Glucose-dependent insulin secretion-stimulating polypeptide receptor antagonists and their use

Abstract

In this specification, compounds of formula I and their pharmaceutically acceptable salts (wherein R 1 , R 2 , R 3 , L 1 , T 1 , T 2 , T 3 , T 4 , t1, and t2 are as defined herein), their use as GIPR antagonists, pharmaceutical compositions containing such compounds and salts, and the use of such compounds and salts for treating or preventing, for example, obesity, weight gain, and / or T2DM are described. 【Chemical Formula 1】 TIFF2026516633000207.tif175168

Description

[Technical Field]

[0001] The present invention relates to novel pharmaceutical compounds, pharmaceutical compositions containing the compounds, and the use of the compounds as glucose-dependent insulin secretion-stimulating polypeptide receptor (GIPR) antagonists. [Background technology]

[0002] Glucose-dependent insulinotropic polypeptide (GIP, formerly known as gastric suppressor polypeptide) is a 42-amino acid peptide secreted by K cells in the small intestine (duodenum and jejunum). Human GIP arises from the processing of proGIP, a 153-amino acid precursor encoded by a gene located on chromosome 17 (see, e.g., Inagaki et al., Mol Endocrinol 1989;3:1014~1021, and Fehmann et al., Endocr Rev. 1995;16:390~410). GIP secretion is induced by food intake. GIP is a known insulinotropic factor (or "incretin") that enhances glucose-dependent insulin secretion. GIP has further physiological effects in several tissues, including promoting fat storage in adipose tissue. Intact GIP is rapidly inactivated by dipeptidyl peptidase 4 (DPPIV).

[0003] The GIP receptor (GIPR) belongs to the glucagon 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, e.g., Zhao et al., Nat Commun. 2022, 13:1057). The N-terminal extracellular domain forms the receptor's major peptide recognition and binding site. Upon GIP stimulation, GIPR undergoes a structural change from an inactive to an active conformation, thereby inducing increased Gαs-mediated cAMP production. GIPR is expressed in a variety of tissues, including the pancreas, intestine, adipose tissue, blood vessels, heart, and brain (see, e.g., Hammoud et al., Nat Rev Endocrinol 2023;18:201~216). Human GIPR consists of 466 amino acids and is encoded by a gene located on chromosome 19 (see, e.g., Gremlich et al., Diabetes. 1995;44:1202~8, and Volz et al., FEBS Lett. 1995, 373:23~29). Studies have suggested that alternative mRNA splicing can generate GIPR variants of different lengths (see, e.g., Harada et al., Am J Physiol Endocrinol Metab. 2008.294:E61~E68, and Marti-Solano et al., Nature. 2020, 587:650~656).

[0004] GIPR knockout mice are resistant to high-fat diet-induced weight gain and exhibit improved insulin sensitivity and lipid profiles (see, e.g., Yamada et al., Diabetes. 2006, 55:S86, and Miyawaki et al., Nature Med. 2002, 8:738-742). Recent data support that heterozygous loss of GIPR function reduces BMI and obesity risk in humans (see, e.g., Akabari et al., Science. 2021, 373:6550). Small molecule compounds, peptides, and monoclonal antibodies with GIPR antagonist activity have been shown to prevent weight gain and insulin resistance in preclinical obesity models (see, e.g., 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:eaat3392). Combinations of GIPR modulators and GLP-1R agonists have been associated with superior weight loss (see, e.g., Lu et al., Cell Rep Med. 2021, 2(5):100263). In summary, these associations with obesity and metabolic disorders suggest that GIPR inhibition, both as monotherapy and in combination with other agents including GLP-1R agonists, is a useful therapeutic intervention. Furthermore, human epicardial adipose tissue, which plays a crucial role in the onset and progression of coronary artery disease, atrial fibrillation, and heart failure, has been found to express the GIPR gene and protein. See, for example, Malavazos et al., European Journal of Preventive Cardiology (2023) 00, 1-14.

[0005] For the treatment or prevention of conditions, diseases, or disorders related to GIPR, such as those described herein, there remains a need for alternative GIPR antagonists, for example, for the development of novel and / or improved pharmaceuticals (e.g., more effective, more selective, less toxic, improved patient compliance, and / or improved biopharmaceutical properties such as physical stability, solubility, oral bioavailability, appropriate metabolic stability, clearance, half-life, etc.). The present invention is directed to these and other important objectives. Summary of the Invention Problems to be Solved by the Invention

[0006] Means for Solving the Problems

[0007] In one embodiment (Embodiment A1), the present invention provides a compound of Formula I

[0008] [Chemical Formula] or a pharmaceutically acceptable salt thereof [wherein, R 2~8 , 3~6 , 1~4 , 3~6 , 1~4 , 1~8 , 1~4 , 3~6 , 1~8 , 1~4 , 2~8 , 1~4 , 1 , 1~4 , 3~6 is H, halogen, -CN, C 1~8 alkyl, C 2~8 alkenyl, (C​​​​​​​​​​​​​​​​​​​​​​​They may be substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from the haloalkoxy. Each R 2 These are, independently, halogen, -OH, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 3~4 Cycloalkyl, or (C 3~4 Cycloalkyl)-C 1~4 It is alkyl-, and here C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 3~4 Cycloalkyl, or (C 3~4 Cycloalkyl)-C 1~4 Each of the alkyl- groups is a halogen, -OH, or C. 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, and C 1~4 The haloalkoxy may be substituted with one, two, or three substituents independently selected from each of them. or two R's 2 If they are bonded to the same ring carbon atom of the proline ring in formula I, then together with the ring carbon atom to which they are bonded, C 3~6 They may form cycloalkyl or 4- to 7-membered heterocycloalkyl groups, each of which may contain a halogen, -OH, and C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, and C 1~4 The haloalkoxys may be substituted with one, two, three, or four substituents, each independently selected from the haloalkoxys. or two R's 2 If it is bonded to two adjacent ring carbon atoms of the proline ring in formula I, then together with the two ring carbon atoms to which they are bonded, C 3~6 They may form cycloalkyl or 4- to 7-membered heterocycloalkyl groups, each of which may contain a halogen, -OH, and C 1~4Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, and C 1~4 The haloalkoxys may be substituted with one, two, three, or four substituents, each independently selected from the haloalkoxys. R 3 is, R 3a , R 3b , R 3c , or R 3d

[0009] [ka] And, T 1 , T 2 , T 3 , and T 4 Each of them independently, CR 4 or N, however T 1 , T 2 , T 3 , and T 4 The condition is that only 0, 1, or 2 of them may be N, Each R 4 These are independently H, halogen, -CN, and C. 3~6 Cycloalkyl, (C 3~6 Cycloalkyl)-C 1~2 Alkyl-, C 1~4 Alkyl, C 1~4 Cyanoalkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, or C 1~4 It is a haloalkoxy, T 5 , T 6 , T 7 , and T 8 Each of them independently, CR 5 or N, however T 5 , T 6 , T 7 , and T 8 The condition is that only 0, 1, or 2 of them may be N, Each R 5 These are independently H, halogen, -CN, and C. 3~6Cycloalkyl, (C 3~6 Cycloalkyl)-C 1~2 Alkyl-, C 1~4 Alkyl, C 1~4 Cyanoalkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, or C 1~4 Haloalkoxy, and T 9 、T 10 、T 11 、and T 12 each of which is independently CR 6 or N, provided that 9 、T 10 、T 11 、and T 12 only 0, 1, or 2 of them may be N, each R 6 is independently H, halogen, -CN, C 3~6 Cycloalkyl, (C 3~6 Cycloalkyl)-C 1~2 Alkyl-, C 1~4 Alkyl, C 1~4 Cyanoalkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, or C 1~4 Haloalkoxy, and T 13 、T 14 、T 15 、and T 16 each of which is independently CR 7 or N, provided that 13 、T 14 、T 15 、and T 16 only 0, 1, or 2 of them may be N, each R 7 is independently H, halogen, -CN, C 3~6 Cycloalkyl, (C 3~6 Cycloalkyl)-C 1~2 Alkyl-, C 1~4 Alkyl, C 1~4 Cyanoalkyl, C 1~4 Haloalkyl, C<00​1~4 It is a haloalkoxy, T 17 , T 18 , and T 19 Each of them independently, CR 8 or N, however T 17 , T 18 , and T 19 The condition is that only 0, 1, or 2 of them may be N, Each R 8 These are independently H, halogen, -CN, and C. 3~6 Cycloalkyl, (C 3~6 Cycloalkyl)-C 1~2 Alkyl-, C 1~4 Alkyl, C 1~4 Cyanoalkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, or C 1~4 It is a haloalkoxy, T 20 , T 21 , and T 22 Each of them independently, CR 9 or N, however T 20 , T 21 , and T 22 The condition is that only 0, 1, or 2 of them may be N, Each R 9 These are independently H, halogen, -CN, and C. 3~6 Cycloalkyl, (C 3~6 Cycloalkyl)-C 1~2 Alkyl-, C 1~4 Alkyl, C 1~4 Cyanoalkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, or C 1~4 It is a haloalkoxy, Each R 10 These are, independently, halogen, -OH, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 3~4 Cycloalkyl, or (C 3~4 Cycloalkyl)-C1~4 It is alkyl-, and here C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 3~4 Cycloalkyl, or (C 3~4 Cycloalkyl)-C 1~4 Each of the alkyl- groups is a halogen, -OH, or C. 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, and C 1~4 They may be substituted with one, two, or three substituents independently selected from the haloalkoxy, R A -C(=O)-OH, 1H-tetrazole-5-yl, OH, -C(=O)-N(R 11 )(R 12 ), -C(=O)-OR 13 , 3-hydroxyisoxazole-5-yl, or -S(=O)2NHCF3, R 11 and R 12 Each of these is independently H, C 1~6 Alkyl, C 3~6 Cycloalkyl, (C 3~6 Cycloalkyl)-C 1~4 Alkyl-, phenyl, or phenyl-C 1~4 It is alkyl-, and here C 1~6 Alkyl, C 3~6 Cycloalkyl, (C 3~6 Cycloalkyl)-C 1~4 Alkyl-, phenyl, or phenyl-C 1~4 Each of the alkyl- prefixes is a halogen, -OH, -CN, or C. 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 3~4 Cycloalkyl, or (C 3~4 Cycloalkyl)-C 1~4 The alkyl group may be substituted with 1, 2, 3, 4, or 5 substituents, each independently selected from the alkyl group. or R 11 and R 12 Together with the nitrogen atom to which they are bonded, they form halogens, -OH, -CN, and C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 3~4 Cycloalkyl, or (C 3~4 Cycloalkyl)-C 1~4 A 4- to 8-membered heterocycloalkyl group is formed, which may be substituted with 1, 2, 3, 4, or 5 substituents independently selected from each alkyl group, where C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 3~4 Cycloalkyl, or (C 3~4 Cycloalkyl)-C 1~4 Each of the alkyl- groups is a halogen, -OH, or C. 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, and C 1~4 The haloalkoxy may be substituted with one, two, or three substituents independently selected from each of them. R 13 C 1~6 Alkyl, C 3~6 Cycloalkyl, (C 3~6 Cycloalkyl)-C 1~4 Alkyl-, phenyl, or phenyl-C 1~4 They are alkyl-, and each of them is a halogen, -OH, -CN, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 3~4 Cycloalkyl, or (C 3~4 Cycloalkyl)-C 1~4 The alkyl group may be substituted with 1, 2, 3, 4, or 5 substituents, each independently selected from the alkyl group. L 1 C(R L )2, Each R L H and C are independent of each other. 1~2 Alkyl, C 1~2 Haloalkyl, C 1~2 Alkoxy, or C 1~2 It is a haloalkoxy, or two R's L Together with the carbon atoms to which they are bonded, C 3~6 They may form cycloalkyl or 3- to 6-membered heterocycloalkyl groups, each of which may contain a halogen, -OH, and C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, and C 1~4 The haloalkoxys may be substituted with one, two, three, or four substituents, each independently selected from the haloalkoxys. t1 is either 0 or 1, t2 is 0, 1, 2, 3, or 4. t3 is either 1 or 2. t4 is 0, 1, 2, 3, or 4.

[0010] The present invention also provides a pharmaceutical composition containing a compound of formula I or a pharmaceutically acceptable salt of the compound and a pharmaceutically acceptable excipient or carrier.

[0011] The present invention also provides a method for treating or preventing a GIPR-related condition, disease, or disorder in a patient (e.g., a mammal or a human), the method comprising administering to the patient (e.g., a mammal or a human) a compound of formula I or a pharmaceutically acceptable salt of the compound.

[0012] The present invention also provides compounds of formula I or pharmaceutically acceptable salts of the compounds for use in treating or preventing GIPR-related conditions, diseases, or disorders.

[0013] Conditions, diseases, or disorders associated with GIPR include diabetes mellitus [e.g., type 1 diabetes mellitus (T1D), type 2 diabetes mellitus (T2DM), prediabetes], idiopathic T1D (type 1b), latent autoimmune diabetes mellitus in adults (LADA), early-onset T2DM (EOD), juvenile-onset atypical diabetes mellitus (YOAD), juvenile adult-onset diabetes mellitus (MODY), malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, renal diseases [e.g., acute kidney injury, tubular dysfunction, pro-inflammatory changes in the proximal tubules, and] Weight gain such as chronic kidney disease (CKD), diabetic retinopathy, adipocyte dysfunction, visceral fat deposition, sleep apnea [e.g., obstructive sleep apnea (OSA)], obesity (including hypothalamic obesity and monogenic obesity) and associated comorbidities (e.g., osteoarthritis and urinary incontinence), eating disorders (including bulimia nervosa, bulimia nervosa, and symptomatic obesity such as Prader-Willi syndrome and Baldett-Beedl syndrome), and weight gain caused by the use of other medications (e.g., weight gain caused by the use of steroids and / or antipsychotics). (caused by treatment for depression or use of medications for cognitive function), excessive sugar craving, 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 [including fatty liver, non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and related diseases such as hepatocellular carcinoma (NAFLD)], cardiovascular disease, atherosclerosis (coronary artery disease) (including pulmonary 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 dyslipidemia, metabolic acidosis, ketosis, arthritis, osteoporosis, osteoarthritis, Parkinson's disease, left ventricular hypertrophy, peripheral artery disease, macular degeneration, cataracts, glomerulosclerosis, chronic renal failure,This includes a selection of conditions from metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, arteriosclerosis, transient ischemic attack, restenosis, impaired glucose metabolism, abnormal fasting blood glucose levels, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders, psoriasis, foot ulcers, ulcerative colitis, hyperapolipoproteinemia, Alzheimer's disease, schizophrenia, cognitive impairment, inflammatory bowel disease, short bowel syndrome, Crohn's disease, colitis, irritable bowel syndrome, polycystic ovary syndrome (PCOS), and addictions (e.g., alcohol, nicotine, and / or drug addiction).

[0014] The present invention also provides a method for antagonizing glucose-dependent insulin secretion-stimulating polypeptide receptor (GIPR), the method comprising contacting GIPR with a compound of formula I or a pharmaceutically acceptable salt of the compound.

[0015] It should be understood that the above general description and the following detailed description are both illustrative and explanatory, and do not limit the claimed invention. [Modes for carrying out the invention]

[0016] The present invention can be more readily understood by referring to the following detailed description of exemplary embodiments and examples included in the embodiments of the present invention.

[0017] Some additional exemplary embodiments of the present invention are described below in this specification.

[0018] Embodiment A2 is a further embodiment of Embodiment A1, where the compound is the compound of formula Ia.

[0019] [ka] or a pharmaceutically acceptable salt thereof.

[0020] Embodiment A3 is a further embodiment of Embodiment A1, where the compound is a compound of formula II.

[0021] [ka] or a pharmaceutically acceptable salt thereof.

[0022] Embodiment A4 is a further embodiment of Embodiment A1, where the compound is a compound of formula IIa.

[0023] [ka] or a pharmaceutically acceptable salt thereof.

[0024] Embodiment A5 is a further embodiment of Embodiment A1, where the compound is a compound of formula III.

[0025] [ka] or a pharmaceutically acceptable salt thereof. Embodiment A5-a is a further embodiment of Embodiment A5, where L 1 is CH2. When Embodiment A5 is referred to herein below, it includes Embodiment A5 and any of its further embodiments (Embodiment A5-a).

[0026] Embodiment A6 is a further embodiment of Embodiment A1, where the compound is a compound of formula IIIa.

[0027] [ka] or a pharmaceutically acceptable salt thereof. Embodiment A6-a is a further embodiment of Embodiment A6, where L 1 is CH2. When Embodiment A6 is referred to herein below, it includes Embodiment A6 and any of its further embodiments (Embodiment A6-a).

[0028] Embodiment A7 is a further embodiment of Embodiment A1, where the compound is the compound of formula IV.

[0029] [ka] or a pharmaceutically acceptable salt thereof.

[0030] Embodiment A7-a is a further embodiment of Embodiment A7, where the compound is the compound of formula IV-1.

[0031] [ka] or a pharmaceutically acceptable salt thereof, R 1 These are propan-2-yl, propa-1-en-2-yl, trifluoromethyl, or cyclopropyl. R 4 is H, halo, or C 1~2 It is alkyl, T 5 , T 6 , T 7 , and T 8 Each of them independently performs CR 5 is or T 5 , T 6 , T 7 , and T 8 One of them is N, and T 5 , T 6 , T 7 , and T 8 Each of the other three independently underwent CR 5 And, Each R 5 These are independently H, halogen, -CN, and C. 1~2 Alkyl, C 1~2 Haloalkyl, C 1~2 Alkoxy, or C 1~2 It is a haloalkoxy.

[0032] Embodiment A7-a-1 is a further embodiment of Embodiment A7-a, where R 1is propan-2-yl or trifluoromethyl, and R 4 is H, F, Cl, or C 1~2 It is alkyl, T 5 , T 6 , T 7 , and T 8 Each of them independently performs CR 5 And each R 5 These are H, F, Cl, and C, independently. 1~2 Alkyl, C 1~2 Haloalkyl, C 1~2 Alkoxy, or C 1~2 It is a haloalkoxy. Embodiment A7-a-2 is a further embodiment of Embodiment A7-a, where R 1 is propan-2-yl or trifluoromethyl, and R 4 is H, F, or C 1~2 Alkyl (e.g., methyl), T 5 , T 6 , T 7 , and T 8 Each of them independently performs CR 5 And each R 5 These are H, F, and C, independently. 1~2 Alkyl, C 1~2 Haloalkyl, C 1~2 Alkoxy, or C 1~2 It is a haloalkoxy. Embodiment A7-a-3 is a further embodiment of Embodiment A7-a, where R 1 is propan-2-yl or trifluoromethyl, and R 4 is H, F, or C 1~2 Alkyl (e.g., methyl), T 5 , T 6 , T 7 , and T 8 Each of them independently performs CR 5 And each R 5 is H. Embodiment A7-a-4 is a further embodiment of Embodiment A7-a, where R 1 is propan-2-yl or trifluoromethyl, and R 4 is H, F, Cl, or C 1~2 It is alkyl, T 5, T 6 , T 7 , and T 8 One of them is N, and T 5 , T 6 , T 7 , and T 8 Each of the other three independently underwent CR 5 And each R 5 These are H, F, Cl, and C, independently. 1~2 Alkyl, C 1~2 Haloalkyl, C 1~2 Alkoxy, or C 1~2 It is a haloalkoxy.

[0033] Embodiment A7-b is a further embodiment of Embodiment A7, where the compound is the compound of formula IV-2.

[0034] [ka] or a pharmaceutically acceptable salt thereof, R 1 These are propan-2-yl, propa-1-en-2-yl, trifluoromethyl, or cyclopropyl. R 4 is H, halo, or C 1~2 It is alkyl, T 5 , T 6 , T 7 , and T 8 Each of them independently performs CR 5 is or T 5 , T 6 , T 7 , and T 8 One of them is N, and T 5 , T 6 , T 7 , and T 8 Each of the other three independently underwent CR 5 And, Each R 5 These are independently H, halogen, -CN, and C. 1~2 Alkyl, C 1~2 Haloalkyl, C 1~2Alkoxy, or C 1~2 It is a haloalkoxy, Each R 6 These are independently H, halogen, -CN, and C. 1~2 Alkyl, C 1~2 Haloalkyl, C 1~2 Alkoxy, or C 1~2 It is a haloalkoxy, however, it has four R's 6 At least one of them is not H (for example, one or two R 6 The condition is that (is not H).

[0035] Embodiment A7-b-1 is a further embodiment of Embodiment A7-b, where R 1 is propan-2-yl or trifluoromethyl, and R 4 is H, F, Cl, or C 1~2 It is alkyl, T 5 , T 6 , T 7 , and T 8 Each of them independently performs CR 5 And each R 5 These are H, F, Cl, and C, independently. 1~2 Alkyl, C 1~2 Haloalkyl, C 1~2 Alkoxy, or C 1~2 It is a haloalkoxy. Embodiment A7-b-2 is a further embodiment of Embodiment A7-b, where R 1 is propan-2-yl or trifluoromethyl, and R 4 is H, F, or C 1~2 Alkyl (e.g., methyl), T 5 , T 6 , T 7 , and T 8 Each of them independently performs CR 5 And each R 5 These are H, F, and C, independently. 1~2 Alkyl, C 1~2 Haloalkyl, C 1~2 Alkoxy, or C 1~2 It is a haloalkoxy, and each R 6 These are H, halogen, and C, independently.1~2 Alkyl, C 1~2 Haloalkyl, C 1~2 Alkoxy, or C 1~2 It is a haloalkoxy, however, it has four R's 6 The condition is that at least one of them is not H. Embodiment A7-b-3 is a further embodiment of Embodiment A7-b, where R 1 is propan-2-yl or trifluoromethyl, and R 4 is H, F, or C 1~2 Alkyl (e.g., methyl), T 5 , T 6 , T 7 , and T 8 Each of them independently performs CR 5 And each R 5 H is H, and each R 6 These are H, halogen, and C, independently. 1~2 Alkyl, C 1~2 Haloalkyl, C 1~2 Alkoxy, or C 1~2 It is a haloalkoxy, however, it has four R's 6 The condition is that at least one of them is other than H. Embodiment A7-b-4 is a further embodiment of Embodiment A7-b, where R 1 is propan-2-yl or trifluoromethyl, and R 4 is H, F, Cl, or C 1~2 It is alkyl, T 5 , T 6 , T 7 , and T 8 One of them is N, and T 5 , T 6 , T 7 , and T 8 Each of the other three independently underwent CR 5 And each R 5 These are H, F, Cl, and C, independently. 1~2 Alkyl, C 1~2 Haloalkyl, C 1~2 Alkoxy, or C 1~2 It is a haloalkoxy, and each R 6 These are H, halogen, and C, independently. 1~2Alkyl, C 1~2 Haloalkyl, C 1~2 Alkoxy, or C 1~2 It is a haloalkoxy, however, it has four R's 6 The condition is that at least one of them is other than H. Embodiment A7-b-5 is a further embodiment of Embodiment A7-b, where R 1 is propan-2-yl or trifluoromethyl, and R 4 is H, F, Cl, or C 1~2 It is alkyl, T 5 , T 6 , T 7 , and T 8 One of them is N, and T 5 , T 6 , T 7 , and T 8 Each of the other three independently underwent CR 5 And each R 5 These are H, F, Cl, and C, independently. 1~2 Alkyl, C 1~2 Haloalkyl, C 1~2 Alkoxy, or C 1~2 It is a haloalkoxy, and each R 6 These are H, halogen, and C, independently. 1~2 Alkyl, C 1~2 Haloalkyl, C 1~2 Alkoxy, or C 1~2 It is a haloalkoxy, however, it has four R's 6 One of them is not H, and there are four R's. 6 The other three must be H.

[0036] When Embodiment A7 is referred to in this specification, it includes any of Embodiment A7 and any further embodiments thereof (Embodiments A7-a, A7-b, Embodiments A7-a-1 to A7-a-4, and A7-b-1 to A7-b-5).

[0037] Embodiment A8 is a further embodiment of Embodiment A1, where the compound is the compound of formula IVa.

[0038] [ka] or a pharmaceutically acceptable salt thereof.

[0039] Embodiment A8-a is a further embodiment of Embodiment A8, where the compound is the compound of formula IVa-1.

[0040] [ka] or a pharmaceutically acceptable salt thereof, R 1 These are propan-2-yl, propa-1-en-2-yl, trifluoromethyl, or cyclopropyl. R 4 is H, halo, or C 1~2 It is alkyl, T 5 , T 6 , T 7 , and T 8 Each of them independently performs CR 5 is or T 5 , T 6 , T 7 , and T 8 One of them is N, and T 5 , T 6 , T 7 , and T 8 Each of the other three independently underwent CR 5 And, Each R 5 These are independently H, halogen, -CN, and C. 1~2 Alkyl, C 1~2 Haloalkyl, C 1~2 Alkoxy, or C 1~2 It is a haloalkoxy.

[0041] Embodiment A8-a-1 is a further embodiment of Embodiment A8-a, where R 1 is propan-2-yl or trifluoromethyl, and R 4 is H, F, Cl, or C 1~2 It is alkyl, T 5, T 6 , T 7 , and T 8 Each of them independently performs CR 5 And each R 5 These are H, F, Cl, and C, independently. 1~2 Alkyl, C 1~2 Haloalkyl, C 1~2 Alkoxy, or C 1~2 It is a haloalkoxy. Embodiment A8-a-2 is a further embodiment of Embodiment A8-a, where R 1 is propan-2-yl or trifluoromethyl, and R 4 is H, F, or C 1~2 Alkyl (e.g., methyl), T 5 , T 6 , T 7 , and T 8 Each of them independently performs CR 5 And each R 5 These are H, F, and C, independently. 1~2 Alkyl, C 1~2 Haloalkyl, C 1~2 Alkoxy, or C 1~2 It is a haloalkoxy. Embodiment A8-a-3 is a further embodiment of Embodiment A8-a, where R 1 is propan-2-yl or trifluoromethyl, and R 4 is H, F, or C 1~2 Alkyl (e.g., methyl), T 5 , T 6 , T 7 , and T 8 Each of them independently performs CR 5 And each R 5 is H. Embodiment A8-a-4 is a further embodiment of Embodiment A8-a, where R 1 is propan-2-yl or trifluoromethyl, and R 4 is H, F, Cl, or C 1~2 It is alkyl, T 5 , T 6 , T 7 , and T 8 One of them is N, and T 5 , T 6, T 7 , and T 8 Each of the other three independently underwent CR 5 And each R 5 These are H, F, Cl, and C, independently. 1~2 Alkyl, C 1~2 Haloalkyl, C 1~2 Alkoxy, or C 1~2 It is a haloalkoxy.

[0042] Embodiment A8-b is a further embodiment of Embodiment A8, where the compound is the compound of formula IVa-2.

[0043] [ka] or a pharmaceutically acceptable salt thereof, R 1 These are propan-2-yl, propa-1-en-2-yl, trifluoromethyl, or cyclopropyl. R 4 is H, halo, or C 1~2 It is alkyl, T 5 , T 6 , T 7 , and T 8 Each of them independently performs CR 5 is or T 5 , T 6 , T 7 , and T 8 One of them is N, and T 5 , T 6 , T 7 , and T 8 Each of the other three independently underwent CR 5 And, Each R 5 These are independently H, halogen, -CN, and C. 1~2 Alkyl, C 1~2 Haloalkyl, C 1~2 Alkoxy, or C 1~2 It is a haloalkoxy, Each R 6 These are independently H, halogen, -CN, and C. 1~2Alkyl, C 1~2 Haloalkyl, C 1~2 Alkoxy, or C 1~2 It is a haloalkoxy, however, it has four R's 6 At least one of them is not H (for example, one or two R 6 The condition is that (is not H).

[0044] Embodiment A8-b-1 is a further embodiment of Embodiment A8-b, where R 1 is propan-2-yl or trifluoromethyl, and R 4 is H, F, Cl, or C 1~2 It is alkyl, T 5 , T 6 , T 7 , and T 8 Each of them independently performs CR 5 And each R 5 These are H, F, Cl, and C, independently. 1~2 Alkyl, C 1~2 Haloalkyl, C 1~2 Alkoxy, or C 1~2 It is a haloalkoxy. Embodiment A8-b-2 is a further embodiment of Embodiment A8-b, where R 1 is propan-2-yl or trifluoromethyl, and R 4 is H, F, or C 1~2 Alkyl (e.g., methyl), T 5 , T 6 , T 7 , and T 8 Each of them independently performs CR 5 And each R 5 These are H, F, and C, independently. 1~2 Alkyl, C 1~2 Haloalkyl, C 1~2 Alkoxy, or C 1~2 It is a haloalkoxy, and each R 6 These are H, halogen, and C, independently. 1~2 Alkyl, C 1~2 Haloalkyl, C 1~2 Alkoxy, or C 1~2 It is a haloalkoxy, however, it has four R's6 The condition is that at least one of them is not H. Embodiment A8-b-3 is a further embodiment of Embodiment A8-b, where R 1 is propan-2-yl or trifluoromethyl, and R 4 is H, F, or C 1~2 Alkyl (e.g., methyl), T 5 , T 6 , T 7 , and T 8 Each of them independently performs CR 5 And each R 5 H is H, and each R 6 These are H, halogen, and C, independently. 1~2 Alkyl, C 1~2 Haloalkyl, C 1~2 Alkoxy, or C 1~2 It is a haloalkoxy, however, it has four R's 6 The condition is that at least one of them is other than H. Embodiment A8-b-4 is a further embodiment of Embodiment A8-b, where R 1 is propan-2-yl or trifluoromethyl, and R 4 is H, F, Cl, or C 1~2 It is alkyl, T 5 , T 6 , T 7 , and T 8 One of them is N, and T 5 , T 6 , T 7 , and T 8 Each of the other three independently underwent CR 5 And each R 5 These are H, F, Cl, and C, independently. 1~2 Alkyl, C 1~2 Haloalkyl, C 1~2 Alkoxy, or C 1~2 It is a haloalkoxy, and each R 6 These are H, halogen, and C, independently. 1~2 Alkyl, C 1~2 Haloalkyl, C 1~2 Alkoxy, or C 1~2 It is a haloalkoxy, however, it has four R's 6The condition is that at least one of them is not H. Embodiment A8-b-5 is a further embodiment of Embodiment A8-b, where R 1 is propan-2-yl or trifluoromethyl, and R 4 is H, F, Cl, or C 1~2 It is alkyl, T 5 , T 6 , T 7 , and T 8 One of them is N, and T 5 , T 6 , T 7 , and T 8 Each of the other three independently underwent CR 5 And each R 5 These are H, F, Cl, and C, independently. 1~2 Alkyl, C 1~2 Haloalkyl, C 1~2 Alkoxy, or C 1~2 It is a haloalkoxy, and each R 6 These are H, halogen, and C, independently. 1~2 Alkyl, C 1~2 Haloalkyl, C 1~2 Alkoxy, or C 1~2 It is a haloalkoxy, however, it has four R's 6 One of them is not H, and the other three are R 6 The condition is that H.

[0045] When Embodiment A8 is referred to herein below, it includes any of Embodiment A8 and any further embodiments thereof (Embodiment A8-a, Embodiment A8-b, Embodiments A8-a-1 to A8-a-4, and A8-b-1 to A8-b-5).

[0046] Embodiment A9 is a further embodiment of Embodiment A1, where the compound is a compound of formula V.

[0047] [ka] or a pharmaceutically acceptable salt thereof.

[0048] Embodiment A10 is a further embodiment of Embodiment A1, where the compound is a compound of formula Va.

[0049] [ka] or a pharmaceutically acceptable salt thereof.

[0050] Embodiment A11 is a further embodiment of Embodiment A1, where the compound is the compound of formula VI.

[0051] [ka] or a pharmaceutically acceptable salt thereof.

[0052] Embodiment A12 is a further embodiment of Embodiment A1, where the compound is the compound of formula VIa.

[0053] [ka] or a pharmaceutically acceptable salt thereof.

[0054] Embodiment A13 is a further embodiment of Embodiment A1, where the compound is a compound of formula VII.

[0055] [ka] or a pharmaceutically acceptable salt thereof.

[0056] Embodiment A14 is a further embodiment of Embodiment A1, where the compound is the compound of formula VIIa.

[0057] [ka] or a pharmaceutically acceptable salt thereof.

[0058] Embodiment A15 is a further embodiment of any one of Embodiments A1 to A14, which includes further embodiments described herein, where R 1 Halogen, -CN, C 1~8 Alkyl, C 2~8 Alkenil, (C 3~6 Cycloalkyl)-C 1~4 Alkyl-, or C 3~6 It is a cycloalkyl, C 1~8 Alkyl, C 2~8 Alkenil, (C 3~6 Cycloalkyl)-C 1~4 Alkyl-, or C 3~6 Each of the cycloalkyl groups is a halogen, -OH, -CN, or C. 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, and C 1~4 The haloalkoxy may be substituted with 1, 2, 3, 4, 5, or 6 substituents, each independently selected. Embodiment A15-a is a further embodiment of Embodiment A15, where R 1 These are halogens, -OH, -CN, and C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, and C 1~4 C may be substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from each haloalkoxy. 1~8 It is alkyl. Embodiment A15-b is a further embodiment of Embodiment A15, where R 1 These are halogens, -OH, -CN, and C 1~4 Alkoxy, and C 1~4 C may be substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from each haloalkoxy. 2~6 It is alkyl. Embodiment A15-c is a further embodiment of Embodiment A15, where R 1 These are halogens, -OH, -CN, and C 1~4 Alkoxy, and C 1~4 C may be substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from each haloalkoxy.2~4 It is alkyl. Embodiment A15-d is a further embodiment of Embodiment A15, where R 1 These are halogens, -OH, -CN, and C 1~4 Alkoxy, and C 1~4 C may be substituted with 1, 2, 3, or 4 substituents independently selected from each haloalkoxy. 2~4 It is alkyl. Embodiment A15-e is a further embodiment of Embodiment A15, where R 1 is halogen, -OH, C 1~4 Alkoxy, and C 1~4 C may be substituted with 1, 2, 3, or 4 substituents independently selected from each haloalkoxy. 2~4 It is alkyl. When Embodiment A15 is referred to herein below, it includes any of Embodiment A16 and any further embodiments thereof (Embodiments A15-a to A15-e).

[0059] Embodiment A16 is a further embodiment of any one of Embodiments A1 to A14, which includes further embodiments described herein, where R 1 is halogen, C 3~6 Alkyl, C 3~6 Alkenil, (C 3~6 Cycloalkyl)-C 1~4 Alkyl-, or C 3~6 It is a cycloalkyl, C 3~6 Alkyl, C 3~6 Alkenil, (C 3~6 Cycloalkyl)-C 1~4 Alkyl-, or C 3~6 Each of the cycloalkyl groups is a halogen, -OH, -CN, or C. 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, and C 1~4 The haloalkoxy may be substituted with 1, 2, 3, 4, 5, or 6 substituents, each independently selected. Embodiment A16-a is a further embodiment of Embodiment A16, where R 1 These are halogens, -OH, -CN, and C 1~4Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, and C 1~4 The cyclobutyl is substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from the haloalkoxy. Embodiment A16-b is a further embodiment of Embodiment A16, where R 1 These are halogens, -OH, -CN, and C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, and C 1~4 This is a cyclobutyl which may be substituted with one or two substituents independently selected from the haloalkoxy. Embodiment A16-c is a further embodiment of Embodiment A16, where R 1 These are halogens, -OH, -CN, and C 1~4 Alkoxy, and C 1~4 C may be substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from each haloalkoxy. 3~4 It is alkyl. Embodiment A16-d is a further embodiment of Embodiment A16, where R 1 These are halogens, -OH, -CN, and C 1~4 Alkoxy, and C 1~4 C may be substituted with 1, 2, 3, or 4 substituents independently selected from each haloalkoxy. 3~4 It is alkyl. Embodiment A16-e is a further embodiment of Embodiment A16, where R 1 is halogen, -OH, C 1~4 Alkoxy, and C 1~4 C may be substituted with 1, 2, 3, or 4 substituents independently selected from each haloalkoxy. 3~4 It is alkyl. When Embodiment A16 is referred to herein below, it includes any of Embodiment A16 and any further embodiments thereof (Embodiments A16-a to A16-e).

[0060] Embodiment A17 is a further embodiment of any one of Embodiments A1 to A14, which includes further embodiments described herein, where R 1 It is cyclopropyl, cyclobutyl, R 1a , R 1b , or R 1c

[0061] [ka] That is [In the formula, each of cyclopropyl or cyclobutyl is represented by 1, 2, 3, or 4 R S It may also be replaced with Each R 20 These are independently H, halogen, -OH, and C. 1~2 Alkyl, C 1~2 Haloalkyl, C 1~2 Alkoxy, or C 1~2 It is a haloalkoxy, Each R 21 H and C are independent of each other. 1~2 Alkyl, or C 1~2 It is a haloalkyl, R 22 H, halogen, C 1~2 Alkyl, C 1~2 Hydroxylalkyl, C 1~2 Haloalkyl, C 1~2 Alkoxy, or C 1~2 It is a haloalkoxy, Each R 23 These are, independently, halogen, C 1~2 Alkyl, C 1~2 Hydroxylalkyl, C 1~2 Haloalkyl, C 1~2 Alkoxy, or C 1~2 It is a haloalkoxy, Each R S These are, independently, halogen, -OH, C 1~2 Alkyl, C 1~2 Hydroxylalkyl, C 1~2 Haloalkyl, C 1~2 Alkoxy, or C 1~2[It is a haloalkoxy]. Embodiment A17-a is a further embodiment of Embodiment A17, where R 1 is R 1a Embodiment A17-b is a further embodiment of Embodiment A17, where R 1 is R 1a And each R 20 These are independently H, halogen, -OH, and C. 1~2 Alkyl, or C 1~2 It is a haloalkyl. Embodiment A17-b is a further embodiment of Embodiment A17, where R 1 is R 1a And each R 20 These are independently H, -OH, and C 1~2 Alkyl, or C 1~2 It is a haloalkyl. Embodiment A17-c is a further embodiment of Embodiment A17, where R 1 is R 1a And each R 20 These are independently H, -OH, or C 1~2 It is alkyl. Embodiment A17-d is a further embodiment of Embodiment A17, where R 1 is R 1b And each R 21 H or C 1~2 It is alkyl, R 22 H, C 1~2 Alkyl, or C 1~2 It is a hydroxyl alkyl group. Embodiment A17-d is a further embodiment of Embodiment A17, where R 1 is R 1b And each R 21 H or C 1~2 It is alkyl, R 22 is H or C 1~2 It is alkyl. Embodiment A17-e is a further embodiment of Embodiment A17, where R 1 is R 1c Embodiment A17-f is a further embodiment of Embodiment A17, where R 1 is R 1c And each R 23 These are, independently, halogen, C 1~2Alkyl, C 1~2 Hydroxylalkyl, or C 1~2 It is a haloalkyl. Embodiment A17-g is a further embodiment of Embodiment A17, where R 1 is R 1c And each R 23 Independently, C 1~2 Alkyl, C 1~2 Hydroxylalkyl, or C 1~2 It is a haloalkyl. Embodiment A17-h is a further embodiment of Embodiment A17, where R 1 is R 1c And each R 23 Independently, C 1~2 It is alkyl. Embodiment A17-i is a further embodiment of Embodiment A17, where R 1 is R 1c And each R 23 is methyl. Where Embodiment A17 is referred to herein below, it includes any of Embodiment A18 and any further embodiments thereof (Embodiments A17-a to A17-i).

