceutically acceptable salt, or solvate thereof, is administered twice daily, with each dose having a dosage amountof about: 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, or 60 mg of Compound 2.

[0124] In some embodiments, Compound 2, or a pharmaceutically acceptable salt or solvate thereof, is administered once daily, with a dosage amount of about 20 mg of Compound 2. In some embodiments, Compound 2, or a pharmaceutically acceptable salt, or solvate thereof, is administered once daily, with a dosage amount of about 30 mg of Compound 2. In some embodiments, Compound 2, or a pharmaceutically acceptable salt, or solvate thereof, is administered once daily, with a dosage amount of about 60 mg of Compound 2. In some embodiments, Compound 2, or a pharmaceutically acceptable salt, or solvate thereof, is administered once daily, with a dosage amount of about 100 mg of Compound 2. In some embodiments, Compound 2, or a pharmaceutically acceptable salt, or solvate thereof, is administered once daily, with a dosage amount of about 120 mg of Compound 2

[0125] In some embodiments, Compound 2, or a pharmaceutically acceptable salt or solvate thereof, is administered twice daily, with each dose having a dosage amount of about 20 mg of Compound 2. In some embodiments, Compound 2, or a pharmaceutically acceptable salt, or solvate thereof, is administered twice daily, with each dose having a dosage amount of about of about 30 mg of Compound 2. In some embodiments, Compound2, or a pharmaceutically acceptable salt, or solvate thereof, is administered twice daily, with each dose having a dosage amount of about 60 mg of Compound 2. In some embodiments, Compound 2, or a pharmaceutically acceptable salt, or solvate thereof, is ad administered twice daily, with each dose having a dosage amount of about of about 100 mg of Compound 2. In some embodiments, Compound 2, or a pharmaceutically acceptable salt, or solvate thereof, is administered twice daily, with each dose having a dosage amount of about 120 mg of Compound 2.

[0126] In some embodiments, Compound 2, or a pharmaceutically acceptable salt, or solvate thereof, is administered in a daily dose of at least about: 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, or 250 mg of Compound 2.

[0127] In some embodiments, Compound 2, or a pharmaceutically acceptable salt, or solvate thereof, is administered in a daily dose of no more than about: 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, or 250 mg of Compound 2.

[0128] In one embodiment, the daily dosages appropriate for the compound of Compound 2, or a pharmaceutically acceptable salt or solvate thereof, described herein is from about 0.01 to about 50 mg / kg per body weight. In some embodiments, the daily dosage or the amount of active pharmaceutical ingredient in the dosage form is lower or higher than the ranges indicated herein, based on a number of variables in regard to an individual treatment regime. In various embodiments, the daily and unit dosages are altered depending on a number of variables including, but not limited to, the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.

[0129] Toxicity and therapeutic efficacy of such therapeutic regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD50and the ED50. In certain embodiments, thetherapeutic index is the dose ratio between the toxic and therapeutic effects, and it is expressed as the ratio between LD50and ED50. In certain embodiments, the data obtained from cell culture assays and animal studies are used in formulating the therapeutically effective daily dosage range and / or the therapeutically effective unit dosage amount for use in subjects, including humans. In some embodiments, the daily dosage amount of the compounds described herein lies within a range of circulating concentrations that include the ED5o with minimal toxicity. In certain embodiments, the daily dosage range and / or the unit dosage amount varies within this range depending upon the dosage form employed and the route of administration utilized. In other certain embodiments, the therapeutic index is determined based on the tolerability of the compound due to adverse events. In some embodiments, the adverse events (AEs) are GI AEs, such as nausea, vomiting, diarrhea, constipation, and / or abdominal discomfort. In certain aspects, GI AEs are due to the enhanced secretion of gut hormones.

[0130] In some embodiments, Compound 2 administration has been associated with dosedependent GI AEs characteristic of those observed following pharmacologic administration of GLP-1 analogs, for which gradual titration to target doses is used to mitigate GI intolerance. Therefore, in some embodiments up-titration of Compound 2 is used to mitigate GI intolerance and support attainment of the target dose, optimized dose, or final dose level. In some embodiments, up-titration mitigates GI AEs, such as nausea, vomiting, diarrhea, constipation, and / or abdominal discomfort.

[0131] In some embodiments, Compound 2, or a pharmaceutically acceptable salt or solvate thereof, is administered on a dose titration schedule. In some embodiments, the dose titration schedule comprises: 1) an initial dose of Compound 2, or a pharmaceutically acceptable salt or solvate thereof, which is dosed for an initial dosing period; 2) a first increased dose, which is calculated by increasing the initial dose by a first incremental dose, which is dosed for a second dosing period; 3) as required, additional increased dose(s), which have additional incremental doses and dosing periods; and 4) a final or optimized dose which is dosed for the remaining treatment time. An optimized dose provides efficacy of treatment while minimizes side effects with treatment.

[0132] In some embodiments, the initial dose of Compound 2, or a pharmaceutically acceptable salt or solvate thereof, is equivalent to about 10 mg to about 500 mg of Compound 2. In some embodiments, the initial dose of Compound 2, or a pharmaceutically acceptable salt or solvate thereof, is equivalent to about 10 mg to about 250 mg of Compound 2. In some embodiments, the initial dose of Compound 2, or a pharmaceutically acceptable salt orsolvate thereof, is equivalent to about 20 mg to about 120 mg of Compound 2. In some embodiments, the initial dose of Compound 2, or a pharmaceutically acceptable salt or solvate thereof, is equivalent to about 20 mg to about 60 mg of Compound 2.

[0133] In some embodiments, the initial dose of Compound 2, or a pharmaceutically acceptable salt or solvate thereof, is equivalent to about: 10 mg, 15 mg, 20 mg, 25 mg, 30 mg 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, or 250 mg of Compound 2. In some embodiments, the initial dose of Compound 2, or a pharmaceutically acceptable salt or solvate thereof, is equivalent to about: 10 mg, 15 mg, 20 mg, 25 mg, or 30 mg of Compound 2.

[0134] In some embodiments, the first incremental value is equivalent to about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg of Compound 2. In some embodiments, the first incremental value is equivalent to about 10 mg, about 15 mg, about 20 mg, about 25 mg, or about 30 mg of Compound 2.

[0135] In some embodiments, the second incremental value is equivalent to about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about lOO mg of Compound 2. In some embodiments, the second incremental valueis equivalent to about 10 mg, about 15 mg, about 20 mg, about 25 mg, or about 30 mg of Compound 2. In some embodiments, the second incremental valueis equivalent to about20 mg, about 30 mg, about 40 mg, about 50 mg, or about 60 mg, of Compound 2.

[0136] In some embodiments, the titration schedule is repeated until an optimized dose is obtained. An optimized dose provides efficacy of treatment while minimizes side effects with treatment.

[0137] In some embodiments, the optimized dose of Compound 2, or a pharmaceutically acceptable salt or solvate thereof, is equivalent to about: 10 mg, 15 mg, 20 mg, 25 mg, 30 mg 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, or 250 mg of Compound 1 . In some embodiments, the optimized dose of Compound 2, or a pharmaceutically acceptable salt or solvate thereof, is equivalent to about 20 mg to about 120 mg of Compound 2. In some embodiments, the optimized dose of Compound 2, or a pharmaceutically acceptable salt or solvate thereof, is equivalent to about 20 mg to about 60 mg of Compound 2. In some embodiments, the optimized dose of Compound 2, or a pharmaceutically acceptable salt or solvate thereof, is equivalent to about 60 mgto about 120 mg of Compound 2. In some embodiments, the optimized dose of Compound 2, or a pharmaceutically acceptable salt or solvate thereof, is equivalent to about 60 mg of Compound 2. In some embodiments, the optimized dose of Compound 2, or a pharmaceutically acceptable salt or solvate thereof, is equivalent to about 120 mg of Compound 2.

[0138] In some embodiments, Compound 2, or a pharmaceutically acceptable salt or solvate thereof, is administered in amount equivalent to about 20 mg of Compound 2 once daily. In some embodiments, Compound 2, or a pharmaceutically acceptable salt, or solvate thereof, is administered in amount equivalent to about 30 mg of Compound 2 once daily. In some embodiments, Compound 2, or a pharmaceutically acceptable salt, or solvate thereof, is administered in amount equivalent to about 60 mg of Compound 2 once daily. In some embodiments, Compound 2, or a pharmaceutically acceptable salt, or solvate thereof, is administered in amount equivalent to about 100 mg of Compound 2 once daily. In some embodiments, Compound 2, or a pharmaceutically acceptable salt, or solvate thereof, is administered in amount equivalent to about 120 mg of Compound 2 once daily.

[0139] In some embodiments, Compound 2, or a pharmaceutically acceptable salt or solvate thereof, is administered in amount equivalent to about 20 mg of Compound 2 twice daily. In some embodiments, Compound 2, or a pharmaceutically acceptable salt, or solvate thereof, is administered in amount equivalent to about 30 mg of Compound 2 twice daily. In some embodiments, Compound 2, or a pharmaceutically acceptable salt, or solvate thereof, is administered in amount equivalent to about 60 mg of Compound 2 twice daily. In some embodiments, Compound 2, or a pharmaceutically acceptable salt, or solvate thereof, is administered in amount equivalent to about 100 mg of Compound 2 twice daily. In some embodiments, Compound 2, or a pharmaceutically acceptable salt, or solvate thereof, is administered in amount equivalent to about 120 mg of Compound 2 twice daily.

