TW202539633A - Glucose-dependent insulinotropic polypeptide receptor antagonists and uses thereof - Google Patents

Abstract

Described herein are GIPR antagonists; pharmaceutical compositions containing such compounds and salts; and the use of such compounds and salts to treat or prevent, for example, obesity, weight gain, and/or T2DM.

Description

Glucose-dependent insulinotropic peptide receptor antagonists and their uses

This invention relates to new pharmaceutical compounds, pharmaceutical compositions containing the compounds, methods for preparing the compounds; and the use of such compounds as glucose-dependent insulinotropic peptide receptor (GIPR) antagonists, for example, for treating diseases, conditions or symptoms in the human body regulated by GIPR.

Glucose-dependent insulinotropic peptide (GIP, formerly known as gasstatin) is a 42-amino acid peptide secreted by K cells in the small intestine (duodenum and jejunum). Human GIP is derived from the processing of proGIP, a 153-amino acid precursor encoded by a gene located on chromosome 17 (see, for example, Inagaki et al., Mol Endocrinol 1989; 3:1014-1021; and Fehmann et al. Endocr Rev. 1995; 16:390-410). GIP secretion is triggered by ingested food. GIP is a known insulinotropic factor (or "incretin") that enhances glucose-dependent insulinotropic secretion. GIP has additional physiological functions in various tissues, including promoting fat storage in adipose tissue. Intact GIP can be rapidly deactivated by dipeptidyl peptidase 4 (DPPIV).

The GIP receptor (GIPR) belongs to the glucagon receptor subfamily of class B1 G protein-coupled receptors (GPCRs), characterized by an extracellular N-terminal domain, seven transmembrane domains, and an intracellular C-terminus (see, for example, Zhao et al. Nat Commun. 2022, 13:1057). The N-terminal extracellular domain forms the receptor's major peptide recognition and binding site. Upon stimulation by GIP, the GIPR undergoes a structural change from an inactive conformation to an active conformation, thereby triggering an increase in Gαs-mediated cAMP production. GIPR is present in various tissues, including the pancreas, intestines, adipose tissue, vascular system, heart, and brain (see, for example, Hammoud et al. Nat Rev Endocrinol 2023; 18: 201-216). The human GIPR consists of 466 amino acids and is encoded by a gene located on chromosome 19 (see, for example, Gremlich et al., Diabetes. 1995; 44:1202-8; and Volz et al., FEBS Lett. 1995, 373:23-29). Studies have shown that selective mRNA splicing can lead to GIPR variants of varying lengths (see, for example, Harada et al. Am J Physiol Endocrinol Metab. 2008. 294: E61-E68; and Marti-Solano et al. Nature. 2020, 587: 650-656).

GIPR knockout mice are resistant to weight gain induced by a high-fat diet and exhibit improved insulin sensitivity and lipid profile (see, for example, Yamada et al. Diabetes. 2006, 55:S86; and Miyawaki et al. Nature Med. 2002, 8:738-742). Recent data support that loss of function of the heterozygote in GIPR leads to a reduced risk of BMI and obesity in humans (see, for example, Akbari et al. Science. 2021, 373: 6550). Small molecules, peptides, and monoclonal antibodies with GIPR antagonistic activity have been shown to prevent weight gain and insulin resistance in preclinical obesity models (see, for example, Nakamura et al. Diabetes Metab Syndr Obes. 2021,14:1095-1105; Yang et al. Mol Metab. 2022, 66: 101638; and Killion et al. Sci. Transl. Med., 2018, 10:eaat 3392). Combinations of GIPR modulators with GLP-1R agonists are associated with excellent weight loss (see, for example, Lu et al. Cell Rep Med. 2021, 2(5):100263). Overall, these associations with obesity and metabolic diseases suggest that inhibiting GIPR is a useful therapeutic intervention, both as a monotherapy and in combination with other agents, including GLP-1R agonists. Furthermore, GIPR genes and proteins have now been found to express in human epicardial adipose tissue (which plays a crucial role in the development and progression of coronary disease, atrial fibrillation, and heart failure). See, for example, Malavazos et al., European Journal of Preventive Cardiology (2023) 00, 1-14.

There remains a need for new or alternative GIPR antagonists, for example, in the development of new and/or improved drugs (e.g., more effective, more selective, less toxic, with improved patient compliance and/or improved biopharmaceutical properties, such as physical stability; solubility; oral bioavailability; adequate metabolic stability; clearance; half-life) to treat or prevent conditions, diseases, or symptoms associated with GIPR, such as those described herein. This invention is directed to these and other important purposes.

In one embodiment, the present invention provides a compound that is 4'-[(1-{[4-(propyl-2-yl)phenyl]aminomethoxy}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid ionate.

In another embodiment, the present invention provides a compound which is the crystalline form of 4'-[(1-{[4-(propyl-2-yl)phenyl]aminomethylamino}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid ionate.

In another embodiment, the present invention provides a compound in the hydrate form of 4'-[(1-{[4-(propyl-2-yl)phenyl]aminomethoxy}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid ionate salt.

In another embodiment, the present invention provides a compound that is 4'-[(1-{[4-(propyl-2-yl)phenyl]aminomethylamino}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid ionate salt, sesquihydrate.

In another embodiment, the present invention provides a compound in the form 1 of 4'-[(1-{[4-(propyl-2-yl)phenyl]aminomethylamino}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid L-ionate, which is a sesquihydrate.

In another embodiment, the invention provides a compound in form 2 of 4'-[(1-{[4-(propyl-2-yl)phenyl]aminomethoxy}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid L-ionate, which is anhydrous.

In another embodiment, the present invention provides a compound that is 4'-[(1-{[4-(propyl-2-yl)phenyl]aminomethylamino}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid arginine salt.

In another embodiment, the present invention provides a compound which is the crystalline form of 4'-[(1-{[4-(propyl-2-yl)phenyl]aminomethylamino}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid arginine salt.

In another embodiment, the present invention provides a compound that is 4'-[(1-{[4-(propyl-2-yl)phenyl]aminomethoxy}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid L-arginine salt.

In another embodiment, the present invention provides a compound which is the crystalline form of 4'-[(1-{[4-(propyl-2-yl)phenyl]aminomethylamino}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid L-arginine salt.

In another embodiment, the present invention provides a compound which is the anhydrous crystalline form (form 1) of 4'-[(1-{[4-(propyl-2-yl)phenyl]aminomethylamino}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid L-arginine salt.

In another embodiment, the present invention provides a pharmaceutical composition comprising 4'-[(1-{[4-(propyl-2-yl)phenyl]aminomethoxy}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid ionate and a pharmaceutically acceptable excipient or carrier.

This invention also provides a method for treating or preventing GIPR-related conditions, diseases, or ailments in patients (e.g., mammals or humans), the method comprising administering 4'-[(1-{[4-(propyl-2-yl)phenyl]aminomethylamino}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid ionate to the patient (e.g., mammal or human).

This invention also provides a 4'-[(1-{[4-(propyl-2-yl)phenyl]aminomethoxy}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid ionate salt for the treatment or prevention of GIPR-related conditions, diseases or symptoms.

In another embodiment, the present invention provides a compound that is 4'-[(1-{[4-(propyl-2-yl)phenyl]aminomethylamino}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid arginine salt.

In another embodiment, the present invention provides a compound that is 4'-[(1-{[4-(propyl-2-yl)phenyl]aminomethoxy}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid L-arginine salt.

In another embodiment, the invention provides a compound in the form of 4'-[(1-{[4-(propyl-2-yl)phenyl]aminomethylamino}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid L-arginine salt, which is anhydrous.

In another embodiment, the invention provides a pharmaceutical composition comprising 4'-[(1-{[4-(propyl-2-yl)phenyl]aminomethoxy}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid arginine salt and a pharmaceutically acceptable excipient or carrier.

In another embodiment, the invention provides a pharmaceutical composition comprising 4'-[(1-{[4-(propyl-2-yl)phenyl]aminomethoxy}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid L-arginine salt and a pharmaceutically acceptable excipient or carrier.

This invention also provides a method for treating or preventing GIPR-related conditions, diseases, or ailments in patients (e.g., mammals or humans), the method comprising administering 4'-[(1-{[4-(propyl-2-yl)phenyl]aminomethylamino}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid arginine salt to the patient (e.g., mammal or human).

This invention also provides 4'-[(1-{[4-(propyl-2-yl)phenyl]aminomethylamino}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid arginine salt for the treatment or prevention of GIPR-related conditions, diseases or symptoms.

The GIPR-related conditions, diseases, or conditions include those selected from the following: diabetes mellitus [e.g., type 1 diabetes (T1D), type 2 diabetes mellitus (T2DM), including prediabetes], idiopathic T1D (type 1b), latent autoimmune diabetes mellitus in adults (LADA), early-onset T2DM (EOD), adolescent atypical diabetes mellitus (YOAD), juvenile adult-onset diabetes mellitus (MODY), malnutrition-related diabetes mellitus, gestational diabetes mellitus, hyperglycemia, insulin resistance, hepatic insulin resistance, glucose intolerance, diabetic neuropathy, diabetic nephropathy, and kidney disease [e.g., acute nephropathy]. [Diseases including] renal tubular dysfunction, pro-inflammatory changes in the proximal tubules, or chronic nephropathy (CKD), diabetic retinopathy, adipocyte dysfunction, visceral fat deposition, sleep apnea [e.g., obstructive sleep apnea (OSA)], obesity (including hypothalamic obesity and monogenic obesity) and related complications (e.g., osteoarthritis and urinary incontinence), eating disorders (including bulimia syndrome, bulimia nervosa, and syndrome obesity, such as Prader-Willi syndrome and Bardet-Biedl syndrome), weight gain, such as due to the use of other medications. Weight gain caused by factors such as the use of steroids and/or antipsychotics, treatment of depression, or medications that affect cognitive function; excessive sugar cravings; dyslipidemia (including hyperlipidemia, hypertriglyceridemia, elevated total cholesterol, high LDL (low-density lipoprotein) cholesterol, and low HDL (high-density lipoprotein) cholesterol); hyperinsulinemia; non-alcoholic fatty liver disease (NAFLD, including conditions such as steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma); cardiovascular disease; atherosclerosis (including coronary artery disease); and peripheral vascular disease. Diseases, hypertension, endothelial dysfunction, impaired vascular compliance, heart failure [e.g., congestive heart failure, heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF)], myocardial infarction (e.g., necrosis and apoptosis), stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, osteoarthritis, Parkinson's disease, left ventricular hypertrophy, peripheral arterial disease, macular degeneration. Degeneration, cataracts, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attack, restenosis, impaired glucose metabolism, abnormal fasting blood glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue diseases, psoriasis, foot ulcers, ulcerative colitis, high APO B-lipoproteinemia, Alzheimer's disease, schizophrenia, cognitive impairment, inflammatory bowel disease, short bowel syndrome, Crohn's disease, colitis, irritable bowel syndrome, polycystic ovary syndrome (PCOS), and addiction (e.g., alcohol, nicotine, and/or drug addiction).

The present invention also provides a method for antagonizing glucose-dependent insulinotropic peptide receptor (GIPR), the method comprising contacting GIPR with 4'-[(1-{[4-(propyl-2-yl)phenyl]aminomethoxy}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid ionate salt.

It should be understood that the general description above and the detailed description below are exemplary and illustrative only, and not intended to limit the invention as the scope of the patent application suggests.

The invention will be more readily understood by referring to the exemplary embodiments of the invention described in detail below and the embodiments included therein.

Some additional exemplary embodiments of the present invention are described below.

In the first state sample, the present invention provides a compound as 4'-[(1-{[4-(propyl-2-yl)phenyl]aminomethoxy}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid ionate salt.

In some further embodiments, the present invention provides a compound as 4'-[(1-{[4-(propyl-2-yl)phenyl]aminomethylamino}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid L-ionate salt, the chemical structure of which can be represented by, for example, the following chemical structures. or or

Some further embodiments provide a crystalline form of 4'-[(1-{[4-(propyl-2-yl)phenyl]aminomethylamino}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid lysate. In some further embodiments, the present invention provides a crystalline form of 4'-[(1-{[4-(propyl-2-yl)phenyl]aminomethylamino}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid L-lysate.

Some further embodiments provide a crystalline form of 4'-[(1-{[4-(propyl-2-yl)phenyl]aminomethylamino}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid lysate, wherein the crystalline form is anhydrous. Some further embodiments provide a crystalline form of 4'-[(1-{[4-(propyl-2-yl)phenyl]aminomethylamino}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid L-lysate, wherein the crystalline form is anhydrous.

Some further embodiments provide an anhydrous crystalline form 2 of 4'-[(1-{[4-(propyl-2-yl)phenyl]aminomethylamino}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid L-lysine ("Form 2 of L-lysine of Compound 1"), wherein form 2 has a powder X-ray diffraction (PXRD) pattern containing at least one peak selected, in 2θ, from the following positions: 4.4 ± 0.2˚, 5.9 ± 0.2˚, 8.8 ± 0.2˚, and 10.3 ± 0.2˚. In some further embodiments, form 2 has a PXRD pattern containing one peak located at 4.4 ± 0.2˚ in 2θ. In some other embodiments, form 2 has a PXRD containing a single peak located at 8.8 ± 0.2˚ with respect to 2θ. In some further embodiments, form 2 has a PXRD containing a single peak located at 10.3 ± 0.2˚ with respect to 2θ. In some even further embodiments, form 2 has a PXRD containing a single peak located at 5.9 ± 0.2˚ with respect to 2θ.

In some embodiments, the L-lysine form 2 of compound 1 has a powder X-ray diffraction (PXRD) pattern containing at least one peak, which, in 2θ, is selected from the following positions: 4.4±0.2˚, 5.9±0.2˚, 8.8±0.2˚ and 10.3±0.2˚, and another peak, in 2θ, is located at 18.3±0.2˚.

In some embodiments, form 2 of the L-lysine of compound 1 has a PXRD containing at least two peaks, which, with respect to 2θ, are selected from those located at: 4.4±0.2˚, 5.9±0.2˚, 8.8±0.2˚, and 10.3±0.2˚. In some further embodiments, form 2 has a PXRD containing two peaks located at 4.4±0.2˚ and 8.8±0.2˚. In other further embodiments, form 2 has a PXRD containing two peaks located at 4.4±0.2˚ and 10.3±0.2˚. In other further embodiments, form 2 has a PXRD containing two peaks located at 4.4±0.2˚ and 5.9±0.2˚. In other further embodiments, form 2 has a PXRD containing two peaks located at 8.8±0.2˚ and 10.3±0.2˚. In other further embodiments, form 2 has a PXRD containing two peaks located at 8.8±0.2˚ and 5.9±0.2˚. In other further embodiments, form 2 has a PXRD containing two peaks located at 10.3±0.2˚ and 5.9±0.2˚.

In some embodiments, the L-ionate form 2 of compound 1 has a PXRD containing two peaks located at 4.4±0.2˚ and 18.3±0.2˚ in terms of 2θ.

In some embodiments, the L-ionate form 2 of compound 1 has a PXRD containing two peaks located at 5.9±0.2˚ and 18.3±0.2˚ in terms of 2θ.

In some embodiments, the L-lysine form 2 of compound 1 has a PXRD containing at least two peaks, which, in terms of 2θ, are selected from the following positions: 4.4±0.2˚, 5.9±0.2˚, 8.8±0.2˚, 10.3±0.2˚ and 18.3±0.2˚.

In some embodiments, form 2 of the L-lysine of compound 1 has a PXRD comprising at least three peaks, which, with respect to 2θ, are selected from those located at: 4.4±0.2˚, 5.9±0.2˚, 8.8±0.2˚, and 10.3±0.2˚. In some further embodiments, form 2 has a PXRD comprising three peaks located at 4.4±0.2˚, 8.8±0.2˚, and 10.3±0.2˚. In other further embodiments, form 2 has a PXRD comprising three peaks located at 4.4±0.2˚, 8.8±0.2˚, and 5.9±0.2˚. In other further embodiments, Form 2 has a PXRD comprising three peaks located at 8.8±0.2˚, 5.9±0.2˚, and 10.3±0.2˚.

In some embodiments, the L-lysine form 2 of compound 1 has a PXRD containing at least three peaks, which, in terms of 2θ, are selected from the following positions: 4.4±0.2˚, 5.9±0.2˚, 8.8±0.2˚, 10.3±0.2˚ and 18.3±0.2˚.

In some embodiments, the L-lysine form 2 of compound 1 has a PXRD with four peaks located at 4.4±0.2˚, 5.9±0.2˚, 8.8±0.2˚ and 10.3±0.2˚ in terms of 2θ.

In some embodiments, the L-lysine form 2 of compound 1 has a PXRD comprising at least four peaks, which, in 2θ, are selected from the following positions: 4.4±0.2˚, 5.9±0.2˚, 8.8±0.2˚, 10.3±0.2˚ and 18.3±0.2˚.

In some embodiments, the L-lysine form 2 of compound 1 has a PXRD comprising five peaks located at 4.4±0.2˚, 5.9±0.2˚, 8.8±0.2˚, 10.3±0.2˚ and 18.3±0.2˚ in terms of 2θ.

In some embodiments, the L-ionate form 2 of compound 1 has a PXRD essentially as shown in Figure 5.

In some embodiments, form 2 of the L-lysine of compound 1 has a differential scanning calorimetry (DSC) trace that includes an endothermic onset temperature of about 219.9 ± 10.0 °C. In some embodiments, form 2 of the L-lysine of compound 1 has a DSC trace that includes an endothermic onset temperature of about 219.9 ± 2.0 °C. In some further embodiments, form 2 has a DSC trace that includes an endothermic onset temperature of about 219.9 ± 1.5 °C. In some further embodiments, form 2 has a DSC trace that includes an endothermic onset temperature of about 219.9 ± 1.0 °C. In some further embodiments, form 2 has a differential scanning calorimetry trace including an endothermic onset temperature of about 219.9 ± 0.5 °C. In some further embodiments, form 2 of the L-lysine of compound 1 has a differential scanning calorimetry trace as shown in Figure 4.

In some embodiments, the L-lysine form 2 of compound 1 has an FT-Raman spectrum containing at least one peak, which, in terms of wavenumber ( ^cm⁻¹ ) ^, is selected from positions located at: ¹²⁸³ ±2 ^cm⁻¹ , 1606±2 ^{cm⁻¹ ,} and 1666±2 ^{cm⁻¹ .} In some further embodiments, the L-lysine form 2 of compound 1 has an FT-Raman spectrum containing two peaks, which, in terms of wavenumber ( ^cm⁻¹ ) ^, are selected from positions located at: 1283±2 ^cm⁻¹ , 1606± ^{2 cm⁻¹} , and 1666± ^{2 cm⁻¹ .} In some further embodiments, the L-lysine form 2 of compound 1 has a FT-Raman spectrum containing two peaks in terms of wavenumber ( ^cm⁻¹ ) selected from the following positions: 1283± ^{2 cm⁻¹ ,} 1606± ^{2 cm⁻¹ and} 1666± ^{2 cm⁻¹} .

In some embodiments, the L-ionate form 2 of compound 1 has an FT-Raman spectrum substantially as shown in Figure 10.

In some embodiments, the L-lysine form 2 of compound 1 has a ¹³ C ss NMR spectrum containing at least one peak, which, in terms of chemical shift, is selected from the following: 32.2 ± 0.2 ppm, 120.9 ± 0.2 ppm, 127.3 ± 0.2 ppm, and 177.4 ± 0.2 ppm. In some further embodiments, the L-lysine form 2 of compound 1 has a ¹³ C ss NMR spectrum containing at least two peaks, which, in terms of chemical shift, are selected from the following: 32.2 ± 0.2 ppm, 120.9 ± 0.2 ppm, 127.3 ± 0.2 ppm, and 177.4 ± 0.2 ppm. In some further embodiments, the L-lysine form 2 of compound 1 has a ¹³ C ss NMR spectrum comprising at least three peaks, the at least three peaks being selected, in terms of chemical shift, from the following: 32.2 ± 0.2 ppm, 120.9 ± 0.2 ppm, 127.3 ± 0.2 ppm, and 177.4 ± 0.2 ppm. In some further embodiments, the L-lysine form 2 of compound 1 has a ¹³ C ss NMR spectrum comprising a plurality of peaks, the peaks being selected, in terms of chemical shift, from the following: 32.2 ± 0.2 ppm, 120.9 ± 0.2 ppm, 127.3 ± 0.2 ppm, and 177.4 ± 0.2 ppm.

In some embodiments, the L-ionate form 2 of compound 1 has a ¹³ C ss NMR spectrum containing at least one peak located at 127.3 ± 0.2 ppm in terms of chemical shift.

In some embodiments, the L-ionate form 2 of compound 1 has a ¹³ C ss NMR spectrum containing at least one peak located at 32.2 ± 0.2 ppm in terms of chemical shift.

In some embodiments, the L-ionate form 2 of compound 1 has a ¹³ C ss NMR spectrum containing at least one peak located at 120.9 ± 0.2 ppm in terms of chemical shift.

In some embodiments, the L-ionate form 2 of compound 1 has a ¹³ C ss NMR spectrum containing two peaks located at 127.3 ± 0.2 ppm and 32.2 ± 0.2 ppm in terms of chemical shift.

In some embodiments, the L-lysine form 2 of compound 1 has a ^13C ssNMR spectrum containing three peaks located at 127.3±0.2 ppm, 32.2±0.2 ppm and 120.9±0.2 ppm in terms of chemical shift.

In some embodiments, the L-ionate form 2 of compound 1 has a ¹³ C ss NMR spectrum that is substantially as shown in Figure 11.

Some further embodiments provide a crystalline form of 4'-[(1-{[4-(propyl-2-yl)phenyl]aminomethylamino}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid ionate, wherein the crystalline form is a solvent.

Some further embodiments provide a crystalline form of 4'-[(1-{[4-(propyl-2-yl)phenyl]aminomethoxy}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid L-ionate, wherein the crystalline form is a solvent compound.

Some further embodiments provide a crystalline form of 4'-[(1-{[4-(propyl-2-yl)phenyl]aminomethylamino}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid ionate, wherein the crystalline form is a hydrate.

Some further embodiments provide a crystalline form of 4'-[(1-{[4-(propyl-2-yl)phenyl]aminomethoxy}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid L-ionate, wherein the crystalline form is a hydrate.

Some further embodiments provide 4'-[(1-{[4-(propyl-2-yl)phenyl]aminomethylamino}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid ionate (including L-ionate).

Some further embodiments provide an amorphous form of 4'-[(1-{[4-(propyl-2-yl)phenyl]aminomethoxy}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid L-ionate.

In the second state, the present invention provides a compound as a hydrate of 4'-[(1-{[4-(propyl-2-yl)phenyl]aminomethylamino}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid ionamine salt.

In some further embodiments, the hydrate of 4'-[(1-{[4-(propyl-2-yl)phenyl]aminomethylamino}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid ionate salt is the hydrate of 4'-[(1-{[4-(propyl-2-yl)phenyl]aminomethylamino}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid L-ionate salt.

In the third embodiment, the present invention provides a compound as a sesquihydrate of 4'-[(1-{[4-(propyl-2-yl)phenyl]aminomethylamino}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid ionate. In some further embodiments, the present invention provides a compound as a sesquihydrate of 4'-[(1-{[4-(propyl-2-yl)phenyl]aminomethylamino}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid L-ionate.

Some further embodiments provide a crystalline form 1 of the sesquihydrate of 4'-[(1-{[4-(propyl-2-yl)phenyl]aminomethylamino}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid L-lysate ("Form 1 of L-lysate of Compound 1"), wherein Form 1 of L-lysate of Compound 1 has a powder X-ray diffraction (PXRD) pattern containing at least one peak selected, in 2θ, from the following positions: 16.7±0.2˚, 17.9±0.2˚, 18.6±0.2˚, and 19.7±0.2˚. In some further embodiments, the L-lysine form 1 of compound 1 has a PXRD pattern containing a single peak located at 18.6 ± 0.2˚ in 2θ. In some other embodiments, the L-lysine form 1 of compound 1 has a PXRD pattern containing a single peak located at 19.7 ± 0.2˚ in 2θ. In some further embodiments, the L-lysine form 1 of compound 1 has a PXRD pattern containing a single peak located at 17.9 ± 0.2˚ in 2θ. In some further embodiments, the L-lysine form 1 of compound 1 has a PXRD pattern containing a single peak located at 16.7 ± 0.2˚ in 2θ.

In some embodiments, the L-lysine form 1 of compound 1 has a PXRD comprising at least two peaks, which, with respect to 2θ, are selected from the following positions: 16.7±0.2˚, 17.9±0.2˚, 18.6±0.2˚, and 19.7±0.2˚. In some further embodiments, the L-lysine form 1 of compound 1 has a PXRD comprising two peaks located at 18.6±0.2˚ and 19.7±0.2˚. In other further embodiments, the L-lysine form 1 of compound 1 has a PXRD comprising two peaks located at 18.6±0.2˚ and 17.9±0.2˚. In another further embodiment, the L-lysine salt of compound 1 in form 1 has a PXRD pattern comprising two peaks located at 18.6 ± 0.2˚ and 16.7 ± 0.2˚. In another further embodiment, the L-lysine salt of compound 1 in form 1 has a PXRD pattern comprising two peaks located at 19.7 ± 0.2˚ and/or 17.9 ± 0.2˚. In another further embodiment, the L-lysine salt of compound 1 in form 1 has a PXRD pattern comprising two peaks located at 16.7 ± 0.2˚ and 19.7 ± 0.2˚. In other further embodiments, the L-lysine salt of compound 1 in form 1 has a PXRD containing two peaks located at 16.7±0.2˚ and/or 17.9±0.2˚.