[0062] Embodiment A18 is a further embodiment of any one of Embodiments A1 to A14, which includes further embodiments described herein, where R 1 is propan-2-yl, propa-1-en-2-yl, trifluoromethyl, or cyclopropyl. Embodiment A18-a is a further embodiment of Embodiment A18, where R 1 is propan-2-yl, propa-1-en-2-yl, or cyclopropyl. Embodiment A18-b is a further embodiment of Embodiment A18, where R 1 is propan-2-yl, propa-1-en-2-yl, or trifluoromethyl. Embodiment A18-c is a further embodiment of Embodiment A18, where R 1 Where Embodiment A18 is referred to herein, it includes any of Embodiment A18 and any of its further embodiments (Embodiments A18-a to A18-c).

[0063] Embodiment A19 is a further embodiment of any one of Embodiments A1 to A14, which include further embodiments described herein, where R 1 It is propane-2-yl.

[0064] Embodiment A20 is a further embodiment of any one of Embodiments A1 to A14, which include further embodiments described herein, where R 1 It is a propane-1-en-2-il.

[0065] Embodiment A21 is a further embodiment of any one of Embodiments A1 to A14, which include further embodiments described herein, where R 1 is cyclopropyl or cyclobutyl, each of which may be substituted with one or two substituents, each substituent independently being C 1~2 Alkyl or C 1~2 It is a haloalkyl. Embodiment A21-a is a further embodiment of Embodiment A21, where R 1 These are cyclopropyl or cyclobutyl, each containing one C 1~2 Alkyl or C 1~2 It may be substituted with a haloalkyl (e.g., CF3). Embodiment A21-b is a further embodiment of Embodiment A21, where R 1 is one C 1~2 Alkyl or C 1~2 This is a cyclopropyl which may be substituted with a haloalkyl (e.g., CF3). Embodiment A21-c is a further embodiment of Embodiment A21, where R 1 is cyclopropyl. Embodiment A21-d is a further embodiment of Embodiment A21, where R 1 is cyclobutyl. When Embodiment A21 is referred to herein below, it includes any of Embodiment A21 and any of its further embodiments (Embodiments A21-a to A21-d).

[0066] Embodiment A22 is a further embodiment of any one of Embodiments A1 to A14, which include further embodiments described herein, where R 1 C 1~4 It is a haloalkyl or halo. Embodiment A22-a is a further embodiment of Embodiment A22, where R 1 is C 1~4 It is a haloalkyl, for example, R 1 is C 1~2 It is a haloalkyl. Embodiment A22-b is a further embodiment of Embodiment A22, where R 1 is C 1~2 It is a haloalkyl, for example, R 1 is C 1~2 It is a fluoroalkyl. Embodiment A22-c is a further embodiment of Embodiment A22, where R 1 is trifluoromethyl. Embodiment A22-d is a further embodiment of Embodiment A22, where R 1 is a halo, for example, Cl. When Embodiment A22 is referred to herein below, it includes any of Embodiment A22 and any of its further embodiments (Embodiments A22-a and A22-d).

[0067] Embodiment A23 is a further embodiment of any one of embodiments A1 to A22, which include further embodiments described herein, where T 1 , T 2 , T 3 , and T 4 Each of them independently performs CR 4 Embodiment A23-a is a further embodiment of Embodiment A23, where T 1 , T 2 , and T 4 Each of them is CH, and T 3 CR 4 Embodiment A23-b is a further embodiment of Embodiment A23, where T 1 , T 2 , and T 4 Each of them is CH, and T 3 CR 4 And R4 H, Halo, C 1~2 Alkyl, or C 1~2 It is a haloalkyl. Embodiment A23-c is a further embodiment of Embodiment A23, where T 1 , T 2 , and T 4 Each of them is CH, and T 3 CR 4 And R 4 is H, F, or methyl. When Embodiment A23 is referred to herein below, it includes any one of Embodiment A23 and any further embodiments thereof (Embodiments A23-a to A23-c).

[0068] Embodiment A24 is a further embodiment of any one of embodiments A1 to A22, which include further embodiments described herein, where T 1 , T 2 , T 3 , and T 4 One of them is N, and the other three are each independently CR 4 Embodiment A24-a is a further embodiment of Embodiment A24, where T 1 is N, and T 2 , T 3 , and T 4 Each of them independently performs CR 4 When Embodiment A24 is referred to herein below, it includes any one of Embodiment A24 and any further embodiment thereof (Embodiment A24-a).

[0069] Embodiment A25 is a further embodiment of any one of embodiments A1 to A22, which include further embodiments described herein, where T 2 is N, and T 1 , T 3 , and T 4 Each of them independently performs CR 4 That is the case.

[0070] Embodiment A26 is a further embodiment of any one of embodiments A1 to A22, which include further embodiments described herein, where T 1 , T 2 , T 3 , and T 4 Two of them are N, and the other two are CR, each independently. 4 That is the case.

[0071] Embodiment A27 is a further embodiment of any one of Embodiments A1 to A26, which include further embodiments described herein, where each R 4 These are H, Halo, and C, independently. 1~2 Alkyl, or C 1~2 It is a haloalkyl group.

[0072] Embodiment A28 is a further embodiment of any one of Embodiments A1 to A26, which includes further embodiments described herein, where each R 4 These are independently H, halo, or C 1~2 It is alkyl. Embodiment A28-a is a further embodiment of Embodiment A28, where each R 4 is independently H, F, or methyl. Embodiment A28-b is a further embodiment of Embodiment A28, where each R 4 These are independently H or F. Embodiment A28-c is a further embodiment of Embodiment A28, where each R 4 Independently, these are H or F. When Embodiment A28 is referred to herein below, it includes any one of Embodiment A28 and any further embodiments thereof (Embodiments A28-a and A28-b).

[0073] Embodiment A29 is a further embodiment of any one of Embodiments A1 to A26, which include further embodiments described herein, where each R 4 H or C 1~2 It is alkyl. Embodiment A29-a is a further embodiment of Embodiment A29, where each R 4is, independently, H or methyl. When referring to Embodiment A29 in the following specification, any one of Embodiment A29 and its further embodiments (Embodiment A29-a) is included.

[0074] Embodiment A30 is a further embodiment of any one of Embodiments A1 - A26 including the further embodiments described herein, where each R 4 is H.

[0075] Embodiment A31 is a further embodiment of any one of Embodiments A1 - A30 including the further embodiments described herein, where each R 2 is, independently, halogen, -OH, C 1~4 alkyl, C 1~4 hydroxyalkyl, C 1~4 haloalkyl, C 1~4 alkoxy, C 1~4 haloalkoxy, C 3~4 cycloalkyl, or (C 3~4 cycloalkyl)-C 1~4 alkyl-, and t2 is 0 or 1. Embodiment A31-a is a further embodiment of Embodiment A31, where each R 2 is, independently, halogen, -OH, C 1~2 alkyl, C 1~2 hydroxyalkyl, C 1~2 haloalkyl, C 1~2 alkoxy, C 1~2 haloalkoxy, or C 3~4 cycloalkyl, and t2 is 0 or 1. Embodiment A31-b is a further embodiment of Embodiment A31, where R 2 is -OH, C 1~2 alkyl, C 1~2 hydroxyalkyl, C 1~2 haloalkyl, C 1~2 alkoxy, or C 1~2 haloalkoxy, and t2 is 0 or 1. Embodiment A31-c is a further embodiment of Embodiment A31, where R 2 is -OH, C 1~2is alkyl or C 1~2 is alkoxy, and t2 is 0 or 1. When referring to Embodiment A31 in the following specification, any one of Embodiment A31 and its further embodiments (Embodiments A31-a to A31-c) is included.

[0076] Embodiment A32 is a further embodiment of any one of Embodiments A1 to A30 including further embodiments described herein, where t2 is 0.

[0077] Embodiment A33 is a further embodiment of any one of Embodiments A1 to A30 including further embodiments described herein, where t2 is 2 or 3, and two Rs attached to two adjacent ring carbon atoms of the proline ring in Formula I 2 together with the two ring carbon atoms to which they are attached are substituted with 1, 2, 3, or 4 substituents each independently selected from halogen, -OH, C 1~4 alkyl, C 1~4 haloalkyl, C 1~4 alkoxy, and C 1~4 haloalkoxy to form C 3~6 cycloalkyl which may be optionally substituted. Embodiment A33-a is a further embodiment of Embodiment A33, where t2 is 2, and two Rs attached to two adjacent ring carbon atoms of the proline ring in Formula I 2 together with the two ring carbon atoms to which they are attached are substituted with 1, 2, 3, or 4 substituents each independently selected from halogen, -OH, C 1~4 alkyl, C 1~4 haloalkyl, C 1~4 alkoxy, and C 1~4 haloalkoxy to form C 3~6 cycloalkyl which may be optionally substituted. Embodiment A33-b is a further embodiment of Embodiment A33, where t2 is 2, and two Rs attached to two adjacent ring carbon atoms of the proline ring in Formula I 2 together with the two ring carbon atoms to which they are attached are substituted with 1, 2, 3, or 4 substituents each independently selected from halogen, -OH, C 1~4 alkyl, C1~4 Haloalkyl, C 1~4 Alkoxy, and C 1~4 A cyclopropyl is formed which may be substituted with 1, 2, 3, or 4 substituents independently selected from the haloalkoxy. Embodiment A33-c is a further embodiment of Embodiment A33, where t2 is 2 and two R atoms bonded to two adjacent ring carbon atoms of the proline ring in formula I. 2 Together with the two ring carbon atoms to which they are bonded, they form a cyclopropyl condensed to the proline ring, and the resulting condensed bicyclic ring is a 3-azabicyclo[3.1.0]hexane ring. When Embodiment A33 is referred to herein below, it includes any one of Embodiment A33 and its further embodiments (Embodiments A33-a to A31-c).

[0078] Embodiment A34 is a further embodiment of any one of embodiments A1 to A10 and A15 to A33, which include further embodiments described herein, where T 5 , T 6 , T 7 , and T 8 Each of them independently performs CR 5 Embodiment A34-a is a further embodiment of Embodiment A34, where T 5 , T 6 , T 7 , and T 8 Each of these is CH. Embodiment A34-b is a further embodiment of Embodiment A34, where T 5 , T 6 , T 7 , and T 8 Three of them are CH, and T 5 , T 6 , T 7 , and T 8 One of them is CR 5 And R 5 Halogen, -CN, C 1~2 Alkyl, C 1~2 Haloalkyl, C 1~2 Alkoxy, or C 1~2is a haloalkoxy. Embodiment A34-c is a further embodiment of Embodiment A34, where T 5 , T 6 , T 7 , and T 8 three of which are CH, and T 5 , T 6 , T 7 , and T 8 one of which is CR 5 , and R 5 is F, Cl, C 1~2 alkyl, C 1~2 haloalkyl, C 1~2 alkoxy, or C 1~2 haloalkoxy. Embodiment A34-d is a further embodiment of Embodiment A34, where T 5 , T 6 , T 7 , and T 8 three of which are CH, and T 5 , T 6 , T 7 , and T 8 one of which is CR 5 , and R 5 is F, methyl, or methoxy. Embodiment A34-e is a further embodiment of Embodiment A34, where T 5 , T 6 , T 7 , and T 8 at least one of the four Rs 5 among is other than H. When referring to Embodiment A34 in the following specification, any one of Embodiment A34 and its further embodiments (Embodiments A34-a to A34-e) is included.

[0079] Embodiment A35 is a further embodiment of any one of Embodiments A1 to A10 and A15 to A33 including further embodiments described herein, where T 5 , T 6 , T 7 , and T 8 one of which is N, and the other three are each independently CR 5Embodiment A35-a is a further embodiment of Embodiment A35, where three R 5 Each of these is H. Embodiment A35-b is a further embodiment of Embodiment A35, where three R 5 One of them is halogen, -CN, C 1~2 Alkyl, C 1~2 Haloalkyl, C 1~2 Alkoxy, or C 1~2 It is a haloalkoxy, and the other two R 5 is H. Embodiment A35-c is a further embodiment of Embodiment A35, where three R 5 One of them is F, Cl, C 1~2 Alkyl, C 1~2 Haloalkyl, C 1~2 Alkoxy, or C 1~2 It is a haloalkoxy, and the other two R 5 is H. Embodiment A35-d is a further embodiment of Embodiment A35, where three R 5 One of them is F, methyl, or methoxy, and the other two are R 5 H is the same as, in the following herein, when Embodiment A35 is referred to, it includes any one of Embodiment A35 and any further embodiments thereof (Embodiments A35-a to A35-d).

[0080] Embodiment A36 is one further embodiment of any of embodiments A1 to A10 and A15 to A33, which include further embodiments described herein, where T 5 is N, and T 6 , T 7 , and T 8 Each of them independently performs CR 5 Embodiment A36-a is a further embodiment of Embodiment A36, where three R 5 Each of these is H. Embodiment A36-b is a further embodiment of Embodiment A36, where there are three R 5 One of the following (for example, T 8 R 5 ) are halogen, -CN, C 1~2 Alkyl, C1~2 Haloalkyl, C 1~2 Alkoxy, or C 1~2 It is a haloalkoxy, and the other two R 5 is H. Embodiment A36-c is a further embodiment of Embodiment A36, where three R 5 One of the following (for example, T 8 R 5 ) are F, Cl, C 1~2 Alkyl, C 1~2 Haloalkyl, C 1~2 Alkoxy, or C 1~2 It is a haloalkoxy, and the other two R 5 is H. Embodiment A36-d is a further embodiment of Embodiment A36, where three R 5 One of the following (for example, T 8 R 5 ) is F, methyl, or methoxy, and the other two R 5 H is the same as, when referred to in this specification, Embodiment A36 includes any one of Embodiment A36 and any further embodiments thereof (Embodiments A36-a to A36-d).

[0081] Embodiment A37 is one further embodiment of any of embodiments A1 to A10 and A15 to A33, which include further embodiments described herein, where T 6 is N, and T 5 , T 7 , and T 8 Each of them independently performs CR 5 Embodiment A37-a is a further embodiment of Embodiment A37, where three R 5 Each of them is H. Embodiment A37-b is a further embodiment of Embodiment A37, where three R 5 One of them is halogen, -CN, C 1~2 Alkyl, C 1~2 Haloalkyl, C 1~2 Alkoxy, or C 1~2 It is a haloalkoxy, and the other two R 5is H. Embodiment A37-c is a further embodiment of Embodiment A37, where three R 5 One of them is F, Cl, C 1~2 Alkyl, C 1~2 Haloalkyl, C 1~2 Alkoxy, or C 1~2 It is a haloalkoxy, and the other two R 5 is H. Embodiment A37-d is a further embodiment of Embodiment A37, where three R 5 One of them is F, methyl, or methoxy, and the other two are R 5 H is the same as, when referred to in this specification, Embodiment A37 is included, and any one of its further embodiments (Embodiments A37-a to A37-d).

[0082] Embodiment A38 is a further embodiment of any one of embodiments A1 to A10 and A15 to A33, which include further embodiments described herein, where T 5 , T 6 , T 7 , and T 8 Two of them are N, and the other two are CR, each independently. 5 That is the case.

[0083] Embodiment A39 is a further embodiment of any one of embodiments A1 to A10 and A15 to A38, where each R 5 These are H, Halo, and C, independently. 1~2 Alkyl, or C 1~2 It is a haloalkyl group.

[0084] Embodiment A40 is one further embodiment of any of embodiments A1 to A10 and A15 to A38, which include further embodiments described herein, where each R 5 These are independently H, halo, or C 1~2 It is alkyl.

[0085] Embodiment A41 is one further embodiment of any of embodiments A1 to A10 and A15 to A38, which include further embodiments described herein, where each R 5 These are independently H or halo.

[0086] Embodiment A42 is one further embodiment of any one of embodiments A1 to A10 and A15 to A38, which include further embodiments described herein, where each R 5 H is H.

[0087] Embodiment A43 is one further embodiment of any of embodiments A1 to A8 and A15 to A42, which include further embodiments described herein. 9 , T 10 , T 11 , and T 12 Each of them independently performs CR 6 Embodiment A43-a is a further embodiment of Embodiment A43, where T 9 , T 10 , T 11 , and T 12 Each of these is CH. Embodiment A43-b is a further embodiment of Embodiment A43, where T 9 , T 10 , T 11 , and T 12 Three of them are CH, and T 9 , T 10 , T 11 , and T 12 one of the (for example, T 9 ) is CR 6 And R 6 Halogen, -CN, C 1~2 Alkyl, C 1~2 Haloalkyl, C 1~2 Alkoxy, or C 1~2 It is a haloalkoxy. Embodiment A43-c is a further embodiment of Embodiment A43, where T 9 , T 10 , T 11 , and T 12 Three of them are CH, and T 9 , T10 , T 11 , and T 12 one of the (for example, T 9 ) is CR 6 And R 6 F, Cl, C 1~2 Alkyl, C 1~2 Haloalkyl, C 1~2 Alkoxy, or C 1~2 It is a haloalkoxy. Embodiment A43-d is a further embodiment of Embodiment A43, where T 9 , T 10 , T 11 , and T 12 Three of them are CH, and T 9 , T 10 , T 11 , and T 12 one of the (for example, T 9 ) is CR 6 And R 6 is F, methyl, or methoxy. Embodiment A43-e is a further embodiment of Embodiment A43, where T 9 , T 10 , T 11 , and T 12 The four R's 6 At least one of them is other than H. When Embodiment A43 is referred to in this specification below, it includes any one of Embodiment A43 and any further embodiments thereof (Embodiments A43-a to A43-e).

[0088] Embodiment A44 is a further embodiment of any one of embodiments A1 to A8 and A15 to A42, which include further embodiments described herein, where T 9 , T 10 , T 11 , and T 12 One of them is N, and the other three are each independently CR 6 Embodiment A44-a is a further embodiment of Embodiment A44, where three R 6 Each of these is H. Embodiment A44-b is a further embodiment of Embodiment A44, where there are three R 6One of them is halogen, -CN, C 1~2 Alkyl, C 1~2 Haloalkyl, C 1~2 Alkoxy, or C 1~2 It is a haloalkoxy, and the other two R 5 is H. Embodiment A44-c is a further embodiment of Embodiment A44, where three R 6 One of them is halogen, C 1~2 Alkyl, or C 1~2 It is a haloalkyl and the other two R 6 is H. Embodiment A44-d is a further embodiment of Embodiment A44, where three R 6 One of them is F or methyl, and the other two are R 5 is H. Embodiment A44-e is a further embodiment of Embodiment A44, where three R 6 One of them is methyl, and the other two R 5 is H. Embodiment A44-e is a further embodiment of Embodiment A44, where three R 6 One of them is halogen, and the other two R 5 H is the same as, when referred to in this specification, Embodiment A44 includes any one of Embodiment A44 and any further embodiments thereof (Embodiments A44-a to A44-e).

[0089] Embodiment A45 is a further embodiment of any one of embodiments A1 to A8 and A15 to A42, which include further embodiments described herein, where T 9 is N, and T 10 , T 11 , and T 12 Each of them independently performs CR 6 Embodiment A45-a is a further embodiment of Embodiment A45, where three R 6 Each of these is H. Embodiment A45-b is a further embodiment of Embodiment A45, where three R 6 One of the following (for example, T 10 or T 12 R6 ) are halogen, -CN, C 1~2 Alkyl, C 1~2 Haloalkyl, C 1~2 Alkoxy, or C 1~2 It is a haloalkoxy, and the other two R 5 is H. Embodiment A45-c is a further embodiment of Embodiment A45, where three R 6 One of the following (for example, T 10 R 6 ) is C 1~2 Alkyl or C 1~2 It is a haloalkyl and the other two R 6 is H. Embodiment A45-d is a further embodiment of Embodiment A45, where three R 6 One of the following (for example, T 10 R 6 ) is methyl, and the other two R 5 is H. Embodiment A45-e is a further embodiment of Embodiment A45, where three R 6 One of the following (for example, T 12 R 6 ) is halogen, C 1~2 Alkyl, C 1~2 Haloalkyl, C 1~2 Alkoxy, or C 1~2 It is a haloalkoxy, and the other two R 5 is H. Embodiment A45-f is a further embodiment of Embodiment A45, where three R 6 One of the following (for example, T 12 R 6 ) is halogen or C 1~2 It is alkyl, and the other two R 5 is H. Embodiment A45-g is a further embodiment of Embodiment A45, where three R 6 One of the following (for example, T 12 R 6 ) is F, and the other two R 5 H is the same as, when referred to in this specification, Embodiment A45 is included, which is any one of Embodiment A45 and any further embodiments thereof (Embodiments A45-a to A45-g).

[0090] Embodiment A46 is a further embodiment of any one of embodiments A1 to A8 and A15 to A42, which include further embodiments described herein, where T 10 is N, and T 9 , T 11 , and T 12 Each of them independently performs CR 6 Embodiment A46-a is a further embodiment of Embodiment A46, where three R 6 Each of these is H. Embodiment A46-b is a further embodiment of Embodiment A46, where three R 6 One of the following (for example, T 9 or T 11 R 6 ) are halogen, -CN, C 1~2 Alkyl, C 1~2 Haloalkyl, C 1~2 Alkoxy, or C 1~2 It is a haloalkoxy, and the other two R 5 is H. Embodiment A46-c is a further embodiment of Embodiment A46, where three R 6 One of the following (for example, T 9 R 6 ) is C 1~2 Alkyl or C 1~2 It is a haloalkyl and the other two R 6 is H. Embodiment A46-d is a further embodiment of Embodiment A46, where three R 6 One of the following (for example, T 9 or T 11 R 6 ) is methyl, and the other two R 5 is H. Embodiment A46-e is a further embodiment of Embodiment A46, where three R 6 One of the following (for example, T 11 R 6 ) is halogen, C 1~2 Alkyl, C 1~2 Haloalkyl, C 1~2 Alkoxy, or C 1~2It is a haloalkoxy, and the other two R 5 is H. Embodiment A46-f is a further embodiment of Embodiment A46, where three R 6 One of the following (for example, T 11 R 6 ) is halogen or C 1~2 It is alkyl, and the other two R 5 is H. Embodiment A46-g is a further embodiment of Embodiment A46, where three R 6 One of the following (for example, T 11 R 6 ) is F, and the other two R 5 H is the same as, when referred to in this specification, Embodiment A46 includes any one of Embodiment A46 and any further embodiments thereof (Embodiments A46-a to A46-g).

[0091] Embodiment A47 is a further embodiment of any one of embodiments A1 to A8 and A15 to A42, which include further embodiments described herein, where T 9 is N, and T 10 is CH or C(CH3), T 11 CH is T 12 is CH. Embodiment A47-a is a further embodiment of Embodiment A47, where T 9 is N, and T 10 is C(CH3), and T 11 CH is T 12 is CH. When Embodiment A47 is referred to in this specification, it includes Embodiment A47 and any of its further embodiments (Embodiment A47-a).

[0092] Embodiment A48 is a further embodiment of any one of embodiments A1 to A8 and A15 to A42, which include further embodiments described herein, where T 9 , T 10 , T 11 , and T 12 Two of them are N, and the other two are CR, each independently. 6 That is the case.

[0093] Embodiment A48 is a further embodiment of any one of embodiments A1 to A8 and A15 to A42, which include further embodiments described herein, where T 10 and T 11 Each of these is N, and T 9 and T 12 Each of them independently performs CR 6 That is the case.

[0094] Embodiment A49 is one further embodiment of any one of embodiments A1 to A8 and A15 to A48, which include further embodiments described herein, where each R 6 These are H, Halo, and C, independently. 1~2 Alkyl, or C 1~2 It is a haloalkyl group.

[0095] Embodiment A50 is one further embodiment of any of embodiments A1 to A8 and A15 to A48, which include further embodiments described herein, where each R 6 These are independently H, halo, or C 1~2 It is alkyl.

[0096] Embodiment A51 is one further embodiment of any of embodiments A1 to A8 and A15 to A48, which include further embodiments described herein, where each R 6 These are independently H or halo.

[0097] Embodiment A52 is one further embodiment of any of embodiments A1 to A8 and A15 to A48, which include further embodiments described herein, where each R 6 H or C 1~2 It is alkyl.

[0098] Embodiment A53 is one further embodiment of any of embodiments A1-A6, A9, A10, A15-A33, and A34-A42, which include further embodiments described herein, where T 13, T 14 , T 15 , and T 16 Each of them independently performs CR 7 That is the case.

[0099] Embodiment A54 is one further embodiment of any of embodiments A1-A6, A9, A10, A15-A33, and A34-A42, which include further embodiments described herein, where T 13 , T 14 , T 15 , and T 16 One of them is N, and the other three are each independently CR 7 That is the case.

[0100] Embodiment A55 is one further embodiment of any one of embodiments A1-A6, A9, A10, A15-A33, and A34-A42, which include further embodiments described herein, where T 13 is N, and T 14 , T 15 , and T 16 Each of them independently performs CR 7 That is the case.

[0101] Embodiment A56 is one further embodiment of any one of embodiments A1-A6, A9, A10, A15-A33, and A34-A42, which include further embodiments described herein, where T 13 , T 14 , T 15 , and T 16 Two of them are N, and the other two are CR, each independently. 7 That is the case.

[0102] Embodiment A57 is one further embodiment of any of embodiments A1-A6, A9, A10, A15-A33, A34-A42, and A53-A56, which include further embodiments described herein, where each R 7 These are H, Halo, and C, independently. 1~2 Alkyl, or C 1~2 It is a haloalkyl group.

[0103] Embodiment A58 is one further embodiment of any of embodiments A1-A6, A9, A10, A15-A33, A34-A42, and A53-A57, which include further embodiments described herein, where each R 7 These are independently H, halo, or C 1~2 It is alkyl.

[0104] Embodiment A59 is one further embodiment of any of embodiments A1-A6, A9, A10, A15-A33, A34-A42, and A53-A57, which include further embodiments described herein, where each R 7 These are independently H or halo.

[0105] Embodiment A60 is one further embodiment of any of embodiments A1-A6, A9, A10, A15-A33, A34-A42, and A53-A57, which include further embodiments described herein, where each R 7 H or C 1~2 It is alkyl.

[0106] Embodiment A61 is one further embodiment of any of embodiments A1-A6, A9, A10, A15-A33, A34-A42, and A53-A57, which include further embodiments described herein, where each R 7 H is H.

[0107] Embodiment A62 is one further embodiment of any of embodiments A1 to A6 and A11 to A61, which include further embodiments described herein, where T 17 , T 18 , and T 19 Each of them independently performs CR 8 That is the case.

[0108] Embodiment A63 is one further embodiment of any of embodiments A1 to A6 and A11 to A33, which include further embodiments described herein, where T 17 , T18 , and T 19 One of them is N, and the other two are independently CR 8 That is the case.

[0109] Embodiment A64 is one further embodiment of any one of embodiments A1 to A6, A11 to A33, A62, and A63, which include further embodiments described herein, where each R 8 These are H, Halo, and C, independently. 1~2 Alkyl, or C 1~2 It is a haloalkyl group.

[0110] Embodiment A65 is one further embodiment of any one of embodiments A1 to A6, A11 to A33, A62, and A63, which include further embodiments described herein, where each R 8 These are independently H, halo, or C 1~2 It is alkyl.

[0111] Embodiment A66 is one further embodiment of any one of embodiments A1 to A6, A11 to A33, A62, and A63, which include further embodiments described herein, where each R 8 H or C 1~2 It is alkyl.

[0112] Embodiment A67 is one further embodiment of any one of embodiments A1 to A6, A11 to A33, A62, and A63, which include further embodiments described herein, where each R 8 These are independently H or halo.

[0113] Embodiment A68 is one further embodiment of any one of embodiments A1 to A6, A11 to A33, A62, and A63, which include further embodiments described herein, where each R 8 H is H.

[0114] Embodiment A69 is one further embodiment of any of embodiments A1-A6, A11, A12, A15-A33, and A62-A68, which include further embodiments described herein, where T 20 , T 21 , and T 22 Each of them independently performs CR 9 That is the case.

[0115] Embodiment A70 is one further embodiment of any of embodiments A1-A6, A11, A12, A15-A33, and A62-A68, which include further embodiments described herein, where T 20 , T 21 , and T 11 One of them is N, and the other two are CR, each independently. 9 That is the case.

[0116] Embodiment A71 is one further embodiment of any of embodiments A1-A6, A11, A12, A15-A33, and A62-A68, which include further embodiments described herein, where T 20 is N, and T 21 and T 22 Each of them independently performs CR 9 That is the case.

[0117] Embodiment A72 is one further embodiment of any of embodiments A1-A6, A11, A12, A15-A33, and A62-A71, which include further embodiments described herein, where each R 9 These are H, Halo, and C, independently. 1~2 Alkyl, or C 1~2 It is a haloalkyl group.

[0118] Embodiment A73 is one further embodiment of any of embodiments A1-A6, A11, A12, A15-A33, and A62-A71, which include further embodiments described herein, where each R 9 These are independently H, halo, or C 1~2 It is alkyl.

[0119] Embodiment A74 is one further embodiment of any of embodiments A1-A6, A11, A12, A15-A33, and A62-A71, which include further embodiments described herein, where each R 9 These are independently H or halo.

[0120] Embodiment A75 is one further embodiment of any of embodiments A1-A6, A11, A12, A15-A33, and A62-A71, which include further embodiments described herein, where each R 9 H or C 1~2 It is alkyl.

[0121] Embodiment A76 is one further embodiment of any of embodiments A1-A6, A11, A12, A15-A33, and A69-A71, which include further embodiments described herein, where each R 9 H is H.

[0122] Embodiment A77 is one further embodiment of any one of embodiments A1 to A6, A13, A14, A15 to A33, and A62 to A76, including further embodiments described herein, where t3 is 1.

[0123] Embodiment A78 is a further embodiment of any one of Embodiments A1-A6, A13, A14, A15-A33, and A62-A76, including further embodiments described herein, where t3 is 2 (for example, a compound having the structure of formula VII or formula VIIa, where t3 is 2, or a pharmaceutically acceptable salt thereof). Embodiment A78-a is a further embodiment of Embodiment A78, where T 17 and T 18 Each of them independently performs CR 8 And, T 19 is N. Embodiment A78-b is a further embodiment of Embodiment A78, where T 17 and T 18 Each of them is CH, and T 19is N. Embodiment A78-c is a further embodiment of Embodiment A78, where T 17 and T 18 Each of them independently performs CR 8 And, T 19 is N, and R A is C(=O)OH. Embodiment A78-d is a further embodiment of Embodiment A78, where T 17 and T 18 Each of them is independently CH, and T 19 is N, and R A is C(=O)OH. When Embodiment A78 is referred to in this specification below, it includes any of Embodiment A78 and any further embodiments thereof (Embodiments A78-a to A78-d).

[0124] Embodiment A79 is one further embodiment of any of embodiments A1-A6, A13, A14, A15-A33, and A62-A78, which include further embodiments described herein, where t4 is 0, 1, or 2, and each R 10 These are, independently, halogen, -OH, C 1~4 Alkyl, C 1~4 Hydroxylalkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 3~4 Cycloalkyl, or (C 3~4 Cycloalkyl)-C 1~4 It is alkyl-.

[0125] Embodiment A80 is one further embodiment of any of embodiments A1-A6, A13, A14, A15-A33, and A62-A78, which include further embodiments described herein, where t4 is 0 or 1, and each R 10 is halogen, -OH, C 1~4 Alkyl, C 1~4 Hydroxylalkyl, C 1~4 Haloalkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 3~4Cycloalkyl, or (C 3~4 Cycloalkyl)-C 1~4 It is alkyl-.

[0126] Embodiment A81 is a further embodiment of any one of embodiments A1 to A80, which include further embodiments described herein, where R A It is -C(=O)-OH.

[0127] Embodiment A82 is a further embodiment of any one of embodiments A1 to A80, which include further embodiments described herein, where R A It is -C(=O)-NH2.

[0128] Embodiment A83 is a further embodiment of any one of Embodiments A1 to A80, which includes further embodiments described herein, where R A It is -OH.

[0129] Embodiment A84 is a compound selected from the following: 5-{4-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]phenyl}pyridine-2-carboxylic acid; 6-{4-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]phenyl}pyridine-3-carboxylic acid; 4'-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino][1,1'-biphenyl]-3-carboxylic acid; 4'-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid; 4-{6-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]pyridine-3-yl}benzoic acid; 3'-Fluoro-4'-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid; 4'-({1-[(4-cyclopropylphenyl)carbamoyl]-D-prolyl}amino)[1,1'-biphenyl]-4-carboxylic acid; 2-{4-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]phenyl}pyrimidine-5-carboxylic acid; 6-{4-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]phenyl}pyridine-2-carboxylic acid; 6-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]naphthalene-2-carboxylic acid; 8-Methyl-6-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]quinoline-2-carboxylic acid; 4'-[(1-{[4-(propa-1-en-2-yl)phenyl]carbamoyl}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid; 4'-({1-[(4-chlorophenyl)carbamoyl]-D-prolyl}amino)[1,1'-biphenyl]-4-carboxylic acid; 4-{4-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]phenyl}pyridine-2-carboxylic acid; and 3',5'-difluoro-4'-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid, or a pharmaceutically acceptable salt thereof.

[0130] Embodiment A85 is a compound selected from the following: 4'-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid; 5-{4-[(1-{[3-methyl-4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]phenyl}pyridine-2-carboxylic acid; 6-methyl-5-{4-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]phenyl}pyridine-2-carboxylic acid; 3-Methoxy-4'-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid; 5-{4-[(1-{[3-fluoro-4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]phenyl}-6-methylpyridine-2-carboxylic acid; 3-Fluoro-4'-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid; 4-{6-[(1-{[4-(trifluoromethyl)phenyl]carbamoyl}-D-prolyl)amino]pyridine-3-yl}benzoic acid; 4'-[(1-{[3-fluoro-4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]-3-methoxy[1,1'-biphenyl]-4-carboxylic acid; 4-{3-fluoro-5-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]pyridine-2-yl}benzoic acid; and 6-methyl-5-{4-[(1-{[3-methyl-4-(trifluoromethyl)phenyl]carbamoyl}-D-prolyl)amino]phenyl}pyridine-2-carboxylic acid, or a pharmaceutically acceptable salt thereof.

[0131] Embodiment A86 is a compound selected from Examples 1 to 229 (for example, a compound selected from Examples 16 to 38), or a pharmaceutically acceptable salt thereof (or its free acid form, or, if an example is a salt, a pharmaceutically acceptable salt of its free acid form).

[0132] Embodiment B1 is a pharmaceutical composition comprising one compound from any of Embodiments A1 to A86, including further embodiments described herein, and a pharmaceutically acceptable excipient.

[0133] Embodiment C1 is a method for treating or preventing a patient condition, disease, or disorder, comprising administering to a patient any one compound from Embodiments A1 to A86, including further embodiments described herein, the condition, disease, or disorder being diabetes [e.g., including type 1 diabetes mellitus (T1D), type 2 diabetes mellitus (T2DM), prediabetes], idiopathic T1D (type 1b), latent autoimmune diabetes mellitus in adults (LADA), early-onset T2DM (EOD), juvenile-onset atypical diabetes mellitus (YOAD), juvenile adult-onset diabetes mellitus (MODY), malnutrition-related diabetes, pregnancy Diabetes mellitus, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease [e.g., acute kidney injury, tubular dysfunction, pro-inflammatory changes in the proximal tubules, or chronic kidney disease (CKD)], diabetic retinopathy, adipocyte dysfunction, visceral fat deposition, sleep apnea [e.g., obstructive sleep apnea (OSA)], obesity (including hypothalamic obesity and monogenic obesity) and associated comorbidities (e.g., osteoarthritis and urinary incontinence), eating disorders (bulimia nervosa, bulimia nervosa, and Prader-Willi syndrome and Baldett syndrome). Weight gain (including symptomatic obesity such as Beedle syndrome), weight gain caused by the use of other medications (e.g., caused by the use of steroids and / or antipsychotics, or by the treatment of depression, or by the use of medications for cognitive function), overweight, excessive sugar craving, dyslipidemia [including hyperlipidemia, hypertriglyceridemia, increased total cholesterol, high LDL (low-density lipoprotein) cholesterol, and low HDL (high-density lipoprotein) cholesterol], hyperinsulinemia, non Alcoholic fatty liver disease [including fatty liver, non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and related diseases such as hepatocellular carcinoma (NAFLD)], 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 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 dyslipidemia, metabolic acidosis, ketosis, arthritis, osteoporosis, osteoarthritis, Parkinson's disease, left ventricular hypertrophy, peripheral artery disease (PAD), macular degeneration, cataracts, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, arteriosclerosis, transient ischemic attack, restenosis, impaired glucose metabolism, abnormal fasting blood glucose levels, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders, psoriasis, foot ulcers, ulcerative colitis, high apobeta-lipoprotein levels A method selected from the group consisting of citrate, 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., addiction to alcohol, nicotine, and / or drugs), or a method for human weight management (e.g., chronic weight management), comprising administering to a human being one of the compounds of Embodiments A1 to A86, including further embodiments described herein.

[0134] As used herein, treating diabetes (e.g., T2DM) in diabetic patients (e.g., patients with T2DM) includes, among other things, improving blood glucose control.

[0135] Embodiment C2 is a further embodiment of Embodiment C1, wherein the condition, disease, or disorder is selected from the group consisting of obesity, weight gain, T2DM, heart failure (e.g., HFpEF and HFrEF), CKD, NAFLD, NASH, atherosclerosis, PAD, obstructive sleep apnea, diabetic retinopathy, and diabetic neuropathy.

[0136] Embodiment C3 is a further embodiment of Embodiment C1, wherein the method is a method for preventing weight gain.

[0137] Embodiment C4 is a further embodiment of Embodiment C1, wherein the method is a method for preventing obesity.

[0138] Embodiment C5 is a further embodiment of Embodiment C1, wherein the method is a method for treating obesity.

[0139] Embodiment C6 is a further embodiment of Embodiment C1, wherein the method is a method for human weight management, e.g., chronic weight management. In some further embodiments, the person is obese or overweight at the time weight management (e.g., chronic weight management) is initiated, and in such circumstances, weight management (e.g., chronic weight management) is also a method for treating obesity or overweight. In some further embodiments, the person is obese at the time weight management (e.g., chronic weight management) treatment is initiated, and in such circumstances, weight management (e.g., chronic weight management) is also a method for treating obesity.