[0140] In some embodiments, Compound 2, or a pharmaceutically acceptable salt or solvate thereof, is administered in an initial dose amount equivalent to about 30 mg ofCompound 2 once daily for 1 day, 2 days, 3 days, 4 days, 5 days, 6, days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16, days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26, days, 27 days, 28 days, 29 days, or 30 days; followed by a first incremental dose amount equivalent to about 30 mg ofCompound 2 twice daily for 1 day, 2 days, 3 days, 4 days, 5 days, 6, days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16, days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26, days, 27 days, 28 days, 29 days, or 30 days; followed by an optimized dose amount equivalent to about 60 mg of Compound 2 twice daily. In some embodiments, Compound 2, or a pharmaceutically acceptable salt or solvate thereof, is administered in an initial dose amount equivalent to about 30 mg of Compound 2 once daily for about 7 days; followed by a first incremental dose amount equivalent to about 30 mg of Compound 2 twice daily for 7 days; followed by optimized dose amount equivalent to about 60 mg of Compound 2 twice daily.

[0141] In some embodiments, Compound 2, or a pharmaceutically acceptable salt or solvate thereof, is administered in an initial dose amount equivalent to about 30 mg of Compound 2 once daily for 1 day, 2 days, 3 days, 4 days, 5 days, 6, days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16, days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26, days, 27 days, 28 days, 29 days, or 30 days; followed by a first incremental dose amount equivalent to about 30 mg ofCompound 2 twice daily for 1 day, 2 days, 3 days, 4 days, 5 days, 6, days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16, days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26, days, 27 days, 28 days, 29 days, or 30 days; followed by a second incremental dose amount equivalent to about 60 mg of Compound 2 twice daily for 1 day, 2 days, 3 days, 4 days, 5 days, 6, days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16, days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26, days, 27 days, 28 days, 29 days, or 30 days; followed by an optimized dose amount equivalent to about 120 mg of Compound 2 twice daily. In some embodiments, Compound 2, or a pharmaceutically acceptable salt or solvate thereof, is administered in an initial dose amount equivalent to about 30 mg of Compound 2 once daily for about 7 days; followed by a first incremental dose amount equivalent to about 30 mg of Compound 2 twice daily for 7 days; followed by a second incremental dose amount equivalent to about 60 mg of Compound 2 twice daily for 7 days; followed by an optimized dose amount equivalent to about 120 mg of Compound 2 twice daily.Dosage and Administration of Compound 1 in Combination with Compound 2

[0142] Any and all combinations listed for dosing of Compound 1 above can be combined with the dosing of Compound 2. All permutations are envisioned within the invention herein.

[0143] As a non-limiting example, in some embodiments, Compound 1 is dosed in an amount equivalent to about 100 mg once or twice daily, and Compound 2 is dosed in an amount equivalent to about20mg, 30 mg, 60 mg, 100 mg, or 120 mg once or twice daily. In some embodiments, Compound 1 is dosed in an amount equivalent to about 100 mg or 200 mg once daily, and Compound 2 is dosedin an amount equivalent to about20 mg, 30 mg, 60 mg, 100 mg, 120 mg, or 240 mg once daily.

[0144] As a non-limiting example, in some embodiments, Compound 1 is dosed in an amount equivalent to about 100 mg once or twice daily, and Compound 2 is dosed in an amount equivalent to about 30 mg, 60 mg, or 120 mg once or twice daily.

[0145] As a non-limiting example, in some embodiments, in some embodiments, Compound 1 is administered in an initial dose amount equivalent to about 100 mg and Compound 2 is administered in an initial dose amount equivalent to about 30 mg once daily for about? days; followed by a first incremental dose amount of Compound 1 equivalent to about 100 mg and Compound 2 equivalent to about 30 mg twice daily for about 7 days; followed by a second incremental dose amount of Compound 1 equivalent to about 100 mg and Compound 2 equivalent to about 60 mg twice daily for about 7 days; followed by an optimized dose of Compound 1 equivalent to about 100 mg and Compound 2 equivalent to about 120 mg twice daily.

[0146] As a non-limiting example, in some embodiments, in some embodiments, Compound 1 is administered in an initial dose amount equivalent to about 100 mg and Compound 2 is administered in an initial dose amount equivalent to about 30 mg once daily for about? days; followed by a first incremental dose amount of Compound 1 equivalent to about 100 mg and Compound 2 equivalent to about 30 mg twice daily for about 7 days; followed by optimized dose amount of Compound 1 equivalent to about 100 mg and Compound 2 equivalent to about 60 mg twice daily.Additional Therapeutic Agents

[0147] In certain embodiments, it is appropriate to administer Compound 1, or a pharmaceutically acceptable salt or solvate thereof, and Compound 2, or a pharmaceutically acceptable salt or solvate thereof, as described herein in combination with one or more additional therapeutic agents. In certain embodiments, it is appropriate to administerCompound 2, or a pharmaceutically acceptable salt or solvate thereof, as described herein in combination with one or more additional therapeutic agents.

[0148] In some embodiments, the combination therapies described herein are administered in further combination with a TGR5 agonist, an SSTR5 antagonist, an SSTR5 inverse agonist, a CCK1 agonist, a PDE4 inhibitor, a DPP-4 inhibitor (such as, for example, sitagliptin), a GLP-1 receptor agonist, a ghrelin O-acyltransferase (GOAT) inhibitor, metformin, or combinations thereof.

[0149] In some embodiments, the combination therapies described herein for the treatment of type 2 diabetes are administered in further combination with a TGR5 agonist, an SSTR5 antagonist, an SSTR5 inverse agonist, a CCK1 agonist, a PDE4 inhibitor, a GLP-1 receptor agonist, a ghrelin O-acyltransf erase (GOAT) inhibitor, metformin, or combinations thereof.

[0150] In some embodiments, the combination therapies described herein are administered in combination with a DPP-4 inhibitor (such as, for example, sitagliptin), a GLP-1 receptor agonist, metformin, or combinations thereof. In some embodiments, the combination therapies described herein are administered in combination with a GLP-1 receptor agonist, metformin, or combinations thereof. In some embodiments, the combination therapies described herein are administered in combination with a DPP-4 inhibitor. In some embodiments, the combination therapies described herein are administered in combination with a GLP-1 receptor agonist. In some embodiments, the combination therapies described herein are administered in combination with metformin.

[0151] In certain embodiments, the pharmaceutical composition further comprises one or more anti-diabetic agents. In certain embodiments, the pharmaceutical composition further comprises one or more anti-obesity agents. In certain embodiments, the pharmaceutical composition further comprises one or more agents to treat nutritional disorders.Pharmaceutical Compositions

[0152] In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate processing of the active compounds into preparations that are used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein is found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical DosageForms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkinsl999), herein incorporated by reference for such disclosure.

[0153] In some embodiments, the compounds described herein are administered either alone or in combination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition. Administration of the compounds and compositions described herein can be effected by any method that enables delivery of the compounds to the site of action. These methods include oral administration.

[0154] In some embodiments, pharmaceutical compositions suitable for oral administration are presented as discrete units such as capsules, cachets, or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. In some embodiments, the active ingredient is presented as a bolus, electuary or paste.

[0155] Pharmaceutical compositions which can be used orally include tablets, push -fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. In some embodiments, the tablets are coated or scored and are formulated so as to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration. The push -fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In some embodiments, stabilizers are added. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or Dragee coatings for identification or to characterize different combinations of active compound doses.

[0156] It should be understood that in addition to the ingredients particularly mentioned above, the compounds and compositions described herein may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.Certain Terminology

[0157] Unless otherwise stated, the following terms used in this application have the definitions given below. The use of the term “including” as well as other forms, such as “include”, “includes,” and “included,” is not limiting. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0158] As used in the specification and claims, the singular forms “a”, “an” and “the” include plural references unless the context clearly dictates otherwise. For example, the term “a sample” includes a plurality of samples, including mixtures thereof.

[0159] As used herein, the term “about” a number refers to that number plus or minus 10% of that number. The term “about” a range refers to that range minus 10% of its lowest value and plus 10% of its greatest value.

[0160] The terms “determining,” “measuring,” “evaluating,” “assessing,” “assaying,” and “analyzing” are often used interchangeably herein to refer to forms of measurement. The terms include determining if an element is present or not (for example, detection). These terms can include quantitative, qualitative or quantitative and qualitative determinations. Assessing can be relative or absolute. “Detecting the presence of’ can include determining the amount of something present in addition to determining whether it is present or absent depending on the context.

[0161] The term “acceptable” with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.

[0162] The term “modulate” or “modulating” or “modulation” refers to an increase or decrease in the amount, quality, or effect of a particular activity, function or molecule. By way of illustration and not limitation, agonists, inverse agonists, antagonists, and allosteric modulators of a G protein-coupled receptor are modulators of the receptor.

[0163] The term “modulator” as used herein, refers to a molecule that interacts with a target either directly or indirectly. The interactions include, but are not limited to, the interactions of an agonist, partial agonist, an inverse agonist, antagonist, degrader, or combinations thereof. In some embodiments, a modulator is an agonist.

[0164] The term “agonism” as used herein refers to the activation of a receptor or enzyme by a modulator, or agonist, to produce a biological response.

[0165] The term “agonist” as used herein refers to a modulator that binds to a receptor or enzyme and activates the receptor to produce a biological response. By way of example only, “GPR119 agonist” can be used to refer to a compound that exhibits an EC50with respect to GPR119activity of no more than about 100 pM, as measured in the cAMP production assay and glucagon-like peptide-1 (GLP-1) secretion assays. In some embodiments, the term “agonist” includes full agonists or partial agonists.

[0166] The term “full agonist” refers to a modulator that binds to and activates a receptor with the maximum response that an agonist can elicit at the receptor.