In some embodiments, form 1 of the L-lysine of compound 1 has a PXRD comprising at least two peaks, which, with respect to 2θ, are selected from the following positions: 7.3±0.2˚, 16.7±0.2˚, 17.9±0.2˚, 18.6±0.2˚, and 19.7±0.2˚. In some further embodiments, form 1 has a PXRD comprising two peaks located at 7.3±0.2˚ and 18.6±0.2˚. In some further embodiments, form 1 has a PXRD comprising two peaks located at 7.3±0.2˚ and 19.7±0.2˚. In some further embodiments, Form 1 has a PXRD comprising two peaks located at 7.3±0.2˚ and 17.9±0.2˚. In some further embodiments, Form 1 has a PXRD comprising two peaks located at 7.3±0.2˚ and 16.7±0.2˚.

In some embodiments, the L-lysine form 1 of compound 1 has a PXRD comprising at least three peaks, which, with respect to 2θ, are selected from the following positions: 7.3±0.2˚, 16.7±0.2˚, 17.9±0.2˚, 18.6±0.2˚, and 19.7±0.2˚. In some further embodiments, the L-lysine form 1 of compound 1 has a PXRD comprising three peaks located at 7.3±0.2˚, 18.6±0.2˚, and 19.7±0.2˚. In another further embodiment, the L-lysine form 1 of compound 1 has a PXRD pattern comprising three peaks located at 7.3±0.2˚, 18.6±0.2˚, and 17.9±0.2˚. In another further embodiment, the L-lysine form 1 of compound 1 has a PXRD pattern comprising three peaks located at 7.3±0.2˚, 18.6±0.2˚, and 16.7±0.2˚. In another further embodiment, the L-lysine form 1 of compound 1 has a PXRD pattern comprising three peaks located at 7.3±0.2˚, 19.7±0.2˚, and 17.9±0.2˚. In other further embodiments, the L-lysine form 1 of compound 1 has a PXRD comprising three peaks located at 7.3±0.2˚, 19.7±0.2˚, and 16.7±0.2˚.

In some embodiments, the L-lysine form 1 of compound 1 has a PXRD comprising at least four peaks, which, in 2θ, are selected from those located at: 7.3±0.2˚, 16.7±0.2˚, 17.9±0.2˚, 18.6±0.2˚, and 19.7±0.2˚. In some further embodiments, the L-lysine form 1 of compound 1 has a PXRD comprising four peaks located at 7.3±0.2˚, 18.6±0.2˚, 19.7±0.2˚, and 17.9±0.2˚. In other further embodiments, the L-lysine salt of compound 1 in form 1 has a PXRD pattern comprising four peaks located at 7.3±0.2˚, 18.6±0.2˚, 19.7±0.2˚, and 16.7±0.2˚. In other further embodiments, the L-lysine salt of compound 1 in form 1 has a PXRD pattern comprising four peaks located at 16.7±0.2˚, 17.9±0.2˚, 18.6±0.2˚, and 19.7±0.2˚.

In some embodiments, the L-lysine salt of compound 1 in form 1 has a PXRD comprising five peaks located at 7.3±0.2˚, 16.7±0.2˚, 17.9±0.2˚, 18.6±0.2˚ and 19.7±0.2˚ in terms of 2θ.

In some embodiments, the L-ionate form 1 of compound 1 has a PXRD essentially as shown in Figure 1.

In some embodiments, the L-lysine form 1 of compound 1 has an FT-Raman spectrum containing at least one peak, which, in terms of wavenumber ( ^cm⁻¹ ), is selected from positions located ^at 1284± ^{2 cm⁻¹} , 1604±2 ^{cm⁻¹ ,} and 1636±2 ^cm⁻¹ . In some embodiments, the L-lysine form 1 of compound ¹ has an FT-Raman spectrum containing at least one peak, which, in terms of wavenumber ( ^cm⁻¹ ) ^, is located at 1284±2 ^{cm⁻¹ .} In some embodiments, the L-lysine form 1 of compound 1 has an FT-Raman spectrum containing at least one peak located at a wavenumber ( ^cm⁻¹ ) of 1604 ± ^{2 cm⁻¹ .} In some embodiments, the L-lysine form 1 of compound 1 has an FT-Raman spectrum containing at least one peak located at a wavenumber ( ^cm⁻¹ ) of 1636 ± ^{2 cm⁻¹ .}

In some embodiments, the L-lysine form 1 of compound 1 has an FT-Raman spectrum comprising at least two peaks, the at least two peaks being selected, in terms of wavenumber ( ^cm⁻¹ ) ^, from positions located at ¹²⁸⁴ ±2 ^cm⁻¹ , 1604±2 ^cm⁻¹ , and 1636±2 ^{cm⁻¹ .} In some embodiments, the L-lysine form 1 of compound ¹ has an FT-Raman spectrum comprising two peaks, the two peaks being located, in terms of wavenumber ( ^cm⁻¹ ) ^, at positions of 1284±2 ^{cm⁻¹ and} 1604±2 ^{cm⁻¹ .}

In some embodiments, the L-lysine form 1 of compound 1 has an FT-Raman spectrum containing peaks located at 1284±2 ^cm⁻¹ , 1604±2 ^{cm⁻¹ ,} and 1636±2 ^cm⁻¹ in terms of wavenumber ^{( cm⁻¹ ) .}

In some embodiments, the L-ionate form 1 of compound 1 has an FT-Raman spectrum substantially as shown in Figure 8.

In some embodiments, the L-lysine form 1 of compound 1 has a ^13C ssNMR spectrum containing at least one peak, which, in terms of chemical shift, is selected from those located at 24.5 ± 0.2 ppm, 47.1 ± 0.2 ppm, 131.3 ± 0.2 ppm, and 169.6 ± 0.2 ppm. In some embodiments, the L-lysine form 1 of compound 1 has a ^13C ssNMR spectrum containing one peak, which, in terms of chemical shift, is located at 169.6 ± 0.2 ppm. In some embodiments, the L-lysine form 1 of compound 1 has a ^13C ssNMR spectrum containing one peak, which, in terms of chemical shift, is located at 131.3 ± 0.2 ppm.

In some embodiments, the L-lysine form 1 of compound 1 has a ^13C ss NMR spectrum containing at least two peaks selected from 24.5 ± 0.2 ppm, 47.1 ± 0.2 ppm, 131.3 ± 0.2 ppm, and 169.6 ± 0.2 ppm in terms of chemical shift. In some embodiments, the L-lysine form 1 of compound 1 has a ^13C ss NMR spectrum containing two peaks located at 131.3 ± 0.2 ppm and 169.6 ± 0.2 ppm in terms of chemical shift. In some embodiments, the L-lysine form 1 of compound 1 has a ^13C ss NMR spectrum containing two peaks located at 24.5 ± 0.2 ppm and 131.3 ± 0.2 ppm in terms of chemical shift. In some embodiments, the L-lysine form 1 of compound 1 has a ^13C ss NMR spectrum containing two peaks located at 24.5 ± 0.2 ppm and 169.6 ± 0.2 ppm in terms of chemical shift. In some embodiments, the L-lysine form 1 of compound 1 has a ^13C ss NMR spectrum containing two peaks located at 47.1 ± 0.2 ppm and 131.3 ± 0.2 ppm in terms of chemical shift. In some embodiments, the L-ionate form of compound 1 has a ^13C ssNMR spectrum containing two peaks located at 47.1 ± 0.2 ppm and 169.6 ± 0.2 ppm in terms of chemical shift.

In some embodiments, the L-lysine form 1 of compound 1 has a ^13C ss NMR spectrum comprising at least three peaks selected, in terms of chemical shifts, from 24.5 ± 0.2 ppm, 47.1 ± 0.2 ppm, 131.3 ± 0.2 ppm, and 169.6 ± 0.2 ppm. In some embodiments, the L-lysine form 1 of compound 1 has a ^13C ss NMR spectrum comprising three peaks located, in terms of chemical shifts, from 24.5 ± 0.2 ppm, 131.3 ± 0.2 ppm, and 169.6 ± 0.2 ppm. In some embodiments, the L-lysine form of compound 1 has a ^13C ss NMR spectrum containing three peaks located at 47.1 ± 0.2 ppm, 131.3 ± 0.2 ppm, and 169.6 ± 0.2 ppm in terms of chemical shift.

In some embodiments, the L-lysine form 1 of compound 1 has a ^13C ss NMR spectrum containing peaks located at 24.5 ± 0.2 ppm, 47.1 ± 0.2 ppm, 131.3 ± 0.2 ppm and 169.6 ± 0.2 ppm in terms of chemical shift.

In some embodiments, the L-ionate form 1 of compound 1 has a ¹³ C ss NMR spectrum that is substantially as shown in Figure 9.

In the fourth state, the present invention provides a compound as 4'-[(1-{[4-(propyl-2-yl)phenyl]aminomethylamino}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid arginine salt, the structure of which can be represented by, for example, the following formula.

In some further embodiments, the present invention provides a compound as 4'-[(1-{[4-(propyl-2-yl)phenyl]aminomethoxy}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid L-arginine salt.

In some further embodiments, the present invention provides a compound in the crystalline form of 4'-[(1-{[4-(propyl-2-yl)phenyl]aminomethoxy}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid L-arginine salt.

In some further embodiments, the present invention provides an anhydrous crystalline form 1 of 4'-[(1-{[4-(propyl-2-yl)phenyl]aminomethylamino}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid L-arginine ("Form 1 of L-arginine of Compound 1"), wherein form 1 has a powder X-ray diffraction (PXRD) pattern containing at least one peak located at 14.6 ± 0.2˚, 17.6 ± 0.2˚, 18.3 ± 0.2˚, and 20.0 ± 0.2˚ with respect to 2θ. In some further embodiments, form 1 has a PXRD pattern containing one peak located at 20.0 ± 0.2˚ with respect to 2θ. In some other embodiments, form 1 has a PXRD containing a single peak located at 18.3 ± 0.2˚ with respect to 2θ. In some further embodiments, form 1 has a PXRD containing a single peak located at 17.6 ± 0.2˚ with respect to 2θ. In some further embodiments, form 1 has a PXRD containing a single peak located at 14.6 ± 0.2˚ with respect to 2θ.

In some embodiments, form 1 of the L-arginine of compound 1 has a PXRD containing at least two peaks located at 14.6 ± 0.2˚, 17.6 ± 0.2˚, 18.3 ± 0.2˚, and 20.0 ± 0.2˚ with respect to 2θ. In some further embodiments, form 1 has a PXRD containing two peaks located at 20.0 ± 0.2˚ and 18.3 ± 0.2˚. In other further embodiments, form 1 has a PXRD containing two peaks located at 20.0 ± 0.2˚ and 17.6 ± 0.2˚. In other further embodiments, form 1 has a PXRD containing two peaks located at 20.0 ± 0.2˚ and 14.6 ± 0.2˚. In other further embodiments, Form 1 has a PXRD comprising two peaks located at 18.3±0.2˚ and 17.6±0.2˚. In other further embodiments, Form 1 has a PXRD comprising two peaks located at 18.3±0.2˚ and/or 14.6±0.2˚. In other further embodiments, Form 1 has a PXRD comprising two peaks located at 17.6±0.2˚ and 14.6±0.2˚.

In some embodiments, form 1 of compound 1, the L-arginine salt, has a PXRD pattern containing at least two peaks located at 7.3±0.2˚, 14.6±0.2˚, 17.6±0.2˚, 18.3±0.2˚, and 20.0±0.2˚ with respect to 2θ. In some further embodiments, form 1 has a PXRD pattern containing two peaks located at 7.3±0.2˚ and 20.0±0.2˚. In other further embodiments, form 1 has a PXRD pattern containing two peaks located at 7.3±0.2˚ and 18.3±0.2˚. In other further embodiments, form 1 has a PXRD pattern containing two peaks located at 7.3±0.2˚ and 17.6±0.2˚. In other further embodiments, Form 1 has a PXRD containing two peaks located at 7.3±0.2˚ and 14.6±0.2˚.

In some embodiments, form 1 of the L-arginine of compound 1 has a PXRD comprising at least three peaks located at 7.3±0.2˚, 14.6±0.2˚, 17.6±0.2˚, 18.3±0.2˚, and 20.0±0.2˚ with respect to 2θ. In some further embodiments, form 1 has a PXRD comprising three peaks located at 7.3±0.2˚, 20.0±0.2˚, and 18.3±0.2˚. In other further embodiments, form 1 has a PXRD comprising three peaks located at 7.3±0.2˚, 20.0±0.2˚, and 17.6±0.2˚. In other further embodiments, Form 1 has a PXRD comprising three peaks located at 7.3±0.2˚, 20.0±0.2˚, and 14.6±0.2˚. In other further embodiments, Form 1 has a PXRD comprising three peaks located at 7.3±0.2˚, 18.3±0.2˚, and 14.6±0.2˚. In other further embodiments, Form 1 has a PXRD comprising three peaks located at 7.3±0.2˚, 17.6±0.2˚, and 14.6±0.2˚.

In some embodiments, form 1 of compound 1, the L-arginine salt, has a PXRD pattern comprising at least four peaks located at 7.3 ± 0.2˚, 14.6 ± 0.2˚, 17.6 ± 0.2˚, 18.3 ± 0.2˚, and 20.0 ± 0.2˚ with respect to 2θ. In some further embodiments, form 1 has a PXRD pattern comprising four peaks located at 7.3 ± 0.2˚, 20.0 ± 0.2˚, 18.3 ± 0.2˚, and 17.6 ± 0.2˚. In other further embodiments, form 1 has a PXRD pattern comprising four peaks located at 7.3 ± 0.2˚, 20.0 ± 0.2˚, 18.3 ± 0.2˚, and 14.6 ± 0.2˚. In other further embodiments, Form 1 has a PXRD comprising four peaks located at 7.3±0.2˚, 20.0±0.2˚, 17.6±0.2˚, and 14.6±0.2˚. In other further embodiments, Form 1 has a PXRD comprising four peaks located at 7.3±0.2˚, 18.3±0.2˚, 17.6±0.2˚, and 14.6±0.2˚. In other further embodiments, Form 1 has a PXRD comprising four peaks located at 20.0±0.2˚, 18.3±0.2˚, 17.6±0.2˚, and 14.6±0.2˚.

In some embodiments, the L-arginine form of compound 1 has a PXRD comprising five peaks located at 7.3±0.2˚, 14.6±0.2˚, 17.6±0.2˚, 18.3±0.2˚ and 20.0±0.2˚ in terms of 2θ.

In some embodiments, the L-arginine form 1 of compound 1 has a PXRD essentially as shown in Figure 7.

In some embodiments, form 1 of the L-arginine of compound 1 has a differential scanning calorimetry (DSC) trace that includes an endothermic onset temperature of about 221.2 ± 10.0 °C. In some embodiments, form 1 of the L-arginine of compound 1 has a DSC trace that includes an endothermic onset temperature of about 221.2 ± 2.0 °C. In some further embodiments, form 1 has a DSC trace that includes an endothermic onset temperature of about 221.2 ± 1.5 °C. In some further embodiments, form 1 has a DSC trace that includes an endothermic onset temperature of about 221.2 ± 1.0 °C. In some further embodiments, form 1 has an endothermic differential scanning calorimetry trace including an initial temperature of about 221.2 ± 0.5 °C. In some further embodiments, form 1 of the L-arginine of compound 1 has a differential scanning calorimetry trace substantially as shown in FIG. 6.

In some embodiments, the L-arginine form 1 of compound 1 has an FT-Raman spectrum containing at least one peak, which, in terms of wavenumber ( ^cm⁻¹ ) ^, is selected from positions located at: ¹²⁷⁹ ±2 ^cm⁻¹ , 1602±2 ^{cm⁻¹ ,} and 1611±2 ^cm⁻¹ . In some further embodiments, the L-arginine form ¹ of compound 1 has an FT-Raman spectrum containing two peaks, which, in terms of wavenumber ( ^cm⁻¹ ) ^, are selected from positions located at: 1279±2 ^cm⁻¹ , 1602± ^{2 cm⁻¹} , and 1611± ^{2 cm⁻¹ .} In some further embodiments, the L-arginine form of compound 1 has an FT-Raman spectrum containing peaks selected in terms of wavenumber ( ^cm⁻¹ ) from the following positions: 1279± ^{2 cm⁻¹ ,} 1602±2 ^{cm⁻¹ and} 1611±2 ^{cm⁻¹ .}

In some embodiments, the L-arginine form 1 of compound 1 has an FT-Raman spectrum containing a single peak located at a wavenumber ( ^{cm⁻¹ )} of 1279 ± ^{2 cm⁻¹} . In some embodiments, the L-arginine form 1 of compound 1 has an FT-Raman spectrum containing a single peak located at a wavenumber ( ^cm⁻¹ ) of 1602 ± ^{2 cm⁻¹} . In some embodiments, the L-arginine form 1 of compound 1 has an FT-Raman spectrum containing a ^single peak located at a wavenumber ( ^{cm⁻¹ )} of ¹⁶¹¹ ± 2 ^cm⁻¹ .

In some embodiments, the L-arginine form 1 of compound 1 has an FT-Raman spectrum containing two peaks located at wavenumbers ( ^{cm⁻¹ )} of 1279 ± 2 ^{cm⁻¹ and} 1602 ± ^{2 cm⁻¹} . In some embodiments, the L-arginine form 1 of compound 1 has an FT-Raman spectrum containing two peaks located at wavenumbers ( ^cm⁻¹ ) of ¹⁶⁰² ± ^{2 cm⁻¹} and 1611 ± 2 ^cm⁻¹ . In some embodiments, the L-arginine form 1 of compound ¹ has an FT ^- Raman spectrum containing two peaks located at wavenumbers ( ^{cm⁻¹ )} of 1279 ± 2 ^cm⁻¹ and 1611 ± ^{2 cm⁻¹} .

In some embodiments, the L-arginine form of compound 1 has an FT-Raman spectrum substantially as shown in Figure 12.

In some embodiments, the L-arginine form 1 of compound 1 has a ^13C ssNMR spectrum containing at least one peak, which, in terms of chemical shift, is selected from the following: 46.3 ± 0.2 ppm, 138.2 ± 0.2 ppm, 140.1 ± 0.2 ppm, and 176.3 ± 0.2 ppm. In some further embodiments, the L-arginine form 1 of compound 1 has a ^13C ssNMR spectrum containing at least two peaks, which, in terms of chemical shift, are selected from the following: 46.3 ± 0.2 ppm, 138.2 ± 0.2 ppm, 140.1 ± 0.2 ppm, and 176.3 ± 0.2 ppm. In some further embodiments, the L-arginine form 1 of compound 1 has a ^13C ss NMR spectrum containing at least three peaks, which are selected, in terms of chemical shift, from the following: 46.3 ± 0.2 ppm, 138.2 ± 0.2 ppm, 140.1 ± 0.2 ppm, and 176.3 ± 0.2 ppm. In some further embodiments, the L-arginine form 1 of compound 1 has a ^13C ss NMR spectrum containing peaks, which are selected, in terms of chemical shift, from the following: 46.3 ± 0.2 ppm, 138.2 ± 0.2 ppm, 140.1 ± 0.2 ppm, and 176.3 ± 0.2 ppm.

In some embodiments, the L-arginine form of compound 1 has a ^13C ssNMR spectrum containing a peak located at 46.3 ± 0.2 ppm in terms of chemical shift.

In some embodiments, the L-arginine form of compound 1 has a ^13C ssNMR spectrum containing a peak located at 138.2 ± 0.2 ppm in terms of chemical shift.

In some embodiments, the L-arginine form of compound 1 has a ^13C ssNMR spectrum containing a peak located at 140.1 ± 0.2 ppm in terms of chemical shift.

In some embodiments, the L-arginine form of compound 1 has a ^13C ssNMR spectrum containing a peak located at 176.3 ± 0.2 ppm in terms of chemical shift.

In some embodiments, the L-arginine form 1 of compound 1 has a ^{13C ss} NMR spectrum containing two peaks located at 46.3 ± 0.2 ppm and 138.2 ± 0.2 ppm in terms of chemical shift.

In some embodiments, the L-arginine form of compound 1 has a ^13C ss NMR spectrum containing three peaks located at 46.3±0.2 ppm, 138.2±0.2 ppm and 140.1±0.2 ppm in terms of chemical shift.

In some embodiments, the L-arginine form of compound 1 has a ^13C ss NMR spectrum containing three peaks located at 46.3±0.2 ppm, 138.2±0.2 ppm and 176.3±0.2 ppm in terms of chemical shift.

In some embodiments, the L-arginine form of compound 1 has a ^13C ssNMR spectrum containing three peaks located at 46.3±0.2 ppm, 140.1±0.2 ppm and 176.3±0.2 ppm in terms of chemical shift.

In some embodiments, the L-arginine form of compound 1 has a ^13C ssNMR spectrum that is substantially as shown in Figure 13.

In the fifth embodiment, the present invention provides a pharmaceutical composition comprising a compound of any embodiment of the first, second, third and fourth embodiments of the present invention (including all further embodiments described herein) and a pharmaceutically acceptable excipient.

In the sixth embodiment, the invention provides a method for treating or preventing a patient's condition, disease, or symptom, comprising administering to a patient a compound of any of the embodiments of the first, second, third, and fourth embodiments of the invention (including all further embodiments described herein), wherein the condition, disease, or symptom is selected from the group consisting of: diabetes [e.g., type 1 diabetes (T1D), type 2 diabetes (T2DM), including prediabetes], idiopathic T1D (type 1b), latent autoimmune diabetes mellitus in adults (LADA), early-onset T2DM (EOD), adolescent atypical diabetes (YOAD), juvenile adult-onset diabetes (MODY), malnutrition-associated diabetes, gestational diabetes, hyperglycemia, insulin resistance, Hepatic insulin resistance, glucose intolerance, diabetic neuropathy, diabetic nephropathy, renal diseases [e.g., acute nephropathy, renal tubular dysfunction, pro-inflammatory changes in the proximal tubules, or chronic nephropathy (CKD)], diabetic retinopathy, adipocyte dysfunction, visceral fat deposition, sleep apnea [e.g., obstructive sleep apnea (OSA)] Obesity (including hypothalamic obesity and monogenic obesity) and related complications (such as osteoarthritis and urinary incontinence), eating disorders (including bulimia syndrome, bulimia nervosa, and syndrome obesity, such as Prad-Willi syndrome and Budd-Bieder syndrome), and weight gain, such as weight gain caused by the use of other medications (e.g., weight gain caused by the use of steroids and/or antipsychotics). (Initial onset, or caused by treatment of depression, or by the use of medications affecting cognitive function), overweight, excessive sugar cravings, dyslipidemia [including hyperlipidemia, hypertriglyceridemia, elevated total cholesterol, high LDL (low-density lipoprotein) cholesterol and low HDL (high-density lipoprotein) cholesterol], hyperinsulinemia, non-alcoholic fatty liver disease [NAFLD, including fatty liver disease, etc.] [Related diseases including degeneration, non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma], cardiovascular diseases, atherosclerosis (including coronary artery disease), peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, and heart failure [e.g., congestive heart failure, heart failure with preserved ejection fraction (HFpEF), and heart failure with reduced ejection fraction]. Heart failure (HFrEF), myocardial infarction (e.g., necrosis and apoptosis), stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, osteoarthritis, Parkinson's disease, left ventricular hypertrophy, peripheral arterial disease (PAD), macular degeneration Diseases, cataracts, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attack, restenosis, impaired glucose metabolism, abnormal fasting blood glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue diseases, psoriasis, foot ulcers, ulcerative colitis, high APO B-lipoproteinemia, Alzheimer's disease, schizophrenia, cognitive impairment, inflammatory bowel disease, short bowel syndrome, Crohn's disease, colitis, irritable bowel syndrome, polycystic ovary syndrome (PCOS), and addiction (e.g., alcohol, nicotine, and/or drug addiction); or methods for human weight management (e.g., long-term weight management) comprising administering a compound to humans in any of the methods A1 to A86 (including the further methods described herein).

As used in this article, the treatment of diabetes (e.g., T2DM) in patients with diabetes includes, but is not limited to, improving glycemic control.

In some further implementations, the condition, disease, or symptom is selected from the following groups: obesity, weight gain, type 2 diabetes mellitus (T2DM), heart failure (e.g., HFpEF and HFrEF); CKD; NAFLD, NASH, atherosclerosis, PAD, obstructive sleep apnea, diabetic retinopathy, and diabetic neuropathy.

In some further implementations, this method is used to prevent weight gain.

In some further implementations, this method is used to prevent obesity.

In some further implementations, the method is used to treat obesity.

In some further implementations, the method is used for weight management in humans, such as long-term weight management. In some further implementations, when weight management (e.g., long-term weight management) is initiated, the person is obese or overweight; in such cases, weight management (e.g., long-term weight management) is also a method for treating obesity or overweight. In some further implementations, when weight management (e.g., long-term weight management) treatment is initiated, the person is obese; in such cases, weight management (e.g., long-term weight management) is also a method for treating obesity.