[0140] Embodiment D1 is the use of any one of the compounds in Embodiments A1 to A86, including further embodiments described herein, for treating or preventing a condition, disease, or disorder, or the use of the compound in the manufacture of a medicament for treating or preventing a condition, disease, or disorder, wherein the condition, disease, or disorder is diabetes [e.g., including type 1 diabetes mellitus (T1D), type 2 diabetes mellitus (T2DM), prediabetes], idiopathic T1D (type 1b), latent autoimmune diabetes mellitus in adults (LADA), early-onset T2DM (EOD), juvenile-onset atypical diabetes mellitus (YOAD), juvenile Adult-onset diabetes mellitus (MODY), malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, renal disease [e.g., acute kidney injury, tubular dysfunction, pro-inflammatory changes in the proximal tubules, or chronic kidney disease (CKD)], diabetic retinopathy, adipocyte dysfunction, visceral fat deposition, sleep apnea [e.g., obstructive sleep apnea (OSA)], obesity (including hypothalamic obesity and monogenic obesity) and associated comorbidities (e.g., osteoarthritis and urinary incontinence), eating disorders (bulimia nervosa, neurotic nervosa) Weight gain such as bulimia nervosa and symptomatic obesity such as Prader-Willi syndrome and Baldett-Beedl syndrome, weight gain caused by the use of other medications (e.g., caused by the use of steroids and / or antipsychotics, or by the treatment of depression, or by the use of medications for cognitive function), overweight, excessive sugar cravings, dyslipidemia [hyperlipidemia, hypertriglyceridemia, elevated total cholesterol, high LDL (low-density lipoprotein) cholesterol, and low HDL (high-density lipoprotein) cholesterol], overweight, excessive sugar cravings, dyslipidemia [hyperlipidemia, hypertriglyceridemia, elevated total cholesterol, high LDL (low-density lipoprotein) cholesterol, and low HDL (high-density lipoprotein) cholesterol]. Lipoproteins (including cholesterol), hyperinsulinemia, non-alcoholic fatty liver disease [NAFLD including fatty liver, non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and related diseases such as 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 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 dyslipidemia, metabolic acidosis, ketosis, arthritis, osteoporosis, osteoarthritis, Parkinson's disease, left ventricular hypertrophy, peripheral artery disease (PAD), macular degeneration, cataracts, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, arteriosclerosis, transient ischemic attack, vascular restenosis, impaired glucose metabolism, abnormal fasting blood glucose levels, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders Uses selected from the group consisting of plague, psoriasis, foot ulcers, ulcerative colitis, hyperapolipoproteinemia, 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., addiction to alcohol, nicotine, and / or drugs), or use of any one compound of Embodiments A1 to A86, including further embodiments described herein for weight management (e.g., chronic weight management).

[0141] Embodiment D2 is a further embodiment of Embodiment D1, wherein the condition, disease, or disorder is selected from the group consisting of obesity, weight gain, T2DM, heart failure (e.g., HFpEF and HFrEF), CKD, NAFLD, NASH, atherosclerosis, PAD, obstructive sleep apnea, diabetic retinopathy, and diabetic neuropathy.

[0142] Embodiment D3 is a further embodiment of Embodiment D1, and the use of any one of the compounds in Embodiments A1 to A86, including the further embodiments described herein, is for the purpose of preventing weight gain.

[0143] Embodiment D4 is a further embodiment of Embodiment D1, and the use of any one compound of Embodiments A1 to A86, including the further embodiments described herein, is for use in the manufacture of a pharmaceutical for preventing weight gain.

[0144] Embodiment D5 is a further embodiment of Embodiment D1, and the use of any one compound of Embodiments A1 to A86, including the further embodiments described herein, is for the treatment of obesity.

[0145] Embodiment D6 is a further embodiment of Embodiment D1, and the use of any one compound of Embodiments A1 to A86, including the further embodiments described herein, is for use in the manufacture of a pharmaceutical for obesity.

[0146] Embodiment D7 is a further embodiment of Embodiment D1, and the use of any one compound of Embodiments A1 to A86, including the further embodiments described herein, is for use in the manufacture of a medicament for weight management, e.g., chronic weight management in humans. In some further embodiments, the human is obese or overweight when weight management (e.g., chronic weight management) is initiated, and in such circumstances, weight management is also a method for treating obesity or overweight. In some further embodiments, the human is obese when weight management (e.g., chronic weight management) treatment is initiated, and in such circumstances, weight management is also a method for treating obesity.

[0147] Embodiment E1 is one compound from any of Embodiments A1 to A86, including further embodiments described herein, for use in a method for treating or preventing a patient condition, disease, or disorder, wherein the condition, disease, or disorder is diabetes [e.g., including type 1 diabetes mellitus (T1D), type 2 diabetes mellitus (T2DM), prediabetes], idiopathic T1D (type 1b), latent autoimmune diabetes mellitus in adults (LADA), early-onset T2DM (EOD), juvenile-onset atypical diabetes mellitus (YOAD), juvenile adult-onset diabetes mellitus (MODY), malnutrition-related diabetes mellitus, gestational diabetes mellitus, etc. Diabetic urinary tract disease, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease [e.g., acute kidney injury, tubular dysfunction, pro-inflammatory changes in the proximal tubules, or chronic kidney disease (CKD)], diabetic retinopathy, adipocyte dysfunction, visceral fat deposition, sleep apnea [e.g., obstructive sleep apnea (OSA)], obesity (including hypothalamic obesity and monogenic obesity) and associated comorbidities (e.g., osteoarthritis and urinary incontinence), eating disorders (bulimia nervosa, bulimia nervosa, and Prader-Willi syndrome and Baldet-B). Weight gain (including symptomatic obesity such as dolphin syndrome), weight gain caused by the use of other medications (e.g., caused by the use of steroids and / or antipsychotics, or by the treatment of depression, or by the use of medications for cognitive function), overweight, excessive sugar craving, dyslipidemia [including hyperlipidemia, hypertriglyceridemia, increased total cholesterol, high LDL (low-density lipoprotein) cholesterol, and low HDL (high-density lipoprotein) cholesterol], hyperinsulinemia, non-alcoholic Alcoholic fatty liver disease [NAFLD including fatty liver, non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and related diseases such as 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 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 dyslipidemia, metabolic acidosis, ketosis, arthritis, osteoporosis, osteoarthritis, Parkinson's disease, left ventricular hypertrophy, peripheral artery disease (PAD), macular degeneration, cataracts, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, arteriosclerosis, transient ischemic attack, restenosis, impaired glucose metabolism, abnormal fasting blood glucose levels, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders, psoriasis, foot ulcers, ulcerative colitis, hyperapesthetic B A compound selected from the group consisting of 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., addiction to alcohol, nicotine, and / or drugs), or one of the compounds from Embodiments A1 to A86, including further embodiments described herein for use in methods for weight management (e.g., chronic weight management).

[0148] Embodiment E2 is a further embodiment of Embodiment E1, wherein the condition, disease, or disorder is selected from the group consisting of obesity, weight gain, T2DM, heart failure (e.g., HFpEF and HFrEF), CKD, NAFLD, NASH, atherosclerosis, PAD, obstructive sleep apnea, diabetic retinopathy, and diabetic neuropathy.

[0149] Embodiment E3 is a further embodiment of Embodiment E1, and any one of the compounds in Embodiments A1 to A86, including the further embodiments described herein, is a compound for use in a method for preventing weight gain.

[0150] Embodiment E4 is a further embodiment of Embodiment E1, and any one of the compounds in Embodiments A1 to A86, including the further embodiments described herein, is a compound for use in a method for treating obesity.

[0151] Embodiment E5 is a further embodiment of Embodiment E1, and any one of the compounds in Embodiments A1 to A86, including the further embodiments described herein, is a compound for use in a method for weight management (e.g., chronic weight management). In some further embodiments, the person is obese or overweight when weight management (e.g., chronic weight management) is initiated, and in such circumstances, weight management is also a method for treating obesity or overweight. In some further embodiments, the person is obese when weight management (e.g., chronic weight management) treatment is initiated, and in such circumstances, weight management is also a method for treating obesity.

[0152] Embodiment F1 is a method (either in vitro or in vivo) for modulating (e.g., antagonizing) GIPR, comprising contacting (including incubation) GIPR with any one compound from Embodiments A1 to A86, which include further embodiments described herein.

[0153] Embodiment F2 is a further embodiment of Embodiment F1, wherein the adjustment is to counteract.

[0154] It should be understood that the present invention is not limited to the specific synthesis methods of the adjustments described in the scheme herein. It should also be understood that the technical terms used herein are intended solely to describe specific embodiments and are not intended to limit them. In this specification and the following claims, several terms are defined as having the following meanings.

[0155] As used herein, "a" or "an" may mean one or more. As used in the claims(s) herein, "a" or "an," when used in conjunction with the word "including," may mean one or more. As used herein, "another" may mean at least the second or third and subsequent.

[0156] The term "approximately" refers to a relative term indicating an approximate value of plus or minus 10% of the nominal value it refers to, in one embodiment, plus or minus 5%, and in another embodiment, plus or minus 2%. In the art of this disclosure, this level of approximation is appropriate unless it is specifically stated that the value requires a narrower range of values.

[0157] As used herein, “compound” includes conformational isomers (e.g., cis and trans isomers) and all optical isomers (e.g., enantiomers and diastereomers), racemates, diastereomers and other mixtures of such isomers, as well as any pharmaceutically acceptable derivatives or variants, including solvates, hydrates, isomorphs, polymorphs, tautomers, esters, salt forms, and prodrugs.

[0158] When used in this specification, the wavy line "

[0159] [ka] The symbol '' indicates that a substituent is bonded to another group.

[0160] The term "alkyl" refers to an acyclic saturated aliphatic hydrocarbon group that can be linear or branched. Examples of such groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, sec-butyl, isobutyl, and tert-butyl. The carbon atom content of alkyl and various other hydrocarbon-containing moieties is indicated by prefixes that show the lower and upper limits of the number of carbon atoms in that moiety, namely the prefix C i~j This represents the portion of carbon atoms that includes both ends, from integer "i" to integer "j". Therefore, for example, C 1~8 Alkyl refers to an alkyl group containing 1 to 8 carbon atoms, including both ends. Another example is C 1~6 Alkyl refers to an alkyl group containing 1 to 6 carbon atoms, including both ends, and in yet another example, C 1~4Alkyl refers to an alkyl group containing 1 to 4 carbon atoms, including both ends. 1~4 Typical examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl. Another example is C 1~2 Alkyl refers to an alkyl group (i.e., methyl or ethyl) with one or two carbon atoms including both ends. Alkyl groups may be substituted with one or more (e.g., 1 to 5) preferred substituents, as specified.

[0161] In various parts of this specification, substituents of the compounds of the present invention are disclosed in groups or ranges. The present invention is specifically intended to include all individual subcombinations of members of such groups and ranges. For example, "C 1~4 The term "alkyl" specifically refers to C1 alkyl (methyl), C2 alkyl (ethyl), C3 alkyl, and C4 alkyl. In another example, the term "4- to 7-membered heterocycloalkyl" specifically refers to any 4, 5, 6, or 7-membered heterocycloalkyl group. In yet another example, "C 3~6 The term "cycloalkyl" is specifically intended to include any saturated or unsaturated, non-aromatic, monocyclic or polycyclic (such as bicyclic) hydrocarbon ring with 3, 4, 5, or 6 ring-forming carbon atoms.

[0162] As used herein, the term “n-membered” (where n is an integer) typically describes the number of ring-forming atoms in a part of which the number of ring-forming atoms is n. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, and pyrrolidinyl is an example of a 5-membered heterocycloalkyl group.

[0163] As used herein, the terms “alkoxy” or “alkyloxy” refer to an -O-alkyl group. For example, “C 1~4 "alkoxy" or "C 1~4 The term "alkyloxy" is -O-(C 1~4This refers to an alkyl group, and in another example, "C 1~2 "alkoxy" or "C 1~2 The term "alkyloxy" is -O-(C 1~2 This refers to an alkyl group. Examples of alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), tert-butoxy, and analogues. The alkoxy or alkyloxy group may be substituted with one or more (e.g., 1 to 5) preferred substituents, where specified.

[0164] The terms "halo" or "halogen" as used herein mean -F, -Cl, -Br, or -I.

[0165] As used herein, the term “haloalkyl” refers to an alkyl group having one or more halogen substituents (up to perhaloalkyl, i.e., all hydrogen atoms of the alkyl group are replaced by halogen atoms). For example, “C 1~4 The term "haloalkyl" refers to a C having one or more halogen substituents. 1~4 This refers to alkyl groups (up to perhaloalkyl groups, i.e., all hydrogen atoms in an alkyl group are replaced by halogen atoms), and "C 1~2 The term "haloalkyl" refers to a C having one or more halogen substituents. 1~2 This refers to alkyl groups (i.e., methyl or ethyl) (up to perhaloalkyl groups, i.e., all hydrogen atoms of the alkyl group are replaced by halogen atoms). Examples of haloalkyl groups include -CF3, -CHF2, -CH2F, -CH2CF3, -C2F5, -CH2Cl, and analogues.

[0166] As used herein, "fluoroalkyl" means an alkyl group as defined herein that is substituted with one or more fluoro(-F) substituents (up to perfluoroalkyl groups, i.e., all hydrogen atoms of the alkyl group are replaced by fluorine atoms). 1~2The term "fluoroalkyl" refers to a C molecule having one or more fluorine substituents (up to perfluoroalkyl, i.e., all hydrogen atoms of the alkyl group are replaced by fluorine atoms). 1~2 The term "C1 fluoroalkyl" refers to an alkyl group (i.e., methyl or ethyl), and the term "C1 fluoroalkyl" refers to a methyl group having one, two, or three fluorine substituents. Examples of C1 fluoroalkyls include fluoromethyl, difluoromethyl, and trifluoromethyl, while some examples of C2 fluoroalkyls include 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 1,2-difluoroethyl, 2,2,2-trifluoroethyl, 1,1,2-trifluoroethyl, and analogues.

[0167] When used here, the term "haloalkoxy" refers to an -O-haloalkyl group. For example, "C 1~4 The term "haloalkoxy" is -O-(C 1~4 (Haloalkyl) group refers to "C 1~2 The term "haloalkoxy" is -O-(C 1~2 This refers to a haloalkyl group. In yet another example, the term "C1 haloalkoxy" refers to a methoxy group having one, two, or three halogen substituents. Examples of haloalkoxys are -OCF3 or -OCHF2.

[0168] When used here, the term "fluoroalkoxy" refers to an -O-fluoroalkyl group. For example, "C 1~2 The term "fluoroalkoxy" is -O-(C 1~2 The term "C1 fluoroalkoxy" refers to the -O-(C1 fluoroalkyl) group. Examples of C1 fluoroalkoxys include -O-CH2F, -O-CHF2, and -O-CF3. Some examples of C2 fluoroalkoxys include -O-CH2CHF2, -O-CH2-CHF2, -O-CH2CF3, -O-CF2CH3, and -O-CF2CF3.

[0169] As used herein, the terms "hydroxylalkyl" or "hydroxyalkyl" refer to an alkyl group having one or more (e.g., one, two, or three) OH substituents. 1~4 "Hydroxyalkyl" or "C 1~4 The term "hydroxyalkyl" refers to a C molecule having one or more (e.g., 1, 2, or 3) OH substituents. 1~4 It refers to an alkyl group, "C 1~2 "Hydroxyalkyl" or "C 1~2 The term "hydroxyalkyl" refers to a C molecule having one or more (e.g., 1, 2, or 3) OH substituents. 1~2 This refers to alkyl groups. Examples of hydroxyl alkyl groups are -CH2OH or -CH2CH2OH.

[0170] As used herein, the term “cyanoalkyl” refers to an alkyl group having one or more (e.g., 1, 2, or 3) -CN (i.e., -C≡N or cyano) substituents. For example, “C 1~4 The term "cyanoalkyl" refers to a C molecule having one or more (e.g., 1, 2, or 3) -CN substituents. 1~4 This refers to alkyl groups. Examples of cyanoalkyl groups are -CH2-CN or -CH2CH2-CN.

[0171] As used herein, the term “alkenyl” refers to an aliphatic hydrocarbon having at least one carbon-carbon double bond, including straight and branched chains having at least one carbon-carbon double bond. In some embodiments, the alkenyl group has 2 to 20 carbon atoms, 2 to 10 carbon atoms, 2 to 6 carbon atoms, 3 to 6 carbon atoms, or 2 to 4 carbon atoms. For example, as used herein, “C 2~8 The term "alkenyl" refers to a straight or branched unsaturated radical (having at least one carbon-carbon double bond) of 2 to 8 carbon atoms. 3~6 The term "alkenyl" refers to a straight or branched unsaturated radical (having at least one carbon-carbon double bond) of 3 to 6 carbon atoms.3~4 The term "alkenyl" refers to a straight or branched unsaturated radical of 3-4 carbon atoms (having at least one carbon-carbon double bond). 3~6 Examples of "alkenyl" include, but are not limited to, propa-2-en-1-yl, propa-1-en-2-yl, buta-2-en-1-yl, buta-2-en-2-yl, 2-methylbuta-2-en-1-yl, and analogues. The alkenyl group may be substituted with one or more (e.g., 1 to 5) preferred substituents. If a compound of formula I contains an alkenyl group, the alkenyl group may exist as a pure E-isomer, a pure Z-isomer, or any mixture thereof, as applicable.

[0172] As used herein, the term “cycloalkyl” refers to saturated or unsaturated, non-aromatic, monocyclic or polycyclic (such as bicyclic) hydrocarbon rings (e.g., monocyclic rings such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclic rings including spiro, condensed, or crosslinked systems (e.g., bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.2.1]octanyl, or bicyclo[5.2.0]nonanyl, decahydronaphthalenyl, etc.)). Cycloalkyl groups have 3 to 15 carbon atoms (e.g., 3 to 14, 3 to 10, 3 to 6, 3 to 4, or 4 to 6). In some embodiments, cycloalkyl groups may contain one, two, or more non-cumulative non-aromatic double or triple bonds and / or one to three oxo groups. In some embodiments, the bicycloalkyl group has 6 to 14 carbon atoms. 3~6 The term "cycloalkyl," as used herein, means a saturated or unsaturated (but non-aromatic) cyclic hydrocarbon group containing 3 to 6 carbon atoms. 3~4 As used herein, the term "cycloalkyl" means a saturated cyclic hydrocarbon group containing 3 to 4 carbon atoms. 3~4Examples of cycloalkyls include cyclopropyl and cyclobutyl. The definition of a cycloalkyl includes moieties having one or more aromatic rings (including aryl and heteroaryl) condensed to a cycloalkyl ring, such as benzo or pyridinyl derivatives of cyclopentane (5-membered cycloalkyl), cyclopentene, cyclohexane (6-membered cycloalkyl), and analogues, such as 6,7-dihydro-5H-cyclopenta[b]pyridinyl, 5,6,7,8-tetrahydroquinolinyl, or 15,6,7,8-tetrahydroisoquinolinyl, each of which contains a 5-membered or 6-membered cycloalkyl moiety condensed to a heteroaryl ring (i.e., a pyridinyl ring). 3~4 The cycloalkyl group may be substituted by one or more (e.g., 1 to 5) preferred substituents, as specified.

[0173] "C 3~6 Cycloalkyl-C 1~4 The term "alkyl-" is used herein, as defined herein, for C 3~4 C as defined herein, attached to the parent molecule via an alkyl group. 3~6 It means cycloalkyl. 3~4 Cycloalkyl-C 1~4 The term "alkyl-" is used herein, as defined herein, for C 3~4 C as defined herein, attached to the parent molecule via an alkyl group. 3~4 It means cycloalkyl. 3~4 Cycloalkyl-C 1~4 Some examples of alkyl groups include cyclopropylmethyl, 2-cyclopropylethyl, 2-cyclopropylpropyl, 3-cyclopropylpropyl, cyclobutylmethyl, 2-cyclobutylethyl, 2-cyclobutylpropyl, and 3-cyclobutylpropyl.

[0174] "C 3~6 Cycloalkyl-C 1~2 The term "alkyl-" is used herein, as defined herein, for C1~2 C as defined herein, attached to the parent molecule via an alkyl group. 3~6 It means cycloalkyl. 3~4 Cycloalkyl-C 1~2 The term "alkyl-" is used herein, as defined herein, for C 1~2 C as defined herein, attached to the parent molecule via an alkyl group. 3~4 It means cycloalkyl.

[0175] As used herein, the term “heterocycloalkyl” refers to a monocyclic or polycyclic, saturated or unsaturated, non-aromatic 4- to 15-membered ring system (such as a 4- to 14-membered ring system, a 4- to 12-membered ring system, a 5- to 10-membered ring system, a 4- to 7-membered ring system, a 4- to 6-membered ring system, or a 5- to 6-membered ring system, including spiro, condensed, or bridging systems, containing two or more rings fused together, e.g., a bicyclic ring system) containing 1 to 14 ring-forming carbon atoms and 1 to 10 ring-forming heteroatoms independently selected from O, S, and N (and optionally P or B, if present). Heterocycloalkyl groups may also contain one or more oxo groups (i.e., =O) or thiono groups (i.e., =S). For example, the term “4- to 7-membered heterocycloalkyl” refers to a monocyclic or polycyclic, saturated or unsaturated, non-aromatic 4- to 7-membered ring system containing one or more ring-forming heteroatoms independently selected from O, S, and N. In another example, the term “5- to 6-membered heterocycloalkyl” refers to a monocyclic or polycyclic, saturated or unsaturated, non-aromatic 5 or 6-membered ring system containing one or more ring-forming heteroatoms independently selected from O, S, and N. The heterocycloalkyl group may be substituted, where so specified, by one or more (e.g., 1 to 5) preferred substituents.

[0176] Some examples of 4- to 7-membered heterocycloalkyls include azetidinyl, oxetanyl, tetrahydrofuranil, imidazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, thiomorpholinyl, tetrahydrothiadinyl, tetrahydrothiadiazinyl, morpholinyl, tetrahydrodiadinyl, and tetrahydropyranil (also known as oxanil). Some further examples of 4- to 7-membered heterocycloalkyls include tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydropyranyl (e.g., tetrahydro-2H-pyran-4-yl), imidazolidine-1-yl, imidazolidine-2-yl, imidazolidine-4-yl, pyrrolidine-1-yl, pyrrolidine-2-yl, pyrrolidine-3-yl, piperidine-1-yl, piperidine-2-yl, piperidine-3-yl, piperidine-4-yl, piperazine-1-yl, piperazine-2-yl, 1,3- Examples include oxazolidine-3-yl, 1,4-oxazepan-2-yl, isothiazolidinyl, 1,3-thiazolidinyl-3-yl, 1,2-pyrazolidinyl-2-yl, 1,2-tetrahydrothiadin-2-yl, 1,3-thiadinan-3-yl, 1,2-tetrahydrodiazine-2-yl, 1,3-tetrahydrodiazine-1-yl, 1,4-oxazine-4-yl, oxazolidinonyl, 2-oxo-piperidinyl (e.g., 2-oxo-piperidine-1-yl), 2-oxoazepan-3-yl, and analogues.

[0177] As used herein, the term “heteroaryl” refers to a monocyclic or fused polycyclic aromatic heterocyclic group having at least one ring containing one or more heteroatom ring members (ring-forming atoms) independently selected from O, S, and N. A heteroaryl group has 5 to 14 ring-forming atoms containing 1 to 13 carbon atoms, and 1 to 8 heteroatoms selected from O, S, and N. In some embodiments, a heteroaryl group has 5 to 10 ring-forming atoms containing 1 to 4 heteroatoms. A heteroaryl group may also contain 1 to 3 oxo or thiono (i.e., =S) groups. In some embodiments, a heteroaryl group has 5 to 8 ring-forming atoms containing 1, 2, or 3 heteroatoms. For example, the term “5-membered heteroaryl” refers to the monocyclic heteroaryl group defined above, having five ring-forming atoms in a monocyclic heteroaryl ring; the term “6-membered heteroaryl” refers to the monocyclic heteroaryl group defined above, having six ring-forming atoms in a monocyclic heteroaryl ring; and the term “5 or 6-membered heteroaryl” refers to the monocyclic heteroaryl group defined above, having five or six ring-forming atoms in a monocyclic heteroaryl ring. The heteroaryl group may be substituted by one or more (e.g., 1 to 5) preferred substituents, where specified. Examples of monocyclic heteroaryls include those having five ring-forming atoms containing 1 to 3 heteroatoms, or those having six ring-forming atoms containing 1, 2, or 3 nitrogen heteroatoms. Examples of fused bicyclic heteroaryls include two fused 5 and / or 6-membered monocyclic rings containing 1 to 4 heteroatoms.

[0178] Some examples of heteroaryl groups include pyridinyl (e.g., pyridine-2-yl, pyridine-3-yl, pyridine-4-yl), pyrazinyl, pyrimidinyl (e.g., pyrimidine-2-yl, pyrimidine-4-yl, or pyrimidine-5-yl), pyridazinyl (e.g., pyridazine-3-yl, or pyridazine-4-yl), thienyl, furyl, imidazolyl (e.g., 1H-imidazole-4-yl), pyrrolyl, oxazolyl (e.g., 1,3-oxazolyl, 1,2-oxazolyl), thiazolyl (e.g., 1,2-thiazolyl), 1,3-thiazolyl), pyrazolyl (e.g., pyrazole-1-yl, pyrazole-3-yl, pyrazole-4-yl), tetrazolyl (e.g., 2H-tetrazole-5-yl), triazolyl (e.g., 1,2,3-triazolyl, 1,2,4-triazolyl), oxadiazolyl (e.g., 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, or 1,3,4-oxadiazolyl), thiadiazolyl (e.g., 1,3,4-thiadiazolyl, or 1,2,4-thiadiazolyl), quinolyl, isoquinolyl, benzothienyl, Benzofuryl, indolyl, benzothiazolyl, 1,2-benzoxazolyl, 1H-imidazo[4,5-c]pyridinyl, imidazo[1,2-a]pyridinyl, 1H-pyrrolo[3,2-c]pyridinyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-c][1,2,4]triazinyl, imidazo[1,5-a]pyridinyl, imidazo[1,2-a]pyrimidinyl, 1H-indazolyl, 9H-purinyl, imidazo[1,2-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridinyl, [1,2,4]triazolo[1 ,5-a]pyrimidinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, isoxazolo[5,4-c]pyridazinyl, isoxazolo[3,4-c]pyridazinyl, pyrazolo[1,5-a]pyrimidinyl, 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazolyl, pyridone, pyrimidone, pyrazinon, pyrimidinone, 1H-imidazole-2(3H)-one, 1H-pyrrole-2,5-dione, 3-oxo-2H-pyridazinyl, 1H-2-oxo-pyrimidinyl, 1H-2-oxo-pyridinyl, 2,4(1H,Examples include 3H)-dioxopyrimidinyl, 1H-2-oxopyrazine, and analogues.

[0179] When used herein, the compounds of Formula I described herein include optional substituents and variables. It is understood that the valence of each specified (or possibly substituted) atom or part does not exceed the normal valence of each atom or part, and that any of the optional substituents result in a stable compound. It is also understood that any combination of optional substituents and / or variables is permissible only if such a combination results in a stable compound.

[0180] Where used herein, if it is stated that a group may be substituted, it means that the group may not be substituted, or may be substituted with one or more of the specified substituents.

[0181] As used herein, unless otherwise specified, the bonding site of a substituent may be any preferred position of the substituent. For example, piperidinyl may be piperidin-1-yl (bonded via the N atom of piperidinyl), piperidin-2-yl (bonded via the C atom at position 2 of piperidinyl), piperidin-3-yl (bonded via the C atom at position 3 of piperidinyl), or piperidin-4-yl (bonded via the C atom at position 4 of piperidinyl). In another example, propanyl (or propyl) may be propan-1-yl (or 1-propyl) or propan-2-yl (or 2-propyl).

[0182] As used herein, the bonding site of a substituent may be identified to indicate the location where the substituent is bonded to another part. For example, "(C 3~4 Cycloalkyl)-C 1~4 "Alkyl-" means that the bond point is "(C 3~4 Cycloalkyl)-C 1~4 "C" 1~4 This means that it occurs in the "alkyl" portion.

[0183] If a substituted or potentially substituted portion is described without indicating the atom to which such portion is bonded to the substituent, the substituent may be bonded via any suitable atom in such portion. For example, if the substituted "(C 3~4 Cycloalkyl)-C 1~4 In "alkyl-", cycloalkylalkyl [that is, (C 3~4 Cycloalkyl)-C 1~4 Substituents on the alkyl- can be bonded to either the alkyl or cycloalkyl carbon atom of the cycloalkylalkyl group. Combinations of substituents and / or variables are permitted only if such combinations result in a stable compound.

[0184] As used herein, the term “adjacent” when describing the relative positions of two substituents on a ring structure refers to two substituents bonded to two ring-forming atoms of the same ring, where these two ring-forming atoms are directly bonded via a chemical bond. For example, in the following structure,

[0185] [ka] R 60 and R 80 Any of the following is R 70 It is an adjacent group to [another group].

[0186] "Mammals" refer to warm-blooded vertebrates characterized by the females producing milk to nourish their offspring, such as guinea pigs, mice, rats, gerbils, cats, rabbits, dogs, cattle, goats, sheep, horses, monkeys, chimpanzees, and humans.

[0187] The term "pharmaceutically acceptable" means a substance (e.g., the compound of the present invention) and any salt thereof, or a composition containing the substance or salt of the present invention, that is suitable for administration to a patient.

[0188] 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 materials, reagents, intermediates, or product in a manner that negatively affects the yield of the desired product.

[0189] As used herein, the terms “selectivity” or “selective” refer to the fact that the effect of a compound in a first assay is greater than the effect of the same compound in a second assay. For example, with an “enteric-selective” compound, the first assay is an assay for the half-life of the compound in the intestinal tract, and the second assay is an assay for the half-life of the compound in the liver.

[0190] "Therapeutic dose" means the amount of the compound of the present invention that (i) treats or prevents a particular disease, condition or disorder, (ii) reduces, alleviates or eliminates one or more symptoms of a particular disease, condition or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition or disorder as described herein.

[0191] The terms “to treat,” “to treat,” or “treatment,” as used herein, encompass both preventive, i.e., protective and mitigating treatments, including reversing, mitigating, reducing, or slowing the progression of any tissue damage associated with a disease (or disorder or condition) or one or more symptoms of a disease (or disorder or condition).

[0192] As used herein, the term “contact” refers to bringing together a specified portion in an in vitro or in vivo system. For example, “contact” GIPR with the compound of the present invention includes administering the compound of the present invention to a mammal such as a human having GIPR, and introducing the compound of the present invention into a sample containing, for example, a cell preparation or purified preparation containing GIPR.

[0193] All embodiments, examples, or pharmaceutically acceptable salts thereof may be claimed individually or combined in any combination with any number of embodiments described herein.

[0194] The compounds of the present invention [including compounds of formula I or pharmaceutically acceptable salts thereof (compounds of formulas Ia, II, IIa, III, IIIa, IV, IV-1, IV-2, IVa, IVa-1, IVa-2, V, Va, VI, VIa, VII, VIIa, or pharmaceutically acceptable salts thereof)] can be used in any of the pharmaceutical compositions, uses, and methods of the present invention described herein.

[0195] Pharmaceutical composition The present invention also provides compositions (e.g., pharmaceutical compositions) comprising the compounds of the present invention. Accordingly, in one embodiment, the present invention provides a pharmaceutical composition comprising (a therapeutically effective amount) the compound of the present invention and which may also comprise a pharmaceutically acceptable carrier. In addition to the compound of the present invention, the pharmaceutical composition of the present invention may also comprise, or be administered in combination with, one or more pharmacological agents of value in treating one or more disease conditions referred to herein (e.g., simultaneously, sequentially, together, or separately). In a further embodiment, the present invention provides a pharmaceutical composition comprising (a therapeutically effective amount) the compound of formula I or a pharmaceutically acceptable salt thereof and which may comprise a pharmaceutically acceptable carrier and which may comprise at least one additional agent or pharmaceutical (such as an antidiabetic agent or a weight management agent). In one embodiment, the additional agent or pharmaceutical is an antidiabetic agent as described below.

[0196] The “pharmaceutical composition” of the present invention refers to a mixture of (1) one or more of the compounds of the present invention as an active ingredient (for example, the compound of formula I, or any solvate, hydrate, solid form, stereoisomer, tautomer, or pharmaceutically acceptable salt including a prodrug), and (2) at least one pharmaceutically acceptable excipient.

[0197] The term "excipient" is used herein to describe any component other than the compound(s) of the present invention. The choice of excipient largely depends on factors such as the method of administration, the effect of the excipient on solubility and stability, and the properties of the dosage form.

[0198] As used herein, “excipients” include any physiologically compatible solvent, dispersion medium, coating, antimicrobial agent, antifungal agent, isotonic agent, absorption retarder, carrier, diluent, and analogues. Examples of excipients include water, physiological saline, phosphate-buffered saline, glucose, glycerol, ethanol, and analogues, one or more of these, and combinations thereof. The composition may also contain isotonic agents, such as sugars, sodium chloride, or polyhydric alcohols such as mannitol or sorbitol. Examples of excipients also include various organic solvents (such as hydrates and solvates). The pharmaceutical composition may optionally contain additional excipients such as flavorings, binders / binding agents, lubricants, disintegrants, sweeteners or flavorings, colorants or dyes, and analogues. For example, in oral administration, tablets containing various excipients such as citric acid can be used together with various disintegrants such as starch, alginic acid, and certain complex silicates, as well as binders such as sucrose, gelatin, and acacia. Examples of excipients, though not limited to, include calcium carbonate, calcium phosphate, various sugars, various types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycol. Additionally, lubricants such as magnesium stearate, sodium lauryl sulfate, and talc are often useful for tableting. Similar types of solid compositions can also be used in soft and hard-filled gelatin capsules. Therefore, non-limiting examples of excipients include lactose and high molecular weight polyethylene glycol. If an aqueous suspension or elixir is preferred for oral administration, the active compound therein may be combined with various sweeteners or flavorings, colorants or dyes, and optionally emulsifiers or suspending agents, along with additional excipients such as water, ethanol, propylene glycol, glycerin, or combinations thereof.

[0199] Examples of excipients include pharmaceutically acceptable substances such as wetting agents, or small amounts of auxiliary substances such as wetting agents, emulsifiers, preservatives, or buffers, which improve the shelf life or effectiveness of the compound.

[0200] The compositions of the present invention may be in various forms. These include, for example, liquid, semi-solid, and solid dosage forms, such as liquid solutions (e.g., injectable and injectable solutions), dispersions or suspensions, tablets, capsules, pills, powders, liposomes, and suppositories. The form is determined according to the intended method of administration and therapeutic use.

[0201] Some compositions are in the form of injectable or injectable solutions, for example, compositions similar to those commonly used for passive immunization in humans using antibodies. One method of administration is parenteral (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular). In another embodiment, the compound is administered by intravenous infusion or injection. In yet another embodiment, the compound is administered by intramuscular or subcutaneous injection.

[0202] The oral administration of solid dosage forms can be presented in separate units, such as hard or soft capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of at least one of the compounds of the present invention. In another embodiment, the oral administration may be in the form of a powder or granules. In another embodiment, the oral dosage form is sublingual, such as a lozenge. In such solid dosage forms, the compounds of the present invention are typically combined with one or more adjuvants. Such capsules or tablets may include controlled-release formulations. In the case of capsules, tablets, and pills, the dosage forms may also include a buffer or may be prepared with an enteric coating.

[0203] In another embodiment, oral administration may be in liquid dosage form. Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing an inert diluent commonly used in the art (e.g., water). Such compositions may also contain adjuvants such as one or more humectants, emulsifiers, suspending agents, flavoring agents (e.g., sweeteners), or fragrances.

[0204] In another embodiment, the present invention includes parenteral dosage forms. "Pareral administration" includes, for example, subcutaneous injection, intravenous injection, intraperitoneal injection, intramuscular injection, intrasternal injection, and infusion. Injectable preparations (i.e., sterile aqueous or oily suspensions for injection) can be formulated according to known techniques using one or more suitable dispersants, wetting agents, or suspending agents.

[0205] In another embodiment, the present invention includes topical dosage forms. "Topical administration" includes, for example, dermal and transdermal administration via transdermal patches or iontophoresis devices, intraocular administration, or intranasal or inhalation administration. Compositions for topical administration also include, for example, topical gels, sprays, ointments, and creams. Topical formulations may contain compounds that enhance the absorption or penetration of the active ingredient through the skin or other affected area. When the compounds of the present invention are administered by a transdermal device, administration is achieved using either a reservoir and porous membrane type or a solid matrix type patch. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, sprays, dressings, foams, films, skin patches, wafers, 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. Penetration enhancers may also be incorporated. See, for example, BCFinnin and TMMorgan, J.Pharm.Sci., vol.88, pp.955-958, 1999.

[0206] Formulations suitable for topical administration to the eye include, for example, eye drops in which the compound of the present invention is dissolved or suspended in a suitable excipient. Typical formulations suitable for administration to the eye or ear may be in the form of particulate suspensions or droplets of solution in isotonic, pH-adjusted sterile saline. Other formulations suitable for administration to the eye and ear include ointments, biodegradable (i.e., absorbent gel sponges, collagen) and non-biodegradable (i.e., silicone) implants, wafers, lenses, and particle or vesicle systems such as niosomes or liposomes. Polymers such as cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulosic polymers such as hydroxypropyl methylcellulose, hydroxyethylcellulose, or methylcellulose, or heteropolysaccharide polymers such as gellan gum can be incorporated together with preservatives such as benzalkonium chloride. Such formulations can also be delivered by iontophoresis.

[0207] For intranasal administration, the compounds of the present invention are conveniently delivered in the form of a solution or suspension from a pump spray container squeezed or pumped by the patient, or as an aerosol spray presentation from a pressurized container or nebulizer using a suitable propellant. Formulations suitable for intranasal administration are typically administered in the form of a dry powder (alone, as a mixture, e.g., a dry blend with lactose, or as particles that are mixed components, e.g., particles mixed with phospholipids such as phosphatidylcholine) from a dry powder inhaler, or as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer that uses electrohydrodynamics to produce a fine mist) or nebulizer, with or without a suitable propellant such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. For intranasal use, the powder may contain a bioadhesion agent, e.g., chitosan or cyclodextrin.

[0208] In another embodiment, the present invention includes a rectal dosage form. Such a rectal dosage form may be, for example, a suppository. Cocoa butter is a traditional suppository base, but various alternatives can be used where appropriate.

[0209] Other excipients and administration methods known in the pharmaceutical field may also be used. The pharmaceutical compositions of the present invention can be prepared by any of the well-known compounding techniques, 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. The formulation of drugs is discussed, for example, in 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 Britain, Harry G., Ed. *Polymorphism in Pharmaceutical Solids*, New York: Informa Healthcare USA, Inc., 2016.