[0167] The term “partial agonist” refers to a modulator that binds to and activates a given receptor, but has partial efficacy, that is, less than the maximal response, at the receptor relative to a full agonist.

[0168] The term “positive allosteric modulator” refers to a modulator that binds to a site distinct from the orthosteric binding site and enhances or amplifies the effect of an agonist.

[0169] The term “antagonism” as used herein refers to the inactivation of a receptor or enzyme by a modulator, or antagonist. Antagonism of a receptor, for example, is when a molecule binds to the receptor and does not allow activity to occur.

[0170] The term “antagonist” or “neutral antagonist” as used herein refers to a modulator that binds to a receptor or enzyme and blocks a biological response. An antagonist has no activity in the absence of an agonist or inverse agonist but can block the activity of either, causing no change in the biological response.

[0171] The term “inverse agonist” refers to a modulator that binds to the same receptor as an agonist but induces a pharmacological response opposite to that agonist, i.e., a decrease in biological response.

[0172] The term “negative allosteric modulator” refers to a modulator that binds to a site distinct from the orthosteric binding site and reduces or dampens the effect of an agonist.

[0173] As used herein, “EC50” is intended to refer to the concentration of a substance (e.g., a compound or a drug) that is required for 50% activation or enhancement of a biological process. In some instances, EC50 refers to the concentration of agonist that provokes a response halfway between the baseline and maximum response in an in vitro assay. In some embodiments as used herein, EC50refers to the concentration of a modulator (e.g., an agonist) that is required for 50% activation of a GPCR, for example, GPR40 or GPR119.

[0174] As used herein, “IC50” is intended to refer to the concentration of a substance (e.g, a compound or a drug) that is required for 50% inhibition of a biological process. For example, IC50refers to the half maximal (50%) inhibitory concentration (IC) of a substance as determined in a suitable assay. In some instances, an IC50 is determined in an in vitro assay system. In some embodiments as used herein, IC50refers to the concentration of a modulator (e.g., an antagonist or inhibitor) that is required for 50% inhibition of a receptor, for example, SSTR5, or an enzyme, for example, DPP -4, or PDE4.

[0175] The terms “administer,” “administering,” “administration,” and the like, as used herein, refer to the methods that may be used to enable delivery of compounds or compositions to the desired site of biological action. These methods include, but are not limited to oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical and rectal administration. Those of skill in the art are familiar with administration techniques that can be employed with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

[0176] The terms “co-administration” or the like, as used herein, are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time.

[0177] The term “continuous dosing schedule” refers to the administration of a particular therapeutic agent at regular intervals. In some embodiments, continuous dosing schedule refers to the administration of a particular therapeutic agent at regular intervals without any drug holidays from the particular therapeutic agent. In some other embodiments, continuous dosing schedule refers to the administration of a particular therapeutic agent in cycles. In some other embodiments, continuous dosing schedule refers to the administration of a particular therapeutic agent in cycles of drug administration followed by a drug holiday (for example, a wash out period or other such period of time when the drug is not administered) from the particular therapeutic agent. For example, in some embodiments the therapeutic agent is administered once a day, twice a day, three times a day, once a week, twice a week, three times a week, four times a week, five times a week, six times a week, seven times a week, every other day, every third day, every fourth day, daily for a week followed by a week of no administration of the therapeutic agent, daily for a two weeks followed by one or two weeks of no administration of the therapeutic agent, daily for three weeks followed by one, two or three weeks of no administration of the therapeutic agent, daily for four weeksfollowed by one, two, three or four weeks of no administration of the therapeutic agent, weekly administration of the therapeutic agent followed by a week of no administration of the therapeutic agent, or biweekly administration of the therapeutic agent followed by two weeks of no administration of the therapeutic agent. In some embodiments, daily administration is once a day. In some embodiments, daily administration is twice a day. In some embodiments, daily administration is three times a day. In some embodiments, daily administration is more than three times a day.

[0178] The term “continuous daily dosing schedule” refers to the administration of a particular therapeutic agent every day at roughly the same time each day. In some embodiments, daily administration is once a day. In some embodiments, daily administration is twice a day. In some embodiments, daily administration is three times a day. In some embodiments, daily administration is more than three times a day.

[0179] The terms “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound being administered, which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result includes reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate “effective” amount in any individual case is optionally determined using techniques, such as a dose escalation study.

[0180] The terms “enhance” or “enhancing,” as used herein, means to increase or prolong either in potency or duration a desired effect. Thus, in regard to enhancing the effect of therapeutic agents, the term “enhancing” refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system. An “enhancingeffective amount,” as used herein, refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system.

[0181] The term “pharmaceutical combination” as used herein, means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term “fixed combination” means that the active ingredients are both administered to a patient simultaneously in the form of a single entity or dosage. The term “non-fixed combination” means that the active ingredients and a co-agent, are administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific intervening time limits, wherein such administration provideseffective levels of the two compounds in the body of the patient. The latter also applies to cocktail therapy, e.g. the administration of three or more active ingredients.

[0182] The terms “article of manufacture” and “kit” are used as synonyms.

[0183] The terms “subject,” “individual,” and “patient” are used interchangeably. These terms encompass mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one aspect, the mammal is a human.

[0184] The terms “treat,” “treating” or “treatment,” as used herein, include alleviating, abating or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibitingthe disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and / or therapeutically.

[0185] The term “gut-restricted” as used herein refers to a compound, e.g., a receptor modulator, that is predominantly active in the gastrointestinal system. In some embodiments, the biological activity of the gut-restricted compound, e.g., a gut-restricted receptor modulator, is restricted to the gastrointestinal system. In some embodiments, gastrointestinal concentration of a gut-restricted modulator, is higher than the IC50value or the EC50value of the gut-restricted modulator against its receptor, while the unbound plasma levels of said gut- restricted modulator are lower than the IC50value or the EC50value of the gut-restricted modulator against its receptor. In some embodiments, the gut-restricted compound, e.g., a receptor modulator, is non-systemic. In some embodiments, the gut-restricted compound, e.g., a receptor modulator, is a non-absorbed compound. In other embodiments, the gut- restricted compound is minimally absorbed and rapidly metabolized to metabolites that are significantly less active than the modulator itself toward the target receptor.

[0186] In some embodiments, the gut-restricted modulator is non-systemic but is instead localized to the gastrointestinal system. In some instances, the modulator is present in high levels in the gut, but low levels in serum. In some embodiments, the systemic exposure of a gut-restricted modulator is, for example, less than 100, less than 50, less than 20, less than 10, or less than 5 nM, bound or unbound, in blood serum. In some embodiments, the intestinal exposure of a gut-restricted modulator is, for example, greater than 1000, 5000, 10000, 50000, 100000, or 500000 nM. In some embodiments, a modulator is gut-restricted due topoor absorption of the modulator itself, or because of absorption of the modulator which is rapidly metabolized in serum resulting in low systemic circulation, or due to both poor absorption and rapid metabolism in the serum. In some embodiments, a modulator is covalently bonded to a kinetophore, optionally through a linker, which changes the pharmacokinetic profile of the modulator. In other embodiments, two or more modulators are covalently bonded, optionally through a linker, to each other.

[0187] The term “gastrointestinal system” (GI system) or “gastrointestinal tract” (GI tract) as used herein, refers to the organs and systems involved in the process of digestion. The gastrointestinal tract includes the esophagus, stomach, small intestine, which includes the duodenum, jejunum, and ileum, and large intestine, which includes the cecum, colon, and rectum. In some embodiments herein, the GI system refers to the “gut,” meaning the stomach, small intestines, and large intestines or to the small and large intestines, including, for example, the duodenum, jejunum, and / or colon.

[0188] Throughout this application, various embodiments may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the disclosure. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

[0189] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.EXAMPLES

[0190] The following examples are included for illustrative purposes only and are not intended to limit the scope of the invention.Example 1. In Vitro Activity AssaysExample 1A: GPR119Cell Line Expressing GPR119

[0191] CHO-K1 cells stably expressing human GPR119 (hGPRl 19) were prepared by transfection of a GPR119-carrying plasmid using Lipofectamine 2000 (followingmanufacturer instructions). A stable cell line was established using the limiting dilution method with geneticine selection. Assay -ready frozen (ARF) cells were prepared and used throughout the study. cAMP Accumulation Assay

[0192] The assay was performed in a 384-well plate format using the cAMP Gs dynamic assay kit from Cisbio. ARF cells expressing hGPRl 19 were thawed, washed and then resuspended in cAMP stimulation buffer at a cell density of l. lxlO6cells / mL. Cells were plated at a density of -10,000 cells / well (9 pL / well). Dose response curves for the tested compounds were prepared in a cAMP stimulation buffer, containing 0.1% Tween 80 at 4 fold the final concentration. The compounds were then transferred to the cell plates using BRAVO (3 pL / well) and the plates were incubated for 60 minutes at 37 °C / 5 % CO2. Detection buffer (10 pL, prepared as described in the cAMP Gs dynamic kit) were added to each well, and the plates were incubated at ambient temperature for 1 hr.

[0193] RT-FRET was measured using a ClarioSTAR plate reader, calculating the ratio between emissions at 665 nm and 620 nm (HTRF ratio). The HTRF ratio for positive (Max) and negative (Min) controls were used to normalize HTRF data and generate values for % activity. EC50 and Max activity values were determined using a standard 4-parameter fit.