In the seventh embodiment, the present invention provides the use of a compound of any embodiment of the first, second, third, and fourth embodiments of the present invention (including all further embodiments described herein) in the treatment or prevention of a condition, disease, or symptom, or in the manufacture of a medicament for the treatment or prevention of a condition, disease, or symptom, wherein the condition, disease, or symptom is selected from the group consisting of: diabetes [e.g., type 1 diabetes (T1D), type 2 diabetes (T2DM), including prediabetes], idiopathic T1D (type 1b), latent autoimmune diabetes mellitus in adults (LADA), early-onset T2DM (EOD), adolescent atypical diabetes (YOAD), juvenile adult-onset diabetes (MODY), malnutrition-associated diabetes, pregnancy-related diabetes, etc. Gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, glucose intolerance, diabetic neuropathy, diabetic nephropathy, renal diseases [e.g., acute nephropathy, renal tubular dysfunction, pro-inflammatory changes in the proximal tubules, or chronic nephropathy (CKD)], diabetic retinopathy, adipocyte dysfunction, visceral fat deposition, sleep apnea [e.g., obstructive sleep apnea] [Obstructive sleep apnea (OSA)], obesity (including hypothalamic obesity and monogenic obesity) and related complications (such as osteoarthritis and urinary incontinence), eating disorders (including bulimia syndrome, bulimia nervosa, and syndrome obesity, such as Prad-Willi syndrome and Budd-Bieder syndrome), weight gain, such as weight gain caused by the use of other medications (e.g., due to the use of steroids). Caused by (and/or) antipsychotic medications, or by treatment of depression, or by the use of medications that affect cognitive function; overweight; excessive sugar cravings; dyslipidemia (including hyperlipidemia, hypertriglyceridemia, elevated total cholesterol, high LDL (low-density lipoprotein) cholesterol and low HDL (high-density lipoprotein) cholesterol); hyperinsulinemia; non-alcoholic fatty liver disease (NAFLD). This includes conditions such as steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and related diseases of hepatocellular carcinoma; cardiovascular diseases; atherosclerosis (including coronary artery disease); peripheral vascular disease; hypertension; endothelial dysfunction; impaired vascular compliance; and heart failure [e.g., congestive heart failure, heart failure with preserved ejection fraction (HFpEF), and heart failure with reduced ejection fraction]. [Decreased heart failure (HFrEF)], myocardial infarction (e.g., necrosis and apoptosis), stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial hyperlipidemia, metabolic acidosis, ketosis, arthritis, osteoporosis, osteoarthritis, Parkinson's disease, left ventricular hypertrophy, peripheral arterial disease (PAD), yellowing Macular degeneration, cataracts, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attack, restenosis, impaired glucose metabolism, abnormal fasting blood glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue diseases, psoriasis, foot ulcers, ulcerative colitis, high APO levels. B-lipoproteinemia, Alzheimer's disease, schizophrenia, cognitive impairment, inflammatory bowel disease, short bowel syndrome, Crohn's disease, colitis, irritable bowel syndrome, polycystic ovary syndrome (PCOS), and addiction (e.g., alcohol, nicotine, and/or drug addiction); or use of compounds in weight management (e.g., long-term weight management) in any of embodiments A1 to A86 (including the further embodiments described herein).

In some further implementations, the condition, disease, or symptom is selected from the following groups: obesity, weight gain, type 2 diabetes mellitus (T2DM), heart failure (e.g., HFpEF and HFrEF); CKD; NAFLD, NASH, atherosclerosis, PAD, obstructive sleep apnea, diabetic retinopathy, and diabetic neuropathy.

In some further implementations, this purpose is to prevent weight gain.

In some further embodiments, the use is to manufacture drugs for preventing weight gain.

In some further implementations, the use is for the treatment of obesity.

In some further embodiments, the use is to manufacture drugs for treating obesity.

In some further embodiments, the use is to manufacture a drug for weight management in humans (e.g., long-term weight management). In some further embodiments, the human being is obese or overweight when weight management (e.g., long-term weight management) is initiated; and in such cases, the weight management is also a method for treating obesity or overweight. In some further embodiments, the human being is obese when weight management (e.g., long-term weight management) treatment is initiated; and in such cases, the weight management is also a method for treating obesity.

In the eighth embodiment, the present invention provides a compound of any embodiment of the first, second, third, and fourth embodiments of the present invention (including all further embodiments described herein) for use in a method of treating or preventing a patient’s condition, disease, or symptom, wherein the condition, disease, or symptom is selected from the group consisting of: diabetes [e.g., type 1 diabetes (T1D), type 2 diabetes (T2DM), including prediabetes], idiopathic T1D (type 1b), latent autoimmune diabetes mellitus in adults (LADA), early-onset T2DM (EOD), adolescent atypical diabetes (YOAD), juvenile adult-onset diabetes (MODY), malnutrition-associated diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatocellular pancreatitis Insulin resistance, glucose intolerance, diabetic neuropathy, diabetic nephropathy, kidney disease [e.g., acute nephropathy, renal tubular dysfunction, pro-inflammatory changes in the proximal tubules, or chronic nephropathy (CKD)], diabetic retinopathy, adipocyte dysfunction, visceral fat deposition, sleep apnea [e.g., obstructive sleep apnea (OSA)], obesity (Including hypothalamic obesity and monogenic obesity) and related complications (such as osteoarthritis and urinary incontinence), eating disorders (including bulimia syndrome, bulimia nervosa, and syndromes of obesity, such as Prad-Willi syndrome and Budd-Bieder syndrome), weight gain, such as weight gain caused by the use of other medications (e.g., weight gain caused by the use of steroids and/or antipsychotics), This could be caused by treatment for depression or the use of medications that affect cognitive function; being overweight; excessive sugar cravings; dyslipidemia (including hyperlipidemia, hypertriglyceridemia, elevated total cholesterol, high LDL (low-density lipoprotein) cholesterol and low HDL (high-density lipoprotein) cholesterol); hyperinsulinemia; or non-alcoholic fatty liver disease (NAFLD, including conditions such as steatosis). [Non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis and hepatocellular carcinoma-related diseases], cardiovascular diseases, atherosclerosis (including coronary artery disease), peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, heart failure [e.g., congestive heart failure, heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction] Heart failure (HFrEF), myocardial infarction (e.g., necrosis and apoptosis), stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, osteoarthritis, Parkinson's disease, left ventricular hypertrophy, peripheral arterial disease (PAD), macular degeneration Species, cataracts, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attack, restenosis, impaired glucose metabolism, abnormal fasting blood glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue diseases, psoriasis, foot ulcers, ulcerative colitis, high APO Use of compounds of any of the first, second, third, and fourth embodiments of the present invention (including all further embodiments described herein) in methods for use in weight management (e.g., long-term weight management) in conditions such as hyperlipoproteinemia, Alzheimer's disease, schizophrenia, cognitive impairment, inflammatory bowel disease, short bowel syndrome, Crohn's disease, colitis, irritable bowel syndrome, polycystic ovary syndrome (PCOS), and addiction (e.g., alcohol, nicotine, and/or drug addiction); or in methods for use in weight management (e.g., long-term weight management).

In some further implementations, the condition, disease, or symptom is selected from the following groups: obesity, weight gain, type 2 diabetes mellitus (T2DM), heart failure (e.g., HFpEF and HFrEF); CKD; NAFLD, NASH, atherosclerosis, PAD, obstructive sleep apnea, diabetic retinopathy, and diabetic neuropathy.

In some further implementations, the compound is used in methods to prevent weight gain.

In some further embodiments, the compound is used in the treatment of obesity.

In some further embodiments, the compound is used in methods of weight management (e.g., long-term weight management). In some further embodiments, the person is obese or overweight when weight management (e.g., long-term weight management) is initiated; and in such cases, the weight management is also a method for treating obesity or overweight. In some further embodiments, the person is obese when weight management (e.g., long-term weight management) treatment is initiated; and in such cases, the weight management is also a method for treating obesity.

In the ninth state, the present invention provides a method for regulating (e.g., antagonizing) GIPR (in a glass tube or in vivo), which comprises contacting (including incubating) GIPR with a compound of any of the embodiments of the first, second, third and fourth states of the present invention (including all further embodiments described herein).

In some further implementations, this adjustment is antagonistic.

It should be understood that this invention is not limited to the specific synthetic preparation method described herein. It should also be understood that the terminology used herein is only for describing specific embodiments and is not intended to be limiting. Many terms will be referenced in this patent specification and the subsequent claims, and these terms should be defined as having the following meanings:

As used in this patent specification, "a" or "an" may refer to one or more. As used by users within the scope of this patent application, "a" or "an" may refer to one or more than one when used in conjunction with the word "comprising". As used herein, "another" may mean at least a second or more.

The term "approximately" refers to a relative term indicating an approximation of the nominal value plus or minus 10%. In one embodiment, it means plus or minus 5%, and in another embodiment, it means plus or minus 2%. This level of approximation is appropriate for the field of this disclosure unless specifically indicated that a more stringent range is required.

The term "compound" as used herein includes any pharmaceutically acceptable form, derivative or variant, including solvent compounds, hydrates, anhydrous forms, amorphous forms, isomorphs, polymorphs and tautomers.

The term "patient" refers to mammals, such as humans.

"Mammalians" refers to warm-blooded vertebrates, characterized by the fact that females secrete milk to feed their young, such as guinea pigs, mice, rats, gerbils, cats, rabbits, dogs, cows, goats, sheep, horses, monkeys, chimpanzees, and humans.

The term "medically acceptable" means a substance (such as the compound of the present invention) suitable for administration to a patient, any salt thereof, or a composition containing the substance or salt of the present invention.

As used herein, the terms "reaction-inert solvent" and "inert solvent" refer to a solvent or mixture thereof that does not interact with the starting material, reagent, intermediate, or product in a manner that adversely affects the yield of the desired product.

As used herein, the term "selective" or "selective" means that the compound has a greater effect in the first analysis than the same compound in the second analysis. For example, in "gut-selective" compounds, the first analysis is used for the compound's half-life in the intestine, and the second analysis is used for the compound's half-life in the liver.

"Therapeutic effective amount" means an amount of the compound of the invention that (i) treats or prevents a particular disease, condition or symptom; (ii) alleviates, improves or eliminates one or more symptoms of a particular disease, condition or symptom; or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition or symptom described herein.

As used in this article, “treating (treat or treatment)” includes preventative, that is, prophylactic and palliative treatment, which includes reversing, relieving, reducing or slowing the progression of the disease (or symptom or condition) or any tissue damage associated with one or more of the symptoms of the disease (or symptom or condition).

As used herein, the term "contact" means bringing together a specified portion in a glass tube system or a living organism system. For example, "contacting" a GIPR with a compound of the invention includes administering a compound of the invention to a mammal (such as a human) that possesses a GIPR, and, for example, introducing a compound of the invention into a sample containing cells or a purified product containing the GIPR.

Each embodiment, example, or pharmaceutically acceptable salt may be individually patented or combined with any number of the embodiments described herein in any combination.

The compounds of this invention may be used in any pharmaceutical composition, use, and method of application of this invention as described herein. Pharmaceutical composition

The present invention also provides compositions comprising the compounds of the present invention (e.g., pharmaceutical compositions). Therefore, in one embodiment, the present invention provides a pharmaceutical composition comprising (therapeuticly effective amount) the compounds of the present invention and, where necessary, a pharmaceutically acceptable carrier. In addition to the compounds of the present invention, the pharmaceutical compositions of the present invention may also contain, or be co-administered with, one or more agents valuable in treating the disease conditions mentioned herein (e.g., simultaneously, sequentially, together, or separately). In a further embodiment, the present invention provides a pharmaceutical composition comprising (therapeuticly effective amount) a compound of formula I or a pharmaceutically acceptable salt thereof, and, where necessary, a pharmaceutically acceptable carrier, and, where necessary, at least one additional drug or agent (e.g., an antidiabetic agent or a weight management agent). In one embodiment, the additional drug or agent is an antidiabetic agent as described below.

"Pharmaceutical composition" in this invention means a mixture of the following (1) and (2): (1) one or more compounds of the invention as active ingredients (e.g., compounds of formula I or their pharmaceutically acceptable salts, including any solvent, hydrate, solid form, stereoisomer, tautomer or prodrug), and (2) at least one pharmaceutically acceptable excipient.

The term "adjuvant" as used herein refers to any component other than the compounds of the present invention. The selection of an adjuvant depends to a great extent on factors such as the method of application, the effect of the adjuvant on solubility and stability, and the properties of the dosage form.

As used herein, "entrainer" includes any and all physiologically compatible solvents, dispersing matrices, coatings, antibacterial agents, antifungal agents, isotropic agents, absorption delay agents, carriers, diluents, etc. Examples of entrainers include one or more of the following: water, brine, phosphate-buffered brine, dextran, glycerol, ethanol, etc., and combinations thereof, and such composition may include isotropic agents such as sugars, sodium chloride, or polyols such as mannitol or sorbitol. Examples of entrainers also include various organic solvents (such as hydrates and solvent compounds). If necessary, the pharmaceutical composition may contain additional excipients, such as flavoring agents, binders/binding agents, lubricants, disintegrants, sweeteners or flavorings, colorants or dyes, etc. For example, for oral administration, tablets containing various excipients (such as citric acid) and various disintegrants (such as starch, alginate, and certain complex silicates) and binding agents (such as sucrose, gelatin, and gum arabic) may be used. Examples of excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and starch types, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycol. In addition, lubricants such as magnesium stearate, sodium lauryl sulfate, and talc are commonly used in the manufacture of tablets. Similar types of solid compositions can also be used in soft-filled or hard-filled gelatin capsules. Therefore, non-limiting examples of excipients also include lactose or lactose syrup and high molecular weight polyethylene glycol. When an aqueous suspension or elixir is required for oral administration, the active compound therein may be combined with various sweeteners or flavorings, colorants or dyes, and, if necessary, emulsifiers or suspending agents, together with additional excipients (such as water, ethanol, propylene glycol, glycerin, or combinations thereof).

Examples of excipients also include pharmaceutically acceptable substances, such as humectants or small amounts of excipients, such as humectants or emulsifiers, preservatives, or buffers, which can extend the shelf life or effectiveness of compounds.

The components of this invention can take many forms. These forms include, for example, liquid, semi-solid, and solid dosage forms, such as liquid solutions (e.g., injectable and infusionable solutions), dispersions or suspensions, tablets, capsules, pellets, powders, liposomes, and suppositories. The form depends on the desired mode of administration and therapeutic application.

Some components are in the form of injectable or infusion solutions, such as those commonly used for passive immunization of humans with antibodies. One mode of administration is parenteral administration (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular). In another administration method, the compound is administered by intravenous infusion or injection. In yet another administration method, the compound is administered by intramuscular or subcutaneous injection.

The oral administration of the solid dosage form may be, for example, in discrete units, such as hard capsules or soft capsules, pills, flat capsules, rhomboid tablets, or tablets, each unit containing a predetermined amount of at least one compound of the invention. In another embodiment, the oral administration may be in powder or granule form. In another embodiment, the oral dosage form is a sublingual dosage form, such as, for example, rhomboid tablets. In these solid dosage forms, the compound of the invention is typically combined with one or more adjuvants. These capsules or tablets may contain a controlled-release formulation. In the case of capsules, tablets, and pills, the dosage form may also contain a buffer or may be prepared using an enteric coating.

In another embodiment, oral administration may be in liquid form. Liquid forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing an inert diluent (e.g., water) commonly used in the art. These compositions may also contain adjuvants, such as one or more humectants, emulsifiers, suspending agents, flavoring agents (e.g., sweeteners), or aromatizers.

In another embodiment, the invention includes a parenteral dosage form. "Parenteral administration" includes, for example, subcutaneous injection, intravenous injection, intraperitoneal injection, intramuscular injection, intrasternal injection, and infusion. The injectable preparation (i.e., a sterile injectable aqueous or oily suspension) can be formulated using one or more suitable dispersants, humectants, or suspending agents according to known techniques.

In another embodiment, the invention includes a topical formulation. "Topical application" includes, for example, skin and transdermal application, such as via a transdermal patch or iontophoresis device, intraocular application, intranasal application, or inhalation application. Compositions for topical application also include, for example, topical gels, sprays, ointments, and creams. Topical formulations may include compounds that enhance the absorption or penetration of the active ingredient through the skin or other affected areas. When the compounds of the invention are applied via a transdermal device, the application will be accomplished using storage tanks and porous membrane types of patches or various solid-matrix types of patches. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, talcum powders, dressings, foams, films, skin patches, sheets, implants, sponges, fibers, bandages, and microemulsions. Liposomes may also be used. Typical excipients include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol, and propylene glycol. Permeation enhancers that may be incorporated—see, for example, B. C. Finnin and T. M. Morgan, J. Pharm. Sci., vol. 88, pp. 955-958, 1999.

Formulations suitable for topical application to the eye include, for example, eye drops, wherein the compounds of the invention are dissolved or suspended in a suitable excipient. Typical formulations suitable for ocular or ear application may be drop forms of micronized suspensions or solutions in isotonic, pH-adjusted sterile brine. Other formulations suitable for ocular and ear application include ointments, biodegradable (i.e., absorbable gel sponges, collagen) and non-biodegradable (i.e., silicone) implants, tablets, lenses, and particle or vesicle systems, such as nonionic surfactant vesicles (niosomes) or liposomes. Polymers, such as cross-linked acrylic acid, polyvinyl alcohol, hyaluronic acid, cellulose polymers (e.g., hydroxypropyl methylcellulose, hydroxyethylcellulose, or methylcellulose), or heteropolysaccharide polymers (e.g., gelatan gum), can be combined with preservatives (e.g., benzalkonium chloride). These formulations can also be delivered by iontophoresis.

For intranasal administration, the compound of the invention can be conveniently delivered in the form of a solution or suspension from a pump-type spray container (squeezed or pumped by the patient), or in the form of an atomizing spray from a pressurized container or atomizer, using an appropriate propellant. Formulations suitable for intranasal administration are typically administered as dry powder (alone or in mixtures, such as in a dry admixture with lactose, or as a mixture of component particles, such as with phospholipids, like phosphatidylcholine) from a dry powder inhaler or as a nebulizer spray from a pressurized container, pump, sprayer, nebulizer (preferably one that uses hydrodynamics to generate a fine mist) or spray nozzle, with or without suitable propellants such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. For intranasal use, the powder may contain a bio-adhesive, such as chitosan or cyclodextrin.

In another embodiment, the invention includes rectal formulations. These rectal formulations may be, for example, suppositories. Cocoa butter is a traditional suppository base, but various alternatives may be used as needed.

Other excipients and administration methods known in pharmaceutical technology may also be used. The pharmaceutical composition of the present invention can be prepared by any well-known pharmaceutical technique, such as effective formulation and administration procedures. The above considerations regarding effective formulation and administration procedures are well known in the art and are described in standard textbooks. Drug formulation is discussed in the following references, for example: Ansel, Howard C., et al ., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al . Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005; Stahl, P. Heinrich and Camilli G. Wermuth, Eds. Handbook of Pharmaceutical Salts: Properties, Selection, and Use. New York: Wiley-VCH, 2011; and Brittany, Harry G., Ed. Polymorphism in Pharmaceutical Solids. New York: Informa Healthcare USA, Inc., 2016.

Acceptable excipients are non-toxic to subjects at the dosage and concentration used and may contain one or more of the following: 1) buffers, such as phosphates, citrates or other organic acids; 2) salts, such as sodium chloride; 3) antioxidants, such as ascorbic acid or methionine; 4) preservatives, such as octadecyl dimethyl benzyl ammonium chloride, etc. 5) Alkyl hydroxybenzoate, such as methyl or propyl hydroxybenzoate, catechol, resorcinol, cyclohexanol, 3-pentanol, or m-cresol; 6) Low molecular weight (less than about 10 residues) polypeptides; 7) Proteins, such as serum albumin, gelatin. 8) Immunoglobulins; 9) Hydrophilic polymers, such as polyvinylpyrrolidone; 10) Amino acids, such as glycine, glutamic acid, asparagine, histidine, arginine, or lysine; 11) Monosaccharides, disaccharides, or other carbohydrates, including glucose, mannose, or dextrin; 12) Chelating agents, such as EDTA; 13) Sugars, such as sucrose, mannitol, trehalose, or sorbitol; 14) Salt-forming counterions, such as sodium, metal complexes (e.g., zinc-protein complexes), or 15) Nonionic surfactants, such as polysorbates (e.g., polysorbate 20 or polysorbate 80), poloxamer, or polyethylene glycol (PEG).

For oral administration, the formulation may be provided to the patient in tablet or capsule form, containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 75.0, 100, 125, 150, 175, 200, 250, or 500 mg of the active ingredient for symptom adjustment. The drug typically contains about 0.01 mg to about 500 mg, about 0.01 mg to about 100 mg, about 1.0 mg to about 20.0 mg, or about 5.0 mg to about 10.0 mg of the active ingredient, or in another embodiment, about 1 mg to about 100 mg of the active ingredient. For intravenous administration, the dose range can be approximately 0.01 to approximately 10 mg/kg/min during a constant rate of infusion.

In some embodiments, the oral composition of the present invention (e.g., tablets or capsules) contains about 0.01, about 0.05, about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 1.0, about 1.5, about 2.0, about 2.5, about 3.0, about 3.5, about 4.0, about 4.5, about 5.0, about 5.5, about 6.0, about 6.5, or about 7.0. , about 7.5, about 8.0, about 8.5, about 9.0, about 9.5, about 10.0, about 10.5, about 11.0, about 11.5, about 12.0, about 12.5, about 13 .0, about 13.5, about 14.0, about 14.5, about 15.0, about 15.5, about 16.0, about 16.5, about 17.0, about 17.5, about 18.0, about 18 0.5, approximately 19.0, approximately 19.5, approximately 20.0, approximately 21.0, approximately 22.0, approximately 23.0, approximately 24.0, approximately 25.0, approximately 30.0, approximately 35.0, approximately 40.0, approximately 45.0, approximately 50.0, approximately 75.0, approximately 100, approximately 125, approximately 150, approximately 175, approximately 200, approximately 250, approximately 500, approximately 0.01 to 0.0 5. Approximately 0.05 to approximately 0.1, approximately 0.1 to approximately 0.5, approximately 0.5 to approximately 1.0, approximately 1.0 to approximately 2.0, approximately 2.0 to approximately 20.0, approximately 2.0 to approximately 10.0, approximately 4.0 to approximately 8.0, approximately 5.0 to approximately 10.0, approximately 6.0 to approximately 10.0, approximately 6.0 to approximately 8.0, approximately 10.0 to approximately 15.0, or approximately 15.0 to approximately 20.0 mg of the active ingredient (e.g., compounds of the present invention, such as L-lysine of compound 1, or form 1 or form 2 thereof; or L-arginine of compound 1, or form 1 thereof). In some further embodiments, the oral composition of the present invention is administered to a patient (e.g., a human) once or twice daily. In some further embodiments, the oral composition of the invention is administered to a patient (e.g., a human) once daily.

In some embodiments, the oral formulation of the present invention (e.g., tablets or capsules) contains a compound of the present invention (e.g., L-lysine of compound 1, or form 1 or form 2 thereof; or L-arginine of compound 1, or form 1 thereof), in an amount equivalent to about 0.01, about 0.05, about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 1.0, about 1.5, about 2.0, or about 2.5). , about 3.0, about 3.5, about 4.0, about 4.5, about 5.0, about 5.5, about 6.0, about 6.5, about 7.0, about 7.5, about 8.0, about 8.5, about 9.0, about 9.5, about 1 0.0, about 10.5, about 11.0, about 11.5, about 12.0, about 12.5, about 13.0, about 13.5, about 14.0, about 14.5, about 15.0, about 15.5, about 16 .0, about 16.5, about 17.0, about 17.5, about 18.0, about 18.5, about 19.0, about 19.5, about 20.0, about 21.0, about 22.0, about 23.0, about 24. 0, about 25.0, about 30.0, about 35.0, about 40.0, about 45.0, about 50.0, about 75.0, about 100, about 125, about 150, about 175, about 200, about 250 Compound 1 is present in doses of approximately 500, approximately 0.01 to 0.05, approximately 0.05 to approximately 0.1, approximately 0.1 to approximately 0.5, approximately 0.5 to approximately 1.0, approximately 1.0 to approximately 2.0, approximately 2.0 to approximately 20.0, approximately 2.0 to approximately 10.0, approximately 4.0 to approximately 8.0, approximately 5.0 to approximately 10.0, approximately 6.0 to approximately 10.0, approximately 6.0 to approximately 8.0, approximately 10.0 to approximately 15.0, or approximately 15.0 to approximately 20.0 mg. In some further embodiments, the oral composition of the invention is administered to a patient (e.g., a human) once or twice daily. In some even further embodiments, the oral composition of the invention is administered to a patient (e.g., a human) once daily.

The liposome-containing compounds of this invention can be prepared by methods known in this art (see, for example, Chang, H.I.; Yeh, M.K.; Clinical development of liposome-based drugs: formulation, characterization, and therapeutic efficacy; Int J Nanomedicine 2012; 7; 49-60). Particularly useful liposomes can be produced by reverse-phase evaporation using a lipid composition comprising phosphatidylcholine, cholesterol, and PEG-derived phosphatidylethanolamine (PEG-PE). The liposomes are extruded through a filter with defined pore sizes to produce liposomes with the desired diameter.

The compounds of this invention can also be encapsulated in microcapsules, which are prepared by, for example, coagulation techniques or interfacial polymerization, such as hydroxymethyl cellulose or gelatin microcapsules and poly(methyl methacrylate) microcapsules in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or macroemulsions. These techniques are disclosed in Remington, The Science and Practice of Pharmacy, 20th Ed., Mack Publishing (2000).