[0210] Acceptable excipients are nontoxic to the subject at the dosage and concentration used and may include one or more of the following: 1) buffering agents such as phosphoric acid, citrate, or other organic acids; 2) salts such as sodium chloride; 3) antioxidants such as ascorbic acid or methionine; 4) preservatives such as octadecyldimethylbenzylammonium chloride, hexamethonium chloride, benzalkonium chloride, benzethonium chloride, phenol, butyl alcohol, or benzyl alcohol; 5) alkylparabens such as methylparaben or propylparaben, catechol, resorcinol, cyclohexanol, 3-pentanol, or m-cresol; 6) low molecular weight (less than approximately 10 residues) polypeptides. 7) Proteins such as serum albumin, gelatin, or immunoglobulin; 8) Hydrophilic polymers such as polyvinylpyrrolidone; 9) Amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; 10) Monosaccharides, disaccharides, or other carbohydrates including glucose, mannose, or dextrin; 11) Chelating agents such as EDTA; 12) Sugars such as sucrose, mannitol, trehalose, or sorbitol; 13) Salt-forming counterions such as sodium or metal complexes (e.g., Zn-protein complex); or 14) Nonionic surfactants such as polysorbates (e.g., polysorbate 20 or polysorbate 80), poloxamer, or polyethylene glycol (PEG).

[0211] For oral administration, the composition can be provided in the form of tablets or capsules 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 milligrams of the active ingredient, to adjust the dosage according to the patient's symptoms. The pharmaceutical product typically contains about 0.01 mg to about 500 mg of the active ingredient, or in another embodiment, about 1 mg to about 100 mg of the active ingredient. Intravenously, the dose may range from about 0.01 to about 10 mg / kg / min during constant-rate infusion.

[0212] The liposome-containing compounds of the present invention can be prepared by methods known in the art (see, for example, Chang, HI; Yeh, MK; 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 containing phosphatidylcholine, cholesterol, and PEG-derivativeized phosphatidylethanolamine (PEG-PE). The liposomes are extruded through a filter of a specified pore size to obtain liposomes with a desired diameter.

[0213] The compounds of the present invention can also be encapsulated in microcapsules prepared, for example, by coacervation technology or interfacial polymerization, such as hydroxymethylcellulose or gelatin microcapsules and poly(methyl methacrylate) microcapsules, in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules), or in macroemulsions. Such techniques are disclosed in Remington, The Science and Practice of Pharmacy, 20th Ed., Mack Publishing (2000).

[0214] Sustained-release preparations may be used. Preferred examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the compounds of the present invention, these matrices in the form of molded articles, such as films or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (e.g., poly(2-hydroxyethyl methacrylate) or poly(vinyl alcohol)), polylactides, copolymers of L-glutamic acid and 7-ethyl-L-glutamic acid, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers, for example, those used for leuprolide acetate for depot suspensions (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), sucrose acetate isobutyrate, and poly-D-(-)-3-hydroxybutyrate.

[0215] Preparations used for intravenous administration must be sterile. This can be easily achieved, for example, by filtration through a sterile filtration membrane. The compounds of the present invention are generally placed in containers having a sterile access port, such as a bag or vial of intravenous solution with a stopper that can be punctured by a subcutaneous needle.

[0216] Suitable emulsions can be prepared using commercially available lipid emulsions, such as lipid emulsions containing soybean oil, lipid emulsions for intravenous administration (e.g., containing safflower oil, soybean oil, egg phospholipids, and glycerin in water), emulsions containing soybean oil and medium-chain triglyceride fatty acids, and lipid emulsions of cottonseed oil. The active ingredient can be dissolved in a pre-mixed emulsion composition or, alternatively, in an oil (e.g., soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil, or almond oil) and mixed with phospholipids (e.g., egg phospholipids, soybean phospholipids, or soybean lecithin) and water to form an emulsion. It will be understood that other components, such as glycerol or glucose, may be added to adjust the osmotic pressure of the emulsion. Suitable emulsions typically contain up to 20% oil, for example, between 5% and 20%. The lipid emulsion may contain lipid droplets between 0.1 and 1.0 μm, particularly between 0.1 and 0.5 μm, and may have a pH in the range of 5.5 to 8.0.

[0217] For example, the emulsion composition may be a composition prepared by mixing the compound of the present invention with a lipid emulsion containing soybean oil or its components (soybean oil, egg phospholipids, glycerol, and water).

[0218] Compositions for inhalation or inhalation include solutions and suspensions in pharmaceutically acceptable aqueous solvents or organic solvents, or mixtures thereof, as well as powders. Liquid or solid compositions may contain pharmaceutically acceptable excipients suitable as described above. In some embodiments, compositions are administered orally or via nasal respiratory routes for topical or systemic effects. Compositions in preferably sterile, pharmaceutically acceptable solvents may be sprayed using gas. The sprayed solution can be inhaled directly from a spraying device, or the spraying device can be attached to a face mask, tent, or intermittent positive airway pressure (PAP) respirator. Solutions, suspensions, or powder compositions can be administered preferably orally or nasally from a device that delivers the formulation in an appropriate manner.

[0219] Drug product intermediates (DPIs) are partially processed substances that must undergo further processing steps before becoming bulk drug products. The compounds of the present invention can be formulated into drug product intermediate DPIs containing the active ingredient in a form with a higher free energy than the crystalline form. One reason for using DPIs is to improve oral absorption characteristics due to their low solubility, slow dissolution, improved transport of substances through the mucous layer adjacent to epithelial cells, and, in some cases, limitations by biological barriers such as metabolism and transporters. Other reasons may include improved solid-state stability and downstream manufacturability. In one embodiment, the drug product intermediate contains the compound of the present invention (e.g., an amorphous solid dispersion (ASD)) isolated and stabilized in an anhydrous state. Many techniques for producing ASDs that produce materials suitable for integration into bulk drug products are known in the art, such as spray-dried dispersions (SDDs), melt extrudes (often called HMEs), co-precipitates, amorphous drug nanoparticles, and nanoadsorbents. In one embodiment, the amorphous solid dispersion contains the compound of the present invention and a polymer excipient. The concentrations of other excipients, as well as the concentrations of the excipients and the compounds of the present invention, are well known in the art and are described in standard textbooks. See, for example, "Amorphous Solid Dispersions Theory and Practice" by Navnit Shah et al.

[0220] The pharmaceutical composition may be in a form suitable for oral administration, such as a tablet, capsule, pill, powder, sustained-release formulation, solution, or suspension; in a form suitable for parenteral injection, such as a sterile solution, suspension, or emulsion; in a form suitable for topical administration, such as an ointment or cream; or in a form suitable for rectal administration, such as a suppository.

[0221] Examples of parenteral administration forms include solutions or suspensions of the active compound in a sterile aqueous solution, such as propylene glycol or glucose. Such dosage forms may be preferably buffered as desired.

[0222] Pharmaceutical compositions may be in unit dosage forms suitable for single-dose administration of precise dosages. Those skilled in the art will understand that compositions may be formulated in doses below therapeutic levels, anticipating multiple doses.

[0223] In one embodiment, the composition comprises a (therapeutably effective amount) compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0224] Administration and medication When used herein, the terms “to treat,” “to treat,” or “treatment” encompass both preventive, i.e., protective treatment and mitigating treatment, i.e., treatment that mitigates, reduces, or slows the progression of a patient’s disease (or condition) or any tissue damage associated with the disease.

[0225] As used herein, the terms “subject,” “individual,” or “patient” are interchangeable and refer to any animal, including mammals. Mammals according to the present invention include dogs, cats, cattle, goats, horses, sheep, pigs, rodents, rabbits, primates, humans, and similar animals, and encompass mammals in utero. In one embodiment, humans are preferred subjects. Human subjects may be of any sex and at any developmental stage.

[0226] As used herein, the term “therapeutic dose” means the amount of an active compound or drug that elicits a biological or pharmacokinetic response in a tissue, system, animal, individual, or human, as determined by a researcher, veterinarian, physician, or other clinician, which may include one or more of the following responses: (1) To prevent a condition, disease, or disorder, for example, in an individual who is susceptible to a condition, disease, or disorder but has not yet experienced or exhibited the pathology or symptoms of that disorder. (2) inhibiting a condition, disease, or disorder, for example, inhibiting a condition, disease, or disorder in an individual who is experiencing or exhibiting the pathology or symptoms of a condition, disease, or disorder [i.e., preventing (or slowing) the further progression of the pathology or symptoms or both], and (3) To alleviate a condition, disease, or disorder, for example, in an individual experiencing or exhibiting the pathology or symptoms of a condition, disease, or disorder, to alleviate that condition, disease, or disorder [i.e., to restore the pathology or symptoms or both].

[0227] Typically, the compounds of the present invention are administered in amounts effective to treat the conditions, diseases, or disorders described herein. The compounds of the present invention may be administered as free forms of the compounds, or alternatively, as pharmaceutically acceptable salts. For the purposes of administration and drug delivery, the free forms of the compounds or their pharmaceutically acceptable salts are simply referred to as the compounds of the present invention.

[0228] The compounds of the present invention are administered by any preferred route, in the form of a pharmaceutical composition adapted to such route, in a dose effective for the intended treatment. Administration of the compounds of the present invention can be carried out by any method that delivers the compounds systemically and / or topically. The compounds of the present invention can be administered orally, rectally, vaginally, parenterally (including, for example, intravenously, subcutaneously, intramuscularly, intravascularly, or by infusion), topically, intranasally, or by inhalation.

[0229] The compounds of the present invention can be administered orally. Oral administration may involve swallowing so that the compounds enter the gastrointestinal tract, or buccal or sublingual administration may be used so that the compounds enter the bloodstream directly from the mouth.

[0230] In another embodiment, the compounds of the present invention may also be administered parenterally, for example, into the bloodstream, intramuscularly, or directly to the internal organs. Suitable means of parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) syringes, needleless syringes, and injection techniques.

[0231] In another embodiment, the compounds of the present invention may be administered topically to the skin or mucous membrane, i.e., dermally or transdermally. In another embodiment, the compounds of the present invention may be administered intranasally or by inhalation. In another embodiment, the compounds of the present invention may be administered rectally or vaginally. In another embodiment, the compounds of the present invention may be administered directly to the eyes or ears.

[0232] The administration regimen of the compound of the present invention or a composition containing the compound is determined based on various 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 administration regimen can vary considerably. In one embodiment, the total daily dose of the compound of the present invention for the treatment of the indications discussed herein is typically about 0.0001 to about 100 mg / kg (i.e., mg of the compound of the present invention per kg of body weight). In another embodiment, the total daily dose of the compound of the present invention is about 0.01 to about 50 mg / kg, in another embodiment about 0.1 to about 50 mg / kg, and in yet another embodiment about 0.5 to about 30 mg / kg. It is not uncommon for the administration of the compound of the present invention to be repeated multiple times a day (typically four times or less). To increase the total daily dose as desired, typically multiple doses per day may be used.

[0233] Method and Use Another embodiment of the present invention comprises a compound of formula I or a pharmaceutically acceptable salt of the compound for use as a pharmaceutical, the pharmaceutical in particular being a pharmaceutical for use in the treatment or prevention of a GIPR-related condition, disease, or disorder, including administration to a mammal, such as a human, that requires such treatment.

[0234] Another embodiment of the present invention involves the use of a compound of formula I or a pharmaceutically acceptable salt of the compound as a pharmaceutically acceptable substance, in particular a pharmaceutically acceptable substance for use in the treatment or prevention of GIPR-related symptoms, diseases, or disorders, including administration to a mammal, such as a human, that requires such treatment.

[0235] Another embodiment of the present invention involves the use of a compound of formula I or a pharmaceutically acceptable salt of the compound in the manufacture of a medicament for treating or preventing a GIPR-related symptom, disease, or disorder, including administering a therapeutically effective dose to a mammal, such as a human, that requires such treatment.

[0236] Another embodiment of the present invention comprises compounds of the present invention for use as pharmaceuticals, and in particular the pharmaceuticals include diabetes [e.g., including type 1 diabetes mellitus (T1D), type 2 diabetes mellitus (T2DM), and prediabetes], idiopathic T1D (type 1b), latent autoimmune diabetes mellitus in adults (LADA), early-onset T2DM (EOD), juvenile-onset atypical diabetes mellitus (YOAD), juvenile adult-onset diabetes mellitus (MODY), malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, and renal diseases [e.g., acute kidney injury, renal tubular dysfunction]. [Conditions related to the renal tract include: harm, pro-inflammatory changes in the proximal tubules, or chronic kidney disease (CKD)], diabetic retinopathy, adipocyte dysfunction, visceral fat deposition, sleep apnea [e.g., obstructive sleep apnea (OSA)], obesity (including hypothalamic obesity and monogenic obesity) and associated comorbidities (e.g., osteoarthritis and urinary incontinence), eating disorders (including bulimia nervosa, bulimia nervosa, and symptomatic obesity such as Prader-Willi syndrome and Baldett-Beedl syndrome), weight gain such as weight gain caused by the use of other medications (e.g., steroids and / or antiseptics). (caused by the use of antipsychotic drugs, treatment for depression, or use of medications for cognitive function), excessive sugar craving, 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 [including fatty liver, non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and related diseases such as hepatocellular carcinoma, NAFLD], cardiovascular disease Diseases including 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 dyslipidemia, metabolic acidosis, ketosis, arthritis, osteoporosis, osteoarthritis, Parkinson's disease, left ventricular hypertrophy, peripheral artery disease (PAD),This is a pharmaceutical product intended for use in treating or preventing conditions, diseases, or disorders selected from macular degeneration, cataracts, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, arteriosclerosis, transient ischemic attack, restenosis, impaired glucose metabolism, abnormal fasting blood glucose levels, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders, psoriasis, foot ulcers, ulcerative colitis, hyperapolipoproteinemia, Alzheimer's disease, schizophrenia, cognitive impairment, inflammatory bowel disease, short bowel syndrome, Crohn's disease, colitis, irritable bowel syndrome, polycystic ovary syndrome (PCOS), and addictions (e.g., addiction to alcohol, nicotine, and / or drugs).

[0237] Another embodiment of the present invention involves the use of the compounds of the present invention as pharmaceuticals, in particular the pharmaceuticals for diabetes [e.g., including type 1 diabetes mellitus (T1D), type 2 diabetes mellitus (T2DM), prediabetes], idiopathic T1D (type 1b), latent autoimmune diabetes mellitus in adults (LADA), early-onset T2DM (EOD), juvenile-onset atypical diabetes mellitus (YOAD), juvenile adult-onset diabetes mellitus (MODY), malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, renal diseases [e.g., acute kidney injury, tubular dysfunction, etc.]. Weight gain such as weight gain caused by the use of other medications (e.g., steroids and / or antipsychotics), including: pro-inflammatory changes in the renal tubules or chronic kidney disease (CKD), diabetic retinopathy, adipocyte dysfunction, visceral fat deposition, sleep apnea [e.g., obstructive sleep apnea (OSA)], obesity (including hypothalamic obesity and monogenic obesity) and associated comorbidities (e.g., osteoarthritis and urinary incontinence), eating disorders (including bulimia nervosa, bulimia nervosa, and symptomatic obesity such as Prader-Willi syndrome and Baldett-Beedl syndrome), and weight gain caused by the use of other medications (e.g., steroids and / or antipsychotics). (caused by use, treatment for depression, or use of medications for cognitive function), excessive sugar craving, 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 [including fatty liver, non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and related diseases such as hepatocellular carcinoma, NAFLD], cardiovascular disease, aterostomy Arteriosclerosis (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 dyslipidemia, metabolic acidosis, ketosis, arthritis, osteoporosis, osteoarthritis, Parkinson's disease, left ventricular hypertrophy, peripheral artery disease (PAD), macular degeneration,This is a pharmaceutical product intended for use in the treatment or prevention of conditions, diseases, or disorders selected from cataracts, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, arteriosclerosis, transient ischemic attack, restenosis, impaired glucose metabolism, abnormal fasting blood glucose levels, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders, psoriasis, foot ulcers, ulcerative colitis, hyperapolipoproteinemia, Alzheimer's disease, schizophrenia, cognitive impairment, inflammatory bowel disease, short bowel syndrome, Crohn's disease, colitis, irritable bowel syndrome, polycystic ovary syndrome (PCOS), and addictions (e.g., addiction to alcohol, nicotine, and / or drugs).

[0238] Another embodiment of the present invention includes diabetes mellitus [e.g., including type 1 diabetes mellitus (T1D), type 2 diabetes mellitus (T2DM), and prediabetes], idiopathic T1D (type 1b), latent autoimmune diabetes mellitus in adults (LADA), early-onset T2DM (EOD), juvenile-onset atypical diabetes mellitus (YOAD), juvenile adult-onset diabetes mellitus (MODY), malnutrition-related diabetes mellitus, gestational diabetes mellitus, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, renal disease [e.g., acute kidney injury, tubular dysfunction, pro-inflammatory changes in the proximal tubules, or chronic kidney disease (CK)]. D), diabetic retinopathy, adipocyte dysfunction, visceral fat deposition, sleep apnea [e.g., obstructive sleep apnea (OSA)], obesity (including hypothalamic obesity and monogenic obesity) and associated comorbidities (e.g., osteoarthritis and urinary incontinence), eating disorders (including bulimia nervosa, bulimia nervosa, and symptomatic obesity such as Prader-Willi syndrome and Baldett-Beedl 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 or depression) (caused by treatment or by the use of medications for cognitive function), excessive sugar craving, 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 [including fatty liver, non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and related diseases such as hepatocellular carcinoma, NAFLD], 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 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 dyslipidemia, metabolic acidosis, ketosis, arthritis, osteoporosis, osteoarthritis, Parkinson's disease, left ventricular hypertrophy, peripheral artery disease (PAD), macular degeneration, cataracts, glomerulosclerosis, chronic renal failure,The present invention includes the use of compounds for the manufacture of pharmaceuticals to treat or prevent conditions, diseases, or disorders selected from metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, arteriosclerosis, transient ischemic attack, restenosis, impaired glucose metabolism, abnormal fasting blood glucose levels, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders, psoriasis, foot ulcers, ulcerative colitis, hyperapolipoproteinemia, Alzheimer's disease, schizophrenia, cognitive impairment, inflammatory bowel disease, short bowel syndrome, Crohn's disease, colitis, irritable bowel syndrome, polycystic ovary syndrome (PCOS), and addictions (e.g., addiction to alcohol, nicotine, and / or drugs).

[0239] In some further embodiments of the methods and uses of the present invention described herein, conditions, diseases, or disorders that can be treated or prevented in accordance with the present invention are selected from obesity, T2DM, heart failure (e.g., HFpEF and HFrEF), CKD, NAFLD, NASH, atherosclerosis, PAD, obstructive sleep apnea, diabetic retinopathy, and diabetic neuropathy.

[0240] The compounds of the present invention are GIPR antagonists. Accordingly, the present invention further provides a method (either in vitro or in vivo) for modulating (e.g., antagonizing) GIPR, comprising contacting (including incubation) GIPR with a compound of formula I described herein or a pharmaceutically acceptable salt thereof (such as one selected from Examples 1 to 229 herein).

[0241] In some embodiments, the amount of the compound of the present invention used in any one of the methods (or uses) of the present invention is effective in antagonizing GIPR.

[0242] stereoisomer The compounds of the present invention may contain chiral or asymmetric centers and therefore may exist in two or more stereoisomers. Unless otherwise specified, all stereoisomers of the compounds of the present invention, and mixtures thereof, including racemic mixtures, are intended to form part of the present invention. In addition, the present invention encompasses all geometric and positional isomers. For example, if the compounds of the present invention incorporate double bonds or fused rings, both cis and trans forms, as well as mixtures, are included within the scope of the present invention.

[0243] Stereoisomers of a compound may include cis and trans isomers (geometric isomers), optical isomers such as R and S enantiomers, diastereomers, rotational isomers, atrop isomers, and conformational isomers. For example, a compound of the present invention containing one or more chiral carbon atoms may exist as two or more stereoisomers. If the compound of the present invention contains an alkenyl group or an alkenylene group, geometric cis / trans (or Z / E) isomers are possible. Cis / trans isomers may also exist for saturated rings.

[0244] The pharmaceutically acceptable salts of the compounds of the present invention may also contain optically active counterions (e.g., D-lactic acid or L-lysine) or racemic mixtures (e.g., DL-tartaric acid or DL-arginine).

[0245] The cis / trans isomers can be separated by conventional techniques well known to those skilled in the art, such as chromatography and fractional crystallization.

[0246] Conventional techniques for preparing / isolating individual enantiomers include chiral synthesis from suitable optically pure precursors, or separation of racemates (or racemates of salts or derivatives) using, for example, chiral high-pressure liquid chromatography (HPLC). Alternatively, racemates (or racemic precursors) can be reacted with suitable optically active compounds, such as alcohols, or, if the compounds of the present invention contain an acidic or basic moiety, with a base or acid such as 1-phenylethylamine or tartaric acid. The resulting diastereomer mixture can be separated by chromatography, fractional crystallization, or by using both of the above techniques, and one or both of the diastereomers can be converted to the corresponding pure enantiomers by means well known to those skilled in the art. The chiral compounds of the present invention (and their chiral precursors) can be obtained in enantiomer-concentrated forms by chromatography, typically using HPLC. Concentration of the eluent yields the concentrated mixture. Chiral chromatography using subcritical and supercritical fluids can be used. Methods of chiral chromatography useful in some embodiments of the present invention are known in the art (see, for example, Smith, Roger M., Loughborough University, Loughborough, UK, Chromatographic Science Series (1998), 75 (Supercritical Fluid Chromatography with Packed Columns), pp. 223-249 and the references cited in that literature).

[0247] When any racemic mixture crystallizes, two different types of crystals are possible. The first type is the racemic compound described above (a true racemic mixture), in which case a single homogeneous crystalline form is produced containing equimolar amounts of both enantiomers. The second type is a racemic mixture or aggregate in which two equimolar crystalline forms are produced, each containing a single enantiomer. While both crystalline forms present in the racemic mixture may have the same physical properties, they may also have different physical properties compared to a true racemic mixture. Racemic mixtures can be separated by prior art known to those skilled in the art, see, for example, Stereochemistry of Organic Compounds by ELEEliel and SHWilen (Wiley, 1994).

[0248] The chiral compounds of the present invention (and their chiral precursors) can be obtained in an enantiomer-concentrated form by chromatography, typically high-pressure liquid chromatography (HPLC) or supercritical fluid chromatography (SFC), using a mobile phase consisting of 0-50%, typically 2-20%, isopropanol, and 0-5%, alkylamine, typically 0.1%, diethylamine (DEA) or isopropylamine, hydrocarbons, typically heptane or hexane, on a resin having an asymmetric stationary phase. Concentration of the elutes yields a concentrated mixture. When SFC is used, the mobile phase may consist of a supercritical fluid containing 2-50% methanol, ethanol or isopropanol, or other alcohols, typically carbon dioxide.

[0249] Diastereomer mixtures can be separated into individual diastereomers based on their physicochemical differences by methods well known to those skilled in the art, such as chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomer mixture into a diastereomer mixture by reaction with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or moscherate), separating the diastereomers, and converting the individual diastereomers back to their corresponding pure enantiomers (e.g., by hydrolysis). Enantiomers can also be separated by the use of a chiral HPLC column. Alternatively, specific stereoisomers can be synthesized by using optically active starting materials, by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one stereoisomer to the other by asymmetric transformation.

[0250] In some embodiments, the compounds of the present invention may have an asymmetric carbon atom. The carbon-carbon bond of the compound of formula I is shown herein by a solid line (

[0251] [ka] ), wavy line (

[0252] [ka] ), solid wedge shape (

[0253] [ka] ), or dotted wedge shape (

[0254] [ka] ) may be used to illustrate. The use of a solid line to illustrate a bond to a chiral carbon atom means that all possible stereoisomers at that carbon atom (e.g., specific enantiomers, racemic mixtures, etc.) are included. The use of a solid wedge or dotted wedge to illustrate a bond to a chiral carbon atom means that only the indicated stereoisomer is included. The use of a dashed line to illustrate a bond to a chiral carbon atom means that the stereochemistry is unknown (unless otherwise specified). Compounds of the present invention may contain more than one chiral carbon atom. In those compounds, the use of a solid line to illustrate a bond to a chiral carbon atom means that all possible stereoisomers are included. For example, unless otherwise stated, compounds of the present invention are intended to exist as enantiomers and diastereomers, or as racemates and mixtures thereof. The use of solid lines to illustrate bonds to one or more chiral carbon atoms in the compounds of the present invention, and the use of solid or dotted wedge shapes to illustrate bonds to other chiral carbon atoms in the same compounds, means that a mixture of diastereomers is present.

[0255] If a compound of the present invention has two or more stereocenters and its absolute or relative stereochemistry is given a name, the notations R and S refer to each stereocenter in ascending order (1, 2, 3, etc.) according to the conventional IUPAC numbering scheme for each molecule. If a compound of the present invention has one or more stereocenters and its stereochemistry is not given a name or structure, it is understood that the name or structure is intended to encompass all forms of the compound, including racemic forms.

[0256] The compounds of the present invention may contain olefin-like double bonds or ring structures. When such bonds or ring structures are present, the compounds of the present invention may exist in cis and / or trans configurations, as well as mixtures thereof. For example, when a double bond is present, the stereoisomer is called cis when the two higher-priority groups (on either side of the double bond) are oriented in the same direction, while the stereoisomer is called trans when the two higher-priority groups are oriented in opposite directions. The term "cis" can also refer to the two substituents being oriented relative to each other and relative to the plane of the ring (either both "up" or both "down"). Similarly, the term "trans" can also refer to the two substituents being oriented relative to each other and relative to the plane of the ring (the substituents being on opposite sides of the ring).

[0257] The claimed scope of the compounds of the present invention includes all stereoisomers, geometric isomers, and tautomers of the compounds of the present invention, including compounds exhibiting more than one type of isomerism, and mixtures thereof. It also includes acid addition salts or base salts whose counterions are optically active, such as D-lactic acid or L-lysine, or acid addition salts or base salts that are racemic, such as DL-tartaric acid or DL-arginine.

[0258] Tautomerism Tautomeric isomerism ("tautomerism") can occur when structural isomers are interconvertible over low energy barriers. This can take the form of proton tautomerism in the compounds of the present invention containing imino / amino, keto / enol, or oxime / nitroso groups, or so-called valence tautomerism in compounds containing lactam / lactim or aromatic moieties. Thus, a single compound may exhibit more than one type of isomerism.

[0259] For the sake of brevity, the compounds of the present invention are illustrated herein as a single tautomer, but it is important to emphasize that all possible tautomers are within the scope of the invention.

[0260] The intermediates and compounds of the present invention may exist as different tautomers, and all such forms may be included within the scope of the present invention. The terms “tautomer” or “tautomer” refer to structural isomers of different energies that are interconvertible across a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton transfer, such as keto-enol isomerization and imine-enamine isomerization.

[0261] Valence tautomerism involves interconversion through the rearrangement of some of the bonded electrons.

[0262] Isotopes The present invention comprises all pharmaceutically acceptable isotope-labeled compounds of the present invention, wherein one or more atoms are replaced by atoms having the same atomic number but having an atomic mass or mass number different from those normally found naturally.

[0263] Examples of isotopes suitable for inclusion in the compounds of the present invention include hydrogen isotopes, for example. 2 H and 3 H, an isotope of carbon, for example 11 C, 13 C and 14 C, an isotope of chlorine, for example 36 Cl, fluorine isotopes, for example 18 F, an isotope of iodine, for example 123 I, 124 I and 125 I. Isotopes of nitrogen, for example 13 N and 15 N, an isotope of oxygen, for example 15 O, 17 O and 18 O, phosphorus isotopes, for example 32 P, as well as sulfur isotopes, for example35 S is one example.

[0264] Certain isotope-labeled compounds of formula I, such as those incorporating radioactive isotopes, are useful for studying the tissue distribution of drugs and / or substrates. For example, tritium, a radioactive isotope, is 3 H and carbon-14, that is 14 C is particularly useful for this purpose because it is easy to incorporate and easy to detect.

[0265] Deuterium, that is 2 Substitution with heavier isotopes, such as 1H, can lead to certain therapeutic benefits resulting from greater metabolic stability, such as an extended in vivo half-life or a reduced required dose, and may therefore be preferable in certain situations.

[0266] In some embodiments, the disclosure provides deuterium-labeled (or deuterated) compounds and salts, where the formulas and variables of such compounds and salts are, respectively, as independently described herein. “Deuterated” means that at least one atom in the compound is deuterium in an abundance greater 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 atoms are actually a mixture of H and D, of which about 0.015% is D. The concentration of deuterium incorporated into the deuterium-labeled compounds and salts of the present invention may be defined by the deuterium concentration factor. Under physiological conditions, it is understood that one or more deuterium atoms may be exchanged for hydrogen.

[0267] In some embodiments, one or more hydrogen atoms on a specific metabolic site of the compound of the present invention may be deuterated. MetaSite (moldiscovery.com / software / metasite / ) may be useful in predicting some of the metabolic sites of the compound of the present invention.

[0268] 11 C, 18 F, 15 O and13 Substitution with positron-emitting isotopes such as 12N can be useful in positron emission tomography (PET) studies to investigate substrate receptor occupancy.

[0269] The isotope-labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art, or by processes similar to those described in the attached examples and preparation examples, using appropriate isotope-labeled reagents instead of unlabeled reagents already in use.

[0270] pharmaceutically acceptable solvates (including hydrates) according to the present invention include those in which the crystallization solvent can be isotope-substituted, such as D2O, d6-acetone, and d6-DMSO.

[0271] salt The compounds of the present invention can be isolated and used on their own, or, where possible, in the form of their pharmaceutically acceptable salts. The term "salt" refers to inorganic and organic salts of the compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds, or by separately treating the compounds with a suitable organic or inorganic acid or base and isolating the salts thus formed.

[0272] The term "pharmaceutically acceptable salt" generally refers to a salt of the present invention prepared by reacting a free base with a suitable organic or inorganic acid to obtain a salt of the present invention suitable for administration to a patient, or by reacting a free acid with a suitable organic or inorganic base to obtain a salt of the present invention suitable for administration to a patient.

[0273] In addition, the compounds of the present invention may include other salts of such compounds that are not necessarily pharmaceutically acceptable salts, and these salts may be useful as intermediates for one or more of the following: 1) preparing the compound of formula I, 2) purifying the compound of formula I, 3) separating the enantiomer of the compound of formula I, or 4) separating the diastereomer of the compound of formula I.

[0274] Suitable base salts are formed from bases that form non-toxic salts. Examples include, but are not limited to, aluminum, ammonium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine, and zinc salts.

[0275] Hemi salts of acids and bases, such as hemisulfates and hemicalcium salts, can also be formed.

[0276] For an overview of suitable salts, see Paulekun, GS et al., Trends in Active Pharmaceutical Ingredient Salt Selection Based on Analysis of the Orange Book Database, J.Med.Chem. 2007;50(26), 6665-6672.

[0277] A pharmaceutically acceptable salt of the compound of the present invention can be prepared by methods well known to those skilled in the art, including, but not limited to, the following procedures. (i) Reacting the compound of the present invention with a desired acid or base, (ii) Remove an acid- or base-unstable protecting group from a suitable precursor of the compound of the present invention, or open a suitable cyclic precursor, such as a lactone or lactam, using a desired acid or base, or (iii) Converting one salt of the compound of the present invention to another salt. This can be achieved by reaction with a suitable acid or base, or by using a suitable ion exchange procedure.

[0278] These procedures are typically carried out in solution. The resulting salt can precipitate and be collected by filtration or recovered by evaporation of the solvent.

[0279] solvate The compounds of the present invention (e.g., compounds of formula I or pharmaceutically acceptable salts thereof) may exist in non-solvated and solvated forms. The term "solvate" is used herein to describe molecular complexes comprising the compounds of the present invention and one or more pharmaceutically acceptable solvent molecules, such as ethanol. The term "hydrate" is used when the solvent is water.

[0280] In addition, the compounds of the present invention may include other solvates of such compounds, which are not necessarily pharmaceutically acceptable solvates, and these may be useful as intermediates for one or more of the following: 1) preparing a compound of formula I or a salt thereof; 2) purifying a compound of formula I or a salt thereof; 3) separating an enantiomer of a compound of formula I or a salt thereof; or 4) separating a diastereomer of a compound of formula I or a salt thereof.

[0281] The currently accepted classification systems for organic hydrates define them as isolation site, channel, or metal ion coordinated hydrates. See Polymorphism in Pharmaceutical Solids by KRMorris (HGBrittain, Marcel Dekker, 1995). Isolation site hydrates are hydrates in which water molecules are isolated from direct contact with each other by intervening organic molecules. In channel hydrates, water molecules exist within lattice channels, where they are adjacent to other water molecules. In metal ion coordinated hydrates, water molecules are bound to a metal ion.

[0282] When the solvent or water is strongly bound, the complex may have a well-defined stoichiometry that is independent of humidity. However, when the solvent or water is weakly bound, such as in channel solvates and hygroscopic compounds, the water / solvent content can be dependent on humidity and dry conditions. In such cases, non-stoichiometry is the norm.

[0283] complex The scope of the present invention also includes multi-component complexes (other than salts and solvates) in which a drug and at least one other component are present in stoichiometric or non-stoichiometric amounts. This type of complex includes clathrates (drug-host inclusion complexes) and cocrystals. The latter is typically defined as a crystalline complex of neutral molecular components bound together by non-covalent interactions, but may be a complex of a neutral molecule and a salt. Cocrystals can be prepared by melt crystallization, 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 multi-component complexes, see Haleblian, J. Pharm.Sci., 64(8), 1269-1288 (1975).

[0284] Prodrug The scope of the present invention also includes prodrugs of the compounds of the present invention. The compounds of the present invention can be administered in the form of prodrugs. Thus, certain derivatives of the compounds of the present invention that themselves have little or no pharmacological activity may, when administered in the body or to the body surface, be converted to the compounds of the present invention having the desired activity, for example, by hydrolytic cleavage, particularly hydrolytic cleavage facilitated by esterase or peptidase enzymes. Such derivatives are called “prodrugs.” Further information on the use of prodrugs can be found in The Expanding Role of Prodrugs in Contemporary Drug Design and Development, Nature Reviews Drug Discovery, 17, 559-587 (2018) (J. Rautio et al.).

[0285] The prodrugs according to the present invention can be produced, for example, by replacing a suitable functional group present in the compound of the present invention with a specific part known to those skilled in the art as a "pro part" as described, for example, in "Design of Prodrugs" by H. Bundgaard (Elsevier, 1985).

[0286] Therefore, the prodrug according to the present invention may be (a) an ester or amide derivative of a carboxylic acid when present in the compound of the present invention, (b) an ester, carbonate, carbamate, phosphate or ether derivative of a hydroxyl group when present in the compound of the present invention, (c) an amide, imine, carbamate or amine derivative of an amino group when present in the compound of the present invention, (d) a thioester, thiocarbonate, thiocarbamate or sulfide derivative of a thiol group when present in the compound of the present invention, or (e) an oxime or imine derivative of a carbonyl group when present in the compound of the present invention.

[0287] Some specific examples of prodrugs according to the present invention include the following: (i) If the compound of the present invention contains a carboxylic acid functional group (-COOH), then its ester, for example, the hydrogen of the carboxylic acid functional group of the compound is C1-C8 alkyl (e.g., ethyl) or (C1-C8 alkyl)C(=O)OCH2- (e.g., t Compounds that are replaced by BuC(=O)OCH2-), (ii) If the compound of the present invention contains an alcohol functional group (-OH), then an ester thereof, for example, a compound in which the hydrogen of the alcohol functional group of the compound is replaced by -CO(C1~C8 alkyl) (e.g., methylcarbonyl), or in which the alcohol is esterified with an amino acid, (iii) If the compound of the present invention contains an alcohol functional group (-OH), then the ether, for example, a compound in which the hydrogen of the alcohol functional group of the compound is replaced by (C1~C8 alkyl)C(=O)OCH2- or -CH2OP(=O)(OH)2, (iv) If the compound of the present invention contains an alcohol functional group (-OH), then the phosphate, for example, the hydrogen of the alcohol functional group of the compound is -P(=O)(OH)2 or -P(=O)(O - Na + )2 or -P(=O)(O - )2Ca2 + Compounds that are replaced by (v) If the compound of the present invention contains a primary or secondary amino functional group (-NH2 or -NHR, where R≠H), then the amide, for example, one or both hydrogens of the amino functional group of the compound as may be (C1~C 10 ) Compounds in which the alkanoyl group is replaced by -COCH2NH2, or in which the amino group is derivatized with an amino acid. (vi) If the compound of the present invention contains a primary or secondary amino functional group (-NH2 or -NHR, where R≠H), the amine thereof, for example, a compound in which one or both hydrogens of the amino functional group of the compound are replaced by -CH2OP(=O)(OH)2 as may be.

[0288] Certain compounds of the present invention can act as prodrugs of other compounds of the present invention. Furthermore, two compounds of the present invention can be combined in the form of a prodrug. In certain circumstances, a prodrug of a compound of the present invention can be created, for example, by internally linking two functional groups in the compound of the present invention to form a lactone.

[0289] metabolite The scope of the present invention also includes active metabolites of compounds of formula I (including prodrugs) or pharmaceutically acceptable salts thereof, i.e., compounds formed in vivo, often by oxidation or dealkylation, upon administration of the drug. Some examples of metabolites according to the present invention include: (i) If the compound of formula I or a pharmaceutically acceptable salt thereof contains a methyl group, its hydroxymethyl derivative (-CH3-→-CH2OH), and (ii) If the compound of formula I or a pharmaceutically acceptable salt thereof contains an alkoxy group, its hydroxy derivative (-OR- → -OH).

[0290] The scope of the present invention also includes active metabolites of the compounds of the present invention, i.e., compounds formed in vivo, often by oxidation or dealkylation, upon administration of the drug. Some examples of metabolites according to the present invention include, but are not limited to, the following: (i) If the compound of the present invention contains an alkyl group, its hydroxyalkyl derivative (-CH-→-COH) (ii) If the compound of the present invention contains an alkoxy group, its hydroxy derivative (-OR-→-OH) (iii) If the compound of the present invention contains a tertiary amino group, its secondary amino derivative (-NRR'- → -NHR or -NHR'), (iv) If the compound of the present invention contains a secondary amino group, its primary derivative (-NHR- → -NH2), (v) If the compound of the present invention contains a phenyl moiety, its phenol derivative (-Ph- → -PhOH) (vi) If the compound of the present invention contains an amide group, its carboxylic acid derivative (-CONH2-→COOH), and (vii) If the compound of the present invention contains a hydroxyl group or a carboxylic acid group, the compound may be metabolized, for example, by conjugation with glucuronic acid to form a glucuronide. Other conjugation metabolic pathways also exist. These pathways are often known as phase II metabolism and include, for example, sulfation or acetylation. Other functional groups, such as NH groups, can also be conjugated.