[0194] Compound 1 demonstrated an EC50of 42.6 nM and an Efficacy of 110 ± 2.1%. Example IB: GPR40Cell Lines Expressing GPR40 / FFAR1

[0195] CHO-K1 cells expressing human GPR40 were purchased from DiscoverX (95- 1005C2). HEK293 cells expressing mouse FFAR1 were prepared using a mouse FFAR1 carrying plasmid purchased from OriGene Technologies (MR222997). The cells were transfected using Lipofectamine 2000 using manufacturer instructions and stable cell line was established from a single cell using geneticine selection. Assay ready frozen (ARF) cells were prepared and used throughout the study.Inositol Phosphate Accumulation Assay

[0196] The assay was performed in a 384-well plate format using IP1 assay kit from CisBio. ARF cells expressing FF ARI (mouse and human) were thawed, washed and then plated in the appropriate medium (Fl 2 based medium for CHO hFFARl and DMEM based medium for HEK293 mFFARl - both were supplemented with 10% FBS and penicillin / streptomycin). 20 pL of 3.5*105cells / mL were plated on a Poly D-Lysine coated 384-well white plate. The cells were then incubated for 16 hr at 37 °C / 5 % CO2. After 16 hr the medium was removed and 15 pL of stimulation buffer containing the test compounds wasadded to the cells. The plates were then incubated for 90 min at 37 °C / 5 % CO2. 5 pL of detection buffer (prepared as described in the IP-one kit) was added to each well and the plates were incubated at RT for Ihr.

[0197] RT-FRET was measured using ClarioSTAR plate reader, calculating the ratio between emissions at 665 nm and 620 nm (HTRF ratio). HTRF ratio for positive (Max) and negative (Min) controls were used to normalize HTRF data and generate values for % activity. EC50 and Max activity values were determined using a standard 4 -parameter fit.

[0198] Compound 2 demonstrated an EC50of 2.1 nM.Example 2. Effect of Compounds Alone and in Combination on GLP-1 Secretion in Human Ileal Crypt Cultures

[0199] The potential for the combination of Compound 1 and Compound 2 to induce gut hormone secretion from EECs was assessed using primary human ileal crypt cultures and compared to the effect of the individual agents.

[0200] Compound 1 alone induced a 1.9-fold increase in GLP-1 secretion.

[0201] Compound 2 alone induced a 4.0-fold increase in GLP-1 secretion.

[0202] The combination of Compound 1 and Compound 2 induced a more than additive 13.9-fold increase in GLP-1 secretion.Example 3. Gut Hormone Secretion in Mice with Compounds Alone and in Combination

[0203] The potential for the combination of Compound 1 and Compound 2 to induce gut hormone secretion from EECs was assessed in vivo. GLP-1 was measured at 5 and 17 h post dose. For the dose titration study, male C57BL / 6J mice were acclimated to the facility and the dosing procedure. Mice were weighed and then fasted for 4 h. The mice were administered vehicle, Compound 2 alone at 30 mg / kg, Compound 1 alone at 30 mg / kg, Compound 2 at 30 mg / kg doses in combination with Compound 1 at 30 mg / kg by oral gavage. Blood was collected at 5 h post-dose or 17 h post-dose, and plasma was assayed for GLP-1.

[0204] Each compound dosed alone at 30 mg / kg led to modest but significant release of GLP-1 when compared to vehicle at 5h post dose. However, when Compound 2 was administered with Compound 1, larger increases in GLP-1 secretion were observed. Similar additive increases in GLP-1 secretion were observed at the 17h timepoint.

[0205] Results are shown in the following table. The data displayed corresponds to administration of doses of 30 mg / kg of each of the compounds listed.Example 4. Effect of Compounds Alone or in Combination on 14-day Weight Loss in DIO Mice

[0206] The effects of Compound 2 alone and in combination with Compound 1 on body weight were assessed in diet-induced-obese (DIO) mice over 14 days.

[0207] Male C57BL / 6J DIO mice, approximately 16 weeks old (Jackson Laboratories), were provided 60% high fat diet and water ad libitum. Animals were dosed BID (two times a day) with vehicle for an approximately 3 -week until body weight had stabilized. At approximately 20 weeks of age, the mice were randomized into treatment groups (n = 8 / group) by body weight (range of 37 to 55 g) as well as food intake, and body weight change measured over a two-day baseline period. In order to maximize time on target throughout the day, compounds were administered BID, 8 h apart. Food intake and body weight were measured daily.

[0208] Across two parallel studies, the combination of Compound 1 and Compound 2 resulted in >10% body weight loss vs. vehicle. In these parallel studies, the compounds were administered for 13 or 14 days. Compound 1 as a single agent does not cause appreciable weight loss and Compound 2 alone results in less than approximately half the weight loss observed with the combination.

[0209] Results for exemplary compounds and combinations are shown in the following table.Example 5. Effect of Compounds Alone or in Combination with Other Agents on Glucose Excursion in Mice

[0210] The effects of Compound 1 and Compound 2 alone and in combination on glucose excursion during an oral glucose tolerance test were assessed in mice. The effects of the combination of Compound 1 and Compound 2 with linagliptin (a DPP-4 inhibitor) were also assessed.

[0211] Male C57BL / 6J mice, approximately 10 weeks old, were acclimated to the facility and the oral dosing procedure. Mice were randomized into balanced treatment groups using body weight. Baseline glucose was assessed immediately before compound administration. One hour after compound dosing, glucose levels were again assessed immediately prior to oral administration of D-(+)-glucose (5 g / kg in water) at 10 mL / kg. Blood was assessed for glucose levels 20 min, 40 min, 60 min, and 120 min post D-(+)-glucose administration. The AUCs for blood glucose measures were calculated for each treatment from 0 to 120 min. Statistical analysis was performed on AUCs using one-way ANOVA versus vehicle, with Tukey’s post-test.

[0212] Compound 1, Compound 2, and linagliptin alone all suppressed post-prandial glucose excursion. The combination of Compound 1 and Compound 2 resulted in a greater reduction in post-prandial glucose excursion compared to the individual agents. Similarly, the combination of Compound 1 and Compound 2 with linagliptin resulted in greater glucose control compared to the combination of Compound 1 and Compound 2 alone.

[0213] Results for exemplary compounds and combinations are shown in the following table.Example 6: A Clinical Trial to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Compound 1 in Healthy Subjects

[0214] A non -limiting example of a clinical trial of the GPR119 agonist Compound 1 in humans is described below.Study Design:

[0215] This study was a randomized, double-blind, placebo-controlled, single ascending dose study to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of Compound 1 in healthy subjects. The study was composed of 2 panels of 8 subj ects. The Treatment Period included up to 4 dosing periods per panel. Subjects were randomized to participate in either Panel A or Panel B and then randomized to a treatment sequence within a panel (Table 2). This resulted in subjects being assigned to Compound 1 or placebo in a 3 :1 ratio. Dosing was generally in the fasted state except for Panel B Period 4 where dosing was in the fed state following a medium calorie / medium fat meal. Standardized meals were provided throughout the day. Safety and tolerability were assessed through physical examination including vital sign assessment, 12 lead electrocardiogram (ECG), clinical laboratory assessments, and collection of serious and non-serious adverse events (AEs).Plasma was obtained for PK and PD assessments pre-dose and for up to 24 hours post dose in each Period. Urine was collected pre-dose and up to 24 hours post dose to assess PK. No formal hypothesis testing was pre-specified.Table 1. Summary of Study DesignTable 2. Sample Sequence DesignPBO=placeboStudy Objectives:

[0216] Primary Objective: To characterize the safety and tolerability of single oral doses of Compound 1 in healthy subjects.

[0217] Secondary Objectives: To characterize the plasma PK of Compound 1 (area under the concentration-time curve [AUC0.oo, AUCo-iast]), maximum concentration [Cmax], concentration at 24 hours [C24hr], time of maximum concentration [Tmax], terminal half-life[ti / 2], volume of distribution [Va], and clearance [Cl]) following single oral doses in healthy subjects.

[0218] Exploratory Objectives: To characterize the pharmacodynamics (gut peptide hormones) of Compound 1 following single oral doses in healthy subjects. To characterize urine PK of Compound 1 (amount excreted [Ae], renal clearance [C1R], fraction excreted unchanged [fe]) following single oral doses of Compound 1 in healthy subjects, if available. Results:

[0219] Primary Objective: Single oral doses of Compound 1 of up to 500 mg are sufficiently safe and well -tolerated to permit further clinical investigation.

[0220] Secondary Objectives: Compound 1 pharmacokinetics are dose-proportional in the fed state. Food decreases the extent of systemic exposure (AUC) and maximal exposure (Cmax) to Compound 1 .

[0221] Exploratory Objectives: Compound 1 augments the nutrient-stimulated secretion of GLP-1 and PYY.Example 7: A Clinical Trial to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Compound 2 in Healthy Subjects

[0222] A non-limiting example of a clinical trial of the GPR40 agonist Compound 2 in humans is described below.Study Design:

[0223] This study was a randomized, placebo-controlled, double blind single ascending dose study to assess safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) in healthy subjects. The study utilized an alternating panel design. The study was composed of 2 panels of 8 subjects, each participating in up to 4 dosing periods per panel (Table 3). Subjects were assigned to participate in either Panel A or Panel B and then randomized to a treatment sequence within a panel which resulted in subjects being assigned to Compound 2 or placebo in a 3 : 1 ratio for each treatment period. Dosing was generally in the fasted state except for Panel B Period 4 where dosing was in the fed state following a medium calorie / medium fat meal. Standardized meals were provided throughout the day. Safety and tolerability were assessed through physical examination including vital sign assessment, 12 lead electrocardiogram (ECG), clinical laboratory assessments, and collection of serious and non-serious adverse events (AEs). Plasma was obtained for PK and PD assessments pre -dose and for up to 24 hours post dose in each Period. Urine was collected pre-dose and up to 24 hours post dose to assess PK. No formal hypothesis testing was pre-specified.Table 3. Summary of Study Design

[0224] The doses of Compound 2 administered in this study are shown in the table above (Table 3). The top dose administered in this study was 250 mg.Study Objectives:

[0225] Primary Objective: To characterize the safety and tolerability of single oral doses of Compound 2 in healthy subjects.