Sustained-release formulations may be used. Suitable examples of sustained-release formulations include semi-permeable matrices containing solid hydrophobic polymers of the present invention, in the form of molded articles, such as films or microcapsules. Suitable examples of sustained-release matrices include polyesters, hydrogels (e.g., poly(2-hydroxyethyl-methyl acrylate) or poly(vinyl alcohol)), polylactic acid, copolymers of L-glutamic acid and 7-ethyl-L-glutamic acid, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers, such as those used in leuprolide sustained-release suspensions (injectable microspheres composed of lactic acid-glycolic acid copolymers and leuprolide acetate), sucrose isobutyrate acetate, and poly-D-(-)-3-hydroxybutyrate.

Preparations intended for intravenous administration must be sterile. This can be easily achieved, for example, by filtration through a sterile filtration membrane. The compounds of this invention are typically placed in containers with sterile access ports, such as intravenous solution bags or vials with stoppers that can be punctured by a hypodermic needle.

Suitable emulsions can be prepared using commercially available fat emulsions, such as fat emulsions containing soybean oil, fat emulsions for intravenous administration (e.g., containing safflower oil, soybean oil, lecithin, and glycerin in water), emulsions containing soybean oil and medium-chain triglycerides, and fat emulsions containing cottonseed oil. The active ingredient can be dissolved in a pre-mixed emulsion composition, or it can be dissolved in an oil (e.g., soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil, or almond oil), and then mixed with phospholipids (e.g., lecithin, soybean lecithin, or soybean lecithin) and water to form an emulsion. It should be understood that other ingredients, such as glycerin or glucose, can be added to adjust the emulsion's tension. Suitable emulsions typically contain up to 20% oil, for example, between 5% and 20%. The fat emulsion may contain fat droplets ranging from 0.1 to 1.0 μm, particularly from 0.1 to 0.5 μm, and its pH value is in the range of 5.5 to 8.0.

For example, the emulsion composition may be prepared by mixing the compound of the present invention with a lipid emulsion containing soybean oil or its components (soybean oil, lecithin, glycerol and water).

Compositions intended for inhalation or inhalation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, as well as powders. The liquid or solid composition may contain suitable pharmaceutically acceptable excipients as listed above. In some embodiments, the composition may be administered via oral or nasal breathing to achieve local or systemic effects. Preferably, compositions in sterile, pharmaceutically acceptable solvents may be nebulized using a gas. The nebulized solution may be inhaled directly from the nebulizer, or the nebulizer may be connected to a face mask, tent hood, or intermittent positive pressure respirator. The solution, suspension or powder composition may be administered from a device capable of delivering the formulation in an appropriate manner, preferably by oral or nasal administration.

Pharmaceutical product intermediates (DPIs) are partially processed raw materials that require further processing steps before becoming bulk pharmaceutical products. The compounds of this invention can be formulated into pharmaceutical intermediate DPIs containing active ingredients in a higher free energy form than their crystalline counterparts. One reason for using DPIs is to improve oral absorption characteristics due to low solubility and slow dissolution, enhancing transport of the substance through the mucus layer adjacent to epithelial cells, and in some cases, overcoming limitations imposed by biological barriers (such as metabolic and transport proteins). Other reasons may include improved solid-state stability and downstream manufacturability. In one embodiment, the pharmaceutical intermediate contains a stable, isolated, amorphous form of the compound of this invention (e.g., an amorphous solid dispersion (ASD)). This art is familiar with many techniques for manufacturing ASDs that produce substances suitable for integration into bulk pharmaceutical products, such as spray-dried dispersions (SDDs), melt extrusions (commonly referred to as HMEs), co-precipitates, amorphous drug nanoparticles, and nanoadsorbents. In one embodiment, the amorphous solid dispersion comprises the compound of the invention and a polymeric excipient. Other excipients and the concentrations of these excipients and the compound of the invention are well known in this art and described in standard textbooks. See, for example, Navnit Shah et al. , Amorphous Solid Dispersions Theory and Practice .

The pharmaceutical composition may be in a form suitable for oral administration, such as tablets, capsules, pills, powders, sustained-release formulations, solutions or suspensions, sterile solutions, suspensions or emulsions for parenteral injection, ointments or creams for topical administration, or suppositories for rectal administration.

Exemplary parenteral administration forms include solutions or suspensions of the active compound in sterile aqueous solutions (e.g., aqueous propylene glycol solution or dextrose solution). Such dosage forms may be appropriately buffered if necessary.

The pharmaceutical composition can be a unit dosage form suitable for a single, precise dose. Those skilled in the art will understand that the composition can be formulated into subtherapeutic doses, thereby enabling the formulation of multiple doses.

In one embodiment, the composition comprises (a therapeutically effective amount) a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. Administration and delivery.

The terms “treating,” “treatment,” or “treatment” as used in this article include both preventative (i.e., preventive) treatment and palliative treatment, that is, relieving, reducing, or slowing the progression of the patient’s disease (or condition) or any tissue damage associated with the disease.

As used herein, the terms "subject," "individual," or "patient" are used interchangeably and refer to any animal, including mammals. Mammals according to this invention include canines, felines, bovines, capillaries, equines, sheep, pigs, rodents, rabbits, primates, humans, and include intrauterine mammals. In one embodiment, humans are suitable subjects. Human subjects may be of any sex and may be at any stage of development.

As used herein, "therapeutic effective amount" refers to an amount of an active compound or drug that can elicit a biological or medical response sought by researchers, veterinarians, physicians or other clinicians in a tissue, system, animal, individual or human body, which may include one or more of the following: (1) prevention of a condition, disease or symptom; for example, prevention of a condition in individuals who may be susceptible to the condition, disease or symptom but have not yet experienced or shown the pathology or symptoms of the disease, (1) Disease or symptom; (2) Suppressing a disease or symptom; for example, suppressing the disease, symptom or symptom in an individual who is experiencing or exhibiting the pathology or symptoms of the disease, symptom or symptom [i.e., halting (or slowing) the pathology or symptoms or both]; and (3) Improving a disease or symptom; for example, improving the disease, symptom or symptom in an individual who is experiencing or exhibiting the pathology or symptoms of the disease, symptom or symptom [i.e., reversing the pathology or symptoms or both].

Typically, the compounds of this invention are administered in an amount effective in treating the condition, disease, or ailment described herein. The compounds of this invention may be administered in free form or in the form of a pharmaceutically acceptable salt. For administration and drug delivery purposes, the free form of the compound or its pharmaceutically acceptable salt will be simply referred to as the compound of this invention.

The compounds of the present invention are administered by any suitable route, in a pharmaceutical composition suitable for such route, and at a dose effective for the desired treatment. Administration of the compounds of the present invention may be carried out by any systemic and/or local delivery method. The compounds of the present invention may be administered orally, rectally, vaginally, parenterally (including, for example, intravenously, subcutaneously, intramuscularly, intravascularly, or by infusion), locally, intranasally, or by inhalation.

The compound of the present invention can be administered orally. Oral administration may involve swallowing, thereby allowing the compound to enter the gastrointestinal tract, or it may be administered via the cheek or sublingual route, thereby allowing the compound to enter the bloodstream directly from the mouth.

In another embodiment, the compounds of the invention can also be administered parenterally, for example, directly to the bloodstream, muscles, or internal organs. Suitable methods of parenterally administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, and subcutaneous administration. Suitable devices for parenterally administration include needle (including microneedle) injectors, needle-free injectors, and infusion techniques.

In another embodiment, the compound of the invention may also be applied topically to the skin or mucous membranes, i.e., via the dermis or transdermal application. In another embodiment, the compound of the invention may also be administered via the nose or inhalation. In another embodiment, the compound of the invention may be administered via the rectum or vagina. In another embodiment, the compound of the invention may also be applied directly to the eyes or ears.

The dosage regimens of the compounds of the present invention or compositions containing such compounds are based on a variety of factors, including the patient's type, age, weight, sex, and medical condition; the severity of the condition; the route of administration; and the activity of the specific compound used. Therefore, the dosage regimens can vary considerably. In one embodiment, the total daily dose of the compounds of the present invention for the treatment of the indications discussed herein is typically from about 0.0001 to about 100 mg/kg (i.e., mg of the compounds of the present invention per kilogram of body weight). In another embodiment, the total daily dose of the compounds of the present invention is from about 0.01 to about 50 mg/kg; in another embodiment, it is from about 0.1 to about 50 mg/kg; and in yet another embodiment, it is from about 0.5 to about 30 mg/kg. It is not uncommon to administer the compound of this invention multiple times a day (usually no more than four times). If necessary, multiple daily doses can usually be used to increase the total daily dose. Methods and Uses

Another embodiment of the invention includes using the compounds of the invention as a medicine, particularly where the medicine is used to treat or prevent GIPR-related conditions, diseases or symptoms, including administration to mammals (such as humans) in need of such treatment.

Another embodiment of the invention includes using the compounds of the invention as a medicine, particularly where the medicine is used to treat or prevent GIPR-related conditions, diseases or symptoms, including administration to mammals (such as humans) in need of such treatment.

Another embodiment of the invention includes using the compounds of the invention to manufacture drugs for the treatment or prevention of GIPR-related conditions, diseases, or symptoms, including administering therapeutically effective amounts to mammals (such as humans) in need of such treatment.

Another embodiment of the invention includes using the compounds of the invention as a drug, particularly wherein the drug is used to treat or prevent conditions, diseases, or illnesses selected from the following: diabetes [e.g., type 1 diabetes (T1D), type 2 diabetes (T2DM), including prediabetes], idiopathic T1D (type 1b), latent autoimmune diabetes mellitus in adults (LADA), early-onset T2DM (EOD), adolescent atypical diabetes (YOAD), juvenile adult-onset diabetes (MODY), malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, glucose intolerance, diabetic neuropathy, diabetic nephropathy, renal diseases [e.g., acute nephropathy] [Diseases, renal tubular dysfunction, pro-inflammatory changes in the proximal tubules or chronic nephropathy (CKD)], diabetic retinopathy, adipocyte dysfunction, visceral fat deposition, sleep apnea [e.g., obstructive sleep apnea (OSA)], obesity (including hypothalamic obesity and monogenic obesity) and related complications (e.g., osteoarthritis and urinary incontinence), eating disorders (including bulimia syndrome, bulimia nervosa, and syndrome obesity, such as Prader-Willi syndrome and Budd-Bieder syndrome), weight gain, such as weight gain caused by the use of other medications (e.g., due to the use of steroids and/or antipsychotics, or due to the treatment of depression, or due to the use of medications that affect cognitive function). Excessive sugar cravings, dyslipidemia [including hyperlipidemia, hypertriglyceridemia, elevated total cholesterol, high LDL (low-density lipoprotein) cholesterol and low HDL (high-density lipoprotein) cholesterol], hyperinsulinemia, non-alcoholic fatty liver disease [NAFLD, including diseases such as steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis and hepatocellular carcinoma], cardiovascular disease, atherosclerosis (including coronary artery disease), peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, heart failure [e.g. congestive heart failure, heart failure with preserved ejection rate (HFpEF), heart failure with reduced ejection rate (HFrEF)], myocardial infarction (e.g., necrosis and apoptosis), stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, osteoarthritis, Parkinson's disease, left ventricular hypertrophy, peripheral arterial disease (PAD), macular degeneration, cataract, kidney disease. Glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina, thrombosis, atherosclerosis, transient ischemic attack, restenosis, impaired glucose metabolism, abnormal fasting blood glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders, psoriasis, foot ulcers, ulcerative colitis, hyperapoB lipoproteinemia, Alzheimer's disease, schizophrenia, cognitive impairment, inflammatory bowel disease, short bowel syndrome, Crohn's disease, colitis, irritable bowel syndrome, polycystic ovary syndrome (PCOS), and addiction (e.g., alcohol, nicotine, and/or drug addiction).

Another embodiment of the invention includes using the compounds of the invention as a drug, particularly wherein the drug is used to treat or prevent conditions, diseases, or illnesses selected from the following: diabetes [e.g., type 1 diabetes (T1D), type 2 diabetes (T2DM), including prediabetes], idiopathic T1D (type 1b), latent autoimmune diabetes mellitus in adults (LADA), early-onset T2DM (EOD), adolescent atypical diabetes (YOAD), juvenile adult-onset diabetes (MODY), malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, glucose intolerance, diabetic neuropathy, diabetic nephropathy, renal diseases [e.g., acute nephropathy] [Diseases, renal tubular dysfunction, pro-inflammatory changes in the proximal tubules or chronic nephropathy (CKD)], diabetic retinopathy, adipocyte dysfunction, visceral fat deposition, sleep apnea [e.g., obstructive sleep apnea (OSA)], obesity (including hypothalamic obesity and monogenic obesity) and related complications (e.g., osteoarthritis and urinary incontinence), eating disorders (including bulimia syndrome, bulimia nervosa, and syndrome obesity, such as Prader-Willi syndrome and Budd-Bieder syndrome), weight gain, such as weight gain caused by the use of other medications (e.g., due to the use of steroids and/or antipsychotics, or due to the treatment of depression, or due to the use of medications that affect cognitive function). Excessive sugar cravings, dyslipidemia [including hyperlipidemia, hypertriglyceridemia, elevated total cholesterol, high LDL (low-density lipoprotein) cholesterol and low HDL (high-density lipoprotein) cholesterol], hyperinsulinemia, non-alcoholic fatty liver disease [NAFLD, including diseases such as steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis and hepatocellular carcinoma], cardiovascular disease, atherosclerosis (including coronary artery disease), peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, heart failure [e.g. congestive heart failure, heart failure with preserved ejection rate (HFpEF), heart failure with reduced ejection rate (HFrEF)], myocardial infarction (e.g., necrosis and apoptosis), stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, osteoarthritis, Parkinson's disease, left ventricular hypertrophy, peripheral arterial disease (PAD), macular degeneration, cataract, kidney disease. Glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina, thrombosis, atherosclerosis, transient ischemic attack, restenosis, impaired glucose metabolism, abnormal fasting blood glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders, psoriasis, foot ulcers, ulcerative colitis, hyperapoB lipoproteinemia, Alzheimer's disease, schizophrenia, cognitive impairment, inflammatory bowel disease, short bowel syndrome, Crohn's disease, colitis, irritable bowel syndrome, polycystic ovary syndrome (PCOS), and addiction (e.g., alcohol, nicotine, and/or drug addiction).

Another embodiment of the invention includes the use of the compounds of the invention in the manufacture of a pharmaceutical for the treatment or prevention of conditions, diseases, or illnesses selected from the following: diabetes [e.g., type 1 diabetes (T1D), type 2 diabetes (T2DM), including prediabetes], idiopathic T1D (type 1b), latent autoimmune diabetes mellitus in adults (LADA), early-onset T2DM (EOD), adolescent atypical diabetes (YOAD), juvenile adult-onset diabetes (MODY), malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, glucose intolerance, diabetic neuropathy, diabetic nephropathy, and renal diseases [e.g., acute nephropathy]. [Renal tubular dysfunction, pro-inflammatory changes in the proximal tubules, or chronic nephropathy (CKD)], diabetic retinopathy, adipocyte dysfunction, visceral fat deposition, sleep apnea [e.g., obstructive sleep apnea (OSA)], obesity (including hypothalamic obesity and monogenic obesity) and related complications (e.g., osteoarthritis and urinary incontinence), eating disorders (including bulimia syndrome, bulimia nervosa, and syndrome obesity, such as Prader-Willi syndrome and Budd-Bieder syndrome), weight gain, such as weight gain caused by the use of other medications (e.g., due to the use of steroids and/or antipsychotics, or due to the treatment of depression, or due to the use of medications that affect cognitive function). Excessive sugar cravings, dyslipidemia [including hyperlipidemia, hypertriglyceridemia, elevated total cholesterol, high LDL (low-density lipoprotein) cholesterol and low HDL (high-density lipoprotein) cholesterol], hyperinsulinemia, non-alcoholic fatty liver disease [NAFLD, including diseases such as steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis and hepatocellular carcinoma], cardiovascular disease, atherosclerosis (including coronary artery disease), peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, heart failure [e.g., congestive heart failure, heart failure with preserved ejection rate (HFpEF), heart failure with reduced ejection rate (HFrEF)], myocardial infarction (e.g., necrosis and apoptosis), stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, osteoarthritis, Parkinson's disease, left ventricular hypertrophy, peripheral arterial disease (PAD), macular degeneration, cataract, kidney disease. Glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina, thrombosis, atherosclerosis, transient ischemic attack, restenosis, impaired glucose metabolism, abnormal fasting blood glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders, psoriasis, foot ulcers, ulcerative colitis, hyperapoB lipoproteinemia, Alzheimer's disease, schizophrenia, cognitive impairment, inflammatory bowel disease, short bowel syndrome, Crohn's disease, colitis, irritable bowel syndrome, polycystic ovary syndrome (PCOS), and addiction (e.g., alcohol, nicotine, and/or drug addiction).

In some further embodiments of the methods and uses of the invention described herein, the conditions, diseases or symptoms that may be treated or prevented according to the invention are selected from obesity, type 2 diabetes mellitus (T2DM), heart failure (e.g., HFpEF and HFrEF); CKD; NAFLD, NASH, atherosclerosis, PAD, obstructive sleep apnea, diabetic retinopathy and diabetic neuropathy.

The compounds of this invention are GIPR antagonists. Therefore, this invention further provides a method for regulating (e.g., antagonizing) GIPR (intratubally or in vivo), comprising contacting (including incubation) the GIPR with a compound of Formula I described herein or a pharmaceutically acceptable salt thereof (such as selected from Examples 1 to 229 herein).

In some embodiments, the amount of the compound of the invention used in any method (or application) of the invention is sufficient to effectively antagonize GIPR. Stereoisomer

The compounds of this invention may contain asymmetric or chiral centers, and therefore, two or more stereoisomers exist. Unless otherwise stated, all stereoisomers of the compounds of this invention, and mixtures thereof (including racemic mixtures), are intended to form part of this invention. Furthermore, this invention covers all geometric and positional isomers. For example, if the compounds of this invention incorporate double bonds or fused rings, both the cis and trans forms, as well as mixtures thereof, are covered within the scope of this invention.

The pharmaceutically acceptable salts of the compounds of this invention may also contain optically active (e.g., D-lactic acid or L-lysine) or racemic (e.g., DL-tartaric acid or DL-arginine) counterions.

This includes all stereoisomers, geometric isomers, and tautomers of the compounds of the present invention within the scope of the compounds claimed in this invention application, including compounds exhibiting more than one type of isomer, and mixtures thereof. It also includes acid addition salts or bases wherein the counterion is photoactive, such as D-lactate or L-lysine, or racemic, such as DL-tartrate or DL-arginine. Tautomerism

When structural isomers can interconvert through a low-energy barrier, tautomerism ("tautomerism") can occur. This may occur as proton tautomerism in compounds of the present invention containing, for example, imine/amine, ketone/enol, or oxime/nitroso groups, or lactamine/lactiimine, or as valence tautomerism in compounds containing aromatic moieties. Therefore, a single compound may exhibit more than one type of isomerism.

It must be emphasized that, although for the sake of brevity, the compounds of the present invention are illustrated herein in a single tautomer form, all possible tautomer forms are included within the scope of the present invention.

The intermediates and compounds of this invention may exist in different tautomer forms, and all such forms are encompassed within the scope of this invention. The terms "tautomer" or "tautomer form" refer to structural isomers with different energies that can interconvert through a low-energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions that occur via proton transfer, such as keto-enol isomerization and imine-enamine isomerization.

Valence tautomers are isomers that undergo interconversion by rearranging some of their bonding electrons. Isotopes

This invention includes all pharmaceutically acceptable isotopically labeled compounds of the invention, wherein one or more atoms are replaced by atoms having the same atomic number but with an atomic mass or mass number different from those found in nature.

Examples of isotopes suitable for inclusion in compounds of the present invention (compound 1 or its pharmaceutically acceptable salts, such as L-lysine or L-arginine of compound 1) include isotopes of hydrogen, such as ^2H and ^3H ; isotopes of carbon, such as ^11C , ^13C and ^14C ; isotopes of chlorine, such as ^36Cl ; isotopes of fluorine, such as ^18F ; isotopes of iodine, such as ^123I , ^124I and ^125I ; isotopes of nitrogen, such as ^13N and ^15N ; isotopes of oxygen, such as ^15O , ^17O and ^18O ; isotopes of phosphorus, such as ^32P ; and isotopes of sulfur, such as ^35S .

In some embodiments, this disclosure provides deuterated (or deuterated) compounds and salts, wherein the chemical formulas and variables of such compounds and salts are independent as described herein. "Deuterated" means that at least one atom in the compound is deuterium, with an abundance higher than the natural abundance of deuterium (typically about 0.015%). Those skilled in the art will recognize that in compounds containing hydrogen atoms, the hydrogen atom actually represents a mixture of H and D, with about 0.015% being D. The concentration of deuterium incorporated into the deuterated compounds and salts of this invention can be defined by a deuterium enrichment factor. It is understood that under physiological conditions, one or more deuterium atoms may exchange with hydrogen.

In some embodiments, the deuterium compound is selected from any of the compounds listed in Table X-1 shown in the embodiments section. In some embodiments, one or more hydrogen atoms at certain metabolic sites on the compound of the invention are deuterated. In some embodiments, one or more of the deuterium compounds in Table X-1 can be converted into their pharmaceutically acceptable salts, such as L-lysine or L-arginine.

Certain isotopically labeled compounds 1 or their salts (e.g., L-lysine or L-arginine of compound 1) (e.g., those incorporating radioisotopes) can be used for drug and/or recipient tissue distribution studies. Given that the radioisotopes tritium (i.e., ^3H ) and carbon-14 (i.e., ^14C ) are readily incorporated and easily detected, they are particularly suitable for this purpose.

Substitution with heavier isotopes, such as deuterium (i.e., ^2H ), can provide certain therapeutic advantages due to higher metabolic stability (e.g., increased in vivo half-life or reduced dose requirements), and therefore may be superior in some cases.

In some embodiments, this disclosure provides deuterated (or deuterated) compounds and salts, wherein the chemical formulas and variables of such compounds and salts are independent as described herein. "Deuterated" means that at least one atom in the compound is deuterium, with an abundance higher than the natural abundance of deuterium (typically about 0.015%). Those skilled in the art will recognize that in compounds containing hydrogen atoms, the hydrogen atom actually represents a mixture of H and D, with about 0.015% being D. The concentration of deuterium incorporated into the deuterated compounds and salts of this invention can be defined by a deuterium enrichment factor. It is understood that under physiological conditions, one or more deuterium atoms may exchange with hydrogen.

In some embodiments, one or more hydrogen atoms at certain metabolic sites on the compound of the invention may be deuterated. MetaSite (moldiscovery.com/software/metasite/) may be helpful in predicting certain metabolic sites on the compound of the invention.

Substitution using isotopes of positron emission (such as ^11C , ^18F , ^15O , and ^13N ) can be used in positron emission tomography (PET) studies to examine mass acceptor occupancy.

The isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described in the accompanying embodiments and preparation methods, using appropriate isotopically labeled reagents instead of previously used unlabeled reagents.

Pharmaceutically acceptable solvent compounds (including hydrates) according to the present invention include those in which the crystalline solvent may be an isotopically substituted solvent (e.g., _D₂O , d₆-acetone, d₆-DMSO). Salts

The compounds of this invention can be used directly after separation , or, where possible, in the form of pharmaceutically acceptable salts. The term "salt" refers to both inorganic and organic salts of the compounds of this invention. These salts can be prepared in situ during the final separation and purification of the compound, or by treating the compound separately with a suitable organic or inorganic acid or alkali and separating the salts formed therefrom.

The pharmaceutically acceptable salts of the compounds of the present invention can be prepared by methods skilled in the art, including, but not limited to, the following steps: (i) reacting the compounds of the present invention with a desired acid or base; (ii) removing the acid or base unstable protecting group from a suitable precursor of the compounds of the present invention using the desired acid or base, or ring-opening a suitable cyclic precursor (e.g., lactone or lactamine) using the desired acid or base; or (iii) converting one salt of the compounds of the present invention into another salt. This can be achieved by reaction with a suitable acid or base or by a suitable ion exchange procedure.

These procedures are typically carried out in solution. The resulting salts can be precipitated and collected by filtration or recovered by solvent evaporation. Solvent compounds

The compounds of this invention may exist in either solvent-free or solvent-based forms. The term "solvent compound" as used herein is used to describe molecular complexes comprising the compounds of this invention and one or more pharmaceutically acceptable solvent molecules (e.g., ethanol). The term "hydrate" may be used when the solvent is water.

Furthermore, the compounds of the present invention may also include other solvent compounds of such compounds, which are not necessarily pharmaceutically acceptable solvent compounds and may serve as one or more of the following intermediates: 1) preparation of compound 1 or its ionized amino acid salt; 2) purification of compound 1 or its ionized amino acid salt; 3) separation of compound 1 or its ionized amino acid salt; or 4) separation of diastereomeric isomers of compound 1 or its ionized amino acid salt.

The currently accepted classification system for organic hydrates defines them as separation sites, channels, or metal ion coordination hydrates – see K.R. Morris, *Polymorphism in Pharmaceutical Solids* (Ed. H. G. Brittain, Marcel Dekker, 1995). Separation site hydrates are those in which the water molecule is separated by intercalation into an organic molecule and does not directly contact it. In channel hydrates, the water molecule is located in a lattice channel, adjacent to other water molecules. In metal ion coordination hydrates, the water molecule is bound to a metal ion.