[0291] solid form The compounds of the present invention can exist in a range of solid states, from perfectly amorphous to perfectly crystalline. The term "amorphous" refers to a state in which a material lacks long-range order at the molecular level and can exhibit solid or liquid physical properties depending on the temperature. Typically, such materials do not exhibit a distinct X-ray diffraction pattern and are described more formally as liquids, although they exhibit solid properties. Upon heating, a change in properties occurs from solid to liquid, which is typically characterized by a secondary phase change ("glass transition"). The term "crystalline" refers to a solid phase in which a material has an internal structure with regularly aligned molecules and exhibits a distinct X-ray diffraction pattern with defined peaks. Such materials also exhibit liquid properties when sufficiently heated, but the change from solid to liquid is typically characterized by a primary phase change ("melting point").

[0292] The compounds of the present invention may also exist in intermediate states (intermediate phases or liquid crystals) when subjected to suitable conditions. Intermediate states are between the true crystalline state and the true liquid state (either molten or in solution) and consist of a two-dimensional order at the molecular level. Intermediate states resulting from temperature changes are described as "thermotropic," and intermediate states resulting from the addition of a second component, such as water or another solvent, are described as "lyotropic." Compounds with the potential to form a lyotropic intermediate phase are described as "amphiphilic" and ionic (-COO - Na + , -COO - K + , or -SO3 - Na + (etc.) or nonionic (-N - N + It consists of molecules having a polar head group (such as (CH3)3). For further information, see Crystals and the Polarizing Microscope, 4 by NH. Hartshorne and A. Stuart. th See Edition (Edward Arnold, 1970).

[0293] Some compounds of the present invention may exist in more than one crystalline form (generally referred to as "polymorphs"). Polymorphs can be prepared, for example, by crystallization under various conditions, crystallization at different temperatures, and / or by various cooling modes ranging from very rapid to very slow cooling during crystallization, using different solvents or mixtures of different solvents for recrystallization. Polymorphs can also be obtained by heating or melting the compounds of the present invention and then cooling them slowly or rapidly. The presence of polymorphs can be determined by solid-state probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray diffraction, or other such techniques.

[0294] In general, the compounds of the present invention can be prepared by processes that are similar to processes known in the chemical art, particularly in view of the description contained herein. Certain processes for producing the compounds of the present invention are provided as further features of the invention and are described by the reaction scheme below. Other processes may be described in the experimental section. A specific synthetic scheme for the preparation of the compound of formula I or its pharmaceutically acceptable salt is outlined below. It should be noted that tetrazoles are generally high-energy functional groups and care must be taken in the synthesis and handling of tetrazole-containing molecules.

[0295] synthesis The compounds of the present invention can be synthesized by synthetic routes involving processes similar to those well known in the chemical art, particularly in view of the description contained herein. 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 can be obtained from compounds that give rise to one or more scientific interests or commercial needs. Thus, 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 generally available substances using materials reported in the literature.

[0296] For illustrative purposes, the reaction scheme illustrated below provides a potentially possible route for synthesizing the compounds and key intermediates of the present invention. For a more detailed description of the individual reaction steps, please refer to the Examples section below. Those skilled in the art will understand that other synthetic routes may be used to synthesize the compounds of the present invention. Specific starting materials and reagents are discussed below, but these can be substituted with other starting materials and reagents to provide one or more of the various derivatives or reaction conditions. In addition, many of the compounds prepared by the methods described below can be further modified using conventional chemistry well known to those skilled in the art in view of this disclosure.

[0297] Those skilled in the art will understand that the experimental conditions described in the following scheme are illustrative of suitable conditions for performing the transformations shown, and that it may be necessary or desirable to modify the exact conditions used in preparing the compounds of the present invention. Furthermore, it will be understood that it may be necessary or desirable to perform the transformations in a different order than those described in the scheme, or to modify one or more transformations, in order to provide the desired compounds of the present invention.

[0298] In preparing the compounds of the present invention, it should be noted that some of the preparation methods useful for preparing the compounds described herein may require protection of remote functional groups (e.g., primary amines, secondary amines, carboxyls, etc., in the precursors of the compounds of the present invention). The need for such protection will vary depending on the nature of the remote functional groups and the conditions of the preparation method. The need for such protection will be readily determined by those skilled in the art. The use of such protection / deprotection methods is also within the scope of the art. For a general description of protecting groups and their uses, see March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 8th Edition.

[0299] For example, if a compound contains an amine or carboxylic acid functional group, such a functional group may interfere with reactions at other parts of the molecule if it is not protected. Therefore, such a functional group can be protected with a suitable protecting group (PG), which can then be removed in a subsequent step. Suitable protecting groups for amines and carboxylic acids include those commonly used in peptide synthesis (such as Nt-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), and 9-fluorenylmethyleneoxycarbonyl (Fmoc) for amines, and lower alkyl esters or benzyl esters for carboxylic acids), and these protecting groups are generally chemically unreactive under the reaction conditions described and can typically be removed without chemically altering other functional groups in the compounds of the present invention.

[0300] The reaction can be monitored according to any preferred method known in the art. For example, the formation of the product can be monitored by nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C) It can be monitored by spectroscopic means such as infrared spectroscopy, spectrophotometer (e.g., UV-Vis), and mass spectrometry, or by chromatographic methods such as high-performance liquid chromatography (HPLC) or thin-layer chromatography (TLC).

[0301] Compounds of formula I, their salts, and intermediates can be prepared according to the following reaction schemes and accompanying discussions. The reaction schemes described below are intended to provide a general explanation of the methodology used in the preparation of the compounds of the present invention. Some compounds of the present invention contain a single chiral center having a stereochemical name (R or S), while others contain two distinct chiral centers having stereochemical names (R or S). It will be apparent to those skilled in the art that most synthetic transformations can be carried out in similar manner, regardless of whether the material is enantioenriched or racemic. Furthermore, the separation into the desired optically active substance can be carried out at any desired point in the sequential reaction using well-known methods, such as those described herein and in the chemical literature.

[0302] Unless otherwise specified, in the following reaction schemes, the variables R and R in the following reaction schemes and discussions are used. 1 , R 2 , R 3 , R 3a , R A , L 1 , T 1 , T 2 , T 3 , T 4 , T 5 , T 6 , T 7 , T 8 , T 9 , T 10 , T 11 , T 12t1, t2, and structural formula I (including, for example, formula Ia) are as defined herein or as described in the claims and embodiments herein. For each of the variables, its meaning remains the same as initially described unless otherwise specified in later events. In general, the compounds of the present invention can be prepared by processes that are similar to processes known in the chemical art, particularly in view of the descriptions contained herein. Certain processes for the preparation of the compounds of the present invention and their intermediates are provided as further features of the invention and are illustrated by the following reaction schemes. Other processes are described in the experimental section. The schemes and examples provided herein (including the corresponding descriptions) are for illustrative purposes only and are not intended to limit the scope of the invention.

[0303] In general, the compounds of the present invention can be prepared by the processes described herein and similar processes known to those skilled in the art. Certain processes for the preparation of the compounds of the present invention are described in the following reaction schemes. Other processes are described in the Experiments section. The schemes and examples provided herein (including corresponding descriptions) are for illustrative purposes only. Those skilled in the art will recognize that intermediates and compounds of formula I prepared according to the following schemes may be isolated as salts or unsalted, depending on the conditions of reaction, isolation, or purification. 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 in the series of synthesis. Those skilled in the art will further recognize that, in other cases, certain functional groups may be supported throughout the series of synthesis described and then converted into alternative substituents present in the compounds of formula I.

[0304] Scheme 1 refers to the preparation of compounds of formula I from amino acids of structure 1-1. The compound of structure 1-1 can be reacted with an isocyanate of structure 1-2 in a suitable solvent (such as tetrahydrofuran) in the presence of a base (such as N,N-diisopropylethylamine) to obtain ureas of structure 1-4. Alternatively, an amine of structure 1-3 can be reacted with a suitable reactant (such as triphosgene or 1,1'-carbonyldiimidazole) to form an intermediate, and then the resulting intermediate can be reacted with the compound of structure 1-1 to obtain ureas of structure 1-4. Those skilled in the art will recognize that numerous alternative conditions can be selected for the formation of ureas (such as ureas of structure 1-4). (See, e.g., J.Med.Chem.2020, 63, 2751-2788). Compounds of formula I can be prepared from amide bond formation reactions between carboxylic acid intermediates 1-4 and amine intermediates 1-5. This type of amide bond formation reaction can be achieved by combining a carboxylic acid (such as carboxylic acid structures 1-4) and an amine (such as an amine of structures 1-5) in a suitable solvent (such as dichloromethane) in the presence of an activating reagent (such as 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide and 1-hydroxybenzotriazole) and a base (such as N,N-diisopropylethylamine). Those skilled in the art will recognize that numerous alternative conditions can be selected to form amides (such as compounds of formula I) from carboxylic acids (such as carboxylic acids of structures 1-4) and amines (such as amines of structures 1-5). (See, for example, Chem. Rev. 2011, 111, 6557-6602).

[0305] [ka] Scheme 2 refers to the preparation of compounds of formula I from aminoesters of structure 2-1 (where R is alkyl, cycloalkyl, cycloalkylalkyl, benzyl, or analogues). The aminoester of structure 2-1 can be reacted with the isocyanate of structure 1-2 in a suitable solvent (such as tetrahydrofuran) in the presence of a base (such as N,N-diisopropylethylamine) to obtain the urea of ​​structure 2-2. Alternatively, the amine of structure 1-3 can be reacted with a suitable reactant (such as triphosgene or 1,1'-carbonyldiimidazole) to form an intermediate, which is then reacted with the aminoester of structure 2-1 to obtain the urea of ​​structure 2-2. Esters of the urea of ​​structure 2-2 can be converted to carboxylic acids by methods known in the art. The conditions chosen for converting the ester to an acid depend on the type of ester present. For example, a compound of structure 2-2 in which R is methyl (i.e., has a methyl ester functional group) can be converted to a carboxylic acid by treatment with lithium hydroxide in a mixed solvent of tetrahydrofuran and water. Alternatively, a compound of structure 2-2 in which R is t-butyl (i.e., has a tert-butyl ester functional group) can be converted to a carboxylic acid by treatment with an acid such as trifluoroacetic acid. In either case, the resulting acid can be further converted by an amide bond formation reaction to obtain the compound of formula I (as shown in Scheme 1).

[0306] [ka] Scheme 3 refers to the preparation of the compound of formula I from the nitrogen-protected amino acid of structure 3-1. The carboxylic acid of structure 3-1 can be reacted with the amine of structure 1-5 under amide bond formation conditions as described in Scheme 1. The tert-butyloxycarbonyl protecting group remaining in the resulting amide can be removed by treatment with an acid such as trifluoroacetic acid to obtain the amine intermediate of structure 3-2. The intermediate of structure 3-2 can be coupled with the isocyanate of structure 1-2 or the amine of structure 1-3 under urea formation conditions as already described in Schemes 1 and 2 to obtain the compound of formula I. Those skilled in the art will recognize that alternative protecting groups to Boc shown in structure 3-1 may be used. For example, fluorenylmethyloxycarbonyl (Fmoc), another protecting group, can be used instead of the Boc group in structure 3-1. After amidation, Fmoc can then be removed under conditions known to those skilled in the art, for example, by stirring with piperidine in a solvent such as N,N-dimethylformamide.

[0307] [ka] In some cases, the preparation of the compound of formula I requires amine R 3Preparation of NH2 (structures 1-5) is required. Scheme 4 outlines the exemplary preparation of the amine of structure 4-5 (a representative example of the amines of structure 1-5) and the subsequent transformation to obtain the compound of formula I. Intermediate 4-5 can be obtained by coupling the compounds of structure 4-1 and 4-2 with the compounds of structure 4-3 and 4-4, respectively, via the Suzuki reaction (Acc ChemRes. 2008, 1461-1473). The Suzuki reaction is a coupling reaction of an arylboronic acid or vinylboronic acid with an aryl halide or vinyl halide using a palladium catalyst. For example, an aryl bromide of structure 4-1 can be reacted with an arylboronic acid of structure 4-3 in a suitable solvent (such as 1,4-dioxane) in the presence of a base (such as sodium carbonate) and a palladium catalyst (such as [(di(1-adamantyl)-butylphosphine)-2-(2'-amino-1,1'-biphenyl)]palladium(II)methanesulfonate) to obtain an intermediate of structure 4-5. The intermediate of structure 4-5 is a compound of structure 1-5 (R 3 This is an example of NH2). The intermediate of structure 4-5 is further transformed according to the method described in scheme 1-3, and R 3 R 3a A compound of formula I can be obtained.

[0308] [ka] Scheme 5 refers to the preparation of the compound of formula I, thereby R 3 Base (R here) 3 is R 3aThe intermediates of structure 1-4 (which can be prepared according to scheme 1 or scheme 2) can be reacted with the amine of structure 4-1 by an amide bond formation reaction according to the method described in scheme 1 to obtain the intermediate of structure 5-1. The aryl halide or heteroaryl halide of structure 5-1 can be coupled with the arylboronic acid or heteroarylboronic acid of structure 4-3 by a Suzuki reaction to obtain the compound of formula I. For example, the intermediate of structure 5-1 can be reacted with the arylboronic acid or heteroarylboronic acid of structure 4-3 in a suitable solvent (such as 1,4-dioxane) in the presence of a base (such as sodium carbonate) and a palladium catalyst (such as [(di(1-adamantyl)-butylphosphine)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate) to obtain the compound of formula I. Alternatively, intermediate 5-3 can be obtained by reacting intermediate 1-4 with the amine of structure 5-2 via an amide bond formation reaction according to the method described in Scheme 1. In addition, intermediate 5-3 can also be prepared by reacting intermediate 5-1 with 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane in a suitable solvent (such as 2-methyltetrahydrofuran) in the presence of a base (such as potassium acetate), a ligand (such as 2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)). The intermediate of structure 5-3 can be coupled with the aryl halide or heteroaryl halide of structure 4-4 by the Suzuki reaction to obtain the compound of formula I. For example, the intermediate of structure 5-3 can be reacted with the aryl halide or heteroaryl halide of structure 4-4 in a suitable solvent (such as 1,4-dioxane), in the presence of a base (such as sodium carbonate) and a palladium catalyst (such as [(di(1-adamantyl)-butylphosphine)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate), to obtain the compound of formula I.3 R 3a A compound of formula I can be obtained.

[0309] [ka] Scheme 6 refers to the preparation of non-racemic compounds of formula Ia. Non-racemic compounds (such as those of structures 1-1a, 2-1a, and 3-1a) can be converted according to the methods described in Schemes 1-5 and 7-10 to obtain non-racemic compounds of formula Ia. Those skilled in the art will recognize that the enantiomer purity observed for compounds of formula Ia can be affected by many factors, such as the order of synthesis used, the reagents selected for each conversion, and the purification methods used.

[0310] [ka] Scheme 7 is derived from the nitrogen-protected aminoamide of structure 7-1, R 3 R 3a The preparation of the compound of formula I is described below. First, the tert-butyloxycarbonyl protecting group can be removed by treatment with an acid such as trifluoroacetic acid to obtain an amine intermediate. Then, this amine intermediate can be coupled with the isocyanate of structure 1-2 or the amine of structure 1-3 under urea formation conditions as already described in schemes 1 and 2 to obtain intermediate 1-4. The aryl halide or heteroaryl halide of structure 1-4 can be coupled with the arylboronic acid or heteroarylboronic acid of structure 4-3 by the Suzuki reaction to obtain the compound of formula I. For example, the reactions of 1-4 and 4-3 can be carried out in a suitable solvent (such as 1,4-dioxane) in the presence of a base (such as sodium carbonate) and a palladium catalyst (such as [(di(1-adamantyl)-butylphosphine)-2-(2'-amino-1,1'-biphenyl)]palladium(II)methanesulfonate) to obtain R 3 R 3a A compound of formula I can be obtained.

[0311] [ka] In some cases, R A is -C(=O)OH [for example, R 3 is R 3a And R A For the preparation of the compounds of formula I, which is -C(=O)OH, a protecting group on the carboxylic acid, such as an ester, is required. Scheme 8 outlines an example of the preparation of ester 8-2 from acid 8-1. Ester 8-2 can be prepared by reacting it with tert-butanol in the presence of pyridine and 4-methylbenzene-1-sulfonyl chloride, and by other methods. The aryl halide or heteroaryl halide of structure 8-2 can be coupled with the arylboronic acid or heteroarylboronic acid of structure 4-2 by the Suzuki reaction to obtain intermediate 8-3. For example, the reactions of 8-2 and 4-2 can be carried out in a suitable solvent (such as 1,4-dioxane), in the presence of a base (such as sodium carbonate) and a palladium catalyst (such as [(di(1-adamantyl)-butylphosphine)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate). Next, intermediate 8-3 can be converted to structure 8-4 by an amidation reaction as shown in scheme 1-4. The final ester hydrolysis of 8-4 using an acid such as trifluoroacetic acid yields R 3 R 3a And R A A compound of formula I can be obtained where is -C(=O)OH. Those skilled in the art will recognize that other esters other than tert-butyl can be used in the variant of compound 8-2.

[0312] [ka] Scheme 9 is R 3 R 3a Compounds of formula I [for example, R AAnother series of bond formations for obtaining compounds containing -C(=O)OH is described in detail. Boc-protected amino acid 3-1 can be reacted with the amine of structure 4-1 by an amide bond formation reaction according to the method described in Scheme 1 to obtain the intermediate of structure 7-1. The aryl halide or heteroaryl halide of structure 7-1 can be coupled with the arylboronic acid or heteroarylboronic acid of structure 4-3 via a Suzuki reaction to obtain intermediate 9-2. For example, the intermediate of structure 7-1 can be reacted with the arylboronic acid or heteroarylboronic acid of structure 4-3 in a suitable solvent (such as 1,4-dioxane) in the presence of a base (such as sodium carbonate) and a palladium catalyst (such as [(di(1-adamantyl)-butylphosphine)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate) to obtain 9-2. Alternatively, Boc-protected amino acid 3-1 can be reacted with the amine of structure 4-2 by an amide bond formation reaction according to the method described in Scheme 1 to obtain the intermediate of structure 9-1. The arylboronic acid or heteroarylboronic acid of structure 9-1 can be coupled with the aryl halide or heteroaryl halide of structure 4-4 by the Suzuki reaction to obtain intermediate 9-2. Next, the tert-butyloxycarbonyl protecting group of 9-2 can be removed by treatment with an acid such as trifluoroacetic acid to obtain an amine intermediate, which can then be coupled with the isocyanate of structure 1-2 or the amine of structure 1-3 under the urea formation conditions already described in Schemes 1-3 and 7 to obtain R 3 R 3a A compound of formula I can be obtained. Using scheme 9, other variations of the substitution patterns of structures 4-3 and 4-4 can be obtained, for example, meta-substituted R A Base (in this case, R 3 R 3b It is also possible to synthesize compounds of formula I, which can be prepared.

[0313] [ka] Scheme 10 details another reaction type for obtaining the compound of formula I. 3 As part of the process, an aminoamide 3-2, which can contain an ester protecting group in the carboxylic acid, can be reacted with a carboxylic acid of structure 10-1 via a Curtius rearrangement to obtain a urea bond-containing intermediate. This Curtius rearrangement can be carried out in an organic solvent such as toluene, in the presence of a base such as diphenyl phosphorazidate and triethylamine. The resulting intermediate is R 3 If the compound contains an ester protecting group, it can be deprotected using an acid such as trifluoroacetic acid to obtain the compound of formula I.

[0314] [ka] Detailed descriptions of each reaction step are provided in the Examples section below. Those skilled in the art will understand that other synthetic routes may be used to synthesize the compounds. Specific starting materials and reagents are discussed below, but they can be readily substituted with other starting materials and reagents to provide a variety of derivatives and / or reaction conditions. In addition, many of the compounds prepared by the methods described below can be further modified using conventional chemistry well known to those skilled in the art, in view of this disclosure.

[0315] Concomitant administration The compounds of the present invention can be used alone or in combination with one or more other therapeutic agents. The present invention provides any of the uses, methods, or compositions defined herein for using the compounds of the present invention, or pharmaceutically acceptable salts thereof, in combination with one or more other therapeutic agents discussed herein.

[0316] Administering two or more compounds "in combination" means that all compounds are administered in sufficient time proximity to perform the treatment in question. Two or more compounds may be administered simultaneously or sequentially, via the same or different routes of administration, on the same or different administration schedules, and with or without specific time constraints, depending on the treatment regimen. Additionally, simultaneous administration can be achieved by mixing the compounds before administration, or by administering the compounds at the same time, but in different dosage forms, to the same or different administration sites. Examples of "in combination" include, but are not limited to, "simultaneous administration," "combined administration," "simultaneous administration," "sequential administration," and "simultaneous administration."

[0317] The compounds of the present invention and one or more other therapeutic agents can be administered as fixed or unfixed combinations of active ingredients. The term "fixed combination" means that the compounds of the present invention or pharmaceutically acceptable salts thereof and one or more therapeutic agents are administered together to a subject simultaneously in a single composition or dosage. The term "unfixed combination" means that the compounds of the present invention or pharmaceutically acceptable salts thereof and one or more therapeutic agents can be administered simultaneously to a subject requiring them, or at different times with variable intervention time limits, and are formulated as separate compositions or dosages such that such administration brings effective levels of two or more compounds into the subject's body.

[0318] The combination of drugs is administered to the patient (e.g., mammal or human) in a therapeutically effective dose. "Therapeutically effective dose" means the amount of the compound of the present invention that, when administered to a mammal alone or in combination with additional therapeutic agents, is effective in treating the desired disease / disorder / condition (e.g., T2DM or obesity).

[0319] In some embodiments, the compounds of the present invention include orlistat, TZD and other insulin resistance improvers, FGF21 analogs, metformin, ethyl omega-3 acid (e.g., Lovaza), fibrates, HMG CoA-reductase inhibitors, ezetimibe, propucol, ursodeoxycholic acid, TGR5 agonists, FXR agonists, vitamin E, betaine, pentoxifylline, CB1 antagonists, carnitine, N-acetylcysteine, reduced glutathione, lorcaserin, combinations of naltrexone and buproprion, and SGLT2 inhibitors (dapagliflozin, canagliflozin, empagliflozin, tofogliflozin, ertugliflozin, ASP-19). 41, THR1474, TS-071, ISIS388626 and LX4211, and those listed in 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., tilzepatide (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, pembidutide, pegapamodutide, sulvodutide, L M-008, IBI-362, AZD9550), dual GLP-1 receptor / GLP-2 receptor agonists (e.g., dapiglutide), dual GLP-1 receptor / amylin receptor agonists (e.g., amicretin), caglilinitide / semaglutide, GLP-1 receptor agonist / GIP receptor antagonist (maridebath caflagrutide), dual GLP-1 receptor / FGF21 receptor agonists (e.g., HEC-88473, BI3006337), GLP-1 receptor / glucagon receptor / GIP receptor triple agonists (e.g., lettoltide), GLP-1 receptor / glucagon receptor / FGF21 receptor triple agonists (e.g., DR10624), NPY2 receptor agonists (e.g., BI It can be administered in combination with one or more other drugs, such as 1820237), activin receptor 2B modulators (e.g., bimaglumab), amyrin receptor agonists, GPR75 modulators, delta-5 desaturase inhibitors, orexin 2 receptor modulators, angiotensin receptor blockers, acetyl-CoA carboxylase (ACC) inhibitors, ketohexokinase (KHK) inhibitors, ASK1 inhibitors, branched-chain alpha-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.

[0320] Examples of GLP-1 receptor agonists include liraglutide, albiglutide, exenatide, lixisenatide, dulaglutide, semaglutide, danuglypron, orfolglypron, rotiglypron, PF-06954522, HM15211, LY3298176, Medi-0382, NN-9924, TTP-054, TTP-273, efpeglenatide, CT-996, ECC5004, XW004, XW014, MDR-001, ZT002, KN-056, GL0034, GSBR-1290, Examples include Neuglutide, RGT-075, TTP-273, HRS-7535, GMA-105, TG103, GZR-18, GX-G6, Eknoglutide, PB-119, QLG2065, Beinaglutide, those described in WO2018109607, those described in WO2019239319 (PCT / IB2019 / 054867, filed June 11, 2019), and those described in WO2019239371 (PCT / IB2019 / 054961, filed June 13, 2019).

[0321] Examples of ACC inhibitors include 4-(4-[(1-isopropyl-7-oxo-1,4,6,7-tetrahydro-1'H-spiro[indazole-5,4'-piperidine]-1'-yl)carbonyl]-6-methoxypyridine-2-yl)benzoic acid, gemcabene, and filsocostat (GS-0976), as well as their pharmaceutically acceptable salts.

[0322] Examples of FXR agonists include tropifexol (2-[(1R,3R,5S)-3-({5-cyclopropyl-3-[2-(trifluoromethoxy)phenyl]-1,2-oxazole-4-yl}methoxy)-8-azabicyclo[3.2.1]octan-8-yl]-4-fluoro-1,3-benzothiazole-6-carboxylic acid), silofexol (GS-9674), obeticholic acid, LY2562175, Met409, TERN-101 and EDP-305, as well as their pharmaceutically acceptable salts.

[0323] Examples of KHK inhibitors include [(1R,5S,6R)-3-{2-[(2S)-2-methylazetidine-1-yl]-6-(trifluoromethyl)pyrimidine-4-yl}-3-azabicyclo[3.1.0]hexa-6-yl]acetic acid and its pharmaceutically acceptable salts.

[0324] An example of a DGAT2 inhibitor is (S)-2-(5-((3-ethoxypyridine-2-yl)oxy)pyridine-3-yl)-N-(tetrahydrofuran-3-yl)pyrimidine-5-carboxamide [including its crystalline solid forms (Form 1 and Form 2)]. See U.S. Patent No. 10,071,992.

[0325] Some exemplary BCKDK inhibitors are those described in U.S. Patent Nos. 11542270 and 11059833, including: 5-(5-chloro-4-fluoro3-methylthiophen-2-yl)-1H-tetrazol; 5-(5-chloro-3-difluoromethylthiophen-2-yl)-1H-tetrazol; 5-(5-fluoro-3-methylthiophen-2-yl)-1H-tetrazol; 5-(5-chloro-3-methylthiophen-2-yl)-1H-tetrazol; 5-(3,5-dichlorothiophen-2-yl)-1H-tetrazol; 5-(4-bromo-3-methylthiophen-2-yl)-1H-tetrazol; 5-(4-bromo-3-ethylthiophen-2-yl)-1H-tetrazol; 5-(4-chloro-3-ethylthiophen-2-yl)-1H-tetrazol; 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, examples include pharmaceutically acceptable salts thereof.

[0326] Some further exemplary BCKDK inhibitors include those described in U.S. Patent Application No. 18 / 060,027, filed November 30, 2022, including: 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-methylphenyl)-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; 3-(6-chloro-2,4-difluoro-3-methoxyphenyl)-6-fluoro-1-benzothiophene-2-carboxylic acid, TROP-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 Ammonium 3-(3-ethyl-2,4,5-trifluorophenyl)-6-fluoro-1-benzothiophene-2-carboxylate; Or, examples include pharmaceutically acceptable salts thereof.

[0327] In some embodiments, the compounds of the present invention can be administered in combination with one or more antidiabetic agents. Suitable antidiabetic agents include insulin, metformin, GLP-1 receptor agonists (as specified above), acetyl-CoA carboxylase (ACC) inhibitors (as specified above), SGLT2 inhibitors (as specified above), monoacylglycerol O-acyltransferase inhibitors, phosphodiesterase (PDE)-10 inhibitors, AMPK activators [e.g., ETC-1002 (bempedoic acid)], sulfonylureas (e.g., acetohexamide, chlorpropamide, diabinese, glibenclamide, glipizide, glybrid, glimepiride, gliclazide, glypentide, glikidone, glisoramide, trazamide, and tolbutamide), meglitinide, α-amylase inhibitors (e.g., tendamistat, trestatin, and AL-36) 88) α-glucoside hydrolase inhibitors (e.g., acarbose), α-glucosidase inhibitors (e.g., adiposin, camiglibose, emiglitate, miglitol, voglibose, prazimycin Q, and salvostatin), PPARγ agonists (e.g., paraglitazone, siglitazone, dalglitazone, englitazone, isaglitazone, pioglitazone, and rosiglitazone), PPARα / 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., trodasquemin, hilythiosal extract, and Zhang, S.Compounds disclosed in Drug Discovery Today, 12(9 / 10), 373-381(2007), SIRT-1 activators (e.g., resveratrol, GSK2245840 or GSK184072), dipeptidyl peptidase IV (DPP-IV) inhibitors (e.g., those of WO2005116014, sitagliptin, vildagliptin, alogliptin, dutogliptin, linagliptin and saxagliptin), insulin secretory stimulants, fatty acid oxidation inhibitors, A2 antagonists, c-jun amino-terminal kinase (JNK) Inhibitors, glucokinase activators (GKa) such as those listed in WO2010103437, WO2010103438, WO2010013161, WO2007122482, TTP-399, TTP-355, TTP-547, AZD1656, ARRY403, MK-0599, TAK-329, AZD5658 or GKM-001, insulin, insulin mimetic, glycogen phosphorylase inhibitors (e.g., GSK1362885), VPAC2 receptor agonists, Demong, DE et al., Annual Glucagon receptor modulators such as those described in Reports in Medicinal Chemistry 2008, 43, 119-137; GPR119 modulators, especially agonists (e.g., MBX-2982, GSK1292263, APD597 and PSN821), such as those described in Annual Reports in Medicinal Chemistry 2009, 44, 149-170, such as those described in Reports in Medicinal Chemistry 2008, 43, 119-137, such as those described in Reports in Medicinal Chemistry 2008, 43, 119-137, such as those described in Reports in Medicinal Chemistry 2009, 44, 149-170, such as those described in Reports in Medicinal Chemistry 2009, 44, 149-170, such as those described in Reports in Medicinal Chemistry 2008, 43, 119-137These include TGR5 (also known as GPBAR1) receptor modulators, particularly agonists, such as those described in Current Topics in Medicinal Chemistry, 2010, 10(4), 386-396, and GPR40 agonists, such as those described in Medina, JC, Annual Reports in Medicinal Chemistry, 2008, 43, 75-85, including, but not limited to, INT777, TAK-875, GPR120 modulators, particularly agonists, and high-affinity nicotinic acid receptor (HM74A) activators, as well as SGLT1 inhibitors such as GSK1614235. A further representative list of antidiabetic agents that can be combined with the compounds of the present invention can be found, for example, on pages 28, line 35 to page 30, line 19 of WO2011005611.

[0328] Other antidiabetic agents may include carnitine palmitoyltransferase enzyme inhibitors or modulators, fructose 1,6-diphosphatase inhibitors, aldose reductase inhibitors, mineralocorticoid receptor inhibitors, TORC2 inhibitors, CCR2 and / or CCR5 inhibitors, PKC isoform inhibitors (e.g., PKCα, PKCβ, PKCγ), fatty acid synthase inhibitors, serine palmitoyltransferase inhibitors, modulators of GPR81, GPR39, GPR43, GPR41, GPR105, Kv1.3, retinol-binding protein 4, glucocorticoid receptors, somatostatin receptors (e.g., SSTR1, SSTR2, SSTR3, and SSTR5), PDHK2 or PDHK4 inhibitors, MAP4K4 inhibitors, modulators of the IL1 family including IL1 beta, and modulators of RXR alpha. In addition, suitable antidiabetic agents include those with mechanisms of action as enumerated by Carpino, PA, Goodwin, B. Expert Opin. Ther. Pat., 2010, 20(12), 1627-51.

[0329] The compounds of the present invention are ACE inhibitors (e.g., captopril, enalapril, hosinopril, lisinopril, perindopril, quinapril, ramipril, trandolapril), angiotensin II receptor blockers (e.g., candesartan, losartan, valsartan), angiotensin receptor neprilysin inhibitors (sacubitril / valsartan), I f It can be administered in combination with antiheart failure agents such as channel blockers ivabradine, beta-adrenergic blockers (e.g., bisoprolol, metoprolol succinate, carvedilol), aldosterone antagonists (e.g., spironolactone, eplerenone), hydralazine and isosorbide dinitrate, diuretics (e.g., furosemide, bumetanide, torsemide, chlorothiazide, amiloride, hydrochlorothiazide, indapamide, metrazone, triamterene), or digoxin.

[0330] The compounds of the present invention can also be administered in combination with cholesterol or lipid-lowering agents, including the following exemplary agents: HMGCoA reductase inhibitors (e.g., pravastatin, pitavastatin, lovastatin, atorvastatin, simvastatin, fluvastatin, NK-104 (also known as itavastatin, or nisvastatin or nisbastatin) and ZD-4522 (also known as rosuvastatin, or atavastatin or bisastatin)); squalene synthase inhibitors; fibrates (e.g., gemfibrozil, pemafibrate) , fenofibrate, clofibrate); bile acid adsorbents (Questran, Colestipol, Coleseveram, etc.); ACAT inhibitors; MTP inhibitors; lipoxygenase inhibitors; cholesterol absorption inhibitors (e.g., ezetimibe); nicotinic acid agents (e.g., niacin, niacol, slow-niacin), omega-3 fatty acids (e.g., Epanova, fish oil, eicosapentaenoic acid); cholesterol ester transfer protein inhibitors (e.g., ovicetrapib) and PCSK9 modulators [e.g., alirocumab, evolocumab, vococizumab, ALN-PCS (incrisiran)].

[0331] The compounds of the present invention can also be used in combination with antihypertensive agents, and such antihypertensive activity can be easily determined by those skilled in the art according to a standard assay (e.g., blood pressure measurement). Examples of suitable antihypertensive agents include alpha-adrenergic blockers; beta-adrenergic blockers; calcium channel blockers (e.g., diltiazem, verapamil, nifedipine, and amlodipine); vasodilators (e.g., hydralazine); diuretics (e.g., chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, ethacrylic acid). Triclinafen, chlorthalidone, torsemide, furosemide, musolimin, bumetanide, triamtrenene, amyloride, spironolactone); renin inhibitors; ACE inhibitors (e.g., captopril, zofenopril, hosinopril, enalapril, seranopril, cilazopril, delapril, pentopril, quinapril, ramipril, lisinopril); AT-1 receptor antagonists (e.g., losartan, irbesartan, valsartan); ET receptor antagonists Examples include antagonists (e.g., sitaxentane, atorsentan, and compounds disclosed in U.S. Patents 5,612,359 and 6,043,265); dual ET / AII antagonists (e.g., compounds disclosed in WO00 / 01389); neutral endopeptidase (NEP) inhibitors; and vasopepsidase inhibitors (dual NEP-ACE inhibitors) (e.g., gemopatrilat and nitrate). An exemplary antianginal agent is ivabradine.

[0332] Suitable calcium channel blockers (L-type or T-type) include diltiazem, verapamil, nifedipine, amlodipine, and mibefragil.

[0333] Suitable examples of cardiac glycosides include digitalis and ouabain.

[0334] In one embodiment, the compound of the present invention can be administered in combination with one or more diuretics. Examples of suitable diuretics include (a) loop diuretics such as furosemide (LASIX®, etc.), torsemide (DEMADEX®, etc.), bemetanide (BUMEX®, etc.), and ethacrine (EDECRIN®, etc.), (b) chlorothiazide (DIURIL®, ESIDRIX®, or HYDRODIURIL®, etc.), hydrochlorothiazide (MICROZIDE®, or Oretic®, etc.), benzthiazide, hydroflumethiazide (SALURON®, etc.), and bendroflumethiazide. Examples include thiazide diuretics such as azide, methylchlorthiazide, polythiazide, trichlormethiazide, and indapamide (LOZOL®, etc.), (c) phthalimidine diuretics such as chlorthalidone (HYGROTON®, etc.) and metrazone (ZAROXOLYN®, etc.), (d) quinazoline diuretics such as quinetazone, and (e) potassium-sparing diuretics such as triamterene (DYRENIUM®, etc.) and amiloride (MIDAMOR® or MODURETIC®, etc.).

[0335] In another embodiment, the compounds of the present invention can be administered in combination with a loop diuretic. In yet another embodiment, the loop diuretic is selected from furosemide and torsemide. In yet another embodiment, one or more compounds of formula I or pharmaceutically acceptable salts thereof can be administered in combination with furosemide. In yet another embodiment, one or more compounds of formula I or pharmaceutically acceptable salts thereof can be administered in combination with torsemide, where torsemide may be a controlled-release or regulated-release form of torsemide.

[0336] In another embodiment, the compounds of the present invention can be administered in combination with a thiazide diuretic. In yet another embodiment, the thiazide diuretic is selected from the group consisting of chlorothiazides and hydrochlorothiazides. In yet another embodiment, one or more compounds of formula I or pharmaceutically acceptable salts thereof can be administered in combination with a chlorothiazide. In yet another embodiment, one or more compounds of formula I or pharmaceutically acceptable salts thereof can be administered in combination with a hydrochlorothiazide.

[0337] In another embodiment, one or more compounds of formula I or pharmaceutically acceptable salts thereof may be administered in combination with a phthalimidine diuretic. In yet another embodiment, the phthalimidine diuretic is chlorthalidone.

[0338] Examples of suitable mineralocorticoid receptor antagonists include spironolactone and eplerenone.

[0339] Suitable examples of phosphodiesterase inhibitors include PDE III inhibitors (such as cilostazol) and PDE V inhibitors (such as sildenafil).

[0340] Those skilled in the art will recognize that the compounds of the present invention can be used in combination with other cardiovascular or cerebrovascular procedures, 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.

[0341] In particular, when provided as a single dose unit, there is a potential for chemical interactions between the combined active ingredients. Therefore, when the compound of the present invention and the second therapeutic agent are combined into a single dose unit, the active ingredients are combined into a single dose unit, but the formulation can be designed so that physical contact between the active ingredients is minimized (i.e., reduced). For example, one of the active ingredients can be enterically coated. Enteric coating one of the active ingredients not only minimizes contact between the combined active ingredients, but also allows for control over the release of one of these components in the gastrointestinal tract, such that one of these components is released in the intestines rather than the stomach. One of the active ingredients can also be coated with a material that provides sustained release throughout the gastrointestinal tract and also works to minimize physical contact between the combined active ingredients. Furthermore, the sustained-release component can be additionally enterically coated so that the release of this component occurs only in the intestines. Another approach may involve formulating a composite product in which, to further isolate the active components, one component is coated with a sustained-release and / or enteric polymer, and the other component is also coated with a polymer such as low-viscosity grade hydroxypropyl methylcellulose (HPMC) or other suitable material known in the art. The polymer coating acts to form an additional barrier against interaction with the other components.

[0342] These and other methods for minimizing contact between the components of the composite product of the present invention will be readily apparent to those skilled in the art upon understanding this disclosure, whether administered in a single dosage form or in separate forms but simultaneously administered in the same manner.

[0343] Another approach could involve formulating a compound product in which both active components are combined with a substance that sustainably releases both active components throughout the gastrointestinal tract.