[0226] Secondary Objectives: To characterize the plasma PK of Compound 2 (area under the concentration-time curve [AUC0.oo, AUCo-iast]), maximum concentration [Cmax], concentration at 24 hours [C24hr], time of maximum concentration [Tmax], terminal half-life [ti / 2], volume of distribution [Va], and clearance [Cl]) following single oral doses in healthy subjects.

[0227] Exploratory Objectives: To characterize the pharmacodynamics (gut peptide hormones) of Compound 2 following single oral doses in healthy subjects. To characterize urine PK of Compound 2 (amount excreted [Ae], renal clearance [C1R], fraction excreted unchanged [fe]) following single oral doses of Compound 2 in healthy subjects, if available.Results:

[0228] Primary Objective: Single doses of Compound 2 are sufficiently safe and tolerable to permit further clinical investigation.

[0229] Secondary Objectives: Plasma exposure to Compound 2 increases with dose. Food results in a -50% and a -33% increase in AUC0-iast and Cmax, respectively. Pharmacokinetic parameters for Compound 2 are found in Table 3 A, below.

[0230] Exploratory Objectives: Single doses of Compound 2 result in dose-dependent, sustained augmentation of GLP- 1 and PYY secretion over 24 hours of up to 3.3 -fold and 2.5- fold compared to placebo (i.e., the GMRs for the GLP-1 and PYY AUC0-2411 of Compound 2 / PBO). Although single doses of Compound 2 result in transient nutrient -independent GIP secretion, total GIP secretion over 24 h is not different from placebo. No Compound 2 was detected in the urine after administration of single doses of Compound 2.Table 3A. Pharmacokinetics of Compound 2 Following Single Oral Doses in Healthy Human SubjectsN= number of subj ects in dose group; n = Number of observations with parameter data; Calculation of percentages based onN SD = Standard deviation; CV= Coefficientof Variation; NA=Not Applicable * Subject 005 was assigned 60mgBIDforperiod4,andonly receivedonedose, therefore data from period 4 is included in the 60 mg (fasted) group. As a result, this subject was included in the 60 mg (fasted) treatment groupfor both period 3 and period 4. ** Subject 014 received 30 mgfasted for period 1 and dropped out of the study because of adverse event, therefore did notreceive any dose for periods 2,3 and 4.Example 8: A Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Combination of Compound 2 and Compound 1

[0231] A non-limiting example of a clinical trial of the GPR40 agonist Compound 2 in combination with the GPR119 agonist Compound 1 in humans is described below.Study Design (Part 1):

[0232] This was a 4 Period, single-blind (subjects blinded), placebo-controlled single ascending dose study to evaluate the safety, tolerability, PK, and PD of combination Compound 2 and Compound 1 in healthy subjects. Planned enrollment was up to 22 subjects in two Panels (10 in Panel A and 12 in panel B). 11 Subjects were enrolled in Panel A and 8 were enrolled in Panel B. The Treatment Period included up to four dosing periods. In each Panel, the dose of one drug was held constant with the second investigational agent beingtitrated over the dosing periods. Dose escalation for the titrated drug proceeded in the manner outlined in the below table. Doses were administered in the fasted state.Table 4. Summary of Study Design (Part 1)a Washout was at least 5 days from the last dose in the preceding Period.Study Design (Part 2):

[0233] This was a randomized, double-blind, placebo-controlled multiple ascending dose study in healthy volunteers to evaluate the safety, tolerability, PK and PD of Compound 2 when administered as once daily multiple doses in the fed state. Two panels of 8 subjects were enrolled. Within each Panel, subjects were randomized in a 3 :1 to Compound 2 or placebo (Table 5).Table 5. Summary of Study Design (Part 2)Study Objectives (Part 1):

[0234] Primary Objective: To characterize the safety and tolerability of single oral doses of the combination of Compound 2 and Compound 1 in healthy subjects.

[0235] Secondary Objectives: To compare the plasma pharmacokinetics (PK) of Compound 2 and Compound 1 (area under the concentration-time curve [AUC0.oo, AUCo-iast], maximum concentration [Cmax], time of maximum concentration [Tmax]), and half-life [ti / 2]) following coadministration of Compound 2 and Compound 1 vs administration of Compound 2 or Compound 1 alone.

[0236] Exploratory Objectives: To compare the single dose PD (gut peptide hormones) following co-administration of Compound 2 and Compound 1 vs placebo in healthy subjects. To compare the single dose PD (gut peptide hormones) following co-administration of Compound 2 and Compound 1 vs administration of Compound 2 or Compound 1 alone in healthy subjects.Results:

[0237] Primary Objective: The combination of single doses of Compound 2 (up to 60 mg) and Compound 1 (up to 200 mg) per day are sufficiently safe and tolerable to permit further clinical investigation.

[0238] Secondary Objectives: Plasma exposures to Compound 2 and Compound 1 are similar following single doses of the combination compared to individual agents.

[0239] Exploratory Objectives: GLP-1 and PYY secretion are greater following single doses of the combination of Compound 2 60 mg + Compound 1 200 mg compared to that following single doses of the individual agents.Study Objectives (Part 2):

[0240] Primary Objective: To characterize the safety and tolerability of multiple oral doses of Compound 2 in healthy subjects.

[0241] Secondary Objectives: To characterize the plasma pharmacokinetics (PK) of Compound 2 (AUC0.24hr, AUC0.iast, Cmax, Tmax, clearance (Cl), volume of distribution at steady-state (Vdss), and ti / 2) following multiple oral doses of Compound 2.

[0242] Exploratory Objectives: To compare the PD (gut peptide hormones) following multiple oral dose administration of Compound 2 vs placebo in healthy subjects.Results:

[0243] Primary Objective: Multiple doses of Compound 2 up to 60 mg per day are sufficiently safe and tolerable to permit further clinical investigation.

[0244] Secondary Objectives: Following multiple days of daily dosing in the fed state, exposures to Compound 2 increase in a less than dose proportional manner. Following Compound 2 20 mg QD for 6 days, Compound 2 AUC and Cmaxaccumulate ~1.5- and -1.7- fold. Following Compound 2 60 mg QD for 6 days, the observed changes in pharmacokinetic parameters (earlier Tmax, lower C24h trough, unchanged AUCo-24h, and higher Cmax) suggest earlier drug absorption on Day 6 compared to Day 1 with a shorter absorption window.

[0245] Exploratory Objectives: Following Compound 2 20 mg QD for 6 days, PYY and GLP-1 Cmaxand AUC0.24h are lower on Day 6 compared to Day 1. Following Compound 2 60mg QD for 6 days, PYY and GLP-1 Cmax is unchanged but AUC0-24h is lower on Day 6 compared to Day 1 which may be due to the change in PK on Day 6 compared to Day 1 .Example 9: A Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Combination Compound 2 and Compound 1 in Healthy Volunteers

[0246] A non-limiting example of a clinical trial of the GPR40 agonist Compound 2 in combination with the GPR119 agonist Compound 1 in humans is described below.Study Design:

[0247] This was a randomized, double-blind, placebo-controlled multiple ascending dose study to evaluate the safety, tolerability, PK, and PD of combination Compound 2 and Compound 1 in healthy subjects. Three Panels of 12 subjects each were enrolled (Panels A through C); within each panel, subjects were randomized (3:1) to receive active drug or placebo (Table 6)Table 6. Summary of Study DesignaCompound 2 20 mgwas administered Days 1 through 5, followed by 40 mg Days 6 through 14.bCompound 2 30 mgwas administered Days 1 through 5, followed by 60 mg Days 6 through 14.Study Objectives:

[0248] Primary Objectives: To characterize the safety and tolerability of multiple oral doses of Compound 1 in healthy subjects. To characterize the safety and tolerability of multiple oral doses of the combination of Compound 2 and Compound 1 in healthy subjects.

[0249] Secondary Objectives: To characterize the plasma pharmacokinetics (PK) of Compound 2 (area under the concentration-time curve [AUC0.24hr, AUCo-iast], maximum concentration [Cmax], time of maximum concentration [Tmax], clearance (Cl), volume of distribution at steady-state (Vdss), and half-life [ti / 2]) following multiple oral doses of Compound 2 + Compound 1. To characterize the plasma PK of Compound 1 (AUC0.24hr, AUCo-last, Cmax, Tmax, Cl, Vdss, and ti / 2) following multiple oral doses of Compound 2 + Compound 1 and Compound 1 alone.

[0250] Exploratory Objectives: To compare the pharmacodynamics (PD) (gut peptide hormones) following multiple oral dose administration of the combination of Compound 2 +Compound 1 vs Placebo in healthy subjects. To compare the PD (gut peptide hormones) following multiple oral dose administration of the combination of Compound 2 + Compound 1 vs Compound 1 alone in healthy subjects. To compare the PD (gut peptide hormones) following multiple oral dose administration Compound 1 alone and vs placebo in healthy subjects.Results:

[0251] Primary Objectives: The combination of multiple doses of Compound 2 (up to 60 mg) and Compound 1 (100 mg) per day are safe and tolerable.

[0252] Secondary Objectives: When co-administered with Compound 1 in the fed state, Compound 2 AUC increases in a roughly dose -proportional manner. After multiple doses of Compound 1 100 mg alone in the fed state, there is no significant accumulation of Compound 1. After multiple days of co-administration of Compound 2 + Compound 1, Compound 1 AUC and Cmaxare increased compared to that following Compound 1 alone.