When the solvent or water is tightly bound, the complex may have a well-defined stoichiometry independent of humidity. However, when the binding force between the solvent or water is weak (as in channel solvent compounds and hygroscopic compounds), the water/solvent content may depend on humidity and drying conditions. In such cases, a non-stoichiometric ratio becomes the norm.

The scope of this invention also includes multicomponent complexes (other than salt and solvent complexes) wherein the drug and at least one other component are present in stoichiometric or non-stoichiometric amounts. This type of complex includes clathrates (drug-host inclusion complexes) and eutectics. The latter is generally defined as a crystalline complex of neutral molecular components bound together by non-covalent interactions, but can also be a complex of a neutral molecule and a salt. Eutectics can be prepared by melt crystallization, by recrystallization from a solvent, or by physically grinding the components together – see O. Almarsson and MJ Zaworotko, Chem. Commun ., 17, 1889-1896 (2004). For a general overview of multicomponent complexes, see Haleblian, J. Pharm. Sci., 64(8), 1269-1288 (1975). Metabolites

The scope of this invention also includes active metabolites of Formula I compounds (including precursor drugs) or their pharmaceutically acceptable salts, i.e., compounds formed in vivo upon administration of the drug, typically by oxidation or dealkylation. Some examples of metabolites according to this invention include: (i) hydroxymethyl derivatives ( _-CH3 ->- _CH2OH ) where the Formula I compound or its pharmaceutically acceptable salt contains a methyl group, and (ii) hydroxyl derivatives (-OR->-OH) where the Formula I compound or its pharmaceutically acceptable salt contains an alkoxy group.

The scope of this invention also includes the active metabolites of the compounds of this invention, that is, compounds formed in the body when the drug is administered, usually formed by oxidation or dealkylation. Examples of metabolites according to the present invention include, but are not limited to: (i) hydroxyl derivatives (-CH-＞-COH) where the compound of the present invention contains an alkyl group; (ii) hydroxyl derivatives (-OR-＞-OH) where the compound of the present invention contains an alkoxy group; (iii) secondary amino derivatives (-NRR'-＞-NHR or -NHR') where the compound of the present invention contains a tertiary amino group; (iv) primary derivatives (-NHR-＞- _NH2 ) where the compound of the present invention contains a secondary amino group; (v) phenolic derivatives (-Ph-＞-PhOH) where the compound of the present invention contains a phenyl moiety; (vi) carboxylic acid derivatives ( _-CONH2- ＞COOH) where the compound of the present invention contains a amide group; and (vii) When the compounds of this invention contain a hydroxyl or carboxylic acid group, the compounds can undergo conjugation metabolism, for example, by combining with glucuronic acid to form glucuronide. Other pathways of conjugation metabolism exist. These pathways are generally referred to as second-stage metabolism and include, for example, sulfation or acetylation. Other functional groups, such as NH groups, can also undergo conjugation. Solid form

The compounds of this invention can exist in a continuous solid state, ranging from completely amorphous to completely crystalline. The term "amorphous" refers to a state in which the raw material lacks long-range order at the molecular level and may exhibit solid or liquid physical properties depending on temperature. Typically, such raw materials do not produce unique X-ray diffraction patterns and, although exhibiting solid properties, are more formally described as liquids. Upon heating, the properties change from solid to liquid, characterized by a change of state, usually a second-order change ("glass transition"). The term "crystalline" refers to a solid phase in which the substance has a regular, ordered internal structure at the molecular level and produces a unique X-ray diffraction pattern with distinct peaks. When these substances are heated sufficiently, they will also exhibit the properties of a liquid, but the change from solid to liquid is characterized by a phase change, usually a first-order phase transition ("melting point").

Under suitable conditions, the compounds of this invention can also exist in a mesomorphic state (intermediate phase or liquid crystal). This intermediate state is an intermediate between a true crystalline state and a true liquid state (melt or solution), and is composed of a two-dimensional sequence at the molecular level. Intermediate states caused by temperature changes are described as "thermotropic," while those caused by the addition of a second component (such as water or other solvents) are described as "lyotropic." Compounds with the potential to form lyotropic mesophases are described as "amphiphilic" and are composed of molecules with ionic (e.g., -COO ^- Na ⁺ , -COO ^- K ⁺ , or _-SO3 ^- Na ⁺ ) or nonionic (e.g., -N ^- N ⁺ ( _CH3 ) ₃ ) polar head groups. For more information, see Crystals and the Polarizing Microscope by NH Hartshorne and A. Stuart, ^4th Edition (Edward Arnold, 1970).

Some compounds of the present invention may exist in more than one crystalline form (commonly referred to as "polymorphs"). Polymorphs can be prepared by crystallization under various conditions, such as using different solvents or mixtures of different solvents for recrystallization; crystallization at different temperatures; and/or various cooling modes, ranging from very rapid cooling during crystallization to very slow cooling. Polymorphs can also be obtained by heating or melting the compounds of the present invention and then gradually or rapidly cooling them. The presence of polymorphs can be determined by solid-state NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray diffraction, or other such techniques.

Generally, the compounds of this invention can be prepared by methods that include those similar to those known in chemical technology, especially those described herein. Certain methods for preparing the compounds of this invention are provided as further characteristics of this invention and are illustrated by the following reaction schemes. Other processes may be described in the experimental section. Specific synthetic schemes for preparing compounds of Formula I or their pharmaceutically acceptable salts are outlined below. Note that tetrazolium is generally a high-energy functional group, and caution should be exercised when synthesizing and handling tetrazolium-containing molecules. Synthesis

The compounds of this invention can be synthesized by synthetic routes including methods similar to those known in chemical techniques, particularly as described herein. The starting materials are generally available from commercial sources or can be prepared using methods well known to those skilled in the art. Many of the compounds used herein relate to, or may be derived from, compounds from which one or more scientific or commercial interests have emerged. Therefore, such compounds may be one or more of the following: 1) commercially available; 2) reported in the literature; or 3) prepared by those skilled in the art from other common substances using starting materials reported in the literature.

For illustrative purposes, a detailed description of each reaction step is provided in the Examples section below. Those skilled in the art will understand that other synthetic routes can be used to synthesize the compounds of this invention. Although specific starting materials and reagents are discussed below, other starting materials and reagents can be used instead to provide one or more different derivatives or reaction conditions. Furthermore, given the content of this disclosure, many compounds prepared by the methods described below can be further modified using conventional chemical methods familiar to those skilled in the art.

Those skilled in the art will understand that the experimental conditions listed in the following schemes are merely illustrative of suitable conditions for enabling the illustrated transformations to take effect, and that altering the precise conditions used to prepare the compounds of the invention may be necessary or desirable. It should be further understood that performing the transformations in a different order than described in the schemes may be necessary or desirable, or that one or more of such transformations may be modified to provide the desired compounds of the invention.

When preparing the compounds of this invention, it should be noted that some preparation methods used to prepare the compounds described herein may require protection of distal functional groups (e.g., primary amines, secondary amines, carboxyl groups, etc. in the precursors of the compounds of this invention). The need for such protection will depend on the nature of the distal functional group and the conditions of the preparation method. Those skilled in the art can easily determine whether such protection is required. The use of such protection/deprotection methods is also within the scope of this technique. For a general description of protecting groups and their uses, see March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure 8th Edition.

For example, if a compound contains amine or carboxylic acid functional groups, these functional groups may interfere with the reactions at other sites of the molecule if not protected. Therefore, these functional groups can be protected by appropriate protecting groups (PGs) and then removed in subsequent steps. Suitable protecting groups for amines and carboxylic acids include those commonly used in peptide synthesis (such as N-tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), and 9-furomethoxycarbonyl (Fmoc) for amines, and lower alkyl or benzyl esters for carboxylic acids). These protecting groups are generally not chemically reactive under the stated reaction conditions and can usually be removed without altering other functional groups in the compound.

The reaction can be monitored using any suitable method known in this technique. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., ^¹H or ^¹³C ), infrared spectroscopy, spectrophotometry (e.g., UV-Vis), mass spectrometry, or by chromatographic analysis (e.g., high performance liquid chromatography (HPLC) or thin-layer chromatography (TLC)).

The compounds of this invention can be prepared according to the following reaction schemes and accompanying discussion. The following reaction schemes are intended to provide a general description of the methodology used to prepare the compounds of this invention. Some compounds of this invention contain a single chiral center with a stereochemical name (R or S), while other compounds will contain two separate chiral centers with stereochemical names (R or S). Those skilled in the art will readily understand that most synthetic transformations can be carried out in a similar manner, regardless of whether the starting material is enantiomerically enriched or racemic. Furthermore, the resolution of the desired optically active starting material can be performed at any desired point in the sequence using methods well-known as described herein and in chemical literature.

Generally, the compounds of this invention can be prepared by the methods described herein and similar methods known to those skilled in the art. Some methods for preparing the compounds of this invention are described in the following reaction schemes. Other processes are described in the experimental section. The schemes and examples provided herein (including corresponding descriptions) are for illustrative purposes only. Those skilled in the art will recognize that the intermediates and compounds of this invention prepared according to the following schemes can be isolated in salt or non-salt form depending on the reaction, separation, or purification conditions. Those skilled in the art will also recognize that in some cases, additional synthetic steps may be required to protect and deprotect certain functional groups present within the synthetic sequence. Those skilled in the art will further recognize that, in other cases, certain functional groups can be carried by the described synthetic sequence and then transformed into alternative substituents present in the compounds of the present invention.

Detailed descriptions of the individual reaction steps are provided in the following embodiments section. Those skilled in the art will understand that other synthetic routes can be used to synthesize this compound. Although specific starting materials and reagents have been discussed below, other starting materials and reagents can be readily substituted to provide various derivatives and/or reaction conditions. Furthermore, many compounds prepared by the methods described below can be further modified using conventional chemical methods familiar to those skilled in the art, based on this disclosure.

The compounds of this invention may be used alone or in combination with one or more other therapeutic agents. This invention provides for any use, method or composition as defined herein, wherein the compounds of this invention or their pharmaceutically acceptable salts are used in combination with one or more other therapeutic agents discussed herein.

"Combined" administration of two or more compounds means that all compounds are administered at sufficiently close times to affect the subject's treatment. The two or more compounds may be administered simultaneously or sequentially via the same or different routes of administration, at the same or different time schedules, and may or may not have specific time restrictions depending on the treatment regimen. Alternatively, simultaneous administration may be achieved by mixing the compounds before administration or by administering the compounds at the same time point, but in separate dosage forms, at the same or different application sites. Examples of "combined" administration include, but are not limited to, "concurrent administration," "joint administration," "simultaneous administration," "sequential administration," and "simultaneous administration."

The compounds of the present invention and one or more other therapeutic agents may be administered in fixed or non-fixed combinations of the active ingredient. The term "fixed combination" means that the compounds of the present invention or their pharmaceutically acceptable salts, and one or more therapeutic agents are administered simultaneously to a subject in a single composition or dosage. The term "non-fixed combination" means that the compounds of the present invention or their pharmaceutically acceptable salts, and one or more therapeutic agents are formulated as separate compositions or dosages, so that they can be administered simultaneously or at different times with variable intermediate time limits to a subject in need, wherein such administration can provide effective levels of two or more compounds in the subject's body.

The combination drug is administered to a patient (e.g., a mammal or a human) at a therapeutically effective amount. "Therapeutically effective amount" means the amount of the compound of the invention that is effective in treating the desired disease/condition/condition (e.g., T2DM or obesity) when administered alone or in combination with other treatments to a mammal.

In some embodiments, the compounds of the present invention may be administered in combination with one or more other agents, such as orlistat, TZD and other insulin sensitizers, FGF21 analogs, metformin, ethyl omega-3-acid (e.g., Lovaza), fibrate derivatives, HMG CoA reductase inhibitors, ezetimibe, probucol, ursodeoxycholic acid, TGR5 agonists, FXR agonists, vitamin E, betaine, pentoxifylline, CB1 antagonists, carnitine, N... - Acetylcysteine, reduced glutathione, lorcaserin, combinations of naltrexone and buproprion, SGLT2 inhibitors (including dapagliflozin, canagliflozin, empagliflozin, tofogliflozin, ertugliflozin), ASP-1941, T HR1474, TS-071, ISIS388626, LX4211, and WO2010023594), phentermine, topiramate, GLP-1 receptor agonists, GIP receptor agonists, GIP receptor inhibitors and/or antagonists, dual GLP-1 receptor/glucagon receptor agonists (e.g., OPK88003, MEDI0382, JNJ-64565111, NN9277, BI 456906), dual GLP-1 receptor/GIP receptor agonists [e.g., Tirzepatide] (LY3298176), NN9423, NN9541, HS-20094, SCO-094, VK2735, CT-388, GMA-106, CT-868, HRS9531], dual GLP-1 receptor/glucagon receptor agonists (e.g., DD-01, PB-718, mazdutide, pemvidutide, pegapamodutide, survodutide), LM-008, IBI-362, AZD9550), GLP-1 receptor/GLP-2 receptor dual agonists (e.g., dapiglutide), dual GLP-1 receptor/amylin receptor agonists (e.g., amycretin), cangrilinitide/semaglutide, GLP-1 receptor agonists/GIP receptor antagonists (maridebart... Cafraglutide), GLP-1 receptor/FGF21 receptor dual agonists (e.g., HEC-88473, BI 3006337), GLP-1 receptor/glucagon receptor/GIP receptor triple agonists (e.g., retatrutide), GLP-1 receptor/glucagon receptor/FGF21 receptor triple agonists (e.g., DR10624), NPY2 receptor agonists (e.g., BI 3006337), and NPY2 receptor agonists (e.g., BI 3006337). 1820237), activin receptor type 2B regulators (e.g., bimagrumab, amyloid peptide receptor agonists, GPR75 regulators, Δ-5 desaturase inhibitors, orexin 2 receptor regulators, angiotensin receptor blockers, acetyl-CoA carboxylase (ACC) inhibitors, ketohexokinase (K... HK) inhibitors, ASK1 inhibitors, branched-chain α-keto acid dehydrogenase kinase inhibitors (BCKDK inhibitors), CCR2 and/or CCR5 inhibitors, PNPLA3 inhibitors, DGAT1 inhibitors, DGAT2 inhibitors, FGF21 analogs, FGF19 analogs, PPAR agonists, FXR agonists, AMPK activators [e.g., ETC-1002 (bempedoic acid)], SCD1 inhibitors, or MPO inhibitors.

Exemplary GLP-1 receptor agonists include liraglutide, albiglutide, exenatide, lixisenatide, dulaglutide, semaglutide, danuglipron, orforglipron, lotigliron, PF-06954522, HM15211, LY3298176, Medi-0382, and NN-9924. TTP-054, TTP-273, efpeglenatide, CT-996, ECC5004, XW004, XW014, MDR-001, ZT002, KN-056, GL0034, GSBR-1290, noiiglutide, RGT-075, TTP-273, HRS-7535, GMA-105, TG103, GZR-18, GX-G6, ecnoglutide, PB-119, QLG2065, beinaglutide, described in The items described in WO2018109607, WO2019239319 (PCT/IB2019/054867 submitted on June 11, 2019), and WO2019239371 (PCT/IB2019/054961 submitted on June 13, 2019).

Exemplary ACC inhibitors include 4-(4-[(1-isopropyl-7-oxy-1,4,6,7-tetrahydro- 1'H -spiro[indazole-5,4'-hexahydropyridine]-1'-yl)carbonyl]-6-methoxypyridin-2-yl)benzoic acid, gemcabene, and firsocostat (GS-0976) and their pharmaceutically acceptable salts.

Exemplary FXR agonists include tropifexor (2-[( 1R , 3R , 5S )-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-) [3.2.1][oct-8-yl]-4-fluoro-1,3-benzothiazol-6-carboxylic acid, cilofexor (GS-9674), obeticholic acid, LY2562175, Met409, TERN-101 and EDP-305, and their pharmaceutically acceptable salts.

Exemplary KHK inhibitors include [( 1R , 5S , 6R )-3-{2-[( 2S )-2-methylazacyclobutane-1-yl]-6-(trifluoromethyl)pyrimidin-4-yl}-3-azabicyclo[3.1.0]hex-6-yl]acetic acid and its pharmaceutically acceptable salts.

Exemplary DGAT2 inhibitors include ( S )-2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(tetrahydrofuran-3-yl)pyrimidin-5-carboxamide [including its crystalline solid forms (form 1 and form 2)]. See U.S. Patent 10,071,992.

Some exemplary BCKDK inhibitors include those described in U.S. Patents 1,154,2270 and 1,105,9833, including the following: 5-(5-chloro-4-fluoro-3-methylthiophen-2-yl) -1H -tetrazolium; 5-(5-chloro-3-difluoromethylthiophen-2-yl) -1H -tetrazolium; 5-(5-fluoro-3-methylthiophen-2-yl) -1H -tetrazolium; 5-(5-chloro-3-methylthiophen-2-yl)-1H-tetrazolium; 5-(3,5-dichlorothiophen-2-yl) -1H -tetrazolium; 5-(4-bromo-3-methylthiophen-2-yl) -1H -tetrazolium; 5-(4-bromo-3-ethylthiophen-2-yl) -1H -tetrazolium; 5-(4-chloro-3-ethylthiophen-2-yl) -1H -tetrazolium; 5-(4-chloro-3-ethylthiophen-2-yl) -1H -tetrazolium; -Tetraazole; 3-chloro-5-fluorothieno[3,2-b]thiophene-2-carboxylic acid; 3-bromo-5-fluorothieno[3,2-b]thiophene-2-carboxylic acid; 3-(difluoromethyl)-5-fluorothieno[3,2-b]thiophene-2-carboxylic acid; 5,6-difluorothieno[3,2-b]thiophene-2-carboxylic acid; and 3,5-difluorothieno[3,2-b]thiophene-2-carboxylic acid; or a pharmaceutically acceptable salt thereof.

Some other exemplary BCKDK inhibitors include those described in U.S. Patent Application No. 18/060,027, filed November 30, 2022, including the following: 6-fluoro-3-(2,4,6-trifluoro-3-methoxyphenyl)-1-benzothiophene-2-carboxylic acid; 6-fluoro-3-(2,4,5-trifluoro-3-methoxyphenyl)-1-benzothiophene-2-carboxylic acid; 6-chloro-3-(2,4,5-trifluoro-3-tolyl)-1-benzothiophene-2-carboxylic acid; 6-chloro-3-(2,4-difluoro-3-methoxyphenyl)-1-benzothiophene-2-carboxylic acid; 3-(6-chloro-2,4-difluoro-3-methoxyphenyl)-6-fluoro-1-benzothiophene-2-carboxylic acid. Acid; 3-(6-chloro-2,4-difluoro-3-methoxyphenyl)-6-fluoro-1-benzothiophene-2-carboxylic acid, ATROP-2; 3-(3-chloro-2,4,5-trifluorophenyl)-6-fluoro-1-benzothiophene-2-carboxylic acid; 3-(4-chloro-2,6-difluoro-3-methoxyphenyl)-6-fluoro-1-benzothiophene-2-carboxylic acid; 6-chloro-3-(2,4,6-trifluoro-3-methoxyphenyl)-1-benzothiophene-2-carboxylic acid; 6-chloro-3-(3-ethyl-2,4,5-trifluorophenyl)-1-benzothiophene-2-carboxylic acid; or 3-(3-ethyl-2,4,5-trifluorophenyl)-6-fluoro-1-benzothiophene-2-carboxylic acid ammonium; or a pharmaceutically acceptable salt thereof.

In some embodiments, the compounds of the present invention may be administered in combination with one or more antidiabetic drugs. Suitable antidiabetic drugs include insulin, metformin, GLP-1 receptor agonists (as described above), acetyl-CoA carboxyltransferase (ACC) inhibitors (as described above), SGLT2 inhibitors (as described above), monoacylglycerol O-acetyltransferase inhibitors, phosphodiesterase (PDE)-10 inhibitors, and AMPK activators [e.g., ETC-1002 (bempedoic acid)]. Sulfonylureas (e.g., hexamethylenetetramine acetate, chlorpropamide, diabinese, glibenclamide, glipizide, glyburide, glimepiride, gliclazide, glipentide, gliquidone, glisolamide, tolazamide, and tolbutamide), meglitinide, α-amylase inhibitors (e.g., tendamistat, trestatin, and AL-3688), α-glucosidase inhibitors (e.g., sulfonylureas, gliclazide, glipentide, gliquidone, glisolamide, tolazamide, and tolbutamide), α-glucosidase inhibitors (e.g., sulfonylureas, glibenclamide, gliclazide, glipentide, gliquidone, glisolamide, tolazamide, and tolbutamide), α-amylase inhibitors (e.g., sulfonylureas, glibenclamide, gliclazide, glipentide, gliquidone, glisolamide, tolazamide, and tolbutamide), α-glucosidase inhibitors (e.g., sulfonylureas, glibenclamide, gliclazide, glisolamide, tolazide, tolbutamide, glisolamide, tolazide, tolbutamide), meglitinide, α-amylase inhibitors (e.g., sulfonylureas, glibenclamide, gliclazide, glisolamide, tolazide, tolbutamide, glisolamide, tolazide, tolbutamide), α-glucosidase inhibitors (e.g., sulfonylureas, sulfonylureas, glibenclamide, glisolamide, gliclazide, tolazide, tolbutamide, tolbutamide), α-glucosidase inhibitors (e.g Acarbose, α-glucosidase inhibitors (such as adiposine, camiglibose, emiglitate, miglitol, voglibose, pradimicin-Q, and salbostatin), PPARγ agonists (such as balaglitazone, ciglitazone, darglitazone, empaglitazone, isaglitazone, pioglitazone, and rosiglitazone), PPARγ agonists α/γ agonists (e.g., CLX-0940, GW-1536, GW-1929, GW-2433, KRP-297, L-796449, LR-90, MK-0767, and SB-219994), protein tyrosine phosphatase-1B (PTP-1B) inhibitors [e.g., trodusquemine, hyrtiosal extract, and Zhang, S. et al., Drug Discovery Today , 12(9/10),] [Compounds disclosed in 373-381 (2007)], SIRT-1 activators (e.g., resveratrol, GSK2245840 or GSK184072), dipeptidyl peptidase IV (DPP-IV) inhibitors (e.g., those described in WO2005116014, sitagliptin, vildagliptin, alogliptin, dutogliptin, linagliptin and saxagliptin)), insulin secretagogues, fatty acid oxidation inhibitors A2 antagonists, c-junokinase (JNK) inhibitors, glucokinase activators (GKa), such as those described in WO2010103437, WO2010103438, WO2010013161, WO2007122482, TTP-399, TTP-355, TTP-547, AZD1656, ARRY403, MK-0599, TAK-329, AZD5658 or GKM-001, insulin, insulin mimics, glycogen phosphorylase inhibitors (e.g., GSK1362885), VPAC2 receptor agonists, glucagon receptor modulators, such as Demong, GPR119 modulators, particularly agonists, such as those described in DE et al., Annual Reports in Medicinal Chemistry 2008, 43, 119-137, WO2010140092, WO2010128425, WO2010128414, WO2010106457, Jones, RM et al., Annual Reports in Medicinal Chemistry 2009, 44, 149-170 (e.g., MBX-2982, GSK1292263, APD597, and PSN821), and FGF21 derivatives or analogues, such as those described in Kharitonenkov, A. et al., Current Opinion in Investigational Drugs 2009, The following are included in 10(4)359-364: TGR5 (also known as GPBAR1) receptor modulators, especially agonists, such as those described in Zhong, M., Current Topics in Medicinal Chemistry , 2010, 10(4), 386-396; and INT777 and GPR40 agonists, such as those described in Medina, JC, Annual Reports in Medicinal Chemistry , 2008, 43, 75-85, including, but not limited to, TAK-875 and GPR120. Modulators (especially agonists), high-affinity niacin receptor (HM74A) activators, and SGLT1 inhibitors, such as GSK1614235. A further representative list of antidiabetic agents that can be combined with the compounds of this invention can be found, for example, on page 28, line 35 to page 30, line 19 of WO2011005611.

Other antidiabetic medications may include carnitine palmitate transaminase inhibitors or modulators, fructose-1,6-bisphosphatase inhibitors, aldose reductase inhibitors, mineralocorticoid receptor inhibitors, TORC2 inhibitors, CCR2 and/or CCR5 inhibitors, PKC isoform (e.g., PKCα, PKCβ, PKCγ) inhibitors, fatty acid synthase inhibitors, serine palmitate transaminase inhibitors, GPR81, GPR39, and GP. R43, GPR41, GPR105, Kv1.3, retinol-binding protein 4, glucocorticoid receptors, somatostatin receptors (e.g., SSTR1, SSTR2, SSTR3, and SSTR5) regulators, PDHK2 or PDHK4 inhibitors or regulators, MAP4K4 inhibitors, IL1 family regulators (including IL1β) regulators, and RXRα regulators. In addition, suitable antidiabetic agents include those with the mechanisms listed in Carpino, PA, Goodwin, B. Expert Opin. Ther. Pat. , 2010, 20(12), 1627-51.