[0344] In some embodiments of combined treatments, both the compounds of the present invention and other drug therapies are administered to a patient, such as a mammal (e.g., human, male or female), by conventional methods.

[0345] kit Another aspect of the present invention provides a kit comprising the compound of the present invention or a pharmaceutical composition comprising the compound of the present invention. The kit may include a diagnostic agent or a therapeutic agent in addition to the compound of the present invention or its pharmaceutical composition. The kit may also include instructions for use in a diagnostic or therapeutic method. In some embodiments, the kit comprises the compound or its pharmaceutical composition and a diagnostic agent. In other embodiments, the kit comprises the compound or its pharmaceutical composition and one or more therapeutic agents as described in the combined dosing section above.

[0346] In yet another embodiment, the present invention includes a kit suitable for use in carrying out the treatment methods described herein. In one embodiment, the kit contains a first dosage form comprising one or more of the compounds of the present invention in an amount sufficient to carry out the method of the present invention. In another embodiment, the kit includes one or more of the compounds of the present invention in an amount sufficient to carry out the method of the present invention, as well as a container for dosage and a container for dosage. [Examples]

[0347] The synthesis of various compounds of the present invention is shown below. Further compounds within the scope of the present invention can be prepared using the methods shown in these examples alone or in combination with techniques generally known in the art. All starting materials in these preparation examples and examples are commercially available or can be prepared by methods known in the art or described herein.

[0348] The reactions were carried out in air, or under an inert atmosphere (nitrogen or argon) if reagents or intermediates sensitive to oxygen or moisture were used. Where appropriate, the reaction apparatus was dried under dynamic vacuum using a heat gun, and anhydrous solvents (Sure-Seal® products from Aldrich Chemical Company, Milwaukee, Wisconsin, or DriSolv® products from EMD Chemicals, Gibbstown, New Jersey) were used. In some cases, some commercially available solvents were passed through a column packed with 4Å molecular sieves until the following QC standards for water were met: a) less than 100 ppm for dichloromethane, toluene, N,N-dimethylformamide, and tetrahydrofuran; b) less than 180 ppm for methanol, ethanol, 1,4-dioxane, and diisopropylamine. For very sensitive reactions, some solvents were further treated with metallic sodium, calcium hydride, or molecular sieves and distilled immediately before use. Other commercially available solvents and reagents were used without further purification. For synthesis that refers to the procedures of other examples or methods, the reaction conditions (reaction time and temperature) may differ. The products were generally dried under vacuum before proceeding to further reactions or before undergoing biological testing.

[0349] Where specified, the reactants were heated by microwave irradiation using a Biotage Initiator or Personal Chemistry Emrys Optimizer microwave instrument. The progress of the reaction was monitored using thin-layer chromatography (TLC), liquid chromatography-mass spectrometry (LCMS), high-performance liquid chromatography (HPLC), and / or gas chromatography-mass spectrometry (GCMS). TLC was performed on silica gel plates pre-coated with a fluorescent indicator (excitation wavelength 254 nm) and visualized under UV light and / or using I2, KMnO4, CoCl2, phosphomolybdic acid, or cerium ammonium molybdate stains. LCMS data were acquired using an Agilent 1100 series instrument with a Leap Technologies autosampler, Gemini C18 column, acetonitrile / water gradient, and one of the following: trifluoroacetic acid, formic acid, or ammonium hydroxide modifier. Column elutes were analyzed using a Waters ZQ mass spectrometer, scanned in positive and negative ion modes from 100 to 1200 Da. Other similar instruments were also used. HPLC data were generally acquired using Agilent 1100 series instruments with Gemini or XBridge C18 columns, acetonitrile / water gradients, and either trifluoroacetic acid or ammonium hydroxide-modified substances. GCMS data were acquired using a Hewlett Packard 6890 oven with an HP6890 injector, HP-1 column (12 m × 0.2 mm × 0.33 μm), and helium carrier gas. Samples were analyzed by scanning at 50–550 Da using electron ionization with an HP 5973 mass-selective detector. Purification was performed by medium-pressure liquid chromatography (MPLC) using Isco CombiFlash Companion, AnaLogix IntelliFlash 280, Biotage SP1, or Biotage Isolera One instruments and pre-filled Isco RediSep or Biotage Snap silica cartridges.Chiral purification was generally performed by chiral supercritical fluid chromatography (SFC) using Berger or Thar equipment; ChiralPAK-AD, -AS, -IC, Chiralcel-OD, or -OJ columns; and a mixture of CO2 and methanol, ethanol, propan-2-ol, or acetonitrile (either alone or modified with trifluoroacetic acid or propan-2-amine). UV detection was used to induce fraction collection. For synthesis referring to procedures in other examples or methods, purification may differ, and generally, the solvent and solvent ratio used for the eluate / gradient should be appropriate. f The selection was made to obtain the s-value or retention time.

[0350] Mass spectrometry data are reported from LC-MS analysis. Mass spectrometry (MS) was performed using atmospheric pressure chemical ionization (APCI), electrospray ionization (ESI), electron impact ionization (EI), or electron scattering (ES) ionization sources. Proton nuclear magnetic resonance ( 1Chemical shifts (H NMR) were expressed in parts per million (ppm, δ) relative to the deuterated solvent residual peaks (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: single, d: double, t: triple, q: quadruple, quin: quintuple, m: multiline, brs: broad single, app: apparent. Analytical SFC data were acquired using a Berger analyzer as described above. Optical rotation data were acquired using a Perkin-Elmer Model 343 polarimeter with a 1 dm cell. Silica gel chromatography was performed primarily using Biotage or ISCO medium-pressure systems, employing pre-packed columns from various commercial suppliers, including Biotage or ISCO. Trace analysis was performed by Quantitative Technologies Inc., and was within 0.4% of the calculated values.

[0351] Unless otherwise stated, chemical reactions were carried out at room temperature (approximately 23 degrees Celsius).

[0352] Unless otherwise stated, all reaction products were obtained commercially without further purification or prepared using methods known in the literature.

[0353] The terms "concentrated," "evaporated," and "concentrated in vacuum" refer to the removal of a solvent under reduced pressure at a bath temperature below 60°C using a rotary evaporator. The abbreviations "min" and "h" represent "minutes" and "hours," respectively. The term "TLC" refers to thin-layer chromatography, "room temperature or ambient temperature" means 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.

[0354] Hydrogenation can be carried out in a Parr shaker under pressurized hydrogen gas, or in a Thales-nano H-Cube flow hydrogenator at a flow rate of 1-2 mL / min in a total hydrogen state at a specific temperature.

[0355] Retention times for HPLC, UPLC, LCMS, GCMS, and SFC were measured using the methods described in the procedure.

[0356] In some examples, chiral separation was performed to separate enantiomers or diastereomers of a particular compound of the present invention (in some examples, the separated enantiomers were designated ENANT-1 and ENANT-2 according to their elution order, and similarly, the separated diastereomers were designated DIAST-1 and DIAST-2 according to their elution order). In some examples, the optical rotation of the enantiomers was measured using a polarimeter. According to the observed optical rotation data (or specific optical rotation data), the enantiomer that rotates clockwise was designated as the (+)-enantiomer, and the enantiomer that rotates counterclockwise was designated as the (-)-enantiomer. Racemic compounds are indicated by the absence of a stereochemical structure being illustrated or described, or by the presence of (+ / -) adjacent to the structure, in the latter case, the indicated stereochemistry represents only one of the two enantiomers constituting the racemic mixture.

[0357] The compounds and intermediates described below were named using the nomenclature provided in ACD / ChemSketch 2020.2.1.1, file version C25H41, Build 121153 (Advanced Chemistry Development, Inc., Toronto, Ontario, Canada). The nomenclature provided in ACD / ChemSketch 2020.2.1.1 is well known to those skilled in the art and is generally considered to conform to the IUPAC (International Union of Pure and Applied Chemistry) recommendations on organic chemical nomenclature and the CAS index rules.

[0358] (Example 1) Ammonium 5-{4-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]phenyl}pyridine-2-carboxylate(1)

[0359] [ka] Step 1.1 Synthesis of {[4-(propan-2-yl)phenyl]carbamoyl}-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°C-3°C. After 2 minutes, 1-isocyanate-4-(propan-2-yl)benzene (25.0 g, 155 mmol) was added over 30 seconds, and stirring was continued for 5 minutes. The reaction mixture was then removed from the ice bath and stirred at room temperature. After 2 hours, LC-MS analysis showed the formation of C1: LC-MS m / z 277.4 [M+H] +Water (500 mL) was added, followed by solid sodium bicarbonate (19.5 g, 233 mmol) to adjust the pH to 7-8. The resulting mixture was washed with methyl tert-butyl ether (2 × 600 mL), and the aqueous layer was then acidified to pH 2 by adding concentrated hydrochloric acid and stirred for 20 minutes. C1 was obtained as a white solid by filtration and subsequent rinsing of the filter cake with water. Yield: 39.1 g, 141 mmol, 91%. 1 H 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).

[0360] Step 2: (2R)-N 1 -[4-(propan-2-yl)phenyl]-N 2 Synthesis of [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrrolidine-1,2-dicarboxamide (C2). A solution of C1 (3.00 g, 10.9 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.38 g, 10.9 mmol), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (2.71 g, 14.1 mmol) was stirred overnight at room temperature in dichloromethane (54 mL). The reaction mixture was then diluted with dichloromethane, sequentially washed with water and saturated sodium chloride aqueous solution, dried over sodium sulfate, filtered, and concentrated under vacuum. C2 was obtained as an off-white solid by rubbing with diethyl ether. Yield: 4.37 g, 9.15 mmol, 84%. LCMS m / z 478.4 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 10.09 (s, 1H), 8.18 (s, 1H), 7.61 (AB quartet, J AB = 8.7 Hz, Δν AB = 10.3 Hz, 4H), 7.39 (d, J = 8.6 Hz, 2H), 7.08 (d, J = 8.6 Hz, 2H), 4.45 (dd, J = 8.2, 3.6 Hz, 1H), 3.68 - 3.59 (m, 1H), 3.54 - 3.45 (m, 1H), 2.80 (Septet, J = 6.9 Hz, 1H), 2.23 - 2.10 (m, 1H), 2.08 - 1.86 (m, 3H), 1.28 (s, 12H), 1.16 (d, J = 6.9 Hz, 6H).

[0361] Step 3. Synthesis of ammonium 5-{4-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]phenyl}pyridine-2-carboxylate (1). In a mixture of 1,2-dimethoxyethane (1.25 mL), water (0.5 mL), and ethanol (0.1 mL), a mixture of C2 (125 mg, 0.262 mmol), 5-bromopyridine-2-carboxylic acid (63.5 mg, 0.314 mmol), tetrakis(triphenylphosphine)palladium (0) (15.1 mg, 13.1 μmol), and sodium carbonate (98%, 142 mg, 1.31 mmol) was heated overnight at 90°C. Immediately afterward, the reaction mixture was added to 1 M hydrochloric acid. The resulting mixture was extracted three times with ethyl acetate, and during extraction, the insoluble white solid was collected by filtration (75 mg). The ethyl acetate filtrate was washed with saturated sodium chloride aqueous solution, dried with sodium sulfate, filtered, and concentrated under vacuum to obtain a pale yellow solid (55 mg). The solids from these two batches were purified by reverse-phase HPLC (column: Waters XBridge C18, 19 × 100 mm, 5 μm; mobile phase A: water containing 0.03% ammonium hydroxide; mobile phase B: acetonitrile containing 0.03% ammonium hydroxide; gradient: 5%~95% B; flow rate: 25 mL / min) to obtain ammonium 5-{4-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]phenyl}pyridine-2-carboxylate (1). Total yield: 10.7 mg, 21.8 μmol, 8%. LCMS m / z 473.4 [M+H] + . 1 1H NMR (600 MHz, DMSO-d6), Characteristic peak: δ 10.20 (s, 1H), 9.02 - 8.99 (m, 1H), 8.23 ​​(dd, J = 8.2, 2.4 Hz, 1H), 8.20 (s, 1H), 8.08 (d, J = 8.2 Hz, 1H), 7.78 (AB quartet, J AB = 9.0 Hz, Δν AB = 9.7 Hz, 4H), 7.39 (br d, J = 8.6 Hz, 2H), 7.08 (d, J = 8.6 Hz, 2H), 4.47 (dd, J = 8.3, 3.8 Hz, 1H), 3.67 - 3.61 (m, 1H, estimated; partially unclear due to water peak), 2.80 (Septet, J = 6.9 Hz, 1H), 2.23 - 2.15 (m, 1H), 2.07 - 2.00 (m, 1H), 2.00 - 1.89 (m, 2H), 1.16 (d, J = 6.8 Hz, 6H).

[0362] Alternative synthesis of Example 1 (methanesulfonate) 5-{4-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]phenyl}pyridine-2-carboxylic acid, methanesulfonate (1, methanesulfonate)

[0363] [ka] Step 1. Synthesis of tert-butyl 5-(4-aminophenyl)pyridine-2-carboxylate (C8). A mixture of tert-butyl 5-bromopyridine-2-carboxylate (1.06 g, 4.11 mmol), (4-aminophenyl)boronic acid hydrochloride (710 mg, 4.09 mmol), and bis(triphenylphosphine)palladium(II) dichloride (287 mg, 0.409 mmol) in 1,4-dioxane (30 mL) was sparged with nitrogen for 10 minutes, and then gradually heated to 50°C. Simultaneously, an aqueous solution of tripotassium phosphate (1.5 M, 8.19 mL, 12.3 mmol) was prepared and sparged with nitrogen for 10 minutes. This aqueous base solution was added to the reaction mixture, and then gradually heated to 90°C, stirring overnight at 90°C. After cooling to room temperature, the reaction mixture was added to a mixture of water (300 mL) and saturated sodium chloride aqueous solution (100 mL). The resulting suspension was extracted with ethyl acetate (2 × 250 mL), and then with a 10% methanol solution in dichloromethane (2 × 150 mL). The combined organic layers were concentrated under vacuum and purified by silica gel chromatography (gradient: 0% to 100% ethyl acetate in heptane). The fraction containing the product was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain C8 as a solid. Yield: 736 mg, 2.72 mmol, 66%. LCMS m / z 271.2 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 8.90 (br d, J = 2 Hz, 1H), 8.07 (dd, ABX system component, J = 8.3, 2.4 Hz, 1H), 7.95 (br d, half of AB quadruplet, J = 8.2 Hz, 1H), 7.51 (d, J = 8.6 Hz, 2H), 6.69 (d, J = 8.6 Hz, 2H), 5.51 (br s, 2H), 1.56 (s, 9H).

[0364] Step 2: Synthesis of tert-butyl 5-{4-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]phenyl}pyridine-2-carboxylate (C9). 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (98%, 1.10 g, 5.62 mmol) was added to a solution of C1 (1.29 g, 4.67 mmol) and C8 (1.26 g, 4.66 mmol) in N,N-dimethylacetamide (20 mL). The reaction mixture was stirred overnight at room temperature and then added to a mixture of water (250 mL) and saturated sodium chloride aqueous solution (50 mL). The resulting mixture was extracted with ethyl acetate (2 × 200 mL), then extracted with methanol (10%, 2 × 100 mL) in dichloromethane, and the combined organic layer was dried over sodium sulfate, filtered, and concentrated under vacuum to obtain C9 as a solid. Yield: 785 mg, 1.48 mmol, 32%. LCMS m / z 529.3 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 9.01 (br d, J = 2 Hz, 1H), 8.24 - 8.18 (m, 2H), 8.03 (br d, J = 8.2 Hz, 1H), 7.78 (s, 4H), 7.40 (d, J = 8.6 Hz, 2H), 7.09 (d, J = 8.6 Hz, 2H), 4.48 (dd, J = 8.3, 3.7 Hz, 1H), 3.70 - 3.60 (m, 1H), 3.57 - 3.46 (m, 1H), 2.80 (septet, J = 6.9 Hz, 1H), 2.26 - 2.13 (m, 1H), 2.10 - 1.88 (m, 3H), 1.57 (s, 9H), 1.16 (d, J = 6.9 Hz, 6H).

[0365] Step 3.5 - Synthesis of {4-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]phenyl}pyridine-2-carboxylic acid, methanesulfonate (1, methanesulfonate). Methanesulfonic acid (0.198 mL, 3.05 mmol) was added to a solution of C9 (785 mg, 1.48 mmol) in 1,1,1,3,3,3-hexafluoropropan-2-ol (7.8 mL). The reaction mixture was stirred overnight, then concentrated under reduced pressure. The residue was macerated with diethyl ether, and then macerated with water (150 mL) and diethyl ether (150 mL). The resulting solid was milled in methyl tert-butyl ether, filtered, dried, and immediately macerated with ethyl acetate to obtain 5-{4-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]phenyl}pyridine-2-carboxylic acid, methanesulfonate (1, methanesulfonate) as a pale yellow solid. Yield: 690 mg, 1.21 mmol, 82%. LCMS m / z 473.3 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 9.02 (br d, J = 2 Hz, 1H), 8.27 (dd, J = 8.2, 2.4 Hz, 1H), 8.20 (br s, 1H), 8.10 (br d, J = 8.2 Hz, 1H), 7.79 (AB quartet, J AB = 9.2 Hz, Δν AB = 7.5 Hz, 4H), 7.40 (d, J = 8.6 Hz, 2H), 7.09 (d, J = 8.6 Hz, 2H), 4.48 (dd, J = 8.3, 3.7 Hz, 1H), 3.70 - 3.61 (m, 1H), 3.56 - 3.47 (m, 1H), 2.80 (septet, J = 6.9 Hz, 1H), 2.34 (s, 3H), 2.26 - 2.14 (m, 1H), 2.10 - 1.88 (m, 3H), 1.16 (d, J = 6.9 Hz, 6H).

[0366] (Example 2) 6-{4-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]phenyl}pyridine-3-carboxylic acid(2)

[0367] [ka] In a mixture of 1,2-dimethoxyethane (2.5 mL), water (1 mL), and ethanol (0.2 mL), a mixture of C2 (240 mg, 0.503 mmol), 6-bromopyridine-3-carboxylic acid (122 mg, 0.604 mmol), tetrakis(triphenylphosphine)palladium (0) (29.0 mg, 25.1 μmol), and sodium carbonate (98%, 272 mg, 2.51 mmol) was heated at 90°C for 4 hours, and then stirred at room temperature for 3 days. The reaction mixture was added to 1 M hydrochloric acid, and the resulting mixture was extracted three times with ethyl acetate. The combined organic layer was washed with saturated sodium chloride aqueous solution, dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was polished with diethyl ether to obtain a solid, which was then purified by reverse-phase HPLC (column: Waters Sunfire C18, 19 × 100 mm, 5 μm, mobile phase A: 0.05% trifluoroacetic acid (v / v) in water, mobile phase B: 0.05% trifluoroacetic acid (v / v) in acetonitrile, gradient: 5% to 95% B over 8.54 minutes, followed by 95% B over 1.46 minutes, flow rate: 25 mL / min) to obtain 6-{4-[(1-{[4-propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]phenyl}pyridine-3-carboxylic acid (2). Yield: 58.0 mg, 0.123 mmol, 24%. LCMS m / z 473.4 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 10.22 (s, 1H), 9.10 (br d, J = 2.2 Hz, 1H), 8.28 (dd, J = 8.4, 2.3 Hz, 1H), 8.20 (s, 1H), 8.13 (d, J = 8.8 Hz, 2H), 8.05 (br d, J = 8.4 Hz, 1H), 7.77 (d, J = 8.8 Hz, 2H), 7.39 (d, J = 8.6 Hz, 2H), 7.08 (d, J = 8.6 Hz, 2H), 4.48 (dd, J = 8.3, 3.7 Hz, 1H), 3.64 (ddd, J = 9.3, 7.6, 4.7 Hz, 1H), 3.54 - 3.48 (m, 1H, estimated; partially unclear due to water peak), 2.80 (seven-line, J = 6.9 Hz, 1H), 2.23 - 2.15 (m, 1H), 2.08 - 1.99 (m, 1H), 1.99 - 1.90 (m, 2H), 1.16 (d, J = 6.9 Hz, 6H).

[0368] (Example 3) 4'-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino][1,1'-biphenyl]-3-carboxylic acid(3)

[0369] [ka] Step 1. (2R)-N 2 -(4-bromophenyl)-N 1 Synthesis of [4-(propan-2-yl)phenyl]pyrrolidine-1,2-dicarboxamide (C3). A mixture of 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) in dichloromethane (50 mL) was stirred at room temperature for 16 hours. Immediately after stirring, LC-MS analysis showed conversion to C3: LC-MS m / z 430.2 (bromine isotope pattern observed) [M+H] + The reaction mixture was poured into water, extracted with dichloromethane, the organic layer was dried over magnesium sulfate, filtered, and concentrated under vacuum to obtain C3 as a white solid. Yield: 4.82 g, 11.2 mmol, 99%. 1¹H NMR (400 MHz, chloroform-d) δ 9.94 (br s, 1H), 7.41 (AB quadruplet, 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).

[0370] Step 2. Synthesis of methyl 4'-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino][1,1'-biphenyl]-3-carboxylate (C4). To a solution of C3 (30 mg, 70 μmol) and [3-(methoxycarbonyl)phenyl]boronic acid (15.3 mg, 85.0 μmol) in 1,4-dioxane (1.0 mL), an aqueous solution of sodium carbonate (2 M, 71.0 μL, 0.142 mmol) was added, followed by the addition of mesylate [(di(1-adamantyl)-n-butylphosphine)-2-(2'-amino-1,1'-biphenyl)]palladium(II) (cataCXium® A Pd G3, 5.17 mg, 7.10 μmol). The reaction mixture was degassed for 5 minutes and immediately heated overnight at 90°C. After cooling to room temperature, one-third of the reaction mixture was partitioned into ethyl acetate (20 mL) and water (10 mL). The organic layer was sequentially washed with water (10 mL) and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated under vacuum. C4 was obtained by purification using reversed-phase HPLC (column: Waters Sunfire C18, 19 × 100 mm, 5 μm; mobile phase A: 0.05% trifluoroacetic acid (v / v) in water; mobile phase B: 0.05% trifluoroacetic acid (v / v) in acetonitrile; gradient: 45% to 85% B over 8.5 minutes, then 85% to 95% B over 0.5 minutes, then 95% B over 1.0 minute; flow rate: 25 mL / min). Yield: 6.8 mg, 14 μmol, approximately 60%. LCMS m / z 486.5 [M+H] + . 1 1H NMR (600 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.19 (s, 1H), 8.17 (br s, 1H), 7.93 (br d, J = 7.9 Hz, 1H), 7.91 (br d, J = 7.7 Hz, 1H), 7.70 (AB quartet, J AB = 8.6 Hz, Δν AB = 38.9 Hz, 4H), 7.60 (t, J = 7.7 Hz, 1H), 7.39 (d, J = 8.4 Hz, 2H), 7.08 (d, J = 8.4 Hz, 2H), 4.47 (dd, J = 8.3, 3.7 Hz, 1H), 3.88 (s, 3H), 3.68 - 3.61 (m, 1H), 3.54 - 3.47 (m, 1H, estimated; perturbation due to adjacent water peaks), 2.79 (seven-line, J = 7.0 Hz, 1H), 2.23 - 2.14 (m, 1H), 2.08 - 2.00 (m, 1H), 2.00 - 1.88 (m, 2H), 1.16 (d, J = 6.9 Hz, 6H).

[0371] The remaining two-thirds of the crude reaction mixture was carried over to the next step.

[0372] Step 4. Synthesis of 4'-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino][1,1'-biphenyl]-3-carboxylic acid (3). The reaction mixture from the previous step, containing C4 (less than 47 μmol), was treated with an aqueous sodium hydroxide solution (2 M, 71.0 μL, 0.142 mmol) and stirred at room temperature for 3 days. The aqueous sodium hydroxide solution (2 M, 71.0 μL, 0.142 mmol) was added again, and stirring was continued at 50°C for 18 hours. Immediately afterward, the reaction mixture was cooled to room temperature, and the pH was adjusted to approximately 3 by adding 1 M hydrochloric acid. The resulting mixture was partitioned into ethyl acetate (20 mL) and water (10 mL), the organic layer was sequentially washed with water (2 × 10 mL) and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated under vacuum. 4'-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino][1,1'-biphenyl]-3-carboxylic acid (3) was obtained by reverse-phase HPLC (column: Waters Sunfire C18, 19 × 100 mm, 5 μm; mobile phase A: 0.05% trifluoroacetic acid (v / v) in water; mobile phase B: 0.05% trifluoroacetic acid (v / v) in acetonitrile; gradient: 5% to 95% B over 8.54 minutes, followed by 95% B over 1.46 minutes; flow rate: 25 mL / min). Yield: 4.3 mg, 9.1 μmol, approximately 19% over the two steps. LCMS m / z 472.4 [M+H] + . 1 1H NMR (600 MHz, DMSO-d6), Characteristic peaks: δ 10.11 (s, 1H), 8.19 (s, 1H), 8.15 (s, 1H), 7.92 - 7.85 (m, 2H), 7.69 (AB quartet, J AB = 8.3 Hz, Δν AB = 41.6 Hz, 4H), 7.59 - 7.52 (m, 1H), 7.39 (d, J = 8.3 Hz, 2H), 7.08 (d, J = 8.5 Hz, 2H), 4.47 (dd, J = 8.3, 3.7 Hz, 1H), 3.68 - 3.61 (m, 1H), 2.84 - 2.76 (m, 1H), 2.23 - 2.14 (m, 1H), 2.08 - 2.00 (m, 1H), 2.00 - 1.89 (m, 2H), 1.16 (d, J = 6.9 Hz, 6H).

[0373] Alternative synthesis in Example 3 4'-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino][1,1'-biphenyl]-3-carboxylic acid(3)

[0374] [ka] Step 1. Synthesis of tert-butyl 4'-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino][1,1'-biphenyl]-3-carboxylate (C10). A vial containing C2 (250 mg, 0.524 mmol), sodium carbonate (98%, 170 mg, 1.57 mmol), tetrakis(triphenylphosphine)palladium (0) (45.4 mg, 39.3 μmol), and tert-butyl 3-bromobenzoate (202 mg, 0.786 mmol) was flushed three times with nitrogen, and immediately afterward, 1,2-dimethoxyethane (2.6 mL) and water (0.7 mL) were added. After heating the reaction mixture at 90°C for 24 hours, conversion to C10 was shown by LC-MS analysis: LC-MS m / z 528.5 [M+H] + Water was added, and the resulting mixture was extracted with ethyl acetate. The combined organic layer was washed with saturated sodium chloride aqueous solution, dried over sodium sulfate, filtered, and concentrated under vacuum. C10 was obtained as a white solid by silica gel chromatography (gradient: 0% to 35% ethyl acetate in heptane). Yield: 134 mg, 0.254 mmol, 48%. 1 H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.19 (s, 1H), 8.12 - 8.09 (m, 1H), 7.89 (br d, J = 7.8 Hz, 1H), 7.85 (br d, J = 7.8 Hz, 1H), 7.69 (AB quartet, J AB = 8.7 Hz, Δν AB = 32.9 Hz, 4H), 7.56 (t, J = 7.8 Hz, 1H), 7.40 (d, J = 8.6 Hz, 2H), 7.09 (d, J = 8.6 Hz, 2H), 4.48 (dd, J = 8.3, 3.6 Hz, 1H), 3.70 - 3.60 (m, 1H), 3.56 - 3.46 (m, 1H), 2.80 (septet, J = 6.9 Hz, 1H), 2.25 - 2.13 (m, 1H), 2.11 - 1.88 (m, 3H), 1.57 (s, 9H), 1.16 (d, J = 6.9 Hz, 6H).

[0375] Step 2: Synthesis of 4'-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino][1,1'-biphenyl]-3-carboxylic acid (3). Trifluoroacetic acid (0.194 mL, 2.52 mmol) was added to a solution of C10 (134 mg, 0.254 mmol) in dichloromethane (1.3 mL), and the reaction mixture was stirred at room temperature. After 23 hours, complete conversion to 3 was shown by LC-MS analysis: LC-MS m / z 472.4 [M+H] + The reaction mixture was diluted with dichloromethane and treated with saturated sodium bicarbonate aqueous solution. Next, the aqueous layer was acidified to pH 2 by adding 1 M hydrochloric acid, extracted with dichloromethane, and immediately washed with saturated sodium chloride aqueous solution. The combined extract was dried with sodium sulfate, filtered, and concentrated under vacuum. The resulting solid was mixed with dichloromethane, stirred for 1 minute, and collected by filtration to obtain 4'-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino][1,1'-biphenyl]-3-carboxylic acid (3) as a white solid. Yield: 65 mg, 0.138 mmol, 54%. 1 H NMR (600 MHz, DMSO-d6) δ 13.05 (br s, 1H), 10.11 (s, 1H), 8.19 (s, 1H), 8.16 (br s, 1H), 7.92 - 7.87 (m, 2H), 7.70 (AB quartet, J AB = 8.6 Hz, Δν AB = 42.1 Hz, 4H), 7.57 (t, J = 7.7 Hz, 1H), 7.40 (d, J = 8.6 Hz, 2H), 7.09 (d, J = 8.5 Hz, 2H), 4.47 (dd, J = 8.3, 3.7 Hz, 1H), 3.68 - 3.62 (m, 1H), 3.54 - 3.48 (m, 1H), 2.80 (septet, J = 6.9 Hz, 1H), 2.23 - 2.15 (m, 1H), 2.08 - 1.99 (m, 1H), 1.99 - 1.90 (m, 2H), 1.16 (d, J = 6.9 Hz, 6H).

[0376] (Example 4) 4'-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid(4)

[0377] [ka] To a mixture of C3 (1.50 g, 3.49 mmol) and 4-boronobenzoic acid (694 mg, 4.18 mmol) in 1,4-dioxane (22 mL), aqueous sodium carbonate solution (2 M, 5.23 mL, 10.5 mmol) was added, followed by the addition of mesylate [(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 partitioned into ethyl acetate (200 mL) and water (100 mL) to produce an insoluble solid. This solid was isolated by filtration and washed with ethyl acetate. This material was ground with propane-2-ol, first at 70°C for 5 hours, then at room temperature for 20 hours. Immediately after grinding, the suspension was filtered, and the filtered cake was washed with dichloromethane to obtain 4'-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid (4) as a white solid. Yield: 435 mg, 0.922 mmol, 26%. LCMS m / z 472.3 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 12.90 (br s, 1H), 10.13 (s, 1H), 8.19 (s, 1H), 7.88 (AB quartet, J AB = 8.4 Hz, ΔνAB = 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).

[0378] The combined organic layers from the above were sequentially washed with water (2 × 50 mL) and saturated sodium chloride aqueous solution, dried over magnesium sulfate, filtered, and concentrated under vacuum. Purification was performed by silica gel chromatography (gradient: 0% to 5% methanol in dichloromethane), followed by maceration with a mixture of dichloromethane and methanol at room temperature for 20 hours to obtain additional 4'-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid (4) as a white solid. Yield: 410 mg, 0.869 mmol, 25%, total yield: 51%.

[0379] Alternative synthesis of Example 4 4'-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid(4)

[0380] [ka] Step 1. Synthesis of tert-butyl 4'-amino[1,1'-biphenyl]-4-carboxylate (C11). To a mixture of 1,4-dioxane (400 mL) and water (100 mL), a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (20.0 g, 91.3 mmol) was added, to which tert-butyl 4-bromobenzoate (25.8 g, 100 mmol) and potassium carbonate (37.8 g, 274 mmol) were added. Next, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (3.34 g, 4.56 mmol) was added, and the reaction mixture was heated at 95°C for 16 hours and immediately 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 layers were washed with saturated sodium chloride aqueous solution (2 × 500 mL), dried over sodium sulfate, filtered, and concentrated under vacuum. A solid was obtained by silica gel chromatography (gradient: 0% to 50% ethyl acetate in petroleum ether). This solid was treated with propane-2-yl acetate (20 mL) and heptane (80 mL), stirred for 30 minutes, and then collected by filtration. The filtration cake was washed with heptane (3 × 15 mL) to obtain C11 as a pinkish-white solid. Yield: 18.5 g, 68.7 mmol, 75%. LCMS m / z 270.1 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) 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).

[0381] Step 2: Synthesis of tert-butyl 4'-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylate (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, the presence of the product was confirmed by LC-MS analysis: LC-MS m / z 528.5 [M+H] + Water (50 mL) was added, the mixture was stirred for 8 minutes, then filtered, the collected solid was washed with water, and stirred in diethyl ether (60 mL) for 10 minutes. The solid was isolated again by filtration, suspended in a solution of methanol in dichloromethane (5%, 50 mL), stirred for 25 minutes, and filtered. C12 was obtained as a white solid by washing the filtered cake with dichloromethane. Yield: 5.43 g, 10.3 mmol, 72%. 1 H 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 = 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).

[0382] Step 3. Synthesis of 4'-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid (4). 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-hexafluoropropan-2-ol (10 mL). The reaction mixture was stirred at room temperature for 15 minutes and immediately concentrated under vacuum. The residue was slurried in diethyl ether for 5 minutes, the solid was collected by filtration, washed with diethyl ether, and suspended in propane-2-yl acetate (15 mL). Methanol (2 mL) was added, and the mixture was stirred at room temperature for 3 days. The solid 4'-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid (4) was obtained by isolation by filtration and subsequent washing of the filtration cake with propane-2-yl acetate (3 mL). Yield: 668 mg, 1.42 mmol, 75%. LCMS m / z 472.4 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) 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).

[0383] (Example 5) Ammonium 4-{6-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]pyridine-3-yl}benzoate (5)

[0384] [ka] A mixture of C1 (50 mg, 0.18 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (45.1 mg, 0.235 mmol) in dichloromethane (0.90 mL) was stirred for approximately 30 minutes. Immediately afterward, 4-(6-aminopyridine-3-yl)benzoic acid (38.8 mg, 0.181 mmol) was added, and the reaction mixture was stirred overnight at room temperature. The mixture was then filtered, and the filtrate was acidified by adding 1 M hydrochloric acid, followed by four extractions with ethyl acetate. The combined organic layers were washed with saturated sodium chloride aqueous solution, dried over sodium sulfate, filtered, and concentrated under vacuum. Ammonium 4-{6-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]pyridine-3-yl}benzoate (5) was obtained by purification using reversed-phase HPLC (column: Waters XBridge C18, 19 × 100 mm, 5 μm; mobile phase A: water containing 0.03% ammonium hydroxide; mobile phase B: acetonitrile containing 0.03% ammonium hydroxide; gradient: 5%~95% B; flow rate: 25 mL / min). Yield: 1.0 mg, 2.0 μmol, 1%. LCMS m / z 473.4 [M+H] + . 1 1H NMR (600 MHz, DMSO-d6), Characteristic peak: δ 10.65 (s, 1H), 8.74 - 8.70 (m, 1H), 8.22 (s, 1H), 8.17 (br s, 2H), 8.02 (d, J = 8.3 Hz, 2H), 7.85 (d, J = 8.1 Hz, 2H), 7.38 (d, J = 8.1 Hz, 2H), 7.09 (d, J = 8.6 Hz, 2H), 4.64 - 4.59 (m, 1H), 3.66 - 3.60 (m, 1H, estimated; partially unclear due to water peak), 2.80 (seven-line, J = 7.0 Hz, 1H), 2.21 - 2.13 (m, 1H), 2.05 - 1.91 (m, 3H), 1.16 (d, J = 6.9 Hz, 6H).

[0385] Alternative synthesis of Example 5 (free acid) 4-{6-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]pyridine-3-yl}benzoic acid (5, free acid)

[0386] [ka] Step 1. Synthesis of tert-butyl 4-(6-aminopyridine-3-yl)benzoate (C13). Sodium carbonate (3.68 g, 34.7 mmol) and water (9 mL) were added to a solution of 5-bromopyridine-2-amine (2.00 g, 11.6 mmol) and [4-(tert-butoxycarbonyl)phenyl]boronic acid (2.57 g, 11.6 mmol) in 1,4-dioxane (36 mL). The solution was degassed with nitrogen for 10 minutes and immediately after, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (423 mg, 0.578 mmol) was added, and the reaction mixture was heated at 80 °C for 18 hours. After cooling to room temperature, the reaction mixture was partitioned into water (60 mL) and ethyl acetate (30 mL). The aqueous layer was extracted with ethyl acetate (2 × 30 mL), the combined organic layers were dried over sodium sulfate, filtered, concentrated under vacuum, and C13 was obtained as a yellow solid by silica gel chromatography (gradient: 40% to 100% ethyl acetate in heptane). Yield: 2.37 g, 8.77 mmol, 76%. 1 ¹H NMR (400 MHz, chloroform-d) δ 8.34 (d, J = 2.2 Hz, 1H), 8.03 (d, J = 8.5 Hz, 2H), 7.72 (dd, J = 8.6, 2.4 Hz, 1H), 7.54 (d, J = 8.5 Hz, 2H), 6.62 (d, J = 8.6 Hz, 1H), 4.71 (br s, 2H), 1.61 (s, 9H).

[0387] Step 2. Synthesis of tert-butyl 4-{6-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]pyridine-3-yl}benzoate (C14). 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.11 g, 5.79 mmol) was added to a solution of C1 (1.33 g, 4.81 mmol) in dichloromethane (16 mL) at 0°C. The reaction mixture was stirred at 0°C for 40 minutes, and immediately afterward, a solution of C13 (1.30 g, 4.81 mmol) in dichloromethane (5 mL) was added. Stirring was continued at 0°C for 70 minutes, then stirred at room temperature for 2.25 hours. The solid was collected by filtration to obtain C14 as a white solid. Yield: 797 mg, 1.51 mmol, 31%. LCMS m / z 529.5 [M+H] + . 1 1H NMR (600 MHz, DMSO-d6) δ 10.67 (s, 1H), 8.74 - 8.71 (m, 1H), 8.22 (s, 1H), 8.18 (br s, 2H), 7.97 (d, J = 8.3 Hz, 2H), 7.85 (d, J = 8.3 Hz, 2H), 7.39 (d, J = 8.5 Hz, 2H), 7.09 (d, J = 8.4 Hz, 2H), 4.66 - 4.60 (m, 1H), 3.67 - 3.60 (m, 1H), 3.55 - 3.48 (m, 1H), 2.85 - 2.76 (m, 1H), 2.22 - 2.13 (m, 1H), 2.06 - 1.91 (m, 3H), 1.57 (s, 9H), 1.16 (d, J = 6.9 Hz, 6H).