[0253] Exploratory Objectives: GLP-1, PYY, and CCK secretion are greater following multiple doses of the combination of Compound 2 + Compound 1 compared to that following Compound 1 alone or placebo alone. After multiple doses, QD dosing of the combination of Compound 2 + Compound 1 did not have a meaningful effect on GIP secretion over 24 h. Compared to placebo and following multiple doses of the combination of Compound 2 + Compound 1, the maximal observed increases in AUC0-24h for GLP-1, PYY, and CCK were 2.64-fold, 3.6-fold, and 3.18-fold, respectively.Example 10: A Multiple Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Compound 2 in Healthy Overweight / Obese Volunteers Alone, or in Combination with Compound 1

[0254] A non -limiting example of a clinical trial of Compound 2 in combination with other therapeutics, such as Compound 1 or sitagliptin, in humans is described below.Purpose:

[0255] This was a multiple dose study to evaluate the safety, tolerability, PK, and PD of Compound 2 alone, in combination with sitagliptin, or in combination with Compound 1 .Study Design:

[0256] Five panels of 12 subjects were enrolled (Panels A through E); within each panel, subjects were randomized (3 : 1) to receive active drug or placebo. While Compound 2, Compound 1 , and placebo were administered in a double-blinded manner, sitagliptin (Panel Conly) was administered in an open-label fashion. Compound 2 (and Compound 1 in Panels D and E) were titrated within each Panel (Table 7)

[0257] In Panels A and B, Compound 2was administered QD and two different titration regimens were explored.

[0258] In Panel C, Compound 2and sitagliptin were co-administered QD. Subjects randomized to placebo also received open -label sitagliptin.

[0259] In Panels D and E, Compound 2and Compound 1 were co-administered BID.Dosing in Panels D and E was identical through Day 21. While doses in Panel D were stable from Day 15-28 in Panel D, in Panel E the dose of Compound 2was titrated higher on Day 22.

[0260] Subjects were domiciled throughout the treatment period. On intensive PK and PD sampling days (Days 1, 14, and 28 in Panels A-C; Days 14, 21 [PD only], and 28 in Panels D, E) all subjects consumed an identical diet and were directed to consume all meals / snacks in their entirety. Portions not consumed on these days were noted as minor protocol deviations. On all other days, subjects were provided standardized weight maintaining diets based on estimated individual caloric requirements and instructed to consume only as much of the provided food as they wished to.Table 7. Summary of Study DesignStudy Objectives:

[0261] Primary Objectives: To characterize the safety and tolerability of titration regimens of Compound 2 in healthy overweight and obese subjects when administered alone, when coadministered with sitagliptin and when co-administered with Compound 1. To characterizethe safety and tolerability of Compound 1 when co-administered with Compound 2in healthy overweight and obese subjects.

[0262] Secondary Objectives: To characterize the plasma pharmacokinetics (PK) of Compound 2 (area under the concentration-time curve [AUCo-24hr, AUCo-iast], maximum concentration [Cmax], time of maximum concentration [Tmax], clearance [Cl], volume of distribution at steady-state [Vdss], and half-life [ti / 2]) following multiple once-daily (QD) oral doses of Compound 2. To characterize the plasma PK of Compound 2 (AUCo-24hr, AUCo-iast, Cmax, Tmax, Cl, Vdss, and ti / 2) following multiple once daily (QD) oral doses of Compound 2when co-administered with sitagliptin. To characterize the plasma PK of Compound 2 (AUCo-24hr, AUCo-iast, Cmax, Tmax, Cl, Vdss, and ti / 2) following multiple twice-daily (BID) oral doses of Compound 2when co-administered with BID oral doses of Compound 1 . To characterize the plasma PK of Compound 1 (AUC0-24hr, AUCo-iast, Cmax, Tmax, Cl, Vdss, and ti / 2) following multiple BID oral doses of Compound 1 when co-administered with BID oral doses of Compound 2.

[0263] Exploratory Objectives: To characterize the plasma PK of sitagliptin (AUC0-24hr, Cmax, Tmax, and ti / 2) following multiple oral doses of sitagliptin when co-administered with QD oral doses of Compound 2. To compare the pharmacodynamics (PD) (gut peptide hormones) following multiple QD oral dose administration of Compound 2 in healthy overweight / obese subjects vs. placebo. To compare the PD (gut peptide hormones) following multiple QD oral doses of Compound 2 co-administered with sitagliptin in healthy overweight / obese subjects vs. placebo and vs sitagliptin alone. To compare the PD (gut peptide hormones) following multiple BID co-administration of oral doses of Compound 2 and Compound 1 in healthy overweight / obese subjects vs. placebo. To compare the effects on body weight following multiple QD oral dose administration of Compound 2 in healthy overweight / obese subjects vs placebo. To compare the effects on body weight following multiple BID co-administration of oral doses of Compound 2 and Compound 1 in healthy overweight / obese subjects vs placebo.Results:

[0264] Primary Objectives: Compound 2 doses up to 120 mg QD alone and up to 120 mg BID in combination with Compound 1 100 mg BID are safe and tolerable over 28 days of dosing in overweight / obese subjects. Compound 2 doses up to 120 mg QD in combination with sitagliptin 100 mg QD are safe and tolerable over 28 days of dosing in overweight / obese subjects. Compound 1 doses up to 100 mg BID in combination with Compound 2 up to 120 mg BID are safe and tolerable over 28 days of dosing in overweight / obese subjects.

[0265] Secondary Objectives: When co-administered with Compound 1, exposures to Compound 2 following 60 mg BID are similar to those following administration of Compound 2 120 mg QD alone. Sitagliptin did not appreciably alter the PK of coadministered Compound 2.

[0266] Exploratory Objectives: Sitagliptin AUC and Cmaxwere reduced by -30% when coadministered with Compound 2. All regimens of Compound 2 (±Compound 1) resulted in increases in the plasma concentrations of total GLP-1, aGLP-1, PYY, and CCK compared to placebo. Co-administration of Compound 2 with sitagliptin resulted in increased tGLP-1, aGLP-1, PYY and CCK compared to sitagliptin alone and compared to placebo alone. A trend toward body weight reduction was observed with Compound 2 alone or in combination with Compound 1 .Example 11: A 28-Day Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Compound 2 in Combination with Compound 1 in Overweight / Obese Patients with Type 2 Diabetes Mellitus

[0267] A non-limiting example of a clinical trial of Compound 2 in combination with Compound 1, in humans is described below.Purpose:

[0268] This study assessed the safety / tolerability, pharmacokinetics, gut hormone responses, and glycemic response with co-administration of Compound 2 and Compound 1 over 28 days in overweight / obese subjects with T2DM on a stable dose of metformin. Metformin is the widely accepted first line anti-hyperglycemic agent (AHA) for T2DM patients, and so is appropriate background therapy for this initial assessment of the combination of Compound 2 and Compound 1 in the T2DM population.Study Design:

[0269] Twenty-four (24) subjects were enrolled (Panel A = 12, Panel B = 12) and within each panel were randomized in a 1 :1 ratio to receive placebo or the combination of Compound 2 / Compound 1. Study Drug was titrated with the goal of achieving the maintenance dose of Compound 2 60 mg BID + Compound 1 100 mg BID by Day 15 (Table 8).Table 8. Summary of Study Design

[0270] Subjects were domiciled throughoutthe treatment period. On days of intensive PK (Days 14, 28), hormones (Days 14, 21, 28) and glucose (Days -1, 14, 28) sampling, all subjects consumed an identical diet and were directed to consume all meals / snacks in their entirety. On all other days, subjects were provided standardized weight maintaining diets based on estimated individual caloric requirements (Harris-Benedict equation) and instructed to consume only as much of the provided food as they wished to.Study Objectives:

[0271] Primary Objective: To characterize the safety and tolerability of titration regimens of the combination of Compound 2 and Compound 1 .

[0272] Secondary Objectives: To characterize the plasma pharmacokinetics (PK) of Compound 2 (area under the concentration-time curve [AUCo-24hr, AUCo-iast], maximum concentration [Cmax], time of maximum concentration [Tmax], clearance [Cl], volume of distribution at steady-state [Vdss], and half-life [ti / 2]) following multiple oral doses of Compound 2 when co-administered with Compound 1 . To characterize the plasma PK of Compound 1 (AUCo-24hr, AUCo-iast, Cmax, Tmax, Cl, Vdss, and ti / 2) following multiple oral doses of Compound 1 when co-administered with Compound 2.

[0273] Exploratory Objectives: To characterize the pharmacodynamics (PD) (gut peptide hormones) on Days 14, 21 and 28 following multiple oral doses of the combination of Compound 2 and Compound 1 , and placebo. To characterize the change from baseline (Day - 1) in 24-hour weighted mean glucose (WMG) on Days 14 and 28 following multiple oral doses of the combination of Compound 2 and Compound 1, and placebo. To characterize the change from baseline (Day 1 predose) in fasting plasma glucose (FPG) on Days 14 and 28 following multiple oral doses of the combination of Compound 2 and Compound 1 , and placebo. To characterize the effects on body weight following multiple oral doses of the combination of Compound 2 and Compound 1 , and placebo.Results:

[0274] Primary Objective: Compound 2 doses up to 60 mg BID in combination with Compound 1 100 mg BID are safe and tolerable over 28 days of dosing in overweigh t / obese subjects with T2DM on a stable regimen of metformin.

[0275] Secondary Objectives: Compound 2 exposures increase in a dose proportional manner when co-administered with Compound 1. Exposures to Compound 1 increased as the dose of concomitantly administered Compound 2 increases. For both Compound 2 and Compound 1 exposures following the evening dose (after 5 h fast and before dinner) were similar to those following the morning dose (fed state) which supports dosing without regard to food.