The compounds of this invention can be co-administered with anti-heart failure agents, such as ACE inhibitors (e.g., captopril, enalapril, fosinopril, lisinopril, perindopril, quinapril, ramipril, trandolapril), angiotensin II receptor blockers (e.g., candesartan, losartan, valsartan), angiotensin II receptor neprilysin agonists (sacubitril/valsartan), I... _f- channel blockers include Ivabradine, β-adrenergic receptor blockers (such as bisoprolol, metoprolol succinate, and carvedilol), aldosterone antagonists (such as spironolactone and eplerenone), hydralazine, isosorbide nitrate, diuretics (such as furosemide, bumetanide, torsemide, chlorothiazide, amiloride, hydrochlorothiazide, indapamide, metolazone, and triamterene), or digoxin.

The compounds of this invention can also be administered in combination with cholesterol-lowering or lipid-lowering agents, including the following exemplary agents: HMG CoA reductase inhibitors (e.g., pravastatin, pitavastatin, lovastatin, atorvastatin, simvastatin, fluvastatin, NK-104 (also known as itavastatin, nisvastatin, or nisbastatin)) and ZD-4522 (also known as rosuvastatin, atavastatin, or visastatin)); squalene synthase inhibitors; and fiberates (e.g., gemfibrozil, pemafibrate, fenofib). 1. chlorhexidine gluconate (chlorhexidine); 2. chlorhexidine diphosphate (chlorhexidine diphosphate), ... 3 fatty acids (e.g., epanova, fish oil, eicosapentaenoic acid); cholesterol ester transfer protein inhibitors (e.g., obicetrapib) and PCSK9 regulators [e.g., alirocumab, evolocumab, bococizumab, ALN-PCS (inclisiran)].

The compounds of this invention can also be used in combination with antihypertensive agents, and such antihypertensive activity can be easily determined by those skilled in the art using standard analysis (e.g., blood pressure measurement). Examples of suitable antihypertensive agents include: α-adrenergic receptor blockers; β-adrenergic receptor blockers; calcium channel blockers (e.g., diltiazem, verapamil, nifedipine, and amlodipine); vasodilators (e.g., hydralazine); and diuretics (e.g., chlorothiazide, hydrochlorothiazide). thiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichlorothiazide, polythiazide, benzthiazide, ethacrynic acid (e.g., acid), tricynafen, chlorthalidone, torsemide, furosemide, musolimine, bumetanide, triamtrenene, amiloride, spironolactone; renal inhibitors; ACE inhibitors (e.g., captopril, zofenopril, fosinopril, enalapril, ceramide). anopril), cilazopril, delapril, pentopril, quinapril, ramipril, lisinopril; AT-1 receptor antagonists (e.g., losartan, irbesartan, valsartan); ET receptor antagonists (e.g., sitaxentan, atrsentan, and compounds disclosed in U.S. Patents 5,612,359 and 6,043,265); dual ET/AII antagonists (e.g., WO Compounds disclosed in 00/01389); neutral endopeptidase (NEP) inhibitors; angiopeptidase inhibitors (dual NEP-ACE inhibitors) (e.g., gemopeptidase and nitrates). An exemplary antianginal agent is ivabradine.

Examples of suitable calcium channel blockers (L-type or T-type) include diltiazem, verapamil, nifedipine, amlodipine, and mibeladil.

Examples of suitable cardiac glycosides include digitalis and ouabain.

In one embodiment, the compound of the invention may be administered co-administered with one or more diuretics. Examples of suitable diuretics include (a) cyclic diuretics, such as furosemide (e.g., LASIX™), torasemide (e.g., DEMADEX™), bemetanide (e.g., BUMEX™), and ethacrynic acid (e.g., ECECRIN™); (b) thiazide diuretics, such as chlorothiazide (e.g., DIURIL™, ESIDRIX™, or HYDRODIURIL™), hydrochlorothiazide (e.g., MICROZIDE™ or ORETIC™), benzylthiazide, and hydrofluorothiazide (e.g., SALUR). (c) Phthalothiazide diuretics, such as chlorothiazide (e.g., LOZOL™), benzylfluthiazide, methazothiazide, polythiazide, trichlorothiazide and indapamide (e.g., LOZOL™); (d) Phthaloimide diuretics, such as chlorothiazide (e.g., HYGROTON™) and metolazone (e.g., ZAROXOLYN™); (e.g., quinazoline diuretics, such as quinethane; and (e.g., potassium-sparing diuretics, such as triamterene (e.g., DYRENIUM™) and amiloride (e.g., MIDAMOR™ or MODURETIC™).

In another embodiment, the compound of the invention may be administered co-administered with a cyclic diuretic. In yet another embodiment, the cyclic diuretic is selected from furosemide and torasemide. In yet another embodiment, one or more compounds of formula I or their pharmaceutically acceptable salts may be administered co-administered with furosemide. In yet another embodiment, one or more compounds of formula I or their pharmaceutically acceptable salts may be administered co-administered with torasemide, wherein the torasemide may optionally be a controlled-release or modulated-release form of torasemide.

In another embodiment, the compound of the invention may be administered co-administered with a thiazide diuretic. In yet another embodiment, the thiazide diuretic is selected from the group consisting of chlorothiazide and hydrochlorothiazide. In yet another embodiment, one or more compounds of formula I or their pharmaceutically acceptable salts may be administered co-administered with chlorothiazide. In yet another embodiment, one or more compounds of formula I or their pharmaceutically acceptable salts may be administered co-administered with hydrochlorothiazide.

In another embodiment, one or more compounds of Formula I or their pharmaceutically acceptable salts may be administered co-administered with an phthalimide diuretic. In yet another embodiment, the phthalimide diuretic is chlorthalidone.

Examples of suitable saponin receptor antagonists include spironolactone and eplerenone.

Examples of suitable phosphodiesterase inhibitors include: PDE III inhibitors (such as cilostazol); and PDE V inhibitors (such as sildenafil).

Those skilled in the art will understand that the compounds of this invention can also be used in combination with other cardiovascular or cerebrovascular treatments, including percutaneous coronary intervention (PCI), stent placement, drug-eluting stents, stem cell therapy, and medical devices such as implantable pacemakers, defibrillators, or cardiac resynchronization therapy.

In particular, when provided in a single dosage unit, chemical interactions may occur between the active ingredients in the combination. Therefore, when the compounds of the present invention are combined with a second therapeutic agent in a single dosage unit, the formulation minimizes (i.e., reduces) the physical contact between the active ingredients, even though they are combined in a single dosage unit. For example, an enteric coating can be used to coat one active ingredient. By enteric coating one of the active ingredients, not only is it possible to minimize the contact between the active ingredients in the combination, but it is also possible to control the release of one of these ingredients in the gastrointestinal tract, thereby preventing one of these ingredients from being released in the stomach and instead releasing it in the intestines. One of these active ingredients may also be coated with a material to allow for sustained release throughout the gastrointestinal tract while minimizing physical contact between the active ingredients in the combination. Alternatively, the sustained-release component may be further enteric-coated, allowing release only in the intestines. Another approach involves formulating a combination product in which one component is coated with a sustained-release and/or enteric-release polymer, and another component is also coated with a polymer (such as low-viscosity hydroxypropyl methylcellulose (HPMC) or other suitable materials known in this art) to further separate the active ingredients. The polymer coating serves to form an additional barrier against interactions with other components.

Those skilled in the art will readily understand these and other methods for minimizing contact between the components of the combined product of the present invention (whether administered in a single dose or separately, but administered in the same manner at the same time).

Another approach may involve formulating combination products in which two active ingredients are combined with a material that enables the continuous release of the two active ingredients throughout the gastrointestinal tract.

In some implementations of combination therapy, the compounds of this invention and other drug therapies are administered to patients, such as mammals (e.g., humans, males or females), using conventional methods. Kit

Another embodiment of the invention provides a kit containing the compounds of the invention or pharmaceutical compositions containing the compounds of the invention. In addition to the compounds of the invention or pharmaceutical compositions thereof, the kit may contain diagnostic agents or treatments. The kit may also include instructions for use for diagnosis or treatment. In some embodiments, the kit contains a compound or pharmaceutical composition thereof and a diagnostic agent. In other embodiments, the kit contains a compound or pharmaceutical composition thereof, and one or more treatments as described in the common administration section above.

In another embodiment, the invention includes a kit suitable for carrying out the treatment methods described herein. In one embodiment, the kit contains a first dosage form comprising one or more compounds of the invention in an amount sufficient to carry out the methods of the invention. In another embodiment, the kit contains one or more compounds of the invention in an amount sufficient to carry out the methods of the invention, and a container for dispensing the dosage. [ Examples ]

The synthesis of various compounds of the present invention is described below. Other compounds within the scope of the present invention may be prepared using the methods described in these embodiments, or using a single technique or in combination with techniques generally known in this art. All starting materials in these preparation methods and embodiments are commercially available or may be prepared by methods known in this art or as described herein.

The reaction is carried out in air, or in an inert atmosphere (nitrogen or argon) when using reagents or intermediates sensitive to oxygen or moisture. Where appropriate, the reaction apparatus is dried under dynamic vacuum using a hot air gun and an anhydrous solvent is used (Sure-Seal ^™ from Aldrich Chemical Company, Milwaukee, Wisconsin, or DriSolv ^™ from EMD Chemicals, Gibbstown, New Jersey). In some cases, commercial solvents may have been passed through columns packed with 4Å molecular sieves until the following QC standards for water were met: a) dichloromethane, toluene, N,N -dimethylformamide, and tetrahydrofuran < 100 ppm; b) methanol, ethanol, 1,4-dichloromethane, and tetrahydrofuran. Alkane and diisopropylamine <180 ppm. For highly sensitive reactions, some solvents may be further treated with sodium metal, calcium hydroxide, or molecular sieves, and distilled before use. Other commercial solvents and reagents can be used directly without further purification. Reaction conditions (reaction time and temperature) may vary in reference synthetic procedures in other embodiments or methods. The product is typically dried under vacuum before further reactions or submission for bioassays.

When specified, the reaction is heated by microwave radiation using a Biotage Initiator or a Personal Chemistry Emrys Optimizer microwave instrument. The reaction process is monitored using thin-layer chromatography (TLC), liquid chromatography-mass spectrometry (LCMS), high-performance liquid chromatography (HPLC), and/or gas chromatography-mass spectrometry (GCMS). TLC is performed on a pre-coated silicone plate using a fluorescent indicator (254 nm excitation wavelength), and visualized under UV light and/or using _I₂ , _KMnO₄ , _CoCl₂ , molybdenum phosphate, or ammonium cerium molybdate dyes. LC-MS data were acquired on an Agilent 1100 series instrument equipped with a Leap Technologies automated sampler, a Gemini C18 column, an acetonitrile/water gradient, and trifluoroacetic acid, formic acid, or ammonium hydroxide modifiers. The column eluent was analyzed using a Waters ZQ mass spectrometer in both positive and negative ion modes (from 100 to 1200 Da). Other similar instruments were also used. HPLC data were typically obtained on an Agilent 1100 series instrument using a Gemini or XBridge C18 column, an acetonitrile/water gradient, and trifluoroacetic acid or ammonium hydroxide modifiers. GCMS data were obtained using a Hewlett Packard 6890 oven equipped with an HP 6890 syringe, an HP-1 column (12 m x 0.2 mm x 0.33 μm), and helium carrier gas. Samples were analyzed using electron ionization in the range of 50 to 550 Da on an HP 5973 mass selective detector. Purification was performed by medium-performance liquid chromatography (MPLC) using an Isco CombiFlash Companion, AnaLogix IntelliFlash 280, Biotage SP1, or Biotage Isolera One instrument and pre-filled Isco RediSep or Biotage Snap silicone cartridges. Chiral purification is typically performed using Berger or Thar instruments via chiral supercritical fluid chromatography (SFC); ChiralPAK-AD, -AS, -IC, Chiralcel-OD, or -OJ columns; and a _CO2 mixture containing methanol, ethanol, propan-2-ol, or acetonitrile (alone or modified with trifluoroacetic acid or propan-2-amine). UV detection is used to trigger distillate collection. Purification may differ from the synthetic reference procedures in other embodiments or methods: typically, the solvent and solvent ratio used for the eluent/gradient are selected to provide an appropriate _Rfs or retention time.

Mass spectrometry data were obtained from LCMS analysis reports. Mass spectrometry (MS) was performed using atmospheric pressure chemical ionization (APCI), electrospray ionization (ESI), electron collision ionization (EI), or electron scattering (ES) ionization sources. Proton nuclear magnetic resonance ( ^¹H NMR) chemical shifts were expressed as low magnetic fields per millionth from tetramethylsilane and recorded on Varian, Bruker, or Jeol spectrometers at 300, 400, 500, or 600 MHz. Chemical shifts are expressed as parts per million (ppm, δ) relative to the residual peak of the deuterated solvent (chloroform, 7.26 ppm; _CD₂HOD , 3.31 ppm; acetonitrile- d₂ _, 1.94 _{ppm; dimethyl sulfoxide-d₅} , 2.50 ppm; DHO, 4.79 ppm). Peak shapes are described as follows: s, singlet; d, doublet; t, triplet; q, quartet; quintet; m, multiplet; br s, broad singlet; app, apparent. Analytical SFC data were acquired on a Berger analyzer as described above. Optical rotation data were acquired on a PerkinElmer Mode 343 polarimeter using a 1 dm cell. Silicone chromatography primarily employs medium-pressure Biotage or ISCO systems, using pre-filled columns from various commercial suppliers of Biotage and ISCO. Trace analysis was performed by Quantitative Technologies and was conducted within 0.4% of the calculated values.

Unless otherwise stated, chemical reactions are carried out at room temperature (approximately 23 degrees Celsius).

Unless otherwise stated, all reactants are commercially available and do not require further purification or preparation using methods known in the literature.

The terms "concentration," "evaporation," and "concentration in vacuum" refer to the removal of solvent in a rotary evaporator under reduced pressure at a water bath temperature below 60°C. The abbreviations "min" and "h" represent "minutes" and "hours," respectively. The terms "TLC" refer to thin-layer chromatography; "room temperature or ambient temperature" refers to a temperature between 18 and 25°C; "GCMS" refers to gas chromatography-mass spectrometry; "LCMS" refers to liquid chromatography-mass spectrometry; "UPLC" refers to ultra-high performance liquid chromatography; "HPLC" refers to high performance liquid chromatography; and "SFC" refers to supercritical fluid chromatography.

Hydrogenation can be carried out in a Parr oscillator, under pressurized hydrogen or in a Thales-nano H-Cube fluid hydrogenation device, at a specified temperature and filled with hydrogen, at a flow rate between 1 and 2 mL/min.

Use the methods specified in the procedure to measure HPLC, UPLC, LCMS, GCMS, and SFC retention times.

In some instances, chiral separation is performed to separate certain compounds of the invention into mirror isomers or non-mirror isomers (in some instances, the separated mirror isomers are named ENANT-1 and ENANT-2 according to their elution order; similarly, the separated non-mirror isomers are named DIAST-1 and DIAST-2 according to their elution order). In some instances, the optical rotation of the mirror isomers is measured using a polarimeter. Based on the observed optical rotation data (or specific optical rotation data), mirror isomers exhibiting clockwise rotation are named (+)-mirror isomers, and those exhibiting counterclockwise rotation are named (-)-mirror isomers. Racemic compounds are indicated by the absence of drawn or described stereochemistry, or by the presence of (+/-) next to the structure; in the latter case, the indicated stereochemistry represents only one of the two mirror isomers constituting the racemic mixture.

The compounds and intermediates described below are named using the naming conventions provided by ACD/ChemSketch 2020.2.1.1, document version C25H41, Build 121153 (Advanced Chemistry Development, Inc., Toronto, Ontario, Canada). The naming conventions provided by ACD/ChemSketch 2020.2.1.1 are well known to those skilled in the art and are generally believed to be consistent with the recommendations of IUPAC (International Union for Pure and Applied Chemistry) regarding the Nomenclature of Organic Chemistry and the CAS Index. Example 1: 4'-[(1-{[4-(propyl-2-yl)phenyl]aminomethylamino}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid ( Compound 1 ) Step 1. Synthesize 1-{[4-(propyl-2-yl)phenyl]aminomethoxy}-D-proline ( C1 ).

4-Methylmorpholine (20.5 mL, 186 mmol) was added to a mixture of D-proline (21.4 g, 186 mmol) in tetrahydrofuran (520 mL) at 2-3°C. After 2 minutes, 1-isocyanate-4-(propan-2-yl)benzene (25.0 g, 155 mmol) was added over 30 seconds, and the mixture was stirred for 5 minutes. The reaction mixture was then removed from the ice bath and allowed to stir at room temperature. After 2 hours, LCMS analysis showed the formation of Cl⁺ : LCMS m/z 277.4 [M+H] ^⁺ . Water (500 mL) was added, followed by solid sodium bicarbonate (19.5 g, 233 mmol), resulting in a pH of 7-8. The resulting mixture was washed with methyl tributyl ether (2 × 600 mL); the aqueous layer was then acidified to pH 2 by adding concentrated hydrochloric acid and stirring for 20 minutes. The mixture was filtered, and the filter cake was then rinsed with water to obtain a white solid, C1 . Yield: 39.1 g, 141 mmol, 91%. ^¹H NMR (400 MHz, DMSO _-d⁶ ) δ 12.36 (br s, 1H), 8.16 (s, 1H), 7.38 (d, J = 8.6 Hz, 2H), 7.09 (d, J = 8.5 Hz, 2H), 4.34 - 4.26 (m, 1H), 3.58 - 3.50 (m, 1H), 3.49 - 3.41 (m, 1H), 2.81 (septet, J = 6.9 Hz, 1H), 2.22 - 2.11 (m, 1H), 1.97 - 1.83 (m, 3H), 1.17 (d, J = 6.9 Hz, 6H). Step 2. Synthesis of ( 2R ) -N2- (4-bromophenyl) ^{-N1- [} 4- (propyl-2-yl)phenyl]pyrrolidine-1,2-dicarboxymethylamine ( C3 ).

4-Bromoaniline (1.94 g, 11.3 mmol), C1 (3.12 g, 11.3 mmol), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (2.60 g, 13.6 mmol) were stirred in dichloromethane (50 mL) at room temperature for 16 hours. LCMS analysis at this time showed conversion to C3 : LCMS m/z 430.2 (bromine isotope pattern observed) [M+H] ⁺ . The reaction mixture was poured into water and extracted with dichloromethane; the organic layer was dried on magnesium sulfate, filtered, and concentrated under vacuum to produce C3 as a white solid. Yield: 4.82 g, 11.2 mmol, 99%. ^¹H NMR (400 MHz, chloroform- d ) δ 9.94 (br s, 1H), 7.41 (AB quartet, J _{_AB} = 8.9 Hz, Δν_{_AB} = 27.9 Hz, 4H), 7.25 (AB quartet, J_{_AB} = 8.5 Hz, Δν_{_AB} = 46.6 Hz, 4H), 6.30 (br s, 1H), 4.74 (br d, J = 8.0 Hz, 1H), 3.55 (ddd, J = 8, 8, 1.9 Hz, 1H), 3.44 - 3.36 (m, 1H), 2.89 (septet, J = 7.0 Hz, 1H), 2.64 (dd, J = 12.6, 6.3 Hz, 1H), 2.29 - 2.07 (m, 2H), 1.89 (tdd, J = 12.4, 8.0, 6.8 Hz, 1H), 1.24 (d, J = 6.9 Hz, 6H). Step 3. Synthesis of 4'-[(1-{[4-(propyl-2-yl)phenyl]aminomethylamino}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid ( compound 1 )

A sodium carbonate aqueous solution (2 M; 5.23 mL, 10.5 mmol) was added to a mixture of C3 (1.50 g, 3.49 mmol) and 4-boron benzoic acid (694 mg, 4.18 mmol) in 1,4-dioxane (22 mL), followed by the addition of methanesulfonic acid [(di(1-adamantyl) -n -butylphosphine)-2-(2'-amino-1,1'-biphenyl)]palladium(II) ( ^cataCXium® A Pd G3; 127 mg, 0.174 mmol). The reaction mixture was degassed for 5 minutes, heated overnight at 90°C, and then cooled to room temperature. The pH was adjusted to 4-5 by adding 1 M hydrochloric acid, and the resulting mixture was distributed between ethyl acetate (200 mL) and water (100 mL); this produced an insoluble solid, which was separated by filtration and washed with ethyl acetate. The substance was milled using propan-2-ol, first at 70°C for 5 hours, then at room temperature for 20 hours. The suspension was filtered, and the filter cake was washed with dichloromethane to produce a white solid, 4'-[(1-{[4-(propan-2-yl)phenyl]aminomethylmethyl}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid ( compound 1 ). Yield: 435 mg, 0.922 mmol, 26%. LCMS m/z 472.3 [M+H] ⁺ . ^1H NMR (400 MHz, DMSO- d ₆ ) δ 12.90 (br s, 1H), 10.13 (s, 1H), 8.19 (s, 1H), 7.88 (AB quartet, J _AB = 8.4 Hz, Δν _AB = 83.3 Hz, 4H), 7.72 (AB quartet, J _AB = 9.0 Hz, Δν _AB = 12.2 Hz, 4H), 7.40 (d, J = 8.6 Hz, 2H), 7.09 (d, J = 8.6 Hz, 2H), 4.47 (dd, J = 8.3, 3.6 Hz, 1H), 3.70 - 3.60 (m, 1H), 3.56 - 3.47 (m, 1H), 2.80 (septet, J = 6.9 Hz, 1H), 2.26 - 2.12 (m, 1H), 2.10 - 1.87 (m, 3H), 1.16 (d, J = 6.9 Hz, 6H).

The combined organic layers from the above steps were washed sequentially with water (2 × 50 mL) and a saturated sodium chloride aqueous solution, dried on magnesium sulfate, filtered, and concentrated under vacuum. Purification was performed by silica gel chromatography (gradient: 0% to 5% methanol in dichloromethane), followed by milling at room temperature with a mixture of dichloromethane and methanol for 20 hours to provide an additional white solid of 4'-[(1-{[4-(propyl-2-yl)phenyl]aminomethylmethyl}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid ( compound 1 ). Yield: 410 mg, 0.869 mmol, 25%; combined yield: 51%. Alternative Synthesis of Compound 1 : 4'-[(1-{[4-(propyl-2-yl)phenyl]aminomethylamino}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid ( Compound 1 ) Step 1. Synthesize 4'-amino[1,1'-biphenyl]-4-carboxylic acid tributyl ester ( C11 ).

Tertiary butyl 4-bromobenzoate (25.8 g, 100 mmol) and potassium carbonate (37.8 g, 274 mmol) were added to a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)aniline (20.0 g, 91.3 mmol) in a mixture of 1,4-dioxane (400 mL) and water (100 mL). Then, [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (3.34 g, 4.56 mmol) was added; the reaction mixture was heated at 95 °C for 16 hours and then filtered. The filtrate was concentrated under reduced pressure, the residue was diluted with water (500 mL) and extracted with ethyl acetate (2 × 500 mL). The combined organic layer was washed with a saturated sodium chloride aqueous solution (2 × 500 mL), dried on sodium sulfate, filtered, and concentrated under vacuum. A solid was produced by silica gel chromatography (gradient: 0% to 50% ethyl acetate in petroleum ether), treated with propyl-2-acetate (20 mL) and heptane (80 mL) and stirred for 30 minutes, and then collected by filtration. The filter cake was washed with heptane (3 × 15 mL) to produce a powdery white C11 solid. Yield: 18.5 g, 68.7 mmol, 75%. LCMS m/z 270.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.88 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.5 Hz, 2H), 6.66 (d, J = 8.5 Hz, 2H), 5.39 (s, 2H), 1.55 (s, 9H). Step 2. Synthesis of 4'-[(1-{[4-(propyl-2-yl)phenyl]aminomethylamino}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid tributyl ester ( C12 ).

1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (3.46 g, 18.0 mmol) was added to a solution of C1 (3.95 g, 14.3 mmol) and C11 (4.05 g, 15.0 mmol) in N,N -dimethylacetamide (38 mL). After 1.5 hours, LCMS analysis indicated the presence of a product: LCMS m/z 528.5 [M+H] ⁺ . Water (50 mL) was added, the mixture was stirred for 8 minutes and then filtered; the collected solid was washed with water and stirred in diethyl ether (60 mL) for 10 minutes. The solid was separated again by filtration, suspended in a 5% methanol solution in dichloromethane (50 mL), stirred for 25 minutes, and then filtered. The filter cake was washed with dichloromethane to produce a white solid of C12 . Yield: 5.43 g, 10.3 mmol, 72%. ^¹H NMR (400 MHz, DMSO _- d⁶ ) δ 10.14 (s, 1H), 8.19 (s, 1H), 7.94 (d, J = 8.5 Hz, 2H), 7.78 (d, J = 8.5 Hz, 2H), 7.72 (AB quartet, J AB = 8.9 Hz, Δν AB = 15.6 Hz, 4H), 7.40 (d, J = 8.6 Hz, 2H), 7.09 (d, _J = 8.6 Hz, 2H), 4.47 ( dd , J = 8.2, 3.6 Hz, 1H), 3.69 - 3.60 (m, 1H), 3.56 - 3.47 (m, 1H), 2.79 (septet, J _AB = 8.2, 3.6 Hz, 1H), δ 10.14 (s, 1H), 8.19 (s, 1H), 7.94 (d, J = 8.5 Hz, 2H), 7.78 (d, J = 8.5 Hz, 2H), 7.72 (AB quartet, J AB = 8.9 Hz, Δν AB = 15.6 Hz, 4H), 7.40 (d, J = 8.6 Hz, 2H), 7.09 (d, J = 8.6 Hz, 2H), 4.47 (dd, J = 8.2, 3.6 Hz, 1H), 3.69 - 3.60 (m, 1H), 3.56 - 3.47 (m, 1H), 2.79 (septet, J AB = 8.9 Hz, Δν AB = 15.6 = 6.9 Hz, 1H), 2.25 - 2.13 (m, 1H), 2.10 - 1.88 (m, 3H), 1.56 (s, 9H), 1.16 (d, J = 6.9 Hz, 6H). Step 3. Synthesis of 4'-[(1-{[4-(propyl-2-yl)phenyl]aminomethylamino}-D-prolylamino)amino][1,1'-biphenyl]-4-carboxylic acid ( compound 1 ).