[0388] Step 3.4 - Synthesis of {6-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]pyridine-3-yl}benzoic acid (5, free acid). Trifluoroacetic acid (98.1 mg, 0.860 mmol) was added dropwise to a solution of C14 (455 mg, 0.861 mmol) in dichloromethane (4.3 mL). The reaction mixture was stirred at room temperature for 3.5 hours, then concentrated under vacuum and evaporated three times with toluene. The resulting solid was treated with propane-2-yl acetate (7.5 mL), followed by methanol (1 mL), and the slurry was stirred overnight at room temperature. By filtration, 4-{6-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]pyridine-3-yl}benzoic acid (5, free acid) was obtained as a white solid. Yield: 374 mg, 0.791 mmol, 92%. LCMS m / z 473.4 [M+H] + . 1 1H NMR (600 MHz, DMSO-d6), Characteristic peak: δ 10.67 (s, 1H), 8.74 - 8.72 (m, 1H), 8.22 (s, 1H), 8.19 - 8.17 (m, 2H), 8.02 (d, J = 8.4 Hz, 2H), 7.85 (d, J = 8.3 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 7.09 (d, J = 8.5 Hz, 2H), 4.66 - 4.58 (m, 1H), 3.67 - 3.61 (m, 1H), 3.54 - 3.48 (m, 1H, estimated; partially unclear due to water peaks), 2.85 - 2.76 (m, 1H), 2.21 - 2.13 (m, 1H), 1.16 (d, J = 6.8 Hz, 6H).

[0389] (Example 6) 3'-Fluoro-4'-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid(6)

[0390] [ka] Step 1. (2R)-N 2 -(4-bromo-2-fluorophenyl)-N 1 Synthesis of -[4-(propan-2-yl)phenyl]pyrrolidine-1,2-dicarboxamide (C5). 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (416 mg, 2.17 mmol) was added to a mixture of C1 (500 mg, 1.81 mmol) in dichloromethane (7.9 mL) at 0°C. The reaction mixture was stirred at 0°C for 1 hour, and immediately afterward, 4-bromo-2-fluoroaniline (344 mg, 1.81 mmol) was added all at once, and stirring was continued at 0°C for 80 minutes. Next, the cooling bath was removed, and the reaction mixture was stirred overnight, then poured into water and extracted three times with dichloromethane. The combined organic layers were sequentially washed with water and saturated sodium sulfate aqueous solution, dried over magnesium sulfate, filtered, and concentrated under vacuum to obtain C5 as a white foamy substance. Yield: 830 mg, quantitative. LCMS m / z 448.3 (bromine isotope pattern observed) [M+H] + . 1 H NMR (600 MHz, DMSO-d6) δ 9.94 (s, 1H), 8.21 (s, 1H), 7.90 (t, J = 8.6 Hz, 1H), 7.59 (dd, J = 10.4, 2.2 Hz, 1H), 7.39 (d, J = 8.4 Hz, 2H), 7.36 (br d, J = 8.9 Hz, 1H), 7.09 (d, J = 8.4 Hz, 2H), 4.60 (dd, J = 8.2, 2.8 Hz, 1H), 3.64 - 3.59 (m, 1H), 3.51 - 3.45 (m, 1H), 2.81 (septet, J = 7.0 Hz, 1H), 2.17 - 2.08 (m, 1H), 2.02 - 1.91 (m, 3H), 1.17 (d, J = 6.9 Hz, 6H).

[0391] Step 2. Synthesis of tert-butyl 3'-fluoro-4'-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylate (C6). In a mixture of 1,4-dioxane (3.0 mL) and water (0.5 mL), a mixture of C5 (400 mg, 0.892 mmol), [4-(tert-butoxycarbonyl)phenyl]boronic acid (218 mg, 0.982 mmol), potassium carbonate (370 mg, 2.68 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) [Pd(dppf)Cl2, 32.6 mg, 44.6 μmol] was sparged three times with nitrogen and then heated at 65°C for 3 hours. After the reaction mixture cooled to room temperature, it was filtered through a diatomaceous earth plug. The filtrate was partitioned into ethyl acetate and water, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with saturated sodium sulfate aqueous solution, dried over magnesium sulfate, filtered, concentrated under vacuum, and C6 was obtained as a white solid by silica gel chromatography (gradient: 0% to 80% ethyl acetate in heptane). Yield: 101 mg, 0.185 mmol, 21%. LCMS m / z 546.5 [M+H] + . 1 1H NMR (600 MHz, DMSO-d6), Characteristic peaks: δ 9.99 (s, 1H), 8.22 (s, 1H), 8.10 (t, J = 8.4 Hz, 1H), 7.89 (AB quartet, J AB = 8.4 Hz, Δν AB = 72.3 Hz, 4H), 7.70 (br dd, J = 12.2, 2 Hz, 1H), 7.58 (br d, J = 8.4 Hz, 1H), 7.40 (d, J = 8.3 Hz, 2H), 7.10 (d, J = 8.4 Hz, 2H), 4.67 - 4.63 (m, 1H), 3.67 - 3.60 (m, 1H), 3.53 - 3.47 (m, 1H), 2.84 - 2.78 (m, 1H), 2.19 - 2.10 (m, 1H), 1.56 (s, 9H), 1.17 (d, J = 6.8 Hz, 6H).

[0392] Step 3. Synthesis of 3'-fluoro-4'-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid (6). Trifluoroacetic acid (0.2 mL) was added dropwise to a solution of C6 (88.0 mg, 0.161 mmol) in dichloromethane (0.8 mL). The reaction mixture was stirred at room temperature for 2.5 hours and immediately concentrated under vacuum, then evaporated three times with toluene. The resulting material was combined with the product of a similar reaction using C6 (43 mg, 79 μmol) and purified by silica gel chromatography (gradient: 0% to 10% methanol in dichloromethane) to obtain 3'-fluoro-4'-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid (6) as a white solid. Total yield: 60 mg, 0.12 mmol, 75%. LCMS m / z 490.5 [M+H] + . 1 1H NMR (600 MHz, DMSO-d6) δ 12.98 br (s, 1H), 9.99 (s, 1H), 8.22 (s, 1H), 8.10 (t, J = 8.4 Hz, 1H), 8.00 (d, J = 8.5 Hz, 2H), 7.83 (d, J = 8.5 Hz, 2H), 7.70 (dd, J = 12.3, 2.1 Hz, 1H), 7.58 (dd, J = 8.5, 2.1 Hz, 1H), 7.41 (d, J = 8.6 Hz, 2H), 7.10 (d, J = 8.6 Hz, 2H), 4.65 (dd, J = 8.2, 2.8 Hz, 1H), 3.67 - 3.60 (m, 1H), 3.53 - 3.47 (m, 1H), 2.81 (septet, J = 6.9 Hz, 1H), 2.20 - 2.10 (m, 1H), 2.05 - 1.93 (m, 3H), 1.17 (d, J = 6.9 Hz, 6H).

[0393] (Example 7) Ammonium 4'-({1-[(4-cyclopropylphenyl)carbamoyl]-D-prolyl}amino)[1,1'-biphenyl]-4-carboxylate(7)

[0394] [ka] Step 1. (2R)-N 2 -(4-bromophenyl)-N 1 Synthesis of (4-cyclopropylphenyl)pyrrolidine-1,2-dicarboxamide (C7). Trifluoroacetic acid (0.414 mL, 5.37 mmol) was added to a solution of tert-butyl(2R)-2-[(4-bromophenyl)carbamoyl]pyrrolidine-1-carboxylate (see VHThorat et al., Eur. J. Org. Chem. 2013, 3529-3542; 100 mg, 0.271 mmol) in dichloromethane (2.7 mL) at 0°C. The reaction mixture was stirred at 0°C for 30 minutes, then at room temperature for 1.5 hours, and then concentrated under a nitrogen stream, and then under high vacuum. The residue was dissolved in tetrahydrofuran (1.5 mL) and treated with 1-cyclopropyl-4-isocyanate-benzene (64.7 mg, 0.406 mmol), and stirred at room temperature for approximately 2 hours. After removing the solvent under a nitrogen stream, the residue was purified by silica gel chromatography (gradient: 0% to 50% ethyl acetate in dichloromethane) to obtain C7 as a solid. Yield: 67 mg, 0.16 mmol, 59%. LC-MS m / z 428.2 (bromine isotope pattern observed) [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.10 (s, 1H), 8.17 (s, 1H), 7.52 (AB quartet, J AB = 8.8 Hz, Δν AB = 43.6 Hz, 4H), 7.36 (d, J = 8.6 Hz, 2H), 6.92 (d, J = 8.6 Hz, 2H), 4.42 (dd, J = 8.2, 3.7 Hz, 1H), 3.66 - 3.57 (m, 1H), 3.54 - 3.44 (m, 1H), 2.22 - 2.10 (m, 1H), 2.07 - 1.86 (m, 3H), 1.86 - 1.77 (m, 1H), 0.90 - 0.83 (m, 2H), 0.61 - 0.54 (m, 2H).

[0395] Step 2. Synthesis of ammonium 4'-({1-[(4-cyclopropylphenyl)carbamoyl]-D-prolyl}amino)[1,1'-biphenyl]-4-carboxylate (7). A mixture of C7 (67 mg, 0.16 mmol), 4-boronobenzoic acid (31.1 mg, 0.187 mmol), and mesylate [(di(1-adamantyl)-n-butylphosphine)-2-(2'-amino-1,1'-biphenyl)]palladium(II) (cataCXium® A Pd G3, 11.4 mg, 15.6 μmol) in 1,4-dioxane (1.6 mL) was sparged with nitrogen for 10 minutes. Degassed aqueous solution of sodium carbonate (2.0 M, 0.274 mL, 0.548 mmol) was added, and the reaction mixture was heated at 90°C overnight. The reaction mixture was cooled, acidified by adding 1 M hydrochloric acid, and then diluted with ethyl acetate. The aqueous layer was extracted with ethyl acetate, the combined organic layers were dried over sodium sulfate, filtered, concentrated under vacuum, and purified by reverse-phase HPLC (column: Waters XBridge C18, 19 × 100 mm, 5 μm, mobile phase A: water containing 0.03% ammonium hydroxide, mobile phase B: acetonitrile containing 0.03% ammonium hydroxide, gradient: 5%~95% B, flow rate: 25 mL / min) to obtain ammonium 4'-({1-[(4-cyclopropylphenyl)carbamoyl]-D-prolyl}amino)[1,1'-biphenyl]-4-carboxylate (7). Yield: 8.1 mg, 17 μmol, 11%. LCMS m / z 470.5 [M+H] + . 1 1H NMR (600 MHz, DMSO-d6) δ 10.13 (s, 1H), 8.18 (s, 1H), 7.99 (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 = 16.1 Hz, 4H), 7.37 (d, J = 8.6 Hz, 2H), 6.93 (d, J = 8.7 Hz, 2H), 4.46 (dd, J = 8.3, 3.7 Hz, 1H), 3.64 (ddd, J = 9.3, 7.6, 4.7 Hz, 1H), 3.53 - 3.47 (m, 1H), 2.23 - 2.14 (m, 1H), 2.07 - 1.98 (m, 1H), 1.98 - 1.89 (m, 2H), 1.82 (tt, J = 8.4, 5.1 Hz, 1H), 0.89 - 0.84 (m, 2H), 0.59 - 0.55 (m, 2H).

[0396] (Example 16) Ammonium 4'-[(1-{[4-(trifluoromethyl)phenyl]carbamoyl}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylate(16)

[0397] [ka] Step 1. Synthesis of N-(4-bromophenyl)-D-prolineamide, trifluoroacetate (C15). Trifluoroacetic acid (2.07 mL, 26.9 mmol) was added to a solution of tert-butyl(2R)-2-[(4-bromophenyl)carbamoyl]pyrrolidine-1-carboxylate (see VHThorat et al., Eur. J. Org. Chem. 2013, 3529-3542; 500 mg, 1.35 mmol) in dichloromethane (13.5 mL) at 0°C. The reaction mixture was stirred at 0°C for 30 minutes, then at room temperature for 1.5 hours, and then concentrated under a nitrogen stream to obtain C15 as a solid. Yield: 364 mg, 0.950 mmol, 70%. LCMS m / z 269.5 (bromine isotope pattern observed) [M+H] + .

[0398] Step 2. (2R)-N 2 -(4-bromophenyl)-N1 Synthesis of -[4-(trifluoromethyl)phenyl]pyrrolidine-1,2-dicarboxamide (C16). A solution of 4-(trifluoromethyl)aniline (40.2 mg, 0.249 mmol) in 1 mL of dichloromethane was mixed with a solution of bis(trichloromethyl)carbonate (25.6 mg, 86.3 μmol) in 0.5 mL of dichloromethane, followed by the addition of 4-(dimethylamino)pyridine (93.8 mg, 0.768 mmol). The reaction mixture was stirred at room temperature for 1 hour, and then treated with a solution of C15 (73.5 mg, 0.192 mmol) in 1 mL of dichloromethane. After stirring for a further 40 minutes at room temperature, conversion to C16 was shown by LC-MS analysis: LC-MS m / z 456.1 (bromine isotope pattern observed) [M+H] + After stirring at room temperature for a further 30 minutes, the reaction mixture was diluted with dichloromethane, sequentially washed with 1M hydrochloric acid and saturated sodium bicarbonate aqueous solution, dried over sodium sulfate, filtered, and concentrated under vacuum. C16 was obtained as a solid by silica gel chromatography (gradient: 0% to 50% ethyl acetate in dichloromethane). Yield: 43 mg, 94 μmol, 49%. 1 H NMR (400 MHz, DMSO-d6) δ 10.14 (s, 1H), 8.68 (s, 1H), 7.74 (d, half AB quartet, J = 8.5 Hz, 2H), 7.62 - 7.54 (m, 4H), 7.48 (d, half AB quartet, J = 8.9 Hz, 2H), 4.45 (dd, J = 8.3, 3.8 Hz, 1H), 3.71 - 3.62 (m, 1H), 3.60 - 3.51 (m, 1H), 2.26 - 2.14 (m, 1H), 2.08 - 1.86 (m, 3H).

[0399] Step 3. Synthesis of ammonium 4'-[(1-{[4-(trifluoromethyl)phenyl]carbamoyl}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylate (16). In 0.9 mL of 1,4-dioxane, a mixture of C16 (43.0 mg, 94.2 μmol), 4-boronobenzoic acid (18.8 mg, 0.113 mmol), and mesylate [(di(1-adamantyl)-n-butylphosphine)-2-(2'-amino-1,1'-biphenyl)]palladium(II) (cataCXium® A Pd G3, 6.86 mg, 9.42 μmol) was spurged with nitrogen for 10 minutes, and immediately afterward, a 2.0 M aqueous solution of degassed sodium carbonate (0.165 mL, 0.330 mmol) was added. The reaction mixture was heated overnight at 90°C, then acidified by adding 1 M hydrochloric acid and diluted with ethyl acetate. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum. The obtained solid was purified using reverse-phase HPLC (column: Waters XBridge C18, 19 × 100 mm, 5 μm, mobile phase A: 0.03% ammonium hydroxide (v / v) in water, mobile phase B: 0.03% ammonium hydroxide (v / v) in acetonitrile, gradient: 5.0%~95% B, flow rate: 25 mL / min) to obtain ammonium 4'-[(1-{[4-(trifluoromethyl)phenyl]carbamoyl}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylate (16). Yield: 17.9 mg, 36.0 μmol, 38%. LCMS m / z 498.4 [M+H] + . 1 1H NMR (600 MHz, DMSO-d6) δ 12.9 (v br s, 1H), 10.17 (s, 1H), 8.70 (s, 1H), 7.99 (d, J = 8.5 Hz, 2H), 7.78 (d, J = 8.5 Hz, 2H), 7.77 - 7.73 (m, 4H), 7.71 (d, half AB quartet, J = 8.9 Hz, 2H), 7.58 (d, J = 8.7 Hz, 2H), 4.50 (dd, J = 8.4, 3.9 Hz, 1H), 3.68 (ddd, J = 9.4, 7.6, 4.9 Hz, 1H), 3.60 - 3.54 (m, 1H), 2.27 - 2.18 (m, 1H), 2.08 - 2.00 (m, 1H), 2.00 - 1.90 (m, 2H).

[0400] Alternative synthesis of Example 16 (free acid) 4'-[(1-{[4-(trifluoromethyl)phenyl]carbamoyl}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid (16, free acid)

[0401] [ka] Step 1.1 Synthesis of {[4-(trifluoromethyl)phenyl]carbamoyl}-D-proline (C17). 4-Methylmorpholine (0.846 mL, 778 mg, 7.69 mmol) and 1-isocyanate-4-(trifluoromethyl)benzene (1.20 g, 6.41 mmol) were added to a solution of D-proline (886 mg, 7.70 mmol) in tetrahydrofuran (21.4 mL). The reaction mixture was stirred at room temperature for 3 hours and immediately diluted with water (20 mL). The pH was adjusted to 7-8 by adding solid sodium bicarbonate. The aqueous layer was washed with methyl tert-butyl ether (2 × 20 mL), then acidified to pH 2-3 with concentrated hydrochloric acid and extracted with ethyl acetate (3 × 20 mL). The combined ethyl acetate layer was washed with saturated sodium chloride aqueous solution (60 mL), dried over magnesium sulfate, and concentrated under vacuum to obtain C17 as a white solid. Yield: 1.00 g, 3.31 mmol, 52%. LCMS m / z 301.1 [MH] - . 1 1H NMR (400 MHz, DMSO-d6) δ 8.68 (s, 1H), 7.73 (d, J = 8.5 Hz, 2H), 7.58 (d, J = 8.6 Hz, 2H), 4.40 - 4.28 (m, 1H), 3.63 - 3.54 (m, 1H), 3.54 - 3.45 (m, 1H), 2.24 - 2.12 (m, 1H), 1.96 - 1.85 (m, 3H).

[0402] Step 2. Synthesis of tert-butyl 4'-[(1-{[4-(trifluoromethyl)phenyl]carbamoyl}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylate (C18). Solutions of C17 (400 mg, 1.32 mmol) and C11 (374 mg, 1.39 mmol) in N,N-dimethylacetamide (3.3 mL) were treated with 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (304 mg, 1.59 mmol). After 3 hours at room temperature, the reaction mixture was diluted with water (5 mL). The aqueous layer was extracted with ethyl acetate (3 × 5 mL), and the combined organic layers were sequentially washed with water (2 × 15 mL) and saturated sodium chloride aqueous solution (15 mL). The mixture was dried over magnesium sulfate, filtered, and concentrated under vacuum. C18 was obtained by grinding the resulting material with dichloromethane (5 mL). Yield: 330 mg, 0.596 mmol, 45%. LCMS m / z 554.4 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 10.17 (s, 1H), 8.70 (s, 1H), 7.95 (d, J = 8.5 Hz, 2H), 7.81 - 7.73 (m, 6H), 7.70 (d, half of the AB quadruple line, J = 8.9 Hz, 2H), 7.58 (d, J = 8.6 Hz, 2H), 4.51 (dd, J = 8.4, 3.8 Hz, 1H), 3.74 - 3.64 (m, 1H), 3.63 - 3.52 (m, 1H), 2.29 - 2.16 (m, 1H), 2.11 - 1.89 (m, 3H), 1.56 (s, 9H).

[0403] Step 3: Synthesis of 4'-[(1-{[4-(trifluoromethyl)phenyl]carbamoyl}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid (16, free acid). Methanesulfonic acid (45.0 μL, 0.693 mmol) was added to a solution of C18 (320 mg, 0.578 mmol) in 1,1,1,3,3,3-hexafluoropropan-2-ol (5.8 mL). The reaction mixture was stirred at room temperature for 15 minutes, then treated with an additional methanesulfonic acid (20 μL, 0.31 mmol), and stirring was continued for 10 minutes. The reaction mixture was cooled to 0°C and treated with methanol (5 mL, pre-cooled to 0°C), whereupon a precipitate formed over 30 minutes. A solid was obtained by filtration, and the solid was slurryed in ethanol (3 mL) at 50°C for 8 hours, then cooled to room temperature and allowed to stand for 72 hours. The solid was collected by filtration to obtain 4'-[(1-{[4-(trifluoromethyl)phenyl]carbamoyl}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid (16, free acid) as a white solid. Yield: 192 mg, 0.386 mmol, 67%. LCMS m / z 498.2 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 10.17 (s, 1H), 8.70 (s, 1H), 7.99 (d, J = 8.5 Hz, 2H), 7.80 - 7.73 (m, 6H), 7.71 (d, half of the AB quadruple line, J = 8.9 Hz, 2H), 7.58 (d, J = 8.7 Hz, 2H), 4.50 (dd, J = 8.3, 3.7 Hz, 1H), 3.74 - 3.64 (m, 1H), 3.62 - 3.52 (m, 1H), 2.28 - 2.16 (m, 1H), 2.11 - 1.89 (m, 3H).

[0404] (Example 17) 5-{4-[(1-{[3-methyl-4-(trifluoromethyl)phenyl]carbamoyl}-D-prolyl)amino]phenyl}pyridine-2-carboxylic acid(17)

[0405] [ka] Step 1. Synthesis of tert-butyl(2R)-2-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamoyl}pyrrolidine-1-carboxylate (C19). To a mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (4.00 g, 18.3 mmol) and 1-(tert-butoxycarbonyl)-D-proline (3.93 g, 18.3 mmol) in 90 mL of dichloromethane, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (4.55 g, 23.7 mmol) was added all at once. The reaction mixture was stirred at room temperature for 18 hours, then diluted with dichloromethane, washed with water, dried over magnesium sulfate, filtered, and concentrated under vacuum. The residue was polished with diethyl ether to obtain C19 as a white solid. 1 According to 1H NMR analysis, this material exists as a mixture of rotational isomers at room temperature. Yield: 6.82 g, 16.4 mmol, 90%. LCMS m / z 417.4 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6, 25℃) δ 10.09 (s, 1H), 7.64 - 7.59 (m, 4H), [4.26 (br dd, J = 8.4, 3.2 Hz) and 4.19 (dd, J = 8.2, 4.5 Hz), Total 1H], 3.46 - 3.37 (m, 1H), 3.37 - 3.3 (m, 1H, estimated; partially unclear due to water peaks), 2.25 - 2.10 (m, 1H), 1.96 - 1.72 (m, 3H), 1.39 (s, 3H), 1.28 (s, 12H), 1.25 (s, 6H). 1 1H NMR (400 MHz, DMSO-d6, 60℃) δ 9.91 (s, 1H), 7.61 (s, 4H), 4.32 - 4.17 (m, 1H), 3.48 - 3.40 (m, 1H), 3.40 - 3.31 (m, 1H), 2.27 - 2.12 (m, 1H), 1.98 - 1.74 (m, 3H), 1.50 - 1.17 (m, 21H).

[0406] Step 2: Synthesis of tert-butyl 5-(4-{[1-(tert-butoxycarbonyl)-D-prolyl]amino}phenyl)pyridine-2-carboxylate (C20). A mixture of tert-butyl 5-bromopyridine-2-carboxylate (744 mg, 2.88 mmol), C19 (1.00 g, 2.40 mmol), sodium carbonate (764 mg, 7.21 mmol), and tetrakis(triphenylphosphine)palladium(0) (208 mg, 0.180 mmol) was treated with 1,2-dimethoxyethane (12 mL) and water (3 mL). Immediately after treatment, the reaction vessel was evacuated and filled with nitrogen. After repeating this vacuum cycle twice, the reaction mixture was heated at 100 °C for 18 hours, cooled to room temperature, and filtered. The filtered cake was washed with diethyl ether and ethyl acetate, and then polished with methanol to obtain C20 as a white solid (634 mg). The filtrate was diluted with water and ethyl acetate, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, concentrated under vacuum, and polished with methanol to obtain C20 as a white solid (92 mg). The products from two lots were combined and concentrated three times from dichloromethane to obtain C20 as a white solid. Yield: 700 mg, 1.50 mmol, 62%. LCMS m / z 468.4 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 9.01 (br s, 1H), 8.22 (dd, ABX system component, J = 8.2, 2.4 Hz, 1H), 8.03 (d, half of AB quadruplet, J = 8.2 Hz, 1H), 7.78 (s, 4H), [4.29 (br dd, J = 8.5, 3.1 Hz) and 4.22 (dd, J = 8.3, 4.4 Hz), total 1H], 3.48 - 3.39 (m, 1H), 3.39 - 3.3 (m, 1H, estimated; partially unclear due to water peak), 2.29 - 2.13 (m, 1H), 1.98 - 1.74 (m, 3H), 1.58 (s, 9H), 1.40 (s, 3H), 1.28 (s, 6H).

[0407] Step 3.5 - Synthesis of [4-(D-prolylamino)phenyl]pyridine-2-carboxylic acid, dihydrochloride (C21). A suspension of C20 (700 mg, 1.50 mmol) in 1,4-dioxane (4 mL) was mixed with a solution of hydrogen chloride in 1,4-dioxane (4 M, 3.74 mL, 15.0 mmol). After stirring the reaction mixture for 17 hours, conversion to C21 was shown by LC-MS analysis: LC-MS m / z 312.2 [M+H]. + A filter cake was obtained by filtration, and this filter cake was washed with 1,4-dioxane to obtain C21 as a yellow solid (628 mg). A portion of this material was carried over to the next step. 1 H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 10.01 - 9.87 (m, 1H), 9.03 (br d, J = 2 Hz, 1H), 8.77 - 8.66 (m, 1H), 8.27 (dd, ABX system component, J = 8.2, 2.4 Hz, 1H), 8.11 (d, half of the AB quadruplet, J = 8.2 Hz, 1H), 7.84 (AB quadruplet, J AB = 8.8 Hz, Δν AB = 15.4 Hz, 4H), 4.50 - 4.38 (m, 1H), 3.36 - 3.19 (m, 2H), 2.5 - 2.38 (m, 1H, estimated; partially unclear due to solvent peaks), 2.05 - 1.89 (m, 3H).

[0408] Step 4.5 - Synthesis of {4-[(1-{[3-methyl-4-(trifluoromethyl)phenyl]carbamoyl}-D-prolyl)amino]phenyl}pyridine-2-carboxylic acid (17). To a solution of 3-methyl-4-(trifluoromethyl)aniline (19.4 mg, 0.111 mmol) in 1 mL of dichloromethane, a solution of bis(trichloromethyl)carbonate (11.5 mg, 38.8 μmol) in 0.5 mL of dichloromethane was added, followed by the addition of 4-(dimethylamino)pyridine (67.8 mg, 0.555 mmol). After stirring the reaction mixture at room temperature for 1 hour, C21 (from the previous step; 38 mg, ≤91 μmol) was added all at once, and stirring was continued for 45 minutes. Immediately after adding dichloromethane and water, the pH was adjusted to 4-5 by adding 1 M hydrochloric acid. The organic layer was concentrated to dryness, azeotropically distilled twice with dichloromethane, and purified by reverse-phase HPLC (column: Waters Sunfire C18, 19 × 100 mm, 5 μm; mobile phase A: 0.05% trifluoroacetic acid (v / v) in water; mobile phase B: 0.05% trifluoroacetic acid (v / v) in acetonitrile; gradient: 20% to 60% B over 8.5 minutes, then 60% to 95% B over 0.5 minutes, then 95% B over 1.0 minute; flow rate: 25 mL / min) to obtain 5-{4-[(1-{[3-methyl-4-(trifluoromethyl)phenyl]carbamoyl}-D-prolyl)amino]phenyl}pyridine-2-carboxylic acid (17). Yield: 10.2 mg, 19.9 μmol, 22% over two steps. LCMS m / z 513.3 [M+H] + . 1 1H NMR (600 MHz, DMSO-d6) δ 10.22 (s, 1H), 9.01 (d, J = 2.3 Hz, 1H), 8.61 (s, 1H), 8.24 (dd, ABX system component, J = 8.2, 2.4 Hz, 1H), 8.09 (br d, half of the AB quadruple line, J = 8.2 Hz, 1H), 7.79 (AB quadruple line, J AB = 9.0 Hz, Δν AB = 11.1 Hz, 4H), 7.61 (br s, 1H), 7.53 (AB quadruple, low-field double line is spreading, J AB = 8.8 Hz, Δν AB = 23.8 Hz, 2H), 4.49 (dd, J = 8.3, 3.9 Hz, 1H), 3.70 - 3.64 (m, 1H), 3.59 - 3.53 (m, 1H), 2.36 (br s, 3H), 2.27 - 2.18 (m, 1H), 2.08 - 1.90 (m, 3H).

[0409] (Example 18) 4-{5-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]pyridine-2-yl}benzoic acid (18)

[0410] [ka] Step 1. (2R)-N 2 -(6-bromopyridine-3-yl)-N 1 Synthesis of [4-(propan-2-yl)phenyl]pyrrolidine-1,2-dicarboxamide (C22). 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (166 mg, 0.866 mmol) was added in one step to a solution of C1 (200 mg, 0.724 mmol) in dichloromethane (3.6 mL) at 0°C. The reaction mixture was stirred at 0°C for 30 minutes, and immediately afterward, 6-bromopyridine-3-amine (125 mg, 0.723 mmol) was added, and stirring was continued at 0°C for 4 hours. The reaction mixture was poured into water, and the resulting mixture was extracted twice with dichloromethane. The combined organic layers were sequentially washed with water and saturated sodium chloride aqueous solution, dried over sodium sulfate, filtered, and concentrated under vacuum to obtain C22 as a pale orange solid. Yield: 320 mg, estimated to be quantitative. LCMS m / z 431.3 (bromine isotope pattern observed) [M+H] + . 1 H NMR (600 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.62 (d, J = 2.8 Hz, 1H), 8.21 (s, 1H), 7.99 (dd, J = 8.7, 2.8 Hz, 1H), 7.58 (d, J = 8.7 Hz, 1H), 7.38 (d, J = 8.5 Hz, 2H), 7.08 (d, J = 8.5 Hz, 2H), 4.43 (dd, J = 8.4, 3.8 Hz, 1H), 3.66 - 3.60 (m, 1H), 3.54 - 3.47 (m, 1H), 2.80 (septet, J = 6.9 Hz, 1H), 2.23 - 2.14 (m, 1H), 2.05 - 1.88 (m, 3H), 1.16 (d, J = 6.9 Hz, 6H).

[0411] Step 2. Synthesis of tert-butyl 4-{5-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]pyridine-2-yl}benzoate (C23). In a mixture of 1,4-dioxane (0.7 mL) and water (0.1 mL), a mixture of [4-(tert-butoxycarbonyl)phenyl]boronic acid (34.0 mg, 0.153 mmol), C22 (60.0 mg, 0.139 mmol), potassium carbonate (57.7 mg, 0.418 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (5.09 mg, 6.96 μmol) was heated overnight at 60°C immediately after sparging three times with nitrogen. The reaction temperature was then increased to 80°C, and after 2.5 hours, the reaction mixture was cooled to room temperature and filtered through a diatomaceous earth plug. The filtrate was partitioned into ethyl acetate and water, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were sequentially washed with water and saturated sodium chloride solution, dried with magnesium sulfate, filtered, and concentrated in vacuum to obtain C23 as an orange oily substance (76.4 mg). The majority of this material was carried over to the next step. LCMS m / z 529.5[M+H] + .

[0412] Step 3.4 Synthesis of {5-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]pyridine-2-yl}benzoic acid (18). Trifluoroacetic acid (0.2 mL) was added dropwise to a solution of C23 (from the previous step; 74.0 mg, ≤0.135 mmol) in dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 3.75 hours and immediately concentrated under vacuum. The residue was purified by reverse-phase HPLC (column: Waters Sunfire C18, 19 × 100 mm, 5 μm; mobile phase A: 0.05% trifluoroacetic acid (v / v) in water; mobile phase B: 0.05% trifluoroacetic acid (v / v) in acetonitrile; gradient: 20% to 60% B over 8.5 minutes, then 60% to 95% B over 0.5 minutes, then 95% B over 1.0 minute; flow rate: 25 mL / min) to obtain 4-{5-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]pyridine-2-yl}benzoic acid (18). Yield: 16.4 mg, 34.7 μmol, 26% over two steps. LCMS m / z 473.4 [M+H] + .1 1H NMR (600 MHz, DMSO-d6) δ 10.40 (s, 1H), 8.89 (d, J = 2.4 Hz, 1H), 8.23 ​​(s, 1H), 8.20 (dd, J = 8.7, 2.4 Hz, 1H), 8.17 (d, J = 8.4 Hz, 2H), 8.06 - 8.01 (m, 3H), 7.40 (br d, J = 8.3 Hz, 2H), 7.09 (d, J = 8.6 Hz, 2H), 4.49 (dd, J = 8.4, 3.8 Hz, 1H), 3.69 - 3.63 (m, 1H), 3.55 - 3.49 (m, 1H, estimated; partially unclear due to water peak), 2.80 (seven-line, J = 6.9 Hz, 1H), 2.26 - 2.18 (m, 1H), 2.09 - 1.92 (m, 3H), 1.16 (d, J = 6.9 Hz, 6H).

[0413] Alternative synthesis of Example 18 4-{5-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]pyridine-2-yl}benzoic acid (18)

[0414] [ka] Step 1. Synthesis of tert-butyl 4-(5-aminopyridine-2-yl)benzoate (C24). In a mixture of 1,4-dioxane (30 mL) and water (15 mL), solutions of [4-(tert-butoxycarbonyl)phenyl]boronic acid (750 mg, 3.38 mmol), 6-bromopyridine-3-amine (643 mg, 3.72 mmol), and potassium carbonate (1.40 g, 10.1 mmol) were spurged with nitrogen for 10 minutes, and immediately afterward, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (124 mg, 0.169 mmol) was added. The reaction mixture was heated at 95°C for 3 hours, and then partitioned into ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (5 × 20 mL), and the combined organic layers were washed with saturated sodium chloride aqueous solution, dried with sodium sulfate, filtered, and concentrated under vacuum. LCMS m / z 271.3[M+H] + C24 was obtained as a white powder by purification using silica gel chromatography (gradient: 0% to 40% ethyl acetate in heptane). Yield: 669 mg, 2.47 mmol, 73%. 1 H NMR (400 MHz, DMSO-d6) δ 8.05 (d, J = 2.8 Hz, 1H), 8.03 (d, J = 8.6 Hz, 2H), 7.90 (d, J = 8.5 Hz, 2H), 7.73 (d, J = 8.6 Hz, 1H), 7.00 (dd, J = 8.6, 2.8 Hz, 1H), 5.64 (br s, 2H), 1.56 (s, 9H7).

[0415] Step 2: Synthesis of tert-butyl 4-{5-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]pyridine-2-yl}benzoate (C23). 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (361 mg, 1.88 mmol) was added to a solution of C1 (400 mg, 1.45 mmol) and C24 (391 mg, 1.45 mmol) in dichloromethane (7 mL). After stirring the reaction mixture for 30 minutes, LC-MS analysis showed the formation of C23: LC-MS m / z 529.5 [M+H]+ The reaction mixture was diluted with dichloromethane, sequentially washed with water and saturated sodium bicarbonate aqueous solution, dried over sodium sulfate, filtered, and concentrated under vacuum. C23 was obtained as a white solid by silica gel chromatography (gradient: 0% to 75% ethyl acetate in heptane). Yield: 492 mg, 0.931 mmol, 64%. 1 H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 8.88 (d, J = 2.5 Hz, 1H), 8.24 - 8.18 (m, 2H), 8.16 (d, J = 8.5 Hz, 2H), 8.03 (d, J = 8.7 Hz, 1H), 7.98 (d, J = 8.5 Hz, 2H), 7.40 (d, J = 8.6 Hz, 2H), 7.09 (d, J = 8.6 Hz, 2H), 4.49 (dd, J = 8.4, 3.6 Hz, 1H), 3.70 - 3.61 (m, 1H), 3.57 - 3.48 (m, 1H), 2.80 (Septet, J = 6.9 Hz, 1H), 2.27 - 2.15 (m, 1H), 2.11 - 1.89 (m, 3H), 1.57 (s, 9H), 1.16 (d, J = 6.9 Hz (6H).

[0416] Step 3.4 Synthesis of {5-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]pyridine-2-yl}benzoic acid (18). Methanesulfonic acid (0.442 mL, 6.81 mmol) was added to a mixture of C23 (300 mg, 0.567 mmol) in acetonitrile (2.8 mL). After stirring the reaction mixture for 1 hour, LC-MS analysis showed complete cleavage of the ester: LC-MS m / z 473.4 [M+H]. +The reaction mixture was concentrated under vacuum, and immediately after removing half of the acetonitrile, water (10 mL) was added. The resulting mixture was adjusted to pH 7-8 by adding saturated sodium bicarbonate aqueous solution, and then stirred for 10 minutes. The solid was isolated by filtration and washed with water to obtain 4-{5-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]pyridine-2-yl}benzoic acid (18) as an off-white solid. Yield: 162 mg, 0.343 mmol, 60%. 1 H NMR (400 MHz, DMSO-d6) δ 12.98 (br s, 1H), 10.37 (s, 1H), 8.88 (d, J = 2.5 Hz, 1H), 8.24 - 8.17 (m, 2H), 8.17 (d, J = 8.5 Hz, 2H), 8.03 (d, J = 8.4 Hz, 1H), 8.02 (d, J = 8.5 Hz, 2H), 7.40 (d, J = 8.6 Hz, 2H), 7.09 (d, J = 8.6 Hz, 2H), 4.49 (dd, J = 8.5, 3.6 Hz, 1H), 3.71 - 3.61 (m, 1H), 3.58 - 3.48 (m, 1H), 2.79 (septet, J = 6.9 Hz, 1H), 2.27 - 2.15 (m, 1H), 2.11 - 1.89 (m, 3H), 1.16 (d, J = 6.9 Hz, 6H).

[0417] (Example 19) 5-{4-[(1-{[3-methyl-4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]phenyl}pyridine-2-carboxylic acid(19)

[0418] [ka] To a solution of 3-methyl-4-(propan-2-yl)aniline hydrochloride (20.6 mg, 0.111 mmol) in 1 mL of dichloromethane, a solution of bis(trichloromethyl)carbonate (11.5 mg, 38.8 μmol) in 0.5 mL of dichloromethane was added, followed by the addition of 4-(dimethylamino)pyridine (67.8 mg, 0.555 mmol). After stirring the reaction mixture at room temperature for 1 hour, C21 (from Example 17, Step 3; 38 mg, ≤91 μmol) was added all at once, and stirring was continued for 45 minutes. Next, the reaction mixture was diluted with dichloromethane and water, and the pH was adjusted to approximately 5 by adding 1 M hydrochloric acid. The organic layer was collected using a pipette, the remaining aqueous mixture was filtered, and the residue in the reaction vessel and on the filter paper was dissolved in a 1:1 mixture of dichloromethane and methanol, which was added to the organic layer. This solution was concentrated under vacuum, azeotropically mixed twice with dichloromethane, and purified twice by reverse-phase HPLC (Purification No. 1. Column: Waters Sunfire C18, 19×100mm, 5μm, Mobile phase A: 0.05% trifluoroacetic acid (v / v) in water, Mobile phase B: 0.05% trifluoroacetic acid (v / v) in acetonitrile, Gradient: 15%~55%B over 8.5 minutes, then 55%~95%B over 0.5 minutes, then 95%B over 1.0 minute, Flow rate: 25mL / min. Purification No. 2. Column: Waters Sunfire C18, 19×100mm, 5μm, Mobile phase A: 0.05% trifluoroacetic acid (v / v) in water, Mobile phase B: 0.05% trifluoroacetic acid (v / v) in acetonitrile, Gradient: 20% to 60% B over 8.5 minutes, then 60% to 95% B over 0.5 minutes, then 95% B over 1.0 minute, Flow rate: 25 mL / min), yielding 5-{4-[(1-{[3-methyl-4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]phenyl}pyridine-2-carboxylic acid (19). Yield: 14.1 mg, 29.0 μmol, 32% over two steps. LCMS m / z 487.5 [M+H] + . 1 1H NMR (600 MHz, DMSO-d6), Characteristic peak: δ 10.19 (s, 1H), 9.02 - 8.98 (m, 1H), 8.24 (dd, ABX component, J = 8.2, 2.4 Hz, 1H), 8.12 (s, 1H), 8.08 (br d, J = 8.2 Hz, 1H), 7.78 (AB quartet, J AB = 9.0 Hz, Δν AB = 10.1 Hz, 4H), 7.28 - 7.24 (m, 2H), 7.06 (d, J = 8.2 Hz, 1H), 4.46 (dd, J = 8.3, 3.8 Hz, 1H), 3.66 - 3.60 (m, 1H), 3.01 (septet, J = 6.9 Hz, 1H), 2.22 (s, 3H), 2.22 - 2.15 (m, 1H), 2.07 - 1.98 (m, 1H), 1.98 - 1.88 (m, 2H), 1.13 (d, J = 6.8 Hz, 6H).