[0276] Exploratory Objectives: After 28 days of dosing in subjects with T2DM on a stable regimen of metformin, the combination of Compound 2 + Compound 1 results in increases in aGLP-1, tGLP-1, PYY, and CCK AUCo-24h of to 2. Ox, 2.4x, 4. Ox, and 4.5x, respectively, compared to placebo. Increases of GIP were minimal. In subjects with T2DM on a stable regimen of metformin, the combination of Compound 2 + Compound 1 results in robust reductions in FPG and 24-h WMG vs placebo. In subjects with T2DM on a stable regimen of metformin, body weight reductions were observed following the combination of Compound 2 + Compound 1.Example 12: A 13-Week Study to Evaluate the Safety, Tolerability, and Weight Loss Efficacy of Compound 2 Alone and in Combination with Compound 1 in Participants who are Obese

[0277] A non-limiting example of a clinical trial of Compound 2 in combination with Compound 1, in humans is described below.Purpose:

[0278] This study is designed to assess the weight loss efficacy and safety / tolerability of Compound 2 alone and in combination with Compound 1 in comparison to placebo as pharmacologic therapy for weight loss. Up-titration of Compound 2 or the combination is being used to mitigate mechanism -related GI intolerance as was observed in Phase 1 trial examples above and has been consistently reported for GLP-1 analogs.

[0279] As weight loss agents are prescribed as adjuncts to healthy lifestyle modification, all participants will be advised on calorie restriction and appropriate physical activity . The weight related endpoints are standard for weight loss trials. Heart rate (HR), blood pressure (BP), lipids are other endpoints sometimes impacted by incretin-based therapies.Overall Study Design:

[0280] This is a randomized, double-blind, placebo-controlled 13-week study to evaluate the efficacy of Compound 2 alone and in combination with Compound 1 versus placebo in participants who are obese without T2DM. Approximately 150 participants will be enrolled and randomized (1 :1 :1) to receive Compound 2 alone, Compound 2 + Compound 1, or matching placeboes (Table 9).Table 9. Dosing Tablepbo = placebo; D = day

[0281] The study will be comprised of a Screening period (up to 28 days prior to the treatment period), a 13 -week double-blind Treatment Period (dosing on Days 1 to 91; end-of- treatment visit Day 92), and a post-study Follow-Up period (approximately 14 days after their last dose). There will be 13 weeks of dosing (Days 1 through 91). The total duration of the study for each participant will be up to approximately 19 weeks. Randomization will be stratified by gender (male / female). Enrollment into each gender strata will be capped at 70% (i.e., neither gender may exceed 70% of total enrollment).

[0282] No dose adjustment will be allowed, as this is a forced titration study.Outcome measures:

[0283] In participants who are obese:

[0284] Primary Objective: To assess relative (%) change from baseline in body weight after 13 weeks of treatment with Compound 2 alone and in combination with Compound 1, in comparison to placebo.

[0285] Secondary Objectives: To assess the proportion of participants achieving >5% weight loss from baseline after 13 weeks of treatment with Compound 2 alone and incombination with Compound 1, in comparison to placebo. To assess the absolute change from baseline in body weight after 13 weeks of treatment with Compound 2 alone and in combination with Compound 1, in comparison to placebo. To characterize the safety and tolerability of Compound 2 alone and in combination with Compound 1 over 13 weeks of treatment.

[0286] Exploratory Objectives: To assess the change from baseline in hemodynamic parameters (systolic blood pressure, diastolic blood pressure and heart rate) after 13 weeks of treatment with Compound 2 alone and in combination with Compound 1 , in comparison to placebo. To assess the change from baseline in total cholesterol, low -density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides after 13 weeks of treatment with Compound 2 alone and in combination with Compound 1 , in comparison to placebo.

[0287] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

CLAIMSWHAT IS CLAIMED IS:

1. A method of treating a metabolic disorder, nutritional disorder, eating disorder, or a combination thereof in a human, the method comprising administering to the human in need thereof: a. 2-(4-(3-(l-(5-chloropyrimidin-2-yl)piperidin-4-yl)propoxy)-2 -fluorophenyl)- l-(3 -((((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexyl)amino)methyl)azetidin-l- yl)ethan-l-one (Compound 1), which has the following structure:(Compound 1), or a pharmaceutically acceptable salt or solvate thereof; and b. ((2S)-2-cyclopropyl-2-(3-((l-(2-(4,4-dimethylpentyl)-5- methoxyphenyl)piperidin-4-yl)methoxy)phenyl)ethyl)(methyl)phosphinicacid(Compound 2), which has the following structure:(Compound 2), or a pharmaceutically acceptable salt or solvate thereof; wherein Compound 1, or a pharmaceutically acceptable salt or solvate thereof, and Compound 2, or a pharmaceutically acceptable salt or solvate thereof, are administered to the human in need thereof by oral administration.

2. The method of claim 1, wherein the metabolic disorder is type 2 diabetes, hyperglycemia, metabolic syndrome, obesity, hypercholesterolemia, or nonalcoholic steatohepatitis.

3. The method of claim 1, wherein the metabolic disorder is type 2 diabetes.

4. The method of claim 1, wherein the metabolic disorder is obesity.

5. The method of claim 1, wherein the nutritional disorder is short bowel syndrome, intestinal failure, or intestinal insufficiency.

6. The method of claim 1, wherein the eating disorder is hyperphagia or binge eating disorder.

7. The method of any one of claims 1 -6, wherein treating the metabolic disorder, nutritional disorder, eating disorder, or a combination thereof comprises an increase in plasma levels of total GLP-1, active GLP-1, PYY, or a combination thereof.

8. The method of any one of claims 1 -6, wherein treating the metabolic disorder, nutritional disorder, eating disorder, or combination thereof comprises a decrease in body weight.

9. The method of any one of claims 1 -8, wherein the dose of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is between about 3 mg and about 500 mg.

10. The method of any one of claims 1 -8, wherein the dose of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is about 3 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 80 mg, about 100 mg, about 120 mg, about 150 mg, about 200 mg, about250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, or about 500 mg.

11. The method of any one of claims 1 -8, wherein the dose of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is between about 20 mg and about 100 mg.

12. The method of any one of claims 1 -8, wherein the dose of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, or about 100 mg.

13. The method of any one of claims 1 -12, wherein the dose of Compound 2, or a pharmaceutically acceptable salt or solvate thereof, is between about 10 mg and about 500 mg.

14. The method of any one of claims 1 -12, wherein the dose of Compound 2, or a pharmaceutically acceptable salt or solvate thereof, is about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 80 mg, about 100 mg, about 120 mg, about 150 mg, about 200 mg, about250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, or about 500 mg.

15. The method of any one of claims 1 -12, wherein the dose of Compound 2, or a pharmaceutically acceptable salt or solvate thereof, is between about 20 mg and about 120 mg.

16. The method of any one of claims 1 -12, wherein the dose of Compound 2, or a pharmaceutically acceptable salt or solvate thereof, is about 20 mg, about 30 mg,about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, or about 120 mg.

17. The method of any one of claims 1 -16, wherein Compound 1, or a pharmaceutically acceptable salt or solvate thereof, and Compound 2, or a pharmaceutically acceptable salt or solvate thereof, are administered sequentially.

18. The method of any one of claims 1 -16, wherein Compound 1, or a pharmaceutically acceptable salt or solvate thereof, and Compound 2, or a pharmaceutically acceptable salt or solvate thereof, are administered simultaneously.

19. The method of any one of claims 1 -18, wherein Compound 1, or a pharmaceutically acceptable salt or solvate thereof, and Compound 2, or a pharmaceutically acceptable salt or solvate thereof, are administered once daily, twice daily, three times daily, or four times daily.

20. The method of any one of claims 1 -18, wherein Compound 1, or a pharmaceutically acceptable salt or solvate thereof, and Compound 2, or a pharmaceutically acceptable salt or solvate thereof, are administered once or twice daily.

21. The method of any one of claims 1 -20, wherein Compound 1, or a pharmaceutically acceptable salt or solvate thereof, and Compound 2, or a pharmaceutically acceptable salt or solvate thereof, are administered with food.

22. The method of any one of claims 1-20, wherein Compound 1, or a pharmaceutically acceptable salt or solvate thereof, and Compound 2, or a pharmaceutically acceptable salt or solvate thereof, are administered without food.

23. The method of any one of claims 1 -8, wherein the method comprises administering to the human in need thereof : a. between about 20 mg and about 100 mg of Compound 1, or a pharmaceutically acceptable salt or solvate thereof; and b. between about 20 mg and about 120 mg of Compound 2, or a pharmaceutically acceptable salt or solvate thereof; wherein Compound 1 and Compound 2 are simultaneously administered to the human in need thereof once or twice daily.

24. A method of treating a metabolic disorder, nutritional disorder, eating disorder, or a combination thereof in a human, the method comprising administering to the human in need thereof: a. between about 20 mg and about 100 mg 2-(4-(3-(l-(5-chloropyrimidin-2- yl)piperidin-4-yl)propoxy)-2-fhrorophenyl)-l-(3-((((2S,3R,4R,5R)-2,3,4,5,6-pentahy droxyhexy l)amino)methy l)azetidin - 1 -y l)ethan- 1 -one (Compound 1 ), which has the following structure:(Compound 1), or a pharmaceutically acceptable salt or solvate thereof; and b. between about 20 mg and about 120 mg of ((2S)-2-cyclopropyl-2-(3-((l-(2- (4,4-dimethylpentyl)-5-methoxyphenyl)piperidin-4- yl)methoxy)phenyl)ethyl)(methyl)phosphinic acid (Compound 2), which has the following structure:(Compound 2), or a pharmaceutically acceptable salt or solvate thereof; wherein Compound 1, or a pharmaceutically acceptable salt or solvate thereof, and Compound 2, or a pharmaceutically acceptable salt or solvate thereof, are administered to the human in need thereof by oral administration.