Methanesulfonic acid (0.129 mL, 1.99 mmol) was added to a solution of C12 (1.00 g, 1.90 mmol) in 1,1,1,3,3,3-hexafluoroprop-2-ol (10 mL), and the reaction mixture was stirred at room temperature for 15 minutes, followed by concentration under vacuum. The residue was stirred in diethyl ether for 5 minutes; the solid was collected by filtration, washed with diethyl ether, and suspended in propyl-2-acetate (15 mL). Methanol (2 mL) was added, and the mixture was stirred at room temperature for 3 days. The filter cake was separated by filtration and then washed with propionic acid 2-ethyl acetate (3 mL) to produce 4'-[(1-{[4-(propionic acid 2-ethyl)phenyl]aminomethylamino}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid ( compound 1 ) as a solid. Yield: 668 mg, 1.42 mmol, 75%. LCMS m/z 472.4 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) 12.90 (v br s, 1H), 10.13 (s, 1H), 8.19 (s, 1H), 7.99 (d, J = 8.5 Hz, 2H), 7.78 (d, J = 8.5 Hz, 2H), 7.72 (AB quartet, J _AB = 9.0 Hz, Δν _AB = 12.7 Hz, 4H), 7.40 (d, J = 8.6 Hz, 2H), 7.09 (d, J = 8.6 Hz, 2H), 4.47 (dd, J = 8.3, 3.6 Hz, 1H), 3.70 - 3.61 (m, 1H), 3.56 - 3.47 (m, 1H), 2.80 (septet, J = 6.9 Hz, 1H), 2.25 - 2.13 (m, 1H), 2.10 - 1.88 (m, 3H), 1.16 (d, J = 6.9 Hz, 6H). Example 2 4'-[(1-{[4-(propyl-2-yl)phenyl]aminomethylamino}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid L-lysine (L-lysine form 1 of compound 1)

Compound 1 (21.3 g, 45.2 mmol) was stirred in 1.03 L of acetone. A 100 mg/mL aqueous solution of L-lysine (6.60 g, 66.0 mL, 45.2 mmol) was added, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was then filtered. The filter cake was resuspended in a mixture of 575 mL of acetone and 145 mL of _H₂O and stirred at room temperature for 18 hours. The resulting suspension was then filtered, and the collected solid was dried under vacuum to obtain 17.8 g (27.6 mmol, 64% yield) of a white solid (LCMS m/z 472.4 [M+H] ^⁺ ). This white solid was determined to be crystalline and sesquihydrate (here designated as form 1). Acquiring Powder X- ray Diffraction (PXRD) Data

The white solid sample of 4'-[(1-{[4-(propyl-2-yl)phenyl]aminomethylamino}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid L-lysine salt prepared according to the above method was subjected to PXRD analysis, and the results showed that it was a crystalline substance (here it is named Form 1).

Powder X-ray diffraction analysis was performed using a Bruker AXS D8 Endeavor diffractometer equipped with a Cu radiation source (K-α average). A 15 mm continuous illumination slit was set. Diffraction radiation was detected using a PSD-Lynx Eye detector with the PSD opening set to 4.10 degrees. The X-ray tube voltage and current were set to 40 kV and 40 mA, respectively. Data was collected in a Theta-Theta goniometer at Cu wavelengths from 3.0° to 40.0° 2-θ using a step size of 0.01 degrees and a step time of 1.0 second. The anti-scattering screen was set to a fixed distance of 3.0 mm. The sample was rotated at a rate of 15 rpm during collection. Samples were prepared by placing them in a sample holder with a low silica background and rotating them during collection. Data were collected using Bruker DIFFRAC Plus software and analyzed using EVA diffract Plus software.

The PXRD file was not processed before peak searching. The peak search algorithm in EVA software was used to perform initial peak assignment using peaks selected at a threshold of 10. To ensure effectiveness, manual adjustments were made; the output of the automatic assignment was visually checked, and the peak positions were adjusted to the maximum. Peaks with a relative intensity ≥3.0% were typically selected. Generally, unresolved peaks or peaks consistent with the noise were not selected. The typical error related to PXRD peak positions specified in the USP is +/-0.2° 2-θ (USP-941). Figure 1 shows a representative PXRD pattern of form 1 of L-lysine of compound 1. The following provides a list of PXRD diffraction peaks from the L-lysine form 1 of compound 1, expressed as relative intensities of 2θ degrees and ≥3.0%. Single-crystal X -ray analysis .

A white solid sample of L-lysine of compound 1 was added to 2 mL of a 1:1 ethanol/water (v/v) solution to form a slurry. The slurry was then heated to 40°C for approximately 10 minutes and centrifuged. The filtrate (i.e., the L-lysine solution of compound 1 dissolved in 1:1 ethanol/water) was transferred to a 2 mL glass vial (a hole was punched in the septum of the vial cap, leaving a needle in the cap), and the solution was allowed to slowly evaporate at room temperature for approximately one day to form crystals. The characteristics of the crystals (form 1) were determined by single-crystal X-ray diffraction analysis to confirm the chemiostoichiometry of the sesquihydrate.

Data were collected on representative crystals at room temperature (298 K) using a Bruker D8 Venture diffractometer with a rotating copper anode (Cu Ka (1.54178 Å)). Data collection included ω and φ scans.

Using the SHELX software suite (SHELXTL, version 5.1, Bruker AXS, 1997), the structure was resolved by intrinsic phase determination in the monoclinic space group P2 _1. The structure was then refined using the full-matrix least squares method. Using the OLEX2 software (OLEX2, Dolomanov, OV; Bourhis, LJ; Gildea, RJ; Howard, JAK; Puschmann, H., (2009). J. Appl. Cryst., 42, 339-341.), all non-hydrogen atoms were discovered and refined using anisotropic displacement parameters.

Following the initial single-crystal X-ray diffraction analysis, an update analysis was performed. In both analyses, hydrogen atoms located at N1A, N1B, N3A, N3B, N4A, N5A, and O9 were identified from the Fourier difference diagram and refined within a limited distance. The remaining hydrogen atoms were then placed in their calculated positions, allowing them to mount on their carrier atoms. The final refinement included isotropic displacement parameters for all hydrogen atoms.

The N4BA/N4BB segments were considered unordered with a group ratio of approximately 60:40 and refined using appropriate constraints.

An absolute structural analysis was performed using PLATON (see AL Spek, J. Appl. Cryst. 2003, 36, 7-13) in a similar manner (see RWW Hooft et al. J. Appl. Cryst. (2008). 41. 96-103).

The final R-index for both the initial and updated analyses was 6.2%. The final Fourier transform of the difference showed electron densities with no missing or misaligned electrons. The refined structure was plotted using the SHELXTL plotting package (SHELXTL, version 5.1, Bruker AXS, 1997) (see, for example, Figures 2 and 14, showing plots with complete asymmetric elements whose anisotropic displacement parameters were plotted with a 50% probability; while Figures 3 and 15 show partially asymmetric elements with representative labeling schemes, both plots prepared using Mercury software (MERCURY, C.F. Macrae, P.R. Edington, P. McCabe, E. Pidcock, G.P. Shields, R. Taylor, M. Towler and J. van de Streek, J. Appl. Cryst. 39, 453-457, 2006.). Based on this refined structure, Form 1 is a sesquihydrate of the L-lysine salt of Compound 1.

The main difference between the initial and updated analyses lies in the placement of hydrogen atoms on O7. Other changes are primarily related to subsequent refinements.

Tables 2 and 2A summarize the relevant crystals, data collection, and refinement. Atomic coordinates, bond lengths, bond angles, and displacement parameters are listed in Tables 3 through 6 (the initial analyses are in Tables 3A through 6A, respectively). Raman spectroscopy

Raman spectra were collected using a Thermo Scientific iS50 FT-Raman accessory connected to an FT-IR stage. A _CaF2 spectroscope was used in the FT-Raman configuration. The spectrometer was equipped with a 1064 nm diode laser and a room-temperature InGaAs detector. Samples were analyzed in glass NMR tubes. Spectra were collected using a 0.5 W laser power and 512 co-addition scans. The collection range was 3700–200 ^cm⁻¹ . The spectrum of form 1 (sesquihydrate) of L-lysine of compound 1 was recorded using ^{a 2 cm⁻¹ resolution} , and all spectra were obtained using the Happ-Genzel apodization method. Multiple spectra were recorded, and representative spectra are shown in Figure 8. ^The peak positions varied within ±2 ^cm⁻¹ using this experimental configuration.

Use the automatic peak analysis function in ACD/Spectrus Processor software (2023.2.0) to select peaks. Use a noise factor of 0.3 and a minimum peak level of 3% of the maximum intensity to select peaks. To ensure effectiveness, visually inspect the output of the automatic peak selection. If a peak exists but is not selected by the automatic peak analysis function, select it manually. If a peak is selected by the automatic peak analysis function but has poor resolution or is not located at its maximum, delete the peak. Generally, unresolved peaks or peaks consistent with noise will not be selected.

Table Raman- ¹ lists the peak positions ( ^cm⁻¹ ) and relative intensities of the observed spectra shown in Figure 8. Variations in peak positions using this experimental configuration are within ±2 ^{cm⁻¹ .} solid-state NMR

^13C solid-state NMR (ssNMR) analysis was performed on a CPMAS probe placed in a Bruker-BioSpin Avance NEO 500 MHz (1H frequency) NMR spectrometer. The L-ionate form 1 (sesquihydrate) of compound 1 was packed into a ZrO2 rotor. A magic angle rotation rate of 15 kHz was used. Spectra were collected at ambient temperature (temperature uncontrolled).

^13C ssNMR spectra were collected using a proton-decoupled cross-polarized magic angle rotation (CPMAS) experiment. A phase-tuned proton decoupling field of 80–100 kHz was applied during spectral acquisition. For the L-lysine form 1 (sesquihydrate) of compound 1, the cross-polarization contact time was set to 2 ms and the cycle delay to 3.5 seconds. The scan number was adjusted to obtain an appropriate signal-to-noise ratio. ^{The 13C} chemical shift scale reference was obtained using a ^13C MAS experiment on an external standard crystalline diamond, with its upper-field resonance set to 29.5 ppm.

Automated peak selection was performed using Bruker-BioSpin TopSpin version 4.1 software. Generally, a 5% relative intensity threshold was used to select the initial peak. The output of the automated peak selection was visually inspected to ensure effectiveness, and manual adjustments were made if necessary. Although specific solid-state NMR peaks are reported in this paper, these peaks do exist as values within a range due to differences in instrumentation, samples, and sample preparation methods. This is frequently performed in solid-state NMR techniques due to inherent variations in peak position. The typical variation in the chemical shift x-axis value is approximately ±0.2 ppm for crystalline solids and approximately ±0.5 ppm for amorphous solids. The solid-state NMR peak heights reported in this paper are relative intensities. The intensity of solid-state NMR can vary depending on the actual settings of the experimental parameters and the thermal history of the sample.

The representative ^13C ss NMR spectra of the observed L-lysine form 1 (sesquihydrate) of compound 1 are shown in Figure 9. Peaks marked with hash marks represent rotational bands. Table C13NMR-1 lists the ^13C ss NMR peaks of the observed L-lysine form ¹ (sesquihydrate) of compound 1 as shown in Figure 9. The typical variation of the chemical shift x-axis value is approximately ±0.2 ppm in crystalline solids and approximately ±0.5 ppm in amorphous solids. Example 3. 4' - [(1 - {[4- ( propyl - 2 - yl ) phenyl ] aminomethylamino } -D - prolyl ) amino ] [1,1' - biphenyl ] -4 - carboxylic acid L - lymine salt ( form 2 of L - lymine salt of compound 1 )

Compound 1 (574.2 mg) was added to 10 mL of methanol to form a slurry. 1.8 mL of an aqueous solution of L-lysine (0.68 M, 1.05 equivalents) was added to the slurry to form a mixture. The mixture was heated to approximately 55°C and stirred for approximately 12 hours. The solid was separated by vacuum filtration and washed with methanol. The solid was dried under ambient conditions. The solid was determined to be crystalline and anhydrous (referred herein to as form 2 of L-lysine of compound 1). Differential scanning calorimetry (DSC) analysis of form 2 of L - lysine of compound 1 .

DSC measurements were performed using a Discovery DSC (TA instrument) equipped with a refrigerated cooling attachment. Battery constant was determined using indium, and temperature calibration was performed using indium and tin as standards. All measurements were performed under continuous dry nitrogen purging (50 mL/min). Approximately 1 to 5 mg of solid sample was weighed into a Tzero aluminum pan, loosely sealed, and heated from -50°C to 260°C at a heating rate of 10°C/min. Experimental data were analyzed using commercially available software (TA Universal Analysis 2000/Trios software, TA instrument).

A representative differential scanning calorimetry (DSC) chromatogram of Form 2 is shown in Figure 4. As shown in Figure 4, the thermal event was not observed until approximately 219 °C. Therefore, Form 2 of the L-lysine of Compound 1 was determined to be anhydrous. Those skilled in the art will understand that the endothermic initiation can be significantly affected by factors such as crystallinity, the presence of impurities, instrument parameters (e.g., heating/cooling rates, sample quality), and chemical degradation occurring concurrently with other events (e.g., melting, etc.). Therefore, the initiation temperature of approximately 219 °C can be significantly affected by factors that may cause variation (e.g., ±10 °C). Powder X- ray diffraction (PXRD) data were obtained.

The sample of compound 1 in L-lysine form 2, prepared according to the above method, was subjected to PXRD analysis and found to be a crystalline raw material.

Powder X-ray diffraction analysis was performed using a Bruker AXS D8 Endeavor diffractometer equipped with a Cu radiation source. The divergence slit was set to 11 mm for continuous illumination. Diffraction radiation was detected using a PSD-Lynx Eye detector with the PSD opening set to 4.1 degrees. The X-ray tube voltage and current were set to 40 kV and 40 mA, respectively. Data was collected in a Theta-Theta goniometer at Cu wavelengths from 3.0° to 40.0° 2-θ using a step size of 0.02 degrees and a step time of 0.4 seconds. The anti-scattering screen was set to a fixed distance of 3.0 mm. The sample was rotated at a rate of 15 rpm during collection. Samples were prepared by placing them in a sample holder with a low silica background and rotating them during collection. Data were collected using Bruker DIFFRAC Plus software and analyzed using EVA diffract Plus software.

The PXRD file was not processed before peak search. The peak search algorithm in EVA software was used to perform initial peak assignment using peaks selected at a threshold of 10. To ensure effectiveness, manual adjustments were made; the output of the automatic assignment was visually checked, and the peak positions were adjusted to the maximum. Peaks with a relative intensity ≥3.0% were typically selected. Generally, unresolved peaks or peaks consistent with the noise were not selected. The typical error related to the peak position of the PXRD specified in USP is +/- 0.2° 2-θ (USP-941).

A representative PXRD pattern of form 2 of L-lysine of compound 1 is shown in Figure 5. A list of PXRD diffraction peaks from samples of form 2 of L-lysine of compound 1 is provided below, with the peaks expressed in 2θ degrees and relative intensities of ≥3.0%. Raman spectroscopy

Raman spectra were collected using a Thermo Scientific iS50 FT-Raman accessory connected to an FT-IR stage. A _CaF2 spectroscope was used in the FT-Raman configuration. The spectrometer was equipped with a 1064 nm diode laser and a room-temperature InGaAs detector. Samples were analyzed in glass NMR tubes. Spectra were collected using a 0.4 W laser power and 512 co-addition scans. The collection range was 3700–200 ^{cm⁻¹ .} The L-ionate form 2 spectrum of compound 1 was recorded using a 2 ^cm⁻¹ resolution, and all spectra were obtained using the Happ-Genzel apodization method. Multiple spectra were recorded, ^and representative spectra are shown in Figure 10. ^The peak positions varied within ±2 ^cm⁻¹ using this experimental configuration.

Use the automatic peak analysis function in ACD/Spectrus Processor software (2023.2.0) to select peaks. Use a noise factor of 0.3 and a minimum peak level of 3% of the maximum intensity to select peaks. To ensure effectiveness, visually inspect the output of the automatic peak selection. If a peak exists but is not selected by the automatic peak analysis function, select it manually. If a peak is selected by the automatic peak analysis function but has poor resolution or is not located at its maximum, delete the peak. Generally, unresolved peaks or peaks consistent with noise will not be selected.

Table Raman- ² lists the peak positions ( ^cm⁻¹ ) and relative intensities of ^the observed spectra shown in Figure 10. Variations in peak positions using this experimental configuration are within ±2 ^cm⁻¹ . solid-state NMR

^13C solid-state NMR (ssNMR) analysis was performed on a CPMAS probe placed in a Bruker-BioSpin Avance NEO 500 MHz (1H frequency) NMR spectrometer. The material was packed into a ZrO2 rotor. The magic angle rotation rate used was 15 kHz. Spectra were collected at ambient temperature (temperature uncontrolled).

^13C ssNMR spectra were collected using a proton-decoupled cross-polarized magic angle rotation (CPMAS) experiment. A phase-tuned proton decoupling field of 80–100 kHz was applied during spectral acquisition. For the L-lysine form 2 of compound 1, the cross-polarization contact time was set to 2 ms and the cycle delay to 3.5 seconds. The scan number was adjusted to obtain an appropriate signal-to-noise ratio. ^{The 13C} chemical shift scale reference was obtained using ^{a 13C} MAS experiment on an external standard crystalline diamond, with the upper-field resonance set to 29.5 ppm.

Automated peak selection was performed using Bruker-BioSpin TopSpin version 4.1 software. Generally, a 5% relative intensity threshold was used to select the initial peak. The output of the automated peak selection was visually inspected to ensure effectiveness, and manual adjustments were made if necessary. Although specific solid-state NMR peaks are reported in this paper, these peaks do exist as values within a range due to differences in instrumentation, samples, and sample preparation methods. This is frequently performed in solid-state NMR techniques due to inherent variations in peak position. The typical variation in the chemical shift x-axis value is approximately ±0.2 ppm for crystalline solids and approximately ±0.5 ppm for amorphous solids. The solid-state NMR peak heights reported in this paper are relative intensities. The intensity of solid-state NMR can vary depending on the actual settings of the experimental parameters and the thermal history of the sample.

The representative ^13C ss NMR spectra of the L-lysine form 2 of compound 1 are shown in Figure 11. Peaks marked with hash marks represent rotational bands. Table C13NMR-2 lists the ^13C ss NMR peaks of the observed L-lysine form 2 of compound 1 as shown in Figure ^11. The typical variation of the chemical shift x-axis value is approximately ±0.2 ppm in crystalline solids and approximately ±0.5 ppm in amorphous solids. Example 4. 4' - [(1 - {[4- ( propyl - 2 - yl ) phenyl ] aminomethylamino } -D - prolyl ) amino ] [1,1' - biphenyl ] -4 - carboxylic acid L - arginine salt ( L - arginine salt form 1 of compound 1 )

Compound 1 (50.0 g) was added to a mixture of isopropanol (210 mL) and water (90 mL). Then, L-arginine (17.1 g) was added. The resulting mixture was stirred and heated to 70°C to achieve complete dissolution. Isopropanol (700 mL) was then added over 4 hours. The mixture was cooled to 65°C. Seed crystals of form 1 (1000 mg) of L-arginine of compound 1 were added. The resulting slurry was then cooled from 65°C to 20°C at a rate of 0.15°C/min. The product (52.25 g, 95% yield) was separated by filtration, washed with IPA (150 mL), and dried under vacuum at 50°C (this product can also be used as a seed crystal in another method for preparing L-arginine form 1 of compound 1). Seed crystals for preparing L - arginine form 1 of compound 1 .

A slurry was prepared by adding approximately 29 mg of PF-07976016 (free acid) to 2 mL of methanol. The slurry was stirred at 50°C for several minutes. Approximately 62 μL of aqueous L-arginine (0.99 M) was added to the slurry. The slurry was observed to become quite thin.

The resulting slurry was stirred at 55°C for several minutes, then cooled to ambient temperature and stirred for 72 hours. The resulting solid was separated by centrifugal filtration. Differential scanning calorimetry (DSC) analysis of form 1 of L - arginine of compound 1.

DSC measurements were performed using a DSC 2500 (TA instrument) equipped with a refrigerated cooling attachment. Electrode constants were determined using indium, and temperature calibration was performed using indium and tin as standards. All measurements were performed under continuous dry nitrogen purging (50 mL/min). Approximately 1 to 5 mg of solid sample was weighed into a Tzero aluminum pan, loosely sealed, and heated from 0°C to 250°C at a heating rate of 10°C/min. Experimental data were analyzed using commercially available software (TA Universal Analysis 2000/Trios software, TA instrument).

A representative differential scanning calorimetry (DSC) chromatogram of form 1 of L-arginine of compound 1 is shown in Figure 6. As shown in Figure 6, the thermal event was not observed until approximately 221 °C. Therefore, form 1 of L-arginine of compound 1 was determined to be anhydrous. Those skilled in the art will understand that the endothermic initiation can be significantly affected by factors such as crystallinity, the presence of impurities, instrumental parameters (e.g., heating/cooling rates, sample quality), and chemical degradation occurring simultaneously with another event (e.g., melting, etc.). Therefore, the initiation temperature of approximately 221 °C can be significantly affected by factors that may cause variation (e.g., ±10 °C). Powder X- ray diffraction (PXRD) data were obtained.

The sample of compound 1 in form 1 of L-arginine prepared according to the above method was subjected to PXRD analysis and it was found to be a crystalline material.

Powder X-ray diffraction analysis was performed using a Bruker AXS D8 Endeavor diffractometer equipped with a Cu radiation source. The divergence slit was set to 15 mm for continuous illumination. Diffraction radiation was detected using a PSD-Lynx Eye detector with the PSD opening set to 4.1 degrees. The X-ray tube voltage and current were set to 40 kV and 40 mA, respectively. Furthermore, a nickel filter was used to filter out unwanted wavelengths using the energy dispersive detector. Data was collected in a Theta-Theta goniometer from 3.0 degrees to 40.0 degrees 2-θ of Cu wavelength, with a step size of 0.01 degrees and a step time of 1.0 second. The antiscattering screen was set to a fixed distance of 3.0 mm. Samples were rotated at a rate of 15 rpm during collection. Samples were prepared by placing them in a sample holder with a low silica background and rotating them during collection. Data were collected using Bruker DIFFRAC Plus software and analyzed using EVA diffract Plus software.

Data was collected using Bruker DIFFRAC Plus software and analyzed using EVA diffract plus software. The PXRD data file was not processed before peak searching. An initial peak assignment was performed using the peak search algorithm in EVA software, selecting peaks with a threshold of 10. To ensure effectiveness, manual adjustments were made; the output of the automatic assignment was visually checked, and the peak positions were adjusted to the maximum. Peaks with a relative intensity ≥3.0% were typically selected. Generally, unresolved peaks or those consistent with noise were not selected. The typical error related to PXRD peak positions specified in USP is +/-0.2° 2-θ (USP-941).

A representative PXRD pattern of form 1 of L-arginine of compound 1 is shown in Figure 7. A list of PXRD diffraction peaks from the sample of form 1 of L-arginine of compound 1 is provided below, with the peaks expressed in 2θ degrees and relative intensities of ≥3.0%. Raman spectroscopy

Raman spectra were collected using a Thermo Scientific iS50 FT-Raman accessory connected to an FT-IR stage. A _CaF2 spectroscope was used in the FT-Raman configuration. The spectrometer was equipped with a 1064 nm diode laser and a room-temperature InGaAs detector. Samples were analyzed in glass NMR tubes. Spectra were collected using a 0.5 W laser power and 512 co-addition scans. The collection range was 3700–200 ^{cm⁻¹ .} The spectrum of form 1 of L-arginine of compound 1 was recorded using a 2 ^cm⁻¹ resolution, and all spectra were obtained using the ^Happ -Genzel apodization method. Multiple spectra were recorded, and representative spectra are shown in Figure 12. ^The peak positions varied within ±2 ^cm⁻¹ using this experimental configuration.

Use the automatic peak analysis function in ACD/Spectrus Processor software (2023.2.0) to select peaks. Use a noise factor of 0.3 and a minimum peak level of 3% of the maximum intensity to select peaks. To ensure effectiveness, visually inspect the output of the automatic peak selection. If a peak exists but is not selected by the automatic peak analysis function, select it manually. If a peak is selected by the automatic peak analysis function but has poor resolution or is not located at its maximum, delete the peak. Generally, unresolved peaks or peaks consistent with noise will not be selected.