[0419] (Example 20) 6-methyl-5-{4-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]phenyl}pyridine-2-carboxylic acid (20)

[0420] [ka] A 1.5 M aqueous solution of tripotassium phosphate was prepared and sparged with nitrogen. A solution of C2 (40.0 mg, 83.8 μmol), 5-bromo-6-methylpyridine-2-carboxylic acid (19.9 mg, 92.1 μmol), and bis(triphenylphosphine)palladium(II) dichloride (5.88 mg, 8.38 μmol) in 1.0 mL of 1,4-dioxane was sparged with nitrogen for 10 minutes and immediately heated to 50°C. After 5 minutes, an aqueous solution of tripotassium phosphate (1.5 M, 0.168 mL, 0.252 mmol) was added, and the reaction mixture was heated overnight at 90°C and immediately cooled to room temperature. The solvent was removed using a nitrogen stream, and the residue was dissolved in a 9:1 mixture of dichloromethane and methanol. This was acidified by adding 1 M hydrochloric acid, and the organic layer was concentrated under vacuum. Purification by reverse-phase HPLC (column: Waters Sunfire C18, 19 × 100 mm, 5 μm; mobile phase A: 0.05% trifluoroacetic acid (v / v) in water; mobile phase B: 0.05% trifluoroacetic acid (v / v) in acetonitrile; gradient: 15% to 55% B over 8.5 minutes, then 55% to 95% B over 0.5 minutes, then 95% B over 1.0 minute; flow rate: 25 mL / min) yielded 6-methyl-5-{4-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]phenyl}pyridine-2-carboxylic acid (20). Yield: 19.3 mg, 39.7 μmol, 47%. LCMS m / z 487.5 [M+H] + . 1 1H NMR (600 MHz, DMSO-d6), Characteristic peaks: δ 10.16 (s, 1H), 8.20 (s, 1H), 7.93 (d, J = 7.9 Hz, 1H), 7.77 (d, J = 7.9 Hz, 1H), 7.74 (d, J = 8.6 Hz, 2H), 7.41 - 7.37 (m, 4H), 7.09 (d, J = 8.6 Hz, 2H), 4.47 (dd, J = 8.3, 3.8 Hz, 1H), 3.67 - 3.62 (m, 1H), 2.80 (septet, J = 7.0 Hz, 1H), 2.51 (s, 3H, estimated; partially unclear due to solvent peaks), 2.24 - 2.15 (m, 1H), 2.08 - 1.99 (m, 1H), 1.99 - 1.90 (m, 2H), 1.16 (d, J = 6.9 Hz, 6H).

[0421] Alternative synthesis of Example 20 6-methyl-5-{4-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]phenyl}pyridine-2-carboxylic acid (20)

[0422] [ka] Step 1.5 Synthesis of (4-{[1-(tert-butoxycarbonyl)-D-prolyl]amino}phenyl)-6-methylpyridine-2-carboxylic acid (C25). In 50 mL of 1,4-dioxane, a solution of C19 (3.00 g, 7.21 mmol) and 5-bromo-6-methylpyridine-2-carboxylic acid (1.71 g, 7.92 mmol) was added, to which an aqueous solution of sodium carbonate (2.0 M, 14.4 mL, 28.8 mmol) was added, followed by the addition of bis(triphenylphosphine)palladium(II) dichloride (253 mg, 0.360 mmol). The reaction mixture was degassed for 5 minutes and immediately heated overnight at 90°C. After cooling to room temperature, the reaction mixture was partitioned into ethyl acetate (100 mL) and water (50 mL), and the aqueous layer was adjusted to pH 4 by adding 3 M hydrochloric acid. The resulting mixture was extracted with ethyl acetate (3 × 200 mL), the combined organic extract was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated under vacuum to obtain C25 as a yellow solid. 1 ¹H NMR analysis indicates that this material exists as a mixture of rotational isomers. Yield: 2.95 g, 6.93 mmol, 96%. LCMS m / z 426.4 [M+H] + . 1 ¹H NMR (400 MHz, methanol-d4) δ 8.06 (d, J = 7.9 Hz, 1H), 7.87 (d, J = 7.8 Hz, 1H), 7.74 (br d, J = 8 Hz, 2H), 7.44 - 7.33 (m, 2H), [4.41 - 4.34 (m) and 4.30 (dd, J = 8.2, 4.7 Hz), total 1H], 3.62 - 3.53 (m, 1H), 3.53 - 3.43 (m, 1H), 2.58 (s, 3H), 2.41 - 2.22 (m, 1H), 2.11 - 1.97 (m, 2H), 1.97 - 1.85 (m, 1H), [1.48 (s) and 1.39 (s), total 9H].

[0423] Step 2: Synthesis of 6-methyl-5-[4-(D-prolylamino)phenyl]pyridine-2-carboxylic acid, dihydrochloride (C26). A solution of hydrogen chloride in 1,4-dioxane (4.0 M, 6.93 mL, 27.7 mmol) was added to a solution of C25 (2.95 g, 6.93 mmol) in a mixture of dichloromethane (40 mL) and 1,1,1,3,3,3-hexafluoropropan-2-ol (5 mL). The reaction mixture was stirred at room temperature for 18 hours, and immediately afterward, conversion to C26 was shown by LC-MS analysis: LC-MS m / z 326.3 [M+H]. + The precipitate was collected by filtration to obtain C26 as a yellow solid. Yield: 2.55 g, 6.40 mmol, 92%. 1 H NMR (400 MHz, DMSO-d6) δ 11.20 (s, 1H), 10.17 - 10.04 (m, 1H), 8.77 - 8.65 (m, 1H), 7.93 (AB quartet, J AB = 7.9 Hz, Δν AB = 46.6 Hz, 2H), 7.80 (d, J = 8.6 Hz, 2H), 7.47 (d, J = 8.6 Hz, 2H), 4.51 - 4.39 (m, 1H), 3.37 - 3.19 (m, 2H), 2.54 (s,...

Claims

1. Compound of formula I 【Chemistry 1】 or a pharmaceutically acceptable salt thereof [in the formula, R １ is H, halogen, -CN, C １～８ alkyl, C ２～８ alkenyl, (C ３～６ cycloalkyl)-C １～４ alkyl-, or C ３～６ cycloalkyl, where each of C １～８ alkyl, C ２～８ alkenyl, (C ３～６ cycloalkyl)-C １～４ alkyl-, or C ３～６ cycloalkyl may each be substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halogen, -OH, -CN, C １～４ alkyl, C １～４ haloalkyl, C １～４ alkoxy, and C １～４ haloalkoxy, respectively. Each R ２ These are, independently, halogen, -OH, C １～４ Alkyl, C １～４ Haloalkyl, C １～４ Alkoxy, C １～４ Haloalkoxy, C ３～４ Cycloalkyl, or (C ３～４ Cycloalkyl)-C １～４ It is alkyl-, and here C １～４ Alkyl, C １～４ Haloalkyl, C １～４ Alkoxy, C １～４ Haloalkoxy, C ３～４ Cycloalkyl, or (C ３～４ Cycloalkyl)-C １～４ Each alkyl- is a halogen, -OH, or C. １～４ Alkyl, C １～４ Haloalkyl, C １～４ Alkoxy, and C １～４ They may be substituted with one, two, or three substituents independently selected from the haloalkoxy. or two R's ２ When they are bonded to the same ring carbon atom of the proline ring in formula I, they become C together with the ring carbon atom to which they are bonded. ３～６ They may form cycloalkyl or 4- to 7-membered heterocycloalkyl groups, each of which contains a halogen, -OH, and C. １～４ Alkyl, C １～４ Haloalkyl, C １～４ Alkoxy, and C １～４ The haloalkoxy may be substituted with one, two, three, or four substituents independently selected from each of them. or two R's ２ When bonded to two adjacent ring carbon atoms of the proline ring in formula I, they combine with the two ring carbon atoms to which they are bonded, C ３～６ They may form cycloalkyl or 4- to 7-membered heterocycloalkyl groups, each of which contains a halogen, -OH, and C. １～４ Alkyl, C １～４ Haloalkyl, C １～４ Alkoxy, and C １～４ The haloalkoxy may be substituted with one, two, three, or four substituents independently selected from each of them. R ３ R ３ａ , R ３ｂ , R ３ｃ , or R ３ｄ 【Chemistry 2】 And, T １ , T ２ , T ３ , and T ４ Each of these independently, CR ４ or N, where T １ , T ２ , T ３ , and T ４ The condition is that only 0, 1, or 2 of them may be N, Each R ４ These are independently H, halogen, -CN, and C. ３～６ Cycloalkyl, (C ３～６ Cycloalkyl)-C １～２ Alkyl-, C １～４ Alkyl, C １～４ Cyanoalkyl, C １～４ Haloalkyl, C １～４ Alkoxy, or C １～４ It is a haloalkoxy, T ５ , T ６ , T ７ , and T ８ Each of these independently, CR ５ or N, where T ５ , T ６ , T ７ , and T ８ The condition is that only 0, 1, or 2 of them may be N, Each R ５ These are independently H, halogen, -CN, and C. ３～６ Cycloalkyl, (C ３～６ Cycloalkyl)-C １～２ Alkyl-, C １～４ Alkyl, C １～４ Cyanoalkyl, C １～４ Haloalkyl, C １～４ Alkoxy, or C １～４ It is a haloalkoxy, T ９ 、 T １０ 、 T １１ 、 and T １２ each of which is independently CR ６ or N, provided that ９ 、 T １０ 、 T １１ 、 and T １２ only 0, 1, or 2 of them may be N Each R ６ is independently H, halogen, -CN, C ３～６ cycloalkyl, (C ３～６ cycloalkyl)-C １～２ alkyl-, C １～４ alkyl, C １～４ cyanoalkyl, C １～４ haloalkyl, C １～４ alkoxy, or C １～４ haloalkoxy, and T １３ , T １４ , T １５ , and T １６ Each of these is independently CR ７ or N, where T １３ , T １４ , T １５ , and T １６ The condition is that only 0, 1, or 2 of them may be N, Each R ７ These are independently H, halogen, -CN, and C. ３～６ Cycloalkyl, (C ３～６ Cycloalkyl)-C １～２ Alkyl-, C １～４ Alkyl, C １～４ Cyanoalkyl, C １～４ Haloalkyl, C １～４ Alkoxy, or C １～４ It is a haloalkoxy, T １７ , T １８ , and T １９ Each of these independently, CR ８ or N, where T １７ , T １８ , and T １９ The condition is that only 0, 1, or 2 of them may be N, Each R ８ These are independently H, halogen, -CN, and C. ３～６ Cycloalkyl, (C ３～６ Cycloalkyl)-C １～２ Alkyl-, C １～４ Alkyl, C １～４ Cyanoalkyl, C １～４ Haloalkyl, C １～４ Alkoxy, or C １～４ It is a haloalkoxy, T ２０ , T ２１ , and T ２２ Each of these independently, CR ９ or N, where T ２０ , T ２１ , and T ２２ The condition is that only 0, 1, or 2 of them may be N, Each R ９ These are independently H, halogen, -CN, and C. ３～６ Cycloalkyl, (C ３～６ Cycloalkyl)-C １～２ Alkyl-, C １～４ Alkyl, C １～４ Cyanoalkyl, C １～４ Haloalkyl, C １～４ Alkoxy, or C １～４ It is a haloalkoxy, Each R １０ These are, independently, halogen, -OH, C １～４ Alkyl, C １～４ Haloalkyl, C １～４ Alkoxy, C １～４ Haloalkoxy, C ３～４ Cycloalkyl, or (C ３～４ Cycloalkyl)-C １～４ It is alkyl-, and here C １～４ Alkyl, C １～４ Haloalkyl, C １～４ Alkoxy, C １～４ Haloalkoxy, C ３～４ Cycloalkyl, or (C ３～４ Cycloalkyl)-C １～４ Each alkyl- is a halogen, -OH, or C. １～４ Alkyl, C １～４ Haloalkyl, C １～４ Alkoxy, and C １～４ They may be substituted with one, two, or three substituents independently selected from the haloalkoxy, R Ａ is -C(=O)-OH, 1H-tetrazole-5-yl, OH, -C(=O)-N(R １１ ) (Caution １２ ), -C(=O)-OR １３ , 3-hydroxyisoxazole-5-yl, or -S (=O) ２ NHCF ３ And, R １１ and R １２ Each of these is independently H, C １～６ Alkyl, C ３～６ Cycloalkyl, (C ３～６ Cycloalkyl)-C １～４ Alkyl-, phenyl, or phenyl-C １～４ It is alkyl-, and here C １～６ Alkyl, C ３～６ Cycloalkyl, (C ３～６ Cycloalkyl)-C １～４ Alkyl-, phenyl, or phenyl-C １～４ Each of the alkyl- groups is a halogen, -OH, -CN, or C. １～４ Alkyl, C １～４ Haloalkyl, C １～４ Alkoxy, C １～４ Haloalkoxy, C ３～４ Cycloalkyl, or (C ３～４ Cycloalkyl)-C １～４ It may be substituted with 1, 2, 3, 4, or 5 substituents independently selected from each alkyl group. or R １１ and R １２ Together with the nitrogen atom to which they are bonded, they form halogens, -OH, -CN, and C １～４ Alkyl, C １～４ Haloalkyl, C １～４ Alkoxy, C １～４ Haloalkoxy, C ３～４ Cycloalkyl, or (C ３～４ Cycloalkyl)-C １～４ A 4- to 8-membered heterocycloalkyl group is formed, which may be substituted with 1, 2, 3, 4, or 5 substituents independently selected from the alkyl- group, where C １～４ Alkyl, C １～４ Haloalkyl, C １～４ Alkoxy, C １～４ Haloalkoxy, C ３～４ Cycloalkyl, or (C ３～４ Cycloalkyl)-C １～４ Each alkyl- is a halogen, -OH, or C. １～４ Alkyl, C １～４ Haloalkyl, C １～４ Alkoxy, and C １～４ They may be substituted with one, two, or three substituents independently selected from the haloalkoxy. R １３ C １～６ Alkyl, C ３～６ Cycloalkyl, (C ３～６ Cycloalkyl)-C １～４ Alkyl-, phenyl, or phenyl-C １～４ They are alkyl-, and each of them is a halogen, -OH, -CN, C １～４ Alkyl, C １～４ Haloalkyl, C １～４ Alkoxy, C １～４ Haloalkoxy, C ３～４ Cycloalkyl, or (C ３～４ Cycloalkyl)-C １～４ It may be substituted with 1, 2, 3, 4, or 5 substituents independently selected from each alkyl group. L １ C(R) Ｌ ) ２ And, Each R Ｌ H and C are independent of each other. １～２ Alkyl, C １～２ Haloalkyl, C １～２ Alkoxy, or C １～２ It is a haloalkoxy, or two R's Ｌ Together with the carbon atoms to which they are bonded, C ３～６ They may form cycloalkyl or 3- to 6-membered heterocycloalkyl groups, each of which contains a halogen, -OH, and C １～４ Alkyl, C １～４ Haloalkyl, C １～４ Alkoxy, and C １～４ The haloalkoxy may be substituted with one, two, three, or four substituents independently selected from each of them. t1 is either 0 or 1. t2 is 0, 1, 2, 3, or 4. t3 is 1 or 2, t4 is 0, 1, 2, 3, or 4.

2. Compound of formula Ia 【Transformation 3】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

3. Compound of formula II 【Chemistry 4】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

4. Compound of formula IIa 【Transformation 5】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

5. Compounds of formula III or IIIa 【Transformation 6】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

6. Compounds of formula IV or IVa 【Transformation 7】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

7. Compounds of formula V or Va 【Transformation 8】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

8. Compounds of formula VI or VIa 【Chemistry 9】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

9. Compounds of formula VII or VIIa 【Chemistry 10】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

10. R １ However, cyclopropyl, cyclobutyl, R １ａ , R １ｂ , or R １ｃ 【Chemistry 11】 The compound according to any one of claims 1 to 9. [In the formula, each of cyclopropyl or cyclobutyl is represented by 1, 2, 3, or 4 R Ｓ It may also be replaced with Each R ２０ These are independently H, halogen, -OH, and C. １～２ Alkyl, C １～２ Haloalkyl, C １～２ Alkoxy, or C １～２ It is a haloalkoxy, Each R ２１ H and C are independent of each other. １～２ Alkyl, or C １～２ It is a haloalkyl, R ２２ H, halogen, C １～２ Alkyl, C １～２ Hydroxylalkyl, C １～２ Haloalkyl, C １～２ Alkoxy, or C １～２ It is a haloalkoxy, Each R ２３ These are, independently, halogen, C １～２ Alkyl, C １～２ Hydroxylalkyl, C １～２ Haloalkyl, C １～２ Alkoxy, or C １～２ It is a haloalkoxy, Each R Ｓ These are, independently, halogen, -OH, C １～２ Alkyl, C １～２ Hydroxylalkyl, C １～２ Haloalkyl, C １～２ Alkoxy, or C １～２ It is a haloalkoxy.

11. R １ The compound according to any one of claims 1 to 10, wherein the compound is propan-2-yl, propa-1-en-2-yl, or cyclopropyl.

12. R １ The compound according to any one of claims 1 to 11, wherein is propan-2-yl.

13. T １ , T ２ , T ３ , and T ４ Each of them independently ４ The compound according to any one of claims 1 to 12.

14. T １ , T ２ , T ３ , and T ４ One of them is N, and the other three are each independently CR ４ The compound according to any one of claims 1 to 12.

15. Each R ２ However, independently, halogen, -OH, C １～４ Alkyl, C １～４ Hydroxylalkyl, C １～４ Haloalkyl, C １～４ Alkoxy, C １～４ Haloalkoxy, C ３～４ Cycloalkyl, or (C ３～４ Cycloalkyl)-C １～４ The compound according to any one of claims 1 to 14, wherein it is alkyl- and t2 is 0, 1, or 2.

16. T ５ , T ６ , T ７ , and T ８ Each of them independently ５ The compound according to any one of claims 1 to 7 and 10 to 15.

17. T ５ , T ６ , T ７ , and T ８ One of them is N, and the other three are each independently CR ５ The compound according to any one of claims 1 to 7 and 10 to 15.

18. T ９ , T １０ , T １１ , and T １２ Each of them independently ６ The compound according to any one of claims 1 to 6 and 10 to 17.

19. T ９ , T １０ , T １１ , and T １２ One of them is N, and the other three are each independently CR ６ The compound according to any one of claims 1 to 6 and 10 to 17.

20. T １３ , T １４ , T １５ , and T １６ Each of them independently ７ The compound according to any one of claims 1 to 5, 7, and 10 to 15.

21. T １３ , T １４ , T １５ , and T １６ One of them is N, and the other three are each independently CR ７ The compound according to any one of claims 1 to 5, 7, and 10 to 15.

22. T １７ , T １８ , and T １９ Each of them independently ８ The compound according to any one of claims 1 to 5, 8, 9, and 10 to 15.

23. T １７ , T １８ , and T １９ One of them is N, and the other two are CR independently ８ The compound according to any one of claims 1 to 5, 8, 9, and 10 to 15.

24. T ２０ , T ２１ , and T ２２ Each of them independently ９ The compound according to any one of claims 1 to 5, 8, 10 to 15, 22, and 23.

25. T ２０ , T ２１ , and T ２２ One of them is N, and the other two are CR independently ９ The compound according to any one of claims 1 to 5, 8, 10 to 15, 22, and 23.

26. A compound according to any one of claims 1 to 5, 9, 10 to 15, 22, and 23, wherein t3 is 2.

27. t4 is 0, 1, or 2, and each R １０ However, independently, halogen, -OH, C １～４ Alkyl, C １～４ Hydroxylalkyl, C １～４ Haloalkyl, C １～４ Alkoxy, C １～４ Haloalkoxy, C ３～４ Cycloalkyl, or (C ３～４ Cycloalkyl)-C １～４ A compound according to any one of claims 1 to 5, 9, 10 to 15, 22, 23, and 26, wherein the compound is alkyl-.

28. R Ａ The compound according to any one of claims 1 to 27, wherein is -C(=O)-OH.

29. Compounds selected from the following: 5-{4-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl)amino]phenyl}pyridine-2-carboxylic acid; 6-{4-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl)amino]phenyl}pyridine-3-carboxylic acid; 4'-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl)amino][1,1'-biphenyl]-3-carboxylic acid; 4'-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid; 4-{6-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl)amino]pyridine-3-yl}benzoic acid; 3'-Fluoro-4'-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid; 4'-({1-[(4-cyclopropylphenyl)carbamoyl]-DL-prolyl}amino)[1,1'-biphenyl]-4-carboxylic acid; 2-{4-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl)amino]phenyl}pyrimidine-5-carboxylic acid; 6-{4-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl)amino]phenyl}pyridine-2-carboxylic acid; 6-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl)amino]naphthalene-2-carboxylic acid; 8-methyl-6-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl)amino]quinoline-2-carboxylic acid; 4'-[(1-{[4-(propa-1-en-2-yl)phenyl]carbamoyl}-DL-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid; 4'-({1-[(4-chlorophenyl)carbamoyl]-DL-prolyl}amino)[1,1'-biphenyl]-4-carboxylic acid; 4-{4-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl)amino]phenyl}pyridine-2-carboxylic acid; and 3',5'-difluoro-4'-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid, or a pharmaceutically acceptable salt thereof.

30. Compounds selected from the following: 5-{4-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]phenyl}pyridine-2-carboxylic acid; 6-{4-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]phenyl}pyridine-3-carboxylic acid; 4'-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino][1,1'-biphenyl]-3-carboxylic acid; 4'-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid; 4-{6-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]pyridine-3-yl}benzoic acid; 3'-Fluoro-4'-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid; 4'-({1-[(4-cyclopropylphenyl)carbamoyl]-D-prolyl}amino)[1,1'-biphenyl]-4-carboxylic acid; 2-{4-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]phenyl}pyrimidine-5-carboxylic acid; 6-{4-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]phenyl}pyridine-2-carboxylic acid; 6-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]naphthalene-2-carboxylic acid; 8-methyl-6-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]quinoline-2-carboxylic acid; 4'-[(1-{[4-(propa-1-en-2-yl)phenyl]carbamoyl}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid; 4'-({1-[(4-chlorophenyl)carbamoyl]-D-prolyl}amino)[1,1'-biphenyl]-4-carboxylic acid; 4-{4-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]phenyl}pyridine-2-carboxylic acid; and 3',5'-difluoro-4'-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid, or a pharmaceutically acceptable salt thereof.

31. Compounds selected from the following: 4'-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid; 5-{4-[(1-{[3-methyl-4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl)amino]phenyl}pyridine-2-carboxylic acid; 6-methyl-5-{4-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl)amino]phenyl}pyridine-2-carboxylic acid; 3-Methoxy-4'-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid; 5-{4-[(1-{[3-fluoro-4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl)amino]phenyl}-6-methylpyridine-2-carboxylic acid; 3-Fluoro-4'-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid; 4-{6-[(1-{[4-(trifluoromethyl)phenyl]carbamoyl}-DL-prolyl)amino]pyridine-3-yl}benzoic acid; 4'-[(1-{[3-fluoro-4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl)amino]-3-methoxy[1,1'-biphenyl]-4-carboxylic acid; 4-{3-fluoro-5-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl)amino]pyridine-2-yl}benzoic acid; and 6-methyl-5-{4-[(1-{[3-methyl-4-(trifluoromethyl)phenyl]carbamoyl}-DL-prolyl)amino]phenyl}pyridine-2-carboxylic acid, or a pharmaceutically acceptable salt thereof.

32. Compounds selected from the following: 4'-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid; 5-{4-[(1-{[3-methyl-4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]phenyl}pyridine-2-carboxylic acid; 6-methyl-5-{4-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]phenyl}pyridine-2-carboxylic acid; 3-Methoxy-4'-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid; 5-{4-[(1-{[3-fluoro-4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]phenyl}-6-methylpyridine-2-carboxylic acid; 3-Fluoro-4'-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid; 4-{6-[(1-{[4-(trifluoromethyl)phenyl]carbamoyl}-D-prolyl)amino]pyridine-3-yl}benzoic acid; 4'-[(1-{[3-fluoro-4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]-3-methoxy[1,1'-biphenyl]-4-carboxylic acid; 4-{3-fluoro-5-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]pyridine-2-yl}benzoic acid; and 6-methyl-5-{4-[(1-{[3-methyl-4-(trifluoromethyl)phenyl]carbamoyl}-D-prolyl)amino]phenyl}pyridine-2-carboxylic acid, or a pharmaceutically acceptable salt thereof.

33. Compounds selected from the following: 4'-[(1-{[4-(trifluoromethyl)phenyl]carbamoyl}-DL-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid; 5-{4-[(1-{[3-methyl-4-(trifluoromethyl)phenyl]carbamoyl}-DL-prolyl)amino]phenyl}pyridine-2-carboxylic acid; 4-{5-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl)amino]pyridine-2-yl}benzoic acid; 5-{4-[(1-{[3-methyl-4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl)amino]phenyl}pyridine-2-carboxylic acid; 6-methyl-5-{4-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl)amino]phenyl}pyridine-2-carboxylic acid; 3-Methoxy-4'-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid; 4-{5-[(1-{[4-(trifluoromethyl)phenyl]carbamoyl}-DL-prolyl)amino]pyridine-2-yl}benzoic acid; 4'-({1-[(4-cyclobutylphenyl)carbamoyl]-DL-prolyl}amino)[1,1'-biphenyl]-4-carboxylic acid; 4-{5-fluoro-6-[(1-{[4-(trifluoromethyl)phenyl]carbamoyl}-DL-prolyl)amino]pyridine-3-yl}benzoic acid; 4-{5-fluoro-6-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl)amino]pyridine-3-yl}benzoic acid; 4'-[(1-{[4-cyclopropyl-3-(trifluoromethyl)phenyl]carbamoyl}-DL-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid; 5-{4-[(1-{[3-fluoro-4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl)amino]phenyl}-6-methylpyridine-2-carboxylic acid; 3-Fluoro-4'-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid; 2-Methoxy-4'-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid; 3-Methoxy-4'-[(1-{[3-methyl-4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid; 4-{6-[(1-{[4-(trifluoromethyl)phenyl]carbamoyl}-DL-prolyl)amino]pyridine-3-yl}benzoic acid; 4'-[(1-{[3-fluoro-4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl)amino]-3-methoxy[1,1'-biphenyl]-4-carboxylic acid; 4-{3-fluoro-5-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl)amino]pyridine-2-yl}benzoic acid; 4'-{[3-methyl-1-{[4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl]amino}[1,1'-biphenyl]-4-carboxylic acid; 4'-{[(trans)-3-methyl-1-{[4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl]amino}[1,1'-biphenyl]-4-carboxylic acid; 4'-{[3-methyl-1-{[4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl]amino}[1,1'-biphenyl]-4-carboxylic acid; 4'-{[(3-trans)-3-methyl-1-{[4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl]amino}[1,1'-biphenyl]-4-carboxylic acid; 4'-{[4-methoxy-1-{[4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl]amino}[1,1'-biphenyl]-4-carboxylic acid; 4'-{[(4-cis)-4-methoxy-1-{[4-(propan-2-yl)phenyl]carbamoyl}-DL-prolyl]amino}[1,1'-biphenyl]-4-carboxylic acid; 4'-{[1-({1-[4-(propan-2-yl)phenyl]ethyl}carbamoyl)-DL-prolyl]amino}[1,1'-biphenyl]-4-carboxylic acid; and 3-[6-({1-[(4-cyclobutylphenyl)carbamoyl]-DL-prolyl}amino)pyridine-3-yl]benzoic acid, or a pharmaceutically acceptable salt thereof.

34. Compounds selected from the following: 4'-[(1-{[4-(trifluoromethyl)phenyl]carbamoyl}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid; 5-{4-[(1-{[3-methyl-4-(trifluoromethyl)phenyl]carbamoyl}-D-prolyl)amino]phenyl}pyridine-2-carboxylic acid; 4-{5-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]pyridine-2-yl}benzoic acid; 5-{4-[(1-{[3-methyl-4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]phenyl}pyridine-2-carboxylic acid; 6-methyl-5-{4-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]phenyl}pyridine-2-carboxylic acid; 3-Methoxy-4'-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid; 4-{5-[(1-{[4-(trifluoromethyl)phenyl]carbamoyl}-D-prolyl)amino]pyridine-2-yl}benzoic acid; 4'-({1-[(4-cyclobutylphenyl)carbamoyl]-D-prolyl}amino)[1,1'-biphenyl]-4-carboxylic acid; 4-{5-fluoro-6-[(1-{[4-(trifluoromethyl)phenyl]carbamoyl}-D-prolyl)amino]pyridine-3-yl}benzoic acid; 4-{5-fluoro-6-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]pyridine-3-yl}benzoic acid; 4'-[(1-{[4-cyclopropyl-3-(trifluoromethyl)phenyl]carbamoyl}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid; 5-{4-[(1-{[3-fluoro-4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]phenyl}-6-methylpyridine-2-carboxylic acid; 3-Fluoro-4'-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid; 2-Methoxy-4'-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid; 3-Methoxy-4'-[(1-{[3-methyl-4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino][1,1'-biphenyl]-4-carboxylic acid; 4-{6-[(1-{[4-(trifluoromethyl)phenyl]carbamoyl}-D-prolyl)amino]pyridine-3-yl}benzoic acid; 4'-[(1-{[3-fluoro-4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]-3-methoxy[1,1'-biphenyl]-4-carboxylic acid; 4-{3-fluoro-5-[(1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl)amino]pyridine-2-yl}benzoic acid; 4'-{[(3S)-3-methyl-1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl]amino}[1,1'-biphenyl]-4-carboxylic acid; 4'-{[(3R)-3-methyl-1-{[4-(propan-2-yl)phenyl]carbamoyl}-L-prolyl]amino}[1,1'-biphenyl]-4-carboxylic acid; 4'-{[(3R)-3-methyl-1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl]amino}[1,1'-biphenyl]-4-carboxylic acid; 4'-{[(3S)-3-methyl-1-{[4-(propan-2-yl)phenyl]carbamoyl}-L-prolyl]amino}[1,1'-biphenyl]-4-carboxylic acid; 4'-{[(4R)-4-methoxy-1-{[4-(propan-2-yl)phenyl]carbamoyl}-D-prolyl]amino}[1,1'-biphenyl]-4-carboxylic acid; 4'-{[1-({(1S)-1-[4-(propan-2-yl)phenyl]ethyl}carbamoyl)-D-prolyl]amino}[1,1'-biphenyl]-4-carboxylic acid; and 3-[6-({1-[(4-cyclobutylphenyl)carbamoyl]-D-prolyl}amino)pyridine-3-yl]benzoic acid, or a pharmaceutically acceptable salt thereof.

35. A pharmaceutical composition comprising a compound according to any one of claims 1 to 34 and a pharmaceutically acceptable excipient.

36. A method for treating or preventing a patient's condition, disease, or disorder, comprising administering to the patient a compound according to any one of claims 1 to 34, wherein the condition, disease, or disorder is diabetes [e.g., including type 1 diabetes mellitus (T1D), type 2 diabetes mellitus (T2DM), prediabetes], idiopathic T1D (type 1b), latent autoimmune diabetes mellitus in adults (LADA), early-onset T2DM (EOD), juvenile-onset atypical diabetes mellitus (YOAD), juvenile adult-onset diabetes mellitus (MODY), malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, Impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, renal disease [e.g., acute kidney injury, tubular dysfunction, pro-inflammatory changes in the proximal tubules, or chronic kidney disease (CKD)], diabetic retinopathy, adipocyte dysfunction, visceral fat deposition, sleep apnea [e.g., obstructive sleep apnea (OSA)], obesity (including hypothalamic obesity and monogenic obesity) and associated comorbidities (e.g., osteoarthritis and urinary incontinence), eating disorders (including bulimia nervosa, bulimia nervosa, and symptomatic obesity such as Prader-Willi syndrome and Baldett-Biedl syndrome), and use of other medications. Weight gain caused by (e.g., steroid and / or antipsychotic use, treatment for depression, or use of medications for cognitive function), overweight, excessive sugar craving, 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 [fatty liver, non-alcoholic fatty liver disease] [NAFLD including related diseases such as hepatitis 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 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 dyslipidemia, metabolic acidosis,Ketosis, arthritis, osteoporosis, osteoarthritis, Parkinson's disease, left ventricular hypertrophy, peripheral artery disease (PAD), macular degeneration, cataracts, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, arteriosclerosis, transient ischemic attack, restenosis, impaired glucose metabolism, abnormal fasting blood glucose levels, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders, psoriasis, foot ulcers, ulcerative colitis, hyperuricemia A method selected from the group consisting of poly-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., addiction to alcohol, nicotine, and / or drugs), or a method for managing human weight, comprising administering a compound according to any one of claims 1 to 32 to a human.

37. The use of a compound according to any one of claims 1 to 34 for treating or preventing a condition, disease, or disorder, or the use of a compound according to any one of claims 1 to 34 in the manufacture of a medicament for treating or preventing a condition, disease, or disorder, wherein the condition, disease, or disorder is diabetes mellitus [including, for example, type 1 diabetes mellitus (T1D), type 2 diabetes mellitus (T2DM), and prediabetes], idiopathic T1D (type 1b), latent autoimmune diabetes mellitus in adults (LADA), early-onset T2DM (EOD), juvenile-onset atypical diabetes mellitus (YOAD), and juvenile adult-onset diabetes mellitus (M ODY), malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease [e.g., acute kidney injury, tubular dysfunction, pro-inflammatory changes in the proximal tubules, or chronic kidney disease (CKD)], diabetic retinopathy, adipocyte dysfunction, visceral fat deposition, sleep apnea [e.g., obstructive sleep apnea (OSA)], obesity (including hypothalamic obesity and monogenic obesity) and associated comorbidities (e.g., osteoarthritis and urinary incontinence), eating disorders (bulimia nervosa, bulimia nervosa, and Prader's disease) Weight gain including symptomatic obesity such as Willie syndrome and Valdet-Beedl syndrome, weight gain caused by the use of other medications (e.g., caused by the use of steroids and / or antipsychotics, or by the treatment of depression, or by the use of medications for cognitive function), overweight, excessive sugar craving, dyslipidemia [hyperlipidemia, hypertriglyceridemia, increased total cholesterol, high LDL (low-density lipoprotein) cholesterol, and low HDL (high-density lipoprotein) cholesterol] [including alcohol], hyperinsulinemia, non-alcoholic fatty liver disease [including fatty liver, non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and related diseases such as hepatocellular carcinoma, NAFLD], 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 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 dyslipidemia, metabolic acidosis, ketosis, arthritis, osteoporosis, osteoarthritis, Parkinson's disease, left ventricular hypertrophy, peripheral artery disease (PAD), macular degeneration, cataracts, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, arteriosclerosis, transient ischemic attack, vascular restenosis, impaired glucose metabolism, abnormal fasting blood glucose levels, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders, psoriasis, foot ulcers, ulcerative colitis, hyperapoglycemia B12 Uses selected from the group consisting of proteinemia, 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., addiction to alcohol, nicotine, and / or drugs), or use of the compound according to any one of claims 1 to 32 for weight management (e.g., chronic weight management), or use of the compound according to any one of claims 1 to 32 in the manufacture of a medicament for weight management (e.g., chronic weight management).

38. A compound according to any one of claims 1 to 34 for use in a method for treating or preventing a patient's condition, disease, or disorder, wherein the condition, disease, or disorder is diabetes [e.g., including type 1 diabetes mellitus (T1D), type 2 diabetes mellitus (T2DM), prediabetes], idiopathic T1D (type 1b), latent autoimmune diabetes mellitus in adults (LADA), early-onset T2DM (EOD), juvenile-onset atypical diabetes mellitus (YOAD), young adult-onset diabetes mellitus (MODY), malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, glucose Diabetic neuropathy, diabetic nephropathy, kidney disease [e.g., acute kidney injury, tubular dysfunction, pro-inflammatory changes in the proximal tubules, or chronic kidney disease (CKD)], diabetic retinopathy, adipocyte dysfunction, visceral fat deposition, sleep apnea [e.g., obstructive sleep apnea (OSA)], obesity (including hypothalamic obesity and monogenic obesity) and associated comorbidities (e.g., osteoarthritis and urinary incontinence), eating disorders (including bulimia nervosa, bulimia nervosa, and symptomatic obesity such as Prader-Willi syndrome and Baldett-Beedl syndrome), and conditions caused by the use of other medications. Weight gain (e.g., caused by the use of steroids and / or antipsychotics, or by the treatment of depression, or by the use of medications for 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 [fatty liver, non-alcoholic steatohepatitis (NASH)] [NAFLD, including related diseases such as 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 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 dyslipidemia, metabolic acidosis, ketosis, arthritis,Compounds selected from the group consisting of osteoporosis, osteoarthritis, Parkinson's disease, left ventricular hypertrophy, peripheral artery disease (PAD), macular degeneration, cataracts, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, arteriosclerosis, transient ischemic attack, restenosis, impaired glucose metabolism, abnormal fasting blood glucose levels, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders, psoriasis, foot ulcers, ulcerative colitis, hyperapobelipoproteinemia, 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., addiction to alcohol, nicotine, and / or drugs), or compounds according to any one of claims 1 to 34 for use in a method for human weight management (e.g., chronic weight management).

39. A method for modulating glucose-dependent insulin-stimulating polypeptide receptors (GIPRs), comprising contacting GIPRs with a compound according to any one of claims 1 to 34.

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