25. The method of claim 24, wherein the metabolic disorder is type 2 diabetes, hyperglycemia, metabolic syndrome, obesity, hypercholesterolemia, or nonalcoholic steatohepatitis.

26. The method of claim 24, wherein the metabolic disorder is type 2 diabetes.

27. The method of claim 24, wherein the metabolic disorder is obesity.

28. The method of claim 24, wherein the nutritional disorder is short bowel syndrome, intestinal failure, or intestinal insufficiency.

29. The method of claim 24, wherein the eating disorder is hyperphagia or binge eating disorder.

30. The method of any one of claims 24-29, wherein treating the metabolic disorder, nutritional disorder, eating disorder, or a combination thereof comprises an increase in plasma levels of total GLP-1, active GLP-1, PYY, or a combination thereof.31 . The method of any one of claims 24-29, wherein treating the metabolic disorder, nutritional disorder, eating disorder, or combination thereof comprises a decrease in body weight.

32. The method of any one of claims 24-31, wherein:the dose of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, or about 100 mg; and the dose of Compound 2, or a pharmaceutically acceptable salt or solvate thereof, is about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, or about 120 mg.

33. The method of any one of claims 24-32, wherein Compound 1, or a pharmaceutically acceptable salt or solvate thereof, and Compound 2, or a pharmaceutically acceptable salt or solvate thereof, are administered once or twice daily.

34. A method of treating obesity in a human, the method comprising administering to the human in need thereof: a. between about 20 mg and about 100 mg 2-(4-(3-(l-(5-chloropyrimidin-2- yl)piperidin-4-yl)propoxy)-2-fluorophenyl)-l-(3-((((2S,3R,4R,5R)-2,3,4,5,6- pentahy droxyhexy l)amino)methy l)azetidin - 1 -y l)ethan- 1 -one (Compound 1 ), which has the following structure:(Compound 1), or a pharmaceutically acceptable salt or solvate thereof; and b. between about 20 mg and about 120 mg of ((2S)-2-cyclopropyl-2-(3-((l-(2- (4,4-dimethylpentyl)-5-methoxyphenyl)piperidin-4- yl)methoxy)phenyl)ethyl)(methyl)phosphinic acid (Compound 2), which has the following structure:(Compound 2), or a pharmaceutically acceptable salt or solvate thereof; wherein Compound 1, or a pharmaceutically acceptable salt or solvate thereof, and Compound 2, or a pharmaceutically acceptable salt or solvate thereof, are administered to the human in need thereof by oral administration.

35. The method of claim 34, wherein treating obesity comprises a decrease in body weight.

36. The method of claim 34 or claim 35, wherein:the dose of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, or about 100 mg; and the dose of Compound 2, or a pharmaceutically acceptable salt or solvate thereof, is about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, or about 120 mg.

37. The method of any one of claims 34-36, wherein Compound 1, or a pharmaceutically acceptable salt or solvate thereof, and Compound 2, or a pharmaceutically acceptable salt or solvate thereof, are administered once or twice daily.

38. A method of treating obesity in a human, the method comprising orally administering to the human in need thereof ((2S)-2-cyclopropyl-2-(3-((l-(2-(4,4-dimethylpentyl)-5- methoxyphenyl)piperidin-4-yl)methoxy)phenyl)ethyl)(methyl)phosphinic acid (Compound 2), which has the following structure:(Compound 2), or a pharmaceutically acceptable salt or solvate thereof.

39. The method of claim 38, wherein treating obesity comprises a decrease in body weight.

40. The method of claim 38 or claim 39, wherein the dose of Compound 2, or a pharmaceutically acceptable salt or solvate thereof, is between about 10 mg and about 500 mg.

41. The method of claim 38 or claim 39, wherein the dose of Compound 2, or a pharmaceutically acceptable salt or solvate thereof, is about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 80 mg, about 100 mg, about 120 mg, about 150 mg, about 200 mg, about250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, or about 500 mg.

42. The method of claim 38 or claim 39, wherein the dose of Compound 2, or a pharmaceutically acceptable salt or solvate thereof, is between about 20 mg and about 120 mg.

43. The method of claim 38 or claim 39, wherein:the dose of Compound 2, or a pharmaceutically acceptable salt or solvate thereof, is about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, or about 120 mg.

44. The method of any one of claims 38-43, wherein Compound2, or a pharmaceutically acceptable salt or solvate thereof, are administered once or twice daily.

45. The method of any one of claim 38-44, further comprising orally administering to the human in need thereof2-(4-(3-(l-(5-chloropyrimidin-2-yl)piperidin-4-yl)propoxy)-2- fluorophenyl)-l-(3-((((2S,3R,4R,5R)-2,3,4,5,6- pentahydroxyhexyl)amino)methyl)azetidin-l-yl)ethan-l-one (Compound 1), which has the following structure:or a pharmaceutically acceptable salt or solvate thereof.

46. The method of claim 45, wherein the dose of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is between about 3 mg and about 500 mg.

47. The method of claim 45, wherein the dose of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is about 3 mg, about 10 mg, about 20 mg, about 30 mg, about40 mg, about 50 mg, about 60 mg, about 80 mg, about 100 mg, about 120 mg, about 150 mg, about200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, or about 500 mg.

48. The method of claim 45, wherein the dose of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is between about 20 mg and about 100 mg.

49. The method of claim 45, wherein the dose of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, or about 100 mg.

50. The method of any one of claims 45-48, wherein Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is administered once or twice daily.51 . The method of any one of claims 45-50, wherein Compound 1, or a pharmaceutically acceptable salt or solvate thereof, and Compound 2, or a pharmaceutically acceptable salt or solvate thereof, are administered sequentially.

52. The method of any one of claims 45-50, wherein Compound 1, or a pharmaceutically acceptable salt or solvate thereof, and Compound 2, or a pharmaceutically acceptable salt or solvate thereof, are administered simultaneously.

53. The method of any one of claims 1 -52, further comprising administering one or more additional therapeutic agents to the human in need thereof; wherein the one or more additional therapeutic agents are selected from: a TGR5 agonist, an SSTR5 antagonist, an SSTR5 inverse agonist, a CCK1 agonist, a PDE4 inhibitor, a DPP -4 inhibitor, a GLP-1 receptor agonist, a GOAT inhibitor, metformin, sitagliptin, and combinations thereof.

54. The method of claim 53, wherein the one or more additional therapeutic agents are selected from: metformin, sitagliptin, and combinations thereof.

55. A method of treating type 2 diabetes in a human, the method comprising administering to the human in need thereof : a. between about 20 mg and about 100 mg 2-(4-(3-(l-(5-chloropyrimidin-2- yl)piperidin-4-yl)propoxy)-2-fluorophenyl)-l-(3-((((2S,3R,4R,5R)-2,3,4,5,6- pentahy droxyhexy l)amino)methy l)azetidin - 1 -y l)ethan- 1 -one (Compound 1 ), which has the following structure:(Compound 1), or a pharmaceutically acceptable salt or solvate thereof; and b. between about 20 mg and about 60 mg of ((2S)-2-cyclopropyl-2-(3-((l-(2- (4,4-dimethylpentyl)-5-methoxyphenyl)piperidin-4- yl)methoxy)phenyl)ethyl)(methyl)phosphinic acid (Compound 2), which has the following structure:(Compound 2), or a pharmaceutically acceptable salt or solvate thereof; wherein Compound 1, or a pharmaceutically acceptable salt or solvate thereof, and Compound 2, or a pharmaceutically acceptable salt or solvate thereof, are administered to the human in need thereof by oral administration.

56. The method of claim 55, wherein treating type 2 diabetes comprises an increase in plasma levels of total GLP-1, active GLP-1, PYY, or a combination thereof.

57. The method of claim 55, wherein treating type 2 diabetes comprises a decrease in body weight.

58. The method of any one of claims 55-57, wherein the dose of Compound 1, or a pharmaceutically acceptable salt or solvate thereof, is about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, or about 100 mg.

59. The method of any one of claims 55-58, wherein the dose of Compound 2, or a pharmaceutically acceptable salt or solvate thereof, is about 20 mg, about 30 mg, about 40 mg, about 50 mg, or about 60 mg.

60. The method of any one of claims 55-59, wherein Compound 1, or a pharmaceutically acceptable salt or solvate thereof, and Compound 2, or a pharmaceutically acceptable salt or solvate thereof, are administered once or twice daily.61 . The method of any one of claims 55-60, wherein Compound 1, or a pharmaceutically acceptable salt or solvate thereof, and Compound 2, or a pharmaceutically acceptable salt or solvate thereof, are administered sequentially.

62. The method of any one of claims 55-60, wherein Compound 1, or a pharmaceutically acceptable salt or solvate thereof, and Compound 2, or a pharmaceutically acceptable salt or solvate thereof, are administered simultaneously.

63. The method of any one of claims 55-62, further comprising administering one or more additional therapeutic agents to the human in need thereof; wherein the one or more additional therapeutic agents are selected from: a TGR5 agonist, an SSTR5 antagonist, an SSTR5 inverse agonist, a CCK1 agonist, a PDE4 inhibitor, a DPP -4 inhibitor, a GLP-1 receptor agonist, a GOAT inhibitor, metformin, and combinations thereof.

64. The method of claim 63, wherein the one or more additional therapeutic agents is metformin.

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