Table Raman- ³ lists the peak positions ( ^cm⁻¹ ) and relative intensities of ^the observed spectra shown in Figure 12. Variations in peak positions using this experimental configuration are within ±2 ^cm⁻¹ . solid-state NMR

Solid-state NMR (ssNMR) analysis was performed ^{at 13} C on a CPMAS probe placed in a Bruker-BioSpin Avance NEO 500 MHz (1H frequency) NMR spectrometer. The L-arginine form of compound 1 was packed into a ZrO2 rotor. A magic angle rotation rate of 15 kHz was used. Spectra were collected at ambient temperature (temperature uncontrolled).

^13C ssNMR spectra were collected using a proton-decoupled cross-polarized magic-angle rotation (CPMAS) experiment. A phase-tuned proton decoupling field of 80–100 kHz was applied during spectral acquisition. For the L-arginine form 1 of compound 1, the cross-polarization contact time was set to 2 ms and the cycle delay to 3.5 seconds. The scan number was adjusted to obtain an appropriate signal-to-noise ratio. ^{The 13C} chemical shift scale reference was obtained using ^{a 13C} MAS experiment on an external standard crystalline diamond, with its upper-field resonance set to 29.5 ppm.

Automated peak selection was performed using Bruker-BioSpin TopSpin version 4.1 software. Generally, a 5% relative intensity threshold was used to select the initial peak. The output of the automated peak selection was visually inspected to ensure effectiveness, and manual adjustments were made if necessary. Although specific solid-state NMR peaks are reported in this paper, these peaks do exist as values within a range due to differences in instrumentation, samples, and sample preparation methods. This is frequently performed in solid-state NMR techniques due to inherent variations in peak position. The typical variation in the chemical shift x-axis value is approximately ±0.2 ppm for crystalline solids and approximately ±0.5 ppm for amorphous solids. The solid-state NMR peak heights reported in this paper are relative intensities. The intensity of solid-state NMR can vary depending on the actual settings of the experimental parameters and the thermal history of the sample.

The representative ^13C ss NMR spectra of the L-arginine form 1 of compound 1 are shown in Figure 13. Peaks marked with hash marks represent rotational bands. Table C13NMR-3 lists the ^13C ss NMR peaks of the observed L-arginine form 1 of compound 1 as shown in Figure ^13. The typical variation of the chemical shift x-axis value is approximately ±0.2 ppm in crystalline solids and approximately ±0.5 ppm in amorphous solids. Example X - 1 of predictive deuterated analogues (PDAs) of certain compounds of the present invention: Some predictive deuterated analogues (PDAs) of compound 1

The compounds provided in Table X - 1 are some predictive deuterated analogs (PDAs) of compound 1. Formula (XA) is the general chemical formula of deuterated compound 1, wherein ^Y1a , ^Y1b , ^Y2 , ^Y3 , Y4a, ^Y4b , ^Y5a , ^Y5b , ^Y5c , ^Y6a , ^Y6b , Y6c ^{, Y7a} , ^Y7b , ^Y8a , ^Y8b , Y9a, ^Y9b , ^Y10a , ^Y10b , ^Y11a and ^Y11b , ^Y12a , ^Y12b , ^{Y13a and Y13b} are each independently H or D (deuterium ⁾ and at least one of them is D. The analogues of deuterated compound 1 in Table X - 1 can be predicted using MetaSite (moldiscovery.com/software/metasite/) based on the metabolic spectrum of compound 1. ^Y1a , ^Y1b , Y2, ^Y3 , ^Y4a , ^Y4b , ^Y5a , ^Y5b , Y5c, ^Y6a , ^Y6b , ^Y6c , ^Y7a , ^Y7b , Y8a, ^Y8b , ^Y9a , ^Y9b , ^Y10a , ^Y10b , ^Y11a , ^Y11b , ^Y12a , ^{Y12b , Y13a ,} and ^Y13b are predicted metabolic ^positions based on MetaSite predictions.

The predictive deuterated analogues (PDAs) of compound 1 in Table X-1 can also form their pharmaceutically acceptable salts, such as their L-lysine or L-arginine. Example AA. Efficacy analysis of functional GIPR antagonists in glass tubes .

The intracellular cyclic adenosine monophosphate (cAMP) levels of test compounds were monitored in Chinese hamster ovary (CHO)-K1 cells stably expressing the human glucose-dependent insulinotropic peptide receptor (hGIPR) to determine their in-tube functional antagonist potency. Upon activation of the agonist, hGIPR binds to a G protein complex, leading to the exchange of bound guanosine diphosphate (GDP) for guanosine triphosphate (GTP) by the Gαs subunit, followed by dissociation of the Gαs-GTP complex. The activated Gαs subunit can couple to downstream effectors to regulate the intracellular level of the second messenger, or cAMP. Therefore, measuring intracellular cAMP levels allows for the determination of pharmacological characteristics. Intracellular cAMP levels were quantified using homogeneous time-resolved fluorescence (HTRF) technology from Perkin Elmer. This method is a competitive immunoassay between naturally occurring cAMP produced by the cell and cAMP labeled with the receptor dye d2. These two substances compete with a monoclonal anti-cAMP antibody labeled with a cryptate compound. This specific signal is inversely proportional to the intracellular cAMP concentration.

The test compound was dissolved in 100% dimethyl sulfoxide (DMSO) to a concentration of 30 mM. An 11-point serial dilution series was created in 100% DMSO using a continuous dilution ratio of 1:3.162 to achieve a maximum concentration of 8 mM. The serially diluted compound was spotted at 50 nL/well into a 384-well analytical dish (Corning, catalog number 3824) using an Echo Acoustic liquid processor (Beckman Coulter), with two replication sites for each concentration, and a final analytical concentration (FAC) of 200x. The final compound concentrations in this analysis ranged from 40 μM to 400 pM, with a final DMSO concentration of 0.5%.

Frozen, ready-to-analyze CHO-K1 cell vials (1 × ^10⁷ cells per vial) (Eurofins, DiscoverX, catalogue number 95-0146C2) containing stable human GIPR receptors coupled to Gs were thawed, counted, and resuspended at a density of 4 × ^10⁵ cells/mL in an analytical buffer. This buffer consisted of 20 mM 4-(2-hydroxyethyl)-1-hexahydropyridine ethanesulfonic acid (HEPES, Lonza, catalogue number 17-737E), 0.1% bovine serum albumin (BSA, Sigma, catalogue number A7979), and 200 μM... The solution consisted of 3-isobutyl-1-methylxanthine (IBMX, Sigma, catalog number I5879) in Hank's balanced salt solution (HBSS, Lonza, catalog number 10-527). Cells were added to analytical plates containing 50 nL of 200x FAC test compound (5 μL/well of 4 × ^10⁵ cells/mL stock solution, final concentration 2,000 cells/well) and incubated for 2 hours at 37°C (95% _O₂ : 5% _CO₂ ) using a microclimate cover (Labcyte, catalog number LLS-0310). After 2 hours of cell and compound incubation, the cells were incubated in an analytical buffer/0.1% DMSO stimulus mixture to estimate EC _80. FAC (based on the previous hGIP agonist curve) was added to the analytical dish (5 μL/well) and incubated for 30 minutes at 37°C (95% _O2 : 5% _CO2 ) using a microclimate cover. The stimulation mixture consisted of the hGIPR agonist human glucose-dependent insulinotropic peptide (hGIP, full length, Sigma catalog number G2269). Intracellular cAMP levels were then quantified according to Perkin Elmer's protocol (5 μL of d2 followed by 5 μL of cage compound, then incubated at room temperature for 1 hour). The emission spectra of the samples were measured using an HTRF protocol (excitation, 320 nm; emission, 665 nm/620 nm) on a Pherastar dish analyzer (BMG Labtech Inc.).

Cells (5 μL/well of 4 × ^10⁵ cells/mL storage medium, ultimately 2,000 cells/well) were incubated with 50 nL of 100% DMSO at 37°C (95% _O₂ : 5% _CO₂ ) for 2 hours and hGIP EC ₅₀ was measured daily using a microclimate cover. After 2 hours of cell incubation with DMSO, 5 μL/well of hGIP concentration response curve (12-point curve, using 1:3 continuous dilution, with three replicates for each concentration, and a final maximum concentration of 100 nM) of 2x FAC in analytical buffer/1% DMSO was added and the cells were further incubated at 37°C (95% _O2 : 5% _CO2 ) with a microclimate cover for 30 minutes. Intracellular cAMP levels were then quantified and samples were measured as previously described. The experiment passed quality control if the concentration of the stimulator used was between _EC50 and _EC90 of the day.

Data for each well was analyzed using the fluorescence intensity ratio at 620 and 665 nm, and the data for each well was expressed as nanomoles (nM) cAMP, inferred from the cAMP standard curve. The data expressed as nM cAMP were then standardized against the control well using ActivityBase (IDBS data management software). Zero effect (ZPE) was defined as nM cAMP produced from the hGIP stimulus mixture, while 100% effect or 100% effect (HPE) was defined as nM cAMP produced from the antagonistic combination of the hGIP simulation mixture and 80 μM (-)-3-(6-(2-methyl-1-(4'-(trifluoromethyl)biphenyl-4-yl)propylamino)nicotinamide)propionic acid as a GIPR antagonist. Using ActivityBase, the concentrations and % efficacy values of each compound were plotted using a four-parameter logical dose-response equation, and the concentration required for 50% inhibition ( _IC50 ) was determined.

Table AA-1 lists the biological activity (IC ₅₀ value) and compound name of the test compounds. 1. The numerical value represents the geometric mean. 2. The numerical value includes the overall geometric mean of the various forms of the test (including salt).

This application references various publications in their entirety. The full text of the disclosures in such publications is incorporated herein by reference for all purposes.

Those skilled in the art will clearly understand that various modifications and variations can be made to this invention without departing from its scope or spirit. Those skilled in the art will clearly understand other embodiments of this invention by considering the patent specification and embodiments disclosed herein. The patent specification and embodiments should be considered exemplary only, and the true scope and spirit of this invention are indicated by the appended patent claims.

[Figure 1] shows the powder X-ray diffraction pattern (PXRD) of the sesquihydrate crystal form (form 1) of compound 1, which was observed on a Bruker AXS D8 Endeavor diffractometer equipped with a Cu radiation source.

[Figure 2] shows the illustrative single-crystal structure of L-lysine form 1 (sesquihydrate) of compound 1 based on preliminary analysis.

[Figure 3] shows a portion of the asymmetric unit of a representative labeling scheme for the single crystal structure of L-lysine form 1 (sesquihydrate) of compound 1 according to preliminary analysis.

[Figure 4] shows the differential scanning calorimetry (DSC) thermal analysis diagram of the anhydrous crystal form (form 2) of the observed compound 1, L-lysine.

[Figure 5] shows the powder X-ray diffraction pattern of the anhydrous crystalline form (form 2) of compound 1, L-lysine, as observed on a Bruker AXS D8 Endeavor diffractometer equipped with a Cu radiation source.

[Figure 6] shows the differential scanning calorimetry (DSC) thermal analysis curve of the anhydrous crystal form (form 1) of the observed compound 1, L-arginine (anhydrous).

[Figure 7] shows the powder X-ray diffraction pattern of form 1 of L-arginine of compound 1 as observed on a Bruker AXS D8 Endeavor diffractometer equipped with a Cu radiation source.

[Figure 8] shows the Raman spectrum of the observed compound 1 in the form of L-ionate (sesquihydrate).

[Figure 9] shows the representative ^13C ssNMR spectrum of the L-ionate form 1 (sesquihydrate) of compound 1 observed.

[Figure 10] shows the Raman spectrum of the observed compound 1 in its L-ionate form 2.

[Figure 11] shows the representative ^13C ssNMR spectrum of the L-ionate form 2 of compound 1 observed.

[Figure 12] shows the Raman spectrum of the observed compound 1 in the form of L-arginine salt 1.

[Figure 13] shows the representative ^13C ssNMR spectrum of the L-arginine form of compound 1 observed.

[Figure 14] shows the illustrative single-crystal structure of L-lysine form 1 (sesquihydrate) of compound 1 according to the updated analysis.

[Figure 15] shows a representative marked partial asymmetric unit of the single crystal structure of compound 1 in the form of L-lysine salt 1 (sesquihydrate) according to the updated analysis.

Claims (36)

A compound that is 4'-[(1-{[4-(propyl-2-yl)phenyl]aminomethoxy}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid ionate. A crystalline form of a compound as described in claim 1. A hydrated form of a compound as requested in claim 1. A crystalline form of the compound as claimed in claim 1, wherein the crystalline form is anhydrous. A compound, which is 4'-[(1-{[4-(propyl-2-yl)phenyl]aminomethylamino}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid ionate salt, sesquihydrate. An amorphous form of a compound as described in claim 1. The compound of any one of claims 1 to 6, wherein the 4'-[(1-{[4-(propyl-2-yl)phenyl]aminomethylamino}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid ionate is 4'-[(1-{[4-(propyl-2-yl)phenyl]aminomethylamino}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid L-ionate. The compound of claim 1, wherein the compound is a sesquihydrate crystal form of 4'-[(1-{[4-(propyl-2-yl)phenyl]aminomethylamino}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid L-ionate ("Form 1 of L-ionate of Compound 1"), wherein Form 1 has a powder X-ray diffraction (PXRD) pattern containing at least one peak selected, in 2θ, from the following positions: 16.7±0.2˚, 17.9±0.2˚, 18.6±0.2˚ and 19.7±0.2˚. The compound of claim 8, wherein the L-lysine salt of compound 1 in form 1 has a PXRD comprising at least two peaks, the at least two peaks being selected, in 2θ, from the following positions: 7.3±0.2˚, 16.7±0.2˚, 17.9±0.2˚, 18.6±0.2˚ and 19.7±0.2˚. The compound of claim 8 or 9, wherein the L-lysine form 1 of compound 1 has an FT-Raman spectrum containing at least one peak, which is selected in terms of wavenumber ( ^{cm⁻¹ )} from the following positions: 1284± ^{2 cm⁻¹} , 1604±2 ^{cm⁻¹ and} 1636± ^{2 cm⁻¹} . The compound of claim 8 or 9, wherein the L-lysine form 1 of compound 1 has an FT-Raman spectrum containing at least two peaks, the at least two peaks being selected in terms of wavenumber ( ^{cm⁻¹ ) from} the following positions: 1284±2 ^cm⁻¹ , 1604±2 ^{cm⁻¹ and} 1636±2 ^{cm⁻¹ .} The compound of claim 8 or 9, wherein the L-ionate form 1 of compound 1 has a ^13C ss NMR spectrum containing two peaks located at 131.3 ± 0.2 ppm and 169.6 ± 0.2 ppm in terms of chemical shift. The compound of claim 8 or 9, wherein the L-ionate form 1 of compound 1 has a ^13C ss NMR spectrum containing at least three peaks selected, in terms of chemical shift, from the following: 24.5 ± 0.2 ppm, 47.1 ± 0.2 ppm, 131.3 ± 0.2 ppm and 169.6 ± 0.2 ppm. The compound of claim 1, wherein the compound is an anhydrous crystalline form of 4'-[(1-{[4-(propyl-2-yl)phenyl]aminomethylamino}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid L-lysine ("Form 2 of L-lysine of Compound 1"), wherein Form 2 has a powder X-ray diffraction (PXRD) pattern containing at least one peak selected, in 2θ, from the following positions: 4.4±0.2˚, 5.9±0.2˚, 8.8±0.2˚, and 10.3±0.2˚. The compound of claim 14, wherein the L-lysine form 2 of compound 1 has a PXRD comprising at least two peaks, the at least two peaks being selected, with respect to 2θ, from the following positions: 4.4±0.2˚, 5.9±0.2˚, 8.8±0.2˚, 10.3±0.2˚ and 18.3±0.2˚. The compounds of claims 14 or 15, wherein the L-lysine form 2 of compound 1 has an endothermic differential scanning calorimetry trace comprising an initial temperature of about 219.9 ± 10.0 °C. ^The compounds of claim 14 or 15, wherein the L-lysine form 2 of compound 1 has an FT-Raman spectrum containing two peaks selected in terms of wavenumber ( ^cm⁻¹ ) from the following positions: 1283± ^{2 cm⁻¹} , 1606±2 ^{cm⁻¹ and} 1666± ^{2 cm⁻¹} . The compounds of claim 14 or 15, wherein the L-lysine form 2 of compound 1 has an FT-Raman spectrum containing peaks located at the following positions in terms of wavenumber ( ^{cm⁻¹ )} : 1283± ^{2 cm⁻¹} , 1606±2 ^{cm⁻¹ and} 1666±2 ^{cm⁻¹ .} The compounds of claim 14 or 15, wherein the L-lysine form 2 of compound 1 has a ^13C ss NMR spectrum containing at least one peak selected, in terms of chemical shift, from the following: 32.2 ± 0.2 ppm, 120.9 ± 0.2 ppm, 127.3 ± 0.2 ppm and 177.4 ± 0.2 ppm. The compound of claim 14 or 15, wherein the L-ionate form 2 of compound 1 has a ^13C ss NMR spectrum containing at least two peaks selected, in terms of chemical shift, from the following: 32.2 ± 0.2 ppm, 120.9 ± 0.2 ppm, 127.3 ± 0.2 ppm and 177.4 ± 0.2 ppm. A compound that is 4'-[(1-{[4-(propyl-2-yl)phenyl]aminomethylamino}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid arginine salt. A crystalline form of a compound as described in claim 21. A crystalline form of the compound as claimed in claim 21, wherein the crystalline form is anhydrous. An amorphous form of a compound as described in claim 21. The compound of any one of claims 21 to 24, wherein the 4'-[(1-{[4-(propyl-2-yl)phenyl]aminomethylamino}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid arginine salt is 4'-[(1-{[4-(propyl-2-yl)phenyl]aminomethylamino}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid L-arginine salt. The compound of claim 21, wherein the compound is an anhydrous crystalline form of 4'-[(1-{[4-(propyl-2-yl)phenyl]aminomethylamino}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid L-arginine ("Form 1 of L-arginine of Compound 1"), wherein the powder of Form 1 has an X-ray diffraction pattern (PXRD) containing at least one peak located at 14.6±0.2˚, 17.6±0.2˚, 18.3±0.2˚ and 20.0±0.2˚ with respect to 2θ. The compound of claim 26, wherein the L-arginine form 1 of compound 1 has a PXRD comprising at least two peaks located at 7.3±0.2˚, 14.6±0.2˚, 17.6±0.2˚, 18.3±0.2˚ and 20.0±0.2˚ in terms of 2θ. The compounds of claims 26 to 27, wherein the L-arginine form of compound 1 has an endothermic differential scan calorimetric trace comprising an initial temperature of about 221.2 ± 10.0 °C. The compound of any one of claims 26 to 28, wherein the L-arginine form 1 of compound 1 has an FT-Raman spectrum containing at least one peak, which, in terms of wavenumber ( ^cm⁻¹ ) ^, is selected from the following positions: 1279±2 ^{cm⁻¹ ,} 1602±2 ^{cm⁻¹ and} 1611±2 ^{cm⁻¹ .} The compound of claim 26 or 27, wherein the L-arginine form 1 of compound 1 has an FT-Raman spectrum containing at least two peaks, which are selected in terms of wavenumber ( ^cm⁻¹ ) ^from the following positions: 1279± ^{2 cm⁻¹} , 1602±2 ^{cm⁻¹ and} 1611±2 ^{cm⁻¹ .} The compound of claim 26 or 27, wherein the L-arginine form of compound 1 has a ^13C ss NMR spectrum containing at least one peak, the at least one peak being selected in terms of chemical shift from the following: 46.3 ± 0.2 ppm, 138.2 ± 0.2 ppm, 140.1 ± 0.2 ppm and 176.3 ± 0.2 ppm. The compound of claim 26 or 27, wherein the L-arginine form 1 of compound 1 has a ^13C ss NMR spectrum containing at least two peaks selected, in terms of chemical shift, from the following: 46.3 ± 0.2 ppm, 138.2 ± 0.2 ppm, 140.1 ± 0.2 ppm and 176.3 ± 0.2 ppm. A pharmaceutical composition comprising a compound as described in any of claims 1 to 32 and a pharmaceutically acceptable excipient. Use of any compound of claims 1 to 32 in the manufacture of a medicament for the treatment or prevention of a condition, disease, or symptom, wherein the condition, disease, or symptom is selected from the group consisting of: diabetes [e.g., type 1 diabetes (T1D), type 2 diabetes (T2DM), including prediabetes], idiopathic T1D (type 1b), latent autoimmune diabetes mellitus in adults (LADA), early-onset T2DM (EOD), adolescent atypical diabetes (YOAD), juvenile adult-onset diabetes (MODY), malnutrition-associated diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, glucose intolerance, Diabetic neuropathy, diabetic nephropathy, kidney diseases [e.g., acute nephropathy, renal tubular dysfunction, pro-inflammatory changes in the proximal tubules, or chronic nephropathy (CKD)], diabetic retinopathy, adipocyte dysfunction, visceral fat deposition, sleep apnea [e.g., obstructive sleep apnea (OSA)], obesity (including hypothalamic obesity and monogenic obesity) and related complications (e.g., osteoarthritis and urinary incontinence), eating disorders (including bulimia syndrome, bulimia nervosa, and syndrome obesity, such as Prader-Willi syndrome and Bardet-Biedl syndrome) Weight gain, such as weight gain due to the use of other medications (e.g., steroids and/or antipsychotics, treatment of depression, or medications affecting cognitive function), being overweight, excessive sugar cravings, dyslipidemia [including hyperlipidemia, hypertriglyceridemia, elevated total cholesterol, high LDL (low-density lipoprotein) cholesterol and low HDL (high-density lipoprotein) cholesterol], hyperinsulinemia, non-alcoholic fatty liver disease [NAFLD, including conditions such as steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma], cardiovascular disease, and atherosclerosis (including coronary artery disease). Peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, heart failure [e.g., congestive heart failure, heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF)], myocardial infarction (e.g., necrosis and apoptosis), stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, osteoarthritis, Parkinson's disease, left ventricular hypertrophy, peripheral arterial disease (PAD), macular degeneration. Degeneration, cataracts, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attack, restenosis, impaired glucose metabolism, abnormal fasting blood glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue diseases, psoriasis, foot ulcers, ulcerative colitis, high APO B-lipoproteinemia, Alzheimer's disease, schizophrenia, cognitive impairment, inflammatory bowel disease, short bowel syndrome, Crohn's disease, colitis, irritable bowel syndrome, polycystic ovary syndrome (PCOS), and addiction (e.g., alcohol, nicotine, and/or drug addiction); or the use of a compound as described in any of claims 1 to 32 in weight management (e.g., chronic weight management); or the use of a compound as described in any of claims 1 to 20 in the manufacture of a drug for weight management (e.g., long-term weight management). A compound of any one of claims 1 to 32, used in a method for treating or preventing a patient’s condition, disease, or symptom, wherein the condition, disease, or symptom is selected from the group consisting of: diabetes [e.g., type 1 diabetes (T1D), type 2 diabetes (T2DM), including prediabetes], idiopathic T1D (type 1b), latent autoimmune diabetes mellitus in adults (LADA), early-onset T2DM (EOD), adolescent atypical diabetes (YOAD), juvenile adult-onset diabetes (MODY), malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, glucose intolerance, diabetic neuropathy, diabetic nephropathy, renal disease [e.g., acute nephropathy] [Diseases, renal tubular dysfunction, pro-inflammatory changes in the proximal tubules or chronic nephropathy (CKD)], diabetic retinopathy, adipocyte dysfunction, visceral fat deposition, sleep apnea [e.g., obstructive sleep apnea (OSA)], obesity (including hypothalamic obesity and monogenic obesity) and related complications (e.g., osteoarthritis and urinary incontinence), eating disorders (including bulimia syndrome, bulimia nervosa, and syndrome obesity, such as Prader-Willi syndrome and Bardet-Biedl syndrome), weight gain, such as weight gain due to the use of other medications (e.g., due to the use of steroids and/or antipsychotics, or due to the treatment of depression). Caused by or due to the use of medications that affect cognitive function; overweight; excessive sugar cravings; dyslipidemia [including hyperlipidemia, hypertriglyceridemia, elevated total cholesterol, high LDL (low-density lipoprotein) cholesterol and low HDL (high-density lipoprotein) cholesterol]; hyperinsulinemia; non-alcoholic fatty liver disease [NAFLD, including diseases such as steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis and hepatocellular carcinoma]; cardiovascular disease; atherosclerosis (including coronary artery disease); peripheral vascular disease; hypertension; endothelial dysfunction; impaired vascular compliance; heart failure [e.g. congestive heart failure, heart failure with preserved ejection rate (HFpEF), heart failure with reduced ejection rate (H... FrEF), myocardial infarction (e.g., necrosis and apoptosis), stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, osteoarthritis, Parkinson's disease, left ventricular hypertrophy, peripheral arterial disease (PAD), macular degeneration Cataracts, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attack, restenosis, impaired glucose metabolism, abnormal fasting blood glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue diseases, psoriasis, foot ulcers, ulcerative colitis, high APO levels B-lipoproteinemia, Alzheimer's disease, schizophrenia, cognitive impairment, inflammatory bowel disease, short bowel syndrome, Crohn's disease, colitis, irritable bowel syndrome, polycystic ovary syndrome (PCOS), and addiction (e.g., alcohol, nicotine, and/or drug addiction); or a compound of any of claims 1 to 32 for use in human weight management (e.g., long-term weight management). Use of a compound as claimed in any one of claims 1 to 32 in the manufacture of a medicine for regulating glucose-dependent insulinotropic peptide receptors (GIPR).